Total synthesis of (+)-thiazinotrienomycin E

Article abstract of DOI:10.1021/ol991049g

(equation presented) The first total synthesis of (+)-thiazinotrienomycin E (1), member of a novel class of cytotoxic ansamycin antibiotics, has been achieved. The synthesis features a highly efficient construction of the aromatic fragment 3 incorporating

Full text of DOI:10.1021/ol991049g

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1491-1494
Total Synthesis of
(+)-Thiazinotrienomycin E
Amos B. Smith, III,* and Zehong Wan
Department of Chemistry, Monell Chemical Senses Center and Laboratory
for Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received September 15, 1999
ABSTRACT
The first total synthesis of (+)-thiazinotrienomycin E (1), member of a novel class of cytotoxic ansamycin antibiotics, has been achieved. The
synthesis features a highly efficient construction of the aromatic fragment 3 incorporating TBS protection of the aniline, a significantly improved
synthesis of (−)-19, an intermediate employed in our trienomycins A and F total syntheses, application of the Kocienski modified Julia protocol
to elaborate the E,E,E-triene subunit, an efficient union of 3 and (+)-4, and Mukaiyama macrolactamization to access the thiazinotrienomycin
macrolide.
In 1995 Hosokawa and co-workers reported the isolation and
planar structures of the thiazinotrienomycins (A-E), a new
family of ansamycin antibiotics produced by Streptomyces
sp. MJ672-m3,1 having significant in vitro cytotoxic activity
against a variety of human cancer cell lines.1 As a prelude
to total synthesis, we, in collaboration with Hosokawa and
co-workers, assigned the complete relative and absolute
stereochemistries of (+)-thiazinotrienomycin E (1) via
degradation and chemical correlation.2 We report here the
first total synthesis of (+)-1.
From the retrosynthetic perspective (Scheme 1), we
planned to install the C(29-38) side chain at a late stage in
the synthesis, thereby developing a unified strategy for the
thiazinotrienomycins from (+)-thiazinotrienomycinol (2). A
(1) Hosokawa, N.; Naganawa, H.; Inuma, H.; Hamada, M.; Takeuchi,
T.; Kanbe, T.; Hori, M. J. Antibiot. 1995, 48, 471-478. Hosokawa, N.;
Yamamoto, S.; Uehara, Y.; Hori, M.; Tsuchiya, K. S. J. Antibiot. 1999,
52, 485-490.
(2) Smith, A. B., III; Barbosa, J.; Hosokawa, N.; Naganawa, H.; Takeuchi,
T. Tetrahedron Lett. 1998, 39, 2891-2894.
(3) Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem.
Soc. 1995, 117, 10777-10778. Smith, A. B., III; Wood, J. L.; Wong, W.;
Gould, A. E.; Rizzo, C. J.; Barbosa, J.; Komiyama, K.; Ohmura, S. J. Am.
Chem. Soc. 1996, 118, 8308-8315. Smith, A. B., III; Barbosa, J.; Wong,
W.; Wood, J. L. J. Am. Chem. Soc. 1996, 118, 8316-8328. For other
synthetic approaches to the trienomycins and related mycotrienins, see:
Masse, C. E.; Yang, M.; Solomon, J.; Panek, J. S. J. Am. Chem. Soc. 1998,
120, 4123-4134. Yadav, J. S.; Praveen Kumar, T. K.; Maniyan, P. P.
Tetrahedron Lett. 1993, 34, 2965-2968. Fu¨rstner, A.; Baumgartner, J.
Tetrahedron 1993, 49, 8541-8560.
(4) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 1, 26-28. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O.
Tetrahedron Lett. 1991, 32, 1175-1178.
(5) Olah, G. A.; Kuhn, S. J.; Flood, S. H. J. Am. Chem. Soc. 1961, 83,
4571-4580.
(6) The structural assignment to each new compound is in accord with
1
its IR, H and 13C NMR, and high-resolution mass spectra.
10.1021/ol991049g CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/25/1999

salt of methyl thioglycolate7 and reduction of the nitro groups
with concomitant cyclization8 then furnished benzolactam
96 in modest overall yield. Protection of the aniline (CbzCl),
followed in turn by reduction of the ester (LiHBEt3,
15-crown-5 ether, THF),9 tosylation of the resultant alcohol,
and displacement with sodium benzenesulfinate, provided
10.6 Both the methyl and Cbz groups were then removed
(BBr3, CH2Cl2)10 and the resultant intermediate N- and
O-protected (TBSOTf, DMF).
Scheme 1
Synthesis of subtarget 5 began with methylation of known
alcohol (+)-1111 (Scheme 3). Selective reductive ozonoly-
Scheme 3
sis,12 followed by AIBN-promoted hydrostannylation, fur-
nished trans vinyl stannane (+)-12,13 contaminated with 6%
of the cis isomer. Separation of the isomers via flash
chromatography, protection of the primary hydroxyl
(TBSOTf), and treatment with iodine afforded (+)-13.6
Construction of (-)-5 was then achieved via palladium-
catalyzed Stille cross-coupling14 with 1415 followed by Swern
oxidation.16
similar tactic was employed for the trienomycins.3 Continuing
with this analysis, disconnection at the C(16-17) and C(1)
linkages leads to subtargets 3 and 4: assembly of the
macrolide would entail sulfone alkylation and macrolactam-
ization. Further disconnection at the C(8-9) olefin suggested
a Kocienski-modified4a Julia olefination4b between 5 and 6
to construct the E,E,E-triene, a structural element that has
proven problematic in the past.3
For the synthesis of subtarget (+)-4, we required (-)-19
(Scheme 4), first prepared in conjunction with our trieno-
Scheme 4
We began with the construction of subtarget 3. DIBAL
reduction of 7, followed by oxidation, esterification, and
dinitration5 (NO2BF4), furnished 86 in 86% yield for the four
steps (Scheme 2). Substitution of fluorine with the lithium
Scheme 2
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Org. Lett., Vol. 1, No. 9, 1999

mycin synthesis.3 We report here a significant improvement
in the construction of (-)-19. Protection of known alcohol
(+)-1517 followed by reductive ozonolysis furnished aldehyde
(+)-16.6 Addition of the vinyl anion derived from 17, the
latter available in two steps from 2-butyn-1-ol,18 afforded a
mixture of alcohols (ca. 2:1). After removal of the TMS
group, selective oxidation of the allylic alcohol furnished
(+)-18.6 Completion of (-)-19 entailed directed reduction
of â-hydroxyl ketone with Me4NBH(OAc)3 (95% de),19
generation of the 1,3-acetonide, and selective removal of the
primary BPS moiety.20 Alcohol (-)-19, identical to that
prepared previously,3 was thus available in eight steps and
49% overall yield, compared to 15 steps and 25% overall
yield.
Scheme 5
Continuing with assembly of (+)-4, protection of the
hydroxyl (PivCl), desilylation (TBAF), and Mitsunobu
reaction21 with 1-phenyl-1H-tetrazole-5-thiol (21), followed
by oxidation (H2O2), furnished4a sulfone (+)-22.6 Elaboration
of the triene entailed addition of aldehyde (-)-5 to the anion
derived from (+)-22 (KHMDS, THF, -78 °C); a mixture
of the E,E,E- and Z,E,E-trienes (ca. 10:1) was obtained in
85% yield. Reductive removal of the pivaloate moiety
(DIBAL) and conversion of the resultant allylic alcohol to
the chloride furnished (+)-4.6
With fragments 3 and (+)-4 in hand, we turned to
assembly of the macrolide (Scheme 5). Allyl chloride (+)-4
was converted to iodide 23, and then without isolation added
to the anion derived from 3 (NaHMDS, THF, -78 °C); a
diastereomeric mixture of sulfones (ca. 2:1; 64%) resulted.
Following reductive removal of the sulfone, the aniline was
selectively liberated via treatment with silica gel in chloro-
form and subsequently protected as the Alloc carbamate. The
phenolic TBS ether was then removed and the phenol
protected as the MOM ether to furnish (+)-24.6 A two-step
(7) Teulade, J. C.; Grassy, G.; Escale, R.; Chapat, J. P. J. Org. Chem.
1981, 46, 1026-1030.
oxidation protocol (Parikh-Doering22 and NaClO223) after
unmasking of the primary alcohol led to acid (+)-256 as a
mixture of rotamers (ca. 4:1). Palladium(0)-promoted re-
moval of the Alloc group furnished the amino acid, precursor
for macrocyclization. To our delight, slow addition of this
acid via syringe pump to a mixture of 2-chloro-1-methylpy-
ridinium iodide24 and TEA in toluene effected macrolac-
tamization (61%, two steps). Removal of the acetonide
completed construction of (+)-thiazinotrienomycinol (2).6
All that remained to arrive at (+)-thiazinotrienomycin E
(1) was installation of the amino acid side chain. To this
end, C(11) acylation of (+)-2 with the symmetrical anhydride
of FMOC-D-alanine,25 liberation of the primary amine (Et2-
NH, THF), followed by BOP-mediated coupling with cy-
clohexanecarboxylic acid, and removal of the MOM group
furnished (+)-thiazinotrienomycin E (1), identical in all
respects with natural material (1H and 13C NMR, IR, HRMS,
optical rotation, and TLC in three solvent systems).
(8) Kelly, T. R.; Kim, M. H.; Curtis, A. D. M. J. Org. Chem. 1993, 58,
5855-5857.
(9) The reduction initially proved troublesome because the amide was
unexpectedly more easily reduced than the ester under a variety of reducing
conditions.
(10) Combes, S.; Finet, J.-P. Synth. Commun. 1997, 27, 3769-3778.
(11) Prepared in two steps from propargyl alcohol, see: Smith, A. B.,
III; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095-13096.
(12) Chen, S.-Y.; Joullie´, M. M. Synth. Commun. 1984, 14, 591-597.
(13) Interestingly, the aldehyde was also reduced under these conditions.
(14) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813-817.
(15) Prepared from propargyl alcohol in one step, see: Jung, M. E.; Light,
L. A. Tetrahedron Lett. 1982, 23, 3851-3854.
(16) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(17) Alcohol (+)-15 is readily available in three steps from 3-buten-1-
ol, see: Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T.
K.; Minowa, N.; Koide, K. Chem. Eur. J. 1995, 1, 318-333.
(18) Takemoto, T.; Sdeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem.
Soc. 1993, 115, 8477-8478.
(19) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(20) To the best of our knowledge, this is the first example of such
selectivity.
(21) Mitsunobo, O. Synthesis 1981, 1-28.
(22) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
(23) Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; Hollis, W. G., Jr.;
O’Mahony, R.; Lever, J. G.; Bankaitis-Davis, D. M. J. Am. Chem. Soc.
1996, 118, 7513-7528.
(24) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163-1166.
(25) The selectivity was 2:1 in favor of acylation at C(11). In addition,
a small amount (<7%) of bis acylated material was isolated.
Org. Lett., Vol. 1, No. 9, 1999
1493

In summary, the first total synthesis of (+)-thiazinotrieno-
mycin E has been achieved. The efficient assembly of the
E,E,E-triene and the improved synthesis of advanced alcohol
(-)-19 are particularly noteworthy.
acknowledges a SAS dissertation fellowship from the
University of Pennsylvania.
Supporting Information Available: Spectroscopic and
analytical data for 1-6, 8-10, 12-13, 16, 18-20, 22, and
24-26 as well as representative experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through Grant GM 29028. Z.W. gratefully
OL991049G
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