A unified strategy for enantioselective total synthesis of cladiellin and briarellin diterpenes: Total synthesis of briarellins E and F and the putative structure of alcyonin and revision of its structure assignment

Article abstract of DOI:10.1021/jo9010156

(Chemical Equation Presented) Enantioselective total syntheses of briarellin E (12) and briarellin F (13), as well as the structure originally proposed for the cladiellin diterpene alcyonin (10), have been realized. Comparison of the spectral data for synthetic 10, natural alcyonin, cladiellisin (33), and cladiellaperoxide (34), as well as chemical transformations of 10 and natural alcyonin, suggest that the structure of this coral metabolite is allylic peroxide 11. The unified approach detailed herein can be used to access both C4-deoxygenated and C4-oxygenated cladiellins and briarellins. The central step in these syntheses is acid-promoted condensation of (Z)-α,β- unsaturated aldehydes 17 with cyclohexadienyl diols 18 to form intermediates 16 incorporating the hexahydroisobenzofuran core and five stereocenters of these marine diterpenes (Scheme 1).

Full text of DOI:10.1021/jo9010156

pubs.acs.org/joc
A Unified Strategy for Enantioselective Total Synthesis of Cladiellin and
Briarellin Diterpenes: Total Synthesis of Briarellins E and F and the
Putative Structure of Alcyonin and Revision of Its Structure Assignment
Olivier Corminboeuf,† Larry E. Overman,* and Lewis D. Pennington‡
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025
† Current address: Actelion Pharmaceuticals, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. ‡ Current
address: Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320-1799
leoverma@uci.edu
Received May 20, 2009
Enantioselective total syntheses of briarellin E (12) and briarellin F (13), as well as the structure
originally proposed for the cladiellin diterpene alcyonin (10), have been realized. Comparison of the
spectral data for synthetic 10, natural alcyonin, cladiellisin (33), and cladiellaperoxide (34), as well as
chemical transformations of 10 and natural alcyonin, suggest that the structure of this coral
metabolite is allylic peroxide 11. The unified approach detailed herein can be used to access both
C4-deoxygenated and C4-oxygenated cladiellins and briarellins. The central step in these syntheses is
acid-promoted condensation of (Z)-R,β-unsaturated aldehydes 17 with cyclohexadienyl diols 18 to
form intermediates 16 incorporating the hexahydroisobenzofuran core and five stereocenters of these
marine diterpenes (Scheme 1).
Introduction
ing, pollution, and overfishing are believed to have led to
detrimental increases in ocean acidity and temperature,
disease from normally symbiotic bacteria, and adverse com-
petition with macroalgae.4 The possible loss of this rich
source of molecules with potential value in human medicine
is one motivation to develop efficient chemical syntheses of
coral secondary metabolites. These efforts are further war-
ranted because, despite remarkable advances in spectrosco-
py and parallel synthesis over the last 20 years, the total
synthesis of natural products continues to play an important
Corals are among myriad marine invertebrates serving as
repositories of bioactive molecules.1 Several studies suggest
that soft corals and gorgonian octocorals produce a number
of secondary metabolites to deter predation by mollusks and
fishes.2 With regard to human medicine, many of these
molecules show promising cytotoxicity against a variety of
cancer cell lines, and some display antimalarial activity.2,3
However, coral reef ecosystems are under accelerating de-
cline worldwide as a result of human activity: global warm-
(1) For reviews, see:(a) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M.
H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2007, 24, 31–86 and
earlier reviews in this series. (b) Marris, E. Nature 2006, 443, 904–905.
(c) Bhakuni, D. S.; Rawat, D. S. Bioactive Marine Natural Products;
Springer: New York, and Anamaya: New Delhi, 2005.
(2) (a) O’Neal, W.; Pawlik, J. R. Mar. Ecol.: Prog. Ser. 2002, 240, 117–
126. (b) Puglisi, M. P.; Paul, V. J.; Biggs, J.; Slattery, M. Mar. Ecol.: Prog.
Ser. 2002, 239, 105–114. (c) Maia, L. F.; de Epifanio, A. R.; Eve, T.; Fenical,
W. J. Nat. Prod. 1999, 62, 1322–1324. (d) Harvell, C. D.; West, J. M.; Griggs,
C. Invertebr. Reprod. Dev. 1996, 30, 239–247. (e) Harvell, C. D.; Fenical, W.;
Roussis, V.; Ruesink, J. L.; Griggs, C. C.; Greene, C. H. Mar. Ecol.: Prog.
Ser. 1993, 93, 165–173.
(4) (a) Mumby, P. J.; Dahlgren, C. P.; Harborne, A. R.; Kappel, C. V.;
Micheli, F.; Brumbaugh, D. R.; Holmes, K. E.; Mendes, J. M.; Broad, K.;
Sanchirico, J. N.; Buch, K.; Box, S.; Stoffle, R. W.; Gill, A. B. Science 2006,
311, 98–101. (b) Pandolfi, J. M.; Jackson, J. B. C.; Baron, N.; Bradbury, R.
H.; Guzman, H. M.; Hughes, T. P.; Kappel, C. V.; Micheli, F.; Ogden, J. C.;
Possingham, H. P.; Sala, E. Science 2005, 307, 1725–1726. (c) Pelejero, C.;
Calvo, E.; McCulloch, M. T.; Marshall, J. F.; Gagan, M. K.; Lough, J. M.;
Opdyke, B. N. Science 2005, 309, 2204–2207. (d) Palumbi, S. R. Nature 2005,
€
434, 713–715. (e) Bellwood, D. R.; Hughes, T. P.; Folke, C.; Nystrom, M.
Nature 2004, 429, 827–833. (f) Hughes, T. P.; Baird, A. H.; Bellwood, D. R.;
Card, M.; Connolly, S. R.; Folke, C.; Grosberg, R.; Hoegh-Guldberg, O.;
€
Jackson, J. B. C.; Kleypas, J; Lough, J. M.; Marshall, P.; Nystrom, M.;
Palumbi, S. R.; Pandolfi, J. M.; Rosen, B.; Roughgarden, J. Science 2003,
^
301, 929–933. (g) Gardner, T. A.; Cote, I. M.; Gill, J. A.; Grant, A.;
Watkinson, A. R. Science 2003, 301, 958–960.
(3) For reviews, see: (a) Mayer, A. M. S.; Gustafson, K. R. Eur. J. Cancer
2004, 40, 2676–2704. (b) Lee, S.-S.; Chang, W.-L. Curr. Med. Chem. 2004, 11,
1461–1477.
5458 J. Org. Chem. 2009, 74, 5458–5470
Published on Web 06/17/2009
DOI: 10.1021/jo9010156
r
2009 American Chemical Society

Corminboeuf et al.
JOCArticle
role in structure elucidation5 and drug discovery,6 as well as
inspiring the development of new chemical transformations
for the expeditious synthesis of molecular complexity.7
A striking array of diterpene cyclic ethers has been isolated
from soft corals and gorgonian octocorals.1 In particular, the
cladiellins (also known as the eunicellins, e.g., 1),8 asbestinins
(e.g., 2 and 3),9 and briarellins (e.g., 4 and 5)10,11 comprise a
sizable portion of a large and diverse family of C2-C11-cyclized
cembranoid diterpenes (Figure 1).12 Over the past 40 years,
approximately 60 cladiellins, 15 briarellins, and 30 asbestinins
have been discovered in corals inhabiting the Caribbean and
Mediterranean seas and the Atlantic, Pacific, and Indian
oceans.12,13 The cladiellins, briarellins, and asbestinins have in
common an otherwise rare oxatricyclic ring system composed
of hexahydroisobenzofuran (2-oxabicyclo[4.3.0]nonane) and
oxacyclononane units. With the exception of C14 of the
FIGURE 1. Representative cladiellin (eunicellin), briarellin, and
asbestinin diterpenes.
(5) (a) For a review, see: Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int.
Ed. 2005, 44, 1012–1044. (b) Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int.
Ed. 2005, 44, 2050. For interesting recent examples, see: (c) Nicolaou, K. C.;
Frederick, M. O. Angew. Chem., Int. Ed. 2007, 46, 5278–5282. (d) Porco, J. A.
Jr; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2006,
45, 5790–5792. (e) Nicolaou, K. C.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Bella,
M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888–12896.
(6) For reviews, see:(a) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem.
2006, 71, 8329–8351. (b) Paterson, I.; Anderson, E. A. Science 2005, 310,
451–453. (c) Butler, M. S. Nat. Prod. Rep. 2005, 22, 162–195. (d) Cragg, G.
M.; Newman, D. J. Pure Appl. Chem. 2005, 77, 7–24. (e) Butler, M. S. J. Nat.
Prod. 2004, 67, 2141–2153.
pachyclavulariaenones,11,13g,13h six stereogenic centers (carbons
1-3, 9, 10, and 14) of these diterpenes are identical.12,13 Although
the structures of several members of this family have been
corroborated by X-ray analysis,14,15 structure elucidation in this
area has generally relied upon MS and NMR, IR, and UV
spectral analyses, as well as chemical correlations.12,13 Prior to the
synthesis studies carried out in our laboratory16 and subsequent
ones by the groups of Paquette,16c,17 Molander,18 Crimmins,19
Hoppe,20a and Kim,21 absolute configurations had not been
unambiguously established for any of these coral metabolites.22
€
(7) For reviews, see: (a) Kundig, P. Science 2006, 314, 430–431. (b)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134–7186. (c) Nicolaou, K. C.; Snyder, S. A. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11929–11936. (d) Overman, L. E.; Pennington, L. D. J.
Org. Chem. 2003, 68, 7143–7157. (e) Nicolaou, K. C.; Montagnon, T.;
Snyder, S. A. Chem. Commun. 2003, 551–564.
(8) Kennard, O.; Watson, D. G.; Riva, L.; Tursch, B.; Bosmans, R.;
Djerassi, C. Tetrahedron Lett. 1968, 9, 2879–2884.
ꢀ
(9) (a) Isolation of the first asbestinins: Stierle, D. B.; Carte, B.; Faulkner,
D. J.; Tagle, B.; Clardy, J. J. Am. Chem. Soc. 1980, 102, 5088–5092. (b)
(15) The X-ray crystal structure of sclerophytin F methyl ether was
incorrectly depicted in the original account: Sarma, N. S.; Chavakula, R.;
Rao, I. N.; Kadirvelraj, R.; Guru Row, T. N.; Saito, I. J. Nat. Prod. 1993, 56,
1977–1980. The configuration at C3 should be R. The coordinates (PIJ-
DAN) can be obtained from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, U.K.
ꢀ
Isolation of asbestinin-12: Rodrıguez, A. D.; Cobar, O. M.; Martınez, N. J.
´ ´
Nat. Prod. 1994, 57, 1638–1655.
ꢀ
(10) (a) Rodrı
6880. (b) Ospina, C. A.; Rodrı
Nat. Prod. 2003, 66, 357–363.
´
guez, A. D.; Cobar, O. M. Tetrahedron 1995, 51, 6869–
(16) (a) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995,
117, 10391–10392. (b) Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2,
2683–2686. (c) Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette,
L. A.; Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 135–137.
(d) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2001, 123, 9033–9044. (e) Corminboeuf, O.; Overman, L. E.; Pennington,
L. D. Org. Lett. 2003, 5, 1543–1546. (f) Corminboeuf, O.; Overman, L. E.;
Pennington, L. D. J. Am. Chem. Soc. 2003, 125, 6650–6652.
(17) (a) Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. Org.
Lett. 2000, 2, 1875–1878. (b) 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.
´
guez, A. D.; Ortega-Barria, E.; Capson, T. L. J.
(11) Wang, G.-H.; Sheu, J.-H.; Chiang, M. Y.; Lee, T.-J. Tetrahedron
Lett. 2001, 42, 2333–2336.
(12) For reviews, see: (a) Radhika, P. Biochem. Syst. Ecol. 2006, 34, 781–
789. (b) Sung, P.-J.; Chen, M.-C. Heterocycles 2002, 57, 1705–1715. (c)
Cobar, O. M. Rev. Latinoam. Quim. 2000, 28, 46–54. (d) Bernardelli, P.;
Paquette, L. A. Heterocycles 1998, 49, 531–556. (e) Rodrıguez, A. D.
Tetrahedron 1995, 51, 4571–4618. (f) Coll, J. C. Chem. Rev. 1992, 92, 613–
631. (g) Wahlberg, I.; Eklund, A.-M. In Progress in the Chemistry of Organic
Natural Products; Springer-Verlag: New York, 1992; Vol. 60, pp 1-141.
(13) For cladiellin, briarellin, and asbestinin diterpenes isolated since the
publication of the most recent comprehensive review,12d see: (a) References 10b
ꢀ
´
(18) Molander, G. A.; St. Jean, D. J. Jr.; Haas, J. J. Am. Chem. Soc. 2004,
126, 1642–1643.
and 11. (b) Ospina, C. A.; Rodrı
´
guez, A. J. Nat. Prod. 2006, 69, 1721–1727.
(19) (a) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126,
10264–10266. (b) Crimmins, M. T.; Ellis, J. M. J. Am. Chem. Soc. 2005, 127,
17200–17201. (c) Crimmins, M. T.; Brown, B. H.; Plake, H. R. J. Am. Chem.
Soc. 2006, 128, 1371–1378. (d) Crimmins, M. T.; Ellis, J. M. J. Org. Chem.
2008, 73, 1649–1660.
(c) Kyeremeh, K.; Baddeley, T. C.; Stein, B. K.; Jaspars, M. Tetrahedron
2006, 62, 8770–8778. (d) Su, J.-H.; Huang, H.-C.; Chao, C.-H.; Yan, L.-Y.;
Wu, Y.-C.; Wu, C.-C.; Sheu, J.-H. Bull. Chem. Soc. Jpn. 2005, 78, 877–879.
(e) Ahmed, A. F.; Wu, M.-H.; Wang, G.-H.; Wu, Y.-C.; Sheu, J.-H. J. Nat.
Prod. 2005, 68, 1051–1055. (f) Chill, L.; Berrer, N.; Benayahu, Y.; Kashman,
Y. J. Nat. Prod. 2005, 68, 19–25. (g) Wang, G.-H.; Sheu, J.-H.; Duh, C.-Y.;
Chiang, M. Y. J. Nat. Prod. 2002, 65, 1475–1478. (h) Sheu, J.-H.; Wang, G.-
H.; Sung, P.-J.; Duh, C.-Y.; Chiang, M. Y. Tetrahedron 2001, 57, 7639–7648.
(i) Chen, S.-P.; Sung, P.-J.; Duh, C.-Y.; Dai, C.-F.; Sheu, J.-H. J. Nat. Prod.
2001, 64, 1241–1242. (j) Mancini, I.; Guella, G.; Zibrowius, H.; Pietra, F.
Helv. Chim. Acta 2000, 83, 1561–1575. (k) Seo, Y.; Cho, K. W.; Chung, S.;
Shin, J. Nat. Prod. Lett. 2000, 14, 197–203. (l) Mancini, I.; Guella, G.;
Zibrowius, H.; Laurent, D.; Pietra, F. Helv. Chim. Acta 1999, 82, 1681–1689.
(m) Kakonikos, C.; Vagias, C.; Roussis, V. Nat. Prod. Lett. 1999, 13, 89–95.
(14) (a) References 8, 9, and 11. (b) Miyamoto, T.; Yamada, K.; Ikeda, N.;
Komori, T.; Higuchi, R. J. Nat. Prod. 1994, 57, 1212–1219. (c) Su, J.; Zheng, Y.;
Zeng, L.; Pordesimo, E. O.; Schmitz, F. J.; Hossain, M. B.; van der Helm, D. J.
Nat. Prod. 1993, 56, 1601–1604. (d) Uchio, Y.; Nakatani, M.; Hase, T.;
Kodama, M.; Usui, S.; Fukazawa, Y. Tetrahedron Lett. 1989, 30, 3331–3332.
(e) Alam, M.; Sharma, P.; Zektzer, A. S.; Martin, G. E.; Ji, X.; van der Helm, D.
J. Org. Chem. 1989, 54, 1896–1900. (f) Kazlauskas, R.; Murphy, P. T.; Wells, R.
€
(20) (a) Becker, J.; Bergander, K.; Frohlich, R.; Hoppe, D. Angew.
Chem., Int. Ed. 2008, 47, 1654–1657. For a synthesis of racemic vigulariol,
see: (b) Clark, J. S.; Hayes, S. T.; Wilson, C.; Gobbi, L. Angew. Chem., Int.
Ed. 2007, 46, 437–440.
(21) Kim, H.; Lee, H.; Kim, J.; Kim, S.; Kim, D. J. Am. Chem. Soc. 2006,
128, 15851–15855.
(22) Absolute configurations have been proposed for a number of
cladiellins by a variety of techniques; these studies indicate the R absolute
configuration for each of the six common stereogenic centers. X-ray diffrac-
tion:(a) Reference 14e. CD analyses: (b) Reference 14b. (c) Ochi, M.;
Yamada, K.; Futatsugi, K.; Kotsuki, H.; Shibata, K. Chem. Lett. 1990, 2183–
2186. (d) Ochi, M.; Futatsugi, K.; Kume, Y.; Kotsuki, H.; Asao, K.; Shibata, K.
Chem. Lett. 1988, 1661–1662. NMR experiments: (e) Yamada, K.; Ogata, N.;
Ryu, K.; Miyamoto, T.; Komori, T.; Higuchi, R. J. Nat. Prod. 1997, 60, 393–396.
(f) Ortega, M. J.; Zubía, E.; Salva, J. J. Nat. Prod. 1994, 57, 1584–1586. The
opposite absolute configuration has been suggested for one cladiellin as a result of
a potentially problematic Horeau analysis: (g) Bowden, B. F.; Coll, J. C.; Dai, M.
C. Aust. J. Chem. 1989, 42, 665–673.
€
J.; Schonholzer, P. Tetrahedron Lett. 1977, 18, 4643–4646.
J. Org. Chem. Vol. 74, No. 15, 2009 5459

Corminboeuf et al.
SCHEME 1. Unified Plan for Synthesis of Cladiellin and
Briarellin Diterpenes
JOCArticle
FIGURE 2. Cladiellin and briarellin diterpene total synthesis tar-
gets of the Overman group.
accomplished by the Molander,18 Crimmins,19a,19c Clark,20b
Hoppe,20a and Kim21 groups.
Additionally, our total synthesis studies16b-16e and those of
Paquette16c,17,23 led to the structure reassignment of several
cladiellins. The challenges these complex molecules pose for
structure elucidation are further highlighted by the efforts of
Three cladiellin diterpenes and most briarellin and asbes-
tinin diterpenes contain additional oxygen substitution at C4
of the oxacyclononane ring.12,13 To address the unmet
synthesis challenges posed by this C4 functionalization,
and the additional oxepane ring found in the briarellins
and asbestinins, we undertook the total synthesis of alcyonin
(originally proposed structure 10)27 and briarellins E (12)
and F (13).28 A full description of these studies, which led to a
revised structure assignment for alcyonin (11)16e and the first
total syntheses of briarellin diterpenes (12 and 13), is the
subject of this report.16f Subsequent to the completion of
these studies, incisive inaugural total syntheses of asbestinin
diterpenes,19b,19d 11-acetoxy-4-deoxyasbestinin D (2)29 and
asbestinin-12 (3),9b were reported by Ellis and Crimmins.
ꢀ
natural products researchers: in 1995, Rodrıguez and Cobar
´
disclosed their originally proposed structure of briarellin A and
several congeners;10a eight years later, after reexamination of its
spectral data and comparison with data obtained for newly
isolated briarellins, these workers revised their structure assign-
ment for briarellin A to allylic peroxide 4.10b Analysis of new
data also led recently to revisions of the structure assignment of
four asbestinin diterpenes.13b
This group of C2-C11-cyclized cembranoid diterpenes
has been the subject of numerous synthetic investigations
over many years.24 The enantioselective total synthesis of 6-
acetoxycladiell-7(16),11-dien-3-ol (6),25 reported in 1995 by
MacMillan and Overman,16a was the first total synthesis
accomplishment in this area (Figure 2). Subsequently, in-
dependent total syntheses of the originally proposed struc-
ture of sclerophytin A (7)26 by Paquette17a and our
laboratory16b prompted revision of the structure assignment
of this cladiellin diterpene.23a By photochemical isomeriza-
tion of the endocyclic alkene of cladiell-11-ene-3,6,7-triol
(8),14d another cladiellin diterpene synthesized in our labora-
tory, we were able to confirm the revised structure assign-
ment for sclerophytin A (9)16c proposed by Paquette and co-
workers;23a this group also completed a total synthesis of
diterpene 9 by a different approach.16c More recently, total
syntheses of additional cladiellin diterpenes have been
Results and Discussion
In our third-generation synthesis approach to the C2-
C11-cyclized cembranoid diterpenes,16d we envisioned diter-
penes 6-13 arising from a common intermediate, cis-3,4-
epoxy alcohol 15 (Scheme 1). Elaboration of precursors of
this type by regio- and stereoselective opening of the epoxide
functionality with either hydride or oxygen nucleophiles
should afford 14 (X = H or OR), which would possess the
requisite C3-C4 substitution pattern present in 6-13. If the
C14 side chain of intermediate 14 is an isopropyl group (R =
H), we could target cladiellins, whereas a (S)-1-methyl-2-
hydroxyethyl side chain (R = OH) would allow access to the
briarellins. A logical precursor to cis-3,4-epoxy alcohol 15 is Z
alkene 16, which we anticipated could arise from acid-cata-
lyzed Prins-pinacol condensation7d of a (Z)-R,β-unsaturated
(23) (a) Friedrich, D.; Doskotch, R. W.; Paquette, L. A. Org. Lett. 2000,
2, 1879–1882. (b) Paquette, L. A. Chem. Record 2001, 1, 311–320. (c)
Friedrich, D.; Paquette, L. A. J. Nat. Prod. 2002, 65, 126–130.
(24) For a comprehensive review, see: Ellis, J. M.; Crimmins, M. T.
Chem. Rev. 2008, 108, 5278–5298.
(27) Kusumi, T.; Uchida, H.; Ishitsuka, M. O.; Yamamoto, H.; Kakisawa,
H. Chem. Lett. 1988, 1077–1078.
ꢀ
´
guez, A. D.; Cobar, O. M. Chem. Pharm. Bull. 1995, 43, 1853–
(25) Uchio, Y.; Kodama, M.; Usui, S.; Fukazawa, Y. Tetrahedron Lett.
1992, 33, 1317–1320.
(26) Sharma, P.; Alam, M. J. Chem. Soc., Perkin Trans. 1 1988, 2537–
2540.
(28) Rodrı
1858.
(29) Morales, J. J.; Lorenzo, D.; Rodrı
1368–1382.
´
guez, A. D. J. Nat. Prod. 1991, 54,
5460 J. Org. Chem. Vol. 74, No. 15, 2009

Corminboeuf et al.
JOCArticle
SCHEME 2. Epoxy Ester Rearrangement and Confirmation of
the Relative Configuration at C3 and C4
epoxide of intermediate 21 and alcohol-protected congeners
with exogenous oxygen nucleophiles failed, we acetylated the
hydroxyl group of 21 to afford epoxy ester 22. Employing the
method of Giner,31 epoxy ester 22 was treated sequentially
with trifluoroacetic acid to effect internal opening of the
epoxide (A f B) and H2O, unraveling intermediate B to give
a mixture of primary and secondary acetates. Analysis of the
unpurified product by 1H NMR revealed that ring-opening
of the epoxide had occurred with high regio- and stereo-
selectivity, as no trace of other isomers was seen. Reduction
of this crude mixture of acetates with LiAlH4 gave triol 23.
Standard acetylation of this intermediate at room tempera-
ture afforded diacetate 24. Alternatively, triol 23 could be
elaborated to crystalline carbonate derivative 25 by sequen-
tial treatment with pivaloyl chloride and triphosgene. Single-
crystal X-ray analysis of 1,3-dioxolan-2-one 25 corroborated
its structure,32 rigorously establishing the relative configura-
tion at C3 and C4, which we had assigned initially on the
basis of precedent31 and the mechanistic considerations
depicted in Scheme 2.
As the proposed structure 10 of alcyonin has an acetyl
group at C4, we initially tried to advance diacetate 24 to
intermediate 26 as a prelude to closing the oxacyclononane
ring by Nozaki-Hiyama-Kishi cyclization (eq 1).16d,33
However, we were never able to elaborate the delicate γ-
hydroxy-β-acetoxyaldehyde functionality.
In an alternative approach, we saw the dioxolanone unit of
25 serving as a late-stage progenitor of the C3 hydroxy and C4
acetoxy substituents of 10 because the related conversion of a
dioxolane fragment to a hydroxy benzoate had been reported
with a derivative of Taxol.34 However, the lability of inter-
mediates derived from 25 eventually demanded recourse to a
lengthier sequence to arrive at a viable precursor for forming
the oxacyclononane ring (Scheme 3). Thus, triol 23 was
selectively protected by sequential reaction with pivaloyl
chloride and TBDMSOTf to yield protected triol 28. Using
a sequence introduced by Suzuki,35 alkyne 28 was iodobo-
rated by reaction with B-iodo-9-borabicyclo[3.3.1]nonane
(B-I-9-BBN) in hexane,36 and the resulting vinyl borane
intermediate was protonolyzed by the addition of acetic acid
at -78 °C. Oxidative workup with sodium perborate37 then
provided vinyl iodide intermediate 29 in 80% yield. Yields of
the iodoboration step were higher when hexane, rather than
the more commonly used solvent CH2Cl2,35 was employed.
aldehyde 17 and an alkynyl dienyl diol 18. If successful, this
transformation would deliver the hexahydroisobenzofuran core
and five stereocenters of these coral metabolites. Alkynyl dienyl
diol 18 was expected to arise from (S)-(þ)-carvone (19) and
(S)-(-)-glycidol (20). We have previously described the evolu-
tion and successful implementation of this approach for the
total synthesis of cladiellins 6-9 that lack substitution at C4.16d
Herein, we discuss the ultimate fruition of this unified strategy
toward C2-C11-cyclized cembranoid diterpenes having an
acyloxy substituent at C4, specifically the originally proposed
structure 10 of alcyonin and briarellins E (12) and F (13).30
Enantioselective Total Synthesis of the Originally Pur-
ported Structure 10 of Alcyonin. To explore the prospects
for accessing cladiellins and briarellins bearing oxygenation
at C4, we chose alcyonin as our initial total synthesis target.27
This marine metabolite was reported by Kakisawa and co-
workers in 1988 from specimens of the soft coral Sinularia
flexibilis found in waters off Okinawa. On the basis of
spectroscopic data, augmented by some chemical transfor-
mations, structure 10 was proposed for alcyonin (Figure 2).27
The starting point for our total synthesis effort was the
known cis-3,4-epoxy alcohol 21, which is available in nine
steps and 14% overall yield from (S)-dihydrocarvone
(Scheme 2).16b,16d After a number of attempts to open the
(31) Faraldos, J. A.; Giner, J.-L. J. Org. Chem. 2002, 67, 4659–4666.
(32) Crystal structures have been deposited at the Cambridge Cystallo-
graphic Data Centre: (a) Cyclic carbonate 25: CCDC 718037. (b) Diols 36a
and 36b: CCDC 718038 and 718039.
€
(33) For a review, see: Furstner, A. Chem. Rev. 1999, 99, 991–1045.
(34) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. J. Chem. Soc.,
Chem. Commun. 1994, 295–296.
(35) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett. 1983,
24, 731–734.
(36) Brown, H. C.; Kulkarni, S. U. J. Organomet. Chem. 1979, 168, 281–
293.
(37) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem.
1989, 54, 5930–5933.
(30) For preliminary reports of these syntheses, see refs 16e and 16f.
J. Org. Chem. Vol. 74, No. 15, 2009 5461

Corminboeuf et al.
JOCArticle
SCHEME 3. Completion of the Total Synthesis of the Origin-
ally Proposed Structure 10 of Alcyonin
To complete the total synthesis of structure 10, the silyl
protecting groups of 31 were discharged by reaction with n-
Bu4NF at room temperature, a process that was likely
facilitated by 1,2-migration of the TBDMS group of the
tertiary siloxy substituent. Finally, selective acetylation of
the C4 alcohol of 32 by reaction in pyridine at 0 °C with
excess acetic anhydride and a catalytic amount of 4-(N,N-
dimethylamino)pyridine (DMAP) delivered 10, the pur-
ported structure of alcyonin in good yield. The selectivity
observed in acetylation of the C4 alcohol is consistent with
the expected low-energy conformation of triol 32. Computa-
tional modeling39 of this triol suggests that its nine-mem-
bered ring adopts the same conformation as observed for this
ring in both the X-ray model and computational models of 6-
acetoxycladiell-7(16),11-dien-3-ol (6).16d This conformation
projects the C4 alcohol away from the ring in a sterically
unencumbered environment.
Revision of the Structure Assignment for Natural Alcyonin.
The structure of 10 was fully supported by NMR and mass
spectral data. For example, the position of the acetate
substituent of this product was evident from the diagnostic
1H NMR chemical shifts of H4 (δ 4.99) and H6 (δ 4.17).
However, the NMR data of synthetic 10 did not match those
reported for natural alcyonin.27 A comparison of the NMR
data for 10, 6-acetoxycladiell-7(16),11-dien-3-ol (6),16a,25
natural alcyonin,27 and several structurally related cladiel-
lins,40 showed that the acetate functionality of alcyonin did
not reside at C6.
Unfortunately, a sample of natural alcyonin is no longer
available;41 however, reexamination of the published NMR
data of natural alcyonin reveals that the signal at δ 4.76,
assigned to H6 of the S. flexibilis isolate, is downfield by 0.3-
0.4 ppm from signals for this hydrogen in other cladiell-7
(16),11-diene-3,6-diols as is the absorption for C6; for ex-
ample the C6 methine hydrogen of cladiellisin (33) is ob-
served at δ 4.40 (Figure 3).40 Furthermore, no signal for the
hydrogen of the putative allylic hydroxyl group was re-
ported,27 nor is such a signal found in the 1H NMR spectrum
of natural alcyonin. However, a distinct signal at δ 8.0,
1
corresponding to one hydrogen, is clearly visible in the H
NMR obtained in the Kakizawa group (Figure 4).41
We conclude that the actual structure of alcyonin is allylic
hydroperoxide 11 (Figure 3). Strong support for this propo-
1
sal comes from the H and 13C NMR data reported for
The pivaloyl group of 29 was cleaved with i-Bu2AlH, and the
resulting primary alcohol was oxidized with Dess-Martin
periodinane (DMP)38 to give vinyl iodide aldehyde 30 in
excellent yield for the two-step sequence.
cladiellisin (33)40a and cladiellaperoxide (34).42 The molecu-
lar masses of structures 10 (MW = 378) and 11 (MW = 394)
are obviously different. Nonetheless, the mass spectral data
As in our previous syntheses of cladiellins 6-9 lacking
oxygen substituents at C4, the oxacyclononane ring of 10
was successfully forged by Nozaki-Hiyama-Kishi cycliza-
tion.16d,33 Using reaction conditions identical to those em-
ployed previously,16d vinyl iodide aldehyde 30 was converted
to oxatricyclic intermediate 31 in good yield (Scheme 3).
Analysis of the crude product by 1H NMR revealed that this
cyclization occurred with exquisite stereoselection: only one
allylic alcohol epimer was detected. Based on our previous
modeling studies,16d we postulate that the observed product
31 in this instance arises from the plausible four-centered
assembly C, which minimizes transannular and eclipsing
interactions in the incipient nine-membered ring.
(39) Conformer distribution searching using Spartan 06 and the Merck
Molecular Force Field.
(40) (a) Cladiellisin (33): H6 δ 4.40, C6 δ 72.9: Liu, J.; Zeng, L.; Wu, D.
Chin. Sci. Bull. 1992, 37, 1627–1630. (b) Cladiell-7(16),11(17)-diene-3,6-diol:
H6 δ 4.40, C6 δ 77.5: Sreenivasa Rao, D.; Sreedhara, C.; Venkata Rao, D.;
Bheemasankara Rao, C. Ind. J. Chem., Sect. B 1994, 33B, 198–199.
(c) 3-Acetoxycladiell-7(16),11(17)-dien-6-ol: H6 δ 4.39, C6 δ 72.2:
Bheemasankara Rao, C.; Sreenivasa Rao, D.; Satyanarayana, C.;
€
Venkata Rao, D.; Kassuhlke, K. E.; Faulkner, D. J. J. Nat. Prod. 1994,
57, 574–580. (d) Palomine F: H6 δ 4.29, C6 δ 73.7: Ortega, M. J.; Zubıa, E.;
´
ꢀ
Salva, J. J. Nat. Prod. 1994, 57, 1584–1586.
(41) Copies of 1H and 13C NMR spectra of natural alcyonin and tetra-
cyclic hemiacetal 35 formed from alcyonin upon attempted benzoylation were
kindly provided by Prof. T. Kusumi of the University of Tokushima,
Japan.
(42) (a) Yamada, K.; Ogata, N.; Ryu, K.; Miyamoto, T.; Komori, T.;
Higuchi, R. J. Nat. Prod. 1997, 60, 393–396. (b) These investigators demon-
strated that 34 is reduced to 33 using NaBH4.
(38) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
5462 J. Org. Chem. Vol. 74, No. 15, 2009

Corminboeuf et al.
JOCArticle
SCHEME 4. Conversion of 10 and 11 to Hemiacetal 35
FIGURE 3. Diagnostic NMR data for synthetic 10, natural alcyo-
nin (11), cladiellisin (33), and cladiellaperoxide (34).
Enantioselective Total Synthesis of Briarellin E (12) and
Briarellin F (13). Having established that we could efficiently
access cladiellins containing a hydroxyl substituent at C4, we
desired to extend our approach to the total synthesis of the
more complex briarellin diterpenes.28 Like most briarellin
diterpenes,45 briarellins E (12) and F (13) were isolated by
FIGURE 4. 1H NMR spectrum of natural alcyonin.
reported for natural alcyonin (m/e 378.2403)27 could be
consistent with the newly proposed structure, as electrospray
or FAB ionization is often required to observe the molecular
ion of an alkyl hydroperoxide.43
Rodrıguez and co-workers from Caribbean gorgonian octo-
´
cocorals belonging to the genus Briareum (Figure 2).10,28 The
constitution and relative configuration of these coral meta-
bolites were established on the basis of NMR studies and
chemical correlations.
Additionally, chemical transformations reported for nat-
ural alcyonin coincide better with the revised structure
assignment 11. It was reported that attempted benzoylation
of alcyonin afforded tetracyclic hemiacetal 35 rather than the
expected C6 benzoate, an outcome that was ascribed to air
oxidation of the putative allylic alcohol (Scheme 4).27 How-
ever, numerous reports have documented the successful
acylation of 6-hydroxy cladiell-7(16),11-dienes.16d,44
Furthermore, we have never observed air oxidation of 10
or related structures.16 However, if alcyonin were indeed
hydroperoxide 11, the formation of 35 upon attempted
benzoylation is the anticipated outcome, as the benzoyl
peroxide intermediate D would be expected to fragment to
the C6 keto derivative E in the presence of triethylamine. The
constitutional relationship of our synthetic product 10 and
natural alcyonin was confirmed by oxidation of synthetic 10
with Dess-Martin periodinane (DMP)38 to form hemiacetal
35. The NMR and mass spectrometric data of this product
were indistinguishable from those of 35 derived from natural
alcyonin.27,41
The briarellin diterpenes contain a number of structural
features that pose additional challenges for synthesis. Be-
sides the hexahydroisobenzofuran core and oxacyclononane
ring found in cladiellins 6-11, briarellins E (12) and F (13)
possess an oxepane ring arising from etherification between
C3 and C19, a methyl-substituted stereocenter at C15, and a
tertiary hydroxyl group at C11. We envisioned that briar-
ellins 12 and 13 could arise from intermediate 14 depicted in
Scheme 1, wherein R and X would be hydroxyl groups or
appropriately protected variants. The proper choice of
orthogonal protecting groups for the primary alcohol func-
tionality of the precursor aldehyde 17 and cyclohexadienyl
diol 18 (R = OP) in Scheme 1 likely would be important for
the success and efficiency of this strategy.
These syntheses began by installing the C15 stereocenter
starting from (S)-(þ)-carvone (19). Reaction of 19 with 2.2
equiv of 9-borabicyclo[3.3.1]nonane (9-BBN), followed by
oxidation of the derived organoborane with basic hydrogen
peroxide, afforded diol 36 as a ∼1:1 mixture of methyl
epimers in 73% yield (Scheme 5).46 Resolution of diol
(43) (a) Schwarz, H.; Schiebel, H. M. In The Chemistry of Peroxides;
Patai, S., Ed.; Wiley: New York, 1983; p 279. (b) These ionization techniques
were not widely used in 1988 when the structure of natural alcyonin was originally
determined.
(44) See, inter alia: (a) Reference 14b. (b) Ochi, M.; Yamada, K.;
Futatsugi, K.; Kotsuki, H.; Shibata, K. Heterocycles 1991, 32, 29–32.
(c) In our laboratory, 10 was readily acetylated.
(45) The only exceptions are the pachyclavulariaenones; see refs 11 and
13g,13h.
(46) (a) de Pascual, T.; Mateos, A. F.; Gonzalez, R. R. Tetrahedron Lett.
1982, 23, 3405–3406. (b) The stereoselectivity of this process was not
described previously.
J. Org. Chem. Vol. 74, No. 15, 2009 5463

Corminboeuf et al.
JOCArticle
SCHEME 5. Installation of the C15 Stereocenter from (S)-(þ)-
was also examined. Again, diastereoselection was unsatis-
factory.
Carvone (19)
With the C15 stereocenter of the briarellins in place, we
turned to elaborating diol 36b to an appropriate precursor
for the critical the Prins-pinacol reaction. Selective protec-
tion of the primary alcohol of 36b with a triisopropylsilyl
group (TIPS), followed by oxidation of the secondary alco-
hol with pyridinium chlorochromate (PCC) in the presence
of sodium acetate (NaOAc)53 provided enone 40 in high yield
(Scheme 6). Transformation of 40 to its derived kinetic enol
triflate54 using LDA and 2-[N,N-bis(trifluoromethylsulfo-
nyl)amino]-5-chloropyridine (Comins’ reagent),55 followed
by palladium-catalyzed coupling with (Me3Sn)256 and in situ
iodination of the resulting vinylstannane with N-iodosucci-
nimide (NIS)57 delivered cyclohexadienyl iodide 41.58 Cou-
pling of R-alkoxy aldehyde 4216d with the dienyllithium
species generated from 41, followed by removal of the
1-methyl-1-methoxyethyl protecting group gave cyclohexa-
dienyl diol 43 in 62% yield as an inconsequential 3:1 mixture
of allylic alcohol epimers.59
Our efforts turned to the assembly of the hexahydroiso-
benzofuran core of briarellins E (12) and F (13) along the
lines we had developed previously in our syntheses of
cladiellins 6-11.16d Wittig reaction of 3-(tert-butyldiphenyl-
siloxy)propanal 4460 with iodophosphorane 4561 afforded
Z vinyl iodide 46 in 47% yield (Scheme 7).62 We chose the
tert-butyldiphenylsilyl (TBDPS) ether63 as the side-chain
protecting group with the expectation that it would tolerate
the acidic conditions used in the Prins-pinacol condensa-
tion-rearrangement sequence and could be selectively
cleaved in the presence of the C19 TIPS ether at a later
stage.64 Lithium-halogen exchange of 46 with tert-butyl-
lithium, followed by reaction of the resulting vinyllithium
species with N,N-dimethylformamide (DMF) provided
mixture 36 by medium-pressure liquid chromagraphy
(MPLC) on silica gel afforded pure samples of crystalline
diols 36a and 36b, the relative configurations of which
were secured by single-crystal X-ray analysis.32 Diol 36b
possesses the configuration at C15 found in briarellin
diterpenes. Because diol mixture 36 was difficult to resolve
chromatographically on a practical scale, we developed
a stereoselective process for converting (S)-(þ)-carvone to
diol 36b. Thus, chemoselective oxidation of the primary
alcohol of epimer mixture 36 with 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO) and N-chlorosuccinimide
(NCS) using a modification of Einhorn’s procedure47 gave
bicyclic lactone 37, a 1:1 mixture of methyl epimers, in 79%
yield.48-50 The silyl ketene acetal derivative of lactone 37
was generated by sequential treatment with lithium diiso-
propylamide (LDA) and trimethylsilyl chloride (TMSCl).
Protonation of this intermediate with acetic acid at 0 °C
took place with high stereoselectivity from the less hindered
face.51 Reduction of the crude lactone product with LiAlH4
then delivered diol 36b in 78% overall yield after recrystal-
lization.51
Several alternate approaches for securing pure samples
of diol 36a from intermediates generated from (S)-(þ)-
carvone were also examined. As methyl epimers of
an intermediate generated by hydroboration of limonene
had been separated using Amano PS lipase,52 we examined
acetylation of 38 with isopentenyl acetate using this
enzyme. However, diastereoselection was found to be
low (∼2:1) in diisopropyl ether, both with and without
added H2O. In a more speculative approach, hydrobora-
tion of diene ketal 39 with 9-borabicyclo[3.3.1]nonane
(53) Patel, D. V.; VanMiddlesworth, F.; Donaubauer, J.; Gannett, P.;
Sih, C. J. J. Am. Chem. Soc. 1986, 108, 4603–4614.
(54) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979–982.
(55) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.
(56) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K.
L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org.
Chem. 1986, 51, 277–279.
(57) Seyferth, D. J. Am. Chem. Soc. 1957, 79, 2133–2136.
(58) A trace of cyclohexadienyl side product was removed by flash
chromatography on AgNO3-impregnated silica gel.
(59) The major epimer is assigned the anti configuration (resulting from
Felkin-Ahn addition) by analogy to similar couplings in our syntheses of
cladiellins; see ref 16d.
(60) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.;
Somfai, P.; Whritenour, D. C.; Masamune, S.; Kageyama, M.; Tadashi, T. J.
Org. Chem. 1989, 54, 2817–2825.
(47) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem.
1996, 61, 7452–7454.
(48) Because of the insolubility of the diol mixture in the typical solvent
CH2Cl2, CHCl3 was used as the solvent in this oxidation.
(61) Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827–2828.
(62) (a) For a discussion of the Z selectivity of Wittig reactions with R-
iodophosphoranes, see:Arimoto, H.; Kaufman, M. D.; Kobayashi, K.; Qiu,
Y.; Smith, A. B. Synlett 1998, 765–767. (b) The minor E vinyl iodide isomer
(∼5%) formed in this instance was removed by flash chromatography on
AgNO3-impregnated silica gel prior to the next step of the reaction sequence.
(63) Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975–2977.
(64) For useful reviews of silyl ether protecting groups, see: (a) Crouch,
R. D. Tetrahedron 2004, 60, 5833–5871. (b) Nelson, T. D.; Crouch, R. D.
Synthesis 1996, 1031–1069.
(49) The enantiomer of lactone 37 had previously been prepared in four
steps from (R)-(þ)-limonene.50 The optical rotation of 37 ([R]23D -235, c 1.2,
CHCl3) is equal in magnitude to that reported ([R]23D þ226, c 1.1, CHCl3).
ꢀ
(50) Frater, G. Helv. Chim. Acta 1979, 62, 641–643.
(51) Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem. 1988, 53, 1584–
1586.
(52) Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777–
12782.
5464 J. Org. Chem. Vol. 74, No. 15, 2009

Corminboeuf et al.
JOCArticle
SCHEME 6. Preparation of Cyclohexadienyl Diol 43
SCHEME 7. Preparation of Hexahydroisobenzofuran Inter-
mediate 52
isomerically pure (Z)-R,β-unsaturated aldehyde 47 in high
yield.65 Condensation of this aldehyde and cyclohexadienyl
diol 43 at -20 °C in the presence of p-toluenesulfonic acid
(TsOH) and MgSO4 provided the corresponding acetal,66
which was exposed to 10 mol % of SnCl4 at -78 °C to room
temperature to give formyl tetrahydroisobenzofuran 48 as a
single stereoisomer in excellent yield for the two-step se-
quence.67 The critical Prins-pinacol conversion was readily
scaled, with 84% yield being realized in runs that provided
up to 3 g of formyl tetrahydroisobenzofuran product 48.
Stereospecific photolytic deformylation of 48,68 followed by
selective cleavage of the TBDPS and TMS protecting groups
with aqueous KOH yielded homoallylic alcohol 49 in mod-
erate yield for the two steps.64,69 Hydroxyl-mediated epox-
idation of this intermediate with (t-BuO)3Al/t-BuO2H70
afforded cis-3,4-epoxy alcohol 50 in 79% yield.71 Stereose-
lection in this transformation was 10:1, which is readily
rationalized by epoxidation occurring by way of conformer
F, in which the side chain is oriented to minimize destabiliz-
ing A1,3 interactions.16d Acetylation of alcohol 50, followed
by sequential reaction of epoxy acetate 51 with trifluoroa-
cetic acid (TFA),31 H2O, and excess Ac2O and catalytic
DMAP provided hydroxy diacetate 52 in 86% yield for the
three-step sequence.
group of intermediate 52 with trifluoromethanesulfonic anhy-
dride (Tf2O) and 2,6-lutidine.72 However, attack of the C19
primary triflate intermediate by the alkene π-bond was pre-
ferred over displacement by the C3 tertiary hydroxyl group.
This result necessitated functionalization of the double bond
prior to oxepane formation (Scheme 8). Epoxidation of hex-
ahydroisobenzofuran intermediate 52 with m-chloroperoxy-
benzoic acid (m-CPBA) at 0 °C proceeded with 10:1
stereoselectivity from the R-face to deliver epoxide 53 in 77%
The stage was set to complete the assembly of the dioxa-
tricyclic moiety of briarellins E (12) and F (13). In early
scouting experiments, we attempted to form the oxepane ring
by reaction of the diol resulting from cleavage of the TIPS
1
yield.73 Diagnostic H NOE enhancements between the C11
methyl substituent and the C10 and C12 methine hydrogens
signaled the relative configuration of this product. Stereoselec-
tion in forming epoxide 53 is believed to result from oxidation
taking place via cis-hexahydroisobenzofuran conformer G
wherein the 1-methyl-2-siloxyethyl substituent adopts a pseu-
doaxial orientation to avoid a syn-pentane interaction with the
(65) The Z configuration of enal 47 was established by NOE difference
experiments; see also ref 16d.
(66) This acetal was an inconsequential mixture of four diastereomers.
(67) The Z configuration of the TBDPS-protected 1-methyl-4-hydroxy-
1-butenyl side chain of 48 was confirmed by NOE difference experiments; see
also ref 16d.
(68) Baggiolini, E.; Hamlow, H. P.; Schaffner, K. J. Am. Chem. Soc.
1970, 92, 4906–4921.
(69) The tetrasubstituted alkene regioisomer (∼10%) formed in the
deformylation step was removed by flash chromatography on silica gel.
(70) Takai, K.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1983, 56,
3791–3795.
(72) Trost, B. M.; Greenspan, P. D.; Geissler, H.; Kim, J. H.; Greeves, N.
Angew. Chem., Int. Ed. 1994, 33, 2182–2184.
(73) The minor epoxide stereoisomer (∼10% yield) was removed by flash
chromatography on silica gel and fully characterized (see the Supporting
Information).
(71) The minor epoxide stereoisomer (∼10%) was removed by flash
chromatography on silica gel.
J. Org. Chem. Vol. 74, No. 15, 2009 5465

Corminboeuf et al.
SCHEME 9. Synthesis of Tricyclic Hydroxy Diester 58
JOCArticle
SCHEME 8. Stereoselective Epoxidation and Formation of the
Oxepane Ring
C2 side chain, thereby shielding the convex β-face (Scheme 8).
Removal of the TIPS protecting group of 53 with n-Bu4NF
gave diol 54. Exposure of this intermediate to Tf2O and 2,6-
lutidine72 delivered dioxatricycle 55 after 4 days at room
temperature in yields ranging from 55-68%. Under these
conditions, the ratio of intramolecular etherification to elim-
ination was ∼6:1 (1H NMR analysis). Attempts to accelerate
this process by heating the reaction led to a greater proportion
of the propylidene byproduct arising from elimination of the
primary triflate intermediate.
membered ring. The iodoboration/protonolysis sequence we
had employed in our synthesis of the putative structure of
alcyonin and in our earlier cladiellin diterpene total synth-
eses,16 promoted elimination of the tertiary alcohol func-
tionality of 58. Palladium-catalyzed hydrostannylation/
iodination75 and stannylcupration/protonolysis76 proceeded
with low regioselectivity (eq 2). Also unsuccessful was hydro-
stannylation catalyzed by Wilkinson’s catalyst77 and R-
stannylation by reaction with a di-n-butyliodotin hydride
ate complex.78 Successful regioselective functionalization of
the terminal alkyne functionality of intermediate 58 was finally
realized using a stannylalumination/protonolysis sequence
reported by Oehlschlager (Scheme 10).79 Thus, CuCN-cata-
lyzed addition of Bu3SnAlEt2 to alkyne 58 at -30 °C, followed
by quenching with aqueous NH4Cl, cleanly generated the
internal vinylstannane regioisomer, which was directly iodi-
nated to provide vinyl iodide 59 in 66% overall yield.
With the dioxatricyclic ring system and eight of the nine
stereocenters common to 12 and 13 in place, we turned to
elaboration of the cyclohexane ring and the side chains of
intermediate 55 in preparation for forming the final oxacy-
clononane ring. Regio- and stereoselective hydration of the
epoxide of 55 with dilute aqueous H2SO4 gave diol 56 in 80%
yield (Scheme 9). Introduction of the C11 tertiary alcohol
with the required R configuration in this step results from the
tertiary carbenium ion H produced by SN1 opening of the
epoxide being trapped by water from the less-congested,
convex β-face. Low-temperature mesylation of the second-
ary alcohol of diol 56, followed by in situ reduction with
LiAlH4 removed the extraneous hydroxyl substituent at C12
and the two acetate protecting groups to generate triol 57 in
high yield. The β C11,C12 epoxide was an observable inter-
mediate in this sequence. The relative configuration of the
1
tertiary alcohol stereocenter of 57 was established by H
NMR NOE experiments, with a strong NOE between the
C11 methyl substituent and the C9 methine hydrogen being
particularly diagnostic. Selective acetylation of the primary
alcohol of triol 57 upon reaction with isopropenyl acetate
and Bu8Sn4Cl4O2,74 followed by appendage of the octanoyl
side chain gave tricyclic hydroxy diester intermediate 58.
One of the more challenging transformations encountered
in our efforts to extend our existing chemistry to the pre-
paration of briarellins E (12) and F (13) was elaboration of
the 2-propynyl side chain of intermediate 58 to a 2-iodo-2-
propenyl group in preparation for closing the final nine-
(75) For a review of metal-catalyzed hydrostannylation, see: Smith, N.
D.; Mancuso, J.; Lautens, M. Chem. Rev. 2000, 100, 3257–3282.
(76) Piers, E.; Chong, J. M. J. Chem. Soc., Chem. Commun. 1983, 934–935.
(77) Kikukawa, K.; Umekawa, H.; Wada, F.; Matsuda, T. Chem. Lett.
1988, 881–883.
(78) Shibata, I.; Suwa, T.; Ryu, K.; Baba, A. J. Am. Chem. Soc. 2001, 123,
4101–4102.
(79) Sharma, S.; Oehlschlager, A. C. J. Org. Chem. 1989, 54, 5064–5073.
(74) Orita, A.; Sakamoto, K.; Hamada, Y.; Mitsutome, A.; Otera, J.
Tetrahedron 1999, 55, 2899–2910.
5466 J. Org. Chem. Vol. 74, No. 15, 2009

Corminboeuf et al.
JOCArticle
The total synthesis of briarellin E (12) was completed in
three steps from vinyl iodide intermediate 59 as summarized
in Scheme 10. Selective removal of the acetate protecting
group of 59 using (t-Bu)2(OH)ClSn/MeOH80 and oxidation
of the resulting primary alcohol with Dess-Martin period-
inane38 gave vinyl iodide aldehyde 60 in 74% overall yield.
Nozaki-Hiyama-Kishi cyclization33 of this intermediate,
using reaction conditions we had employed in our earlier
syntheses in this area, provided briarellin E (12) in 79% yield.
Cyclization proceeded with high stereoselectivity, with none
SCHEME 10. Completion of the Synthesis of Briarellins E (12)
and F (13)
1
of the allylic alcohol epimer being apparent in H NMR
spectra of the crude reaction product. The mildness of this
chromium-mediated cyclization is showcased in this trans-
formation, as neither the acyloxy group β to the aldehyde nor
the tertiary alcohol was problematic. Finally, Dess-Martin
oxidation of 12 afforded briarellin F (13) in good yield.
Synthetic briarellin E (12) was identical in all respects with
a natural sample;81 spectral and optical rotation data for
briarellin F (13) also compared well with those reported for
the natural isolate.28
Preliminary Examination of Late-Stage Ring-Closing
Methathesis To Form the Oxacyclononane Ring of Briarellin
and Asbestinin Diterpenes. The studies summarized herein
define a useful sequence for assembling the tricyclic core of
briarellin and asbestinin diterpenes. Using these fully func-
tionalized precursors, the nine-membered oxacyclononane
ring of briarellins E (12) and F (13) was readily fashioned by
Nozaki-Hiyama-Kishi cyclization. This cyclization pro-
vides direct access to C2-C11 cyclized cembranoids that
contain a C6 alcohol and Δ7,16 unsaturation and appears less
attractive for the construction of briarellin and asbestinin
diterpenes possessing an internal trisubstituted Δ6,7 double
bond in the oxacyclononane ring.12,13 As a result, we briefly
investigated the possibility of forming of this latter structural
motif at a late stage using ring-closing metathesis (RCM).82
Although one previous attempt to realize this transforma-
tion in the cladiellin series was unsuccessful,83 we hoped that
a combination of the conformational constraints imposed by
the oxepane ring of briarellin and asbestinin diterpenes and
the newer generation RCM catalysts would enable ring
closure.
SCHEME 11. Attempted Late-Stage RCM for Re-forming
11-Acetoxy-4-deoxyasbestinin D
To rapidly explore the feasibility of such an approach, the
Δ6,7 double bond of natural 11-acetoxy-4-deoxyasbestinin D
(2)29,84 was cleaved by sequential treatment with O3 and
Me2S, and the resulting keto aldehyde was exposed to excess
methylenetriphenylphosphine to provide diene 61 in good
yield for the two-step sequence (Scheme 11). Unfortunately,
several attempts85 to effect ring-closing metathesis of dioxa-
tricyclic diene 61 using either the second-generation Grubbs
catalyst (62)86 or the Schrock catalyst (63)87 did not regen-
erate 11-acetoxy-4-deoxyasbestinin D (2).88,89 This result,
which likely derives from the conformational constraints in
tricyclic precursor 61, contrasts with others’ successful ef-
forts to form an oxacyclononane product by ring-closing
metathesis. Crimmins and Ellis’ realized closure of an acyclic
diene with catalyst 62, which was subsequently elaborated
in a multistep sequence to 11-acetoxy-4-deoxyasbestinin
D,19b,19d,29 and Hoppe and co-workers’ effected cyclization
(80) Orita, A.; Hamada, Y.; Nakano, T.; Toyoshima, S.; Otera, J.
Chem.;Eur. J. 2001, 7, 3321–3327.
´ ´
(81) We thank Prof. A. Rodrıguez of the University of Puerto Rico, Rıo
Piedras, for providing a sample of natural briarellin E.
ꢀ
(82) For reviews, see: (a) Gradillas, A.; Perez-Castells, J. Angew. Chem.,
Int. Ed. 2006, 45, 6086–6101. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4490–4527. (c) Deiters, A.; Martin, S. F.
Chem. Rev. 2004, 104, 2199–2238.
(83) Joe, D.; Overman, L. E. Tetrahedron Lett. 1997, 38, 8635–8638.
(84) We thank Prof. A. Rodrıguez of the University of Puerto Rico, Rıo
´ ´
Piedras, for providing a sample of natural 11-acetoxy-4-deoxyasbestinin D.
(85) The limited amount of diene 61 available (∼8 mg) precluded an
extensive investigation of RCM conditions.
(86) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
(88) The only recognized, although not fully characterized, product using
catalyst 62 contained one methylene unit less than anticipated, suggesting
that, as in our earlier study,83 isomerization of the terminal alkene to its
internal isomer89 had preceded ring closure.
(87) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875–3886.
(89) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 8, 5481-
5484 and references therein.
J. Org. Chem. Vol. 74, No. 15, 2009 5467

Corminboeuf et al.
JOCArticle
of a bicyclic diene with catalyst 62, which was later transformed
in several steps to a cladiellin diterpene, (þ)-vigulariol.20a
(500 MHz, CDCl3) δ 5.40-5.39 (m, 1 H), 4.29-4.19 (m, 2 H),
3.89 (ddd, J=4.9, 4.9, 4.9 Hz, 1 H), 3.64 (d, J=8.9 Hz, 1 H), 2.91
(dd, J=9.2, 2.9 Hz, 1 H), 2.62 (ddd, J=16.9, 5.5, 2.6 Hz, 1 H),
2.59-2.54 (m, 1 H), 2.54 (ddd, J=16.9, 4.5, 2.6 Hz, 1 H), 2.46-
2.40 (m, 1 H), 2.13-2.02 (m, 1 H), 2.06 (s, 3 H), 2.05-1.98 (m,
1H), 2.00 (dd, J=2.6 Hz, 1H), 1.97-1.89 (m, 1 H), 1.86-1.77
(m, 1 H), 1.67 (d, J=1.1 Hz, 3 H), 1.66-1.58 (m, 1 H), 1.37 (s, 3
H), 1.28-1.21 (m, 1 H), 0.95 (d, J=6.7 Hz, 3H), 0.87 (d, J=6.7
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 132.4, 120.9,
81.8, 81.4, 80.3, 70.4, 62.4, 61.4, 61.1, 45.7, 42.7, 37.5, 29.2, 28.6,
Conclusions
A unified strategy for the total synthesis of cladiellin and
briarellin diterpenes has been realized (Scheme 1). This
efficient and flexible approach has been shown to be amen-
able to accessing both C4-deoxygenated and C4-oxygenated
cladiellins and briarellins: cladiellin diterpenes 6-11 were
synthesized in 19-21 steps and 1-4% overall yield, and
briarellin diterpenes 12 and 13 were prepared in 30-31 steps
and 0.3-0.4% overall yield, starting from (S)-(þ)-carvone
(19). The defining transformation in this unified approach is
acid-promoted condensation of an (Z)-R,β-unsaturated al-
dehyde with a cyclohexadienyl diol and concomitant Prins-
pinacol rearrangement of the derived (Z)-R,β-unsaturated
oxocarbenium ion, forming with complete stereocontrol the
hexahydroisobenzofuran core of these coral metabolites
(Scheme 1). The oxacyclononane ring of these natural pro-
ducts was forged by diastereoselective Nozaki-Hiyama-
Kishi cyclization, and the oxepane ring of 12 and 13 was
formed by dehydrative cyclization of diol 54.
The viability of this unified strategy was initially verified
by total synthesis of the simpler C4-deoxygenated cladiellins
6-9,16d and in this paper we have documented the extension
of this approach to the putative C4-oxygenated cladiellin 10
and briarellins E (12) and F (13). The enantioselective total
synthesis of the originally proposed structure of alcyonin
(10) and the discrepancy of its spectral data with those
reported for the natural isolate demanded that the structure
assignment for this marine diterpene be revised. Reexamina-
tion of NMR spectra, MS data, and chemical transforma-
tions of natural alcyonin suggest that the structure of this
coral metabolite is allylic peroxide 11. These first total
syntheses of briarellin diterpenes, briarellin E (12) and
briarellin F (13), verified their structure assignments and
established their absolute configurations. The total syntheses
detailed in this account further highlight the power of
pinacol-terminated cationic cyclizations for assembling
complex oxacyclic natural products.7d
26.2, 24.1, 22.1, 21.4, 21.2, 20.5, 18.2; IR (film) 1740 cm-1
;
HRMS (CI) m/z 361.2377 (M þ H, 361.2380 calcd for
C22H32O4).
Following the general method of Giner,31 trifluoroacetic acid
(0.08 mL, 1.0 mmol) was added dropwise to a solution of the
epoxy ester (370 mg, 1.0 mmol) and PhMe (20 mL) at 0 °C. After
2 h, H2O (20 mL, 1.1 mol) was added, and the resulting mixture
was stirred for 1.5 h and then quenched with saturated aqueous
NaHCO3 (15 mL). Ethyl acetate (50 mL) was added, the layers
were separated, the aqueous layer was washed with ethyl acetate
(2 ꢀ 50 mL), and the combined organic extracts were dried
(Na2SO4), filtered, and concentrated. A THF solution of
LiAlH4 (3.4 mL of a 1.0 M solution, 3.4 mmol) was added
dropwise to a solution of this mixture of crude acetoxy diols and
THF (10 mL) at rt. After 45 min, the reaction mixture was
cooled to 0 °C and treated dropwise with Rochelles’s salt (30
mL), stirred for 1 h at rt, and extracted with ethyl acetate (100
mL). The organic extract was washed brine (100 mL), dried
(Na2SO4), filtered, and concentrated to afford pure 23, 330 mg
(95%, two steps), as a clear yellow oil: [R]23D þ7.7, [R]23577 þ7.9,
1
[R]23 þ8.5, [R]23 þ13.1, [R]23 þ14.8 (c 1.0, CHCl3); H
546
435
405
NMR (500 MHz, CDCl3) δ 5.53-5.49 (m, 1 H), 4.03-4.00 (m, 1
H), 3.92 (d, J=3.5 Hz, 1H), 3.89-3.85 (m, 3 H), 3.68 (s, 1 H),
3.08 (s, 1 H), 2.99-2.97 (m, 1 H), 2.78 (ddd, J=17.3, 3.9, 2.6 Hz,
1 H), 2.72-2.66 (m, 1 H), 2.56 (ddd, J=17.3, 4.2, 2.6 Hz, 1 H),
2.41 (ddd, J=10.7, 7.6, 3.5, Hz, 1 H), 2.02-1.93 (m, 1 H), 1.92-
1.83 (m, 1 H), 1.80-1.67 (m, 3H), 1.69 (d, J=1.5 Hz, 3 H), 1.47-
1.33 (m, 1 H), 1.25 (dd, J=7.0, 1 H), 1.04 (s, 3 H), 0.96 (d, J=7.0
Hz, 3H), 0.79 (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
130.3, 123.6, 87.4, 81.0, 80.5, 76.6, 75.7, 72.0, 61.8, 46.7, 41.7,
39.4, 32.9, 27.6, 25.1, 23.6, 22.6, 22.2, 18.6, 17.1; IR (film) 3420,
3310 cm-1; HRMS (CI) m/z 337.2367 (M þ H, 337.2380 calcd
for C20H32O4).
Acetic Acid (6R,7R,8R,9R,12S,14S,15R,16R)-9,12-Dihy-
droxy-6-isopropyl-3,9-dimethyl-13-methylene-15-oxatricyclo
[6.6.1.00,0]pentadec-3-en-10-yl Ester (10). A solution of the triol
32 (8.0 mg, 0.024 mmol), dry pyridine (0.3 mL), and 4-(N,N-
dimethylamino)pyridine (1.0 mg, 0.01 mmol) at 0 °C was treated
with acetic anhydride until TLC analysis (70:30 hexane-ethyl
acetate) showed complete consumption of the starting material.
Saturated aqueous NH4Cl (5.0 mL) was then added, the aqu-
eous layer was extracted with ethyl acetate (3ꢀ5.0 mL), and the
combined organic extracts were washed sequentially with satu-
rated aqueous CuSO4 (2ꢀ10 mL) and brine (2ꢀ10 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified
by flash chromatography on silica gel (70:30 hexane-ethyl
acetate) to give 6.0 mg (68%) of 10 as a clear colorless oil:
Experimental Section90
(3R,4R)-Dihydroxy-4-(1R,3R,3aR,7R,7aR)-(7-isopropyl-4-
methyl-3-prop-2-ynyl-1,3,3a,6,7,7a-hexahydroisobenzofuran-
1-yl)pentyl alcohol (23). 4-(N,N-Dimethylamino)pyridine (12 mg,
0.11 mmol) was added to a solution of epoxy alcohol 21 (340 mg,
1.1 mmol), pyridine (11 mL), and Ac2O (0.12 mL, 1.3 mmol),
and the solution was maintained at room temperature. After
30 min, the reaction mixture was added to saturated aqueous
NH4Cl (120 mL), the resulting mixture was extracted with ethyl
acetate (120 mL), and the organic extract was washed sequen-
tially with saturated aqueous CuSO4 (2 ꢀ 100 mL) and brine
(2 ꢀ 100 mL), dried (Na2SO4), filtered, and concentrated. The
residue was purified by flash chromatography on silica gel
(80:20 hexane-ethyl acetate) to afford 370 mg (95%) of acetate
[R]23 -64.5, [R]23
-68.7, [R]23
-78.5, [R]23
-147.1,
D
577
546
435
[R]23405 -182.5 (c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ
5.63-5.61 (m, 1H, H16), 5.43-5.41 (m, 1H, H12), 5.23-5.21
(m, 1 H, H16), 4.99 (app t, J=4.0 Hz, 1H, H4), 4.21-4.19 (m,
2H, H6 and H9), 3.84 (d, J=8.4 Hz, 1 H, H2), 3.53-3.47 (m, 1
H), 3.02-2.98 (m, 1H), 2.77-2.71 (m, 1 H), 2.67-2.61 (m, 1H),
2.34 (app d, J=3.5 Hz, 2 H), 2.15 (s, 3 H), 2.00-1.91 (m, 1 H),
1.88-1.83 (m, 1H), 1.80 (ddd, J=16.1, 4.35, 4.3 Hz, 1 H), 1.68 (s,
3 H), 1.56-1.52 (m, 2H), 1.39 (s, 3H), 1.30-1.21 (m, 1H), 0.91
(d, J=6.2 Hz, 3H), 0.83 (d, J=6.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.7, 147.8, 132.2, 122.0 (C12), 115.1 (C6), 86.9 (C2),
22 as a clear yellow oil: [R]23 þ15.7, [R]23
þ16.4, [R]23
D
577
546
1
þ18.4, [R]23 þ30.0, [R]23 þ35.1 (c 1.0, CHCl3); H NMR
435
405
(90) Experimental procedures for key steps in the total syntheses of
the purported structure of alcyonin and briarellins E and F. General
experimental details and experimental procedures for other steps can be
found in the Supporting Information for this paper or the Supporting
16e,16f
Information deposited with the preliminary communications.
5468 J. Org. Chem. Vol. 74, No. 15, 2009

Corminboeuf et al.
JOCArticle
81.1 (C9), 74.7, 73.8 (C4), 72.8 (C6), 44.6, 40.0, 39.6, 39.0, 37.5,
28.7, 22.9, 22.5, 22.0, 21.5, 21.3, 20.8; IR (film) 3443, 1714,
1640 cm-1; HRMS (ESI) m/z 401.2310 (M þ Na, 401.2304 calcd
for C22H34O5).
(1R,3R,3aR,7R,7aR)-4-{4-Methyl-7-[1(S)-methyl-2-(triiso-
propylsilyloxy)ethyl]-3-prop-2-ynyl-1,3,3a,6,7,7a-hexahydroi-
MHz, CDCl3) δ 5.33 (dd, J=11.0, 2.1 Hz, 1 H), 4.11-4.05 (m, 2
H), 3.98 (ddd, J=9.6, 3.8, 3.8 Hz, 1 H), 3.78 (d, J=2.6 Hz, 1 H),
3.66 (dd, J=9.6, 3.6 Hz, 1 H), 3.44 (dd, J=9.5, 7.8 Hz, 1 H), 3.01
(d, J=4.7 Hz, 1 H), 2.93 (dd, J=9.5, 7.3 Hz, 1 H), 2.82 (ddd, J=
17.4, 3.2, 3.2 Hz, 1 H), 2.77 (br s, 1 H), 2.58 (ddd, J=17.4, 3.2, 3.2
Hz, 1 H), 2.46-2.39 (m, 1 H), 2.18 (t, J=2.5 Hz, 1 H), 2.10-2.00
(m, 2 H), 2.07 (s, 3 H), 2.03 (s, 3 H), 1.81-1.66 (m, 3 H), 1.41-
1.32 (m, 1 H), 1.29 (s, 3 H), 1.07-1.00 (m, 27 H); 13C NMR (125
MHz, CDCl3) δ 171.2, 170.9, 84.4, 80.4, 76.7, 76.6, 74.2, 72.3,
64.5, 61.2, 59.4, 56.7, 45.4, 40.8, 36.2, 35.8, 29.1, 24.5, 23.6, 22.6,
21.0, 20.9, 18.1, 18.0, 17.4, 11.9; IR (film) 3519, 3309, 3284, 1742
cm-1; HRMS (ES) m/z 631.3632 (M þ Na, 631.3642 calcd for
C33H56NaO8Si).
sobenzofuran-1-yl}-(Z)-pent-3-en-1-ol (49).
A solution of
formyl tetrahydroisobenzofuran 48 (5.0 g, 6.1 mmol) and
degassed dioxane (1.2 L) in a Pyrex reaction vessel was irra-
diated at room temperature with a Canrad-Hanovia medium-
pressure mercury lamp (100 W) for 36 h, and then the reaction
mixture was concentrated. A solution of this residue, THF (120
mL), and MeOH (60 mL) at room temperature was treated with
1.0 M aqueous KOH (25 mL, 25 mmol) and then heated to
reflux. After 15 h, the reaction mixture was allowed to cool to
room temperature and then poured into saturated aqueous
NH4Cl (500 mL), the aqueous layer was extracted with CH2Cl2
(3 ꢀ 500 mL), and the combined organic extracts were dried
(NaSO4), filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (5:1 hexane-ethyl acetate) to
Acetic Acid 3-Acetoxy-1(S)-[(2R,2aS,3S,4S,5aR,6S,9R,9aR,
9bR)-3,4-dihydroxy-3,6,9-trimethyl-2-prop-2-ynyl-2a,5,5a,6,7,9,9a,
9b-octahydro-2H-1,8-dioxabenzo[cd]azulen-9-yl]propyl Ester (56).
Sulfuric acid (0.61 mL) was added dropwise to a solution of
epoxide 55 (930 mg, 2.1 mmol), THF (40 mL), and H2O (40 mL)
at room temperature. After 6 h, saturated aqueous NaHCO3 (80
mL) was added, the mixture was stirred vigorously for 20 min, the
aqueous layer was extracted with ethyl acetate (2 ꢀ 50 mL), and the
organic extract was dried (Na2SO4), filtered, and concentrated. The
residue was purified by flash chromatography on silica gel (50:50
hexane-ethyl acetate) to give 770 mg (80%) of 56 as a waxy
afford 1.6 g (55%, two steps) of 49 as a clear colorless oil: [R]23
D
þ15.5, [R]23
þ16.5, [R]23
þ18.3, [R]23
þ33.5, [R]23
577
546
435
405
þ41.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.44 (t, J=
7.1 Hz, 1 H), 5.41-5.39 (m, 1 H), 4.55 (d, J=9.9 Hz, 1 H), 3.91-
3.87 (m, 1 H), 3.61 (dd, J=9.7, 4.0 Hz, 1 H), 3.63-3.53 (m, 2 H),
3.48 (dd, J=9.7, 6.1 Hz, 1 H), 2.59-2.38 (m, 5 H), 2.27-2.20 (m,
1 H), 2.09-1.98 (m, 2 H), 1.99 (t, J=2.6 Hz, 1 H), 1.95-1.92 (m,
1 H), 1.76 (d, J=0.9 Hz, 3 H), 1.68 (br s, 3 H), 1.62-1.54 (m, 1
H), 1.49-1.44 (m, 1 H), 1.05-1.01 (m, 21 H), 0.97 (d, J=6.8 Hz,
3 H); 13C NMR (125 MHz, CDCl3) δ 136.0, 132.7, 127.1, 120.9,
81.1, 79.6, 78.6, 69.9, 66.7, 62.2, 45.4, 41.6, 37.5, 31.9, 31.1, 26.3,
24.4, 21.8, 18.1, 18.0, 15.8, 11.9; IR (film) 3418, 3313, 2121, 1654
cm-1; HRMS (CI) m/z 474.3526 (M, 474.3529 calcd for
C29H50O3Si).
colorless solid: [R]23D -14.1, [R]23577 -14.0, [R]23546 -15.8, [R]23
435
-26.1, [R]23405 -30.5 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 5.13 (dd, J=9.6, 2.3 Hz, 1 H), 4.10-3.96 (m, 3 H), 3.64-3.57 (m,
2 H), 3.48 (dd, J=13.0, 3.2 Hz, 1 H), 3.47 (d, J=8.8 Hz, 1 H), 2.77
(ddd, J=12.3, 12.3, 8.9 Hz, 1 H), 2.70-2.40 (m, 1 H), 2.64 (ddd, J=
17.0, 4.6, 2.7 Hz, 1 H), 2.52 (ddd, J=17.0, 6.2, 2.7 Hz, 1 H), 2.21
(ddd, J=14.6, 7.2, 2.4 Hz, 1 H), 2.11 (t, J=2.7 Hz, 1 H), 2.02 (s, 3
H), 2.01 (s, 3H), 2.04-1.80 (m, 5 H), 1.63-1.56 (m, 1 H), 1.46 (ddd,
J=18.3, 9.2, 9.2 Hz, 1 H), 1.26 (s, 3 H), 1.24 (s, 3H), 0.98 (d, J=7.0
Hz, 3 H); 13C NMR (125 MHz, CDCl3) d 171.1, 170.1, 92.5, 81.5,
78.6, 76.2, 74.4, 73.3, 72.6, 71.0, 67.6, 61.9, 53.4, 39.1, 38.4, 36.4,
30.5, 29.7, 24.6, 21.2, 21.0, 20.5, 19.6, 10.6; IR (film) 3455, 3289,
1733 cm-1; HRMS (CI) m/z 453.2491 (M þ H, 453.2488 calcd for
C24H37O8).
Acetic Acid (3S,4S)-3-Acetoxy-4-hydroxy-4-{(1R,3R,3aS,4R,
5S,7R,7aR)-4,5-epoxy-4-methyl-7-[1(S)-methyl-2-(triisopro-
pylsilyloxy)ethyl]-3-prop-2-ynyl-1,3,3a,6,7, 7a-hexahydroisobenzo-
furan-1-yl}pentyl Ester (53) and Acetic Acid (3S,4S)-3-Acetoxy-
4-hydroxy-4-{(1R,3R,3aS,4S,5R,7R, 7aR)-4, 5-epoxy-4-methyl-
7-[1(S)-methyl-2-(triisopropylsilyloxy)ethyl]-3-prop-2-ynyl-1,3,3a,6,
7,7a-hexahydroisobenzofuran-1-yl}pentyl Ester. m-Chloroperoxy-
benzoic acid (0.32 g, 1.8 mmol) was added to a stirring mixture of
52 (0.91 g, 1.5 mmol), KHCO3 (1.5 g, 15 mmol), and CH2Cl2
(31 mL) at 0 °C. After 4 h, the reaction mixture was poured into 1:1
(v/v) saturated aqueous Na2CO3-brine (100 mL) and the aqueous
layer was washed with CH2Cl2 (3 ꢀ 100 mL), the combined organic
extracts were washed with brine (200 mL), dried (MgSO4), filtered,
and concentrated. The residue was purified by flash chromatogra-
phy on silica gel (6:1 hexane-ethyl acetate) to provide 0.72 g (77%)
of 53 and 0.094 g (10%) of the β-epoxide epimer as a clear pale
Briarellin E (12). A mixture of vinyl iodide aldehyde 60
(51 mg, 0.080 mmol), a 100:1 mixture of CrCl2 and NiCl2 (1.1
g), and a dry, degassed 100:1 mixture of DMSO-Me2S (91 mL)
was stirred at room temperature. After 20 h, the resulting dark
green mixture was transferred to a stirring mixture of sodium
serinate (91 mL of a 1.0 M aqueous solution) and ethyl acetate
(60 mL) at 0 °C, and then the cooling bath was removed. After
1 h, the layers were separated, the aqueous layer was extracted
with ethyl acetate (2 ꢀ 30 mL), and the combined organic
extracts were washed with brine (2 ꢀ 20 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel (1:1 hexane-ethyl acetate) to
yellow oil. Major isomer 53: [R]23D -2.5, [R]23577 -1.7, [R]23
-
afford 31 mg (79%) of 12 as a clear yellow oil: [R]23 -8.3,
546
D
[R]23577 -8.7, [R]23546 -10.1, [R]23435 -21.6, [R]23405 -28.7 (c 0.7,
2.6, [R]23435 -4.6, [R]23405 -5.4 (c0.5, CHCl3); 1H NMR(500MHz,
CDCl3) δ 5.35 (dd, J=11.1, 2.1 Hz, 1 H), 4.11-4.00 (m, 3 H), 3.78
(d, J=2.1 Hz, 1 H), 3.68 (dd, J=9.4, 3.7Hz, 1H), 3.38(t, J=8.7 Hz,
1 H), 3.04 (br s, 1 H), 2.91 (ddd, J=16.3, 3.3, 3.3 Hz, 1 H), 2.79 (br s,
1 H), 2.62-2.55 (m, 2 H), 2.16-1.98 (m, 3 H), 2.14 (t, J=2.5 Hz, 1
H), 2.06 (s, 3 H), 2.03 (s, 3 H), 1.80-1.66 (m, 2 H), 1.47-1.36 (m, 2
H), 1.34 (s, 3 H), 1.07-0.99 (m, 27 H); 13C NMR (125 MHz,
CDCl3) δ 171.2, 170.9, 84.7, 80.5, 77.0, 76.9, 74.0, 71.8, 64.6, 61.2,
60.2, 54.8, 43.7, 40.7, 35.2, 34.3, 29.1, 24.5, 23.6, 23.5, 21.0, 20.8,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 5.47 (s, 1 H), 5.18 (s,
1 H), 5.17 (s, 1 H), 4.50 (s, 1 H), 4.19-4.17 (m, 1 H), 3.82 (d, J=
9.2 Hz, 1 H), 3.60 (d, J=12.9 Hz, 1 H), 3.38 (dd, J=13.2, 2.6 Hz,
1 H), 2.97 (s, 1 H), 2.59 (s, 1 H), 2.39-2.25 (m, 5 H), 1.94-1.86
(m, 1 H), 1.83-1.76 (m, 1 H), 1.70-1.53 (m, 6 H), 1.52-1.41 (m,
2 H), 1.33 (s, 3 H), 1.32 (s, 3 H), 1.34-1.20 (m, 9 H), 0.89-0.85
(m, 3 H), 0.81 (d, J=6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 175.2, 148.1, 115.1, 92.0, 81.9, 76.7, 73.9, 71.6, 67.3, 51.6, 39.7,
39.3, 38.8, 36.3, 35.8, 34.8, 31.6, 29.0, 28.9, 28.7, 25.2, 24.9, 22.6,
17.8, 14.0, 10.4; IR (film) 3432, 1706, 1640 cm-1; HRMS (ES)
m/z 501.3202 (M þ Na, 501.3192 calcd for C28H46NaO6).
Briarellin F (13). Dess-Martin periodinane38 (28 mg,
0.05 mmol) was added to a solution of briarellin E (12) (14
mg, 0.03 mmol) and CH2Cl2 (3.5 mL), and the resulting mixture
was stirred at room temperature. After 45 min, 1.5 M aqueous
Na2S2O3 (5.0 mL) was added, and the mixture was stirred
18.0, 17.8, 17.3, 11.9; IR (film) 3520, 3309, 3287, 1743 cm-1
;
HRMS (ES) m/z 631.3658 (M þ Na, 631.3642 calcd for
C33H56NaO8Si).
Minor β-epoxide epimer:91 [R]23D þ2.0, [R]23577 þ2.0, [R]23
546
þ1.3, [R]23435 þ2.6, [R]23405 þ2.4 (c 0.4, CHCl3); 1H NMR (500
(91) The structure for this compound (S4) can be found in the Supporting
Information.
J. Org. Chem. Vol. 74, No. 15, 2009 5469

Corminboeuf et al.
JOCArticle
vigorously. After 1 h, CH2Cl2 (10 mL) was added, and the
organic layer was washed with saturated aqueous NaHCO3 (2 ꢀ
15 mL) and brine (15 mL), dried (Na2SO4), filtered, and con-
centrated. The residue was purified by flash chromatography on
silica gel (70:30 hexane-ethyl acetate) to afford 11 mg (79%) of
Graduate Fellowship in Synthetic Organic Chemistry and O.
C. from the Swiss National Science Foundation is appreciated.
We thank Professor Takenori Kusumi of the University of
Tokushima, Japan, for sharing copies of NMR spectra
of natural alcyonin and its hemiacetal derivative, Professor
13 as a waxy colorless solid: [R]23D -63.2, [R]23577 -66.0, [R]23
546
´
Abimael D. Rodrıguez of the University of Puerto Rico,
Rıo Piedras, for providing samples of natural briarellin E
-73.8, [R]23435 -125.5, [R]23405 -148.3 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 5.77 (dd, J=9.6, 5.4 Hz, 1 H), 5.43 (s, 1 H),
5.35 (s, 1 H), 4.45 (dt, J=3.6, 3.3, 1 H), 3.81 (d, J=9.3 Hz, 1 H),
3.62 (d, J=13.1 Hz, 1 H), 3.40 (dd, J=12.9, 3.3 Hz, 1 H), 3.32
(ddd, J=13.2, 6.6, 0.7 Hz, 1 H), 2.84-2.73 (m, 2 H), 2.70-2.62
(m, 1 H), 2.38 (dd, J=13.2, 3.0 Hz, 1 H), 2.34-2.29 (m, 2 H), 2.16
(dd, J=11.7, 3.9 Hz, 1 H), 1.91-1.83 (m, 1 H), 1.75-1.47 (m, 7
H), 1.33 (s, 3 H), 1.30 (s, 3 H), 1.34-1.20 (m, 9 H), 0.90-0.85 (m,
6 H); 13C NMR (125 MHz, CDCl3) δ 200.7, 173.2, 146.4, 116.1,
92.1, 80.0, 77.2, 72.0, 71.1, 67.6, 53.8, 45.7, 42.7, 40.1, 38.6, 36.3,
34.5, 31.7, 29.0, 28.9, 28.6, 25.1, 24.1, 22.6, 18.4, 14.1, 10.6; IR
(film) 3462, 1733, 1691 cm-1; HRMS (ES) m/z 499.3033 (M þ
Na, 499.3036 calcd for C28H44NaO6).
´
ꢀ
and 11-acetoxy-4-deoxyasbestinin D, and Professor Jose-Luis
Giner of SUNY-ESF, New York, for valuable discussions
regarding the epoxy ester rearrangement. We also thank Dr.
John Greaves and Dr. John Mudd for acquiring mass spectra
and Dr. Joseph W. Ziller for obtaining X-ray crystal struc-
tures. NMR and mass spectra were obtained at UC Irvine
using instrumentation acquired with the assistance of NSF and
NIH Shared Instrumentation programs.
Supporting Information Available: Experimental proce-
1
dures, tabulated characterization data, and copies of H and
13C NMR spectra for new compounds not previously reported;
CIF files for X-ray structures of 25, 36a, and 36b; PDB file of the
MMFF model of triol 32. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by the NIH
Neurological Disorders and Stroke Institute (NS-12389);
fellowship assistance for L.D.P. from a Pharmacia & Upjohn
5470 J. Org. Chem. Vol. 74, No. 15, 2009