Enantioselective total synthesis of FD-891

Article abstract of DOI:10.1021/ja060018v

The enantioselective synthesis of FD-891 has been achieved with a longest linear sequence of 21 steps. The synthetic strategy involves the use of aldol additions of a chlorotitanium enolate of N-acylthiazolidinethiones as the key reaction to establish 6 o

Full text of DOI:10.1021/ja060018v

Published on Web 02/14/2006
Enantioselective Total Synthesis of FD-891
Michael T. Crimmins* and Franck Caussanel
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at Chapel
Hill, Chapel Hill, North Carolina 27599-3920
Received January 2, 2006; E-mail: crimmins@email.unc.edu
Scheme 1. Retrosynthetic Analysis of FD-891
FD-891, a 16-membered macrolide isolated from the fermentation
broth of Streptomyces graminofaciens A-8890, has been shown to
have cytotoxic activity in vitro against several tumor cell lines.1
The activity is reportedly similar to that of concanamycin A, a
specific inhibitor of vascular-type H+-ATPase.2 Recently, concana-
mycin A has been shown to specifically inhibit perforin-dependent
cytotoxic T lymphocyte (CTL)-mediated cytotoxicity, but not affect
Fas ligand (FasL)-dependent CTL-mediated cytotoxicity; these two
cytotoxic pathways play an essential role in the maintenance of
tissue homeostasis.3 Conversely, FD-891 was found to potently
prevent both perforin and FasL-dependent CTL-mediated killing
pathways, but did not inhibit vacuolar acidification.4
The relative and absolute configuration of FD-891 was elucidated
after extensive spectroscopic analysis and partial degradation.5 The
structure was subsequently revised based on X-ray analysis of partial
structures.6 While substantial synthetic accomplishments have been
made on related plecomacrolides,7 to date only three reports of
synthesis of fragments of FD-891 have appeared.8
Scheme 2. Synthesis of Epoxide 2a
Herein we report the first total synthesis of FD-891. A convergent
strategy exploiting the assembly of three subunits 2, 3, and 4 of
similar complexity was anticipated for the synthesis of FD-891
(Scheme 1). Fragments 2 and 3 were envisioned to undergo selective
cross-metathesis leading to a subsequent lactonization to give the
macrocyclic core. The late-stage installation of the C19-C25
fragment 4 would be accomplished via a Julia olefination. The three
key fragments would derive from synthons 5 and 6 accessible
through the application of the versatile aldol additions of chloroti-
tanium enolates of N-acylthiazolidinethiones recently advanced in
our laboratory.9
a Conditions: (a) TiCl4, (-)-sparteine, NMP, CH2Cl2, -78 to -40 °C,
78% (dr >20:1); (b) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 92%; (c) i-Bu2-
AlH, CH2Cl2, -78 °C, 74%; (d) Ph3PdC(CH3)CO2Et, toluene, 80 °C, 92%;
(e) i-Bu2AlH, THF, -78 °C, 98%; (f) pyridine, PivCl, CH2Cl2, 99%; (g)
NH4F, MeOH, 85%; (h) (+)-DET, (i-PrO)4Ti, t-BuOOH, molecular sieves
4 Å, CH2Cl2, -23 °C, 72% (dr 15:1); (i) Dess-Martin periodinane, Na-
HCO3, CH2Cl2, 97%; (j) MgBr2(Et2O), CH2dCHCH2SiMe3, CH2Cl2, -20
to -10 °C, 70% (dr >20:1); (k) TBSCl, imidazole, DMAP, CH2Cl2, 99%.
Scheme 3. Synthesis of the C13-C18 Fragment 3a
The synthesis of the C3-C12 unit 2 began with addition of
known aldehyde 710 to the chlorotitanium enolate of thioimide 8
to deliver the protected EVans syn adduct 5 after silylation of the
alcohol (Scheme 2). Reductive removal of the auxiliary directly
gave aldehyde 9, which was rapidly transformed to pivaloate 10 in
three steps. Selective removal of the primary silyl ether11 followed
by Sharpless epoxidation12 gave epoxide 11 in 72% yield. Dess-
Martin13 oxidation of alcohol 11 and subsequent chelate-controlled
allylation of the resultant aldehyde14 delivered the expected
epoxyalcohol as a single detectable diastereomer (dr >20:1).
Protection of the alcohol as its TBS ether produced the required
C3-C12 unit 2.
The synthesis of fragment 3 commenced with an aldol addition
between 3-butenal15 and the enolate of thiazolidinethione 8 under
conditions9a to give the non-EVans syn aldol adduct 6 in 73% yield
(dr >15:1) (Scheme 3). Protection of the alcohol delivered silyl
ether 12 whereupon reduction of the N-acylthioimide gave alcohol
13. Homologation of alcohol 13 was accomplished by displacement
of the hydroxyl with cyanide under Mitsunobu conditions16 to
provide nitrile 14. Two-stage reduction gave the corresponding diol,
which underwent selective protection to provide alcohol 15.
a Conditions: (a) TiCl4, (-)-sparteine, 3-butenal, CH2Cl2, 0 °C, 73%;
(b) TESOTf, 2,6-lutidine, CH2Cl2, -78 °C, 96%; (c) LiBH4, Et2O, MeOH,
0 °C to room temperature, 98%; (d) acetone cyanohydrin, DEAD, Ph3P,
toluene, 70 °C, 90%; (e) i-Bu2AlH, toluene, -78 °C, 88%; (f) NaBH4,
CH2Cl2, MeOH, then HCl, 84%; (g) TBSCl, imidazole, CH2Cl2, 92%; (h)
Ac2O, DMAP, Et3N, CH2Cl2, 0 to 25 °C, 98%.
Protection of the secondary alcohol as its acetate gave the C13-
C18 fragment 3 in 98% yield.
The synthesis of sulfone 4 began with the thioimide 12 also used
in the synthesis of the C13-C18 fragment. The aldehyde obtained
by the direct reduction of thioimide 12 was subjected to a second
aldol iteration to provide the aldol adduct 16 in 87% yield. The
methyl ketone 17 was obtained by transacylation of the auxiliary
9
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J. AM. CHEM. SOC. 2006, 128, 3128-3129
10.1021/ja060018v CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Synthesis of Sulfone 4a
The completion of the macrolactone required the extension at
C3 to the dienoate. To this end, reductive removal of the pivaloate
preceded oxidation of the allylic alcohol with manganese dioxide
and Horner-Wadsworth-Emmons olefination to deliver the di-
enoate 21. Hydrolysis of ester 21 followed by Yamaguchi macro-
lactonization20 gave the desired macrocycle 22. Selective depro-
tection of the primary silyl ether and oxidation of the resultant
alcohol provided aldehyde 23 in 70% yield, ready to be coupled
with the C19-C26 fragment 4 via a Julia reaction.
Julia olefination21 between aldehyde 23 and sulfone 4 provided
exclusively the E-olefin 24 (Scheme 5). Global deprotection by
the action of H2SiF622 gave FD-891 in 90% yield. The spectral data
of synthetic FD-891 were consistent in all respects with those
reported for the natural product.1,5,6
a Conditions: (a) i-Bu2AlH, CH2Cl2, -78 °C, 84%; (b) thioimide 8,
TiCl4, (-)-sparteine, NMP, CH2Cl2, -78 to 0 °C, then add aldehyde, 87%
(dr >20:1); (c) CH3N(OCH3)H‚HCl, imidazole, CH2Cl2, 78%; (d) MOMCl,
i-Pr2NEt, DMF, 50 °C, 87%; (e) MeMgCl, Et2O, 0 °C, 97%; (f) NaBH4,
CeCl3‚7(H2O), MeOH, 0 °C, 75% 18 + 15% C25 isomer which was
recycled; (g) NaH, MeI, THF, 0 °C to room temperature, 81%; (h) HCl
(concentrated), MeOH, 78%; (i) 2,2-dimethoxypropane, p-TSA, 88%; (j)
O3, CH2Cl2, MeOH, -78 °C, then NaBH4 -78 to 25 °C, 81%; (k) DIAD,
2-mercaptobenzothiazole, PPh3, CH2Cl2, 93%; (l) H2O2 30%, (NH4)6Mo7O24‚
4H2O, EtOH, 89%.
In conclusion, we have completed the first total synthesis of the
macrolide FD-891 in 21 steps (longest linear sequence). The
versatile aldol reaction of N-acylthiazolidinethione 8 was used to
create 8 of the 12 stereocenters with the same enantiomer of the
chiral auxiliary.
Acknowledgment. This work was supported by a research grant
from The National Cancer Institute (CA63572). We are grateful to
Scheme 5. Completion of FD-891a
1
professor T. Eguchi for providing authentic H and 13C spectra of
the natural product.
Supporting Information Available: Experimental procedures, as
well as 1H and 13C NMR spectra for all new compounds, and synthetic
FD-891. This material is available free of charge via the Internet at
http://pubs.acs.org.
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