Chemoselective syntheses of γ-butyrolactams using vinyl sulfilimines and dichloroketene

Article abstract of DOI:10.1021/ol050245m

(Chemical Equation Presented) Reactions between vinyl sulfilimines and dichloroketene generated in situ from trichloroacetyl chloride in the presence of zinc-copper couple give mixtures of α-dichloro-γ-butyrolactams and a-dichloro-γ-butyrolactone imines.

Full text of DOI:10.1021/ol050245m

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1915-1917
Chemoselective Syntheses of
-Butyrolactams Using Vinyl Sulfilimines
and Dichloroketene
Joseph P. Marino* and Nanfei Zou
γ
Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556
marino.12@nd.edu
Received February 4, 2005
ABSTRACT
Reactions between vinyl sulfilimines and dichloroketene generated in situ from trichloroacetyl chloride in the presence of zinc
−copper couple
give mixtures of -dichloro- -butyrolactams and -dichloro- -butyrolactone imines. Fine-tuning of substituents within vinyl sulfilimines results
r
γ
r
γ
in reactions with good chemoselectivity and yield for lactams.
The γ-butyrolactam moiety is a very important component
of many natural products.1 It serves not only as an important
pharmacophore in the drug discovery process2 but also as a
key intermediate in the synthesis of biologically and phar-
maceutically relevant molecules.3
Over the past decade, our group has been interested in
developing and utilizing a γ-lactonization reaction involving
chiral vinyl sulfoxides with dichloroketene (Scheme 1, X )
O).4 This reaction can transfer the chirality of sulfur to as
many as three contiguous carbon centers through a novel
[3,3]-sigmatropic rearrangement of an intermediate vinyl
oxsulfonium enolate 2. The γ-lactonization reaction was later
applied by our group and others to the total syntheses of
natural products and medicinally useful compounds.5 It had
been recently demonstrated as a powerful tool for the
construction of quarternary carbon centers in a stereoselective
formation of a functionalized γ-lactone key intermediate
toward enantioselective synthesis of (+)-aspidospermidine.6
While sulfilimines are generally treated as the nitrogen
analogues of sulfoxides, they have received less attention
than sulfoxides.7 Herein, by applying our knowledge of
γ-lactonization reaction, we report a novel chemoselective
synthesis of γ-butyrolactams based on the reaction between
vinyl sulfilimine and dichoroketene.8
When p-tolyl styryl N-p-toluenesulfonyl (tosyl or Ts)
sulfilimine 5f was treated with trichloroacetyl chloride in
Scheme 1. Lactonization Reaction and Proposed
Lactamization Reaction
(1) (a) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355. (b) Masse,
C. E.; Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org. Chem. 2000,
2513. (c) Corey, E. J.; Li, W.-D. Chem. Pharm. Bull. 1999, 47, 1.
(2) (a) Schreiber, S. L.; Standaert, R. F.; Fenteany, G.; Jamison, T. F.
U.S. Patent 6 645 999, 2003. (b) Baldwin, J. E.; Lynch, G. P.; Pitlik, J. J.
Antibiotics 1991, 44, 1.
(3) Zhang, J.; Blazecka, P. G.; Davidson, J. G. Org. Lett. 2003, 5, 553
and references therein.
(4) (a) Marino, J. P.; Neisser, M. J. Am. Chem. Soc. 1981, 103, 7687.
(b) Marino, J. P.; Perez, A. D. J. Am. Chem. Soc. 1984, 106, 7643. (c)
Marino, J. P.; Laborde, E.; Paley, R. S. J. Am. Chem. Soc. 1988, 110, 966.
(d) Marino, J. P. Pure Appl. Chem. 1993, 65, 667.
10.1021/ol050245m CCC: $30.25
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the presence of zinc-copper couple in THF at -30 °C, the
sulfilimine reacted with dichloroketene generated in situ and
converted to two products as observed on thin-layer chro-
matography. Upon purification, these two products were
identified as N-tosyl dichlorolactam 6f and dichlorolactone
Table 1. Lactam Reaction of Styryl Sulfilimines with
Dichloroketene
1
N-tosylimine 7f in a ratio of 62:38 according to H NMR
analysis on the crude reaction mixture. Even though these
two compounds behaved similarly on 1H and 13C NMR, their
IR spectra showed quite different characteristic absorption
bands. While the CdO stretching frequency of the N-tosyl
lactam occurred at 1765 cm-1, 1665 cm-1 was assigned to
that of CdN in the lactone N-tosylimine.9 Given the poor
nucleophilicity property of N-tosyl-stabilized amido anion,
it is not surprising that both N-alkylation and O-alkylation10
occurred competitively at the stage of the sulfonium inter-
mediate 3 (Scheme 1, X ) NR2), leading to N-tosyl lactam
and lactone N-tosylimine, respectively.
It was found that the ratio of lactam to lactone imine
showed no response to temperature variation (-30, 0, and
25 °C). Suspecting that N-tosyl group further diminished the
nucleophilicity of the amido anion within sulfonium inter-
mediate 3, we changed the substituents on nitrogen of
sulfilimine and synthesized a series of N-arylsulfonyl sul-
filimines (Table 1, entries a-d) with either an electron-
donating group (EDG) or an electron-withdrawing group
(EWG) on benzene to adjust the electronic character of the
sulfonyl group.11 N-Benzyloxycarbonyl (Cbz) sulfilimine 5e
was also synthesized in hope that the desired product N-Cbz
lactam would allow simple deprotection to give the free
lactam. First, only a 4% improvement in the lactam/lactone
ratio was observed as the N-sulfonyl substituent was changed
from electron-withdrawing to electron-donating group. To
our delight, the overall conversion and combined yield of
lactam and lactone imine improved, which may indicate
favorable lactamization and lactonization with electron-rich
sulfilimines. Therefore, it is not surprising that strong EWGs
such as p-nitrobenzenesulfonyl in sulfilimine 5d shut down
the reaction completely. On the other hand, N-Cbz sulfilimine
lactam:lactone yield
entry
R1
R2
imineb
(%)c
a
b
c
d
e
f
g
h
i
Ph
Ph
Ph
Ph
Ph
Tol
Ts
59:41
57:43
61:39
N/A
71
65
78
NRd
N/Ae
74
55
84
81
82
70f
80
p-ClC6H4SO2
p-MeOC6H4SO2
p-NO2C6H4SO2
Cbz
Ts
Ts
N/A
62:38
57:43
66:34
90:10
95:5
p-ClC6H4
p-MeOC6H4 Ts
n-C6H13
c-C6H11
t-Bu
Ts
Ts
Ts
Ts
j
k
l
88:12
95:5
Bn
a Reaction conditions: trichloroacetyl chloride 5 equiv, zinc 20 equiv,
copper(I) chloride 20 equiv, THF, -30 °C, 0.5 h. b Determined by 1H NMR
analysis. c Combined, isolated yield of lactam and lactone imine and isolated
yield of lactams 7i-l. d No reaction. e Phenyl styryl sulfide was isolated in
90%. f N-Tosylstyryl sulfenamide was isolated in 20%.
5e denitrogenated to give 92% yield of phenyl styryl sulfide.8
When R1 was varied from an EWG (p-chlorobenzene) to an
EDG (p-methoxybenzene) within N-tosyl sulfilimines 5g and
5h, the lactam/lactone ratio increased only a marginal 9%
but the overall yield increased 29%. Better selectivity for
the lactam was reached when R1 was switched to alkyl
groups (Table 1, entries i-l). Both primary and secondary
alkyl groups worked well in terms of chemoselectivity and
yields for lactams. As for tert-butyl N-tosyl sulfilimine 5k,
about 20% N-p-tolylstyryl sulfenamide was obtained in
addition to an 88:12 ratio of lactam and lactone imine in
70% yield. This sulfenamide was likely generated from the
sulfilimine 5k with nitrogen abstracting a proton from the
tert-butyl group and eliminating it as isobutene.12
Functionalized vinyl sulfilimines were tested for compat-
ibility with lactamization conditions (Table 2, entries 2-4).
High selectivity for lactams was found in crude reaction
mixtures, and good isolated yields were obtained. Cyclo-
hexenyl sulfilimine 22 also reacted smoothly to give 79%
yield of ring-fused lactam 23.
(5) (a) Marino, J. P.; Bogdan, S.; Kimura, K.J. Am. Chem. Soc. 1992,
114, 5566. (b) Kosugi, H.; Mirura, Y.; Kanna, H.; Uda, H. Tetrahedron:
Asymmetry 1993, 4, 1409. (c) Burke, S. D.; Shankaran, K.; Helber, M. J.
Tetrahedron Lett. 1991, 32, 4655. (d) Bravo, P.; Arnone, A.; Bandiera, P.;
Bruche, L.; Ohashi, Y.; Ono, T.; Sekine, A.; Zanda, M. Eur. J. Org. Chem.
1999, 111.
(6) Marino, J. P.; Rubio, M. B.; Cao, G.; de Dios, A. J. Am. Chem. Soc.
2002, 124, 13398.
(7) (a) Ruano, J. L. G.; Alemparte, C.; Clemente, F. R.; Gutierrez, L.
G.; Gordillo, R.; Castro, A. M. M.; Ramos, J. H. R. J. Org. Chem. 2002,
67, 2919. (b) Taylor, P. C. Sulfur Rep. 1999, 21, 241. (c) Gilchrist, T. L.;
Moody, C. J. Chem. ReV. 1977, 77, 409. (d) Johnson, C. R. In Compre-
hensiVe Organic Chemistry; Barton, D. H., Ollis, W. D., Eds.; Pergamon:
New York, 1979; Vol. 3, Chapter 11. (e) Oae, S.; Furukawa, N. Sulfilimines
and Related DeriVatiVes; ACS Monograph 179; American Chemical
Society: Washington DC, 1983.
However, it was found that â-disubstituted vinyl sulfil-
imine 20 reacted slowly even when 20% more trichloroacetyl
chloride was added to the reaction and the reaction was held
at -30 °C for extended time. Similarly, cis-vinyl sulfilimines
16 and 18 reacted slower than their trans counterparts 5j
and 8, respectively. This may indicate that the approach by
dichloroketene to the N-tosyl nitrogen was hindered by the
cis substituents.
(8) For a report on N-acyl sulfilimine reacting with diphenylketene to
give oxazolinone and sulfide, see: Abou-Gharbia, M.; Ketcha, D. M.;
Zacharias, D. E.; Swern, D. J. Org. Chem. 1985, 50, 2224.
(9) Fretschi, S.; Vasella, A. HelV. Chim. Acta 1991, 74, 2024.
(10) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792.
(11) (a) N-Arylsulfonyl sulfilimines 5b-d (Table 1) and N-Cbz sulfil-
imines 5e (Table 1) were prepared according to methods in ref 11b. Sodium
N-chloro-N-arylsulfonamides and sodium N-chloro-N-carbamate were made
by procedures adapted from refs 11c,d. (b) Marzinzik, A. L.; Sharpless, K.
B. J. Org. Chem. 2001, 66, 594. (c) Rudolph, J.; Sennhenn, P. C.; Vlaar,
C. P.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2810. (d)
Campbell, M. M.; Johnson, G. Chem. ReV. 1978, 78, 65.
The relative stereochemistry of N-tosyl dichlorolactam was
confirmed by an NOE study. Analogous to the previously
(12) Mukaiyama, T.; Matsuo, J.-I.; Kitagawa, H. Chem. Lett. 2000, 1250.
Org. Lett., Vol. 7, No. 10, 2005
1916

Table 2. Lactam Reaction of Functionalized Vinyl Sulfilminesa
Scheme 2
Pummerer-type intermediate;13 and (3) N-tosylamido anion
and N-tosylimino oxyanion intramolecularly trap this inter-
mediate to produce the observed N-tosyl lactam and lactone
N-tosylimine, respectively.
Dechlorination of dichlorolactam 24 with zinc, HOAc, and
TMEDA proceeded in excellent yield (Scheme 2).14 Selective
detosylation was obtained when N-tosyl lactam 25 was
treated with sodium anthrathene10 in THF at -70 °C to give
lactam 26 with a labile γ-alkylthio group. This lactam would
be a useful precursor for acyliminium ion chemistry.15
In conclusion, we have disclosed a γ-lactamization reaction
between vinyl sulfilimines and dichloroketene. Upon judi-
cious selection of substituents within the sulfilimine, good
selectivity of γ-lactam over γ-lactone imine has been
established. We are currently exploring an asymmetric entry
to this reaction and its applications to natural products
synthesis, and our results will be reported in due course.
Acknowledgment. We thank University of Notre Dame
for its generous support of this program. We also thank Mr.
Anthony Turpoff for making compound 6a. During our
preparation of this manuscript, we were informed by Prof.
Albert Padwa of Emory University of their recent work on
similar systems of this reaction.16
Supporting Information Available: Experimental pro-
cedures and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050245M
a Abbreviation: Cy ) cyclohexyl. b Isolated yield.
(13) Kosugi, H.; Uda, H.; Yamagawa, S. J. Chem. Soc., Chem. Commun.
1975, 192.
proposed mechanism of γ-lactonization,4 it is suggested that
(1) the highly eletrophilic dichloroketene acylates the sul-
filimine nitrogen atom to generate the vinyl aminosulfonium
enolate; (2) a [3,3]-sigmatropic rearrangement gives a
(14) Danheiser, R. L.; Savariar, S. Tetrahedron Lett. 1987, 28, 3299.
(15) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431.
(16) Wang, Q.; Nara, S.; Padwa, A. Org. Lett. 2005, 7, 839.
Org. Lett., Vol. 7, No. 10, 2005
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