Total synthesis and stereochemical assignment of the salicylate antitumor macrolide lobatamide C

Article abstract of DOI:10.1021/ja026025a

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C is reported. The synthesis involves Cu(I)-mediated enamide formation and Na₂CO₃-mediated esterification of a β-hydroxy acid and a salicylate cyanomethyl ester. Macrolactonization was accomplished using a Mitsunobu protocol. The stereochemical assignment of lobatamide C was achieved by Mosher ester analysis and comparison with prepared stereoisomers. Copyright

Full text of DOI:10.1021/ja026025a

Published on Web 04/24/2002
Total Synthesis and Stereochemical Assignment of the Salicylate Antitumor
Macrolide Lobatamide C1
Ruichao Shen, Cheng Ting Lin, and John A. Porco, Jr.*
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for Science and Engineering,
Boston UniVersity, 590 Commonwealth AVenue, Boston, Massachusetts 02215
Received February 25, 2002
The salicylate enamide macrolides are an emerging class of
antitumor natural products that have attracted considerable interest
regarding both chemical synthesis2 and biochemical mechanism of
action studies.3 Lobatamides A-F, unique members of this class
containing a 15-membered ring macrodilactone, were isolated in
1998 by Boyd et. al. from southwestern Pacific tunicates.4a
The absolute stereochemistry of the C15 divinylcarbinol of
YM-75518A4b (identical to lobatamide A) was determined to be
(S) using modified Mosher ester analysis.4c The stereogenic centers
at C8 and C11 await confirmation by chemical synthesis. Like the
salicylihalamides,2a the lobatamides display high potency against
human tumor cell lines (mean panel GI50 values approximately 1.6
nM),4a which may be derived from their ability to inhibit vacuolar-
type proton ATPase.3 In light of the impressive biological activity
and unique functionality of the lobatamides, including a Z-
Figure 1. Retrosynthesis of lobatamide C
trisubstituted olefin, divinylcarbinol moiety, and O-methyloxime
enamide side chain, we have targeted lobatamide C for synthesis.
Herein, we report the first total synthesis and stereochemical
assignment of lobatamide C.
Scheme 1 a
Retrosynthetic analysis of lobatamide C reveals two principal
fragments: the C11-26 salicylate subunit 3 and the C1-C10
enamide sector 4 (Figure 1). To construct the macrodilactone ring
system, we planned to utilize macrolactonization of precursor 2,
which is derived from esterification of 3 and 4. Although the
configuration at C8 and C11 has not been determined, we first
focused our attention on the preparation of the 8S enantiomer of 4
based on consideration of the absolute configuration of related
natural products salicylihalamide A2b and the oximidines.2g Further
disconnection of fragment 3 at the C18-C19 bond leads to benzylic
bromide 5 and Z-vinyl stannane 6 via Stille cross-coupling.5
Enamide subunit 4 was envisaged to be derived from Cu (I)-
catalyzed amidation of vinyl iodide 7 with E-O-methyloxime amide
8.6
The synthesis of the enamide segment 4 commenced with
addition of the acetylenic alane7 reagent derived from trimethylsilyl
acetylene to (R)-ethyl-3,4-epoxybutanoate 98 to afford 10 (Scheme
1). Hydroxyl protection using chlorodiethylisopropylsilane followed
by treatment of the resulting silyl ether 11 with AgNO3/NBS9/H2O10
afforded a bromoalkyne 12, which was converted to (E)-stannyl-
alkene 13 using Pattenden’s method.11 Iodine exchange of 13
furnished vinyl iodide 7 with full retention of olefin stereochemistry.
After considerable experimentation, we found that copper(I)
thiophenecarboxylate (CuTC)-mediated vinylic substitution of 7
with E-O-methyloxime amide 86 (1.2 equiv), Cs2CO3 (1.2 equiv),
1,10-phenanthroline (0.5 equiv), and dba (0.2 equiv)12 (DMA, 65
°C, 17 h) led to a 45% yield of enamide 14, along with 10% of the
easily separable Z-oxime stereoisomer. Desilylation of 14 using
a Conditions: (a) trimethylsilyl acetylene, n-BuLi, -35 °C, toluene;
Et2AlCl, 0 °C; then 9, 0 °C, 72%; (b) DEIPSCl, imidazole, DMF, 97%; (c)
NBS, AgNO3, H2O, 98%; (d) Bu3SnH, Pd(PPh3)4, THF, -78 °C, 1 h, rt, 1
h, 86%; (e) I2, THF, 0 °C, 93%; (f) 8, CuTC (0.5 equiv), Cs2CO3, 1,10-
phenanthroline, dba, DMA, 65 °C, 17 h, 45% (14), 10% (Z-oxime isomer);
(g) TBAF, THF, rt, 99%; (h) aq LiOH, THF/MeOH, rt, 77%.
TBAF afforded enamide alcohol 15, which was hydrolyzed with
LiOH to provide the labile enamide acid fragment 4.
Benzylic bromide 5 was prepared from readily available aryl
triflate 1613 (Scheme 2). Treatment of 16 with lithium dimethyl-
cuprate14/MeI10 led to the production of 1,3-benzodioxan-4-one (17).
Hydrolysis with KOH13 provided 6-methylsalicylic acid, which was
converted to cyanomethyl ester 18.15 Protection of 18 as a silyl
ether, followed by benzylic bromination,16 afforded 5. Synthesis
of the vinyl stannane 6 required for sp2-sp3 coupling with 5 began
with hydrozirconation of protected alkyne 20. Zirconocene-zinc
transmetalation17 followed by addition to configurationally stable
enal 2118 afforded divinylcarbinol 23 as a 1:1 nonseparable mixture
of diastereomers. Extensive studies were performed to establish the
proposed S configuration of the divinylcarbinol at C15, including
screening of various chiral amino alcohols. However, the best result
was obtained with 2:1 (S:R) with Wipf’s amino thiol ligand 22.17
Compound 23 (inseparable 2:1 mixture of diastereomers) was
further advanced by silylation of the secondary alcohol followed
by lithiation-trimethylstannylation to afford vinyl stannane 6, which
* To whom correspondence may be sent. E-mail: porco@chem.bu.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 5650-5651
10.1021/ja026025a CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
confirmed to be identical with data reported for natural lobatamide
1
C by H and 13C NMR, [R]D, and TLC Rf values in three solvent
systems.
In summary, the first total synthesis of the antitumor natural
product lobatamide C has been accomplished and its absolute
configuration has been determined to be 8S, 11S, 15S. Further
studies on the lobatamides and simplified analogues, as well as
their biological evaluation, are in progress and will be reported in
due course.
Acknowledgment. We thank Dr. Michael R. Boyd (NCI) for
providing authentic lobatamide C and spectral data, and Mr. Scott
R. Magee for initial studies. Acknowledgment is made to the
National Institutes of Health (GM62842) and the donors of the
Petroleum Research Fund, administered by the ACS (PRF No.
35497-G1) for financial support.
a Conditions: (a) Me2CuLi, THF, -78 °C; 0 °C, MeI, 85%; (b) aq KOH/
THF, 100%; (c) ClCH2CN, Et3N, acetone, 80%; (d) TBSCl, imidazole,
DMF, 99%; (e) NBS, AIBN, CCl4, 72%; (f) DEIPSCl, imidazole, DMF,
91%; (g) Cp2ZrHCl, CH2Cl2, rt; Et2Zn, -78 °C, 10 min; 22, -78f -30
°C, 1 h; 21, -30 °C, 20 h, 68% (S:R ) 2:1); (h) TBSCl, imidazole, DMF,
93%; (i) n-BuLi, Et2O; Me3SnCl, 98%; (j) Pd2(dba)3-CHCl3, AsPh3, THF,
rt; 5, 6, 70 °C, 3 h, 66%; (k) TBAF, 0 °C, 67%.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 3 a
References
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a Conditions: (a) NBu4OH, MeOH, rt; azeotropic removal of water; 3,
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was coupled with benzylic bromide 5 using the conditions of
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cyanomethyl ester 3.
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Initial base-catalyzed fragment couplings between salicylate
cyanomethyl ester 3 and hydroxy ester 15 failed to effect esteri-
fication without extensive levels of elimination of the â-salicyloxy
ester. However, after extensive optimization, we found that the
tetrabutylammonium salt of enamide acid 4 participated in smooth
esterification reactions with cyanomethyl ester 3 (Na2CO3, DMF/
o
2-butanone, 80 C) to provide the desired salicylate 26 (Scheme
3). The tetralkylammonium salt of 4 both increases solubility of
the enamide alcohol fragment, and likely blocks an R-deprotonation/
elimination pathway. Treatment of 26 with HF-pyridine afforded
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27 and 28 with HF-pyridine led to efficient production of 1 (52%)
and its C15 epimer 29 (78%). The absolute configuration of 1 at
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(10) See Supporting Information for experimental details.
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(22) We thank Dr. K. Suzumura (Yamanouchi Pharmaceutical Co.) for
providing experimental details on Mosher ester analysis of YM75518A.
JA026025A
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