Total synthesis of the originally proposed and revised structures of palmerolide A

Article abstract of DOI:10.1002/anie.200702243

(Chemical Equation Presented) In the palm of your hand: Total syntheses of the originally proposed and revised structures of the marine antitumor agent palmerolide A (see picture, originally proposed structure had opposite configurations at the positions indicated in red) were accomplished through a modular strategy that features a ring-closing metathesis to stereoselectively form the C8=C9 bond and concurrently form the macrocycle.

Full text of DOI:10.1002/anie.200702243

Communications
DOI: 10.1002/anie.200702243
Natural Products
Total Synthesis of the Originally Proposed and Revised Structures of
Palmerolide A**
K. C. Nicolaou,* Ramakrishna Guduru, Ya-Ping Sun, Biswadip Banerji, and David Y.-K. Chen*
Palmerolide A (Figure 1) is a recently reported polyketide
secondary metabolite with an impressive molecular architec-
ture and biological profile.[1] This marine natural product was
isolated from the circumpolar tunicate Synoicum adareanum,
which is commonly found in the shallow waters around
Anvers Island on the Antarctic Peninsula, and exhibits
unusual selectivity against a number of cell lines in the
60 cell panel of the National Cancer Institute (NCI). Specif-
ically, palmerolide A was found to exhibit potent activity
against the melanoma cell line UACC-62 (LC50 = 18 nm), only
modest cytotoxicity against the colon cancer cell line HCC-
2998 (LC50 = 6.5 mm) and the renal cancer cell line RXF 393
(LC50 = 6.5 mm), and virtually no effect (LC50 > 10 mm) against
other cell lines, thus demonstrating a selectivity index of 103
among the cell lines tested. Interestingly, palmerolide A
displayed an activity profile in the NCI 60 cell line panel
that correlated with that of vacuolar ATPase inhibitors.[2]
Palmerolide A was shown to inhibit V-ATPase with an
IC50 value of 2 nm and to be active in the NCIꢀs hollow fiber
assay. The intriguing biological properties of palmerolide A,
along with its relative scarcity, prompted us to undertake its
chemical synthesis.
Figure 1. Originally proposed (1a) and revised (1b) structures of
palmerolide A.
Inspection of the proposed structure of palmerolide A
(1a) reveals a 20-membered macrolide, an enamide-contain-
ing side chain, 7 olefinic bonds (3 of which are trisubstituted),
and a carbamate moiety. Based on detailed NMR spectro-
scopic analysis, the relative and absolute configuration of this
natural product was put forward as that shown in structure 1a
(Figure 1), although the structural assignments at C19 and
C20 were not error proof. Specifically, while the NOE
interactions and coupling constants exhibited by palmero-
lide A may exclude the two anti C19/C20 diastereomers, both
syn structures could be possible. Furthermore, while Mosher
ester studies suggested the absolute stereochemistry at the
C7, C10, and C11 positions, the low optical rotation of the
natural product[1] did not bode well for its diagnostic value as
a means to confirm its absolute stereochemistry. Most
recently, these suspicions were confirmed by an elegant
study by De Brabander and co-workers (which culminated in
the total synthesis of the unnatural enantiomer of palmero-
lide A),[3] with the structural revision of not only the relative
stereochemistry between the C7–C11 and C19–C20 domains,
but also of the absolute configuration of the molecule. Herein,
we report our own efforts in this area that culminated in total
syntheses of, among several isomers, the originally proposed
structure 1a and the revised structure 1b (Figure 1) of
palmerolide A by a modular and flexible strategy that
allows access to variants of the palmerolide A molecule as
depicted retrosynthetically in Scheme 1.
[*] Prof. Dr. K. C. Nicolaou,[+] Dr. R. Guduru, Dr. Y.-P. Sun, Dr. B. Banerji,
Dr. D. Y.-K. Chen
Chemical Synthesis Laboratory@Biopolis
Institute of Chemical and Engineering Sciences (ICES)
Agency for Science, Technology, and Research (A*STAR)
11 Biopolis Way, The Helios Block, #03–08
Singapore 138667 (Singapore)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
david_chen@ices.a-star.edu.sg
[+] Also at:
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank D. Tan (ICES) for assistance with high-resolution mass
spectrometry (HRMS). Financial support for this work was provided
by A*STAR, Singapore.
It was envisioned that a Stille coupling reaction, a
Yamaguchi esterification, a ring-closing metathesis, and an
enamide coupling reaction would serve to assemble and
Supporting information for this article (including selected data for
compounds 23, 25, 1a, 25b, and 1b) is available on the WWW
under http://www.angewandte.org or fromthe author.
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Chemie
Scheme 1. Retrosynthetic analysis of the originally proposed palmero-
lide A structure (1a). MOM=methoxymethyl, TBS=tert-butyldimethyl-
silyl.
elaborate the three key building blocks 2–4 shown in
Scheme 1 into the final structure 1a. The adopted routes to
these intermediates were designed with maximum flexibility
to deliver all possible stereoisomers and other variants of the
palmerolide molecule for structural and biological studies.
Scheme 2 summarizes the construction of the vinyl iodide
fragment 2 that began with imide 5 (prepared in 92% yield by
reaction of (S)-(ꢀ)-4-benzyl-2-oxazolidinone with propionic
acid chloride in the presence of nBuLi). Thus, treatment of 5
with nBu2BOTf/Et3N[4] followed by reaction of the resulting
boron enolate with vinyl iodide aldehyde 7 (prepared in
2 steps and 81% overall yield from 3-butyn-1-ol by standard
methods),[5] and silylation (TBSOTf/iPr2NEt) of the so-
obtained hydroxy intermediate furnished the TBS ether 6 in
40% overall yield and greater than 95% de. Reductive
removal of the oxazolidinone chiral auxiliary (NaBH4, 66%
yield), followed by oxidation (DMP) and Wittig homologa-
tion (PPh3 = C(Me)CO2Et, 56% yield for the 2 steps) led to
the ethyl ester 8, whose conversion into the targeted iodide 2
was readily accomplished in 3 steps: 1) DIBAlH, 80% yield,
2) TBAF, 85% yield, and 3) TBSCl/Et3N/DMAP, 92% yield.
Alternatively, starting from dienolate 5a (prepared by
coupling (R)-(+)-4-benzyl-2-oxazolidinone with (E)-2-
methyl-2-pentenoic acid in the presence of PivCl/Et3N/LiCl
in 91% yield, followed by dienolate formation under the
influence of sodium hexamethyldisilazane, and trapping with
TBSCl in 94% yield), vinylogous Mukaiyama aldol reaction
with the vinyl iodide aldehyde 7 under the conditions
described by Kobayashi and co-workers[6] (TiCl4, 83% yield,
> 95% de) furnished the expected hydroxy compound.[7] The
chiral auxiliary was then reductively removed (NaBH4, 84%
yield) to afford, after selective silylation (TBSCl/Et3N/
DMAP, 92% yield), the intermediate 19-epi-2. The latter
compound was then converted into 2 by oxidation/reduction
(DMP, 90% yield; LiAlH(OtBu)3/LiI, 92% yield ca. 3:1 syn/
anti mixture) followed by desilylation/chromatographic sep-
aration (TBAF, 85% yield, silica gel) and selective silylation
Scheme 2. Construction of C16–C23 vinyl iodide fragments 2 and 19-
epi-2. Reagents and conditions: a) 7 (2.5 equiv), nBu2BOTf (1.0m in
CH2Cl2, 1.2 equiv), Et3N (1.0 equiv), CH2Cl2, ꢀ788C, 12 h, 46%
(>95% de); b) TBSOTf (1.2 equiv), iPr2NEt (1.5 equiv), CH2Cl2, 08C,
30 min, 86%; c) NaBH4 (5.0 equiv), THF/H2O (5:1), 0!238C, 3 h,
66%; d) DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 238C, 30 min;
=
e) PPh3 C(Me)CO2Et (2.5 equiv), CH2Cl2, 238C, 12 h, 56% for the
2 steps; f) DIBAlH (1.0m in toluene, 2.5 equiv), CH2Cl2, ꢀ788C,
30 min, 80%; g) TBAF (1.0m in THF, 1.5 equiv), THF, reflux, 2 h, 85%;
h) TBSCl (1.2 equiv), Et3N (1.5 equiv), DMAP (0.2 equiv), CH2Cl2, 0!
238C, 2 h, 92%; i) 7 (2.0 equiv), TiCl4 (1.0 equiv), CH2Cl2, ꢀ788C, 19 h,
83% (>95% de); j) NaBH4 (4.0 equiv), THF/H2O (20:1), 238C, 12h,
84%; k) TBSCl (1.2 equiv), Et3N (1.5 equiv), DMAP (0.2 equiv), CH2Cl2,
0!238C, 2 h, 92%; l) DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2,
238C, 20 min, 90%; m) LiAlH(OtBu)3 (1.0m in THF, 3.0 equiv), LiI
(5.0 equiv), Et2O, ꢀ788C, 1 h, 92% (ca. 3:1 mixture of syn/anti
diastereomers); n) TBAF (1.0m in THF, 1.2 equiv), THF, 238C, 1 h,
85%; o) TBSCl (1.2 equiv), Et3N (1.5 equiv), DMAP (0.2 equiv),
CH2Cl2, 0!238C, 2 h, 92%. Bn=benzyl, DIBAlH=diisobutylalumi-
numhydride, DMAP =4-dimethylaminopyridine, DMP=Dess–Martin
periodinane, TBAF=tetra-n-butylammonium fluoride, Tf=trifluoro-
methanesulfonyl.
(TBSCl/Et3N/DMAP, 92% yield). The isomeric vinyl iodides
ent-2 and 20-epi-2 were similarly prepared from ent-5 and
ent-5a.
Scheme 3 depicts the construction of the stannane frag-
ment 3. Reaction of aldehyde 9 (prepared in 2 steps from 4-
pentyn-1-ol by standard methods)[8] with [(Z)-g-(methoxy-
methoxy)allyl]-(ꢀ)-diisopinocampheylborane (10, freshly
prepared from methoxymethyl allyl ether, sBuLi, (ꢀ)-
Ipc2BOMe and BF3·Et2O)[9] in THF at ꢀ788C afforded,
upon desilylation (K2CO3/MeOH), the hydroxy acetylene 11
in good overall yield (74% for the 2 steps) and excellent
stereoselectivity (>95% de (NMR) and > 90% ee (Mosher
ester)). Finally, installation of the carbamate group
(Cl3CC(O)NCO/K2CO3/MeOH, quant.),[10] followed by
manipulation of the acetylenic moiety 1) AgNO3/NBS;
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balt(II) catalyst (5 mol%), AcOH (0.01 equiv) and H2O
(0.5 equiv) in CH2Cl2, led smoothly to enantiomerically
enriched (> 99% ee, Mosher ester analysis) epoxide 14 in
47% yield (maximum 50%).[12b] Epoxide opening with the
sulfur ylide derived from Me3S+Iꢀ and nBuLi[13] led to allylic
alcohol 15 (90% yield), whose conversion into carboxylic acid
4 involved MOM protection (16, 85% yield), desilylation (17,
95% yield), oxidation (DMP, 95% yield), Wittig reaction with
=
Ph3P CHCO2Me (18, 90% yield), and saponification (aq
KOH, 85% yield). Employing the same starting material 13,
the identical sequence, and the corresponding (S,S)-Jacobsen
CoII catalyst allowed the construction of ent-4 via ent-14.
With all three key building blocks 2–4 in hand, we then
turned our attention to their assembly and elaboration to our
original target 1a. In considering the sequence of reactions to
construct the macrocycle, we opted for the one shown in
Scheme 5 in which the ring-closing metathesis[14] was reserved
as the last step, while the Stille coupling[15] reaction was
chosen to begin the process, thus leaving the Yamaguchi
esterification[16] as the middle reaction. Thus, reaction of the
vinyl iodide 2 with stannane 3 in the presence of catalytic
Scheme 3. Synthesis of C9–C15 vinyl stannane fragment 3. Reagents
and conditions: a) 10 (1.0 equiv), THF, ꢀ78!238C, 12 h; b) K2CO3
(5.0 equiv), MeOH, 238C, 5 h, 74% for the 2 steps from 10; c) tri-
chloroacetyl isocyanate (3.0 equiv), CH2Cl2, 238C, 1 h; then K2CO3
(3.0 equiv), MeOH, 238C, 1 h, quant.; d) NBS (1.1 equiv), AgNO3
(0.05 equiv), acetone, 238C, 30 min, 81%; e) [Pd(dba)2] (0.2 equiv),
PPh3 (0.8 equiv), nBu3SnH (2.2 equiv), THF, 238C, 30 min, 77%
(>95:5 E/Z stereoselectivity). Ipc=isopinocampheyl; NBS=N-bromo-
succinimide; dba=dibenzylideneacetone.
2) cat. [Pd(dba)2]/nBu3SnH, 62% overall yield)[11] gave the
desired vinyl stannane 3. A similar sequence from 9 employ-
ing (+)-Ipc2BOMe led sequentially to ent-11 and ent-3.
The third required fragment 4 was prepared through a
Jacobsen resolution[12] as outlined in Scheme 4. Thus,
mCPBA-mediated epoxidation of the TBS-protected 5-
hexene-1-ol (13), followed by exposure to (R,R)-N,N’-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamineco-
Scheme 5. Coupling of fragments 2, 3, and 4, and completion of the
total synthesis of the originally proposed structure 1a. Reagents and
conditions: a) [Pd(dba)2] (0.25 equiv), AsPh3 (3.0 equiv), LiCl
(3.0 equiv), NMP, 238C, 12 h, 67%; b) 2,4,6-trichlorobenzoyl chloride
(1.1 equiv), Et3N (1.5 equiv), 4 (1.1 equiv), DMAP (1.1 equiv), toluene,
238C, 12 h, 61%; c) TBAF (1.0m in THF, 1.5 equiv), THF, 238C, 2 h;
d) DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 238C, 30 min, 79%
for the 2 steps; e) CrCl2 (10.0 equiv), CHI3 (6.0 equiv), THF/dioxane
(1:6), 238C, 2 h, 80% (>95:5 E/Z); f) BF3·Et2O (6.0 equiv), Me2S,
238C, 30 min, 46% (+10% of mono-MOM intermediates; g) Grubb-
s II cat. (0.2 equiv), CH2Cl2, 238C, 1 h, 76%; h) 26 (2.0 equiv), CuI
(1.0 equiv), Cs2CO3 (1.0 equiv), N,N’-dimethylethylenediamine
(2.0 equiv), DMF, 238C, 7 h, 44% based on 36% recovered starting
material (+10% of decarbamated 1a). NMP=N-methylpyrrolidone;
DMF=N,N’-dimethylformamide.
Scheme 4. Construction of C1–C8 carboxylic acid fragment 4. Reagents
and conditions: a) mCPBA (1.3 equiv), CH2Cl2, 0!238C, 3 h, 90%;
b) (R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine-
cobalt(II) (5 mol%), AcOH (0.01 equiv), H2O (0.5 equiv), CH2Cl2,
0!238C, 24 h, 47% (>99% ee); c) Me3S+Iꢀ (4.0 equiv), nBuLi (1.6m
in hexanes, 5.8 equiv), THF, ꢀ30!238C, 5 h, 90%; d) MOMCl
(4.0 equiv), iPr2NEt (2.0 equiv), CH2Cl2, 0!238C, 6 h, 85%; e) TBAF
(1.0m in THF, 1.2 equiv), THF, 238C, 2 h, 95%; f) DMP (1.5 equiv),
=
NaHCO3 (5.0 equiv), CH2Cl2, 238C, 2 h, 95%; g) Ph3P CHCO2Me
(1.2 equiv), CH2Cl2, 238C, 16 h, 90%; h) KOH (5.0 equiv), dioxane/
H2O (4:1), 238C, 24 h, 85%. mCPBA=meta-chloroperoxybenzoic acid.
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[Pd(dba)2], AsPh3, and LiCl provided tetraene 19 in 67%
yield. Incorporation of carboxylic acid 4 into the growing
molecule was then facilitated by 2,4,6-trichlorobenzoyl chlo-
ride in the presence of Et3N and DMAP, to furnish ester 20
(61% yield). Conversion of 20 into vinyl iodide 23 was
achieved in three steps: 1) TBAF-induced desilylation to 21,
unambiguously validated its absolute configuration and, thus,
of the natural product.[3] The CD spectra of both synthetic
palmerolide A enantiomers 1b and ent-1b shown in Figure 2,
corresponded with those published for the natural product
and its enantiomer.[3]
2) oxidation with DMP to 22 (79% for the two steps), and
[17]
3) olefination with CrCl2/CHI3
to give 23 in 80% yield.
Removal of the two MOM groups from 23 (BF3·Et2O/
Me2S)[18] led to the desired precursor 24 (46% yield with
10% of recovered mono-MOM intermediates, which were
recycled), thus setting the stage for the much-anticipated ring-
closing metathesis. Gratifyingly, exposure of bisallylic com-
pound 24 to Grubbs II catalyst in CH2Cl2 solution at ambient
temperature led to the smooth and exclusive formation of the
macrocycle 25 (76% yield) with trans geometry at the newly
formed double bond as confirmed by NMR spectroscopy
H–H
(
J =15.5 Hz). Finally, installation of the enamide moiety
8,9
to afford structure 1a was achieved through application of the
Buchwald copper-catalyzed protocol (26, CuI/Cs2CO3/N,N’-
dimethylethylenediamine)[19] in 44% yield based on 36%
recovered starting material and 10% decarbamated 1a.
Although similar, the 1H NMR spectroscopic data of
synthetic 1a did not match those reported[1] for the natural
palmerolide A, with notable differences for H7 and H10. At
this stage we became convinced that the true structure of
palmerolide A must be 19-epi-20-epi-1a (ent-1b) which
became our next target. After reaching ent-1b (from ent-2,
3, and 4, and following the developed synthetic technology),
Figure 2. CD spectra of ent-1b (top, CHCl3, 258C, 0.0013m) and of 1b
(bottom, CHCl3, 258C, 0.0025m).
The described chemistry once again demonstrates the
power of the olefin metathesis reaction in complex molecule
construction,[14b,c] and delivered the originally proposed[1]
structure 1a, the revised structure 1b,[3] and its enantiomer
ent-1b of palmerolide A.[20] Furthermore, the flexibility of the
strategy to deliver either configuration at each stereocenter
allows construction of all stereoisomers of this valuable
substance for biological studies.
1
whose H NMR data corresponded to those reported for the
natural substance, we learned[3] of the revised structure of
palmerolide A (1b), which immediately became our next
priority to synthesize. The total synthesis of 1b was accom-
plished from fragments 2, ent-3, and ent-4 following the same
strategy as that described for the synthesis of 1a (and ent-1b)
as delineated in Scheme 5. The final stages and advanced
intermediates of the total synthesis of 1b are shown in
Scheme 6. Synthetic 1b exhibited identical physical proper-
ties (1H and 13C NMR spectra, and MS) to those reported[1]
for natural palmerolide A. In particular, the identical circular
dichroism (CD) spectrum and sign of optical rotation of
synthetic 1b to those reported for natural palmerolide A
Received: May 21, 2007
Published online: June 28, 2007
Keywords: antitumor agents · macrolides · metathesis ·
.
natural products · total synthesis
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