shown to bind to Hsp90. Given these considerations, and
given some interesting structural issues which we hoped to
address, we identified radicicol as an appropriate focusing
target for a program in total synthesis.
Scheme 2. Synthesis of 2 and 3a
To date, only one synthesis of radicicol has been recorded,9
by a route which is distinct from that practiced here. In this
Letter, we describe the results of research which has led to
a rather concise and stereoselective entry to the radicicol
series. Our interim report contains several instances of
differential chemoselectivity successes which could not have
been anticipated with confidence in advance of experiment.
The strategy employed relied on a highly convergent three-
stage coupling for macrolide formation (Scheme 1). The first
Scheme 1. Three-Stage Strategy for Macrolide Formation
tions11 (LiCl, DIPEA, 95%) followed by a second reduction
(DIBAL-H, 96%) yielded the desired trans-allylic alcohol
(8). Sharpless asymmetric epoxidation ((-)-DET, Ti(OiPr)4,
TBHP, 90%) gave the desired epoxyalcohol (9) with excel-
lent (>20:1) selectivity. The resulting epoxyalcohol was then
oxidized (SO3‚pyridine, Et3N, DMSO, 90%) and the product
aldehyde was converted to the vinyl epoxide (10) via Wittig
olefination (PPh3CH3Br, NaHMDS, 82%). Fluoride-catalyzed
removal of the TBDPS group proceeded smoothly (nBu4-
NF, 89%) to yield the desired secondary alcohol (3). The
latter, in principle, contains the sp3 stereochemical network
appropriate for reaching radicicol.
stage would entail esterification of an appropriately substi-
tuted benzoic acid (2) with an enanatiomerically defined
chiral secondary alcohol (3), which contains all three
stereocenters of radicicol. The second stage requires chemo-
and regioselective alkylation of an allylic dithiane (4) by the
resulting benzylic chloride of 2 + 3. Last, stereospecific ring-
closing metathesis of an olefin with a vinyl epoxide in place
would give the desired 14-membered novel lactone cycliza-
tion.
The synthesis commenced with construction of the ho-
mochiral allylic alcohol (3) via a procedure that closely
follows that described by Waldmann and co-workers.10 Thus,
methyl (R)-3-hydroxybutyric acid (5) was silylated
(TBDPSCl, imidazole, 95%) and the product reduced at low
temperature (DIBAL-H, -78 °C, 92%) to provide directly
the desired aldehyde (6) (Scheme 2). Wadsworth-Horner-
Emmons homologation of 6 under Roush-Masamune condi-
The remaining two building blocks were then synthesized.
The allylic dithiane (4) was secured in one step from
commercially available 2,4-hexadienal (11) (MgClO4, H2-
SO4, H2S(CH2)3SH2, 64%).12 The substituted benzoic acid
(2) was synthesized in two steps from commercially available
3,5-dimethoxybenzyl alcohol (12) (Scheme 3). Concomitant
formylation and conversion of the alcohol to the chloride
was effected13 (POCl3, DMF, 93%) to give the desired
aldehyde (13). Careful oxidation of this aldehyde (NaClO2,
sulfamic acid, 85%) yielded the desired benzoic acid (2) with
no observed cyclization and tolerably minimal14 aromatic ring
chlorination (<15%).
(7) Soga, S.; Neckers, L. M.; Schulte, T. W.; Shiotsu, Y.; Akasaka, K.;
Narumi, H.; Agatsuma, T.; Ikuina, Y.; Murakata, C.; Tamaoki, T.; Akinaga,
S. Cancer Res. 1999, 59, 2931-2938.
(8) Kuduk, S. D.; Zheng, F. F.; Sepp-Lorenzino, L.; Rosen, N.;
Danishefsky, S. J. Bioorg. Med. Chem. Lett. 1999, 9, 1233-1238. Kuduk,
S. D.; Harris, C. R.; Zheng, F. F.; Sepp-Lorenzino, L.; Ouerfelli, Q.; Rosen,
N.; Danishefsky, S. J. Bioorg. Med. Chem. Lett. 2000, 10, 4325-4328.
(9) Lampilas, M.; Lett, R. Tetrhedron Lett. 1992, 33, 773-776 and 777-
780.
(10) Schlede, U.; Nazare´, M.; Waldmann, H. Tetrahedron Lett. 1998,
39, 1143-1144.
Assembly of the fragments could then be initiated.
Esterification of the benzoic acid (2) proceeded smoothly
via the acid chloride (COCl2, DMF, Et3N, 3, 80%) to provide
the benzoic ester (14). Addition of the lithiated dithiane
(nBuLi, -30 °C) to 14 at -78 °C gave chemoselective
addition15 at the benzylic center to give 15 (60% yield).
(11) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. Tetrahedron Lett. 1984, 25, 2183.
(12) Fang, J.-M.; Liao, L.-F.; Hong, B.-C. J. Org. Chem. 1986, 51, 2828-
2829.
(13) Makara, G. M.; Klubek, K.; Anderson, W. K. Synth. Commun. 1996,
26, 1935-1942.
(14) The chlorinated benzoic acid did not undergo esterification and thus
easily dropped out of the sequence following purification of 14.
3128
Org. Lett., Vol. 2, No. 20, 2000