Asymmetric conjugate addition for the preparation of syn-1,3-dimethyl arrays: Synthesis and structure elucidation of capensifuranone

Article abstract of DOI:10.1021/jo049567e

The synthesis of capensifuranone (1) has been achieved by the application of developments for asymmetric conjugate addition reactions of organocopper reagents with nonracemic N-enoyl-4-phenyl-1,3-oxazolidinones for the preparation of 1,3-syn-dimethyl arra

Full text of DOI:10.1021/jo049567e

Asym m etr ic Con ju ga te Ad d ition for th e P r ep a r a tion of
syn -1,3-Dim eth yl Ar r a ys: Syn th esis a n d Str u ctu r e Elu cid a tion of
Ca p en sifu r a n on e
David R. Williams,* Andrea L. Nold, and Richard J . Mullins
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405
williamd@indiana.edu
Received March 16, 2004
The synthesis of capensifuranone (1) has been achieved by the application of developments for
asymmetric conjugate addition reactions of organocopper reagents with nonracemic N-enoyl-4-
phenyl-1,3-oxazolidinones for the preparation of 1,3-syn-dimethyl arrays. The assignment of relative
and absolute stereochemistry of 1 has been made following the high-field NMR characterizations
of synthetic diol derivatives. The previously unassigned C4 stereochemistry of 1 was determined to
be of the (S)-configuration. The thermodynamic equilibration of capensifuranone and its C4
diastereomer has been examined.
In tr od u ction
An interesting structural feature shared by the me-
tabolites of genus Siphonaria is the alternating 1,3-syn
arrangement of methyl substituents in their respective
aliphatic chains.5 This structural motif offers a significant
challenge for asymmetric synthesis and has inspired
synthesis efforts toward members of the family.6 Our
previous efforts toward the syntheses of myxovirescin A1,7
sambutoxin,8 and funiculosin9 required the construction
of an acyclic 1,3-anti-dimethyl array. The use of nonra-
cemic 4-phenyl-1,3-oxazolidin-2-ones as chiral auxiliaries
introduced by Hruby and co-workers10 facilitated our
studies. Thus, general methodology was developed for
effecting facial selectivity in the asymmetric conjugate
addition reactions of Yamamoto organocopper reagents11
with enantiopure N-enoyl-1,3-oxazolidinones.12 Our re-
cent report of the conjugate additions of the Yamamoto
Marine mollusks of the genus Siphonaria have yielded
a number of structurally interesting secondary metabo-
lites.1 While it had been previously proposed that these
metabolites were produced as a defense mechanism
against natural predators,1f this concept is currently
subject to debate.1m A common structural feature of this
family of natural products is the occurrence of an
aliphatic desoxygenated polypropionate side chain at-
tached to either an unsaturated furanone, a pyranone,
or a cyclic hemiacetal, in which the C1 carboxylic acid
headgroup of the biogenetic chain is embedded. Recently,
the South African pulmonate mollusk Siphonaria cap-
ensis yielded three new polypropionates, capensifuranone
1, capensinone 2, and a biogentic precursor, (2E,4S,6S,8S)-
2,4,6,8-tetramethyl-2-undecenoic acid 3 (Figure 1).2
A
related metabolite, pectinatone 4, exhibits antibiotic
activity.1h,i,3 However, the biological activity of compounds
1 and 2 has yet to be fully investigated. Additional
examples of interest include siphonarienfuranone (5)1a,3
and siphonarienolone (6).4
(4) Norte, M.; Cataldo, F.; Gonza´lez, A. G. Tetrahedron Lett. 1988,
29, 2879.
(5) Hoffman has provided significant insights for conformational
organization of flexible molecules bearing 1,3-dimethyl substitution,
which may contribute to the understanding of molecular recognition
and biochemical properties. For an overview of conformational analy-
ses, see: Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054.
(6) (a) Ziegler, F. E.; Becker, M. R. J . Org. Chem. 1990, 55, 2800-
2805 (b) Sundram, W. N.; Albizati, K. F. Tetrahedron Lett. 1992, 33,
437 (c) Paterson, I.; Perkins, M. V. J . Am. Chem. Soc. 1993, 115, 1608
(d) Norte, M.; Ferna´ndez, J . J .; Padilla, A. Tetrahedron Lett. 1994, 35,
3413 (e) Garson, M. J .; J ones, D. D.; Small, C. J .; Liang, J .; Clardy, J .
Tetrahedron lett. 1994, 35, 6921 (f) Carballeira, N. M.; Cruz, H.; Hill,
C. A.; De Voss, J . J .; Garson, M. J . Nat. Prod. 2001, 64, 1426 (g)
Birkbeck, A. A.; Enders, D. Tetrahedron Lett. 1998, 39, 7823 (h) Calter,
M. A.; Liao, W. J . Am. Chem. Soc. 2002, 124, 13127 (i) Calter, M. A.;
Liao, W.; Struss, J . A. J . Org. Chem. 2001, 66, 7500.
(7) Williams, D. R.; Li, J . J . Tetrahedron Lett. 1994, 35, 5113.
(8) Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217.
(9) Williams, D. R.; Lowder, P. D.; Gu, Y. Tetrahedron Lett. 2000,
41, 9397.
(1) (a) Paul, M. C.; Zub´ıa, E.; Ortega, M. J .; Salva´, J . Tetrahedron
1997, 53, 2303. (b) Faulkner, D. J . Nat. Prod. Rep. 1996, 13, 75. (c)
Manker, D. C.; Garson, M. J ., Faulkner, D. J . J . Chem. Soc., Chem.
Commun. 1988. 1061. (d) Garson, M. J .; J ones, D. D.; Small, C. J .;
Liang, J .; Clardy, J . Tetrahedron Lett. 1994, 35, 6921. (e) Garson, M.
J .; Goodman, J . M.; Paterson, I. Tetrahedron Lett. 1994, 35, 6929. (f)
Hochlowski, J . E.; Faulkner, D. J . J . Org. Chem. 1984, 49, 3838. (g)
Manker, D. C.; Faulkner, D. J .; Stout, T. J .; Clardy, J . J . Org. Chem.
1989, 54, 5371 (h) Biskupiak, J . E.; Ireland, C. M. Tetrahedron Lett.
1983, 24, 3055 (i) Hochlowski, J . E.; Faulkner, J . D.; Tetrahedron Lett.
1983, 24, 1917. (j) Davies-Coleman, M. T.; Garson, M. J . Nat. Prod.
Rep. 1998, 15, 477. (k) Roll, D. M.; Biskupiak, J . E.; Mayne, C. L.;
Ireland, C. M. J . Am. Chem. Soc. 1986, 108, 6680. (l) Hochlowski, J .
E.; Coll, J . C.; Faulkner, D. J .; Biskupiak, J . E.; Ireland, C. M.; Qi-tai,
Z.; Cun-heng, H.; Clardy, J . J . Am. Chem. Soc. 1984, 106, 6748. (m)
Manker, D. C.; Faulkner, D. J . J . Org. Chem. 1989, 54, 5374.
(2) Beukes, D. R.; Davies-Coleman, M. T. Tetrahedron 1999, 55,
4051.
(10) Nicola´s, E.; Russel, K.; Hruby, V. J . J . Org. Chem. 1993, 58,
766. (b) For a related approach: Captain, L. F.; Xia, X.; Liotta, D. C.
Tetrahedron Lett. 1996, 37 4293.
(11) For a review: Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986,
25, 947.
(3) Norte, M.; Cataldo, F.; Gonza´lez, A. G.; Rodr´ıguez M. L.; Ruiz-
Perez, C. Tetrahedron 1990, 46, 1669.
(12) Williams, D. R.; Kissel, W. S.; Li, J . J . Tetrahedron Lett. 1998,
39, 8593.
10.1021/jo049567e CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/08/2004
5374
J . Org. Chem. 2004, 69, 5374-5382

Synthesis and Structure Elucidation of Capensifuranone
F IGURE 1. Secondary metabolites of marine mollusks of genus Siphonaria.
methylcopper reagent demonstrated features of double
asymmetric induction, and provided accessibility to 1,3-
and 1,2-syn- and anti-dimethyl arrays with excellent
diastereoselectivity.13 As illustrated in the production of
syn-7 (eq 1) and anti-8 (eq 2), these results were par-
ticularly encouraging for the prospects of reiterative
introduction of 1,3-asymmetry as posed in capensifura-
none (1). Since the relative stereochemistry at C4 of 1
could not be assigned in earlier isolation and character-
ization efforts, opportunities for establishing the relative
and absolute configuration of 1 through synthesis pro-
vided further interest for these studies.
SCHEME 1. Retr osyn th etic An a lysis of
Ca p en sifu r a n on e
in an “all-syn” stereotriad. General strategies for the
reiterative development of 1,3-stereorelationships are
rare. However, recent findings by Negishi and co-work-
ers14 offer a noteworthy advancement via directed car-
bometalation of homoallylic alcohols. Asymmetric conju-
gate addition reactions play a central role in molecule
constructions,15-17 and previous efforts in our laboratories
provided sufficient generality in the methodology to
achieve this goal in an iterative fashion. This task was
accomplished as shown in Scheme 2, beginning with the
N-enoyl-4(S)-phenyl-1,3-oxazolidinon-2-one 11.18 Our stud-
Herein, we describe our studies of asymmetric conju-
gate addition methodology which have led to the synthe-
sis of (-)-capensifuranone (1). As summarized by the
retrosynthetic analysis of Scheme 1, our plan would
examine nucleophilic addition to the nonracemic alde-
hyde 9 to provide diastereomeric C4 alcohols toward the
assignment of relative stereochemistry in 1. Conjugate
addition to the enone 10 would establish the all-syn
relationship in 9 and would require a one-carbon trunca-
tion of the aliphatic chain upon removal of the auxiliary.
Thus, the iterative introduction of stereochemical fea-
tures from 11 would provide a suitable starting point for
these investigations.
(14) Tan, Z.; Negishi, E. Angew. Chem., Int. Ed. 2004, 43, in press.
Recently, Professor Negishi has informed us of adaptation of his
enantioselective carboalumination methodology for synthesis of sipho-
narienolone and siphonarienone: Magnin-Lachaux, M.; Tan, Z.; Liang,
B. Negishi, E. Org. Lett. 2004, 6, 1425.
(15) For a recent review of organocopper reagents: (a) Krause, N.;
Gerold, A. Angew. Chem., Int. Ed. Engl. 1998, 37, 283. (b) Krause, N.
Angew. Chem., Int. Ed. Engl. 1998, 37, 283.
(16) For leading references of related free-radical mediated conjugate
additions: (a) Sibi, M. P.; J i, J .; Sausker, J . B.; J asperse, C. P. J . Am.
Chem. Soc. 1999, 121, 7517. (b) Sibi, M. P.; Rheault, T. R.; Chan-
dramouli, S. V.; J asperse, C. P. J . Am. Chem. Soc. 2002, 124, 2924.
(17) The syn-1,3-dimethyl arrays of borrelidin have been prepared
utilizing substrate control in the conjugate addition o organocopper
reagents: Hanessian, S.; Yang, Y.; Giroux, S.; Mascitti, V.; Ma, J .;
Raeppel, F. J . Am. Chem. Soc. 2003, 125, 13784.
Resu lts a n d Discu ssion
The synthesis of the C4-C12 carbon chain of capensi-
furanone (1) required the production of 1,3-asymmetry
(13) Williams, D. R.; Kissel, W. S.; Li, J .; Mullins, R. J . Tetrahedron
Lett. 2002, 43, 4841.
J . Org. Chem, Vol. 69, No. 16, 2004 5375

Williams et al.
SCHEME 2. Iter a tive Ster eocon tr olled Syn th esis
of P olym eth yla ted 20a
F IGURE 2. Chelation complexes of the syn-S-cis conformer
of 11.
conjugate addition of organocopper reagents under the
same conditions with a general trend of a reversal of
facial selectivity.12 Furthermore, modeling indicates that
the 4-phenyl substituent would not extend into the local
environment of the â-carbon of the planar enone 11. This
suggests it would be more likely that the phenyl ring
could sterically destabilize the initial synclinal metal
complexation of copper reagent at the R-carbon as sug-
gested in C of Figure 2 versus the diastereomeric
arrangement in B. While these reactions may initially
involve π-coordination, the four-centered mechanism in
complex B is no longer favored in the case of lithium
dialkylcuprate additions.20 These studies feature a six-
atom arrangement with lithium cation activation of the
carbonyl oxygen. An analogous role could be proposed for
BF3 in complex D, in which a bridging fluoride provides
for activation. The new C-C bond is made by reductive
elimination from a Cu3+ intermediate. Indeed, this
mechanistic picture is particularly challenging owing to
the lack of structural information regarding the Yama-
moto organocopper species.21 Although we have not
attempted a systematic study of cuprate reactivity,
lithium dialkylcuprates appear to lead to substantial
amounts of byproduct, some of which stems from attack
at the C2 carbonyl of the oxazolidinone system.22 On the
other hand, recent results from our laboratories have
shown that bis-chelated A undergoes diastereocontrolled
conjugate additions of allylstannanes with the opposite
sense of facial selectivity compared to allyl Yamamoto
reagents.23
a
Reagents and conditions: (a) nPrMgBr, CuBr‚DMS, BF3‚OEt2,
THF, -78 °C, then oxazolidinone 11, -78 f -20 °C, 16 h (95%,
91:9 dr); (b) LiBH4, MeOH, Et2O, 0 °C (86%); (c) Dess-Martin
periodinane, NaHCO3, CH2Cl2, 1 h (98%); (d) ylide 14, CH2Cl2, 16
h (99%, 2.5:1 E/Z); (e) I2, hν, CH2Cl2. (95%, >20:1 E/Z); (f) MeMgBr,
THF, CuBr‚DMS, BF3‚OEt2, -78 °C, then oxazolidinone 15, -78
f -20 °C, 16 h (89%, >95:5 dr); (g) LiBH4, MeOH, Et2O, 0 °C
(90%); (h) Dess-Martin periodinane, NaHCO3, CH2Cl2, 1 h (100%);
(i) ylide 14, CH2Cl2, 16 h (99%, 2.5:1 E/Z); (j) I2, hν, CH2Cl2 (95%,
>20:1 E/Z); (k) MeMgBr, THF, CuBr‚DMS, BF3‚OEt2, -78 °C, then
oxazolidinone 19, -78 f -20 °C, 16 h (86%).
ies12 had shown that alkenyl and allylic Yamamoto
reagents are more reactive than alkyl species, and the
methyl reagent, generated in this manner, is the least
reactive. In addition, stereochemical selectivity was
generally enhanced in accord with increasing steric bulk
of the carbon nucleophile. Thus, alkenyl and allyl con-
jugate additions are often completed at -78 °C, whereas
alkyl and methyl reagents required warming to -20 °C.
This temperature differential may contribute to the
observed stereoselectivity in some cases. The Yamamoto
organocopper reagent was prepared at -78 °C by the
combination of equimolar proportions of n-propylmagne-
sium bromide, copper(I) bromide‚dimethyl sulfide com-
plex, and boron trifluoride etherate. Low-temperature
addition of 11 with gradual warming to -20 °C resulted
in formation of 12 with high yield and good diastereose-
lectivity (dr 91:9). Bis-coordination in the restricted
conformer A (Figure 2) provides a predictive model for
conjugate addition which avoids nonbonded interactions
with the 4-phenyl substituent. Indeed, low-temperature
NMR data have supported formation of a single species
with bidentate Lewis acids.19 While this viewpoint pro-
vides a consistent rationale for diastereoselectivity in the
observed behavior of organocopper species, the model has
a number of shortcomings. For example, homochiral
4-benzyl and 4-isopropyl analogues of 11 demonstrate the
The asymmetric conjugate addition was scaleable and
produced multigram quantities of optically pure 12
(Scheme 2) after flash chromatography. Reductive re-
moval of the chiral auxiliary and oxidation gave aldehyde
13 for chain elongation. Homologation was accomplished
in an efficient manner utilizing ylide 1424 which afforded
nearly quantitative conversion to the expected enone.
(19) (a) Castellino, S.; Dwight, W. J . J . Am. Chem. Soc. 1993, 115,
2986. (b) Castellino, S. J . Org. Chem. 1990, 55, 5197. (c) Additionally,
our low temeperature 13C NMR studies of complexes of 11 with ZrCl4,
Sc(OTf)3, and Sm(OTf)3 confirm the presence of a single complex in
complete agreement with the bidentate complexes described in ref 18a
and 18b.
(20) For a review: Nakamura, E.; Mori, S. Angew. Chem., Int. Ed.
2000, 39, 3750.
(21) Neutral RCu species would be expected to behave as Lewis
acids. However, polymeric complexes, dimers or tetramers could be
involved in nucleophilic conjugate additions.
(22) We have noted that a study of conjugate addition reactions of
vinylmagnesium bromide has led to a major correction of product
structures demonstrating nucleophilic attack at the C2 carbonyl of the
oxazolidin-2-one system rather than the anticipated 1,4 addition. Han,
Y.; Hruby, V. J . Tetrahedron Lett. 1997, 38, 7317 and Han, Y.; Hruby,
V. J . Tetrahedron Lett. 1998, 39, 8561.
(23) Williams, D. R.; Mullins, R. J .; Miller, N. A. Chem. Commun.
2003, 2220.
(24) Lee, K.; Cha, J . K. J . Am. Chem. Soc. 2001, 123, 5590.
(18) Evans, D. A.; Chapman, K. T.; Hung, D. T.; Kawaguchi, A. T.
Angew. Chem. 1987, 99, 1197.
5376 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis and Structure Elucidation of Capensifuranone
TABLE 1. Com p a r ison of 13C NMR Da ta for Syn th etic
a n d Na tu r a l Ca p en sifu r a n on e 1 a n d 27a
a
a
natural 1 δC
synthetic 1 δC
synthetic 27 δC
carbon
(ppm)
(ppm)
(ppm)
F IGURE 3. Conformations of γ-methyl substitution with bis-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
174.8
124.6
158.0
87.8
32.1
36.6
29.8
44.5
27.7
38.4
19.8
14.4
8.4
174.7
124.5
158.1
87.8
32.0
36.5
29.7
44.3
27.5
38.2
19.8
14.4
8.4
175.0
124.1
158.5
85.0
31.5
39.0
29.6
45.3
27.3
41.3
20.0
14.4
8.4
chelation.
However, inspection of the NMR data of crude product
indicated the presence of a 2.5:1 mixture of E/Z-olefin
isomers. Fortunately, a solution of the mixture containing
a crystal of iodine was exposed to sunlight, which
facilitated complete isomerization to the desired E-enone
15 (95% yield over these two steps).25
Conjugate 1,4-addition of methylcopper reagent to 15
proceeded with excellent diastereoselectivity (dr >95:5)
in high overall yield (89%). The preexisting γ-stereo-
genecity at the homoallylic site in 15 led to a stereo-
chemically reinforcing situation with respect to the
chirality of the auxiliary. Our rationalization of the
matched scenario is based upon a conformational analysis
of 1,4-nonbonded interactions as summarized in Figure
3. Conformer A would minimize gauche interactions with
a staggered butane geometry (alkenyl/methyl). This
arrangement eliminates one gauche interaction compared
to conformer B providing 0.6 kcal/mol of additional
stability. As a result, the acyclic chain of A impedes
nucleophilic attack to the R-face of the planar enoyl unit
enhancing the role of the phenyl group of the chiral
auxiliary. In conformer B, the acyclic chain is projected
above the plane of the enoyl unit. Conformer B is
mismatched in this regard and otherwise introduces the
additional gauche butane interaction owing to the posi-
tion of the homoallylic methyl group. In fact, the conju-
gate addition of methylcopper reagent in the case of the
corresponding tert-butyldiphenylsilyl ethers (R ) OSi-t-
C4H9Ph2) has led to greater than 97% diastereoselectivity
via the synergy of the phenyl substituent and the bulk
of the silyl ether.13
12.4
17.5
21.2
20.7
12.4
17.4
21.2
20.7
12.3
11.9
20.4
20.3
a
Spectra recorded at 100 MHz
While a number of alternatives were considered to
address the issue of stereochemistry at C4 of 1, we have
found that oxidation of the enolate of 20 with the Davis
oxaziridine 2126,27 led to the R-hydroxyimide 22 with high
diastereoselectivity (dr 10:1). Purification and LiBH4
reduction gave the optically active diol 23 which was
assigned as the C4-(R)-isomer for subsequent compari-
sons. To ensure formation of both C4 diastereomers of 1,
sodium periodate cleavage of diol 23 gave aldehyde 24
which was then utilized for direct assembly of the
butyrolactone via nucleophilic addition of the dianion
derived from (E)-3-bromo-2-methyl-2-propenoic acid.28
The reaction cleanly provided a 4:1 mixture of separable
C4 diastereomers 25 and 26, wherein product 25, corre-
sponding to the expected result of Felkin-Anh addition,
was assumed to predominate. Each isomeric lactone was
independently subjected to the conditions of Negishi
coupling29 using dimethylzinc in the presence of pal-
ladium catalyst to replace the C3 bromide with a methyl
substituent without epimerization of the labile C4 posi-
tion. In the event, synthetic capensifuranone (1) was
exclusively formed from the minor condensation product
26 while the major butyrolactone 25 gave rise to the
diastereomer 27. Spectral characterization of synthetic
1 was in agreement with the NMR spectra and published
physical data for natural capensifuranone.2 Table 1
provides a listing of carbon assignments from our 13C
NMR data for synthetic 1 and the C4 diastereomer 27 as
Installation of asymmetry at C5 proceeded with the
iterative introduction of the methyl substituent via
reductive removal of the auxiliary in 16 (Scheme 2),
followed by oxidation of the resulting primary alcohol 17
to yield aldehyde 18 and Wittig homologation to 19. Once
again, conjugate addition of the Yamamoto methylcopper
species in enone 19 proceeded with reinforcing elements
of stereochemistry and provided the single diastereomer
20 in 86% yield.
(25) As an alternative, the use of the corresponding phosphonate
reagent i was explored in an attempt to secure the E-enone in a single
operation. The phosphonate was prepared in accordance with published
procedure: Broka, C. A.; Ehrler, J . Tetrahedron Lett. 1991, 32, 5907.
While these efforts led to exclusive E-olefin selectivity, poor yields
(∼30%) were obtained in gram-scale reactions.
(26) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919.
(27) Evans, D. A.; Morissey, M. M.; Dorrow, R. L. J . Am. Chem. Soc.
1985, 107, 4346.
(28) (a) Caine, D.; Samuels, W. D. Tetrahedron Lett. 1980, 21, 4057.
(b) Caine, D.; Ukachukwu, V. C. J . Org. Chem. 1985, 50, 2195 (c) Caine,
D.; Ukachukwu, V. C. Tetrahedron Lett. 1983, 24, 3959. (d) Caine, D.;
Frobese, A. S. Tetrahedron Lett. 1978, 5167.
(29) (a) Wipf, P.; Soth, M. J . Org. Lett. 2002, 4, 1787 (b) Tamara,
Y.; Kagotani, M.; Yushida, Z. I. J . Org. Chem. 1980, 45, 5223 (c)
Negishi, E. I.; Luo, F. T.; Frisbee, R.; Matsushita, H. Heterocycles 1982,
18, 117.
J . Org. Chem, Vol. 69, No. 16, 2004 5377

Williams et al.
SCHEME 3. Com p letion of th e Tota l Syn th esisa
a
Reagents and conditions employed: (a) NaHMDS, THF, -78 °C, then Davis oxaziridine, 15 s, then CSA, THF (10:1 dr); (b) LiBH4,
MeOH, Et2O, 0 °C, 1 h (93% from 20); (c) NaIO4, THF, pH 7 buffer, 2 h (84%); (d) (E)-3-bromo-2-methyl-2-propenoic acid, BuLi (2 equiv),
THF, 30 min, -78 °C, then aldehyde 24, -78 f rt, 16 h, H3O+ (97%, 4:1 dr); (e) Me2Zn, Pd(PPh3)4, THF, -78 °C, 16 h (99%).
SCHEME 4. Absolu te Ster eoch em istr y Deter m in a tion of La cton es 1 a n d 27 by th e Mosh er Meth od a ,b
a
∆δ values ((S)-MTPA - (R)-MTPA) obtained for the MTPA esters of 1 and 27. ∆δ values are expressed in hertz (400 MHz). bReagents
and conditions employed: (a) LiAlH4, Et2O, 0 °C , 1/27, 0 °C f rt, 16 h, (98%); (b) Imid, TBDPSCl, CH2Cl2, 1 h, (95%); (c) DMAP, Et3N,
Mosher acid chloride, CH2Cl2, 45 min.
SCHEME 5. Equ ilibr a tion of Ca p en sifu r a n on e 1 a n d epi-Ca p en sifu r a n on e 27
well as the reported data for natural 1. Proton NMR
spectra of natural and synthetic 1 were identical in all
respects.30
to four products 32a b and 33a b for modified Mosher
analysis.31 Chemical shift differences (∆δ) for the 1H
NMR data ((S)-MTPA - (R)-MTPA) were obtained for
the pairs of R-methoxy-R-trifluromethyl phenylacetic acid
(MTPA) esters 32a b and 33a b as summarized in Scheme
4. The treatment unambiguously validated our assign-
ment of (S)-stereochemistry at C4 in 33 and (R)-32. This
corroborating evidence also established the absolute
stereochemistry of 1.
Finally, we considered the possibility that facile C4
epimerization of the butyrolactone moiety of capensifura-
none in the marine environment could account for the
observed stereochemistry in 1 as a result of its thermo-
dynamic stability. Thus, methanol solutions of synthetic
1 and 4-epi-capensifuranone 27 were individually equili-
brated in the presence of DBU (Scheme 5). In each case,
this study gave rise to a 2.5:1 mixture of diastereomers
favoring the epimeric C4 isomer 27, a derivative which
has not been found to date as a naturally occurring
metabolite.
To confirm our assumptions regarding the assignment
of C4 stereochemistry, a series of chemical conversions
were undertaken. First, the lithium aluminum hydride
reduction of the major diastereomer 25 gave the expected
alkenyl diol which was treated with ozone (O3, CH2Cl2,
-78 °C) followed by a lithium borohydride quench. This
procedure yielded a diol which proved to be identical with
23 (Scheme 3) in all respects. Thus, substantial literature
precedent26,27 for the stereocontrolled hydroxylation of the
Z(O)-enolate leading to 22 coincides with the stereochem-
istry of Felkin-Anh addition in 25. Second, lactones 1
and 27 were independently subjected to lithium alumi-
num hydride reductions to yield a pair of nonracemic
diols 28 and 29 (Scheme 4). Protection of the primary
alcohol and acylation of the secondary allylic alcohol led
(30) We are indebted to Professor Mike Davies-Coleman, Rhodes
University (Grahamstown, South Africa) for providing 1H, 13C and
DEPT spectra of authentic capensifuranone which were used to confirm
the identity of our synthetic 1.
(31) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092.
5378 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis and Structure Elucidation of Capensifuranone
NaHCO3 (150 mL), pH 7 buffer (150 mL), and saturated aq
Na2S2O3 (150 mL). After vigorously stirring for 2.5 h, the
phases were separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 100 mL). The combined organic phases were
dried over MgSO4, filtered, and concentrated in vacuo to afford
0.91 g (98%) of 13 as a clear oil, which was used in the next
step without further purification. This product was character-
Con clu sion
The synthesis of capensifuranone has been completed
leading to the assignment of C4 stereochemistry and the
absolute configuration of 1. We have demonstrated the
applicability of asymmetric 1,4-conjugate additions of
organocopper reagents using nonracemic 4-phenyl-1,3-
oxazolidin-2-ones for the reiterative generation of 1,3-
syn-dimethyl arrays. The generality of the process offers
promise for widespread applications in natural products
synthesis.
ized as follows: Rf ) 0.5 (hexanes/EtOAc 6:1); [R]20 -7.9 (c
D
1
0.09, CHCl3); H NMR (400 MHz) δ 9.76 (t, J ) 2.4 Hz, 1H),
2.39 (ddd, J ) 17.0, 5.6, 2.4 Hz, 1H), 2.22 (ddd, J ) 17.0, 7.8,
2.4 Hz, 1H), 2.13-2.02 (m, 1H), 1.42-1.18 (m, 4H), 0.96 (d, J
) 6.7 Hz, 3H), 0.90 (t, J ) 7.1 Hz, 3H); 13C NMR: 203.1, 51.1,
39.2, 27.9, 20.0, 19.9, 14.1; IR (thin film) 2958, 2929, 2715,
1726, 1151, 1115 cm-1; HRMS (DEI) calcd for C7H15O (M+
H) 115.1123, found 115.1122.
+
Exp er im en ta l Section
(R)-4-P h en yl-3-[(tr ip h en ylp h osp h or a n ylid en e)a cetyl]-
oxa zolid in -2-on e (14).24 Phosphonium ylide 14 was prepared
by standard methods and was characterized according to the
following spectral data: Rf ) 0.3 (hexanes/EtOAc 1:2); mp
170-174 °C; [R]21D ) -80.1 (c 1.7, CHCl3); 1H NMR (400 MHz,
CDCl3) 7.59-7.47 (m, 8H), 7.39-7.29 (m, 12H), 5.57 (dd, J )
8.6, 3.5 Hz, 1H), 4.73 (d, J ) 23.5 Hz, 1H), 4.58 (t, J ) 8.6 Hz,
1H), 4.12 (dd, J ) 8.6, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 164.5, 155.2, 141.4, 132.9, 131.9, 128.6, 127.5, 127.0, 126.1,
125.7, 68.9, 40.8, 39.7; IR (thin film): 3057, 2905, 1751, 1587,
1434, 1359, 1137 cm-1; HRMS (EI) calcd for C29H24O3NP (M+)
465.1494, found 465.1497.
(4R)-3-((5S)-(2E)-Meth yl-oct-2-en oyl)-4-p h en yloxa zoli-
d in -2-on e (15). Phosphonium ylide 14 (23 g, 49 mmol) was
added to a solution of aldehyde 13 (3.7 g, 32 mmol) in CH2Cl2
(65 mL). The reaction mixture was stirred for 24 h and
subsequently concentrated in vacuo. The residue was purified
by flash silica gel chromatography (8:1 hexanes/EtOAc f 3:1
hexanes/EtOAc) to afford a 2.5:1 mixture (E/Z) of olefin isomers
which were used directly as described below. Characteristic
1H NMR signals for the olefin isomers are as follows: E-isomer
[â-H: δ 7.03 (dt, J ) 15.3, 7.3 Hz, 1H)], Z-isomer [â-H: δ 6.29
(dt, J ) 11.7, 7.3 Hz, 1H)].
(4S)-3-((3S)-3-Meth ylh exa n oyl)-4-p h en yloxa zolid in -2-
on e (12). A solution of propylmagnesium bromide (2.0 M
solution in Et2O, 61.0 mL, 122 mmol) was added dropwise to
a suspension of recrystallized CuBr‚DMS (24.9 g, 121 mmol)
in THF (400 mL) at -40 °C. After 1 h, the mixture was cooled
to -78 °C for the dropwise addition of freshly distilled BF3‚
OEt2 (15.3 mL, 121 mmol), and a precooled solution of
oxazolidinone 1117 (12.7 g, 54.9 mmol) in THF (100 mL) was
added 5 min later. The suspension was stirred for 3 h at -78
°C and was then transferred with its dry ice/acetone bath to a
freezer where it was stirred for 18 h while warming to -20
°C. The reaction was quenched by the addition of saturated
aqueous NH4Cl (500 mL) and diluted with Et2O (500 mL). The
phases were separated, and the aqueous layer was extracted
with Et2O (2 × 500 mL). Combined organic phases were
washed with H2O (100 mL) and brine (100 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel chromatography (4:1 hexanes/
EtOAc) to afford 14.4 g (95%, 91:9 dr) of 12 as a white solid:
Rf ) 0.6 (hexanes/EtOAc 2:1); [R]20 +32.2 (c 0.90, CHCl3); 1H
D
NMR (400 MHz) δ 7.40-7.28 (m, 5H), 5.43 (dd, J ) 8.9, 3.8
Hz, 1H), 4.68 (t, J ) 8.9 Hz, 1H), 4.27 (dd, J ) 8.9, 3.8 Hz,
1H), 2.98 (A of ABX, J AB ) 16.0 Hz, J AX ) 5.3 Hz, 1H), 2.67 (B
of ABX, J AB ) 16.0 Hz, J BX ) 8.6 Hz, 1H), 2.06-1.96 (m, 1H),
1.34-1.14 (m, 4H), 0.85 (d, J ) 6.6 Hz, 3H), 0.84 (t, J ) 6.2
Hz, 3H); 13C NMR (100 MHz) δ 172.2, 153.6, 139.2, 129.0,
128.5, 125.8, 69.7, 57.5, 42.4, 39.0, 29.3, 19.8, 19.4, 14.0; IR
(thin film) 3031, 2958, 2929, 2872, 1783, 1705, 1457, 1384,
1321, 1198, 1081, 1045, 761, 707 cm-1; HRMS (DEI) calcd for
The mixture of olefin isomers was dissolved in CH2Cl2 (30
mL) and treated with iodine (two crystals). After being stirred
in sunlight for 2 d, the reaction mixture was quenched with
saturated aq Na2S2O3 (30 mL) and diluted with EtOAc (50 mL).
The phases were separated, and the aqueous layer was
extracted with EtOAc (2 × 50 mL). The combined organic
phases were washed with brine (50 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified
by flash silica gel chromatography (9:1 hexanes/EtOAc) to
afford 8.0 g (82%, two steps from 13) of 15 as a white solid:
C
16H21O3N (M+) 275.1521, found 275.1513.
(3S)-3-Meth ylh exa n a l (13). Lithium borohydride (0.59 g,
27 mmol) was added in one portion to a solution of imide 12
(5.0 g, 18 mmol) in Et2O (180 mL) at -20 °C. Methanol (1.1
mL, 27 mmol) was then added dropwise to this reaction
mixture at -20 °C, and the reaction was stirred for 1 h while
warming to room temperature. The reaction was carefully
diluted with saturated aqueous NaHCO3 (100 mL), and the
phases were separated with additional extractions of the
aqueous layer with Et2O (3 × 200 mL). The combined organic
phases were washed with H2O (50 mL) and brine (50 mL),
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash silica gel chromatography (4:1
pentane/Et2O) to afford 1.8 g (86%) of (3S)-3-methylhexanol
Rf ) 0.5 (hexanes/EtOAc 2:1); mp 48-49 °C; [R]20 ) -84.0 (c
D
1
0.63, CHCl3); H NMR (400 MHz, CDCl3) 7.36-7.24 (m, 5H),
7.20 (d, J ) 15.3 Hz, 1H), 7.03 (dt, J ) 15.3, 7.3 Hz, 1H), 5.43
(dd, J ) 8.9, 3.7 Hz, 1H), 4.65 (t, J ) 8.9 Hz, 1H), 4.23 (dd, J
) 8.9, 3.7 Hz, 1H), 2.24-2.16 (m, 1H), 2.09-2.01 (m, 1H),
1.62-1.52 (m, 1H), 1.26-1.20 (m, 3H), 1.11-1.05 (m, 1H), 0.82
(d, J ) 6.7 Hz, 3H), 0.84-0.79 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.5, 153.7, 151.3, 139.1, 129.1, 128.6, 125.9, 121.1,
69.9, 57.7, 40.1, 38.9, 32.3, 20.0, 19.6, 14.2; IR (thin film) 2958,
2927, 2872, 1780, 1688, 1634, 1457, 1284, 1102 cm-1; HRMS
(DEI) calcd for C18H23O3N (M+) 301.1678, found 301.1678.
as a clear oil: Rf ) 0.5 (hexanes/EtOAc 2:1); [R]20 ) -0.94 (c
D
0.91, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.73-3.63 (m, 2H),
1.64-1.51 (m, 2H), 1.43-1.34 (m, 2H), 1.33-1.24 (m, 2H),
1.16-1.08 (m, 1H), 0.89 (d, J ) 6.6 Hz, 3H), 0.88 (t, J ) 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 61.2, 40.0, 39.4, 29.2,
20.0, 19.6, 14.3; IR (thin film): 3327, 2957, 2929, 2873, 1456,
1056 cm-1; HRMS (DEI) calcd for C7H14 (M+ - H2O) 98.1096,
found 98.1092.
(4R)-3-((3S,5S)-3,5-Dim eth ylocta n oyl)-4-p h en yloxa zo-
lid in -2-on e (16). A solution of methylmagnesium bromide (3.0
M solution in Et2O, 35.6 mL, 107 mmol) was added dropwise
to a suspension of recrystallized CuBr‚DMS (22.0 g, 107 mmol)
in THF (150 mL) at -40 °C. After 1 h, the mixture was cooled
to -78 °C, and freshly distilled BF3‚OEt2 (13.6 mL, 107 mmol)
was added dropwise. After the mixture was stirred at -78 °C,
oxazolidinone 15 (6.44 g, 21.4 mmol) in THF (60 mL) was
slowly added. The suspension was stirred for 3 h at -78 °C
and was then transferred with its dry ice/acetone bath to a
freezer where it was allowed to slowly warm to -20 °C with
stirring for 18 h. The reaction was quenched by the addition
of saturated aqueous NH4Cl (100 mL) and saturated aqueous
Solid NaHCO3 (10.2 g, 122 mmol) was added in one portion
to a solution of (3S)-3-methylhexanol (1.0 g, 8.1 mmol) in dry
methylene chloride (41 mL) at rt and was followed by the
addition of Dess-Martin periodinane (6.9 g, 16 mmol). The
mixture was stirred for 2.5 h, and the contents of the reaction
were then poured into a solution comprised of saturated aq
J . Org. Chem, Vol. 69, No. 16, 2004 5379

Williams et al.
NaHCO3 (50 mL) and then diluted with Et2O (200 mL). The
phases were separated, and the aqueous layer extracted with
Et2O (2 × 200 mL). The combined organic phases were washed
with H2O (100 mL) and brine (100 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified
by flash silica gel chromatography (4:1 hexanes/EtOAc) to
afford 5.2 g (89%, >20:1 dr) of 16 as a white solid: Rf ) 0.5
follows: E-isomer [â-H: δ 7.04 (dt, J ) 15.3, 7.3 Hz, 1H)],
Z-isomer [â-H: δ 6.33 (dt, J ) 11.7, 7.3 Hz, 1H)].
This mixture of olefin isomers was dissolved in CH2Cl2 (9
mL) and treated with iodine (two crystals). After being stirred
in sunlight for 2 d, the reaction mixture was quenched with
saturated aq Na2S2O3 (25 mL) and diluted with EtOAc (25 mL).
The phases were separated, and the aqueous layer was
extracted with EtOAc (2 × 50 mL). Combined organic phases
were washed with brine (25 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by flash
silica gel chromatography (9:1 hexanes/EtOAc) to afford 1.2 g
(82%, two steps from 18) of 19 (dr > 20:1) as a white solid: Rf
(hexanes/EtOAc 2:1); mp 76-78 °C; [R]20 ) -51.0 (c 0.63,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38-7.22 (m, 5H), 5.39
(dd, J ) 8.9, 3.7 Hz, 1H), 4.63 (t, J ) 8.9 Hz, 1H), 4.21 (dd, J
) 8.9, 3.7 Hz, 1H), 2.77 (app d, J ) 6.7 Hz, 2H), 2.10-2.00
(m, 1H), 1.44-1.36 (m, 1H), 1.22-1.12 (m, 2H), 0.98-0.90 (m,
2H), 0.80 (d, J ) 6.4 Hz, 3H), 0.77 (d, J ) 6.7 Hz, 3H), 0.82-
0.72 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 153.7, 139.2,
129.1, 128.6, 125.9, 69.8, 57.6, 44.6, 42.5, 38.6, 29.7, 27.2, 20.2,
20.1, 19.9, 14.3; IR (thin film) 2956, 2928, 2872, 1784, 1704,
1457, 1196, 1060 cm-1; HRMS (DEI) calcd for C19H27O3N (M+)
317.1991, found 317.1990.
) 0.4 (hexanes/EtOAc 4:1); mp 60-64 °C; [R]20 ) -71.8 (c
D
2.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 5H),
7.22 (d, J ) 15.3 Hz, 1H), 7.04 (dt, J ) 15.3, 7.3 Hz, 1H), 5.44
(dd, J ) 8.9, 4.0 Hz, 1H), 4.64 (t, J ) 8.9 Hz, 1H), 4.22 (dd, J
) 8.9, 4.0 Hz, 1H), 2.27-2.19 (m, 1H), 2.05-1.97 (m, 1H),
1.72-1.64 (m, 1H), 1.48-1.40 (m, 1H), 1.30-1.24 (m, 1H),
1.24-1.14 (m, 3H), 1.08-1.00 (m, 1H), 0.96-0.88 (m, 1H), 0.82
(d, J ) 6.4 Hz, 3H), 0.79 (d, J ) 6.7 Hz, 3H), 0.77 (t, J ) 6.7
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.4, 153.7, 151.1,
139.1, 129.1, 128.6, 125.9, 121.1, 69.9, 57.7, 44.5, 39.8, 39.0,
29.9, 29.6, 20.1, 20.0, 19.9, 14.3; IR (thin film) 2957, 2918, 1780,
1690, 1634, 1197, 1061 cm-1; HRMS (EI) calcd for C21H29O3N
(M+) 343.2147, found 343.2147.
(3S,5S)-3,5-Dim eth ylocta n ol (17). Lithium borohydride
(0.23 g, 11 mmol) was added in one portion to a solution of
imide 16 (1.7 g, 5.3 mmol) in Et2O (53 mL) at -10 °C. Methanol
(0.43 mL, 11 mmol) was added dropwise to this mixture at
-10 °C, and the reaction was stirred for 1 h while slowly
warming to room temperature. The reaction was quenched by
addition of saturated aqueous NaHCO3 (50 mL), phases were
separated and the aqueous layer was extracted with Et2O (3
× 100 mL). The combined organic phases were washed with
H2O (50 mL) and brine (50 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash
silica gel chromatography (4:1 pentane/Et2O) to afford 0.77 g
(4R)-3-((3S,5S,7S)-3,5,7-Tr im eth yld eca n oyl)-4-p h en yl-
oxa zolid in -2-on e (20). A solution of methylmagnesium bro-
mide (3.0 M solution in Et2O, 5.9 mL, 18 mmol) was added
dropwise to a suspension of recrystallized CuBr‚DMS (3.6 g,
18 mmol) in THF (35 mL) at -40 °C. After 1 h, the mixture
was cooled to -78 °C, and freshly distilled BF3‚OEt2 (2.2 mL,
18 mmol) was added dropwise. Upon stirring at -78 °C, the
oxazolidinone 19 (1.2 g, 3.5 mmol) in THF (35 mL) was slowly
introduced. This suspension was stirred for 3 h at -78 °C and
was then transferred with its dry ice/acetone bath to a freezer
where it was allowed to slowly warm to -20 °C with continu-
ous stirring for 18 h. The reaction was quenched by the
addition of saturated aqueous NH4Cl (50 mL) and saturated
aqueous NaHCO3 (25 mL) and diluted with Et2O (100 mL).
The phases were separated and the aqueous layer extracted
with Et2O (2 × 100 mL). The combined organic phases were
washed with H2O (50 mL) and brine (50 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel chromatography (4:1 hexanes/
EtOAc) to afford 1.1 g (86%, >20:1 dr) of 20 as a white solid:
(90%) of 17 as a clear oil: Rf ) 0.5 (hexanes/EtOAc 2:1); [R]20
D
1
) -3.85 (c 0.68, CHCl3); H NMR (400 MHz, CDCl3) δ 3.74-
3.62 (m, 2H), 1.70-1.56 (m, 2H), 1.55-1.46 (m, 1H), 1.36-
1.28 (m, 2H), 1.27-1.18 (m, 3H), 1.10-0.95 (m, 2H), 0.88 (d,
J ) 6.7 Hz, 3H), 0.85 (t, J ) 6.6 Hz, 3H), 0.84 (d, J ) 6.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 61.2, 45.3, 39.8, 39.1, 29.7,
26.9, 20.2, 20.2, 20.0, 14.4; IR (thin film) 3328, 2957, 2927,
2872, 1458, 1379, 1058 cm-1; HRMS (EI) calcd for C10H20
O
(M+ - H) 157.1592, found 157.1594.
(3S,5S)-3,5-Dim eth ylocta n a l (18). Solid NaHCO3 (5.4 g,
64 mmol) was added in one portion to a solution of alcohol 17
(0.68 g, 4.3 mmol) in dry methylene chloride (21 mL) at rt,
followed immediately by the addition of Dess-Martin perio-
dinane (3.6 g, 8.6 mmol). The mixture was stirred for 2.5 h, at
which point the contents of the reaction were poured into a
solution containing saturated aq NaHCO3 (75 mL), pH 7 buffer
(75 mL), and saturated aq Na2S2O3 (75 mL). After the mixture
was stirred vigorously for 2.5 h, the phases were separated
and the aqueous layer was extracted with CH2Cl2 (2 × 100
mL). The combined organic phases were dried over MgSO4,
filtered, and concentrated in vacuo to afford 0.67 g (100%) of
18 as a clear oil, which could be used in the next step without
further purification. Characterization of aldehyde 18 is de-
Rf ) 0.4 (hexanes/EtOAc 4:1); mp 63-65 °C; [R]24 ) -41.7 (c
D
0.85, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38-7.22 (m, 5H),
5.39 (dd, J ) 8.9, 3.7 Hz, 1H), 4.63 (t, J ) 8.9 Hz, 1H), 4.21
(dd, J ) 8.9, 3.7 Hz, 1H), 2.80-2.74 (m, 2H), 2.11-2.02 (m,
1H), 1.52-1.44 (m, 1H), 1.46-1.38 (m, 1H), 1.30-1.24 (m, 1H),
1.24-1.10 (m, 5H), 0.97-0.90 (m, 2H), 0.81 (d, J ) 6.4 Hz,
3H), 0.77 (d, J ) 6.7 Hz, 3H), 0.77 (d, J ) 6.7 Hz, 3H), 0.84-
0.73 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 139.2, 129.1,
128.6, 125.9, 125.6, 69.8, 57.6, 44.8, 44.7, 42.3, 38.6, 29.6, 27.3,
27.1, 20.6, 20.5, 20.3, 19.9, 14.4; IR (thin film) 2957, 2925, 2871,
1784, 1703, 1456, 1193, 1060 cm-1; HRMS (EI) calcd for
scribed as follows: Rf ) 0.9 (hexanes/EtOAc 2:1); [R]20
)
D
1
-3.26 (c 3.1, CHCl3); H NMR (400 MHz, CDCl3) δ 9.74 (d, J
) 2.1 Hz, 1H), 2.41-2.33 (m, 1H), 2.20-2.10 (m, 2H), 1.50-
1.41 (m, 1H), 1.36-1.27 (m, 2H), 1.27-1.19 (m, 2H), 1.09-
1.00 (m, 2H), 0.94 (d, J ) 6.3 Hz, 3H), 0.86 (t, J ) 6.8 Hz,
3H), 0.84 (d, J ) 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
203.2, 50.9, 44.8, 39.0, 31.6, 29.7, 25.7, 22.6, 19.9, 14.3; IR (thin
film) 2947, 2926, 2873, 1723, 1375 cm-1; HRMS (EI) calcd for
C
22H33O3N (M+) 359.2460, found 359.2460.
(4R )-3-((2R ,3S ,5S ,7S )-2-H yd r oxy-3,5,7-t r im e t h yld e -
ca n oyl)-4-p h en yloxa zolid in -2-on e (22). Sodium bis(tri-
methylsilyl)amide (1.0 M solution in THF, 6.1 mL, 6.1 mmol)
was added to a solution of 20 (2.0 g, 5.6 mmol) in THF (22
mL) at -78 °C. After the mixture was stirred for 30 min, a
solution of Davis oxaziridine25 21 (2.2 g, 8.3 mmol) in THF
(11 mL) was added rapidly via cannula. A solution of CSA (6.5
g, 28 mmol) in THF (56 mL) was cannulated into the flask
after 15 s. Upon completion, the reaction mixture was diluted
with Et2O (200 mL) and washed with water (100 mL). The
phases were separated, and the organic layer was washed with
saturated aq NaHCO3 (2 × 100 mL) and brine (100 mL). The
aqueous phases were combined and extracted with Et2O (3 ×
150 mL), and organic phases were then combined, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
C
10H20O (M+) 156.1514, found 156.1514.
(4R)-3-((5S,7S)(2E)-5,7-Dim eth yld ec-2-en oyl)-4-p h en yl-
oxa zolid in -2-on e (19). Phosphonium ylide 14 (3.0 g, 6.4
mmol) was added in one portion to a solution of aldehyde 18
(0.67 g, 4.3 mmol) in CH2Cl2 (9.0 mL). The reaction mixture
was stirred for 24 h and then was concentrated in vacuo. The
residue was purified by flash silica gel chromatography using
a solvent gradient of 8:1 hexanes/EtOAc to 3:1 hexanes/EtOAc
affording a 2.5:1 mixture (E/Z) olefin isomers. Characteristic
1H NMR signals for the olefin isomers are described as
5380 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis and Structure Elucidation of Capensifuranone
purified by flash silica gel chromatography (75:24:1 hexanes/
EtOAc/MeOH) to afford 22, which contained small amounts
of imine impurities, suitable for use in the subsequent step. A
sample of 22 was purified by flash silica gel chromatography
(8:1 hexanes/EtOAc) for extensive characterization of the major
product: Rf ) 0.7 (hexanes/EtOAc 2:1); [R]20D ) -68.4 (c 0.81,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38-7.22 (m, 5H), 5.39
(dd, J ) 8.9, 2.7 Hz, 1H), 5.10 (d, J ) 5.1 Hz, 1H), 4.77 (t, J )
8.9 Hz, 1H), 4.36 (dd, J ) 8.9, 2.7 Hz, 1H), 3.05 (d, J ) 7.8 Hz,
1H), 2.14-2.06 (m, 1H), 1.74-1.64 (m, 1H), 1.61-1.50 (m, 2H),
1.40-1.28 (m, 1H), 1.30-1.18 (m, 3H), 1.07-0.99 (m, 3H), 0.92
(d, J ) 6.4 Hz, 3H), 0.88 (t, J ) 7.0 Hz, 3H), 0.86 (d, J ) 6.6
Hz, 3H), 0.77 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 175.1, 153.0, 138.5, 129.3, 129.0, 125.7, 73.0, 70.8, 58.1, 45.1,
41.5, 39.0, 33.1, 29.7, 27.1, 20.7, 20.3, 20.0, 14.4, 13.7; IR (thin
film) 3518, 2957, 2926, 2871, 1788, 1696, 1381, 1324, 1198
cm-1; HRMS (EI) calcd for C22H33O4N (M+) 375.2410, found
375.2410.
extracted with Et2O (3 × 20 mL). The organic phases were
combined, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash silica gel chromatog-
raphy (6:1 hexanes/EtOAc) to afford 131 mg (97%) of 25 and
26 (25:26 4:1) as a clear oil. The major product, (5R)-4-br om o-
3-m et h yl-5-((1′S,3′S,5′S)-1,3,5-t r im et h yloct yl)-5H-fu r a n -
2-on e (25), was characterized as follows: Rf ) 0.5 (hexanes/
EtOAc 8:1); [R]21D ) +32.6 (c 0.82, CHCl3); 1H NMR (400 MHz)
δ 4.89 (t, J ) 1.9 Hz, 1H), 2.27-2.17 (m, 1H), 1.91 (d, J ) 1.9
Hz, 3H), 1.70-1.55 (m, 2H), 1.55-1.45 (m, 2H), 1.40-1.20 (m,
3H), 1.20-1.05 (m, 2H), 1.00-0.95 (m, 1H), 0.90 (d, J ) 6.6
Hz, 3H), 0.86 (d, J ) 6.2 Hz, 3H), 0.86 (t, J ) 6.6 Hz, 3H),
0.66 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz) δ 171.5, 143.9,
129.4, 85.1, 45.2, 40.7, 40.0, 31.7, 29.6, 27.2, 20.2, 20.2, 20.0,
14.4, 12.0, 10.1; IR (thin film) 2958, 2925, 1771, 1664, 1380,
1272, 1083 cm-1; HRMS (EI) calcd for C16H27O2Br (M+)
330.1194, found 330.1193.
The minor adduct, (5S)-4-br om o-3-m eth yl-5-((1′S,3′S,5′S)-
1,3,5-tr im eth yloctyl)-5H-fu r a n -2-on e (26), was character-
ized by the following spectral information: Rf ) 0.50 (hexanes/
EtOAc 8:1); [R]21D ) -29.9 (c 0.77, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 4.84 (t, J ) 1.9 Hz, 1H), 2.26-2.17 (m, 1H), 1.90 (d,
J ) 1.9 Hz, 3H), 1.54-1.42 (m, 2H), 1.35-1.15 (m, 5H), 1.12
(d, J ) 7.0 Hz, 3H), 1.02-0.90 (m, 3H), 0.87 (t, J ) 7.0 Hz,
3H), 0.84 (d, J ) 6.8 Hz, 3H) 0.82 (d, J ) 6.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.3, 143.2, 129.8, 87.7, 44.2, 38.4,
36.1, 32.2, 29.7, 27.5, 21.2, 20.6, 19.8, 17.1, 14.4, 10.1; IR (thin
film): 2957, 2925, 1770, 1663, 1380, 1274, 1089 cm-1; HRMS
(EI) calcd for C16H28O2Br (M+ + H) 331.1273, found 331.1272.
(2R,3S,5S,7S)-3,5,7-Tr im eth yldecan e-1,2-diol (23). Metha-
nol (1.95 mL, 48.2 mmol) and lithium borohydride (1.05 g, 48.2
mmol) were added to a solution of 22 in Et2O (100 mL) at 0
°C. The reaction was stirred for 3 h at 0 °C, and the reaction
was then quenched by the slow dropwise addition of saturated
aq NaHCO3 (50 mL). After the mixture was stirred for 12 h,
the phases were separated and the aqueous layer extracted
with Et2O (3 × 100 mL). The organic phases were combined,
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash silica gel chromatography (4:1
hexanes/EtOAc, 1% MeOH) to afford 1.1 g (93% over two steps)
of 23 as a clear oil: Rf ) 0.3 (hexanes/EtOAc 2:1); [R]24
)
D
Ca p en sifu r a n on e (1) a n d epi-Ca p en sifu r a n on e (27). A
general procedure was used to prepare capensifuranone 1 and
epi-capensifuranone 27. A solution of 3-bromo-2-butenolide 26
(24.1 mg, 0.073 mmol) and Pd(PPh3)4 (8.4 mg, 7.3 × 10-3 mmol)
in THF (1 mL) was subjected to three freeze-pump-thaw
cycles to remove traces of oxygen. After cooling to 0 °C, Me2-
Zn (2.0 M solution in toluene, 0.18 mL, 0.36 mmol) was added.
The reaction mixture was then stirred for 16 h at rt and was
subsequently poured into Et2O (5 mL) and quenched by the
addition of H2O (1 mL). The phases were separated, and the
aqueous layer was extracted with Et2O (3 × 20 mL). The
organic phases were combined, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash silica
gel chromatography (20:1 hexanes/EtOAc) to afford 19.2 mg
(99%) of ca p en sifu r a n on e (1), which was characterized as
follows: Rf ) 0.50 (hexanes/EtOAc 4:1); [R]22D ) -14.5 (c 0.29,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.68 (app s, 1H), 2.06-
2.00 (m, 1H), 1.93-1.92 (m, 3H), 1.82-1.81 (m, 3H), 1.51-
1.42 (m, 2H), 1.35-1.28 (m, 1H), 1.28-1.23 (m, 2H), 1.21-
1.12 (m, 2H), 1.10 (d, J ) 7.0 Hz, 3H), 1.00-0.91 (m, 3H), 0.87
(t, J ) 7.0 Hz, 3H), 0.83 (d, J ) 6.6 Hz, 3H), 0.82 (d, J ) 6.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.7, 157.9, 124.7,
87.7, 44.6, 38.5, 36.7, 32.2, 29.8, 27.8, 21.2, 20.7, 19.9, 17.5,
-30.6 (c 0.78, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.63-
3.50 (m, 3H), 2.73 (br s, 2H), 1.67-1.60 (m, 1H), 1.62-1.54
(m, 1H), 1.52-1.45 (m, 1H), 1.38-1.28 (m, 2H), 1.26-1.16 (m,
4H), 1.01-0.91 (m, 2H), 0.88 (d, J ) 6.8 Hz, 3H), 0.86 (t, J )
7.0 Hz, 3H), 0.84 (d, J ) 6.4 Hz, 3H), 0.83 (d, J ) 6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 75.3, 65.4, 44.8, 41.2, 38.6, 32.8,
29.7, 27.4, 20.9, 20.5, 19.9, 14.9, 14.4; IR (thin film) 3382, 2957,
2841, 1709, 1641, 1456, 1379, 1261, 1017 cm-1; HRMS (EI)
calcd for C13H28O2Na (M + Na+) 239.1987, found 239.1997.
(2S,4S,6S)-2,4,6-Tr im eth yln on a n a l (24). Sodium m-pe-
riodate (191 mg, 0.893 mmol) was added to a solution of 23
(129 mg, 0.595 mmol) in THF (1.5 mL) containing pH 7 buffer
(1.5 mL) at rt. The reaction mixture was stirred for 2 h at rt
and was then diluted with Et2O (10 mL) and H2O (10 mL).
The phases were separated and the aqueous layer was
extracted with Et2O (4 × 20 mL). The organic phases were
combined, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash silica gel chromatog-
raphy (40:1 hexanes/EtOAc) to afford 91.7 mg (84%) of 24 as
a clear oil: Rf ) 0.8 (hexanes/EtOAc 6:1); [R]21 ) +6.70 (c
D
1
0.88, CHCl3); H NMR (400 MHz, CDCl3) δ 9.57 (d, J ) 2.6
Hz, 1H), 2.50-2.40 (m, 1H), 1.75-1.67 (m, 1H), 1.62-1.54 (m,
1H), 1.53-1.46 (m, 1H), 1.39-1.32 (m, 1H), 1.32-1.27 (m, 1H),
1.27-1.22 (m, 1H), 1.24-1.16 (m, 2H), 1.08 (d, J ) 7.0 Hz,
3H), 1.06-1.00 (m, 1H), 0.98-0.92 (m, 1H), 0.88 (d, J ) 6.4
14.4, 12.3, 8.4; IR (thin film) 2958, 2925, 2866, 1756, 1381 cm-1
;
HRMS (EI) calcd for C17H30O2Na (M+ + Na) 289.2143, found
289.2143.30
Hz, 3H), 0.87 (t, J ) 7.2 Hz, 3H), 0.84 (d, J ) 6.6 Hz, 3H); 13
C
The reaction was repeated with the bromide 25 to yield
(97%) the diastereomer described as Epi-ca p en sifu r a n on e
(27), which was characterized as follows: Rf ) 0.50 (hexanes/
EtOAc 4:1); [R]21D ) +37.6 (c 0.55, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 4.73 (app s, 1H), 2.04-1.96 (m, 1H), 1.92 (s, 3H),
1.81 (s, 3H), 1.70-1.56 (m, 2H), 1.56-1.48 (m, 2H), 1.38-1.32
(m, 1H), 1.32-1.27 (m, 1H), 1.27-1.19 (m, 2H), 1.17-1.10 (m,
1H), 1.06-0.92 (m, 1H), 0.89 (d, J ) 6.3 Hz, 3H), 0.87 (t, J )
6.9 Hz, 3H), 0.85 (d, J ) 6.4 Hz, 3H), 0.61 (d, J ) 6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 175.0, 158.5, 124.1, 85.0, 45.3,
41.3, 39.0, 31.5, 29.6, 27.3, 20.4, 20.3, 20.0, 14.4, 12.3, 11.9,
8.4; IR (thin film): 2958, 2925, 1755, 1685, 1089 cm-1; HRMS
(EI) calcd for C17H30O2 (M+) 266.2246, found 266.2247.
NMR (100 MHz, CDCl3) δ 205.5, 45.1, 44.1, 38.9, 38.4, 29.7,
27.9, 20.4, 20.2, 19.9, 14.4, 14.3; IR (thin film) 2958, 2924, 2874,
1730, 1453, 1261 cm-1; HRMS (EI) calcd for C12H24O (M+)
184.1827, found 184.1827.
(5R)- a n d (5S)-4-Br om o-3-m eth yl-5-((1′S,3′S,5′S)-1,3,5-
tr im eth yloctyl)-5H-fu r a n -2-on e (25) a n d (26). A solution
of n-butyllithium (2.5 M solution in THF, 352 µL, 0.88 mmol)
was added to a solution of (E)-3-bromo-2-methyl-2-propenoic
acid (72.5 mg, 0.439 mmol) in THF (8.8 mL) at -78 °C, and
the reaction was stirred for 3 h. Aldehyde 24 (81.0 mg, 0.439
mmol) in a solution of THF (3.0 mL) was introduced dropwise
via syringe. The reaction was stirred for 2 h at -78 °C and
then allowed to warm to room temperature over 16 h. The
reaction was quenched with H2O (10 mL), acidified with a 1.0
M solution of HCl (10 mL), and diluted with Et2O (20 mL).
The phases were separated, and the aqueous layer was
2Z-(4R,5S,7S,9S)-2,3,5,7,9-P en t a m et h yl-d od ec-2-en e-
1,4-d iol (28) a n d 2Z-(4S,5S,7S,9S)-2,3,5,7,9-P en ta m eth yl-
d od ec-2-en e-1,4-d iol (29). A general procedure was used to
prepare diols 28 and 29. A solution of epi-capensifuranone 27
J . Org. Chem, Vol. 69, No. 16, 2004 5381

Williams et al.
(17.8 mg, 67.0 µmol) in Et2O (0.15 mL) was added to a solution
of LAH (1.0 M in Et2O, 60.0 µL, 60.0 µmol) in Et2O (0.45 mL)
at 0 °C. After being stirred at 0 °C for 10 min, the reaction
was warmed to rt, allowed to stir for 16 h prior to dilution
with Et2O (5 mL), and quenched of excess reagent by the slow
addition of H2O (1 mL) and 2 M NaOH (1 mL). The phases
were separated, and the aqueous layer was extracted with
Et2O (6 × 5 mL). The organic phases were combined, dried
over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash silica gel chromatography (2:1 hexanes/
EtOAc) to afford 17.7 mg (98%) of 2Z-(4R,5S,7S,9S)-2,3,5,7,9-
p en ta m eth yl-d od ec-2-en e-1,4-d iol (28), which was charac-
terized as follows: Rf ) 0.5 (hexanes/EtOAc 1:1); [R]21D ) -33.9
4H), 7.46-7.36 (m, 6H), 4.31 (A of AB, J AB ) 11.7 Hz, 1H),
4.04 (B of AB, J AB ) 11.7 Hz, 1H), 3.86 (d, J ) 8.9 Hz, 1H),
1.78 (s, 3H), 1.58 (s, 3H), 1.34-1.24 (m, 3H), 1.24-1.17 (m,
4H), 1.04 (s, 9H), 0.96-0.90 (m, 1H), 0.86 (t, J ) 6.9 Hz, 3H),
0.84 (d, J ) 6.0 Hz, 3H), 0.83 (d, J ) 6.7 Hz, 3H), 0.80-0.74
(m, 2H), 0.52 (d, J ) 6.8 Hz, 3H).
Gen er a l P r oced u r e for th e F or m a tion of Mosh er
Ester s of 32 a n d 33. A methylene chloride (0.20 mL) solution
containing 4-(dimethylamino)pyridine (16.8 mg, 0.138 mmol)
and (R)-(+)-R-methoxy-R-(trifluoromethyl)phenylacetic acid
chloride (20.0 mg, 0.079 mmol) was added to allylic alcohol
30 (3.5 mg, 0.0069 mmol) in dry Et3N (0.040 mL) at ambient
temperature. The solution was stirred for 45 min at rt and
applied directly for preparative thin-layer chromatography
(10:1 hexanes/EtOAc). Recovery and identification of the
purified Mosher ester derivative was undertaken.
The (S)-Mosher ester derivative 32a , prepared from alcohol
30, was characterized as follows: 1H NMR (400 MHz, CDCl3)
δ 7.74-7.68 (m, 4H), 7.46-7.34 (m, 11H), 5.39 (d, J ) 9.7 Hz,
1H), 4.49 (d, J ) 11.5 Hz, 1H), 4.23 (d, J ) 11.7 Hz, 1H), 3.54
(s, 3H), 1.88-1.80 (m, 1H), 1.72 (s, 3H), 1.50-1.40 (m, 2H),
1.31 (s, 3H), 1.34-1.20 (m, 4H), 1.20-1.14 (m, 2H), 1.06 (s,
9H), 1.04-0.98 (m, 1H), 0.94-0.86 (m, 2H), 0.87 (d, J ) 6.3
Hz, 3H), 0.86 (t, J ) 7.1 Hz, 3H), 0.80 (d, J ) 6.6 Hz, 3H),
0.77 (d, J ) 6.3 Hz, 3H).
The corresponding (R)-Mosher ester derivative 32b, pre-
pared from alcohol 30, was characterized as follows: 1H NMR
(400 MHz, CDCl3) δ 7.74-7.67 (m, 4H), 7.46-7.34 (m, 11H),
5.48 (d, J ) 9.7 Hz, 1H), 4.50 (d, J ) 11.7 Hz, 1H), 4.22 (d, J
) 11.7 Hz, 1H), 3.49 (s, 3H), 1.86-1.80 (m, 1H), 1.76 (s, 3H),
1.57 (s, 3H), 1.50-1.40 (m, 1H), 1.34-1.20 (m, 4H), 1.20-1.14
(m, 2H), 1.05 (s, 9H), 1.04-0.98 (m, 1H), 0.94-0.86 (m, 2H),
0.85 (t, J ) 7.1 Hz, 3H), 0.80 (d, J ) 6.6 Hz, 3H), 0.76 (d, J )
6.6 Hz, 3H), 0.71 (d, J ) 6.3 Hz, 3H).
The (S)-Mosher ester derivative 33a obtained from 31 was
characterized as follows: 1H NMR (400 MHz, CDCl3) δ 7.74-
7.68 (m, 4H), 7.48-7.34 (m, 11H), 5.43 (d, J ) 9.8 Hz, 1H),
4.51 (d, J ) 11.7 Hz, 1H), 4.24 (d, J ) 11.5 Hz, 1H), 3.49 (s,
3H), 1.84-1.76 (m, 1H), 1.77 (s, 3H), 1.59 (s, 3H), 1.44-1.34
(m, 1H), 1.34-1.20 (m, 4H), 1.20-1.14 (m, 2H), 1.05 (s, 9H),
1.04-0.98 (m, 1H), 0.90-0.86 (m, 2H), 0.86 (t, J ) 7.0 Hz, 3H),
0.78 (d, J ) 6.6 Hz, 3H), 0.74 (d, J ) 6.6 Hz, 3H), 0.63 (d, J )
6.7 Hz, 3H).
The (R)-Mosher ester derivative 33b, prepared from alcohol
31, using the same procedure, was characterized by the
following data: 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 4H),
7.48-7.34 (m, 11H), 5.36 (d, J ) 9.8 Hz, 1H), 4.54-4.46 (m,
1H), 4.24 (d, J ) 11.5 Hz, 1H), 3.50 (s, 3H), 1.88-1.80 (m,
1H), 1.72 (s, 3H), 1.54-1.44 (m, 1H), 1.35 (s, 3H), 1.34-1.20
(m, 4H), 1.20-1.14 (m, 2H), 1.06 (s, 9H), 1.04-0.98 (m, 1H),
0.94-0.86 (m, 2H), 0.86 (t, J ) 7.0 Hz, 3H), 0.81 (d, J ) 6.6
Hz, 3H), 0.81 (d, J ) 6.6 Hz, 3H), 0.65 (d, J ) 6.7 Hz, 3H).
1
(c 0.87, CHCl3); H NMR (400 MHz, CDCl3) δ 4.31 (A of AB,
J AB ) 11.5 Hz, 1H), 4.20 (d, J ) 9.0 Hz, 1H), 3.95 (B of AB,
J AB ) 11.5 Hz, 1H), 2.15-1.95 (br s, 2H), 1.79 (s, 3H), 1.70-
1.65 (m, 1H), 1.64 (s, 3H), 1.55-1.50 (m, 1H), 1.48-1.43 (m,
1H), 1.38-1.33 (m, 1H), 1.33-1.24 (m, 2H), 1.23-1.16 (m, 2H),
1.00 (d, J ) 6.4 Hz, 3H), 0.97-0.92 (m, 1H), 0.87 (t, J ) 7.0
Hz, 3H), 0.83 (d, J ) 6.6 Hz, 3H), 0.83 (d, J ) 6.6 Hz, 3H),
0.80-0.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 134.4, 131.6,
75.8, 62.7, 44.3, 41.6, 38.4, 34.3, 29.9, 27.6, 21.5, 20.8, 19.9,
17.6, 16.6, 14.4, 13.1; IR (thin film): 3353, 2957, 2926, 2871,
2839, 1459 cm-1; HRMS (EI) calcd for C17H34O2 (M+) 270.2559,
found 270.2567.
Application of the procedure described above to capensi-
furanone (1) gave 2Z-(4S,5S,7S,9S)-2,3,5,7,9-p en ta m eth yl-
d od ec-2-en e-1,4-d iol (29), which was characterized as fol-
lows: Rf ) 0.5 (hexanes/EtOAc 1:1); [R]21 ) -21.0 (c 0.30,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.27 (A of AB, J AB
11.5 Hz, 1H), 4.22 (d, J ) 9.1 Hz, 1H), 4.06 (B of AB, J AB
)
)
11.5 Hz, 1H), 1.80 (d, J ) 0.8 Hz, 3H), 1.72-1.62 (m, 3H), 1.67
(s, 3H), 1.61-1.57 (m, 2H), 1.40-1.20 (m, 3H), 1.02-0.92 (m,
1H), 0.90 (d, J ) 6.2 Hz, 3H), 0.88 (t, J ) 7.1 Hz, 3H), 0.86 (d,
J ) 6.6 Hz, 3H), 0.85-0.80 (m, 3H), 0.77-0.70 (m, 1H), 0.67
(d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.5, 131.6,
76.1, 62.8, 44.2, 42.2, 38.2, 34.1, 29.7, 28.0, 21.6, 20.9, 19.9,
17.4, 16.4, 14.4, 12.8; IR (thin film): 3403, 2957, 2925, 2871,
1460, 1375 cm-1; HRMS (EI) calcd for C17H34O2Na (M+ + Na)
293.2457, found 293.2465.
2Z-(4R,5S,7S,9S)-1-ter t-Bu tyld ip h en ylsilyloxy-2,3,5,7,9-
p en ta m eth yld od ec-2-en e-4-ol (30) a n d 2Z-(4S,5S,7S,9S)-
1-ter t-Bu tyldiph en ylsilyloxy-2,3,5,7,9-p en ta m eth yld odec-
2-en e-4-ol (31). A general procedure was used to prepare the
alcohols 30 and 31. Imidazole (11.1 mg, 0.163 mmol) and tert-
butyldiphenylsilyl chloride (16 µL, 0.060 mmol) were added
to a solution of diol 28 (15 mg, 0.054 mmol) in methylene
chloride (200 µL). The reaction mixture was stirred at ambient
temperature for 1.25 h and diluted with Et2O (5 mL). The
organic layer was washed with H2O (3 mL) and the resulting
aqueous layer was then extracted with Et2O (4 × 5 mL).
Organic phases were combined, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash silica
gel chromatography (20:1 hexanes/EtOAc) to afford 26.3 mg
(95%) of 2Z-(4R,5S,7S,9S)-1-ter t-bu tyld ip h en ylsilyloxy-
2,3,5,7,9-p en ta m eth yl-d od ec-2-en e-4-ol (30), which was
characterized as follows: 1H NMR (400 MHz, CDCl3) δ 7.72-
7.66 (m, 4H), 7.46-7.36 (m, 6H), 4.29 (A of AB, J AB ) 11.8
Hz, 1H), 4.04 (B of AB, J AB ) 11.8 Hz, 1H), 3.86 (d, J ) 8.7
Hz, 1H), 1.78 (s, 3H), 1.55 (s, 3H), 1.34-1.24 (m, 3H), 1.20-
1.10 (m, 4H), 1.04 (s, 9H), 0.87 (d, J ) 6.8 Hz, 3H), 0.86 (t, J
) 7.3 Hz, 3H), 0.80 (d, J ) 6.6 Hz, 3H), 0.75 (d, J ) 6.6 Hz,
3H), 0.72-0.66 (m, 1H), 0.62-0.54 (m, 2H).
Ack n ow led gm en t. We gratefully acknowledge sup-
port from the National Institutes of Health (GM41560
and GM42897). Eli Lilly & Co. and Pfizer, Inc., are
gratefully acknowledged for undergraduate research
fellowships (A.L.N.).
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information and proton and carbon NMR spectra for
compounds 11-27 of the synthesis pathway and synthetic
capensifuranone (1). This material is available free of charge
via the Internet at http://pubs.acs.org.
The procedure was also applied to diol 29 yielding (91%) of
2Z-(4S,5S,7S,9S)-1-ter t-b u t yld ip h en ylsilyloxy-2,3,5,7,9-
p en ta m eth yl-d od ec-2-en e-4-ol (31), which was character-
ized as follows: 1H NMR (400 MHz, CDCl3) δ 7.72-7.66 (m,
J O049567E
5382 J . Org. Chem., Vol. 69, No. 16, 2004