Total synthesis of (+)-komaroviquinone

Article abstract of DOI:10.3987/COM-07-S(U)37

(+)-Komaroviquinone (1) was synthesized from enone 8 in twelve steps. Three novel routes were developed to produce key intermediate dienone 11. Two additional noteworthy steps are a regiospecific bromohydrin formation to oxidize C(7) and a second regio- and stereospecific bromohydrin formation to introduce the β-C(10)alcohol.

Full text of DOI:10.3987/COM-07-S(U)37

HETEROCYCLES, Vol. 73, 2007
227
HETEROCYCLES, Vol. 73, 2007, pp. 227 - 235. © The Japan Institute of Heterocyclic Chemistry
Received, 29th June, 2007, Accepted, 27th August, 2007, Published online, 28th August, 2007. COM-07-S(U)37
§
TOTAL SYNTHESIS OF (+)-KOMAROVIQUINONE
†
George Majetich,* Jianhua Yu, and Yang Li
Department of Chemistry, The University of Georgia, Athens, Georgia 30602,
U.S.A. majetich@chem.uga.edu
Abstract – (+)-Komaroviquinone (1) was synthesized from enone 8 in twelve
steps. Three novel routes were developed to produce key intermediate dienone
11. Two additional noteworthy steps are a regiospecific bromohydrin formation
to oxidize C(7) and a second regio- and stereospecific bromohydrin formation to
introduce the β-C(10) alcohol.
During a systematic study of the organic extracts of the semishrub Dracocephalum komarovi Lipsky,1
which grows between 2300-3600 meters above sea level in mountains of western Uzbekistan, Honda and
co-workers isolated komaroviquinone (1)2 and coulterone (2).2,3 These compounds exhibit trypanocidal
activity against the causative agent of Chagas’ disease in Central and South America.4 The preceding
manuscript detailed our synthesis of (±)-15 (Scheme 1) featuring a cyclialkylation strategy6 to construct
Scheme 1
O
HO
O
CH O
OCH
OCH
OCH
OH
3
OCH
14
3
3
3
3
11
OH
H
OH
H
OH
Ag(II)O
O
O
O
7 N
HNO3
(54%)
OCH
3
H
OH
O
O
H
O
(±)-coulterone (3)
(±)-2
(±)–komaroviquinone (1)
(±)-4
four
steps
CH O
3
OCH
OCH
3
AcO
H
AcO
OEt
O
H
regiospecific
oxidation
three
steps
two
(61%)
steps
3
O
H
H
O
8
(±)-5
(±)-6
7

228
HETEROCYCLES, Vol. 73, 2007
6,7,6-fused enone 7, a selective benzylic oxidation of acetate 6 to provide ketone 5, and the introduction
of a β-oriented C(10) hydroxyl group (cf. 5 → 4). The strongly acidic conditions used to deprotect the
C(11) and C(14) methyl ethers of ketone 4 did not permit the isolation and characterization of coulterone
(3) or p-benzoquinone 2, both of which must be formed before intramolecular hemi-acetal formation
produces komaroviquinone.
In this study an enantiospecific synthesis of (+)-komaroviquinone was achieved without having to oxidize
the non-functionalized C(7) methylene unit.7,8 In related studies9 we have converted achiral enone 7 into
alkene (S)-10 via a two-step process (Scheme 2), with the requisite C(5) chirality and a
C(1),C(10)–double bond. If achiral enone 7 can be converted into dienone 11, then 11 should be
converted into chiral diene 12 using the same reactions that transformed enone 7 into alkene (S)-10.
Several well-known strategies can be envisioned to selectively oxidize the C(6),C(7)–double bond of
diene (S)-12. The conversion of the trisubstituted double bond of (S)-13 to a β-oriented C(10) hydroxyl
group (cf. 4) utilizes the same route that we reported in our synthesis of racemic komaroviquinone.
Thus, our initial goal was to develop an efficient synthesis of dienone 11.
Scheme 2
OCH3
CH3O
O
O
OH
1
i) introduce
C(6),C(7)–
allylic
trans-
10
1,2-chiral
5
double
bond
reduction9, 18
(87% yield,
96% ee)
position9,18
(60%)
CH3O
7
6
H
7
(R)-9
(S)–10
11
ii) 1,2-asymmetric reduction and allylic
transposition to introduce the C(5) chirality
CH3O
OCH3
OCH3
CH3O
OH
CH3O
OCH3
OCH3
11
1
iv) stereospecific
hydration of the
10
10
iii) selective
14
OCH3
7
5
7
OCH3
oxidation at C(7)
C(1), C(10)–
double bond
H
H
O
H
O
(S)–13
(S)–12
(S)–4
Several reactions were tried to extend the conjugation of enone 7, however, these attempts either failed to
effect reaction or gave unwanted products (Scheme 3). Stirring 7 with 30% aqueous hydrogen peroxide
and 6 M aqueous NaOH10 produced epoxide 14 in 91% yield. When 14 was treated with
p-toluenesulfonic acid in refluxing dichloromethane, allylic alcohol 15 was generated, which rapidly
dehydrated to give diene 16. We hoped that diene 16 would rearrange to dienone 11 under acidic
conditions via intermediate 17, but prolonged reaction times and/or harsher reaction conditions failed to
achieve this isomerization. Knowing that transition metals can rearrange isolated double bonds to a

HETEROCYCLES, Vol. 73, 2007
229
styrenyl position,11 we heated diene 16 in the presence of a catalytic amount of Ru(PPh3)3Cl2. These
conditions produced dienone 11 in 78% yield.
Scheme 3
CH O
CH O
CH O
3
OCH
OCH
OCH
3
3
3
H
3
3
i) SeO2 or
O
O
O
ii) NBS /AIBN or
OCH
OCH
OCH
3
3
3
iii) Br2 / base
7
17
11
30% H2O2, 6 M NaOH10
(91%)
H+
cat.
RuCl2(PPh3)3
(78%) or 53%
from 7
CH O
CH O
CH O
OCH
OCH
OCH
OCH
3
3
3
3
3
3
O
O
O
reflux 24 h
(75%)
p-TsOH
O
OH
C6H6
OCH
OCH
3
3
3
14
16
15
Concurrent with our efforts to prepare dienone 11 from enone 7 were efforts to synthesize additional
cyclialkylation precursors having an ether substituent either at C(6) or at C(7), i.e., dienones 19 and 23,
respectively (Scheme 4). We believed that treatment of either dienone with a Lewis acid would form the
central seven-membered ring (cf. 20 and 24), followed by the in situ loss of ethanol, to give dienone 11.
Scheme 4
CH3O
CH3O
OCH3
OCH3
OCH3
O
OCH3
OCH3
OEt
EtO
O
(18)
/ H3O+
(85%)
OCH3
BF3-Et2O
(65%)
OCH3
O
8
OEt
21
19
BF3-Et2O
+
(22)
/ H3O (85%)
OEt
CH3O
OCH3
CH3O
CH3O
OCH3
OCH3
OCH3
O
O
O
TiCl4 or
BF3-Et2O
loss
of
loss
of
11
OCH3
OEt
OCH3
30%-40%
yield
EtOH
EtOH
OEt
OEt
24
23
20
Addition of 1-lithio-1-ethoxyethylene (18)12 to ketone 8,13 followed by careful hydrolysis, gave an 85%
yield of cyclialkylation precursor 19. To our disappointment, treatment of 19 with a Lewis acid did not

230
HETEROCYCLES, Vol. 73, 2007
produce tricycle 20 but instead gave compound 2114 in 65% yield. Similarly, cyclialkylation precursor
23 was obtained in 85% yield by adding the anion derived from Z-2-ethoxyvinyl bromide (22)15 to 8,
followed by mild acid hydrolysis. In contrast to dienone 19, exposure of cyclialkylation precursor 23 to
excess BF -Et O provided dienone 11 in 30% yield along with several unknowns; TiCl gave a 40%
3
2
4
yield of 11 and similar byproducts.
Besides vinyl anions 18 and 22, we found that the anion of ethoxyacetylene, or Aren’s reagent (25),16,17
also reacts in 1,2-fashion with sterically hindered enone 8 (Scheme 5). In theory, enynone 26 could
cyclize to produce dienone 27, having a latent C(7) carbonyl moiety. However, analysis of Drieding
models of enynone 26 indicated that the distance between the terminal C(7) alkyne carbon and the “6”
carbon of the aryl ring is much greater than that of a carbon–carbon single bond; not surprisingly,
enynone 26 does not undergo cyclialkylation. Lindlar reduction of the triple bond of 26 cleanly gave
dienone 23, which formed dienone 11 in 66% yield upon treatment with excess Lewis acid. In
retrospect, our initial synthesis of dienone 11 began with enone 7 and required only three steps to give a
53% overall yield of 11 (Scheme 3). The most direct sequence (i.e., Scheme 4) converted enone 8 to
cyclization precursor 23, but formed tricyclic dienone 11 in <34% overall yield. However, reacting
Aren’s reagent with enone 8, followed by Lindlar hydrogenation and cyclialkylation, gave a 51% yield of
dienone 11 and avoided the conversion of enone 8 into enone 7. Thus, the Aren’s reagent/Lindlar
reduction/cyclialkylation sequence represents our best route to prepare key intermediate 11.
Scheme 5
CH3O
CH3O
OCH3
OCH3
CH3O
OCH3
OCH3
OCH3
OCH3
O
O
OEt
Li
OEt
C C
(25)
Lewis acid
"6"
/ H3O+ (79%)
O
OEt
7
8
27
OEt
H2/ 5% Pd /
BaSO4
(98%)
26
OCH3
CH3O
CH3O
CH3O
OCH3
OCH3
OCH3
O
O
O
Lewis acid
promoted
TiCl4 or
OCH3
OEt
loss of
EtOH
(66%)
BF3 - Et2O
OCH3
OEt
23
28
11
As outlined in Scheme 2, the asymmetric 1,2-reduction of the C(1) carbonyl of 7 using Corey’s CBS
procedure18 produced allylic alcohol 9 in excellent chemical yield and high ee, while the use of Meyer’s

HETEROCYCLES, Vol. 73, 2007
231
Mitsunobu-based allylic transposition19 to alcohol 9 furnished alkene (S)-10 in good yield. The
application of these procedures to dienone 11 gave (S)-diene 12 (Scheme 6). Diene (S)-12 was treated
with Jones reagent in hopes of first hydrating the styrenyl double bond, followed by the in situ oxidation
of the intermediate benzylic alcohol. However, dienone 11 was obtained in quantitative yield.20
Conformational analysis indicated that diene (S)-12 favors a conformation (cf. 12i) in which the
C(6),C(7)-π system is not coplanar with, and hence not conjugated with, the aromatic ring; therefore, it
reacts as a simple alkene. Treating (S)-diene 12 with m-CPBA gave epoxide 30 through addition to the
more accessible α-face of the molecule. Exposure of 30 to LAH produced tertiary alcohol 31 in high
yield.21
Scheme 6
O
OH
Corey's CBS
asymmetric reduction
Meyers' allylic
transposition
91% yield, 95% ee
H
11
(S)-12
(R)-29
Jones oxidation (95%)
m-CPBA
addition
from the
!-face
OH
O
LAH
H
H
H
31
(12i)
30
Examination of a Drieding molecular model of dienone 11 suggested that, while the C(5), C(10)–double
bond was coplanar with the C(1) carbonyl, the C(6),C(7)–double bond was not conjugated with either the
aryl ring or the A-ring enone. This suggested that bromohydrin formation would involve only the
electron–rich C(6),C(7)–double bond to give bromonium ion 32 and that the steric influence of the C(4)
gem-dimethyl group would cause the nucleophile present to add in a trans fashion to the C(7) benzylic
position (Scheme 7). When dienone 11 was treated with NBS in glacial acetic acid as the solvent, trans
bromo acetate 33 was produced as a racemic mixture. Removal of the C(6) bromine atom from 33 was
accomplished using free radical conditions to provide racemic 34. Asymmetric reduction of the C(1)
carbonyl of 34 using Corey’s CBS procedure afforded diastereomeric allylic alcohols 35 and 36, which
were then converted into isomeric alkenes 37 and 38 in 88% combined yield using Meyer’s allylic
transposition protocol. Removal of the acetate moiety by means of LAH reduction, followed by
oxidation of the resulting benzylic alcohols with Jones reagent, gave ketone (S)-39 in excellent overall
yield.

232
HETEROCYCLES, Vol. 73, 2007
Scheme 7 also depicts the final steps needed to convert alkene 39 into the dimethyl ether of coulterone (4).
Treatment of alkene 39 with NBS in the presence of water introduces a C(10) β-oriented hydroxyl group,
as well as an α-oriented bromine atom at C(1). The stereochemistry shown ensues because
Scheme 7
CH3O
O
O
OCH3
OCH3
O
trans addition
NBS in AcOH
10
5
7
by AcOH
6
OAc
Br
+
Br
11
33
(32)
n-Bu3SnH,
AIBN (90%)
O
OH
DEAD, P(C6H5)3
Corey's CBS
SO2
asymmetric
reduction
NHNH2
O2N
R2
R1
H
R2
OAc
R1
34
R1 = OAc; R2 = H; 37 (45%)
R1 = H, R2 = OAc; 38 (43%)
R1 = OAc; R2 = H; 35 (45%)
R1 = H, R2 = OAc; 36 (43%)
i) LAH
ii) Jones oxidation
(85% overall)
CH3O
OH
OCH3
OCH3
Br
+
OH
n-Bu3SnH,
AIBN
Br
NBS
1
10
wet
acetone
(83%)
(100%)
H
H
O
H
O
H
O
O
(S)-4
41
(40)
(S)-39
bromonium ion formation (cf. 40) occurs from the α-face of the trisubstituted double bond which
introduces the C(10) hydroxyl group from the β-face of the molecule. Removal of the C(6) bromine
atom from ketone 41 using n-Bu3SnH and AIBN produced hydroxy ketone (S)-4 as a single product in
83% overall yield from ketone (S)-40. Treatment with Ag(II)O / 7 N HNO3 deprotected the methyl aryl
ethers and oxidized coulterone to p-benzoquinone 2 which underwent rapid intramolecular hemi-acetal
1
formation to give komaroviquinone in good yield. Our synthetic (+)-komaroviquinone displays H and
13C NMR, IR, and MS spectra which are indistinguishable from those reported for the natural material
and the optical rotation matches that of the natural material within experimental error.2

HETEROCYCLES, Vol. 73, 2007
233
ACKNOWLEDGMENTS
We thank the National Science Foundation (CHE-0506486) for support of this research. Appreciation is
also extended to Professor Greg Dudley (Florida State University) for helpful advice on working with
Aren’s reagent.
REFERENCES AND NOTES
§
In memory of Professor Ivar Ugi who died on September 27, 2005.
†
Taken in part from the Ph.D. dissertation of Yang Li, University of Georgia (2006).
A. I. Vvednski, Flora Uzbekistana; Editio Academiae Scientiarum USSR: Tashkent, 1961; Vol. 5,
p. 313.
1.
2.
3.
4.
5.
N. Uchiyama, F. Kiuchi, M. Ito, G. Honda, Y. Takeda, O. K. Khodzhimatov, and O. A.
Ashurmetov, J. Nat. Prod., 2003, 66, 128.
For the isolation of coulterone from other plants, see: B. Frontana, J. Cardenas, and L.
Rodriguez-Hahn, Phytochem., 1994, 36, 739.
J. W. Bastien, “The Kiss of Death, Chagas’ Disease in the Americas,” University of Utah Press,
1998.
For the first synthesis of (±)-komaroviquinone, see: S. Sengupta, M. G. B. Drew, R.
Mukhopadhyay, B. Achari, and A. K. Banerjee, J. Org. Chem., 2005, 70, 7694.
H. A. Brunson and J. W. Kroeger, J. Am. Chem. Soc., 1940, 62, 36.
6.
7.
8.
For our synthesis of (±)-komaroviquinone, see the preceding manuscript.
The spectroscopic data obtained for all new compounds were fully consistent with the assigned
structures. Reaction conditions have not been optimized. All yields are isolated yields.
For a synthesis of (±)-perovskone, see: G. Majetich and Y. Zhang, J. Am. Chem. Soc., 1994, 116,
4979. A manuscript describing a synthesis of (+)-perovskone is under review [G. Majetich, Y.
Zhang, X. Tian, J. F. Britton, Y. Wang, and Yang Li]. For our synthesis of (+)-salvadione-A,
see: G. Majetich, Y. Wang, Y. Li, J. K. Vohs, and G. H. Robinson, Org. Lett., 2003, 5, 3847.
G. B. Payne and P. H. Williams, J. Org. Chem., 1961, 26, 651; B. Zwanenburg and J. Ter Wiel,
Tetrahedron Lett., 1970, 11, 935.
9.
10.
11.
S. K. Sharma, V. K. Srivastava, P. H. Pandya, and R. V. Jasra, Cat. Commun., 2005, 6, 205; T. A.
Stephenson and G. J. Wilkinson, J. Inorg. Nucl. Chem., 1966, 28, 945; A. Zoran, Y. Sasson, and
J. Blum, J. Org. Chem., 1981, 46, 255.
12.
J. E. Baldwin, G. A. Höfle, and O. W. Lever, Jr., J. Am. Chem. Soc., 1974, 96, 7126; U.
Schöllkopf and P. Hanssle, Liebigs. Ann. Chem., 1972, 763, 20; J. S. Brimacombe and A. M.

234
HETEROCYCLES, Vol. 73, 2007
Mather, J. Chem. Soc., Perkin Trans. 1, 1980, 269.
13.
14.
The preparation of enone 8 is detailed in the preceding manuscript of this journal.
We believe that capricious water causes the Lewis acid to hydrolyze the enol ether to form
enedione 19a. Intramolecular addition of the arene to ketone 19a, followed by rearomatization
of the C ring, produces 19b.
Dehydration of the tertiary alcohol results in the aromatization of
the B-ring.
CH O
3
OCH
OCH
3
O
O
OCH
CH O
3
CH O
3
3
OCH
OCH
OCH
3
-
BF3
Et2O
OCH
3
arene
adds
to
ketone
3
loss
of
H2O
A
B
B
C
trace
water
3
OCH
3
OCH
19b
3
OEt
HO
3
20
19
O
19a
15.
16.
M. A. Pericas, F. Serratosa, and E. Valenti, Tetrahedron, 1987, 43, 2311; R. H. Wollenberg, K. F.
Albizati, and R. Peries, J. Am. Chem. Soc., 1977, 99, 7365.
T. L. Jacobs, R. Cramer, and J. E. Hanson, J. Am. Chem. Soc., 1942, 64, 233; S. Raucher and B. L.
Bray, J. Org. Chem., 1987, 52, 2332; D. L. J. Clive, T. L. B. Boivin, and A. G. Angoh, J. Org.
Chem., 1987, 52, 4943; L. Duhamel, F. Tombret, and Y. Miller, J. Organomet. Chem., 1995, 280,
1; D. A. Engel and G. B. Dudley, Org. Lett., 2006, 8, 4027.
17.
For experimental conditions, see: L. E. Overman and A. S. Thompson, J. Am. Chem. Soc., 1988,
110, 2248; B. H. Lipshutz and R. Tirado, J. Org. Chem., 1994, 59, 8307.
18.
19.
E. J. Corey and C. J. Helal, Angew. Chem. Int. Ed., 1998, 37, 1986.
A. G. Meyers and B. Zheng, Tetrahedron Lett., 1996, 37, 4841; A. G. Meyers, B. Zheng, and M.
Movassaghi, J. Org. Chem., 1997, 62, 7507.
20.
In related work, we have found that the C(1),C(10)-double bond of diene 12 readily isomerizes
into conjugation with the C(6),C (7)-double bond upon exposure to either protic or Lewis acids.
Thus in the first step, the oxidant adds to the C(1) carbon with migration of the double bond into
the ring fusion (cf. 12ii). This intermediate is then further oxidized to generate conjugated
dienone 11.
O
O
CH3O
_
Cr
OCH3
OCH3
CH3O
OCH3
OCH3
O
O
O
Jones
reagent
12
11
(12ii)

HETEROCYCLES, Vol. 73, 2007
235
21.
Crystal data for C23H34O4 (31); MW = 374.50, orthorhombic, Pbca, a = 20.550(5)Å, b = 8.198(2) Å,
o
o
o
3
c = 25.071(7) Å , α = 90 , β = 90 , γ = 90 , V = 4223.7(19) Å , Z = 8, T = 273(2) K, µ =
0.079 mm-1, d = 1.178 g/cm3, R(1) = 0.0842 for 1721 observed reflections (I > 2 σ(Ι)). All
non-hydrogen atoms were refined anisotropically. Hydrogen atoms were treated as idealized
contributions.