Ah intramolecular Diels-Alder approach to the eunicelins: Enantioselective total synthesis of ophirin B

Article abstract of DOI:10.1021/ja046574b

The enantioselective synthesis of the eunicellin ophirin B has been completed. A ring-closing metathesis provides efficient access to the oxonene ring, and a highly diastereoselective intramolecular Diels-Alder reaction results in the formation of the hyd

Full text of DOI:10.1021/ja046574b

Published on Web 07/28/2004
An Intramolecular Diels-Alder Approach to the Eunicelins: Enantioselective
Total Synthesis of Ophirin B
Michael T. Crimmins* and Brandon H. Brown
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at Chapel
Hill, Chapel Hill, North Carolina 27599-3290
Received June 10, 2004; E-mail: crimmins@email.unc.edu
Scheme 1. Retrosynthesis Plan for Ophirin B
The eunicellins, briarellins, and asbestinins are related subclasses
of the C2,C11-cyclized cembranoid diterpenes produced as second-
ary metabolites of gorgonian octocoral.1 An unusual oxatricyclic
ring system with stereogenic centers at C1-3, 9, 10, and 14 are
common to all three subclasses, while they differ in location of the
cyclohexyl methyl group (C11 vs C12) and in oxidation level of
the six- and nine-membered rings. The diverse biological activity
displayed by members of these classes2 has piqued interest in the
chemical synthesis of these intriguing structures.
Previous synthetic approaches to the eunicellins and briarellins
have relied entirely on strategies wherein the hydroisobenzofuran
unit was incorporated prior to the oxonane ring.3 Astrogorgin 14
and ophirin B 25,6 seemed particularly attractive targets because of
the additional oxidation at C13 and C18, which offered an
opportunity for the simultaneous installation of the C1, C10, C13,
and C14 stereogenic centers by a strategic intramolecular Diels-
Alder cycloaddition of tetraene 3. We report here the successful
implementation of this plan in the context of the first total synthesis
of a C13, C18 oxygenated eunicellin, specifically ophirin B.
Our strategy (Scheme 1) for the synthesis of the Diels-Alder
substrate 3 was predicated on our recent successes in the construc-
tion of medium ring ethers. We had previously demonstrated that
unsaturated seven-,7 eight-,8 and nine-membered9 cyclic ethers could
be prepared by ring-closing metathesis through exploitation of
acyclic conformational constraints. Thus, Diels-Alder substrate 3
would be derived from diene 4, which would be fashioned through
an asymmetric glycolate alkylation10 of the N-acyloxazolidinone
derived from glycolic acid 5.
Scheme 2. Synthesis of Diene 4a
The preparation of diene 4 is illustrated in Scheme 2. The reaction
of (S)-benzylglycidyl ether with dimethyl-sulfonium methylide11
was followed by protection of the resulting allylic alcohol as its
p-methoxybenzyl ether to afford alkene 8 in excellent yield. The
alkene 8 was treated under modified Wacker oxidation12 conditions
to deliver the methyl ketone 6. The chelation-controlled addition
of 3-butenylmagnesium bromide to ketone 6 supplied the tertiary
carbinol 9 as a single detectable stereoisomer. The tertiary alcohol
was protected as a benzyl ether providing ether 10. The PMB ether
was cleaved by exposure of ether 10 to acidic methanol at 65 °C
followed by alkylation of the ensuing alcohol with sodium hydride
and sodium bromoacetate to produce a high yield of the glycolic
acid 5. Acylation of the glycolic acid 5 through its mixed anhydride
delivered the N-acyloxazolidinone 11 in 89% yield. The C9
stereogenic center was installed by alkylation of the sodium enolate
of oxazolidinone 11 with methallyliodide to stereoselectively
provide the diene 4 (93%, >98:2 d.r.).10
a (a) Me3SI, n-BuLi, THF, -10 °C to 25 °C, 99%; (b) NaH, THF,
p-MeOC6H4CH2Cl, 90%; (c) Hg(OAc)2, H2O; then PdCl2, LiCl, CuCl2, H2O,
O2, 89%; (d) CH2dCHCH2CH2MgBr, THF, -78 °C; 94%; (e) NaH,
C6H5CH2Br, Bu4NI, THF, 93%; (f) MeOH, HCl, 65 °C, 85%; (g) NaH,
BrCH2CO2H, THF, DMF, 98%; (h) Me3CCOCl, Et3N, THF, -78 °C to 0
°C; (S)-lithio-4-isopropyl-oxazolidin-2-one, 89%; (i) NaN(SiMe3)2, THF,
CH2dC(CH3)CH2I, -78 to -45 °C, 93%.
With diene 4 in hand, the stage was set for the closure of the
oxonene ring as illustrated in Scheme 3. Confident because of our
prior success in the formation of oxonene rings by ring closing
metathesis,9 we subjected diene 4 to the Grubbs catalyst [Cl2(Cy3P)2-
RudCHPh, CH2Cl2, 40 °C],13 but only dimer 12 was obtained from
the reaction. Even the more reactive ruthenium carbene [Cl2(Cy3P)-
(sIMes)RudCHPh,14 CH2Cl2, 40 °C] led to exclusive formation of
the dimer 12. Inspection of models and preliminary molecular
9
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C O M M U N I C A T I O N S
Scheme 3. Formation of the Oxonene Ringa
Scheme 4. Synthesis of Tetraene 3a
a (a) Cl2(Cy3P)2RudCHPh, CH2Cl2, 40 °C, dimer only; (b) Cl2(Cy3P)-
(sIMes)RudCHPh, CH2Cl2, 40 °C, dimer only; (c) LiBH4, MeOH, Et2O, 0
°C, 92%; (d) Cl2(Cy3P)(sIMes)RudCHPh, CH2Cl2, 40 °C; 75%, 3:1 RCM/
dimer (e) Cl2(Cy3P)(sIMes)RudCHPh, C6H6, 80 °C, 89%, >15:1 oxonene
14/dimer.
modeling calculations led to speculation that the dipole-stabilized
conformation of the N-acyloxazolidinone portion of 4 was position-
ing the two alkenes distally. We reasoned that reductive removal
of the auxiliary to provide alcohol 13 would not only alleviate the
unfavorable conformational bias, but might also introduce the
possibility for a stabilizing intramolecular hydrogen bond between
the primary hydroxyl of diene 13 and the incipient ring ether
oxygen. Thus, imide 4 was reduced to the alcohol 13, which was
then exposed to the Grubbs catalyst [Cl2(Cy3P)(sIMes)RudCHPh,
CH2Cl2, 40 °C], leading to a 75% yield of a 3:1 mixture of oxonene
14 and the dimer of 13. However, when the temperature for the
reaction was increased, [Cl2(Cy3P)(sIMes)RudCHPh, C6H6, 80 °C]
89% of oxonene 14 and only trace amounts of the dimer were
obtained. To determine if the dimer was being reprocessed at higher
temperature, the dimer was separated and exposed to the same
conditions as before. Once again, a >15:1 mixture of oxonene 14/
dimer was obtained. When oxonene 14 was resubjected to the
catalyst in the presence of ethylene, no evidence of ring opening
was observed. On the basis of the success of closure of diene 13 at
80 °C, diene 4 was also exposed to the Grubbs catalyst at higher
temperature [Cl2(Cy3P)(sIMes)RudCHPh, C6H6, 80 °C], which
effected closure to the corresponding oxonene. This leads to the
conclusion that the dimers are kinetic products that are reprocessed
to the oxonenes, which are unreactive in this metathesis.
a (a) Dess-Martin periodinane, CH2Cl2; (b) Ph3PdC(Me)CO2Et, C6H6,
80 °C, 99%, two steps; (c) i-Bu2AlH, CH2Cl2, -78 °C, 93%; (d) DHP,
PPTS CH2Cl2, 98%. (e) Na, NH3, THF, 91%; f) Dess-Martin periodinane,
CH2Cl2; (g) Ph3PdCHCO2Me, CH2Cl2, 40 °C, 91%, two steps; (h)
Et3SiOTf, CH2Cl2, lutidine, 95%; (i) PPTS, MeOH, 97%; (j) Dess-Martin
periodinane, CH2Cl2; (k) Ph3P+CH2OBnCl, t-BuOK, THF, -78 °C.
stereomer in about 2h.17 The diene 21, however, was unchanged.
When the mixture of cycloadduct 22 and diene 21 was irradiated
in the presence of catalytic PhSSPh,16 adduct 22 was unaffected,
but diene 21 was converted to a 1:1 mixture of diene 3 and the Z,E
diene isomer 23. Again, after standing, diene 3 was transformed to
cycloadduct 22 and the Z,E diene 23 was unaltered. This process
was repeated on the mixture until all the diene had been consumed,
resulting in an 80% overall isolated yield (from the alcohol prior
to the Wittig olefination) of a single exo Diels-Alder adduct 22.
With the cycloadduct 22 available, the completion of the synthesis
seemed imminent.
The oxonene 14 was converted to the Diels-Alder substrate 3,
as shown in Scheme 4. Dess-Martin15 oxidation of alcohol 14 and
subsequent Wittig reaction led to the (E)-enoate 15. Reduction of
the ester 15 followed by protection of the alcohol as its THP ether
provided ether 16, and the benzyl ethers were reductively removed
to afford diol 17. Oxidation of the primary alcohol and conversion
of the resultant aldehyde to enoate 18 proceeded in 91% yield. The
tertiary alcohol was then protected as its TES ether 19. The THP
ether was selectively removed under mild acidic conditions, and
the alcohol was oxidized to the aldehyde 20. Upon exposure of
aldehyde 20 to benzyloxymethylenetriphenylphosphorane, a 3:1
mixture of dienes 3:21 was obtained.
Addition of methylmagnesium chloride to ester 22 smoothly led
to the tertiary alcohol 24 (Scheme 5). The benzyl and triethylsilyl
ethers were easily cleaved to access the triol 25. Unfortunately,
attempts to directly form the triacetate ophirin B (2) from the triol
under a wide variety of acetylation conditions resulted in the
formation of the bridged ether 26. The axial disposition of the C14
hydroxypropyl group suitably positions the hydroxyl for an allylic
displacement of the C13 allylic acetate. Accordingly, the failure
of the direct acetylation necessitated a more circuitous solution.
The problem was eventually circumvented by a stepwise acetylation
of the three hydroxyl groups. The triethylsilyl ether was cleaved
with
While the Wittig olefination to form the diene 3 was not highly
selective, a fortuitous event ensued during the Diels-Alder reaction.
When the mixture of dienes 3 and 21 was allowed to stand at room
temperature, diene 3 was rapidly and quantitatively converted to
the desired oxatricyclic system 22 (Scheme 4) as a single dia-
n-Bu4NF to give the diol 27. Diol 27 could be converted to the
monoacetate 28 (but not the diacetate) by exposure to KHMDS
and acetic anhydride.3c The C3 acetate was then installed by
treatment of monoacetate 28 with Bi(OTf)318 and acetic anhydride
to deliver the diacetate 29. Careful hydrogenolysis of the C13 benzyl
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Scheme 5. Completion of the Synthesis of Ophirin B (2)a
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Acknowledgment. This work was supported by a research grant
(GM60567) from the National Institutes of General Medical
Sciences. We gratefully acknowledge a generous gift of (S)-
benzylglycidyl ether from Daiso, Inc.
Supporting Information Available: Experimental procedures as
well as 1H and 13C NMR spectra for all new compounds and synthetic
(-)-orphirin B. This material is available free of charge via the Internet
at http://pubs.acs.org.
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