The discovery of a novel route to highly substituted -tropolones enables expedient entry to the core of the gukulenins

Article abstract of DOI:10.1021/acs.orglett.5b00841

A simple and general method for the synthesis of highly substituted α-tropolone ethers that allows rapid access to the bis(tropolone) core of the antiproliferative metabolites (-)-gukulenins A and F (3, 4) is described. The reaction proceeds by thermolyti

Full text of DOI:10.1021/acs.orglett.5b00841

Letter
pubs.acs.org/OrgLett
The Discovery of a Novel Route to Highly Substituted α‑Tropolones
Enables Expedient Entry to the Core of the Gukulenins
Roman Kats-Kagan and Seth B. Herzon*
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: A simple and general method for the synthesis of highly
substituted α-tropolone ethers that allows rapid access to the
bis(tropolone) core of the antiproliferative metabolites (−)-gukulenins
A and F (3, 4) is described. The reaction proceeds by thermolytic
opening of gem-dibromobicyclo[4.1.0]heptane intermediates, which are
readily accessed from simple starting materials. Mechanistic studies
suggest the reaction proceeds via an autocatalytic process mediated by
methyl hypobromite. This synthetic sequence allows access to a broad
array of highly substituted α-tropolones.
atural α-tropolones are found in hundreds of natural
products and have received significant interest from the
Our interest in methods for tropolone syntheses derive from
the pseudodimeric bis(tropolone) natural products (−)-guku-
lenins A and F (3 and 4, respectively), which were recently
isolated from the marine sponge Phorbas gukulensis.12 Both 3
and 4 display 50 percent inhibitory potencies in the nanomolar
range against various cancer cell lines. We envisioned a
synthetic route to 3 and 4 that involves preparation of a C2-
symmetric bis(tropolone) core followed by attachment of the
substituted cyclopentyl rings and desymmetrization. As few
methods to access 4,6,7-trisubstituted α-tropolones have been
reported,5 we set out to develop a new process. Herein we
report the discovery of a simple method that allows access to a
broad range of substituted tropolones containing this
substitution pattern as well as the core of the targets 3 and 4.
Our tropolone synthesis begins with benzylic reduction and
bromination of ortho-vanillin (5), to provide 4-bromo-2-
methoxy-6-methylphenol (6, Scheme 1). Oxidation of 6
[bis(acetoxy)iodobenzene, methanol]13 then forms the masked
ortho-benzoquinone 7 in 78% yield over three steps. Cyclo-
propanation (bromoform, sodium hexamethyldisilazide) gen-
erates the bicyclo[4.1.0]heptane 8a (74%). Due to the electron-
deficient nature of 7, we believe the formation of 8a proceeds
by the 1,4-addition of a tribromomethyl anion, followed by
cyclization,14 rather than addition of dibromocarbene.15 The
bicyclo[4.1.0]heptane 8a is a suitable substrate for the ring
expansion reaction (vide infra), but in our optimization studies,
we employed the more stable carbomethoxy derivative 8b,
which is obtained in 81% yield by palladium-mediated
methoxycarbonylation of 8a.
N
scientific community due to their unique structural features and
manifold therapeutic properties.1 Of the diverse array of natural
products containing the tropolone substructure, none have
enjoyed as much attention from synthetic chemists as
(−)-colchicine (1)2 and imerubrine (2, Figure 1).3 The
Figure 1. Structures of (−)-colchicine (1), imerubrine (2), and
(−)-gukulenins A and F (3, 4, respectively).
structure of 1 was first proposed in a seminal paper by
Dewar,4 and synthetic studies of 1 and 2 have motivated several
methods for the construction of functionalized tropolone
skeletons.5 Selected approaches include 1,3-dipolar cyclo-
addition reactions,6 oxidative ring opening of 7-halogeno-
bicyclo[4.1.0]heptane-diols,7 ring expansion of bicyclo[3.2.0]-
heptane derivatives,8 acid-catalyzed rearrangement of bicyclo-
[4.1.0]heptanols,9 oxopyrylium cycloadditions,10 and
cycloadditions between tetrabromocyclopropene and furan.11
We envisioned conversion of 8b to the tropolone 11b by a
cascade comprising 1,2-reduction of the ketone, elimination of
methanol (8b → 9), [3,3]-sigmatropic rearrangement (9 →
10), and bromide elimination (10 → 11b, Scheme 2).
Received: March 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00841
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
borohydride−1,4-dioxane system led us to postulate the
involvement of alternative mechanistic pathways.
Scheme 1. Synthesis of the Bicyclo[4.1.0]heptanes 8a and 8b
We then considered Lewis acid activation as a means of
promoting the reaction; however, treatment of 8b with boron
trifluoride−etherate complex (1.1 or 2.2 equiv, entries 3 and 4,
respectively) led predominantly to cleavage of the dimethyl
acetal, to produce the α-dicarbonyl 12 in 24% or 48% yield (5%
or 3% yield of 11b). Thermolysis of 8b in the presence of
alumina (introduced to maintain mildly basic reaction
conditions) afforded the desired product 11b in 59% yield,
but significant decomposition of the starting material 8b was
still observed (entry 5). As an alternative mechanism we
posited that the ring expansion may proceed by generation of a
diradical intermediate, as is often proposed in the thermal
rearrangement of vinylcyclopropanes.16 As formal reduction of
the substrate is required in the mechanism, tributyltin hydride
(entry 6) and triethylsilane (entry 7) were evaluated as
hydrogen atom donors. In the presence of either reagent, the
yield of the product 11b was substantial (61% and 81% yield
for tributyltin hydride and triethylsilane, respectively) and the
α-dicarbonyl 12 was observed as a minor product (9% or 13%).
Surprisingly, a control experiment revealed that the rearrange-
ment proceeded smoothly upon heating to 70 °C in
tetrahydrofuran alone (86%, entry 8). Addition of 4 Å MS
completely inhibited the reaction, which we believe has
bearings on the mechanism (entry 9, vide infra).
Scheme 2. Original Pathway Conceived for the Conversion
of 8b to 11b
The sequence outlined above provides straightforward access
to a broad range of highly substituted tropolone derivatives
(Table 2). The substrates 8c−8j were prepared by site-selective
metal-catalyzed functionalization of 8a.17 The parent substrate
8a underwent ring expansion to the dibromotropolone 11a in
93% yield, and the structure of the product was verified by X-
ray analysis (entry 1).18 The trimethylsilylacetylene derivative
8c opened smoothly to the alkynyltropolone 11c in 78% yield
(entry 2). Furthermore, the aryl derivatives 8d and 8e
underwent high-yielding ring expansion (94% each, entries 3
and 4). In these cases, the yields were dramatically improved by
the addition of 1 equiv of triphenylphosphine to the reaction
mixture. In its absence, competitive bromination of the arene
rings was observed. The formyl and silyl derivatives 8f and 8g
underwent ring expansion in 82% and 83% yield, respectively,
to provide the tropolones 11f and 11g (entries 5 and 6).
Cyclopropanation of 7 with iodoform generated the diiodo
cyclopropane 8h17 which underwent ring expansion to provide
the bromoiodotropolone 12h in 71% yield. Surprisingly, small
amounts of the corresponding 4,6-dibromo- and 4,6-diiodo-
tropolones were also produced, potentially by electrophilic
transhalogenation of the product. The addition of iodine (1
equiv) was found to suppress formation of these side products
(7% and 9% yield of the dibromo- and diiodo-tropolones,
respectively). The pyrrolidinyl amide 8i underwent smooth ring
expansion to generate the amide-substituted tropolone 11i in
83% yield (entry 8). Finally, the bis(dibromocyclopropane)
dimer 8j was prepared in one step from 8a by Stille coupling
with trans-1,2-di(tributylstannyl)ethylene (entry 9).17 This
dimeric substrate underwent smooth ring expansion to provide
11j in 76% yield. The successful synthesis of 11j establishes a
six-step route to the gukulenin skeleton.
Treatment of the bicyclo[4.1.0]heptane 8b with sodium
borohydride in refluxing dioxane resulted primarily in
decomposition, though the desired product 11b was produced
in 6% yield (entries 1 and 2, Table 1). An evaluation of a range
of hydride sources, solvents, and temperature profiles did not
improve the yield of 11b (data not shown). Moreover,
significant variability in the conversion of 8b in the sodium
a
Table 1. Optimization of the Ring Expansion
yield
11b
yield
12
entry reagent (equiv)
solvent t (°C)
conv
1
2
3
4
5
6
7
8
9
NaBH4 (1.1)
NaBH4 (2.2)
BF3·OEt2 (1.1)
BF3·OEt2 (2.2)
Al2O3 (0.8)
HSnBu3 (0.3)
HSiEt3 (1.0)
none
dioxane
dioxane
CH2Cl2
CH2Cl2
dioxane
dioxane
dioxane
THF
110
110
23
>99%
>99%
51%
6%
6%
0%
0%
5%
24%
48%
0%
23
91%
3%
110
110
110
70
>99%
>99%
>99%
>99%
0%
59%
61%
81%
86%
0%
9%
13%
0%
The vinyl bromide substituent of the ring expansion products
provides a useful handle for further diversification. For example,
treatment of 11b with benzenethiol in the presence of
triethylamine induced clean addition−elimination, to provide
the sulfide 13 (97%, Scheme 3). Alternatively, Stille coupling of
4 Å MS
THF
70
0%
a
Yields and conversions determined by 1H NMR spectroscopy against
an internal standard or by isolation; see Supporting Information.
B
DOI: 10.1021/acs.orglett.5b00841
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
11b with 2-(trimethylstannyl)-3-isopropyl-cyclopent-2-ene-1-
one provided the cross-coupling product 14 in 96% yield.
Table 2. Thermal Ring Expansion of Bicyclo[4.1.0]heptane
Derivatives
a
Scheme 3. Functionalization of the Tropolone 11b
Several experiments were conducted to gain insight into the
mechanism of this ring expansion. Conducting the ring
expansion of 8b in tetrahydrofuran-d8 formed the expected
product 11b, without detectable levels of deuterium-atom
incorporation (1H NMR analysis). This result would seem to
exclude a pathway involving the generation of free radical
intermediates and hydrogen atom abstraction from the solvent.
In addition, continuous monitoring of this reaction (at 60 °C)
1
at 10 min intervals by H NMR spectroscopy revealed a long
induction period (ca. 9 h) followed by rapid reaction, with full
conversion observed within 10 min and no intermediates
detectable by NMR analysis (Figure S1). This suggested to us
the possibility of an autocatalytic process, potentially mediated
by protic species or methyl hypobromite, the latter of which is
formally generated in the transformation of 8b to 11b. In
accord with this, treatment of 8b with hydrogen bromide (1.0
equiv) at ambient temperature formed 11b in 72% yield within
1 h (Scheme 4). To probe for mediation of the reaction by
Scheme 4. Mechanistic Experiments To Evaluate the Role of
Acidic and Electrophilic Species in the Ring Opening of 8b
methyl hypobromite, 8b was treated with 5 mol % methyl
hypobromite (generated by the addition of bromine to sodium
methoxide)19 at ambient temperature and immediately warmed
to 70 °C. Under these conditions, the ring-expanded product
11b was obtained in quantitative yield within 10 min. Exposure
of 8b to 1 equiv of methyl hypobromite at ambient temperature
provided 11b in 54% yield, along with unidentified
decomposition products.
Based on these data, we suggest the pathway shown in
Scheme 5, which shares some similarities to the ring expansion
of 2-(dihalomethyl)cyclohexanedienones developed by Barton
and co-workers.7b O-Protonation with concomitant opening of
the cyclopropane would provide the bromonium ion 15.
Collapse of the ion by elimination of bromine (the microscopic
reverse of electrophilic alkene bromination) would provide the
cycloheptatriene 16. Finally, 1,8-elimination of methanol would
afford the ring-expanded product 11b. The reaction may be
initiated by hydrogen-bonding activation of the carbonyl by
adventitious water, which is consistent with the observation
that 4 Å MS inhibit the reaction. The reaction may be
propagated via O-bromination by methyl hypobromite, which is
a
b
0.18−2.00 mmol scale. Isolated yield after purification by flash-
c
column chromatography. 1 equiv of triphenylphosphine was added.
d
1 equiv of iodine was added. Obtained as an inseparable mixture
containing the corresponding 4,6-diiodotropolone (9%) and 4,6-
dibromotropolone (7%); see Supporting Information.
C
DOI: 10.1021/acs.orglett.5b00841
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(d) Lee, J. C.; Cha, J. K. Tetrahedron 2000, 56, 10175. (e) Lee, J. C.;
Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243.
(7) (a) Banwell, M. G.; Onrust, R. Tetrahedron Lett. 1985, 26, 4543.
(b) Barbier, M.; Barton, D. H. R.; Devys, M.; Topgi, R. S. Tetrahedron
1987, 43, 5031.
Scheme 5. Proposed Mechanism for the Ring Expansion of
8b
(8) (a) Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; De Mayo,
P. J. Org. Chem. 1969, 34, 794. (b) Kelly, T. R.; Echavairen, A.;
Whiting, A.; Weibel, F. R.; Miki, Y. Tetrahedron Lett. 1986, 27, 6049.
(9) Evans, D. A.; Hart, D. J.; Koelsch, P. M. J. Am. Chem. Soc. 1978,
100, 4593.
(10) Meck, C.; Mohd, N.; Murelli, R. P. Org. Lett. 2012, 14, 5988.
(11) Oblak, E. Z.; Bolstad, E. S. D.; Ononye, S. N.; Priestley, N. D.;
Hadden, M. K.; Wright, D. L. Org. Biomol. Chem. 2012, 10, 8597.
(12) (a) Park, S. Y.; Choi, H.; Hwang, H.; Kang, H.; Rho, J.-R. J. Nat.
Prod. 2010, 73, 734. (b) Jeon, J.-e.; Liao, L.; Kim, H.; Sim, C. J.; Oh,
D.-C.; Oh, K.-B.; Shin, J. J. Nat. Prod. 2013, 76, 1679.
(13) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Kameswara Rao, N. S.;
Liao, C.-C. J. Org. Chem. 2002, 67, 6493.
(14) (a) Nanjo, K.; Suzuki, K.; Sekiya, M. Chem. Lett. 1977, 6, 553.
(b) Baird, M. S.; Gerrard, M. E.; Searle, R. J. G. Tetrahedron Lett. 1985,
26, 6353. (c) Cooke, M. P.; Jaw, J. Y. J. Org. Chem. 1993, 58, 267.
(15) Mahon, M. F.; Molloy, K.; Pittol, C. A.; Pryce, R. J.; Roberts, S.
M.; Ryback, G.; Sik, V.; Williams, J. O.; Winders, J. A. J. Chem. Soc.,
Perkin Trans. 1 1991, 1255.
(16) Baldwin, J. E. Chem. Rev. 2003, 103, 1197.
(17) See Supporting Information.
(18) CCDC 1047787 contains the supplementary crystallographic
data for 11a. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.
uk/data_request/cif.
formed in equimolar quantities with the product. An alternative
initiation mechanism involving slow thermolysis of 8b (to
produce the oxyanion corresponding to 15) may be operative,
although this would seem to be inconsistent with the
observation that molecular sieves impede the reaction.
In summary, we have discovered a novel ring-expansion
reaction that provides access to a broad array of highly
substituted α-tropolones in high yield from simple, readily
accessible precursors. The reaction sequence establishes a short,
six-step route to the bis(tropolone) core of the gukulenins and
is likely to be of general utility in the synthesis of highly
substituted tropolones.
(19) Dicks, P. F.; Glover, S. A.; Goosen, A.; McCleand, C. W.
Tetrahedron 1987, 43, 923.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and spectroscopic data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: seth.herzon@yale.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Camille and Henry Dreyfus
Foundation is gratefully acknowledged.
■
REFERENCES
(1) Bentley, R. Nat. Prod. Rep. 2008, 25, 118.
(2) For reviews, see: (a) Boye, O.; Brossi, A. Alkaloids (Academic
Press) 1992, 41, 125. (b) Graening, T.; Schmalz, H.-G. Angew. Chem.,
Int. Ed. 2004, 43, 3230.
■
(3) (a) Cava, M. P.; Buck, K. T.; Noguchi, I.; Srinivasan, M.; Rao, M.
G.; DaRocha, A. I. Tetrahedron 1975, 31, 1667. (b) Silverton, J. V.;
Kabuto, C.; Buck, K. T.; Cava, M. P. J. Am. Chem. Soc. 1977, 99, 6708.
(4) Dewar, M. J. S. Nature 1945, 155, 141.
(5) For reviews, see: (a) Banwell, M. G. Aust. J. Chem. 1991, 44, 1.
(b) Liu, N.; Song, W.; Schienebeck, C. M.; Zhang, M.; Tang, W.
Tetrahedron 2014, 70, 9281.
(6) (a) Murray, D. H.; Albizati, K. F. Tetrahedron Lett. 1990, 31,
4109. (b) Davies, H. M. L.; Jeffrey Clark, T. Tetrahedron 1994, 50,
9883. (c) Harmata, M.; Jones, D. E. Tetrahedron Lett. 1997, 38, 3861.
D
DOI: 10.1021/acs.orglett.5b00841
Org. Lett. XXXX, XXX, XXX−XXX