Complete diastereocontrol in intramolecular 1,3-dipolar cycloadditions of 2-substituted 5-hexenyl and 5-heptenyl nitrones: Application to the synthesis of the β-lactam antibiotic 1β-methylthienamycin

Article abstract of DOI:10.1021/jo952254m

The diastereoselectivity of intramolecular 1,3-dipolar cycloadditions of 2-substituted 5-hexenyl and 5-heptenyl nitrones to give 6-substituted and 3,6-disubstituted perhydrocyclopenta[c]isoxazoles has been investigated. An alkyl or aryl substituent at C2 completely controls the stereochemistry of the ring juncture and, in the case of the 5-heptenyl systems, also the stereochemistry of the 3-methyl group. Thus one stereocenter controls the formation of the other three to give a product with four contiguous stereocenters. The use of an ethylene ketal substituent in these systems allows the reaction to be carried out at much lower temperatures, an example of the gem-dialkoxy effect. This cycloaddition process has been used in an efficient formal total synthesis of the potent β-lactam antibiotic, 1β-methylthienamycin.

Full text of DOI:10.1021/jo952254m

J . Org. Chem. 1996, 61, 4427-4433
4427
Com p lete Dia ster eocon tr ol in In tr a m olecu la r 1,3-Dip ola r
Cycloa d d ition s of 2-Su bstitu ted 5-Hexen yl a n d 5-Hep ten yl
Nitr on es: Ap p lica tion to th e Syn th esis of th e â-La cta m An tibiotic
1â-Meth ylth ien a m ycin
Michael E. J ung*,1 and Binh T. Vu
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569
Received December 22, 1995X
The diastereoselectivity of intramolecular 1,3-dipolar cycloadditions of 2-substituted 5-hexenyl and
5-heptenyl nitrones to give 6-substituted and 3,6-disubstituted perhydrocyclopenta[c]isoxazoles has
been investigated. An alkyl or aryl substituent at C2 completely controls the stereochemistry of
the ring juncture and, in the case of the 5-heptenyl systems, also the stereochemistry of the 3-methyl
group. Thus one stereocenter controls the formation of the other three to give a product with four
contiguous stereocenters. The use of an ethylene ketal substituent in these systems allows the
reaction to be carried out at much lower temperatures, an example of the gem-dialkoxy effect. This
cycloaddition process has been used in an efficient formal total synthesis of the potent â-lactam
antibiotic, 1â-methylthienamycin.
In tr od u ction
enolates.5 In our recent study of substituent effects on
intramolecular dipolar cycloadditions of 3-substituted
5-hexenyl nitrile oxides, we observed good diastereose-
lectivity when C3 was monosubstituted.6 When the
nitrile oxide derived from the oximes 4 underwent
intramolecular dipolar cycloaddition, it gave mainly the
endo diastereomer 5 rather than the exo one 5′ in
agreement with calculated transition structures for these
reactions.7 The size of the diastereoselectivity is in good
agreement with the relative size of the substituents (Ph
> Me > COOMe).8
The development of thienamycin,2 a potent broad
spectrum â-lactam antibiotic isolated from Streptomyces
catteleya, as a clinical drug candidate was unsuccessful
because of its instability at high concentration and
susceptibility to renal dehydropeptidase-I (DHP-I). Then,
in 1984, Shih and co-workers at Merck3 reported that the
presence of a â-methyl group at the C1 position of the
carbapenem skeleton, namely, 1â-methylthienamycin 1,
increased the chemical stability of thienamycin, pre-
vented it from being readily metabolized by DHP-I
enzyme, while retaining the antibacterial activity of
thienamycin.
We have further investigated the diastereoselectivity
of such 1,3-dipolar cycloadditions when C2 is monosub-
stituted and have utilized our findings in an efficient
synthesis of the key intermediate 2 for the synthesis of
1â-methylthienamycin 1. The recent report of Kang and
Lee9 of the synthesis of 2 via the intramolecular 1,3-
dipolar cycloaddition of a 2-substituted 5-heptenyl ni-
trone prompts us to report the results of our study, which
culminated in a formal total synthesis of 1â-methylthien-
amycin 1.
Since then, several approaches for the stereoselective
synthesis of 1 have been reported.4 Nearly every syn-
thesis proceeds through the key intermediate 2 of the
original synthesis reported by Shih et al.3 Common
synthetic approaches to 2 involve an aldol-type condensa-
tion of 4-acetoxy-2-azetidinone 3 with various kinds of
X Abstract published in Advance ACS Abstracts, May 15, 1996.
(1) American Chemical Society Arthur C. Cope Scholar, 1995.
(2) (a) Merck & Co., Inc., U.S. Patent 3 950 357 (April 12, 1976). (b)
Albers-Scho¨nberg, G.; Arison, B. H.; Hensens, O. D.; Hirshfield, J .;
Hoogsteen, K.; Kaczka, E. A.; Rhodes, R. E.; Kahan, J . S.; Kahan, F.
M.; Ratcliffe, R. W.; Walton, E.; Ruswinkle, L. J .; Morin, R. B.;
Christensen, B. G. J . Am. Chem. Soc. 1978, 100, 6491 and references
cited therein.
(3) (a) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G.
Hetereocycles 1984, 21, 29. (b) Shih, D. H.; Fayter, J . A.; Cama, L.;
Christensen, B. G. Tetrahedron Lett. 1985, 26, 583. (c) Shih, D. H.;
Cama, L.; Christensen, B. G. Tetrahedron Lett. 1985, 26, 587.
(4) (a) Yamamoto, Y.; Tsukada, T.; Shimada, T.; Gyoung, Y. S.; Asao,
N. J . Org. Chem. 1995, 60, 143. (b) Yamamoto, Y.; Tsukada, T.; Asao,
Naoki, A. Bull. Chem. Soc. J pn. 1995, 68, 2102. (c) Nakai, T.; Shirai,
F. Chem. Lett. 1989, 445. (d) Ihara, M.; Masanobu, T.; Fukumoto, K.;
Kametami, T. J . Chem. Soc., Perkin Trans. 1 1989, 2215. (e) Kawabata,
T.; Kimura, Y.; Ito, Y.; Terashima, S.; Sasaki, A.; Sunagawa, M.
Tetrahedron Lett. 1988, 44, 1988. (f) Hatanaka, M. Tetrahedron Lett.
1987, 28, 83. (g) Shibasaki, M.; Iimori, T. Tetrahedron Lett. 1986, 27,
2149.
S0022-3263(95)02254-7 CCC: $12.00 © 1996 American Chemical Society

4428 J . Org. Chem., Vol. 61, No. 13, 1996
J ung and Vu
Resu lts a n d Discu ssion
We examined the cyclizations of the 2-substituted
nitrones prepared from the corresponding alcohols 6 by
Swern oxidation10 followed by condensation with N-
benzylhydroxylamine11 in the presence of anhydrous
potassium carbonate. We prepared the alcohols 6a and
6c by alkylation of the lithium enolate of methyl phen-
ylacetate with 4-bromo-1-butene (or 5-bromo-2-pentene12)
followed by reduction with lithium aluminum hydride
(LAH). Alkylation of dimethyl methylmalonate with
4-bromo-1-butene (or 5-bromo-2-pentene), followed by
decarboalkoxylation using Krapcho’s procedure13 and
reduction with LAH, furnished the alcohols 6b and 6d .
Heating the nitrones derived from the alcohols 6a -d in
toluene at ∼100 °C for 12 h gave the bicyclic compounds
7a -d in good yields as single diastereomers.14 Thus the
C2 stereochemistry completely controls the stereochem-
istry of the other three centers in the cyclization process.
This complete diastereocontrol in the formation of four
contiguous stereocenters of the bicyclic isoxazolidine led
us to use this process as the key step in the synthesis of
2.
be much more stable than the other while this effect is
less pronounced in the less sterically demanding nitrile
oxide.
We also studied the cyclization of the nitrile oxides
generated from the 2-substituted 5-hexenal oximes, but
the observed diastereoselectivity was not as good as with
the nitrones. Treatment of the oxime 8 with N-chloro-
succinimide and triethylamine in chloroform gave a
mixture of diastereomers 9 and 9′ (81:19 ratio, favoring
the exo isomer) via the nitrile oxide.15 Presumably the
larger bulk of the nitrone with its N-alkyl substituent
causes one of the two diastereomeric transition states to
The bicyclic compound 7d has the four contiguous
stereocenters needed for the construction of 2 but needs
to have the bond between C4 and C5 replaced by carbonyl
groups and the N-O bond reductively cleaved. In order
to introduce functionality in the molecule to carry out
the eventual oxidative cleavage of the C4-C5 bond, we
decided to utilize an ethylene ketal at C4 since it should
not change the diastereocontrol observed in formation of
7. Moreover, previous studies in our group indicated that
the gem-dialkoxy group greatly facilitates cyclization of
small-membered rings.16 Thus our synthetic approach
to 2 would involve the formation of the bicyclic compound
14 by intramolecular 1,3-dipolar cycloaddition of the
nitrone 19 (Scheme 1). This bicyclic isoxazolidine ketal
could then be taken on by either of two routes. In route
A, the N-O bond of the isoxazole ring would be cleaved
first to give the alcohol and amine functional groups.
With these two groups protected, the ethylene ketal
would then be removed with subsequent ozonolysis of the
corresponding silyl enol ether and construction of the
â-lactam ring. In route B, the ethylene ketal would be
removed first with the alcohol and amine functional
groups remaining masked until the cleavage of the silyl
enol ether to give the carboxylic acid moiety; reduction
and cyclization would then afford the desired â-lactam.
We began the synthesis of 2 with the addition of the
dianion generated from 3-chloro-2-methyl-1-propanol to
crotonaldehyde to give the diol 10 in 74% yield, using
the procedure of Seebach.17 Normant et al.18 also re-
(5) (a) Maslerz, H.; Menard, M. J . Org. Chem. 1994, 59, 3223. (b)
Hirai, K.; Iwano, Y.; Mikoshiba, I.; Koyama, H.; Nishi, T. Heterocycles
1994, 38, 277. (c) Uyero, S.; Itani, H. Tetrahedron Lett. 1994, 35, 4377.
(d) Choi, W. B.; Churchill, H. R. O.; Lynch, J . E.; Thompson, A. S.;
Humprey, G. R.; Volante, R. P.; Reider, P. J .; Shinkai, I. Tetrahedron
Lett. 1994, 35, 2275. (e) Miura, T.; Murayama, T.; Yoshida, A.;
Kobayashi, T. Tetrahedron Lett. 1994, 35, 2271. (f) Ito, Y.; Sasaki, A.;
Tamoto, K.; Sunagawa, M.; Tereshima, S. Tetrahedron 1991, 47, 2801.
(g) Ueyo, S.; Itani, H. Tetrahedron Lett. 1991, 32, 2143. (h) Noyori, R.;
Hsiao, Y.; Kitamura, M. Tetrahedron Lett. 1990, 31, 549. (i) Shirai,
F.; Nakai, T. J . Org. Chem. 1987, 52, 5492. (j) Fuentes, L. M.; Shinkai,
I.; King, A.; Purick, R.; Reamer, R. A.; Schmitt, S. M.; Cama, L.;
Christensen, B. G. J . Org. Chem. 1987, 52, 2563. (k) Deziel, R.;
Favreau, D. Tetrahedron Lett. 1986, 27, 5687. (l) Fuentes, L. M.;
Shinkai, I.; Salzmann, T. N. J . Am. Chem. Soc. 1986, 108, 4675. (m)
Sugimura, Y.; Shibata, T.; Iino, K.; Tanaka, T.; Hashimoto, T.;
Kameyama, Y. Tetrahedron Lett. 1985, 26, 4739.
(6) J ung, M. E.; Vu, B. T. Tetrahedron Lett. 1996, 37, 451.
(7) (a) Brown, F. K.; Raimondi, L.; Wu, Y.-D.; Houk, K. N. Tetra-
hedron Lett. 1992, 33, 4405. (b) Houk, K. N.; Raimondi, L. Private
communication.
(8) For example, the conformational free energy differences for these
three groups in the axial vs equatorial position on a cyclohexane (A
values) are (kcal/mol): CO2Me, 1.3; Me, 1.7; Ph, 2.7. In addition, we
have carried out calculations of the transition structures and energies
for these nitrile oxide cycloadditions and they are in good agreement
with the experimental results. The calculated ratios of 5:5′ are as
follows: CO2Me, 77:23; Me, 84:16; Ph, 90:10. Heitkamp, H. J . Ph.D.
Thesis, UCLA, 1995.
(9) Kang, S. H.; Lee, H. S. Tetrahedron Lett. 1995, 36, 6713.
(10) (a) Swern, D.; Omura, K. Tetrahedron 1978, 34, 1651. (b) Swern,
D.; Mancuso, A. J . Synthesis 1981, 165.
(11) Both N-benzyl- and N-(p-methoxybenzyl)hydroxylamine were
prepared according the literature procedure: J encks, W. P.; Maskill,
H. J . Am. Chem. Soc. 1987, 109, 2062.
(12) (E)-5-Bromo-2-pentene was prepared according to the literature
procedure: J ulia, M.; J ulia, S.; Tchen, S. Y. Bull. Soc. Chim. Fr. 1961,
1849. It contains ∼7% of the cis isomer which was carried through to
7c and 7d .
(13) Krapcho, A. P.; Weismaster, J . F.; Eldridge, J . M.; J ahngen, E.
G. E., J r.; Lovey, A. J .; Stephens, W. P. J . Org. Chem. 1978, 43, 138.
(14) The relative stereochemistry of 7b, 7d , and 14a was proven by
NOESY experiments. The methyl group (not next to the oxygen, at
the 6-position in the 1H-cyclopent[c]isoxazole numbering) was shown
to be syn to the ring juncture hydrogens by NOESY, while the
structures of 7a and 7c were assigned by analogy to 7b and 7d .
(15) (a) Grundmann, C.; Grunanger, P. The Nitrile Oxides; Springer-
Verlag: New York, 1971. (b) Caramella, P.; Grunanger, P. In 1,3-
Dipolar Cycloaddition; Padwa, A., Ed.; J ohn Wiley & Sons, Inc.: New
York, 1984; pp 291-392. (c) Curran, D. P. In Advances in Cycloaddi-
tion; J AI Press: Greewich, CT, 1988; Vol. 1, p 150. (d) The structures
of compounds 9 and 9′ were assigned by analogy to similar compounds
reported in the literature: Hassner, A.; Murthy, K. S. K.; Padwa, A.;
Chiacchio, U.; Dean, D. C.; Schoffstall, A. M. J . Org. Chem. 1989, 54,
5277. Kim, H. R.; Kim, H. J .; Duffy, J . L.; Olmstead, M. M.; Ruhlandt-
Senge, K.; Kurth, M. J . Tetrahedron Lett. 1991, 32, 4259.
(16) (a) J ung, M. E.; Trifunovich, I. D.; Lensen, N. Tetrehedron Lett.
1992, 33, 6719. (b) J ung, M. E.; Vu, B. T. Unpublished results.
(17) Seebach, D.; Yus, M.; von Carmen, N. Helv. Chim. Acta 1984,
67, 289.
(18) Normant, J . F.; Alexakis, A.; Cahiez, G. Tetrahedron Lett. 1978,
19, 3013.

Synthesis of 1â-Methylthienamycin
J . Org. Chem., Vol. 61, No. 13, 1996 4429
Sch em e 1
Sch em e 2
Sch em e 3
selective removal of the ketal protecting group failed.22
For this reason, we abandoned this approach to 1â-
methylthienamycin.
ported a similar procedure using Grignard reagents. Both
enantiomers of 3-chloro-2-methyl-1-propanol are com-
mercial available or readily prepared from ethyl 3-hy-
droxy-2-methylpropionate.17 The allylic alcohol of diol 10
was selectively oxidized by activated manganese oxide
to the enone 11, and the primary alcohol was protected
as the benzoate to give 12 in 74% yield for the two steps.
Ketalization with ethylene glycol and saponification gave
the alcohol 13.19 Swern oxidation of the alcohol to the
aldehyde and heating the aldehyde in toluene at 60-70
°C with N-benzylhydroxylamine and anhydrous potas-
sium carbonate for 10 h gave the desired diastereomer
14a in 84% yield as a single diastereomer (Scheme 2).
Thus, as expected, the ketal did not affect the diastereo-
control and only the desired diastereomer was obtained.
Moreover, the cyclization could be carried out under
much milder conditions than that of 6, presumably due
to the gem-dialkoxy effect.
With 14a in hand, we examined route A first (Scheme
3). The isoxazolidine was hydrogenated over Pd on
activated carbon in ethanol to give the amino alcohol 15
in 93% yield. Hydrogenation in other solvents, such as
ethyl acetate or benzene, failed to give 15. The alcohol
was then protected as a bulky silyl ether and the amine
protected with the phenylfluorenyl group.20 Rapoport
reported that the phenylfluorenyl protecting group can
be used as a steric pocket that shields the hydrogen on
the R-carbon of amino acid derivatives.20 In addition, the
phenylfluorenyl group is much more stable to solvolysis
than the trityl group.21 However, several efforts at
Since the first approach (route A) failed, we decided
to keep the amine and alcohol functional groups masked
as the isoxazolidine ring until the later steps (route B,
see Scheme 4). After several failed attempts to remove
the ethylene ketal of 14a under mild conditions such as
p-TsOH or pyridinium p-toluenesulfonate (PPTS) in
acetone, we were able to obtain 18a in 72% yield by
heating 14a with 50% H2SO4 in methanol for 4 h.
Presumably the presence of the basic nitrogen in 14
requires the formation of a dicationic species in order to
remove the ketal to give the ketone 18, and thus strongly
acidic conditions are necessary.
In order to allow greater possibilities for deprotection
of the amine functionality later in the synthetic scheme,
we also prepared the corresponding N-p-methoxybenzyl
derivative. Thus reaction of the aldehyde derived by
Swern oxidation of 13 with N-[(4-methoxyphenyl)methyl]-
hydroxylamine11 in toluene with potassium carbonate at
90 °C for 4 h afforded the desired bicyclic isoxazolidine
ketal 14b in 83% yield, again as a single diastereomer.
Acidic hydrolysis of 14b under the conditions described
above for 14a furnished the ketone 18b in 82% yield.
Comparison of the spectroscopic data of our sample of
18b with that kindly provided by Professor Kang showed
them to be identical. Since Kang and Lee reported the
(21) Shorter, J .; Bolton, R.; Chapman, N. B. J . Chem. Soc. 1964,
1895.
(22) In one case, with the amino being protected by the benzoyl
group, only 31% of the desired ketone was obtained in p-TsOH and
aqueous acetone conditions.
(23) Compound 6b was prepared according to the literature proce-
dure: Beckwith, A. L. J .; Easton, C. J .; Lawrence, T.; Serelis, A. K.
Aust. J . Chem. 1983, 36, 345.
(24) Attenburrow, J .; Cameron, A. F. B.; Chapman, J . H.; Evans,
R. M.; Hems, B. A.; J ansen, A. B. A.; Walker, T. J . Chem. Soc. 1952,
1094.
(19) The alcohol 13 contains ∼6-7% of the cis isomer resulting from
isomerization of the double bond during ketalization, which was carried
on to 14.
(20) (a) Rapoport, H.; Christie, B. D. J . Org. Chem. 1985, 50, 1239.
(b) Rapoport, H.; Lubell, W. D. J . Am. Chem. Soc. 1987, 109, 236.

4430 J . Org. Chem., Vol. 61, No. 13, 1996
J ung and Vu
Sch em e 4
67.36, 47.88, 31.25, 31.03; IR (neat) 3359, 3063, 3029, 2928,
1640, 1057, 1032.
synthesis of 2 in eight steps from 18b, we have thus
completed a formal total synthesis of both 2 and the
â-lactam antibiotic 1â-methylthienamycin 1.
2-Meth yl-5-h exen -1-ol (6b):21 1H NMR (CDCl3, 500 MHz)
δ 5.86 (1H, m), 5.02 (2H, m), 3.55 (1H, dd, J ) 10.5, 5.8 Hz),
3.54 (1H, dd, J ) 10.5, 5.8 Hz), 2.14 (2H, m), 1.64 (1H, m),
1.56 (1H, m), 1.51 (1H, m), 1.25 (1H, m), 0.97 (3H, d, J ) 6.7
Hz).
Con clu sion
Thus we have observed remarkable diastereocontrol in
intramolecular 1,3-dipolar cycloadditions of 2-substituted
5-hexenyl and 5-heptenyl nitrones in which only one
diastereomer of the 6-substituted and 3,6-disubstituted
perhydrocyclopenta[c]isoxazoles is isolated. An alkyl or
aryl substituent at C2 completely controls the stereo-
chemistry of both the ring juncture and the 3-substituent,
and thus one stereocenter controls the formation of the
other three to give a product with four contiguous
stereocenters. We have also observed a gem-dialkoxy
effect in the cyclization of an analogous ethylene ketal.
Finally this cycloaddition process has been used as the
key step in an efficient formal total synthesis of the
potent â-lactam antibiotic, 1â-methylthienamycin. Fur-
ther work in the area of substituent effectssgem dialkyl,
dialkoxy, dicarbalkoxy, etc.sis currently underway in our
laboratory and will be described in due course.
(E)-2-P h en yl-5-h ep ten -1-ol (6c). To the solution of diiso-
propylamine (0.684 mL, 5.216 mmol) in 50 mL of THF at -78
°C was added n-butyllithium (5.216 mmol). After 15 min,
methyl phenylacetate (0.625 mL, 4.346 mmol) was added.
Stirring was continued for another 15 min, and then 5-bromo-
2-pentene12 (713.6 mg, 4.781 mmol) was added dropwise. After
about 2 h, the reaction was worked up with diethyl ether and
a saturated brine solution. Flash column chromatography
(silica gel, 3-5% EtOAc-hexane) of the crude residue gave
methyl 2-phenyl-5-heptenoate (503.1 mg, 53%): 1H NMR
(CDCl3, 400 MHz) δ 7.29 (5H, m), 5.39 (2H, m), 3.65 (3H, s),
3.56 (1H, t, J ) 7.6 Hz), 2.18-1.80 (3H, m), 1.64 (3H, bd, J )
3.7 Hz), 1.35 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 174.41,
138.95, 129.88, 128.48, 127.88, 126.91, 125.88, 64.65, 51.83,
33.05, 30.21, 17.82.
Methyl 2-phenyl-5-heptenoate (503.1 mg, 2.304 mmol) was
stirred with LAH (96.2 mg, 2.535 mmol) in 30 mL of diethyl
ether overnight at room temperature to give 6c (310 mg, 71%)
after chromatography (silica gel, 15% EtOAc-hexane): 1H
NMR (CDCl3, 500 MHz) δ 7.39-7.25 (5H, m), 5.42 (2H, m),
3.78 (2H, m), 2.85 (1H, m), 1.93 (2H, m), 1.79 (1H, m), 1.71
(1H, m), 1.67 (3H, bd, J ) 5.3 Hz), 1.37 (1H, bs); 13C NMR
(CDCl3, 125 MHz) δ 142.07, 130.65, 128.54, 128.02, 126.63,
125.20, 67.40, 47.85, 31.71, 30.03, 17.81; IR (neat) 3358, 3028,
2921, 1603, 1029.
(E)-2-Meth yl-5-h ep ten -1-ol (6d ). To the solution of meth-
yl methylmalonate (1.464 g, 10 mmol) in 100 mL of THF was
added 60% sodium hydride in mineral oil (440 mg, 11 mmol).
After 15 min, 5-bromo-2-pentene12 (1.6396 g, 11 mmol) was
added. The solution was refluxed for 10 h. A saturated NH4-
Cl solution was then added, and the product was extracted
with petroleum ether. The ethereal extracts were washed with
brine, dried over MgSO4, and concentrated in vacuo. Column
chromatography (silica gel, 5% EtOAc-hexane) of the crude
residue gave dimethyl 2-methyl-2-(5-pentenyl)propanedioate
(1.920 g, 90%). The solution of dimethyl 2-methyl-2-(5-
pentenyl)propanedioate (1.920 g, 8.960 mmol), lithium chloride
(1.520 g, 35.84 mmol), and water (0.160 mL, 8.960 mmol) in
DMSO (20 mL) was refluxed for 2 h. Water was added, and
the monoester was extracted with petroleum ether. The
ethereal extracts were washed with saturated brine and dried
over MgSO4. Chromatography of the crude residue (silica gel,
5% EtOAc-hexane) gave methyl 2-methyl-5-heptenoate (1.1256
g, 80%).
The solution of methyl 2-methyl-5-heptenoate (1.0581 g,
6.772 mmol) and LAH (257 mg, 6.772 mmol) in ∼50 mL of
diethyl ether was refluxed for 2 h to give the alcohol 6d (801.2
mg, 92%) after chromatography (silica gel, 15% EtOAc-
hexane): 1H NMR (CDCl3, 500 MHz) δ 5.47 (2H, m), 3.55 (1H,
dd, J ) 10.5, 5.8 Hz), 3.46 (1H, dd, J ) 10.5, 6.5 Hz), 2.08
(1H, m), 2.01 (1H, m), 1.68 (3H, bd, J ) 3.5 Hz), 1.67 (1H, m),
1.51 (1H, m), 1.41 (1H, bs), 1.20 (1H, m), 0.96 (3H, d, J ) 6.7
Hz); 13C NMR (CDCl3, 125 MHz) δ 131.28, 124.85, 68.20, 35.14,
32.94, 29.90, 17.88, 16.45; IR (neat) 3341, 2919, 2857, 1657,
1038.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under argon with
the exclusion of moisture. Reagents were purchased from
Fisher Scientific Co. and Aldrich Chemical Co. and were used
without further purification unless otherwise specified. The
following solvents and reagents were distilled from the indi-
cated agent under argon: tetrahydrofuran (THF) and diethyl
ether from sodium benzophenone ketyl, methylene chloride,
benzene, and toluene from calcium hydride, and triethylamine
from potassium hydroxide. Flash column chromatography was
carried out in the indicated solvent system (in the percentage
of volume) on 230-400 mesh silica gel. Analytical thin layer
chromatography was done on Merck silica gel F254 0.2 mm
precoated plates.
2-P h en yl-5-h exen -1-ol (6a ). To the solution of diisopro-
pylamine (0.721 mL, 5.5 mmol) in 40 mL of THF at -78 °C
was added n-butyllithium (5.5 mmol). After 15 min, methyl
phenylacetate (0.719 mL, 5.0 mmol) was added. Stirring was
continued for another 15 min, and then 4-bromo-1-butene
(0.533 mL, 5.25 mmol) was added dropwise. After 1 h, the
reaction was worked up with diethyl ether and saturated brine
solution. Flash column chromatography (silica gel, 3-5%
EtOAc-hexane) of the crude residue gave methyl 2-phenyl-
5-hexenoate (547.1 mg, 54%): 1H NMR (CDCl3, 400 MHz) δ
7.29 (5H, m), 5.78 (2H, m), 5.01 (2H, m), 3.65 (3H, s), 3.58
(1H, t, J ) 7.6 Hz), 2.19 (1H, m), 2.01 (2H, m), 1.88 (1H, m);
13C NMR (CDCl3, 100 MHz) δ 174.30, 138.80, 137.4, 128.50,
127.90, 127.20, 115.30, 51.90, 50.60, 33.40, 31.40; IR (neat)
3065, 2952, 1736, 1641, 1255, 1163.
The solution of methyl 2-phenyl-5-hexenoate (517.1 mg,
2.531 mmol) and LAH (115.3 mg, 3.037 mmol) in 30 mL of
diethyl ether was refluxed for 3 h to give 6a (379.2 mg, 85%)
after chromatography (silica gel, 20% EtOAc-hexane): 1H
NMR (CDCl3, 500 MHz) δ 7.38 (2H, t, J ) 7.0 Hz), 7.30 (1H,
t, J ) 7.2 Hz), 7.27 (2H, d, J ) 7.0 Hz), 5.83 (1H, m), 5.01
(2H, m), 3.79 (2H, m), 2.86 (1H, m), 2.02 (2H, m), 1.85 (1H,
m), 1.75 (1H, m), 1.41 (1H, bt, J ) 5.9 Hz); 13C NMR (CDCl3,
125 MHz) δ 141.91, 138.22, 128.58, 128.00, 126.70, 114.67,
(3,3a r,4,5,6â,6a r)-Hexa h yd r o-6-p h en yl-1-(p h en ylm eth -
yl)-1H-cyclop en t[c]isoxa zole (7a ). Oxalyl chloride (122 µL,
1.402 mmol) was added to a solution of dimethyl sulfoxide (199

Synthesis of 1â-Methylthienamycin
J . Org. Chem., Vol. 61, No. 13, 1996 4431
µL, 2.805 mmol) in 10 mL of methylene chloride at -78 °C.
After 15 min, a solution of 6a (100 mg, 0.561 mmol) in 1 mL
of methylene chloride was added dropwise. Stirring was
continued for 45 min, and the reaction was quenched with
triethylamine (626 µL, 4.488 mmol). The cooling bath was
removed, and the reaction flask was allowed to warm to about
-20 °C. Workup involved addition of 1 M NaHSO4 and
extraction with petroleum ether. The organic layers were
washed with saturated NaCl solution and dried over MgSO4.
Evaporation of solvents gave the crude aldehyde (98 mg, 98%)
which was used without further purification. To a solution of
the aldehyde (98 mg, 0.556 mmol) in 10 mL of toluene were
added potassium carbonate (154.7 mg, 1.112 mmol) and
N-benzylhydroxylamine11 (82.2 mg, 0.667 mmol). After the
solution was heated at ∼100 °C for 12 h, the solids were then
filtered out, and the solvent was removed in vacuo to give an
oily residue. 1H NMR of the crude oil shows only one
diasteremer. Flash column chromatography (silica gel, 5%
EtOAc-hexane) gave 7a (127.4 mg, 82%): 1H NMR (CDCl3,
400 MHz) δ 7.23 (10H, m), 4.21 (1H, dd, J ) 8.6, 7.6 Hz), 3.98
(1H, d, J ) 13.2 Hz), 3.78 (1H, d, J ) 13.2 Hz), 3.67 (1H, dd,
J ) 8.6, 3.6 Hz), 3.55 (1H, bdd, J ) 8.0, 8.0 Hz), 3.23 (1H, m),
3.08 (1H, m), 2.15 (2H, m), 1.77-1.59 (2H, m); 13C NMR
(CDCl3, 100 MHz) δ 143.51, 137.26, 128.85, 128.20, 128.16,
127.25, 127.08, 125.97, 78.59, 72.40, 60.36, 50.68, 47.70, 33.85,
31.47; IR (neat) 3029, 2951, 2566, 1495, 1030; high-resolution
MS (EI, m/ z) 279.1620, calcd for C19H21NO 279.1623.
(3,3a r,4,5,6â,6a r)-Hexa h yd r o-6-m eth yl-1-(p h en ylm eth -
yl)-1H-cyclop en t[c]isoxa zole (7b). Using the aldehyde from
6b (61.2 mg, 0.545 mmol), the procedure used for the formation
of 7a from 6a was followed to give 7b (61.7 mg, 52%) after
flash column chromatography (silica gel, 10% EtOAc-hex-
ane): 1H NMR (CDCl3, 500 MHz) δ 7.44 (2H, d, J ) 7.1 Hz),
7.38 (2H, t, J ) 7.3 Hz), 7.31 (1H, t, J ) 7.2 Hz), 4.19 (1H, dd,
J ) 8.5, 7.9 Hz), 4.06 (1H, d, J ) 12.9 Hz), 3.83 (1H, d, J )
12.9 Hz), 3.58 (1H, dd, J ) 8.5, 4.5 Hz), 3.11 (1H, m), 3.01
(1H, dd, J ) 8.4, 4.6 Hz), 1.94 (3H, m), 1.52 (1H, m), 1.23 (1H,
m), 0.89 (3H, d, J ) 6.9 Hz); 13C NMR (CDCl3, 125 MHz) δ
137.45, 129.08, 128.21, 127.20, 78.88, 72.53, 61.00, 47.02,
39.39, 33.19, 30.50, 18.00; IR (neat) 3063, 2953, 2868, 1455,
of methylene chloride was added dropwise. Stirring was
continued for 1 h, and the reaction was quenched with
triethylamine (476 µL, 3.416 mmol). The cooling bath was
removed, and the reaction flask was allowed to warm to -20
°C. Workup involved addition of 1 M NaHSO4 and extraction
with petroleum ether. The organic layers were washed with
saturated NaCl solution and dried over MgSO4. Evaporation
of solvents gave the crude aldehyde (∼74 mg) which was used
without further purification. The crude aldehyde was dis-
solved in 10 mL of pyridine, and hydroxylamine hydrochloride
(44.5 mg, 0.641 mmol) was added. The reaction mixture was
stirred overnight (∼12 h) and then worked up with 1 N HCl
and diethyl ether. The ethereal extracts were washed with 1
N HCl and brine, dried over MgSO4, and concentrated to give
a oily residue. Flash column chromatography (silica gel, 20%
EtOAc-hexane) of the crude residue gave 8 (66.2 mg, 82%)
as a mixture of Z and E isomers. E-isomer: 1H NMR (CDCl3,
400 MHz) δ 8.47 (1H, bs), 7.52 (1H, d, J ) 6.9 Hz), 7.34 (2H,
t, J ) 6.2 Hz), 7.27 (1H, t, J ) 6.1 Hz), 7.22 (2H, d, J ) 6.1
Hz), 5.81 (1H, m), 5.03 (2H, m), 3.53 (1H, app q, J ) 7.1 Hz),
2.03 (4H, m); 13C NMR (CDCl3, 100 MHz) δ 154.05, 140.38,
137.67, 128.70, 127.76, 126.79, 115.19, 45.50, 32.43, 31.23; IR
(neat) 3262, 3068, 2930, 1642, 1601.
(3a r,4,5,6â)-Tetr a h yd r o-6-p h en yl-3H-cyclop en t[c]isox-
a zole (9). N-Chlorosuccinimide (22.1 mg, 0.165 mmol) was
added to a solution of 8 (31.3 mg, 0.165 mmol) in chloroform
(3 mL) at 0 °C. After 3 h, triethylamine (23 µl, 0.165 mmol)
was added. The reaction was worked up after 12 h with water
and methylene chloride. The CH2
Cl2 layers were washed with
water, dried over anhydrous Na2SO4, and concentrated in
vacuo. 1H NMR of the crude residue showed a mixture of
diastereomers (81:19 ratio). Preparative chromatography
(silica gel, 20% EtOAc-hexane) gave 17.8 mg of 9 and 3.9 mg
of 9′. Yield: 70%. Compound 9:
1H NMR (CDCl3, 500 MHz)
δ 7.37 (2H, bt, J )7.4 Hz), 7.32 (2H, bd, J ) 7.5 Hz), 7.29 (1H,
bt, J )7.2 Hz), 4.64 (1H, m), 4.04 (1H, app t, J ) 8.5 Hz), 3.95
(2H, m), 2.90 (1H, m), 2.35 (1H, m), 2.22 (1H, m), 1.65 (1H,
m); 13C NMR (CDCl3, 125 MHz) δ 173.08, 140.52, 128.63,
126.83, 126.71, 74.73, 55.61, 39.45, 38.56, 28.13; IR (neat) 2936,
2870, 1603, 1497, 1269; high-resolution MS (EI, m/ z) 187.1004,
calcd for C12H13NO 187.0997. Compound 9′: 1H NMR (CDCl3,
400 MHz) δ 7.20-7.15 (5H, m), 4.61 (1H, m), 4.00-3.90 (3H,
1030; high-resolution MS (EI, m/ z) 217.1471, calcd for C14H19
-
NO 217.1467.
m), 2.70 (1H, m), 2.33 (1H, m), 2.18 (1H, m), 1.76 (1H, m); 13
C
(3r,3a â,4,5,6â,6a r)-H exa h yd r o-3-m et h yl-6-p h en yl-1-
(p h en ylm eth yl)-1H-cyclop en t[c]isoxa zole (7c). Using the
alcohol 6c (77.7 mg, 0.408 mmol), the procedure used for the
formation of 7a from 6a was followed to give 7c (99.5 mg, 83%)
after flash column chromatography (silica gel, 5% EtOAc-
hexane): 1H NMR (CDCl3, 500 MHz) δ 7.41-7.10 (10H, m),
4.06 (1H, d, J ) 13.8 Hz), 3.97 (1H, d, J ) 13.8 Hz), 3.87 (1H,
bdq, J ) 6.9, 6.1 Hz), 3.54 (1H, dd, J ) 8.8, 2.0 Hz), 3.08 (1H,
m), 2.78 (1H, dq, J ) 3.3, 7.8 Hz), 2.41 (1H, m), 1.96 (1H, m),
1.85 (1H, m), 1.66 (1H, m), 1.39 (3H, d, J ) 6.1 Hz); 13C NMR
(CDCl3, 125 MHz) δ 143.87, 137.50, 128.90, 128.23, 128.10,
127.29, 127.02, 125.92, 80.11, 79.97, 62.06, 56.28, 49.77, 34.15,
28.30, 18.33; IR (neat) 3029, 2931, 2868, 1496, 1454, 1117;
high-resolution MS (EI, m/ z) 293.1780, calcd for C20H23NO
293.1780.
(3r,3a â,4,5,6r,6a â)-Hexa h yd r o-3,6-d im eth yl-1-(p h en yl-
m eth yl)-1H-cyclop en t[c]isoxa zole (7d ). Using the alcohol
6d (123.5 mg, 0.963 mmol), the procedure used for the
formation of 7a from 6a was followed to give 7d (162.8 mg,
73%) after flash column chromatography (silica gel, 5%
EtOAc-hexane): 1H NMR (CDCl3, 400 MHz) δ 7.51 (2H, dd,
J ) 7.5, 1.4 Hz), 7.25 (2H, tt, J ) 7.6, 1.4 Hz), 7.16 (1H, tt, J
) 7.4, 1.3 Hz), 4.09 (1H, d, J ) 13.1 Hz), 3.86 (1H, d, J ) 13.1
Hz), 3.65 (1H, bdq, J ) 8.5, 6.1 Hz), 2.91 (1H, bd, J ) 8.5 Hz),
2.51 (1H, dq, J ) 1.8, 8.5 Hz), 2.01 (1H, m), 1.74 (2H, m), 1.47
(1H, m), 1.31 (1H, m), 1.27 (3H, d, J ) 6.1 Hz), 0.73 (1H, d, J
) 7.3 Hz); 13C NMR (CDCl3, 100 MHz) δ 137.42, 129.15,
128.09, 127.11, 80.74, 79.57, 62.41, 55.00, 37.99, 31.74, 27.19,
18.04, 17.76; IR (neat) 2955, 2869, 1455, 1100; high-resolution
MS (EI, m/ z) 231.1624, calcd for C15H21NO 231.1623.
2-P h en yl-5-h exen -1-a l Oxim es 8. Oxalyl chloride (93 µL,
1.066 mmol) was added to a solution of dimethyl sulfoxide (151
µL, 2.133 mmol) in 10 mL of methylene chloride at -78 °C.
After 15 min, a solution of 6a (75.2 mg, 0.427 mmol) in 1 mL
NMR (CDCl3, 100 MHz) δ 173.50, 139.98, 128.52, 127.80,
126.89, 75.34, 54.77, 40.46, 37.79, 29.59.
(E)-2-Meth yl-5-h ep ten e-1,4-d iol (10). n-Butyllithium (10
mmol) was added to a solution of 3-chloro-3-methyl-1-propanol
(1.0858 g, 10 mmol) in 10 mL of THF at -78 °C under argon.
After 15 min, a solution of lithium naphthalenide (prepared
by stirring 173.4 mg of lithium and 3.2 g of naphthalene in 50
mL of THF overnight) was added via cannula. The reaction
mixture was then stirred at -78 °C for 6-8 h. Crotonaldehyde
(0.830 mL, 10 mmol) was then added dropwise. After an
additional 2 h at -78 °C, the cooling bath was removed, and
the reaction mixture was allowed to warm up to room tem-
perature. After the solution was stirred at room temperature
overnight, the reaction was quenched with saturated NH4Cl
solution, and the product was extracted with diethyl ether.
The ethereal extracts were washed with brine, dried over
MgSO4
, and evaporated in vacuo. Flash column chromatog-
raphy (silica gel, 50-60% EtOAc-hexane) of the crude residue
gave 1.0713 g of the diol 10 as a ∼1:1 mixture of diastereomers.
Yield: 74%. 10: 1H NMR of one diastereomer (CDCl3, 400
MHz) δ 5.64 (1H, dd, J ) 15.2, 6.3 Hz), 5.47 (1H, dm, J )15.2
Hz), 4.18 (1H, dt, J ) 6.0, 6.2 Hz), 3.5 (4H, m), 1.81 (1H, m),
1.67 (3H, m), 1.52 (2H, m), 0.90 (3H, d, J ) 6.9 Hz); 13
C NMR
(CDCl3, 100 MHz) δ 133.85, 126.42, 70.37, 67.81, 41.66, 31.97,
17.56, 17.12; IR (neat) 3334, 2919, 1675, 1040; high-resolution
MS (EI, m/ z) 143.1069 (M - H)+, calcd for C8H15O2 143.1072.
(E)-7-Hyd r oxy-6-m eth yl-2-h ep ten -4-on e (11). The solu-
tion of 10 (867 mg, 6.011 mmol) and activated manganese
dioxide24 (5.229 g, 60.108 mmol) in 60 mL of methylene
chloride was stirred for 48 h at room temperature. The black
solids were filtered out and washed with chloroform. The
filtrate was then concentrated in vacuo and chromatographed
on silica gel (neutralized with triethylamine, 40% EtOAc-

4432 J . Org. Chem., Vol. 61, No. 13, 1996
J ung and Vu
hexane) to give the enone 11 (641.2 mg, 75%): 1H NMR
(CDCl3, 400 MHz) δ 6.87 (1H, dq, J ) 15.8, 6.9 Hz), 6.12 (1H,
dq, J ) 15.8, 1.6 Hz), 3.53 (1H, m), 3.42 (1H, m), 2.67 (1H, dd,
J ) 16.1, 6.6 Hz), 2.44 (1H, dd, J ) 16.1, 6.6 Hz), 2.23 (1H,
m), 2.20 (1H, bs), 1.89 (3H, dd, J ) 6.8, 1.7 Hz), 0.93 (3H, d,
J ) 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 200.71, 143.18,
132.16, 67.82, 44.13, 32.23, 18.25, 16.98; IR (neat) 3433, 2960,
2934, 2875, 1666, 1632, 1443, 1042; high-resolution MS (EI,
m/ z) 143.1073 (M - H)+, calcd for C8H15O2 143.1072.
extracted with diethyl ether. The ethereal extracts were
washed with brine, dried over MgSO4, and concentrated to give
94 mg of the crude aldehyde. The aldehyde was dissolved in
10 mL of toluene, and N-benzylhydroxylamine (75.6 mg, 0.614
mmol) and anhydrous potassium carbonate (141.5 mg, 1.024
mmol) were added. The reaction mixture was heated at 60-
70 °C for 10 h. The solids were then filtered out, and toluene
was removed in vacuo. Flash column chromatography (silica
gel, 10% EtOAc-hexane) of the crude residue gave 14a (124.5
mg, 84%): 1H NMR (CDCl3, 500 MHz) δ 7.44 (2H, bd, J ) 7.4
Hz), 7.36 (2H, bt, J ) 7.5 Hz), 7.30 (1H, bt, J ) 7.3 Hz), 4.16
(1H, m), 4.11 (1H, d, J ) 13.2 Hz), 3.98-3.80 (5H, m), 3.07
(1H, d, J ) 8.7 Hz), 2.52 (1H, dt, J ) 1.2, 8.3 Hz), 2.38 (1H,
dd, J ) 13.5, 8.1 Hz), 1.81 (1H, m), 1.54 (1H, bd, J ) 13.5 Hz),
1.33 (3H, d, J ) 6.1 Hz), 0.92 (3H, d, J ) 7.5 Hz); 13C NMR
(CDCl3, 125 MHz) δ 137.14, 129.15, 128.18, 127.26, 117.06,
78.89, 75.19, 64.49, 63.98, 62.21, 40.96, 34.51, 19.06, 18.82 (1
carbon not resolved); IR (neat) 2973, 2932, 2874, 1740, 1455,
1341, 1119, 1032; high-resolution MS (EI, m/ z) 289.1667, calcd
for C17H23NO3.
(E)-7-(Ben zoyloxy)-6-m eth yl-2-h ep ten -4-on e (12). To a
solution of 11 (568 mg, 3.994 mmol) in 5 mL of methylene
chloride and 1 mL of dry pyridine was added benzoyl chloride
(1.0 mL, 8.615 mmol). After being stirred overnight at room
temperature, the reaction mixture was worked up by addition
of brine and extraction with petroleum ether. Pyridine was
removed by washing the ethereal extracts with diluted HCl.
Evaporation of ether gave an oily residue which after chro-
matography on a short column of silica gel (15% EtOAc-
hexane) gave 12 (973.2 mg, 98%): 1H NMR (CDCl3, 400 MHz)
δ 8.00 (2H, bd, J ) 7.1 Hz), 7.54 (1H, bt, J ) 7.5 Hz), 7.42
(2H, bt, J ) 7.4 Hz), 6.83 (1H, dq, J ) 15.8, 6.8 Hz), 6.12 (1H,
dq, J ) 15.8, 1.5 Hz), 4.18 (2H, m), 2.70 (1H, dd, J ) 15.7, 5.6
Hz), 2.57 (1H, m), 2.45 (1H, dd, J ) 15.7, 7.6 Hz), 1.85 (3H,
dd, J ) 6.8, 1.6 Hz), 1.03 (3H, d, J ) 6.7 Hz); 13C NMR (CDCl3,
100 MHz) δ 198.82, 166.38, 142.84, 132.87, 132.05, 130.11,
129.46, 128.28, 69.03, 43.66, 29.22, 18.14, 17.03; IR (neat) 2967,
1790, 1721, 1698, 1674, 1275, 1113; high-resolution MS (EI,
m/ z) 247.1329 (M + H)+, calcd for C15H19O3 247.1334.
(E)-7-Hyd r oxy-6-m eth yl-2-h ep ten -4-on e Eth ylen e Ket-
a l (13). To the solution of 12 (1.0910 g, 4.429 mmol) in 40
mL were added ethylene glycol (1 mL, 16 mmol) and several
crystals of p-TsOH. The reaction was refluxed for 12 h using
a Dean-Stark trap. TLC (10% EtOAc-hexane) showed a
mixture of 12 and the product. A saturated NaHCO3 solution
was added, and the products were extracted with ether. The
organic layers were washed with brine, dried over MgSO4, and
concentrated. Flash column chromatography (silica gel, 8-10%
EtOAc-hexane) gave 325.1 mg (30%) of starting material and
429.9 mg (55% yield) of the ketal: 1H NMR (CDCl3, 500 MHz)
δ 8.09 (2H, bd, J ) 7.1 Hz), 7.60 (1H, bt, J ) 7.1 Hz), 7.48
(2H, bt, J ) 7.5 Hz), 5.87 (1H, dq, J ) 15.4, 6.6 Hz), 5.43 (1H,
dq, J ) 15.4, 1.6 Hz), 4.34 (1H, dd, J ) 10.7, 5.2 Hz), 4.17
(1H, dd, J ) 10.6, 6.9 Hz), 3.99-3.89 (4H, m), 2.23 (1H, m),
1.94 (1H, dd, J ) 14.4, 6.0 Hz), 1.75 (3H, dd, J ) 6.7, 1.7 Hz),
1.70 (1H, dd, J ) 14.4, 6.4 Hz), 1.13 (3H, d, J ) 6.8 Hz); 13C
NMR (CDCl3, 125 MHz) δ 166.63, 132.75, 130.81, 130.55,
129.52, 128.30, 126.81, 108.84, 69.94, 64.30, 64.22, 41.46,
28.59, 18.51, 17.31; IR (neat) 2961, 2886, 1717, 1603, 1452,
1280, 1115, 1028; high-resolution MS (EI, m/ z) 291.1587 (M
+ H)+, calcd for C17H23O4 291.1596.
The solution of the ketal (415.6 mg, 1.432 mmol) and 5 mL
of 5% NaOH in 20 mL of MeOH was stirred at room temper-
ature for 2 h. Workup involved removal of methanol by
evaporation in vacuo, addition of water, and extraction with
diethyl ether. The ethereal extracts were washed with brine,
dried over MgSO4, and concentrated in vacuo. Flash column
chromatography (silica gel, 25-30% EtOAc-hexane) of the
residue gave the alcohol 13 (240 mg, 91%): 1H NMR (CDCl3,
400 MHz) δ 5.80 (1H, dq, J ) 15.4, 6.6 Hz), 5.37 (1H, dq, J )
15.4, 1.6 Hz), 3.99-3.84 (4H, m), 3.51 (1H, bm), 3.38 (1H, bm),
2.87 (1H, m), 1.89 (1H, m), 1.74 (2H, m), 1.70 (3H, dd, J )
6.6, 1.7 Hz), 0.92 (3H, d, J ) 6.9 Hz); 13C NMR (CDCl3, 100
MHz) δ 130.38, 126.94, 108.82, 68.43, 64.37, 63.90, 42.87,
31.13, 18.88, 17.20; IR (neat) 3426, 2954, 2886, 11675, 1451,
1201, 1036; high-resolution MS (EI, m/ z) 187.1327 (M + H)+,
calcd for C10H19O3 187.1334.
(3r,3a â,5,6r,6a â)-H exa h yd r o-3,6-d im et h yl-1-(p h en yl-
m et h yl)-4H -cyclop en t [c]isoxa zol-4-on e E t h ylen e Ket a l
(14a ). Oxalyl chloride (112 µL, 1.28 mmol) was added to a
solution of dimethyl sulfoxide (182 µL, 2.56 mmol) in 6 mL of
methylene chloride at -78 °C. After 15 min, a solution of the
alcohol 13 (95.3 mg, 0.512 mmol) in 1 mL of methylene chloride
was added dropwise. After the solution was stirred at -78
°C for 1 h, triethylamine (571 µL, 4.096 mmol) was added, and
the cooling bath was removed. The reaction was worked up
at -20 °C with addition of water, and the product was
(3r,3a â,5,6r,6a â)-H exa h yd r o-1-N-(4-m et h oxyb en zyl)-
3,6-dim eth yl-4H-cyclopen t[c]isoxazol-4-on e Eth ylen e Ket-
a l (14b). The alcohol 13 (92.3 mg, 0.495 mmol) was oxidized
to give 88.5 mg of the corresponding aldehyde using the
procedure described for 14a . The aldehyde (88.5 mg, 0.480
mmol) was dissolved in toluene (5 mL), and N-(4-methoxy-
phenyl)methylhydroxylamine11
(88.2 mg, 0.576 mmol) and
potassium carbonate (132.7 mg, 0.960 mmol) were added. The
reaction mixture was heated at 90-100 °C for 4 h. The solids
were then filtered out, and toluene was evaporated in vacuo.
Column chromatography (25% EtOAc-hexane) of the crude
residue gave 14b (127.6 mg, 83%): 1H NMR (CDCl3, 500 MHz)
δ 7.30 (2H, d, J ) 8.7 Hz), 6.85 (2H, d, J ) 8.7 Hz), 4.10 (1H,
m), 4.06 (1H, d, J ) 12.9 Hz), 3.92 (1H, m), 3.85 (2H, m), 3.79
(3H, s), 3.77 (2H, m), 3.00 (1H, d, J ) 8.7 Hz), 2.46 (1H, dt, J
) 1.2, 8.3 Hz), 2.32 (1H, dd, J ) 13.5, 8.1 Hz), 1.73 (1H, m),
1.45 (1H, bd, J ) 13.5 Hz), 1.28 (3H, d, J ) 6.1 Hz), 0.86 (3H,
d, J ) 7.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 158.87, 130.45,
129.10, 117.07, 113.57, 78.71, 75.14, 64.49, 63.98, 62.21, 61.70,
55.19, 40.92, 34.57, 19.03, 18.85; IR (neat) 2969, 2876, 1514,
1341, 1250, 1117, 1034; high-resolution MS (EI, m/ z) 319.1785,
calcd for C18H25O4 319.1784.
(()-(2S,3R,4S)-3-Am in o-2-((R)-1-h yd r oxyeth yl)-4-m eth -
ylcyclop en ta n on e Eth ylen e Keta l (15). The isoxazole 14a
(280.8 mg, 0.970 mmol) was hydrogenated for 12 h in absolute
ethyl alcohol (10 mL) over Pd-C under a balloon of hydrogen
gas. The black solids were then filtered out and washed with
ethyl acetate. Evaporation of solvents in vacuo gave the amino
alcohol 15 (182.2 mg, 93%) which is sufficiently pure to be used
without further purification: 1H NMR (CDCl3, 500 MHz) δ 4.14
(1H, dq, J ) 8.1, 6.2 Hz), 4.00-3.87 (4H, m), 3.12 (1H, dd, J
) 8.5, 4.9 Hz), 2.99 (3H, bs), 2.18 (1H, dd, J ) 8.3, 8.3 Hz),
2.10 (1H, dd, J ) 13.2, 7.7 Hz), 1.82 (1H, m), 1.33 (1H, dd, J
) 13.2, 8.9), 1.28 (3H, d, J ) 6.2 Hz), 1.08 (3H, d, J ) 7.0 Hz);
13C NMR (CDCl3, 125 MHz) δ 116.45, 64.38, 64.29, 63.86,
59.04, 52.98, 43.04, 41.34, 22.01, 19.30.
(()-(2S,3R,4S)-2-[(R)-1-((ter t-Bu tyld im eth ylsilyl)oxy)-
et h yl]-3-[(9-(9-p h en ylflu or en yl)a m in o]-4-m et h ylcyclo-
p en ta n on e Eth ylen e Keta l (16). To a solution of 15 (182.2
mg, 0.905 mmol) in 10 mL of methylene chloride were added
triethylamine (139 µL, 0.996 mmol), tert-butyldimethylsilyl
chloride (150.7 mg, 0.996 mmol), and DMAP (4.9 mg, 0.04
mmol). The reaction mixture was stirred at room temperature
for 24 h; then phenylfluorenyl bromide20 (312 mg, 1.0 mmol),
triethylamine (139 µL, 0.996 mmol), and Pb(NO3)2 (331.2 mg,
1.0 mmol) were added. The reaction mixture was stirred for
another 24 h. The reaction was worked up with water and
diethyl ether. The organic layers were washed with saturated
NH4Cl solution and brine, dried over MgSO4, and evaporated
in vacuo to give an oil. Flash column chromatography of the
crude residue gave the protected amino alcohol 16 (210.9 mg,
42%): 1H NMR (CDCl3, 400 MHz) δ 7.71 (1H, d, J ) 7.5 Hz),
7.66 (1H, d, J ) 7.5 Hz), 7.50-7.12 (11H, m), 4.22 (1H, dq, J
) 6.1, 6.2 Hz), 3.82-3.71 (3H, m), 3.69 (1H, bs), 3.55 (1H, m),
2.52 (1H, m), 2.13 (1H, dd, J ) 13.9, 9.9 Hz), 1.74 (1H, m),
1.46 (1H, bt, J ) 5.8 Hz), 1.13 (1H, m), 1.12 (3H, d, J ) 6.2

Synthesis of 1â-Methylthienamycin
J . Org. Chem., Vol. 61, No. 13, 1996 4433
Hz), 0.81 (9H, s), 0.56 (3H, d, J ) 7.0 Hz), 0.08 (3H, s), 0.07
(3H, s); 13C NMR (CDCl3, 100 MHz) δ 150.83, 146.10, 140.80,
140.14, 127.85, 127.80, 127.74, 127.29, 127.27, 126.68, 126.53,
126.23, 125.98, 119.62, 119.55, 116.47, 73.02, 68.00, 64.12,
63.07, 62.46, 52.88, 41.68, 35.97, 25.95, 24.67, 19.22, 18.00,
-3.98, -4.33; high-resolution MS (EI, m/ z) 555.3165, calcd
for C35H45NO3 555.3165.
was then neutralized with a saturated NaHCO3 solution, and
the product was extracted with diethyl ether. The ethereal
extracts were washed with saturated solutions of NaHCO3 and
NaCl, dried over MgSO4, and concentrated. Column chroma-
tography of the crude residue gave the ketone 18b (70.6 mg,
82%): 1H NMR (CDCl3, 500 MHz) δ 7.29 (2H, d, J ) 8.6 Hz),
6.86 (2H, d, J ) 8.7 Hz), 4.00 (1H, m), 3.99 (1H, d, J ) 13.3
Hz), 3.98 (1H, d, J ) 13.5 Hz), 3.80 (3H, s), 3.21 (1H, d, J )
7.5 Hz), 2.82 (1H, dd, J ) 18.2, 8.0 Hz), 2.73 (1H, ddd, J )
7.5, 6.5, 1.5 Hz), 2.03 (1H, m), 1.94 (1H, bd, J ) 18.2 Hz), 1.36
(3H, d, J ) 6.2 Hz), 0.96 (3H, d, J ) 7.3 Hz); 13C NMR (CDCl3,
125 MHz) δ 217.97, 158.98, 130.11, 128.94, 113.72, 76.43,
76.05, 61.90, 60.58, 55.22, 44.13, 30.99, 20.13, 20.10; IR (neat)
2961, 2872, 1740, 1613, 1514, 1250, 1034; high-resolution MS
(EI, m/z) 275.1520, calcd for C16H21NO3 275.1521.
(3r,3a â,5,6r,6a â)-H exa h yd r o-3,6-d im et h yl-1-(p h en yl-
m eth yl)-4H-cyclop en t[c]isoxa zol-4-on e (18a ). The ketal
14a (190 mg, 0.6565 mmol) was dissolved in 5 mL of methanol,
and 2 mL of 50% sulfuric acid was added. The solution was
heated at reflux for 4 h and then neutralized with dilute
sodium hydroxide. The product was extracted with diethyl
ether, washed with saturated solutions of NaHCO3 and NaCl,
and dried over anhydrous MgSO4. The solvents were then
removed in vacuo. Flash column chromatography (15%
EtOAC-hexane) of the residue gave the ketone 18a (116.8 mg,
72%): 1H NMR (CDCl3, 500 MHz) δ 7.39 (5H, m), 4.07 (3H,
m), 3.27 (1H, d, J ) 7.4 Hz), 2.89 (1H, dd, J ) 18.2, 8.0 Hz),
2.79 (1H, bdd, J ) 7.4, 5.8 Hz), 2.11 (1H, m), 1.98 (1H, d, J )
18.2 Hz), 1.41 (3H, d, J ) 6.13 Hz), 1.02 (3H, d, J ) 7.3 Hz);
13C NMR (CDCl3, 125 MHz) δ 217.81, 136.90, 128.71, 128.24,
127.35, 76.49, 76.05, 61.79, 60.95, 44.06, 30.86, 20.03 (2 C’s);
IR (neat) 2973, 2930, 2872, 1740, 1456, 1380, 1103; high-
resolution MS (EI, m/ z) 245.1408, calcd for C15H19NO2 245.1416.
(3r,3a â,5,6r,6a â)-Hexa h yd r o-3,6-d im eth yl-1-[(4-m eth -
oxyp h en yl)m eth yl]-4H-cyclop en t[c]isoxa zol-4-on e (18b).
To a solution of 14b (100 mg, 0.313 mmol) in 4 mL of MeOH
were added water (1 mL) and several drops of concentrated
H2SO4. The reaction mixture was heated at reflux for 5 h. It
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM-31349) and the Agricultural Re-
search Division of American Cyanamid Co. for financial
support. We also thank Professor Kang for providing
us with a sample and the spectroscopic data of 18b.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra (42 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 O952254M