Total synthesis of (-)-pseudolaric acid B

Article abstract of DOI:10.1021/ja076165q

We report the enantioselective synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon, which displays interesting antifungal, antifertility, and cytotoxic activity against multidrug resistant cell lines. Our synthesis utilizes a highly efficient metal-catalyzed [5 + 2] vinylcyclopropane-alkyne intramolecular cycloaddition to construct the polyhydroazulene core of the natural product. Elaboration to the tricyclic scaffold of the pseudolaric acids was completed with an intramolecular alkoxycarbonyl radical cyclization to form the quaternary center and a highly diastereoselective cerium acetylide addition to a methyl ketone for introduction of the acid side chain. Copyright

Full text of DOI:10.1021/ja076165q

Published on Web 11/07/2007
Total Synthesis of (-)-Pseudolaric Acid B
Barry M. Trost,* Jerome Waser, and Arndt Meyer
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received August 15, 2007; E-mail: bmtrost@stanford.edu
Scheme 1. Retrosynthesis of Pseudolaric Acid B (1a)
Pseudolaric acids B and A (1a and 1b, Scheme 1) are diterpene
acids isolated from the extract of the root bark of Pseudolarix
kaempferi Gordon (pinaceae), which is also used in tujinpi, a
traditional Chinese medicine for the treatment of fungal infections
of the skin and nails.1 Pseudolaric acid B (1a) has been identified
as a potent antifungal, antifertility, and cytotoxic agent, displaying
much higher activity than pseudolaric acid A (1b).2 More recently,
the discovery that pseudolaric acid B (1a) displays significant
activity against multidrug resistant cancer cell lines has revitalized
interest in this natural product.3
Pseudolaric acid B (1a) displays a compact tricyclic core which
includes a fused [5-7] ring system (polyhydroazulene) with an
unusual trans substitution pattern at the ring fusion site (C4-C10)
and four contiguous stereocenters, one of them being quaternary
(C10). Taken together, these structural features make pseudolaric
acid B (1a) a challenging substrate for modern synthetic chemistry.
As a result, several approaches toward the pseudolaric acids have
been published.4 In 2006, the unique successful synthesis of
pseudolaric acid A (1b) based on a carbene cyclization cycloaddition
cascade to build the polyhydroazulene core was reported.4h Herein,
we report the first asymmetric synthesis of pseudolaric acid B (1a)
highlighting the use of a metal-catalyzed [5+2] cycloaddition and
an intramolecular alkoxycarbonyl radical addition to construct the
ring system.
Scheme 2. Synthesis of the Polyhydroazulene Corea
The Rh and Ru catalyzed [5+2] intramolecular cycloaddition
reaction of an alkyne and a vinylcyclopropane developed by
Wender5 and us,6 respectively, is ideally suited for accessing the
polyhydroazulene core of pseudolaric acid B (1a). To reveal this
key structure in the natural product, we envisioned a late stage
introduction of the C13-C17 side chain (Scheme 1). An intra-
molecular alkoxycarbonyl radical addition to the C9-C10 double
bond of intermediate 2 was planned for the installation of the
quaternary center. Adjustment of the oxidation state and double-
bond isomerization leads to 1,4-diene 3, which would result from
an intramolecular [5+2] cycloaddition reaction of easily accessible
precursor 4.
a Conditions: (a) 1.4 mol % [RuI2(p-cymene)]2, 2.8 mol % (R)-BINAP,
1800 psi H2, methanol, CH2Cl2, 40 °C, 95%, >95:5 dr, >90% ee; (b)
TBSCl, imidazole, DMAP, DMF; (c) DIBALH, toluene, -78 °C; (d)
TMSCHN2, LDA, THF, -78 °C, then TMSCl, 73% over three steps; (e)
PPh3, I2, imidazole, toluene, 90%; (f) TBDPSCl, imidazole, THF, 92%;
(g) Et2Zn, DME, CH2I2, Charette’s auxiliary,8 CH2Cl2, -10 f 23 °C, 91%,
>90% ee; (h) (COCl)2, DMSO, NEt3, CH2Cl2, quant; (i) (1) MePh3P+Br-,
PhLi/LiBr, THF; (2) 7, 0 °C, then PhLi/LiBr; (3) 9, -78 °C, then PhLi/
LiBr, 23 °C; (4) HCl, -78 °C, then KOtBu, 23 °C; (j) K2CO3, MeOH,
-
58% over two steps (53% (E)-4); (k) 23 mol % [CpRu(CH3CN)3]+PF6
(11), acetone, 48% 3, 15% 10 or 11 mol % [(C8H10)Rh(COD)]+SbF6- (12),
DCE, 88% 3.
of protonation upon work up. We expected Rh catalysts to be less
pronetothisundesiredsidereaction.Indeed,[(C8H10)Rh(COD)]+SbF6-
(12)5b gave the desired product 3 exclusively in 88% isolated yield,
although the reaction still required an unusually high catalyst loading
(11 mol %).
A novel method for the regioselective isomerization of 1,4-diene
3 to a 1,3-diene 13 was then examined (Scheme 3). Activation of
TBAF with molecular sieves provided a reagent that affected
desilylation as well as isomerization to conjugated diene 13 in 94%
yield.9 Protection of diol 13 allowed for a diastereoselective
epoxidation of the tetrasubstituted double bond. Vinylogous
eliminative opening of the resulting epoxide mediated by LDA
completed the installation of the C4 alcohol of pseudolaric acid B
(1a). Oxidation of the allylic silyl ether of the resultant diene 14
followed by deprotection provided diol 2.
The synthesis of precursor 4 for the [5+2] cycloaddition reaction
is shown in Scheme 2. Iodide 7 was synthesized in five steps and
62% overall yield from 2-acetylbutyrolactone (5), using Noyori
reduction to install the adjacent stereocenters.7 Aldehyde 9 was
obtained in three steps and 84% overall yield from cis-butenediol
(8) via Charette cyclopropanation.8 Homologation of iodide 7,
followed by Schlosser-Wittig olefination with aldehyde 9 and
deprotection gave vinylcyclopropane 4 with 10:1 E/Z selectivity.
We then proceeded to examine the key [5+2] cycloaddition
-
reaction (Scheme 2). Using [CpRu(CH3CN)3]+PF6 (11), 23 mol
% catalyst was needed to obtain full conversion. The desired
polyhydroazulene 3 was isolated with 15:1 diastereoselectivity but
only 48% yield. Conjugated diene 10 was also obtained in 15%
yield. We speculated that the insertion of the Ru catalyst in the
labile bisallylic C-H bond leads to a Ru pentadienyl complex,
which then deactivates the catalyst. Diene 10 then is a consequence
At this point, we turned toward introduction of the C13-C17
side chain and the quaternary center at C10 (Scheme 3). We
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10.1021/ja076165q CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Introduction of the Quaternary Centera
to allow full conversion at -78 °C. At higher temperature a retro-
aldol reaction became favored. Complete selectivity was observed
in the formation of the C11-alcohol, as expected by a Felkin-Ahn
approach on ketone 18. Lactonization to tricycle 19 was achieved
using Otera’s catalyst.12 Deprotection of the terminal acetylene,
acetylation, hydrostannylation, and Stille coupling with known
iodide 2113 completed the total synthesis of pseudolaric acid B (1a).
All physical and spectroscopic data were in agreement with the
published values for natural pseudolaric acid B (1a) (melting point,
1
optical rotation, H and 13C NMR, IR, and mass).2a,c
In summary, we report the asymmetric synthesis of pseudolaric
acid B (1a) based on a metal-catalyzed [5+2] cycloaddition reaction
to build the polyhydroazulene core directly from a simple linear
precursor and a selective access to a 1,3-diene from the initially
formed 1,4 diene. An efficient alkoxycarbonyl radical cyclization
and a highly selective cerium acetylide addition were additional
key steps toward the stereoselective formation of the tricyclic core
of pseudolaric acid B (1a).
a Conditions: (a) TBAF, 3 Å MS, THF, 94%; (b) TESCl, imidazole,
DMAP, DMF, 85%; (c) m-CPBA, NaHCO3, CH2Cl2, -20 °C; (d) LDA,
THF, 0 °C, 72% over two steps; (e) DDQ, pH ) 7 buffer, CH2Cl2; (f)
MnO2, KCN, AcOH, MeOH, 85% over two steps; (g) TBAF, AcOH, THF,
87%; (h) Dess-Martin periodinane, CH2Cl2, 85%; (i) Ac2O, pyridine,
DMAP, quant; (j) TMSCtCCeCl2, THF, -78 °C, then CDI, -78 f
23 °C, 91%, 8:1 dr; (k) Ph2Se2, NaBH4, DMF, 76% (84% brsm); (l) CDI,
THF, quant; (m) Ph2Se2, NaBH4, DMF, 92%; (n) PMBOC(NH)CCl3, 2 mol
% Sc(OTf)3, toluene, 0 °C, 94%; (o) Bu3SnH, 1,1′-azo(biscyclohexane
carbonitrile), benzene, 70 °C, then DBU, 23 °C, 85% (92% purity).
Acknowledgment. We thank the NSF and the NIH (Grant
GM13598) for their generous support of our programs. J.W. thanks
the Swiss National Science Foundation and the Roche Research
Foundation for postdoctoral fellowships. A.M. thanks the German
Academic Exchange Service (DAAD) for a postdoctoral fellowship.
Mass spectra were provided by the Mass Spectrometry Regional
Center of the University of California, San Francisco, supported
by the NIH Division of Research Resources. We thank Johnson
Matthey for a generous supply of palladium and ruthenium salts.
Scheme 4. Completion of the Synthesisa
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
a Conditions: (a) KOTMS, toluene, 120 °C, 30 min, then Me2SO4, buffer
(TsOH, Hu¨nig’s base 1:2), 100 °C, 5 min; (b) Dess-Martin periodinane,
NaHCO3, CH2Cl2, 0 °C, 59% over two steps (73% brsm); (c) DDQ, pH )
7 buffer, CH2Cl2, 76%. (d) TMSCtCCeCl2‚2LiCl, THF, -78 °C, 87%
(98% brsm); (e) Otera’s catalyst,12 toluene, 130 °C, 30 min, 94%; (f) TBAF,
THF, 0 f 23 °C, 87%; (g) Ac2O, 8 mol % Sc(OTf)3, 0 °C, 98%; (h)
Bu3SnH, 5 mol % Pd(PPh3)2Cl2, THF, 90%; (i) Iodide 21, 25 mol %
Pd2dba3, Hu¨nig’s base, NMP, 62%.
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