Thieme Chemistry Journal awardees - Where are they now? Efforts towards the total synthesis of vinigrol

Article abstract of DOI:10.1055/s-0028-1087378

A strategy for the total synthesis of vinigrol is detailed with two key steps - oxidative dearomatization and intramolecular Diels-Alder cycloaddition - providing the cis-decalin core. A novel and mild means for the formation of ortho-quinone methides is

Full text of DOI:10.1055/s-0028-1087378

LETTER
23
Thieme Chemistry Journal Awardees – Where are They Now?
Efforts towards the Total Synthesis of Vinigrol
E
ffortstow
a
ards
V
inig
s
r
ol on 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
Fax +1(607)2554137; E-mail: jn96@cornell.edu
Received 12 September 2008
Abstract: A strategy for the total synthesis of vinigrol is detailed
with two key steps – oxidative dearomatization and intramolecular
Diels–Alder cycloaddition – providing the cis-decalin core. A novel
and mild means for the formation of ortho-quinone methides is also
described.
Key words: vinigrol, oxidative dearomatization, cycloaddition,
ortho-quinone methide, trichloroacetylisocyanate
Isolated from a fungus, Virgaria nigra, found at the foot
of Mount Aso in Japan, the diterpenoid vinigrol (1,
Jón T. Njarðarson was born and raised in the small town of Akranes,
Iceland. After graduating from high school, he left his hometown and
moved to Reykjavik to start his chemistry studies at the University of
Iceland. During this time he worked in the laboratory of Professor Jón
K. F. Geirsson. Jón then followed in the footsteps of his Icelandic
ancestors and moved west, which brought him to New Haven Con-
necticut, where he chose to pursue a graduate career in Organic Che-
mistry at Yale University in the laboratories of Professor John L.
Wood working on the total synthesis of CP-263,114. At the end of his
graduate studies Jón was presented with the irresistible offer of mo-
ving to New York City and join the laboratory of Professor Samuel J.
Danishefsky at the Memorial Sloan-Kettering Cancer Center, where
he worked on the total syntheses of the natural products epothilone
490 and migrastatin. Jón arrived in Ithaca in the summer of 2004 to
start his independent career at Cornell University. His laboratory is fo-
cused on the development of useful new synthetic methods and the to-
tal synthesis of natural products.
Figure 1) has attracted much interest due to a challenging
and unique skeletal framework and potentially useful
pharmacological properties. These latter include activity
as an antihypertensive and platelet aggregation inhibi-
tor,1a,b tumor necrosis factor antagonist,1c and nerve stem
cell proliferation promoter.1d Yet despite work spanning
more than 15 years from at least nine independent labora-
tories,2 a total synthesis of this molecule has not been re-
alized.
Me
Me
Me
OH
H
H
OH
Me
OH
OH
i-Pr
H
HO
Me
OH
H
Me
H
O
O
vinigrol (1)
Me
Me
Figure 1 Representations of vinigrol
Me
OR1
Me
OR1
strain-assisted
radical bond scission
Our strategy for constructing an advanced vinigrol precur-
sor such as I consists of four key operations (Scheme 1).
As it has been well established that endgame closure of
the eight-membered ring is infeasable,2j–m it is our belief
that selective bond cleavage of a bicyclo[2.2.2]octane sys-
tem such as II will ‘unravel’ the latent cyclooctane. Func-
tional-group manipulation then leads us back to III, which
we envision being generated from a 6-exo-trig or 6-exo-
dig olefin reduction ring-closure protocol of IV. We
imagine this bicyclic structure being produced in turn by
the intramolecular Diels–Alder cycloaddition of a diene-
containing o-benzoquinol V, itself generated via oxidative
dearomatization of a suitably substituted phenol VI.
OH
2 OH
OR
OR2
Me
I
II
EtO2C
R2O
EtO2C
R2O
O
Me
OR1
OR1
α-deoxygenation,
radical ring cyclization
IMDA
OH
OAc
IV
III
O
OR1
OH OR1
CO2Et
CO2Et
OAc
OR2
V
oxidative
OR2
dearomatization
VI
SYNLETT 2009, No. 1, pp 0023–0027
x
x.
x
x.
2
0
0
8
Scheme 1 Retrosynthetic strategy
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087378; Art ID: S08208ST
© Georg Thieme Verlag Stuttgart · New York

24
J. G. M. Morton et al.
LETTER
O
O
1) KOt-Bu, PhMe, 0 °C
(EtO)2P
OEt
TBSO
CO2Et
O
2)
TBSO
PhMe, –78 °C, 82%
3
2
4
6
OTHP
Li
1) 1 M HCl, THF, 0 °C
OTHP
CO2Et
O
2) Swern oxidation
85% (2 steps)
TMEDA, THF
–78 to 0 °C, 67%
5
THPO
OH
O
O
1) 1 M H2SO4
THF, 0 °C, 78%
CO2Et
CO2Et
2) PPTS, CH2Cl2
5 Å MS, r.t.,
7
8
OTHP
OH
MeO
62%
O
O
O
O
O
see text
X
rather,
CO2Et
CO2Et
OAc
O
9
10
AcO OAc
Scheme 2 First attempt at oxidative dearomatization
We initially focused on construction of the phenol 8 While the mechanism of oxidative dearomatization is de-
(Scheme 2) in the belief that, during oxidative dearomati- pendent largely on the oxidant and conditions used, the
zation, the intramolecular acetonide tether would affect Wessely oxidation, employing Pb(OAc)4, generally pro-
nucleophilic trapping from the opposite face as the large vides selectivity for nucleophilic incorporation of acetate
dienophile-bearing side chain. Furthermore, this ace- at the most electron-rich site ortho to the phenol.8 We
tonide would bring the dienophile into the proximity of were thus disappointed to find that reaction of lead tet-
the o-benzoquinol ring, facilitating the Diels–Alder cy- raacetate in CH2Cl2 with 8 gave no detectable quinol 9,
cloaddition. Towards this goal, a Z-selective Horner– but rather only the undesired and readily hydrolyzed
Wadsworth–Emmons protocol3,4 between phosphonate 2 masked quinone 10 along with small amounts of its para
and aldehyde 35 generated the tribustituted olefin 4. For- isomer. Further efforts with other oxidants – LTA/
mation of the ortho-lithiated6 resorcinol derivative 67 and BF3·OEt2,9 PIDA or PIFA,10 benzeneseleninic anhy-
12
electrophilic trapping with 3 then provided the benzylic dride,11 and Cu(II)/morpholine/O2 – were also unsuc-
alcohol 7. Careful deprotection to the unstable triol and cessful in generating 9.13
acetonide formation gave the desired 8, and we were
ready to attempt the first key step of our synthetic plan.
This failure in site selectivity led us to pursue a path
(Scheme 3) in which use of an intramolecular nucleophile
would enforce attack at the proper position. A carbamate
THPO
THPO
OH
Li
11
1 M H2SO4, THF
r.t., 89%
CO2Et
OMe
5
TMEDA, THF
–78 to 0 °C, 83%
OMe
12
OEt
O
OH OH
O
Cl3C
NCO
CO2Et
CO2Et
OEt, CH2Cl2
–78 to 0 °C, 81%
OMe
OMe
13
14
endo/exo > 9:1
Scheme 3 o-Quinone methide-mediated hetero Diels–Alder reaction.
Synlett 2009, No. 1, 23–27 © Thieme Stuttgart · New York

LETTER
Efforts towards Vinigrol
25
was chosen as an analogue to an amide, where the more 17 and a nearly equal combined amount of the two
electron-rich carbonyl oxygen is known to out-compete spirobenzoquinol diastereomers 18 (dr = 2.5:1). The bicy-
the nitrogen as nucleophile and hydrolysis of the resultant cle, whose structure was confirmed by X-ray crystallogra-
iminolactone provides the lactone.14 Beginning with the phy of a pivaloate derivative,18 probably results from a
same aldehyde 5 used in our first route, a similar nucleo- polar cationic [5+2] cycloaddition made possible by the
philic addition with the ortho-lithiated resorcinol deriva- electron-donating character of the methoxy substituent.19
tive 11 formed the benzylic alcohol 12 (Scheme 3). While While separation of the spirobenzoquinol diastereomers
it was possible to form various carbamates from this alco- 18 proved intractable, heating the mixture at reflux in ben-
hol, successive deprotection of the THP moiety inevitably zene or toluene failed to afford any Diels–Alder adduct
led to elimination through an ortho-quinone methide path- 19, with more forcing or Lewis acidic conditions eventu-
way and subsequent decomposition. In an effort to put this ally leading only to decomposition.
proclivity to good use, however, it was discovered that
Altering the dienophile electronics might have enabled
treatment of the diol 13 with trichloroacetylisocyanate15
the Diels–Alder cyclization of 18, but this would have no
in ethyl vinyl ether and CH2Cl2 as co-solvents efficiently
effect on the poor diastereoselectivity20 of the oxidative
led to the hetero-Diels–Alder product 14 in one pot with
dearomatization and the formation of 17 as a major
byproduct. We thus sought to synthesize a construct
good yield.7,16
which would exhibit both a predetermined stereoselectiv-
ity in the oxidative dearomatization and geometrical inhi-
O
bition of the [5+2] adduct. To this end, the known
O
benzaldehyde 2021 was monocrotonylated and engaged in
1) CSA, MeCN,
H2O, 40 °C, 87%
CO2Et 1 M NaOH, THF
0 °C, quant.
an intramolecular Stetter reaction22 to form the chro-
manone 22 (Scheme 5). Reduction with NaBH4 led to the
diol, after which use of our quinone methide-generating
protocol yielded the adduct 23 with nearly complete facial
diastereoselectivity.23 Reduction to the aldehyde was ac-
complished with DIBAL-H, after which Horner–Wads-
worth–Emmons olefination was employed to generate 25.
Deprotection to the lactol and Jones oxidation gave lac-
tone 26.
14
2) Jones oxidation, 89%
OMe
15
O
EtO2C
OH
OH
O
IBDA, HFIP, 0 °C
CO2Et
17/18 = 1:0.9
65% overall
MeO
H
O
OMe
O
16
17
While opening to the free acid was again facile, the oxida-
tive dearomatization proceeded in exceedingly poor yield
despite extensive testing of oxidants, solvents, and tem-
perature conditions. Reasons for this difficulty are un-
clear. Gratifyingly, however, the intramolecular Diels–
Alder cycloaddition proceeded well, allowing us to indeed
access the desired bicyclic structure 27.24
O
EtO2C
MeO
O
O
see text
O
CO2Et
X
+
OMe
O
18
O
19
dr = 2.5:1
With 27 in hand, it was then incumbent to affect closure
of the posterior six-membered ring. We had initially envi-
sioned a radical cyclization for this purpose (Scheme 6);
Scheme 4 Formation of [5+2] product 17
Intrigued by this mild means for the in situ formation of however, employment of SmI2 proved unsuccessful, giv-
ortho-quinone methides,17 we have tested this protocol ing only an intractable mixture of unidentified com-
with other 2-hydroxybenzylic alcohols and dienophiles, pounds. Changing tack, treatment of 27 with Br-9-BBN
have found it to be quite general, and will report this work gave the vinyl bromide 28 with which we hoped to em-
ploy a ‘top-down’ cyclization approach. Unfortunately,
efforts at transmetalation employing t-BuLi25 and n-
Bu2CuLi26 were unsuccessful in forming identifiable
products, while Nozaki–Hiyama–Kishi27 coupling condi-
tions likewise failed to close the posterior six-membered
ring. The difficulty might lie in the extreme steric crowd-
ing of the compact and rigid bicyclic ring systems pre-
venting the incoming nucleophile from approaching the
carbonyl at the requisite Bürgi–Dunitz trajectory.28
at a later time.
Continuing with our efforts towards vinigrol (Scheme 4),
hydrolysis of the acetal 14 with camphorsulfonic acid
(CSA), and subsequent Jones oxidation realized lactone
15, which could be readily opened under alkaline condi-
tions to the free acid 16. Optimized oxidative dearomati-
zation of 16 with iodobenzene diacetate (IBDA) in
1,1,1,3,3,3-hexafluoroisopropanol (HFIP), however, re-
sulted in three products: the unanticipated bicyclic adduct
Synlett 2009, No. 1, 23–27 © Thieme Stuttgart · New York

26
J. G. M. Morton et al.
LETTER
Bn
OH
O
OH
O
O
CO2Et
N
Cl
HO
Br
CO2Et
S
K2CO3, DMF
82%
DIPEA, CH2Cl2
86%
OH
20
21
OEt
OH
O
O
O
1) NaBH4, MeOH, 0 °C
CO2Et
CO2Et
2)
O
O
OEt
Cl3C
NCO ,
22
23
–78 to 0 °C, 85% (2 steps)
endo/exo > 9:1
1) DIBAL-H, PhMe, –78 °C
2) KOt-Bu, PhMe, –78 °C,
OEt
O
EtO2C
1) CSA, THF,
MeCN, H2O
24
O
P(OEt)2
2) Jones oxidation
CO2Et
80% (2 steps)
70% (2 steps)
O
25
O
O
EtO
1) 1 M NaOH, THF, 0 °C
2) LTA, HFIP, 0 °C
3) PhMe, 100 °C
O
O
CO2Et
8.4% (3 steps)
O
O
26
O
27
O
Scheme 5 Formation of the bicyclic adduct 27
difficulty in closing the posterior ring, we have ceased fur-
ther efforts in this particular route. Instead, we are concen-
trating on a newer strategy for the synthesis of vinigrol,
which still retains the four key ideas of our original ret-
rosynthesis: oxidative dearomatization, intramolecular
Diels–Alder cycloaddition, radical cyclization, and selec-
tive bond scission. This work will be communicated in
due course.
O
O
EtO
EtO
SmI2, HMPA
X
THF, t-BuOH
–78 °C
O
OH
O
O
O
O
O
O
27
29
Br
O
BrBBN
CH2Cl2, –78 °C
EtO
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
see text
X
O
O
O
Acknowledgment
O
28
Thanks to Ivan Keresztes and Anthony Condo for NMR aid and
Emil Lobkovsky for the X-ray structure of the [5+2] bicycle. Mari-
ya Morar provided the stereoviews of this structure shown in the
Supporting Information. This material is based upon work suppor-
ted under a National Science Foundation Graduate Research Fel-
lowship (J.G.M.M.).
Scheme 6 Attempted posterior ring closure
Given the synthetically untenable yields for the transfor-
mation of 26 to the bicyclic adduct 27 and this unexpected
Synlett 2009, No. 1, 23–27 © Thieme Stuttgart · New York

LETTER
Efforts towards Vinigrol
27
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