(S)-proline-derived new chiral ligands with phosphino, organosulfur or organoselenenyl functionality as an enantiocontrollable coordinating element

Article abstract of DOI:10.1016/S0957-4166(99)00105-6

The synthesis of (S)-proline-derived chiral ligands bearing phosphino, organosulfur or selenenyl groups and their use as chiral ligands in palladium-catalyzed asymmetric allylic alkylations has been accomplished. In particular, the (S)-proline-derived phosphine ligands bearing alkylsulfenyl groups provided high enantioselectivity, and the degree of asymmetric induction was dependent upon the steric bulk of the alkyl substituents in sulfenyl groups. The stereochemical results are rationalized by a plausible mechanism involving the assistance of chelates formed by the participation of the two preferred heteroatoms involved.

Full text of DOI:10.1016/S0957-4166(99)00105-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1173–1188
(S)-Proline-derived new chiral ligands with phosphino,
organosulfur or organoselenenyl functionality as an
enantiocontrollable coordinating element
Kunio Hiroi,∗ Yoshio Suzuki and Ikuko Abe
Department of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai,
Miyagi 981-8558, Japan
Received 17 February 1999; accepted 15 March 1999
Abstract
The synthesis of (S)-proline-derivedchiral ligands bearing phosphino, organosulfuror selenenyl groups and their
use as chiral ligands in palladium-catalyzed asymmetric allylic alkylations has been accomplished. In particular,
the (S)-proline-derived phosphine ligands bearing alkylsulfenyl groups provided high enantioselectivity, and the
degree of asymmetric induction was dependent upon the steric bulk of the alkyl substituents in sulfenyl groups.
The stereochemical results are rationalized by a plausible mechanism involving the assistance of chelates formed
by the participation of the two preferred heteroatoms involved. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The increasing usefulness of catalytic asymmetric synthesis has been demonstrated for the synthesis
of optically active compounds,1 particularly biologically active chiral compounds, in the pharmaceutical
field,2 and as a result, the development of new efficient chiral ligands has received much attention.3
Hitherto, various types of chiral ligands, possessing coordinating elements such as phosphorus,4,5
nitrogen,6 oxygen,7 or sulfur groups,8 have been developed. Currently, we are developing new efficient
chiral ligands bearing chiral sulfinyl groups as the sole chiral source.9 We describe in this paper
(S)-proline-derived new chiral ligands having phosphino, organosulfur or organoselenenyl groups and
demonstrate their usefulness in palladium-catalyzed asymmetric synthesis.10 We also discuss herein the
mechanism for the asymmetric induction according to the priority of the heteroatoms involved in terms of
coordination ability, focused on the structure of the intermediary palladium complexes with the chelation
by the phosphino, amino, sulfenyl, sulfinyl and selenenyl groups.
∗
Corresponding author. E-mail: khiroi@tohoku-pharm.ac.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00105-6

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2. Results and discussion
2.1. Synthesis of (S)-proline-derived chiral ligands
(S)-Proline-derived chiral ligands bearing heteroatoms as coordinating functions such as sulfur,
selenium and phosphorus groups were obtained as follows. (S)-N-(2-Bromobenzoyl)proline derivatives
2a,b were reduced with BH3·THF followed by sulfenylation with diphenyl disulfide, sulfinylation
with (−)-menthyl (S)-p-toluenesulfinate,11 selenenylation with diphenyl diselenide, phosphinylation with
chlorodiphenylphosphine of (S)-3a, or sulfenylation with dimethyl or diphenyl disulfide, sulfinylation
with (−)-menthyl (R)- or (S)-p-toluenesulfinate, or selenenylation with diphenyl diselenide of (S)-3b,
producing (S)-4a, (Ss,S)-4b, (S)-4c,d, (S)-6a,b, (Rs,S)-7a, (Ss,S)-7b, or (S)-8, respectively (Fig. 1).
Figure 1. Synthesis of (S)-proline-derived ligands
Chiral phosphine ligand (S)-10 was prepared by the palladium–copper-catalyzed coupling reaction12 of
(S)-proline with 2-fluoroiodobenzene followed by the esterification of carboxylic acid (S)-9a, the reduc-
tion of the ester in (S)-9b with LiAlH4, the benzylation of the alcohol in (S)-9c, and the phosphinylation
of (S)-9d (Scheme 1).
Scheme 1.
Chiral phosphine ligands (S)-12a–g bearing sulfenyl groups were prepared by N-acylation of (S)-
2-(diphenylphosphinomethyl)pyrrolidine13 with 2-(alkylthio)benzoic acids 11a–g, which were obtain-
ed from commercially available 2-mercaptobenzoic acid, employing N,N0-dicyclohexylcarbodiimide
(DCC) as a dehydrating reagent. N-Acylation of (S)-2-(diphenylphosphinomethyl)pyrrolidine with 2-
(alkylsulfinyl)benzoic acids obtained by oxidation of the sulfides 11b,f,g with m-chloroperbenzoic acid
(MCPBA) afforded the corresponding diastereomeric sulfoxides (Rs,S)-13Aa–c and (Ss,S)-13Ba–c in

K. Hiroi et al. / Tetrahedron: Asymmetry 10 (1999) 1173–1188
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a 1:1 diastereomeric ratio. The diastereoisomeric sulfoxides (Rs,S)-13Aa–c and (Ss,S)-13Ba–c were
isolated in a 1:1 ratio by flash column chromatography over silica gel (Scheme 2).
Scheme 2.
Chiral phosphine ligands (S)-15a,b bearing selenenyl groups were obtainable by N-acylation of (S)-2-
(diphenylphosphinomethyl)pyrrolidine with 2-(alkylselenenyl)benzoic acids 14a,b, which were derived
from 2-bromobenzoic acid via lithiation with n-BuLi and the subsequent selenenylation with diselenides
(Scheme 3).
Scheme 3.
Chiral phosphine ligands (S)-16 and (S)-17, possessing a pyridine or thiophene ring, were prepared in
a similar way to that mentioned above by N-acylation with 2-pyridine- and 2-thiophenecarboxylic acid
(Fig. 2).
Figure 2. (S)-Proline-derived ligands with pyridine and thiophene rings
2.2. Palladium-catalyzed asymmetric allylic alkylation with chiral ligands
Initially, the asymmetric alkylations of (ꢀ)-1,3-diphenyl-2-propenyl acetate 18 with dimethyl malonate
sodium enolate (generated by treating with NaH) using (S)-2-(benzyloxymethyl)pyrrolidine derivatives
(S)-4a–d and (S)-10 (0.12 equiv.) as chiral ligands were carried out in the presence of [PdCl(π-allyl)]2,
Pd(dba)2, or Pd(OAc)2 (0.06 equiv.) in THF or DME at 0°C, room temperature, or 50°C to give (S)-19
(Scheme 4).14 The enantiomeric excess (e.e.) of the product 19 was calculated by HPLC analysis with a
Chiralpak AD column.14 The results obtained are summarized in Table 1.
The palladium-catalyzed reactions using (S)-4a–c provided low chemical yields of (S)-19 with mod-
erate e.e., whereas the reactions with the similar ligands (S)-4d and (S)-10 bearing phosphinyl groups

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Scheme 4.
Table 1
Palladium-catalyzed asymmetric allylic alkylation of (ꢀ)-18 with dimethyl malonate using chiral
ligands (S)-4a–d and (S)-10a)
gave (S)-19 in higher chemical yields with similar moderate e.e.s. This indicates that the phosphine
groups in the ligands seem to play a prominent role in providing high chemical yields. Introduction of a
chiral sulfinyl function on the aromatic nucleus in the place of the sulfenyl and the selenenyl groups in
the ligands (S)-4a,c provided, unexpectedly, no asymmetric induction, presumably due to the mismatch
of the two chiralities involved in the ligand (Ss,S)-4b.
With (S)-proline-derived phosphine ligands, (S)-6a,b and (S)-8, bearing a sulfenyl or selenenyl
function as another stereocontrolling element for coordination, rather high chemical yields and extremely
high e.e.s of product (R)-19 were obtained as expected. The reactions of (ꢀ)-18 with dimethyl malonate
using [PdCl(π-allyl)]2 (0.06 equiv.) and (S)-6a,b or (S)-8 (0.12 equiv.) were carried out in CH2Cl2 for
2 or 60 h at room temperature in the presence of N,O-bis(trimethylsilyl)acetamide (BSA)15 (3.0 equiv.)
and a catalytic amount of NaOAc to give (R)-19 in 73 or 39% yield with 75 or 79% e.e., respectively.
Surprisingly, introduction of a chiral sulfinyl function, instead of the sulfenyl group, into the ligands
(Ss,S)-7a and (Rs,S)-7b resulted in almost no effect on the asymmetric induction, affording (R)-19. The
results obtained are listed in Table 2.
However, the chiral amide ligands provided different stereochemical results depending on the ligands
used. The reactions of (ꢀ)-18 with dimethyl malonate (3.0 equiv.) under the conditions with BSA (3.0
equiv.) and a catalytic amount of NaOAc were carried out in dichloromethane in the presence of [PdCl(π-
allyl)]2 (0.03 equiv.) and chiral sulfenyl ligands 12a–d,f,g, or a selenenyl ligand (S)-15b (0.06 equiv.) to
give an alkylated product (S)-19, as summarized in Table 2. The table shows that the more bulky sulfenyl
substituents in (S)-12a–g provided a higher degree of the asymmetric induction in proportion to the steric

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1177
Table 2
Palladium-catalyzed asymmetric allylic alkylation of (ꢀ)-18 with dimethyl malonate using chiral
ligandsa)
bulk, except for (S)-12d,e. Interestingly, the same reaction using (S)-1 or (S)-12e as a ligand gave (R)-19.
The (S)-proline-derived chiral phosphines (S)-15b and (S)-16, or (S)-15a and (S)-17 provided (S)- or (R)-
19, respectively. These results indicate that the benzylselenenyl group and the pyridinyl nitrogen served
as coordinating elements, whereas the phenylselenenyl and the phenylsulfenyl or thiophene sulfur groups
could not participate in the formation of a chelate of a palladium catalyst with the phosphine, because
of the rather low coordination ability of the aromatic sulfenyl and selenenyl groups compared with other
alkyl sulfenyl and selenenyl functions. Introduction of a chiral sulfinyl functionality [(Rs,S)-13Aa–c and
(Ss,S)-13Ba–c] into the systems, instead of the sulfenyl groups, presented a little less enantioselectivity
of (S)-19 with a different degree of asymmetric induction depending on the diastereomers used, as listed
in Table 2.

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In comparison, use of amino phosphines (S)-5–8 as ligands in the above reaction provided (R)-
19. These results indicate that the organosulfur or selenenyl functionality in (S)-12a–d,f,g, (S)-13a–c,
and (S)-15b served as an alternative stereocontrollable coordinating element in the above palladium-
catalyzed alkylation, whereas the same groups in (S)-6–8 could not function as coordinating elements
and instead, the amino nitrogen atoms would participate in the formation of five-membered chelates with
the phosphine groups, as mentioned later.
2.3. The mechanism for asymmetric induction with chiral ligands
The mechanism for the asymmetric induction with these new ligands is rationalized on the basis of
the stereochemical results obtained. The (S)-proline-derived ligand 4d would provide a six-membered
chelate 20a by coordination of the rather more electron-donating nitrogen groups and phosphorus groups
to palladium catalysts. In the conformational equilibrium of sterically favored six-membered chelated π-
allylpalladium complexes 20Aa and 20Bb, the palladium complex 20Bb would be preferentially formed
because of the existence of rather severe steric interference between the benzyloxymethyl group and both
the axial phenyl substituent on the phosphine and the phenyl ring at the allylic site in 20Aa. Therefore,
the nucleophile (malonate anion) would attack the allylic terminus in 20Ba trans to the better π-acceptor,
which is the phosphine group16 in the present case, from the back side of the palladium catalyst in the
π-allyl system as designated in 20Ba, affording (S)-19.
The reactions with chiral ligands (S)-4a,c bearing sulfenyl or selenenyl groups instead of the phosphine
group are elucidated in a similar way. In the conformational equilibrium of the intermediary six-
membered chelated π-allylpalladium complex 20b,c coordinated by the sulfenyl or selenenyl group and
the amino group in the ligands ((S)-4a,c), a π-allylpalladium complex 20Bb,c, having the sterically
preferred M-type allyl system due to the steric interaction between the two phenyl rings on the sulfur
or selenenyl group and at the allylic site in the corresponding W-type one, is assumed to be a favorable
isomer in preference to 20Ab,c, which has the W-type allyl system based on the same steric reason,
because of the steric interaction between the substituent at the stereogenic center and the phenyl group at
the allylic site in 20Ab,c. Thus, the nucleophile (malonate anion) would attack the allylic site trans to the
better π-acceptor16 which is the sulfenyl or the selenenyl function in the current case, affording (S)-19.
In the case of the amino phosphine ligands (S)-5–8, the formation of the intermediary nine-membered
chelates with phosphino and sulfenyl groups similar to those mentioned later or six-membered chelates
with amino and sulfenyl groups as mentioned earlier in Scheme 5 is not valid for the rationalization
of the stereochemical results observed. Thus, the results may certainly be understandable by another
plausible mechanism via five-membered chelates formed by the participation of the phosphino and the
amino groups as the preferred more electron-donating elements. In the five-membered chelates, the π-
allylpalladium complex 21a is preferred to 21b, due to the steric interference between the pyrrolidine ring
and the phenyl substituent at the C1 allyl terminus in 21b. The nucleophile attacks the C1 allyl terminus
in 21a trans to the better π-acceptor,16 which is the phosphine group in the current case, affording (R)-19
(Scheme 6).
As described earlier, the reaction using (S)-1 provided (R)-19, whereas the use of (S)-12a–d,f,g,
and (S)-15b as ligands afforded (S)-19. Therefore, with (S)-12a–d,f,g and (S)-15b as ligands, a nine-
membered chelate formed by coordination of the organosulfur or selenenyl functionality and the
phosphine group to the palladium catalyst is very crucial for the rationalization of the stereochemical
results, otherwise it will be too hard to understand the absolute configuration of the product, the high
enantioselectivity, and especially the steric effect of the alkyl substituents of the sulfenyl groups in the
asymmetric induction, in proportion to the steric bulk as mentioned earlier. Inspection of a model of the

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Scheme 5.
Scheme 6.
nine-membered chelated intermediary palladium complex shows that an M-type π-allylpalladium com-
plex 22a would be preferred to an M-type complex 22b in the conformational equilibrium of the rather
flexible nine-membered chelated π-allylpalladium complex, due to the steric 1,3-diaxial-like interaction
between the substituent on the sulfenyl or selenenyl group and the phenyl ring on the phosphine group
in 22b, as illustrated in Scheme 7. The nucleophile (malonate carbanion) would attack the allyl terminus
(C3) in 22a trans to the better π-acceptor,16 which is the sulfenyl or selenenyl group in the present case,
to furnish (S)-19. Increasing the size of the substituents on the sulfenyl groups resulted in enhanced
enantiocontrol in the alkylation, presumably owing to the more selective alkylation at the C3 site due
to the steric reason of the large substituent for the alkylation at C1. The rather low enantioselectivity
obtained by (S)-12d is rationalized by the inaccessibility to the formation of the corresponding nine-
membered chelate because of the steric effect exerted by the secondary alkyl group on the sulfenyl sulfur
atom.
Scheme 7.
Thus, the high level of the asymmetric induction presented by (S)-12a–d,f,g is rationalized by genera-
tion of another new stereogenic center on the sulfenyl sulfur atoms in the formation of the intermediary
nine-membered chelates. This rationalization is also supported by the results with diastereomeric sulf-
oxides (Rs,S)-13Aa–c and (Ss,S)-13Ba–c. One of the diastereomers, presumably (Rs,S)-13Aa–c, present-
ed a higher asymmetric induction than (Ss,S)-13Ba–c; namely, the (Rs,S)-13Aa–c would be a matched

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pair for the formation of the sterically favorable chelate 23a in this palladium catalysis, whereas the
(Ss,S)-13Ba–c would be a mismatched one because of the sterical inaccessibility to the palladium
catalyst for the formation of 23b,c (Scheme 8). In the confomational equilibrium of 23b,c, the M-
type π-allylpalladium complex 23b is slightly preferred to the W-type one (23c) because of the steric
interference between the two phenyl rings on the phosphine group and at the C3 allyl terminus in 23c.
Therefore, the preferential alkylation occurs at the C3 allyl terminus in 23a or 23b, trans to the better π-
acceptor,16 which is presumably the sulfinyl group in this case, furnishing (S)-19 with high or rather low
enantioselectivity, respectively. The higher degree of the asymmetric induction with the sulfenyl ligands
presumably also arises from the stronger coordination ability of the sulfenyl groups than the sulfinyl
sulfur atoms.
Scheme 8.
Thus, in conclusion, it is worth noting that the alkyl sulfenyl groups introduced in chiral phosphine
ligands derived from (S)-proline served as enantiocontrollable coordinating elements, providing high
enantioselectivity in proportion to the steric bulk of the primary alkyl groups in the palladium-catalyzed
asymmetric allylic alkylation.
3. Experimental
Infrared (IR) spectra were obtained in the indicated state with a JASCO DR-81 Fourier-transform IR
spectrometer. NMR spectra were determined in the indicated solvent with a JEOL JNM-LA 400 (1H
NMR; 400 MHz) and JEOL EX-270 (1H NMR; 270 MHz) high-resolution NMR spectrometer; chemical
shifts are given in ppm from tetramethylsilane as an internal standard. Splitting patterns are designated
as s: singlet, ss: singlet singlet, bs: broad singlet, d: doublet, dd: double doublet, dt: triple doublet, t:
triplet, td: double triplet, q: quartet, quint: quintet, m: multiplet. Mass spectra were taken on a JEOL
JMS-DX 303/JMA-DA 5000 system. High performance liquid chromatography (HPLC) was performed
with a Tosoh UV-8010 CCPM (column: Daicel Chiralpak AD, hexane:i-PrOH 1:20, 0.5 ml/min, 254 nm).
Optical rotations were measured with a JASCO DIP-370 polarimeter. Flash column chromatography was
performed with Merck silica gel 60 (230–400 mesh). Thin layer or thick layer plates (preparative TLC)
were made of Merck silica gel 60PF-254 activated by drying at 140°C for 3.5 h.
3.1. Synthesis of (S)-N-benzyl-2-(benzyloxy- or diphenylphosphinomethyl)pyrrolidine derivatives
3.1.1. (S)-N-(2-Bromobenzoyl)-2-(benzyloxymethyl)pyrrolidine 2a
A solution of 2-bromobenzoyl chloride (457 mg, 2.01 mmol) in acetonitrile (CH3CN) (12 ml) was
added at 0°C to a solution of (S)-2-(benzyloxymethyl)pyrrolidine (329 mg, 2.01 mmol) and triethylamine
(Et3N) (843 mg, 6.03 mmol) in CH3CN (8 ml), and the reaction mixture was stirred at room temperature
for 6 h. The reaction mixture was then diluted with chloroform (CHCl3), and the solution was washed

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1181
with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude
product was subjected to preparative TLC (ether:hexane=2:1) to give (S)-2a (465 mg, 65% yield).
The reaction of (S)-2-(diphenylphosphinomethyl)pyrrolidine with 2-bromobenzoyl chloride
was carried out with the same procedure as described above to give (S)-N-(2-bromobenzoyl)-2-
(diphenylphosphinomethyl)pyrrolidine 2b.
(S)-2a: [α]D −89 (c=1.0, CHCl3). IR νmfilamx cm−1: 1585 (aromatic), 1625 (amide). NMR (270 MHz;
CDCl3) δ: 1.76–2.17 (m, 4H, (CH2)2), 3.16–3.41 (m, 2H, CH2), 3.73–3.86 (m, 2H, CH2), 4.45–4.54 (m,
1H, CH), 4.59 (s, 2H, CH2), 7.15–7.36 (m, 8H, ArH), 7.52–7.57 (m, 1H, ArH). m/z: 373 (M+). Exact
mass determination: 373.0676 (calcd C19H20NO2Br: 375.0677).
(S)-2b: 75% yield. [α]D −110 (c=3.3, CHCl3). IR νmfilamx cm−1: NMR (270 MHz; CDCl3) δ: 1.95–2.13
(m, 4H, (CH2)2), 3.16–3.24 (m, 2H, CH2), 3.66–3.84 (m, 2H, CH2), 4.40 (br, 1H, CH), 6.82–6.88 (m,
1H, ArH), 7.08–7.57 (m, 14H, ArH), 7.70–7.75 (m, 1H, ArH). m/z: 451 (M+). Exact mass determination:
451.0667 (calcd C24H23NOPBr: 451.0700).
3.1.2. (S)-N-(2-Bromobenzyl)-2-(benzyloxymethyl)pyrrolidine 3a
A solution of (S)-2a (596 mg, 1.66 mmol) in THF (5 ml) was added at 0°C to a 1 M borane:THF
complex solution (8 ml, 8.28 mmol), and the reaction mixture was stirred under heating at reflux for 6
h. Then after cooling, a solution of methanol (MeOH) (10 ml) and 10% aqueous potassium hydroxide
(5 ml) was added to the reaction mixture. The mixture was stirred under heating at reflux for a further
1 h. The solution was concentrated to dryness in vacuo. The residue was then dissolved with CHCl3,
and the solution was washed with saturated aqueous NaCl. The organic layer was separated, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product was subjected to preparative TLC
(ether:hexane=1:1) to give (S)-3a (565 mg, 98% yield).
The reduction of (S)-2b with a borane:THF complex solution was carried out in the same way as
described above to give (S)-N-(2-bromobenzyl)-2-(boranatodiphenylphosphinomethyl)pyrrolidine 3b.
(S)-3a: [α]D −38 (c=9.2, CHCl3). IR νmfilamx cm−1: 1585 (aromatic). NMR (270 MHz; CDCl3) δ:
1.59–2.02 (m, 4H, (CH2)2), 2.23–3.01 (m, 2H, CH2), 2.86–2.93 (m, 1H, CH), 3.33–3.57 (m, 2H, CH2),
3.59–4.19 (m, 2H, CH2), 4.51 (s, 2H, CH2), 7.04–7.23 (m, 1H, ArH), 7.26–7.32 (m, 6H, ArH), 7.47–7.53
(m, 2H, ArH). m/z: 375 (M+). Exact mass determination: 375.0676 (calcd C19H22NOBr: 375.0657).
(S)-3b: 61% yield. [α]D −71 (c=4.0, CHCl3). IR νmfilamx cm−1: 1585 (aromatic). NMR (400 MHz;
CDCl3) δ: 1.05–1.31 (m, 3H, BH3), 1.32–1.39 (m, 1H, CH), 1.60–1.73 (m, 2H, CH2), 1.82–1.91 (m,
1H, CH), 2.13–2.20 (m, 1H, CH), 2.28–2.36 (m, 1H, CH), 2.71–2.79 (m, 1H, CH), 2.84–2.96 (m,
2H,CH2), 3.38 (d, J=14.1 Hz, 1H, CH), 3.94 (d, J=14.1 Hz, 1H, CH), 7.09 (td, J=7.6, 1.7 Hz, 1H,
ArH), 7.22–7.26 (m, 1H, ArH), 7.37–7.53 (m, 8H, ArH), 7.66–7.44 (m, 4H, ArH). m/z: 452 (M++1).
Exact mass determination: 451.1188 (calcd C24H28BNPBr: 451.1236)
3.1.3. (S)-N-[2-(Phenylthio)benzyl]-2-(benzyloxymethyl)pyrrolidine 4a
A 1.56 M cyclopentane solution of n-BuLi (0.4 ml, 0.52 mmol) was added at −78°C to a solution of
(S)-3a (150 mg, 0.43 mmol) in THF (3 ml), and the reaction mixture was stirred at −78°C for 1 h. A
solution of diphenyl disulfide (114 mg, 0.52 mmol) in THF (4 ml) was added to the above solution, and
the mixture was stirred at 0°C for 12 h. The reaction solution was diluted with ether, and the ether solution
was washed with saturated aqueous NH4Cl and saturated aqueous NaCl, dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude product was subjected to preparative TLC (ether:hexane=1:5) to
give (S)-4a (111 mg, 66% yield).
The substitution reactions of ortho-lithiated carbanions of (S)-3a,b obtained in the same way with
(−)-menthyl (S)-p-toluenesulfinate, diphenyl diselenide or chlorodiphenylphosphine were carried out

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using the procedure similar to that described above to give (Ss,S)-N-[2-(p-toluenesulfinyl)-, (S)-N-[2-
(phenylseleno)- or (S)-N-[2-(diphenylphosphino)benzyl]-2-(benzyloxymethyl)pyrrolidine 4b–d, respec-
tively.
(S)-4a: [α]D −66 (c=1.4, CHCl3). IR νmfilamx cm−1: 1580 (aromatic). NMR (270 MHz; CDCl3) δ:
1.64–2.06 (m, 4H, (CH2)2), 2.17–3.25 (m, 2H, CH2), 2.82–2.84 (m, 1H, CH), 3.34–3.60 (m, 2H, CH2),
3.62–4.23 (m, 2H, CH2), 4.49 (s, 2H, CH2), 7.12–7.31 (m, 13H, ArH), 7.49–7.51 (m, 1H, ArH). m/z: 389
(M+). Exact mass determination: 389.1848 (calcd C25H27NOS: 389.1813).
(Ss,S)-4b: 30% yield. [α]D +68 (c=4.6, CHCl3). IR νmfilamx cm−1: 1595 (aromatic), 1032 (SO). NMR
(270 MHz; CDCl3) δ: 1.37–1.76 (m, 4H, (CH2)2), 1.87–1.98 (m, 1H, CH), 2.01–2.16 (m, 1H, CH),
2.33 (s, 3H, CH3), 2.52–2.58 (m, 1H, CH), 2.52–2.82 (m, 1H, CH), 3.33, 3.38 (ss, 1H, CH), 3.46 (dd,
J=9.4, 4.8 Hz, 1H, CH), 3.63–3.72 (m, 1H, CH), 4.51 (d, J=7.2 Hz, 2H, CH2), 7.14–7.45 (m, 10H, ArH),
7.51–7.59 (m, 2H, ArH), 7.89–7.92 (m, 1H, ArH). m/z: 420 (M++1). Exact mass determination: 419.1960
(calcd C26H29NO2S: 419.1919).
(S)-4c: 48% yield. [α]D −29 (c=2.3, CHCl3). IR νmfilamx cm−1: 1580 (aromatic). NMR (270 MHz; CDCl3)
δ: 1.43–2.02 (m, 4H, (CH2)2), 2.16–2.86 (m, 1H, CH), 3.36–3.67 (m, 2H, CH2), 3.60–4.25 (m, 2H,
CH2), 4.49 (s, 2H, CH2), 7.01–7.34 (m, 13H, ArH), 7.48–7.52 (m, 1H, ArH). m/z: 437 (M+). Exact mass
determination: 437.1254 (calcd C25H27NOSe: 437.1258).
(S)-4d: 29% yield. [α]D −35 (c=3.9, CHCl3). IR νmfilamx cm−1: 1580 (aromatic). NMR (270 MHz;
CDCl3) δ: 1.09–1.82 (m, 4H, (CH2)2), 1.99–2.78 (m, 2H, CH2), 2.55–2.61 (m, 1H, CH), 3.20–3.26 (m,
2H, CH2), 3.59–3.67 (m, 2H, CH2), 4.49 (dd, J=12.0, 21.2 Hz, 2H, CH2), 6.86–6.91 (m, 1H, ArH),
7.10–7.35 (m, 18H, ArH). m/z: 465 (M+). Exact mass determination: 465.2251 (calcd C31H32NOP:
465.2221).
3.1.4. (S)-N-[2-(Methylthio)benzyl]-2-(diphenylphosphinomethyl)pyrrolidine 6a
The reaction of an ortho-lithiated carbanion of (S)-3b (84 mg, 0.23 mmol), obtained in the
same way as described above, with dimethyl or diphenyl disulfide, (−)-menthyl (Rs)- or (Ss)-p-
toluenesulfinate or diphenyl diselenide, was carried out with the procedure similar to that described above
(Section 3.1.3) to give (S)-N-(2-methylthiobenzyl)-, (S)-N-[2-(phenylthio)benzyl]-, (Rs,S)- or (Ss,S)-
N-[2-(p-toluenesulfinyl)benzyl]- or (S)-N-[2-(phenylseleno)benzyl]-2-(boranatodiphenylphosphino-
methyl)pyrrolidine, respectively.
1,4-Diazabicyclo[2.2.2]octane (DABCO) (26 mg, 0.23 mmol) was added to a solution of the crude
products (0.23 mmol), obtained as above, in toluene (5 ml). The reaction mixture was stirred for 2
h at 40°C. The solution was concentrated in vacuo. The crude product was subjected to preparative
TLC (ether:hexane=1:1) to give (S)-N-[2-(methylthio)benzyl]-, (S)-N-[2-(phenylthio)benzyl]-, (Rs,S)-
or (Ss,S)-N-[2-(p-toluenesulfinyl)benzyl]- or (S)-N-[2-(phenylseleno)benzyl]-2-(diphenylphosphino-
methyl)pyrrolidine 6a,b, 7a,b or 8, respectively.
(S)-6a: 77% yield. [α]D −165 (c=1.1, CHCl3). IR νmfilamx cm−1:1595 (aromatic). NMR (270 MHz;
CDCl3) δ: 1.62–1.77 (m, 4H, (CH2)2), 1.97–2.18 (m, 4H, 2×CH2), 2.43 (s, 3H, CH3), 2.49–2.68 (m,
1H, CH), 2.76–2.90 (m, 1H, CH), 2.92–2.95 (m, 1H, CH), 3.28 (d, J=13.5 Hz, 1H, CH), 4.05 (d, J=13.5
Hz, 1H, CH), 7.04–7.09 (m, 1H, ArH), 7.17–7.39 (m, 9H, ArH), 7.40–7.48 (m, 4H, ArH). m/z: 406
(M++1). Exact mass determination: 405.1692 (calcd C25H28NPS: 405.1680).
(S)-6b: 74% yield. [α]D −71 (c=2.8, CHCl3). IR νmfilamx cm−1: 1595 (aromatic). NMR (270 MHz;
CDCl3) δ: 1.62–1.76 (m, 4H, (CH2)2), 1.97–2.12 (m, 4H, 2×CH2), 2.46–2.65 (m, 2H, CH2), 2.91–2.96
(m, 1H, CH), 3.39 (d, J=13.7 Hz, 1H, CH), 4.06 (d, J=13.7 Hz, 1H, CH), 7.12–7.48 (m, 1H, CH). m/z:
468 (M++1). Exact mass determination: 467.1857 (calcd C30H30NPS: 467.1837).
(Rs,S)-7a: 72% yield. [α]D +36 (c=2.0, CHCl3). IR νmfilamx cm−1: 1595 (aromatic), 1032 (SO). NMR

K. Hiroi et al. / Tetrahedron: Asymmetry 10 (1999) 1173–1188
1183
(270 MHz; CDCl3) δ: 1.40–2.10 (m, 6H, (CH2)3), 2.34 (s, 3H, CH3), 2.51–2.54 (m, 2H, 2×CH), 2.74
(dt, J=13.2, 3.3 Hz, 1H, CH), 3.04 (d, J=12.7 Hz, 1H, CH), 4.33 (d, J=12.7 Hz, 1H, CH), 7.18–7.21 (m,
2H, ArH), 7.25–7.48 (m, 14H, ArH), 7.58–7.61 (m, 2H, ArH), 7.94 (d, J=7.6 Hz, 1H, ArH). m/z: 498
(M++1). Exact mass determination: 497.1950 (calcd C31H32NOPS: 497.1942).
(Ss,S)-7b: 65% yield. [α]D −122 (c=2.6, CHCl3). IR νmfilamx cm−1: 1595 (aromatic), 1030 (SO). NMR
(270 MHz; CDCl3) δ: 1.53–1.89 (m, 4H, (CH2)2), 1.92–2.08 (m, 2H, CH2), 2.21 (dt, J=13.2, 3.5 Hz, 1H,
CH), 2.32 (s, 3H, CH3), 2.44–2.48 (m, 1H, CH), 2.82–2.87 (m, 1H, CH), 3.46 (d, J=13.7 Hz, 1H, CH),
3.79 (d, J=13.7 Hz, 1H, CH), 7.14–7.49 (m, 17H, ArH), 8.03 (d, J=1.2 Hz, 1H, ArH). m/z: 497 (M+).
Exact mass determination: 497.1989 (calcd C31H32NOPS: 497.1942).
(S)-8: 46% yield. [α]D −26 (c=1.6, CHCl3). IR νmfilamx cm−1: 1603 (aromatic). NMR (270 MHz; CDCl3)
δ: 1.54–1.86 (m, 4H, (CH2)2), 2.05–2.15 (m, 1H, CH), 2.25–2.35 (m, 1H, CH), 2.60–2.90 (m, 3H, CH,
CH2), 3.23 (d, J=13.0 Hz, 1H, CH), 3.93 (d, J=13.0 Hz, 1H, CH), 7.22–7.51 (m, 15H, ArH), 7.61–7.74
(m, 4H, ArH). m/z: 516 (M++1). Exact mass determination: 515.1331 (calcd C30H30NPSe: 515.1281).
3.2. Synthesis of (S)-N-2-substituted phenylprolinol derivative
3.2.1. (S)-N-(2-Fluorophenyl)-2-proline methyl ester 9b
A mixture of (S)-proline (1.0 g, 8.70 mmol), 2-fluoroiodobenzene (1.9 g, 8.70 mmol),
bis(triphenylphosphine)nickel(II) chloride [Ni(PPh3)2Cl2] (284 mg, 0.44 mmol), copper iodide
(CuI) (82 mg, 0.44 mmol), potassium carbonate (1.2 g, 8.70 mmol), benzyltriethylammonium chloride
(TEBA) (298 mg, 1.31 mmol), Et3N (2.3 g, 23.00 mmol), N,N-dimethylformamide (16 ml) and water
(2 ml) was heated at 100°C for 22 h.12 A solution of 6 N HCl was added to adjust the pH to 2–3
and the mixture was then diluted with ethyl acetate. The organic layers were combined, washed with
saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. Thionyl chloride (3
ml, 34.80 mmol) was added at 0°C to a solution of the crude product obtained in MeOH (20 ml), and
the reaction mixture was stirred under heating at reflux for 2 h. The reaction solution was concentrated
in vacuo. It was then diluted with CHCl3, and the solution washed with saturated aqueous NaHCO3 and
saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product
was subjected to preparative TLC (ether:hexane=1:1) to give (S)-9b (969 mg, 50% yield).
(S)-9b: [α]D −78 (c=6.7, CHCl3). IR νmfilamx cm−1: 1748 (ester), 1615 (aromatic). NMR (270 MHz;
CDCl3) δ: 1.90–2.35 (m, 6H, (CH2)3), 3.37–3.46 (m, 1H, CH), 3.58–3.66 (m, 1H, CH), 3.69 (s, 3H,
CH3), 4.50–4.56 (m, 1H, CH), 6.61–6.70 (m, 2H, ArH), 6.89–7.01 (m, 2H, ArH). m/z: 223 (M+). Exact
mass determination: 223.0994 (calcd C12H14NO2F: 223.1009).
3.2.2. (S)-N-(2-Fluorophenyl)-2-prolinol 9c
Lithium aluminum hydride (169 mg, 6.04 mmol) was added at 0°C to a solution of (S)-9b (672 mg,
3.02 mmol) in THF (20 ml), and the reaction mixture stirred at room temperature for 4 h. The reaction
solution was diluted with ether, and 10% aqueous sodium hydroxide (5 ml) was added to the solution.
The solution was filtered, and the filtrate was dried over anhydrous Na2SO4, and concentrated in vacuo.
The crude product was subjected to preparative TLC (ether:hexane=1:1) to give (S)-9c (497 mg, 85%
yield).
(S)-9c: [α]D +27 (c=1.1, CHCl3). IR νmfilamx cm−1: 3350 (OH), 1610 (aromatic). NMR (270 MHz;
CDCl3) δ: 1.79–2.12 (m, 5H, (CH2)2, OH), 3.13–3.22 (m, 1H, CH), 3.53–3.69 (m, 3H, CH, CH2),
3.93–4.04 (m, 1H, CH), 6.68–6.84 (m, 2H, ArH), 6.94–7.02 (m, 2H, ArH). m/z: 195 (M+). Exact mass
determination: 195.1053 (calcd C11H14NOF: 195.1059).

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K. Hiroi et al. / Tetrahedron: Asymmetry 10 (1999) 1173–1188
3.2.3. (S)-N-(2-Fluorophenyl)-2-(benzyloxymethyl)pyrrolidine 9d
A 25 ml two-necked flask equipped with a septum inlet and a magnetic stirring bar, and containing
sodium hydride (50% oil dispersion; 197 mg, 4.10 mmol) was flushed with argon, and maintained under
a positive pressure of argon. A solution of (S)-9c (667 mg, 3.42 mmol) in THF (15 ml) was added to
the above flask. The reaction mixture was stirred at 0°C for 30 min. A solution of benzyl bromide (567
mg, 4.10 mmol) in THF (5 ml) was added to the above solution, and the reaction mixture was stirred at
room temperature for 36 h. The reaction solution was diluted with ether, washed with saturated aqueous
NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was subjected to preparative
TLC (ether:hexane=1:3) to give (S)-9d (809 mg, 83% yield).
(S)-9d: [α]D −44 (c=2.4, CHCl3). IR νmfilamx cm−1: 1610 (aromatic). NMR (270 MHz; CDCl3) δ:
1.87–2.06 (m, 4H, (CH2)2), 3.19–3.34 (m, 2H, CH2), 3.54–3.59 (m, 2H, CH2), 4.12–4.16 (m, 1H, CH),
4.44 (d, J=3.6 Hz, 2H, CH2), 6.62–6.76 (m, 2H, ArH), 6.91–7.00 (m, 2H, ArH), 7.24–7.34 (m, 5H, ArH).
m/z: 286 (M++1). Exact mass determination: 285.1512 (calcd C18H20NOF: 285.1529).
3.2.4. (S)-N-[2-(Diphenylphosphino)phenyl]-2-(benzyloxymethyl)pyrrolidine 10
A 0.5 M THF solution of potassium diphenylphosphatide (KPPh2)17 was added at room temperature
to a solution of (S)-9d (809 mg, 2.84 mmol) in THF (34 ml), and the reaction mixture was stirred at
reflux for 38 h. The reaction mixture was diluted with ether and filtered. The filtrate was concentrated in
vacuo. The crude product was subjected to preparative TLC (ethyl acetate:hexane=1:15) to give (S)-10
(144 mg, 11% yield).
(S)-10: [α]D −62 (c=3.0, CHCl3). IR νmfilamx cm−1: 1582 (aromatic). NMR (270 MHz; CDCl3) δ:
1.62–1.80 (m, 3H, CH, CH2), 2.06–2.17 (m, 1H, CH), 2.71–2.77 (m, 1H, CH), 2.83 (dd, J=9.3, 8.1
Hz, 1H, CH), 7.17 (dd, J=9.3, 4.1 Hz, 1H, CH), 3.47–3.55 (m, 1H, CH), 3.78–3.85 (m, 1H, CH), 4.27
(dd, J=18.5, 12.0 Hz, 2H, CH2), 6.78–6.82 (m, 1H, ArH), 6.91–6.95 (m, 1H, ArH), 7.15–7.35 (m, 17H,
ArH). m/z: 452 (M++1). Exact mass determination: 451.2069 (calcd C30H30NOP: 451.2065).
3.3. Synthesis of (S)-N-benzyloxy-2-(diphenylphosphinomethyl)pyrrolidine derivatives
3.3.1. (S)-N-[2-(Methylthio)benzoyl]-2-(diphenylphosphinomethyl)pyrrolidine 12a
A solution of N,N0-dicyclohexylcarbodiimide (DCC) (119 mg, 0.64 mmol) in CH2Cl2 (2 ml) was
added at 0°C to a solution of 2-methylthiobenzoic acid 11a (130 mg, 0.70 mmol) in CH2Cl2 (1
ml), and the reaction mixture was stirred at room temperature for 15 min. A solution of (S)-2-
(diphenylphospinomethyl)pyrrolidine (156 mg, 0.58 mmol) in Et3N (293 mg) was added to the above
solution, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was
diluted with ether and filtered. The filtrate was concentrated in vacuo. The crude product was subjected
to preparative TLC (ether:hexane=2:1) to give (S)-12a (63 mg, 28% yield).
The reactions of (S)-2-(diphenylphosphinomethyl)pyrrolidine with 2-(ethylthio)-, 2-(ethylsulfinyl)-,
2-(n-propylthio)-, 2-(isopropylthio)-, 2-(phenylthio)-, 2-(benzylthio)-, 2-(benzylsulfinyl)-, 2-
(naphthylmethylthio)-, 2-(naphthylmethylsulfinyl)-, 2-(phenylseleno)-, 2-(benzylseleno)benzoic acid,
picolinic acid or 2-thiophenecarboxylic acid were carried out using the same procedure as described
above to give (S)-N-[2-(ethylthio)benzoyl]-, (Rs,S)- or (Ss,S)-N-[2-(ethylsulfinyl)benzoyl]-, (Rs,S)- or
(Ss,S)-N-[2-(benzylsulfinyl)benzoyl]-, (Rs,S)- or (Ss,S)-N-[2-(naphthylmethylsulfinyl)benzoyl]-, (S)-N-
[2-(n-propylthio)benzoyl]-, (S)-N-[2-(isopropylthio)benzoyl]-, (S)-N-[2-(phenylthio)benzoyl]-, (S)-N-
[2-(benzylthio)benzoyl]-, (S)-N-[2-(benzylsulfinyl)benzoyl]-, (S)-N-[2-(naphthylmethylthio)benzoyl]-,
(S)-N-[2-(naphthylmethylsulfinyl)benzoyl]-,
(S)-N-[2-(phenylseleno)benzoyl]-,
(S)-N-[2-(benzyl-
seleno)benzoyl]-, (S)-N-2-picolinoyl- or (S)-N-2-thenoyl-2-(diphenylphosphinomethyl)pyrrolidine

K. Hiroi et al. / Tetrahedron: Asymmetry 10 (1999) 1173–1188
1185
((S)-12a–g, (Rs,S)-13Aa, (Ss,S)-13Ba, (Rs,S)-13Ab, (Ss,S)-13Bb, (Rs,S)-13Ac, (Ss,S)-13Bc, (S)-15a,b,
(S)-16,17), respectively.
(S)-12a: [α]D −170 (c=1.9, CHCl3). IR νmfilamx cm−1: 1628 (amide), 1590 (aromatic). NMR (270 MHz;
CDCl3) δ: 1.96–2.13 (m, 4H, (CH2)2), 2.45 (s, 3H, CH3), 3.12–3.33 (m, 2H, CH2), 3.69–3.76 (m, 2H,
CH2), 4.41–4.42 (m, 1H, CH), 6.78–6.84 (m, 1H, ArH), 7.06–7.47 (m, 12H, ArH), 7.71 (dd, J=4.5, 1.3
Hz, 1H, ArH). m/z: 420 (M++1). Exact mass determination: 419.1451 (calcd C25H26NOPS: 419.1473).
(S)-12b: 42% yield. [α]D −120 (c=2.9, CHCl3). IR νmfilamx cm−1: 1628 (amide), 1588 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.26 (t, J=7.4 Hz, 3H, CH3), 1.88–2.15 (m, 4H, (CH2)2), 2.93 (q, J=7.4 Hz,
2H, CH2), 3.10–3.28 (m, 2H, CH2), 3.65–3.83 (m, 2H, CH2), 6.78–6.84 (m, 1H, ArH), 7.06–7.48 (m,
12H, ArH), 7.69–7.76 (m, 1H, ArH). m/z: 434 (M++1). Exact mass determination: 433.1632 (calcd
C26H28NOPS: 433.1629).
(S)-12c: 33% yield. [α]D −141 (c=4.5, CHCl3). IR νmfilamx cm−1: 1626 (amide), 1588 (aromotic). NMR
(270 MHz; CDCl3) δ: 0.90–1.01 (m, 3H, CH3), 1.43–1.79 (m, 4H, (CH2)2), 1.91–2.20 (m, 4H, (CH2)2),
3.09–3.30 (m, 2H, CH2), 3.61–3.83 (m, 2H, CH2), 4.21–4.45 (m, 1H, CH), 6.81 (dd, J=8.1, 9.1 Hz, 1H,
CH), 7.06–7.46 (m, 12H, ArH), 7.70–7.76 (m, 1H, ArH). m/z: 448 (M++1). Exact mass determination:
447.1751 (calcd C27H30NOPS: 447.1786).
(S)-12d: 44% yield. [α]D −128 (c=4.5, CHCl3). IR νmfilamx cm−1: 1626 (amide), 1588 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.22 (dd, J=8.9, 6.8 Hz, 6H, (CH3)2), 1.90–2.11 (m, 4H, (CH2)2), 3.12–3.27 (m,
2H, CH2), 3.42–3.65 (m, 1H, CH), 3.68–3.75 (m, 2H, CH2), 4.38–4.45 (m, 1H, CH), 6.78–6.84 (m, 1H,
CH), 7.06–7.47 (m, 12H, ArH), 7.72–7.75 (m, 1H, ArH). m/z: 448 (M++1). Exact mass determination:
447.1786 (calcd C27H30NOPS: 447.1786).
(S)-12e: 46% yield. [α]D −71 (c=2.8, CHCl3). IR νmfilamx cm−1: 1622 (amide), 1576 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.54–2.25 (m, 4H, (CH2)2), 3.06–3.14 (m, 2H, CH2), 3.39–3.52 (m, 3H, CH,
CH2), 4.40–4.42 (m, 1H, CH), 7.13–7.54 (m, 17H, ArH), 7.65–7.70 (m, 2H, ArH). m/z: 481 (M+). Exact
mass determination: 481.1612 (calcd C30H28NOPS: 481.1629).
(S)-12f: 37% yield. [α]D −117 (c=5.6, CHCl3). IR νmfilamx cm−1: 1616 (amide), 1588 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.66–2.40 (m, 4H, (CH2)2), 2.94–3.28 (m, 2H, CH2), 3.66–3.76 (m, 2H, CH2),
4.11 (s, 2H, CH2), 4.38–4.45 (m, 1H, CH), 6.77–6.82 (m, 1H, ArH), 7.07–7.10 (m, 2H, ArH), 7.17–7.46
(m, 14H, ArH), 7.70–7.76 (m, 2H, ArH). 496 (M++1). Exact mass determination: 495.1789 (calcd
C31H30NOPS: 495.1786).
(S)-12g: 24% yield. [α]D −125 (c=2.0, CHCl3). IR νmfilamx cm−1: 1622 (amide), 1588 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.73–2.40 (m, 4H, (CH2)2), 2.82–3.27 (m, 2H, CH2), 3.61–3.83 (m, 2H, CH2),
4.17–4.57 (m, 3H, CH, CH2), 6.80 (dd, J=14.3, 6.6 Hz, 1H, ArH), 7.02–7.50 (m, 16H, ArH), 7.59–7.84
(m, 4H, ArH). m/z: 546 (M++1). Exact mass determination: 545.1943 (calcd C35H32NOPS: 545.1942).
(Rs,S)-13Aa: 15% yield. [α]D −72 (c=1.7, CHCl3). IR νmfilamx cm-1: 1622 (amide), 1589 (aromatic), 1026
(SO). NMR (400 MHz; CDCl3) δ: 1.19 (t, J=7.6 Hz, 3H, CH3), 1.81–2.49 (m, 4H, (CH2)2), 3.05–3.14
(m, 2H, CH2), 3.21–3.39 (m, 4H, 2×CH2), 6.87–6.93 (m, 1H, ArH), 7.23–7.70 (m, 12H, ArH), 7.82–7.90
(m, 1H, ArH). m/z: 449 (M+). Exact mass determination: 449.1587 (calcd C26H28NO2PS: 449.1579).
(Ss,S)-13Ba: 18% yield. [α]D −106 (c=1.3, CHCl3). IR νmfilamx cm−1: 1622 (amide), 1589 (aromatic),
1026 (SO). NMR (400 MHz; CDCl3) δ: 1.29 (t, J=7.6 Hz, 3H, CH3), 1.67–2.27 (m, 4H, (CH2)2), 2.44
(dd, J=13.9, 8.8 Hz, 1H, CH), 2.80–2.96 (m, 2H, CH2), 4.45–4.54 (m, 1H, CH), 6.98 (dd, J=7.6, 1.2
Hz, 1H, ArH), 7.23–7.61 (m, 12H, ArH), 8.04 (dd J=7.8, 1.0 Hz, 1H). m/z: 449 (M+). Exact mass
determination: 449.1606 (calcd C326H28NO2PS: 449.1579).
(Rs,S)-13Ab: 10% yield. [α]D +41 (c=2.7, CHCl3). IR νmfilamx cm−1: 1620 (amide), 1589 (aromatic),
1017 (SO). NMR (270 MHz; CDCl3) δ: 1.69–2.28 (m, 4H, (CH2)2), 2.19–2.28 (m, 1H, CH), 2.97 (dt,
J=13.7, 3.5 Hz, 1H, CH), 3.23–3.43 (m, 2H, CH2), 4.08 (d, J=12.9 Hz, 1H, CH), 4.47–4.52 (m, 1H, CH),

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K. Hiroi et al. / Tetrahedron: Asymmetry 10 (1999) 1173–1188
4.55 (d, J=12.9 Hz, 1H, CH), 7.05–7.70 (m, 19H, aromatic). m/z: 512 (M++1). Exact mass determination:
511.1779 (calcd C31H30NO2PS: 511.1735).
(Ss,S)-13Bb: 11% yield. [α]D −235 (c=1.4, CHCl3). IR νmfilamx cm−1: 1620 (amide), 1590 (aromatic),
1015 (SO). NMR (270 MHz; CDCl3) δ: 1.76–2.28 (m, 6H, 3×CH2), 3.23–3.32 (m, 2H, CH2), 3.97
(d, J=12.9 Hz, 1H, CH), 4.26–4.39 (m, 1H, CH), 4.44 (d, J=12.9 Hz, 1H, CH), 7.13–7.48 (m, 17H,
aromatic), 7.65–7.78 (m, 2H, aromatic). m/z: 512 (M++1). Exact mass determination: 511.1750 (calcd
C31H30NO2PS: 511.1735).
(Rs,S)-13Ac: 12% yield. [α]D +35 (c=1.4, CHCl3). IR νmfilamx cm−1: 1618 (amide), 1590 (aromatic),
1017 (SO). NMR (270 MHz; CDCl3) δ: 1.70–2.27 (m, 4H, (CH2)2), 2.36–2.44 (m, 1H, CH), 4.73 (m,
1H, CH), 2.95–3.07 (m, 1H, CH), 4.46 (d, J=12.9 Hz, 1H, CH), 4.55–4.65 (m, 1H, CH), 7.10–7.58 (m,
13H, aromatic), 7.63–7.81 (m, 8H, aromatic). m/z: 562 (M++1). Exact mass determination: 561.1893
(calcd C35H32NO2PS: 561.1891).
(Ss,S)-13Bc: 10% yield. [α]D −165 (c=1.5, CHCl3). IR νmfilamx cm−1: 1620 (amide), 1590 (aromatic),
1015 (SO). NMR (270 MHz; CDCl3) δ: 1.75–2.27 (m, 6H, 3×CH2), 3.28–3.33 (m, 2H, CH2), 4.39–4.48
(m, 1H, CH), 4.41 (d, J=12.9 Hz, 1H, CH), 4.63 (d, J=12.9 Hz, 1H, CH), 7.07–7.81 (m, 21H, aromatic).
m/z: 562 (M++1). Exact mass determination: 561.1895 (calcd C35H32NO2PS: 561.1891).
(S)-15a: 48% yield. [α]D −129 (c=1.9, CHCl3). IR νmfilamx cm−1: 1622 (amide), 1578 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.84–2.24 (m, 4H, (CH2)2), 3.06–3.52 (m, 4H, 2×CH2), 4.38–4.44 (m, 1H, CH),
6.80–6.90 (m, 1H, ArH), 7.08–7.54 (m, 17H, ArH), 7.64–7.68 (m, 2H, ArH). m/z: 529 (M+). Exact mass
determination: 529.1026 (calcd C30H28NOPSe: 529.1074).
(S)-15b: 20% yield. [α]D −125 (c=1.4, CHCl3). IR νmfilamx cm−1: 1622 (amide), 1578 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.62–1.70 (m, 2H, CH2), 1.82–2.24 (m, 2H, CH2), 2.91–3.09 (m, 2H, CH2),
3.61–3.82 (m, 2H, CH2), 4.04, 4.14 (ss, 2H, CH2), 4.37–4.41 (m, 1H, CH), 6.77–6.83 (m, 1H, ArH),
7.06–7.56 (m, 16H, ArH), 7.69–7.75 (m, 2H, ArH). m/z: 544 (M++1). Exact mass determination:
543.1202 (calcd C31H30NOPSe: 543.1230).
(S)-16: 23% yield. [α]D −152 (c=1.3, CHCl3). IR νmfilamx cm−1: 1624 (amide), 1587 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.82–2.21 (m, 4H, (CH2)2), 3.21–3.29 (m, 2H, CH2), 3.46–3.89 (m, 2H, CH2),
4.36–4.39 (m, 1H, CH), 7.11–7.44 (m, 10H, ArH), 7.67–7.82 (m, 3H, ArH), 8.55–8.58 (m, 1H, ArH).
m/z: 375 (M++1). Exact mass determination: 374.1580 (calcd C23H23N2OP: 374.1548).
(S)-17: 89% yield. [α]D −47 (c=4.6, CHCl3). IR νmfilamx cm−1: 1624 (amide), 1580 (aromatic). NMR
(270 MHz; CDCl3) δ: 1.68–2.13 (m, 5H, CH, (CH2)2), 3.12–2.52 (m, 1H, CH), 3.66–3.81 (m, 3H, CH,
CH2), 4.35–4.40 (m, 1H, CH), 7.01–7.03 (m, 1H, ArH), 7.25–7.44 (m, 1H, ArH), 7.58–7.67 (m, 2H,
ArH). m/z: 380 (M++1). Exact mass determination: 379.1123 (calcd C22H22NOPS: 379.1160).
3.4. Palladium-catalyzed asymmetric nucleophilic substitution reactions of 1,3-diphenyl-2-propenyl ace-
tate 18 with chiral sulfoxide ligands
3.4.1. General procedure A
A 25 ml two-necked flask equipped with a septum inlet and a magnetic stirring bar, and containing
sodium hydride (50% oil dispersion, 18 mg, 0.38 mmol), was flushed with argon, and maintained under a
positive pressure of argon. A solution of dimethyl malonate (84 mg, 0.63 mmol) in THF (3 ml) was added
at 0°C to the above flask. Another 25 ml two-necked flask equipped with a septum inlet and a magnetic
stirring bar, and containing di-µ-chlorobis(π-allyl)dipalladium ([PdCl(CH2_CHCH2)]2) (7 mg, 0.02
mmol) and chiral sulfoxide ligands (0.04 mmol), was flushed with argon, and maintained under a positive
pressure of argon. A solution of (ꢀ)-1,3-diphenyl-2-propenyl acetate 18 (80 mg, 0.32 mmol) in THF (3
ml) was added at room temperature to the above solution, and the mixture was stirred at room temperature

K. Hiroi et al. / Tetrahedron: Asymmetry 10 (1999) 1173–1188
1187
for 30 min. The solution was added to the above solution including sodium dimethyl malonate, and the
reaction mixture was stirred under the conditions listed in Table 1. The reaction solution was then diluted
with ether, and the solution washed with saturated aqueous NH4Cl and saturated aqueous NaCl, dried
over anhydrous Na2SO4, and concentrated in vacuo. The crude product was subjected to preparative
TLC (ethyl acetate:hexane=1:7) to give optically active diethyl (1,3-diphenyl-2-propenyl) propanedioate
19.14 The e.e. and the absolute configuration of the product were determined by HPLC analysis with a
chiral column, Chiralpak AD (hexane:i-propanol, 20:1).14 The results obtained are listed in Table 1.
3.4.2. General procedure B
A solution of chiral sulfoxide ligands (0.04 mmol) and [PdCl(CH2_CHCH2)]2 (7 mg, 0.02 mmol) in
CH2Cl2 (2 ml) was stirred under argon for 30 min, and then a solution of (ꢀ)-18 (80 mg, 0.32 mmol)
in THF (1 ml), dimethyl malonate (84 mg, 0.63 mmol), N,O-bis(trimethylsilyl)acetamide (BSA)15 (0.3
ml, 1.19 mmol), and a catalytic amount of anhydrous sodium acetate was added to the above solution.
The reaction mixture was stirred at −20°C to room temperature for 1–92 h. The reaction mixture
was then diluted with ether. The organic layer was washed with 10% aqueous sodium hydroxide and
saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product
was subjected to preparative TLC (ethyl acetate:hexane=1:7) to give 19.14 The results obtained are listed
in Table 2.
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