A concise approach to vinigrol

Article abstract of DOI:10.1002/anie.200800167

Short and sweet: A simple and practical route to the unusual tricyclic ring system foundin the biologically active diterpene vinigrol is described. A remarkable proximity-induced intramolecular cycloaddition and mild Grob fragmentation allow rapidconstruction of the core ring system in less than 10 steps and with a minimal reliance on protecting groups. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200800167

Communications
DOI: 10.1002/anie.200800167
Natural Products
A Concise Approach to Vinigrol**
Thomas J. Maimone, Ana-Florina Voica, and Phil S. Baran*
In 1987 Hashimoto and co-workers isolated the unusual
diterpene vinigrol (1) from the fungal strain Virgaria nigra F-
5408.[1] The promising biological properties[2] of 1 combined
with its unique terpene framework has attracted significant
attention from the synthetic community (17 publications and
4dissertations on studies towards 1, no total synthesis
reported).[3] From a chemical standpoint, vinigrol provides a
particularly difficult challenge, as it is the only natural product
to contain the decahydro-1,5-butanonaphthalene carbon
skeleton. As such, it holds a special place alongside other
historically challenging diterpene systems such as the ingen-
anes, taxanes, and phomactins (see Figure 1).[4] Although 1 is
Scheme 1. a) Views of vinigrol (1). b) Inherent challenge of building
the ring system of 1 from a cis-decalin as studied by Paquette et al.[3a–d]
Figure 1. Historically challenging carbogenic ring systems in terpene
synthesis.
membered ring of vinigrol from a pre-existing cis-decalin
framework (2 to 3) utilizing a variety of approaches
(Scheme 1b).[3a–d] Indeed, calculations by Paquette and co-
workers on related model compound 4 point to a largely
unfavorable equilibrium between two conformers (4a and 4b,
DE ꢀ 12.5 kcalmolꢁ1), with the major conformer (4a) lacking
the proximity needed for ring closure.
In light of the unusually close proximity of C-4and C-11
(vinigrol numbering, see Scheme 1a) in 1, we reasoned that
the tricyclic carbon skeleton (5) could be formed by a Grob
fragmentation of a more accessible tetracyclic ring system
typified by construct 6 (Scheme 2). Our retrosynthetic blue-
print (Scheme 2) of 1 incorporates this bond disconnection
and offers a potentially rapid solution to the construction of
the vinigrol carbon skeleton.[3e] Indeed, this key fragmenta-
tion step could be tested in short order from simple starting
materials by using two sequential inter- and intramolecular
Diels–Alder reactions.
relatively small in size (molecular weight < 325 Da), the
presence of eight contiguous stereocenters and multiple sites
of oxygenation make it a particularly challenging synthetic
problem which can be analyzed from several seemingly
different topological viewpoints (Scheme 1a). Herein we
posit a logical blueprint and the necessary empirical valida-
tion for an exceptionally concise total synthesis of 1.
Continuous efforts by the Paquette group have vividly
demonstrated the difficulty in forming the bridging eight-
[*] T. J. Maimone, A.-F. Voica, Prof. P. S. Baran
Department of Chemistry, The Scripps Research Institute
10650 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7375
E-mail: pbaran@scripps.edu
Thus, (E)-methyl 4-methyl-2-pentenoate and diene 8
smoothly participated in an endo-selective Diels–Alder
reaction to produce bicyclic ketone 9 in 65% yield (unopti-
mized, d.r. = 2:1) (Scheme 3).[5] Triflation of 9 and subsequent
Stille coupling formed requisite diene 10 in 78% yield.[6]
After an oxidation state adjustment, allyl magnesium bro-
mide was added to the corresponding aldehyde (d.r. ꢀ 6:1),
[**] We thank Dr. D.-H. Huang and Dr. L. Pasternack for NMR
spectroscopic assistance, Dr. G. Siuzdak for mass spectrometric
and Dr. Arnold Rheingold (UCSD) for X-ray crystallographic
assistance. Financial support for this work was provided by Bristol-
Myers Squibb (predoctoral fellowship to T. J. M.), Merck, and Roche.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
ates in this one-pot tandem reaction were confirmed
unequivically by aqueous workup and X-ray crystallographic
analysis of alcohol 13. Although the olefinic units of 11 are not
electronically complimentary for a Diels–Alder reaction, it
was anticipated that a strong proximity effect would encour-
age bond formation to occur. Remarkably, this reaction even
takes place at room temperature over the course of two weeks
(Scheme 4). To the best of our knowledge, this is the only
example of a completely electron-neutral diene and simple
olefin taking part in a noncatalyzed cycloaddition at ambient
temperature.[7]
Since alcohol 14 does not possess the correct antiperipla-
nar atomic arrangement required for Grob fragmentation[8] it
was inverted by oxidation/reduction followed by mesylation
to provide 6. The stereochemistry of the intermediate alcohol
(15) was verified by X-ray crystallography. Although the
diastereoselectivity of the reduction step was modest (d.r.
ꢀ 2.5:1), the undesired alcohol isomer could be easily
separated and reoxidized with almost no loss in material
throughput. Deprotonation of 6 with KHMDS smoothly
afforded the vinigrol core structure in high yield (93%). It
should be noted that the conditions required (08C) are
unusually mild for this type of bond cleavage. It is likely that
Scheme 2. Retrosynthetic analysis of the tricyclic carbon skeleton 5.
producing an intermediate alkoxide 11 which was directly
heated to 1058C for 90 min followed by treatment of
intermediate 12 with TBAF to furnish tetracycle 14 in 75%
overall yield. The structure of 12 and all previous intermedi-
Scheme 3. Synthesis of the vinigrol core (5). a) (E)-methyl 4-methyl-2-pentenoate (1.0 equiv), diene 8 (2.0 equiv), AlCl3 (1.5 equiv), DCM, ꢁ788C,
1 h, ꢁ458C, 3 h, 65% (d.r.ꢀ2:1); b) LDA (1.2 equiv), Tf2O (1.3 equiv), THF, ꢁ788C!238C, 2 h, 87% (based on recovered starting material);
c) vinyltributyl tin (1.2 equiv), LiCl (4.8 equiv), [Pd(PPh3)4] (0.1 equiv), THF, reflux, 3 h, 90%; d) DIBAL (2.5 equiv), DCM, ꢁ788C, 30 min, then
DMP (1.25 equiv), DCM, 238C, 30 min, 80% over two steps; e) allylmagnesium chloride (1.0 equiv), PhMe, ꢁ788C!1058C, 90 min, then TBAF
(4.8 equiv), 658C, 45 min, 75%; f) DMP (1.1 equiv), DCM, 238C, 30 min, 92%; g) DIBAL (3.2 equiv), DCM, ꢁ788C, 30 min, then MsCl
(1.25 equiv), Et3N (1.5 equiv), 238C, 20 min, 79% over two steps (d.r.ꢀ2.5:1); h) KHMDS (1.1 equiv), THF, 08C, 15 min, 93%; i) m-CPBA
(1.5 equiv), NaHCO3 (2.0 equiv), DCM, ꢁ158C, 45 min, 95%; j) DIBAL (3.2 equiv), DCM, ꢁ788C, 30 min, 96% (d.r.ꢀ2.5:1); k) aqueous NH4Cl,
238C, 81% (d.r.ꢀ6:1). DCM = dichloromethane, LDA = lithium diisopropylamide, DIBAL = diisobutylaluminum hydride, DMP = Dess–
Martin periodinane, KHMDS = potassium hexamethyldisilazide, TBAF = tetrabutylammonium fluoride, m-CPBA = meta-chloroperoxybenzoic
acid.
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Scheme 4. A remarkable proximity-induced spontaneous Diels–Alder
reaction.
strict enforcement of orbital alignment by the rigid bicyclic
system greatly facilitates this process. A high-yielding (95%)
chemo- and stereoselective epoxidation of the less hindered
trisubstituted olefin in 16 completed the synthesis of 5 as
confirmed by X-ray crystallography.
The concise, high-yielding (ca. 20% yield from 8) route to
5 attests to the strength of the underlying logic of this
synthesis plan. In particular, of the eight contiguous stereo-
centers in 1, five have been partially addressed in compound
5. A proximity-induced intramolecular Diels–Alder cyclo-
addition and mild Grob fragmentation make this rapid route
possible. Approximately half of the steps in this approach
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Received: January 13, 2008
Published online: March 12, 2008
Keywords: cascade reactions · natural products · total synthesis ·
.
vinigrol
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[10] Full characterization and experimental details can be found in
Supporting Information. CCDC-675358, 675356, and 675357 (5,
13, and 15, respectively) contain the supplementary crystallo-
graphic 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_request/cif.
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