Chemoenzymatic synthesis of conduritol analogues

Article abstract of DOI:10.1016/j.tetlet.2004.10.072

Several conduritol and conduramine analogues have been synthesized from β-substituted naphthalenes via a chemoenzymatic approach, in a high regio- and stereocontrolled way. Several conduritol and conduramine analogues have been synthesized from β-substituted naphthalenes via a chemoenzymatic approach, in a high regio- and stereocontrolled way.

Full text of DOI:10.1016/j.tetlet.2004.10.072

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9253–9255
Chemoenzymatic synthesis of conduritol analogues
Fulvia Orsini,* Guido Sello, Silvana Bernasconi and Gianfranco Fallacara
Dipartimento di Chimica Organica e Industriale, Via Venezian, 21-20133 Milano, Italy
Received 16 September 2004; revised 7 October 2004; accepted 12 October 2004
Available online 28 October 2004
Abstract—Several conduritol and conduramine analogues have been synthesized from b-substituted naphthalenes via a chemoenzy-
matic approach, in a high regio- and stereocontrolled way.
Ó 2004 Elsevier Ltd. All rights reserved.
OH
OH
1. Introduction
OH
OH
OH
R
R
R
a
Cyclohex-5-ene-1,2,3,4-tetrols are an important class of
cyclitols named conduritols. Ten different stereoisomers
exist of which six are diastereoisomers (conduritols A–
F) indicated by alphabetical letters in order of their dis-
covery.1 Only conduritol A and (+) conduritol F have
been found in nature, albeit in small amounts. All 10
stereoisomers of conduritols have been prepared by
multi-steps chemical syntheses in nonracemic form.1,2
Several chemoenzymatic syntheses have also been
performed, based on the ability of some microbial dioxy-
genases to convert aromatic compounds to vic-diols in
a high stereospecific manner.3 Some conduritol deriva-
tives have shown antibiotic, antileukemic and growth
regulating activity.1 In view of their promising therapeu-
tic potential in the management of disorders like diabe-
tes, viral infections (including HIV) and cancer, many
analogues and structural variants of conduritols have
been synthesized, including nonnatural bicyclic and tri-
cyclic mimics4–6 and their biological activities evaluated,
in particular glycosidase inhibition which plays a funda-
mental role in the development of new drugs. The prom-
ising results stimulated the study of other bicyclic
compounds of general formula 1,7 where the double
bond of conduritols is formally replaced by an aromatic
ring, which may confer valuable properties to the mole-
cule and enhance its lipophilicity, that can be further
modulated by properly located substituents. Further-
more, a substituent on the aromatic ring could be used
X
1
X = OH, OR, NH2, NR2
Scheme 1. (a) E. coli JM109 (pVL1343A + pMS13).
to introduce additional functionalities properly devised
and tailored to fit specific biological targets. In retrosyn-
thetic analysis compounds of general formula 1 can be
prepared from 7-substituted (1R,2S)-1,2-dihydroxy-1,2-
dihydronaphthalenes (cis-diols) that we previously
obtained by bioconversion of the corresponding naph-
thalenes using the naphthalene dioxygenase from Pseu-
domonas fluorescens N3 expressed in E. coli JM109
(Scheme 1).8
2. Result and discussion
We already reported the conversion of 1,2-dihydroxy-
1,2-dihydronaphthalene 2a to the 3,4-epoxide 4a in
two steps (80% total yield).9a The cis-diol 2a was first
converted to isopropylidene derivative 3a with 2,2-
dimethoxypropane in the presence of a catalytic amount
of p-toluenesulfonic acid and then the double bond was
oxidized in a high stereospecific manner at 0°C with m-
chloroperbenzoic acid in methylene chloride. The ketal-
ization and epoxidation steps were therefore applied to
the 7-substituted cis-diols 2b–f, obtained as single stereo-
isomers by bioconversion of the corresponding b-sub-
stituted naphthalenes.
Keywords: 1,2-Dihydroxy-1,2-dihydronaphthalenes; Diastereoselective
synthesis; 1,2,3,4-Tetrahydro-1,2,3,4-tetrahydroxynaphthalenes; 1,2,3-
Trihydroxy-4-aminonaphthalenes.
*
Corresponding author. Tel.: +39 250314113; fax: +39 250314106;
e-mail: silvana.bernasconi@unimi.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.072

9254
F. Orsini et al. / Tetrahedron Letters 45 (2004) 9253–9255
Whereas the isopropylidene derivatives 3a–f were always
obtained in quantitative yields, the expected 3,4-epoxides
were obtained with variable yields, depending on the sub-
stituent R: generally in good yields (70–80%), albeit lower
with respect to the unsubstituted ketal 3a, but with some
exceptions. Ketals 3e,f, having in position 7 an electron-
donating substituent (MeO- or Et-), able to stabilize by
resonance an incipient carbocation in position 4, afforded
derivatives 8e,f. The reported relative cis-stereochemistry
of the substituents in position 3 and 4 is relative to the
main product (85/15 cis/trans for 8e and 78/22 cis/trans
for 8f) and is consistent with the 1H NMR coupling con-
stant (J3,4 = 2.8Hz observed for cis product and 7.6Hz
observed for the minor trans product).
sodium azide (Scheme 3). The carbonate was obtained
from the protected cis-diols 3 via di-hydroxylation with
b-AD-mix,10 followed by reaction with triphosgene.
This new protocol was first tested on 3a and then ex-
tended to 3d and 3e. The reaction with AD-mix afforded
the cis-diols 10a,b,d,e in good yields (70–90%). As ob-
served in the epoxidation step, also in this case oxidation
of the 3,4-double bond proceeded in a high stereospecific
way on the side of the molecule opposite to the sterically
demanding 1,2-ketalic function. Upon treatment with
triphosgene (solid and more convenient to use with re-
spect to the toxic phosgene) in methylene chloride at
0°C in the presence of pyridine, diols 10a,b,e afforded,
in almost quantitative yields, the corresponding carbon-
ates 11a,b,e (Scheme 3). With the exception of the nitro-
derivative 11b (which once again afforded a mixture of
unidentified products), they were subsequently con-
verted to the corresponding azides with better yields
(80–85%) with respect to those observed via epoxides.
The hydrolysis of diols 10a,d,e by hydrochloric acid in
methanol or by trifluoroacetic acid in THF–water gave
tetrols 12a,d,e.
Epoxides 4a–d are useful intermediates for the synthesis
of conduritols and conduramine analogues.
Stereospecific ring opening of the 3,4-epoxides 4a,c and
d at the benzylic position was achieved with sodium
azide in dimethylformamide at 110°C and afforded the
corresponding azides 5a (86%), 5c (85%) and 5d (50%)
(only one diastereoisomer was obtained in these cases).
The nitro epoxide 4b afforded a mixture of unidentified
products (Scheme 2). Catalytic reduction of the azides
5a,d in methanol in the presence of palladium on carbon
afforded the amines 6a,d (90–95%) which were depro-
tected in excellent yields (85–90%) to the corresponding
1,2,3-trihydroxy-4-amino-derivatives 7a,d upon treat-
ment with either hydrochloric acid in methanol or tri-
fluoroacetic acid in tetrahydrofuran–water (4:1). The
same protocol (sodium azide in dimethylformamide) ap-
plied to the m-chlorobenzoate 8e afforded the derivative
9e (55 % with 35% recovery of starting 8e), reasonably
coming from an intramolecular transesterification
involving the free hydroxyl function in position 3.
Synthetic work is now in progress in order to: (a) extend
the synthetic sequences reported above to regioisomeric
8- and 5-substituted (1R,2S)-1,2-dihydroxy-1,2-dihydro-
naphthalene diols obtained by bioconversion of a-sub-
stituted naphthalenes;9 (b) obtain a different relative
stereochemistry of the stereo centers in the molecule
and (c) test their influence on biological activity. To sat-
isfy the point (b), the epoxidation reaction has been di-
rectly tested on 1,2-dihydroxy-1,2-dihydronaphthalenes
obtained by bioconversion, without any protection of
the cis-diol function. Diol 2a, chosen as model com-
pound to optimize the reaction protocol, has been trea-
ted with m-chloroperbenzoic acid in methylene chloride
in the presence of sodium monohydrogenphosphate11
and afforded the epoxide with the diol and epoxy func-
tions on the same side in quantitative yield. The presence
The difficulties encountered in the synthesis of the azides
5b,e,f prompted us to devise a different and alternative
synthetic strategy, by opening of a carbonate 11 with
OH
O
O
O
OH
O
R
R
O
R
O
R
a
b
c
OH
OCOR1
OCOR1
OH
b
2a-f
3a-f
8e,f
9e
O
O
OH
O
O
R
c
O
R
OH
OH
R
O
R
e
d
OH
OH
O
N3
NH2
NH2
4a-d
5a,d
7a,d
6a,d
Scheme 2. Reagents and conditions: R = (a) H, (b) NO2, (c) Br, (d) COOCH3, (e) OCH3, (f) CH2CH3; R1 = m-Cl–C6H5 (a) DME, PTS, CH2Cl2, rt;
(b) m-chloroperbenzoic acid, 0°C; (c) NaN3, DMF, 110°C; (d) H2, Pd/C, MeOH, rt; (e) HCl, MeOH, 0°C.

F. Orsini et al. / Tetrahedron Letters 45 (2004) 9253–9255
9255
OH
O
O
OH
OH
R
O
O
R
R
a
b
OH
O
H
OH
3a,b,d,e
10a,b,d,e
12a,d,e
c
O
O
OH
O
O
O
R
O
R
OH
OH
R
d,e
b
OH
O
NH2
NH2
11a,b,e
6a,e
7a,e
Scheme 3. Reagents and conditions 3 (a): b-AD-mix, tert-BuOH, H2O, 0°C; (b) HCl, MeOH, 0°C; (c) triphosgene, pyridine, CH2Cl2, 0°C; (d) NaN3,
DMF, 110°C; (e) H2, Pd/C, MeOH, rt.
Chem. 1999, 64, 9613–9624; (g) McDonouhh, N.; Stick, R.
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of the free diol function oriented the epoxidation pro-
viding an entry to inverted stereochemistry at positions
3 and 4.
3. Conclusions
3. (a) Sanfilippo, C.; Patti, A.; Piattelli, M.; Nicolosi, G.
Tetrahedron: Asymmetry 1997, 8(10), 1569–1573; (b)
Carless, H. A. J.; Busia, K.; Dove, Y.; Malik, S. S.
J. Chem. Soc., Perkin Trans. 1 1993, (21), 2505–2506; (c)
Carless, H. A. J. Tetrahedron Lett. 1992, 33(42), 6379–
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1992, (3), 234–235; (e) Carless, H. A. J.; Oak, O. Z. J.
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licky, T.; Luna, H.; Olivo, H. F.; Andersen, C.; Nugent,
T.; Price, J. D. J. Chem. Soc., Perkin Trans. 1 1991, 2907–
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We have devised synthetic chemoenzymatic strategies to
obtain bicyclic conduritols and conduramine analogues,
namely
7-substituted
1,2,3,4-tetrahydroxy-1,2,3,4-
tetrahydronaphthalenes (R = H, OCH3, COOCH3)
and 7-substituted 1,2,3-trihydroxy-4-amino-1,2,3,4-tetra-
hydronaphthalenes (R = H, OCH3, COOCH3) with
different relative configurations.
Work is also in progress to verify if some of the synthe-
sized compounds possess biological activities, screening
them against commercial glycosidases that accept p-
nitrophenyl glycosides as substrates.
4. Kara, Y.; Balci, M.; Bourne, A. S.; Watson, N. H.
Tetrahedron Lett. 1994, 35, 3349–3352.
5. Mehta, G.; Ramesh, S. S. Chem. Commun. 2000, 2429–
2430.
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S.; Duhualt, J.; Espinal, J.; Challal, S. Bioorg. Med. Chem.
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Acknowledgements
`
The Ministero dellÕIstruzione, dellÕUniversita e della
Ricerca (MIUR) is acknowledged for financial support
(Cofin 2002- Protocol n. 200258141-007).
7. Some of them (R = H, X = OH, F, OMe, N3) have been
already synthesized and have given interesting results:
Ref. 2h.
References and notes
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