Transition metal-catalyzed asymmetric cycloaddition reactions of a chiral (β-sulfinyl)vinylcyclopropane derivative: Asymmetric synthesis of a cyclopentane derivative using a chiral sulfinyl functionality as the chiral source

Article abstract of DOI:10.1016/S0957-4166(00)00120-8

Asymmetric synthesis of a cyclopentane derivative using a chiral sulfinyl functionality as the chiral source has been successfully executed by a transition metal-catalyzed asymmetric cycloaddition reaction of a chiral (β-sulfinyl)vinylcyclopropane derivative with acrylonitrile. The effects of the catalysts, ligands, and solvent were examined. The degree of the asymmetric induction and the chemical yield were highly dependent on the catalyst and, especially, the ligand used. A plausible mechanism of the asymmetric induction is proposed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00120-8

Tetrahedron: Asymmetry 11 (2000) 1835±1841
Transition metal-catalyzed asymmetric cycloaddition
reactions of a chiral (b-sul®nyl)vinylcyclopropane derivative:
asymmetric synthesis of a cyclopentane derivative using a
chiral sul®nyl functionality as the chiral source
Kunio Hiroi* and Akio Yamada
Department of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku,
Sendai, Miyagi 981-8558, Japan
Received 6 March 2000; accepted 27 March 2000
Abstract
Asymmetric synthesis of a cyclopentane derivative using a chiral sul®nyl functionality as the chiral
source has been successfully executed by a transition metal-catalyzed asymmetric cycloaddition reaction of
a chiral (b-sul®nyl)vinylcyclopropane derivative with acrylonitrile. The e€ects of the catalysts, ligands, and
solvent were examined. The degree of the asymmetric induction and the chemical yield were highly
dependent on the catalyst and, especially, the ligand used. A plausible mechanism of the asymmetric
induction is proposed. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Much attention has been devoted to organic synthesis with transition metal catalysts in recent
years.1 We have taken much interest in stereochemically advantageous synthetic reactions using
the characteristics of transition metal catalysts, especially quite recently in asymmetric synthesis
with these catalysts.2 We have developed novel methodologies for asymmetric carbon±carbon
bond formation using chiral allyl esters,3 chiral enamines,4 imines, and hydrazones bearing
phosphine groups,5 intramolecular metallo-type ene reactions of chiral allylic sulfones6 and
transition metal-catalyzed asymmetric vinylcyclopropane±cyclopentene rearrangements via chiral
p-allyl transition metal complexes bearing chiral sul®nyl groups.7 We have focused, furthermore,
on the chemistry of chiral p-allyl transition metal complexes bearing a chiral sul®nyl function-
ality8 originated from cyclopropane derivatives,9 and the asymmetric induction via the chiral
intermediary complexes.
* Corresponding author.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00120-8

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K. Hiroi, A. Yamada / Tetrahedron: Asymmetry 11 (2000) 1835±1841
We wish to communicate herein the asymmetric synthesis of a cyclopentane derivative by
transition metal-catalyzed asymmetric cycloaddition reaction of a chiral (b-sul®nyl)vinylcyclo-
propane derivative with an electrophilic ole®n. Much attention has been paid to the synthesis of
cyclopentane derivatives,10 owing to the usefulness of the skeletons in organic synthesis and the
inaccessibility of the structures. In particular, an asymmetric synthesis of cyclopentane compounds
has received much attention; however, few reports have been published on [3+2] asymmetric
cycloaddition reactions.11
2. Results and discussion
2.1. The transition metal-catalyzed asymmetric cycloaddition reactions
A model compound, chiral (b-sul®nyl)vinylcyclopropane derivative (Ss)-4, was prepared by the
addition of lithium ester enolate of t-butyl (R)-p-toluenesul®nylacetate 2 (treated with LDA) to
aldehyde 1 (in THF at ^78ꢀC for 4 h) followed by the mesylation of the alcohol (Rs)-3a (with
MsCl±Et3N in CH2Cl2 at 0ꢀC for 1 h) and the dehydromesylation of the mesylate (Rs)-3b (with
DBU in THF at ^20ꢀC for 28 h). The asymmetric carbon center on the cyclopropane ring of (Ss)-
4 obtained above was con®rmed as racemic by HPLC analysis. The structure of (Ss)-4 was
determined by the NMR spectral analysis with NOE measurements. The geometry of the ole®n
bond in 4 was con®rmed as (Z)-con®guration between the p-toluenesul®nyl group and the
cyclopropane ring by the observation of strong NOE between the methyl in the tolyl group and
the hydrogen (Ha) on the cyclopropane ring (A), and between the t-butyl group in the ester and
the ole®nic hydrogen (Hb) (B) in the NMR spectral analysis (Scheme 1).
Scheme 1.
The asymmetric cycloaddition reactions of (Ss)-4 with acrylonitrile were carried out under
heating in THF, DME, CH3CN, or DMSO in the presence of a palladium catalyst (0.1 equiv.)
.
such as Pd(PPh3)4, Pd(dba)2, or Pd2(dba)3 CHCl3, and a phosphine ligand (0.2 equiv.) such as
PPh3, bis(diphenylphosphino)methane (dppm), 1,2-bis(diphenylphosphino)ethane (dppe), or 1,4-
bis(diphenylphosphino)butane (dppb), to give stereoselectively an optically active cyclopentane
derivative (3R,4R,Ss)-5 (Scheme 2). The results obtained are summarized in Table 1. The highest

K. Hiroi, A. Yamada / Tetrahedron: Asymmetry 11 (2000) 1835±1841
1837
chemical yield of the product (3R,4R,Ss)-5 was obtained on the use of Pd(PPh3)4 as the catalyst
and PPh3 as the ligand, whereas the use of other bidentate-phosphine ligands resulted in poor
yields of (3R,4R,Ss)-5. It should be noted that the degree of the asymmetric induction was especially
dependent on the phosphine ligand used. Use of PPh3 as a ligand with Pd(PPh3)4, Pd(dba)2, or
.
Pd2(dba)3 CHCl3 a€orded rather enantiomeric excess (66, 70, and 56%, respectively) of the
product (3R,4R,Ss)-5. The nickel-catalyzed asymmetric cycloaddition of (Ss)-4 with acrylonitrile
was carried out under heating in THF, DME, or CH3CN in the presence of Ni(COD)2 (0.1 equiv.)
and PPh3 (0.2 equiv.). The highest chemical yield and diastereoselectivity of (3R,4R,Ss)-5 were
obtained under re¯ux in THF for 3 h in the Ni(COD)2-catalyzed reaction, as shown in Table 2.
The stereochemistry of the product obtained by the nickel-catalyzed reactions was the same as
that by the palladium-catalyzed reactions. The diastereomeric excess (d.e.) of the product
(3R,4R,Ss)-5 was determined by HPLC analysis.
Scheme 2.
Table 1
The palladium-catalyzed asymmetric cycloaddition reactions of (Ss)-4(a)
The stereochemistry of the product 5 was con®rmed by NMR spectral analysis with NOE
measurements. The trans con®guration between the ole®nic group and the cyano group was
assigned by the observation of a strong NOE (C) between the ole®nic hydrogen (Hb) and

1838
K. Hiroi, A. Yamada / Tetrahedron: Asymmetry 11 (2000) 1835±1841
Table 2
The nickel-catalyzed asymmetric cycloaddition reactions of (Ss)-4(a)
the a-hydrogen (Hc) to the cyano group. The (Z)-con®guration between the p-toluenesul®nyl
group and the cyclopentyl group was con®rmed by the observation of strong NOE between the
methyl substituent in the p-toluenesul®nyl group and the hydrogen (Ha) on the cyclopentyl group
(A), and between the t-butyl group in the ester and the ole®nic hydrogen (Hb) (B). The absolute
con®guration of the product was deduced on the basis of the mechanism of the asymmetric
induction mentioned below.
2.2. The mechanism of the asymmetric reaction
A possible mechanism of this asymmetric cycloaddition reaction is proposed as follows. It was
con®rmed by the HPLC analysis of the starting (Ss)-4 recovered before completion of the reac-
tion that the asymmetric carbon center on the cyclopropane ring of (Ss)-4 used still remained
racemic. This means that this asymmetric cyclization reaction would not result from kinetic
resolution. Therefore, an intermediary p-allylpalladium complex would be formed by the e€ect of
Scheme 3.

K. Hiroi, A. Yamada / Tetrahedron: Asymmetry 11 (2000) 1835±1841
1839
the chiral sul®nyl goup, without steric control by the racemic carbon center. The palladium
catalyst would react from the sterically less crowded downward direction on the same side as the
sterically smallest lone pair side of the chiral sul®nyl group in the conformationally most stable
conformer (as shown in 6) having coplanarity between the ole®nic bond and the sulfur±oxygen
bond of the sul®nyl group,12 a€ording a chiral p-allylpalladium complex 7 possessing a chiral
sul®nyl group at the a site. The intermediary p-allylpalladium complex 7a would be preferred to 7b
in the equilibrium of p-allyl intermediates due to the steric e€ect in 7b. Therefore, the carbanion
formed would undergo a conjugate addition to acrylonitrile in preference to the intramolecular
substitution reaction via 7b (giving 9), to form 8. The a carbanion to the cyano group would react
from the back side of the palladium catalyst at the sterically less crowded g site in the p-allyl-
palladium system via path c to a€ord (3R,4R,Ss)-5. The reaction at the sterically crowded a site
via path d (giving 10) was not observed (Scheme 3).
Thus, this novel method is characterized by the transition metal-catalyzed asymmetric
cycloaddition utilizing chiral sul®nyl groups as chiral sources, and is advantageous for the highly
stereoselective asymmetric synthesis of cyclopentane derivatives.
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
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;
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 AS, hexane:i-PrOH 1:20, 0.5 ml/min, 254 nm). Optical rotations were
measured with a JASCO DIP-370 polarimeter. Thin layer or thick layer plates (preparative TLC)
were made of Merck silica gel 60PF-254 activated by drying at 140ꢀC for 3.5 h.
3.1. Dimethyl (Rs)-2-[1-hydroxy-2-(tert-butoxycarbonyl)-2-(p-toluenesul®nyl)ethyl]cyclopropane-
1,1-dicarboxylate 3a
A solution of tert-butyl (R)-p-toluenesul®nylacetate 2 (500 mg, 1.97 mmol) in THF (5 ml) was
added at ^78ꢀC to a solution of lithium diisopropylamide in THF (5 ml) [generated from diiso-
propylamine (238 mg, 2.36 mmol) and a 1.7N n-hexane solution of n-butyllithium (1.38 ml, 2.36
mmol)], and the solution was stirred for 1.5 h. Then, a solution of dimethyl 2-formylcyclo-
propane-1,1-dicarboxylate 1 (439 mg, 2.36 mmol) in THF (5 ml) was added to the above solution
and the reaction mixture was stirred at ^78ꢀC for 4 h. The reaction solution was diluted with
ether, then washed successively with a 10% aqueous HCl solution, an aqueous saturated
NaHCO3 solution and an aqueous saturated NaCl solution, and dried over anhydrous Na2SO4.
The ®ltrate was evaporated in vacuo and the crude product was submitted to preparative TLC
cm^1: 3480 (OH),
film
max
over silica gel (ether:n-hexane 8:1) to give (Rs)-3a (869 mg, yield 70%). IR ꢀ
1
1730 (ester), 1600 (aromatic), 1035 (SO). H NMR (270 MHz) (CDCl3) ꢁ: 1.19±1.38 (m, 9H,
C(CH3)3), 1.39±1.58 (m, 3H, CH2 and OH), 1.62±1.69 (m, 1H, CH2CH), 2.41 (s, 3H, C6H4CH3),
3.30±3.55 (m, 2H, SCHCH), 3.65, 3.83 (s, s, 6H, (CO2CH3)2), 7.25±7.62 (m, 4H, C6H4). m/z: 440
(M+). Exact mass determination: 440.1422 (calcd C21H28O8S: 440.1505).

1840
K. Hiroi, A. Yamada / Tetrahedron: Asymmetry 11 (2000) 1835±1841
3.2. Dimethyl (Ss)-2-[2-(tert-butoxycarbonyl)-2-(p-toluenesul®nyl)vinyl]cycloropane-1,1-dicar-
boxylate 4
Methanesulfonyl chloride (0.07 ml, 0.92 mmol) was added at 0ꢀC to a mixture of (Rs)-3a (200
mg, 0.44 mmol) obtained above and triethylamine (0.19 ml, 1.36 mmol) in dichloromethane (10
ml), and the reaction mixture was stirred at 0ꢀC for 1 h. The mixture was diluted with ether, ®l-
tered by Celite, and evaporated in vacuo. The crude mesylate (Rs)-3b obtained was submitted to
dehydromesylation. 1,8-Diazabicyclo[5.4.0]undecene-7 (208 mg, 1.36 mmol) was added at 0ꢀC to
a solution of (Rs)-3b obtained above in THF (5 ml) and the reaction mixture was stirred at ^20ꢀC
for 28 h. The reaction mixture was diluted with chloroform, then washed successively with a 10%
aqueous HCl solution, an aqueous saturated NaHCO3 solution and an aqueous saturated NaCl
solution, and dried over anhydrous Na2SO4. The ®ltrate was evaporated in vacuo and the crude
product was submitted to preparative TLC over silica gel (ether:n-hexane 5:1) to give (Ss)-4 (190
cm^1: 1730 (ester), 1630 (ole®n), 1600
film
max
mg, yield 99%). [ꢂ]D +231.4 (c=1.8, MeOH). IR ꢀ
1
(aromatic), 1035 (SO). H NMR (270 MHz) (CDCl3): 1.35 (s, 9H, C(CH3)3), 1.39±1.58 (m, 2H,
CH2), 2.41 (s, 3H, C6H4CH3), 2.61±2.74 (m, 1H, CH2CH), 3.65, 3.83 (s, s, 6H, (CO2CH3)2), 6.39±
6.47 (m, 1H, CˆCH), 7.25±7.62 (m, 4H, C6H4). m/z: 422 (M+). Exact mass determination:
422.1095 (calcd C21H26O7S: 422.1824).
3.3. Dimethyl (3R,4R,Ss)-3-cyano-4-[2-(tert-butoxycarbonyl)-2-(p-toluenesul®nyl)vinyl]cyclopent-
ane-1,1-dicarboxylate 5
3.3.1. A general procedure
A 25 ml two-necked ¯ask equipped with a septum inlet and a magnetic stirring bar, and con-
taining tetrakis(triphenylphosphine)palladium (13.7 mg, 0.012 mmol) and triphenylphosphine
(6.2 mg, 0.024 mmol), was ¯ushed with nitrogen and maintained under a positive pressure of
nitrogen, and then THF (1 ml) was added to the above ¯ask. A solution of (Ss)-4 (50 mg, 0.12
mmol) in THF (1 ml) and a solution of acrylonitrile (0.1 ml, 2.36 mmol) in THF (1 ml) were
successively added to the above mixture. The reaction mixture was re¯uxed for 3 h. The reaction
mixture was ®ltered and the ®ltrate was evaporated in vacuo. The crude product was submitted to
preparative TLC over silica gel (ether:n-hexane 8:1) to give (3R,4R,Ss)-5 (29 mg, yield 51%).
The results obtained under other reaction conditions using a palladium or nickel catalyst are
cm^1: 2249
film
max
summarized in Tables 1 and 2. (3R,4R,Ss)-5: [ꢂ]D +100.0 (c=0.6, MeOH). IR ꢀ
1
(nitrile), 1735 (ester), 1635 (ole®n), 1600 (aromatic), 1035 (SO). H NMR (270 MHz) (CDCl3):
1.33 (s, 9H, C(CH3)3), 1.40±1.58 (m, 4H, CH2CCH2), 1.88±1.98 (m, 2H, CHCHCN), 2.38 (s, 3H,
C6H4CH3), 3.77, 3.83 (s, s, 6H, (CO2CH3)2), 6.41±6.50 (m, 1H, CHˆC), 7.35±7.80 (m, 4H, C6H4).
m/z: 475 (M+). Exact mass determination: 475.1190 (calcd C24H29NO7S: 475.1665).
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