A versatile preparation of alpha,beta-unsaturated lactones from homoallylic alcohols.

Article abstract of DOI:10.1021/ol990632u

[formula: see text] A new method for the synthesis of alpha,beta-unsaturated lactones from beta-acetoxy aldehydes by reaction with the lithium enolate of methyl acetate was developed. The reaction is relatively insensitive to structural changes in the ald

Full text of DOI:10.1021/ol990632u

ORGANIC
LETTERS
1999
Vol. 1, No. 3
411-413
A Versatile Preparation of
r,â-Unsaturated Lactones from
Homoallylic Alcohols
Gary E. Keck,* Xiang-Yi Li, and Chad E. Knutson
Department of Chemistry, UniVersity of Utah, 315 South 1400 East RM Dock,
Salt Lake City, Utah 84112-0850
keck@chemistry.chem.utah.edu
Received May 3, 1999
ABSTRACT
A new method for the synthesis of r,â-unsaturated lactones from â-acetoxy aldehydes by reaction with the lithium enolate of methyl acetate
was developed. The reaction is relatively insensitive to structural changes in the aldehyde substrates. The process was extended to the
synthesis of five-ring lactones from r-acetoxy aldehydes. Experimental evidence regarding the mechanism of this one-pot transformation was
obtained. The observations are consistent with a pathway involving an initial aldol condensation with subsequent acyl migration, lactonization,
and â-elimination and not an enolate equilibration−aldol mechanism.
The addition of various allylmetals to aldehydes is now well
established as an important and useful synthetic method.
Stereoselectivity in such reactions has been achieved using
“substrate controlled” processes,1 chiral reagents,2 and most
recently via catalytic enantioselective reactions.3 Our interest
in these reactions and the structures of certain natural
products of interest to us has led us to investigate general
methods for the conversion of the products of such reactions
to R,â-unsaturated lactones. We report herein a general
method for accomplishing this transformation as outlined in
Scheme 1.
Scheme 1
(1) For a review on the use of allylmetals, see: Yamamoto, Y.; Asao,
N. Chem. ReV. 1993, 93, 2207. (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.;
Yang, M. G.; Livingston, A. B. J. Am. Chem. Soc. 1995, 117, 6619. (b)
Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265. (c) Keck, G.
E.; Abbott, D. E.; Boden, E. P.; Enholm, E. J. Tetrahedron Lett. 1984, 25,
3927. (d) Keck, G. E.; Abbott, D. E.; Wiley M. R. Tetrahedron Lett. 1987,
28, 139. (e) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E.
J. Org. Chem. 1994, 59, 7889.
(2) (a) Brown, H. C.; Vara Prasad, J. V. N.; Zee. S.-H. J. Org. Chem.
1986, 51, 432. (b) Corey, E. J.; Yu, C.-M.; Kim, S.-S. J. Am. Chem. Soc.
1989, 111, 5495. (c) Roush, W. R.; Park, J. C. J. Org. Chem. 1990, 55,
1143. (d) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Scwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321. (e) Marshall, J. A.;
Gung, W. Y. Tetrahedron 1989, 45, 1043.
(3) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467. (b) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827.
(c) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58,
6543. (d) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111,
1940. (e) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-
Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001. (f) Keck, G. E.;
Krishnamurthy, D. Org. Synth. 1998, 62, 12.
The actual substrates for the reaction are â-acetoxy
aldehydes, which are readily available by acetylation of the
homoallylic alcohols, followed by processing of the homo-
allylic acetates to yield the corresponding aldehyde. For most
of the cases described herein, this was accomplished by
ozonolysis of the olefin followed by reductive workup with
either Me2S/MeOH or triphenylphosphine.4 As expected, the
â-acetoxy aldehydes proved to be very labile with respect
to â-elimination and decomposed upon attempts at chroma-
tography (Scheme 2).
Reaction of the â-acetoxy aldehydes with the lithium
enolate of methyl acetate,5 initially at -78 °C followed by
10.1021/ol990632u CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/16/1999

acetate enolate generated by a proton transfer-equilibration
process is considered extremely unlikely on the basis of the
following evidence.
Scheme 2
Scheme 3
warming to -20 °C and allowing the mixture to stand at
that temperature for several hours, afforded the R,â-unsatur-
ated lactones in the isolated yields shown in Table 1. Since
the â-acetoxy aldehydes could not be purified without
decomposition, these represent overall yields for the two-
step process including the aldehyde-forming step of ozo-
nolysis or oxidation, respectively.4
Mechanistically, we envisioned these reactions as proceed-
ing via initial addition of the lithium enolate to the aldehyde
carbonyl, followed by acetate migration and subsequent
lactonization and â-elimination (Scheme 3). An alternative
possibility involving an intramolecular condensation of an
First of all, with substrate 5, conversion to 4a was found
to occur (albeit in lower yield) when the benzoate derivative
was used in place of the acetate (Table 1, entries 4 and 5).
This is consistent with the suggested pathway, and also with
the expectation that the benzoate would undergo the critical
migration step less readily than the acetate. Second, when
the propionate (7) rather than the acetate derivative of
substrate 3 was employed in a reaction with the enolate of
methyl acetate, 3a was again obtained in essentially the same
yield, demonstrating that the propionate group was lost in
the reaction (Scheme 4). This result is compatible with the
Table 1. Preparation of Lactone Products
Scheme 4
proposed overall pathway, but not with one involving ester
enolate equilibration followed by intramolecular aldol con-
densation, which would have led to a different product (7a)
containing an additional methyl group.
(4) The exceptions were substrate 6, which was prepared by hydrogena-
tion of 5, and substrates 10 and 11. These materials were prepared by
deprotection (DDQ) of the corresponding primary PMB ethers, followed
by oxidation using the TPAP/NMO protocol of Ley. It should be noted
that this approach to the preparation of â-acetoxy aldehydes for use in these
reactions is complicated by the very acetate migration which makes the
overall reaction possible. The only deprotection/oxidation sequences which
we have been able to carry out successfully to date involve either
412
Org. Lett., Vol. 1, No. 3, 1999

Attempts to extend this reaction to more highly substituted
enolates have not as yet been successful with â-acetoxy
aldehydes as substrates. For example, reaction of substrate
2 with the lithium enolate of methyl propionate led largely
to â-elimination with very little of the desired lactone
observed. Apparently, nucleophilic addition is retarded
sufficiently by the additional steric demand of the substituted
enolate that proton transfer from the aldehyde methylene and
subsequent elimination competes. Likewise, reaction of the
aldehyde substrate 4 (with an R-OTBS group) with the
enolate of methyl propionate did not afford the desired
annulation product. Although â-elimination was not observed
in this case, consistent with the expectation that â-elimination
would be slowed by the presence of the bulky R-substituent,
starting material was recovered along with a complex mixture
of diasteromeric hydroxy acetates.
alcohol 9a. Apparently in this particular instance base-
induced cleavage of the acetate is faster than â-elimination.
It is presently unclear whether the use of less sterically
encumbered ketone substrates will provide unsaturated
lactone products (Scheme 6).
Scheme 6
As expected, this pathway for the production of R,â-
unsaturated lactones is not limited to â-acetoxy aldehydes
but can be carried out with R-acetoxy aldehydes as well.
Thus substrate 8 was converted to the five-ring lactone 8a
using this protocol in 62% overall yield. With such R-acetoxy
aldehydes, the use of more substituted enolates proved viable
since competing â-elimination is not possible. Thus, reaction
of aldehyde 8 with the lithium enolate of methyl propionate
provided the R-substituted lactone 8b in 77% yield (Scheme
5).
Given the ready availability of a variety of homoallylic
alcohols via the addition of a diverse array of allyl reagents
to aldehydes, we anticipate that the simple method described
herein will prove to be of considerable utility in synthesis.
In this regard, it is noteworthy that no epimerization of
potentially sensitive stereocenters R to the aldehyde was
detected in the reactions described herein. To further test
for epimerization, the diastereomeric substrates 10 and 11
were each subjected to the reaction conditions and led cleanly
to the diastereomeric products 10a and 11a with no crossover
1
detected by H NMR (Scheme 7).
Scheme 5
Scheme 7
One attempt has been made toward extending this method
to the use of an R-acetoxy ketone. Treatment of 9 under the
typical reaction conditions resulted in the formation of tertiary
Acknowledgment. Financial assistance provided by the
National Institutes of Health (through Grant GM-28961) and
by Pfizer, Inc., is gratefully acknowledged.
hydrogenolysis of benzyl ethers or removal of PMB ethers using DDQ,
followed by either TPAP or Dess-Martin oxidation. It is interesting to
note that, although the removal of benzyl ethers using DDQ is also well
established, the conditions (time and temperature) required are such that
adventitious acetate migration complicates these reactions as well.
(5) The enolate of methyl acetate was generated by dropwise addition
of methyl acetate to a stirred solution of LDA (typically 0.1 M) maintained
at -78 °C and used 15-30 min after addition was completed.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL990632U
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