A formal total synthesis of pahnerolide A

Article abstract of DOI:10.1002/chem.201000428

(Figure Presented) Under the sea: An efficient formal total synthesis of the marine natural product palmerolide A is reported herein, involving 24 longest linear steps. The key features of our synthesis involve a combination of Sharpless epoxidation and Shimizu reaction to construct the syn aldol moiety, a JuliaKocienski reaction to construct the diene, and ring-closing metathesis to form the macrocycle (see scheme; PG = protecting group).

Full text of DOI:10.1002/chem.201000428

DOI: 10.1002/chem.201000428
A Formal Total Synthesis of ACTHNUTRGNEPNUG almerolide A
Parthasarathy Gowrisankar, Sandip A. Pujari, and Krishna P. Kaliappan*[a]
The marine environment continues to be a rich source for
novel secondary metabolites with complex molecular archi-
tectures that show exceptional biological activity. In particu-
lar, the Antarctic Ocean provides a unique chemical diversi-
ty, since this ecosystem was isolated and not explored for
more than 20 million years.[1] However, the Antarctic
treaty[2] prohibiting commercial exploitation of marine sour-
ces hinders the progress of promising drug-like natural prod-
ucts isolated from this area. Nevertheless, it provides an op-
portunity for synthetic chemists to play a significant role to
convert this promise into reality by synthesizing these natu-
ral products in sufficient quantities. One such natural prod-
uct, a polyketide macrolide palmerolide A, was recently iso-
lated by Bakerꢀs group from the circumpolar tunicate Synoi-
cum adareanum.[3a] It exhibits cytotoxic activity against mel-
anoma cell line UACC-62 with the LC50 of 18 nm and
modest activity against colon cancer cell line HCC-2998.
This marine natural product appears to act on melanoma
cells through inhibition of vacuolar ATPase with an IC50 of
2 nm. The structure of palmerolide A was assigned as 1
based on a high-field NMR spectroscopy and Mosherꢀs ester
stereochemical studies.[3a]
The promising antitumor properties of palmerolide A
coupled with its extremely limited supply have attracted
much attention from the synthetic community. From a syn-
thetic point of view, palmerolide A is a challenging 20-mem-
bered macrolide with an enamide side chain, a labile carba-
mate moiety, five chiral centers, and a 1,3-diene system in
the core of an a,b-unsaturated macrocyclic lactone. De
Brabander and co-workers reported the first total synthesis
of originally assigned structure 1 and also deduced the cor-
rect relative stereochemistry and synthesized ent-palmeroli-
de A.[4] Nicolaou and co-workers independently reported
the synthesis of the revised structure of palmerolide A (1a),
its enantiomer, and the originally proposed structure by
using ring-closing metathesis (RCM) as the key reaction.[5]
Recently Hall and co-workers explored the organoboron
methodology to synthesize palmerolide A.[6] Apart from
these total syntheses, one formal synthesis,[7e] and a few par-
tial synthetic approaches have been reported,[7] including
one from our group.[7a] Nicolaou and co-workers also dis-
closed the synthesis and evaluation of a library of palmero-
lide analogues.[8]
As a part of our ongoing research program on the synthe-
sis of biologically active natural and unnatural products
using a metathetic approach,[9] we became interested in the
total synthesis of palmerolide A and herein we disclose the
synthesis of macrocycle 2, which is the key intermediate in
the total synthesis of palmerolide A reported by Nicolaou
and co-workers.
The key steps in our convergent strategy for palmero-
AHCTUNGTREGlNNNU ide A, as illustrated in Scheme 1, involve the formation of a
syn aldol by Shimizu reaction,[10] assembly of subunits 3 and
4 by Julia–Kocienski reaction,[11] Yamaguchi esterification,[12]
and finally cyclization by RCM.[13]
[a] Dr. P. Gowrisankar, S. A. Pujari, Prof. Dr. K. P. Kaliappan
Department of Chemistry
Indian Institute of Technology, Bombay
Powai, Mumbai-400076 (India)
Fax : (+22)2576 3480
The synthesis of C15–C23 fragment 3 began with the oxi-
dation of known alcohol 6[14] by 1-hydroxy-1,2-benziodoxol-
3(1H)-one-1-oxide (IBX) to the corresponding aldehyde,
E-mail: kpk@chem.iitb.ac.in
which upon Wittig reaction furnished the ester
(Scheme 2). Reduction of this ester with LAH provided the
7
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000428.
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COMMUNICATION
Scheme 1. Retrosynthesis of palmerolide A (1a). TIPS=triisopropylsilyl,
TBDPS=tert-butyldiphenylsilyl, MOM=methoxymethyl.
Scheme 3. Synthesis of fragment 3. a) Diisobutylaluminum hydride
(DIBAL-H), CH2Cl2, À788C, 1 h, 74%; b) TBDPSCl, CH2Cl2, imidazole,
RT, 2 h, 85%; c) PdCl2·2CH3CN, acetone, 08C, 30 min, 89%;
d) CH2CHMgBr, THF, 08C to RT, 5 h, 73%; e) Ac2O, py, 4-dimethylami-
nopyridine (DMAP), 508C, 16 h, 78%; f) PdCl2·2CH3CN, THF, RT, 6 h,
88%; g) NH3/MeOH, RT, 16 h, 70% 19, 9% 18; h) MnO2, CH2Cl2, RT,
2 h, 92%.
the ketal 13 under mild acidic conditions led to the forma-
tion of elimination product significantly. After some experi-
mentation, this difficulty was circumvented by transketaliza-
tion using PdCl2·2CH3CN and acetone to furnish the ketone
14 in good yield.[16] Addition of vinyl Grignard reagent to
the ketone 14 followed by acetylation of the resultant diol
afforded the diacetate 16. A palladium(II)-catalyzed rear-
rangement of allylic acetate[17] gave an inseparable diaste-
reomeric mixture of 17. Selective cleavage of terminal ace-
tate, achieved by treating with saturated solution of NH3-
MeOH, made it possible to separate the diastereomers 18
and 19 by column chromatography (E/Z=7.5:1), which
were identified by 2D-NOE NMR spectroscopy experi-
ments. The required E isomer 19 was then subjected to oxi-
dation with MnO2 to give the fragment 3 required for Julia–
Kocienski reaction.
Scheme 2. Synthesis of intermediate 11. a) i) IBX, ethyl acetate, reflux,
6 h; ii) PPh3C
aluminum hydride (LAH), diethyl ether, 08C to RT, 2 h, 96%; c) d-(À)-
diisopropyl tartrate (DIPT), Ti(iPrO)4, CH2Cl2, 4 ꢂ molecular sieves,
CaH2, tBuOOH, À258C, 4 h, 90%; d) i) IBX, ethyl acetate, reflux, 6 h;
ii) PPh3C(CH3)CO2Et, toluene, RT, 3 h, 89% (2 steps); e) [Pd2-
(dba)3]·CHCl3 (dba=dibenzylideneacetone), HCO2H, nBu3P, E t3N, 1,4-
ACHTUNGTRENNUNG(CH3)CO2Et, toluene, RT, 3 h, 85% (2 steps); b) lithium
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
dioxane, RT, 16 h, 94%.
alcohol 8, which was then subjected to Katsuki–Sharpless
asymmetric epoxidation[15] to produce epoxide 9 (90% enan-
tiomeric excess (ee) based on 19F NMR spectroscopy analy-
sis of its Mosher ester derivative) in 90% yield.
Oxidation of 9 followed by one more Wittig reaction
smoothly afforded the ester 10. At this stage, a stereoselec-
tive Pd-catalyzed hydrogenolysis[10] was carried out to give
the syn-alkoxy ester 11 in 94% yield. Earlier synthetic ap-
proaches reported for this molecule involve the construction
of syn C19–C20 chiral centers by using classical asymmetric
aldol approaches. This non-aldol approach, developed by
Shimizu and co-workers,[10] is a high-yielding reaction and
has been rarely explored in the synthesis of natural prod-
ucts.
With good quantities of 3 in hand, our next task was to
synthesize the other fragment 4 required for Julia-Kocienski
reaction, which commenced with the halogenation of known
allyl alcohol 20[18] to allyl chloride 21 by using an Appel re-
action (Scheme 4).[19] Sharpless dihydroxylation of allyl chlo-
ride 21 gave a chlorohydrin, which upon treatment with
K2CO3 provided the epoxy alcohol 22 (88% ee based on
19F NMR spectroscopy analysis of the Mosherꢀs ester deriva-
tive). The secondary alcohol was then protected as its
MOM-ether 23 before treating with dimethylsulfonium ylide
to obtain the allylic alcohol 24 in 81% yield.[20] Protection
of the free alcohol as the TIPS ether and selective cleavage
of the primary tert-butyldimethylsilyl (TBS) group yielded
The hydroxy ester 11 was easily reduced with DIBAL-H
to diol 12 (Scheme 3), and the primary alcohol was then se-
lectively protected as TBDPS ether 13. Attempts to cleave
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K. P. Kaliappan et al.
Having synthesized all the three fragments, we then fo-
cused our attention on coupling these fragments to accom-
plish the synthesis of palmerolide A. As anticipated, the key
Julia–Kocienski olefination between sulfone 4 and aldehyde
3 proceeded smoothly to afford the required E olefin 32 in
80% yield (Scheme 6). A one-pot cleavage of TBDPS ether
Scheme 4. Synthesis of fragment 4. a) PPh3, CCl4, NaHCO3, reflux, 6 h,
82%; b) AD-mix-a, CH3SO2NH2, NaHCO3, tBuOH/H2O, 0 8C, 24 h,
92%; c) K2CO3, MeOH, RT, 3 h, 82%; d) MOMCl, iPr2NEt, CH2Cl2, 2 h,
92%; e) (CH3)3SI, nBuLi, THF, À188C to RT, 1 h, 81%; f) triisopropyl-
silyl trifluoromethanesulfonate (TIPSOTf), 2,6-lutidine, CH2Cl2, 08C to
RT, 1 h, 87%; g) AcOH/THF/H2O (3:1:1), RT, 6 h, 86%; h) 28, PPh3, di-
isopropyl azodicarboxylate (DIAD), THF, À208C, 1 h, 92%;
i) (NH4)6Mo7O24, H2O2, EtOH, 08C to RT, 12 h, 94%.
the alcohol 26 in good yield. The synthesis of key sulfone
fragment 4 was accomplished by a Mitsunobu reaction on 26
with N-phenyl-tetrazolethiol 28 followed by oxidation.
Synthesis of the remaining fragment 5 began with the
Sharpless kinetic resolution[21] of known alcohol rac-29,[22]
affording the enantiomerically enriched allylic alcohol 29
(95% ee based on Mosherꢀs ester derivative) in good yield.
Protection of the alcohol as its TIPS ether followed by selec-
tive cleavage of primary TBS ether delivered the primary al-
cohol 30.[23] IBX oxidation followed by Horner–Wadsorth–
Emmons reaction of the resulting aldehyde afforded the
conjugated ester 31, which upon saponification with LiOH
furnished the acid 5 (Scheme 5).
Scheme 6. Synthesis of macrocycle 2. a) LiHMDS (HMDS=hexamethyl-
disilazane), 3, THF, À788C, 45 min. 80% (>95:5 E/Z); b) NaOH,
CH3OH, reflux, 10 h, 78%; c) i) MnO2, CH2Cl2, RT, 6 h; ii) CrCl2, CHI3,
THF, 08C, 1 h, 72 % (>95:5 E/Z) (2 steps); d) 5, 2,4,6-trichlorobenzoyl
chloride, Et3N, benzene, RT, 1 h, then DMAP, 34, RT, 1 h, 68%; e) AcCl,
EtOH, THF, 608C, 10 min. 70%; f) Cl3CCONCO, CH2Cl2, 08C, 1 h, then
basic Al2O3, 08C to RT, 1 h, 80%; g) tetrabutylammonium fluoride
(TBAF), THF, 08C, 4 h, 66%; h) Grubbs second generation catalyst
(5 mol%) CH2Cl2, RT, 1 h, 70%.
and acetate was successfully achieved by an alkaline solu-
tion in methanol at elevated temperature led to the diol
33.[24] The allylic alcohol was then selectively oxidized with
MnO2 to an aldehyde, which upon Takai olefination[25]
paved the way to the vinyl iodide 34. Yamaguchi esterifica-
tion with acid 5 provided the ester 35, which was then sub-
jected to MOM ether cleavage. After screening various con-
ditions, the MOM group was successfully cleaved by a mix-
ture of acetyl chloride, EtOH, and THF at elevated temper-
ature to furnish the desired alcohol 36 in good yield.[26]
Treatment of this alcohol with trichloroacetylisocyanate fol-
Scheme 5. Synthesis of fragment 5. a) d-(À)-DIPT, Ti
ACHTUNGTNERN(UNG iPrO)4, CH2Cl2,
4 ꢂ molecular sieves, CaH2, tBuOOH, À228C, 6 d, 42%; b) TIPSOTf,
2,6-lutidine, CH2Cl2, 08C to RT, 1 h, 87%; c) AcOH/THF/H2O (3:1:1),
RT, 6 h, 76% d) i) IBX, EtOAc, reflux, 5 h.; ii) EtO2CCH2P(O)ACTHNURGTNEUNG(OEt)2,
diisopropylethylamine (DIPEA), LiCl, THF, RT, 12 h, 80% (2 steps, E/Z
>95:5); e) LiOH, H2O/THF/CH3OH (2:1:1), 08C to RT, 8 h, 68%.
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Total Synthesis of Palmerolide A
COMMUNICATION
Leung, D. H. Dethe, R. Guduru, Y.-P. Sun, C. S. Lim, D. Y.-K. Chen,
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lowed by basic alumina afforded the carbamate 37. Both
TIPS groups were cleaved by using TBAF (5 equiv) at 08C
to afford the desired diol 38, an advanced intermediate in
Nicolaouꢀs synthesis of palmerolide A. The key RCM reac-
tion of 38 with the Grubbs catalyst (G-II) also proceeded
smoothly to provide the macrocyclic core 2 of palmeroli-
de A, as reported by Nicolaou and co-workers.[5] The spec-
tral data of 2 matches with that reported,[5,7e] and thus a
formal synthesis of palmerolide A has been successfully ac-
complished.
In summary, we have successfully completed a concise
formal synthesis of palmerolide A by synthesizing the mac-
rocycle 2, an advanced intermediate in Nicolaouꢀs synthesis
of palmerolide A, in 0.87% overall yield for a longest linear
sequence of 24 steps, starting from alcohol 6. The key fea-
tures of our synthesis involve the installation of syn stereo-
centers at C19–C20 by exploring Sharpless epoxidation prior
to Pd-catalyzed hydrogenolysis, while the other three stereo-
centers at C10, C11, and C7 were introduced by Sharpless
asymmetric dihydroxylation and Sharpless kinetic resolu-
tion. The 14E–16E diene was installed through a Pd-cata-
lyzed allylic rearrangement coupled with Julia–Kocienski re-
action. Towards the end, Yamaguchi esterification and RCM
were employed to construct the 20-membered macrocycle.
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Acknowledgements
K.P.K. thanks the DST, New Delhi for the award of Swarnajayanti fel-
lowship and financial support. P.G. and S.A.P. thank CSIR for fellow-
ships. SAIF IIT Bombay is sincerely acknowledged for spectral facilities.
Keywords: antitumor agents · Julia–Kocienski reaction ·
metathesis · natural products · structure elucidation
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Received: February 18, 2010
Published online: April 15, 2010
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Chem. Eur. J. 2010, 16, 5858 – 5862