Formal total syntheses of the β-lactam antibiotics thienamycin and PS-5

Article abstract of DOI:10.1021/jo952092u

Chiral nonracemic acetylenic acids of general structure 11, prepared using the Schreiber modification of the Nicholas reaction, have been converted to β-amino acid derivatives of type 12 by a two-step sequence involving Curtius rearrangement followed by o

Full text of DOI:10.1021/jo952092u

J . Org. Chem. 1996, 61, 2413-2427
2413
F or m a l Tota l Syn th eses of th e â-La cta m An tibiotics Th ien a m ycin
a n d P S-5
Peter A. J acobi,* Shaun Murphree, Frederic Rupprecht, and Wanjun Zheng
Hall-Atwater Laboratories, Wesleyan University, Middletown, Connecticut 06459-0180
Received November 28, 1995X
Chiral nonracemic acetylenic acids of general structure 11, prepared using the Schreiber
modification of the Nicholas reaction, have been converted to â-amino acid derivatives of type 12
by a two-step sequence involving Curtius rearrangement followed by oxidative cleavage of the
acetylenic bond. Amino acid derivatives 12 are excellent precursors for â-lactams of the carbapenem
class, including the important antibiotics thienamycin (1) and PS-5 (4).
In tr od u ction
Thienamycin (1) is a member of the carbapenem class
of antibiotics, which was initially isolated in 1976 from
Streptomyces cattleya,1a and whose structure was deter-
mined by an elegant combination of degradative, spectral,
and X-ray crystallographic studies (Figure 1).1b Interest
in 1 derives from its broad spectrum of antibacterial
activity, which includes excellent response against both
Gram-(+)- and Gram-(-)-bacteria, as well as certain
â-lactamase-producing species. This range of activity is
exceptional among members of the â-lactam family of
antibiotics, whether naturally occurring or semisynthetic.
Imipenem (2), the N-formimidoyl derivative of 1, is
currently marketed in a formulation containing a â-lac-
tamase inhibitor.1c
F igu r e 1.
F igu r e 2.
A variety of related carbapenem-type â-lactam antibi-
otics have been isolated and characterized during the
past 10-15 years, some of which have antibacterial
activity approaching that of 1. These include side-chain
deoxygenated compounds, such as PS-5 (4) and PS-6 (5),2
and members of the olivanic acid class of antibiotics, such
as MM-22381 (6).3 MM-22381 (6) is isolated from Strep-
tomyces olivaceus and differs from thienamycin (1) in
having the S-configuration at C8. In addition, various
synthetic analogs, such as 1â-methylcarbapenem (3),
have attracted considerable attention because of their
increased chemical stability and resistance to dehydro-
peptidase-I (DHP-I).4 The broad spectrum activity of
thienamycin (1) and other potent carbapenem antibiotics,
taken together with their challenging structural features,
has fostered intense and varied synthetic efforts in this
area. These studies are important since 1 cannot be
efficiently produced in culture, and both 1 and 2 are
currently manufactured by total synthesis.5
Most of the reported syntheses of 1 involve as a key
step the preparation of 6-substituted azetidinones of type
7 (X ) leaving group), followed by additional elaboration
at N4 and C5 (carbapenem numbering) (Figure 2).6 This
approach has the advantage of being highly convergent,
and the requisite azetidinones 7 are accessible utilizing
[2 + 2] cycloaddition methodology.6 Alternatively, con-
siderable effort has also been devoted to the synthesis of
(4) (a) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G.
Heterocycles 1984, 21, 29. (b) Hatanaka, M. Tetrahedron Lett. 1987,
28, 83. (c) Udodong, U. E.; Fraser-Reid, B. J . Org. Chem. 1989, 54,
2103. (d) Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S.; Sasaki, A.;
Sunagawa, M. Tetrahedron 1988, 44, 2149 and references cited therein.
Kaga, H.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30, 113.
(e) Rama Rao, A. V.; Gurjar, M. K.; Khare, V. B.; Ashok, B.; Deshmukh,
M. N. Tetrahedron Lett. 1990, 31, 271.
(5) (a) Melillo, D. G.; Cvetovich, R. J .; Ryan, K. M.; Sletzinger, M.
J . Org. Chem. 1986, 51, 1498. (b) Melillo, D. G.; Shinkai, I.; Liu, T.;
Ryan, K.; Sletzinger, M. Tetrahedron Lett. 1980, 21, 2783. (c) Melillo,
D. G.; Liu, T.; Ryan, K.; Sletzinger, M.; Shinkai, I. Tetrahedron Lett.
1981, 22, 913. (d) Liu, T. M. H.; Melillo, D. G.; Ryan, K. M.; Shinkai,
I.; Setzinger, M. U.S. Patent 4,349,687, 1982, Merck & Co.
X Abstract published in Advance ACS Abstracts, March 1, 1996.
(1) (a) Kahan, J . S.; Kahan, F. M.; Stapley, E. O.; Goegelman, R.
T.; Hernandez, S. U.S. Patent 3950357, 1976; Chem. Abstr. 1976, 85,
92190t. See also: Kahan, J . S.; Kahan, F.; Goegelman, R.; Currie, S.
A.; J ackson, M.; Stapely, E. O.; Miller, T. W.; Miller, A. K.; Hendlin,
D.; Mochales, S.; Hernandez, S.; Woodruff, H. B.; Birnbaum, J . J .
Antibiot. 1979, 32, 1. (b) Albers-Scho¨nberg, G.; Arison, B. H.; Hensens,
O. D.; Hirshfield, J .; Hoogsteen, K.; Kaczka, E. A.; Rhoads, R. E.;
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J .; Morin, R. B.; Christensen, B. G. J . Am. Chem. Soc. 1978, 100, 6491.
(c) Leanza, W. J .; Wildonger, K. J .; Miller, T. W.; Christensen, B. G.
J . Med. Chem. 1979, 22, 1435.
(2) (a) Yamamoto, K.; Yoshioka, T.; Kato, Y.; Shibamoto, N.;
Okamura, K.; Shimauchi, Y.; Ishikura, T. J . Antibiot. 1980, 33, 796.
For references to early syntheses of PS-5 (4), see: (b) Wasserman, H.
H.; Han, W. T. Tetrahedron Lett. 1984, 25, 3747 (cf. also ref 12i and
references cited therein).
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Am. Chem. Soc. 1981, 103, 6765. (b) Barrett, A. G. M.; Quayle, P. J .
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D. W. T. Tetrahedron Lett. 1981, 22, 5335. (e) Reider, P. J .; Rayford,
R.; Grabowski, E. J . Tetrahedron Lett. 1982, 23, 379. (f) Koller, W.;
Linkies, A.; Pietsch, H.; Rehling, H.; Reuschling, D. Tetrahedron Lett.
1982, 23, 1545. (g) Reider, P. J .; Grabowski, E. J . J . Tetrahedron Lett.
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dron Lett. 1982, 23, 3921. (i) Kraus, G. A.; Neuenschwander, K. J .
Chem. Soc., Chem. Commun. 1982, 134. (j) Kametani, T.; Kanaya, N.;
Mochizuki, T.; Honda, T. Heterocycles 1982, 19, 1023. (k) Fujimoto,
K.; Iwano, Y.; Hirai, K. Tetrahedron Lett. 1985, 26, 89. (l) Hua, D. H.;
Verma, A. Tetrahedron Lett. 1985, 26, 547. (m) Tijima, Y.; Yoshida,
A.; Takeda, N.; Oida, S. Tetrahedron Lett. 1985, 26, 637. (n) Chiba,
T.; Nagatsuma, M.; Nakai, T. Chem. Lett. 1985, 1343. (o) Fliri, H.; Mak,
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(3) Corbett, D. F.; Coulton, S.; Southgate, R. J . Chem. Soc., Perkin
Trans. 1 1982, 3011 and references cited therein.
0022-3263/96/1961-2413$12.00/0 © 1996 American Chemical Society

2414 J . Org. Chem., Vol. 61, No. 7, 1996
J acobi et al.
Sch em e 1
Schreiber reaction for preparing chiral, enantiomerically
pure acetylenic acids of general structure 11 and ent-11
(Scheme 1; ent ) mirror image of compound shown).13
Acetylenic acids 11/ent-11 were then converted to pro-
tected â-amino acids 12/ent-12 by a two-step sequence
involving Curtius rearrangement,14 followed by oxidative
cleavage of the acetylenic bond.15 The considerable
synthetic potential of this methodology derives from its
highly convergent nature and the fact that both relative
and absolute stereochemistry at all stereogenic centers
can be readily controlled.16 These studies culminated in
efficient formal total syntheses of thienamycin (1) and
PS-5 (4).
Discu ssion a n d Resu lts
â-amino acid precursors such as 8. Recent approaches
include (a) addition of ester enolates or silylketene acetals
to imines;7 (b) Michael addition of amines to unsaturated
esters;8 (c) 1,3-dipolar cycloaddition of nitrones to al-
kenes;9 and (d) hydrogenation of acrylic acid derivatives,10
among others.11,12 In these examples the 5-substituent
is generally introduced prior to cyclization of the â-lactam
ring. In principle, this approach is applicable to the
synthesis of a broader range of substrates, and it formed
the basis of the first commercial synthesis of 1.5 How-
ever, in many cases absolute stereochemistry is difficult
to control.
I. Mod el Stu d ies w ith Sim p le Nich ola s Su b-
str a tes (R ) Me). a . Syn th esis of Hom och ir a l
Acetylen ic Acid s. The Nicholas reaction takes advan-
tage of the fact that cobalt complexes of general structure
14 greatly facilitate the heterolytic cleavage of adjacent
alcohols or ethers,13 which upon HBF413b or Lewis acid13e
catalysis afford cobalt-stabilized carbocations of type 15
(Figure 3). Capture of these carbocations with nucleo-
In this paper we describe a new approach to â-amino
acids of type 8 which takes advantage of a Nicholas-
(7) (a) Ha, D.-C.; Hart, D. J .; Yang, T.-K. J . Am. Chem. Soc. 1984,
106, 4819. (b) Shibasaki, M.; Iimori, T. Tetrahedron Lett. 1985, 26,
1523. (c) Cainelli, G.; Contento, M.; Giacomini, D.; Panunzio, M.
Tetrahedron Lett. 1985, 26, 937. (d) Hatakana, M.; Nitta, H. Tetrahe-
dron Lett. 1987, 28, 69. (e) Yamada, T.; Suzuki, H.; Mukaiyama, T.
Chem. Lett. 1987, 293. (f) Gennari, C.; Venlurini, S.; Gislon, G.;
Schimperna, G. Tetrahedron Lett. 1987, 28, 227. (g) Kunz, H.; Schan-
zenbach, D. Angew. Chem., Int. Ed. Engl. 1989, 28, 1068. (h) Corey,
E. J .; Decicco, C. P.; Newbold, C. N. Tetrahedron Lett. 1991, 32, 5287.
(8) (a) d’Angelo, J .; Maddaluno, J . J . Am. Chem. Soc. 1986, 108,
8112. (b) Estermann, H.; Seebach, D. Helv. Chim. Acta 1988, 71, 1824.
(c) Davies, S. G.; Ichihara, O. Tetrahedron Asymmetry 1991, 2, 183.
(9) (a) Kametani, T.; Chu, S.-D.; Honda, T. J . Chem. Soc., Perkin
Trans. 1 1988, 1593. (b) Ihara, M.; Takahashi, M.; Fukumoto, K.;
Kametani, T. J . Chem. Soc., Perkin Trans. 1 1989, 2215.
F igu r e 3.
philes such as electron-rich aromatics,13a ketone or ester
enolates,13d,e and enol ethers13c then affords the products
of nucleophilic displacement 16, which can be conve-
niently cleaved to the parent acetylenes 17 under a
variety of mild oxidative conditions.13c This methodology
avoids complications arising from the formation of allenic
byproducts, which frequently predominate upon direct
displacement of propargyl tosylates and halides.13f Since
propargyl alcohols are readily derived by addition of
acetylides to carbonyl compounds, the overall transfor-
(10) (a) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron
Asymmetry 1991, 2, 543. (b) Potin, D.; Dumas, F.; d’Angelo, J . J . Am.
Chem. Soc. 1990, 112, 3483.
(11) (a) Andres, C.; Gonzalez, A.; Pedrosa, R.; Perez-Encabo, A.
Tetrahedron Lett. 1992, 33, 2895 and references cited therein. (b)
J uaristi, E.; Quintana, D. Tetrahedron Lett. 1992, 33, 723 and
references cited therein. (c) Amoroso, R.; Cardillo, G.; Tomasini, C.
Tetrahedron Lett. 1992, 33, 2725 and references cited therein.
(12) For recent reviews on the synthesis of thienamycin (1) and
related materials, see: (a) Nagahara, T.; Kametani, T. Heterocycles
1987, 25, 729. (b) Georg, G. I. In Studies in Natural Product Chemistry;
Rahman, A-ur, Ed.; Elsevier Science: Amsterdam, 1989; Vol. 4. (c)
Bateson, J . H. In Progress in Heterocyclic Chemistry; Suschitzky, H.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1991; Vol. 3. See
also: (d) Hanessian, S.; Desilets, D.; Bennani, Y. L. J . Org. Chem. 1990,
55, 3098 and references cited therein. (e) Grieco, P. A.; Flynn, D. L.;
Zelle, R. E. J . Am. Chem. Soc. 1984, 106, 6414. (f) Melillo, D. G.;
Cvetovich, R. J .; Ryan, K. M.; Sletzinger, M. J . Org. Chem. 1986, 51,
1498. (g) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1986, 27, 4961.
(h) Corbett, D. F.; Coulton, S.; Southgate, R. J . Chem. Soc., Perkin
Trans. 1 1982, 3011 and references cited therein. (i) Evans, D. A.;
Sjogren, E. B. Tetrahedron Lett. 1986, 27, 3119. (j) Yamamoto, K.;
Yoshioka, T.; Kato, Y.; Shibamoto, N.; Okamura, K.; Shimauchi, Y.;
Ishikura, T. J . Antibiot. 1980, 33, 796. (k) Shono, T.; Kise, N.; Sanda,
F.; Ohi, S.; Yoshioka K. Tetrahedron Lett. 1989, 30, 1253. (l) Melillo,
D. G.; Cvetovich, R. J .; Ryan, K. M.; Sletzinger, M. J . Org. Chem. 1986,
51, 1498 and references cited therein. (m) Evans, D. A.; Bartroli, J .
Tetrahedron Lett. 1982, 23, 807. (n) Georg, G. I.; Akgu¨n, E. Tetrahedron
Lett. 1990, 31, 3267. (o) Chackahamannil, S.; Fett, N.; Kirkup, M.;
Afonso, A.; Ganguly, A. K. J . Org. Chem. 1988, 53, 450. (p) Salzmann,
T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J . Am. Chem.
Soc. 1980, 102, 6161. For an alternative synthesis of â-lactams
involving intramolecular alkylation, see: (q) Wasserman, H. H.; Hlasta,
D. J . Tetrahedron Lett. 1979, 20, 549.
(13) (a) Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977,
18, 4163. (b) Nicholas, K. M.; Nestle, M. O.; Seyferth, D. In Transition
Metal Organometallics in Organic Synthesis; Alper, H., Ed.; Academic
Press: New York, 1978; Vol. 2, p 1. (c) Schreiber, S. L.; Sammakia, T.;
Crowe, W. E. J . Am. Chem. Soc. 1986, 108, 3128. (d) Nicholas, K. M.;
Mulvaney, M.; Bayer, M. J . Am. Chem. Soc. 1980, 102, 2508. (e) Hodes,
H. D.; Nicholas, K. M. Tetrahedron Lett. 1978, 19, 4349. (f) Bramwell,
A. F.; Crombie, L.; Knight, M. H. Chem Ind. (London) 1965, 1265 and
references cited therein. (g) Saha, M.; Bogby, B.; Nicholas, K. M.
Tetrahedron Lett. 1986, 27, 915. (h) Schreiber, S. L.; Klimas, M. T.;
Sammakia, T. J . Am. Chem. Soc. 1987, 109, 5749.
(14) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc.
1972, 94, 6203. (b) Benalil, A.; Roby, P.; Carboni, B.; Vaultier, M.
Synthesis, 1991, 787.
(15) (a) Pappo, R.; Allen, D. S., J r.; Lemieux, R. U.; J ohnson, W. S.
J . Org. Chem. 1956, 21, 478. (b) Moriarty, R. M.; Penmasta, R.;
Awasthi, A. K.; Prakash, I. J . Org. Chem. 1988, 53, 6164 and references
cited therein.
(16) For previous papers in this series see: (a) J acobi, P. A.; Guo, J .
Tetrahedron Lett. 1995, 36, 2717. (b) J acobi, P. A.; Guo, J .; Zheng, W.
Tetrahedron Lett. 1995, 36, 1197. (c) J acobi, P. A.; Brielmann, H. L.;
Hauck, S. I. Tetrahedron Lett. 1995, 36, 1193. (d) J acobi, P. A.; Zheng,
W. Tetrahedron Lett. 1993, 34, 2581. (e) J acobi, P. A.; Zheng, W.
Tetrahedron Lett. 1993, 34, 2585. (f) J acobi, P. A.; Rajeswari, S.
Tetrahedron Lett. 1992, 33, 6231; (g) 1992, 33, 6235. (g) J acobi, P. A;
DeSimone, R. W. Tetrahedron Lett. 1992, 33, 6239.

Total Syntheses of Thienamycin and PS-5
J . Org. Chem., Vol. 61, No. 7, 1996 2415
Ta ble 1
yield,a
%
yield,a
%
no. compd
[R]25 (c)d
compd
[R]25 (c)d
D
D
1
2
3
4
5
24a
ent-24a
24b
24c
ent-24c
94b
80c
20b
93b
78c
+28.7 (12.4) 25a
-26.0 (30.6) ent-25a
+15.9 (4.5) 25b
-33.1 (6.4) 25c
+37.4 (14.7) ent-25c
91
91
56
86
79
+11.7 (27.8)
-11.5 (60.7)
-1.3 (45.8)
-31.6 (7.8)
+30.2 (19.5)
a
b
Average yield for several runs. Yield employing 2 equiv of
22. c Yield employing 1 equiv of 22. Measured in MeOH (c ) mg/
mL).
d
Sch em e 3
F igu r e 4.
Sch em e 2
Sch em e 4
In general, yields for this reaction were excellent (85-
98%), utilizing a ratio of 22:23 ) 2:1 (entries 1 and 4,
Table 1), and only slightly less satisfactory (75-85%),
employing a ratio of 22:23 ) 1:1 (entries 2 and 5, Table
1). Not surprisingly, however, 24b (R′ ) Me) was
obtained in considerably lower yield (20%, entry 3, Table
1), presumably due to steric hindrance and competing
elimination reactions in the stabilized carbocation de-
rived from 23b.13 Diastereo- and enantioselectivities
were also generally excellent, with syn:anti ratios of
>98:2 employing chiral enolates 22 and ent-22 with
achiral cobalt complexes 23a ,b (entries 1-3, Table 1;
slightly lower syn-selectivity was observed employing
chiral enolates 18 and ent-18; cf. Figure 4). Equally
impressive ratios (>98:2) were obtained with the
“matched” chiral substrates 22 + 23c f 25c, and ent-22
+ ent-23c f ent-24c (entries 4 and 5, Table 1; the case
of “mismatched” substrates will be discussed below).
These results are in full accord with the transition state
model proposed by Schreiber et al. (vide supra).13h
Once in hand, oxazolidinones 24/ent-24 were readily
converted to the corresponding acetylenic acids 25/ent-
25 by hydrolysis with excess lithium hydroperoxide,17
which effected concomitant cleavage of the TMS group
(Scheme 2). As indicated (Table 1), yields for this step
were excellent (80-98%), except for the special case
where R′ ) Me (entry 3, Table 1). In this example, steric
hindrance once again had a deleterious effect on reactiv-
ity. Finally, 5R,6R-diastereoselectivity of >98:2 was also
obtained upon condensation of chiral cobalt complex 23c
with the achiral enolate 26 (Scheme 4), as judged by
conversion of the derived adduct 27c to the identical
homochiral acetylenic acid 25c obtained employing chiral
enolate 22 (cf. Scheme 2).18 This result provides some
mation constitutes a flexible carbonyl-to-geminal dialkyl
transposition.
In 1987, Schreiber et al. described the first example of
a Nicholas reaction involving a homochiral nucleophile.
Thus, alkylation of boron enolate 18 with cobalt complex
19 afforded a 12:1 mixture of syn-adduct 20s together
with the corresponding 2,3-anti-isomer 20a (Figure 4;
20a not shown).13h Oxidative cleavage of 20s with cerric
ammonium nitrate (CAN) then gave an excellent yield
of the parent acetylene 21s. This result was rationalized
on the basis of a novel double stereodifferentiating
process, in which the racemic carbocation derived from
19 interconverts via enantiomerization at a rate which
is fast relative to alkylation (kinetic resolution).13h In
principle, this observation provides the basis for a general
synthesis of homochiral acetylenic acid derivatives that
might find widespread utility in organic synthesis.
However, until recently little was known about the effect
of chiral substituents on such transformations.16
In order to explore the generality of the Nicholas-
Schreiber methodology, we initially studied the prepara-
tion of acetylenic acids 25a -c (Scheme 2). Cobalt
derivatives 23a -c were readily obtained by condensation
of lithio(trimethylsilyl)acetylene with the appropriate
aldehydes R′CHMeCHO (R′ ) H, Me, S-OBn), followed
by in situ methylation (DMS),16 and complexation of the
resulting methylpropargyl ethers with Co2(CO)8.13 Imide
enolate 22 was prepared following the general procedure
of Schreiber et al.,13h employing 1.0 equiv each of (i-
C3H7)2NEt and Bu2BOTf at 0 °C in CH2Cl2. The resulting
enolate solutions were then cooled to -78 °C, treated with
an additional 0.5-1.0 equiv of Bu2BOTf, followed by an
equimolar quantity of 23 (based on excess Bu2BOTf), and
warmed to 0 °C to afford the desired adducts 24 after
oxidative cleavage with CAN (Table 1). In identical
fashion, imide enolate ent-22 afforded the enantiomeric
adducts ent-24 upon condensation with cobalt complexes
ent-23 (Scheme 3).
(17) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141.
(18) We are grateful to Ms. Gayle Schulte, of Yale University, for
carrying out an X-ray analysis of acetylenic acid 25c.

2416 J . Org. Chem., Vol. 61, No. 7, 1996
J acobi et al.
Ta ble 2
afford pure 30a ,b in >90% overall yield (entries 1 and 3,
Table 2). With 28c (R′ ) OBN), however, KMnO4/NaIO4
caused extensive decomposition due to oxidation of the
benzyl protecting group to give benzoic acid. This dif-
ficulty was eventually circumvented with our finding that
OsO4/NaIO4 provided the desired chemoselectivity,15
leading exclusively to the N-formyl derivative 29c. As
with 29a ,b described above, 29c was then readily cleaved
with KOH to afford the desired carbamate 30c (entry 4,
Table 2). The utility of these amino acid derivatives for
the synthesis of â-lactams was then convincingly dem-
onstrated by their facile conversion to amino acids 31a -c
and subsequently to lactams 32a -c upon cyclization with
dicyclohexylcarbodiimide (DCC).12e Finally, in identical
fashion, acetylenic acids ent-25a ,c were converted in four
steps to the enantiomeric â-lactams ent-32a ,c (Scheme
6), which were also obtained as single isomers (entries 2
and 5, Table 2).
yield,a
%
yield,a
%
no. compd
[R]25 (c)b
compd
[R]25 (c)b
D
D
1
2
3
4
5
28a
ent-28a
28b
28c
ent-28c
82
74
64
92
82
+61.1 (24.8) 30a
-64.0 (20.1) ent-30a
+55.2 (20.4) 30b
+34.9 (19.8) 30c
-34.4 (4.7) ent-30c
97
92
86
68
68
+12.7 (2.7)
-13.8 (7.2)
+23.8 (15.1)
+62.4 (16.3)
-64.7(12.8)
no.
compd
yield,a
%
[R]25 (c)c
D
1
2
3
4
5
32a
ent-32a
32b
32c
ent-32c
71
81
82
76
83
+19.8 (10.3)
-18.3 (19.5)
+11.3 (23.0)
+35.5 (19.8)
-36.5 (10.5)
a
b
Average yield for several runs. Measured in MeOH (c ) mg/
mL). c Measured in CH2Cl2 (c ) mg/mL).
Sch em e 6
F igu r e 5.
indication of the powerful directing influence which chiral
substituents can exert on the Nicholas reaction.
b. Con ver sion of Acetylen ic Acid s 25/en t-25 to
â-Am in o Acid s 30/en t-30 a n d â-La cta m s 32/en t-32.
We next studied the conversion of acetylenic acids 25 to
homochiral amino acid derivatives 30 (Scheme 5). As
II. F or m a l Syn t h esis of P S-5. â-Lactam 32a (cf.
Scheme 5) bears a close structural resemblance to the
known alcohol derivative 33 (5R,6R-stereochemistry),
which has previously been employed in the synthesis of
the potent antibiotic PS-5 (4) (Figure 6).19 We envisioned
Sch em e 5
F igu r e 6.
that precursors of type 33 might be conveniently pre-
pared using methodology analogous to that described in
Schemes 2 and 5. In order to explore this possibility it
was first necessary to prepare the chiral oxazolidinone
derivative 39, which was derived in excellent overall yield
beginning with 1,4-butanediol (34) (Scheme 7). Thus,
Sch em e 7
indicated, Curtius rearrangement of 25 to afford car-
bamates 28 was conveniently carried out with diphenyl
phosphorazidate (DPPA),14a followed by HCl-catalyzed
capture of the intermediate isocyanate (not isolated) with
2-methyl-2-propanol.14b Within the limits of detection,
this step occurred with complete retention of stereochem-
istry, as determined by NMR analysis and comparison
of the specific rotations for 28a ,c and ent-28a ,c (Table
2). However, we experienced some initial difficulties in
effecting the oxidative cleavage of acetylenic carbamates
28 to the desired amino acid derivatives 30. For 28a ,b,
this transformation was best accomplished with KMnO4/
NaIO4,12e which afforded ∼50:50 mixtures of the corre-
sponding acids 30a ,b together with the N-formyl deriva-
tives 29a ,b. We believe that formyl derivatives 29 were
derived by intramolecular formylation involving oxidation
intermediates of type I (Figure 5), since 30 itself was
unreactive to formic acid.
selective monoprotection of 34 with TBDPSCl gave a 90%
yield of the corresponding alcohol 35, which upon oxida-
tion with PDC in DMF afforded carboxylic acid derivative
36 in 75% yield. Treatment of 36 with oxalyl chloride in
benzene then provided the acid chloride 37 (99%), which
(19) (a) Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 619. See also:
(b) Shono, T.; Kise, N.; Sanda, F.; Ohi, S.; Yoshioka, K. Tetrahedron
Lett. 1989, 30, 1253.
In any event, these mixtures were usually not sepa-
rated, but rather were directly hydrolyzed (KOH) to

Total Syntheses of Thienamycin and PS-5
J . Org. Chem., Vol. 61, No. 7, 1996 2417
Sch em e 8
derived by initial coordination of Li cation with adduct
40 (40 f II). This result is in qualitative agreement with
the suggestion of Evans et al. that the rate-determining
step in cleavage by HOO- is collapse of the initially
formed tetrahedral intermediate.17 In the case of endo-
attack (II f III), collapse of intermediate III to 41 is
presumably accelerated by chelation of the type il-
lustrated in III, which renders the oxazolidinone C-N
bond relatively labile. In contrast, intermediate IV,
derived by exo-attack (II f IV), is most likely stabilized
by chelation. Therefore, collapse of IV to the desired
carboxylic acid 42 is relatively slow. As expected on the
basis of this hypothesis, DMF had no effect on the
regioselectivity of hydrolysis by HO-, where the rate-
determining step is formation of the tetrahedral inter-
mediate (steric control).17 In both cases (with and
without added DMF), hydrolytic cleavage was predomi-
nantly endocyclic to afford 41.
The remaining steps necessary for the conversion of
42 to the PS-5 (4) precursor 33 were then accomplished
in a straightforward fashion, in exact analogy to our
model studies described in Scheme 5. Thus, Curtius
rearrangement of 42 with DPPA afforded an 83% yield
of the carbamate derivative 43,14 which upon oxidative
cleavage with KMnO4/NaIO4 gave the desired protected
amino acid 44 in 91% yield (Scheme 9). This last
compound, upon TFA-catalyzed deprotection, then gave
a quantitative yield of the â-amino acid 45, which in turn
afforded 91% of the target â-lactam 33 upon cyclization
with DCC. The material thus prepared had chemical and
physical properties identical to those reported in the
literature19a and was obtained as a single enantiomer.
III. F or m a l Syn th esis of Th ien a m ycin . a . Mod el
Stu d ies w ith Ma tch ed a n d Mism a tch ed Su bstr a tes.
In Schemes 2 and 5 we described an efficient synthesis
of â-amino acid derivative 31c, making use of a “matched”
condensation of oxazolidinone enolate 22 with cobalt
complex 23c (Figure 8). Amino acid 31c has the 5R,6S,8S-
F igu r e 7.
Sch em e 9
was directly converted to the desired acyl derivative 39
by condensation with the lithium anion derived from
oxazolidinone 38 (89% yield from 36).20
Once in hand, oxazolidinone 39 was readily converted
to the corresponding boron enolate (vide supra),13h which
underwent smooth Nicholas condensation with cobalt
complex 23a to give syn-adduct 40 in 88% overall yield
after decomplexation (Scheme 8; >98:2 syn-selectivity).
Surprisingly, however, hydrolysis of 40 under the stand-
ard conditions (LiOOH, 3:1 THF/H2O) afforded complex
mixtures of products,17 consisting in part of endo-ring-
opened alcohol 41, together with lesser amounts of the
desired carboxylic acid 42 derived by exo-hydrolysis
(conditions A). This unexpected reaction pathway might
be due to complexation of Li cation between the exo-
carbonyl group and the -OTBDPS functionality (cf. II,
Figure 7), since related alkyl derivatives (OTBDPS ) Me)
underwent normal hydrolysis (vide infra). In any event,
addition of DMF to the hydrolysis reaction completely
reversed the regioselectivity (3:3:1 DMF/THF/H2O) and
afforded an 81% yield of the desired acetylenic acid 42
with no trace of endo-ring opened product 41 (conditions
B).
F igu r e 8.
stereochemistry characteristic of MM-22381 (6) (cf. Fig-
ure 1), and it served as a useful probe of stereochemical
control in the Nicholas reaction. As employed in this
case, the term “matched” refers to those condensations
in which the chirality of the oxazolidinone precursor
reinforces the directing effect of the C-8 stereogenic
center in cobalt complexes 23. As previously noted
(Scheme 4), chiral cobalt complex 23c combines even with
achiral oxazolidinone 26 to provide adduct 27c with
excellent diastereo- and enantioselectivity.
On the basis of these results, it was of interest to
determine if a similar approach could be applied to the
synthesis of amino acids having the 5R,6S,8R-configu-
ration found in thienamycin (1) (cf. Figure 1).1 In
principle, this substitution pattern was available by
“mismatched” condensation of oxazolidinone 39 with
cobalt complex ent-23c (Figure 9). This combination
We believe that DMF functions by solvating chelated
intermediates of type II-IV (Figure 7), themselves
(20) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem Soc. 1981,
103, 2127.

2418 J . Org. Chem., Vol. 61, No. 7, 1996
J acobi et al.
exact analogy to our earlier studies with 30c and ent-
30c (P ) CO2t-Bu; cf. Schemes 5 and 6).
Upon cyclization of 51 to â-lactam 53 the cis-relation-
ship between H5-H6 was immediately apparent from
their relatively large coupling constant (J 5,6 ) 6.0 Hz)
(Scheme 11). For trans-â-lactams this coupling constant
is typically <3 Hz.19b The remaining question pertaining
to the absolute stereochemistry at C5-C6 was then
resolved by epimerization studies. As expected, 53 was
readily epimerized to the desired trans-isomer 54 (J 5,6
)
1.8 Hz),21 which proved to be identical to the material
obtained directly from the minor syn-adduct 48s (cf.
Experimental Section). If 53 had been of opposite
absolute configuration at C5-C6 (i.e., 55), epimerization
would have afforded the previously synthesized â-lactam
ent-32c (cf. Scheme 6). These results provide further
testimony to powerful directing influence which chiral
substituents can exert on the Nicholas reaction (see also
Scheme 4). At present we have no detailed rationale for
this difference in reaction pathway between “matched”
and “mismatched” condensations. However, with further
study we hope to develop a transition state model which
will permit logical predictions regarding the stereochem-
ical outcome of Nicholas reactions with chiral substrates.
b. Syn th esis of th e Key Th ien a m ycin P r ecu r sor
63. Finally, these model studies were readily extended
to a formal total synthesis of thienamycin (1).12 As
described above for 39 (Scheme 7), the requisite precursor
56 was prepared by acylation of oxazolidinone 38b with
acid chloride 37 (Figure 10). Condensation of the boron
enolate of 56 with cobalt complex ent-23c then provided
a 79% yield of the Nicholas adduct 57, which was
obtained with ∼17:1 anti-selectivity (Scheme 12) (Note
F igu r e 9.
Sch em e 10
Sch em e 11
F igu r e 10.
Sch em e 12
would ultimately lead to the known thienamycin precur-
sor 46 (P ) OTBDPS) if transition state interactions were
dominated by chiral auxiliary 39.12e,13h However, our
initial model studies in this direction were not encourag-
ing. Thus, all attempts at the condensation of boron
enolate 22 with ent-23c provided only complex mixtures
of products, which contained at least three isomeric
adducts 47 in a ratio of ∼7:3:1 (29% combined yield,
Figure 9). This result stands in marked contrast to that
obtained in the “matched” condensation of oxazolidinone
22 with 23c (cf. Scheme 2), which gave adduct 24c in
93% yield with >98:2 syn-selectivity.
In contrast to the case with 22, oxazolidinone ent-18
underwent clean “mismatched” condensation with ent-
23c to provide an ∼12:1 mixture of two isomeric acetyl-
enic acid derivatives (Scheme 10). These were subse-
quently identified as syn-adduct 48s and anti-isomer 48a .
Interestingly, however, the major isomer proved to be the
anti-adduct 48a , as demonstrated by chemical correlation
(it was impossible to distinguish between 48s and 48a
on the basis of spectral data alone). Thus, 48a was
readily converted to the carboxylic acid 49a ,17 which upon
Curtius rearrangement (81%)14 followed by oxidative
cleavage (71%)15 afforded amino acid derivative 51a in
that ent-23c combines with achiral oxazolidinones to
provide syn-adducts of 5S,6S,8R-stereochemistry, the
incorrect configuration at C5 and C6; cf. Scheme 4). As
in the case with 40 (cf. Scheme 8), hydrolysis of 57 under
standard conditions (LiOOH, 3:1 THF/H2O) afforded a
complex mixture of products,17 from which endo-ring
opened product 58 could be isolated in 30% yield (condi-
(21) Chiba, T.; Nakia, T. Tetrahedron Lett. 1985, 26, 4647.

Total Syntheses of Thienamycin and PS-5
J . Org. Chem., Vol. 61, No. 7, 1996 2419
diethyl ether. The combined organic layers were dried (Mg-
SO4), filtered, and concentrated under reduced pressure.
Purification by either chromatography or distillation then
afforded the methyl propargylic ether.
Sch em e 13
Gen er a l P r oced u r e for th e P r ep a r a tion of Hexa ca r -
bon yld icoba lt-Com p lexed Alk yn es 23a -c. A solution of
octacarbonyldicobalt (1.05 or 1.1 equiv) in anhydrous diethyl
ether was stirred at rt under nitrogen and was treated in a
dropwise fashion with a solution of the desired methyl pro-
pargylic ether (1.0 equiv) in anhydrous diethyl ether (see
above). The resulting mixture was then stirred at rt for 3-8
h. Following this period, the solvent was concentrated under
reduced pressure, and the residue was chromatographed to
afford the corresponding cobalt-complexed alkyne.
3-Meth oxy-1-(tr im eth ylsilyl)p en tyn e, Hexa ca r bon yl-
d icoba lt Com p lex (23a ). 3-Methoxy-1-(trimethylsilyl)pen-
tyne was prepared following the general procedure described
above, using 12.1 mL (86.2 mmol, 1.0 equiv) of (trimethylsilyl)-
acetylene in 350 mL of THF, 34.3 mL (1.0 equiv) of 2.5 M
n-butyllithium/hexanes, 6.20 mL (1.0 equiv) of propionalde-
hyde, and 8.10 mL (1.0 equiv) of dimethyl sulfate. After the
mixture was stirred at rt for 23 h, isolation and distillation
gave 12.5 g (85%) of 3-methoxy-1-(trimethylsilyl)pentyne as a
colorless oil, bp 65-67 °C/18 mm: IR (CH2Cl2) 2966, 2168,
tions A). No trace of the desired carboxylic acid 59
derived from exo-nucleophilic attack could be detected.
Once again, however, addition of DMF to the hydrolysis
reaction completely reversed the regioselectivity (3:3:1
DMF/THF/H2O) and afforded a 74% yield of the desired
acetylenic acid 59 together with only traces of 58 (condi-
tions B).
As described above for 49 (cf. Scheme 10), 59 was then
converted in two steps to the homochiral amino acid
derivative 61, which upon deprotection and cyclization
with DCC afforded the cis-â-lactam 62 in 56% yield
(Scheme 13). Finally, epimerization of 62 according to
the procedure of Nakai et al. afforded the known thiena-
mycin precursor 63,12e,21 which had spectral data identical
to that reported by Grieco et al. for the racemic material.22
1
1675, 1463, 1334, 1252, 1132, 1052 cm-1; H NMR (CDCl3) δ
0.16 (s, 9H), 0.97 (t, J ) 7.0 Hz, 3H), 1.68 (m, 2H), 3.38 (s,
3H), 3.85 (t, J ) 7.0 Hz, 1H). Following the general procedure
described above, a solution of 1.90 g (11.1 mmol, 1.0 equiv) of
3-methoxy-1-(trimethylsilyl)pentyne in 10 mL of diethyl ether
and 4.00 g (11.7 mmol, 1.05 equiv) of octacarbonyldicobalt in
60 mL of diethyl ether was stirred for 3.5 h at rt. Concentra-
tion and chromatography (100:1 hexanes/EtOAc) then afforded
4.90 g (96%) of 23a as a dark solid: IR (CH2Cl2) 2962, 2096,
2059, 2026, 1671, 1562 cm-1; 1H NMR (CDCl3) δ 0.32 (bs, 9H),
1.11 (bs, 3H), 1.76 (bs, 2H), 3.56 (bs, 3H), 4.50 (bs, 1H).
3-Meth oxy-4-m eth yl-1-(tr im eth ylsilyl)p en tyn e, Hexa -
ca r bon yld icoba lt Com p lex (23b). 3-Methoxy-4-methyl-1-
(trimethylsilyl)pentyne was prepared following the general
procedure described above, using 12.1 mL (86.2 mmol, 1.0
equiv) of (trimethylsilyl)acetylene in 250 mL of THF, 34.3 mL
(1.0 equiv) of 2.5 M n-butyllithium/hexanes, 7.80 mL (1.0
equiv) of 2-methylpropionaldehyde, and 8.10 mL (1.0 equiv)
of dimethyl sulfate. After the mixture was stirred at rt for 36
h, isolation and distillation gave 13.0 g (82%) of 3-methoxy-
4-methyl-1-(trimethylsilyl)pentyne as a colorless oil, bp 77-
79 °C/21 mm: MS m/ e 169 (M+ - Me), 141, 126, 113, 97, 89,
83, 59; IR (CH2Cl2) 2963, 2168, 1469, 1349, 1250, 1088, 1028
cm-1; 1H NMR (CDCl3) δ 0.20 (s, 9H), 1.00 (t, J ) 7.5 Hz, 6H),
1.92 (m, 1H), 3.42 (s, 3H), 3.72 (d, J ) 6.5 Hz, 1H); 13C NMR
(CDCL3) δ 0.08, 17.65, 18.39, 32.80, 56.52, 77.29, 90.89, 103.40.
Anal. Calcd for C10H20OSi: C, 65.15; H, 10.93. Found: C,
65.25; H, 10.94. Following the general procedure described
above, a solution of 2.05 g (11.1 mmol, 1.0 equiv) of 3-methoxy-
4-methyl-1-(trimethylsilyl)pentyne in 10 mL of diethyl ether
and 4.00 g (11.7 mmol, 1.05 equiv) of octacarbonyldicobalt in
55 mL of diethyl ether was stirred for 3.5 h at rt. Concentra-
tion and chromatography (100:1 hexanes/EtOAc) then afforded
5.05 g (99%) of 23b as a dark solid: IR (CH2Cl2) 2962, 2087,
Su m m a r y
The control of relative and absolute stereochemistry
at three and more contiguous centers is an important
problem in organic synthesis. In some cases we believe
that the Nicholas reaction could provide an attractive
alternative to more traditional methodology in this area.
This will be especially true for molecules containing
carboxylate, alkene, amino, and related functionalities
which are easily derived from acetylenic acid derivatives
of type 11. To illustrate this potential, we have developed
unequivocal syntheses of two of the most important
members of the carbapenem class of antibiotics. Exten-
sion of this methodology to the synthesis of other biologi-
cally important molecules is currently under investiga-
tion.
Exp er im en ta l Section
Melting points were determined in open capillaries and are
uncorrected. 1H NMR spectra were recorded at either 200 or
400 MHz and are expressed as ppm downfield from tetra-
methysilane.
1
2047, 2021, 1578, 1270, 1088 cm-1; H NMR (CDCl3) δ 0.32
Gen er a l P r oced u r e for th e P r ep a r a tion of Meth yl
P r op a r gylic Eth er s. A solution of (trimethylsilyl)acetylene
(1.0 equiv) in THF was cooled to -78 °C under nitrogen and
was treated in a dropwise fashion, with vigorous stirring, with
2.5 M n-butyllithium/hexanes (1.0 equiv). The resulting
mixture was stirred at -78 °C for an additional 10 min and
was then treated over 5 min with a solution of the desired
aldehyde (1.0 equiv) in THF. After the mixture was stirred
for an additional 15 min, dimethyl sulfate (1.0 equiv) was
added to the mixture and the cooling bath was removed. The
reaction mixture was then stirred at rt for 18-48 h and
monitored by TLC. When complete, the reaction was quenched
by addition of 140 mL of saturated aqueous NH4Cl, and the
separated aqueous layer was extracted with 3 × 100 mL of
(s, 9H), 1.06 (d, J ) 7.5 Hz, 3H), 1.10 (d, J ) 7.5 Hz, 3H), 1.88
(m, 1H), 3.54 (s, 3H), 3.98 (d, J ) 6.0 Hz, 1H).
4(S )-(Be n zyloxy)-3-m e t h oxy-1-(t r im e t h ylsilyl)p e n -
tyn e, Hexa ca r bon yld icoba lt Com p lex (23c). 4(S)-(Ben-
zyloxy)-3-methoxy-1-(trimethylsilyl)pentyne was prepared fol-
lowing the general procedure described above, using 3.50 mL
(24.5 mmol, 1.0 equiv) of (trimethylsilyl)acetylene in 100 mL
of THF, 9.80 mL (1.0 equiv) of 2.5 M n-butyllithium/hexanes,
4.02 g (1.0 equiv) of 2-(S)-(benzyloxy)propionaldehyde in 20
mL of THF, and 2.30 mL (1.0 equiv) of dimethyl sulfate. After
the mixture was stirred at rt for 22 h, isolation and chroma-
trography (20:1 hexanes/EtOAc) gave 6.64 g (98%) of 4(S)-
(benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne as a colorless
oil: MS m/ e 232 (M+ - 44), 217, 201, 185, 170, 155, 141, 135,
123, 113; IR (CH2Cl2) 3033, 2962, 2170, 1453, 1252, 1098, 1028
cm-1; 1H NMR (CDCl3) δ 0.21 (s, 9H), 1.29 (d, J ) 6.5 Hz, 3H),
3.45 (s, 3H), 3.67 (m, 1H), 4.02 (m, 1H), 4.67 (m, 2H), 7.27-
(22) We are grateful to Professor Paul Grieco, of Indiana University,
for providing an NMR spectra of (()-63 (cf. ref 12e).

2420 J . Org. Chem., Vol. 61, No. 7, 1996
J acobi et al.
7.41 (m, 5H). Anal. Calcd for C16H24O2Si: C, 69.52; H, 8.75.
Found: C, 69.65; H, 8.76. Following the general procedure
described above, a solution of 2.00 g (7.23 mmol, 1.0 equiv) of
4(S)-(benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne in 10 mL
of diethyl ether and 2.70 g (1.1 equiv) of octacarbonyldicobalt
in 38 mL of diethyl ether was stirred for 3.5 h at rt.
Concentration and chromatography (100:1 hexanes/EtOAc)
then afforded 3.86 g (95%) of 23c as a dark liquid: IR (CH2Cl2)
of i-Pr2NEt, 10.1 and 10.1 mL (1.0 and 1.0 equiv) of 1.0 M
Bu2BOTf/CH2Cl2, a solution of 4.60 g (1.0 equiv) of the cobalt
complexed alkyne ent-23a in 27 mL of CH2Cl2, and 60 mL of
acetone with excess CAN gave 2.61 g (80%) of adduct ent-24a
as a light yellow oil: [R]25 -26.0° (c ) 30.6, MeOH); IR and
D
1H NMR are identical to those of adduct 24a .
Nich ola s Ad d u ct 24b. Following method A, above, a
solution of 4.21 g (22.7 mmol, 2.0 equiv) of (S)-4-isopropyl-N-
propionyl-2-oxazolidone (22) in 80 mL of CH2Cl2, 3.93 mL of
i-Pr2NEt, 22.7 and 11.4 mL (2.0 and 1.0 equiv) of 1.0 M
Bu2BOTf/CH2Cl2, a solution of 5.35 g (1.0 equiv) of the cobalt-
complexed alkyne 23b in 15 mL of CH2Cl2, and 50 mL of
acetone with excess CAN gave 0.76 g (20%) of adduct 24b as
a white solid, mp 93.0-93.5 °C (hexanes, colorless needles):
3050, 2957, 2088, 2049, 2022, 1585, 1454, 1376, 1101 cm-1
;
1HNMR (CDCl3) δ 0.28 (two s, 9H), 1.26 (d, J ) 6.5 Hz, 3H),
1.32 (d, J ) 6.5 Hz, 3H), 3.60 (s, 3H), 3.45-3.75 (m, 1H), 4.27-
4.70 (m, 3H), 7.24-7.40 (m, 5H).
4(R )-(Be n zyloxy)-3-m e t h oxy-1-(t r im e t h ylsilyl)p e n -
tyn e, Hexa ca r bon yld icoba lt Com p lex (en t-23c). This
material was prepared in 98% yield from 4.62 g of 4(R)-
(benzyloxy)-3-methoxy-1-(trimethylsilyl)pentyne following the
same procedure as that described above for 23c. Cobalt
complex ent-23c had spectral data identical to that provided
for 23c.
[R]25 +15.9° (c ) 4.5, MeOH); MS m/ e 337 (M+), 322, 294,
D
208, 193, 165, 130, 123; IR (CH2Cl2) 2966, 2168, 1778, 1700,
1465, 1386, 1251, 1207 cm-1; 1H NMR (CDCl3) δ 0.10 (s, 9H),
0.93 (m, 9H), 1.04 (d, J ) 7.0 Hz, 3H), 1.12 (d, J ) 7.5 Hz,
3H), 1.90 (m, 1H), 2.42 (m, 1H), 2.73 (dd, J ) 2.9, 10.8 Hz,
1H), 4.04 (m, 1H), 4.23 (m, 2H), 4.48 (m, 1H); 13C NMR (CDCl3)
δ 0.1, 14.6, 15.3, 16.1, 21.8, 26.6, 39.4, 42.3, 54.7, 78.4, 87.5,
105.6, 125.5, 128.6, 133.4, 152.4, 176.0. Anal. Calcd for
C18H31NO3Si: C, 64.05; H, 9.26; N, 4.15. Found: C, 63.85; H,
9.31; N, 4.09.
Gen er a l P r oced u r es for th e Nich ola s Rea ction a n d
Oxid a tive Decom p lexa tion . Meth od A. A solution con-
sisting of 11.0 mmol (2.0 equiv) of the appropriate oxazolidone
in 37 mL of anhydous methylene chloride was cooled to 0 °C
under nitrogen and was treated in dropwise fashion, with
vigorous stirring, with 2.0 equiv of freshly distilled N,N-
diisopropylethylamine and 2.0 equiv of a 1.0 M solution of
dibutylboron triflate/methylene chloride. After the mixture
was stirred for 15 min at 0 °C, an additional 1.0 equiv of
dibutylboron triflate was added and the resulting mixture was
cooled to -78 °C. A solution consisting of 5.50 mmol (1.0
equiv) of the appropriate cobalt-complexed alkyne in 15 mL
of methylene chloride was then added in dropwise fashion and
with vigorous stirring. After the addition was complete, the
resulting mixture was allowed to warm to 0 °C, and stirring
was continued for 20 min each at 0 °C and at rt, respectively.
The reaction was then quenched with 90 mL of ice-cold pH 7
buffer, and the separated aqueous layer was extracted with 3
× 40 mL of methylene chloride. The combined organic extracts
were dried (MgSO4), filtered, concentrated under reduced
pressure, and chromatographed (20:1 or 10:1 hexanes/EtOAc)
to afford the desired cobalt complexed Nicholas adduct together
with excess oxazolidone. The crude material thus obtained
was dissolved in 100 mL of acetone and treated portionwise,
at rt and with vigorous stirring, with ammonium cerium(IV)
nitrate (CAN) until gas evolution ceased. A slight excess of
CAN was then added, and the solvent was removed under
reduced pressure at rt. The resultant residue was partitioned
between 70 mL of water and 55 mL of diethyl ether, and the
separated aqueous layer was extracted with 5 × 55 mL of
diethyl ether. The combined organic layers were dried (Mg-
SO4), filtered, concentrated under reduced pressure, and
chromatographed (20:1 or 10:1 hexanes/EtOAc) to give the
desired product.
Nich ola s Ad d u ct 24c. Following method A, above, a
solution of 8.89 g (48.0 mmol, 2.0 equiv) of (S)-4-isopropyl-N-
propionyl-2-oxazolidone (22) in 180 mL of CH2Cl2, 8.28 mL of
i-Pr2NEt, 48.0 and 24.0 mL (2.0 and 1.0 equiv) of 1.0 M
Bu2BOTf/CH2Cl2, a solution of 13.5 g (1.0 equiv) of the cobalt-
complexed alkyne 23c in 45 mL of CH2Cl2, and 250 mL of
acetone with excess CAN gave 9.56 g (93%) of adduct 24c as
a pale yellow oil: [R]25 -33.1° (c ) 6.4, MeOH); MS m/ e 370
D
(M+ - 59), 294, 256, 245, 202, 165, 123, 91; IR (CH2Cl2) 3062,
2968, 2170, 1780, 1700, 1385, 1256, 1206, 1097 cm-1; 1H NMR
(CDCl3) δ 0.12 (s, 9H), 0.92 (d, J ) 7.5 Hz, 6H), 1.05 (d, J )
6.8 Hz, 3H), 1.35 (d, J ) 6.2 Hz, 3H), 2.39 (m, 1H), 2.89 (dd,
J ) 3.1, 10.3 Hz, 1H), 3.73 (m, 1H), 4.15-4.48 (m, 4H), 4.47
(d, J ) 12.2 Hz, 1H), 4.67 (d, J ) 12.2 Hz, 1H), 7.23-7.42 (m,
5H); 13C NMR (CDCl3) δ 0.0, 15.0, 15.6, 17.0, 17.9, 28.4, 39.2,
41.0, 58.3, 62.9, 69.8, 72.0, 87.3, 105.5, 127.2, 127.4, 128.1,
138.5, 153.2, 175.5; HRMS(CI) calcd for (C24H35NO4Si + H)
([M + H]+) 430.2415, found 430.2398.
Nich ola s Ad d u ct en t-24c. Following method B, above, a
solution of 1.67 g (9.02 mmol, 1.0 equiv) of (R)-4-isopropyl-N-
propionyl-2-oxazolidone (ent-22) in 30 mL of CH2Cl2, 1.55 mL
of i-Pr2NEt, 9.0 and 9.0 mL (1.0 and 1.0 equiv) of 1.0 M
Bu2BOTf/CH2Cl2, a solution of 5.07 g (1.0 equiv) of the cobalt
complexed alkyne ent-23c in 25 mL of CH2Cl2, and 100 mL of
acetone with excess CAN gave 3.04 g (78%) of the adduct ent-
24c as a pale yellow oil: [R]25 +37.4° (c ) 14.7, MeOH); IR
D
and 1H NMR are identical to those of adduct 24c.
Nich ola s Ad d u ct 27c. Following method A, above, a
solution of 0.91 g (34.9 mmol, 2.0 equiv) of N-propionyl-2-
oxazolidone (26) in 123 mL of CH2Cl2, 5.53 mL of i-Pr2NEt,
34.9 and 17.5 mL (2.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2,
a solution of 9.82 g (1.0 equiv) of the cobalt-complexed alkyne
23c in 34 mL of CH2Cl2, and 250 mL of acetone with excess
CAN gave 6.30 g (93%) of the adduct 27c as a pale yellow oil:
Meth od B. Method B was identical to method A but
employed equimolar quantities of the appropriate oxazolidones
and cobalt-complexed acetylenes.
Nich ola s Ad d u ct 24a . Following method A, above, a
solution of 2.03 g (11.0 mmol, 2.0 equiv) of (S)-4-isopropyl-N-
propionyl-2-oxazolidone (22) in 37 mL of CH2Cl2, 1.89 mL of
i-Pr2NEt, 11.0 and 5.50 mL (2.0 and 1.0 equiv) of 1.0 M
Bu2BOTf/CH2Cl2, a solution of 2.50 g (1.0 equiv) of the cobalt-
complexed alkyne 23a in 15 mL of CH2Cl2, and 100 mL of
acetone with excess CAN gave 1.66 g (94%) of adduct 24a as
[R]25 -66.9° (c ) 9.2, CH2Cl2); MS m/ e 372 (M+ - 15), 328,
D
256, 252, 192, 165, 160, 143, 123, 97, 91; IR (CH2Cl2) 3031,
2967, 2171, 1782, 1701, 1480, 1454, 1385, 1250, 1221, 1106,
1
1044 cm-1; H NMR (CDCl3) δ 0.10 (s, 9H), 1.10 (d, J ) 6.9
Hz, 3H), 1.31 (d, J ) 6.3 Hz, 3H), 2.80 (dd, J ) 9.3 , 3.3 Hz,
1H), 3.77 (m, 2H), 3.92 (m, 1H), 4.13 (m, 1H), 4.28 (m, 2H),
4.39 (d, J ) 12.0 Hz, 1H), 4.62 (d, J ) 12.0 Hz, 1H), 7.31 (m,
5H); 13C NMR (CDCl3) δ 0.0, 15.6, 17.0, 38.1, 42.4, 42.6, 61.5,
69.9, 73.0, 88.2, 104.8, 127.3, 127.4, 128.1, 138.6, 153.0, 175.7;
HRMS(CI) calcd for (C21H29NO4Si + H) ([M + H]+) 388.1944,
found 388.1936.
a light yellow oil: [R]25 +28.7° (c ) 12.4, MeOH); MS m/ e
D
323 (M+), 308, 194, 179, 151, 130, 97, 73; IR (CH2Cl2) 2967,
1
2167, 1778, 1701, 1386, 1208 cm-1; H NMR (CDCl3) δ 0.12
(s, 9H), 0.92 (t, J ) 7.0 Hz, 6H), 1.03 (t, J ) 7.5 Hz, 3H), 1.17
(d, J ) 7.5 Hz, 3H), 1.40 (m, 1H), 1.56 (m, 1H), 2.38 (m, 1H),
2.73 (m, 1H), 3.98 (quint, J ) 7.0 Hz, 1H), 4.20 (dd, J ) 3.5,
6.5 Hz, 1H), 4.27 (t, J ) 8.5 Hz, 1H), 4.41 (m, 1H); 13C NMR
(CDCl3) δ -0.3, 11.0, 13.8, 14.6, 17.5, 23.1, 28.1, 36.2, 40.9,
57.9, 62.7, 85.7, 107.8, 153.1, 174.6; HRMS(CI) calcd for
(C17H29NO3Si + H) ([M + H]+) 324.1995, found 324.2012.
Nich ola s Ad d u ct en t-24a . Following method B, above, a
solution of 1.87 g (10.1 mmol, 1.0 equiv) of (R)-4-isopropyl-N-
propionyl-2-oxazolidone (ent-22) in 33 mL of CH2Cl2, 1.74 mL
Nich ola s Ad d u ct en t-27c. Following method A, above, a
solution of 0.91 g (6.33 mmol, 2.0 equiv) of N-propionyl-2-
oxazolidone (26) in 22 mL of CH2Cl2, 1.10 mL of i-Pr2NEt, 6.33
and 3.16 mL (2.0 and 1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a
solution of 1.78 g (1.0 equiv) of the cobalt-complexed alkyne
ent-23c in 6.3 mL of CH2Cl2, and 50 mL of acetone with excess
CAN gave 1.01 g (83%) of the adduct ent-27c as a pale yellow

Total Syntheses of Thienamycin and PS-5
J . Org. Chem., Vol. 61, No. 7, 1996 2421
oil: [R]25 +63.5° (c ) 17.1, CH2Cl2); 1HNMR and IR are
4(S )-Isop r op yl-N -[4′-[(t er t -b u t yld ip h e n ylsilyl)oxy]-
bu tyr yl-2-oxa zolid on e (39). A solution of 0.55 g (4.29 mmol,
1.0 equiv) of (S)-4-isopropyl-2-oxazolidone (38) in 55 mL of THF
was cooled to -78 °C under nitrogen and was treated in
dropwise fashion, with vigorous stirring, with 1.72 mL (1.0
equiv) of 2.5 M n-butyllithium/hexanes. After being stirred
for an additional 10 min at -78 °C, the reaction was treated
with a solution of 1.55 g (1.0 equiv) of acid chloride 37 in 10
mL of THF. The reaction mixture was then allowed to warm
slowly to rt and was treated with 50 mL of saturated aqueous
NH4Cl solution. The aqueous layer was extracted with 3 ×
50 mL of diethyl ether, and the combined organic extracts were
dried (MgSO4), filtered, concentrated, and chromatographed
(10:1 hexanes/EtOAc) to afford 1.74 g (89%) of 39 as a colorless
oil: [R]25D +40.6° (c ) 8.4, CH2Cl2); MS m/ e 396 (M+ - CMe3),
324, 318, 310, 267, 224, 199, 181, 161, 135, 105; IR (CH2Cl2)
3072, 2963, 2932, 2859, 1780, 1702, 1472, 1428, 1387, 1302,
1208, 1112, 1022, 971, 909 cm-1; 1H NMR (CDCl3) δ 0.83 (d, J
) 6.9 Hz, 3H), 0.87(d, J ) 7.2 Hz, 3H), 1.02 (s, 9H), 1.90 (quint,
J ) 6.8 Hz, 2H), 2.33 (m, 1H), 3.03 (t, J ) 7.4 Hz, 2H), 3.70 (t,
J ) 6.3 Hz, 2H), 4.18 (m, 2H), 4.37 (m, 1H), 7.32-7.65 (m,
10H). Anal. Calcd for C26H35NO4Si: C, 68.84; H, 7.78; N, 3.09.
Found: C, 68.67; H, 7.86; N, 2.95.
4(S)-Me t h yl-5(R )-p h e n yl-N -[4′-[(t er t-b u t yld ip h e n yl-
silyl)oxy]bu tyr yl-2-oxa zolid on e (56). A solution of 2.47 g
(13.9 mmol, 1.0 equiv) of 4(S)-methyl-5(R)-phenyl-2-oxazoli-
done (38b) in 180 mL of THF was cooled to -78 °C under
nitrogen and was treated in dropwise fashion, with vigorous
stirring, with 5.60 mL (1.0 equiv) of 2.5 M n-butyllithium/
hexanes. After being stirred for an additional 10 min at -78
°C, the reaction mixture was treated with a solution of 5.03 g
(1.0 equiv) of acid chloride 37 in 30 mL of THF. The resulting
light brown solution was stirred for 20 min at -78 °C, warmed
to 0 °C, and stirred for 20 min at 0 °C. The reaction mixture
was then treated with 50 mL of saturated aqueous NH4Cl and
10 mL of water, and the aqueous layer was extracted with 3
× 60 mL of diethyl ether. The combined organic extracts were
dried (MgSO4), filtered, concentrated, and chromatographed
(silica gel; 100:5 hexanes/EtOAc) to afford 5.22 g (75%) of 56
as a colorless oil: [R]25D -17.8° (c ) 18.1, CH2Cl2); IR (CH2Cl2)
3071, 2932, 1781, 1703, 1472, 1428, 1348, 1198, 1111, 1032
cm-1; 1H NMR (CDCl3) δ 0.88 (d, J ) 7.0 Hz, 3H), 1.08 (s, 9H),
1.96 (quint, J ) 7.0 Hz, 2H), 3.09 (t, J ) 7.4 Hz, 2H), 3.74 (t,
J ) 6.2 Hz, 2H), 4.73 (quint, J ) 6.9 Hz, 1H), 5.62 (d, J ) 7.3
Hz, 1H), 7.28-7.69 (m, 15H); 13C NMR (CDCl3) δ 14.6, 19.2,
26.9, 27.0, 32.3, 54.7, 62.9, 78.8, 125.5, 127.6, 128.6, 129.5,
133.3, 133.7, 135.5, 152.9, 172.7.
Nich ola s Ad d u ct 40. A solution of 1.50 g (3.31 mmol, 2.0
equiv) of 4(S)-isopropyl-N-[4-[(tert-butyldiphenylsilyl)oxy]-
butyryl]-2-oxazolidone (39) in 12 mL of anhydrous methylene
chloride was cooled to 0 °C under nitrogen and was treated in
dropwise fashion, with vigorous stirring, with 0.57 mL (3.31
mmol, 2.0 equiv) of freshly distilled N,N-diisopropylethylamine
and 3.3 mL (3.30 mmol, 2.0 equiv) of a 1.0 M solution of
dibutylboron triflate/methylene chloride. After being stirred
for 15 min, the reaction mixture was cooled to -78 °C and
treated with an additional 1.65 mL (1.65 mmol, 1.0 equiv) of
1.0 M dibutylboron triflate/methylene chloride. A solution of
0.75 g (1.65 mmol, 1.0 equiv) of the cobalt-complexed alkyne
23a in 3.5 mL of methylene chloride was then added in
dropwise fashion and with vigorous stirring. The resulting
mixture was stirred for 5 min at -78 °C and was then warmed
to 0 °C and stirred for 20 min at 0 °C. The reaction was then
quenched with 15 mL of pH 7 buffer, and the aqueous layer
was extracted with 3 × 15 mL of methylene chloride. The
combined organic extracts were dried (MgSO4), filtered, con-
centrated, and chromatographed (10:1 hexanes/EtOAc) to
afford the desired cobalt-complexed product together with a
small amount of excess oxazolidone 39. The material thus
obtained was dissolved in 50 mL of acetone and treated
portionwise, at rt and with vigorous stirring, with ammonium
cerium(IV) nitrate (CAN) until gas evolution ceased. The
solvent was then concentrated under reduced pressure at rt,
and the residue was partitioned between 20 mL of water and
20 mL of diethyl ether. The aqueous layer was extracted with
5 × 20 mL of diethyl ether, and the combined organic extracts
D
identical to those of adduct 27c.
Nich ola s Ad d u cts 48a a n d 48s. Following method A,
above, a solution of 3.22 g (13.8 mmol, 2.0 equiv) of (S)-4-
methyl-(R)-5-phenyl-N-propionyl-2-oxazolidone (ent-18) in 60
mL of CH2Cl2, 2.35 mL of i-Pr2NEt, 13.8 and 6.90 mL (2.0 and
1.0 equiv) of 1.0 M Bu2BOTf/CH2Cl2, a solution of 3.88 g (1.0
equiv) of the cobalt-complexed alkyne ent-23c in 15 mL of
CH2Cl2, and 100 mL of acetone with excess CAN gave 2.68 g
(81%) of adduct 48a and 0.24 g (7%) of adduct 48s.
Analytical data for 48a : mp 96.5-97.0 °C (hexanes, color-
less cotton-like crystals); [R]25 -27.6° (c ) 3.5, MeOH); IR
D
(CH2Cl2) 3032, 2963, 2170, 1780, 1698, 1496, 1456, 1346, 1197,
1
1121 cm-1; H NMR (CDCl3) δ 0.17 (s, 9H), 0.65 (d, J ) 6.7
Hz, 3H), 1.36 (d, J ) 6.5 Hz, 6H), 3.36 (dd, J ) 5.0, 9.5 Hz,
1H), 3.67 (quint, J ) 5.5 Hz, 1H), 4.20 (quint, J ) 8.0 Hz, 1H),
4.42 (d, J ) 12.5 Hz, 1H), 4.50 (d, J ) 12.5, 1H), 4.72 (quint,
J ) 7.0 Hz, 1H), 6.62 (d, J ) 7.5 Hz, 1H), 7.22-7.42 (m, 10H).
Anal. Calcd for C28H35NO4Si: C, 70.41; H, 7.39; N, 2.93.
Found: C, 70.48; H, 7.40; N, 2.89.
Analytical data for 48s: mp 117.0-117.5 °C (pentane,
colorless cotton-like crystals); [R]25 +1.9° (c ) 13.3, CH2Cl2);
D
IR (CH2Cl2) 3033, 2974, 2170, 1780, 1703, 1456, 1344, 1250,
1198, 1121 cm-1; 1H NMR (CDCl3) δ 0.18 (s, 9H), 0.77 (d, J )
6.6 Hz, 3H), 1.31 (d, J ) 7.0 Hz, 3H), 1.40 (d, J ) 6.1 Hz, 3H),
3.13 (t, J ) 7.2 Hz, 1H), 3.74 (quint, J ) 6.2 Hz, 1H), 4.15 (m,
1H), 4.49 (d, J ) 11.9 Hz, 1H), 4.57 (d, J ) 11.9, 1H), 4.80
(quint, J ) 6.7 Hz, 1H), 5.67 (d, J ) 7.6 Hz, 1H), 7.23-7.47
(m, 10H). Anal. Calcd for C28H35NO4Si: C, 70.41; H, 7.39;
N, 2.93. Found: C, 70.48; H, 7.42; N, 2.89.
1-O-(ter t-Bu t yld ip h en ylsilyl)-1,4-b u t a n ed iol (35).
A
solution of 6.0 g (66.6 mmol, 3.0 equiv) of 1,4-butanediol in 35
mL of THF was cooled to -78 °C under nitrogen, and the
resulting white suspension was treated in dropwise fashion,
with vigorous stirring, with 8.9 mL (22.2 mmol, 1.0 equiv) of
2.5 M n-butyllithium/hexanes. The reaction mixture became
very viscous. After being stirred for additional 5 min, the
reaction mixture was treated in dropwise fashion with 5.76
mL (22.2 mmol, 1.0 equiv) of TBDPSCl, and the resulting
mixture was allowed to warm to rt to give a white suspension.
After being stirred at rt for 40 min, the reaction mixture was
treated with 35 mL of water and 35 mL of saturated aqueous
NH4Cl solution, and the separated aqueous layer was extracted
with 3 × 50 mL of diethyl ether. The combined organic
extracts were dried (MgSO4), filtered, concentrated under
reduced pressure, and chromatographed (100:15 hexanes/
EtOAc) to yield 6.58 g (90%) of 35 as a colorless oil: IR
(CH2Cl2) 3616, 3436, 3048, 2933, 2859, 1472, 1427, 1390, 1267,
1111, 1056 cm-1; 1H NMR (CDCl3) δ 1.06 (s, 9H), 1.67 (m, 4H),
3.68 (m, 4H), 7.37-7.69 (m, 10H).
4-[(ter t-Bu tyld ip h en ylsilyl)oxy]bu tyr ic Acid (36).
A
solution of 5.70 g (17.4 mmol, 1.0 equiv) of 35 in 45 mL of DMF
was cooled to 0 °C under nitrogen and was treated portionwise
with 22.9 g (60.7 mmol, 3.5 equiv) of PDC. The resulting
mixture was allowed to warm to rt and was stirred overnight
(15 h). The reaction was then poured into a separatory funnel
containing 320 mL of water and extracted with 5 × 180 mL of
diethyl ether. The combined organic extracts were dried
(MgSO4), filtered, concentrated under reduced pressure, and
chromatographed (100:5 hexanes/EtOAc and 75:25:0.3 hex-
anes/EtOAc/AcOH) to afford 4.43 g (75%) of 36 as a colorless
oil: IR (CH2Cl2) 3288-2500, 1749, 1711, 1472, 1428, 1288,
1
1111 cm-1; H NMR (CDCl3) δ 1.07 (s, 9H), 1.91 (quint, J )
6.6 Hz, 2H), 2.53 (t, J ) 7.4 Hz, 2H), 3.73 (t, J ) 6.0 Hz, 2H),
7.36-7.69 (m, 10H); 13CNMR (CDCl3) δ 19.2, 26.8, 27.5, 30.8,
62.8, 127.6, 129.6, 133.6, 135.5, 180.1.
4-[(ter t-Bu tyld ip h en ylsilyl)oxy]bu tyr yl Ch lor id e (37).
A solution of 4.77 g (13.9 mmol, 1.0 equiv) of 36 in 48 mL of
benzene was treated with 6.9 mL (79.4 mmol, 5.7 equiv) of
oxalyl chloride at rt, and the reaction was stirred at rt for 6 h.
The solvent and excess oxalyl chloride were then removed
under reduced pressure to afford a quantitative yield of acid
chloride 37 as a pale yellow, unstable oil: IR (CH2Cl2) 3072,
1
2932, 1797, 1472, 1428, 1112 cm-1; H NMR (CDCl3) δ 1.07
(s, 9H), 1.95 (quint, J ) 6.0 Hz, 2H), 3.07 (t, J ) 7.2 Hz, 2H),
3.70 (t, J ) 5.7 Hz, 2H), 7.38-7.68 (m, 10H).

2422 J . Org. Chem., Vol. 61, No. 7, 1996
J acobi et al.
were dried (MgSO4), filtered, concentrated, and chromato-
graphed (10:1 hexanes/EtOAc) to give 859 mg (88%) of adduct
ing 3.54 g (10.9 mmol, 1.0 equiv) of N-acyloxazolidone 24a in
120 mL of THF and 40 mL of water, 4.96 g (4.0 equiv) of 30%
aqueous hydrogen peroxide, 0.92 g (2.0 equiv) of lithium
hydroxide monohydrate for 17 h, 32 mL of 1.5 N sodium sulfite,
and 140 mL of saturated aqueous sodium bicarbonate. Chro-
matography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave
40 as a pale yellow oil: [R]25 +14.3° (c ) 2.9, CH2Cl2); IR
D
(CH2Cl2) 3072, 2964, 2932, 2859, 2168, 1777, 1701, 1464, 1428,
1387, 1256, 1204, 1112, 845 cm-1; 1H NMR (CDCl3) δ 0.12 (s,
9H), 0.88 (t, J ) 6.8 Hz, 3H), 1.03 (m, 15H), 1.19-1.54 (m,
2H), 1.96 (m, 1H), 2.07 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H),
3.66 (m, 2H), 4.01-4.14 (m, 2H), 4.23 (m, 1H), 4.33 (m, 1H),
7.33-7.68 (m, 10 H). Anal. Calcd for C34H49NO4Si2: C, 68.99;
H, 8.34; N, 2.37. Found: C, 68.91; H, 8.36; N, 2.36.
1.40 g (91%) of 25a as a colorless oil: [R]25 +11.7° (c ) 27.8,
D
MeOH); MS m/ e 140 (M+
), 125, 111, 97, 83, 74, 67; IR (CH2Cl2)
3303, 3303-2428, 2115, 1748, 1711, 1463, 1416, 1288, 1233
cm-1; 1H NMR (CDCl3) δ 1.06 (t, J ) 7.0 Hz, 3H), 1.27 (d, J )
7.0 Hz, 3H), 1.46-1.63 (m, 2H), 2.14 (d, J ) 2.0 Hz, 1H), 2.63-
2.74 (m, 2H); 13C NMR (CDCl3) δ 11.8, 13.5, 24.0, 35.9, 43.1,
70.8, 84.6, 181.1; HRMS(CI) calcd for (C8H12O2 + H) ([M +
H]+) 141.0916, found 141.0925.
Nich ola s Ad d u ct 57. A solution of 5.03 g (10.0 mmol, 2.0
equiv) of 4(S)-methyl-5(R)-phenyl-N-[4-[(tert-butyldiphenyl-
silyl)oxy]butyryl]-2-oxazolidone (56) in 35 mL of anhydrous
methylene chloride was cooled to 0 °C under nitrogen and was
treated in dropwise fashion, with vigorous stirring, with 1.74
mL (10.0 mmol, 2.0 equiv) of freshly distilled N,N-diisopropyl-
ethylamine and 10.0 mL (10.0 mmol, 2.0 equiv) of a 1.0 M
solution of dibutylboron triflate/methylene chloride. After
being stirred for 15 min, the reaction mixture was cooled to
-78 °C and treated with an additional 5.00 mL (5.00 mmol,
1.0 equiv) of 1.0 M dibutylboron triflate/methylene chloride.
A solution of 2.82 g (5.00 mmol, 1.0 equiv) of the cobalt-
complexed alkyne ent-23c in 10.0 mL of methylene chloride
was then added in dropwise fashion and with vigorous stirring.
The resulting mixture was stirred for 5 min at -78 °C and
was then warmed to 0 °C and stirred for 20 min at 0 °C. The
reaction was then quenched with 65 mL of pH 7 buffer, and
the aqueous layer was extracted with 3 × 55 mL of methylene
chloride. The combined organic extracts were dried (MgSO4),
filtered, concentrated, and chromatographed (10:1 hexanes/
EtOAc) to afford the desired cobalt complexed product together
with a small amount of excess oxazolidone 56. The material
thus obtained was dissolved in 225 mL of acetone and treated
portionwise, at rt and with vigorous stirring, with ammonium
cerium(IV) nitrate (CAN) until gas evolution ceased. The
solvent was then concentrated under reduced pressure at rt,
and the residue was partitioned between 90 mL of water and
80 mL of diethyl ether. The aqueous layer was extracted with
5 × 80 mL of diethyl ether, and the combined organic extracts
were dried (MgSO4), filtered, concentrated, and chromato-
graphed (10:1 hexanes/EtOAc) to give 2.97 g (79%) of adduct
Acetylen ic Acid en t-25a . This material was prepared in
91% yield following a procedure identical to that described
above for acetylenic acid 25a , employing 2.58 g (7.98 mmol,
1.0 equiv) of N-acyloxazolidone ent-24a in 87 mL of THF and
29 mL of water, 3.62 g (4.0 equiv) of 30% aqueous hydrogen
peroxide, 0.67 g (2.0 equiv) of lithium hydroxide monohydrate
for 16 h, 23 mL of 1.5 N sodium sulfite, and 102 mL of
saturated aqueous sodium bicarbonate. Chromatography
(silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave 1.02 g (91%)
of ent-25a as a colorless oil: [R]25 -11.5° (c ) 60.7, MeOH);
D
IR and 1H NMR are identical to those of acid 25a .
Acetylen ic Acid 25b. This material was prepared in 56%
yield following the general procedure described above, employ-
ing 0.83 g (2.45 mmol, 1.0 equiv) of N-acyloxazolidone 24b in
36 mL of THF and 12 mL of water, 1.11 g (4.0 equiv) of 30%
aqueous hydrogen peroxide, 0.21 g (2.0 equiv) of lithium
hydroxide monohydrate for 2.5 days, 7 mL of 1.5 N sodium
sulfite, and 31 mL of saturated aqueous sodium bicarbonate.
Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc)
gave 0.21 g (56%) of 25b as a white solid: mp 68.5-70.0 °C
(hexanes, colorless needles); [R]25 -1.3° (c ) 45.8, MeOH);
D
IR (CH2Cl2) 3303, 3303-2562, 1748, 1711, 1462 cm-1; 1H NMR
(CDCl3) δ 0.94 (d, J ) 6.6 Hz, 3H), 1.03 (d, J ) 6.6 Hz, 3H),
1.22 (d, J ) 7.0 Hz, 3H), 1.90 (m, 1H), 2.11 (d, J ) 2.4 Hz,
1H), 2.47 (m, 1H), 2.66 (m, 1H). Anal. Calcd for C9H14O2: C,
70.10; H, 9.15. Found: C, 70.11; H, 9.18.
Acetylen ic Acid 25c. From N-acyloxazolidone 24c: This
material was prepared in 86% yield following the general
procedure described above, employing 4.00 g (9.31 mmol, 1.0
equiv) of N-acyloxazolidone 24c in 118 mL of THF and 39 mL
of water, 4.22 g (4.0 equiv) of 30% aqueous hydrogen peroxide,
0.78 g (2.0 equiv) of lithium hydroxide monohydrate for 18 h,
27 mL of 1.5 N sodium sulfite, and 118 mL of saturated
aqueous sodium bicarbonate. Chromatography (silica gel; 75:
25:0.3 hexanes/EtOAc/HOAc) gave 1.97 g (86%) of 25c as a
white solid: mp 62.0-62.5 °C (8:1 hexanes/ether, colorless
57 as a pale yellow oil: [R]25 0.00° (c ) 68.3, CH2Cl2); IR
D
(CH2Cl2) 3055, 2935, 1781, 1704, 1348, 1198, 1112 cm-1; H
1
NMR (CDCl3) δ 0.17 (s, 9H), 0.64 (d, J ) 6.5 Hz, 3H), 1.09 (s,
9H), 1.42 (d, J ) 6.2 Hz, 3H), 2.21 (m, 2H), 3.35 (m, 1H), 3.69-
3.88 (m, 3H), 4.37 (m, 1H), 4.46 (d, J ) 12.3 Hz, 1H), 4.52 (d,
J ) 12.3 Hz, 1H), 4.53 (m, 1H), 5.16 (d, J ) 6.3 Hz, 1H), 7.13-
7.73 (m, 20 H); 13C NMR (CDCl3) δ 0.1, 14.2, 16.6, 19.2, 27.0,
33.8, 39.3, 40.6, 54.7, 62.0, 70.5, 75.8, 78.3, 89.4, 104.8, 125.5,
127.2, 127.3, 127.5, 127.6, 128.1, 128.4, 129.6, 133.4, 133.7,
133.9, 135.5, 138.7, 152.4, 173.9. Anal. Calcd for C45H55NO5-
Si2: C, 72.44; H, 7.43; N,1.88. Found: C, 72.70; H, 7.47;
N,1.84.
needles); [R]25 -31.6° (c ) 7.8, MeOH); MS m/ e 246 (M+),
D
202, 140, 111, 91, 65; IR (CH2Cl2) 3303, 3302-2550, 1750,
1
1712, 1455, 1379, 1140, 1082 cm-1; H NMR (CDCl3) δ 1.13
Gen er a l P r oced u r e for th e P r ep a r a tion of Acetylen ic
Acid s by Hyd r olysis of N-Acyloxa zolid on es. A solution
of 10.9 mmol (1.0 equiv) of the N-acyloxazolidone in 120 mL
of THF and 40 mL of water was cooled to 0 °C with stirring
and was treated with 4.0 equiv of 30% aqueous hydrogen
peroxide and 2.0 equiv of lithium hydroxide monohydrate. The
reaction mixture was then allowed to warm to rt and was
stirred overnight (12-17 h) before being cooled back to 0 °C
and treated with 32 mL of a 1.5 N sodium sulfite solution.
The resulting mixture was warmed to rt, and stirring was
continued for 1 h. At the end of this period, the reaction was
treated with 140 mL of a saturated aqueous sodium bicarbon-
ate solution, and the THF was evaporated under reduced
pressure. The remaining alkaline aqueous solution was then
washed with 3 × 50 mL of methylene chloride and acidified
to pH ) 1-3 first with concd HCl and then with 5 N aqueous
HCl. The resulting suspension was then extracted with 6 ×
80 mL of ethyl acetate, and the combined extracts were dried
(MgSO4), filtered, concentrated under reduced pressure, and
chromatographed (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc)
to afford the corresponding acetylenic acid.
(d, J ) 7.0 Hz,3H), 1.37 (d, J ) 6.0 Hz, 3H), 2.20 (d, J ) 2.5
Hz, 1H), 2.66 (m, 1H), 2.84 (quint, J ) 7.5 Hz, 1H), 3.73 (m,
1H), 4.46 (d, J ) 12.0 Hz, 1H), 4.70 (d, J ) 12.0 Hz, 1H), 7.34
(m, 5H). Anal. Calcd for
Found: C, 73.22; H, 7.31.
C15H18O3: C, 73.15; H, 7.37.
From N-acyloxazolidone 27c: 6.30 g (16.26 mmol, 1.0 equiv)
of N-acyloxazolidone 27c in 180 mL of THF and 60 mL of
water, 7.38 g (4.0 equiv) of 30% aqueous hydrogen peroxide,
0.98 g (2.0 equiv) of lithium hydroxide monohydrate for 18 h,
47 mL of 1.5 N sodium sulfite, and 210 mL of saturated
aqueous sodium bicarbonate gave 3.64 g (91%) of 25c as a
white solid, having identical physical and spectral properties
as those described above: [R]25 -31.7° (c ) 5.5, MeOH).
D
Acetylen ic Acid en t-25c. From N-acyloxazolidone ent-
24c: This material was prepared in 79% yield following the
general procedure described above, employing 2.36 g (5.49
mmol, 1.0 equiv) of N-acyloxazolidone ent-24c in 70 mL of THF
and 23 mL of water, 2.49 g (4.0 equiv) of 30% aqueous
hydrogen peroxide, 0.46 g (2.0 equiv) of lithium hydroxide
monohydrate for 16 h, 16 mL of 1.5 N sodium sulfite, and 70
mL of saturated aqueous sodium bicarbonate. Chromatogra-
phy (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave 1.06 g
Acetylen ic Acid 25a . This material was prepared in 91%
yield following the general procedure described above, employ-

Total Syntheses of Thienamycin and PS-5
J . Org. Chem., Vol. 61, No. 7, 1996 2423
(79%) of ent-25c: [R]25 +30.2° (c ) 19.5, MeOH). Melting
Acetylen ic Acid 59. A solution of 2.16 g (2.89 mmol, 1.0
equiv) of N-acyloxazolidone 57 in 39 mL of THF, 39 mL of
DMF, and 13 mL of water was cooled 0 °C with stirring and
was treated with 2.63 g (8.0 equiv) of 30% aqueous hydrogen
peroxide and 0.48 g (4.0 equiv) of lithium hydroxide monohy-
drate. The reaction mixture was then allowed to warm to rt
and was stirred overnight (20 h) before being cooled back to 0
°C and treated with 17.5 mL of 1.5 N sodium sulfite solution.
The reaction was then warmed to rt, stirred for an additional
1 h, diluted with 40 mL of water, acidified to pH ) 2 with 5 N
aqueous HCl, and extracted with 6 × 80 mL of ethyl acetate.
The combined extracts were dried (MgSO4), filtered, and
concentrated at rt under high vacuum to remove DMF. The
remaining residue was then dissolved in 27 mL of THF and
27 mL of water, and the resulting solution was treated with
0.73 g (6.0 equiv) of lithium hydroxide monohydrate at rt for
two days to complete cleavage of the TMS group. The reaction
mixture was then diluted with 40 mL of water, acidified with
5 N aqueous HCl to pH ) 3.5, and extracted with 6 × 60 mL
of ethyl acetate. The combined organic extracts were dried
(MgSO4), filtered, concentrated under reduced pressure, and
chromatographed (silica gel; 100:10:0.2 hexanes/EtOAc/HOAc)
to afford 1.06 (74%) of acetylenic acid 59 as a pale yellow oil:
[R]25D +9.6° (c ) 25.7, CH2Cl2); IR (CH2Cl2) 3302, 3350-2413,
D
point, IR, and 1H NMR are identical to those of acid 25c.
From N-acyloxazolidone ent-27c: 0.406 g (1.05 mmol, 1.0
equiv) of N-acyloxazolidone ent-27c in 12 mL of THF and 4
mL of water, 0.476 g (4.0 equiv) of 30% aqueous hydrogen
peroxide, 0.088 g (2.0 equiv) of lithium hydroxide monohydrate
for 16 h, 3 mL of 1.5 N sodium sulfite, and 13 mL of saturated
aqueous sodium bicarbonate gave 0.242 g (94%) of ent-25c,
having physical and spectral properties identical to those
described above: [R]25 +28.2° (c ) 14.9, MeOH).
D
Acetylen ic Acid 49a . This material was prepared in 85%
yield following the general procedure described above, employ-
ing 3.25 g (7.56 mmol, 1.0 equiv) of N-acyloxazolidone 48a in
96 mL of THF and 32 mL of water, 3.43 g (4.0 equiv) of 30%
aqueous hydrogen peroxide, 0.63 g (2.0 equiv) of lithium
hydroxide monohydrate for 16 h, 22 mL of 1.5 N sodium sulfite,
and 96 mL of saturated aqueous sodium bicarbonate. Chro-
matography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave
1.43 g (85%) of 49a as a pale yellow oil: [R]25D +4.1° (c ) 25.8,
MeOH); IR (CH2Cl2) 3303, 3303-2500, 1747, 1706, 1456, 1286,
1
1065 cm-1; H NMR (CDCl3) δ 1.35 (d, J ) 6.5 Hz, 3H), 1.41
(d, J ) 7.0 Hz, 3H), 2.21 (d, J ) 2.5 Hz,1H), 2.86 (m, 1H), 2.95
(m, 1H), 3.69 (m, 1H), 4.49 (d, J ) 11.5 Hz, 1H), 4.50 (d, J )
11.5 Hz, 1H), 7.25-7.39 (m, 5H); 13CNMR (CDCl3) δ 16.4, 17.3,
39.4, 40.7, 70.9, 72.9, 74.1, 81.4, 127.5, 127.7, 128.2, 138.1,
181.7; HRMS(CI) calcd for (C15H18O3 + H) ([M + H]+) 247.1335,
found 247.1337.
1
1746, 1706, 1472, 1428, 1144, 1112 cm-1; H NMR (CDCl3) δ
1.05 (s, 9H), 1.35 (d, J ) 6.1 Hz, 3H), 2.01 (m,1H), 2.17 (d, J
) 2.4 Hz, 1H), 2.26 (m, 1H), 2.88 (m, 1H), 3.06 (m, 1H), 3.66
(m, 1H), 3.75 (m,1H), 4.45 (d, J ) 11.8 Hz, 1H), 4.56 (d, J )
11.8 Hz, 1H), 7.21-7.70 (m, 15H); 13C NMR (CDCl3) δ 17.5,
19.2, 26.8, 33.6, 40.4, 42.2, 61.9, 71.0, 73.1, 74.3, 81.5, 127.5,
127.6, 128.3, 129.6, 133.4, 133.5, 135.6, 138.2, 179.8; HRMS-
(CI) calcd for (C32H38O4Si + H) ([M + H]+) 515.2619, found
515.2642.
Gen er a l P r oced u r es for th e Cu r tiu s Rea r r a n gem en t
of Acetylen ic Acid s. Meth od A. A solution consisting of 5.56
mmol (1.0 equiv) of the appropriate acetylenic acid in 32 mL
of benzene was treated in dropwise fashion, and with vigorous
stirring, with 1.0 equiv each of DPPA and triethylamine at rt
under a nitrogen atmosphere. After addition was complete,
the reaction mixture was heated at reflux for 3.5 h, and the
solvent was evaporated under reduced pressure. The residue
was taken up in 32 mL of t-BuOH containing 0.1 equiv of CuCl,
and the resulting mixture was heated at reflux under nitrogen
for 1-2 h before t-BuOH was removed under reduced pressure.
The remaining residue was partitioned between 30 mL of
diethyl ether and 25 mL of saturated aqueous NaHCO3. The
aqueous layer was extracted with 3 × 30 mL of diethyl ether,
and the combined organic extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure and chro-
matographed (silica gel; 20:1-50:1 hexanes/EtOAc) to give the
corresponding acetylenic N-Boc-amine.
Meth od B. A solution consisting of 3.37 mmol (1.0 equiv)
of the appropriate acetylenic acid in 19 mL of benzene or
toluene was treated in dropwise fashion, and with vigorous
stirring, with 1.0 equiv each of DPPA and triethylamine at rt
under a nitrogen atmosphere. After addition was complete,
the reaction mixture was heated at reflux for 3.5 h, and the
solvent was evaporated under reduced pressure. The residue
was taken up in 14 mL of methylene chloride containing 3.0
equiv of t-BuOH and 5% (v/v) of TMSCl, and the resulting
mixture was stirred at rt under nitrogen for 10-36 h until
reaction was complete (TLC). The reaction was then quenched
by slow addition of 15 mL of saturated aqueous NaHCO3. The
mixture was then diluted with 20 mL of diethyl ether, and
the separated aqueous layer was extracted with 3 × 15 mL of
diethyl ether. The combined organic extracts were dried
(MgSO4), filtered, concentrated under reduced pressure, and
chromatographed (silica gel; 20:1-50:1 hexanes/EtOAc) to give
the corresponding acetylenic N-Boc-amine.
Acetylen ic Acid 49s. This material was prepared in 39%
yield following the general procedure described above, employ-
ing 0.28 g (0.65 mmol, 1.0 equiv) of N-acyloxazolidone 48s in
8.2 mL of THF and 2.7 mL of water, 0.30 g (4.0 equiv) of 30%
aqueous hydrogen peroxide, 0.05 g (2.0 equiv) of lithium
hydroxide monohydrate for 16 h, 1.9 mL of 1.5 N sodium
sulfite, and 8.2 mL of saturated sodium bicarbonate. Chro-
matography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) gave
62 mg (39%) of 49s as a pale yellow oil: [R]25 -38.6° (c )
D
12.2, CH2Cl2); IR (CH2Cl2) 3303, 3303-2400, 1708, 1454, 1376,
1285, 1242, 1111 cm-1 1H NMR (CDCl3) δ 1.28 (d, J ) 7.5
;
Hz, 3H), 1.39 (d, J ) 6.5 Hz, 3H), 2.18 (d, J ) 2.5 Hz, 1H),
2.85 (m, 1H), 3.02 (m, 1H), 3.79 (m, 1H), 4.47 (d, J ) 11.5 Hz,
1H), 4.60 (d, J ) 11.5 Hz, 1H), 7.25-7.36 (m, 5H); 13C NMR
(CDCl3) δ 13.9, 18.0, 39.4, 42.1, 71.0, 72.2, 74.2, 82.0, 127.5,
127.9, 128.2, 137.9, 180.2.
Acetylen ic Acid 42. A solution of 859 mg (1.45 mmol, 1.0
equiv) of N-acyloxazolidone 40 in 24 mL of THF, 24 mL of
DMF, and 8 mL of water was cooled to 0 °C with stirring and
was treated with 1.67 g (10.0 equiv) of 30% aqueous hydrogen
peroxide and 304 mg (5.0 equiv) of lithium hydroxide mono-
hydrate. The reaction mixture was then allowed to warm to
rt and was stirred overnight (12 h) before being cooled back
to 0 °C and treated with 11 mL of 1.5 N sodium sulfite solution.
The reaction was then warmed to rt, stirred for an additional
1 h, acidified to pH ) 3 with 5 N aqueous HCl, and extracted
with 6 × 40 mL of ethyl acetate. The combined extracts were
dried (MgSO4), filtered, and concentrated at rt under high
vacuum to remove DMF. The remaining residue was then
dissolved in 14 mL of THF and 14 mL of water, and the
resulting solution was treated with 304 mg (5.0 equiv) of
lithium hydroxide monohydrate at rt for 1 day to complete
cleavage of the TMS group. The reaction mixture was then
diluted with 10 mL of water, acidified with 5 N aqueous HCl
to pH ) 3.5, and extracted with 6 × 30 mL of ethyl acetate.
The combined organic extracts were dried (Na2SO4), filtered,
concentrated under reduced pressure, and chromatographed
(silica gel; 100:10:0.2 hexanes/EtOAc/HOAc) to afford 481 mg
(81%) of acetylenic acid 42 as a pale yellow oil: [R]25 +12.4°
D
(c ) 13.4, CH2Cl2); MS m/ e 199 (M+ - 209), 181, 139, 135,
123, 105, 91, 77; IR (CH2Cl2) 3304, 3304-2400, 3056, 2964,
2934, 2860, 1747, 1709, 1473, 1428, 1391, 1112 cm-1; 1H NMR
(CDCl3) δ 1.05 (m, 12H), 1.55 (m, 2H), 1.88-2.10 (m, 2H), 2.11
(d, J ) 2.4 Hz, 1H), 2.67 (m, 1H), 2.86 (m, 1H), 3.74 (t, J ) 6.0
Hz, 2H), 7.33-7.69 (m, 10H); 13C NMR (CDCl3) δ 12.0, 19.2,
24.9, 26.8, 31.7, 35.6, 45.2, 61.9, 71.1, 84.3, 127.7, 129.7, 133.6,
135.6, 179.4. Anal. Calcd for C25H32O3Si: C, 73.49; H, 7.89.
Found: C, 73.55; H, 7.94.
Acet ylen ic Am in e 28a . This material was prepared in
82% yield following method A above, employing 779 mg (5.57
mmol, 1.0 equiv) of acetylenic acid 25a , 1.20 mL (1.0 equiv) of
DPPA, and 0.78 mL (1.0 equiv) of triethylamine in 32 mL of
benzene for 3.5 h and 55 mg (0.1 equiv) of CuCl in 32 mL of
t-BuOH for 1.25 h. Chromatography (silica gel; 20:1-50:1
hexanes/EtOAc) gave 963 mg (82%) of acetylenic amine 28a

2424 J . Org. Chem., Vol. 61, No. 7, 1996
J acobi et al.
as a pale yellow solid: mp 46.0-47.0 °C (hexanes, colorless
rectangular crystals); [R]25D +61.1° (c ) 24.8, MeOH); MS m/ e
155 (M+ - 56), 144, 138, 126, 109, 96, 88, 67, 57; IR (CH2Cl2)
3429, 3302, 2974, 2112, 1708, 1503, 1455, 1367, 1232, 1164,
1.44 (s, 9H), 2.18 (d, J ) 2.5 Hz, 1H), 2.69 (m, 1H), 3.68 (quint,
J ) 6.2 Hz, 1H), 3.86 (m, 1H), 4.52 (d, J ) 11.7 Hz, 1H), 4.66
(d, J ) 11.7 Hz, 1H), 4.99 (bs, 1H), 7.26-7.40 (m, 5H); 13C
NMR (CDCl3) δ 17.4, 18.0, 28.3, 44.1, 46.9, 70.9, 72.3, 73.9,
79.0, 81.7, 127.4, 127.7, 128.2, 138.1, 154.9. Anal. Calcd for
C19H27NO3: C, 71.89; H, 8.57; N, 4.41. Found: C, 71.82; H,
8.63; N, 4.40.
Acetylen ic Am in e 50s. This material was prepared in
72% yield following method B above, employing 55.6 mg (0.23
mmol, 1.0 equiv) of acetylenic acid 49s, 0.049 mL (1.0 equiv)
of DPPA, and 0.032 mL (1.0 equiv) of triethylamine in 1.4 mL
of toluene at 100 °C for 4.5 h and 0.064 mL (3.0 equiv) of
t-BuOH in 1 mL of methylene chloride containing 5% (v/v) of
TMSCl for 11 h. Chromatography (silica gel; 20:1-50:1
hexanes/EtOAc) gave 51.5 mg (72%) of acetylenic amine 50s
as a pale yellow oil: IR (CH2Cl2) 3427, 3302, 3033, 2980, 2141,
1711, 1501, 1454, 1367, 1231, 1164, 1092, 1021 cm-1; 1H NMR
(CDCl3) δ 1.22 (d, J ) 6.6 Hz, 3H), 1.36 (d, J ) 6.1 Hz, 3H),
1.46 (s, 9H), 2.18 (d, J ) 2.4 Hz, 1H), 2.59 (m, 1H), 3.55 (m,
1H), 4.33 (m, 1H), 4.46 (d, J ) 10.6 Hz, 1H), 4.53 (d, J ) 10.6
Hz, 1H), 4.86 (bd, J ) 9.9 Hz, 1H), 7.24-7.45 (m, 5H); HRMS-
(CI) calcd for (C19H27NO3 + H) ([M + H]+) 318.2069, found
318.2090.
1
1095 cm-1; H NMR (CDCl3) δ 0.99 (t, J ) 7.0 Hz, 3H), 1.18
(d, J ) 7.0 Hz, 3H), 1.42 (s, 9H), 1.49 (m, 2H), 2.09 (d, J ) 2.5
Hz, 1H), 2.28 (m, 1H), 3.79 (m, 1H), 4.64 (d, J ) 10.0 Hz, 1H).
Anal. Calcd for C12H21NO2: C, 68.21; H, 10.01; N, 6.63.
Found: C, 68.12; H, 10.07; N, 6.60.
Acetylen ic Am in e en t-28a . This material was prepared
in 74% yield following method A above, employing 673 mg
(4.80 mmol, 1.0 equiv) of ent-25a , 1.04 mL (1.0 equiv) of DPPA,
and 0.67 mL (1.0 equiv) of triethylamine in 27 mL of benzene
for 3.5 h and 48 mg (0.1 equiv) of CuCl in 27 mL of t-BuOH
for 1.25 h. Chromatography (silica gel; 20:1-50:1 hexanes/
EtOAc) gave 748 mg (74%) of acetylenic amine ent-28a as a
pale yellow solid: mp 46.0-47.0 °C (hexanes, colorless rec-
1
tangular crystals); [R]25 -64.0° (c ) 20.1, MeOH); IR and H
D
NMR are identical those of acetylenic amine 28a .
Acetylen ic Am in e 28b. This material was prepared in
64% yield following method B above, employing 380 mg (2.46
mmol, 1.0 equiv) of acetylenic acid 25b, 0.53 mL (1.0 equiv) of
DPPA, and 0.34 mL (1.0 equiv) of triethylamine in 14 mL of
benzene for 3.5 h and 0.70 mL (3.0 equiv) of t-BuOH in 9.7
mL of methylene chloride containing 5% (v/v) of TMSCl for 14
h. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc)
gave 357 mg (64%) of acetylenic amine 28b as a pale yellow
Acetylen ic Am in e 43. This material was prepared in 83%
yield following method B above, employing 481 mg (1.18 mmol,
1.0 equiv) of acetylenic acid 42, 0.25 mL (1.0 equiv) of DPPA,
and 0.17 mL (1.0 equiv) of triethylamine in 7.5 mL of toluene
at 100 °C for 5 h and 1.7 mL (15.0 equiv) of t-BuOH in 4.5 mL
of methylene chloride containing 5% (v/v) of TMSCl for 4 days.
Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc) gave
oil: [R]25 +55.2° (c ) 20.4, MeOH); IR (CH2Cl2) 3429, 3302,
D
2977, 1708, 1504, 1454, 1367, 1231, 1164, 1096, 1022 cm-1
;
1H NMR (CDCl3) δ 0.99 (d, J ) 6.6 Hz, 3H), 1.05 (d, J ) 6.7
Hz, 3H), 1.21 (d, J ) 6.6 Hz, 3H), 1.44 (S, 9H), 1.72 (m, 1H),
2.06 (m, 1H), 2.15 (d, J ) 2.4 Hz. 1H), 3.97 (m, 1H), 4.69 (bs,
1H); 13C NMR (CDCl3) δ 20.5, 20.8, 21.1, 26.2, 29.6, 45.6, 45.8,
72.4, 78.8, 82.7, 155.0; HRMS(CI) calcd for (C13H23NO2 + H)
([M + H]+) 226.1807, found 226.1799.
469 mg (83%) of acetylenic amine 43 as a colorless oil: [R]25
D
+28.1° (c ) 6.3, CH2Cl2); MS m/ e 225 (M+ - 254), 211, 199,
197, 183, 181, 155, 135, 121, 105; IR (CH2Cl2) 3429, 3302, 3073,
2963, 2933, 2860, 2139, 1712, 1504, 1428, 1392, 1367, 1236,
1
1172, 1112 cm-1; H NMR (CDCl3) δ 1.03 (t, J ) 7.5 Hz, 3H),
1.06 (s, 9H), 1.43 (s, 9H), 1.57 (m, 2H), 1.59 (d, J ) 1.5 Hz,
1H), 1.82 (m, 2H), 2.48 (m, 1H), 3.64-3.81 (m, 2H), 3.91 (m,
1H), 4.70 (d, J ) 10.0 Hz, 1H), 7.34-7.70 (m, 10H). Anal.
Calcd for C29H41NO3Si: C, 72.61; H, 8.61; N, 2.92. Found: C,
72.44; H, 8.68; N, 3.20.
Acetylen ic Am in e 28c. This material was prepared in
92% yield following method B above, employing 587 mg (2.38
mmol, 1.0 equiv) of acetylenic acid 25c, 0.51 mL (1.0 equiv) of
DPPA, and 0.33 mL (1.0 equiv) of triethylamine in 14 mL of
benzene for 3.5 h and 0.68 mL (3.0 equiv) of t-BuOH in 9.5
mL of methylene chloride containing 5% (v/v) of TMSCl for 18
h. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc)
gave 698 mg (92%) of acetylenic amine 28c as a pale yellow
solid: mp 58.0-58.5 °C (hexanes, colorless fluffy crystals);
Acetylen ic Am in e 60. This material was prepared in 75%
yield following method B above, employing 697 mg (1.35 mmol,
1.0 equiv) of acetylenic acid 59, 0.29 mL (1.0 equiv) of DPPA,
and 0.19 mL (1.0 equiv) of triethylamine in 8.4 mL of toluene
at 100 °C for 4.5 h and 1.3 mL (10.0 equiv) of t-BuOH in 5.5
mL of methylene chloride containing 5% (v/v) of TMSCl for 16
h. Chromatography (silica gel; 20:1-50:1 hexanes/EtOAc)
gave 597 mg (75%) of acetylenic amine 60 as a pale yellow oil:
[R]25 +34.9° (c ) 19.8, MeOH); MS m/ e 261 (M+ - 56), 244,
D
217, 183, 154, 144, 108, 91, 57; IR (CH2Cl2) 3429, 3302, 3033,
2979, 2174, 1708, 1491, 1188, 1175, 1100 cm-1 1H NMR
;
(CDCl3) δ 1.22 (d, J ) 6.5 Hz, 3H), 1.28 (d, J ) 6.5 Hz, 3H),
1.41 (s, 9H), 2.12 (d, J ) 2.5 Hz, 1H), 2.51 (m, 1H), 3.60 (quint,
J ) 6.5 Hz, 1H), 3.94 (m, 1H), 4.53 (d, J ) 12.0 Hz, 1H), 4.62
(d, J ) 12.0 Hz, 1H), 4.83 (d, J ) 8.0 Hz, 1H), 7.31 (m, 5H).
Anal. Calcd for C19H27NO3: C, 71.89; H, 8.57; N, 4.41.
Found: C, 71.81; H, 8.61; N, 4.43.
[R]25 +20.8° (c ) 6.8, CH2Cl2); IR (CH2Cl2) 3427, 3302, 3072,
D
2931, 1711, 1501, 1366, 1172, 1112, 1067 cm-1
;
1H NMR
(CDCl3) δ 1.08 (s, 9H), 1.32 (d, J ) 6.1 Hz, 3H), 1.43 (s, 9H),
2.16 (d, J ) 2.5 Hz, 1H), 2.82 (m, 1H), 3.71 (m, 2H), 3.80 (m,
1H), 3.98 (m, 1H), 4.51 (d, J ) 11.7 Hz, 1H), 4.66 (d, J ) 11.7
Hz, 1H), 5.13 (d, J ) 8.7 Hz, 1H), 7.25-7.69 (m, 15H); 13C
NMR (CDCl3) δ 17.8, 19.2, 26.9, 28.4, 34.0, 43.2, 49.4, 61.3,
71.0, 72.3, 73.7, 78.9, 82.0, 127.5, 127.6, 127.9, 128.3, 129.6,
133.4, 133.5, 135.5, 138.4, 155.4; HRMS(CI) calcd for (C36H47O4-
Si + H) ([M+ + H]) 586.3354, found 586.3339.
Gen er a l P r oced u r es for th e Oxid a tive Clea va ge of th e
Acetylen ic Bon d . Meth od A. A solution of 2.47 mmol (1.0
equiv) of the appropriate acetylenic N-Boc-amine in 58 mL of
t-BuOH was treated in dropwise fashion, and with vigorous
stirring, with a solution consisting of 0.3 equiv of KMnO4, 6.0
equiv of NaIO4, and 5.0 equiv of NaHCO3 in 58 mL of water.
After being stirred at rt for 3 h, the reaction mixture was
treated with 8.1 mL of ethanol, and the resulting mixture was
filtered through Celite and washed with 145 mL of 50%
aqueous t-BuOH. The filtrate was concentrated to about 90
mL, acidified with 122 mL of 10% aqueous acetic acid, and
extracted with 6 × 80 mL of ethyl acetate. The extracts were
dried (MgSO4) and concentrated under reduced pressure, and
the residue was taken up in 50 mL of benzene. The benzene
was concentrated again under reduced pressure to remove any
traces of acetic acid. The remaining residue was dissolved in
8 mL of THF and 8 mL of 15% aqueous KOH and stirred at rt
for 2.5 h to cleave any N-formyl substituent. The reaction
Acetylen ic Am in e en t-28c. This material was prepared
in 82% yield following method B above, employing 793 mg
(3.22 mmol, 1.0 equiv) of acetylenic acid ent-25c, 0.69 mL (1.0
equiv) of DPPA, and 0.45 mL (1.0 equiv) of triethylamine in
18.5 mL of benzene for 3.5 h and 0.91 mL (3.0 equiv) of t-BuOH
in 12.8 mL of methylene chloride containing 5% (v/v) of TMSCl
for 18 h. Chromatography (silica gel; 20:1-50:1 hexanes/
EtOAc) gave 838 mg (82%) of acetylenic amine ent-28c as a
pale yellow solid: mp 58.0-58.5 °C (hexanes, colorless fluffy
crystals); [R]25 -34.4° (c ) 4.7, MeOH); IR and 1H NMR are
D
identical to those of acetylenic amine 28c.
Acetylen ic Am in e 50a . This material was prepared in
81% yield following method B above, employing 390 mg (1.59
mmol, 1.0 equiv) of acetylenic acid 49a , 0.34 mL (1.0 equiv) of
DPPA, and 0.22 mL (1.0 equiv) of triethylamine in 9.6 mL of
toluene at 105 °C for 4.5 h and 0.45 mL (3.0 equiv) of t-BuOH
in 6.4 mL of methylene chloride containing 5% (v/v) of TMSCl
for 18 h. Chromatography (silica gel; 20:1-50:1 hexanes/
EtOAc) gave 409 mg (81%) of acetylenic amine 50a as a pale
yellow solid: mp 54.5-55.0 °C (hexanes, colorless needles);
[R]25D +12.8° (c ) 15.0, MeOH); IR (CH2Cl2) 3430, 3302, 3050,
2980, 1708, 1501, 1367, 1266, 1165, 1052 cm-1
;
1H NMR
(CDCl3) δ 1.22 (d, J ) 6.7 Hz, 3H), 1.30 (d, J ) 6.2 Hz, 3H),

Total Syntheses of Thienamycin and PS-5
J . Org. Chem., Vol. 61, No. 7, 1996 2425
mixture was then acidified to pH ) 2 with 5 N aqueous HCl
and extracted with 6 × 35 mL of ethyl acetate. The combined
organic extracts were dried (MgSO4), filtered, concentrated
under reduced pressure, and chromatographed (silica gel; 75:
25:0.3 hexanes/EtOAc/HOAc) to afford the corresponding
carboxylic acid.
179.7; HRMS(CI) calcd for (C12H23NO4 + H) ([M + H]+)
246.1706, found 246.1708.
â-Am in o Acid 30c. This material was prepared in 68%
yield following method B above, employing 297 mg (0.94 mmol,
1.0 equiv) of acetylenic amine 28c in 4 mL of THF and 4 mL
of water, 52 mg (0.2 equiv) of OsO4, and 2.20 g (11.0 equiv) of
NaIO4 for 6 days at rt. After cleavage, chromatography (silica
gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 215 mg (68%)
Meth od B. A solution of 2.10 mmol (1.0 equiv) of the
appropriate acetylenic N-Boc-amine in 12 mL of THF and 12
mL of water was treated portionwise, with vigorous stirring,
with 103 mg (0.2 equiv) of OsO4 at rt to give a dark reaction
mixture. After addition was complete (∼5 min), the reaction
was treated with 6.0 equiv of NaIO4, and the mixture im-
mediately turned light yellow in color. After the mixture was
stirred for 3 days, an additional 1.5 equiv of NaIO4 was added
and stirring was continued until reaction was complete (TLC;
2-3 days). The reaction mixture was then diluted with 50
mL of water and extracted with 6 × 50 mL of ethyl acetate.
The combined extracts were dried (MgSO4), filtered, and
concentrated under reduced pressure to give a dark sticky oil.
This material was dissolved in 11 mL of THF and 2.4 mL of
water and was treated with 1.0 equiv of NaIO4 for 5 min to
give a bright yellow solution. This solution was then treated
with 10 mL of 15% aqueous KOH, and the resulting mixture
was stirred at rt for 1.5 h to cleave the N-formyl substituent.
The THF was then removed under reduced pressure, and the
remaining aqueous solution was diluted with 24 mL of water,
washed with 3 × 40 mL of methylene chloride, acidified to pH
) 2 with 5 N aqueous HCl, and extracted with 6 × 40 mL of
ethyl acetate. The combined extracts were dried (MgSO4),
filtered, concentrated under reduced pressure, and chromato-
graphed (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) to afford
the corresponding carboxylic acid.
of â-amino acid 30c as a colorless oil: [R]25 +62.4° (c ) 16.3,
D
MeOH); IR (CH2Cl2) 3429, 3429-2538, 1707, 1502, 1368, 1163,
1
1088 cm-1; H NMR (CDCl3) δ 1.20 (d, J ) 6.7 Hz, 3H), 1.34
(d, J ) 7.0 Hz, 3H), 1.44 (m, 9H), 2.60 (dd, J ) 4.0, 9.0 Hz,
1H), 3.86 (m, 1H), 4.04 (m, 1H), 4.42 (d, J ) 11.5 Hz, 1H),
4.64 (d, J ) 11.5 Hz, 1H), 5.33 (d, J ) 10.0 Hz, 1H), 7.30 (m,
5H); HRMS(CI) calcd for (C18
H27NO5 + H) ([M + H]+)
338.1968, found 338.1986.
â-Am in o Acid en t-30c. This material was prepared in 68%
yield following method B above, employing 665 mg (2.10 mmol,
1.0 equiv) of acetylenic amine ent-28c in 12 mL of THF and
12 mL of water, 103 mg (0.2 equiv) of OsO4
, and 4.93 g (11.0
equiv) of NaIO4 for 6 days at rt. After cleavage, chromatog-
raphy (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 482
mg (68%) of â-amino acid ent-30c as a colorless oil: [R]25
D
-64.7° (c ) 12.8, MeOH); IR and 1H NMR are identical to those
of compound â-amino acid 30c.
â-Am in o Acid 51a . This material was prepared in 71%
yield following method B above, employing 696 mg (2.19 mmol,
1.0 equiv) of acetylenic amine 50a in 12.5 mL of THF and 12.5
mL of water, 99 mg (0.2 equiv) of OsO4, and 5.16 g (11.0 equiv)
of NaIO4 for 6 days at rt. After cleavage, chromatography
(silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 527 mg
(71%) of â-amino acid 51a as a white solid: mp 81.0-82.0 °C
(15:1 hexanes/diethyl ether, colorless cotton-like crystals);
[R]25D +14.7° (c ) 19.8, MeOH); IR (CH2Cl2) 3431, 3431-2500,
â-Am in o Acid 30a . This material was prepared in 97%
yield following method A above, employing 522 mg (2.47 mmol,
1.0 equiv) of acetylenic amine 28a in 58 mL of t-BuOH, a
solution consisting of 0.72 mmol (0.3 equiv) of KMnO4, 14.7
mmol (6.0 equiv) of NaIO4, and 12.2 mmol (5.0 equiv) of
NaHCO3 in 58 mL of water at rt for 3 h, and a solution of 8
mL of THF and 8 mL of 15% aqueous KOH at rt for 2.5 h.
Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc)
afforded 554 mg (97%) of â-amino acid 30a as a white solid:
1750, 1710, 1503, 1455, 1392, 1368, 1237 cm-1 1H NMR
;
(CDCl3) δ 1.20 (d, J ) 6.2 Hz, 3H), 1.34 (d, J ) 5.1 Hz, 3H),
2.73 (m, 1H), 3.88 (m, 1H), 4.06 (m, 1H), 4.51 (d, J ) 11.2 Hz,
1H), 4.66 (d, J ) 11.2 Hz, 1H), 5.02 (d, J ) 8.5 Hz, 1H), 7.23-
7.45 (m, 5H). Anal. Calcd for C18H27NO5: C, 64.07; H, 8.07;
N, 4.15. Found: C, 64.10; H, 8.10; N, 4.12.
â-Am in o Acid 51s. This material was prepared in 57%
yield following method B above, employing 49 mg (0.15 mmol,
1.0 equiv) of acetylenic amine 50s in 1 mL of THF and 1 mL
of water, 11 mg (0.3 equiv) of OsO4, and 361 mg (11.0 equiv)
of NaIO4 for 6 days at rt. After cleavage, chromatography
(silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 29 mg
(57%) of â-amino acid 51s as a colorless oil: IR (CH2Cl2) 3430,
3430-2500, 1709, 1501, 1367, 1166, 1095, 1038 cm-1; 1H NMR
(CDCl3) δ 1.19 (d, J ) 6.8 Hz,3H), 1.27 (d, J ) 6.2 Hz, 3H),
1.44 (s, 9H), 2.64 (bd, J ) 6.5 Hz, 1H), 3.88 (m, 1H), 4.33 (m,
1H), 4.45 (d, J ) 10.8 Hz, 1H), 4.55 (d, J ) 10.8 Hz, 1H), 5.57
(bs, 1H), 7.25-7.43 (m, 5H).
mp 72.0-74.0 °C (hexanes, colorless fluffy crystals); [R]25
D
+12.7° (c ) 2.7, MeOH); MS m/ e 158 (M+ - 73), 144, 116, 98,
88, 73, 57; IR (CH2Cl2) 3433, 3500-2350, 1706, 1504, 1368,
1165 cm-1; 1H NMR (CDCl3) δ 0.98 (t, J ) 7.4 Hz,3H), 1.19 (d,
J ) 6.8 Hz, 3H), 1.44 (s, 9H), 1.61 (m, 1H), 1.71 (m, 1H), 2.41
(m, 1H), 3.97 (m, 1H), 5.20 (bd, J ) 10.0 Hz, 1H). Anal. Calcd
for C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C, 57.16;
H, 9.18; N, 6.08.
â-Am in o Acid en t-30a . This material was prepared in 92%
yield following method A above, employing 722 mg (3.42 mmol,
1.0 equiv) of acetylenic amine ent-28a in 80 mL of t-BuOH, a
solution consisting of 1.01 mmol (0.3 equiv) of KMnO4, 20.3
mmol (6.0 equiv) of NaIO4, and 16.9 mmol (5.0 equiv) of
NaHCO3 in 80 mL of water at rt for 2.5 h, and a solution of 12
mL of THF and 10 mL of 15% aqueous KOH at rt for 2 h.
Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc)
afforded 724 mg (92%) of â-amino acid ent-30a as a white
solid: mp 72.0-74.0 °C (hexanes, colorless fluffy crystals);
â-Am in o Acid 44. This material was prepared in 91% yield
following method A above, employing 361 mg (0.75 mmol, 1.0
equiv) of acetylenic amine 43 in 19 mL of t-BuOH, a solution
consisting of 0.22 mmol (0.3 equiv) of KMnO4, 4.51 mmol (6.0
equiv) of NaIO4, and 3.76 mmol (5.0 equiv) of NaHCO3 in 19
mL of water at rt for 6 h, and a solution of 6 mL of THF and
3 mL of 15% aqueous KOH at rt for 2.5 h. Chromatography
(silica gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 342 mg
1
[R]25D -13.8° (c ) 7.2, MeOH); IR and HNMR are identical to
(91%) of â-amino acid 44 as a colorless oil: [R]25 +7.5° (c )
those of â-amino acid 30a .
D
5.1, CH2Cl2); IR (CH2Cl2) 3430, 3400-2500, 3073, 2969, 2932,
â-Am in o Acid 30b. This material was prepared in 86%
yield following method A above, employing 348 mg (1.54 mmol,
1.0 equiv) of acetylenic amine 28b in 37 mL of t-BuOH, a
solution consisting of 0.46 mmol (0.3 equiv) of KMnO4, 9.25
mmol (6.0 equiv) of NaIO4, and 7.71 mmol (5.0 equiv) of
NaHCO3 in 37 mL of water at rt for 3 h, and a solution of 5
mL of THF and 5 mL of 15% aqueous KOH at rt for 2.5 h.
Chromatography (silica gel; 75:25:0.3 hexanes/EtOAc/HOAc)
afforded 326 mg (86%) of â-amino acid 30b as a colorless oil:
[R]25D +23.8° (c ) 15.1, MeOH); IR (CH2Cl2) 3430, 3430-2425,
2857, 1707, 1504, 1468, 1392, 1367, 1242, 1170, 1111 cm-1
;
1H NMR (CDCl3) δ 1.00 (t, J ) 7.4 Hz, 3H), 1.06 (s, 9H), 1.42
(s, 9H), 1.55-1.83 (m, 4H), 2.58 (m, 1H), 3.73 (m, 2H), 4.05
(m, 1H), 5.19 (d, J ) 8.6 Hz, 1H), 7.35-7.70 (m, 10H); 13CNMR
(CDCl3) δ 12.1, 19.1, 22.6, 26.9, 28.4, 36.5, 48.5, 50.7, 61.1,
79.1, 127.7, 129.7, 133.5, 133.6, 135.3, 135.5, 155.7, 179.9.
HRMS(FAB) calcd for (C28H41NO5Si + H) ([M + H]+) 500.2832,
found 500.2844.
â-Am in o Acid 61. This material was prepared in 71% yield
following method B above, employing 410 mg (0.70 mmol, 1.0
equiv) of acetylenic amine 60 in 4.2 mL of THF and 4.2 mL of
water, 37 mg (0.2 equiv) of OsO4, and 1.65 g (11.0 equiv) of
NaIO4 for 6 days at rt. After cleavage, chromatography (silica
gel; 75:25:0.3 hexanes/EtOAc/HOAc) afforded 302 mg (71%)
1
1703, 1504, 1368, 1234, 1166, 1098 cm-1; H NMR (CDCl3) δ
0.90 (d, J ) 6.4 Hz, 3H), 0.92 (d, J ) 6.8 Hz, 3H), 1.09 (d, J )
6.8 Hz, 3H), 1.36 (s, 9H), 1.90 (m, 1H), 2.05 (dd, J ) 4.5, 10.0
Hz, 1H), 3.99 (m, 1H), 5.32 (d, J ) 10.0 Hz, 1H); 13C NMR
(CDCl3) δ 20.2, 20.5, 21.0, 28.0, 28.3, 44.4, 57.3, 79.3, 155.6,

2426 J . Org. Chem., Vol. 61, No. 7, 1996
J acobi et al.
of â-amino acid 61 as a colorless oil: [R]25 -1.3° (c ) 17.4,
2.97 (dd, J ) 2.0, 5.0 Hz, 1H), 3.70 (dq, J ) 2.0, 6.1 Hz, 1H),
3.85 (quint, J ) 6.0 Hz, 1H), 4.50 (d, J ) 12.0 Hz, 1H), 4.62
(d, J ) 12.0 Hz, 1H), 6.04 (bs, 1H), 7.24-7.32 (m, 5H); 13C
NMR (CDCl3) δ 16.7, 20.3, 46.1, 62.6, 70.4, 71.1, 127.4, 128.1,
138.2, 168.6; HRMS(CI) calcd for (C13H17NO2 + H) ([M + H]+)
220.1338, found 220.1346.
D
CH2Cl2); IR (CH2Cl2) 3430, 3500-2500, 1753, 1712, 1656, 1501,
1
1368, 1169, 1111 cm-1; H NMR (CDCl3) δ 1.06 (s, 9H), 1.37
(d, J ) 6.1 Hz, 3H), 1.44 (s, 9H), 1.69 (m, 1H), 1.84 (m, 1H),
2.85 (bt, J ) 6.0 Hz, 1H), 3.68 (m, 1H), 3.80 (m, 1H), 3.92 (m,
1H), 4.21 (m, 1H), 4.52 (d, J ) 10.9 Hz, 1H), 4.66 (d, J ) 10.9
Hz, 1H), 5.23 (d, J ) 8.8 Hz, 1H), 7.26-7.68 (m, 15); HRMS-
(CI) calcd for (C35H47NO6Si + H) ([M + H]+) 606.3252, found
606.3253.
â-La cta m en t-32c. This material was prepared in 83%
yield following the general procedure described above, employ-
ing 386 mg (1.14 mmol, 1.0 equiv) of â-amino acid derivative
ent-30c, 21 mL of trifluoroacetic acid, 81 mL of acetonitrile,
0.48 mL (3.0 equiv) of triethylamine, and 520 mg (2.2 equiv)
of dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatog-
raphy (silica gel; 7:3 hexanes/EtOAc) afforded 208 mg (83%)
of ent-32c as a pale yellow oil: [R]25D -36.5° (c ) 10.5, CH2Cl2);
IR and 1H NMR are identical to those of â-lactam 32c.
â-La cta m 53. This material was prepared in 61% yield
following the general procedure described above, employing
53 mg (0.16 mmol, 1.0 equiv) of â-amino acid derivative 51, 3
mL of trifluoroacetic acid, 22 mL of acetonitrile, 0.066 mL (3.0
equiv) of triethylamine, and 71 mg (2.2 equiv) of dicyclohexyl-
carbodiimide at 65-68 °C for 8 h. Chromatography (silica gel;
7:3 hexanes/EtOAc) afforded 21 mg (61%) of 53 as a pale yellow
Gen er a l P r oced u r e for t h e Cycliza t ion of â-Am in o
Acid s. A solution of 0.85 mmol (1.0 equiv) of the appropriate
â-amino acid derivative in 16 mL of trifluoroacetic acid (TFA)
was kept at 0 °C for 20 min under nitrogen to cleave the t-BOC
protecting group. The reaction was then concentrated under
reduced pressure, and the residue was concentrated once more
from 30 mL of dry benzene to remove any remaining TFA. The
resulting oil was dissolved in 60 mL of acetonitrile and was
treated sequentially with 3.0 equiv of triethylamine and 2.2
equiv of dicyclohexylcarbodiimide (DCC) at rt. The reaction
mixture was then stirred at 65-68 °C for 5 h, cooled to rt,
and concentrated under reduced pressure. The residue was
dissolved in a small amount of diethyl ether and filtered to
remove suspended material (thorough washing with ether).
The filtrate was then concentrated under reduced pressure and
chromatographed (silica gel; 7:3 hexanes/EtOAc) to give the
corresponding â-lactam.
oil: [R]25 -56.8° (c ) 11.4, CH2Cl2); IR (CH2Cl2) 3407, 3034,
D
2977, 1759, 1381, 1060 cm-1; H NMR (CDCl3) δ 1.32 (d, J )
1
6.4 Hz, 3H), 1.36 (d, J ) 6.3 Hz, 3H), 3.24 (m, 1H), 3.80 (m,
2H), 4.52 (d, J ) 11.8 Hz, 1H), 4.67 (d, J ) 11.8 Hz, 1H), 6.39
(bs, 1H), 7.23-7.39 (m, 5H); 13C NMR (CDCl3) δ 16.2, 18.8,
47.2, 58.6, 70.2, 71.0, 127.3, 127.5, 128.2, 138.4, 168.8; HRMS-
(CI) calcd for (C13H17NO2 + H) ([M + H]+) 220.1338, found
220.1342.
â-La cta m 32a . This material was prepared in 71% yield
following the general procedure described above, employing
198 mg (0.85 mmol, 1.0 equiv) of â-amino acid derivative 30a ,
16 mL of trifluoroacetic acid, 60 mL of acetonitrile, 0.36 mL
(3.0 equiv) of triethylamine, and 388 mg (2.2 equiv) of
dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatogra-
phy (silica gel; 7:3 hexanes/EtOAc) afforded 68 mg (71%) of
â-La cta m 54. Meth od A. This material was prepared in
70% yield following the general procedure described above,
employing 29 mg (0.09 mmol, 1.0 equiv) of â-amino acid
derivative 48s, 1.6 mL of trifluoroacetic acid, 12 mL of
acetonitrile, 0.036 mL (3.0 equiv) of triethylamine, and 38 mg
(2.2 equiv) of dicyclohexylcarbodiimide at 65-68 °C for 5 h.
Chromatography (silica gel; diethyl ether) afforded 13 mg
(70%) of 54 having identical chemical and physical properties
as described below in method B.
32a as a pale yellow oil: [R]25 +19.8° (c ) 10.3, CH2Cl2); IR
D
(CH2Cl2) 3408, 2968, 1754, 1462, 1382, 1272, 1181 cm-1; H
1
NMR (CDCl3) δ 0.96 (t, J ) 7.4 Hz, 3H), 1.30 (d, J ) 6.4 Hz,
3H), 1.61 (m, 1H), 1.74 (m, 1H), 2.61 (bt, J ) 6.8 Hz, 1H), 3.40
(dq, J ) 2.0, 6.1 Hz, 1H), 6.58 (bs, 1H); 13C NMR (CDCl3) δ
11.3, 20.6, 21.2, 50.2, 59.4, 171.3; HRMS(CI) calcd for (C6H11
-
NO + H) ([M + H]+) 114.0920, found 114.0923.
Meth od B: Ep im er iza tion of â-La cta m 53. A solution
of 27 mg (0.12 mmol, 1.0 equiv) of â-lactam 53 in 0.5 mL of
dry methylene chloride was stirred at rt under nitrogen and
was treated with 0.052 mL (3.0 equiv) of triethylamine and
0.059 mL (2.5 equiv) of trimethylsilyl triflate. After the
mixture was stirred for 3 h, the reaction was treated with 1
mL of 1 N aqueous hydrogen chloride and 0.5 mL of THF. The
resulting mixture was stirred at rt for 1.5 h, diluted with 1
mL of water and 1 mL of saturated aqueous NaHCO3, and
extracted with 3 × 6 mL of methylene chloride and 6 mL of
diethyl ether. The combined organic extracts were dried
(MgSO4), filtered, concentrated under reduced pressure, and
chromatographed (silica gel; diethyl ether) to afford 20 mg
(74%) of 54 as a pale yellow oil: [R]25D -26.4° (c ) 7.7, CH2Cl2);
IR (CH2Cl2) 3408, 3033, 2974, 1761, 1496, 1454, 1381, 1348,
â-La cta m en t-32a . This material was prepared in 81%
yield following the general procedure described above, employ-
ing 201 mg (0.87 mmol, 1.0 equiv) of â-amino acid derivative
ent-30a , 16 mL of trifluoroacetic acid, 70 mL of acetonitrile,
0.36 mL (3.0 equiv) of triethylamine, and 361 mg (2.0 equiv)
of dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatog-
raphy (silica gel; 7:3 hexanes/EtOAc) afforded 80 mg (81%) of
ent-32a as a pale yellow oil: [R]25 -18.3° (c ) 19.5, CH2Cl2);
D
IR and 1HNMR are identical to those of â-lactam 32a .
â-La cta m 32b. This material was prepared in 82% yield
following the general procedure described above, employing
320 mg (1.30 mmol, 1.0 equiv) of â-amino acid derivative 30b,
25 mL of trifluoroacetic acid, 91 mL of acetonitrile, 0.55 mL
(3.0 equiv) of triethylamine, and 592 mg (2.2 equiv) of
dicyclohexylcarbodiimide at 65-68 °C for 5 h. Chromatogra-
phy (silica gel; 7:3 hexanes/EtOAc) afforded 136 mg (82%) of
32b as a pale yellow solid: mp 37.0-38.0 °C (diethyl ether,
1
1274, 1197, 1160, 1096, 1055 cm-1; H NMR (CDCl3) δ 1.31
(d, J ) 6.2 Hz, 3H), 1.38 (d, J ) 6.2 Hz, 3H), 2.81 (dd, J ) 2.0,
6.4 Hz, 1H), 3.73 (dq, J ) 1.9, 6.1 Hz, 1H), 3.89 (quint, J )
6.3 Hz, 1H), 4.51 (d, J ) 11.7 Hz, 1H), 4.64 (d, J ) 11.7 Hz,
1H), 6.21 (bs, 1H), 7.25-7.36 (m, 5H); 13CNMR (CDCl3) δ 18.1,
20.8, 48.0, 64.0, 70.6, 72.3, 127.5, 128.2, 138.4, 168.4; HRMS-
(CI) calcd for (C13H17NO2 + H) ([M + H]+) 220.1338, found
220.1342.
colorless cubes); [R]25 +11.3° (c ) 23.0, CH2Cl2); IR (CH2Cl2)
D
3407, 2965, 1751, 1468, 1368, 1274, 1173, 1053 cm-1; 1H NMR
(CDCl3) δ 1.00 (d, J ) 6.8 Hz, 3H), 1.08 (d, J ) 6.4 Hz, 3H),
1.36 (d, J ) 6.3 Hz, 3H), 2.01 (octet, J ) 7.0 Hz, 1H), 2.53 (bd,
J ) 8.2 Hz, 1H), 3.52 (dt, J ) 1.4, 7.0 Hz, 1H); 13C NMR
(CDCl3) δ 19.8, 20.1, 20.6, 27.6, 48.4, 64.7, 170.8. Anal. Calcd
for C7H13NO: C, 66.11; H, 10.35; N, 11.01. Found: C, 66.26;
H, 10.35; N, 10.93.
â-La cta m 33. This material was prepared in 91% yield
following the general procedure described above, employing
213 mg (0.43 mmol, 1.0 equiv) of â-amino acid derivative 44,
8.4 mL of trifluoroacetic acid, 30 mL of acetonitrile, 0.018 mL
(3.0 equiv) of triethylamine, and 191 mg (2.2 equiv) of
dicyclohexylcarbodiimide at 70 °C for 5 h. Chromatography
(silica gel; 7:3 hexanes/EtOAc) afforded 147 mg (91%) of 33 as
â-La cta m 32c. This material was prepared in 76% yield
following the general procedure described above, employing
448 mg (1.33 mmol, 1.0 equiv) of â-amino acid derivative 30c,
25 mL of trifluoroacetic acid, 93 mL of acetonitrile, 0.56 mL
(3.0 equiv) of triethylamine, and 603 mg (2.2 equiv) of
dicyclohexylcarbodiimide at 65-68 °C for 5.5 h. Chromatog-
raphy (silica gel; 7:3 hexanes/EtOAc) afforded 220 mg (76%)
a colorless oil: [R]25 +11.8° (c ) 6.6, CH2Cl2); MS m/ e 281
D
(M+ - 100), 254, 224, 199, 183, 181, 176, 135, 105, 77; IR
(CH2Cl2) 3406, 3072, 2962, 2933, 2860, 1755, 1472, 1428, 1388,
of 32c as a pale yellow oil: [R]25 +35.5° (c ) 19.8, CH2Cl2);
1362, 1188, 1112 cm-1; H NMR (CDCl3) δ 1.02 (m, 3H), 1.07
1
D
MS m/ e 176 (M+ - 43), 161, 128, 113, 98, 91, 69; IR (CH2Cl2)
3408, 3033, 2974, 1759, 1375, 1186, 1099, 1055 cm-1; 1H NMR
(CDCl3) δ 1.30 (d, J ) 6.5 Hz, 3H), 1.32 (d, J ) 6.1 Hz, 3H),
(s, 9H), 1.66-1.87 (m, 4H), 2.75 (m, 1H), 3.47 (m, 1H), 3.74
(m, 2H), 5.74 (bs, 1H), 7.38-7.68, (m, 10H); 13C NMR (CDCl3)
δ 11.3, 19.1, 21.4, 26.9, 37.5, 52.7, 58.4, 61.9, 170.8.19a

Total Syntheses of Thienamycin and PS-5
J . Org. Chem., Vol. 61, No. 7, 1996 2427
â-La cta m 62. This material was prepared in 56% yield
following the general procedure described above, employing
153 mg (0.25 mmol, 1.0 equiv) of â-amino acid derivative 61,
5 mL of trifluoroacetic acid, 35 mL of acetonitrile, 0.11 mL
(3.0 equiv) of triethylamine, and 115 mg (2.2 equiv) of
dicyclohexylcarbodiimide at 65-68 °C for 10 h. Chromatog-
raphy (silica gel; 7:3 hexanes/EtOAc) afforded 68 mg (56%) of
reduced pressure, and chromatographed (silica gel; 1:1 hex-
anes/EtOAc) to afford 39 mg (66%) of 63 as a pale yellow oil:
[R]25 -1.9° (c ) 6.3, CH2Cl2); IR (CH2Cl2) 3414, 3072, 2932,
D
1753, 1472, 1428, 1112 cm-1; 1H NMR (CDCl3) δ 1.04 (s, 9H),
1.27 (d, J ) 6.2 Hz, 3H), 1.79 (m, 1H), 1.88 (m, 1H), 2.85 (dd,
J ) 1.5, 5.9 Hz, 1H), 3.74 (m, 3H), 3.87 (quint, J ) 6.2 Hz,
1H), 4.48 (d, J ) 11.7 Hz, 1H), 4.61 (d, J ) 11.7 Hz, 1H), 5.78
(bs, 1H), 7.24-7.65 (m, 15H); 13C NMR (CDCl3) δ 18.2, 19.1,
26.9, 37.5, 50.4, 62.0, 62.8, 70.7, 72.2, 127.5, 127.8, 128.3,
129.78, 129.82, 133.2, 135.4, 138.4, 168.2; HRMS(CI) calcd for
(C30H37NO3Si + H) ([M + H]+) 488.2622, found 488.2628.12e,22
62 as a pale yellow oil: [R]25 -24.6° (c ) 12.2, CH2Cl2); IR
D
(CH2Cl2) 3406, 3071, 2932, 1758, 1389, 1112 cm-1; H NMR
1
(CDCl3) δ 1.04 (s, 9H), 1.37 (d, J ) 6.4 Hz, 3H), 1.81 (m, 1H),
2.02 (m, 1H), 3.27 (m, 1H), 3.70 (m, 2H), 3.80 (m, 2H), 4.43 (d,
J ) 11.9 Hz, 1H), 4.65 (d, J ) 11.9 Hz, 1H), 5.87 (bs, 1H),
7.21-7.66 (m, 15H); 13C NMR (CDCl3) δ 18.5, 19.1, 26.9, 32.8,
50.1, 58.7, 62.3, 70.0, 70.6, 127.3, 127.5, 127.7, 128.2, 128.4,
129.8, 133.1, 133.2, 135.4, 138.2, 168.3; HRMS(CI) calcd for
(C30H37NO3Si + H) ([M + H]+) 488.2622, found 488.2639.
â-La cta m 63. A solution of 59 mg (0.12 mmol, 1.0 equiv)
of â-lactam 62 in 0.5 mL of dry methylene chloride was stirred
at rt under nitrogen and was treated with 0.05 mL (3.0 equiv)
of triethylamine and 0.06 mL (2.5 equiv) of trimethylsilyl
triflate. After the mixture was stirred for 3.5 h, the reaction
was treated with 1 mL of 1 N aqueous hydrogen chloride and
0.5 mL of THF. The resulting mixture was stirred at rt for
1.5 h, diluted with 1 mL of water and 1 mL of saturated
aqueous NaHCO3, and extracted with 3 × 6 mL of methylene
chloride and 6 mL of diethyl ether. The combined organic
extracts were dried (MgSO4), filtered, concentrated under
Ack n ow led gm en t. Financial support of this work
by the National Science Foundation, Grant Nos. CHE-
9001485 and CHE-9424476, is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 24a -c, 25a -c, 27c, 28a -c, 30a -
c, 32a -c, 33, 39, 40, 42, 43a , 44, 49a , 49s, 50a , 50s, 51a ,
51s, 53, 54, 56, 57, and 59-63 (31 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O952092U