Rapid assembly of vinigrol's unique carbocyclic skeleton

Article abstract of DOI:10.1021/ol901519k

Detailed In this account are our efforts toward the total synthesis of vinigrol. A highly expedient and convergent synthetic approach made possible by the use of a strategic oxidative dearomatization reaction coupled with a series of ensuing substrate con

Full text of DOI:10.1021/ol901519k

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4492-4495
Rapid Assembly of Vinigrol’s Unique
Carbocyclic Skeleton
Jason G. M. Morton, Cristian Draghici, Laura D. Kwon, and Jon T. Njardarson*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell
UniVersity, Ithaca, New York 14853-1301
jn96@cornell.edu
Received July 2, 2009
ABSTRACT
Detailed in this account are our efforts toward the total synthesis of vinigrol. A highly expedient and convergent synthetic approach made
possible by the use of a strategic oxidative dearomatization reaction coupled with a series of ensuing substrate controlled transformations
is discussed.
In 1987, researchers at Fujisawa Pharmaceutical Co.
reported the isolation of a novel diterpenoid they had
named vinigrol (Figure 1, 1), with an unprecedented 1,5-
butane-tethered cis-decalin core.1 Vinigrol has since been
shown to be potent as an antihypertensive and platelet-
inhibiting agent, as well as have an inhibitory effect on
Ca2+ movement.2 Subsequently, vinigrol was shown to
be a tumor necrosis factor (TNF) antagonist3 with the
ability to inhibit the progression of AIDS-related complex
to AIDS.4 Giving this promising biological profile and
structure, it is not surprising that a number of synthetic
research groups took notice.5 Twenty years since its
isolation, vinigrol has yet to succumb to total synthesis.
Figure 1. Structure of vinigrol.
Interestingly, the first published route by Hanna remains
one of the most advanced progresses toward vinigrol.
In our quest toward completing an expedient total
synthesis of vinigrol we have focused our efforts on
synthetic strategies utilizing an oxidative dearomatization
coupled with an intramolecular Diels-Alder reaction as
the key steps. Toward that end, we have disclosed our
efforts employing the Wessely and Adler-Becker oxida-
tive dearomatization reactions.6 Although these discon-
nections were shown to be conceptually sound, they both
suffered from weakness in either one of the key transfor-
mations. This paper details our current route, which
overcomes the limitations encountered in the previous
routes in addition to being more efficient and easily
processable.
(1) Uchida, I.; Ando, T.; Fukami, N.; Yoshida, K.; Hashimoto, M.; Tada,
T.; Koda, S.; Morimoto, Y. J. Org. Chem. 1987, 52, 5292–5293.
(2) (a) Ando, T.; Tsurumi, Y.; Ohata, N.; Uchida, I.; Yoshida, K.;
Okahura, M. J. Antibiot. 1988, 41, 25–30. (b) Ando, T.; Yoshida, K.;
Okahura, M. J. Antibiot. 1998, 41, 31–35.
(3) Norris, D. B.; Depledge, P.; Jackson, A. P. Chem. Abstr. 1991, 115,
64776h, PCT Int. Appl. WO 91 07 953.
(4) (a) Onodera, H.; Ichimura, M.; Sakurada, K.; Kawabata, A.; Octa,
T. PCT Int. Appl. WO 2006077954. (b) Onodera, H.; Ichimura, M.;
Sakurada, K.; Kawabata, A.; Ota, T. PCT Int. Appl. WO 2006077954.
10.1021/ol901519k CCC: $40.75
Published on Web 09/03/2009
 2009 American Chemical Society

Retrosynthetic analysis for our proposed total synthesis
of vinigrol (1) is detailed in Scheme 1. Late stage substrate-
tion with 4-halopyrogallols was not sufficient, thus leading
us to investigate the reactivity profile of monotosylated
derivative 9 (Scheme 2). This strategy was shown to be very
Scheme 1. Vinigrol Retrosynthesis
Scheme 2. Identifying Optimal Pyrogallol Substrate
effective, as first demonstrated by the hypervalent iodide-
mediated oxidation of 9 in the presence of allyl alcohol,
which afforded cycloadduct 10. Unfortunately, more relevant
trisubstituted allylic alcohols were not trapped very efficiently
in our early attempts. We therefore turned our attention to
lead(IV) acetate oxidations. Gratifyingly, these oxidations
proceeded smoothly forming mixed quinone ketal 11 and
more importantly allowing incorporation of tiglic acid (12).
Unlike the dialkyl ketal o-quinones, these ketals are more
stable as a result of the acyl group’s inductive effects and
need to be heated to access the [2.2.2] cycloadducts.7
Our initial efforts have focused on establishing the viability
of the proposed oxidative dearomatization strategy (Scheme
3). A suitable carboxylate side chain (17) was accessed in
three steps. This was accomplished by alkylation of triethyl
phosphonoacete (13) with bromide 14, followed by a
controlled hydrogenation of both olefins followed by forma-
tion of an enol triflate, cross coupling of the triflate to form
the allylic alcohol, and deprotection will advance intermedi-
ate 2 to vinigrol. The natural product core will be revealed
using a retro-Michael fragmentation of caged structure 3,
which in turn can be rapidly accessed via 4 following
substrate-controlled hydrogenation of the exo olefin and
samarium-mediated deoxygenation of the mixed ketal moiety.
Tandem 6-exo radical cyclizations will deliver the pre-
fragmentation polycyclic core (4) from cycloadduct 5. This
intermediate will be assembled from the oxidative dearo-
matization/Diels-Alder union of pyrogallol derivative 6 and
acrylic acid 7. In the ideal synthetic scenario, a one-pot
samarium cascade can be envisioned starting from 5 directly
to ring-expanded 3 via consecutive 6-exo ketyl mediated
radical cyclizations followed by double R-keto deoxygenation
and a retro-Michael fragmentation of the resulting enolate.
Our studies first focused on dearomatizing commercially
available symmetrical 1,3-dimethoxypyrogallol. Unfortu-
nately, it was quickly realized that the resulting monoquinone
ketal was very unstable and rearomatized before the desired
Diels-Alder cycloaddition could occur. Electronic deactiva-
Scheme 3. Synthesis of Radical Cascade Precursors
(5) (a) Devaux, J.-F.; Hanna, I.; Lallemand, J.-Y. J. Org. Chem. 1993,
58, 2349–2350. (b) Devaux, J.-F.; Hanna, I.; Lallemand, J.-Y.; Prange, T.
J. Chem. Res. Synth. 1996, 32–33. (c) Devaux, J.-F.; Hanna, I.; Lallemand,
J.-Y. J. Org. Chem. 1997, 62, 5062–5068. (d) Gentric, L.; Hanna, I.; Ricard,
L. Org. Lett. 2003, 5, 1139–1142. (e) Gentric, L.; Hanna, I.; Huboux, A.;
Zaghdoudi, R. Org. Lett. 2003, 5, 3631–3634. (f) Mehta, G.; Reddy, K. S.
Synlett 1996, 625–627. (g) Kito, M.; Sakai, T.; Haruta, N.; Shirahama, H.;
Matsuda, F. Synlett 1996, 1057–1060. (h) Kito, M.; Sakai, T.; Shirahama,
H.; Miyashita, M.; Matsuda, F. Synlett 1997, 219–220. (i) Matsuda, F.;
Kito, M.; Sakai, T.; Okada, N.; Miyashita, M.; Shirahama, H. Tetrahedron
1999, 55, 14369–14380. (j) Paquette, L. A.; Guevel, R.; Sakamoto, S.; Kim,
I. H.; Crawford, J. J. Org. Chem. 2003, 68, 6096–6107. (k) Paquette, L. A.;
Efremov, I.; Liu, Z. J. Org. Chem. 2005, 70, 505–509. (l) Paquette, L. A.;
Efremov, I. J. Org. Chem. 2005, 70, 510–513. (m) Paquette, L. A.; Liu, Z.;
Efremov, I. J. Org. Chem. 2005, 70, 514–518. (n) Morency, L.; Barriault,
L. Tetrahedron Lett. 2004, 45, 6105–6107. (o) Morency, L.; Barriault, L.
J. Org. Chem. 2005, 70, 8841–8853. (p) Tessier, G.; Barriault, L. Org.
Prep. Proc. Int. 2007, 37, 313–353. (q) Grise, C. M.; Tessier, G.; Barriault,
L. Org. Lett. 2007, 9, 1545–1548. (r) Souweha, M. S.; Enright, G. D.; Fallis,
A. G. Org. Lett. 2007, 9, 5163–5166. (s) Maimone, T. J.; Voica, A.-F.;
Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 3054–3056.
(6) (a) Morton, J. G. M.; Kwon, L. D.; Freeman, D. J.; Njardarson, J. T.
Synlett 2009, 23–27. (b) Morton, J. G. M.; Kwon, L. D.; Freeman, D. J.;
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Org. Lett., Vol. 11, No. 20, 2009
4493

Horner-Wadsworth-Emmons condensation with aldehyde
168 and hydrolysis to form trisubstituted acrylic acid 17. We
were delighted to learn that when phenol 9 was oxidized in
the presence of 17 a union of the two took place to form a
stable adduct, which upon heating provided desired bicyclic
cycloadduct 18 in good yield. Deprotection of the silyl ether
and Swern oxidation of the primary alcohol then afforded
aldehyde 19. This substrate provided us with several 6-exo/
6-exo cyclization strategies by initiating cyclization either
at the aldehyde or alkyne terminus. We decided to first
explore samarium-mediated cyclizations. Upon treatment of
19 with samarium diiodide in the presence of HMPA a rapid
cyclization took place forming 20 as a single diastereomer,
with the desired correct stereochemistry of the newly formed
secondary hydroxyl group. For this substrate (19), the
expected second 6-exo radical cyclization did not take place
to form the tetracyclic core (21) of vinigrol.9
product 27, with no sign of any products arising from the
desired 6-exo/6-exo radical cascade.
Having not succeeded in forming the vinigrol core using
a radical cyclization cascade, we decided to evaluate a
stepwise approach that would build upon our existing route
and the lessons learned but employ instead a substituted
pyrogallol precursor. We postulated that commercially avail-
able pyrogallol 30 would offer us an excellent entry point
(Scheme 5). All eight of its core carbon atoms and an oxygen
Scheme 5. New Front to Back Cyclization Substrate
We had predicted that there might be both steric and
conformational challenges with the second radical cycliza-
tion. One way to improve the cyclization chances would be
to use cyclization partners that were mostly sp2- and sp3-
hybridized in order to create more space for the more
challenging second cyclization to occur. We decided to
evaluate such a less encumbered system in combination with
a more reactive starting vinyl radical. The rapid synthesis
and evaluation of this substrate (26) is shown in Scheme 4.
Scheme 4. Back to Front Radical Cyclization Attempt
atom would end up in the final structure. Moreover, it is
symmetrical and has a deactivating group (acyl group instead
of a phenolic tosylate). Toward that end, acrylic acid 29 was
accessed using classic chemical transformations from phospho-
noacetate 28. The oxidative dearomatization union of acid
29 and phenol 30 afforded bicyclic ketal 31 in very good
yield. X-ray crystallography of the vinyl bromide analogue
(32) confirmed chemical connectivity.11
Radical cyclization of 31 yielded a single diastereomer
(Scheme 6), which was shown to be the desired ketone 33
having trapped the radical from the bottom face. Olefination
attempts to access RCM precursor 34 proved extremely
challenging and were met with no success. We were able to
olefinate the less hindered radical cyclization precursor (32).
When the resulting tetraene (36) was used for the radical
cyclization en route to metathesis precursor 34, triene 37
was instead isolated as the only product. Following cycliza-
tion the intermediate allylic radical had migrated to form a
tetrasubstituted alkene.
Known bromide 2210 was utilized to afford phosphonate 23.
Condensation of aldehyde 24 and ester hydrolysis furnished
acrylic acid 25, which again was reliably and selectively
coupled to pyrogallol derivative 9 using the same lead(IV)
oxidative dearomatization protocol. Upon heating, cycload-
duct 26 was obtained in only seven steps from propargylic
alcohol 22. Unfortunately, all attempted radical cyclizations
of this vinyl iodide substrate only afforded monocyclized
Inspired by the convergent and rapid union of pyrogallol
ketone 30 and carboxylate moiety 29 we decided to make
(9) Similar monocyclization results were also obtained when an acyl
selenide was used. This substrate could be accessed in two steps from
aldehyde 19 via a Pinnick oxidation followed by treatment of the resulting
carboxylic acid with Bu3P/PhSeCl.
(10) (a) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488–6499. (b)
Piers, E.; Harrison, C. L.; Zetina-Rocha, C. Org. Lett. 2001, 3, 3245–3247.
(11) Bromide 32 was obtained from a route identical the one shown in
Scheme 5, the only difference being the use of Br-BBN. For further
information, see the Supporting Information.
(7) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004, 104,
1383–1430.
(8) Tius, M. A.; Trehan, S. J. Org. Chem. 1986, 51, 765–767.
4494
Org. Lett., Vol. 11, No. 20, 2009

Scheme 6
.
Front to Back Vinyl Radical Cyclizations
Scheme 7. Efficient Synthesis of the Tetracyclic Cage
This seemingly simple core contains all except three of the
carbon atoms needed for the total synthesis.
two critical modifications. We felt that the oxidative dearo-
matization union could be further improved and we were
eager to suppress the acyl migration often observed during
the intramolecular Diels-Alder reaction. Additionally, al-
though the lactone was clearly attractive for eventual
oxidation economy in the short term it was complicating our
search for the optimal cyclization sequence. By using an
alcohol instead of a carboxylate in the oxidative dearoma-
tization step we would access a more stable ketal, which
would be helpful for later steps. We also expected that the
intermediate ketal would more likely undergo the intramo-
lecular Diels-Alder reaction in situ while not suffering from
any competing acyl migrations. The main question we faced
was whether we could use the allylic alcohol as a nucleophile,
which challenged us earlier (Scheme 2), or alternatively to
pre-tether it to the aromatic core. Our efforts are detailed in
Scheme 7.
In summary, we have detailed a new and efficient synthetic
strategy for vinigrol. It relies on a strategic oxidative
dearomatization/Diels-Alder reaction followed by a short
sequence of critical substrate controlled transformations. This
latest approach constructs vinigrol’s tetracyclic core (43) in
only four steps from commercially available ketone 30. Our
efforts toward the completion of the total synthesis of vinigrol
(1) will be reported in due course.
Acknowledgment. We would like to thank NIH-NIGMS
(RO1 GM086584) and Cornell University for support of this
synthetic program. This material is also based upon work
supported under a National Science Foundation Graduate
Research Fellowship (J.G.M.M.). We gratefully thank Emil
Lobkovsky (Cornell University) for X-ray structure analysis.
Note Added after ASAP Publication. There were errors
in the bottom structures of Figure 1 and in the toc/abstract
graphic in the version published ASAP September 3, 2009;
the corrected version published ASAP September 11, 2009.
We used the sequence detailed in Scheme 5 to obtain
allylic alcohol 38. This was done by reducing the ester
obtained from the Horner-Wadsworth-Emmons reaction
with Dibal-H. We were delighted to learn that when alcohol
38 was coupled with phenol 30 in the presence of iodoben-
zene bis(trifluoroacetate) the mixed o-quinone monoketal was
formed, and as predicted underwent an in situ Diels-Alder
reaction to cycloadduct 39. As for the previous substrates
the radical cyclization proceeded smoothly, exclusively
forming exo-ketone 40.12 This hindered ketone was success-
fully bis-olefinated (41) using the Peterson olefination
protocol. Gratifyingly, and despite significant steric hin-
drance, tetraene 41 could be cyclized using the Grubbs-
Hoveyda catalyst (42)13 in the presence of benzoquinone14
to the desired vinigrol prefragmentation cage structure 43.
Supporting Information Available: Experimental details
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901519K
(12) When tris(trimethylsilyl)silane (TTMSS) was used as reducing agent
instead of tributylstannane, the radical cyclization proceeded smoothly, but
analysis of the product revealed that both the exo-methylene and methyl
ketone groups had isomerized during the reaction to a trisubstituted endo-
olefin and an endo-ketone, respectively.
(13) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791–799.
(14) The use of benzoquinone was necessary to suppress competing
isomerization of the allyl group. Hong, S. H.; Sanders, D. P.; Lee, C. W.;
Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160–17161.
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