Asymmetric synthesis of trans-2,5-disubstituted pyrrolidines from enantiopure homoallylic amines. Synthesis of pyrrolidine (-)-197B

Article abstract of DOI:10.1021/jo052566h

Iodocyclization of sulfinimine-derived enantiopure homoallylic sulfonamides affords trans-2,5-disubstituted 3-iodopyrrolidines and represents valuable methodology for the asymmetric synthesis of this important heterocyclic ring system.

Full text of DOI:10.1021/jo052566h

Asymmetric Synthesis of trans-2,5-Disubstituted Pyrrolidines from
Enantiopure Homoallylic Amines. Synthesis of Pyrrolidine (-)-197B
Franklin A. Davis,* Minsoo Song, and Alexander Augustine
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
ReceiVed December 13, 2005
Iodocyclization of sulfinimine-derived enantiopure homoallylic sulfonamides affords trans-2,5-disubstituted
3-iodopyrrolidines and represents valuable methodology for the asymmetric synthesis of this important
heterocyclic ring system.
The trans-2,5-disubstituted pyrrolidine ring system is found
in numerous natural products, medicinally relevant molecules,
and the pyrrolizidine and indolizidine alkaloids.1,2 Enantiopure
C2-symmetrical trans-2,5-disubstituted pyrrolidines have found
utility as organocatalysts,3 as chiral ligands for asymmetric
catalysis,3 and as chiral auxiliaries.4 Although many racemic
syntheses of this ring system have been reported,5 fewer general
methods are available for their preparation in enantiomerically
pure form.1c,d,6-8 Furthermore, many of these methods are target
specific, require difficult separations of diastereoisomers, and
are multistep. These methods also necessitate enantiomerically
pure starting materials, which can be difficult to obtain. For
these reasons the development of new methods for the concise
asymmetric synthesis of this class of heterocycles continues to
be an important challenge.
In this context we describe an iodocyclization of sulfinimine-
derived enantiopure homoallylic sulfonamides that represents
a valuable new route for the asymmetric synthesis of trans-
2,5-disubstituted pyrrolidines (Scheme 1). Our work was
inspired by the studies of Knight et al., who explored the racemic
system.9 In their research these workers reported that racemic
E-homoallylic sulfonamides underwent the iodocyclization
reaction with I2/K2CO3 to give trans-2,5-disubstituted pyrro-
lidines in high yield and selectivity. However, the Z-homoallylic
sulfonamides or multisubstituted examples resulted in poor
yields and lower selectivity.
(1) Natural products: (a) Leclercq, S.; Braekman, J. C.; Daloze, D.;
Pasteels, J. M. In Progress in the Chemistry of Organic Natural Products;
Herz, W., Falk, H., Kirby, G. W., Moore, R. E., Eds.; Springer-Verlag:
New York, 2000; Vol. 79, p 115. (b) Trost, B. M.; Horne, D. B.; Woltering,
M. J. Angew. Chem., Int. Ed. 2003, 42, 5987. (c) Chandrasekhar, S.;
Jagadeshwar, V.; Prakash, S. J. Tetrahedron Lett. 2005, 46, 3127. (d) Goti,
A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna, F.; Merino, P.; Tejero,
T. Org. Lett. 2003, 5, 4235. (e) Severino, E. A.; Correira, C. R. D. Org.
Lett. 2000, 2, 3039. (f) Daly, J. W.; Spande, T. F.; Whittaker, N.; Highet,
R. J.; Feigl, D.; Nishimori, N.; Tokuyama, T.; Myers, C. W. J. Nat. Prod.
1986, 49, 265.
(2) Medicinal compounds: (a) DeGoey, D. A.; Chen, H.-J.; Flosi, W.
J.; Grampovnik, D. J.; Yeung, C. M.; Klein, L. L.; Kempf, D. J. J. Org.
Chem. 2002, 67, 5445. (b) Hanessian, S.; Bayrakdariyan, M.; Luo, X. J.
Am. Chem. Soc. 2002, 124, 4716.
(3) For reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Shi, Y. Acc. Chem. Res. 2004,
37, 488. Issue 8 is a special issue on organocatalysis. Chiral catalysts: (c)
R-Chlorination of aldehydes: Halland, N.; Braunton, A.; Bachmann, S.;
Marigo, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790. (d) Diels-
Alder reactions: Sprott, K. T.; Corey, E. J. Org. Lett. 2003, 5, 2465. (e) [3
+ 3] Cycloadditions: Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer,
B. J. Org. Chem. 2005, 3, 2141.
(5) (a) Harding, K. E.; Burks, S. R. J. Org. Chem. 1984, 49, 40. (b)
Harding, K. E.; Marman, T. H. J. Org. Chem. 1984, 49, 2838. (c) Williams,
D. R.; Osterhout, M. H.; McGill, J. M. Tetrahedron Lett. 1989, 30, 1327.
(d) Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.; Hosomi, A. Org.
Lett. 2000, 2, 385. (e) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4,
1471. (f) Galliford, C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt, K. A.
Org. Lett. 2003, 5, 3487. (g) Young, I. S.; Williams, J. L.; Kerr, M. A.
Org. Lett. 2005, 7, 953.
(6) For a review see: Pichon, M.; Figade`re, B. Tetrahedron: Asymmetry
1996, 7, 927.
(7) Wang, Q.; Sasaki, N. A.; Riche, C.; Potier P. J. Org. Chem. 1999,
64, 8602 and references therein.
(8) For references to recent procedures, see: (a) Katritzky, A. R.; Cui,
X.-L.; Yang, B.; Steel, P. J. J. Org. Chem. 1999, 64, 1979. (b) Arredondo,
V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999,
121, 3633. (c) Cheng, Y.; Huang, Z.-T.; Wang, M.-X. Curr. Org. Chem.
2004, 8, 325. (d) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini,
M. Chem. ReV. 2005, 105, 933.
(4) Chiral auxiliaries or ligands: (a) Whitesell, J. K. Chem. ReV. 1989,
89, 1581. (b) Sweet, J. A.; Cavallari, J. M.; Price, W. A.; Ziller, J. W.;
McGrath, D. V. Tetrahedron: Asymmetry 1997, 8, 207. (c) Kim, B. H.;
Lee, H. B.; Hwang, J. K.; Kim, Y. G. Tetrahedron: Asymmetry 2005, 16,
1215.
(9) Jones, A. D.; Knight D. W.; Hibbs, D. E. J. Chem. Soc., Perkin Trans.
1, 2001, 1182.
10.1021/jo052566h CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/24/2006
J. Org. Chem. 2006, 71, 2779-2786
2779

Davis et al.
SCHEME 1
SCHEME 3
SCHEME 2
The aldehyde was next treated with 5.0 equiv of the Wittig
reagent generated from n-butyllithium and benzyltriphenylphos-
phonium bromide to give the homoallylic sulfinamide (SS,4R)-
(+)-3 as an inseparable 66:34 mixture of E and Z isomers.14
The 1H NMR chemical shifts of the two vinyl protons centered
at δ 6.47 (J ) 16 Hz) and δ 6.6 (J ) 11 Hz) for the E and Z
isomers, respectively, were used to establish the E:Z ratio. Next
the mixture of homoallylic sulfinamides (+)-3 was treated with
3.0 equiv of I2, along with 3.0 equiv of K2CO3 in aqueous
acetonitrile (Scheme 2). However, none of the expected 3-io-
dopyrrolidine 5 was detected, but rather the N-sulfinyl group
in 3 was oxidized to the corresponding homoallylic sulfonamide
(R)-4 in 69% yield, again as an inseparable mixture of 66:34
E:Z isomers. Longer reactions times also failed to give the
iodocyclization product 5. However, when 4 was resubjected
to the iodocyclization protocol, (2S,3R,5R)-(-)-5 was obtained
in 58% yield as the major isomer of a 95:5 mixture. The
Z-homoallylic amide (S)-(+)-6 was isolated in 22% yield
(Scheme 2). The structure of (-)-5 was established by conver-
sion into the known (2R,5R)-(+)-2,5-diphenylpyrrolidine (13)
as outlined below. In (+)-6 the vinyl proton centered at δ 6.6
(J ) 11.7 Hz) is consistent with its structure.
Because N-sulfinyl â-amino aldehydes slowly decompose
after several days at 0 °C, it was found to be more efficient to
prepare the requisite N-tosyl â-amino aldehydes 9 by selective
DIBAL-H reduction of the corresponding N-tosyl â-amino esters
(R)-8 (Scheme 3). Oxidation of the N-sulfinyl â-amino esters 7
with 5.0 equiv of m-CPBA gave 8 in 85-99% yield. Although
the N-tosyl â-amino aldehydes (R)-9 were stable to chroma-
tography, they were also observed to slowly decompose on
storage after several days. For this reason, they were quickly
transformed into the corresponding homoallylic sulfonamides
4, 10, and 11 by treatment with the appropriate nonstabilized
Wittig reagent at -78 °C. In all cases mixtures of inseparable
E:Z isomers were obtained.
A general method for the asymmetric synthesis of trans-2,5-
disubstituted pyrrolidines using the iodocyclization protocol
requires easy access to structurally diverse enantiopure homo-
allylic sulfonamides. However, most of the methods reported
for the asymmetric synthesis of homoallylic amines appear to
be of limited scope and restricted to examples containing
terminal olefins.10 Furthermore, many examples of substituted
homoallylic amines do not provide convenient access to the
requisite N-sulfonyl derivatives.11
Recently we introduced a general method for the asymmetric
synthesis of â-amino carbonyl compounds, including â-amino
aldehydes, that involves the use of sulfinimine-derived N-sulfinyl
â-amino Weinreb amides (Scheme 2).12,13 This method involves
the selective reduction of sulfinimine-derived N-sulfinyl â-amino
Weinreb amides with DIBAL-H. Thus treatment of Weinreb
amide (SS,3R)-(+)-1 with 5 equiv of DIBAL-H at -78 °C
afforded N-sulfinyl â-amino aldehyde (SS-3R)-(+)-2 in 84%.
(10) (a) Kleinman, E. F.; Volkmann, R. A. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, pp 975-1006. (b) Risch, N.; Arend, M. In
Methods of Organic Chemistry (Houben-Weyl); Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart,
1995; Vol. E21b, pp 1894-1907. (c) Bloch, R. Chem. ReV. 1998, 98, 1407.
(d) Hirabayashi, R.; Ogawa, C.; Sugiura, M.; Kobayashi, S. J. Am. Chem.
Soc. 2001, 123, 9493. (e) Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed.
2001, 40, 4491.
Subjecting the homoallylic sulfonamide mixtures to the
iodocyclization protocol I2/K2CO3/H2O/MeCN afforded the
corresponding 3-iodo trans-2,5-disubstituted pyrrolidines 5 along
with the unreacted Z-homoallylic sulfonamides 6 (Scheme 4,
Table 1). Although modest yields of the 3-iodopyrrolidines 5
were obtained because mixtures of the E:Z homoallylic sul-
fonamide were employed, it is important to note that it was not
necessary to purify the precursor sulfonamide. However, the
(11) Schaus, J. V.; Jain, N.; Panek, J. S. Tetrahedron 2000, 56, 10263
and references therein.
(12) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.;
Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184.
(13) For recent reviews on the chemistry of sulfinimines, see: (a) Zhou,
P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (b) Ellman, J.
A.; Owens, T. D.; Tang. T. P. Acc. Chem. Res. 2002, 35, 984-995. (c)
Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I.
Aldrichimica Acta 2005, 38, 93-104.
(14) For examples of the addition of unstabilized Wittig reagents to
N-protected R-amino aldehydes, see: Jurczak, J.; Golebiowski, A. Chem.
ReV. 1989, 89, 149.
2780 J. Org. Chem., Vol. 71, No. 7, 2006

Asymmetric Synthesis of trans-2,5-Disubstituted Pyrrolidines
SCHEME 4
FIGURE 1.
TABLE 1. Iodocyclization of Homoallylic Sulfonamides to
3-Iodopyrrolidines 5 and Z-Homoallylic Sulfonamides
the Z-olefin compare to those in TS-B for the E-olefin makes
the latter lower in energy. This results in the exclusive reaction
of the E-homoallylic sulfonamide under the reaction conditions
to produce the trans-2,5-pyrrolidines 5. The poorer diastereo-
selectivity observed in the iodocyclization of homoallylic
sulfonamides having a phenyl group on the terminal carbon for
R2 ) Ph (Table 1, entry 1) could be explained by extra
stabilization of a benzylic carbocation, which could result in
isomerization. In a related study, Harding et al. reported that
equilibration of the products from amidomercuration of δ-alk-
enylcarbamates resulted in scrambling in the product.5b
homoallylic sulfonamide
entry
R1, R2 (E:Z)
5 (% yield)a [dr]b 6 (% yield)a
1
2
3
4
4 R1 ) R2 ) Ph (55:45)
5a (40) [88:12]
5b (46) [>95:5]
5c (39) [>95:5]
5c (71) [>95:5]
6a (45)
6b (31)
6c (49)
6c (20)
10 R1 ) Ph; R2 ) Et (55:45)
11 R1 ) Me; R2 ) Et (4:6)
11 R1 ) Me; R2 ) Et (8:2)c
a Isolated yield of major product. b Determined by 1H NMR. c Prepared
using photoisomerization and PhSSPh.
SCHEME 5
The utility of our new trans-2,5-disubstituted pyrrolidine
synthesis is highlighted by a total asymmetric synthesis of (-)-
pyrrolidine 197B (22), trans-2-n-butyl-5-n-pentylpyrrolidine
(Scheme 6). In addition to many other alkaloids (-)-pyrrolidine
197B (22) has been detected in the poison frogs of the family
Dendrobates histrionicus1a,f and in the venom of fire ants of
the genus Solenopsis and Monomorium latinode.17 These
alkaloids exhibit a wide range of biological activities including
hemolytic and antibiotic activity,18 but because they are isolated
in only minute quantities the biological properties of the majority
of these alkaloids remains unknown. A single asymmetric
synthesis of (-)-197B has been reported by Machinaga and
Kibayashi.19 Their synthesis required in excess of 16 steps
starting from C2-symmetric diepoxides derived from D-mannitol.
fact that the starting homoallylic sulfonamide is not completely
transformed into product could be a liability in a long synthetic
sequence. To address this issue we briefly explored the radical-
induced photoisomerization of the Z-olefin in (R)-11 to the E
isomer.15 Photolysis of the 4:6 E:Z mixture of 11 at 300 nm in
the presence of 2 equiv of phenyl disulfide for 6 h in
cyclohexane improved the E:Z ratio to 8:2. Iodocyclization of
(R)-11 (8:2 E:Z) afforded 5c in 71% isolated yield (Table 1,
entry 4).
The trans relationship of the 2- and 5-substituents in 5a was
confirmed by treatment of (2S,3R,5R)-(-)-5a with tributyltin
hydride to give (2R,5R)-2,5-diphenyl-1-tosylpyrrolidine (12) in
nearly quantitative yield (Scheme 5). Reductive removal of the
N-tosyl group with Na/NH3 (liq) afforded (2R,5R)-(+)-2,5-
diphenylpyrrolidine (13) with properties identical to literature
values.16 Pyrrolidine (+)-13 is a popular chiral auxiliary with
C2-symmetry, and the homoallylic sulfonamide iodocyclization
protocol represents a potentially general method for the asym-
metric synthesis of this valuable class of auxiliaries and
ligands.3-5
Our synthesis of (-)-197B begins with the preparation of
the E-homoallylic sulfonamide (R)-18 from (R)-(-)-N-(penty-
lidine)-p-toluenesulfinamide (14), using the standard conditions.
This procedure affords (R)-18 in 50% yield for the four-step
sequence (Scheme 6). The modest E:Z ratio of 18 from the
Wittig reaction was improved by photoisomerization. Irradiation
of compound (R)-18 at 300 nm in the presence of 2.0 equiv of
PhSSPh improved the E:Z isomer ratio from 54:46 to 85:15
with an isolated yield of 84%. When (R)-18 was subjected to
the iodocyclization protocol, the major diastereoisomer of
pyrrolidine (+)-20 was isolated in 82% yield along with 10%
of the Z-olefin (R)-(+)-19. Finally, deiodination of (+)-20 with
Bu3SnH gave pyrrolidine (-)-21 in quantitative yield, which
was followed by removal of the N-tosyl group with Na/NH3
(liq) to give the target (-)-pyrrolidine 197B (22) in 62% yield
(Scheme 6). Although the spectral properties of (-)-22 were
in agreement with literature values, our specific rotation of
-25.3 was considerably larger than the value of -5.8 reported
by Kibayashi and co-workers.19b This group also prepared the
N-benzoyl derivative of the enantiomer of 22. Their specific
rotation was +125.5, whereas ours was considerable higher at
-231.5.19b These discrepancies suggests that racemization may
As shown in Table 1, E-homoallylic sulfonamides were the
only active partner in the iodocyclization reaction with Z-
homoallylic sulfonamides inert to the cyclization conditions. The
lack of reactivity of the Z-homoallylic sulfonamides 6 can be
explained in terms of the chairlike transition states depicted in
Figure 1. The existing A1,3 strain in transition state TS-A for
(15) (a) Hatakeyama, S.; Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie,
H.; Kawamoto, T.; Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1997,
38, 7887. (b) Harrowven, D. C.; Hannam, J. C. Tetrahedron 1999, 55, 9341.
(16) (a) Aldous, D. J.; Dutton, W. M.; Steel, P. G. Tetrahedron:
Asymmetry 2000, 11, 2455. (b) Chong, J. M.; Clarke, I. S.; Koch, I.; Olbach,
P. C.; Taylor, N. J. Tetrahedron: Asymmetry 1995, 6, 409. (c) Higashiyama,
K.; Inoue, H.; Takahashi, H. Tetrahedron 1994, 50, 1083.
(17) Brown, K. S.; Trigo, J. R. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, CA, 1995; Vol. 47, pp 227-354.
(18) (a) Jones, T. H.; Blum, M. S.; Fales, H. M. Tetrahedron 1982, 38,
1949. (b) Pedder, D. J.; Fales, H. M.; Jaouni, T.; Blum, M.; MacConnell,
J.; Crewe, R. M. Tetrahedron 1976, 32, 2275.
(19) (a) Machinaga, N.; Kibayashi, C. Tetrahedron Lett. 1990, 31, 3637.
(b) Machinaga, N.; Kibayashi, C. J. Org. Chem. 1991, 56, 1386.
J. Org. Chem, Vol. 71, No. 7, 2006 2781

Davis et al.
SCHEME 6
(R)-(+)-N-(1,4-Diphenylbut-3-enyl)-4-methylbenzenesulfona-
mide (4). In an oven-dried one-neck round-bottom flask equipped
with a magnetic stirring bar and argon inlet was placed (+)-3 (0.015
g, 0.042 mmol) and K2CO3 (0.02 g, 0.145 mmol) in MeCN (1 mL)
and H2O (0.01 mL). The solution was stirred for 30 min at room
temperature, and I2 (0.032 g, 0.145 mmol) was added. After
consumption of starting material as judged by TLC analysis (1 h
at room temperature), the mixture was quenched by addition of
saturated aqueous Na2S2O3 (1 mL). The resulting clear yellow
solution was extracted with CH2Cl2 (2 × 5 mL), and the combined
organic phases were dried (MgSO4) and concentrated. Chromatog-
have occurred in the earlier preparations of this material.
Attempts to make the Mosher amide of (-)-22 were un-
successful.
In conclusion, we have developed a useful stereoselective
synthesis of enantiopure trans-2,5-pyrrolidine derivatives from
homoallylic sulfonamides using iodocyclization. The homo-
allylic sulfonamides were prepared from readily available
sulfinimine-derived â-amino aldehydes using the Wittig reaction
and were obtained as E:Z mixtures. Because only the E-
homoallylic sulfonamides undergo the cyclization reaction, it
was not necessary to separate E:Z sulfonamide mixtures. The
utility of this methodology was highlighted in the total asym-
metric synthesis of toxic frog/fire ant venom alkaloid (-)-197B
(22).
raphy (10% EtOAc/hexane) gave 0.011 g (69%) of a colorless oil:
1
[R]20 +72.4 (c 0.55, CHCl3); H NMR (CDCl3) major isomer δ
D
2.27 (s, 3H), 2.52 (dt, J ) 0.8, 7.1 Hz, 2H), 4.34 (m, 1H), 4.98 (d,
J ) 6.4 Hz, 1H), 5.74 (dt, J ) 7.4, 16.0 Hz, 1H), 6.29 (d, J ) 15.6
Hz, 1H), 6.91-7.25 (m, 12H), 7.49 (d, J ) 8.0 Hz, 2H); minor
isomer δ 2.27 (s, 3H), 2.66 (m, 2H), 4.83 (d, J ) 6.8 Hz, 1H),
5.35 (dt, J ) 7.2, 12.0 Hz, 1H), 6.4 (d, J ) 11.6 Hz, 1H), 7.43 (d,
J ) 8.4 Hz, 2H); 13C NMR (CDCl3) major isomer δ 21.8, 41.6,
57.9, 124.8, 126.6, 126.9, 127.46, 127.5, 127.8, 128.8 (2C), 129.8,
134.4, 137.1, 137.8, 141.0, 143.5; minor isomer δ 30.7, 36.5, 58.3,
127.0, 127.4, 127.86, 127.9, 128.7, 129.0, 129.7, 132.7, 140.7,
143.4; IR (film) 3279, 3061, 2928, 2858, cm-1; HRMS calcd for
C23H23NO2SNa (M + Na) 400.1347, found 400.1352.
Experimental Section
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino N-Methoxy-N-meth-
yl-3-phenylpropionamide (1),12 (SS,3R)-(+)-N-(p-Toluenesulfinyl)-
3-amino-3-phenyl-propionaldehyde (2),12 (SS,R)-(+)-Methyl 3-(p-
toluenesulfinylamino)-3-phenylpropanoate (7a),12 and (SS,3S)-(+)-
Methyl N-(p-Toluenesulfinyl)-3-aminobutanoate (7b)12 were prepared
as previously described.
(2S,3R,5R)-(-)-3-Iodo-2,5-diphenyl-1-tosylpyrrolidine (5). In
an oven-dried one-neck round-bottom flask equipped with a
magnetic stirring bar and argon inlet was placed (+)-4 (0.027 g,
0.072 mmol) and K2CO3 (0.033 g, 0.239 mmol) in MeCN (1 mL)
and H2O (0.01 mL), the solution was stirred for 30 min at room
temperature, and I2 (0.061 g, 0.239 mmol) was added. After
consumption of starting material as judged by TLC analysis (3 h
at room temperature), the mixture was quenched by addition of
saturated aqueous Na2S2O3 (1 mL). The resulting clear solution
was extracted with CH2Cl2 (2 × 5 mL), and the combined organic
phases were dried (MgSO4) and concentrated. Chromatography
(10% EtOAc/hexane) gave 0.021 g (58%) of a light yellow solid
as a mixture of inseparable diastereoisomers in a ratio of 95:5 and
(Ss,4R)-(+)-N-(p-Toluenesulfinyl)-4-amino-1,4-diphenylbut-1-
en (3). In an oven-dried, one-neck, round-bottom flask equipped
with a magnetic stirring bar, rubber septum, and argon inlet was
placed benzyltriphenylphosphonium bromide (0.676 g, 1.56 mmol)
in THF (6 mL). The solution was cooled to 0 °C, n-BuLi (0.610
mL, 1.53 mmol, 1.6 M in hexanes) was added, and the solution
was stirred for 1 h at room temperature. At this time the reaction
mixture was cooled to -78 °C, and a solution of (+)-2 (0.088 g,
0.305 mmol) in THF (2 mL) was added via cannula. After
consumption of starting material as judged by TLC (2.5 h at 0 °C),
the reaction mixture was quenched with water (1 mL) at 0 °C,
warmed to room temperature, and extracted with EtOAc (2 × 20
mL). The combined organic phases were washed with brine (2 ×
5 mL), dried (MgSO4), and concentrated. Chromatography (50%
Et2O/hexane) gave 0.06 g (54%) of a colorless oil as an inseparable
66:34 E:Z mixture: [R]20D +76.4 (c 0.75, CHCl3); 1H NMR (CDCl3)
major isomer δ 2.46 (s, 3H), 2.74 (m, 2H), 4.41 (d, J ) 3.0 Hz,
1H), 4.73 (m, 1H), 6.06 (dt, J ) 7.6, 15.5 Hz, 1H), 6.41 (d, J )
15.9 Hz, 1H), 6.47 (d, J ) 15.9 Hz, 1H), 7.19-7.53 (m, 12H),
7.64 (m, 2H); minor isomer δ 2.88 (m, 2H), 4.32 (bs, 1H), 4.68
(m, 1H), 5.61 (m, 1H), 6.57 (d, J ) 11.4 Hz, 1H); 13C NMR
(CDCl3) major isomer δ 21.4, 42.2, 57.7, 125.1, 125.5, 126.3, 127.5,
128.6, 128.7, 128.8, 129.59, 129.6, 134.0, 141.3, 141.46, 141.5,
142.3; minor isomer δ 37.3, 57.9, 127.0, 127.2, 127.7, 127.9, 128.0,
128.3, 132.3, 137.0; IR (film) 3193, 3058, 3027, cm-1; HRMS (EI)
m/e calcd for C23H23NONaS (M + Na) 384.139806, found
384.1391.
0.006 g (22%) of Z-homoallylic sulfonamide (+)-6: mp 164-165
1
°C; [R]20 -7.9 (c 0.067, CHCl3); H NMR (CDCl3) δ 2.26 (s,
D
3H), 2.45 (dt, J ) 5.2, 15.2 Hz, 1H), 3.15 (m, 1H), 4.28 (dt, J )
8.6, 8.6 Hz, 1H), 5.19 (dd, J ) 5.7, 9.6 Hz, 1H), 5.3 (d, J ) 4.5
Hz, 1H), 6.85-7.36 (m, 14H); 13C NMR (CDCl3) δ 21.5, 25.0,
45.9, 65.3, 77.2, 127.1, 127.3, 127.7, 128.1, 128.3, 128.7, 128.8,
128.9, 138.3, 139.0, 139.8, 142.4; IR (film) 3031, 2921 cm-1
;
HRMS calcd for C23H22NO2SINa (M + Na) 526.0314, found
526.0321. (R,Z)-(+)-1,4-Diphenyl-N-tosyulbut-3-en-1-amine (6):
1
[R]20 +42.7 (c 0.33, CHCl3); H NMR (CDCl3) δ 2.43 (s, 3H),
D
2.81 (m, 2H), 4.47 (q, J ) 6.8 Hz, 1H), 4.77 (d, J ) 6.9 Hz, 1H),
5.48 (m, 1H), 6.56 (d, J ) 11.7 Hz, 1H), 7.08-7.40 (m, 12H),
7.56 (d, J ) 8.1 Hz, 2H); 13C NMR (CDCl3) δ 21.5, 36.2, 58.0,
126.7, 127.2, 128.5, 128.7, 129.3, 132.4, 136.8, 137.5, 138.3, 139.0,
2782 J. Org. Chem., Vol. 71, No. 7, 2006

Asymmetric Synthesis of trans-2,5-Disubstituted Pyrrolidines
139.8, 140.3, 142.4, 143.1; IR (film) 3276, 3026, 2923 cm-1; HRMS
calcd for C23H23NO2SNa (M + Na) 400.1347, found 400.1349.
Typical Procedure for the Preparation of N-Tosyl â-Amino
Esters. (R)-(+)-Methyl 3-(4-Methylphenylsulfonamido)-3-phen-
ylpropanoate (8a). In an oven-dried one-neck round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon
inlet was placed (+)-7a (0.157 g, 0.496 mmol) in CH2Cl2 (10 mL).
The solution was cooled to 0 °C, m-CPBA (0.144 g, 1.984 mmol)
was added, and the solution was stirred for 1.5 h at 0 °C. At this
time the reaction mixture was quenched by addition of saturated
aqueous Na2S2O3 (5 mL), diluted with CHCl3 (10 mL), and
saturated aqueous NaHCO3 (5 mL) was added. The solution was
stirred vigorously with warming to room temperature, and the
organic phase was dried (MgSO4) and concentrated to provide 0.140
g (85%) of a white solid: mp 100-101 °C; [R]20D +50.6° (c 1.62,
of starting material as judged by TLC analysis (2.5 h at -78 °C),
the reaction mixture was quenched with H2O (1 mL) at 0 °C,
warmed to room temperature, and extracted with EtOAc (3 mL).
The organic phase was washed with brine, dried (MgSO4), and
concentrated. Chromatography (20% Et2O/hexane) gave 0.15 g
(61%) of a colorless oil as an inseparable 55:45 Z:E mixture of
isomers: [R]20D +23.9° (c 1.30, CHCl3); 1H NMR (CDCl3) major
isomer δ 2.41 (s, 3H), 2.66 (t, J ) 6.8 Hz, 2H), 4.48 (pent, J ) 6.8
Hz, 1H), 5.03 (d, J ) 6.8 Hz, 1H), 5.89 (dt, J ) 15.6, 7.5 Hz, 1H),
6.43 (d, J ) 15.9 Hz, 1H), 7.0-7.34 (m, 12H), 7.64 (m, 2H); minor
isomer δ 2.42 (s, 3H), 2.80 (m, 2H), 5.14 (d, J ) 6.9 Hz, 1H),
5.50 (dt, J ) 11.7, 7.0 Hz, 1H), 6.54 (d, J ) 11.1 Hz, 1H), 7.58
(m, 2H); 13C NMR (CDCl3) major isomer δ 21.5, 41.2, 58.0, 124.5,
126.3, 126.6, 127.1, 127.2, 127.54, 128.4, 128.51, 128.52, 129.37,
134.1, 136.77, 140.6, 143.2; minor isomer δ 36.2, 57.6, 126.5,
127.05, 127.51, 127.6, 127.7, 128.3, 128.53, 128.7, 129.43, 132.4,
1
CHCl3); H NMR (CDCl3) δ 2.43 (s, 3H), 2.87 (q, J ) 15.6 Hz,
2H), 3.62 (s, 3H), 4.80 (q, J ) 6.5 Hz, 1H), 5.89 (d, J ) 8.1 Hz,
1H), 7.15-7.3 (m, 7H), 7.67 (d, J ) 8.7 Hz, 2H); 13C NMR(CDCl3)
δ 21.5, 41.2, 51.9, 54.4, 126.4, 127.2, 127.8, 128.6, 129.5, 137.5,
139.4, 143.3, 171.1; IR (film) 3280, 1739 cm-1; HRMS calcd for
C17H19NO4Na (M + Na) 356.0932, found 356.0927.
136.78, 140.3, 143.1; IR (film) 3279, 3061, 3028, 2928, 2858 cm-1
;
HRMS calcd for C23H23NO2SNa (M + Na) 400.1347, found
400.1352.
(R)-(+)-4-Methyl N-(1-phenylhex-3-enyl)benzenesulfonamide
(10). Following the typical procedure, (+)-9a (0.137 g, 0.452
mmol), triphenylphosphoranepropylbromide (0.871 g, 2.26 mmol),
and n-BuLi (0.904 mL, 2.26 mmol) were employed. Chromatog-
raphy (20% Et2O/hexane) gave 0.111 g (75%) of a colorless oil as
an inseparable 45:55 Z:E mixture of isomers: [R]20D +59.9 (c 2.0,
(S)-(-)-Methyl 3-(4-Methylphenylsulfonamido)butanoate (8b).
Chromatography (20% Et2O/hexane) gave 0.247 g (88%) of a
colorless oil: mp 78-79 °C; [R]20 -22.4 (c 1.16, CHCl3) [lit.20
D
mp 78-79 °C, [R]20D -27.4 (c 0.71, CHCl3)]. Spectral properties
1
were consistent with literature values.
CHCl3); H NMR (CDCl3) major isomer δ 0.97 (t, J ) 5.9 Hz,
Typical Procedure for the Preparation of N-Tosyl â-Amino
Aldehydes. (R)-(+)-4-Methyl N-(3-Oxo-1-phenylpropyl)ben-
zenesulfonamide (9a). In an oven-dried round-bottom one-neck
flask equipped with a magnetic stirring bar, rubber septum, and
argon inlet was placed (+)-8a (0.222 g, 0.667 mmol) in toluene (7
mL). The solution was cooled to -78 °C, and DIBAL-H (0.670
mL, 0.667 mmol, 1.0 M solution in CH2Cl2) was added dropwise.
After consumption of starting material as judged by TLC analysis
(5 h at -78 °C), the reaction mixture was quenched with by addition
3H), 1.99 (sextet, J ) 7.5 Hz, 2H), 2.43 (m, 1H), 2.44 (s, 3H),
2.53 (q, J ) 7.7 Hz, 1H), 4.38 (m, 1H), 5.15 (m, 2H), 5.54 (m,
1H), 7.13-7.23 (m, 7H), 7.64 (d, J ) 7.8 Hz, 1H); minor isomer
δ 0.93 (t, J ) 5.9 Hz, 3H); 13C NMR (CDCl3) major isomer δ
15.9, 21.8, 25.9, 41.2, 57.8, 123.7, 126.95, 126.98, 127.5, 128.6,
129.7, 137.7, 140.9, 141.3, 143.4; minor isomer δ 14.4, 21.0, 35.6,
58.1, 123.3, 127.7, 128.7, 136.2, 137.9; IR (film) 2849, 2917, 1329,
1157 cm-1; HRMS (EI) m/e calcd for C19H22INO2NaS (M + Na)
478.031373, found 478.0330.
.
of saturated aqueous NaKC4H4O6 H2O (Rochell salt) (5 mL), diluted
(S)-(-)-N-(hept-4-en-2-yl)-4-methylbenzenesulfonamide (11).
Following the typical procedure, (-)-9c (0.274 g, 1.137 mmol),
triphenylphosphoranepropylbromide (2.23 g, 5.799 mmol), and
n-BuLi (2.3 mL, 5.685 mmol) were employed. Chromatography
(20% Et2O/hexane) gave 0.162 g (53%) of a colorless oil as an
with EtOAc (10 mL), and vigorously stirred with warming to room
temperature. The organic phase was dried (MgSO4) and concen-
trated. Chromatography (50% Et2O/hexane) gave 0.090 g (56%)
of a colorless oil and 0.095 g (43%) of starting material: [R]20
D
1
inseparable 4:6 E:Z mixture of isomers: [R]20 -31.4 (c 2.6,
+41.3° (c 1.37, CHCl3); H NMR (CDCl3) δ 2.44 (s, 3H), 3.06
D
1
(m, 2H), 4.86 (q, J ) 6.8 Hz, 1H), 5.52 (d, J ) 7.2 Hz, 1H), 7.13
(m, 2H), 7.24 (m, 5H), 7.65 (d, J ) 8.4 Hz, 2H), 9.70 (t, J ) 1.2
Hz, 1H); 13C NMR (CDCl3) δ 21.5, 50.1, 53.3, 126.5, 127.2, 128.0,
CHCl3); H NMR (CDCl3) major isomer δ 0.83 (t, J ) 7.5 Hz,
3H), 0.98 (d, J ) 6.6 Hz, 3H), 1.86 (m, 2H), 1.96 (m, 1H), 2.04
(m, 1H), 2.35 (s, 3H), 3.22 (m, 1H), 4.69 (d, J ) 7.6 Hz, 1H), 5.04
(m, 1H), 5.36 (m, 1H), 7.22 (d, J ) 8.2 Hz, 2H), 7.69 (m, 2H);
minor isomer δ 0.84 (t, J ) 7.5 Hz, 3H), 1.0 (d, J ) 6.6 Hz, 3H),
4.64 (d, J ) 7.2 Hz, 1H), 5.14 (m, 1H), 5.43 (m, 1H); 13C NMR
(CDCl3) major isomer δ 14.5, 21.0, 21.4, 21.8, 35.0, 50.2, 123.8,
127.5, 130.0, 135.6, 138.5, 143.5; minor isomer δ 13.9, 21.7, 25.9,
40.5, 50.0, 124.0, 136.9; IR (film) 3279, 2967, 2933, 1329, 1184
cm-1; HRMS (EI) m/e calcd for C14H21NO2NaS (M + Na)
290.119071, found 290.1195.
128.8, 129.6, 137.1, 139.3, 143.5, 199.6; IR (film) 3254, 1726 cm-1
;
HRMS calcd for C16H17NO3SNa (M + Na) 326.0827, found
326.0820.
(S)-(-)-4-Methyl N-(4-Oxobutan-2-yl)benzenesulfonamide (9b).
Chromatography (20% EtOAc/hexane) gave 0.227 g (81%) of a
colorless oil and 0.047 g (15%) of starting material: [R]20D -22.0
1
(c 1.98, CHCl3); H NMR (CDCl3) δ 1.13 (d, J ) 6.6 Hz, 3H),
2.46 (s, 3H), 2.65 (m, 2H), 3.81 (septet, J ) 6.8 Hz, 1H), 5.51 (d,
J ) 7.8 Hz, 1H), 7.35 (d, J ) 8.1 Hz, 2H), 7.8 (d, J ) 8.1 Hz,
2H), 9.68 (s, 1H); 13C NMR (CDCl3) δ 21.3, 21.6, 45.5, 50.4, 127.1,
Typical Procedure for the Iodocyclization of Homoallylic
Sulfonamide. (2S,3R,5R)-(-)-3-Iodo-2,5-diphenyl-1-(p-tolyl-
sulfonyl)-pyrrolidine (5a). In an oven-dried, one-neck, round-
bottom flask equipped with a magnetic stirring bar, rubber septum,
and argon inlet was placed (+)-4 (0.053 g, 0.147 mmol) and K2-
CO3 (0.0648 g, 0.44 mmol) in CH3CN (1.5 mL) and H2O (0.016
mL), the solution stirred for 30 min at room temperature, and I2
(0.112 g, 0.440 mmol) was added. After consumption of the starting
material as judged by TLC analysis (3 h at room temperature), the
reaction mixture was quenched with saturated aqueous Na2S2O3 (1
mL), the phases were separated, and the aqueous phase was
extracted with CH2Cl2 (2 × 10 mL). The combined organic phases
were dried (MgSO4) and concentrated. Chromatography (1:9 Et2O/
hexanes) gave 0.024 g (40%) of a white solid as inseparable mixture
of diastereomers in a ratio of 88:12 and 0.024 g (45%) of recovered
Z homoallylic sulfonamide 6a: mp 163-164 °C; [R]20D -10.3° (c
0.76, CHCl3); 1H NMR (CDCl3) major isomer δ 2.26 (s, 3H), 2.45
129.9, 137.7, 143.7, 200.9; IR (film) 3275, 2978, 2739, 1715 cm-1
;
HRMS (EI) m/e calcd for C11H15NO3NaS (M + Na) 264.067035,
found 264.0668.
Typical Procedure for the Preparation of Homoallylic Sul-
fonamide. (R)-(+)-N-(1,4-Diphenylbut-3-enyl)-4-methyl-benzen-
sulfonamide (4). In an oven-dried one-neck round-bottom flask,
equipped with a magnetic stirring bar, rubber septum, and argon
inlet was placed benzyltriphenylphosphonium bromide (1.49 g, 3.43
mmol) in THF (18 mL). The solution was cooled to 0 °C, n-BuLi
(2.14 mL, 3.43 mmol, 1.6 M in hexanes) was added, and the
solution was stirred for 1 h at room temperature. At this time the
reaction mixture was cooled to -78 °C, and a solution of (+)-9a
(0.20 g, 0.686 mmol) in THF (3 mL) was added. After consumption
(20) Wang, J.; Hou, Y. J. Chem. Soc., Perkin Trans. 1 1998, 1919.
J. Org. Chem, Vol. 71, No. 7, 2006 2783

Davis et al.
(dt, J ) 15.0, 5.4 Hz, 1H), 3.16 (dt, J ) 14.4, 8.6 Hz, 1H), 4.28
(dt, J ) 7.5, 4.7 Hz, 1H), 5.20 (dd, J ) 8.9, 5.5 Hz, 1H), 5.34 (d,
J ) 4.2 Hz, 1H), 6.86 (d, J ) 8.4 Hz, 1H), 6.96 (d, J ) 8.4 Hz,
1H), 7.1-7.4 (m, 12H); Minor isomer δ 2.57 (m, 1H), 2.74 (m,
1H), 4.12 (m, 1H), 5.21 (d, J ) 9.0 Hz, 1H); 13C NMR (CDCl3) δ
21.4, 24.9, 45.8, 65.2, 77.1, 126.6, 127.2, 126.9, 127.7, 128.1, 128.4,
) 7.8, 3H), 1.07 (d, J ) 6.5 Hz, 3H), 1.94 (dq, J ) 1.5, 7.5 Hz,
2H), 2.12 (q, J ) 6.5 Hz, 2H), 2.43 (s, 3H), 3.32 (quint, J ) 6.8
Hz, 1H), 4.46 (d, J ) 7.5 Hz, 1H), 5.13 (m, 1H), 5.46 (m, 1H),
7.30 (d, J ) 8.0 Hz, 2H), 7.76 (m, 2H); 13C NMR (CDCl3) δ 14.8,
21.3, 21.8, 35.2, 35.3, 50.41, 123.9, 127.8, 130.3, 136.1, 138.6,
143.9; IR (film) 3279, 2967, 2933, 1329, 1184 cm-1; HRMS (EI)
m/e calcd for C14H21NO2NaS (M + Na) 290.119071, found
290.1195.
Photolysis of (S)-(-)-N-(Hept-4-en-2-yl)-4-methylbenzene-
sulfonamide and Its Iodocyclization. In an oven-dried one-neck
round-bottom flask, equipped with magnetic stirring bar and rubber
septum, was placed PhSSPh (0.082 g, 0.375 mmol) and the mixture
of 4:6 E:Z isomers of (-)-11 (0.082 g, 0.375 mmol) in cyclohexane
(3 mL). The solution was irradiated by mercury lamp (300 nm,
450 W) for 6 h with stirring. The reaction was quenched with
saturated aqueous NaHCO3 (1 mL) and extracted with EtOAc (3
mL), and the organic phases were dried (MgSO4) and concentrated.
Chromatography (20% Et2O/hexane) provided 0.004 g (80%) of a
colorless oil as an inseparable 8:2 E and Z mixture of 11. Following
the typical procedure for the iodocyclization, (-)-11 (0.04 g, 0.150
mmol, E:Z 8:2), K2CO3 (0.062 g, 0.45 mmol), and I2 (0.114 g,
0.45 mmol) were employed. Chromatography (10% Et2O/hexane)
gave 0.042 g (71%) of a yellow oil and 0.008 g (20%) of recovered
Z-homoallylic sulfonamide 6c.
(2R,5R)-(+)-2,5-Diphenyl-1-tosylpyrrolidine (12). In an oven-
dried, argon-purged 25-mL, one-neck flask attached to reflux
condenser and equipped with stir bar was placed toluene (5 mL),
(-)-5a (0.047 g, 0.096 mmol), and Bu3SnH (0.255 mL, 0.96 mmol).
The reaction mixture was refluxed at 130 °C for 4 h at which time
the solvent and excess Bu3SnH were evaporated off under reduced
pressure. Chromatography (3:17 Et2O/hexanes) afforded 0.034 g
(98%) of a colorless oil: [R]20D +116.6° (c 1.10, CHCl3); 1H NMR
(CDCl3) δ 1.80 (m, 2H), 2.32 (s, 3H), 2.62 (m, 2H), 5.27 (d, J )
7.0 Hz, 2H), 6.93 (d, J ) 8.0 Hz, 2H), 7.14 (d, J ) 8 Hz, 2H),
7.16-7.27 (m, 10H); 13C NMR (CDCl3) δ 34.0, 65.3, 65.5, 127.0,
127.5, 127.6, 128.9, 129.4, 139.1, 142.8, 143.5; IR (film) 3027,
2961, 2922, cm-1; HRMS calcd for C23H23NO2SNa (M + Na)
400.1347, found 400.1354.
128.6, 128.7, 138.2, 138.9, 139.7, 142.3; IR (film) 3031, 2921 cm-1
;
HRMS calcd for C23H22NO2SINa (M + Na) 526.0314, found
526.0321.
(R,Z)-(+)-N-(1,4-Diphenylbut-3-enyl)-4-methylbenzenesulfon-
1
amide (6a): [R]20 +28.8° (c 1.45, CHCl3); H NMR (CDCl3) δ
D
2.36 (s, 3H), 2.74 (m, 2H), 4.41 (q, J ) 7.4 Hz, 1H), 5.69 (dt, J )
11.1, 7.5 Hz, 1H), 6.10 (d, J ) 7.5 Hz, 1H), 6.47 (d, J ) 11.4 Hz,
1H), 7.01 (d, J ) 8.4 Hz, 2H), 7.05-7.35 (m, 10H), 7.62 (d, J )
8.4 Hz, 2H); 13C NMR (CDCl3) δ 21.5, 36.2, 58.0, 126.7, 127.2,
128.5, 128.7, 129.3, 132.4, 136.8, 137.5, 138.3, 139.0, 139.8, 140.3,
142.4, 143.1; IR (film) 3276, 3026, 2923 cm-1; HRMS calcd for
C23H23NO2SNa (M + Na) 400.1347, found 400.1349.
(2S,3R,5R)-(+)-2-Ethyl-3-iodo-5-phenyl-1-tosylpyrrolidine (5b).
Chromatography (20% Et2O/hexane) gave 0.031 g (46%) of a
yellow oil and 0.015 g (31%) of recovered Z-homoallylic sulfona-
mide 6b: [R]20D +3.7 (c 3.1, CHCl3); 1H NMR (CDCl3) δ 1.00 (t,
J ) 7.4 Hz, 3H), 1.67 (m, 1H), 2.12 (m, 1H), 2.24 (s, 3H), 2.37
(m, 1H), 3.18 (ddd, J ) 9.7, 16.1, 7.4 Hz, 1H), 4.34 (m, 2H), 4.80
(dd, J ) 9.8, 5.6 Hz, 1H), 6.87-7.0 (m, 5H), 7.17 (m, 4H); 13C
NMR (CDCl3) δ 11.0, 21.4, 21.7, 26.5, 46.4, 62.9, 76.7, 127.5,
127.8, 128.2, 129.0, 129.8, 138.5, 139.2, 142.7; IR (film) 2849,
2917, 1329, 1157 cm-1; HRMS (EI) m/e calcd for C19H22INO2-
NaS (M + Na) 478.031373, found 478.0330.
Upon irradiation of the C-5 proton at δ 4.8, a positive NOE was
observed on the C-4 proton at δ 3.18 (5.25%), confirming the cis
relationship between the C-5 proton and the C-4 proton and
determining the C-4 proton at δ 3.18 as HR of two methylene C-4
protons. Upon irradiation of the C-4 proton HR at δ 3.18, positive
NOEs were observed on the C-5 proton at δ 4.8 (7.87%) and on
the C-3 proton at δ 4.34 (5.55%), confirming the cis relationship
between the C-5 proton and the C-3 proton. Upon irradiation of
the C-2 methyl at δ 1.0, a positive NOE was observed on the C-5
proton at δ 4.80 (3.21%), confirming the trans relationship between
the C-2 proton and the C-5 proton.
(2R,5R)-(+)-2,5-Diphenylpyrrolidine (13). In an oven-dried,
argon-purged 50-mL, three-neck round-bottom flask equipped with
a magnetic stir bar and dry ice condenser and cooled to -78 °C
was collected NH3 (∼10 mL). Sodium metal (∼0.9 g) was added,
and the solution was stirred for 15 min. At this time (+)-15 (0.021
g, 0.058 mmol) in THF (3 mL) was then added dropwise. The
reaction was quenched after 30 min by addition of solid NH4Cl
(1.3 g), and the NH3 was allowed to evaporate by warming to room
temperature. Water (10 mL) was then added, and the solution was
extracted with Et2O (2 × 5 mL), dried (MgSO4), and evaporated.
Chromatography (1:9 EtOAc/hexanes) afforded 0.0053 g (47%) of
clear film: [R]20 +102.1° (c 0.47, CHCl3), [lit.16b [R]20 +104.5
(R,Z)-(+)-4-Methyl-N-(1-phenylhex-3-enyl)benzenesulfon-
amide (6b): [R]20D +47.3 (c 1.5, CHCl3); 1H NMR (CDCl3) δ 0.70
(t, J ) 7.5 Hz, 3H), 1.74 (quint, J ) 7.4 Hz, 1H), 2.20 (s, 3H),
2.32 (m, 2H), 4.14 (q, J ) 7.0, 1H), 4.67 (d, J ) 6.0 Hz, 2H), 4.88
(m, 1H), 5.28 (m, 1H), 6.94 (m, 7H), 7.39 (d, J ) 7.8 Hz, 2H); 13
C
NMR (CDCl3) δ 14.4, 21.0, 21.8, 35.6, 58.1, 123.2, 127.0, 127.5,
127.7, 128.7, 129.7, 136.3, 137.9, 140.9, 143.4; IR (film) 3278,
2964, 1622, 1325, 1184 cm-1; HRMS (EI) m/e calcd for C19H23-
NO2NaS (M + Na) 352.1347, found 352.1346.
(2S,3R,5S)-(+)-2-Ethyl-3-iodo-5-methyl-1-tosylpyrrolidine (5c).
Chromatography (20% Et2O/hexane) gave 0.026 g (39%) of a
D
D
(c 1.00, CHCl3)]; 1H NMR (CDCl3) δ 1.97 (m, 2H), 2.43 (m, 2H),
2.7-3.2 (s, br, 1H), 4.59 (t, J ) 7.0 Hz, 2H), 7.26 (t, J ) 7.3 Hz,
2H), 7.34 (t, J ) 7.3 Hz, 4H), 7.43 (d, J ) 7.5 Hz, 4H); 13C NMR
(CDCl3) δ 35.1, 62.4, 126.3, 127.2, 128.6, 144.4; IR (film) 3400,
2921, 2851 cm-1; HRMS calcd for C16H18N (M + H) 224.1439,
found 224.1436.
yellow oil and 0.022 g (49% recovery) of recovered Z-homoallylic
1
sulfonamide 6c: [R]20 +2.9 (c 1, CHCl3); H NMR (CDCl3) δ
D
0.96 (t, J ) 7.5 Hz, 3H), 1.42 (d, J ) 6.5 Hz, 3H), 1.47 (m, 1H),
2.06 (m, 1H), 2.10 (m, 1H), 2.43 (s, 3H), 2.87 (ddd, J ) 8.5, 15.0,
6.5 Hz, 1H), 4.15 (m, 1H), 4.21 (dd, J ) 3.0, 10.0 Hz, 1H), 4.26
(dt, J ) 6.5, 1.8 Hz, 1H), 7.30 (d, J ) 8.0 Hz, 2H), 7.84 (d, J )
8.5 Hz, 2H); 13C NMR (CDCl3) δ 11.1, 21.2, 21.9, 28.5, 44.1, 56.16,
56.2, 76.3, 127.9, 130.0, 140.2, 143.7; IR (film) 2971, 2932, 2876,
1457, 1338, 1157 cm-1; HRMS (EI) m/e calcd for C14H20INO2-
NaS (M + Na) 416.015723, found 416.0148.
(R)-(-)-N-(Pentenylidene)-p-toluenesulfonamide (14). In a
100-mL round-bottom, one-neck flask equipped with a magnetic
stirring bar, rubber septum, and argon inlet was placed valeralde-
hyde (0.422 mL, 3.852 mmol), Ti(OEt)4 (0.377 mL, 12.84 mmol),
and (R)-(-)-p-toluenesulfonamide (0.298 g, 2.568 mmol) in CH2-
Cl2 (40 mL), and the solution was stirred for 2.5 h at 0 °C. At this
time the reaction mixture was quenched with water (10 mL) and
filtered through Celite, rinsing with CH2Cl2 (20 mL), and the
organic phases concentrated. Chromatography (35% Et2O/hexane)
Upon irradiation of the C-2 methyl at δ 0.96, a positive NOE
was observed on the C-3 proton at δ 4.26 (6.4%), confirming trans
relationship between the C-2 proton and C-3 proton. Upon
irradiation of the C-5 methyl at δ 1.42, a positive NOE was
observed on the C-2 proton at δ 4.15 (2.0%), confirming a trans
relationship between the C-5 proton and C-2 proton.
gave 0.550 g (96%) of a colorless oil: [R]20 -292.9 (c 0.97,
D
CHCl3); 1H NMR (CDCl3) δ 0.86 (t, J ) 7.2 Hz, 3H), 1.31 (sextet,
J ) 7.4 Hz, 2H), 1.55 (m, 2H), 2.36 (s, 3H), 2.44 (m, 2H), 7.26 (d,
J ) 7.8 Hz, 2H), 7.51 (d, J ) 7.8 Hz, 2H), 8.18 (t, J ) 4.95 Hz,
(S,Z)-(-)-N-(Hept-4-en-2-yl)-4-methylbenzenesulfonamide
1
(6c): [R]20 -31.5 (c 1.0, CHCl3); H NMR (CDCl3) δ 0.92 (t, J
D
2784 J. Org. Chem., Vol. 71, No. 7, 2006

Asymmetric Synthesis of trans-2,5-Disubstituted Pyrrolidines
1H); 13C NMR (CDCl3) 13.1, 20.7, 21.6, 26.8, 35.0. 123.9, 129.1,
141.2, 143.7, 166.8; IR (film) 2957, 2931, 2872 cm-1; HRMS calcd
for C12H18NOS (M + H) 224.1109, found 224.1108.
solution of (R)-(+)-17 (0.086 g, 0.304 mmol) in THF (1 mL) was
added. The reaction mixture stirred for 8 h at -78 °C, quenched
with H2O (1 mL), warmed to room temperature, extracted with
EtOAc (2 × 5 mL), dried (MgSO4), and concentrated. Chroma-
tography (20% Et2O/hexane) gave 0.08 g (75%) of a colorless oil
as an inseparable 54:46 E and Z mixture. In an oven-dried, one-
neck, round-bottom flask equipped with a magnetic stirring bar and
rubber septum was placed the E and Z mixture of (+)-18 (0.077 g,
0.219 mmol) and PhSSPh (0.096 g, 0.439 mmol) in cyclohexane
(4 mL). The reaction mixture was irradiated by mercury lamp (300
nm, 450 W) for 6 h with stirring, quenched with saturated aqueous
NaHCO3 (1 mL), and extracted with EtOAc (5 mL) The organic
phases were dried (MgSO4) and concentrated. Chromatography
(20% Et2O/hexane) provided 0.065 g (84%) of a colorless oil as
an inseparable 85:15 E and Z mixture: [R]20D +24.4 (c 1.0, CHCl3);
1H NMR (CDCl3) δ 0.73 (t, J ) 6.6 Hz, 3H), 0.81 (t, J ) 7.0 Hz,
3H), 1.01-1.39 (m, 12H), 1.82 (m, 2H), 1.94 (t, J ) 6.2 Hz, 2H),
2.35 (s, 3H), 3.13 (m, 1H), 4.41 (d, J ) 8.0 Hz, 1H), 5.02 (m, 1H),
5.27 (m, 1H), 7.22 (d, J ) 8.0 Hz, 2H), 7.68 (d, J ) 8.0 Hz, 2H);
13C NMR (CDCl3) δ 14.2, 14.3, 21.8, 22.7, 22.8, 27.9, 29.6, 31.7,
32.9, 34.7, 38.1, 54.0, 124.7, 127.5, 129.8, 135.5, 138.8, 143.4; IR
(film) 2917, 2849 cm-1; HRMS (EI) m/e calcd for C20H33NO2NaS
(M + Na) 374.212971, found 374.2136.
(RS,R)-(-)-Methyl-N-(p-toluenesulfinyl)-3-aminopehtanoate
(15). In an oven-dried, 100-mL, round-bottom one-neck flask
equipped with a magnetic stirring bar, rubber septum, and argon
inlet was placed NaHMDS (3.6 mL, 3.57 mmol, 1.0 M solution in
THF) in ether (20 mL). The solution was cooled to -78 °C, and
anhydrous MeCO2Me (0.283 mL, 3.57 mmol) was added dropwise
via syringe. After the solution was stirred for 1 h at this temperature,
(-)-14 (0.53 g, 2.377 mmol) in Et2O (4 mL) was added via cannula.
The resulting mixture was stirred for 2 h at -78 °C and quenched
with saturated aqueous NH4Cl (5 mL) at this temperature. The
solution was warmed to room temperature, diluted with H2O (10
mL), and extracted with EtOAc (2 × 50 mL), and the combined
organic phases were washed with brine (2 × 10 mL), dried
(MgSO4), and concentrated. Chromatography (50% Et2O/hexane)
gave 0.648 g (92%) of a colorless oil as a single diastereomer:
[R]20D - 89 (c 1.25, CHCl3); 1H NMR (CDCl3) δ 0.83 (d, J ) 6.6
Hz, 3H), 1.2-1.7 (m, 6H), 2.32 (s, 3H), 2.51 (m, 2H), 3.57 (s,
4H), 4.59 (d, J ) 9.0 Hz, 1H), 7.2 (d, J ) 8.1 Hz, 2H), 7.49 (d, J
) 8.1 Hz, 2H); 13C NMR (CDCl3) δ 13.9, 21.3, 22.3, 28.2, 35.5,
40.4, 51.6, 52.5, 76.7, 125.5, 129.4, 141.1, 142.3, 171.9; IR (film)
3210, 2955, 2862, 1734, 1050 cm-1; HRMS (EI) m/e calcd for
C15H23NO3NaS (M + Na) 320.129635, found 320.1303.
(2R,3S,5R)-(+)-5-Butyl-3-iodo-2-pentyl-1-tosylpyrrolidine (20).
Following typical procedure for the iodocyclization, (+)-18 (0.062
g, 0.177 mmol, E:Z 85:15), K2CO3 (0.073 g, 0.531 mmol), and I2
(0.135 g, 0.531 mmol) were employed. Chromatography (5% Et2O/
hexane to 20% Et2O/hexane) gave 0.069 g (82%) of a yellow oil
as a separable 84:16 mixture of diastereomers and 0.006 g (10%)
(R)-(+)-Methyl 3-(4-methylphenylsulfonamido)heptanoate (16).
In an oven-dried, 100-mL one-neck round-bottom, flask equipped
with a magnetic stirring bar, rubber septum, and argon inlet was
placed (Rs,R)-(-)-methyl-N-(p-toluenesulfinyl)-3-aminopheptanoate
15 (0.645 g, 2.172 mmol) in CH2Cl2 (43 mL). The solution was
cooled to 0 °C, and m-CPBA (0.614 g, 6.515 mmol) was added.
The reaction mixture was stirred for 3 h at 0 °C, quenched with
saturated aqueous Na2S2O3 (5 mL), diluted with CHCl3 (20 mL),
and stirred vigorously. The organic phases were dried (MgSO4)
and concentrated. Chromatography (50% Et2O/hexane) gave 0.647
g (95%) of a colorless oil: [R]20D +21.9 (c 1.05, CHCl3); 1H NMR
(CDCl3) δ 0.80 (d, J ) 6.8 Hz, 3H), 1.19 (m, 4H), 1.46 (m, 2H),
2.37-2.52 (m, 5H), 3.55 (m, 1H), 3.64 (s, 3H), 5.44 (d, J ) 9.0
Hz, 1H), 7.33 (d, J ) 8.1 Hz, 2H), 7.80 (d, J ) 7.8 Hz, 2H); 13C
NMR (CDCl3) δ 13.9, 21.5, 22.2, 27.8, 34.5, 38.9, 50.7, 51.7, 127.1,
of recovered Z homoallylic sulfonamide. Major diastereomer: [R]20
D
+52.8 (c 3.6, CHCl3); 1H NMR (C6D6) δ 0.79 (t, J ) 7.3 Hz, 3H),
0.87 (t, J ) 7.0 Hz, 3H), 1.0 (m, 2H), 1.15-1.3 (m, 9H), 1.74 (m,
1H), 1.88 (m, 1H), 1.89 (s, 3H), 2.1 (ddd, J ) 6.6, 8.6, 15.2 Hz,
1H), 2.19 (m, 2H), 3.79 (dt, J ) 1.9, 6.7 Hz, 1H), 3.88 (m, 1H),
4.37 (dd, J ) 1.7, 8.1, 1H), 6.83 (m, 2H), 7.98 (m, 2H); 13C NMR
(C6D6) δ 14.5, 14.6, 21.5, 22.9, 23.1, 23.3, 26.6, 29.5, 32.3, 34.0,
35.3, 40.6, 60.7, 74.8, 127.9, 129.8, 141.9, 143.0; IR (film) 2956,
2927, 2859, 1339, 1156 cm-1; HRMS (EI) m/e calcd for C20H32-
INO2NaS (M + Na) 500.109623, found 500.1099.
The C-4 proton Hâ at δ 2.1 was assigned from COSY spectrum
and NOE experiments. Upon irradiation of the C-4 proton Hâ at δ
2.1, a positive NOE was observed on the C-3 proton at δ 3.79
(9.3%) and on the C-5 proton at δ 3.88 (11.2%), confirming the
cis relationship between the C-3 proton and the C-5 proton. The
trans relationship between the C-2 proton and the C-3 proton was
confirmed by the trans vicinal coupling constant of J ) 6.7 of the
C-3 proton at δ 3.79 originating from coupling between the C-3
proton and the C-2 proton.
129.7, 138.1, 143.4, 171.8; IR (film) 3288, 2956, 1330, 1160 cm-1
;
HRMS (EI) m/e calcd for C15H23NO4NaS (M + Na) 336.12455,
found 336.1251.
(R)-(+)-4-Methyl N-(1-oxoheptan-3-yl)benzenesulfonamide
(17). In an oven-dried, 50-mL, round-bottom one-neck flask
equipped with a magnetic stirring bar, rubber septum, and argon
inlet was placed (R)-(+)-16 (0.645 g, 2.061 mmol) in toluene (21
mL). The solution was cooled to -78 °C, and then DIBAL-H (2.1
mL, 2.1 mmol, 1.0 M solution in CH2Cl2) was added dropwise.
The reaction mixture was stirred for 3 h at -78 °C and quenched
with aqueous Rochell salt (5 mL) at -78 °C. The resulting mixture
was warmed to room temperature, diluted with EtOAc (10 mL),
and stirred vigorously until the solution becomes two clear layers.
Chromatography (35% Et2O/hexane) provided 0.432 g (76%) of a
colorless oil and 0.125 g (19%) of starting material: [R]20D +24.8
(c 1.0, CHCl3); 1H NMR (CDCl3) δ 0.76 (d, J ) 6.6 Hz, 3H), 1.14
(m, 5H), 1.42 (m, 2H), 2.44 (s, 3H), 2.62 (d, J ) 5.7 Hz, 1H), 3.64
(m, 1H), 5.45 (bs, 1H), 7.33 (d, J ) 8.1 Hz, 2H), 7.78 (d, J ) 8.1
Hz, 2H), 9.66 (s, 1H); 13C NMR (CDCl3) δ 13.8, 21.5, 22.1, 27.7
34.7, 48.8, 49.5, 127.1, 129.8, 137.8, 143.6, 201.0; IR (film) 3281,
2957, 2735, 1719, 1327, 1159 cm-1; HRMS (EI) m/e calcd for
C14H21NO3NaS (M + Na) 306.113985, found 306.1132.
(R,Z)-(+)-4-Methyl-N-(tridec-7-en-5-yl)benzenesulfonamide
1
(19): [R]20 +18.8 (c 2.8, CHCl3); H NMR (CDCl3) δ 0.85 (t,
D
J ) 6.5 Hz, 3H), 0.94 (t, J ) 6.6 Hz, 3H), 1.16-1.53 (m, 12H),
1.84 (m, 2H), 2.08 (m, 2H), 2.48 (s, 3H), 3.29 (sext, J ) 6.8 Hz,
1H), 4.61 (d, J ) 8.1 Hz, 1H), 5.22 (m, 1H), 5.49 (m, 1H), 7.35
(d, J ) 7.8 Hz, 2H), 7.83 (d, J ) 8.1 Hz, 2H); 13C NMR (CDCl3)
δ 14.0, 14.1, 21.6, 22.4, 22.6, 27.4, 27.6, 29.3, 31.6, 32.6, 34.3,
53.9, 123.8, 127.2, 129.6, 133.7, 138.3, 143.2; IR (film) 2917, 2849
cm-1; HRMS (EI) m/e calcd for C20H33NO2NaS (M + Na)
374.212971, found 374.2136.
Upon irradiation of one of the alkenyl protons at δ 5.49, a
positive NOE was observed on the other alkenyl proton at δ 5.22
(2.9%), confirming the Z geometry of olefin.
(2R,5R)-(-)-2-Butyl-5-pentyl-1-tosylpyrrolidine (21). In an
oven-dried, 10-mL, round-bottom one-neck flask equipped with a
magnetic stirring bar, rubber septum, and argon inlet was placed
(+)-20 (0.037 g, 0.078 mmol) in dry toluene (4 mL) and Bu3SnH
(0.194 mL, 0.73 mmol), and the reaction mixture was refluxed for
1 h at 125 °C. The resulting mixture was cooled to room
temperature and concentrated. Chromatography (10% Et2O/hexane)
(R)-(+)-4-Methyl N-(tridec-7-en-5-yl)benzenesulfonamide (18).
In an oven-dried, 50-mL, round-bottom one-neck flask equipped
with a magnetic stirring bar, rubber septum, and argon inlet was
placed hexyltrophenylphosphonium bromide (0.65 g, 1.52 mmol)
in THF (5 mL), and n-BuLi (0.6 mL, 1.52 mmol, 2.5 M solution
in hexane) was added dropwise at 0 °C. The resulting mixture was
stirred for 1 h at room temperature and cooled to -78 °C, and a
provided 0.027 g (99%) of a colorless oil: [R]20 -43.5 (c 2.7,
D
J. Org. Chem, Vol. 71, No. 7, 2006 2785

Davis et al.
CHCl3); 1H NMR (CDCl3) δ 0.79 (t, J ) 7.2 Hz, 3H), 0.81 (t, J )
7.2 Hz, 3H), 1.0-1.40 (m, 12H), 1.60 (m, 2H), 1.86 (m, 4H), 2.37
(s, 3H), 3.75 (m, 2H), 7.21 (m, 2H), 7.67 (m, 2H); 13C NMR
(CDCl3) δ 13.9, 14.3, 16.8, 21.7, 22.9, 26.4, 26.9, 28.4, 29.0, 29.5,
32.0, 34.0, 34.2, 62.1, 127.3, 129.8, 140.6, 142.8; IR (film) 2957,
2927, 1342, 1156 cm-1; HRMS (EI) m/e calcd for C20H33NO2NaS
(M + Na) 374.212971, found 374.2134.
magnetic stirring bar, rubber septum, and argon inlet were placed
(-)-22 (0.02 g, 0.01 mmol) in CH2Cl2 (1 mL) and 20% aqueous
K2CO3 (1 mL, 1.45 mmol) at 0 °C. The solution was stirred for 5
min, and benzoyl chloride (0.012 mL, 0.1 mmol) was added. After
being stirred for 1 h at 0 °C, the reaction mixture was dissolved in
Et2O (3 mL), and the organic phase was washed with brine (2 ×
2 mL), dried (MgSO4), and concentrated. Chromatography (5%
(-)-Pyrrolidine 197B (22). In a 25-mL, two-neck, round-bottom
flask equipped with a magnetic stirring bar, a rubber septum, argon
inlet, and an acetone-dry ice cooled coldfinger condenser, cooled
to -78 °C, was passed NH3 (g) until approximately 7 mL of liquid
NH3 (1/3 of flask volume) was collected. A solution of (-)-21
(0.023 g, 0.066 mmol) in THF (3 mL) was added, and enough Na
was introduced until a permanent deep navy blue color persisted.
After 1.5 h of stirring at -78 °C, the reaction mixture was quenched
by addition of solid NH4Cl (∼1 g), and the excess NH3 was
removed by passing argon through the solution with warming to
room temperature. At this time the residue was diluted with Et2O
(5 mL) and water (2 mL). The solution was extracted with ether (2
× 10 mL), and the combined organic phases were dried (MgSO4).
Since the product was volatile, the organic phase was concentrated
carefully at 0 °C. Chromatography (CHCl3/MeOH-NH3 10:1) gave
EtOAc/hexane) provided 0.01 g (33%) of a colorless oil: [R]20
D
-231.5 (c 0.1, CHCl3) [lit.19b enantiomer, [R]27 +125.5 (c 1.0,
D
CHCl3)]; 1H NMR (CDCl3) δ 0.55, 0.64 (1:1 ratio, total 6H, t, J )
7.0, 7.2 Hz, respectively, due to rotamers), 0.66-1.11 (m, 10H),
1.26 (m, 3H), 1.63 (m, 2H), 1.84-2.07 (m, 3), 3.89, 4.19 (1:1 ratio,
total 2H, m, due to rotamers), 7.3 (m, 3H), 7.4 (m, 2H); 13C NMR
(CDCl3) δ 14.0, 14.1, 14.3, 21.2, 22.5, 22.9, 26.1, 26.5, 26.9, 28.6,
29.0, 32.1, 33.1, 33.4, 34.6, 34.8, 58.0, 59.7, 59.9, 105.5, 127.3,
128.5, 129.7, 140.0, 170.6. Spectral properties were consistent with
literature values.19b
Acknowledgment. This work was supported by a grant from
the National Institutes of General Medicinal Sciences (NIGMS
51982).
0.008 g (62%) of a yellow oil: [R]20D -25.3 (c 0.6, CHCl3) [lit.19b
Note Added after ASAP Publication. There were errors in
the Abstract/TOC graphic and Scheme 1 in the version published
ASAP February 24, 2006; the corrected version was published
ASAP February 27, 2006.
1
[R]25 -5.8 (c 0.61, CHCl3)]; H NMR (CDCl3) δ 0.87 (m, 6H),
D
1.22-1.47 (m, 16H), 1.93 (m, 2H), 2.1 (bs, 1H), 3.1 (m, 2H); 13
C
NMR (CDCl3) δ 14.4, 14.43, 23.0, 23.2, 27.4, 29.9, 32.4, 32.8 (2C),
37.1, 37.4, 58.5 (2C); IR (film) 2955, 2926, 2860 cm-1; HRMS
(EI) m/e calcd for C13H28N (M + H) 198.222175, found 198.2218,
m/e calcd for C13H26N (M - H) 196.206525, found 196.2061.
Spectral properties are consistent with literature values.19b
Supporting Information Available: 1H and 13C NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(2R,5R)-(-)-N-Benzoyl-2-butyl-5-pentylpyrrolidinine. In an
oven-dried, 5-mL round-bottom one-neck flask equipped with a
JO052566H
2786 J. Org. Chem., Vol. 71, No. 7, 2006