Enantioselective synthesis of (+)- and (-)-dihydroepiepoformin and (+)-epiepoformin

Article abstract of DOI:10.1021/ol050287a

(Chemical Equation Presented) The enantioselective synthesis of both enantiomers of dihydroepiepoformin (1) and (+)-epiepoformin (2) was achieved from (p-tolylsulfinyl)-methyl-p-quinols (SR)- or (SS)-3 and (4R,SR)-4, respectively. Key features include the

Full text of DOI:10.1021/ol050287a

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1419-1422
Enantioselective Synthesis of (
+
)- and
(−)-Dihydroepiepoformin and
(+
)-Epiepoformin
M. Carmen Carren˜o,* Est´ıbaliz Merino, Mar´ıa Ribagorda, A
Ä lvaro Somoza, and
Antonio Urbano
Departamento de Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
carmen.carrenno@uam.es
Received February 11, 2005
ABSTRACT
The enantioselective synthesis of both enantiomers of dihydroepiepoformin (1) and (+)-epiepoformin (2) was achieved from (p-tolylsulfinyl)-
methyl-p-quinols (SR)- or (SS)-3 and (4R,SR)-4, respectively. Key features include the stereocontrolled conjugate addition of AlMe3 to p-quinol
3 and retrocondensation to the ketone functionality, previous to oxidation of the
corresponding sulfone.
â-hydroxy sulfoxide moiety of advanced intermediates to the
Dihydroepiepoformin (1) and (+)-epiepoformin (2) belong
to a family of highly oxygenated cyclohexane-based me-
tabolites that have been isolated from fungi and higher plants.
These derivatives share a cyclohexene oxide skeleton, a
recurring structural motif found in a number of natural
products.1 The wide range of biological properties that
embrace these compounds have stimulated important syn-
thetic efforts to achieve the stereoselective formation of this
moiety.2 Although several efficient solutions are now avail-
able, the development of new approaches are welcome.
ertheless, the authors did not report the specific rotation of
the isolated compound or its absolute configuration. (+)-
Epiepoformin (2) was isolated by Nagasawa4 in 1978 from
the culture filtrate of an unidentified fungus separated from
a diseased leaf and showed marked inhibition activity against
the germination of lettuce seeds.
(+)-Epiepoformin (2) has been previously synthesized by
several authors using different strategies. Ogasawara et al.
used a retro Diels-Alder reaction to recover the cyclohex-
enone fragment from a stereoselectively functionalized
quinone Diels-Alder adduct.5 The formation of a bicyclic
adduct in the cinchonine-catalyzed reaction between 3-hy-
droxy-2-pyrone and an acrylamide derived from a chiral
oxazolidinone was the key step in the more recent approach
of Okamura et al.6 In the synthesis reported by Maycock et
al. in 2000,7 (-)-quinic acid was the starting material,
Dihydroepiepoformin (1) was isolated by Kuo et al.3 in
1995 from fermentation of Penicillium patulum and was
found to have antagonistic activity for interleukin-1. Nev-
(1) Thebtaranonth, Ch.; Thebtaranonth, Y. Acc. Chem. Res. 1986, 19,
84-90.
(2) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. ReV. 2004,
104, 2857-2859.
(4) Nagasawa, H.; Suzuki, A.; Tamura, S. Agric. Biol. Chem. 1978, 42,
(3) Kuo, M.-S.; Yurek, D. A.; Mizsak, S. A.; Marshall, V. P.; Liggett,
W. F.; Cyaldella, J. I.; Laborde, A. L.; Shelly, J. A.; Truesdell, S. E. J.
Antibiot. 1995, 888-890.
1303-1304.
(5) Kamikuwo, T.; Ogasawara, K. Tetrahedron Lett. 1995, 36, 1685-
1688.
10.1021/ol050287a CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/11/2005

whereas a chiral building block obtained by enzymatic
reduction was used by Kitahara et al.8 to synthesize (+)-2
in 2003. To the best of our knowledge, there is no synthetic
approach to racemic or enantioenriched dihydroepiepoformin
(1).
Scheme 1. Enantioselective Total Synthesis of
(+)-Dihydroepiepoformin (1)
In connection with a program devoted to asymmetric
synthesis mediated by sulfoxides,9 we have recently reported
that the â-hydroxysulfoxide moiety present in several (p-
tolylsulfinyl)methyl-p-quinols such as 3 and 4 can be
regarded as a chiral ketone equivalent,10 opening an easy
access to differently substituted enantiopure cyclic ketones
by combining stereoselective organoaluminum conjugate
additions,11 stereoselective reductions, and elimination of the
sulfur function by retrocondensation in a basic medium.10,12
In this communication, we report the synthesis of several
epoxy cyclohexene derivatives and their use as key inter-
mediates for the first total synthesis and determination of
the absolute configuration of both enantiomers of dihy-
droepiepoformin (1) and a new enantioselective approach
to (+)-epiepoformin (2).
The synthesis of (+)-dihydroepiepoformin (1), depicted
in Scheme 1, started with (p-tolylsulfinyl)methyl-p-quinol
(SS)-3,12 easily available in two steps and 78% yield by
reaction of p-benzoquinone dimethyl monoacetal 513 with
the lithium anion derived from (SS)-methyl p-tolylsulfoxide
(6),14 followed by the hydrolysis of the acetal group using
oxalic acid.
(6) Tachihara, T.; Kitahara, T. Tetrahedron 2003, 59, 1773-1780.
(7) Okamura, H.; Shimizu, H.; Yamashita, N.; Iwagawa, T.; Nakatani,
M. Tetrahedron 2003, 59, 10159-10164.
The diastereo- and chemoselective addition of AlMe3 to
(SS)-3 occurred at the pro-R conjugate position, on the same
face of the OH group of 3, giving rise exclusively to
cyclohexenone (4R,5R,SS)-7. After MCPBA oxidation to
sulfone and stereoselective DIBALH reduction of the car-
bonyl group, cyclohexenoid derivative (1R,4S,6R)-8 was
obtained in excellent yield. Finally, protection of the carbinol
at C-4 of 8 followed by elimination of methyl p-tolyl sulfone
under Cs2CO3 conditions afforded cyclohexenone (4S,6R)-9
in optically pure form.12 The stereoselective epoxidation of
the double bond of 9 was troublesome. After several trials
using different epoxidation agents (H2O2/triton B,15 TBHP/
n-BuLi,16 TBHP/triton B,17 CF3COCH3/oxone18), the best
(8) Barros, M. T.; Maycock, Ch. D.; Ventura, M. R. Chem. Eur. J. 2000,
6, 3991-3996.
(9) Overviews: (a) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717-1760.
(b) Carren˜o, M. C.; Urbano, A. Synlett 2005, 1-25. Recent work: (c)
Carren˜o, M. C.; Gonza´lez-Lo´pez, M.; Urbano, A. Chem. Commun. 2005,
611-613. (d) Brinkman, Y.; Carren˜o, M. C.; Urbano, A.; Colobert, F.;
Solladie´, G. Org. Lett. 2004, 6, 4335-4338. (e) Carren˜o, M. C.; Des Mazery,
R.; Urbano, A.; Colobert, F.; Solladie´, G. Org. Lett. 2004, 6, 297-299. (f)
Carren˜o, M. C.; Des Mazery, R.; Urbano, A.; Colobert, F.; Solladie´, G. J.
Org. Chem. 2003, 68, 7779-7787. (g) Carren˜o, M. C.; Garc´ıa-Cerrada, S.;
Urbano, A. Chem. Eur. J. 2003, 9, 4118-4131. (h) Almor´ın, A.; Carren˜o,
M. C.; Somoza, AÄ .; Urbano, A. Tetrahedron Lett. 2003, 44, 5597-5560.
(i) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A. J.
Org. Chem. 2003, 68, 4315-4321.
(10) Carren˜o, M. C.; Pe´rez-Gonza´lez, M.; Ribagorda, M.; Somoza, A.;
Urbano, A. Chem. Commun. 2002, 3052-3053.
(11) (a) Carren˜o, M. C.; Pe´rez-Gonza´lez, M.; Ribagorda, M.; Houk, K.
N. J. Org. Chem. 1998, 63, 3687-3693. (b) Carren˜o, M. C.; Pe´rez Gonza´lez,
M.; Ribagorda, M.; Fischer, J. J. Org. Chem. 1996, 61, 6758-6759.
(12) Carren˜o, M. C.; Ribagorda, M.; Somoza, A.; Urbano, A. Angew.
Chem., Int. Ed. 2002, 41, 2755-2757.
(14) (SS)-6 was prepared as previously described for the (SR)-enanti-
omer: Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173-175.
(15) Barros, M. T.; Matias, P. M.; Maycock, Ch. D.; Ventura, M. R.
Org. Lett. 2003, 5, 4321-4323.
(13) Buchanan, G. L.; Raphael, R. A.; Taylor, R. J. Chem. Soc., Perkin
Trans. 1 1973, 373-375.
1420
Org. Lett., Vol. 7, No. 7, 2005

results were achieved in the presence of Ph3COOH19 and
Triton B. Under these conditions (THF, -78 to -30 °C),
an unseparable 75:25 mixture of diastereomeric epoxides 10
and 11 was obtained in quantitative yield. Deprotection of
the OTBDMS of this mixture (TBAF in THF) followed by
chromatographic separation furnished (+)-dihydroepiepo-
formin (1) (61% yield) and alcohol (2S,3S,4S,6R)-12 (16%
yield). Synthetic dihydroepiepoformin (1) {[R]20D +34 (c 0.1,
structure, (+)-epiepoformin (2). The synthetic sequence to
(+)-2 is depicted in Scheme 3 and started with (p-tolyl-
Scheme 3. Enantioselective Synthesis of (+)-Epiepoformin
(2)
CHCl3), [R]20 +22 (c 0.1, acetone), 96% ee},20 with the
D
(2R,3R,4S,6R)- absolute configuration, showed NMR pa-
rameters identical to those described for the isolated natural
product.3
The synthesis of (-)-dihydroepiepoformin (1), summarized
in Scheme 2, required the use of (SR)-321 as starting material.
Scheme 2. Enantioselective Total Synthesis of
(-)-Dihydroepiepoformin (1)
This enantiomer was synthesized following the sequence
shown in Scheme 1 for (SS)-3 but using (SR)-methyl-p-
tolylsulfoxide (6)14 as the source of chirality. Conjugate
addition of AlMe3 to (SR)-3 occurred at the pro-S position.11
The resulting compound (4S,5S,SR)-7 was transformed, as
described in Scheme 1 for the corresponding enantiomer,
into cyclohexenone (4R,6S)-910 and further elaborated to (-)-
dihydroepiepoformin (1). This enantiomer showed the same
spectral data as the natural dihydroepiepoformin and a
specific rotation value of {[R]20D -27 (c 1.2, CHCl3), [R]20
D
-21 (c 1.2, acetone), 96% ee}20 having the (2S,3S,4R,6S)-
absolute configuration.
With both enantiomers of dihydroepiepoformin (1) syn-
thesized, we turned out our attention to the other target
sulfinyl)methyl-p-quinol (SR)-3.21 The stereoselective addi-
tion of Me3Al followed by trapping of the enolate intermedi-
ate with N-bromosuccinimide furnished R-bromoketone 13
as a mixture of epimers at C-6. After HBr elimination in the
presence of lithium carbonate and lithium chloride, methyl-
susbtituted p-quinol (4R,SR)-411 was obtained in good yield.
Transformation of 4 into (+)-epiepoformin (1) was then
achieved in only four steps. MCPBA oxidation of 4 gave
rise to the sulfone 14 in nearly quantitative yield. The
epoxidation of derivative 14 was carried out with tert-
butylhydroperoxide (TBHP) in the presence of Triton B,
affording epoxide 15 as the unique diastereoisomer in 72%
(16) Ferna´ndez de la Pradilla, R.; Ferna´ndez, J.; Manzano, P.; Me´ndez,
P.; Priego, J.; Tortosa, M.; Viso, A. Mart´ınez-Ripoll, M.: Rodr´ıguez, A. J.
Org. Chem. 2002, 67, 8166-8177.
(17) (a) Evarts, J. B.; Fuchs, P. L. Tetrahedron Lett. 2001, 42, 3673-
3675. (b) Evarts, J. B.; Fuchs, P. L. Tetrahedron Lett. 1999, 40, 2703-
2706.
(18) (a) Yang, D. Acc. Chem. Res. 2004, 37, 497-505. (b) Shi, Y. Acc.
Chem. Res. 2004, 37, 488-496.
(19) Lei, X.; Johnson, R. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed.
2003, 42, 3913-3917.
(20) Optical purity of both enantiomers of dihydroepiepoformin (1) was
determined by chiral HPLC: Daicel Chiralcel AD, i-PrOH/hexane 10:90,
flow rate 0.7 mL/min, tR ) 15.3 min for the (2S,3S,4R,6S)-enantiomer and
17.5 min for the (2R,3R,4R,6S)-enantiomer, 211 nm.
(21) Carren˜o, M. C.; Pe´rez-Gonza´lez, M.; Houk, K. N. J. Org. Chem.
1997, 62, 9128-9137.
Org. Lett., Vol. 7, No. 7, 2005
1421

yield. This highly stereoselective epoxidation took place on
the more electrophilic unsubstituted double bond of 14
exclusively on the upper face of the enone system, which
bears the OH group. The diisobutyl aluminum hydride
(DIBALH) reduction of the carbonyl group of 15 afforded
a 77:23 mixture of the two possible diastereoisomeric
carbinols from which major compound 16, bearing the (S)-
absolute configuration at the newly created stereogenic
center, could be isolated after flash chromatography in 67%
yield. The diastereoselectivity of the reduction process could
be explained from the axial attack of the small hydride
DIBALH to the most stable B conformation of ketone 15,
where severe interactions between the methyl group at C-3
and the equatorial (p-tolylsulfonyl)methyl substituent at C-4
present in the other possible conformation A, are avoided
(Scheme 3).
0 °C) yielded a 41% of (+)-epiepoformin (2). Regardless
of the excellent yield achieved in the elimination of methyl
p-tolyl sulfone on the TBDMS-protected carbinol 17, the
overall yield for the direct transformation of carbinol 16 into
(+)-epiepoformin (2) was higher than that obtained in the
three-step sequence through intermediates 17 and 18.
In summary, we have reported that (p-tolylsulfinyl)methyl
quinols such as 3 and 4 are useful starting materials for the
asymmetric synthesis of naturally occurring cyclohexenone
epoxides. We have described the first total synthesis of both
enantiomers of dihydroepiepoformin (1) from known p-
quinols (RS)- and (SS)-3 in seven steps with 32% overall
yield and established their absolute configuration, as well
as a new enantioselective approach to (+)-epiepoformin (2)
in only four steps from methyl-substituted p-quinol (4R,SR)-4
with 26% overall yield.
Further treatment of carbinol 16 with Cs2CO3 (CH3CN,
rt, 30 min) afforded, after elimination of methyl p-tolyl
sulfone, a 54% yield of (+)-epiepoformin (2) {[R]20D +303
(c 1.1, EtOH), 96% ee}.22 All physical and spectroscopic
data of our synthetic compound were in agreement with those
published in the literature for the natural enantiomer of
epiepoformin.4-8
With the aim of increasing the yield of the elimination
step, we performed the protection of the free OH group of
16 as TBDMS (TBDMSOTf, 2,6-lutidine, 52% yield). The
elimination of methyl p-tolyl sulfone on the resulting
compound 17 under mild basic conditions (Cs2CO3, CH3-
CN, rt, 24 h) afforded ketone 18 in an excellent 99% yield.
Final deprotection of the TBDMS group of 18 (TBAF, THF,
Further applications of this methodology to the asymmetric
synthesis of more functionalized cyclohexanes-epoxide
natural products are now in progress.
Acknowledgment. We thank Ministerio de Ciencia y
Tecnolog´ıa (Grant BQU2002-03371) for financial support.
M.R. and E.M. wish to thank Ministerio de Ciencia y
Tecnolog´ıa for a Ramo´n y Cajal contract and a fellowship,
respectively, and A.S. wishes to thank Comunidad Auto´noma
de Madrid for a fellowship.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H NMR and 13
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) Optical purity of (+)-epiepoformin (2) was determined after 1H
NMR analysis (500 MHz) from the corresponding Mosher’s esters: Dale,
J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
OL050287A
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Org. Lett., Vol. 7, No. 7, 2005