The diterpene vinigrol (3), isolated from Virgaria nigra F-5408, has eluded
total synthesis for more than twenty years. 1403257-80-6 manufacturer Attempts to construct the
four-carbon bridge on a preformed cis-decalin have been unavailing. Phil S. 2322869-99-6 supplier
Baran of Scripps/LaJolla solved
(Angew. Chem. Int. Ed. 2008, 47, 3054,
DOI: 10.1002/anie.200800167;
J. PMID:24957087 Am. Chem. Soc. 2009, 131, 17066,
DOI: 10.1021/ja908194b)
this problem by adding the extra C-C bond of 1, that could then be
cleaved in course of a Grob fragmentation, leading to 2.
The preparation of 1 started with the dihydroresorcinol derivative
4. Diels-Alder addition of the ester 5 gave 6, with a modest
2:1 dr. Addition of allyl magnesium chloride to the derived aldehyde 7
proceeded with 6:1 dr. The resulting triene was conformationally sufficiently
constrained that cyclization to 8 proceeded at room temperature over two
weeks, or more conveniently at 105°C for 90 minutes. With 8 in hand,
oxidation to the ketone allowed installation of the additional methyl group of
9. Desilylation followed by OH-directed reduction set the relative
configuration of 1 correctly for the Grob fragmentation to the Z-alkene
2.
There were two remaining problems in the synthesis. The alkene of 2
had to be converted to the methylated tertiary alcohol, and the ketone had to be
elaborated to the ene diol. While seemingly straightforward, the congested
tricyclic skeleton of 2 made many common transformations difficult. The
solution to the former problem was found in the selective dipolar addition of
bromonitrile oxide. Reduction of the ketone then enabled HO-directed
hydrogenation of the alkene, that otherwise was resistant. Dehydration followed
by reduction with
LiAlH4 gave the desired methyl group bearing a
primary amine, that was removed by free radical reduction of the corresponding
isonitrile, to give 12.
With 12 in hand, the end of the synthesis appeared to be in sight. In
fact, the reduction of a variety of oxidized intermediates proved difficult. In
the end, a sequence that did not require reduction proved effective.
Dihydroxylation of 12 gave a diol, selective oxidation of which delivered
the α-hydroxy ketone 13. Formation of the trisylhydrazone followed by
Shapiro
reaction gave the intermediate alkenyl anion, that was trapped with formaldehyde
to give the long-sought Vinigrol (3).
Vinigrol (3) produced by this sequence was racemic. The absolute configuration
of the ring system was set in the course of the Diels-Alder addition of 5 to
4. Use of a chiral catalyst in this step could set the stage for an
enantioselective synthesis of 3.
