Diastereoselective brook rearrangement-mediated [3 + 4] annulation: Application to a formal synthesis of (+)-laurallene

Article abstract of DOI:10.1021/ol8003595

The formal synthesis of (+)-laurallene, a halogenated eight-membered ring ether, was accomplished. The synthesis involves construction of a trans α,α -disubstituted oxocene structure 16 through a Brook rearrangement-mediated [3 + 4] annulation using acryloylsilane 10 and 6-oxa-2-cycloheptenone 9 and its conversion into 2, which has been transformed into (+)-laurallene by Crimmins and co-workers.

Full text of DOI:10.1021/ol8003595

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1803-1806
Diastereoselective Brook
Rearrangement-Mediated [3 + 4]
Annulation: Application to a Formal
Synthesis of (+)-Laurallene
Michiko Sasaki,† Azusa Hashimoto,† Koudai Tanaka,† Masatoshi Kawahata,‡
Kentaro Yamaguchi,‡ and Kei Takeda†,*
Department of Synthetic Organic Chemistry, Graduate School of Medical Sciences,
Hiroshima UniVersity, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553, Japan, and
Tokushima Bunri UniVersity, Shido, Sanuki, Kagawa 769-2193, Japan
takedak@hiroshima-u.ac.jp
Received February 18, 2008
ABSTRACT
The formal synthesis of (+)-laurallene, a halogenated eight-membered ring ether, was accomplished. The synthesis involves construction of
a trans r,r′-disubstituted oxocene structure 16 through a Brook rearrangement-mediated [3 + 4] annulation using acryloylsilane 10 and
6-oxa-2-cycloheptenone 9 and its conversion into 2, which has been transformed into (+)-laurallene by Crimmins and co-workers.
Laurallene (1) belongs to a laurenane structural subclass that is
one of two basic structural types of halogenated eight-membered
ring ethers isolated from red algae of the genus Laurencia.1
Although much interest has been shown in the synthesis of 1
due to its unique structural feature, few syntheses have been
reported,2 probably because of the difficulty in establishing a
trans R,R′-disubstituted oxocene structure.1–3 That is in contrast
to the extensive studies on the synthesis of another subclass,
the lauthisan type, that involves a cis R,R′-disubstituted
pattern at the ether oxygen.4 The first total synthesis of 1
was reported by Crimmins and co-workers, who used ring-
closing metathesis to close the eight-membered ring, allowing
construction of the oxocene core.
As part of our ongoing program on the development of new
synthetic reactions featuring a tandem carbon-carbon bond
formation, we have recently reported a Brook rearrangement-
mediated [3 + 4] annulation methodology for the construction
of eight-membered oxacycles.5–7 In this paper, we report a
(4) (a) Fujiwara, K. In Topics in Heterocyclic Chemistry; Kiyota, H.,
Ed.; Springer: Berlin, 2006; Vol. 5, pp, 97-148. (b) Fujiwara, K.;
Yoshimoto, S.; Takizawa, A.; Souma, S.; Mishima, H.; Murai, A.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 6819–6822. (c) Baek, S.; Jo,
H.; Kim, H.; Kim, H.; Kim, S.; Kim, D. Org. Lett. 2005, 7, 75–77. (d)
Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653–5660.
(e) Kru¨ger, J.; Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119, 7499–7504.
(f) 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. (g) Bratz, M.; Bullock,
W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem. Soc. 1995, 117, 5958–
5966. (h) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345–4348.
† Hiroshima University
‡ Tokushima Bunri University
(1) Fukuzawa, A.; Kurosawa, E. Tetrahedron Lett. 1979, 2797–2800.
(2) (a) Crimmins, M. T.; Elie, A. T. J. Am. Chem. Soc. 2000, 122, 5473–
5476. (b) Saitoh, T.; Suzuki, T.; Sugimoto, M.; Hagiwara, H.; Hoshi, T.
Tetrahedron Lett. 2003, 44, 3175–3178.
(3) (a) Fujiwara, K. J. Synth. Org. Chem. Jpn. 2007, 65, 502–510. (b)
Fujiwara, K.; Souma, S.; Mishima, H.; Murai, A. Synlett 2002, 1493–1495.
(c) Kim, H.; Lee, H.; Lee, D.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2007,
129, 2269–2274. (d) Sugimoto, M.; Suzuki, T.; Hagiwara, H.; Hoshi, T.
Tetrahedron Lett. 2007, 48, 1109–1112
.
(5) Sawada, Y.; Sasaki, M.; Takeda, K. Org. Lett. 2004, 6, 2277–2279.
10.1021/ol8003595 CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

formal synthesis of (+)-laurallene carried out to show the
synthetic utility of the methodology. The target molecule is
the Crimmins’ intermediate (2), which has been converted
by Crimmins and co-workers2a into laurallene (1) and
prelaureatin,8 the biogenetic precursor of several members
of the laurenan structural subclass including 1 (Figure 1).
Scheme 2. Synthesis of 9
Figure 1. Laurallene 1 and Crimmins’ intermediate 2.
When acryloylsilane 107c was added to a solution of
lithium enolate 11, generated from 9 by LDA at -80 °C,
and then the solution was warmed to room temperature, the
annulation product 12a was obtained in 76% yield as a single
isomer (Scheme 3).
Our synthetic plan involves conversion of 5, which is a [3
+ 4] annulation product from acryloylsilane 3 and 6-oxa-2-
cycloheptenone enolate 4 and has a latent trans R,R′-functional-
ity, into 2 via functional group manipulation (Scheme 1). Crucial
Scheme 3. [3 + 4] Annulation of 10 and 11
Scheme 1. Synthetic Plan for Crimmins’ Intermediate 2
to the successful implementation of this strategy is the facial
selectivity in the [3 + 4] annulation, which controls the relative
stereochemistry of the R,R′-substituents.
The requisite 6-oxa-2-cycloheptenone 9 for the annulation
was prepared starting from (S)-glycidol derivative 79 via ring-
closing metathesis of 8 (Scheme 2).10
The use of sodium enolate generated by NaHMDS also
worked well. The relative stereochemistry was determined
on the basis of X-ray analysis of the MOM-protected
derivative 12b. This indicates that the addition of enolate
11 to acryloylsilane 10 occurred selectively at the same side
as the benzyloxymethyl group. The exclusive formation of
the product resulting from attack from the more hindered
side can be explained by invoking that there exists a rapid
equilibrium7c,g between a 1,2-adduct and the starting materi-
als at -80 °C in reactions of acryloylsilanes with ketone
enolates.11 Thus, the transition state from the major 1,2-
adduct 13 to a divinylcyclopropanediolate intermediate 14
leading to epi-12a should be higher energy than that for the
minor 1,2-adduct, which was generated via attack from
the more hindered side. This may be due to the fact that the
(6) For the construction of eight-membered carbocycles, see: Takeda,
K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031–1033
.
(7) For the original Brook rearrangement-mediated [3 + 4] annulation
protocol for seven-membered carbocycles, see: (a) Takeda, K.; Takeda, M.;
Nakajima, A.; Yoshii, E. J. Am. Chem. Soc. 1995, 117, 6400–6401. (b)
Takeda, K.; Nakajima, A.; Yoshii, E. Synlett 1996, 753–754. (c) Takeda,
K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi,
T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947–4959. (d) Takeda, K.;
Nakajima, A.; Takeda, M.; Yoshii, E.; Zhang, J.; Boeckman, R. K., Jr. Org.
Synth. 1999, 76, 199–213. (e) Takeda, K.; Ohtani, Y. Org. Lett. 1999, 1,
677–679. (f) Takeda, K.; Nakane, D.; TakedaM., Org. Lett. 2000, 2, 1903–
1905. (g) Nakai, Y.; Kawahata, M.; Yamaguchi, K.; Takeda, K. J. Org.
Chem. 2007, 70, 1379–1387.
(8) Fukuzawa, A.; Takasugi, Y.; Murai, A. Tetrahedron Lett. 1991, 32,
5597–5598.
(9) (a) Gravestock, M. B.; Knight, D. W.; Lovell, J. S.; Thornton, S. R.
J. Chem. Soc., Perkin Trans. 1 1994, 1661–1663. (b) Takano, S.; Sekiguchi,
Y.; Sato, N.; Ogasawara, K. Synthesis 1987, 139–141.
(10) Cossy, J.; Taillier, C.; Bellosta, V. Tetrahedron Lett. 2002, 43,
7263–7266.
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Org. Lett., Vol. 10, No. 9, 2008

transition state is product-like in which unfavorable steric
interactions between the benzyloxymethyl group and the
hydrogen atom on the cyclopropane ring as shown in 14 can
develop upon the formation of the cyclopropane ring. Our
previous studies7c also indicate that the existence of an
equilibrium between a 1,2-adduct and divinylcyclopropane-
diolate via a retro-aldol/retro-Brook sequence is unlikely.
Having obtained the bicyclo[3.3.2]decene skeleton with
the desired stereoselectivity, we next examined the annulation
and subsequent oxidation of the resultant enolate to an
R-hydroxyketone in a one-pot operation. When Davis’
oxaziridine 1512 was added to a THF solution of sodium
enolate13 of 12a with an extra amount of NaHMDS and 18-
crown-6, R-hydroxy ketone 16 was obtained in 64% yield,
which was a better yield than that obtained by the procedure
with isolation of 12a (Scheme 4). Oxidative cleavage of the
Scheme 5. Transformation of 17 to Crimmins’ Intermediate
Scheme 4
.
Synthesis of 17 via One-Pot [3 + 4] Annulation/
Oxidation
overall yield from 18) by methanolysis. The migration of a
double bond from the C4-C5 position to the C5-C6
position and selective removal of the hydroxymethyl group
at C6 could be achieved by a five-step sequence. Thus,
treatment of 20 with 2-methoxypropene in the presence of
pyridinium p-toluenesulfonate (PPTS) followed by reaction
with TBSOTf and 2,6-lutidine and then methanolysis of the
resulting 1-methoxyethyl group afforded the selectively
protected alcohol 21 in 63% overall yield. Swern oxidation
of 21 using trifluoroacetic anhydride15 and then removal of
the resulting aldehyde using the Wilkinson catalyst gave
Crimmins’ intermediate (2) in 67% overall yield. Comparison
of the spectroscopic data and the specific optical rotation of
our sample of 2 with those kindly provided by Professor
Crimmins showed them to be identical.
In summary, we have accomplished a formal synthesis of
(+)-laurallene using Brook rearrangement-mediated [3 + 4]
annulation, demonstrating the synthetic utility of the methodol-
ogy.
two-atom internal tether was achieved with Pb(OAc)4 in
MeOH-benzene to give 17 in 95% yield.
The remaining steps necessary for the conversion of 17
into Crimmins’ intermediate (2) are shown in Scheme 5. The
R-silyl enol silyl ether in 17 was transformed into enone 19
by a three-step sequence involving conversion into the
diacetate 18 by reduction of the aldehyde and ester moieties
followed by acetylation and reaction with NBS followed by
n-Bu4NF (TBAF).7c Stereoselective reduction of the ketone
in 19 was achieved by NaBH4 to give an alcohol as a single
diastereomer,14 which was converted into triol 20 (62%
Acknowledgment. We thank Professor M. T. Crimmins
of the University of North Carolina at Chapel Hill for sending
us the spectra of compound 2. This research was partially
supported by a Grant-in-Aid for Scientific Research (B)
19390006 and a Grant-in-Aid for Scientific Research on
Priority Areas (17035054, 18032049) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT).
We thank the Research Center for Molecular Medicine,
Faculty of Medicine, Hiroshima University and N-BARD,
Hiroshima University for the use of their facilities.
(11) An alternative explanation for the observed diastereoselectivity is
that the approach of the acylsilane to the enolate occurrs from the same
side as the benzylozymethyl substituent due to its psuedo equatorial
disposition on the seven membered ring, as suggested by a reviewer.
(12) (a) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A.; Pribish, J.;
Vedejs, E. Org. Synth. 1987, 66, 203–210. (b) Davis, F. A.; Vishwakarma,
L. C.; Billmers, J. M.; Finn, J. J. Org. Chem. 1984, 49, 3241–3243.
(13) In this case, the use of lithium enolate resulted in a sluggish reaction
in the stage of the oxidation even with the addition of an extra amount of
NaHMDS and the crown ether.
Supporting Information Available: Full experimental
details and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL8003595
(14) The relative stereochemistry of the resulting alcohol was determined
to be that shown after conversion into 2.
(15) The use of oxalyl chloride gave much lower yield.
Org. Lett., Vol. 10, No. 9, 2008
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