From the synthetic perspective (Scheme 1), we maintained
the triply convergent approach utilized in our first-generation
crystalline aldol (+)-58 in 52-55% yield from (+)-2
(Scheme 2). In practice, the first three intermediates of this
Scheme 2
Scheme 1
sequence can be carried forward without purification and
the aldol product (+)-5 crystallized from the crude reaction
mixture. Transamidation of (+)-5 then gave (-)-CP9 in
excellent yield. Purification of (-)-CP was facilitated by
isolation of the recyclable oxazolidinone auxiliary (80-90%)
by efficient crystallization from the reaction mixture. Im-
portantly, this concise, five-step sequence required only one
chromatographic purification and could be performed rou-
tinely on a 60-g scale.
Fragments (+)-A and (+)-B were next prepared in large
scale, upon optimization of the chemistry developed in our
first-generation synthesis (Scheme 3).5b The synthesis of
(+)-A (20-g scale) proceeded in six steps (55% overall), and
all intermediates en route proved crystalline. The (Z)-vinyl
iodide (+)-B (30-g scale) was prepared in 40-46% from
(-)-CP and required only a single chromatographic purifica-
tion.
Preparation of the C(1-8) fragment (-)-C began with
silylation (TBSOTf) of (-)-CP, removal of the PMB group
[H2, Pd(OH)2], and oxidation (SO3‚Pyr)10 to furnish crystal-
line aldehyde (-)-89 (Scheme 3). Addition of silyl enol ether
911 to a premixed solution of (-)-8 and TiCl4 at -78 °C
then afforded, after acid-catalyzed lactonization of the
corresponding hydroxy amide, lactone (-)-10.9 Importantly,
this Mukaiyama aldol proceeded with 20:1 selectivity,
favoring the desired anti-Felkin product. Reduction of enone
(-)-10 with K-Selectride then furnished the corresponding
allylic alcohol with 9:1 selectivity, favoring the desired
R-isomer (not shown). The structure of this alcohol was
secured by single-crystal X-ray analysis. Silylation of the
hydroxyl (TBSCl) and oxidative cleavage of the trisubstituted
alkene (O3; PPh3) completed the synthesis of crystalline
aldehyde (-)-C. 9
synthesis, dissecting the natural product at the C(8-9) and
C(13-14) alkenes to generate subunits A-C, each to be
prepared from a common precursor (CP). In contrast to our
first-generation approach, we chose to maintain the lactone
oxidation state in fragment C, in anticipation of a chemo-
selective Wittig olefination with phosphonium salt AB, the
latter comprising the C(9-24) carbons of the natural product.
Such a second-generation approach would greatly simplify
the end-game of the synthesis and thus facilitate material
throughput for large-scale synthesis.
Our point of departure entailed protection of (+)-2 as the
PMB ether, followed by reduction (LAH), oxidation (Swern),6
and reaction with oxazolidinone (+)-47 to furnish the highly
We are pleased to note that this second-generation route
to (-)-C eliminated seven steps from our original fragment
(7) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77.
(8) Walkup, R. D.; Kahl, J. D.; Kane, R. R. J. Org. Chem. 1998, 63,
9113.
(5) Total syntheses of 1 and ent-1 to date: (a) Nerenberg, J. B.; Hung,
D. T.; Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621.
(b) Smith, A. B., III.; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 1995, 117, 12011. (c) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles,
D. C. J. Org. Chem. 1997, 62, 6098. (d) Marshall, J. A.; Johns, B. A. J.
Org. Chem. 1998, 63, 7885.
(9) The structure assigned to each new compound is in accord with its
1
infrared, 500-MHz H NMR, and 125-MHz 13C NMR spectra, as well as
appropriate ion identification by HRMS.
(10) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505.
(11) Paterson, I. Tetrahedron Lett. 1979, 1519.
(6) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
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Org. Lett., Vol. 1, No. 11, 1999