An intramolecular Diels-Alder approach to the eunicellins: Enantioselective total syntheses of ophirin B and astrogorgin

Article abstract of DOI:10.1021/ja056334b

The enantioselective syntheses of the eunicellins ophirin B and astrogorgin have been completed. Ring-closing metatheses provide efficient access to the oxonene rings, and highly diastereoselective intramolecular Diels-Alder reactions resulted in the form

Full text of DOI:10.1021/ja056334b

Published on Web 01/05/2006
An Intramolecular Diels-Alder Approach to the Eunicellins:
Enantioselective Total Syntheses of Ophirin B and
Astrogorgin
Michael T. Crimmins,*,† Brandon H. Brown,‡,1 and Hilary R. Plake†
Contribution from the Department of Chemistry, Venable and Kenan Laboratories of Chemistry,
UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, and
Gilead Sciences, Inc., Foster City, California, 94404
Received September 14, 2005; E-mail: crimmins@email.unc.edu.
Abstract: The enantioselective syntheses of the eunicellins ophirin B and astrogorgin have been completed.
Ring-closing metatheses provide efficient access to the oxonene rings, and highly diastereoselective
intramolecular Diels-Alder reactions resulted in the formation of the hydrobenzofuran portion of the
molecules.
Introduction
chemical synthesis of members of these subclasses has piqued
in recent years due to their novel structures and diverse
The eunicellins, briarellins, asbestinins, and sarcodyctins are
related subclasses of the C2,C11-cyclized cembranoid diterpenes
isolated as secondary metabolites of gorgonian octocoral found
in the Caribbean and West Pacific Ocean.2-4 The presence of
all four structural types of natural products in the same organism
provides circumstantial evidence for the biosynthetic pathway
proposed by Faulkner in which a cembrane skeleton is the
precursor to all these metabolites. An unusual oxatricyclic ring
system containing a hydroisobenzofuran and an oxacyclononane
unit with stereogenic centers at C1-3, 9, 10, and 14 are common
to the eunicellins, briarellins, and asbestinins. However, the
location of the cyclohexyl methyl groups (C11 vs C12) and the
oxidation level of the six- and nine-membered rings differ
among the three classes. It has been postulated that upon
oxidation at C16, the eunicellins (cladiellins) are converted to
the briarellins (Scheme 1). Further, a suprafacial 1,2-methyl shift
from C11 to C12 could transform the briarellins to the
asbestinins.
Since the original report of the isolation of eunicellin from
Eunicella stricta appeared in 1968,5 extensive investigation of
gorgonian soft coral has resulted in the isolation of over 50
novel secondary metabolites in the class. Preliminary investiga-
tions into the biological activity have shown that a variety of
the eunicellin, briarellin, and asbestinin metabolites exhibit insect
growth inhibition activity and in vitro cytotoxity against several
cancer cell lines. On the basis of mollusk and fish lethality
assays, the natural role of C2-C11-cyclized cembranoids has
been suggested to be predatory deterrence. Interest in the
biological activities.6-9
The first total synthesis of a eunicellin diterpene was the
synthesis of (-)-7-deacetoxyalcyonin acetate reported by Over-
man in 1995 (Figure 1).10,11 The subsequent synthesis and
structural reassignment of sclerophytin A by both the Paquette12,13
and Overman11,14,15 laboratories was followed by Molander’s16
disclosure of the second synthesis of (-)-7-deacetoxyalcyonin
acetate. Briarellins E and F are the only members of the
briarellin class that have been prepared by chemical synthe-
sis.17,18 Each of the early synthetic approaches to the eunicellins
and briarellins employed a strategy where the hydroisobenzo-
furan unit was incorporated prior to oxonene ring formation.19
While these strategies were clearly effective, an alternate
approach was envisioned wherein the medium ring ether moiety
might be used as a stereochemical control element for stereo-
selective intramolecular Diels-Alder reaction to construct the
(6) Yamada, K.; Ogata, N.; Ryu, K.; Miyamoto, T.; Komori, T.; Higuchi, R.
J. Nat. Prod. 1997, 60, 393-396.
(7) Kusumi, T.; Uchida, H.; Ishitsuka, M. O.; Yamamoto, H.; Kakisawa, H.
Chem. Lett. 1988, 1077-1078.
(8) Ochi, M.; Yamada, K.; Futatsugi, K.; Kotsuki, H.; Shibata, K. Heterocycles
1991, 32, 29-32.
(9) Ochi, M.; Yamada, K.; Shirase, K.; Kotsuki, H.; Shibata, K. Heterocycles
1991, 32, 19-21.
(10) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117, 10391-
10392.
(11) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2001, 123, 9033-9044.
(12) Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. Org. Lett. 2000,
2, 1875-1878.
(13) Bernardelli, P.; Moradei, O. M.; Friedrich, D.; Yang, J.; Gallou, F.; Dyck,
B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. A. J. Am. Chem. Soc.
2001, 123, 9021-9032.
(14) Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683-2686.
(15) Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L. A.;
Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 135-137.
(16) Molander, G. A.; St. Jean, D. J., Jr.; Haas, J. J. Am. Chem. Soc. 2004, 126,
1642-1643.
† University of North Carolina at Chapel Hill.
‡ Gilead Sciences, Inc.
(1) Abstracted from the Ph.D. Thesis of B. H. Brown, University of North
Carolina at Chapel Hill, 2004.
(2) Sung, P.-J.; Chen, M.-C. Heterocycles 2002, 57, 1705-1715.
(3) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531-556.
(4) Rodriguez, A. D. Tetrahedron 1995, 51, 4571-4618.
(5) Kennard, O.; Watson, D. G.; Riva di Sanseverino, L.; Tursch, B.; Bosmans,
R.; Djerassi, C. Tetrahedron Lett. 1968, 9, 2879-2884.
(17) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. Org. Lett. 2003, 5,
1543-1546.
(18) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc.
2003, 125, 6650-6652.
(19) Chai, Y.; Vicic, D. A.; McIntosh, M. C. Org. Lett. 2003, 5, 1039-1042.
9
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J. AM. CHEM. SOC. 2006, 128, 1371-1378
1371

A R T I C L E S
Crimmins et al.
Figure 1. C2-C11 Cyclized Cembranoid Natural Products.
Scheme 1. Proposed Biosynthesis of the C2-C11 Cyclized Cembranoids
hydrobenzofuran unit. Our previous successes in the construction
of medium ring ethers encouraged the investigation of this
strategy. We have demonstrated the preparation of unsaturated
seven-,20,21 eight-,22-25 and nine-membered26-28 cyclic ethers
by employing acyclic conformational constraints to facilitate
the formation of medium rings by ring-closing metathesis
reactions. Ophirin B (1)29 and astrogorgin (2)29,30 were attractive
targets because their additional oxidation at C13 and C18 offered
the opportunity for the simultaneous installation of the C1, C10,
C13, and C14 stereogenic centers by a strategic intramolecular
Diels-Alder cycloaddition of the tetraene 3 (Scheme 2). The
medium ring of each of the Diels-Alder substrates would be
formed through a ring-closing metathesis of the appropriate
dienes 4, which could arise from a common intermediate 5
through an asymmetric glycolate alkylation.31 Thus, a divergent
synthesis of both 1 and 2 could result from N-acyloxazolidinone
5, ultimately derivable from methyl ketone 6.
The synthesis of the N-acyloxazolidinone 5 began by exposure
of (S)-benzylglycidyl ether to dimethyl-sulfonium methylide as
described by Mioskowski32 to install the desired olefin func-
tionality (Scheme 3). The resulting allylic alcohol 7 was then
protected as its p-methoxybenzyl ether to afford alkene 8 in
excellent yield. Alkene 8 was converted to methyl ketone 6
under modified Wacker conditions.33,34 Alkene 8 could also be
(20) Crimmins, M. T.; DeBaillie, A. C. Org. Lett. 2003, 5, 3009-3011.
(21) Crimmins, M. T.; Emmitte, K. A. Synthesis 2000, 899-903.
(22) Crimmins, M. T.; Cleary, P. A. Heterocycles 2003, 61, 87-92.
(23) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029-2032.
(24) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653-5660.
(25) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473-5476.
(26) Crimmins, M. T.; Powell, M. T. J. Am. Chem. Soc. 2003, 125, 7592-
7595.
(27) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Tetrahedron 2002, 58,
1817-1834.
(31) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2, 2165-
(28) Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123, 1533-
1534.
2167.
(32) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin,
D.-S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449-5452.
(33) Rodeheaver, G. T. H., D. F. J. Chem. Soc., Chem. Commun. 1971, 818-
819.
(29) Seo, Y.; Rho, J.-R.; Cho, K. W.; Shin, J. J. Nat. Prod. 1997, 60, 171-174.
(30) Fusetani, N.; Nagata, H.; Hirota, H.; Tsuyuki, T. Tetrahedron Lett. 1989,
30, 7079-7082.
9
1372 J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006

Total Syntheses of Ophirin B and Astrogorgin
A R T I C L E S
Scheme 2. Retrosynthetic Plan
Scheme 3. Synthesis to Divergent Pointa
converted to methyl ketone 6 through Lemieux-Johnson
cleavage of the alkene followed by addition of methylmagne-
sium chloride to the aldehyde and subsequent oxidation of the
intermediate secondary alcohol to the ketone 6. The critical C9
stereogenic center was introduced by a chelation-controlled
addition of 3-butenylmagnesium bromide to ketone 6, which
supplied the tertiary carbinol in high yield as a single detectable
stereoisomer 9 by 1H NMR. The tertiary alcohol was protected
as a benzyl ether providing ether 10, whereupon exposure to
acidic methanol at 65 °C, the PMB ether was cleaved to reveal
the secondary alcohol 11. Alkylation of the secondary alcohol
(NaH, BrCH2CO2H) produced the glycolic acid 12 in high yield.
N-Acyloxazolidinone 5 was then obtained in 89% yield through
acylation of lithio-(S)-4-isopropyloxazolidinone with the mixed
anhydride of acid 12.
The C9 stereogenic centers for both natural products were
installed by alkylation of the sodium enolate of oxazolidinone
5. For ophirin B (1) methallyliodide was employed to stereo-
selectively provide the diene 13 (93%, >98:2 d.r.).31 Asym-
metric alkylation with iodide 14 was used for the route to
astrogorgin (2) and provided the diene 15 in excellent yield.
With the appropriate dienes in hand, attention was turned
toward closure of the oxonene ring. Prior success in the
formation of oxonene rings for the synthesis of isolaurallene
and obtusenyne using ring-closing metathesis provided confi-
dence for this crucial transformation. Diene 13 was subjected
to the Grubbs catalyst (Cl2(Cy3P)2RudCHPh, CH2Cl2, 40 °C),35
but only dimer 17 was obtained (Scheme 4). Even the more
reactive ruthenium carbene (Cl2(Cy3P)(sIMes)RudCHPh, CH2-
a (a) Me3SI, n-BuLi, THF, -10 °C to 25 °C, 99%; (b) NaH, THF, DMF,
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 °C to -45 °C, 93%; (j) NaN(SiMe3)2, THF, -78
°C to -45 °C, 90%; (k) OsO4, NaIO4, H2O, THF; (l) MeMgCl, THF; (m)
DMSO, (COCl2), Et3N, CH2Cl2.
Cl2, 40 °C)36 led to exclusive formation of 17. Inspection of
models and preliminary molecular modeling calculations led
to speculation that the dipole-stabilized conformation of the
N-acyloxazolidinone portion of 13 was positioning the two
alkenes distally. It was reasoned that removal of the auxiliary
providing alcohol 18 would not only alleviate the unfavorable
conformational bias but might also introduce the possibility for
a stabilizing intramolecular hydrogen bond between the primary
hydroxy of diene 18 and the incipient ring ether oxygen. Thus,
imide 13 was reduced with sodium borohydride to provide the
alcohol 18, which was then exposed to the Grubbs catalyst (Cl2-
(34) Nicolaou, K. C.; Xu, J. Y.; Kim, S.; Pfefferkorn, J.; Ohshima, T.;
Vourloumis, D.; Hosokawa, S. J. Am. Chem. Soc. 1998, 120, 8661-8673.
(35) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,
100-110.
(36) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-
956.
9
J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006 1373

A R T I C L E S
Crimmins et al.
Scheme 4. Ring-Closing Metathesis to Form Oxononenea
Scheme 5 a
a (a) Dess-Martin periodinane, C5H5N, CH2Cl2; (b) Ph3PdC(Me)CO2Et,
C6H6, 80 °C, 100% over two steps; (c) i-Bu2AlH, CH2Cl2, -78 °C, 86%;
(d) Dess-Martin periodinane, CH2Cl2; (e) Ph3P+CH2OBnCl, t-BuOK, THF,
-78 °C, 82% over two steps; (f) n-Bu4NF, THF, 92%; (g) Dess-Martin
periodinane, C5H5N, CH2Cl2; (h) DMSO, (COCl)2, Et3N, CH2Cl2; (i) TPAP,
NMO, CH2Cl2.
(sIMes)RudCHPh, C6H6, 80 °C). Once again, excellent conver-
sion to the corresponding oxonene 16 was observed. Therefore,
it appears that the dimers are kinetic products that are
reprocessed to the oxonenes, which are unreactive in the
metathesis. To examine the use of a cyclic conformational
constraint for the metathesis, benzylidene 21 was prepared.
Surprisingly, with the conformational rigidifying element in
place, less than 10% of the corresponding oxonene 22 was
formed (Cl2(Cy3P)(sIMes)RudCHPh, CH2Cl2, 40 °C). The
failure of benzylidine 21 to undergo ring-closing metathesis
reinforces the importance of the gauche effect and related subtle
acyclic conformational constraints in these medium ring me-
tathesis reactions.
With the key oxonene ring in place, attention was turned
toward the preparation of the intramolecular Diels-Alder
precursor. Initial attempts (on a slightly different substrate 23)
focused on incorporating the diene prior to the enoate with the
hope that the formation of the enoate and the Diels-Alder
reaction might occur sequentially in the same reaction. To this
end, alcohol 23 was converted to the enoate 24 by Dess-Martin
oxidation37-39 and subsequent Wittig olefination to deliver the
ester 24 in quantitative yield (Scheme 5). The ester was reduced
to alcohol 25, which was then oxidized to the corresponding
aldehyde. Treatment of the aldehyde with benzyloxymethylen-
etriphenylphosphorane produced a 1.5:1 mixture of the diene
diastereomers 26 in good yield. The removal of the TIPS
protecting group from 26 proceeded smoothly, but attempts to
oxidize the alcohol 27 to the aldehyde 28 led to decomposition.
The aldehyde was apparently undergoing rapid reaction with
a (a) Cl2(Cy3P)2RudCHPh, CH2Cl2, 40 °C, 17 only; (b) Cl2(Cy3P)(sIMes)-
RudCHPh, CH2Cl2, 40 °C, 17 only; (c) LiBH4, MeOH, Et2O, 0 °C, 92%;
(d) Cl2(Cy3P)2RudCHPh, CH2Cl2, 40 °C,75%, 3:1 19:20; (e) Cl2(Cy3P)-
(sIMes)RudCHPh, C6H6, 80 °C, 89%, >15:1 19:20; (f) Ac2O, pyridine,
DMAP, CH2Cl2, 95%; (g) BCl3-SMe2, CH2Cl2, 0 °C, 71%; (h)
C6H5CH(OMe)2, CSA, C6H6, 93%; (i) Cl2(Cy3P)(sIMes)RudCHPh, CH2Cl2,
40 °C, <10%.
(Cy3P)(sIMes)RudCHPh, CH2Cl2, 40 °C), leading to a 75%
yield of a 3:1 mixture of oxonene 19 and dimer 20. However,
when the solvent was changed to benzene and the temperature
for the reaction was increased, (Cl2(Cy3P)(sIMes)RudCHPh,
C6H6, 80 °C) 89% of oxonene 19 and only trace amounts of
the dimer 20 were obtained. To determine if the dimer was being
reprocessed at a higher temperature, dimer 20 was purified and
exposed to the same conditions as before. Once again, a >15:1
mixture of oxonene 19 to dimer 20 was obtained. When oxonene
19 was subjected 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 18 at 80 °C, diene 13 was also
exposed to the Grubbs catalyst at higher temperature (Cl2(Cy3P)-
(37) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(38) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(39) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
9
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Total Syntheses of Ophirin B and Astrogorgin
A R T I C L E S
Scheme 6. Intramolecular Diels-Alder to Form Eunicellin Corea
of dienes 34 and 35 was allowed to stand at room temperature,
diene 34 was rapidly and quantitatively converted to the desired
oxatricyclic system 36 as a single diastereomer. Next, the
possibility of isomerizing diene 35 to diene 34 was explored.
Exposure of the diene 35 to iodine in benzene caused hydrolysis
of the enol ether, while irradiation in benzene in the presence
of Me6Sn2 or Bu6Sn2 did not effect isomerization. However,
when a mixture of cycloadduct 36 and diene 35 was irradiated
in the presence of catalytic PhSSPh,40 adduct 36 was unaffected,
but diene 35 was converted to a 1:1 mixture of diene 34 and
the Z,E-diene isomer 37. Again, after standing, diene 34 was
transformed to cycloadduct 36 and the Z,E-diene 37 was
unaltered. This process was repeated on the mixture until
essentially all the diene had been consumed, resulting in a 78%
overall isolated yield (from the THP ether) of a single exo
Diels-Alder adduct 36. It is interesting to note that when the
C3-O was the free OH a 3:1 mixture of exo:endo diastereomers
of the cycloaddition was obtained. The Diels-Alder cyclo-
addition of a similar system, with a benzyl ether at the C3-O
position resulted in a 4.5:1 exo:endo ratio of Diels-Alder
adducts. Thus, it is suggested that the size of the group at the
C3-O position effects the diastereoselectivity of the cycload-
dition with hydrogen < benzyl < triethylsilyl increasing exo
selectivity. The stereochemical assignments of the two Diels-
Alder adducts 36 (exo) and 38 (endo) were made based on two-
dimensional NOESY experiments. In the exo adduct 36, a strong
interaction was observed between the hydrogens at C1-C10,
at C14-C2, and between the C2 hydrogen and the C3 methyl
group. In contrast, in the endo adduct 38, a strong interaction
was observed between the hydrogens at C1-C2, as well as the
C3 methyl group with the hydrogens at both C1 and C2 (Scheme
7).
Inspection of the transition states 39 and 40 in Scheme 7
provides a rationale for the observed selectivity based on
changing the protecting group of the C3 hydroxyl. In transition-
state 40, which leads to the endo Diels-Alder adduct, a
significant nonbonding interaction develops between the OR
group and the alpha hydrogen of the enoate, whereas the
nonbonded interaction between the beta hydrogen of the enoate
and the OR group in transition state 39 appears to be less
significant. Thus as R progresses from hydrogen to benzyl to
triethylsilyl, the exo selectivity of the intramolecular Diels-
Alder increases. This is further supported by a report by Holmes,
wherein similar Diels-Alder reactions of substrates with a
protected secondary alcohol at C3 (of opposite configuration
to 34, i.e., H instead of OR and OR instead of Me for a substrate
similar to 34) undergo endo selective Diels-Alder cycloaddi-
tions.41 Another interesting point is that even heating diene 35
to 80 °C in benzene did not effect cycloaddition, presumably
due to the inability of the diene of 35 to adopt the required
s-cis conformation for cycloaddition to occur.
With the cycloadduct in hand, attention turned to completion
of the synthesis of ophirin B. Addition of methylmagnesium
chloride to ester 36 smoothly provided the tertiary alcohol 41
in excellent yield (Scheme 8). Fluoride mediated cleavage of
the triethylsilyl ether followed by reductive cleavage of the
benzyl ether delivered the triol 43. Attempts to directly form
the triacetate ophirin B (1) from triol 43 were thwarted by the
formation of the bridged ether 44. A wide variety of standard
a (a) Dess-Martin periodinane, C5H5N, CH2Cl2; (b) Ph3PdC(Me)CO2Et,
C6H6, 80 °C, 99% over 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% over two
steps; (h) Et3SiOTf, CH2Cl2, 2,6-lutidine, 95%; (i) PPTS, MeOH; (j) Dess-
Martin periodinane, CH2Cl2; (k) Ph3P+CH2OBnCl, t-BuOK, THF, -78 °C;
(l) C6H6, 25 °C (78% from 33); (m) hν, PhSSPh, C6H6.
the diene enol ether. It was therefore decided to introduce the
enoate at C2 prior to completion of the diene moiety.
Reordering the sequence allowed for efficient introduction
of the diene and the enoate for the intramolecular Diels-Alder
reaction. The alcohol 19 was oxidized using Dess-Martin
conditions, and the resulting aldehyde underwent a Wittig
olefination to afford the (E)-enoate 29 (Scheme 6). Reduction
of 29 followed by protection of the alcohol as the THP ether
provided 30. The benzyl ethers were then reductively cleaved
giving diol 31. Oxidation of the primary alcohol and conversion
of the resultant aldehyde to enoate 32 proceeded in excellent
yield. The tertiary alcohol was then protected as the TES ether
giving 33. Next, the THP ether was selectively removed under
mild acidic conditions, and the resulting alcohol was oxidized
to the aldehyde. Exposure to benzyloxymethylenetriphe-
nylphosphorane resulted in a 3:1 mixture of 34:35 dienes.
Although the Wittig olefination was not selective, a fortuitous
event ensued during the Diels-Alder reaction. When the mixture
(40) Moussebois, C. D., Jr. J. Chem. Soc. C 1966, 3, 260-264.
9
J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006 1375

A R T I C L E S
Scheme 7
Crimmins et al.
Scheme 9. Revised End Game for Ophirin Ba
a (a) KH, THF, Ac2O, 90%, 1:1 ratio of 45:46; (b) Bi(OTf)3, Ac2O, THF,
75%; (c) H2, Pd/C, EtOAc, 70%; (d) Ac2O, DMAP, C5H5N, CH2Cl2, 95%.
of the bridged ether 44 might be suppressed. On the basis of
this rationale, a stepwise approach was undertaken. After the
triethylsilyl ether was cleaved providing the diol 42, several
conditions were explored to afford the diacetylated product 47
(Scheme 9). Ultimately, it was determined that diol 42 could
be converted to a 1:1 mixture of monoacetates 45 and 46 by
exposure to KH and acetic anhydride.12 While conditions were
never found to selectively form either of the monoacetates or
to directly produce the diacetate, a plausible solution was
identified. The two monoacetates 45 and 46 were separated by
chromatography and the C3 acetate 45 could be converted to a
1:1 mixture of monoacetates 45 and 46 by treatment with KH
and acetic anhydride in THF through an acetyl migration.
Recycling the undesired acetate eventually produced the mono-
acetate 46 in 90% yield. The C3 acetate was finally installed
by treatment of the monoacetate 46 with Bi(OTf)342,43 and acetic
anhydride at -40 °C (warming resulted in elimination of both
acetates) to deliver the desired diacetate 47 in 75% yield. Careful
hydrogenolysis of the C13 benzyl ether led to the allylic alcohol
48, which was transformed to ophirin B (1) under standard
conditions (Ac2O, C5H5N, DMAP). Synthetic ophirin B dis-
played identical spectral characteristics (1H, 13C NMR, IR) and
optical rotation to those reported for the isolated natural product.
Scheme 8. End Game for Ophirin Ba
a (a) MeMgCl, THF, 0-25 °C, 85% (b) n-Bu4F, THF, 94%; (c) Na,
naphthalene, THF -78 °C, 90%.
With the completion of ophirin B, an application of the same
synthetic strategy to the synthesis of the more complex natural
product astrogorgin (2) was investigated. The auxiliary was
reductively removed from the alkylation product 15 providing
the alcohol 49 (Scheme 10). The oxonene 50 was formed in
excellent yield utilizing ring-closing metathesis with Grubbs
catalyst (Cl2(Cy3P)(sIMes)RdCHPh, C6H6, 80 °C). Dess-
Martin oxidation of the alcohol 50 followed by Wittig reaction
basic acetylation conditions, such as Et3N, Ac2O, DMAP or Ac-
(imidazole), imidazole, CH2Cl2 or Ac2O, KH, and THF, resulted
in cyclization to the bridged ether 44. Lewis acid catalyzed
acetylations conditions, such as Sc(OTf)3, Ac2O or Bi(OTf)2,
and Ac2O, produced either the tetracycle 44 or effected
decomposition. It was postulated that sterically less hindered
C13 allylic alcohol was first to undergo acetylation and that
the axial disposition of the C14 hydroxypropyl group suitably
positioned the hydroxy for allylic displacement of the C13 allylic
acetate. Thus, it seemed reasonable that if the C18 hydroxyl on
the hydroxypropyl group could be acetylated first, the formation
(41) Davidson, J. E. P.; Gilmour, R.; Ducki, S.; Davies, J. E.; Green, R.; Burton,
J. W.; Holmes, A. B. Synlett 2004, 1434-1436.
(42) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. J. Org. Chem. 2001, 66,
8926-8934.
(43) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. Angew. Chem., Int. Ed.
Engl. 2000, 39, 2877-2879.
9
1376 J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006

Total Syntheses of Ophirin B and Astrogorgin
A R T I C L E S
Scheme 10. Synthesis of Astrogorgin Corea
Scheme 11. End Game for Astrogorgina
a (a) MeMgCl, THF, 0-25 °C, 89%; (b) NaHMDS, THF, Ac2O, 0 °C,
54%, quant. BRSM; (c) H2, Pd/C, THF, 85%, quant. BRSM; (d) Ac2O,
DMAP, C5H5N, CH2Cl2, 91%; (e) n-Bu4F, THF, quant.; (f) o-NO2C6H4SeCN,
n-Bu3P, THF; (g) H2O2, C5H5N, CH2Cl2, 0 °C, 94% for two steps; (h) TPAP,
NMO, CH2Cl2, quant.; (i) NaBH4, CeCl3, MeOH, 0 °C, 89% (j) Ac2O,
DMAP, C5H5N, CH2Cl2, 92%; (k) n-Bu4F, THF, 80%; (l) Bi(OTf)3, Ac2O,
THF, -78 °C to - 31 °C, 26%.
stereoselectivity of this olefination was improved by employing
i
the Pr ester rather than the methyl ester in the Wittig reagent
i
(14:1 with Pr vs 4:1 with Me). The tertiary alcohol 54 was
then protected as its triethylsilyl ether 55. The primary allylic
triethylsilyl ether was selectively cleaved under mild acidic
conditions to give the allylic alcohol in excellent yield. Oxidation
of the alcohol to the aldehyde followed by exposure to
benzyloxymethylenetriphenylphosphorane resulted in a 1.4:1
mixture of dienes 56:57. As before, with the ophirin B
intermediate, when the mixture of dienes was allowed to stand
at room temperature, diene 56 was quantitatively converted to
the desired oxatricycle 58 as a single diastereomer within 13 h.
Once again, the diene 57 was unchanged. By irradiation of the
mixture of cycloadduct 58 and diene 57 with PhSSPh, only the
diene 57 was affected and converted to a mixture of diene 56
and the Z,E-diene isomer. After standing for 13 h, diene 56
was completely transformed to the tricycle 58 and the Z,E-diene
was unaltered. This sequence was repeated until all the diene
had been consumed to provide an overall 78% yield (from the
allylic alcohol) of a single exo Diels-Alder adduct 58.
a (a) LiBH4, MeOH, Et2O, 0 °C, 90%; (b) Cl2(Cy3P)(sIMes)RudCHPh,
C6H6, 80 °C, 96%; (c) Dess-Martin periodinane, C5H5N, CH2Cl2; (d)
Ph3PdC(Me)CO2Et, C6H6, 80 °C, 85% over two steps; (e) i-Bu2AlH,
CH2Cl2, -78 °C, 98%; (f) Et3SiOTf, 2,6-lutidine, CH2Cl2, -78 °C, quant.;
(g) Na, NH3, THF, 70%; (h) TPAP, NMO, CH2Cl2; (i) Ph3PdCHCO2i-Pr,
CH2Cl2, 40 °C, 14:1 (E:Z), 85% over two steps; (j) Et3SiOTf, CH2Cl2, 2,6-
lutidine, quant.; (k) PPTS, MeOH, 85%; (l) Dess-Martin periodinane,
C5H5N, CH2Cl2; (m) Ph3P+CH2OBnCl, t-BuOK, THF, -78 °C; (n) C6H6,
25 °C, 78% over four steps; (o) hν, PhSSPh, C6H6.
provided the (E)-enoate 51. Reduction of the ester and subse-
quent protection of the resulting alcohol gave the triethylsilyl
ether 52. The benzyl ethers were cleaved under reductive
conditions (Na, NH3, THF) to afford the diol 53 without
cleavage of the triethylsilyl group. Mild oxidation of the primary
alcohol with nPr4NRuO4 and NMO (Dess-Martin conditions
resulted in the cleavage of the triethylsilyl ether) and olefination
of the resulting aldehyde led to the enoate 54. The (E)-
The ester 58 was treated with methylmagnesium chloride,
and the resulting alcohol was immediately acetylated to give
9
J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006 1377

A R T I C L E S
Crimmins et al.
59 (Scheme 11). Careful hydrogenolysis of the C13 benzyl ether
led to the allylic alcohol 60, which was further transformed into
the diacetate 61. Next, the triisopropylsilyl ether was selectively
cleaved without affecting the hindered C3 triethylsilyl ether to
provide the allylic alcohol 62.
In summary, highly stereoselective synthesis of ophirin B and
astrogorgin has been completed. The highlights of the syntheses
include a diastereoselective glycolate alkylation to establish the
absolute configuration of C9, ring-closing metathesis to construct
the oxonene ring, and intramolecular Diels-Alder reactions to
simultaneously install C1, C10, C13, and C14 stereocenters.
Allylic transposition using the Grieco reagent smoothly
provided the exo cyclic olefin 63 as a single diastereomer.44,45
Unfortunately, the stereochemistry of the C6 allylic alcohol was
opposite that required for astrogorgin. Thus, mild oxidation to
the enone and selective reduction under Luche conditions46
afforded the desired allylic alcohol 64 as a single diastereomer
in good yield. The allylic alcohol was then acetylated under
standard conditions, and the C3 oxygen was unmasked. Treat-
ment with Bi(OTf)3 and Ac2O provided astrogorgin in 26% yield
(the bis elimination product and recovered starting material were
the other major components of the reaction). Synthetic astrogor-
gin displayed identical spectral characteristics (1H, 13C NMR,
IR) and optical rotation to those reported for the isolated natural
product.
Acknowledgment. This work was supported by a research
grant (GM60567) from the National Institutes of General
Medical Sciences. H.R.P. was supported by Postdoctoral Fel-
lowship Grant #PF-04-098-01-CDD from the American Cancer
Society. We thank Professors S. Matsunaga and N. Fusetani
for providing copies of NMR spectral data. 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 (-)-ophirin B and (-)-astrogorgin. This material is
available free of charge via the Internet at http://pubs.acs.org.
(44) Kato, N.; Wu, X.; Tanaka, S.; Takeshita, H. Bull. Chem. Soc. Jpn. 1990,
63, 1729-1734.
(45) Clive, D. L. C., G.; Curtis, N. J.; Menchen, S. M. J. Chem. Soc., Chem.
Commun. 1978, 770-771.
(46) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454-5459.
JA056334B
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1378 J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006