Formal synthesis of (-)-apicularen A

Article abstract of DOI:10.1021/ol0353417

(Matrix Presented) A formal synthesis of (-)-apicularen A has been completed. The synthesis features a cyanohydrin acetonide coupling as a convergent approach to the C9-C18 segment and an intramolecular Diels-Alder addition sequence to create both the 10-membered macrocycle and the aromatic ring.

Full text of DOI:10.1021/ol0353417

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3357-3360
Formal Synthesis of (−)-Apicularen A
Benjamin R. Graetz and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California-IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
Received July 18, 2003
ABSTRACT
A formal synthesis of (−)-apicularen A has been completed. The synthesis features a cyanohydrin acetonide coupling as a convergent approach
to the C9−C18 segment and an intramolecular Diels−Alder addition sequence to create both the 10-membered macrocycle and the aromatic
ring.
Isolated in a screening of the myxobacterial genus Chon-
dromyces, (-)-apicularen A (1) was found to be a potent
inhibitor of human cancer cell lines.1 Additionally, apicularen
was found to be active against the drug-resistant cell line
KB-V1.1b Apicularen A and the related salicylihalamides
appear to function by inhibiting growth-factor-induced an-
giogenesis, a mode of action distinct from that of other
known antitumor compounds.2 The structure of apicularen
A is characterized by a macrocyclic salicylate, a trans-
tetrahydropyran, and an unusual enamide side chain. Because
of its potent biological activity and interesting structure, the
synthesis of apicularen A has been investigated by a number
of groups,3 and three total or formal syntheses have been
reported.4 We describe a formal synthesis of (-)-apicularen
A based on an intramolecular Diels-Alder reaction that
simultaneously closes the macrocycle and assembles the
salicylate ring.
Figure 1. Structure of (-)-apicularen A.
Initially, a total synthesis was envisioned in which the
enamide would be introduced in the final step by coupling
of the amide 25 and the vinyl iodide 3 (vide infra), Figure 2.
An alternative route to a formal synthesis was envisioned
that proceeded through the macrolactone 4, synthesized by
De Brabander en route to apicularen A.4a In a retrosynthetic
analysis, the macrolactone would be generated from a
sequence involving a transesterification of methyl 3-
bromopropiolate6 with diol 6. The transesterification would
(1) (a) Kunze, B.; Jansen, R.; Reichenbach, H.; Ho¨fle, G. J. Antibiot.
1998, 51, 1075-1080. (b) Jansen, R.; Kunze, B.; Reichenbach, H.; Ho¨fle,
G. Eur. J. Org. Chem. 2000, 913-919.
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Biotechnol. 2002, 12, 702-705.
(3) (a) Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407-408. (b) Hilli,
F.; White, J. M.; Rizzacasa, M. A. Tetrahedron Lett. 2002, 43,
8507-8510. (c) Kuehnert, S. M.; Maier, M. E. Org. Lett. 2002, 4, 643-
646.
(4) (a) Bhattacharjee, A.; Seguil, O. R.; De Brabander, J. K. Tetrahedron
Lett. 2001, 42, 1217-1220. (b) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith,
S. A.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 5549-5552. (c) Lewis,
A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K. Org. Biomol.
Chem. 2003, 1, 104-116. (d) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew.
Chem., Int. Ed. 2002, 41, 3701-3704.
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(6) (a) Leroy, J. Synth. Commun. 1992, 22, 567-572. (b) Leroy, J. Org.
Synth. 1996, 74, 212-216.
10.1021/ol0353417 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/15/2003

Scheme 1. Synthesis of Cyanohydrin Acetonide Electrophilea
a Reagents and conditions: (a) (i) n-BuLi, THF, -78 °C, (ii)
BF3‚OEt2, (S)-epichlorohydrin, 60%; (b) NaI, acetone, 4, 99%; (c)
TESOTf, Et3N, CH2Cl2, 99%.
The synthesis of the cyanohydrin acetonide employed a
Noyori hydrogenation12 of â-ketoester 1413 and was achieved
in 96% yield and 94% ee, as determined by HPLC analysis
on a chiral column, Scheme 2. The cyanohydrin acetonide
Scheme 2. Synthesis of Cyanohydrin Acetonidea
Figure 2. Retrosynthetic analysis of apicularen A.
a Reagents and conditions: (a) [(R)-(+)-BINAP]-RuCl2(C6H6),
H2, EtOH, 1200 psi, 96%, 94% ee; (b) TMSCl, Et3N, CH2Cl2; (c)
DIBAL-H, Et2O, -78 °C; (d) (i) TMSCN, 18-crown-6/KCN (cat.),
CH2Cl2, (ii) 2,2-dimethoxypropane, acetone, CSA (cat.), 80% from
15.
be mediated by Otera’s distannoxane catalyst7 with con-
comitant Diels-Alder cyclization of one of the newly formed
alkynoate to generate the desired 10-membered macrolactone
preferentially over the alternative eight-membered Diels-
Alder product. The diene for the Diels-Alder reaction would
be generated from the addition of 2,4-pentadienyltrimethyl-
silane8 to an oxocarbenium ion generated from the methyl
acetal 7, setting the trans-tetrahydropyran geometry. Methyl
acetal 7 itself would be prepared by dissolving metal
reduction of nitrile 8, followed by oxidation of the resultant
primary alcohol and acidic deprotection. Nitrile 8 would
result from a cyanohydrin acetonide coupling between iodide
10 and nitrile 9. A cyanohydrin acetonide9 was envisioned
as an appropriate synthon for the requisite syn-1,3-diol
embedded in the structure of apicularen. The cyanohydrin
acetonide coupling10 facilitates a convergent synthesis of the
core of the molecule.
The synthesis of the electrophile for the cyanohydrin
acetonide coupling began with a tin-lithium exchange of
1111 followed by treatment with BF3‚OEt2 and (S)-epi-
chlorohydrin to produce enantiopure chlorohydrin 12 in 60%
yield as a single olefin isomer, Scheme 1. Finkelstein reaction
followed by protection of the secondary alcohol as the TES
ether was achieved in >95% yield over two steps to provide
iodide 10.
9 was synthesized in a four-step, three-pot procedure starting
with protection of the secondary alcohol in 15 as a TMS
ether. Reduction of the ester to the aldehyde with DIBALH,
cyanohydrin formation with TMSCN and catalytic 18-crown-
6/KCN complex, and acetonide formation by treatment with
acetone, 2,2-dimethoxypropane, and catalytic camphor-
sulfonic acid provided 9 as a 1:1 mixture of diastereomers
in 80% yield from ester 15.
With both coupling partners in hand, the polyol segment
of apicularen was ready for assembly, Scheme 3. Treatment
of cyanohydrin acetonide 9 with LDA in the presence of
iodide 10 and N,N-dimethylpropyleneurea (DMPU) provided
8 as a single diastereomer in 92% yield on a gram scale.
The nitrile and the benzyl protecting group of the coupled
product were reduced under dissolving metal conditions,
generating 16 as a single diastereomer in 88% yield. It was
important that the excess lithium in the reduction be
quenched with isoprene; otherwise reduction of the vinyl
silane to the saturated silane was observed. Additionally, the
ammonia solution required rapid neutralization to avoid loss
of the TES ether. Alcohol 16 was converted to methyl acetal
(7) Otera, J.; Yano, T.; Kawabata, A.; Nozaki, H. Tetrahedron Lett. 1986,
27, 2383.
(8) Seyferth, D.; Pornet, P.; Weinstein, R. Organometallics 1982, 1,
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Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856-58.
(b) Kitamura, M.; Tokunaga, M.; Ohkum, T.; Noyori, R. Org. Synth. 1992,
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4793-4795. (b) Claffey, M. M.; Hayes, C. J.; Heathcock, C. H. J. Org.
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2917-2920.
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Org. Lett., Vol. 5, No. 18, 2003

Scheme 3. Synthesis of Macrocycle Precursora
Scheme 4. Construction of the Macrocycle via Intramolecular
Diels-Alder Reactiona
a Reagents and conditions: (a) LDA, DMPU, THF, -78 to -40
°C, 92%; (b) (i) Li0, NH3(l), (ii) isoprene quench, 88%; (c) Dess-
Martin periodinane, CH2Cl2; (d) (i) DOWEX, MeOH, (ii) TFAA,
DMAP, pyridine, CH2Cl2, 89% from 16; (e) (i) 2,4-pentadienyl-
trimethylsilane, BF3‚OEt2, CH3CN, 0 °C, (ii) K2CO3, MeOH, H2O,
98%.
a Reagents and conditions: (a) toluene, 110 °C; (b) toluene,
DDQ, 100 °C; (c) NaOH, MeOH; (d) TBSOTf, Et3N, CH2Cl2, 44%
from 6; (e) DDQ, toluene, 90 °C, 8 h.
7 with a three-step sequence. The primary alcohol was
oxidized to the aldehyde with Dess-Martin periodinane. The
TES ether and the acetonide were removed with DOWEX
in methanol, and the revealed secondary alcohols were
protected as trifluoroacetates, producing acetal 7 in 89% yield
over the three steps. THP acetal 7 was treated with
2,4-pentadienyltrimethylsilane8 and BF3‚OEt2 to provide
exclusively the trans-tetrahydropyran14 6 in 98% yield.
After initial screening of a variety of methods to esterify
diol 6 with 3-bromopropiolic acid, it was discovered that
3-bromopropiolic acid decomposed under most standard
coupling conditions and that none of the desired ester was
detected. Otera has shown that a number of sensitive esters
can be prepared with his distannoxane catalyst 17, which
requires only heat to promote transesterification.7 Otera’s
method seemed ideal for our system since the next step would
involve a Diels-Alder reaction under thermal conditions
followed by oxidation with DDQ, all of which might be
carried out in the same flask, Scheme 4. Although this proved
to be true, namely, diol 6 in the presence of methyl
3-bromopropiolate and distannoxane catalyst 17 could be
heated in toluene followed by addition of DDQ to provide
the macrocyclic salicylate 19 in low yield (ca 10-20%), in
practice, yields were improved if the excess methyl 3-
bromopropiolate was removed by passing the reaction
through a plug of silica after the transesterification step. The
mixture could then be heated with DDQ in toluene to cyclize
the diester and to aromatize the Diels-Alder adduct. Once
the aromatic moiety was formed, removal of the extraneous
alkynoate on the THP was achieved with NaOH in methanol.
The resultant alcohol was protected as the TBS ether in 44%
yield from diol 6.
15% yield from an Otera esterification reaction (in addition
to the expected Diels-Alder adduct). Cyclization of 18 in
toluene with DDQ at 90 °C produced the aromatized
macrolide in a remarkable 78% yield. Cyclization in the
absence of DDQ did not proceed to completion under the
same conditions, suggesting that the DDQ played a catalytic
role in the Diels-Alder reaction. The intramolecular Diels-
Alder reaction itself is very efficient.
To complete the synthesis it was necessary to convert the
aryl bromide to a phenol, Scheme 5. This transformation was
Scheme 5. Completion of Formal Synthesis of Apicularen Aa
a Reagents and conditions: (a) (i) n-BuLi, THF, -78 °C, (ii)
(TMSO)2, 50%; (b) Ac2O, DMAP, pyridine, CH2Cl2, 94%; (c) (i)
N-iodosuccinimide, CH3CN, (ii) K2CO3, MeOH, (iii) DOWEX,
MeOH, 78%; (d) Bu3SnH, AIBN, PhH, 80%.
The moderate overall yield in the transformation of diol
6 to macrolide 5 is primarily a function of the inefficient
esterification. We found that diester 18 could be isolated in
achieved by halogen-lithium exchange followed by treat-
ment with trimethylsilyl peroxide15 to provide phenol 20 in
50% yield. Interestingly, treatment of phenol 20 with a
(14) Martin, M. G. G.; Horton, D. Carbohydr. Res. 1989, 191, 223-
229.
Org. Lett., Vol. 5, No. 18, 2003
3359

number of desilylation reagents such as TBAF or HF, which
would have generated alkene 4 directly, only removed the
TBS ether and not the vinyl silane. The vinyl silane could
be converted to a vinyl iodide in a two-step process. First,
the phenol 20 was protected as an acetate in quantitative
yield. The vinyl silane was converted to a vinyl iodide by
treatment with N-iodosuccinimide,16 and the acetate and TBS
protecting groups were removed with K2CO3 and then
DOWEX in methanol in 78% overall yield. Unfortunately,
attempts to couple the vinyl iodide 3 with the amide side
chain 2 using Porco’s conditions,17 which would have
completed the synthesis of apicularen A, were unsuccessful.
Removal of the iodine atom with Bu3SnH and AIBN
produced macrolide 4 in 80% yield. Macrolide 4 was an
intermediate in De Brabander’s total synthesis of apicularen
A, and this work thus constitutes a formal synthesis of
apicularen A.
A formal synthesis of (-)-apicularen A has been com-
pleted. The synthesis provides another example of the utility
of the convergent cyanohydrin acetonide coupling strategy
for the synthesis of oxygenated natural products. The key
transformation in the synthesis is an interesting intramolecu-
lar Diels-Alder sequence that assembled the aromatic ring
and the macrocycle in a single laboratory operation.
Acknowledgment. The National Institutes of Health
(GM-43854) provided financial support. Rhodia ChiRex
kindly provided samples of optically pure epichlorohydrin
to support this work.
Supporting Information Available: Preparation and
characterization of the compounds described. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) Taddei, M.; Ricci, A. Synthesis 1986, 633-635.
(16) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37,
8647-8650.
(17) Shen, R.; Porco, J. A. Org. Lett. 2000, 2, 1333-1336.
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