Conformationally constrained 7-azabicyclo[2.2.1]heptane amino acids. Synthesis of a glutamic acid analogue

Article abstract of DOI:10.1021/jo982327c

We report the synthesis of 2-substituted 7-azabicyclo[2.2.1]heptane glutamic acid analogue 27 from L-serine. Hemiaminal intermediate 2 can be converted to the 2S,3S,5S-trisubstituted pyrrolidine 3 by a tandem Wittig/Michael reaction or to the 2S,3S,5R-trisubstituted pyrrolidine 4 via an iodosulfonamidation reaction. The key transannular alkylation step to form the [2.2.1] ring system involves a β-elimination of a silyl ether followed by cyclization to afford tert-butyl 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]- 2-heptene-1-carboxylate (20). Selective functionalization at C-2 was accomplished by the direct reduction with SmI₂ of 2-keto-3-silyl ether 23 to the C-2 ketone 24, which was converted to α,β-unsaturated ester 25. Stereospecific reduction of the double bond from the exo face leads to a single protected glutamate analogue, tert-butyl (1S,2R,4R)-7- benzyloxycarbonyl-2-(methoxycarbonylmethyl)-7-azabicyclo[2.2.1]heptane-1- carboxylate (27).

Full text of DOI:10.1021/jo982327c

2050
J . Org. Chem. 1999, 64, 2050-2056
Con for m a tion a lly Con str a in ed 7-Aza bicyclo[2.2.1]h ep ta n e Am in o
Acid s. Syn th esis of a Glu ta m ic Acid An a logu e
Barry P. Hart and Henry Rapoport*
Department of Chemistry, University of California, Berkeley, California 94720
Received November 24, 1998
We report the synthesis of 2-substituted 7-azabicyclo[2.2.1]heptane glutamic acid analogue 27 from
L-serine. Hemiaminal intermediate 2 can be converted to the 2S,3S,5S-trisubstituted pyrrolidine
3 by a tandem Wittig/Michael reaction or to the 2S,3S,5R-trisubstituted pyrrolidine 4 via an
iodosulfonamidation reaction. The key transannular alkylation step to form the [2.2.1] ring system
involves a â-elimination of a silyl ether followed by cyclization to afford tert-butyl 7-benzyloxycar-
bonyl-7-azabicyclo[2.2.1]-2-heptene-1-carboxylate (20). Selective functionalization at C-2 was
accomplished by the direct reduction with SmI2 of 2-keto-3-silyl ether 23 to the C-2 ketone 24,
which was converted to R,â-unsaturated ester 25. Stereospecific reduction of the double bond from
the exo face leads to a single protected glutamate analogue, tert-butyl (1S,2R,4R)-7-benzyloxycar-
bonyl-2-(methoxycarbonylmethyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate (27).
In tr od u ction
The use of conformationally constrained R-amino acid
analogues has been actively pursued as a means of
overcoming some inherent limitations of natural R-amino
acids in biologically active molecules.1 The strategy of
replacing a natural amino acid with a conformationally
constrained amino acid has led to enhanced stability of
peptide chains to proteolytic enzymes,2 increased potency
of ligand receptor interactions,3 and the ability to further
elucidate receptor-bound ligand conformations.4
We now describe the chirospecific synthesis of a
2-substituted 7-azabicyclo[2.2.1]heptane glutamic acid
analogue. The synthesis of this 2-substituted 7-azabicyclo-
[2.2.1]heptane R-amino acid complements the synthesis
of 3-substituted 7-azabicyclo[2.2.1]heptane R-amino acids
previously reported from this laboratory.5 Molecules
containing the 7-azabicyclo[2.2.1]heptane ring system
have been popular synthetic targets6 with several meth-
ods reported7 for the synthesis of R-amino acids of this
structural type. The strategy we describe affords chi-
rospecific products and versatile intermediates that could
lead to the development of a variety of amino acid
analogues with substitution at C-2 or disubstitution at
the C-2 and C-3 positions.
F igu r e 1. Proposed route to the synthesis of 2-substituted
azabicyclo[2.2.1]heptane R-amino acids.
Homologation and cyclization of the hemiaminal 2 to
form pyrrolidines 3 and 4 can proceed through a tandem
Wittig/Michael sequence, affording only pyrrolidine 3
after crystallization (Scheme 1). Alternatively, the syn-
thesis of (2S,3S,5R)-pyrrolidine 4 can be realized by an
iodosulfonamidation cyclization reaction establishing the
R stereochemistry at the ring-closure site, C-5. A series
of functional group transformations will then provide the
substrate for the transannular alkylation reaction leading
to a â,γ-unsaturated, 7-azabicyclo[2.2.1]heptane R-amino
acid 20 and subsequently to the glutamate analogue 27.
The route we propose to follow (Figure 1) employs
L-serine (1) as the starting material that is to be
converted to the hemiaminal 2 as previously reported.8a,b
Resu lts a n d Discu ssion
Th e Ster eocon tr olled Syn th esis of Tr isu bstitu ted
P yr r olid in es 3 a n d 4. From the hemiaminal intermedi-
ate 2, two strategies for pyrrolidine formation were
developed. The first plan involves a tandem Wittig/
Michael reaction9 to afford the 2S,3S,5S, all cis, pyrro-
lidine 3. The kinetics and stereochemistry of this reaction
sequence are temperature dependent as shown in Table
1. At temperatures between -15 °C and room tempera-
(1) (a) Gante, J . Angew. Chem. Int. Ed. Engl. 1994, 33, 1699. (b)
Mendel, D.; Ellman, J .; Schultz, P. G. J . Am. Chem. Soc. 1993, 115,
4359.
(2) Ogawa, T.; Yoshitomi, H.; Kodama, H.; Waki, M.; Stammer, C.
H.; Shimohigashi, Y. FEBS Lett. 1989, 250, 227.
(3) 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, 455.
(4) (a) Tellier, F.; Acher, F.; Brabet, I.; Pin, J .-P.; Azerad, R. Bioorg.
Med. Chem. 1998, 6, 195. (b) Charette, A. B.; Cote´, B. J . Am. Chem.
Soc. 1995, 117, 12721. (c) Bun˜uel, E.; Cativiela, C.; Diaz-de-Villegas,
M. D. Tetrahedron: Asymmetry 1996, 7, 1521.
(5) Campbell, J . A.; Rapoport, H. J . Org. Chem. 1996, 61, 6313.
(6) Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179.
(7) (a) Avenoza, A.; Cativiela, C.; Busto, J . H.; Peregrina, J . M.
Tetrahedron Lett. 1995, 36, 7123. (b) Sato, T.; Mori, T.; Sugiyama, T.;
Ishibashi, H.; Ikeda, M. Heterocycles 1994, 37, 245.
(8) (a) Folmer, J . F.; Acero, C.; Thai, D. L.; Rapoport, H. J . Org.
Chem., in press. (b) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1989,
54, 1866.
(9) Reitz, A. B.; J ordan, A. D., J r.; Maryanoff, B. D. J . Org. Chem.
1987, 52, 4800.
10.1021/jo982327c CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/25/1999

Constrained 7-Azabicyclo[2.2.1]heptane Amino Acids
J . Org. Chem., Vol. 64, No. 6, 1999 2051
Sch em e 1. Ster eoselective Syn th esis of 2S,3S,5S-Tr isu bstitu ted P yr r olid in e 3 a n d 2S,3S,5R-Tr isu bstitu ted
P yr r olid in e 4
Ta ble 1. Rea ction of Hem ia m in a l 2 w ith Tr im eth yl
P h osp h on oa ceta te
reaction
combined
yield (%)
ratio of reaction
products (3/4/5)
conditionsa
T °C
time (h)
A
B
C
D
E
23
0
-15
-30
-30
2
23
96
4
86
82
88
83
81
67/33/0
80/20/0
85/15/0
0/0/100
7/2/91
40
a
Conditions for reactions A-E; trimethyl phosphonoacetate
(150 mol%), NaH (150 mol %), THF.
F igu r e 2. Structure of (2S,4S,5S)-4-hydroxy-5-hydroxymeth-
yl-2-(methoxycarbonyl)methyl-1-(phenylsulfonyl)pyrrolidine iso-
propylidine ketal (3) as determined by X-ray crystallography.
ture, the reaction sequence proceeds in high yields. Thus,
at room temperature the products are obtained in 86%
combined yield and the ratio of pyrrolidines 3/4 is 2/1
after 2 h. On the other hand, at -15 °C the ratio of 3/4
is 5.6/1 in 88% combined yield, but 96 h is required. After
recrystallization, pyrrolidine 3 was isolated in 64% yield
with the stereochemistry shown in Figure 2 as estab-
lished by X-ray crystallography. When the reaction of 2
is carried out at -30 °C for 4 h, only olefin 5 is isolated
in 83% yield.
The second strategy for pyrrolidine formation involves
the intramolecular iodosulfonamidation cyclization of
olefin 5 to establish stereochemistry at C-5. The olefin 5
was treated with Na2CO3 and I2 under biphasic reaction
conditions10a,b to afford a mixture of 6a and 6b in 71%
yield. The mixture of 6a and 6b was reduced with H2
and Pd/C to afford the deiodinated products 4/3 in 80%
yield with a significant amount (20%) of the byproduct,
methyl (5S,6S)-5,7-dihydroxy-6-phenylsulfonylaminohep-
tanoate isopropylidine ketal. Byproduct formation was
avoided by the use of Ni2B as a reductant,11 yielding only
pyrrolidines 3 and 4 (4/96, 86% yield). The mixtures 6a /
6b or 3/4 were not separable by silica gel column
chromatography. The iodoamidation sequence from 2
allows for the synthesis of a 2S,3S,5R-trisubstituted
pyrrolidine 4 with high level of diastereomeric excess that
complements the synthesis of the (2S,3S,5S)-pyrrolidine
3.
Th e Syn th esis of 7-Aza bicyclo[2.2.1]-2-h ep ten e-1-
ca r boxyla te 20. The conversion of crystalline 3 to the
(10) (a) Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M.
C. J . Am. Chem. Soc. 1983, 105, 5819. (b) Labelle, M.; Guindon, Y. J .
Am. Chem. Soc. 1989, 111, 2204.
(11) Yoon, N. M.; Lee, H. J .; Ahn, J . H.; Choi, J . J . Am. Chem. Soc.
1994, 59, 4687.

2052 J . Org. Chem., Vol. 64, No. 6, 1999
Sch em e 2. Syn th esis of 7-Aza bicyclo[2.2.1]-2-h ep ten e-1-ca r boxyla te 20
Hart and Rapoport
Sch em e 3. Syn th esis of a 2-Su bstitu ted 7-Aza bicyclo[2.2.1]h ep ta n e Glu ta m ic Acid An a logu e 27
rigid R-amino acid analogue 20 is described in Scheme
2. Thus, pyrrolidine 3 was converted to the bis-silyl ether
7 by treatment with HCl/MeOH followed by bis-silylation
in 96% yield for each step. Selective desilylation of 7 was
accomplished in 87% yield to give the primary alcohol
9.12 Other selective desilylation protocols were examined,
including sonication in MeOH/CCl4,13 TBAF in THF,14
and p-TsOH in THF/H2O,15 but all led to incomplete
reaction or poor selectivity. Oxidation of primary alcohol
9 with catalytic RuCl3 and NaIO4 in a biphasic system16
followed by esterification with N,N′-diisopropyl-O-tert-
butylisourea17 afforded the diester 10 in 79% yield.
Selective reduction of the methyl ester of 10 provided
trisubstituted pyrrolidine alcohol 11 in 86% yield, which
was converted to bromide 12 in 95% yield. Attempts to
cyclize 12 with KHMDS led to none of the transannular
alkylation product 14 under numerous variations of
stoichiometry, concentration, and temperature. The loss
of the benzenesulfonyl protecting group and the silyl
ether were observed in all cases leading to pyrrole
formation and other products; pyrrole 16 was isolated
(12) Kawai, A.; Hara, T.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1988, 29, 6331.
(13) Lee, A. S.-Y.; Yeh, H.-C.; Tsai, M.-H. Tetrahedron Lett. 1995,
36, 6891.
(14) Nakata, T.; Fukui, M.; Oishi, T. Tetrahedron Lett. 1988, 29,
2223.
(16) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(15) Thomas, E. J .; Williams, A. C. J . Chem. Soc., Chem. Commun.
1987, 992.
(17) Gibson, F. S.; Park, M. S.; Rapoport, H. J . Org. Chem. 1994,
59, 7503.

Constrained 7-Azabicyclo[2.2.1]heptane Amino Acids
J . Org. Chem., Vol. 64, No. 6, 1999 2053
from the complex reaction mixture. On the assumption
that alkoxide formation would prevent â-elimination of
the protected alcohol, silyl ether 12 was treated with
TBAF, affording the free alcohol 13 in 64% yield. Treat-
ment of 13 with KHMDS, however, again afforded a
complex mixture of products and none of the desired
[2.2.1]bicyclic amino acid analogue 15. Also, to prevent
the facile elimination of the nitrogen protecting group as
benzenesulfinate, the benzenesulfonyl group was re-
moved from 11 by electrolysis18 in 78% yield. Reprotection
of the secondary amine 17 with CbzCl (85% yield)
followed by bromide formation from alcohol 18 in 96%
yield afforded 19, the target substrate for transannular
cyclization. Treatment of 19 with KHMDS did not cause
elimination of the amine protecting group, but elimina-
tion of the silyl ether was observed and the 7-azabicyclo-
[2.2.1]heptene-1-carboxylate 20 was obtained in 77%
yield. Presumably, the cyclization reaction proceeds by
elimination of the silyl ether to form the R,â-unsaturated
ester, deconjugation of the double bond, and alkylation
of the resulting R-anion.
ates for the synthesis of amino acid analogues and may
be extrapolated to other biologically active molecules.
Exp er im en ta l Section
Gen er a l P r oced u r es. All melting points are uncorrected.
All reactions were conducted under an atmosphere of dry
nitrogen unless otherwise noted. Final solutions before evapo-
ration were dried over Na2SO4. THF and Et2O were distilled
from Na/benzophenone, CH2Cl2 was distilled from CaH2, and
CH3CN was distilled first from P2O5 and then CaH. Chroma-
1
tography was carried out using 230-400 mesh silica gel. H
NMR were taken in CDCl3 and referenced to internal TMS
unless otherwise noted; coupling constants are reported in
hertz. HPLC analyses were conducted with a normal-phase
HPLC (Microsorb Si column, 0.46 × 25 cm) using a spectro-
photometer set at 254 nm. The mobile phase consisted of a
mixture of EtOAc/hexane specific to each compound analyzed,
and retention times are reported as tR in min. Elemental
analyses were performed by the Microanalytical Laboratories,
University of California, Berkeley.
(2S,4S,5S)-4-H yd r oxy-5-h yd r oxym et h yl-2-(m et h oxy-
ca r bon yl)m eth yl-1-(p h en ylsu lfon yl)p yr r olid in e Isop r o-
p ylid in e Keta l (3). To a suspension of THF (500 mL) and
NaH (95%, 0.98 g, 40.7 mmol) cooled to -15 °C was added
trimethyl phosphonoacetate (6.41 mL, 40.7 mmol). The result-
ing slurry was mechanically stirred, and a precooled solution
of aldehyde 2 (8.50 g, 27.2 mmol), in THF (200 mL), was added,
maintaining the temperature at -15 °C. After the mixture was
stirred for 96 h between -10 °C and -15 °C, a saturated
solution of NaH2PO4 (250 mL) was added, and the resulting
mixture was evaporated at room temperature to 300 mL. To
the suspension was added CHCl3/IPA (4/1, 200 mL). The
aqueous and organic layers were separated, and the aqueous
layer was extracted with CHCl3/IPA (4/1, 3 × 200 mL). The
combined organic layer was dried, filtered, and passed through
a plug of silica (hexane/EtOAc, 2/1). The resulting solution,
analyzed by HPLC, was determined to be a 5.6/1.0 mixture of
3/4, 8.83 g, 88% yield (4, tR 10.5 min; 3, tR 11.2 min, 7/1 hexane/
EtOAc). Crystallization from hexane/EtOAc afforded 3 (6.85
Th e Syn th esis of Glu ta m ic Acid An a logu e 27 fr om
Olefin 20. Dihydroxylation19 of olefin 20 proceeded to
exodiol 21 in 88% yield and selective protection of the
less hindered C-3 alcohol with TBDPSCl in 96% yield
followed to afford monoalcohol 22. Oxidation of 22 to the
ketone 23 proceeded in 78% yield under Dess-Martin
conditions.20 Direct reductive removal of the silyl ether
function R to the carbonyl of ketone 23 was effected with
21
SmI2 in 72% yield to give the 2-substituted ketone 24.
Strict stoichiometric control of the SmI2 is critical for the
reduction of 23 to avoid reducing the resulting ketone
24. The 2-oxo 7-azabicyclo[2.2.1]heptane was clearly
differentiated from the possible 3-regioisomer by direct
comparison of the spectroscopic data with that of the
corresponding 3-oxo-7-azabicyclo[2.2.1]heptane,5 confirm-
ing the regiospecific reaction of diol 21. Treatment of 24
with a large excess of trimethyl phosphonoacetate and
NaH led to a separable mixture of cis and trans olefins
25 and 26 in a ratio of 92/8 and a combined yield of 62%.
The major isomer 25 was submitted to hydrogenation
(Pd/C) and carbamoylation to afford fully protected
glutamate analogue 27 in 88% yield. Selectivity in the
reduction was predicted on the basis of the relative
accessibility to the exo face of the double bond versus the
sterically congested endo face, thus resulting in a single
reduction product.
g, 69%) as a pure diastereomer: mp 97-98 °C; [R]23 +5.8° (c
D
1
1.0, CHCl3); H NMR δ 1.32 (s, 3H), 1.37 (s, 3H), 1.50-1.59
(m, 1H), 1.81 (d, J ) 14.2, 1H), 2.95 (m, 2H), 3.52 (m, 1H),
3.66 (s, 3H), 3.97-4.24 (m, 4H), 7.51-7.57 (m, 3H), 7.80-7.83
(m, 2H); 13C NMR δ 172.0, 137.0, 133.1, 129.3, 127.4, 99.0,
70.9, 62.8, 59.7, 58.1, 51.6, 41.6, 36.1, 26.1, 21.3. Anal. Calcd
for C17H23NO6S: C, 55.3; H, 6.3; N, 3.8. Found: C, 55.2; H,
6.4; N, 3.8.
(2R,4S,5S)-4-H yd r oxy-5-h yd r oxym et h yl-2-(m et h oxy-
ca r bon yl)m eth yl-1-(p h en ylsu lfon yl)p yr r olid in e Isop r o-
p ylid in e Keta l (4). To a solution of Ni(OAc)2‚H2O (10 mg,
0.04 mmol) in MeOH (5 mL), cooled to 0 °C, was added 6a /6b
(96/4, 0.20 g, 0.41 mmol) followed by the addition of NaBH4
(0.16 g, 4.1 mmol) in five portions over 5 min. The reaction
mixture turned dark brown upon addition of the NaBH4, and
H2O (20 mL) was added immediately after the final portion of
NaBH4. The resulting mixture was extracted with CHCl3/IPA
(4/1, 3 × 20 mL), and the combined organic phase was dried,
filtered, and evaporated. The residue was chromatographed
(hexane/EtOAc,7/1) to afford 4/3 (0.13 g, 86%) as a colorless
oil: 4/3 by HPLC, 96/4; [R]23D +57.5 (c 1.0, CHCl3); 1H NMR δ
1.07 (s, 3H), 1.32 (s, 3H), 1.94 (m, 1H), 2.17 (m, 1H), 2.50 (m,
1H), 3.17 (dd, J ) 4.3, 16.1, 1H), 3.64 (s, 3H), 3.89 (dd, J )
4.9, 5.1, 1H), 4.01 (dd, J ) 4.9, 12.5, 1H), 4.10 (dd, J ) 5.9,
12.5, 1H), 4.35-4.40 (m, 2H), 7.48-7.57 (m, 3H), 7.82 (d, J )
7.3, 2H); 13C NMR δ 171.2, 140.3, 132.3, 128.8, 126.9, 98.6,
69.1, 59.5, 59.3, 56.6, 51.6, 39.2, 38.2, 26.4, 21.2. Anal. Calcd
for C17H23NO6S: C, 55.3; H, 6.3; N, 3.8. Found: C, 55.4; H,
6.2; N, 3.7.
Con clu sion
A method for the synthesis of a 2-substituted 7-azabi-
cyclo[2.2.1]heptane glutamic acid analogue 27 from L-
serine has been developed. This method could provide an
entry into a variety of 2-substituted 7-azabicyclo[2.2.1]-
heptane R-amino acid analogues through further func-
tionalization of the ketone 23.5 It proceeds via the
stereospecific synthesis of (2S,3S,5S)-pyrrolidine 3 or
(2S,3S,5R)-pyrrolidine 4, both of which can be effected
from aminal 2, depending on the mode of cyclization.
These trisubstituted pyrrolidines are versatile intermedi-
Meth yl (2E,5S,6S)-5,7-Dih yd r oxy-6-p h en ylsu lfon yla m i-
n o-2-h ep ten oa te Isop r op ylid in e Keta l (5). To a stirred
suspension of sodium hydride (95%, 50 mg, 2.10 mmol) in THF
(10 mL) at room temperature was added trimethyl phospho-
noacetate (0.35 mL, 2.10 mmol) in 5 mL of THF, and the
(18) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1988, 53, 2367.
(19) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron 1984, 40, 2247.
(20) (a) Dess, D. B.; Martin, J . C.; J . Am. Chem. Soc. 1991, 113,
7277. (b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(21) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135.

2054 J . Org. Chem., Vol. 64, No. 6, 1999
Hart and Rapoport
mixture was stirred for 30 min. Hemiaminal 2 (0.57 g, 1.80
mmol) was added, and the mixture was stirred for 4 h at -30
°C, saturated NaH2PO4 (10 mL) was added, and it was
evaporated to 10 mL and extracted with CHCl3/IPA (4 × 15
mL). The combined organic layer was dried, filtered, and
evaporated, and the resulting oil was chromatographed (hex-
ane/EtOAc, 2/1) to afford 5 (0.55 g, 83%) as a colorless oil:
[R]23D -47.6 (c 0.25, CHCl3); Rf 0.65 (1/1, Hex/EtOAc); 1H NMR
δ 1.33 (s, 3H), 1.35 (s, 3H), 1.88-2.26 (m, 1H), 2.36 (m, 1H),
3.12 (dd, J ) 10.2, 1.7, 1H), 3.27 (dd, J ) 12.2, 1.8, 1H), 3.68
(s, 3H), 3.82 (dd, J ) 12.2, 1.6, 1H), 5.49 (d, J ) 10.2, 1H, D2O
exchangeable), 5.76 (d, J ) 15.7, 1H), 6.74-6.81 (m, 1H), 7.24-
7.55 (m, 3H), 7.84-7.86 (m, 2H); 13C NMR δ 166.7, 144.1,
141.1, 132.8, 129.3, 126.8, 123.3, 99.5, 70.4, 64.0, 51.5, 50.0,
34.8, 29.4, 18.4. Anal. Calcd for C17H23NO6S: C, 55.3; H, 6.3;
N, 3.8. Found: C, 55.5; H, 6.5; N, 3.7.
Meth yl (2R,4S,5S)-4-Hydr oxy-5-h ydr oxym eth yl-1-ph en -
ylsu lfon ylp yr r olid in e-2-iod oa ceta te Isop r op ylid in e Ket-
a l (6a /6b). To a solution of unsaturated ester 5 (0.30 g, 0.81
mmol) in Et2O (20 mL) were added I2 (1.03 g, 4.1 mmol) and
NaHCO3 (1.0 M aqueous, 2.44 mmol) at room temperature.
After 48 h, sodium thiosulfate (2 M, 50 mL) was added, the
aqueous layer was extracted with CHCl3/IPA (4/1, 3 × 50 mL),
and the combined organic layer was dried, filtered, and
evaporated. The resulting oil was purified by chromatography
(hexane/EtOAc, 3/1) to afford a mixture of 6a and 6b (0.29 g,
71%) as a light yellow oil and recovered 5 (50 mg): 1H NMR
δ 0.78 (s, 3H), 1.22 (s, 3H),2.08 (m, 1H), 2.27 (m, 1H), 3.75 (s,
3H), 3.80-3.98 (m, 3H), 3.99 (dd, J ) 3.8, J ) 13.4, 1H), 4.36
(s, 1H), 4.46 (dd, J ) 3.4, J ) 13.4, 1H), 5.85 (d, J ) 3.3, 1H),
7.42-7.57 (m, 3H), 7.82 (d, J ) 7.2, 2H); 13C NMR δ 169.8,
141.1, 132.4, 128.7, 127.3, 98.0, 69.5, 61.6, 59.4, 58.1, 52.9, 38.3,
32.9, 27.4, 19.7. Anal. Calcd for C17H23NO6S‚0.5H2O: C, 40.5;
H, 4.6; N, 2.7. Found: C, 40.5; H, 4.8; N, 2.3.
trace of diol 7. A single resubjection of the recovered 8 to the
above conditions afforded additional 9 (1.4 g): total yield of 9,
87%; [R]20 -13.9 (c 3.6, CHCl3); 1H NMR δ -0.11 (s, 3H),
D
-0.083 (s, 3H), 0.77 (s, 9H), 1.66 (m, 1H), 1.83 (m, 1H), 2.76
(dd, J ) 10.1, 16.4, 1H), 2.88 (dd, J ) 5.2, 8.1, 1H), 3.08 (dd,
J ) 4.2, 16.4 1H), 3.52 (dd, J ) 5.6, 11.5, 1H), 3.62 (s, 3H),
3.84 (m, 2H), 4.00 (m, 1H), 7.54 (m, 3H), 7.81 (d, J ) 7.1, 2H);
13C NMR δ 171.6, 136.5, 133.2, 129.3, 127.5, 72.2, 64.9, 63.1,
56.2, 51.5, 41.9, 38.3, 25.5, 17.8. Anal. Calcd for C20H33NO6-
SSi: C, 54.2; H, 7.5; N, 3.2. Found: C, 54.5; H, 7.7; N, 3.2.
(2R,3S,5S)-3-ter t-Bu tyld im eth ylsilyloxy-5-m eth oxyca r -
bon ylm eth yl-1-p h en ylsu lfon ylp r olin e ter t-Bu tyl Ester
(10). To a solution of alcohol 9 (1.18 g, 2.67 mmol) in CH3CN
(12 mL) and CCl4 (12 mL) was added a mixture of H2O (9 mL),
NaIO4 (1.71 g, 8.0 mmol), and RuCl3‚3H2O (50 mg). The
biphasic mixture was vigorously stirred (magnetic) for 3 h, the
phases were separated, and the aqueous phase was extracted
with CHCl3/IPA (4/1, 4 × 50 mL). The combined organic phase
was dried, filtered, and evaporated, and the resulting oil was
passed through a plug of silica gel (EtOAc/hexane, 2/1) to afford
crude carboxylic acid (1.04 g) as a yellow foam. To the crude
carboxylic acid dissolved in CH2Cl2 (10 mL) and t-BuOH (40
mL) was added N,N′-diisopropyl-O-tert-butylisourea (0.48 g,
2.40 mmol) and the mixture stirred at room temperature for
105 min. The mixture was evaporated at room temperature,
and to the residue was added H2O (100 mL) followed by CHCl3/
IPA (4/1, 50 mL). The aqueous phase was extracted with
additional CHCl3/IPA (4/1, 3 × 50 mL), the combined organic
phase was dried, filtered, and evaporated, the resulting solid
was digested in hexane/EtOAc (5/1, 10 mL) and filtered, and
the filtrate was evaporated and chromatographed (hexane/
EtOAc, 5/1) to afford the tert-butyl ester 10 (1.02 g, 79% from
9) as a colorless oil: [R]23 -5.28 (c 2.5, CHCl3); 1H NMR δ
D
-0.076 (s, 3H), -0.053 (s, 3H), 0.76 (s, 9H), 1.38 (s, 9H), 2.17
(m, 1H), 2.91 (dd, J ) 10.1, 16.6, 1H), 3.45 (dd, J ) 4.1, 16.6,
1H), 3.63 (s, 3H), 3.89 (dd, J ) 8.4, 7.1, 1H), 4.04 (m, 1H),
4.10 (d, J ) 7.6, 1H), 7.56 (m, 3H), 7.81 (d, J ) 7.4, 2H); 13C
NMR δ 171.9, 168.1, 138.2, 133.0, 129.2, 127.2, 81.9, 71.5, 65.4,
Meth yl (2S,4S,5S)-4-Hydr oxy-5-h ydr oxym eth yl-1-ph en -
ylsu lfon ylp yr r olid in e-2-a ceta te (7). To a stirred solution
of acetonide 3 (1.40 g, 3.79 mmol) in MeOH (30 mL) was added
concentrated HCl (0.3 mL) at room temperature. After 24 h,
the reaction was evaporated to dryness, and the resulting oil
was chromatographed (hexane/EtOAc, 1/1) to afford 7 (1.20 g,
96%) as a colorless oil. Addition of Et2O followed by evapora-
55.2, 51.5, 41.0, 38.7, 28.0, 25.6, 18.0. Anal. Calcd for C24H39
-
NO7SSi: C, 56.1; H, 7.7; N, 2.7. Found: C, 56.3; H, 7.7; N,
2.8.
tion afforded 7 as a white solid: mp 76-78 °C; [R]21 -12.6 (c
D
1
1.0, CHCl3); H NMR δ 1.80 (m, 2H), 2.86 (dd, J ) 8.8, 16.2,
(2R,3S,5S)-3-ter t-Bu t yld im et h ylsilyloxy-5-â-h yd r oxy-
eth yl-1-p h en ylsu lfon ylp r olin e ter t-Bu tyl Ester (11). To
a solution of diester 10 (0.96 g, 1.87 mmol) in Et2O was added
LiBH4 (2M in THF, 1.3 mL). After 8 h, K2CO3 (1M, 30 mL)
was added, and the mixture was concentrated at room tem-
perature and extracted with CHCl3/IPA (4/1, 4 × 50 mL). The
combined organic layer was dried, filtered, and evaporated,
and the resulting oil was chromatographed (hexane/EtOAc,
1H), 3.01 (dd, J ) 4.7, 16.1, 1H), 3.55 (m, 2H), 3.66 (s, 3H),
4.05 (m, 4H), 7.55 (m, 3H), 7.75 (d, J ) 7.8, 2H); 13C NMR δ
172.0, 136.1, 133.3, 129.3, 127.5, 72.1, 64.2, 62.8, 56.5, 51.8,
41.2, 38.3. Anal. Calcd for C14H19NO6S: C, 51.1; H, 5.8; N, 4.3.
Found: C, 51.2; H, 5.8; N, 4.3.
Meth yl (2S,4S,5S)-4-ter t-Bu tyld im eth ylsilyloxy-5-ter t-
bu tyld im eth ylsilyloxy-m eth yl-1-p h en ylsu lfon ylp yr r oli-
d in e-2-a ceta te (8). To a solution of diol 7 (8.0 g, 24.3 mmol)
in DMF (10 mL) were added imidazole (10.05 g, 146 mmol)
and TBDMSCl (11.0 g, 73.0 mmol) at room temperature. The
mixture was stirred for 12 h, extracted with hexane (6 × 50
mL), and evaporated. The resulting oil was chromatographed
2/1) to afford 11 (0.78 g, 86%) as a colorless oil: [R]22 +44.2
D
(c 1.15, CHCl3); 1H NMR δ -0.064 (s, 3H), -0.049 (s, 3H), 0.77
(s, 9H), 1.40 (s, 9H), 1.70-1.99 (m, 3H), 2.24 (m, 1H), 2.87 (dd,
J ) 5.7, 6.5, 1H), 3.70 (m, 1H), 3.92-4.14 (m, 4H), 7.54 (m,
3H), 7.86 (d, J ) 7.7); 13C NMR δ 168.4, 137.8, 133.1, 129.3,
127.4, 82.1, 72.5, 66.7, 59.3, 57.3, 39.2, 38.3, 28.1, 25.8, 18.1.
Anal. Calcd for C23H39NO6SSi: C, 56.9; H, 8.1; N, 2.9. Found:
C, 56.7; H, 8.0; N, 2.9.
(hexane/EtOAc, 5/1), affording 8 as a colorless oil (12.96 g,
1
96%): [R]21 +20.5 (c 1.8, CHCl3); H NMR δ -0.089 (s, 3H),
D
-0.058 (s, 3H), 0.067 (s, 6H), 0.80 (s, 9H), 0.88 (s, 9H), 1.76
(m, 2H), 2.87 (dd, J ) 10.2, 16.4, 1H), 3.20 (dd, 4.19, 16.4, 1H),
3.33 (m, 1H), 3.63 (s, 3H), 3.82 (m, 2H), 4.01 (m, 2H), 7.54 (m,
3H), 7.82 (d, J ) 7.3, 2H); 13C NMR δ 172.1, 137.0, 132.9, 129.1,
127.5, 71.1, 65.3, 61.9, 56.3, 51.4, 41.5, 38.3, 26.0, 25.7, 18.4,
18.0. Anal. Calcd for C26H47NO6SSi2: C, 56.0; H, 8.5; N, 2.5.
Found: C, 56.1; H, 8.4; N, 2.6.
(2R,3S,5S)-3-ter t-Bu tyld im eth ylsilyloxy-5-â-br om oeth -
yl-1-p h en ylsu lfon ylp r olin e ter t-Bu tyl Ester (12). To a
solution of alcohol 11 (0.78 g, 1.72 mmol) in CH2Cl2 (20 mL)
were added CBr4 (0.80 g, 2.40 mmol) and Ph3P (0.54 g, 2.06
mmol) at room temperature. The reaction mixture was stirred
for 2 h, H2O (20 mL) was added, and the aqueous phase was
extracted with CHCl3/IPA (4/1, 4 × 50 mL). The combined
organic phase was dried, filtered, and evaporated, and the
resulting oil was chromatographed (hexane/EtOAc, 5/1) to
Meth yl (2S,4S,5S)-4-ter t-Bu tyld im eth ylsilyloxy-5-h y-
d r oxym eth yl-1-p h en ylsu lfon ylp yr r olid in e-2-a ceta te (9).
A solution of bis-silyl ether 8 (11.42 g, 20.5 mmol) in AcOH/
H2O/THF (13/7/3, 500 mL) was stirred for 22 h at room
temperature, the volatiles were evaporated at room temper-
ature, and to the residue was added EtOAc (200 mL) followed
by saturated NaHCO3. The resulting aqueous layer was
extracted with EtOAc (4 × 200 mL), the combined organic
layer was washed with saturated NaCl, dried, and evaporated,
and the resulting oil was chromatographed (hexane/EtOAc,
3/1) to afford 9 (6.54 g, 72%), recovered 8 (2.44 g, 21%), and a
afford 12 (0.85 g, 95%) as a colorless oil that crystallized from
1
CHCl3: mp 98-99 °C; [R]21 +3.4 (c 2.4, CHCl3); H NMR δ
D
-0.051 (s, 3H), -0.034 (s, 3H), 0.78 (s, 9H), 1.40 (s, 9H), 1.75
(m, 1H), 1.88 (m, 1H), 2.20 (m, 1H), 2.68 (m, 1H), 3.40 (dd, J
) 9.8, 7.4, 1H), 3.54 (m, 1H), 3.90 (m, 1H), 3.99 (dd, J ) 13.8,
7.0, 1H), 4.17 (d, J ) 7.4, 1H), 7.55 (m, 3H), 7.81 (d, J ) 7.5,
2H); 13C NMR δ 168.2, 138.2, 132.9, 129.2, 127.3, 81.9, 71.9,

Constrained 7-Azabicyclo[2.2.1]heptane Amino Acids
66.1, 58.0, 38.8, 38.3, 30.5, 28.0, 25.7, 18.1. Anal. Calcd for
J . Org. Chem., Vol. 64, No. 6, 1999 2055
60 °C) δ 0.037 (s, 3H), 0.087 (s, 3H), 0.94 (s, 9H), 1.39 (s, 9H),
2.10-1.71 (m, 3H),2.45 (m, 1H), 3.38 (m, 1H), 3.76 (m, 1H),
3.92 (m, 1H),, 4.22 (m, 2H), 4.41 (m, 1H), 5.00-5.22 (m, 2H),
7.10-7.37 (m, 5H); 13C NMR (C6D6 at 333K) δ 168.3, 155.0,
136.8, 128.2, 127.1, 127.8, 127.6, 127.3, 80.7, 72.5, 66.9, 65.9,
59.3, 54.8, 39.5, 38.1, 27.9, 25.6,17.9, -5.0, -5.4. Anal. Calcd
for C25H42NO6Si: C, 62.5; H, 8.8; N, 2.9. Found: C, 62.5; H,
8.7; N, 2.9.
C
23H38NO5SSiBr: C, 50.4; H, 7.0; N, 2.6. Found: C, 50.5; H,
7.2; N, 2.5.
(2R,3S,5S)-5-â-Br om oeth yl-3-h yd r oxy-1-p h en ylsu lfon -
ylp r olin e ter t-Bu tyl Ester (13). A solution of 12 (100 mg,
0.20 mmol) in THF (5 mL) was cooled to 0 °C, and TBAF (1 M
in THF, 0.21 mL, 0.21 mmol) was added dropwise. The solution
was stirred for 30 min at 0 °C, phosphate buffer, pH 7 (1 M,
25 mL), was added, and the mixture was concentrated under
reduced pressure and extracted with CHCl3/IPA (4/1, 3 × 25
mL). The combined organic phase was dried, filtered, and
evaporated, and the resulting oil was chromatographed (hex-
ane/EtOAc, 2/1) to afford 13 (50 mg, 64%) as a colorless oil:
(2R,3S,5S)-3-ter t-Bu t yld im et h ylsilyloxy-1-b en zyloxy-
ca r bon yl-5-â-br om oeth ylp r olin e ter t-Bu tyl Ester (19). To
a solution of alcohol 18 (0.52 g, 1.00 mmol) in CH2Cl2 (20 mL)
at 0 °C were added triphenylphosphine (0.82 g, 2 mmol) and
CBr4 (0.46 g, 1.4 mmol). The cooling bath was removed, the
reaction mixture was stirred for 2 h at room temperature, and
H2O (50 mL) was added. The aqueous phase was extracted
with CHCl3/IPA (4/1, 3 × 20 mL), the combined organic phase
was dried, filtered, and evaporated, and the resulting oil was
chromatographed (hexane/EtOAc/CHCl3, 4/1/1) to afford 19
[R]22 +20.3 (c 0.3, CHCl3); 1H NMR δ 1.43 (s, 9H), 1.69-1.76
D
(m, 2H), 2.10 (m, 1H), 2.56 (m, 1H), 2.79 (bs, 1H), 3.42 (m,
1H), 3.53 (m, 1H), 3.91 (m, 1H), 4.26 (m, 2H), 7.48-7.61 (m,
3H), 7.81 (d, 2H); 13C NMR δ 169.1, 137.2, 128.5, 128.0, 127.8,
82.8, 72.2, 68.1, 66.3, 57.7, 57.0, 38.5, 31.8, 28.0; HRMS calcd
for C17 H24 NO5 SBr 433.0559, found 433.0524.
(0.49 g, 96%) as a colorless oil: [R]22 -10.1 (c 1.3, CHCl3); 1H
D
ter t-Bu tyl 5-â-Br om oeth ylp yr r ole-2-ca r boxyla te (16).
To a solution of bromide 12 (0.10 g, 0.19 mmol) in THF (3 mL)
at -78 °C was added KHMDS (0.92 M, 0.2 mL) dropwise. After
45 min, KH2PO4 (1M, 20 mL) was added, and the mixture was
concentrated at room temperature and extracted with CHCl3/
IPA (4/1, 4 × 50 mL). The combined organic phase was dried,
filtered, and evaporated, and the resulting oil was purified by
preparative thin-layer chromatography (hexane/EtOAc, 5/1) to
NMR 0.028 (s, 3H), 0.034 (s, 3H), 0.92 (s, 9H), 1.38 (s, 6.4H,
major rotomer), 1.43 (s, 2.6H, minor rotomer), 1.81 (m, 1H),
2.20 (m, 2H), 2.63 (m, 0.3H), 2.82 (m, 0.7H), 3.32-3.58 (m,
2H), 4.06 (m, 1H), 4.35-4.57 (m, 2H), 5.02-5.09 (m, 2H), 7.25-
1
7.42 (m, 5H); H NMR (C6D6, 60 °C) δ 0.028 (s, 3H), 0.078 (s,
3H), 0.94 (s, 9H), 1.42 (s, 9H), 1.72 (m, 1H), 1.85 (m, 1H), 2.25
(m, 1H), 2.63-2.95 (m, 1H), 3.21-3.50 (m, 2H), 3.94 (m, 1H),
4.16 (m, 1H), 4.38 (m, 1H) 5.07-5.10 (m, 2H). 7.09-7.69 (m,
5H); 13C NMR (C6D6, 60 °C) δ 169.2, 154.8, 137.7, 129.0, 128.6,
128.4, 128.1, 81.5, 72.5, 67.6, 65.9, 56.8, 39.6, 39.0, 30.9, 28.7,
26.5, 18.7, -4.3, -4.6. Anal. Calcd for C25H40NO5BrSi: C, 55.2;
H, 7.6; N, 2.6. Found: C, 55.4; H, 7.6; N, 2.6.
ter t-Bu tyl 7-Ben zyloxyca r bon yl-7-a za bicyclo[2.2.1]-2-
h ep ten e-1-ca r boxyla te (20). To a solution of bromide 19
(0.10 g, 0.20 mmol) in THF (5 mL) at -78 °C was added
KHMDS (0.92 M in toluene, 0.40 mmol). The mixture stirred
at -78 °C for 1 h, -40 °C for 2 h, and 0 °C for 1 h, and then
KH2PO4 (1 M, 15 mL) was added. After evaporation to remove
the THF, the aqueous residue was extracted with CHCl3/IPA
(4/1, 3 × 20 mL). The combined organic layer was dried,
filtered, and evaporated, and the resulting oil was chromato-
1
afford 16 (8 mg, 22%) as a white solid: mp 118-119 °C; H
NMR δ 1.54 (s, 9H), 3.19 (t, J ) 7.17, 2H), 3.56 (t, J ) 7.15,
2H), 6.01 (t, J ) 3.06, 1H), 6.75 (t, J ) 2.61, 1H); 13C NMR δ
160.6, 133.8, 123.7, 115.1, 108.7, 80.7, 31.4, 30.9, 28.3; HRMS
calcd for C11H16NO2Br 273.0364, found 273.0401.
(2R,3S,5S)-3-ter t-Bu t yld im et h ylsilyloxy-5-â-h yd r oxy-
eth ylp r olin e ter t-Bu tyl Ester (17). A solution of Et4NBr
dissolved in CH3CN (0.1 M) was used to fill the electrolysis
cell, and argon was bubbled through the solution for 15 min.
The current was set at 1.73 eV, and pre-electrolysis of the Hg
resulted in a stable background reading of 1.7 mA after 2 h.
4-Phenylphenol (6.6 mmol) was added to the cathode solution,
and argon was bubbled through the solution for 15 min. Pre-
electrolysis of the solution resulted in a background reading
of 1.9 mA in 15 h. The protected amine 11 (1.00 g, 2.2 mmol)
dissolved in CH3CN was added, and the initial current reading
was 13 mA. After 6 h the current was 1.4 mA. The reaction
mixture was decanted into a round-bottom flask, 100 mL of
H2O was added, the mixture was evaporated at room temper-
ature to remove the acetonitrile, and the resulting mixture
was extracted with CHCl3/IPA (4/1, 4 × 50 mL). The combined
organic phase was dried, filtered, and evaporated, and the
resulting oil was chromatographed (hexane/EtOAc, 1/2) to
graphed (hexane/EtOAc, 7/1) to afford 20 (51 mg, 77%) as a
1
colorless oil: [R]22 +9.0 (c 1.0, CHCl3); H NMR δ 1.17 (ddd,
D
J ) 11.3, 8.8, 3.5, 1H), 1.44 (m, 1H), 1.49 (s, 9H), 2.05 (m,
1H), 2.23 (m, 1H), 4.83 (dd, J ) 4.1, 2.2, 1H), 5.07 (S, 3H),
6.28 (dd, J ) 5.8, 2.1, 1H), 6.46 (d, J ) 5.8, 1H), 7.33 (m, 5H);
13C NMR δ 168.4, 156.5, 136.1, 135.2, 134.6, 128.3, 127.9,
127.8, 81.6, 73.3, 67.1, 62.7, 29.2, 27.8, 24.8. Anal. Calcd for
C
19H23NO4: C, 69.3; H, 7.0; N, 4.3. Found: C, 68.9; H, 7.0; N,
4.5.
ter t-Bu tyl (1S,2S,3R,4R)-7-Ben zyloxyca r bon yl-2,3-d i-
afford 17 (0.49 g, 78%) as a colorless oil: [R]22 +21.2 (c 0.7,
h yd r oxy-7-a za bicyclo[2.2.1]h ep ta n e-1-ca r boxyla te (21).
To a solution of olefin 20 (0.22 g, 0.67 mmol) in acetone (18
mL) and H2O (2 mL) were added NMMO (0.13 g, 1.10 mmol)
and OsO4 (2% solution in H2O, 0.45 mL). The solution was
stirred for 12 h at room temperature, saturated aqueous
NaHSO3 (50 mL) was added, the mixture was extracted with
CHCl3/IPA (4/1, 3 × 20 mL), and the combined organic layer
was dried, filtered, and evaporated. The resulting oil was
chromatographed (hexane/EtOAc, 3/1) to afford 21 (0.21 g,
D
CHCl3); 1H NMR δ 0.06 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.47
(s, 9H), 1.47-1.49 (m, 1H), 1.91-1.74 (m, 2H), 2.2 (m, 1H),
2.35 (bs, 1H), 3.21 (m, 1H), 3.55 (d, J ) 5.3, 1H), 3.88-3.69
(m, 2H), 4.48 (dd, J ) 9.5, 5.5); 13C NMR δ 169.5, 81.2, 74.3,
67.6, 60.6, 55.2, 41.9, 38.2, 28.1, 25.8, 18.0, -4.8, -4.6. Anal.
Calcd for C17H35NO4Si: C, 59.0; H, 10.2; N, 4.0. Found: C,
58.6; H, 10.4; N, 4.0.
(2R,3S,5S)-3-ter t-Bu t yld im et h ylsilyloxy-1-b en zyloxy-
ca r bon yl-5-â-h yd r oxyeth ylp r olin e ter t-Bu tyl Ester (18).
To a suspension of 17 (0.49 g, 1.56 mmol) dissolved in EtOAc
(10 mL) were added H2O (10 mL), K2CO3 (0.52 g, 3.12 mmol),
and CbzCl (0.45 mL, 3.12 mmol) at 0 °C. The cooling bath was
removed, and after 1.5 h, KH2PO4 (1 M, 50 mL) was added to
the mixture, the aqueous phase was extracted with EtOAc (3
× 50 mL), and the combined organic layer was dried, filtered,
and evaporated. The resulting oil was chromatographed (hex-
88%) as a colorless oil: [R]24 -13.8 (c 2.1, CHCl3); 1H NMR δ
D
1.13 (m 1H), 1.48 (s, 9H), 1.72 (m, 1H), 2.05 (dt, J ) 4.3, 12.5,
1H), 3.81 (m, 2H), 3.96 (dd, J ) 3.5, 5.1, 1H), 4.24 (d, J ) 5.2,
1H), 4.50 (d, J ) 3.3, 1H), 5.08 (m, 2H), 7.33 (m, 5H); 13C NMR
δ 168.7, 157.3, 136.2, 128.2, 127.8, 83.1, 75.2, 74.0, 70.0, 67.1,
64.8, 29.3, 27.8, 23.9. Anal. Calcd for C19H25NO6: C, 62.8; H,
6.9; N, 3.9. Found: C, 62.4; H, 7.2; N, 3.9.
ter t-Bu tyl (1S,2S,3R,4R,)-7-Ben zyloxyca r bon yl-3-ter t-
bu tyld ip h en ylsilyloxy-2-h yd r oxy-7-a za bicyclo[2.2.1]h ep -
ta n e-1-ca r boxyla te (22). To a solution of diol 21 (0.40 g, 1.10
mmol) in CH2Cl2 (50 mL) were added imidazole (0.23 g, 3.3
mmol) and TBDPSCI (0.61 mL, 2.22 mmol). The mixture was
stirred at room temperature for 48 h, extracted with hexane
(6 × 50 mL), dried, filtered, and evaporated. The resulting oil
was chromatographed (hexane/EtOAc, 10/1), affording 22 as
a colorless oil (0.64 g, 96%): HPLC, tR 6.6 min (hexane/EtOAc,
ane/EtOAc, 1/1) to afford 18 (0.60 g, 85%) as a colorless oil:
1
[R]22 +49.4 (c 0.95, CHCl3); H NMR 0.024 (s, 3H), 0.027 (s,
D
3H), 0.82 (s, 9H), 1.32 (s, 7.8H major rotomer), 1.44 (s, 1.2H,
minor rotomer), 1.73 (m, 2H), 2.05-2.20 (m, 2H), 3.61 (m, 1H),
3.70-3.90 (m, 2H), 4.23 (m, 1H), 4.47 (d, 1H), 4.56 (m, 1H),
5.00-5.22 (m, 2H). 7.18-7.39 (m, 5H); 13C NMR (rotomers) δ
168.4, 155.8, 136.1, 128.5, 128.2, 128.1, 127.9, 81.6, 73.0, 67.4,
66.5, 60.4, 59.2, 54.9, 40.0, 37.8, 28.1, 25.9,18.1; 1H NMR (C6D6,

2056 J . Org. Chem., Vol. 64, No. 6, 1999
Hart and Rapoport
1
9/1, 3 mL/min); H NMR δ 0.98 (m, 1H), 1.11 (s, 9H), 1.46-
etate (0.60 mL, 3.7 mmol) at 0 °C, and the suspension was
warmed to room temperature and stirred for 1 h. To the
mixture was added a solution of ketone 24 (0.14 g, 0.41 mmol)
in THF (5 mL), the mixture was stirred for 72 h at room
temperature, saturated NaHCO3 (20 mL) was added, and the
mixture was concentrated to 60 mL and extracted with CHCl3/
IPA (4/1, 3 × 20 mL). The combined organic layer was dried,
filtered, and evaporated, leaving an oil that was chromato-
graphed (hexane/EtOAc, 15/1) to afford a separable mixture
1.51 (m, 12H), 1.95 (m, 1H), 3.49 (d, J ) 3.6, 1H), 3.88-3.91
(m, 2H), 4.99 (d, J ) 4.6, 1H), 5.15 (m, 2H), 7.76-7.33 (m, 15
H); 13C NMR δ 166.8, 157.7, 136.5, 135.7, 135.6, 133.0, 132.6,
129.9, 129.8, 128.2, 127.8, 127.7, 127.6, 81.2, 77.6, 74.9, 72.5,
67.1, 64.6, 28.3, 27.9, 26.8, 24.1, 19.2. Anal. Calcd for C35H43
NO6Si: 69.8; H, 7.2; N, 2.3. Found: C, 68.9; H, 7.4; N, 2.3.
-
ter t-Bu tyl (1S,3R,4R)-7-Ben zyloxyca r bon yl-3-ter t-bu -
tyld ip h en ylsilyloxy-2-oxo-7-a za bicyclo[2.2.1]h ep ta n e-1-
ca r boxyla te (23). To a suspension of periodinane20 (0.22 g,
0.53 mmol) in CH2Cl2 (10 mL) was added alcohol 22 (0.21 g,
0.35 mmol) in CH2Cl2 (3 mL). The suspension was stirred at
room temperature for 36 h, Na2S2O3‚5H2O (1.0 g, 4.0 mmol)
and H2O (20 mL) were added, and the aqueous layer was
extracted with CHCl3/IPA (4/1, 3 × 20 mL). The combined
organic layer was dried, filtered, and evaporated, and the
residual oil was chromatographed (hexane/EtOAc, 3/1) to
afford ketone 23 (0.164 g, 78%): mp 103-104 °C; HPLC, tR
of 25 (92 mg, 57%) and 26 (8 mg, 5%) as a colorless oils. 25:
1
[R]23 -32.4 (c 1.6, CHCl3); H NMR δ 1.49 (s, 9H), 1.73 (m,
D
1H), 1.87 (m, 1H), 2.32 (m, 1H), 2.75-2.96 (m, 2H), 3.71 (s,
1H), 4.51 (t, J ) 4.5, 1H), 5.14 (s, 2H), 5.86 (s, 1H), 7.78-7.33
(m, 15H); 13C NMR δ 167.2, 166.8, 162.2, 156.6, 136.0, 128.5,
128.2, 128.0, 110.5, 82.2, 74.4, 67.4, 58.7, 51.2, 39.7, 31.4, 29.7,
28.8, 27.8. Anal. Calcd for C22H27NO6: C, 65.8; H, 6.8; N, 3.5.
Found: C, 66.1; H, 7.0; N, 3.2. 26: [R]23D -34.8 (c 1.7, CHCl3);
1H NMR δ 1.43 (s, 9H), 1.90 (m, 2H), 2.22 (d, 1H), 2.24 (m,
1H), 2.81 (d, 1H), 3.63 (s, 1H), 4.48 (t, J ) 4.5, 1H), 5.14 (m,
2H), 5.84 (s, 1H), 7.40-7.33 (m, 5H); 13C NMR δ 165.3, 158.8,
154.5, 136.3, 128.4, 127.9, 127.8, 112.2, 81.8, 81.2, 74.7, 67.0,
11.4 min (hexane/EtOAc, 9/1 mL/min); [R]23 -28.7 (c 0.7,
D
CHCl3); 1H NMR δ 1.11 (s, 9H), 1.21 (m, 1H), 1.53 (s, 9H),
1.66-1.81 (m, 3H), 2.18 (dt, J ) 4.3, 12.6, 1H), 3.69 (s, 1H),
4.35 (dt, J ) 3.7, 1H), 5.2 (m, 2H), 7.78-7.33 (m, 15H); 13C
NMR δ 201.7, 164.3, 156.3, 136.1, 135.8, 135.7, 133.2, 132.4,
129.9, 128.4, 128.1, 127.8, 127.7, 82.2, 75.7, 74.3, 67.4, 63.6,
27.3, 26.6, 26.0, 24.0, 19.2. Anal. Calcd for C35H41NO6Si: C,
70.1; H, 6.9; N, 2.3. Found: C, 69.7; H, 6.9; N, 2.3.
56.6, 51.4, 51.2, 41.7, 31.2, 27.8, 27.7. Anal. Calcd for C22H27
-
NO6: C, 65.8; H, 6.8; N, 3.5. Found: C, 66.1; H, 7.0; N, 3.2.
ter t-Bu t yl (1S,2R,4R)-7-Ben zyloxyca r b on yl-2-(m et h -
oxyca r b on ylm et h yl)-7-a za b icyclo[2.2.1]h ep t a n e-1-ca r -
boxyla te (27). To a solution of 25 (50 mg, 0.12 mmol) dissolved
in MeOH (5 mL) was added 10%Pd/C (10 mg). The reaction
was shaken under H2 (50 psi) for 20 h at room temperature,
and then the mixture was filtered through Celite. The filtrate
was evaporated, and the residue was dissolved in EtOAc. To
this solution were added CbzCl (7 µL, 0.47 mmol) and K2CO3
(80 mg, 0.47 mmol) at 0 °C, the ice bath was removed, and
the biphasic mixture was stirred for 12 h at room temperature.
The aqueous phase was extracted with CHCl3/IPA (4/1, 3 ×
20 mL); the combined organic phase was dried, filtered, and
evaporated; and the resulting oil was chromatographed (hex-
ane/EtOAc, 10/1) to afford 27 (44 mg, 88%) as a colorless oil:
ter t-Bu tyl (1S,4R)-7-Ben zyloxyca r bon yl-2-oxo-7-a za bi-
cyclo[2.2.1]h ep ta n e-1-ca r boxyla te (24). A solution of 23
(0.59 g, 1.0 mmol) in THF (30 mL) was degassed by bubbling
N2 through the solution for 30 min; degassed MeOH (10 mL)
was added, and the solution was cooled to -78 °C. To this
solution was added a solution of SmI2 in THF (10 mL, 0.22 M,
0.22 mmol) over 10 min, maintaining the temperature at -78
°C, and then the reaction mixture was stirred for 5 min at
-78 °C and saturated aqueous NaHCO3 (50 mL) was added.
The mixture was concentrated to 60 mL and was extracted
with CHCl3/IPA (4/1, 3 × 20 mL). The combined organic layer
was dried, filtered, and evaporated, and the resulting oil was
[R]23 -54.0 (c 0.45, CHCl3); 1H NMR δ 1.47 (s, 9h), 1.67-
D
chromatographed (hexane/EtOAc, 3/1) to afford 24 (0.25 g,
1.87 (m, 3H), 2.13-2.30 (m, 2H), 2.44-2.50 (m, 1H), 2.78 (dd,
J ) 5.4, 16.4, 1H), 3.71 (s, 1H), 4.51 (t, J ) 4.5, 1H), 5.14 (s,
2H), 5.86 (s, 1H), 7.78-7.33 (m, 15H); 13C NMR δ 172.9, 168.4,
158.2, 136.2, 128.4, 127.9, 81.6, 71.1, 67.1, 59.4, 51.4, 42.6, 38.2,
37.5, 32.9, 29.5, 27.8. Anal. Calcd for C22H29NO6: C, 65.5; H,
7.2; N, 3.5. Found: C, 65.8; H, 7.6; N, 3.3.
72%): mp 97-98 °C; [R]22 -27.0 (c 1.4, CHCl3); H NMR δ
1
D
1.45 (s, 9H), 1.64 (m, 1H), 1.78 (m, 1H), 1.84 (m, 1H), 2.11 (d,
J ) 17.5, 1H), 2.28 (m, 1H), 2.65 (d, J ) 14.3, 1H), 5.16 (s,
2H), 7.38-7.35 (m, 5H); 13C NMR δ 204.5, 165.0, 156.4, 135.7,
128.5, 128.4, 128.1, 82.5, 76.3, 67.7, 57.1, 44.7, 31.6, 28.4, 27.8,
25.7, 22.6, 14.1. Anal. Calcd for C19 H23NO5: C, 66.1; H, 6.7;
N, 4.1. Found: C, 66.0; H, 6.5; N, 4.0.
Su p p or tin g In for m a tion Ava ila ble: Tables of X-ray
crystallographic data, bond lengths and angles, atomic coor-
dinates, and anisotropic thermal parameters are available for
compound 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
ter t-Bu tyl (1S,4R)-7-Ben zyloxycar bon yl-2-E-[(m eth oxy-
ca r b on yl)m et h ylen e]-7-a za b icyclo[2.2.1]h ep t a n e-1-ca r -
boxylate (25) an d ter t-Bu tyl (1S,4R)-7-Ben zyloxycar bon yl-
2-Z-[(m eth oxy-ca r bon yl)m eth ylen e]-7-a za bicyclo-[2.2.1]-
h ep ta n e-1-ca r boxyla te (26). To a suspension of NaH (88 mg,
3.7 mmol) in THF (10 mL) was added trimethyl phosphonoac-
J O982327C