A direct method for the conversion of terminal epoxides into γ-butanolides

Article abstract of DOI:10.1021/ja025604c

A new and efficient process for the conversion of terminal epoxides to γ-butanolides is described involving Lewis acid promoted epoxide ring-opening by 1-morpholino-2-trimethylsilyl acetylene. Addition of a terminal epoxide to a solution of the ynamine an

Full text of DOI:10.1021/ja025604c

Published on Web 02/22/2002
A Direct Method for the Conversion of Terminal Epoxides into γ-Butanolides
Mohammad Movassaghi and Eric N. Jacobsen*
HarVard UniVersity, Department of Chemistry and Chemical Biology, 12 Oxford Street,
Cambridge, Massachussetts 02138
Received January 15, 2002
Scheme 1
Ring-opening of epoxides, particularly with carbon-based nu-
cleophiles, is a highly valuable synthetic strategy for the stereo-
specific elaboration of organic compounds.1-3 Despite the venerable
place held by enolates as carbon-based nucleophiles for organic
synthesis, γ-hydroxy carboxylic acid derivatives are rarely accessed
via epoxide ring opening by acetate enolates,3 largely because of
the paucity of reliable and efficient methodology for such
transformations.4-6 Herein we describe a new and efficient route
to γ-butanolides in a single step and under mild reaction conditions
from terminal epoxides (Scheme 1). Coupled with existing highly
effective methods for the asymmetric synthesis of terminal ep-
oxides,7,8 this procedure provides ready access to a wide variety of
poration at the R-methylene position.12 This new epoxide opening-
keteneaminal cyclization sequence is thereby mechanistically
distinct from metal acetylide ring-opening of epoxides, which
involves formation of homopropargylic alcohols.2c,6
γ-lactone derivatives in enantiopure form.
Our strategy was based on the expectation that a neutral, electron-
rich carbon-carbon triple bond might serve as a functional
equivalent of an enolate in epoxide additions. Specifically, we
sought a reactive alkynyl nucleophile for a Lewis acid mediated
opening of epoxides. Evaluation of a series of alkyne/Lewis acid
combinations led to the discovery that use of 1-morpholino-2-
trimethylsilyl acetylene9 (1) and boron trifluoride diethyl etherate
(BF3‚OEt2) allows the rapid and efficient conversion of terminal
epoxides to the corresponding cyclic keteneaminals. Subsequent
hydrolysis and protodesilylation affords the corresponding γ-
butanolide (Scheme 1). The net transformation is equivalent to an
acetate enolate opening of terminal epoxides that is compatible with
a wide range of functional groups (Table 1). Enantiomerically
enriched terminal epoxides led to γ-butanolides without loss of
optical purity throughout the ring-opening, hydrolysis, protode-
silylation sequence, thus establishing the applicability of this
methodology toward the preparation of enantiopure γ-butanolide
building blocks.10
The intermediacy of cyclic keteneaminals in the ring-opening
of epoxides with 1 is not only mechanistically significant but also
provides an opportunity for the direct synthesis of more highly
functionalized γ-butanolides by simply varying the method for
reaction workup. Addition of N-bromosuccinimide (NBS) to a cold
solution of the keteneaminal derived from (R)-1-epoxy-3-phenyl-
propane (>99% ee) led to the efficient synthesis of the correspond-
ing R,R-dibromo-γ-butanolide (96%, >99% ee, Scheme 2). Fur-
thermore, treatment of the crude R,R-dibromo-γ-butanolide with
LiCl and Li2CO3 in DMF at 70 °C rapidly afforded the R-bromo-
γ-butenolide without loss of optical purity (82%, >99% ee).13
Both the regioselectivity and efficiency of the chemistry de-
scribed above are compromised in the case of vinyl- and aryl-
substituted epoxides. Styrene oxide undergoes BF3‚OEt2-promoted
rearrangement to phenylacetaldehyde faster than reaction with 1.12,14
Interestingly, the use of (R)-3-nitrostyrene oxide (>99% ee) led to
a stereospecific epoxide ring-opening at the benzylic center to
provide the corresponding γ-butanolide (62%, >99%ee).12 More
substituted epoxides and aziridine derivatives failed to provide the
desired ring-opened products.12
Ynamine 1 was found to possess superior reactivity for Lewis
acid mediated ring-opening of epoxides as compared to a range of
other electron-rich alkyne and keteneacetal derivatives.12 While the
amine component provides the necessary nucleophilicity for the
Lewis acid-catalyzed epoxide ring-opening, the trimethylsilyl
substituent inhibits the rapid decomposition of 1 in the presence of
BF3‚OEt2. Ynamine 1 is readily available in multigram quantities,12
either by the sequential treatment of N-trichlorovinyl morpholine
with n-BuLi followed by chlorotrimethylsilane (Scheme 3)9 or by
the addition of lithium morpholide to chlorotrimethylsilylacetylene,9b
and is stable for months at 0 °C.
Unambiguous evidence for the formation of a cyclic keteneaminal
(Scheme 1) as the direct addition product between ynamine 1 and
terminal epoxides was provided through a series of spectroscopic
and reactivity studies. The addition of phenylglycidyl ether to a
solution of 1 and BF3‚OEt2 in anhydrous dichloromethane was
monitored at 0 °C by React-IR and solution-cell FTIR spectroscopy.
Immediate loss of the ynamine absorption band9 at 2149 cm-1 was
detected, with concomitant appearance of a strong keteneaminal
absorption band at 1618 cm-1 11c,d Similarly, 13C NMR analysis of
.
the reaction between ethylene oxide and ynamine 1/BF3‚OEt2 in
chloroform-d1 at 0 °C revealed rapid formation of the corresponding
keteneaminal with characteristic resonances at δ 165.1 and 82.1
ppm.11d
A
29Si resonance due to the vinylic silane group was
observed as a signal at δ -10.5 in a variable-temperature 29Si-1H
HMQC NMR experiment.11a,b Consistent with the intermediacy of
a cyclic keteneaminal, the addition of trifluoroacetic acid-d1 (5
equiv) to a solution of the keteneaminal derived from 1-epoxy-3-
phenylpropane provided, after aqueous workup, the corresponding
γ-butanolide in 90% isolated yield with >96% deuterium incor-
The present methodology provides a highly efficient and expedi-
ent new route to homoenolate aldols in the form of γ-butanolides.
Furthermore, the interception of a cyclic keteneaminal intermediate
9
2456 VOL. 124, NO. 11, 2002 J. AM. CHEM. SOC.
10.1021/ja025604c CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Conversion of Terminal Epoxides to γ-Butanolides
of epoxides. We anticipate that the building blocks rendered readily
accessible by this chemistry will prove useful for the asymmetric
synthesis of more complex targets.
Acknowledgment. This work was supported by the NIH (GM-
59316) and by a postdoctoral fellowship to M.M. from the Damon
Runyon Cancer Research Foundation.
Supporting Information Available: Representative experimental
procedures and analytical and spectroscopic characterization data for
the products of Table 1 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
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Scheme 2
(10) The following experimental procedure is illustrative: (R)-1-Epoxy-5-
hexene (Table 1, entry 1, 1.10 g, 11.2 mmol, 1 equiv, >99% ee) was
added to a clear and yellow solution of ynamine 1 (2.94 g, 16.0 mmol,
1.4 equiv) and BF3‚OEt2 (2.03 mL, 11.2 mmol, 1.4 equiv) in anhydrous
dichloromethane (68 mL) at 0 °C. After 30 min, the yellow reaction
solution was diluted sequentially with acetonitrile (15 mL) and an aqueous
potassium hydrogen bifluoride solution (3.7 M, 15 mL) and the resulting
mixture was warmed to 23 °C for 30 min. After extractive isolation and
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Scheme 3. Preparation of Ynamine 1
(12) See the Supporting Information for details.
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allows direct access to a variety of functionalized γ-lactones. The
mild reaction conditions, wide functional group compatibility,
overall efficiency, and ease of operation render this methodology
a potentially powerful addition to the list of useful transformations
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