Stereoselective synthesis of highly substituted γ-lactams by the [3+2] annulation of α-siloxy allylic silanes with chlorosulfonyl isocyanate

Article abstract of DOI:10.1021/ol060596g

A stereoselective synthesis of γ-lactams by the [3+2] annulation of α-siloxy allylic silanes with N-chlorosulfonyl isocyanate (CISO ₂NCO) was developed. The use of these allylic silanes allowed for further diastereoselective substitution of the

Full text of DOI:10.1021/ol060596g

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2127-2130
Stereoselective Synthesis of Highly
Substituted -Lactams by the [3 2]
Annulation of -Siloxy Allylic Silanes
γ
+
r
with Chlorosulfonyl Isocyanate
Antonio Romero and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
kwoerpel@uci.edu
Received March 11, 2006
ABSTRACT
A stereoselective synthesis of
developed. The use of these allylic silanes allowed for further diastereoselective substitution of the resultant N,O-acetal to give highly substituted
-lactams. Oxidation of the silyl group afforded access to complex -hydroxy- -lactams.
γ-lactams by the [3+2] annulation of r-siloxy allylic silanes with N-chlorosulfonyl isocyanate (ClSO2NCO) was
γ
â
γ
The γ-lactam functionality represents an important core
structure in numerous biologically active compounds.1,2
Functionalized chiral γ-lactams have also proven to be
valuable intermediates for the synthesis of γ-amino acids.3
In this letter, we report the stereoselective construction of
γ-lactams by the [3+2] annulation reaction of R-siloxy allylic
silanes with N-chlorosulfonyl isocyanate (ClSO2NCO). The
resultant γ-lactam could be elaborated by diastereoselective
nucleophilic substitution via an N-acyliminium ion4 to afford
highly substituted â-hydroxy-γ-lactams after oxidation of the
carbon-silicon bond.5
substituted five-membered rings.6 For example, the [3+2]
annulation of allylic silanes with ClSO2NCO7 provides the
key ring systems for the syntheses of (+)-blastmycinone8
and (()-peduncularine.9 These two syntheses illustrate the
two reaction pathways through which ClSO2NCO can
proceed.8 Annulation across the CdO bond yields the
N-chlorosulfonyl iminolactone, which was utilized in the
synthesis of (+)-blastmycinone.8 The more common annu-
lation involves addition across the CdN bond to afford the
N-chlorosulfonyl lactam, the intermediate required for the
synthesis of (()-peduncularine.9 The general preference for
annulation across the CdN bond can be overridden by steric
effects, as shown in the (+)-blastmycinone synthesis.8,9 In
the absence of any steric or electronic preference, a mixture
of both products is observed.8
The [3+2] annulation reaction of allylic silanes has proven
to be a powerful transformation for the preparation of highly
(1) Corey, E. J.; Li, W.-D. Z. Chem. Pharm. Bull. 1999, 47, 1-10.
(2) Gouliaev, A. H.; Senning, A. Brain Res. ReV. 1994, 19, 180-222.
(3) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119-125.
(6) Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. J. Org. Chem. 1992,
57, 6094-6097.
(4) For reviews of N-acyliminium ion chemistry, see: (a) Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-3856. (b) Maryanoff,
B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
ReV. 2004, 104, 1431-1628.
(5) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694-1696. (b) Tamao, K. In AdVances in Silicon Chemistry;
JAI: Greenwich, CT, 1996; Vol. 3, pp 1-62. (c) Fleming, I.; Henning, R.;
Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J. J. Chem. Soc., Perkin Trans.
1 1995, 317-337. (d) Fleming, I. Chemtracts-Org. Chem. 1996, 9, 1-64.
(7) (a) Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434-
1435. (b) Isaka, M.; Williard, P. G.; Nakamura, E. Bull. Chem. Soc. Jpn.
1999, 72, 2115-2116. (c) Colvin, E. W.; Loreto, M. A.; Monteith, M.;
Tommasini, I. In Frontiers in Organosilicon Chemistry; Bassindale, A. R.,
Gaspar, P. P., Eds; The Royal Society of Chemistry: Cambridge, U.K.,
1991; pp 356-365. (d) Colvin, E. W.; Monteith, M. J. Chem. Soc., Chem.
Commun. 1990, 1230-1232.
(8) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675-678.
(9) Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2, 621-623.
10.1021/ol060596g CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/13/2006

In our efforts to expand the scope of [3+2] annulations,
we investigated annulation reactions of R-siloxy allylic
silanes. Although the reactions of R-siloxy allylic silanes
have been reported,10 these silanes have not been utilized in
[3+2] annulations. Application of R-siloxy allylic silanes in
[3+2] annulations was desired because of their expedient
syntheses,11 the facile preparation of asymmetric variants,12
and the functionality available in the annulation products.
A preliminary investigation of R-siloxy allylic silanes with
ClSO2NCO provided promising results. Allylic silane 1 was
treated with ClSO2NCO to provide γ-lactam 2, after reductive
removal of the chlorosulfonyl moiety, as the only annulation
product (Scheme 1). Lactam 2 was formed as a single
Table 1. Annulation Reactions of R-Siloxy Allylic Silanesa
with ClSO2NCOb
Scheme 1. [3+2] Annulation of R-Siloxy Allylic Silanes 1
with ClSO2NCO
diastereomer as determined by 1H NMR spectroscopic
analysis, and its relative stereochemistry, which is consistent
with other annulations,7-9 was proven by X-ray crystal-
lography. No formation of the N-chlorosulfonyl iminolactone
was observed, a marked difference from previous annulation
studies involving ClSO2NCO.8
The [3+2] annulation to form γ-lactams was general for
a wide range of R-siloxy allylic silanes (3-10). In all cases,
γ-lactams were formed exclusively. The stereospecificity of
this reaction was illustrated by the annulation reactions of
the isomeric allylic silanes 1 and 6, which provided diaster-
eomeric lactams 2 and 14 (Table 1). Compounds bearing
tetrasubstituted carbon stereocenters13 and bicyclic structures
were accessed through this methodology with the appropriate
allylic silanes (7 and 8). The annulation was also shown to
proceed with retention of stereochemical integrity. Enan-
tioenriched allylic silanes (S)-1 afforded γ-lactam (+)-2 with
no loss of optical purity, thus providing a route to chiral,
nonracemic γ-lactams.14
A study of various silyl moieties demonstrated that more
electron-donating15 and more sterically encumbering silyl
(10) Hosomi, A.; Hashimoto, H.; Sakurai, H. J. Org. Chem. 1978, 43,
2551-2552.
(11) Synthesis of R-siloxy allylic silanes was achieved by the protection
of R-hydroxy allylic silanes. Numerous reports have been published for
the synthesis of R-hydroxy allylic silanes: (a) Brook, A. G. Acc. Chem.
Res. 1974, 7, 77-84. (b) Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai,
Y.-M.; Szczepanski, S. W. J. Org. Chem. 1985, 50, 5393-5396. (c) Ager,
D. J.; Fleming, I.; Patel, S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2520-
2526. (d) Burke, S. D.; Saunders, J. O.; Oplinger, J. A.; Murtiashaw, C.
W. Tetrahedron Lett. 1985, 26, 1131-1134. (e) Cirillo, P. F.; Panek, J. S.
J. Org. Chem. 1994, 59, 3055-3063. (f) Koreeda, M.; Koo, S. Tetrahedron
Lett. 1990, 31, 831-834.
(12) Asymmetric syntheses of R-hydroxy allylic silanes: (a) Takeda, K.;
Ohnishi, Y.; Koizumi, T. Org. Lett. 1999, 1, 237-239. (b) Sakaguchi, K.;
Higashino, M.; Ohfune, Y. Tetrahedron 2003, 59, 6647-6658.
(13) Dennisova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146.
a R1 ) Ph2CH. R2 ) PhCMe2. b All transformations were performed in
CH2Cl2 at 0 °C unless otherwise stated. c Analysis of unpurified mixtures
by 1H NMR spectroscopy revealed only lactam products. d Isolated yields.
1
e A 5:1 mixture of diastereomers was observed by H NMR spectroscopy
of the unpurified annulation products. f Annulation was performed at -78
°C. g As determined by chiral HPLC.
groups16 led to improved yields for the [3+2] annulation.
Replacing the phenyl group of the silicon with benzhydryl
or cumyl functionalities (allylic silanes 9 and 10) resulted
2128
Org. Lett., Vol. 8, No. 10, 2006

in improved yields of the desired product as compared to
analogous substrates 1 and 4.
Scheme 2. Annulation of R-Acetoxy Allylic Silane 19 with
The exclusive formation of γ-lactam products in the [3+2]
annulation of R-siloxy allylic silanes with ClSO2NCO
demonstrated that R-siloxy allylic silanes do not behave like
other allylic silanes. The difference in behavior may be
understood by analyzing the reactivities of the zwitterionic
intermediates.7a These intermediates possess different char-
acteristics depending on the substitution at the R-position.
In previous studies, allylic silanes without an R-heteroatom
were used, resulting in â-silyl stabilized carbocation inter-
mediate IA.17 These electrophiles would be attacked along
a trajectory of 90° from the carbon plane (Figure 1).18 Allylic
ClSO2NCO
nium ion character in this intermediate produces an inter-
mediate that behaves more like IA (Figure 1). The lower
Table 2. Substitution of γ-Lactams Using N-Acyliminium Ion
Chemistry
Figure 1. Ring-closing intermediates in the [3+2] annulation
mechanism.
silanes possessing an R-heteroatom lead to a â-silyl oxo-
carbenium ion intermediate IB.19 The trajectory of approach
for attack onto an oxocarbenium ion is likely to be closer to
the Burgi-Dunitz angle (109°).20 The difference in trajec-
tories diminishes any steric interactions that disfavor cy-
clization on the nitrogen (Figure 1).8
A [3+2] annulation with an R-acetoxy allylic silane
demonstrates how a small perturbation in the intermediate
affects product distribution. Treatment of R-acetoxy allylic
silane 19 with ClSO2NCO afforded a mixture of N-chloro-
sulfonyl γ-lactam 20 and N-chlorosulfonyl iminolactone
21 (Scheme 2). Utilizing an R-acetoxy allylic silane would
generate an intermediate possessing an R-oxygen with
less electron-donating ability.21 The diminished oxocarbe-
(14) The stereochemistry of (S)-1 was assigned by analogy. See ref 12a.
The stereochemistry of the lactam (+)-2 was assigned utilizing the accepted
[3+2] annulation mechanism. For the mechanism of the [3+2] annulation,
see ref 7a.
(15) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-
957.
(16) (a) Kno¨lker, H.-J.; Foitzik, N.; Goesmann, H.; Graf, R. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1081-1083. (b) Akiyama, T.; Ishikawa,
K.; Ozaki, S. Chem. Lett. 1994, 627-630. (c) Groaning, M. D.; Brengel,
G. P.; Meyers, A. I. J. Org. Chem. 1998, 63, 5517-5522.
(17) (a) Lambert, J. B. Tetrahedron 1990, 46, 2677-2689. (b) Lambert,
J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu, X.; So, J.-H.; Chelius,
E. C. Acc. Chem. Res. 1999, 32, 183-190.
a R1 ) Ph2CH. R2 ) PhCMe2. b For reaction conditions, see Supporting
Information. c All reactions afforded one diastereomer as determined by
1H NMR spectroscopy of the unpurified products. d Isolated yield.
(18) Laube, T. Acc. Chem. Res. 1995, 28, 399-405 and references
therein.
selectivity of the [3+2] annulation of R-acetoxy allylic
silanes with ClSO2NCO, as compared with R-siloxy allylic
(19) Stabilization of an oxocarbenium ion by a â-silyl group is consistent
with IR studies that show hyperconjugation between σCSi and π*CO. Peddle,
G. J. D. J. Organomet. Chem. 1968, 14, 115-121.
(20) Rakhmankulov, D. L.; Akhmatdinov, R. T.; Kantor, E. A. Russ.
Chem. ReV. 1984, 53, 888-899.
(21) Begue, J.-P.; Charpentier-Morize, M. Acc. Chem. Res. 1980, 13,
207-212.
Org. Lett., Vol. 8, No. 10, 2006
2129

silanes, suggests that the electron-donating ability of the
heteroatom is critical for selective product formation.
The [3+2] annulation of R-siloxy allylic silanes with
ClSO2NCO provided γ-lactams possessing an N,O-acetal
moiety, which is ideal for substitution via N-acyliminium
ion chemistry.4 Initial attempts to substitute γ-lactams
possessing the phenyldimethylsilyl group were unsuccessful.
The products obtained from these experiments had undergone
desilylation. To suppress desilylation, the sterically encum-
bered benzhydryldimethylsilyl and cumyldimethylsilyl groups
were utilized.22
A series of γ-lactams 16-18 possessing these larger
silyl groups were converted to γ-substituted γ-lactams
via N-acyliminium ion intermediates. High diastereoselec-
tivity was observed for a range of nucleophiles, including
allylic silanes, silyl enol ethers, and zinc and aluminum
complexes (Table 2).23 The products were formed by
nucleophilic attack anti to the silyl group, in accord with
previous studies.24
Scheme 3. Oxidation of the Silyl Group
In summary, the [3+2] annulation reaction of R-siloxy
allylic silanes with chlorosulfonyl isocyanate provides an
efficient stereoselective synthesis of γ-lactams. These γ-lac-
tams can be further substituted at the γ-position with high
diastereoselectivity. Oxidative cleavage of the C-Si bond
allowed access to highly substituted â-hydroxy-γ-lactams.
Acknowledgment. This research was supported by the
National Science Foundation (CHE-0315572). A.R. thanks
the National Institute of Health for a predoctoral fellowship.
We thank Dr. Phil Dennison for assistance with NMR
spectroscopy, Dr. Joseph Ziller and Dr. Bob Doedens for
X-ray crystallography, and Dr. John Greaves and Dr. John
Mudd for mass spectrometry.
Oxidation of the silyl moiety afforded â-hydroxy-γ-
lactams.25 Exposing γ-lactam 27 to Tamao-Fleming oxida-
tion conditions5 provided â-hydroxy-γ-lactam 28 in 63%
1
yield as a single diastereomer as determined by H NMR
spectroscopic analysis (Scheme 3).
(22) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2000, 2, 1379-1381.
(23) The stereochemistry of γ-lactam 25 was confirmed by X-ray
crystallography and nOe studies. The stereochemistry of all other substituted
γ-lactams were proven by nOe studies.
(24) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868-9870.
(25) The benzhydryldimethylsilyl group led to better oxidation yields
as compared to the cumyldimethylsilyl group.
Supporting Information Available: Full experimental
procedures and product characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL060596G
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