Chiral cyclobutane synthesis by exploiting a heteroatom-directed conjugate addition

Article abstract of DOI:10.1021/ol102383g

The syntheses of both enantiomers of cyclobutanes B and ent-B are achieved through heteroatom-directed conjugate addition (HADCA) of nucleophiles to the epoxyvinylsulfone-substituted carbohydrates A and ent-A, which provided carbanions that intramolecularly attacked the epoxide with concomitant formation of the cyclobutane ring.

Full text of DOI:10.1021/ol102383g

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5338-5341
Chiral Cyclobutane Synthesis by
Exploiting a Heteroatom-Directed
Conjugate Addition
Kuo-Wei Tsao and Minoru Isobe*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 300, Taiwan
minoru@mx.nthu.edu.tw
Received October 3, 2010
ABSTRACT
The syntheses of both enantiomers of cyclobutanes B and ent-B are achieved through heteroatom-directed conjugate addition (HADCA) of
nucleophiles to the epoxyvinylsulfone-substituted carbohydrates A and ent-A, which provided carbanions that intramolecularly attacked the
epoxide with concomitant formation of the cyclobutane ring.
Reactions to generate chiral cyclobutanes are important as
four-membered carbocycles are substructures in many natu-
rally occurring compounds, including solanoeclepin A,1a (-)-
ampullicin,1b and (-)-copaene.1c Establishing new methods
to synthesize diversified cyclobutane compounds in optically
active forms would also provide strained intermediates, which
can be further transformed into a variety of compounds via
ring-opening and ring-expansion reactions.2 However, the
synthesis of enantiomerically pure cyclobutane derivatives
is still a challenging task. Although the photochemical [2 +
2] cycloaddition is a popular method for constructing the
cyclobutyl moiety,2 the analogous reaction between two
alkenes possessing chiral auxiliaries can be a synthetic
problem when the preparation of optically active cyclobu-
tanes is required on a large scale.2a Alternative strategies
for constructing four-membered rings3 have been reported
by other researchers, including Paquette and co-workers,4
while Taguchi and co-workers5 reported a “Cp2Zr”-mediated
method for the preparation of optically pure cyclobutyl
carbohydrate derivatives.
In 1974, Stork reported the first example of a cyclization
to yield a four-membered ring through the nucleophilic attack
of an epoxide by a carbanion stabilized by a nitrile group.6
Krohn reported an alternative intramolecular epoxide opening
by a 1,3-dithiane anion.7 However, neither cyclization could
accommodate many substituents in the substrate, which
(1) (a) Solanoeclepin A is the most active natural hatching agent of potato
cyst nematodes. Its structure contains three-, four-, five-, six-, and seven-
membered rings in which cyclobutane moiety of fully functional groups,
see: Schenk, H.; Driessen, R. A. J.; Gelder, R. d.; Goubitz, K.; Nieboer,
H.; Bru¨ggemann-Rotgans, I. E. M.; Diepenhorst, P. Croat. Chem. Acta 1999,
72, 593. (b) (-)-Ampullicin shows remarkable growth-regulating properties,
see: Kimura, Y.; Nakajima, H.; Hamasaki, T.; Matsumoto, T.; Matsuda,
Y.; Tsuneda, A. Agric. Biol. Chem. 1990, 54, 813. (c) (-)-Copaene:
Jacobson, M.; Uebel, E.; Lusby, W. R.; Waters, R. M. J. Agric. Food Chem.
1987, 35, 798.
(3) (a) Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht, C. L.;
Schenk, H. P. J. Am. Chem. Soc. 1971, 93, 3208. (b) Ihara, M.; Ohnishi,
M.; Takano, M.; Makita, K.; Taniguchi, N.; Fukumotol, K. J. Am. Chem.
Soc. 1992, 114, 4408. (c) Tanino, K.; Aoyagi, K.; Kirihara, Y.; Ito, Y.;
Miyashita, M. Tetrahedron Lett. 2005, 46, 1169. (d) Roskamp, E. J.;
Johnson, C. R. J. Am. Chem. Soc. 1986, 108, 6062. (e) Meek, S. J.; Pradaux,
F.; Demont, E. H.; Harrity, J. P. A. Org. Lett. 2006, 8, 5597. (f) Redlich,
H. Angew. Chem., Int. Ed. Engl. 1994, 33, 1345.
(4) (a) Paquette, L. A.; Cunie`re, N. Org. Lett. 2002, 4, 1927. (b) Paquette,
L. A. J. Organomet. Chem. 2006, 691, 2083.
(2) For recent reviews, see: (a) Lee-Ruff, E.; Mladenova, G. Chem. ReV.
2003, 103, 1449. (b) Namyslo, J. C.; Kaufmann, D. E. Chem. ReV. 2003,
103, 1485. (c) Sadana, A. K.; Saini, R. K.; Billups, W. E. Chem. ReV. 2003,
103, 1539.
(5) Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem. Soc.
1993, 115, 8835.
(6) Stork, G.; Cohen, J. F. J. Am. Chem. Soc. 1974, 96, 5270.
(7) Krohn, K.; Bo¨rner, G. J. Org. Chem. 1994, 59, 6063.
10.1021/ol102383g  2010 American Chemical Society
Published on Web 10/28/2010

limited the wide applicability of these intramolecular opening
processes for the synthesis of substituted cyclobutanes.
We have recently reported our first construction of
polyfunctionalized cyclobutanes 3 from an acyclic precur-
sor 1, through intramolecular epoxide opening by carban-
ion intermediates 2 generated from conjugate addition
(Scheme 1).8 In this letter, enantiomerically pure fused
was subjected to hydrosilylation10 with dimethylphenylsilane
in the presence of 10 mol % of cobalt catalyst 6 to afford
vinylsilane 7 in 88% yield, in which the olefin geometry was
100% regio- and stereoselective. Alcoholysis generated
4-hydroxyvinylsulfide 8, which was bis-oxidized with mCP-
BA to give the epoxy vinylsulfone 9. In this reaction,
epoxidation was hydroxyl-directed according to Henbest’s
rule, to generate the desired epoxide stereochemistry for
cyclobutane formation.
Next, the diastereoinduction in the conjugate addition was
examined.11 When treated with 2.5 equiv of methyllithium-
lithium bromide complex, the D-series epoxy vinylsulfone 9
underwent conjugate addition on the si-face directed by
R-chelation rather than ꢀ-chelation (Scheme 3). Desilylation
Scheme 1. Intramolecular Epoxide Opening in an Acyclic
System by Carbanions Generated through Conjugate Addition
Scheme 3. Heteroatom-Directed Conjugate Addition of MeLi to
Vinylsulfone-Substituted Pyrans 9 and 11 to Afford syn-Adducts
10a and 12
cyclobutanes are synthesized by exploiting the heteroatom-
directed conjugate addition of carbanion nucleophiles to
the epoxyvinylsulfone-substituted carbohydrates which
produce carbanions that intramolecularly attack epoxides
to form enantiomerically pure cyclobutanes.
Accordingly, we developed a four-step regio- and stereo-
controlled synthesis of precursor 9 from D-arabinal (Scheme
2). Commercially available di-O-acetyl-D-arabinal 4 was
Scheme 2. Synthesis of Epoxy Vinylsulfone 9
with TBAF yielded exclusively diastereomer 10a. The
stereochemistry of the product was deduced from the NOE
correlations as shown. The stereochemistry of the methyl
group of 10a was further correlated with 12, which was
obtained from the reaction of D-series alkenyl vinylsulfone
11 without any epoxide that could competitively direct the
conjugate addition. The 13C methyl group of 10a showed a
peak at δ 14.4 ppm, while the methyl group of 12 showed
a peak at δ 14.3 ppm, consistent with both methyl groups
being in a similar stereochemical environment.
converted into C-alkynylated 5 in 88% yield with high 1,4-
anti selectivity (de > 95:5).9 Similarly, the enantiomer of 5
is available from L-arabinal or L-xylal derivatives. Alkyne 5
Other nucleophiles were examined for comparison, and
the results are summarized in Table 1. In the case of both
(9) Hosokawa, S.; Kirschbaum, B.; Isobe, M. Tetrahedron Lett. 1998,
39, 1917.
(8) Adachi, M.; Yamauchi, E.; Komada, T.; Isobe, M. Synlett 2009, 7,
1157. Formally we called it a hetero-conjugate addition, but recently, it
has often been used for heteroatom nucleophiles. Now we propose HADCA
instead to make it clearer.
(10) Isobe, M.; Nishizawa, R.; Nishikawa, T.; Yoza, K. Tetrahedron
Lett. 1999, 40, 6927.
(11) Isobe, M.; Kitamura, M.; Goto, T. Tetrahedron Lett. 1981, 22, 239.
Org. Lett., Vol. 12, No. 22, 2010
5339

addition of lithium acetylide was further investigated for the
construction of the cyclobutane moiety. When precursor 9
was treated with an excess (10.0 equiv) of lithium acetylide
and then addition of 0.7 equiv of BF3·OEt2 (Scheme 4), an
Table 1. HADCA of Various Nucleophiles to D-Series Epoxy
Vinylsulfone 9
Scheme 4. Cyclobutane 13 and Cyclobutene 14 Formation
under Condition B Followed by BF3·OEt2
a Conditions: (A) THF, -78 °C; (B) THF, -40 °C; (C) hexane/ether,
-40 °C. b The trimethylsilylacetylene was deprotonated with MeLi-LiBr
at -20 °C for 1 h. c The trimethylsilylacetylene was deprotonated with MeLi
at -20 °C for 1 h, then mixed with LiBr/NaBr (1:0.05) at -20 °C for 2 h.
d Isolated yields after column chromatography; the ratios were determined
1
by H NMR.
inseparable mixture of cyclobutane 13 and cyclobutene 1413
was formed, which was subsequently acetylated and sepa-
rated by silica gel chromatography to yield cyclobutane 13a
(45%) and cyclobutene 14a (30%). The structures of cy-
clobutane 13a and cyclobutene 14a were identified by
HMQC and HMBC NMR experiments. Fortunately the bis-
PNB ester 14b was crystallized, and the structure was
established by X-ray crystallographic analysis.14
Gratifyingly, when the reaction was carried out using
lithium acetylide·LiBr in the presence of NaBr (Condition
C), cyclobutane 15 was procured as the only product (Scheme
5). Addition of the sodium salt and cosolvents to the reaction
mixture of 9 and acetylide made the first heteroatom-directed
conjugate addition at higher velocity and selectivity as the
Condition C. To this anionic intermediate was further added
1 equiv of zinc chloride-THF at -40 °C, and the temper-
ature was raised to 34 °C to result in the formation of epoxide
opening product 15 to isolate as a single stereoisomer in 65%
yield (Scheme 5). When we employed the same Condition
C and changed the Lewis acid to BF3·OEt2 (0.7 equiv), the
isolation yield of 15 was improved to 78% yield. The
stereochemistry of this product was analyzed by NMR on
methyllithium and the methyllithium-lithium bromide com-
plex, the syn-adduct 10a was obtained under Condition A
(THF, -78 °C) in g90% yield with a high de ratio (entries
1 and 2).12 The diastereoselectivity of the addition of
n-butyllithium was somewhat lower (de ) 83:17, entry 3).
When 9 was treated with vinylmagnesium bromide (entry
4), no reaction took place at -78 °C. When the reaction
temperature was raised to -40 °C (Condition B), adduct 10c
was formed in 73% yield with high de (>99:1). Similarly,
the weaker nucleophile, lithium acetylide, did not undergo
conjugate addition at -78 °C but reacted at -40 °C. When
5.0 equiv of lithium acetylide was employed (entry 5), 10d
was obtained in 63% with de ) 85:15, but when 10 equiv
of lithium acetylide was used, a lower yield of 10d was
obtained (55%, entry 6). However, we could enhance the
nucleophilicity of lithium acetylide by adding 5 mol % of
sodium bromide salt (Condition C). The acetylide thus
prepared reacted to give syn-adduct 10d in 80% yield and
with high diastereoselectivity (de >99:1, entry 7). In a similar
manner, the conjugate addition of nucleophiles to L-series
epoxy vinylsulfone systems ent-9 generated the enantiomeric
syn-adducts ent-10a-d as major products (Table 2 in
Supporting Information).
(13) This may have stereospecifically happened, after the cyclobutane
formation, to one of the diastereomers, which posessed the stereochemistry
orienting the sulfonyl group trans to the propargylic proton. An excess
carbanion attacked the propargylic proton and eliminated the trans-sulfonyl
group to give cyclobutene 14.
(14) The ORTEPs of cyclobutene 14b and the p-nitrobenzoate derivative
of ent-15a are also included in the Supporting Information.
To study the application of this reaction toward the
synthesis of the eastern hemisphere of solanoeclepin A, the
(12) In this case, the syn-isomer is defined as the same face of the
incoming methyl group and neighboring oxygen atom, when drawn in zig-
zag main carbon chain according to S. Masamune’s definition.
5340
Org. Lett., Vol. 12, No. 22, 2010

Scheme 5
. HADCA Addition Followed by Cyclobutane Ring
Formation with Assistance by Lewis Acid
Figure 1. ORTEP of the crystal structure of cyclobutane 13b.
forms in a stereocontrolled manner through intramolecular
epoxide ring opening by trans-metalated carbanions, which
Scheme 6. Formation of Cyclobutane ent-15a
its diacetate 13a; thus, formation of the cyclobutane is shown
by the correlation between H2 and C2′ (HMBC), and the
stereochemistry is shown as 1′S- and 2′R-configuration from
NOE experiments (Scheme 5). Conversion to the crystalline
di-p-nitrobenzoate derivative 15a was achieved with loss of
the phenyldimethylsilyl group. The crystal structure is shown
in Figure 1.
was generated in situ from an R-heteroatom directed
conjugate addition followed by epoxide opening reactions
by the assistance of a Lewis acid. Our studies to apply this
synthetic method toward the asymmetric synthesis of natural
products are in progress.
The enantiomer of ent-9 was also successfully converted
to ent-15a by the same method starting from L-arabinal
(Scheme 6). Furthermore, the absolute stereochemistry of
both enantiomers has been established through X-ray crystal-
lographic analysis of their p-nitrobenzoate derivatives cy-
clobutane ent-15a.14
Acknowledgment. We acknowledge the National Science
Council, Taiwan, and NTHU for financial support.
Supporting Information Available: H NMR, C NMR,
2D NMR, and typical experimental details. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have accomplished the synthesis of both
enantiomers of tetrasubstituted cyclobutanes in optically pure
OL102383G
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