Enantioselective total synthesis of (+)-obtusenyne

Article abstract of DOI:10.1021/ja029956v

A total synthesis of the laurencia metabolite (+)-obtusenyne has been completed. The key steps include a Sharpless kinetic resolution and an asymmetric glycolate alkylation to establish the stereogenic centers adjacent to the ether linkage and a ring-clos

Full text of DOI:10.1021/ja029956v

Published on Web 05/21/2003
Enantioselective Total Synthesis of (+)-Obtusenyne
Michael T. Crimmins* and Mark T. Powell
Contribution from the Department of Chemistry, Venable and Kenan Laboratories of Chemistry,
UniVersity of North Carolina
Received December 30, 2002; E-mail: crimmins@email.unc.edu
Abstract: A total synthesis of the laurencia metabolite (+)-obtusenyne has been completed. The key steps
include a Sharpless kinetic resolution and an asymmetric glycolate alkylation to establish the stereogenic
centers adjacent to the ether linkage and a ring-closing metathesis reaction to construct the nine-membered
ether without the aid of a cyclic conformational constraint. The synthesis was completed in 20 linear steps
from commercially available 1,5-hexadiene-3-ol.
The oceans have become a rich source of topographically
unique molecules, many of which have potential for the
treatment of human diseases. Invertebrates such as sponges,
coral, and dinoflagellates are now a common origin of interesting
natural products. Three main classes of compounds that contain
medium ring ethers have been identified from marine sources.
The ladder ether toxins include such ostentatious structures as
brevetoxins A1 and B,2 and the ciguatoxins,3 all of which contain
medium ring ethers in a complex polyether skeleton. The
members of the topographically unique eunicellin class of
marine metabolites represented by astrogorgin,4 sclerophytin,5
4-deoxyasbestinin A6 display a nine-membered ether embedded
in a tricyclic or tetracyclic scaffold. Finally, the Laurencia red
algae, in particular, have produced a large number of metabolites
containing medium ring ether acetogenins.7 These C15 metabo-
lites include a variety of ring sizes such as those found in
laurencin,8 trans-isoprelaurefucin,9 isolaurallene,10 and ob-
tusenyne.11,12,13 The identification of these interesting metabo-
lites has inspired a number of clever solutions to the construction
of medium ring ethers. Recent examples of synthesis of nine-
membered ether metabolites include Denmark’s synthesis of
brasilenyne14 through a new intramolecular cross-coupling to
form the nine-membered ring, Overman’s synthesis of sclero-
phytin15 via an intramolecular Nozaki-Kishi reaction to con-
struct the oxonin, Murai’s total synthesis of obtusenyne
exploiting a medium ring lactonization16 and the synthesis of
isolaurallene through a nine-membered ring-closing metathesis
from our laboratory.17
Figure 1. Representative medium ring ether marine metabolites.
(1) Shimizu, Y.; Chou, H. N.; Bando, H.; Van Duyne, G.; Clardy, J. J. Am.
Chem. Soc. 1986, 108, 514-515.
As part of a continuing program directed toward the develop-
ment of a general strategy for the construction of medium ring
ether metabolites, we wished to extend the strategy we employed
in the synthesis of laurencin,18 prelaureatin,19 and isolaurallene17
to a metabolite with a nine-membered ring with substituents in
a trans orientation at the R and R′ positions to the ether linkage.
Obtusenyne seemed a suitable test given that its lone synthesis
(2) Lin, Y. Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golik, J.;
James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773-6775.
(3) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T. J. Am. Chem.
Soc. 1989, 111, 8929-8931. Murata, M.; Legrand, A. M.; Ishibashi, Y.;
Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380-4386.
(4) Fusetani, N.; Nagata, H.; Hirota, H.; Tsuyuki, T. Tetrahedron Lett. 1989,
30, 7079-7082.
(5) Sharma, P.; Alam, M. J. Chem. Soc., Perkin Trans. 1 1988, 2537-2540.
Alam, M.; Sharma, P.; Zektzer, A. S.; Martin, G. E.; Ji, X.; van der Helm,
D. J. Org. Chem. 1989, 54, 1896-1900.
(6) Morales, J. J.; Lorenzo, D.; Rodriguez, A. D. J. Nat. Prod. 1991, 54, 1368-
1382.
(14) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2002, 124, 15 196-15 197.
(15) Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L. A.;
Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 135-137. MacMillan, D.
W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc. 2001, 123,
9033-9044.
(16) Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma, T.;
Murai, A. J. Org. Chem. 1999, 64, 2616.
(17) Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123, 1533-
1534. Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Tetrahedron 2002,
58, 1817-1834.
(18) Crimmins, M. T.; Emmitte, K. A. Organic Lett. 1999, 1, 2029-2032.
Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5663-5660.
(19) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473-5476.
(7) Faulkner, J. D. Nat. Prod. Rep. 2002, 19, 1-48.
(8) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 1091. Irie, T.;
Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193.
(9) Kurosawa, E.; Fukuzawa, A.; Irie, T. Tetrahedron Lett. 1973, 42, 4135.
(10) Kurata, K.; Furusaki, A.; Suehiro, K.; Katayama, C.; Suzuki, T. Chem.
Lett. 1982, 1031.
(11) King, T. J.; Imre, S.; Oztunc, A.; Thomson, R. H.; Tetrahedron Lett. 1979,
1453.
(12) Howard, B. M.; Schulte, G. R.; Fenical, W.; Solheim, B.; Clardy, J.
Tetrahedron 1980, 36, 1747.
(13) Norte, M.; Gonzalez, A. G.; Cataldo, F.; Rodriguez, M. L.; Brito, I.
Tetrahedron 1991, 47, 9411.
9
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J. AM. CHEM. SOC. 2003, 125, 7592-7595
10.1021/ja029956v CCC: $25.00 © 2003 American Chemical Society

Enantioselective Total Synthesis of (+)-Obtusenyne
A R T I C L E S
Scheme 1. Synthesis of the N-glycolyloxazolidinone 4
incorporated the R and R′ substituents to the ether linkage with
approximately 2:1 stereoselectivity favoring the trans isomer.
(+)-Obtusenyne (1) was independently isolated from Lau-
rencia obtusa by Imre11 in the Agean Sea and Fenical12 at
Positano, Italy. The structure was established as 1 by single-
crystal X-ray analysis.11 The key structural features of the
molecule are the two halogens, which must be incorporated
stereoselectively, the nine-membered ether ring with a trans
relationship of the R and R′ ether substituents, and the attached
(Z)-enyne substituent. The only previous total synthesis of (+)-
obtusenyne was reported by Murai in 1999.16
Strategically, (+)-obtusenyne would be derived from oxonene
2 through selective incorporation of the required halogens and
introduction of the Z-enyne. The core oxonene 2 would be
constructed from triene 3 through a ring-closing metathesis20,21
reaction after selective functionalization of the trisubstituted
alkene. The crucial stereochemistry of the R and R′ positions
of the ether linkage would be established by an asymmetric
glycolate alkylation22 of glycolyl oxazolidinone 4 which would
be prepared from epoxide 5. Epoxide 5 would be easily prepared
through a kinetic resolution23 of the commercially available
hexadienol 6.
a (-)-Dicyclohexyltartrate, Ti(O-i-Pr)4, t-BuOOH, 4 Å molecular sieves,
CH2Cl2, 47% conversion, 98% e.e. bNaH, BnBr, THF, 89%. cMeMgBr,
CuI, THF, 90%. dNaH, BrCH2CO2H, THF, 90%. eMe3CCOCl, Et3N, THF,
-78 °C to 0 °C; (R)-lithio-4-isopropyl-oxazolidin-2-one, 78%.
Scheme 2. Synthesis of Triene 13
Figure 2. Retrosynthesis of (+)-obtusenyne
The synthesis of oxazolidinone 4 is illustrated in Scheme 1.
1,5-Hexadien-3-ol 6 was exposed to a standard Sharpless kinetic
resolution.23 At 47% completion, the epoxide 5 was obtained
in 98% e.e. The secondary alcohol was protected as its benzyl
ether by exposure to sodium hydride and benzyl bromide in
THF to provide 89% of epoxide 7. The epoxide 7 was readily
converted in 90% yield to the secondary alcohol 8 by treatment
with methylmagnesium bromide and copper (I) iodide. Alkyl-
ation of the alcohol with sodium hydride and bromoacetic acid
a NaN(SiMe3)2, THF, -78 to -45 °C, Z-ICH2CHdCHBr, 85%. bNaBH4,
THF, H2O, 82%. c(COCl)2, DMSO, Et3N, CH2Cl2, 97%. d2-
dICr2BCH2CHdCH2, Et2O, -78 °C, 92%. eTBSOTf, Et3N, CH2Cl2, 90%;
f(Cy3P)2Cl2RudCHPh, CH2Cl2, 40 °C, 0.005 M, 80%.
delivered the glycolic acid 9. Acylation of (R)-lithio-4-isopro-
pyloxazolidin-2-one with the mixed anhydride of the glycolate
acid 9 afforded the N-acyloxazolidinone 4 in good overall yield.
(20) 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 applica-
tions of ring-closing metathesis in the synthesis of medium ring ethers
see: Maier, M. C. Angew. Chem., Int. Ed. Engl. 2000, 39, 2073-2077.
Fu¨rstner, A. Angew. Chem. In. Ed. Engl. 2000, 39, 3012-3043. Clark, J.
S.; Hamelin, O. Angew. Chem. In. Ed. Engl. 2000, 39, 372-374 and
references therein.
(21) For approaches to nine membered ring ethers: see ref 18.
(22) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2, 2165.
Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104,
1737.
(23) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
In a first attempt, it was hoped to incorporate a direct
precursor to the enyne through alkylation22 of the N-glycoly-
loxazolidinone 4. To this end, the sodium enolate of oxazoli-
dinone 4 was alkylated with Z-1-bromo-3-iodo propene to
produce the diene 10 (82%, >98:2 d.r.). Reductive removal of
the auxiliary produced alcohol 11. Swern oxidation24 of the
alcohol 11 followed by exposure of the resultant aldehyde 12
(24) Swern, D.; Mancuso, A. J.; Huang, S.-L. J. Org. Chem. 1978, 43, 2480.
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A R T I C L E S
Crimmins and Powell
Scheme 4. Completion of the First Generation Endgame
Scheme 3. Synthesis of the Oxonene Core
a 0.1 N HClO4, THF. bNaIO4, THF, H2O. cNaBH4, EtOH, 0 °C 65% (3
steps). dn-Bu4NF, THF, 90%. et-BuPh2SiCl, imidazole, CH2Cl2, 91%.
fP(Oct)3, CCl4, 1-Methylcyclohexene, PhCH3, 75%; 6:1 Cl:elimination.
gBCl3-SMe3, CH2Cl2, 87%. hP(Oct)3, CBr4, PhCH3, 86%. i47% HF,
CH3CN, 98%. jDess-Martin periodinane, CH2Cl2, 90%; k) Ph3P+CH2I,I-,
a NaN(SiMe3)2, THF, -78 to -45 °C, prenyl iodide, 82%. bNaBH4, THF,
H2O, 82%. c(COCl)2, DMSO, Et3N, CH2Cl2, 97%. d2-dICr2BCH2CHdCH2,
Et2O, -78 °C, 92%. eTBSOTf, Et3N, CH2Cl2, 99%. f) (Cy3P)2Cl2RudCHPh,
CH2Cl2,3:118:14;80%.gm-CPBA,CH2Cl2;-25°C,85%.h(Cy3P)2Cl2RudCHPh,
CH2Cl2, 40 °C, 0.005M, 82%.
l
NaN(SiMe3)2, THF, HMPA, 72% (9:1, Z:E). (Ph3P)4Pd, CuI, Et3SiCCH,
THF, 0 °C, 95%. mn-Bu4NF, THF, -78-0 °C, 95%.
competitively with the cyclohexene, we opted to improve the
reaction by first epoxidizing the trisubstituted alkene. Thus,
exposure of triene 3 to m-CPBA in dichloromethane at low
temperature afforded the epoxides 19 in high yield. Treatment
of diene 19 with the Grubbs catalyst26 effected rapid closure to
the oxonene 20 (82%). This is the first example of the metathetic
formation of an oxonene with a trans orientation of the
substituents at the R and R′ positions without the aid of a cyclic
conformational constraint.17,19
to a Brown allylation25 (>98:2 d.r.) delivered triene 12 in
excellent yield. Conversion of alcohol 12 to the TBS ether 13
was accomplished under standard conditions. Unfortunately,
attempts to form the oxonene ring by ring-closing metathesis
of triene 13 resulted in loss of the vinyl halide functionality via
the formation of the cyclohexene rather than the desired
oxonene. Although this result was not entirely unexpected, we
had hoped to avoid extensive functional group manipulation to
accomplish the installation of the enyne.
The completion of the synthesis of (+)-obtusenyne 1 from
oxonene 20 is illustrated in Scheme 4. At this stage, the epoxide
20 was converted to the alcohol 21 by hydrolysis of the epoxide
to the diol, oxidative cleavage of the diol to the aldehyde and
subsequent reduction of the aldehyde to give alcohol 21 in 65%
overall yield. Removal of the secondary TBS ether gave the
diol 22 and selective protection of the primary alcohol as its
TBDPS ether then provided the alcohol 23. Incorporation of
the secondary chloride was accomplished by heating the
secondary alcohol in toluene in the presence of trioctylphosphine
and CCl4.27 A 6:1 mixture of chloride 24 and the diene from
elimination was formed in 75% yield. Competing elimination
was somewhat suppressed by the slow addition of the phosphine
to the heated solution of the alcohol. Removal of the benzyl
ether under Holmes conditions28 provided alcohol 25. Installa-
The problem was readily corrected by alkylation of the
oxazolidinone 4 with prenyl iodide (Scheme 3) to provide the
diene 15 in 82% yield (>98:2 d.r.). The oxazolidinone was
reductively removed with sodium borohydride resulting in the
isolation of alcohol 16 in 82% yield. Swern oxidation of the
alcohol produced the corresponding aldehyde which was im-
mediately treated with 2-dICr2BCH2CHdCH2 under Brown’s
conditions25 to give a 92% yield of the alcohol 17 (>97:3 d.r.).
Protection of the secondary alcohol 17 as a TBS ether furnished
the desired triene 3. Direct exposure of triene 3 to 5 mol % of
the Grubbs carbene [(Cy3P)2Cl2RudCHPh]26 provided a 3:1
mixture of the oxonene 18: cyclohexene 14. Although this result
was gratifying, in that the nine-membered oxonene was formed
(25) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla, U. S.
J. Am. Chem. Soc. 1990, 112, 2389.
(26) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,
100-110.
(27) Matsumura, R.; Suzuki, T.; Hagiwara, H.; Hoshi, T.; Ando, M.; Tetrahedron
Lett. 2001, 42, 1543.
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Enantioselective Total Synthesis of (+)-Obtusenyne
Scheme 5. Second Generation Endgame
A R T I C L E S
immediately converted to (+)-obtusenyne by Sonogashira32
coupling and deprotection of the silyl acetylene. Synthetic (+)-
obtusenyne 1 displayed identical physical ([R]D) and spectro-
scopic properties (1H NMR, 13C NMR at various temperatures,
IR) to those previously reported.11,12,16
In an effort to streamline the endgame of installation of the
enyne and the two halogens, we undertook a series of experi-
ments to reorder the final steps to minimize protecting group
manipulations. The final solution is illustrated in Scheme 5.
Epoxide 20 was treated with aqueous perchloric acid resulting
in the formation of diol 29 in high yield with no significant
loss of the TBS ether. The benzyl ether was reductively cleaved
with sodium naphthalenide in THF at -78 °C producing the
triol 30 which was immediately cleaved to the aldehyde 31 with
sodium periodate in aqueous THF. Installation of the enyne at
this juncture avoided a series of functional manipulations. In
the event, Stork-Wittig olefination31 of the aldehyde produced
vinyl iodide 32 as a single geometric isomer. Subsequent
Sonagashira coupling32 cleanly afforded the enyne 33 in 95%
yield. Sequential incorporation of the two halogens completed
the synthesis. Thus, bromination of alcohol 33 led to the
formation of bromide 34 in 86% yield, followed by removal of
the two silicon protecting groups and chlorination of the alcohol
led to the completion of the synthesis of (+)-obtusenyne. The
final seqence required 20 linear synthetic steps from com-
mercially available 1,5-hexadiene-3-ol.
a 0.1 N HClO4, THF, 65%. bNa-naphthalenide, THF, 90%. cNaIO4, THF,
H2O, 95%. dPh3P+CH2I,I-, NaN(SiMe3)2, THF, HMPA, 72%. e(Ph3P)4Pd,
CuI, Et3SiCCH, THF, 0 °C, 95%. fP(Oct)3, CBr4, PhCH3, 86%. gn-Bu4NF,
THF, 91%. hP(Oct)3, CCl4, 1-Methylcyclohexene, PhCH3, 70%; 6:1 Cl:
eliminaiton.
In summary, a highly diastereoselective synthesis of the
Laurencia metabolite (+)-obtusenyne has been completed. The
key steps are an asymmetric glycolate alkylation to establish
the stereochemical relationship of the R,R′ disubstituted ether
linkage and a ring-closing metathesis to construct the nine-
membered oxocene.
tion of the bromide29 using Murai’s method gave 86% of
bromide 26, which was spectroscopically identical to an
intermediate prepared in the Murai synthesis of obtusenyne,16
verifying the stereochemistry of the four tetrahedral stereogenic
carbons on the oxonene ring.
The final stage of the synthesis required attachment of the
Z-enyne. To this end, the TBDPS ether 26 was cleaved to the
resultant primary alcohol 27 with n-Bu4NF in THF. Oxidation
of the alcohol 27 to the aldehyde with the Dess-Martin
periodinane30 followed by Stork-Wittig olefination31 provided
vinyl iodide 28 as an 9:1 mixture Z:E isomers. The iodide was
Acknowledgment. This work was supported by a research
grant (GM60567) and a minority postdoctoral supplement for
M.T.P. from the National Institutes of General Medical Sciences.
Supporting Information Available: Experimental procedures
as well as 1H and 13C NMR spectra for all new compounds and
synthetic (+)-obtusenyne. This material is available free of
charge via the Internet at http://pubs.acs.org.
(28) Congreve, M. S.; Davison, E. C.; Fuhry, M. M.; Holmes, A.; Payne, A.
N.; Robinson, A.; Ward, S. E. SynLett. 1993, 663.
(29) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345-4348.
(30) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156. Ireland, R. E.;
Liu, L. J. Org. Chem. 1993, 58, 2899. J. Am. Chem. Soc. 1991, 113, 7277.
(31) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
JA029956V
(32) Sonogashira, R. K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 12,
4467-4470.
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