New aminocyclitols with quaternary stereocentres via acylnitroso cycloaddition with an ipso,ortho arene dihydrodiol

Article abstract of DOI:10.1016/j.tet.2013.04.033

Microbial ipso,ortho-dihydroxylation of benzoic acid by the B9 mutant strain of Ralstonia eutropha permits rapid construction of aminocyclitols containing a quaternary stereocentre. Installation of the amine functionality is achieved by use of an acylnitroso dienophile for a hetero-Diels-Alder reaction. Both aminotetrols and aminohexols are accessible as single enantiomers by this route. Both NOESY spectroscopic and X-ray crystallographic analyses were required to distinguish cycloadduct isomers. Notably, subsequent to the biooxidation step, all new stereocentres are installed under substrate control. Thus, all stereochemical information is ultimately of enzymatic origin.

Full text of DOI:10.1016/j.tet.2013.04.033

Tetrahedron 69 (2013) 5989e5997
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New aminocyclitols with quaternary stereocentres via acylnitroso
cycloaddition with an ipso,ortho arene dihydrodiolq
a
a
a
b
€
Julia A. Griffen , Jenifer C. White , Gabriele Kociok-Kohn , Matthew D. Lloyd ,
Andrew Wells c, Tom C. Arnot a, Simon E. Lewis a
,
*
a Doctoral Training Centre in Sustainable Chemical Technologies, University of Bath, Bath BA2 7AY, United Kingdom
b Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom
c Charnwood Technical Consulting Ltd, Loughborough, Leicestershire, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Microbial ipso,ortho-dihydroxylation of benzoic acid by the B9 mutant strain of Ralstonia eutropha per-
mits rapid construction of aminocyclitols containing a quaternary stereocentre. Installation of the amine
functionality is achieved by use of an acylnitroso dienophile for a hetero-DielseAlder reaction. Both
aminotetrols and aminohexols are accessible as single enantiomers by this route. Both NOESY spectro-
scopic and X-ray crystallographic analyses were required to distinguish cycloadduct isomers. Notably,
subsequent to the biooxidation step, all new stereocentres are installed under substrate control. Thus, all
stereochemical information is ultimately of enzymatic origin.
Received 30 January 2013
Received in revised form 23 March 2013
Accepted 8 April 2013
Available online 18 April 2013
Dedicated to the memory of Professor
J. Grant Buchanan (1926e2012)
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Microbial arene oxidation
Biotransformation
Aminocyclitol
Acylnitroso
Cycloaddition
1. Introduction
However, organisms expressing benzoate dioxygenase (BZDO)8
oxidise benzoic acids with both different regioselectivity and also
The dearomatisationedihydroxylation of an arene by a micro-
organism was first reported by Gibson in 1968.1 In the ensuing
period, the arene cis-diol products of such biotransformations have
been shown to be exceedingly versatile starting materials for syn-
thesis.2 For example, many natural products,3 drug molecules,4
polymers5 and dyes6 have all been synthesised by routes, which
take advantage of the diverse functionality in these building blocks.
Such syntheses are often of single enantiomers, as the metabolism
of substituted arenes gives rise to enantiopure diols in most in-
stances. The microorganisms employed for the production of arene
cis-diols are usually those expressing benzene dioxygenase (BDO),
toluene dioxygenase (TDO), naphthalene dioxygenase (NDO) and
biphenyl dioxygenase (BPDO) enzymes. The regio- and stereo-
chemical outcome of these biotransformations may be predicted by
Boyd’s model;7 the sense of enantioinduction is conserved across
organisms and substrates (Scheme 1a, ortho,meta-dihydroxylation).
the opposite absolute sense of enantioinduction (Scheme 1b,
ipso,ortho-dihydroxylation). Certain substituted benzoic acids also
undergo dearomatisationedihydroxylation.9 The synthetic exploi-
tation of ipso,ortho arene cis-diols such as 4 has been infrequent
compared to ortho,meta arene cis-diols of type 2. Nevertheless,
we3a,j,9a,10 and others3m,4,n,o,11 have reported uses of 4 in various
synthetic contexts.
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are credited.
* Corresponding author. E-mail address: S.E.Lewis@bath.ac.uk (S.E. Lewis).
Scheme 1. Regio- and stereoselectivity of dioxygenases.
0040-4020/$ e see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.033

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J.A. Griffen et al. / Tetrahedron 69 (2013) 5989e5997
ꢀ
Aminocyclitols (or ‘azacarbasugars’) are a privileged class of
purpose. The first report36a dates from 1991, wherein Hudlicky
reported introducing the amino functionality by means of an
acylnitroso cycloaddition (Scheme 2a). This approach has also been
used on two subsequent occasions.36b,c Other reported methods
for introduction of the nitrogen(s) are (i) alkene epoxidation
and ring-opening with azide,36b,37 phthalimide,37d ammonia38 or
other amines36b,39 (Scheme 2b), (ii) alkene aziridination37b,e,38b,40
(Scheme 2c), including aziridine opening with nitrogen nucleo-
philes to access vicinal diaminocyclitols,38b,40b (iii) displacement of
a triflate by azide34c (Scheme 2d) and (iv) addition of trimethylsi-
lylazide to an enone41 (Scheme 2e).
structures for drug development as they can serve as effective
mimics of natural carbohydrates. The amino functionality can impart
modified biological activity with respect to the parent carbohydrate
and the lack of an endocyclic oxygen leads to enhanced hydrolytic
stability.12 Various aminocyclitols are currently in clinical use;13 most
notably, voglibose 514 and acarbose 615 are
a-glucosidase inhibitors
used to treat type II diabetes, as is the structurally related iminosugar
miglitol 716 (Fig.1). Voglibose is an N-alkylated derivative of a natural
product, valiolamine 8, which itself possesses
a-glucosidase in-
hibitory activity.17 Aminocyclitols are also being used or evaluated as
therapies for other diseases of carbohydrate metabolism, such as N-
octylvalienamine 9,18 amino derivatives 10e11 of myo-inositol,19
bicyclic analogues 12e13,20 triazolylamino derivatives 1421 of
scyllo-inositol and homologated calystegine 1522 for Gaucher disease
and 4-epi-N-octylvalienamine 1613b,18,23 for GM1-gangliosidosis.
Aminocyclitols are core structural motifs of aminoglycoside anti-
biotics12e,24 such as validamycin A 17 and antifungal activity of
aminocyclitols such as salbostatin 18 has also been reported.24e,25
In contrast to ortho,meta arene cis-diols of type 2, the ipso,ortho
arene cis-diols had not been used for aminocyclitol synthesis until
our report in 2011 on the preparation from 4 of ‘inosaminoacids’
(44), zwitterionic aminocyclitols bearing
a C-carboxy sub-
stituent.42 In the present paper we describe the synthesis from 4
of aminocyclitols in which the side chain is in a lower oxidation
state (45); these aminocyclitols were anticipated to have markedly
different solubilities (due to their non-zwitterionic nature) and
Fig. 1. Aminocyclitols of medicinal relevance.
In view of the many current and potential therapeutic applica-
tions of aminocyclitols, they have attracted a great degree of at-
tention from the synthetic community. For example, syntheses of
natural and non-natural aminocyclitols have been reported starting
glycosidase inhibitory activities to those we have previously re-
ported (Fig. 3).
2. Results and discussion
from carbohydrates by the Ferrier reaction,26 from tricarbonyl(h5
-
cyclohexadienyl)iron complexes,27 from inositols28 and quercitols
(deoxy-inositols),29 from quinic acid30 and by ring-closing meta-
thesis.30e,31 The impetus to discover new glycosidase inhibitors has
led chemists to target not only naturally occurring aminocyclitols
but also novel structural variants such as medium rings31h,32 (e.g.,
19e21), polycyclics30e,32d,33 (e.g., 22e25) and fluorinated deriva-
tives33a,34 (e.g., 26e27, Fig. 2).
Arene cis-diols are ideal starting materials for the synthesis of
aminocyclitols35dthe first two hydroxyl groups are introduced in
the biotransformation and additional hydroxyls may be introduced
by a variety of further oxidative transformations. The ortho,meta
arene cis-diols of type 2 have been used extensively for this
Primary alcohol 46 is accessible from ipso,ortho arene cis-diol 4
by previously reported transformations:11a,b,e ketalisation, esteri-
fication and reduction (we have found LiBH4 to be the most effec-
tive reductant3a). We intended to introduce nitrogen functionality
by means of an acylnitroso DielseAlder reaction whereby the
dienophile is generated in situ under oxidative conditions (cf.
Scheme 2a). Thus, protection of the free hydroxyl group was
needed; introduction of a silyl ether proceeded to give 47 without
any competing rearomatisation (a side reaction that can occur upon
exposure of arene cis-diols to extremes of pH43). Fully protected
diene 47 underwent cycloaddition to afford two isomeric products,
48 and 49 (Scheme 3).

J.A. Griffen et al. / Tetrahedron 69 (2013) 5989e5997
5991
Fig. 2. Selected non-natural aminocyclitols.
The selectivity of cycloadditions employing dienes derived from
arene cis-diols has been studied previously;44 precedent suggested
that approach of the dienophile to the diene face opposite the
acetonide would be favoured.11e,36a,45 NOESY spectra for both ad-
ducts showed correlations between the olefinic protons and the
acetonide endo methyl protons, confirming the approach of the
dienophile to the upper face. Distinguishing the two structures in
which the Cbz group is distal (48) or proximal (49) to the silyl ether
was not possible by NMR methods and required crystallographic
analysis of a derivative (see below).
The final removal of acid-labile protecting groups could be ex-
ecuted in a succinct manner simply by exposing 56e59 to aqueous
hydrochloric acid, followed by an organic extraction to remove the
lipophilic silanol byproduct. Concentration of the aqueous phase
gave pure novel aminocyclitols 60e63 (Scheme 6). Aminotetrols 61
and 62 and aminohexols 63 and 64 were evaluated for the in-
hibition of glycosidase activity46 against
Saccharomyces cerevisiae), -glucosidase (almond),
dases (from Aspergillus oryzae and Escherichia coli) and
ronidases (from bovine liver, E. coli and Patella vulgata); no
a
-glucosidase (type I from
-galactosi-
-glucu-
b
b
b
The residual alkenes in 48 and 49 were dihydroxylated under
Upjohn conditions; cycloadduct 48 afforded a single cis-diol 50 in
good yield, but surprisingly the corresponding transformation of 49
to cis-diol 51 was lower yielding and hampered by the formation of
tetracyclic carbonate side-product 52. The structure of 52 was
inhibitory activity at 100 mM was observed.
3. Conclusion
We have described herein the synthesis of novel, densely
functionalised aminocyclitols from a simple aromatic precursor,
using a biotransformation and a hetero-DielseAlder reaction. The
brevity of this route (nine steps from benzoic acid to products
bearing six contiguous stereocentres, including a quaternary ster-
eocentre) underscores the utility of microbial arene oxidation for
the rapid introduction of complexity.
assigned on the basis of its molecular mass, a characteristic n(C
]
O)
absorbance at 1808 cmꢀ1 and a 13C NMR resonance at
d¼154.4 ppm.
We propose that 52 is formed from 51 by attack of a newly in-
troduced hydroxyl group on the carbamate carbonyl and CeN bond
cleavage, followed by attack of the other hydroxyl group and ex-
trusion of benzyl alcohol (Scheme 4). Also in support of the struc-
ture of 52, treatment of cis-diol 50 with TBAF did not give the
expected desilylated structure 54, but instead gave cyclic carbonate
55, the structure of which was secured by X-ray crystallographic
4. Experimental section
4.1. General
analysis (Fig. 4). Cyclic carbonate 55 has n(C
]
¼1800 cmꢀ1 and
O)
a
13C NMR resonance at
d¼154.6 ppm, comparable with 52.
Hydrogenolysis of diols 50 and 51, as well as their less highly
For general experimental methods, please see the Supplementary
data.
oxygenated precursors 48 and 49 proceeded smoothly over palla-
dium on carbon, effecting multiple reductive transformations in
one-pot (NeO bond scission, Cbz deprotection, alkene reduction;
Scheme 5). The more functionalised products 58 and 59 were iso-
lated in lower yield than 56 and 57, which we ascribe to their un-
avoidable partial retention on Celite and/or silica.
4.1.1. tert-Butyl(((3aR,7aR)-2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]
dioxol-3a-yl)methoxy)dimethylsilane (47). To alcohol 46 (548 mg,
3.01 mmol, 1.00 equiv) dissolved in dichloromethane (30 mL),
triethylamine (1.06 mL, 7.52 mmol, 2.50 equiv) was added and

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J.A. Griffen et al. / Tetrahedron 69 (2013) 5989e5997
Scheme 2. Representative examples of reported strategies for introduction of nitrogen in the synthesis of aminocyclitols from ortho,meta arene cis-diols.
Fig. 3. Contrasting current and previous work.
stirred at 0 ꢁC. tert-Butyldimethylsilyl trifluoromethanesulfonate
(0.829 mL, 3.61 mmol, 1.20 equiv) was added dropwise at 0 ꢁC over
5 min. The resulting mixture was stirred at 0 ꢁC for 1 h. The reaction
mixture was transferred to a separating funnel, saturated brine
(10 mL) was added then extracted with ethyl acetate (3ꢂ10 mL).
The organic phase was dried over magnesium sulfate and filtered.
The filtrate was concentrated under reduced pressure and purified
via column chromatography (15% ethyl acetateepetrol) to give 47
Scheme 3. Cycloaddition of diene derived from ipso,ortho arene cis-diol 4. Reagents
and conditions: (a) TBDMSOTf, Et3N, CH2Cl2, 0 ꢁC, 1 h, 72%; (b) BnOC(O)NHOH 30,
Bu4NIO4 CH2Cl2, ꢀ78 ꢁC, 20 h.
(s, 3H), 1.36 (s, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR
(636 mg, 72%) as a colourless oil: Rf 0.56 (15% ethyl acetateepetrol);
(75 MHz, CDCl3) d 129.6, 125.1, 124.5, 122.6, 105.7, 80.1, 71.2, 65.8,
25
[
a]
ꢀ137.5 (c 9.4, CH2Cl2); nmax (neat)/cmꢀ1 2987, 2954, 2930,
27.1, 26.5, 25.7, 18.2, ꢀ5.3, ꢀ5.5; HRMS m/z (ESþ) [found (MþNa)þ
D
2898, 2857, 1472, 1463, 1414, 1378, 1368, 1251, 1214, 1172, 1151, 1130,
319.1705, C16H28NNaO3Si requires Mþ, 319.1688].
1093, 1076, 1038, 1006, 938, 915, 834, 775, 709, 664, 641; 1H NMR
(250 MHz, CDCl3);
(d, J¼5.0 Hz,1H), 3.55 (d, J¼12.0 Hz,1H), 3.44 (d, J¼12.0 Hz,1H),1.43
d
6.10e5.94 (m, 3H), 5.67 (d, J¼10.0 Hz, 1H), 4.52
4.1.2. (3aR,4R,7S,7aR)-Benzyl 3a-(((tert-butyldimethylsilyl)oxy)met-
hyl)-2,2-dimethyl-3a,4,7,7a-tetrahydro-4,7-(epoxyimino)benzo[d]

J.A. Griffen et al. / Tetrahedron 69 (2013) 5989e5997
5993
Scheme 4. Dihydroxylation of cycloadducts. Reagents and conditions: (a) 2 mol % OsO4, 1 equiv NMO, acetone/H2O 4:1, rt, 48 h, 81% (50), 44% (51), 17% (52); (b) 1 equiv TBAF, THF,
ꢁC, 12 h, 24%.
0
[1,3]dioxole-8-carboxylate (48) and (3aR,4S,7R,7aR)-benzyl 7a-
(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-3a,4,7,7a-tetra-
hydro-4,7-(epoxyimino)benzo[d][1,3]dioxole-8-carboxylate (49). To
a solution of diene 47 (446 mg, 1.50 mmol, 1.00 equiv) and
tetrabutylammonium periodate (1.30 g, 3.01 mmol, 2.00 equiv) in
dichloromethane (30 mL) at ꢀ78 ꢁC was added N-(benzylox-
ycarbonyl)hydroxylamine (503 mg, 3.01 mmol, 2.00 equiv) in
dichloromethane (10 mL) dropwise via cannula over 5 min. The
reaction mixture was stirred at ꢀ78 ꢁC under N2 for 20 h, then
diluted with ethyl acetate (10 mL) and washed with saturated
aqueous sodium thiosulfate solution (5 mL) and then brine (5 mL).
The organic layer was separated and dried over magnesium sulfate,
then concentrated under reduced pressure and purified by column
chromatography (5% ethyl acetateepetrol) to give 48 (217 mg, 31%)
as a colourless oil and 49 (403 mg, 58%) as a colourless oil. Com-
25
pound 48: Rf 0.19 (15% ethyl acetateepetrol); [
a
]
þ1.53 (c 0.66,
D
CH2Cl2); nmax (neat)/cmꢀ1 3515, 2929, 2857, 1747, 1713, 1497, 1455,
1379, 1312, 1284, 1248, 1211, 1184, 1151, 1097, 1061, 1024, 984, 929,
910, 776, 751, 731, 696, 616; 1H NMR (300 MHz, CDCl3); 7.25 (s, 5H),
6.46 (br t, J¼5.0 Hz, 1H), 6.28 (ddd, J¼7.5, 2.5, 1.5 Hz, 1H), 5.10 (d,
J¼10.0 Hz, 1H), 5.06 (dd, J¼6.0, 3.0 Hz, 1H), 5.02 (d, J¼10.0 Hz, 1H),
4.82 (ddd, J¼6.0, 3.0, 1.5 Hz, 1H), 4.07 (d, J¼3.0 Hz, 1H), 3.80 (d,
J¼12.0 Hz, 1H), 3.76 (d, J¼12.0 Hz, 1H), 1.30 (s, 3H), 1.21 (s, 3H), 0.08
(s, 9H), 0.01 (s, 3H), ꢀ0.01 (s, 3H); 13C NMR (75 MHz, CDCl3);
d
158.2, 135.5, 132.4, 129.0, 128.4, 128.2, 128.0, 112.3, 84.0, 75.7, 72.2,
68.0, 66.2, 53.6, 28.0, 27.0, 25.9, 18.4, ꢀ5.5, ꢀ5.6; HRMS m/z (ESþ)
[found (MþNa)þ 484.2140, C24H35NaO6Si requires Mþ, 484.2131].
25
Compound 49: Rf 0.28 (15% ethyl acetateepetrol); [
a
]
þ12.6 (c
D
0.87, CH2Cl2); nmax (neat)/cmꢀ1 2930, 2857, 1748, 1709, 1498, 1462,
1380, 1370, 1327, 1295, 1248, 1214, 1170, 1150, 1096, 1080, 1065,
1026, 1005, 934, 904, 836, 776, 736, 696, 683, 670; 1H NMR
(300 MHz, CDCl3)
6.42 (br t, J¼5.0 Hz, 1H), 5.22 (d, J¼12.0 Hz, 1H), 5.19 (d, J¼12.0 Hz,
d
7.34 (s, 5H), 6.53 (ddd, J¼7.5, 2.5, 1.5 Hz, 1H),
Fig. 4. ORTEP diagram of 55 showing ellipsoids at 50% probability. H atoms are shown
as spheres of arbitrary radius.

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J.A. Griffen et al. / Tetrahedron 69 (2013) 5989e5997
1.00 equiv) as a solid. Osmium tetroxide (2.5% in tert-butanol, 80
mL,
8.4 mol, 2.0 mol %) was added via syringe and the reaction mixture
m
was stirred at room temperature for 48 h. A colour change from
colourless to pale yellow was observed. The reaction mixture was
transferred to a separating funnel, diluted with ethyl acetate
(15 mL) and washed with saturated aqueous sodium thiosulfate
(5 mL) and brine (5 mL). The organic phase was separated and dried
over magnesium sulfate, concentrated under reduced pressure and
purified by column chromatography (50% ethyl acetateepetrol) to
give 50 (172 mg, 81%), as a colourless oil. Rf 0.38 (40% ethyl aceta-
25
teepetrol); [
a
]
ꢀ27 (c 8.2, CHCl3); nmax (neat)/cmꢀ1 3419, 2959,
D
2929, 2886, 2857, 1708, 1553, 1498, 1460, 1408, 1384, 1258, 1212,
1071, 836, 779; 1H NMR (250 MHz, CDCl3)
d 7.36e7.30 (m, 5H), 5.18
(s, 2H), 4.66 (br s, 1H), 4.38 (br s, 1H), 4.24e4.17 (m, 3H), 3.82 (d,
J¼12.5 Hz, 1H), 3.75 (d, J¼12.5 Hz, 1H) 3.75e3.63 (m, 2H), 1.43 (s,
3H), 1.40 (s, 3H), 0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
156.8, 135.4, 128.2, 128.1, 127.9, 111.1, 82.0, 78.0, 76.4, 72.3, 67.9,
64.9, 61.8, 61.2, 26.5, 26.4, 25.7, 18.2, ꢀ5.6, ꢀ5.7; HRMS m/z (ESþ)
[found (MþNa)þ 496.2400, C24H37NNaO8Si requires Mþ, 496.2367].
4.1.4. (3aR,4S,5S,6R,7R,7aR)-Benzyl
7a-(((tert-butyldimethylsilyl)
oxy)methyl)-5,6-dihydroxy-2,2-dimethylhexahydro-4,7-(epox-
yimino)benzo[d][1,3]dioxole-8-carboxylate (51) and (3aS,4S,4aR,7-
aR,8R,8aR)-7a-(((tert-butyldimethylsilyl)oxy)methyl)-6,6-
dimethylhexahydro-4,8-(epoxyimino)benzo[1,2-d:4,5-d0]bis([1,3]di-
oxole)-2-one (52). To alkene 49 (489 mg, 1.06 mmol, 1.00 equiv) in
acetoneewater (4/1, 20 mL) was added N-methylmorpholine N-
oxide (124 mg, 1.06 mmol, 1.00 equiv) as a solid. Osmium tetroxide
(2.5% in tert-butanol, 160 mL, 0.011 mmol, 2.0 mol %) was added via
syringe and the reaction mixture was stirred at room temperature
for 48 h. A colour change from colourless to pale yellow was ob-
served and the reaction mixture was transferred to a separating
funnel, diluted with ethyl acetate (10 mL) and washed with satu-
rated aqueous sodium thiosulfate (5 mL) then brine (5 mL). The
organic phase was separated and dried over magnesium sulfate,
concentrated under reduced pressure and purified by column
chromatography (50% ethyl acetateepetrol) to give 51 (230 mg,
44%) and 52 (70 mg, 17%) both as colourless oils. Also isolated was
recovered 49 (97 mg, 19%). Compound 51: Rf 0.36 (50% ethyl ace-
Scheme 5. Hydrogenolysis. Reagents and conditions: (a) H2, Pd/C, EtOAc, rt, 24 h, 99%
(56), 98% (57), 50% (58), 45% (59).
1H), 5.06 (ddd, J¼5.0, 5.0, 1.5 Hz, 1H), 4.89 (dd, J¼5.0, 2.5 Hz, 1H),
4.18 (d, J¼2.5 Hz, 1H), 3.90 (s, 2H), 1.39 (s, 3H), 1.28 (s, 3H), 0.90 (s,
9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3);
d 157.5,
tateepetrol); [
a
]
D
25 þ17 (c 11.5, CHCl3); nmax (neat)/cmꢀ1 3428, 2929,
135.5, 131.1, 129.8, 128.4, 128.3, 128.1, 112.5, 84.1, 75.1, 71.5, 68.1,
65.6, 53.6, 28.3, 27.1, 26.0, 18.5, ꢀ5.3, ꢀ5.4; HRMS m/z (ESþ) [found
(MþNa)þ 484.2108, C24H35NaO6Si requires Mþ, 484.2131].
2856, 1710, 1498, 1454, 1383, 1256, 1102, 1064, 835, 777; 1H NMR
(250 MHz, CDCl3)
d 7.38e7.32 (m, 5H), 5.20 (s, 2H), 4.67 (br s, 1H),
4.39 (br s, 1H), 4.25e4.21 (m, 3H), 3.84 (d, J¼10.0 Hz, 1H), 3.78 (d,
4.1.3. (3aR,4R,5S,6R,7S,7aR)-Benzyl
3a-(((tert-butyldimethylsilyl)
J¼10.0 Hz, 1H) 3.54 (br s, 1H), 3.32 (d, J¼5.0 Hz, 1H) 1.44 (s, 3H), 1.42
oxy)methyl)-5,6-dihydroxy-2,2-dimethylhexahydro-4,7-(epox-
yimino)benzo[d][1,3]dioxole-8-carboxylate (50). To alkene 48
(195 mg, 0.422 mmol, 1.00 equiv) in acetoneewater (4/1, 20 mL)
was added N-methylmorpholine N-oxide (49 mg, 0.422 mmol,
(s, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 158.9,
135.5, 128.5, 128.3, 128.3, 111.7, 83.1, 76.2, 73.2, 68.3, 66.0, 62.5, 61.4,
58.9, 26.7, 26.6, 25.9, 18.4, ꢀ5.5, ꢀ5.6; HRMS m/z (ESþ) [found
(MþNa)þ 518.2210, C24H37NNaO8Si requires Mþ, 518.2186].
Scheme 6. One-pot deprotection. Reagents and conditions: (a) 1 M HCl(aq), rt, 24 h; EtOAc extraction, 80% (62), 94% (63), 88% (64), 99% (65).

J.A. Griffen et al. / Tetrahedron 69 (2013) 5989e5997
5995
Compound 52: Rf 0.57 (50% ethyl acetateepetrol); [
a
]
25 ꢀ6.5 (c 3.5,
6H); 13C NMR (75 MHz, CDCl3)
d
108.4, 83.1, 79.8, 67.3, 65.8, 52.3,
D
CHCl3); nmax (neat)/cmꢀ1 3270, 2955, 2930, 2857, 1808, 1463, 1361,
27.5, 26.3, 26.0, 25.9, 23.7, 18.3, ꢀ5.3, ꢀ5.5; HRMS m/z (ESþ)
[found (MþNa)þ 354.2076, C16H33NNaO4Si requires Mþ,
354.2076].
1254, 1166, 1077, 836, 779; 1H NMR (300 MHz, CDCl3)
1H), 5.03e5.02 (m, 2H), 4.33 (d, J¼6.0 Hz,1H), 4.21 (d, J¼6.0 Hz,1H),
4.08 (d, J¼12.0 Hz,1H), 3.90 (d, J¼12.0 Hz,1H), 3.67 (br s,1H) 1.45 (s,
3H), 1.44 (s, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR
d 6.06 (br s,
4.1.8. (3aS,4R,5R,6R,7S,7aR)-7-Amino-3a-(((tert-butyldimethylsilyl)
oxy)methyl)-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-4,5,6-triol
(58). To diol 50 (28 mg, 0.056 mmol, 1.0 equiv) in ethyl acetate
(20 mL) was added palladium on carbon (5.0 mg, 20 mass %). The
reaction mixture was stirred under an atmosphere of H2 at room
temperature for 24 h, then filtered through Celite. The filtrate was
concentrated under reduced pressure and purified by column
chromatography (10% methanole89% chloroforme1% triethyl-
(75 MHz, CDCl3) d 154.4, 110.9, 81.8, 73.7, 71.7, 69.9, 68.3, 66.2, 53.4,
26.9, 26.6, 25.8, 18.3, ꢀ5.4, ꢀ5.5; HRMS m/z (ESþ) [found (MþNa)þ
410.1664, C17H29NNaO7Si requires Mþ, 410.1611].
4.1.5. (3aS,4R,4aR,7aR,8S,8aR)-4a-(Hydroxymethyl)-6,6-
dimethylhexahydro-4,8-(epoxyimino)benzo[1,2-d:4,5-d0]bis([1,3]di-
oxole)-2-one (55). To silyl ether 50 (165 mg, 0.333 mmol,
1.00 equiv) in THF (20 mL) at 0 ꢁC was added tetrabutylammonium
fluoride (0.33 mL, 1.0 M in THF, 1.00 equiv) dropwise over 5 min.
The reaction mixture was stirred at 0 ꢁC for 12 h, then transferred
to a separating funnel and diluted with ethyl acetate (20 mL) and
washed with water (2ꢂ10 mL). The organic phase was then
washed further with brine (5 mL), dried over magnesium sulfate,
concentrated under reduced pressure and purified by column
amine) to give 58 as a colourless oil (11 mg, 50%). Rf 0.25 (15%
25
methanole84% ethyl acetatee1% triethylamine); [
a
]
þ43 (c 0.6,
D
H2O); nmax (neat)/cmꢀ1 3324, 3256, 2965, 2813, 2787, 1432, 1376,
1244, 1156, 1020, 978, 836, 774; 1H NMR (300 MHz, CDCl3)
d
4.46e3.93 (m, 10H), 1.45 (s, 3H), 1.39 (s, 3H), 0.92 (s, 9H), 0.12 (s,
6H); 13C NMR (75 MHz, CDCl3)
d
108.9, 83.8, 74.3, 70.6, 67.6, 65.3,
64.7, 51.9, 29.6, 27.9, 26.6, 26.0, 25.9, 18.4, ꢀ5.3, ꢀ5.4; HRMS m/z
(ESþ) [found (MþNa)þ 386.1968, C16H33NNaO6Si requires Mþ,
386.1907].
chromatography (50% ethyl acetateepetrol) to give 55 (34 mg,
25
24%), as a colourless oil. Rf 0.20 (50% ethyl acetateepetrol); [a]
D
ꢀ1.5 (c 1.7, CHCl3); nmax (neat)/cmꢀ1 3268, 2992, 2923, 1800, 1780,
1454, 1369, 1165, 1067, 770; 1H NMR (400 MHz, (CD3)2CO)
d
6.88
4.1.9. (3aR,4S,5S,6S,7R,7aR)-7-Amino-7a-(((tert-butyldimethylsilyl)
oxy)methyl)-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-4,5,6-triol
(59). To diol 51 (120 mg, 0.242 mmol, 1.00 equiv) in ethyl acetate
(20 mL) was added palladium on carbon (12 mg, 10 mass %). The
reaction mixture was stirred under an atmosphere of H2 at room
temperature for 24 h, then filtered through Celite. The filtrate was
concentrated under reduced pressure and purified by column
chromatography (50% ethyl acetateepetrol) to give 59 as a colour-
(br s, 1H), 5.16 (dd, J¼8.0, 4.0 Hz, 1H), 5.09 (d, J¼8.0 Hz, 1H), 4.42 (d,
J¼4.0 Hz, 1H), 4.27 (t, J¼4.0 Hz, 1H), 4.19 (br s, 1H), 3.97e3.84 (m,
3H), 1.50 (s, 3H), 1.48 (s, 3H); 13C NMR (100 MHz, (CD3)2CO)
d 154.5,
110.1, 81.7, 73.7, 72.0, 70.6, 69.4, 64.5, 51.6, 25.8, 25.6; HRMS m/z
(ESþ) [found (MþNa)þ 296.0787, C11H16NNaO7Si requires Mþ,
296.0746].
4.1.6. (3aS,4R,7S,7aR)-7-Amino-3a-(((tert-butyldimethylsilyl)oxy)
methyl)-2,2-dimethylhexahydrobenzo[d][1,3]dioxol-4-ol (56). To al-
kene 48 (61 mg, 0.13 mmol, 1.0 equiv) in ethyl acetate (20 mL)
was added palladium on carbon (6.0 mg, 10 mass %). The reaction
mixture was stirred under an atmosphere of H2 at room tem-
perature for 24 h, then filtered through Celite. The filtrate was
concentrated under reduced pressure and purified by column
less oil (39 mg, 45%). Rf 0.35 (50% ethyl acetateepetrol); [
a
]
25 þ33 (c
D
0.39, CHCl3); nmax (neat)/cmꢀ1 3404, 2958, 2930, 2857, 1463, 1382,
1255, 1210, 1101, 1060, 863, 779; 1H NMR (500 MHz, CDCl3)
d
4.25e4.20 (m, 2H), 4.18e4.15 (m, 2H), 4.03 (d, J¼15.0 Hz, 1H), 3.91
(d, J¼15.0 Hz, 1H), 3.30 (s, 1H), 1.46 (br s, 3H), 1.43 (s, 3H), 0.92 (s,
9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3)
110.3, 81.9,
d
73.8, 72.9, 66.7, 62.7, 60.2, 58.3, 26.8, 26.8, 25.9, 18.4, ꢀ5.3, ꢀ5.4;
HRMS m/z (ESþ) [found (MþH)þ 364.2093, C16H33NO6Si requires
Mþ, 364.2155].
chromatography (50% ethyl acetateepetrol) to give 56 as a col-
25
ourless oil (43 mg, 99%). Rf 0.85 (50% ethyl acetateepetrol); [a]
D
ꢀ15 (c 0.55, CHCl3); nmax (neat)/cmꢀ1 2961, 2927, 2854, 1590,
1519, 1463, 1392, 1300, 1251, 1215, 1151, 1033, 747; 1H NMR
4.1.10. (1S,2R,3S,4R)-2,3,4-Trihydroxy-3-(hydroxymethyl)cyclo-
hexylammonium chloride (60). Hydroxyamine 56 (43 mg,
0.13 mmol) was stirred in aqueous hydrochloric acid (1.0 M, 20 mL)
at room temperature for 24 h. The aqueous phase was washed with
ethyl acetate (2ꢂ10 mL) to remove the silanol byproduct. The
aqueous phase was concentrated under reduced pressure to give 60
(300 MHz, CDCl3)
d
4.05 (d, J¼3.0 Hz, 1H), 3.97 (d, J¼12.0 Hz, 1H),
3.83 (d, J¼12.0 Hz, 1H), 3.80 (app q, J¼3.0 Hz, 1H), 3.46e3.42 (m,
1H), 2.76 (br s, 3H), 2.02e1.87 (m, 1H), 1.83e1.72 (m, 2H),
1.61e1.51 (m, 1H), 1.46 (s, 3H), 1.37 (s, 3H), 0.91 (s, 9H), 0.10 (s,
3H), 0.09 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 108.1, 83.6, 80.1,
73.2, 65.1, 47.4, 28.1, 26.7, 25.9, 25.4, 24.5, 18.3, ꢀ5.5, ꢀ5.6; HRMS
m/z (ESþ) [found (MþNa)þ 354.2054, C16H33NNaO4Si requires Mþ,
354.2076].
as a colourless oil (26 mg, 94%). [
a
]
25 þ22 (c 1.3, H2O); nmax (neat)/
D
cmꢀ1 3336, 2981, 2482, 1602, 1383, 1233, 1156, 1069, 1021, 956, 797;
1H NMR (300 MHz, D2O)
(d, J¼12.0 Hz, 1H), 3.55 (d, J¼9.0 Hz, 1H), 3.37e3.18 (m, 1H),
d
3.85 (s, 1H), 3.64 (d, J¼12.0 Hz, 1H), 3.57
4.1.7. (3aR,4S,7R,7aR)-7-Amino-7a-(((tert-butyldimethylsilyl)oxy)
methyl)-2,2-dimethylhexahydrobenzo[d][1,3]dioxol-4-ol (57). To al-
kene 49 (253 mg, 0.548 mmol, 1.00 equiv) in ethyl acetate
(20 mL) was added palladium on carbon (26 mg, 10 mass %). The
reaction mixture was stirred under an atmosphere of H2 at room
temperature for 24 h, then filtered through Celite. The filtrate
was concentrated under reduced pressure and purified by col-
umn chromatography (20% methanole79% ethyl acetatee1%
1.80e1.55 (m, 4H); 13C NMR (75 MHz, D2O)
d 76.0, 69.9, 68.6, 63.5,
52.1, 25.8, 22.7; HRMS m/z (ESþ) [found (MþNa)þ 200.0906,
C7H15NNaO4 requires Mþ, 200.0898].
4.1.11. (1R,2R,3R,4S)-2,3,4-Trihydroxy-2-(hydroxymethyl)cyclo-
hexylammonium chloride (61). Hydroxyamine 57 (30 mg,
0.090 mmol) was stirred in aqueous hydrochloric acid (1.0 M,
20 mL) at room temperature for 24 h. The aqueous phase was
washed with ethyl acetate (2ꢂ10 mL) to remove the silanol
byproduct. The aqueous phase was concentrated under reduced
triethylamine) to give 57 as a colourless oil (179 mg, 98%). Rf 0.43
25
(20% methanole79% ethyl acetatee1% triethylamine); [
a
]
ꢀ37
D
(c 3.5, CHCl3); nmax (neat)/cmꢀ1 3282, 2998, 2930, 2856, 1472,
pressure to give 61 as a pale yellow oil (17 mg, 88% yield). [
a
]
25 þ35
D
1378, 1250, 1216, 1087, 963, 835; 1H NMR (300 MHz, CDCl3)
(c 0.85, H2O); nmax (film)/cmꢀ1 3317, 2940, 2508, 1400, 1071, 1027,
d
4.03 (br s, 1H), 3.96e3.93 (m, 2H), 3.70 (d, J¼11.0 Hz, 1H), 3.36
972, 799; 1H NMR (300 MHz, D2O)
d
3.86 (d, J¼12.0 Hz,1H), 3.81 (td,
(br s, 3H), 3.12 (br s, 1H), 2.00e1.88 (m, 1H), 1.82e1.72 (m, 2H),
1.62e1.58 (m, 1H), 1.41 (s, 3H), 1.32 (s, 3H), 0.88 (s, 9H), ꢀ0.09 (s,
J¼7.5, 4.0 Hz, 1H), 3.55 (d, J¼12.0 Hz, 1H), 3.49 (d, J¼6.0 Hz, 1H),
3.38e3.34 (m, 1H), 1.92e1.63 (m, 3H), 1.52e1.40 (m, 1H); 13C NMR

5996
J.A. Griffen et al. / Tetrahedron 69 (2013) 5989e5997
Banwell, M. G.; Lehmann, A. L.; Menon, R. S.; Willis, A. C. Pure Appl. Chem. 2011,
83, 411; (o) Adams, D. R.; Aichinger, C.; Collins, J.; Rinner, U.; Hudlicky, T. Synlett
(75 MHz, D2O)
d 74.1, 72.3, 69.8, 63.4, 54.0, 26.0, 22.8; HRMS m/z
ꢀ
(ESþ) [found (MþH)þ 179.1129, C7H16NO4 requires Mþ 179.1157].
2011, 725; (p) Labora, M.; Schapiro, V.; Pandolfi, E. Tetrahedron: Asymmetry
2011, 22, 1705.
ꢀ
4. For selected examples, see: (a) Vshyvenko, S.; Scattolon, J.; Hudlicky, T.; Ro-
4.1.12. (1S,2R,3R,4R,5R,6R)-2,3,4,5,6-Pentahydroxy-3-(hydrox-
ymethyl)cyclohexylammonium chloride (62). Aminotriol 58 (11 mg,
0.030 mmol) was stirred in aqueous hydrochloric acid (1.0 M,
20 mL) at room temperature for 24 h. The aqueous phase was
washed with ethyl acetate (2ꢂ10 mL) to remove the silanol
byproduct. The aqueous phase was concentrated under reduced
mero, A. E.; Kornienko, A.; Ma, D.; Tuffley, I.; Pandey, S. Can. J. Chem. 2012, 90,
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932; (b) Ma, D.; Tremblay, P.; Mahngar, K.; Akbari-Asl, P.; Collins, J.; Hudlicky,
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Tremblay, P.; Mahngar, K.; Collins, J.; Hudlicky, T.; Pandey, S. PLoS One 2011, 6,
e28780; (d) Ma, D.; Tremblay, P.; Mahngar, K.; Akbari-Asl, P.; Collins, J.;
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Hudlicky, T.; Pandey, S. Am. J. Biomed. Sci. 2011, 3, 278; (e) Werner, L.; Ma-
ꢀ
chara, A.; Sullivan, B.; Carrera, I.; Moser, M.; Adams, D. R.; Hudlicky, T. J. Org.
pressure to give 62 as a colourless oil (8 mg, 99%). [
a
]
25 ꢀ47 (c 0.4,
ꢀ
Chem. 2011, 76, 10050; (f) Vshyvenko, S.; Scattolon, J.; Hudlicky, T.; Romero,
D
H2O); nmax (neat)/cmꢀ1 3302, 2958, 2511, 1629, 1508, 1077, 1028,
A. E.; Kornienko, A. Bioorg. Med. Chem. Lett. 2011, 21, 4750; (g) Collins, J.;
ꢀ
Rinner, U.; Moser, M.; Hudlicky, T.; Ghiviriga, I.; Romero, A. E.; Kornienko, A.;
808, 723; 1H NMR (300 MHz, D2O)
d
4.24 (q, J¼3.0 Hz, 1H),
Ma, D.; Griffin, C.; Pandey, S. J. Org. Chem. 2010, 75, 3069; (h) Werner, L.;
4.04e3.99 (m, 3H), 3.89 (d, J¼12.0 Hz, 1H), 3.75 (d, J¼12.0 Hz, 1H),
ꢀ
Machara, A.; Hudlicky, T. Adv. Synth. Catal. 2010, 352, 195; (i) Fabris, F.; Collins,
3.57 (dd, J¼10.5, 3.0 Hz, 1H); 13C NMR (75 MHz, D2O)
d 75.5, 72.6,
ꢀ
J.; Sullivan, B.; Leisch, H.; Hudlicky, T. Org. Biomol. Chem. 2009, 7, 2619; (j)
ꢀ
Sullivan, B.; Carrera, I.; Drouin, M.; Hudlicky, T. Angew. Chem., Int. Ed. 2009,
70.4, 65.6, 65.1, 62.8, 53.3; HRMS m/z (ESþ) [found (MþNa)þ
48, 4229; (k) Matveenko, M.; Willis, A. C.; Banwell, M. G. Tetrahedron Lett.
2008, 49, 7018 2009, 50, 2982; (l) Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew.
Chem., Int. Ed. 2008, 47, 5788; (m) Omori, A. T.; Finn, K. J.; Leisch, H.; Carroll,
232.0783, C7H15NNaO6 requires Mþ 232.0797].
ꢀ
R. J.; Hudlicky, T. Synlett 2007, 2859; (n) Charest, M. G.; Lerner, C. D.; Bru-
4.1.13. (1R,2R,3R,4S,5S,6S)-2,3,4,5,6-Pentahydroxy-2-(hydrox-
ymethyl)cyclohexylammonium chloride (63). Triol 59 (35 mg,
0.096 mmol) was stirred in aqueous hydrochloric acid (1.0 M,
20 mL) at room temperature for 24 h. The aqueous phase was
washed with ethyl acetate (2ꢂ10 mL) to remove the silanol
baker, J. D.; Siegel, D. R.; Myers, A. G. Science 2005, 308, 395; (o) Charest, M.
G.; Siegel, D. R.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 8292.
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5. (a) Bui, V. P.; Hudlicky, T. Tetrahedron 2004, 60, 641; (b) Williams, M. G.; Olson,
P. E.; Tautvydas, K. J.; Bitner, R. M.; Mader, R. A.; Wackett, L. P. Appl. Microbiol.
Biotechnol. 1990, 34, 316; (c) Ballard, D. G. H.; Courtis, A.; Shirley, I. M.; Taylor, S.
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Taylor, S. C. J. Chem. Soc., Chem. Commun. 1983, 954.
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byproduct. The aqueous phase was concentrated under reduced
25
pressure to give 63 as a pale yellow oil (21 mg, 80%). [
a
]
þ32 (c
D
0.5, H2O); nmax (neat)/cmꢀ1 3272, 2943, 2507, 1622, 1496, 1398,
1184, 1155, 1074, 1025, 928, 892, 814, 712; 1H NMR (250 MHz, D2O)
d
4.16e4.14 (m, 2H), 3.91 (d, J¼12.0 Hz, 1H), 3.83e3.70 (m, 3H),
7. Boyd, D. R.; Sharma, N. D.; Hand, M. V.; Groocock, M. R.; Kerley, N. A.; Dalton,
H.; Chima, J.; Sheldrake, G. N. J. Chem. Soc., Chem. Commun. 1993, 974.
8. (a) Sun, S.-Y.; Zhang, X.; Zhou, Q.; Chen, J.-C.; Chen, G.-Q. Appl. Microbiol. Bio-
technol. 2008, 80, 977; (b) Cass, A. E. G.; Ribbons, D. W.; Rossiter, J. T.; Williams,
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chemistry 1971, 10, 2530; (d) Johnson, B. F.; Stanier, R. Y. J. Bacteriol. 1971, 107,
476.
3.59e3.56 (br t, J¼2.5 Hz, 1H); 13C NMR (75 MHz, D2O)
d 75.9, 75.6,
72.4, 69.3, 66.3, 66.1, 59.9; HRMS m/z (ESþ) [found (MþH)þ
210.0965, C7H16NO6 requires Mþ, 210.0978].
Acknowledgements
€
9. (a) Griffen, J. A.; le Coz, A. M.; Kociok-Kohn, G.; Ali Khan, M.; Stewart, A. J. W.;
Lewis, S. E. Org. Biomol. Chem. 2011, 9, 3920; (b) Engesser, K.-H.; Schmidt, E.;
Knackmuss, H.-J. Appl. Environ. Microbiol. 1980, 39, 68; (c) Reineke, W.; Otting,
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H.-J. Biochim. Biophys. Acta 1978, 542, 412; (e) Knackmuss, H.-J.; Reineke, W.
Chemosphere 1973, 2, 225.
We thank the Royal Society (Research Grant RG110149) and
EPSRC (DTC studentship for J.A.G., Grant EP/G03768X/1) for fund-
ing. We are grateful to Prof. Andrew G. Myers (Harvard University)
for a generous gift of R. eutropha B9 cells.
10. (a) Ali Khan, M.; Mahon, M. F.; Lowe, J. P.; Stewart, A. J. W.; Lewis, S. E. Chem.
dEur. J. 2012, 18, 13480; (b) van der Waals, D.; Pugh, T.; Ali Khan, M.; Stewart,
A. J. W.; Johnson, A. L.; Lewis, S. E. Chem. Cent. J. 2011, 5, 80; (c) Ali Khan, M.;
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215; (d) Ali Khan, M.; Mahon, M. F.; Stewart, A. J. W.; Lewis, S. E. Organometallics
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Myers, A. G.; Siegel, D. R.; Buzard, D. J.; Charest, M. G. Org. Lett. 2001, 3, 2923; (e)
Jenkins, G. N.; Ribbons, D. W.; Widdowson, D. A.; Slawin, A. M. Z.; Williams, D. J.
J. Chem. Soc., Perkin Trans. 1 1995, 2647.
Supplementary data
1H and 13C NMR spectra for all novel compounds, as well as
selected 2D NMR spectra. X-ray crystallographic data for 55 (CCDC:
#908420). Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2013.04.033.
12. For reviews, see: (a) Diaz, L.; Delgado, A. Curr. Med. Chem. 2010, 17, 2393; (b)
ꢀ
ꢀ
Delgado, A. Eur. J. Org. Chem. 2008, 3893; (c) Arjona, O.; Gomez, A. M.; Lopez, J.
C.; Plumet, J. Chem. Rev. 2007, 107, 1919; (d) Chen, X.; Fan, Y.; Zheng, Y.; Shen, Y.
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