Total synthesis of (+)-brasilenyne. Application of an intramolecular silicon-assisted cross-coupling reaction

Article abstract of DOI:10.1021/ja0466863

The first enantioselective total synthesis of (+)-brasilenyne (1) has been achieved in 19 linear steps, with 5.1% overall yield from L-(S)-malic acid. The construction of the oxonin core containing a 1,3-cis, cis diene unit was accomplished with a tandem ring-closing metathesis/silicon-assisted intramolecular cross-coupling reaction. In addition, a key propargylic stereogenic center was created through a novel, highly diastereoselective ring opening of a 1,3-dioxolanone promoted by TiCl₄. This reaction proceeded through an oxocarbenium ion intermediate and the asymmetric induction was fully controlled by L-malic acid residue. The C(8) stereogenic center was set by a reagent-controlled asymmetric allylboration.

Full text of DOI:10.1021/ja0466863

Published on Web 09/14/2004
Total Synthesis of (+)-Brasilenyne. Application of an
Intramolecular Silicon-Assisted Cross-Coupling Reaction
Scott E. Denmark* and Shyh-Ming Yang
Contribution from the Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
Received June 5, 2004; E-mail: denmark@scs.uiuc.edu
Abstract: The first enantioselective total synthesis of (+)-brasilenyne (1) has been achieved in 19 linear
steps, with 5.1% overall yield from L-(S)-malic acid. The construction of the oxonin core containing a 1,3-
cis,cis diene unit was accomplished with a tandem ring-closing metathesis/silicon-assisted intramolecular
cross-coupling reaction. In addition, a key propargylic stereogenic center was created through a novel,
highly diastereoselective ring opening of a 1,3-dioxolanone promoted by TiCl4. This reaction proceeded
through an oxocarbenium ion intermediate and the asymmetric induction was fully controlled by L-malic
acid residue. The C(8) stereogenic center was set by a reagent-controlled asymmetric allylboration.
Introduction and Background
Red algae and marine organisms that feed on red algae, in
particular Laurencia species, have produced various C15 non-
terpenoid acetogenenins containing halogenated medium-ring
ethers.1 These metabolites contain a number of different ring
sizes, such as those found in (+)-laurencin,2 (+)-prelaureatin,3
(+)-laurallene,4 (-)-isolaurallene,5 and (+)-obtusenyne6 (Figure
1). Among them, (+)-brasilenyne (1), isolated from the digestive
gland of a sea hare (Aplysia brasiliana) by Fenical et al.7 in
1979, has a novel nine-membered cyclic ether skeleton contain-
ing a 1,3-cis,cis-diene unit. Because sea hares are incapable of
evasive maneuvering, yet lack significant predators, it suggests
that secondary metabolites, such as 1, are produced and/or
concentrated in the digestive gland to act as defensive chemicals.
Indeed, the in vivo studies of 1 and (+)-cis-dihydrorhodophytin,
a major component from same natural source, have been
demonstrated to be potent antifeedants.7a
Biosynthetic investigations on cyclic ether metabolites of
Laurencia species have demonstrated that lactoperoxidase (LPO)
directly transforms 3Z,6S,7S-laurediol, which occurs in nature
as various stereoisomers, into (+)-prelaureatin through a bro-
monium ion-induced ether formation.8 Moreover, (+)-laurallene,
(+)-laureatin, and (+)-isolaureatin are assumed to arise from
(+)-prelaureatin by a similar biogenetic pathway.3,9 Therefore,
Figure 1. Representative C15 medium-sized ring ether marine metabolites.
the hypothetical intermediate, Cl-substituted laurediol, has been
postulated to produce (+)-obtusenyne by a similar biotransfor-
mation, and further dehydrobromination affords (+)-brasilenyne.7
The speculation was supported by the finding that those
compounds have the same configuration at C(6) and C(7) of
the Cl-substituted intermediate10 (Scheme 1).
The interesting structure of these marine metabolites has
stimulated a significant level of effort for the construction of
oxonin and oxocene ring systems.11 Recent representative
examples include Crimmins’ syntheses of (+)-prelaureatin11b
and (+)-obtusenyne11e through an aldol or alkylation/ring-
(1) (a) Erickson, K. L. In Marine Natural Products; Scheuer, P. J., Ed.;
Academic Press: New York, 1983; Vol. 5, pp 131-257. (b) Faulkner, D.
J. Nat. Prod. Rep. 2001, 18, 1-49.
(2) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 6, 1091-1099.
(3) Fukuzawa, A.; Takasugi, Y.; Murai, A. Tetrahedron Lett. 1991, 32, 5597-
5598.
(8) (a) Ishihara, J.; Kanoh, N.; Murai, A. Tetrahedron Lett. 1995, 36, 737-
740. (b) Fukuzawa, A.; Aye, M.; Nakamura, M.; Tamura, M.; Murai, A.
Chem. Lett. 1990, 1287-1290. (c) Kurosawa, E.; Fukuzawa, A.; Irie, T.
Tetrahedron Lett. 1972, 13, 2121-2124. For transformation of 3E,6R,7R-
laurediol to deacetyl-laurencin by LPO, see: (d) Fukuzawa, A.; Aye, M.;
Murai, A. Chem. Lett. 1990, 1579-1580. (e) Irie, T.; Suzuki, M.;
Masamune, T. Tetrahedron 1968, 24, 4193-4205.
(9) In vitro studies have shown that laureatin and isolaureatin were derived
from Z-prelaureatin by LPO and laurallene was derived from E-prelaureatin
by bromoperoxidase (BPO), see: Ishihara, J.; Shimada, Y.; Kanoh, N.;
Takasugi, Y.; Fukuzawa, A.; Murai, A. Tetrahedron 1997, 53, 8371-8382.
(10) Norte, M.; Gonzalez, A. G.; Cataldo, F.; Rodriguez, M. L.; Brito, I.
Tetrahedron 1991, 47, 9411-9418.
(4) Fukuzawa, A.; Kurosawa, E. Tetrahedron Lett. 1979, 20, 2797-2800.
(5) Kurata, K.; Furusaki, A.; Suehiro, K.; Katayama, C.; Suzuki, T. Chem.
Lett. 1982, 1031-1034.
(6) (a) King, T. J.; Imre, S.; Oztunc, A.; Thomson, R. H. Tetrahedron Lett.
1979, 20, 1453-1454. (b) Howard, B. M.; Schulte, G. R.; Fenical, W.
Tetrahedron 1980, 36, 1747-1751.
(7) (a) Kinnel, R. B.; Dieter, R. K.; Meinwald, J.; Engen, D. V.; Clardy, J.
Eisner, T.; Stallard, M. O.; Fenical, W. Proc. Natl. Acad. Sci. U.S.A. 1979,
76, 3576-3579. (b) Fenical, W.; Sleeper, H. L.; Paul, V. J.; Stallard, M.
O.; Sun, H. H. Pure Appl. Chem. 1979, 51, 1865-1874.
9
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J. AM. CHEM. SOC. 2004, 126, 12432-12440
10.1021/ja0466863 CCC: $27.50 © 2004 American Chemical Society

Total Synthesis of (
+
)-Brasilenyne
A R T I C L E S
Scheme 1
silyl ether by RCM. The creation of the C(2) stereogenic center
is the other critical part of the strategy needed for the synthesis
of 1. This problem stimulated the development of a new ring-
opening reaction of a 1,3-dioxolanone with an acetylenic
nucleophile to create the requisite stereogenic center at a
propargylic position.
Scheme 2
closing metathesis (RCM) sequence, Overman’s syntheses of
(-)-laurenyne11j and (+)-laurencin11k by Lewis-acid-promoted
alkene-acetal cyclization, and Holmes’s synthesis of (+)-
laurencin11l that features a Claisen rearrangement. These
methods are particularly well suited for the construction of
medium-ring ethers containing a single carbon-carbon double
bond. The synthetic challenge of the oxonin core of 1, however,
requires the formation of a medium ring bearing a conjugated
diene. Two recent reports from Negishi et al.12 and Isobe et
al.13 describe viable methods for the synthesis of medium rings
that contain a 1,3-diene. These reports feature the carbopalla-
dation of an allene and the acid-catalyzed cyclization of an
acetylene dicobalt complex.
As part of our program on the development of new silicon-
based cross-coupling reactions, we have recently demonstrated
the synthetic potential of the sequential ring-closing metathesis
(RCM)/silicon-assisted intramolecular cross-coupling reaction
for constructing medium-sized, carbo- and heterocyclic systems
bearing a 1,3-cis,cis-diene unit.14 This coupling process is ideally
suited to generate the oxonin core of 1, with its internal 1,3-
diene. However, this approach introduces several challenges that
require additional synthetic manipulations (Scheme 2). In
contrast to the foregoing methodological studies on simpler
systems, the side chain at C(9) and the ethyl group at C(2)
presented potential difficulties for the intramolecular coupling
process. In addition, the presence of the chlorine-bearing center
at C(8) requires the creation of a hydroxyl functional group at
C(8) of opposite configuration. This, in turn, allows the use of
a temporary silicon tether for the construction a cyclic alkenyl-
The synthetic plan formulated for the synthesis of (+)-
brasilenyne is outlined retrosynthetically in Scheme 2. Simpli-
fication of the enyne side chain and chloride functionality
reduces the challenge to the intermediate 2, which was projected
to arise from a palladium-catalyzed, silicon-assisted intramo-
lecular cross-coupling reaction of 3. By use of the six-membered
cyclic siloxane, the hydroxyl group liberated in the cross-
coupling is perfectly situated for installation of the chloride at
C(8). Cyclic alkenylsilyl ether 3 would arise from diastereo-
selective allylation of aldehyde 4 and application of ring-closing
metathesis (RCM) of the vinyl alkenylsilyl ether derivative. The
aldehyde 4 with a protected primary hydroxyl group, as well
as the geometrically defined vinyl iodide could be, without
difficulty, elaborated from 5. The diastereo- and enantioselective
synthesis of 5 represented an intriguing synthetic challenge,
namely the construction of a doubly branched ether with
flanking stereogenic centers (Scheme 3). The straightforward
solution to this problem would involve a nucleophilic displace-
ment reaction. Because both enantiomers of 615 and 716 are
available, the doubly branched ether linkage can proceed in
either direction. This approach was considered plausible, as both
hydroxy groups are activated (flanked by carboxyl or alkynyl
groups). However, in recognition of the difficulty of effecting
displacements at sterically congested centers, an alternative
approach featuring a diastereoselective ring opening of the 1,3-
dioxolanone 8 was envisioned. This plan calls for the Lewis-
acid-promoted addition of bis(trimethylsilyl)acetylene to the
activated acetal.17 Thus, the C(2) and C(8) stereocenters were
to be installed through a reaction controlled by the stereocenter
in the malic acid residue. Either approach is attractive, as both
6 and 8 could be easily derived from natural L-(S)-malic acid.
(11) For a review of construction of medium-ring ethers, see: (a) Elliott, M. C.
Contemp. Org. Synth. 1994, 1, 457-474. For total syntheses of (+)-
prelaureatin, see: (b) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc.
2000, 122, 5473-5476. (c) Fujiwara, K.; Souma, S.-i.; Mishima, H.; Murai,
A. Synlett 2002, 1493-1495. For total syntheses of (+)-obtusenyne, see:
(d) Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma,
T.; Murai, A. J. Org. Chem. 1999, 64, 2616-2617. (e) Crimmins, M. T.;
Powell, M. T. J. Am. Chem. Soc. 2003, 125, 7592-7595. For total syntheses
of (-)-isolaurallene, see: (f) Crimmins, M. T.; Emmitte, K. A.; Choy, A.
L. Tetrahedron 2002, 58, 1817-1834. (g) Crimmins, M. T.; Emmitte, K.
A. J. Am. Chem. Soc. 2001, 123, 1533-1534. For total synthesis of (+)-
laurallene, see: (h) Saitoh, T.; Suzuki, T.; Sugimoto, M.; Hagiwara, H.;
Hoshi, T. Tetrahedron Lett. 2003, 44, 3175-3178. Also see ref 11b. For
total synthesis of natural (+)-laurenyne, see: (i) Boeckman, R. K., Jr.;
Zhang, J.; Reeder, M. R. Org. Lett. 2002, 4, 3891-3894. For (-)-laurenyne,
see: (j) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110,
2248-2256. For representative examples of total syntheses of (+)-laurencin,
see: (k) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am.
Chem. Soc. 1995, 117, 5958-5966. (l) Burton, J. W.; Clark, J. S.; Derrer,
S.; Stork, T. C.; Bendall, J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997,
119, 7483-7498. (m) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992,
33, 4345-4348. (n) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1,
2029-2032. For total synthesis of (+)-isolaurepinnacin, see: (o) Berger,
D.; Overman, L. E.; Renhowe, P. A. J. Am. Chem. Soc. 1997, 119, 2446-
2452.
(15) For synthesis of 6, see: (a) Green, D. L. C.; Kiddle, J. J.; Thompson, C.
M. Tetrahedron 1995, 51, 2865-2874. (b) White, J. D.; Hrnciar, P. J. Org.
Chem. 2000, 65, 9129-9142. (c) Mulzer, J.; Mantoulidis, A.; Ohler, E. J.
Org. Chem. 2000, 65, 7456-7467.
(16) For synthesis of 7, see: (a) Allevi, P.; Ciuffreda, P.; Anastasia, M.
Tetrahedron: Asymmetry 1997, 8, 93-99. (b) Niwa, S.; Soai, K. J. Chem.
Soc., Perkin Trans. 1 1990, 937-943. (c) Mukaiyama, T.; Suzuki, K. Chem.
Lett. 1980, 255-258. (d) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38,
6233-6236.
(12) Ma, S.; Negishi, E.-i. J. Am. Chem. Soc. 1995, 117, 6345-6357.
(13) (a) Yenjai, C.; Isobe, M. Tetrahedron 1998, 54, 2509-2520. (b) Hosokawa,
S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609-2612. (c) Kira, K.; Isobe,
M. Tetrahedron Lett. 2000, 41, 5951-5955.
(14) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2002, 124, 2102-2103.
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12433

A R T I C L E S
Denmark and Yang
Scheme 4 a
Therefore, the crucial components in this approach would be
the sequential RCM/Pd-catalyzed, silicon-assisted intramolecular
cross-coupling reaction for construction of the oxonin core
structure, as well as the diastereoselective installation of a
propargylic stereogenic center in key intermediate 5. We
describe herein the first total synthesis of (+)-brasilenyne by
application of these new transformations as key strategic
elements.18
Scheme 3
a Reagents and conditions: (a) 2,2-methoxypropane, p-TSA‚H2O (1.0
mol %), room temperature, 3 h, 84%. (b) BH3‚THF, THF, 0 °C to room
temperature, 12 h. (c) p-TSA‚H2O (1.0 mol %), benzene, 3 h, room
temperature, 85% (two steps). (d) propanal, n-BuLi, THF, -70 °C to room
temperature, 1 h, 94%. (e) PDC, 4Å MS, CH2Cl2, room temperature, 15 h,
85%. (f) {[(1R,2R)-TsDPEN]RuCl(η6-p-cymene)} (0.5 mol %), i-PrOH,
room temperature, 8 h, 95%.
by 1H NMR analysis. Reversing the roles through activation of
the hydroxyl group of 6 was another option. Activated substrates
14 and 15 were easily prepared from 6. Treatment of compounds
14 or 15 with propargylic alcohols 16 or 17 using i-Pr2NEt led
to no reaction. By using K2CO3 or NaH as the base, complete
consumption of 14 or 15 was observed, with no detectable
amount of 5.
Results
Scheme 5 a
Construction of the Ether Linkage. To evaluate the
possibility to prepare the branched ether linkage by a direct
displacement strategy, the enantiomerically pure alcohols 6 and
7 were prepared. The (S)-R-hydroxy-γ-butyrolactone 6 is
commercially available but can also be easily prepared from
L-(S)-malic acid in a three-step sequence in high chemical yield
(Scheme 4).15 Furthermore, highly enantiomerically enriched
(98.8% ee) 7 was obtained in 95% yield by an efficient transfer
hydrogenation reaction of the corresponding ketone 10 in i-PrOH
with a catalytic amount of {[(1R,2R)-TsDPEN]RuCl(η6-p-
cymene)}, as developed by Noyori et al.19 The enantiomeric
purity of 7 was determined by CSP SFC analysis of the derived
3,5-dinitrobenzoate ester.
With both enantiomerically pure precursors in hand, the next
objective was the union of 6 and 7 into intermediate 5. An initial
study on the activation of the propargylic hydroxyl group with
Tf2O, followed by displacement with 6, was unsuccessful
(Scheme 5). To identify the problem with this transformation,
the stable mesylate 11 was prepared (by treatment of rac-7 with
MsCl and Et3N) and then subjected to ether formation with 6
under various conditions. Unfortunately, no reaction occurred
at all by using i-Pr2NEt as the base. Both reactants, 6 and 7,
were stable under these, and even harsher, conditions (50-60
°C and/or neat). By employing K2CO3 or NaH as the base,
silylated compound 12 and desilylated product 13 were observed
a Reagents and conditions: (a) Tf2O, Et3N, CH2Cl2, 0 °C to room
temperature. (b) MsCl, Et3N, CH2Cl2, -70 °C to room temperature, 30
min, 94%. (c) i-Pr2NEt, CDCl3 or neat, room temperature or 50-60 °C.
(d) K2CO3, DMF, room temperature. (e) NaH, DMF, 0 °C to room
temperature. (f) MsCl, Et3N, CH2Cl2, -70 °C to room temperature, 15 min,
82%. (g) TsCl, Et3N, cat. pyridine, room temperature, 2 h, 87%. (h) NaI,
acetone, room temperature, 8 h, 85%.
(17) To the best of our knowledge, the ring opening of 1,3-dioxolanone with
bis(trimethylsilyl)acetylene is unprecedented. Ring opening of acetal
templates with silylacetylenic compounds promoted by Lewis acid have
been reported, see: (a) Johnson, W. S.; Elliott, R.; Elliott, J. D. J. Am.
Chem. Soc. 1983, 105, 2904-2905. (b)Yamamoto, Y., Nishii, S.; Yamada,
J.-i. J. Am. Chem. Soc. 1986, 108, 7116-7117. (c) Rychnovsky, S. D.;
Dahanukar, V. H. J. Org. Chem. 1996, 61, 7648-7649.
Ring Opening of a 1,3-Dioxolanone. The failure to directly
conjoin the two subunits 6 and 7 shifted the focus to the
formation of a doubly branched ether 5 by the diastereoselective
ring opening of a 1,3-dioxolanone. Asymmetric synthesis by
ring opening of chiral acetal templates promoted by Lewis acids
provides a route for selectively generating chiral secondary
alcohols and/or ethers. Over the past two decades, many different
nucleophilic organometallic reagents, as well as Lewis acids,
have been successfully employed.20 The diastereoselectivity of
(18) Previous communication, see: Denmark, S. E.; Yang, S.-M. J. Am. Chem.
Soc. 2002, 124, 15196-15197.
(19) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285-288. (b) Matsumura, K.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738-8739. The
air-stable, purple Ru complex was easily prepared from (1R,2R)-1,2-
diphenyl-N-(4-toluenesulfonyl)-ethylenediamine with [RuCl2(η6-p-cymene)]2
in 87% yield.
9
12434 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

Total Synthesis of (
+
)-Brasilenyne
A R T I C L E S
this process strongly depends on the structure of the acetal,
solvent, Lewis acid, as well as the nucleophilic reagent. Among
them, acetylenic organometallic compounds have been employed
as nucleophilic reagents to create a stereogenic center at
propargylic positions with high diastereoselectivity.17 In fact,
ring opening of 1,3-dioxolanones with various nucleophilic
reagents and Lewis acids has been extensively investigated.21
However, the ring opening of a 1,3-dioxolanone with acetylenic
organometallic reagents is unprecedented.
The 1,3-dioxolanone 8 was chosen to test this approach
because (1) 8 can be rapidly obtained from the natural L-(S)-
malic acid and (2) propanal can act both as the protecting group
and as a part of the target compound 5 (Scheme 6). The
lanone 18 (85%) as an epimeric mixture slightly favoring the
cis isomer (cis/trans ) 81:19).22 Selective reduction of the
carboxylic acid using BH3‚THF at 0 °C provided 19 (82% yield)
followed by protection of the primary alcohol thus formed with
tert-butylchlorodimethylsilane, and pyridine afforded 8 in 85%
yield (ca. 60-65% overall yield in three steps from L-(S)-malic
acid). The poor selectivity in the preparation of the dioxolanone
18 was unexpected. On the basis of literature precedent, the
construction of the 1,3-dioxolanone normally favors the more
thermodynamically stable cis isomer with high diastereoselec-
tivity.22 Fortunately, this was subsequently shown to be
inconsequential. Direct transformation of the cis/trans mixture
of 18 to alcohol 19 and TBS ether 8 maintained the ratio (cis/
trans ) 83:17). The hydroxy 1,3-dioxolanone intermediate 19
was labile to both acid and bases, such as Et3N, i-Pr2NEt,
imidazole, and N,N-(dimethylamino)pyridine, producing (S)-R-
hydroxy-γ-butyrolactone 6. However, by carrying out the
reduction of 18 at 0 °C and protection of 19 using pyridine as
the base, these transformations could be performed reproducibly
on a large scale.
Scheme 6
The Lewis-acid-mediated ring opening of 8 with bis(tri-
methylsilyl)acetylene employed TiCl4 as the Lewis acid in a
procedure similar to the ring opening of acetal templates
developed by Johnson et al.17a Gratifyingly, ring opening of
dioxolanone 8 proceeded smoothly to afford only two products
after quenching with MeOH: the desired lactone 5 and the
methyl ester 20. Furthermore, treatment of the crude mixture
with a catalytic amount of p-toluenesulfonic acid in refluxing
benzene for 1 h gave 5 exclusively in 86% yield as a single
1
diastereomer by H NMR analysis. The S configuration of the
propargylic position was further established by conversion of
5 to a dicobalt complex 21 with Co2(CO)8 in 95% yield. Slow
sublimation of 21 at 65-68 °C (0.1 mmHg) gave deep red
crystals, whose full stereostructure was confirmed by a single-
crystal X-ray diffraction (Figure 2).23
synthesis of 8 began by the condensation of L-(S)-malic acid
with propanal promoted by BF3‚Et2O to afford the 1,3-dioxo-
(20) For some representative examples of ring opening of acetal templates,
see: (a) Mori, A.; Ishihara, K.; Arai, I.; Yamamoto, H. Tetrahedron 1987,
43, 755-764. (b) Ishihara, K.; Hanaki, N.; Yamamoto, H. J. Am. Chem.
Soc. 1993, 115, 10695-10704. (c) Lindell, S. D.; Elliott, J. D.; Johnson,
W. S. Tetrahedron Lett. 1984, 25, 3947-3950. (d) Harada, T.; Nakamura,
T.; Kinugasa, M.; Oku, A. J. Org. Chem. 1999, 64, 7594-7600. (e) Bartlett,
P. A. J. Am. Chem. Soc. 1983, 105, 2088-2089. (f) Elliott, J. D.; Choi, V.
M. F.; Johnson, W. S. J. Org. Chem. 1983, 48, 2294-2295. (g) For
examples using acetylenic organometallic reagents, see ref 17. For
mechanism studies, see: (h) Denmark, S. E.; Almstead, N. G. J. Am. Chem.
Soc. 1991, 113, 8089-8110. (i) Denmark, S. E.; Almstead, N. G. J. Org.
Chem. 1991, 56, 6485-6487. (j) Denmark, S. E.; Willson, T. M. J. Am.
Chem. Soc. 1989, 111, 3475-3476. (k) Mori, I.; Ishihara, K.; Flippin, L.
A.; Nozaki, K.; Yamamoto, H.; Bartlett, P. A.; Heathcock, C. H. J. Org.
Chem. 1990, 55, 6107-6115. (l) Sammakia, T.; Smith, R. S. J. Org. Chem.
1992, 57, 2997-3000.
Figure 2. Chem3D image of X-ray crystal structure of cobalt complex
21.
(21) For some representative examples of ring opening of 1,3-dioxolanones,
see: (a) Mashraqui, S. H.; Kellogg, R. M. J. Org. Chem. 1984, 49, 2513-
2516. (b) Heckmann, B.; Mioskowski, C.; Yu, J.; Flack, J. R. Tetrahedron
Lett. 1992, 33, 5201-5204. (c) Heckmann, B.; Mioskowski, C.; Lumin,
S.; Flack, J. R.; Wei, S.; Capdevila, J. H. Tetrahedron Lett. 1996, 37, 1425-
1428. (d) Heckmann, B.; Mioskowski, C.; Bhatt, R. K.; Flack, J. R.
Tetrahedron Lett. 1996, 37, 1421-1424.
Implementation of the RCM/Cross-Coupling Sequence.
To construct the oxonin core, the geometrically defined Z-vinyl
iodide was next prepared for the key intramolecular cross-
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12435

A R T I C L E S
Denmark and Yang
Scheme 8
coupling reaction. Accordingly, the conversion of the trimethyl-
silyl group in 5 to alkynyl iodide 22 was efficiently accom-
plished by treatment of 5 with N-iodosuccinimide and a catalytic
amount of silver nitrate in DMF (95% yield).24 Furthermore,
cis-reduction of 22 with diimide, generated in situ from
potassium azodicarboxylate in AcOH/pyridine, gave the Z-
alkenyl iodide 23 in 80% yield (Scheme 7).25 The trace amount
of over-reduction product can be removed by stirring the crude
mixture in pyridine for 12 h at ambient temperature. Installation
of the third stereogenic center (C(8)) calls for a diastereoselective
allylation reaction of an aldehyde bearing a protected hydroxyl
group, such as 25. Thus, reduction of 23 with DIBAL-H
afforded lactol 24 in good yield and in a 1:2 diastereomeric
ratio. Unfortunately, all attempts to selectively protect the ring-
opened hydroxy aldehyde intermediate with TIPSCl or TBDP-
SCl were unsuccessful. Only moderate conversion and a small
amount of desired product 25 were obtained after a difficult
separation from compound 26.26
Scheme 7
group with p-methoxybenzyl chloride (PMBCl) under conditions
that tolerate the vinyl iodide functionality (Ag2O) afforded 28
in 82% yield.28 Amide 28 could be converted to aldehyde 4 by
reduction with DIBAL-H (87% yield)29 or to homoallyl ketone
29 by treatment with allylmagnesium bromide (94% yield).30
With both precursors 4 and 29 in hand, the next critical
stage was to introduce the third stereogenic center of 1. Initial
studies on reduction of homoallylic ketone of 29 into homo-
allyl alcohol 30 are compiled in Table 1. The use of DIBAL-
H as the reducing agent (to tolerate the vinyl iodide functional-
ity) gave an excellent chemical yield (Table 1, entry 1), but
with unsatisfactory diastereoselectivity, slightly favoring the
undesired S isomer. All attempts to improve the selectivity by
employing MgBr2 and ZnI2 were fruitless (entries 2 and 3).31
The LS-Selectride led to formation of the undesired S isomer
(entry 4).
Table 1. Reduction of Homoallyl Ketone 29
Alternatively, the lactone 5 could be converted to the Weinreb
amide 28, which provided additional options for generation of
the homoallylic alcohol 30. For example, through the influence
of an R-alkoxy group, homoallyl alcohol 30 could be obtained
either by a chelation-controlled reduction of homoallyl ketone
29 or a nonchelation-controlled allylation of 4 (Scheme 8).
Therefore, treatment of 23 with N,O-dimethylhydroamine
hydrochloride salt in the presence of trimethylaluminum gave
the amide 27 in 93% yield.27 Further, protection of the hydroxyl
entry
conditions
30 yield, % (ratio; S/R)a
1
2
3
4
DIBAL-H, THF, -73 °C
93 (57:43)
94 (60:40)
92 (52:48)
- (ca. 85:15)b
DIBAL-H, MgBr2, CH2Cl2, -73 °C
DIBAL-H, ZnI2, CH2Cl2, -75 °C
LS-Selectride, THF, -72 °C
a Number was corresponding to isolated yield and the ratio was
1
determined by H NMR integration. b Product contained small amount of
residue from the reducing agent.
Next, the influence of the R-alkoxy group on the selective
allylation of 4 by non-chelation-controlled addition was assayed
(22) (a) Roush, W. R.; Brown, B. B. J. Org. Chem. 1992, 57, 3380-3387. (b)
Roush, W. R.; Barda, D. A. Tetrahedron Lett. 1997, 38, 8781-8784.
(23) The crystallographic coordinates of the dicobalt complex have been
deposited with the Cambridge Crystallographic Data Centre, deposition no.
CCDC-195245.
(27) A modified procedure, see: Nemoto, H.; Nagamochi, M.; Ishibashi, H.;
Fukumoto, K. J. Org. Chem. 1994, 59, 74-79.
(24) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994, 485-
(28) Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945-5948.
(29) For modified procedures, see: (a) Wernic, D.; DiMaio, J.; Adams, J. J.
Org. Chem. 1989, 54, 4224-4228. (b) Evans, D. A.; Ratz, A. M.; Huff, B.
E.; Sheppard, G. S. J. Am. Chem. Soc. 1995, 117, 3448-3467.
(30) For modified procedures, see: (a) Guanti, G.; Banfi, L.; Riva, R.
Tetrahedron 1995, 51, 10343-10360. (b) Berts, W. B.; Luthman, K.
Tetrahedron 1999, 55, 13819-13830.
486.
(25) For modified procedures, see: (a) Nicolaou, K. C.; Marron, B. E.; Veale,
C. A.; Webber, S. E.; Serhan, C. N. J. Org. Chem. 1989, 54, 5527-5535.
(b) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40, 3667-
3670.
(26) (a) Kazuta, Y.; Matsuda, A.; Shuto, S. J. Org. Chem. 2002, 67,
1669-1677. (b)Yau, E. K.; Coward, J. K. J. Org. Chem. 1990, 55, 3147-
3158.
(31) (a) For using MgBr2, see ref 30a. (b) For using ZnI2, see: Solladie, G.;
Hanquet, G.; Rolland, C. Tetrahedron Lett. 1999, 40, 177-180.
9
12436 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

Total Synthesis of (
+
)-Brasilenyne
A R T I C L E S
(Table 2). By using allyltrimethylsilane as the allylating reagent
and BF3‚Et2O as the Lewis acid, only a 26:74 (S/R) ratio of
alcohol 30 was obtained in 78% isolated yield, favoring the
desired R isomer (Table 2, entry 1). Increasing the amount of
Lewis acid (4.0 equiv) did not have a significant effect on either
the yield or the selectivity (entry 2).32 Allyltributyltin was also
employed as the allylation reagent,33 but poor selectivity was
obtained with this reagents as well (entry 3). Direct addition
with allylmagnesium bromide in the presence of ZnCl2 gave
30 in a 91% yield as a ca. 1:1 mixture of diastereomers (entry
4).34
addition.14 The reaction proceeded smoothly to afford the
corresponding nine-membered ether 2 in 61% yield. Surpris-
ingly, no significant influence by either the bulky side chain or
the ethyl group was observed.
Scheme 9
Table 2. Allylation of Aldehyde 4
entry
conditions
30 yield, % (S/R)a
1
2
3
4
5
allylSiMe3, BF3‚Et2O, CH2Cl2, -73 °C
allylSiMe3, BF3‚Et2O, CH2Cl2, -73 °C
allylSnBu3, BF3‚Et2O, CH2Cl2, -74 °C
allylMgBr, ZnCl2, Et2O, -78 °C
78 (26:74)b
73 (27:73)c
87 (38:62)d
91 (49:51)e
72 (7:93)
allylB((-)-Ipc)2, Et2O, -74 °C
a Yield of isolated product; the ratio was determined by 1H NMR
integration. b AllylSiMe3 (2.0 equiv) and BF3‚Et2O (2.0 equiv) were
employed. c AllylSiMe3 (2.5 equiv) and BF3‚Et2O (4.0 equiv) were
employed. d AllylSnMe3 (2.0 equiv) and BF3‚Et2O (2.0 equiv) were
employed. e AllylMgBr (1.5 equiv) and ZnCl2 (1.75 equiv) were employed.
The successful generation of 30 was eventually achieved by
employing the chiral allylborane reagent, allylB((-)-Ipc)2,
developed by Brown et al.35 Treatment of 4 with the reagent
generated in situ from (+)-B-chlorodiisopinocampheylborane
[(+)-DIP-Cl] and allylmagnesium bromide afforded 30 in 72%
yield with a 93:7 diastereoselectivity (entry 5). This reagent has
been shown to exhibit a strong intrinsic selectivity bias. Thus,
the allylation with allylB((-)-Ipc)2, derived from (-)-R-pinene,
should give the corresponding R configuration at the homoallylic
position.35
A significant improvement in yield (89%) and selectivity
(>97:3) in the allylation was obtained under Mg2+-salt free
conditions at -100 °C (Scheme 9).35b Subsequent silylation of
the secondary alcohol with chlorodimethylvinylsilane provided
vinyl silyl ether 31 in 91% yield. This silylvinyl ether was
subjected to the RCM reaction using Schrock’s molybdenum
complex [(CF3)2MeCO]2Mo(dCHCMe2Ph)(dNC6H3-2,6-i-Pr2)
as the catalyst.36 By using a 5.0 mol % catalyst loading in
benzene at room temperature, the ring closure went to comple-
tion efficiently within 1 h to afford 3 in excellent yield (92%).
The crucial intramolecular cross-coupling reaction of 3 was
carried out under the optimized conditions established previ-
ously: 7.5 mol % of [allylPdCl]2 as the catalyst and 10 equiv
of 1.0 M TBAF solution as the activator using a syringe-pump
Completion of the Synthesis of 1. The completion of the
total synthesis of 1 required transformation of the enyne side
chain as well as introduction of the chloride functionality
(Scheme 10). To avoid the potential elimination of hydrochlo-
ride, the installation of the chloride was chosen to be the final
step. Elaboration of the enyne side chain began by protection
of the hydroxyl group with TBSOTf using pyridine and a
catalytic amount of DMAP to afford 32 in 88% yield. Depro-
tection of the PMB group with DDQ in CH2Cl2/H2O (19/1)37
gave 33 efficiently in 84% yield. Oxidation of 33 with Dess-
Martin periodinane38 afforded aldehyde 34 in 83% yield (61%
overall yield from coupling product 2). Peterson-type olefination
as described by Corey et al.39 was employed to introduce the
required Z-enyne side chain. Thus, treatment of 34 with lithiated
1,3-bis(triisopropyl)propyne at low temperature, followed by
slow warming of the mixture to room temperature, produced
the enyne product 35 in 83% yield with ca. 6:1 Z/E geometric
selectivity. Attempts to improve the geometric selectivity by
employment of MgBr2 led to failure. Mainly, elimination of
the â-alkoxy group forming an R,â-unsaturated aldehyde was
observed by 1H NMR analysis [characteristic signals: 9.55 (d,
J ) 8.0, 1H, CHO); 6.78 (dd, J ) 15.5, 4.5, 1 H, Hâ); 6.27
(dd, J ) 16.0, 8.0, 1 H, HR)].40 Subsequently, deprotection of
the TBS group, as well as the TIPS group, with a 1.0 M TBAF
solution in THF afforded hydroxy enyne 36 in 93% yield.
Finally, inversion of the 8R hydroxyl group into the 8S chloride
using CCl4/(n-Oct)3P in toluene11m at 60-65 °C completed the
first total synthesis of (+)-brasilenyne (1). The physical and
spectroscopic data for the synthetic sample were nearly identical
(32) (a) Danishefsky, S. J.; Deninno, M. P.; Phillips, G. B.; Zelle, R. E.
Tetrahedron 1986, 42, 2809-2819. (b) Veloo, R. A.; Wanner, M. J.;
Koomen, G.-J. Tetrahedron 1992, 48, 5301-5316.
(33) Heck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265-268.
(34) Scarlato, G. R.; DeMattei, J. A.; Chong, L. S.; Ogawa, A. K.; Lin, M. R.;
Armstrong, R. W. J. Org. Chem. 1996, 61, 6139-6152.
(35) (a) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54,
1570-1576. (b) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56,
401-404.
1
in all respects [mp 37-38 °C (lit. 36-37 °C), H NMR, 13C
(36) The Schrock molybdenum complex is commercially available (Strem) and
can be prepared according to the reported procedure with consistent purity
and reactivity, see: (a) Fox, H. H.; Yap, K. B.; Robbins, J.; Cai, S.; Schrock,
R. R. Inorg. Chem. 1992, 31, 2287-2289. (b) Schrock, R. R.; Murdzek, J.
S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem.
Soc. 1990, 112, 3875-3886. (c) Oskam, J. H.; Fox, H. H.; Yap, K. B.;
McConville, D. H.; O’Dell, R.; Lichtenstein, B. J.; Schrock, R. R. J.
Organomet. Chem. 1993, 459, 185-198. (d) Fox, H. H.; Lee, J.-K.; Park,
L. Y.; Schrock, R. R. Organometallics 1993, 12, 759-768.
(37) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021-3028.
(38) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(39) Corey, E. J.; Rucker, C. Tetrahedron Lett. 1982, 23, 719-722.
(40) Yamakado, Y.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am. Chem. Soc.
1981, 103, 5568-5570.
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12437

A R T I C L E S
Denmark and Yang
NMR, IR, and [R]24D +228.0 (c ) 1.08, CHCl3)]; lit. +216 (c
) 0.017, CHCl3) to those reported for natural (+)-brasilenyne.7a
Scheme 11
Scheme 10
after 24 h. However, using a catalytic amount of p-toluene-
sulfonic acid in refluxing benzene gave 5 more efficiently.
Diastereoselectivity of Ring Opening of 8. The ring opening
of acetal templates, with weakly nucleophilic acetylenic re-
agents, such as bis(trimethylsilyl)acetylene, presumably react
in the SN1 region of the mechanistic continuum (i.e., by Lewis-
acid-assisted ring opening prior to nucleophilic attack).20h In
these cases, the asymmetric induction was rationalized by
invoking Cram’s rule as applied to the oxocarbenium ion
intermediate.17b Indeed, the fact that a single diastereomer 5
was obtained from a cis/trans mixture of 8 strongly indicated
that (1) the mechanism of ring opening of the 1,3-dioxolanone
also proceeded through an oxocarbenium ion intermediate and
(2) the high diastereoselectivity was fully controlled by the
stereogenic center of the L-(S)-malic acid residue.21a It is worth
noting that the more-labile C-OCO bond in the 1,3-dioxolanone
can facilitate the formation of the reactive oxocarbenium ion
intermediate, particularly in the presence of a strong Lewis acid
such as TiCl4.
A rationale for the convergent diastereoselectivity is formu-
lated in Figure 3. The equilibration of intermediates A and B
could presumably be achieved easily in the presence of a strong
Lewis acid.21a To minimize dipole-dipole repulsion, oxocar-
benium ion and Ti-coordinated carboxylate are arranged in an
antiperiplanar conformation. In addition, the ring-opened E-
oxocarbenium ion A is proposed to be thermodynamically
favored. This is due to the reduced steric interaction between
the malic acid residue and the ethyl group. Furthermore,
nucleophilic attack from the Re-face avoids significant steric
repulsion from the bulky R group (CH2CH2OTBS), thus
affording the desired diastereomer 5.
Allylboration of Aldehyde 4. The inability to accomplish
substrate-controlled diastereoselectivity in the nucleophilic
addition of hydrides to ketone 29 or organometallic reagents to
aldehyde 4 prompted the use of Brown’s allylB((-)-Ipc)2
reagent, which exhibits an overwhelming intrinsic bias.35 The
highest yield (89%) and diastereoselectivity (>97:3) was
achieved under a magnesium-salt-free condition at -100 °C
(Scheme 9).35b In the presence of magnesium salt, the allylbo-
ration proceeded less efficiently, presumably due to the forma-
tion of a stable borate-magnesium complex, which can slow
the rate of allylboration. On the basis of much literature
precedent, allylB((-)-Ipc)2 prepared from (+)-B-chlorodiiso-
pinocampheylborane should produce the R-configuration at the
homoallyl position.35a To confirm this stereochemical outcome,
the allylboration product 30 was elaborated to lactone 39, which
could be structurally correlated to the known compounds,
Discussion
Although the synthesis of (+)-brasilenyne was undertaken
to test the applicability of the tandem RCM/silicon-directed
cross-coupling to a challenging synthetic target, this transforma-
tion proceeded, happily, without difficulty. On the basis of prior
studies in these laboratories, the conditions optimized for each
of the two reactions could be directly applied to the more-
complex substrate 31 with excellent results. Therefore, the key
strategic maneuver shall occasion only minor comment, and,
instead, relinquish the spotlight to the supporting players
assigned to create the stereogenic centers in (+)-brasilenyne.
Formation of Intermediate 5. The failure to create a doubly
branched ether by classic substitution reactions necessitated the
development of an alternative strategy that could control the
introduction of the propargylic center from a preexisting
enantiopure material. The diastereoselective opening of a malic-
acid-derived 1,3-dioxolanone offered an attractive solution.
In initial studies on the Lewis-acid-promoted ring opening
of 8 with bis(trimethylsilyl)acetylene, TMSOTf was found to
be unsuitable for this reaction, giving complex mixtures along
with deprotection of the dioxolanone. Titanium tetrachloride was
the most effective promoter. Moreover, the workup procedure
greatly influenced the product distribution. For example, direct
aqueous workup produced several components, such 37a-c and
5 with 37b as major product, whereas 20 and 5 were obtained
after quenching with methanol (Scheme 11). Notably, each
component comprised only a single diastereomer, indicating that
the ring-opening process was highly diastereoselective. The
conversion of 20 to the desired lactone was easily achieved by
treatment with imidazole in CH2Cl2 to afford 5 in 73% yield
9
12438 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

Total Synthesis of (
+
)-Brasilenyne
A R T I C L E S
Scheme 12
methylene group at the propargylic position gave rise to a
substantial amount of the over-reduction product, typically ca.
20-30%.14 Furthermore, the branched ether flanking the vinyl-
dimethylsilyl subunit of 31 (C(9) of 1) provided an important
conformational constraint that facilitated the RCM process. The
cyclic alkenylsilyl ether 3 was obtained in excellent yield (92%)
within 1 h, using only 5 mol % of Schrock’s catalyst (Scheme
9). In previously reported methodological investigations, sub-
strates bearing a simple methylene group in this position required
a higher catalyst loading (8.0 mol %) and a longer reaction time
(9-24 h) to reach completion.14 Fortunately, the intramolecular
cross-coupling reaction in the formation of the oxonin core was
only minimally influenced by the steric hindrance of branched
ether as established in model studies.14
The completion of the synthesis from coupling product 2
focused on the introduction of the enyne side chain and the
chloride function. To achieve high geometric selectivity, the
lithiated reagent from 1,3-bis(triisopropylsilyl)propyne was
employed for Peterson-type olefination, as described by Corey
et al.39 However, only moderate geometric selectivity (ca. Z/E,
6/1) was obtained in the case of 34 (Scheme 10). Attempts to
increase the geometric selectivity by the use of magnesium
bromide, as described by Yamamoto et al.,40 were unsuccessful.
The coordination of the â-alkoxy group with Mg2+ apparently
facilitated the elimination process, producing an R,â-unsaturated
aldehyde. Additionally, an oft-used two-step sequence, which
features the Stork-Wittig reaction to generate a Z-alkenyl
iodide, followed by Sonogashira coupling,11b,e provided similar
yields and selectivities to the Petersen protocol. Finally, the
installation of (8S)-Cl was effected using the CCl4/(n-Oct)3P
combination, as described by Murai et al.11m The high yield
(92%) obtained in this case was particularly satisfying, as
Figure 3. Proposed mechanism of ring opening of 1,3-dioxolanone 8.
403,4-trans and 403,4-cis (Scheme 12).41 Treatment of 30 with
DDQ in CH2Cl2/H2O (19/1) gave diol 38 in 81% yield.
Subsequent oxidation was carried out with a catalytic amount
of tetrapropylammonium perruthenate and N-methylmorpholine-
1
N-oxide to furnish lactone 39 in 82% yield.42 In the H NMR
spectra of 39, the coupling constants J2,3-cis, J2,3-trans, and
J3,4-trans are 7.0, 3.5, and 2.8 Hz, respectively. These data are
well matched to those calculated (7.0, 3.2, and 2.8 Hz) and
experimentally determined (6.5, 3.6, 2.8 Hz) for 403,4-trans
.
Importantly, strong NOE enhancements between HC(4) and
HC(3′) were also observed. A 4.7% enhancement of HC(3′)
was observed when HC(4) was irradiated, whereas a 7.4%
enhancement of HC(4) was observed. These results strongly
suggest that HC(4) and the alkenyl iodide residue exist in a
cis-relationship, which therefore further supports the expectation
that the R configuration was obtained in the asymmetric
allylboration reaction.
Synthesis of 1. Despite the difficulty of creating the doubly
branched ether linkage from 6 and 7, several subsequent
transformations did benefit from this sterically congested
subunit. For instance, the branched ether at the propargylic
position of 22 (C(2) of 1) suppressed the over-reduction of the
acetylene group with diimide (Scheme 7).25 The desired product
23 was obtained in good yield (80%), with only a trace amount
of over-reduction product. By contrast, the presence of a simple
(41) Jaime, C.; Segura, C.; Dinares, I.; Font, J. J. Org. Chem. 1993, 58, 154-
158.
(42) (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639-666. (b) Burke, S. D.; Austad, B. C.; Hart, A. C. J. Org. Chem. 1998,
63, 6770-6771.
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12439

A R T I C L E S
Denmark and Yang
significantly lower yields (ca. 60-75%) have been observed,
in eight- and nine-membered-ring unsaturated ethers, apparently
from competitive dehydration.11e,i
a homoallyl alcohol with excellent diastereoselectivity, which
is perfectly set for installation of the (S)-C(8)-Cl center. Further
extension of this strategy to the construction of other medium-
sized ring and macrocyclic compounds is underway.
Conclusion
Acknowledgment. Funding was provided by the National
Institutes of Health (GM63167-01A1). We are grateful to
Professor William Fenical (UCSD) for generously providing
IR, 1H NMR, and 13C NMR spectra of natural (+)-brasilenyne.
The first total synthesis of (+)-brasilenyne has been ac-
complished in a linear approach (19 steps, 5.1%) from com-
mercially available L-(S)-malic acid. The significant features of
the strategy include (1) a highly diastereoselective ring-opening
of 1,3-dioxolanone promoted by TiCl4 for the novel creation
of a propargylic stereogenic center and (2) the successful
application of the sequential RCM/silicon-assisted intramolecular
cross-coupling reaction for construction of a medium-sized ether
ring with 1,3-cis,cis-diene unit. In addition, the reagent-
controlled asymmetric allylboration was employed to generate
Supporting Information Available: Detailed procedures and
full characterization of all synthetic intermediates and products
are provided, along with spectral comparison of natural and
synthetic (+)-brasilenyne. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA0466863
9
12440 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004