Asymmetric stereodivergent strategy towards aminocyclitols

Article abstract of DOI:10.1002/chem.201402175

A concise asymmetric synthesis of aminocyclitols, such as diastereomeric 2-deoxystreptamine analogues and conduramine A, is described. The Pd-catalyzed asymmetric desymmetrization of meso 1,4-dibenzolate enables the synthesis of highly oxidized cyclohexane architectures. These scaffolds can potentially be used to access new aminoglycoside antibiotics and enantiomerically pure α-glucosidase inhibitors.

Full text of DOI:10.1002/chem.201402175

DOI: 10.1002/chem.201402175
Communication
&
Synthetic Methods
Asymmetric Stereodivergent Strategy Towards Aminocyclitols
Barry M. Trost*[a] and Sushant Malhotra[b]
Abstract: A concise asymmetric synthesis of aminocycli-
tols, such as diastereomeric 2-deoxystreptamine ana-
logues and conduramine A, is described. The Pd-catalyzed
asymmetric desymmetrization of meso 1,4-dibenzolate en-
ables the synthesis of highly oxidized cyclohexane archi-
tectures. These scaffolds can potentially be used to access
new aminoglycoside antibiotics and enantiomerically pure
a-glucosidase inhibitors.
Figure 1. Clinically relevant aminoglycoside antibiotics.
Aminocyclitols, such as 2-deoxystreptamine (DOS; 1) and con-
duramine A (2) are important structural motifs found in several
aminoglycoside antibiotics and a-glucosidase inhibitors
(Figure 1).[1] Although the synthesis of 2-deoxystreptamine has
received significant attention,[2] the need for structural replace-
ments continues to be an essential area of research.[3] Toxicity
was observed when natural 2-deoxystreptamine containing
aminoglycosides, such as kanamycin (3) and tobramycin (4),
are employed in treating bacterial infections.[4] In addition, the
continual emergence of resistant bacterial strains against such
aminoglycosides justifies the further exploration of new antibi-
otics that are less susceptible to enzymatic inactivation.[5]
A majority of the strategies towards the synthesis of new an-
alogues of 3 and 4 have focused on modifying one or more of
the aminosugars (rings I and III in Figure 1). A strategy that has
received less attention involves the modification of DOS itself
(ring II). The ubiquity, the central location of DOS, and the hy-
drogen bonds that it forms with 16S RNA may suggest its sig-
nificance. Further, recent studies on the modification of ring II
have resulted in several potent aminoglycosides.[6,7,8]
RNA and accessibility to scaffolds that may be less prone to
enzymatic modification.
We chose 2-deoxy-4,5,6-tris-epi- (5a) and 2-deoxy-3,4-bis-epi-
streptamine (6a), the former because it retains the symmetry,
and the latter because it does not (Figure 2). Similar to 2-DOS,
diamine 5a possesses a plane of symmetry; however, when in-
corporated into an aminoglycoside, it becomes a chiral motif.
Thus, a synthetic equivalent must possess a differentiation ele-
ment that allows for the asymmetric incorporation as envi-
sioned in 5b (Figure 3).
To efficiently access and investigate the biological properties
of aminoglycosides that are diastereomeric at ring II, differen-
One strategy for modifying ring II that has received virtually
no attention, involves the replacement of DOS with its diaste-
reomer.[9] This modification would have a minimal influence on
the overall positive-charge density and conformational flexibili-
ty of the aminoglycoside, yet, it would significantly modify the
three dimensional structure of the molecule. This altered struc-
ture may present new opportunities for differential binding to
Figure 2. Diastereomeric 2-deoxystreptamine targets.
[a] Prof. B. M. Trost
Department Of Chemistry, Stanford University
Stanford, CA (USA)
E-mail: bmtrost@stanford.edu
[b] Dr. S. Malhotra
Discovery Chemistry, Genentech
1 DNA Way, South San Francisco, CA 94080 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402175.
Figure 3. Stereodivergent strategy towards 5b and 6b.
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tially protected diastereomeric DOS analogues must
be readily accessible. The challenge associated with
a selective synthesis of such analogues lies in the
presence of five highly oxidized contiguous stereo-
centers. Although, several racemic syntheses of dia-
stereomeric DOS exist,[10] current methods to access
enantiomerically pure diastereomeric DOS analogues
require multistep sequences that employ the use of
chiral pool starting materials (sugars).[11] Herein, we
describe an efficient synthesis of differentially pro-
tected diastereomeric deoxystreptamines 5b and 6b
by using asymmetric catalysis, in which both enantio-
mers of the desired products can be obtained.
Scheme 2. Initial strategies for second nitrogen incorporation. Ts=tosyl.
To access DOS analogues 5b and 6b, our goal
(Figure 3) was to maximize efficiency by: 1) designing a flexible
route that allows the synthesis of either enantiomer of several
aminocyclitols; and 2) employing diastereoselective transfor-
mations to fully utilize stereochemical information embedded
in the molecule. We have previously described a palladium-cat-
alyzed asymmetric allylic azidization reaction for the desym-
metrization of meso dibenzoate 8 as a method for preparing
enantiomerically pure amino alcohols (Scheme 1).[12] We envi-
sioned that employing such a strategy would provide an effi-
cient entry into various aminocyclitols that could be later func-
tionalized.
termediate 7, respectively (Figure 3). Initially, two strategies
were examined to incorporate the second nitrogen in analogy
with 5b as outlined in Scheme 2. First, the depicted primary
carbamate was subjected to the Rh-catalyzed intramolecular
nitrogen insertion;[13] however, this resulted in the exclusive
formation of the corresponding ketone. Second, when the
tosyloxime was subjected to base, instead of the a-aminoke-
tone (Neber rearrangement), aromatized products were ob-
tained.
In an alternative strategy, we envisioned that the second ni-
trogen of analogue 5 could be installed by a nitrosation. Anal-
ogously, the second nitrogen of analogue 6b would be instal-
led through the regioselective opening of an epoxide. Carba-
mate 7 could be obtained by the Pd-catalyzed asymmetric de-
symmetrization of meso dibenzoate 8.
Retrosynthetically, diastereomeric DOS 5b and 6b can be
obtained by the trans- and cis-dihydroxylation of a common in-
Previous work has shown that a catalyst derived from p-allyl-
palladium chloride dimer and ligand 9 gave a mixture of the
desired product 11 and the regioisomeric azide 12, whereas
a catalyst derived from ligand 10 gave a mixture of azide ent-
11 and diazide 13 (Scheme 1).[12c] Gratifyingly, the desired car-
bamate 7 was obtained as the sole product in 87% yield and
97% enantiomeric excess (ee) through a one-pot protocol by
using ligand 9.[14] The low catalyst loadings and low-tempera-
ture manipulation of the reactive azide for the desymmetriza-
tion process and the Staudinger reduction contributed to the
exclusive formation of carbamate 7 (Scheme 1).
With a reliable method to obtain intermediate 7 in hand, we
proceeded with the hydrolysis of the benzoate group to pro-
vide allylic alcohol 14 (Scheme 3). Directed epoxidation of this
alcohol 14 gave epoxide 15 as a single diastereomer, further
oxidation of which provided epoxyketone 16. Enolization of
epoxyketone 16 with potassium tert-butoxide, followed by
quenching with iso-amyl nitrite, gave oxime 17 as a single
isomer of undetermined geometry. Reduction of the carbonyl
carbon from the least hindered face by using sodium borohy-
dride gave alcohol 18 as a single diastereoisomer.
The selective reduction of oxime 18 proved to be challeng-
ing. Ultimately, we determined that a nickel boride-mediated
reduction followed by acylation with acetic anhydride gave di-
acetate 19 as a single diastereomer (Scheme 4). The opening
of epoxide 19 was attempted with several Lewis and Brønsted
acids. Clean trans diaxial opening of epoxide 19 with aqueous
trifluoroacetic acid provided an intermediate triol that was im-
Scheme 1. Desymmetrization of dibenzoate 8. TMS=trimethylsilyl; Bz=ben-
zyl; Boc=tert-butyloxycarbonyl; [Pd2dba3]=tris(dibenzylideneacetone)dipal-
ladium(0).
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Scheme 3. Synthesis of oxime 18. Reaction conditions: a) K2CO3, MeOH,
93%; b) meta-chloroperoxybenzoic acid (m-CPBA), CHCl3, 99%; c) tetrapro-
pylammonium perruthenate (TPAP), N-methylmorpholine N-oxide (NMO),
CH2Cl2, 86%; d) KOtBu, i-amyl nitrite, THF, À788C; e) NaBH4, MeOH, 56%
over two steps.
Scheme 5. Synthesis of diastereomer 6b. Reaction conditions: a) OsO4, NMO,
acetone; then 2,2-dimethoxypropane, PPTS, 62% over two steps; b) MsCl,
DIPEA, 95%, CH2CI2; c) DBU, microwave, 1508C, 55%; d) m-CPBA, CHCl3,
83%; e) NaN3, NH4Cl, n-propanol, reflux; then Boc2O, 82%.
To evaluate synthetic flexibility enabled by the Pd-catalyzed
desymmetrization, we pursued the synthesis of diastereomer
6b through an alternative route (Scheme 5). To this end, a dia-
stereoselective osmium tetroxide-catalyzed cis-dihydroxylation
of allylic alcohol 14 gave an intermediate triol that was imme-
diately protected to generate acetonide 23 (Scheme 5). The
treatment of alcohol 23 with methanesulfonyl chloride gave
mesylate 24. Elimination of mesylate 24 initially proved to be
problematic. Ultimately, high-temperature microwave condi-
tions gave olefin 25. Epoxidation of olefin 25 gave epoxide 26
as a single diastereomer (structure confirmed by NMR and X-
ray analyses).[15] The stereoselectivity of this reaction is con-
trolled by both the steric bulk of the proximal acetonide and,
to a larger extent, by the ability of the carbamate in 26 to
direct the epoxidation.[16] Racemic epoxide 26 has been previ-
ously converted to conduramine A (2); therefore, our synthetic
approach constitutes an asymmetric formal synthesis of this
essential building block used in the synthesis of a-glycosidase
inhibitors (Scheme 5).[17,18]
Scheme 4. Synthesis of diastereomers 5b and 20. Reaction conditions:
a) NaBH4, NiCl2·6H2O, MeOH, À788C; then Ac2O, 52%; b) trifluoroacetic acid
(TFA), H2O (1:1), 1108C; then BnOCOCl, K2CO3, MeOH:H2O (3:1), 50%; c) BzCl,
Et3N, THF, 70%; d) NaBH4, NiCl2·6H2O, MeOH, À788C to RT, 88%; e) TFA, H2O
(1:1), 758C, 55% (d.r. 5:1).
mediately trapped with benzyl choloroformate. NMR spectro-
scopic analyses, which were later corroborated by optical rota-
tion and X-ray studies, showed that under these conditions we
had not only opened the epoxide but also unexpectedly de-
protected both nitrogens, destroying chirality by forming meso
triol 20, which also establishes the stereoselectivity of the
oxime reduction.
To complete the synthesis of diastereomeric DOS 6b, the
opening of epoxide 26 was attempted. Due to the electron-de-
ficient nature of the ring, forcing conditions were required. By
heating at reflux epoxide 26 with sodium azide in n-propanol,
the expected trans diaxal addition product was formed, but
with the concomitant loss of the tert-butoxycarbonyl group.
Trapping the amine by the addition of di-tert-butyldicarbonate
gave the final diastereomer 6b.
In conclusion, we have developed a concise, asymmetric
synthesis of two diastereomers of 2-deoxystreptamine and an
asymmetric formal synthesis of conduramine A. Our approach
demonstrates the utility of a one-pot catalytic asymmetric de-
symmetrization in the synthesis of epimers of ring II in amino-
glycosides. The two synthetic strategies presented are concise
and display a range of highly diastereoselective transforma-
The solution to this problem lay in the installation of a more
robust differentiating group with the dibenzoylation of oxime
18. Gratifyingly, the reduction of the resulting oxime 21 was
greatly facilitated by the incorporation of an electron-with-
drawing group (Scheme 3). The reduction of oxime 21 pro-
gressed with the in situ migration of the benzoyl group from
O to N to give epoxide 22 (structure confirmed by NMR and X-
ray analyses).[15] When conditions similar to those attempted
for the opening of epoxide 19 were attempted, we were
pleased to find that the opening of the epoxide proceeded
with 5:1 regioselectivity and that the benzoyl group was stable
to the reaction conditions. This completed the synthesis of our
first diastereomeric DOS core 5b.
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tions that provide several intermediates that can potentially be
of value in the design of a range of unnatural aminocyclitols,
such as 2-deoxystreptamine analogues and other condura-
mines.
1S,4R-(5-Oxo-7-oxa-bicyclo[4.1.0]hept-2-yl)-carbamic acid
tert-butyl ester
Tetra-n-propylammonium perruthenate (0.66 g, 1.88 mmol) and ac-
tivated 4 ꢁ molecular sieves (19 g) were added to a solution of 15
(8.62 g, 37.62 mmol) in dichloromethane (268 mL). Solid 4-methyl-
morpholine N-oxide (6.61 g, 56.43 mmol) was added, and the slurry
was stirred at RT for 8 h. The reaction was poured onto a bed of
silica gel and eluted with dichloromethane. The eluent was con-
centrated, and the crude product was purified by using silica-gel
flash chromatography (30% ethyl acetate/hexanes) to afford 7.36 g
(86%) of the title compound as solid. A white Rf =0.25 in 20%
ethyl acetate/hexanes; m.p. 86–888C; [a]2D3 = +178.0 (c 0.2,
Experimental Section
1S,4R- Benzoic acid 4-tert-butoxycarbonylamino-cyclohex-2-
enyl ester
To a flame-dried round-bottomed flask was added [(h3-C3H5)PdCl]2
(29.0 mg, 0.079 mmol), (S,S)-9 (164 mg, 0.2376 mmol), and diben-
zoate 8 (12.5 g, 39.62 mmol). The flask was the placed under re-
duced pressure (vacuum pump) for ten seconds and refilled with
Ar; this purging procedure was repeated three times to ensure
that no oxygen remained in the reaction vessel. After being placed
in an Ar atmosphere, degassed THF (17 mL) was added, and the
mixture was stirred for 10 min at RT. Freshly distilled azidotrime-
thylsilane (6.31 mL, 47.54 mmol) was added dropwise at 08C, and
the reaction was stirred at this temperature for 1.5 h. Water
(30 mL) was added to the reaction mixture followed by a dropwise
addition of solution of trimethyl phosphine (100 mL of a 1m solu-
tion in THF) over 2 h. Upon complete disappearance of the inter-
mediate allylic azide, triethylamine (13.0 mL) and di-tert-butyl-dicar-
bonate (13.3 g, 66.66 mmol) were added, and the reaction was
stirred for 12 h at RT. The reaction was diluted with diethyl ether
(300 mL) and washed with saturated sodium bicarbonate, brine,
dried (MgSO4), and concentrated. Silica-gel chromatography by
using 10% ethyl acetate/hexanes gave 10.69 g (87%) of the title
compound as oil. A clear Rf =0.5 in 20% ethyl acetate/hexanes;
[a]2D4 =À75.84 (c 0.18, CH2Cl2); 1H (400 MHz, CDCl3): d=8.03 (dd,
J=8.0, 1.6 Hz, 2H), 7.54 (dd, J=8.0, 8.0 Hz, 1H), 7.42 (dd, J=
8.0 Hz, 2H), 5.93 (ddd, J=10.1, 3.4, 1.0 Hz, 1H), 5.89 (dd, J=10.1,
2.4 Hz, 1H), 5.42 (m, 1H), 4.60 (bd, J=7.9 Hz, 1H), 4.19 (m, 1H),
2.01–1.89 (m, 3H), 1.72 (m, 1H), 1.4 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3): d=166.1, 155.2, 133.8, 133.0, 130.4, 129.6, 128.4, 128.1,
79.6, 67.4, 46.0, 28.4, 26.0 ppm; IR (thin film): n˜max =3411, 3315,
3065, 3027, 2943, 2867, 1702, 1530, 1246, 1064 cmÀ1; HRMS (EI,
[MC18H23NO4À(C4H9)]+) calcd for C14H15NO4: 261.1001; found:
261.1010.
1
CH2Cl2); H NMR (400 MHz, CDCl3): d=4.86 (d, J=9 Hz, 1H), 4.25 (q,
J=9 Hz, 1H), 3.65 (d, J=4 Hz, 1H), 3.29 (d, J=4 Hz, 1H), 2.53 (ddd,
J=18.0, 4.0, 4.0 Hz, 1H), 2.18 (ddd, J=18.0, 4.0, 4.0 Hz, 1H), 1.85
(m, 1H), 1.46 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d=203.2,
155.1, 80.2, 57.5, 55.9, 46.3, 34.9, 28.3, 22.9 ppm; IR (thin film):
n˜max =3331, 2976, 1693, 1524, 1455, 1391, 1365, 1306, 1249, 1167,
1056, 1007, 957, 876 cmÀ1; HRMS (EI, [MC11H17NO4À(C4H9)]+) calcd
for C7H9NO4: 171.0532; found: 171.0539; elemental analysis calcd
(%) for C7H9NO4: C 58.14, H 7.54, N 6.16; found C 57.96, H 7.54, N
6.04.
Acknowledgements
We thank NIH-GM and the National Science Foundationfor the
generous support of our programs. S.M. thanks Eli Lilly (for
a graduate fellowship). Palladium salts were generously sup-
plied by Johnson-Matthey. The authors would like to thank Vic-
tor G. Young, Jr., and the X-Ray crystallographic laboratory for
elucidating.
Keywords: aminoglycoside · azidization · conduramines ·
palladium · synthetic methods
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1S,4R-(5-Hydroxy-7-oxa-bicyclo[4.1.0]hept-2-yl)-carbamic
acid tert-butyl ester
To a solution of alcohol 14 (56 mg, 0.26 mmol) in anhydrous
chloroform (20 mL) was added m-chloroperoxybenzoic acid
(50 mg, 0.29 mmol). The reaction was stirred at RT for 24 h (con-
sumption of starting material was monitored by GC). Upon com-
pletion, the reaction mixture was washed with saturated sodium
hydrogen carbonate, brine, dried (MgSO4), and concentrated to
afford 60 mg (99%) of title compound as a clear oil that slowly
crystallized to solid. A white Rf =0.7 in 100% ethyl acetate; [a]D26
=
1
+22.12 (c 2.2, CH2Cl2); H NMR (400 MHz, [D6]DMSO) : d=6.72 (d,
J=8.0 Hz), 4.82 (d, J=5.3 Hz, 1H), 3.82 (m, 1H), 3.74 (m, 1H), 3.24
(dd, J=4.0 Hz, 1H), 3.17 (dd, J=4.0, 2.6 Hz, 1H), 1.48–1.27 ppm (m,
4H), 1.38 (s,1H); 13C NMR (100 MHz, [D6]DMSO): d=155.1, 77.7,
64.6, 56.1, 54.7, 44.7, 28.2, 26.4, 24.7 ppm; IR (thin film) n˜max =3348,
2977, 2938, 2871, 1702, 1506, 1456, 1392, 1367, 1326, 1249, 1170,
1068, 1003, 929, 895, 848, 776 cmÀ1; HRMS (EI, [M]+) calcd for
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[14] Reaction could be conducted on a 20 g scale by using this protocol, in
which the stepwise procedure, when conducted on smaller scales, re-
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[15] See the Supporting Information.
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Received: February 13, 2014
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Published online on && &&, 0000
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COMMUNICATION
&
Synthetic Methods
B. M. Trost,* S. Malhotra
&& – &&
Asymmetric Stereodivergent Strategy
Towards Aminocyclitols
Very synthetic! Pd-catalyzed asymmet-
ric desymmetrization enables a concise
synthesis of aminocyclitols, such as dia-
stereomeric 2-deoxystreptamine ana-
logues and conduramine A (see
scheme).
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