Scheme 1. Retrosynthetic Analysis of the Proposed Structure of
Briarellin J
Figure 1. Proposed biosynthesis of the briarellins.
thetically (Scheme 1), the proposed structure of briarellin J
(1) was envisioned to arise from a late stage substrate-
controlled hydroboration of hexahydroisobenzofuran 2 to
install the C15 stereocenter, followed by oxidative lacton-
ization to install the ε-lactone and final acetylation of the
C11 hydroxyl. Hexahydroisobenzofuran 2 would be derived
from methyllithium addition to diketone 3. Diketone 3 would
ultimately result from an intramolecular Diels-Alder reaction
of triene 4. Triene 4 would be readily available from oxonene
Figure 2. Reported structures of briarellins.
1
2a
5
,
previously prepared in our laboratories in eight steps
from (R)-benzylglycidyl ether.
The synthesis of diketone 3 (Scheme 2) began from known
oxonene 5, prepared via our glycolate aldol/ring-closing
correlation between the C11 methyl and the R C14 methine,
whereas this correlation is clearly present in briarellins E-I.
The proposed ꢀ C11 methyl in briarellins A-D and J-P
conflicts with Faulkner’s biosynthetic proposal since a very
unlikely 1,2-antarafacial methyl shift would be required to
13
metathesis strategy. Swern oxidation of the primary alcohol
14
and Wittig olefination of the resultant aldehyde afforded
(Z)-unsaturated ester 6 in good yield. A sequence of reduction
1
b
generate an asbestinin (Figure 1).
of ester 6 to the allylic alcohol, manganese dioxide oxidation
to the aldehyde, and a methylene Wittig olefination was
performed with only a single final chromatographic purifica-
Although the relative and absolute stereochemistry of
9
briarellins E and F have been established via total synthesis
by the Overman group, no synthetic efforts toward briarellins
A-D or J-P have been reported to date.
(
10) (a) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029–
We previously reported the enantioselective preparation
2032. (b) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653–5660. (c) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000,
22, 5473–5476. (d) Crimmins, M. T.; Emmitte, K. A. Synthesis 2000, 6,
1
0
of medium ring ethers via a glycolate aldol/ring-closing
metathesis strategy and have applied this method to the
1
899–903. (e) Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001,
123, 1533–1534. (f) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L.
Tetrahedron 2002, 58, 1817–1834. (g) Crimmins, M. T.; DeBaillie, A. C.
Org. Lett. 2003, 5, 3009–3011. (h) Crimmins, M. T.; Cleary, P. A.
Heterocycles 2003, 61, 87–92. (i) Crimmins, M. T.; Powell, M. T. J. Am.
Chem. Soc. 2003, 125, 7592–7595.
1
1
synthesis of members of the eunicellin and asbestinin
12
classes. Due to the interesting inconsistency with Faulkner’s
proposed biosynthesis and our experience in the synthesis
of C2-C11 cyclized cembranoid diterpenes, we chose
briarellin J as a prime target for total synthesis. Retrosyn-
(
11) (a) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126,
10264–10266. (b) Crimmins, M. T.; Brown, B. H.; Plake, H. R. J. Am.
Chem. Soc. 2006, 128, 1371–1378.
(
12) (a) Crimmins, M. T.; Ellis, J. M. J. Am. Chem. Soc. 2005, 127,
(
8) Rodr ´ı guez, A. D.; Cobar, O. M. Chem. Pharm. Bull. 1995, 43, 1853–
858.
9) (a) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am.
17200–17201. (b) Crimmins, M. T.; Ellis, J. M. J. Org. Chem. 2008, 73,
1649–1660.
1
(
(13) Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 4537–4538.
(14) Seneci, P.; Leger, I.; Souchet, M.; Nadler, G. Tetrahedron 1997,
53, 17097–17114.
Chem. Soc. 2003, 125, 6650–6652. (b) Corminboeuf, O.; Overman, L. E.;
Pennington, L. D. J. Org. Chem. 2009, 74, 5458–5470.
Org. Lett., Vol. 12, No. 21, 2010
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