Synthesis of carbacephems from serine

Article abstract of DOI:10.1021/jo980592s

Carbacephems have been synthesized from D-serine by two routes involving construction first of the six-membered ring followed by cyclization to give the bicyclic β-lactam. In one route, alkylation of a lactim ether was accomplished with Ni(Acac)₂ as a catalyst. The desired R stereochemistry at the carbon corresponding to C-6 of the cephem was obtained by stereospecific hydrogenation of a vinylogous carbamate. The second route involved a stereospecific Michael cyclization to give the same C-6 stereochemistry. Closure of a piperidyl β-amino acid intermediate common to both routes was accomplished using a modified Mukaiyama reagent found to be superior in our system to the traditional reagent. The resulting carbacephem core was stereospecifically substituted at C-7 with an ethyl or amino functionality. The ethylated intermediate was transformed into a stable enol triflate useful for the further elaboration of biologically important carbacephems.

Full text of DOI:10.1021/jo980592s

8170
J . Org. Chem. 1998, 63, 8170-8182
Syn th esis of Ca r ba cep h em s fr om Ser in e
J ames J . Folmer, Carles Acero, Dung L. Thai, and Henry Rapoport*
Department of Chemistry, University of California, Berkeley, California 94720
Received March 31, 1998
Carbacephems have been synthesized from D-serine by two routes involving construction first of
the six-membered ring followed by cyclization to give the bicyclic â-lactam. In one route, alkylation
of a lactim ether was accomplished with Ni(Acac)2 as a catalyst. The desired R stereochemistry at
the carbon corresponding to C-6 of the cephem was obtained by stereospecific hydrogenation of a
vinylogous carbamate. The second route involved a stereospecific Michael cyclization to give the
same C-6 stereochemistry. Closure of a piperidyl â-amino acid intermediate common to both routes
was accomplished using a modified Mukaiyama reagent found to be superior in our system to the
traditional reagent. The resulting carbacephem core was stereospecifically substituted at C-7 with
an ethyl or amino functionality. The ethylated intermediate was transformed into a stable enol
triflate useful for the further elaboration of biologically important carbacephems.
In tr od u ction
Our objective was to develop a synthetic route ap-
plicable to the carbacephems that would allow control of
stereochemistry at C-6 of the carbacephem skeleton, an
important chiral center directly related to the biological
activity of the carbacephems. In addition, we sought to
install an initial functionality from which the double bond
and enol ether at C-3 of the carbacephem could be easily
generated, thus facilitating further elaboration on the six-
membered ring.
Beginning from D-serine, two potential pathways were
projected to arrive at the carbacephem skeleton (Figure
1). Both rely on the intermediate A, which in path I
would be used to form a lactam possessing two chiral
centers that would serve as stereochemical directors for
inducing the necessary R stereochemistry at C-6 in the
carbacephem. For example, hydrogenation of compound
C should occur preferentially from the rear of the
molecule, guided by the bulky protecting groups blocking
approach from the front. Conversely, should the opposite
(S) stereochemistry at C-6 be desired, this could be
effected by starting with L-serine. Also, there is the
potential for alkylating compound B, perhaps stereose-
lectively, which would correspond to C-5 of the [4.2.0]
carbacephem skeleton (C-1 in cephalosporin numbering
regimen).
An alternative strategy involves a potentially stereo-
selective Michael cyclization utilizing the same chiral
directors (path II, Figure 1) as in path I. A suitably
protected amine D should add in a Michael sense
stereoselectively to an ene-ester if the other face of the
double bond was sufficiently blocked, thus generating the
needed stereochemistry at C-6 of the carbacephem.
Once the six-member ring intermediate E is in hand,
what remains to complete the carbacephem skeleton is
closure of the fused â-lactam. This late closure has
proven to be inefficient for many syntheses of the
carbacephems using this sequence.5 We have been able
to overcome this hurdle, however, through development
of a new carboxylate activating group, which is related
to the classical Mukaiyama pyridinium iodides.6
Since the discovery of penicillin in 1928, â-lactam
antibiotics have remained a premier class of drugs used
for the treatment of bacterial infections.1 Carbacephems
represent a recently developed class of this â-lactam type
antibiotic closely related to the widely used cephalospor-
ins.2 While both have similar antibacterial profiles, the
carbocyclic 1-carba-1-dethiacephems are chemically more
stable and possess enhanced pharmacokinetic properties
relative to cephalosporins. These advantageous proper-
ties have engendered major interest in carbacephems as
clinically viable drugs.
The vast majority of syntheses of carbacephems begin
with the formation of the azetidinone, followed by closure
of appropriate tethers to form the fused six-membered
ring portion of the molecule.3 A widely used method of
forming the initial â-lactam is still the classical (2 + 2)
addition of a ketene to an imine,4 and an extensive
number of reports have appeared that elegantly utilize
this reaction to enter into the carbacephem framework.1b
There have been only a few examples, however, of
carbacephem syntheses that form the six-membered ring
first, followed by the closure of the â-lactam.5 The
advantage of this latter strategy may be that by closing
the sensitive four-membered ring later in the synthesis,
conditions may be used prior to its closure that otherwise
might be incompatible with the labile azetidinone moiety.
This strategy has seen limited use, due in part to the
perceived difficulty in closing a four-membered ring to
form the bicyclic â-lactam.
(1) Overviews of â-lactam antibiotics are presented in the follow-
ing: (a) The Chemistry of â-Lactams; Page, M. I., Ed.; Blackie Academic
& Professional: New York, 1992. (b) The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH Press: New York, 1993. (c)
Samarendra, C. I.; Maiti, N.; Micetich, R. G.; Daneshtalab, M.;
Atchison, K.; Phillips, O. A.; Kunugita, C. J . Antibiot. 1994, 47, 1030
and references therein.
(2) (a) Hornback, W. J .; Munroe, J . E.; Counter, F. T. J . Antibiot.
1994, 47, 1052. (b) Cooper, R. D. G. Am. J . Med. 1992, 92, 6A-2S.
(3) Ternansky, R. J .; Morin, J . M., J r. Novel Methods for the
Construction of the â-Lactam Ring. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH Press: New York, 1993; p 257.
(4) Staudinger, H.; Klever, H. W.; Kober, P. Liebigs Ann. Chem.
1910, 1, 374.
(5) Benrien, J .-F.; Billion, M.-A.; Husson, H.-P.; Royer, J . J . Org.
Chem. 1995, 60, 2922.
(6) Mukaiyama, T. Angew. Chem., Int. Ed. Eng. 1979, 18, 707 and
references therein.
10.1021/jo980592s CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/16/1998

Synthesis of Carbacephems from Serine
J . Org. Chem., Vol. 63, No. 23, 1998 8171
F igu r e 1. Strategies to the carbacephem core via D-serine.
Sch em e 1. P r ep a r a tion of Am in o Alcoh ol 7 fr om Ser in e
Ta ble 1. Allyla tion of P r otected D-Ser in e (2 f 3) in
Resu lts a n d Discu ssion
THF /Hexa n e
P r epar ation of th e Com m on In ter m ediate (4R,5R)-
5-[(P h en ylsu lfon yl)a m in o]-4-(3-h yd r oxyp r op yl)-2,2-
d im eth yl-1,3-d ioxa n e (7a ). To explore both synthetic
routes depicted in Figure 1, an efficient, high-yielding
procedure to generate the amino alcohol 7a (Scheme 1)
was required. This was accomplished by converting the
carboxyl group of N-protected D-serine 2 to the allyl
ketone 3 under nonracemic conditions, using methodology
that had been developed previously, with some important
modifications (Scheme 1).7 Interestingly, the yield in the
conversion of acid 2 to ketone 3 was found to be directly
related to the proportion of hexane present in the reaction
mixture (Table 1).8 The greater the proportion of hexane
in the mixture, resulting from the molarity in hexane of
the n-BuLi used, the lower the yield of the resultant
ketone 3. For example, using 1.6 M n-BuLi as the base
gave a yield of 62% (entry 2), but by using 10 M n-BuLi
as the base (entry 5), the yield of ketone 3 was increased
to 90-95%. Initially, it was not clear whether this effect
was caused by the presence of hexane in the solvent or
the concentration of the n-BuLi. Experiments (entries
6 and 7) in which the ratio of hexane in the reaction
mixture was kept constant and the concentration of the
entry n-BuLi (M) hexane (mL) % hexane in solvent % yield
1
2
3
4
5
6
7
1
10
6.3
17
46
62
76
80
93
67
71
1.6
2.5
5
10
7.4
1.6
11.2
7.4
3.8
2
2.6
2.4
4.0
2.0
1.0
1.4
1.4
added n-BuLi was varied gave very similar yields, leading
to the conclusion that it is the amount of hexane present
in the reaction mixture not the concentration of the added
n-BuLi that influences the yield. Clearly the polarity of
the solvent has a major role in the reactivity of the
polyanions involved.
The mode of quenching in the transformation of 2 to 3
was also found to be pivotal to the success of the reaction.
If the quench of the reaction mixture was not kept below
0 °C, a small percentage of the recovered product was
the R,â-unsaturated ketone 4. Also, â,γ-unsaturated
ketone 3 slowly isomerizes to conjugated ketone 4 on
storage at room temperature for a few months, causing
some initially low yields in the reduction of the ketone
carbonyl of 3 to form the diols 5a ,b. The ease of
isomerization of ketone 3 to 4 was demonstrated by
treating ketone 3 with 290 mol % of triethylamine in THF
for 19 h at room temperature, resulting in complete
conversion to the R,â-unsaturated ketone 4. Subsequent
(7) (a) Knudsen, C. G.; Rapoport, H. J . Org. Chem. 1983, 48, 2260.
(b) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1989, 54, 1866.
(8) Initial observation of this effect was made by N. Atanes of this
laboratory.

8172 J . Org. Chem., Vol. 63, No. 23, 1998
Sch em e 2. P r ep a r a tion of Ca r ba cep h em Cor e via La ctim Eth er Rou te
Folmer et al.
NMR doping experiments on stored â,γ-unsaturated
ketone 3 revealed that 4-5% of the ketone had undergone
double-bond migration over 4 months of storage at room
temperature. This small amount of ketone 4 impurity
can be diminished by recrystallization from ethyl acetate
to <1.5%. Storage, however, at 0 °C for no longer than
2 weeks before use completely eliminates ketone 4.
Reduction of ketone 3 to the diols 5a ,b was ac-
complished using L-selectride in a modification of the
reported7b procedure, resulting in a 9/1 mixture of dia-
stereomers 5a and 5b in 84% yield. The mixture was
converted into the corresponding isopropylidine ketals,
from which the major diastereomer 6 was easily isolated
by crystallization from ethyl acetate in high overall yield.
Conversion of olefin 6 to the primary alcohol 7a by
hydroboration was investigated to determine conditions
under which minimal secondary alcohol 7b would be
formed. Previous studies7b reported only primary alcohol
7a using borane; however, in our hands, hydroboration
with BH3‚THF at room temperature followed by oxidation
gave a mixture of alcohols 7a and 7b in a ratio of 9.5/1
and an overall yield of 73%. Conducting the hydrobora-
tion at -10 to 0 °C decreased the yield to 53% with a
7a /7b ratio of 4.6/1, while hydroboration at 40 °C resulted
in a 74% overall yield and a 10/1 ratio. Borane therefore
was abandoned, and instead, treatment of 6 with the
more hindered 9-BBN at room temperature followed by
oxidation gave only primary alcohol 7a in 81% yield. With
7a in hand, the two potential routes (I and II, Figure 1)
to carbacephem could be explored.
the potential for incorporation of functionality at C-5 in
the [4.2.0] octane system 18 via substitution at the
R-methylene in lactam 12.
Oxidation of amino alcohol 7a with catalytic ruthenium
trichloride and NaIO4 to amino acid 8 (75% yield) was
followed by closure to lactam 9 using EDC/DMAP in 92%
yield. Removal of the N-benzenesulfonyl group with Na/
naphthalene gave the unprotected lactam 10 in 82%
yield, but attempted conversion of lactam 10 to lactim
ether 11 using methyl triflate failed; only recovered
starting material was obtained. On the assumption that
lactim ether 11 is formed but because of strain is unstable
to the isolation conditions, the isopropylidine ring was
opened and the diol was reprotected as silyl ether.
Reaction of the resulting disilyl ether lactam 12 with
methyl triflate gave the lactim ether 13 in 90% yield.
Conversion of lactim ether 13 to the amino ene-ester
15 was accomplished by first condensing the lactim ether
with Meldrum’s acid in the presence of catalytic Ni(Acac)2
giving the 2,2-dimethyl-4,6-dioxo-1,3-dioxanylidene de-
rivative 14 in 73% yield;9 monodecarboxylation using
NaOEt/ethanol gave the amino ene-ester 15 (79% yield).
Subsequent hydrogenation using Pt as a catalyst gave
only the cis diastereomer, 6R-ethoxycarbonylmethyl-
substituted piperidine 16, in 80% yield. Hydrolysis of
ester 16 with LiOH gave the amino acid 17 in 97% yield.
With the amino acid 17 in hand, the next step was
cyclization of the amino acid to form the bicyclic â-lactam
18. To accomplish this transformation, either the car-
boxyl or the amino group must be activated. Increasing
the nucleophilicity of the nitrogen was explored using
various metallo intermediates. Strategies using orga-
P r ep a r a tion of th e Ca r ba cep h em Cor e by th e
La ctim Eth er Rou te (Sch em e 2). The lactim route to
the carbacephem core relies on the generation of the
lactim ether 13, followed by conversion to the amino ene-
ester 15 and subsequent stereospecific hydrogenation to
the cis ester 16. A perceived advantage of this route is
(9) Other examples of lactim ether condensations using Ni(Acac)2
are presented in the following: Provot, O.; Celerier, J . P.; Petit, H.;
Lhommet, G. Synthesis 1993, 69 and references therein.

Synthesis of Carbacephems from Serine
J . Org. Chem., Vol. 63, No. 23, 1998 8173
Sch em e 3. Mich a el Cycliza tion Rou te to Ca r ba cep h em Cor e
noaluminum reagents to activate amines in the formation
of amides from carboxylic esters have been reported,10
and there are also reports of similar aluminum reagents
being utilized in â-lactam formation.11 Other elements
that have been utilized to activate amines to induce
â-lactam formation include silicon12 and magnesium.13
Of particular interest is the use of mesitylmagnesium
bromide, which is less likely to attack the carbonyl of the
ester moiety.13d,e All attempts at using nitrogen activa-
tion with amino ester 16, however, met with limited
success, giving low yields of 18 with many side products.
Activation of the carboxyl group was next explored
using an activated ester. Both the p-nitrophenyl and
pentafluorophenyl esters were prepared. In the former
case, the amino group was protected as its BOC deriva-
tive and in the latter as its CBZ.14 Subsequent removal
of the protecting groups (BOC by acid followed by
pyridine; CBZ by hydrogenolysis) under appropriate
dilution conditions produced little â-lactam.
A common method for activating carboxylic acids
toward nucleophilic substitution is the use of N-methyl-
2-chloropyridinium iodide (Mukaiyama’s reagent). It has
also been used to generate monocyclic â-lactams15 and
also a bicyclic â-lactam.5 Applying Mukaiyama’s reagent
to amino acid 17 did result in cyclization. Yields,
however, were poor; examination of a number of param-
eters (solvent, dilution, time, and temperature) gave
yields in the 50% range at best.
Any further improvement in the cyclization to â-lactam
with this reagent probably would require modification
of the reagent. What this modification might be was
suggested by the reported16 halogen exchange of N-alkyl-
2-halopyridinium halides at elevated temperatures. The
importance of this report was underlined by the observa-
tion that N-alkyl-2-iodopyridinium salts are poor car-
boxylate activating agents.17 Possibly the Mukaiyama
reagent was undergoing this exchange, leading to lower
yields of the desired cyclization; even a large excess of
N-methyl-2-chloropyridinium iodide did not produce higher
yields in the closure.
(10) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 18, 4171. (b) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth.
Commun. 1982, 12, 989. (c) Sidler, D. R.; Lovelace, T. C.; McNamara,
J . M.; Reider, P. J . J . Org. Chem. 1994, 59, 1231.
(11) Vorbru¨ggen, H.; Woodward, R. B. Tetrahedron 1993, 49, 1625
and references therein.
A less nucleophilic anion than iodide in the pyridinium
salt would prevent this potentially deactivating halogen
exchange and might give higher yields in the cyclization.
Although several different counterions have been exam-
ined,6 they did not include triflate. The triflate ion would
be the most attractive candidate for use as a counterion
due to its lack of nucleophilicity. Thus, N-methyl-2-
(12) Colvin, E. W.; McGarry, D.; Nugent, M. J . Tetrahedron 1988,
44, 4157.
(13) (a) Breckpot, R. Bull. Soc. Chim. Belg. 1923, 32, 412. (b)
Tufariello, J . J .; Lee, G. E.; Senaratne, P. A.; Al-Nuri, M. Tetrahedron
Lett. 1979, 20, 4359. (c) Kametani, T.; Nagahara, T.; Suzuki, Y.;
Yokohama, S.; Huang, S.-P.; Ihara, M. Heterocycles 1980, 14, 403. (d)
Searles, S., J r.; Wann, R. E. Chem. Ind. (London) 1964, 2097. (e)
Shibuya, M.; Kuretani, M.; Kubota, S. Tetrahedron Lett. 1981, 22, 4453.
(14) (a) Lagarias, J . C.; Houghten, R. A.; Rapoport, H. J . Am. Chem.
Soc. 1978, 100, 8202. (b) Schmidt, U.; Lieberknecht, A.; Bo¨kens, H.;
Griesser, H. J . Org. Chem. 1983, 48, 2680.
(15) (a) Amin, S. G.; Glazer, R. D.; Manhas, M. S. Synthesis 1979,
210. (b) Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984,
1465.
(16) Bradlow, H. L.; Vanderwerf, C. A. J . Org. Chem. 1951, 16, 1143.
(17) Sutherland, J . K.; Widdowson, D. A. J . Chem. Soc. 1964, 4650.

8174 J . Org. Chem., Vol. 63, No. 23, 1998
Sch em e 4. F u n ction a liza tion of th e Cep h em Cor e
Folmer et al.
chloropyridinium and N-methyl-2-bromopyridinium tri-
flates were prepared in quantitative yield using methyl
triflate and the respective 2-halopyridine in CH2Cl2.
N-methyl-2-chloropyridinium triflate was indeed superior
as a cyclizing agent consistently giving 90% yields in the
conversion of amino acid 17 to bicyclic â-lactam 18.
P r ep a r a tion of th e Ca r ba cep h em Cor e Usin g a
Ster eosp ecific Mich a el Cycliza tion (Sch em e 3). As
a more direct alternative to the lactim ether route
(Scheme 2) for the formation of the carbacephem core,
we explored the possibility of using a stereocontrolled
Michael cyclization on an amino ene-ester such as 22 or
23 (Scheme 3) to generate the piperidine 24 possessing
the R stereochemistry of the methoxycarbonylmethyl
tether required in the â-lactam. The steric bulk of the
isopropylidine ring should block one face of attack onto
the ene-ester, giving at the least a favorable mixture of
diastereomers.
Thus, the amino alcohol 7a was oxidized to aldehyde
19 using the Dess-Martin periodinane.18 Attempted
purification of aldehyde 19 using SiO2, neutral alumina,
or Florisil led to the recovery of enamine 21, presumably
due to dehydration of the hemiaminal form 20 of the
aldehyde; a similar observation has been reported re-
cently.19 If crude aldehyde 19, however, is used directly
in the next step, no enamine is formed. In this manner,
reaction of crude aldehyde 19 with the potassium salt of
trimethoxy phosphonoacetate gave the diastereomeric
amino ene-esters 22 and 23 in a ratio of 11/1 in 82% yield
from amino alcohol 7a .20 Reaction of either diastereomer
22 or 23 with catalytic NaH in DME at 50 °C gave only
a single diastereomeric product, in 50-60% overall yield,
as well as recovered starting material.21 The mass
balance for the conversion was 97-100%. If higher
temperatures were used, the mass balance decreased
considerably and the reaction mixture became more
complicated. With one recycling of the recovered starting
material 22 or 23, the yield for the cyclization is 75%,
with 20-25% recovered starting material. The structure
of the cyclized product was determined by single-crystal
X-ray analysis to be as shown in 24 (Scheme 3).
The next step in the sequence required the removal of
the benzenesulfonyl moiety in 24 in the presence of the
methyl ester. Classical cleavage methods for arylsul-
fonamides such as Na/naphthalene led to reduction of the
ester as well as removal of the benzenesulfonyl group.
However, an electrochemical method for removing aryl-
sulfonyl groups from amines has been described22 in
which phenol is used to quench the amine anion as well
as the arylsulfonyl anion and to absorb any bromine
liberated from the electrolyte. Use of this protocol led
to a mixture of amino acid 28, amino ester 27, and
unchanged substrate 24, undoubtedly due to the presence
of moisture that caused ester hydrolysis. The difficulty
in working with the very hygroscopic phenol was over-
come by simply changing the proton source to the
(20) A critical review of Wittig chemistry is presented in the
following: Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(21) A related example is presented in the following: Shishido, K.;
Sukegawa, Y.; Fukumoto, K. J . Chem. Soc., Perkin Trans. 1 1987, 993.
(22) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1988, 53, 2367.
(18) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(19) Dieter, R. K.; Sharma, R. R. J . Org. Chem. 1996, 61, 4180.

Synthesis of Carbacephems from Serine
J . Org. Chem., Vol. 63, No. 23, 1998 8175
nonhygroscopic 4-phenylphenol. With this change, the
benzenesulfonyl group could be removed electrolytically
from 24 to produce amino ester 27 in 90% yield. Using
4-phenylphenol as the proton source has been found to
be of general use in the electrolysis of a variety of
different substrates and is a significant improvement to
the published procedure using phenol, especially for
compounds possessing other sensitive functionalities.
Hydrolysis of the ester in 27 to acid 28 with LiOH
proceeded in 98% yield. Isolation of the zwitterionic
species 28, however, was difficult and capricious. None-
theless, once in hand, cyclization of the amino acid 28
with N-methyl-2-chloropyridinium iodide gave the â-lac-
tam 29 in 53% yield. The difficulties in handling 28 led
us to abandon this path and attempt a crossover route
from amino ester 24 to the disilyl protected amino acid
17 (Scheme 3). An interchange at this point would allow
determination of the absolute stereochemistry of com-
pound 17 obtained from the lactim ether route (Scheme
2) based on the X-ray crystal structure of compound 24
and also would allow the use of the more efficient Michael
cyclization chemistry in the preparation of amino acid
17. Following this plan, cleavage of the isopropylidine
group in acetonide 24 with HCl/MeOH, followed by
reprotection of the intermediate diol with TBSOTf, gave
the piperidine derivative 25 in 97% yield. Electrolytic
removal of the benzenesulfonyl group in bissilyl ether 25
followed by hydrolysis of the resultant amino ester 26
using LiOH gave the amino acid 17 in 85% yield for the
two steps. The amino acid 17 obtained from this route
was identical to amino acid 17 obtained from the lactim
ether route.
P r ep a r a t ion of C-7-Su b st it u t ed An a logu es
(Sch em e 4). The three chiral centers at C-2, C-3, and
C-6 in â-lactam 18 should be dominant in directing the
stereochemistry of any substitution at C-7. For example,
deprotonation at C-7 in â-lactam 18 with LDA, followed
by reaction with isoamyl nitrite, gave the oxime 30 as a
mixture of isomers.23 The oxime was hydrogenated using
PtO2 as a catalyst, and the resultant amine was protected
as the tert-butyl carbamate in 76% overall yield. The
stereochemistry at C-7 was determined to be S based on
the coupling constants between H-6 and H-7. This is also
the predicted stereochemistry based on the fact that the
C-2 and C-3 silyloxy moieties and the C-6 alkyl group
block attack from the â face of the molecule. While
compound 31 was not carried further, the methodology
developed for the preparation of the target enol triflate
from disilyl 32 bearing a C-7 alkyl substituent should
be applicable to the 7â-amino-substituted carbacephem.
On the basis of these steric considerations, alkylation
at C-7 was predicted to provide the R-alkyl derivative.
When â-lactam 18 was ethylated using LDA followed by
EtI, a 12/1 mixture was obtained of 7R-ethyl 32 and its
7S-epimer 33 in 95% overall yield. The diastereomers
could be easily separated by chromatography, and it was
found that 33 fortuitously could be obtained in crystalline
form, suitable for X-ray analysis. The X-ray crystal
structure of 33 (Figure 2) thus confirms all previous
stereochemical assignments.
F igu r e 2. Structure of (2R,3R,6R,7S)-3-tert-butyldimethyl-
siloxy-2-ter t-bu t yldim et h ylsiloxym et h yl-7-et h yl-8-oxo-1-
azabicyclo[4.2.0]octane (33) as determined by X-ray crystal-
lography (arbitrary numbering system).
to this hydroxy ester were envisioned from disilyl 32. The
first route involved removal of both protecting groups
with excess TBAF in THF to give diol 35 in 98% yield.
Selective oxidation of the primary alcohol in the presence
of the secondary hydroxyl group to give hydroxy acid 39
was attempted using a Pt/O2 protocol previously applied
to similar systems.7b While Pt/O2 oxidation was success-
ful in the synthesis of cyclic and acyclic â-hydroxy
R-amino acids, we were unable to obtain 39 by this
method. Alternatively, monodeprotection of the primary
silyl group of 32 with catalytic p-TsOH in THF/H2O gave
the alcohol 34 in 96% yield.24 Ruthenium-catalyzed
oxidation25 of 34 followed by esterification of acid 36 using
excess p-nitrobenzyl bromide gave PNB ester 37 in 79%
yield. Attempts to remove the silyl ether of 37 in the
presence of the p-nitrobenzyl ester using TBAF led to
elimination and formation of the R,â-unsaturated ester
38. Reversing the sequence from 36 by first removing
the silyl ether and then esterifying hydroxy acid 39
provided hydroxy ester 40 in 63% overall yield from 35.
With the key intermediate 40 in hand, completion of
the synthesis of the target carbacephem only required
oxidation to the â-keto ester. The objective was to obtain
the enol triflate 42 protected as a p-nitrobenzyl ester,
since structurally related carbacephems are known to be
stable intermediates useful for extrapolation to biologi-
cally active â-lactam antibiotics.26 Oxidations of â-hy-
droxy esters to â-keto esters are challenging because of
the potential fragmentation of the C-C bonds R and â to
the ester.27 This was readily apparent when application
of a DMSO-based oxidation led to a very complex reaction
mixture containing very minor amounts of 41. On the
other hand, â-keto esters have been successfully prepared
(24) Thomas, E. J .; Williams, A. C. J . Chem. Soc., Chem. Commun.
1987, 992.
(25) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(26) Crowell, T. A.; Halliday, B. D.; McDonald, J . H., III; Indelicato,
J . M.; Pasini, C. E.; Wu, E. C. Y. J . Med. Chem. 1989, 32, 2436.
(27) (a) Stachulski, A. V. Tetrahedron Lett. 1982, 23, 3789. (b)
Delacotte, J .-M.; Galons, H.; Schott, D.; Morgat, J .-L. Synth. Commun.
1992, 22, 3075.
The â-hydroxy ester 40 is a crucial intermediate in the
preparation of the target molecule. Two possible routes
(23) For
a related example, see: Yamashita, H.; Minami, N.;
Sakakibara, K.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1988,
36, 469.

8176 J . Org. Chem., Vol. 63, No. 23, 1998
Folmer et al.
under mild conditions using Dess-Martin periodinane.28
With this reagent, â-keto ester 41 was obtained as an
unstable mixture of keto and enol forms from 200 mol %
of the periodinane in CH2Cl2. After an aqueous wash,
the isolated oil was treated with 200 mol % of triflic
anhydride to trap the enol form and to give the target
carbacephem 42 in 73% yield from hydroxy ester 40.
%) was added dropwise over 35 min, keeping the temperature
of the reaction mixture below -69 °C. The orange mixture
was stirred an additional 20 min and allowed to warm to 0 °C
over 1 h. Allylmagnesium bromide (950 mL, 0.85 M in Et2O,
0.81 mol, 282 mol %) was added dropwise over 1.5 h. After
the addition was complete, the olive-green mixture was stirred
for an additional 25 min at 0 °C and allowed to warm to room
temperature over 1 h. Stirring was continued at room tem-
perature for 17 h, and the mixture was then cooled to 0 °C
and cannulated below the surface of 3 L of a 0.75 M solution
of H3PO4 at 0 °C at such a rate as to keep the temperature of
the quenched mixture below 2 °C. The layers were separated,
and the aqueous phase was extracted with Et2O (4 × 500 mL).
The combined organic phase was washed with saturated
aqueous NaHCO3 (2 × 300 mL) and brine (300 mL), dried,
and evaporated, leaving a white solid, which as determined
by NMR analysis, was pure ketone 3 (71.7 g, 93%): mp 110-
Con clu sion
A process has been developed for the synthesis of
carbacephems from D-serine. The process proceeds by
preparing the suitably substituted piperidine-2-acetic
acid, which is then very efficiently cyclized to the â-lac-
tam. Both the relative and absolute stereochemistry are
specifically controlled, with the prospect for inversion,
should L-serine be used as the educt. The process
presents various opportunities for introduction of sub-
stituents.
111 °C (lit.7b mp for S-3, 1.09-110 °C); [R]22 -99.4 (c 1,
D
CHCl3); (lit.7b for S-3, [R]20 +72.4 (c 2, CHCl3); 1H NMR δ
D
2.19 (bs, 1H), 3.14-3.26 (m, 2H), 3.82-3.99 (m, 3H), 5.02-
5.15 (m, 2H), 5.65-5.71 (m, 1H), 5.81-5.83 (m, 1H), 7.48-
7.62 (m, 3H), 7.79-7.83 (m, 2H). Anal. Calcd for C12H15
-
NO4S: C, 53.5; H, 5.6; N, 5.2. Found: C, 53.7; H, 5.7; N, 5.2.
(R,E)-5-[(P h en ylsu lfon yl)a m in o]-6-h yd r oxy-2-h exen -4-
on e (4). To a solution of â,γ-unsaturated ketone 3 (0.995 g,
3.7 mmol) in 40.0 mL of dry THF was added Et3N (1.50 mL,
10.8 mmol). The yellow solution was stirred at room temper-
ature for 19.5 h and then quenched with 10 mL of saturated
aqueous KH2PO4. The quenched mixture was stirred for an
additional 5 min, then evaporated, and the aqueous residue
was extracted with Et2O (50 mL) and EtOAc (50 mL). The
pH of the aqueous phase was adjusted to 4.0 with 1 M H3PO4,
and the solution was extracted with EtOAc (2 × 20 mL). The
combined organic phase was dried and evaporated, leaving an
off-white solid, which as determined by NMR analysis, was
Exp er im en ta l Section
Gen er a l. All reactions were conducted under an atmo-
sphere of nitrogen or argon, and solvents were distilled
immediately before use unless otherwise noted. THF and
diethyl ether were distilled from sodium/benzophenone, CH3-
CN was distilled from P2O5 and then from CaH2, DMF was
dried over 4 Å molecular sieves, methylene chloride and
toluene were distilled from CaH2, and ethyl acetate, hexanes,
2-propanol, and chloroform were used as purchased. Tetra-
ethylammonium bromide (TEAB) was recrystallized 4 times
from abs EtOH, and 4-phenylphenol was recrystallized from
abs EtOH then sublimed at 100 °C/25 Torr. 1H and 13C NMR
were taken in CDCl3 unless otherwise stated, and chemical
shifts are reported in ppm (δ) downfield from tetramethylsi-
lane. Numbers in parentheses following the chemical shifts
in 13C NMR data correspond to the number of hydrogens
attached to that carbon atom, as determined by DEPT 90 and
DEPT 135 NMR experiments. Column chromatography was
performed using EM Science silica gel 60 (70-230 mesh).
Preparative TLC was carried out using preformed plates
(Analtech) of 250-2000 µm thickness. All final organic
extracts were dried over Na2SO4 and filtered before evapora-
tion unless otherwise noted. Melting points are uncorrected.
Elemental analyses were determined by the Microanalytical
Laboratories, University of California, Berkeley.
the R,â-unsaturated ketone 4 (0.980 g, 98%): recrystallization
1
from EtOAc, mp 122-123 °C; [R]24 -53.9 (c 1.1, CHCl3); H
D
NMR δ 1.89 (dd, J ) 6.9, 1.6 Hz, 3H), 2.37 (bs, 1H), 3.80-
3.90 (m, 2H), 4.13-4.16 (m, 1H), 5.97 (d, J ) 6.7 Hz, 1H), 6.19
(dq, J ) 15.5, 1.6 Hz, 1H), 6.97 (dq, J ) 15.5, 6.9 Hz, 1H),
7.48-7.60 (m, 3H), 7.84-7.86 (m, 2H); 13C NMR δ 18.6 (3),
61.8 (1), 63.4 (2), 127.07 (1), 127.10 (1), 129.2 (1), 133.0 (1),
139.4 (0), 146.9 (1), 193.7 (0). Anal. Calcd for C12H15NO4S:
C, 53.5; H, 5.6; N, 5.2. Found: C, 53.5; H, 5.7; N 5.1.
(4R/S,5R)-5-[(P h en ylsu lfon yl)a m in o]-4,6-d ih yd r oxy-2-
h exen e (5a ,b). To a 500 mL three-neck flask equipped with
a magnetic stirrer and an addition funnel was added a solution
of l-selectride (96 mL, 96 mmol, 1.0 M in THF) followed by an
additional 140 mL of THF, and the solution was cooled to -78
°C. The addition funnel was charged with a solution of ketone
3 (12.0 g, 44.56 mmol)30 in 60 mL of THF, which was added to
the vigorously stirred L-selectride solution, keeping the tem-
perature of the reaction mixture below -73 °C. After the
addition was complete (ca. 15 min), the reaction mixture was
stirred at -78 °C for 2 h, 200 mL of a 1/1 solution of glacial
acetic acid and water was added to the cold reaction mixture
over 1 min, the cold bath was removed, and the mixture was
allowed to warm to room temperature over 1 h. The mixture
was concentrated to 40% of its original volume and diluted
with saturated aqueous NaHCO3 (196 mL), the pH (4.5) was
adjusted to 10.5 using 6 M NaOH (ca. 220 mL), and 70 mL of
30% H2O2 was added. (Caution! exothermic reaction.) The
warm mixture was stirred at room temperature for 1 h and
washed with hexanes (2 × 75 mL); this wash was set aside.
The aqueous layer was next extracted with a 1/3 IPA/CHCl3
(4 × 150 mL), and the combined organic layer was dried and
evaporated to give 7.68 g (63%) of the diastereomeric diols 5a ,b
as a thick, colorless oil, which slowly crystallized under high
vacuum. The hexanes wash was evaporated to a thick, opaque
residue, which was diluted with 50 mL of saturated aqueous
N-P h en ylsu lfon yl-D-ser in e (2). 2 was prepared by treat-
ing D-serine (50.0 g, 476 mmol) with Na2CO3‚H2O (148 g, 1.19
mol) and phenylsulfonyl chloride (100 g, 563 mmol) as de-
scribed for L-serine29 with the following changes. The reaction
mixture was stirred at room temperature for 24 h and then
was washed with hexanes (3 × 300 mL). The aqueous phase
was acidified to pH 1.2 with 85% H3PO4 whereupon a white
precipitate formed. After being stored at 0 °C for 24 h, the
mixture was filtered, and the crystals were washed with Et2O
(400 mL) and air-dried to give the protected serine 2 as fluffy
white crystals (110 g, 95%): mp 232-233 °C (lit.7b 222-224
1
°C, dec); [R]22 -10.3 (c 1, CH3OH); H NMR (400 MHz, Me2-
D
SO-d6) δ 3.48-3.52 (m, 2H), 3.71-3.80 (m, 1H), 7.53-7.61 (m,
3H), 7.79 (d, J ) 7.1 Hz, 2H), 8.0 (d, J ) 8.4 Hz, 1H) [lit.25
3.56 (d, J ) 6 Hz, 2H), 3.83 (m, 1H), 7.5-8.2 (m, 7H)].
δ
(R )-5-[(P h e n y ls u lfo n y l)a m i n o ]-6-h y d r o x y -4-h e x -
en on e (3). A mixture of the protected d-serine 2 (70.1 g, 286
mmol) in 2.3 L of dry THF in a 5 L three-neck Morton flask
equipped with a mechanical stirrer, a reflux condenser, and a
gas inlet was heated at reflux for 45 min until the solution
became homogeneous. The solution was then cooled to -75
°C, and n-BuLi (70.0 mL, 10.0 M in hexanes, 0.7 mol, 245 mol
(30) Ketone 3 was recrystallized from EtOAc prior to use in order
to remove any traces of the R,â-unsaturated ketone 4. The presence of
as little as 4% of conjugated ketone 4 in a sample of ketone 3 produces
significantly lower yields of diol.
(28) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 3604.
(29) Maurer, P. J .; Takahata, H.; Rapoport, H. J . Am. Chem. Soc.
1984, 106, 1095.

Synthesis of Carbacephems from Serine
J . Org. Chem., Vol. 63, No. 23, 1998 8177
NaHCO3. The pH was adjusted to 10.5 by the addition of 17
mL of 6 M NaOH, 8 mL of 30% H2O2 was added, and the
mixture was stirred at room temperature overnight (12 h). The
mixture was then extracted with 1/3 IPA/CHCl3 (3 × 50 mL),
and the combined organic phases were dried and evaporated
to a yellow oil. Chromatography (40/1, w/w) using 2/1 EtOAc/
hexanes as an eluent afforded the diols 5a ,b as a thick,
colorless oil, which solidified under high vacuum (2.37 g, 20%).
As a precaution, the combined aqueous layers were allowed
to stand at room temperature overnight and re-extracted with
IPA/CHCl3 1/3 (75 mL). The organic layer was dried and
evaporated to yield a small amount of diols 5a ,b, as a white
solid (0.062 g, 0.5%); 1H NMR was identical to that reported.7b
The total yield of diols 5a ,b was 84%, and the product was
used in the next step without further purification.
(4R,5R)-5-[(P h en ylsu lfon yl)am in o]-4-(3-h ydr oxypr opyl)-
2,2-d im eth yl-1,3-d ioxa n e (7a ). Alternatively, 7a was pre-
pared by adding to a solution of 9-BBN (2.68 g, 11 mmol, 190
mol %) in 20 mL of THF a solution of olefin 6 (1.80 g, 5.8 mmol)
in 20 mL of THF dropwise over 5 min at room temperature.
The mixture was stirred for 4 h at room temperature then
quenched at 0 °C with 8 mL of EtOH, followed by careful
addition of 4.5 mL of 3 M aqueous NaOH and 4.5 mL of 30%
H2O2. The mixture was allowed to reach room temperature,
heated at reflux for 90 min, cooled to room temperature,
concentrated to 40% of its original volume, and diluted with
200 mL of Et2O. The aqueous phase was diluted with 10 mL
of H2O, the pH was adjusted from 11.6 to 7 using 0.5 M H3-
PO4, and the solution was extracted with IPA/CHCl3, 1/4 (4 ×
30 mL). The combined organic phase was dried and evapo-
rated, and the residue was chromatographed (130 g SiO2) using
1-2% MeOH/CH2Cl2 (gradient elution) as an eluent to afford
the alcohol 7a as a white solid (1.55 g, 81%): mp 124-126 °C.
(4R,5R-5-[P h en ylsu lfon yl)a m in o]-4-(2-ca r b oxyet h yl)-
2,2-d im eth yl-1,3-d ioxa n e (8). To the vigorously stirred
mixture of alcohol 7a (2.94 g, 8.92 mmol) in 330 mL of CH3-
CN/CCl4/phosphate buffer (pH 7.0) (4/4/5) was added NaIO4
(8.81 g, 41.2 mmol, 462 mol %), followed by RuCl3‚3H2O (55
mg, 0.24 mmol, 2.7 mol %). The mixture was stirred at room
temperature for 90 h, 150 mL of CH2Cl2 was added, stirring
was continued for 1 h, and the layers were separated. The
aqueous layer was extracted with IPA/CHCl3, 1/4 (4 × 50 mL),
and the combined organic phase was filtered through a fritted
glass disk and evaporated to a gray foam, which was diluted
with Et2O (30 mL) and filtered through Celite. The filtrate
was washed with 5% aqueous NaHSO3 (2 × 15 mL), dried,
and evaporated. Chromatography (SiO2, 45/1, w/w) of the
residue using 2-10% MeOH/CH2Cl2 (gradient elution) afforded
(4R,5R)-5-[(P h en ylsu lfon yl)am in o]-4-allyl-2,2-dim eth yl-
1,3-d ioxa n e (6). To a solution of diols 5a ,b (8.40 g, 31.0 mmol)
in 400 mL of THF at room temperature was added p-
toluenesulfonic acid (0.41 g, 2.20 mmol), followed by 2,2-
dimethoxypropane (39.0 g, 46.0 mL, 374 mmol, 1200 mol %).
The reaction mixture was stirred at room temperature for 48
h, 250 mL of saturated aqueous NaHCO3 was added, and
stirring was continued for an additional 1 h; then, it was
poured into 200 mL of Et2O. The aqueous phase was extracted
with Et2O (2 × 100 mL), and the combined organic phase was
washed with brine (150 mL), dried, and evaporated to give
9.70 g of a white solid, which was recrystallized from EtOAc
to give the cis diastereomer 6 (5.79 g, 60%): mp 140-142 °C
(lit. mp 143-144 °C); [R]22 -15.6 (c 1, CHCl3); [lit.,7b
D
enantiomer of 6, [R]22 +13.6 (c 2.12, CHCl3)]. The 1H NMR
D
and analytical data for 6 were identical to reported values.7b
The mother liquor from the recrystallization above was stored
and combined with the mother liquors of subsequent runs,
from which more of the cis diastereomer 6 was obtained by
further recrystallizations or by chromatography (80/1, w/w)
using EtOAc/hexanes 1/9 as eluent, for a total yield of 80%.
(4R,5R)-5-[(P h en ylsu lfon yl)a m in o]-4-(3-h yd r oxylp r o-
p yl)-2,2-d im eth yl-1,3-d ioxa n e (7a ) a n d (4R,5R)-5-[(P h en -
ylsu lfon yl)a m in o]-4-(2-h yd r oxylp r op yl)-2,2-d im eth yl-1,3-
d ioxa n e (7b). On the basis of the reported procedure,7b to a
solution of olefin 6 (4.0 g, 12.9 mmol) in 250 mL of THF at
room temperature was added BH3‚THF (6.0 mL, 1.0 M in THF,
47 mol %). The colorless solution was stirred at room tem-
perature for 2.5 h then quenched by the addition of 38 mL of
H2O. The mixture was heated at reflux for 25 min, and 42
mL of 3 M aqueous NaOH was added. The heating bath was
removed, and 48 mL of 30% H2O2 was added carefully to the
warm mixture over 5 min. The mixture was again heated at
reflux for 1.5 h and cooled to room temperature over 1 h, after
which the aqueous layer was extracted with 1/4 IPA/CHCl3 (3
× 75 mL) and the combined organic phase was washed with
H2O (25 mL), dried, and evaporated to give a crude white solid
(4.0 g). This crude product was recrystallized from EtOAc to
give pure primary alcohol 7a (2.39 g). The mother liquor was
purified by chromatography using EtOAc/hexanes, 3/2, as an
eluent to give secondary alcohol 7b (270 mg, 6.4%) followed
by additional 7a (420 mg). The combined yield of 7a was 66%.
Primary alcohol 7a : mp 124-126 °C (lit.,7b reported as an oil);
1
acid 8 (2.32 g, 75%): mp 45 °C (dec); H NMR δ 1.36 (s, 3H),
1.38 (s, 3H), 1.65 (m, 1H), 1.85 (m, 1H), 2.37 (t, J ) 7.1 Hz,
2H), 3.17 (m, 1H), 3.32 (dd, J ) 11, 1.6 Hz, 1H), 3.86 (dd, J )
11, 1.6 Hz, 1H), 3.95 (m, 1H), 5.58 (d, J ) 10.2 Hz, 1H), 7.55
(m, 3H), 7.90 (m, 2H); 13C NMR δ 18.4, 26.7, 29.0, 29.3, 50.1
(1), 64.1 (2), 70.1 (1), 99.4 (1), 126.8 (1), 129.2 (1), 132.7 (1),
141.1, 178.8. Acid 8 is hygroscopic; it was immediately
converted to lactam 9.
(2R,3R)-6-Oxo-3-h yd r oxy-2-h yd r oxym eth yl-1-p h en syl-
su lfon ylp ip er id in e Aceton id e (9). To a solution of acid 8
(1.11 g, 3.23 mmol) in 315 mL of CH2Cl2 was added 4-(di-
methylamino)pyridine (0.380 g, 3.1 mmol, 96 mol %), followed
by a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC, 0.750 g, 3.91 mmol, 121 mol %) in 25 mL
of CH2Cl2. The mixture was stirred at 0 °C for 12 h, diluted
with 100 mL of CH2Cl2, washed with 0.5 M HCl (4 × 40 mL),
saturated aqueous NaHCO3 (40 mL), and brine (40 mL), dried,
and evaporated. Sublimation of the residue (140 °C, 0.3 Torr)
afforded lactam 9 (0.970 g, 92%): mp 176-178 °C; [R]23
D
-136.2 (c 0.5, CHCl3); 1H NMR δ 1.34 (s, 3H), 1.42 (s, 3H),
1.81 (m, 1H), 2.03 (m, 1H), 2.34 (m, 1H), 2.76 (ddd, J ) 12, 5
Hz, 1H), 3.84 (dd, 1H, J ) 12, 7 Hz, 1H), 4.24 (dd, J ) 12.6
Hz, 1H), 4.47 (m, 1H), 4.56 (m, 1H), 7.52 (m, 2H), 7.59 (m,
1H), 8.01 (m, 2H); 13C NMR δ 22.3 (3), 24.6 (2), 25.4 (3), 29.0
(2), 56.1 (1), 62.2 (2), 62.9 (1), 99.9 (0), 128.6 (1), 128.7 (1),
133.6 (1), 139.7 (0), 171.2 (0). Anal. Calcd for C15H19NO5S:
C, 55.4; H, 5.9; N, 4.3. Found: C, 55.3; H, 6.1; N, 4.2.
[R]22 -15.9 (c 1, CHCl3); 1H NMR δ 1.38 (s, 3H), 1.40 (s, 3H),
D
1.42-1.76 (m, 5H), 3.15-3.19 (m, 1H), 3.33-3.38 (m, 1H),
3.55-3.57 (m, 2H), 3.84-3.88 (m, 2H), 5.32-5.35 (m, 1H),
7.48-7.61 (m, 3H), 7.88-7.92 (m, 2H); 13C NMR δ 18.4 (3),
28.1 (2), 28.5 (2), 29.4 (3), 50.2 (1), 62.3 (2), 64.1 (2), 71.5 (1),
99.2 (0), 126.8 (1), 129.1 (1), 132.6 (1), 141.2 (0). Anal. Calcd
for C15H23NO5S: C, 54.7; H, 7.0; N, 4.2. Found: C, 54.3; H,
(2R ,3R )-6-O x o -3-h y d r o x y -2-h y d r o x y m e t h y lp ip e r i-
d in e Aceton id e (10). To a solution of naphthalene (1.65 g,
12.9 mmol) in 20 mL of DME was added sodium (0.49 g, 21.5
mmol). The mixture was stirred at room temperature for 3 h,
giving a green-black suspension. A solution of lactam 9 (1.16
g, 3.56 mmol) in 42 mL of THF was cooled to -78 °C, and the
solution of sodium naphthalenide was added via syringe until
a green-black color persisted (ca. 15 mL). During the addition,
the internal temperature of the reaction mixture was main-
tained just below -75 °C. The mixture was stirred at -78 °C
for 2.5 h, and then 2.3 g of NH4Cl was added quickly, followed
by removal of the cooling bath. The mixture, which warmed
to room temperature over 45 min, was filtered, the filtrate was
evaporated, and the residue was chromatographed (SiO2, 230-
400 mesh, 40 g) eluting with hexanes to 15% MeOH/CH2Cl2.
1
6.9; N, 4.2. Secondary alcohol 7b: mp 118-119 °C; H NMR
δ 1.14 (d, J ) 6.3, 3H), 1.34 (s, 3H), 1.40 (s, 3H), 1.61 (d, J )
6.9 Hz, 1H), 1.65-1.68 (m, 1H), 3.17 (d, J ) 10.0 Hz, 1H), 3.27
(d, J ) 12.1 Hz, 1H), 3.86 (d, J ) 12.1 Hz, 2H), 4.15 (m, 1H),
5.30 (d, J ) 10.1 Hz, 1H), 7.49 (t, J ) 7.2 Hz, 2H), 7.55 (d, J
) 7.2 Hz, 1H), 7.86 (d, J ) 7.2 Hz, 2H); 13C NMR δ 18.5 (3),
24.2 (3), 29.5 (3), 40.8 (2), 51.0 (1), 64.2 (2), 64.7 (1), 68.8 (1),
99.3 (0), 126.9 (1), 129.2 (1), 132.7 (1), 141.1 (0). Anal. Calcd
for C15H23NO5S: C, 54.7; H, 7.0; N, 4.2. Found: C, 54.8; H,
7.2; N, 4.0.

8178 J . Org. Chem., Vol. 63, No. 23, 1998
Folmer et al.
Sublimation (110 °C, 0.3 Torr) gave lactam 10 (0.541 g, 82%):
mixture was extracted with CH2Cl2 (4 × 10 mL), followed by
washing the combined organic phase with saturated aqueous
NaHCO3 (2 × 10 mL) and brine (10 mL). The organic phase
was dried and evaporated to a yellow oil, which was chro-
matographed (SiO2, 73/1, w/w) using EtOAc/hexanes, 1/2, as
mp 165 °C (dec); [R]23 -64.1 (c 0.6, CHCl3); IR 3020, 1700,
D
1450, 1360, 1220, 1170 cm-1
;
1H NMR δ 1.40 (m, 3H), 1.49
(m, 3H), 1.83 (m, 1H), 2.02 (m, 1H), 2.26 (ddd, J ) 12.8, 1H),
2.59 (m, 1H), 3.27 (m, 1H), 3.75 (dd, J ) 1.7, 12.8, 1H), 4.09
(dd, J ) 2.4, 12.8, 1H), 4.22 (m, 1H), 6.88 (bs, 1H); 13C NMR
δ 18.8 (3), 25.7 (2), 25.8 (2), 29.0 (3), 49.0 (1), 61.9 (1), 63.0 (2),
98.2 (0), 173.1 (0). Anal. Calcd for C9H15NO3: C, 58.4; H, 8.2;
N, 7.6. Found: C, 58.4; H, 8.4; N, 7.4.
(2R,3R)-6-Oxo-3-ter t-bu tyld im eth ylsilyloxy-2-(ter t-bu -
tyld im eth ylsilyloxym eth yl)p ip er id in e (12). To a solution
of lactam 10 (0.420 g, 2.27 mmol) in 6 mL of MeOH was added
concd HCl (0.1 mL). The mixture was stirred at room
temperature for 15 h, the solvent was evaporated, and the
residue was diluted with MeOH (5 mL) and evaporated; this
addition-evaporation was repeated twice. The oily residue
was dissolved in 3 mL of DMF, imidazole (0.770 g, 11.3 mmol)
and TBDMSCl (1.01 g, 6.70 mmol) were added, and the
mixture was stirred at room temperature for 72 h then
extracted with hexanes (5 × 10 mL). The combined organic
phase was washed with pH 4 phosphate buffer (3 × 10 mL),
saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried,
and evaporated. The residue was chromatographed (SiO2, 40
an eluent to afford the enamine 15 as a light-yellow oil (0.182
1
g 79%): [R]23 +6.5 (c 0.85, CHCl3); H NMR δ 0.07 (s, 6H),
D
0.09 (s, 6H), 0.88 (s, 9H), 0.91 (s, 9H), 1.24 (t, J ) 7.1 Hz, 3H),
1.6-1.9 (m, 2H), 2.15-2.25 (m, 1H), 2.6-2,75 (m, 1H), 3.25-
3.35 (m, 1H), 3.55-3.75 (m, 2H), 4.08 (q, J ) 7.1 Hz, 2H), 4.12
(s, 1H), 4.39 (s, 1H), 8.74 (s, 1H); 13C NMR δ -5.5 (3), -5.4
(3), -5.1 (3), -4.6 (3), 14.7 (0), 18.0 (0), 18.3 (0), 24.3 (2), 25.7
(1), 25.9 (1), 27.6 (2), 57.6 (1), 58.1 (2), 63.7 (2), 64.4 (1), 80.3
(1), 161.3 (0), 170.3 (0). Anal. Calcd for C22H45NO4Si2: C, 59.5;
H, 10.2; N, 3.2. Found: C, 59.6; H, 10.3; N, 3.3.
(2R,3R,6R)-6-Eth oxycar bon ylm eth yl-3-ter t-bu tyldim eth -
ylsilyloxy-2-ter t-bu tyld im eth ylsilyloxym eth ylp ip er id in e
(16). A solution of enamine 15 (0.182 g, 0.41 mmol) in 4 mL
of EtOAc was degassed with N2, and 5% Pt/C (0.060 g, 1.6%
w/w) was added. The mixture was agitated under an atmo-
sphere of H2 (50 psi) for 30 h, and the catalyst was removed
by filtration through Celite. Evaporation of the solvent
afforded amino ester 16 as a light-yellow oil (0.146 g, 80%):
g) using EtOAc/hexanes, 1/1, as an eluent to give lactam 12
[R]23 +13.2 (c 1.04, CHCl3); 1H NMR δ -0.05-0.05 (m, 12H),
D
1
(0.650 g, 77%): mp 48-51 °C; [R]23 +21.3 (c 1.4, CHCl3); H
0.80 (s, 9H), 0.83 (s, 9H), 1.17 (t, J ) 7.1 Hz, 3H), 1.40-1.70
(m, 3H), 1.70-1.85 (m, 1H), 2.40-2.62 (m, 2H), 2.65-2.74 (m,
1H), 3.0-3.1 (m, 1H), 3.40-3.50 (m, 1H), 3.55-3.65 (m, 1H),
3.91 (bs, 1H), 4.05 (q, J ) 7.1 Hz, 2H); 13C NMR δ -5.3 (3),
-5.29 (3), -4.8 (3), -4.6 (3), 14.2, 18.1, 18.2, 25.9 (3), 26.6 (2),
32.1 (2), 41.9 (2), 53.4 (1), 60.2 (2), 61.9 (1), 63.7 (2), 63.9 (1),
172.0 (0). Anal. Calcd for C22H47NO4Si2: C, 59.3; H, 10.6; N,
3.1. Found: C, 59.5; H, 11.0; N, 3.2.
D
NMR δ 0.05 (s, 6H), 0.07 (s, 6H), 0.87 (s, 9H), 0.88 (s, 9H),
1.72 (m, 2H), 2.2-2.4 (m, 1H), 2.5-2.65 (m, 1H), 3.4-3.5 (m,
1H), 3.6-3.7 (m, 2H), 4.03 (m, 1H), 5.93 (s, 1H); 13C NMR δ
-5.8 (3), -5.79 (3), -5.5 (3), -4.8 (3), 17.7, 17.9, 25.3 (3), 25.4,
25.5, 25.6 (3), 26.2, 27.8, 58.5 (1), 63.7 (1), 171.1 (0). Anal.
Calcd for C18H39NO3Si2; C, 57.9; H, 10.5; N, 3.8. Found: C,
58.1; H, 10.5; N, 3.7.
(5R,6R)-2-Meth oxy-5-ter t-bu tyld im eth ylsilyloxy-6-ter t-
b u t yld im et h ylsilyloxym et h yl-1,2-d id eh yd r op ip er id in e
(13). To a solution of lactam 12 (0.500 g, 1.34 mmol) in 5 mL
of CH2Cl2 was added methyl triflate (0.17 mL, 1.50 mmol, 112
mol %), and the mixture was stirred at room temperature for
8 h. The solvent and excess methyl triflate were evaporated,
and to the residue was added 10 mL of cold 5% aqueous Na2-
CO3 followed by extraction with CH2Cl2 (4 × 10 mL). Evapo-
ration gave crude lactim ether 13, which was used without
further purification (0.468 g, 90%): 1H NMR δ 0.04 (s, 6H),
0.05 (s, 6H), 0.85 (s, 9H), 0.88 (s, 9H), 1.63-1.71 (m, 1H), 1.88-
1.95 (m, 1H), 2.04-2.1 (m, 1H), 2.29-2.39 (m, 1H), 3.30 (m,
1H), 3.59 (s, 3H), 3.60-3.65 (m, 1H), 3.69-3.75 (m, 1H), 4.03-
4.08 (m, 1H); 13C NMR δ -5.2 (3), -5.19 (3), -5.0 (3), -4.6
(3), 18.0 (0), 18.2 (0), 22.0 (2), 25.8 (3), 25.9 (3), 27.7 (2), 51.8
(3), 61.9 (1), 63.7 (1), 63.9 (2), 162.6 (0).
(2R,3R,6R)-6-Ca r b oxym et h yl-3-ter t-b u t yld im et h ylsi-
lyloxy-2-ter t-bu tyldim eth ylsilyloxym eth ylpiper idin e (17).
A solution of amino ester 16 (30 mg, 0.067 mmol) in 2 mL of
a 4/1 MeOH/H2O solution was cooled to 0 °C and LiOH‚H2O
(15 mg, 0.36 mmol, 537 mol %) was added. The mixture was
warmed to room temperature and stirred for 12 h. The pH of
the solution was adjusted to pH 7 using pH 4 phosphate buffer
and extracted with IPA/CHCl3 (1/4), and the combined layers
were dried and evaporated to afford the amino acid 17 (27 mg,
97%): mp 108-110 °C; 1H NMR δ 0.04-0.1 (m, 12H), 0.89 (s,
9H), 0.91 (s, 9H), 1.5-1.95 (m, 4H), 2.31 (dd, J ) 16.9, 9.2 Hz,
1H), 2.54 (dd, J ) 16.9, 3.2 Hz, 1H), 2.76 (t, J ) 7 Hz, 1H),
2.92-3.05 (m, 1H), 3.51-3.69 (m, 2H), 3.96 (bs, 1H); 13C NMR
δ -5.4 (3), -5.3 (3), -5.1 (3), -4.5 (3), 18.0 (0), 18.1 (0), 24.5
(2), 25.8 (3), 25.9 (3), 31.0 (2), 39.2 (2), 53.8 (1), 61.1 (1), 61.4
(2), 63.2 (1), 174.4 (0).
(2R,3R)-6-[5-(2,2-Dim eth yl-4,6-dioxo-1,3-dioxan yliden e)]-
3-ter t-bu tyld im eth ylisilyloxy-2-ter t-bu tyld im eth ylsilyl-
oxym eth ylp ip er id in e (14). To a solution of lactim ether 13
(0.520 g, 1.34 mmol) in 5 mL of CHCl3 was added 2,2-dimethyl-
4,6-dioxo-1,3-dioxane (0.220 g, 1.53 mmol, 114 mol %) and
nickel acetylacetonate monohydrate (4 mg, 0.015 mmol, 1 mol
%). The mixture was heated at reflux for 22 h and evaporated
to a yellow residue, which was chromatographed (SiO2, 35 g)
using EtOAc/hexanes as an eluent to give the enamine 14
N-Meth yl-2-ch lor op yr id in iu m Tr ifla te. In a resealable
tube was placed a solution of 2-chloropyridine (2.0 mL, 2.4 g,
21.1 mmol) in 3.5 mL of CH2Cl2. The solution was degassed
by three freeze/thaw cycles, and the tube was then purged with
Ar. The colorless solution was cooled to -78 °C, and with
stirring, methyl trifluoromethanesulfonate (2.4 mL, 3.48 g,
21.2 mmol) was added over 45 s, as a white precipitate began
to form. The cooling bath was removed, the tube was closed
under Ar, and the cloudy mixture was stirred for 16 h.
Toluene (20 mL) was added to the white mixture, and after
stirring for 30 min more, the precipitate slowly settled to the
bottom of the tube, leaving a clear supernatant, which was
removed via syringe. An additional 20 mL of dry toluene was
added to wash the precipitate, and the toluene was removed
via syringe, with all operations being done under a stream of
Ar. The washed precipitate was dried under high vacuum for
48 h at room temperature to afford 5.5 g (94%) of N-methyl-
(0.490 g, 73%): mp 142-144 °C; [R]23 +39.6 (c 1.2, CHCl3);
D
1H NMR δ 0.05 (s, 6H), 0.07 (s, 6H), 0.85 (s, 9H), 0.91 (s, 9H),
1.64 (s, 3H), 1.66 (s, 3H), 1.7-1.8 (m, 1H), 1.9-2.0 (m, 1H),
3.0-3.15 (m, 1H), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 3.65-3.8
(m, 2H), 4.08-4.15 (m, 1H), 9.84 (s, 1H); 13C NMR δ -5.8 (3),
-5.5 (3), -5.2 (3), -4.5 (3), 17.9 (0), 18.2 (0), 24.6 (2), 25.6 (3),
25.8 (3), 26.0 (3), 26.4 (2), 26.7 (3), 58.8 (1), 62.9 (1), 63.4 (2),
82.9 (0), 102.2 (0), 163.1 (0), 166.9 (0), 172.9 (0). Anal. Calcd
for C24H45NO6Si2: C, 57.7; H, 9.1; N, 2.8. Found: C, 57.4; H,
9.2; N, 2.7.
1
2-chloropyridinium triflate: mp 162-164 °C; H NMR (CD3-
CN) δ 4.30 (s, 3H), 7.93-7.96 (m, 1H), 8.12-8.14 (m, 1H),
8.45-8.49 (m, 1H), 8.78-8.80 (m, 1H); 13C NMR (CD3CN) δ
48.7 (3), 126.6 (0), 123.8 (0), 127.4 (1), 131.0 (1), 148.4 (1), 149.1
(1). Anal. Calcd for C7H7C1F3NO3S: C, 30.3; H, 2.5; N, 5.0.
Found: C, 30.0; H, 2.5; N, 4.9.
(2R,3R)-6-Eth oxyca r bon ylm eth ylid en e-3-ter t-bu tyld i-
m eth ylsilyloxy-2-ter t-bu tyldim eth ylsilyloxym eth ylpiper i-
d in e (15). To a solution of enamine 14 (0.260 g, 0.52 mmol)
in 4 mL of absolute EtOH was added a freshly made solution
of sodium ethoxide (1 mL, 0.56 M in EtOH, 0.56 mmol). The
mixture was heated at reflux for 40 h, the solvent was
evaporated, the residue was diluted with 10 mL of H2O, and
the pH of the mixture was adjusted to 5 using 0.5 M HCl. The
(2R,3R,6R)-8-Oxo-3-ter t-b u t yld im et h ylsilyloxy-2-ter t-
bu tyld im eth ylsilyloxym eth yl-1-a za bicyclo[4.2.0]octa n e
(18). To a solution of 2-chloro-1-methylpyridinium triflate
(1.08 g, 3.90 mmol) in 230 mL of dry CH3CN was added N,N-

Synthesis of Carbacephems from Serine
J . Org. Chem., Vol. 63, No. 23, 1998 8179
diisopropylethylamine (2.0 mL, 1.48 g, 11.5 mmol), and the
colorless solution was heated at 65-70 °C as a solution of the
amino acid 17 (0.50 g, 1.2 mmol) in 230 mL of dry CH3CN
was slowly added via syringe pump over 4 h. After the
addition was complete, the slightly yellow solution was heated
at 65-70 °C for an additional 15 min and then was stirred at
room temperature for 12 h. The solution was diluted with 150
mL of CH2Cl2 and concentrated to 5% of its original volume.
An additional 200 mL of CH2Cl2 was added, and the solution
was concentrated to 10 mL and partitioned between 500 mL
of CH2Cl2 and 400 mL of H2O. The cloudy aqueous phase was
extracted with CH2Cl2 (4 × 120 mL), and the combined organic
layer was washed with brine (100 mL), dried, and evaporated
to a dark-red oil, which was chromatographed on a 7 cm × 15
cm plug of SiO2 using EtOAc/hexanes, 1/3, as an eluent to give
6.6; N, 3.6. Found: C, 56.4; H, 6.8; N, 3.5. Z isomer 23: 1H
NMR δ 1.36 (s, 6H), 1.45-1.54 (m, 1H), 1.59-1.68 (m, 1H),
2.53-2.72 (m, 2H), 3.19 (dd, J ) 10.1, 1.7 Hz, 1H), 3.34 (dd, J
) 12.1, 1.8 Hz, 1H), 3.70 (s, 3H), 3.83-3.86 (m, 2H), 5.30 (d,
J ) 10.1 Hz, 1H), 5.76 (d, J ) 11.5 Hz, 1H), 6.11 (dt, J ) 11.5,
3.9 Hz, 1H), 7.48-7.62 (m, 3H), 7.88-7.90 (m, 2H); 13C NMR
δ 18.4 (3), 24.5 (2), 29.5 (3), 31.0 (2), 50.1 (1), 51.0 (3), 64.2 (2),
71.0 (1), 99.3 (0), 119.7 (1), 126.8 (1), 129.1 (1), 132.6 (1), 141.3
(0), 149.5 (1), 166.7 (0).
(2R,3R,6R)-6-(Met h oxylca r b on ylet h yl)-3-h yd r oxy-2-
h yd r oxym et h yl-1-p h en ylsu lfon ylp ip er id in e Acet on id e
(24). To a solution of the amino ester 22 (0.993 g, 2.59 mmol)
in 67 mL of DME was added NaH (17 mg, 95%, as a powder,
0.71 mmol, 27 mol %). Using an air condenser, the reaction
mixture was heated at 50-55 °C for 2.5 days, then cooled to
0 °C, and 4 mL of saturated aqueous KH2PO4 was added. After
being stirred for 10 min, the mixture was concentrated, and
the aqueous residue was diluted with 60 mL of CH2Cl2 and
stirred with 1.5 g of anhydrous Na2SO4 for 15 min, filtered
through a fritted glass disk, and evaporated to an orange oil.
Chromatography (SiO2, 82 g, 3 cm × 4 cm plug) using EtOAc/
hexanes, 1/3, as an eluent afforded the cyclized product 24 as
a single diastereomer (0.63 g, 64%) as well as unreacted 22
(0.230 g, 23%). Resubjection of the recovered amino ester 22
to the above conditions gave an additional amount of the
cyclized product 24 (110 mg, 11%) as well as unreacted 22 (93
the â-lactam 18 (433 mg, 90%): mp 58-59 °C; [R]22 -1.5 (c
D
1, CHCl3); 1H NMR δ 0.02-0.1 (m, 12H), 0.88 (s, 9H), 0.91 (s,
9H), 1.48-1.55 (m, 1H), 1.68-1.94 (m, 3H), 2.49 (dd, J ) 14.3,
1.6 Hz, 1H), 2.98-3.03 (m, 2H), 3.25-3.28 (m, 1H), 4.0-4.02
(m, 1H), 4.1-4.19 (m, 2H); 13C NMR δ -5.4 (3), -5.2 (3), -5.1
(3), -4.5 (3), 18.0 (0), 18.1 (0), 23.6 (2), 25.7 (3), 25.9 (3), 30.0
(2), 44.0 (2), 46.5 (1), 59.0 (2), 62.6 (1), 63.4 (1), 166.3 (0). Anal.
Calcd for C20H41NO3Si2: C, 60.1; H, 10.3; N, 3.5. Found: C,
60.1; H, 10.7; N, 3.5.
(4R,5R,E/Z)-5-[(P h en ylsu lfon yl)a m in o]-4-(m eth oxyca r -
bon yl-3-bu ten yl)-2,2-d im eth yl-1,3-d ioxa n e (22/23). To 180
mL of CH2Cl2 was added fresh Dess-Martin reagent (13.6 g,
32.0 mmol) followed, after 5 min of stirring, by pyridine (4.92
mL, 61.4 mmol) and, after 5 min of stirring, a solution of
alcohol 7a (10.0 g, 30.4 mmol) in 40 mL of CH2Cl2; the cloudy
mixture was stirred at room temperature for 2 h. After the
addition of 90 mL of EtOH, the mixture was evaporated to a
white residue. To this residue was added 500 mL of Et2O and
400 mL of a 1/1 solution of 10% aqueous Na2S2O3‚5H2O (w/w)
and saturated aqueous NaHCO3, and the organic phase was
washed with H2O (100 mL). The combined aqueous phase was
stirred with Et2O (400 mL), the aqueous layer was extracted
with Et2O (2 × 200 mL), and the combined organic phase was
washed with H2O (2 × 200 mL) and brine (200 mL), dried,
and evaporated (bath at room temperature) to afford aldehyde
19 as a colorless, thick oil after 2 h under high vacuum (10.3
g): 1H NMR δ 1.35 (s, 6H), 1.54-1.72 (m, 1H), 1.83-2.06 (m,
1H), 2.38-2.50 (m, 1H), 3.15 (dd, J ) 12.2, 1.9 Hz, 1H), 3.30
(dd, J ) 10.2, 1.8 Hz, 1H), 3.80-3.98 (m, 3H), 5.29 (d, J )
10.2 Hz, 1H), 7.50-7.63 (m, 3H), 7.88-7.98 (m, 2H), 9.68 (t, J
) 1.5 Hz, 1H); 13C NMR δ 18.4 (3), 24.6 (2), 29.4 (3), 39.1 (3),
39.1 (2), 50.1 (1), 64.1 (2), 70.3 (1), 99.4 (0), 126.8 (1), 129.3
(1), 132.8 (1), 201.7 (0).
Crude aldehyde 19 (10.3 g), as a solution in 180 mL of THF,
was added to a pre-formed mixture of the potassium trimeth-
ylphosphonoacetate [prepared by the addition of trimethyl
phosphonoacetate (10.0 mL, 61.8 mmol) to a -78 °C solution
of KHMDS (67.0 mL, 0.92 M in toluene, 61.6 mmol) in 180
mL of THF, followed by stirring at -78 °C for 15 min, then at
0 °C for 6 h, then cooling to -78 °C] over 30 min followed by
stirring at -78 °C for 3 h. The reaction mixture was then
slowly warmed to 0 °C over 2 h and stirred at 0 °C for 12 h,
followed by addition at 0 °C of 140 mL of saturated aqueous
KH2PO4 and 200 mL of brine. After 15 min at 0 °C, organic
volatile components were evaporated and 500 mL of EtOAc
was added to the remaining aqueous layer. The aqueous phase
was extracted with EtOAc (3 × 150 mL), and the combined
organic phase was dried and evaporated to an orange oil.
Chromatography using EtOAc/hexanes, 2/3 then 1/1, as an
eluent afforded an 11/1 mixture of the E isomer 22 and the Z
mg, 9%). The total yield of 24 was 75%: mp 104-105 °C; [R]22
D
+19.6 (c 1, CHCl3); 1H NMR δ 0.56-0.63 (m, 1H), 1.34 (s, 3H),
1.37 (s, 3H), 1.51-1.61 (m, 2H), 1.82-1.88 (m, 1H), 2.70-2.76
(m, 1H), 2.97-3.02 (m, 1H), 3.70-3.74 (m, 4H), 3.84-3.88 (m,
1H), 4.02-4.07 (m, 2H), 4.26-4.31 (m, 1H), 7.52-7,62 (m, 3H),
7.83-7.86 (m, 2H); 13C NMR δ 21.6 (2), 23.1 (3), 24.1 (2), 25.9
(3), 44.2 (2), 29.5 (3), 44.2 (2), 29.5 (1), 51.7 (3), 51.9 (1), 62.5
(2), 63.2 (1), 99.5 (0), 126.9 (1), 129.3 (1), 1.32.8 (1), 139.6 (0),
171.3 (0), 171.3 (0). Anal. Calcd for C18H25NO6S: C, 56.4; H,
6.6; N, 3.6. Found: C, 56.7; H, 6.6; N, 3.6.
(2R,3R,6R)-6-Meth oxyca r bon yleth yl)-3-h yd r oxy-2-h y-
d r oxym eth yl-1-p h en ylsu lfon ylp ip er id in e Aceton id e (24).
24 also was prepared from the Z isomer. To a solution of
Z-amino ester 23 (27 mg, 0.07 mmol) in 2.0 mL of dry DME
was added NaH (∼1 mg, 95%, as a powder). The reaction
mixture was stirred at room temperature for 6 days, and then
0.5 mL of saturated aqueous KH2PO4 was added. The mixture
was evaporated, to the white residue was added 10 mL of CH2-
Cl2 and 1 g of solid Na2SO4, the mixture was filtered through
a small plug of MgSO4 using 20 mL of CH2Cl2 as an eluent,
and the filtrate was evaporated. Preparative TLC (SiO2, 250
µm) using EtOAc/hexanes, 1/3, as an eluent gave the cyclized
product 24 (13 mg, 48%) and recovered 23 (8 mg, 30%). The
yield of 24 based on recovered starting material was 68%.
Spectral data (1H NMR, 13C NMR) for the product obtained
from Z isomer 23 were identical to those for the product
obtained from E isomer 22. Alternatively, a mixture of E/ Z
isomers 22 and 23 was subjected to the process described for
the preparation of acetonide 24 from pure E-22, giving 24 in
75% yield.
(2R,3R,6R)-6-Met h oxyca r b on ylm et h yl-3-ter t-b u t yld i-
m et h ylsilyloxy-2-b u t yld im et h ylsilyloxym et h yl-1-p h en -
ylsu lfon ylp ip er id in e (25). To a solution of ester 24 (0.425
g, 1.11 mmol) in 35 mL of MeOH was added concd HCl (0.15
mL). The mixture was stirred at room temperature for 14 h
then evaporated, and 5 mL of MeOH was added and evapo-
rated. This addition/evaporation process was repeated once
with MeOH (5 mL) and twice with benzene (5 mL). The
residual oil was dissolved in 25 mL of CH2Cl2 and cooled to
-10 °C, and 2,6-lutidine (0.60 mL, 5.15 mmol) was added,
followed by tert-butyldimethylsilyl trifluoromethanesulfonate
(0.65 mL, 2.83 mmol). The reaction mixture was stirred at
-10 °C for 2 h, 30 mL of 1/1 EtOAc/H2O was added, the
mixture was allowed to reach room temperature and then
extracted with CH2Cl2 (2 × 15 mL) and the combined organic
layer was washed with pH 4 phosphate buffer (2 × 15 mL)
and brine (15 mL), dried, and evaporated. Chromatography
(SiO2, 66 g) of the residue using EtOAc/hexanes, 1/4, as an
eluent gave ester 25 as an oil (0.62 g, 97%): [R]23D -6.9 (c 1.3,
isomer 23 (9.55 g, 82% from 7a ). E isomer 22: bp 180 °C/1.2
1
Torr; mp 82-84 °C; [R]24 -2.1 (c 1, CHCl3); H NMR δ 1.37
D
(s, 6H), 1.40-1.52 (m, 1H), 1.65-1.74 (m, 1H), 2.09-2.24 (m,
2H), 3.12 (dd, J ) 10.1, 1.8 Hz, 1H), 3.36 (dd, J ) 12.1, 1.8
Hz, 1H), 3.73 (s, 3H), 3.79-3.91 (m, 2H), 5.33 (d, J ) 10.1 Hz,
1H), 5.74 (dt, J ) 15.7, 1.5 Hz, 1H), 6.86 (dt, J ) 15.7, 7.0 Hz,
1H), 7.49-7.60 (m, 3H), 7.87-7.89 (m, 2H); 13C NMR δ 18.4
(3), 27.2 (2), 29.5 (3), 30.0 (2), 50.2 (1), 51.4 (3), 64.2 (2), 70.3
(1), 99.3 (0), 121.4 (1), 126.8 (1), 129.2 (1), 132.7 (1), 141.2 (0),
148.3 (1), 166.9 (0). Anal. Calcd for C18H25NO6S: C, 56.4; H,

8180 J . Org. Chem., Vol. 63, No. 23, 1998
Folmer et al.
1
CHCl3); H NMR δ 0.001-0.1 (m, 12H), 0.86 (s, 9H), 0.92 (s,
The combined organic phase was evaporated to a white solid,
to which was added 20 mL of benzene, and the solvent was
evaporated again, affording amino acid 28 (0.119 g, 98%),
sufficiently pure to be used in the next step: mp 55-57 °C
9H), 1.30-1.50 (m, 2H), 1.51-1.60 (m, 1H), 1.70-1.90 (m, 3H),
2.75 (dd, J ) 16.2, 3.5 Hz, 1H), 2.85-3.0(m, 1H), 3.45-3.59
(m, 1H), 3.65 (s, 3H), 3.85-3.95 (m, 2H), 4.05-4.15 (m, 1H),
4.25-4.37 (m, 1H), 7.40-7.60 (m, 3H), 7.80-7.90 (m, 2H); 13
C
(dec); H NMR (MeOH-d4) δ 1.46 (s, 3H), 1.51 (s, 3H), 1.70-
1
NMR δ -5.6 (3), -5.5 (3), -5.2 (3), -4.9 (3), 17.9 (0), 18.3 (0),
24.8 (2), 25.6 (3), 25.9 (3), 26.5 (2), 38.8 (2), 47.5 (1), 51.5 (3),
57.7 (1), 61.5 (2), 68.9 (1), 126.8 (1), 128.9 (1), 132.2 (1), 141.1
(0), 171.8 (0). Anal. Calcd for C27H49NO6Si2S: C, 56.7; H, 8.6;
N, 2.5. Found: C, 56.9; H, 8.7; N, 2.5.
1.96 (m, 4H), 2.61-2.73 (m, 2H), 3.24-3.25 (m, 1H), 3.46-
3.52 (m, 1H), 3.83-3.87 (m, 1H), 4.28-4.34 (m, 2H); 13C NMR
(MeOH-d4) δ 18.9 (3), 23.4 (2), 28.7 (2), 29.4 (3), 38.2 (2), 53.3
(1), 55.1 (1), 62.2 (2), 64.1 (1), 101.1 (0), 175.6 (0).
(2R ,3R ,6R )-8-O x o -3-h y d r o x y -2-h y d r o x y m e t h y l-1-
a za bicyclo[4.2.0]octa n e Aceton id e (29). To 2-chloro-1-
methylpyridinium iodide (0.17 g, 0.66 mmol, 372 mol %) was
added 30 mL of CH3CN and Et3N (0.21 mL, 0.152 g, 1.50 mmol,
838 mol %). The resulting yellow solution was heated at 70-
73 °C (oil bath), and to this was slowly added a solution of 28
(41 mg, 0.18 mmol) in 17 mL of CH3CN over the course of 11
h. The deep-red reaction mixture was cooled to room temper-
ature and stirred for an additional 14 h, whereupon the solvent
was evaporated, leaving a reddish residue. The residue was
diluted with 50 mL of EtOAc, filtered through a cotton plug,
concentrated under reduced pressure, and applied directly to
a 1 × 15 cm plug of SiO2. Elution with EtOAc/hexanes, 1/1,
afforded â-lactam 29 as a yellowish oil, which solidified upon
(2R,3R,6R)-6-Met h oxyca r b on ylm et h yl-3-ter t-b u t yld i-
methylsilyloxy-2-(tert-butyldimethylsilyloxymethyl)piperi-
d in e (26). The ester 25 (2.60 g, 4.55 mmol) was electrolyzed
at -1.73 V [in 200 mL of 0.1 M TEAB in CH3CN containing
4-phenylphenol (2.02 g, 11.9 mmol)] for 26 h as described for
the formation of amino ester 27 (see below). The isolated
residue was chromatographed (SiO2, 150 g) using CH2Cl2
followed by 4% MeOH/CH2Cl2 as an eluent to give the amino
ester 26 as an oil (1.69 g, 86%): 1H NMR δ 0.005-0.015 (m,
12H), 0.84 (s, 9H), 0.86 (s, 9H), 1.35-1.60 (m, 3H), 1.70-1.85
(m, 1H), 2.25-2.47 (m, 2H), 2.55-2.65 (m, 1H), 2.85-3.0 (m,
1H), 3.35-3.50 (m, 2H), 3.62 (s, 3H), 3.84 (bs, 1H); 13C NMR
δ -5.6 (3), -5.5 (3), -5.2 (3), -4.9 (3), 18.0 (0), 18.1 (0), 25.8
(3), 26.6 (2), 32.0 (2), 41.6 (2), 51.4 (3), 53.2 (1), 61.8 (1), 63.6
(2), 63.8 (1), 172.4 (0). This material was used directly for the
preparation of 17.
(2R,3R,6R)-6-Met h oxyca r b on ylm et h yl-3-ter t-b u t yld i-
methylsilyloxy-2-(tert-butyldimethylsilyloxymethyl)piperi-
d in e (17). 17 was prepared from a solution of ester 26 (105
mg, 0.24 mmol) in 7 mL of 4/1 MeOH/H2O at 0 °C, to which
was added LiOH‚H2O (60 mg, 1.43 mmol, 595 mol %). The
mixture was warmed to room temperature and stirred for 12
h, and the pH was adjusted to 7.0 using 0.5 M aqueous H3-
PO4. The reaction mixture was extracted with IPA/CHCl3, 1/4
(4 × 10 mL), and the combined organic phase was dried and
evaporated to give the amino acid 17 as a white solid (99 mg,
99%). The analytical data for this product were identical to
those for amino acid 17 obtained from the lactim ether route
(cf 15 f 17, Scheme 2).
(2R,3R,6R)-6-(Met h oxyca r b on ylm et h yl)-3-h yd r oxy-2-
h yd r oxym eth ylp ip er id in e Aceton id e (27). By use of a 250
mL capacity H-cell fitted with a Pt foil anode, a 3 mm deep
Hg pool cathode, and a Ag wire reference electrode, the amino
ester 24 (0.400 g, 1.04 mmol) was electrolyzed at 1.73 V in
180 mL of a 0.12 M solution of TEAB in CH3CN containing
4-phenylphenol (0.444 g, 2.61 mmol, 250 mol %) for 12.7 h,
during which time the current flowing through the cell dropped
from an initial 14 mA to 0.8 mA. The contents of the cathode
chamber were decanted from the Hg, the Hg was washed with
CH2Cl2 (3 × 30 mL), and this wash was combined with the
cathode solution, which was then evaporated (at or slightly
below room temperature) to a grayish solid residue. This
residue was dissolved in 350 mL of CH2Cl2, which was washed
with cold 0.1 M KOH (3 × 100 mL, then 1 × 30 mL) and brine
(150 mL). The organic phase was dried and evaporated to a
residue (400 mg of a yellow-white solid), which was chromato-
graphed (90/1, w/w) using 3% MeOH/CH2Cl2 as an eluent to
standing (20 mg, 53%): mp 122-125 °C; [R]22 +19.8 (c 0.55,
D
CHCl3); 1H NMR δ 1.43 (s, 3H), 1.46 (s, 3H), 1.51-1.59 (m,
1H), 1.70-1.79 (m, 2H), 1.94-2.00 (m, 1H), 2.69 (dd, J ) 14.4,
2.0 Hz, 1H), 2.98-3.03 (m, 1H), 3.05-3/06 (m, 1H), 3.27-3.33
(m, 1H), 3.94-3.96 (m, 1H), 4.05 (dd, J ) 12.7, 3.4 Hz, 1H),
4.67 (dd, J ) 12.7, 1.6 Hz, 1H): 13C NMR δ 19.0 (3), 23.4 (2),
27.8 (2), 29.2 (3), 44.3 (2), 47.2 (1), 50.5 (1), 59.0 (2), 63.2 (1),
98.2 (0), 165.8 (0); FABMS, 212 (MH+). Anal. Calcd for
C
11H17NO3: C, 62.5; H, 8.1; N, 6.6. Found: C, 62.6; H, 8.1; N,
6.4.
(2R ,3R ,6R )-3-t er t -Bu t yld im e t h ylsilyloxy-2-(t er t -b u -
t yld im e t h ylsilyloxym e t h yl)-7-h yd r oxyim in o-8-oxo-1-
a za bicyclo[4.2.0]octa n e (30). To a solution of diisopropyl-
amine (26 µL, 19 mg, 0.19 mmol) in 3.5 mL of dry THF at
-78 °C was added n-BuLi (0.016 mL, 1.6 M in hexanes, 0.19
mmol). The solution was stirred at -78 °C for 35 min, a
solution of â-lactam 18 (57 mg, 0.14 mmol) in 1.2 mL of THF
was added dropwise, the resulting yellow solution was stirred
at -78 °C for 1 h, and isoamyl nitrite (25 µL, 22 mg, 0.19
mmol) was added. The reaction mixture was stirred at -78
°C for 4 h, 1 mL of saturated aqueous KH2PO4 and 3.5 mL of
brine were added, the cooling bath was removed, and the
mixture was warmed to room temperature. After dilution with
15 mL of EtOAc, the aqueous layer was extracted with EtOAc
(3 × 7 mL) and the combined organic layer was washed with
5 mL of brine, dried, and evaporated to an oil. Chromatog-
raphy (1 cm × 9.5 cm plug of SiO2) using EtOAc/ hexanes, 1/3,
as an eluent afforded the oxime 30 as a mixture of isomers
(20 mg, 33%).
(2R ,3R ,6R ,7S )-7-(t er t -Bu t yloxyc a r b on yl)a m in o]-3-
ter t-bu tyld im eth ylsilyloxy-2-(ter t-bu tyld im eth ylsilyloxy-
m eth yl)-8-oxo-1-a za bicyclo[4.2.0]octa n e (31). To a solu-
tion of oxime 30 (20 mg, 0.047 mmol) in 5 mL of EtOAc was
added 1 mg of PtO2 followed by di-tert-butyl dicarbonate (30
mg, 0.14 mmol). The mixture was stirred vigorously under
an atmosphere of H2 (balloon) for 4 h and filtered through
Celite using an additional 15 mL of EtOAc, and the resultant
filtrate was evaporated to an oil. Chromatography (SiO2,
EtOAc/hexanes, 1/3, as an eluent) gave carbamate 31 as an
oil (18 mg, 76%): [R]22D +4.2 (c 0.9, CHCl3); 1H NMR δ 0.055-
0.087 (m, 12H), 0.88 (s, 9H), 0.92 (s, 9H), 1.44 (s, 9H), 1.57-
1.60 (m, 1H), 1.64-1.82 (m, 1H), 1.90-2.01 (m, 1H), 2.96-
3.02 (m, 1H), 3.49-3.52 (m, 1H), 3.96-4.08 (m, 4H), 4.78-
4.88 (m, 1H), 4.92-4.95 (m, 1H); 13C NMR δ -5.4 (3), -5.3
(3), -5.1 (3), -4.5 (3), 17.3 (2), 18.1 (0), 18.2 (0), 25.8 (3), 28.2
(3), 29.3 (2), 53.0 (1), 59.2 (2), 59.3 (1), 62.2 (1), 63.8 (1), 80.2
(0), 155.2 (0), 166.1 (0). Anal. Calcd for C25H50N2O5Si2: C,
58.3; H, 9.8; N, 5.4. Found: C, 58.2; H, 9.8; N, 5.1.
give amino ester 27 as a clear, colorless oil (0.220 g, 87%):
1
[R]22 -1.3 (c 1, CHCl3); H NMR δ 1.43 (s, 3H), 1.45 (s, 3H),
D
1.63-1.72 (m, 1H), 1.87-1.93 (m, 1H), 2.07 (bs, 2H), 2.40-
2.52 (m, 3H), 2.99-3.06 (m, 1H), 3.69-3.75 (m, 4H), 3.87-
3.91 (m, 1H), 4.08-4.12 (m, 1H); 13C NMR δ 18.6 (3), 25.7 (2),
29.8 (3), 29.8 (2), 41.5 (2), 51.5 (3), 51.8 (1), 63.8 (1), 64.9 (2),
98.4 (0), 172.4 (0). Anal. Calcd for C12H21NO4: C, 59.2; H,
8.7; N, 5.8. Found: C, 59.1; H, 8.8; N, 5.7.
(2R,3R,6R)-6-(Ca r b oxym et h yl)-3-h yd r oxy-2-h yd r oxy-
m eth ylp ip er id in e Aceton id e (28). To a solution of amino
ester 27 (0.130 g, 0.53 mmol) in 4 mL of 10/1 MeOH/H2O at 0
°C was added LiOH‚H2O (48 mg, 1.14 mmol, 214 mol %). The
mixture was stirred at 0 °C for 20 min, warmed to room
temperature, and stirred for an additional 15 h, then diluted
with H2O (7 mL) and Et2O (5 mL). The aqueous layer was
acidified to pH 6.2 with 0.4 M H3PO4, extracted with 1/4 IPA/
CHCl3 (4 × 5 mL), stirred with 1 g of NaCl and 10 mL of 1/4
IPA/CHCl3 for 12 h, and then filtered through a cotton plug.
(2R,3R,6R,7R)-3-ter t-Bu tyld im eth ylsilyloxy-2-(ter t-bu -
t yld im et h ylsilyloxym et h yl)-7-et h yl-8-oxo-1-a za b icyclo-
[4.2.0]octa n e (32) a n d Dia ster eom er (2R,3R,6R,7S)-33. To
a -78 °C solution of diisopropylamine (0.195 mL, 0.141 g, 1.39

Synthesis of Carbacephems from Serine
J . Org. Chem., Vol. 63, No. 23, 1998 8181
mmol) in 10 mL of THF was slowly added a solution of n-BuLi
(0.867 mL, 1.6 M in hexanes, 1.39 mmol). After being stirred
at -78 °C for 1 h, a solution of â-lactam 18 (0.482 g, 1.21 mmol)
in 3 mL of dry THF was added over 5 min. The solution
gradually turned yellow and was stirred at -78 °C for 1 h,
followed by the addition of EtI (0.125 mL, 0.247 g, 1.56 mmol).
The reaction mixture was stirred at -78 °C for 3.5 h, 8 mL of
saturated aqueous KH2PO4 was added, and the mixture was
partitioned between 100 mL of EtOAc and 20 mL of brine. The
aqueous phase was extracted with EtOAc (4 × 30 mL), the
combined yellow organic phase was washed with saturated
aqueous Na2S2O3 (2 × 30 mL), and the resulting colorless
organic phase was washed with brine (60 mL), dried, and
evaporated to an oil. Chromatography over SiO2, using EtOAc/
hexanes, 1/9, as an eluent, afforded the ethylated â-lactams
mL of CH2Cl2 was added. The aqueous layer was extracted
with CH2Cl2 (4 × 15 mL), and the combined organic layer was
evaporated to a dark-gray residue, which was diluted with
Et2O (50 mL) and filtered through a plug of Celite. The Et2O
was evaporated, and the resulting residue was redissolved in
EtOAc (25 mL) and extracted with 5% Na2CO3 (6 × 15 mL).
The alkaline layer was acidified to pH 3.0 with concd H3PO4
and extracted with IPA/CHCl3, 1/3 (5 × 20 mL), and the
organic layer was dried and evaporated to provide 36 as a
1
colorless oil (110 mg); H NMR δ 0.005 (s, 3H), 0.014 (s, 3H),
0.819 (s, 9H), 0.982 (t, J ) 7.4 Hz, 3H), 1.55-1.91 (m, 6H),
2.82 (t, J ) 7.3 Hz, 1H), 3.17-3.21 (m, 1H), 3.95 (d, J ) 1.9
Hz, 1H), 4.35 (t, J ) 1.9 Hz, 1H); 13C NMR δ -5.6 (3), -4.8
(3), 11.2 (3), 17.7 (0), 21.4 (2), 22.4 (2), 25.5 (3), 29.4 (2), 54.7
(1), 57.6 (1), 66.3 (1), 67.4 (1), 168.4 (0), 173.4 (0). This material
was used in the next reaction without further purification.
(2S,3R,6R,7R)-2-Ca r b oxyl-7-et h yl-3-h yd r oxy-8-oxo-1-
a za bicyclo-[4.2.0]octa n e (39). To a solution of crude acid
36 (110 mg) in 8 mL of THF was added TBAF (0.505 mL, 1.0
M in THF, 150 mol %), the reaction was stirred at room
temperature for 18 h, saturated NaHCO3 solution (5 mL) was
added, and the THF was evaporated. The resulting solution
was diluted with 5% Na2CO3 (15 mL) and EtOAc (25 mL), and
the EtOAc layer was washed with 5% Na2CO3 (4 × 15 mL).
The combined alkaline layer was acidified at 0 °C to pH 2.5
with concd H3PO4 and extracted with IPA/CHCl3, 1/3 (5 × 15
mL), and the combined organic phase was dried and evapo-
32 and 33. 7R-Ethyl (32), slightly yellow oil (0.455 g, 88%):
1
[R]22 -8.8 (c 1.7, CHCl3); H NMR δ 0.056-0.084 (m, 12H),
D
0.88 (s, 9H), 0.90 (s, 9H), 0.98 (t, J ) 7.4 Hz, 3H), 1.45-1.93
(m, 6H), 2.62-2.66 (m, 1H), 2.96-3.00 (m, 2H), 4.00-4.01 (m,
1H), 4.10-4.18 (m, 2H); 13C NMR δ -5.4 (3), -5.2 (3), -5.1
(3), -4.5 (3), 11.7 (3), 18.0 (0), 18.1 (0), 21.8 (2), 23.1 (2), 25.7
(3), 25.9 (3), 36.0 (2), 52.9 (1), 58.9 (2), 59.3 (1), 62.3 (1), 63.3
(1), 169.1 (0). Anal. Calcd for C22H45NO3Si2: C, 61.8; H, 10.6;
N, 3.3. Found: C, 61.6; H, 10.7; N, 3.2. 7â-Ethyl (33), white
1
solid (40 mg, 7%): mp 90-92 °C; [R]24 -4.2 (c 1, CHCl3); H
D
NMR δ 0.056-0.083 (m, 12H), 0.88 (s, 9H), 0.91 (s, 9H), 0.97
(t, J ) 7.4 Hz, 3H), 1.41-1.66 (m, 3H), 1.71-1.78 (m, 1H),
1.93-1.99 (m, 2H), 2.97-3.02 (m, 2H), 3.35-3.41 (m, 1H),
3.98-3.99 (m, 1H), 4.08-4.18 (m, 2H); 13C NMR δ -5.3 (3),
-5.2 (3), -5.1 (3), -4.6 (3), 12.7 (3), 17.9 (2), 18.1 (0), 18.17
(0), 18.2 (2), 25.8 (3), 25.9 (3), 29.7 (2), 50.6 (1), 54.3 (1), 59.2
(2), 62.1 (1), 63.8 (1), 169.5 (0). Anal. Calcd for C22H45NO3-
Si2: C, 61.7; H, 10.6; N, 3.3. Found: C, 61.8; H, 10.4; N, 3.2.
(2R,3R,6R,7R)-3-ter t-Bu tyld im eth ylsilyloxy-7-eth yl-2-
h yd r oxym eth yl-8-oxo-1-a za bicyclo[4.2.0]octa n e (34). To
a solution of â-lactam 32 (455 mg, 1.06 mmol) in 15 mL of a
40/1 solution of THF/H2O was added p-TsOH (60 mg, 0.32
mmol). The reaction mixture was stirred at room temperature
for 37.5 h then partitioned between 15 mL of H2O and 75 mL
of Et2O. The aqueous layer was extracted with EtOAc (4 ×
20 mL), and the combined organic phase was washed with
brine (30 mL), dried, and evaporated to an oil. Chromatog-
raphy (SiO2, 3.5 cm × 10 cm plug), using EtOAc/hexanes, 1/3,
1
rated to provide 39 as a colorless oil (80 mg); H NMR δ 1.04
(t, J ) 7.4 Hz, 3H), 1.60-1.66 (m, 2H), 1.69-1.81 (m, 1H),
1.82-1.87 (m, 2H), 2.11-2.18 (m, 1H), 2.95 (t, J ) 7.4 Hz, 1H),
3.19-3.26 (m, 2H), 4.05 (d, J ) 2.1 Hz, 1H), 4.42 (t, J ) 1.9
Hz, 1H); 13C NMR δ 11.3 (3), 21.3 (2), 22.1 (2), 28.6 (2), 55.1
(1), 57.6 (1), 64.2 (1), 65.4 (1), 169.4 (0), 172.7 (0). This material
was used in the next reaction without further purification.
(2S,3R,6R,7R)-2-(p-Nitr oben zyloxyca r bon yl)-7-eth yl-8-
oxo-3-h yd r oxy-1-a za bicyclo-[4.2.0]octa n e (40). To a solu-
tion of crude hydroxy acid 39 (80 mg) in 4 mL of DMF was
added N,N-diisopropylethylamine (0.160 mL, 119 mg, 0.919
mmol), followed by p-nitrobenzyl bromide (0.159 g, 0.734
mmol). The reaction mixture was stirred for 16 h at room
temperature and then suspended between EtOAc (30 mL) and
saturated NaHCO3 (30 mL). The aqueous layer was extracted
with EtOAc (4 × 20 mL), and the combined organic layer was
washed with 0.1 M H3PO4 (2 × 20 mL) and brine (3 × 20 mL),
dried, and evaporated to an orange oil. Chromatography of
the residue on SiO2 using EtOAc/hexanes, 3/2, as an eluent
afforded ester 40 as a yellow solid (80 mg, 63% from 34): mp
as an eluent gave the monodeprotected â-lactam 34 as an oil
1
(320 mg, 96%): [R]22 +52.8 (c 1 CHCl3); H NMR δ 0.039-
D
0.044 (m, 6H), 0.89 (s, 9H), 1.00 (t, J ) 7.4 Hz, 3H), 1.50-
1.92 (m, 6H), 2.83-2.87 (m, 1H), 3.06-3.11 (m, 1H), 3.23-
3.27 (m, 1H), 3.53-3.60 (m, 1H), 3.82-3.83 (m, 1H), 4.15-
4.21 (m, 1H), 4.29-4.33 (m, 1H); 13C NMR δ -5.1 (3), -4.5
(3), 11.6 (3), 18.0 (0), 21.2 (2), 22.5 (2), 25.7 (3), 30.6 (2), 54.0
(1), 58.6 (1), 61.6 (1), 61.7 (2), 64.8 (1), 169.8 (0). Anal. Calcd
for C16H31NO3Si: C, 61.3; H, 10.0; N, 4.5. Found: C, 61.0; H,
10.2; N, 4.8.
113-114 °C; [R]22 +61.7 (c 1, CHCl3); 1H NMR δ 1.02 (t, J )
D
7.4 Hz, 3H), 1.67-2.01 (m, 4H), 2.10-2.15 (m, 1H), 2.84-2.89
(m, 1H), 3.18-3.22 (m, 1H), 3.71-3.72 (m, 1H), 3.80 (bs, 1H),
4.16 (bs, 1H), 5.35 (s, 2H), 7.60 (d, J ) 8.8 Hz, 2H), 8.22 (d, J
) 8.8 Hz, 2H); 13NMR δ 11.5 (3), 21.7 (2), 22.2 (2), 28.0 (2),
53.5 (1), 57.5 (1), 60.8 (1), 63.6 (1), 66.5 (2), 123.7 (1), 129.0
(1), 142.0 (0), 147.9 (0), 169.2 (0), 169.9 (0). Anal. Calcd for
(2R,3R,6R,7R)-7-Eth yl-3-h yd r oxy-2-h yd r oxym eth yl-8-
oxo-1-a za bicyclo[4.2.0]octa n e (35). To a solution of dipro-
tected lactam 32 (55 mg, 0.129 mmol) in 2 mL of THF was
added TBAF (0.283 mL, 1.0 M in THF, 220 mol %). The
solution was stirred at room temperature for 2 h and diluted
with EtOAc (25 mL) and saturated aqueous KH2PO4 (25 mL).
The aqueous layer was extracted with EtOAc (3 × 25 mL),
dried, and evaporated to a white residue. Chromatography
of the residue on SiO2 using EtOAc/hexanes, 2/1, as an eluent
afforded diol 35 as an opaque oil (25 mg, 98%): 1H NMR δ
1.03 (t, J ) 7.2 Hz, 3H), 1.51 (t, J ) 13.7 Hz, 1H), 1.67-2.03
(m, 5H), 2.81-2.85 (m, 1H), 2.99-3.01 (m, 1H), 3.14-3.18 (m,
1H), 3.99-4.08 (m, 2H), 4.19-4.24 (m, 1H), 4.40 (br s, 1H),
4.94 (dd, J ) 4.5, 10.6 Hz, 1H); 13C NMR δ 11.4 (3), 21.5 (2),
22.3 (2), 29.1 (2), 53.5 (1), 58.1 (1), 58.9 (1), 62.3 (2), 68.0 (1),
171.1 (0).
C
17H20N2O6: C, 58.6; H, 5.8; N, 8.0. Found: C, 58.4; H, 5.5;
N, 7.8.
(2S ,3R ,6R ,7R )-3-t er t -Bu t yld im e t h ylsilyloxy-2-(p -n i-
tr oben zyloxyca r bon yl)-7-eth yl-8-oxo-1-a za bicyclo[4.2.0]-
octa n e (37). To a solution of crude acid 36 (66 mg in 3 mL of
DMF) was added N,N-diisopropylethylamine (53 µL, 39 mg,
0.30 mmol), followed by p-nitrobenzyl bromide (65 mg, 0.30
mmol). The reaction mixture was stirred for 24 h at room
temperature then suspended between EtOAc (20 mL) and
saturated NaHCO3 (40 mL). The aqueous layer was extracted
with EtOAc (3 × 25 mL), and the combined organic layer was
washed with 0.2 M HCl (50 mL), dried, and evaporated to a
yellow oil. Chromatography on SiO2 using EtOAc/hexanes, 1/4,
as an eluent afforded ester 37 as an oil (84 mg, 79% from 34):
1
[R]22 +23.2 (c 1.4, CHCl3); H NMR δ 0.030 (s, 3H), 0.071 (s,
D
(2S,3R,6R,7R)-3-ter t-Bu tyld im eth ylsilyloxy-2-ca r boxyl-
7-eth yl-8-oxo-1-a za bicyclo[4.2.0]octa n e (36). To a solution
of monoprotected lactam 34 (115 mg, 0.367 mmol) in 4 mL of
a 2/2/3 mixture of CH3CN/CCl4/H2O was added NaIO4 (314 mg,
1.47 mmol), followed by RuCl3‚3H2O (2 mg). The tan mixture
was stirred vigorously at room temperature for 3 h, and 20
3H), 0.84 (s, 9H), 1.02 (t, J ) 7.4 Hz, 3H), 1.60-1.94 (m, 6H),
2.73-2.77 (m, 1H), 3.15-3.18 (m, 1H), 3.83 (d, J ) 2.3 Hz,
1H), 4.31-4.33 (m, 1H), 5.23 (d, J ) 13.4 Hz, 1H), 5.37 (d, J
) 13.4 Hz, 1H), 7.65 (d, J ) 8.7 Hz, 2H), 8.20 (d, J ) 8.7 Hz,
2H); 13C NMR δ -5.3 (3), -4.6 (3), 11.6 (3), 17.9 (0), 21.9 (2),
23.3 (2), 25.5 (3), 29.8 (2), 52.8 (1), 60.3 (1), 61.0 (1), 65.2 (1),

8182 J . Org. Chem., Vol. 63, No. 23, 1998
Folmer et al.
65.7 (2), 123.6 (1), 128.6 (1), 142.9 (0), 147.6 (0), 166.8 (0), 168.9
(0). Anal. Calcd for C23H34N2O6Si: C, 59.7; H, 7.4; N, 6.1.
Found: C, 59.6; H, 7.6; N, 5.8.
NaHCO3 (2 × 20 mL), dried, and evaporated to afford enol 41
as a crude yellow oil (60 mg): 1H NMR δ 1.05 (t, J ) 7.4 Hz,
3H), 1.72-1.91 (m, 2H), 2.02-2.13 (m, 1H), 2.38-2.51 (m, 1H),
2.69-2.72 (m, 2H), 2.89-2.93 (m, 1H), 3.72-3.76 (m, 1H), 5.29
(d, J ) 13.0 Hz, 1H), 5.47 (d, J ) 13.0 Hz, 1H), 7.51 (d, J )
8.7 Hz, 2H), 8.23 (d, J ) 8.7 Hz, 2H).
(6R,7R)-2-(p-Nitr oben zyloxyca r bon yl)-7-eth yl-8-oxo-1-
a za bicyclo[4.2.0]-2-octen e (38). To a solution of ester 37
(0.140 g, 0.30 mmol) in 10 mL of dry THF was added TBAF
(0.32 mL, 0.320 mmol). The colorless solution immediately
darkened and was stirred for 1 h at room temperature then
cooled to 0 °C, and H2O (2 mL) and Et2O (40 mL) were added.
The mixture was warmed to room temperature, H2O (5 mL)
was added, the aqueous phase was extracted with EtOAc (4
× 10 mL), and the combined organic phase was washed with
H2O (2 × 10 mL) and brine (10 mL), dried, and evaporated.
Chromatography on SiO2 (3 cm × 12 cm) using EtOAc/hexanes,
1/3 then 1/1, gave the olefin 38 as a solid (89 mg, 89%): mp
Crude enol 41 (60 mg) was dissolved in CH2Cl2 (4.0 mL),
the solution was cooled to -40 °C in a dry ice/CH3CN bath,
and to this solution was added N,N-diisopropylethylamine (44
µL, 32.6 mg, 0.25 mmol) followed by triflic anhydride (39 µL,
65.4 mg, 0.232 mmol). The reaction mixture turned yellow
and was stirred at -40 °C for 20 min. Aqueous saturated
NaHCO3 (15 mL) was added, the solution was allowed to warm
to room temperature, it was extracted with CH2Cl2 (4 × 20
mL), and the combined organic layer was washed with 0.1 M
HCl (2 × 20 mL) and brine (20 mL). Drying and evaporating
gave an orange oil, which was chromatographed on SiO2 using
hexanes/EtOAc, 3/1, as an eluent to give enol triflate 42 as a
1
83-86 °C; H NMR δ 1.07 (t, J ) 7.4 Hz, 3H), 1.46-1.50 (m,
1H), 1.79-1.95 (m, 2H), 2.26-2.33 (m, 2H), 2.33-2.45 (m, 1H),
2.83-2.87 (m, 1H), 3.28-3.31 (m, 1H), 5.29-5.45 (m, 2H),
6.38-6.40 (m, 1H), 7.64 (d, J ) 8.9 Hz, 2H), 8.23 (d, J ) 8.9
Hz, 2H); 13C NMR δ 11.6 (3), 21.7 (2), 22.8 (2), 25.4 (2), 52.0
(1), 59.6 (1), 65.6 (2), 123.3 (1), 123.7 (1), 127.9 (1), 128.4 (0),
142.9 (0), 161.7 (0), 167.5 (0).
yellow oil (40 mg, 73% from 40): [R]22 +20.1 (c 1, CHCl3); 1H
D
NMR δ 1.06 (t, J ) 7.4 Hz, 3H), 1.71-1.96 (m, 3H), 2.35-2.41
(m, 1H), 2.62-2.65 (m, 2H), 2.88-2.93 (m, 2H), 3.42-3.46 (m,
1H), 5.36 (d, J ) 13.2 Hz, 1H), 5.47 (d, J ) 13.2 Hz, 1H), 7.62
(d, J ) 8.5 Hz, 2H), 8.23 (d, J ) 8.6 Hz, 2H); 13C NMR δ 11.5
(3), 21.7 (2), 26.0 (2), 26.6 (2), 52.1 (1), 58.9 (1), 66.6 (2), 120.0
(q, J ) 318.4 Hz), 122.8 (0), 123.8 (1), 142.0 (0), 142.4 (0), 148.0
(0), 159.1 (0), 168.2 (0). Anal. Calcd for C18H17F3N2O8S: C,
45.2; H, 3.6; N, 5.9. Found: C, 45.0; H, 3.3; N, 5.5.
(6R,7R)-2-(p-Nitr oben zyloxyca r bon yl)-7-eth yl-8-oxo-3-
t r iflu o r o m e t h a n e s u lfo n y lo x y -1-a za b ic y c lo [4.2.0]-2-
octen e (p-Nitr oben zyl 7r-Eth yl-3-tr iflu or om eth a n esu l-
fon yloxy-1-ca r ba -1-d eth ia -3-cep h em -4-ca r boxyla te) (42).
To a solution of hydroxy ester 40 (40 mg, 0.115 mmol) in CH2-
Cl2 (2.5 mL) was added solid Dess-Martin reagent (100 mg,
0.234 mmol). The reaction mixture was stirred for 3 h at room
temperature then suspended between CH2Cl2 (40 mL) and a
1/1 solution of 10% Na2S2O3 and saturated NaHCO3 (30 mL).
The layers were separated, the aqueous layer was extracted
with CH2Cl2 (4 × 10 mL), and the combined organic layer was
washed with a 1/1 solution of 10% Na2S2O3 and saturated
Ack n ow led gm en t. C.A. thanks the Direccio Gen-
eral de Recerca, Generalitat de Catalunya for fellowship
support.
J O980592S