Divergent synthesis of various iminocyclitols from d-ribose

Article abstract of DOI:10.1039/c5ob01042j

A very efficient route to the diastereoselective synthesis of polyhydroxy pyrrolidines, piperidines and azepanes from an aldehyde derivative of ribose is reported. Asymmetric α-amination of aldehydes using proline catalysed hydrazination is the key step in the synthesis. The method utilizes the stereocenters present in ribose and the extra carbon atoms present in the target molecules are incorporated using Wittig reactions. The incorporation of the amino group is carried out asymmetrically to account for additional stereocenters. This synthetic route to iminocyclitols has the potential to be extended for the synthesis of a large class of such compounds starting from other sugar derived aldehydes.

Full text of DOI:10.1039/c5ob01042j

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Divergent synthesis of various iminocyclitols
from D-ribose†
Cite this: DOI: 10.1039/c5ob01042j
Ramu Petakamsetty, Vipin Kumar Jain, Pankaj Kumar Majhi and
Ramesh Ramapanicker*
A very efficient route to the diastereoselective synthesis of polyhydroxy pyrrolidines, piperidines and aze-
panes from an aldehyde derivative of ribose is reported. Asymmetric α-amination of aldehydes using
proline catalysed hydrazination is the key step in the synthesis. The method utilizes the stereocenters
present in ribose and the extra carbon atoms present in the target molecules are incorporated using
Wittig reactions. The incorporation of the amino group is carried out asymmetrically to account for
additional stereocenters. This synthetic route to iminocyclitols has the potential to be extended for the
synthesis of a large class of such compounds starting from other sugar derived aldehydes.
Received 22nd May 2015,
Accepted 30th June 2015
DOI: 10.1039/c5ob01042j
www.rsc.org/obc
Dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP, 1a) along
with its isomers are first among the pyrrolidine class of imino-
Introduction
Iminocyclitols are sugar analogues with a secondary or tertiary sugars to be isolated from natural sources. They are known to
amino group replacing the oxygen atom in the ring. These inhibit both α- and β-glycosidases.3 1- and 2-deoxynojirimycin
compounds, consisting of a 5, 6 or 7 membered polyhydroxy derivatives 2a, 2b, 3a and 3b are among the 6-membered
N-heterocyclic frameworks are generally referred to as imino- iminosugars, which exhibit inhibitory activity towards α-gluco-
sugars or azasugars (Fig. 1). They are potential inhibitors of sidases and ceramide glucosyltransferases (CGT).4 Compounds
various carbohydrate processing enzymes1 and are key to the 4a and 4b are polyhydroxyazepane derivatives and are
development of therapeutics for a wide range of diseases such examples of 7-membered iminocyclitols, which have received
as diabetes, cancer and viral infections including AIDS.2 2,5- relatively less attention in terms of synthesis and evaluation of
inhibitory activity.5 Stereoselective routes to the synthesis of
these compounds are of great interest and significance due to
their potential in therapeutics.
Incorporation of an amino group stereoselectively into a
cyclic or linear polyhydroxy system is the important step in
most of the reported syntheses of these compounds. The in-
corporation of the amino group is achieved by nucleophilic
displacement of a leaving group with azide anions or with alkyl
amines.6–11 These routes are generally limited to the possi-
bility of synthesizing only one diastereomer of the molecule
from a starting compound. It will therefore, be useful to have
strategies, where at least two diastereomers of the target mole-
cules can be synthesized from the same intermediate by
switching a chiral catalyst to generate new stereocentres with
control. The incorporation of additional carbon atoms into a
synthetic intermediate is achieved either by Wittig reaction or
using organometallic reagents in general. Generation of new
Fig. 1 Iminosugars synthesized in this report.
stereocentres during or after the incorporation of additional
Department of Chemistry and Center for Environmental Science and Engineering,
carbon atoms on a synthetic intermediate is often done
through the asymmetric induction offered by the existing
stereocentres within the intermediate.
We report here a divergent method for the synthesis of
various iminocyclitols starting from ribose. The method opens
Indian Institute of Technology Kanpur, Kanpur, 208016, India.
E-mail: rameshr@iitk.ac.in
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of all the compounds, 2D NMR spectra of the final compounds
and HPLC data. See DOI: 10.1039/c5ob01042j
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up the possibility of synthesizing target molecules with higher
The aldehyde 9 was treated with dibenzyl azodicarboxylate
number of carbon atoms and stereocentres than the starting in the presence of both L- and D-proline (0.1 equiv.) in separate
material used. Wittig reactions were used to incorporate reactions to get the hydrazino aldehydes, which were reduced
additional carbon atoms and organocatalytic asymmetric to the corresponding primary alcohols 10a and 10b in one-pot.
amination of aldehydes12 was used for the generation of new The diastereomeric ratios of these compounds were estimated
chiral centres functionalized with nitrogen atoms. The use of using chiral HPLC and were established by comparing the
L- and D-proline separately as catalysts offers the possibility to chromatograms with that of a 1 : 1 mixture of the diastereo-
generate two different diastereomers with high selectivity.13 mers obtained through reactions catalyzed by DL-proline.17 The
Although, proline catalysed asymmetric amination has been asymmetric α-hydrazination reaction follows a very ordered
used widely in synthesis13d,e,14 it has not been explored to the transition state, which is similar to the one proposed by List
same extent in carbohydrate chemistry.13a,15
and Jorgensen.12 The orientation of the carboxylic acid func-
tion of proline decides the outcome of the reaction and thus
the stereochemistry of the products. While L-proline prefers
the attack on the Re-face, the reaction using D-proline proceeds
on the Si-face.12 While asymmetric hydrazination catalyzed by
L-proline gave 10a as a single diastereomer, the reaction cata-
lyzed by D-proline yielded 10b and 10a in a 90 : 10 ratio. The
lower selectivity achieved in one of these α-functionalization
reactions is expected and is accounted for based on the influ-
ence of the stereochemistry of the β-carbon. Such differences
in selectivity during asymmetric hydrazination using L- and
D-proline on the same substrate can be more prominent depend-
ing on the nature of the substrate.13b,e Similar observations in
the case of proline catalyzed aldol reactions have extensively
been studied.7k
Hydrogenolysis of the hydrazino groups in 10a and 10b
using freshly prepared RANEY® Ni and H2 yielded the corres-
ponding amino compounds, which underwent immediate
cyclization by displacing the mesylate to give the pyrrolidine
derivatives 11a and 11b in 78% and 73% yields respectively.
The targeted iminocyclitols 1a and 1b were obtained in overall
yields of 27% and 21%, respectively by acidolysis of the pro-
tecting groups using 4 N HCl in EtOAc (Scheme 3). The absol-
ute stereochemistry of 1a was established by detailed NMR
analysis of a dibenzyl derivative prepared from 11a.18 Com-
pound 1b was a meso derivative with no optical activity. The
spectral data for 1a and 1b were compared with those available
in the literature and found to be matching.6c
Results and discussion
Our strategy towards the synthesis of these molecules is based
on the synthesis of an amino alcohol derivative with a suitably
positioned leaving group (mesylate). These amino alcohols are
prepared by proline catalyzed asymmetric amination of alde-
hydes derived from ribose. A nucleophilic substitution of the
mesylate group by the free amino group leading to the for-
mation of 5, 6 or 7 membered rings was expected (Scheme 1).
The syntheses of the 5-membered iminocyclitols 1a and 1b
were achieved from the aldehyde 9, synthesized from the com-
mercially available ribose derivative 5 (Scheme 2). Wittig reac-
tion of 5 using methyltriphenylphosphonium bromide yielded
the alkene 6.16 The secondary hydroxyl group in 6 was con-
verted to a mesylate to get 7 in very high yield. Hydroboration/
oxidation of 7 gave the primary alcohol 8, which on Swern oxi-
dation yielded the aldehyde 9 (Scheme 2).
Scheme 1 Retrosynthetic strategy for 5,
6
and
7
membered
iminosugars.
The deoxynojirimycin derivatives 2a and 2b were syn-
thesized using a similar strategy as the one used for the syn-
thesis of 1a and 1b through 9. An aldehyde derivative 16 was
prepared from 6 by using a different strategy for protecting
and activating the hydroxyl groups. Accordingly, the secondary
hydroxyl group in 6 was protected using MOMCl to get 12 in
89% yield. The TBDPS group in 12 was removed with TBAF to
get the primary alcohol 13, which was treated with MsCl to get
14. Hydroboration/oxidation of 14 gave the primary alcohol 15,
which on Swern oxidation yielded the required aldehyde 16
(Scheme 4). Following the strategy used for the synthesis of 1a
and 1b from 9, 2a and 2b were synthesized from 16 with
overall yields of 19% and 17%, respectively (Scheme 5). The
diastereoselectivity of the L-proline catalyzed reaction was very
high (95 : 5) in favour of 17a. However, the corresponding
D-proline catalyzed reaction was only moderately selective. It has
to be noted that the DL-proline catalyzed reaction on 16 pro-
ceeded to give 17a and 17b as a 60 : 40 mixture. Although 17a
Scheme 2 Synthesis of aldehyde 9.
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Scheme 3 Synthesis of 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine
derivatives 1a and 1b.
Scheme 5 Synthesis of deoxynojirimycin derivatives 2a and 2b.
ester obtained was reduced using Pd/C and H2 to get the
hydroxy ester 19 in 85% yield (Scheme 6). The secondary
hydroxyl group was converted to a mesylate using MsCl in the
presence of triethylamine to get 20. The ester group in 20 was
reduced using DIBAL-H to get the aldehyde 21 required for the
preparation of 3a and 3b (Scheme 6).
Hydrazination of 21 under similar conditions used for the
synthesis of 10 from 9, using both L- and D-proline yielded 22a
and 22b in good yields. Unlike the α-functionalization of 9 and
16, the reaction of the aldehyde 21 proceeded with very high
diastereoselectivity with L- and D-proline. The absence of
inherent chirality on the β-carbon atom allows the asymmetric
Scheme 4 Synthesis of aldehyde 16.
and 17b are not separable by column chromatography, the imino-
cyclitol derivatives 18a and 18b are separated easily. If 2a
and 2b are required to be synthesized, use of DL-proline as a
catalyst and separation of 18a and 18b are preferred. The
stereochemistry of 2a and 2b was confirmed using NMR
studies18 and the spectral data were also found to match with
those reported in the literature.7i,10d
The homonojirimycin derivatives 3a and 3b and the
7-hydroxymethyl-3,4,5-trihydroxyazepane derivatives 4a and 4b
were synthesized by increasing the number of carbon atoms in
the ribose derivative 5 by two through a Wittig reaction using
the stabilized ylide, Ph3PvCHCOOEt. The α,β-unsaturated Scheme 6 Synthesis of aldehyde 21.
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induction to be controlled entirely by proline. The amine gen-
erated by hydrogenolysis of 22 with RANEY® Ni did not
undergo cyclization in situ unlike the reaction of 17. The crude
reaction mixture had to be heated in the presence of triethyl-
amine to displace the mesylate and get the piperidine deriva-
tives 23a and 23b. It may be assumed that the secondary
mesylate was difficult to be displaced in the presence of an
adjacent O-TBDPS group. The homonojirimycin derivatives 3a
and 3b were obtained by acidolysis of 23a and 23b, respectively
using 4 N HCl in EtOAc (Scheme 7). Detailed NMR analysis of
the benzyl derivatives of 3a and 3b prepared by the dibenzyl-
ation of 23 confirmed their structures to be as given in
Scheme 7.18
The aldehyde 27 required for the preparation of 4a and 4b
was prepared from 19 by using a different protection and acti-
vation strategy for the hydroxyl groups. Similar to the prepa-
ration of aldehyde 16, the primary hydroxyl group was converted
to a mesylate and the adjacent secondary hydroxyl group was
protected as a MOM derivative to get 27 (Scheme 8). Asymmetric
hydrazination of 27 using L- and D-proline proceeded in good
yield and high diastereoselectivity, as in the case of 22a and
22b, to give 28a and 28b, respectively (Scheme 9).17 Hydrogeno-
lysis followed by cyclization using triethylamine yielded the
azepane derivatives 29a and 29b from 28a and 28b, respectively.
Acidolysis of 29a and 29b gave the target molecules 4a and 4b in
overall yields of 20% and 19% (Scheme 9). Dibenzyl derivatives
made from 29 were analyzed using NMR spectroscopy to
confirm the stereochemistry of 4a and 4b.18
Scheme 8 Synthesis of aldehyde 27.
Scheme 9 Synthesis of 7-hydroxymethyl-3,4,5-trihydroxyazepanes 4a
and 4b.
Conclusions
We have developed a divergent strategy for synthesizing
various iminocyclitols from ribose and have successfully
applied this in the synthesis of 5, 6 and 7 membered imino-
sugars. The absolute configuration of the stereocenter bearing
the imino group is switched by changing the catalyst from
L-proline to D-proline. While most of these reactions proceeded
with very high diastereoselectivity, induction by the adjacent
chiral centres reduced the diastereoselectivity achieved in the
Scheme 7 Synthesis of homonojirimycin derivatives 3a and 3b.
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reactions catalyzed by D-proline in two of the examples. In (c 1.3, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.69–7.66 (m, 4H),
comparison with other methods available for the synthesis of 7.45–7.37 (m, 6H), 6.01 (ddd, J = 16.6, 10.3, 6.3 Hz, 1H), 5.40
similar compounds, the current strategy allows the preparation (d, J = 17.1 Hz, 1H), 5.27 (d, J = 10.3 Hz, 1H), 4.69 (t, J = 6.5 Hz,
of target molecules with increased number of carbon atoms 1H), 4.15 (dd, J = 8.6, 6.3 Hz, 1H), 3.86 (dd, J = 10.3, 2.9 Hz,
and stereocenters to that of the starting compounds. The 1H), 3.82–3.78 (m, 1H), 3.71 (bs, 1H), 2.55 (bs, 1H), 1.39
method reported here has the potential to be a very useful (s, 3H), 1.34 (s, 3H), 1.07 (s, 9H) ppm; 13C NMR (125 MHz,
strategy for making a large number of iminocyclitols by CDCl3): δ 135.6, 134.1, 129.9, 127.8, 117.7, 108.7, 78.9, 77.5,
varying the sugar unit used as the starting compound. It pro- 69.9, 65.3, 27.8, 26.9, 25.5, 19.4 ppm; IR νmax (thin film): 3460,
vides a general method for the synthesis of imino and aza- 2030, 1585 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
sugars from a lower sugar homolog.
C25H34NaO4Si 449.2124; found 449.2128.
Procedure for mesylation of 6 to get 7. Triethylamine
(0.6 mL, 4.4 mmol, 2.2 equiv.) followed by mesyl chloride
(0.17 mL, 2.2 mmol, 1.1 equiv.) were added to a stirred solu-
tion of 6 (0.85 g, 2 mmol, 1 equiv.) in dichloromethane
(10 mL) at 0 °C, and stirred the reaction mixture for 2 h at
room temperature. After the complete disappearance of 6 on
TLC, the reaction mixture was quenched with water. The
organic layer was extracted with dichloromethane (2 × 10 mL),
and the combined organic phases were washed with water
(1 × 20 mL), dried over anhydrous Na2SO4, filtered, concen-
trated, and purified by column chromatography.
Experimental section
General experimental methods
All the commercially available reagents were used directly
without any further purification. All the reactions were carried
out under an inert atmosphere unless otherwise mentioned.
Acetonitrile was distilled initially from phosphorus pentoxide
and subsequently from calcium hydride; DCM was distilled
from calcium hydride. Yields reported are for purified com-
pounds using column chromatography. All the reactions were
monitored by analytical thin layer chromatography carried
out on 0.25 mm Merck silica gel plates (60F-254) using UV
light as a visualizing agent and ninhydrin, 5% H2SO4 as a
staining agent. Merck silica gel (particle size 60–120 and
100–200 mesh) was used for column chromatography. All
proton NMR spectra were recorded at either 400 or 500 MHz
using a Jeol spectrometer and 13C NMR spectra were recorded
The same procedure was used for the preparation of 14, 20
and 26.
Compound 7. Column chromatography (petroleum ether/
EtOAc, 8 : 2); oily liquid (0.96 g, 1.9 mmol, 95%); [α]2D5 = −0.45
(c 0.20, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.68–7.64 (m,
4H), 7.45–7.37 (m, 6H), 5.79 (ddd, J = 17.1, 8.6, 6.8 Hz, 1H),
5.35 (d, J = 18.6 Hz, 1H), 5.28–5.25 (m, 1H), 4.74–4.71 (m, 1H),
4.68 (t, J = 6.8 Hz, 1H), 4.51–4.48 (m, 1H), 3.98–3.95 (m, 1H),
3.92–3.88 (m, 1H), 3.02 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H), 1.07
(s, 9H) ppm; 13C NMR (125 MHz, CDCl3): δ 135.7, 132.8, 132.7,
132.4, 130.1, 130.0, 127.9, 127.8, 119.5, 109.0, 81.9, 78.0, 76.3,
63.0, 39.3, 27.0, 26.8, 25.0, 19.2 ppm; IR νmax (thin film): 3072,
1
at 100 or 125 MHz. H NMR splitting pattern was designated
as singlet (s), doublet (d), doublet of doublets (dd), triplet (t),
multiplet (m), and broad singlet (bs). IR spectra were recorded
as a thin film for liquids and as KBr pellets for solids. High-
resolution mass spectra were recorded using a Waters Q/Tof
Premier micromass HAB 213 spectrometer with an ESI source.
Optical rotation was measured using a 5.0 ml cell with a 10
dm path length and is reported as [α]2D5 (c in g per 100 mL
solvent). The diastereoselectivity was determined by chiral
HPLC analysis using a Daicel chiralpack OD-H column with a
254 nm UV detector and by using a mixture of isopropanol
and n-hexane as the eluent at 25 °C.
Procedure for the synthesis of 6 from 5. Potassium t-butox-
ide (0.8 g, 7.8 mmol, 3.9 equiv.) was added to the stirred solu-
tion of methyl triphenylphosphonium bromide (2.8 g, 8 mmol,
4 equiv.) in THF (30 mL) at 0 °C and the stirring was continued
at this temperature for 30 min; after 30 min the aldehyde (5)
(0.85 g, 2 mmol, 1 equiv.) in THF (10 mL) was added to the
reaction mixture dropwise and further stirred at room temp-
erature for 5 h. After the complete disappearance of 5 on TLC,
the reaction mixture was quenched with saturated ammonium
chloride (10 mL). The organic layer was extracted with diethyl
ether (2 × 20 mL), and the combined organic phases were
dried over anhydrous Na2SO4, filtered, concentrated, and puri-
fied by column chromatography.
1589 cm−1
; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for
C26H36NaO6SSi 527.1900; found 527.1897.
Compound 14. Column chromatography (petroleum ether/
EtOAc, 6 : 4); oily liquid (0.56 g, 1.8 mmol, 90%); [α]2D5 = +9.34
(c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3): δ 5.91–5.84 (m, 1H),
5.41 (d, J = 17.2 Hz, 1H), 5.26 (d, J = 10.3 Hz, 1H), 4.71 (t, J =
6.5 Hz, 1H), 4.66 (d, J = 6.9 Hz, 1H), 4.64 (d, J = 6.9 Hz, 1H),
4.53 (dd, J = 10.9, 2.3 Hz, 1H), 4.34 (dd, J = 10.8, 4.0 Hz, 1H),
4.26 (dd, J = 7.7, 6.5 Hz, 1H), 3.68–3.69 (m, 1H), 3.39 (s, 3H),
3.02 (s, 3H), 1.45 (s, 3H), 1.35 (s, 3H) ppm; 13C NMR
(125 MHz, CDCl3): δ 133.1, 118.0, 108.9, 97.3, 78.0, 76.1, 75.2,
70.0, 56.3, 37.3, 27.6, 25.2 ppm; IR νmax (thin film): 2988,
1643, 1546 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C12H22NaO7S 333.0984; found 333.0987.
Compound 20. Column chromatography (petroleum ether/
EtOAc, 9 : 1); oily liquid (1.04 g, 1.8 mmol, 90%); [α]2D5 = −1.08
(c 0.74, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.70–7.68
(m, 4H), 7.44–7.37 (m, 6H), 4.76 (m, 1H), 4.39 (t, J = 6.6 Hz,
1H), 4.22–4.18 (m, 1H), 4.13 (q, J = 7.4 Hz, 2H), 3.99–3.98
(m, 2H), 3.06 (s, 3H), 2.52–2.38 (m, 2H), 2.03–1.96 (m, 1H),
1.77–1.69 (m, 1H), 1.29 (s, 3H), 1.26–1.23 (m, 6H), 1.07 (s, 9H)
ppm; 13C NMR (125 MHz, CDCl3): δ 173.1, 135.7, 132.8, 130.0,
129.9, 127.9, 127.8, 108.5, 80.6, 76.2, 75.0, 63.4, 60.4, 39.4,
Compound 6. Column chromatography (petroleum ether/
EtOAc, 9 : 1); oily liquid (0.76 g, 1.78 mmol, 89%); [α]2D5 = −7.23
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30.9, 27.6, 26.8, 25.5, 24.9, 19.3, 14.3 ppm; IR νmax (thin film): Alcohol (1.04 g, 2 mmol, 1 equiv.) 8 in dichloromethane
3072, 1737, 1589 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd (1 mL) was added to the reaction mixture followed by dropwise
for C29H42NaO8SSi 601.2267; found 601.2270.
addition of triethyl amine (1.4 mL, 10 mmol, 5 equiv.), and
stirring was continued at the same temperature for 1 h. The
reaction mixture was allowed to attain room temperature and
was stirred for 2 h at this temperature. The reaction mixture
was diluted with dichloromethane (10 mL) and quenched by
the addition of water. The aqueous layer was acidified with 2 N
HCl, and extracted with dichloromethane (2 × 15 mL). The
organic phases were combined and were washed sequentially
with 1% HCl and saturated NaCl, followed by 5% NaHCO3.
The aqueous layer was extracted with dichloromethane
(10 mL), the combined organic phases were washed with
brine, dried using Na2SO4, filtered, concentrated and purified
by column chromatography.
Compound 26. Column chromatography (petroleum ether/
EtOAc, 1 : 1); oily liquid (0.73 g, 1.9 mmol, 95%); [α]2D5 = −1.1
(c 0.35, CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.76 (d, J =
6.8 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H), 4.58 (d, J = 11 Hz, 1H),
4.35 (dd, J = 10.9, 3.4 Hz, 1H), 4.21–4.17 (m, 1H), 4.17–4.13
(m, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.79 (d, J = 7.9 Hz, 1H), 3.40
(s, 3H), 3.03 (s, 3H), 2.56–2.50 (m, 1H), 2.44–2.37 (m, 1H),
1.99–1.92 (m, 1H), 1.80–1.72 (m, 1H), 1.38 (s, 3H), 1.30 (s, 3H),
1.23 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
δ 173.2, 108.4, 96.7, 76.5, 75.2, 74.4, 69.7, 60.4, 56.4, 37.3, 31.1,
28.0, 25.6, 24.9, 14.2 ppm; IR νmax (thin film): 1734 cm−1
;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H28NaO9S
407.1352; found 407.1351.
The same procedure was used for the preparation of 16
from 15.
Compound 9. Column chromatography (petroleum ether/
Procedure for hydroboration followed by oxidation of 7 to
get 8. Borane (1 M solution in THF – 4 mL, 4 mmol, 2 equiv.)
was added to the stirred solution of 7 (1.00 g, 2 mmol, EtOAc, 9 : 1); oily liquid (0.98 g, 1.9 mmol, 95%); [α]2D5 = +9.3
1 equiv.) in THF at 0 °C under a nitrogen atmosphere, and (c 0.8, CHCl3); 1H NMR (500 MHz, CDCl3): δ 9.73 (s, 1H),
stirred for 2 h. After the disappearance of 7 on TLC, 2 N NaOH 7.69–7.64 (m, 4H), 7.44–7.37 (m, 6H), 4.75–4.66 (m, 2H),
(8 mL, 16 mmol) and then 30% H2O2 (8 mL) were added and 4.42–4.39 (m, 1H), 4.00–3.95 (m, 2H), 3.02 (s, 3H), 2.88–2.70
stirring was continued for further 30 min at 0 °C. The reaction (m, 2H), 1.32 (s, 3H), 1.26 (s, 3H), 1.04 (s, 9H) ppm; 13C NMR
was quenched with saturated ammonium chloride, the organic (125 MHz, CDCl3): δ 199.5, 135.7, 132.6, 130.2, 130.0, 128.0,
layer was separated and the aqueous layer was extracted with 127.9, 108.8, 80.2, 74.1, 71.8, 63.2, 43.8, 39.5, 27.6, 26.9, 25.4,
ethyl acetate (2 × 25 mL). The combined organic phases were 19.2 ppm; IR νmax (thin film): 2740, 1728, 1589 cm−1; HRMS
dried over Na2SO4, filtered, concentrated, and purified by (ESI-TOF) m/z [M + NH4]+ calcd for C26H40NO7SSi 538.2295;
column chromatography.
found 538.2299.
Compound 16. Column chromatography (petroleum ether/
The same procedure was used for the preparation of 15
from 14.
EtOAc, 7 : 3); oily liquid (0.62 g, 1.92 mmol, 96%); [α]2D5 = +13.1
Compound 8. Column chromatography (petroleum ether/ (c 0.32, CHCl3); 1H NMR (500 MHz, CDCl3): δ 9.77 (s, 1H),
EtOAc, 7 : 3); oily liquid (0.75 g, 1.44 mmol, 72%); [α]D25
=
4.76–4.72 (m, 2H), 4.67 (d, J = 6.8 Hz, 1H), 4.59 (dd, J = 8.7 Hz,
−0.877 (c 0.23, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.69–7.66 1H), 4.34 (dd, J = 10.9, 3.2 Hz, 1H), 4.21 (dd, J = 5.9, 5.5 Hz,
(m, 4H), 7.43–7.37 (m, 6H), 4.77–4.75 (m, 1H), 4.40–4.35 1H), 3.71 (d, J = 8.7 Hz, 1H), 3.39 (s, 3H), 3.03 (s, 3H),
(m, 2H), 4.02–3.95 (m, 2H), 3.79–3.73 (m, 2H), 3.03 (s, 3H), 2.80–2.03 (m, 2H), 1.40 (s, 3H), 1.34 (s, 3H) ppm; 13C NMR
1.88–1.69 (m, 2H), 1.30 (s, 3H), 1.37 (s, 3H), 1.08 (s, 9H) ppm; (125 MHz, CDCl3): δ 199.7, 108.9, 96.5, 74.6, 74.4, 72.1, 69.1,
13C NMR (125 MHz, CDCl3): δ 135.7, 132.7, 130.1, 130.0, 127.9, 56.4, 43.8, 37.4, 27.9, 25.4 ppm; IR νmax (thin film): 2937, 2726,
127.8, 108.6, 81.1, 76.2, 75.2, 63.3, 61.0, 39.5, 32.3, 27.5, 26.9, 1727, 1455 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
25.4, 19.3 ppm; IR νmax (thin film): 3486, 3080, 1546 cm−1
;
C12H23O8S 327.1114; found 327.1118.
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C26H38NaO7SSi
545.2005; found 545.2009.
Procedure for asymmetric α-hydrazination of 9 to get
10. The aldehyde 9 (1.04 g, 2 mmol, 1 equiv.) in dry aceto-
nitrile (15 mL) was treated with dibenzylazodicarboxylate
(0.59 g, 2 mmol, 1 equiv.) and proline (either D or L, 0.02 g,
10 mol%) at 0 °C. The mixture was stirred for 2 h and the
temperature was raised to 20 °C over a period of 1 h. The
mixture was stirred until the solution turned colorless from
yellow (1 to 2 h) and was cooled to 0 °C and then treated with
sodium borohydride (0.05 g) in ethanol (15 mL). The stirring
was continued for 5 min and the reaction was quenched
with saturated ammonium chloride solution (20 mL). The
organic layer was extracted with ethyl acetate (3 × 30 mL)
and the combined organic phases were dried over anhydrous
Na2SO4, filtered, concentrated, and purified by column
chromatography.
Compound 15. Column chromatography (petroleum ether/
EtOAc, 4 : 6); oily liquid (0.46 g, 1.4 mmol, 70%); [α]2D5 = −3.16
(c 0.32, CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.74 (d, J =
6.8 Hz, 1H), 4.69 (d, J = 6.8 Hz, 1H), 4.58 (dd, J = 10.9, 1.7 Hz,
1H), 4.39–4.30 (m, 2H), 4.17–4.14 (m, 1H), 3.83–3.77 (m, 3H),
3.39 (s, 3H), 3.03 (s, 3H), 1.85–1.77 (m, 2H), 1.40 (s, 3H), 1.32
(s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 108.6, 96.7, 76.3,
75.3, 74.6, 69.7, 61.0, 56.4, 37.3, 31.6, 27.9, 25.5 ppm; IR νmax
(thin film): 3460, 2938, 1455 cm−1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C12H24O8S 329.1270; found 329.1273.
Procedure for oxidation of 8 to get 9. Anhydrous dimethyl
sulfoxide (0.34 mL, 4.8 mmol, 2.4 equiv.) was added dropwise
to a stirred solution of oxalyl chloride (0.19 mL, 2.3 mmol,
1.15 equiv.) in dry dichloromethane (5 mL) at −78 °C under a
nitrogen atmosphere and stirring was continued for 15 min.
Note: The hydrazine derivatives give complex NMR spectra
at room temperature due to the existence of rotamers.
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The same procedure was used for the preparation of 17, 22 (c 0.8, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.69–7.63 (m, 4H),
and 28.
7.42–7.30 (m, 16H), 6.49–6.44 (m, 1H), 5.25–5.12 (m, 4H),
4.69–4.62 (m, 1H), 4.30–4.19 (m, 2H), 4.14–4.03 (m, 1H),
3.69–3.84 (m, 2H), 1.30 (s, 3H), 3.55–3.39 (m, 2H), 3.04–2.97
(m, 3H), 1.70–1.45 (m, 1H), 1.09–1.02 (m, 14H) ppm; 13C NMR
(125 MHz, CDCl3): δ 159.0, 158.3, 156.9, 156.6, 135.9, 135.7,
135.2, 132.6, 130.1, 130.0, 128.7, 128.6, 128.5, 128.2, 127.9,
127.8, 127.7, 127.6, 108.7, 108.5, 81.0, 80.8, 75.5, 75.4, 75.2,
68.6, 68.4, 68.1, 63.5, 63.3, 61.8, 61.6, 59.9, 58.7, 39.6, 39.5,
39.4, 27.2, 27.1, 26.9, 24.8, 24.6, 19.3 ppm; IR νmax (thin film):
3473, 1721, 1588 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C43H54N2NaO11SSi 857.3115; found 857.3115.
Compound 10a. Column chromatography (petroleum ether/
EtOAc, 8 : 2); oily liquid (1.25 g, 1.52 mmol, 76%); [α]2D5 = +2.80
(c 0.25, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.74–7.62
(m, 4H), 7.46–7.26 (m, 16H), 5.19–5.09 (m, 3H), 4.84–4.67
(m, 2H), 4.52–4.27 (m, 4H), 4.03–3.91 (m, 2H), 3.80 (d, J =
12 Hz, 1H), 3.57–3.55 (m, 1H), 2.81 (s, 3H), 1.27 (s, 3H), 1.23
(s, 3H), 1.10 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.5,
155.9, 141.0, 135.8, 135.6, 135.1, 132.5, 132.3, 130.3, 130.1,
128.7, 128.6, 128.5, 128.2, 128.1, 127.9, 127.6, 127.0, 109.5,
82.7, 76.7, 73.5, 68.6, 65.3, 62.9, 60.4, 57.6, 38.5, 26.9, 26.5,
25.2 ppm; IR νmax (thin film): 3464, 3378, 1717, 1588 cm−1
;
Compound 22b. Column chromatography (petroleum ether/
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C42H52N2O11SSi EtOAc, 7 : 3); oily liquid (1.25 g, 1.5 mmol, 75%); [α]D25 = +23.5
843.2959; found 843.2962.
(c 1.6, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.68–7.65 (m, 4H),
7.44–7.30 (m, 16H), 7.11–7.03 (m, 1H), 5.22–5.12 (m, 4H),
4.70–4.64 (m, 1H), 4.29–4.20 (m, 2H), 4.14–4.05 (m, 1H),
3.96–3.88 (m, 2H), 3.50–3.42 (m, 2H), 3.01–2.97 (m, 3H),
1.76–1.47 (m, 2H), 1.32–1.23 (m, 6H), 1.06 (s, 9H) ppm;
13C NMR (125 MHz, CDCl3): δ 159.1, 158.7, 156.9, 156.2, 136.0,
135.7, 135.6, 135.5, 135.3, 132.7, 132.6, 130.2, 130.0, 128.7,
128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.7, 127.6,
109.1, 108.7, 108.5, 81.0, 80.8, 80.6, 80.2, 75.5, 75.4, 75.2, 74.3,
74.1, 73.6, 68.6, 68.4, 68.3, 68.2, 68.1, 67.9, 63.7, 63.6, 63.5,
63.3, 62.3, 62.2, 39.6, 39.4, 28.2, 28.1, 27.1, 26.9, 25.9,
25.8, 24.8, 24.6, 19.3 ppm; IR νmax (thin film): 3317,
1722, 1586 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C43H55N2O11SSi 835.3296; found 835.3292.
Compound 10b. Column chromatography (petroleum ether/
EtOAc, 8 : 2); oily liquid (1.13 g, 1.38 mmol, 69%); [α]2D5 = +4.6
(c 0.46, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.72–7.64 (m,
4H), 7.42–7.24 (m, 16H), 6.74 (bs, 1H), 5.30–5.05 (m, 4H),
4.86–4.36 (m, 2H), 4.20–3.90 (m, 4H), 3.73–3.55 (m, 2H),
3.16–3.03 (m, 3H), 2.66 (bs, 1H), 1.19–1.06 (m, 15H) ppm;
13C NMR (125 MHz, CDCl3): δ 159.2, 158.5, 157.2, 156.0, 135.8,
135.6, 135.1, 133.1, 132.9, 132.8, 130.3, 130.1, 129.9, 129.8,
128.8, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.8, 127.7,
108.4, 108.2, 79.6, 78.5, 74.2, 73.2, 73.6, 73.4, 69.6, 68.8, 68.4,
68.2, 67.8, 64.4, 62.9, 62.6, 60.0, 59.8, 58.7, 53.5, 39.4, 39.1,
26.9, 26.8, 25.4, 25.3, 19.4, 19.3 ppm; IR νmax (thin film): 3464,
3378, 1717, 1588 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C42H52N2O11SSi 843.2959; found 843.2962.
Compound 28a. Column chromatography (petroleum ether/
EtOAc, 1 : 1); oily liquid (0.98 g, 1.53 mmol, 77%); [α]D25
=
Compound 17a. Column chromatography (petroleum ether/
EtOAc, 1 : 1); oily liquid (0.91 g, 1.46 mmol, 73%); [α]D25
=
−33.93 (c 0.28, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.37–7.26
(m, 10H), 6.60 (bs, 1H), 5.26–5.10 (m, 4H), 4.74–4.70 (m, 1H),
4.65–4.48 (m, 3H), 4.34–4.28 (m, 2H), 4.16–4.00 (m, 2H),
3.69–3.67 (m, 1H), 3.66–3.41 (m, 1H), 3.36 (s, 3H), 3.00 (s, 3H),
1.89–1.79 (m, 1H), 1.50–1.46 (m, 1H), 1.34–1.30 (m, 3H),
1.10–1.09 (m, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.0,
158.4, 156.9, 156.8, 135.9, 135.6, 135.3, 128.7, 128.6, 128.5,
128.4, 128.2, 127.6, 108.6, 108.5, 96.5, 75.8, 75.5, 75.3, 74.5,
69.2, 68.6, 68.5, 68.4, 68.1, 61.9, 61.8, 59.8, 58.6, 65.5, 37.4,
29.7, 27.7, 26.9, 24.9, 24.8 ppm; IR νmax (thin film): 3463,
−22.85 (c 0.14, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.39–7.13
(m, 10H), 5.33–5.05 (m, 4H), 4.53–4.16 (m, 8H), 3.94–3.84 (m,
1H), 3.61 (bs, 1H), 3.28 (s, 3H), 2.99–2.93 (d, 3H), 1.42 (s, 3H),
1.29 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.2, 158.8,
155.8, 155.6, 135.5, 135.4, 135.1, 128.9, 128.7, 128.6, 128.3,
108.8, 96.9, 75.3, 74.7, 74.4, 74.2, 69.9, 69.4, 68.9, 68.6, 60.4,
58.6, 57.6, 56.3, 56.2, 37.1, 27.6, 25.6 ppm; IR νmax (thin film):
3422, 1704, 1720, 1650, 1596 cm−1; HRMS (ESI-TOF) m/z
[M + NH4]+ calcd for C28H42N3O12S 644.2489; found 644.2494.
Compound 17b. Column chromatography (petroleum ether/
1719 cm−1
; HRMS (ESI-TOF) m/z [M +
H]+ calcd for
EtOAc, 1 : 1); oily liquid (0.82 g, 1.32 mmol, 66%); [α]D25
=
C29H41N2O12S 641.2380; found 641.2388.
1
+18.33 (c 0.12, CHCl3); H NMR (500 MHz, CDCl3): δ 7.37–7.19
(m, 10H), 6.61 (bs, 1H), 5.33–5.06 (m, 4H), 4.68–4.63 (m, 1H),
4.59–4.39 (m, 2H), 4.30–4.26 (m, 2H), 4.02–3.89 (m, 2H),
3.74–3.47 (m, 3H), 3.32–3.28 (m, 3H), 3.03–2.99 (d, 3H), 1.29
(s, 3H), 1.27 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.1,
158.3, 157.4, 156.4, 135.7, 135.5, 135.0, 128.8, 128.7, 128.6,
128.5, 128.4, 128.3, 127.7, 108.8, 108.3, 108.2, 96.9, 96.6, 75.3,
74.9, 74.7, 74.3, 74.2, 74.0, 68.9, 68.7, 68.6, 68.4, 60.1, 59.9,
59.0, 57.7, 56.8, 56.6, 56.3, 56.2, 37.2, 29.7, 29.6, 27.7,
27.6 ppm; IR νmax (thin film): 3422, 1704, 1720, 1650,
1596 cm−1; HRMS (ESI-TOF) m/z [M + NH4]+ calcd for
C28H42N3O12S 644.2489; found 644.2494.
Compound 28b. Column chromatography (petroleum ether/
EtOAc, 1 : 1); oily liquid (1.00 g, 1.56 mmol, 79%); [α]2D5 = +22.1
(c 0.16, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.88–7.27
(m, 10H), 6.63–6.59 (m, 1H), 5.27–5.10 (m, 4H), 4.74–4.71
(m, 1H), 4.66–4.62 (m, 1H), 4.55–4.49 (m, 1H), 4.35–4.28
(m, 2H), 4.16–4.04 (m, 2H), 3.70–3.66 (m, 1H), 3.52–3.41
(m, 2H), 3.38–3.35 (m, 3H), 3.01–3.00 (m, 3H), 1.90–1.79
(m, 1H), 1.55–1.47 (m, 1H), 1.34–1.31 (m, 3H), 1.11–1.10
(m, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ 159.3, 158.6, 157.2,
157.0, 136.1, 135.9, 135.5, 129.0, 128.9, 128.8, 128.7, 128.6,
128.5, 127.8, 108.8, 108.7, 96.8, 76.0, 75.7, 75.6, 74.8, 69.4, 68.9,
68.8, 68.6, 68.4, 62.2, 62.1, 60.1, 58.9, 56.8, 37.6, 27.9, 25.1 ppm;
IR νmax (thin film): 3463, 1719 cm−1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C29H41N2O12S 641.2380; found 641.2388.
Compound 22a. Column chromatography (petroleum ether/
EtOAc, 7 : 3); oily liquid (1.21 g, 1.46 mmol, 73%); [α]2D5 = −16.3
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Procedure for the hydrogenolysis of compound 10 to get 4.57 (dd, J = 8.0, 2.8 Hz, 1H, C3H), 4.42 (dd, J = 7.4, 3.4 Hz, 1H,
11. Freshly prepared RANEY® nickel (around 0.80 g, pre- C2H), 3.80 (dd, J = 9.7, 6.9 Hz, 1H, C4H), 3.76–3.71 (m, 2H,
washed with absolute ethanol) was added to the stirred solu- C6H), 3.33 (s, 3H, –OCH3), 2.98 (dd, J = 10.9, 10.8 Hz, 1H,
tion of 10 (2 mmol) in dry methanol (15 mL) followed by C5H), 2.92–2.89 (m, 1H, C1H), 2.44 (dd, J = 15.0, 5.0 Hz, 1H,
40 drops of acetic acid. The reaction mixture was hydrogenated C1H), 1.56 (s, 3H, C7H), 1.37 (s, 3H, C8H) ppm; 13C NMR
at atmospheric pressure for 16 h at room temperature. After (125 MHz, CDCl3) δ 109.1 (C-9), 95.2 (–O–CH2–O–), 75.4 (C-2),
the complete disappearance of the starting material on TLC, 72.9 (C-3), 69.3 (C-4), 59.2 (C-6), 57.5 (–OCH3), 55.5 (C-5), 46.3
the reaction mixture was passed over Celite and concentrated, (C-1), 26.2 (C-8), 24.4 (C-8) ppm; IR νmax (thin film):
and purified by column chromatography.
The same procedure was used for the preparation of 18 248.1498; found 248.1499.
3486 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C11H22NO5
Compound 23a. Column chromatography (petroleum ether/
from 17. Compounds 23 and 29 were also prepared using
a similar procedure, however refluxing with triethylamine
(2 equiv.) was required for the desired cyclization to occur.
EtOAc, 1 : 1); oily liquid (0.63 g, 1.38 mmol, 69%); [α]2D5 = +12.6
1
(c 0.1, CHCl3); H NMR (500 MHz, CDCl3): δ 7.70–7.67 (m, 4H,
Compound 11a. Column chromatography (petroleum ether/ Ar–H), 7.43–7.35 (m, 6H, Ar–H), 4.52–4.49 (m, 1H, C3H),
EtOAc, 4 : 6); oily liquid (0.69 g, 1.56 mmol, 78%); [α]D25 = +12.3 4.36–4.34 (m, 1H, C2H), 3.65–3.63 (m, 2H, C7H), 3.41–3.36
(c 0.31, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.68–7.66 (m, (m, 1H, C1H), 3.19–3.13 (m, 2H, C6H), 2.77–2.74 (m, 1H, C5H),
4H, Ar–H), 7.40–7.32 (m, 6H, Ar–H), 4.75–4.71 (m, 1H, C3H), 1.84–1.79 (m, 2H, C4H), 1.44 (s, 3H, C10H), 1.35 (s, 3H, C11H),
4.59–4.52 (m, 1H, C2H), 3.99–3.54 (m, 6H, C1H, C4H, C5H, 1.05 (s, 9H, (CH3)3C–Si) ppm; 13C NMR (125 MHz, CDCl3):
C6H), 1.44 (s, 3H, C7H), 1.25 (s, 3H, C8H), 1.02 (s, 9H, δ 135.7 (C–Ar), 135.6 (C–Ar), 133.7 (C–Ar), 133.5 (C–Ar), 129.8
(CH3)3C–Si) ppm; 13C NMR (100 MHz, CDCl3): δ 135.7 (C–Ar), (C–Ar), 129.7 (C–Ar), 127.7 (C–Ar), 127.6 (C–Ar), 127.4 (C–Ar),
133.0 (C–Ar), 132.9 (C–Ar), 129.8 (C–Ar), 127.8 (C–Ar), 127.7 107.8 (C-12), 71.9 (C-3), 71.7 (C-2), 64.8 (C-7), 63.9 (C-6), 52.0
(C–Ar), 112.3 (C-9), 81.8 (C-3), 79.4 (C-2), 66.3 (C-5), 62.8 (C-6), (C-1), 47.9 (C-5), 29.2 (C-4), 26.9 (C-12), 26.3 ((CH3)3C–Si), 26.0
60.2 (C-1), 60.0 (C-4), 26.8 ((CH3)3C–Si), 26.2 (C-8), 24.3 (C-7), (C-11), 19.3 (C–Si) ppm; IR νmax (thin film): 3408, 3071,
19.2 (C–Si) ppm; IR νmax (thin film): 3407, 3470, 1669 cm−1
;
1670 cm−1 H]+ calcd for
; HRMS (ESI-TOF) m/z [M +
HRMS (ESI-TOF) m/z [M + H]+ calcd for C24H36NO4Si 442.2414; C26H38NO4Si 456.2570; found 456.2572.
Compound 23b. Column chromatography (petroleum ether/
found 442.2417.
Compound 11b. Chromatography (petroleum ether/EtOAc, EtOAc, 1 : 1); oily liquid (0.63 g, 1.4 mmol, 70%); [α]2D5 = +14.8
1
4 : 6); oily liquid (0.65 g, 1.46 mmol, 73%); [α]2D5 = +10.5 (c 0.2, (c 0.6, CHCl3); H NMR (500 MHz, CDCl3): δ 7.68–7.65 (m, 4H,
CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.71–7.67 (m, 4H, Ar–H), Ar–H), 7.41–7.33 (m, 6H, Ar–H), 4.50–4.48 (m, 1H, C3H),
7.43–7.33 (m, 6H, Ar–H), 4.67–4.64 (m, 2H, C2H, C3H), 4.35–4.33 (m, 1H, C2H), 3.64–3.60 (m, 2H, C7H), 3.41–3.36
3.98–3.83 (m, 4H, C5H, C6H), 3.11–3.08 (m, 1H, C1H), (m, 1H, C1H), 3.18–3.12 (m, 2H, C6H), 2.76–2.74 (m, 1H, C5H),
2.96–2.93 (m, 1H, C4H), 1.41 (s, 3H, C7H), 1.27 (s, 3H, C8H), 2.02–1.99 (m, 1H, C4H), 1.81–1.77 (m, 1H, C4H), 1.42 (s, 3H,
1.04 (s, 9H, (CH3)3C–Si) ppm; 13C NMR (100 MHz, CDCl3): C10H), 1.34–1.28 (s, 3H, C11H), 1.03 (s, 9H, (CH3)3C–Si) ppm;
δ 135.7 (C–Ar), 135.6 (C–Ar), 133.6 (C–Ar), 133.4 (C–Ar), 129.7 13C NMR (125 MHz, CDCl3): δ 134.2 (C–Ar), 134.1 (C–Ar), 132.1
(C–Ar), 127.7 (C–Ar), 127.6 (C–Ar), 111.4 (C-9), 82.3 (C-3), 81.2 (C–Ar), 131.9 (C–Ar), 128.2 (C–Ar), 126.2 (C–Ar), 126.1 (C–Ar),
(C-2), 63.6 (C-5), 62.7 (C-6), 61.7 (C-1), 60.9 (C-4), 26.9 106.3 (C-12), 70.3 (C-3), 70.1 (C-2), 63.1 (C-7), 62.2 (C-6), 50.5
((CH3)3C–Si), 25.6 (C-8), 23.9 (C-7), 19.3 (C–Si) ppm; IR νmax (C-1), 46.4 (C-5), 30.5 (C-4), 28.2 (C-12), 27.9 ((CH3)3C–Si), 25.3
(thin film): 3407, 3470, 1669 cm−1; HRMS (ESI-TOF) m/z (C-11), 20.0 (C–Si) ppm; IR νmax (thin film): 3408, 3071,
[M + H]+ calcd for C25H36NO4Si 441.2414; found 442.2416.
Compound 18a. Column chromatography (DCM/MeOH,
95 : 5); oily liquid (0.37 g, 1.5 mmol, 75%); [α]2D5 = −16.25
1670 cm−1
C26H38NO4Si 456.2570; found 456.2572.
Compound 29a. Column chromatography (DCM/MeOH,
; HRMS (ESI-TOF) m/z [M +
H]+ calcd for
(c 0.24, CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.76 (s, 2H, 9.5 : 0.5); oily liquid (0.35 g, 1.34 mmol, 67%); [α]D25 = −10.37
–O–CH2–O–), 4.46 (dd, J = 4, 3.4 Hz, 1H, C3H), 3.92–3.87 (c 0.27, CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.82 (d, J =
(m, 3H, C2H, C4H), 3.57 (dd, J = 10.9, 6.3 Hz, 1H, C5H), 3.40 6.9 Hz, 1H, –O–CH2–O–), 4.71 (d, J = 6.8 Hz, 1H, –O–CH2–O–),
(s, 3H, –OCH3), 3.15 (dd, J = 11.4, 5.1 Hz, 1H, C1H), 2.89 (dd, 4.56 (d, J = 8.5 Hz, 1H, C4H), 4.48–4.45 (m, 1H, C3H), 4.20–4.18
J = 11.4, 11.4 Hz, 1H, C1H), 2.76 (bs, 1H, –OH), 1.53 (s, 3H, (m, 1H, C5H), 3.77 (dd, J = 11.4, 2.8 Hz, 1H, C7H), 3.62 (dd, J =
C8H), 1.38 (s, 3H, C7H) ppm; 13C NMR (125 MHz, CDCl3): 10.9, 8.6 Hz, 1H, C7H), 3.39 (s, 3H, (–OCH3)), 3.38–3.30
δ 110.2 (C-9), 96.5 (–O–CH2–O–), 74.5 (C-2), 74.0 (C-3), 72.5 (m, 3H, C1H, C6H), 2.07–1.94 (m, 2H, C2H), 1.54 (s, 3H, C10H),
(C-4), 62.7 (C-6), 58.9 (–OCH3), 55.7 (C-5), 44.2 (C-1), 28.3 (C-8), 1.37 (s, 3H, C11H) ppm; 13C NMR (125 MHz, CDCl3): δ 108.3
26.4 (C-7) ppm; IR νmax (thin film): 3486 cm−1; HRMS (C-12), 96.0 (–O–CH2–O–), 78.4 (C-4), 74.0 (C-3), 71.8 (C-5), 64.0
(ESI-TOF) m/z [M + H]+ calcd for C11H22NO5 248.1498; found (C-7), 55.9 (–OCH3), 55.2 (C-1), 45.1 (C-6), 32.5 (C-2), 25.7
248.1499.
(C-11), 23.5 (C-10) ppm; IR νmax (thin film): 3439 cm−1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C12H24NO5 262.1654; found
262.1651.
Compound 18b. Column chromatography (DCM/MeOH,
95 : 5); oily liquid (0.37 g, 1.52 mmol, 76%); [α]2D5 = −12.1
(c 0.22, CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.66 (d, J =
Compound 29b. Column chromatography (DCM/MeOH,
6.9 Hz, 1H, –O–CH2–O–), 4.60 (d, J = 6.8 Hz, 1H, –O–CH2–O–), 95 : 5); oily liquid (0.33 g, 1.28 mmol, 64%); [α]2D5 = +18.6
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(c 0.22, CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.84 (d, J = 6.8 Hz,
Compound 3a. White solid (0.10 g, 0.5 mmol, 80%); [α]D25
=
1H, –O–CH2–O–), 4.71 (d, J = 6.3 Hz, 1H, –O–CH2–O–), 4.41 +3.8 (c 0.22, MeOH); mp 162–163 °C; 1H NMR (500 MHz,
(q, J = 8.0 Hz, 1H, C4H), 4.19 (dd, J = 8.0, 2.8 Hz, 1H, C3H), 3.91 CD3OD): δ 3.94–3.90 (m, 2H, C3H, C4H), 3.88–3.83 (m, 2H,
(dd, J = 5.7, 2.2 Hz, 1H, C5H), 3.51 (dd, J = 10.3, 4.5 Hz, 1H, C8H), 3.81–3.74 (m, 2H, C7H), 3.60–3.55 (m, 1H, C6H),
C1H), 3.38 (s, 3H, (–OCH3)), 3.32–3.23 (m, 2H, C7H), 2.64 (d, J = 3.46–3.43 (m, 1H, C2H), 2.13–2.05 (m, 2H, C5H) ppm; 13C NMR
14.8 Hz, 1H, C6H), 2.56–2.52 (m, 1H, C6H), 1.91–1.88 (m, 2H, (125 MHz, CD3OD): δ 66.4 (C-3), 64.9 (C-4), 58.8 (C-7), 58.7
C2H), 1.47 (s, 3H, C10H), 1.33 (s, 3H, C11H) ppm; 13C NMR (C-8), 56.2 (C-2), 52.7 (C-6), 26.7 (C-5) ppm; IR νmax (KBr):
(125 MHz, CDCl3): δ 109.8 (C-12), 97.5 (–O–CH2–O–), 80.6 (C-4), 3353 cm−1; HRMS (ESI-TOF) m/z [(M + H) − (HCl)]+ calcd for
76.3 (C-3), 76.1 (C-5), 65.7 (C-7), 56.3 (–OCH3), 55.7 (C-1), 48.3 C7H16NO4 178.1079; found 178.1080.
Compound 3b. In a similar manner as described for the
molecule 1a, white solid (0.10 g, 0.5 mmol, 81%); [α]2D5 = +6.3
(c 0.18, MeOH); mp 158–159 °C; 1H NMR (400 MHz, D2O):
δ 3.95 (bs, 1H, C3H), 3.91 (dd, J = 6.3, 3.4 Hz, 1H, C4H), 3.87
(dd, J = 5.9, 3.2 Hz, 1H, C7H), 3.80–3.78 (m, 2H, C8H), 3.72 (dd,
J = 16, 4.5 Hz, 1H, C7H), 3.65–3.59 (m, 1H, C6H), 3.40 (dt, J =
8.5, 2.3 Hz, 1H, C2H), 1.78–1.73 (m, 2H, C4H) ppm; 13C NMR
(100 MHz, D2O): δ 66.0 (C-3), 64.5 (C-4), 58.9 (C-7), 58.1 (C-8),
(C-6), 35.8 (C-2), 26.6 (C-11), 24.0 (C-10), ppm; IR νmax (thin
film): 3401 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C12H24NO5 262.1654; found 262.1655.
Procedure for acidolysis of 11 to get 1. 4 N HCl in ethyl
acetate (4 mL) was added to the cyclic amino alcohol 11a or
11b (0.44 g, 1 mmol, 1 equiv.), and stirred for 24 h at room
temperature. After the disappearance of the starting material
on TLC, the ethyl acetate was decanted carefully and the white
solid was washed with fresh ethyl acetate (3 × 5 mL) and
concentrated.
55.3 (C-2), 52.8 (C-6), 25.5 (C-5) ppm; IR νmax (KBr): 3456 cm−1
;
HRMS (ESI-TOF) m/z [(M + H) − (HCl)]+ calcd for C7H16NO4
178.1079; found 178.1078.
The same procedure was used for the preparation of 2, 3
and 4 from 18, 23 and 29, respectively.
Compound 4a. White solid (0.10 g, 0.5 mmol, 85%); [α]D25
=
1
−9.6 (c 0.64, H2O); mp 145–146 °C; H NMR (400 MHz, D2O):
δ 4.10–4.06 (m, 2H, C4H, C5H), 3.73–3.62 (m, 3H, C8H, C6H),
3.49 (dd, J = 12.3, 8.2 Hz, 1H, C2H), 3.21–3.17 (m, 2H, C7H),
1.99 (ddd, 15.6, 7.8, 4.3 Hz, 1H, C3H), 1.72 (dd, 15.5, 10.5 Hz,
1H, C3H) ppm; 13C NMR (100 MHz, D2O): δ 74.1 (C-4), 68.8
(C-5), 67.8 (C-6), 61.4 (C-8), 54.4 (C-2), 43.3 (C-7), 28.1 (C-3)
ppm; IR νmax (KBr): 3436 cm−1; HRMS (ESI-TOF) m/z [(M + H)
− (HCl)]+ calcd for C7H16NO4 178.1079; found 178.1080.
Compound 1a. White solid; (0.161 g, 0.81 mmol, 81%);
[α]D25 = −23.1 (c 0.4, H2O) [lit.6b [α]D25 −25.5 (c 0.90, H2O)]; mp
122–125 °C; 1H NMR (500 MHz, D2O): δ 4.25–4.23 (m, 1H,
C3H), 4.17 (dd, J = 9.1, 4.0 Hz, 1H, C4H), 3.91–3.85 (m, 2H,
C6H), 3.82–3.73 (m, 2H, C7H), 3.68–3.65 (m, 1H, C2H),
3.56–3.53 (m, 1H, C5H) ppm; 13C NMR (125 MHz, D2O): δ 71.2
(C-3), 70.1 (C-4), 62.2 (C-7), 61.8 (C-6), 58.2 (C-2), 57.5 (C-5)
ppm; IR νmax (KBr): 3356 cm−1; HRMS (ESI-TOF) m/z [(M + H)
− (HCl)]+ calcd for C6H14NO4 164.0923; found 164.0923.
Compound 1b. White solid (0.165 g, 0.83 mmol, 83%);
[α]2D5 = 0.00 (c 0.39, MeOH); mp 138–139 °C; 1H NMR
(400 MHz, D2O): δ 4.34–4.28 (m, 2H, C3H), 3.92–3.86 (m, 4H,
C4H), 3.61–3.56 (m, 2H, C2H) ppm; 13C NMR (100 MHz, D2O):
δ 70.2 (C-3), 61.9 (C-4), 57.9 (C-2) ppm; IR νmax (KBr):
3356 cm−1; HRMS (ESI-TOF) m/z [(M + H) − (HCl)]+ calcd for
C6H14NO4 164.0923; found 164.0923.
Compound 4b. White solid (0.10 g, 0.5 mmol, 84%); [α]D25
=
1
+6.0 (c 0.82, H2O); mp 149–150 °C; H NMR (400 MHz, D2O):
4.10 (dd, J = 8.6, 3.2 Hz, 1H, C4H), 4.00 (bs, 1H, C5H), 3.90 (dt,
10.9, 2.9 Hz, 1H, C6H), 3.69 (dd, J = 12.3, 4.1 Hz, 1H, C8H),
3.49 (dd, J = 11.8, 8.2 Hz, 1H, C8H), 3.37–3.28 (m, 2H, C7H,
C2H), 3.17 (dd, 13.7, 4.1 Hz, 1H, C7H), 1.98–1.88 (m, 1H, C3H),
1.75–1.71 (m, 1H, C3H) ppm; 13C NMR (100 MHz, D2O): δ 75.4
(C-4), 69.5 (C-5), 65.7 (C-6), 62.1 (C-8), 55.7 (C-2), 44.5 (C-7),
29.4 (C-3) ppm; IR νmax (KBr): 3456 cm−1; HRMS (ESI-TOF) m/z
Compound 2a. White solid (0.08 g, 0.41 mmol, 83%); [α]D25
=
−35.2 (c 0.43, MeOH) [lit.7i [α]D25–37.7 (c 1.00, MeOH)]; mp [(M + H) − (HCl)]+ calcd for C7H16NO4 178.1079; found
152–153 °C; 1H NMR (500 MHz, D2O): δ 4.01 (bs, 1H, C3H), 178.1080.
3.86–3.85 (m, 1H, C4H), 3.77–3.69 (m, 3H, C5H, C7H),
Procedure for MOM protection of 6 to get 12. Hünig’s base,
3.19–3.11 (m, 1H, C2H), 3.12–3.10 (m, 1H, C6H), 2.98–2.96 (m, DIPEA (3.49 mL, 20 mmol, 10 equiv.) followed by MOM
1H, C6H) ppm; 13C NMR (125 MHz, D2O): δ 69.9 (C-3), 65.4 chloride (0.60 mL, 8 mmol, 4 equiv.) were added to the stirred
(C-4), 64.6 (C-5), 57.7 (C-7), 54.7 (C-2), 41.6 (C-6) ppm; IR νmax solution of compound 6 (0.8 g, 2 mmol, 1 equiv.) in dichloro-
(KBr): 3436 cm−1; HRMS (ESI-TOF) m/z [(M + H) − (HCl)]+ methane at 0 °C, and stirred for 12 h at room temperature.
calcd for C6H14NO4 164.0923; found 164.0923.
After the complete disappearance of the starting material on
TLC, the reaction mixture was quenched with water. The
organic layer was extracted with dichloromethane (2 × 10 mL),
and the combined organic phases were washed with 4% HCl
(2 × 20 mL), dried over anhydrous Na2SO4, filtered, concen-
trated, and purified by column chromatography.
The same procedure was used for the preparation of 24
from 19.
Compound 12. Column chromatography (petroleum ether/
Compound 2b. White solid (0.08 g, 0.42 mmol, 84%); [α]D25
=
−23.4 (c 0.4, MeOH), [lit.10d [α]2D3 −21.7 (c 0.8, MeOH)]; mp
153–155 °C; 1H NMR (400 MHz, D2O): δ 4.10–4.09 (m, 1H,
C3H), 4.02–4.01 (m, 1H, C4H), 3.74 (m, 2H, C5H, C2H), 3.71
(t, J = 3.2 Hz, 1H, C7H), 3.37 (dd, J = 13.7, 3.0 Hz, 1H, C7H),
3.26 (dt, J = 1.3, 6.8 Hz, 1H, C6H), 3.13 (dd, J = 13.7, 1.8 Hz,
1H, C6H) ppm; 13C NMR (100 MHz, D2O): δ 69.8 (C-3), 65.2
(C-4), 64.5 (C-5), 57.5 (C-7), 54.6 (C-2), 41.4 (C-6) ppm; IR νmax
(KBr): 3436 cm−1; HRMS (ESI-TOF) m/z [(M + H) − (HCl)]+ EtOAc, 9 : 1); oily liquid (0.84 g, 1.78 mmol, 89%); [α]D25 = −9.4
calcd for C6H14NO4 164.0923; found 164.0924.
(c 0.32, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.72–7.36
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(m, 10H), 5.86–5.83 (m, 1H), 5.32 (d, J = 17.1 Hz, 1H), 5.20 (d, 76.3, 63.8, 60.4, 56.1, 31.1, 28.0, 25.6, 25.2, 14.2 ppm; IR νmax
J = 10.4 Hz, 1H), 4.76 (d, J = 6.7 Hz, 1H), 4.68 (d, J = 6.7 Hz, (thin film): 3472, 1735 cm−1; HRMS (ESI-TOF) m/z [M + Na]+
1H), 4.66 (d, J = 6.7 Hz, 1H), 4.45 (t, J = 7.0 Hz, 1H), 3.92 (dd, calcd for C14H26NaO7 329.1576; found 329.1571.
J = 11.0, 2.45 Hz, 1H), 3.87 (dd, J = 11.0, 4.25 Hz, 1H),
3.71–3.61 (m, 1H), 3.34 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H), 1.07
(s, 9H) ppm; 13C NMR (125 MHz, CDCl3): δ 135.8, 135.7, 134.3,
133.6, 133.4, 129.7, 129.6, 127.7, 127.6, 117.9, 108.4, 96.9, 78.7,
Acknowledgements
77.4, 76.5, 64.0, 56.0, 27.7, 26.9, 25.3, 19.3 ppm; IR νmax (thin The authors thank Department of Science and Technology,
film): 3072, 3049, 1589, 1472 cm−1; HRMS (ESI-TOF) m/z Ministry of Science and Technology for financial support
[M + Na]+ calcd for C27H38NaO5Si 493.2386; found 493.2381.
(grant number: SR/FT/CS-12/2011) and R. P. thanks University
Grants Commission for a senior research fellowship and
V. K. J. thanks CSIR India for a JRF.
Compound 24. Column chromatography (petroleum ether/
EtOAc, 9.5 : 0.5); oily liquid (0.92 g, 1.7 mmol, 85%); [α]D25
=
−8.6 (c 0.18, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.71–7.68
(m, 4H), 7.41–7.35 (m, 6H), 4.85 (d, J = 6.9 Hz, 1H), 4.69 (d, J =
6.9 Hz, 1H), 4.30 (t, J = 7.1 Hz, 1H), 4.19–4.15 (m, 1H), 4.12
(q, J = 7.4 Hz, 2H), 3.98–3.94 (m, 1H), 3.87–3.83 (m, 1H),
3.72–3.70 (m, 1H), 3.36 (s, 3H), 2.56–2.49 (m, 1H), 2.42–2.36
(m, 1H), 2.01–1.94 (m, 1H), 1.79–1.70 (m, 1H), 1.33 (s, 3H),
1.30 (s, 3H), 1.24 (t, J = 7.4 Hz, 3H), 1.03 (s, 9H) ppm; 13C NMR
(125 MHz, CDCl3): δ 173.5, 135.8, 135.7, 133.5, 133.4, 129.7,
129.6, 127.7, 127.6, 108.0, 96.2, 76.8, 76.4, 75.7, 63.9, 60.3,
56.2, 31.1, 28.1, 26.9, 25.8, 25.4, 19.3, 14.1 ppm; IR νmax
(thin film): 3049, 1735, 1587 cm−1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C30H44NaO7Si 567.2754; found 567.2751.
Procedure for TBDPS deprotection of 12 to get 13. TBAF
(1 M solution in THF 2.4 mL, 2.4 mmol, 1.2 equiv.) was added
to the stirred solution of compound 12 (0.94 g, 2 mmol,
1 equiv.) in THF at room temperature and stirred for 1 h. After
the disappearance of the starting material on TLC, the reaction
was quenched with saturated ammonium chloride solution
(10 mL). The organic layer was extracted with ethyl acetate
(2 × 20 mL) and the combined organic phases were dried over
anhydrous Na2SO4, filtered, concentrated, and purified by
column chromatography.
Notes and references
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The same procedure was used for the preparation of 25
from 24.
Compound 13. Column chromatography (petroleum ether/
EtOAc, 6 : 4); oily liquid (0.42 g, 1.8 mmol, 90%); [α]2D5 = +7.33
(c 2.4, CHCl3); 1H NMR (500 MHz, CDCl3): δ 5.89–5.82 (m, 1H),
5.35 (d, J = 17.1 Hz, 1H), 5.22 (d, J = 10.4 Hz, 1H), 4.65 (t, J =
6.7 Hz, 1H), 4.60 (q, J = 6.7 Hz, 1H), 4.12 (t, J = 7.3 Hz, 1H),
3.83 (d, J = 10.4 Hz, 1H), 3.62 (q, J = 6.4 Hz, 1H), 3.51 (t, J =
6.4 Hz, 1H), 3.40 (s, 3H), 3.70–3.33 (m, 1H), 1.45 (s, 3H), 1.34
(s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 133.8, 117.7, 108.9,
97.7, 81.4, 78.7, 77.1, 63.9, 56.0, 27.7, 25.3 ppm; IR νmax (thin
film): 3460, 1590 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C11H20NaO5 255.1208; found 255.1201.
Compound 25. Column chromatography (petroleum ether/
EtOAc, 1 : 1); oily liquid (0.56 g, 1.84 mmol, 92%); [α]2D5 = +13.1
(c 0.42, CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.72 (d, J =
6.8 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H), 4.17–4.14 (m, 1H), 4.11
(q, J = 6.8 Hz, 2H), 4.03 (dd, J = 8.0, 5.7 Hz, 1H), 3.86 (dd, J =
11.5, 2.8 Hz, 1H), 3.66–3.58 (m, 2H), 3.41 (s, 3H), 2.55–2.49
(m, 1H), 2.42–2.36 (m, 1H), 1.92–1.86 (m, 1H), 1.79–1.71
(m, 1H), 1.38 (s, 3H), 1.29 (s, 3H), 1.23 (t, J = 7.4 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3): δ 173.4, 108.3, 97.1, 80.3, 76.7,
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Organic & Biomolecular Chemistry
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mated using chiral HPLC and was established by compar-
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diastereomers obtained through reactions catalyzed by
DL-proline (given in the ESI†).
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2013, 78, 11756; (b) V. Jha, N. B. Kondekar and P. Kumar,
analysis are provided in the ESI.†
Org. Biomol. Chem.
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