An Adler-Becker oxidation approach to vinigrol

Article abstract of DOI:10.1016/j.tetlet.2009.01.134

Detailed in this Letter is an Adler-Becker oxidation strategy towards vinigrol. The effects of substitution were shown to greatly impact successes of both the oxidative dearomatization and Diels-Alder reactions.

Full text of DOI:10.1016/j.tetlet.2009.01.134

Tetrahedron Letters 50 (2009) 1684–1686
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Tetrahedron Letters
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An Adler–Becker oxidation approach to vinigrol
*
Jason G. M. Morton, Laura D. Kwon, John D. Freeman, Jon T. Njardarson
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Detailed in this Letter is an Adler–Becker oxidation strategy towards vinigrol. The effects of substitution
were shown to greatly impact successes of both the oxidative dearomatization and Diels–Alder reactions.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 December 2008
Revised 30 December 2008
Accepted 9 January 2009
Available online 1 February 2009
Vinigrol (1, Scheme 1) is a structurally novel diterpenoid, first
isolated from the fungus Virgaria nigra.1 From a medicinal point
of view, vinigrol is of interest due to demonstrated antihyperten-
sive and platelet-inhibiting properties and tumour necrosis factor
antagonist activity.2 Given the combination of a structurally un-
ique, synthetically challenging carbon framework and potential
pharmaceutical applications, it is of no surprise that several re-
search groups have published reports towards the synthesis of vin-
igrol.3 Yet despite an elapsed sixteen years of work by the synthetic
community, a total synthesis of vinigrol has yet to be seen.
Our retrosynthetic approach relies on three key synthetic oper-
ations: An oxidative dearomatization of a resorcinol core (5), intra-
molecular Diels–Alder reaction of the resulting dienone (4) and a
fragmentation of a tetracyclic precursor (2). The spiro-epoxide moi-
ety in 4 would rigidify the tether, bring the dienophile closer to the
diene and following a successful intramolecular Diels–Alder reac-
tion be reductively opened4 to the desired secondary alcohol. Fol-
lowing this general blueprint, we recently reported our initial
vinigrol synthetic efforts employing the underutilized Wessely oxi-
dation reaction for the critical dearomatization step.5 Concurrent
with these efforts, which have suffered from poor Wessely oxida-
tion yields, we have pursued a similar approach using instead an
Adler–Becker oxidative dearomatization protocol (Scheme 2) in
hopes of addressing this limitation.
First reported in 1971, the Adler–Becker reaction is the perio-
date-mediated oxidative dearomatization of salicyl alcohols (6)
to spiro-epoxydienones (7).6 The majority of examples utilizing this
reaction do so with primary benzylic alcohols (R = H).7 Only a
handful of reports in the literature8 utilize secondary alcohols
(R = C), indicating that oxidation of such substrates is far more
challenging. A notable exception is the oxidation of reduced tetra-
lone derivatives, which have been most famously utilized for the
total synthesis of the natural product triptolide.9 This handful of
secondary alcohol examples suggests that fused alcohol substrates
would fair better than acyclic ones in a synthetic strategy.
Our initial explorations utilized the common synthetic inter-
mediates 8 and 10 (Scheme 3) from our Wessely oxidation ef-
forts.5 In agreement with precedence, acyclic resorcinol
substrates such as 8 failed to form spiro-epoxy dienones (9)
using either classical or modified Adler–Becker reaction condi-
tions. On the other hand, Stetter cyclization substrate 10 pro-
ceeded smoothly in methanol-water to form the bright yellow,
fused spiro-dienone pyran 11.
Turning our attention towards advancing a more functional-
ized variant (Scheme 4), our keto ester 12 was selectively re-
duced in the presence of DIBAL-H to aldehyde 13. Horner–
Wadsworth–Emmons homologation using phosphonate 14 affor-
ded enoate 15. Ketone reduction provided an Adler–Becker oxi-
dation substrate that dearomatized readily to 16 upon
treatment with sodium periodate. Disappointingly, this tetraene
did not undergo the desired intramolecular Diels–Alder reaction
to cycloadduct 17. Mild heating returned only starting material,
with higher temperature (>150 °C) leading to decomposition. At-
Me
Me
H
OH
iPr
Vinigrol (1)
OH
Me
H
OH
Me
OH
H
OH
Me
OH
Me
H
H
O
O
RO
RO
O
Me
OR
2
OR' OH
3
OR'
O
OH
OH
O
O
OR
OR
O
O
OR'
4
5
OR'
* Corresponding author. Tel.: +1 354 607 255 4137; fax: +1 354 607 254 5035.
E-mail address: jn96@cornell.edu (J.T. Njardarson).
Scheme 1. Vinigrol retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.134

J. G. M. Morton et al. / Tetrahedron Letters 50 (2009) 1684–1686
1685
OH OH
O
OH
O
O
OH
O
O
O
Adler-Becker
Oxidation
NaIO4
a,b
c,d
R
R
MeOH, H2O
6
75%
85%
7
21
22
Scheme 2. The Adler–Becker dearomatization reaction.
O
O
e
O
88%
O
O
O
f
O
OH OH
23
24
O
OEt
OEt
X
O
O
OMe
OMe
O
9
O
8
68%
25
OH
O
OH
O
OH
O
Scheme 5. Adler–Becker oxidation of chromanones. Reagents and conditions: (a)
NaH, allyl bromide, DMF; (b) Pd(OAc)2, TFA, EtOH, 50 °C; (c) NaBH4, MeOH, (d)
NaIO4, MeOH, H2O; (e) PhMe, 150 °C; (f) Cp2TiCl, THF, rt.
NaIO4
CO2Et
CO2Et
MeOH, H2O
85%
10
O
11
Scheme 3. Acyclic versus rigid secondary alcohol Adler–Becker substrates.
O
OH
TMSO
O
a
b
92%
OH
O
O
OH
OH
O
99%
OH
O
OTMS
O
26
28
27
29
a
OH
CO2Et
12
OH
O
13
O
61%
c,d
e,f
O
O
57%
49%
O
O
O
O
OEt
13,b
75%
(EtO)2P
O
OEt
g
O
O
O
O
14
15
20%
O
30
31
O
O
O
OEt
e
O
c,d
O
O
80%
O
X
54%
O
O
O
16
O
X
32
33
O
O
Scheme 6. Adler–Becker oxidation of benzofuranone framework. Reagents and
conditions: (a) LDA, THF, then TMSCl; (b) NBS, then KOH, MeOH, H2O; (c) NaH, allyl
bromide, DMF; (d) Pd(OAc)2, TFA, EtOH; (e) LiAlH4, THF, (f) NaIO4, MeOH, H2O; (g)
PhMe, 150 °C.
OH
EtO
OH
O
CO2Et
17
18
O
O
O
oxidation of the resulting alcohol yielded desired dienone 23 in
good yield. We were delighted to learn that, upon prolonged heat-
ing in toluene at 150 °C, the tetracyclic cycloadduct 24 was formed
in excellent yield. Finally, Cp2TiCl-mediated radical opening of the
epoxide4 gave the alcohol 25. This simple model substrate contains
much of the vinigrol pre-fragmentation core, with the all the chal-
lenging hydroxyl groups in their respective positions.
Catalyzed by this success, and in parallel with our chromanone
model studies, we argued that a smaller fused framework might
bring the dienophile closer to the dienone and hence enable cyc-
loadditions at temperatures low enough to preclude decomposi-
tion of our sensitize spiro-quinols. Models and our calculations
suggested a spiro-dienone product such as 30 would indeed bring
the two cycloadduct components closer together, and thus a five-
membered ring (benzofuran derivative, Scheme 6) variant of the
chromanone model system was born. Our studies utilized known
benzofuranone 2811 as a starting point, which is readily accessed
in two high yielding steps from commercially available 2,6-dihy-
droxyacetophenone. Ketone 29 was obtained as 22 before, by first
exhaustively allylating and then selectively deallylating to the free
phenol. This new structure is both more rigid and more sterically
o
O o
EtO2C
90%
O
O
CO2Et
O
O
19
20
O
Scheme 4. Acyclic versus rigid secondary alcohol Adler–Becker substrates.
Reagents and conditions: (a) 2.2 equiv DIBAL-H, PhMe, À78 °C; (b) t-BuOK, PhMe,
À78 °C; (c) NaBH4, Et2O, 0 °C; (d) NaIO4, MeOH, H2O; e) EtAlCl2, 0 °C.
tempts at low temperature, Lewis-acid-mediated Diels–Alder
cycloadditions also failed in generating the desired bicycle.
Rather, reaction with EtAlC2 at 0 °C led to the rearrangement
product 18. This is in stark contrast with our Wessely oxidation
results, wherein the oxidation reaction to 19 proved very chal-
lenging while the cycloaddition to 20 proceeded smoothly.
Unsatisfied with this result, we regrouped to a simpler sub-
strate to explore this approach further. Beginning from known
chromanone 2110 (Scheme 5), exhaustive allylation was followed
by deprotection to afford ketone 22. Reduction and Adler–Becker

1686
J. G. M. Morton et al. / Tetrahedron Letters 50 (2009) 1684–1686
Supplementary data
OH O
MOMO
MOMO
O
MOMO
OH
a,b
c,d
O
OEt
Supplementary data (experimental details and spectral data)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.01.134.
CN
82%
87%
O
O
e
OH
35
34
36
37
CO2Et
38
O
O
References and notes
f,g
61%
Br
CO2Et
CN
O
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53%
OH
CO2Et
CO2Et
OH
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CN
40
CN
39
X
O
O
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Scheme 7. Synthesis and evaluation of a more complex benzofuranone. Reagents
and conditions: (a) MOMCl, iPr2NEt, DCM; (b) EtOH, K2CO3; (c) ClCH2CN, K2CO3,
MeCN, rt; (d) tBuOK, PhH, 0–25 °C; (e) NaH, THF, then NaI, 35, rt; (f) 5% aq HCl,
EtOH; (g) NaBH4, MeOH, 0 °C.
congested than its predecessor. This is reflected in a slower reduc-
tion and lower yielding Adler–Becker oxidation (30). Careful heat-
ing of the dearomatized core afforded the highly strained
cycloadduct 31, albeit in non-optimized yields. In order to better
assess the scope of this approach we also accessed prenylated core
32 using an identical synthetic approach. This tetraene resisted all
attempts to form 33, with decomposition occurring at elevated
temperatures.
Having realized moderate success in both the oxidative dearo-
matization and subsequent Diels–Alder cycloaddition to 31, we
investigated this benzofuran framework further using more ad-
vanced synthetic components (Scheme 7). Transesterification of
the known benzodioxanone 3412 with EtOH gave 35. Alkylation
of the free phenol with chloroacetonitrile and subsequent conden-
sation yielded the b-ketonitrile 36. Keeping in mind the failure of
the bis-prenyl derivative 32 to undergo Diels–Alder cycloaddition,
we decided to use an electronically matched enoate dienophile in
this route. Selective C-alkylation with bromo enoate 3713 was thus
used, affording 38. Deprotection of the phenolic MOM-group and
reduction of the ketone set the stage for the critical dearomatiza-
tion step. Unfortunately, diol 39 resisted all our attempts14 to con-
vert it to spiro-dienone 40. Indeed, when any reaction at all
occurred it was reoxidation to the ketone.
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In summary, despite this route being a dead end for our vinigrol
campaign it does serve to highlight both the incredible untapped
synthetic potential of the Adler–Becker dearomatization in rapidly
accessing complex structures and the need that still exists for reac-
tive, selective oxidizing agents for such processes.
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Acknowledgements
14. Conditions attempted include: NaIO4, MeOH/H2O; NaIO4, AcOH; NaBiO3,
AcOH; Cu(CH3CN)4PF6, morpholine, DIEA, CH2Cl2, O2; CuCl2–morpholine,
MeCN, MeOH, O2; CuCl2, pyridine, MeOH, H2O; PhI(OAc)2, CF3CH2OH; H5IO6,
wet MeOH; H5IO6, THF.
We thank Cornell University for support. We are grateful for an
Einhorn Summer Undergraduate Research Fellowship (JDF). This
material is based upon work supported under a National Science
Foundation Graduate Research Fellowship (JGMM).