A novel stereodivergent synthesis of optically pure cis- and trans-3-substituted proline derivatives

Full text of DOI:10.1021/jo961790r

J . Org. Chem. 1997, 62, 765-770
765
Sch em e 1
A Novel Ster eod iver gen t Syn th esis of
Op tica lly P u r e cis- a n d tr a n s-3-Su bstitu ted
P r olin e Der iva tives
N. Andre´ Sasaki,* Michael Dockner, Ange`le Chiaroni,
Claude Riche, and Pierre Potier
Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
stereochemistry of the alkyl group at C-3 be diverted by
reversing the order of alkylation, namely, by first alky-
lating on the C-3 position and then by forming hetero-
cyclic ring so as to obtain a C-3 diastereomer?
Received September 18, 1996
In tr od u ction
As a continuation of our studies in developing a novel
methodology for the synthesis of optically pure disubsti-
tuted pyrrolidines,6 we have been interested in investi-
gating the above question to explore a new stereodiver-
gent route to enantio- and diastereoselective synthesis
of 3-substituted proline derivatives in optically pure form.
In this paper, we describe our new findings.
During the last several years, a number of optically
active cis- and trans-2,3-disubstituted pyrrolidines have
been synthesized for the preparation of appropriate
starting materials in the syntheses of indolizidine1 and
pyrrolizidine alkaloids2 and in search of potent ligands
for the NMDA receptor.3 More recently, effort in the
synthesis of 2,3-disubstituted pyrrolidines has been
reinforced in terms of the synthesis of 3-substituted
prolines, which have been viewed as conformationally
constrained analogues of natural R-amino acids bridged
by an ethylene group between the R-nitrogen and the
â-carbon.4 Introduction of rigidity into bioactive peptides
has been considered as a useful means to study confor-
mational prerequisites for their biological activities. One
of the easily conceivable ways of inducing conformational
constrains is to replace a natural amino acid with a
3-monosubstituted proline. Despite a growing interest
in this type of R-amino acids, there are as yet very few
practical methods for their preparation in optically pure
form.4c,5
Resu lt a n d Discu ssion
We chose trans- and cis-3-allyl-L-proline derivatives 8a
and 8c, respectively, as our target molecules. This choice
was based on the anticipation that in the course of
1
syntheses, H and 13C NMR spectra of the allyl group
might provide some useful information concerning its
stereochemical relationship with the neighboring func-
tionalities. Allyl is also a masked group to be trans-
formed into another functionality. In addition, N-Boc-
trans-3-allyl-L-proline, 8a , was reported by Holladay et
al. in the synthesis of a highly potent analogue of
C-terminal tetrapeptide of cholecystokinin, which con-
tains trans-3-n-propyl-L-proline in place of L-meth-
ionine.4b, 5a
Upon treatment of 17 with freshly prepared 2-bromo-
ethyl triflate in THF at -78 °C, the pyrrolidine 28 was
generated and purified by flash chromatography (EtOAc-
heptane ) 1:2) (92%). Alkylation of the monolithiate of
2 with 1.2 equiv of allyl bromide in THF at -78 °C
afforded an inseparable mixture of 4a and the corre-
sponding C-3 diastereomer 4b in 85% yield (route A) after
purification by flash chromatography on silica gel (EtOAc-
heptane ) 1:2). Removal of THP by treatment with
PPTS in ethanol gave a mixture of 5a /5b in excellent
yield. HPLC analysis of this mixture showed the ratio
of the diastereomers to be 6:94.9 Then, we reversed the
order of alkylation on the sulfonyl carbanion. The
dilithiated anion of 1 was treated with allyl bromide at
-78 °C to give 3 in 95% yield after chromatographic
purification. Allylic sulfone 3 was treated with 2 equiv
of n-BuLi in THF at -78 °C, and then 1.2 equiv of
2-bromoethyl triflate was added. After standard workup,
a mixture of pyrrolidine products 4a /4b was purified by
flash chromatography (EtOAc-heptane ) 1:2) (route B).
Treatment of this mixture with a catalytic amount (0.1
Previously, we have reported that nucleophilic attack
of the sulfonyl carbanion of 2, derived from 1 by one-
step pyrrolidine ring formation, takes place with very
high diastereofacial selectivity, as shown in Scheme 1.3a
This prompted us to raise the question as to whether
the same trend of high diastereoselectivity could be
observed in the alkylation on the carbanion of 2 with
other alkylating groups. And if this is the case, can the
(1) (a) Cooper, J .; Gallagher, P. T.; Knight, D. W. J . Chem. Soc.,
Chem. Commun. 1988, 509. (b) Sibi, M. P.; Christensen, F. W.
Tetrahedron Lett. 1995, 36, 6213.
(2) (a) Ewing, W. R.; J oullie´, M. M. Heterocycles 1988, 27, 2843. (b)
Thaning, M.; Wistrand, L.-G. Acta Chem. Scand. 1989, 43, 290. (c)
Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1989, 54, 1866. (d) Bhide,
R.; Mortezaei, R.; Scilimati, A.; Sih, C. J . Tetrahedron Lett. 1990, 31,
4827. (e) J urczak, J .; Prokopowicz, P.; Golebiowski, A. Ibid. 1993, 34,
7107. (f) Cooper, J .; Gallagher, P. T.; Knight, D. W. J . Chem. Soc.,
Perkin Trans. 1 1993, 1313. (g) Sundram, H.; Golebiowski, A.; J ohnson,
C. R. Tetrahedron Lett. 1994, 35, 6975. (h) Herdeis, C.; Hubmann, H.
P.; Lotter, H. Tetrahedron: Asymmetry 1994, 5, 119. (i) Mulzer, J .;
Meier, A.; Buschmann, J .; Luger, P. J . Org. Chem. 1996, 61, 566. (j)
Dell’Uomo, N.; Di Giovanni, M. C.; Misiti, D.; Zappia, G.; Delle
Monache, G. Tetrahedron: Asymmetry 1996, 7, 181. (k) Kanemasa,
S.; Tatsukawa, A.; Wada, E. J . Org. Chem. 1991, 56, 2875.
(3) (a) Sasaki, N. A.; Pauly, R.; Fontaine, C.; Chiaroni, A.; Riche, C.
Potier, P. Tetrahedron Lett. 1994, 35, 241. (b) Humphrey, J . M.;
Bridges, R. J .; Hart, J . A.; Chamberlin, A. R. J . Org. Chem. 1994, 59,
2467. (c) Hashimoto, K.; Yamamoto, O.; Horikawa, M.; Ohfune, Y.;
Shirahama, H. Bioorg. Med. Chem. Lett. 1994, 4, 1851. (d) Langlois,
N.; Andriamialisoa, R. Z. Tetrahedron Lett. 1991, 32, 3057.
(4) (a) Belokon, Y. N.; Bulychev, A. G.; Pavlov, V. A.; Fedorova, E.
B.; Tsyryapkin, V. A.; Bakhmutov, V. A.; Belikov, V. M. J . Chem. Soc.,
Perkin Trans. 1 1988, 2075. (b) Holladay, M. W.; Lin, C. W.; May, C.
S.; Garvey, D. S.; Witte, D. G.; Miller, T. R.; Wolfram, C. A. W.; Nadzan,
A. M. J . Med. Chem. 1991, 34, 457. (c) Herdeis, C.; Hubmann, H. P.;
Lotter, H. Tetrahedron: Asymmetry 1994, 5, 351.
(6) (a) Sasaki, N. A.; Sagnard, I. Tetrahedron 1994, 50, 7093. (b)
Dockner, M.; Sasaki, N. A.; Potier, P. Heterocycles 1996, 42, 529.
(7) Sasaki, N. A.; Hashimoto, C.; Potier, P. Tetrahedron Lett. 1987,
28, 6069.
(8) Pauly, R.; Sasaki, N. A.; Potier, P. Tetrahedron Lett. 1994, 35,
237.
(9) HPLC conditions for the determination of the ratio of 5a and
5b: column, Novapack Si 4 µm; column size, 3.9 × 150 mm; eluent,
(5) (a) Chung, J . Y. L.; Wasicak, J . T.; Arnold, W. A.; May, C. S.;
Nadzan, A. M.; Holladay, M. W. J . Org. Chem. 1990, 55, 270. (b) Waid,
P. P.; Flynn, G. A.; Huber, E. W.; Sabol, J . S. Tetrahedron Lett. 1996,
37, 4091.
heptane/AcOEt/AcOH ) 80/20/0.1; flow rate
1 mL/min; detector,
refractometer R 410 (Waters); retention time, (5a ) 9.45 min, (5b) 10.75
min.
S0022-3263(96)01790-2 CCC: $14.00 © 1997 American Chemical Society

766 J . Org. Chem., Vol. 62, No. 3, 1997
Notes
Sch em e 2a
a
Reaction conditions: (a) n-BuLi/THF, BrCH2CH2OTf, -78 °C; (b) n-BuLi/THF, allylbromide, -78 °C; (c) PPTS/EtOH, 50 °C.
F igu r e 1. ORTEP drawings of 5a and 5b.
mol equiv) of PPTS in EtOH at 50 °C provided an 89:11
mixture of 5a /5b (Scheme 2). Analytically pure 5b and
5a were easily available by recrystallization of the 5a /
5b mixutures obtained via routes A and B, respectively.
diastereomeric mixture was determined on the basis of
HPLC analysis of the derived (R)-(+)-R-methylbenzyla-
mides.11 Treatment of the thus obtained mixture of 8a /
8b with diazomethane followed by selective saponification
resulted in an easily separable mixture of cis-methyl ester
8c (55% overall yield from 8a /8b) and trans-acid 8a (10%
recovery). On the other hand, when the mixture of 5a /
5b obtained via route A was subjected to the sequential
desulfonylation-J ones oxidation procedure (route D), the
diastereomeric ratio of 8a and 8b (65% overall yield from
4a /4b) turned out to be 84:16. This result indicates that,
whereas the protonation (direct or mediated by the
solvent) of the desulfonylated anion species of 5b provides
thermodynamically favored trans product 7a , that of the
desulfonylated anion species of 4b takes place from the
sterically less hindered side of the molecule so as to
provide 6b as a major kinetic product (Scheme 3).
As far as the mixture of 5a /5b obtained via route B is
concerned, desulfonylation by 6% Na-Hg in methanol
afforded a single diastereomeric alcohol 7a in 80% yield.
This was then oxidized by J ones reagent in acetone to
provide 8a in 73% yield. The optical purity of 8a was
assessed to be more than 98% based on the HPLC
analysis of its amide prepared from (R)-(+)-R-methyl-
benzylamine.11 Catalytic hydrogenation of 8a on Pd/C
1
It is noteworthy that H and 13C NMR spectra of 5a and
5b are indicative of their C-3 configuration. While 5a
exhibits a multiplet centered at 6.08 ppm that is at-
tributed to one of the allylic protons, its counterpart of
5b appears somewhat upfield centered at 5.70 ppm,
suggesting a cis relationship between the allyl and the
hydroxymethyl groups. In 13C NMR spectra, signals at
40.0, 40.5, 120.0, and 130.7, 131.0 ppm are attributed to
the allylic carbons in 5a . Equally, 13C NMR spectrum of
5b shows corresponding signals at 34.8, 119.1, and 132.4
ppm. These characteristic differences in allylic signals
serve as a useful indication for the evaluation of approxi-
mative diastereomeric purity of the derivatives of 5a and
5b.
Finally, the absolute stereochemistry of 5a and 5b was
determined by single-crystal X-ray analysis, which un-
ambiguously demonstrates diastereomeric relationship
between (3R)-5a and (3S)-5b as shown in Figure 1.10
Desulfonylation of the mixtue of 4a /4b obtained via
route A with 6% Na-Hg in methanol, followed by
removal of THP and subsequent J ones oxidation in
acetone, provided a 37:63 mixture of 8a and 8b in 52%
overall yield from 4a /4b (route C). This ratio of the
(11) A mixture of 8a /8b was converted to (R)-(+)-R-methylbenzyla-
mides according to the method described by Chung et al.5a HPLC
conditions for the determination of the ratio of (R)-(+)-R-methyl-
benzylamide of 8a and 8b: column, Novapack Si 4 µm; column size,
3.9 × 150 mm; eluent, heptane/AcOEt/AcOH ) 80/20; flow rate 1 mL/
min; detector, refractometer R 410 (Waters); retention time ((R)-(+)-
R-methylbenzylamide of 8a ) 9.66 min, ((R)-(+)-R-methylbenzylamide
of 8b) 10.80 min.
(10) 5a : torsional angle, S-C2-C3-C3-callyl ) +71°. 5b: torsional
angle, S-C2-C3-C3-callyl ) -69°. Positive sign is characteristic for
the R configuration. Atomic coordinates have been deposited at the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.

Notes
J . Org. Chem., Vol. 62, No. 3, 1997 767
Sch em e 3a
a
Reaction conditions: (a) PPTS, EtOH, 50 °C; (b) 6% Na-Hg/Na2HPO4, MeOH; (c) J ones oxidation; (d) CH2N2; (e) 1 N NaOH, MeOH,
24 h.
Sch em e 4a
F igu r e 2.
silyloxy groups,14 we postulate that the stereochemical
outcome of the above reaction is due to a preferred
pyramidal sulfonyl carbanion configuration controlled by
the geometry and disposition of substituents at C-2. In
the lithiated species of 2 and 11, trans orientation of the
adjacent protected hydroxymethyl and phenylsulfonyl
groups is supposed to be the cause of the observed high
stereofacial selectivity.
a
Reaction conditions: (a) 6% Na-Hg, MeOH, Na2HPO4; (b)
J ones oxidation; (c) H2, Pd/C.
afforded optically pure N-Boc-trans-3-n-propyl-L-proline,
95a (Scheme 4).
Thus, this sequence provides an efficient entry into
enantiomerically and diastereomerically pure cis- and
trans-2,3-disubstituted pyrrolidines.
Con clu sion s
A novel stereodivergent method has been developed for
the synthesis of optically pure cis- and trans-3-substi-
tuted proline derivatives starting from readily available
1 (or its antipode 7) simply by reversing the order of
double alkylation on sulfonyl carbanion. This relatively
short step approach can provide access to all four possible
diastereomers in a stereocontrolled manner. The exten-
sion of this methodology for the preparation of other
constrained R-amino acids and for the synthesis of 2,3-
disubstituted piperidines continues in our laboratory.
In order to find out whether or not this high diaste-
reoselectivity is due to an intramolecular chelation of the
lithium atom in a lithiosulfone to oxygen in the neighbor-
ing functionality, which renders the phenyl group to such
an orientation that incoming electrophile takes anti
approach to the phenyl group, as depicted in Figure 2,12,13
preparation of 5a and 5b was carried out starting from
10, the tert-butyldimethylsilyl analogue of 1. This is
demonstrated in Scheme 5.
Although the diastereoselectivity via route B was less
significant in this case, we observed that, to our surprise,
allylation of 11 was a highly diastereoselective process.
Taking into account of the absence of chelation with
Exp er im en ta l Section
Gen er a l Meth od s. All melting points are uncorrected.
Unless otherwise noted, all reagents obtained from commercial
sources were used without further purification. THF was
distilled from sodium benzophenone ketyl. All other organic
solvents were dried and distilled prior to use. Flash chroma-
(12) (a) Gais, H-J .; Hellmann, G.; Gunther, H.; Lopez, F.; Lindner,
H. J .; Braun, S. Angew. Chem., Int. Ed. Engl. 1989, 28, 1025. (b) Gais,
H-J .; Hellmann, G.; Lindner, J . Ibid. 1990, 29, 100.
(13) Trost, B. M.; Schmuff, N. R. J . Am. Chem. Soc. 1985, 107, 396.
(14) Keck, G. E.; Castellino, S. Tetrahedron Lett. 1987, 28, 281.

768 J . Org. Chem., Vol. 62, No. 3, 1997
Notes
Sch em e 5a
a
Reaction conditions: (a) n-BuLi/THF, BrCH2CH2OTf, -78 °C; (b) n-BuLi/THF, allylbromide, -78 °C; (c) n-Bu4N+F-/THF, rt.
tography was performed using 230-400 mesh silica gel. Ana-
lytical thin layer chromatography (TLC) was carried out on
plates precoated with 0.25 mm of silica gel containing 60F-254
indicator. 1H NMR spectra were recorded at 300, 250, and 200
MHz, and 13C NMR spectra were recorded 75.5 MHz with
chemical shifts reported in ppm (δ) downfield from TMS (internal
reference) for 1H and relative to the center line of the triplet of
CDCl3 at 77.14 ppm for 13C, unless otherwise specified. Mass
spectra were obtained by CI (isobutane), and the high-resolution
mass spectrum was obtained by CI (methane). Elemental
analyses were carried out by the microanalytical laboratory at
the ICSN.
of 1 (4.0 g, 10 mmol) in THF (40 mL) at -78 °C was added
dropwise n-BuLi (12.6 mL, 1.6 M in hexane) under dry nitrogen,
and the reaction mixture was stirred at -78 °C for 15 min while
allyl bromide (1.45 g, 12 mmol) in THF (2 mL) was added. The
reaction mixture was allowed to warm to 0 °C while being stirred
for 2.5 h and then concentrated under reduced pressure. The
residue was diluted with EtOAc and washed with H2O. The
organic phase was dried over MgSO4 and filtered, and the
solvent was evaporated. Flash chromatography on silica gel
(EtOAc/hexane ) 1:2) afforded 4.20 g (9.56 mmol) of 3 in 95%
yield: viscous oil; 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.40-1.85
(m, 6H), 2.50-2.65 (m, 2H), 3.40-3.55 (m, 2H), 3.60-4.05 (m,
4H), 4.34-4.47 (m, 1H), 4.55-4.67 (m, 1H), 5.04-5.18 (m, 2H),
5.30 (m, 1H), 5.55-5.83 (m, 1H), 7.56 (t, J ) 7.5 Hz, 2H), 7.68
(t, J ) 7.5 Hz, 1H), 7.90 (d, J ) 7.5 Hz, 2H); 13C NMR (CDCl3)
δ 18. 86, 18.94, 19.22, 25.05, 27.74, 28.06, 30.14, 30.27, 30.52,
30.73, 49.04, 49.25, 49.55, 61.75, 62.00, 62.16, 62.74, 62.95, 63.22,
64.77, 65.17, 66.23, 66.64, 67.29, 79.35, 97.81, 98.31, 98.90,
118.40, 118.52, 128.04, 128.14, 128.46, 128.97, 132.95, 133.13,
133.38, 133.57, 138.43, 139.56, 155.07; MS (CI) m/ z 440 ((M +
H)+, base), 356, 300. Anal. Calcd for C22H33NO6S: C, 60.11;
H, 7.56; N, 3.18; S, 7.29. Found: C, 60.29; H, 7.66; N, 3.04; S,
7.21.
(2R )-1-(t er t -B u t y lo x y c a r b o n y l)-2-[[(2-t e t r a h y d r o -
p yr a n yl)oxy]m e t h yl]-3-a llyl-3-(p h e n ylsu lfon yl)p yr r oli-
d in e (4a /4b) (via Rou te B). To a solution of 3 (4.16 g, 9.47
mmol) in THF (40 mL) was added dropwise n-BuLi (12.0 mL,
1.6 M in hexane) at -78 °C under dry nitrogen. The mixture
was stirred for 30 min at -50 °C and then cooled back to -78
°C to add freshly prepared 2-bromoethyl triflate15 (2.92 g, 11.3
mmol) in THF (4 mL). The reaction mixture was allowed to
warm to 0 °C while being stirred for 2.5 h and then concentrated
under reduced pressure. The residue was diluted with EtOAc
(30 mL), washed with H2O (10 mL), and dried over MgSO4, and
the solvent was removed under reduced pressure. Purification
of the crude product was effected by flash chromatography on
silica gel, eluting with EtOAc-heptane (1:2). Evaporation of
the solvent afforded 3.43 g of a mixture of 4a /4b in 79% yield:
1H NMR (CDCl3) δ 1.45 (s, 9H), 1.15-1.95 (m, 7H), 2.02-2.41
(m, 2H), 2.88-3.14 (m, 1H), 3.33-3.65 (m, 3H), 3.65-3.82 (m,
0.5H), 3.77-3.4.04 (m, 1.5H), 4.10-4.40 (m, 2H), 4.70 (br s, 1H),
5.00 (d, J ) 17.2 Hz, 1H), 5.12 (d, J ) 9.5 Hz, 1H), 5.60-5.90
(m, 1H), 7.54-7.64 (m, 2H), 7.65-7.71 (m, 1H), 7.85-7.96 (m,
2H); 13C NMR (CDCl3) δ 18.56, 25.03, 25.27, 28.16, 30.05, 30.28,
30.67, 31.03, 39.88, 40.23, 43.50, 44.20, 60.65, 61.03, 65.11, 65.79,
71.74, 79.62, 97.90, 119.38, 128.86, 129.09, 131.46, 133.69; MS
(CI) m/ z 466 (M + H)+, 382 (base), 326, 143.
(2R )-1-(t er t -B u t y lo x y c a r b o n y l)-2-[[(2-t e t r a h y d r o -
p yr a n yl)oxy]m e t h yl]-3-a llyl-3-(p h e n ylsu lfon yl)p yr r oli-
d in e (4a /4b) (via Rou te A). To a solution of 2 (3.50 g, 8.2
mmol) in THF (35 mL) was added dropwise n-BuLi (5.2 mL, 1.6
M in hexane) at -78 °C under dry nitrogen. The mixture was
stirred for 30 min at -50 °C and then cooled back to -78 °C to
add allyl bromide (1.2 g, 9.8 mmol) in THF (2 mL). The reaction
mixture was allowed to warm to 0 °C while being stirred for 3
h and then diluted with EtOAc (30 mL), washed with H2O (3 ×
10 mL), dried over MgSO4, and concentrated. Purification of
the crude product was effected by flash chromatography on silica
gel, eluting with EtOAc/heptane (1:2). Evaporation of the
solvent afforded 3.25 g of a mixture of 4a /4b in 85% yield: 1H
NMR (CDCl3) δ 1.45 (s, 9H), 1.25-1.90 (m, 6H), 2.12-2.40 (m,
1H), 2.40-3.05 (m, 3H), 3.05-3.35 (m, 1H), 3.37-4.15 (m, 5H),
4.30-4.66 (m, 2H), 5.00-5.27 (m, 2H), 5.45-5.80 (m, 0.1H),
6.07-6.33 (m, 0.9H), 7.40-7.73 (m, 3H), 7.80-8.00 (m, 2H). 13
C
NMR (CDCl3) δ 18.53, 18.75, 19.48, 25.30, 28.46, 30.37, 30.79,
31.35, 36.00, 44.44, 45.03, 60.06, 60.58, 60.93, 62.52, 64.83, 65.41,
66.22, 66.99, 79.91, 96.98, 100.09, 118.32, 128.97, 129.39, 129.66,
129.90, 133.61, 134.01, 137.28: MS (CI) m/ z 466 ((M + H)+,
base), 382, 326, 143, 101. Anal. Calcd for C24H35NO6S: C, 61.91;
H, 7.57; N, 3.00; S, 6.88. Found: C, 62.04; H, 7.55; N, 2.83; S,
6.83.
(2R,3S)-1-(ter t-Bu tyloxyca r bon yl)-2-(h yd r oxym eth yl)-3-
a llyl-3-(p h en ylsu lfon yl)p yr r olid in e (5b). A solution of 3.10
g (6.6 mmol) of the mixture of 4a /4b in ethanol (25 mL) was
warmed to 50 °C for 4 h in the presence of 0.1 equiv of PPTS.
After evaporation of ethanol, the residue was diluted with CH2-
Cl2, washed with H2O, and then dried and concentrated to
provide 2.43 g of a mixture of 5a and 5b in 96% yield. The ratio
of the 5a /5b mixture was determined to be 6:94 by HPLC.9.
Recrystallization (twice from EtOAc/heptane) provided 2.10 g
of pure 5b: mp 122-122.5 °C; [R]25 ) +7.9° (c 1.0, CH3OH);
D
[R]25 ) +3.5° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 1.45 (s, 9H),
D
2.10-2.24 (m, 1H), 2.44-2.92 (m, 3H), 3.21-3.41 (m , 1H), 3.55-
3.95 (m, 3H), 4.35 (m, 1H), 5.16 (d, J ) 17.5 Hz, 1H), 5.17 (d, J
) 10.0 Hz, 1H), 5.94-6.18 (m, 1H), 7.58 (t, J ) 7.5 Hz, 2H),
7.68 (t, J ) 7.5 Hz, 1H), 7.94 (d, J ) 7.5 Hz, 2H); 13C NMR
(CDCl3) δ 28.45, 30.22, 34.81,45.08, 62.59, 63.34, 73.47, 80.59,
119.18, 129.19, 130.18, 132.58, 134.19, 136.29; MS (CI) m/ z 382
(M + H)+, 326 (base), 282. Anal. Calcd for C19H27NO5S: C,
59.81; H, 7.13; N, 3.67; S, 8.40. Found: C, 59.81; H, 7.17; N,
3.54; S, 8.34.
(2R,3R)-1-(ter t-Bu tyloxyca r bon yl)-2-(h yd r oxym eth yl)-3-
a llyl-3-(p h en ylsu lfon yl)p yr r olid in e (5a ). A solution of 3.43
g (7.37 mmol) of the mixture of 4a /4b obtained via route B in
ethanol (30 mL) was warmed to 50 °C for 4 h in the presence of
0.1 equiv of PPTS. After evaporation of ethanol, the residue
was diluted with CH2Cl2 (30 mL), washed with H2O, and then
dried and concentrated to provide 2.64 g of a mixture of 5a /5b
in 94% yield. The ratio of the 5a /5b mixture was determined
(2R)-1-[(2-Tetr a h yd r op yr a n yl)oxy]-2-[(ter t-bu tyloxyca r -
bon yl)a m in o]-3-(p h en ylsu lfon yl)-5-h exen e (3). To a solution
(15) Subramanian, P. K.; Woodard, R. W. J . Org. Chem. 1987, 52,
15.

Notes
J . Org. Chem., Vol. 62, No. 3, 1997 769
to be 89:11 by HPLC.9 Recrystallization (twice from EtOAc/
156. Anal. Calcd for C13H21NO4: C, 61.15; H, 8.29; N, 5.48.
Found: C, 61.12; H, 8.35; N, 5.46.
heptane) provided 2.11 g of pure 5a : mp 133-134 °C; [R]25
)
D
+74.5° (c 1.0, CH3OH); [R]25D ) +64.5° (c 1.0, CHCl3). 1H NMR-
(CDCl3) δ 1.45 (s, 9H), 1.63-1.82 (m, 1H), 2.04-2.24 (m, 1H),
2.33 (dd, J ) 15.0, 4.5 Hz, 0.5H), 2.48 (dd, J ) 15.0, 4.5 Hz,
0.5H), 2.73-3.01 (m, 1H), 3.30-3.52 (m, 1H), 3.58-3.72 (m, 1H),
3.92-4.22 (m, 2H), 4.26-4.38 (m, 1H), 5.02 (d, J ) 17.6 Hz, 1H),
5.12 (d, J ) 9.8 Hz, 1H), 5.59-5.85 (m, 1H), 7.61 (t, J ) 7.5 Hz,
2H), 7.75 (t, J ) 7.5 Hz, 1H), 7.91 (d, J ) 7.5 Hz, 2H); 13C NMR
(CDCl3) δ 28.35, 31.67, 40.27, 40.77, 44.37, 44.88, 61.97, 62.29,
63.73, 64.53, 72.20, 72.46, 80.11, 120.11, 120.18, 129.29, 129.46,
130.70, 131.06, 134.43; MS (CI) m/ z 382 ((M + H)+, base), 326,
282. Anal. Calcd for C19H27NO5S: C, 59.81; H, 7.13; N, 3.67;
S, 8.40. Found: C, 59.66; H, 7.21; N, 3.56; S, 8.26.
(2S,3R)-N-(ter t-Bu tyloxyca r bon yl)-3-a llylp r olin e Meth yl
Ester (8c). A mixture of 8a /8b (285 mg, 1.11 mmol) obtained
via route C was esterified with CH2N2 in ether. After evapora-
tion of ether, the residue was dissolved in MeOH (1.5 mL) and
was treated with 1 N NaOH (1.2 mL) with stirring at room
temperature for 24 h. The solution was concentrated to remove
MeOH and then extracted with EtOAc (3 × 2 mL). The extracts
were dried over MgSO4, filtered, and concentrated to afford 163
mg of 8c in 54% yield: viscous oil; [R]25D ) +25.5° (c 1.0, CHCl3);
1H NMR (CDCl3) (two conformers) δ 1.41 (s, 5H), 1.46 (s, 4H),
1.65-1.82 (m, 1H), 1.76-1.91 (m, 1H), 1.91-2.04 (m, 1H), 2.17-
2.44 (m, 1H), 2.44-2.48 (m, 1H), 3.25-3.36 (m, 1H), 3.58-3.75
(m, 1H), 3.72 (s, 3H), 4.25 (d, J ) 8.6 Hz, 0.6H), 4.35 (d, J ) 8.3
Hz, 0.4H), 5.00-5.11 (m, 2H), 5.70-5.88 (m, 1H); 13C NMR
(CDCl3) δ 28.30, 28.43, 28.95, 29.71, 34.43, 34.48, 42.54, 45.63,
51.52, 61.96, 62.49, 79.87, 116.46, 116.54, 135.82, 172.37; MS
(2S )-1-(t er t -B u t y lo x y c a r b o n y l)-2-[[(2-t e t r a h y d r o -
p yr a n yl)oxy]m eth yl]-3-a llylp yr r olid in e (6a /6b). To a solu-
tion of 4a /4b obtained via route A (2.12 g, 4.56 mmol) and Na2-
HPO4 (1.94 g, 13.68 mmol) in HPLC-grade MeOH (30 mL) was
added 6% Na-Hg (5.2 g, 13.5 mmol). The mixture was vigor-
ously stirred for 1 h at room temperature. After concentration
of the solution, the residue was dissolved in CH2Cl2 (30 mL),
washed with H2O (4 × 10 mL), dried over MgSO4, and concen-
trated. Flash chromatography of the crude product on silica gel,
eluting with EtOAc/heptane (1:4), afforded a mixture of 1.14 g
(CI) m/ z 270 ((M + H)+, 204 (base), 170. Anal. Calcd for C14H23
-
NO4: C, 62.43; H, 8.61; N, 5.20. Found: C, 62.43; H, 8.53; N,
5.14.
(2S,3S)-N-(ter t-Bu tyloxyca r bon yl)-3-n -p r op ylp r olin e (9).
Catalytic hydrogenation of 8a (60 mg, 0.23 mml) in MeOH (1.5
mL) on palladium on activated carbon (5 mg, 10% Pd/C) was
carried out for 30 min to afford 55 mg of 9 in 89% yield: mp
1
of 6a /6b in 77% yield: colorless oil; H NMR (CDCl3) δ 1.45 (s,
88-90 °C (lit.5a mp 88-89 °C); [R]25 ) -17.8° (c 1.0, MeOH);
D
9H), 1.40-1.65 (m, 6H), 1.60-2.10 (m, 2H), 1.92-2.45 (m, 2H),
3.19-3.63 (m, 4H), 3.50-4.05 (m, 4H), 4.50-4.66 (m, 1H), 4.92-
5.14 (m, 2H), 5.70-5.94 (m, 1H); 13C NMR (CDCl3) δ 18.64,
18.96, 19.23, 19.61, 25.43, 28.36, 28.46, 29.35, 30.27, 30.53, 30.72,
31.38, 31.53, 34.02, 38.09, 40.94, 41.66, 41.82, 45.47, 45.78, 58.41,
58.77, 60.85, 61.42, 61.59, 61.89, 62.46, 65.04, 65.42, 65.83, 66.57,
67.55, 68.15, 69.75, 79.06, 97.29, 97.84, 98.49, 99.09, 99.53,
114.77, 115.49, 116.25, 136.48, 137.27, 138.03; MS (CI) m/ z 326
((M + H)+, base), 270, 242, 226, 186, 142. Anal. Calcd for
[R]25 ) -42.5° (c 1.0, CHCl3) [lit.5a [R]25 ) -42.5° (c 1.0,
D
D
CHCl3)]; 1H NMR (CDCl3) (two conformers) δ 0.93 (t, J ) 7.1
Hz, 3H), 1.28-1.69 (m, 14H), 2.00-2.18 (m, 1H), 2.20-2.48 (m,
1H), 3.34-3.70 (m, 2H), 3.84 (d, J ) 6.2 Hz, 0.4H), 3.98 (d, J )
4.4 Hz, 0.6H); 13C NMR (CDCl3) δ 14.07, 20.88, 28.39, 30.10,
30.28, 35.63, 42.48, 44.72, 45.83, 46.12, 64.70, 80.50, 153.95,
155.95, 176.53, 179.06; MS (CI) m/ z 258 ((M + H)+, 219 (base),
202, 158. Anal. Calcd for C13H23NO4: C, 60.67; H, 9.00; N, 5.44.
Found: C, 60.81; H, 8.89 ; N, 5.25.
C
18H31NO4: C, 66.42; H, 9.60; N, 4.30. Found: C, 66.43; H, 9.47;
N, 4.11.
(2S,3S)-1-(ter t-Bu tyloxyca r bon yl)-2-(h yd r oxym eth yl)-3-
(2R)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-2-[(ter t-b u t yloxy-
ca r bon yl)a m in o]-3-(p h en ylsu lfon yl)p r op a n e (10). Prepared
from (2S)-2-[(tert-butyloxycarbonyl)amino]-3-(phenylsulfonyl)-1-
propanol7 in 88% yield according to the standard procedure:16
a llylp yr r olid in e (7a ). To a solution of a mixture of 5a /5b
obtained via route B (2.87 g, 7.52 mmol) and Na2HPO4 (3.20 g,
22.6 mmol) in HPLC-grade MeOH (30 mL) was added 6% Na-
Hg (8.6 g, 22.4 mmol). The mixture was vigorously stirred for
1 h at room temperature. After concentration of the solution,
the residue was dissolved in CH2Cl2 (50 mL), washed with H2O
(4 × 15 mL), dried over MgSO4, and concentrated. Flash
chromatography of the crude product on silica gel, eluting with
viscous oil; [R]25 ) -0.8° (c 1.0, CH3OH); 1H NMR (CDCl3) δ
D
0.02 (s, 6H), 0.86 (s, 9H), 1.40 (s, 9H), 3.30-3.42 (m, 2H), 3.55-
3.64 (m, 1H), 3.70-3.81 (m, 1H), 3.91-4.03 (m, 1H), 4.94 (d, J
) 6.0 Hz, 1H), 7.53 (t, J ) 7.5 Hz, 2H), 7.62 (t, J ) 7.5 Hz, 1H),
7.90 (d, J ) 7.5 Hz, 2H); 13C NMR (CDCl3) δ 18.03, 25.67, 28.17,
48.28, 56.32, 63.62, 79.69, 127.84, 129.17, 133.61, 139.49, 154.62;
MS (CI) m/ z 430 ((M + H)+, base), 374, 330, 143. Anal. Calcd
for C20H35NO5SSi: C, 55.90; H, 8.21; N, 3.26; S, 7.46. Found:
C, 55.81; H, 8.38; N, 3.09; S, 7.35.
EtOAc/heptane (1:1), afforded 1.50 g of 7a in 83% yield: viscous
1
oil; [R]25 ) -20.5° (c 1.5, CH3OH); H NMR (CDCl3) δ 1.47 (s,
D
9H), 1.74-2.40 (m, 5H), 3.15-3.35 (m, 1H), 3.42-3.88 (m, 3H),
4.92 (br s, 1H), 5.05 (d, J ) 7.0 Hz, 1H), 5.07 (d, J ) 13.7 Hz,
1H), 5.75 (m, 1H); 13C NMR (CDCl3) δ 28.50, 29.58, 37.46, 41.05,
46.38, 64.53, 65.32, 66.96, 80.27, 116.84, 135.93; MS (CI) m/ z
242 ((M + H)+, base), 186, 142. Anal. Calcd for C13H23NO3: C,
64.69; H, 9.60; N, 5.80. Found: C, 64.95; H, 9.47; N, 5.79.
(2R)-1-(ter t-Bu tyloxyca r bon yl)-2-[[(ter t-bu tyld im eth yl-
silyl)oxy]m eth yl]-3-(p h en ylsu lfon yl)p yr r olid in e (11). To a
solution of 10 (860 mg, 2 mmol) in THF (10 mL) was added
n-BuLi (2.7 mL, 1.6 M in hexane) at -78 °C under dry nitrogen.
The mixture was stirred for 30 min at -78 °C while 2-bromoethyl
triflate (620 mg, 2.4 mmol) in THF (1 mL) was added. The
reaction mixture was allowed to warm to 0 °C while being stirred
for 2 h and then concentrated under reduced pressure. The
residue was diluted with EtOAc (10 mL) and was washed with
H2O (3 × 5 mL) and dried over MgSO4, and the solvent was
removed under reduced pressure. Flash chromatography of the
crude product on silica gel eluting with EtOAc/heptane (1:2)
provided 650 mg of 11 in 71% yield: viscous oil; 1H NMR (CDCl3)
δ 0.02, 0.03 (s, 6H), 0.84 (s, 4.2H), 0.89 (s, 2.8H), 0.91 (s, 2H),
1.45 (s, 6.5H), 1.51 (s, 2.5H), 2.15-2.51 (m, 2H), 3.17-3.30 (m,
1H), 3.35-3.50 (m, 1.5H), 3.50-3.88 (m, 2.5H), 4.24-4.38 (m,
1H), 7.62 (t, J ) 7.5 Hz, 2H), 7.72 (t, J ) 7.5 Hz, 1H), 7.96 (d, J
) 7.5 Hz, 2H); 13C NMR (CDCl3) δ -5.51, 18.11, 24.99, 25.32,
25.81, 28.35, 28.46, 45.60, 46.08, 59.20, 59.49, 62.95, 63.75, 65.19,
65.86, 79.72, 80.02, 128.01, 128.79, 129.40, 133.78, 133.95,
134.08, 137.71; HRMS (CI) calcd for C22H38NO5SSi (M + H)+
456.2239, found 456.2226.
(2S,3S)-N-(ter t-Bu tyloxyca r bon yl)-3-a llylp r olin e (8a ). To
a solution of 7a (1.28 g, 5.3 mmol) in acetone (120 mL) was added
J ones reagent (5.5 mL, 2 equiv). The mixture was vigorously
stirred for 1 h at room temperature. After evaporation of acetone
under reduced pressure, the residue was diluted with EtOAc
(10 mL). The organic phase was washed with H2O (3 × 10 mL)
and extracted with 1 N NaOH (8 mL). The resultant solution
was extracted with EtOAc (20 mL) and then was acidified to
pH 2 with 1 N HCl. The precipitate was extracted into CH2Cl2
(20 mL), and the aqueous phase was extracted twice with CH2-
Cl2 (10 mL). The combined CH2Cl2 extracts were washed with
brine, dried over MgSO4, and concentrated. The residue was
dried under reduced pressure over P2O5 to give 1.17 g of 8a in
86% yield: viscous oil; [R]25 ) -2.3° (c 1.0, CH3OH); [R]25
)
D
D
-27.5° (c 1.0, CHCl3); 1H NMR (CDCl3) (two conformers) δ 1.41
(s, 6H), 1.45 (s, 3H), 1.56-1.68 (m, 1H, 4-H), 2.00-2.09 (m, 1H,
4-H), 2.09-2.20 (m, 1H, allyl), 2.30-2.45 (m, 1H, allyl), 2.35-
2.50 (m, 1H, 3-H), 3.37-3.55 (m, 1H, 5-H), 3.45-3.63 (m, 1H,
5-H), 3.89 (d, J ) 4.5 Hz, 0.6H, 2-H), 3.95 (d, J ) 4.1 Hz, 0.4H,
2-H), 5.08 (d, J ) 10.5 Hz, 1H), 5.09 (d, J ) 16.5 Hz, 1H), 5.70-
5.86 (m, 1H), 7.20 (br s, 1H); 13C NMR (CDCl3) δ 28.37, 29.22,
29.55, 37.35 (CH2CHdCH2), 42.25, 44.04, 45.51, 45.86, 63.95,
80.56, 80.83, 117.47 (CHdCH2), 135.24 (CHdCH2), 154.10,
155.53, 176.91, 178.71; MS (CI) m/ z 256 (M + H)+, 200 (base),
(2R)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-2-[(ter t-b u t yloxy-
ca r bon yl)a m in o]-3-(p h en ylsu lfon yl)-5-h exen e (12). To a
solution of 10 (1.28 g, 2.97 mmol) in THF (20 mL) at -78 °C
was added dropwise n-BuLi (3.8 mL, 1.6 M in hexane) under
dry nitrogen, and the reaction mixture was stirred at -78 °C
(16) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.

770 J . Org. Chem., Vol. 62, No. 3, 1997
Notes
for 20 min when allyl bromide (430 mg, 3.56 mmol) in THF (1
mL) was added. The reaction mixture was allowed to warm to
0 °C while being stirred for 2 h and then concentrated under
reduced pressure. The residue was diluted with EtOAc (25 mL)
and washed with H2O (3 × 5 mL). The organic phase was dried
over MgSO4 and filtered, and the solvent was evaporated. Flash
chromatography on silica gel (EtOAc/hexane ) 1:2) gave 865 mg
X-r a y Str u ctu r e An a lysis of 5a . Crystal data: C19H27NO5S,
molecular weight 381.49; colorless crystal of 0.03 × 0.20 × 0.53
mm monoclinic system; space group P21, Z ) 2, a ) 10.723(5)
Å, b ) 7.110(3) Å, c ) 12.992(5) Å, â ) 101.15(2)°, V ) 971.8(7)
Å3, dcalc ) 1.30 g cm-3, F (000) ) 408, λ (Cu KR) ) 1.5418 Å, µ
) 1.68 mm-1. Intensity data were measured on an Enraf-Nonius
CAD-4 diffractometer using graphite-monochromated Cu KR
radiation and the (θ - 2θ) scan technique up to θ ) 65°. From
the 2553 collected reflexions (-12 e h e 12, -6 e k e 8, 0 e l
e 15), 2430 were independent (Rint ) 0.05), and 2255 were
considered as observed with I g 3σ(I). Cell parameters were
refined from 25 well-centered reflexions with 9.7 e θ e 23.9°.
The structure was solved by direct methods using SHELXS8617
and refined by full-matrix least-squares methods with
SHELX76,18 minimizing the function ∑w(Fo - |Fc|)2. The
hydrogen atoms, located in difference Fourier maps, were fitted
at theoretical positions (d(C-H) ) 1.00 Å) and assigned an
isotropic thermal factor equivalent to that of the bonded carbon
atom, plus 10%. Convergence was reached at R ) 0.053 and
1
(1.84 mmol) of 12 in 62% yield: viscous oil; H NMR (CDCl3) δ
0.02, 0.03 (s, 6H), 0.86 (s, 9H), 1.45 (s, 9H), 2.43-2.70 (m, 2H),
3.50 (m, 1H), 3.70 (m, 1H), 3.80 (m, 1H), 4.25 (m, 1H), 4.96-
5.18 (m, 3H), 5.78 (m, 1H), 7.56 (t, J ) 7.5 Hz, 2H), 7.66 (t, J )
7.5 Hz, 1H), 7.92 (d, J ) 7.5 Hz, 2H); 13C NMR (CDCl3) δ -5.74,
17.76, 25.49, 28.02, 30.71, 31.13, 50.94, 51.24, 62.37, 63.97, 79.24,
117.78, 118.50, 127.95, 128.50, 128.64, 128.88, 128.92, 133.49,
133.69, 138.04, 139.36, 155.01; MS (CI) m/ z 470 ((M + H)+,
base), 414, 370. Anal. Calcd for C23H39NO5SSi: C, 58.81; H,
8.36; N, 2.98; S, 6.82. Found: C, 58.82; H, 8.23; N, 2.81; S, 6.76.
(2R,3S)-1-(ter t-Bu tyloxyca r bon yl)-2-[[(ter t-bu tyld im eth -
ylsilyl)oxy]m et h yl]-3-a llyl-3-(p h en ylsu lfon yl)p yr r olid in e
(13b) (via Rou te A). To a solution of 11 (1.22 g, 2.6 mmol) in
THF (15 mL) was added dropwise n-BuLi (1.7 mL, 1.6 M in
hexane) at -78 °C under dry nitrogen. The mixture was stirred
for 30 min at -50 °C and then cooled back to -78 °C to add ally
bromide (0.38 g, 3.1 mmol) in THF (1 mL). The reaction mixture
was allowed to warm to 0 °C while being stirred for 3 h and
then diluted with EtOAc (10 mL) and was washed with H2O (3
× 5 mL), dried over Na2SO4, and concentrated. Purification of
the crude product was effected by flash chromatography on silica
gel, eluting with EtOAc/heptane (1:2). Evaporation of the
solvent afforded 0.82 g of 13b in 63% yield: viscous oil; 1H NMR
(CDCl3) δ 0.02, 0.03 (s, 6H), 0.84, 0.85 (s, 9H), 1.35 (s, 3.6H),
1.45, 1.46 (s, 5.4H), 2.14-2.35 (m, 1H), 2.43-2.62 (m, 1H), 2.53-
2.71 (m, 1H), 2.82-2.96 (m, 2H), 3.12-3.25 (m, 1H), 3.64-3.72
(m, 1H), 3.75-3.86 (m, 0.6H), 3.97-4.04 (m, 0.4H), 4.35-4.40
(m, 1H), 5.04-5.21 (m, 2H), 6.18-6.33 (m, 1H), 7.58 (t, J ) 7.5
Hz, 2H), 7.67 (t, J ) 7.5 Hz, 1H), 7.86-7.98 (m, 2H); 13C NMR
(CDCl3) δ -5.69, -5.60, -5.46, -5.37, 17.96, 25.79, 25.85, 28.49,
28.67, 31.36, 31.70, 35.75 (CH2CHdCH2), 35.94 (CH2CHdCH2),
44.63, 45.18, 61.22, 75.27, 79.50, 79.87, 118.17 (CHdCH2),
128.90, 129.02, 129.24, 129.71, 129.96, 133.83 (CHdCH2), 134.06
(CHdCH2), 137.36, 153.10; MS (CI) m/ z 496 ((M + H)+, base),
440, 414. Anal. Calcd for C25H41NO5SSi: C, 60.56; H, 8.33; N,
2.82; S, 6.46. Found: C, 60.34; H, 8.18; N, 2.71; S, 6.33.
Rw ) 0.069 (with Rw ) [∑w(Fo - |Fc|)2/∑wFo
]
and w )
2
1/2
1/[σ2(Fo) + 0.0043Fo2]. The residual electron density in the final
difference map was located between 0.98 and -0.39 e Å-3. An
intermolecular hydrogen bond links the hydroxy group O7 to the
carbonyl of the Boc group (O7-H‚‚‚O12 ) 2.889(6) Å).
X-r a y Str u ctu r e An a lysis of 5b. Crystal data: C19H27NO5S,
molecular weight 381.49; colorless crystal of 0.02 × 0.10 × 0.20
mm, monoclinic system; space group P21, Z ) 4, a ) 7.020(6) Å,
b ) 11.608(6) Å, c ) 26.313(16) Å, â ) 105.54(5)°, V ) 2065(2)
Å3, dcalc ) 1.23 g cm-3, F(000) ) 816, λ (Cu KR) ) 1.5418 Å, µ )
1.58 mm-1. Intensity data were measured on an Enraf-Nonius
CAD-4 diffractometer using graphite-monochromated Cu KR
radiation and the (θ - 2θ) scan technique up to θ ) 64°. From
the 3667 collected reflections (-8 e h e 7, 0 e k e 13, 0 e l e
30), 3602 were independent (Rint ) 0.11), and 3071 were
considered as observed with I g 3σ(I). Cell parameters were
refined from 25 well-centered reflexions with 10.2 e θ e 19.9°.
The structure was solved by direct methods using SHELXS86
17
and refined by full-matrix least-squares methods with
SHELX76,18 minimizing the function ∑w(Fo - |Fc|)2. The
hydrogen atoms, located in difference Fourier maps, were fitted
at theoretical positions (d(C-H) ) 1.00 Å) and assigned an
isotropic thermal factor equivalent to that of the bonded carbon
atom, plus 10%. Convergence was reached at R ) 0.072 and
(2R,3R)-1-(ter t-Bu tyloxyca r bon yl)-2-[[(ter t-bu tyld im eth -
ylsilyl)oxy]m et h yl]-3-a llyl-3-(p h en ylsu lfon yl)p yr r olid in e
(13a ). For the comparison of its NMR spectra with those of 13b,
13a was prepared. To a mixture of 13a /13b (580 mg, 1.1 mmol)-
in tetrahydrofuran (10 mL), prepared from 3 in 70% yield using
the same procedure as described for the preparation of 4a /4b
via route A, was added tetrabutylammonium fluoride (2 mL, 2
mmol, 1.0 M in THF). The mixture was stirrred at room
temperature and the progress of the reaction monitored by TLC.
After 30 min, the solution was treated with H2O (20 mL), the
phases were separated, and the aqueous phase was extracted
with CH2Cl2. The combined organic phases were dried over
MgSO4 and concentrated in vacuo to give a 70:30 mixture of 5a /
5b (assessed by HPLC9) in 92% yield. The residue was recrys-
tallized three times from EtOAc/hexane to afford 5a (252 mg).
To a solution of 5a (120 mg, 0.3 mmol) in DMF (1.5 mL) at room
temperature were added tert-butyldimethylsilyl chloride (60 mg,
0.4 mmol) and imidazole (54 mg, 0.8 mmol). After 48 h, diethyl
ether (10 mL) was added and the mixture washed with saturated
NH4Cl solution (6 mL). The organic layer was separated and
dried over MgSO4, and the solvents were evaporated in vacuo.
The crude product was purified by flash chromatography (EtOAc/
heptane ) 1:1) to provide 130 mg of 13a in 83% yield: viscous
oil; 1H NMR (CDCl3) δ 0.03, 0.06 (s, 6H), 0.89 (s, 9H), 1.40 (s,
9H), 1.55-1.70 (m, 1H), 1.95-2.25 (m, 2H), 2.97 (q, J ) 9.7 Hz,
1H), 3.30-3.52 (m, 2H), 4.00-4.23 (m, 3H), 4.82-5.05 (m, 2H),
5.66-5.82 (m, 1H), 7.50 (t, J ) 7.5 Hz, 2H), 7.63 (t, J ) 7.5 Hz,
1H), 7.82 (d, J ) 7.5 Hz, 2H); 13C NMR (CDCl3) δ -5.65, -5.50,
18.31, 25.96, 28.48, 31.12, 40.37 (CH2CHdCH2), 40.57 (CH2-
CHdCH2), 44.43, 44.85, 61.21, 61.91, 62.56, 62.89, 72.00, 79.86,
119.54 (CHdCH2), 129.11, 129.34, 131.81, 133.87 (CHdCH2),
138.29; MS (CI) m/ z 496 ((M + H)+, base), 440, 414. Anal.
Calcd for C25H41NO5SSi: C, 60.56; H, 8.33; N, 2.82; S, 6.46.
Found: C, 60.29; H, 8.28; N, 2.69; S, 6.41.
Rw ) 0.089 (with Rw ) [∑w(Fo - |Fc|)2/∑wFo
]
and w ) 1/[σ2-
2
1/2
(Fo) + 0.008Fo2]. The residual electron density in the final
difference map was located between -0.87 and +0.59 e Å-3. The
two molecules of the asymmetric unit are linked through a
hydrogen bond between the hydroxy group O7 (molecule B) and
the carbonyl of the Boc group O12 of molecule A (O7-H‚‚‚O12
)
2.733(8) Å). The hydroxy O7-H (A) is linked in a similar manner
to the carbonyl O12 of a neighboring molecule (B, 1 + x, y, z),
2.742(8) Å).
Ack n ow led gm en t. A postdoctoral fellowship from
The Commission of the European Communities for M.D.
is gratefully ackowledged.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 1, 2, 3, 4a ,b, 5a ,b, 6a , 7a , 8a ,c, 9-12, and 13a ,b,
13C NMR spectra for compounds 1, 5a ,b, 7a , 8a ,c, 9-11, 13a ,b,
1
and 2D H-1H, 1H-13C spectra for compounds 5a , 8a ,c, 9, 11,
and 13b (37 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O961790R
(17) Sheldrick, G. M. SHELXS86. Program for the solution of crystal
structures. University of Go¨ttingen, Germany, 1986.
(18) Sheldrick, G. M. SHELX76. Program for crystal determination.
University of Cambridge, England, 1976.