A straightforward synthesis of (-)-phaseolinic acid

Article abstract of DOI:10.1021/jo048705x

A concise approach to (-)-phaseolinic acid starting from commercially available (S)-oct-1-yn-3-ol is disclosed. The key steps are a ring-closing metathesis reaction to prepare a C₂-symmetrical allylic diol and its desymmetrization to a γ-butyrolactone by using an Ireland-Claisen rearrangement. The 2S,3S,4S configuration of the levogyre natural product has been confirmed.

Full text of DOI:10.1021/jo048705x

A Straightforward Synthesis of
(-)-Phaseolinic Acid
Marta Amador, Xavier Ariza,* Jordi Garcia,* and
Jordi Ortiz
FIGURE 1. Structure of paraconic acids.
Departament de Quı´mica Orga`nica, Universitat de
Barcelona, C/ Martı´ i Franque`s 1-11, E-08028 Barcelona,
Catalonia, Spain
In the course of studies directed toward the synthesis
of natural products from unsaturated 1,4-diols,4 we
addressed our attention to the synthesis of (-)-phaseo-
linic acid (3). This compound, isolated from the culture
filtrate of the phytotoxic fungus Macrophomina phaseo-
lina, constitutes a representative example of the above-
mentioned cis â,γ-substituted paraconic acid. The ster-
eochemistry of 3 was initially assigned to be 2R,3R,4R
on the basis of a single-crystal X-ray analysis and its CD
spectrum in 1987.5 Later publications6,7 on the enanti-
oselective syntheses of (-)-phaseolinic acid seemed to
confirm the proposed absolute configuration. However,
a more recent report from Valentin et al.8 based on
enzymatic and chemical processes surprisingly concluded
that the configuration of natural phaseolinic acid having
negative specific rotation is 2S,3S,4S and not 2R,3R,4R
as previously described. Prompted by these dissenting
reports, we disclose herein a straightforward, stereo-
selective synthesis of (-)-phaseolinic acid from com-
mercially available (S)-oct-1-yn-3-ol, (S)-4, which con-
cludes that the levogyre phaseolinic acid is the 2S,3S,4S
isomer in agreement with Valentin’s results.
As depicted in Scheme 1, our synthetic strategy
involves two key steps: (i) the preparation of the en-
antiopure symmetrical diol (S,S)-5 from (S)-4 and (ii) the
desymmetrization of that allylic diol through an Ireland-
Claisen rearrangement to an open-chain compound 6 that
possesses the adequate stereoarray.
As far as the first goal is concerned, we envisioned that
diol (S,S)-5 might be prepared through an olefin metath-
esis of (S)-oct-1-en-3-ol, (S)-8, which is readily obtained
by partial reduction of (S)-4. Despite the widespread
application of homodimerization of terminal olefins via
self-metathesis,9 we were aware that such dimerization
could be a difficult task. Expected troubles included low
cis/trans selectivity and also the potential isomerization
of secondary allylic alcohols to ketones under metathesis
jordigarciagomez@ub.edu
Received July 27, 2004
Abstract: A concise approach to (-)-phaseolinic acid start-
ing from commercially available (S)-oct-1-yn-3-ol is disclosed.
The key steps are a ring-closing metathesis reaction to
prepare a C2-symmetrical allylic diol and its desymmetri-
zation to a γ-butyrolactone by using an Ireland-Claisen
rearrangement. The 2S,3S,4S configuration of the levogyre
natural product has been confirmed.
Introduction
Paraconic acids are a class of γ-butyrolactones (1 or 2)
isolated from various species of lichens, mosses, and fungi
(Figure 1). They possess a very similar substitution
pattern at the R-position (methyl or methylene group)
and â-position (carboxyl group). However, these com-
pounds differ in the residue attached to the γ-position
as well as in the stereochemical relationship between
these substituents. Since many paraconic acids exhibit
important biological activities, such as antifungal, anti-
tumor, and antibacterial,1 the preparation of these lac-
tones have attracted considerable attention of synthetic
chemists. As a result, some efficient methods have been
reported for the enantioselective preparation of trans â,γ-
substituted butyrolactones,2 but fewer syntheses of cis
â,γ-substituted products have been described.3
(1) (a) Mu¨ller, K. Appl. Microbiol. Biotechnol. 2001, 56, 9-16. (b)
Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama, M. J. Antibiot.
1988, 41, 751-758. (c) Petragnani, N.; Ferraz, H. M. C.; Silva, G. V.
J. Synthesis 1986, 157-183. (d) Hoffmann, H. M. R.; Rabe, J. Angew.
Chem., Int. Ed. 1985, 24, 94-110.
(2) (a) Chhor, R. B.; Nosse, B.; So¨rgel, S.; Bo¨hm, C.; Seitz, M.; Reiser,
O. Chem. Eur. J. 2003, 9, 260-270. (b) Sibi, M. P.; Liu, P.; Ji, J.; Hajra,
S.; Chen, J.-X. J. Org. Chem. 2002, 67, 1738-1745. (c) Kongsaeree,
P.; Meepowpan, P.; Thebtaranonth, Y. Tetrahedron: Asymmetry 2001,
12, 1913-1922. (d) Jacobi, P. A.; Herradura, P. Can. J. Chem. 2001,
79, 1727-1735. (e) Bella, M.; Margarita, R.; Orlando, C.; Orsini, M.;
Parlanti, L.; Piancatelli, G. Tetrahedron Lett. 2000, 41, 561-565. (f)
Masaki, Y.; Arasaki, H.; Itoh, A. Tetrahedron Lett. 1999, 40, 4829-
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Tetrahedron: Asymmetry 1995, 6, 885-892. (m) Zhu, G.; Lu, X. J. Org.
Chem. 1995, 60, 1087-1089. (n) Takahata, H.; Uchida, Y.; Momose,
T. J. Org. Chem. 1995, 60, 5628-5633. (o) Mawson, S. D.; Weavers,
R. T. Tetrahedron 1995, 51, 11257-11270. (p) Banks, M. R.; Dawson,
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1995, 36, 3567-3570. (q) Honda, T.; Kimura, N. J. Chem. Soc., Chem.
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A. E. J. Org. Chem. 1993, 58, 7537-7541. (s) Mulzer, J.; Salimi, N.;
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X.; Garcia, J.; Lo´pez, M.; Montserrat, L. Synlett 2001, 120-122.
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10.1021/jo048705x CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/05/2004
8172
J. Org. Chem. 2004, 69, 8172-8175

SCHEME 1. Retrosynthetic Analysis for
(3S,4S,5S)-3
SCHEME 3. Formation of (S,S)-12 by RCMa
a
Reagents and conditions: (a) Ph2SiCl2, 2,6-dimethylpyridine,
SCHEME 2. Formation of 1,4-Diols by Direct
Olefin Metathesis
CH2Cl2, 85%; (b) H2, Lindlar’s catalyst, EtOAc, 91%; (c)
(PCy3)2Cl2RudCHPh cat., CH2Cl2, 76%.
rearrangement of allylic 1,4-diacetates,4a,d we envisioned
that the key intermediate 6 could be attainable through
an Ireland-Claisen rearrangement14 of the Z(O)-tert-
butyldimethylsilylketene acetal Z(O)-14 arising from the
stereoselective enolization of dipropanoate (S,S)-13
(Scheme 4). Since both propanoate groups present in
(S,S)-13 are homotopics, we expected that the Z(O)
enolization followed by thermal rearrangement of either
of the propanoate groups should converge on the same
compound 6, immediate precursor of lactone (3S,4S,5S)-
7. Alternatively, E(O) enolization of (S,S)-13 would lead
to the 3R,4S,5S isomer (see Scheme 4). Our first attempt
was carried out by treatment of (S,S)-13 with an excess
of t-butyldimethylsilyl chloride (TBDMSCl) and potas-
sium bis(trimethylsilyl)amide (KHMDS) in THF at -78
°C and then heating the mixture in refluxing toluene.
The resultant crude mixture containing the tert-bu-
tyldimethylsilyl ester 6a and the carboxylic acid 6b was
subjected to basic hydrolysis with LiOH. Further lacton-
ization under acidic conditions cleanly afforded the
desired lactone (3S,4S,5S)-7 and its epimer (3R,4S,5S)-
7, easily separable by flash chromatography, but in a
disappointing 1:2 ratio. No other stereoisomer of 7 was
detected.15 Looking for a more extensive Z(O) enoliza-
tion,16 other experimental conditions of the Ireland-
conditions.10 In practice, when we explored the metath-
esis of (S)-8 and its acetate derivative (S)-9 in the
presence of Grubbs’ catalyst [(P(Cy)3)2Cl2RudCHPh]
under different conditions, we did not obtain the expected
allylic 1,4-diols in significant amounts (Scheme 2).
This failure was attributed to the presence of a vicinal
heteroatom next to the olefin that might decrease the
catalyst activity by chelation and/or by sterical conges-
tion.11 This problem has sometimes been solved by using
a temporary protecting group that links the two olefins
in a single molecule and favors ring-closing metathesis.12
This strategy has been particularly successful by using
a silicon-tethered protection.13 Furthermore, the struc-
tural requirements to form a cyclic molecule would lead
to the exclusive formation of Z-isomer (Scheme 3).
Accordingly, the protection of (S)-4 as the dimeric silyl
ether 10 with Ph2SiCl2 followed by partial hydrogenation
under Lindlar’s conditions afforded diolefin 11. Ring-
closing metathesis of 11 in the presence of Grubbs’
catalysts gave protected diol (S,S)-12 in good yield.
Finally, treatment of the cyclic silyl ether with TBAF in
THF afforded the desired diol (S,S)-5 in 96% yield.
(13) (a) Van de Weghe, P.; Aoun, D.; Boiteau, J.-G.; Eustache, J.
Org. Lett. 2002, 4, 4105-4108. (b) Postema, M. H. D.; Piper, J. L.
Tetrahedron Lett. 2002, 43, 7095-7099. (c) Harrison, B. A.; Verdine,
G. L. Org. Lett. 2001, 3, 2157-2159. (d) Yao, Q. Org. Lett. 2001, 3,
2069-2072. (e) Ahmad, I.; Falck-Pedersen, M. L.; Undheim, K. J.
Organomet. Chem. 2001, 625, 160-172. (f) Boiteau, J.-G.; Van de
Weghe, P.; Eustache, J. Tetrahedron Lett. 2001, 42, 239-242. (g)
Gierasch, T. M.; Chytil, M.; Didiuk, M. T.; Park, J. Y.; Urban, J. J.;
Nolan, S. P.; Verdine, G. L. Org. Lett. 2000, 2, 3999-4002. (h) Barrett,
A. G. M.; Beall, J. C.; Braddock, D. C.; Flack, K.; Gibson, V. C.; Salter,
M. M. J. Org. Chem. 2000, 65, 6508-6514. (i) Lobbel, M.; Koll, P.
Tetrahedron: Asymmetry 2000, 11, 393-396. (j) Hoshi, T.; Yasuda,
H.; Sanji, T.; Sakurai, H. Bull. Chem. Soc. Jpn. 1999, 72, 821-827.
(k) Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429-1432.
(l) Evans, P. A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768-6769.
For a review on synthesis of oxygen-containing heterocycles by ring-
closing metathesis, see: (m) Deiters, A.; Martin, S. F. Chem. Rev. 2004,
104, 2199-2238.
(14) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem.
Soc. 1976, 98, 2868-2877. For a review on Ireland-Claisen rearrange-
ment, see: (b) Chai, Y.; Hong, S.-P.; Lindsay, H. A.; McFarland, C.;
McIntosh, M. C. Tetrahedron 2002, 58 , 2905-2928. (c) Pereira, S.;
Srebnik, M. Aldrichim. Acta 1993, 26, 17-29. For a more general
review on [3,3]-sigmatropic rearrangements, see: (d) Nubbemeyer, U.
Synthesis 2003, 961-1008. (e) Enders, D.; Knopp, M.; Schiffers, R.
Tetrahedron: Asymmetry 1996, 7, 1847-1882. (f) Frauenrath, H. In
Houben-Weyl Methods of Organic Chemistry, Vol. E21; Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart,
1995; pp 3301-3756.
Then, we turned our attention to the desymmetrization
of (S,S)-5. Based on our previous experience on the
(9) (a) Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem.
2002, 74, 7-10. (b) Choi, T.-L.; Lee, C. W.; Chatterjee, A. K.; Grubbs,
R. H. J. Am. Chem. Soc. 2001, 123, 10417-10418. (c) Blackwell, H.
E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann,
D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58-71.
(10) Gurjar, M. K.; Yakambram, P. Tetrahedron Lett. 2001, 42,
3633-3636.
(11) For a discussion on metathesis of allylic alcohols: Maishal, T.
K.; Sinha-Mahapatra, D. K.; Paranjape, K.; Sarkar, A. Tetrahedron
Lett. 2002, 43, 2263-2267 and references therein.
(12) See, for example: (a) McReynolds, M. D.; Sprott, K. T.; Hanson,
P. R. Org. Lett. 2002, 4, 4673-4676. (b) Sprott, K. T.; McReynolds, M.
D.; Hanson, P. R. Org. Lett. 2001, 3, 3939-3942. (c) Sakamoto, Y.;
Okazaki, M.; Miyamoto, K.; Nakata, T. Tetrahedron Lett. 2001, 42,
7633-7636. (d) Baylon, C.; Heck, M.-P.; Mioskowski, C. J. Org. Chem.
1999, 64, 3354-3360.
J. Org. Chem, Vol. 69, No. 23, 2004 8173

SCHEME 4. Ireland-Claisen Rearrangementa
SCHEME 5. Preparation of Phaseolinic Acid and
Its Epimera
a
Reagents and conditions: (a) DBU, pyridine, ∆; (b) (i) O3,
CH2Cl2, -78 °C, (ii) Me2S; (iii) NaClO2, H2O2, NaH2PO4, H2O/
CH3CN, 93-98%.
that reported in the literature5,21 for phaseolinic acid and
exhibited a negative optical rotation in agreement with
Valentin’s results. In analogous fashion, we transformed
(3R,4S,5S)-7 into the carboxylic acid (2S,3S,4R)-3 in 98%
yield.
a
Reagents and conditions: (a) (EtCO)2O, Et3N, DMAP, CH2Cl2,
100%; (b) (i) KHMDS, TBDMSCl, THF/30% DMPU, -78 °C to rt,
(ii) toluene, ∆; (c) (i) LiOH, H2O/THF, ∆, (ii) aq HCl/THF, ∆, 85%.
Conclusion
In this paper, we have reported the synthesis of (-)-
phaseolinic acid in eight steps and 40% overall yield from
commercially available (S)-oct-1-yn-3-ol as the single
source of chirality. The key intermediate (6S,7Z,9S)-
tetradec-7-ene-6,9-diol, (S,S)-5, was prepared by self-
metathesis of an enantioenriched allylic alcohol. This
homodimerization has been very effective by using a
temporary silicon-protecting group that favored the in-
tramolecular metathesis (RCM) with total control of the
stereochemistry of the alkene. Lactone skeleton of
(2S,3S,4S)-3 was achieved by a stereoespecific Ireland-
Claisen rearrangement of the dipropanoate of (S,S)-5
followed by consecutive basic and acid treatment in a very
efficient one-pot process. This synthesis illustrates the
value of C2-symmetrical allylic 1,4-diols in the synthesis
of natural products and also corroborates that the (-)-
phaseolinic acid is the 2S,3S,4S isomer.
Claisen rearrangement were explored: changing base
(KHMDS, LDA, LHMDS), silylating agent (TMSCl, tert-
butyldimethylsilyl chloride or triflate), order of addition
of the reagents, and the presence of cosolvents as N,N′-
dimethyl-.N,N′-propyleneurea (DMPU).17 The best tan-
dem of yield/selectivity was obtained when the enoliza-
tion was performed by slow addition of (S,S)-13 to
KHMDS (3.03 mmol) and TBDMSCl(4.03 mmol) in 30%
DMPU/THF at -78 °C. In such conditions and in a one-
pot process without isolation of any intermediate, we
obtained a gratifying 85% overall yield of lactones 7 with
a 4:1 ratio in favor of the desired stereoisomer (3S,4S,5S)-
7.
A further improvement in the final yield of that lactone
was accomplished by base-catalyzed isomerization of the
minor lactone (3R,4S,5S)-7 to the 3S,4S,5S (DBU/pyri-
dine,18 ∼70:30 equilibrium mixture in favor of the S,S,S
isomer).
Experimental Section
Finally, transformation of lactone (3S,4S,5S)-7 into the
carboxylic acid (2S,3S,4S)-3 was successfully accom-
plished by ozonolysis followed by oxidation of the crude
(S,S)-4,7-Dipentyl-2,2-diphenyl-4,7-dihydro[1,3,2]di-
oxasilepine [(S,S)-12]. Diene 11 (74 mg, 0.17 mmol) was
dissolved in CH2Cl2 (1 mL) under Ar atmosphere. The solution
was sonicated for 20 min. Then, Grubbs’ catalyst (15 mg, 0.017
mmol) was dissolved in anhyd CH2Cl2 (0.6 mL) and added via
cannula. The solution was heated to reflux and the reaction was
followed by TLC (95:5 hexane/EtOAc). Additional Grubbs’
catalyst (8 mg, 5%mol) was added 7 h later. A last addition of
catalyst (4 mg) was added 15 h later. The reaction was quenched
after 28 h. The solvent was evaporated in a vacuum. The residue
was purified by flash chromatography (95:5 hexane/CH2Cl2) to
give (52 mg, 76%) as colorless oil: Rf ) 0.56 (80:20 hexane/CH2-
Cl2); [R]D -62.5 (c 1.01, CHCl3); IR (film) 3072, 1654, 1592, 1090;
1H NMR (CDCl3, 300 MHz) δ 0.80-0.84 (m, 6H), 1.18-1.40 (m,
12H), 1.40-1.75 (m, 4H), 4.71 (td, J ) 5.8, 1.6 Hz, 2H), 5.54 (m,
19
aldehyde with NaClO2 without loss of stereochemical
purity (Scheme 5). This two-step process gave better yield
(93%) than direct olefin cleavage with RuCl3.20 As ex-
pected, compound 3 showed identical spectral data as
(15) The relative stereochemistry of lactones 7 was confirmed by
NOE experiments. It is noteworthy that after isolation, both lactones
demostrated to be stereochemical stables under the experimental
conditions used to transform 6 into 7.
(16) (a) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III. J. Org. Chem.
1991, 56, 650-657. (b) Ireland, R. E.; Wipf, P.; Xiang, J.-N. J. Org.
Chem. 1991, 56, 3572-3582. See also ref 14.
(17) In our hands, the Claisen rearrangement of (S,S)-13 mediated
by trimethylsilyl triflate and a tertiary amine according to a reported
protocol was completely unsuccessful. See: Kobayashi, M.; Masumoto,
K.; Nakai, E.; Nakai, T. Tetrahedron Lett. 1996, 37, 3005-3008.
(18) Similar ratios were obtained when (2R,3S,4S)-7 was heated
with an excess of DBU in toluene, acetonitrile, hexane, or even neat,
as the equilibrium balance did not greatly affect the polarity of the
solvent.
(20) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936-3938.
(21) 1H NMR spectra of phaseolinic acid and its C-4 epimer as a
racemic mixtures have been described: Pohmakotr, M.; Harnying, W.;
Patoomratana, T.; Reutrakul, V. Helv. Chim. Acta 2002, 85, 3792-
3813.
(19) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567-569.
8174 J. Org. Chem., Vol. 69, No. 23, 2004

2H), 7.31-7.50 (m, 6H), 7.65-7.75 (m, 4H); 13C NMR (CDCl3,
100.6 MHz) δ 14.0, 22.6, 24.9, 31.5, 37.9, 70.5, 127.7, 130.3,
132.9, 134.1, 134.8; HRMS (FAB+) calcd for C26H37O2Si [M +
H]+ 409.2563, found 409.2567.
(2S,3S,4S)-4-Methyl-5-oxo-2-pentyltetrahydrofuran-3-
carboxylic Acid [(2S,3S,4S)-3]. Ozone was bubbled through
a solution of lactone (3S,4S,5S)-7 (165 mg, 0.62 mmol) in anhyd
CH2Cl2 (10 mL) at -78 °C until TLC (CH2Cl2) showed complete
disappearance of the starting material (∼30 min). Then, nitrogen
was bubbled through the blue solution for a few minutes before
Me2S (∼100 µL) was added and stirring continued at rt for 2 h.
Then, the solution was diluted with CH2Cl2 (10 mL) and a
phosphate buffer (pH ) 7; 4 mL). The aqueous layer was washed
with CH2Cl2 (3 × 10 mL). The combined organic layer was dried
over anhyd MgSO4. Removal of volatiles under vacuum afforded
the crude aldehyde (TLC, CH2Cl2/MeOH 98:2 Rf ) 0.52) that
was dissolved in CH3CN (3.6 mL). An aqueous solution of NaH2-
PO4 (67 mg in 2.5 mL) and H2O2 (33% p/v, 0.70 mL) was added,
and the mixture was cooled to 0-4 °C. Then, aq NaClO2 (115
mg in 2.5 mL) was added, and the green homogeneous solution
was stirred at rt until starting material was consumed (TLC).
The reaction mixture was quenched by addition of aq NaHSO3
(150 mg, 2 mL). The mixture was stirred for 30 min and then
basified with NaOH 2 M. The aqueous layer was washed with
EtOAc (5 mL), acidified with HCl 2 M, and extracted with EtOAc
(3 × 5 mL). The combined organic layers were dried over anhyd
MgSO4 and filtered, and the solvent was removed to give
(2S,3S,4S)-4-methyl-5-oxo-2-pentyltetrahydrofuran-3-carboxyl-
ic acid, (2S,3S,4S)-3, (124 mg, 93%) as a white solid: mp 136-
137 °C (lit.5 mp 139-140 °C; lit.8a mp 140-141 °C); [R]D -114.4
(c 1.46, CHCl3) [lit.5 [R]D -150 (c 0.20, CHCl3); lit.8a [R]D -112.3
(c 0.26, CHCl3)]; IR (KBr) 2958, 1760, 1739, 1260, 1418, 1183;
1H NMR (CDCl3, 400 MHz) δ 0.89 (t, J ) 6.9, 3H), 1.32 (d, J )
7.1, 3H), 1.26-1.44 (m, 5H), 1.55-1.60 (m, 3H), 3.04 (dq, J )
10.0, 7.1, 1H), 3.22 (dd, J ) 10.0, 8.2, 1H), 4.69 (m, 1H); 13C
NMR (CDCl3, 100.6 MHz) δ 13.9, 14.4, 22.4, 25.2, 31.0, 31.3,
36.4, 51.6, 77.3, 174.9, 177.4; HRMS (EI) calcd for C11H18O4 [M]+
214.1205, found 214.1209.
Preparation of Lactone (3S,4S,5S)-7: Optimized Pro-
cedure. A toluene solution of KHMDS (0.5 M, 1.74 mL, 0.87
mmol) was added dropwise to a solution of TBDMSCl (176 mg,
1.17 mmol) in anhyd THF (2 mL) and anhyd DMPU (1.35 mL)
at -78 °C under argon. Then, a solution of (S,S)-13 (100 mg,
0.29 mmol) in anhyd THF (0.5 mL) was added dropwise via
cannula, followed by an additional 0.5 mL of THF to wash the
flask. After the addition, the mixture was stirred for 45 min and
then was allowed warm to rt for 5 h. Then, most of the volatiles
were removed under vacuum, anhyd toluene (3 mL) was added,
and the mixture was heated (130 °C bath temperature) for 16
h. The progress of the reaction was monitored by TLC (98:2 CH2-
Cl2/MeOH, disappearance of the starting material, Rf ) 0.92,
and appearance of 6a, Rf ) 0.90, and 6b, Rf ) 0.24). Adding
diethyl ether (8 mL) and brine (8 mL) partitioned the reaction
mixture. The aqueous layer was washed with additional diethyl
ether, and the combined organic layers were dried (MgSO4) and
concentrated in a vacuum. The crude mixture was treated with
THF (2 mL) and aq LiOH (6 M, 1 mL) at 70 °C for 16 h. Then,
the solution was acidified with aq HCl (2 M, 6 mL), additional
THF (3 mL) was added, and the mixture was heated at 50 °C
for 2 h. The mixture was partitioned by adding CH2Cl2 (10 mL),
and the aqueous layer was washed with additional CH2Cl2 (2 ×
5 mL). The organic layers were dried (MgSO4). Evaporation of
solvents and purification by flash chromatography on silica gel
(9:1 hexane/EtOAc) yielded lactone (3S,4S,5S)-7 (53 mg, 68%)
and lactone (3R,4S,5S)-7 (13 mg, 17%).
(3S,4S,5S)-4-[(E)-Hept-1-enyl]-3-methyl-5-pentyldihydro-
furan-2-one [(3S,4S,5S)-7]: colorless oil; Rf ) 0.59 (9:1 hexane/
EtOAc); [R]D -75.3 (c 1.57, CHCl3); IR (film) 2931, 2860, 1777,
1459, 1171; 1H NMR (CDCl3, 300 MHz) δ 0.87-0.93 (m, 6H),
1.19 (d, J ) 7.2, 3H), 1.24-1.41 (m, 12H), 1.46-1.56 (m, 2H),
2.05 (m, 2H), 2.43 (dq, J ) 10.8, 7.2, 1H), 2.74 (m, 1H), 4.45 (m,
1H), 5.32 (ddt, J ) 15.2, 9.0, 1.2, 1H), 5.58 (dt, J ) 15.2, 6.8,
1H); 13C NMR (CDCl3, 75.4 MHz) δ 13.4, 13.9, 14.0, 22.4, 22.5,
25.5, 28.9, 30.8, 31.3, 31.6, 32.5, 38.8, 50.5, 81.4, 125.4, 135.5,
179.1; HRMS (EI) calcd for C17H30O2 [M]+ 266.2246, found
266.2241. Anal. Calcd for C17H30O2: C, 76.64; H, 11.35. Found:
C, 76.82; H 11.21.
(3R,4S,5S)-4-[(E)-Hept-1-enyl]-3-methyl-5-pentyldihy-
drofuran-2-one [(3R,4S,5S)-7]: colorless oil; Rf ) 0.41 (9:1
hexane/EtOAc); [R]D -37.7 (c 1.03, CHCl3); IR (film) 2958, 2931,
2860, 1777, 1457, 1175; 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J
) 6.8, 6H), 1.08 (d, J ) 7.2, 3H), 1.22-1.50 (m, 12H), 1.62-1.68
(m, 2H), 2.06 (m, 2H), 2.79 (dq, J ) 7.2, 7.2, 1H), 2.90 (m, 1H),
4.32 (dt, J ) 7.2, 5.2, 1H), 5.13 (dd, J ) 15.2, 10.8, 1H), 5.54 (dt,
J ) 15.2, 7.2, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 10.7, 13.9,
14.0, 22.4, 22.5, 25.0, 28.9, 30.8, 31.2, 31.6, 32.4, 40.3, 48.5, 82.0,
122.5, 136.4, 179.2; HRMS (EI) calcd for C17H30O2 [M]+ 266.2246,
found 266.2247. Anal. Calcd for C17H30O2: C, 76.64; H, 11.35.
Found: C, 76.40; H 11.25.
Isomerization of Lactones 7 under Basic Conditions. An
excess of DBU (28 µL, 0.188 mmol) was added to a solution of
(3R,4S,5S)-7 (10 mg, 0.038 mmol) in refluxing toluene (1 mL).
The reaction was monitored by TLC. After 56 h, no more changes
were observed. The solution was diluted with CH2Cl2 (5 mL) and
washed with 2 M aq HCl (2 mL), and the organic layer was dried
over anhyd MgSO4. Removal of solvent afforded a crude mixture
of (3S,4S,5S)-7 and its 3R epimer in a 66:34 ratio (1H NMR).
Experiments performed in other solvents gave similar results
(CH3CN or hexane, 42 h, 68:32; pyridine, 43 h, 69:31; neat, 42
h, 70:30).
A similar oxidation of (3R,4S,5S)-7 (80 mg, 0.30 mmol)
afforded (2S,3S,4S)-4-methyl-5-oxo-2-pentyltetrahydrofuran-3-
carboxylic acid, (2S,3S,4R)-3 (62 mg, 98%), as a white solid: mp
109-110 °C; [R]D -60.6 (c 1.81, CHCl3); IR (KBr) 2925, 1767,
1700, 1214, 1136. 1H NMR (CDCl3, 400 MHz) δ 0.89 (t, J ) 6.9,
3H), 1.31 (d, J ) 6.8, 3H), 1.16-1.88 (m, 8H), 2.95 (dq, J ) 7.2,
7.2, 1H), 3.33 (dd, J ) 7.2, 5.2, 1H), 4.44 (m, 1H), 9.52 (bs, 1H);
13C NMR (CDCl3, 100.6 MHz) δ 10.2, 13.9, 22.3, 25.5, 30.7, 31.3,
39.1, 50.3, 78.9, 175.2, 177.1; HRMS (EI) calcd for C11H18O4 [M]+
214.1205, found 214.1199. Anal. Calcd for C11H18O4: C, 61.66;
H, 8.47. Found: C, 61.50; H 8.22.
Acknowledgment. This work has been supported
by the Ministerio de Ciencia y Tecnologia (BQU2003-
01269) and Direccio´ General de Recerca, Generalitat de
Catalunya (2001SGR00051). We also thank to the
Generalitat de Catalunya for a doctorate studentship
to J.O. and the Universitat de Barcelona for a doctorate
studentship to M.L.
Supporting Information Available: Experimental de-
tails for preparation of compounds 10, 11, (S,S)-5, and (S,S)-
13. Rearrangement of (S,S)-13 in THF. 1H and 13C spectra
(PDF) of compounds (2S,3S,4S)-3, (2S,3S,4R)-3, (3S,4S,5S)-
7, (3R,4S,5S)-7, (S,S)-12, and (S,S)-13. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO048705X
J. Org. Chem, Vol. 69, No. 23, 2004 8175