Cycloaldol approach to the isobenzofuran core of eunicellin diterpenes

Article abstract of DOI:10.1021/ol034052f

(Matrix presented) A novel cycloaldol approach to the isobenzofuran core common to many of the eunicellin diterpenes is described. The cycloaldol precursor was prepared by aldol addition of (S)-(+)-carvone and methacrolein followed by etherification to a

Full text of DOI:10.1021/ol034052f

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1039-1042
Cycloaldol Approach to the
Isobenzofuran Core of Eunicellin
Diterpenes
Yonghai Chai, David A. Vicic,† and Matthias C. McIntosh*
Department of Chemistry and Biochemistry, UniVersity of Arkansas,
FayetteVille, Arkansas 72701
mcintosh@uark.edu
Received January 11, 2003
ABSTRACT
A novel cycloaldol approach to the isobenzofuran core common to many of the eunicellin diterpenes is described. The cycloaldol precursor
was prepared by aldol addition of (S)-(+)-carvone and methacrolein followed by etherification to a glycolate ester. Chemoselective enolization
of the glycolate ester led to the cycloaldol adduct in high yield and diastereoselectivity. An oxidative rearrangement−allylic diazene rearrangement
sequence established the requisite cis ring fusion.
The 2,11-cyclized cembranoids are a large family of cem-
brane-derived natural products of marine origin that include
the eunicellins, briarellins, and asbestinins.1 The eunicellin
diterpenes have in common an [8.4.0]tetradecane carbon
skeleton. They possess varying levels of oxidation in the
cyclohexyl and cyclodecyl rings (Figure 1).1,2 A common
As part of a general approach to the eunicellin diterpenes,
we have begun to explore both aldol and Ireland-Claisen
rearrangement strategies toward representative members of
the eunicellin diterpene family.3 From a retrosynthetic
perspective, we imagined forming the oxononane ring in the
latter stages of the synthesis (Scheme 1).4 We considered
the possibility of accessing the isobenzofuran bicycle via a
novel cycloaldol reaction of an appropriately substituted
(1) Reviews: Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod.
1992, 60, 1-141. Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49,
531-556.
(2) Alcyonin: Kusumi, T.; Uchida, H.; Ishitsuka, M. O.; Yamamoto,
H.; Kakisawa, H. Chem. Lett. 1988, 1077-1078. Astrogorgin: Fusetani,
N.; Nagata, H.; Hirota, H.; Tsuyuki, T. Tetrahedron Lett. 1989, 30, 7079-
7082. Massileunicellin-D: Mancini, I.; Guella, G.; Zibrowius, H.; Pietra,
F. HelV. Chim. Acta 2000, 83, 1561-1575.
(3) Hong, S.-p.; Lindsay, H. A.; Yaramasu, T.; Zhang, X.; McIntosh,
M. C. J. Org. Chem. 2002, 67, 2042-2055.
(4) For previous syntheses of eunicellin diterpenes, see: MacMillan, D.
W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117, 10391-10392.
Nicolaou, K. C.; Ohshima, T.; Hosokawa, S.; van Delft, F. L.; Vourloumis,
D.; Xu, J. Y.; Pfefferkorn, J.; Kim, S. J. Am. Chem. Soc. 1998, 120, 8674-
8680. Nicolaou, K. C.; Xu, J. Y.; Kim, S.; Pfefferkorn, J.; Ohshima, T.;
Vourloumis, D.; Hosokawa, S. J. Am. Chem. Soc. 1998, 120, 8661-8673.
Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.; Pettus, T. R.
R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 6563-6579. Gallou,
F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L. A.; Pennington, L.
D.; Yang, J. Org. Lett. 2001, 3, 135-137. 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.
Figure 1. Representative eunicellin diterpenes.
feature of most of the eunicellins is a cis-fused hydroiso-
benzofuran bicycle.1
† To whom correspondence regarding X-ray crystallographic analyses
should be addressed.
10.1021/ol034052f CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/07/2003

sensitive aldol product initially proved to be troublesome.
Competitive retro-aldol and â-elimination resulted in only
low yields of the desired glycolate being isolated.9 After
considerable experimentation, we found that the combination
of Ag2O and 2,6-lutidine in DMF resulted in formation of
glycolate 6 in acceptable yield on a multigram scale. The
optimal yield (65-70%) was obtained by performing the
reaction for 7 days at 4 °C. The reaction could be performed
at considerably shorter reaction times at higher temperatures
(24 h, rt), although the yield decreased to ca. 50%.
Scheme 1
We were gratified to find that the key cycloaldol reaction
occurred smoothly to give isobenzofuran 7 upon treatment
of glycolate 6 with KHMDS in THF at -78 °C (Scheme 3).
Scheme 3a
ketoglycolate. The glycolate would in turn be derived from
aldol addition of (S)-(+)-carvone and the corresponding
aldehyde. The intermolecular aldol addition of the (E)-enolate
derived from carvone would be used install the desired anti
stereochemical relationship at C-1 and C-2 common to the
eunicellins (cf. Figure 1).
There are scattered reports in the literature of chemo-
selective enolization of esters or lactones in the presence of
nominally more acidic ketones or aldehydes.5,6 In a few cases,
the enolates undergo cycloaldol reactions with the ketone
or aldehyde carbonyl group,5 while in others a different
reaction pathway ensues.6 Burke reported the selective
enolization of a glycolate ester in the presence of a cyclo-
pentenone for a subsequent Ireland-Claisen rearrangement.6a
We felt that a similar chemoselective enolization could be
used to induce a cycloaldolization.7
a Conditions: (a) KHMDS, THF, -78 °C; (b) PCC, silica gel,
CH2Cl2, rt.
The â-C-9 stereoisomer was the only isomer detected by 1H
NMR analysis of the crude reaction mixture. The structural
assignment was confirmed by X-ray crystallographic analysis
of a derivative (see Supporting Information). The isobenzo-
furan bicycle was thus accessible in only three steps from
(S)-(+)-carvone. However, it was necessary to adjust the
oxidation level of the cycloaldol product, since the eunicellin
diterpenes are not oxygenated at C-10.1 To this end, an
oxidative rearrangement of allylic alcohol 7 was effected to
generate enone 8.10 The enone could be used to activate the
C-13 position as well as introduce the â-hydrogen at C-10
(vide infra).
The key cycloaldol precursor 6 was prepared from (S)-
(+)-carvone in two steps (Scheme 2). Intermolecular aldol
Scheme 2a
We sought to install the C-10 hydrogen via an allylic
diazene rearrangement (Scheme 4). Such rearrangements
have previously been employed to install angular hydrogens
in carbocyclic systems via reduction of the corresponding
R,â-unsaturated tosylhydrazones.11 A critical feature of the
strategy is the stereochemistry of reduction of the tosyl-
hydrazone, since the rearrangement is a suprafacial process.
a Conditions: (a) LDA, THF, -78 °C, methacrolein, HOAc; (b)
Ag2O, BrCH2CO2Et, 2,6-lutidine, DMF, 4 °C, 7 days.
(7) For leading references on cycloaldol reactions that do not involve
deprotonation, see: Fang, C.; Suganuma, K.; Suemune, H.; Sakai, K. J.
Chem. Soc., Perkin Trans. 1 1991, 1549-1554. Heathcock, C. H.; Ruggeri,
R. B.; McClure, K. F. J. Org. Chem. 1992, 57, 2585-2594. Kanai, K.;
Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549-2551. Molander, G.
A.; Brown, G. A.; Storch de Gracia, I. J. Org. Chem. 2002, 67, 3459-
3463.
addition of (S)-(+)-carvone and methacrolein gave anti-aldol
5 in excellent yield.8 Williamson etherification of the
(8) Martin, S. F.; White, J. B. Tetrahedron Lett. 1982, 23, 23-26.
(9) Patel, D. V.; VanMiddlesworth, F.; Donaubauer, J.; Ganett, P.; Sih,
C. J. J. Am. Chem. Soc. 1986, 108, 4603-4614. Burk, R. M.; Gac, T. S.;
Roof, M. B. Tetrahedron Lett. 1994, 35, 8111-8112.
(5) Creary, X. J. Org. Chem. 1980, 45, 2419-2425. Rassu, G.; Auzzas,
L.; Pinna, L.; Zambrano, V.; Battistini, L.; Zanardi, F.; Marzocchi, L.;
Acquotti, D.; Casiraghi, G. J. Org. Chem. 2001, 66, 8070-8075. Suzuki,
T. Bull. Chem. Soc. Jpn. 1985, 58, 2821-2825. Pinto, A. C.; Epifanio, R.
d. A.; Camargo, W. Tetrahedron 1993, 49, 5039-5046.
(6) (a) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J. J. Org. Chem. 1983,
48, 5221-5228. (b) Paterson, I.; Hulme, A. N. J. Org. Chem. 1995, 60,
3288-3300.
(10) Majetich, G.; Condon, S.; Hull, K.; Ahmad, S. Tetrahedron Lett.
1989, 30, 1033-1036.
(11) Harapanhalli, R. S. J. Chem. Soc., Perkin Trans. 1 1988, 3149-
3154. Chu, M.; Coates, R. M. J. Org. Chem. 1992, 57, 4590-4597. Greco,
M. N.; Maryanoff, B. E. Tetrahedron Lett. 1992, 33, 5009-5012.
1040
Org. Lett., Vol. 5, No. 7, 2003

Scheme 4a
Scheme 5a
a Conditions: (a) TsNHNH2, EtOH, reflux; (b) catecholborane,
NaOAc‚3H2O, CHCl3, from 0 °C to reflux.
a Conditions: (a) LiAlH4, THF, from -78 °C to room temper-
ature; (b) TIPSOTf, 2,6-lutidine; (c) PCC, Celite, CH2Cl2, rt; (d)
KHMDS, THF, -78 °C, TMSCl; (e) mCPBA, NaHCO3, hexanes,
-20 °C; (f) TsNHNH2, CH2Cl2, HOAc, rt; (g) catecholborane,
NaOAc-3H2O, CHCl3, from 0 °C to reflux.
Stereoelectronically preferred axial attack of the hydride onto
the tosylhydrazone would afford the desired â-stereoisomer
of the allylic diazene.11
To this end, enone 8 was converted to tosylhydrazone 9
in quantiative yield. Treatment of tosylhydrazone 9 with
catecholborane in CHCl3, followed by heating of the reaction
mixture under reflux, yielded cis-isobenzofuran 11 possessing
the alcyonin oxidation level (cf. Figure 1) in 81% yield. The
cis ring fusion was assigned on the basis of the J1,10 coupling
(7.1 Hz).
Our strategy for accessing eunicellins bearing C-13 oxygen
substituents was via R-oxidation of the C-12 ketone of enone
8 (cf. Scheme 3). However, the acidity of the C-9 proton
led only to oxidation at C-9 or to complex mixtures.
Competing enolization at C-9 was circumvented by LAH
reduction of the initial cycloaldol 7 to yield diol 12 (Scheme
5). Protection of the primary alcohol as the TIPS ether and
oxidative rearrangement as before yielded enone 14.
would have to attack the concave face of the cis-fused
bicycle. In the event, epimerization of â-alcohol 17 under
Mitsunobu conditions occurred smoothly to afford the desired
R-p-nitrobenzoate ester 18 in 75% yield (Scheme 6).14
Reductive cleavage of the ester then gave R-alcohol 19.
Scheme 6a
Surprisingly, Rubottom oxidation of enone 14 preferen-
tially afforded the undesired â-alcohol 15 as a 7:1 mixture
of diastereomers.12 We elected to defer the epimerization of
the C-13 stereocenter until after the allylic diazene re-
arrangement. Alcohol 15 was treated with tosylhydrazide and
HOAc at room temperature in CH2Cl2 to afford tosylhydra-
zone 16.13 Reduction with catechol borane as before and
allylic diazene rearrangement gave a 4.5:1 ratio of cis-
hydroisobenzofuran 17 and C-10 epi-17 in 72 and 16%
yields, respectively. The stereochemical assignments were
consistent with the J1,10 couplings.
a Conditions: (a) DIAD, PPh3, p-nitrobenzoic acid, THF; (b)
LiAlH4, ether -78 °C.
In summary, we have found that a novel cycloaldol
reaction allows rapid access to the isobenzofuran ring system
of the eunicellin diterpenes and related 2,11-cyclized cem-
branoids. Diastereoselective allylic diazene rearrangements
were used to install the requisite cis ring fusion. Applications
to the synthesis of several eunicellin diterpenes are currently
under investigation.
We were concerned that epimerization of the C-13
â-alcohol would prove to be difficult since the nucleophile
(12) Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599-
1602.
(13) Under these conditions no epimerization of the C-13 hydroxy group
occurred: (a) Garner, C. M.; Mossman, B. C.; Prince, M. E. Tetrahedron
Lett. 1993, 34, 4273-4276. Avery, M. A.; Chong, W. K. M.; Jennings-
White, C. J. Am. Chem. Soc. 1992, 114, 974-979. (b) See also: Steinmeyer,
A.; Neef, G. Tetrahedron Lett. 1992, 33, 4879-4882.
(14) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59,
234-236. Hughes, D. L. Org. React. 1992, 42, 335-656.
Org. Lett., Vol. 5, No. 7, 2003
1041

Acknowledgment. We thank NIH for support of this
work (GM-59406 and RR-15569).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
OL034052F
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Org. Lett., Vol. 5, No. 7, 2003