Chemoenzymatic synthesis and biological evaluation of (-)-conduramine C-4

Article abstract of DOI:10.1080/00397910701555725

Previously unreported (-)-conduramine C-4 was synthesized in six steps from a bacterial bromobenzene metabolite in 23% overall yield. The chemoenzymatic route involved toluene dioxygenase dihydroxylation, β-epoxidation, epoxide ring-opening, Staudinger reduction, radical debromination, and Amberlite- catalyzed hydrolysis. (-)-Conduramine C-4 and other related compounds synthesised were assayed for galactosidase-activity inhibition against β-D-galactoside galactohidrolase isolated from Aspergillus oryzae. Copyright Taylor & Francis Group, LLC.

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Chemoenzymatic Synthesis and Biological
Evaluation of (-)‐Conduramine C‐4
Ana Bellomo a , Cecilia Giacomini b , Beatriz Brena b , Gustavo Seoane a &
David Gonzalez a
a Faculty of Chemistry, Department of Organic Chemistry, University of the
Republic, Montevideo, Uruguay
b Faculty of Chemistry, Department of Bioscience, University of the
Republic, Montevideo, Uruguay
Version of record first published: 05 Oct 2007.
To cite this article: Ana Bellomo , Cecilia Giacomini , Beatriz Brena , Gustavo Seoane & David Gonzalez
(2007): Chemoenzymatic Synthesis and Biological Evaluation of (-)‐Conduramine C‐4, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:20,
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Synthetic Communicationsw, 37: 3509–3518, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701555725
Chemoenzymatic Synthesis and Biological
Evaluation of (2)-Conduramine C-4
Ana Bellomo
Faculty of Chemistry, Department of Organic Chemistry, University of
the Republic, Montevideo, Uruguay
Cecilia Giacomini and Beatriz Brena
Faculty of Chemistry, Department of Bioscience, University of the
Republic, Montevideo, Uruguay
Gustavo Seoane and David Gonzalez
Faculty of Chemistry, Department of Organic Chemistry, University of
the Republic, Montevideo, Uruguay
Abstract: Previously unreported (2)-conduramine C-4 was synthesized in six steps
from a bacterial bromobenzene metabolite in 23% overall yield. The chemoenzymatic
route involved toluene dioxygenase dihydroxylation, b-epoxidation, epoxide ring-
opening, Staudinger reduction, radical debromination, and Amberlite- catalyzed
hydrolysis. (2)-Conduramine C-4 and other related compounds synthesised were
assayed for galactosidase-activity inhibition against b-D-galactoside galactohidrolase
isolated from Aspergillus oryzae.
Keywords: chemoenzymatic, conduramine, glycosidase inhibitors, toluene dioxygenase
INTRODUCTION
The cyclitols are a diverse class of compounds that share a polyhydroxylated
cycloalkane ring as a common structural motif. The major subclasses among
Received in the USA February 23, 2007
Address correspondence to David Gonzalez, Faculty of Chemistry, Department of
Organic Chemistry, University of the Republic, C.C. 1157, Gral. Flores 2124, Monte-
video, Uruguay. E-mail: davidg@fq.edu.uy
3509

3510
A. Bellomo et al.
the cyclitols are inositols, conduritols, and their deoxygenated analogs. The
chemoenzymatic approach to several of these cyclitols and cyclitol analogs
via whole-cell oxidation of aromatics by toluene dioxygenase has been exten-
sively explored by Hudlicky,[1–6] Carless,[7–9] Nicolosi,[10–14] and
ourselves.[15,16] As a result, syntheses of six of the nine possible inositol
isomers have been disclosed.[15,17–20]
Conduritols (5-cyclohexen-1,2,3,4-tetrols) are a prominent class of
compounds useful for the preparation of inositol derivatives.[21,22] In view
of the presence of four stereogenic centers, conduritols exist as 10 stereoi-
somers: four enantiomeric pairs and two meso-forms (Fig. 1). Conduramines
and other deoxygenated congeners of conduritols arise in even greater struc-
tural diversity (32 isomers) because of their decreased number of symmetry
planes and axes.
Interest in conduritols and conduramines has expanded in recent years for
various reasons.[23–28] Conduritols and conduramines inhibit certain glycosi-
dases,[29–31] they are important building blocks for the synthesis of more
complex natural products,[32] and the densely functionalised nature of these
compounds (four stereogenic centers on a cyclohexene ring) is synthetically
challenging.
Conduramines are purely synthetic aminocyclohexentriols formally
derived from conduritols. Some conduramines have significant glycosidase-
inhibitory activity;[33] they are well-known synthetic precursors of amino- and
diaminocyclitols, many of which are the aglycon portions of the therapeutically
useful aminoglycoside antibiotics. In addition, conduramines have been utilized
as intermediates in the preparation of azasugars,[34] aminosugars, sphingo-
sines,[32] and narcissus alkaloids.[35] Given the importance of conduramines as
synthetic building blocks, significant effort has been devoted to the development
of useful preparative routes to these compounds[36,37] and their derivatives.[38]
Hudlicky et al. have devised an enantiomerically controlled approach to
Figure 1. Structures of all conduritol isomers.

(2)-Conduramine C-4
3511
several conduramines from a single, optically pure 1-halo-cis-2,3-dihidroben-
zene-2,3-diol.[23]
As a part of our program for the synthesis of cyclitol conjugates and gly-
cosides to be tested as glycosidase inhibitors and insect repellents,[39] we
needed to prepare a series of known and unknown cyclitols. We have
recently published the synthesis of phenylthioconduritol F,[16] and in continu-
ation with our studies, we report the preparation of the previously unknown
(2)-conduramine C-4 (8) in an optically pure form.
RESULTS AND DISCUSSION
Whole-cell fermentation of bromobenzene with Pseudomonas putida 39/D
furnished the chiral cis-cyclohexenedienediol 1 in an isolated yield of 1.5 g
of optically pure metabolite per liter of cell-free broth. After the chirality
transfer through the biocatalytic step, the homochiral cis-cyclohexadienediol
was subjected to a precisely defined sequence of stereospecific chemical trans-
formations. The absolute stereochemistry of the next quiral centers introduced
after the enzymatic oxidation was controlled by the syn-directing effect of the
free diol or by the anti-directing effect of the rigid acetonide protective group.
cis-Diol 1 was protected as the corresponding acetonide 2, which reacted with
N-bromosuccinimide in the presence of water to render a mixture of bromohy-
drins 3a and 3b.[40] These products resulted from the hydrolytic ring opening
at the allylic carbon of two stereochemically different bromonium intermedi-
ates. Treatment of the crude mixture of bromohydrins with sodium hydroxide
promoted the formation of epoxides 4a and 4b,[41,42] which were isolated after
column chromatography in a relative ratio of 7:1. Azido alcohol 5 was
prepared in high yield by ring opening of epoxide 4a with NaN3 in an
aqueous/organic media (Scheme 1).[43]
To generate the desired conduramine, two different routes starting from
azide 5 were tested (Scheme 2). We first attempted a classical two-step
Scheme 1. Synthesis of homochiral azide 5 from bromobenzene.

3512
A. Bellomo et al.
Scheme 2. Synthesis of (2)-conduramine C-4 from bromoazide 5.
sequence for the consecutive reduction of both functional groups. Staudinger-
type reduction of the azide group[44] rendered the aminoalcohol 6 in reason-
able yield. This operation was followed by radical dehalogenation using
SnBu3H as the hydrogen donor and azobiscyclohexancarbonitrile (ABCC)
as initiator to furnish amine 7. The overall yield for both steps was 56% of
isolated conduramine derivative 7. Because LiAlH4 is a known azide group
reducer and debrominating agent, we decided to use it in an alternative one-
step procedure for the complete reduction of key intermediate 5. Our results
showed that the reaction of 5 with LiAlH4 in THF did furnished 7, albeit in
poorer yield (31%). Derivative 7 is a very hygroscopic and unstable
compound that repeatedly failed elemental analysis. Therefore, for synthetic
purposes, the material was carried to the next step with only minimal purifi-
cation. Intermediate 7 was subjected to Amberlite resin–catalyzed hydrolysis
to render enantiopure (2)-conduramine C-4 as the only product in high yield.
This last step was conducted inside a chromatography column loaded with
Amberlite in its acidic form and in a mass ratio of 20:1 relative to the crude
amine 7. In that sense, this last reaction overlapped with the purification
procedure for the previous step, which therefore become redundant and
unnecessary from a purely synthetic perspective.
Synthetic (2)-conduramine C-4 is a new compound; consequently its
optical rotation has not been previously reported. Nevertheless, the recorded
value –166 (c 0.3, MeOH) was compared to the reported number for the
known enantiomer (þ)-conduramine C-4 þ155 (c 0.7, MeOH) synthesized
by Nicolosi et al. by lipase-catalyzed desymmetrisation.[13]
The compound was included in a small library of compounds structurally
related to conduritols and assayed for galactosidase-activity inhibition against
b-D-galactoside galactohidrolase (EC 3.2.1.23) isolated from Aspergillus

(2)-Conduramine C-4
Table 1. Comparison of inhibitory activities
3513
Inhibition
activity (%)
Entry
Compound
1
2
3
4
5
6
8
9
—
13
17
—
3
10
11
12
13
—
oryzae. Neither (2)-conduramine C-4 nor its brominated analog 11 exhibited
activity at a concentration range of 0.069 mM to 2.76 mM (Table 1). The
deprotected derivatives of other intermediates in the synthesis were also
tested (Fig. 2). The bromoazidotriol 10 afforded from the hydrolysis of bro-
moazide 5 showed the highest activity: 17% inhibition at a concentration of
10 mM. Its debrominated analog 12 was much less active, and a similar
effect was observed for the diasteromeric bromoazidotriol 9. Finally,
compound 13, which lacks the vinyl bromine atom and presents the
opposite configuration at C-1 and C-6, was completely inactive. These
results could suggest that the concomitant presence of an azido group and a
bromide atom is required to obtain high inhibition degrees and that the
presence of three contiguous cis-hydroxyl groups is important for bioactivity.
Furthermore, these results are useful to determine the structure–activity
relation for these inhibitors and to design alternative strategies to improve
their potency.
Several other conduritol-like compounds as well as conduritol conjugates
have been prepared in our laboratory and are being evaluated as glycosidase
inhibitors. The synthetic strategy and the biological testing results for all
libraries will be reported in due course.
Figure 2. Compounds tested for galactosidase-activity inhibition.

3514
A. Bellomo et al.
EXPERIMENTAL
General
All nonhydrolytic reactions were carried out under a nitrogen atmosphere, with
standard techniques for the exclusion of moisture. All solvents were distilled
prior to use. Melting points were determined on a Leitz Microscope Heating
Stage model 350 apparatus and are uncorrected. Optical rotations were
measured on a Perkin-Elmer 241 polarimeter using a 7-mL cell. Infrared
spectra were recorded on a Matheson Excalibur spectrometer. Mass spectra
were recorded on a Shimadzu GS-MS QP 1100 EX instrument using the
electron impact mode. Nuclear magnetic resonance spectra were recorded on
Bruker Avance DPX-400 instrument with Me4Si as the internal standard and
chloroform-d as solvent unless otherwise indicated. Chemical shifts are
reported in parts per million(ppm). Elemental analyses were performed in a
Fisons EA 1108 CHNS-O analyzer or submitted to Atlantic Microlabs, North-
cross, GA, USA. Analytical thin-layer chromatography(TLC) was performed
on silica-gel 60F-254 plates and visualized with UV light (254 nm) and/or ani-
saldehyde-H2SO4-AcOH as detecting agent. Flash-column chromatography
was performed in silica gel (Kieselgel 60, EM Reagents, 230–400 mesh).
Compound 5 has been previously reported;[43] therefore, some spectral
data are omitted here. Compound 7 was so unstable that we could not
obtain acceptable CHN results in spite of using spectroscopically pure
samples and performing the analysis four times on this compound using
different operators in different machines.
(1S,2R,3S,6R)-6-Amino-4-bromocyclohexene-2,3-isopropylidendioxy-
1-ol (6)
Azide 5 was dissolved in tetrahydrofuran (15 mL) containing 1 equivalent of
acetic acid. Triphenylphosphine (0.73 g, 2.78 mmol) was added under N2.
The reaction was stirred for 24 h at rt followed by addition of water (25 eq.)
and stirred for a further 24 h at rt. The reaction mixture was concentrated at
reduced pressure, and the yellow residue was subjected to flash chromatography
on silica, eluting first with EtOAc (to remove triphenylphosphine and triphenyl-
phosphine oxide) and then a gradient of 10:90–30:70 MeOH–EtOAc to afford
the amino compound 6. Yield: 78%; white needles; mp 87–898C; [a]1D9 ¼ 298
(c 0.73, CH2Cl2). Anal. calcd. for C11H18BrNO5 (amine 6 acetate): C, 41.06; H,
5.76; N, 4.52. Found: C, 40.76; H, 5.60; N, 4.32. IR (KBr): 3539–2575 b, 1589,
1231, 1059, 864 cm21; MS (m/z, %): 263 (Mþ, 0.10), 190 (5), 165 (83), 109
(38), 101 (100), 80 (19), 55 (54), 43 (37); 1H RMN (CDCl3): d ¼ 1.39
(s, 6H), 3.67 (bs, 2H, H-3 and H-6), 4.44 (bs, 3H), 4.48 (d, 1H, H-1), 4.60
(d, 1H, J23 5.0 Hz, H-2), 6.03 (s, 1H, H-5); 13C NMR (CDCl3): d ¼ 26.9,
27.8, 51.9, 72.5, 77.8, 78.8, 111.1, 124.2, 132.3.

(2)-Conduramine C-4
3515
(1S,2R,3R,6R)-6-Amino-cyclohex-4-ene-2,3-isopropylidendioxy-
1-ol (7)
Bu3SnH (0.42 g, 1.44 mmol) was added to a mixture of azobiscyclohexancar-
bonitrile (0.09 g, 0.36 mmol) and the amino compound 5 in dry tetrahydro-
furan (15 mL). The reaction mixture was refluxed for 4 h. Concentration at
reduced pressure and purification of the oily residue by flash chromatography
(AcOEt–MeOH 70:30) furnished the pure product 7. Yield: 75%; white solid;
mp 99–1008C; [a]2D0 ¼ 276 (c 0.51, CH2Cl2); IR (KBr): 3450–2882 b, 1237,
1086, 1036, 882 cm21; MS (m/z, %): 170 (Mþ-CH3, 5), 149 (4), 110 (11), 98
(21), 85 (100), 55 (42), 43 (29); 1H NMR (CDCl3): d ¼ 1.39 (s, 6H), 2.14 (bs,
3H), 3.40 (d, 1H, J16 8.1 Hz, H-1), 3.50 (bd, 1H, H-6), 4.51 (bs, 1H, H-2), 4.63
(d, 1H, J32 2.6 Hz, H-3), 5.64 (m, 2H, H-4 and H-5); 13C NMR (CDCl3):
d ¼ 26.9, 27.9, 50.2, 74.4, 75.3, 76.3, 110.1, 126.8, 132.6.
An alternative procedure for 7 is as follows: To a solution of azide 5
(0.30 g, 1.05 mmol) in dry tetrahydrofuran (10 mL), LiAlH4 (0.05 g,
1.31 mmol) was added. The resulting mixture was stirred at rt for 36 h. The
reaction was quenched with water and treated with 20% aqueous sodium
hydroxide (1 mL). The layers were separated, and the organic phase was
dried (anh. MgSO4), filtered, and concentrated under reduced pressure to
provide the crude amine (7), which was purified by flash chromatography as
described above. Yield: 31%.
(1S,2R,3R,6R)-6-Amino-cyclohex-4-ene-1,2,3-triol (Conduramine
C-4, 8)
Compound 7 was dissolved in methanol and applied to a Dowex-50 (Hþ form)
column, which was eluted with 2 N NH4OH (20 mL). The alkaline eluate was
concentrated at 508C (20 Torr) to afford (2)-8. Yield: 98%; white solid; mp
82–848C (d); [a]2D0 ¼ 2160 (c 0.30, MeOH), Anal. calcd. for C6H11NO3: C,
49.63; H, 7.65; N, 9.65. Found: C, 49.54; H, 8.01; N 9.44, IR (KBr) 3385–
3279 b, 1613, 1305, 1050, 1024, 847, 690 cm21; MS (m/z, %) 128
1
(Mþ 221, 0.25), 110 (3), 85 (100), 68 (6), 56 (12), 42 (5); H NMR (D2O):
d ¼ 3.44 (m, 1H, H-2), 3.49 (m, 1H, H-3), 4.04 (s, 1H, H-1), 4.36 (s, 1H,
H-6), 5.56 (d, 1H, J54 10.3 Hz, H-5), 5.59 (d, 1H, J45 10.3 Hz, H-4); 13C
NMR (D2O): d ¼ 50.2, 68.6, 72.8, 75.0, 128.6, 130.0.
ACKNOWLEDGMENT
The authors are grateful to IFS (Grants F/3078-1 and F/3078-2) and
CONICYT (FCE 8068) for financial support of this work. A. B. is grateful
to PEDECIBA and DINACYT for a doctoral fellowship. The authors

3516
A. Bellomo et al.
acknowledge Jorge Adum for carrying out the fermentation process and
Horacio Pezzaroglo for recording nuclear magnetic resonance (NMR) spectra.
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