Asymmetric synthesis of the carbapenam core from serine

Article abstract of DOI:10.1021/jo026499s

The stereospecific synthesis of the functionalized carbapenam core 16 from the serine-derived trisubstituted pyrrolidine 9 is reported. The synthetic strategy relies on synthesizing an appropriately functionalized pyrrolidine, followed by an intramolecular azetidone formation utilizing a modified Mukiyama reagent. The efficient one-pot conversion of the benzenesulfonamide-protected pyrrolidine 9 to the Cbz-protected pyrrolidine 10 is also reported.

Full text of DOI:10.1021/jo026499s

Asym m etr ic Syn th esis of th e Ca r ba p en a m
Cor e fr om Ser in e
Barry P. Hart,*,1 Sharad K. Verma,1 and
Henry Rapoport†
Department of Chemistry, University of California,
Berkeley, Berkeley, California 94720
barry.hart.b@bayer.com
Received September 30, 2002
Abstr a ct: The stereospecific synthesis of the functionalized
carbapenam core 16 from the serine-derived trisubstituted
pyrrolidine 9 is reported. The synthetic strategy relies on
synthesizing an appropriately functionalized pyrrolidine,
followed by an intramolecular azetidone formation utilizing
a modified Mukiyama reagent. The efficient one-pot conver-
sion of the benzenesulfonamide-protected pyrrolidine 9 to
the Cbz-protected pyrrolidine 10 is also reported.
Since the discovery of penicillin in 1928, â-lactam
antibiotics have remained a class of drugs used for the
treatment of bacterial infections.2 The discovery of thien-
emycin,3 reported in 1976, by a Merck research group4
provided the impetus for an intensive derivitization
program to identify carbapenams having potent, broad
spectrum antibacterial properties. Because of the inac-
cesibility associated with obtaining carbapenams in large
quantity from naturally occurring sources, there has been
a great deal of interest to develop routes to this class of
synthetically challenging compounds. It is remarkable
that commercially utilized carbapenams are still most
efficiently produced from multistep total synthesis, in-
stead of processes such as fermentation or semisynthe-
sis.5 In this note we wish to report an enantioselective
approach to the carbapenam core 6 from the amino acid
F IGURE 1. Serine-derived heterocycles.
F IGURE 2. Approaches to the carbapenam core.
serine 1. Variations of this approach have been described
in previous reports from this laboratory for the enantio-
selective preparation of numerous chiral heterocycles,
including conformationally constrained azabicyclo[2.2.1]-
heptane amino acids 3, tetrasubstituted pyrrolidines 4,
and carbacephems 5 (Figure 1).6
Unlike many approaches to carbapenams that entail
five-membered ring closure of a substituted azetidinone
(such as 7),7 the method reported herein involves closure
of a four-membered ring from a five-membered ring
intermediate,8 such as 8. The primary advantage con-
ferred by four-membered ring closure late in the synthe-
sis is that it allows for reaction conditions that might
otherwise be incompatible with the labile azetidinone
(Figure 2).
A functionalized pyrrolidine intermediate containing
the γ-amino-carboxy terminus as in 8 was envisaged to
be attainable from 9, whose enantioselective preparation
from D-serine has previously been reported from this
laboratory.6a Because of difficulties associated with ben-
zenesulfonamide deprotection later in the synthesis, it
was determined to exchange protecting groups at an
† Dedicated to the memory of Professor Henry Rapoport (1918-
2002).
(1) Present address: Bayer Pharmaceuticals, Department of Chem-
istry, 400 Morgan Lane, West Haven, CT 06516.
(2) (a) Overviews of â-lactam antibiotics: The Chemistry of â-Lac-
tams; Page, M. I., Ed.; Blackie Academic & Professional: New York,
1992. (b) The Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH
Press: New York, 1993. (c) Chemistry and Biology of â-Lactam
Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic Press: New
York, 1982; Vols. 1-3. (d) Samarendra, C. I.; Maiti, N.; Micetich, R.
G.; Daneshtalab, M.; Atchison, K.; Phillips, O. A.; Kunugita, C. J .
Antibiot. 1994, 47, 1030.
(3) Kahan, J . S.; Kahan, F.; Goegelman, R.; Currie, S. A.; J ackson,
M.; Stapley, E. O.; Miller, T. W.; Miller, A. K.; Hendlin, D.; Mochales,
S.; Hernandez, S.; Woodruff, H. B.; Birnbaum, J . J . Antibiot. 1979,
32, 1.
(4) (a) Ratcliffe, R. W.; Albers-Schonberg, G. The Chemistry of
Thienamycin and Other Carbapenem Antibiotics. In Chemistry and
Biology of â-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.;
Academic Press: New York, 1982; Vol. 2, p 227. (b) Kametani, T.;
Fukumoto, K.; Ihara, M. Heterocycles 1982, 17, 463. (c) Albers-
Schonberg, G.; Arison, B. H.; Hensens, O. D.; Hirshfield, J .; Hoogsteen,
K.; Kaczka, E. A.; Rhodes, R. E.; Kahan, J . S.; Kahan, F. M.; Ratcliffe,
R. W.; Walton, E.; Ruswinkle, L. J .; Morin, R. B.; Christensen, B. G.
J . Am. Chem. Soc. 1978, 100, 6491.
(5) For a review on the state of carbapenem antibiotics, see: (a)
Coulton, S.; E. Hunt. In Progress in Medicinal Chemistry; Ellis, G. P.,
Luscombe, D. K., Eds.; Elsevier: New York, 1996; Vol. 33, pp 99-
145. (b) Kim, O.; Fung-Tomc, J . Expert Opin. Ther. Pat. 2001, 11, 8.
(c) Bonfiglio, G.; Russo, G.; Nicoletti, G. Expert Opin. Invest. Drugs
2002, 11, 4.
(6) (a) Hart, B. P.; Rapoport, H. J . Org. Chem. 1999, 64, 2050. (b)
Verma, S. K.; Atanes, M. N.; Busto, J . H.; Thai, D. L.; Rapoport, H. J .
Org. Chem. 2002, 67, 1314. (c) Folmer, J . J .; Acero, C.; Thai, D. L.;
Rapoport, H. J . Org. Chem. 1998, 63, 8170.
(7) (a) Berks, A. H. Tetrahedron 1996, 52, 331. (b) Humphrey, G.;
Miller, R. A.; Pye, P. J .; Rossen, K.; Reamer, R. A.; Maliakal, A.; Ceglia,
S. S.; Grabowski, E. J . J .; Volante, R. P.; Reider, P. J . J . Am. Chem.
Soc. 1999, 121, 11261 and references therein.
(8) (a) Tanaka, H.; Sakagami, H.; Ogasawara, K. Tetrahedron Lett.
2002, 43, 93. (b) Miyashita, M.; Chida, N.; Yoshikoshi, A. J . Chem.
Soc., Chem. Commun. 1984, 195.
10.1021/jo026499s CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/26/2002
J . Org. Chem. 2003, 68, 187-190
187

SCHEME 1a
a
Conditions: (a) (1) sodium naphthalenide, DME, -78 °C, (2) 1 M AcOH, warm to rt, (3) EtOAc, K2CO3, CbzCl; (b) HCl, MeOH, rt, 3
h; (c) TBDMSCl, DMF, imidazole, rt, 12 h; (d) AcOH/H2O/THF (13:7:3), rt, 24 h; (e) NaIO4, RuCl3‚xH2O, CH3CN/CCl4 (1:1), rt, 3 h; (f)
N,N′-diisopropyl-O-tert-butylisourea, CH2Cl2, tert-butanol, rt, 2 h; (g) H2, Pd/C, MeOH, rt, 2 h; (h) LiOH, 4:1 THF/H2O, rt, 3 h.
SCHEME 2
activity. Conversely, the synthesis of a carbapenam
derived from L-serine would afford the diastereomer,
having S absolute stereochemistry at C-5, and C-2 and
C-3 substituents as a single enantiomer.
We have reported a method for the enantioselective
synthesis of a functionalized carbapenam core from
D-serine-derived pyrrolidines. The methods reported
herein provide an efficient, stereocontrolled route to the
carbapenam core, with substitution at C-2, and C-3.
These methods complement previous efforts of the group
in illustrating the synthetic utility of pyrrolidines derived
from amino acids. This core can be further functionalized
to provide a variety of novel synthetic carbapenems and
their analogues aimed at increasing potency, metabolic
stability, and activity against resistant bacteria.
appropriate point earlier in the synthesis. The criteria
for an alternative protecting group were that it provide
robust enough protection through ensuing reaction condi-
tions and it’s removal conditions be mild enough so as
not to affect other functionality present in the molecule.
The chlorobenzyloxycarbonyl (Cbz) group was found to
be suitable for this purpose. Reductive cleavage of the
sulfonamide bond in 9 via sodium naphthalenide reduc-
tion and reprotection as the Cbz derivative proceeded
smoothly, giving 10 in 70% yield from 9 (Scheme 1).
Compound 10 was treated with HCl in MeOH to afford
its corresponding diol, which was converted to the bis-
silyl ether 11 under standard conditions. Selective depro-
tection of the primary silyl group furnished 12.10 The
primary alcohol of 12 was oxidized to the corresponding
carboxylic acid, and esterification afforded the function-
alized pyrrolidine 13. Deprotection of the Cbz group was
carried out under mild conditions, by way of hydrogena-
tion, affording 14 in excellent yield. Hydrolysis of the
methyl ester in 14 was accomplished with LiOH, from
which the pyrrolidine amino acid 15, the envisaged
carbapenam precursor, was isolated after pH adjustment
and extraction.
Exp er im en ta l Section
Gen er a l. All reactions were conducted under an atmosphere
of nitrogen, and solvents were distilled before use unless
otherwise noted. THF and Et2O were distilled from sodium/
benzophenone; CH3CN was distilled from P2O5 and then from
CaH2; DMF was dried over 4 Å molecular sieves; CH2Cl2 was
distilled from CaH2; EtOAc, hexane, 2-propanol, and chloroform
1
were used as purchased. H and 13C NMR were taken in CDCl3
at room temperature, unless otherwise stated. Chemical shifts
are reported in ppm (δ) in reference to tetramethylsilane (TMS).
Coupling constants are reported in Hertz. Column chromatog-
raphy was performed using EM Science silica gel (230-400
mesh). Melting points were taken in duplicate and are uncor-
rected. Elemental analyses were determined by the Microana-
lytical Laboratories, University of California, Berkeley.
(2R,4R,5R)-4-Hyd r oxy-5-h yd r oxym eth yl-2-m eth oxyca r -
bon ylm eth yl-1-(ben zyloxyca r bon yl)-isop r op ylid en e Keta l-
p yr r olid in e (10). To a -78 °C THF solution of 96a (1.0 g, 2.7
mmol) was added 8 mL of a DME solution of sodium naphtha-
lenide, dropwise via syringe, until the end point was reached
(indicated by persistence of a dark olive green color).9a The
contents were quenched with a 50% solution of 1 M aqueous
AcOH/THF (16 mL) at -78 °C and were allowed to warm to room
temperature with stirring. The homogeneous mixture was then
diluted with EtOAc (24 mL), followed by the addition of K2CO3
(0.94 g, 6.7 mmol) and benzyl chloroformate (0.85 mL, 6.0 mmol).
After stirring at room temperature for 2 h, the contents were
diluted with 1 M KH2PO4 (50 mL). The aqueous layer was
separated and extracted with EtOAc (3 × 100 mL), and the
combined organic layers were dried over MgSO4, filtered, and
concentrated. Chromatography (1:2 EtOAc/hexanes) afforded 693
The intramolecular cyclization of 15, employing a
modified Mukiyama reagent developed in the Rapoport
laboratory,6c afforded carbapenam 16 in 60% yield (Scheme
2). This carbapenam has the desired 5R absolute stereo-
chemistry at the C-5 position, required for antibiotic
(9) Sodium naphthalenide was generated as described by: (a)
Bergmeir, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40, 6181. (b) J i,
S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W. D.;
Wriede, P. J . Am. Chem. Soc. 1967, 89, 5311.
(10) Kawai, A.; Hara, T.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1988, 29, 6331.
188 J . Org. Chem., Vol. 68, No. 1, 2003

1
mg (70%) of 10 as a pale oil: [R]23 -70.5 (c ) 1.0, CHCl3); H
quantitative yield. To the crude carboxylic acid dissolved in
CH2Cl2 (15 mL) were added tert-butyl alcohol (38 g, 0.51 mol)
and N,N′-diisopropyl-O-tert -butylisourea (3 g, 0.015 mol), and
the mixture was stirred at room temperature for 2 h. The
mixture was evaporated, and to the residue was added H2O (50
mL) followed by CHCl3/IPA (4:1, 50 mL). The aqueous phase
was extracted with additional CHCl3/IPA (4:1, 4 × 50 mL), and
the combined organic layers were dried over MgSO4, filtered,
and concentrated. The resulting solid was dissolved in hexanes/
EtOAc (5:1, 10 mL) and filtered. The filtrate was concentrated
and chromatographed (4:1 hexanes/EtOAc) to afford 1.12 g (91%)
D
NMR (400 MHz, rotomers) δ 1.33-1.38 (m, 12H), 1.94 (dd, J )
14.2, 3.1, 2H), 2.10-2.19 (m, 2H), 2.79-2.97 (m, 4H), 3.60 (s,
3H), 3.64 (s, 3H), 3.66-3.69 (m, 1H), 3.79-3.82 (m, 1H), 3.86-
3.90 (m, 1H), 3.97-4.07 (m, 2H), 4.12 (dd, J ) 12.5, 5.4, 1H),
4.36-4.43 (m, 4H), 5.06-5.17 (m, 4H), 7.32-7.34 (m, 10H); 13
C
NMR (100 MHz, rotomers) δ 172.2, 172.1, 155.2, 154.6, 136.5,
136.3, 128.5, 128.2, 128.1, 127.8, 99.2, 98.6, 71.3, 70.3, 67.2, 67.0,
62.3, 61.0, 57.8, 57.6, 55.9, 55.2, 51.5 (2C), 40.0, 39.4, 36.3, 35.5,
26.8, 25.6, 21.9, 20.9. Anal. Calcd for C19H25NO6: C, 62.8; H,
6.9; N, 3.9. Found: C, 62.5; H, 6.9; N, 3.7.
of 13 as a thick, colorless oil: [R]22 +8.65 (c ) 11.7, CHCl3); 1H
(2R,4R,5R)-4-ter t-Bu tyld im eth ylsilyloxy-5-ter t-bu tyld i-
m eth ylsilyloxym eth yl-2-m eth oxyca r bon ylm eth yl-1-(ben -
zyloxyca r bon yl)p yr r olid in e (11). Compound 10 (1.1 g, 3.03
mmol) was dissolved in MeOH (27 mL), and concentrated HCl
(0.8 mL) was added dropwise. After 90 min of stirring at room
temperature, the mixture was concentrated to an oil. Chroma-
tography (1:2 hexanes/EtOAc) afforded 781 mg (80%) of the diol
as an oil. The diol (812 mg, 2.51 mmol) was dissolved in DMF
(14 mL), followed by addition of imidazole (0.98 g, 14.4 mmol)
and tert-butyldimethylsilyl chloride (1.07 g, 7.10 mmol) at room
temperature. The reaction mixture was stirred for 12 h, after
which time saturated aqueous Na2CO3 (1.5 mL) was added. The
mixture was evaporated to dryness, and the residue was
dissolved in CH2Cl2 (25 mL) and H2O (25 mL). The aqueous
phase was separated and extracted with CH2Cl2 (4 × 25 mL),
and the combined organic layers were dried over MgSO4, filtered,
and evaporated. The resulting oil was chromatographed (1:5
EtOAc/hexanes) to give 1.16 g (84%) of 11 as a colorless oil (67%
D
NMR (400 MHz, CDCl3, major rotomer) δ 0.056 (s, 6H), 0.856
(s, 9H), 1.35 (s, 9H), 1.86-1.96 (m, 1H), 2.35-2.41 (m, 1H), 2.69
(dd, J ) 16.3, 10.1, 1H), 3.36 (dd, J ) 16.3, 4.0, 1H), 3.64 (s,
3H), 4.18-4.24 (m, 1H), 4.31 (d, J ) 7.5, 1H), 4.49-4.51 (m,
1H), 5.02-5.17 (m, 2H), 7.27-7.37 (m, 5H); 13C NMR (100 MHz,
CHCl3, rotomers) δ -5.0 (6C), -4.9, -4.8, 18.2, 25.8 (3C), 28.1,
28.2, 38.4, 38.8, 39.5 (2C), 51.4, 53.5, 64.9, 65.7, 66.9, 67.1, 71.4,
71.7, 73.4, 74.9, 81.48, 81.53, 127.7, 127.9, 128.4, 128.5, 128.8,
128.9, 136.4, 136.5, 153.9, 154.4, 168.6, 168.9, 172.3 (2C). Anal.
Calcd for C26H41NO7Si: C, 61.5; H, 8.1; N, 2.8. Found: C, 61.3;
H, 8.2; N, 2.8.
(2S,4R,5R)-3-ter t-Bu tyld im eth ylsilyloxy-5-m eth oxyca r -
bon yl-p r olin e ter t-Bu tyl Ester (14). To a methanolic solution
(20 mL) of 13 (565 mg, 1.11 mmol) was added 20% Pd(OH)2/C
(255 mg), followed by hydrogenation (1 atm) for 3 h. The
heterogeneous mixture was filtered through Celite, and the filter
pad was washed copiously with methanol. The combined filtrate
was concentrated to an oil, which was diluted with methanol (2
mL) and passed through a cotton plug. Concentration followed
by drying on high vacuum gave 410 mg (99%) of 14 as a white
foam: [R]22D -10.0 (c ) 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 0.054 (s, 3H), 0.063 (s, 3H), 0.867 (s, 9H), 1.46 (s, 9H), 1.51-
1.58 (m, 1H), 2.13-2.23 (m, 1H), 2.30-2.40 (bs, 1H), 2.53 (dd, J
) 15.5, 6.9, 1H), 2.67 (dd, J ) 15.5, 7.2, 1H), 3.46-3.51 (m, 1H),
3.58 (d, J ) 5.0, 1H), 3.67 (s, 3H), 4.44 (q, J ) 4.4, 1H); 13C NMR
(100 MHz, CDCl3) δ -4.8, -4.6, 18.0, 25.9 28.2, 41.2, 41.3, 51.6,
53.3, 67.6, 74.3, 81.2, 169.8, 172.3. Anal. Calcd for C18H35NO5-
Si: C, 57.9; H, 9.5; N, 3.8. Found: C, 58.2; H, 9.2; N, 3.6.
(2S,4R,5R)- 5-Acet ic-3-ter t-b u t yld im et h ylsilyloxy-p r o-
lin e ter t-Bu t yl E st er (15). To a THF/H2O solution (4:1, 25
mL) of 14 (667 mg, 1.79 mmol) was added LiOH‚H2O (0.981 g,
23.4 mmol), and the contents were stirred at room temperature
for 3 h. The basic mixture was adjusted to pH ) 5 with 5%
NaH2PO4 (65 mL) and extracted with CHCl3/IPA (3:1, 5 × 75
mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated. After drying on high vaccuum, 566
overall from 10): [R]23 -18.7 (c ) 3.4, CHCl3); 1H NMR (400
D
MHz, C6D6 at 60 °C) δ -0.07 (s, 3H), -0.05 (s, 3H), 0.04 (s, 6H),
0.85 (s, 9H), 0.91 (s, 9H), 1.87-1.93 (m, 1H), 1.98-2.08 (m, 1H),
2.70-2.76 (dd, J ) 9.6, 5.6, 1H), 3.27 (s, 3H), 3.70-3.80 (m, 1H),
3.86-3.88 (m, 1H), 3.92-4.03 (m, 3H), 4.28-4.38 (m, 1H), 5.00-
5.03 (d, J ) 12.4, 1H), 5.01-5.13 (d, J ) 12.4, 1H), 6.99-7.01
(d, J ) 7.6, 1H), 7.05-7.08 (dd, J ) 7.6, 2H), 7.21-7.23 (d, J )
8.0, 2H); 13C NMR (100 MHz, CHCl3, rotomers) δ -5.3, -5.4,
-4.9, -3.7, 18.0, 18.3, 25.7 (3C), 26.0 (3C), 38.5, 39.0, 40.0, 51.2,
53.4, 59.9, 60.4, 62.2, 63.2, 66.7, 70.9 (2C), 127.6, 127.9, 128.4,
136.5, 155.1, 172.2. Anal. Calcd for C28H49NO6Si2: C, 60.9; H,
9.0; N, 2.5. Found: C, 60.9; H, 9.0; N, 2.7.
(2R ,4R ,5R )-4-t er t -Bu t yld im e t h ylsilyloxy-5-h yd r oxy-
m eth yl-2-m eth oxyca r bon ylm eth yl-1-(ben zyloxyca r bon yl)-
p yr r olid in e (12). To a stirring THF solution (7 mL) of 11 (1.16
g, 2.10 mmol) was added a mixture of AcOH/H2O (29 mL:16 mL)
dropwise at room temperature. The initially milky white mixture
was stirred at room temperature for 24 h, after which time it
was clear and homogeneous. The mixture was concentrated to
an oil, which was diluted with EtOAc (50 mL) and washed with
H2O (50 mL). The aqueous layer was separated and extracted
with EtOAc (4 × 50 mL), and the combined organic layers were
dried over MgSO4, filtered, and concentrated. Chromatography
(2:1 hexanes/EtOAc) furnished 570 mg (62%) of 12 as a colorless
oil. (Other products observed in minor amounts include the diol,
which results from deprotection of both silyl groups, and starting
compound 11.) [R]22D -10.4 (c ) 5.2, CHCl3); 1H NMR (400 MHz,
C6D6 at 60 °C) δ 0.20 (s, 6H), 0.77 (s, 9H), 1.67 (m, 1H), 1.85-
1.95 (bs, 1H), 2.61-2.68 (m, 1H), 3.00-3.10 (bs, 1H), 3.24 (s,
3H), 3.80-3.83 (m, 2H), 3.89-3.92 (m, 3H), 4.16-4.23 (m, 1H),
4.98 (q, J ) 11.4, 2H), 6.98 (d, J ) 7.2, 1H), 7.03-7.07 (m, 2H),
7.20 (d, J ) 7.2, 2H); 13C NMR (100 MHz, CHCl3, rotomers) δ
-5.3, -4.7, 17.9, 25.7 (3C), 38.7, 40.1, 51.5, 54.4, 64.0, 65.4, 67.5,
72.9, 128.0, 128.2 (2C), 128.6 (2C), 136.0 (weak), 158.5 (weak),
171.9. Anal. Calcd for C22H35NO6Si: C, 60.4; H, 8.1; N, 3.2.
Found: C, 60.1; H, 8.1; N, 3.2.
mg (88%) of 15 was collected as a colorless foam: [R]22 -53.0
D
(c ) 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.067 (s, 3H),
0.076 (s, 3H), 0.855 (s, 9H), 1.48 (s, 9H), 1.71 (d, J ) 13.5, 2H),
2.38 (d, J ) 13.5, 2H), 2.80-2.86 (m, 1H), 3.85-3.92 (m, 1H),
4.32 (d, J ) 5.2, 1H), 4.66-4.68 (m, 1H), 6.60-6.70 (bs, 1H);
13C NMR (100 MHz, CDCl3) δ -4.8, -4.7, 17.9, 25.8, 28.1, 40.1,
41.9, 55.3, 65.0, 73.5, 83.3, 166.3 (weak), 176.3 (weak). Anal.
Calcd for C17H33NO5Si: C, 56.8; H, 9.3; N, 3.9. Found: C, 56.5;
H, 8.9; N, 3.8.
(2R,3S,7R)-3-ter t-Bu tyl Ester -2-ter t-bu tyld im eth ylsiloxy-
5-oxo-a za bicyclo[3.2.0]h ep ta n e (16). To a solution of 2-chloro-
1-methylpyridinium triflate (2.17 g, 7.90 mmol) and N,N-
diisopropylethylamine (5.20 mL, 29.8 mmol) in CH3CN (475 mL)
was added a CH3CN/CH2Cl2 solution (160 mL:10 mL) of amino
acid 15 (0.835 g, 2.32 mmol), dropwise over 4 h at 65 °C. After
the addition was complete, the solution was heated at 65 °C for
an additional 15 min, allowed to cool to room temperature, and
stirred for 12 h. The solution was diluted with CH2Cl2 (150 mL)
and concentrated to 50% of its original volume. An additional
200 mL of CH2Cl2 was added, and the solution was concentrated
to 100 mL and then partitioned between CH2Cl2 (300 mL) and
H2O (300 mL). The aqueous phase was extracted with CH2Cl2
(3 × 100 mL), and the combined organic layers were dried over
MgSO4, filtered, and concentrated to afford a dark red oil.
Chromatography on silica (4:1 hexanes/EtOAc) gave 0.477 g
(2S,4R,5R)-3-ter t-Bu tyld im eth ylsilyloxy-5-m eth oxyca r -
bon yl-1-ben zyloxyca r bon ylp r olin e ter t-Bu tyl Ester (13). To
a solution of alcohol 12 (1.06 g, 2.42 mmol) in CH3CN (11 mL),
CCl4 (11 mL), and H2O (8.5 mL) were added NaIO4 (1.81 g, 8.5
mmol) and RuCl3‚xH2O (50 mg). The biphasic mixture was
vigorously stirred (magnetically) for 3 h. The phases were
separated, and the aqueous phase was extracted with CHCl3/
IPA (4:1, 4 × 50 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated to a dark foam, in nearly
(60%) of the â-lactam 16 as a white solid: Mp ) 41-42 °C; [R]22
D
J . Org. Chem, Vol. 68, No. 1, 2003 189

+135.0 (c ) 0.01, CHCl3); 1H NMR 0.060 (6H), 0.86 (s, 9H), 1.46
(s, 9H), 2.03-2.15 (m, 2H), 2.89 (dd, J ) 15.6, 2.7, 1H), 3.09
(dd, J ) 15.6, 2.7, 1H), 3.52-3.58 (m, 1H), 3.77 (d, J ) 7.0, 1H),
4.63-4.69 (m, 1H); 13C NMR δ -5.1 (2C), 18.2, 25.7 (3C), 28.0
(3C), 36.7, 43.6, 49.0, 64.7, 79.1, 82.3, 166.3, 172.8. Anal. Calcd
for C17H31NO4Si: C, 59.79; H, 9.15; N, 4.10. Found: C, 59.90; H,
9.01; N, 3.94.
for fellowship support in the form of a National Re-
search Service Award, NIH, DHHS. B.P.H. and S.K.V.
are grateful to Prof. Henry Rapoport for his invaluable
tutelage and support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra and elemental analysis for compounds 10-16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. The authors wish to thank col-
leagues J . Hector Busto, M.N. Atanes, C. Varela, and
Larry Anderson for their input on this project and also
the University of California, Berkeley. S.K.V. is thankful
J O026499S
190 J . Org. Chem., Vol. 68, No. 1, 2003