Approach to the synthesis of cladiell-11-ene-3,6,7-triol

Article abstract of DOI:10.1021/ol061072j

The synthesis of an advanced intermediate in the synthesis of the title compound has been achieved. Key steps include an Ireland-Claisen rearrangement to install the C7 tertiary alcohol stereocenter, an S_N2′ reaction of an alkoxymethyl Cu reage

Full text of DOI:10.1021/ol061072j

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3663-3665
Approach to the Synthesis of
Cladiell-11-ene-3,6,7-triol
John M. Hutchison, Harriet A. Lindsay, Silvana S. Dormi, Gavin D. Jones,
David A. Vicic,† and Matthias C. McIntosh*
115 Chemistry Building, UniVersity of Arkansas, FayetteVille, Arkansas 72701
mcintosh@uark.edu
Received May 2, 2006
ABSTRACT
The synthesis of an advanced intermediate in the synthesis of the title compound has been achieved. Key steps include an Ireland−Claisen
rearrangement to install the C7 tertiary alcohol stereocenter, an SN2
′
reaction of an alkoxymethyl Cu reagent, and a diastereoselective Re-
catalyzed allylic alcohol transposition.
The 2,11-cyclized cembranoids constitute a large class of
marine-derived diterpenoids, some of which have been
reported to possess anticancer activity in vitro.1 Most
members of this family of compounds contain a cis-fused
hydroisobenzofuran bicycle (Figure 1). Since the first
briarellins E and F,5 11-acetoxy-4-deoxyasbestinin D,6 al-
cyonin, cladiell-11-ene-3,6,7-triol, and sclerophytin A.7,8
Sclerophytin A (1b) was reported to exhibit growth
inhibitory activity toward the L1210 leukemia cell line at
1.0 ng/mL. The originally formulated structure of sclero-
phytin A was corrected by independent total syntheses by
the Overman and Paquette groups.7-9 Cladiell-11-ene-3,6,7-
triol (1a) is the ∆11-12 isomer of sclerophytin A. Overman
has demonstrated that 1a can be photochemically converted
to 1b, so a synthesis of 1a also constitutes a formal synthesis
of 1b.
(2) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117,
10391-10392.
(3) Molander, G. A.; St. Jean, D. J.; Haas, J. J. Am. Chem. Soc. 2004,
126, 1642-1643.
Figure 1. Cladiell-11-ene-3,6,7-triol (1a ∆11-12). Sclerophytin A
(1b ∆11-17).
(4) Crimmins, M. T.; Brown, B. H.; Plake, H. R. J. Am. Chem. Soc.
2006, 128, 1371-1378.
(5) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2003, 125, 6650-6652.
(6) Crimmins, M. T.; Ellis, J. M. J. Am. Chem. Soc. 2005, 127, 17200-
synthesis of deacetoxyalcyonin acetate by Overman and
MacMillan in 1995,2,3 several other members of this family
have been synthesized, including ophirin B,4 astrogorgin,4
17201.
(7) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am.
Chem. Soc. 2001, 123, 9033-9044.
(8) 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.
† To whom correspondence regarding X-ray crystallographic analyses
should be addressed.
(1) Wahlberg, I.; Eklund, A.-M. Prog. Chem. Org. Nat. Prod. 1992, 60,
1-141. Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531-556.
(9) Friedrich, D.; Doskotch, R. W.; Paquette, L. A. Org. Lett. 2000, 2,
1879-1882. Friedrich, D.; Paquette, L. A. J. Nat. Prod. 2002, 65, 126-
130.
10.1021/ol061072j CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/29/2006

We have been interested in preparing several of the 2,11-
cyclized cembranoids by total synthesis. For those targets
lacking stereocenters at C7 and/or C8, we have pursued a
cycloaldol approach.10 Our approach to a cladiellene triol,
which possesses a 3° alcohol stereocenter at C7, employs
the Ireland-Claisen rearrangement.11 We felt that the re-
arrangement could be productively employed both to estab-
lish the stereochemistry at C7 and to provide a functional
handle for formation of the tetrahydrofuran ring via the C9-
C10 alkene.
Taylor,16 and Dieter17 suggested that such a transformation
would be plausible.18 The success of this approach was
predicated on an initial syn-selective SN2′ reaction of allylic
chloride 3 to lactone 4.19 In the event, a Ag-mediated SN2′
cyclization proceeded in a syn fashion to afford the corre-
sponding lactone in an 8:1 dr favoring â isomer 4. To our
satisfaction, Cu-mediated anti SN2′ reaction of an alkoxy-
methyl nucleophile proceeded in excellent yield on scale to
afford a single stereoisomeric product. Zn(II) salts (ZnCl2
or ZnBr2) proved to be critical to the success of the
transformation; no substitution occurred in the absence of
the Zn salt.20
At this stage in the synthesis, we hoped to close the
tetrahydrofuran ring via an electrophilic cyclization of the
C2 hydroxy group onto the C9-C10 alkene. The isopropenyl
alkene was hydrogenated to avoid competing cyclizations
to give diene 6 after cleavage of the MOM protecting group
(Scheme 2). Although the electrophilic cyclization approach
Treatment of ester 2 (available in three steps from (S)-
(+)-carvone)12 with KHMDS and TIPSOTf afforded a single
stereoisomeric product 3 possessing the Z-alkene and the (S)-
stereochemistry at C7 (Scheme 1). The Ireland-Claisen
Scheme 1
Scheme 2
rearrangement presumably proceeded via a chairlike transi-
tion state analogous to conformer i, with the larger C11
substituent occupying the pseudoequatorial position. The
stereochemistry of the chlorine atom at C1 was critical to
the success of the Claisen rearrangement. Because the
chlorine atom is situated in a pseudoaxial position with
respect to the cyclohexene ring, the effective steric bulk of
the C1 carbon was smaller than that of the methyl-substituted
C11 carbon.13
met with some limited success when ICl was employed, the
yields proved to be too low to be synthetically useful. Other
electrophilic reagents (Br2, I2, Pb(OAc)4/ZnBr2, NBS,
Hg(O2CCF3)2, etc.) gave poor yields and/or undesired side
products.
We next considered reversing the sense of ring closure so
that the C2-O bond would be established in the tetra-
hydrofuran ring-forming step rather than the C9-O bond.
To this end, Swern oxidation of alcohol 6 and Horner-
Wadsworth-Emmons Wittig reaction afforded E-sulfone 7.
Sharpless dihydroxylation of triene 7 gave C11-C12 R-diol
8.
With the success of the Ireland-Claisen rearrangement,
15 of the 20 carbons of the carbon framework were in place.
It was at this point that we chose to install the C1-C2 bond.
Rather than attempting a direct displacement of the â-Cl
substituent, we sought to employ a Cu-mediated SN2′ ring
opening of the allylic lactone using an alkoxy Cu nucleo-
phile.14 SN2′ reactions of alkoxyalkyl Cu nucleophiles are
not well precedented, although earlier work by Fuchs,15
(16) Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2002, 4, 119-122.
(17) Dieter, R. K.; Watson, R. T.; Goswami, R. Org. Lett. 2004, 6, 253-
256.
(18) See also: Falck, J. R.; Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995,
117, 5973-5982.
(19) For a review, see: Paquette, L. A.; Stirling, C. J. M. Tetrahedron
1992, 48, 7383-7423.
(20) Nakamura, E.; Sekiya, K.; Arai, M.; Aoki, S. J. Am. Chem. Soc.
1989, 111, 3091-3093. Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett.
2003, 5, 1059-1061. For a review, see: Knochel, P.; Calaza, M. I.; Hupe,
E. Carbon-Carbon Bond-Forming Reactions Mediated by Organozinc
Reagents. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp
619-670.
(10) (a) Chai, Y.; Vicic, D. A.; McIntosh, M. C. Org. Lett. 2003, 5,
1039-1042. (b) Chai, Y.; McIntosh, M. C. Tetrahedron Lett. 2004, 45,
3269-3272.
(11) Hong, S.-P.; Lindsay, H. A.; Yaramasu, T.; Zhang, X.; McIntosh,
M. C. J. Org. Chem. 2002, 67, 2042-2055.
(12) Lindsay, H. A.; Salisbury, C. L.; Cordes, W.; McIntosh, M. Org.
Lett. 2001, 3, 4007-4010.
(13) McFarland, C.; Hutchison, J. M.; McIntosh, M. C. Org. Lett. 2005,
7, 3641-3644.
(14) Trost, B. M.; Klun, T. P. J. Org. Chem. 1980, 45, 4256-4257.
(15) Hutchinson, D. K.; Fuchs, P. L. J. Am. Chem. Soc. 1987, 109, 4930-
4939.
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Org. Lett., Vol. 8, No. 17, 2006

On the basis of the Sharpless mnemonic, the (DHQ)2PYR
ligand could in principle give either the observed product
or the C9-C10 â-diol (Figure 2).21 We postulate that the
Scheme 3
Figure 2. Regioselectivity of the dihydroxylation of triene 7.
the C9 alkoxide would be restricted to the re face of the
vinyl sulfone due to allylic strain (cf. Figure 2), resulting in
the â stereochemistry at C2 in isobenzofuran 11. Fortuitously,
the isolated product possessed the (S)-stereochemistry at C3,
although it is of no consequence for the synthesis per se.
The requisite cis ring fusion stereochemistry of the bicycle
was set by axially selective reduction of tosylhydrazone 12
and in situ allylic diazene rearrangement.10a,24
X-ray crystallographic analysis of sulfone 13 revealed that
all six stereocenters that are present in cladiellene triol (and
sclerophytin A) were of the desired configuration. Addition
of the C4-C5 fragment and cyclization of the oxonane ring
remain. Further efforts toward these goals will be reported
in due course.
observed regioselectivity is a result of 2-fold allylic strain.22
A molecular mechanics conformational search of a substruc-
ture of triene 7 (R ) H) indicated that conformations within
ca. 3 kcal/mol of the global minimum have the C1 alkenyl
and C14 isopropyl substituents disposed pseudoaxially to
avoid allylic strain between the C1 substituent and the C8
carbon. Similarly, the C2-C3 alkene is oriented so as to
place the C15 methyl syn to the allylic hydrogen at C1. As
a consequence, the effective size of the C1 alkene substituent
is significantly smaller than the C14 isopropyl substituent.
The 1,3-diaxial interactions between the ligated OsO4 would
therefore be smaller for R attack at C11-C12 than for â
attack at C9-C10.
Oxidation of the C12 hydroxy group of diol 8 gave ketone
9. MeReO3-catalyzed allylic alcohol transposition23 of un-
conjugated enone 9 afforded conjugated enone 10 (Scheme
3). The concerted nature of the transposition was evident by
the retention of stereochemistry at the C9 stereocenter in the
rearranged product. The stereochemistry at C9 of hydroxy
ester 10 was supported by NOESY analysis of the derived
lactone and was later confirmed by X-ray crystallographic
analysis (vide infra).
Acknowledgment. We thank the NIH (GM59406 and
RR15569) and the Arkansas Biosciences Institute for support
of this work.
Note Added after ASAP Publication. In the Figure 1
caption, ∆11-17 was incorrectly listed as ∆11-18 in the version
published ASAP July 29, 2006. The corrected version was
published ASAP July 31, 2006.
The tetrahydrofuran ring was then formed by base-
mediated cyclization of unsaturated sulfone 10. Addition of
Supporting Information Available: Characterization
data for compounds 3-11 and 13. CIF file for compound
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
(21) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(22) For reviews, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem.
ReV. 1993, 93, 1307-1370. Hoffman, R. W. Chem. ReV. 1989, 89, 1841-
1860.
OL061072J
(23) Jacob, J.; Espenson, J. H.; Jensen, J. H.; Gordon, M. S. Organo-
metallics 1998, 17, 1835-1840. Morrill, C.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 2842-2843.
(24) Kabalka, G. W.; Yang, D. T. C.; Baker, J. D., Jr. J. Org. Chem.
1976, 41, 574-575.
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