γ-Lactone-tethered ring-closing metathesis. A route to enantiomerically enriched γ-lactones α,β-fused to medium-sized rings

Article abstract of DOI:10.1021/ol0478739

(Chemical Equation Presented) The stereoselective alkylation of α(phenylsulfonyl)-β-[(methoxycarbonyl)methyl]-γ-lactones obtained by the base-induced cyclization of enantiomericaily enriched α-[(phenylthio)acyl]-α,β-unsaturated esters and ring-closing olefin metathesis (RCM) are the basis of a new approach for gaining access to γ-lactones that are α,β-fused to medium-sized carbocycles and cyclic ethers.

Full text of DOI:10.1021/ol0478739

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4787-4789
γ
-Lactone-Tethered Ring-Closing
Metathesis. A Route to Enantiomerically
Enriched -Lactones -Fused to
Medium-Sized Rings
γ
r,â
Carmen M. Rodr´ıguez, Jose´ Luis Ravelo, and V´ıctor S. Mart´ın*
Instituto UniVersitario de Bio-Orga´nica “Antonio Gonza´lez”, UniVersidad de La
Laguna, C/Astrof´ısico Francisco Sa´nchez, 2, 38206 La Laguna, Tenerife, Spain
Vmartin@ull.es
Received October 14, 2004
ABSTRACT
The stereoselective alkylation of
enantiomerically enriched -[(phenylthio)acyl]-
for gaining access to -lactones that are -fused to medium-sized carbocycles and cyclic ethers.
r
-(phenylsulfonyl)-
â-[(methoxycarbonyl)methyl]-γ-lactones obtained by the base-induced cyclization of
r
r,â-unsaturated esters and ring-closing olefin metathesis (RCM) are the basis of a new approach
γ
r,â
γ-Lactones are widely distributed in nature in many biologi-
cally important natural products.1 This structural unit is often
found fused to medium-sized rings.2 In addition, γ-lactone
chemistry plays a very important role in the synthesis of
biologically active natural products.3 Direct approaches to
the stereocontrolled synthesis of such complex systems are
highly desirable.4 The alkylation of R-(phenylsulfonyl)-â-
[(methoxycarbonyl)methyl]-γ-lactones obtained by the base-
induced cyclization of enantiomerically enriched R-[(phen-
ylthio)acyl]-R,â-unsaturated esters produces highly substi-
tuted butyrolactones with a high degree of stereocontrol.5
On the other hand, ring-closing metathesis (RCM) has been
extensively utilized in the synthesis of various organic
frameworks.4,6 Merging both methodologies, we describe in
Scheme 1. Synthesis of Fused Oxa- and Carbocycles to
γ-Lactones
(1) The Merck Index, 13th ed.; Merck & Co., Inc.: Whitehouse Station,
NY, 2001.
(2) Dictionary of Organic Compounds, 6th ed.; Chapman & Hall/CRC:
England, 1995.
(3) (a) Corey, E. J.; Cheng, X. M. In The Logic of Chemical Synthesis;
John Wiley & Sons: New York, 1989. (b) Holton, R. A.; Kim, H.-B.;
Somoza, C.; Liang, F.; Biediger, R. J.; Boatman, D.; Shindo, M.; Smith,
C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang,
P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116,
1599-1600. (c) Hayakawa, K.; Nagatsugi, F.; Kanematsu, K. J. Org. Chem.
1988, 53, 860-863. (d) Mitsuhashi, H.; Muramatsu, T. Tetrahedron 1964,
20, 1971-1982.
(4) For a precedent in the synthesis of carbocycles â,γ-fused to γ-lactones
using RCM, see: Paquette, L. A.; Me´ndez-Andino, J. Tetrahedron Lett.
1999, 40, 4301-4304.
10.1021/ol0478739 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/09/2004

this communication a new, general, and stereoselective
methodology for accessing highly substituted oxa- and
carbocycles fused to γ-lactones 1 (Scheme 1).
Previous work in our laboratory was directed to the
synthesis of 2 in accordance with Scheme 2. Key steps in
the said work are the regioselective opening of 2,3-epoxy
alcohols using thiophenyl acetic acid and the stereoselective
intramolecular Michael addition of the R,â-unsaturated ester
3.7
with slightly longer chains produced the O-alkylation 5 as
the preferred product (entries 4 and 5). In these cases also
the reaction times were longer.
To introduce the necessary terminal olefin at the â-chain
relative to the carbonyl of the γ-lactone, two major ap-
proaches were used depending on whether the final oxa- or
carbocycles were the desired products. For the preparation
of the carbon-unsaturated chain, a protocol consisting in
oxidation of the primary alcohol and a Wittig reaction with
Ph3PdCH2 provided the desired diene 6. For the ether, simple
alkylation under Williamson conditions of the â-hydroxyalkyl
group at 4 provided the desired linear ether 7 (Scheme 3).9
In a similar manner, the alkylation of 5 yielded also the
dialkylated lactone 8.
Scheme 2. Stereoselective Synthesis of Trisubstituted
γ-Lactones
Scheme 3. Representative Syntheses of the Diene Precursors
for RCM
The alkylation of 2 with a series of alkylating agents (alkyl
halides) proceeded in most cases chemo- and stereoselec-
tively leading to the contrasteric alkylation product 4 as the
only isolated stereoisomer (Table 1).8 Surprisingly, small
Table 1. Contrasteric Alkylation of â-Hydroxyalkyl-R-sulfonyl
γ-Lactones
With the double-unsaturated systems in our hands, we
performed ring-closing metathesis (RCM) using second-
generation Grubbs’ catalysts 9.10 The results summarized in
Table 2 show that cyclic compounds were obtained in all
attempted cases, with yields depending on the ring size to
be formed.
Depending on the ring size, the reaction occurred in most
cases with acceptable yields. Maximum yields and rates were
achieved for the seven-membered ring formations. The
internal coupling between geminal disubstituted olefins with
terminal alkenes proceeded with excellent yield providing
the trisubstituted cycloalkene (entry 6). For the larger rings
a competition between intra- and intermolecular reaction
appeared, lowering the yield of the monomeric species
(entries 4 and 5).11 In our opinion, such competition is more
the cause of low yields than the presence of oxygen or
methylene in the unsaturated chains.12
entry
R2X
timea (h)
4/5
yield (%)
1
2
3
4
5
6
CH2dCHCH2Br
4
8
8
12
12
4
100:0
100:0
100:0
0:100
0:100
100:0
75
60
58
58
42
60
CH2dCH(CH2)2Br
CH2dCH(CH2)3Br
CH2dCH(CH2)4Br
CH2dCH(CH2)6Br
CH2dC(CH3)CH2Cl
a NaH, R2X, DMF, 0 °C to rt.
Another interesting feature of the presented methodology
is that further manipulations of the created double bond
structural changes in the used halides were critical since the
simple use of reagents under the same reaction conditions
(5) (a) Rodriguez, C. M.; Mart´ın, T.; Ram´ırez, M. A.; Mart´ın, V. S. J.
Org. Chem. 1994, 59, 4461-4472. (b) Rodriguez, C. M.; Mart´ın, T.;
Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem. 1994, 59, 8081-8091.
(6) (a) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382.
(b) Nicolaou, K. C.; Snyder, S. A. In Classics in Total Synthesis II; Wiley-
VCH: Weinheim 2003. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (d) Yet, L. Chem. ReV. 2000, 100, 2963-3007.
(8) For a rationalization of the stereochemical course of this reaction
see ref 5b.
(9) Feuer, H.; Hooz, J. in Patai, S. The Chemistry of the Ether Linkage;
Wiley: New York, 1967; pp 446-450, 460-468.
(10) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-1753.
(11) We were unable to characterize the polymeric products.
(12) Delgado, M.; Mart´ın, J. D. J. Org. Chem. 1999, 64, 4798-4816.
(7) See the Supporting Information for experimental details.
4788
Org. Lett., Vol. 6, No. 25, 2004

procedure over the cycloheptene 12 yielded cleanly the diol
15 as the sole isomer.13 It seems that depending on the ring
size, preferred conformations and steric interactions are
responsible for the stereochemical outcome.
Table 2. RCM of γ-Lactone-Tethered Dienes
Scheme 4. Influence of Ring Size in the Stereoselective
cis-Hydroxylation of Cycloalkenes Fused to Sulfonyl γ-Lactones
In summary, a general protocol for accessing enantio-
merically enriched γ-lactones fused to a cyclic system is
reported.14 The method is tunable in terms of the kind of
cyclic system to be obtained. In addition, the double bond
created during the RCM process permits further synthetic
transformations. The development of a related methodology
for accessing fused systems at different positions in the
γ-lactone unit is under way.
Acknowledgment. This research was supported by the
Ministerio de Ciencia y Tecnolog´ıa of Spain (PPQ2002-
04361-C04-02) and the Canary Islands Government.
Supporting Information Available: Preparation of the
1
compounds of Scheme 2, H and 13C NMR spectra for the
new compounds, and NOE studies of acetonides of 13-15.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a The product was contaminated with unidentified polymeric substances.
OL0478739
permit the introduction of additional substituents (Scheme
4). However, in such reactions the stereochemistry is strongly
dependent on ring size. Thus, while the cis-dihydroxylation
of the cyclohexene 11, using standard conditions (OsO4,
NMO), provided a 1:1 mixture of diols (13, 14), a similar
(13) The stereochemistry was determined by NOE studies over the
corresponding acetonides (see Supporting Information).
(14) For the stereoselective cleavage of the R-benzenesulfonyl group in
fused γ-lactones, see: Mart´ın, T.; Rodr´ıguez, C. M.; Mart´ın, V. S.
Tetrahedron: Asymmetry 1995, 6, 1151-1164.
Org. Lett., Vol. 6, No. 25, 2004
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