Enantioselective total synthesis of (+)-rogioloxepane A

Article abstract of DOI:10.1021/ol034923l

(Matrix presented) The enantioselective synthesis of (+)-rogioloxepane A has been achieved in 21 steps from 1,5-hexadien-3-ol. The key steps in the synthesis are an asymmetric glycolate alkylation leading to the diene 2 and a subsequent ring-closing metat

Full text of DOI:10.1021/ol034923l

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3009-3011
Enantioselective Total Synthesis of
(+)-Rogioloxepane A
Michael T. Crimmins* and Amy C. DeBaillie
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received May 27, 2003
ABSTRACT
The enantioselective synthesis of (+)-rogioloxepane A has been achieved in 21 steps from 1,5-hexadien-3-ol. The key steps in the synthesis
are an asymmetric glycolate alkylation leading to the diene 2 and a subsequent ring-closing metathesis to construct the oxepene core.
Seven-, eight-, and nine-membered medium ring ethers are
a common structural unit of many ladder ether marine toxins
and simpler Laurencia acetogenin metabolites.1 The chal-
lenge of efficient construction of medium ring ethers has
led to the development of numerous strategies for their
synthesis.2-5 Until recently, the majority of these approaches
had focused on the R,R′-cis-disubstitution pattern rather than
R,R′-trans-disubstituted medium ring ethers,2 despite their
similar frequency of occurrence. Murai’s synthesis of ob-
tusenyne,3 Suzuki’s synthesis of rogioloxepane A,4 and our
own syntheses of obtusenyne,5 prelaureatin, and laurallene6
constitute the only syntheses, to date, of medium ring ether
natural products with the R,R′-trans arrangement.
disubstituted oxepene ring. As part of a continuing program
directed toward the development of a general strategy for
the construction of medium-ring ethers of various ring sizes
and substitution patterns,5-7 we embarked on a synthesis of
rogioloxepane A (1).8 The R,R′-trans-disubstituted oxepene
ring of rogioloxepane A (1) seemed a suitable test for our
general asymmetric alkylation-ring-closing metathesis strat-
egy for the construction of medium ring ethers.
Rogioloxepane A (1) was isolated from Laurencia micro-
cladia off the Torrent II Rogiolo in the Mediterranean in
1992 by Pietra’s group.8 Suzuki and co-workers have recently
reported the first total synthesis of (+)-rogioloxepane A,
confirming the proposed configuration of the halogenated
carbons at C6 and C13.
Rogioloxepane A (1) is a representative member of the
Laurencia-derived C15 acetogenins containing an R,R′-trans-
Strategically, it was anticipated that rogioloxepane A (1)
would be derived from diene 2 by a ring-closing metathesis
to prepare the oxepene with subsequent introduction of the
Z-enyne and the two halogen substituents. The relative and
absolute stereochemistry at C7 and C12 R-to the ether oxygen
would be established by an asymmetric glycolate alkylation9
of glycolyloxazolidinone 3 which would be obtained from
epoxide 4. The synthesis of diene 11 with the key C7 and
(1) Faulkner, J. D. Nat. Prod. Rep. 2002, 19, 1-48. Faulkner, J. D. Nat.
Prod. Rep. 2001, 18, 1-49. Faulkner, J. D. Nat. Prod. Rep. 2000, 17, 7-55.
Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155-198. Faulkner, D. J. Nat.
Prod. Rep. 1998, 15, 113-158 and earlier reviews in the same series.
Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897-1909.
(2) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem. 1989,
54, 5153-5161. Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela,
J. A. Tetrahedron Lett. 1994, 35, 3401-3404. Davies, M. J.; Moody, C. J.;
Taylor, R. J. Synlett 1990, 93-96.
(3) Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma,
T.; Murai, A. J. Org. Chem. 1999, 64, 2616-2617.
(4) Matsumura, R.; Suzuki, T.; Hagiwara, H.; Hishi, T.; Ando, M.
Tetrahedron Lett. 2001, 42, 1543-1546.
(7) Crimmins, M. T.; Emmitte, K. A. Synthesis 2000, 899-903.
(8) Guella, G.; Mancini, I.; Chiasera, G.; Pietra, F. HelV. Chim. Acta
1992, 75, 310-322.
(9) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165-2167. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737-1738.
(5) Crimmins, M. T. Powell, M. T. J. Am. Chem. Soc. 2003, 125, 7592-
7595.
(6) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473-
5476.
10.1021/ol034923l CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/22/2003

Scheme 1. Preparation of diene 11
Figure 1. Retrosynthesis of rogioloxepane A (1).
C12 stereocenters in place is shown in Scheme 1. Racemic,
commercially available 1,5-hexadien-3-ol was exposed to
standard conditions for a Sharpless kinetic resolution10 [(-)-
DCHT, Ti(O-i-Pr)4, t-BuOOH, 4 Å molecular sieves]. The
reaction was quenched at 40% conversion providing epoxy
alcohol 4 in 98% ee. The secondary alcohol 4 was protected
as its THP ether affording the product in near-quantitative
yield. Immediate treatment of the epoxide with methylmag-
nesium chloride in the presence of cuprous iodide delivered
the alcohol 6 in 89% yield over two steps. Protection of the
C13 alcohol (KH, BnBr, Bu4NI, THF) provided the benzyl
ether 7 in 94% yield. The THP ether was readily cleaved by
exposure of 7 to acidic methanol, delivering 91% yield of
the alcohol 8. The alcohol 8 was converted to the acid 9 by
alkylation of the sodium alkoxide of 8 with sodium bro-
moacetate in THF. The glycolic acid 9 was then converted
to its mixed pivaloyl anhydride whereupon the anhydride
was added to (S)-3-lithio-4-isopropyloxazolidin-2-one to
provide the N-acyloxazolidinone 3 in 70% overall yield.
Exposure of the oxazolidinone 3 to NaN(SiMe3)2 in THF
(-78 °C, 1 h) followed by addition of allyl iodide and
warming to -45 °C for 2 h led to the isolation of the
alkylation product 11 in 86% yield (>98:2 dr).9
With the diene 11 in hand, closure of the oxepene with
the Grubbs catalyst11 was attempted. Exposure of diene 11
to 10 mol % of (Cy3P)2Cl2RudCHPh in dichloromethane
produced the desired oxepene 12; however, reductive re-
moval of the auxiliary with sodium borohydride produced
not only the desired oxepene 13, but also varying amounts
of the oxepane 14. We postulated that trace ruthenium-
derived materials in the presence of hydrogen produced from
sodium borohydride in THF-H2O was causing partial
hydrogenation of the alkene. We had previously observed
this complication with a cyclopentene substrate;12 thus, we
opted to remove the oxazolidinone by reduction with sodium
borohydride producing the primary alcohol 2 prior to the
olefin metathesis. We felt this held the added advantage of
a possible hydrogen bond between the C6 primary hydroxyl
and the ether oxygen, which might further bias the diene
conformation toward ring closure.13 In the event, treatment
of diene 2 as before [10 mol % (Cy3P)2Cl2RudCHPh, CH2-
Cl2, 40 °C, 0.002 M] rapidly provided the core oxepene 13.
Alcohol 13 was readily oxidized to the aldehyde 15 under
standard Swern conditions.14
Installation of the C6 stereogenic center required consider-
able experimentation. Attempted addition of the chlorotita-
nium enolate of an N-acetylthiazolidinethione15 proved
unsatisfactory in its diastereoselectivity. However, use of the
protocol reported by Phillips16 led to improved yields and
significantly improved diastereoselectivity (5:1) for the
formation of the aldol adduct 16. Silylation of the mixture
(12) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192-
4193.
(13) For a discussion of conformational effects on rates of ring-closing
metathesis of medium-ring ethers, see: Crimmins, M. T.; Emmitte, K. A.;
Choy, A. L. Tetrahedron 2002, 58, 1817- and references therein. For other
applications of ring-closing metathesis in the synthesis of medium-ring
ethers, see: Maier, M. C. Angew. Chem., Int. Ed. 2000, 39, 2073-2077.
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. Clark, J. S.;
Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372-374 and references
therein.
(14) Swern, D.; Mancuso, A. J.; Huang, S.-L. J. Org. Chem. 1978, 43,
2480-2482.
(10) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(11) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(15) Gonza´lez, AÄ ; Aiguade´, J.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett.
1996, 37, 8949-8952. Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999,
1, 2029-2032.
(16) Phillips, A. J.; Guz, N. R. Org. Lett. 2002, 4, 2253-2256.
3010
Org. Lett., Vol. 5, No. 17, 2003

Scheme 2
Scheme 3
acetlyene cleanly accomplished the first of these tasks
affording the enyne 19 in 88% yield. Removal of the
trimethylsilyl group from the acetylene and cleavage of the
C1 TBS ether were achieved concomitantly by the action of
n-Bu4NF in THF. The C6 chloride was incorporated by
heating a solution of alcohol 20 in toluene and CCl4 while
trioctylphosphine was slowly added to the solution over 2
h. The chloride 21 was produced in 74% yield accompanied
by 16% of diene from elimination. Slow addition of
phosphine was found to significantly reduce the amount of
competing elimination. The rogioloxepane A synthesis was
completed by oxidative removal of the benzyl ether with
DDQ and installation of the C13 bromide by Murai’s
method.19 Synthetic rogioloxepane A was identical in all
respects (1H, 13C NMR, [R]24 MS) to the natural product.
D
In summary, the total synthesis of rogioloxepane A (1) has
been completed in 21 steps from commercially available 1,5-
hexadien-3-ol. The use of a combination of the asymmetric
glycolate alkylation and a ring-closing metathesis established
the trans-disubstituted oxepene ring.
Acknowledgment. We thank the National Institutes of
Health (NIGMS, GM60567) for generous financial support.
of diastereomers followed by reductive removal of the
oxazolidinethione afforded the primary alcohols, which were
readily separated by flash chromatography. Swern oxidation
of alcohol 17 and immediate exposure to the Stork ylide17
resulted in exclusively the Z-vinyl iodide 18 in 79% yield.
The final stage of the synthesis required the completion of
the enyne and installation of the two halogen substituents.
Sonogashira coupling18 of the vinyl iodide with trimethylsilyl
Supporting Information Available: Experimental pro-
cedures and spectral data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034923L
(18) Sonogashira, R. K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
(19) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345-4348.
(17) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
Org. Lett., Vol. 5, No. 17, 2003
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