Protected cyanohydrins in the synthesis of rotenoids: (±)- Munduserone and (±)-cis-12a-hydroxymunduserone

Article abstract of DOI:10.1021/jo900648n

(Chemical Equation Presented) Short synthetic routes to the natural products (±)-munduserone 1 and (±)-cis-12a-hydroxymunduserone 9 from protected cyanohydrin 5 and nitrochromene 4 are described. The key coupling reaction of 4 and 5 gave under inverse add

Full text of DOI:10.1021/jo900648n

interesting but quite inefficient routes have also been reported.5
Despite limited biological activity, 1 captured our attention as
a convenient target for demonstrating novel synthetic strategies,
for development of general approaches to more complex
rotenoids. Herein, we report concise syntheses of 1 and its
natural cis-12a-hydroxy derivative 9, which to our knowledge
is the first total synthesis of this compound.6
Protected Cyanohydrins in the Synthesis of
Rotenoids: (()-Munduserone and
(()-cis-12a-Hydroxymunduserone
Evin H. Granados-Covarrubias and Luis A. Maldonado*
Instituto de Qu´ımica, UniVersidad Nacional Auto´noma de
Me´xico, Circuito Exterior, Ciudad UniVersitaria, Me´xico,
04510, D.F., Me´xico
On the basis of the premise that rotenoids are indeed
isoflavanones with an additional six-membered oxygen hetero-
cycle, the strategy for 1 was an elaboration of our recent
methodology to synthesize isoflavanones.7 The key step was
thus envisioned to be the coupling of protected cyanohydrin 5
(easily available, in principle, from commercial 7) and the
known8 nitrochromene 4 (prepared in one step from 6) to give
3 (Scheme 1). After removal of protecting/activating groups,
the known enone 2a should be obtained, which has been
cyclized into munduserone in high yield,5e under mildly basic
catalytic conditions (AcONa/EtOH). This is important for an
eventual formal synthesis of munduserone.
lammg@serVidor.unam.mx
ReceiVed April 2, 2009
Nitrochromene 4 was prepared as reported8 by using the one-
step di-n-butylamine-catalyzed condensation of 4,5-dimethox-
ysalicylaldehyde 69 and freshly prepared nitroethylene in CHCl3
solution. Unfortunately, in our hands, yields were only 20-25%
(the reported yield is 72%) but unreacted aldehyde could be
recovered and recycled until total consumption was achieved.
On the other hand, the “protected cyanohydrin” 5 was pre-
pared in 78% overall yield from 7 by methoxymethylation
Short synthetic routes to the natural products (()-mundu-
serone 1 and (()-cis-12a-hydroxymunduserone 9 from
protected cyanohydrin 5 and nitrochromene 4 are described.
The key coupling reaction of 4 and 5 gave under inverse
addition conditions 9 (28%) and 2b (21%), while under
normal addition conditions, a mixture of 9 (20%), dehydro-
munduserone 10 (9%), and enone 2b (10%) was obtained.
(()-Munduserone 1 is easily obtained from both 2b and 9
by 10% methanolic HCl (86%) and Zn/AcOH (71%)
treatments, respectively.
(3) (a) Gills, J. J.; Kosmeder, J.W., II; Moon, R. C.; Lantvit, D. D.; Pezzuto,
J. M. J. Chemother. 2005, 17, 297–301. (b) Lee, H.-Y.; Suh, Y.-A.; Kosmeder,
J.W., II; Pezzuto, J. M.; Hong, W. K.; Curie, J. M. Clin. Cancer Res. 2004, 10,
1074–1079. (c) Chun, K. H.; Kosmeder, J.W., II; Sun, S.; Pezzuto, J. M.; Lotan,
R.; Hong, W. K.; Lee, Y. H. J. Natl. Cancer Inst. 2003, 95, 291–302. (d)
Kinghorn, A. D.; Su, B.-N.; Lee, D.; Gu, J.-Q.; Pezzuto, J. M. Curr. Org. Chem.
2003, 7, 213–216. (e) Kinghorn, A. D.; Fong, H. H. S.; Farnsworth, N. R.; Mehta,
R. G.; Moon, R. C.; Moriarty, R. M.; Pezutto, J. M. Curr. Org. Chem. 1998, 2,
597–612.
(4) (a) Marzouk, M. S. A.; Ibrahim, M. T.; El-Gindi, O. R.; Bakr, M. S. A.
Z. Naturforsch. C 2008, 63, 1–7. (b) Dagne, E.; Yenesew, A.; Waterman, P. G.
Phytochemistry 1989, 11, 3207–3210. (c) Finch, N.; Ollis, W. D. Proc. Chem.
Soc. 1960, 176.
(5) (a) Crombie, L.; Josephs, J. L. J. Chem. Soc., Perkin Trans. 1993, 1,
2591–2597. (b) Ahmad-Junan, S.; Amos, P. C.; Whiting, D. A. J. Chem. Soc.,
Perkin Trans. 1992, 1, 539–545. (c) Amos, P. C.; Whiting, D. A. J. Chem. Soc.,
Chem. Commun. 1987, 510–511. (d) Crombie, L.; Freeman, P. W.; Whiting,
D. A. J. Chem. Soc., Perkin Trans. 1 1973, 1277–1285. (e) Omokawa, H.;
Yamashita, K. Agr. Biol. Chem. 1973, 37, 195–196, and 1717-1723. (f) Nakatani,
N.; Matsui, M. Agr. Biol. Chem. 1968, 32, 769–772. (g) Chandrashekar, V.;
Krishnamurthi, M.; Seshadri, T. R. Tetrahedron 1967, 23, 2505–2511. (h) Fukui,
K.; Nakayama, M.; Harano, T. Experientia 1967, 23, 613–614. (i) Herbert, J. R.;
Ollis, W. D.; Russell, R. C. Proc. Chem. Soc. 1960, 177.
The rotenoids are a biogenetically derived class of flavonoids
featuring the chromano[3,4-b]chromanone framework.1 Interest
in this class of compounds is high because many members
exhibit impressive antitumor activity in human tumor cell lines.2
In this context, it is also worth mentioning that the rotenoid
deguelin is considered a highly promising cancer chemopre-
ventive agent.3
In 1960, Finch and Ollis reported the isolation and structural
elucidation of the simplest natural rotenoid munduserone 1,
obtained from the bark of Mundulea sericea.4c This was
followed by a report from the same group on the total synthesis
of 1, though in an unstated overall yield.5i Later on, other
(6) (a) Dagne, E.; Yenesew, A.; Waterman, P. G. Phytochemistry 1989, 28,
3207–3210. (b) Kalra, A. J.; Krishnamurthi, M.; Nath, M. Indian J. Chem. B
1977, 15, 1084–1086.
(7) (a) Granados-Covarrubias, E. H.; Maldonado, L. A. Tetrahedron Lett.
2009, 50, 1542–1545. (b) Ferrin˜o, S. A.; Maldonado, L. A. Synth. Commun.
1980, 10, 717–723.
(8) Neirabeyeh, M. A.; Koussini, R.; Guillaumet, G. Synth. Commun. 1990,
20, 783–788.
(9) Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.; Mallon, R.;
Kim, S. C.; Roll, D. M.; Feldberg, L.; Van Soest, R.; Andersen, R. J. Org. Lett.
2006, 8, 321–324. In this report the authors used BBr3 as the chemoselective
demethylating agent, but we obtained comparable yields with the less expensive
BCl3.
(1) For a summary of the extensive work by Crombie and co-workers on
the biosynthesis of rotenoids, see: Crombie, L.; Whiting, D. A. Phytochemistry
1998, 49, 1479–1507.
(2) (a) Fang, N. B.; Casida, J. E. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
3380–3384. (b) Konoshima, T.; Terada, H.; Kokumai, M.; Kozuka, M.; Tokuda,
H.; Estes, J. R.; Li, L.; Wang, H. K.; Lee, K. H. J. Nat. Prod. 1993, 56, 843–
848. (c) Li, L.; Wang, H. K.; Chang, J. J.; McPhail, A. T.; McPhail, D. R.;
Terada, H.; Konoshima, T.; Kokumai, M.; Kozuka, M.; Estes, J. E.; Lee, K. H.
J. Nat. Prod. 1993, 56, 690–698. (d) Lin, L. J.; Ruangrungsi, N.; Cordell, G. A.;
Shieh, H. L.; You, M.; Pezzuto, J. M. Phytochemistry 1992, 31, 4329–4331. (e)
Blasco, G.; Shieh, H.-L.; Pezzuto, J. M.; Cordell, G. A. J. Nat. Prod. 1989, 52,
1363–1366.
(10) Reggelin, M.; Doerr, S. Synlett 2004, 1117.
(11) Greenlee, W. J.; Hangauer, D. G. Tetrahedron Lett. 1983, 24, 4559–
4562.
10.1021/jo900648n CCC: $40.75  2009 American Chemical Society
Published on Web 05/28/2009
J. Org. Chem. 2009, 74, 5097–5099 5097

SCHEME 1. Retrosynthetic Analysis for Munduserone
Based on Protected Cyanohydrin Chemistry
SCHEME 2. Total Synthesis of (()-Munduserone (1) and
(()- cis-12a-Hydroxymunduserone (9)
hydroxyenone 2a was not isolated. Furthermore, we have also
converted 9 into 1 in 71% yield with Zn in hot AcOH,12
a
considerable improvement for this four-step known conversion.13
On the other hand, from conditions A two fractions were also
obtained with identical Rf values as those obtained for the
corresponding fractions of conditions B. The less polar fraction
was identified as 2b (10% yield), but the more polar fraction
contained 9 in admixture with dehydromunduserone 10. These
compounds, separable only by further preparative TLC (99:1,
C6H6/MeOH, three elutions), were obtained in yields of 20%
and 9%, respectively. Dehydromunduserone 10 is also a known
compound prepared as an intermediate in some previous
munduserone syntheses.5f-i Hence, our preparation of 10
represents a new formal synthesis of munduserone.
(NaH, ClCH2OMe,10 THF) and cyano-O-trimethylsilylation11
(Me3SiCN, catalytic KCN and 18-crown ether, C6H6).
With the precedent that lithium bases promoted hydride
migration during the conjugate addition of an analogue of
protected cyanohydrin 5 to (E)-4-methoxy-ꢀ-nitrostyrene to give
a 1:1 mixture of “normal” and “dehydro” adducts, our first
choice to perform this coupling was using KH as base in DME,
as was previously found useful in our formononetine synthesis.7
However, complex product mixtures were obtained, from which
only the isomeric 6,7-dimethoxy-3-nitro-2-chromene could be
isolated in low yield and characterized. Probably the basicity
of the potassium carbanion of 5 was responsible for isomer-
ization, but attempts to avoid the problem by working under
inverse addition conditions also failed, at least in part because
of the relatively low solubility of the potassium carbanion in
DME, which resulted in clogging of the transfer cannula.
Hence, we decided to use LDA as the coupling reaction base
with the expectation that chromatographic separation of the
“normal” and “dehydro” adducts from the reaction mixture
would be feasible. Coupling between 4 and 5 was performed
under both normal (A) and inverse (B) addition conditions to
give mixtures of adducts which, without purification, were
successively submitted to our usual mild acid (5% aqueous
H2SO4, THF, 50 °C) and base treatments (Et3N, Me2CO, rt) for
O-trimethylsilyl cleavage and HCN and HNO2 removals,
respectively. After silica gel column chromatography, from
conditions B two fractions were obtained and identified as the
desired less polar “normal” enone adduct 2b (21% yield) and
surprisingly, the more polar natural product cis-12a-hydroxymun-
duserone 96 (28% yield) (Scheme 2). Rotenoid 9 is clearly
derived from the dehydro adduct 8a whose preferential forma-
tion in this experiment can be rationalized by the stronger
electron donor effect of the trioxy-substituted ring, facilitating
the required hydride migration to the lithium cation, as compared
with the single methoxy-substituted aromatic ring used in our
formononetine synthesis.7
Regarding the mechanism of this unusual reaction, and though
our analysis remains speculative, we propose the formation of
a common intermediate 11 that can undergo proton loss to
dehydromunduserone 10 (path a) or a 1,2-hydride shift to the
p-quinoid cation 12 followed by water addition, to give cis-
12a-hydroxymunduserone 9 (path b). The common intermediate
11 is, in turn, obtained from nitroenone 8c, the expected product
obtained after deprotection of the initially formed dehydro
adduct 8a, as depicted in Scheme 3. Although we have not
attempted to isolate the presumably formed, acid-sensitive
“normal” adducts 3 (four stereoisomers are possible) and
“dehydro” adduct 8a from the complex reaction mixture for
characterization, the latter is a reasonable starting point for the
mechanistic proposal based on our previous results.7,14
In summary, concise total synthesis of the rotenoids (()-
munduserone 1 and (()-cis-12a-hydroxymunduserone 9 have
been achieved by using a new approach that involves conjugate
addition of the lithium carbanion of an aromatic protected
cyanohydrin 5 to nitrochromene 4 as the key reaction. Although
the coupling reaction yielded mixtures of two or three products,
depending on whether inverse or normal addition conditions
were used, all these compounds converged into 1 by simple
transformations. Furthermore, as (with few exceptions) natural
rotenoids have the same dimethoxy-substituted ring A, which
is delivered by nitrochromene 4, this approach can be applied,
in principle, to other biologically more interesting rotenoids.
This should be very simple because selection of the appropriate
aromatic aldehyde is the only challenge. We are pursuing further
The structure of enone 2b was derived from its spectroscopic
data and its acid-catalyzed conversion into the natural product
munduserone 1 (86% yield). In this cyclization, the intermediate
(12) To the best of our knowledge, this reaction has been attempted only
with the unnatural trans isomer of 12a-hydroxymunduserone.5b,c
(13) See ref 6b for the two-step conversion of 9 f dehydromunduserone 10
and refs 5f-i for the two-step conversion of 10 f 1.
(14) However, we are aware that the absence of 10 under inverse addition
conditions is the main challenge of our view of the mechanism. See the
Supporting Information for additional data on this issue.
5098 J. Org. Chem. Vol. 74, No. 14, 2009

SCHEME 3. Mechanistic Proposal for Rotenoid Formation
106.8, 101.6, 100.9, 100.4, 94.9, 64.8, 56.2, 55.9, 55.5 ppm; MS
(EI) (m/z, %) 386 (M+, 50), 341 (56), 190 (25), 178 (46), 151 (38),
57 (100); HRMS (FAB) calcd for C21H22O7 (M+) 386.1366, found
386.1364.
(()-cis-12a-Hydroxymunduserone 9: white solid; mp 284-286
°C; IR (KBr) ν 3448, 1676, 1610, 1509, 1259, 1200, 1162, 1104,
1
1035 cm-1; H NMR (300 MHz, C3D6O) δ 7.79 (d, J ) 9 Hz,
1H), 6.62 (dd, J ) 9, 2.7 Hz, 1H), 6.62 (s, 1H), 6.48 (s, 1H), 6.41
(d, J ) 2.7 Hz, 1H), 5.49 (s, OH, exchanges with D2O), 4.69 (dd,
J ) 2.1, 1.2 Hz, 1H), 4.58 (dd, J ) 12, 2.1 Hz, 1H), 4.47 (dd, J )
12, 1.2 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.59 (s, 3H) ppm; 13C
NMR (75 MHz, C3D6O) δ 191.7, 167.5, 163.1, 152.5, 149.7, 144.6,
129.6, 112.7, 112.3, 111.4, 109.8, 101.9, 101.2, 77.0, 68.5, 64.6,
56.8, 56.2, 55.9 ppm; MS (EI) (m/z, %) 358 (M+, 38), 208 (100),
151 (12); HRMS (FAB) calcd for C19H18O7 (M+) 358.1053, found
358.1053.
(()-Munduserone 1: (a) From Enone 2b. To a stirred solution
of 2b (0.03 g, 0.078 mmol) in dry MeOH (1.5 mL) was added a
10% solution of HCl in MeOH (1.5 mL). The reaction mixture
was stirred and heated in an oil bath at 65 °C for 2 h, cooled at rt,
and quenched with saturated aqueous NaHCO3 solution. The
volatiles were removed at reduced pressure then extracted with
CH2Cl2, and the combined organic fractions were washed with brine
and dried. Concentration afforded a crystalline brown solid that
was chromatographed on flash silica gel (17:3, hexanes/AcOEt) to
give 0.023 g (86%) of crystalline (()-1. Mp 169-170 °C (lit.4c
mp 171-172 °C); IR (KBr) ν 2939, 1675, 1615, 1516, 1452, 1277,
1159 cm-1; 1H NMR (CDCl3) δ 7.87 (d, J ) 8.7 Hz, 1 H), 6.76 (s,
1 H), 6.57 (dd, J ) 8.8, 2.4 Hz, 1 H), 6.46 (s, 1 H), 6.42 (d, J )
2.4 Hz, 1 H), 4.9 (dt, J ) 12.0, 4.2, 3.0 Hz, 1 H), 4.62 (dd, J )
12.0, 3.0 Hz, 1 H), 4.18 (d, J )12.0 Hz, 1 H), 3.84 (d, J ) 4.2 Hz,
1 H), 3.79 (s, 3 H), 3.79 (s, 3 H), 3.75 (s, 3 H) ppm; 13C NMR
(CDCl3) δ 189.2, 166.5, 162.7, 149.5, 147.4, 143.9, 129.3, 112.7,
110.6, 110.4, 104.7, 101.0, 100.6, 72.4, 66.2, 56.3, 55.8, 55.6, 44.5;
MS (EI) (m/z, %) 342 (M+, 53), 192 (100), 83 (45); HRMS (EI)
calcd for C19H18O6 (M+) 342.1103, found 342.1107.
(b) From (()-cis-12a-Hydroxymunduserone 9. A stirred
mixture of 9 (0.15 g, 0.43 mmol), AcOH (15 mL), and Zn dust
(3 g, 45 atom ·mg) was heated in an oil bath at 115 °C for 45 min.
The suspension was cooled at rt, filtered, and thoroughly washed
with hot CH2Cl2. The solution was evaporated to dryness with the
aid of first a rotavapor and then an oil pump, then the residue was
dissolved again in CH2Cl2 (25 mL) and washed with a saturated
aqueous solution of NaHCO3 and brine. The dried solution was
concentrated and the solid residue was cromatographed on flash
silica gel (17:3, hexanes/AcOEt) to give 0.102 g of (()-1 (71%).
experiments to improve yields, to learn more about the mech-
anism of the unusual coupling reaction, and hopefully, to find
experimental conditions suitable for fine-tuning the preferential
formation of normal enone adducts or rotenoids, as desired.
Experimental Section
Coupling of Protected Cyanohydrin 5 and 6,7-Dimethoxy-
3-nitro-3-chromene 4 (Inverse Addition). To a stirred solution
of 1.7 mmol of LDA in 5 mL of dry THF (prepared in the usual
way from 0.17 g (1.7 mmol) of dry diisopropylamine and 1.2 mL
of a 1.47 M solution of n-BuLi in hexanes (1.7 mmol)) at -70 °C
was added a THF solution (3 mL) of protected cyanohydrin 5 (0.386
g, 1.3 mmol). The resulting yellow solution was stirred at -70 °C
for 15 min, and added dropwise via cannula to a cooled (-70 °C)
stirred solution of 4 (0.31 g, 1.3 mmol) in 5 mL of THF. The red
solution was stirred at -70 °C for 40 min, warmed at rt, quenched
with 6 mL of Na2HPO4 buffer (pH 7.3), and extracted with AcOEt.
The combined organic layer was washed with brine and dried.
Concentration afforded a thick red oil that was dissolved in THF
(5 mL) and 5 mL of 5% aqueous H2SO4 was added. The stirred
mixture was heated in an oil bath at 55 °C for 14 h, cooled at rt,
quenched with saturated NaHCO3 aqueous solution, and extracted
with AcOEt. The combined organic layer was washed with brine
and dried. Concentration afforded a red gum that was dissolved in
10 mL of Me2CO, 0.7 mL of Et3N was added, and the dark solution
was stirred at rt for 14 h. The volatiles were removed at reduced
pressure, the residue was partitioned between AcOEt and brine,
and the organic layer was dried. Concentration afforded a red
viscous oil that was chromatographed on flash silica gel (4:1,
hexanes/AcOEt) to give two main fractions. The fast moving
fraction was enone 2b (0.131 g, 21%) and the slow moving fraction
was (()-9 (0.163 g, 28%).
Acknowledgment. We thank Dr. Guillermo E. Delgado L.
(Instituto de Qu´ımica, UNAM) and Dr. J. Alfredo Va´zquez M.
(Facultad de Qu´ımica, UNAM), members of the Tutorial
Committee of E.H.G.-C. for their valuable suggestions to this
research. We also thank Ere´ndira Garc´ıa, Elizabeth Huerta,
He´ctor R´ıos, Luis Velasco, and Francisco J. Pe´rez, for running
spectra, and Signa S.A. (through the courtesy of M.Sc. J. Miguel
Lazcano) for a generous gift of chemicals. E.H.G.-C. thanks a
CONACYT scholarship for graduate studies.
Supporting Information Available: Preparation and char-
acterization of 5, experimental conditions for coupling of 4 and
5 by the normal addition protocol, spectroscopic data for 10,
Enone 2b: pale yellow oil; IR (film) ν 1655, 1603, 1508, 1462,
1262, 1157, 1035 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J
) 8.4 Hz, 1H), 7.13 (s, 1H), 6.7 (d, J ) 2.4 Hz, 1H), 6.6 (dd, J )
8.5, 2.4 Hz, 1H), 6.48 (s, 1H), 6.08 (t, J ) 4.2 Hz, 1H), 5.02 (s,
2H), 4.76 (d, J ) 4.2 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.73 (s,
3H), 3.36 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 193.9, 163.8,
158.0, 149.9, 148.7, 143.4, 136.8, 132.2, 126.2, 122.3, 112.4, 108.8,
1
additional data for the proposed reaction mechanism, and H
and 13C NMR spectra for all compounds prepared. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO900648N
J. Org. Chem. Vol. 74, No. 14, 2009 5099