A formal synthesis of vinigrol

Article abstract of DOI:10.1002/anie.201108779

Two key reactions in a rapid assembly of the tricyclic core of vinigrol are a stereoselective Claisen rearrangement and an intramolecular Diels-Alder reaction. The method paves the way for a total synthesis of this synthetically challenging and biologically interesting natural product. Copyright

Full text of DOI:10.1002/anie.201108779

Angewandte
Chemie
DOI: 10.1002/anie.201108779
Natural Product Synthesis
A Formal Synthesis of Vinigrol**
Jason Poulin, Christiane M. Grisꢀ-Bard, and Louis Barriault*
In memory of Keith Fagnou
In 1987, Hashimoto and co-workers isolated an unprece-
dented compact diterpene, vinigrol (1, Scheme 1), from the
fungal strain Virgaria nigra F-5408, found at the foot of Mount
Aso in the Kumamoto Prefecture in Japan.[1] The relative
to an inability of the substrates to adopt the requisite
conformation for direct cyclization to form the ansa belt.
We realized that an approach involving the generation of
two rings in one step would avoid this fundamental cyclization
problem. Specifically, we envisaged the formation of the
vinigrol carbocyclic core 4 by a type 2 intramolecular Diels–
Alder reaction[8] of triene 3 (Scheme 2), which should favor
the less-strained transition state A over B, thus leading to the
preferential formation of cycloadduct 4. In early 2007, we
Scheme 1. Structure of vinigrol (1).
stereochemistry of the natural product was established by
NMR and X-ray crystallographic analysis of the oxidized
derivative 2. Its tricyclic core is comprised of a cis-fused [4.4.0]
system with a four-carbon bridge between C1 and C5 and
features eight contiguous stereocenters. The rare boat half
chair conformation of the eight-membered ring (highlighted
in Scheme 1 in bold) makes vinigrol a unique structure among
diterpenoids.
Biological testing of vinigrol (1) has revealed a number of
interesting properties, including an influence on platelet
aggregation[2] and tumor necrosis factor (TNF) antagonism.[3]
These results prompted investigations into the application of
vinigrol in medicine.[4,5] Not surprisingly, the impressive
biological activities of vinigrol (1), combined with its unique
and synthetically challenging structure, have resulted in
considerable attention from the synthetic community.[6,7]
In 1993, Hanna et al. unveiled the first synthesis of the
tricyclic core of vinigrol featuring an anionic oxy-Cope ring
expansion.[6a] Subsequent investigations by our group and
others,[6d,e,h,l–n] focused on a direct cyclization of the eight-
membered ring (the ansa belt) of vinigrol from functionalized
decalin precursors. Unfortunately, all such approaches were
thwarted by an inability to find reaction conditions for the
cyclization. The failure of these approaches can be attributed
Scheme 2. IMDA approaches to synthesize the vinigrol core. LA=Le-
wis Acid, TBS=tert-butyldimethylsilyl.
reported a highly regioselective IMDA reaction of 3 to give 4
in high yield, thus validating our idea.[6p] Subsequent work
from Baran and co-workers[6r] confirmed the effectiveness of
the intramolecular Diels–Alder approach by converting
triene 6 into tetracycle 7, which was converted into the core
of vinigrol (8) through a subsequent Grob fragmentation. In
2009, the same group extended the IMDA–Grob approach to
the first total synthesis of vinigrol.[6w]
Herein, we report a sterecontrolled formal total synthesis
of vinigrol that exploits the synthetic efficiency of our direct
type 2 IMDA approach. Our retrosynthetic analysis, depicted
in Scheme 3, takes advantage of the compact and conforma-
tionally restricted nature of IMDA adduct 11 to install the
requisite functionalities of the natural product. Tricycle 11 is
the result of an IMDA reaction of triene 12. The latter could
be readily prepared from ketone 13, which in turn could be
efficiently assembled through a Claisen rearrangement of 14,
which could be generated in situ from alcohol 15 and ketal 16.
A chair-like transition state would secure the correct relative
stereochemistry at C1 and C12 in 13.
[*] J. Poulin, C. M. Grisꢀ-Bard, Prof. L. Barriault
Department of Chemistry, University of Ottawa
10 Marie Curie, Ottawa, ON K1N 6N5 (Canada)
E-mail: lbarriau@uottawa.ca
[**] We thank the NSERC, Merck Frosst Canada, and the University of
Ottawa for generous funding. C.M.G.-B. thanks NSERC and the
Government of Ontario for postgraduate scholarships (CGS-D and
OGSST). J.P. thanks the Gouvernement du Quꢀbec for a postgrad-
uate scholarship (FQRNT). We thank Dr. I. Korobkov for X-ray
analysis. We are grateful to Prof. M. Sherburn (Australian National
University) and Prof. P. Baran (Scripps) for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108779.
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À788C to give the desired vinigrol cores 21a and 21b as the
sole isomers in 79% and 67% yield respectively.
Wittig olefination of ketones 21a and 21b using Coniaꢀs
conditions[15] afforded olefins 22a and 22b in 72% and 74%
yield, respectively (Scheme 5). At this point, we envisaged
a chemo- and diastereoselective hydrogenation of the exocy-
Scheme 3. Retrosynthetic analysis of vinigrol (1). DPS=tert-butyldiphe-
nylsilyl, Piv=trimethylacetyl.
The synthesis began with a thermal Claisen rearrange-
ment[9] of alcohol 15[10] and ketal 16[11] in the presence of
propionic acid to give ketone 13 in 62% yield. The product
possessed the required relative stereochemistry at C1 and C12
and was a 50:50 epimeric mixture at C3 (Scheme 4).[12] After
PtO2-catalyzed hydrogenation of the isopropenyl group, the
ketone was converted into the enol triflate 17. Next,
a Kumada–Negishi coupling reaction with vinyl magnesium
bromide[13] afforded the diene 18 in 93% yield.[14] Removal of
the DPS group was achieved using TBAF to provide a 50:50
mixture of epimeric alcohols 19 in 68% yield. At this point,
the epimers were separated and carried independently
through the following steps. A sequence of oxidation,
nucleophilic addition with vinyl magnesium bromide, and
oxidation led to unstable enones 20a and 20b in 72% and
82% yields respectively. Enones 20a and 20b underwent
a SnCl4-mediated IMDA reaction in dichloromethane at
Scheme 5. Synthesis of vinigrol core 23.[19] a) Ph3PCH3I, KOtBu, PhMe;
b) PtO2, H2, EtOAc; c) Dibal-H, CH2Cl2, À788C; d) p-NO2C6H4COCl,
Et3N, CH2Cl2, RT, 56% over three steps. Dibal-H=diisobutylaluminum
hydride.
clic alkene to establish the C9 stereocenter and its associated
methyl group. We had apprehensions about this transforma-
tion because poor stereoselectivity was reported in a similar
reduction by Hanna et al.[6i] To our delight, the hydrogenation
of epimer 22a gave the desired product 23a as the sole
diastereomer (d.r. > 25:1) in quantitative yield. In contrast, an
inseparable mixture of diastereomers at C9 was obtained for
22b, with the desired isomer still being favored (d.r. = 3:1).
Single-crystal X-ray analysis was employed to secure the
stereochemistry of products in this sequence (Scheme 5). A
crown conformation is adopted by the eight-membered ring
in both 21a and 21b.
With tricycle 23a in hand, an overall trans hydration of the
olefin to give diol 26 was necessary to place the C8 methyl and
the C8a hydroxy groups in a syn orientation [Eq. (1)].
Scheme 4. Synthesis of the vinigrol skeleton (21). a) propionic acid,
neat, 1358C, 62%, (d.r. at C1–C12 >25:1); b) PtO2, H2, EtOAc, 76%;
=
c) KHMDS, THF, À788C then PhNTf2, 99%; d) CH2 C(Me)MgBr,
ZnBr2, Pd(OAc)2, DPPB, THF, RT to 608C, 93%; e) nBu4NF, THF,
68%; f) (COCl)2, Me2SO, CH2Cl2, À788C then Et3N, À788C to RT;
Frustratingly, our many attempts to bring about this trans-
formation have thus far been unsuccessful.[16] The problem
was solved through the synthesis of the des-methyl analogue
of 23a, tricycle 27 (Scheme 6), which would be the precursor
for a regio- and stereoselective introduction of the C8 methyl
=
g) CH2 CHMgBr, PhMe, À788C; h) (COCl)2, Me2SO, CH2Cl2, À788C
then Et3N, À788C to RT; i) SnCl4, CH2Cl2, À788C. DPPB=diphenyl-
phosphinobutane, KHMDS=potassium hexamethylsilazide, Tf=tri-
fluoromethanesulfonyl, THF=tetrahydrofuran.
2112
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Angewandte
Chemie
transformed into the benzyl ether 32 in readiness for an
overall syn addition of methyl and hydroxy moieties to the
trisubstituted olefin. Thus, the tricyclic alkene 32 was
converted into isocyanate 33 by a [3+2] cycloaddition of
bromonitrile oxide and subsequent hydride reduction.[17]
A
Saegusa deamination[18] and removal of the benzyl group
revealed diol 26 in 76% yield over two steps. TEMPO
oxidation of the secondary alcohol to ketone 34 was achieved
in 94% yield. As expected, the conformationally restricted
nature of 34 favored the regioselective a-oxygenation at C4 to
afford diol 9 in 40% yield (65% based on recovered starting
material). The manipulation of the ketone functionality of 9
into the allylic alcohol of vinigrol (1) has been realized in two
steps by Baran and co-workers.[6w] The interception of a late-
stage intermediate in the Baran synthesis thus completes the
formal total synthesis of the natural product.
In conclusion, a formal synthesis of vinigrol (1) was
achieved in 24 steps from commercially available starting
materials. A unique strategic feature of our synthesis involves
the construction of the vinigrol carbocyclic core in only 12
steps through a sequence involving a sterecontrolled Claisen
rearrangement and an intramolecular Diels–Alder reaction as
key steps. This work serves as a platform for further synthetic
and biological studies with this unique and important natural
product.[19]
=
Scheme 6. Formal synthesis of vinigrol (1). a) Bu3SnCH CH2, [Pd-
(PPh3)4] (10 mol%), LiCl, THF, 608C (80%); b) i) Dibal-H, CH2Cl2,
À788C; ii) pNO2C6H4CO2H, DIAD, PPh3, THF, 08C; iii) NaOH, MeOH,
RT; iv) PivCl, Et3N, DMAP, CH2Cl2, RT (60% over 4 steps); c) nBu4NF,
THF, RT, (84%); d) (COCl)2, Me2SO, CH2Cl2, À788C then Et3N, À78 to
Received: December 13, 2011
Published online: January 19, 2012
=
08C; e) CH2 CHMgBr, toluene, À788C; f) (COCl)2, Me2SO, CH2Cl2,
Keywords: Claisen rearrangement · Diels–Alder reaction ·
.
À788C then Et3N, À78 to 08C; g) SnCl4, CH2Cl2, À788C, (65% over 4
steps); h) Ph3PCH3I, KOtBu, THF/PhMe (1:1), RT (88%); i) PtO2, H2,
EtOAc, 08C (99%, d.r.>25:1); j) Dibal-H, CH2Cl2, À788C; k) NaH,
natural products · total synthesis · vinigrol
+
À
=
BnBr, Bu4N I , DMF, 08C to RT (90% over 2 steps); l) Br2C NOH,
KHCO3, wet EtOAC, RT (71%), m) LAH (10 equiv), 4 ꢁ MS, THF, 08C
to RT; n) HCO2H, CDMT, NMM, DMAP, CH2Cl2, RT, (83% over 2
steps); o) COCl2, Et3N, CH2Cl2, À108C (71%); p) AIBN, Bu3SnH,
PhMe, 1208C (91%); q) Li, naphthalene, THF, 08C, (83%); r) TEMPO,
KBr, NaOCl, CH2Cl2/NaHCO3(aq), RT (94%); s) KHMDS (6 equiv),
Davis’ oxaziridine, À78 to 08C, THF, (40%, 65% brsm); t) see Ref.
[6w] (two steps). AIBN=2,2’-azobis(2-methylpropionitrile), Bn=ben-
zyl, brsm=based on recovered starting material, CDMT=2-chloro-4,6-
dimethoxy-1,3,5-triazine, DIAD=diisopropyl azodicarboxylate,
DMAP=4-dimethylaminopyridine, NMM=N-methylmorpholine,
LAH=lithium aluminum hydride, TEMPO=2,2,6,6-tetramethylpiperi-
dine-1-oxyl.
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CCDC 858016 (22a), 858017 (22b), and 858018 (25) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
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