A Versatile Method for the Facile Synthesis of Enantiopure trans-and cis-2,5-Disubstituted Pyrrolidines

Article abstract of DOI:10.1021/jo991052d

Treatment of (2S)-1-O-benzylglycerol-2,3-bistriflate (2) with the trilithiated species of chiral building blocks 5-7 provided 2,3,5-trisubstituted pyrrolidines that were subjected to reductive desulfonylation to give trans-2,5-disubstituted pyrrolidines 11-13, respectively. The same reaction sequence with the (2R)-bistriflate 4 and trilithiated 5 afforded the eis isomer 19. This two-step synthetic mehodology can furnish any one of the four possible diastereomers of enantiopure 2,5-disubstituted pyrrolidines in 60-72% overall yields.

Full text of DOI:10.1021/jo991052d

8602
J . Org. Chem. 1999, 64, 8602-8607
A Ver sa tile Meth od for th e F a cile Syn th esis of En a n tiop u r e tr a n s-
a n d cis-2,5-Disu bstitu ted P yr r olid in es
Qian Wang, N. Andre´ Sasaki,* Claude Riche, and Pierre Potier
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received J une 30, 1999
Treatment of (2S)-1-O-benzylglycerol-2,3-bistriflate (2) with the trilithiated species of chiral building
blocks 5-7 provided 2,3,5-trisubstituted pyrrolidines that were subjected to reductive desulfony-
lation to give trans-2,5-disubstituted pyrrolidines 11-13, respectively. The same reaction sequence
with the (2R)-bistriflate 4 and trilithiated 5 afforded the cis isomer 19. This two-step synthetic
mehodology can furnish any one of the four possible diastereomers of enantiopure 2,5-disubstituted
pyrrolidines in 60-72% overall yields.
In tr od u ction
chiral auxiliaries, in particular, it is desirable to prepare
both of the enantiopure 2S,5S and 2R,5R isomers. With
this in mind, we have previously described two synthetic
approaches starting from readily available chiral building
block 69a,10 and chiral glycidyl triflate or 711 and chiral
Preparation of enantiopure polysubstituted pyrrolidine
derivatives is quite a challenging subject. Among this
class of compounds, 2,5-disubstituted pyrrolidines are
particularly interesting due to the fact that many of them
occur in nature and possess a broad range of physiological
properties.1 They often serve as pivotal key intermediates
in the synthesis of pyrrolizidine and indolizidine deriva-
tives.2 Furthermore, trans-2,5-disubstituted pyrrolidines
have proven to be of considerable importance as chiral
auxiliaries.3-5 This is demonstrated by a large number
of reports focused on their asymmetric synthesis.6 The
most recent example is an efficient method developed by
Katritzky et al.7 that is based on the Husson’s 2-cyano-
6-oxazolopiperidine synthon methodology.8 However, a
majority of the methods reported so far has been plagued
by the need of the separation of a diastereomeric mixture,
which by no means is trivial. In the case of the pyrrolidine
(4) trans-2,5-Dialkoxymethylpyrrolidines: (a) Kawanami, Y.; Ito, Y.;
Kitagawa, T.; Taniguchi, Y.; Katsuki, T.; Yamaguchi; M. Tetrahedron
Lett. 1984, 25, 857. (b) Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron
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P.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 2211. (l) Vo Thanh,
G.; Ce´le´rier, J .-P.; Lhommet, G. Tetrahedron Lett. 1999, 40, 3713.
(3) trans-2,5-Dialkylpyrrolidines: (a) Schlessinger, R. H.; Iwanowicz,
E. J . Tetrahedron Lett. 1987, 28, 2083. (b) Short, R. P.; Kennedy, R.
M.; Masamune, S. J . Org. Chem. 1989, 54, 1755. (c) Porter, N. A.; Scott,
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10.1021/jo991052d CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/22/1999

Synthesis of trans- and cis-2,5-Disubstituted Pyrrolidines
J . Org. Chem., Vol. 64, No. 23, 1999 8603
Sch em e 1
Sch em e 3a
–
–
Sch em e 2
–
–
a
Reagents and conditions: (a) BuLi (3 equiv), THF, -70 °C,
2,3-O-isopropylideneglycerol triflate. Although these meth-
ods are efficient, the diastereomeric excess of the newly
formed pyrrolidines according to the first protocol re-
mains to be about 85%,10 and the second one requires a
multistep reaction sequence.11 In this paper, we report a
new and versatile one-step cyclization method that
provides any one of the four possible stereoisomers of 2,5-
disubstituted pyrrolidines in an enantiomerically pure
form. The basic principle of this new approach is il-
lustrated in Scheme 1.
30 min then 2, -70 °C, 1 h; (b) 6% Na-Hg, Na2HPO4, MeOH, 0
°C, 2 h; (c) TFA, rt, 6 h.
F igu r e 1.
Ta ble 1. Su r vey of An n u la tion Con d ition s
T
8
5
entry base (equiv)
solvent
THF
THF
THF-HMPA -70
Et2O
(°C) (% yield) (% recovery)
Resu lts a n d Discu ssion
1
2
3
4
5
6
7
8
BuLi (2)
BuLi (2)
BuLi (2)
BuLi (2)
BuLi (2)
KHMDS (2) THF
KHMDS (2) Et2O
BuLi (3)
-70
-95
58
40
0
18
49
83
50
46
80
85
21
Syn th esis of (2S,5S)-tr a n s-2,5-Disu bstitu ted P yr -
r olid in e Der iva tives. The bistriflate of (R)-1-O-benzyl
glycerol required for annulation process was prepared as
shown in Scheme 2. Treatment of diol 1, which was in
turn prepared from (S)-(+)-2,3-O-isopropylideneglycerol
by a two-step sequence,12 with 2 equiv of trifluoromethane-
sulfonic anhydride in dichloromethane in the presence
of 2.2 equiv of pyridine at -30 °C furnished the bistriflate
2 in 95% isolated yield.
The reaction temperature should be carefully con-
trolled. In fact, when the reaction was carried out at 0
°C under otherwise identical conditions, the yield of
bistriflate 2 dropped significantly. The bistriflate can be
purified by flash chromatography and can be kept in the
refrigerator for several months without decomposition.
A similar procedure applied to (S)-diol 3 gave the (R)-
bistriflate 4 in 93% yield.
With the bistriflate 2 and the chiral synthon 5 (R )
TBDMS) in hand,9b the key coupling reaction was then
investigated. Treatment of 5 with 2 equiv of n-BuLi
(Scheme 3) generated the corresponding dianion, which
was then trapped by the bistriflate 2 to give the pyrro-
lidine 8 in 58% overall yield together with 18% of
recovered synthon 5 (Table 1, entry 1). The major
byproducts isolated from this reaction derived from the
bistriflate 2. In fact, olefins 15-17 have been isolated
-70
-70
-70
-70
-70
10
10
0
0
70
THF-Et2O
THF
and identified (Figure 1). To avoid this side reaction, a
detailed survey of reaction conditions was carried out,
and some of the results varying base (the counterion),
reaction temperature, solvent, additive and equivalents
of bases are summarized in Table 1. It is seen from these
studies that the reaction is subjected to a significant
countercation effect as the annulation did not proceed
at all when KHMDS was used as a base. Addition of
highly coordinating solvent (HMPA, 3 equiv) exhibited
an adverse effect (Entry 3), while the reaction proceeded
very slowly in Et2O. Although most of the unreacted
sulfone can be recovered, the uncoupled bistriflate was
transformed completely to the olefins under all these
conditions. Interestingly, acyclic coupling product was not
isolated, which may indicate that the second SN2 cycliza-
tion reaction proceeds relatively fast and that the overall
efficiency of the annulation depends on the first inter-
molecular SN2 reaction. Finally, under the optimal condi-
tions found in our hands (3 equiv of BuLi, THF, -70 °C),
the desired annulation process proceeded smoothly to
afford the pyrrolidine 8 in 70% yield (89% based on 79%
of conversion) as a mixture of two diastereoisomers (8a
and 8b, cf. Scheme 4) in a 2.7/1 ratio. About 21% of the
starting sulfone was recovered, which accounted for the
overall mass balance. We speculated that the trianion
was formed under these conditions13 and that the gem-
dianion of sulfone was more nucleophilic favoring the
attack of carbanion to the triflate leading to a high yield
(9) (a) Sasaki, N. A.; Hashimoto, C.; Potier, P. Tetrahedron Lett.
1987, 28, 6069. (b) Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.;
Potier, P. J . Org. Chem. 1997, 62, 765. (c) Dockner, M.; Sasaki, N. A.;
Riche, C.; Potier, P. Liebigs Ann./ Recuel. 1997, 1267. (d) Wang, Q.;
Sasaki, N. A.; Potier, P. Tetrahedron 1998, 54, 15759.
(10) Sasaki, N. A.; Sagnard, I. Tetrahedron 1994, 50, 7093.
(11) Dockner, M.; Sasaki, N. A.; Potier, P. Heterocycles 1996, 42,
529.
(12) Iguchi, K.; Kitade, M.; Kashiwagi, T.; Yamada, Y. J . Org. Chem.
1993, 58, 5690.

8604 J . Org. Chem., Vol. 64, No. 23, 1999
Wang et al.
Sch em e 4a
F igu r e 2.
preferred trans orientation of the adjacent C-2 protected
hydroxymethyl group and phenyl sulfonyl group in the
lithiated species of 8. This control experiment is in
accordance with our previous observations9b and paved
the way for the projected stereoselective synthesis of
2,3,5-trisubstituted pyrrolidines. In this respect, an
interesting observation has been made en route to
compound 21a from the two diastereomers 8a and 8b.
Thus, treatment of diastereomerically pure compound 8a
or 8b with tetrabutylammonium fluoride (TBAF) in THF
gave the same desilylated product 21a . Apparently, the
basicity of these conditions (fluoride anion) is strong
enough to epimerize the C-3 asymmetric center (Scheme
4). Desilylation while keeping the stereochemical integ-
rity of compound 8b could be realized by treatment with
1% of I2 in methanol at reflux temperature.15 The
stereochemistry of 21a was fully established by single-
crystal X-ray analysis (Figure 2). While the stereochem-
istry of C-3 was of no consequence in the present studies
as it will be destroyed in following transformation, it
nevertheless provided important background information
regarding the introduction of substituent at the C-3
position of pyrrolidine derivatives.
Applying the same synthetic sequence to chiral syn-
thons 6 (R ) THP) and 7 (R ) Bn, Scheme 3),9c
pyrrolidines 12 and 13 were synthesized in 72% and 62%
overall yields, respectively. The stereochemistry of com-
pounds 9a and 9b was determined by their conversion
to the corresponding alcohols 21a and 21b by treatment
with PPTS in EtOH at 50 °C (Scheme 4). The fact that
different protective groups of the primary hydroxy group
were tolerated enhances the generality of this efficient
synthetic approach.
a
Reagents amd conditions: (a) Bu4NF, THF, rt, 1 h; (b) 1% I2/
MeOH, reflux, 24 h; (c) PPTS, EtOH, 50 °C, overnight.
of pyrrolidine 8. That the stereoisomerism of 8 was due
to the newly formed chiral center at the R-position of the
sulfone (C-3 of pyrrolidine) was proved during the
subsequent chemical transformations (vide infra). It is
worthy to note that the N-alkylation of triflate occurred
exclusively in an SN2 manner without the interference
of the SN1 mechanism, which is prone to epimerization.
In the previous paper,14 we have reported that reaction
of chiral synthon (R)- or (S)-6 with 1-chloro-2-bromo-
ethane can lead to the formation of either pyrrolidine or
cyclopropane derivatives depending on the quantity of
the base used. In the present case, the reaction was
highly regioselective to give exclusively the pyrrolidine
8 without comcommitant formation of cyclopropane
derivative even in the presence of 3 equiv of base.
The transformation of 8 to final 2,5-disubstituted
pyrrolidine was straightforward. Desulfonylation of 8a
(6% Na-Hg in methanol at 0 °C) afforded compound 11
as two rotamers in 85% yield. Simultaneous removal of
N-Boc and O-TBDMS groups under mild acidic conditions
(TFA) furnished compound 14 as a single isomer. The
same synthetic sequence applied to compound 8b af-
forded a product identical in all respects with that
obtained from 8a , confirming that 8a and 8b were C-3
epimers. In practical synthesis, a mixture of two diaster-
eomers 8a and 8b were used for the above-mentioned
transformations without lowering the overall yields.
To provide further information about the stereoisom-
erism of 8a and 8b, an epimerization experiment through
the protonation of intermediate sulfonyl stabilized car-
banion was performed. Treatment of a mixture of 8a and
8b with 1 equiv of n-BuLi followed by quenching with
aqueous NH4Cl solution gave exclusively compound 8a .
This result can be account for on the basis of preferred
pyramidal sulfonyl carbanion configuration as well as the
Syn th esis of (2S,5R)-cis-2,5-Disu bstitu ted P yr r o-
lid in e Der iva tive. To access this type of compound, (R)-
bistriflate 4 was required (Scheme 2). The coupling
reaction of bistriflate (R)-4 with the trianion of the
synthon 5 proceeded cleanly to afford compound 18 in
89% yield (Scheme 5), and no trace of 8a or 8b was found
from this reaction. Interestingly, only one diastereomer
was observed in this case, indicating the much higher
thermodynamic stability of 18 vs its C-3 epimer. De-
sulfonylation of 18 with 6% Na-Hg in methanol afforded
(2S,5R)-cis-2,5-disubstituted pyrrolidine derivative 19 in
(13) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993; pp 158-172.
(14) Pauly, R.; Sasaki, N. A.; Potier, P. Tetrahedron Lett. 1994, 35,
237.
(15) Vaino, A. R.; Szarek, W. A. J . Chem. Soc., Chem. Commun.
1996, 2351.

Synthesis of trans- and cis-2,5-Disubstituted Pyrrolidines
J . Org. Chem., Vol. 64, No. 23, 1999 8605
Sch em e 5a
+21 (c 4.4, CHCl3); IR (CHCl3) 3035, 2871, 1497, 1455, 1428,
1
1366 cm-1; H NMR (300 MHz, CDCl3) δ 7.42-7.30 (m, 5H),
5.15 (quintet, J ) 4.8 Hz, 1H), 4.80-4.68 (m, 2H), 4.59 (s, 2H),
3.78 (d, J ) 5.0 Hz, 2H); 13C NMR (62.5 MHz, CDCl3) δ 136.5,
128.7, 128.4, 128.0, 118.6 (q, J ) 319 Hz), 118.5 (q, J ) 319
Hz), 82.8, 74.0, 72.7, 67.0; MS (CI, NH3) m/z 464 [M + NH4]+.
Anal. Calcd for C12H12O7S2F6: C, 32.29; H, 2.71; S, 14.61.
Found: C, 32.24; H, 2.79; S, 14.11.
(2R)-1-O-Ben zylglycer ol-2,3-b ist r iflu or om et h a n esu l-
fon a te (4). Starting from (S)-1-O-benzylglycerol 3 (690 mg,
3.79 mmol), exactly the same procedure as described for the
preparation of compound 2 furnished 4 (1.56 g, 93%): [R]22
D
-21 (c 5.2, CHCl3); IR (CHCl3) 3035, 2870, 1497, 1455, 1422,
1
1366 cm-1; H NMR (300 MHz, CDCl3) δ 7.44-7.28 (m, 5H),
5.15 (quintet, J ) 4.8 Hz, 1H), 4.81-4.68 (m, 2H), 4.59 (s, 2H),
3.78 (d, J ) 5.0 Hz, 2H); 13C NMR (62.5 MHz, CDCl3) δ 136.6,
128.8, 128.4, 128.0, 118.7 (q, J ) 319 Hz), 118.5 (q, J ) 319
Hz), 82.9, 74.0, 72.8, 67.0; MS (CI, NH3) m/z 464 [M+NH4]+.
Anal. Calcd for C12H12O7S2F6: C, 32.29; H, 2.71; S, 14.61.
Found: C, 32.33; H, 2.78; S, 14.21.
a
Reagents and conditions: (a) BuLi (3 equiv), THF, -70 °C,
30 min then 4, -70 °C, 1 h, 89%; (b) 6% Na-Hg, Na2HPO4, MeOH,
0 °C, 3 h, rt, overnight, 78%; (c) TFA, rt, 6 h, then concd HCl,
100%.
78% yield as a mixture of two rotamers. The physical
properties (IR, NMR, Rf) of compound 19 were completely
different from those of 11. This observation confirms that
the synthetic sequences shown in Schemes 3 and 5 are
free of epimerization. Treatment of 19 with TFA then HCl
in methanol furnished compound 20 as a single isomer
in quantitative yield.
(2R,3S,5S)- a n d (2R,3R,5S)-1-ter t-Bu toxyca r bon yl-2-
ter t-b u t yld im et h ylsilyloxym et h yl-3-p h en ylsu lfon yl-5-
ben zyloxym eth ylp yr r olid in e (8). To a solution of 5 (R )
TBDMS) (140 mg, 0.33 mmol) in THF (5 mL) was added
dropwise BuLi (1.6 M, 0.62 mL, 0.99 mmol) at -70 °C. After
the solution was stirred for 30 min at the same temperature,
a solution of 2 (189 mg, 0.42 mmol) in THF (1.5 mL) was added
dropwise, and stirring was continued for 1 h before quenching
by addition of saturated NH4Cl. The reaction mixture was
extracted with ether. The ether extracts were washed with
brine, dried, and evaporated. Preparative TLC (silica gel,
dichloromethane/acetone ) 50/1) afforded 8 as a mixture of
two isomers (132 mg, 70%; 89% based on 71% of conversion)
and starting material 5 (29 mg, 21%) was recovered. Com-
pounds 8a and 8b could be separated by PTLC (silica gel,
heptane/EtOAc ) 4/1)
(2R,3S,5S)-1-ter t-Bu toxyca r bon yl-2-ter t-bu tyld im eth -
ylsilyloxym eth yl-3-ph en ylsu lfon yl-5-ben zyloxym eth ylpyr -
r olid in e (8a ). Major isomer (two rotamers): [R]20D -20 (c 3.5,
CHCl3); IR (CHCl3) 2956, 2931, 1688, 1475, 1450, 1394, 1369,
1306, 1256 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.92-7.85 (m,
2H), 7.68-7.53 (m, 3H), 7.36-7.27 (m, 5H), 4.65-4.47 (m, 2H),
4.40-4.31 (m, 1H), 4.19-3.79 (m, 3H), 3.76-3.71 (m, 1H),
3.64-3.17 (m, 2H), 2.69-2.24 (m, 2H), 1.46, 1.38 (two s, 9H),
0.82, 0.80 (two s, 9H), -0.016, -0.060, -0.068 (three s, 6H);
13C NMR (62.5 MHz, CDCl3) δ 153.0, 138.3, 138.0, 133.9, 129.3,
128.7, 128.3, 127.7, 80.2, 73.2, 70.5, 70.0, 65.5, 65.2, 63.7, 62.2,
60.9, 60.3, 57.7, 57.5, 28.6, 28.4, 28.3, 25.8, 18.0, -5.6; MS (CI)
m/z 576 [M + H]+. Anal. Calcd for C30H45NO6SSi: C, 62.58;
H, 7.88; N, 2.43; S, 5.55. Found: C, 62.16; H, 8.08; N, 2.41; S,
5.42.
(2R,3R,5S)-1-ter t-Bu toxyca r bon yl-2-ter t-bu tyld im eth -
ylsilyloxym eth yl-3-ph en ylsu lfon yl-5-ben zyloxym eth ylpyr -
r olid in e (8b). Minor isomer (two rotamers): [R]20D -26 (c 1.25,
CHCl3); IR (CHCl3) 2929, 2857, 1696, 1654, 1559, 1456, 1394,
1306, 1255 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.89-7.86 (m,
2H), 7.68-7.51 (m, 3H), 7.29-7.21 (m, 3H), 7.11-7.07 (m, 1H),
7.01-6.97 (m, 1H), 4.51-3.95 (m, 7H), 3.82 (dd, J ) 9.7, 3.8
Hz, 0.5H), 3.54 (dd, J ) 9.6, 4.7 Hz, 0.5H), 3.36 (dt, J ) 9.5,
2.5 Hz, 1H), 2.97-2.75 (m, 1H), 1.89 (dd, J ) 11.3, 6.6 Hz, 0.5
H), 1.74 (dd, J ) 11.3, 6.6 Hz, 0.5H), 1.46, 1.40 (two s, 9H),
0.91, 0.90 (two s, 9H), 0.13, 0.092, 0.067, 0.036 (four s, 6H);
13C NMR (62.5 MHz, CDCl3) δ 153.2, 153.1, 140.3, 140.2, 138.4,
138.1, 133.7, 129.3, 128.5, 128.4, 128.2, 127.8, 127.6, 127.5,
127.4, 80.2, 73.4, 73.2, 71.5, 70.4, 64.2, 63.6, 61.0, 59.5, 59.4,
59.2, 57.5, 57.1, 30.2, 29.7, 28.6, 28.6, 26.0, 18.2, -5.5, -5.6,
-5.7; MS (CI) m/z 576 [M + H]+.
(2R,3S,5S)- an d (2R,3R,5S)-1-ter t-Bu toxycar bon yl-2-tet-
r a h yd r op yr a n yloxym et h yl-3-p h en ylsu lfon yl-5-b en zyl-
oxym eth ylp yr r olid in e (9). Starting from 6 (172 mg, 0.43
mmol), exactly the same procedure as described for the
preparation of compound 5 furnished 9 as four isomers (195
mg, 83%), and 27 mg (16%) of the starting sulfone 7 was
recovered.
Con clu sion
We have developed a new, highly stereoselective syn-
thesis of optically pure (2S,5S)-trans- and (2S,5R)-cis-
2,5-disubstituted pyrrolidine derivatives from readily
available chiral synthons. By docking two units with
appropriate stereochemistry, all four diastereomers are
readily accessible. The efficient and modulable approach
described here should find application in the syntheses
of pyrrolidine and indolizidine type natural products as
well as pyrrolidine based C2-symmetry chiral ligands.10
The extension of this methodology for the synthesis of
2,3,5-trisubstituted pyrrolidine derivatives in a stereo-
controlled manner is undergoing in our laboratory.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents obtained from commercial
sources were used without further purification. THF was
distilled from sodium benzophenone ketyl. Flash chromatog-
raphy was performed using 230-400 mesh silica gel. Analyti-
cal thin-layer chromatography (TLC) was carried out on plates
precoated with 0.25 mm of silica gel containing 60F-254
indicator. (R)- and (S)-2,3-O-isopropylideneglycerol (99% ee,
1
CHEMI S.p.A., Italy) were used as received. H NMR spectra
were recorded at 300, 250, and 200 MHz, and 13C NMR spectra
were recorded at 75.5, 62.5, and 50 MHz with chemical shifts
reported in ppm (δ) downfield from TMS (internal reference)
1
for H 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 high-resolution mass
spectrum was obtained by CI (methane). Elemental analyses
were carried out by the microanalytical laboratory at the ICSN.
(2S)-1-O-Ben zylglycer ol-2,3-b ist r iflu or om et h a n esu l-
fon a te (2). To a solution of triflic anhydride (1.17 g, 0 70 mL,
4.16 mmol) in dry dichloromethane (40 mL) at -30 °C was
added dropwise a solution of (R)-1-O-benzylglycerol 1 (379 mg,
2.08 mmol) and pyridine (362 mg, 369 µL, 4.58 mmol) in dry
dichloromethane (2 mL) over a period of 10 min. After being
stirred for 15 min, the reaction mixture was washed with ice-
cold water and satd NaHCO3, dried over Na2SO4, and concen-
trated under reduced pressure. The light-brown residual oil
was purified through silica gel (heptane/EtOAc ) 2/1) to give
the pure bistriflate 2 as a colorless oil (877 mg, 95%): [R]22
D

8606 J . Org. Chem., Vol. 64, No. 23, 1999
Wang et al.
1
(2R,3R,5S)-1-ter t-Bu t oxyca r b on yl-2-t et r a h yd r op yr a -
n yloxym eth yl-3-p h en ylsu lfon yl-5-ben zyloxym eth ylp yr -
r olid in e (9a ) (â-Su lfon e). Less polar isomers, two isomers
(four rotamers): IR (CHCl3) 3019, 2977, 1688, 1522, 1477,
1368 cm-1; H NMR (250 MHz, CDCl3) δ 7.32 (m, 5H), 4.60-
4.45 (m, 3H), 4.02-3.25 (m, 8H), 2.08-1.43 (m, 10H), 1.46,
1.39 (two s, 9H); 13C NMR (50 MHz, CDCl3) δ 153.9, 153.8,
138.8, 138.5, 128.5, 128.4, 127.6, 99.5, 98.8, 98.1, 79.5, 73.3,
70.8, 70.7, 70.1, 68.5, 67.7, 67.5, 66.7, 62.1, 61.9, 57.6, 57.4,
57.1, 30.7, 28.6, 27.1, 27.0, 26.8, 26.4, 26.2, 25.9, 25.6, 19.6,
1
1423, 1393, 1368 cm-1; H NMR (250 MHz, CDCl3) δ 7.91-
7.88 (m, 2H), 7.72-7.52 (m, 3H), 7.36-7.00 (m, 5H), 4.73-
4.60 (m, 1H), 4.46-4.22 (m, 4H), 4.17-3.95 (m, 4H), 3.88-
3.76 (m, 1H), 3.57-3.50 (m, 1H), 3.43-3.34 (m, 1H), 2.92-
2.71 (m, 1H), 2.05-1.81 (m, 1H), 1.80-1.40 (m, 6H), 1.46, 1.39
(two s, 9H); 13C NMR (50 MHz, CDCl3) δ 153.2, 140.1, 140.0,
138.2, 138.0, 133.7, 129.5, 129.3, 128.4, 128.4, 128.1, 127.7,
127.6, 127.4, 127.3, 99.3, 99.2, 97.7, 97.3, 80.3, 80.2, 73.3, 73.1,
71.3, 70.2, 65.5, 65.3, 63.9, 63.2, 61.0, 58.1, 57.0, 56.9, 30.6,
30.3, 29.8, 29.4, 28.5, 25.6, 18.7; MS (CI) m/z 546 [M + H]+;
HRMS calcd for C29H40NO7S (M + H) 546.2526, found 546.2519.
(2R,3S,5S)-1-ter t-Bu toxyca r bon yl-2-tetr a h yd r op yr a n -
yloxym eth yl-3-p h en ylsu lfon yl-5-ben zyloxym eth ylp yr r o-
lid in e (9b) (r-Su lfon e). More polar isomers, two isomers (four
rotamers): IR (CHCl3) 3019, 2977, 1690, 1522, 1477, 1423,
19.5, 19.3; MS (CI) m/z 406 [M + H]+. Anal. Calcd for C23H35
NO5: C, 68.12; H, 8.70; N, 3.45. Found: C, 67.85; H, 8.66; N,
3.24.
-
(2R,5S)-1-ter t-Bu t oxyca r b on yl-2-b en zyloxym et h yl-5-
ben zyloxym eth ylp yr r olid in e (13). Starting from 10 (127
mg, 0.23 mmol), exactly the same procedure as described for
the preparation of 11 furnished compound 13 as two rotamers
(75 mg, 78%): [R]21 -81 (c 2.25, CHCl3); IR (CHCl3) 3030,
D
2981, 1680, 1504, 1483, 1455, 1391, 1363 cm-1; 1H NMR (250
MHz, CDCl3) δ 7.31 (m, 10H), 4.57 (d, J ) 12.1 Hz, 1H), 4.54
(d, J ) 11.9 Hz, 1H), 4.48 (d, J ) 11.9 Hz, 1H), 4.47 (d, J )
12.1 Hz, 1H), 4.03-3.98 (m, 1H), 3.93-3.85 (m, 1H), 3.67 (dd,
J ) 9.2, 3.0 Hz, 1H), 3.57 (dd, J ) 9.0, 3.0 Hz, 1H), 3.46 (dd,
J ) 9.1, 7.6 Hz, 1H), 3.29 (t, J ) 8.6 Hz, 1H), 2.11-1.89 (m,
4H), 1.40 (s, 9H); 13C NMR (50 MHz, CDCl3) δ 153.8, 138.7,
138.4, 128.4, 128.4, 127.5, 79.5, 73.2, 70.6, 69.9, 57.1, 28.5, 26.9,
25.9; MS (CI) m/z 412 [M + H]+; HRMS calcd for C25H34NO4
(M + H) 412.2488, found 412.2493.
1
1392 cm-1; H NMR (250 MHz, CDCl3) δ 7.89-7.86 (m, 2H),
7.66-7.51 (m, 3H), 7.37-7.29 (m, 5H), 4.68-4.38 (m, 4H),
4.22-3.27 (m, 8H), 2.84-2.40 (m, 2H), 1.57-1.38 (m, 6H), 1.47,
1.38 (two s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 153.1, 138.6,
138.4, 138.2, 138.0, 133.9, 129.4, 128.9, 128.4, 127.8, 127.6,
99.5, 98.1, 97.6, 80.4, 73.4, 70.6, 70.2, 67.3, 66.0, 65.8, 65.4,
62.6, 61.8, 61.6, 59.2, 58.5, 57.7, 57.2, 30.6, 30.2, 28.6, 28.4,
28.2, 25.3, 19.5, 19.3, 19.2, 18.9; MS (CI) m/z 546 [M + H]+;
HRMS calcd for C29H40NO7S (M + H) 546.2526, found 546.2539.
(2R,3S,5S)- a n d (2R,3R,5S)-1-ter t-Bu toxyca r bon yl-2-
b en zyloxym et h yl-3-p h en ylsu lfon yl-5-b en zyloxym et h -
ylp yr r olid in e (10). Starting from 7(151 mg, 0.37 mmol),
exactly the same procedure as described for the preparation
of compound 5 furnished 10 as two isomers (165 mg, 80%) and
27 mg (18%) of the starting sulfone 7 was recovered. Com-
pound 10: IR (CHCl3) 3015, 2978, 1688, 1496, 1478, 1455,
(2R,5S)-2-Hyd r oxym eth yl-5-ben zyloxym eth ylp yr r oli-
d in e (14). A solution of 11 (73 mg, 0.17 mmol) in trifluoroacetic
acid was stirred at room temperature for 4 h. The solvent was
evaporated, and the residue was purified by preparative TLC
(silica gel, CH2Cl2/MeOH ) 10/1) to give compound 14 (45 mg,
80%): [R]22 +14 (c 0.8, CHCl3); IR (CHCl3) 3338, 3013, 2963,
D
2875, 1675, 1456, 1431, 1369 cm-1; 1H NMR (250 MHz, CDCl3)
δ 7.34-7.29 (m, 5H), 4.82 (br s, 3H, OH and NH2+), 4.55 (d, J
) 11.8 Hz, 1H), 4.49 (d, J ) 11.8 Hz, 1H), 3.68-3.51 (m, 6H),
2.01-1.85 (m, 2H), 1.71-1.49 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 137.5, 128.5, 128.0, 73.4, 69.3, 61.5, 58.9, 27.3, 26.5;
MS (CI) m/z 278 [M + 57], 222 [M + H]+; HRMS calcd for
1
1393, 1368, 1251 cm-1; H NMR (250 MHz, CDCl3) δ 7.90-
7.79 (m, 2H), 7.70-7.48 (m, 3H), 7.39-7.00 (m, 10H), 4.70-
4.28 (m, 5H), 4.20-3.28 (m, 6H), 2.96-2.67, 2.52-2.34, 1.98-
1.77 (m, 2H), 1.40, 1.39 (two s, 9H); 13C NMR (62.5 MHz,
CDCl3) δ 153.1, 153.0, 139.9, 138.4, 138.2, 137.9, 133.8, 133.7,
129.3, 129.2, 128.7, 128.3, 128.2, 128.1, 127.7, 127.5, 127.4,
127.2, 80.3, 80.1, 73.2, 73.0, 71.2, 70.3, 70.2, 68.8, 67.9, 66.6,
65.7, 65.1, 64.0, 63.4, 59.2, 58.5, 58.1, 58.0, 57.6, 57.3, 56.9,
56.6, 30.1, 29.5, 28.4; MS (CI) m/z 552 [M + H]+; HRMS calcd
for C31H38NO6S (M + H) 552.2420, found 552.2407.
C
13H20NO2 (M + H) 222.1494, found 222.1489.
(2R,3S,5S)- a n d (2R,3R,5S)-1-ter t-Bu toxyca r bon yl-2-
h ydr oxym eth yl-3-ph en ylsu lfon yl-5-ben zyloxym eth ylpyr -
r olid in e (21). Compound 8 (110 mg, 0.19 mmol) was treated
with a 1% (m/v) solution of iodine in methanol. The mixture
was refluxed for 24 h. The solvent was removed, and the
residue was dissolved into ether and aqueous Na2S2O3 solution.
The aqueous layer was extracted with ether. The ether layer
was washed with brine, dried over Na2SO4, and evaporated.
Preparative TLC on silica gel (heptane/EtOAc ) 1/2) gave
alcohols 21a (45 mg, 51%) 21b (17 mg, 19%).
(2R,5S)-1-ter t-Bu toxyca r bon yl-2-ter t-bu tyld im eth ylsi-
lyloxym eth yl-5-ben zyloxym eth ylp yr r olid in e (11). To a
solution of the sulfone 8 (109 mg, 0.19 mmol) in HPLC-grade
MeOH (4 mL) containing Na2HPO4 (215 mg, 1.52 mmol) was
added 6% Na-Hg (437 mg, 1.14 mmol) at 0 °C. The mixture
was vigorously stirred at 0 °C for 2 h. Mercury was removed
by decanting the reaction mixture. After evaporation of MeOH
in vacuo, the residue was dissolved in water and CH2Cl2. The
aqueous layer was extracted with CH2Cl2. The CH2Cl2 extracts
were washed with brine, dried, and evaporated. Flash chro-
matography on silica gel (heptane/EtOAc ) 20/1) gave com-
(2R,3S,5S)-1-ter t-Bu toxyca r bon yl-2-h yd r oxym eth yl-3-
p h en ylsu lfon yl-5-ben zyloxym eth ylp yr r olid in e (21a ). Ma-
jor isomer (two rotamers): [R]20 -7.9 (c 1.4, CHCl3); IR
D
(CHCl3) 3400, 3006, 2981, 1688, 1463, 1394, 1369 cm-1
;
1H
NMR (250 MHz, CDCl3) δ 7.91-7.89 (m, 2H), 7.69-7.53 (m,
3H), 7.39-7.29 (m, 5H), 4.58 (d, J ) 11.7 Hz, 1H), 4.49 (d, J
) 11.7 Hz, 1H), 4.29 (m, 1H), 4.09-4.01 (m, 1H), 3.80 (m, 2H),
3.64-3.58 (m, 3H), 3.10 (br s, 1H, OH), 2.56 (m, 1H), 2.38-
2.28 (m, 1H), 1.40 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 153.8,
138.3, 137.7, 134.1, 129.4, 128.8, 128.4, 127.7, 80.9, 73.2, 69.8,
65.0, 63.2, 61.0, 57.5, 28.3, 28.0; MS (CI) m/z 462 [M + H]+;
HRMS for C24H32NO6S (M + H) 462.1950, found 462.1928.
(2R,3R,5S)-1-ter t-Bu toxyca r bon yl-2-h yd r oxym eth yl-3-
p h en ylsu lfon yl-5-ben zyloxym eth ylp yr r olid in e (21b). Mi-
pound 11 as two rotamers (70 mg, 85%): [R]20 -71 (c 1.0,
D
CHCl3); IR (CHCl3) 3006, 2963, 2931, 1681, 1475, 1456, 1394,
1
1369 cm-1; H NMR (250 MHz, CDCl3) δ 7.34-7.27 (m, 5H),
4.58, 4.54, 4.49, 4.47 (four d, J ) 12.0 Hz, 2H), 4.04-3.62 (m,
4H), 3.58 (dd, J ) 8.9, 3.0 Hz, 0.5H), 3.46 (t, J ) 7.7 Hz, 0.5H),
3.43 (t, J ) 7.6 Hz, 0.5H), 3.27 (t, J ) 8.6 Hz, 0.5H), 2.18-
1.85 (m, 4H), 1.46, 1.40 (two s, 9H), 0.88, 0.87 (two s, 9H),
0.041, 0.030, 0.020 (three s, 6H); 13C NMR (75 MHz, CDCl3) δ
153.9, 153.8, 138.8, 138.5, 128.5, 128.4, 127.7, 127.6, 79.4, 79.3,
73.3, 70.8, 70.1, 63.4, 62.8, 59.1, 57.5, 28.7, 28.6, 27.2, 26.3,
26.0, 25.9, 18.3, -5.2, -5.3; MS (CI) m/z 436 [M + H]+. Anal.
Calcd for C24H41NO4Si: C, 66.16; H, 9.49; N, 3.22; Found: C,
66.14; H, 9.21; N, 3.32.
nor isomer (two rotamers): [R]20 -12 (c 0.9, CHCl3); IR
D
(CHCl3) 3531, 3020, 2983, 1688, 1455, 1448, 1394, 1369 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.91-7.84 (m, 2H), 7.77-7.56
(m, 3H), 7.30-7.00 (m, 5H), 4.41, 4.40, 4.34, 4.31 (four d, J )
12.0 Hz, 2H), 4.25-4.08 (m, 4H), 3.90 (dd, J ) 9.8, 3.4 Hz,
0.5H), 3.60 (dd, J ) 9.5, 4.2 Hz, 0.5H), 3.33 (dt, J ) 9.7, 2.3
Hz, 1H), 3.21 (m, 0.5H), 3.02 (m, 0.5H), 2.79-2.58 (m, 1H),
1.90 (dd, J ) 11.9, 6.0 Hz, 0.5H), 1.79-1.72 (m, 0.5H), 1.47,
1.41 (two s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 153.3, 152.9,
138.9, 138.3, 138.0, 134.3, 129.6, 128.6, 128.5, 128.2, 127.9,
127.7, 127.5, 127.4, 80.6, 73.4, 73.2, 71.3, 70.2, 64.1, 63.4, 61.4,
60.6, 60.5, 60.3, 56.7, 56.4, 31.0, 30.4, 28.6; MS (CI) m/z 462
[M + H]+; HRMS for C24H32NO6S (M + H) 462.1950, found
462.1950.
(2R,5S)-1-ter t-Bu t oxyca r b on yl-2-t et r a h yd r op yr a n yl-
oxym eth yl-5-ben zyloxym eth ylp yr r olid in e (12). Starting
from 9 (109 mg, 0.2 mmol), exactly the same procedure as
described for the preparation of 11 furnished compound 12 as
two isomers (four rotamers) (70 mg, 87%): [R]20 -83 (c 1.05,
D
CHCl3); IR (CHCl3) 3009, 2947, 2870, 1683, 1476, 1455, 1394,

Synthesis of trans- and cis-2,5-Disubstituted Pyrrolidines
J . Org. Chem., Vol. 64, No. 23, 1999 8607
(2R,3S,5S)- a n d (2R,3R,5S)-1-ter t-Bu toxyca r bon yl-2-
h ydr oxym eth yl-3-ph en ylsu lfon yl-5-ben zyloxym eth ylpyr -
r olid in e (21). Ma jor Isom er 21a . A solution of 9a (12 mg,
0.022 mmol) in EtOH (2 mL) containing PPTS (0.6 mg, 0.0022
mmol) was stirred at 50 °C for 24 h. The solvent was
evaporated. The residue was dissolved in dichloromethane,
washed with water, saturated NaHCO3, and brine, respec-
tively, dried over Na2SO4, and evaporated. Preparative TLC
on silica gel (heptane/EtOAc ) 1/2) afforded cmpound 21a (10
mg (99%).
acid was stirred at room temperature for 4 h. The solvent was
evaporated, and the residue was purified by preparative TLC
(silica gel, CH2Cl2/MeOH ) 10/1) to give the product as a salt
of trifluoroacetic acid that was then treated with concd HCl
in MeOH and evaporated to afford compound 20 (26 mg,
100%): [R]20D -4.2 (c 0.52, MeOH); IR (Nujol) 3401, 2924, 2854,
1641, 1586, 1500, 1454, 1378, 1366 cm-1; 1H NMR (250 MHz,
CDCl3) δ 7.30-7.16 (m, 5H), 4.81 (br s, 3H, OH and NH2+),
4.51 (s, 2H), 3.78-3.55 (m, 6H), 2.06-2.04 (m, 2H), 1.76-1.75
(m, 2H); 13C NMR (75 MHz, CD3OD) δ 138.8, 129.3, 128.9,
128.7, 74.2, 69.5, 63.3, 61.3, 61.1, 26.8, 26.4; MS (CI) m/z 278
[M + 57], 222 [M + H]+; HRMS calcd for C13H20NO2 (M + H)
222.1494, found 222.1487.
The minor isomer 21b was obtained from 9b (25 mg, 0.046
mmol) by exactly the same procedure as described for the
preparation of compound 21a (18 mg, 85%).
(2R,3S,5R)-1-ter t-Bu toxyca r bon yl-2-ter t-bu tyld im eth -
ylsilyloxym eth yl-3-ph en ylsu lfon yl-5-ben zyloxym eth ylpyr -
r olid in e (18). To a solution of 5 (185 mg, 0.43 mmol) in THF
(5 mL) was added dropwise BuLi (1.6 M, 0.81 mL, 1.29 mmol)
at -70 °C. After the mixture was stirred for 30 min at the
same temperature, a solution of 4 (250 mg, 0.56 mmol) in THF
(3 mL) was added dropwise, and stirring was continued for 1
h before quenching by addition of saturated NH4Cl. The
reaction mixture was extracted with ether. The ether extracts
were washed with brine, dried, and evaporated. Preparative
TLC (silica gel, toluene/EtOAc ) 6/1) afforded 18 as a single
isomer (two rotamers) (220 mg, 89%), and starting material 5
2-Tr iflu or om et h ylsu lfon yloxy-3-b en zyloxyp r op en e-1
(15): IR (CHCl3) 3034, 2864, 1673, 1497, 1455, 1421 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.37-7.33 (m, 5H), 5.34-5.28 (m,
2H), 4.58 (s 2H), 4.10 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
152.2, 137.1, 128.7, 128.2, 128.0, 118.6 (q, J ) 320 Hz), 106.9,
72.8, 68.2; MS (CI, NH3) m/z 314 [M + NH4]+.
(E )-1-Tr iflu or om e t h ylsu lfon yloxy-3-b e n zyloxyp r o-
p en e-1 (16): IR (CHCl3) 3033, 2863, 1674, 1497, 1454, 1426
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.43-7.27 (m, 5H), 6.78
(br d, J ) 11.8 Hz, 1H), 5.88 (dt, J ) 11.8, 5.8 Hz, 1H), 4.53
(s, 2H), 4.05 (dd, J ) 5.8, 1.6 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 138.4, 137.5, 128.4, 128.1, 127.9, 118.7 (q, J ) 319
Hz), 118.5, 72.8, 64.9; MS (CI, NH3) m/z 314 [M + NH4]+.
(Z)-1-Tr iflu or om e t h ylsu lfon yloxy-3-b e n zyloxyp r o-
p en e-1 (17): IR (CHCl3) 3034, 2928, 1672, 1496, 1455, 1429
(40 mg, 22%) was recovered. Compound 18: [R]20 +10 (c 3.2,
D
CHCl3); IR (CHCl3) 2956, 2931, 2863, 1688, 1456, 1400, 1369,
1313, 1256 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.92-7.89 (m,
2H), 7.66-7.54 (m, 3H), 7.32-7.26 (m, 5H), 4.51-4.40 (m, 2H),
4.30 (m, 1H), 4.08-4.00 (m, 1H), 3.83-3.77 (m, 1H), 3.66-
3.33 (m, 4H), 2.69-2.27 (m, 2H), 1.48, 1.41 (two s, 9H), 0.80,
0.75 (two s, 9H), -0.069, -0.10, -0.12 (three s, 6H); 13C NMR
(62.5 MHz, CDCl3) δ 154.0, 153.7, 138.0, 137.6, 133.9, 129.3,
128.7, 128.6, 128.3, 127.4, 80.1, 73.1, 70.8, 70.2, 63.6, 62.8, 62.5,
61.7, 60.2, 56.9, 28.4, 28.3, 28.0, 27.3, 25.8, 18.1, -5.6; MS (CI,
NH3) m/z 576 [M + H]+. Anal. Calcd for C30H45NO6SSi: C,
62.58; H, 7.88; N, 2.43; S, 5.55. Found: C, 62.16; H, 7.85; N,
2.61; S, 5.52.
1
cm-1; H NMR (200 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 6.63
(br d, J ) 5.8 Hz, 1H), 5.50 (q, J ) 6.2 Hz, 1H), 4.52 (s, 2H),
4.21 (dd, J ) 6.4, 1.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
137.5, 136.4, 128.6, 128.0, 127.9, 118.7 (q, J ) 319 Hz), 117.3,
72.9, 62.5; MS (CI, NH3) m/z 314 [M + NH4]+.
X-r a y Cr ysta l Str u ctu r e of 21a . Crystal data: C24H31
-
NO6S, Mw ) 461.56; colorless crystal of 0.30 × 0.20 × 0.10
mm, monoclinic, space group P21, Z ) 2, a ) 12.600(4) Å,
b ) 5.781(2) Å, c ) 16.649(8) Å, â ) 96.32(2)°, V ) 1205.4(8)
Å3, dcalcd ) 1.272 g cm-3, F(000) ) 492, λ ) 1.541 80 Å (Cu
KR), µ ) 1.517 mm-1, Nonius CAD-4 diffractometer, θ range:
(2R,5R)-1-ter t-Bu toxyca r bon yl-2-ter t-bu tyld im eth ylsi-
lyloxym eth yl-5-ben zyloxym eth ylp yr r olid in e (19). To a
solution of the sulfone 18 (1.10 g, 1.91 mmol) in HPLC-grade
MeOH (20 mL) containing Na2HPO4 (2.17 g, 15.28 mmol) was
added 6% Na-Hg (4.39 g, 11.46 mmol) at 0 °C. The mixture
was vigorously stirred at 0 °C for 3 h and then at room
temperature overnight. Mercury was removed by decanting
the reaction mixture. After evaporation of MeOH in vacuo, the
residue was dissolved in water and CH2Cl2. The aqueous layer
was extracted with CH2Cl2. The CH2Cl2 extracts were washed
with brine, dried over Na2SO4, and evaporated. Flash chro-
matography on silica gel (heptane/EtOAc ) 20/1) gave com-
2.67-67.97, 2920 collected reflections, 2675 unique (Rint
)
0.0801), 2262 observed (I > 2σ(I)). Full-matrix least-squares
(SHELXL93),16 R ) 0.0458 for 2262 observed reflections,
wR2 ) 0.1313 for 2675 unique reflections, goodness of fit )
0.997. Residual electron density between -0.256 and 0.304
e A-3. Absolute configuration was established by refinement
of the Flack parameter17 (-0.01(3), using the 329 most
significative pairs of Frieded with θ < 32%) and examina-
tion of selected bijvoet pairs for which the absolute value of
∆Fc ) (F(hkl) - F(-h -k -l) is greater than 1.0 e (maximum
∆Fc ) 1.9 e). For these 68 pairs, only three are incorrectly
predicted.
pound 19 as two rotamers (648 mg, 78%): [R]20 +1 (c 1.0,
D
CHCl3); IR (CHCl3) 3006, 2956, 2931, 1681, 1475, 1456, 1394,
1
1369 cm-1; H NMR (250 MHz, CDCl3) δ 7.32-7.25 (m, 5H),
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 2, 4, 8a ,b, 9a ,b, 10-20, and 21a ,b and
X-ray data for compound 21a . This material is available free
of charge via the Internet at http:/pubs.acs.org.
4.50 (d, J ) 2.6 Hz, 2H), 4.00-3.90 (m, 1H), 3.80-3.30 (m,
5H), 2.01-1.79 (m, 4H), 1.42 (s, 9H), 0.85 (s, 9H), -0.012,
-0.015 (two s, 6H); 13C NMR (75 MHz, CDCl3) δ 154.8, 138.7,
128.4, 127.6, 79.4, 73.3, 71.5, 64.0, 63.0, 59.7, 57.9, 28.6, 27.4,
26.8, 26.1, 18.4, -5.2; MS (CI) m/z 436 [M + H]+. Anal. Calcd
for C24H41NO4Si: C, 66.16; H, 9.49; N, 3.22. Found: C, 65.98;
H, 9.54; N, 3.15.
J O991052D
(16) Sheldrick, G. M. SHELXL93. Program for the solution of crystal
structures; University of Go¨ttingen: Germany, 1993.
(17) Flack, H. D. Acta Crystallogr. 1983, A38, 876.
(2R,5R)-2-Hyd r oxym eth yl-5-ben zyloxym eth ylp yr r oli-
d in e (20). A solution of 19 (44 mg, 0.10 mmol) in trifluoroacetic