Total synthesis of pseudolaric acid A

Article abstract of DOI:10.1002/anie.200602056

(Chemical Equation Presented) The antiangiogenic and cytotoxic natural product pseudolaric acid A ((-)-1) has been obtained by a 26-step synthetic route. This enantioselective synthesis employed an intramolecular carbene cyclization cycloaddition cascade

Full text of DOI:10.1002/anie.200602056

Angewandte
Chemie
Total Synthesis
DOI: 10.1002/anie.200602056
Total Synthesis of Pseudolaric Acid A**
Scheme 1. Pseudolaric acid A (1), R=Me; pseudolaric acid B( 2),
R=CO2Me
Zhe Geng, Bin Chen, and Pauline Chiu*
The pseudolaric acids A and B, first isolated in 1965, are the
main biologically active constituents of tujinpi, a traditional
Chinese medicinal herb in use since the 17th century for the
treatment of dermatological fungal infections.[1] This medic-
inal preparation is harvested from the root bark of the tree
Pseudolarix kaempferi Gordon (Pinaceae). The antifertile,
antifungal, and cytotoxic properties of the pseudolaric acids
have been recognized for quite some time.[2] However, the
past few years have seen a resurgence of interest in these
natural products for several reasons. The pseudolaric acids
were identified as a new class of peroxisome proliferator-
activated receptor (PPAR) agonists.[3] Additionally, pseudo-
laric acid B was found to activate c-Jun N-terminal kinase and
caspase-3 in HeLa cells.[4] Studies recently disclosed the
antiangiogenic effects of both pseudolaric acid A and B.[5,6]
Our own studies revealed that pseudolaric acids A and B
inhibit tubulin polymerization in vitro.[7] The resultant anti-
mitotic activity and disruption of normal microtubule assem-
bly appears to be their mode of anticancer action. Notably,
pseudolaric acid B is able to circumvent the action of the P-
glycoprotein (Pgp) efflux pump, which is responsible for the
acquired resistance to many tubulin-binding agents, which
allows pseudolaric acid B to maintain its activity, even on
some multidrug-resistant cancers. We have further demon-
strated the in vivo antitumor effects of pseudolaric acid B
towards a liver cancer resistant to taxol in a murine xenograft
model.
acetoxy group at the fused-ring junction is an unusual
arrangement in natural perhydroazulenes, but is a represen-
tative structural feature of this family of compounds. The
central d-lactone is characterized by contiguous quaternary or
tertiary stereocenters at all four tetrahedral carbon atoms. All
of these structural elements congested within a relatively
small space constitute the synthetic challenge at hand. The
biological activity and molecular architecture of the pseudo-
laric acids have already attracted a number of synthetic
efforts.[8–11] Herein, we describe our studies on pseudolaric
acid A, which culminated in the first total synthesis of this
natural product.[12]
Our retrosynthetic strategy towards pseudolaric acid A
(1) is illustrated in Scheme 2, in which cleavage of the lactone
ꢀ
functionality and a Wittig-type disconnection at C13 C14
Structurally, the pseudolaric acids are novel diterpenoids
with a highly oxygenated perhydroazulene skeletal frame-
work (Scheme 1). The trans arrangement of the lactone and
Scheme 2. Retrosynthetic analysis of pseudolaric acid A. HWE=
Horner–Wadsworth–Emmons; CCCC=carbene cyclization cycloaddi-
tion cascade; PG, PG’, PG’’=protecting groups.
[*] Z. Geng, B. Chen, Prof. Dr. P. Chiu
Department of Chemistry and
Open Laboratory of Chemical Biology
Institute of Molecular Technology for Drug Discovery and Synthesis
The University of Hong Kong
Pokfulam Road, Hong Kong (P.R. China)
Fax: (+852)2857-1586
E-mail: pchiu@hku.hk
Homepage: http://chem.hku.hk/~chemhome/staff/pchiu/
pchiu.htm
yields the stereochemically loaded aldehyde 3. Redox inter-
conversions at C11 and C19, and a crucial reductive cleavage
reveal key oxatricyclic intermediate 4 as the precursor. In this
way, the tertiary hydroxy acetate/hydroxy group at C4 is
protected from dehydration and other side reactions in the
form of the oxygen bridge. This oxatricyclic intermediate 4
could be obtained through an intramolecular carbene cycli-
zation cycloaddition cascade (CCCC) reaction of acyclic
diazoketone 5.[13–15] This reaction would be the key step in the
construction of the stereochemically defined perhydroazu-
lene platform in the present synthetic strategy.[16] Diazo-
ketone 5 could be constructed from three carbon fragments,
as shown. The stereochemically defined southern portion of
diazoketone 5 could be obtained from an Evans catalytic
[**] The work was supported by the Research Grants Council of Hong
Kong SAR, P.R. China (Project No. HKU 7017/04P), the Areas of
Excellence Scheme (Project No. AoE/P-10/01) administered by the
University Grants Committee (HKSAR), and The University of Hong
Kong. B.C. acknowledges the award of a postgraduate student
exchange scholarship from the University of Hong Kong. We thank
Prof. G. W. Qin of the Shanghai Institute of Materia Medica for a
sample of pseudolaric acid A, and W.-T. Ma and Prof. Z. Cai (HKBU)
for obtaining high-resolution mass spectra.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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asymmetric aldol reaction,[17] another key reaction in this total
synthesis.
Following this retrosynthetic analysis, and based on results
Protection of the newly generated tertiary alcohol was
achieved using TBSOTf to give 12.
Direct homologation of thioester 12 was surprisingly
difficult. Nucleophilic addition to the thioester functionality
was hampered by branching at the b carbon atom, and further
complicated by the competitive reactivity of the proximate
carbomethoxy functional group. Although the more reactive
aldehyde derivative 13 could be obtained from thioester 12
through a Fukuyama reduction,[20] homologation of this
substrate also failed. Under more forcing conditions, side
products arose, apparently from reaction of both the ester and
the aldehyde.[21] To circumvent these problems, the interfering
ester functionality was removed by reduction. Direct treat-
ment of 11 with LAH resulted in a significant portion of the
hydroxyketone undergoing a retroaldol reaction. Therefore,
the protected aldol 12 was subjected to exhaustive reduction
instead. This reaction resulted in migration of the TBS group
and led to isolation of a mixture of diols. However, after
desilylation a single triol 14 was obtained as the sole product
in good yield. Treatment of triol 14 with 3,3-dimethoxypen-
tane resulted in the exclusive formation of desired dioxolane
15, in which the alcohol derived from the thioester remained
available for further elaboration.[22] Alcohol 15 was converted
into aldehyde 16 by a Dess–Martin oxidation.
from model studies,[12] we began the synthesis with commer-
cially available allyl dichloride 6. Reaction of 6 with sodium p-
methoxybenzyl alcoholate produced a mixture of substitution
products, the major one being 3-chloro-2-benzyloxymethyl-
propene (7; Scheme 3). Coupling 7 with the zinc homoenolate
derived from methyl 3-iodopropionate smoothly afforded
homologated ester 8,[18] which was subsequently converted
into thioester 10 via acid 9.
The Evans catalytic asymmetric aldol reaction was
employed to introduce the initial stereochemical elements
in the molecule.[17] Thus, 10 was converted into its silyl enol
ether and treated with methyl pyruvate under catalysis by the
[Cu{(S,S)-tBu-box}][OTf]2 complex (Scheme 3). Substrate 10
is one of the more demanding cases for this reaction, because
of the longer alkyl chain, which leads to a more hindered enol
ether derivative. The use of the trimethylsilyl enol ether of 10
gave capricious results in the aldol reaction, but the use of the
triethylsilyl enol ether led to consistent yields of aldol 11,
albeit at a noticeably slower reaction rate. The use of
dichloromethane as the solvent was also critical, since the
conversion rate was low in the more common solvent THF.
The increased reaction rate in dichloromethane is indicative
of a change in the rate-determining step from copper catalyst
decomplexation to aldol condensation. In this manner, aldol
diastereomer 11 bearing vicinal tertiary stereocenters was
synthesized in a yield of 76% and with an ee value of 88%.[19]
Homologation was then attempted on aldehyde 16.
Although aldehyde 16 has steric hindrance comparable to
that in substrate 13, but lacks the electrophilic group at the
b position, it could be smoothly converted into diol 17 in 90%
yield, using the variant of the Grignard reagent ClMgO-
Scheme 3. Reagents and conditions: a) NaH, PMBOH, THF, reflux, 61%; b) ICH2CH2CO2Me, Zn(Cu), CuCN, DMA, THF, 608C, 12 h, 91%;
c) 20% NaOH, MeOH, RT, 4 h, 96%; d) EtSH, DCC, DMAP, CH2Cl2, 3 h, 97%; e) 1. LDA, TESCl, THF, ꢀ788C-RT; 2. [Cu{(S,S)-tBu-box}][OTf]2 ,
methyl pyruvate, CH2Cl2, ꢀ788C, 76%, 88% ee; f) TBSOTf, 2,6-lutidine, CH2Cl2, RT, 97%; g) Et3SiH, Pd/C, CH2Cl2, 81%; h) 1. LAH, THF, 08C, 4 h;
2. TBAF, THF, RT, 2 h; i) 3,3-dimethoxypentane, PTSA, RT, 1 h, 66% from 12; j) Dess–Martin periodinane, CH2Cl2, RT, 88%; k) ClMgO(CH2)3MgCl,
THF, 08C, 90%; l) Swern oxidation, 90%; m) NaClO2, NaH2PO4, tBuOH, 2-methyl-2-butene, RT, 96%; n) 1. iBuOCOCl, Et3N, THF/Et2O, ꢀ20!
08C, 0.5 h; 2. CH2N2, Et2O, 08C–RT, 3 h, 71%; o) 3% [Rh2{(S)-bptv}4], PhCF3, ꢀ408C, 82% yield (50% 21a, 32% 21b). PMB=p-methoxybenzyl,
DMA=N,N-dimethylacetamide, DCC=N,N’-dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine, LDA=lithium diisopropylamide, TES=
triethylsilyl, box=bis(oxazoline), Tf=trifluoromethanesulfonyl, TBS=tert-butyldimethylsilyl, LAH=lithium aluminum hydride, TBAF=tetra-n-
butylammonium fluoride, PTSA=p-toluenesulfonic acid, bptv=a-(tert-butyl)-1,3-dihydro-1,3-dioxo-2H-benz[f]isoindole-2-acetato.
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(CH2)3MgCl reported by Normant et al.[23] Oxidation of both
alcohols was accomplished under Swern conditions, followed
by Lindgren oxidation to cleanly yield ketoacid 19. Activation
with isobutylchloroformate and treatment with diazomethane
by using standard methods[24] afforded diazoketone 20.
With chiral diazoketone 20 in hand, the carbene cycliza-
tion cycloaddition cascade reaction was studied.[14,15] This
transformation would complete the stereochemical configu-
ration of the molecule, as well as assemble the polycyclic
carboskeleton of pseudolaric acid A from acyclic precursor 20
in one step. We have studied various model substrates in the
context of this reaction.[12] With achiral dirhodium catalysts,
the CCCC reaction of 20 was found to favor the formation of
undesired diastereomer 21b. For example, the CCCC reaction
of 20 catalyzed by [Rh2(OAc)4] at 08C in CH2Cl2 generated a
61% yield of a 1:3 mixture of 21a/21b. The preference for this
mode of cycloaddition arose from the unfavorable interac-
tions between the sterically demanding dioxolane and the
PMB ether, which would be syn on the same face of the ring,
in the transition state of the intramolecular cyclcoaddition
leading to 21a . We have examined various factors in this
reaction, including catalysts, solvents, and temperature, and
after optimization found that 3% of the chiral catalyst,
developed by Hashimoto and co-workers, [Rh2{(S)-bptv}4] in
benzotrifluoride at ꢀ408C, afforded the desired isomer 21a as
the major product.[25] Under these conditions, a 82% yield of
the CCCC cycloadducts 21a and 21b was obtained in a ratio
of 1.6:1, which translates to a 50% yield of the desired
diastereomer 21a to carry forward in the total synthesis. Thus,
the remaining two stereocenters and the carbocyclic skeleton
in pseudolaric acid A were efficiently constructed.
Our synthetic strategy was to mask the acetate group in
pseudolaric acid A as an oxygen bridge to prevent dehydra-
tion or elimination side reactions, as observed in previous
approaches. However, the oxabicyclic nucleus turned out to
be quite robust and did not yield easily to reaction.
Exploratory experiments on 21a demonstrated that the
construction of the final ring was difficult, if not impossible,
in the presence of the bridging oxygen atom, because of
rigidification of the carbobicyclic ring system. Thus, cleavage
of the oxygen bridge in 21a proved to be another challenge.
This crucial transformation was finally achieved through a
reductive elimination protocol (Scheme 4).[26] Ketone 21a
was treated with MeMgCl to give alcohol 22 as a single
diastereomer. The diastereoselective syn approach of the
nucleophile with respect to the oxygen bridge is well
established. Conversion of the tertiary alcohol into the
diastereomeric chlorides 23 was achieved using thionyl
chloride. Both diastereomers of 23 underwent reductive
elimination with sodium in refluxing diethyl ether with
concomitant opening of the oxygen bridge to reveal perhy-
droazulene 24 in 78% yield over two steps from 21a. At this
stage, the central nucleus in pseudolaric acid A bearing all of
the required stereocenters in their correct absolute config-
urations had been constructed.
Scheme 4. Reagents and conditions: a) MeMgCl, THF, 08C, 96%;
b) SOCl2, DMPU, 08C–RT; c) Na, Et2O, reflux, 78% over 2 steps from
22; d) DDQ, CH2Cl2/H2O, RT, 86%; e) Dess–Martin periodinane,
CH2Cl2, RT, 91%; f) MeOH, CSA, RT, 95%; g) Dess–Martin periodi-
=
nane, CH2Cl2, RT, 93%; h) (E)-(EtO)2POCH2CH C(CH3)CO2MEM 28,
nBuLi, THF, 83%; i) 60% AcOH, 608C, 1 h; j) Dess–Martin periodi-
nane, CH2Cl2; k) 3n HCl/THF, RT, 66% over 3 steps from 29; l) AcCl,
DMAP, 80%. DMPU=1,3-dimethylhexahydro-2-pyrimidinone,
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, CSA=camphorsul-
fonic acid, MEM=2-(methoxyethoxy)methyl.
Subsequent treatment with camphorsulfonic acid in methanol
to deprotect the diol also induced spontaneous acetalization,
engaging only the tertiary alcohol, to give the mixed acetal 26
in excellent yield as a single diastereomer. With this trans-
formation we had achieved the construction of the final ring
in pseudolaric acid A, opportunely leaving the primary
alcohol free for oxidation to aldehyde 27 by Dess–Martin
periodinane, in preparation for the Wittig homologation. In
the event, the Horner–Emmons reagent 28, the methoxy-
methyl diethylphosphonate of (E)-2-methylbut-2-enoate,
reacted with aldehyde 27 under basic conditions to yield
compound 29.[10a] As expected, only the (E,E)-diene 29 was
obtained. Hydrolysis of the mixed acetal and oxidation gave
the lactone functionality, and acid-induced deprotection of
the MEM group afforded acid 30. Finally, acetylation of the
hindered tertiary alcohol at C4 afforded pseudolaric acid A
(1). The spectroscopic data of pseudolaric acid A obtained
from this synthesis was in accordance with the natural
product;[27] for example, the optical rotation of the synthetic
With the ring-opened compound 24 in hand, the final
functionalizations were accomplished as follows. Oxidative
removal of the PMB group in 24 yielded the deprotected
alcohol 25, which was further oxidized to the aldehyde.
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material is [a]2D0 = ꢀ37.18, and that of natural pseudolaric acid
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is [a]2D0 = ꢀ39.68.[28] Pseudolaric acid B (2) has been docu-
mented to be available from 1 by chemical transformations.[29]
In conclusion, we have accomplished the synthesis of
pseudolaric acid A. The highlights of this synthetic route are
the Evans catalytic asymmetric aldol reaction to establish the
absolute stereochemistry of the first two tertiary carbon
stereocenters, the carbene cyclization cycloaddition cascade
reaction to install the remainder of the stereochemical
elements and the polycyclic framework, as well as a reductive
elimination protocol to unmask the oxatricyclic structure to
reveal the perhydroazulene nucleus and facilitate cyclization
to construct the final lactone ring. The present synthetic
approach is amenable for the preparation of analogues and
derivatives of pseudolaric acids that will be useful to the
evaluation of the biological potential of these kinds of
compounds.
Received: May 23, 2006
Published online: August 14, 2006
Keywords: antitumor agents · carbenoids · domino reactions ·
.
natural products · total synthesis
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occurred, apparently in the chiral [Rh2{(S)-bptv}4]-induced
CCCC reaction.
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