(4 f 5) and the subsequent lactone ring formation via a
carbonyl insertion reaction en route to 1.
In practice, iodo enone 2, readily accessible from 4,4-
dimethyl-2-cyclohexenone11 (Scheme 2), was subjected to
sium bromide16 and 3-furyltitanium triisopropoxide,17 were
also examined in an attempt to improve the stereoselectivity.
These reagents, however, were shown to be inferior in terms
of both yield and product ratio. To circumvent the stereo-
chemical problem, alcohol 8 with the incorrect stereochem-
istry was oxidized to the corresponding ketone 9 with Dess-
Martin periodinane (Scheme 3). It was hoped that this
Scheme 2
Scheme 3
compound could be selectively reduced, resulting in the
preferential formation of the desired epimer (-)-5. The
reduction was attempted with a number of reducing agents,
including sodium borohydride, lithium aluminum hydride,
diisobutylaluminum hydride, and lithium aluminum tri-tert-
butoxy hydride. Unfortunately, all of these reagents were
found to be ineffective; in all cases studied, the undesired
epimer (-)-8 was generated predominantly. Even in the best
case involving sodium borohydride, the amount obtained for
the desired alcohol (-)-5 was merely 60% of that of (-)-8.
In an alternate approach to rectify the stereochemistry,
alcohol (-)-8 was treated with diethyl azodicarboxylate,
triphenylphosphine, and p-nitrobenzoic acid in benzene, and
the resulting ester was hydrolyzed with lithium hydroxide
in methanol. This Mitsunobu inversion approach proved to
be more satisfactory; the desired alcohol (-)-5 was formed
in 51% yield over two steps. Thus, with the assistance of
the latter process, alcohol (-)-5 could be obtained in a total
yield of 60% from aldehyde (-)-7.
To complete the synthesis of ricciocarpin A (1) from (-)-
5, it remains to introduce the lactone ring and to reduce the
cyclohexene double bond. The former was carried out by
treatment of alcohol (-)-5 with a catalytic amount of
palladium acetate (0.06 equiv) and triphenylphosphine (0.12
equiv) in methanol and N,N′-dimethylpropyleneurea in the
presence of triethylamine at 55 °C under an atmosphere of
carbon monoxide for 24 h18 (Scheme 4). The intramolecular
carbonyl insertion occurred smoothly to give an 89% yield
of (+)-lactone 10, which on reduction with sodium boro-
asymmetric reduction according to the procedure developed
by Knochel and Soorukram9b to give the corresponding iodo
alcohol 3 in high optical purity (98% ee).12 This alcohol was
treated with trimethyl ortho ester at 165 °C in the presence
of a small amount of propanoic acid. Apart from the
somewhat slow reaction rate (83% conversion after 48 h),
most likely due to the involvement of a neopentyl trigonal
center, the ortho ester rearrangement proceeded cleanly to
furnish the desired iodo ester (-)-4 in good yield (91% based
on consumed starting material) with no observable optical
scrambling.12 To install the furan moiety, iodo ester (-)-4
was first reduced with lithium aluminum hydride to give the
corresponding alcohol (-)-6. This was followed by Dess-
Martin periodinane13 oxidation to provide aldehyde (-)-7
in 77% yield over two steps. Aldehyde (-)-7 was subjected
to treatment with 3-lithiofuran, prepared in situ from 3-bro-
mofuran and n-butyllithium.14 Although the addition reaction
occurred readily, to our disappointment, regardless of the
conditions applied, the desired alcohol (-)-515 was formed
as the minor product in deference to its epimer (-)-8. The
best results were obtained when the addition reaction was
carried out in ether at -60 °C for 3 h. Under these conditions,
alcohols (-)-5 and (-)-8 were obtained in a 1:2 ratio in a
combined yield of 89%. Two other reagents, 3-furylmagne-
(11) Bovonsombat, P.; Angara, G. J.; McNelis, E. Tetrahedron Lett. 1994,
35, 6787.
(16) (a) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303.
(b) Oppolzer, W.; Froelich, O.; Wiaux-Zamar, C.; Bernardinelli, G.
Tetrahedron Lett. 1997, 37, 2825.
(17) Boukouvalas, J.; Cheng, Y.-X.; Robichaud, J. J. Org. Chem. 1998,
63, 228.
(18) Quirante, J.; Vila, X.; Escolano, C.; Bonjoch, J. J. Org. Chem. 2002,
67, 2323.
(12) The optical purity was determined by HPLC using chiral column
Chiralcel OD. The analysis was calibrated with a sample of the racemate.
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(14) Ly, T. W.; Liao, J. H.; Shia, K. S.; Liu, H. J. Synthesis 2004, 271.
(15) The stereochemical assignment of this compound follows from its
transformation to the natural product 1.
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Org. Lett., Vol. 8, No. 1, 2006