Asymmetric Total Synthesis of an Important 3-(Hydroxymethyl)carbacephalosporin

Article abstract of DOI:10.1021/jo971772p

Carbacephalosporins have gained much attention as important antibacterial agents. Recently, 3-(hydroxymethyl)carbacephalosporins have been linked to quinolones for the production of multifunctional antibiotics. A short, practical asymmetric total synthesis of carbacephalosporin 3, suitable for conjugating to other chemical moieties, is reported. The synthesis was achieved by Mitsunobu cyclization of dipeptide 12, prepared from L-erythro-anti-β-hydroxy-α-amino acid 11, and subsequent Horner-Wadsworth-Emmons cyclization of ketone 16.

Full text of DOI:10.1021/jo971772p

J . Org. Chem. 1998, 63, 1221-1225
1221
Asym m etr ic Tota l Syn th esis of a n Im p or ta n t
3-(Hyd r oxym eth yl)ca r ba cep h a losp or in
Mark G. Stocksdale, Savithri Ramurthy, and Marvin J . Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556
Received September 23, 1997
Carbacephalosporins have gained much attention as important antibacterial agents. Recently,
3-(hydroxymethyl)carbacephalosporins have been linked to quinolones for the production of
multifunctional antibiotics. A short, practical asymmetric total synthesis of carbacephalosporin
3, suitable for conjugating to other chemical moieties, is reported. The synthesis was achieved
by Mitsunobu cyclization of dipeptide 12, prepared from L-erythro-anti-â-hydroxy-R-amino acid 11,
and subsequent Horner-Wadsworth-Emmons cyclization of ketone 16.
In tr od u ction
The development of resistance to current antibacterial
therapy continues to drive the search for more effective
agents. Several groups have been approaching this
problem through the synthesis of dual-action antibiotics
that incorporate a â-lactam antibiotic covalently linked
to a quinolone antibiotic. Dual-action drugs in which
penems, carbapenems, and cephalosporins are linked to
quinolones through carbamate, ester, or quaternary
ammonium moieties have been reported.1-6 Most re-
cently, the Proctor and Gamble group has described the
synthesis of highly active carbacephalosporin quinolonyl
conjugate 1.7-9 We also have reported on the synthetic
progress toward novel carbacephalosporin-quinolone
dual-action antibiotic 2.10
These recent reports demonstrate the continued inter-
est in carbacephalosporin antibiotics. Although our
group11 and others12-17 have reported racemic syntheses
of carbacephalosporins, there have been few asymmetric
routes.12,18-24 We now report a short, practical asym-
metric total synthesis of carbacephalosporin 3 that could
be elaborated to a variety of dual-drug and siderophore-
drug25-36 conjugates of interest. Although we have
* To whome correspondence should be addressed. Tel.: (219) 631-
7571. Fax: (219) 631-6652. E-mail: Marvin.J .Miller.2@nd.edu.
(1) Keith, D. D.; Albrecht, H. A.; Beskid, G.; Chan, K. K.; Christen-
son, J . G.; Cleeland, R.; Deitcher, K.; Delaney, M.; Georgopapadakou,
N. H.; Konzelmann, F.; Okabe, M.; Pruess, D.; Rossman, P.; Specian,
A.; Then, R.; Wei, C.-C.; Weigele, M. In Recent Advances in the
Chemistry of Anti-Infective Agents; Bentley, P. M., Ponsford, R., Eds.;
Royal Society of Chemistry: Cambridge, 1993; pp 79-92.
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R.; Unowsky, J .; Wei, C. J . Med. Chem. 1992, 35, 1828-1839.
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Fallat, V.; Georgopapadakou, N. H.; Keith, D. D.; Konzelmann, F. M.;
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Yang, R. J . Med. Chem. 1991, 34, 669-675.
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M.; Paule, S. M.; Twinem, T. L.; DeVries, C. A.; Zoutendem, P. H.;
Imbus, R.; Kraft, W. G.; Leunk, R. D.; Demuth, T. P. 214th National
Meeting of the American Chemical Society, Las Vegas, NV, 1997;
ORGN 048.
(8) Randall, J . L.; Godlewski, J . E. Patent 1996, WO 9604286A1.
(9) Randall, J . L.; Godlewski, J . E. Patent 1996, WO 9604247A1.
(10) Stocksdale, M. G.; Ramurthy, S.; Miller, M. J . 35th National
Organic Symposium, San Antonio, TX, 1997; T216.
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Lett. 1993, 34, 3051-3054.
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Hegedus, L. S. J . Org. Chem. 1992, 57, 5453-5462.
(21) Bodurow, C. C.; Boyer, B. D.; J ., B.; Bunnell, C. A.; Burks, J .
E.; Carr, M. A.; Doecke, C. W.; Eckrich, T. M.; Fisher, J . W.; Gardner,
J . P.; Graves, B. J .; P., H.; Hoying, R. C.; J ackson, B. G.; Kinnick, M.
D.; Kochert, C. D.; Lewis, J . S.; Luke, W. D.; Moore, L. L.; Morin, J .
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Pharm. Bull. 1989, 37, 315-321.
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(11) Lotz, B. T.; Miller, M. J . J . Org. Chem. 1993, 58, 618-625.
(12) Cooper, R. D. G. In The Chemistry of â-Lactams; Page, M. I.,
Ed.; Chapman & Hall: London, 1992; pp 272-305.
(25) Ghosh, A.; Ghosh, M.; Niu, C.; Malouin, F.; Moellmann, U.;
Miller, M. J . Chem. Biol. 1996, 3, 1011-1019.
(26) Miller, M. J .; Malouin, F. Acc. Chem. Res. 1993, 26, 241-249.
S0022-3263(97)01772-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

1222 J . Org. Chem., Vol. 63, No. 4, 1998
Stocksdale et al.
Sch em e 1
Sch em e 2a
a
Reaction conditions: (a) NaOH, dioxane, Ph2P(O)Cl; -8 °C, 5
min, 66%; (b) CH2(P(O)(OEt)2)(CO2-tert-butyl), NaH, THF, 0 °C;
9, THF, -78 °C, 2 h, rt, 16 h, 50%.
Sch em e 3
chosen to incorporate the D-phenylglycine side chain
found in the commercial carbacephalosporin, Lorabid, the
design of our synthetic route will accommodate numerous
substitutions and elaborations of the amino side chain
in either the final compound or in precursor 20. The
3-(hydroxymethyl) chemical handle allows for convenient
incorporation into valuable multifunctional compounds
such as 1 and 2.
Resu lts a n d Discu ssion
Retrosynthetic analysis of 3 revealed that this impor-
tant carbacephalosporin could be constructed from â-lac-
tam 4, which is directly obtainable from dipeptide 5
(Scheme 1). The synthesis of 5 required an appropriately
substituted L-erythro-anti-â-hydroxy-R-amino acid, which
is the only requirement for the preparation of carba-
cephalosporin 3 in optically active form if the â-lactam
is prepared by N-C4 bond closure.37 In previous studies,
our laboratory has shown that an enzymatic approach
could be used to synthesize these amino acids.38 The
stereochemistry of the carbacephalosporin is determined
by choosing the appropriate â-hydroxy-R-amino acid (i.e.
6).
noacetate 10 was the only remaining starting material
needed for preparation of the key dipeptide. O-(Diphe-
nylphosphinyl)hydroxylamine (9) was prepared in 66%
yield from hydroxylamine hydrochloride and diphe-
nylphosphinic chloride according to the method of Colvin.40
Treatment of tert-butyl diethylphosphonoacetate with
sodium hydride followed by 9 afforded racemic amino-
phosponoacetate 10 in 50% yield (Scheme 2). Although
the use of racemic 10 immediately introduced a diaster-
eomeric mixture when coupled to 11, it should be noted
that the introduction of diastereomers was not a serious
problem since those centers were later destroyed.
Next, with both starting materials in hand, the syn-
thesis of the carbacephalosporin framework was ef-
ficiently carried out (Scheme 3). Dipeptide 12 was
obtained in 83% yield by coupling â-hydroxy-R-amino acid
11 to 10 with 1-[3-(dimethylamino)propyl]-3-ethylcarbo-
diimide hydrochloride (EDC) and 1-hydroxybenzotriazole
(HOBT). Cyclization of 12 using Mitsunobu condi-
tions,37,41 di-tert-butyl azadicarboxylate (DBAD) and tri-
phenylphosphine, afforded â-lactam 13 in 91% yield.
The expected cis stereochemistry was confirmed by
proton NMR with J ) 5.7 Hz for the C3-C4 protons.
â-Lactam 13 was then dihydroxylated by treatment of
OsO4 and N-methylmorpholine N-oxide in a mixture of
aqueous tetrahydrofuran and acetone42 to provide a
mixture of diastereomeric diols 14 in 85% crude yield.
With â-hydroxy-R-amino acid 11 made available through
methodology developed by our group,39 aminophospho-
(27) Miller, M. J .; Malouin, F.; Dolence, E. K.; Gasparski, C. M.;
Ghosh, M.; Guzzo, P. R.; Lotz, B. T.; McKee, J . A.; Minnick, A. A.; Teng,
M. In Recent Advances in the Chemistry of Anti-Infective Agents;
Bentley, P. H., Ponsford, R., Eds.; Royal Society of Chemistry:
Cambridge, 1993; Special Publication No. 119, pp 135-159.
(28) Miller, M. J . Chem. Rev. (Washington, D.C.) 1989, 89, 1563-
1579.
(29) Ghosh, A.; Miller, M. J . J . Org. Chem. 1993, 58, 7652-7659.
(30) Ghosh, M.; Miller, M. J . J . Org. Chem. 1994, 59, 1020-1026.
(31) Ghosh, M.; Miller, M. J . Bioorg. Med. Chem. 1995, 3, 1519-
1525.
(32) McKee, J . A.; Sharma, S. K.; Miller, M. J . Bioconjugate Chem.
1991, 2, 281-291.
(33) Minnick, A. A.; McKee, J . A.; Dolence, E. K.; Miller, M. J .
Antimicrob. Agents Chemother. 1992, 36, 840-850.
(34) Miller, M. J .; McKee, J . A.; Minnick, A. A.; Dolence, E. K. Biol.
Metals 1991, 4, 62-69.
(35) Dolence, E. K.; Minnick, A. A.; Lin, C.-E.; Miller, M. J . J . Med.
Chem. 1991, 34, 968-978.
(36) Stocksdale, M. G.; Miller, M. J . 30th Meeting of the American
Chemical Society Great Lakes Region, Chicago, IL, 1997; ORGN 124.
(37) Miller, M. J . Acc. Chem. Res 1986, 19, 49-56.
(38) Lotz, B. T.; Gasparski, C. M.; Peterson, K. A.; Miller, M. J . J .
Chem. Soc., Chem. Commun. 1990, 1107-1109.
(39) â-Hydroxy-R-amino acid 11 was a generous gift of Eli Lilly and
Co. It was prepared at Lilly by large-scale serinehydroxymethyltrans-
ferase (SHMT)-mediated condensation of glycine and pentenal with
subsequent protection of the R-amino group as a phthalimido group.
J ackson, W. C. et. al., Chiral, Reston, VA, May 5-6, 1994.
(40) Colvin, E. W.; Kirby, G. W.; Wilson, A. C. Tetrahedron Lett.
1982, 23, 3835-3836.
(41) Mitsunobu, O. Synthesis 1981, 1-28.

Synthesis of a 3-(Hydroxymethyl)carbacephalosporin
J . Org. Chem., Vol. 63, No. 4, 1998 1223
Sch em e 4
Using tert-butyldimethylsilyl chloride and a catalytic
amount of (dimethylamino)pyridine,43 this crude mixture
of diastereomers was selectively silylated to give an 83%
yield (based on recovered starting material) of 15. Treat-
ment of 15 with PDC and 4 Å molecular sieves afforded
ketone 16 in 80% yield. Horner-Wadsworth-Emmons
cyclization of the sodium salt of ketone 16 provided
carbacephalosporin 17 as a single diastereomer in 85%
yield.
Next, the removal of the phthalimido protecting group
of 17 followed by elaboration of the carbacephalosporin
side chain was necessary. The usual method of phthal-
imido deprotection involving treatment with hydrazine
or methylhydrazine has not typically worked for these
bicyclic â-lactams since the azetidinone carbonyl function
is more reactive toward the hydrazine than the phthal-
imido carbonyl. In fact, all of our attempts to deprotect
phthalimido carbacephalosporin 17 with methylhydra-
zine have resulted in opening of the â-lactam ring.
Therefore, the three-step deprotection methodology of
Kukolja et al. was utilized.44 In this method, to enhance
the activity of the phthalimido function relative to the
â-lactam, the imido functionality was first converted to
the corresponding isoimide.
Treatment of phthalimido protected 17 with sodium
sulfide in THF and water provided phthalamic acid
derivative 18 in quantitative yield. Compound 18 was
then treated with N,N-dicyclohexylcarbodiimide (DCC)
in dichloromethane to give phthalisoimide 19, which was
taken on directly to the next step without further
purification. Treatment of 19 with methylhydrazine in
dry THF afforded deprotected carbacephalosporin 20,
which was also used directly without further purification.
Coupling of 20 to N-(tert-butyloxycarbonyl)-D-phenylgly-
cine (21)35 using EDC and HOBT in dichloromethane
gave Boc-D-phenylglycylamino carbacephalosporin 22 in
79% overall yield for the four steps beginning with 17.
Finally, compound 22 was treated with tetrabutyl-
ammonium fluoride (TBAF) and acetic acid in THF to
give molecule 3 as a single diastereomer in 87% yield
(Scheme 4).
3 × 75 mL). The aqueous extracts were made basic (pH ) 8)
by treatment with solid potassium biphosphate. This solution
was then extracted with dichloromethane (3 × 75 mL), dried
(MgSO4), filtered, and evaporated to afford 2.62 g (50%) of
10 as a yellow oil. No further purification was necessary.
Spectroscopic data were equivalent to the known com-
pound:46,47 1H NMR (300 MHz, CDCl3) δ 4.21 (q, 2H, J ) 7.2
Hz), 4.18 (q, 2H, J ) 7.2 Hz), 3.86 (d, 1H, J ) 19.8 Hz), 2.16
(br s, 2H), 1.50 (s, 9H), 1.36 (t, 3H, J ) 7.2 Hz), 1.34 (t, 3H, J
) 7.2 Hz); 13C NMR (75.4 MHz, CDCl3) δ 168.24, 82.59, 63.06,
63.04, 62.97, 62.95, 55.08, 53.23, 27.87, 16.44, 16.36; IR (TF)
3433, 2982, 1736, 1642 cm-1; HRMS calcd for C10H23NO5
268.1314, found 268.1295.
er yth r o-N-[ter t-Bu tyl-2-(d ieth ylp h osp h on o)-2-a cetyl]-
2-p h th a lim id o-3-h yd r oxy-7-h ep ten oa m id e (12). To a so-
lution of â-hydroxy amino acid 1139 (1.95 g, 6.74 mmol) in
dichloromethane (20 mL) was added a solution of 10 (1.80 g,
6.74 mmol) in dichloromethane (30 mL) followed by HOBT
(1.14 g, 80%, 6.74 mmol). The reaction mixture was cooled to
0 °C, and EDC (1.94 g, 10.1 mmol) was added. After being
warmed to rt and stirred for 18 h, the reaction mixture was
diluted with dichloromethane (50 mL), washed with 1 M citric
acid (2 × 50 mL), aqueous saturated sodium bicarbonate (2 ×
50 mL), and brine (50 mL), dried (MgSO4), filtered, and
evaporated. Flash chromatography (silica gel; eluted with 50-
75% ethyl acetate/hexanes gradient) afforded 3.02 g (83%) of
12 as a white amorphous solid: 1H NMR (300 MHz, CDCl3) δ
7.92 (dd, 1H, J ) 49, 9.5 Hz), 7.89-7.73 (m, 4H), 5.84-5.70
(m, 1H), 5.13-4.93 (m, 3H), 4.76-4.73 (m, 1H), 4.25-4.10 (m,
5H), 2.34-2.12 (m, 2H), 1.58-1.54 (m, 2H), 1.51 and 1.48 (s,
9H, due to diastereomers), 1.39-1.30 (m, 6H); 13C NMR (75.4
MHz, CDCl3) δ 167.91, 167.84, 167.82, 167.78, 167.71, 165.11,
164.94, 137.80, 134.23, 134.19, 131.73, 131.68, 123.60, 123.57,
115.10, 83.64, 83.56, 68.71, 68.54, 64.02, 63.93, 63.80, 63.71,
63.66, 63.62, 63.57, 63.54, 57.53, 57.19, 52.70, 52.61, 50.77,
50.68, 33.31, 33.25, 28.88, 28.78, 27.77, 16.37, 16.29, 16.25,
We have described the efficient asymmetric total
synthesis of an important carbacephalosporin and its
precursors. These compounds are ideal for evaluation
as antibiotics as well as for construction of multifunc-
tional conjugates and prodrugs.
Exp er im en ta l Section
Gen er a l Meth od s. Instruments and general methods used
have been described previously.45
ter t-Bu tyl r-Am in o(dieth ylph osph on o)acetate (10). So-
dium hydride (0.87 g, 60% dispersion in mineral oil, 22 mmol)
was suspended in anhydrous THF (100 mL) and cooled to
0 °C. tert-Butyl diethylphosphonoacetate (5.0 g, 20 mmol) was
added, and stirring was continued for 0.5 h at 0 °C. The
resulting solution was transferred via cannula to a stirred
suspension of 940 (4.6 g, 20 mmol) in anhydrous THF (100 mL)
at -78 °C. The reaction mixture was stirred for 2 h at -78
°C and then allowed to warm to rt and stir for 16 h. Excess
THF was removed, and the residue was taken up in dichlo-
romethane (150 mL) and extracted with aqueous p-TsOH (5%,
16.16; IR (TF) 3300, 3070, 2980, 1720, 1690, 1520, 1380 cm-1
HRMS calcd for C25H36N2O9P 539.2158, found 539.2139.
;
(42) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973-1976.
(45) Teng, M.; Miller, M. J . J . Am. Chem. Soc. 1993, 115, 548-554.
(46) Shiraki, C.; Saito, H.; Takahashi, K.; Urakawa, C.; Hirata, T.
Synthesis 1988, 399-401.
(47) Hakimelah, G. H.; J ust, G. Synth. Commun. 1980, 10, 429-
435.
(43) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 99-
102.
(44) Kukolja, S.; Lammert, S. R. J . Am. Chem. Soc. 1975, 97, 5582-
5583.

1224 J . Org. Chem., Vol. 63, No. 4, 1998
Stocksdale et al.
N-[ter t-Bu tyl-2-a m in o-2-(d ieth ylp h osp h on o)a cetyl]-3-
p h th a lim id o-4-[4-(1-bu ten yl)]a zetid in -2-on e (13). Dipep-
tide 12 (3.97 g, 7.38 mmol) was dissolved in anhydrous THF
(30 mL) and cooled to -8 °C. To this stirred solution was
added triphenylphosphine (3.88 g, 14.8 mmol) in anhydrous
THF (20 mL) followed by DBAD (3.40 g, 14.8 mmol) in
anhydrous THF (20 mL). After the solution was warmed to
rt and stirred for 16 h, the THF was removed and the resulting
oil was triturated with ether and seeded with a crystal of
triphenylphosphine oxide. The crystallized triphenylphos-
phine oxide byproduct was filtered, and the filtrate was
concentrated. Two separations via flash chromatography
(silica gel; eluted with 5-20% THF/dichloromethane gradient)
afforded 3.50 g (91%) of 13 as a light yellow oil: 1H NMR (300
MHz, CDCl3) δ 7.91-7.75 (m, 4H), 5.71-5.56 (m, 1H), 5.46
and 5.45 (dd, 1H, J ) 18 Hz, J ) 5.7 Hz due to both dia-
stereomers), 5.07 and 5.07 (d, 1H, J ) 24.6 Hz, due to both
diastereomers), 4.91-4.81 (m, 2H), 4.55-4.49 (m, 1H), 4.35-
4.20 (m, 4H), 2.42-1.80 (m, 4H), 1.55 and 1.54 (s, 9H, due to
both diastereomers), 1.45-1.35 (m, 6H); 13C NMR (75.4 MHz,
CDCl3) δ 167.22, 167.20, 165.27, 165.18, 164.66, 164.58, 163.96,
163.91, 163.84, 163.78, 136.89, 136.85, 134.44, 131.52, 123.74,
123.71, 115.34, 115.30, 84.20, 83.78, 63.64, 63.62, 63.56, 63.53,
63.44, 63.36, 63.27, 60.52, 60.48, 60.06, 57.00, 56.94, 54.61,
53.77, 52.66, 51.74, 30.00, 29.72, 28.20, 27.97, 27.87, 27.38,
16.43, 16.35, 16.23; IR (TF) 2980, 1770, 1720, 1380, 1260, 1150
cm-1; HRMS calcd for C25H33N2O8P 521.2053, found 521.2081.
N-[ter t-Bu tyl-2-a m in o-2-(d ieth ylp h osp h on o)a cetyl]-3-
p h t h a lim id o-4-[4-[1-[(ter t-b u t yld im et h ylsilyl)oxy]-2-h y-
d r oxybu tyl]]a zetid in -2-on e (15). To a stirred solution of
13 (1.57 g, 3.02 mmol) in THF (10 mL), water (10 mL), and
acetone (1 mL) was added NMO-monohydrate (0.600 g, 4.44
mmol) followed by OsO4 (0.010 g). After being stirred at rt
for 2 h, the reaction was quenched with sodium metabisulfite
(1.5 g) and stirred for 30 min. The mixture was extracted with
ethyl acetate (3 × 30 mL). The combined organic extracts were
washed with water (30 mL) and brine (30 mL), dried (MgSO4),
filtered, and evaporated to give 1.431 g (85%) of N-[tert-butyl-
2-amino-2-(diethylphosphono)acetyl]-3-phthalimido-4-[4-(1,2-
dihydroxy butyl)]azetidin-2-one (14) as a crude tan oil. The
diastereomeric mixture of compounds was taken on to the next
step with no further purification: 1H NMR (300 MHz, CDCl3)
δ 7.89-7.75 (m, 4H), 5.49-5.40 (m, 1H), 5.15-5.01 (m, 1H),
4.57-4.48 (m, 1H), 4.38-4.15 (m, 4H), 3.58-3.20 (m, 3H),
2.30-2.12 (m, 2H), 1.78-1.60 (m, 2H), 1.54-1.53 (m, 9H),
1.48-1.35 (m, 6H); 13C NMR (75.4 MHz, CDCl3) δ 167.23,
167.15, 165.46, 165.37, 165.23, 165.15, 164.60, 164.56, 164.52,
164.48, 163.95, 163.90, 163.57, 163.51, 163.49, 163.42, 134.40,
131.51, 123.67, 84.49, 84.08, 84.03, 71.63, 71.49, 70.85, 70.72,
66.51, 66.35, 66.19, 65.62, 64.20, 64.15, 64.10, 63.98, 63.89,
63.85, 63.75, 63.37, 63.32, 63.28, 63.22, 61.00, 60.78, 60.39,
60.21, 57.04, 56.91, 54.59, 54.50, 53.66, 53.60, 52.62, 52.52,
51.62, 51.54, 29.43, 29.35, 28.99, 27.93, 27.82, 25.00, 24.72,
24.58, 24.00, 16.38, 16.31, 16.24, 16.20; IR (TF) 3450, 2950,
1770, 1720, 1390, 1250, 1150 cm-1; HRMS calcd for C25H35N2-
165.38, 165.29, 165.21, 164.73, 164.65, 164.58, 164.00, 163.94,
163.87, 163.82, 163.74, 163.69, 134.36, 134.27, 134.22, 131.67,
131.58, 123.66, 123.63, 123.55, 84.24, 84.21, 83.84, 71.11,
70.99, 70.76, 67.13, 67.10, 66.88, 63.78, 63.69, 63.62, 63.60,
63.53, 63.36, 63.28, 57.09, 57.00, 54.62, 54.58, 53.76, 53.71,
52.66, 52.62, 51.72, 51.68, 29.21, 28.96, 28.93, 28.71, 27.97,
27.86, 27.65, 25.77, 25.18, 24.92, 24.38, 24.17, 18.14, 16.44,
16.37, 16.28, -5.52; IR (TF) 3500, 1780, 1730, 1390, 1310,
1250, 1160 cm-1; HRMS calcd for C31H49N2O10PSi 669.2972,
found 669.2957.
N-[ter t-Bu tyl-2-a m in o-2-(d ieth ylp h osp h on o)a cetyl]-3-
p h th a lim id o-4-[4-[1-[(ter t-bu tyld im eth ylsilyl)oxy]-2-ox-
obu tyl]]a zetid in -2-on e (16). To a stirred solution of 15 (1.68
g, 2.52 mmol) in dry dichloromethane (30 mL) was added
pyridinium dichromate (1.89 g, 5.03 mmol) and powdered 4 Å
molecular sieves (8 g). After being stirred at rt for 2 h, the
reaction mixture was diluted with ether (100 mL) and filtered
through a pad of Celite and silica gel. Radial chromatography
of the crude reddish-brown oil using a Chromatotron (4 mm
silica plate; eluted with 8% THF/dichloromethane) gave 1.35
g (80%) of 16 as a tan gum: 1H NMR (300 MHz, CDCl3) δ
7.88-7.73 (m, 4H), 5.43 and 5.43 (dd, 1H, J ) 5.4, 16.8, 5.4,
18 Hz due to both diastereomers), 5.08 and 5.07 (d, 1H, J )
22.8, 24.3 Hz due to both diastereomers), 4.55-4.47 (m, 1H),
4.31-4.18 (m, 4H), 4.04-4.02 (m, 2H), 2.60-2.25 (m, 2H),
1.93-1.77 (m, 2H), 1.54 and 1.53 (s, 9H, due to both diaster-
eomers), 1.44-1.34 (m, 6H), 0.84 (s, 9H), -0.01 and -0.02 (s,
6H); 13C NMR (75.4 MHz, CDCl3) δ 209.02, 208.93, 167.16,
165.07, 164.63, 164.56, 164.04, 134.46, 131.52, 123.80, 123.75,
84.27, 83.98, 69.06, 63.72, 63.64, 63.39, 63.29, 60.58, 60.22,
57.03, 34.35, 34.25, 27.98, 27.88, 25.69, 22.47, 21.70, 18.19,
16.37, -5.65; IR (TF) 2990, 2850, 1770, 1720, 1470, 1390, 1250,
1150 cm-1; HRMS calcd for C31H47N2O10PSi 667.2816, found
667.2818.
ter t-Bu tyl (7S,6R)-7-p h th a lim id o-3-[[(ter t-bu tyld im eth -
ylsilyl)oxy]m eth yl]-1-ca r ba -1-d eth ia -3-cep h em -4-ca r box-
yla te (17). To a suspension of sodium hydride (0.036 g, 60%
dispersion in mineral oil, 0.91 mmol) in anhydrous THF (3 mL)
cooled to 0 °C was added compound 16 (0.603 g, 0.904 mmol)
in anhydrous THF (3 mL). After being stirred for 30 min the
reaction mixture was allowed to warm to rt and stir an
additional 1.5 h. The reaction mixture was then diluted with
ether (15 mL) and treated with brine (5 mL). The resulting
two-phase mixture was separated, and the aqueous layer was
further extracted with ether (3 × 15 mL). The combined
organic extracts were washed with water (10 mL) and brine
(10 mL), dried (MgSO4), filtered, and evaporated to give a
white solid. Recrystallization from ether and hexanes yielded
0.329 g (71%) of 17 as white crystals. Radial chromatography
using a Chromatotron (1 mm silica plate; eluted with 2:1
hexanes:ethyl acetate) of the mother liquor afforded an ad-
ditional 0.064 g of 17 as a white solid. Total yield for the
1
reaction was 85%: [R]26 -9.3° (c 1.0, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.88-7.74 (m, 4H), 5.58 (d, 1H, J ) 5.1 Hz),
4.80 (d, 1H, J ) 14.2 Hz), 4.38 (d, 1H, J ) 14.2 Hz), 3.90 (ddd,
1H, J ) 5.0, 5.0 Hz, J ) 10.6 Hz), 2.55-2.30 (m, 2H), 2.00-
1.85 (m, 2H), 1.55 (s, 9H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s,
3H); 13C NMR (75.4 MHz, CDCl3) δ 167.47, 160.98, 160.81,
135.33, 134.50, 131.54, 123.73, 123.10, 82.54, 62.06, 56.93,
53.25, 27.95, 25.86, 24.11, 20.38, 18.26, -5.37, -5.41; IR (TF)
2955, 2860, 1775, 1725, 1470, 1385, 1160 cm-1; HRMS calcd
for C27H36N2O6Si 512.2343, found 512.2325; mp 147-150 °C.
Anal. Calcd for C27H36N2O6Si: C, 63.26; H, 7.08; N, 5.46.
Found: C, 63.37; H, 7.01; N, 5.22.
O
10P 555.2108, found 555.2108.
To a stirred solution of 14 (0.735 g, 1.33 mmol) in dry
dichloromethane (15 mL) was added triethylamine (0.19 mL,
1.4 mmol), N,N-(dimethylamino)pyridine (0.007 g, 0.05 mmol),
and tert-butyldimethylsilyl chloride (0.200 g, 1.33 mmol). After
being stirred at rt for 20 h, the reaction mixture was quenched
with saturated aqueous ammonium chloride (10 mL). The
organic layer was separated, washed with water (10 mL) and
brine (10 mL), dried (MgSO4), filtered, and evaporated. Radial
chromatography using a Chromatotron (4 mm silica plate;
eluted with 10-15% THF/dichloromethane gradient and then
10% MeOH/dichloromethane) afforded 0.534 g (83% based on
recovered starting material) of a diastereomeric mixture of 15
as a light yellow gum and 0.199 g of recovered starting
material: 1H NMR (300 MHz, CDCl3) δ 7.89-7.72 (m, 4H),
5.50-5.41 (m, 1H), 5.12-5.02 (m, 1H), 4.58-4.46 (m, 1H),
4.34-4.18 (m, 4H), 3.50-3.37 (m, 2H), 3.26-3.15 (m, 1H),
2.40-2.10 (m, 2H), 1.88-1.80 (m, 2H), 1.54-1.53 (m, 9H),
1.46-1.34 (m, 6H), 0.81-0.80 (m, 9H), -0.04--0.06 (m, 6H);
13C NMR (75.4 MHz, CDCl3) δ 167.37, 167.31, 167.21, 165.48,
ter t-Bu tyl (7S,6R)-7-[[N-(ter t-Bu tyloxyca r bon yl)-D-p h e-
n ylglycylam in o]am in o]-3-[[(ter t-bu tyldim eth ylsilyl)oxy]m -
eth yl]-1-ca r ba -1-d eth ia -3-cep h em -4-ca r boxyla te (22). Ph-
thalimido-protected carbacephalosporin 17 (0.513 g, 1.00
mmol) was dissolved in a 1:1 mixture of THF/H2O (20 mL)
and cooled to 0 °C. To this stirred solution was added
Na2S‚9H2O (0.240 g, 1.00 mmol). After 15 min, the reaction
was treated with 0.5 M citric acid until pH ) 3.5. The
resulting mixture was extracted with ethyl acetate (3 × 25
mL), and the combined organic extracts were washed with
brine (40 mL), dried (Na2SO4), filtered, and evaporated to give

Synthesis of a 3-(Hydroxymethyl)carbacephalosporin
J . Org. Chem., Vol. 63, No. 4, 1998 1225
0.530 g (100%) of tert-butyl (7S,6R)-7-N-phthalamic acid-3-
[[(tert-butyldimethylsilyl)oxy]methyl]-1-carba-1-dethia-3-cephem-
4-carboxylate (18) as a white gum. No further purification was
necessary: 1H NMR (300 MHz, CDCl3) δ 7.92-7.47 (m, 5H),
5.48 (dd, 1H, J ) 6.9, 4.8 Hz), 4.76 (d, 1H, J ) 14.1 Hz), 4.20
(d, 1H, J ) 14.1 Hz), 3.80 (ddd, 1H, J ) 11.6, 4.8, 4.8 Hz),
2.43-2.36 (m, 2H), 2.02-1.93 (m, 2H), 1.21 (s, 9H), 0.87 (s,
9H), 0.037 and 0.019 (2s, 6H); 13C NMR (75.4 MHz, CDCl3) δ
170.96, 170.30, 165.15, 160.70, 138.20, 137.08, 132.52, 130.29,
130.04, 128.96, 128.59, 122.10, 81.99, 61.75, 59.02, 52.79,
27.64, 25.84, 24.14, 21.14, 18.24, -5.37; IR (TF) 3050-3400
(br), 2980, 1750, 1710, 1390, 1365, 835 cm-1; HRMS calcd for
0.88 (s, 9H), 0.050 and 0.038 (2s, 6H); 13C NMR (75.4 MHz,
CDCl3) δ 170.71, 164.84, 160.82, 154.86, 138.11, 136.87, 129.04,
128.47, 127.17, 122.42, 82.33, 80.24, 61.83, 58.95, 58.32, 52.79,
28.29, 27.87, 25.87, 23.83, 20.33, 18.27, -5.38, -5.42; IR (TF)
3310 (br), 2980, 2940, 1750, 1710, 1540, 1490, 1365, 1160, 840
cm-1; HRMS calcd for C32H49N3O7SiNa 638.3237, found
638.3234. Anal. Calcd for C32H49N3O7Si: C, 62.41; H, 8.02;
N, 6.82. Found: C, 62.21; H, 7.87; N, 6.79.
ter t-Bu tyl (7S,6R)-7-[[N-(ter t-Bu tyloxyca r bon yl)-D-p h e-
n ylglycyla m in o]a m in o]-3-(h yd r oxym eth yl)-1-ca r ba -1-d e-
th ia -3-cep h em -4-ca r boxyla te (3). To THF (4 mL) cooled to
0 °C was added TBAF (0.63 mL of 1 M solution in THF, 0.63
mmol) followed by acetic acid (0.036 mL, 0.63 mmol). To this
stirred solution was added compound 22 (0.257 g, 0.417 mmol)
in THF (4 mL). After being stirred for 1 h at 0 °C, the reaction
was warmed to rt and stirred for an additional 16 h. The
reaction was quenched with brine (8 mL) and extracted with
ethyl acetate (3 × 15 mL). The combined organic extracts were
washed with brine (15 mL), dried (Na2SO4), filtered, and
evaporated. Radial chromatography using a Chromatotron (2
mm silica plate; eluted with 1:1 hexanes:ethyl acetate) gave
0.181 g (87%) of 3 as a white foam: [R]26D -26° (c 0.20, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.36-7.30 (m, 5H), 7.16 (br s,
1H), 5.76 (d, 1H, J ) 6.3 Hz), 5.43 (dd, 1H, J ) 8.1 Hz, J )
4.8 Hz), 5.16 (br s, 1H), 4.43 (d, 1H, J ) 12.0 Hz), 3.81-3.70
(m, 2H), 3.15 (br m, 1H), 2.55-2.47 (m, 1H), 2.18-2.06 (m,
1H), 1.62-1.55 (m, 1H), 1.50 (s, 9H), 1.42 (s, 9H); 13C NMR
(75.4 MHz, CDCl3) δ 170.77, 165.36, 161.66, 154.84, 138.12,
135.40, 129.02, 128.50, 127.15, 125.16, 83.44, 80.26, 61.57,
58.91, 58.50, 52.87, 28.29, 27.78, 25.68, 20.44; IR (TF) 3420,
3300, 2980, 1760, 1750, 1710, 1370, 1160 cm-1; HRMS calcd
for C26H35N3O7Na 524.2373, found 524.2386.
C
27H38N2O7SiNa 553.2346, found 553.2316.
To a stirred solution of 18 (0.530 g, 1.00 mmol) in dry CH2-
Cl2 (20 mL) cooled to 0 °C was added DCC (0.217 g, 1.05 mmol).
After 30 min, the reaction was warmed to rt and stirred for
an additional 30 min. The reaction mixture was again cooled
to 0 °C and filtered to remove dicyclohexylurea (DCU) byprod-
uct. The filtrate was evaporated, giving crude tert-butyl
(7S,6R)-7-phthalisoimido-3-[[(tert-butyldimethylsilyl)oxy]methyl]-
1-carba-1-dethia-3-cephem-4-carboxylate (19) as a yellow solid
that was used in the next step without further purification.
1H NMR of the crude product indicated mostly phthalisomide
19 with only slight contamination of DCC and DCU.
To a stirred solution of phthalisoimide 19 (1.00 mmol,
assuming a quantitative yield in the previous step) in dry THF
(20 mL) cooled to -8 °C was added methylhydrazine (0.53 mL
of 1.9 M solution in THF, 1.0 mmol). After 10 min, the THF
was removed, and the residue was taken up in CHCl3. After
the solids were filtered off, the filtrate was concentrated to
give crude tert-butyl (7S, 6R)-7-amino-3-[[(tert-butyldimeth-
ylsilyl)oxy]methyl]-1-carba-1-dethia-3-cephem-4-carboxylate (20)
as a yellow foam that was used in the next step without further
purification.
To a stirred solution of N-(tert-butyloxycarbonyl)-D-phenylg-
lycine35 (0.251 g, 1.00 mmol) in dry CH2Cl2 (20 mL) were added
amino carbacephalosporin 20 (1.00 mmol, assuming a quan-
titative yield in the previous step) and HOBT (0.17 g, 80%,
1.0 mmol). This solution was cooled to 0 °C, and EDC (0.230
g, 1.20 mmol) was added. After being warmed to rt and stirred
for 6 h, the reaction mixture was filtered to remove solids. The
filtrate was diluted with CH2Cl2 (40 mL), washed with 1 M
citric acid (2 × 40 mL) and brine (40 mL), dried (Na2SO4),
filtered, and evaporated. Flash chromatography (silica gel;
eluted with 3:1 hexanes:ethyl acetate) gave 0.488 g (79%
overall yield starting with phthalimido protected carbacepha-
losporin 17) of 22 as a white foam: [R]26D -17° (c 0.15, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 6.93 (br s,
1H), 5.74 (d, 1H, J ) 6.0 Hz), 5.37 (dd, 1H, J ) 7.6 Hz, J )
4.9 Hz), 5.17 (br s, 1H), 4.69 (d, 1H, J ) 14.1 Hz), 4.33 (d, 1H,
J ) 14.1 Hz), 3.72 (ddd, 1H, J ) 11.4, 4.8 Hz, J ) 3.4 Hz),
2.39 2.20 (m, 2H), 1.70-1.56 (m, 2H), 1.48 (s, 9H), 1.41 (s, 9H),
Ack n ow led gm en ts. We gratefully acknowledge sup-
port from the NIH (GM 25845), and we thank Eli Lilly
and Co. for the gift of 11. M.G.S. wishes to acknowledge
financial support from the University of Notre Dame
in the form of Nieuwland and J . Peter Grace Prize
Fellowships. We appreciate the use of the NMR facilities
of the Lizzadro Magnetic Resonance Research Center
at Notre Dame. We also thank Dr. Bill Boggess and
Nonka Sevova of the University of Notre Dame for
conducting our mass spectroscopy experiements.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra (18 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 O971772P