Functionalization of N-[(silyl)methyl]-β-lactam carbanions with carbon electrophiles

Article abstract of DOI:10.1021/jo060537g

Latent acidity of α-alkyl-α-amino-N-[(silyl)methyl]-β- lactams enabled a concise entry to lithium nonenolate N-methyl-azetidinone carbanions lithiated α′ to the β-lactam nitrogen, owing to the stabilizing "α-effect" of one or two trimethylsilyl groups.

Full text of DOI:10.1021/jo060537g

Functionalization of N-[(Silyl)methyl]-â-lactam Carbanions with
Carbon Electrophiles
Claudio Palomo,*,† Jesus M. Aizpurua,*,† Ana Benito,† Lourdes Cuerdo,†
Raluca M. Fratila,† Jose´ I. Miranda,† and Anthony Linden‡
Departamento de Qu´ımica Orga´nica-I, Facultad de Qu´ımica, UniVersidad del Pa´ıs Vasco, Apdo 1072,
20080 San Sebastia´n, Spain, and Organisch-chemisches Institut der UniVersita¨t Zu¨rich,
Winterthurerstrasse 190, CH-8057 Zu¨rich, Switzerland.
qoppanic@sc.ehu.es(C.P.); jesusmaria.aizpurua@ehu.es(J.M.A.)
ReceiVed March 10, 2006
Latent acidity of R-alkyl-R-amino-N-[(silyl)methyl]-â-lactams enabled a concise entry to lithium nonenolate
N-methyl-azetidinone carbanions lithiated R′ to the â-lactam nitrogen, owing to the stabilizing “R-effect”
n
t
of one or two trimethylsilyl groups. BuLi/TMEDA and BuLi/TMEDA were the bases of choice for
complete deprotonation of di- and monosilylated â-lactams, respectively. Trapping of the resulting
carbanions with alkyl halides provided the corresponding N-[(R′-silyl)-alkyl]-â-lactams, while carbon
dioxide and related electrophiles such as benzyl chloroformates or isocyanates, afforded the corresponding
silicon-free N-carboxymethyl-, N-benzyloxycarbonylmethyl-, and N-amidomethyl-â-lactams in a single
synthetic step. Likely structures of these unprecedented lithiated N-[(silyl)methyl]-â-lactams were studied
by MO calculations (B3LYP/6-31G*), and the origin of their relative stability was briefly discussed.
Introduction
cycloexpansions (2 f 3) have been proposed thereafter to
explain it, either involving the intermediacy of radical-radical
Since the advent of semisynthetic antibiotics in the early
1970s R′-metalated â-lactams N-carboxymethyl enolates 1 and
their sulfonyl and phosphoryl analogues have been used
extensively as intermediates to prepare bicyclic cephem-,
clavam-, or carbapenems and tricyclic trinem nuclei via R′-â
cyclization reactions.1 In addition, their stereoselective alkylation
has been employed to prepare synthons en route to nonpro-
teinogenic amino acids.2 Surprisingly, the chemistry of simple
â-lactam carbanions metalated R′- to the azetidin-2-one nitrogen
atom, has been virtually ignored3 and, to the best of our
knowledge, only R′-lithiated N-benzyl â-lactams 2 (Figure 1)
fall into this category. In a seminal work, Durst4 reported more
than 30 years ago the LDA-promoted formation of R′-lithiated
â-lactams 2 as well as their transformation into cycloexpanded
γ-lactams 3, and several [2,3]-shift rearranged ꢀ-lactams 4 (from
2, R4 ) vinyl). The well-acknowledged â-lactam ring strain
was believed to be at the origin of this reactivity, and,
accordingly, different cleavage-recombination processes for
(1) General review on â-lactam synthesis can be found in the follow-
ing: (a) Backes, J. In Houben-Weyl, Methoden der Organischen Chemie,
Band E16 B; Muller, E., Bayer, O. Eds., Thieme: Stuttgart, 1991; p 31.
Cyclization methodologies to bicyclic â-lactams can be found in the
following: (b) Kant, J.; Walker, D. G. in The Organic Chemistry of
â-Lactams, Georg, G. I., Ed.; VCH Publishers: New York, 1993; pp 121-
196. Additional representative examples on the use of N-carboxymethyl-
â-lactam enolates to prepare polycyclic â-lactams can be found in the
following: (c) Jacobsen, M. F.; Turks, M.; Hazell, R.; Skrydstrup, T. J.
Org. Chem. 2002, 67, 2441-2417. (d) Alcaide, B.; Polanco, C.; Saez, E.;
Sierra, M. A. J. Org. Chem. 1996, 61, 7125-7132. (f) Chmielewski, M.;
Kaluza, Z.; Furman, B. Chem. Commun. 1996, 2689-2696. (g) Roland,
S.; Durand, J. O.; Savignac, M.; Genet, J. P. Tetrahedron Lett. 1995, 36,
3007-3010. (h) Crocker, P. J.; Karison-Andreasson, U.; Lotz, T.; Miller,
M. J. Heterocycles 1995, 40, 691-716.
(2) (a) Ojima, I.; Delaloge, F. Chem. Soc. ReV. 1997, 26, 377-386. (b)
Ojima, I. Acc. Chem. Res. 1995, 28, 383-389. (c) Ojima, I. in The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York, 1992; p.
197-255.
(3) R′-Deprotonation in â-lactams stabilized by a remote conjugate ester
group has been described: Ruano, G.; Anaya, J.; Grande, M. Synlett 1999,
1441-1443.
(4) Durst, T.; Van der Elzen, R.; LeBelle, M. J. J. Am. Chem. Soc. 1972,
94, 9261-9263.
† Universidad del Pais Vasco.
‡ Organisch-chemisches Institut der Universita¨t Zu¨rich.
10.1021/jo060537g CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/20/2006
6368
J. Org. Chem. 2006, 71, 6368-6373

Functionalization of N-[(silyl)methyl]-â-lactam
desilylation, and can be trapped “in situ” with carbonyl
compounds to afford Peterson-like olefination products.7 Re-
cently, we also have described the completely stereocontrolled
R-alkylation of â-lactams 5 to R-alkyl-R-amino-N-[(trimethyl-
silyl)methyl-â-lactams 7,8 demonstrating their utility as precur-
sors of â-turned peptidomimetic â-lactam surrogates.9
On the basis of the existing methods to metalate amides or
carbamates adjacent to the nitrogen atom,10 and considering the
well-known ability of silyl groups to facilitate weak R-carbanion
stabilization in N-[(trimethylsilyl)methyl]-R-amino derivatives,11
we envisaged to study the base-promoted R′-metalation of
â-lactams 7. Herein we report the first access to enantiopure
â-lactams 8 lithiated R′ to the â-lactam nitrogen and their
reaction with carbon electrophiles to afford a variety of
R′-functionalized N-methyl azetidin-2-ones.
Results and Discussion
FIGURE 1. R′-Metalated â-lactams stabilized by enolate formation
and benzylic effect.
To establish the conditions and scope of metalation (7 f 8),
a set of structurally different N-silylmethyl-â-lactams 10-17
was prepared according to procedures previously described in
our laboratory (Scheme 1). Suitable â-lactams with the R-amino
function protected as cyclic carbamate (Xc) or alkyl carbamate
(BocHN-) were selected, bearing either R-alkyl- or R,â-dialkyl
substitution patterns at the azetidin-2-one ring and having one
or two trimethylsilyl groups at the N-methyl position.
Some of the N-[(silyl)methyl]-â-lactams prepared were first
submitted to a test R′-deprotonation reaction with alkyllithium
bases, followed by in situ trapping of the intermediate carbanions
using deuteriomethanol or highly reactive carbon electrophiles
(e.g., MeI, BnBr) (Table 1).
It was found that R-monoalkyl-bis-silyl-â-lactam 10 was
s
cleanly deprotonated with BuLi at -78 °C in THF (entry 1).
n
Attempted deprotonation with BuLi under similar conditions
caused product decomposition, whereas tBuLi resulted in
residual deuteration (<5% by NMR) and recovery of the starting
material. Deprotonation of â-lactam 10 could also be driven
with LDA or LHMDS bases, but they only led to partial
FIGURE 2. Desilylation and sequential deprotonation of R-amino-
R,â-disubstituted-N-[(trimethylsilyl)methyl]-â-lactams.
(7) Palomo, C.; Aizpurua, J. M.; Garc´ıa, Tetrahedron Lett. 1990, 31,
1239-1241.
(8) (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Benito, A.; Cuerdo, L.;
Fratila, R. M.; Jimenez, A.; Loinaz, I.; Miranda, J. I.; Pytlewska, K. R.;
Micle, A.; Linden, A. Org. Lett., 2004, 6, 4443-4446. (b) Palomo, C.;
Aizpurua, J. M.; Galarza, R.; Benito, A.; Khamrai, U. K.; Eikeseth, U.;
Linden, A. Tetrahedron, 2000, 56, 5563-5570. For the preparation of related
racemic R-alkyl-R-amino-â-lactams, see: (c) Wu, Z.; Georg, G. I.; Cathers,
B. E.; Schloss, J. V. Bioorg. Med. Chem. Lett., 1996, 6, 983-986. (d)
Broadrup, R. L.; Wang, B.; Malachowski, W. P. Tetrahedron, 2005, 61,
10277-10284.
(9) (a) Palomo, C.; Aizpurua, J. M.; Benito, A.; Miranda, J. I.; Fratila,
R. M.; Matute, C.; Domercq, M.; Gago, F.; Martin-Santamaria, S.; Linden,
A. J. Am. Chem. Soc. 2003, 125, 16243-16260. (b) Palomo, C.; Aizpurua,
J. M.; Benito, A.; Galarza, R.; Khamrai, U. K.; Vazquez, J.; de Pascual-
Teresa, B.; Nieto, P. M.; Linden, A. Angew. Chem., Int. Ed. 1999, 38, 3056-
3058.
anions, or the participation of N-acyl imine â-carbanions.5 As
a result of their instability, examples of the intramolecular
reaction of benzyl anions 2 with electrophiles are very rare:
only single examples of R′-deuteration4 and R′-acylation5(b) have
been described.
As part of our ongoing interest for 3-amino-N-[(trimethyl-
silyl)methyl]-2-azetidinones 5,6 we have established previously
their usefulness as a source of naked N-[(trimethylsilyl)methyl]-
â-lactam carbanions 6 (Figure 2). These species are generated
under formally neutral conditions, through fluoride ion-promoted
(5) (a) Ahn, C.; Shin, D.-S.; Park, J.-H. J. Korean Chem. Soc. 1999, 43,
489-490. (b) Escalante, J.; Gonzalez-Tototzin, M. A. Tetrahedron:
Asymmetry 2003, 14, 981-985. (c) Park, J.-H.; Ha, J.-R.; Oh, S.-J.; Kim,
J.-A.; Shim, D.-S.; Won, T.-J.; Lan, Y.-F.; Ahn, C. Tetrahedron Lett. 2005,
46, 1755-1757.
(6) In contrast to other N-aryl- or N-alkyl-substituted conventional
azetidinones, â-aryl-, â-alkyl-, â-unsubstituted â-lactams 5 are accessible
in a fully stereocontrolled manner from N-[bis(trimethylsilyl)methyl]imines.
See the following for example: (a) Palomo, C.; Aizpurua, J. M.; Legido,
M.; Mielgo, A.; Galarza, R. Chem. Eur. J. 1997, 3, 1432-1441. (b) Palomo,
C.; Aizpurua, J. M.; Legido, M.; Galarza, R.; Deya, P. M.; Dunogues, J.;
Picard, J. P.; Ricci, A.; Seconi, G. Angew. Chem., Int. Ed. Engl. 1996, 35,
1239-1241.
(10) (a) Whisler, M. C.; Macneil, S.; Snieckus, V.; Beak, P. Angew.
Chem., Int. Ed. 2004, 43, 2206-2225. (b) Beak, P.; Basu, A.; Gallagher,
D. J.; Park, Y. S.; Thayumanyan, S. Acc. Chem. Res. 1996, 24, 552-560.
(11) For reviews on silyl carbanions, see (a) Wang, D.; Chan, T. H.
Silylmethyl Anions. In Science of Synthesis: Houben-Weyl, Methods of
Molecular Transformations, Fleming, I., Ed.; Thieme: Stuttgart-New York,
2002; Vol. 4, p 481-498. (b) J. S. Panek, Silicon Stabilization. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 1, p. 579. (c) Itami, K.; Kamei, T.;
Mitsudo, K.; Nokami, T.; Yoshida J. J. Org. Chem. 2001, 66, 3970-3976
and references therein. For metalation of N-(silylmethyl)amides and
carbamates, see (d) Sieburth, S. M. N.; Somers, J. J.; O’Hare, H. K.,
Tetrahedron 1996, 52, 5669-5682.
J. Org. Chem, Vol. 71, No. 17, 2006 6369

Palomo et al.
SCHEME 1. Preparation of N-[(silyl)Methyl]-â-lactams
10-17
(compounds 10, 14, and 15, respectively), whereas R-isobutyl
â-lactams 11 and 16 showed the typical pale-yellow or pale-
brown colors of ordinary R-carbanions of N-[(silyl)methyl]-
amides or carbamates.11(c) These observations suggested that,
at least in the former instances, R′-lithiated â-lactam species
might have a complex structure involving some radical delo-
calization within the R-benzyl moiety. Conversely, participation
of the phenyl group of the oxazolidinyl cyclic carbamate (Xc)
in such delocalization seemed to be not essential to carbanion
formation (compare entries 7 and 10).
Next, we extended the scope of the reaction to other carbon
electrophiles such as carbon dioxide, benzyl chloroformate, and
isocyanates14 (Table 2). They were reacted with N-[(silyl)-
methyl]-â-lactam carbanions, generated under optimized condi-
tions, to furnish moderate to good yields of the corresponding
desilylated15 and R′-functionalized N-methyl-â-lactams 26-36.
Interestingly, the method was applicable to all the R,â-
substitution and N-protection patterns studied, including monosilyl-
â-lactams 14 and 17, and some of the R-N-Boc-R′-carboxy-â-
lactams prepared (e.g., 34-36) could be considered as internally
constrained peptidomimetics, ready for incorporation into pep-
tide chains by standard peptide synthesis techniques.16
Depending on the bases selected to deprotonate the â-lactams
or the reaction conditions used to trap the carbanions, unex-
pected products were obtained in some instances. For example,
attempted acylation of the carbanion derived from 10 with
benzyl chloroformate (entry 2) afforded exclusively the R′-
methylated product 19 instead of the expected benzyl ester 27.
The transformation was rationalized by means of a reaction
pathway involving the participation of a TMEDA/ClCO2Bn
complex (Scheme 2) as the methylating agent.17 Indeed, carrying
out the same reaction using TMEDA-free sBuLi to deprotonate
the â-lactam 10 gave the expected product 27 (entry 3). For
the reaction of the carbanion derived from 11 with trimethylsilyl
isocyanate, different products (nitrile 30 or amide 31) were
obtained, depending on the trapping reaction temperature (entries
6 and 7). The expected amide 31 was obtained in good yield
only when the trapping reaction was conducted entirely at -78
°C and was quenched at the same temperature, whereas
performing the trapping step at room-temperature resulted in
the exclusive formation of nitrile 30.
deuteration (typically 60-80%), even when 2-3 equiv of base
were used. To our satisfaction, when â-lactam 10 was depro-
tonated with sBuLi/TMEDA at -78 °C or with nBuLi/TMEDA
at -100 °C, the resulting carbanion was trapped with MeI and
BnBr to give R′-alkylated N-[bis(silyl)methyl]-â-lactams
19-21 in fair to good isolated yields (entries 2-5). Nonactivated
primary alkyl iodides (e.g., nBuI, entry 6) also gave successful
trapping, whereas secondary ones (e.g., iPrI) failed to react with
n
the carbanion. As BuLi/TMEDA proved to be slightly more
A key question arising from the successful R′-deprotonation
of N-[(silyl)methyl]-â-lactams disclosed above was the likely
s
efficient than BuLi/TMEDA, it was adopted as the standard
base for successive deprotonations. Lithiation of R,â-dialkyl-
substituted bis-silyl â-lactam 13 failed12 (entry 8), and its
monosilyl analogue 14 provided the unexpected N-benzyl-â-
lactam 23 (entry 9), likely through the desilylmethylation of
intermediate R′-lithio carbanion to the corresponding â-lactam
N-lithio amide. Metalation was compatible with the presence
of an additional acidic proton from the BocHN group, provided
2.5 equiv of base were used. Under none of the conditions tested
did R′-lithiated â-lactams 10-16 produce any detectable pyr-
rolidones arising from eventual cycloexpansion reactions, neither
any byproducts from the competitive deprotonation of SiMe3
methyl groups nor â-lactam ring-opening side products from
butyllithium nucleophilic attack to the azetidin-2-one carbonyl.13
It was worth mentioning that, irrespective of the base used,
a very characteristic deep color (purple, red, or green) developed
from carbanions bearing an R-benzyl group at the â-lactam ring
(13) Nucleophilic addition of alkyllithiums to amide carbonyls can be
blocked by increasing the steric hindrance at the CR position: (a) Schlecker,
R.; Seebach, D.; Lubosch, W.; HelV. Chim. Acta, 1978, 61, 512-516. (b)
Schlecker, R.; Seebach, D.; HelV. Chim. Acta, 1977, 60, 1459-1471. For
azetidin-2-one ring opening with alkyllithium reagents, see (c) Pearsons,
P. J.; Camp, N. P.; Underwood, J. M.; Harvey, D. M. Tetrahedron, 1996,
52, 11637-11368.
(14) We previously described the R′-carbamoilation of 11 with trimeth-
ylsilyl isocyanate, see ref 9a.
(15) Spontaneous desilylation of R-trimethylsilyl-carbonyl compounds
under acidic aqueous workup conditions is a well-established process. See,
for example, the following: Landais, Y. R-Silyl Carbonyl Compounds. In
Science of Synthesis: Houben-Weyl, Methods of Molecular Transformations;
Fleming, I., Ed.; Thieme: Stuttgart-New York, 2002; Vol. 4, p 757-772.
(16) An alternative four-step transformation of N-[bis(trimethylsilyl)-
methyl]-â-lactams into N-(carboxymethyl)-â-lactams was developed previ-
ously in our laboratory, involving Ce(IV)-promoted degradation of bis-
(trimethylsilyl)methyl group and N-alkylation of intermediate NH-â-lactams
with benzyl iodoacetate (see ref 9). For a related approach to R-alkyl-N-
carboxymethyl-γ-lactams, see the following: Raghavan, B.; Johnson, R.
L. J. Org. Chem. 2006, 71, 2151-2154.
(12) Additional deprotonation trials conducted with several butyllithium/
TMEDA combinations at temperatures up to -30 °C provided no evidence
of carbanion formation. Above this temperature, only decomposition of
compound 12 was observed.
(17) A similar reaction using sBuLi/TMEDA base and (Boc)2O electro-
phile also gave R′-methylated â-lactam 19 as the only reaction product,
instead of the expected N-[(tert-butoxycarbonyl)methyl]-â-lactam.
6370 J. Org. Chem., Vol. 71, No. 17, 2006

Functionalization of N-[(silyl)methyl]-â-lactam
TABLE 1. Deprotonation of N-[(silyl)Methyl]-Substituted â-Lactams with Alkyllithium Basesa
entry
â-lactam
Y
R1
R3
base
anion colorb
electrophile
product
E
yield (%)c
1
2
3
4
5
6
7
8
10
10
10
10
10
10
11
13
14
15
16
Xc
Xc
Xc
Xc
Xc
Xc
Xc
Xc
Xc
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
iBu
Bn
Bn
Bn
iBu
sBuLi
sBuLi
A
A
A
A
A
A
B
B
C
D
B
MeODd
MeI
MeI
18
19
19
20
20
21
22
D
82
40
51
61
70
40
77
Me
Me
Bn
Bn
nBu
Bn
sBuLi/TMEDA
sBuLi/TMEDA
nBuLi/TMEDA
nBuLi/TMEDA
nBuLi/TMEDA
nBuLi/TMEDA
nBuLi/TMEDA
nBuLi/TMEDAg
tBuLi/TMEDAg
BnBr
BnBr
nBuI
BnBr
iBu
iBu
H
MeODd
BnBr
(<5)e
50f
75
9
10
11
23
24
25
BocHN
BocHN
MeODd
MeODd
D
D
H
67
n
a Deprotonation step was run with 1.3 equiv of base during 30 min at -100 °C for BuLi/TMEDA and at -78 °C for other bases. After addition of the
electrophiles (2 equiv), trapping was conducted at room temperature for 5 h. b A: deep purple; B: slight yellow-orange; C: deep red; D: deep green.
1
c Yields of isolated pure products. d 20 equiv of MeOD used. e Conversion determined by H NMR (500 MHz) analysis of the reaction crude. f Unchanged
starting material partially recovered (40%). g 2.5 equiv of base used.
TABLE 2. Functionalization of N-[(silyl)Methyl]-â-lactams with Carbon Dioxide and Related Electrophiles
entry
â-lactam
Y
R1
R2
R3
base
electrophilea
product
E
yield (%)b
1
2
3
4
5
6
7
8
10
10
10
10
11
11
11
12
14
15
16
17
Xc
Xc
Xc
Xc
Xc
Xc
Xc
Xc
Xc
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
Bn
Bn
Bn
Bn
iBn
iBn
iBn
Bn
Bu
Bn
iBu
Bn
sBuLi (-78)
CO2
26
19
27
28
29
30
31
32
33
34
35
36
CO2H
58
77
45
63
90
60
80
74
81
64
68
45e
sBuLi/TMEDA (-78)
sBuLi (-78)
ClCO2Bn
ClCO2Bn
PhNCO
CO2
Me3SiNCO
Me3SiNCOc
PhNCO
CO2
CO2Bn
CONHPh
CO2H
nBuLi/TMEDA (-100)
nBuLi/TMEDA (-100)
nBuLi/TMEDA (-100)
nBuLi/TMEDA (-100)
nBuLi/TMEDA (-100)
tBuLi/TMEDA (-78)
nBuLi/TMEDAd (-100)
nBuLi/TMEDAd (-100)
tBuLi/TMEDAd (-78)
CN
CONH2
CONHPh
CO2H
CO2H
CO2H
H
9
iBn
H
10
11
12
BocHN
BocHN
BocHN
CO2
CO2
CO2
H
iBu
CO2H
a Trapping with electrophiles (2 equiv; excess for CO2 gas) was conducted warming the mixture to room temperature for 5 h. b Yields of isolated pure
products. c Trapping reaction conducted at -78 °C. d A total of 2.5 equiv of base used. e Unchanged starting material partially recovered (38%).
SCHEME 2. Reaction Pathway to r′-Methylated â-Lactam
19
around the â-lactam ring. Geometry of the lithium cation was
assumed to be tetrahedral, monocoordinated to the â-lactam or
(18) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
role played by the carbonyl groups of the â-lactam and
oxazolidinone moieties on the stabilization of R′-lithiated
â-lactams. To shed light on this problem, some ab initio B3LYP/
6-31G* calculations18 were conducted on structures 37-39
(Figure 3), featuring two simplified SiH3 groups and a R-methyl
substitution to discard additional conformational complexity
J. Org. Chem, Vol. 71, No. 17, 2006 6371

Palomo et al.
FIGURE 4. X-ray crystal structures for the N-[bis(silyl)methyl]-â-
lactams 10 (â-unsubstituted) and 13 (â-substituted), showing the
opposite spatial disposition of the CH(SiMe3)2 methine protons.
â-lactam carbonyl on R′-lithiated carbanions. A detailed inspec-
tion of the crystal structures of 10 and 13 revealed that in the
former case the CH(SiMe3)2 proton was pointing toward the
â-lactam carbonyl group, whereas in 13 the steric hindrance
between the â-isobutyl and trimethylsilyl groups blocked the
methine C-H bond into the opposite spatial orientation. It was
logical to assume that a similar conformational trend could be
kept up in the corresponding R′-lithiated carbanion from 13,
preventing any coordination between the lithium cation and
â-lactam carbonyl. As commented above (see Table 1, entry 8)
this agreed fully with the experimental observation that com-
pound 13 was the only N-[(silyl)methy]-â-lactam studied unable
to undergo R′-deprotonation. Indeed, cancellation of such
â-isobutyl/trimethylsilyl steric hindrance by elimination of one
trimethylsilyl group, restored the reactivity of the monosilylated
analogue 14 (see Table 1, entry 9 and Table 2, entry 9).
FIGURE 3. Relative B3LYP/6-31G* energies of R′-lithio-N-[bis(silyl)-
methyl]-â-lactams 37-39 solvated with two molecules of THF.
Hydrogen atoms omitted for clarity.
Conclusion
the oxazolidinone carbonyl groups in 37 and 38, respectively,
or chelated to both carbonyl oxygen atoms in 39. Two additional
THF molecules were incorporated as lithium cation solvates,
one of them external to the complex in the case of 39.
Computation was conducted following standard geometry-
optimization and energy-minimization protocols and yielded
relative destabilization of 4.48 and 12.68 kcal/mol for 38 and
39 with respect to the more stable structure 37. This energy
difference might arise from the considerable pyramidalization
strain imposed to the â-lactam planar nitrogen atom to reach
the structures 38 and 39 and also from the increased electronic
repulsion between the oxazolidinone and â-lactam carbonyl
oxygen electron lone pairs in the latter complex. While the
present results strongly suggested that coordination imparted
by the oxazolidinone (or Boc-) carbonyls is not strictly necessary
for R′-carbanion formation in R-alkyl-R-amino-N-[(silyl)-
methyl]-â-lactams, extension of the lithium carbanion model
37 to R-benzyl substituted â-lactams of the type 10, 12, or 14
could not be necessarily straightforward. Indeed, some additional
interaromatic π-stacking or even charge-transfer complex for-
mation between the benzylic and oxazolidinone phenyl groups
could come into play in these cases.
We have demonstrated that R-alkyl-R-amino-N-[(silyl)-
methyl]-â-lactams can be regarded as new N-methyl-â-lactam
cryptocarbanion sources. Compared to previously reported
nonenolate N-benzyl-â-lactams, the R-lithiated derivatives of
N-[(silyl)methyl]-â-lactams are remarkably stable, with no
apparent tendency to nucleophilic ring opening or ring-cyclo-
expansion side reactions. According to MO calculations and
experimental observations, the origin of such stability seems to
lie primarily on the coordination of the lithium cation by the
â-lactam carbonyl, and in a less extent, on the “R-effect” of
the trimethylsilyl groups. Alkylation at the R′-position preserving
the silyl moiety represents a new entry to elaborated N-
substituted â-lactams, potentially reactive under fluoride ion-
triggered conditions, while the spontaneous loss of the silyl
groups after trapping with carbon dioxide-derived electrophiles,
renders the N-[(trimethylsilyl)methyl]- groups directly amenable
to a variety of carboxylic acid derived functional groups. The
synthetic utility of the method has been illustrated with the direct
preparation of some dipeptide â-lactam surrogates, ready for
incorporation into inverse turn peptidomimetics under standard
peptide synthesis conditions.
Finally, X-ray analysis of compounds 10 and 13,19 R-alkylated
and R,â-dialkylated, respectively (Figure 4), provided an ad-
ditional indication of the relevant stabilizing effect of the
Experimental Section
General Procedure for the r′-Functionalization of N-[(tri-
methylsilyl)methyl]-azetidin-2-ones. A 0.60 M solution of nBuLi/
TMEDA in THF was prepared under nitrogen by adding dried
TMEDA (1.2 mmol, 0.18 mL) and 2.5 M BuLi (1.2 mmol, 0.48
mL) to anhydrous THF (1.30 mL) cooled to -100 °C (MeOH/
liquid nitrogen bath). This solution was immediately used after
(19) The crystallographic data for structures 10 and 13 have previously
been deposited at the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC-113859 and 132758, respectively, in
connection with refs 9b and 9a.
n
6372 J. Org. Chem., Vol. 71, No. 17, 2006

Functionalization of N-[(silyl)methyl]-â-lactam
preparation. In a separate flask, the corresponding 1-[(trimethylsi-
lyl)methyl]-azetidin-2-one (1 mmol) was dissolved in anhydrous
THF (3 mL), cooled to -100 °C (methanol/liquid nitrogen bath)
mL x 3) to yield the pure carboxylic acid. Analytically pure samples
were obtained after purification by column chromatography (silica
gel, eluent: EtOAc/hexanes).
n
under nitrogen, and 0.60 M BuLi/TMEDA solution (1.2 mmol,
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (Spain) (Project BQU2002-01737) and Gobierno
Vasco (ETORTEK-BiomaGUNE IE-05/143) for financial sup-
port, and SGIker UPV/EHU for NMR facilities and allocation
of computational resources (SGI/IZO). Grants from Gobierno
Vasco to A.B., from the University of the Basque Country to
L.C., and from the European Comission (Marie Curie HMPT-
CT-2000-00173) to R.M.F. are acknowledged.
2.0 mL) was added dropwise. The mixture was stirred at -100 °C
for 30 min and a 1 M solution of the corresponding electrophile
(2-10 mmol) in THF was added. The cooling bath was removed,
and the reaction mixture was allowed to warm to room temperature
for 5 h. For carboxylation reactions CO2 gas was collected in a
balloon, dried through a molecular sieves tube, and bubbled into
the carbanion solution until color disappearance (1-2 min). The
reaction mixture was quenched with saturated aqueous NH4Cl (4
mL) and extracted with CH2Cl2 (5 mL x 3), and the resulting organic
phase was dried (MgSO4) and evaporated. For the carboxylation
reaction, the crude was redissolved in CH2Cl2 (5 mL) and extracted
again with NaOH (0.2 M, 10 mL). The aqueous phase was
separated, acidified with 6 M HCl, and extracted with CH2Cl2 (5
Supporting Information Available: Physical and spectroscopic
data for compounds 10-36. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060537G
J. Org. Chem, Vol. 71, No. 17, 2006 6373