Enantioselective total synthesis of briarellins E and F: The first total syntheses of briarellin diterpenes

Article abstract of DOI:10.1021/ja035445c

Enantioselective total syntheses of briarellin E (4) and briarellin F (5) have been achieved starting with (S)-(+)-carvone and (S)-(-)-glycidol. These total syntheses are the first of briarellin diterpenes. The central step in these syntheses is acid-prom

Full text of DOI:10.1021/ja035445c

Published on Web 05/07/2003
Enantioselective Total Synthesis of Briarellins E and F: The First Total
Syntheses of Briarellin Diterpenes
Olivier Corminboeuf,† Larry E. Overman,* and Lewis D. Pennington‡
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, California 92697-2025
Received April 3, 2003; E-mail: leoverma@uci.edu
Marine invertebrates continue to serve as invaluable repositories
of structurally novel and biologically active secondary metabolites.1
In particular, a striking diversity of diterpene cyclic ethers has been
isolated from soft corals and gorgonian octocorals.2 The cladiellins
(e.g., 1-3), briarellins (e.g., 4 and 5), and asbestinins (e.g., 6) belong
to the C2,C11-cyclized cembranoid diterpene family2 and have in
common a rare oxatricyclic ring system as well as six stereogenic
centers (carbons 1-3, 9, 10, and 14).3 Although the natural role of
these oxacyclic diterpenes is believed to be predation deterrence,2,4
they also display interesting activity in human cell assays;2 for
example, briarellin diterpenes have recently been shown to be active
against the malaria parasite Plasmodium falciparum.5 Briarellins
E (4) and F (5), like most briarellin diterpenes,3 were isolated by
Rodr´ıguez and co-workers from Caribbean gorgonian octocorals
belonging to the genus Briareum.5,6 The constitution and relative
configuration of these diterpenes were established on the basis of
NMR studies and chemical correlations. Herein we report asym-
metric total syntheses of briarellins E (4) and F (5). These first
Figure 1. Representative cladiellin, briarellin, and asbestinin diterpenes.
Scheme 1
total syntheses of briarellin diterpenes confirm the structure
assignments for 4 and 5 and establish their absolute configurations.
Our plan for preparing briarellins E (4) and F (5) was based on
chemistry we developed recently for the total synthesis of cladiellin
diterpenes.7 We foresaw these briarellin diterpenes evolving from
a formyl tetrahydroisobenzofuran 7 that, in the central strategic step
of the synthesis, would be formed by Prins-pinacol condensation
of a (Z)-R,â-unsaturated aldehyde 8 and an (S)-carvone-derived
alkynyl dienyl diol 9 (Scheme 1). Stereoselective trans dihydroxy-
lation of the (Z)-1-methyl-1-butenyl side chain of 77e would allow
elaboration of the oxepane ring and installation of the R C4
caprylate substituent of 4, whereas regio- and stereoselective
hydration of the cyclohexene moiety would introduce the â C11
hydroxyl group. As in our earlier syntheses of cladiellin diterpenes,7
the bridging nine-membered ring was to be formed at a late stage
by Nozaki-Hiyama-Kishi ring closure.8
The syntheses commenced by preparing an appropriately sub-
stituted cyclohexadienyl diol for use in the Prins-pinacol reaction
(Scheme 2). Protonolysis of the silyl ketene acetal derived from
bicyclic lactone 109,10 with AcOH, followed by reduction with
LiAlH4 provided diol 11.11 Selective protection of the primary
alcohol of 11 as a TIPS ether and subsequent oxidation of the
secondary alcohol with PCC/NaOAc12 gave enone 12. Conversion
of 12 to the corresponding kinetic enol triflate13 using LDA and
2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine,14 fol-
lowed by palladium-catalyzed coupling with (Me3Sn)215 and in situ
iodination of the resulting vinylstannane with N-iodosuccinimide
(NIS)16 delivered cyclohexadienyl iodide 13. Coupling of R-alkoxy
aldehyde 147b with the dienyllithium species generated from 13
gave the desired adduct, which was exposed to PPTS/MeOH to
produce cyclohexadienyl diol 15 as a 3:1 mixture of anti (Felkin-
Ahn) and syn allylic alcohol epimers.17
We next directed our efforts toward assembly of the oxepane-
containing dioxatricyclic moiety of briarellins E (4) and F (5).
Condensation of 15 and (Z)-R,â-unsaturated aldehyde 1618 at low
temperature in the presence of p-TsOH/MgSO4 gave the corre-
sponding acetal,19 which was exposed to 0.1 equiv of SnCl4 to give
formyl tetrahydroisobenzofuran 17 as a single stereoisomer in 84%
yield for the two steps (Scheme 3). Stereospecific photolytic
deformylation of 17,20 followed by selective cleavage of the TBDPS
and TMS protecting groups with aqueous KOH provided homoal-
lylic alcohol 18.21 This intermediate was stereoselectively epoxi-
dized using (t-BuO)3Al/t-BuO2H22,23 and the product was acetylated
to afford epoxy ester 19. Acetate-assisted opening of the epoxide
of 19,24 followed by in situ hydrolysis and acetylation delivered
diacetoxy alcohol 20 as a single isomer in good yield. Stereose-
lective epoxidation of 2025 with m-CPBA, followed by removal of
the TIPS protecting group and triflation (Tf2O/2,6-lutidine) of the
resulting primary alcohol triggered cyclization to provide tricyclic
epoxide 21.
† Current address: Actelion Pharmaceuticals Ltd, Building 14, third floor,
Gewerbestrasse 16, 4123 Allschwil, Switzerland.
‡ Current address: Array BioPharma, 2620 Trade Center Avenue, Longmont,
CO 80501.
The conversion of intermediate 21 to briarellins E (4) and F (5)
is summarized in Scheme 4. Regio- and stereoselective hydration
9
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C O M M U N I C A T I O N S
Scheme 2 a
Scheme 4 a
a (a) LDA, THF, -78 °C; TMSCl, -78 °C f rt; AcOH, 0 °C f rt. (b)
LiAlH4, THF, -78 f 0 °C; recrystallization (78%, 2 steps). (c) TIPSCl,
imidazole, DMF, rt. (d) PCC, NaOAc, CH2Cl2, rt (87%, 2 steps). (e) LDA,
THF, -78 °C; 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine,
-78 °C f rt (86%). (f) (Ph3P)4Pd, LiCl, (Me3Sn)2, THF, reflux; NIS, 0 °C
(76%). (g) 13, t-BuLi, THF, -78 °C f rt. (h) PPTS, MeOH, rt (62%, 2
steps).
Scheme 3 a
a (a) H2SO4, H2O, THF, rt (80%). (b) MsCl, Et3N, THF, rt; LiAlH4 (89%).
(c) Bu8Sn4Cl4O2, isopropenyl acetate, 50 °C (95%). (d) C7H15COCl,
pyridine, rt (80%). (e) Bu3SnAlEt2, CuCN, THF, -30 °C (78% after 1
recycle). (f) I2, CH2Cl2, rt (84%). (g) (t-Bu)2(OH)ClSn, MeOH, rt (93%).
(h) Dess-Martin periodinane, CH2Cl2, rt (80%). (i) CrCl2-NiCl2 (100:1),
DMSO-Me2S (100:1), rt (79%). (j) Dess-Martin periodinane, CH2Cl2, rt
(79%).
2-propynyl side chain of 23 was elaborated to a 2-iodo-2-propenyl
fragment by regioselective stannylalumination-protonolysis with
Bu3SnAlEt2/CuCN28 and subsequent iododestannylation to provide
vinyl iodide 24. Selective removal of the acetate protecting group
of 24 with (t-Bu)2(OH)ClSn/MeOH29 followed by oxidation of the
resulting primary alcohol with Dess-Martin periodinane30 gave
vinyl iodide aldehyde 25. Nozaki-Hiyama-Kishi cyclization8 of
25 then provided briarellin E (4) in 79% yield as a single
stereoisomer; oxidation of 4 yielded briarellin F (5). Synthetic 4
was identical in all respects with a natural sample; spectral and
optical rotation data for 5 compared well with those reported for
the natural isolate.6b
In conclusion, the first total syntheses of briarellin diterpenes
has been accomplished. Briarellins E (4) and F (5) were prepared
in 28 and 29 steps (longest linear sequence), respectively, and 0.7%
overall yield from lactone 10.9 These enantioselective total syntheses
verify the structure assignments6 and establish the absolute con-
figurations for these complex oxacyclic diterpenes. These total
syntheses further illustrate the power of pinacol-terminated Prins
cyclizations for assembling complex polycyclic ethers.
a (a) p-TsOH‚H2O, MgSO4, CH2Cl2, -78 f -20 °C. (b) 0.1 equiv SnCl4,
CH2Cl2, -78 °C f rt (84%, 2 steps). (c) hν, 1,4-dioxane, rt. (d) aq KOH,
THF, MeOH, reflux (55%, 2 steps). (e) (t-BuO)3Al, t-BuO2H, powdered 4
Å molecular sieves, PhMe, -20 °C (79%). (f) Ac2O, DMAP, pyridine, rt
(quant.). (g) TFA, PhMe, 0 °C f rt; H2O. (h) Ac2O, DMAP, pyridine, rt
(86%, 2 steps). (i) m-CPBA, KHCO3, CH2Cl2, 0 °C (77%). (j) n-Bu4NF,
THF, 0 °C (85%). (k) Tf2O, 2,6-lutidine, CHCl3, 0 °C f rt (55-68%).
Acknowledgment. We are grateful to Professor Abimael D.
Rodr´ıguez of the University of Puerto Rico for providing a sample
of natural briarellin E and Professor Jose´-Luis Giner of SUNY-
ESF, New York, for valuable discussions. This research was
supported by the NIH Neurological Disorders and Stroke Institute
(NS-12389); fellowship support for O.C. from the Swiss National
Science Foundation and for L.D.P. from a Pharmacia & Upjohn
Graduate Fellowship in Synthetic Organic Chemistry are gratefully
acknowledged. NMR and mass spectra were obtained at UC Irvine
using instrumentation acquired with the assistance of NSF and NIH
Shared Instrumentation programs.
of the epoxide of 21 with dilute H2SO4 gave diol 22. Mesylation
of the secondary alcohol of 22, followed by treatment with LiAlH4
reductively cleaved the secondary mesylate26 and removed the two
acetate groups. Selective acetylation of the primary alcohol of the
resulting triol using isopropenyl acetate/Bu8Sn4Cl4O2,27 followed
by appendage of the octanoyl side chain produced 23. The
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C O M M U N I C A T I O N S
(b) 2,2,6,6-Tetramethyl-1-piperidinyloxy, NCS, n-Bu4NCl, 2:1:1 CHCl3-
0.5 M aq NaHCO3-0.05 M aq K2CO3, rt (79%).
(10) The antipode of 10 was prepared previously in four steps from (R)-(+)-
limonene: Fra´ter, G. HelV. Chim. Acta 1979, 62, 641-643.
(11) The relative configuration of 11 was corroborated by single-crystal X-ray
analysis.
Supporting Information Available: Experimental procedures for
key steps (preparation of 11, 17, 20, 24, and 4); tabulated characteriza-
tion data and copies of 1H and 13C NMR spectra for all new compounds
10-13 and 15-25 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) Patel, D. V.; VanMiddlesworth, F.; Donaubauer, J.; Gannett, P.; Sih, C.
J. J. Am. Chem. Soc. 1986, 108, 4603-4614.
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