Novel Applications of the Sch?llkopf Chiral Auxiliary: A New and Efficient Enantioselective Synthesis of β-Lactams Possessing a C-4 Quaternary Stereocenter

Article abstract of DOI:10.1055/s-2003-42103

A new method for the enantioselective synthesis of substituted β-lactams is described based upon an improved alkylation of substituted Scho?llkopf chiral auxiliaries by α-haloacetate esters, employing tert-butyllithium as the deprotonating base, and the efficient conversion of the resulting quaternary 2,5-diketopiperazines to the targeted β-lactams.

Full text of DOI:10.1055/s-2003-42103

2398
LETTER
Novel Applications of the Schöllkopf Chiral Auxiliary: A New and Efficient
Enantioselective Synthesis of b-Lactams Possessing a C-4 Quaternary
Stereocenter
N
ovel Applica
t
tions
o
a
f
the Schöl
m
A
uxilia
a
ry tia Vassiliou,a Constantinos Dimitropoulos,a Plato A. Magriotis*b
a
Department of Chemistry, University of Athens, 15711 Athens, Greece
b
Department of Chemistry, St. Peter’s College, 2641 Kennedy Boulevard, Jersey City, NJ 07306, USA
E-mail: pmagriotis@earthlink.net
Received 15 September 2003
Abstract: A new method for the enantioselective synthesis of sub-
stituted b-lactams is described based upon an improved alkylation
of substituted Schöllkopf chiral auxiliaries by a-haloacetate esters,
employing tert-butyllithium as the deprotonating base, and the effi-
cient conversion of the resulting quaternary 2,5-diketopiperazines
to the targeted b-lactams.
1. n-BuLi
THF, –78 °C
H3CO
H3CO
N
6
3
N
N
N
OCH3
OCH3
2. BrCH2CO2Bn
THF, –78 °C
R1
CO2Bn
R1
0 °C
Key words: Schöllkopf chiral auxiliary, b-lactam, tert-butyllithi-
um, quaternary stereocenter, a-haloacetate ester, enantioselective
synthesis
1
2 ( R1= CH3)
a R1= CH3
b R1= H
1.TFA
CH3CN/H2O
25 °C
c R1= CH2Ph
2. ArSO2Cl
(i-Pr)2NEt
THF/CH2Cl2
DMAP,25 °C
d R1= CH2CH2PO(OC2H5)2
b-Lactams can serve as mechanism-based inhibitors of
serine proteases1 and as inhibitors of acyl-CoA cholester-
ol acyltransferase (ACAT), which is mainly responsible
for artherosclerotic coronary heart disease.2 For this rea-
son, the development of new methodology for enantiose-
lective synthesis of b-lactams could prove useful in
synthesizing novel antimicrobial agents and new drugs.
Despite numerous advances,3 we envisioned that the more
established chiral auxiliary-based enantioselective meth-
odology might lead to improved routes to b-lactams.4 Spe-
cifically, it was thought that alkylation of substituted
Schöllkopf chiral auxiliary 1a5 with benzyl bromoacetate,
followed by hydrolysis and b-lactam ring closure of the
derived b-arylsulfonamide acid,6 might deliver enantio-
merically pure b-lactams 4 as shown in Scheme 1.
CO2CH3
R1
1. H2(1Atm), 10%
Pd/C
SO2Ar
N CO2CH3
H
N
O
O
R1
CO2Bn
MeOH, 25 °C
S O
Ar
2. EDC,4-Pyrrolidino-
pyridine, CH2Cl2, 25 °C
4 (R1= CH3)
Ar = Pmc
3 ( R1= CH3)
Ar = Pmc
Scheme 1
tert-BuLi was employed as the deprotonating base in sub-
sequent experiments. Gratifyingly, in this case, the yield
of 2 (Scheme 1) increased from 24% to 72%.8
This significant yield improvement is attributed to the ex-
clusively basic action of t-BuLi toward the less hindered
C-3 hydrogen as opposed to the one at C-6 as well as its
negligible nucleophilicity toward the imino esters. It also
prompted us to examine the same alkylation of 1b, which
represents by far the most widely used auxiliary of this
type. In the event, n-BuLi proved to be the base of choice
for the glycine-derived auxiliary 1b, a result, which is
consistent with numerous literature reports (85% isolated
yield after reaction of the corresponding enolate with ben-
zyl bromoacetate; 60% yield employing t-BuLi). This lat-
ter result strongly suggests that the reduced acidity of 1a
as compared to that of 1b, might be the most important
factor in explaining this disparate deprotonation protocols
established for 1a and 1b. In accordance with these re-
sults, when the phenylalanine-derived Schöllkopf’s chiral
auxiliary 1c (Scheme 1), was deprotonated (in separate
experiments) with n-BuLi and t-BuLi followed by reac-
tion with benzyl bromoacetate, the isolated yields of 2
(R1 = CH2Ph, Scheme 1) were 54% and 81% respectively.
In this Letter, we report the successful execution of this
concept. At the outset, it was expected that deprotonation
of the bis-lactim ether 1a (Schöllkopf’s chiral auxiliary)
derived from the 2,5-diketopiperazine corresponding to
cyclo(L-Val-Ala-), with n-BuLi as usual,5,7 followed by
reaction with benzyl bromoacetate, would give rise to
alkylated bis-lactim ether 2 in good yield and high diaste-
reomeric excess (>95%).5,7 However, when this deproto-
nation-alkylation protocol was applied, the isolated yield
of 2 (R1 = CH3, Scheme 1) or 2a (Table 1) was found to be
rather low (24%). This result was initially attributed to the
high nucleophilicity of n-BuLi toward the imino ester
functionalities of bis-lactim ether 1a due to the streaky be-
haviour of the crude reaction mixture on TLC (decompo-
sition of 1a). As a result, the bulkier (less nucleophilic)
SYNLETT 2003, No. 15, pp 2398–2400
0
1
.1
2
.2
0
0
3
Advanced online publication: 22.10.2003
DOI: 10.1055/s-2003-42103; Art ID: S09403ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Applications of the Schöllkopf Chiral Auxiliary
2399
In fact, brief inspection of Table 1, clearly indicates that almost quantitative b-lactam ring closure (one-pot con-
tert-BuLi should be the base of choice for the deprotona- version of 3 to 4).15 Work is in progress on the conversion
tion–alkylation of substituted Schöllkopf’s chiral auxilia- of 2e and 2f (Table 1) to the corresponding 3,4-trisub-
ries 1 (Scheme 1),9 an operation which is expected to stituted b-lactams.
serve well in the enantioselective construction of quater-
nary stereocenters.10
Acknowledgment
Table 1 Deprotonation–Alkylation of Schöllkopf Chiral Auxiliary
1a with Various Electrophilic Bromides
This work was supported by the research program Kapodistrias
(70/4/6490) administered by the University of Athens. Support by
St. Peter’s College (Department of Chemistry) is also gratefully
acknowledged. We are warmly thankful to our colleague Professor
Athanasios Yiotakis for sustained encouragement and advice.
1. n-BuLi or t-BuLi
THF, –78 °C
H3CO
N
H3CO
N
N
OCH3
N
2. RBr
THF, –78 °C
OCH3
R
CH3
0 °C
References
1a
2
(1) (a) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14,
127. (b) Mascaretti, O. A.; Boschetti, C. E.; Danelon, G. O.;
Mata, E. G.; Roveri, O. A. Curr. Med. Chem. 1995, 1, 441.
(c) Wilmouth, R. C.; Kassamaly, S.; Westwood, N. J.;
Sheppard, R. J.; Clatridge, T. D.; Aplin, R. T.; Wright, P. A.;
Pritchard, G. J.; Schofield, C. J. Biochemistry 1999, 38,
7989.
(2) (a) Burnett, D. A.; Caplen, M. A.; Davis, H. R. Jr.; Burrier,
R. E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733.
(b) Chen, L.-Y.; Zaks, A.; Chackalamanil, S.; Dugar, S. J.
Org. Chem. 1996, 61, 8341.
Entry R-Br
1
Product
n-BuLi
Yield (%) Yield (%)
tert-BuLi
2a
2b
2c
2d
2e
24
51
63
54
44
72
83
90
71
58
BnO2C
Br
2
3
4
5
Ph
Br
Br
Br
Ph
H3C
(3) (a) For a recent highlight, see: Magriotis, P. A. Angew.
Chem. Int. Ed. 2001, 40, 4377. (b) For catalytic
H
BnO2C
Br
enantioselective methods published prior to and
6
2f
27
35
H
CH3
Br
inadvertently omitted from this highlight, see: Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Daniel, K. L.
Tetrahedron Lett. 1992, 33, 7819. (c) Doyle, M. P.; Kalinin,
A. V. Synlett 1995, 1075. (d) Watanabe, N.; Anada, M.;
Hashimoto, S.; Ikegami, S. Synlett 1994, 1031. (e) Anada,
M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 9063.
(f) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org.
Chem. 1995, 60, 4099. (g) For catalytic, enantioselective b-
lactam synthetic methodology published after this highlight,
see: (h) Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed. 2003,
42, 3921. (i) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc.
2002, 124, 1578. (j) Cordova, A.; Watanabe, S.; Tanaka, F.;
Notz, W.; Barbas, C. F. III J. Am. Chem. Soc. 2002, 124,
1866. (k) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 4572. (l) Shah, M. H.; France, S.; Lectka, T. Synlett
2003, 1937. (m) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc.
Chem. Res. 2003, 36, 10.
BnO2C
Specifically, products 2a–f were obtained in much higher
yield when the deprotonation of 1a was performed with
tert-BuLi as opposed to n-BuLi.8,9 Interestingly, alkyla-
tion of 1a with (R)-2-bromopropionic acic benzyl ester
(entry 5, Table 1)11 was much more efficient than that em-
ploying benzyl (S)-2-bromopropionate (entry 6, Table 1),
a result representing a case of kinetic resolution which
was corroborated by the fact that the alkylation yield of 1a
using tert-BuLi and racemic benzyl-2-bromopropionate
was 45%.12
Hydrolysis of the alkylated 2,5-diketopiperazine 2a
(Table 1) followed by sulfonylation (Pmc-Cl, Et3N)13,14 of
the derived a,b-amino diester produced a,b-arylsulfona-
mide diester 3 (Scheme 1) in very good overall yield
(75%). Catalytic hydrogenolysis of 3 and cyclodehydra-
tion of the resulting b-arylsulfonamide acid provided the
desired b-lactam 4 (R1 = CH3, Scheme 1) in 91% yield
and high optical purity (>95%).
(4) Seyden-Penne, J. Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; John Wiley and Sons: New York,
1995.
(5) (a) Schöllkopf, U. Topics in Current Chemistry 1983, 109,
65. (b) Schöllkopf, U. Pure Appl. Chem. 1983, 55, 1799.
(6) Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 613.
(7) (a) Schöllkopf, U.; Westphalen, K.-O.; Schröder, J.; Horn,
K. Liebigs Ann. Chem. 1988, 781. (b) Ma, C.; Liu, X.; Li,
X.; Flippen-Anderson, J.; Yau, S.; Cook, J. M. J. Org. Chem.
2001, 66, 4525.
(8) The diastereomeric excess of 2 is estimated to be >95% since
the minor diastereomer could not be detected by 1H NMR
analysis of the crude reaction mixture.
(9) Schöllkopf and coworkers have previously reported the use
of tert-BuLi for the deprotonation-alkylation of 1d (Scheme
1) with benzyl bromide in 75% yield, but they stated that use
of n-BuLi gave the same result (compare with entry 2, Table
1): Schöllkopf, U.; Busse, U.; Lonsky, R.; Hinrichs, R.
Liebigs Ann. Chem. 1986, 2150.
In summary a new enantioselective b-lactam synthesis
employing the Schöllkopf chiral auxiliary has been dem-
onstrated. The success of this new method giving rise to
b-lactams possessing a C-4 quaternary stereocenter, lies
in the development of an effective deprotonation protocol
for substituted Schöllkopf chiral auxiliaries 1 (Scheme 1)
employing t-BuLi instead of the widely accepted for this
purpose n-BuLi.5,7 Furthermore, the efficiency of this new
methodology relies on the one-pot conversion of 2 to 3
(Scheme 1)14 in very good isolated yield as well as on the
Synlett 2003, No. 15, 2398–2400 © Thieme Stuttgart · New York

2400
S. Vassiliou et al.
LETTER
(10) For recent reviews on the enantioselective construction of
quaternary stereocenters, see: (a) Fuji, K. Chem. Rev. 1993,
93, 2037. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem.
Int. Ed. 1998, 37, 388. (c) Christoffers, A.; Mann, A.
Angew. Chem. Int. Ed. 2001, 40, 4591.
(11) Kim, S.; Lee, S. I.; Kim, Y. C. J. Org. Chem. 1985, 50, 560.
(12) For precedent on kinetic resolution observed in the
alkylation of 1a with certain racemic epoxides, see: Gull, R.;
Schöllkopf, U. Synthesis 1985, 1052.
(13) Ramage, R.; Green, J. Tetrahedron Lett. 1987, 28, 2287.
(14) Typical Experimental Procedure for the One-Pot
Conversion of 2 to 3 (Scheme 1): To a solution of 2 (0.30
g, 0.87 mmol) in MeCN–H2O (2 mL each), trifluoroacetic
acid (0.5mL) was added and the resulting solution was
stirred at ambient temperature for 10 h. Then it was
Hz), 3.66 (s, 3 H), 4.95 (AB, 2 H, JAB = 15 Hz), 6.00 (s, 1 H),
7.32 (br s, 5 H).
13C NMR (62.90 MHz, CDCl3): d = 12.4, 17.4, 18.3, 21.7,
24.2, 26.9, 32.9, 42.9, 53.3, 60.1, 66.9, 74.1, 118.6, 128.3,
128.4, 128.7, 135.7, 136.1, 170.2, 173.9, 195.6.
MS (EI): 518.65 [M + 1]+.
(15) Typical Experimental Procedure for the One-Pot
Conversion of 3 to 4 (Scheme 1): To a solution of 3 (260
mg, 0.5 mmol) in MeOH (20 mL) containing a few drops of
H2O, 10% Pd/C (40 mg) was added and the suspension was
hydrogenated at ambient temperature for 3 h. Filtration over
celite and evaporation to dryness afforded the desired b-
Pmc-sulfonamide acid as a white solid (210 mg, quant.)
which was dissolved in CH2Cl2 (5 mL) and stirred at ambient
temperature while N-(3-dimethylaminopropyl)-N-ethyl-
carbodiimide hydrochloride (EDC·HCl, 120 mg, 0.6 mmol)
and 4-pyrrolidinopyridine (4-PPY, 5 mg) were added. The
resulting solution was stirred for 2 h at ambient temperature
and then CH2Cl2 (20 mL) was added and the organic phase
was washed with 0.1 N HCl and H2O, dried over Na2SO4,
and evaporated to dryness. The resulting solid was purified
by column chromatography using EtOAc/petroleum ether
(9:1) as eluent to furnish 4 as a white solid (186 mg, 91%
overall yield).
evaporated to dryness (azeotrope with toluene) and further
dried in a desiccator over phosphorus pentoxide. This crude
material was suspended in CH2Cl2 (1.5 mL), cooled in an ice
bath and 2,2,5,7,8-pentamethyl-chromane-6-sulfonyl
chloride (Pmc-Cl)13 (0.60 g, 2.00 mmol) was added followed
by Et3N (0.52 mL, 3.74 mmol). The resulting solution was
stirred at ambient temperature for 2 h and then CH2Cl2 (20
mL) was added. The organic phase was successively washed
with 0.1 N HCl, 5% NaHCO3, H2O, evaporated to dryness
and the resulting crude solid was purified by column
chromatography using petroleum ether/EtOAc (4:1) as
eluent to give 3 as an oil (336 mg, 75% overall yield).
1H NMR (250 MHz, CDCl3): d = 1.25 (s, 6 H), 1.41 (s, 3 H),
1.78 (d, 2 H J = 6.6 Hz), 2.10 (s, 3 H), 2.54 (s, 3 H), 2.56 (s,
3 H), 2.60 (t, 1 H, J = 6.6 Hz), 2.83, 3.20 (AB, 2 H, JAB = 15
1H NMR (250 MHz, CDCl3): d = 1.30 (s, 6 H), 1.70 (s, 3 H),
1.82 (d, 2 H J = 6.6 Hz), 2.11 (s, 3 H), 2.52 (s, 3 H), 2.53 (s,
3 H), 2.62 (t, 1 H, J = 6.6 Hz), 2.87, 3.40 (AB, 2 H,
J
AB = 15.4 Hz), 3.50 (s, 3 H).
13C NMR (62.90 MHz, CDCl3): d = 12.4, 14.4, 17.4, 18.4,
20.9, 21.6, 26.8, 26.9, 29.9, 49.6, 53.0, 61.7, 74.7, 118.9,
125.2, 138.7, 138.7, 156.2, 162.5, 170.4.
MS (EI): 410.50 [M + 1]+.
Synlett 2003, No. 15, 2398–2400 © Thieme Stuttgart · New York