A shimizu non-aldol approach to the formal total synthesis of palmerolide A

Article abstract of DOI:10.1002/asia.201100429

A formal total synthesis of palmerolide A has been accomplished by assembling three fragments by means of successive Julia-Kocienski olefination, Yamaguchi esterification, and ring-closing metathesis (RCM). Our initial efforts to combine the first two fragments through a Julia-Kocienski reaction between a secondary sulfone and a ketone were not successful; nevertheless, it was feasible between a primary sulfone and aldehyde. Yamaguchi esterification with the third fragment then set the stage for a RCM reaction. Initial failure of the RCM with a PMB-ether adjacent to the olefins and the difficulty in cleaving the PMB-ether prompted us to change the choice of protecting groups, which then paved the way to the macrocyclic core of palmerolide A.

Full text of DOI:10.1002/asia.201100429

DOI: 10.1002/asia.201100429
A Shimizu Non-Aldol Approach to the Formal Total Synthesis of
Palmerolide A
Sandip A. Pujari, Parthasarathy Gowrisankar, and Krishna P. Kaliappan*[a]
Abstract: A formal total synthesis of
fone and a ketone were not successful;
nevertheless, it was feasible between a
primary sulfone and aldehyde. Yama-
guchi esterification with the third frag-
palmerolide A has been accomplished
by assembling three fragments by
means of successive Julia–Kocienski
olefination, Yamaguchi esterification,
and ring-closing metathesis (RCM).
Our initial efforts to combine the first
two fragments through a Julia–Kocien-
ski reaction between a secondary sul-
ment then set the stage for a RCM re-
action. Initial failure of the RCM with
a PMB-ether adjacent to the olefins
and the difficulty in cleaving the PMB-
ether prompted us to change the
choice of protecting groups, which then
paved the way to the macrocyclic core
of palmerolide A.
Keywords: Julia–Kocienski
reac-
tion · macrolides · melanoma · ring-
closing metathesis
esterification
·
Yamaguchi
Introduction
sential to make these natural products as well as their ana-
logues for further biological studies and hence they are at-
tractive target molecules for total synthesis. Recently, during
the course of their investigation of the bioactivity among the
Antarctic ecosystem, Baker and co-workers isolated a mac-
rocyclic polyketide palmerolide A (1) from Antarctic tuni-
cate Synoicum adareanum.[4] Palmerolide A (Scheme 1) ex-
hibits potent and selective cytotoxicity against melanoma, a
deadly form of skin cancer. It is interesting to note that pal-
merolide A has been isolated from a place where there is no
sunlight, and yet it has the potential to fight a disease that
comes from exposure to the sun. Among all skin cancers,
melanoma is known to spread aggressively and requires che-
motherapy for its treatment. Unfortunately, current chemo-
therapeutic agents used for the treatment of melanoma are
less selective. However, preliminary biological studies on
The chemical and biological diversity found in nature has
always inspired and fascinated synthetic chemists and at the
same time provided opportunities for the isolation, structur-
al elucidation, and synthesis of various complex natural
products. In the past, most of these biologically potent mole-
cules were mainly isolated from plants or microorganisms
such as bacteria and fungi.[1] In recent times, there has been
a steady growth in the isolation of lead compounds from
marine sources because of advances in technology used for
their isolation and characterization, and developments in
synthetic chemistry.[2] The ocean is a rich source of marine
natural products, many of which have been found to be
potent therapeutic agents against many deadly diseases,
such as cancer and acquired immuno-deficiency syndrome
(AIDS).[3] Among the various sources of marine natural
products, the chemical diversity available in the Antarctic
Ocean has not been explored for several decades owing to
the extreme climate and difficulties associated with product
isolation. Furthermore, as natural products isolated from
this area are only available in limited quantities, it was es-
[a] S. A. Pujari, Dr. P. Gowrisankar, Prof. Dr. K. P. Kaliappan
Department of Chemistry
Indian Institute of Technology, Bombay
Powai, Mumbai-400076 (India)
Fax : (+22)2576-7152
E-mail: kpk@chem.iitb.ac.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100429.
Scheme 1. Proposed structure of palmerolide A.
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palmerolide A are very promising in terms of selectively tar-
geting the melanoma cells. Palmerolide A exhibits cytotoxic
activity against melanoma cell line UACC-62 with a LC50
value of 18 nm. Further biological studies revealed that it
shows modest activity against colon cancer cell line HCC-
2998 as well as renal cancer cell line RXF 393 (LC50 =
6.5 mm), whereas all other cell lines tested by the NCI-60
cell line panel (National Cancer Institute) remains inactive.
The in vitro selectivity index of this molecule falls in the
range of ca. 103 for the melanoma cells over the most-sensi-
tive cell lines that were tested. Palmerolide A also appears
to act on melanoma cells through the inhibition of vacuolar-
ATPase with an IC50 of 2 nm.
The structure of palmerolide A 1 has been assigned based
on high-field NMR spectroscopic and Mosher’s ester stereo-
chemical studies.[4] The relative and absolute configurations
of 7R and 10R were determined based on the Mosher’s ester
derivative of the two free secondary alcohols at the C7 and
C10 positions, whilst the stereochemistry at C11, C19, and
C20 were assigned by using through-space coupling NMR
analysis, such as rotating frame nuclear Overhauser effect
spectroscopy (ROESY) and nuclear Overhauser effect spec-
troscopy (NOESY) experiments with respect to C10 interac-
tions through space. Intriguing structural features of palmer-
olide A include an enamide side-chain, a carbamate moiety,
five chiral centers, and a 1,3-diene system in the core of the
20-membered macrocyclic lactone.
Scheme 2. Retrosynthesis of proposed structure 1.
ꢀ
and C15 C21 connected via C19 oxygen atom), a southern
ꢀ
ꢀ
hemisphere (C10 C14), and a side-chain (C22 C24 and
ꢀ
C1’ C4’ connected through a nitrogen atom). From a syn-
thetic point of view, we opted to construct the southern
hemisphere at a late stage as it could be easily synthesized
by a Sharpless asymmetric dihydroxylation route. We also
felt that the northern hemisphere looked more challenging
because of the presence of adjacent chiral centers, a substi-
tuted double bond with E geometry, and therefore a conven-
ient route for this fragment will facilitate our plan to achieve
the total synthesis of palmerolide A.
Although palmerolide A has shown impressive and prom-
ising biological properties against melanoma cancer cells,
only a few milligrams of the material could be derived from
each sea squirt. Furthermore, the Antarctic treaty,[5] which
prohibits the commercial exploitation of marine sources,
hinders the isolation of this promising drug-like natural
product from this source. The promising antitumor proper-
ties of palmerolide A, coupled with its extremely limited
supply, have attracted much attention from the synthetic
community. As a result three total syntheses,[6–8] a couple of
formal syntheses,[9] and six par-
Thus, the northern hemisphere of palmerolide A 1 was
targeted as an initial phase of our inquiry by means of cou-
pling of acid (8) and alcohol (12) fragments (Scheme 3). The
acid fragment (8) was obtained by asymmetric a-alkylation
of oxazolidinone 5 with Davis reagent 6 followed by cross-
metathesis with methyl acrylate as key steps. Alcohol 12 has
been successfully synthesized through a chelation-controlled
tial syntheses[10a–f] have already
been reported in the literature.
In view of its novel molecular
architecture coupled with bio-
logical properties, we became
interested in the synthesis of
palmerolide A. We initiated a
program for the total synthesis
of palmerolide A as soon as the
isolation of this interesting nat-
ural product was reported and
so our initial synthetic strategy
has been mainly focused on the
proposed
structure
(1;
Scheme 2). A closer look at the
molecule suggested that pal-
merolide A could be divided
into three portions, namely a
ꢀ
Scheme 3. Synthesis of the northern hemisphere of proposed structure 1. NaHMDS=sodium bis(trimethylsily-
l)amide, THF=tetrahydrofuran, Bn=benzyl, PMB=para-methoxybenzyl, Ac=acetyl, DDQ=2,3-dichloro-
northern hemisphere (C1 C9 5,6-dicyano-1,4-benzoquinone, DMAP=4-dimethylaminopyridine.
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Formal Total Synthesis of Palmerolide A
addition of allyl stannane to aldehyde 9 and palladium-cata-
lyzed allylic rearrangement of allyl acetate 11 as the key
steps. A DCC-mediated esterification of acid 8 and alcohol
12 furnished the northern hemisphere (13) of palmeroli-
de A.[10a]
Subsequently, during the course of our work on the total
synthesis of palmerolide A, De Brabanderꢁs group report-
ed[6] the first total synthesis of the originally assigned struc-
ture of palmerolide A (1). However, the spectral data of the
synthetic isomer did not match with that of the natural
product, thereby suggesting that its structure needed to be
revised. Although the absolute configuration at the C7 and
C10 positions were assigned based on Mosher’s ester analy-
sis, the stereochemical assignment at the C19 and C20 posi-
tions was less convincing. Taking this into account, assuming
that these two stereocenters might have the opposite config-
uration, De Brabanderꢁs group synthesized 19-epi-20-epi dia-
Scheme 5. Synthesis employed by Baker and co-workers and comparison
of triol 19. DMP=2,2-dimethoxypropane, LAH=lithium aluminum hy-
dride.
reochemistry of the natural product at the C7, C10, and C11
positions should be (S,S,S), and not (R,R,R).
stereomer 14 of the originally proposed structure
1
This assignment was further confirmed by the total syn-
thesis of 15 from Nicolaouꢁs[7a,b] group. These findings have
been taken into account to revise the originally proposed
structure 1 as 15 (Scheme 4). Furthermore, Nicolaouꢁs group
carried out systematic biological studies on several ana-
logues of palmerolie A,[7c] which revealed that the carba-
mate and enamide moieties are essential for its biological
properties, whereas the C7 hydroxy group is not necessary.
(Scheme 4). Interestingly, this time, the spectral data and its
HPLC behavior matched with that of the natural isolate;
however, the CD (circular dichroism) spectra obtained was
found to be the mirror image of the naturally occurring
isomer. This provided the indirect evidence for the absolute
configuration of chiral centers present in palmerolide A and
they proposed that the structure of palmerolide A should be
revised as 15 (ent-19-epi-20-epi-1).
ꢀ
Moreover, the steric environment around the C1 C8
domain of palmerolide A could not be tolerated at the
active site of the enzyme.[7d]
After the disclosure of the revised structure of palmeroli-
de A, we modified our strategy and accomplished the
formal synthesis of palmerolide A using palladium-catalyzed
hydrogenolysis, Julia–Kocienski olefination, Yamaguchi
esterification, and ring-closing metathesis (RCM) as the key
steps.[9b] Herein, we present a full account which highlights
our cumulative efforts that eventually led to the synthesis of
an advanced intermediate present in Nicolaouꢁs synthesis of
palmerolide A.
Scheme 4. Structures of palmerolide A.
Results and Discussion
First-Generation Strategy
Meanwhile, in order to verify the assignment of absolute
configuration, Bakerꢁs group carried out a controlled reduc-
tive ozonolysis of the natural isolate to obtain the triol (16)
as one of the fragments (Scheme 5).[10g] Although, the mag-
nitude of its optical rotation closely matched to that of same
triol obtained through chemical synthesis, the sign of rota-
tion was found to be opposite. These studies also suggested
that the natural product has the S configuration at the C7
position rather than the originally proposed R configuration.
After revisiting the absolute stereochemical assignment,
Bakerꢁs group realized that Cahn–Ingold–Prelog prioritiza-
tion of their Mosher ester derivatives to assign the stereo-
chemistry at the C7 and C10 positions was incorrect. Be-
cause the configuration at the C11 position was derived
from the C10 stereocenter, it was also revised. Thus, the ste-
Encouraged from our earlier experience and success in syn-
thesizing natural and unnatural products using a metathetic
approach,[11] we planned to exploit a RCM[12] as a key step
for the synthesis of palmerolide A. Accordingly, our retro-
synthetic analysis featured the strategic disconnection of the
ꢀ
target molecule into three different fragments: 20 (C17
ꢀ
ꢀ
C24), 21 (C9 C16), and 22 (C1 C8). A Julia–Kocienski re-
action[13] between fragments 20 and 21 could be envisioned
ꢀ
to construct the C9 C24 framework (Scheme 6). We also
anticipated that the Yamaguchi esterification[14] of the C9
ꢀ
C24 fragment with acid 22 would then set the stage for the
key RCM[12a,b] to assemble the macrocyclic core of palmero-
lide A. The acid sensitive N-acyl dienamine functionality
could be introduced at a late stage of the synthesis by using
a Curtius rearrangement.[15]
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K. P. Kaliappan et al.
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could be synthesized starting from inexpensive ethylacetoa-
cetate 27 in a few steps.
Thus, our synthesis of the C17 C24 fragment 20 began
ꢀ
with the oxidation of known alcohol 28[18] to the correspond-
ing aldehyde, which upon Wittig reaction gave ester 29 as
the sole product (Scheme 8). Subsequent reduction of ester
29 with LAH furnished alcohol 26 which was then subjected
to Katsuki–Sharpless asymmetric epoxidation[19] to produce
epoxide 30 in good yield (90% ee based on 19F NMR analy-
sis of its Mosher’s ester derivative). The latter compound
was then oxidized to the corresponding aldehyde with IBX
and subsequent Wittig reaction of the resultant aldehyde af-
forded ester 25 (85% yield over two steps). With sufficient
quantities of ester 25 in hand, we next examined the appli-
cation of stereoselective palladium-mediated hydrogenoly-
sis.[20] Gratifyingly, exposure of 25 to [Pd
2ACHTNUTRGNEUNG(dba)3CHCl3] and
Bu3P in the presence of Et3N and HCOOH at ambient tem-
perature furnished compound 31 in excellent yield.
Scheme 6. Retrosynthesis of 15.
Protection of alcohol 31 as its TBS ether 32 (Scheme 9)
followed by reduction of ester with LAH afforded the alco-
hol (24). The aldehyde obtained upon oxidation of 24 with
MnO2, was homologated with Ph3PCHCO2Et to furnish
ester 33 in 78% yield over two steps (trace amounts of read-
ily separable Z-isomer were also formed). The geometry of
As a part of our new synthesis of this molecule, we also
deliberated utilizing the non-aldol approach developed by
Shimizu and co-workers[16] to construct the C7 C24 frag-
ꢀ
1
ment (20), as against the classical aldol reaction. This meth-
odology, a palladium-catalyzed hydrogenolysis of alkenylox-
irane, although a powerful tool to construct syn or anti tetra-
hedral centers, has been rarely explored in the synthesis of
natural products.
We envisioned that the sulfone (20), a first building block
required for the Julia–Kocienski olefination, could arise
from the ketodiene ester 23, which could then be converted
into an acid azide at the C24 position, which is required for
the Curtius rearrangement (Scheme 7). The ester (23) could
be obtained from allylic alcohol 24, which, in turn, could be
synthesized from alkenyloxirane 25 using the key reaction
mentioned above. Sharpless asymmetric epoxidation[17] of al-
lylic alcohol 26 followed by oxidation and Wittig olefination
could afford chiral alkenyloxirane 25. In turn, alcohol 26
the major E isomer of 33 was confirmed by H NMR spec-
troscopy from its coupling constant (J=15.6 Hz). However,
removal of the ketal was found to be more difficult than ini-
tially anticipated owing to concomitant elimination even
under mild acid treatment. After examining several condi-
tions, we found that the neutral conditions developed by
Lipshutz et al.[21] resolved this issue to afford ketone 23 in
good yield. Thus, ketone 23 was reduced with NaBH4 to fur-
nish a mixture of alcohols 34 that were then converted into
sulfide 35 under Mitsunobu conditions. Subsequent oxida-
tion with ammonium molybdate delivered the sulfone 20, a
key intermediate and one of the fragments required for the
Julia–Kocienski reaction.
Scheme 8. Synthesis of intermediate 31 a) i: Ethylene glycol, cat. PTSA,
toluene, reflux, 4 h, 83%; ii: LAH, Et2O, 1 h, RT, 92%; b) i: IBX,
EtOAc, reflux, 6 h; ii: Ph3PC
steps; c) LAH, Et2O, 1 h, RT, 96%; d) d-(ꢀ)-DIPT, Ti
4 ꢂ M.S., cat. CaH2, TBHP, ꢀ258C, 4 h, 90%; e) i: IBX, EtOAc, reflux,
6 h; ii: Ph3PC(CH3)CO2Et, toluene, RT, 3 h, 89% over 2 steps; f) [Pd2
AHCUTNRTGEG(NNNU dba)3CHCl3], HCO2H, nBu3P, Et3N, 1,4-dioxane, RT, 16 h, 94%.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
PTSA=4-toluene sulphonic acid, DIPT=diisopropyl tartarate, M.S.=
molecular seives, TBHP=tert-butyl hydroperoxide, IBX=2-iodoxy ben-
zoic acid, dba=dibenzylideneacetone.
Scheme 7. Retrosynthesis of fragment 20.
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Formal Total Synthesis of Palmerolide A
Scheme 11. Synthesis of intermediate 47. a) KOH, DMSO, PMBCl, 08C,
2 h, 76%; b) i: oxalylchloride, DMSO, CH2Cl2, ꢀ788C, 30 min, Et3N, RT;
ii: Ph3PCHCO2Et, toluene, RT, 5 h, 80% over 2 steps; c) DIBAL-H,
CH2Cl2, ꢀ788C, 1 h, 92%; d) AD-mix-a, CH3SO2NH2, NaHCO3, tBuOH/
H2O, 0 8C, 24 h, 56%; e) TsCl, Py, DMAP, 08C, 5 h; f) K2CO3, MeOH,
08C, 2 h, 71% over 2 steps; g) TBSCl, CH2Cl2, imidazole, RT, 16 h, 68%;
h) (CH3)3SI, nBuLi, Et2O, ꢀ158C to RT, 85%. DMSO=dimethyl sulfox-
ide, PMBCl=4-methoxybenzyl chloride, DIBAL-H=diisobutylalumini-
um hydride, TsCl=4-toluenesulfonyl chloride, Py=pyridine, DMAP=4-
N,N-dimethylaminopyridine.
Scheme 9. Synthesis of intermediate 20. a) TBSOTf, CH2Cl2, Et3N, 08C,
1 h, 82%; b) LAH, Et2O, 2 h, RT, 82%; c) i: MnO2, CH2Cl2, RT, 3 h; ii:
the corresponding allylic alcohol, which upon Sharpless
asymmetric dihydroxylation with AD-mix-a, afforded the
triol 44 in moderate yield. The selective tosylation of pri-
mary alcohol 44 using TsCl/Py at 08C followed by treatment
with K2CO3/MeOH afforded the epoxy-alcohol 45, and the
secondary alcohol was subsequently protected as its TBS
ether 46. However, opening of the epoxide 46 with trime-
thylsulfonium ylide using tetrahydrofuran as a solvent did
not proceed as anticipated, to afford the alcohol 47. When
tetrahydrofuran was replaced by diethyl ether, complete
consumption of the starting material was observed;[25] how-
ever, product 47 has always been accompanied by an unex-
pected compound (48) in the ratio of 2:1 which underscored
the change of protecting groups and so the scheme was
modified accordingly.
Ph3PCHCO2Et, toluene, reflux, 18 h, 80% over
2 steps; d) [PdCl2
ACHTUNGTRENNUNG(CH3CN)2], acetone, RT, 2 h, 78%; e) NaBH4, EtOH, 08C to RT, 3 h,
93%; f) DIAD, PPh3, THF, 36, 08C to RT, 6 h, 60%; (g) (NH4)6Mo7O24,
EtOH, H2O2, RT, 12 h, 90%. TBSOTf=tert-butyldimethylsilyl trifluro-
methane sulphonate, DIAD=diisopropyl azodicarboxylate.
ꢀ
The C9 C16 fragment 21, the second building block re-
quired for Julia–Kocienski coupling could arise from the ho-
mologation of alcohol 37 which, in turn, could be accessed
through opening of the epoxide (38) with trimethylsulfoni-
um ylide.[22] Epoxide 38 could be traced back to triol 39 by a
selective tosylation of the primary alcohol followed by treat-
ment with base. It was clear that triol 39 could be easily ob-
tained through a Sharpless asymmetric dihydroxylation[23] of
allylic alcohol 40, which could be easily realized by manipu-
lation of the commercially available 1,4-butanediol 41
(Scheme 10).
As indicated by the modified strategy, known allylic alco-
hol 49[26] was halogenated to deliver an allylic chloride
(Scheme 12), which was then subjected to Sharpless asym-
ꢀ
Thus, the synthesis of the C9 C16 subunit began with the
selective monoprotection of 1,4-butane diol as its PMB
ether (42;[24] Scheme 11). The Swern oxidation of alcohol 42
led to an aldehyde that was immediately homologated using
Wittig olefination to afford the a,b-unsaturated ester 43 in
good yield. Ester 43 was then reduced with DIBAL-H to
Scheme 12. Synthesis of fragment 21. 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) MEMCl, iPr2NEt, CH2Cl2,
16 h, 83%; e) (CH3)3SI, nBuLi, THF, ꢀ158C to RT, 90%; f) NaH, DMF,
PMBBr, RT, 1 h, 87%; g) TBAF, THF, RT, 2 h, 88%; h) i: DMP, CH2Cl2,
RT, 3 h; ii: Ph3PCHCO2Et, CH2Cl2, RT, 5 h, 77% over 2 steps;
i) DIBAL-H, CH2Cl2, ꢀ788C, 1 h, 88%; j) MnO2, CH2Cl2, RT, 92%.
MEMCl=methoxyethoxymethyl chloride, TBAF=tetra n-butylammoni-
um fluoride, DMP=Dess–Martin periodinane.
Scheme 10. Retrosynthesis of fragment 21.
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K. P. Kaliappan et al.
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metric dihydroxylation with AD-mix-a in buffer solution[27]
to give the syn diol (50) in excellent yield. The treatment of
halohydrin 50 with anhydrous K2CO3 in methanol led to the
formation of the epoxide (51; 88% ee was observed based
on 19F NMR analysis of the Mosher’s ester derivative).
Epoxy-alcohol 41 was then protected as its MEM-ether,
which upon treatment with trimethylsulfonium ylide gave al-
lylic alcohol 52. It is interesting to note that this reaction
proceeded smoothly in tetrahydrofuran, unlike 46. After
protecting the free hydroxy group as its PMB ether, the
TBS group was removed by TBAF to afford compound 53
in good yield. Oxidation of alcohol 53 with the Dess–Martin
reagent, followed by Wittig reaction of the resultant alde-
hyde furnished ester 54 as a single isomer. The complete re-
duction of ester 54 with DIBAL-H followed by allylic oxida-
tion with MnO2 provided aldehyde 21, the other key frag-
ment required for Julia–Kocienski reaction.
products,[29] all our attempts to successfully accomplish this
key reaction between 20 and 21 were unsuccessful
(Scheme 14). Presumably, the failure of the reaction can be
attributed to the bulky nature of the secondary sulfone (20)
which might not be a good nucleophile.
Scheme 14. Attempted Julia–Kocienski reaction.
The synthesis of third fragment 22 began with the Swern
oxidation of the known alcohol 56[26] to corresponding alde-
hyde, which upon treatment with vinyl Grignard gave the
racemic allylic alcohol 57 (Scheme 13). Katsuki–Sharpless
kinetic resolution[28] using d-(ꢀ)-diisopropyltartrate fur-
nished enantiomerically enriched alcohol 57 in 42% yield
(95% ee based on analysis of the Mosher’s ester derivative).
The alcohol 57 was then protected as its PMB ether 58 and
subsequent cleavage of the silyl ether provided the alcohol
59. Wittig reaction of the aldehyde derived from alcohol 59,
afforded ester 60 in good yield. Saponification of ester 60
using LiOH gave the required acid (22).
Alternatively, the desired product (61) could also be ob-
tained from a Julia–Kocienski reaction between primary sul-
fone 64 and ketone 23.[30] Accordingly, the alcohol 62 de-
rived from DIBAL-H reduction of ester 54 was treated with
thiol 36 under Mitsunobu conditions, and subsequent oxida-
tion of the resulting thio-ether afforded sulfone 64. Howev-
er, sulfone 64 also failed to undergo a Julia–Kocienski reac-
tion with ketone 23 (Scheme 15).
Attempted Julia–Kocienski Reaction
Having synthesized the three fragments required for the
synthesis of palmerolide A, the next decisive task was to
couple these fragments sequentially. Though the Julia–Ko-
cienski coupling between a secondary sulfone and an alde-
hyde has been utilized in the synthesis of several natural
Scheme 15. Attempted Julia–Kocienski reaction. a) DIAD, PPh3, THF,
36, 08C, 2 h, 86%; b) (NH4)6Mo7O24, EtOH, H2O2, RT, 12 h, 55%.
Second-Generation Strategy
These disappointing results underlined the need for a re-
vised synthetic strategy at this stage. As an alternative, a
more-feasible strategy for the completion of the synthesis
Scheme 13. Synthesis of intermediate 22. a) NaH, THF, TBSCl, RT, 3 h,
66%; b) i: oxalylchloride, DMSO, CH2Cl2, ꢀ788C, 30 min, Et3N, RT; ii :
CH2CHMgBr, THF, 08C to RT, 5 h, 60% over 2 steps; c) d-(ꢀ)-DIPT,
ꢀ
was pursued, wherein the C15 C23 fragment (65) was
Ti
(iPrO)4, CH2Cl2, 4 ꢂ M.S., cat. CaH2, TBHP, ꢀ228C, 4 d, 42%;
changed so that it will now act as an electrophile and the
d) NaH, DMF, PMBBr, RT, 1 h, 82%; e) TBAF, THF, RT, 2 h, 96%; f) i:
oxalylchloride, DMSO, CH2Cl2, ꢀ788C, 30 min, Et3N, RT; ii :
Ph3PCHCO2Et, CH2Cl2, RT, 5 h, 91% over 2 steps; g) LiOH, THF/
MeOH/H2O (1:1:2), 4 h, RT, 90%.
ꢀ
C9 C14 fragment (66) was altered to incorporate a primary
ꢀ
sulfone group and no change was made to the C1 C8 subu-
nit 22 (Scheme 16).
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Formal Total Synthesis of Palmerolide A
In the case of E isomer 74, a strong NOE cross-peak was
observed between the C15 methylene group and C25 methyl
group, but the same information was absent for 73. Further-
more, a NOE cross-peak was observed for the protons of
the C25 methyl group and the C16 olefinic hydrogen atom
in the Z isomer (73), but it was not observed in the case of
E isomer (74, Scheme 18).
Scheme 18. NOE correlation.
Scheme 16. Revised retrosynthesis of 15.
ꢀ
With ready access to the C15 C23 subunit 65, we then
ꢀ
With these considerations in mind, construction of the
took up the task of synthesizing the C9 C14 subunit. Ac-
ꢀ
C15 C23 subunit commenced with the reduction of hydroxy
cordingly, exposure of alcohol 53 to thiol 36 under Mitsuno-
bu conditions afforded thio-ether 75, which upon further ox-
idation furnished the sulfone 66 in 91% yield (Scheme 19).
ester 31 with DIBAL-H to afford diol 67 (Scheme 17). The
primary alcohol was then selectively protected as its TBDPS
ether and subsequent removal of the ketal under neutral
conditions gave the ketone (69) in good yield. Addition of
the vinyl Grignard to this ketone, followed by acetylation of
the resulting diol, afforded the diacetate 71. A palladiu-
m(II)-catalyzed isomerization of allylic acetate[31] gave an in-
separable diastereomeric mixture of 72. The selective cleav-
age of terminal acetate was achieved using ammonia/metha-
nol, and at this stage it became possible to separate the two
diastereomers (73 and 74) by column chromatography on
silica gel (E/Z=7.5:1). The required E isomer (74) was then
subjected to MnO2 oxidation to give aldehyde 65, which was
used immediately for the Julia–Kocienski olefination.
Scheme 19. Synthesis of fragment 66. a) DIAD, PPh3, THF, 36, 08C, 2 h,
89%; b) (NH4)6Mo7O24, EtOH, H2O2, RT, 12 h, 91%.
Now with the revised subunits in hand, we then examined
ꢀ
the feasibility of a Julia–Kocienski olefination of the C15
ꢀ
C23 and C9 C14 fragments. Accordingly, sulfone 66 was
treated with aldehyde 65 using an excess of LiHMDS
(3 equiv) under “Barbier-type” reaction conditions.[32] To
our delight, the reaction proceeded smoothly to provide the
diene 76 in 60% yield with good selectivity (E/Z=92:8 by
1H NMR spectroscopy; J=14.9 Hz for the E isomer). After
successfully coupling the above two fragments, the acetate
group in 76 was reductively removed with DIBAL-H to give
free alcohol 77, which on esterification with acid 22 follow-
ing a Yamaguchi procedure, afforded the RCM precursor 78
in 67% yield (Scheme 20).
Having the RCM precursor 78 in hand, the supposed last
hurdle in the synthesis, ring closure, was then attempted.
Anticipating that the PMB group adjacent to the olefin
would enhance the RCM reaction to afford the trans prod-
uct,[33] the diene 78 was subjected to RCM with Grubbs’
second generation catalyst. Unfortunately, under a variety
of conditions the reaction did not proceed to give the re-
quired product (79) and, more often than not, only starting
material was recovered. We reasoned that perhaps the steric
Scheme 17. Synthesis of fragment 60. a) DIBAL-H, CH2Cl2, ꢀ788C, 1 h,
74%; b) TBDPSCl, CH2Cl2, imidazole, RT, 2 h, 85%; c) [PdCl2
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
THF, RT, 6 h, 88%; g) sat. NH3-MeOH, RT, 16 h, 70%; h) MnO2,
CH2Cl2, RT, 2 h, 92%. TBDPSCl=tert-butyldiphenylsilyl chloride.
Chem. Asian J. 2011, 6, 3137 – 3151
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3143

K. P. Kaliappan et al.
FULL PAPERS
Now, the synthesis of the revised sulfone fragment 86
commenced with the opening of epoxide 81, derived from
alcohol 51, with trimethylsulfonium ylide to afford the allyl-
ic alcohol 82 in 81% yield (Scheme 22). Alcohol 82 was
then protected as its TIPS ether and subsequent cleavage of
the TBS ether gave the alcohol 84. Mitsunobu reaction of
alcohol 84 with N-phenyltetrazolethiol afforded the sulfide
(85), which upon further oxidation afforded the sulfone
(86).
Scheme 20. Attempted RCM reaction. a) LiHMDS, THF, 65, ꢀ788C, 1 h,
60%; b) DIBAL-H, CH2Cl2, ꢀ788C, 2 h, 78%; c) 2,4,6-trichlorobenzoyl
chloride, Et3N, 22, DMAP, toluene, RT, 2 h, 67%. LiHMDS=lithium
bis(trimethylsilyl)amide.
Scheme 22. Synthesis of fragment 86. a) MOMCl, iPr2NEt, CH2Cl2, 16 h,
83%; b) (CH3)3SI, nBuLi, THF, ꢀ188C to RT, 1 h, 81%; c) TIPSOTf,
2,6-lutidine, CH2Cl2, 08C to RT, 1 h, 87%; d) AcOH/THF/H2O (3:1:1),
RT, 6 h, 86%; e) 36, PPh3, DIAD, THF, ꢀ208C, 1 h, 92%;
f) (NH4)6Mo7O24, H2O2, EtOH, 08C to RT, 12 h, 94%. MOMCl=me-
thoxymethyl chloride, TIPSOTf=triisopropylsilyl trifluromethane sulfo-
nate.
crowding near olefins could not be tolerated to achieve the
ring-closure. At this stage it had become clear that the free
hydroxy group is required to trigger the RCM (also consid-
ering Nicolaouꢁs synthesis[7a,b]). However, attempts to gener-
ate the free hydroxy groups by cleaving the PMB ether
failed to deliver the desired product 80 (Scheme 21). It ap-
pears that the presence of a highly substituted 1,3-diene
might have caused the decomposition of 78, as a similar
problem has been encountered in the literature during de-
protection of a PMB ether in the presence of a conjugated
diene.[9a,34]
The synthesis of acid fragment 90 embarked with the pro-
tection of allylic alcohol 57 as its TIPS ether and subsequent
cleavage of TBS ether generated the alcohol 88.[35] After the
oxidation of alcohol 88, the resultant aldehyde was subject-
ed to the Wittig reaction to produce the conjugated ester 89.
Saponification of ester 89 using LiOH gave acid 90 in 66%
yield (Scheme 23).
Having secured all the coupling partners in sufficient
quantities, the key Julia–Kocienski olefination between com-
pound 86 and aldehyde 65 was attempted and, without any
further surprises, this reaction proceeded smoothly to afford
Scheme 21. Attempted cleavage of PMB-ether. a) DDQ, pH 7 buffer,
CH2Cl2, 08C to RT, 16 h; b) DDQ, CH2Cl2, H2O, 0 8C to RT, 16 h;
c) DDQ, pH 7 buffer, tBuOH, CH2Cl2, H2O, 0 8C to RT, 16 h; d) CAN,
CH3CN, H2O, 0 8C to RT, 2 h. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone, CAN=ceric ammonium nitrate.
The failure of the RCM reaction with the PMB ether, and
subsequent difficulty in the cleavage of the PMB group,
forced us to replace the PMB group with a TIPS protecting
group. The TIPS group could be removed easily without af-
fecting other functionalities present in the molecule. Ac-
cordingly we have revised fragments 66 and 22, whilst keep-
ing fragment 65 intact.
Scheme 23. Synthesis of fragment 90. a) TIPSOTf, 2,6-lutidine, CH2Cl2,
08C to RT, 1 h, 87%; b) AcOH/THF/H2O (3:1:1), RT, 6 h, 76% c) i:
IBX, EtOAc, reflux, 5 h; ii: EtO2CCH2(O)PACTHNUTRGEN(UNG OEt)2, iPr2NEt, LiCl, THF,
RT, 12 h, 80% (2 steps); d) LiOH, H2O/THF/CH3OH (2:1:1), 08C to RT,
8 h, 66%.
3144
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Chem. Asian J. 2011, 6, 3137 – 3151

Formal Total Synthesis of Palmerolide A
lide A using Buchwald coupling by Nicolaouꢁs group[7b] and
hence we have successfully accomplished the formal total
synthesis of palmerolide A.
Summary
In summary, we have developed an efficient strategy for the
formal total synthesis of palmerolide A. The key features of
our synthesis include the installation of syn stereocenters in
ꢀ
the C15 C23 fragment by employing a Sharpless epoxida-
tion prior to palladium-catalyzed hydrogenolysis, whilst the
other three stereocenters at C10, C11 and C7 present in the
molecule were introduced by Sharpless asymmetric dihy-
droxylation and Sharpless kinetic resolution, respectively.
ꢀ
Initial efforts to construct the 14E 16E diene using a Julia–
Kocienski reaction either with secondary sulfone 20 or with
the ketone 23 were not successful but the same could be ob-
tained with primary sulfone 66 and an aldehyde 65. Yama-
guchi esterification was employed to afford the RCM pre-
cursor. The RCM reaction was found to be ineffective with
a PMB-ether adjacent to olefins, but proceeded smoothly
with the free diol, affording the macrocycle (97).
Experimental Section
Unless otherwise noted, all starting materials and reagents were obtained
from commercial suppliers and used after further purification. Tetrahy-
drofuran was distilled from sodium benzophenone ketyl and toluene
from sodium. Dichloromethane, hexanes, and pyridine were freshly dis-
tilled from calcium hydride. All solvents used for the routine isolation of
products and chromatography were reagent grade and glass distilled. Air-
and moisture-sensitive reactions were performed under an argon/ultra-
high-purity nitrogen atmosphere. Flash chromatography was performed
on silica gel (100–200 mesh, Aceme) with indicated solvents. All reac-
tions were monitored by thin-layer chromatography carried out on
0.25 mm E. Merck silica plates (60F-254) using UV light as the visualiz-
ing agent and 7% ethanolic phosphomolybdic acid and heat as the devel-
oping agents. 1H and 13C NMR spectra were recorded either on a Varian
AS 400, a Varian ASM 300, or a Bruker 700 MHz instrument. (For the
spectral data of compounds 25, 26, 29–31, 50, 51, 57, 67–69, 73, 74, and
81–97; see the Supporting Information of Ref. [9b].
Scheme 24. Synthesis of macrocycle 97. a) LiHMDS, 65, THF, ꢀ788C,
45 min. 80%; b) NaOH, CH3OH, reflux, 10 h, 70%; c) i: MnO2, CH2Cl2,
RT, 6 h; ii: CrCl2, CHI3, THF, 08C, 1 h, 72% (2 steps); d) 2,4,6-trichloro-
benzoylchloride, Et3N, benzene, RT, 1 h, then DMAP, 90, RT, 1 h. 68%;
e) AcCl, EtOH, THF, 608C, 10 min. 62%; f) Cl3CCONCO, CH2Cl2, 08C,
1 h, then basic Al2O3, 08C to RT, 1 h, 78%; g) TBAF, THF, 08C, 4 h,
66%; h) Grubbs II catalyst (5 mol%), CH2Cl2, RT, 1 h, 70%.
the required E olefin (91) in 80% yield (Scheme 24). Then,
a one-pot cleavage of TBDPS ether and the acetyl group
was successfully accomplished using alkaline methanolic so-
lution heated to reflux without affecting the TIPS ether.[36]
The introduction of a vinyl iodide, required for the Buch-
wald coupling, was then accomplished in a couple of steps
through selective oxidation of the allylic alcohol and Takai
olefination.[37] Yamaguchi esterification of 93 with acid 90
proceeded smoothly to afford ester 94 in 63% yield. At this
point, selective-cleavage of the MOM-ether and introduc-
tion of the carbamate group were investigated.
After screening several conditions, we observed that ex-
posure of the MOM-ether (94) to the AcCl in mixture of
ethanol and tetrahydrofuran at elevated temperature found
to be an effective method to afford the alcohol (95) in good
yield.[38] Treatment of this alcohol with trichloroacetylisocya-
nate followed by hydrolysis with basic alumina afforded car-
bamate 96. Both of the TIPS groups were then easily
cleaved using TBAF to afford the corresponding diol which
smoothly underwent RCM in the presence of Grubbs’
second generation catalyst to afford the macrocycle (97).
This intermediate has been already converted into palmero-
Compound 32
To a solution of alcohol 31 (500 mg, 1.84 mmol) in anhydrous CH2Cl2
(10 mL) was added triethylamine (770 mL, 5.51 mmol), and the solution
was allowed to stir for 5 min. TBSOTf (850 mL, 3.6 mmol) was added
dropwise over 5 min and reaction mixture was stirred for 1 h at 08C. The
reaction was quenched by adding a saturated solution of NaHCO3. The
organic layer was separated and the aqueous layer was extracted with
CH2Cl2 (3ꢃ10 mL). The combined organic layers were washed with
brine, dried with Na2SO4, and concentrated in vacuo. The crude product
was purified by flash chromatography (20–30% ethyl acetate/hexanes) to
give the silyl ether 32 (610 mg, 86%) as a viscous liquid. Rf =0.68 (30%
ethyl acetate/hexanes); ½aꢁD25 =+6.03 (c=0.65, CHCl3); IR (neat): n˜ =
1712, 1378, 1253, 1147, 1074, 1029, 836 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d=6.78 (dq, J=10.1, 1.2 Hz, 1H), 4.25–4.10 (m, 2H), 3.98–3.84
(m, 4H), 3.81 (dt, J=8.5, 2.7 Hz, 1H), 2.82–2.78 (m, 1H), 2.08 (dd, J=
14.9, 8.8 Hz, 1H), 1.84 (d, J=1.5 Hz, 3H), 1.76 (dd, J=14.6, 3.1 Hz, 1H),
1.32 (s, 3H), 1.28 (t, J=7.3 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H), 0.89 (s,
9H), 0.04 (s, 3H), 0.03 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
168.4, 146.6, 125.9, 108.9, 70.8, 64.5, 64.1, 60.3, 43.6, 37.8, 25.8, 24.5, 18.0,
Chem. Asian J. 2011, 6, 3137 – 3151
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3145

K. P. Kaliappan et al.
FULL PAPERS
14.2, 12.4, 12.1, ꢀ4.4, ꢀ4.9 ppm; HRMS (ESI-TOF): calcd. for
C20H38O5SiNa m/z 409.2386, found m/z 409.2371.
and then at RT for 30 min. The reaction was quenched by adding 1 mL
of water, and the solvent was removed in vacuo. The product was extract-
ed with ethyl acetate (3ꢃ10 mL), and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash column chromatography (20–
40% ethyl acetate/hexanes) to afford (1:3, based on 1H NMR) diastereo-
meric mixture of alcohol 34 (290 mg, 93%) as a viscous liquid. Rf =0.41
(20% ethyl acetate/hexanes); ½aꢁ2D5 =+12.83 (c=0.75, CHCl3); IR (neat):
Compound 24
To a stirred solution of ester 32 (570 mg, 1.47 mmol) in diethyl ether
(15 mL) at 08C was added LAH (112 mg, 2.95 mmol) in portions over a
period of 20 min. The resultant mixture was warmed to RT and stirred
for 1 h. The reaction was quenched by the careful addition of mixture of
NaSO4·10·H20/Celite (4 g, 1:1) at 08C and the resulting suspension was al-
lowed to stir at RT for 3 h. The mixture was passed through a pad of
Celite and the filtrate was concentrated under reduced pressure. The resi-
due was then purified by flash chromatography (30–40% ethyl acetate/
hexanes) to afford 24 (420 mg, 82%) as colorless oil. Rf =0.42 (30%
ethyl acetate/hexanes); ½aꢁD25 =ꢀ5.07 (c=0.68, CHCl3); IR (neat): n˜ =
1
n˜ =3367 (b), 1723, 1650, 1462, 1374, 1257, 1216, 1032, 761 cmꢀ1; H NMR
of major isomer (400 MHz, CDCl3): d=7.31 (d, J=15.6 Hz, 1H), 5.87 (d,
J=9.8 Hz, 1H), 5.81 (dd, J=15.6, 4.6 Hz, 1H), 4.22 (q, J=7.3 Hz, 2H),
3.94–3.84 (m, 1H), 3.79–3.76 (m, 1H), 2.86–2.78 (m, 1H), 2.37–2.34 (m,
1H), 1.79 (d, J=1.2 Hz, 3H), 1.66–1.59 (m, 1H), 1.31 (t, J=7.0 Hz, 3H),
1.19 (d, J=6.1 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 0.88 (s, 9H), 0.095 (s,
3H), 0.094 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=167.45, 167.41,
149.4, 149.3, 143.8, 143.6, 132.5, 132.3, 116.3, 116.0, 109.9, 76.6, 75.3, 74.9,
66.1, 64.6, 60.17, 60.13, 42.3, 42.2, 38.8, 38.4, 25.8, 25.7, 24.1, 23.9, 17.9,
17.2, 15.7, 14.2, 12.47, 12.42, ꢀ4.24, ꢀ4.27, ꢀ4.48, ꢀ4.58 ppm; HRMS
(ESI-TOF): calcd. for C20H38O4SiNa m/z 393.2437, found m/z 393.2428.
3272 (b), 1472, 1378, 1254, 1132, 1029, 947, 836, 774 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d=5.40 (dd, J=9.5, 1.2 Hz, 1H), 3.98–3.88 (m, 6H),
3.76 (dt, J=7.9, 3.4 Hz, 1H), 2.68–2.63 (m, 1H), 2.03 (dd, J=14.7, 7.9 Hz,
1H), 1.68 (d, J=1.2 Hz, 3H), 1.16 (dd, J=14.7, 3.4 Hz, 1H), 1.33 (s, 3H),
0.92 (d, J=6.7 Hz, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.01 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=133.2, 131.3, 109.1, 71.9, 69.2, 64.5, 64.1,
43.7, 37.0, 25.9, 24.6, 18.1, 13.8, 13.6, ꢀ4.38, ꢀ4.63 ppm; HRMS (ESI-
TOF): calcd. for C18H36O4SiNa m/z 367.2281, found m/z 367.2287.
Compound 35
To
a stirred solution of triphenylphosphine (330 mg, 1.25 mmol), 1-
phenyl-1H-tetrazole-5-thiol (210 mg, 1.17 mmol) and alcohol 34 (290 mg,
0.78 mmol) in anhydrous THF (6 mL) at 08C was added DIAD (230 mL,
1.17 mmol). The solution was stirred at the same temperature for 1 h and
then at RT for 12 h. The solvent was evaporated to one fourth of its
volume under vacuum and the resultant residue was purified by flash
column chromatography (5–15% ethyl acetate/hexanes) to afford 35
(250 mg, 60%) as viscous oil. Rf =0.38 (15% ethyl acetate/hexanes);
½aꢁ2D5 =+19.16 (c=0.53, CHCl3); IR (neat): n˜ =1715, 1626, 1500, 1388,
Compound 33
To a solution of alcohol 24 (380 mg, 1.1 mmol) in anhydrous CH2Cl2
(8 mL) was added MnO2 (960 mg, 11 mmol) under a nitrogen atmos-
phere. The suspension was stirred at the RT for 2 h. The mixture was fil-
tered through a pad of Celite and filtrate was concentrated in vacuo to
afford the aldehyde (320 mg) which was used in the next step without fur-
ther purification.
1258, 1175, 1028, 837 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.60–7.52
;
A mixture of the above aldehyde (320 mg, 0.94 mmol) and carboethoxy-
methylenetriphenyl phosphorane (490 mg, 1.4 mmol) in anhydrous tolu-
ene (8 mL) was refluxed for 16 h. After evaporation of the solvent in
vacuo, the resultant residue was purified by flash chromatography (10–
15% ethyl acetate/hexanes) to afford 33 (310 mg, 80%) as a colorless oil.
Rf =0.42 (10% ethyl acetate/hexanes); ½aꢁ2D5 =+8.7 (c=0.58, CHCl3); IR
(m, 5H), 7.28 (d, J=15.9, 13.7 Hz, 1H), 5.84–5.76 (m, 2H), 4.24–4.18 (m,
2H), 4.13–4.01 (m, 1H), 3.82–3.72 (m,1H), 2.74–2.68 (m, 1H), 1.97–1.80
(m, 2H), 1.78 (d, J=1.2 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H), 0.98 (d, J=
6.7 Hz, 3H), 0.86 (s, 9H), 0.038 (s, 3H), 0.015 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=167.3, 167.2, 153.4, 149.25, 149.22, 144.1, 143.7,
133.7, 132.4, 132.2, 129.9, 129.64, 129.62, 123.9, 123.8, 116.2, 73.4, 73.0,
60.0, 41.6, 41.4, 41.3, 41.2, 38.6, 37.8, 25.7, 22.7, 22.4, 17.9, 15.4, 14.7, 14.2,
12.4, 12.3, ꢀ4.21, ꢀ4.25, ꢀ4.43, ꢀ4.49 ppm; HRMS (ESI-TOF): calcd. for
C27H43O3N4SSiNa m/z 531.2825, found m/z 531.2831.
(neat): n˜ =1722, 1657, 1463, 1378, 1257, 1178, 1034, 836, 776 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.29 (dd, J=15.6, 0.61 Hz, 1H), 5.89 (d,
J=9.5 Hz, 1H), 5.79 (d, J=15.6 Hz, 1H), 4.21 (q, J=7.0 Hz, 2H), 3.99–
3.79 (m, 5H), 2.87–2.82 (m, 1H), 2.05 (dd, J=14.7, 7.9 Hz, 1H), 1.79 (d,
J=1.2 Hz, 3H), 1.33 (s, 3H), 1.30 (t, J=7.3 Hz, 3H), 0.97 (d, J=6.7 Hz,
3H), 0.88 (s, 9H), 0.04 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=167.5, 149.8, 146.7, 131.2, 115.7, 108.9, 71.4, 64.5, 64.1, 60.0,
43.5, 38.0, 25.8, 24.5, 18.0, 14.3, 13.0, 12.3, ꢀ4.4, ꢀ4.7 ppm; HRMS (ESI-
TOF): calcd. for C22H40O5SiNa m/z 435.6253, found m/z 435.6248.
Compound 20
To a solution of 35 (210 mg, 0.39 mmol) in 1.3 mL of ethanol at 08C was
added ammonium heptamolybdate tetrahydrate (49 mg, 0.039 mmol) and
H2O2 (230 mL, 30% w/v aq. solution). The reaction mixture was stirred at
RT for 16 h, quenched with 10% aq. solution of Na2SO3 (8 mL), the eth-
anol was distilled off and the aqueous layer was extracted with dichloro-
methane (3ꢃ10). The combined organic layer was washed with brine,
dried over Na2SO4, and evaporated. The residue was purified by flash
chromatography (10–20% ethyl acetate/hexanes) to afford the sulfone 20
(200 mg, 90%) as a pale yellow oil. Rf =0.42 (20% ethyl acetate/hex-
anes); ½aꢁ2D5 =+16.44 (c=0.68, CHCl3); IR (neat): n˜ =1713, 1625, 1498,
Compound 23
To a solution of ketal 33 (180 mg, 0.44 mmol) in 4.0 mL of acetone was
added a solution of [PdCl2ACHTNUTRGNE(UGN CH3CN)2] (1.2 mg, 0.004 mmol, 1 mol%) in
acetone (0.5 mL) at 08C. The mixture was allowed to stir at RT for 2 h.
After removing solvents, the residue was purified by flash chromatogra-
phy on silica gel (5–10% ethyl acetate/hexanes) to afford the ketone 23
(120 mg, 78%) as a viscous oil. Rf =0.40 (8% ethyl acetate/hexanes);
½aꢁ2D5 =+24.53 (c=0.60, CHCl3); IR (neat): n˜ =1718, 1625, 1472, 1367,
1462, 1339, 1260, 1097, 1028, 838 cmꢀ1 1H NMR (400 MHz, CDCl3): d=
;
7.68–7.57 (m, 5H), 7.27 (d, J=15.6, 1H), 5.82 (d, J=15.8 Hz, 1H), 5.73
(d, J=9.5 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H), 3.97–3.93 (m, 1H), 2.76–2.65
(m, 1H), 2.41–2.31 (m, 1H), 1.80 (d, J=6.7 Hz, 3H), 1.76–1.61 (m, 1H),
1.52 (d, J=7.0 Hz, 3H), 1.30 (t, J=7.3 Hz, 3H), 0.92 (d, J=7.0 Hz, 3H),
0.89 (s, 9H), 0.09 (s, 3H), 0.07 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=167.3, 167.2, 152.57, 152.54, 149.0, 148.9, 142.9, 142.2, 133.1,
133.09, 133.07, 131.4, 131.3, 129.6, 129.56, 129.52, 125.3, 129.2, 123.9,
116.7, 116.5, 73.5, 72.5, 60.2, 58.7, 58.5, 39.2, 38.5, 33.6, 32.6, 25.7, 18.0,
17.9, 16.0, 15.3, 15.1, 14.2, 14.1, 13.8, 12.54, 12.52, ꢀ4.06, ꢀ4.25, ꢀ4.27,
ꢀ4.3 ppm; HRMS (ESI-TOF): calcd. for C27H43O5N4SSiNa m/z 585.2543,
found m/z 585.2568.
1257, 1175, 1097, 1029, 837 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.27
;
(d, J=15.6 Hz, 1H), 5.81 (d, J=15.6 Hz, 1H), 5.72 (d, J=10.1 Hz, 1H),
4.20 (q, J=7.0 Hz, 2H), 4.11 (dd, J=11.3, 5.8 Hz, 1H), 2.67–2.59 (m,
1H), 2.56 (t, J=6.4 Hz, 1H), 2.19–2.09 (m, 1H), 2.12 (s, 3H), 1.79 (d, J=
1.2 Hz, 3H), 1.29 (t, J=7.0 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H), 0.85 (s,
9H), 0.09 (s, 3H), 0.04 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
206.9, 167.3, 149.2, 143.9, 132.5, 116.3, 71.7, 60.0, 48.9, 39.3, 31.3, 25.7,
17.9, 15.4, 14.2, 12.4, ꢀ4.6, ꢀ4.7 ppm; HRMS (ESI-TOF): calcd. for
C20H37O4SiNa m/z 369.2461, found m/z 369.2445.
Compound 34
Compound 44
To a stirred solution of ketone 23 (310 mg, 0.842 mmol) in ethanol
(5.0 mL) was added sodium borohydride (64 mg, 1.68 mmol) in one por-
tion at 08C and stirring was continued for 3 h at the same temperature
A solution of DIBAL-H (1m in toluene, 60 mL, 60 mmol) was added at
ꢀ788C to a solution of ester 43 (6.0 g, 21.58 mmol) in CH2Cl2 (150 mL)
3146
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Chem. Asian J. 2011, 6, 3137 – 3151

Formal Total Synthesis of Palmerolide A
and stirred for 1 h. The reaction mixture was treated with a saturated so-
lution of sodium potassium tartrate (25 mL) and the mixture was stirred
until the solution became clear. The organic layer was separated from
the reaction mixture and the aqueous layer was extracted with CH2Cl2
(3ꢃ30 mL). The combined organic extracts were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. Purifica-
tion by column chromatography (30–40% ethyl acetate/hexanes) afford-
ed the alcohol (4.72 g, 92%) as a viscous oil.[24a] Rf =0.40 (30% ethyl ace-
tate/hexanes); IR (neat): n˜ =3423, 1687, 1612, 1513, 1463, 1302, 1248,
The reaction mixture was quenched with water and extracted with
CH2Cl2 (3ꢃ10 mL). The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated. Flash column chromatography
(20–30% ethyl acetate/hexanes) of the crude product gave compound 46
(480 mg, 68%) as a colorless oil. Rf =0.48 (20% ethyl acetate/hexanes);
½aꢁ2D5 =ꢀ3.82 (c=0.65, CHCl3); IR (neat): n˜ =2950, 2930, 2856, 1613,
1514, 1464, 1249, 1099, 837 cmꢀ1 1H NMR (CDCl3, 400 MHz): d=7.25
;
(d, J=8.2 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 4.42 (s, 2H), 3.80 (s, 3H),
3.46–3.42 (m, 2H), 3.28–3.23 (m, 1H), 2.91 (ddd, J=6.7, 4.3, 2.7 Hz, 1H),
2.77 (dd, J=4.9, 4.0 Hz, 1H), 2.54 (dd, J=4.9, 2.7 Hz, 1H), 1.76–1.56 (m,
4H), 0.89 (s, 9H), 0.11 (s, 3H), 0.05 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=159.1, 130.5, 129.2, 113.7, 74.4, 72.5, 69.8, 55.9, 55.2, 44.8,
31.3, 25.8, 25.6, 18.1, ꢀ4.4, ꢀ5.0 ppm; HRMS (ESI-TOF): calcd. for
C20H34O4SiNa m/z 389.2124, found m/z 389.2109.
1174, 1093, 1034, 970 cmꢀ1 1H NMR (CDCl3, 400 MHz): d=7.26 (d, J=
;
8.8 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 5.71–5.59 (m, 2H), 4.43 (s, 2H),
4.07 (d, J=4.6 Hz, 2H), 3.80 (s, 3H), 3.45 (t, J=6.4 Hz, 2H), 2.16–2.10
(m, 2H), 1.76 (s, 1H), 1.72–1.65 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=159.0, 132.3, 130.5, 129.3, 129.2, 113.6, 72.4, 69.2, 63.5, 55.2,
29.0, 28.7 ppm.
Compound 47
To a stirred solution of AD-mix a (7.0 g) in 23 mL of tBuOH/H2O (1:1),
methanesulfonamide (485 mg, 5.08 mmol), and K2OsO2(OH)4 were
added and the mixture was stirred for 15 min. The reaction mixture was
cooled to 08C and a solution of above alcohol (750 mg, 3.18 mmol) in
1 mL of tBuOH/H2O (1:1) was added and stirred for overnight at 08C.
The mixture was quenched with a saturated solution of Na2SO3 and
stirred for 1 h. The aqueous layer was extracted with CH2Cl2, and the
combined organic extracts were dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The product was purified by flash chroma-
To a suspension of trimethylsulfonium iodide (800 mg, 3.9 mmol) in di-
ethyl ether (6.5 mL) at ꢀ188C was added nBuLi (1.6m in hexanes,
2.3 mL, 3.51 mmol) and the reaction was warmed to ꢀ138C for 20 min.
A solution of epoxy alcohol 46 (180 mg, 0.50 mmol) in diethyl ether
(2.5 mL) was added via syringe at ꢀ188C and the reaction was warmed
to ꢀ108C. The white slurry was stirred for 2 h at this temperature and
quenched by the addition of MeOH (1 mL) at RT. The mixture was fil-
tered through Celite and washed with ethyl acetate. The filtrate was con-
centrated and purified by flash chromatography (5–20% ethyl acetate/
hexanes) to afford 47 (110 mg) and 48 (50 mg) as a clear liquid.
tography (60–80% ethyl acetate/hexanes) to afford triol 44 (500 mg,
25
58%) as a viscous liquid. Rf =0.19 (80% ethyl acetate/hexanes); ½aꢁD
=
ꢀ4.44 (c=0.50, CHCl3); IR (neat): n˜ =3392 (b), 2618, 1731(b), 1464,
Data for 47: Rf =0.37 (10% ethyl acetate/hexanes); ½aꢁ2D5 =ꢀ1.56 (c=
1248, 1175, 1090, 1032, 820 cmꢀ1 1H NMR (CDCl3, 400 MHz): d=7.25
;
0.64, CHCl3); IR (neat): n˜ =3400, 1613, 1513, 1463, 1249, 1099, 836 cmꢀ1
;
(d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 4.46 (s, 2H), 3.81 (s, 3H),
3.75–3.62 (m, 6H), 1.79–1.61 ppm (m, 4H); 13C NMR (100 MHz, CDCl3):
d=159.3, 129.8, 129.4, 113.8, 73.8, 72.8, 72.3, 70.1, 64.7, 55.2, 31.2,
26.1 ppm; HRMS (ESI-TOF): calcd. for C14H22O5Na m/z 293.1365 found
m/z 293.1378.
1H NMR (CDCl3, 400 MHz): d=7.25 (d, J=8.2 Hz, 2H), 6.87 (d, J=
8.5 Hz, 2H), 5.83 (ddd, J=16.2, 10.4, 5.5 Hz, 1H), 5.31 (dt, J=17.1,
1.8 Hz, 1H), 5.18 (dt, J=10.4, 1.5 Hz, 1H), 4.43 (s, 2H), 3.99–3.98 (m,
1H), 3.81 (s, 3H), 3.63–3.59 (m, 1H), 3.42–3.93 (m, 2H), 2.33 (d, J=
6.1 Hz, 1H), 1.70–1.50 (m, 4H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=159.0, 138.4, 130.5, 129.2, 116.0,
113.7, 75.0, 74.2, 72.4, 70.0, 55.2, 30.2, 25.8, 25.2, 18.0, ꢀ4.2, ꢀ4.5 ppm;
HRMS (ESI-TOF): calcd. for C21H36O4SiNa m/z 403.2281, found m/z
403.2273.
Compound 45
p-TsCl (1.06 g, 5.56 mmol) was added to a mixture of triol 44 (1.0 g,
3.7 mmol) and DMAP (catalytic amount) in pyridine (8 mL) at 08C over
1 h, and the mixture was stirred at same temperature for overnight. After
quenching with H2O and extracting with ethyl acetate (5ꢃ20 mL), the or-
ganic layer was washed with CuSO4 solution, dried over Na2SO4, and
concentrated. The crude tosylate product was immediately used in the
next step. Rf =0.63 (70% ethyl acetate/hexanes); ½aꢁ2D5 =+1.43 (c=0.63,
CHCl3); 1H NMR (CDCl3, 400 MHz): d=7.79 (d, J=8.2 Hz, 2H), 7.34
(d, J=8.5 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 4.44
(s, 2H), 4.09 (dd, J=10.4, 4.9 Hz, 1H), 4.03 (dd, J=10.4, 6.4 Hz, 1H),
3.81 (s, 3H), 3.77–3.43 (m, 4H), 2.45 (s, 3H), 1.75–1.58 ppm (m, 4H);
13C NMR (100 MHz, CDCl3): d=159.3, 145.0, 132.6, 129.9, 129.6, 129.4,
127.9, 113.8, 72.8, 71.8, 71.2, 70.3, 70.0, 55.2, 31.4, 26.2, 21.6 ppm.
Data for 48: Rf =0.67 (10% ethyl acetate/hexanes); ½aꢁ2D5 =+2.89 (c=
0.63, CHCl3); IR (neat): n˜ =3446, 1611, 1513, 1463, 1250, 1097, 1036,
836 cmꢀ1 1H NMR (CDCl3, 400 MHz): d=7.26 (d, J=8.5 Hz, 2H), 6.86
;
(d, J=8.5 Hz, 2H), 5.78 (ddd, J=17.1, 10.4, 6.1 Hz, 1H), 5.13 (dt, J=
17.1, 1.2 Hz, 1H), 5.02 (dt, J=10.4, 1.2 Hz, 1H), 4.43 (s, 2H), 4.10 (q, J=
6.1 Hz, 1H), 3.81 (s, 3H), 3.44 (t, J=6.1 Hz, 2H), 1.71–1.52 (m, 4H), 0.89
(s, 9H), 0.04 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
159.0, 141.6, 130.7, 129.2, 113.7, 113.6, 73.6, 72.4, 70.0, 55.2, 34.5, 25.8,
25.4, 18.2, ꢀ4.4, ꢀ4.8 ppm; HRMS (ESI): calcd. for C20H34O3SiNa m/z
373.2175, found m/z 373.2159.
Compound 52
Anhydrous K2CO3 (325 mg, 2.4 mmol) was added to a solution of the
above tosylate (1 g, 4 mmol) in methanol (6 mL) at 08C and the mixture
was stirred at RT for 45 min. The reaction mixture was filtered through a
pad of Celite and washed thoroughly with ethyl acetate. The filtrate was
concentrated and the residue was purified by silica gel chromatography
(50–60% ethyl acetate/hexanes) to give epoxy alcohol 45 (420 mg, 71%
for two steps) as viscous oil. Rf =0.44 (50% ethyl acetate/hexanes);
½aꢁ2D5 =ꢀ3.35 (c=0.65, CHCl3); IR (neat): n˜ =3412, 1611, 1513, 1358,
To a solution of above epoxide 51 (2.8 g, 11.43 mmol) in anhydrous
CH2Cl2 was added diisopropylethylamine (7.1 mL, 41.2 mmol) and
MEM-Cl (2.3 mL, 20.5 mmol) successively at 08C under nitrogen atmos-
phere. After being stirred for 16 h at RT, the reaction mixture was dilut-
ed with ethyl acetate and washed with water. Two layers were separated
and the organic layer was washed with brine and dried over Na2SO4. The
solvent was evaporated and the crude compound was purified by column
chromatography (10–20% ethyl acetate/hexanes) to afford MEM-ether
(3.1 g, 83%) as a colorless liquid. Rf =0.43 (20% ethyl acetate/hexanes);
½aꢁ2D5 =ꢀ21.01(c=0.78, CHCl3); IR (neat): n˜ =1472, 1256, 1102, 1040, 836,
1248, 1175, 1097, 1034, 971, 816 cmꢀ1 1H NMR (CDCl3, 400 MHz): d=
;
7.26 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 4.45 (s, 2H), 3.81 (s,
3H), 3.49 (t, J=5.8 Hz, 2H), 3.49–3.47 (m, 1H), 2.98 (ddd, J=4.9, 4.0,
2.7 Hz, 1H), 2.79 (dd, J=4.9, 4.0 Hz, 1H), 2.71 (dd, J=4.9, 2.7 Hz, 1H),
1.80–1.66 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=159.1, 130.1,
129.3, 113.7, 72.6, 71.3, 69.8, 55.27, 55.23, 44.8, 31.5, 25.8 ppm; HRMS
(ESI-TOF): calcd. for C14H20O4Na m/z 275.1259, found m/z 275.1254.
775 cmꢀ1 1H NMR (400 MHz, CDCl3): d=4.94 (d, J=6.7 Hz, 1H), 4.77
;
(d, J=7.0 Hz, 1H), 3.78–3.68 (m, 2H), 3.64–3.60 (m, 2H), 3.56 (t, J=
4.6 Hz, 2H), 3.38 (s, 3H), 3.36–3.31 (m, 1H), 2.98 (ddd, J=7.0, 4.2,
2.7 Hz, 1H), 2.77 (dd, J=4.8, 4.3 Hz, 1H), 1.67–1.56 (m, 4H), 0.88 (s,
9H), 0.04 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=94.4, 71.6, 67.0,
62.7, 58.8, 54.5, 43.8, 28.5, 25.8, 18.2, ꢀ5.4 ppm; HRMS (ESI-TOF):
calcd. for C16H34O5SiNa m/z 357.2073, found m/z 357.2079.
Compound 46
To a stirred solution of epoxy alcohol 45 (500 mg, 1.98 mmol) and imida-
zole (405 mg, 5.95 mmol) in CH2Cl2 (30 mL) was added TBSCl (655 mg,
4.36 mmol) at 08C, and the reaction mixture was stirred at RT for 12 h.
To a suspension of trimethylsulfonium iodide (6.20 g, 30.54 mmol) in
THF (58 mL) at ꢀ188C was added nBuLi (1.6m in hexanes, 18.4 mL,
Chem. Asian J. 2011, 6, 3137 – 3151
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3147

K. P. Kaliappan et al.
FULL PAPERS
29.5 mmol) and the reaction mixture was stirred at the same temperature
for 5 min, then warmed to between ꢀ10 and ꢀ128C for 30 min. A solu-
tion of the above epoxide (1.7 g, 5.09 mmol) in THF (15 mL) was added
via cannula at ꢀ188C and the reaction was allowed to warm slowly to
RT over a period of 1 h. The white slurry was quenched by the addition
of MeOH (1 mL), and stirred for 10 min at RT. The mixture was filtered
through a pad of Celite and the filtrate was concentrated to dryness. The
residue was purified by flash column chromatography (15–25% ethyl
acetate/hexanes) to provide 52 (1.6 g, 90%) as a clear liquid. Rf =0.29
(20% ethyl acetate/hexanes); ½aꢁ2D5 =+12.4 (c=1.70, CHCl3); IR (neat):
under reduced pressure. The crude product was used for further reaction
without any purification.
A mixture of the above aldehyde (65 mg) and carboethoxymethylenetri-
phenyl phosphorane (110 mg, 0.31 mmol) in anhydrous toluene (4 mL)
was stirred at RT for 5 h under nitrogen atmosphere. After evaporation
of the solvent in vacuo, the resultant residue was purified by flash chro-
matography (20–30% ethyl acetate/hexanes) to afford 54 (50 mg, 77%
for 2 steps). Rf =0.51 (30% ethyl acetate/hexanes); ½aꢁ2D5 =ꢀ6.4 (c=0.78,
CHCl3); IR (neat): n˜ =2930, 1718, 1655, 1613, 1514, 1249, 1037, 932,
759 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.23 (d, J=8.5 Hz, 2H), 6.93
;
n˜ =3435, 3051, 2771, 1472, 1256, 1103, 1041, 926, 836, 774 cmꢀ1 1H NMR
;
(dt, J=15.8, 6.7 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 5.84–5.75 (m, 2H),
5.35–5.28 (m, 2H), 4.83 (d, J=7.0 Hz, 1H), 4.76 (d, J=7.0 Hz, 1H), 4.56
(d, J=11.6 Hz, 1H), 4.28 (d, J=11.6 Hz, 1H), 4.18 (q, J=7.3 Hz, 2H),
3.85–3.76 (m, 1H), 3.80 (s, 3H), 3.75–3.60 (m, 3H), 3.51 (t, J=4.9 Hz,
2H), 3.37 (s, 3H), 2.31–2.22 (m, 1H), 2.18–2.10 (m, 1H), 1.79–1.71 (m,
1H), 1.61–1.53 (m, 1H), 1.28 ppm (t, J=7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=166.5, 159.1, 148.6, 135.0, 130.3, 129.3, 121.4,
118.8, 113.6, 95.9, 81.2, 79.0, 71.6, 70.0, 67.3, 60.0, 58.9, 55.1, 29.0, 28.0,
14.1 ppm; HRMS (ESI-TOF): calcd. for C23H34O7Na m/z 445.2202, found
m/z 445.2219.
(400 MHz, CDCl3): d=5.84 (ddd, J=17.1, 10.7, 6.4 Hz, 1H), 5.36 (ddd,
J=17.1, 3.1, 1.5 Hz, 1H), 5.21 (ddd, J=10.4, 3.1, 1.5 Hz, 1H), 4.81 (ABq,
J=7.3 Hz, 2H), 4.03 (t, J=6.4 Hz, 1H), 3.82 (ddd, J=9.2, 4.8, 4.0 Hz,
1H), 3.72 (dt, J=9.2, 4.3 Hz, 1H), 3.60 (t, J=5.8 Hz, 2H), 3.56 (t, J=
4.5 Hz, 2H), 3.48–3.45 (m, 1H), 3.39 (s, 3H), 1.69–1.45 (m, 4H), 0.89 (s,
9H), 0.04 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=137.3, 116.8,
96.1, 83.3, 74.8, 71.6, 67.7, 62.9, 58.9, 28.3, 27.6, 25.9, 18.3, ꢀ5.4 ppm;
HRMS (ESI-TOF): calcd. for C17H36O5SiNa m/z 371.2230, found m/z
371.2230.
Compound 53
Compound 21
To a stirred suspension of NaH (350 mg, 8.75 mmol) in DMF (2 mL) at
08C was added a solution of alcohol 52 (1.5 g, 4.31 mmol) in DMF
(8 mL). After stirring for 30 min. at RT, para-methoxybenzyl bromide
(0.95 mL, 6.46 mmol) was added in one portion at 08C. The reaction mix-
ture was stirred for 2 h at RT and diluted with ethyl acetate (20 mL) fol-
lowed by addition of saturated NH4Cl solution (20 mL) and stirred for
12 h in order to decompose excess para-methoxybenzyl bromide. The or-
ganic phase was separated and the aqueous layer was further extracted
with ethyl acetate (3ꢃ20 mL) and the combined organic layers were
washed with brine, dried over Na2SO4, filtered, and evaporated. The
crude product was purified by column chromatography using 10–20% of
ethyl acetate/hexanes as eluent to afford the corresponding PMB-ether
(1.75 g, 87%) as a colorless oil. Rf =0.74 (20% ethyl acetate/hexanes);
½aꢁ2D5 =ꢀ1.67 (c=0.80, CHCl3); IR (neat): n˜ =1614, 1514, 1471, 1462,
To a stirred solution of ester 54 (340 mg, 0.81 mmol) in dry CH2Cl2
(8 mL) was added a solution of DIBAL-H (2.0 mL, 2.0 mmol, 1m solu-
tion in toluene) at ꢀ788C. After being stirred at same temperature for
1 h, the reaction mixture was quenched with saturated solution of potassi-
um-sodium-tartrate (5 mL), and stirred for 3 h at RT and extracted with
CH2Cl2 (3ꢃ50 mL). The organic layer was washed with brine, dried over
Na2SO4, concentrated, and the crude product was purified by flash
column chromotography (50–70% ethyl acetate/hexanes) to afford the
alcohol 62 (270 mg, 88%) as colorless oil. Rf =0.18 (50% ethyl acetate/
hexanes); ½aꢁ2D5 =ꢀ7.34 (c=0.88, CHCl3); IR (neat): n˜ =3445, 2930, 1612,
1514, 1248, 1036, 931 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.24 (d, J=
;
8.5 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.80 (ddd, J=17.4, 10.7, 7.6 Hz,
1H), 5.69–5.57 (m, 2H), 5.34–5.27 (m, 2H), 4.83 (d, J=7.0 Hz, 1H), 4.76
(d, J=7.0 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 4.29 (d, J=11.6 Hz, 1H),
4.06 (s, 2H), 3.83–3.81 (m, 1H), 3.80 (s, 3H), 3.77–3.60 (m, 3H), 3.51 (t,
J=4.5 Hz, 2H), 3.37 (s, 3H), 2.15–1.99 (m, 2H), 1.74–1.61 (m, 1H), 1.56–
1.47 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=159.0, 135.2, 132.4,
130.4, 129.3, 118.6, 95.8, 81.3, 78.9, 71.6, 70.0, 67.2, 63.5, 58.9, 55.1, 30.1,
28.0 ppm; HRMS (ESI-TOF): calcd. for C21H32O6Na m/z 403.2097, found
m/z 403.2104.
1250, 1099, 1039, 836 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.23 (d, J=
;
8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.79 (ddd, J=17.1, 10.4, 7.6 Hz,
1H), 5.32–5.26 (m, 2H), 4.84 (d, J=7.0 Hz, 1H), 4.77 (d, J=7.0 Hz, 1H),
4.55 (d, J=11.3 Hz, 1H), 4.30 (d, J=11.4 Hz, 1H), 3.80 (s, 3H), 3.71 (q,
J=4.6 Hz, 2H), 3.57 (t, J=5.8 Hz, 2H), 3.50 (t, J=4.8 Hz, 2H), 3.37 (s,
3H), 1.69–1.42 (m, 6H), 0.88 (s, 9H), 0.03 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=159.0, 135.5, 130.6, 129.2, 118.5, 113.6, 95.8, 81.8,
79.5, 71.7, 70.1, 67.1, 63.1, 58.9, 55.2, 28.7, 27.1, 25.9, 18.2, ꢀ5.4 ppm;
HRMS (ESI-TOF): calcd. for C25H44O6SiNa m/z 491.2805, found m/z
491.2828.
To a stirred suspension of MnO2 (160 mg, 1.85 mmol) in dry CH2Cl2
(4 mL), a solution of alcohol 62 (70 mg, 0.185 mmol) in CH2Cl2 (2 mL)
was added dropwise and stirred for 2 h at RT. The mixture was filtered
through a pad of Celite and filtrate was concentrated in vacuo to afford a
crude aldehyde 21 (150 mg, 92%) which was used in the next step with-
out further purification. Rf =0.51 (50% ethyl acetate/hexanes).
To a stirred solution of above TBS-ether (1.68 g, 3.4 mmol) in THF
(10 mL) at 08C was added TBAF (5.8 mL, 5.8 mmol, 1m in THF) and
then allowed to stir at RT for 2 h. The reaction mixture was concentrated
and purified by silica gel column chromatography (50–70% ethyl acetate/
hexanes) to afford the alcohol 53 (0.97 g, 88%) as colorless oil. Rf =0.14
(50% ethyl acetate/hexanes); ½aꢁ2D5 =ꢀ13.98 (c=0.73, CHCl3); IR (neat):
Compound 58
To a stirred suspension of NaH (470 mg, 11.7 mmol, 60% in mineral oil)
in DMF (1 mL) at 08C was added dropwise a solution of alcohol 57
(1.3 g, 5.32 mmol). After stirring for 20 min at 08C, a freshly prepared
para-methoxybenzyl bromide (1.5 mL, 10.7 mmol) was added in one por-
tion at the same temperature. The reaction mixture was stirred for 1 h at
RT and diluted with ethyl acetate (20 mL) followed by addition of a satu-
rated NH4Cl solution (15 mL). The organic phase was separated and the
aqueous layer was further extracted with ethyl acetate (3ꢃ15 mL). The
combined organic layers were washed with brine, dried over Na2SO4, fil-
tered, and evaporated. The crude product was purified by flash column
chromatography (5–10% ethyl acetate/hexanes) to afford the compound
58 (1.6 g, 82%) as colorless oil. Rf =0.75 (10% ethyl acetate/hexanes);
½aꢁ2D5 =ꢀ24.4 (c=0.80, CHCl3); IR (neat): n˜ =2932, 2857, 1614, 1514,
n˜ =3417, 2931, 2712, 1613, 1248, 1036, 931 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.23 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.79 (ddd,
J=17.1, 10.7, 7.6 Hz, 1H), 5.34–5.28 (m, 2H), 4.87 (d, J=7.0 Hz, 1H),
4.77 (d, J=7.0 Hz, 1H), 4.56 (d, J=11.3 Hz, 1H), 4.29 (d, J=11.6 Hz,
1H), 3.84–3.49 (m, 1H), 3.38 (s, 3H), 1.7–1.47 ppm (m, 4H); 13C NMR
(100 MHz, CDCl3): d=158.9, 135.1, 130.4, 129.2, 118.7, 113.6, 95.9, 81.7,
79.5, 71.7, 70.1, 67.2, 62.6, 58.9, 55.1, 28.4, 27.1 ppm; HRMS (ESI-TOF):
calcd. for C19H30O6Na m/z 377.1940, found m/z 377.1923.
Compound 54
To a stirred solution of alcohol 53 (55 mg, 0.15 mmol) in CH2Cl2 (3 mL)
at 08C was added DMP (130 mg, 0.31 mmol) in a single portion. The re-
action mixture was stirred for 3 h at RT. It was then quenched with satu-
rated NaHCO3 (2 mL, containing 0.5 g of Na2S2O3) and the crude alde-
hyde was isolated by extraction with CH2Cl2 (2ꢃ10 mL). The organic ex-
tracts were washed with brine, dried over Na2SO4, and concentrated
1249, 1100, 1039, 836 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.25 (d, J=
;
8.3 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.72 (ddd, J=17.1, 10.4, 7.6 Hz,
1H), 5.23–5.17 (m, 2H), 4.52 (d, J=11.3 Hz, 1H), 4.28 (d, J=11.6 Hz,
1H), 3.80 (s, 3H), 3.69 (q, J=6.7 Hz, 1H), 3.58 (t, J=6.4 Hz, 2H), 1.65–
1.60 (m, 1H), 1.52–1.33 (m, 5H), 0.89 (s, 9H), 0.03 ppm (s, 6H);
3148
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 3137 – 3151

Formal Total Synthesis of Palmerolide A
13C NMR (100 MHz, CDCl3): d=158.9, 139.1, 130.8, 129.2, 116.9, 113.6,
80.2, 69.6, 63.0, 55.1, 35.2, 32.6, 25.9, 21.6, 18.3, ꢀ5.3 ppm; HRMS (ESI-
TOF): calcd. for C21H36O3SiNa m/z 387.2331, found m/z 387.2354.
Compound 63
To stirred solution of triphenylphosphine (105 mg, 0.39 mmol), 1-
a
phenyl-1H-tetrazole-5-thiol (57 mg, 0.31 mmol) and alcohol 62 (100 mg,
0.26 mmol) in anhydrous THF (5 mL) was added DIAD (80 mL,
0.39 mmol) at 08C. The solution was stirred at the same temperature for
2 h. The solvent was evaporated to one fourth of its volume under
vacuum and the resultant residue was treated with saturated solution of
NaHCO3 (5 mL) and diluted with ethyl acetate (10 mL). The organic
layer was separated and the aqueous layer was extracted with ethyl ace-
tate (3ꢃ10 mL). The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated. The crude product was purified by
flash column chromatography (5–15% ethyl acetate/hexanes) to give 63
(120 mg, 86%). Rf =0.25 (20% ethyl acetate/hexanes); ½aꢁ2D5 =ꢀ0.70 (c=
0.63, CHCl3); IR (neat): n˜ =1613, 1514, 1500, 1386, 1247, 1174, 1111,
Compound 59
To a solution of silyl ether 58 (1.50 g, 4.12 mmol) in THF (20 mL) was
added TBAF (8.5 mL, 8.5 mmol, 1m in THF) at 08C. After being stirred
at RT for 2 h, the reaction mixture was concentrated and purified by
flash chromatography (40–50% ethyl acetate/hexanes) to afford alcohol
59 (1.04 g, 96%) as a colorless oil. Rf =0.28 (30% ethyl acetate/hexanes);
½aꢁ2D5 =ꢀ35.17 (c=0.78, CHCl3); IR (neat): n˜ =3401 (b), 2937, 2861, 1612,
1513, 1248, 1173, 1034, 927 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.25
;
(d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 5.73 (ddd, J=17.1, 10.4,
7.9 Hz, 1H), 5.24–5.18 (m, 2H), 4.52 (d, J=11.6 Hz, 1H), 4.27 (d, J=
11.3 Hz, 1H), 3.74–3.68 (m, 1H), 3.62 (t, J=6.4 Hz, 2H), 1.69–1.37 ppm
(m, 6H); 13C NMR (100 MHz, CDCl3): d=158.9, 138.9, 130.6, 129.3,
117.0, 113.6, 80.0, 69.6, 62.6, 55.2, 35.0, 32.4, 21.4 ppm; HRMS (ESI-
TOF): calcd. for C15H22O3Na m/z 273.1467, found m/z 273.1463.
1036, 762 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.73–7.50 (m, 5H), 7.22
;
(d, J=8.5 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.78 (ddd, J=17.8, 10.8,
7.5 Hz, 1H), 5.64–5.55 (m, 1H), 5.34–5.24 (m, 2H), 4.81 (d, J=7.0 Hz,
1H), 4.74 (d, J=7.0 Hz, 1H), 4.55 (d, J=11.3 Hz, 1H), 4.28 (d, J=
11.6 Hz, 1H), 3.98 (d, J=7.3 Hz, 2H), 3.84–3.80 (m, 1H), 3.79 (s, 3H),
3.78–3.65 (m, 2H), 3.64–3.52 (m, 1H), 3.49 (t, J=4.6 Hz, 2H), 3.36 (s,
3H), 2.15–1.95 (m, 2H), 1.76–1.25 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=159.0, 153.8, 136.5, 135.1, 133.6, 130.4, 129.9, 129.6, 129.2,
124.2, 123.8, 123.7, 123.1, 118.6, 113.6, 95.8, 81.2, 79.0, 71.6, 70.0, 67.2,
58.9, 55.1, 35.4, 29.8, 28.1, 21.8 ppm; HRMS (ESI-TOF): calcd. for
C26H36O5N4SNa m/z 563.2304, found m/z 563.2289.
Compound 60
Anhydrous DMSO (630 mL, 8.85 mmol) was added dropwise to a cold
(ꢀ788C) solution of oxalylchloride (630 mL, 7.2 mmol) in dry CH2Cl2
(14 mL) and stirred for 15 min. A solution of the alcohol 59 (1.0 g,
4.0 mmol) in dry CH2Cl2 (7 mL) was added dropwise and stirred at
ꢀ788C for 30 min. Et3N (2.8 mL, 20 mmol) was added to the reaction
mixture and stirred at ꢀ788C for 5 min and then it was allowed to warm
to 08C over 20 min. The reaction mixture was quenched with water and
extracted with CH2Cl2 (3ꢃ10 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated to afford a
crude aldehyde (1.0 g) as pale yellow oil.
Compound 64
To a solution of 63 (120 mg, 0.22 mmol) in 750 mL of ethanol at 08C was
added ammonium heptamolybdate tetrahydrate (28 mg, 0.022 mmol) and
H2O2 (130 mL, 30% w/v aq. solution). The reaction mixture was stirred at
RT for 12 h and quenched with 10% aq. solution of Na2SO3 (5 mL). Eth-
anol was distilled off and the aqueous layer was extracted with dichloro-
methane (3ꢃ10 mL). The combined organic layer was washed with brine,
dried over Na2SO4 and evaporated. The residue was purified by flash
chromatography (20–30% ethyl acetate/hexanes) to give sulfone 64
(70 mg, 55%) as a pale yellow oil. Rf =0.20 (20% ethyl acetate/hexanes);
½aꢁ2D5 =ꢀ1.03 (c=1.28, CHCl3); IR (neat): n˜ =2928, 1966, 1514, 1498,
To a stirred solution of the above aldehyde (1.0 g, 3.95 mmol) in CH2Cl2
(15 mL) was added carboethoxymethylenetriphenyl phosphorane (2.1 g,
6.0 mmol) at RT. The mixture was stirred for 5 h and then concentrated
in vacuo. The residue was purified by column chromatography (15–30%
ethyl acetate/hexanes) to provide the ester 60 (1.05 g, 91% for 2 steps) as
colorless oil. Rf =0.33 (20% ethyl acetate/hexanes); ½aꢁ2D5 =ꢀ29.21 (c=
0.50, CHCl3); IR (neat): n˜ =2924, 2852, 1720, 1653, 1514, 1464, 1248,
1173, 1038 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.25 (d, J=8.6 Hz,
;
1346, 1248, 1153, 1036, 930, 822 cmꢀ1 1H NMR (400 MHz, CDCl3): d=
;
2H), 6.93 (dt, J=15.6, 7.0 Hz, 1H), 6.88 (d, J=8.6 Hz, 2H), 5.79 (dt, J=
15.6, 1.5 Hz, 1H), 5.71 (ddd, J=17.4, 10.4, 7.9 Hz, 1H), 5.25–5.18 (m,
2H), 4.52 (d, J=11.3 Hz, 1H), 4.26 (d, J=11.6 Hz, 1H), 3.80 (s, 3H),
3.72–3.67 (m, 1H), 2.17 (q, J=6.7 Hz, 2H), 1.63–1.47 (m, 4H), 1.28 ppm
(t, J=4.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166, 158.9, 148.3,
138.8, 130.6, 129.2, 121.3, 117.0, 113.6, 79.6, 69.6, 59.9, 55.1, 34.8, 31.8,
23.7, 14.1 ppm; HRMS (ESI-TOF): calcd. for C19H26O4Na m/z 341.1729,
found m/z 341.1722.
7.73–7.55 (m, 5H), 7.22 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.93
(dt, J=15.6, 6.7 Hz, 1H), 5.77 (ddd, J=17.6, 10.7, 7.6 Hz, 1H), 5.50–5.43
(m, 1H), 5.33–5.25 (m, 2H), 4.79 (d, J=7.0 Hz, 1H), 4.73 (d, J=7.0 Hz,
1H), 4.54 (d, J=11.6 Hz, 1H), 4.35 (d, J=7.0 Hz, 2H), 4.28 (d, J=
11.3 Hz, 1H), 3.81–3.78 (m, 1H), 3.79 (s, 3H), 3.58–3.51 (m, 1H), 3.49 (t,
J=4.9 Hz, 2H), 2.19–2.01 (m, 2H), 1.68–1.45 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=159.0, 153.0, 144.4, 135.0, 132.9, 131.3, 130.3,
129.5, 129.3, 125.1, 118.7, 113.6, 113.1, 95.9, 81.1, 78.9, 71.6, 70.0, 67.3,
59.6, 58.8, 55.1, 29.4, 28.6 ppm; HRMS (ESI-TOF): calcd. for
C28H36O7N4SNa m/z 595.2202, found m/z 595.2193.
Compound 22
A solution of compound 60 (300 mg, 0.94 mmol) in THF/MeOH/H2O
(1:1:2, 6 mL) was treated with LiOH (120 mg, 2.86 mmol) at RT. The re-
action mixture was stirred at the same temperature for 4 h, and solvents
were removed in vacuo. The aqueous phase was washed with diethyl
ether and the aqueous layer was acidified with 10% aq. citric acid, and
extracted with ethyl acetate (3ꢃ5 mL). The combined organic extracts
were dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The resultant acid was purified by silica gel column chromatography
(20–40% ethyl acetate/hexanes) to afford the acid 22 (250 mg, 90%) as a
colorless viscous oil. Rf =0.25 (20% ethyl acetate/hexanes); ½aꢁ2D5 =ꢀ31.9
(c=0.55, CHCl3); IR (neat): n˜ =1697, 1652, 1613, 1513, 1248, 1036,
Compound 75
To a solution of 53 (500 mg, 1.42 mmol), triphenylphosphine (560 mg,
2.12 mmol) and 1- phenyl-1H-tetrazole-5-thiol 36 (300 mg, 1.70 mmol) in
dry THF (20 mL) at 08C was added DIAD (420 mL, 2.12 mmol) drop-
wise. The reaction mixture was stirred at the same temperature for 2 h,
then quenched with saturated NaHCO3 solution and extracted with ethyl
acetate (3ꢃ10). The combined organic extracts were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. Purifica-
tion by chromatography on silica gel (20–30% ethyl acetate/hexanes)
gave 75 (650 mg, 89%) as a colorless viscous oil. Rf =0.40 (20% ethyl
acetate/hexanes); ½aꢁ2D5 =ꢀ4.75 (c=0.85, CHCl3); IR (neat): n˜ =2927,
821 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.25 (d, J=8.5 Hz, 2H), 7.05
;
(dt, J=15.6, 6.7 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 5.79 (dt, J=15.6,
1.5 Hz, 1H), 5.72 (ddd, J=17.1, 10.4, 7.9 Hz, 1H), 5.25–5.5.18 (m, 2H),
4.53 (d, J=11.6 Hz, 1H), 4.26 (d, J=1.6 Hz, 1H), 3.80 (s, 3H), 3.79–3.67
(m, 1H), 2.22–2.17 (m, 2H), 1.66–1.47 ppm (m, 4H); 13C NMR
(100 MHz, CDCl3): d=171.7, 159.1, 151.9, 138.8, 130.6, 129.4, 120.7,
117.3, 113.7, 79.6, 69.6, 55.2, 34.8, 32.0, 23.7 ppm; HRMS (ESI-TOF):
calcd. for C17H22O4Na m/z 313.1416, found m/z 313.1415.
1613, 1514, 1500, 1387, 1247, 1037, 931, 762 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.58–7.51 (m, 5H), 7.22 (d, J=8.6 Hz, 2H), 6.85 (d, J=
8.6 Hz, 2H), 5.79 (ddd, J=18.0, 10.7, 7.6 Hz, 1H), 5.33–5.27 (m, 2H),
4.83 (d, J=7.0 Hz, 1H), 4.75 (d, J=7.3 Hz, 1H), 4.55 (d, J=11.6 Hz,
1H), 4.27 (d, J=11.6 Hz, 1H), 3.83–3.51 (m, 4H), 3.78 (s, 3H), 3.49 (t,
J=4.6 Hz, 2H), 3.42–3.17 (m, 2H), 3.35 (s, 3H), 1.93–1.54 ppm (m, 4H);
13C NMR (100 MHz, CDCl3): d=159.1, 154.2, 135.0, 133.7, 130.3, 129.9,
129.6, 129.3, 123.7, 118.8, 113.6, 95.8, 81.2, 78.9, 71.6, 70.1, 67.3, 58.8, 55.1,
Chem. Asian J. 2011, 6, 3137 – 3151
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
3149

K. P. Kaliappan et al.
FULL PAPERS
33.2, 29.6, 25.1 ppm; HRMS (ESI-TOF): calcd. for C26H35O5N4SNa m/z
515.2328, found m/z 515.2328.
4.56 (d, J=11.3 Hz, 1H), 4.29 (d, J=11.6 Hz, 1H), 4.07 (s, 2H), 3.83–3.75
(m, 1H), 3.79 (s, 3H), 3.72 (q, J=4.6 Hz, 2H), 3.68–3.61 (m, 1H), 3.55–
3.38 (m, 1H), 3.51 (t, J=4.9 Hz, 2H), 3.37 (s, 3H), 2.50–2.44 (m, 1H),
2.32 (d, J=13.4 Hz, 1H), 2.22–2.04 (m, 2H), 1.94 (dd, J=13.8, 10.4 Hz,
1H), 1.76–1.49 (m, 2H), 1.73 (s, 3H), 1.62 (s, 3H), 1.06 (s, 9H), 1.04 ppm
(d, J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=159.0, 135.5, 135.3,
134.6, 133.9, 133.8, 133.1, 132.8, 130.5, 129.5, 129.3, 127.8, 127.6, 126.7,
126.5, 118.7, 113.6, 95.9, 81.4, 79.2, 73.0, 71.7, 70.0, 68.8, 67.2, 58.9, 55.1,
45.5, 38.2, 30.5, 28.8, 26.8, 19.3, 16.7, 16.5, 13.9 ppm; HRMS (ESI-TOF):
calcd. for C47H66O7SiNa m/z 793.4476, found m/z 793.4460.
Compound 66
To a solution of 75 (530 mg, 1.03 mmol) in EtOH (3.5 mL) were added
ammonium heptamolybdate tetrahydrate (128 mg, 0.103 mmol) and 30%
H2O2 (600 mL) at 08C and the mixture was stirred for 12 h at RT. The re-
action mixture was diluted with 10% aqueous Na2S2O3, ethanol was con-
centrated under reduced pressure and the aqueous layer was extracted
with ethyl acetate (3ꢃ15 mL). The organic layer was washed with brine,
dried over Na2SO4, and evaporated to give a crude residue, which was
purified by flash chromatography (20% ethyl acetate/hexanes) to deliver
the sulfone 66 (520 mg, 91%) as colorless viscous oil. Rf =0.40 (20%
ethyl acetate/hexanes); ½aꢁD25 =ꢀ7.34 (c=0.88, CHCl3); IR (neat): n˜ =
Compound 78
A mixture of compound 22 (110 mg, 0.38 mmol), 2,4,6-trichlorobenzoyl
chloride (60 mL, 0.38 mmol) and Et3N (100 mL, 0.68 mmol) in toluene
(1.5 mL) was stirred at rt for 2 h to give a solution of mixed anhydride.
This solution (600 mL) was then added to a solution of compound 77
(110 mg, 0.14 mmol) and DMAP (36 mg, 0.30 mmol) in toluene (2 mL)
under argon atmosphere at RT and stirred for 2 h. The reaction mixture
was quenched with water and the mixture was extracted with ethyl ace-
tate (3ꢃ10 mL). The combined organic layers were dried and concentrat-
ed to afford a residue that was purified by column chromatography (15–
25% ethyl acetate/hexanes) to afford the ester 78 (105 mg, 67%) as a vis-
cous oil. Rf =0.46, (20% ethyl acetate/hexanes); ½aꢁ2D5 =ꢀ5.54 (c=0.48,
2931, 2890, 1613, 1514, 1498, 1463, 1342, 1248, 1153, 1036, 764 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.73–7.65 (m, 2H), 7.63–7.55 (m, 3H),
7.22 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.77 (ddd, J=17.7, 10.7,
7.3 Hz, 1H), 5.36–5.29 (m, 2H), 4.85 (d, J=7.0 Hz, 1H), 4.75 (d, J=
7.3 Hz, 1H), 4.55 (d, J=11.3 Hz, 1H), 4.28 (d, J=11.6 Hz, 1H), 3.84 (dd,
J=6.7, 0.6 Hz, 1H), 3.79 (s, 3H), 3.77–3.61 (m, 5H), 3.48 (t, J=4.6 Hz,
2H), 3.35 (s, 3H), 2.08–1.92 (m, 2H), 1.82–1.74 (m, 1H), 1.66–1.58 ppm
(m, 1H); 13C NMR (100 MHz, CDCl3): d=158.9, 153.2, 134.5, 132.8,
131.2, 130.0, 129.4, 129.1, 124.8, 120.9, 119.0, 113.5, 95.8, 81.0, 78.4, 71.4,
70.0, 67.3, 58.7, 55.6, 54.9, 28.9, 18.2 ppm; HRMS (ESI-TOF): calcd. for
C26H35O7N4SNa m/z 569.2046, found m/z 569.2023.
CHCl3); IR (neat): n˜ =3071, 2930, 2857, 1716, 1514, 1249, 1038, 823 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.70–7.65 (m, 4H), 7.44–7.35 (m, 6H),
7.27–7.22 (m, 4H), 6.89–6.82 (m, 5H), 6.15 (dd, J=14.9, 10.7 Hz, 1H),
5.84–5.66 (m, 4H), 5.50–5.43 (m, 4H), 5.36–5.17 (m, 5H), 4.98–4.93 (m,
1H), 4.83 (d, J=7.0 Hz, 1H), 4.77 (d, J=7.0 Hz, 1H), 4.55 (d, J=
11.6 Hz, 1H), 4.51 (d, J=11.6 Hz, 1H), 4.27 (d, J=12.2 Hz, 1H), 4.25 (d,
Compound 76
A solution of sulfone 66 (490 mg, 0.89 mmol) and aldehyde 65 (400 mg,
0.81 mmol) in anhydrous THF (4 mL) was cooled to ꢀ788C. To this, a so-
lution of freshly prepared LiHMDS (0.5m in THF, 5.2 mL, 2.6 mmol) was
added. After being stirred for 1 h at ꢀ788C, the reaction was quenched
with water and extracted with ethyl acetate (4ꢃ15 mL). The combined
organic extract was dried over Na2SO4 and purified by silica gel column
chromatography (20–40% ethyl acetate/hexanes) to afford the diene 76
(360 mg, 60%) as a colorless viscous material. Rf =0.48 (20% ethyl ace-
tate/hexanes); ½aꢁ2D5 =+1.43 (c=0.63, CHCl3); IR (neat): n˜ =2930, 2857,
J=11.9 Hz, 1H), 4.04 (s, 2H), 3.84–3.75ACHTNUTGRNEUNG(m, 1H), 3.79 (s, 3H), 3.79 (s,
3H), 3.74–3.54 (m, 4H), 3.49 (t, J=4.3 Hz, 2H), 3.36 (s, 3H), 2.69–2.64
(m, 1H), 2.32 (dd, J=14.4, 4.0 Hz, 1H), 2.26–1.98 (m, 5H), 1.83–1.42 (m,
6H), 1.72 (s, 3H), 1.57 (s, 3H), 1.05 (s, 9H), 0.96 ppm (d, J=6.7 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=116.2, 159.0, 148.6, 138.9, 135.4,
135.3, 134.7, 133.8, 133.7, 132.3, 132.1, 130.7, 130.5, 129.5, 129.3, 129.2,
127.6, 126.8, 125.7, 121.5, 118.6, 117.1, 113.7, 113.6, 95.9, 81.4, 79.7, 79.2,
77.3, 77.1, 75.7, 71.6, 70.0, 69.6, 68.6, 67.2, 58.9, 55.2, 55.1, 42.3, 35.7, 34.9,
31.9, 30.6, 28.8, 26.8, 23.8, 19.2, 16.7, 16.6, 13.8 ppm; HRMS (ESI-TOF):
calcd. C64H86O10SiNa for m/z 1065.5888, found m/z 1065.5919.
1
1736, 1613, 1514, 1372, 1246, 1112, 1039, 824, 705 cmꢀ1; H NMR (CDCl3,
400 MHz): d=7.71–7.66 (m, 4H), 7.44–7.35 (m, 6H), 7.24 (d, J=8.5 Hz,
2H), 6.86 (d, J=8.5 Hz, 2H), 6.16 (dd, J=14.9, 10.9 Hz, 1H), 5.85–5.73
(m, 2H), 5.50 (dt, J=14.3, 6.7 Hz, 1H), 5.35–5.27 (m, 2H), 4.93–4.88 (m,
1H), 4.84 (d, J=7.0 Hz, 1H), 4.78 (d, J=7.0 Hz, 1H), 4.55 (d, J=
11.6 Hz, 1H), 4.29 (d, J=11.6 Hz, 1H), 4.05 (s, 2H), 3.84–3.61 (m, 5H),
3.51 (t, J=4.9 Hz, 2H), 3.37 (s, 3H), 2.67–2.61 (m, 1H), 2.28 (dd, J=
13.7, 2.8 Hz, 1H), 2.18–1.94 (m, 3H), 1.98 (s, 3H), 1.74–1.49 (m, 2H),
1.72 (s, 3H), 1.59 (s, 3H), 1.06 (s, 9H), 0.96 ppm (d, J=6.7 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=170.5, 159.0, 135.4, 135.3, 134.9, 133.8,
133.7, 132.3, 132.2, 130.5, 129.6, 129.3, 127.6, 126.9, 125.6, 118.6, 113.6,
95.9, 81.4, 79.2, 75.7, 71.7, 70.1, 68.5, 67.2, 58.9, 55.2, 42.6, 35.8, 30.5, 28.7,
26.7, 20.9, 16.7, 16.6, 16.5, 13.8 ppm; HRMS (ESI-TOF): calcd. for
C49H68O8SiNa m/z 835.4581 found m/z 835.4594.
Acknowledgements
We thank the DST, New Delhi and SAIF, IIT Bombay for financial sup-
port and the use of spectral facilities, respectively. KPK thanks the DST
for the award of a Swarnajayanti fellowship. P.G. and S.A.P. thank the
CSIR, New Delhi, for a fellowship.
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Compound 77
To a solution of acetate 76 (320 mg, 0.40 mmol) in CH2Cl2 (10 mL) was
added DIBAL-H (1.18 mL, 1.18 mmol, 1m in toluene) at ꢀ788C. The so-
lution was stirred at the same temperature for 2 h. The reaction mixture
was treated with a saturated solution of sodium potassium tartarate
(5 mL) and the mixture was stirred until the solution became clear. The
organic layer was separated from the reaction mixture and the aqueous
layer was extracted with ethyl acetate (3ꢃ10 mL). The combined organic
extracts were washed with water, brine, and dried over Na2SO4. Concen-
tration of the solution followed by column purification on silica gel (20–
30% ethyl acetate/hexanes) afforded the alcohol 77 (220 mg, 78%) as a
viscous oil. Rf =0.40 (20% ethyl acetate/hexanes); ½aꢁ2D5 =+4.10 (c=0.60,
CHCl3); IR (neat): n˜ =3469 (b), 2930, 2857, 1612, 1514, 1462, 1249, 1112,
1037, 824, 704 cmꢀ1;1H NMR (400 MHz, CDCl3): d=7.69–7.66 (m, 4H),
7.44–7.35 (m, 6H), 7.24 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 6.22
(dd, J=14.9, 10.9 Hz, 1H), 5.86–5.76 (m, 2H), 5.57 (dt, J=14.9, 6.7 Hz,
1H), 5.35–5.27 (m, 3H), 4.84 (d, J=7.0 Hz, 1H), 4.78 (d, J=7.0 Hz, 1H),
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Chem. Asian J. 2011, 6, 3137 – 3151

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Received: May 3, 2011
Published online: September 13, 2011
Chem. Asian J. 2011, 6, 3137 – 3151
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
3151