Cyclohexadiene-trans-diols as versatile starting material in natural product synthesis: Short and efficient synthesis of iso-crotepoxide and ent-senepoxide

Article abstract of DOI:10.1039/b110420a

A new synthesis of ent-senepoxide and iso-crotepoxide starting from microbially produced (+)-trans-2,3-dihydroxy-2,3-dihydrobenzoic acid via regio- and stereoselective epoxidation is described.

Full text of DOI:10.1039/b110420a

Cyclohexadiene-trans-diols as versatile starting material in natural
product synthesis: short and efficient synthesis of iso-crotepoxide and
ent-senepoxide
Volker Lorbach,a Dirk Franke,a Martin Niegerb and Michael Müller*a
a Institute of Biotechnology 2, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany.
E-mail: mi.mueller@fz-juelich.de; Fax: (+49)2461-61-3870
b Department of Inorganic Chemistry, University of Bonn, Gerhard Domagk Str. 1, 53121 Bonn, Germany
Received (in Cambridge, UK) 14th November 2001, Accepted 21st January 2002
First published as an Advance Article on the web 7th February 2002
A new synthesis of ent-senepoxide and iso-crotepoxide
starting from microbially produced (+)-trans-2,3-dihydroxy-
2,3-dihydrobenzoic acid via regio- and stereoselective epox-
idation is described.
Highly functionalized cyclohexane derivatives like conduritols
and cyclitols have attracted considerable attention because of
their useful biological activity.1 Cyclohexadiene-cis-diols (cis-
CHD), substituted at the diene unit, have been established as
valuable chiral building blocks in the synthesis of such
substances, in particular because of their good accessibility.2
Functionalized cyclohexadiene diols possessing a trans-config-
uration of the two hydroxy groups (trans-CHD) have not been
established as chiral building blocks in syntheses in the same
way so far. Due to the difficult access to enantiomerically
enriched trans-CHD by multistep syntheses3,4 or starting from
cis-CHD through inversion of configuration,5 they have been
relatively rarely used in natural product synthesis.
Scheme 1 Reagents and conditions: i, trimethylsilyl diazomethane (2
hexane), MeOH, rt, 6 h; ii, m-CPBA, NaHCO3, CH2Cl2, rt, 3 h; iii, TBS-
OTf, NEt3, CH2Cl2, rt, 2 h; iv, aqueous HF (40%), acetonitrile, rt, 2 h.
M in
lectively from the b-face. Compound 5 was obtained as a single
diastereomer in 85% yield.3 The relative configuration of the
oxirane ring in 3 and 5 with regard to the substituent at C2 was
confirmed by 1H-NMR experiments. A coupling constant of J1,2
= 7.9 Hz in 3 indicates the two hydroxy groups are in a
diequatorial position due to the favoured twist conformation.
On the other hand a J1,2 coupling of 2.1 Hz shows the diaxial
position of the protected hydroxy groups in 5. In addition, the
relative configuration of 3 was proven by X-ray structure
analysis (Fig. 1).9 Deprotection of 5 could be achieved by using
hydrogen fluoride to give 6 in 76% yield.
The reduction of the ester group of 4 to the corresponding
alcohol 7 was performed with diisobutylaluminium hydride
(DIBAL-H) in 88% yield.10 Epoxidation of 7 with equimolar
amounts of m-CPBA at low temperatures led to 8 in 91%
yield.11 Reaction of 7 as well as 8 with an excess of the
oxidizing agent at higher temperatures and prolonged reaction
Recently, we have shown that trans-CHD are also available
in multigram scale by cultivation of recombinant Escherichia
coli cells.6 This offers the possibility of establishing new short
and efficient synthetic strategies to biologically active and
pharmaceutically interesting compounds.
In order to demonstrate the potential of trans-CHD as
versatile chiral building blocks, we present investigations
towards regio- and stereoselective epoxidation of either one or
both olefinic double bonds and the usage of this reaction in the
synthesis of ent-senepoxide 12 and iso-crotepoxide 15
(1,2,3,4-tetra-epi-crotepoxide).
(2S,3S)-trans-Dihydroxy-2,3-dihydrobenzoic
acid†
(2,3-trans-CHD; 1) occurs in E. coli as a metabolite derived
from the shikimate–chorismate pathway. Using techniques of
metabolic engineering microbial producer of 1 could be
obtained.6 Enantiopure compound 1 was isolated from the
cultivation broth by ion exchange chromatography in high yield
and was used as the starting material for the following reaction
steps.
The syntheses started with an esterification of the carboxylic
group of 1 (Scheme 1). Due to the electron withdrawing effect
of the ester group, epoxidation of diol 2 and TBS-protected diol
4 using meta-chloroperoxybenzoic acid (m-CPBA) took place
exclusively at double bond C3-C4.3,7 The stereochemistry of
the peroxide attack and the configuration of the resulting
epoxide is directed by the functionality at C2. In the case of an
allylic hydroxyl group, m-CPBA coordinates via hydrogen
bonds and forces the C2-C3 cis-configuration of 3.8
Applying the same conditions to the protected diol 4 the
bulky 2-siloxy group shields the a-face of the cyclohexadiene
plane hence the attack of the peracid takes place regiose-
Fig. 1 Molecular structure of epoxide 3 showing the C2–C3 cis-
configuration.
494
CHEM. COMMUN., 2002, 494–495
This journal is © The Royal Society of Chemistry 2002

Fig. 2 Molecular structure of bisepoxide 14. The epoxide moieties are
arranged in a trans-configuration to each other.
Scheme 2 Reagents and conditions: i, DIBAL-H, hexane, 0 °C, 3 h; ii, 1 eq.
m-CPBA, NaHCO3, CH2Cl2, rt, 3 h; iii, 2.5 eq. m-CPBA, NaHCO3,
CH2Cl2, 50 °C, 16 h; iv, 1.5 eq. m-CPBA, NaHCO3, CH2Cl2, 50 °C,
16 h.
Notes and references
† The numbering scheme of the ring atoms here is deduced from the
traditional view of cyclohexadienes as derivatives of aromatic compounds.
This scheme is different to that used in the equations and molecular
structures.
time resulted in the formation of bisepoxide 9 in high yields
(Scheme 2).12
Compounds 8 and 9 possess already the core structure of ent-
senepoxide 12 and iso-crotepoxide 15. Benzoylation and
subsequent cleavage of the siloxy groups with tetrabutyl-
ammonium fluoride (TBAF) led to 11 and 14, respectively.
Acetylation of 11 and 14 quantitatively gave the stereoisomers
of the natural products (Scheme 3). The yield over seven steps
starting from 1 is 26% for ent-senepoxide 12 and 24 % for iso-
crotepoxide (1,2,3,4-tetra-epi-crotepoxide) 15. In comparison,
Shing et al. synthesized senepoxide starting from quinic acid in
17 steps.13
1 M. Balci, Y. Sütbeyaz and H. Secen, Tetrahedron, 1990, 46, 3715;
Carbohydrate Mimics. Concepts and Methods, ed. Y. Chapleur, Wiley-
VCH, Weinheim, Germany, 1998.
2 T. Hudlicky, D. Gonzalez and D. T. Gibson, Aldrichimica Acta, 1999,
32, 35; and references cited therein.
3 B. M. Trost, L. S. Chupak and T. Lübbers, J. Am. Chem. Soc., 1998, 120,
1732.
4 S. Ogawa and T. Takagaki, J. Org. Chem., 1985, 50, 2356; T. K. M.
Shing and E. K. W. Tam, Tetrahedron: Asymmetry, 1996, 353.
5 T. Hudlicky, G. Seoane and T. Pettus, J. Org. Chem., 1989, 54, 4239; B.
P. McKibben, G. S. Barnosky and T. Hudlicky, Synlett, 1995, 806; D. R.
Boyd, N. D. Sharma, H. Dalton and D. A. Clarke, Chem. Commun.,
1996, 45; D. R. Boyd, N. D. Sharma, C. R. O’Dowd and F. Hempenstall,
Chem. Commun., 2000, 2151.
6 D. Franke, G. A. Sprenger and M. Müller, Angew. Chem., Int. Ed., 2001,
40, 555; cf. R. Müller, M. Breuer, A. Wagener, K. Schmidt and E.
Leistner, Microbiology, 1996, 142, 1005.
7 S. Ogawa and T. Takagaki, Bull. Chem. Soc. Jpn., 1988, 61, 1413.
8 H. B. Henbest and R. A. L. Wilson, J. Chem. Soc., 1959, 1958; K. B.
Sharpless and T. R. Verhoeven, Aldrichimica Acta, 1979, 12, 63; M.
Freccero, R. Gandolfi, M. Sarzi-Amadé and A. Rastelli, J. Org. Chem.,
2000, 65, 8948.
9 Crystallographic data for 3: C8H10O5, M
= 186.2, T = 123 K,
monocyclic, space group P21 (No.4), a = 8.6140(2), b = 4.5655(1), c
= 11.0991(4) Å, b = 112.512(2)°, V = 403.23 Å3, Z = 2, Dc 1.53 g
cm23, F(000) = 196, m(Mo-Ka) = 0.13 mm21, 8907 reflections
measured, 1418 unique which were used in all calculations, wR2(F2) =
0.078 (all data), R1 = 0.029 [I > 2s (I)], flack parameter x = 0.5(10).
CCDC 174631. See http://www.rsc.org/suppdata/cc/b1/b110420a/ for
crystallographic files in .cif format.
Scheme 3 Reagents and conditions: i, benzoyl chloride, pyridine, 25 °C,
6 h; ii, 2.5 eq. TBAF, THF, 278 °C ? rt, 2 h; iii, acetic anhydride, pyridine,
0 °C ? rt, 1 h.
10 N. M. Yoon and Y. S. Gyoung, J. Org. Chem., 1985, 50, 2443.
11 R. H. Schlessinger and A. Lopes, J. Org. Chem., 1981, 46, 5253; S.
Ogawa, T. Toyokuni, M. Ara, M. Suetsung and T. Suami, Bull. Chem.
Soc. Jpn., 1983, 56, 1710; H. A. J. Carless and O. Z. Oak, Tetrahedron
Lett., 1991, 32, 1671.
12 S. Ogawa and T. Takagaki, Bull. Chem. Soc. Jpn., 1987, 60, 800.
13 T. K. M. Shing and E. K. W. Tam, J. Org. Chem., 1998, 63, 1547.
14 M. R. Demuth, P. E. Garrett and J. D. White, J. Am. Chem. Soc., 1976,
98, 634.
Analytical data of ent-senepoxide 12 were identical with the
literature data of Shing.13 Analytical data we found for
1,2,3,4-tetra-epi-crotepoxide 15 are identical with those White
and coworkers reported for 3,4,5,6-tetra-epi-crotepoxide.14,15
However, evidence of the relative stereochemistry was given by
X-ray structure analysis of 14 that revealed the C2–C3 trans-
configuration (Fig. 2).16
15 1H-NMR data of 15: d (CDCl3) 2.11 (3H, s), 2.16 (3H, s), 3.28 (1H, s),
3.62 (1H, s), 3.66 (1H, s), 4.11 (1H, d, J 12.5 Hz), 4.73 (1H, d, J 2.5 Hz),
5.18 (1H, s), 5.42 (1H, s), 7.47 (2H, t, J 7.6 Hz), 7.59 (1H, t, J = 6.8 Hz),
8.03 (2H, d, J = 7.4 Hz). The 1H-NMR data Shing et al. [Lit. 13]
published for 3,4,5,6-tetra-epi-crotepoxide show significant differences
to the data of 15 resp. White’s 3,4,5,6-tetra-epi-crotepoxide.
16 Crystallographic data for 14: C14H14O6, M = 278.3, T = 123 K
In summary, we developed a short and efficient synthesis of
stereoisomers of the biologically active cyclohexane epoxides
senepoxide and crotepoxide. The synthetic approach is based on
the regio- and stereoselective epoxidation of microbially
produced enantiopure 1. By choosing appropriate conditions
and reasonable protecting groups it is possible to selectively
introduce the oxirane moiety in senepoxide directly via peracid
oxidation, contrary to other statements.13
orthorhombic, space group P212121 (No.19), a
= 8.8867(2), b =
11.7119(2), c = 12.0177(3) Å, V = 1250.80 Å3, Z = 4, F(000) = 584,
Dc 1.48 g cm23, m(Mo-Ka) = 0.12 mm21, 24670 reflections measured,
2206 unique which were used in all calculations, wR2(F2) = 0.056 (all
data), R1 = 0.022 [I > 2s(I)], flack parameter x = 20.1(6). CCDC
174632.
All epoxides shown in this contribution, especially 3, 6, 8 and
9, might also be ideal starting materials in the preparation of
numerous other cyclitols and carbohydrate mimics.
M. N. thanks DAAD for financial support.
CHEM. COMMUN., 2002, 494–495
495