Asymmetric synthesis of 2-alkyl-substituted 2,5-dihydropyrroles from optically active aza-baylis-hillman adducts. Formal synthesis of (-)-trachelanthamidine

Article abstract of DOI:10.1021/jo100315j

Figure presented A series of optically active 2-alkyl-substituted 2,5-dihydropyrroles were prepared via the asymmetric aza-Baylis-Hillman equivalent reaction and subsequent ring-closure metathesis reaction. Optically active aza-Baylis-Hillman adducts underwent a smooth two-step conversion to N-allyl-β-amino-α-methylene esters in high yield, which gave chiral 2,5-dihydropyrroles, potential precursors for the aza-heterocyclic synthesis, almost quantitatively through RCM reaction catalyzed by Grubbs catalyst. The conversion was carried out without loss of the optical purity of the starting material. Synthetic application of the method to (-)-trachelanthamidine was examined. Hydrogenation of 2,5-dihydropyrrole took place smoothly to give the corresponding 2,3-disubstituted pyrrolidine in good yield. The stereoselectivity of the hydrogenation was sensitive to the presence or absence of the protective group in the C2-side chain. The TBS-protected 2,5-dihydropyrrole gave a 1:1 mixture of the cis/trans isomers, while free alcohol afforded the trans-2,3-disubstituted pyrrolidine in a selectivity of 6:1. The formal synthesis of (-)-trachelanthamidine was achieved in 11 steps from a chiral sulfinimine. This methodology provided a convenient procedure for the preparation of C2-alkyl-substituted 2,5-dihydropyroles with retention of high optical purity.

Full text of DOI:10.1021/jo100315j

pubs.acs.org/joc
Asymmetric Synthesis of 2-Alkyl-Substituted 2,5-Dihydropyrroles
from Optically Active Aza-Baylis-Hillman Adducts. Formal Synthesis
of (-)-Trachelanthamidine.
Shingo Ishikawa, Fumiaki Noguchi, and Akio Kamimura*
Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University,
Ube 755-8611, Japan
ak10@yamaguchi-u.ac.jp
Received February 22, 2010
A series of optically active 2-alkyl-substituted 2,5-dihydropyrroles were prepared via the asymmetric aza-
Baylis-Hillman equivalent reaction and subsequent ring-closure metathesis reaction. Optically active aza-
Baylis-Hillman adducts underwent a smooth two-step conversion to N-allyl-β-amino-R-methylene esters
in high yield, which gave chiral 2,5-dihydropyrroles, potential precursors for the aza-heterocyclic synthesis,
almost quantitatively through RCM reaction catalyzed by Grubbs catalyst. The conversion was carried
out without loss of the optical purity of the starting material. Synthetic application of the method to
(-)-trachelanthamidine was examined. Hydrogenation of 2,5-dihydropyrrole took place smoothly to give
the corresponding 2,3-disubstituted pyrrolidine in good yield. The stereoselectivity of the hydrogenation
was sensitive to the presence or absence of the protective group in the C2-side chain. The TBS-protected
2,5-dihydropyrrole gave a 1:1 mixture of the cis/trans isomers, while free alcohol afforded the trans-2,3-
disubstituted pyrrolidine in a selectivity of 6:1. The formal synthesis of (-)-trachelanthamidine was
achieved in 11 steps from a chiral sulfinimine. This methodology provided a convenient procedure for the
preparation of C2-alkyl-substituted 2,5-dihydropyroles with retention of high optical purity.
Introduction
sufficient steric bias in the nucleophilic addition to the imino
group and is readily removed by acidic treatment. Use of chiral
sulfinimines in the aza-Baylis-Hillman reaction has been re-
ported by Aggarwal, but only moderate levels of diastereomeric
selectivity were observed.4 Recently, we have reported an alter-
native method, in which we disclosed that a Michael/imino-
aldol domino reaction of an acrylate and a chiral sulfinimine
followed by a subsequent thermal elimination of sulfoxide gave
aza-Baylis-Hillman products.5 This methodology enabled us
to prepare aza-Baylis--Hillman adducts from aliphatic imines
in high enantiomeric excesses, although the method requires a
two-step sequence. To the best of our knowledge, there are only
a few practical methods to prepare aza-Baylis-Hillman adducts
from aliphatic imines.6 To enhance the potential of this meth-
odology in organic synthesis, we attempted to prepare chiral
2,5-dihydropyrroles, which are recognized as potential precur-
sors for the preparation of aza-multicyclic organic compounds
and often seen among natural products such as alkaloids.7 With
our method, the C2 aliphatic side chain is introduced with
sufficient control of chirality. We also examined the preparation
of (-)-trachelanthamidine in highly optically pure form.
The aza-Baylis-Hillman reaction has been recognized as a
potentially useful reaction in organic synthesis because it
provides a one-step preparation of R-methylene-β-amino esters
from readily available R,β-unsaturated esters and imines.1
Recently, asymmetric syntheses of these compounds have
been of interest. Many methods on the catalytic asymmetric
modification of the reaction have been published.2 For example,
chiral amines derived from quinine derivatives2b,d-f or chiral
phosphines2c,g-i,m,q-w have been examined as good catalysts for
the asymmetric aza-Baylis-Hillman reaction. Most of the
reports, however, are usually useful for aromatic imines; the
use of aliphatic imines is very limited. This is probably due to the
instability of aliphatic imines under the reaction conditions. To
overcome this drawback, stable and readily accessible aliphatic
imines are desired. Chiral sulfinimines are frequently used as
stable imines in organic synthesis.3 The sulfinyl group affords
(1) (a) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905. (b) Declerck, V.;
Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1.
3578 J. Org. Chem. 2010, 75, 3578–3586
Published on Web 05/13/2010
DOI: 10.1021/jo100315j
r
2010 American Chemical Society

Ishikawa et al.
JOCArticle
Results and Discussion
SCHEME 1
The optically active aza-Baylis-Hillman adducts 1 were
prepared through the domino reaction of chiral sulfinimines3
and tert-butyl acrylate.5d N-Allylation of 1 was carried out
via oxidation to 28 and subsequent basic treatment with allyl
bromide to give 3 (Scheme 1). The ring-closure metathesis
reaction of 3 proceeded smoothly to give 2,5-dihydropyr-
roles 4 in the presence of Grubbs’ second-generation
catalyst.9 These results are summarized in Table 1.
For example, treatment of 1a with m-CPBA at room
temperature resulted in the oxidation of the sulfinimine unit
to give the corresponding sulfonamine 2a in 93% yield (entry 1).
Subsequent N-allylation progressed under the weak basic
conditions by the presence of K2CO3 and furnished 3a in
90% yield. It should be mentioned that no loss of enantio-
meric excess in compound 3 was observed during the trans-
formation. We have also examined homoallyl bromide for
the alkylation, but the alkylation progressed sluggishly and a
trace amount of alkylated products was obtained.
(2) (a) Li, G.; Wei, H.-X.; Whittlesey, B. R.; Batrice, N. N. J. Org. Chem.
1999, 64, 1061. (b) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507.
(c) Shi, M.; Chen, L.-H. Chem. Commun. 2003, 1310. (d) Balan, D.;
Adolfsson, H. Tetrahedron Lett. 2003, 44, 252. (e) Kawahara, S.; Nakano,
A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103. (f) Shi,
M.; Xu, Y.-M.; Shi, Y.-L. Chem.;Eur. J. 2005, 11, 1794. (g) Shi, M.; Chen,
L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. (h) Shi, M.; Chen, L.-H.;
Teng, W.-D. Adv. Synth. Catal. 2005, 347, 1781. (i) Shi, M.; Li, C.-Q.
Tetrahedron: Asymmetry 2005, 16, 1385. (j) Matsui, K.; Takizawa, S.; Sasai,
H. J. Am. Chem. Soc. 2005, 127, 3680. (k) Raheem, I. T.; Jacobsen, E. N. Adv.
Synth. Catal. 2005, 347, 1701. (l) Shi, Y.-L.; Shi, M. Tetrahedron 2006, 62,
461. (m) Liu, Y.-H.; Chen, L.-H.; Shi, M. Adv. Synth. Catal. 2006, 348, 973.
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2006, 17, 578. (p) Gausepohl, R.; Buskens, P.; Kleiner, J.; Bruckmann, A.;
Lehmann, C. W.; Klankermayer, J.; Leitner, W. Angew. Chem., Int. Ed. 2006,
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K.; Nishida, K.; Gotanda, T. Tetrahedron Lett. 2007, 48, 6147. (s) Lei, Z.-Y.;
Ma, G.-N.; Shi, M. Eur. J. Org. Chem. 2008, 3817. (t) Shi, Y.-L.; Shi, M. Adv.
Synth. Catal. 2007, 349, 2129. (u) Qi, M.-J.; Ai, T.; Shi, M.; Li, G.
Tetrahedron 2008, 64, 1181. (v) Guan, X.-Y.; Jiang, Y.-Q.; Shi, M. Eur. J.
Org. Chem. 2008, 2150. (w) Liu, Y.-H.; Shi., M. Adv. Synth. Catal. 2008,
350, 122.
The ring-closure metathesis reaction of compound 3a was
examined. We employed the Grubbs’ second-generation
catalyst for the reaction. The transformation to 2,5-dihy-
dropyrrole 4a was achieved smoothly with an isolated yield
of 97% (entry 1). The optical purity of 4a was examined by
HPLC analysis using a Chiral-Pak IC column, which revealed
that the enantiomeric excess of 4a was 90%, the same value
as the starting material 2a. Thus, no significant loss of
enantiomeric excess was observed during the three-step
transformation. Thus, we have successfully provided a new
preparation of optically active 2-alkyl-substituted 2,5-dihy-
dropyrroles from chiral aza-Baylis-Hillman adducts which
are prepared in a few short steps from chiral sulfinimines.
Having established the methodology, we then examined
the synthesis of a pyrrolizidine alkaloid. Pyrrolizidine alka-
loids are important class of natural products, and due to their
unique biological activity, there have been many efforts to
synthesize these compounds.10 Among these alkaloids, we
chose (-)-trachelanthamidine as a synthetic target.11
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Our synthesis started from the preparation of the optical
active sulfinimine 6 (Scheme 2). This chiral sulfinimine was
prepared from 1,4-butanediol 5 in three steps. Monoprotec-
tion of 5 was carried out using the literature method to give
the diol mono-TBS ether in 83% yield,12 which was then
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Tetrahedron Lett. 2006, 47, 2141. (h) Scherer, A.; Gladysz, J. A. Tetrahedron
(10) Liddell, J. R. Nat. Prod. Rep. 2002, 773.
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Chem. Soc., Chem. Commun. 1986, 654. (b) Nagao, Y.; Dai, W.-M.; Ochiai,
M.; Tsukagoshi, S.; Fujita, E. J. Am. Chem. Soc. 1988, 110, 289. (c) Nagao,
Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.; Fujita, E. J. Org. Chem. 1990,
55, 1148. (d) Dieter, R. K.; Chen, N.; Arai, Y.; Kotani, T.; Koizumi, T. J.
Chem. Soc. Trans. 1 1994, 15. (e) Arai, Y.; Kontani, T.; Koizumi, T. Chem.
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Sato, T.; Nakamura, N.; Ikeda, M. J. Org. Chem. 1993, 58, 2360. (g) Murray,
A.; Proctor, G. R. Tetrahedron 1996, 52, 3757. (h) Jolly, R. S.; Livinghouse,
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(l) Craig, D.; Hyland, C. J. T.; Ward, S. E. Synlett 2006, 2142. (m) Ishibashi,
H.; Sasaki, M.; Taniguchi, T. Tetrahedron 2008, 64, 7771. For racemic
syntheses: (n) Mori, M.; Kanda, N.; Oda, I.; Ban, Y. Tetrahedron 1985, 41,
5465. (o) Ojima, I.; Donovan, R. J.; Eguchi, M.; Shay, W.; Ingallina, P.;
Korda, A.; Zeng, Q. Tetrahedron 1993, 49, 5431. (p) Eguchi, M.; Zeng, Q.;
Korda, A.; Ojima, I. Tetrahedron Lett. 1993, 34, 915. (q) Pandey, G.;
Lakshmaiah, G. Tetrahedron Lett. 1993, 30, 4861. Murray, A.; Proctor, G.
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K. J. Org. Chem. 1999, 64, 6771.
ꢀ
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Soc. 2008, 130, 5660. (k) Zheng, S.; Lu, X. Org. Lett. 2008, 10, 4481. (l) Pinto,
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X.-Y.; Shi, M. J. Org. Chem. 2009, 74, 1977. (n) Schuler, M.; Duvvuru, D.;
Retailleau, P.; Betzer, J.-F.; Marinetti, A. Org. Lett. 2009, 11, 4406.
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TABLE 1. Preparation of Optically Active 2,5-Dihydropyrroles 4
entry
R
2; yielda (%)
eeb (%)
3; yielda (%)
eeb (%)
4; yielda (%)
eeb (%)
1
2
3
4
5
6
7
Et
Pr
i-Pr
i-Bu
C5H11
c-C6H11
p-Tol
2a; 93
2b; 97
2c; 98
2d; 97
2e; 97
2f; 96
2g; 91
90
92
98
92
92
96
94
3a; 90
3b; 89
3c; 86
3d; 89
3e; 73
3f; 83
3g; 83
90
94
98
92
92
94
94
4a; 97
4b; 96
4c; 94
4d; 98
4e; 95
4f; 92
4g; 100
90
94
98
92
92
96
98
aIsolated yields. bEnantiomeric excesses determined by chiral HPLC analyses (ChiralPak-IC, AD).
SCHEME 2
SCHEME 3
converted into the aldehyde by Swern oxidation. Treatment
of the aldehyde with (-)-p-toluenesulfinamine gave the
desired chiral sulfinimine 6 in 64% yield (Scheme 2). The
Michael/imino-aldol domino reaction with 6 gave a diastereo-
meric mixture of chiral β-amino-R-phenylthiomethyl esters 7 in
85% yield. In the preparation of 7, it was possible to scale up
to 7 g in a one-pot manipulation. HPLC analysis revealed
that the diastereomeric ratio of 7 was 85:15, indicating that
the reaction progressed in a highly stereoselective manner.
As we reported previously,5d the formation of the mixture of
diastereomers was mainly caused by epimeric occurrence at
the C2 position; thus, the asymmetric induction from the
chiral of sulfinimine to the C3 position was almost 100%.
Treatment of 7 with m-CPBA resulted in the formation of the
corresponding sulfoxide which was treated under toluene
refluxing conditions, giving 8 in 76% yield. HPLC analysis of
8 revealed that the diastereomeric ratio was 97:3. Oxidation
and N-allylation of compound 8 was carried out in a manner
similar to that shown in Scheme 1, and compound 9 was
isolated in 78% yield in two steps. The ring-closure metath-
esis was achieved using the Grubbs’ second-generation cat-
alyst to afford chiral 2,5-dihydropyrrole 10 as a solid in 90%
yield. HPLC examination of compound 10 indicated that the
enantiomeric excess of 10 was 94%. Recrystallization of 10
enhanced the enantiomeric excess over 99%.
10% Pd/C catalyst gave 11 in 88% yield. Unfortunately, 11
was isolated as a 1:1 mixture of diastereomers. Thus, the
hydrogenation of 10 took place in a nonstereoselective
manner. To improve the stereoselectivity of the reaction,
we examined the hydrogenation of the deprotected com-
pound 12. The removal of the O-protecting group was
accomplished quantitatively by acidic treatment to give
alcohol 12. No pyrrole formation was observed during the
reaction. Free alcohol 12 was then reduced under standard
hydrogenation conditions, giving 13 in 98% yield over two
steps. Fortunately, the reduction of alcohol 12 progressed
stereoselectively, and the diastereomeric ratio of compound
13 was estimated to be 86:14. The major isomer was
separated by flash chromatography, and it was used for
the next reaction.
We next examined the reduction of compound 10
(Scheme 3).13 Hydrogenation of 10 in the presence of a
€
(13) Linda, A.; Minkkila, A.; Blay, G.; Jørgensen, K. A. Chem.;Eur. J.
2006, 12, 3472.
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JOCArticle
SCHEME 4
SCHEME 5
The configuration of compound 13 was determined in the
following way (Scheme 4). The major isomer of compound
13 was an oil and did not yield good crystals for X-ray
analysis. Then, we tried to isolate the minor isomer of 13 by
using the 1:1 mixture of 11. Compound 11 was desilylated by
treatment with TBAF to give the mixture of isomers of
compound 13 in 96% yield. Careful flash chromatography
of the mixture of 13 enabled the separation of the two
diastereomers of 13. The hydroxyl group of minor-13 was
protected by a TBS group, and minor-11 was prepared in
92% yield. Fortunately, minor-11 gave a good crystal that
was suitable for X-ray crystallographic analysis. The stere-
ochemistry of minor-11 was unambiguously determined to
be the 2,3-cis configuration. Thus, the major-11 and major 13
were determined to be 2,3-trans. As the absolute stereogenic
center at C2 should be S,5d the absolute configuration of
major-13 was determined to be 2S,3S.
According to the reports by Lamaty, the hydrogenation of
a 2,5-dihydropyrrole was expected to take place in a trans-
selective manner, although a N-SES group was necessary to
achieve high selectivity.14 In our case, even starting with an
N-tosylpyrrolidine, the high trans-selectivity in the hydro-
genation are observed. The stereoselectivity for the hydro-
genation step was very sensitive to the presence or absence of
an O-protecting group in the C2 aliphatic side chain. Epi-
merization at the C3 position during hydrogenation was less
likely.14 Thus, we believe that the trans-selectivity is coming
from the hydrogenation process itself. We are unsure of
precise origin of the trans-selectivity, but the free hydroxyl
group might be interacting with Pd/C surface which may
cause good steric bias to achieve the trans-selectivity during
the hydrogenation of dihydropyrrole.
the C2 side chain occurred simultaneously to give pyrolizi-
dinone 15 in 76% yield in one step. The reduction step has
already been reported in Nagao’s total synthesis, and com-
pound 15 was also known a compound.17 The specific
rotation of 15 was negative and had a value similar to the
reported data.17a Thus, we have achieved the formal synth-
esis of (-)-trachelanthamidine 16.
In conclusion, we have successfully developed the efficient
synthesis of chiral 2-alkyl-substituted 2,5-dihydropyrroles
from optically active aza-Baylis-Hillman adducts. The con-
version requires three steps and was achieved in high yields
with simple manipulation. No loss of enantiomeric excesses
was observed. This conversion was also successfully employed
in the preparation of an optically active pyrrolidine alkaloid.
The formal synthesis of (-)-trachelanthamidine was achieved
in 11 steps in 22% overall yield from a chiral sulfinimine. Dur-
ing the synthesis, the high trans-selectivity in the hydrogenation
was observed. Since optically active 2,5-dihydropyrroles are
regarded as potential precursors in many heterocyclic synth-
eses, our methodology will provide a convenient route in the
synthesis of these natural products.
Experimental Section
General Methods. All of the reactions in this paper were
performed under nitrogen atmosphere unless otherwise men-
tioned. CH2Cl2 was dried over CaH2 and distilled under nitro-
gen before use. High-resolution mass spectra (HRMS) were
performed by EI or FAB for ionization method.
Preparation of (S)-tert-Butyl 2-Methylene-3-(4-methylphenyl-
sulfonamido)pentanoate (2a). Typical Procedure. To a solution
of 1a (741.2 mg, 2.29 mmol) in CH2Cl2 (20 mL) was added
m-CPBA (77%, 567.7 mg, 2.52 mmol) at room temperature, and
the resulting mixture was stirred for 2 h. The reaction mixture
was washed with Na2S2O3-NaHCO3(aq) (10 mL xꢀ 2) and
brine (10 mL). The organic phase was separated and dried over
Na2SO4. After filtration, the solution was concentrated under
reduced pressure, and the residue was subjected flash chroma-
tography (hexane-EtOAc, 10:1) to give 2a in 93% yield (2.12 mmol)
as a colorless oil: enantiomeric purity was determined by HPLC
analysis (230 nm, 40 °C) tR 16.8 min (minor), tR 22.1 min (major)
To complete the total synthesis of (-)-trchelanthamidine,
obtained alcohol 13 was exposed to PDC to give the corre-
sponding carboxylic acid;15 subsequent esterification gave
diester 14 in 75% yield over two steps (Scheme 5). In the
esterification stage, the tert-butyl ester was also hydrolyzed
under the acidic conditions and converted to methyl ester in
14. The N-tosyl protecting group was removed on treatment
with magnesium metal in MeOH. Recently, this method has
been widely used for the deprotection of the tosyl group
because of the mild conditions.16 In our case, intramolecular
cyclization between the deprotected amine and the ester in
(14) Declerck, V.; Allouchi, H.; Martinez, J.; Lamaty, F. J. Org. Chem.
2007, 72, 1518.
(15) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 5, 399.
(16) Pattenden, L. C.; Adams, H.; Smith, S. A.; Harrity, J. P. A.
Tetrahedron 2008, 64, 2951.
(17) (a) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Shiro, M. Tetrahedron 1990,
46, 6361. (b) Kraus, G.; Neuenschwander, K. Tetrahedron Lett. 1980, 21,
3841.
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[Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/i-PrOH, 80/20, 0.70
mL/min] as 90% ee; [R]D þ7.4 (CHCl3, c 1.04); 1H NMR
(CDCl3, 500 MHz) δ 7.66 (d, 2 H, J = 7.9 Hz), 7.23 (d, 2 H,
J = 7.9 Hz), 5.83 (s, 1 H), 5.53 (d, 1 H, 9.8 Hz), 5.37 (s, 1 H), 3.88
(dd, 1 H, J = 7.6, 17.0 Hz), 2.40 (s, 3 H), 1.56-1.64 (m, 2 H),
1.41 (s, 9 H), 0.82 (t, 3 H, J = 7.3 Hz); 13C NMR (CDCl3, 126
MHz) δ 164.8, 142.9, 139.6, 138.2, 129.4, 127.1, 126.5, 81.5, 58.9,
28.4, 27.9, 21.4, 10.8; HRMS (EI M) m/z 339.1504, calcd for
C17H25NO4S 339.1504.
(S)-tert-Butyl 2-methylene-3-(4-methylphenylsulfonamido)hexa-
noate (2b): colorless oil; enantiomeric purity was determined by
HPLC analysis (230 nm, 40 °C) tR 10.2 min (minor), tR 14.6 min
(major) [Chiralpak IC (0.46 cm ꢀ 25 cm)) hexane/i-PrOH, 80/20,
1.00 mL/min] as 92% ee; [R]D þ10.0 (CHCl3, c 0.99); 1H NMR
(CDCl3, 500 MHz) δ7.66 (d, J= 8.2 Hz, 2 H), 7.22 (d, J =8.1Hz,
2 H), 5.80 (s, 1 H), 5.57 (d, J = 9.5 Hz, 1 H), 5.38 (s, 1 H), 3.99 (dd,
J = 7.5, 17.2 Hz, 1 H), 2.39 (s, 3 H), 1.70-1.15 (m, 4 H), 1.41 (s,
9 H), 0.84 (t, J = 7.3 Hz, 3 H); 13C NMR (CDCl3, 126 MHz) δ
164.7, 142.9, 139.9, 138.1, 129.3, 127.1, 126.1, 81.4, 56.8, 37.3, 27.9,
21.4, 19.2, 13.4. Anal. Calcd for C18H27NO4S: C, 61.16; H, 7.70;
N, 3.96. Found: C, 60.93; H,7.32; N, 3.64.
1.78-1.44 (s, 5 H), 1.41 (s, 9 H), 1.13 (m, 3 H), 0.94-0.72 (m, 2 H);
13C NMR (101 MHz, CDCl3) δ 165.1, 142.8, 138.5, 138.3, 129.3,
127.2, 127.1, 81.5, 62.6, 40.8, 30.3, 29.8, 28.0, 26.2, 25.9, 25.8, 21.5;
HRMS (EI M) m/z 393.1984, calcd for C21H31NO4S 393.1974.
(S)-tert-Butyl 2-((4-methylphenylsulfonamido)(p-tolyl)methyl)-
acrylate (2g): yellow semisolid; enantiomeric purity was deter-
mined by HPLC analysis (230 nm, 40 °C) tR 11.3 min (minor), tR
12.3 min (major) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/
i-PrOH, 80/20, 1.00 mL/min] as 94% ee; [R]D þ23.4 (CHCl3,
c 1.13); 1H NMR (CDCl3, 500 MHz) δ 7.67 (d, J = 8.1 Hz, 1 H),
7.22 (d, J = 8.0 Hz, 1 H), 7.01 (s, 4 H), 6.09 (s, 1 H), 5.67 (s, 1 H),
5.63 (d, J = 8.9 Hz, 1 H), 5.22 (d, J = 8.9 Hz, 1 H), 2.40 (s, 3 H),
2.27 (s, 3 H), 1.30 (s, 9 H); 13C NMR (CDCl3, 126 MHz) δ 164.6,
143.2, 140.0, 137.8, 137.2, 136.0, 129.4, 129.1, 127.2, 126.6, 126.3,
81.7, 58.9, 27.8, 21.4, 20.9; HRMS (EI M) m/z 401.1655, calcd for
C22H27NO4S 401.1661.
Preparation of (S)-tert-Butyl 3-(N-Allyl-4-methylphenylsulfon-
amido)-2-methylenepentanoate (3a). Typical Procedure. A mix-
ture of 2a (678.2 mg, 2.00 mmol), allyl bromide (0.19 mL, 2.20
mmol), and K2CO3 (830.7 mg, 6.00 mmol) in DMF (2.0 mL) was
stirred at room temperature for 1 h. Additional allyl bromide (0.08
mL) was added, and the reaction mixture was stirred for an
additional 5 h. Water (10 mL) was added, and the resulting
aqueous solution was extracted with ether (10 mL ꢀ 3). The
organic phase was combined, washed with brine (10 mL), and
dried over Na2SO4. After filtration, the ether solution was con-
centrated by rotary evaporator and the residue was subjected to
flash chromatography (hexane-EtOAc 10:1) to give 3a in 90%
yield (681.4 mg): colorless oil; enantiomeric purity was determined
by HPLC analysis (230 nm, 40 °C) tR 23.4 min (minor), tR 24.7
min (major) [CHIRALPAK IC (0.46 cm ꢀ 25 cm) hexane/
i-PrOH, 80/20, 0.70 mL/min] as 90% ee: [R]D -48.4 (CHCl3, c
1.06); 1H NMR (CDCl3, 500 MHz) δ 7.71 (d, J = 8.1 Hz, 2 H),
7.23 (d, J = 8.0 Hz, 2 H), 6.23 (s, 1 H), 5.87-5.68 (m, 1 H), 5.63 (s,
1 H), 5.10 (d, J = 17.2 Hz, 1 H), 5.04 (d, J = 10.1 Hz, 1 H), 4.77 (t,
J = 7.5 Hz, 1 H), 3.86-3.69 (m, 2 H), 2.39 (s, 3 H), 1.94-1.70 (m,
2 H), 1.42(s, 9H), 0.87(t, J= 7.3 Hz, 3 H); 13CNMR(CDCl3, 126
MHz) δ 165.7, 142.7, 139.8, 138.3, 135.8, 129.2, 127.7, 126.2,
117.2, 81.1, 58.9, 47.8, 27.9, 25.0, 21.4, 11.4; HRMS (EI M) m/z
379.1817, calcd for C20H29NO4S 379.1817.
(S)-tert-Butyl 3-(N-allyl-4-methylphenylsulfonamido)-2-methyl-
enehexanoate (3b): colorless oil; enantiomeric purity was deter-
mined by HPLC analysis (230 nm, 40 °C) tR 13.0 min (minor), tR
13.8 min(major) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/i-PrOH,
80/20, 0.70 mL/min] as 94% ee; [R]D -41.4 (CHCl3, c 1.02); 1H
NMR (CDCl3, 400 MHz) δ 7.71 (d, J = 8.2 Hz, 2 H), 7.23 (d, J =
7.9 Hz, 2 H), 6.20 (s, 1 H), 5.98-5.68 (m, 1 H), 5.61 (s, 1 H), 5.10
(td, J = 1.3, 17.2 Hz, 1 H), 5.04 (td, J = 1.3, 10.1 Hz, 1 H), 4.88 (t,
J = 7.5 Hz, 1 H), 3.79 (d, J =6.5Hz, 2 H), 2.39 (s, 3H), 2.01-1.55
(m, 2 H), 1.43 (s, 9 H), 1.35-1.19 (m, 2 H), 0.88 (t, J = 7.3 Hz,
3 H); 13C NMR (CDCl3, 101 MHz) δ 165.6, 142.7, 140.1, 138.2,
135.7, 129.1, 127.6, 126.0, 117.1, 81.1, 57.0, 47.7, 33.9, 27.9, 21.4,
19.8, 13.7; HRMS (EIþ M) m/z 393.1974, calcd for C21H31NO4S
393.1974.
(S)-tert-Butyl 3-(N-allyl-4-methylphenylsulfonamido)-4-meth-
yl-2-methylenepentanoate (3c): colorless oil; enantiomeric purity
was determined by HPLC analysis (230 nm, 40 °C) tR 13.2 min
(minor), tR 16.1 min (major) [CHIRALPAK IC (0.46 cm ꢀ 25
cm) hexane/i-PrOH, 80/20, 1.00 mL/min] as 98% ee; [R]D -48.9
(CHCl3, c 0.99); 1H NMR (CDCl3, 500 MHz) δ 7.69 (d, J = 8.0
Hz, 2 H), 7.20 (d, J = 7.8 Hz, 2 H), 6.29 (s, 1 H), 6.20-6.17 (m,
1 H), 5.86-5.74 (m, 1 H), 5.73 (s, 1 H), 5.10 (d, J = 17.2 Hz, 1 H),
5.02 (d, J = 10.1 Hz, 1 H), 4.53 (d, J = 11.2 Hz, 1 H), 3.92-3.74
(m, 2 H), 2.38 (s, 3 H), 2.35-2.24 (m, 1 H), 1.41 (s, 9 H), 1.05 (d,
J = 6.4 Hz, 3 H), 0.83 (d, J = 6.4 Hz, 3 H); 13C NMR (CDCl3,
126 MHz) δ 165.8, 142.6, 139.3, 138.3, 135.8, 129.1, 127.9, 127.6,
117.2, 81.0, 63.5, 47.8, 29.2, 27.9, 21.4, 20.6, 20.4; HRMS (FAB
M þ 1) m/z 394.2054, calcd for C21H32NO4S 394.2052.
(S)-tert-Butyl 4-methyl-2-methylene-3-(4-methylphenylsulfon-
amido)pentanoate (2c): colorless oil; enantiomeric purity was
determined by HPLC analysis (230 nm, 40 °C) tR 12.2 min
(minor), tR 16.0 min (major) [Chiralpak IC (0.46 cm ꢀ 25 cm)
hexane/i-PrOH, 80/20, 1.00 mL/min] as 98% ee; [R]D þ8.0
1
(CHCl3, c 1.00); H NMR (CDCl3, 500 MHz) δ 7.64 (d, J =
8.1 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 5.79 (s, 1 H), 5.56 (d, J =
10.0 Hz, 1 H), 5.27 (s, 1 H), 3.59 (t, J = 9.4 Hz, 1 H), 2.39 (s, 3 H),
2.12-1.71 (m, 1 H), 1.41 (s, 9 H), 0.97 (d, J = 6.6 Hz, 3 H), 0.74
(d, J = 6.7 Hz, 3 H); 13C NMR (CDCl3, 126 MHz) δ 165.1,
142.8, 138.8, 138.2, 129.3, 127.2, 127.0, 81.5, 63.6, 31.8, 27.9,
21.4, 19.9, 19.4; HRMS (EI M) m/z 353.1662, calcd for
C18H27NO4S 353.1661.
(S)-tert-Butyl 5-methyl-2-methylene-3-(4-methylphenylsulfon-
amido)hexanoate (2d): colorless oil; enantiomeric purity was
determined by HPLC analysis (230 nm, 40 °C) tR 8.1 min
(minor), tR 12.9 min (major) [Chiralpak IC (0.46 cm ꢀ 25 cm)
hexane/i-PrOH, 80/20, 1.00 mL/min] as 92% ee; [R]D þ14.8
(CHCl3, c 1.01); 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, J = 8.3
Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 5.78 (s, 1 H), 5.49 (d, J = 9.8
Hz, 1 H), 5.38 (s, 1 H), 4.13-3.99 (m, 1 H), 2.39 (s, 3 H),
1.73-1.47 (m, 2 H), 1.41 (s, 9 H), 1.38-1.28 (m, 1 H), 0.85 (d,
J = 6.4 Hz, 3 H), 0.84 (d, J = 6.4 Hz, 3 H); 13C NMR (CDCl3,
101 MHz) δ 164.8, 142.9, 140.1, 138.2, 129.3, 127.1, 126.0, 81.5,
55.4, 44.4, 27.9, 24.5, 22.4, 21.8, 21.4; HRMS (EI M) m/z
367.1819, calcd for C19H29NO4S 367.1817.
(S)-tert-Butyl 2-methylene-3-(4-methylphenylsulfonamido)octa-
noate (2e): colorless oil; enantiomeric purity was determined by
HPLC analysis (230 nm, 40 °C) tR 8.6 min (minor), tR 12.8 min
(major) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/i-PrOH, 80/20,
1
1.00 mL/min] as 92% ee: [R]D þ8.4 (CHCl3, c 1.01); H NMR
(CDCl3, 400 MHz) δ7.66 (d, J = 8.1 Hz, 2 H), 7.23 (d, J = 8.0 Hz,
2 H), 5.81 (s, 1 H), 5.55 (d, J = 9.4 Hz, 1 H), 5.38 (s, 1 H), 3.96 (dt,
J = 7.5, 9.7 Hz, 1 H), 2.39 (s, 3 H), 1.72-1.45 (m, 2 H), 1.41 (s, 9
H), 1.34-1.08 (m, 6 H), 0.83 (t, J = 6.3 Hz, 3 H); 13C NMR
(CDCl3, 101 MHz) δ164.8, 142.9, 140.0, 138.1, 129.3, 127.1, 126.1,
81.4, 57.1, 35.2, 31.1, 27.9, 25.7, 22.3, 21.4, 13.9. Anal. Calcd for
C20H31NO4S: C, 62.96; H, 8.19; N, 3.67. Found: C, 63.04; H,8.19;
N, 3.63.
(S)-tert-Butyl 2-(cyclohexyl(4-methylphenylsulfonamido)methyl)-
acrylate (2f): colorless oil; enantiomeric purity was determined by
HPLC analysis (230 nm, 40 °C) tR 10.1 min (minor), tR 12.6 min
(major) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/i-PrOH, 80/20,
1.00 mL/min] as 96% ee; [R]D þ19.2 (CHCl3, c1.09); 1HNMR(400
MHz, CDCl3) δ7.64 (d, J = 8.3 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H),
5.77 (d, J = 1.1 Hz, 1 H), 5.59 (d, J = 10.1 Hz, 1 H), 5.24 (s, 1 H),
3.65 (t, J = 9.6 Hz, 1 H), 2.39 (s, 3 H), 2.05 (d, J = 13.0 Hz, 1 H),
3582 J. Org. Chem. Vol. 75, No. 11, 2010

Ishikawa et al.
JOCArticle
(S)-tert-Butyl 3-(N-allyl-4-methylphenylsulfonamido)-5-meth-
yl-2-methylenehexanoate (3d): colorless oil; enantiomeric purity
was determined by HPLC analysis (230 nm, 40 °C) tR 8.0 min
(minor), tR 8.4 min (major) [Chiralpak IC (0.46 cm ꢀ 25 cm)
hexane/i-PrOH, 80/20, 1.00 mL/min] as 92% ee; [R]D -40.8
(CHCl3, c 1.00); 1H NMR (CDCl3, 400 MHz) δ 7.70 (d, J = 8.1
Hz, 2 H), 7.23 (d, J = 8.3 Hz, 2 H), 6.17 (s, 1 H), 6.00-5.65 (m,
J = 6.1, 10.2, 16.4 Hz, 1 H), 5.55 (s, 1 H), 5.11 (d, J = 17.2 Hz, 1
H), 5.05 (d, J = 10.1 Hz, 1 H), 4.98 (t, J = 7.2 Hz, 1 H),
3.88-3.70 (m, 2 H), 2.39 (s, 3 H), 1.76-1.65 (m, 1 H), 1.57-1.46
(m, 2 H), 1.44 (s, 9 H), 0.90 (d, J = 6.1 Hz, 3 H), 0.87 (d, J = 6.1
Hz, 3 H); 13C NMR (CDCl3, 101 MHz) δ 165.6, 142.7, 140.2,
138.1, 135.9, 129.2, 127.6, 125.8, 117.0, 81.1, 55.4, 47.6, 40.7,
27.9, 24.7, 22.6, 22.0, 21.4. Anal. Calcd for C22H33NO4S: C,
64.83; H, 8.16; N, 3.44. Found: C, 64.85; H, 8.22; N, 3.65.
(S)-tert-Butyl 3-(N-allyl-4-methylphenylsulfonamido)-2-methyl-
eneoctanoate (3e): colorless oil; enantiomeric purity was deter-
mined by HPLC analysis (230 nm, 40 °C) tR 12.2 min (major), tR
21.0 min (minor) [Chiralpak AD (0.46 cm ꢀ 25 cm) hexane/i-
PrOH, 98/2, 1.00 mL/min] as 92% ee; [R]D -46.6 (CHCl3, c 0.99);
1H NMR (CDCl3, 500 MHz) δ 7.71 (d, J = 8.1 Hz, 2 H), 7.23 (d,
J = 8.0 Hz, 2 H), 6.21 (s, 1 H), 5.86-5.68 (m, J = 6.3, 16.5 Hz, 1
H), 5.61 (s, 1 H), 5.10 (d, J = 17.2Hz, 1 H), 5.04 (d, J = 10.1 Hz, 1
H), 4.83 (t, J = 7.4 Hz, 1 H), 3.79 (d, J = 6.0 Hz, 2 H), 2.39 (s, 3
H), 1.91-1.60 (m, 2 H), 1.43 (s, 9 H), 1.36-1.15 (m, 6 H),
1.04-0.80 (m, 3 H); 13C NMR (CDCl3, 126 MHz) δ 166.0,
142.6, 140.4, 138.5, 135.8, 129.2, 127.6, 126.0, 117.2, 81.1, 57.5,
47.7, 31.8, 31.4, 27.9, 26.2, 22.4, 21.4, 13.9; HRMS (FAB M þ 1)
m/z 422.2363, calcd for C23H36NO4S 422.2365.
(S)-tert-Butyl 2-((N-allyl-4-methylphenylsulfonamido)(cyclohexyl)-
methyl)acrylate (3f): white solid; mp 108-109 °C; the enantiomeric
purity was determined by HPLC analysis (230 nm, 40 °C) tR 8.8 min
(minor), tR 9.4 min (major) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/
i-PrOH, 80/20, 1.00 mL/min] as 94% ee; [R]D -34.8 (CHCl3, c 1.04);
1H NMR (400 MHz, CDCl3) δ7.68 (d, J= 8.3 Hz, 2 H), 7.20 (d, J=
8.0 Hz, 2 H), 6.27 (d, J = 0.9 Hz, 1 H), 5.76 (dddd, J = 5.6, 7.3, 10.1,
17.3 Hz, 1 H), 5.70 (s, 1 H), 5.10 (dd, J= 1.4, 17.2 Hz, 1 H), 5.02 (dd,
J = 1.3, 10.1 Hz, 1 H), 4.63 (d, J = 11.2 Hz, 1 H), 3.86 (dd, J = 7.3,
16.3 Hz, 1 H), 3.77 (dd, J = 5.6, 16.3 Hz, 1 H), 2.38 (s, 3 H),
2.05-1.48 (m, 7 H), 1.41 (s, 9 H), 1.24-0.79 (m, 4 H); 13CNMR(101
MHz, CDCl3) δ 165.9, 142.6, 139.0, 138.3, 135.8, 129.1, 127.9, 127.6,
117.1, 81.0, 62.4, 47.7, 38.4, 30.8, 30.6, 27.9, 26.3, 26.1, 25.9, 21.4;
HRMS(FABMþ 1) m/z434.2365, calcd for C24H36NO4S 434.2365.
(S)-tert-Butyl 2-((N-allyl-4-methylphenylsulfonamido)(p-tolyl)-
methyl)acrylate (3g): colorless oil; enantiomeric purity was deter-
mined by HPLC analysis (230 nm, 40 °C) tR 16.7 min (major), tR
38.1 min (minor) [Chiralpak AD (0.46 cm ꢀ 25 cm) hexane/-
i-PrOH, 98/2, 1.00 mL/min] as 94% ee; [R]D þ141.7 (CHCl3, c
1.04); 1H NMR (CDCl3, 500 MHz) δ 7.71 (d, J = 8.1 Hz, 2 H),
7.26 (d, J = 8.5 Hz, 2 H), 7.01 (d, J = 7.7 Hz, 2 H), 6.86 (d, J = 7.9
Hz, 2 H), 6.31 (s, 1 H), 6.03 (s, 1H), 5.61 (s, 1 H), 5.41-5.08 (m,
1 H), 4.84 (d, J = 19.0 Hz, 1 H), 4.81 (d, J = 11.2 Hz, 1 H), 3.81
(dd, J= 7.3, 16.0 Hz, 1 H), 3.73 (dd, J=5.2, 16.0Hz, 1H), 2.43(s,
3 H), 2.29 (s, 3 H), 1.26 (s, 9 H); 13C NMR (CDCl3, 126 MHz) δ
165.1, 143.1, 140.9, 137.9, 137.6, 134.5, 134.4, 129.3, 129.0, 128.5,
127.5, 126.0, 117.4, 81.2, 61.8, 48.3, 27.7, 21.5, 21.0; HRMS(EI M)
m/z 441.1959, calcd for C25H31NO4S 441.1974.
(CDCl3, 500 MHz) δ 7.71 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 8.0
Hz, 2 H), 6.48 (s, 1 H), 4.76 (s, 1 H), 4.20 (s, 2 H), 2.42 (s, 3 H),
2.02 (dqd, J = 4.3, 7.4, 14.7 Hz, 1 H), 1.91 (dqd, J = 3.9, 7.3,
14.5 Hz, 1 H), 1.45 (s, 9 H), 0.83 (t, J = 7.4 Hz, 3 H); 13C NMR
(CDCl3, 126 MHz) δ 161.6, 143.5, 135.9, 135.4, 134.8, 129.7,
127.3, 81.5, 66.8, 55.2, 28.0, 26.7, 21.5, 7.6; HRMS (EI M) m/z
351.1503, calcd for C18H25NO4S 351.1504.
(S)-tert-Butyl 2-propyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-car-
boxylate (4b): brown oil; enantiomeric purity was determined by
HPLC analysis (230 nm, 40 °C) tR 10.0 min (major), tR 11.7 min
(minor) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/i-PrOH, 80/20,
1.00 mL/min] as 92% ee: [R]D þ104.1 (CHCl3, c 1.02); 1H NMR
(CDCl3, 500 MHz) δ 7.70 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 6.8
Hz, 2 H), 6.44 (s, 1 H), 4.75 (s, 1 H), 4.20 (s, 2 H), 2.41 (s, 3 H),
2.08-1.63 (m, 2 H), 1.44 (s, 9 H), 1.43-1.14 (m, 2 H), 0.90 (t, J =
7.3 Hz, 3 H); 13C NMR (CDCl3, 126 MHz) δ 161.5, 143.5, 136.5,
135.0, 134.6, 129.7, 127.2, 81.4, 66.0, 54.9, 36.0, 27.9, 21.4, 16.9,
14.0; HRMS (EI M) m/z 365.1661, calcd for C19H27NO4S
365.1661.
(S)-tert-Butyl 2-isopropyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-
carboxylate (4c): brown oil; enantiomeric purity was determined
by HPLC analysis (230 nm, 40 °C) tR 9.9 min (major), tR 11.0
min (minor) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/i-PrOH,
80/20, 1.00 mL/min] as 98% ee: [R]D þ105.6 (CHCl3, c 0.63); 1H
NMR (CDCl3, 400 MHz) δ 7.68 (d, J = 8.1 Hz, 2 H), 7.27 (d,
J = 8.1 Hz, 2 H), 6.39 (s, 1 H), 4.69 (s, 1 H), 4.20 (dd, J = 2.7,
18.2 Hz, 1 H), 4.07 (dd, J = 4.1, 18.2 Hz, 1 H), 2.40 (s, 3 H), 2.14
(dtd, J = 3.2, 6.9, 13.8 Hz, 1 H), 1.43 (s, 9 H), 1.07 (d, J = 6.9 Hz,
3 H), 0.88 (d, J = 6.9 Hz, 3 H); 13C NMR (CDCl3, 101 MHz) δ
161.8, 143.5, 136.9, 135.6, 134.4, 129.5, 127.4, 81.3, 71.3, 55.7,
33.0, 27.8, 21.4, 19.3, 17.0; HRMS (EI M) m/z 365.1662, calcd
for C19H27NO4S 365.1661.
(S)-tert-Butyl 2-isobutyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-
carboxylate (4d): brown oil; enantiomeric purity was determined
by HPLC analysis (230 nm, 40 °C) tR 8.9 min (major), tR 11.3
min (minor) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/i-PrOH,
80/20, 1.00 mL/min] as 92% ee: [R]D þ128.4 (CHCl3, c 0.99); 1H
NMR (CDCl3, 400 MHz) δ 7.68 (d, J = 8.3 Hz, 2 H), 7.28 (d,
J = 8.5 Hz, 2 H), 6.37 (s, 1 H), 4.78-4.69 (m, 1 H), 4.21 (s, 2 H),
2.41 (s, 3 H), 1.90 (tq, J = 6.4, 12.8 Hz, 1 H), 1.74-1.54 (m, 2 H),
1.44 (s, 9 H), 1.01 (d, J = 6.5 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H);
13C NMR (CDCl3, 101 MHz) δ 161.6, 143.6, 138.0, 134.9, 134.5,
129.7, 127.4, 81.4, 68, 65.1, 54.6, 43.1, 28.0, 24.2, 23.9, 22.5, 21.5.
Anal. Calcd. for C20H29NO4S: C, 63.30; H, 7.70; N, 3.69.
Found: C, 63.47; H, 7.58; N, 3.77.
(S)-tert-Butyl 2-pentyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-car-
boxylate (4e): brown oil; enantiomeric purity was determined
by HPLC analysis (230 nm, 40 °C) tR 8.7 min (major), tR 10.4
min (minor) [CHIRALPAK IC (0.46 cm ꢀ 25 cm) hexane/
i-PrOH, 80/20, 1.00 mL/min] as 92% ee: [R]D þ118.4 (CHCl3, c
1.01); 1H NMR (CDCl3, 400 MHz) δ 7.70 (d, J = 8.1 Hz, 2 H),
7.30 (d, J = 8.5 Hz, 2 H), 6.46 (s, 1 H), 4.80-4.57 (br, 1 H), 4.20
(s, 1 H), 2.41 (s, 3 H), 2.08-1.75 (m, 2 H), 1.45 (s, 9 H),
1.40-1.03 (m, 6 H), 0.86 (t, J = 6.5 Hz, 3 H); 13C NMR
(CDCl3, 101 MHz) δ 161.5, 143.5, 136.4, 135.1, 134.7, 129.7,
127.3, 81.4, 66.1, 55.0, 33.6, 31.6, 27.9, 23.0, 22.4, 21.4, 13.9;
HRMS (EI M) m/z 393.1969, calcd for C21H31NO4S 393.1974.
(S)-tert-Butyl 2-cyclohexyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-
carboxylate (4f): brown solid; mp 88-89 °C; enantiomeric
purity was determined by HPLC analysis (230 nm, 40 °C) tR
9.9 min (major), tR 10.6 min (minor) [Chiralpak IC (0.46 cm ꢀ25
cm) hexane/i-PrOH, 80/20, 1.00 mL/min] as 96%ee. [R]D þ119.4
(CHCl3, c 0.68); 1H NMR (270 MHz, CDCl3) δ 7.67 (d, J = 8.3
Hz, 2H), 7.26 (d, J = 7.9 Hz, 2 H), 6.36-6.33 (m, 1H), 4.65 (t,
J = 2.8 Hz, 1 H), 4.18 (ddd, J = 0.8, 2.7, 18.2 Hz, 1H), 4.04 (ddd,
J = 1.8, 4.1, 18.3 Hz, 1 H), 2.39 (s, 3 H), 1.57-1.85 (m, 6 H), 1.42
(s, 9 H), 1.57-0.99 (m, 5 H); 13C NMR (CDCl3, 101 MHz) δ
161.9, 143.5, 136.9, 135.4, 129.9, 129.5, 127.1, 81.3, 71.0, 55.7,
Preparation of (S)-tert-Butyl 2-Ethyl-1-tosyl-2,5-dihydro-1H-
pyrrole-3-carboxylate (4a). Grubbs’ catalyst (70.6 mg, 0.084
mmol) was added to a solution of 3a (633.6 mg, 1.67 mmol) in
CH2Cl2 (167 mL), and the reaction mixture was stirred at
refluxing temperature for 1 h. The resulting solution was con-
centrated in vacuo, and the residue was subjected to flash chro-
matohgraphy (hexane-EtOAc 10:1) to give 4a in 97% yield.
(566.0 mg): brown oil; enantiomeric purity was determined by
HPLC analysis (230 nm, 40 °C) tR 27.5 min (major), tR 32.5 min
(minor) [Chiralpak IC (0.46 cm ꢀ 25 cm) hexane/i-PrOH, 80/20,
0.70 mL/min] as 90% ee: [R]D þ93.9 (CHCl3, c 1.02); 1H NMR
J. Org. Chem. Vol. 75, No. 11, 2010 3583

Ishikawa et al.
JOCArticle
43.1, 29.9, 27.9, 27.8, 27.6, 26.4, 26.2, 21.4; HRMS (EI M) m/z
405.1972. Calcd for C22H31NO4S 405.1974.
Preparation of (2R,3S)-tert-Butyl 6-(tert-Butyldimethylsilyl-
oxy)-3-((S)-4-methylphenylsulfinamido)-2-(phenylthiomethyl)hex-
anoate (7). Under nitrogen atmosphere, methylmagnesium bro-
mide (13.59 mL, 19.02 mmol, 1.4 M in toluene/tetrahydrofuran
(75:25)) was added to a solution of thiophenol (1.62 mL, 15.85
mmol) in CH2Cl2 (40 mL) at -50 °C, and the mixture was stirred
for 10 min. tert-Butyl acrylate (2.32 mL, 15.85 mmol) and a
solution of sulfinimine (5.3831 g, 15.85 mmol) in CH2Cl2 (13 mL)
were added to the mixture at -50 °C, and the mixture was stirred
at -50 °C for 37 h. Saturated NH4Cl(aq) (50 mL) was added to
the mixture and the mixture allowed to warm to 0 °C for 10 min.
The organic phase was separated, and the water phase was
extracted with EtOAc (100 mL ꢀ 3). The organic phase was
combined, washed with brine (50 mL), and dried over anhydrous
Na2SO4. After filtration, the resulting solution was concentrated
under reduced pressure, and crude residue was purified by flash
chromatography (hexane-EtOAc 50:1, 20:1, 10:1, then 5:1) to
give 7 in 85% yield as a mixture of the two diastereoisomers
(7.7611 g): pale yellow oil; HPLC analysis revealed the syn/anti
ratio was 85:15. syn-7, major isomer, was separated by further
careful chromatography: [R]D þ42.8 (CHCl3, c 1.02); 1H NMR
(400 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2 H), 7.37-7.17 (m,
7 H), 4.73 (d, J = 8.8 Hz, 1 H), 3.67-3.58 (m, 3 H), 3.05 (d, J =
5.3 Hz, 1 H), 3.02 (d, J = 5.3 Hz, 1 H), 2.77 (td, J = 6.0, 7.4 Hz,
1 H), 2.40 (s, 3 H), 1.80-1.48 (m, 4 H), 1.42 (s, 9 H), 0.88 (s, 9 H),
0.04 (s, 3H), 0.04 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 171.7,
142.5, 141.4, 135.8, 129.6, 129.0, 126.6, 125.7, 125.4, 81.9, 62.7,
55.8, 51.2, 33.6, 29.4, 25.8, 25.7, 21.3, 21.2, 18.2, -5.2. Anal.
Calcd. for C30H47NO4S2Si: C, 62.35; H, 8.20; N, 2.42. Found: C,
62.47; H, 8.26; N, 2.46.
(S)-tert-Butyl 2-p-tolyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-car-
boxylate (4g): brown solid; mp 121-122 °C; enantiomeric purity
was determined by HPLC analysis (230 nm, 40 °C) tR 19.4 min
(major), tR 32.9 min (minor) [Chiralpak IC (0.46 cm ꢀ 25 cm)
hexane/i-PrOH, 80/20, 1.00 mL/min] as 98% ee: [R]D -46.6
(CHCl3, c 0.99); 1H NMR (CDCl3, 500 MHz) δ 7.40 (d, J = 7.9
Hz, 2 H), 7.11 (d, J = 7.9 Hz, 2 H), 7.07 (d, J = 7.7 Hz, 2 H), 7.01
(d, J = 7.7 Hz, 2 H), 6.69 (s, 1 H), 5.62 (s, 1 H), 4.45 (d, J = 16.8
Hz, 1 H), 4.31 (dd, J = 5.6, 16.7 Hz, 1 H),2.35 (s, 2 H), 2.30 (s, 3
H), 1.25 (s, 9 H); 13C NMR (CDCl3, 126 MHz) δ 161.0, 142.9,
137.4, 137.3, 136.5, 135.7, 134.4, 129.2, 128.6, 127.6, 127.0, 81.4,
68.7, 54.6, 27.7, 21.3, 21.0; HRMS (EI M) m/z 413.1642, calcd
for C23H27NO4S 413.1661.
Preparation of (S)-N-(4-(tert-Butyldimethylsilyloxy)butylidene)-
4-methylbenzenesulfinamide (6). Under nitrogen atmosphere, a
solution of 1,4-butanediol 5 (9.013 g, 100.0 mmol) in cyclopentyl
methyl ether (CPME, 25 mL) was added to a solution of t-BuOK
(11.225 g, 100.0 mmol) in CPME (150 mL) at 0 °C. After being
stirred for 30 min, a solution of TBSCl (15.088 g, 100.0 mmol) in
CPME (25 mL) was added. The reaction mixture was stirred for 6 h
at room temperature. Water (50 mL) was added to the solution, and
the organic phase was separated. The water phase was extracted
with CPME (50 mL ꢀ 3). The organic phase was combined and
dried over Na2SO4. After filtration and concentration in vacuo, the
residue was subjected to flash chromatography (hexane-EtOAc
20:1 then 5:1) to give 4-(tert-butyldimethylsilyl)oxy-1-butanol in
83% yield (16.885 g): colorless oil; 1H NMR (CDCl3, 500 MHz) δ
3.57-3.69 (m, 4 H), 2.78-2.82 (br, 1 H, J= 6.8 Hz), 1.57-1.66 (m,
4 H), 0.88 (s, 9 H), 0.05 (s, 6 H); 13C NMR (CDCl3, 126 MHz) δ
63.4, 62.7, 30.2, 29.9, 25.9, 25.7, 18.3, -5.4.
Under nitrogen atmosphere, DMSO (4.58 mL, 64.48 mmol)
was added slowly over 10 min to a solution of oxalyl chloride
(3.32 mL, 38.69 mmol) in CH2Cl2 (119 mL) at -50 °C. 4-(tert-
Butyldimethylsilyl)oxy-1-butanol (6.5886 g, 32.24 mmol) in
CH2Cl2 (10 mL) was added to the solution, and the resulting
solution was stirred at -50 °C for 10 min. Et3N (9.82 mL, 70.93
mmol) was added to the solution, and the reaction mixture was
stirred at -50 °C for 10 min and gradually warmed to room
temperature over 1.5 h. Water (60 mL) was added to the reaction
mixture, and the organic phase was separated. The water phase
was extracted with CH2Cl2 (60 mL ꢀ 2). The organic phase was
combined, washed with brine (30 mL), and dried over Na2SO4.
After filtration, concentration of the filtrate in vacuo gave crude
4-(tert-butyldimethylsilyl)oxybutraldehyde, which was used for
the next stage without further purification: 96% yield (6.236 g);
pale yellow oil; 1H NMR (CDCl3, 270 MHz) δ 9.72 (t, 1 H, J =
1.7 Hz), 3.65 (t, 2 H, J = 6.0 Hz), 2.50 (dt, 2 H, J = 1.7, 7.0 Hz),
1.80-1.91 (m, 2 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
Preparation of (3S)-tert-Butyl 6-(tert-butyldimethylsilyloxy)-
2-methylene-3-(4-methylphenylsulfinamido)hexanoate (8). m-CPBA
(75 wt %, 1.1568 g, 5.03 mmol) was added to a solution of 7 (2.6325
g, 4.56 mmol) in CH2Cl2 (45 mL) at 0 °C, and the resulting mixture
was stirred at the same temperature for 1 h. The reaction mixture
was washed with NaHCO3(aq) (10 mL ꢀ 2) and brine (10 mL) and
dried over anhydrous Na2SO4. After filtration, the filtrate was
concentrated under reduced pressure. The residue was dissolved in
toluene (40 mL) and heated at 110 °C for 1 h. The reaction mixture
was subjected to flash chromatography (hexane-EtOAc 10:1 then
5:1) to give 8 in 76% yield (1.6246 g). HPLC analysis revealed 94%
1
de: white solid; mp 92-93 °C; [R]D þ74.7 (CHCl3, c 1.06); H
NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2 H), 7.25 (d, J =
7.9 Hz, 2 H), 5.98 (s, 1 H), 5.40 (s, 1 H), 4.92 (d, J = 8.8 Hz, 1 H),
4.05 (q, J = 7.4 Hz, 1 H), 3.61 (t, J = 6.1 Hz, 2 H), 2.39 (s, 3 H),
1.89-1.71 (m, 2 H), 1.63-1.49 (m, 2 H), 1.47 (s, 9 H), 0.88 (s, 9 H),
0.04 (s, 6 H); 13C NMR (126 MHz, CDCl3) δ 165.0, 142.5, 142.0,
141.0, 129.3, 125.8, 125.2, 81.2, 62.7, 56.3, 32.76, 29.5, 28.0, 26.0,
21.3, 18.3, -5.1, -5.3. Anal. Calcd for C24H41NO4SSi: C, 61.63; H,
8.84; N, 2.99. Found: C, 61.55; H, 8.65; N, 2.90.
Preparation of (S)-tert-Butyl 3-(N-allyl-4-Methylphenylsulfon-
amido)-6-(tert-butyldimethylsilyloxy)-2-methylenehexanoate (9).
m-CPBA (77 wt %, 1.4292 g, 6.38 mmol) was added to a solution
of 9 (2.9745 g, 6.37 mmol) in CH2Cl2 (64 mL) at room tempera-
ture, and the resulting solution was stirred for 2 h. An additional
portion of m-CPBA (0.1420 g, 0.63 mmol) was added to the
mixture, and the mixture was stirred for 30 min at room
temperature. The reaction mixture was washed with NaHCO3-
(aq) (20 mL ꢀ 2) and brine (20 mL) successively and dried over
Na2SO4. After filtration, concentration of the filtrate in vacuo
gave crude sulfonamide which was used for the next step without
further purification.
The crude sulfonamide was dissolved in DMF (10 mL), and
K2CO3 (2.6777 g, 19.37 mmol) and allyl bromide (0.60 mL, 7.10
mmol) were added at room temperature. The resulting mixture
was stirred at room temperature for 21 h. The reaction mixture
was poured into water (50 mL), and the resulting mixture was
extracted Et2O (50 mL ꢀ 3). The organic phase was combined,
A mixture of the aldehyde (6.236 g, 30.81 mmol), Ti(OEt)4
(28.96 mL), and (S)-(þ)-p-toluenesulfinamide (4.777 g, 30.81
mmol) in CH2Cl2 (350 mL) was heated at refluxing temperature
overnight. The mixture was cooled and water (90 mL) was
added. The resulting precipitate was filtered over a glass filter
and washed with CH2Cl2 (100 mL ꢀ 2). The organic phase of the
filtrate was separated, washed with water (60 mL ꢀ 2) and brine
(60 mL), and dried over Na2SO4. After filtration, concentration
of the filtrate gave crude product which was purified by flash
chromatography (hexane-EtOAc 20:1, 15:1, 10:1 then 5:1) to
give 6 in 64% yield for two steps (6.6874 g): yellow oil; [R]D
þ174.5 (CHCl3, c 1.08); 1H NMR (270 MHz, CDCl3) δ 8.25 (t,
J = 4.6 Hz, 1 H), 7.55 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 7.9 Hz,
2 H), 3.62 (t, J = 6.1 Hz, 2 H), 2.55 (td, J = 4.6, 7.4 Hz, 2 H),
2.39 (s, 3 H), 1.89-1.74 (m, 2 H), 0.86 (s, 9 H), 0.00 (s, 3 H),
-0.01 (s, 3 H); 13C NMR (CDCl3, 126 MHz) δ 167.6, 142.0,
141.5, 129.6, 124.4, 61.7, 32.1, 28.0, 25.6, 21.0, 18.0; HRMS
(FAB M þ 1) m/z 340.1776, calcd for C17H30NO2SSi 340.1767.
3584 J. Org. Chem. Vol. 75, No. 11, 2010

Ishikawa et al.
JOCArticle
washed with brine (20 mL), and dried over Na2SO4. After
filtration, concentration of the filtrate under reduced pressure
gave crude 9 which was purified by flash chromatography
(hexane-EtOAc 20:1) to give 9 in 78% yield as colorless oil:
96% ee; [R]D -23.2 (CHCl3, c 1.04); 1H NMR (500 MHz,
CDCl3) δ 7.71 (d, J = 8.1 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H),
6.22 (s, 1 H), 5.76 (td, J = 6.3, 16.6 Hz, 1 H), 5.65 (s, 1 H), 5.10
(d, J = 17.2 Hz, 1 H), 5.03 (d, J = 10.1 Hz, 1 H), 4.87 (t, J = 7.5
Hz, 1 H), 3.78 (d, J = 6.1 Hz, 2H), 3.64-3.50 (m, 2 H), 2.39 (s,
3 H), 1.97-1.67 (m, 2 H), 1.45-155 (m, 2 H), 1.42 (s, 9 H), 0.88
(s, 9 H), 0.03 (s, 6 H); 13C NMR (126 MHz, CDCl3) δ 165.6,
142.7, 140.0, 138.3, 135.8, 129.2, 127.7, 126.3, 117.3, 81.2, 62.6,
57.2, 47.7, 30.0, 28.5, 27.9, 25.9, 21.4, 18.3, -5.4. Anal. Calcd for
C27H45NO5SSi: C, 61.91; H, 8.66; N, 2.67. Found: C, 61.76; H,
8.53; N, 2.71.
Preparation of (S)-tert-Butyl 2-(3-(tert-Butyldimethylsilyloxy)-
propyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (10). Under
nitrogen atmosphere, Grubbs’ second-generation catalyst (0.3658
g, 0.43 mmol) was added to a solution of 9 (4.6330 g, 8.69 mmol) in
CH2Cl2 (869 mL) at room temperature, and the reaction mixture
was heated at refluxing temperature for 3 h. After the mixture was
heated to room temperature, DMSO (0.30 mL) was added, and the
mixture was stirred at room temperature for 12 h. The reaction
mixture was concentrated under reduced pressure, and the residue
was purified by flash chromatography (hexane-EtOAc 20:1 then
5:1) to give 10 in 90% yield as a white solid (3.8589 g). The
enantiomeric excess of the product was enhanced to >99% ee by
recrystallization from MeOH: mp 101-102 °C; [R]D þ99.7
(CHCl3, c 1.01); 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.1
Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 6.46 (s, 1 H), 4.79 (s, 1 H), 4.19
(s, 1 H), 3.62 (dd, J = 8.1, 14.5 Hz, 1 H), 3.55 (dd, J = 6.8, 16.0 Hz,
1 H), 2.42 (s, 1 H), 1.99-1.90 (m, 1 H), 1.64-1.69 (m, 1 H),
1.51-1.63 (m, 2 H), 1.44 (s, 9 H), 0.89 (s, 9 H), 0.04 (s, 3 H), 0.03 (s,
3 H); 13C NMR (126 MHz, CDCl3) δ 161.5, 143.6, 136.3, 135.3,
134.3, 129.7, 127.4, 81.5, 65.9, 63.2, 55.0, 30.3, 28.0, 27.0, 26.0, 21.5,
18.3, -5.3, -5.4. Anal. Calcd for C25H41NO5SSi: C, 60.57; H, 8.34;
N, 2.83. Found: C, 60.42; H, 8.13; N, 2.83.
Preparation of (2S,3S)- and (2S,3R)-tert-Butyl 2-(3-Hydroxy-
propyl)-1-tosylpyrrolidine-3-carboxylate (13). 10% Pd-C (145
mg) was added to a solution of 10 (1.4485 g, 2.92 mmol) in
MeOH (30 mL), and the resulting suspension was stirred
vigorously under hydrogen atmosphere at room temperature
for 24 h. The reaction mixture was filtered through a pad of
Celite. The filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography (hexane-
EtOAc 3:1 then EtOAc) to give a 1:1 diastereomeric mixture of
11 in 88% yield (1.3600 g), which was used for the next step
without further purification.
A THF solution of TBAF (1.0 M, 1.85 mL) was added to a
solution of 1:1 mixture of 11 (833 mg, 1.68 mmol) in THF (10
mL) at 0 °C, and the reaction mixture was stirred at room
temperature for 1 h. NH4Cl(aq) (10 mL) was added, and organic
solvent was removed by rotary evaporator. The aqueous residue
was extracted with EtOAc (30 mL ꢀ 3), and the organic phase
was washed with brine (10 mL). After being dried over Na2SO4,
the organic solution was concentrated and the residue was
subjected to flash chromatography (hexane-EtOAc 5:1. 3:1,
then 1:1) to give a diastereomeric mixture of 13 in 96% yield
(617.8 mg). This mixture was separated by careful chromatog-
raphy. cis-13: colorless oil; [R]D þ65.9 (CHCl3, c 0.99); 1H NMR
(500 MHz, CDCl3) δ 7.73 (d, J = 7.7 Hz, 2 H), 7.33 (d, J = 7.8
Hz, 2 H), 4.10 (dd, J = 6.6, 12.9 Hz, 1 H), 3.77-3.63 (m, 2 H),
3.49 (t, J = 9.6 Hz, 1 H), 3.21 (dd, J = 8.7, 19.2 Hz, 1 H), 2.44 (s,
3 H), 2.41-2.35 (m, 1 H), 2.21-2.10 (m, 1 H), 1.86-1.73 (m,
3 H), 1.58 (m, 1 H), 1.52-1.45 (m, 1 H), 1.43 (s, 9 H); 13C NMR
(126 MHz, CDCl3) δ 170.0, 143.8, 134.9, 129.9, 127.6, 81.6,
62.9, 61.1, 48.2, 46.7, 29.0, 28.1, 28.0, 26.0, 21.6; HRMS (FAB
M þ 1) m/z 384.1853, calcd for C19H30NO5S 384.1845. trans-13:
colorless oil; [R]D þ63.3 (CHCl3, c 0.99); 1H NMR (500 MHz,
CDCl3) δ 7.72 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 7.9 Hz, 2 H),
3.89-3.82 (m, 1 H), 3.75-3.67 (m, 2 H), 3.42 (dd, J = 6.5, 16.7
Hz, 1 H), 3.30 (dd, J = 7.1, 17.0 Hz, 1 H), 2.64 (dd, J = 5.9, 10.8
Hz, 1 H), 2.41 (s, 3 H), 2.03-1.87 (m, 2 H), 1.60-1.79 (d, 4 H),
1.27 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 171.8, 143.6, 134.4,
129.7, 127.8, 81.2, 62.7, 62.6, 50.0, 48.6, 33.2, 28.7, 27.8, 27.6,
21.6; HRMS (FAB M þ 1) m/z 384.1833, calcd for C19H30NO5S
384.1845.
Preparation of cis-(2S,3S)-tert-Butyl 2-(3-tert-Butyldimethyl-
silyloxypropyl)-1-tosylpyrrolidine-3-carboxylate (cis-11) by TBS
Protection of cis-13. A solution of TBSCl (55.1 mg, 0.35 mmol),
imidazole (66.1 mg, 0.96 mmol), and cis-13 (124.1 mg, 0.32 mmol)
in DMF (2 mL) was stirred at room temperature for 24 h. TBSCl
(55.1 mg) was added, and the reaction mixture was stirred for an
additional 24 h. Water (10 mL) was added, and the resulting
mixture was extracted with ether (10 mL ꢀ 4). The combined
organic phase was washed with brine (10 mL) and dried over
Na2SO4. After filtration, the filtrate was concentrated, and the
residue was purified by flash chromatography (hexane-EtOAc
10:1) to give cis-11 in 93% yield (145.7 mg): white solid; mp 67-
68 °C; [R]D þ53.7 (CHCl3, c 1.03); 1H NMR (270 MHz, CDCl3) δ
7.71 (d, J = 8.3 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 4.04 (ddd, J =
4.3, 7.7, 8.9 Hz, 1 H), 3.71-3.53 (m, 2 H), 3.50-3.39 (m, 1 H), 3.22
(dt, J = 8.3, 11.0 Hz, 1 H), 2.42 (s, 3 H), 2.30-2.41 (m, 1 H),
2.22-2.04 (m, 1 H), 1.85-1.44 (m, 5 H), 1.40 (s, 9 H), 0.87 (s, 9 H),
0.02 (s, 3 H), 0.02 (s, 3 H); 13C NMR (68 MHz, CDCl3) δ 170.1,
143.7, 135.1, 130.0, 127.6, 81.4, 62.9, 61.4, 48.0, 46.5, 29.2, 28.0,
27.7, 25.9, 25.8, 21.5, 18.3, -5.4, -5.4; Anal. Calcd for
C25H43NO5SSi: C, 60.32; H, 8.71; N, 2.81. Found: C, 60.21; H,
8.50; N, 2.82.
Preparation of (2S,3R)-tert-Butyl 2-(3-Hydroxypropyl)-1-to-
sylpyrrolidine-3-carboxylate (trans-13) by Hydrogenation Reac-
tion of Free Alcohol 12. CSA (0.3206 g, 1.28 mmol) was added to
a solution of 10 (3.1719 g, 6.40 mmol) in MeOH/CH2Cl2 (1:1)
(64 mL) at room temperature, and the mixture was stirred for 1
h. The reaction mixture was poured into NaHCO3(aq) (20 mL)
and extracted with CH2Cl2 (30 mL ꢀ 4). The organic phase was
washed with brine (20 mL) and dried over Na2SO4. After
filtration, concentration of the solution in vacuo to give crude
12 which was used for the next step without further purification:
1H NMR (270 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 2 H), 7.30 (d,
J = 8.0 Hz, 2 H), 6.46 (d, J = 1.7 Hz, 1 H), 4.77 (t, J = 4.8 Hz,
1 H), 4.24-4.17 (m, 2 H), 3.65 (t, J = 7.2 Hz, 2 H), 2.42 (s, 3 H),
2.10-1.85 (m, 2 H), 1.57 (s, 3 H), 1.44 (s, 9H).
Crude 12 was dissolved in MeOH (60 mL), and 10% Pd-C
was added to the solution. The reaction mixture was stirred
vigorously under hydrogen atmosphere for 48 h. The reaction
mixture was filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure. The residue was purified
by flash chromatography (hexane-EtOAc 3:1, then EtOAc) to
give a diastereomeric mixture of 13 in 98% yield (2.3995 g). The
diastereomeric ratio was determined by HPLC analysis, which
revealed the ratio was cis/trans = 14/86. Anal. Calcd for C19-
H29NO5S: C, 59.51; H, 7.62; N, 3.65. Found: C, 59.26; H, 7.31;
N, 3.90.
Preparation of (2S,3R)-Methyl 2-(3-Methoxy-3-oxopropyl)-
1-tosylpyrrolidine-3-carboxylate (14). PDC (1.8333 g, 4.88
mmol) was added to a solution of trans-13 (0.4690 g, 1.22 mmol)
in DMF (3.77 mL) at room temperature, and the mixture was
stirred for overnight. The reaction mixture was poured into
water (20 mL) and extracted with ether (20 mL ꢀ 4). The organic
phase was dried over anhydrous Na2SO4. After filtration, the
filtrate was concentrated under reduced pressure to give crude
carboxylic acid which was used for the next step without further
purification. The carboxylic acid was dissolved in MeOH (20
mL), and SOCl2 (0.39 mL, 3.28 mmol) was added to the solution
at 0 °C under nitrogen atmosphere. The reaction mixture was
J. Org. Chem. Vol. 75, No. 11, 2010 3585

Ishikawa et al.
JOCArticle
heated at refluxing temperature for 12 h. After cooling, the mixture
was concentrated under reduced pressure. The residue was purified
by flash chromatography (hexane-EtOAc 3:1) to give 14 in 75%
was extracted with EtOAc (50 mL ꢀ 4). The organic phase was
washed with brine (20 mL) and dried over anhydrous Na2SO4.
After filtration, the solution was concentrated under reduced
pressure. The residue was purified by flash chromatography
(hexane-EtOAc 1:3, then EtOAc) to give 15 in 76% yield as a
yellow oil (0.1528 g): [R]D -59.7 (CHCl3, c 1.06) [lit.14 [R]D
-58.3 (CHCl3, c 0.65)]; 1H NMR (400 MHz, CDCl3) δ 4.10 (td,
J = 7.2, 16.2 Hz, 1 H), 3.74 (s, 3 H), 3.65 (td, J = 8.3, 11.7 Hz,
1 H), 3.22 (ddd, J = 3.9, 8.0, 11.7 Hz, 1 H), 2.76 (td, J = 9.6, 16.9
Hz, 1 H), 2.62-2.47 (m, 2 H), 2.47-2.28 (m, 3 H), 1.89 (dtd, J =
7.3, 10.1, 13.0 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 175.0,
172.4, 64.4, 52.2, 49.3, 40.7, 34.4, 30.7, 25.9; HRMS (EI M) m/z
183.0892, calcd for C9H13NO3 183.0895.
1
yield as a yellow oil (0.3375 g): [R]D þ68.9 (CHCl3, c 0.35); H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.3 Hz, 2 H), 7.32 (d, J =
7.9 Hz, 2 H), 4.01 (td, J = 3.9, 6.5 Hz, 1 H), 3.71 (s, 3 H), 3.42 (s, 3
H), 3.47-3.32 (m, 2 H), 2.73-2.66 (m, 1 H), 2.54 (dd, J = 1.5, 7.9
Hz, 1 H), 2.52 (d, J = 8.2 Hz, 1 H), 2.43 (s, 3 H), 2.14-1.90 (m, 3
H), 1.79 (td, J=5.7, 12.8Hz,1H);13C NMR (101 MHz, CDCl3) δ
173.5, 172.5, 143.5, 134.2, 129.5, 127.8, 62.2, 52.0, 51.7, 48.7, 48.3,
31.7, 30.4, 27.3, 21.5. Anal. Calcd for C17H23NO6S: C, 55.27; H,
6.28; N, 3.79. Found: C, 55.18; H, 6.09; N, 3.92.
Preparation of (1R,7aS)-Methyl 5-Oxohexahydro-1H-pyrro-
lizine-1-carboxylate (15). To a solution of 14 (0.4048 g, 1.10
mmol) in MeOH (20 mL) was added Mg (0.5364 g, 22.06 mmol),
and the mixture was stirred for 2 h. The reaction mixture was
then heated at refluxing temperature for 4 h. After the mixture
was cooled to room temperature, dilute HCl was added to the
mixture until all precipitates dissolved. The reaction mixture
Supporting Information Available: Spectroscopic charts for
compounds 2-4, 6-10, cis-11, cis-13, trans-13, 14, and 15, chiral
HPLC charts for 2-4, preparation and spectral data for 1f,g,
and X-ray crystallographic data for cis-11. This material is
available free of charge via the Internet at http://pubs.acs.org.
3586 J. Org. Chem. Vol. 75, No. 11, 2010