Stereoselective synthesis of substituted γ-butyrolactones by the [3 + 2] annulation of allylic silanes with chlorosulfonyl isocyanate: Enantioselective total synthesis of (+)-blastmycinone

Article abstract of DOI:10.1021/ol0069960

Equation presented (+)-blastmycinone A stereoselective synthesis of γ-butyrolactones by the [3 + 2] annulation of allylic silanes with N-chlorosulfonyl isocyanate (CSI) was developed. An enantioselective total synthesis of (+)-blastmycinone was accomplish

Full text of DOI:10.1021/ol0069960

ORGANIC
LETTERS
2001
Vol. 3, No. 5
675-678
Stereoselective Synthesis of Substituted
γ-Butyrolactones by the [3 + 2]
Annulation of Allylic Silanes with
Chlorosulfonyl Isocyanate:
Enantioselective Total Synthesis of
(+)-Blastmycinone
Zhi-Hui Peng and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
kwoerpel@uci.edu
Received December 13, 2000
ABSTRACT
A stereoselective synthesis of γ-butyrolactones by the [3 + 2] annulation of allylic silanes with N-chlorosulfonyl isocyanate (CSI) was developed.
An enantioselective total synthesis of (+)-blastmycinone was accomplished using this annulation as the key step.
The γ-butyrolactone skeleton represents an important core
structure in many biologically active natural products.1
Functionalized chiral γ-butyrolactones are also particularly
useful synthetic building blocks.2 Consequently, the develop-
ment of new methods for the synthesis of γ-butyrolactones,
particularly in a stereocontrolled fashion, has received
considerable attention.2,3 Herein we report a method for the
stereoselective construction of the γ-butyrolactone subunit
by the [3 + 2] annulation reaction of substituted allylic
silanes with N-chlorosulfonyl isocyanate (ClSO2NCO). An
enantioselective synthesis of the polyketide metabolite (+)-
blastmycinone (1) was achieved using this annulation to
establish the configurations of the three contiguous stereo-
centers simultaneously.
We recently developed a stereoselective route to substi-
tuted 2-pyrrolidinones by the [3 + 2] annulation reaction of
allylic silanes with ClSO2NCO.4 Our studies on this reaction
showed that while annulation across the CdN bond of ClSO2-
NCO was usually favored, annulation across the CdO bond
was found in one case as a minor product.4a Previously,
cycloadditions across both the CdN and CdO bonds were
observed in cycloaddition reactions of ClSO2NCO with
unactivated alkenes.5
(1) Connolly, J. D.; Hill, R. A. Dictionary of Terpenoids; Chapman and
Hall: London, 1991; Vol. 1, pp 476-541.
(2) Koch, S. S. C.; Chamberlin, A. R. J. Org. Chem. 1993, 58, 2725-
2737 and references therein.
(3) For selected recent examples, see: (a) Zhang, Q.; Lu, X. J. Am. Chem.
Soc. 2000, 122, 7604-7605. (b) Kiegiel, J.; Nowacki, J.; Tarnowska, A.;
Stachurska, M.; Jurczak, J. Tetrahedron Lett. 2000, 41, 4003-4006. (c)
Gagnier, S. V.; Larock, R. C. J. Org. Chem. 2000, 65, 1525-1529. (d)
Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999, 121, 11680-11683. (e)
Chatani, N.; Tobisu, M.; Asaumi, T.; Fukumoto, Y.; Murai, S. J. Am. Chem.
Soc. 1999, 121, 7160-7161. (f) Fukuzawa, S.-i.; Seki, K.; Tatsuzawa, M.;
Mutoh, K. J. Am. Chem. Soc. 1997, 119, 1482-1483. (g) Harcken, C.;
Bru¨ckner, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 2750-2752. (h) Brown,
H. C.; Kulkarni, S. V.; Rachera, U. S. J. Org. Chem. 1994, 59, 365-369.
(4) (a) Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434-
1435. (b) Nakamura also reported the preparation of γ-lactams from allylic
silanes and ClSO2NCO: Isaka, M.; Williard, P. G.; Nakamura, E. Bull.
Chem. Soc. Jpn. 1999, 72, 2115-2116.
10.1021/ol0069960 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/14/2001

In studies of the reactivity of R-silylmethyl-substituted
allylic silanes such as 2a6 in the [3 + 2] annulation reactions,7
we made a surprising discovery. The reaction of 2a with
ClSO2NCO gave the N-chlorosulfonyl iminolactone 3a, the
product of annulation across the CdO bond, as the major
product. The hydrolysis of the unpurified intermediates
afforded γ-lactone 5a in 79% yield,8 which could be easily
separated from N-chlorosulfonyl lactam 4a (8% yield), the
product of annulation across the CdN bond (Scheme 1).
Table 1. Annulation Reactions of Allylic Silanes with
ClSO2NCOa
Scheme 1
Lactone 5a and lactam 4a were both formed as single
diastereomers as determined by using 1H NMR spectroscopic
analysis, and the stereochemistry of 5a was confirmed by
X-ray crystallography.
A series of allylic silanes were synthesized to investigate
the competition between annulation across the CdN and the
CdO bonds in order to develop the reaction into a route to
γ-butyrolactones (Table 1). First, reaction of ClSO2NCO with
allylic silane 2b,6 which possessed an allylic benzhydryldi-
methylsilyl group, gave essentially the same result as our
previous work with dimethylphenylsilyl allylic silanes.4a,9
This result indicated that the nature of silyl substituent does
not control the outcome of the reaction. To eliminate cation
stabilization by the terminal â-silyl group of 2a as the cause
for the preferential annulation across the CdO bond, the
reaction of allylic silane 2c was investigated. The stabilization
offered by the phenyl group did not strongly influence the
product ratio. These results showed that the electronic effects
of the allylic silyl group and the R-substituent were not
a A solution of allylic silane 2 in CH2Cl2 was treated with an excess of
chlorosulfonyl isocyanate at 0 °C. After consumption of 2, the unpurified
intermediate was then treated with either 25% Na2SO3 in CH2Cl2 (2b, 2c,
2g) or 1 N HCl in THF (2d, 2e, 2f). b R3Si ) (Ph2CH)Me2Si. c The CdO
and CdN annulation ratio was determined by 1H NMR spectroscopy of
the unpurified annulation intermediates. d Isolated yield of pure material.
e Diastereomer ratios determined by GC analyses of the unpurified products.
f Alkene ratios of the allylic silanes 2 determined by GC analyses. g Because
significant amount of protodesilylation occurred for this substrate, the
reaction was conducted at -50 °C with 10 mol % of proton scanvenger
2,6-di-tert-butyl-4-methylpyridine.
responsible for the observed preference for the CdO
annulation path for silane 2a.
The steric size of the R-substituent of the allylic silane
exerted a strong influence on the annulation. The CdO
annulation pathway was strongly favored for (E)-crotysilane
2d, (Z)-crotylsilane 2e, and the terminal allylic silane 2f with
a large neopentyl group at the R-position. Consistent with
the CdN annulation pathway,4 the CdO annulation pathway
was also stereospecific and highly stereoselective. Terminal
alkene 2g also favored the CdO annulation pathway.4a
Apparently, steric effects exerted by the substituents in allylic
silanes 2 play an important role in determining the outcome
of the reaction.
(5) (a) Malpass, J. R.; Tweddle, N. J. J. Chem. Soc., Perkin Trans. 1
1977, 874-884. (b) Barends, R. J. P.; Speckamp, W. N.; Huisman, H. O.
Tetrahedron Lett. 1970, 12, 5301-5304. (c) Dunkelblum, E. Tetrahedron
Lett. 1972, 14, 1551-1554.
(6) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2000, 2, 1379-1381.
(7) For leading references on the [3 + 2] annulation of allylic silanes,
see: (a) Kno¨lker, H.-J.; Foitzik, N.; Goesmann, H.; Graf, R. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1081-1083. (b) Panek, J. S.; Yang, M. J. Am.
Chem. Soc. 1991, 113, 9868-9870. (c) Akiyama, T.; Ishikawa, K.; Ozaki,
S. Chem. Lett. 1994, 627-630. (d) Danheiser, R. L.; Dixon, B. R.; Gleason,
R. W. J. Org. Chem. 1992, 57, 6094-6097.
(8) The optimal solvent proved to be CH2Cl2. Temperature did not greatly
affect the CdO to CdN annulation ratio.
(9) Only the CdN annulation product lactam 4b was obtained if the
annulation reaction was conducted in toluene, see ref 6.
676
Org. Lett., Vol. 3, No. 5, 2001

The proposed mechanism of the annulation4 and the origin
of the competition between CdN and CdO annulations are
illustrated in Scheme 2. The electrophilic attack by chloro-
centers, mostly in a stepwise fashion. The [3 + 2] annulation
reaction of allylic silanes provides an efficient way to access
all three stereocenters in one key step with high enantio-
and diastereocontrol.
The enantioselective synthesis of (+)-blastmycinone started
with the THP-protected propargyl alcohol 10 (Scheme 3).
Scheme 2
Scheme 3
sulfonyl isocyanate onto the allylic silane yields the â-silyl
carbocation 7. A [1,2]-silyl migration provides the 1,3-dipolar
intermediate 8, which can undergo cyclization on nitrogen
through 8a or cyclization on oxygen through its rotamer 8b.
A steric interaction between the R-substituent R2 and the
NSO2Cl group destabilizes N-cyclization intermediate 8a. On
the other hand, O-cyclization intermediate 8b suffers from
steric repulsion between the terminal substituent R1 and the
NSO2Cl group, which is trans to oxygen. Therefore, an allylic
silane with a large R2 group and a small R1 group prefers
the O-cyclization pathway, leading to lactone 9b. In contrast,
an allylic silane with a small R2 group and a large R1 group
favors the N-cyclization pathway to provide the lactam
product. The dominant factor controlling lactone and lactam
formation in the [3 + 2] annulation of allylic silanes with
ClSO2NCO is therefore the steric interactions of the sub-
stituents.10
Silylation of 10 with benzhydryldimethylsilyl chloride6
followed by deprotection and oxidation of the resultant
alcohol afforded an aldehyde, which was then treated with
n-butyllithium and oxidized to give the acetylenic ketone
11. Asymmetric transfer hydrogenation13 of 11 afforded the
chiral alcohol (R)-12 with high enantioselectivity (97.4%
ee).14 The chiral alcohol 12 was then protected as the THP
ether. Hydroboration, protonolysis, and deprotection afforded
the (Z)-allylic alcohol, which was then treated with phenyl
isocyanate to give the carbamate 13. A copper-mediated SN2′
reaction15 provided chiral allylic silane 14 with high (E)-
selectivity and enantioselectivity (95% ee).16
With the chiral allylic silane 14 in hand, subsequent
[3 + 2] annulation and functionalization of the two silyl
To demonstrate the synthetic utility of the [3 + 2]
annulation of allylic silanes with chlorosulfonyl isocyanate
to form γ-butyrolactones, we synthesized (+)-blastmycinone
with this reaction as the key step. (+)-Blastmycinone is a
degradation product of the macrocyclic dilactone (+)-
antimycin A3 (blastmycin), an antifungal antibiotic isolated
(12) For selected examples of the asymmetric synthesis of (+)-blast-
mycinone, see: (a) Chen, M.-J.; Lo, C.-Y.; Chin, C.-C.; Liu, R.-S. J. Org.
Chem. 2000, 65, 6362-6367. (b) Sibi, M. P.; Lu, J.; Talbacka, C. L. J.
Org. Chem. 1996, 61, 7848-7855. (c) Ishibashi, T.; Ochifuji, N.; Mori,
M. Tetrahedron Lett. 1996, 37, 6165-6168. (d) Wasserman, H. H.; Gamble,
R. J. Tetrahedron 1992, 48, 7059-7070.
(13) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738-8739. (b) Hashiguchi, S.; Fujii, A.; Haack,
K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl.
1997, 36, 288-290.
from several members of the Streptomyces species.11
A
number of approaches have been developed to access this
molecule and related γ-butyrolactone natural products.12 Most
of the efforts have focused on diastereoselectively and
enantioselectively building the three contiguous stereogenic
(14) The enantiomeric excess of 12 was determined by GC analysis of
its Mosher ester: Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543-2549.
(15) (a) Smitrovich, J. H.; Woerpel, K. A. J. Am. Chem. Soc. 1998, 120,
12998-12999. (b) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 2000,
65, 1601-1614.
(10) A control experiment showed that no interconversion occurred
between iminolactone 3a and N-chlorosulfonyl lactam 4a.
(11) (a) Yohehara, H.; Takeuchi, S. J. Antibiot. 1958, 11, 254-263. (b)
Kinoshita, M.; Aburaki, S.; Umezawa, S. J. Antibiot. 1972, 25, 373-376.
(16) The enantiomeric excess of 14 and 15 was determined by HPLC
analysis using a Chiracel OD-H column, and the enantiomerically enriched
material was compared with racemic material.
Org. Lett., Vol. 3, No. 5, 2001
677

groups completed the total synthesis. The key [3 + 2]
annulation of 14 with ClSO2NCO proceeded with a CdO/
CdN annulation ratio of g20:1 as determined by H NMR
spectroscopic analysis. After hydrolysis with aqueous HCl
in THF, γ-lactone 15 was obtained in 72% yield with a
diastereomeric ratio of 97:3 and an ee of 94%16 (Scheme
4). This result demonstrated that the annulation occurred with
mycinone 1. The spectral data of 1 are identical to those
reported.12b
1
In summary, the [3 + 2] annulation reaction of allylic
silanes with chlorosulfonyl isocyanate provides an efficient
stereospecific and stereoselective synthesis of γ-butyro-
lactones. The synthetic utility of this method was demon-
strated by a concise enantioselective synthesis of the γ-
butyrolactone natural product (+)-blastmycinone.19
Acknowledgment. This research was supported by a
CAREER Award from the National Science Foundation
(CHE-9701622). K.A.W. thanks the American Cancer So-
ciety, AstraZeneca, Glaxo-Wellcome, the Camille and Henry
Dreyfus Foundation, Merck, and the Research Corporation
for awards to support research. Z.P. thanks Pharmacia &
Upjohn for a graduate fellowship in synthetic organic
chemistry. We thank Dr. John Greaves and Dr. John Mudd
for mass spectrometric data and Dr. Joseph Ziller for X-ray
crystallographic analyses.
Scheme 4
Supporting Information Available: Full experimental
and analytical data for all new compounds; X-ray data for
1
5a; H NMR and 13C NMR spectra of 5a, 5d, 5e, 14, 15,
retention of enantiomeric purity.4,7b The oxidation of the
benzhydryldimethylsilyl group with CsF/H2O2 yielded the
corresponding alcohol without epimerization.17 The resultant
alcohol was then acylated with isovaleroyl chloride to afford
16. Finally, oxidation of the terminal dimethylphenylsilyl
group with KBr-AcOOH,18 followed by bromination and
reduction of the resultant bromide, furnished (+)-blast-
and 1; and GC and HPLC traces. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0069960
(18) (a) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317-337. (b) Fleming, I.;
Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229-4232.
(19) For the utilization of the [3 + 2] annulation of an allylic silane
with ClSO2NCO in the formal synthesis of a lactam natural product, see:
Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2, 621-623.
(17) Brengel, G. P.; Meyers, A. I. J. Org. Chem. 1996, 61, 3230-3231.
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