Diversity-oriented synthesis of aminocyclohexitols from Garner's aldehyde

Article abstract of DOI:10.1055/s-0032-1317962

A short and efficient synthetic route to three stereoisomeric aminocyclohexane tetrols of the quercitol type has been developed from l-serine, which featured stereoselective allylation, stereocontrolled dihydroxylation, and ring-closing metathesis as key steps. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317962

536▌
PAPER
paper
Diversity-Oriented Synthesis of Aminocyclohexitols from Garner’s Aldehyde
Diversity-Oriented Synthesis of Aminocyclohexitols
Ayan Bandyopadhyay,a Partha Mitra,b Shital K Chattopadhyay*a
a
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Fax +91(33)25828282; E-mail: skchatto@yahoo.com
b
Division of X-ray Crystallography, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
Received: 25.09.2012; Accepted after revision: 10.12.2012
diene II, thus obtainable, on ring-closing metathesis
Abstract: A short and efficient synthetic route to three stereoiso-
(RCM) should deliver the carbocyclic template III on
meric aminocyclohexane tetrols of the quercitol type has been de-
which functional group manipulation of the alkene part
veloped from L-serine, which featured stereoselective allylation,
would create further diversity in the substitution pattern as
well as their steric disposition leading to the aminocarba-
sugar derivative IV with six different points of diversity
all together. We have recently reported12 a stereodivergent
synthesis of three stereoisomeric aminocyclopentitol de-
rivatives from the aldehyde I. We were interested to de-
velop our methodology further as a general platform to
access new compounds. Herein, we describe a synthesis
of three aminocyclohexitol derivatives as a partial realiza-
tion of our stated objectives.
stereocontrolled dihydroxylation, and ring-closing metathesis as
key steps.
Key words: allylation, carbocycles, dihydroxylation, metathesis,
stereoselective synthesis
Carbasugars have received considerable attention as mim-
ics of natural sugars, a property associated with drug de-
velopment related to a myriad of diseases including
diabetes, viral and bacterial infections, immunological
disorders, and cancer.1 Amino-substituted carbasugars,
also known as aminocyclohexitols, are distinctly impor-
tant since the protonated amino group mimics the oxoni-
um ion structure in the transition state of a glycosidase
reaction.2 Several naturally occurring aminocyclohexitol
derivatives such as valienamine (1),3 validamine (2),4
valiolamine (3),5 and synthetic modifications thereof, for
example, voglibose (4)6 (Figure 1) have provided impetus
for further search of new aminocarbasugar derivatives.
Thus, several elegant synthetic methodologies directed to-
wards the development of new entities as well as classical
targets have been reported.7 Three general concepts,
which have emerged from these studies for the design of
glycomimetics include: (i) N-alkylation of aminocarba-
sugars;8 (ii) variation of ring size to fine tune the hydro-
phobic-hydrophylic balance;9 and (iii) use of
stereoisomeric compounds10 to address the fundamental
difference prevalent in sugars. Although great advances
have been made, the need for the development of a com-
mon synthetic route that would encompass the three broad
objectives stated above, for the ultimate preparation of
distinguished aminocarbasugars from a common starting
material does exist.
CH2OH
CH2OH
HO
HO
HO
NH2
HO
NH2
OH
OH
validamine (2)
valienamine (1)
HOH2C
HO
HOH2C
OH
HO
OH
OH
OH
HO
N
HO
NH2
H
OH
OH
voglibose (4)
Figure 1 Selected examples of aminocyclohexitol derivatives
point of
diversity
ring-size
variation
O
OR
OH OTBDPS
n M
H
n
NHBoc
NHBoc
new
Our synthetic strategy (Scheme 1) towards the synthesis
of new aminocarbasugar derivatives involves elaboration
of the α-chiral aldehyde of the type I (obtainable from
Garner’s aldehyde11), having two points of stereochemi-
cal diversity, with suitable organometallic reagent having
a terminal alkenyl residue to induce two further degrees of
diversities, namely, chain length variation and variation in
the stereogenicity of the newly created stereocenter. The
point of
diversity
I
point of
diversity
II
further
diversity
OH
OH
RCM
n
FGI
n
HO
OR
NHBoc
HO
OR
NHBoc
III
IV
SYNTHESIS 2013, 45, 0536–0544
Advanced online publication: 09.01.2013
Scheme 1 Synthetic planning for aminocarbasugars
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317962; Art ID: SS-2012-Z0754-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diversity-Oriented Synthesis of Aminocyclohexitols
537
Our synthesis started from the known13 allyl alcohol 5,
which was protected as its TBDPS ether 6 under standard
conditions. Hydrolytic deprotection of the oxazolidine
unit in the latter provided the primary alcohol 7, which
was smoothly oxidized to the aldehyde 8 using Dess–
Martin periodinane14 following precedence15 for similar
conversion (Scheme 2). The latter proved to be essentially
pure and could be preserved at –20 °C for days without
any appreciable damage as could be seen from repeated
optical rotation and spectroscopic measurement. Howev-
er, for practical reasons, it was used as such in the next
step. Thus, addition of allylzinc bromide to the aldehyde
8 under controlled conditions provided a separable mix-
ture of alcohols 9 and 10 with modest selectivity16 in favor
of 9 in a combined yield of 93%. On the other hand, addi-
tion of allylmagnesium bromide to the aldehyde 8 pro-
duced the syn-alcohol 9 with somewhat better selectivity
(~2.3:1) but in lesser yield (69%). Configuration of the
newly created stereocenter in each of the alcohols 9 and
10 was not determined at this stage, but followed from
synthetic work described later. Similarly, the known allyl
alcohol 11 was converted to the required aldehyde 14 over
three identical steps in a combined yield of 73%. Similar
addition of allylzinc bromide to 14 indeed proceeded well,
but the product was obtained as a mixture (~3:1) of epi-
meric alcohols 15 (93%), which could not be separated at
this stage. On the other hand, use of allylmagnesium bro-
mide produced a mixture of alcohols 15 in a lower yield
(73%) but with a better isomeric composition (~5.6:1) in
the same sense (Scheme 2). However, the exact nature of
the diastereoselection could not be deciphered at this
stage. The dienes 9 and 10 were then separately subjected
to ring-closing metathesis with Grubbs’ catalyst benzyli-
dene bistricyclohexylphosphinoruthenium(IV) dichloride
(16). Pleasingly, the corresponding cyclohexene deriva-
tives 17 and 23 (Scheme 3) were obtained in excellent
yields. Compound 17 on hydrogenation in the presence of
tetrabutylammonium fluoride provided the cycloalkane
20, which was found to be devoid of any symmetry as
judged from number of signals in its 13C NMR spectrum.
This led to the establishment of the configuration at the
free hydroxyl bearing carbon as shown. Dihydroxylation
of the alkene 17 proved to be exceedingly facile and gave
only one product 18 in 95% yield.
OTBDPS
OH
ii
i
O
H
O
NBoc
NBoc
5
6
OTBDPS
O
OTBDPS
iii
iv
or v
HO
NHBoc
NHBoc
8
7
OH OTBDPS
OH OTBDPS
+
NHBoc
NHBoc
10
9
OTBDPS
OH
ii
i
O
O
NBoc
NBoc
11
12
O
OTBDPS
OTBDPS
iii
H
HO
NHBoc
14
NHBoc
13
OH
OTBDPS
iv
or v
NHBoc
15
Scheme 2 Reagents and conditions: (i) TBDPSCl, imidazole,
CH2Cl2, 6 (98%), 12 (97%); (ii) p-TsOH, MeOH, 7 (80%), 13 (77%);
(iii) Dess–Martin periodinane, CH2Cl2, 8 (97%), 14 (98%); (iv) allyl-
zinc bromide,NH4Cl, THF, 9 (57%), 10 (36%), 15 (93%); (v) allyl-
magnesium bromide, THF, 9 (48%), 10 (21%), 15 (73%).
the starting diene 10 was indirectly established as shown.
Dihydroxylation of the alkene 23 also proved to be a high-
ly diastereoselective as well as high-yielding reaction
leading to the triol 24.The stereochemistry of the dihy-
droxylation reaction was surmised from the belief that it
took place anti to the bulky OTBDPS group. Deprotection
of the TBDPS group from 24 then neatly afforded the de-
sired tetrol derivative 25 in an overall yield of 23% over
seven steps from 5 (Scheme 3).
The latter was converted into the acetonide 21 as the only
product, and thence to the diol 22 after simple deprotec-
tion of the TBDPS ether. Compound 22 was found to be
suitable for single crystal X-ray analysis. The crystal
structure17 is depicted in Figure 2, which clearly establish-
es the relative stereochemistry of the stereogenic centers
in the molecule. Further deprotection of the TBDPS group
from the triol 18 then delivered the targeted tetrol 19 in an
overall yield of 38% over seven steps from 5. Similar
treatment of the diene 10 provided quick access to the epi-
meric cyclohexenol 23 under comparable conditions. Hy-
drogenation of the latter resulted in the symmetric diol 26
and hence the stereochemistry at the carbinol carbon in
Figure 2 ORTEP plot of compound 22
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 536–544

538
A. Bandyopadhyay et al.
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We then became interested to carry forward the mixture of On the other hand, dihydroxylation of the isomeric cyclo-
dienes 15 with the hope that the products will be separable hexene 28 proved to be high-yielding but nonselective.
at some stage down the line. Pleasingly, ring-closing me- Moreover, the isomeric diols 32 resisted purification by
tathesis of the mixture 15 neatly provided a separable conventional means in our hands. Removal of the TBDPS
mixture of the corresponding cycloalkenes 27 and 28.The group from this diol mixture provided the corresponding
stereochemical identity of the major product 27 was re- tetrol derivatives 33 also as an inseparable mixture
vealed from its conversion to the symmetric diol 29 (Scheme 3).
through the one-pot protocol involving hydrogenation and
In short, we have developed a convenient route to three
TBDPS removal. Dihydroxylation of the hydroxyalkene
stereoisomeric aminocyclohexitol derivatives from a
27 delivered only one isomer in this instance too and the
common starting material and using a common set of
transformations involving easily available reagents and
simple reaction conditions. The targeted compounds 19,
25, and 31 were obtained in good overall yields and high
stereochemistry of the resulting triol 30 followed from
similar arguments. Final removal of the TBDPS group
then provided the tetrol 31 in an overall yield of 44% over
seven steps from 11 (Scheme 3).
OH
OH
OH
OH
OH
iii
i
ii
9
HO
OTBDPS
HO
HO
OTBDPS
NHBoc
17
NHBoc
NHBoc
18
19
O
O
v
iv
HO
OR
HO
OH
NHBoc
NHBoc
21, R = TBDPS
22, R = H
20
OH
OH
OH
OH
OH
ii
iii
i
10
HO
OTBDPS
HO
OTBDPS
HO
NHBoc
NHBoc
NHBoc
23
24
25
iv
HO
OH
NHBoc
26
OH
OH
OH
OH
ii
iii
HO
OTBDPS
NHBoc
HO
OTBDPS
HO
OH
NHBoc
NHBoc
27
30
31
i
+
OH
OH
15
OH
OH
OH
ii
iii
HO
OTBDPS
NHBoc
28
HO
OTBDPS
HO
NHBoc
NHBoc
33
32
iv
27
HO
OH
NHBoc
29
Scheme 3 Reagents and conditions: (i) catalyst 16 (5 mol%), CH2Cl2, 17 (95%), 23 (94%), 27 (70%), 28 (23%); (ii) OsO4, NMMO, acetone–
H2O, 18 (97%), 24 (95%), 30 (96%), 32 (94%); (iii) TBAF·H2O, THF, 19 (96%), 22 (96%), 25 (93%), 31 (97%), 33 (91%); (iv) H2, Pd/C, THF,
and then TBAF·H2O, THF, 20 (94%), 26 (93%), 29 (96%); (v) 2,2-dimethoxypropane, p-TsOH, CH2Cl2, 96%.
Synthesis 2013, 45, 536–544
© Georg Thieme Verlag Stuttgart · New York

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Diversity-Oriented Synthesis of Aminocyclohexitols
539
tert-Butyl (2S,3R)-3-(tert-Butyldiphenylsilyloxy)-1-hydroxy-
pent-4-en-2-ylcarbamate (7) and tert-Butyl (2S,3S)-3-(tert-Bu-
tyldiphenylsilyloxy)-1-hydroxypent-4-en-2-ylcarbamate (13)
To a stirred solution of 6 (990 mg, 2 mmol) in MeOH (6 mL) was
added a catalytic amount of p-TsOH (114 mg, 0.6 mmol, 0.3 equiv)
and the reaction mixture was stirred at r.t. for 2 h by which time the
reaction was complete. The mixture was then quenched with sat. aq
NaHCO3 (20 mL) and extracted with EtOAc (2 × 50 mL). The com-
bined organic extracts were washed with brine (50 mL), dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo. The
crude residue was purified by column chromatography over silica
gel using 30% EtOAc in hexane as eluent to give the alcohol 7 as a
colorless viscous liquid (1.94 g, 98%); [α]D +8.2 (c = 0.95, CHCl3).
optical purity. Although several aminocyclitol derivatives
are known, quercitol like aminocyclitols are less docu-
mented.18 This diversity oriented approach19 may there-
fore complement to those existing in the literature and
hence find application.
Optical rotations were measured in spectroscopic grade CHCl3 on a
Rudolph Autopol IV polarimeter at 25 °C and the [α]D values are re-
corded in units of 10–1 deg cm2 g–1. IR spectra were recorded on a
PerkinElmer Spectrum-1 spectrophotometer. Liquid samples were
sandwiched between two KBr plates and solid samples were pel-
leted with KBr. 1H and 13C NMR spectra were recorded on a Bruker
Avance-400 spectrometer purchased through a DST-FIST grant.
Data for rotamers are presented within parentheses wherever appro-
priate. Chemical shifts are recorded relative to residual solvent
peak. Mass spectra were recorded on a JEOL-JMS 600 instrument
from I. I. C. B., Kolkata or IACS, Kolkata. Petroleum ether (PE) re-
fers to the fraction boiling in the range 60–80 °C. Silica gel (60–
120, 100–120, or 200–230 mesh) for column chromatography was
purchased from Spectrochem, India.
IR (KBr): 3436, 2963, 2858, 1697, 1505, 1366, 1171, 1112, 1050,
933, 821 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.55 (4 H, m), 7.38–7.27 (6
H, m), 5.72 (1 H, ddd, J = 17.2, 10.4, 6.8 Hz), 5.00–4.97 (3 H, m),
4.34 (1 H, t, J = 4 Hz), 3.79 (1 H, dd, J = 11.2, 4.4 Hz), 3.54–3.48
(2 H, m), 1.41 (1 H, br s), 1.33 (9 H, s), 1.01 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 156.1, 136.8, 136.0, 135.9,
133.1, 133.0, 130.1, 130.0, 127.8, 127.6, 117.4, 79.5, 76.4, 62.7,
56.3, 28.3, 27.1, 19.4.
tert-Butyl (S)-4-[(R)-1-(tert-Butyldiphenylsilyloxy)allyl]-2,2-di-
methyloxazolidine-3-carboxylate (6) and tert-Butyl (S)-4-[(S)-1-
(tert-Butyldiphenylsilyloxy)allyl]-2,2-dimethyloxazolidine-3-
carboxylate (12)
MS (TOFMS ES+): m/z = 478 (M + Na).
Anal. Calcd for C26H37NO4Si: C, 68.53; H, 8.18; N, 3.07. Found: C,
68.68; H, 8.37; N, 2.91.
To a stirred solution of the anti-allyl alcohol 5 (1.03 g, 4 mmol) in
CH2Cl2 (3 mL) was added imidazole (0.40 gm, 6 mmol, 1.5 equiv).
After 5 min, TBDPSCl (1.15 mL, 4.4 mmol, 1.1 equiv) was added
slowly at r.t. and the resulting reaction mixture was stirred for 4 h at
r.t. The mixture was then diluted with EtOAc (60 mL) and the
EtOAc layer was washed successively with aq 1 N HCl (50 mL),
H2O (50 mL), and brine (50 mL), and dried (Na2SO4). It was filtered
and the filtrate was concentrated in vacuo to leave to leave a yellow-
ish crude oil, which on purification by silica gel chromatography us-
ing 5% EtOAc in hexane afforded 6 as a syrupy liquid (1.94 g,
98%); [α]D –18.2 (c = 0.74, CHCl3).
13
Similarly, compound 13 was prepared from 12; yield: 1.40 g (77%);
colorless liquid; [α]D –13.62 (c = 0.92, CHCl3).
IR (KBr): 3445, 2962, 1696, 1498, 1428, 1391, 1366, 1249, 1171,
1112, 1084, 1027, 999, 927, 821, 740 cm–1.
1H NMR (400 Mz, CDCl3): δ = 7.68–7.63 (4 H, m), 7.47–7.35 (6
H, m), 5.86–5.82 (1 H, m), 5.03–4.86 (3 H, m), 4.31–4.29 (1 H, m),
3.68–3.57 (3 H, m), 2.1 (1 H, br s), 1.43 (9 H, s), 1.1 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 156.4, 136.6, 135.6, 135.4, 132.9,
132.6, 129.5, 129.3, 127.3, 127.0, 116.9, 79.2, 73.7, 62.7, 56.3,
27.8, 26.6, 18.9.
IR (KBr): 2976, 2933, 1704, 1474, 1385, 1366, 1257, 1175, 1112,
822 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.66–7.63 (1 H, m), 7.59–7.57 (3
H, m), 7.36–7.26 (6 H, m), 5.67–5.56 (1 H, m), 4.67 (1 H, dt,
J = 10.4, 4.8 Hz), 5.55 (1 H, dd, J = 16.8, 6.8 Hz), 4.26 (1 H, t,
J = 7.6 Hz), 4.08–3.99 (1 H, m), 3.84–3.83 (2 H, m), 1.45–1.32 (15
H, m), 0.97 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 152.8 (153.1), 138.1, 136.0,
135.9, 134.2, 133.7, 129.6, 129.5 (129.4), 127.4 (127.3), 117.3
(116.7), 94.3 (93.8), 79.9 (79.8), 76.2, 65.1 (64.6), 62.0 (61.8), 28.4,
27.1 (26.7), 24.8, 23.1, 19.4.
MS (TOFMS ES+): m/z = 578 (M + Na).
Anal. Calcd for C26H37NO4Si: C, 68.53; H, 8.18; N, 3.07. Found: C,
68.76; H, 8.39; N, 3.12.
tert-Butyl (2R,3R)-3-(tert-Butyldiphenylsilyloxy)-1-oxopent-4-
en-2-ylcarbamate (8) and tert-Butyl (2R,3S)-3-(tert-Butyldiphe-
nylsilyloxy)-1-oxopent-4-en-2-ylcarbamate (14)
To a stirred solution of the alcohol 7 (455 mg, 1 mmol) in anhyd
CH2Cl2 (5 mL) was added solid Dess–Martin periodinane (551 mg,
1.3 mmol, 1.3 equiv). The resulting mixture was stirred for 0.5 h at
r.t. It was then diluted with Et2O (30 mL) and quenched with aq 0.5
M NaOH (30 mL). The mixture was stirred for 15 min and the aque-
ous phase was extracted with Et2O (2 × 25 mL). The combined or-
ganic extracts were washed with aq 0.5 M NaOH (20 mL), H2O (20
mL), and brine (20 mL), dried (Na2SO4), filtered, and the filtrate
was concentrated under reduced pressure to provide the crude alde-
hyde 8 as a colorless oil (440 mg, 97%); [α]D –53.2 (c = 1.35,
CHCl3).
Anal. Calcd for C29H41NO4Si: C, 70.26; H, 8.34; N, 2.83. Found: C,
70.06; H, 8.57; N, 2.98.
12
Similarly, compound 12 was prepared from alcohol 11; yield: 1.93
g (97%); colorless liquid; [α]D –20.94 (c = 0.55, CHCl3).
IR (KBr): 1703, 1428, 1389, 1366, 1257, 1173, 1106, 1075, 822
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.72–7.61 (4 H, m), 7.43–7.35 (6
H, m), 5.88–5.81 (1 H, m), 5.07 (1 H, d, J = 10.0 Hz), 4.93 (1 H, d,
J = 17.2 Hz), 4.61 (1 H, t, J = 5.2 Hz), 4.35 (1 H, d, J = 9.2 Hz),
3.99–3.92 (2 H, m), 1.62–1.42 (6 H, m), 1.20 (9 H, m), 1.06 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 151.8, 136.2, (136.0), 135.8,
133.8, 133.6, 129.8 (129.7), 127.6, 127.4, 117.7 (117.4), 94.8
(93.7), 79.9 (79.7), 73.6, 63.4 (63.2), 61.0 (60.5), 28.3, 27.0 (26.4),
24.6, 23.1, 19.4.
IR (KBr): 2963, 2859, 1715, 1496, 1392, 1366, 1167, 1112, 1027,
938, 822, 740 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.64 (1 H, s), 7.60–7.52 (6 H, m),
7.36–7.18 (9 H, m), 5.89 (1 H, ddd, J = 17.2, 10.8, 6.4 Hz), 5.21 (1
H, d, J = 17.2 Hz), 5.13–5.07 (2 H, m), 4.57 (1 H, br s), 4.22 (1 H,
t, J = 6.8 Hz), 1.43 (9 H, s), 0.98 (15 H, s).
13C NMR (100 MHz, CDCl3): δ = 197.5, 154.25, 135.2, 134.9,
134.8, 131.9, 129.0, 128.9, 126.7, 126.6, 126.5, 116.7, 78.8, 74.2,
63.8, 27.2, 25.9, 25.7, 18.4.
Anal. Calcd for C29H41NO4Si: C, 70.26; H, 8.34; N, 2.83. Found: C,
70.13; H, 8.40; N, 2.93.
MS (TOFMS ES+): m/z = 476 (M + Na).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 536–544

540
14
A. Bandyopadhyay et al.
PAPER
Method B: To a stirred solution of the aldehyde 8 (453 mg, 1 mmol)
in anhyd THF (6 mL) was added allylmagnasium bromide (1 M so-
lution in Et2O, 3 mL, 3 mmol, 3 equiv) dropwise at –78 °C. The
mixture was then allowed to warm slowly to –30 °C and stirred at
that temperature for 4 h. It was quenched with sat. aq NH4Cl (15
mL) and allowed to come to r.t., diluted with H2O (20 mL), and ex-
tracted with EtOAc (2 × 50 mL). The combined organic layers were
washed successively with H2O (50 mL) and brine (50 mL), and
dried (Na2SO4). It was filtered and the filtrate was concentrated un-
der reduced pressure to leave a pale yellow crude product, which
was purified by flash column chromatography over silica gel using
15% EtOAc in hexane as eluent to provide the homoallylic alcohols
9 (244 mg, 49%) followed by 10 (98 mg, 20%) each as a colorless
liquid.
Similarly, compound 14 was prepared from 13; yield: 444 mg
(98%); colorless liquid; [α]D –46.1 (c = 1.25, CHCl3).
IR (KBr): 2857, 1716, 1494, 1367, 1168, 1113, 933, 822, 741 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.58 (1 H, s), 7.59–7.53 (5 H, m),
7.38–7.28 (8 H, m), 5.89 (1 H, ddd, J = 17.2, 10.0, 7.2 Hz), 5.12 (1
H, d, J = 8.0 Hz, NH), 4.95 (1 H, d, J = 10.4 Hz), 4.88 (1 H, d,
J = 17.2 Hz), 4.62 (1 H, t, J = 3.2 Hz), 4.27 (1 H, dd, J = 8.0, 3.6
Hz), 1.39 (9 H, s), 0.99 (11 H, s).
13C NMR (100 MHz, CDCl3): δ = 199.5, 155.0, 135.5, 135.3, 135.1,
132.1, 129.6, 129.4, 127.3, 127.0, 117.8, 79.6, 73.5, 63.7, 27.8,
26.5, 18.9.
MS (TOFMS ES+): m/z = 476 (M + Na).
Epimeric Mixture of Alcohols 15
tert-Butyl (3R,4S,5R)-3-(tert-Butyldiphenylsilyloxy)-5-hydroxy-
hepta-1,6-dien-4-ylcarbamate (9) and tert-Butyl (3R,4S,5S)-3-
(tert-Butyldiphenylsilyloxy)-5-hydroxyhepta-1,6-dien-4-ylcar-
bamate (10)
Similarly, the epimeric mixture of alcohols 15 was prepared from
the aldehyde 14 following Method A and B as detailed for the prep-
aration of the dienes 9 and 10; yield of 15: Method A: 94%; Method
B: 76%; colorless liquid. Selectivity: Method A: syn/anti = 3:1;
Method B: syn/anti = 5.5:1.
Method A: To a solution of aldehyde 8 (680 mg, 1.5 mmol) in a mix-
ture of THF (6 mL) and sat. aq NH4Cl (4 mL) were added allyl bro-
mide (0.76 mL, 9 mmol) followed by Zn dust (588 mg, 9 mmol).
The mixture was stirred at r.t. for 6 h and then extracted with EtOAc
(2 × 30 mL). The combined organic extracts were washed succes-
sively with aq 1 M HCl (25 mL), H2O (50 mL), and brine (50 mL),
and dried (Na2SO4). It was filtered and the filtrate was concentrated
in vacuo to leave a pale yellow crude product, which was purified
by flash chromatography on silica gel using 15% EtOAc in hexane
as eluent to provide the dienes in the order 9 (414 mg, 56%) fol-
lowed by 10 (276 mg, 37%) each as a colorless liquid.
IR (KBr): 3442, 2934, 1700, 1643, 1499, 1428, 1366, 1170, 1109,
1180, 925, 854, 703 cm–1.
1H NMR (400 Mz, CDCl3): δ = 7.71–7.64 (6 H, m), 7.45–7.34 (8 H,
m), 5.83–5.76 (2 H, m), 5.14–5.02 (3 H, m), 4.98–4.86 (3 H, m),
4.57 (1 H, d, J = 7.2 Hz), 4.32 (1 H, t, J = 6.4 Hz), 3.98 (1 H, br s),
3.60 (1 H, br s), 3.51 (1 H, d, J = 6.8 Hz), 2.36–2.1 (2 H, m), 1.47
and 1.44 (9 H, s), 1.08 and 1.06 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 156.2, 156.0, 137.6, 137.2, 136.1,
136.0, 134.9, 134.3, 133.7, 133.5, 133.2, 130.0, 129.9, 127.9, 127.7,
127.6, 127.5, 118.1, 118.0, 117.3, 79.5,79.3, 76.2, 74.1, 70.5, 70.1,
58.5, 57.6, 39.0, 38.4, 28.4, 27.1, 27.0, 19.5, 19.4.
9
[α]D +8.84 (c = 1.05, CHCl3).
IR (KBr): 3446, 2934, 1715, 1644, 1500, 1367, 1170, 1109, 1074,
926, 824, 929, 704 cm–1.
MS (TOFMS ES+): m/z = 518 (M + Na).
1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (4 H, m), 7.46–7.34 (6
H, m), 5.77 (2 H, ddd, J = 17.2, 10.4, 6.8 Hz), 5.16–5.06 (3 H, m),
5.0–4.94 (2 H, m,), 4.47 (1 H, t, J = 3.6 Hz), 4.17 (1 H, t, J = 6.8
Hz), 3.46 (1 H, dd, J = 9.2, 3.6 Hz), 3.13 (1 H, s), 2.26 (1 H, dt,
J = 14.0, 6.8 Hz), 2.154 (1 H, dt, J = 17.2, 6.8 Hz), 1.40 (9 H, s),
1.08 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 155.7, 137.2, 136.1, 136.0, 134.4,
132.9, 132.6, 130.1, 129.9, 127.8, 127.6, 117.7, 117.4, 79.2, 78.4,
69.3, 56.6, 38.4, 28.4, 27.1, 19.4.
RCM of the Dienes 9, 10, and 15: Formation of the Cycloalkenes
17, 23, 27, and 28; General Procedure
To a stirred solution of the appropriate diene (0.50 mmol) in de-
gassed anhyd CH2Cl2 (0.01 M, 50 mL) was added Grubbs’ catalyst
16 (21 mg, 5 mol%) and the homogenous mixture was refluxed for
16 h under an argon atmosphere. The solvent was removed in vacuo
and the residual mass was purified by flash column chromatography
over silica gel using 30% EtOAc in hexane as eluent to give the ap-
propriate cyclohexene.
tert-Butyl (1S,2R,6R)-2-(tert-Butyldiphenylsilyloxy)-6-hydroxy-
cyclohex-3-enylcarbamate (17)
MS (TOFMS ES+): m/z = 518 (M + Na).
Yield: 221 mg (95%); colorless liquid; [α]D –101.53 (c = 0.75,
CHCl3).
Anal. Calcd for C29H41NO4Si: C, 70.26; H, 8.16; N, 2.83. Found: C,
70.11; H, 8.33; N, 2.71.
IR (KBr): 3445, 2932, 1700, 1503, 1367, 1242, 1170, 1106, 1066,
956, 762, 704 cm–1.
10
[α]D –5.4 (c = 1.63, CHCl3).
1H NMR (400 Mz, CDCl3): δ = 7.68–7.63 (4 H, m), 7.45–7.26 (6 H,
m), 5.60 (1 H, ddd, J = 7.2, 4.8, 2.4 Hz), 5.32–5.26 (2 H, m), 5.29
(1 H, t, J = 4.0 Hz), 5.03 (1 H, t, J = 4.8 Hz), 3.58 (1 H, t, J = 8.4
Hz), 2.62 (1 H, td, J = 18.0, 4.8 Hz), 2.50 (1 H, br s), 2.05 (1 H, dd,
J = 17.6, 9.2 Hz), 1.45 (9 H, s), 1.25 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 157.1, 136.0, 135.8, 133.7, 133.1,
130.0, 129.8, 128.1, 127.9, 127.5, 127.4, 79.7, 68.8, 66.9, 56.6,
34.6, 28.4, 27.1, 19.5.
IR (KBr): 3437, 2933, 1717, 1642, 1501, 1366, 1171, 1111, 1041,
727, 704 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.69 (2 H, d, J = 6.4 Hz), 7.67 (2
H, d, J = 6.8 Hz), 7.63–7.34 (6 H, m), 5.86–5.84 (1 H, m), 5.79–
5.71 (1 H, m), 5.28 (1 H, d, J = 16.8 Hz), 5.17 (1 H, d, J = 10.4 Hz),
5.08 (2 H, dd, J = 9.2, 4.4 Hz), 5.03 (1 H, s), 4.62 (2 H, d, J = 2.4
Hz), 3.59 (1 H, t, J = 8.0 Hz), 3.48 (1 H, d, J = 4.8 Hz), 2.24–2.21
(1 H, m), 2.05 (1 H, q, J = 7.2 Hz), 1.42 (9 H, s), 1.09 (9 H, s).
MS (TOFMS ES+): m/z = 490 (M + Na).
13C NMR (100 MHz, CDCl3): δ = 156.1, 136.4, 136.1, 135.9, 134.6,
133.6, 133.3, 130.1, 129.9, 129.7, 127.9, 127.7, 118.4, 117.4, 79.3,
73.4, 71.1, 58.9, 38.3, 28.4, 27.1, 26.9, 19.4.
Anal. Calcd for C27H37NO4Si: C, 69.34; H, 7.97; N, 2.99. Found: C,
69.21; H, 8.09; N, 2.85.
MS (TOFMS ES+): m/z = 518 (M + Na).
tert-Butyl (1S,2R,6S)-2-(tert-Butyldiphenylsilyloxy)-6-hydroxy-
cyclohex-3-enylcarbamate (23)
Yield: 219 mg (94%); colorless liquid; [α]D –12.73 (c = 1.16,
CHCl3).
Anal. Calcd for C29H41NO4Si: C, 70.26; H, 8.16; N, 2.83. Found: C,
70.47; H, 8.20; N, 2.98.
Synthesis 2013, 45, 536–544
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diversity-Oriented Synthesis of Aminocyclohexitols
541
IR (KBr): 3441, 2932, 1700, 1499, 1429, 1367, 1240, 1168, 1110,
1050, 854, 761, 703 cm–1.
1H NMR (400Mz, CDCl3): δ = 7.66–7.64 (4 H, m), 7.47–7.37 (6 H,
m), 5.66 (1 H, dd, J = 10, 6.4 Hz), 5.44–5.42 (2 H, m), 4.44 (1 H, d,
J = 8.8 Hz), 4.38 (1 H, br s), 3.80–3.73 (2 H, m), 2.30 (2 H, br s),
1.45 (9 H, s), 1.08 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 157.5, 135.8, 135.7, 133.0, 132.6,
130.2, 130.0, 127.9, 127.8, 127.6, 127.0, 79.8, 69.2, 68.6, 54.0,
32.5, 28.4, 26.9, 19.3.
tert-Butyl (1S,2S,3S,4S,6R)-2-(tert-Butyldiphenylsilyloxy)-3,4,6-
trihydroxycyclohexylcarbamate (18)
Yield: 486 mg (97%); [α]D –10.3 (c = 1.1, CHCl3).
IR (KBr): 3419, 2931, 2859, 1696, 1590, 1513, 1367, 1171, 1111,
1023, 759, 702 cm–1.
1H NMR (400 Mz, DMSO-d6): δ = 7.59–7.55 (4 H, m), 7.50–7.40
(6 H, m), 5.54 (1 H, d, J = 7.6 Hz), 4.62 (1 H, d, J = 3.6 Hz), 4.53
(1 H, d, J = 5.6 Hz), 4.37 (1 H, d, J = 6.8 Hz), 3.96 (1 H, s), 3.83 (1
H, dq, J = 11.2, 6.8 Hz), 3.66 (1 H, ddd, J = 16.0, 10.4, 5.6 Hz), 1.78
(1 H, td, J = 11.6, 6.8 Hz), 1.61 (1 H, q, J = 11.6 Hz), 1.28 (9 H, s),
1.02 (9 H, s).
MS (TOFMS ES+): m/z = 490 (M + Na).
Anal. Calcd for C27H37NO4Si: C, 69.34; H, 7.97; N, 2.99. Found: C,
69.51; H, 8.12; N, 3.08.
13C NMR (100 MHz, CDCl3): δ = 156.7, 135.9, 135.8, 133.1, 132.7,
130.1, 130.0, 127.9, 79.7, 74.1, 71.8, 67.8, 66.9, 54.8, 36.0, 28.3,
27.1, 19.4.
tert-Butyl (1S,2S,6R)-2-(tert-Butyldiphenylsilyloxy)-6-hydroxy-
cyclohex-3-enylcarbamate (27)
Yield from the mixture 15 (prepared via route A): 163 mg (70%);
yield from the mixture 15 (prepared via Method B): 184 mg (78%);
colorless liquid; mp 128–130 °C; [α]D +6.32 (c = 1.14, CHCl3).
HRMS (TOFMS ES+): m/z calcd for C27H39NO6Si + Na: 524.2444;
found: 524.2442 (M + Na).
tert-Butyl (1S,2S,3S,4S,6S)-2-(tert-Butyldiphenylsilyloxy)-3,4,6-
trihydroxycyclohexylcarbamate (24)
Yield: 476 mg (95%); [α]D –16.4 (c = 1.0, CHCl3).
IR (KBr): 3417, 3327, 1680, 1527, 1365, 1320, 1250, 1171, 1106,
1064, 981, 703 cm–1.
IR (KBr): 3444, 2929, 1694, 1504, 1392, 1168, 1112, 1070, 1024,
703 cm–1.
1H NMR (400 Mz, DMSO-d6): δ = 7.65–7.62 (4 H, m), 7.46–7.39
(7 H, m), 6.55 (1 H, d, J = 9.2 Hz), 5.39 (1 H, dd, J = 10.0, 4.8 Hz),
5.05 (1 H, d, J = 10.0 Hz), 4.63 (1 H, d, J = 5.6 Hz), 4.33 (1 H, d,
J = 6.4 Hz), 3.38 (1 H, q, J = 9.6 Hz), 2.22 (1 H, td, J = 18, 12.4 Hz),
1.95 (1 H, dd, J = 16.8, 11.6 Hz), 1.40 (10 H, s), 0.98 (10 H, s).
13C NMR (100 MHz, CDCl3): δ = 157.4, 136.0, 133.6, 133.0, 130.0,
129.9, 129.7, 128.9, 128.0, 127.7, 127.6, 125.8, 80.0, 71.9, 70.1,
59.8, 34.1, 28.3, 29.7, 26.9, 19.3.
1H NMR (400 Mz, CDCl3): δ = 7.65–7.63 (4 H, m), 7.48–7.38 (6 H,
m), 5.20 (1 H, br s), 4.21 (1 H, br s), 4.15 (1 H, br s), 3.92 (1 H, d,
J = 3.2 Hz), 3.83 (1 H, d, J = 3.2 Hz), 3.66 (1 H, br s), 2.26 (1 H, br
s), 2.0–1.97 (1 H, m), 1.9 (1 H, dt, J = 12.0, 2.8 Hz), 1.39 (9 H, s),
1.10 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 156.0, 135.9, 132.2, 130.4, 130.2,
128.0, 127.9, 79.8, 75.4, 71.5, 70.1, 64.3, 50.1, 35.0, 28.3, 27.0,
19.2.
HRMS (TOFMS ES+): m/z calcd for C27H37NO4Si + Na: 490.2390;
found: 490.2356 (M + Na).
HRMS (TOFMS ES+): m/z calcd for C27H39NO6Si + Na: 524.2444;
tert-Butyl (1S,2S,6S)-2-(tert-Butyldiphenylsilyloxy)-6-hydroxy-
cyclohex-3-enylcarbamate (28)
Yield from the mixture 15 (prepared via route A): 54 mg (23%);
yield from the mixture 15 (prepared via Method B): 33 mg (14%);
colorless liquid; [α]D +32.2 (c = 1.2, CHCl3).
found: 524.2441 (M + Na).
tert-Butyl (1S,2R,3R,4R,6R)-2-(tert-Butyldiphenylsilyloxy)-
3,4,6-trihydroxycyclohexylcarbamate (30)
Yield: 481 mg (96%); [α]D –34.9 (c = 1.1, CHCl3).
IR (KBr): 3419, 2931, 2859, 1696, 1590, 1513, 1367, 1171, 1111,
1023, 759, 702 cm–1.
IR (KBr): 3445, 2932, 1700, 1503, 1367, 1242, 1170, 1106, 1066,
956, 762, 704 cm–1.
1H NMR (400 Mz, CDCl3): δ = 7.75–7.73 (2 H, m), 7.67 (2 H, d,
J = 6.4 Hz), 7.39–7.36 (6 H, m), 4.39 (1 H, d, J = 6.4 Hz), 4.07 (1
H, br s), 3.76–3.66 (3 H, m), 3.57–3.48 (2 H, m), 2.41 (1 H, br s),
2.18–2.15 (br s, 2 H), 1.35 (9 H, s), 1.1 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 157.2, 136.0, 135.6, 133.6, 132.0,
130.3, 128.2, 128.1, 80.0, 75.3, 73.7, 70.1, 67.4, 59.4, 35.5, 28.2,
27.0, 19.5.
1H NMR (400 Mz, DMSO-d6): δ = 7.66–7.62 (4 H, m), 7.47–7.40
(6 H, m), 5.12 (1 H, d, J = 8.8 Hz), 5.46 (1 H, d, J = 9.2 Hz), 5.22
(1 H, d, J = 10.0 Hz), 4.73 (1 H, d, J = 2.8 Hz), 4.25 (1 H, br s), 3.91
(1 H, br s), 3.73 (1 H, dt, J = 13.6, 6.8 Hz), 2.26 (1 H, br d, J = 17.2
Hz), 2.04 (1 H, dd, J = 18.4, 6.8 Hz), 1.38 (9 H, s), 1.0 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 156.4, 136.3, 136.0, 135.9, 134.0,
133.3, 130.0, 129.9, 129.6, 127.6, 127.4, 126.7, 79.8, 69.8, 67.5,
57.1, 34.7, 28.3, 27.0, 19.3.
HRMS (TOFMS ES+): m/z calcd for C27H39NO6Si + Na: 524.2444;
found: 524.2473 (M + Na).
MS (TOFMS ES+): m/z = 490 (M + Na).
Anal. Calcd for C27H37NO4Si: C, 69.34; H, 7.97; N, 2.99. Found: C,
69.47; H, 7.84; N, 3.15.
Diastereomeric Mixture of Triols 32
Yield: 471 mg (94%); [α]D –20.6 (c = 1.1, CHCl3).
IR (KBr): 3403, 2931, 1690, 1511, 1428, 1392, 1367, 1249, 1169,
1112, 834, 703 cm–1.
Dihydroxylation: Formation of the Triols 18, 24, 30, and 32;
General Procedure
1H NMR (400 Mz, DMSO-d6): δ = 7.60–7.58 (5 H, m), 7.50–7.41
(7.5 H, m), 5.65 (1 H, d, J = 9.6 Hz), 5.04 (1.2 H, br s), 4.64 (1.2 H,
d, J = 6.0 Hz), 4.56 (1.26 H, d, J = 6.0 Hz), 3.95 (1.26 H, br s), 3.85–
3.81 (3.7 H, m), 3.52 (1.5 H, m), 1.63 (2.5 H, d, J = 7.2 Hz), 1.33
(11 H, s), 1.01 (11 H, s).
13C NMR (100 MHz, CDCl3): δ = 156.0, 136.0, 135.6, 133.9, 132.5,
130.1, 130.0, 128.0, 127.9, 79.6, 75.1, 72.2, 70.1, 56.8, 32.2, 28.3,
27.0, 19.5.
To a stirred solution of the appropriate cyclohexene (467 mg, 1
mmol) in acetone–H2O (5:1, 6 mL) were added N-methylmorpho-
line N-oxide (NMMO; 234 mg, 2 mmol, 2 equiv), followed by OsO4
(12.7 mg, 5 mol% in H2O) at r.t., and the resulting mixture was
stirred for 24 h. It was quenched with sat. aq Na2S2O5 (15 mL). Sol-
vent was removed in vacuo and the residual mass was extracted
with EtOAc (2 × 50 mL). The combined organic extracts were
washed with brine (30 mL) and dried (Na2SO4). It was filtered and
the filtrate was concentrated under reduced pressure to leave a pale
yellow crude product, which on purification by column chromatog-
raphy over silica gel using 60% EtOAc in hexane provided the re-
quired triol as a viscous foamy liquid.
HRMS (TOFMS ES+): m/z calcd for C27H39NO6Si + Na: 524.2444;
found: 524.2447 (M + Na).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 536–544

542
A. Bandyopadhyay et al.
PAPER
Deprotection of TBDPS Ethers: Formation of the Tetrols 19, 25,
31, and 33; General Procedure
HRMS (TOFMS ES+): m/z calcd for C11H21NO6 + Na: 286.1267;
found: 286.1269 (M + Na).
To a stirred solution of the appropriate triol (202 mg, 0.40 mmol) in
anhyd THF (4 mL), was added Bu4NF (157 mg, 0.60 mmol, 1.5
equiv) at r.t. and stirring was continued for 4 h at r.t. The reaction
mixture was concentrated under reduced pressure and the residual
mass was purified by column chromatography over silica gel using
8% MeOH in CHCl3 as eluent to give the corresponding tetrol.
One-Pot Hydrogenation and Removal of TBDPS Ether:
Formation of the Diols 20, 26, and 29; General Procedure
To a stirred solution of the appropriate olefin (0.25 mmol) in anhyd
THF (4 mL) was added 10% Pd/C (20 mg) followed by Bu4NF (98
mg, 0.37 mmol, 1.5 equiv) and the heterogeneous mixture was
stirred for 6 h at r.t. under H2 atmosphere. It was then filtered
through a Celite bed and the filtrate was concentrated under reduced
pressure to leave a crude viscous residual mass, which was directly
purified by column chromatography over silica gel using 55%
EtOAc in hexane as eluent to give the corresponding aminodiol
compound.
tert-Butyl (1S,2S,3S,4S,6R)-2,3,4,6-Tetrahydroxycyclohexyl-
carbamate (19)
Yield: 102 mg (96%); colorless amorphous powder; mp 156–
158 °C; [α]D –56.3 (c = 0.53, MeOH).
IR (KBr): 3395, 1682, 1665, 1528, 1333, 1306, 1249, 1175, 1030,
989, 905 cm–1.
1H NMR (400 Mz, DMSO-d6): δ = 5.85 (1 H, d, J = 7.6 Hz), 4.81 (1
H, br s), 4.61 (1 H, br s,), 4.39–4.34 (2 H, br d), 3.66–3.58 (4 H, m),
1.68 (1 H, br d, J = 10.4 Hz), 1.58 (1 H, q, J = 11.2 Hz), 1.37 (9 H,
s).
tert-Butyl (2R,6R)-2,6-dihydroxycyclohexylcarbamate (20)
Yield: 55 mg (94%); colorless powder; mp 134–136 °C; [α]D –46.0
(c = 0.92, CHCl3).
IR (KBr): 3408, 3289, 1663, 1539, 1368, 1253, 1178, 1070, 1004
cm–1.
1H NMR (400 Mz, CDCl3): δ = 5.23 (1 H, br s), 4.13 (1 H, s), 3.74–
3.67 (1 H, m), 3.38 (1 H, t, J = 12.4 Hz), 2.65 (1 H, br s), 2.06–2.03
(1 H, m), 1.82–1.78 (2 H, m), 1.68–1.64 (3 H, m), 1.46 (9 H, s),
1.32–1.29 (1 H, m).
13C NMR (100 MHz, CDCl3): δ = 155.3, 79.1, 77.4, 72.1, 71.7,
65.5, 54.6, 36.9, 28.2.
HRMS (TOFMS ES+): m/z calcd for C11H21NO6 + Na: 286.1267;
found: 286.1266 (M + Na).
13C NMR (100 MHz, CDCl3): δ = 157.3, 80.0, 70.0, 69.7, 59.2,
33.7, 31.9, 28.4, 18.1.
tert-Butyl (1S,2S,3S,4S,6S)-2,3,4,6-Tetrahydroxycyclohexylcar-
bamate (25)
Yield: 99 mg (93%); colorless powder; mp 144–146 °C; [α]D –8.7
(c = 0.66, MeOH).
MS (TOFMS ES+): m/z = 254 (M + Na).
Anal. Calcd for C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C,
57.24; H, 9.01; N, 5.91.
IR (KBr): 3395, 1682, 1665, 1528, 1333, 1306, 1249, 1175, 1030,
989, 905 cm–1.
1H NMR (400 Mz, DMSO-d6): δ = 6.02 (1 H, d, J = 9.6 Hz), 4.60–
4.48 (3 H, m), 4.17 (1 H, d, J = 5.2 Hz), 3.80 (1 H, br s), 3.67 (1 H,
br s), 3.52 (3 H, br s), 1.57 (2 H, d, J = 4.4 Hz), 1.27 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 155.2, 79.1, 73.0, 71.9, 68.5,
63.1, 49.7, 34.8, 28.2.
tert-Butyl (1S,2R,6S)-2,6-Dihydroxycyclohexylcarbamate (26)
Yield: 53 mg (93%); colorless liquid; mp 90–92 °C.
IR (KBr): 3370, 3289, 1670, 1533, 1372, 1291, 1248, 1178, 1038,
1012, 957 cm–1.
1H NMR (400 Mz, CDCl3): δ = 5.48 (1 H, br s), 4.03 (2 H, d, J = 3.8
Hz), 3.54 (1 H, br s), 2.95 (2 H, br s), 1.92–1.85 (3 H, m), 1.65–1.54
(3 H, m), 1.46 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 155.9, 79.7, 70.7, 53.4, 31.6,
28.4, 13.4.
HRMS (TOFMS ES+): m/z calcd for C11H21NO6 + Na: 286.1267;
found: 286.1265 (M + Na).
tert-Butyl (1S,2R,3R,4R,6R)-2,3,4,6-Tetrahydroxy-cyclohexyl-
carbamate (31)
Yield: 103 mg (97%); colorless powder; mp 196–198 °C; [α]D
–38.4 (c = 0.65, MeOH).
MS (TOFMS ES+): m/z = 254 (M + Na).
Anal. Calcd for C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C,
57.01; H, 9.03; N, 5.95.
IR (KBr): 3484, 3345, 1690, 1527, 1457, 1393, 1333, 1284, 1167,
1078, 1006, 863 cm–1.
1H NMR (400 Mz, DMSO-d6): δ = 6.41 (1 H, d, J = 6.8 Hz, NH),
4.50 (1 H, br s), 4.39–4.38 (3 H, m), 3.76 (1 H, br s), 3.54 (1 H, br
s), 3.34 (1 H, br s), 3.15 (1 H, d, J = 7.6 Hz), 3.04 (1 H, q, J = 8.4
Hz), 1.84 (1 H, br d, J = 12.8 Hz), 1.38 (9 H, s), 1.32–1.28 (1 H, m).
tert-Butyl (1R,2R,6S)-2,6-Dihydroxycyclohexylcarbamate (29)
Yield: 56 mg (96%); colorless powder; mp 176–178 °C.
IR (KBr): 3434, 3306, 1655, 1558, 1449, 1368, 1321, 1170, 1042,
1022, 946 cm–1.
1H NMR (400 Mz, CDCl3): δ = 4.89 (1 H, br s), 3.42–3.35 (2 H, m),
3.25–3.19 (1 H, m), 2.93 (2 H, br s), 2.05–2.00 (2 H, m), 1.76–1.71
(1 H, m), 1.46 (9 H, s), 1.40–1.23 (3 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 157.0, 77.6, 71.2, 63.2, 34.5,
28.8, 20.4.
13C NMR (100 MHz, CDCl3): δ = 156.2, 77.0, 75.2, 70.8, 67.6,
66.4, 60.2, 37.8, 28.3.
HRMS (TOFMS ES+): m/z calcd for C11H21NO6 + Na: 286.1267;
found: 286.1265 (M + Na).
Diastereomeric Mixture of Tetrols 33
Yield (combined): 96 mg (91%); colorless powder; mp 152–
154 °C.
MS (TOFMS ES+): m/z = 254 (M + Na).
Anal. Calcd for C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C,
57.23; H, 9.31; N, 6.18.
IR (KBr): 3482, 2924, 1688, 1664, 1540, 1416, 1369, 1244, 1164,
1131, 1019, 952 cm–1.
tert-Butyl (3aS,4S,5S,6R,7aS)-4-(tert-Butyldiphenylsilyloxy)-6-
hydroxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxol-5-ylcarba-
mate (21)
To a stirred solution of the aminotriol 18 (200 mg, 0.40 mmol) in
anhyd CH2Cl2 (2 mL), was added 2,2-dimethoxypropane (0.20 mL,
1.60 mmol, 4 equiv), followed by a catalytic amount p-TsOH at r.t.
under N2 atmosphere. The resulting solution was stirred for 0.5 h.
After completion of reaction, it was quenched with solid NaHCO3
(0.5 g) and the solvent was removed in vacuo. The crude mass was
1H NMR (400 Mz, DMSO-d6): δ = 6.40 (0.5 H, d, J = 8.4 Hz, NH),
6.02 (1 H, br s), 4.84–4.73 (3 H, m), 4.50 (2 H, br s), 4.40 (0.5 H, br
s), 4.36–4.34 (1 H, m), 4.16–4.15 (0.5 H, br s), 3.77 (3 H, br s), 3.63
(1 H, br s), 3.17 (2 H, m), 1.85 (1 H, m), 1.72 (2 H, br d), 1.38 (16
H, s), 1.17 (1 H, t, J = 7.2 Hz).
13C NMR (100 MHz, CDCl3): δ = 156.2, 155.2, 79.1, 77.6, 75.1,
70.8, 67.6, 66.4, 48.6, 38.7, 33.2, 28.3, 28.2, 23.0, 13.4.
Synthesis 2013, 45, 536–544
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diversity-Oriented Synthesis of Aminocyclohexitols
543
purified by column chromatography over silica gel using 10%
EtOAc in hexane as eluent to give the single acetonide 21 as a col-
orless oily liquid (207 mg, 96%); [α]D –5.9 (c = 1.32, CHCl3).
(3) Kameda, Y.; Asano, N.; Yoshikawa, M.; Matsui, K.
J. Antibiot. 1980, 33, 1573.
(4) Horii, S.; Iwasa, T.; Mizuta, E.; Kameda, Y. J. Antibiot.
1971, 24, 59.
IR (KBr): 3427, 2930, 1701, 1504, 1367, 1219, 1171, 1112, 1051,
740, 703 cm–1.
(5) Kameda, Y.; Asano, N.; Yoshikawa, M.; Takeuchi, M.;
Yamaguchi, T.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot.
1984, 37, 1301.
(6) Mahmud, T. Nat. Prod. Rep. 2003, 20, 137.
1H NMR (400 Mz, CDCl3): δ = 7.66–7.62 (4 H, m), 7.47–7.38 (6 H,
m), 4.82 (1 H, br s), 4.35 (1 H, q, J = 6.4 Hz), 4.16 (1 H, br s), 4.0–
3.97 (1 H, m), 3.85 (1 H, q, J = 5.2 Hz), 3.70 (1 H, dt, J = 7.6, 2.8
Hz), 2.85 (1 H, br s), 2.35 (1 H, td, J = 10.0, 4.8 Hz), 1.88 (1 H, br
s), 1.40 (9 H, s), 1.38 (3 H, s), 1.16 (3 H, s), 1.10 (9 H, s).
13C NMR (100 MHz, CDCl3): δ = 156.8, 135.8, 135.7, 133.0, 132.8,
130.2, 130.1, 128.0, 127.9, 108.8, 79.7, 76.6, 72.3, 72.2, 68.8, 55.8,
34.2, 28.3, 27.5, 27.1, 26.9, 25.1, 19.4.
(7) (a) Pandey, G.; Tiwari, K. N.; Puranik, V. G. Org. Lett.
2008, 10, 3611. (b) Kurbanoglu, N. I.; Celik, M.; Kilic, H.;
Alp, C.; Sahin, E.; Balci, M. Tetrahedron 2010, 66, 3485.
(c) Alegert, C.; Benet-Beholtz, J.; Riera, A. Org. Lett. 2006,
8, 3069. (d) Donohoe, T.; Johnson, P. D.; Pye, R. J.; Keenan,
M. Org. Lett. 2005, 7, 1275. (e) Gupta, P.; Pal, A. P. J.;
Reddy, Y. S.; Vankar, Y. D. Eur. J. Org. Chem. 2011, 1166.
(f) Chakraborty, C.; Vyavahare, V. P.; Puranik, V. G.;
Dhavale, D. D. Tetrahedron 2008, 64, 9574. (g) Mehta, G.;
Lakshminath, S.; Talukdar, P. Tetrahedron Lett. 2002, 43,
335. (h) Radha Krishna, P.; Reddy, P. S. Synlett 2009, 209.
(8) For some reports, see: (a) Gomez, A. M.; Moreno, E.; Uriel,
C.; Jarosz, S.; Valverde, S.; Lopez, J. C.
MS (TOFMS ES+): m/z = 564 (M + Na).
Anal. Calcd for C30H43NO6Si: C, 66.51; H, 8.00; N, 2.59. Found: C,
66.38; H, 8.11; N, 2.72.
tert-Butyl (3aR,4S,5S,6R,7aS)-4,6-Dihydroxy-2,2-dimethyl-
hexahydrobenzo[d][1,3]dioxol-5-ylcarbamate (22)
To a stirred solution of the TBDPS ether 21 (108 mg, 0.2 mmol) in
anhyd THF (2 mL), Bu4NF (80 mg, 0.30 mmol, 1.5 equiv) was add-
ed at r.t. and stirring was continued for 4 h at r.t. The reaction mix-
ture was concentrated under reduced pressure and the residual mass
was purified by column chromatography over silica gel using 60%
EtOAc in PE as eluent to give the diol 22 as a colorless solid (58 mg,
96%); mp 166–168 °C (CHCl3–MeOH); [α]D –39.2 (c = 1.1,
MeOH).
Tetrahedron:Asymmetry 2005, 16, 2401. (b) Diaz, L.; Casas,
J.; Bujons, J.; Llebaria, A.; Delgado, A. J. Med. Chem. 2011,
54, 2069. (c) Diaz, L.; Bujons, J.; Casas, J.; Llebaria, A.;
Delgado, A. J. Med. Chem. 2010, 53, 5248. (d) Ogawa, S.;
Kobayashi, Y.; Kobayama, K.; Jimbo, M.; Inokuchi, J.
Bioorg. Med. Chem. 1998, 6, 1955.
(9) For some reports, see; (a) Mehta, G.; Mohanrao, R.;
Katukojvala, S.; Landais, Y.; Sen, S. Tetrahedron Lett.
2011, 52, 2893. (b) Mehta, G.; Pallavi, K.; Katukojvala, S.
Tetrahedron Lett. 2009, 50, 4519. (c) Shing, T. K. M.;
Wong, W. F.; Ikeno, T.; Yamada, T. Org. Lett. 2007, 9, 207.
(d) Girard, E.; Desvergnes, V.; Tarnus, C.; Landais, Y. Org.
Biomol. Chem. 2010, 8, 5628. (e) Andriuzzi, O.; Gravier-
Pelletier, C.; Bertho, G.; Prange, T.; le Merrer, Y. Beilstein
J. Org. Chem. 2005, 1, 12. (f) Rassu, G.; Auzzas, L.; Pinna,
L.; Zambrano, V.; Zanardi, F.; Battistini, L.; Gaetani, E.;
Curti, C.; Casiraghi, G. J. Org. Chem. 2003, 68, 5881.
(10) For some reports, see: (a) Kummeter, M.; Kazmaier, U. Eur.
J. Org. Chem. 2003, 3325. (b) Jotterand, N.; Vogel, P.;
Schenk, K. Helv. Chim. Acta 1999, 82, 821. (c) Kameda, Y.;
Kawashima, K.; Takeuchi, M.; Ikeda, K.; Asano, N.; Matsui,
K. Carbohydr. Res. 1997, 300, 259. (d) Ahmad, S.; Thomas,
L. H.; Sutherland, A. Org. Biomol. Chem. 2011, 9, 2801.
(e) Sureshan, K. M.; Ikeda, K.; Asano, N.; Watanabe, Y.
Tetrahedron 2008, 64, 4072. (f) Podeschwa, M. A. L.;
Plettenburg, O.; Altenbach, H. Org. Biomol. Chem. 2003, 1,
1919. (g) Shing, T. K. M.; Chen, Y.; Ng, W. Tetrahedron
2011, 67, 6001.
IR (KBr): 3470, 3375, 3422, 2977, 1682, 1519, 1391, 1460, 1370,
1245, 1170, 1042 cm–1.
1H NMR (400 Mz, DMSO-d6): δ = 6.13 (1 H, d, J = 7.6 Hz, NH),
5.10 (1 H, d, J = 4 Hz, OH), 4.47 (1 H, d, J = 5.2 Hz), 4.20 (1 H, q,
J = 7.2 Hz), 3.97 (1 H, t, J = 5.2 Hz), 3.90 (1 H, br s), 3.58–3.46 (2
H, m), 2.03 (1 H, td, J = 10.8, 4.8 Hz), 1.54 (1 H, dq, J = 9.2, 4.8
Hz), 1.42 (3 H, s), 1.39 (9 H, s), 1.24 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 155.9, 108.2, 78.1, 77.8, 72.5,
68.7, 64.3, 55.8, 37.3, 28.7, 28.6, 26.5.
MS (TOFMS ES+): m/z = 326 (M + Na).
Anal. Calcd for C14H25NO6: C, 55.43; H, 8.31; N, 4.62. Found: C,
55.61; H, 8.53; N, 4.50.
Acknowledgment
Financial assistance from DST, New Delhi (Grant No. SR/S1/OC-
35/2009), is gratefully acknowledged. We are also thankful to CSIR
(New Delhi) for a fellowship to A.B.
(11) (a) Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18.
(b) Santoso, S.; Kemmer, T.; Trowitzsch, W. Liebigs Ann.
Chem. 1981, 658. (c) Avenoza, A.; Cativiela, C.; Corzana,
F.; Peregrina, J. M.; Zurbano, M. M. Synthesis 1997, 1146.
(12) Chattopadhyay, S. K.; Bandyopadhyay, A. Tetrahedron
Lett. 2011, 52, 3942.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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(17) CCDC 896721 contains the crystal data for compound 22
[Unit cell parameters: a = 5.4911(8); b = 10.3246 (14);
c = 13.684 (2); β = 101.172 (3). Space group: P21].
These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Synthesis 2013, 45, 536–544
© Georg Thieme Verlag Stuttgart · New York