Chiral oxazolidinones as electrophiles: Intramolecular cyclization reactions with carbanions and preparation of functionalized lactams

Article abstract of DOI:10.1016/j.tetlet.2010.12.062

The intramolecular cyclizations of oxazolidinones with carbanions adjacent to sulfones, sulfoxides, and phosphonates proceed in high yields to obtain functionalized γ and δ lactams. The chiral oxazolidinone precursors can be readily synthesized from comme

Full text of DOI:10.1016/j.tetlet.2010.12.062

Tetrahedron Letters 52 (2011) 887–890
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chiral oxazolidinones as electrophiles: intramolecular cyclization reactions
with carbanions and preparation of functionalized lactams
⇑
Sarah Gibson, Hollie K. Jacobs, Aravamudan S. Gopalan
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003-8001, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The intramolecular cyclizations of oxazolidinones with carbanions adjacent to sulfones, sulfoxides, and
Received 12 November 2010
Revised 8 December 2010
Accepted 13 December 2010
Available online 21 December 2010
phosphonates proceed in high yields to obtain functionalized
c and d lactams. The chiral oxazolidinone
precursors can be readily synthesized from commercial amino acids. The lactams from this study are use-
ful synthetic intermediates, as demonstrated by the synthesis of a precursor for levetiracetam, an antiep-
ileptic drug.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lactam
Chiral oxazolidinone
Intramolecular cyclization
Levetiracetam
Asymmetric synthesis
Carbanions
It is generally thought that carbamates are unreactive toward
nucleophilic attack and it is this feature that has made them the
protecting groups of choice for amines. Benzyloxycarbonyl and
t-butoxycarbonyl derivatives of amines are extensively used in
synthesis due to their stability when exposed to basic nucleophiles
and ease of subsequent removal. In reality, carbamates can serve as
electrophiles in certain situations and have more potential than
appreciated in synthetic transformations.
undergo intramolecular cyclization upon treatment with strong
base to give
-sulfonyl lactams.6
a
The last few decades have witnessed an explosion in the use of
oxazolidinones, cyclic carbamates, as chiral auxiliaries.7 Oxazolid-
inones, like their acyclic carbamates, have not been exploited as
potential electrophiles in carbon–carbon bond forming reactions.
In an interesting example, N-arylsulfonyl derivatives of oxazolidi-
nones were found to undergo ortho or benzylic metalation. Intra-
molecular cyclization of the metalated intermediates on the
oxazolidinone carbonyl led to the formation of various sulfamyl
containing heterocycles including saccharins.8 Intramolecular
cyclization of an aryllithium on an oxazolidinone has been used
to prepare isoindolinones.9 Also, the intramolecular rearrangement
of oxazolidinones to succinamides in the presence of base has been
reported.10
As discussed, so far there has been very little interest in exploit-
ing the electrophilic chemistry of oxazolidinones for synthetic pur-
poses. A broad variety of chiral oxazolidinones can be readily
accessed from commercially available amino acid starting materi-
als.11 In this Letter, we disclose the results of our study on the
intramolecular cyclization reactions of chiral oxazolidinones with
stabilized carbanions and their applications in the preparation of
functionalized lactams.
The reactions of N-Boc amines with internal oxygen and nitro-
gen nucleophiles have been used extensively for the synthesis of
heterocycles including oxazolidinones and imidazolidinones.1
There have been some reports in the literature in which carba-
mates act as electrophiles upon treatment with carbanionic nucle-
ophiles. For example, a general route to amides via treatment of
carbamates of primary amines with highly basic Grignard reagents
has recently been disclosed.2 The reactions of carbamates with sul-
fonyl carbanions have been used to synthesize amidosulfones in
good yields.3 Similar reactions of carbamates with
a-phosphono
carbanions have also been reported.4
In contrast, there are only a few examples of intramolecular
reaction of carbamates with carbon nucleophiles. The formal syn-
thesis of the indole alkaloid deplancheine utilizing the cyclization
of a phosphonate with an internal trichloroethyl carbamate is
one particularly relevant example.5 Previous research in our labo-
ratory demonstrated that carbamate derivatives of aminosulfones
We hypothesized that oxazolidinones such as those shown in
Scheme 1 carrying sulfones, sulfoxides, and phosphonates should
undergo deprotonation with LHMDS and then cyclize to give a
bridged intermediate. Since oxygen is generally a better leaving
group than nitrogen, the intermediate would collapse to give the
lactam product. There was some question as to whether steric
⇑
Corresponding author. Tel.: +1 575 646 2589; fax: +1 575 646 2649.
E-mail address: agopalan@nmsu.edu (A.S. Gopalan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.062

888
S. Gibson et al. / Tetrahedron Letters 52 (2011) 887–890
O
O
R
HSPh, DBU
Benzene, rt, 1h
O-
3a-b
R
N
Bn
LHMDS
O
N
O
N
EWG
EWG
O
SPh
( )n
HPO(OEt)2,
NaH, THF,
0 C - 60 C, 24h
( )n
( )n
EWG = SO2Ph,
SOPh, PO(OEt)2
4a, n = 1 (94%)
4b, n = 2 (94%)
°
°
LHMDS
O
O
°
mCPBA, CH2Cl2, 0 C - rt, 2h
or
NaIO4, H2O/CH3OH, 0 C - rt, 3 - 5h
R
N
Bn
O
N
°
HO
PO(OEt)2
( )n
EWG
Predicted product
( )n
O
Bn
N
7a, n = 1 (89%)
7b, n = 2 (61%)
O
Scheme 1. Proposed cyclization reaction of oxazolidinones.
S(O)mPh
( )n
5a, m = 2, n = 1 (99%)
5b, m = 2, n = 2 (94%)
6a, m = 1, n = 1 (72%)
6b, m = 1, n = 2 (81%)
constraints would allow formation of the bicyclic intermediate in
the intramolecular cyclization. One would expect the size of the
newly generated ring to be critical for the success of this reaction.
The requisite sulfonyl, sulfinyl, and phosphono oxazolidinones
(n = 1) for the cyclization studies were conveniently accessed from
H2, PdCl2, EtOH, rt, 24h
alcohol 1a which has been previously prepared from
(Scheme 2).12 The alcohol 1b (n = 2) was prepared in a similar man-
ner starting from -glutamic acid. Selective N-benzylation of 1a–b
was achieved upon treatment of the substrates with benzyl bro-
mide and KF/Al2O3. Subsequent treatment of N-benzyl oxazolidi-
nones 2a–b with methanesulfonyl chloride in the presence of
triethylamine in DCM gave the corresponding mesylates 3a–b in
good yields.
L-aspartic acid
O
R
L
O
N
SO2Ph
8a, R = H, 98%
8b, R = allyl, 54%
Allyl bromide, KF/Al2O3
CH3CN, rt, 48h
The oxazolidinones 3a–b were easily converted to the corre-
sponding sulfonyl, sulfinyl, and phosphono derivatives (Scheme 3).
Mesylates 3a–b reacted with thiophenol in the presence of DBU in
benzene to give phenyl sulfides 4a–b. These were oxidized to give
the sulfones 5a–b and sulfoxides 6a–b using mCPBA and NaIO4,
respectively. Reaction of the mesylates with the sodium salt of
diethyl phosphite gave phosphonates 7a–b. N-Allyl oxazolidinone
8b was prepared for this study from the N-benzyl oxazolidinone
5b, which was in hand. The oxazolidinone 5b was debenzylated by
hydrogenolysis in the presence of PdCl2 to give 8a, which was then
treated with allyl bromide and KF/Al2O3 to give N-allyl oxazolidi-
none 8b.
With oxazolidinones 5–8 in hand, their intramolecular cycliza-
tion reactions were examined. In a representative example, the sul-
fone 5a was treated with LHMDS (2.1 equiv) in THF at ꢀ78 °C for
5 h and then the reaction mixture warmed to 0 °C for an additional
hour. The reaction mixture was quenched with acetic acid and
worked up using standard procedures. As predicted, the hydroxy-
Scheme 3. Synthesis of sulfone, sulfoxide, and phosphono oxazolidinones 5–8.
methyl lactam 9a was obtained as the major product (ꢁ40%) along
with surprisingly some of its O-trimethylsilyl derivative (presum-
ably formed by the silylation of the alkoxide of 9a with hexameth-
yldisilazane under the reaction conditions). Subsequent reactions
were worked up with 2 N HCl in order to isolate only the desired
product. With this change in work up, the yield of the cyclization
improved dramatically to give 9a in a yield of 95% after chromato-
graphic purification. Using the same reaction protocol, the intra-
molecular cyclizations of the other sulfonyl, sulfinyl, and
phosphono oxazolidinone derivatives 5–8 were found to proceed
in excellent yields (Table 1).13
The intramolecular cyclization of oxazolidinones provided
access to a variety of functionalized chiral lactams. The chemistry
of the sulfoxide and phosphonate lactams was of particular interest
as they have the potential to be valuable synthetic intermediates.
When sulfoxide lactams 9c and 9d were heated at 100 °C in the
presence of PPh3 on polystyrene,
a,b-unsaturated lactams 10a
O
and 10b were obtained in good yields after chromatography
(Scheme 4). It is important to note that stereoselective 1,4-addi-
.
HCl H2N
CO2CH3
CO2CH3
O
NH
ref 12
tions to a,b-unsaturated lactams have found much use in the syn-
OH
( )n
thesis of biologically active targets.14,15 Indeed, the stereoselective
1,4-addition of an aryl cuprate to the O-silylated N-Boc analog of
10a has been used in the asymmetric synthesis of (R)-(ꢀ)-Roli-
pram, a potent inhibitor of cardiac cyclic AMP phosphodiester-
n
1a-b
BnBr, KF/Al2O3
CH3CN, rt, 24h
ase,16 and (R)-Baclofen,
a
derivative of the inhibitory
O
O
neurotransmitter GABA.17 It is our belief that the ready availability
of 10a and 10b should allow preparation of some drugs of interest
and their analogs.
MsCl, TEA
Bn
Bn
O
N
O
N
°
CH2Cl2, 0 C, 2h
OMs
( )n
OH
( )n
It was also of interest to study the Horner–Wadsworth–Em-
mons (HWE) reactions of phosphonolactams 9e and 9f. Lactam
9e was treated with propionaldehyde in the presence of DBU and
3a, n = 1 (98%)
3b, n = 2 (89%)
2a, n = 1 (62%)
2b, n = 2 (80%)
LiCl to give the
a,b-unsaturated lactam which was subjected to
Scheme 2. Synthesis of mesylates 3a and 3b.
Pd/C catalyzed hydrogenation giving 11a in 56% yield after column

S. Gibson et al. / Tetrahedron Letters 52 (2011) 887–890
Bn
889
Table 1
O
Bn
O
1. Propionaldehyde
DBU, LiCl, CH3CN,
rt, 5h, quant.
Results of the cyclization reactions of oxazolidinones 5–8
N
N
HO
HO
Oxazolidinone Conditions
Lactama
Yield
(%)
PO(OEt)2
2. H2, 5% Pd/C, EtOH,
rt, 24h, 56%
9e
11a
Bn
O
O
O
N
LHMDS (2.1 equiv)
THF, N2
ꢀ78 °C, 5 h; 0 °C, 1 h
HO
5a
5b
6a
6b
7a
7b
95
81
90
94
96
98
1. Propionaldehyde,
DBU, LiCl, CH3CN,
rt, 3h
O
O
SO2Ph
SO2Ph
Bn
Bn
PO(OEt)2
9a
O
N
N
2. TBDMSCl, TEA,
DMAP, CH2Cl2,
TBDMSO
HO
Bn
°
0 C-rt, 24h, 79%
LHMDS (2.1 equiv)
THF, N2
ꢀ78 °C, 2 h; 0 °C, 1 h
11b
9f
N
1. H2, 5% Pd/C, EtOH,
rt, 24h
HO
HO
2. TBAF, THF, rt,
3h, 70%
O
9b
Bn
Bn
N
LHMDS (2.1 equiv)
THF, N2
ꢀ78 °C, 5 h; 0 °C, 1 h
N
HO
SOPh
SOPh
11c
9c
O
Scheme 5. HWE reaction and hydrogenation of phosphono lactams 9e and 9f.
Bn
LHMDS (2.1 equiv)
THF, N2
ꢀ78 °C, 5 h; 0 °C, 1 h
N
HO
HO
The intramolecular cyclizations of oxazolidinones 5–8 pro-
ceeded to give functionalized lactams in excellent yields. Now it
was of interest to see whether such cyclization reactions could
be extended to oxazolidinones of the type I, in which the electron
withdrawing moiety is attached to the nitrogen of the oxazolidi-
none ring system and not tethered to a carbon in the ring (Scheme
6). An important driving force for this study was a desire to apply
our new methodology to the synthesis of a key lactam intermedi-
ate 12, which has found use in the synthesis of the anti-epileptic
drug levetiracetam, which is marketed under the name of Kep-
praÒ.19 Although a number of other multi-step racemic and chiral
syntheses have also been reported for levetiracetam,20 our method
would be new and would provide a pathway to make analogs of
the drug including the corresponding d-lactam.
The required starting material for this synthesis, (S)-4-ethyl-2-
oxazolidinone, was readily prepared from (S)-2-amino-1-buta-
nol.21 Treatment of the oxazolidinone with phenylsulfinylpropyl
bromide and KF/Al2O3 gave the sulfide, which was oxidized with
NaIO4 to give cyclization substrate 13 in 73% yield (Scheme 7).
The oxazolidinone 13 underwent cyclization upon treatment with
LHMDS to give sulfinyl lactam 14 in 93% yield after chromato-
graphic purification. Attempts to directly remove the sulfinyl
group using Ni2B led to the isolation of a mixture of products.22
Thus, desulfinylation of lactam 14 was achieved via thermal elim-
ination of the sulfoxide by heating with PS-PPh3 followed by
hydrogenation to give the known intermediate 12,23 which has
been converted to levetiracetam in two steps.
9d
Bn
N
LHMDS (2.1 equiv)
THF, N2
ꢀ78 °C, 2 h; 0 °C, 1 h
PO(OEt)2
PO(OEt)2
9e
O
Bn
LHMDS (2.1 equiv)
THF, N2
ꢀ78 °C, 4 h; 0 °C, 1 h
N
HO
9f
O
SO2Ph
LHMDS (2.1 equiv)
THF, N2
ꢀ78 °C, 3.5 h; 0 °C, 1 h
N
8
Quant.
HO
9g
a
Isolated as mixtures of diastereomers.
O
O
Bn
SOPh
PS-PPh3, Toluene
Bn
N
N
°
100 C, 4.5h
HO
HO
( )n
( )n
9c-d
10a, n = 0, 70%
10b, n = 1, 77%
Scheme 4. Thermal elimination of sulfinyl lactams 9c and 9d.
2 steps
ref 19
n
n
O
O
N
N
chromatography (Scheme 5). Phosphonolactam 9f was treated in a
similar manner with propionaldehyde in the presence of DBU and
LiCl. In this case, in an attempt to aid in product isolation, the crude
HWE product was treated with TBDMSCl, TEA, and DMAP to give
the O-silylated product 11b, which was easily isolated in high pur-
ity after chromatographic purification. The O-silylated product was
then hydrogenated and the silyl group was removed by treatment
with TBAF to give 11c in good yield. In the case of both 11a and
11c, only one stereoisomer, presumed to be cis, was isolated after
purification. Both 1H and 13C NMR spectra clearly indicated that
the hydrogenations proceed with high diastereoselectivity.18
OH
CONH2
Levetiracetam
12
n=1
EWG
O
n
intramolecular
EWG
acylation
O
N
n
O
N
OH
I
Scheme 6. Retrosynthetic analysis of levetiracetam and potential analogs.

890
S. Gibson et al. / Tetrahedron Letters 52 (2011) 887–890
5. Itoh, T.; Matsuya, Y.; Enomoto, Y.; Ohsawa, A. Heterocycles 2001, 55, 1165–
O
O
1171.
1. PhS(CH2)3Br, KF/Al2O3
CH3CN, rt, 24h
6. Hernandez, N. M.; Sedano, M. J.; Jacobs, H. K.; Gopalan, A. S. Tetrahedron Lett.
2003, 44, 4035–4039.
O
NH
SOPh
O
N
°
7. Zappia, G.; Cancelliere, G.; Gacs-Baitz, E.; Delle Monache, G.; Misiti, D.; Nevola,
L.; Botta, B. Curr. Org. Synth. 2007, 4, 238–307.
8. (a) MacNeil, S. L.; Familoni, O. B.; Snieckus, V. J. Org. Chem. 2001, 66, 3662–
3670; (b) Aliyenne, A. O.; Khiari, J. E.; Kraïem, J.; Kacem, Y.; Hassine, B. B.
Tetrahedron Lett. 2006, 47, 6405–6408; (c) Aliyenne, A. O.; Kraïem, J.; Kacem, Y.;
Hassine, B. B. Tetrahedron Lett. 2008, 49, 1473–1475.
9. Ahn, G.; Lorion, M.; Agouridas, V.; Couture, A.; Deniau, E.; Grandclaudon, P.
Synthesis 2011, 147–153.
10. Cheng, M.; De, B.; Wahl, C. T.; Almstead, N. G.; Natchus, M. G.; Pikul, S.
Tetrahedron Lett. 1999, 40, 5975–5977.
2. NaIO4, H2O/CH3OH, 0 C -
rt, 24h, 73%
13
LHMDS (2.1eq),
°
THF, N2, -78 C, 4h;
°
0 C, 1h, 93%
SOPh
1. PS-PPh3, Toluene
°
100 C, 2h, 70%
11. Gawley, R. E.; Aubé, J. Principles of Asymmetric Synthesis; Elsevier Science: New
York, 1996.
12. Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Org. Chem. 2001, 66, 206–215.
O
O
N
N
2. H2, 5% Pd/C, EtOH
rt, 24h, 66%
OH
OH
13. Representative cyclization procedure. Synthesis of 9b. To
a solution of 5b
(0.453 g, 1.26 mmol) in dry THF (25 mL) under N2 at ꢀ78 °C was added LHMDS
(2.6 mL, 2.6 mmol). The mixture was stirred at ꢀ78 °C for 2 h, then warmed to
0 °C and stirred for 1 h. The reaction was quenched with 2 N HCl (10 mL) and
stirred at room temperature for 30 min. The THF was removed in vacuo and the
product was extracted into EtOAc (3 ꢂ 30 mL). The organic layer was washed
with saturated NaHCO3 (2 ꢂ 30 mL), saturated NaCl (30 mL), dried (Na2SO4)
and the solvent removed in vacuo. The crude product was purified by silica gel
chromatography to give 9b (0.368 g, 81%) as a light yellow solid as a ca. 1:1
12
14
Scheme 7. Synthesis of levetiracetam intermediate 12.
In summary, the intramolecular cyclizations of oxazolidinones
with carbanions of sulfones, sulfoxides, and phosphonates are a
useful and hitherto unexplored class of reactions. The results de-
tailed in this Letter clearly demonstrate that these cyclic carba-
mates are effective electrophiles and can serve as precursors to
mixture of diastereomers: IR (KBr) 3437, 2941, 1640 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.97–7.82 (m, 2H), 7.66–7.45 (m, 3H), 7.36–7.13 (m, 5H), 5.27 (d,
J = 15.4 Hz, 0.5H), 5.00 (d, J = 15.3 Hz, 0.5H), 4.28 (d, J = 15.3 Hz, 0.5H), 4.15 (t,
J = 8.0 Hz, 0.5H), 4.07–3.95 (m, 1H), 3.74–3.59 (m, 1.5H), 3.58–3.48 (m, 0.5H),
3.48–3.34 (m, 1H), 2.79–2.53 (m, 2H), 2.49–2.33 (m, 0.5H), 2.30–2.08 (m,
1.5H), 2.97–1.83 (m, 0.5H), 1.80–1.57 (m, 0.5H); 13C NMR (75 MHz, CDCl3) d
163.3, 162.8, 139.5, 139.3, 136.6, 136.5, 133.8, 133.6, 129.1, 129.0, 128.9, 128.8,
128.71, 128.69, 127.51, 127.48, 127.42, 127.40, 65.6, 65.4, 62.3, 62.1, 57.2, 56.5,
49.2, 48.1, 23.1, 22.6, 18.8; HRMS (M++1) m/z calcd for C19H22NO4S 360.12695,
found 360.1277.
prepare functionalized chiral
c and d lactams that can be further
manipulated. The oxazolidinone cyclization chemistry was also
used to access a key intermediate in the synthesis of an important
medicinal compound, levetiracetam. Our studies stress the need
for further investigation on the electrophilic chemistry of oxazolid-
inones. This includes extension of the intramolecular cyclizations
to the corresponding six-membered 1,3-oxazinan-2-ones and
applications to the synthesis of other biologically interesting aza-
cyclic systems.
14. Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon
Press: New York, 1997.
15. (a) Oba, M.; Saegusa, T.; Nishiyama, N.; Nishiyama, K. Tetrahedron 2009, 65,
128–133; (b) Spiess, S.; Berthold, C.; Weihofen, R.; Helmchen, G. Org. Biomol.
Chem. 2007, 5, 2357–2360.
16. Diaz, A.; Siro, J. G.; García-Navío, J. L.; Vaquero, J. J.; Alvarez-Builla, J. Synthesis
1997, 559–562.
17. Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1992, 3, 1213–1221.
18. The cis-geometry for the products is assigned based on steric constraints in the
hydrogenation. Spectral studies (DEPT, gCOSY, and gHSQC, and NOESY) for 11a
and 11c were inconclusive in confirming the stereochemical assignment.
19. (a) Imahori, T.; Omoto, K.; Hirose, Y.; Takahata, H. Heterocycles 2008, 76, 1627–
1632; (b) Kotkar, S. P.; Sudalai, A. Tetrahedron Lett. 2006, 47, 6813–6815.
20. (a) Boschi, F.; Camps, P.; Comes-Franchini, M.; Muñoz-Torrero, D.; Ricci, A.;
Sánchez, L. Tetrahedron: Asymmetry 2005, 16, 3739–3745; (b) Sarma, K. D.;
Zhang, J.; Huang, Y.; Davidson, J. G. Eur. J. Org. Chem. 2006, 3730–3737.
21. Neri, C.; Williams, J. M. J. Adv. Synth. Catal. 2003, 345, 835–848.
22. Sakulsaknimitr, W.; Kuhakarn, C.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M.
ARKIVOC 2009, 81–97.
Acknowledgments
This research was supported in part by a grant from the Na-
tional Institutes of Health under PHS Grant No. 1SC3GM084809-
01. The NSF GRFP and NSF LS-AMP are thanked for fellowships to
S.G.
References and notes
23. Spectral analysis (IR and NMR) of 12 was consistent with those reported in the
1. Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701–2724.
2. Latorre, A.; Rodríguez, S.; Izquierdo, J.; González, F. V. Tetrahedron Lett. 2009, 50,
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literature. However, our value for the optical rotation of 12, ½a D21
ꢀ20.4 (c 0.9,
ꢃ
CHCl3), was higher than the literature value of ½a D28
ꢀ11.8 (c 0.9, CHCl3) (Ref.
ꢃ
19a) reported (% ee not specified). The MTPA ester obtained upon treatment of
12 with (R)-MTPA chloride in pyridine had only one signal by fluorine NMR
analysis, suggesting high enantiomeric purity of alcohol 12 from our studies.