Total Synthesis and Biological Evaluation of (-)Apicularen A and Analogues Thereof

Article abstract of DOI:10.1002/chem.200305230

Apicularen A (1) and related benzolactone acylenamines belong to a growing class of novel natural products possessing highly cytotoxic properties. The challenging structure of 1 includes a 10-membered macrolactone ring, a tetrahydropyran system, an o,m-substituted phenol and a doubly unsaturated acyl group attached on the side chain enamine functionality. The total synthesis of apicularen A described herein involves a strategy equivalent to its proposed biosynthesis and entails a reiterative two-step procedure featuring allylation and ozonolytic cleavage to grow the molecule's chain by one acetate unit at a time. The developed synthetic technology was applied to the construction of a series of apicularen A analogues whose biological evaluation established a set of structure-activity relationships in this new area of potential importance in cancer chemotherapy.

Full text of DOI:10.1002/chem.200305230

FULL PAPER
Total Synthesis and Biological Evaluation of (À)Apicularen A and Analogues
Thereof
K. C. Nicolaou,*[a, b] David W. Kim,[b] Rachid Baati,[a] Aurora O’Brate,[c] and
Paraskevi Giannakakou[c]
Abstract: Apicularen A (1) and related
benzolactone acylenamines belong to a
growing class of novel natural products
possessing highly cytotoxic properties.
The challenging structure of 1 includes
a 10-membered macrolactone ring, a
tetrahydropyran system, an o,m-substi-
tuted phenol and a doubly unsaturated
acyl group attached on the side chain
enamine functionality. The total syn-
thesis of apicularen A described herein
involves a strategy equivalent to its
proposed biosynthesis and entails a re-
iterative two-step procedure featuring
allylation and ozonolytic cleavage to
grow the molecule×s chain by one ace-
tate unit at a time. The developed syn-
thetic technology was applied to the
construction of a series of apicularen A
analogues whose biological evaluation
established a set of structure activity
relationships in this new area of poten-
tial importance in cancer chemothera-
py.
Keywords: acylenamines
tumor agents apicularen
macrolactonization ¥ total synthesis
¥
anti-
¥
¥
Introduction
apicularen A exerts its antitumor properties through inhibi-
tion of angiogenesis.[2]
As part of a search for new cytotoxic agents to be used as
potential anticancer drugs, the Hˆfle Jansen group isolated,
in 1998, apicularen A[1] (1; see Figure 1), a potent substance
with a novel molecular architecture and an impressive bio-
logical profile. Isolated from a variety of strains of the myx-
obacterial genus Chondromyces (i.e. C. apiculatus, C. lanugi-
nosus, C. pediculatus, and C. robustus), this naturally occur-
ring substance exhibits extremely high potency against a
range of human cancer cells, including ovarian, prostate,
lung, kidney, leukemia, cervix, and histocytic cell lines. IC50
values against these cells range from 0.1 to 3.0 ngmLÀ1 and,
most importantly, activity has been found against the multi-
drug-resistant KB-V1 cell line. It was recently reported that
Apicularen is grouped in the so-named benzolactone en-
amide family of compounds (some members of which are
shown in Figure 1) whose mechanism of action remained a
mystery until a team at the National Cancer Institute (NCI)
tested them against their 60-cell antitumor screen.[3,4] These
investigators made the connection between the salicylihala-
e]
mides,[5a] oximidines,[5b] and lobatamides[5c with bafilomy-
cin and concanamycin,[6] natural products whose mode of
action was known to involve inhibition of vacuolar-type (H+
)-ATPases (V-ATPases).[7] Apicularen A was also found to
be implicated in such inhibition, thereby, clarifying some-
what its mechanism of action. In view of the impressive se-
lectivity[8] exhibited against various V-ATPases, these com-
pounds hold considerable promise for the treatment of a
number of diseases, including diabetes, Alzheimer×s disease,
cardiovascular disorders, osteoporosis, and cancer.[9]
[a] Prof. K. C. Nicolaou, Dr. R. Baati
Department of Chemistry and The Skaggs Institute for Chemical Bi-
ology
From the architectural point of view, apicularen A (1)
comprises of a 10-membered macrolide ring that includes a
salicylic acid residue and a bridging oxygen atom forming a
tetrahydropyran residue. In addition, the macrocycle carries
a multiunsaturated chain consisting of an acylenamine
moiety and a Z,Z-diene system. Complicating apicularen×s
total synthesis are, in addition to these sensitive structural
elements, four stereogenic centers, all residing on the macro-
cyclic system. Due to the structural novelty represented by
apicularen A and its potent biological activity, a total syn-
thesis of this natural product and an avenue to analogue
construction was deemed important. Laboratories have re-
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (+1)858-784-2469
E-mail: kcn@scripps.edu
[b] Prof. K. C. Nicolaou, D. W. Kim
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[c] A. O’Brate, Dr. P. Giannakakou
Winship Cancer Institute, Emory University School of Medicine
Atlanta, GA 30322 (USA)
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FULL PAPER
Scheme 1. Molecular structure and retrosynthetic analysis of apicularen
A (1) and its D17,18 Z isomer (2). Ipc=isopinocampheyl; Tf=trifluorome-
thanesulfonate.
successful, such a strategy could be considered ™biomimetic∫
to the extent that the allylation ozonolysis protocol introdu-
ces a two-carbon unit equivalent to the acetate moiety to
the growing chain. Closing the macrolide ring before or
after completing the acylenamine side chain was then ex-
pected to furnish, upon deprotection, the natural product.
The strategy derived from this analysis was ideal for applica-
tion to the construction of side-chain analogues since this
moiety was to be introduced in the final phase of the synthe-
sis.
Figure 1. Apicularen A (1) and related benzolactone acylenamine natural
products.
ported synthetic studies[10] in this area, including a total syn-
thesis[11a] by DeBrabander and co-workers and a formal syn-
Total synthesis of apicularen A: The designed synthetic
strategy towards apicularen A (1) required macrolactone 20
as an advanced intermediate, a substance whose construc-
tion is shown in Scheme 2. Commencing from commercially
available 2,6-dihydroxybenzoic acid, the acetonide triflate 3
was synthesized according to a literature procedure[12a] and
then allowed to react in a Stille[15] fashion with allylstannane
4a in the presence of catalytic [Pd(PPh3)4] and LiCl in re-
fluxing THF to afford terminal olefin 6 in 99% yield. Ozo-
nolytic cleavage (O3; PPh3) at the olefinic bond in 6 gave al-
dehyde 7, whose reaction with Brown×s allylborane at
À1008C (Ipc2Blallyl, prepared from (+)-Ipc2BOMe)[13] al-
lowed asymmetric allylation to furnish 8 in 70% yield and
95% ee (as determined by Mosher ester formation).[16] Pro-
tection of the newly generated alcohol in 8 with TESOTf
and 2,6-lutidine led to silyl ether 9 (83% yield) which was
then subjected to ozonolysis cleavage as described above to
give aldehyde 10. Reiteration of the allylation step on this
new aldehyde using Ipc2Bdallyl (prepared from (À)-Ipc2-
BOMe)[13] at À1008C led to the desired 1,3-diol and its dia-
stereoisomer in a 4:1 ratio. To facilitate chromatographic
separation of the product from the interfering Ipc alcohol,
the TES group was removed by exposing the crude product
mixture to (aq) HCl and then subjecting the resulting mix-
ture to flash column chromatography leading to pure 11
(62% over two steps from 10) plus its diastereoisomer (not
shown, 16%). Ozonolytic cleavage of 11 (O3; PPh3) was ac-
thesis[11c,d] by R. J. K. Taylor and co-workers. In a prelimina-
[11b]
ry communication,
we reported the total synthesis of
apicularen A and its D17,18 Z analogue. Herein, we describe
the details of this strategy and its application to the con-
struction of a number of analogues which were designed for
chemical biology studies that revealed further structure ac-
tivity relationships within this family of compounds.
Results and Discussion
The structure of apicularen A (1) is intriguing from the bio-
synthetic standpoint in that it was determined[1b] to arise
from eleven acetate units which account for all its carbon
atoms except for C-17 (which comes from glycine), C-25
(which derives from methionine), and C-18 whose origin re-
mains unknown. Our intention was to devise both a ™biomi-
metic∫ strategy toward apicularen A and to apply it to the
synthesis of various side-chain analogues.
Retrosynthetic analysis: Scheme 1 depicts a retrosynthetic
analysis of apicularen A (1) that is based on the premise
that an allylation ozonolysis sequence serves as a provider
of the acetate unit (to be reiterated five times). Further dis-
connections of 1 at the macrolactone and acylenamine sites
14]
revealed three key building blocks, 3, 4a c, and 5.[12
If
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Total Synthesis of (À)Apicularen A and Analogues Thereof
6177 6191
companied by lactol formation and the resulting compound
was engaged as its acetate derivative (12, ca. 1:1.2 mixture
of anomers) with Ac2O-py (83% overall yield from 11).
Stereoselective formation (>95%) of the tetrahydropyran
ring was then accomplished by reaction of 12 with allyltri-
methylsilane (4a) in the presence of BF3¥OEt2 in acetoni-
trile. Reiteration of the ozonolysis allylation protocol with
Ipc2Bdallyl as described above then led sequentially to 14
(98% yield) and 15 (74% yield, 85:15 diastereomeric ratio).
The next step, aiming at formation of the macrocycle,
parallels the NaH procedure utilized by DeBrabander and
Bhattacharjee[17] in their synthesis of apicularen A. Howev-
er, in this instance the use of excess NaH (7.0 equiv) in THF
at ambient temperature, followed by addition of 5.0 equiva-
lents of water (after the macrocycle was formed) resulted in
complete deprotection, furnishing the dihydroxylactone 16
in 75% yield. The structure of this compound (16) was un-
ambiguously assigned by X-ray crystallography analysis (see
ORTEP drawing, Figure 2). Having constructed the key ele-
ment of the macrocyclic ring, and diverting from previous
syntheses, we protected the two hydroxy groups of 16 as
TBS ethers (TBSOTf, 2,6-lut., 99% yield) to afford 17,[18]
whose ozonolytic (O3; PPh3) cleavage led to aldehyde 18
(95% yield). Takai iodo-olefination (CrCl2 CHI3)[19] of 18
then furnished trans-iodo-olefin 19 together with its cis
isomer in a 4:1 isomeric ratio (80% combined yield). Final-
ly, desilylation (TBAF) at both oxygen atoms gave the tar-
geted intermediate 20 in 80% yield.
The next projected step in the synthesis was the coupling
of the appropriate doubly unsaturated amide 5 to the syn-
thesized vinyl iodide 20 by employing copper(i) thiophene
carboxylate (CuTC)[20] and Rb2CO3. Primary amide
5
(Scheme 1) was secured by a literature procedure[14a] but un-
fortunately initial attempts to attach it to 20 failed.[11d]
While the reasons for this fruitless attempt are still not
clear, we immediately adopted a second plan which entailed
going through the sequence outlined in Scheme 3. Thus,
Scheme 2. Construction of advanced intermediate 20. a) allyl-tri-n-butyl-
tin (1.2 equiv), LiCl (3.0 equiv), [Pd(PPh3)4] (2.0 mol%), THF, reflux, 12
h, 99%; b) O3, CH2Cl2, À788C, 1 h; Me2S (20 equiv), 258C; then PPh3
(4.0 equiv), 1 h, 92%; c) (Ipc)2Blallyl (2.0 equiv), Et2O, À1008C, 2 h,
70%; d) TESOTf (2.0 equiv), 2,6-lut. (4.0 equiv), CH2Cl2, 258C, 3 h,
83%; e) O3, CH2Cl2, À788C, 1 h; Me2S (20 equiv), 258C; then PPh3 (4.0
equiv), 1 h, 95%; f) (Ipc)2Bdallyl (2.0 equiv), Et2O, À1008C, 2 h; g) 1 n
HCl, 4 h, 62% over two steps; h) O3, CH2Cl2, À788C, 1 h; Me2S ( 20
equiv), 258C; then PPh3 (4.0 equiv), 1 h; i) Ac2O, py, 1 h, 83 % over two
steps; j) allyltrimethylsilane (5.0 equiv), BF3¥OEt2 (1.1 equiv), CH3CN,
08C, 1 h, 97%; k) O3, CH2Cl2, À788C, 1 h; Me2S (20 equiv), 258C; then
PPh3 (4.0 equiv), 4 h, 98%; l) (Ipc)2Bdallyl (2.0 equiv), Et2O, À1008C, 2 h,
74%; m) NaH (7.0 equiv), THF, 258C, 1 h; then H2O (5.0 equiv), 258C,
4 h, 75%; TBSOTf (4.0 equiv), 2,6-lut. (8.0 equiv), CH2Cl2, 258C, 4 h,
99%; o) O3, CH2Cl2, À788C, 1 h; Me2S (20 equiv), 258C; then PPh3 (4.0
equiv), 1 h, 95%; p) CHI3 (4.0 equiv), CrCl2 (12 equiv), THF, 258C, 12 h,
80%; q) TBAF (5.0 equiv), THF, 258C, 8 h, 80%. 2,6-lut.=2,6-lutidine,
py=pyridine, TES=triethylsilyl, TMS=trimethylsilyl, TBS=tert-butyldi-
methylsilyl, TBAF=tetra-n-butylammonium fluoride.
Scheme 3. Synthesis of late stage intermediate 23. a) mCPBA (4.5 equiv),
NaHCO3 (4.5 equiv), CH2Cl2, 258C, 24 h, 87%; b) NaN3 (10.0 equiv),
NH4Cl (5.0 equiv), MeOH/H2O= (1:1 v(v), reflux, 20 h, 72%; c) PPh3
(1.6 equiv), H2O, (2.0 equiv), THF, 408C, 20 h; d) EDC (1.5 equiv),
HOBt (1.7 equiv), acid 5c (1.5 equiv), DIEPA (2.2 equiv), CH2Cl2, 258C,
3 h, 65% over two steps. mCPBA=3-chloroperoxybenzoic acid, EDC=
1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, HOBt=
1-hydroxybenzotriazole hydrate, DIEA=N,N=diisopropylethylamine.
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K. C. Nicolaou et al.
FULL PAPER
time employing an open-chain
vinyl iodide, a substrate which,
it was reasoned, might enjoy
better reactivity by virtue of its
higher flexibility. This hypothe-
sis led us to adopt substrate 15
as a starting point and a new se-
quence for the final drive to-
wards apicularen A (1). Pro-
ceeding as summarized in
Scheme 5, this new strategy
paid handsome dividends, deliv-
ering not only 1 but also its
D17,18 Z stereoisomer (2). Thus,
protection of the free hydroxy
group in 15 with a TBS group
(TBSOTf-2,6-lut., 94% yield)
followed by the usual ozonolyt-
ic cleavage (O3; PPh3, 89%
yield) gave aldehyde 28 via in-
termediate 27. Takai extension
(CrCl2-CHI3) of the latter com-
pound then produced vinyl
iodide 29 in 91% yield (con-
taining ca. 10% cis-isomer), set-
Figure 2. ORTEP drawing (A) obtained from X-ray crystallographic analysis and MM2 calculated minimum
energy conformation (B) of compound 16.
olefin 17 (Scheme 2) was epoxidized with mCPBA to afford
terminal epoxide 21 which was obtained as a diastereomeric
mixture (87% yield, ca. 1:1, inconsequential). Regioselective
opening of the epoxide moiety in 21 with NaN3 yielded hy-
droxy azide 22 as a mixture of two diastereoisomers in 72%
yield. Reduction of this azide mixture according to the Stau-
dinger conditions[21] (PPh3; H2O) furnished the correspond-
ing hydroxy amine mixture which was coupled with carbox-
ylic acid 5c under the influence of EDC and HOBt to
afford hydroxy amide 23 (65% overall yield, mixture of two
diastereoisomers). Expecting to effect elimination of H2O
from 23 to furnish the desired acylenamine functionality, we
then proceeded to subject this intermediate to appropriate
dehydrating conditions, but, unfortunately again, we faced a
resilient substrate, leading either to starting material or de-
composition under a variety of conditions.
ting the stage for the crucial installation of the acylenamine
chain. Pleasantly, exposure of a mixture of (E)-29 and its Z
stereoisomer (Z)-29 to CuTC and Rb2CO3 in the presence
of excess amide 5 in DMA at 908C, furnished smoothly the
desired enamide[26] products 30a and 30b (41 and 4%
yields, respectively). After chromatographic separation, each
silyl ether derivative (30a and 30b) was separately treated
with TBAF in THF at ambient temperature leading to hy-
droxy compounds 31a and 31b in 80 and 60% yields, re-
spectively. Exposure to excess NaH of 31a and 31b in THF
at ambient temperature, followed by addition of water led
In pursuing another elimination-based strategy, we
sought to take advantage of a similar step utilized in the
synthesis of salicylihalamide by Labrecque et al.[14a] as
shown in Scheme 4. Thus, intermediate 17 (Scheme 2) was
now hydroborated with BH3¥Me2S under sonication condi-
tions[22] and the resulting borane oxidatively (NaHCO3
H2O2) converted to primary alcohol 24 (71% yield). Oxida-
tion of 24 under TPAP NMO conditions[23] led to aldehyde
25 in 99% yield and exposure of the latter compound to
two equivalents of amide 5 in the presence of TMSOTf fol-
lowed by TBAF addition furnished bisamide 26. All at-
tempts to eliminate one of the amide groups from 26, how-
ever, including identical conditions (NaH, PhCF3, D) to
those previously employed[24] for such a reaction failed, once
again.
Scheme 4. Synthesis of apicularen A bisamide derivative 26. a) BH3¥Me2S
(5.0 equiv), THF, 258C, ultrasound, 30 min; then NaHCO3, H2O2, 1 h,
718C; b) TPAP (5 mol%), NMO (2.0 equiv), 4 ä MS, CH2Cl2, 258C, 2 h,
99%; c) TMSOTf (0.5 equiv), 5 (2.0 equiv), 1,2-dichloroethane, 258C, 12
h; then TBAF (5.0 equiv), 258C, 1 h, 75%.
Faced with these barricades and in view of the extensive
literature precedent for enamide formation by the CuTC-
mediated route,[25] we decided to revisit this possibility, this
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Total Synthesis of (À)Apicularen A and Analogues Thereof
6177 6191
thesized from the advanced intermediate 29 and the corre-
sponding primary amides according to Scheme 5 (in compa-
rable yields to those for apicularen A). The C-11 acetate de-
rivatives (i.e. 31a, 32, 35, 39, 43, and 44) were found as by-
products in the final step and/or were deliberately synthe-
sized by omission of H2O at the final step. These analogues
were designed to test the effect of esterification at C-11,
substitutions at the acyl moiety site, and whether the macro-
lide ring was necessary or not. Biological evaluation of these
analogues against the 1A9 human ovarian carcinoma cell
line were carried out and the data are reported in Table 1 as
IC50 values (next to the compound structure). These results
indicate that acetylation at the hydroxy group leads to some
loss of activity (except in the case of 35 and 34 although ex-
perimental error has not been ruled out) which may be in
line with the loss of activity in apicularen B where this alco-
hol is glycosylated. In addition, apicularen analogue 32 pos-
sessing the natural side chain still retained extremely high
activity with only a fourfold loss (IC50 =3.2 nm). Interesting-
ly, the D17,18 (Z) apicularen A isomer (2), although less
potent by more than a factor of 100, maintains considerable
cytotoxicity (IC50 =70.7 nm)[29] as compared to the natural
substance (IC50 =0.86 nm). The bisamide analogue 26 does
not exhibit any cytotoxicity at concentrations up to 1500 nm
underscoring the importance of the enamide double bond,
while acyl group substituents proved quite interesting as
modulators of biological activity. Thus, analogues with short
aromatic chains (e.g. 33, 36, and 37) proved inactive or rela-
tively weak whereas those with comparable side chain as
that of apicularen A exhibited significant activity (e.g. 34,
35, and 38 41) with compound 41 being the most potent of
all synthesized analogues (IC50 =1.73 nm). Interestingly, the
significant cytotoxicity associated with the open-chain ana-
logues 31a, 43, and 44, with analogue 31a being the most
active (IC50 =35 nm) which are consistent with the findings
by Porco, Jr. and co-workers[25a] of non-macrolactone lobata-
mide analogues. This finding points the way for a new gener-
ation of potential mimics of apicularen A lacking the macro-
lide ring and which may prove easier to access than the nat-
ural substance.
Scheme 5. Total synthesis of apicularen A (1) and its D17,18 Z isomer (2).
a) TBSOTf (2.0 equiv), 2,6-lut. (4.0 equiv), CH2Cl2, 258C, 4 h, 94%; b)
O3, CH2Cl2, À788C, 1 h; DMS (20 equiv), 258C, then PPh3 (4.0 equiv), 1
h, 89%; c) CHI3 (4.0 equiv), CrCl2 (12 equiv), THF, 258C, 12 h, 91%; d)
CuTC (1.0 equiv), Rb2CO3 (3.0 equiv), amide 5 (3.0 equiv), DMA, 908C,
12 h, 30a 41%, 30b 4%; e) TBAF (5.0 equiv), THF, 258C, 4 h, 80%; f)
NaH (7.0 equiv), THF, 258C, 1 h; then H2O (5.0 equiv), 258C, 4 h, 50%;
g) TBAF (5.0 equiv), THF, 258C, 4 h, 60%; h) NaH (7.0 equiv), THF,
258C, 1 h; then H2O (5.0 equiv), 258C, 4 h, 34%.
Conclusion
A concise total synthesis of apicularen A (1) and its D17,18
(Z) isomer (2) has been devised and executed in 16 linear
steps. This strategy was adopted for the construction of a
series of analogues of the natural substance, biological eval-
uation of which established a set of interesting structure ac-
tivity relationships (SAR). These SAR studies confirmed
the importance of the acylenamine side chain for antitumor
activity and point to some possible new directions for future
studies in this field.
to both macrolactonization and global deprotection, furnish-
ing 1 and 2 (50 and 34% overall yield, respectively). Syn-
thetic 1 exhibited identical chromatographic and spectro-
scopic data to those exhibited by a natural sample[27] and to
those reported in the literature.[1]
Design, synthesis, and biological activity of apicularen A an-
alogues: The assumption that the acylenamine side chain
plays a crucial role in the manifestation of apicularen×s bio-
logical activity strengthen by the observation that compound
16 (Scheme 2) which lacks such a moiety, was devoid of sig-
nificant cytotoxicity[11a] led us to design analogues with the
intact side chain, varying only at the acyl group.[28] Thus, an-
alogues 2, 26, 31a, 32 44 (Table 1) were designed and syn-
Experimental Section
General procedures: All reactions were carried out under an argon at-
mosphere with dry solvents under anhydrous conditions, unless otherwise
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K. C. Nicolaou et al.
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Table 1. Cytotoxicity (IC50 values) of apicularen A (1) and analogues (2, 26, 31a, 32 44) against the 1A9 human ovarian carcinoma cell line.
Compound no.
Strucuture
IC50 value
Compound no.
Strucuture
IC50 value
apicularen A (1)
(0.78Æ0.4) nm
38
(41.3Æ5.8) nm
D17,18 Z-apicularen A (2)
(70.7Æ10.4) nm
>1500 nm
39
40
(102.3Æ20.7) nm
(23.9Æ6.6) nm
26
32
33
3.2 nm
41
42
(1.73Æ0.6) nm
>1500 nm
>1500 nm
34
35
36
37
50 nm
43
357 nm
387 nm
35 nm
(30.3Æ4.6) nm
>1500 nm
44
31a
(805.5Æ145) nm
The antiproliferative effects of these compounds against the 1A9 human ovarian carcinoma cells were assessed in a 72 h growth inhibition assay using
the SRB (sulforhodamine-B) assay.[30] IC50 is defined as the concentration that leads to 50% growth inhibition. IC50 values for each compound are given
in nm and represent the mean of 3 6 independent experimentsÆ standard error of the mean (SEM). IC50 values without an SEM value reflect a single
growth inhibition experiment.
noted. Dry tetrahydrofuran (THF), toluene, diethyl ether (ether), and
methylene chloride (CH2Cl2) were obtained by passing commercially
available pre-dried, oxygen-free formulations through activated alumina
columns. Yields refer to chromatographically and spectroscopically (1H
NMR) homogeneous materials, unless otherwise stated. Reagents were
purchased at the highest commercial quality and used without further pu-
rification, unless otherwise stated. Reactions were monitored by thin-
layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel
plates (60F-254) using UV light as visualizing agent and an ethanolic sol-
ution of phosphomolybdic acid and cerium sulfate, and heat as develop-
ing agents. E. Merck silica gel (60, particle size 0.040 0.063 mm) was
used for flash column chromatography. Preparative thin-layer chromatog-
raphy (PTLC) separations were carried out on 0.25 or 0.50 mm E. Merck
silica gel plates (60F-254). NMR spectra were recorded on Bruker DRX-
600, DRX-500, AMX-500 or AMX-400 instruments and calibrated by
using residual undeuterated solvent as an internal reference. The follow-
ing abbreviations were used to explain the multiplicities: s=singlet, d=
doublet, t=triplet, q=quartet, m=multiplet, quin=quintuplet, sext=
sextet, sep=septet, b=broad. IR spectra were recorded on a Perkin-
Elmer 1600 series FT-IR spectrometer. Electrospray ionization mass
spectrometry (ESIMS) experiments were performed on an API 100
Perkin Elmer SCIEX single quadrupole mass spectrometer at 4000V
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Total Synthesis of (À)Apicularen A and Analogues Thereof
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emitter voltage. High-resolution mass spectra (HRMS) were recorded on
buffer (pH 7, 100 mL). The reaction mixture was warmed to room tem-
perature and stirred for 18 h. The solution was then diluted with water
(100 mL) and extracted with ether (3î200 mL). The combined organic
solution was washed with brine (200 mL), dried with MgSO4, filtered and
concentrated in vacuo. The product was purified by flash column chroma-
tography (silica) to yield homoallylic alcohol 8 as a pale colorless oil (7.2
g, 70%). 8: Rf =0.13 (silica gel, EtOAc:hexanes, 1:4); [a]D =À40.6 (c=
0.79, acetone); IR (film): n˜max =3431, 2920, 1731, 1600, 1582, 1314, 1270,
a
VG ZAB-ZSE mass spectrometer under fast atom bombardment
(FAB) conditions with NBA as the matrix or using MALDI. Melting
points (m.p.) are uncorrected and were recorded on a Thomas-Hoover
Unimelt capillary melting point apparatus. DCE=1,2 dichloroethane.
DMA=N,N-dimethylacetamide. KHMDS=potassium bis(trimethylsily-
l)amide. BORSM=based on recovered starting material. CuTC was pre-
pared according to a published procedure.[20] CuTC was found to be
slightly unstable in solvent, therefore, degassing DMA was deemed nec-
essary. Phosphate buffer used had a 0.01m sodium phophate concentra-
tion.
1208, 1046, 921, 697 cmÀ1 1H NMR (600 MHz, CDCl3): d=7.42 (t, J=
;
7.9 Hz, 1H), 6.96 (d, J=7.4 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 5.89 (dddd,
J=17.3, 10.2, 7.1, 7.1 Hz, 1H), 5.13 (m, 2H), 3.90 (m, 1H), 3.31 (m, 1H),
3.15 (m, 1H), 2.38 (m, 1H), 2.35 (m, 2H), 1.69 (s, 3H), 1.67 ppm (s, 3H);
13C NMR (150 MHz, CDCl3): d=161.6, 157.1, 144.1, 135.3, 134.8, 126.5,
117.9, 116.0, 112.8, 105.3, 72.1, 42.2, 41.1, 25.8, 25.4 ppm; HRMS
(MALDI-FTMS) for C15H18O4 [M+Na+] calcd 285.1097, found 285.1097.
Diene carboxylic acid 5c: To a solution of ester 5b (see reference [14])
(237.1 mg, 1.69 mmol) in MeOH (20 mL) at room temperature was
added in one portion Ba(OH)2¥H2O (4.2 g, 13.3 mmol). The reaction mix-
ture was stirred for 20 h and then added to 1n (aq) HCl (50 mL). More
acid solution was added until the solid formed had completely dissolved
giving a clear solution. The resulting mixture was extracted with ether
(3î15 mL) and the combined organic layer was washed with brine (50
mL), dried with MgSO4, filtered and concentrated in vacuo. The product
was purified by flash column chromatography (silica) to yield carboxylic
acid 5c as a colorless oil (191 mg, 90%). 5c: Rf =0.82 (silica gel, hexane-
s:EtOAc, 1:2); IR (film): n˜max =2966, 1690, 1625, 1590, 1455, 1290, 1243,
TES-protected derivative 9: To a solution of alcohol 8 (3.11 g, 0.012 mol)
in dichloromethane (250 mL) at 08C was sequentially added 2,6-lutidine
(7 mL) followed by dropwise addition of TESOTf (8 mL). The reaction
mixture was stirred at 08C for 2 h, quenched with methanol (50 mL), and
then allowed to warm to room temperature. After stirring for an addi-
tional 30 min, the solution was concentrated in vacuo and the crude prod-
uct was purified by flash column chromatography (silica) to yield TES-
protected derivative 9 as a colorless oil (2.7 g, 83%). 9: Rf =0.68 (silica
gel, EtOAc:hexanes, 1:6); [a]D =À64.6 (c=1.67, acetone); IR (film):
n˜max =2954, 2877, 1739, 1607, 1580, 1476, 1378, 1296, 1208, 1044, 913, 726
1220, 932, 855, 832, 626 cmÀ1 1H NMR (500 MHz, CDCl3): d=7.21 (dd,
;
J=11.5, 11.4 Hz, 1H), 7.03 (dd, J=11.6, 11.5 Hz, 1H), 5.94 (m, 1H), 5.67
(d, J=11.6 Hz, 1H), 2.31 2.25 (m, 2H), 1.03 ppm (t, J=7.5 Hz, 3H); 13C
NMR (150 MHz, CDCl3): d=171.1, 144.0, 140.6, 123.8, 116.7, 20.8, 13.9
ppm; MS (ESI) for C7H10O2 [M+K+] calcd 165, found 165; MS (GC/
MS) for C7H10O2 [H+] calcd 126, found 126.
1
cmÀ1; H NMR (500 MHz, CDCl3): d=7.34 (dd, J=8.1, 6.8 Hz, 1H), 6.94
(d, J=6.8 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 5.97 5.88 (m, 1H), 5.06 5.03
(m, 2H), 4.07 4.02 (m, 1H), 3.48 3.44 (dd, J=12.6, 4.1 Hz, 1H), 2.88
2.84 (dd, J=12.6, 8.3 Hz, 1H), 2.32 2.22 (m, 2H), 1.69 (s, 3H), 1.66 (s,
3H), 0.80 (t, J=7.9 Hz, 9H), 0.45 0.31 ppm (m, 6H); 13C NMR (125
MHz, CDCl3): d=160.4, 157.0, 144.7, 135.0, 134.7, 127.8, 116.9, 115.7,
112.1, 105.0, 71.9, 42.7, 42.2, 25.7, 25.5, 6.8, 4.8 ppm; HRMS (MALDI-
FTMS) for C21H32O4Si [M+Na+] calcd 399.1962, found 399.1967.
Terminal olefin 6: To a solution of [Pd(PPh3)4] (720 mg, 0.62 mmol), LiCl
(4 g, 0.094 mol), in degassed, dry THF (100 mL) at room temperature
was added a solution of acetonide triflate 3 (10 g, 0.031 mol), and allyltri-
butyltin (10 mL, 0.032 mol) in degassed dry THF (200 mL). The reaction
mixture was heated to reflux and stirred at that temperature for 48 h.
The reaction mixture was cooled to room temperature and diluted with
ether (200 mL). The resulting solution was then washed with water (200
mL), 10% (aq) NH4OH (200 mL), and brine (200 mL), dried with
MgSO4, filtered, and concentrated in vacuo. The product was purified by
flash column chromatography (silica) to yield terminal olefin 6 as a color-
less oil (6.62 g, 99%). 6: Rf =0.56 (silica gel, EtOAc:hexanes, 1:4); IR
(film): n˜max =3002, 1731, 1696, 1631, 1602, 1584, 1472, 1449, 1384, 1314,
Aldehyde 10: A solution of olefin 9 (3.29 g, 8.74 mmol) in dichlorome-
thane (200 mL) was cooled to À788C. A flow of ozone was passed
through the solution until it turned blue. The excess ozone was then
purged with oxygen until the solution became clear again. The reaction
mixture was quenched with dimethyl sulfide (13 mL, 0.177 mol) and then
allowed to warm to room temperature. Triphenylphosphine (2.3 g, 8.77
mol) was added and the resulting mixture was stirred at that temperature
for an additional 5 h period. Concentration in vacuo followed by flash
column chromatography (silica) gave aldehyde 10 as a sticky yellow solid
(3.13 g, 95%). 10: Rf =0.39 (silica gel, EtOAc:hexanes, 1:6); [a]D =+33.1
(c=0.8, acetone); IR (film): n˜max =2958, 2883, 1731, 1607, 1582, 1476,
1
1296, 1267, 1208, 1079, 1038, 920, 808, 773, 691 cmÀ1; H NMR (400 MHz,
CDCl3): d=7.41 (dd, J=8.2, 7.6 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H) 6.82 (d,
J=8.2 Hz, 1H), 6.01 (ddt, J=16.7, 10.3, 6.7 Hz, 1H), 5.05 4.99 (m, 2H),
3.87 (d, J=6.7 Hz, 2H), 1.68 ppm (s, 6H); 13C NMR (100 MHz, CDCl3):
d=160.3, 157.1, 145.2, 136.7, 135.3, 124.9, 116.0, 115.6, 112.0, 105.1, 38.2,
25.6 ppm; MS (ESI) for C13H14O3 [M+Na+] calcd 241, found 241.
1389, 1301, 1270, 1208, 1058, 1002, 740 cmÀ1 1H NMR (600 MHz,
;
CDCl3): d=9.81 (dd, J=2.6, 2.2 Hz, 1H), 7.39 (dd, J=7.92, 7.44 Hz,
1H), 6.92 (d, J=7.44 Hz, 1H), 6.85 (d, J=7.92 Hz, 1H), 4.56 4.52 (m,
1H), 3.32 (dd, J=12.5, 5.5 Hz, 1H), 3.24 (dd, J=12.5, 7.2 Hz, 1H), 2.54
(ddd, J=15.3, 5.9, 2.6 Hz, 1H), 2.48 (ddd, J=15.3, 5.1, 2.2 Hz, 1H), 1.69
(s, 3H), 1.68 (s, 3H), 0.84 (t, J=7.9 Hz, 9H), 0.47 ppm (m, 6H); 13C
NMR (150 MHz, CDCl3): d=202.2, 160.4, 157.2, 142.9, 135.1, 127.5,
116.3, 112.2, 105.3, 68.4, 51.1, 42.9, 25.7, 25.6, 6.7, 4.7 ppm; HRMS
(MALDI-FTMS) for C20H30O5Si [M+Na+] calcd 401.1755, found
401.1793.
Dihydroxy olefin 11: A solution of Ipc2Bdallyl (14 mL of 1m solution in
pentane) in ether (40 mL) was cooled to -1008C (methanol liquid nitro-
gen). A solution of aldehyde 10 (3.38 g, 8.93 mmol) in ether (60 mL) and
was also cooled to À1008C and then added dropwise to the Ipc2Bdallyl
solution using a cannula. The resulting mixture was stirred at À1008C for
2 h before quenching at 08C with ethanol (10 mL). Hydrogen peroxide
(30%, 20 mL) was added at 08C followed by phosphate buffer (pH 7, 20
mL). The reaction mixture was warmed to ambient temperature and stir-
red for 18 h. The resulting reaction mixture was then diluted with water
(20 mL) and extracted with ether (3î100 mL). The combined organic
layer was washed with brine (40 mL), dried with MgSO4, filtered, and
concentrated in vacuo. The crude alcohol so obtained was dissolved in
THF (125 mL) and the solution cooled to 08C before 0.5n (aq) HCl (5
mL) was added dropwise. After stirring for 1 h, the solution was warmed
to room temperature and then diluted with water and extracted with
ether (3î100 mL). The combined organic layer was washed with brine
(100 mL), dried with MgSO4, filtered, and concentrated in vacuo. The
Aldehyde 7: A solution of terminal olefin 6 (230 mg, 1.05 mmol) in di-
chloromethane (10 mL) was cooled to À788C. A flow of ozone was
passed through the solution until it turned blue. The excess ozone was
then purged with oxygen until the solution became clear again. The reac-
tion mixture was quenched with dimethyl sulfide (1.55 mL, 21.1 mmol) at
À788C and then allowed to warm to ambient temperature. Triphenyl-
phosphine (276 mg, 1.05 mmol) was added and the resulting mixture was
stirred at room temperature for an additional 5 h period, before concen-
trating under vacuo. The aldehyde was purified by flash column chroma-
tography (silica) to yield aldehyde 7 as a sticky yellow solid (217 mg,
94%). 7: Rf =0.17 (silica gel, EtOAc:hexanes, 1:4); IR (film): n˜max =2995,
2833, 1731, 1700, 1607, 1582, 1482, 1326, 1295, 1202, 1052, 934, 691 cmÀ1
;
1H NMR (600 MHz, CDCl3): d=9.80 (s, 1H), 7.47 (t, J=7.9 Hz, 1H),
6.92 (d, J=8.3 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H), 4.18 (s, 2H), 1.71 ppm
(s, 6 H); 13C NMR (150 MHz, CDCl3): d=198.2, 160.9, 157.2, 137.0, 135.6,
126.4, 117.0, 112.6, 105.8, 49.1, 25.6 ppm; HRMS (MALDI-FTMS) for
C12H12O4 [M+H+] calcd 221.0808, found 221.0805.
Homoallylic alcohol 8: Ipc2Blallyl (60 mL of 1 M solution in pentane)
was added to a flask containing ether (30 mL) and the mixture was
cooled to À1008C (methanol liquid nitrogen). A precooled (À1008C)
solution of aldehyde 7 (8.67 g, 39.37 mmol) in dichloromethane (100 mL)
was then transferred dropwise using a cannula into the Ipc2Blallyl solu-
tion and the resulting mixture was stirred at À1008C for 2 h. The reaction
mixture was warmed to 08C and then quenched with ethanol (50 mL).
Hydrogen peroxide (30%, 100 mL) was added, followed by phosphate
6183
Chem. Eur. J. 2003, 9, 6177 6191
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

K. C. Nicolaou et al.
FULL PAPER
product containing 11 and its diastereoisomer (ca. 4:1 ratio) was purified
by flash column chromatography (silica) to yield pure dihydroxy olefin
11 as a colorless oil (1.7 g, 62%). 11: Rf =0.24 (silica gel, EtOAc:hexanes,
1:1); [a]D =À17.1 (c=1.08, acetone); IR (film): n˜max =3404, 2939, 1728,
51.7 mmol) and then allowed to warm to room temperature. Triphenyl-
phosphine (685 mg, 2.61 mmol) was added and the resulting mixture was
stirred at that temperature for an additional 5 h period. Concentrating in
vacuo followed by flash column chromatography (silica) yielded aldehyde
acetate 14 as a colorless syrup (966.4 mg, 98%). 14: Rf =0.43 (silica gel,
1606, 1584, 1478, 1445, 1390, 1318, 1268, 1207, 1058, 919, 781, 698 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.42 (dd, J=8.1, 7.7 Hz, 1H), 6.96 (d,
J=7.7 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 5.84 5.76 (m, 1H), 5.11 5.07 (m,
2H), 4.16 4.12 (m, 1H), 4.03 3.98 (m, 1H), 3.27 (dd, J=13.1, 4.2 Hz,
1H), 3.20 (dd, J=13.1, 8.1 Hz, 1H), 3.02 (bs, 1H), 2.62 (bs, 1H), 2.30
2.20 (m, 2H), 1.74 1.71 (m, 2H), 1.68 (s, 3H), 1.67 ppm (s, 3H); 13C
NMR (150 MHz, CDCl3): d=161.6, 157.2, 143.9, 135.4, 134.8, 126.5,
117.9, 116.0, 112.7, 105.4, 70.5, 68.3, 42.5, 42.0, 41.9, 25.7, 25.5 ppm;
HRMS (MALDI-FTMS) for C17H22O5 [M+Na+] calcd 329.1359, found
329.1367.
EtOAc:hexanes, 1:1); [a]D =À66.5 (c=3.02, acetone); IR (film): n˜max
=
2942, 1731, 1606, 1585, 1480, 1449, 1381, 1313, 1240, 1042, 922, 781 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=9.52 (dd, J=2.2, 1.8 Hz, 1H), 7.38 (dd,
J=8.4, 7.7 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H),
5.07 5.02 (m, 1H), 4.65 4.60 (m, 1H), 4.01 3.96 (m, 1H), 3.41 3.25 (m,
2H), 2.71 (ddd, J=16.2, 9.1, 2.9 Hz, 1H), 2.41 (ddd, J=16.2, 5.0, 1.5 Hz,
1H), 2.08 2.02 (m, 1H), 2.05 (s, 3H), 1.83 1.73 (m, 2H), 1.69 (s, 3H),
1.68 (s, 3H), 1.62 1.56 ppm (m, 1H); 13C NMR (125 MHz, CDCl3): d=
200.4, 170.3, 160.6, 157.1, 143.5, 135.0, 126.5, 116.0, 112.1, 105.2, 70.5,
67.0, 65.7, 46.5, 39.2, 35.6, 34.3, 25.7, 25.6, 21.3 ppm; HRMS (MALDI-
FTMS) for C20H24O7 [M+Na+] calcd 399.1414, found 399.1419.
Diacetate 12: A solution of diol 11 (700 mg, 2.28 mmol) in dichlorome-
thane (100 mL) was cooled to À788C. A flow of ozone was passed
through the solution until it turned blue. The excess ozone was then
purged with oxygen until the solution became clear again. The reaction
mixture was quenched with dimethylsulfide (3.35 mL, 46.62 mmol) at
À788C and then allowed to warm to room temperature. Triphenylphos-
phine (598 mg, 2.28 mmol) was added and the reaction mixture was stir-
red at room temperature for an additional 5 h period, before concentrat-
ing under vacuo. To a cold (08C) solution of this crude lactol in pyridine
(80 mL) was added 4-DMAP (28 mg, 0.228 mmol) followed by acetic an-
hydride (9.54 mL, 101.1 mmol) and with stirring. The mixture was then
allowed to warm to room temperature and stirred for 14 h before it was
diluted with 1n (aq) HCl (50 mL) and extracted with ether (3î50 mL).
The combined solution was washed with 1 N (aq) HCl (2î40 mL), brine
(50 mL), dried with MgSO4, filtered and concentrated in vacuo. The
product was purified by flash column chromatography (silica) yielding di-
acetate 12 as a sticky white foam, (747.4 mg, 83% from 11). 12 (mixture
of anomer, ca. 1:1.2): Rf =0.26 (silica gel, EtOAc:hexanes, 1:3); IR (film):
n˜max =2929, 1739, 1605, 1585, 1478, 1447, 1370, 1314, 1299, 1268, 1227,
Homoallylic alcohol 15: Ipc2Bdallyl (1.2 mL of a 1m solution in pentane)
was added to a flask containing ether (10 mL) and the reaction mixture
was cooled to À1008C (methanol liquid nitrogen).
A precooled
(À1008C) solution of 14 (219 mg, 0.582 mmol) in ether (15 mL) was then
added dropwise using a cannula into the Ipc2Bdallyl solution and the re-
sulting mixture was stirred at À1008C for 2 h. The reaction mixture was
warmed to 08C and then quenched with ethanol (5 mL). Hydrogen per-
oxide (30%, 10 mL) was added, followed by phosphate buffer (pH 7, 10
mL). The reaction mixture was warmed to room temperature and stirred
for 18 h. The solution was then diluted with water (10 mL) and extracted
with ether (3î30 mL). The combined solution was washed with brine
(40 mL), dried with MgSO4, filtered, and concentrated in vacuo. The
product was purified by flash column chromatography (silica) to yield ho-
moallylic alcohol 15 as a colorless oil (156.0 mg, 64% of the major
isomer) and a small amount of its epimer, epi-15 (24.2 mg, 10%). 15:
Rf =0.4 (silica gel, EtOAc:hexanes, 1:2); [a]D =À103.7 (c=1.34, ace-
tone); IR (film): n˜max =3512, 2930, 1731, 1605, 1584, 1478, 1448, 1316,
1
1171, 1038, 925, 777 cmÀ1; H NMR (600 MHz, CDCl3): d=7.39 (m, 1H),
1240, 1042, 921, 780 cmÀ1 1H NMR (500 MHz, CDCl3): d=7.41 (dd, J=
;
7.00 (d, J=7.9 Hz, minor), 6.94 (d, J=7.4 Hz, major, 1H), 6.83 (d, J=7.9
Hz, 1H), 6.21 (s, major, 1H), 5.58 (d, J=10.1 Hz, minor), 5.16 5.11 (m,
major, 1H), 4.94 4.89 (m, minor), 4.18 4.16 (m, major, 1H), 3.82 3.77
(m, minor), 3.55 3.36 (m, 2H), 3.26 3.20 (m, 1H), 2.20 2.02 (m, 2H),
2.04 1.98 (m, 6H), 1.69 (s, 3H), 1.67 (s, 3H), 1.51 1.40 ppm (m, 1H); 13C
NMR (150 MHz, CDCl3): d=170.2, 170.1, 169.3, 168.8, 160.6, 160.5,
157.0, 142.5, 142.0, 135.1, 135.0, 126.5, 126.3, 116.1, 112.5, 112.3, 105.2
(two peaks), 73.0, 70.3, 68.2, 66.3, 39.7, 39.3, 36.4, 36.0, 35.8, 34.4, 25.7
(two peaks), 25.5, 25.4, 21.2, 21.1 (two peaks), 21.0 ppm; (two isomers);
HRMS (MALDI-FTMS) for C20H24O8 [M+Na+] calcd 415.1316, found
415.1355.
8.4, 7.4 Hz, 1H), 6.93 (d, J=7.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 5.71
5.63 (m, 1H), 5.08 5.03 (m, 1H), 5.00 4.97 (m, 2H), 4.26 4.22 (m, 1H),
4.10 4.05 (m, 1H), 3.65 3.62 (m, 2H), 3.11 3.07 (dd, J=13.2, 9.2 Hz,
1H), 2.70 (bs, 1H), 2.18 1.99 (m, 3H), 2.05 (s, 3H), 1.79 1.68 (m, 3H),
1.77 (s, 3H), 1.70 (s, 3H), 1.59 1.56 (m, 1H), 1.38 1.34 ppm (ddd, J=
14.7, 2.6, 2.6 Hz, 1H); 13C NMR (150 MHz, CDCl3): d=170.3, 160.7,
157.4, 143.2, 135.1, 134.6, 126.4, 117.3, 116.4, 112.1, 105.4, 71.8, 71.5, 70.2,
67.0, 41.6, 39.7, 37.8, 36.0, 35.5, 26.3, 25.0, 21.3 ppm; HRMS (MALDI-
FTMS) for C23H30O7 [M+Na+] calcd 441.1884, found 441.1887.
Cyclized aldehyde 18: A solution of 17 (137.2 mg, 0.251 mmol) in di-
chloromethane (20 mL) was cooled to À788C. A flow of ozone was
passed through the solution until it turned blue. The excess ozone was
then purged with oxygen until the solution became clear again. The reac-
tion mixture was quenched with dimethylsulfide (0.4 mL, 5.45 mol) at
À788C and then allowed to warm to room temperature. Triphenylphos-
phine (100 mg, 0.381 mol) was added and the resulting mixture was stir-
red at room temperature for an additional 5 h period, before concentrat-
ing under vacuo. Aldehyde 18 was purified by flash column chromatogra-
phy (silica) to yield cyclized aldehyde 18 as a sticky yellow solid (97.9
mg, 71%). 18: Rf =0.17 (silica gel, hexanes:EtOAc, 5:1); [a]D =+31.8
(c=0.44, acetone); IR (film): n˜max =3410, 2952, 2929, 2858, 1730, 1695,
Terminal olefin 13: To a solution of diacetate 12 (787.2 mg, 2.00 mmol) in
acetonitrile (50 mL) at 08C was added allyltrimethylsilane (1.6 mL).
Boron trifluoride diethyl etherate (0.29 mL) was added dropwise, and the
reaction mixture was stirred at 08C for 1 h before quenching with saturat-
ed (aq) NaHCO3 (30 mL). The mixture was then extracted with ether
(3î50 mL), washed with brine (100 mL), dried with MgSO4, filtered, and
concentrated in vacuo. The product was purified by flash column chroma-
tography (silica) to yield terminal olefin 13 as a colorless oil (730.0 mg,
97%). 13: Rf =0.54 (silica gel, EtOAc:hexanes, 1:3); [a]D =À55.4 (c=
0.72, acetone); IR (film): n˜max =2929, 1734, 1607, 1585, 1479, 1446, 1380,
1312, 1241, 1041, 925, 781 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.38
1577, 1465, 1383, 1360, 1283, 1254, 1107, 1083, 1066, 837, 778 cmÀ1 1H
;
(dd, J=8.1, 7.7 Hz, 1H), 6.96 (d, J=7.7 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H),
5.60 5.52 (m, 1H), 5.09 5.04 (m, 1H), 4.95 (dd, J=17.1, 1.1 Hz, 1H),
4.89 (dd, J=9.8, 1.1 Hz, 1H), 4.06 4.01 (m, 1H), 3.98 3.93 (m, 1H), 3.36
(dd, J=13.2, 4.2 Hz, 1H), 3.27 (dd, J=13.2, 8.5 Hz, 1H), 2.38 2.32 (m,
1H), 2.16 2.11 (m, 1H), 2.05 2.00 (m, 1H), 2.03 (s, 3H), 1.81 1.77 (m,
1H), 1.72 1.66 (m, 1H), 1.68 (s, 3H), 1.67 (s, 3H), 1.53 1.47 ppm (m,
1H); 13C NMR (150 MHz, CDCl3): d=170.4, 160.5, 157.0, 143.8, 134.9,
134.6, 126.6, 116.9, 115.7, 112.3, 105.1, 70.8, 69.6, 67.4, 39.6, 36.7, 36.4,
33.7, 25.7, 25.6, 21.4 ppm; HRMS (MALDI-FTMS) for C21H26O6 [M+
H+] calcd 375.1802, found 375.1816.
NMR (600 MHz, CDCl3): d=9.83 (s, 1H), 7.14 (dd, J=8.3, 7.9 Hz, 1H),
6.76 (d, J=7.9 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.11 6.09 (m, 1H), 4.40
4.38 (m, 1H), 4.08 4.04 (m, 1H), 3.97 3.93 (m, 1H), 3.58 (dd, J=14.5,
11.0 Hz, 1H), 2.87 2.71 (m, 2H), 2.37 (d, J=14.9 Hz, 1H), 1.94 1.90 (m,
1H), 1.87 1.81 (m, 1H), 1.72 1.69 (m, 1H), 1.64 1.58 (m, 2H), 1.53 1.50
(m, 1H), 0.95 (s, 9H), 0.92 (s, 9H), 0.23 (s, 3H), 0.19 (s, 3H), 0.07 ppm (s,
6H); 13C NMR (150 MHz, CDCl3): d=199.5, 169.4, 151.7, 139.9, 129.8,
127.7, 122.9, 116.8, 74.4, 68.5, 65.3, 64.7, 48.5, 39.8, 39.5, 38.7, 37.7, 25.8,
25.7, 18.2, 18.0, À4.0, À4.4, À4.8, À4.9 ppm; HRMS (MALDI-FTMS) for
C29H48O6Si2 [M+Na+] calcd 571.2881, found 571.2882.
Aldehyde acetate 14: A solution of terminal olefin 13 (983 mg, 2.61
mmol) in dichloromethane (150 mL) was cooled to À788C. A flow of
ozone was passed through the solution until it turned blue. The excess
ozone was then purged with oxygen until the solution became clear
again. The reaction mixture was quenched with dimethyl sulfide (3.8 mL,
Bis-TBS-protected vinyl iodide 19: To a solution of CrCl2 (263 mg, 2.140
mmol) in dry THF (10 mL) was added at room temperature a mixture of
aldehyde 18 (97.9 mg, 0.1784 mmol), and iodoform (284 mg, 0.7213
mmol), in dry THF (20 mL). Almost immediately the reaction mixture
turned reddish-brown and after 3 h of stirring at room temperature, it
6184
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 6177 6191

Total Synthesis of (À)Apicularen A and Analogues Thereof
6177 6191
was poured onto brine (30 mL) and extracted with ether (3î10 mL). The
combined organic layer was then washed with brine (50 mL), dried with
MgSO4, filtered and concentrated in vacuo. The product was purified by
flash column chromatography (silica) to yield bis-TBS-protected vinyl al-
dehyde 19 as a yellow oil (95.4 mg, 80% of trans:cis (4:1) inseparable
mixture of isomers). 19 (ca. 4:1 mixture of trans:cis isomers): Rf =0.51
(silica gel, hexanes:EtOAc, 5:1); IR (film): n˜max =3434, 2952, 2917, 2858,
1730, 1718, 1577, 1465, 1389, 1360, 1289, 1260, 1113, 1083, 1060, 948, 831,
evaporated in vacuo. The product was purified by flash column chroma-
tography (silica) to yield a mixture of diastereoisomers (ca. 1:1) of a light
yellow oil (38.2 mg, 89%). 22 (diastereoisomer B): Rf =0.45 (diaster-
eoisomer B) (silica gel, hexanes:EtOAc, 3:1); [a]D =+29.1 (c=0.44, ace-
tone); IR (film): n˜max =3438, 2952, 2857, 2098, 1717, 1575, 1456, 1284,
1249, 1106, 1065, 840, 774, 668 cmÀ1 1H NMR (600 MHz, CDCl3): d=
;
7.12 (dd, J=7.4, 7.9 Hz, 1H), 6.74 (d, J=7.4 Hz, 1H), 6.70 (d, J=7.9 Hz,
1H) 5.72 5.67, (m, 1H), 4.33 4.30 (m, 1H), 4.06 4.02 (m, 1H), 3.97 3.92
(m, 2H), 3.52 (dd, J=11.2, 14.3 Hz, 1H), 3.36 3.30 (m, 2H), 2.43 (d, J=
3.5 Hz, 1H), 2.35 (d, J=14.9 Hz, 1H), 1.93 1.82 (m, 3H), 1.78 1.74 (m,
1H), 1.61 1.57 (m, 2H), 1.49 1.46 (m, 1H), 1.41 (s, 1H), 0.95 (s, 9H),
0.89 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H), 0.04 ppm (s, 6H); 13C NMR (125
MHz, CDCl3): d=169.6, 151.6, 139.6, 129.7, 128.1, 123.2, 117.5, 74.2, 72.2,
68.4, 65.3, 64.9, 56.7, 39.6 (two peaks), 39.2, 38.8, 37.8, 25.9, 25.8, 18.5,
18.0, À4.0, À4.3, À4.8 ppm (two peaks); HRMS (MALDI-FTMS) for
C30H51N3O6Si2 [M + Na+] calcd 628.3208, found 628.3206.
778, 737, 672 cmÀ1 1H NMR (600 MHz, CDCl3): d=7.13 (dd, J=8.1, 7.7
;
Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 6.59 6.53 (m,
1H), 6.39 6.34 (m, minor), 6.18 (d, J=14.3 Hz, 1H), 5.74 5.70 (m,
minor), 5.66 5.60 (m, 1H), 4.34 4.30 (m, 1H), 4.09 4.05 (m, 1H), 3.97
3.93 (m, 1H), 3.55 (dd, J=14.5, 11.0 Hz, 1H), 2.52 2.35 (m, 3H), 1.94
1.89 (m, 1H), 1.81 1.75 (m, 1H), 1.66 1.48 (m, 4H), 0.98 (s, 9H), 0.92 (s,
9H), 0.26 (s, 3H), 0.22 (s, 3H), 0.07 ppm (s, 6H); 13C NMR (150 MHz,
CDCl3): d=169.7, 151.6, 140.9, 139.7, 136.6, 129.6, 127.9, 122.9, 116.7,
78.0, 74.3, 71.9, 65.4, 41.3, 39.6, 38.8 (two peaks), 37.8, 25.8, 25.7, 18.2,
18.0, À4.0, À4.4, À4.8 ppm (two peaks); (two isomers); HRMS (MALDI-
FTMS) for C30H49IO5Si2 [M + Na+] calcd 695.2055, found 695.2023.
Hydroxy amide 23: To a solution of azide 22 (115.6 mg, 0.1902 mmol) in
THF (20 mL) was added H2O (2 drops) and triphenylphosphine (80 mg,
0.305 mmol). The reaction mixture was then heated to 408C, and stirred
for 18 h. The resulting solution was then cooled to room temperature,
concentrated in vacuo, and dried under high vacuum. To the crude amine
so obtained was added dichloromethane (20 mL), diene carboxylic acid
5c (29.2 mg, 0.2317 mmol), DIEA (0.06 mL, 0.3451 mmol), EDC (44.4
mg, 0.2316 mmol), and HOBt (35.4 mg, 0.2620 mmol). The reaction mix-
ture was stirred at room temperature for 3 h and then concentrated in
vacuo. The product was purified by column chromatography (silica) to
yield hydroxyl amide 23 as a yellow oil (ca. 1:1 mixture of diastereoisom-
ers, 85.1 mg, 65% from 22). 23 (ca. 1:1 mixture of diastereoisomers):
Rf =0.23 (silica gel, hexanes:EtOAc, 2:1); IR (film): n˜max =3349, 2953,
Dihydroxy vinyl iodide 20: To a solution of bis-TBS-protected vinyl
iodide 19 (ca. 4:1 trans:cis mixture of isomers, 35.7 mg, 0.053 mmol) in
THF (10 mL) was added at room temperature TBAF (1.0 m THF solu-
tion, 0.5 mL, 0.50 mmol). The reaction mixture was stirred for 5 h at
room temperature and then quenched with saturated (aq) NH4Cl (10
mL) and extracted with ether (3î10 mL). The combined organic layer
was washed with brine (20 mL), dried with MgSO4, filtered and concen-
trated in vacuo. The product was purified by flash column chromatogra-
phy (silica) to yield dihydroxy vinyl iodide 20 as a yellow oil (23.1 mg,
98% ca. 4:1 ratio of trans:cis isomers). 20 (ca. 4:1 mixture of trans:cis iso-
mers): Rf =0.17 (silica gel, hexanes:EtOAc, 1:1); IR (film): n˜max =3366,
2955, 2920, 1713, 1690, 1643, 1608, 1578, 1461, 1361, 1290, 1261, 1114,
2918, 1860, 1735, 1715, 1645, 1464, 1278, 1255, 1086, 1063, 836, 778 cmÀ1
;
1H NMR (600 MHz, CDCl3): d=7.24 7.20 (m, 1H), 7.13 7.09 (m, 1H),
6.77 6.69 (m, 3H), 5.96 (t, J=5.5 Hz, 1H), 5.82 5.77 (m, 1H), 5.73 5.65
(m, 1H), 5.57 (d, J=11.4 Hz, 1H), 4.33 4.26 (m, 1H), 4.04 3.93 (m, 3H),
3.56 3.50 (m, 2H), 3.36 (dd, J=15.1, 9.4 Hz, 1H), 3.25 3.21 (m, 1H),
2.37 (d, J=14.7 Hz, 1H), 2.26 2.21 (m, 2H), 2.04 1.98 (m, 1H), 1.90 1.70
(m, 3H), 1.64 1.45 (m, 4H), 1.00 (t, J=7.7 Hz, 3H), 0.93 (s, 9H), 0.88 (s,
9H), 0.39 (s, 6H), 0.34 ppm (s, 6H); 13C NMR (150 MHz, CDCl3): d=
170.1, 169.5, 167.4, 166.9, 152.0, 151.9, 141.6, 141.4, 139.6, 139.3, 135.6,
135.4, 129.6, 129.6, 128.3, 127.5, 123.8, 123.8, 123.4, 123.2, 120.0, 119.9,
117.6, 117.3, 74.1, 73.3, 72.7, 72.3, 68.8, 67.3, 66.5, 65.6, 65.3, 65.0, 45.5,
44.7, 39.8, 39.7 (two peaks), 39.5, 39.4, 39.1, 38.8, 38.3, 37.9, 26.0, 25.8
(two peaks), 20.7, 18.6, 18.5, 18.0 (two peaks), 14.0, À3.9 (two peaks),
À4.2, À4.3, À4.8 (three peaks), À4.9 ppm; (two isomers); HRMS
1073, 1055, 732 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.20 (dd, J=8.5,
;
7.3 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.76 (d, J=7.3 Hz, 1H), 6.61 6.54
(m, 1H), 6.26 (d, J=14.7 Hz, 1H), 5.99 (bs, 1H), 5.65 5.58 (m, minor),
5.57 5.50 (m, 1H), 4.34 4.28 (m, 1H), 4.09 4.03 (m, 1H), 3.92 3.84 (m,
1H), 3.52 (dd, J=14.2, 11.0 Hz, 1H), 2.48 2.42 (m, 3H), 2.00 (ddd, J=
12.9, 4.6, 4.6 Hz, 1H), 1.91 1.79 (m, 2H), 1.69 1.54 ppm (m, 4H); 13C
NMR (150 MHz, [D6]acetone): d=169.2, 164.0, 154.3, 142.9, 140.1, 140.3,
125.2, 122.2, 114.3, 78.1, 73.6, 67.9, 64.8, 41.5, 40.3, 39.8, 39.6, 38.9 ppm;
(two isomers); HRMS (MALDI-FTMS) for C18H21IO5 [M+Na+] calcd
467.0326, found 467.0319.
Epoxide 21: To a solution of olefin 17 (21.3 mg, 0.039 mmol) in dichloro-
methane (5 mL) was added mCPBA (98 mg, 0.312 mmol) and NaHCO3
(28.8 mg, 0.343 mmol). The reaction mixture was heated at reflux for 24 h
and then cooled to room temperature. To the solution was added saturat-
ed (aq) NaHCO3 (10 mL) and the resulting mixture was extracted with
ether (3î10 mL). The combined organic layer was washed with brine
(10 mL), dried with MgSO4, filtered, and concentrated in vacuo. The ep-
oxide was purified by flash column chromatography (silica) to yield epox-
ide 21 as a mixture of diastereomeric epoxides (ca. 1:1) as a yellow oil
(20.5 mg, 94%). 21 (ca. 1:1 ratio): Rf =0.34 (silica gel, hexanes:EtOAc,
5:1); IR (film): n˜max =2952, 2852, 1716, 1579, 1460, 1361, 1286, 1249, 1105,
(MALDI-FTMS) for C37H61NO7Si2 [M
+
Na+] calcd 710.3879, found
710.3873.
Primary alcohol 24: To a solution of olefin 17 (192 mg, 0.351 mmol) in
THF (20 mL) was added BH3¥Me2S (0.333 mL, 3.51 mmol) and the reac-
tion mixture was subjected to sonication for 1.5 h at room temperature.
Phosphate buffer (pH7, 1 mL) was then added to the reaction mixture
and the resulting solution was diluted with ether (20 mL). Hydrogen per-
oxide (30%, 1.0 mL) was added dropwise and the reaction mixture was
extracted with ether (3î20 mL). The combined organic layer was washed
with brine (20 mL), dried with MgSO4, filtered, and concentrated in
vacuo. The product was purified by flash column chromatography (silica)
to yield primary alcohol 24 as a light yellow oil (141 mg, 71%). 24: Rf =
0.70 (silica gel, hexanes:EtOAc, 1:1); [a]D =+31.0 (c=0.21, acetone); IR
(film): n˜max =3435, 2953, 2923, 2853, 1714, 1694, 1669, 1649, 1633, 1463,
1068, 837, 775 cmÀ1 1H NMR (600 MHz, CDCl3): d=7.10 (dd, J=8.3,
;
7.4 Hz, 1H), 6.73 (d, J=7.4 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 1.51 1.71
(m, 1H), 4.36 4.31 (m, 1H), 4.05 3.93 (m, 2H), 3.56 3.51 (m, 1H), 3.09
3.05 (m, 1H), 2.78 2.77 (m, 1H), 2.52 2.48 (m, 1H), 2.35 (d, J=14.5 Hz,
1H), 2.08 1.78 (m, 4H), 1.70 1.47 (m, 4H), 0.93 (s, 9H), 0.89 (s, 9H),
0.18 (s, 6H), 0.04 ppm (s, 6H); 13C NMR (150 MHz, CDCl3): d=169.6
(two peaks), 151.7, 139.7 (two peaks), 129.6, 128.1, 128.0, 123.0, 122.9,
117.0, 116.8, 74.2 (two peaks), 71.9, 71.2, 65.4, 65.2, 49.1, 48.8, 47.0, 46.8,
39.7, 39.6 (two peaks), 39.2, 38.9, 38.3, 37.9, 37.6, 25.8, 25.7 (two peaks),
À4.0, À4.1, À4.4, À4.8 ppm (two peaks); (two isomers); HRMS
(MALDI-FTMS) for C30H50O6Si2 [M+Na+] calcd 585.3038, found
585.3037.
1
1393, 1362, 1287, 1252, 1106, 1066 cmÀ1; H NMR (500 MHz, CDCl3): d=
7.12 (dd, J=8.1, 7.4 Hz, 1H), 6.74 (d, J=7.4 Hz, 1H), 6.70 (d, J=8.1 Hz,
1H), 5.62 5.59 (m, 1H), 4.35 4.31 (m, 1H), 4.08 4.05 (m, 1H), 4.00 3.96
(m, 1H), 3.71 3.65 (m, 2H), 3.53 (dd, J=14.7, 10.6 Hz, 1H), 2.38 (dd,
J=14.7, 1.3 Hz, 1H), 1.94 1.83 (m, 2H), 1.79 1.67 (m, 3H), 1.66 1.49 (m,
6H), 0.97 (s, 9H), 0.91 (s, 9H), 0.22 (s, 3H), 0.21 (s, 3H), 0.07 ppm (s,
6H); 13C NMR (100 MHz, CDCl3): d=169.8, 151.7, 139.5, 129.4, 128.3,
123.0, 117.0, 73.9, 73.7, 65.5 (two peaks), 62.6, 39.6, 39.0, 38.2, 31.1, 29.7,
28.4, 25.8, 25.7, 18.3, 18.0, À4.1, À4.2, À4.8 (two peaks); HRMS
Hydroxy azide 22: To a solution of epoxide 21 (ca. 1:1 mixture of iso-
mers, 40 mg, 0.071 mmol) in methanol/water (8:1 v/v, 10 mL) was added
sodium azide (46.2 mg, 0.711 mmol) and ammonium chloride (19 mg,
0.355 mmol). The reaction mixture was refluxed for 20 h and then cooled
to room temperature. The resulting solution was diluted with water (20
mL) and extracted with ether (3î10 mL). The combined organic layer
was then washed with brine (20 mL), dried with MgSO4, filtered, and
(MALDI-FTMS) for C30H52O6Si2 [M
+
Na+] calcd 587.3194, found
587.3205.
Aldehyde 25: To a solution of alcohol 24 (10 mg, 0.018 mmol) in di-
chloromethane (5 mL) was added at 08C, NMO (3.11 mg, 0.027 mmol)
and 4ä molecular sieves (9 mg) followed by TPAP (1 mg, 0.0028 mmol),
6185
Chem. Eur. J. 2003, 9, 6177 6191
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

K. C. Nicolaou et al.
FULL PAPER
in one portion. The reaction mixture was stirred for 1 h at 08C and then
filtered through a short pad of silica and the pad was washed with a solu-
tion of hexanes:EtOAc (1:1). The resulting solution was concentrated in
vacuo and the product was purified by flash column chromatography
(silica) to yield aldehyde 25 as a yellow oil (9.8 mg, 99%). 25: Rf =0.53
(silica gel, hexanes:EtOAc, 7:3); [a]D =+28.6 (c=0.29, acetone); IR
(film): n˜max =3413, 2955, 2919, 2851, 1725, 1572, 1461, 1390, 1361, 1284,
À788C and then allowed to warm to room temperature. Triphenylphos-
phine (90.5 mg, 0.345 mmol) was added and the reaction mixture was stir-
red at room temperature for an additional 5 h period, before concentrat-
ing in vacuo. The aldehyde was purified by flash column chromatography
(silica) to yield aldehyde 28 as a colorless syrup (163.4 mg, 89%). 28:
Rf =0.18 (silica gel, EtOAc:hexanes, 1:4); [a]D =À48.4 (c=3.03, ace-
tone); IR (film): n˜max =2955, 2931, 2861, 1731, 1713, 1608, 1584, 1478,
1449, 1378, 1314, 1296, 1243, 1208, 1079, 1044, 926, 838, 808, 779, 732,
1249, 1108, 1067, 838, 779 cmÀ1 1H NMR (500 MHz, CDCl3): d=9.78 (s,
;
703 cmÀ1 1H NMR (600 MHz, CDCl3): d=9.48 (bs, 1H), 7.37 (dd, J=
;
1H), 7.10 (dd, J=8.1, 7.4 Hz, 1H), 6.72 (d, J=7.3 Hz, 1H), 6.68 (d, J=
8.1 Hz, 1H), 5.59 5.54 (m, 1H), 4.32 4.27 (m, 1H), 4.05 4.01 (m, 1H),
3.96 3.92 (m, 1H), 3.50 (dd, J=14.7, 11.0 Hz, 1H), 2.71 2.57 (m, 2H),
2.35 (dd, J=14.7, 1.1 Hz, 1H), 1.99 1.79 (m, 4H), 1.63 1.46 (m, 4H),
0.94 (s, 9H), 0.88 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H), 0.04 ppm (s, 6H); 13C
NMR (150 MHz, CDCl3): d=201.2, 169.7, 151.7, 139.6, 129.6, 128.0,
123.1, 117.0, 74.1, 72.9, 65.4, 65.3, 39.9, 39.5, 39.1, 39.0, 38.1, 26.7, 25.8,
25.7, 18.4, 18.0, À4.0, À4.1, À4.8 (two peaks); HRMS (MALDI-FTMS)
for C30H50O6Si2 [M + Na+] calcd 585.3038, found 585.3022.
7.9, 7.5 Hz, 1H), 6.96 (d, J=7.5 Hz 1H), 6.83 (d, J=7.9 Hz, 1H), 5.05
5.00 (m, 1H), 4.19 4.17 (m, 1H), 3.99 3.87 (m, 2H), 3.40 (dd, J=12.9,
3.3 Hz, 1H), 3.10 (dd, J=12.9, 8.5 Hz, 1H), 2.39 2.30 (m, 2H), 2.09 2.06
(m, 1H), 2.02 (s, 3H), 1.99 1.94 (m, 1H), 1.72 1.65 (m, 2H), 1.69 (s, 3H),
1.64 (s, 3H), 1.50 1.45 (m, 1H), 1.42 1.38 (m, 1H), 0.78 (s, 9H), À0.06 (s,
3H), À0.10 (s, 3H); 13C NMR (150 MHz, CDCl3): d=202.3, 170.3, 160.4,
157.1, 143.6, 134.8, 127.0, 116.0, 112.3, 105.2, 69.6, 67.4, 67.2, 65.1, 49.6,
39.9, 39.0, 36.4, 34.9, 26.3, 25.6, 25.0, 21.3, 17.8, À4.6, À5.0 ppm; HRMS
(MALDI-FTMS) for C28H42O8Si [M
+
Na+] calcd 557.2541, found
Bisamide 26: To a solution of aldehyde 25 (47 mg, 0.0834 mmol) and
amide 5 (20.9 mg, 0.1672 mmol) in 1,2-dichloroethane (4 mL) was added
dropwise at room temperature TMSOTf (7.55 mL, 0.0417 mmol) and the
resulting mixture was stirred for 24 h. Phosphate buffer (pH 7, 5.0 mL)
was added and the resulting reaction mixture was extracted with di-
chloromethane (3î5 mL). The combined organic layer was washed with
brine (10 mL), dried with MgSO4, filtered, and concentrated in vacuo.
The crude bis-TBS-protected amide was dissolved in THF (10 mL) and
TBAF (1.0 M THF solution, 0.3 mL, 0.30 mmol) was added dropwise to
the resulting solution. The reaction mixture was stirred for 1 h at room
temperature and then quenched with saturated (aq) NH4Cl (10 mL) and
extracted with ether (3î5 mL). The combined organic layer was then
washed with brine (10 mL), dried with MgSO4, filtered, and concentrated
in vacuo. The product was purified by column chromatography (silica) to
yield bisamide 26 as a white solid (35.4 mg, 75%). 26: Rf =0.28 (silica
gel, EtOAc); [a]D =À9.4 (c=3.5, acetone); IR (film): n˜max =3277, 2962,
557.2545.
Vinyl iodide 29: To a solution of CrCl2 (450 mg, 3.6615 mmol) in dry
THF (10 mL) at room temperature was added a solution of aldehyde 28
(163.4 mg, 0.3056 mmol), and iodoform (486 mg, 1.234 mmol), in dry
THF (15 mL). Almost immediately the reaction turned reddish-brown
and after 3 h of stirring at room temperature, the reaction was poured
onto brine (20 mL) and extracted with ether (3î10 mL). The combined
organic layer was then washed with brine (20 mL), dried with MgSO4, fil-
tered, and concentrated in vacuo. The product was purified by flash
column chromatography (silica) to yield vinyl iodide 29 as a yellow oil
(183.2 mg, 91% ca. 9:1 trans:cis mixture). 29: Rf =0.25 (silica gel, EtOA-
c:hexanes, 1:4); IR (film): n˜max =2955, 2951, 2861, 1737, 1608, 1584, 1478,
1449, 1378, 1314, 1296, 1243, 1073, 1044, 967, 920, 838, 803, 773 cmÀ1 1H
;
NMR (600 MHz, CDCl3): d=7.38 (dd, J=8.3, 7.9 Hz, 1H), 6.96 (d, J=
7.9 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 6.34 6.29 (m, 1H), 5.87 (d, J=12.7
Hz, 1H), 5.17 5.12 (m, minor), 5.06 5.01 (m, major, 1H), 4.26 4.24 (m,
minor), 4.14 4.12 (m, major, 1H), 3.94 3.87 (m, 1H), 3.56 3.53 (m,
minor), 3.46 3.38 (m, major, 2H), 3.17 3.08 (m, 1H), 2.09 1.96 (m, 3H),
2.03 (s, major, 3H), 2.02 (s, minor), 1.87 1.75 (m, 1H), 1.70 (s, 3H), 1.64
(s, 3H), 1.70 1.64 (m, 2H), 1.51 1.45 (m, 1H), 1.42 1.32 (m, 1H), 0.83 (s,
minor), 0.81 (s, major, 9H), À0.06 (s, minor), À0.10 ppm (s, major, 6H);
13C NMR (150 MHz, CDCl3): d=170.4, 170.3, 160.4 (two peaks), 157.2,
157.0, 143.8, 143.7, 143.5, 143.4, 135.0, 134.8, 126.8, 126.6, 115.9 (two
peaks), 112.3, 112.2, 105.1 (two peaks), 76.5, 76.4, 70.9, 69.6, 68.1, 67.9,
67.5, 67.4, 66.0, 42.9, 42.4, 42.1, 39.8, 38.9, 37.1, 36.5, 36.0, 34.8, 34.7, 26.3,
25.8 (two peaks), 25.7, 25.4, 25.0, 21.4, 17.9 (two peaks), À4.7, À4.8; (two
2931, 2872, 1707, 1651, 1625, 1584, 1460, 1290, 1255, 1208, 1119 cmÀ1 1H
;
NMR (600 MHz, [D6]acetone) d 8.60 (bs, 1H), 7.62 7.4 (m, 4H), 7.10
(dd, J=8.3, 7.9 Hz, 1H), 6.79 6.74 (m, 3H), 6.69 (d, J=7.9 Hz, 1H),
5.77 5.72 (m, 4H), 5.69 5.62 (m, 1H), 5.46 4.41 (m, 1H), 4.24 4.21 (m,
1H), 3.99 3.75 (m, 3H), 3.32 (dd, J=15.5, 9.7 Hz, 1H), 2.43 (d, J=15.5
Hz, 1H), 2.26 2.21 (m, 4H), 2.03 1.90 (m, 3H), 1.84 1.78 (m, 1H), 1.66
1.43 (m, 6H), 0.97 ppm (t, J=7.6 Hz, 6H); 13C NMR (125 MHz, [D6]ace-
tone): d=169.5, 166.2, 166.1, 154.2, 140.8 (two peaks), 140.0, 135.8, 135.7,
130.2, 125.6, 125.3 (two peaks), 122.3, 121.7, 121.6, 114.5, 74.0, 73.4, 68.4,
64.8, 57.2, 54.5, 40.4, 39.8, 39.3, 31.7, 31.3, 21.0 (two peaks), 14.3 ppm
(two peaks); HRMS (MALDI-FTMS) for C32H42N2O7 [M + Na+] calcd
589.2890, found 589.2903.
isomers); HRMS (MALDI-FTMS) for C29H43IO7Si [M
+
Na+] calcd
681.1715, found 681.1711.
Terminal olefin 27: To a solution of aldehyde 15 (153.7 mg, 0.367 mmol)
in dichloromethane (20 mL) at 08C was added sequentially 2,6-lutidine
(171 mL, 1.468 mmol) followed by dropwise addition of TESOTf (169 mL,
0.7359 mmol). The reaction mixture was stirred at 08C for 2 h, quenched
with methanol (10 mL) and allowed to warm to room temperature. After
stirring for an additional 30 min, the solution was concentrated in vacuo
and purified by flash column chromatography (silica) to yield terminal
olefin 27 as a colorless oil (183.6 mg, 94%). 27: Rf =0.42 (silica gel,
trans-Enamide 30a: To an oven-dried flask was added CuTC (3.5 mg,
0.018 mmol), Rb2CO3 (13.0 mg, 0.056 mmol), and amide 5 (5.0 mg, 0.039
mmol) and dry dimethylacetamide (5 mL) and the mixture was degassed
under high vacuum until bubbling had ceased. To a separate oven-dried
flask was added vinyl iodide 29 (11.9 mg, 0.018 mmol) and dry dimethyla-
cetamide (5 mL) and the solution was degassed under high vacuum until
bubbling ceased. The solution of vinyl iodide 29 was transferred to the
CuTC-Rb2CO3-amide 5 mixture and the reaction mixture was placed
under high vacuum once again. The suspension was purged with argon
and then heated to 908C and stirred for 15 h at that temperature. The re-
sulting dark reddish-brown solution was cooled to room temperature and
poured onto phosphate buffer (pH 7, 5 mL) and extracted with ether
(3î5 mL). The combined organic layer was then washed with brine (10
mL), dried with MgSO4, filtered, and concentrated in vacuo. The crude
mixture so obtained was purified by column chromatography (silica) to
yield in order of elution starting vinyl iodide 29 (6.8 mg), cis-enamide
30b (0.5 mg, 4%), and trans-enamide 30a (4.9 mg, 41%). 30a: Rf =0.5
(silica gel, EtOAc:hexanes, 1:2); [a]D =-7.04 (c=2.8, acetone); IR (film):
n˜max =3450, 3319, 2955, 2931, 2861, 1731, 1713, 1642, 1584, 1455, 1373,
EtOAc:hexanes, 1:4); [a]D =À45.5 (c=3.52, acetone); IR (film): n˜max
=
2955, 2931, 2861, 1731, 1608, 1584, 1478, 1449, 1378, 1314, 1296, 1243,
1
1079, 1043, 914, 838, 808, 773 cmÀ1; H NMR (600 MHz, CDCl3): d=7.37
(dd, J=7.9, 7.4 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H),
5.70 5.63 (m, 1H), 5.05 5.00 (m, 1H), 4.96 4.91 (m, 2H), 4.18 4.14 (m,
1H), 3.91 3.87 (m, 1H), 3.49 3.45 (m, 1H), 3.43 (dd, J=13.4, 3.3 Hz,
1H), 3.12 (dd, J=13.1, 8.8 Hz, 1H), 2.09 2.06 (m, 3H), 2.02 (s, 3H),
1.75 1.66 (m, 3H), 1.68 (s, 3H), 1.64 (s, 3H), 1.51 1.40 (m, 2H), 0.81 (s,
9H), À0.09 (s, 3H), À0.09 ppm (s, 3H); 13C NMR (150 MHz, CDCl3):
d=170.3, 160.4, 157.0, 143.8, 135.0, 134.8, 126.8, 116.8, 115.8, 112.3, 105.0,
69.7, 68.5, 67.6, 67.5, 40.9, 39.7, 38.8, 36.5, 34.4, 26.1, 25.8, 25.1, 21.4, 17.9,
À4.6, À4.8; HRMS (MALDI-FTMS) for C29H44O7Si [M + Na+] calcd
555.2748, found 555.2741.
1242, 1208, 1088, 1044, 838, 779 cmÀ1 1H NMR (600 MHz, [D6]acetone):
;
Aldehyde 28: A solution of olefin 27 (183.6 mg, 0.345 mmol) in dichloro-
methane (20 mL) was cooled to À788C. A flow of ozone was passed
through the solution until it turned blue. The excess ozone was then
purged with oxygen until the solution became clear again. The reaction
mixture was quenched with dimethylsulfide (0.5 mL, 20.0 mmol) at
d=9.05 (bd, J=10.8 Hz, 1H), 7.55 7.50 (m, 2H), 7.08 (d, J=7.44 Hz,
1H), 6.89 (d, J=7.92 Hz, 1H), 6.84 (dd, J=11.9, 11.4 Hz, 1H), 6.77 (dd,
J=14.5, 10.6 Hz, 1H), 5.80 5.76 (m, 1H), 5.73 (d, J=11.4 Hz, 1H), 5.25
(dt, J=14.5, 7.4 Hz, 1H), 5.04 4.97 (m, 1H), 4.21 4.17 (m, 1H), 3.94
3.89 (m, 1H), 3.50 3.46 (m, 1H), 3.41 (dd, J=12.7, 3.5 Hz, 1H), 3.15 (dd,
6186
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 6177 6191

Total Synthesis of (À)Apicularen A and Analogues Thereof
6177 6191
J=12.9, 8.6 Hz, 1H), 2.29 2.24 (m, 2H), 2.16 2.04 (m, 2H), 2.06 2.04 (m,
1H), 2.00 (s, 3H), 1.84 1.79 (m 1H), 1.76 1.74 (m, 1H), 1.70 1.67 (m,
1H), 1.69 (s, 3H), 1.65 (s, 3H), 1.47 1.41 (m, 2H), 1.00 (t, J=7.44 Hz,
3H), 0.83 (s, 9H), À0.6 ppm (s, 6H); 13C NMR (150 MHz, [D6]acetone):
d=170.4, 163.5, 160.7, 157.8, 144.6, 141.3, 136.6, 135.8, 127.9, 125.8, 125.4,
120.9, 116.6, 113.4, 108.8, 105.8, 70.4, 70.0, 68.5, 68.0, 40.5, 39.5 (two
peaks), 37.5, 35.4, 26.3, 26.2, 25.0, 21.2, 21.0, 18.5, 14.3, À4.4, À4.5;
HRMS (MALDI-FTMS) for C36H53NO8Si [M + Na+] calcd 678.3432,
found 678.3439.
ppm; HRMS (MALDI-FTMS) for C30H39NO8 [M
564.2568, found 564.2555.
+
Na+] calcd
Apicularen A (1): To a solution of trans-enamide 31a (25 mg, 0.0462
mmol) in THF (5 mL) at room temperature was added NaH (60%, 12.9
mg, 0.323 mmol) and the reaction mixture was stirred for 2 h at which
time the macrocyclization was complete (monitored by TLC). Water (5.0
equiv) was then added and the reaction mixture was stirred for 24 h. Sa-
turated (aq) NH4Cl (5 mL) was then added and the reaction mixture was
extracted with ether (3î10 mL), dried with MgSO4, filtered and concen-
trated in vacuo. Flash column chromatography (silica) gave apicularen A
(1) as a white solid (10.1 mg, 50%). 1: Rf =0.27 (silica gel, EtOAc:hex-
anes 9:1); [a]D =À21.0 (c=0.2, acetonitrile); HRMS (MALDI-FTMS)
calcd for C25H31NO6 [M + Na+] 464.2043, found 464.2052. The 1H and
13C NMR data for the synthetic material were identical to those reported
for the natural product.[1b]
cis-Enamide 30b: Rf =0.81 (silica gel, EtOAc:hexanes, 1:1); [a]D =À81.8
(c=0.11, acetone); IR (film): n˜max =3412, 2953, 2926, 2860, 1734, 1649,
1504, 1478, 1452, 1386, 1320, 1293, 1241, 1202, 1077, 1044, 834, 808, 775
cmÀ1 1H NMR (500 MHz, [D6]acetone): d=8.69 (bd, J=10.7 Hz, 1H),
;
7.52 7.46 (m, 2H), 7.10 (dd, J=7.7, 1.1 Hz, 1H), 6.92 (dd, J=8.1, 1.1 Hz,
1H), 6.84 (dt, J=11.8, 1.1 Hz, 1H), 6.80 6.76 (m, 1H), 5.84 5.75 (m,
2H), 5.04 4.98 (m, 1H), 4.69 4.64 (m, 1H), 4.28 4.24 (m, 1H), 3.99 3.91
(m, 1H), 3.65 3.61 (m, 1H), 3.43 3.38 (m, 1H), 3.27 3.23 (m, 1H), 2.30
2.15 (m, 4H), 2.06 1.90 (m, 4H), 1.89 1.83 (m, 1H), 1.78 1.73 (m, 1H),
1.70 1.64 (m, 7H), 1.52 1.41 (m, 2H), 0.99 (t, J=7.7 Hz, 3H), 0.86 (s,
9H), À0.01 (s, 3H), À0.02 ppm (s, 3H); 13C NMR (150 MHz, [D6]ace-
tone): d=170.3, 163.9, 160.9, 157.9, 144.5, 141.5, 136.8, 135.8, 127.9, 125.4,
123.4, 120.9, 116.7, 113.5, 107.8, 105.9, 70.7, 69.9, 68.1, 67.9, 40.2, 39.6,
36.9, 35.6, 33.6, 26.2, 26.1, 25.2, 21.2, 21.0, 18.5, 14.3, À4.4, À4.5 ppm;
HRMS (MALDI-FTMS) for C36H53NO8Si [M + Na+] calcd 678.3432,
found 678.3422.
cis-Apicularen A (2): To a solution of cis-enamide 31b (19.9 mg, 0.0367
mmol) in THF (5 mL) at room temperature was added NaH (60%, 29
mg, 0.725 mmol) and the reaction mixture was stirred for 2 h at which
time the macrocyclization was complete (monitored by TLC). Water (5.0
equiv) was then added and the reaction mixture was stirred for 24 h. Sa-
turated (aq) NH4Cl (5 mL) was then added and the reaction mixture was
extracted with ether (3î10 mL), dried with MgSO4, filtered and concen-
trated in vacuo. Flash column chromatography (silica) gave apicularen
analogue (2) as a white solid (5.5 mg, 34%). 2: Rf =0.32 (silica gel,
EtOAc:hexanes 4:1); [a]D =+10.0 (c=0.2, acetone); IR (film): n˜max
=
3354, 2955, 2919, 2849, 1719, 1702, 1684, 1655, 1661, 1237, 1619, 1578,
Hydroxy trans-enamide 31a: To a solution of TBS-protected trans-enam-
ide 30a (39.2 mg, 0.0598 mmol) in THF (10 mL) at room temperature
was added TBAF (1.0m THF solution, 0.3 mL, 0.30 mmol). The reaction
mixture was stirred for 17 h at ambient temperature and then quenched
with saturated (aq) NH4Cl (10 mL) and extracted with ether (3î10 mL).
The combined organic layer was then washed with brine (10 mL), dried
with MgSO4, filtered and concentrated in vacuo. The product was puri-
fied by flash column chromatography (silica) to yield hydroxyl trans-en-
amide 31a as a light yellow oil (25.8 mg, 80%). 31a: Rf =0.40 (silica gel,
1
1508, 1461, 1420, 1372, 1290, 1208, 1102, 1078, 1055, 1020 cmÀ1; H NMR
(500 MHz, [D6]acetone): d=8.80 (bd, J=10.7 Hz, 1H), 8.45 (s, 1H), 7.49
(ddd, J=11.4, 11.4, 1.1 Hz, 1H), 7.10 (dd, J=8.4, 7.4 Hz, 1H), 6.86 6.80
(m, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.69 (d, J=7.4 Hz, 1H), 5.83 (d, J=
12.5 Hz, 1H), 5.82 5.76 (m, 1H), 5.47 (m, 1H), 4.81 (dt, J=9.2, 7.5 Hz,
1H), 4.28 4.24 (m, 1H), 4.00 3.96 (m, 1H), 3.89 3.85 (m, 1H), 3.77 (d,
J=4.0 Hz, 1H), 3.35 (dd, J=14.7, 10.3 Hz, 1H), 2.44 2.37 (m, 3H), 2.29
2.23 (m, 2H), 1.94 1.90 (m, 1H), 1.86 1.79 (m, 1H), 1.68 1.63 (m, 1H),
1.60 1.56 (m, 1H), 1.53 1.46 (m, 2H), 0.99 ppm (t, J=7.5 Hz, 3H); 13C
NMR (150 MHz, [D6]acetone): d=169.3, 164.0, 154.2, 141.6, 140.2, 137.0,
130.2, 125.8, 125.4, 123.9, 122.2, 120.8, 114.3, 106.5, 73.8, 73.7, 67.7, 64.8,
40.1, 39.9, 39.5, 39.1, 32.1, 21.0, 14.3 ppm; HRMS (MALDI-FTMS) calcd
for C25H31NO6 [M + Na+] 464.2043, found 464.2039.
EtOAc:hexanes, 2:8); [a]D =À80.4 (c=0.28, acetone); IR (film): n˜max
=
3416, 2965, 1723, 1640, 1580, 1521, 1485, 1379, 1242, 1212, 1046 cmÀ1 1H
;
NMR (500 MHz, [D6]acetone): d=8.98 (d, J=10.3 Hz, 1H), 7.55 7.49
(m, 2H), 7.05 (dd, J=7.7, 1.1 Hz, 1H), 6.91 (dd, J=8.1, 1.1 Hz, 1H), 6.84
(ddd, J=11.8, 11.8, 1.1 Hz, 1H), 6.77 (ddt, J=14.7, 10.7, 1.5 Hz, 1H),
5.82 5.75 (m, 1H), 5.72 (d, J=11.4 Hz, 1H), 5.16 (dt, J=14.3, 7.4 Hz,
1H), 5.08 5.00 (m, 1H), 4.30 4.22 (m, 1H), 4.04 3.96 (m, 1H), 3.54 (dd,
J=13.2, 3.7 Hz, 1H), 3.52 3.45 (m, 1H), 3.16 (d, J=3.3 Hz, 1H), 3.13
(dd, J=12.8, 8.4 Hz, 1H), 2.31 2.23 (m, 2H), 2.10 1.98 (m, 3H), 2.00 (s,
3H), 1.84 1.72 (m, 2H), 1.71 1.67 (m, 7H), 1.55 1.41 (m, 2H) 0.99 ppm
(t, J=3.9 Hz, 3H); 13C NMR (125 MHz, [D6]acetone): d=170.4, 163.5,
160.8, 158.0, 144.4, 141.3, 136.6, 135.9, 127.7, 125.5, 125.4, 120.9, 116.7,
113.3, 109.2, 106.0, 70.9, 70.8, 70.6, 67.8, 40.5, 39.0, 38.5, 37.3, 35.4, 26.0,
25.4, 21.2, 21.0, 14.3 ppm; HRMS (MALDI-FTMS) for C30H39NO8 [M +
Na+] calcd 564.2568, found 564.2580.
11-OAc Apicularen A (32): To a solution of 31a (10.4 mg, 0.0192 mmol)
in THF (5 mL) was added NaH (60%, 15.4 mg, 0.385 mmol) at room
temperature. The reaction mixture was stirred for 2 h, then quenched
with saturated (aq) NH4Cl (5 mL) and extracted with ether (3î10 mL).
The combined organic layer was then washed with brine (5 mL), dried
with MgSO4, filtered, and concentrated in vacuo. The product was puri-
fied by flash column chromatography (silica) to yield 11-OAc apicularen
A 32 as a yellow oil (6.5 mg, 70%). 32: Rf =0.58 (silica gel, EtOAc:hex-
anes 2:1); [a]D =À10.0 (c=0.06, acetone); IR (film): n˜max =3350, 2962,
2927, 2856, 1729, 1711, 1694, 1681, 1653, 1535, 1517, 1500, 1464, 1365,
1288, 1247, 1118, 1077, 1047, 953, 806, 771 cmÀ1 1H NMR (600 MHz,
;
Hydroxy cis-enamide 31b: To a solution of TBS-protected cis-enamide
30b (40.4 mg, 0.0616 mmol) in THF (10 mL) at room temperature was
added TBAF (1.0m THF solution, 0.31 mL, 0.310 mmol) in THF. The re-
action mixture was stirred for 17 h at ambient temperature and then
quenched with saturated (aq) NH4Cl (10 mL) and extracted with ether
(3î10 mL). The combined organic layer was washed with brine (10 mL),
dried with MgSO4, filtered, and concentrated in vacuo. The product was
purified by flash column chromatography (silica) to yield hydroxyl cis-en-
amide 31b as a yellow oil (19.9 mg, 60%). 31b: Rf =0.61 (silica gel,
[D6]acetone): d=9.08 (bd, J=10.1 Hz, 1H), 8.42 (s, 1H), 7.50 (m, 1H),
7.11 (dd, J=7.9, 7.9 Hz, 1H), 6.91 6.82 (m, 2H), 6.78 (d, J=7.9 Hz, 1H),
6.71 (d, J=7.9 Hz, 1H), 5.81 5.72 (m, 2H), 5.45 5.43 (m, 1H), 5.27 5.21
(m, 1H), 5.01 4.97 (m, 1H), 4.24 (m, 1H), 3.94 3.91 (m, 1H), 3.34 (dd,
J=14.3, 10.3 Hz, 1H), 2.44 (m, 1H), 2.35 2.33 (m, 2H), 2.29 2.24 (m,
2H), 2.05 2.01 (m, 1H), 2.00 (s, 3H), 1.84 1.78 (m, 1H), 1.76 1.72 (m,
1H), 1.65 1.59 (m, 3H), 0.99 ppm (t, J=7.4 Hz, 3H); 13C NMR (150
MHz, [D6]acetone): d=170.3, 169.6, 163.6, 154.2, 141.5, 139.9, 136.8,
130.4, 126.3, 125.5, 125.4, 122.2, 120.8, 114.5, 107.9, 74.1, 73.7, 68.6, 67.2,
39.3, 39.1, 36.3, 36.2, 35.1, 21.2, 21.0, 14.3 ppm; HRMS (MALDI-FTMS)
calcd for C27H33NO7 [M + Na+] 506.2149, found 506.2151.
EtOAc:hexanes, 2:1); [a]D =À40.8 (c=0.6, acetone); IR (film): n˜max
=
3456, 3350, 2962, 2927, 2856, 1729, 1682, 1647, 1606, 1582, 1505, 1482,
1447, 1376, 1318, 1288, 1265, 1241, 1212, 1077, 1047, 965, 923, 812 cmÀ1
;
1H NMR (500 MHz, [D6]acetone): d=8.86 (bd, J=10.7 Hz, 1H), 7.52
Apicularen analogue 33: (see cis-apicularen A (2) for macrocyclization
and simultaneous acetate deprotection procedure): 31% yield; light
yellow oil: Rf =0.29 (silica gel, EtOAc:hexanes, 4:1); [a]D =+3.3 (c=
0.09, acetone); IR (film): n˜max =3417, 2954, 2906, 2859, 1711, 1682, 1652,
7.46 (m, 2H), 7.05 (d, J=7.7 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.84 (dt,
J=11.8, 1.2 Hz, 1H), 6.78 6.73 (m, 1H), 5.82 5.75 (m, 2H), 5.04 4.99 (m,
1H), 4.72 4.66 (m, 1H), 4.29 4.25 (m, 1H), 4.04 3.99 (m, 1H), 3.64 3.58
(m, 1H), 3.52 3.47 (m, 2H), 3.19 (dd, J=13.2, 8.4 Hz, 1H), 2.30 2.23 (m,
2H), 2.18 2.07 (m, 3H), 1.99 (s, 3H), 1.83 1.77 (m, 2H), 1.69 1.67 (m,
7H), 1.53 1.48 (m, 1H), 1.46 1.43 (m, 1H), 0.99 ppm (t, J=7.7 Hz, 3H);
13C NMR (150 MHz, [D6]acetone): d=170.4, 163.9, 160.9, 158.0, 144.3,
141.5, 136.8, 135.9, 127.7, 125.4, 123.7, 121.0, 116.8, 113.3, 107.8, 106.0,
70.9, 70.8, 70.6, 67.8, 40.4, 39.0, 37.1, 35.5, 34.1, 25.9, 25.5, 21.2, 21.0, 14.3
1634, 1575, 1539, 1462, 1290, 1260, 1094, 1076, 1053, 952, 797, 774 cmÀ1
;
1H NMR (500 MHz, [D6]acetone): d=9.52 (bd, J=10.1 Hz, 1H), 8.38 (s,
1H), 7.96 7.94 (m, 2H), 7.55 7.45 (m, 3H), 7.10 (dd, J=8.1, 7.7 Hz, 1H),
7.04 (dd, J=14.5, 10.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 6.69 (d, J=7.7
Hz, 1H), 5.49 5.41 (m, 2H), 4.29 4.25 (m, 1H), 4.00 3.85 (m, 2H), 3.78
(d, J=4.1 Hz, 1H), 3.35 (dd, J=14.7, 9.9 Hz, 1H), 2.45 2.37 (m, 3H),
6187
Chem. Eur. J. 2003, 9, 6177 6191
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

K. C. Nicolaou et al.
FULL PAPER
1.96 1.82 (m, 2H), 1.70 1.46 ppm (m, 4H); 13C NMR (125 MHz, [D6]ace-
tone): d=169.3, 164.4, 154.2, 140.2, 134.9, 132.3, 130.2, 129.2, 128.2, 126.7,
125.4, 122.2, 114.4, 108.9, 74.0, 73.7, 67.9, 64.8, 40.2, 39.9, 39.5, 38.9, 36.4
ppm; HRMS (MALDI-FTMS) for C25H27NO6 [M
460.1730, found 460.1726.
3405, 2953, 2923, 2843, 1729, 1713, 1694, 1659, 1643, 1613, 1583, 1538,
1518, 1463, 1433, 1362, 1347, 1292, 1247, 1122, 1076, 1051, 1031, 981 cmÀ1
;
1H NMR (600 MHz, [D6]acetone): d=9.18 (d, J=10.1 Hz, 1H), 8.43 (s,
1H), 7.61 757 (m, 3H), 7.41 7.36 (m, 3H), 7.11 (dd, J=7.9, 7.4 Hz, 1H),
6.96 (dd, J=14.3, 10.1 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.72 (d, J=7.4
Hz, 1H), 6.67 (d, J=15.8 Hz, 1H), 5.47 5.45 (m, 1H), 5.31 (dt, J=14.3,
7.2 Hz, 1H), 5.01 4.97 (m, 1H), 4.27 4.22 (m, 1H), 3.96 3.92 (m, 1H),
3.34 (dd, J=14.5, 10.6 Hz, 1H), 2.46 2.36 (m, 3H), 2.03 1.96 (m, 1H),
1.99 (s, 3H), 1.86 1.73 (m, 2H), 1.66 1.60 ppm (m, 3H); 13C NMR (150
MHz, [D6]acetone): d=170.3, 169.6, 163.0, 154.2, 141.4, 139.9, 136.0,
130.5, 130.4, 129.7, 128.5, 126.5, 125.5, 122.2, 121.9, 114.5, 108.3, 74.1,
73.7, 68.6, 67.3, 39.3, 39.1, 36.3, 36.2, 35.1, 21.2 ppm; HRMS (MALDI-
FTMS) for C29H31NO7 [M + Na+] calcd 528.1993, found 528.1995.
+
Na+] calcd
Compound 33a: (see trans-enamide 30a for a representative procedure
for CuTC-induced acylenamine formation): 37% yield; colorless oil:
Rf =0.39 (silica gel, hexanes:EtOAc, 2:1); [a]D =À64.3 (c=0.23, ace-
tone); IR (film): n˜max =2955, 2919, 2861, 1731, 1713, 1666, 1643, 1608, 1584,
1537, 1519, 1484, 1455, 1384, 1360, 1320, 1296, 1255, 1079, 1061, 1044, 961,
932, 832, 808, 773, 709 cmÀ1 1H NMR (500 MHz, [D6]acetone): d=9.45
;
(bd, J=10.3 Hz, 1H), 7.93 7.91 (m, 2H), 7.56 7.45 (m, 4H), 7.09 (dd, J=
7.9, 1.1 Hz, 1H), 6.96 6.91 (m, 1H), 6.90 (dd, J=8.1, 1.1 Hz, 1H), 5.41
(dt, J=14.7, 6.6 Hz, 1H), 5.01 (m, 1H), 4.25 3.91 (m, 2H), 3.58 3.37 (m,
2H), 3.19 (dd, J=12.9, 8.1 Hz, 1H), 2.23 2.02 (m, 3H), 1.99 (s, 3H),
1.88 1.75 (m, 2H), 1.71 1.63 (m, 7H), 1.53 1.39 (m, 2H), 0.85 (s, 9H),
À0.03 (s, 3H), À0.04 ppm (s, 3H); 13C NMR (125 MHz, [D6]acetone):
d=170.4, 164.4, 160.8, 157.8, 144.6, 135.9, 135.1, 132.3, 129.2, 128.2, 127.9,
126.2, 116.6, 113.4, 109.7, 105.9, 70.4, 70.1, 68.5, 68.0, 40.5, 39.4, 37.6, 37.5,
35.5, 26.3, 26.2, 25.0, 21.2, 18.5, À4.4, À4.5; HRMS (MALDI-FTMS) for
C36H49NO8Si [M + Na+] calcd 674.3119, found 674.3112.
Apicularen analogue 36: 57% yield; colorless oil: Rf =0.25 (silica gel,
EtOAc:hexanes, 4:1); [a]D =+2.5 (c=0.2, acetone); IR (film): n˜max
=
3378, 2943, 2919, 2849, 1731, 1708, 1684, 1655, 1637, 1602, 1584, 1543,
1496, 1460, 1437, 1420, 1378, 1361, 1284, 1261, 1232, 1161, 1120, 1073,
955, 855, 803 cmÀ1 1H NMR (600 MHz, [D6]acetone): d=9.54 (bd, J=
;
10.1 Hz, 1H), 8.38 (s, 1H), 8.03 8.01 (m, 2H), 7.24 7.21 (m, 2H), 7.10
(dd, J=8.3, 7.4 Hz, 1H), 7.02 (dd, J=14.5, 10.1 Hz, 1H), 6.76 (d, J=8.3
Hz, 1H), 6.69 (d, J=7.4 Hz, 1H), 5.48 5.41 (m, 2H), 4.29 4.24 (m, 1H),
3.99 3.85 (m, 2H), 3.78 (d, J=3.9 Hz, 1H), 3.35 (dd, J=14.7, 10.3 Hz,
1H), 2.44 2.37 (m, 3H), 1.96 1.84 (m, 2H), 1.70 1.46 ppm (m, 4H); 13C
NMR (150 MHz, [D6]acetone): d=169.3, 164.0, 163.4, 154.2, 140.2, 133.3,
130.9, 130.8, 130.2, 130.0, 126.7, 122.2, 116.1, 116.0, 114.4, 109.1, 74.0,
73.7, 67.9, 64.9, 40.2, 39.9, 39.5, 38.9, 36.3 ppm; HRMS (MALDI-FTMS)
for C25H26FNO6 [M + Na+] calcd 478.1636, found 478.1628.
Compound 33b: (see hydroxyl enamide 31a and 31b for a representative
procedure for TBAF-induced deprotections): 73% yield; yellow oil: Rf =
0.38 (silica gel, hexanes:EtOAc, 1:2); [a]D =À80.8 (c=0.25, acetone); IR
(film): n˜max =3452, 3345, 2941, 1729, 1646, 1604, 1580, 1479, 1373, 1295,
1
1248, 1200, 1052, 957 cmÀ1; H NMR (500 MHz, [D6]acetone): d=9.39 (d,
J=10.3 Hz, 1H), 7.97 7.91 (m, 2H), 7.55 7.42 (m, 4H), 7.06 (d, J=7.7
Hz, 1H), 6.96 6.85 (m, 2H), 5.40 (dt, J=14.3, 7.7 Hz, 1H), 5.08 4.96 (m,
1H), 4.33 4.22 (m, 1H), 4.07 3.99 (m, 1H), 3.56 3.52 (m, 2H), 3.21 (d,
J=3.3 Hz, 1H), 3.15 (dd, J=12.9, 8.5 Hz, 1H), 2.17 2.04 (m, 3H), 1.99
(s, 3H), 1.85 1.72 (m, 2H), 1.71 (s, 3H), 1.70 1.68 (m, 1H), 1.66 (s, 3H),
1.59 1.51 (m, 1H), 1.48 1.40 ppm (m, 1H); 13C NMR (150 MHz, [D6]ace-
tone): d=170.4, 164.3, 161.1, 158.0, 144.4, 135.9, 135.1, 132.3, 129.2, 128.2,
127.7, 125.9, 116.8, 113.3, 110.3, 106.4, 70.9, 70.8, 70.7, 67.9, 40.6, 39.0,
38.5, 37.3, 35.5, 26.0, 25.4, 21.2 ppm; HRMS (MALDI-FTMS) for
C30H35NO8 [M + Na+] calcd 560.2255, found 560.2264.
Compound 36a: 47% yield; yellow oil: Rf =0.45 (silica gel, hexanes:
EtOAc, 2:1); [a]D =À52.1 (c=0.33, acetone); IR (film) n˜max 2949, 2928,
2856, 1735, 1683, 1653, 1637, 1606, 1581, 1498, 1473, 1380, 1360, 1319,
1
1293, 1242, 1077, 1056, 1048, 959, 836, 810, 774 cmÀ1; H NMR (600 MHz,
[D6]acetone): d=9.50 (bd, J=10.1 Hz, 1H), 8.00 7.98 (m, 2H), 7.54 (dd,
J=7.9, 7.5 Hz, 1H), 7.25 7.22 (m, 2H), 7.09 (d, J=7.9 Hz, 1H), 6.94 6.89
(m, 2H), 5.39 (dt, J=14.5, 8.2 Hz, 1H), 5.01 (m, 1H), 4.25 4.21 (m, 1H),
3.95 3.91 (m, 1H), 3.57 3.53 (m, 1H), 3.40 3.37 (m, 1H), 3.19 (dd, J=
13.2, 8.3 Hz, 1H), 2.22 2.01 (m, 3H), 1.99 (s, 3H), 1.87 1.75 (m, 2H),
1.71 1.63 (m, 7H), 1.52 1.39 (m, 2H), 0.85 (s, 9H), À0.03 (s, 3H), À0.04
ppm (s, 3H); 13C NMR (150 MHz, [D6]acetone): d=170.4, 166.3, 164.7,
163.4, 160.8, 157.8, 144.5, 135.9, 131.5, 130.9, 130.8, 127.9, 126.1, 116.6,
116.1, 116.0, 113.4, 109.9, 105.9, 70.4, 70.1, 68.5, 68.0, 40.5, 39.4, 37.5, 37.4,
35.5, 26.3, 26.2, 25.0, 21.2, 18.5, À4.4, À4.5 ppm; HRMS (MALDI-FTMS)
for C36H48FNO8Si [M + Na+] calcd 692.3025, found 692.3020.
Apicularen analogue 34: 46% yield; yellow solid: Rf =0.30 (silica gel,
hexanes:EtOAc, 1:9); [a]D =À13.8 (c=0.42, acetone); IR (film): n˜max
3401, 2943, 2919, 2849, 1731, 1713, 1678, 1661, 1614, 1537, 1519, 1455,
1349, 1290, 1261, 1237, 1220, 1120, 1091, 1055, 803, 761 cmÀ1 1H NMR
=
;
(500 MHz, [D6]acetone): d=9.25 (d, J=10.6 Hz, 1H), 8.46 (s, 1H), 7.68
(d, J=15.4 Hz, 1H), 7.66 7.63 (m, 2H), 7.52 7.44 (m, 3H), 7.18 (t, J=
8.1 Hz, 1H), 7.03 (bdd, J=14.3, 10.2 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H),
6.77 (d, J=7.3 Hz, 1H), 6.75 (d, J=15.4 Hz, 1H), 5.57 5.48 (m, 1H), 5.39
(dt, J=14.3, 7.3 Hz, 1H), 4.37 4.30 (m, 1H), 4.12 4.03 (m, 1H), 4.00
3.91 (m, 1H), 3.85 (d, J=4.1 Hz, 1H), 3.42 (dd, J=13.9, 10.1 Hz, 1H),
2.51 (d, J=13.9 Hz, 1H), 2.46 (m, 2H), 2.05 1.97 (m, 1H), 1.95 1.88 (m,
1H), 1.80 1.72 (m, 1H), 1.70 1.65 (m, 1H), 1.62 1.52 ppm (m, 2H); 13C
NMR (125 MHz, [D6]acetone): d=169.3, 163.0, 154.3, 141.4, 140.2, 136.0,
130.5, 130.2, 129.7, 128.5, 126.4, 125.5, 122.2, 121.9, 114.4, 108.5, 74.2,
73.7, 68.0, 64.9, 40.3, 39.9, 39.6, 38.9, 36.3 ppm; HRMS (MALDI-FTMS)
for C27H29NO6 [M + Na+] calcd 486.1887, found 486.1906.
Compound 36b: 42% yield; light yellow oil: Rf =0.16 (silica gel, hexanes:
EtOAc, 1:1); [a]D =À39.4 (c=0.16, acetone); IR (film): n˜max =3436, 2955,
2919, 1731, 1713, 1661, 1642, 1602, 1578, 1531, 1502, 1478, 1455, 1378,
1320, 1296, 1267, 1237, 1208, 1161, 1049, 967, 926, 850 cmÀ1 1H NMR
;
(600 MHz, [D6]acetone): d=9.39 (bd, J=10.1 Hz, 1H), 8.01 7.99 (m,
2H), 7.51 (dd, J=7.9, 7.9 Hz, 1H), 7.24 7.21 (m, 2H), 7.05 (d, J=7.9 Hz,
1H), 6.91 6.87 (m, 2H), 5.39 (dt, J=14.5, 7.3 Hz, 1H), 5.02 (m, 1H),
4.29 4.26 (m, 1H), 4.01 3.99 (m, 1H), 3.54 3.52 (m, 2H), 3.20 (d, J=3.1
Hz, 1H), 3.14 (dd, J=12.9, 8.5, Hz, 1H), 2.14 2.03 (m, 3H), 1.99 (s, 3H),
1.81 1.74 (m, 2H), 1.70 1.64 (m, 7H), 1.55 1.41 ppm (m, 2H); 13C NMR
(150 MHz, [D6]acetone): d=170.4, 166.3, 164.7, 163.3, 160.9, 158.0, 144.4,
135.9, 131.5, 130.8 (two peaks), 127.7, 125.8, 116.8, 116.1, 116.0, 113.3,
110.4, 106.1, 71.0, 70.8, 70.6, 67.9, 40.6, 39.0, 38.5, 37.3, 35.5, 26.0, 25.4,
21.2 ppm; HRMS (MALDI-FTMS) for C30H34FNO8 [M + Na+] calcd
578.2161, found 578.2168.
Compound 34a: 41% yield; colorless oil: Rf =0.40 (silica gel, hexanes:
EtOAc, 2:3); [a]D =À97.5 (c=0.16, acetone); IR (film): n˜max =2953, 2930,
2859, 1729, 1652, 1610, 1527, 1444, 1343, 1289, 1242, 1058, 969, 916, 827,
1
779 cmÀ1; H NMR (600 MHz, [D6]acetone): d=9.16 (d, J=10.6 Hz, 1H),
7.65 7.50 (m, 4H), 7.45 7.32 (m, 3H), 7.09 (d, J=7.7 Hz, 1H), 6.91 (d,
J=8.3 Hz, 1H), 6.86 (dd, J=14.5, 10.5 Hz, 1H), 6.67 (d, J=15.8 Hz, 1H),
5.23 (dt, J=14.5, 7.0 Hz, 1H), 5.05 4.95 (m, 1H), 4.25 4.17 (m, 1H),
3.97 3.88 (m, 1H), 3.54 3.46 (m, 1H), 3.41 (dd, J=12.7, 3.5 Hz, 1H),
3.17 (dd, J=13.2, 8.8 Hz, 1H), 2.19 2.04 (m, 3H), 1.99 (s, 3H), 1.86 1.81
(m, 1H), 1.78 1.74 (m, 1H), 1.69 1.65 (m, 7H), 1.49 1.40 (m, 2H), 0.85
(s, 9H), À0.05 ppm (s, 6H); 13C NMR (150 MHz, [D6]acetone): d=170.4,
162.9, 160.8, 157.8, 144.6, 141.4, 136.1, 135.9, 130.4, 129.7, 128.5, 127.9,
125.9, 121.9, 116.6, 113.4, 109.6, 105.8, 70.4, 70.0, 68.5, 68.0, 40.5, 39.5,
37.5, 37.4, 35.4, 26.4, 26.2, 25.0, 21.2, 18.5, À4.4, À4.5 ppm; HRMS
Apicularen analogue 37: 41% yield; yellow oil: Rf =0.13 (silica gel,
EtOAc:hexanes, 4:1); [a]D =+2.5 (c=0.24, acetone); IR (film): n˜max
3362, 2927, 2856, 1723, 1694, 1635, 1617, 1582, 1535, 1506, 1465, 1418,
1359, 1288, 1265, 1177, 1118, 1077, 1053, 953 cmÀ1 1H NMR (500 MHz,
=
;
[D6]acetone): d=9.51 (bd, J=10.3 Hz, 1H), 8.40 (s, 1H), 7.79 (dd, J=
3.7, 1.1 Hz, 1H), 7.72 (dd, J=5.1, 1.1 Hz, 1H), 7.13 (dd, J=5.1, 3.7, 1H),
7.10 (dd, J=8.4, 7.3 Hz, 1H), 6.95 (dd, J=14.3, 10.3 Hz, 1H), 6.77 (d, J=
8.4 Hz, 1H), 6.69 (d, J=7.3 Hz, 1H), 5.48 5.44 (m, 1H), 5.37 (dt, J=
14.3, 7.4 Hz, 1H), 4.27 4.25 (m, 1H), 4.00 3.85 (m, 2H), 3.78 (d, J=4.1
Hz, 1H), 3.35 (dd, J=14.9, 9.7 Hz, 1H), 2.44 2.35 (m, 3H), 1.96 1.81 (m,
2H), 1.70 1.65 (m, 1H), 1.60 1.46 ppm (m, 3H); 13C NMR (150 MHz,
[D6]acetone): d=169.3, 159.3, 154.2, 140.5, 140.2, 131.9, 130.2, 128.9,
128.6, 126.1, 125.5, 122.2, 114.4, 108.8, 74.0, 73.8, 67.8, 64.8, 40.2, 39.9,
(MALDI-FTMS) for C38H51NO8Si [M
+
Na+] calcd 700.3276, found
700.3295.
Apicularen analogue 35: 85% yield; yellow oil: Rf =0.75 (silica gel, hex-
anes:EtOAc, 15:85), [a]D =À12.4 (c=0.33, acetone); IR (film): n˜max
=
6188
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 6177 6191

Total Synthesis of (À)Apicularen A and Analogues Thereof
6177 6191
39.5, 38.9, 36.3 ppm; HRMS (MALDI-FTMS) for C23H25NO6S [M
+
1H), 7.36 (d, J=3.1 Hz, 1H), 7.15 7.08 (m, 2H), 6.94 (dd, J=14.5, 10.6
Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.71 (d, J=7.5 Hz, 1H), 6.42 (d, J=
15.3 Hz, 1H), 5.51 5.43 (m, 1H), 5.31 (dt, J=14.5, 7.4 Hz, 1H), 5.04 4.96
(m, 1H), 4.30 4.22 (m, 1H), 3.98 3.90 (m, 1H), 3.35 (dd, J=14.5, 10.6
Hz, 1H), 2.45 (d, J=14.5 Hz, 1H), 2.41 2.34 (m, 2H), 2.06 1.94 (m, 2H),
2.00 (s, 3H), 1.87 1.74 (m, 2H), 1.66 1.61 ppm (m, 2H); 13C NMR (150
MHz, [D6]acetone): d=170.2, 169.7, 162.6, 154.1, 140.7, 139.8, 134.1,
131.4, 130.3, 128.9, 128.4, 126.4, 125.4, 122.1, 120.6, 114.4, 108.2, 74.0,
73.6, 68.5, 67.2, 39.2, 38.9, 36.2, 36.1, 35.0, 21.1 ppm; HRMS (MALDI-
FTMS) for C27H29NO7S [M + Na+] calcd 534.1557, found 534.1567.
Na+] calcd 466.1295, found 466.1282.
Compound 37a: 43% yield; light yellow oil: Rf =0.39 (silica gel, hexanes:
EtOAc, 2:1); [a]D =À54.4 (c=0.16, acetone); IR (film): n˜max =3476, 3346,
2954, 2918, 2859, 1729, 1652, 1634, 1605, 1575, 1533, 1474, 1379, 1355,
1320, 1296, 1248, 1076, 1041, 958, 928, 833, 774, 726 cmÀ1 1H NMR (600
;
MHz, [D6]acetone): d=9.44 (bd, J=10.1 Hz, 1H), 7.76 7.71 (m, 2H),
7.54 (dd, J=8.3, 7.4 Hz, 1H), 7.14 7.13 (m, 1H), 7.09 (d, J=7.4 Hz, 1H),
6.90 (d, J=8.3 Hz, 1H), 6.86 (dd, J=14.5, 10.1 Hz, 1H), 5.34 (dt, J=14.5,
6.7 Hz, 1H), 5.03 4.98 (m, 1H), 4.24 4.20 (m, 1H), 3.94 3.91 (m, 1H),
3.57 3.53 (m, 1H), 3.41 3.37 (m, 1H), 3.19 (dd, J=12.7, 8.3 Hz, 1H),
2.21 2.01 (m, 3H), 1.99 (s, 3H), 1.86 1.75 (m, 2H), 1.70 1.64 (m, 7H),
1.51 1.41 (m, 2H), 0.85 (s, 9H), À0.03 (s, 3H), À0.04 (s, 3H); 13C NMR
(150 MHz, [D6]acetone): d=170.4, 160.8, 159.2, 157.8, 144.5, 140.5, 135.8,
131.8, 128.8, 128.6, 127.9, 125.7, 116.6, 113.4, 109.6, 105.8, 70.4, 70.0, 68.5,
68.0, 40.5, 39.3, 37.5, 37.4, 35.5, 26.3, 26.2, 25.0, 21.2, 18.5, À4.4, À4.6;
HRMS (MALDI-FTMS) for C34H47NO8SSi [M + Na+] calcd 680.2684,
found 680.2681.
Apicularen analogue 40: 59% yield; light yellow oil: Rf =0.13 (4:1
EtOAc:hexanes); [a]D =+2.2 (c=0.09, acetone); IR (film): n˜max =3366,
2954, 2919, 2849, 1731, 1713, 1696, 1660, 1643, 1613, 1584, 1555, 1537,
1519, 1455, 1373, 1360, 1284, 1261, 1108, 1261, 1108, 1091, 1078, 961, 797
cmÀ1 1H NMR (600 MHz, [D6]acetone): d=8.85 (bd, J=10.6 Hz, 1H),
;
8.37 (s, 1H), 7.09 (d, J=7.9, 7.4 Hz, 1H), 6.80 (dd, J=14.5, 10.6 Hz, 1H),
6.76 (d, J=7.9 Hz, 1H), 6.69 (d, J=7.4 Hz, 1H), 5.42 5.37 (m, 1H), 5.17
(dt, J=14.5, 7.2 Hz, 1H), 4.26 4.21 (m, 1H), 4.00 3.78 (m, 3H), 3.33 (dd,
J=14.5, 10.1 Hz, 1H), 2.44 2.30 (m, 3H), 2.18 (t, J=7.4 Hz, 2H), 1.95
1.79 (m, 2H), 1.69 1.45 (m, 6H), 1.33 1.24 (m, 4H), 0.87 ppm (t, J=7.0
Hz, 3H); 13C NMR (150 MHz, [D6]acetone): d=170.4, 169.3, 154.2,
140.2, 130.2, 126.4, 125.5, 122.2, 114.4, 106.8, 74.3, 73.7, 67.9, 64.9, 40.2,
39.9, 39.5, 38.9, 36.4, 36.2, 32.1, 25.8, 23.0, 14.2 ppm; HRMS (MALDI-
FTMS) for C24H33NO6 [M + Na+] calcd 454.2200, found 454.2207.
Compound 37b: 74% yield; yellow oil: Rf =0.13 (silica gel, 1:1 hexanes:
EtOAc); [a]D =À50.6 (c=0.17, acetone); IR (film): n˜max =3409, 2927,
2845, 1729, 1711, 1682, 1635, 1606, 1582, 1535, 1506, 1470, 1447, 1418,
1376, 1359, 1318, 1294, 1271, 1241, 1206, 1047 cmÀ1 1H NMR (600 MHz,
;
[D6]acetone): d=9.36 (bd, J=10.1 Hz, 1H), 7.78 7.71 (m, 2H), 7.51 (dd,
J=7.9, 7.4 Hz, 1H), 7.14 (dd, J=5.0, 3.7 Hz, 1H), 7.05 (d, J=7.4 Hz,
1H), 6.90 (d, J=7.9 Hz, 1H), 6.83 (dd, J=14.5, 10.1 Hz, 1H), 5.33 (dt,
J=14.5, 7.4 Hz, 1H), 5.05 5.00 (m, 1H), 4.28 4.25 (m, 1H), 4.02 3.98 (m,
1H), 3.54 3.52 (m, 2H), 3.20 (d, J=3.5 Hz, 1H), 3.14 (dd, J=12.9, 8.5
Hz, 1H), 2.14 2.03 (m, 3H), 1.99 (s, 3H), 1.81 1.73 (m, 2H), 1.70 1.66
(m, 7H), 1.52 (ddd, J=14.5, 4.6, 4.6 Hz, 1H), 1.44 ppm (ddd, J=12.8, 9.6,
9.5 Hz, 1H); 13C NMR (150 MHz, [D6]acetone): d=170.4, 160.9, 159.2,
158.0, 144.4, 140.5, 135.9, 131.9, 128.8, 128.6, 127.7, 125.3, 116.8, 113.3,
110.2, 106.1, 70.9, 70.8, 70.5, 67.9, 40.6, 39.0, 38.4, 37.3, 35.4, 26.0, 25.4,
21.2 ppm; HRMS (MALDI-FTMS) for C28H33NO8S [M + Na+] calcd
566.1819, found 566.1809.
Compound 40a: 50% yield; light yellow oil: Rf =0.38 (silica gel, hexanes:
EtOAc, 2:1); [a]D =À60.0 (c=0.11, acetone); IR (film): n˜max =2955, 2931,
2861, 1731, 1713, 1661, 1643, 1608, 1584, 1537, 1519, 1472, 1455, 1378,
1
1314, 1298, 1249, 1079, 1044, 961, 838, 808, 779 cmÀ1; H NMR (500 MHz,
[D6]acetone): d=8.81 (bd, J=10.3 Hz, 1H), 7.53 (dd, J=8.1, 7.7 Hz,
1H), 7.07 (dd, J=7.5, 1.1 Hz, 1H), 6.89 (dd, J=8.1, 1.1 Hz, 1H), 6.69
(dd, J=14.5, 10.3 Hz, 1H), 5.08 (dt, J=14.5, 6.8 Hz, 1H), 5.03 4.98 (m,
1H), 4.20 3.82 (m, 2H), 3.49 3.38 (m, 2H), 3.15 (dd, J=12.8, 8.4 Hz,
1H), 2.17 (t, J=7.3 Hz, 2H), 2.14 2.02 (m, 3H), 1.99 (s, 3H), 1.84 1.73
(m, 2H), 1.69 1.65 (m, 7H), 1.59 (quin, J=7.3 Hz, 2H), 1.47 1.39 (m,
2H), 1.31 1.26 (m, 4H), 0.89 0.86 (m, 3H), 0.83 (s, 9H), À0.06 ppm (s,
6H); 13C NMR (125 MHz, [D6]acetone): d=170.4, 170.3, 160.7, 157.8,
144.6, 135.8, 127.9, 125.9, 116.6, 113.4, 107.7, 105.8, 70.4, 70.1, 68.4, 68.0,
40.4, 39.6, 37.4, 37.3, 36.5, 35.4, 32.1, 26.4, 26.2, 25.9, 25.0, 23.1, 21.2, 18.5,
14.2, À4.4, À4.5; HRMS (MALDI-FTMS) for C35H55NO8Si [M + Na+]
calcd 668.3589, found 668.3572.
Apicularen analogue 38: 57% yield; colorless oil: Rf =0.25 (silica gel,
hexanes:EtOAc, 5:95); [a]D =À21.8 (c=0.11, acetone); IR (film): n˜max
3307, 3248, 2919, 2848, 1701, 1648, 1607, 1590, 1542, 1460, 1290, 1219,
1114, 1078 cmÀ1 1H NMR (500 MHz, [D6]acetone): d=9.14 (d, J=10.3
=
;
Hz, 1H), 8.38 (s, 1H), 7.73 (d, J=15.4 Hz, 1H), 7.53 (d, J=4.7 Hz, 1H),
7.36 (d, J=3.7 Hz, 1H), 7.15 7.07 (m, 2H), 6.94 (dd, J=13.6, 10.7 Hz,
1H), 6.77 (d, J=8.1 Hz, 1H), 6.69 (d, J=7.7 Hz, 1H), 6.43 (d, J=15.4
Hz, 1H), 5.47 5.40 (m, 1H), 5.32 (dt, J=14.3, 7.3 Hz, 1H), 4.32 4.20 (m,
1H), 4.03 3.94 (m, 1H), 3.92 3.84 (m, 1H), 3.75 (d, J=4.0 Hz, 1H), 3.34
(dd, J=14.7, 10.3 Hz, 1H), 2.44 (d, J=14.7 Hz, 1H), 2.36 (t, J=6.8 Hz,
2H), 1.97 1.81 (m, 2H), 1.73 1.65 (m, 1H), 1.61 1.44 ppm (m, 3H); 13C
NMR (150 MHz, [D6]acetone): d=169.1, 162.7, 154.2, 140.9, 140.1, 134.1,
131.4, 130.4, 128.8, 128.4, 126.3, 125.3, 122.1, 120.6, 114.3, 108.3, 74.2,
73.5, 67.9, 64.8, 40.2, 39.8, 39.5, 38.7, 36.2 ppm; HRMS (MALDI-FTMS)
for C25H27NO6S [M + Na+] calcd 492.1451, found 492.1429.
Compound 40b: 47% yield; light yellow oil: Rf =0.19 (silica gel, hexanes:
EtOAc, 1:1); [a]D =À45.9 (c=0.17, acetone); IR (film): n˜max =3354, 2955,
2929, 2861, 1731, 1713, 1661, 1643, 1608, 1584, 1537, 1519, 1478, 1449,
1378, 1308, 1296, 1261, 1243, 1044, 961, 926, 814 cmÀ1 1H NMR (600
;
MHz, [D6]acetone): d=8.73 (bd, J=10.1 Hz, 1H), 7.50 (dd, J=7.9, 7.4
Hz, 1H), 7.04 (d, J=7.4 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.67 (dd, J=
14.3, 10.1 Hz, 1H), 5.08 (dt, J=14.3, 7.2 Hz, 1H), 5.04 4.99 (m, 1H),
4.27 3.97 (m, 2H), 3.53 (dd, J=12.7, 3.5 Hz, 1H), 3.49 3.42 (m, 1H),
3.13 3.10 (m, 2H), 2.16 (t, J=7.4 Hz, 2H), 2.05 2.01 (m, 3H), 1.99 (s,
3H), 1.80 1.71 (m, 2H), 1.69 1.67 (m, 7H), 1.58 (quin, J=7.4 Hz, 2H),
1.50 1.41 (m, 2H), 1.33 1.24 (m, 4H), 0.87 ppm (t, J=6.8 Hz, 3H); 13C
NMR (150 MHz, [D6]acetone): d=170.4, 170.3, 160.9, 158.0, 144.4, 135.9,
127.7, 125.6, 116.8, 113.3, 108.8, 106.0, 71.0, 70.8, 70.6, 67.8, 40.5, 39.0,
38.4, 37.3, 36.4, 35.4, 32.1, 26.1, 25.8, 25.4, 23.0, 21.2, 14.2 ppm; HRMS
Compound 38a: 41% yield; colorless oil: Rf =0.20 (silica gel, hexanes:
EtOAc, 7:3); [a]D =À113.2 (c=0.23, acetone); IR (film): n˜max =3270,
2954, 2919, 1860, 1725, 1707, 1660, 1613, 1584, 1537, 1454, 1366, 1237,
1084, 967, 831, 773 cmÀ1 1H NMR (500 MHz, [D6]acetone): d=9.11 (d,
;
J=10.3 Hz, 1H), 7.75 (d, J=15.4 Hz, 1H), 7.57 7.50 (m, 2H), 7.38 7.34
(m, 1H), 7.13 7.05 (m, 2H), 6.91 (dd, J=8.5, 1.1 Hz, 1H), 6.82 (bdd, J=
14.3, 10.7 Hz, 1H), 6.41 (d, J=15.4 Hz, 1H), 5.21 (dt, J=14.3, 7.0 Hz,
1H), 5.06 4.98 (m, 1H), 4.25 4.17 (m, 1H), 3.96 3.88 (m, 1H), 3.54 3.46
(m, 1H), 3.42 (dd, J=12.9, 3.7 Hz, 1H), 3.16 (dd, J=12.8, 8.4 Hz, 1H),
2.19 2.03 (m, 3H), 2.00 (s, 3H), 1.87 1.82 (m, 1H), 1.79 1.75 (m, 1H),
1.71 1.66 (m, 7H), 1.50 1.35 (m, 2H), 0.85 (s, 9H), À0.08 ppm (s, 6H);
13C NMR (125 MHz, [D6]acetone): d=170.3, 162.5, 160.6, 157.7, 144.5,
140.9, 135.7, 134.0, 131.3, 128.9, 128.4, 127.8, 125.8, 120.6, 116.5, 113.3,
109.2, 105.7, 70.3, 70.0, 68.3, 67.9, 40.4, 39.5, 37.3 (two peaks), 35.3, 26.3,
26.1, 24.9, 21.1, 18.5, À4.5, À4.6 ppm; HRMS (MALDI-FTMS) for
C36H49NO8SSi [M + Na+] calcd 706.2840, found 706.2831.
(MALDI-FTMS) for C29H41NO8 [M
+
Na+] calcd 554.2724, found
554.2732.
Apicularen analogue 41: 47% yield; white solid: Rf =0.14 (silica gel,
EtOAc:hexanes, 4:1); [a]D =À3.2 (c=0.19, acetone); IR (film): n˜max
3366, 2955, 2919, 2861, 1725, 1713, 1696, 1643, 1590, 1537, 1514, 1461,
1367, 1284, 1261, 1208, 1120, 1079, 1026, 803 cmÀ1 1H NMR (600 MHz,
=
;
[D6]acetone): d=9.08 (bd, J=10.1 Hz, 1H), 8.37 (bs, 1H), 7.58 7.54 (m,
1H), 7.09 (dd, J=8.3, 7.4 Hz, 1H), 6.90 6.83 (m, 2H), 6.76 (d, J=8.3 Hz,
1H), 6.68 (d, J=7.4 Hz, 1H), 5.82 5.78 (m, 1H), 5.73 (d, J=11.4 Hz,
1H), 5.43 5.40 (m, 1H), 5.24 (dt, J=14.5, 7.4 Hz, 1H), 4.27 4.23 (m,
1H), 4.01 3.95 (m, 1H), 3.88 3.84 (m, 1H), 3.76 (bd, J=4.0 Hz, 1H),
3.33 (dd, J=14.7, 9.8 Hz, 1H), 2.42 (d, J=14.9 Hz, 1H), 2.34 2.22 (m,
4H), 1.93 1.79 (m, 2H), 1.69 1.65 (m, 1H), 1.58 1.39 (m, 5H), 0.90 ppm
(t, J=7.4 Hz, 3H); 13C NMR (150 MHz, [D6]acetone): d=169.3, 163.6,
154.3, 140.2, 139.8, 136.9, 130.2, 126.3, 126.2, 125.5, 122.3, 120.8, 114.4,
108.0, 74.2, 73.7, 68.0, 64.9, 40.3, 39.9 (two peaks), 38.9, 36.4, 29.7, 23.3,
Apicularen analogue 39: 20% yield; colorless oil: Rf =0.70 (silica gel,
hexane:EtOAc, 5:95); [a]D =À23.6 (c=0.11, acetone); IR (film): n˜max
3318, 3107, 2954, 2895, 1707, 1642, 1607, 1584, 1460, 1413, 1290, 1243,
1119, 1072, 967 cmÀ1 1H NMR (600 MHz, [D6]acetone): d=9.16 (d, J=
10.1 Hz, 1H), 8.46 (s, 1H), 7.73 (d, J=15.3 Hz, 1H), 7.53 (d, J=4.8 Hz,
=
;
6189
Chem. Eur. J. 2003, 9, 6177 6191
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

K. C. Nicolaou et al.
FULL PAPER
13.9 ppm; HRMS (MALDI-FTMS) for C26H33NO6 [M
478.2200, found 478.2200.
+
Na+] calcd
34.2), 127.7, 124.8, 121.7, 116.8, 113.3, 112.4, 106.0, 70.9, 70.6, 70.5, 67.8,
40.6, 39.1, 38.2, 37.3, 35.4, 26.0, 25.4, 21.2 ppm; HRMS (MALDI-FTMS)
for C27H32F3NO8 [M + Na+] calcd 578.1972, found 578.1957.
Compound 41a: 50% yield; colorless oil: Rf =0.26 (silica gel, hexanes:
EtOAc, 2:1); [a]D =À72.3 (c=0.39, acetone); IR (film): n˜max =3457, 3316,
2952, 2917, 2858, 1736, 1653, 1606, 1583, 1518, 1477, 1454, 1371, 1295,
Compound 43: 65% yield; yellow oil: Rf =0.30 (silica gel, hexanes:
EtOAc, 3:7), [a]D =À64.6 (c=0.15, acetone); IR (film): n˜max =3471, 3283,
2931, 2860, 1731, 1707, 1648, 1607, 1584, 1531, 1478, 1443, 1290, 1237,
1242, 1078, 1054, 954, 931, 837, 778 cmÀ1 1H NMR (500 MHz, [D6]ace-
;
1043, 961 cmÀ1 1H NMR (500 MHz, [D6]acetone): d=9.11 (d, J=10.3
;
tone): d=9.05 (bd, J=10.3 Hz, 1H), 7.60 7.52 (m, 2H), 7.08 (d, J=7.7
Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.85 (dd, J=11.6, 11.4 Hz, 1H), 6.77
(dd, J=14.3, 10.3 Hz, 1H), 5.82 5.77 (m, 1H), 5.73 (d, J=11.4 Hz, 1H),
5.15 (dt, J=14.3, 7.3 Hz, 1H), 5.04 4.98 (m, 1H), 4.21 4.17 (m, 1H),
3.93 3.88 (m, 1H), 3.51 3.46 (m, 1H), 3.43 3.40 (m, 1H), 3.15 (dd, J=
12.8, 8.4 Hz, 1H), 2.28 2.21 (m, 2H), 2.16 2.03 (m, 3H), 1.99 (s, 3H),
1.84 1.74 (m, 2H), 1.69 1.65 (m, 7H), 1.49 1.39 (m, 4H), 0.91 (t, J=7.3
Hz, 3H), 0.83 (s, 9H), À0.06 ppm (s, 6H); 13C NMR (125 MHz, [D6]ace-
tone): d=170.4, 163.5, 160.7, 157.8, 144.6, 139.7, 136.8, 135.8, 127.9, 126.2,
125.8, 120.9, 116.6, 113.4, 108.8, 105.8, 70.4, 70.0, 68.5, 68.0, 40.5, 39.5
(two peaks), 37.5, 35.4, 29.7, 26.3, 26.2, 25.0, 23.3, 21.2, 18.5, 13.9, À4.4,
À4.5 ppm; HRMS (MALDI-FTMS) for C37H55NO8Si [M + Na+] calcd
692.3589, found 692.3569.
Hz, 1H), 7.74 (d, J=15.4 Hz, 1H), 7.55 7.48 (m, 2H), 7.35 (d, J=3.3 Hz,
1H), 7.10 (dd, J=4.8, 3.3 Hz, 1H), 7.05 (dd, J=7.7, 1.1 Hz, 1H), 6.90
(dd, J=8.5, 1.1 Hz, 1H), 6.81 (bdd, J=14.3, 10.7 Hz, 1H), 6.42 (d, J=
15.4 Hz, 1H), 5.24 (dt, J=14.3, 7.4 Hz, 1H), 5.07 4.99 (m, 1H), 4.32 4.24
(m, 1H), 4.04 3.96 (m, 1H), 3.54 (dd, J=13.2, 3.7 Hz, 1H), 3.52 3.47 (m,
1H), 3.22 (d, J=3.3 Hz, 1H), 3.14 (dd, J=12.9, 8.8 Hz, 1H), 2.12 2.03
(m, 3H), 2.00 (s, 3H), 1.85 1.75 (m, 2H), 1.71 1.68 (m, 7H),1.54 1.42
ppm (m, 2H); 13C NMR (125 MHz, [D6]acetone): d=170.3, 162.6, 160.8,
157.9, 144.3, 140.9, 135.8, 134.0, 131.3, 128.9, 128.4, 127.6, 125.6, 120.6,
116.7, 113.2, 109.6, 105.9, 70.8, 70.6, 70.4, 67.7, 40.4, 39.0, 38.3, 37.2, 35.3,
26.9, 25.3, 21.1 ppm; HRMS (MALDI-FTMS) for C30H35NO8S [M
+
Na+] calcd 592.1975, found 592.1969.
Compound 44: 61% yield; yellow oil: Rf =0.40 (silica gel, hexanes:
EtOAc, 2:3); [a]D =À66.2 (c=0.13, acetone); IR (film): n˜max =3416, 1730,
Compound 41b: 39% yield; yellow oil: Rf =0.39 (silica gel, EtOAc:hex-
anes, 2:1); [a]D =À58.0 (c=0.15, acetone); IR (film): n˜max =3413, 2955,
2919, 2861, 1731, 1643, 1608, 1519, 1478, 1449, 1373, 1296, 1243, 1208,
1651, 1604, 1580, 1533, 1479, 1450, 1228, 1049 cmÀ1 1H NMR (500 MHz,
;
1044, 961, 926, 814, 779 cmÀ1 1H NMR (500 MHz, [D6]acetone): d=8.98
;
[D6]acetone): d=9.10 (d, J=10.5 Hz, 1H), 7.63 7.56 (m, 3H), 7.51 (dd,
J=8.1, 7.7 Hz, 1H), 7.44 7.36 (m, 3H), 7.05 (dd, J=7.7, 1.1 Hz, 1H),
6.91 (dd, J=8.5, 1.1 Hz, 1H), 6.83 (dd, J=14.3, 10.3 Hz, 1H), 6.67 (d, J=
15.4 Hz, 1H), 5.24 (dt, J=14.3, 7.3 Hz, 1H), 5.10 4.97 (m, 1H), 4.27
(sext, J=5.2 Hz, 1H), 4.04 3.96 (m, 1H), 3.54 (dd, J=12.8, 3.7 Hz, 1H),
3.52 3.49 (m, 1H), 3.21 (d, J=3.3 Hz, 1H), 3.13 (dd, J=12.8, 8.8 Hz,
1H), 2.11 2.03 (m, 3H), 2.01 (s, 3H), 1.84 1.74 (m, 2H), 1.75 1.73 (m,
7H), 1.55 1.49 (m, 1H), 1.48 1.40 ppm (m, 1H); 13C NMR (125 MHz,
[D6]acetone): d=170.4, 162.9, 160.9, 158.0, 144.4, 141.4, 136.1, 135.9,
130.4, 129.7, 128.5, 127.7, 125.7, 122.0, 116.8, 113.3, 109.7, 106.1, 70.9,
70.7, 70.6, 67.9, 40.5, 39.1, 38.5, 37.3, 35.4, 26.1, 25.4, 21.2 ppm; HRMS
(bd, J=10.3 Hz, 1H), 7.56 (dd, J=11.6, 11.5 Hz, 1H), 7.50 (dd, J=8.3,
7.5 Hz, 1H), 7.04 (dd, J=7.5, 1.0 Hz, 1H), 6.90 (dd, J=8.3, 1.0 Hz, 1H),
6.84 (ddd, J=11.7, 11.6, 1.1 Hz, 1H), 6.75 (dd, J=14.5, 10.3 Hz, 1H),
5.81 5.76 (m, 1H), 5.72 (d, J=11.7, 1H), 5.16 (dt, J=14.5, 7.4 Hz, 1H),
5.05 4.99 (m, 1H), 4.27 4.23 (m, 1H), 4.02 3.96 (m, 1H), 3.54 (dd, J=
13.0, 3.5 Hz, 1H), 3.51 3.46 (m, 1H), 3.16 (d, J=3.7 Hz, 1H), 3.12 (dd,
J=13.0, 8.6 Hz, 1H), 2.26 2.21 (m, 2H), 2.17 2.03 (m, 3H), 1.99 (s, 3H),
1.81 1.71 (m, 2H), 1.70 1.66 (m, 7H), 1.52 1.38 (m, 4H), 0.90 ppm (t,
J=7.4 Hz, 3H); 13C NMR (125 MHz, [D6]acetone): d=170.4, 163.5,
160.9, 158.0, 144.4, 139.7, 136.8, 135.9, 127.7, 126.2, 125.5, 120.9, 116.8,
113.3, 109.2, 106.0, 70.9, 70.8, 70.6, 67.8, 40.5, 39.0, 38.5, 37.3, 35.4, 29.7,
26.1, 25.4, 23.3, 21.2, 13.9 ppm; HRMS (MALDI-FTMS) for C31H41NO8
[M + Na+] calcd 578.2724, found 578.2708.
Apicularen analogue 42: 24% yield; colorless oil: 1H NMR (500 MHz,
[D6]acetone): d=9.52 (bd, J=8.1 Hz, 1H), 8.42 (bs, 1H), 7.09 (J=8.5,
7.7 Hz, 1H), 6.90 6.79 (m, 3H), 6.76 (d, J=8.5 Hz, 1H), 6.69 (d, J=7.7
Hz, 1H), 5.45 5.39 (m, 2H), 4.28 4.19 (m, 1H), 4.01 3.84 (m, 2H), 3.76
(d, J=4.4 Hz, 1H), 3.32 (dd, J=14.0, 9.6 Hz, 1H), 2.44 2.33 (m, 3H),
1.93 1.80 (m, 2H), 1.69 1.46 ppm (m, 4H); HRMS (MALDI-FTMS) for
C22H24F3NO6 [M + Na+] calcd 478.1448, found 478.1450.
(MALDI-FTMS) for C32H37NO8 [M
+
Na+] calcd 586.2411, found
586.2399.
Methyl ester 45a: To a solution of cis-2-hexene-1-ol (2 g, 20.0 mmol) in
dichloromethane (40 mL) was added at 08C, 4ä MS (10 g), and NMO
(3.5 g, 30.0 mmol). TPAP (351 mg, 1.00 mmol) was then added in one
portion. The reaction mixture was stirred at 08C for an additional 1 h to
complete the formation of aldehyde. A separate flask was charged with
bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl) phosphonate (4.22 mL,
20.0 mmol), THF (250 mL), [18]crown-6 (26.4 g, 100.0 mmol), and cooled
to À788C. After the mixture was stirred at À788C for 10 min, KHMDS
(0.5m toluene solution, 40 mL, 20 mmol) was added dropwise to this
second reaction mixture to form the phosphonate anion (0.5 h). The
crude aldehyde solution was then added to the phosphonate solution and
stirred for 20 min before quenching with saturated (aq) NH4Cl (100 mL).
The reaction mixture was allowed to warm to room temperature then ex-
tracted with ether (3î40 mL). The combined organic layer was then
washed with brine (50 mL), dried with MgSO4, filtered, and concentrated
in vacuo. The product was purified by flash column chromatography
(silica) to yield methyl ester 45a as a clear liquid (2.28 g, 74%). 45a:
Rf =0.58 (silica gel, hexanes:EtOAc, 9:1); IR (film): n˜max =2955, 2872,
Compound 42a: 36% yield; colorless oil: Rf =0.28 (silica gel, hexanes:
EtOAc, 2:1); [a]D =À55.0 (c=0.22, acetone); IR (film): n˜max =3281, 2929,
2858, 1736, 1695, 1653, 1577, 1542, 1477, 1448, 1342, 1307, 1248, 1136,
1
1078, 1054, 966, 837, 778 cmÀ1; H NMR (600 MHz, [D6]acetone): d=9.45
(bd, J=9.6 Hz, 1H), 7.53 (dd, J=8.3, 7.4 Hz, 1H), 7.08 (d, J=7.4 Hz,
1H), 6.90 (d, J=8.3 Hz, 1H), 6.85 6.74 (m, 3H), 5.32 (dt, J=14.0, 7.3
Hz, 1H), 5.00 (m, 1H), 4.20 (m, 1H), 3.92 (m, 1H), 3.52 (m, 1H), 3.40
(dd, J=12.8, 3.7 Hz, 1H), 3.17, (dd, J=12.8, 8.3 Hz, 1H), 2.19 2.10 (m,
2H), 2.05 2.02 (m, 1H), 1.99 (s, 3H), 1.88 1.83 (m, 1H), 1.76 1.74 (m,
1H), 1.69 1.65 (m, 7H), 1.48 1.41 (m, 2H), 0.84 (s, 9H), À0.05 (s, 3H),
À0.06 ppm (s, 3H); 13C NMR (150 MHz, [D6]acetone): d=170.3, 160.8,
159.7, 157.8, 144.6, 135.8, 132.8 (q, J=6.1), 127.9, 127.8 (q, J=34.6),
125.1, 121.7, 116.6, 113.4, 112.1, 105.9, 70.4, 69.9, 68.4, 68.0, 40.5, 39.5,
37.4, 37.2, 35.5, 26.4, 26.2, 25.0, 21.2, 18.5, À4.4, À4.5 ppm; HRMS
(MALDI-FTMS) for C33H46F3NO8Si [M + Na+] calcd 692.2837, found
692.2812.
1719, 1631, 1590, 1443, 1367, 1226, 1173, 997, 826, 785 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=7.25 (dd, J=11.4, 11.4 Hz, 1H), 6.92 (ddd, J=
11.7, 11.4, 1.1 Hz, 1H), 5.93 5.86 (m, 1H), 5.65 (d, J=11.7 Hz, 1H), 3.70
(s, 3H), 2.25 2.19 (m, 2H), 1.43 (sext, J=7.3 Hz, 2H), 0.90 ppm (t, J=
7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=167.0, 141.6, 139.2, 124.5,
116.8, 51.1, 29.5, 22.5, 13.7 ppm; MS (GC/MS) for C9H14O2 [H+] calcd
154, found 154.
Compound 42b: 44% yield; colorless oil: Rf =0.36 (silica gel, EtOAc:
hexanes, 2:1); [a]D =À70.0 (c=0.14, acetone); IR (film): n˜max =3401,
2931, 1731, 1713, 1696, 1661, 1649, 1608, 1584, 1537, 1478, 1455, 1378,
Carboxylic acid 45b: To a solution of ester 45a (816.7 mg, 5.296 mmol) in
MeOH (50 mL) was added in one portion Ba(OH)2¥H2O (11.0 g, 58.1
mmol) at room temperature. The reaction mixture was stirred for 20 h,
and then quenched with a solution of 1n (aq) HCl (100 mL). More of
the (aq) HCl solution was added until the solid formed had completely
dissolved giving a clear solution. The reaction mixture was extracted with
ether (3î50 mL) and the combined organic layer was washed with brine
(50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The
product was purified by flash column chromatography to yield a colorless
oil (595 mg, 80%). 45b: Rf =0.80 (silica gel, hexanes:EtOAc, 1:2); IR
(film): n˜max =2966, 2578, 1696, 1625, 1590, 1455, 1290, 1243, 1214, 938,
1349, 1308, 1267, 1138, 1055, 967, 808, 785 cmÀ1 1H NMR (600 MHz,
;
[D6]acetone): d=9.41 (bd, J=9.6 Hz, 1H), 7.50 (dd, J=8.3, 7.4 Hz, 1H),
7.04 (d, J=7.4 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.84 6.73 (m, 3H), 5.34
(dt, J=14.5, 7.4 Hz, 1H), 5.01 (m, 1H), 4.28 4.24 (m, 1H), 4.02 3.97 (m,
1H), 3.54 3.49 (m, 2H), 3.22 (d, J=3.5 Hz, 1H), 3.13 (dd, J=12.9, 8.6
Hz, 1H), 2.13 2.03 (m, 3H), 1.99 (s, 3H), 1.80 1.73 (m, 2H), 1.69 1.67
(m, 7H), 1.52 1.41 ppm (m, 2H); 13C NMR (150 MHz, [D6]acetone): d=
170.4, 160.9, 159.7, 158.0, 144.4, 135.9, 132.8 (q, J=6.1), 127.8 (q, J=
6190
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Chem. Eur. J. 2003, 9, 6177 6191

Total Synthesis of (À)Apicularen A and Analogues Thereof
6177 6191
879, 832, 785, 673, 820 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.25 (dd,
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J=11.6, 11.4 Hz, 1H), 7.03 (dd, J=11.7, 11.6 Hz, 1H), 5.95 (m, 1H), 5.67
(d, J=11.4 Hz, 1H), 2.27 2.21 (m, 2H), 1.44 (sext, J=7.3 Hz, 2H), 0.91
(t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d=171.9, 142.7, 141.3,
124.6, 116.4, 29.5, 22.5, 13.7 ppm; MS (GC/MS) for C8H12O2 [H+] calcd
140, found 140.
Amide 45c: To a solution of carboxylic acid 45b (333.1 mg, 2.376 mmol)
in THF (40 mL) at 08C was added triethylamine (0.36 mL, 2.583 mmol).
Ethyl chloroformate (0.25 mL, 2.615 mmol) was added and the reaction
mixture was stirred at 08C for 30 min. The reaction mixture was then al-
lowed to warm to room temperature and liquid ammonia (ammonia gas
condensed using dry ice and acetone) was added and stirred for an addi-
tional 20 min. The reaction mixture was then stirred and allowed to
warm to ambient temperature then concentrated in vacuo. The product
was purified by column chromatography to yield a white solid (221.2 mg,
67%). 45c: Rf =0.34 (silica gel, hexanes:EtOAc, 1:2); IR (film): n˜max
3389, 3190, 2955, 2872, 1649, 1608, 1455, 1378, 1320, 1267, 1226, 1002,
961, 908, 861, 826, 732 cmÀ1 1H NMR (500 MHz, CDCl3): d=7.25 7.20
=
;
(m, 1H), 6.79 (ddd, J=11.6, 11.4, 1.1 Hz, 1H), 5.85 5.80 (m, 1H), 5.72
(bs, 1H), 5.63 (d, J=11.4 Hz, 1H), 5.52 (bs, 1H), 2.22 2.18 (m, 2H), 1.42
(sext, J=7.3 Hz, 2H), 0.90 ppm (t, J=7.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=168.6, 140.3, 136.4, 124.4, 119.2, 29.4, 22.5, 13.7 ppm; HRMS
(MALDI-FTMS) for C8H13NO [M
140.1070.
+
H+] calcd 140.1070, found
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Acknowledgement
We thank Dr. D. H. Huang, Dr. G. Siuzdak, and Dr. R. Chadha for
NMR spectroscopic, mass spectrometric, and X-ray crystallographic assis-
tance, respectively. This work was financially supported by The Skaggs
Institute for Chemical Biology, American BioSciences, and the National
Institutes of Health (USA).
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Received: June 13, 2003 [F5230]
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