Total Synthesis of (−)-Spirotryprostatin B
A R T I C L E S
side chain, prompted by the fact that such a pathway would
allow for facile access to spirotryprostatin B and, significantly,
side-chain analogues of this natural product from aldehyde 55.
Toward this end, hydrogenation of 52 catalyzed by Pd/BaSO4
poisoned with quinoline yielded olefin 53 in 90% yield
(Scheme 9).46 The transformation of 53 to diol 54 was achieved
with OsO4/NMO‚H2O in THF/tBuOH/H2O. The long reaction
time (3 days) for this cleavage suggested that access to the C-19
olefin in 54 is rather limited, an observation that is consistent
with the associated difficulties with olefination processes
1
extensively examined by Danishefsky. Analysis by H NMR
spectroscopy revealed that diol 54 was formed as a single
1
diastereomer. Interestingly, although the H NMR spectra of
Figure 2. ORTEP drawing of 46.39
all earlier intermediates were complicated by the presence of
multiple rotamers due to restricted amide rotation for the Boc
group, analysis of the spectra for 54 was simplified, as sharp
resonances were uniformly observed (Scheme 9). From 54,
aldehyde 55 was obtained following glycol cleavage with
Pb(OAc)4.41 Aldehyde 55 proved remarkably stable, no doubt
likely as a result of the sterically hindered environment where
it resides, allowing us focus on the critical olefination step.
Among the available procedures for the olefination of
sterically hindered systems, the Wittig reaction is a commonly
used transformation.47 A variety of conditions was examined
by employing the corresponding phosphonium salt (nBuLi, THF,
RT; NaH/DMSO, DMSO, RT; KH/DMSO, Tol, 60 °C) none
of which led to the desired product 59 (Scheme 10).48 Traces
of olefination product could be observed, but under all condi-
tions examined, extensive epimerization at C-18 was observed
to take place, and starting material 55 underwent decomposition.
Addition of iPrMgCl to aldehyde 55, followed by dehydration
of the resulting alcohol, was investigated. Careful control of
the amount of Grignard reagent led to conversion of 55 into
alcohol 56 without epimerization at C-18 in 97% yield.49
Various conditions for the direct dehydration of 56 were
examined (Martin sulfurane (2-5 equiv), CH2Cl2, -20 °C to
RT; POCl3 (2 equiv), Py/CH2Cl2), but none provided the desired
product 58.50,51 The use of a two-step procedure by formation
of triflate 56 or tosylate 57 followed by elimination also failed
due to the reluctance of 56 to form the corresponding triflate
or tosylate (Scheme 10).52
for 46 and 47. Fortunately, suitable crystals for X-ray crystal-
lographic analysis were obtained from 46, allowing for assign-
ment of structure 46 and, therefore, of 47 as well (Figure 2).39
Oxidative cleavage of the olefin in 46 followed by further
elaboration was planned, leading to the C-9 carboxylate required
for subsequent installation of the diketopiperazine. When 46
was submitted to standard dihydroxylation conditions (OsO4 (4
mol%), NMO‚H2O), diol 48 was obtained.40 Cleavage of diol
48 by treatment with Pb(OAc)4 was carried out without its prior
purification and cleanly afforded aldehyde 49 in 97% yield over
two steps.41 Subsequent oxidation of aldehyde 49 to the
corresponding acid 50 following Lindgren’s procedure42,43 and
conversion to the methyl ester with diazomethane afforded 51.44
Removal of the TIPS-protecting group was accomplished in
quantitative yield with TBAF in THF and gave 52.45 For the
large-scale conversion of 46 into 52, it is noteworthy that all
five preceding steps can be carried out without purification of
any of the various intermediates (48-51) in 80% overall yield
(Scheme 8).
At this stage of the synthesis, conversion of the alkyne into
the prenyl side chain was addressed. The success of this
transformation would provide the opportunity for the required
subsequent introduction of the endocyclic olefin and closure of
the diketopiperazine to yield spirotryprostatin B. Theoretically,
conversion of the C-19 alkyne into the corresponding aldehyde
by alkyne semi-hydrogenation followed by oxidative olefin
cleavage would set the stage for introduction of the appropriate
prenyl side chain. However, as shown in Danishefsky’s elegant
study en route to spirotryprostatin A, an aldehyde closely related
to 55 proved recalcitrant to a variety of olefination procedures.4
Nevertheless, we decided to pursue further a plan involving the
use of an olefination reaction for the introduction of the prenyl
We next turned our attention to the Julia-Lythgoe olefination
reaction, as this three-step sequence has proved to be a valuable
(46) (a) Rosenmund, K. W. Chem. Ber. 1918, 51, 585-593. (b) Rao, A. V. R.;
Reddy, S. P.; Reddy, E. R. J. Org. Chem. 1986, 51, 4158-4159. In this
reference, Pd/BaSO4 is misleadingly called Lindlar’s catalyst (Pd/CaCO3/
PbO) in the experimental part. (c) Initial trials were undertaken using
Lindlar’s catalyst; however, only recovered starting material 52 was isolated
under standard conditions. Lindlar, H. HelV. Chim. Acta 1952, 35, 446-
456.
(47) Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318-1330.
(48) (a) Asaoka, M.; Shima, K.; Fujii, N.; Takei, H. Tetrahedron 1988, 44,
4757-4766. (b) Oppolzer, W.; Wylie, R. D. HelV. Chim. Acta 1980, 63,
1198-1203.
(49) Williams, L.; Zhang, Z. D.; Shao, F.; Carroll, P. J.; Joullie´, M. M.
Tetrahedron 1996, 52, 11673-11694. Corrigendum: Williams, L.; Zhang,
Z. D.; Shao, F.; Carroll, P. J.; Joullie´, M. M. Tetrahedron 1997, 53, 1923-
1923.
(39) CCDC 196803 contains the supplementary crystallographic data for 46.
retrieving.html (or from the Cambridge Crystallographic Data Center, 12,
Union Road, Cambridge CB21EZ, U.K.; fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk).
(40) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973-
1976.
(41) Rubottom, G. M. Oxidation in Organic Chemistry; Academic Press: New
York, 1982.
(42) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888-890.
(43) An interesting alternative to obtain 50 directly from 46 through OsO4-
promoted catalytic oxidative cleavage was tested, but only traces of the
desired material was obtained, making this direct method incompatible with
the traditional three-step sequence. Travis, B. R.; Narayan, R. S.; Borhan,
B. J. Am. Chem. Soc. 2002, 124, 3824-3825.
(50) (a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339-2342.
(b) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327-4329.
(c) Dolle, R. E.; Schmidt, S. J.; Erhard, K. F.; Kruse, L. I. J. Am. Chem.
Soc. 1989, 111, 278-284.
(51) (a) Mehta, G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V. J. Am. Chem.
Soc. 1986, 108, 3443-3452. (b) Shizuri, Y.; Yamaguchi, S.; Terada, Y.;
Yamamura, S. Tetrahedron Lett. 1986, 27, 57-60.
(44) CH2N2 was prepared from N-methyl-N′-nitro-N-nitrosoguanidine and was
used as an ethereal solution. Fales, H. M.; Jaouni, T. M.; Babashak, J. F.
Anal. Chem. 1973, 45, 2302-2303.
(52) (a) Lefe`bre, O.; Brigaud, T.; Portella, C. J. Org. Chem. 2001, 66, 1941-
1946. (b) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley:
New York, 1967.
(45) Pattenden, G.; Robertson, G. M. Tetrahedron Lett. 1986, 27, 399-402.
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