First total synthesis and structural reassignment of (-)-aplysiallene

Article abstract of DOI:10.1021/ol701797e

The first total synthesis of (-)-aplysiallene has been completed in 16 steps and features a key sequential Mukaiyama aerobic oxidative cyclization to prepare the fused bis-THF core. The original stereochemical assignment has been revised as shown.

Full text of DOI:10.1021/ol701797e

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3703-3706
First Total Synthesis and Structural
Reassignment of (−)-Aplysiallene
Jian Wang and Brian L. Pagenkopf*
Department of Chemistry, UniVersity of Western Ontario, 1151 Richmond Street,
London, ON, N6A 5B7, Canada
bpagenko@uwo.ca
Received July 26, 2007
ABSTRACT
The first total synthesis of (−)-aplysiallene has been completed in 16 steps and features a key sequential Mukaiyama aerobic oxidative cyclization
to prepare the fused bis-THF core. The original stereochemical assignment has been revised as shown.
Aplysiallene 1 was first isolated in 1985 from the red alga
Laurencia okamurai Yamada by Suzuki and Kurosawa.1 Its
intriguing structural features include (1) a unique cis-fused
2,6-dioxabicyclo[3,3,0]octane skeleton consisting of two
trans-tetrahydrofuran rings, (2) an unusual (E,E)-bromodiene
side chain, and (3) an R-bromoallene2 appendage. The
absolute stereochemistry of 1 was assigned according to its
strong negative optical rotation (due to the allene3), and the
relative stereochemistry was assigned by NOE correlations
and comparison with kumausallene.4 In 2001, Okamoto also
reported the isolation of 1 from the sea hare Aplysia kurodai
and found it functions as a Na+/K+ ATPase inhibitor with
IC50 ) 0.7 µM.5 In this communication, we report the first
asymmetric total synthesis of aplysiallene and provide
evidence for its structural revision.6
introduction of the bromodiene subunit, a plausible derivation
could be from alcohol 4, which would be stereoselectively
prepared by sequential oxidative cyclization8 of the known
(R,R)-diol 5 (Scheme 1).
Scheme 1. Retrosynthetic Analysis of (-)-Aplysiallene
It was envisaged that the R-bromoallene substituent could
be prepared from the corresponding R-propargyl alcohol 2a,
which in turn should be accessible by an anti-selective
alkynylation between aldehyde 3 and trimethylsilylacetylene.7
Although we are unaware of precedence for the direct
(1) Suzuki, M.; Kurosawa, E. Phytochemistry 1985, 24, 1999-2002.
(2) For a review on bromoallene natural products, see: Hoffmann-Ro¨der,
A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196-1216.
(3) Lowe, G. J. Chem. Soc., Chem. Commun. 1965, 411.
(4) Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem. Lett. 1983,
1643-1644.
(5) (a) Okamoto, Y.; Nitanda, N.; Ojika, M.; Sakagami, Y. Biosci.
Biotechnol. Biochem. 2001, 65, 474-476. (b) Okamoto, Y.; Nitanda, N.;
Ojika, M.; Sakagami, Y. Biosci. Biotechnol. Biochem. 2003, 67, 460.
(6) For a review on reassignment of natural products, see: Nicolaou, K.
C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44, 1012-1044.
The synthesis began with reaction of (S,S)-diepoxybutane
6 with vinyl magnesium bromide in the presence of CuBr
to give the (S,S)-diol ent-5 in 72% yield (Scheme 2). Note
that the stereochemistry of ent-5 is opposite to that required
10.1021/ol701797e CCC: $37.00
© 2007 American Chemical Society
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largely precluded the use of olefin coupling strategies,12 and
after having examined several methods,13 the best approach
that emerged was based on Wittig chemistry. Thus, Swern
oxidation of ent-4 gave sensitive aldehyde 9, which was
immediately treated with Wittig reagent 10 to give 11 (76%,
two steps). Introduction of the bromoolefin was accomplished
nonselectively by reaction with the Smithers reagent14 12 to
give dienes 13a and 13b (82% combined yield, 13a/13b )
1.1:1).
Scheme 2. Synthesis of the bis-THF Core
Although the isolated yield of 13b was only 35%, the
dienes 13a and 13b were separable by flash chromatography
on the gram scale, and unwanted 13a can be recycled by
ozonolysis followed by a NaBH4 workup to give alcohol
ent-4 in 53% yield. In contrast, attempted conversion of 13a
directly into 9 by ozonolysis with a PPh3 workup resulted
in complete decomposition of 13a.
With the bromodiene side chain at hand, deprotection of
the silyl ether 13b by treatment with TBAF followed by
Swern oxidation afforded the highly labile aldehyde ent-3
(81%, two steps), which was used immediately in the
following addition step. As expected, alkynylation of ent-3
with the titanium acetylide of trimethylsilylacetylene (gener-
ated in situ with n-BuLi and ClTi(OiPr)3) gave ent-2 and 2b
as an inseparable 4:1 anti/syn mixture in 81% combined
yield.7,10a,15 The mixture of isomers was treated with TBAF
to give the corresponding propargyl alcohols, which were
converted to trisylates 14a and 14b (90%, two steps). In the
final step, the trisylates displaced with LiCuBr2 gave allene
ent-1 and a trace of diastereomer 1b (Scheme 3).16
However, a comparison of the 1H and 13C NMR of ent-1
with the data reported for the natural product revealed several
inconsistencies (Table 1). Specifically, in the 13C NMR,
carbons C2, C3, and C4 (Figure 1) were off by (0.3 ppm,
and in the 1H NMR, the two allene protons were off by (0.02
ppm. The absolute S configuration of the allene in ent-1 was
confirmed by the strong positive optical rotation3 ([R]D )
+166°, CHCl3). Taken together, these data suggested that
for the reported natural product, so this should in principle
lead to a synthesis of ent-1. The diol ent-5 was then
quantitatively desymmetrized by acylation via the intermedi-
ate ortho ester,9 and the resulting material was subjected to
a slightly modified10a Mukaiyama cobalt-catalyzed aerobic
oxidative cyclization to afford mono-THF 8 as a single
diastereomer. Protection of the primary hydroxyl group as
its TBS ether and deprotection of the acetate with EtMgBr
set the stage for the second oxidative cyclization which
afforded the key intermediate ent-4. The Mukaiyama oxida-
tion has recently emerged as a useful tool for the stereose-
lective construction of trans-THFs,10 and the power of this
methodology is illustrated here by the straightforward and
efficient synthesis of ent-4 in 62% yield over five steps.11
The regiospecific and stereospecific introduction of the
bromodiene moiety poses a significant synthetic challenge.
In particular, the presence of the vinyl bromide functionality
Scheme 3. Synthesis of the Proposed Structure of (+)-Aplysiallene
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Org. Lett., Vol. 9, No. 18, 2007

Scheme 4. Synthesis of Revised (-)-Aplysiallene
the reported structure must be incorrect. In this regard,
examination of the 1H and 13C NMR from minor isomer 1b
sistently low yields despite optimization efforts. Attempts
to form the propargyl trisylate 14b directly from ent-2 with
Table 1. Summary of 13C NMR Data
13C
isolation
ent-1
1b
1a
2
3
73.8
201.8
101.0
76.6
73.9
201.5
101.4
76.2
73.8
201.8
101.0
76.6
4
5
40.6
40.8
40.6
6
83.7
83.6
83.7
7
84.0
84.2
84.0
8
41.3
41.3
41.3
9
79.7
79.7
79.7
10
11
12
13
14
15
133.1
125.9
130.4
132.1
29.7
133.1
126.0
130.3
132.1
29.7
133.1
125.9
130.3
132.1
29.7
13.3
13.3
13.3
a
Carbon atom numbering begins at the bromoallene.
appeared to be a match,17 so efforts were undertaken to
prepare 1b as the major isomer.
The most direct approach to prepare 2b, the syn epimer
of ent-2, would be a syn-alkynylation of aldehyde ent-3.
However, we found that Carreira alkynylation11b,18 of a model
THF-2-carbaldehyde with trimethylsilylacetylene gave con-
Figure 1. Structural revision of aplysiallene.
(7) Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org. Chem. 1993,
58, 2468-2477.
(8) Inoki, S.; Mukaiyama, T. Chem. Lett. 1990, 67-70.
(9) Hanessian, S.; Roy, R. Can. J. Chem. 1985, 63, 163-172.
(10) (a) Zhao, H.; Gorman, J. S. T.; Pagenkopf, B. L. Org. Lett. 2006,
8, 4379-4382. (b) Wang, Z.; Tian, S.; Shi, M. Eur. J. Org. Chem. 2000,
349-356. (c) Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem., Int.
Ed. 2002, 41, 4751-4754. (d) Evans, P. A.; Cui, J.; Gharpure, S. J.;
Polosukhin, A.; Zhang, H. J. Am. Chem. Soc. 2003, 125, 14702-14703.
(11) For the synthesis of related fused bis-THF systems, see ref 7 and:
(a) Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L. Angew.
Chem., Int. Ed. 1999, 38, 3175-3177. (b) Boukouvalas, J.; Pouliot, M.;
Robichaud, J.; MacNeil, S.; Snieckus, V. Org. Lett. 2006, 8, 3597-3599.
(c) Feldman, K. S.; Mechem, C. C.; Nader, L. J. Am. Chem. Soc. 1982,
104, 4011-4012.
inversion of stereochemistry under Mitsunobu conditions
were unsuccessful,19 although Kim and co-workers recently
reported a similar reaction.20 Ultimately, the desired syn
(12) For a related example using olefin coupling, see: Qian, M.; Huang,
Z.; Negishi, E. Org. Lett. 2004, 6, 1531-1534. In our case, such a strategy
was initially pursued but abandoned after the failure to prepare (E)-1-iodo-
2-bromobutene, despite a report on the successful preparation of a similar
haloolefin, (E)-1-iodo-2-bromohexene: Barluenga, J.; Rodriguez, M. A.;
Campos, P. J. J. Org. Chem. 1990, 55, 3104-3106.
Org. Lett., Vol. 9, No. 18, 2007
3705

diastereomer was secured by subjecting ent-2 and 2b to
classic Mitsunobu conditions that afforded propargyl p-
nitrobenzoates 15a and 15b, which were separable by flash
chromatography (Scheme 4). Treatment of 15b with K2CO3
in MeOH resulted in global deprotection to the isomerically
pure propargyl alcohol 16b. Finally, 1b was obtained after
trisylation and subsequent reaction with LiCuBr2 (47%, two
completed in 16 steps in 2.3% overall yield. Synthetic high-
lights include the first application of a Mukaiyama aerobic
oxidative cyclization to form the cis-fused 2,6-dioxabicyclo-
[3,3,0]octane skeleton and the use of the Smithers reagent
to secure the bromodiene side chain. Moreover, the stereo-
chemistry of aplysiallene is unambiguously reassigned to 1b.
1
steps). The H and 13C NMR spectra, optical rotation, and
Acknowledgment. We thank NSERC and The University
of Western Ontario for financial support of this work.
mass spectrum fragmentation pattern of 1b were an exact
match to the reported data for the natural product.
In summary, the total synthesis of (-)-aplysiallene has been
Supporting Information Available: General experimen-
tal procedures and characterization of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Initial efforts were undertaken to furnish the bromodiene side chain
on a model system by a one-step olefination strategy, but such reactions
under various conditions consistently gave low (20∼30%) yields consisting
of mixtures of all four olefin isomers.
OL701797E
(17) For spectral comparison between kumausallene and 1-epi-kumaus-
allene, see ref 7.
(18) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687-9688. (b) Kojima, N.; Maezaki, N.; Tominaga, H.; Asai, M.; Yanai,
M.; Tanaka, T. Chem.-Eur. J. 2003, 9, 4980-4990.
(19) (a) Anderson, N. G.; Lust, D. A.; Colapret, K. A.; Simpson, J. H.;
Malley, M. F.; Gougoutas, J. Z. J. Org. Chem. 1996, 61, 7955-7958. (b)
Galynker, I.; Still, W. C. Tetrahedron Lett. 1982, 23, 4461-4464.
(20) Park, J.; Kim, B.; Kim, H.; Kim, S.; Kim, D. Angew. Chem., Int.
Ed. 2007, 46, 4726-4728.
(14) (a) Smithers, R. H. J. Org. Chem. 1978, 43, 2833-2838. (b) In our
case, addition of DMSO gave negligible improvement on E/Z selectivity.
Gao, L.; Murai, A. Heterocycles 1996, 42, 745-774.
(15) Krause, N.; Seebach, D. Chem. Ber. 1987, 120, 1845-1851.
(16) Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W. J. Org. Chem.
1985, 50, 364-367.
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Org. Lett., Vol. 9, No. 18, 2007