Enantioselective synthesis of α-amino acids from N-tosyloxy β-lactams derived from β-keto esters

Article abstract of DOI:10.1021/jo0162437

A novel synthetic sequence has been developed to convert simple β-keto esters into enantiomerically enriched α-amino acids. The key features of this sequence include the addition of azide to the C3 position of β-keto ester derived N-tosyloxy-β-lactams through a concomitant nucleophilic addition/N-O bond reduction reaction, a mild CsF-induced N1 benzylation of α-azido monocyclic β-lactams, the preparation of α-keto-β-lactams through a novel four-step sequence from the corresponding 3-azido-1-benzyl-β-lactams, and TEMPO-mediated ring expansion of these compounds to the corresponding N-carboxy anhydrides (NCAs). In addition, the synthesis, isolation, and characterization of unusual 3-imino and 3-chloramino-β-lactams is reported.

Full text of DOI:10.1021/jo0162437

En a n tioselective Syn th esis of r-Am in o Acid s fr om N-Tosyloxy
â-La cta m s Der ived fr om â-Keto Ester s‡
Timothy B. Durham and Marvin J . Miller*
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame,
Notre Dame, Indiana 46556-5670
Marvin.J .Miller.2@nd.edu.
Received October 29, 2001
A novel synthetic sequence has been developed to convert simple â-keto esters into enantiomerically
enriched R-amino acids. The key features of this sequence include the addition of azide to the C3
position of â-keto ester derived N-tosyloxy-â-lactams through a concomitant nucleophilic addition/
N-O bond reduction reaction, a mild CsF-induced N1 benzylation of R-azido monocyclic â-lactams,
the preparation of R-keto-â-lactams through a novel four-step sequence from the corresponding
3-azido-1-benzyl-â-lactams, and TEMPO-mediated ring expansion of these compounds to the
corresponding N-carboxy anhydrides (NCAs). In addition, the synthesis, isolation, and characteriza-
tion of unusual 3-imino and 3-chloramino-â-lactams is reported.
In tr od u ction
N-tosyloxy â-lactams underwent an unusual nucleophilic
addition at the C3 carbon with concomitant N-O bond
reduction.19 This novel reaction allows ready access to
highly functionalized monocyclic â-lactams in a diaste-
reoselective fashion. While we have provided several
initial reports regarding the qualitative features20-23 and
some synthetic applications of this reaction,24 the full
potential of this method and the utility of the chiral
synthons available from it have not been fully realized.
The goal of this project was to further demonstrate the
synthetic utility of these two technologies as ways to
prepare highly functionalized heterocycles. We felt that
a good target class for such a methodology development
would be the preparation of R-keto â-lactams25 3 (Scheme
1) since these molecules are highly useful synthetic
intermediates for the construction of a number of classes
of molecules.26-30 We were especially interested in their
The use of â-lactams as chiral building blocks in
organic synthesis is now well established and routine.1,2
Additionally, â-lactams have played a key role in the fight
against pathogenic bacteria and the subsequent rise in
quality of life for the world population as a whole. Given
the importance of â-lactams, the need to construct highly
functionalized â-lactams in an asymmetric fashion is of
significance. Over 20 years ago, our group developed a
biomimetic synthesis of chiral N-hydroxy â-lactams from
the corresponding â-hydroxy hydroxamates.3,4 This tech-
nology has been used to prepare scores of biologically and
synthetically important molecules.5-18 Further, in the
early 1990s, our group found that under basic conditions
‡ Dedicated to the memory of Professor Henry Rapoport (November
16, 1918-March 6, 2002), University of CaliforniasBerkeley; a superb
scientist, teacher, mentor, and friend.
(1) Ojima, I. In The Organic Chemistry of â-Lactams; Georg, G. I.,
Ed.; VCH Publishers: New York, 1993; pp 197-255.
(2) Ojima, I. In Advances in Asymmetric Synthesis; J AI Press Inc.:
Greenwich, CT, 1995; Vol. 1, pp 95-146.
(16) Mourey, L.; Kotra, L. P.; Bellettini, J .; Bulychev, A.; O’Brien,
M.; Miller, M. J .; Mobashery, S.; Samama, J .-P. J . Biol. Chem. 1999,
274, 25260-25265.
(17) Sware´n, P.; Massova, I.; Bellettini, J . R.; Bulychev, A.; Mavey-
raud, L.; Kotra, L. P.; Miller, M. J .; Mobashery, S.; Samama, J .-P. J .
Am. Chem. Soc. 1999, 121, 5353-5359.
(3) Mattingly, P. G.; Kerwin, J . F., J r.; Miller, M. J . J . Am. Chem.
Soc. 1979, 101, 3983-3985.
(4) Miller, M. J .; Mattingly, P. G.; Morrison, M. A.; Kerwin, J . K.,
J r. J . Am. Chem. Soc. 1980, 102, 7026-7032.
(5) Mattingly, P. G.; Miller, M. J . J . Org. Chem. 1981, 46, 1557-
1563.
(18) Bulychev, A.; Bellettini, J . R.; O’Brien, M.; Crocker, P. J .;
Samama, J .-P.; Miller, M. J .; Mobashery, S. Tetrahedron 2000, 56,
5719-5728.
(19) Gasparski, C. M.; Teng, M.; Miller, M. J . J . Am. Chem. Soc.
1992, 114, 2741-2743.
(20) Teng, M.; Miller, M. J . J . Am. Chem. Soc. 1993, 115, 548-554.
(21) Guzzo, P. R.; Miller, M. J . Tetrahedron 1994, 50, 11091-11096.
(22) Bellettini, J . R.; Miller, M. J . J . Org. Chem. 1996, 61, 7959-
7962.
(23) Guzzo, P. R.; Miller, M. J . Adv. Nitrogen Heterocycles 1996, 2,
1-34.
(24) Guzzo, P. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4862-4867.
(25) For a discussion of various approaches to functionalize each
position of the 2-azetidinone ring, including other approaches to R-keto
â-lactams, see Wild, H. In The Organic Chemistry of â-Lactams; Georg,
G. I., Ed.; VCH Publishers: New York, 1993; pp 49-119.
(26) Palomo, C.; Arrieta, A.; Coss´ıo, F. P.; Aizpurua, J . M.; Mielgo,
A.; Aurrekoetxea, N. Tetrahedron Lett. 1990, 31, 6429-6432.
(27) Palomo, C.; Coss´ıo, F. P.; Cuevas, C.; Odriozola, J . M.; Ontoria,
J . M. Tetrahedron Lett. 1992, 33, 4827-4830.
(6) Miller, M. J .; Biswas, A.; Krook, M. A. Tetrahedron 1983, 39,
2571-2575.
(7) Biswas, A.; Miller, M. J .; Krook, M. A.; Woulfe, S. R. R. Soc.
Chem. Spec. Publ. 1984, 53, 305-317.
(8) Woulfe, S. R.; Miller, M. J . Tetrahedron Lett. 1984, 25, 3293-
3296.
(9) Krook, M. A.; Miller, M. J . J . Org. Chem. 1985, 50, 1126-1128.
(10) Miller, M. J . Acc. Chem. Res. 1986, 19, 49-55.
(11) Williams, M. A.; Hsiao, C.-N.; Miller, M. J . J . Org. Chem. 1991,
56, 2688-2694.
(12) Gasparski, C. M.; Ghosh, A.; Miller, M. J . J . Org. Chem. 1992,
57, 3546-3550.
(13) Lotz, B. T.; Miller, M. J . J . Org. Chem. 1993, 58, 618-625.
(14) Teng, M.; Gasparski, C. M.; Williams, M. A.; Miller, M. J .
Bioorg. Med. Chem. Lett. 1993, 3, 2431-2436.
(15) Teng, M.; Miller, M. J . Bioorg. Med. Chem. 1993, 1, 151-154.
10.1021/jo0162437 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/29/2002
J . Org. Chem. 2003, 68, 27-34
27

Durham and Miller
SCHEME 1
SCHEME 2
conversion to N-carboxy anhydrides 2 (NCAs, Scheme
1),31,32 since this would represent a novel amino acid
synthesis in which an umpolung occurs allowing the
formal addition of ammonia to the R-position of the
corresponding carboxylic acid. This report describes our
development of two independent routes to both the
targeted R-keto â-lactams and the derived NCAs in
enantiomerically enriched form as well as the synthesis
of novel C3 imino and chloramino monocyclic â-lactams.
Resu lts a n d Discu ssion
We envisioned the target NCAs as being prepared as
outlined retrosynthetically in Scheme 1. The major
synthetic challenges of this proposed strategy include the
transformation of nucleophilic addition product 4 to a
suitably N1 protected form (R3 ) H f R3 ) protecting
group) and subsequent elaboration to the R-keto â-lactam
3. The issue of N1 protection was of paramount impor-
tance since previous studies had shown that NCAs in
which the nitrogen lacks a sufficiently bulky protecting
group were prone to epimerization.33,34 Since a number
of ways to prepare â-keto esters from readily available
starting materials are known, and catalytic asymmetric
reductions of these esters to the corresponding â-hydroxy
esters is routine and substrate tolerant, this approach
should, in theory, allow access to almost any amino acid.
However, we recognized early in our synthetic planning
that the proposed sequence to the targeted NCAs was
relatively lengthy in comparison to other published routes
from Palomo and co-workers31,32 that relied on [2 + 2]
ketene-imine cycloaddition strategies. Regardless, we
felt that the proposed route was interesting not only for
its novel approach but also because it presented a number
of synthetic challenges, as mentioned above, and that
surmounting these synthetic obstacles would provide the
opportunity to develop new â-lactam chemistries and,
therefore, offered sufficient promise to warrant its in-
vestigation.
The first route to target NCA 2 began with N-tosyloxy
â-lactam 9 (Scheme 2) which is easily converted, using
the novel nucleophilic addition/N-O bond reduction
protocol, to C3 acetoxy â-lactam 10.20 Protection of the
N1 position followed by unmasking of the hydroxyl
functionality gave compound 11. Treatment of lactam 11
with buffered sodium hypochlorite and a catalytic amount
of TEMPO using the conditions developed by Palomo et
al.32 provided the desired NCA in moderate yield by
means of in situ oxidation to the R-keto â-lactam followed
by ring expansion. The labile nature of the TBDPS group
was hypothesized to be the agent of inefficiency in this
transformation. The identity of compound 12 was further
confirmed by hydrolysis and subsequent comparison with
commercially available alanine using o-phthaldehyde
(OPA) derivatization/HPLC analysis.35
Encouraged by this initial success, we wanted to test
the generality of this synthetic strategy, as well as
address the lability of our N1 protecting group by
preparing a more amenable model compound. One of the
major inconveniences of compound 9 and its progeny was
their highly polar nature, which complicated product
isolation. To address these concerns, model compound
18a was prepared from lauric acid in six steps (Scheme
3). However, addition of acetic acid to N-tosyloxy â-lactam
18a proceeded in low overall yield. Extensive efforts to
improve the efficiency of this reaction by addressing the
concentration and molar ratios of the reactants, the
source of acetate, use of other carboxylic acids, and
modification of the base proved unsuccessful.
(28) Palomo, C.; Aizpurua, J . M.; Miranda, J . I.; Mielgo, A.; Odrio-
zola, J . M. Tetrahedron Lett. 1993, 34, 6325-6328.
(29) Kant, J .; Schwartz, W. S.; Fairchild, C.; Gao, Q.; Huang, S.;
Long, B. H.; Kadow, J . F.; Langley, D. R.; Farina, V.; Vyas, D.
Tetrahedron Lett. 1996, 37, 6495-6498.
Previous studies from our group had shown that
carboxylic acids were the only oxygen nucleophiles with
reasonable synthetic utility in this transformation.20,21
Additionally, sulfur nucleophiles had been shown to have
low to moderate efficacy.20 Since the proposed synthetic
(30) Paquette, L. A.; Brand, S.; Behrens, C. J . Org. Chem. 1999,
64, 2010-2025.
(31) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Carreaux, F.; Cuevas,
C.; Maneiro, E.; Ontoria, J . M. J . Org. Chem. 1994, 59, 3123-3130.
(32) Palomo, C.; Aizpurua, J . M.; Cuevas, C.; Urchegui, R.; Linden,
A. J . Org. Chem. 1996, 61, 4400-4404.
(33) Romoff, T. T.; Goodman, M. J . Pept. Res. 1997, 49, 281-292.
(34) Sim, T. B.; Rapoport, H. J . Org. Chem. 1999, 64, 2532-2536.
(35) Hill, D. W.; Walters, F. H.; Wilson, T. D.; Stuart, J . D. Anal.
Chem. 1979, 51, 1338-41.
28 J . Org. Chem., Vol. 68, No. 1, 2003

Enantioselective Synthesis of R-Amino Acids
SCHEME 3
SCHEME 5
primary amino groups to ketones36 or invert the C3 amino
stereochemistry.37 However, these strategies have relied
upon the condensation of the primary amine with a
sacrificial aldehyde to first form an initial imine which
must then be isomerized to give the desired ketone
oxidation state at C3. It was anticipated that such a
sequence could be avoided by directly oxidizing the C3
position. Thus, this strategy required the use of an amine
nucleophile bearing no other oxidizable carbons to ensure
selectivity in the oxidation step.
In keeping with the aforementioned goals, N-tosyloxy
â-lactam 18a was treated with tert-butylamine according
to the protocol which this group had originally reported
for the functionalization of compound 9 (Scheme 5).22
Surprisingly, while in the case of N-tosyloxy â-lactam 9
the product was formed in high yields and conversions,
formation of â-lactam 19 was sluggish and resulted in a
low overall conversion with a significant amount of
starting material being recovered. While resubjection of
the recovered material to the reaction conditions allowed
accumulation of reasonable quantities of the amine over
several cycles, we sought to improve this transformation
to make it more synthetically useful. Since one current
mechanistic hypothesis of the N-tosyloxy â-lactam nu-
cleophilic addition/N-O bond reduction reaction invokes
an SN2′ mechanism in which the rate-limiting step is
enolization,20,38 we hypothesized that a buffering effect
by the tert-butylamine salt of the tosylate was responsible
for the inhibition. Further, we anticipated that addition
of a stronger amine base during the course of the reaction
should shift the equilibrium allowing higher conversion.
Gratifyingly, addition of DBU allowed complete consump-
tion of tosylate 18a , providing serviceable quantities of
compound 19.
SCHEME 4
sequence required that the nucleophilic addition product
be produced in high yield, other strategies to access the
targeted R-keto â-lactam demanded consideration. The
use of nitrogen nucleophiles in our synthetic plan rep-
resented an appealing alternative since both amines22
and azide20 had been shown to be highly efficient nu-
cleophiles in this reaction. Although such a strategy
would require an eventual heteroatom exchange with
oxygen, we felt that other benefits in the robustness and
substrate tolerance of this approach could adequately
compensate. Further, the opportunity existed using this
strategy to prepare some unusual â-lactams which might
be useful for the preparation of other synthetically and
biologically interesting molecules such as novel R,â-
diamino acids.
With â-lactam 19 in hand, a series of N1 protected
compounds was required in order to determine which
types of N1 protecting groups could be used in the
subsequent steps. In this regard, we were interested in
(36) Buckley, T. F.; Rapoport, H. J . Am. Chem. Soc. 1982, 104,
4446-4450.
(37) Aoki, T.; Haga, N.; Sendo, Y.; Konoike, T.; Yoshioke, M.; Nagata,
W. Tetrahedron Lett. 1985, 26, 339-342.
(38) For an alternative mechanistic hypothesis, see Hoffman, R. V.
In The Amide Linkage: Selected Structural Aspects in Chemistry,
Biochemistry, and Materials Science; Greenberg, A., Breneman, C. M.,
Liebman, J . F., Eds.; J ohn Wiley & Sons: New York, 2000; pp 137-
155.
Therefore, our newly revised synthetic plan involved
introducing a nitrogen substituent at C3 via the nucleo-
philic addition reaction followed by oxidation to the C3
imino compound and subsequent unmasking of the
ketone functionality (Scheme 4). Similar strategies have
been employed by other groups to either convert C3
J . Org. Chem, Vol. 68, No. 1, 2003 29

Durham and Miller
SCHEME 6
SCHEME 7
further investigating the possibility of using a silyl
protecting group, since we had had some initial success
with the TBDPS group (Scheme 2). Additionally, car-
bamate protecting groups have previously been shown
to be useful for the prevention of NCA epimerization.33
Further, the Palomo group has successfully used the
benzyl group for NCA protection and have shown that
this group can be removed from the amino acid products
via exposure to various hydrogenolysis conditions.31,32
Therefore, we targeted â-lactams 20a -d and 21 for
synthesis (Scheme 5). Treatment with n-BuLi followed
by quenching of the resulting anion allowed differentia-
tion of the amino and amide functionalities providing
access to a number of silyl and carbamate protected
compounds. Similarly, treatment of compound 19 with
NaH followed by BnBr provided the benzyl-protected
derivative.39
stable C3 imino â-lactams which could be adapted for the
preparation of a number of interesting species. Unfortu-
nately, the electron-withdrawing effect of the carbamate
With the preparation of N1-protected â-lactams 20a -d
and 21 accomplished, conditions were then investigated
to allow elaboration to the corresponding R-keto â-lac-
tams. As previously stated, we envisioned that the
exocyclic amine could be oxidized to the imine and then
hydrolyzed to the desired keto compound. To this end,
TBDMS protected lactam 20c was treated with tert-butyl
hypochlorite to give C3 chloramino â-lactam 22 which
was isolable by chromatography (Scheme 6). N-Acyl-
chloramines have been used as transient intermediates
for the introduction of alkoxy substituents at the C3
position of the azetidinone ring40-42 or to allow direct
substitution on the exocyclic nitrogen.43 However, to the
best of the authors’ knowledge, this represents the first
reported isolation and characterization of such an un-
usual C3 chloramino â-lactam compound. Base-induced
elimination provided the desired imine but attempts at
hydrolysis provided the desired keto compound sans
protecting group. Attempts at reinstallation of the pro-
tecting group proved futile.
caused lysis of the ring system under all conditions
attempted to effect hydrolysis of the imine to the corre-
sponding ketone. Surprisingly, when benzyl-protected
â-lactam 21 was oxidized, it was discovered that the
resulting imine was too stable to hydrolysis, and all
attempts instead resulted in the destruction of the
â-lactam ring. This stability is most likely due to the
steric bulk of the tert-butyl moiety. Recognizing the
importance of the electronically neutral benzyl moiety as
the most suitable protecting group choice, efforts were
directed at the preparation of a N1-benzyl-C3-imino
â-lactam which could be readily hydrolyzed. Such a target
required the use of an ammonia equivalent in the
nucleophilic addition reaction. In this regard, the use of
azide seemed appropriate.
Therefore, treatment of lauric acid derived N-tosyloxy
â-lactam 18a with TMSN3 in the presence of Hunig’s base
provided the trans-azide 26a in good yield (Scheme 7).
Extensive experimentation showed that while a number
of other conditions5,24,44-47 were either unsuccessful or
gave inconsistent results, CsF could be used to facilitate
the benzylation (eq 2) of this highly sensitive â-lactam
Focus then turned to oxidation of Boc-protected â-lac-
tam 20a (eq 1). Treatment with t-BuOCl followed by DBU
afforded the desired imine 25 as a mixture of stereoiso-
mers which was stable to chromatography (eq 1). This
sequence represents a synthetically useful approach to
(39) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.; Flack, K.;
Gibson, V. C.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A.; White,
A. J . P.; Williams, D. J . J . Org. Chem. 1998, 63, 7893-7907.
(40) Baldwin, J . E.; Urban, F. J .; Cooper, R. D. G.; J ose, F. L. J .
Am. Chem. Soc. 1973, 95, 2401-2403.
(44) Hirai, Y.; Kamide, I.; Yamazaki, T. Heterocycles 1981, 15, 1101-
(41) Firestone, R. A.; Christensen, B. G. J . Org. Chem. 1973, 38,
1436-1437.
1103.
(45) Yamawaki, J .; Ando, T.; Hanafusa, T. Chem. Lett. 1981, 1143-
1146.
(42) Cimarusti, C. M.; Applegate, H. E.; Chang, H. W.; Floyd, D.
M.; Koster, W. H.; Slusarchyk, W. A.; Young, M. G. J . Org. Chem. 1982,
47, 179-180.
(46) Takahashi, Y.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem.
Pharm. Bull. 1986, 34, 2732-2742.
(47) Storz, T.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1999, 82,
2380-2412.
(43) Micetich, R. G.; Singh, R.; Shaw, C. C. J . Org. Chem. 1986, 51,
1811-1815.
30 J . Org. Chem., Vol. 68, No. 1, 2003

Enantioselective Synthesis of R-Amino Acids
TABLE 1. Ben zyl P r otection of 3-Azid o â-La cta m 26a
entry
1b
base (equiv)
Cs2CO3 (1.2)
solvent
“R-X” (equiv)
yield, %a
CH3CN
BnBr (5.8)
BnBr (3.1)
BnBr (1.1)
BnBr (2.3)
BnBr (2.3)
BnBr (12)
BnBr
37
41
2
Cs2CO3 (1.1)
Cs2CO3 (1.3)
Cs2CO3 (1.3)
Cs2CO3 (1.3)
Ag2O (1.2)
Ag2O (1.2)
DEAD/PPh3
N/A
CsF (10.8)
KF-Al2O3
Et3NBnCl/NaOH
Ag2O (1.2)
CsF (10.2)
CsF (10.3)
DMF
DMF
55
3c
62
4
DMF/CH2Cl2 1:1
DMF (high dilution)
55
5
56
6d
7d
8
none
N/A
N/A
NRi
N/A
66
DMF
BnBr (2.2)
BnOH
THF
9e
CH2Cl2
PhCOH, Et3SiH
BnBr (2.6)
PMBCl (3)
PMBCl (13)
PMBCl (2.3)
PMBCl (3.5)
PMBCl (3)
10f
11g
12h
13d
14
15
DMF
CH3CN
27
1 M NaOH/CH2Cl2 1:2
CH3CN
19
22
DMF
36
DMF/3 Å mol sieves
31
a
b
Isolated yields. Our Group has previously shown that R-azido â-lactams can be alkylated with R-halo esters under these conditions
(see ref 24). c While the use of Cs2CO3 as the base gave comparable results in some cases to the CsF mediated reactions, we found the CsF
d
reaction gave more consistent results. See ref 46 for a related example using these conditions. In the case of entries 6 and 7, subjection
of compound 26a to these conditions resulted in low reactivity and the formation of multiple products. e Azide reduction was observed.
f The use of more than 10 equiv of CsF is necessary to induce complete consumption of â-lactam 26a and maximize the overall yield.g See
h
i
refs 45 and 47 for related examples using these conditions. See ref 5 for a related example using these conditions. NR ) no reaction
observed.
SCHEME 8
to provide benzyl derivative 27a (entry 10, Table 1).
â-Lactam 27a was then elaborated to the target R-keto
â-lactam 28a in a carefully designed four-step procedure
which could be carried out in a “single pot” (Scheme 7).
TEMPO-mediated ring expansion then provided the
desired NCA 29a (Scheme 7). The overall sequence from
N-tosyloxy â-lactam 18a consisted of seven steps and an
mers obtained from coupling with racemic NCAs 29a and
29d .49
overall yield for this sequence of 20%.
To further examine the scope of this method, C3 azido
â-lactams 27b-f were prepared from the corresponding
starting â-keto esters in an analogous manner and
subjected to the synthetic sequence just described
(Schemes 3 and 7). Gratifyingly, the four-step azide to
ketone conversion performed well not only for aryl and
cyclohexyl containing â-lactams 27c,d but was even more
effective with cyclopropane 27b. The main limitation we
have encountered is the preclusion of highly branched
substituents at C4 for the azide to ketone conversion to
be effective. Based on experimental observations, it
appears that in sterically demanding systems such as 27e
and 27f the intermediate chloramine undergoes alterna-
tive reactions to give ring-opened products upon workup.
With an effective sequence in hand, the enantioselec-
tivity of the method was tested by preparing enantio-
merically enriched â-hydroxy esters 31a ,b from â-keto
esters 14a ,b by way of reduction with (S)-RuBINAP
following Taber’s protocol (Scheme 8).48,24 Elaboration of
31a ,b to NCAs 32a ,b, and reaction with (S)-R-methyl-
benzylamine provided the corresponding amides showing
no noticeable stereochemical degradation as determined
Con clu sion
The concomitant nucleophilic addition/N-O bond re-
duction of N-tosyloxy â-lactams has been used to develop
a novel route to enantiomerically enriched R-keto â-lac-
tams which were subsequently converted to the corre-
sponding N-carboxy anhydrides. The key steps in this
process were a mild fluoride-mediated N1 benzylation of
(49) It is interesting to note that Palomo and co-workers have
reported that the condensation of ent-NCA 32b with 2 equiv of (S)-
leucine benzyl ester under several sets of conditions produced varying
mixtures of the corresponding diastereomers due to some epimerization
of the NCA during the reaction. The apparent difference in outcomes
for the results of the Palomo laboratories and our own in the
condensation of the two epimers of NCA 32b with branched amines is
not completely clear. However, it is possible that these differences could
be due to any of the following causes: (1) our use of 1.1 equiv of amine
as opposed to 2.0 equiv as in the report from the Palomo group, (2)
subtle differences in reactivity of (S)-R-methylbenzylamine and (S)-
leucine benzyl ester, (3) given that opposite enantiomers of 32b were
used, a matched vs a mismathced effect for the NCA and amine
nucleophile/base could have been the causative factor. These results
further reinforce the observations previously reported suggesting the
importance of the reaction conditions in the condensation NCAs with
amine nucleophiles (see refs 33 and 34 for more discussion and
examples). For the original report from the Palomo laboratories using
ent-NCA 32b, please see Palomo, C.; Oiarbide, M.; Landa, A.; Esnal,
A.; Linden, A. J . Org. Chem. 2001, 66, 4180-4186.
1
by H NMR comparison to the 1:1 mixture of diastereo-
(48) Taber, D. F.; Silverberg, L. J . Tetrahedron Lett. 1991, 32, 4227-
4230.
J . Org. Chem, Vol. 68, No. 1, 2003 31

Durham and Miller
The TBDPS-protected lactam (194 mg, 0.507 mmol) was
dissolved in MeOH (5 mL) and cooled to 0 °C with an ice bath.
To the cooled solution was added solid K2CO3 (10 mg). Upon
consumption of the starting material, the reaction mixture was
immediately filtered through a plug of silica and the solvent
evaporated. The residue was chromatographed (gradient of 4:1
to 3:1 hexanes/EtOAc), and compound 11 was isolated as a
white solid (134 mg, 78%). An analytical sample was obtained
by recrystallization from diethyl ether/hexanes as a ∼12:1
mixture of trans and cis isomers; mp ) 184.5-185.0 °C; 1H
NMR (CDCl3) δ 7.69 (m, 4H), 7.43 (m, 6H), 5.36 (d, J ) 5.40
Hz, 1H), 5.31 (d, J ) 6.60 Hz, 0.1H), 5.04 (dd, J ) 6.60 Hz, J
) 5.40 Hz, 0.1H), 4.52 (dd, J ) 5.10 Hz, J ) 2.10 Hz, 1H),
3.67 (dd, J ) 6.45 Hz, J ) 5.55 Hz, 0.1H), 3.59 (dq, J ) 6.30
Hz, J ) 2.10 Hz, 1H), 1.208 (s, 9H), 0.920 (d, J ) 6.60 Hz,
0.1H), 0.77 (d, J ) 6.30 Hz, 3H); 13C NMR (CDCl3) δ 176.82,
135.97, 135.88, 131.72, 131.51, 130.40, 130.38,128.22, 128.19,
81.62, 75.68, 58.14, 54.71, 27.78, 19.36, 19.12, 15.52; IR
(KBr): 3310, 2934, 2857, 1715 cm-1; FAB-HRMS: calculated
for C20H26NO2Si(M-H+) 340.1733, found 340.1768.
C3 azido â-lactams and a novel four-step conversion of
R-azido â-lactams to R-keto â-lactams. This method shows
compatibility with reactive functionality like cyclopro-
panes at C4 but has low affinity for sterically crowding
tertiary carbon groups such as adamantyl or tert-butyl.
Additionally, the preparation and isolation of unusual C3
imino and chloramino â-lactams has been realized.
The technologies described in this paper should allow
access to a plethora of highly functionalized â-lactams
and other heterocycles of synthetic and biological interest.
The N-tosyloxy â-lactams generated during these studies
have been submitted for assay against â-lactamases, and
these studies should provide additional SAR information
for this unusual class of â-lactamase inhibitors.15-18
Further, studies are underway to examine the use of C3-
azido-â-lactams as direct precursors to differentially
protected erythro R,â-diamino acids. The results of these
and other related studies will be reported in due course.
(()-Ala n in e N-Ca r boxy An h yd r id e (12). To compound
11 (99 mg, 0.292 mmol), dissolved in dichloromethane (4 mL),
was added a 0.1 M aqueous solution of KBr (20 µL, 0.002
mmol), and the resulting mixture was cooled to 0 °C with an
ice bath. In a test tube, a 0.7 M solution of NaOCl (commercial
bleach, 415 µL, 0.291 mmol) was saturated with sodium
bicarbonate and then diluted with a 4.2 M pH ) 6.9 phosphate
buffer solution (1 mL). To the previously cooled mixture was
then added TEMPO (1 mg) followed by the buffered sodium
hypochlorite solution. The heterogeneous solution was stirred
vigorously. When the color of the solution changed, the reaction
was judged to be over and quenched with a 10% thiosulfate
solution and diluted with dichloromethane (20 mL). The
aqueous layer was discarded, the organic layer washed with
brine (20 mL), dried over Na2SO4, filtered, and concentrated
on a rotary evaporator, and the residue was chromatographed
(4:1 hexanes/EtOAc) to give the title compound as a white solid
Exp er im en ta l Section
Gen er al. tert-Butyl hypochlorite,50 tosyl azide,51 and monom-
ethyl malonate52 were prepared according to the reported
procedures. All solvents were distilled prior to use. Acetonitrile,
triethylamine, and tert-butylamine were distilled from calcium
hydride under argon. Carbon tetrachloride was stored over
molecular sieves. All other reagents were used as received from
either Aldrich or Acros chemical companies. Compound 14e
was obtained from commercial sources. Reactions involving
tert-butyl hypochlorite were conducted in foil-covered round-
bottom flasks in the absence of incidental light. During the
course of this work, gram scale quantities of 3-azido â-lactams
were prepared. Although the authors have noted no explosive
tendencies from any of the compounds reported, caution in
handling is advised. The 3-azido â-lactams showed little to no
decomposition after storage for several months at -4 °C.
Melting points are uncorrected. 1H NMR and 13C NMR spectra
were measured at 300 and 75 MHz, respectively. All chemical
shifts (δ) are relative to either tetramethylsilane or residual
solvent. Silica gel flash chromatography was carried out using
silica gel 60 (0.040-0.063 mm irregular particles).
1
(35 mg, 57% based on recovered 11). H NMR (CDCl3) δ 7.70
(m, 4H), 7.48 (m, 6H), 4.09 (q, J ) 6.60 Hz, 1H), 1.26 (s, 9H),
0.84 (d, J ) 6.60 Hz, 3H); 13C NMR (CDCl3) δ 199.69, 168.54,
135.85, 130.88, 130.84, 128.50, 128.46, 68.96, 27.81, 19.59,
16.27; IR (KBr): 2958, 2936, 2862, 2820, 1791, 1751 cm-1
;
FAB-HRMS: calculated for C20H24NO3Si (M - H+) 354.1525,
found 354.1554.
(()-cis a n d tr a n s-3-H yd r oxy-4-m et h yl-1-(ter t-b u t yl-
(d ip h en yl)silyl)-2-a zetid in on e (11). Compound 1020 (128
mg, 0.895 mmol) was dissolved in dry DMF (0.5 mL) under a
nitrogen atmosphere, and TBDPSCl (0.700 mL, 2.692 mmol)
was added by syringe. To the resulting solution was then added
triethylamine (0.40 mL, 0.287 mmol). The reaction was stirred
for 10 h and then diluted with EtOAc (10 mL). The resulting
solution was washed with water (3 × 10 mL) and then with
brine (10 mL). The organic layer was dried over Na2SO4,
filtered, and evaporated, and the residue was chromatographed
(7:1 hexanes/EtOAc) to give an inseparable 1:10 mixture of
cis and trans stereoisomers of the silyl-protected compound
(219 mg, 64%) as a light yellow oil. 1H NMR (CDCl3) δ 7.69
(m, 4H), 7.44 (m, 6H), 5.80 (d, J ) 5.70 Hz, 0.1H) 5.14 (d, J )
2.10 Hz, 1H), 3.76 (p, J ) 6.15 Hz, 0.1H), 3.52 (dq, J ) 6.35
Hz, J ) 2.02 Hz, 1H), 2.15 (s, 3H), 1.22 (s, 9H), 0.84 (d, J )
6.30 Hz, 3H), 0.77 (d, J ) 6.00 Hz, 0.3H); 13C NMR (CDCl3) δ
170.13, 135.92, 135.82, 131.45, 131.39, 130.43, 128.20, 81.41,
75.73, 56.45, 53.201, 27.69, 20.69, 19.34, 19.10, 15.47; IR
(()-tr a n s-3-(N-(1,1-Dim et h ylet h yl)a m in o)-1-(ter t-b u -
t oxyca r bon yl)-4-u n d ecyl-2-a zet id in on e (20a ). To com-
pound 19 (85 mg, 0.287 mmol) in dry THF (3 mL) at -78 °C
under nitrogen was added n-BuLi (130 µL, 2.36 M in hexanes,
0.316 mmol). After 15 min, the anion was quenched by syringe
addition of a Boc2O/THF solution (0.620 mL, 0.514 M, 0.319
mmol). After 30 min, 10% aqueous citric acid solution (0.1 mL)
was added, and the reaction was then allowed to slowly warm
to room temperature. The solvent was evaporated with a rotary
evaporator and the resulting residue purified by chromatog-
raphy (7:1 hexanes/EtOAc) to give the title compound (98 mg,
1
86%) as a clear oil. H NMR (CDCl3) δ 3.77 (d, J ) 3.00 Hz,
1H), 3.61 (m, 1H), 2.01 (m, 1H), 1.70 (m, 1H), 1.51 (s, 9H),
1.26 (m, 18H), 1.13 (s, 9H), 0.88 (m, 3H); 13C NMR (CDCl3) δ
169.13, 148.67, 83.17, 65.80, 62.95, 51.01, 32.11, 31.73, 30.09,
29.82, 29.70, 29.64, 29.54, 28.26, 24.92, 22.87, 14.32; IR
(neat): 1802 cm-1, 1722 cm-1; FAB-HRMS: calculated for
C
23H45N2O3 (M-H+) 397.3430, found 397.3434.
(()-tr a n s-3-(N-(1,1-Dim eth yleth yl)a m in o)-1-(d im eth yl-
(neat): 2934, 1752 cm-1; FAB-HRMS: calculated for C22H28
NO3Si (M - H+) 382.1838, found 382.1838.
-
(1,1-d im eth yleth yl)silyl)-4-u n d ecyl-2-a zetid in on e (20c).
Compound 19 (131 mg, 0.443 mmol) was placed in a round-
bottom flask under a nitrogen atmosphere and dissolved in
dry THF (4.6 mL). The resulting solution was cooled to -78
°C, and 2.3 M n-BuLi in hexanes (0.200 mL, 0.460 mmol) was
added. After stirring for 15 min, the reaction was quenched
with a solution of TBDMSCl (460 mL, 1.0M, 0.460 mmol) in
THF. The resulting solution was stirred at -78 °C for 20 min
and then allowed to warm to room temperature over 45 min.
(50) Mintz, M. J .; Walling, C. Organic Syntheses; Wiley: New York,
1973; Coll. Vol. V, pp 184-187.
(51) Regitz, M.; Hocker, J .; Liedhegener, A. Organic Syntheses;
Wiley: New York, 1973; Coll. Vol. V, pp 179-184.
(52) Hutchinson, C. R.; Nakane, M.; Gollman, H.; Knutson, P. L.
Organic Syntheses; Wiley: New York, 1990; Coll. Vol. VII, pp 323-
325.
32 J . Org. Chem., Vol. 68, No. 1, 2003

Enantioselective Synthesis of R-Amino Acids
The solvent was removed by rotary evaporator and the residue
chromatographed (gradient 4:1 hexanes/EtOAc to 100% EtOAc)
to give the title compound as a yellow oil (144 mg, 79% overall,
95% based on recovered 19) plus recovered 19 (22 mg). 1H
NMR (CDCl3) δ 3.72 (d, J ) 2.40 Hz, 1H), 3.25 (dt, J ) 8.70
Hz, J ) 3.00 Hz, 1H), 1.81 (m, 1H), 1.27 (bs, 19H), 1.13 (s,
9H), 0.953 (s, 9H), 0.88 (t, J ) 6.75 Hz, 3H), 0.22 (d, J ) 2.70
Hz, 6H); 13C NMR (CDCl3) δ 176.85, 67.32, 61.85, 50.95, 35.16,
32.10, 30.19, 29.92, 29.80, 29.68, 29.51, 26.47, 25.35, 22.87,
18.52, 14.30, -4.98, -5.49; IR (neat): 1743 cm-1; FAB-
HRMS: calculated for C24H51N2OSi (M - H+) 411.3771, found
411.3778.
(()-tr a n s-3-(N,N-(1,1-Dim et h ylet h yl)ch lor oa m in o)-1-
(d im et h yl(1,1-d im et h ylet h yl)silyl)-4-u n d ecyl-2-a zet id i-
n on e (22). To a solution of compound 20c (32 mg, 0.078 mmol)
in dry THF (1 mL) at -78 °C was added tert-butyl hypochlorite
(10.5 µL, 0.093 mmol), and the resulting solution was stirred
for 30 min. The solvent was then removed with a rotary
evaporator and the resulting residue filtered through a plug
of silica (7:1 hexanes/EtOAc) to give the title compound as a
clear oil (23 mg, 66%). 1H NMR (CDCl3) δ 4.25 (d, J ) 2.70
Hz, 1H), 3.70 (dt, J ) 9.20 Hz, J ) 3.07 Hz, 1H), 1.85 (m, 1H)
1.49 (m, 3H), 1.32 (s, 9H), 1.27 (bs, 16H) 0.98 (s, 9H), 0.89 (m,
3H), 0.28 (s, 3H), 0.22 (s, 3H); 13C NMR (CDCl3) δ 171.82,
62.87, 56.33, 34.61, 32.12, 29.99, 29.81, 29.72, 29.68, 29.55,
28.12, 26.42, 25.45, 22.89, 18.78, 14.33, -5.02, -5.47; IR
(neat): 1750 cm-1; FAB-HRMS: calculated for C24H49ClN2-
OSi (M - H+) 445.3384, found 445.3415.
1H), 0.65 (m, 2H), 0.33 (m, 2H); 13C NMR (CDCl3) δ 164.91,
69.80, 60.81, 12.92, 3.16, 2.47; IR (KBr): 3219, 2102, 1755
cm-1; FAB-HRMS calculated for C6H9N4O (M - H+) 153.0776
found 153.0785.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Azid o-1-
ben zyl-2-a zetid in on es. CsF (10-12 equiv) was suspended
in dry DMF (1 mL) under Ar, and to this suspension was added
BnBr (2.5 equiv). To this flask was then added a solution of
the 3-azido â-lactam in dry DMF (total substrate concentra-
tions were kept at 0.1 M) by syringe pump over several hours.
During this addition, and for several hours after it was
completed, the reaction was stirred vigorously. When TLC
analysis indicated complete consumption of the starting lac-
tam, the reaction was diluted with EtOAc and washed with
water (4×) followed by brine. The resulting organic phase was
dried over sodium sulfate, filtered, and concentrated. The
residue was then purified by flash chromatography as de-
scribed to give the title compounds.
(()-3-Azid o-1-b en zyl-4-u n d ecyl-2-a zet id in on e (27a ).
Flash chromatography (gradient 10:1 to 7:1 hexanes/EtOAc)
provided the title compound (76 mg, 66%) as a light yellow
oil. 1H NMR (CDCl3) δ 7.35 (m, 3H), 7.25 (m, 2H), 4.68 (d, J )
15.00 Hz), 4.182 (m, 1H), 4.09 (d, J ) 15.30 Hz), 3.33 (m, 1H),
1.69 (m, 1H), 1.33 (m, 19H), 0.88 (m, 3H); 13C NMR (CDCl3) δ
164.02, 135.25, 129.16, 128.36, 128.22, 68.95, 60.10, 44.82,
32.11, 31.20, 29.77, 29.63, 29.57, 29.53, 29.50, 25.52, 22.87,
14.32; IR (neat): 2106, 1767 cm-1; FAB-HRMS: calculated
for C21H33N4O (M - H+) 357.2654, found 357.2672.
(()-1-(ter t-Bu toxyca r bon yl)-3-(ter t-Bu tylim in o)-4-u n -
d ecyl-2-a zetid in on e (25). Compound 20a (106 mg, 0.267
mmol) was dissolved in dry THF (2.5 mL) under nitrogen and
cooled to -78 °C. To the cooled solution was then added tert-
butyl hypochlorite (45 µL, 0.398 mmol), and the resulting
solution was stirred for 20 min at -78 °C and then warmed
to room temperature. The solvent was removed with a rotary
evaporator and the residue redissolved in dry acetonitrile
under nitrogen. The resulting solution was cooled to 0 °C. To
the cooled solution was then added DBU (44 mL, 0.294 mmol),
and the solution was stirred for 1 h. The solvent was then
removed with a rotary evaporator and the residual material
filtered through a plug of silica (10:1 hexanes/EtOAc) to give
the title compound (60 mg, 57%) as a clear oil. 1H NMR (CDCl3)
δ 4.35 (m, 1H), 1.88 (m, 2H), 1.57 (s, 9H), 1.40 (s, 9H), 1.29
(bs, 18H) 0.88 (m, 3H); 13C NMR (CDCl3) δ 161.06, 155.95,
149.01, 83.92, 64.43, 58.96, 32.11, 30.32, 30.10, 29.81, 29.69,
29.65, 29.54, 29.51, 18.24; IR (neat): 1805, 1793 cm-1; FAB-
HRMS: calculated for C23H43N2O3 (M-H+) 395.3274, found
395.3284.
Gen er a l P r oced u r e for th e P r ep a r a tion of tr a n s-3-
Azid o-â-La cta m s. To the N-tosyloxy â-lactam dissolved in dry
acetonitrile under an inert atmosphere was added TMSN3 (2
equiv) followed by diisopropylethylamine (3 equiv). The result-
ing mixture was stirred at room temperature until all of the
starting material was consumed as determined by TLC
analysis (2-5 days). The solution was then concentrated with
a rotary evaporator and the residue purified by flash chroma-
tography to yield the desired title compounds.
(()-tr a n s-3-Azid o-4-u n d ecyl-2-a zetid in on e (26a ). Flash
chromatography (gradient 10:1 to 4:1 hexanes/EtOAc) yielded
the title compound as a yellow oil (178 mg, 65%). 1H NMR
(CDCl3) δ 6.60 (s, 1H), 4.16 (s, 1H), 3.52 (dt, J ) 9.70 Hz, J )
3.37 Hz, 1H), 1.67 (m, 2H), 1.30 (m, 18H), 0.88 (m, 3H); 13C
NMR (CDCl3) δ 164.89, 69.87, 57.31, 33.67, 32.08, 29.7629.65,
29.58, 29.50, 29.39, 26.17, 22.85, 14.28; IR (neat) 3256, 2108,
1770 cm-1; FAB-HRMS: calculated for C14H27N4O (M - H+)
267.2185, found 267.2174.
(()-tr a n s-3-Azid o-4-cyclop r op yl-2-a zetid in on e (26b).
Flash chromatography (4:1 hexanes/EtOAc) yielded the title
compound as a crystalline solid (206 mg, 66%). Analytically
pure material was obtained by recrystallization from Et2O/
hexanes: mp ) 50.5-51.0 °C; 1H NMR (CDCl3) δ 6.58 (s, 1H),
4.34 (m, 1H), 3.11 (dd, J ) 7.95 Hz, J ) 1.95 Hz, 1H), 1.02 (m,
(()-tr a n s-3-Azid o-1-(p -m et h oxyb en zyl)-4-u n d ecyl-2-
a zetid in on e (27a ′). Flash chromatography (7:1 hexanes/
EtOAc) gave the title compound as a yellow oil (49 mg, 36%).
1H NMR (CDCl3) δ 7.17 (m, 2H), 6.88 (m, 2H), 4.62 (d, J )
15.00 Hz, 1H), 4.15 (d, J ) 1.50 Hz, 1H), 4.02 (d, J ) 15.00
Hz, 1H), 3.81 (s, 3H), 3.31 (m, 1H), 1.69 (m, 2H), 1.33 (m, 18H),
0.88 (m, 3H); 13C NMR (CDCl3) δ 163.92, 159.56, 128.69,
127.22, 114.52, 68.83, 59.88, 55.50, 44.31, 32.10, 31.22, 29.78,
29.65, 29.59, 29.52, 25.52, 22.88, 14.31; IR (neat): 2105, 1764
cm-1; FAB-HRMS: calculated for C22H35N4O2S (M - H+)
387.2760 found 387.2755.
(()-tr a n s-3-Azid o-1-ben zyl-4-cyclop r op yl-2-a zetid in o-
n e (27b). Flash chromatography (gradient 2:1 to 1:1 hexanes/
EtOAc) provided the title compound as a yellow oil (42 mg,
1
64%). H NMR (CDCl3) δ 7.32 (m, 5H), 4.71 (d, J ) 15.00 Hz,
1H), 4.36 (d, J ) 1.5 Hz, 1H), 4.18 (d, J ) 15.00 Hz, 1H), 2.64
(dd, J ) 9.45 Hz, J ) 1.95 Hz), 0.76 (m, 1H), 0.58 (m, 2H),
0.19 (m, 1H), 0.07 (m, 1H); 13C NMR (CDCl3) δ 163.89, 135.40,
129.02, 128.42, 128.09, 69.15, 65.01, 44.76, 11.14, 4.60, 1.56;
IR (neat): 2106 cm-1, 1770 cm-1; FAB-HRMS calculated for
C
13H15N4O (M - H+) 243.1246 found 243.1255.
(()-1-Ben zyl-3-oxo-4-u n d ecyl-2-a zetid in on e (28a ). A 10
mL round-bottom flask was charged with nitrogen, compound
27a (50 mg, 0.140 mmol), dry, deoxygenated THF (1.4 mL),
and 10% Pd/C (12 mg) in that order. The flask was then placed
under a hydrogen atmosphere (1 atm) and stirred vigorously.
Monitoring by TLC showed complete consumption of compound
27a after 20 min. The flask was then purged with nitrogen
for several minutes, and the catalyst was removed from the
solution by filtering through a disposable pipet containing a
cotton plug. (The subsequent reactions could also be carried
out without first removing the catalyst. However, later stage
purification was more convenient if the catalyst was removed
earlier.) The cotton plug was washed with CH2Cl2 (4 mL), and
all of the organic solvents were combined and removed with a
rotary evaporator. The residue was then redissolved in dry
THF (1.4 mL) under a nitrogen atmosphere and cooled to -78
°C. To the cooled solution was then added tert-butyl hypochlo-
rite (18 µL, 0.159 mmol), and the resulting solution was stirred
for 20 min. To the flask was then added DBU (25 µL, 0.167
mmol), and the flask was allowed to slowly warm to room
temperature. After 1.5 h, a saturated aqueous oxalic acid
solution (0.7 mL) was added and the reaction stirred for an
additional 10 min. The reaction was then diluted with EtOAc
J . Org. Chem, Vol. 68, No. 1, 2003 33

Durham and Miller
(20 mL) and washed with water (20 mL), 1.2 M HCl (20 mL),
saturated NaHCO3 (20 mL), and brine (20 mL). The EtOAC
solution was then dried over Na2SO4, filtered, and evaporated.
The residue was purified by flash chromatography (4:1 hex-
anes/EtOAc) to give the title compound as a yellow oil (27 mg,
59%). Prolonged drying of the material under vacuum in some
instances produced a crystalline solid. 1H NMR (CDCl3) δ 7.33
(m, 5 H), 5.02 (d, J ) 15.00 Hz, 1H), 4.42 (d, J ) 14.70 Hz,
1H), 4.02 (dd, J ) 6.90 Hz, J ) 4.80 Hz, 1H), 1.68 (m, 1H),
1.54 (m, 1H), 1.24 (m, 18H), 0.88 (m, 3H); 13C NMR (CDCl3) δ
197.38, 163.44, 134.19, 129.37, 128.72, 128.66, 71.09, 46.06,
32.11, 29.77, 29.62, 29.56, 29.53, 29.43, 28.69, 24.92, 22.90,
14.33; IR (neat): 1823, 1762 cm-1 FAB-HRMS: calculated
for C21H32NO2 (M - H+) 330.2433, found 330.2447.
Meth yl 2-(N-Ben zyla m in o)-2-cycloh exyl-eth a n oa te Hy-
d r och lor id e (30c). Compound 29c (7 mg, 0.0275 mmol) was
dissolved in absolute MeOH (0.7 mL), and TMSCl (0.1 mL)
was added. After 15 min, the solvent was removed with a
rotary evaporator, and the white residue was triturated with
diethyl ether to provide the title compound as a white solid (4
mg, 50%); mp ) 188-198 °C (decomposed); 1H NMR (CD3OD)
δ 7.48 (m, 5H), 4.25 (s, 2H), 3.89 (d, J ) 3.00 Hz, 1H), 3.80 (s,
3H), 1.96 (m, 2H), 1.79 (m, 4H), 1.25 (m, 4H), 1.01 (m, 1H);
13C NMR (CD3OD) δ 169.50, 131.81,131.66, 131.19, 130.46,
65.94, 53.71, 52.56, 40.59, 30.94, 28.88, 27.35, 26.94, 26.84;
IR (KBr): 3448, 1742 cm-1
.
Gen er a l P r oced u r e for F or m a tion of Am id es 33. The
NCA was dissolved in dry THF or CH2Cl2 under an argon
atmosphere. To the resulting solution was added (S)-(-)-R-
methylbenzylamine (1.1 equiv, 98% optical purity, Aldrich
Chemical Co.), and the reaction was stirred at room temper-
ature until all of the starting material was consumed. The
solution was then concentrated on the rotary evaporator and
the residue purified by flash chromatography to provide the
title compounds. The reactions were repeated with the racemic
NCAs to give comparable yields of 1:1 mixtures of diastereo-
(()-1-Ben zyl-3-oxo-4-(cyclop r op yl)-2-a zetid in on e (28b).
The procedure was the same as that used for compound 28a .
Flash chromatography (4:1 hexanes/EtOAc) gave the title
compound as a yellow oil (48 mg, 48%). 1H NMR (CDCl3) δ
7.35 (m, 5H), 5.06 (d, J ) 15.00 Hz, 1H), 4.54 (d, J ) 14.70
Hz, 1H), 3.49 (d, J ) 8.40 Hz, 1H), 0.81 (m, 1H), 0.60 (m, 2H),
0.32 (m, 1H), 0.22 (m, 1H); 13C NMR (CDCl3) δ 196.24, 163.48,
134.26, 129.23, 129.04, 128.65, 128.58, 75.33, 45.87, 9.10, 3.47,
1.86; IR (neat): 1825, 1738 cm-1; FAB-HRMS: calculated for
1
mers by H NMR which were used to determine the enantio-
C
13H13NO2 (M - H+) 216.1025 found 216.1028.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e NCAs.
meric excesses.
(R)-2-(N-Ben zyla m in o)-N-((S)-1-p h en yleth yl)tr id eca n -
a m id e (33a ). Flash chromatography (4:1 hexanes/EtOAc) gave
the title compound as a white solid (16 mg, 70%). 1H NMR
(CDCl3) δ 7.52 (d, J ) 8.70 Hz, 1H), 7.30 (m, 10H), 5.13 (m,
1H), 3.77 (d, J ) 13.20 Hz, 1H), 3.69 (d, J ) 12.90 Hz, 1H),
1.71 (m, 1H), 1.55 (m, 2H), 1.47 (d, J ) 6.90 Hz), 1.26 (m, 18H),
0.879 (m, 3H); 13C NMR (CDCl3) δ 173.54, 143.75, 139.86,
128.85, 128.81, 128.34, 127.56, 127.39, 126.25, 62.99, 53.25,
48.16, 34.01, 32.12, 29.91, 29.82, 29.72, 29.64, 29.55, 26.09,
22.89, 22.31, 14.33; FAB-HRMS calculated for C28H43N2O (M
- H+) 423.3375 found 423.3351.
(R)-2-(N-Ben zyla m in o)-N-((S)-1-p h en yl-et h yl)-4-p h e-
n ylp en ta m id e (33b). Flash chromatography (gradient 4:1 to
2:1 hexanes/EtOAc) gave the title compound as a yellow solid
(10 mg, 40%). 1H NMR (CDCl3) δ 7.48 (d, J ) 8.10 Hz, 1H),
7.23 (m, 9H), 5.14 (p, J ) 7.20 Hz, 1H), 3.73 (d, J ) 12.90 Hz,
1H), 3.64 (d, J ) 12.90 Hz, 1H), 3.19 (dd, J ) 7.50 Hz, J )
3.19 Hz, 1H), 2.64 (t, J ) 7.95 Hz, 1H), 2.07 (m, 1H), 1.86 (m,
1H), 1.68 (s, 1H), 1.47 (d, J ) 6.90 Hz, 1H).
To the 3-oxo-2-azetidinones dissolved in dichloromethane
cooled to 0 °C with an ice bath were added 0.1 M KBr (50 µL,
0.005 mmol), TEMPO (1 mg), and a 1:9 mixture of commercial
Chlorox bleach (≈ 0.7 M in NaOCl) and 4.2 M pH ) 6.9
phosphate buffer solution, in that order. The reaction was
stirred vigorously at 0 °C for 1 h. Upon complete consumption
of starting material as determined by TLC, the reaction was
quenched with 10% sodium thiosulfate solution (4 mL) and
diluted with dichloromethane (10 mL). The aqueous layer was
separated and discarded. The organic phase was washed with
brine (5 mL), dried over Na2SO4, filtered, and evaporated to
give the title compounds.
3-Ben zyl-4-u n d ecyl-oxa zolid in e-2,5-d ion e (29a ). The
1
title compound was obtained as a yellow oil (14 mg, 78%). H
NMR (CDCl3) δ 7.37 (m, 3H), 7.28 (m, 2H), 4.95 (d, J ) 15.30
Hz, 1H), 4.12 (d, J ) 15.30 Hz, 1H), 4.05 (dd, J ) 5.85 Hz, J
) 3.45 Hz, 1H), 1.88 (m, 1H), 1.76 (m, 1H), 1.25 (m, 18 H),
0.87 (m, 3H); 13C NMR (CDCl3) δ 168.90, 152.41, 134.31,
129.45, 128.96, 128.52, 58.89, 45.97, 32.11, 29.77, 29.75, 29.60,
29.53, 29.41, 29.24, 28.56, 23.35, 22.89, 14.32; IR (neat): 1847,
1778 cm-1; FAB-HRMS: calculated for C21H32NO3 (M - H+)
346.2382, found 346.2394.
Ack n ow led gm en t. The authors thank Eli Lilly and
Company and the University of Notre Dame for finan-
cial support of this research. T.B.D. is very grateful for
support in the form of a George Wolf Fellowship. The
authors acknowledge the Lizzadro Nuclear Magnetic
Resonance Research Center for NMR resources and
technical support and the mass spectral facilities of the
University of Notre Dame for analytical services. The
authors are also grateful to Ms. Maureen Metcalf for
valuable assistance in the preparation of this manu-
script.
3-Ben zyl-4-cyclopr opyl-oxazolidin e-2,5-dion e (29b). The
1
title compound was obtained as a yellow oil (44 mg, 85%). H
NMR (CDCl3) δ 7.33 (m, 5H), 5.02 (d, J ) 15.06 Hz, 1H), 4.36
(d, J ) 15.3 Hz, 1H), 3.26 (d, J ) 9.30 Hz, 1H), 0.98 (m, 1H),
0.74 (m, 2H), 0.55 (m, 1H), 0.30 (m, 1H); 13C NMR (CDCl3) δ
167.86, 151.93, 134.67, 129.29, 128.68, 128.14, 63.13, 45.70,
11.22, 4.47, 1.26; IR (neat): 1848 cm-1, 1775 cm-1; FAB-
HRMS: calculated for C13H13NO3 (M - H+) 232.0974 found
232.0959.
Met h yl 2-(N-Ben zyla m in o)-2-cyclop r op yl-et h a n oa t e
(30b). Compound 29b (21 mg, 0.091 mmol) was dissolved in
absolute MeOH under nitrogen, and the resulting solution was
stirred at room temperature for 4d. The solvent was removed
with a rotary evaporator to give the title compound as a brown
oil (21 mg, quantitative). 1H NMR (CDCl3) δ 7.30 (m, 5H), 3.85
(d, J ) 12.90 Hz, 1H), 3.71 (m, 4H), 2.72 (d, J ) 8.40 Hz, 1H),
2.66 (bs, 1H), 1.05 (m, 1H), 0.51 (m, 3H), 0.28 (m, 1H); 13C
NMR (CDCl3) δ 174.76, 139.34, 128.63, 128.58, 127.41, 64.47,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for OPA-HPLC analysis of NCA 12 and the prepara-
tion of compounds 14a -d ,f, 15-18, 19, 20b, 20d , 21, 26c-f,
27c-f, 28c,d , 29c,d , and 31a ,b as well as 1H NMR and 13C
NMR spectra for compounds 11-14d , 14f-29b, 30b, 30c, 33a
1
and the H NMR spectrum for compound 33b can be found in
the Supporting Information for this article. This material is
available free of charge via the Internet at http://pubs.acs.org.
52.13, 52.01, 14.35, 4.25, 2.59; IR (neat): 3336, 1732 cm-1
;
FAB-HRMS: calculated for C13H18NO2 (M - H+) 220.1338
found 220.1332.
J O0162437
34 J . Org. Chem., Vol. 68, No. 1, 2003