Multicomponent Linchpin Couplings of Silyl Dithianes: Synthesis of the Schreiber C(16-28) Trisacetonide Subtarget for Mycoticins A and B

Article abstract of DOI:10.1021/ol991166b

(Matrix Presented) An efficient synthesis of trisacetonide (+)-11, the Schreiber C(16-28) subtarget for mycoticins A and B, is described. The key synthetic transformation entails a one-flask, five-component linchpin coupling tactic.

Full text of DOI:10.1021/ol991166b

ORGANIC
LETTERS
1999
Vol. 1, No. 12
2001-2004
Multicomponent Linchpin Couplings of
Silyl Dithianes: Synthesis of the
Schreiber C(16−28) Trisacetonide
Subtarget for Mycoticins A and B
Amos B. Smith, III,* and Suresh M. Pitram
Department of Chemistry, Laboratory for Research on the Structure of Matter, and
Monell Chemical Senses Center, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received October 19, 1999
ABSTRACT
An efficient synthesis of trisacetonide (+)-11, the Schreiber C(16−28) subtarget for mycoticins A and B, is described. The key synthetic
transformation entails a one-flask, five-component linchpin coupling tactic.
Extended 1,3-hydroxylated chains constitute a central archi-
tectural feature of the polyene class of macrolide antibiotics.1
Some members, such as roxaticin,2 the dermostatins,3 and
the mycoticins4 (Figure 1), vary in ring size but share a
common polyol structural motif possessing the same relative
and absolute stereochemistries. Concise stereocontrolled
routes to such structural elements thus represent a significant
synthetic goal. Although the asymmetric aldol reaction has
proven to be a viable means of accessing 1,3-polyols, the
tactic suffers from the iterative nature required to set correctly
each stereogenic center. Alternatives to the aldol approach
are therefore finding increasing use.5 Rychnovsky and co-
workers employed the cyanohydrin acetonide strategy in their
elegant construction of the polyol moieties of roxaticin,2b
roflamycoin,6 and filipin.7
Recently, we described a one-flask, multicomponent
linchpin coupling of silyl dithianes with epoxides, exploiting
a solvent-controlled Brook rearrangement (Scheme 1).8 The
protocol, based on the work by Tietze,9 Oshima, and
Utimoto,10 involves lithiation of 2-tert-(butyldimethylsilyl)-
1,3-dithiane (6), followed in turn by addition of an epoxide
(1) (a) Omura, S. Macrolide Antibiotics: Chemistry, Biology, Practice;
Academic Press: New York, 1984. (b) Rychnovsky, S. D. Chem. ReV. 1995,
95, 2021.
(2) Structure determination: (a) Maehr, H.; Yang, R.; Hong, L.-N.; Liu,
C.-M.; Hatada, M. H.; Todaro, L. J. J. Org. Chem. 1992, 57, 4793.
Syntheses: (b) Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994,
116, 1753. (c) Mori, Y.; Asai, M.; Okumura, A.; Furukawa, H. Tetrahedron
1995, 51, 5299. (d) Mori, Y.; Asai, M.; Kawade, J.; Furukawa, H.
Tetrahedron 1995, 51, 5315.
(5) For recent reviews of polyol syntheses: (a) Schneider, C. Angew.
Chem. Int. Ed. 1998, 37, 1375. (b) Oishi, T.; Nakata, T. Synthesis 1990,
635.
(3) Rychnovsky, S. D.; Richardson, T. I.; Rogers, B. N. J. Org. Chem.
1997, 62, 2925.
(4) Structure determination: (a) Schreiber, S. L.; Goulet, M. T. Tetra-
hedron Lett. 1987, 28, 6001. (b) Schreiber, S. L.; Goulet, M. T.; Sammakia,
T. Tetrahedron Lett. 1987, 29, 6005. (c) Schreiber, S. L.; Goulet, M. T. J.
Am. Chem. Soc. 1987, 109, 8120. Synthesis: (d) Poss, C. S.; Rychnovsky,
S. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 3360.
(6) Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997,
119, 2058.
(7) Richardson, T. I.; Rychnovsky, S. D. J. Am. Chem. Soc. 1997, 119,
12360.
(8) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925.
(9) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett 1994,
511.
10.1021/ol991166b CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/09/1999

groups. This strategy was exploited to good advantage in
our recently reported syntheses of the spiroketal segments
of the spongistatin antitumor agents.11 We also demonstrated
the feasibility of a five-component coupling process.8
Herein, we report application of this tactic for the
economic (i.e., short) construction of the pseudo-C2-sym-
metric trisacetonide subtarget (+)-11 (Scheme 2), employed
Scheme 2
Figure 1.
to generate alkoxy dithiane 7, Brook rearrangement triggered
by HMPA or DMPU to afford anion 8, and alkylation with
a second epoxide to provide the unsymmetrical adduct 9.
Ether rather than THF is required as solvent for the initial
alkylation to suppress premature silyl migration leading to
the formation of symmetric adducts. Altering the absolute
configuration of the epoxides followed by removal of the
dithiane and stereocontrolled reduction of the derived ketone
provides access to all possible diastereomers of the 1,3-polyol
fragment (10). From the synthetic perspective, this tactic
efficiently furnishes the polyol chain with both full stereo-
chemical control and differentiation between hydroxyl
by Schreiber et al. in their synthesis of (+)-mycoticin A (1).4d
Importantly, fragment (+)-11 also holds promise as an
effective building block for the synthesis of roxaticin and
the dermostatins.
Scheme 1
Trisacetonide (+)-11 can be envisioned to arise from the
C2 symmetric diol 12, an adduct potentially available from
a one-flask, five-component linchpin coupling (Scheme 2).
A key constituent of this procedure would be (-)-(S,S)-1,2:
4,5-diepoxypentane (14), prepared via the Rychnovsky
protocol.12
Toward this end, lithiation of dithiane 6 (2.5 equiv;
Scheme 3), followed by alkylation with (-)-benzyl glycidyl
(10) (a) Shinokubo, H.; Miura, K.; Oshima, K.; Utimoto, K. Tetrahedron
1996, 52, 503. (b) Shinokubo, H.; Miura, K.; Oshima, K.; Utimoto, K.
Tetrahedron Lett. 1993, 34, 1951.
(11) (a) Smith, A. B., III; Zhuang, L.; Brook, C. S.; Lin, Q.; Moser, W.
H.; Trout, R. E. L, Boldi, A. M. Tetrahedron Lett. 1997, 38, 8671. (b)
Smith, A. B., III; Lin. Q.; Nakayama, K.; Boldi, A. M.; Brook, C. S.;
McBriar, M. D.; Moser, W. H.; Sobukawa, M.; Zhuang, L. Tetrahedron
Lett. 1997, 38, 8675.
(12) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. J.
Org. Chem. 1991, 56, 5161.
2002
Org. Lett., Vol. 1, No. 12, 1999

crossover products were observed; thus silyl migration is
intramolecular.
Scheme 3
Elaboration of diol (+)-12 to the Schreiber subtarget [(+)-
11; Scheme 5] began with protection to form the acetonide
Scheme 5
ether (13), addition of a mixture of diepoxypentane (-)-14
(1.0 equiv) and HMPA (1.3 equiv) in THF, furnished the
predicted diol (+)-1213 in 59% yield, accompanied by a
minor amount of epoxide (+)-15 (ca. 13%).13 Notably, use
of THF as cosolvent with HMPA in the second alkylation
resulted in higher yields compared to Et2O (17%). Alterna-
tively, when DMPU was employed as the additive, diol (+)-
12 was obtained in comparable yield (55%), also accompa-
nied by epoxide (+)-15 (18%). Thus, in a single flask, we
generate four carbon-carbon bonds, constructing the carbon
skeleton of the desired polyol fragment in an efficient,
stereocontrolled fashion.
(83%), followed by removal of the silyl groups with TBAF
(93%) and hydrolysis of the dithiane with mercuric perchlo-
rate and 2,6-lutidine in aqueous THF, to provide the bis(â-
hydroxy) C2 symmetric ketone (+)-2013 in 80% yield.15
Hydroxyl-directed syn-reduction of both ketones with NaBH4
in the presence of Et2BOMe (Scheme 5)16 and trisacetonide
formation yielded exclusively (+)-21,13 as determined by
NMR analysis (78%, two steps).17 Hydrogenolysis (93%) and
monosilylation18 (54%) completed construction of the desired
subtarget (+)-11.
During analysis of this multicomponent, linchpin coupling
we conducted mechanistic studies to determine whether silyl
migration preceded via an intra- or intermolecular process
(Scheme 4). Lithiation of a mixture of silyl dithianes (+)-
1613,14 and (-)-1713,14 (1:1) at -78 °C in the presence of
HMPA, followed by warming to ambient temperature,
resulted in rearranged products (+)-1813 and (-)-19.13 No
(13) The structural assignment to each new compound is in accord with
1
its IR, H and 13C NMR, and high-resolution mass spectra.
(14) These compounds were prepared via addition of the corresponding
silyl dithiane to the requisite epoxide (see ref 8).
(15) In our initial studies with the enatiomeric series of compounds,
calcium carbonate proved insufficient as a base. The result was removal of
the isopropylidene group and formation of the bicyclic compound (+)-ii.
Scheme 4
(16) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
(17) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945. (b) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511. (c) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
(18) McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
Org. Lett., Vol. 1, No. 12, 1999
2003

In summary, synthesis of (+)-11, the Schreiber C(16-
28) subtarget for mycoticins A and B, has been achieved by
exploiting a one-flask, five component, linchpin coupling
tactic. The highly convergent synthesis proceeded in eight
steps, five fewer than the previously reported route, and in
17% overall yield from diepoxypentane (-)-14. Importantly,
this multicomponent linchpin coupling protocol should
provide ready access to a wide variety of polyene macrolide
antibiotic analogues.
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through Grant GM 29028.
Supporting Information Available: Spectroscopic and
analytical data for 11, 12, 20, and 21 as well as a
representative experimental procedure. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL991166B
2004
Org. Lett., Vol. 1, No. 12, 1999