Total synthesis of (±)-komaroviquinone

Article abstract of DOI:10.3987/COM-07-S(U)36

(±)-Komaroviquinone (1) was synthesized from 3,4,5-trimethoxybenzoic acid in twenty-two steps. The key transformations in this synthesis are: (1) the construction of the cycloheptane ring via a Friedel-Crafts cyclialkylation; (2) a regiospecific benzylic oxidation; (3) a conformationally controlled introduction of the C(10) hydroxyl group and (4) intramolecular hemi-acetal formation.

Full text of DOI:10.3987/COM-07-S(U)36

HETEROCYCLES, Vol. 73, 2007
217
HETEROCYCLES, Vol. 73, 2007, pp. 217 - 225. © The Japan Institute of Heterocyclic Chemistry
Received, 29th June, 2007, Accepted, 27th August, 2007, Published online, 28th August, 2007. COM-07-S(U)36
§
TOTAL SYNTHESIS OF (±)-KOMAROVIQUINONE
†
George Majetich,* Yang Li, and Ge Zou
Department of Chemistry, The University of Georgia, Athens, Georgia 30602,
U.S.A. majetich@chem.uga.edu
Abstract
–
(±)-Komaroviquinone
(1)
was
synthesized
from
3,4,5-trimethoxybenzoic acid in twenty-two steps. The key transformations in
this synthesis are: (1) the construction of the cycloheptane ring via a
Friedel–Crafts cyclialkylation; (2) a regiospecific benzylic oxidation; (3) a
conformationally controlled introduction of the C(10) hydroxyl group and (4)
intramolecular hemi-acetal formation.
The inhabitants of the mountains of Uzbekistan use the aerial parts of the perennial semishrub known as
“buzbosh” to cure inflammatory diseases and hypertony.1 In 2003, Honda and co-workers isolated
komaroviquinone (1) and coulterone (2)2 from buzbosh (Scheme 1).3 Of these two diterpenoids,
komaroviquinone has the more significant trypanocidal activity against epimastigotes of T. cruzi, the
causative agent of Chagas’ disease in Central and South America,4 with a minimum lethal concentration
(MLC) of 0.4 µM.5 We recognized that komaroviquinone possesses many of the salient features of
faveline (cf. 3),6 an anti-leukemic agent that we synthesized7 by means of an intramolecular Friedel–
Scheme 1
OCH3
OH
HO
OH
13
O
OCH3
12
OH
H
1
5
oxidation and
intramolecular
10
O
7
O
hemi-acetal
formation
H
O
H
O
OH
komaroviquinone (1)
faveline (3)
coulterone (2)
OCH3
OCH3
O
O
BF3-Et2O (97%)
or TiCl4 (98%)
4
5

218
HETEROCYCLES, Vol. 73, 2007
Crafts process (cf. 4 → 5),8-10 also known as a cyclialkylation.11 Both komaroviquinone and faveline
have a carbonyl group at C(7) and alkyl substituents at C(13), whereas komaroviquinone has a β-oriented
hydroxyl group at C(10) instead of a C(1),C(10)–double bond, and a more oxidized aromatic ring.
Because of komaroviquinone’s noteworthy trypanocidal activity and our ability to efficiently assemble
the icetexane skeleton, we decided to attempt a synthesis of komaroviquinone12 and thereby expand the
utility of our methodology. The results of this study are described herein.13
Scheme 2 summarizes our retrosynthetic analysis of komaroviquinone. We were confident that a regio-
and stereospecific hydration of alkene 9, a key intermediate in our synthesis of perovskone,9 would give
alcohol 8.
Selective benzylic oxidation of alcohol 8 would produce key intermediate 7.
Deprotection of the C(11) and C(14) methyl ethers of 7, followed by oxidation of the nascent
hydroquinone, would furnish quinone 6. The inspection of molecular models suggests that the planar
nature of the aromatic ring in ketone 7 introduces sufficent ring strain within the central cycloheptane
ring to favor a conformation which discourages hemi-acetal formation.
In contrast, analysis of
molecular models of quinone 6 reveals that p-quinone moiety (cf. 6) is non-planar and rather flexible
which favors intramolecular acetal formation, thereby producing komaroviquinone. Rather than repeat
the thirteen-step sequence we developed to prepare alkene 9 from vanillin (10), we investigated a new
route to prepare 9 in hope of improving the overall efficiency.
Scheme 2
CH3O
OH
OCH3
OCH3
O
O
OCH3
13
OCH3
12
1
5
OH
H
11
10
H
oxidation
acetal
formation
14
O
O
O
H
7
O
OH
O
7
selective
6
komaroviquinone (1)
oxidation
at C(7)
OH
CH3O
CH3O
OCH3
OCH3
OCH3
OCH3
OH
thirteen steps9
12% overall yield
hydration
7
OCH3
CHO
H
H
vanillin (10)
9
8
Our synthesis of (±)-komaroviquinone began with 3,4,5-trimethoxybenzoic acid (11), which is converted
to ester 12 using the three-step procedure reported by Kotsuki and co-workers (Scheme 3).14 While the
bulky triethylcarbinyl moiety precludes 1,2-addition to the ester carbonyl, it also hampered further

HETEROCYCLES, Vol. 73, 2007
219
functionalization of the aromatic ring. It was only after triethylcarbinyl ester 12 was transesterified to
methyl ester 13 that electrophilic bromination with NBS occurred. The presence of a bromine atom at
C(11) permitted its conversion into an aryl methyl ether by treatment with sodium methoxide in the
presence of copper(I) chloride (i.e., 14 → 15).15 The conversion of ester 15 to tricyclic alkene 9 used
the same steps reported in our perovskone synthesis (cf., ester 15 → enone 16 → enone 17 → alkene
9).9 It is noteworthy that the preparation of alkene 9 from 3,4,5-trimethoxybenzoic acid also required
thirteen steps but proceeded in 30% overall yield.
Scheme 3
i) SOCl2
ii) (Et)3COH
iii) i-PrMgCl
CO2C(CH2CH3)3
CO2CH3
CO2H
CO2CH3
Br
iv) 10% HCl,
MeOH
OCH3
(97%)
v) NBS
(97%)
11
12
(70%
CH3O
overall)14
CH3O
OCH3
CH3O
OCH3
CH3O
OCH3
OCH3
13
14
11
12
vi) Cu(I)Cl,
NaOMe (90%)
Br
CH3O
OCH3
CO2CH3
OCH3
CH3O
OCH3
O
ix)
and NaH
vii) LAH (95%)
viii) PBr3 (98%)
O
OCH3
CH3O
OCH3
CH3O
OCH3
O
16
x) NaH, Me2SO4
(85% over two steps)
15
xi) vinyllithium,
H3O+ (95%)
CH3O
CH3O
OCH3
OCH3
OCH3
O
CH3O
OCH3
O
xiii) NH2NHTs,
catecholborane,
xii) TiCl4
(95%)
OCH3
NaOAc
(82%)
H
OCH3
9
17
Epoxidation of alkene 9 with m-CPBA in methylene chloride gave epoxide 18 in 86% yield (Scheme
4). The facial selectivity of this epoxidation was confirmed by means of an X-ray crystal structure of
epoxide 18.16
Subsequent opening of this epoxide with LAH produced tertiary alcohol 8 in 88% yield.
Scheme 4
CH3O
CH3O
CH3O
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
HO
H
O
H
LAH
m-CPBA
(88%)
(86%)
H
18
8
9
In contrast to the oxidation of acetate 19 which produced ketone 20 in 58% yield, the treatment of

220
HETEROCYCLES, Vol. 73, 2007
alcohol 8 with PCC or CrO3 instead gave only keto-aldehyde 21 via cleavage of the C(10),C(20)–bond
(Scheme 5). The free radical nature of this fragmentation was confirmed when alcohol 8 was treated
with lead tetraacetate and iodine17 and the only product formed was acetate 22.
Scheme 5
OCH3
OCH3
AcO
AcO
H
H
H
H
PCC or CrO3
(58%)
O
19
20
CH3O
20
OCH3
OCH3
OCH3
OCH3
OCH3
OAc
H
O
O
O
HO
10
OCH3
LTA,
PCC or
CrO3
(60%)
H
I2, CaCO3
(80%)
H
OCH3
H
OCH3
21
8
22
After learning that tertiary alcohol 8 would not tolerate oxidative conditions, we decided to protect the
C(10) hydroxyl group in order to preclude this fragmentation (Scheme 6). As one would expect, the
hindered nature of alcohol 8 resisted all efforts to convert it into an acetate, a methyl ether, or a MOM
ether. Surprisingly, treatment of 8 with an excess of both lithium hexamethyldisilazide and
trimethylsilyl chloride produced silyl ether 23 in 68% isolated yield along with a 31% yield of unreacted
alcohol 8. The oxidation of 23 with PCC or CrO3/CH3COOH gave only unreacted starting material.
Less common reagents known to oxidize a benzylic methylene were then studied. For example,
copper(II) sulfate pentahydrate and potassium peroxydisulfate (oxone)18 produced ketone 24 but in low
yield.
Scheme 6
CH3O
CH3O
OCH3
OCH3
OCH3
OCH3
CH3O
OCH3
OCH3
(CH3)3SiO
HO
10
(CH3)3SiO
LiN[SiMe3]2,
TMS-Cl
K2S2O8, CuSO4
(low yield)
7
99% yield based
on recovered 8
H
H
H
O
8
23
24
Since having an alcohol or ether at C(10) did not permit oxidation at C(7), this led us to prepare acetate
26, a more functionalized analogue of acetate 19, in hope that it would oxidize at the C(7) position
(Scheme 5). The preparation of acetate 26 is shown in Scheme 7. Hydrogenation of enone 17 initially
produces a cis-fused ketone, but because of the potassium ethoxide present in the reaction medium,

HETEROCYCLES, Vol. 73, 2007
221
epimerization of the C(10) methine leads to the formation of the thermodynamically favored ketone 25,
having a trans A/B-ring fusion. 1,2-Reduction of ketone 25 with L-Selectride at –78 ˚C gave excellent
facial selectivity (>99:1); this alcohol was directly acetylated. Once again, we fully expected the
oxidation of 26 to mimic our faveline success; however, instead of oxidizing either of the benzylic sites,
PCC, CrO , or PDC only oxidized the electron-rich arene moiety to produce p-benzoquinone 27.
3
Scheme 7
O
O
AcO
CH3O
OCH3
OCH3
OCH3
AcO
O
H
H
H
H
xiv) H2,
Pd-C, KOEt
xv) L-Selectride
(98%)
PCC
or CrO3
xvi) Ac2O
(94%)
O
in EtOH
(91%)
H
H
25
17
26
27
Other conditions known to oxidize a benzylic methylene unit were studied, including IBX/DMSO,19
CAN/HOAc,20 PFC,21 m-CPBA/air/NaHCO ,22 and t-BuOOH/CuI,23 but all gave either no reaction or
3
decomposition.
Fortunately, heating acetate 26 with oxone (K2S2O8) and wet copper sulfate gave a
43% yield of ketone 29 (Scheme 8). The first mechanistic step of this oxidation18 is the formation of a
3+
benzylic free-radical which is further reduced by the Cu species present to generate a benzylic
carbocation; since water is present in the reaction medium, two diastereomeric benzylic alcohols are
produced (cf. 28) prior to their subsequent oxidation to ketone 29 due to excess oxidant. We noted that
the benzylic alcohols were formed rapidly, whereas ketone formation was slow, and that the excess
oxidant also promoted eliminations. These observations caused us to use 1.1 equivalents of oxone but
only 0.5 equivalents of copper sulfate to produce alcohols 28, followed by the addition of Jones reagent,
Scheme 8
CH3O
CH3O
CH3O
OCH3
OCH3
OCH3
OCH3
OCH3
AcO
AcO
AcO
H
H
H
H
xvii) 0.5 equiv.
of CuSO4-5H2O,
H
H
(61% isolated
yield or
91%
1.1 equiv. K2S2O8,
then Jones reagent
CH3O
conversion)
O
OH
29
26
28
(97%)
xviii) KOH
CH3O
CH3O
CH3O
OCH3
OCH3
OCH3
xix-a) POCl3 (52%)
31:32 = 6:1 or
xix-b) MsCl (97%),
OCH3
HO
H
H
H
H
and/or
2,6-lutidine at 170 ˚C
(74%) 31:32 = 2:1 or
xix-c) SOCl2, C6H5N
31 (82%)
OCH3
OCH3
H
O
O
O
32
30
31

222
HETEROCYCLES, Vol. 73, 2007
which is a more powerful oxidant and less prone to cause eliminations. Using these conditions ketone
29 was isolated in 61% yield, along with 33% of unreacted acetate 26 for a 91% conversion.24 Scheme 8
also depicts how we converted key intermediate 29 into trisubstituted alkene 31. Acetate 29 was
saponified with KOH in hot ethanol in 97% yield. Dehydration of secondary alcohol 30 using POCl
3
gave a 6:1 ratio of alkenes 31:32, whereas generation of the corresponding mesylate, followed by
treatment with refluxing 2,6-lutidine, gave a 2:1 mixture of these alkenes.
Treatment of alcohol 30
with excess thionyl chloride25 in pyridine at 0 ˚C produced only alkene 31 in 82% yield.
Extensive work established that the C(1),C(10)–double bond must be hydrated before the aromatic ring
is oxidized, which then allows hemi-acetal formation (Scheme 9). Since acid-catalyzed hydration of the
trisubstituted double bond produced complex mixtures, we considered turning to an epoxidation /
epoxide opening strategy (cf. Scheme 3) to introduce the β-oriented C(10) hydroxyl group. In the case
of alkene 31, however, MM3 calculations indicated that the C(7) carbonyl causes preference for the
chair-like conformer, i.e., 31ii, which leads to epoxidation from the α-face (cf. 33). Even if the
epoxidation of alkene 31 occurred from the β-face via the less favorable boat-like conformer (cf. 31i),
the opening of epoxide 34 using hydride reagents would produce diol 35, which requires another
oxidation in order to produce ketone 7. Indeed, treatment of alkene 31 with m-CPBA produced only
epoxide 33, thus verifying that the α-face of alkene 31 is less hindered.
Scheme 9
CH O
3
OCH
OCH
H CO
3
3
3
3
!-attack
CH
3
OCH
3
OCH
3
OCH
OCH
CH
H
H
3
3
O
O
"-
attack
H
O
OCH
3
31
(31ii)
(31i)
epoxidation from
the less-hindered
"-face
epoxidation from
the less-hindered
!-face
m-CPBA
(90%)
CH O
3
OCH
3
CH O
3
CH O
3
OCH
OCH
OCH
3
3
O
OH
O
oxidation
LAH
(7)
OCH
3
OCH
H
3
3
O
H
H
OH
O
33
35
34
Knowing that electrophilic reagents add to the α-face of alkene 31 led us to treat it with NBS in aqueous
acetone (Scheme 10).26
Bromohydrin 36 results from opening of bromonium ion 31iii by water which

HETEROCYCLES, Vol. 73, 2007
223
introduces a β-oriented hydroxy group at C(10). Treatment of bromohydrin 36 with tri-n-butyltin
hydride and AIBN reduces the bromide substituent without affecting the C(7) carbonyl. While keto
alcohol 7 was inert to mild oxidants such as CAN, PCC, Fremey’s salt, or HgO, harsher oxidizing
conditions, such as Ag(II)O in acetone with 7 N nitric acid,27 gave (±)-komaroviquinone in 54% yield.
In this transformation demethylation of the C(11) and C(14) methyl ethers occurs first, followed by the
rapid oxidation of the resulting hydroquinone intermediate 2, which is itself the natural product
coulterone, with subsequent intramolecular transannular acetal formation.
Our synthetic
(±)-komaroviquinone displays 1H and 13C NMR, IR, and MS spectra that are indistinguishable from those
reported for the natural material.3
Scheme 10
CH3O
CH3O
+
OCH3
OCH3
OCH3
CH3O
OH
OCH3
OCH3
Br
Br
xx) NBS
acetone/H2O
(83%)
OCH3
H
H
O
O
H
O
(31iii)
31
36
n-Bu3SnH,
AIBN
(100%)
xxi)
O
OCH3
HO
OCH3
OH
CH3O
OCH3
OH
H
OH
xxii) Ag(II)O,
7 N HNO3
(54%)
O
O
H
OH
OCH3
O
H
O
komaroviquinone (1)
coulterone (2)
7
In the course of this synthesis, invaluable insight was gained into the oxidation of the benzylic position
of electron-rich arenes. In addition, two seemingly straightforward transformations, the elimination of a
secondary alcohol to produce a trisubstituted double bond, followed by its subsequent hydration, were
governed by conformational biasing. Finally, the knowledge we gained in the course of this study has
enabled us to achieve a chiral synthesis of komaroviquinone.28
ACKNOWLEDGMENTS
We thank the National Science Foundation (CHE-0506486) for support of this research. Appreciation
is extended to Dr. Zhongfang Chen (UGA) for the MM3 calculations of compound 31.

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HETEROCYCLES, Vol. 73, 2007
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§
In memory of Professor Ivar Ugi who died on September 27, 2005.
†
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3
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