Design and synthesis of a novel class of constrained tricyclic pyrrolizidinone carboxylic acids as carbapenem mimics.

Article abstract of DOI:10.1021/jo0111715

A series of tricyclic pyrrolizidinone carboxylic acids harboring an angular methano group were synthesized as mimics of carbapenems and carbapenams. A key reaction involved a novel intramolecular cyclopropanation mediated by a trimethylstannylmethyl group and an adjacent iminium ion. Enolate chemistry on a tricyclic lactam ring unit allowed the introduction of various substituents. Further elaboration afforded tricyclic pyrrolidinone carboxylic acids, which were found to be inactive as inhibitors against a panel of bacterial strains. However, the antibacterial activity of ceftazidine was enhanced in the presence of the tricyclic analogues.

Full text of DOI:10.1021/jo0111715

J . Org. Chem. 2002, 67, 3387-3397
3387
Design a n d Syn th esis of a Novel Cla ss of Con str a in ed Tr icyclic
P yr r olizid in on e Ca r boxylic Acid s a s Ca r ba p en em Mim ics
Stephen Hanessian,* Ronald Buckle, and Malken Bayrakdarian
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale Centre-ville,
Montre´al, Que´bec H3C 3J 7, Canada
stephen.hanessian@umontreal.ca
Received December 21, 2001
A series of tricyclic pyrrolizidinone carboxylic acids harboring an angular methano group were
synthesized as mimics of carbapenems and carbapenams. A key reaction involved a novel
intramolecular cyclopropanation mediated by a trimethylstannylmethyl group and an adjacent
iminium ion. Enolate chemistry on a tricyclic lactam ring unit allowed the introduction of various
substituents. Further elaboration afforded tricyclic pyrrolidinone carboxylic acids, which were found
to be inactive as inhibitors against a panel of bacterial strains. However, the antibacterial activity
of ceftazidine was enhanced in the presence of the tricyclic analogues.
The unique class of â-lactam antibiotics comprising
penams, carbapenems, cephems, and monobactams have
occupied a central role in the vigil against bacterial
infections over the past several decades.1 A great deal of
synthetic effort has been devoted to the synthesis of new
variants or chemically modified analogues.2 Historically
and therapeutically relevant structures such as â-lactam
antibiotics are represented by the venerable penicillin G
(1) and the carbapenem variant thienamycin (2a ),3 for
example (Figure 1).
The susceptibility of the â-lactam antibiotics toward
enzymatic acylation by â-lactamases and target proteins
known as penicillin binding proteins (PBPs) is attributed
to the partial ketonic character of the carbonyl group as
a result of increased pyramidalization of the nitrogen
atom.4 This notion has led to the exploration of penems
as potential antibacterials where the original penam
nucleus was modified into an unsaturated and highly
strained analogue.5 Relatively little effort has been
expended in the design and synthesis of structurally
different, strained â-lactams since then.6
Previous reports from our laboratory7a have shown that
the introduction of a 4,5-trans-methano bridge in N-Boc
D-proline (3) dramatically flattened the pyrrolidine ring
F igu r e 1.
(rms 0.003 Å), compared to the cis-analogue 4 (rms 0.018
Å) and N-Boc L-proline (rms 0.013 Å).8 We surmised that
the presence of a methano bridge in a tricyclic pyrroliz-
idinone carboxylic acid motif such as 5 might be of
* Phone: (514) 343-6738. Fax: (514) 343-5728.
(1) For reviews, see: (a) Setti, E. L.; Micetich, R. G. Curr. Med.
Chem. 1998, 5, 101. (b) Chu, D. T. W.; Plattner, J . J .; Katz, L. J . Med.
Chem. 1996, 39, 3853. (c) Berko, A. H. Tetrahedron 1996, 52, 331. (d)
Mascaretti, O. A.; Boschetti, C. E.; Damelon, G. O.; Mata, E. G.; Roveri,
O. Curr. Med. Chem. 1995, 1, 441. (e) The Organic Chemistry of
â-Lactams; Georg., G. J ., Ed.; VCH: New York, 1993. (f) Neuhaus, F.
C.; Georgeopapadakou, N. H. In Emerging Targets in Antibacterial and
Antifungal Chemotherapy; Sutcliffe, J ., Georgeopapadakou, N. H., Eds.;
Chapman and Hall: New York, 1992.
(2) See, for example: (a) Black, M. T.; Bruton, G. Curr. Pharm. Des.
1998, 4, 133. (b) Setti, E. L.; Quattrocchio, L.; Micetich, R. G. Drug
Int. 1997, 22, 271. (c) Brown, A. G. Pure Appl. Chem. 1987, 59, 475.
(3) (a) Leanza, W. J .; Wildonger, K. J .; Miller, T. W.; Christensen,
B. G. J . Med. Chem. 1979, 22, 1435. (b) Salzmann, T. N.; Ratcliffe, R.
W.; Christensen, B. G. J . Am. Chem. Soc. 1980, 102, 6161.
(4) (a) Imming, P.; Klar, B.; Dir, D. J . Med. Chem. 2000, 43, 4328.
(b) Page, M. I.; Laws, A. P. J . Chem. Soc., Chem. Commun. 1998, 1609.
(c) Takasuka, M.; Nishikawa, J .; Tori, K. J . Antibiot. 1982, 35, 1729.
(d) Strominger, J . L. Antibiotics 1967, 1, 706. (e) Woodward, R. B. In
The Chemistry of Penicillin; Clark, H. T., J ohnson, J . R., Robinson,
R., Eds.; Princeton Unviersity Press: Princeton, NJ , 1949; p 443.
(5) (a) Ernest, J .; Gosteli, J .; Greengrass, L. W.; Holick, W.; J ackman,
D. E.; Pfaendler, H. R.; Woodward, R. B. J . Am. Chem. Soc. 1978, 100,
8214. (b) Franceschi, G.; Foglio, M.; Arcamone, F. J . Antibiot. 1980,
33, 453. (c) Afonso, A.; Hon, F.; Weinstein, J .; Ganguly, A. K.; McPhail,
A. T. J . Am. Chem. Soc. 1982, 104, 6138. (d) Yoshida, H.; Hayashi, T.;
Takeda, N.; Oida, S.; Ohki, E. Chem. Pharm. Bull. 1983, 31, 768. (e)
Hanessian, S.; Bedeschi, A.; Battistini, C.; Mongelli, N. J . Am. Chem.
Soc. 1985, 107, 1438.
(6) (a) Williams, R. M.; Lee, B. H. J . Am. Chem. Soc. 1986, 108,
6431. (b) Williams, R. M.; Lee, B. H.; Miller, S.; Anderson, O. P. Spec.
Publ. R. Soc. Chem. 1989, 70, 106. (c) Buynak, J . D.; Rao, A. S.; Adam,
G.; Nidamenthy, S. D.; Zhang, H. J . Am. Chem. Soc. 1998, 120, 6846.
(7) (a) Hanessian, S.; Reinhold: U.; Gentile, G. Angew. Chem., Int.
Ed. Eng. 1997, 36, 1881. (b) Hanessian, S.; Reinhold, U.; Saulnier,
M.; Claridge, S. Bioorg. Med. Chem. Lett. 1998, 8, 213.
(8) Rms refers to the root-mean-square deviation from planarity
expressed in angstroms.
10.1021/jo0111715 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/06/2002

3388 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
Sch em e 1
interest as potential substrates for serine peptidases and
transpeptidases (PBPs) (Figure 1). It was not known at
the outset if the planarity of the original analogue 3
would also be manifested in the tricyclic structure 5. This
would in effect reduce its acylating power considerably
compared to that of a conventional â-lactam such as 1
as a result of a more facile delocalization into the amide
bond. In designing 5, we chose to maintain an R-oriented
carboxyl group (penam-like, 1) and a â-oriented methano
bridge (1-methylcarbapenem-like, 2b). Bicyclic non-â-
lactam indolizidinone analogues of penams, penems, and
carbapenems9,10 have been previously made and shown
to exhibit moderate to weak antibacterial activity.11
Tricyclic â-lactams such as the trinems have shown
significant interest recently as clinical candidates.12-15
The readily available lactam 616 was alkylated via its
lithium enolate with trimethylstannylmethyl iodide17 to
afford a separable mixture7a of the major anti-adduct 8
(63%) and the corresponding syn-isomer 7 (23%) (Scheme
1). Treatment of 8 with allylmagnesium bromide afforded
the hemiaminal 9, which when treated with TFA at 0 °C
led to the expected 4,5-trans-methano-D-proline analogue
11. The allylic double bond in 11 had migrated, presum-
ably to enter into conjugation with an incipient N-Boc
iminium ion 10. It is of interest that cyclopropanation
takes place under such mild conditions,7 presumably via
an attack of trifluoroacetate anion on the trimethylstan-
nyl group and subsequent ring closure on the iminium
ion. The reaction is also applicable to a 3-trimethylstan-
nyl propyl derivative, which affords the corresponding
fused cyclopentane analogue of 3,7a and to oxonium ions
to give fused oxabicyclic structures. Ozonolytic cleavage
of the 2-propenyl group followed by olefination of the
resulting aldehyde gave the R,â-unsaturated ester 12 in
excellent yield. Reduction, conventional deprotection and
lactam formation gave the tricyclic pyrrolizidinone ana-
logue 13 in 65% yield for four steps.
(9) For reviews, see: Marchand-Brynaert, J .; Ghosez, L. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lukacs, G., Ed.;
Springer-Verlag: Berlin, 1990; Vol. 2, p 729.
Desilylation and a two-step oxidation18 of the hy-
droxymethyl group afforded the desired prototype 5
(CdO, 1645 cm-1). At this juncture, an X-ray crystal
structure of ent 13 confirmed its stereochemistry and
revealed a rms deviation from planarity for the methano-
containing pyrroldine ring of 0.107 Å, indicating consid-
erable flattening compared to 1 and 2 and dimming the
prospects of approaching â-lactam-like reactivity. Nev-
ertheless, we pursued our objective of further function-
alization of this prototype in the hope of achieving some
level of binding to target enzymes. Enolate formation and
allylation afforded a C-allylated product 14 as the major
isomer accompanied by ∼10% of the epimer (Scheme 2).
Hydrogenation and a selenoxide-induced elimination led
to the endocyclic olefin isomer 16 almost exclusively.
Deprotection and oxidation of 16 afforded 17 (CdO, 1639
cm-1). Surprisingly, the carbonyl stretching frequency in
13 and 16 was the same (1679 cm-1) and higher than
the corresponding acids 5 or 17.
(10) See, for example: (a) Baldwin, J . E.; Chan, M. F.; Gallacher,
G.; Monk, P.; Prout, K. J . Chem. Soc., Chem. Commun. 1983, 250. (b)
Baldwin, J . E.; Lee, E. Tetrahedron 1986, 42, 6551. (c) Baldwin, J . E.;
Lowe, C.; Schofield, C. J .; lee, E. Tetrahedron Lett. 1986, 27, 3461. (d)
Baldwin, J . E.; Freeman, R. T.; Schofield, C. Tetrahedron Lett. 1989,
30, 4019. (e) Boyd, D. B.; Foster, B. J .; Hatfield, L. D.; Hornback, W.
J .; J ones, N. D.; Munroe, J . E.; Swartzendruber, J . K. Tetrahedron
Lett. 1986, 27, 3457. (f) Hashigushi, S.; Natsugari, H.; Ochiai, M. J .
Chem. Soc., Perkin Trans. 1 1988, 2345. (g) J unghein, L. N.; Sigmund,
S. K. J . Org. Chem. 1987, 52, 4007. (h) J ungheim, L. N.; Sigmund, S.
K.; J ones, N. D.; Swartzendruber, J . K. Tetrahedron Lett. 1987, 28,
289. (i) J ungheim, L. N. Tetrahedron Lett. 1989, 30, 1889. (j) Ternan-
sky, R. J .; Draheim, S. f. Tetrahedron Lett. 1990, 31, 2805. (k) Smith,
P. W.; Wittington, A. R.; Cobley, K. N.; J axa-Chamiec, A.; Finch, H. J .
Chem. Soc., Perkin Trans. 1 2001, 21. For dopamine receptors, see:
Subasinghe, N. L.; Bontems, R. J .; McIntee, E.; Mishra, R. K.; J ohnson,
R. L. J . Med. Chem. 1993, 36, 2356. Subasinghe, N. L.; Khalil, E. M.;
J ohnson, R. L. Tetrahedron Lett. 1997, 38, 1317.
(11) For a summary, see: Hanessian, S.; McNaughton-Smith, G.;
Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
(12) For a review on nonclassical polycyclic â-lactams, see: Gomez-
Gallego, M.; Mancheno, M. J ., Sierra, M. A. Tetrahedron 2000, 56,
5743.
(13) (a) Marchioro, C.; Pentassuglia, G.; Perboni, A.; Donati, D. J .
Chem. Soc., Perkin Trans. 1 1997, 463. (b) Rossi, T.; Marchioro, C.;
Paio, A.; Thomas, R. J .; Zarantonello, P. J . Org. Chem. 1997, 62, 1653
and references cited therein.
Scheme 3 shows our efforts to introduce heteroatom
functionality in the lactam ring of 13. Thus, catalytic
reduction of 12 led to 18, which was subjected to a highly
stereoselective enolate R-hydroxylation using the Davis
(14) (a) Iso, Y.; Nishitani, Y. Heterocycles 1998, 48, 2287. (b) Ananda,
M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 9063.
(15) (a) Hanessian, S.; Rozema, M. M. J . J . Am. Chem. Soc. 1996,
118, 9884. (b) Hanessian, S.; Griffin, A. M.; Rozema, M. J . Bioorg. Med.
Chem. Lett. 1997, 7, 1857. (c) Hanessian, S.; Rozema, M. J .; Reddy, G.
B.; Braganza, J . F. Bioorg. Med. Chem. Lett. 1995, 5, 2535.
(16) Hanessian, S.; McNaughton-Smith, C. Bioorg. Med. Chem. Lett.
1996, 6, 1657.
(18) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091; See also: Lindgren, B. O.; Nilsson, T. Acta Chem. Scand.
1973, 27, 888. Kraus, G. A.; Tashner, M. J . J . Org. Chem. 1980, 45,
1175.
(17) Seyferth, D.; Andrews, S. B. J . Organomet. Chem. 1971, 30,
151.

Carbapenem Mimics
J . Org. Chem., Vol. 67, No. 10, 2002 3389
Sch em e 2
of the K-enolate with the N-Boc group is responsible for
such a high level of diastereoselectivity. Nuclear Over-
hauser effect studies on bicyclic analogues confirmed the
proposed stereochemistry. Cleavage of the ester and
lactam formation gave the R-hydroxy pyrrolizidinone
analogue 20 (CdO. 1684 cm-1). Conventional acetylation
afforded the acetate ester 21 (CdO, 1711 cm-1) with the
highest lactam carbonyl stretching frequency observed
among the series of methanopyrrolizidinones so far.20
Deprotection and oxidation of 21 led directly to the
carboxylic acid 22 (CdO, 1694 cm-1), which after treat-
ment with lithium hydroxide afforded the corresponding
R-hydroxy analogue 23 (CdO, 1684 cm-1).
Mitsunobu azidation21 of 20 gave the corresponding
inverted azide 24 (CdO, 1702 cm-1), which upon depro-
tection and oxidation afforded the corresponding car-
boxylic acid 25 (CdO, 1699 cm-1). Reduction of the azide
group in 24 and acylation with phenylacetic acid in the
presence of EDC and HOBt led to the phenylacetyl
analogue 26 (CdO, 1682 cm-1), which was finally trans-
formed to the carboxylic acid 27 (CdO, 1672 cm-1) as
described above.
Sch em e 3
In view of the topology of the tricyclic ring system in
13, we also explored the aldol reaction with acetone of
the corresponding lithium enolate generated with sec-
butyllithium. A mixture of adducts was isolated in a
combined yield of 71%, which after desilylation and
chromatographic separation gave 28 and 29 in a ratio of
3:2 (Scheme 4). The structure and absolute stereochem-
istry of the slightly more abundant isomer 28 (CdO, 1645
cm-1) were confirmed by X-ray crystallography. Evi-
dently, the exo- and endo-faces of the enolate from 13 are
not sterically differentiated enough toward acetone as an
electrophile despite the presence of a bulky endo-sub-
stituent. A 2-hydroxypropyl appendage can be found in
carpetimycin A and its congeners22 (Scheme 4).
Since the corresponding proline 4 showed less flatten-
ing in the solid state compared to 3,7a we undertook the
synthesis of the corresponding cis-4,5-methanopyrrolizi-
dine analogue. Scheme 5 illustrates the synthesis, which
follows the same protocol as for 13. Enolate formation
from 8 with LiHMDS and quenching with 2,6-di-tert-
butylphenol led to an enrichment of the desired cis-
isomer 7 (73%, with 13% recovered 8). Addition of
allylmagnesium bromide proceeded uneventfully to give
30. In this case, the destannylation-cyclopropanation to
the intended propenyl analogue 31 proceeded in modest
overall yield compared to that of 11. Ozonolytic cleavage
of 31 and further chemistry led to the cis-fused metha-
nopyrrolizidinone 33, whose carbonyl stretching fre-
quency (CdO, 1692 cm-1) showed only a modest shift
compared to that of its trans-methano isomer 17 (CdO,
1639 cm-1).
In an effort to further constrain the original bicyclic
pyrrolidinone motif we explored the possibility of rear-
ranging the 4,5-methanopyrrolizidinone to the corre-
sponding cyclopentane analogue through solvolytic ring
reagent (2-benzenesulfonyl-3-phenyloxaziridine)19 to give
19 as the major isomer, accompanied by 10% of the
epimer. The preponderance of 19 is noteworthy, particu-
larly in the absence of a vicinal stereodirecting group on
the acyclic chain. Excluding steric effects of the metha-
nopyrrolidine appendage, it is possible that coordination
(20) The â-lactam carbonyl frequencies for penicillin G, N-acetyl
thienamycin methyl ester, and various cephalosporins are 1775, 1779,
and 1700 cm-1, respectively. The rms deviations from planarity for
the five- and five-membered rings from X-ray crystallographic studies
are 0.38, 0.49, and 0.27-0.24 Å, respectively.
(21) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre,
D. J .; Grabowski, E. J . J . J . Org. Chem. 1993, 58, 5886.
(19) (a) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. Org. Synth.
1988, 66, 203. (b) Davis, F. A.; Vishwarkarma, L. C.; Billmers, J . M.;
Finn, J . J . Org. Chem. 1984, 49, 3241.
(22) Nakayama, M.; Iwasaki, A.; Kimura, S.; Mizoguchi, T.; Tanabe,
S.; Murakami, A.; Watanabe, I.; Okuchi, M.; Itoh, H.; Saino, Y.;
Kobayashi, F.; Mori, T. J . Antibiot. 1980, 33, 1388.

3390 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
Sch em e 4
Sch em e 5
Sch em e 6
frequencies compared to the penams and carbapenems
(1695-1700 cm-1 compared to 1775-1779 cm-1).
The pyrrolizidinone carboxylic acids 5, 22, 25, and 27
did not show any antibacterial activity when tested on a
panel of standard sensitive and resistant strains most
likely as a result of their greatly diminished acylating
character toward PBPs. However, the activity of the
antibiotics ceftazidine (Figure 1) as measured by its MIC
against some â-lactamase-producing strains was im-
proved in the presence of a 10 µg/mL concentration of
these analogues.27
Further work will focus on elucidating the mechanisms
of â-lactamase inactivation by nonacylating inhibitors
such as the methanopyrrolizidinone carboxylic acids
described in this paper. Other modifications that activate
the carbonyl or the R-position of these tricyclic γ-lactams
toward nucleophilic attack can be envisaged. Structure-
based inhibitors of â-lactams have been recently studied
with promising results.28
expansion.23 Base-catalyzed addition of nitromethane to
the R,â-unsaturated ester 12 proceeded in high yield to
give adduct 34 with a >20:1 selectivity based on NMR
data after cyclization (Scheme 6). Lactam formation
proceeded uneventfully to give the cis-substituted ni-
tromethyl methanopyrrolizidinone 35 as evidenced by
detailed NOE studies. Subsequent oxidative cleavage24
of the sodium nitronate salt of 35 gave the corresponding
aldehyde, which was reduced to the alcohol 36. Brosyla-
tion and bromination under standard conditions gave the
corresponding brosylate 37 and bromide 38, respectively.
Several attempts to solvolyze these compounds to tricyclic
bridged compounds such as 39 were not successful. Thus,
refluxing a solution of the bromide 38 in aqueous dioxane
left it unchanged. Treatment of the corresponding brosy-
late 37 with formic acid and pyridine25 at 100 °C gave
the corresponding formate and starting material. Under
free radical conditions (Bu3SnH, AIBN, benzene, reflux),
the bromide 38 was simply reduced to the corresponding
C-methyl derivative. Tricyclic cyclopentapyrrolizidine-2-
ones26 related to 39 also exhibit lower carbonyl stretching
Exp er im en ta l Section
Gen er a l. Flash chromatography was performed on 230-
240 mesh silica gel.29 Thin-layer chromatography (TLC) was
(26) Denmark, S. E.; Schmute, M. E.; Marcin, L. R.; Thorarensen,
A. J . Org. Chem. 1995, 60, 3205.
(23) For a review, see: Wong, H. W. C.; Hon, M.-Y.; Tse, C.-W.; Yip,
Y.-C.; Tanko, J .; Hudlicky, T. Chem. Rev. 1989, 89, 165.
(24) (a) Cho, B. P.; Chadha, V. K.; Le Breton, G. C.; Venton, D. L.
J . Org. Chem. 1986, 51, 4279. (b) McMurry, J . E.; Melton, J .; Padgett,
H. J . Org. Chem. 1974, 39, 259.
(27) Against Klebsiella 97P587, the original MIC value of 50 µg/mL
for ceftazidine was reduced to 25 µg/mL when 10 µg/mL of 5 and 27
were present. The activity of ceftazidine against Pseudomonas aerugi-
nosa PAK (MIC value of 25 µg/mL) was enhanced in the presence of 5
and 25 to MIC 3-12 µg/mL and to 12.5 µg/mL with 22 and 27.
(25) Sauers, R. R.; Ubersax, R. W. J . Org. Chem. 1966, 31, 495.

Carbapenem Mimics
J . Org. Chem., Vol. 67, No. 10, 2002 3391
performed on glass plates coated with a 0.02-mm layer of silica
gel 60 F254. All solvents were distilled freshly before use. 1H
NMR (400 MHz) and 13C NMR (100.6 MHz) spectra were
determined in CDCl3 unless otherwise noted. Wherever neces-
sary, 1H NMR assignments were supported by appropriate
homonuclear correlation experiments (COSY). Optical rota-
tions were measured at 25 °C at the sodium line.
room temperature and diluted with EtOAc (100 mL). The
organic layer was washed with H2O (2 × 15 mL) and NaCl
(15 mL) and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residual solvent further removed
using a vacuum pump (1 h). This crude reaction mixture was
dissolved in dry CH2Cl2 (125 mL), and TFA (0.90 g, 0.61 mL,
7.90 mmol) was added dropwise at 0 °C. The resulting orange-
brown solution was stirred for 10 min, quenched with a
saturated solution of NaHCO3 (35 mL), and diluted with
EtOAc (300 mL). The organic layer was washed with NaHCO3
(50 mL), followed by H2O (50 mL) and NaCl (50 mL), then
dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified by silica gel flash chroma-
tography with hexane containing EtOAc (5%) to yield 11 as a
(3S,5R)-5-ter t-Bu tyld ip h en ylsilyloxym eth yl-3-tr im eth -
ylsta n n a n ylm eth yl-1-ter t-bu tyloxyca r bon ylp yr r olid in -2-
on e (8). To solution of 6 (5.97 g, 13.2 mmol) in THF (130 mL)
was added LiHMDS (1 M in THF, 13.5 mL, 13.5 mmol)
dropwise over 1 h using a syringe pump at -78 °C. After
another 1 h of stirring at -78 °C, the Me3SnCH2I (12.1 g, 40.0
mmol) was added over 5 min, and the temperature was
maintained between -25 and -35 °C for 2 h. The reaction
mixture was quenched with a saturated solution of NH4Cl (30
mL) and then diluted with EtOAc (300 mL), and the organic
layer was separated. The aqueous layer was then acidified to
pH 4 with 0.5M HCl, and this was re-extracted with EtOAc
(2 × 200 mL). The combined organic layers were dried (Na2-
SO4), filtered, and concentrated under reduced pressure. The
resulting residue was purified by silica gel flash chromatog-
raphy with hexane containing EtOAc (0-10%) to yield 8 as a
colorless solid (5.18 g, 63%) and 7 (1.9 g, 23%). For 8: mp 60-
1
colorless oil (0.91 g, 58%): [R]D +28.0 (c ) 1.18, CHCl3); H
NMR (CDCl3) δ 0.73 (1H, t, J ) 5.1 Hz), 1.08 (9H, s), 1.30-
1.50 (2H, m), 1.41 (9H, s), 1.63 (3H, dd, J ) 1.6, 6.5 Hz), 1.90
(1H, m), 2.28 (1H, m), 3.64 (1H, dd, J ) 7.0, 9.8 Hz), 3.70 (1H,
dd, J ) 4.7, 9.8 Hz), 4.09 (1H, br s), 5.37 (1H, dq, J ) 6.5, 15.4
Hz), 5.56 (1H, d, J ) 15.4 Hz), 7.36-7.45 (6H, m), 7.66-7.72
(4H, m); 13C NMR (CDCl3) δ 17.5, 19.3, 26.7, 26.8, 28.4, 30.4,
48.8, 64.9, 65.3, 79.2, 122.2, 127.6, 129.5, 129.6, 131.2, 133.7,
133.7, 135.6, 155.6; [M + 1] 492; HRMS, found 492.2925;
C
30H42NO3Si requires 492.2934.
1
(2S,3R,5R)-5-ter t-Bu t yld ip h en ylsilyloxym et h yl-2-(2′-
61 °C; [R]D +13.2 (c ) 1.02, CHCl3); H NMR (CDCl3) δ 0.12
m eth oxyca r bon ylvin yl)-2â-m eth a n o-1-ter t-bu tyloxyca r -
bon ylp yr r olid in e (12). Through a solution of 11 (1.55 g, 3.14
mmol) in CH2Cl2 (55 mL) was bubbled ozone until it became
light blue in color at -78 °C. After 5 min, the ozone was
replaced with nitrogen and bubbling was continued until the
color had dissipated (10 min). Me2S (1.95 g, 2.30 mL, 31.4
mmol) was then added in one portion, and the reaction mixture
was left to warm to room temperature. The solvent and excess
Me2S were removed under reduced pressure, and the residue
was purified by silica gel flash chromatography with hexane
containing EtOAc (15%) to yield the desired aldehyde as a
(9H, s), 0.88 (1H, dd, J ) 8.2, 13.0 Hz), 1.05 (9H, s), 1.16 (1H,
dd, J ) 7.8, 13.0 Hz), 1.42 (9H, s), 1.74 (1H, m), 2.38 (1H, dd,
J ) 8.7, 12.6 Hz), 2.95 (1H, m), 3.70 (1H, dd, J ) 2.6, 10.4
Hz), 3.84 (1H, dd, J ) 4.5, 10.4 Hz), 4.09 (1H, m), 7.36-7.47
(6H, m), 7.60-7.66 (4H, m); 13C NMR (CDCl3) δ -9.1, 13.8,
19.1, 26.8, 27.9, 32.6, 40.7, 56.4, 64.6, 82.5, 127.7, 127.8, 129.8,
132.6, 133.0, 135.4, 135.5, 149.7, 178.2; [M + Na] 654; HRMS,
found 654.2007, C30H45NO4Si120Sn requires 654.2037.
(3R,5R)-5-ter t-Bu tyld ip h en ylsilyloxym eth yl-3-tr im eth -
ylsta n n a n ylm eth yl-1-ter t-bu tyloxyca r bon ylp yr r olid in -2-
on e (7). To a solution of LiHMDS (1 M in THF, 1.7 mL, 1.7
mmol) was added dropwise a solution of 8 (1.0 g, 1.6 mmol) in
THF (25 mL) at -60 °C. The reaction mixture was stirred and
warmed to -30 °C over a period of 2 h, quenched at this
temperature using 2,6-di-tert-butyl phenol. The reaction mix-
ture was diluted with EtOAc (50 mL) and washed with a
saturated solution of NH4Cl (15 mL). The organic layer was
separated, and the aqueous layer was re-extracted with EtOAc
(2 × 20 mL). The combined organic layers were dried (Na2-
SO4), filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel flash chromatog-
raphy with hexane containing EtOAc (0-10%) to yield 7 as a
colorless oil (0.74 g, 73%) and 13% of recovered 8: [R]D +16.4
(c ) 1.7, CHCl3); 1H NMR (CDCl3) δ 0.12 (9H, s), 0.94 (1H, dd,
J ) 9.0, 13.0 Hz), 1.07 (9H, s), 1.27 (1H, dd, J ) 7.1, 13.0 Hz),
1.39 (9H, s), 1.76 (1H, ddd, J ) 2.0, 7.0, 9.0 Hz), 2.37 (1H, dd,
J ) 8.1, 11.6 Hz), 2.60 (1H, dd, J ) 7.2, 9.1 Hz), 3.84 (2H, m,
1
colorless oil (1.40 g, 93%): [R]D +31.1 (c ) 0.83, CHCl3); H
NMR (CDCl3) δ 0.96-1.07 (1H, m), 1.05 (9H, br s), 1.44 (9H,
br s), 2.05-2.20 (3H, m), 2.39 (1H, br s), 3.67-3.70 (1H, dd, J
) 3.3, 10.2 Hz), 3.89 (1H, br s), 4.18 (1H, br s), 7.36-7.46 (6H,
m), 7.64-7.68 (4H, m), 9.84 (1H, br s); 13C NMR (CDCl3) δ
19.2, 26.8, 27.8, 28.3, 56.4, 65.2, 80.7, 127.7, 129.7, 129.8, 133.2,
135.4, 135.5, 155.2, 200.0; [M + 1] 480; HRMS, found 480.2559;
C
28H37NO4Si requires 480.2570.
To a solution of the aldehyde (1.25 g, 2.61 mmol) in dry
benzene (100 mL) was added methyl(triphenylphosphor-
anylidene) acetate (5.49 g, 16.4 mmol) at room temperature.
The reaction mixture was then heated to reflux for a 30 h, the
solvent was evaporated under reduced pressure, and the
resulting residue was purified by silica gel flash chromatog-
raphy with hexane containing EtOAc (12%). The product 12
(1.27 g, 91%) was obtained as a mixture of cis- and trans-
isomers (1:6), which were easily separable. For the trans-
isomer: [R]D -39.5 (c ) 2.02, CHCl3); 1H NMR (CDCl3) δ 1.06
(9H, s), 1.05-1.10 (1H, m), 1.41 (9H, s), 1.57 (1H, m), 1.79 (1H,
m), 1.96 (1H, m), 2.26 (1H, m), 3.60 (1H, dd, J ) 6.8, 9.9 Hz),
3.68 (1H, dd, J ) 5.0, 9.9 Hz), 3.69 (3H, s), 4.17 (1H, br s),
5.81 (1H, d, J ) 15.5 Hz), 6.80 (1H, d, J ) 15.5 Hz), 7.35-
7.44 (6H, m), 7.64-7.69 (4H, m); 13C NMR (CDCl3) δ 19.1, 26.7,
28.2, 30.0, 49.3, 51.1, 65.06, 65.10, 80.0, 116.5, 127.6, 129.5,
133.4, 135.5, 150.2, 155.2, 167.0; [M + 1] 536; HRMS, found
536.2851; C31H41NO5Si requires 536.2832.
CH), 4.05 (1H, m), 7.36-7.47 (6H, m), 7.60-7.66 (4H, m); 13
C
NMR (CDCl3) δ -9.0, 13.9, 19.2, 26.7, 27.8, 31.6, 40.5, 56.3,
64.4, 82.5, 127.6, 127.7, 129.8, 132.9, 133.2, 135.4, 135.5, 149.9,
178.2; [M + Na] 654; HRMS, found 654.2007; C30H45NO4Si120
-
Sn requires 654.2037.
(2S,3R,5R)-5-ter t-Bu tyld ip h en ylsilyloxym eth yl-2-p r o-
p en yl-2â-m et h a n o-1-ter t-b u t yloxyca r b on ylp yr r olid in e
(11). To a solution of lactam 8 (2.0 g, 3.19 mmol) in THF (35
mL) was added allylmagnesium bromide (1 M in Et2O, 7.98
mL, 7.98 mmol) dropwise over 5 min at -78 °C. The reaction
mixture was stirred at -78 °C for 90 min and then quenched
with pH 7 buffer (5 mL). This solution was quickly warmed to
(5S,6R,8R)-8-ter t-Bu tyldiph en ylsilyloxym eth yl-5â-m eth -
a n o-h exa h yd r op yr r olizid in -2-on e (13). To a solution of
ester 12 (1.44 g, 2.68 mmol) in EtOH (55 mL) was added 10%
Pd/C (500 mg) at room temperature. The suspension was
hydrogenated under 1 atm of H2 for 7 h at room temperature.
The suspension was then filtered through a sintered-glass
funnel containing Celite, and the solvent was removed under
reduced pressure to yield the product as a colorless oil (1.44
(28) See, for example: (a) Buynak, J . D.; W. K.; Bachmann, B.;
Khasnis, D.; Hua, L.; Nguyen, H. K.; Carver, C. L. J . Med. Chem. 1995,
38, 1022. (b) Buynak, J . D.; Khasnis, D.; Bachmann, B. W. K.; Lamb,
G. J . Am. Chem. Soc. 1994, 116, 10955. (c) Heinze-krass, I.; Angehrn,
P.; Charnas, R. L.; Gubernator, K.; Gutknecht, E.; Hubschwerlen, C.;
Kami, M.; Oefner, C.; Page, M. G. D.; Sogabe, S.; Specklin, J . L.;
Winkler, F. J . Med. Chem. 1998, 41, 3961. (d) Hubschwerlen, C.;
Angehrn, P.; Gubernator, K.; Page, M. G. P.; Specklin, J . L. J . Med.
Chem. 1998, 41, 3972. (e) Belletini, J .-R.; Miller, M. J . Tetrahedron
Lett. 1997, 38, 167.
1
g, essentially quantitative): [R]D +40.9 (c ) 1.03, CHCl3); H
NMR (CDCl3) δ 0.55 (1H, t, J ) 5.0 Hz), 0.92 (1H, dd, J ) 5.4,
8.4 Hz), 1.06 (9H, s), 1.30 (1H, m), 1.41 (9H, s), 1.45-1.55 (1H,
m), 1.95 (1H, m), 2.17-2.25 (2H, m), 2.34 (1H, ddd, J ) 5.6,
9.8, 15.7 Hz), 2.67 (1H, m), 3.50 (1H, m), 3.50 (1H, m), 3.57
(29) Clark, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

3392 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
(3H, s), 3.77 (1H, dd, J ) 4.8, 9.5 Hz), 3.97 (1H, br s), 7.36-
7.45 (6H, m), 7.65-7.69 (4H, m); 13C NMR (CDCl3) δ 19.1, 23.8,
24.4, 26.8, 28.3, 28.8, 30.4, 21.0, 47.7, 51.3, 63.8, 65.4, 79.5,
127.5, 129.5, 133.5, 133.6, 135.4, 156.5, 173.8; [M + 1] 538;
HRMS, found 538.2976; C31H43NO5Si requires 538.2989.
To a solution of the above ester (94.6 mg, 0.174 mmol) in
CH2Cl2 (3.5 mL) was added trifluoroacetic acid (∼0.50 g, 0.35
mL, 4.4 mmol) dropwise at 0 °C. After stirring at this
temperature for 2.5 h, a saturated solution of NaHCO3 (5 mL)
was added, and the resulting reaction mixture was stirred
vigorously for 5 min. EtOAc (50 mL) was added, and the
organic layer was washed with NaHCO3 (10 mL) and NaCl
(10 mL) and dried (Na2SO4). This was filtered and concen-
trated to give a pale yellow residue, which was used in the
next step.
To a solution of crude aldehyde in tert-BuOH (2 mL) was
added the 2-methyl-2-butene (0.126 g, 0.190 mL, 1.78 mmol)
followed by a solution of the NaClO2 (0.158 g, 1.74 mmol) and
KH2PO4 (0.155 g, 1.14 mmol) in water (1 mL) at room
temperature. The reaction mixture was stirred at room tem-
perature for 12 h, the tert-BuOH was evaporated under
reduced pressure, the resulting residue was acidified using a
2% HCl solution, and the aqueous layer was extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried
(Na2SO4) and filtered, and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel
chromatography with EtOAc containing AcOH (0-5%) to
afford 5 as a colorless oil (19.4 mg, 60%): [R]D +75.5 (c ) 0.29,
CHCl3); 1H NMR (CDCl3) δ 0.79 (1H, dd, J ) 6.4, 8.7 Hz), 0.90
(1H, dd, J ) 4.2, 6.4 Hz), 1.63 (1H, dt, J ) 4.2, 8.7 Hz), 2.04
(1H, dd, J ) 9.5, 12.3 Hz), 2.52-2.67 (3H, m), 2.76, (1H, dd, J
) 9.5, 17.0 Hz), 3.04 (1H, dt, J ) 10.0, 17.0 Hz), 3.92 (1H, t,
J ) 8.6 Hz), 5.74 (1H, br s); 13C NMR (CDCl3) δ 14.0, 15.3,
24.2, 35.6, 35.7, 55.0, 55.6, 169.3, 174.1; IR (cm-1) 3650-2200,
1732, 1645, 1470, 1417, 1201; [M + 1] 182; HRMS, found
182.0823; C9H12NO3 requires 182.0817.
(3S,5R,6R,8R)-3-Allyl-8-ter t-bu tyld ip h en ylsilyloxym e-
th yl-5â-m eth a n o-h exa h yd r op yr r olizid in -2-on e (14). To a
solution of 13 (0.13 g, 0.32 mmol) in THF (6.0 mL) was added
n-BuLi (1.95 mL, 0.44 mmol, 0.227 M in hexanes) dropwise
over 5 min at -78 °C. The solution was stirred for 1 h, and
then allyl iodide (0.186 g, 0.10 mL, 1.11 mmol) was added
dropwise at -78 °C. The reaction mixture was stirred at -78
°C for 2 h and quenched with a saturated solution of NH4Cl
(4 mL), and the aqueous layer was extracted with EtOAc (3 ×
20 mL). The combined organic layers were washed with a
saturated solution of NaCl (10 mL), dried (Na2SO4), filtered,
and evaporated under reduce pressure. The residue was
purified by silica gel column chromatography with hexane
containing EtOAc (20-40%) to yield 14 as colorless oil (114
mg, 81%) and its minor epimer. For 14: [R]D +28.6 (c ) 1.33,
CHCl3); 1H NMR (CDCl3) δ 0.68 (1H, dd, J ) 5.7, 8.6 Hz), 0.77
(1H, dd, J ) 4.2, 5.7 Hz), 1.07 (9H, s), 1.44 (1H, m), 2.05 (1H,
dd, J ) 8.2, 12.4 Hz), 2.14-2.23 (3H, m), 2.40 (1H, ddd, J )
5.5, 8.0, 12.8 Hz), 2.69 (1H, m), 3.02 (1H, m), 3.38 (1H, m),
4.04 (1H, dd, J ) 2.9, 10.2 Hz), 4.34 (1H, dd, J ) 5.6, 10.2
Hz), 5.04 (2H, m), 5.79 (1H, m), 7.35-7.45 (6H, m), 7.65-7.72
(4H, m); 13C NMR (CDCl3) δ 15.6, 16.2, 19.4, 26.5, 26.9, 31.2,
34.7, 35.5, 46.8, 52.1, 54.3, 61.3, 116.4, 127.6, 127.8, 129.6,
133.4, 133.6, 135.6, 135.7, 136.0, 172.0; IR (cm-1) 3079, 2931,
To a solution of crude amine (76.2 mg, 0.174 mmol) in a
mixture of THF and water (3.0 mL, 2:1) was added a 1 M LiOH
solution (0.348 mL, 0.348 mmol) dropwise at 0 °C. The reaction
mixture was stirred for 12 h at room temperature and acidified
with a 2% HCl solution (pH <6), and the aqueous layer was
extracted with EtOAc (3 × 5 mL). The combined organic layer
were dried (Na2SO4) and filtered, and solvent was evaporated
to yield the carboxylic acid, which was dissolved (73.6 mg,
0.174 mmol) in CH2Cl2 (3.5 mL). Diisopropylethylamine (0.16
g, 0.22 mL, 1.22 mmol) was added followed by bis(2-oxo-3-
oxazolidinyl)phosphinic chloride (BOP-Cl) (66.0 mg, 0.261
mmol) at -10 °C. The reaction mixture was then left to slowly
warm to room temperature. After 24 h the reaction mixture
was poured into saturated NaHCO3 (5 mL) and diluted with
EtOAc (50 mL). The organic layer was washed with a 1 M HCl
solution (5 mL) and brine (5 mL) and dried (Na2SO4). The
residue was purified by silica gel flash chromatography with
hexane containing EtOAc (25-45%) to yield 13 as a colorless
solid (44.8 mg, 64% for 4 steps): mp 93-94 °C; [R]D +38.8 (c
1
) 0.77, CHCl3); H NMR (CDCl3) δ 0.68 (1H, dd, J ) 5.8, 8.4
Hz), 0.80 (1H, dd, J ) 4.2, 5.8 Hz), 1.06 (9H, s), 1.45 (1H, m),
1.96 (1H, ddd, J ) 1.4, 9.2, 12.6 Hz), 2.21 (1H, dd, J ) 8.0,
12.8 Hz), 2.38-2.62 (3H, m), 2.88 (1H, m), 3.37 (1H, m), 4.06
(1H, dd, J ) 2.9, 10.2 Hz), 4.32 (1H, dd, J ) 5.7, 10.2 Hz),
7.36-7.44 (6H, m), 7.63-7.72 (4H, m); 13C NMR (CDCl3) δ
15.8, 16.5, 19.3, 24.4, 26.8, 35.0, 36.3, 54.3, 61.3, 127.6, 129.6,
133.4, 133.7, 135.6, 135.7, 171.3; IR (cm-1) 3053, 2931, 1691,
1462, 1410, 1112; [M + 1] 406; HRMS, found 406.2193; C25H32
NO2Si requires 406.2202.
-
(2R,4R,5S)-4â-Meth a n o-h exa h yd r op yr r olizid in -8-on e-
2-ca r boxylic Acid (5). To a solution of 13 (62.5 mg, 0.153
mmol) in THF (1.5 mL) was added TBAF (0.38 mL, 0.38 mmol)
dropwise at room temperature. The reaction mixture was
stirred for 12 h at room temperature, the solvent was evapo-
rated, and the residue was purified by silica gel flash chro-
matography with hexane containing EtOAc (80%) to yield the
alcohol as a colorless oil (24.6 mg, 95%): [R]D -81.8 (c ) 1.23,
CHCl3); 1H NMR (CDCl3) δ 0.68 (1H, dd, J ) 6.4, 8.7 Hz), 0.95
(1H, dd, J ) 4.2, 6.4 Hz), 1.42 (1H, dd, J ) 4.2, 4.4 Hz), 1.77
(1H, symmetrical m), 2.02-2.10 (2H, m), 2.45 (1H, dt, J ) 10.1,
12.8 Hz), 2.66 (1H, ddd, J ) 2.2, 10.1, 16.9 Hz), 2.92 (1H, ddt,
J ) 1.6, 9.9, 16.9 Hz), 3.33 (1H, m), 3.65-3.72 (2H, m), 5.04
(1H, br s); 13C NMR (CDCl3) δ 13.7, 16.5, 23.8, 32.6, 35.4, 53.6,
56.8, 62.9, 172.3; IR (cm-1) 3284, 2934, 1659, 1467, 1418, 1057;
[M + 1] 168; HRMS, found 168.1030; C9H14NO2 requires
168.1024.
To a solution of oxalyl chloride (2 M, 0.35 mL, 0.70 mmol)
in CH2Cl2 (1.0 mL) was added DMSO (0.11 g, 0.10 mL, 1.42
mmol) dropwise at -60 °C. After 20 min, a solution of the
above alcohol (29.7 mg, 0.178 mmol) in CH2Cl2 (1.0 mL) was
added dropwise at -60 °C. The reaction was stirred at -60
°C for 1 h, diisopropylethylamine (0.230 g, 0.31 mL, 1.78 mmol)
was added, and the reaction kept below -50 °C for 30 min
and then slowly warmed to -10 °C over 1 h. The reaction
mixture was quenched with a saturated solution of NH4Cl (5
mL), and the aqueous layer was extracted with EtOAc (3 ×
10 mL). The combined organic layers were washed with NH4-
Cl (2 × 5 mL) and NaCl (7 mL), then dried (Na2SO4), and
filtered, and the solvent was evaporated under reduced pres-
sure.
2857, 1689, 1113; [M + 1] 446; HRMS, found 468.2358; C28H35
NNaO2Si requires 468.2335.
-
For epi-14 (minor isomer): [R]D +35.4 (c ) 0.35, CHCl3); 1H
NMR (CDCl3) δ 0.65 (1H, dd, J ) 6.2, 8.6 Hz), 0.79 (1H, dd, J
) 4.2, 5.8 Hz), 1.06 (9H, s), 1.43 (1H, m), 1.79 (1H, dd, J )
2.0, 12.9 Hz), 2.19 (1H, dd, J ) 8.0, 12.7 Hz), 2.34-2.44 (2H,
m), 2.52-2.60 (2H, m), 2.78 (1H, m), 3.37 (1H, m), 4.05 (1H,
dd, J ) 2.8, 10.2 Hz), 4.36 (1H, dd, J ) 5.7, 10.2 Hz), 5.05-
5.12 (2H, m), 5.82 (1H, m), 7.32-7.44 (6H, m), 7.64-7.73 (4H,
m); [M + 1] 446; HRMS, found 468.2359; C28H35NNaO2Si
requires 468.2335.
(3S,5R,6R,8R)-8-ter t-Bu t yld ip h en ylsilyloxym et h yl-3-
p r op yl-5â-m eth a n o-h exa h yd r op yr r olizid in -2-on e (15). To
a solution of the 14 (76 mg, 0.171 mmol) in EtOH (5.0 mL)
was added 10% Pd on carbon (10 mg), and the suspension was
stirred under a H2 for 2 h at room temperature. The suspension
was filtered through a sintered glass funnel containing Celite
and washed with EtOAc (2 × 5 mL), the filtrate was concen-
trated under reduced pressure, and the residue was purified
by silica gel column chromatography with hexane containing
EtOAc (10-20%) to yield 15 as a colorless oil (72.2 mg, 95%):
[R]D +39.6 (c ) 1.64, CHCl3); 1H NMR (CDCl3) δ 0.67 (1H, dd,
J ) 5.8, 8.5 Hz), 0.77 (1H, dd, J ) 4.2, 5.7 Hz), 0.92 (3H, t, J
) 7.2 Hz), 1.06 (9H, s), 1.27-1.45 (4H, m), 1.91-1.96 (1H, m),
2.05-2.16 (2H, m), 2.20 (1H, dd, J ) 8.0, 12.8 Hz), 2.38 (1H,
m), 2.91 (1H, m), 3.38 (1H, m), 4.07 (1H, dd, J ) 2.9, 10.2 Hz),
4.29 (1H, dd, J ) 5.8, 10.2 Hz), 7.35-7.44 (6H, m), 7.64-7.70
(4H, m); 13C NMR (CDCl3) δ 14.2, 15.8, 16.3, 19.6, 20.7, 27.1,
32.0, 33.6, 35.0, 47.5, 52.4, 54.3, 61.7, 127.8, 129.77, 129.79,
133.6, 133.9, 135.8, 135.9, 173.1; IR (cm-1) 2957, 2858, 1690,

Carbapenem Mimics
J . Org. Chem., Vol. 67, No. 10, 2002 3393
1462, 1409, 1113; [M + 1] 448; HRMS, found 470.2498, C28H37
-
sintered-glass funnel containing Celite, and the filtrate was
removed under reduced pressure to yield 18 as a colorless oil
(1.44 g, essentially quantitative): [R]D +40.9 (c ) 1.03, CHCl3);
1H NMR (CDCl3) δ 0.55 (1H, t, J ) 5.0 Hz), 0.92 (1H, dd, J )
5.4, 8.4 Hz), 1.06 (9H, s), 1.30 (1H, m), 1.41 (9H, s), 1.45-1.55
(1H, m), 1.95 (1H, m), 2.17-2.25 (2H, m), 2.34 (1H, ddd, J )
5.6, 9.8, 15.7 Hz), 2.67 (1H, m), 3.50 (1H, m), 3.50 (1H, m),
3.57 (3H, s), 3.77 (1H, dd, J ) 4.8, 9.5 Hz), 3.97 (1H, br s),
7.36-7.45 (6H, m), 7.65-7.69 (4H, m); 13C NMR (CDCl3) δ
19.1, 23.8, 24.4, 26.8, 28.3, 28.8, 30.4, 21.0, 47.7, 51.3, 63.8,
65.4, 79.5, 127.5, 129.5, 133.5, 133.6, 135.5, 156.5, 173.8; [M
+ 1] 538; HRMS, found 538.2976; C31H43NO5Si requires
538.2989.
NNaO2Si requires 470.2491.
(3S,5R,6R,8R)-8-Hyd r oxym eth yl-3-p r op yl-5â-m eth a n o-
tetr a h yd r op yr r olizid in -2-on e (16). To a solution of 15 (82
mg, 0.184 mmol) in THF (3.0 mL) was added dropwise n-BuLi
(0.227M in hexanes, 1.05 mL, 0.239 mmol) at -78 °C. The
solution was stirred for 1 h at -78 °C, and then a solution of
PhSeBr (0.122 g, 0.515 mmol) in THF (1.0 mL) was added.
The reaction mixture was stirred for 1.5 h at -78 °C, quenched
with a saturated solution of NH4Cl (5 mL), and warmed to
room temperature, and the aqueous layer was extracted with
EtOAc (3 × 15 mL). The combined organic layers were washed
with a saturated solution of NaCl (5 mL), dried (Na2SO4), and
concentrated under reduced pressure. The resulting residue
was purified by silica gel column chromatography with hexane
containing EtOAc (10%) to yield selenide.
To a solution of the above product in CH2Cl2 (5.0 mL) was
added pyridine (36 mg, 0.037 mL, 0.46 mmol) followed by a
solution of 30% H2O2 (0.189 g, 0.166 mmol) in H2O (0.4 mL)
at 0 °C. After 2 h at 0 °C, the reaction mixture was warmed to
room temperature and stirred for a further 3 h and diluted
with CH2Cl2 (25 mL), and a saturated solution of NaHCO3 (15
mL) was added. The aqueous layer was extracted with CH2-
Cl2 (2 × 15 mL), and the combined organic layers were washed
with a saturated solution of NaCl (7 mL), then dried (Na2SO4),
and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with hexane
containing EtOAc (10-20%) to yield the product (60% for 2
steps) as a 10:1 mixture of double bond isomers.
To a solution of unsaturated lactam (50 mg, 0.11 mmol) in
THF (1.0 mL) was added TBAF (1 M in THF, 0.312 mL, 0.313
mmol) at 0 °C. The reaction mixture was stirred at room
temperature for 4 h, the solvent was removed under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography with hexane containing EtOAc (20-
40%) to yield alcohol 16 as a colorless oil (21.5 mg, 97%): [R]D
-211.8 (c ) 0.89, CHCl3); 1H NMR (CDCl3) δ 0.97 (3H, t, J )
7.3 Hz), 1.38 (1H, m), 1.47 (1H, dd, J ) 4.8, 6.1 Hz), 1.58 (2H,
m), 1.99-2.06 (2H, m), 2.23-2.32 (3H, m), 3.67-3.78 (3H, m),
4.75 (1H, br s, OH), 6.60 (1H, t, J ) 1.5 Hz); 13C NMR (CDCl3)
δ 13.7, 16.1, 20.6, 20.9, 28.0, 35.0, 56.8, 62.8 (2), 138.1, 140.6,
171.1; IR (cm-1) 3284, 2957, 2970, 1648, 1458, 1378, 1055; [M
+ 1] 208; HRMS, found 208.1344; C12H17NO2 requires 208.1337.
(5S,6R,8R)-3-P r op yl-5â-m eth a n o-tetr a h yd r op yr r olizi-
d in -3-en -2-on e-8-ca r boxylic a cid (17). To a solution of
oxalyl chloride (27 mg, 19 µL, 0.214 mmol) in CH2Cl2 (0.5 mL)
was added a solution of DMSO (34 mg, 30 µL, 0.429 mmol) in
CH2Cl2 (0.50 mL) at -60 °C. After 10 min, a solution of alcohol
16 (8.9 mg, 0.0429 mmol) in CH2Cl2 (1.0 mL) was added
dropwise at -60 °C. After 45 min at this temperature,
diisopropylethylamine (67 mg, 90 µL, 0.515 mmol) was added,
and the reaction mixture was warmed to -20 °C, stirred for
45 min, and then slowly warmed to 0 °C over 45 min. The
reaction mixture was processed as described above.
(2R,3R,5R)-5-ter t-Bu tyldiph en ylsilyloxym eth yl-2-[(2′R)-
h yd r oxy-2′-m et h oxyca r b on ylet h yl]-2â-m et h a n o-1-ter t-
bu tyloxyca r bon ylp yr r olid in e (19). To a solution 18 (0.10
g, 0.188 mmol) in THF (2.0 mL) was added KHMDS (0.5 M in
toluene, 0.49 mL, 0.244 mmol) dropwise at -78 °C, and the
solution was stirred for 45 min. To this a solution of Davis
reagent (64 mg, 0.244 mmol) in THF (2 mL) was added
dropwise. The reaction mixture was stirred at -78 °C for 90
min, quenched with a saturated solution of NH4Cl (2 mL), and
then warmed to room temperature, and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with NH4Cl (2 × 10 mL) and NaCl (10
mL), then dried (Na2SO4), filtered, and evaporated under
reduce pressure. The resulting residue was purified by silica
gel flash chromatography with hexane containing EtOAc (15-
25%) to yield 19 as a colorless oil (91 mg, 87%, mixture of two
isomers > 10:1). For 19 (major isomer): [R]D +61.5 (c ) 1.09,
CHCl3); 1H NMR (CDCl3) δ 0.66 (1H, t, J ) 5.0 Hz), 0.87 (1H,
m), 1.07 (9H, s), 1.20 (1H, m), 1.35-1.45 (1H, m), 1.40 (9H, s),
1.91 (1H, ddd, J ) 1.5, 8.1, 13.4 Hz), 1.97 (1H, br s), 2.23 (2H,
m), 3.59 (1H, dd, J ) 7.7, 9.8 Hz), 3.69 (3H, s), 3.71 (1H, dd,
J ) 5.2, 9.8 Hz), 4.06 (1H, m), 4.36 (1H, dd, J ) 3.5, 9.2 Hz),
7.36-7.47 (6H, m), 7.65-7.72 (4H, m); 13C NMR (CDCl3) δ
19.2, 23.3, 26.8, 28.2, 30.5, 39.8, 45.2, 52.0, 65.4, 69.5, 80.3,
127.6, 129.5, 129.6, 133.4, 133.4, 135.5, 157.5, 174.2; [M + 1]
554; HRMS, found 554.2959; C31H44NO6Si requires 544.2938.
(3R,5R,6R,8R)-8-ter t-Bu t yld ip h en ylsilyloxym et h yl-3-
h yd r oxy-5â-m eth a n o-h exa h yd r op yr r olizid in -2-on e (20).
To a solution of 19 (0.99 g, 1.78 mmol) in CH2Cl2 (35 mL) was
added trifluoroacetic acid (5.18 g, 3.5 mL, 45.4 mmol) dropwise
at 0 °C. After 2.5 h at this temperature, the reaction mixture
was quenched with a saturated solution of NaHCO3 (20 mL),
and the resulting solution was stirred vigorously for 10 min.
EtOAc (150 mL) was added, and the organic layer was washed
with a saturated solution of NaHCO3 (20 mL) and a saturated
solution of NaCl (20 mL) and dried (Na2SO4). Filtration and
concentration gave a pale yellow residue, which was dissolved
in a mixture of THF and H2O (27 mL, 2:1) and treated with a
1 M LiOH solution (3.20 mL, 3.20 mmol) at 0 °C. The reaction
mixture was stirred for 16 h at room temperature, acidified
with a 2% HCl solution (pH <6), and diluted with EtOAc (30
mL). The layer was separated, the aqueous layer was extracted
with EtOAc (3 × 30 mL), and combined organic layers were
dried (Na2SO4) and filtered, and solvent was evaporated under
reduce pressure to give the crude amino acid, which was
dissolved in CH3CN (150 mL). DMAP (0.761 g, 6.23 mmol) was
added at 0 °C. After 10 min, HOBt (0.312 g, 2.31 mmol) was
added followed by EDC (0.443 g, 2.31 mmol) at 0 °C. The
reaction mixture was stirred for 48 h at room temperature,
quenched with a saturated solution of NaHCO3 (40 mL), and
diluted with EtOAc (150 mL). The layers were separated, and
the organic layer was washed with NaHCO3 (2 × 20 mL), NH4-
Cl (2 × 20 mL), and NaCl (25 mL), then dried (Na2SO4), and
filtered. The solvent was evaporated, and the resulting residue
was purified by silica gel flash chromatography with hexane
containing EtOAc (45-65%) to yield 20 as a colorless oil (452
To a solution of the above aldehyde in t-BuOH (2.0 mL) was
added 2-methyl-2-butene (30 mg, 45 µL, 0.43 mmol) followed
by a solution the NaClO2 (38 mg, 0.420 mmol) and KH2PO4
(37 mg, 0.62 mmol) in water (1.0 mL) at room temperature.
This reaction mixture was stirred for 12 h at room temperature
and processed as described before. The residue was purified
by silica gel chromatography with EtOAc containing AcOH (0-
1%) to yield 17 as a colorless oil (9.0 mg, 95%): [R]D +14.7 (c
1
) 0.81, CH3OH); H NMR (CDCl3) δ 0.99 (3H, t, J ) 7.4 Hz),
1.51-1.67 (4H, m), 2.21-2.34 (3H, m), 2.77-2.81 (2H, m), 4.41
(1H, dd, J ) 8.4, 9.2 Hz), 6.74 (1H, s), 9.70 (1H, br s, OH); 13
C
NMR (CDCl3) δ 13.8, 17.0, 20.9, 22.0, 27.9, 38.5, 56.3, 58.1,
140.0, 140.2, 170.5, 171.9; IR/(cm-1) 3400-2000, 2961, 1742,
1639, 1383, 1215; [M + 1] 222; HRMS, found 222.1353; C12H15
-
NO3 requires 222.1357.
1
(2S,3R,5R)-5-ter t-Bu t yld ip h en ylsilyloxym et h yl-2-(2′-
m eth oxyca r bon yleth yl)-2â-m eth a n o-1-ter t-bu tyloxyca r -
bon ylp yr r olid in e (18). To a solution of 12 (1.44 g, 2.68 mmol)
in EtOH (55 mL) was added 10% Pd on carbon (500 mg), and
the suspension was stirred under 1 atm of H2 at room
temperature. After 7 h, the suspension was filtered through a
mg, 60%): [R]D +84.8 (c ) 0.66, CHCl3); H NMR (CDCl3) δ
0.75-0.79 (2H, m), 1.06 (9H, s), 1.50 (1H, m), 2.21 (1H, dd, J
) 8.1, 12.9 Hz), 2.36-2.43 (2H, m), 2.47 (1H, dd, J ) 9.9, 12.0
Hz), 2.95 (1H, br s), 3.40 (1H, symmetrical m), 4.04 (1H, dd, J
) 2.9, 10.3 Hz), 4.32 (1H, dd, J ) 5.6, 10.3 Hz), 4.74 (1H, dd,
J ) 1.2, 7.9 Hz), 7.36-7.45 (6H, m), 7.64-7.71 (4H, m); 13C

3394 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
NMR (CDCl3) δ 15.3, 15.9, 19.2, 26.7, 33.9, 34.8, 49.9, 55.0,
61.2, 74.2, 127.6, 129.6, 133.1, 133.4, 135.5, 135.6, 171.2; IR
(cm-1) 3327, 2931, 2857, 1684, 1427, 1113; [M + 1] 422; HRMS,
found 422.2151; C25H32NO3Si requires 422.2151.
(3R,5R,6R,8R)-3-Hyd r oxy-5â-m eth a n o-h exa h yd r op yr -
r olizid in -2-on e-8-ca r boxylic Acid (23). To a solution of 22
(12.6 mg, 0.053 mmol) in THF (1.0 mL) was added a 1 M LiOH
solution (80 µL, 0.080 mmol) at 0 °C. The reaction mixture
was stirred for 2 h at room temperature and quenched with a
2% HCl solution, and the aqueous layer was extracted with
EtOAc (3 × 5 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure.
The resulting residue was purified by silica gel flash chroma-
tography with EtOAc containing MeOH (0-10%) and acetic
acid (0-5%) to yield the product 23 as a viscous colorless oil
(3R,5R,6R,8R)-8-ter t-Bu t yld ip h en ylsilyloxym et h yl-3-
a cetoxy-5â-m eth a n o-h exa h yd r op yr r olizid in -2-on e (21).
To a solution of alcohol 20 (32 mg, 0.077 mmol) in CH2Cl2 (1.0
mL) was added DMAP (19 mg, 0.153 mmol) followed by acetic
anhydride (15 mg, 14 µL, 0.15 mmol) at 0 °C. This reaction
mixture was stirred for 1.5 h at 0 °C and quenched with a
saturated solution of NH4Cl (2 mL), and the aqueous layer
was extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with a saturated solution of NH4Cl (5 mL)
and a saturated solution of NaCl (5 mL), then dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue
was purified by silica gel flash chromatography with hexane
containing EtOAc (30%) to yield 21 as a colorless oil (29.5 mg,
82%): [R]D +51.1 (c ) 1.35, CHCl3); 1H NMR (CDCl3) δ 0.75-
0.80 (2H, m), 1.07 (9H, s), 1.52 (1H, dt, J ) 5.2, 8.1 Hz), 2.13
(3H, s), 2.23 (1H, dd, J ) 8.1, 12.9 Hz), 2.38 (1H, m), 2.44 (1H,
dd, J ) 9.6, 12.4 Hz), 2.55 (1H, dd, J ) 8.1, 12.4 Hz), 3.43
(1H, m), 4.07 (1H, dd, J ) 2.8, 10.2 Hz), 4.32 (1H, dd, J ) 5.8,
10.2 Hz), 5.72 (1H, m), 7.36-7.45 (6H, m), 7.65-7.71 (4H, m);
13C NMR (CDCl3) δ 15.4, 16.2, 19.2, 20.8, 26.7, 22.1, 34.0, 49.7,
54.9, 61.2, 75.0, 127.6, 129.6, 133.1, 133.5, 135.5, 135.7, 166.5,
170.2; IR (cm-1) 2933, 2858, 1749, 1711, 1428, 1233, 1113, 703;
[M + 1] 464; HRMS, found 464.2245; C27H34NO4Si requires
464.2257.
(3R,5R,6R,8R)-3-Acet oxy-5â-m et h a n o-h exa h yd r op yr -
r olizid in -2-on e-8-ca r boxylic Acid (22). To a solution of 21
(27.0 mg, 0.058 mmol) in CH3CN (3.0 mL) was added HF/
pyridine (0.067 mL) dropwise at 0 °C. The reaction mixture
was stirred for 12 h at room temperature, quenched with a
saturated solution of NaHCO3 (1 mL), and diluted with EtOAc
(25 mL). The organic layer was washed with saturated aqueous
NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL), then
dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified by silica gel flash chroma-
tography with hexane containing EtOAc (60-75%) to yield the
alcohol as a colorless oil (12.0 mg, 92%): [R]D -24.5 (c ) 0.55,
CHCl3); 1H NMR (CDCl3) δ 0.81 (1H, dd, J ) 6.5, 8.8 Hz), 0.97
(1H, dd, J ) 4.4 6.5 Hz), 1.52 (1H, dt, J ) 4.6, 9.1 Hz), 1.84
(1H, dq, J ) 5.0,10.0 Hz), 2.14 (1H, dd, J ) 7.5, 12.8 Hz), 2.18
(3H, s), 2.47 (1H, dd, J ) 9.5,12.7 Hz), 2.62 (1H, dd, J ) 8.5,
12.7 Hz), 3.41 (1H, m), 3.74 (2H, d, J ) 5.5 Hz), 5.78 (1H, m);
13C NMR (CDCl3) δ 13.5, 16.3, 20.8, 31.7, 32.5, 49.2, 57.4, 62.6,
74.7, 167.7, 170.0; IR (cm-1) 3334, 2934, 1746, 1681, 1469,
1427, 1233. [M + 1] 226; HRMS, found 226.10730, C11H16NO4
requires 226.10794.
1
(7.1 mg, 71%): [R]D +48.3 (c ) 0.53, MeOH); H NMR (CD3-
OD) δ 0.72 (1H, dd, J ) 4.6, 5.5 Hz), 0.81 (1H, dd, J ) 5.6, 8.8
Hz), 1.60 (1H, dt, J ) 4.6, 8.8 Hz), 2.33-2.47 (3H, m), 2.52
(1H, dd, J ) 9.9, 11.9 Hz), 3.58 (1H, t, J ) 8.1 Hz), 4.71 (1H,
m); 13C NMR (CD3OD) δ 16.5, 17.7, 24.2, 37.0, 37.5, 51.7, 75.8,
172.8, 180.5; IR (cm-1) 3000-2500, 1696, 1684, 1576, 1418;
[M + Na] 220; HRMS, found 220.0592; C9H11NO4Na requires
220.0585.
(3S,5R,6R,8R)-3-Azid o-8-ter t-b u t yld ip h en ylsilyloxy-
m eth yl-5â-m eth a n o-h yd r oxyp yr r olizid in -2-on e (24). To a
solution of Ph3P (0.140 g, 0.534 mmol) in THF (2.2 mL) was
added DEAD (0.093 g, 0.084 mL, 0.534 mmol) dropwise at 0
°C. After 15 min, the hydroxy lactam 20 (0.045 g, 0.107 mmol)
was added followed by the diphenylphosphoryl azide (0.147 g,
0.115 mL, 0.534 mmol) at 0 °C. The reaction mixture was
stirred for 16 h, quenched with a saturated solution of NH4Cl
(5 mL), and diluted with diethyl ether (50 mL). The organic
layer was washed with H2O (5 mL) and NaCl (5 mL), then
dried (Na2SO4), filtered, and evaporated under reduced pres-
sure. The resulting residue was purified by silica gel column
chromatography with hexane containing EtOAc (10%) to yield
the 24 as a colorless solid (42 mg, 86%): mp 101-102 °C; [R]D
-26.8 (c ) 0.57, CHCl3); 1H NMR (CDCl3) δ 0.77 (1H, dd, J )
6.4, 8.7 Hz), 0.90 (1H, dd, J ) 4.4, 6.2 Hz), 1.06 (9H, s), 1.55
(1H, m), 1.94 (1H, dd, J ) 1.6, 13.9 Hz), 2.20 (1H, dd, J ) 7.9,
12.8 Hz), 2.41 (1H, m), 2.72 (1H, dd, J ) 8.3, 13.9 Hz), 3.44
(1H, m), 4.00 (1H, dd, J ) 2.7, 10.4 Hz), 4.23 (1H, dd, J ) 1.6,
8.3 Hz), 4.40 (1H, dd, J ) 5.3, 10.4 Hz), 7.34-7.45 (6H, m),
7.64-7.70 (4H, m); 13C NMR (CDCl3) δ 15.6, 16.7, 19.2, 26.7,
31.0, 34.3, 52.4, 54.7, 60.4, 65.3, 127.6, 129.6, 133.0, 133.3,
135.4, 135.6, 166.5; IR (cm-1) 2932, 2104, 1702, 1462, 1428,
1113; [M + 1] 447; HRMS, found 447.2220; C25H31N4O2Si
requires 447.2216.
(3S,5R,6R,8R)-3-Azid o-5â-m eth a n o-h exa h yd r op yr r oliz-
id in -2-on e-8-ca r boxylic Acid (25). To a solution of 24 (30
mg, 0.068 mmol) in CH3CN (3.0 mL) was added HF-pyridine
(∼0.070 mL) at 0 °C. The reaction mixture was stirred at 0 °C
for 30 min, warmed to room temperature over 1 h, quenched
with a saturated solution of NaHCO3 (2 mL), and extracted
with EtOAc (3 × 10 mL). The combined organic layers were
dried (Na2SO4), filtered, and evaporated under reduce pres-
sure. The resulting residue was purified by silica gel column
chromatography with hexane containing EtOAc (60-80%) to
yield the alcohol as a colorless solid (13.0 mg, 93%): mp 94-
94.5 °C; [R]D -254.9 (c ) 0.71, CHCl3); 1H NMR (CDCl3) δ 0.78
(1H, dd, J ) 6.8, 8.7 Hz), 1.06 (1H, dd, J ) 4.3, 6.8 Hz), 1.53
(1H, m), 1.81 (1H, ddd, J ) 4.9, 10.1, 15.0 Hz), 2.03 (1H, dd,
J ) 2.0, 14.2 Hz), 2.12 (1H, dd, J ) 7.3, 12.7 Hz), 2.72 (1H,
dd, J ) 8.6, 14.2 Hz), 3.46 (1H, m), 3.70-3.78 (2H, m), 4.36
(1H, dd, J ) 2.0, 8.6 Hz), 5.20 (1H, br s); 13C NMR (CDCl3) δ
To a solution of oxalyl chloride (31 mg, 21 µL, 0.244 mmol)
in CH2Cl2 (0.4 mL) was added DMSO (0.038 g, 0.035 mL, 0.488
mmol) dropwise at -60 °C. After 15 min, a solution of the
above alcohol (11.0 mg, 0.049 mmol) in CH2Cl2 (0.5 mL) was
added dropwise at -60 °C. The reaction mixture was stirred
at this temperature for 1 h, diisopropylethylamine (76 mg, 0.10
mL, 0.586 mmol) was added, and the reaction was kept below
-40 °C for 30 min and then slowly warmed to 0 °C over 1 h.
The reaction mixture was processed as described above to give
an oil.
To the above aldehyde in t-BuOH (1.0 mL) was added
2-methyl-2-butene (34 mg, 52 µL, 0.488 mmol) followed by a
solution of NaClO2 (43 mg, 0.478 mmol) and KH2PO4 (42 mg,
0.312 mmol) in water (0.5 mL) at room temperature. The
reaction mixture was stirred for 12 h at room temperature,
the t-BuOH was evaporated under reduced pressure, and the
residue was acidified using a 2% HCl solution. After usual
workup the resulting residue was purified by silica gel chro-
matography with EtOAc containing AcOH (0-10%) to yield
22 as a pale yellow oil (8.2 mg, 70%): [R]D +43.2 (c ) 0.65,
14.0, 17.0, 30.8, 32.7, 52.1, 57.7, 62.7, 64.9, 168.2; IR (cm-1
)
3371, 3020, 2107, 1678, 1216; [M + 1] 209; HRMS, found
209.1035; C9H13N4O2 requires 209.1038.
To a solution of oxalyl chloride (43 mg, 30 µL, 0.341 mmol)
in CH2Cl2 (1.0 mL) was added a solution DMSO (53 mg, 48
µL, 0.68 mmol) in CH2Cl2 (0.50 mL) at -60 °C. After 20 min,
a solution of the above alcohol (14 mg, 0.062 mmol) in CH2Cl2
(1.0 mL) was added dropwise. The reaction mixture was stirred
at -60 °C for 1 h, diisopropylethylamine (0.105 g, 0.142 mL,
0.817 mmol) was added and kept below -50 °C for 30 min,
and then the reaction was slowly warmed to -10 °C over 1 h.
The reaction was processed as described above.
1
MeOH); H NMR (CDCl3) δ 0.85-0.90 (2H, m), 1.69 (1H, m),
2.18 (3H, s), 2.52-2.67 (4H, m), 3.17 (1H, br s), 3.96 (1H, t, J
) 8.6 Hz), 5.85 (1H, t, J ) 9.0 Hz); 13C NMR (CDCl3) δ 14.7,
15.9, 20.6, 32.6, 35.0, 50.4, 55.3, 74.3, 168.9, 170.1(2); IR (cm-1
)
3700-2000, 1738, 1694, 1232; [M + 1] 240; HRMS, found
240.0879; C11H14NO5 requires 240.0872.
To the above aldehyde in t-BuOH (1 mL) was added
2-methyl-2-butene (48 mg, 72 µL, 0.681 mmol) at room

Carbapenem Mimics
J . Org. Chem., Vol. 67, No. 10, 2002 3395
temperature. A solution of NaClO2 (60 mg, 0.667 mmol) and
KH2PO4 (60 mg, 0.436 mmol) in water (1 mL) was added
followed by a 6 M HCl solution (pH ≈ 2-3) at room temper-
ature. The reaction mixture was stirred for 2 h, t-BuOH was
evaporated under reduced pressure, and the residue was
acidified using a 2% HCl solution. The aqueous layer was
processed as usual. The residue was purified by silica gel
chromatography with EtOAc containing AcOH (0-5%) to yield
acid 25 as a pale yellow oil (9.7 mg, 70%): [R]D -62.7 (c )
0.62, CHCl3); 1H NMR (CDCl3) δ 0.86 (1H, dd J ) 6.2, 8.5 Hz),
0.94 (1H, dd, J ) 4.3, 6.2 Hz), 1.70 (1H, m), 1.96 (1H, d, J )
13.9 Hz), 2.55 (2H, m), 2.88 (1H, dd, J ) 8.0, 13.8 Hz), 3.91
(1H, m), 4.45 (1H, d, J ) 8.0 Hz), 8.85 (1H, br s); 13C NMR
(CDCl3) δ 15.6, 16.6, 30.8, 35.9, 53.1, 54.7, 64.9, 167.9, 170.5;
IR (cm-1) 3700-2000, 2107, 1739, 1699, 1317, 1230; [M + 1]
223; HRMS, found 223.0828; C9H11N4O3 requires 223.0831.
(3S,5R,6R,8R)-8-ter t-Bu t yld ip h en ylsilyloxym et h yl-3-
p h en yla ceta m id e-5â-m eth a n o-h exa h yd r op yr r olizid in -2-
on e (26). To a solution of 24 (74 mg, 0.165 mmol) in EtOH (6
mL) was added NH4OAc (15 mg) followed by 10% Pd/C (35
mg) at room temperature. The suspension was stirred under
1 atm of H2 for 30 min at room temperature. The suspension
was filtered through a sintered-glass funnel containing Celite
and washed with EtOAc, and then the filtrate was washed
with a saturated solution of NaCl, dried (Na2SO4), filtered, and
evaporated under reduced pressure to give amine that was
used without further purification.
To a solution of phenylacetic acid (67 mg, 0.495 mmol) in
CH3CN (1.0 mL) was added EDC (95 mg, 0.495 mmol) followed
by HOBt (67 mg, 0.495 mmol) at 0 °C. After 10 min, a solution
of the above amine in CH3CN (1 mL) was added followed by
DMAP (91 mg, 0.747 mmol) at 0 °C. The reaction mixture was
stirred for 12 h at room temperature and quenched with a
saturated solution of NaHCO3 (10 mL), and the aqueous layer
was extracted with EtOAc (3 × 15 mL). The combined organic
layers were washed with a saturated solution of NaHCO3 (5
mL), dried (Na2SO4), filtered, and evaporated reduced pres-
sure. The resulting residue was purified by silica gel flash
chromatography with hexane containing EtOAc (50%) to yield
26 as a colorless solid (80 mg, 89%): mp 142-143 °C; [R]D
+19.2 (c ) 2.05, CHCl3); 1H NMR (CDCl3) δ 0.59 (1H, dd, J )
6.3, 8.5 Hz), 0.80 (1H, dd, J ) 4.2, 6.3 Hz), 1.04 (9H, s), 1.53
(1H, m), 2.00 (1H, dd, J ) 4.6, 13.8 Hz), 2.12 (1H, dd, J ) 7.6,
12.6 Hz), 2.31 (1H, ddd, J ) 5.2, 8.8, 12.4 Hz), 2.75 (1H, dd, J
) 9.6, 13.8 Hz), 3.32 (1H, m), 3.58 (2H, s), 4.00 (1H, dd, J )
2.8, 10.4 Hz), 4.35 (1H, dd, J ) 5.5, 10.4 Hz), 4.54 (1H, m),
6.53 (1H, d, J ) 5.9 Hz), 7.23-7.44 (11H, m), 7.62-7.69 (4H,
m); 13C NMR (CDCl3) δ 14.3, 17.3, 19.2, 26.7, 31.1, 34.2, 43.3,
51.5, 55.1, 55.9, 60.3, 127.1, 127.6, 128.8, 129.3, 129.6, 133.0,
133.3, 134.6, 135.4, 135.6, 169.3, 171.3; IR (cm-1) 3274, 3068,
2932, 1682, 1541, 1428, 1113; [M + 1] 539; HRMS, found
539.2747; C33H39N2O3Si requires 539.2730.
(3S,5R,6R,8R)-3-P h en ylacetam ide-5â-m eth an o-h exah y-
d r op yr r olizid in -2-on e-8-ca r boxylic a cid (27). To a solution
of 26 (68 mg, 0.126 mmol) in THF (3.0 mL) was added TBAF
(1 M in THF, 0.252 mL, 0.252 mmol) dropwise at 0 °C. The
reaction mixture was stirred for 3 h at room temperature,
quenched with a saturated solution of NaHCO3 (10 mL), and
extracted with EtOAc (3 × 25 mL). The combined organic
layers were dried (Na2SO4), filtered, and evaporated under
reduced pressure. The resulting residue was purified by silica
gel flash chromatography with hexane containing EtOAc (80-
100%) to yield the alcohol as a colorless oil (29 mg, 86%): [R]D
-66.3 (c ) 1.46, CHCl3); 1H NMR (CDCl3) δ 0.63 (1H, dd, J )
7.0, 8.4 Hz), 1.03 (1H, dd, J ) 4.3, 6.7 Hz), 1.52 (1H, dt, J )
4.3, 8.4 Hz), 1.71 (1H, m), 2.01-2.16 (2H, m), 2.74 (1H, dd, J
) 9.8, 14.0 Hz), 3.43 (1H, m), 3.59 (2H, s), 4.11 (2H, d, J ) 7.2
Hz), 4.68 (1H, dt, J ) 5.5, 10.0 Hz), 6.66 (1H, d, J 6), 7.25-
7.37 (5H, m); 13C NMR (CDCl3) δ 12.8, 17.2, 31.0, 32.3, 43.2,
55.16, 55.26, 57.8, 62.2, 127.2, 128.8, 129.2, 134.4, 170.6, 171.3;
IR (cm-1) 3286, 3062, 2936, 1669, 1656, 1540, 1454; [M + 1]
301; HRMS, found 301.1543; C17H21N2O3 requires 301.1552.
To a solution of oxalyl chloride (24 mg, 17 µL, 0.193 mmol) in
CH2Cl2 (0.5 mL) was added a solution of DMSO (30 mg, 27
µL, 0.386 mmol) in CH2Cl2 (0.30 mL) dropwise at -60 °C. After
10 min, a solution of the above alcohol (14.5 mg, 0.048 mmol)
in CH2Cl2 (1.0 mL) was added dropwise at -60 °C. The
reaction was stirred at -60 °C for 1 h, diisopropylethylamine
(62 mg, 84 µL, 0.482 mmol) was added, and the reaction kept
below -45 °C for 45 min and then slowly warmed to -10 °C
over 1 h. The reaction mixture was processed as described
above. The oil was dissolved in t-BuOH (2.0 mL), and 2-methyl-
2-butene (0.068 g, 0.102 mL, 0.964 mmol) was added followed
by a solution of NaClO2 (85.0 mg, 0.945 mmol) and KH2PO4
(84.0 mg, 0.617 mmol) in water (1.2 mL) at room temperature.
The reaction mixture was stirred for 12 h at room temperature
then processed as usual, and the residue was purified by silica
gel chromatography with EtOAc containing AcOH (0-5%) to
yield the 27 as a colorless oil (18 mg, 61%): [R]D +47.7 (c )
1
0.53, CHCl3); H NMR (CDCl3) δ 0.67 (1H, m), 0.90 (1H, m),
1.26 (1H, s), 1.61 (1H, br s), 1.99 (1H, d, J ) 12.9 Hz), 2.39
(2H, br s), 2.74 (1H, t, J ) 11.3 Hz), 3.56 (2H, s), 3.81 (1H, br
s), 3.90-4.40 (1H, br s), 4.56 (1H, s), 7.25-7.45 (5H, m); 13C
NMR (CDCl3) δ 14.7, 17.5, 29.6, 30.3, 35.5, 42.8, 52.1, 55.6,
127.0, 128.6, 129.2, 134.7, 170.1 (2), 171.9; IR (cm-1) 3600-
2500, 3284, 1727, 1690, 1672, 1538, 1218; [M + 1] 315; HRMS,
found 315.13530, C17H19N2O4 requires 315.13449.
(3R,5R,6R,8R)-3-(1-Hydr oxy-1-m eth yl-eth yl)-8-h ydr oxy-
m et h yl-5â-m et h a n o-h exa h yd r op yr r olizid in -2-on e (28).
To a solution of 13 (48 mg, 0.12 mmol) in THF (3 mL) was
added dropwise a 1.3 M solution of sec-butyllithium (0.18 mL,
0.24 mmol) in cyclohexane at -78 °C. The solution was stirred
for 1 h at -78 °C and warmed to -40 °C over a period of 30
min, and then acetone (35 µL, 0.48 mmol) was added at -78
°C. The reaction mixture was stirred for 1 h at -78 °C and
quenched with a saturated solution of NH4Cl (3 mL), and the
aqueous layer was extracted with a EtOAc (3 × 5 mL). The
combined organic layer was dried (Na2SO4) and filtered, and
solvent was evaporated under reduced pressure. The resulting
residue was purified by silica gel flash chromatography with
hexane containing EtOAc (25%) to yield a nonseparable
mixture of tertiary alcohols (40 mg, 71%, 3:2) as a colorless
oil: IR (cm-1) 3430, 2931, 1667, 1471, 1427, 1401, 1172.
To a solution of the above compound (35 mg, 0.076 mmol)
in THF (1.0 mL) was added TBAF (0.23 mL, 0.23 mmol)
dropwise at room temperature. The reaction mixture was
stirred for 3 h at room temperature, the solvent was evapo-
rated, and the resulting residue was purified by silica gel flash
chromatography with hexane containing EtOAc (30% to 50%)
to yield 28 as colorless crystals (10 mg, 59%) and 29 as a
colorless oil (5 mg; 29%). For 28: mp 97-100 °C; [R]D -96.6
1
(c ) 0.50, CHCl3); H NMR (CDCl3) δ 0.69 (1H, dd, J ) 6.4,
8.4 Hz), 0.99 (1H, dd, J ) 4.2, 6.4 Hz), 1.25 (3H, s); 1.29 (3H,
s); 1.52 (m, 1H); 1.79 (m, 1H); 2.08 (1H, dd, J ) 7.2, 12.6 Hz),
2.58 (dd, 1H, J ) 11.0, 13.8 Hz), 2.97 (1H, dd, J ) 4.1, 11.0
Hz), 3.41 (m, 1H); 3.74 (1H, d, J ) 5.8 Hz), 4.11 (2H, br, 2 ×
OH); 13C NMR (CDCl3) δ 13.6, 17.7, 25.1, 26.4, 27.5, 32.4, 51.9,
56.5, 57.6, 62.2, 71.8, 173.9; IR (cm-1) 3402, 2971, 2934, 2867,
1651, 1459, 1332, 1172; [M + 1] 226; HRMS, found 226.1330,
C
12H20NO3 requires 226.1435.
(2R,3S,5R)-5-ter t-Bu tyld ip h en ylsilyloxym eth yl-2-p r o-
p en yl-2r-m et h a n o-1-ter t-b u t yloxyca r b on ylp yr r olid in e
(31). To a solution of 7 (0.75 g, 1.19 mmol) in THF (15 mL)
was added allylmagnesium bromide (1 M in Et2O, 3.00 mL,
3.0 mmol) dropwise over 5 min at -78 °C. The reaction mixture
was stirred at -78 °C for 90 min, quenched with pH 7 buffer
(5 mL), warmed to room temperature, and diluted with EtOAc
(50 mL). The organic layer was washed with H2O (2 × 10 mL),
dried (Na2SO4), and filtered. The solvent was removed under
reduced pressure, and the residual solvent further removed
using a vacuum pump (∼1 h) to give 30, which was used
without further purification. To a solution of the above product
in CH2Cl2 (50 mL) was then added trifluoroacetic acid (0.23
mL, 2.97 mmol) dropwise at 0 °C. The resulting orange-brown
solution was stirred for 10 min and quenched with a saturated
solution of NaHCO3 (15 mL), and the aqueous layer was
extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with NaHCO3 (25 mL) and NaCl (25 mL),
then dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified by silica gel flash chroma-

3396 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
tography with hexane containing EtOAc (5%) to yield the 31
as a colorless oil (0.176 g, 30%): [R]D +23.9 (c ) 3.8, CHCl3);
1H NMR (CDCl3) δ 0.13 (1H, d, J ) 4.5 Hz) 0.73 (1H, t, J )
5.1 Hz), 1.07 (9H, s), 1.30-1.50 (2H, m), 1.41 (9H, s), 1.62 (3H,
dd, J ) 1.5, 6.4 Hz), 1.90 (1H, m), 2.25 (1H, m), 3.64 (1H, d, J
) 6.9 Hz), 3.68 (1H, dd, J ) 4.7, 9.8 Hz), 4.09 (1H, br s), 5.34
(1H, dq, J ) 6.5, 15.3 Hz), 5.54 (1H, d, J ) 15.3 Hz), 7.36-
7.45 (6H, m), 7.64-7.71 (4H, m); 13C NMR (CDCl3) δ 17.4, 19.2,
26.6, 26.7, 28.3, 30.3, 48.7, 64.8, 65.2, 79.1, 122.0, 127.5, 129.5,
131.1, 133.5, 133.6, 135.5, 155.6; [M + 1] 492; HRMS, found
492.2925; C30H42NO3Si requires 492.2934.
(2R,3S,5R)-5-ter t-Bu t yld ip h en ylsilyloxym et h yl-2-(2′-
m eth oxyca r bon ylvin yl)-2r-m eth a n o-1-ter t-bu tyloxyca r -
bon ylp yr r olid in e (32). Through a solution of 31 (90 mg,
0.183 mmol) in CH2Cl2 (5 mL) was bubbled ozone was until a
light blue color persisted at -78 °C. After 10 min, the ozone
was replaced with nitrogen, and bubbling was continued until
the color had dissipated. Me2S (0.13 mL, 1.83 mmol) was
added, and the reaction mixture was left to warm to room
temperature. The solvent and excess Me2S were removed
under reduced pressure, and the reaction residue was purified
by silica gel flash chromatography with hexane containing
EtOAc (15%) to yield the aldehyde as a colorless oil (75 mg,
85%): 1H NMR (CDCl3) δ 0.94-1.07 (1H, m), 1.05 (9H, br s),
1.44 (9H, br s), 2.04-2.15 (3H, m), 2.40 (1H, br s), 3.67 (1H,
dd, J ) 3.1, 10.1 Hz), 3.90 (1H, br s), 4.14 (1H, br s), 7.36-
7.46 (6H, m), 7.64-7.68 (4H, m), 9.84 (1H, s); 13C NMR (CDCl3)
δ 14.1, 19.1, 26.7, 27.6, 28.2, 28.2, 30.1, 33.4, 56.3, 64.7, 65.1,
80.5, 127.6, 129.6, 133.1, 135.3, 135.4, 155.1, 199.8.
J ) 6.7, 16.6 Hz), 2.47 (1H, m), 3.01 (1H, m), 3.50 (1H, m),
3.52 (3H, s), 3.77 (1H, dd, J ) 4.8, 9.4 Hz), 3.92 (1H, m), 4.66
(1H, m), 4.80 (1H, dd, J ) 3.4, 13.2 Hz), 7.35-7.45 (6H, m),
7.63-7.67 (4H, m); 13C NMR (CDCl3) δ 19.1, 22.0, 26.7, 28.1,
30.5, 33.9, 36.9, 37.8, 49.8, 51.6, 63.8, 65.6, 78.9, 90.6, 127.6,
129.6, 133.3, 135.39, 156.9, 171.6; [M + 1] 597; HRMS, found
597.2454; C27H37N2O5Si(M + C5H7O2) requires 597.2471.
(4S,5S,6R,8R)-8-ter t-Bu t yld ip h en ylsilyloxym et h yl-4-
n it r om et h yl-5â-m et h a n o-h exa h yd r op yr r olizid in -2-on e
(35). To a solution of 34 (0.252 g, 0.422 mmol) in a mixture
THF and water (10 mL, 2:1) was added a 1 M LiOH solution
(0.84 mL, 0.84 mmol) at 0 °C. The reaction mixture was stirred
for 16 h at room temperature and acidified with a 2% HCl
solution (pH <6), and the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic layer were dried
(Na2SO4), filtered, and concentrated to give the crude acid
which was used without further purification.
To a solution of the above acid in CH2Cl2 (8.5 mL) was added
trifluoroacetic acid (1.2 g, 0.85 mL, 10 mmol) dropwise at 0
°C. The reaction mixture was stirred at this temperature for
2.5 h, the solvent removed under reduced pressure, and the
remaining TFA was azeotroped using toluene (3 × 5.0 mL) to
give the crude amino acid, which was used directly for
cyclization. To a solution of the amino acid in CH2Cl2 (30 mL)
was added DMAP (0.165 g, 1.35 mmol), followed by HOBt (71
mg, 0.53 mmol) and EDC (100 mg, 0.528 mmol) at 0 °C. The
reaction mixture was stirred for 48 h at room temperature and
quenched with a saturated solution of NaHCO3 (20 mL), and
the aqueous layer was extracted with EtOAc (3 × 25 mL). The
combined organic layers were washed with NaHCO3 (2 × 10
mL) and NH4Cl (20 mL), then dried (Na2SO4), filtered, and
evaporated under reduce pressure. The resulting residue was
purified by silica gel flash chromatography with hexane
containing EtOAc (30-50%) to yield 35 as a pale yellow oil
(133 mg, 68%): [R]D +29.5 (c ) 0.88, CHCl3); 1H NMR (CDCl3)
δ 0.70 (1H, dd, J ) 4.7, 6.4 Hz), 0.80 (1H, dd, J ) 6.4, 9.2 Hz),
1.07 (9H, s), 1.62 (1H, m), 2.23 (1H, dd, J ) 8.1, 12.9 Hz), 2.45
(1H, m), 2.60 (1H, ddd, J ) 1.1, 10.7, 16.3 Hz), 2.79 (1H, dd,
J ) 8.9, 16.3 Hz), 3.38 (1H, m), 3.57 (1H, m), 3.96 (1H, dd, J
) 2.6, 10.3 Hz), 4.36 (2H, m), 4.44 (1H, dd, J ) 5.9, 13.8 Hz),
7.35-7.45 (6H, m), 7.64-7.70 (4H, m); 13C NMR (100 MHz,
CDCl3) δ 12.1, 16.6, 19.6, 27.1, 33.2, 34.5, 40.1, 54.8, 57.1, 61.1,
76.3, 127.89, 127.92, 129.9, 133.4, 133.7, 135.8, 135.9, 168.2;
IR (cm-1) 2932, 1693, 1462, 1428, 1253, 1113; [M + 1] 465;
HRMS, found 465.2199; C26H33N2O4Si requires 465.2209.
(4R,5S,6R,8R)-8-ter t-Bu t yld ip h en ylsilyloxym et h yl-4-
h yd r oxym et h yl-5â-m et h a n o-h exa h yd r op yr r olizid in -2-
on e (36). To a solution of 35 (0.150 g, 0.323 mmol) in MeOH
(5.5 mL) was added NaOMe (0.5M in MeOH, 0.68 mL, 0.34
mmol) dropwise at 0 °C. After 15 min, the reaction mixture
was cooled to -78 °C, and ozone was then passed through the
solution for about 30 min (no obvious change in color). A flow
of N2 was passed through the mixture for several minutes (to
remove excess ozone), and NaBH4 (0.122 g, 3.23 mmol) was
added in several portions over 1 h and slowly warmed to 0 °C.
The reaction mixture was stirred for 30 min at 0 °C and
quenched with a saturated solution of NH4Cl (10 mL), and the
aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic layers were washed with a saturated solu-
tion of NaCl (10 mL), then dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resulting residue
was purified by silica gel flash chromatography with hexane
containing EtOAc (50-95%) to give 36 as a colorless oil (97.6
To the above aldehyde (70 mg, 0.146 mmol) in benzene (5
mL) was added methyl(triphenylphosphoranylidene) acetate
(0.24 g, 0.73 mmol) at room temperature. The reaction mixture
was heated to reflux for 30 h and processed as usual to give
32 (70 mg, 85%) as a mixture of trans- and cis-isomers, which
were easily separable. For trans-32 (major isomer): [R]D -33.5
1
(c ) 1.9, CHCl3); H NMR (CDCl3) δ 1.05 (9H, s), 1.05-1.09
(1H, m), 1.41 (9H, s), 1.56 (1H, m), 1.77 (1H, m), 1.90 (1H, m),
2.25 (1H, m), 3.60 (1H, m), 3.66 (1H, m), 3.68 (3H, s), 4.15
(1H, br s), 5.79 (1H, d, J ) 15.5 Hz), 6.78 (1H, d, J ) 15.5 Hz),
7.34-7.44 (6H, m), 7.64-7.68 (4H, m); 13C NMR (CDCl3) δ
19.1, 26.7, 28.2, 29.9, 49.2, 51.1, 65.1, 79.9, 116.4, 127.5, 129.5,
133.3, 135.4, 150.3, 155.2, 166.9; [M + 1] 536; HRMS, found
536.2851; C31H41NO5Si requires 536.2832.
(5R,6S,8R)-8-ter t-Bu tyldiph en ylsilyloxym eth yl-5r-m eth -
a n o-h exa h yd r op yr r olizid in -2-on e (33). A quantity of 32 (60
mg, 0.11 mmol) was subjected to the four-step sequence as
described for the preparation of 13, to give 33 as a viscous oil
1
(24.0 mg, 64%): [R]D +2.0 (c ) 0.8, CHCl3); H NMR (CDCl3)
δ 0.68 (1H, dd, J ) 5.8, 8.6 Hz), 0.78 (1H, dd, J ) 4.2, 5.7 Hz),
1.05 (9H, s), 1.44 (1H, m), 1.95 (1H, ddd, J ) 1.3, 8.8, 12.0
Hz), 2.19 (1H, dd, J ) 8.0, 12.8 Hz), 2.41-2.59 (3H, m), 2.86
(1H, m), 3.38 (1H, m), 4.04 (1H, dd, J ) 2.8, 10.2 Hz), 4.30
(1H, dd, J ) 5.6, 10.2 Hz), 7.36-7.44 (6H, m), 7.65-7.71 (4H,
m); 13C NMR (CDCl3) δ 15.7, 16.4, 19.2, 24.2, 26.6, 34.8, 36.1,
54.2, 61.1, 127.5, 129.5, 133.4, 133.7, 135.4, 135.6, 171.2; IR
(cm-1) 2932, 1692, 1460, 1428, 1113; [M + 1] 406; HRMS, found
406.2193; C25H32NO2Si requires 406.2202.
(2S,3R,5R)-5-ter t-Bu t yld ip h en ylsilyloxym et h yl-2-[2′-
m eth oxyca r bon yl-(1′S)-n itr om eth yleth yl]-2â-m eth a n o-1-
ter t-bu tyloxyca r bon ylp yr r olid in e (34). To a solution of 12
(0.28 g, 0.523 mmol) in acetonitrile (2.0 mL) was added
nitromethane (0.32 g, 0.28 mL, 5.2 mmol) dropwise, followed
by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.80 g, 0.78 mL,
5.2 mmol) at room temperature. The resulting yellow-orange
reaction mixture was stirred for 36 h at room temperature,
then diluted with EtOAc (30 mL), and washed with saturated
aqueous NH4Cl (2 × 5 mL) and saturated aqueous NaCl (10
mL). The organic layer was dried (Na2SO4), filtered, and
evaporated under reduced pressure. The resulting residue was
purified by silica gel flash chromatography with hexane
containing EtOAc (12%) to yield 34 as a pale yellow oil (0.29
g, 92%, ratio >20:1 by 1H NMR): [R]D +26.2 (c ) 1.19, CHCl3);
1H NMR (400 MHz, CDCl3) δ 0.62 (1H, t, J ) 5.9 Hz), 1.05
(9H, s), 1.11 (1H, dd, J ) 5.9, 9.0 Hz), 1.38 (9H, s), 1.57 (1H,
m), 2.08 (1H, dd, J ) 9.0, 13.3 Hz), 2.23 (1H, m), 2.37 (1H, dd,
1
mg, 70%): [R]D +16.1 (c ) 1.50, CHCl3); H NMR (CDCl3) δ
0.63 (1H, m), 0.99 (1H, dd, J ) 5.8, 8.9 Hz), 1.06 (9H, s), 1.48
(1H, dt, J ) 4.7, 8.9 Hz), 1.95-2.25 (1H, br s, OH), 2.22 (1H,
dd, J ) 8.0, 12.8 Hz), 2.42 (1H, ddd, J ) 5.6, 8.2, 12.8 Hz),
2.62 (2H, m), 2.94 (1H, m), 3.35 (1H, m), 3.52-3.67 (2H, m),
4.02 (1H, dd, J ) 2.8, 10.2 Hz), 4.33 (1H, dd, J ) 5.5, 10.2
Hz), 7.32-7.44 (6H, m), 7.65-7.73 (4H, m); 13C NMR (CDCl3)
δ 11.7, 16.5, 19.5, 27.0, 34.8, 37.3, 39.4, 54.5, 57.2, 61.3, 63.5,
127.85, 127.87, 129.9, 133.5, 133.8, 135.8, 135.9, 170.3; IR
(cm-1) 3378, 3070, 2930, 2856, 1667, 1462, 1427, 1113, 702;
[M + 1] 436; HRMS, found 435.2298; C26H33NO3Si requires
465.2289.

Carbapenem Mimics
J . Org. Chem., Vol. 67, No. 10, 2002 3397
(4R,5S,6R,8R)-4-p-Br om oben zen esu lfon ica cid Meth yl
E st er -8-ter t-b u t yld ip h en ylsilyloxym et h yl-5â-m et h a n o-
h exa h yd r op yr r olizid in -2-on e (37). To a solution of 36 (15
mg, 0.034 mmol) in pyridine (0.5 mL) was added p-bromoben-
zenesulfonyl chloride (22 mg, 0.086 mmol) at 0 °C. The reaction
mixture was stirred for 48 h at room temperature and
quenched with a 2% HCl solution (2 mL), and the aqueous
layer was extracted with EtOAc (3 × 5 mL). The combined
organic layers were dried (Na2SO4), filtered, and evaporated
under reduced pressure. The resulting residue was purified
by silica gel column chromatography with hexane containing
EtOAc (20%) to give 37 as a colorless oil (10.6 mg, 48%): [R]D
To a solution of the above product in THF (2.0 mL) was
added LiBr (30 mg, 0.342 mmol) at room temperature. The
reaction mixture was heated to reflux for 8 h and quenched
with a saturated solution of NaHCO3 (5 mL), and the aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were dried (Na2SO4), filtered, and evaporated
under reduced pressure. The resulting residue was purified
by silica gel column chromatography with hexane containing
EtOAc (50%) to give 38 as a pale yellow oil (15.5 mg, 91%):
1
[R]D +34.0 (c ) 0.6, CHCl3); H NMR (CDCl3) δ 0.64 (1H, dd,
J ) 4.5, 6.1 Hz), 1.06 (9H, s), 1.08 (1H, m), 1.63 (1H, dt, J )
4.8, 9.3 Hz), 2.24 (1H, dd, J ) 8.0, 12.8 Hz), 2.44 (1H, ddd, J
) 5.4, 8.0, 12.8 Hz), 2.59 (1H, ddd, J ) 1.4, 10.4, 16.4 Hz),
2.75 (1H, dd, J ) 8.0, 16.4 Hz), 3.16-3.27 (2H, m), 3.36-3.42
(2H, m), 3.98 (1H, dd, J ) 2.7, 10.2 Hz), 4.33 (1H, dd, J ) 5.3,
10.2 Hz), 7.36-7.45 (6H, m), 7.64-7.71 (4H, m); 13C NMR
(CDCl3) δ 11.5, 16.5, 19.6, 27.0, 32.8, 34.7, 37.7, 42.6, 54.5,
58.0, 61.3, 127.9, 129.9, 133.4, 133.8, 135.8, 135.9, 168.9; IR
(cm-1) 2931, 2856, 1693, 1460, 1427, 1113; [M + 1,79Br] 498;
HRMS, found 498.3398; C26H32NO2SiBr requires 498.3489.
1
+9.5 (c ) 0.8, CHCl3); H NMR (CDCl3) δ 0.62 (1H, dd, J )
4.6, 6.2 Hz), 0.83 (1H, dd, J ) 6.2, 9.1 Hz), 1.04 (9H, s), 1.50
(1H, dt, J ) 4.6, 9.1 Hz), 2.20 (1H, dd, J ) 8.0, 12.9 Hz), 2.37-
2.51 (2H, m), 2.63 (1H, dd, J ) 8.9, 16.4 Hz), 3.11 (1H, m),
3.33 (1H, m), 3.93-4.05 (3H, m), 4.33 (1H, dd, J ) 5.2, 10.3
Hz), 7.36-7.45 (6H, m), 7.63-7.78 (8H, m); 13C NMR (CDCl3)
δ 11.9, 16.4, 19.5, 27.0, 34.4, 34.5, 39.0, 54.6, 56.7, 61.0, 70.5,
127.8, 127.9, 129.5, 129.7, 129.9, 133.0, 133.4, 133.7, 134.7,
135.8, 135.9, 168.7; IR (cm-1) 2931, 1694, 1471, 1367, 1188,
1113; [M + 1,79Br] 654; HRMS, found 654.3356; C32H36NO5-
SSiBr requires 654.3350.
(4R,5S,6R,8R)-4-Br om om eth yl-8-ter t-bu tyld ip h en ylsil-
yloxym et h yl-5â-m et h a n o-h exa h yd r op yr r olizid in -2-on e
(38). To a solution of 36 (15 mg, 0.034 mmol) in CH2Cl2 (0.5
mL) was added triethylamine (17 mg, 23 µL, 0.17 mmol)
followed by methanesulfonyl chloride (10 mg, 0.086 mmol) at
0 °C. The reaction mixture was stirred for 1 h, water (2 mL)
was added, and the aqueous layer was extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The result-
ing residue was used without further purification.
Ack n ow led gm en t. We thank NSERCC for financial
assistance through the Medicinal Chemistry Chair
Program. We thank Dr. B. Ward, Center for Tropical
Diseases, The Montreal General Hospital for the anti-
bacterial assays, and Dr. Roger Levesque, Laval Uni-
versite´ for the â-lactamase inhibition results.
1
Su p p or tin g In for m a tion Ava ila ble: Selected IR and H
and 13C spectra and X-ray structure data. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0111715