FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR THE PRODUCTION OF ASYMMETRIC TRANSFORMATION CATALYSTS"
2. APPLICANT
(a) NAME: PHOENIX CHEMICALS LIMITED
(b) NATIONALITY: GB company incorporated under GB Act
(c) ADDRESS: 34 Thursby Road, Croft Business Park, Bromborough,
Wirral, CH62 3PW, Great Britain
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it has to be performed.

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PCT/GB2005/000125

PROCESS FOR THE PRODUCTION OF ASYMMETRIC TRANSFORMATION
CATALYSTS
5 This invention relates to a novel process for the production of asymmetric transformation catalysts, in particular to such a process for the production of phosphine and arsine ligands having a chiral centre at phosphorus, or arsenic as the case may be. Such ligands are found to be useful in a wide variety of asymmetric transformation reactions, including hydrogenation and carbon-
10 oxygen and carbon-nitrogen bond formation reactions. The process of the invention may be applicable to the production of chiral catalysts containing aromatic ring systems generally, and is especially useful in the production of metallocene-based phosphine and arsine ligands. The invention also relates to chiral catalysts produced by the process of the invention, and to the use of such
15 catalysts in asymmetric transformation reactions.
Ferrocene as a backbone for diphosphine ligands was introduced by Kumada and Hayashi based on the pioneering work of Ugi related to the synthesis of enantiopure substituted metallocenes1. A number of these ligands are shown
20 below:

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PCT/GB2005/000125

Me Me Me
Fe Fe < Fe ^
" NMe2 xjC^5j^^me2 'cc^yy^^n
^^^

Ugi's Amine PPFA R = Me2N, BPPFA
R = OH, BPPFOH
Ppfa as well as bppfa and bppfoh proved to be effective ligands for the catalysis
5 of a variety of asymmetric transformations. From this starting point, many chiral ferrocene-based bisphosphine ligands with a range of structural variation have been developed in the last few years.
Certain types of known ligands exhibit both planar and carbon chirality:

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^2
^

Me

^

Me
N
.R
Fe ^PPh2PR2

Josiphos: R a Cy, R' * Ph PPF-tBu2: R * t-Bu, R'« Ph Xyliphos: R = 3,5-Me2Ph, R' = Ph cy2PF-Pcy2: R s R*s Cy

Walphos

BoPhoz

R1
Fe ^PPh2

R1 PPh2 Mandyphos (FERRIPHOS)

Taniaphos
1a: R = H, R'= NMe2 1b:RaOMe,R' = H

Fe lQMe^PR2
TRAP

Togni and Spindler2 have reported a class of non-C2-symmetrical ferrocene-based bisphosphines: the Josiphos-type ligands. Josiphos ligands are in
5 widespread commercial use, having been found effective for Rh-catalyzed hydrogenation of a-acetamidocinnamate, dimethyl itaconate, and p-ketoesters. Because the two phosphine groups are introduced into the ligand in consecutive steps with high yields, a variety of ligands are available with widely differing steric and electronic properties. The ligands have already been applied in three
10 production processes3, several pilot processes and many other syntheses. For example, PPF-tBu2, a Josiphos type ligand with a di-(tert-butyl)phosphino group, has been applied as the ligand in asymmetric hydrogenation for commercial synthesis of (+)-biotin.4 Another notable example is the application

WO 2005/068478 - PCT/GB2005/000125
4
of XyliPhos in the Ir-catalyzed hydrogenation of imines for the synthesis of the herbicide (S)-metolachlor5.
Bophoz6 is a combination of a phosphine and an aminophosphine and is
5 prepared in 3 steps from ppfa with high overall yields. The ligand is air stable and effective for the hydrogenation of enamides, itaconates and a-keto acid derivatives. As observed for several ligands forming seven-membered chelates, high activities can be reached and TONs up to 10,000 have been claimed. The full scope of this modular ligand class has not yet been explored.
10
A class of non-C2-symmetrical, ferrocene-based 1,5-diphosphine ligands, Taniaphos, has been developed by Knochel7'8. Compared to the Josiphos ligands, Taniaphos has an additional phenyl ring inserted at the side chain of the Ugi amine. Taniaphos gave excellent results in Rh- and Ru-catalyzed
15 asymmetric hydrogenation. The configuration of a-position of Taniaphos plays an important role in the enantioselectivities and activities. The Taniaphos 1b with αS configuration leads to higher enantioselectivities and activities than 1a with αR configuration in a wide range of asymmetric transformations.
20 Weissensteiner and Spindler9 have reported a series of structurally different ferrocene-based 1,5-diphosphine ligands, Walphos. Like Josiphos, Walphos is modular and is also made from the Ugi amine. It shows promise for the enantioselective hydrogenation of olefins and ketoses.

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Mandyphos is a bidentate version of ppfa with C2 symmetry, where in addition to the PPh2 moieties, R and R' can be used for fine tuning the functionality of the ligand10. The scope of this ligand family has not yet been fully explored, but
5 preliminary results indicate high enantioselectlvities for the Rh-catalyzed hydrogenation of enamides, itaconates and enol acetates.
The TRAP ligands developed by Ito11 form 9-membered metallocycles.
However, it is not clear whether the cis-isomer, present in small amounts, or the
10 major trans-isomer is responsible for the catalytic activity. Up to now only a few
different PR2 fragments have been tested, but it is clear that the choice of R
strongly affects the catalytic performance. The Rh complexes work best at very
low pressures of 0.5 ± 1 bar and effectively reduces indole-derivatives,
enamides and itaconic acid derivatives.
15
Another class of known ligands exhibit only planar chirality:

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O
,CHR2
^T^PPhj Ph2P FT IT'PPtl!
R2HC^ 9^ ^
PPh2 - PPh2 O
ferroPHOS JAFAPhos
Fe >PPh2
Kang12 reported the C2.symmetry FerroPHOS with only planar chirality. FerroPHOS ligands are air-stable and are very efficient for the asymmetric
5 hydrogenation of various dehydroamino acid derivitives (up to 99% ee).
Another C2.symmetry planar chiral diphosphine, JAFAPhos, has been developed by Jendralla13. JAFAPhos gave excellent results In asymmetric hydrogenation, allylic alkylation, Grignard cross coupling and aldol reactions.
10
Kagan14 reported plane chiral ferrocene-based bisphosphorus ligands 2 and 3, and up to 95% ee's have been obtained in asymmetric hydrogenation of dimethyl itaconate using these ligands as catalyst.

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Another class of known diphosphine ligands exhibit chirality only at the phosphorus atoms:
R

R _ /* i
Fe
= Fe I

XXH^
4a: R = o-anisyl 4b: R = 1-naphthyl

5
FerroTane
<^ri
a,.




H^
f-binaphane
The synthesis of chiral 1,1'-bis(phosphetano) ferrocenes (FerroTANE) has been independently reported by Marinetti15 and Burk16. FerroTANE has been successfully applied in Rh-catalyzed hydrogenation of itaconates and (E)-f3-(acylamino) acrylates17.
10 Mezzetti18 and van Leeuwen19 have independently reported P-chiral ferrocenyl bisphosphines 4a and 4b. These two ligands have shown excellent enantioselectivities (up to 99% ee) for asymmetric hydrogenation of o> dehydroamino acid derivatives.

15

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Zhang has reported a 1,1'-bis(Phospholanyl) ferrocene ligand
5 with ketal substitutes at the 3 and 4 positions. 20 The ligand has shown excellent enantioselectivities in hydrogenation of (5-dehydroamino acid derivatives. The ketal groups of the ligand are important for achieving the high enantioselectivity, 5 since the corresponding ligand without ketal groups only provides moderate ee's. Zhang has also developed a 1,1'-bis(dinaphthophosphepinyl) ferrocene ligand, f-binaphane, which has been successfully applied in the Ir-catalyzed hydrogenation of acyclic aryl imines. 21
10 Reetz has developed a binaphthol-derived ferrocene-based bisphosphonite ligand tf2, which has shown excellent reactivities and enantioselectivities in Rh-catalyzed hydrogenation of itaconates and a-dehydroamino acid derivatives.
Another class of known ligands exhibits both planar and phosphorus chirality:

Fe

^

7a:R=1-naphthyl
15 7b: R = 2-biphenylyl
Van Leeuwen has reported ferrocene-based bisphosphines combining planar and phosphorus chirality 7a and 7b23. These two ligands have shown excellent enantioselectivities (up to 99% ee) for asymmetric allylic alkylations .

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9

Me Ph P""
Thus, most of the known ferrocene-based diphosphines contain planar and carbon chirality, only planar chirality or only phosphorus chirality. More recently, Togni reported the first tridentate ferrocene-based phosphine ligand 12
5 combining planar, phosphorus and carbon chirality.24
S3 Fe "PP^2
(R)c-(S)Fe-(R)p-l2
PPh2
Me Fe PPh2
(R)c-(S)Fe-(S)P-12
In our co-pending application GB0400720.9 we describe ligands having Formula (I), (II) or (III):


R3n
irVf1 R3"
w

10 (I)
wherein R1"5, W, Q, n, m and G are variously defined, and a process for making such ligands. However, the process described therein is found to be more generally applicable to the production of various chiral ligands.

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According to the present invention there is provided a process for the production of chiral ligands comprising providing a starting material of Formula
(A): Ox* (A)
5 wherein X* is a chiral or achiral directing group; and
is an optionally substituted mono- or polycyclic aryl or cycloalkyl group; ortholithiating the substrate; converting the ortho-lithiated substrate to a phosphine group having the formula -PR1 R1, R1 and R1" being different from each other and independently selected from substituted and unsubstituted,
10 branched- and straight-chain alkyl, alkoxy, alkylamino, substituted and
unsubstituted cycloalkyl, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryloxy,
15 substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; and optionally or if necessary converting X* to a different grouping to produce a chiral ligand.
20

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PCT/GB200S/000125

is, in one such process according to the invention, one aromatic ring (optionally further substituted) of a metallocene compound. Also provided in accordance with the invention is a process for the production of chiral ligands comprising providing a starting material of Formula (A):
Ox*
5 (A)
wherein X* is a chiral or achiral directing group; and
is an optionally substituted mono- or polycyclic aryl or cycloalkyl group; ortholithiating the substrate; reacting the ortholithiated substrate with an R1 substituted phosphine or arsine, R1 being selected from substituted and
10 unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; and then with an Rr-bearing Grignard reagent or organolithium compound, R1" being different from R1 and
15 being selected from substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; and optionally or if necessary converting X* to a different grouping to produce a
20 chiral ligand;

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PCT/GB2005/000125

with the exception that the chiral ligand is not a ligand having Formula (I), (II) or (III):

(») (ill)
wherein R1'5, W, Q, n, m and G are as defined in GB0400720.9.
5
is, in one such process according to the invention, one aromatic ring (optionally further substituted) of a metallocene compound.
The process of the invention may be used in the production of phosphine or
10 arsine ligands having up to three elements of chirality; planar chirality, chirality at phosphorus (or arsenic), and optionally chirality at carbon.
In the following description reference will be made for convenience to processes for the production of phosphine ligands. It should be understood that although
15 processes for producing phosphine ligands are the preferred processes in accordance with the invention, the corresponding processes for producing arsine ligands are also within the scope of the invention.

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13
Similarly, when the chiral ligand obtained by the process of the invention is a metallocene ligand, processes for producing ferrocene based ligands are preferred, but other suitable metals may be used in the metallocene ligands obtained by the process of the invention, and hence reference is made herein to
5 metallocenes generally.
The invention further provides chiral ligands obtained by the process of the invention. Examples of such ligands include metallocene-based phosphine ligands having planar, phosphorus and carbon chirality.
10
The invention further provides chiral ligands (other than those of Formula (I), (II) or (III)) obtained by the process of the invention. Examples of such ligands include metallocene-based phosphine ligands having planar, phosphorus and carbon chirality.
15
Ligands obtained by a process according to the invention have particular advantages over prior art ligands because the provision of up to three chiralities allows the designer of a ligand greater scope than has hitherto been the case to design ligands for a particular purpose.
20
The introduction of phosphorus chirality may enhance the chiral discrimination produced by the catalyst when a matching among the planar chirality, carbon

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14

chirality and the chirality of phosphorus can be achieved. A matching catalyst may give high ee and a mismatching one may give low ee.
Also provided in accordance with the invention is a transition metal complex
5 containing transition metal coordinated to the ligand produced by the process of the invention. The metal is preferably a Group Vlb or a Group VIII metal.
Preferably X* is an ortho directing group.
10 Synthesis of phosphorus chiral phosphines may be effected in accordance with the invention with the use of a suitable chiral ortho-directing group, for example in accordance with the following scheme:
1)n-BuLior
sec-BuLi or
/"~~^X* t-BuLi ^-^X* R1"Z /^V-x*
,R1"
U" 2) R1PCI2
Ri

Wherein Ο is an optionally substituted mono- or polycyclic aryl or cycloalkyl group and wherein R1”Z is an organoalkali species or Grignard reagent Examples of suitable chiral directing groups:

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PCT/GB2005/000125

OR2 <..,


\AH£) yl^ V^X£. ^

Wherein R, R2 and R3 are independently selected from substituted and , unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and
5 unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen.

O
is, in one such process according to the invention, one aromatic ring (optionally further substituted) of a metallocene compound.
10
And wherein
For example, synthesis of ferrocene-based phosphorus chiral phosphines may be effected with the use of a suitable chiral ortho-directing group, for example in accordance with the following schemes:

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PCT/GB2005/000125

1)n-Bul_ior ^
1)n-BuLior •
Fe ^ Fe |3- ► Fe f»- (2)
^-x* 2)RPC'2.X^^R *x^O

CI^R1 R2-^R1
1)n-BuUor

<-^:i=>?—y* sec-BuLi or ^^^^^TT^
\S=^/ t-BuLl ^s=iC ,CI L
5 wherein Rd is an acyl group, Re is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen, and R1, R1" are as previously
10 defined; and then:
reacting compound D with a secondary phosphine of the formula R6R7PH wherein R6 and R7 are the same or different, and are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl, alkoxy,
15 alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted

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24
carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryloxy, substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen;
5 and R8 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen to obtain the diphosphine combining planar, phosphorus 10 and carbon chirality having formula G:
Re
/^Y^PR6R7
(G) or,
reacting compound D with an amine of the formula R8NH2 wherein R8 is selected from hydrogen, substituted and unsubstituted, branched- and straight-
15 chain alkyl. substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen, to obtain compound H:

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PCT/GB2005/000125

Re
a
^-NHR8 P"R1" R1
(H)
or;
reacting compound D with an amine of the formula J:
^6
DD6D7
>• n (J)
5 wherein R6 and R7 are as previously defined, R9 is selected from hydrogen, halogen, OR10, SR10, NR10R11, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur,
10 nitrogen, and oxygen; wherein R10, R11 are the same or different and are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently
15 selected from sulphur, nitrogen, and oxygen, n' is 0 to 4, and Z is MgY (Y being a halide) or Li, to obtain compound K:

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26
OH PR6R7


or,
reacting compound D with an amine of the formula H2N-R*-NH2 or H2N-R**-NH2
wherein R* and R** are selected from the group consisting of:

R12

R12 wherein R9 is as previously defined; R12 is selected from hydrogen, substituted
and unsubstituted, branched- and straight-chain alkyl, substituted and
unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and
substituted and unsubstituted heteroaryl wherein the or each heteroatom is
10 independently selected from sulphur, nitrogen, and oxygen; or (R12)2 is ■iCHz)m"-
, n' is 0 to 4; and m' is 1 to 8, to obtain compounds L and M:
w * R1,\ Q - R\ 1
(L) (M)
or;
reacting compound E with an amine of the formula H2N-R*-NH2 or H2N-R**-NH2
15 wherein R* and R** are, as previously defined, to obtain compounds 0 and P:

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27

■A"

R1-R >~N—R-N
V 6 H H
P R
(O) (P)
Compound H may be reacted with a halophosphine of the formula R6R7PY wherein R6, R7 are, as previously defined, and Y is chlorine, bromine or iodine, to obtain compound Q
10
Alternatively, compound H may be reacted with an acid derivative of the formula R13COY wherein R13 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen, and Y is a halide, a sulphate, an imidazole, R13COO- or hydrogen, to obtain compound R:
Re

CCx
R1

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Alternatively compound H (in which R8 Is hydrogen) may be reacted with an aldehyde of the formula OHC-R*-CHO or OHC-R**-CHO wherein R* and R are as previously defined to obtain the compounds having Formulae S and T:

1" D6S

R~R V-N N-^ -P-R
R1 Re


R1-F>
Rn R'

//-R"-\\ f R\ Dl

(S)

("0

5 Alternatively compound H may be reacted with an acid derivative of the formula YOC-R*-COY and YOC-R**-COY wherein R*. R** and Y are, as previously defined, to obtain the compounds having Formulae U and V:
R^rvN y< w RI-P, ,. VN8 p-s^j*-*
V R* R8 R8 ^~S R R R R (^

10

(U)

(V)

Compound K may be converted into compound X:
(K)
R14 pR6R7


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PCT/GB2005/000125

wherein R14 is selected from OR10, SR10, NHR10 and NR10R1\ wherein R10, R11 are as previously defined.
Compounds L, M, O, P, S, T, U, V may be reduced to obtain respective 5 compounds L*. M*. O*. P*. S*, T*. U*,V*:

R1-P

N—R-N
H H

P-R1

R1—R

R1

N—R-N
H H

P-R1

(L*)

(M*)

N—R-N
H H

R1

P-R1

N—R~N
H H

P-R1

(O*)

(P*)

Re Rr
,e P1"
IH HN-\ P
R p\ r )~NH HN
R. Re R.
^ P-R1

Q .
R1-R >-W
R1 Re

(S*)

en

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PCT/GB2005/000125

£e R1R' Re
U
" ~ R8 R8 V~S

R' Re

Re R1
^Ti"'

(U*)

(V*)

Synthesis of metallocene-based phosphines chiral at phosphorus may be also effected with the use of enantioselective ortho-lithiation (ferrocene-based
5 substrates are indicated below and are illustrative of aromatic and cycloaliphatic substrates generally in connection with the process of the invention):

Fe °i

^r->
Fe
1)n-BuLior sec-BuLi or t-BuLi, chiral diamine
2) R1PC12
^
X*
1) n-BuLi or sec-BuLi or
^gfS?~x** t-BuLi, chiral \gf^
diamine ^ ^B-"
Fe
* I,
<^->
S^
2) R1PCI2
CKPvR1
**X

R1Z
R'Z

Examples of suitable achiral directing groups:
f—P(0)R2R3
(wherein R2 and R3 are as previously defined)
rr
»NMe2 H
Suitable Chiral diamines include:
JL
PrT^N^Ph H

Accordingly, the invention provides a method for preparing a chiral diphosphine ligand comprising a metallocene-based substrate having an achiral directing

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substituent on one or both rings, and subjecting the substituted metallocene to an enantioselective ortho-lithiation step before subsequently converting the ortho-lithiated substrate to a phosphorus chiral phosphine.
5 Whilst the use of an auxiliary chiral compound (such as the chiral diamine) in the ortholithiation step may be preferred in some circumstances, where direct synthesis of a chiral product (in enantiomeric excess) is desired, it is also possible to ortholithiate in the absence of such a chiral auxiliary, and then resolve the enantiomeric product mixture at the end of the synthesis.
10
(This method is also applicable to arsines.)
Thus, one method according to the present invention for preparing chiral ligands comprises providing a substrate of the formula A*:
x~>^x**
(A*)
wherein
Ο is an optionally substituted mono- or polycyclic aryl or cycloalkyl group;
15
wherein X** is an achiral directing group, and is preferably as previously defined; and subjecting the compound to enantioselective mono-ortho-lithiation using n-butyllithium or sec-butyllithium or tort- butyllithium in the presence of a homochiral tertiary amine, and reacting the resulting chiral monolithium

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compound in situ with a dichlorophosphine of the formula R1PCl2 followed by
reacting with an organometallic reagent of the formula R1M, wherein R1 and Rr
are as defined hereinabove; M is Li or MgX wherein X is a halide, to obtain
phosphorus chiral compound having formula C*:
x**
5 (C)
and optionally or if necessary further converting compound C* to the desired chiral ligand.
One method according to the invention for preparing a ferrocene-based chiral
10 ligand comprises providing a compound of the Formula B*:
Fe
(B*)
wherein X* is as previously defined; and subjecting the compound to bis-ortho-lithiation using n-butyllithium, sec-butyllithium or tert- butyllithium, and reacting the resulting bislithium compound in situ with a dichlorophosphine of the formula
15 R1PCl2 followed by reacting with an organometallic reagent of the formula R1"Z, wherein R1 and R1" are as previously defined; Z is Li or MgY wherein Y is a halide, to obtain a phosphorus chiral compound having formula B***:

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was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (2.24 mL, 16.5 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to
5 room temperature, and stirred for 1.5 h at room temperature. The mixture was then cooled to -78 °C again, and a solution of (2-methoxy)phenyllithium [prepared from 2-bromoanisole (3.32 g, 17.7 mmol) and 1.7 M t-BuLi solution in pentane (20.8 mL, 35.4 mmol) in Et20 (90 mL) at -78 °C] was added slowly via a cannula. The mixture was warmed to room temperature overnight, and filtered
10 through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography (Si02, hexane-EtOAc-Et3N = 85:10:5) to afford the title compound (6.50 g, 92%) as orange crystals. 1H NMR (CDCI3,400.13 MHz):
δ1.29 (d, 3H, J = 6.5 Hz); 1.80 (s, 6H); 3.91 (s, 3H); 3.97 (s, 6H, overlap); 4.11
(m, 1H), 4.25 (t, 1H, J = 2.2 Hz); 4.37 (br. s, 1H); 6.87 (m, 1H); 6.94 (dd, 1H, J =
15 8.3 and 6.7 Hz); 7.12 ~ 7.23 (m, 6H); 7.31 (m, 1H); 31P NMR (CDCI3,162 MHz):
δ -38.82. The absolute configuration of (Re, SFe, SP)-2 was determined by
single-crystal X-ray diffraction analysis.
20 Example 2
(Rc, SFe, SP)-2-[(1-N,N-DimethyIamino)ethylJ-1-[(1-naphthyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-3]:

WO 2005/068478
Me
*NMe2 1) t-BuLi, Et20, -78 °C~rt <^^7^^NMe2
2)PhPCI2,-78°C~rt

35

PCT/GB2005/000125


3) 1-naphthy/lithium, -78 °C~rt
Fe
(R)-1

To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (5.15 g, 20 mmol) in Et20 (60 mL) was added 1.7 M t-BuLi solution in
5 pentane (12.94 mL, 22 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (2.99 mL, 22 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to
10 room temperature, and stirred for 1.5 h at room temperature. The mixture was then cooled to -78 °C again, and a solution of 1-naphthyllithium [prepared from 1-bromonaphthalene (5.38 g, 26 mmol) and 1.7 M t-BuLi solution in pentane (30.6 mL, 52 mmol) in Et20 (120 mL) at -78 °C] was added slowly via a cannula. The mixture was warmed to room temperature overnight, and filtered
15 through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography (Si02, hexane-EtOAc-Et3N = 90:6:4) to afford the title compound (8.75 g, 89%) as orange crystals. 1H NMR (CDCI3,400.13 MHz): δ1.33 (d, 3H, J = 6.8 Hz); 1.91 (s, 6H); 3.59 (s, 5H); 4.00 (m, 1H); 4.17 (m, 1H); 4.26 (t, 1H, J = 2.2 Hz); 4.38 (m, 1H); 7.13 -7.2 (m, 5H); 7.39 (t, 1H, J = 6.7

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Hz); 7.43 -7.54 (m, 2H); 7.60 -7.63 (m, 1H); 7.87 (dd, 2H, J = 9.7 and 9.2 Hz), 9.33 (dd, 1H, J = 7.6 and 7.0 Hz). 31P NMR (CDCI3,162 MHz): 5 -38.73.
Example 3
(Re, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1-[(1-
naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-3] and (Re, SFe, Rp)-2-
[(1-N,N-Dimethylamino)ethyl]-1-[(1-naphthyl)phenylphosphino]ferrocene
[(Re, SFe, RPH]:
10

Me

r?—^>" *NMe2 1)t-BuLi,Et2O,-780C-rt
<^^/ * 2) PhPCI2, -78 °C~rt
Fe
,s====\ <*) i-napmnywtmum, rt ^=^|-Np /CZ5\.
(IVSFe-Sp)-3 (Rc-SF8-Rp)^
(R)-1

To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (1.29 g, 5 mmol) in Et20 (15 mL) was added 1.7 M t-BuLi solution in pentane
15 (3.2 mL, 5.5 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (0.75 mL, 5.5 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room
20 temperature, and stirred for 1.5 h at room temperature. Then to the mixture a

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solution of 1-naphthyllithium [prepared from 1-bromonaphthalene (1.35 g, 6.5 mmol) and 1.7 M t-BuLi solution in pentane (7.6 ml_, 13 mmol) In Et20 (30 ml_) at -78 °C] was added via a cannula at room temperature. The mixture was stirred overnight at room temperature and filtered through a pad of Celite. The
5 filtrate was concentrated, and the residue was purified by chromatography (Si02, hexane-EtOAc-Et3N = 85:10:5) to afford the title compound (2.21 g, 90%) as a mixture of two isomers. The ratio of (Re, SFe, Sp)-3 to (Re, SFe, Rp)-4 Is about 5:1. As (Re, SFe, RP)4 is insoluble in cold hexane and (Re, SFe, SP)-3 is very soluble in cold hexane, the two isomers can be easily separated by
10 crystallization from hexane. (Re, SFe, Rp)-4: 1H NMR (CDCl3,400.13 MHz): 6 1.25 (d, 3H, J = 6.8 Hz); 1.60 (s, 6H); 3.88 (br. s, 1H); 4.00 (s, 5H); 4.16 (m, 1H), 4.29 (t, 1H, J = 2.2 Hz); 4.42 (br. s,, 1H); 7.16 - 7.19 (m, 1H); 7.28 ~ 7.29 (m, 5H), 7.32 - 7.35 (m, 1H); 7.59 - 7.63 (m, 2H); 7.69 (d, J = 8.2 Hz); 7.76 (d, J = 7.6 Hz); 8.45 (m, 1H). 31P NMR (CDCI3,162 MHz): 5 -31.36. The absolute configuration of (Re, SFe, RPH was determined by single-crystal X-ray diffraction analysis.
Example 4
(Rc, SFe, Rp)-2-[(1-N,N-Dimethylamino)ethyl]-1-[(1-
naphthyl)phenylphosphino]ferrocene [(Re, SFe, Rp)-4]:

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NMe2
hexane, reflux

4&
(Rc-SFe-Rp)-4

T

A solution of (Re, SFe, SP)-3 (491 mg, 1.0 mmol) in hexane (5 mL) was refluxed overnight. After cooling to room temperature, the precipitate was filtered and
5 washed with cold hexane to give the pure (Re, SFe, RPH-
Example 5
(Re, SFe, SP)-2-[( 1-N.N-Dimethylamino)ethyI]-1-[(2-
naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-5] and (Re, SFe, RP)-2-
10
[(1-N,N-Dimethylamino)ethyl]-1-[(2-naphthyl)phenylphosphino]ferrocene
[(Re, SFe, RP)-6]:

NMe2 2-Np
Fe

Me
NMe2 1) t-BuLi, Et20, -78 °C~rt
2) PhPa2, -78 °C~rt
»
3) 2-naphthyllithium
-78 °C~rt

(R)-1

(Rc-SFe-SP)-5

(Rc-SFe-RP)-6

15 To a solution of (R)-N,N-dimethyl-1 -ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (2.57 g, 5 mmol) in Et20 (15 mL) was added 1.7 M t-BuLi solution in pentane (6.4 mL, 11 mmol) over 10 min via a syringe at -78 °C. After addition was

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completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.5 mL, 11 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room
5 temperature, and stirred for 1.5 h at room temperature. Then the mixture was cooled to -78 °C again, and a suspension of 2-naphthyllithium [prepared from 2-bromonaphthalene (2.69 g, 13 mmol) and 1.7 M t-BuLi solution in pentane (15.2 mL, 26 mmol) in Et20 (60 mL) at -78 °C] was added via a cannula at -78 °C. The mixture was warmed to room temperature overnight and filtered
10 through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography (Si02, hexane-EtOAc-Et3N = 85:10:5) to afford the title compound (4.42 g, 90%) as a mixture of two isomers. The ratio of (Re, SFe, SP}-5 to (Re. SFe. Rp)-6 is about 5:1. Fractional crystallization from hexane gave (Ro, SFe, SP)-5 (3.10 g, 63%) and (Re, SFe, Rp)-6 (687 mg, 14%). (Ro, SFe, SP)-5:
15 1H NMR (CDCI3, 400.13 MHz): 8 1.28 (d, 3H, J = 6.2 Hz); 1.80 (s, 6H); 3.90 (br. s, 1H); 3.92 (s, 5H); 4.20 (m, 1H), 4.22 (t, 1H, J = 2.2 Hz); 4.38 (br. s,, 1H); 7.18 - 7.26 (m, 5H); 7.48 (m, 2H), 7.58 (ddd, 1H, J= 8.4,5.6 and 1.6 Hz); 7.79 (d, 1H, J = 8.4 Hz); 7.83 (m, 2H); 8.18 (d, 1H, J - 9.5 Hz);. 31P NMR (CDCI3, 162 MHz): 5 -20.88. (Ro, SFe, RP>6 : 1H NMR (CDCI3,400.13 MHz): 51.27 (d, . 20 3H, J = 5.7Hz); 1.76 (s, 6H); 3.90 (br. s, 1H); 3.96 (s, 5H); 4.18 (m, 1H), 4.29 (t, 1H, J = 2.2 Hz); 4.41 (br. s,, 1H); 7.29 (ddd, 1H, J - 8.3, 7.0 and 1.6 Hz); 7.34 (m, 3H); 7.39 (m, 2H); 7.59-7.67 (m, 5H), 7.74 (m, 1H);. 31P NMR(CDCI3,162 MHz): 5 -20.57.

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Example 6
(Re, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1-[(2-
naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-5]:
Me Me
bromide, -78 °C~rt <^-^r,N,J
(R)-1 (RC-SFe-Sp)"5
5 To a solution of (R>-N,N-dimethyl-1-ferrocenylethylamine [(RJ-Ugi's amine, (R)-1] (2.06 g, 8 mmol) in EtzO (15 mL) was added 1.5 M t-BuLi solution in pentane (6.0 mL, 9 mmol) over 10 min via a syringe at -78 °C. After addition was
10 completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.22 mL, 9 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. Then the mixture was
15 cooled to -78 °C again, and a solution of 2-naphthylmagnesium bromide
[prepared from 2-bromonaphthalene (2.20 g, 10.6 mmol) and magnesium (258 mg, 10.6 mmol) in Et20 (20 mL)] was added via a cannula at -78 °C. The mixture was warmed to room temperature overnight. The reaction was quenched with saturated NH4CI solution (20 mL). The organic layer was
20 separated, and the aqueous layer was extracted with Et20 (20 mL). The

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combined organic layers were washed with brine (20 mL), dried (MgS04), and concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAc-Et3N = 85:10:5) to afford the title compound (3.42 g, 87%) as single diastereomer. 1H NMR (CDCI3, 400.13 MHz): 5 1.28 (d, 3H, J = 6.2 Hz); 1.80 (s,
5 6H); 3.90 (br. s, 1H); 3.92 (s, 5H); 4.20 (m, 1H), 4.22 (t, 1H, J = 2.2 Hz); 4.38 (br. s,, 1H); 7.18 - 7:26 (m, 5H); 7.48 (m, 2H), 7.58 (ddd, 1H, J = 8.4, 5.6 and 1.6 Hz); 7.79 (d, 1H, J = 8.4 Hz); 7.83 (m, 2H); 8.18 (d, 1H, J = 9.5 Hz);. 31P NMR (CDCI3, 162 MHz): 6 -20.88.
Example 7
10 (Re, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1-[(2-biphenyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-7]:
Me Me
<^5y^NMe2 1) t-BuLi, Et20, -78 °C~rt ^^T^^^^z
^> >' 2)PhPCI2,-78°C~rt ^==^C „Ph
/^3^ 3)_2^henyllithium ^^v2-Biph
(R\-1 (Rc"SFe-Sp)-7
15 To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (2.57 g, 10 mmol) in Et20 (20 mL) was added 1.5 M t-BuLi solution in pentane (7.33 mL, 11 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C
20 again, and dichlorophenylphosphine (1.50 mL, 11 mmol) was added in one

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portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. Then the mixture was cooled to -78 °C again, and a suspension of 2-biphenyllithium [prepared from 2-bromobiphenyl (2.24 mL, 13 mmol) and 1.5 M t-BuLi solution in pentane
5 (17.3 mL, 26 mmol) in Et20 (30 mL) at -78 °C] was added via a cannula at -78 °C. The mixture was warmed to room temperature overnight and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography (Si02, hexane-EtOAc-Et3N = 85:10:5) to afford the title compound (4.87 g, 94%) as single diastereomer. 1H NMR (CDCI3,400.13
10 MHz): 5 1.25 (d, 3H, J = 6.7Hz); 1.85 (s, 6H); 3.69 (s, 5H); 3.76 (m, 1H), 4.17 (m, 1H), 4.29 (t, 1H, J = 2.4 Hz); 4.32 (m, 1H); 7.10 - 7.19 (m, 5H); 7.31 (m, 1H), 7.37-7.48 (m, 5H), 7.64 (m, 1H); 7.69 (m, 1H); 7.71 (m, 1H). 31P NMR (CDCI3,162 MHz): 5-32.96
15 Example 8
(Rc, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1-(methylphenylphosphino)ferrocene [(Rc, SFe, Rp)-8]:
Me Me
\ MQ
4^^!> bromide,-78 °C~rt 4^^>
(R)-1 (Rc-SFe-RpV8
20

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To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (2.57 g, 10 mmol) in Et20 (20 mL) was added 1.5 M t-BuLi solution in pentane (7.33 mL, 11 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for
5 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.50 mL, 11 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. Then the mixture was cooled to -78 °C again, and 3.0 M solution of MeMgBr in Et20 (4.0 mL, 12
10 mmol) was added via a syringe at -78 °C. The mixture was warmed to room temperature overnight. The reaction was quenched with saturated NH4CI solution (20 mL). The organic layer was separated, and the aqueous layer was extracted with Et20 (20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified by
15 chromatography (SiO2, hexane-EtOAc-Et3N = 85:10:5) to afford the title
compound (3.36 g, 89%) as red oil. 1H NMR (CDCI3,400.13 MHz): δ1.24 (d, 3H, J = 6.7Hz); 1.56 (d, 3H, J = 4.4 Hz); 1.72 (s, 6H); 4.07 (m, 1H), 4.13 (s, 5H); 4.30 (m, 1H), 4.34 (m, 2H); 7.14 ~ 7.20 (m, 3H); 7.30-7.37 (m, 2H). 31P NMR (CDCI3,162 MHz): 5-43.47
20 Example 9
(Re, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1-(cyclohexylphenylphosphino)ferrocene [(Rc, SFe, Rp)-9]:

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Me Me
^^^V^NMea D t-BuLi, Et20, -78 °C~rt ^^y 2)PhPCI2,-78°C~rt >bssS< ^ph
Fe *- Fe •?••/,,.
/^ A 3) cyclohexylmagnesium //=—o< cv"
4^^> chloride, -78 °C~rt <$^>
(R><1 (Rc-SFe-Rp)-9
To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (2.57 g, 10 mmol) in Et20 (20 mL) was added 1.5 M t-BuLi solution in
5 pentane (7.35 mL, 11 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.50 mL, 11 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to
10 room temperature, and stirred for 1.5 h at room temperature. Then the mixture was cooled to -78 °C again, and 2.0 M solution of cyclohexymagnesium chloride in Et20 (6.0 mL, 12 mmol) was added via a syringe at -78 °C. The mixture was warmed to room temperature overnight. The reaction was quenched with saturated NH4CI solution (20 mL). The organic layer was
15 separated, and the aqueous layer was extracted with Et20 (20 mL). The
combined organic layers were washed with brine (20 mL), dried (MgS04), and concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc-Et3N = 90:5:5) to afford the title compound (4.09 g, 92%) as red oil. 1HNMR(CDCI3, 400.13 MHz): 6 1.16 (d, 3H, J = 6.7Hz); 1.19-2.03 (m, 11H); 1.50
20 (s, 6H); 3.99(m, 1H), 4.11 (s, 5H); 4.30 (m, 1H), 4.32 (t, 1H, J = 2.5 Hz); 4.37

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(m, 1H), 7.12 - 7.150 (m, 3H); 7.18-7.23 (m, 2H). 31P NMR (CDCI3,162 MHz): δ -14.86
Example 10
5 (Rc, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1-[methyl(tert-butyl)phenylphosphino)ferrocene [(Rc, SFe, RP)-10]:
Me Me

,,.
/^===\ 3)methyllithium,-78°C~rt ^.jyfe

(RM

(RC-SFO-RPMO

10 To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (1.29 g, 5 mmol) in Et20 (15 mL) was added 1.5M t-BuLi solution in pentane (3.7mL, 5.5 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again,
15 and tert-butyldichlorophosphine (875 mg, 5.5 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. Then to the mixture a 1.6 M solution of methyllithium in Et20 (3.75 mL, 6.0 mmol) was added via a syringe at -78 °C. The mixture was warmed to room temperature overnight and
20 filtered through a pad of Celite. The filtrate was concentrated, and the residue

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was purified by chromatography (Si02, hexane-EtOAc-Et3N = 90:5:5) to afford the title compound (1.54 g, 86%) as red oil. 1H NMR (CDCl3) 250.13 MHz): 5 1.09 (d, 9H, J = 12.0 Hz), 1.27 (d, 3H, J = 6.7Hz); 1.45 (d, 3H, J - 3.3 Hz); 2.08 (s, 6H); 3.92 (m, 1H), 4.10 (s, 5H);, 4.28 (m, 3H). 31P NMR (CDCf3, 101 MHz): 5
5 -6.47
Example 11
(Re, SFe, SP)-2-(1-Acetoxyethyl)-1-[(2-
methoxyphenyl)phenylphosphino]ferrocene [(Re, SFe, SP)-11]:
10
Me Me
Fe J*„. ► Fe *[••„.
/^^ rt /^?**
Rc-SFe-Sp-2 Rc-SFe-Sp-11
A solution of (Re, SFe, Sp)-2 (1.18 g, 2.5 mmol) in acetic anhydride (10 mL) was stirred for 60 h at room temperature. The excess acetic anhydride was removed
15 under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.21 g, 100%) as yellow solid, which is pure enough for the use in the next reaction. 1H NMR (CDCI3, 400.13 MHz): 5 1.19 (s, 3H); 1.64 (d, 3H, J = 6.5 Hz); 3.90 (s, 3H); 3.92 (m, 1H); 4.07 (s, 5H); 4.34 (t, 1H, J = 2.6 Hz); 5.55 (m, 1H);6.15 (m, 1H); 6.87 (td, 1H, J = 7.4 and 0.9 Hz); 6.95 (q, 1H, J = 4.8 Hz); 7.08 ~ 7.21 (m,
20 6H); 7.35 (m, 1H); 31P NMR (CDCl3, 162 MHz): 6 -39.30.

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Example 12
(Re, SFe, SP)-2-(1 -Acetoxyethyl)-1 -[(1 -naphthyl)phenylphosphino]ferrocene
5 [(Re, SFe, SP)-12]:
Me Me
^=^C_Ph AczO >J^=<.D.Ph
Fe •{•»,,. ^ Fe 7%,.
Rc-Spe-Sp-3 Rc-Spe-Sp-12
A solution of (Re, SFe, SP)-3 (1.47 g, 3.0 mmol) in acetic anhydride (20 mL) was stirred for 60 h at room temperature. The excess acetic anhydride was removed under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.52 g,
10 100%) as yellow solid, which is pure enough for the use in the next reaction. 1H NMR (CDCI3, 400.13 MHz): 5 1.29 (s, 3H); 1.67 (d, 3H, J = 6.5 Hz); 3.72 (s, 5H); 3.94 (m, 1H); 4.35 (t, 1H, J = 2.6 Hz); 4
.57 (m, 1H); 6.28 (m, 1H); 7.13 ~ 7.22 (m, 5H); 7.38-7.43 (m, 2H), 7.53 (ddd, 1H, J = 8.0, 6.7 and 1.1 Hz), 7.64(ddd, 1H, J = 8.4,6.8 and 1.4 Hz), 7.89 (t, 2H,
15 J = 7.0 Hz); 9.28 (t, 1H, J = 7.0 Hz); 31P NMR (CDCI3,162 MHz): 5 -39.81.
Example 13
(Rc, SFe, RP)-2-(1-Acetoxyethyl)-1-[(1-naphthyl)phenylphosphino]ferrocene
[(Re, SFe, Rp)-13]:
20
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48

FC"i ma ZUU3/UUU1Z3


Me
"NM62
. xl-Np Fe V'#,.
Rc-Spe-Rp-4

A solution of (Re, SF6, Rp)-4 (1.47 g, 3.0 mmol) in acetic anhydride (20 mL) was stirred for 60 h at room temperature. The excess acetic anhydride was removed
5 under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.52 g, 100%) as yellow solid, which is pure enough for the use in the next reaction. *H NMR (CDCI3, 400.13 MHz): 5 0.83 (s, 3H); 1.62 (d, 3H, J = 6.5 Hz); 3.83 (m, 1H); 4.10 (s, 5H); 4.40 (t, 1H, J = 2.6 Hz); 5.61 (m, 1H); 6.21 (m, 1H); 7.11 (ddd, 1H, J = 7.0,4.6 and 1.1 Hz), 7.28 - 7.41 (m, 6H); 7.55-7.43 (m, 2H), 7.75
10 (m, 2H), 8.29 (m, 1H); 31P NMR (CDCI3,162 MHz): 5 -31.33.
Example 14
(Rc, SFe, SP)-2-(1 -Acetoxyethyl)-1 -[(2-naphthyl)phenylphosphino]ferrocene
KR« SFe, SP)-14]:
Me Me

sNMe2 fry OAc
^D.Ph AC20 ^^ss^^Cp.Ph
15
Rc-Spe-Sp-5 Rc-SFe-Sp-14
A solution of (Rc, SFe, SP)-5 (1.47 g, 3.0 mmol) in acetic anhydride (20 mL) was stirred for 60 h at room temperature. The excess acetic anhydride was removed

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under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.52 g, 100%) as yellow solid, which is pure enough for the use in the next reaction. 1H NMR (CDCI3,400.13 MHz): δ 1.21 (s, 3H); 1.65 (d, 3H, J = 6.5 Hz); 3.83 (m, 1H); 4.03 (s, 5H); 4.33 (t, 1H, J = 2.6 Hz); 4.57 (mf 1H); 6.24 (m, 1H); 7.19 –
5 7.27(m, 5H); 7.46-7.51 (m, 3H), 7.81 (m, 3H), 8.11 (d, 1H, J - 10.4 Hz); 31P NMR (CDCI3,162 MHz): 5 -22.89.
Example 15
(Re, SFe, Rp)-2-(1 -Acetoxyethyl)-1 -[(2-naphthyl)phenylphosphino]ferrocene
10 [(Re, SFe, RP)-15]:



NMe2 2-Np
ACgO
rt

A solution of (Re, SFE, Rp)-6 (1.47 g, 3.0 mmol) in acetic anhydride (20 mL) was
15 stirred for 60 h at room temperature. The excess acetic anhydride was removed under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.52 g, 100%) as yellow solid, which is pure enough for the use in the next reaction. 1H NMR (CDCI3,400.13 MHz): 6 0.92 (s, 3H); 1.64 (d, 3H, J = 6.4 Hz); 3.87 (m, 1H); 4.07 (s, 5H); 4.40 (t, 1H, J = 2.6 Hz); 5.61 (m, 1H); 6.23 (m, 1H); 7.27
20 (ddd, 1H, J = 8.2,6.8 and 1.4 Hz), 7.32 - 7.38(m, 3H); 7.39-7.44 (m, 2H),

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7.53-7.57 (m, 2H), 7.60 (d, 1H, J = 8.0 Hz), 7.69 (m, 2H), 7.74 (m, 1H); 31P NMR (CDC!3> 162 MHz): δ -22.58.
5 Example 16
(Rc, SF6. SP)-2-(1 -Acetoxyethyl)-1 -t(2-biphenyl)phenylphosphino]ferrocene
[(Re, SFe, SP)-16]:
Me Me


Fe fy,,. ^ Fe tt%/.
RC-SF«"SP"7 Rc-Spo-Sp-I®
A solution of (Rc, SF6. SP)-7 (1.47 g, 3.0 mmol) in acetic anhydride (20 mL) was stirred for 60 h at room temperature. The excess acetic anhydride was removed
10 under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.52 g, 100%) as yellow solid, which is pure enough for the use in the next reaction. 1H NMR (CDCI3, 400.13 MHz): δ 1.25 (s, 3H); 1.52 (d, 3H, J = 6.5 Hz); 3.73 (s, 5H); 3.96 (m, 1H); 4.33 (t, 1Hf J = 2.6 Hz); 4.48 (m, 1H); 5.81 (m, 1H); 7.16 ~ 7.27(m, 6H); 7.38-7.51 (m, 6H), 7.70-7.73 (m, 2H). 31P NMR(CDCI3,162
15 MHz): 6-35.03.
20 Example 17

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(Re, SFe, SP)-2-[(1- N-Methylamino)ethyl]-1-[(2-methoxyphenyl)phenylphosphino]ferrocene [(Re, SFe, SP)-17]:
Me Me
^^^C^Ph 40% MeNH2 (aq.) y:=^C^Ph
Fe f -,,. ► Fe ^
y^^^o-An THF-MeOH(4:1) /CZ5>>
Rc-SFe-SP-11 Rc-Spe-Sp-17
5 A solution of (Re, SF6, SP)-11 (1 -21 g, 2.5 mmol) and 40% methylamine aqueous solution (6.0 mL) in THF (20 mL) and MeOH (5 mL) was stirred for 3 days at 40 °C, and concentrated. The residue was dissolved in Et20 (20 mL), washed with brine (10 mL), dried (Na2S04), and evaporated under reduced pressure. The crude product was purified by chromatography (SiO2, hexane-EtOAc-Et3N =
10 80:15:5) to give the title compound (1.07 g, 94%) as orange crystals.1H NMR (CDCI3, 250.13 MHz): δ 1.44 (d, 3H, J = 6.5 Hz); 1.94 (s, 3H); 3.91 (m, 2H); 3.95 (s, 3H); 4.05 (s, 5H); 4.29 (t, 1H, J = 2.5 Hz); 4.46 (m, 1H); 7.90 (dt, 1H, J = 7.3 and 1.0 Hz), 6.97 (ddd, 1H, J = 8.3,5.0 and 1.0 Hz), 7.15 (ddd,1H, J = 7.3, 5.5 and 1.8 Hz),7.23 (m, 5H); 7.36 (ddd, 1H, J = 8.3, 7.3 and 1.8 Hz),. 31P
15 NMR (CDCU, 101 MHz): 5 -41.43.
Example 18
(Re, SFe, SP)-2-[(1- N-Methylamino)ethyl]-1-[(1-
naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-18]:

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Me

"OAc Fe £''»,,.
R(;-S|r0-Sp-12
40%MeNH2(aq.) ^Z3T p"HMe
► ft^sC
THF-MeOH(4:1) v^^jV
Rc-Sj:e-Sp-18

10
A solution of (Re, SFe, SP)-12 (633 mg, 1.25 mmol) and 40% methylamine aqueous solution (3.0 mL) in THF (10 mL) and MeOH (2.5 mL) was stirred for 3 days at 40 °C, and concentrated. The residue was dissolved in Et20 (20 mL), washed with brine (10 mL), dried (Na2S04), and evaporated under reduced pressure. The crude product was purified by chromatography (Si02, hexane-EtOAc-Et3N = 85:10:5) to give the title compound (549 mg, 92%) as orange crystals. 1H NMR (CDCI3,400.13 MHz): 61.49 (d, 3H, J = 6.6 Hz); 2.07 (s, 3H); 3.69 (s, 5H); 3.95 (m, 1H); 4.01 (m, 1H); 4.31 (t, 1H, J = 2.5 Hz); 4.48 (m, 1H); 7.23 (m, 5H); 7.39 - 7.47 (m, 2H); 7.54 (m, 1H); 7.66 (m, 1H); 7.90 (t, 2H, J = 7.9 Hz), 9.25 (dd, 1H, J = 7.9 and 6.7 Hz). 31P NMR (CDCI3,162 MHz): 5 -39.91.

15 Example 19
(Re, SFe, RP)-2-[(1- N-Methylamino)ethyl]-1-[(1-naphthyl)phenylphosphino]ferrocene [(Rc, SFe, Rp)-19]:



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Me
^ZSX^Ac 40% MeNH2 (aq.)
J^Ah'*.' THF-MeOH(4:1)
Rc-SFe-Rp-13 Rc-SFe-Rp-19
A solution of (Re, SFe, Rp)-7 (633 mg, 1.25 mmol) and 40% methylamine aqueous solution (3.0 mL) in THF (10 mL) and MeOH (2.5 mL) was stirred for 3 days at 40 °C, and concentrated. The residue was dissolved in Et20 (20 mL),
5 washed with brine (10 mL), dried (Na2S04), and evaporated under reduced pressure. The crude product was purified by chromatography (Si02, hexane-EtOAc-Et3N = 85:10:5) to give the title compound (537 mg, 90%) as orange crystals. 1H NMR (CDCI3, 400.13 MHz): 5 1.45 (d, 3H, J = 6.5 Hz); 1.83 (s, 3H); 3.82 (m, 1H); 3.97 (m, 1H); 4.07 (s, 5H); 3 4.35 (t, 1H, J = 2.5 Hz); 4.53 (m,
10 1H); 7.20 (m, 1H); 7.30 - 7.36 (m, 5H); 7.40 (m, 1H); 7.56 ~ 7.61 (m, 2H); 7.78 (t, 2H, J - 8.2 Hz), 8.38 (m, 1H). 31P NMR (CDCI3,162 MHz): δ -32.25.
Example 20
(Re, SFe, SP)-2-[(1- N-Methylamino)ethyl]-1-[(2-
naphthyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-20]:
Me Me

S^?* 40%MeNH2,a,.) ——<^ 2-Np
Ah'"«* THF-MeOH (4:1) Fe £'''.*
Ph ^^Ph
Rc-Spe-Rp-21

15 A solution of (Re, SFe, Rp)-15 (633 mg, 1.25 mmol) and 40% methylamine
aqueous solution (3.0 mL) in THF (10 mL) and MeOH (2.5 mL) was stirred for 3 days at room temperature, and concentrated. The residue was dissolved in Et20 (20 mL), washed with brine (10 mL), dried (Na2S04), and evaporated under reduced pressure. The crude product was purified by chromatography

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(Si02, hexane-EtOAc-Et3N = 85:10:5) to give the title compound (537 mg, 90%) as orange crystals.
Example 22
(Re, SFe, SP)-2-[(1~ N-Methylamino)ethyl]-1-[(2-
biphenyl)phenylphosphino]ferrocene [(Re, SFe, SP)-22]:


Me
40% MeNH2 (aq.) THF-MeOH (4:1)

NHMe p^Ph
Fe
Rc-Spe"Sp"22

A solution of (Re, SF6, Sp)-16 (1.063 g, 2 mmol) and 40% methylamine aqueous
10 solution (5.0 mL) in THF (10 mL) and MeOH (2.5 mL) was stirred for 2 days at 40 °C, and concentrated. The residue was dissolved in Et20 (20 mL), washed with brine (10 mL), dried (Na2S04), and evaporated under reduced pressure. The residue was recrystallized from hexane to give the title compound (621 mg, 62%) as orange crystals. 1H NMR (CDCI3, 400.13 MHz): 5 1.34 (d, 3H, J = 6.6 15 Hz); 1.93 (s, 3H); 3.60 (m, 1H); 3.74 (s, 5H); 4.08 (m, 1H); 4.30 (t, 1H, J = 2.5 Hz); 4.39 (m, 1H); 7.19-7.24 (m, 5H); 7.31 (m, 1H); 7.38-7.50 (m, 5H), 7.59 (ddt, 1H, J= 7.6, 3.5 and 1.0 Hz); 7.67 (m, 2H). 31P NMR (CDCI3,162 MHz): 5 -34.29.
20

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Example 23
(Rc, SFe, SP)-2-[1-[(N-Methyl-N-diphenylphosphino)amino]ethyl]-1-[(2-
methoxypheny()phenylphosphino]ferrocene [(Rc, SFe, SP)-23]:
Me Me
^^^^p.Ph Ph2PCI, Et3N >b=i( Ph PPh2
Fe V'>,,. ► Fe ?''',,.
>^=^v o-Ah toluene, rt, 16 h yp==\ o-Ah
Rc-SFe-Sp-17 Rc-SFe-SP-23
5
To a solution of (Rc, SF6, SP)-17 (457 mg, 1.0 mmol) and Et3N (0.28 mL, 2.0 mmol) in toluene (2.5 mL) was added dropwise chlorodiphenylphosphine (188 pL, 1.05 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of
10 neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (570 mg, 89%) as orange foam. 1H NMR (CDCI3,400.13 MHz): δ 1.55 (d, 3H, J = 6.9 Hz); 2.17 (d, 3H, J = 3.4 Hz); 3.87 (s, 8H, overlap); 4.24 (m, 1H); 4.38 (t, 1H, J * 2.4 Hz); 4.53 (m, 1H); 4.88 (m, 1H); 6.88 ~ 6.96 (m, 6H); 7.03 - 7.14 (m, 6H); 7.20 - 7.37 (m, 7H). 31P NMR (CDCI3,162 MHz): δ 56.93,
15 -38.64.
Example 24
(Rc, SFe, SP)-2-[1 -[(N-Methyl-N-diphenylphosphino)amino]ethyl]-1-[(1-
naphthyl)phenylphosphino]ferrocene [(Rc, SFe, Sp)-24]:

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Me
Ph2PCI, Et3N Ph2
->" Fe pf>„.
toluene, rt, 16 h .p==^vi-Np* RC*SFO"SP-24

To a solution of (Re, SFe, SP)-18 (477 mg, 1.0 mmol) and Et3N (0.28 mL, 2.0 mmol) in toluene (2.5 mL) was added dropwise chlorodiphenylphosphine (188
5 pL, 1.05 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (595 mg, 90%) as orange foam. 1H NMR (CDCI3,400.13 MHz): δ 1.53 (d, 3H, J = 6.8 Hz); 2.22 (d, 3H, J = 3.3 Hz); 3.44 (s, 5H); 4.26 (m, 1H); 10 4.39 (t, 1H, J = 2.4 Hz); 4.50 (m, 1H); 5.03 (m, 1H); 6.85 ~ 6.94 (m, 4H); 7.04 (tt, 1H, J= 7.2 and 1.4 Hz); 7.09 ~ 7.19 (m, 4H); 7.27 ~ 7.31 (m, 4H); 7.37 ~ 7.43 (m, 3H); 7.48 ~ 7.56 (m, 2H); 7.68 (m, 1H); 7.89 (dd, 2H, J = 8.1 and 4.8 Hz); 9.44 (t, 1H, J= 7.6 Hz). 31P NMR (CDCI3,162 MHz): δ 59.59, -41.03.
15 Example 25
(Re, SFe, RP)-2-[1 -[(N-Methyl-N-diphenylphosphino)amino]ethyl]-1 -[(1 -naphthyl)phenylphosphino]ferrocene [(Re, SFe, Rp)-25]:

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NHMe 1-Np

Me Fe Rc-SFe-RP-19

Ph2PCI, Et3N toluene, rt, 16 h

^
Rc-Spe-Rp-25

To a solution of (Re, SFe, RP)-19 (239 mg, 0.5 mmol) and Et3N (0.14 ml_, 1.0 mmol) in toluene (2.0 mL) was added dropwise chlorodiphenylphosphine (89
5 pL, 0.50 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (304 mg, 92%) as orange foam. 1H NMR (CDCI3,400.13 MHz): δ 1.51 (d, 3H, J- 6.8 Hz); 2.08(d, 3H, J = 3.5 Hz); 3.90 (s, 5H); 4.15(m, 1H);
10 4.44 (t, 1H, J = 2.4 Hz); 4.58 (m, 1H); 5.02 (m, 1H); 6.44 (td, 2H, J = 8.0 and 1.8 Hz); 6.62 (td, 2H, J = 8.0 and 1.2 Hz); 6.80 (tt, 1H, J = 7.4 and 1.2 Hz); 7.20 (m, 1H); 7.15 ~ 7.30 (m, H); 7.58 ~ 7.64 (m, H); 7.70 (dd, 1H, J = 6.8 and 1.8 Hz); 7.79 (d, 1H, J = 8.0 Hz); 8.20 (dd, 1H, J = 8.2 and 2.4 Hz). 31P NMR (CDCI3, 162 MHz): δ 58.81, -31.16.
15
Example 26
(Rc, SFe, SP)-2-[1-[(N-Methyl-N-diphenylphosphino)amino]ethyl]-1-[(2-
biphenyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-26]:

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Me
'NHMe
_Ph Ph2PCI,Et3N
Fe "?>,,. >■
y^s^-Bip'h toluene, rt, 16 h
RC"SFO"SP"22

s^==^(_.Ph PPh2 Fe %•',,.
Rc-Spe-Sp-26

To a solution of (Re, SFe, SP)-22 (XX mg, 1.0 mmol) and Et3N (0.28 mL, 2.0 mmol) in toluene (2.5 mL) was added dropwise chlorodiphenylphosphine (188
5 pL, 1.05 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (XX mg, X%) as orange foam. 1H NMR (CDCI3,250 MHz): δ 1.50 (d, 3H, J = 6.6 Hz); 2.16 (d, 3H, J = 3.0 Hz); 3.68 (s, 5H); 4.08 (m, 1H); 4.33 (m,
10 1H); 4.42 (m, 2H); 4.56 (m, 1H); 6.98-7.75 (m, 24H). 31P NMR (CDCI3,101 MHz): 5 50.70,-35.51.
Example 27
(Rc, SFe, SP,Ra)-27:



P-CI
15

r?—57" %NHMe
Fe ?> +
Rc"SFe"Sp"^7

Et3N
toluene, rt, 16 h

Rc-Spe-Sp, Ra-27

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To a solution of (Re, SFe, SP)-17 (229 mg, 0.5 mmol) and Et3N (209 pL, 1.5 mmol) in toluene (4 mL) was added (R)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']binaphthalene (175 mg, 0.5 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h)
5 at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (359 mg, 93%) as orange foam. 1H NMR (CDCI3,250 MHz): δ1.73 (d, 3H, J = 3.5 Hz); 1.79 (d, 3H, J = 7.0 Hz); 3.71 (s, 3H), 3.80 (m, 1H); 4.00 (s, 5H); 4.31 (t, 1H, J = 2.3 Hz); 4.46 (m, 1H); 5.34 (m, 1H); 6.60 (ddd, 1H, J = 7.5,4.5 and 1.8 Hz), 6.72 (t, 1H,
10 J = 7.5 Hz), 6.82 (dd, 1H, J = 8.8 and 0.8 Hz), 6.91 (ddd, 1H, J = 8.8,4.5 and 0.8 Hz), 7.15-7.38 (m, 11H), 7.58 (m, 2H), 7.77-7.87 (m, 4H). 31P NMR (CDCI3, 101 MHz): 5 148.51 (d, J - 53.4 Hz); -35.37 (d, J = 53.4 Hz).

15 Example 28
(Re, SF6, Sp,Ra)-28:

Me O
r?—^57^ "NHMe
°, EtaN
P-CI »
O toluene, rt, 16 h

^==
O toluene, it, 16 h

^
Rc"SFe-Rp-19

N^0'
PIT
Rc-Spe"Rpi Ra*30
10 To a solution of (Re, SFe, RP)-1 9(239 mg, 0.5 mmol) and Et3N (209 pL, 1.5 mmol) in toluene (4 mL) was added (R)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-albinaphthalene (175 mg, 0.5 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and
15 eluted with hexane-EtOAc (9:1) to afford the title compound (371 mg, 95%) as orange foam. 1H NMR (CDCI3, 250 MHz): δ 1.64 (d, 3H, J = 3.5 Hz); 1.79 (d, 3H, J = 7.0 Hz); 4.88 (m, 1H); 4.07 (s, 5H); 4.38 (t, 1H, J =» 2.3 Hz); 4.52 (m, 1H); 4.91 (dd, 1H, J = 8.5 and 0.8 Hz), 5.37 (m, 1H); 6.91 (m, 1H); 7.10-7.90

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(m, 21H), 8.44 (m, 1H). 31P NMR (CDCI3,101 MHz): 5 148.18 (d, J = 54.5 Hz); -32.43 (d, J = 54.5 Hz).
Example 31 5(Rc,SFe,Rp,Sa)-31:


p-a

fr—57" NHMe
Fe \-;,. + Ph
^>r
Rc-Spe-Rp-19

EtaN
->~
toluene, rt, 16 h

To a solution of (Rc, SFe, Rp>19(239 mg, 0.5 mmol) and Et3N (209 pL, 1.5 mmol) in toluene (4 mL) was added (S)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']binaphthalene (175 mg, 0.5 mmol) at 0 °C.
10 Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (377 mg, 95%) as orange foam. 1H NMR (CDCI3, 250 MHz): δ 1.69 (d, 3H, J = 6.8 Hz); 1.86 (d, 3H, J = 3.5 Hz); 3.97 (s, 5H); 4.07 (m, 1H); 4.43 (t, 1H, J = 2.3 Hz); 4.58 (m,
15 1H); 5.15 (m, 1H); 5.88 (dd, 1H, J = 8.5 and 0.8 Hz), 6.91 (m, 1H); 7.10-7.92 (m, 22H), 8.31 (m, 1H). 31P NMR (CDCI3,101 MHz): δ 150.64 (d, J = 21.8 Hz); -33.31 (d, J = 21.8 Hz).
Example 32

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(Re, SFO, Sp,Ra)-32:


Me


/-^-JliBh + ^ X f~CI —i ► *T*W
/P==5KBipn ft^a^d toluene, rt. 16 h ^^^-Bip'h
To a solution of (Re, SFe, SP)-22(252 mg, 0.5 mmol) and Et3N (209 pL, 1.5 mmol) in toluene (4 mL) was added (R)-4-chloro-3,5-dioxa-4-
5 phosphacyclohepta[2,1-a:3,4-a']binaphthalene (175 mg, 0.5 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (392 mg, 96%) as orange foam. 1H NMR (CDCI3, 250 MHz): δ 1.63 (d, 3H, J = 7.0 Hz); 1.76 (d,
10 3H, J = 3.5 Hz); 3.69 (s, 5H); 4.09 (m, 1H); 4.30 (t, 1H, J = 2.3 Hz); 4.34 (m, 1H); 4.89 (m, 1H); 6.71 (dd, 1H, J = 8.5 and 0.8 Hz), 7.07-7.84 (m, 25 H). 31P NMR (CDCI3> 101 MHz): δ 149.07 (d, J = 60.5 Hz); -36.59 (d, J = 60.5Hz).
Example 33
15 (Rc, SFe, SP)-2-(1-Dicyclohexylphosphino)ethyl]-1-[(2-
methoxyphenyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-33]:

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Me Me
Fe *[•*,,. ► Fe F^,t.
/,—<\ o-Ah AcOH /-—ov o-An
<^^> rt, 16 h ^^^
Rc-SFe-SP-11 Rc-Spe-Sp-33

A solution of (Re, SFe, SP)-11 (486 mg, 1.0 mmol) and dicyclohexylphosphine (243 pL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room
5 temperature, and poured into 10% K2C03 aqueous solution (60 mL) with stirring, extracted with Et20 (2x25 mL). The combined ether layers were dried (MgS04) and concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAc = 9:1) to afford the title compound (601 mg, 96%) as orange crystals. 1H NMR(CDCI3) 250.13 MHz): δ 1.08-1.68 (m, 25 H), 3.12 (m, 1H),
10 3.91 (s, 5H), 4.07 (m, 1H), 4.29 (t, 1H, J = 2.3 Hz); 4.38 (m, 1H), 6.87-6.98 (m, 2H), 7.15-7.25 (m, 6 H), 7.35 (t, 1 H, J = 7.3 Hz); 31P NMR (CDCf3, 101.25 MHz): 5 15.58 (d, J = 23.2 Hz); -42.23 (d, J = 23.2 Hz).
Example 34
15 (Rc, SFe, Sp)-2-(1 -Dicyclohexylphosphino)ethyl]-1 -[(1 -naphthyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-34]:
Me
► Fe *K.
AcOH /p^^i-Np'
rt,16h <$^£>
Rc-Sp0-Sp"34

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A solution of (Re, SE, SP)-12 (506 mg, 1.0 mmol) and dicyclohexylphosphine (243 pL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with
5 stirring, extracted with Et20 (2x25 mL). The combined ether layers were dried (MgSO4) and concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc = 9:1) to afford the title compound (613 mg, 95%) as orange crystals. 1H NMR (CDCI3, 400.13 MHz): δ1.14 -1.57 (m, 25 H); 3.22 (m, 1H); 3.40 (s, 5H); 4.08 (m, 1H); 4.23 (t, 1H, J = 2.4 Hz); 4.31 (m, 1H); 7.16 ~ 7.22 (m,
10 5H); 7.36 (dd, 1H, J = 8.0 and 7.2 Hz); 7.45 - 7.49 (m, 2H); 7.60 (ddd, 1H, J = 8.5, 6.8 and 1.4 Hz); 7.82 (t, 2H, J = 8.1 Hz); 9.28 (dd, 1H, J * 7.6 and 6.8 Hz). 31P NMR (CDCI3,162 MHz): δ 17.46 (d, J = 27.7 Hz); -42.43 (d, J = 27.7 Hz).
15 Example 35
(Rc, SFe, Rp)-2-(1-Dicyclohexylphosphino)ethyl]-1-[(1-naphthyl)phenylphosphino]ferrocene [(Rc, SFe, Rp)-35]:
Me Me
C^T^ Cy2PH ^^;^2
_ ^.p^1-NP w ^ vDx1-Np
Fe 7''^. ► Fe fy,,.
/7==z\ Ph" AcOH /F=^x Ph"
4^2> rt,16h 4^£"
RC-SF8-RP-13 Rc-SFe-Rp-35

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A solution of (Re, SFe, SP)-13 (506 mg, 1.0 mmol) and dicyclohexylphosphine (243 pL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with stirring, extracted with Et20 (2x25 mL). The combined ether layers were dried
5 (MgSO4) and concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc = 9:1) to afford the title compound (618 mg, 95%) as orange crystals. 1H NMR (CDCI3,250.13 MHz): δ 0.84-1.85 (m, 25 H), 3.16 (m, 1H), 3.96 (s, 5H), 4.00 (m, 1H), 4.35 (t, 1H, J = 2.3 Hz); 4.41 (m, 1H), 7.29-7.40 (m, 7H), 7.62-7.79 (m, 4 H), 8.33 (m, 1H); 31P NMR (CDCI3,101.25 MHz): δ 14.93
10 (d, J = 22.8 Hz); -34.80 (d, J = 22.8 Hz).
Example 36
(Rc, SFe, SP)-2-(1-Dicyclohexylphosphino)ethyl]-H(2-naphthyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-36]:
Me

cy2PH
15 Rc-Spe-Sp-14 Rc-SFe-Sp-36
A solution of (Rc, SF6, SP)-14 (506 mg, 1.0 mmol) and dicyclohexylphosphine (243 pL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with
20 stirring, extracted with Et20 (2x25 mL). The combined ether layers were dried

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(MgS04) and concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc = 9:1) to afford the title compound (599 mg, 93%) as orange crystals. 1H NMR (CDCI3, 250.13 MHz): 5 115-1.71 (m, 25 H), 3.26 (m, 1H), 3.79 (s, 5H), 4.10 (m, 1H), 4.29 (t, 1H, J = 2.3 Hz); 4.37 (m, 1H), 7.17-7.24 (m,
5 H), 7.34 (m, 1 H), 7.50 (d, 1H, J = 9.5 Hz); 7.50 (dd, 1H, J = 3.0 and 1.5 Hz); 7.57 (ddd, 1H, J = 8.3, 5.0 and 1.5 Hz); 7.81 (d, 1H, J = 8.5 Hz); 7.87 (m, 1H), 8.31 (d, 1H, J = 9.5 Hz); 31P NMR (CDCI3,101.25 MHz): 6 15.67 (d, J= 30.9 Hz);-34.20 (d, J « 30.9Hz).
10
Example 37
(Re, SFe, Rp)-2-(1-Dicyclohexylphosphino)ethyl]-1-[(2-
naphthyl)phenylphosphino]ferrocene [(Re, SFe, Rp)-37]:
Me Me

Fe 7'«/,. Ph"
Rc"Spe*Rp"15

AcOH rt, 16 h

^==< .2-Np Fe *J"„.
Rc-Spe-Rp-37

15
A solution of (Re, SFe, SP)-15 (506 mg, 1.0 mmol) and dicyclohexylphosphine (243 pL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with stirring, extracted with Et2O (2*25 mL). The combined ether layers were dried (MgS04) and concentrated. The residue was purified by chromatography (Si02,

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hexane-EtOAc = 9:1) to afford the title compound (608 mg, 94%) as orange crystals. 1H NMR (CDCI3, 250.13 MHz): δ 1.07-1.68 (m, 25 H), 3.26 (m, 1H), 3.85 (s, 5H), 4.07 (m, 1H), 4.34 (t, 1H, J= 2.3 Hz); 4.40 (m, 1H), 7.30-7.77 (m, 12H); 31P NMR (CDCI3,101.25 MHz): 5 15.56 (d, J = 33.1 Hz); -25.12 (d, J =
5 33.1 Hz).
10
Example 38

PCy2
p -p'Ph Fe fy,,.
KZS
(Rc, SFe, SP)-2-(1-Dicyclohexylphosphino)ethyl]-1-[(2-
biphenyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-38]:
Me Me
Cy2PH
AcOH rt,16h

A solution of (Rc, SFe, SP)-16 (531 mg, 1.0 mmol) and dicyclohexylphosphine (243 pL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with
15 stirring, extracted with Et20 (2x25 mL). The combined ether layers were dried (MgS04) and concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc = 9:1) to afford the title compound (650 mg, 97%) as orange crystals. 1H NMR(CDCI3,250.13 MHz): δ 1.02-1.72 (m, 25 H), 2.93 (m, 1H), 3.66 (s, 5H), 3.76 (m, 1H), 4.29 (t, 1H, J = 2.3 Hz); 4.32 (m, 1H), 7.14-7.69 (m,

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14 H); 31P NMR (CDCI3,101.25 MHz): δ 18.44 (d, J = 36.7 Hz); -37.67 (d, J = 36.7 Hz).

5 Example 39
(Re, SFe, SP)-2)2'-Bis[(1-N,N-dimethylamino)ethyl]-1,1'-bis[(2-
methoxyphenyl)phenylphosphino]ferrocene [(Re, SFe, Sp)-40]:

Me Me
vC^y NMe2 2)PhPCI2,-78°C~rt \C_^
: ►
NMe, 1)t-BuUEt20,-78°C~rt
y^Lv 3) o-AnLi, -78 °C~rt
" 1 P-
Me MePh-'l'^'An
(R,R)-39 Rc^Fo-Sp-40

10 To a solution of (R,R)-1,1'-bis(1-N,N-dimethylaminoethyl)ferrocene [(R,R)-20] (986 mg, 3.0 mmol) in Et20 (30 mL) was added 1.5 M t-BuLi solution in pentane (6.0 mL, 9 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again,
15 and dichlorophenylphosphine (1.22 mL, 9.0 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. The mixture was then cooled to -78 °C again, and a solution of (2-methoxy)phenyllithium [prepared from 2-bromoanisole (1.87 g, 10 mmol) and 1.5 M t-BuLi solution in pentane

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(13.3 mL, 20 mmol) in Et20 (50 mL) at -78 °C] was added slowly via a cannula. The mixture was warmed to room temperature overnight, and filtered through a pad of Celite. The filtrate was concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc-Et3N = 80:15:5) to afford the title
5 compound (1.10 g, 48%) as yellow foam. 1H NMR (CDCI3, 400.13 MHz): δ 1.28 (d, 6H, J = 6.7 Hz); 1.71 (s, 12H); 3.16 (m, 2H); 3.84 (s, 6H); 4.05 (m, 2H); 4.16 (m, 2H); 4.53 (t, 2H, J = 2.3 Hz); 6.62 (t, 2H, J = 7.4 Hz); 6.73 (dd, 2H, J = 8.1 and 4.6 Hz); 6.85 (ddd, 2H, J = 7.4, 5.3 and 1.8 Hz); 7.03 ~ 7.11 (m, 10H); 7.17 (td, 2H, J= 8.5 and 1.6 Hz); 31P NMR (CDCI3,162 MHz): δ-39.53 (s).
10
Example 40
(Re, SFe, SP)-2,2'-Bis[(1.N,N-dimethylamino)ethyl]-1,1'-bis[(1-naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-41]: Me


£—2/ NMe2 2)PhPCI2,-78°C~rt \/ J*™*2
Fe 3)1-NpU,-78°C~rt Jl-^ty'
4^^NMe2 ' Me2NY^^^
Me Me phxi''1-Np
(R'R)"20 RC-SFO"SP-41

15 To a solution of (R,R)-1,1,-bis(1-N,N-dimethylaminoethyl)ferrocene [(R,R)-20] (986 mg, 3.0 mmol) in Et20 (30 mL) was added 1.5 M t-BuLi solution in pentane (6.0 mL, 9 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h

(13.3 mL, 20 mmol) in Et20 (50 mL) at -78 °C] was added slowly via a cannula. The mixture was warmed to room temperature overnight, and filtered through a pad of Celite. The filtrate was concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc-EfeN = 80:15:5) to afford the title compound (1.10 g, 48%) as yellow foam. 1H NMR (CDCI3> 400.13 MHz): 6 1.28 (d, 6H, J = 6.7 Hz); 1.71 (s, 12H); 3.16 (m, 2H); 3.84 (s, 6H); 4.05 (m, 2H); 4.16 (m, 2H); 4.53 (t, 2H, J = 2.3 Hz); 6.62 (t, 2H, J = 7.4 Hz); 6.73 (dd, 2H, J = 8.1 and 4.6 Hz); 6.85 (ddd, 2H, J = 7.4, 5.3 and 1.8 Hz); 7.03 ~ 7.11 (m, 10H); 7.17 (td, 2H, J= 8.5 and 1.6 Hz); 31P NMR (CDCI3,162 MHz): 5 -39.53 (s).
Example 40
(Re, SFe, SP)-2,2'-Bis[(1.N,N-dimethylamino)ethyl]-1,1'-bis[(1-naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-41]: Me


£—2/ NMe2 2)PhPCI2,-78°C~rt \/ J*™*2
Fe 3)1-NpU,-78°C~rt Jl-^ty'
4^^NMe2 ' Me2NY^^^
Me Me phxi''1-Np
(R'R)"20 RC-SFO"SP-41

15

To a solution of (R,R)-1,1,-bis(1-N,N-dimethylaminoethyl)ferrocene [(R,R)-20I (986 mg, 3.0 mmol) in Et20 (30 mL) was added 1.5 M t-BuLi solution in pentane (6.0 mL, 9 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h

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at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.22 mL, 9.0 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. The mixture was then
5 cooled to -78 °C again, and a solution of 1-naphthyllithium [prepared from 1-bromonaphthalene (2.07 g, 10 mmol) and 1.5 M t-BuLi solution in pentane (13.3 mL, 20 mmol) in Et20 (50 mL) at -78 °CJ was added slowly via a cannula. The mixture was warmed to room temperature overnight, and filtered through a pad of Celite. The filtrate was concentrated. The residue was purified by
10 chromatography (Si02, hexane-EtOAc-Et3N = 80:15:5) to afford the title
compound (827 mg, 35%) as yellow crystals. 1H NMR (CDCI3, 400.13 MHz): δ1.28 (d, 6H, J = 6.8 Hz); 1.74 (s, 12H); 2.49 (m, 2H); 4.01 (t, 2H, J = 2.3 Hz); 4.06 (m, 2H); 4.08 (m, 2H); 6.87 ~ 6.93 (m, 4H); 6.99 - 7.09 (m, 10H); 7.50 (td, 2H, J = 8.1 and 1.1 Hz); 7.53 (td, 2H, J - 6.8 and 1.3 Hz); 7.70 (d, 2H, J - 8.1
15 Hz); 7.83 (d, 2H, J = 8.1 Hz); 9.16 (t, 2H, J = 7.1 Hz); 31P NMR (CDCI3,162 MHz): δ-39.47 (s).
Example 41
Re, SFe, Sp)-2,2'-Bis[(a-N,N-dimethylamino)phenylmethyl]-1,1 *-bis[(1-20 naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-43J:

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Ph Ph
*NMe2 1> «uU. EfeO -78 °C~rt '^NMe,
^r NMez %*53^KHt" ^^T.Ph 2
J2L 3) 1-NpLi, -78 "C-rt J^1-N£*
Ph Ph ph'A"1-Np
(W"42 Rc-SFe-Sp-43
To a solution of (R,R)-1,1'-bis[(a-N,N-dimethylamino)phenylmethyl]ferrocene [(R,R)-23] (903 mg, 2.0 mmol) in Et20 (20 mL) was added 1.5 M t-BuLi solution
5 in pentane (4.0 mL, 6 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (814 pL, 6.0 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to
10 room temperature, and stirred for 1.5 h at room temperature. The mixture was then cooled to -78 °C again, and a solution of 1-naphthyllithium [prepared from 1-bromonaphthalene (1.45 g, 7 mmol) and 1.5 M t-BuLi solution in pentane (9.3 mL, 14 mmol) in Et20 (40 mL) at -78 °C] was added slowly via a cannula. The mixture was warmed to room temperature overnight, and filtered through a pad
15 of Celite. The filtrate was concentrated. The residue was purified by
chromatography (Si02, hexane-EtOAc = 3:1) to afford the title compound (369 mg, 20%) as orange crystals. 1H NMR (CDCI3,250.13 MHz): δ1.54 (s, 12H); 2.46 (m, 2H); 3.01 (m, 2H); 3.96 (t, 2H, J = 2,5 Hz); 4.42 (d, 2H, J = 5.3 Hz); 6.69 (ddd, 2H, J = 7.3,4.3 and 1.0 Hz); 6.96 - 7.34 (m, 22H); 7.55 (d, 2H, J =

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8.3 Hz); 7.66 (d, 4H, J = 8.3 Hz); 7.81 (d, 2H, J = 7.8 Hz); 9.20 (t, 2H, J = 7.8 Hz); 31P NMR (CDCI3,162 MHz): δ - 41.73 (s).
Example 42
5 (2'S, 4'S, SFe, Rp)r2-[4'-(methoxymethyl-1,3-dioxan-2'-yl]-1-[(2-methoxyphenyl)phenylphosphino]ferrocene [(2'S, 4'S, SFe, Rp)-46]:

(2S,4S)-45 (2'S> 4'S> SFe» RpM®
To a solution of (2S,4S)-4-(methoxymethyl)-2-ferrocenyl-1,3-dioxane [(2S,4S)-
10 45] (1.58 g, 5 mmol) in Et20 (20 mL) was added 1.7 M t-BuLi solution in pentane (3.23 mL, 5.5 mmol) at -40 °C. After stirring for 10 min, the cooling bath was removed and the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting orange suspension was cooled to -78 °C, and dichlorophenylphosphine (750 UL, 5.5 mmol) was added
15 in one portion. After stirring for 10 min, the cooling bath was removed and the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The mixture was cooled to -78 °C again, a solution of 2-methoxyphenyllithium [prepared from 2-bromoanisole (1.22 mL, 6.5 mmol) and 1.7 M t-BuLi solution in pentane (7.6 mL, 13 mmol) in Et20 (40 mL) at -78 °C]
20 was added slowly via a cannula. The mixture was warmed to room temperature

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overnight, and filtered through a pad of Celite. The filtrate was concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc = 6:1) to afford the title compound (2.41 g, 91%) as a mixture of two diastereomers (in about 3.3:1 ratio). Recrystallising from hexane, the major product [(2'S, 4'S, SFe,
5 Rp)-46] (1.41 g, 53%) was obtained. The absolute configuration of (2'S, 4'S, SF6, Rp)-46 was determined by single-crystal X-ray diffraction analysis. 1H NMR (CDCI3, 400.13 MHz): δ 1.42 (dm, 1H, J= 13.3 Hz); 1.74 (m, 1H,); 2.89 (d, 2H, J = 5.1 Hz); 3.03 (s, 3H); 3.59 (m, 1H); 3.60 (s, 3H); 3.74 (m, 1H); 3.91 (td, 1H, J = 12.2 and 2.5 Hz); 4.08 (s, 5H); 4.24 -4.27 (m, 2H); 4.70 (m, 1H); 5.71 (d,
10 1H, J = 2.5 Hz); 6.74 (dd, 1H, J = 7.9 and 4.6 Hz); 6.80 - 6.86 (m, 2H); 7.22 (m, 1H); 7.31 ~ 7.35 (m, 3H); 7.51 -7.56 (m, 2H). 31P NMR (CDCI3,162 MHz): δ -31.46(s).
Example 43
15 (2'S, 4'S, SFe, Rp)-2-[4'-(methoxymethyl-1,3-dioxan-2'-yl]-1-[(1-naphthyl)phenylphosphino]ferrocene [(2'S, 4'S, SFe, Rp)-47]:

(2S,4S)-4S (2'S, 4*S, SFe, RP)-47
To a solution of (2S,4S)-4-(methoxymethyl)-2-ferrocenyl-1,3-dioxane [(2S,4S)-
20 45] (3.16 g, 10 mmol) in Et20 (40 mL) was added 1.5 M t-BuLi solution in

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pentane (7.4 mL, 11 mmol) at -40 °C. After stirring for 10 min, the cooling bath was removed and the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting orange suspension was cooled to -78 °C, and dichlorophenylphosphine (1.49 mL, 11 mmol) was added in one portion.
5 After stirring for 10 min, the cooling bath was removed and the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The mixture was cooled to -78 °C again, a solution of 1-naphthyllithium [prepared from 1-bromonaphthalene (1.67 mL, 12 mmol) and 1.5 M t-BuLi solution in pentane (16 mL, 24 mmol) in Et20 (60 mL) at -78 °C] was added slowly via a
10 cannula. The mixture was warmed to room temperature overnight, and filtered through a pad of Celite. The filtrate was concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAc 6:1) to afford the title compound (4.95 g, 90%) as a mixture of two diastereomers (in about 3.4:1 ratio), which was recrystallised from hexane to give the pure major product [(2'S, 4'S, SFE,
15 Rp)-47 ] (2.53 g, 51 %) as yellow needles. The absolute configuration of (2'S, 4'S, SFE. Rp)-47 was determined by single-crystal X-ray diffraction analysis. 1H NMR (CDCI3,400.13 MHz): δ 1.33 (dm, 1H, J - 13.3 Hz); 1.63 (m, 1H); 2.56 (dd, 1H, J= 10.3 and 4.8 Hz); 2.67 (dd, 1H, J= 10.3 and 5.6 Hz); 2.76 (s, 3H); 3.58 (m, 1H); 3.67(m, 1H); 3.86(td, 1H, J= 12.2 and 2.5 Hz); 4.15 (s, 5H); 3.74
20 (m, 1H); 4.21 (ddd, 1H, J = 11.4, 5.1 and 1.0 Hz); 4.31 (t, 1H, J = 2.5 Hz); 4.74 (m, 1H); 5.69 (d, 1H, J = 2.5 Hz); 7.16 (ddd, 1H, J = 7.1, 5.1 and 1.2 Hz); 7.29 -7.40 (m, 6H); 7.54 ~ 7.58 (m, 2H); 7.74 (d, 1H, J = 8.3 Hz); 7.78 (d, 1H, J = 8.0 Hz); 8.25 -8.28 (m, 1H). 31P NMR (CDCI3,162 MHz): δ - 28.03 (s).

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Example 44
(SFe, RP)-2-t(2-Methoxyphenyl)phenylphosphino]ferrocenecarboxaldehyde [(SFe, RP)-481: or
S(rH P-TsOH (cat.) ^~3r~CHA°
6 v ft'.* CH2CI2-H20 Fe *£"„ .
5 (2,S,4'S,SFe,Rp)^6 (SFe,RPH8
A mixture of acetal [(2'S, 4'S, SFe, RP)-46] (4.0 g, 7.5 mmol), p-TsOH.H20 (2.0
g), CH2CI2 (50 mL) and H20 (30 mL) was stirred for 24 h at room temperature.
The organic layer was separated, washed with saturated NaHC03 solution (20
mL), dried (MgS04), and evaporated under reduced pressure to give the crude
10 product (3.20 g, 100%) as red crystals, which was used directly in next step. 1H
NMR (CDCI3, 250.13 MHz): δ 3.66 (s, 3H); 3.96 (m, 1H); 4.22 (s, 5H); 4.71 (t,
1H, J = 2.3Hz); 5.13 (m, 1H); 6.72 (m, 1H); 6.78 ~ 6.87 (m, 2H); 7.29 (m, 1H);
7.41 (m, 3H); 7.54 (m, 2H); 10.24 (d, 1H, J = 3.3 Hz). 31P NMR (CDCI3,101
MHz): 6 - 34.66 (s).
15
Example 45
(SFe, Rp)-2-[(1-Naphthyl)phenylphosphino]ferrocenecarboxaldehyde[(SFej
RP)-49]:

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HY
(2'S, 4'S, SFe, Rp)-47 (SFe. Rp)-49
A mixture of acetal [(2'S, 4'S, SFe, RP)-46] (4.73 g, 7.5 mmol), p-TsOH.H20 (2.0 g), CH2Cl2(50 mL) and H2O (30 mL) was stirred for 24 h at room temperature. The organic layer was separated, washed with saturated NaHC03 solution (20
5 mL), dried (MgS04), and evaporated under reduced pressure to give the crude product (3.36 g, 100%) as red crystals, which was used directly in next step. 1H NMR (CDCl3, 250.13 MHz): δ 4.04 (m, 1H); 4.28 (s, 5H); 4.76 (t, 1H, J = 2.3Hz); 5.17 (m, 1H); 7.02 (m, 1H); 7.29 ~ 7.48 (m, 6H); 7.52-7.59 (m, 2H); 7.80 (t, 2H, J = 7.5 Hz); 8.26 (m, 1H); 10.20 (d, 1H, J = 3.0 Hz). 31P NMR (CDCI3,101
10 MHz): 6 - 30.50 (s).
Example 46
(SFe,Rp,aS)-2-[(2-Methoxyphenyl)phenylphosphino]-1-
[(diphenylphosphinophenyl)]ferrocenemethanol[(Sp,aS)-51]:

aM9Br OH PPh2
_ ^o-o-An
15
Fe *"''. Fe R- A^=
^**' THF,-78C~rt ^p^
(SFe,Rp)-48 (SFe, Rp,aS)-5l

15 A suspension of magnesium turnings (63 mg, 2.6 mmol) and 2-bromophenyl)diphenylphosphine 50 (887 mg, 2.6 mmol) in THF (10 mL) was

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refluxed until magnesium was dissolved (about 30 min). The resulting Gragnard reagent solution was cooled to -78 °C, and a solution of (SFe, Rp)-2-[(2-methoxyphenyl)phenylphosphino]ferrocenecarbaoxaldehyde [(SFe, Rp)-48] (856 mg, 2.0 mmol) in THF (10 mL) was added slowly via a syringe. After stirring for 5
5 h at -78 °C, the mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction was quenched with saturated NH4CI solution, and extracted with CH2CI2(2*20 mL). The combined extracts were washed with brine (20 mL), dried (MgS04), and evaporated under reduced pressure. The residue was purified by flash chromatography (Si02,
10 hexane-EtOAc - 6:1) to give yellow crystals (1.297 g, 96%) as a mixture of two diastereomers (-9:1). Major product: 1H NMR (CDCI3,250 MHz): δ 2.91 (br. s, 1H), 3.57 (m, 1H), 3.59 (s, 3H), 4.05 (m, 1H), 4.14 (t, 1H, J = 2.4 Hz), 4.18(s, 5H), 4.22 (m, 1H), 6.48-4.56 (m, 2H), 6.68-6.80 (m, 2H), 7.02 - 7.37 (m, 13H); 7.49-7.58 (m, 2H), 7.67 (m, 1H). 31P NMR (CDCI3,101 MHz): δ-18.69 (d, J =
15 14.6 Hz),-32.85 (d, J = 14.6 Hz).
Example 47
(SFe,Rp,aS)-2-[(1 -Naphthyl)phenylphosphino]-1 -[a-
[(diphenylphosphinophenyl)]ferrocenemethanol[(SFe,Rp,aS)-52]:
^.MgBr QH pph2
CHO U A
^Ph'"- THF..78C-T, J^***
(SFo, RP)-49 (SFe, Rp,oS)-52
^%Ph2
20

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A suspension of magnesium turnings (63 mg, 2.6 mmol) and 2-bromophenyl)diphenylphosphine 50 (887 mg, 2.6 mmol) in THF (10 mL) was refluxed until magnesium was dissolved (about 30 min). The resulting Gragnard reagent solution was cooled to -78 °C, and a solution of (Spe, Rp)-2-[(1-
5 naphthyl)phenylphosphino]ferrocenecarbaoxaldehyde [(SFe, Rp)-49] (897 mg, 2.0 mmol) in THF (10 mL) was added slowly via a syringe. After stirring for 5 h at -78 °C, the mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction was quenched with saturated NH4CI solution, and extracted with CH2Cl2(2*20 mL). The combined extracts
10 were washed with brine (20 mL), dried (MgS04), and evaporated under reduced pressure. The residue was purified by flash chromatography (Si02, hexane-EtOAc = 6:1) to give yellow crystals (1.322 g, 93%) as a mixture of two diastereomers (-9:1). Major product: 1H NMR (CDCI3,250 MHz): δ 2.39 (br. s, 1H), 3.66 (m, 1H), 4.24(s, 5H), 4.29 (t, 1H, J = 2.4 Hz), 4.57 (m, 1H), 4.22 (m,
15 2H), 6.40~4.49(m, 3H), 6.61-6.67 (m, 2H), 6.83 - 7.01 (m, 4H); 7.10-7.59 (m, H), 7.75 (br. D, 1H, J = 7.8 Hz), 8.28 (m, 1H). 31P NMR (CDCI3,101 MHz): δ -18.54 (d, J = 21.0 Hz), -29.56 (d, J = 21.0 Hz).
Example 48
20 (SFe,Rp,aS)-2-[(2-Methoxyphenyl)phenylphosphino]-1-[a-methoxy-(2-diphenylphosphinophenylmethyl)]ferrocene[(SFe,Rp,aS)-53]:

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OMe PPh2
KH, Mel j
Fe 'feo-An THF Fe ■fro-An*
(SFe, Rp,aS)-51 (SFe> Rp,aS)-53
To a suspension of KH (30%, 174 mg, 1.3 mmol washed with hexane) in THF (10 mL) was added alcohol [(SP,αS)-51] (690 g, 1.0 mmol) at 0 °C. After stirring for 2 h at 0 °C, iodomethane (68 pL, 1.1 mmoL) was added via a syringe, then
5 the mixture was stirred for 2 h at 0 °C. The reaction was quenched with MeOH (0.5 mL), and the solvents were removed under reduced pressure. The residue was dissolved in CH2CI2 (20 mL), washed with water (10 mL) and brine (10 mL), dried (MgS04), and evaporated under reduced pressure. The residue was purified by flash chromatography (Si02, hexane-EtOAc = 10:1) to give yellow
10 crystals (463 mg, 66%). 1H NMR (CDCI3, 250 MHz): δ 2.82 (s, 3H), 3.50 (m, 1H), 3.57 (s, 3H), 4.11 (t, 1H, J = 2.3 Hz), 4.17 (s, 5H), 4.19 (m, 1H), 5.79 (d, 1H, J = 6.8 Hz), 6.54-6.64 (m, 2H), 6.69 (m, 1H), 6.84 (ddd, 1H, J =7.8, 4.3 and 1.5 Hz), 7.02-7.37 (m, 12H), 7.52 (m, 2H), 7.66 (m, 1H); 31P NMR (CDCI3,101 MHz): δ -18.44 (d, J = 18.7 Hz), -31.19 (d, J = 18.7 Hz).
15
Example 49
(SFe,αS)-2-Bromo-1-[a-(2-diphenylphosphinophenyl)]ferrocenemethanol
[(SFe,aS)-55]:

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aMgBr Fe Br

, .v THF, -78 C~rt
^> . ^
(SFe)-54 (SFefaS)-55
A suspension of Mg (729 mg, 30 mmol) in THF (10 mL) was added dropwise a solution of 2-bromophenyldiphenylphosphine (50) (9.42 g, 27.6 mmol) in THF (30 mL) at about 50 °C. After addition, the mixture was refluxed for 1 h, cooled
5 room temperature, and added to a solution of (SFE)-2-
bromoferrocenecarboxaldehyde [(SF6)-54](6.74 g, 23 mmol) in Et20 (20 mL) at -78 °C After stirring for 6 h at -78 °C, the mixture was warmed to room temperature, and stirred overnight at room temperature. The reaction was quenched with saturated NH4CI solution (50 mL), and diluted with EtOAc (100
10 mL). The organic layer was separated, washed with brine (50 mL), dried
(Na2S04), and evaporated under reduced pressure. The residue was purified by chromatography (Si02, hexane-EtOAc = 5:1) to give yellow crystals (12.51 g, 98%) as a single diastereomer. 1H NMR (CDCI3,250 MHz): δ 2.67 (dd, 1H, J = 3.5 and 2.0 Hz), 4.04 (t, 1H, J = 2.5 Hz), 4.18 (m, 1H), 4.27 (s, 5H), 4.40 (m,
15 1H), 6.47 (dd, 1H, J = 6.5 and 3.5 Hz), 7.00 (m, 1H), 7.18 (m, 1H), 7.15 - 7.37 (m, 12H); 31P NMR (CDCI3, 101 MHz): 5 -17.30.
Example 50
(SFe,αS)-2-Bromo-1 -[a-methoxy-(2-20 diphenylphosphinophenylmethyl)]ferrocene [(SFe,αS)-56]:

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OH PPh2 OMe PPh2
(SFe,oS)-55 (SFe,aS)-56
To a suspension of KH (30%, 3.75 g, 28.1 mmol), washed with hexane) in THF (20 mL) was added a solution of (SP,αS)-2-Bromo-1-[a-(2-diphenylphosphinophenyl)]ferrocenemethanol [SFe,αS)-55] (12.00 g, 21.6
5 mmol) in (S THF (180 mL) at 0 °C. After stirring for 2 h at 0 °C, iodomethane (1.48 mL, 23.8 mmoL) was added via a syringe, then the mixture was stirred for 1 h at 0 °C. The reaction was quenched with MeOH (5 mL), and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (150 mL), washed with water (100 mL) and brine (10o mL), dried (MgS04), and
10 evaporated under reduced pressure. The residue was purified by flash
chromatography (Si02, hexane-EtOAc = 5:1) to give yellow crystals (12.10 g, 98%). 1H NMR (CDCI3, 250 MHz): δ 3.29 (s, 3H), 3.96 (t, 1H, J = 2.5 Hz), 4.01 (m, 1H), 4.27 (s, 5H), 4.33 (m, 1H), 6.09 (d, 1H, J = 7.8 Hz), 7.04 (m, 1H), 7.15 - 7.37 (m, 12H), 7.44 (m, 1H); 31P NMR (CDCI3, 101 MHz): δ -18.46.
15
Example 51
(SFe,SP,αS)-2-[(2-Methoxyphenyl)phenylphosphino]-1-[a-methoxy-(2-
diphenylphosphinophenylmethyl)]ferrocene[(SFe,Sp,aS)-57]:

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OMe PPh2 OMe PPh2



2) PhPCI2
^====^ 3)o-AnLi X^^o-Afi
(SFe,Sp, aS)-56 (SFe,SP, aS)-56
To a solution of bromide [(SFe,αS)-56] (2.85 g, 5 mmol) in THF (30 mL) was added slowly 1.7M t-BuLi (6.5 mL, 11 mmol) via a syringe at -78 °C. After stirring for 10 min at -78 °C, PhPCI2 (746 pL, 5.5 mmoL) was added via a
5 syringe, After stirring for 30 min at -78 °C, the mixture was warmed to room temperature and stirred for 1 h at room temperature, the mixture was cooled to -78 °C again, and a suspension of o-AnLi [prepared from 2-bromoanisole (805 pL, 6.5 mmol) and 1.7 M t-BuLi (7.6 mL, 13 mmol) in Et20 (30 mL) at -78 °C] was added via a cannula, then the mixture was stirred overnight at -78 °C to
10 room temperature. The reaction was quenched with water (20 mL), The organic layer was separated, washed with brine (30 mL), dried (MgS04), and evaporated under reduced pressure. The residue was purified by flash chromatography (Si02, hexane-EtOAc = 10:1) to give yellow crystals (3.21 g, 91%) as a single diastereomer. 1H NMR (CDCI3, 250 MHz): δ 2.71 (s, 3H), 3.67
15 (m, 1H), 3.90 (m, 1H), 3.96 (s, 3H), 4.06 (t, 1H, J = 2.3 Hz), 4.22 (s, 5H), 5.52 (d, 1H, J = 6.5 Hz), 6.80-6.98 (m, 4H), 7.08-7.36 (m, 14H), 7.76 (m, 1H); 31P NMR (CDCI3,101 MHz): δ -17.98 (d, J = 10.0 Hz), -33.15 (d, J = 10.0 Hz).
Example 52

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(SFe,SP,αS)-2-[(1-Naphthyl)phenylphosphino]-1-[a-methoxy-(2-diphenylphosphinophenylmethyl)]ferrocene [(SFe,SP,αS)-58] and (SFe,RP,αS)-2-[(1 -Naphthyl)phenylphosphino]-1 -[a-methoxy-(2-diphenylphosphinophenylmethyI)]ferrocene [(SFe,Rp,aS)-59]:

(SFe,Sp, aS)-56 (SFe,Sp,aS)-58 (SFo,RP, aS)-59
To a solution of bromide [(SFe,αS)-56] (2.85 g, 5 mmol) in THF (30 mL) was added slowly 1.7 M t-BuLi (6.5 mL, 11 mmol) via a
5 syringe at -78 °C. After stirring for 10 min at -78 °C, PhPCI2 (746 pL, 5.5 mmoL) was added via a syringe, After stirring for 30 min at -78 °C, the mixture was warmed to room
10 temperature and stirred for 1 h at room temperature. The mixture was cooled to -78 °C again, and a suspension of o-AnLi [prepared from 1-bromonaphthalene (900 uL, 6.5 mmol) and 1.7 M t-BuLi (7.6 mL, 13 mmol) in Et20 (30 mL) at -78 °C] was added via a cannula, then the mixture was stirred overnight at -78 °C to room temperature. The reaction was quenched with water (20 mL), The organic
15 layer was separated, washed with brine (30 mL), dried (MgS04), and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO2, hexane-EtOAc = 10:1) to give yellow crystals (3.30 g, 91%) as a mixture of two diastereomers (ratio: ~9:1), which was recrystallised from hexane to give pure major product [(SFe,Sp,αS)-58] (2.83 g, 78%) as
20 yellow crystals. The mother liquor was concentrated, and the residue was

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recrystallized from MeOH to afford pure minor product [(SFe,Rp,αS)-59] (217 mg, 6%) as yellow crystals. Major product [(SFe,SP,αS)-58]: 1H NMR (CDCI3, 250 MHz): 5 2.96 (s, 3H), 3.74 (m, 1H), 3.84 (s, 5H), 4.13 (t, 1H, J = 2.5 Hz), 4.20 (m, 1H), 6.04 (d, 1H, J = 7.3 Hz), 6.89-7.41 (m, 20H). 7.55 (ddd, 1H, J =
5 8.0, 6.8 and 1.3 Hz), 7.64 (dd, 1H, J = 6.8 and 1.5 Hz), 7.69 (ddd, 1H. J = 5.3, 3.5 and 1.7 Hz), 7.89 (t, 2H, J = 8.0 Hz), 9.32 (dd, 1H, J = 7.5 and 6.8 Hz). 31P NMR (CDCI3,101 MHz): δ -18.83 (d, J = 21.3 Hz), -35.08 (d, J = 21.3 Hz). Minor product [(SFe,Rp,aS)-59]: 1H NMR (CDCI3, 250 MHz): δ 2.73 (s, 3H), 3.61 (m. 1H). 4.21 (t, 1H, J = 2.5 Hz), 4.22 (s, 5H), 4.28 (m, 1H), 5.86 (d, 1H, J = 7.3
10 Hz), 6.67 (ddd, 1H, J = 7.8, 4.3 and 1.3 Hz), 6.79-7.61 (m, 23H), 7.75 (br. d, 1H, J = 8.0 Hz), 8.29 (m, 1H). 31P NMR (CDCI3,101 MHz): δ -18.52 (d, J = 18.4 Hz), -27.69 (d, J = 18.4 Hz).
Example 53 IS (SFe, RP)-2-[(2-Methoxyphenyl)phenylphosphino]ferrocenemethanol [(SFe, RP)-60]:


Fe "K .
NaBH4
>
THF-MeOH
(SFe, RP)-48 (SFe, RP)-60
To a solution of aldehyde [(SFe, RP)-48] (856 mg, 2.0 mmol) in THF (10 mL) was added NaBH4 (38 mg, 1.0 mmol) at 0 °C, then MeOH (2 mL) was added. After
20 stirring for 2 h at 0 °C, the mixture was warmed to room temperature and stirred overnight at room temperature. The reaction was quenched with saturated

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NH4CI solution (5 mL), and diluted with EtOAc (10 mL). The organic layer was separated, washed with brine (10 mL), dried (MgS04), and evaporated under reduced pressure to give the crude product (857 mg, 100%) as yellow crystals, which was used directly in next step. 1H NMR (CDCI3, 250 MHz): δ 3.63 (m,
5 1H), 3.66 (s, 3H), 4.10 (s, 5H), 4.29 (t, 1H, J = 2.0 Hz), 4.41 (d, 1H, J = 12.5 Hz), 4.53 (m, 1H), 4.58 (dd, 1H, J = 12.5 and 2.0 Hz), 6.77-6.90 (m, 3H), 7.28 (m, 1H), 7.34-7.41 (m, 3H), 7.48-7.55 (m, 2H). 31P NMR (CDCI3,101 MHz): δ -35.05.
10 Example 54
(SFe, Rp)-2-[(1-Naphthyl)phenylphosphino] ferrocenemethanol [(SFe, RP)-61]:
Tr^B-l-NP NaBH4 ^T-^p-1-Np
Fe 1"'/ . ► Fe *£•*, . K
/^^> Ph * THF-MeOH ^Z^> Ph"
(SFe, RpH9 (S,:e, Rp)-61
To a solution of aldehyde [(SFe, Rp)-49] (897 mg, 2.0 mmol) in THF (10 mL) was
15 added NaBH4 (38 mg, 1.0 mmol) at 0 °C, then MeOH (2 mL) was added. After stirring for 2 h at 0 °C, the mixture was warmed to room temperature and stirred overnight at room temperature. The reaction was quenched with saturated NH4CI solution (5 mL), and diluted with EtOAc (10 mL). The organic layer was separated, washed with brine (10 mL), dried (MgSO4), and evaporated under
20 reduced pressure to give the crude product (900 mg, 100%) as yellow crystals, which was used directly in next step. 1H NMR (CDCI3,250 MHz): δ 3.71 (m,

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1H), 4.16 (s, 5H), 4.36 (t, 1H, J = 2.5 Hz), 4.41 (d, 1H, J = 12.5 Hz), 4.54 (dd, 1H, J = 12.5 and 1.3 Hz), 4.58 (m, 1H), 7.11 (ddd, 1H, J = 7.0,4.5 and 1.3 Hz), 7.30-7.57 (m, 8H), 7.80 (m, 2H), 8.26 (m, 1H). 31P NMR (CDCI3,101 MHz): δ -31.14.
5 Example 55
(SFe, Rp)-2-[(2-Methoxyphenyl)phenylphosphino]ferrocenemethanol
acetate [(SFe, RP)-62]:


■OH Fe ^ AC20, pyridine
(SFe, Rp)-60 (SFe, RP)-62
10 A solution of alcohol [(SFe, Rp)-60] (857 mg, 2.0 mmol), Ac2O (2 mL) and pyridine (2 mL) in CH2CI2 (10 mL) was stirred overnight at room temperature. The volatile matters were removed under reduced pressure below 35 °C to give the crude product (880 mg, 100%) as yellow crystals, which was used directly in next step. 1H NMR (CDCI3, 250 MHz): 6 1.62 (s, 3H), 3.64(s, 4H, overlapped),
15 4.10 (s, 5H), 4.30 (t, 1H, J = 2.5 Hz), 4.54 (m, 1H), 5.01 (d, 1H, J = 12.0 Hz), 5.12 (dd, 1H, J = 12.0 and 2.3 Hz), 6.77 (m, 2H), 6.83 (t, 1H, J = 7.5 Hz), 7.25 (m, 1H), 7.37 (m, 3H), 7.51 (m, 2H). 31P NMR (CDCI3,101 MHz): δ -34.60.
Example 56
20 (SFe, RP)-2-[(1-Naphthyl)phenylphosphino]ferrocenemethanol acetate [(SFe, RP)-63]:

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OAC

Ph
^^^-1-Np AczO, pyridine w ^P^,1"^
Ph(SFe, RP)-61 (SFe, RP)-63

A solution of alcohol [(SFe, Rp)-61] (900 mg, 2.0 mmol), Ac2O (2 mL) and pyridine (2 mL) in CH2CI2 (10 mL) was stirred overnight at room temperature. The volatile matters were removed under reduced pressure below 35 °C to give
5 the crude product (983 mg, 100%) as yellow crystals, which was used directly in next step. 1H NMR (CDCI3, 250 MHz): δ 1.46 (s, 3H), 3.74(m, 1H), 4.15 (s, 5H), 4.38(t, 1H, J = 2.5 Hz), 4.59 (m, 1H), 5.00 (d, 1H, J 1.3.5 Hz), 7.28-7.45 (m, 5H), 7.54 (m, 1H), 7.69 (tt, 1H, J = 7.8 and 1.8 Hz), 7.78 (m, 2H), 8.23 (m, 1H), 8.64 (m, 2H). 31P NMR (CDCI3,101 MHz): δ -30.85.
10 Example 57
(SFe, Rp)-1-[(Dicyclohexylphosphino)methyl]-2-[(2-
methoxyphenyl)phenylphosphino]ferrocene [(SFe, Rp)-64]:

PCy2 o-An
Cy2PH
r?—SV-" OAc ^=SU^ ,o-An
4^Z^ Ph' AcOH. rt
(Spoi Rp)-62

(SFe, RP)-64

15
A solution of (SFE, Rp)-62 (472 mg, 1.0 mmol) and dicyclohexylphosphine (243 pL, 1.2 mmol) in acetic acid (3 mL) was stirred for 7 days at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with stirring, extracted

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4.60 (m, 1H); 7.12 (m, 1H), 7.31-7.82 (m, 10 H);8.28 (m, 1H). 31P NMR(CDCI3, 101.25 MHz): 5-2.19;-31.85.
Example 59
5 (Sc, SFe, RP)-67:

(S)-66 (Sc, SFe, RP)-67
To a solution of (S)-66 (1.56 g, 5 mmol) and TMEDA (1.0 mL, 6.5 mmol) in Et20 (50 mL) was added 2.5 M n-BuLi (2.6 mL, 6.5 mmol) at -78 °C, After stirring for 3 h at -78 °C, PhPCI2 (0.95 mL, 7.0 mmol) was added, After stirring for 20 min
10 at -78 °C, the mixture was warmed to room temperature and stirred for 1.5 h at room temperature. The mixture was cooled to -78 °C again, and a suspension of 1-NpLi [prepared from 1-bromonaphthalene (1.39 mL, 10 mmol) and 1.7 M t-BuLi (11.8 mL, 20 mmol) in Et20 (40 mL) at -78 °C] was added via a cannula. The mixture was stirred and warmed to room temperature overnight. The
15 reaction was quenched by water (40 mL). The organic layer was separated, washed with brine (40 mL), dried (MgS04), and concentrated. The residue was purified by chromatography (Si02, EtOAc-hexane = 1:5-1:3) to give the product (2.25 g, 85%) as an orange crystals. 1H NMR and 31P NMR analysis show the de is about 9:1. Major product: 1H NMR (CDCI3,400.13 MHz): δ 0.58 (d, 3H, J =
20 6.7 Hz); 0.73 (d, 3H, J = 6.7 Hz); 1.58 (m, 1H), 3.45 3.52 (m, 2H), 3.61 (m,

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1H), 3.78 (m, 1H), 4.29 (s, 5H); 4.44 (t, 1H, J = 2.6 Hz); 5.05 (m, 1H); 7.08(dd, 1H, J = 7.0 and 4.4 Hz); 7.24 ~ 7.48 (m, 8H); 7.74 (d, 1H, J = 8.0 Hz); 7.80 (d, 1H, J = 8.0 Hz); 8.37 (dd, 1H, J = 8.3 and 4.3 Hz). 31P NMR (CDCI3,162 MHz): δ-23.52 (s).

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References
1. T. Hayashi, in Ferrocenes, (Eds.: A. Togni, T. Hayashi), VCH,
Weinheim, 1995, p. 105.
2. 2. Togni, A.; Breutel, C; Schnyder, A.; Spindler, F.; Landert, H.; Tijani,
5 A. J. Am. Chem. Soc. 1994,116, 4062.
3. 3. a. H. U. Blaser.W. Brieden, B. Pugin, F. Spindler, M. Studer, A.
Togni, Topics in Catalysis 2002,19,3; b. H. U. Blaser, F.Spindler, M.
Studer, Applied Catal. A: General 2001, 221,119.
4. 4. McGarrity, J.; Spindler, F.; Fuchs, R.; Eyer, M. (LONZA AG), EP-A
10 624587 A2,1995; Chem. Abstr. 1995,122, P81369q.
5. 5. a. Blaser, H.-U. Adv. Synth. Catal. 2002,344,17. b. Blaser, H.-U.;
Buser, H.-P.; Coers, K.; Hanreich, R.; Jalett, H.-P.; Jelsch, E.; Pugin, B.;
Schneider, H.-D.; Spindler, F.; Wegmann, A. Chimia 1999, 53,275.
6. 6. a. N. W. Boaz, S. D. Debenham, E. B. Mackenzie, S. E. Large, Org.
15 Lett. 2002, 4, 2421. b. Boaz, N. W.; Debenham, S. D. US 2002/0065417
(2002)
7. a) T. Ireland, G. Grossheimann, C. Wieser-Jeunesse, P. Knochel,
Angew. Chem. Int. Ed. 1999,38,3212. b) T. Ireland, K. Tappe, G.
Grossheimann, P. Knochel, Chem. Eur. J. 2002,8,843;
20 8. a) M. Lotz, K. Polborn, P. Knochel, Angew. Chem. Int. Ed. 2002,41,
4708. b) K. Tappe; P. Knochel, Tetrahedron: Asymmetry 2004,15,12; c) M. Lotz, P. Knochel, A. Monsees, T. Riermeier, R. Kadyrov, J. J. Almena Perea, Ger. Pat. No. DE10219490 (Degussa AG).

WO 2005/068478

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9. a) T. Sturm, L. Xiao, W. Weissenstelner, Chimla 2001,55, 688; b) W.
Weissenstelner, T. Sturm, F. Splndler, Adv. Synth. Catal. 2003,345,160; c)
Weissenstelner, T. Sturm, F. Spindler, US2003212284.
10. a. Perea, A. J. J.; Borner, A.; Knochel, P. Tetrahedron Lett. 1998, 39,
5 8073. b. Perea, A. J. J.; Lotz, M.; Knochel, P. Tetrahedron: Asymmetry
1999,10, 375. cLotz, M.; Ireland, T.; Perea, A. J. J.; Knochel, P. Tetrahedron: Asymmetry 1999,10,1839. d. Knochel, P.; Perea, A. J. J.; Drauz, K.; Klement, I. US 6,284,925 (2001).
11. (a) Sawamura, M.; Hamashima, H.; Sugawara, M.; Kuwano, N.; Ito, Y.
10 Organometallics 1995,14,4549. (b) Sawamura, M.;Kuwano, R.; Ito, Y. J.
Am. Chem. Soc. 1995,117,9602. (c) Kuwano, R.; Sawamura, M.; Ito, Y.
Tetrahedron: Asymmetry 1995,6,2521. (d) Kuwano, R.; Okuda, S.; Ito, Y.
Tetrahedron: Asymmetry 1998,9,2773. (e) Kuwano, R.; Okuda, S.; Ito, Y. J.
Org. Chem. 1998,63,3499. (f) Kuwano, R.; Ito, Y. J. Org. Chem. 1999, 64,
15 1232. (g) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am.
Chem. Soc. 2000,122,7614.
12. a) Kang, J.; Lee, J. H.; Ann, S. H.; Choi, J. S. Tetrahedron Lett. 1998,
39,5523. b) Kang, J.; Lee, J. H.; Kim, J. B.; Kim, G. J. Chirality 2000,12,
378.
20 13. a) Jendralla, H.; Paulus, E. Synlett, 1997,471. b) Jendralla, J. H. US
5,856,540 (1999)

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95
14. a) Argouarch, G.; Samuel, O.; Kagan, H. B. Eur. J. Org. Chem. 2000, 2891. b) Argouarch* G.; Samuel, O.; Riant, O.; Daran, J.-C; Kagan, H. B. Eur. J. Org. Chem. 2000,2893.
15. Marinetti, A.; Labrue, F.; Gene% J.-P. Synlett 1999,1975.
5 16. Berens, U.; Burk, M. J.; Geriach, A.; Hems, W. Angew. Chem., Int. Ed.
Engl. 2000,39,1981.
17. You, J.; Drexler, H.-J.; Zhang, S.; Fischer, C; Heller, D. Angew.
Chem., Int. Ed. Engl. 2003,42,913.
18. Malenza, F.; Wo”rle, M.; Steffanut, P.; Mezzetti, A. Organometallics
10 1999,18,1041.
19. (a) Nettekoven, U.; Widhalm, M.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M. Tetrahedron: Asymmetry 1997,8,3185. (b) Nettekoven, U.; Kamer, P.
C. J.; van Leeuwen, P. W. N. M.; Widhalm, M.; Spek, A. L; Lutz, M. J. Org.
Chem. 1999, 64, 3996.
15 20. Liu, D.; Li, W.; Zhang, X. Org. Lett. 2002, 4, 4471.
21. Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. Engl. 2001,40,3425.
22. a) M. T. Reetz, A. Gosberg, R. Goddard, S.-H. Kyung, Chem. Commun. 1998,2077; b) M. T. Reetz, A. Gosberg, WO 0014096,1998 (assigned to Studiengesellschaft Kohle MBH);
20 23. a. Nettekoven, U.; Widhalm, M.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M.; Mereiter, K.; Lutz, M.; Spek, A. L. Organometallics 2000,19,2299. b. Nettekoven, U.; Kamer, P. C. J.; Widhalm, M.; van Leeuwen, P. W. N. M. Organometallics 2000,19,4596. c. Nettekoven, U.; Widhalm, M.;

WO 2005/068478

96

PCT/GB2005/000125

Kalchhauser, H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A. L. J. Org. Chem. 2001,66, 759-770.
24. Barbara, P.; Bianchini, C; Giambastiani, G.; Togni, A. Chem. Commun.
2002, 2672.
5 25. (a) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J.
Am. Chem. Soc. 1970,92,5389. (b) Marquarding, D.; Klusacek, H.; Gokel,
G.; Hoffmann, P.; Ugi, I. Angew. Chem. Int. Ed. Engl. 1970, 9,371. (c)
Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron Lett. 1974,15,405.
(d) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima, N.;
10 Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishl, M. M.; Yamamoto, K.;
Kumada, M. Bull. Chem. Chem. Soc. Jpn. 1980, 53,1138
26. Riant, O.; Argouarch, G.; Guillaneux, D.; Samuel, O.; Kagan, H. B. J.
Org. Chem. 1998,63,3511.
27. (a) Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B. J.
15 Org. Chem. 1997,62,6733. (b) Riant, O.; Samuel, O.; Kagan.H. B. J. Am.
Chem. Soc. 1993,115,5835.
28. (a) Richards, J.; Damaiidis, T.; Hibbs D. E.; Hursthouse, M. B. Synlett
1995, 74. (b) Sammakai, T.; Latham H. A.; Schaad, D. R. J. Org. Chem.
1995,60,10. (c) Nishibayashi, Y.; Uemura, S. Synlett 1995,79. (d)
20 Sammakai, T.; Latham, H. A. J. Org. Chem. 1995,60,6002.
29. Ganter, C; Wagner, T. Chem. Ber. 1995,128,1157.

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30. (a) Enders, D.; Peters, R.; Lochtman, R.; Runsink, J. Synlett 1997, 1462. (b) Enders, D.; Peters, R.; Lochtman, R.; Runsink, J. Eur. J. Org. Chem. 2000, 2839.
31. Lotz, M.; Ireland f.; Tappe, K.; Knochel, P. Chirality, 2000,12,389.
5 32. KItzler, R.; Xiao, L; Weissenstelner, W. Tetrahedron: Asymmetry 2000,
11,3459.
33. Widhalm, M.; Merelter, K.; Bourghida, M. Tetrahedron: Asymmetry
1998,9,2983.
34. Nishibayashi, Y.; Arikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem. 1996,
10 61,1172.
35. (a) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. J. Am. Chem. Soc. 1996,118,685. (b) Jendralla, H.; Paulus, E. Synlett 1997,471.
36. Price, D.; Simpkins, N. S. Tetrahedron Lett. 1995,36,6135.

98
CLAIMS

1. A process for the production of chiral ligands comprising providing a starting material of Formula (A):

Ο---x

5 wherein X* is a chiral or a achiral directing groups; and
Ο is an optionally substituted mono- or polycyclic aryl or a cycloalkyl group;
Ortholithiating the sustrate; converting the ortho-lithiated substrate to a
Phosphino group having the formula ---PR1 R1, R1 and R1 beimg different from each other and independently selected from substituted and substituted,
10 branched- and straight –chain alkyl , alkoxy, alkylamino, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsusbstituted heteroaryloxy
15 substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen and oxygen;
and optionally or if necessary converting X* to a different grouping to produce a chiral ligand.
20 2. A process according to calim 1 wherein X* is a chiral directing group and the ortholithiation is enantioselective.
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3. A process according to claim 3 wherein X* is selected from:
ft2

Wherein R, R2 and R3 are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted
5 cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen.
4. A process according to any one of claims 1 to 3 wherein X* is an
10 achiral directing group and the ortholithiation proceeds in the presence of a
chiral auxiliary and is enantioselective.
5. A process according to claim 4 wherein X* is selected from:
V^NR2R3 hs02R2 ^X^ f-P(°)R2R3
15 Wherein R2 and R3 are independently selected from substituted and
unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and

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unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen.
6. A process according to any one of claims 1 to 5 wherein^ is one,
5 optionally further substituted, aromatic ring of a metallocene compound.
7. A process according to any one of claims 1 to 6 wherein X* is an ortho
directing group.
10 8. A process according to any one of claims 1 to 7 comprising reacting the
ortholithiated substrate with an R1 substituted phosphine or arsine to form an intermediate compound.
9 A process according to claim 8 comprising reacting the intermediate 15 compound with an R1*-bearing Grignard reagent or organolithium compound.
10 A ligand obtainable by a process according to any one of claims 1 to 9.
11 A ligand according to claim 10 obtained by a process according to any 20 one of claims 1 to 9.
12. A transition metal complex catalyst incorporating at least one ligand
according to claim 10 or claim 11.

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13. Use of the transition metal complex catalyst of claim 12 in asymmetric catalysis.
Dated this the 14h day of July 2006


auut^

Dr. Gopakumar G. Nair
Agent for the Applicant

Abstract:
The present invention relates to process for the production of chiral ligands comprising providing a starting material of Formula (A): wherein X is a chiral or achiral directing group; and (1) is an optionally substituted mono-or polycyclic aryl or cycloalkyl group; ortholithiating the substrate; converting the ortho-lithiated substrate to a phosphine group having the formula -PR1 R1, R1 being selected from substituted and unsubstituted, branched-and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen, R1 being different from R1 and being selected from substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; and optionally or if necessary converting X* to a different grouping to produce a chiral ligand.