Total synthesis of (-)-disorazole C1

Full text of DOI:10.1021/ja0443068

Published on Web 11/04/2004
Total Synthesis of (-)-Disorazole C1
Peter Wipf* and Thomas H. Graham
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received September 18, 2004; E-mail: pwipf@pitt.edu
Disorazole C1 (1) is one of 29 related macrocycles isolated in
1994 by Jansen and co-workers from the fermentation broth of the
myxobacterium Sorangium cellulosum.1 Myxobacteria demonstrate
features of both unicellular and polycellular organisms. They are
able to move in waves by gliding on surfaces of rotten wood, dead
plants, and other bacteria and fungi. Over the past two decades,
myxobacteria have been intensively studied, in part due to their
ability to produce a wide range of anticancer, antibacterial, fungi-
cidal, and immuno-modulating secondary metabolites.2 Disorazoles
possess significant cytotoxic and nM antitubulin activities.3 While
many of the disorazoles have pseudo-dimeric structures, their
macrocyclic-heterocyclic scaffolds and labile polyene segments
render them synthetically challenging,4 and questions about their
definitive structural assignment and their relative and absolute
configuration have remained unresolved.4a We now report the
asymmetric total synthesis of disorazole C1.
Our convergent retrosynthesis paid special consideration to the
known sensitivity of late stage polyene intermediates. The dimer
was separated into four segments that could be assembled under
mild reaction conditions with minimal protecting group manipula-
tions (Figure 1). Two of the (Z)-alkenes of the triene unit were
masked as alkynes. The resulting dieneyne 2 offered an opportunity
for a Sonogashira segment condensation. The 1,3-diol 3 would arise
from the known compound 5.5 The oxazole segment 4 was derived
from the propargyl alcohol 6, obtained from enantioselective
addition of an alkynyl zinc reagent to the corresponding aldehyde.6
Homoallylic alcohol 5 was obtained in 91% yield and 92% ee
by TiF4/(S)-Binol-catalyzed allylation.5 The terminal olefin was then
converted to the alcohol in 88% yield by cleavage with ozone using
Sudan III7 as an indicator, followed by in situ reduction with NaBH4
(Scheme 1).8 1,3-Diol protection and saponification led to acetonide
7 in 80% yield. Swern oxidation to the aldehyde and treatment
with 1-lithiopropyne afforded a mixture of diastereomers 8 and 9
which were readily separated by chromatography on triethylamine-
deactivated SiO2.9
Figure 1. Retrosynthetic analysis of (-)-disorazole C1.
Scheme 1a
Reduction of 8 using Red-Al in THF initially gave the corre-
sponding allylic alcohol in 68% yield. This yield was improved to
83% by rigorously degassing the THF prior to the introduction of
Red-Al. Conversion to diol 10 was completed in 84% yield by first
protecting the allylic hydroxyl group as the PMB ether using freshly
distilled p-methoxybenzyl bromide with Et3N and KHMDS in
THF,10 followed by removal of the acetonide with aqueous acetic
acid in THF. Diol 10 is a key intermediate in this synthesis, since
the primary hydroxyl group allows for a variety of transformations
for the installation of the C11-C12 (Z)-alkene. In the present
synthesis, a Peterson olefination with 1,3-bis(triisopropylsilyl)-
propyne11 was utilized. After protection of both hydroxyl groups
in 10 as triethylsilyl ethers, selective oxidation of the terminal TES-
ether under Swern conditions,12 exposure to lithiated 1,3-bis-
(triisopropylsilyl)propyne,11 and cleavage of the TES ether with
chloroacetic acid in methanol,13 an 8:1 (Z/E)-mixture of enyne 11
was obtained. The isomers were readily separated by chromatog-
a (a) O3/O2, Sudan III, MeOH, CH2Cl2, -78 °C then NaBH4, -78 °C to
rt, 88%; (b) 2,2-dimethoxypropane, PPTS, THF, 0 °C to rt, 36 h, 97%; (c)
1 M LiOH, THF, MeOH, 0 °C to rt, 20 h, 82%; (d) oxalyl chloride, DMSO,
Et3N, -78 °C; (e) propyne, n-BuLi, THF, -78 °C to 0 °C, 1.5 h; (f) Red-
Al, THF (degassed), 70-75 °C, 25 h, 83%; (g) PMB-Br, Et3N, KHMDS,
THF, -78 °C, 1 h then rt, 2 h; (h) AcOH, THF, H2O (4:1:1), 60 °C, 12 h,
84% (2 steps); (i) TES-OTf, 2,6-Lutidine, CH2Cl2, 0 °C, 30 min; (j) oxalyl
choride, DMSO, Et3N, CH2Cl2, 75% (2 steps); (k) 1,3-bis(TIPS)propyne,
n-BuLi, THF, -78 °C, 30 min; (l) chloroacetic acid, MeOH/CH2Cl2, rt, 14
h; (m) TBAF, THF, 0 °C to rt, 14 h, 94%.
raphy on SiO2. Deprotection of (Z)-11 with TBAF in THF afforded
the desired diol segment 3 in 94% yield.
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J. AM. CHEM. SOC. 2004, 126, 15346-15347
10.1021/ja0443068 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2a
Scheme 3a
a (a) TIPS-Cl, imid, DMF, rt, 16 h; (b) DiBAl-H, CH2Cl2, -10 °C, 50
min, 78% (2 steps); (c) TMS-acetylene, Et2Zn, toluene, reflux, 1 h, then
(S)-Binol, Ti(Oi-Pr)4, then 13, rt, 20 h, 66%; (d) benzoyl chloride, DMAP,
pyridine, rt, 4 h, 100%; (e) HF/H2O, CH3CN, rt, 12 h, 93%; (f) Dimethyl
sulfate, n-Bu4NHSO4, NaOH, toluene/H2O, 0 °C to rt, 3.5 h, 95%; (g) HF,
CH3CN, rt, 24 h then NaOCl, NaClO2, TEMPO, CH3CN, phosphate buffer
(pH 6.7), 45 °C, 18 h, 99%; (h) SerOMe‚HCl, EDC, HOBT, NMM, CH2Cl2,
0 °C to rt, 16 h, 55%; (i) DAST, CH2Cl2, -78 °C, 1 h then K2CO3, -78
°C to rt, 40 min; (j) DBU, BrCCl3, CH2Cl2, 0 °C to 4 °C, 20 h; (k) NBS,
AgNO3, acetone, rt, 1 h, 54%; (l) n-Bu3SnH, PdCl2(PPh3)2, THF, -78 °C
to rt, 3 h, then I2, 0 °C, 45 min, 92%; (m) LiOH, H2O, THF, rt, 12 h, 97%.
a (a) 3, PdCl2(PPh3)2, CuI, Et3N, CH3CN, -20 °C to rt, 75 min, 94%;
(b) 19, DCC, DMAP, CH2Cl2, 0 °C to rt, 14 h, 80%; (c) 3, PdCl2(PPh3)2,
CuI, Et3N, CH3CN, -20 °C to rt, 75 min, 94%; (d) LiOH, H2O, THF, rt,
13.5 h, 98%; (e) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, 2 h then
DMAP, toluene, rt, 16 h, 79%; (f) DDQ, phosphate buffer, CH2Cl2, rt, 15
min, 61%; (g) H2, Lindlar catalyst, quinoline, EtOAc, rt, 1 h, 57%.
Silyl ether protection of hydroxy nitrile 12 followed by reduction
with DiBAl-H afforded aldehyde 13 in 78% yield (Scheme 2). The
transformation of 13 to the propargylic alcohol 6 utilized the
methodology of Pu and co-workers.6 The alkynyl zinc reagent
derived from TMS-acetylene and diethylzinc was added to 13 in
the presence of a catalyst formed in situ from Ti(i-OPr)4 and (S)-
Binol. For the determination of the %ee of this transformation, 6
was converted to benzoate 14 and analyzed by chiral HPLC.
Dimethyl sulfate under phase-transfer conditions converted 6 to
the methyl ether 15 in 95% yield with concomitant loss of the
trimethylsilyl group. Carboxylic acid 1614 was obtained by removal
of the TIPS group with aqueous HF in acetonitrile, neutralization
with aqueous NaOH, and oxidation using the Merck protocol.15
Cyclodehydration of the hydroxy amide obtained from 16 and serine
methyl ester was accomplished using diethylaminosulfurtrifluoride
(DAST) followed by BrCCl3 and DBU16 to afford oxazoles 17 and
18. The alkynyl bromide 17 was an unexpected outcome, but
allowed for an efficient conversion to the required vinyl iodide 4
in 92% yield by Pd-catalyzed hydrostannylation.17 Finally, 4 was
converted to the carboxylic acid segment 19 in 97% yield by
saponification with aqueous LiOH in THF.
Both segments 3 and 4 were going to be utilized twice in the
convergent construction of disorazole C1. The chain extension
sequence to the seco-macrodiolide was initiated by Sonogashira
cross-coupling of 3 and 4 to afford the protected monomer 20 in
94% yield (Scheme 3). Acylation of 20 with an excess of 19 led to
21 in 80% yield. A second Sonogashira coupling between 21 and
3 afforded seco-disorazole C1 in 94% yield. Selective mono-
saponification of methyl ester 22 was followed by a Yamaguchi
lactonization18 to give macrocycle 2 in 79% yield. While thus far
the segment assembly had benefited from oustanding yields and
efficiency, the next steps required extensive optimization to avoid
decomposition of the oligo-enyne scaffold of the natural product.
The PMB ethers were removed with DDQ under buffered conditions
to afford the diol in 61% yield. Finally, double alkyne reduction
with Lindlar catalyst in the presence of excess quinoline afforded
1 in 57% yield after HPLC purification.19
complished in 20 steps and 1.5% yield for the longest linear
sequence. Notable features include the concise formation of iodo-
alkene 4 and the selective functional group manipulations including
the conversion of PMB-protected hexaene-diyne 2 to the highly
labile octaene natural product. This total synthesis also establishes
the correct relative and absolute configuration of the disorazoles.
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (GM-55433).
Supporting Information Available: Experimental procedures and
1
spectral data for all new compounds, including copies of H and 13C
NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
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(19) The synthetic material was identical in all regards (1H NMR, 13C NMR,
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Unfortunately, authentic disorazole C1 decomposed and is no longer
available for direct comparison.4a
In conclusion, the highly convergent and stereoselective synthesis
of the myxobacterium metabolite (-)-disorazole C1 was ac-
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