An experimental and theoretical study on the remarkable influence of protecting groups on the selectivity of addition of amines to vinyl sulfone-modified hex-2-enopyranosides

Article abstract of DOI:10.1021/jo902046g

(Chemical Equation Presented) Although phenylmethylene-protected vinyl sulfone-modified carbohydrate 2α reacts with both primary and secondary amines inMichael fashion to afford aminated products, only primary amines react with the dibenzyl-protected 3α, 6-O-trityl-protected 4α, and unprotected 5α, highlighting for the first time the remarkable influence of protecting groups on the reaction patterns of vinyl sulfonemodified carbohydrates. The quantum chemical calculations suggest that the Michael addition of amines and proton transfer to vinyl sulfone-modified carbohydrates 2α and 5α are possible via relay process in a concerted mechanism. These calculations reveal that the addition of primary amines to vinyl sulfone-modified carbohydrate is preferential due to the low activation energy barriers, whereas the addition of secondary amines has relatively higher activation energy barriers. The theoretical conclusions are in line with the experimental observations.

Full text of DOI:10.1021/jo902046g

pubs.acs.org/joc
An Experimental and Theoretical Study on the Remarkable Influence
of Protecting Groups on the Selectivity of Addition of Amines to
Vinyl Sulfone-Modified Hex-2-enopyranosides
Rahul Bhattacharya,† Manoj K. Kesharwani,‡ Chinmoy Manna,† Bishwajit Ganguly,*,‡
Cheravakattu G. Suresh,§ and Tanmaya Pathak*,†
†Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India, ‡Analytical Science
Discipline, Central Salt & Marine Chemicals Research Institute (CSIR), Bhavnagar 364 002, Gujarat, India,
§
and Division of Biochemical Sciences, National Chemical Laboratory, Pune 411 008, India
tpathak@chem.iitkgp.ernet.in; ganguly@csmcri.org
Received September 26, 2008
Although phenylmethylene-protected vinyl sulfone-modified carbohydrate 2r reacts with both
primary and secondary amines in Michael fashion to afford aminated products, only primary amines
react with the dibenzyl-protected 3r, 6-O-trityl-protected 4r, and unprotected 5r, highlighting for
the first time the remarkable influence of protecting groups on the reaction patterns of vinyl sulfone-
modified carbohydrates. The quantum chemical calculations suggest that the Michael addition of
amines and proton transfer to vinyl sulfone-modified carbohydrates 2r and 5r are possible via relay
process in a concerted mechanism. These calculations reveal that the addition of primary amines to
vinyl sulfone-modified carbohydrate is preferential due to the low activation energy barriers, whereas
the addition of secondary amines has relatively higher activation energy barriers. The theoretical
conclusions are in line with the experimental observations.
Introduction
2-amino-2-deoxysugars are the components of various ami-
noglycoside antibiotics.2 The most common methods for the
Aminosugars, in general, are one of the most important
classes of modified carbohydrates.1 A large number of
(2) Selected reviews: (a) Banoub, J.; Boullanger, P.; Lafont, D. Chem.
Rev. 1992, 92, 1167–1195. (b) Debenham, J.; Rodebaugh, R.; Fraser-Reid, B.
Ann. 1997, 791–802. (c) Lee, S. H.; Cheong, C. S. Tetrahedron 2001, 57, 4801–
4815. (d) Busscher, G. F.; Rutjes, F. P. J. T.; Van Delft, F. L. Chem. Rev.
2005, 105, 775–791. (e) Magnet, S.; Blanchard, J. S. Chem. Rev. 2005, 105,
477–497. (f) Hermann, T. Cell. Mol. Life Sci. 2007, 64, 1841–1852. (g) Zhou,
J.; Wang, G.; Zhang, L.-H.; Ye, X.-S. Med. Res. Rev. 2007, 27, 279–316.
(1) (a) Ferrier, R. J. Carbohydrate Chemistry; The Royal Society of Chem-
istry: Cambridge, 1968-2003; Vols. 1-35. (b) Collins, P. M.; Ferrier, R. J.
Monosaccharides: Their Chemistry and Their Roles in Natural Products; John
Wiley & Sons: Chichester, UK, 1996.
DOI: 10.1021/jo902046g
r
Published on Web 12/17/2009
J. Org. Chem. 2010, 75, 303–314 303
2009 American Chemical Society

Bhattacharya et al.
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SCHEME 1. Synthesis of 3r
FIGURE 1. Sugar-derived Michael acceptors.
SCHEME 2. Synthesis of 4r and 5r
synthesis of aminosugars involve the reactions of amines
with sugar-derived epoxides, tosylates, and ketones.1 Our
interest in the area of aminosugars3 including aminonucleo-
sides4 led to the designing of an alternative route based on
the diastereoselective addition of amines to vinyl sulfone-
modified (VSM) carbohydrates 1r and 1β (Figure 1).3a The
strategy, followed by desulfonylation of the Michael ad-
ducts, led to the synthesis of D-lividosamine (2-amino-2,3-
dideoxyglucose) and its analogues.3b
For example, the dependence of the reactivity of a vinyl
sulfone as a Michael acceptor on the nature of the group
attached to the sulfur atom was determined in order to
evaluate the effect of these substituents on the inactivation
kinetics of vinyl-sulfone-based cysteine protease inhibi-
tors.7b On the other hand, it has been reported recently that
the rate of Michael-type addition reactions to conjugated
ethylenic sulfones and sulfoxides is influenced by the size of
the alkyl group attached to the sulfur atom.7c We recently
reported that the diastereoselectivity of addition to vinyl
sulfone-modified 4-sulfonylhex-3-enopyranoside was nu-
cleophile-dependent.3g
Since protection and demasking of functional groups in a
synthetic strategy increase the number of steps, thereby
decreasing the overall yield of the final products, it was
necessary to acquire information on the efficiency of addi-
tion of nucleophiles to VSM carbohydrates in the presence of
protecting groups other than the phenylmethylene group
routinely used so far.3 More importantly, it was clear from
our earlier studies that the directing effects of anomeric
configurations were not sufficient criteria to explain the
pattern of addition of nucleophiles to compounds like
1 and 2.3a,c,g,5,6 We therefore initiated a search for addi-
tional factors contributing to the reaction patterns of VSM
carbohydrates. It should be noted that the biological im-
portance7a,d and synthetic utility of vinyl sulfones triggered
studies of “other factors” controlling their reactivities.7b,c
Results and Discussion
Synthesis of Vinyl Sulfones 3r-5r: As a first step, we
decided to look into the Michael addition reactions of VSM
hex-2-enopyranosyl carbohydrates protected with noncyclic
protecting groups such as a benzyl or trityl group or not
having any protecting group at all. For the preparation of the
dibenzylated VSM carbohydrate 3r, we started the synthesis
from the easily accessible fully protected epoxide 6. Thus,
compound 68 was reacted with p-thiocresol and TMG in
DMF. The sulfide derivative obtained was oxidized using
magnesium bis(monoperoxyphthalate) (MMPP) in metha-
nol to the corresponding sulfone derivative 8 in 89% yield.
Compound 8 was mesylated within 20 h at 0 to þ4 °C using
methanesulfonyl chloride (MsCl) in pyridine. The crude
mesylated product was subjected to an elimination reaction
in refluxing pyridine to afforded 3r in 86% overall yield
within 2 h (Scheme 1). For the synthesis of 6-O-trityl-
protected VSM carbohydrate 4r, and the fully unprotected
VSM carbohydrate 5r, the phenylmethylene-protected com-
pound 2r was deprotected under acidic conditions to gen-
erate the diol 5r in 96% yield. Tritylation of 5r under
standard conditions produced the monoprotected vinyl sul-
fone 4r (Scheme 2).6 The appearance of peaks at δ 6.94 (3r),
(3) (a) Ravindran, B.; Sakthivel, K.; Suresh, C. G.; Pathak, T. J. Org.
Chem. 2000, 65, 2637–2641. (b) Ravindran, B.; Deshpande, S. G.; Pathak, T.
Tetrahedron 2001, 57, 1093–1098. (c) Suresh, C. G.; Ravindran, B.; Pathak,
T.; Narasimha Rao, K.; Sasidhar Prasad, J. S.; Lokanath, N. K. Carbohydr.
Res. 2002, 337, 1507–1512. (d) Das, I.; Suresh, C. G.; Pathak, T. J. Org.
Chem. 2005, 70, 8047–8054. (e) Das, I.; Pathak, T. Org. Lett. 2006, 8, 1303–
1306. (f) Das, I.; Pal, T. K.; Suresh, C. G.; Pathak, T. J. Org. Chem. 2007, 72,
5523–5533. (g) Bhattacharya, R.; Pathak, T. Carbohydr. Res. 2009, 344,
2336–2341.
(4) (a) Pathak, T. Chem. Rev. 2002, 102, 1623-1667 and references cited
therein. (b) Deshpande, S. G.; Pathak, T. Tetrahedron Lett. 2004, 45, 2255–2258.
(c) Maiti, T. K.; De, S.; Dasgupta, S.; Pathak, T. Bioorg. Med. Chem. 2006, 14,
1221–1228. (d) Leonidas, D. D.; Maiti, T. K.; Samanta, A.; Dasgupta, S.; Pathak,
T.; Zographos, S. E.; Oikonomakos, N. G. Bioorg. Med. Chem. 2006, 14, 6055–
6064. (e) Deshpande, S. G.; Pathak, T. Tetrahedron. 2007, 63, 602–608.
(f) Samanta, A.; Leonidas, D. D.; Dasgupta, S.; Pathak, T.; Zographo, S. E.;
Oikonomakos, N. G. J. Med. Chem. 2009, 52, 932–942.
(5) Sanki, A. K.; Suresh, C. G.; Falgune, U. D.; Pathak, T. Org. Lett.
2003, 5, 1285–1288.
(6) Sanki, A. K.; Bhattacharya, R.; Atta, A. K.; Suresh, C. G.; Pathak, T.
Tetrahedron 2008, 64, 10406–10416.
(7) (a) For a review, see: Meadows, D. C.; Gervay-Hague, J. Med. Res.
Rev. 2006, 26, 793–814. (b) Reddick, J. J.; Cheng, J.; Roush, W. R. Org. Lett.
2003, 5, 1967–1970. (c) Usera, A. R.; Posner, G. H. J. Org. Chem. 2007, 72,
2329–2334. (d) Kerr, I. D.; Lee, J. H.; Farady, C. J.; Marion, R.; Rickert, M.;
Sajid, M.; Pandey, K. C.; Caffrey, C. R.; Legac, J.; Hansell, E.; McKerrow,
J. H.; Craik, C. S.; Rosenthal, P. J.; Brinen, L. S. J. Biol. Chem. 2009, 284,
25697–25703.
(8) Wu, X.; Kong, F.; Lu, D.; Li, G. Carbohydr. Res. 1992, 235, 163–178.
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TABLE 1. Comparison of Reaction Patterns of R-Anomeric Vinyl
Sulfones 2r-5r with Primary Amines (5 equiv) in THF at Room
Temperature
on reactions with isopropylamine under similar conditions
produced a single compound 10e-e in 91% yield within 12 h
(Table 1, No. 1.2). Although reactions of 4r with benzyl-
amine (5 equiv) and cyclohexylamine (5 equiv) in THF
remained incomplete even after 5 days at room temperature,
compounds 11e-e (Table 1, No. 1.3) and 12e-e (Table 1, No.
1.4) were obtained in 60-70% yields; however, these reac-
tions could be pushed to completion within 12 h only by
heating the reaction mixtures at 90-100 °C to produce 11e-e
and 12e-e in 91 and 93% yields, respectively (Table 1).
Compound 5r, having no protecting group, on treatment
with isopropylamine (5 equiv in THF) for 10 h at room
temperature, produced a mixture of at least three com-
pounds. It was possible to isolate one of the products 13e-e
in 53% yield (Table 1, No. 1.5), which was identified as the
trityl derivative 10e-e (Table 1). It was necessary to unam-
biguously establish the configurations of C-2 and C-3 centers
of compounds 9e-e-13e-e. The identity of 10e-e was unam-
biguously established with the help of the X-ray crystal-
lography. Since the diol 13e-e was converted to 10e-e, the
identity of the former was also unambiguously established.
It is reported4,6 that, for bisprotected gluco analogues and
6-protected gluco analogues, the chemical shift value of the
H-1 proton varied within δ 4.73-4.89 with the J1,2 values
ranging between 3.2 and 3.8 Hz.10 The chemical shifts
and coupling constant values of the H-1 proton of com-
pounds 9e-e (δ 4.76; 3.6 Hz) and 10e-e (δ 4.79; 3.0 Hz)
prompted us to conclude that these compounds were having
gluco configuration.9
Although reactions of 3r-5r with isopropylamine re-
quired 10-14 h for completion (Table 1), 2r produced 14e-
e within 8 h (Table 1, No. 1.6) with the same amine. On the
other hand, 2r reacted with benzylamine (5 equiv) and
cyclohexylamine (5 equiv) in THF at room temperature to
produce single compounds 15e-e (Table 1, No. 1.7) and 16e-e
(Table 1, No. 1.8) in 26 and 28 h, respectively.9 Notably,
reactions of trityl-protected 4r with both these amines under
similar reaction conditions remained incomplete even after 5
days (Table 1), indicating the influence of changed protecting
groups.
Compounds 2r on reaction with pyrrolidine (5 equiv) in
THF produced a mixture (isomeric at C-2) of gluco (major)
and manno (minor) isomers 17e-e and 17a-e, respectively
(Table 2, No. 2.1) within 12 h, which was in line with the
reported product distribution of the amination of 1r.3a
Interestingly, the reactions of the benzylated 3r, the trity-
lated 4r, and the unprotected 5r with secondary amines
produced unexpected and surprising results. Thus, 3r on
treatment with pyrrolidine (5 equiv in THF) at ambient
temperature led to the isolation of the starting material after
24 h along with some minor impurities (Table 2, No. 2.2).
After prolonged standing in that strongly basic as well as
nucleophilic pyrrolidine solution, complete breakdown of
the starting material was observed. Compounds 4r and 5r
were extremely slow to react with pyrrolidine under identical
conditions, and even after 5 days at room temperature, the
reactions of 4r and 5r did not go to completion (Table 2,
Nos. 2.3 and 2.4). The products were highly unstable, and in
both cases, we were unable to generate clear spectral data.
aIdentified as the trityl derivative 10e-e. bReaction incomplete at
room temperature. c>90% yield at 90-100 °C.
δ 6.83 (4r), and δ 6.88 (5r) confirmed the presence of the
vinyl group.
Reactions of Vinyl Sulfones 2r-5r with Primary and
Secondary Amines: The dibenzylated derivative 3r, on treat-
ment with isopropylamine (5 equiv in THF), produced a
single compound 9e-e in 93% yield within 14 h at ambient
temperature (Table 1, No. 1.1).9 The tritylated derivative 4r
(9) The products of amination reactions of vinyl sulfones 2r-5r and
2β-5β are numbered as follows. 9e-e represents equatorial bonds at C2
(amino) and C3 (sulfone), whereas 17a-e is a compound with C2 axial
(amino) and C3 equatorial (sulfone) bonds.
(10) (a) Guangbin, Y.; Fanzuo, K. Carbohydr. Res. 1998, 312, 77–83.
(b) Ogawa, T.; Takahashi, Y.; Matsui, M. Carbohydr. Res. 1982, 102, 207–215.
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SCHEME 4. Preferential Addition of Primary Amine
JOCArticle
TABLE 2. Comparison of Reaction Patterns of R-Anomeric Vinyl
Sulfones 2r-5r with Pyrrolidine (5 equiv) in THF at Room temperature
SCHEME 5. Synthesis of 4β and 5β from 2β
aMixture of diastereomers as reported (ref 3a) for 1r. bUnidentified
c
products. No reaction/starting material decomposes. dStructure pro-
posed on the basis of HRMS only.
with the reaction patterns of phenylmethylene-protected
vinyl sulfone 2r.
It was therefore clear from the above experiments that the
reaction patterns of 3r-5r were highly selective in reacting
with primary and secondary amines and are in stark contrast
with the same of phenylmethylene-protected vinyl sulfone
2r. To establish this point further, we reacted 4r (1 equiv)
with a mixture of isopropylamine (2.5 equiv) and pyrrolidine
(2.5 equiv) at room temperature. After the disappearance of
the starting material (ca. 10 h), the reaction mixture was
worked up in the usual way and the major product (81%)
was identified as the isopropylamino derivative 10e-e
(Scheme 4). The phenylmethylene-protected analogue 2r
produced a mixture of at least three compounds under the
similar reaction conditions.
Reaction of Vinyl Sulfones 2β, 4β, and 5β with Primary and
Secondary Amines: To extract additional information of the
reaction patterns, we also extended the study to the β-series.
The trityl-protected 4β and free diol 5β were prepared from
2β. Compound 4β was synthesized following the literature
report.6 However, compound 5β was isolated and identified
for the present study (Scheme 5).
Compound 4β reacted smoothly with isopropylamine,
pyrrolidine, and piperidine to afford 21e-e, 22e-e, and 23e-
e, respectively, in excellent yields (Table 3, Nos. 3.1-3.3).
Compound 2β on reaction with isopropylamine and pyrro-
lidine produced single isomers 24e-e and 25e-e, respectively
(Table 3, Nos. 3.4 and 3.5).3a,9 Compound 5β was reacted
with isopropylamine in THF to produce the expected amino
derivative 26e-e (Table 3, No. 3.6), which was identified as its
tritylated analogue 21e-e (Table 3, No. 3.1) obtained from 4β
(mixed 1H NMR). Compound 5β also reacted with pyrroli-
dine to afford 27e-e (Table 3, No. 3.7). In this case also, 27e-e
was tritylated to 22e-e and the structure of 22e-e (Table 3,
No. 3.2), and the structure was established unambiguously
with the help of X-ray crystallography. In all of these cases, a
SCHEME 3. Anomalous Reaction of 5r with Morpholine
However, only in the case of 4r, the HRMS data [ES, (M þ
H)þ) calcd for C37H42NO6S 628.2733, obsd 628.2702] iden-
tified one of the products as the probable amino derivatives
18 in less than 15% yield (Table 2, No. 2.3). Both 4r and 5r
did not react with piperidine in THF at room temperature
but produced inseparable mixture of compounds (devoid
of amine residue) at an elevated temperature when reacted
with piperidine.
Another secondary amine, morpholine, did not react with
4r and 5r at room temperature but reacted at elevated
temperature to produce compounds devoid of the morpho-
lino group. The absence of -CH2- peaks around δ
49.8-51.7 (CH2-N-CH2) and δ 66.9-67.4 (CH2-O-
CH2)3b in the 13C NMR spectrum of the reaction products
confirmed the absence of morpholino residue. Although 4r
produced an inseparable mixture, it was possible to isolate
the major compound from the mixture of products of the
reactions of 5r with morpholine (Scheme 3).
Interestingly, the primary hydroxyl group of 5r intramo-
lecularly attacked the C-2 position to produce a bicyclic
compound 19; compound 19 was benzylated, and the struc-
ture of the product was unambiguously (X-ray) eastablished
as 20. These observations are once again in stark contrast
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TABLE 3. Comparison of Reaction Patterns of β-Anomeric Vinyl
Sulfones with Primary and Secondary Amines (5 equiv) in THF at Room
Temperature
SCHEME 6. Product Distribution of 2r under Amination
Reaction Conditions
SCHEME 7. Product Distribution of 5r under Amination
Reaction Conditions
aIdentified as the corresponding 6-O-trityl derivative 21e-e. Identi-
fied as the corresponding 6-O-trityl derivative 22e-e.
b
difference in selectivity observed during the nucleophilic
addition reaction of amines at VSM carbohydrate for 2r
and 5r, we undertook a computational study employing
quantum chemical ab initio and DFT calculations.11 It is
reported that, in a Michael addition reaction, the addition of
amine is possible via a concerted mechanism.12 We have
computed the activation barriers and reaction energies
for 2r and 5r with isopropylamine and pyrrolidine for
both equatorial and axial approaches (Schemes 6 and 7).
The reaction energies calculated for 2r and 5r with isopro-
pylamine and pyrrolidine are listed in Table 4. The reaction
energies calculated for the equatorial approach of both the
amines toward the VSM carbohydrates 2r and 5r seem to be
preferred over the axial approach in both gas and solvent
phase (THF), which is in agreement with experimental
observations.
single isomer was obtained because of the predominant
equatorial approach of the incoming nucleophile to the
VSM hex-2-enopyranosides.3a
Although the incoming nucleophile added to all the β-
anomeric vinyl sulfones, 2β, 4β, and 5β, with similar diaster-
eoselectivity, the effect of change of protection at the C-6
hydroxyl group was still evident in this case. While pyrroli-
dine in THF reacted with 2β in 15 h, the more flexible
Michael acceptors 4β and 5β took 36-38 h for the complete
conversion to 22e-e and 27e-e (Table 3). The generality of
the reaction pattern was established further because piper-
idine also required around 38 h for consuming 4β to afford
23e-e (Table 3, No. 3.3).9
Computational Results. In order to explain the variation in
product distributions mentioned above and to examine the
Initially, a single amine molecule was considered to calcu-
late the activation barriers for the addition of amines with the
(11) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (c) Hehre, W. J.; Radom,
L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital Theory; Wiley:
New York, 1988.
(12) Okumoto, S.; Yamabe, S. J. Org. Chem. 2000, 65, 1544–1548.
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TABLE 4. Reaction Energies (kcal mol-1) Calculated for VSM Car-
bohydrates 2r and 5r with Isopropylamine and Pyrrolidine for Equator-
ial/Axial Approaches at RHF/6-31G* and B3LYP/6-31þG*//RHF/6-
31G* Levels of Theory (B3LYP/6-31þG* Calculated Single Point En-
ergy in Solvent (THF) Are Given in Square Brackets)
isopropylamine are concerted in nature. The four-membered
transition states formed are strained, and hence, the
computed activation barriers are much higher in energy
(Figure 2). The activation barriers were found to be rela-
tively lower with the 6/6-31þG*//RHF/6-31G* level of
theory. The methods employed here are discussed in the
computational methodology section.
Importantly, the activation barrier for the equatorial
approach of isopropylamine toward VSM carbohydrates
5r and 2r is 4.9 and 5.6 kcal mol-1 lower in energy for
13e-e-TS1 and 14e-e-TS1 compared to that of axial ap-
proach 13a-a-TS1 and 14a-a-TS1, respectively (Figure 2).9
Activation barriers in tetrahydrofuran (THF) were similar to
that of the calculated gas phase barriers at the same level of
theory (Figure 2). The computed free energies of activation
toward the additions of amines with VSM carbohydrates at
the RHF/6-31G* level showed a trend similar to that ob-
served with electronic energies; however, the barriers are
relatively higher in the former case (Table S1, Supporting
Information). It is known that the computed activation
barriers are overestimated at RHF levels of theory.13
The product 14a-e (Scheme 6) was not considered for
computational evaluation due to following reasons. The
product was not observed experimentally, and the formation
of this product would be a stepwise process. Moreover, we
have shown in the other case that a stepwise process would be
unfavored compared to the concerted process. The high
activation barriers obtained for VSM carbohydrates 2r
and 5r with one molecule of isopropylamine are in agree-
ment with reports by Yamabe et al.12 Since it is reported that
two or three amine molecules can reduce the activation
barrier via a proton relay mechanism for such nucleophilic
addition,12 we have also examined the relay mechanism in
this case with two amines. Incorporation of a third amine to
obtain the transition states was not possible due to steric
reasons in these cases. The transition state geometries for the
nucleophilic addition with two molecules of isopropylamine
are shown in Figure 3. In this case, one of the isopropylamine
molecules attacks the most electron-deficient olefinic carbon
of VSM carbohydrates, whereas the second amine molecule
transfers the N-H proton to the other carbon atom. The first
amine transfers its N-H hydrogen to the second nitrogen
atom via hydrogen bonding (Figure 3).
The computed activation barriers were found to be 10-19
kcal mol-1 lower for transition states with two isopropyla-
mines compared to their corresponding single amine transi-
tion states at both ab initio and DFT levels of theory
(Figures 2 and 3). Activation barriers were computed with
the separated reactants; however, in the relay process,
amines were considered as a complexed state, where they
are hydrogen bonded (Figure S1, Supporting Information).
Comparing the calculated activation barriers for transition
states 14e-e-TS2 and 14a-a-TS2, it appears that the former is
kinetically preferred over the latter (Figure 3). This result
supports the experimental observation for the formation of
14e-e from 2r with isopropylamine. Further, the reaction
energies calculated for 14e-e and 14a-a also indicate prefer-
ential formation of the former product (Table 4). Hence, the
equatorial attack of isopropylamine toward 2r is kinetically
RHF/6-31G* basis set. The calculated results suggested
that the N C bond formation and proton transfer take
place simultaneously (Figure 2). Therefore, the transition
states formed with VSM carbohydrates 2r and 5r and
3 3 3
(13) Jones, G. O.; Guner, V. A.; Houk, K. N. J. Phys. Chem. A 2006, 110,
1216–1224.
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FIGURE 2. RHF/6-31G* optimized transition state geometries (distances in A) and activation barriers (kcal mol-1) for 5r and 2r with single
isopropylamine. B3LYP/6-31þG*//RHF/6-31G* calculated activation barriers in the gas phase and in THF are given in parentheses and
square brackets, respectively (gray = carbon; blue = nitrogen; red = oxygen; yellow = sulfur; white = hydrogen).
˚
and thermodynamically preferred. In the case of unprotected
VSM carbohydrate 5r, the activation barriers for transi-
tion states 13e-e-TS2 and 13a-a-TS2 suggested that the
latter transition state was preferred (Figure 3). The activa-
tion energy is 1.8 kcal mol-1 lower for 13a-a-TS2 than
for 13e-e-TS2 at the B3LYP/6-31þG*//RHF/6-31G* level
(Figure 3). However, the reaction energies calculated for
13e-e are ∼8 kcal mol-1 lower than that of 13a-a, which
supports the formation of 13e-e as an experimentally ob-
served product (Table 4).
product, whereas 5r takes a much longer time (10 h) to
complete the reaction process (Table 1). Further, the calcu-
lated activation energies also qualitatively support this ob-
servation as the barriers are relatively lower for 2r with
isopropylamine than that of 5r (Figure 3). Activation barrier
values in solvent (THF) are similar to the gas phase calcu-
lated results at the same level of theory (Figure 3). The free
energies of activation computed at RHF/6-31G* showed the
similar trend though with larger values (Table S2, Support-
ing Information).
It should be noted that the reaction of 5r with isopropy-
lamine produced a mixture of at least three compounds.
Therefore, it appears that the kinetic and thermodynamic
pathways compete with each other for 5r with isopropyla-
mine. Initially, the lower activation barrier can lead to the
formation of product 13a-a; however, it will equilibrate to
the more stable thermodynamic product 13e-e with time.9,14
The above-mentioned interpretation can be corroborated
with the observed reaction time. The reaction of 2r
with isopropylamine completes within 8 h with a single
The secondary amine, pyrrolidine, reacts with 2r to yield a
diastereomeric mixture of 17e-e and 17a-e as major and
minor isomers, respectively (Scheme 6). The diastereomeric
product 17a-e does not seem to form via concerted amine
relay mechanism as observed in other cases. The expected
formation of 17a-a via axial approach of pyrrolidine in a
concerted fashion is absent in this case. Since the reaction of
5r with pyrrolidine does not go to completion even after
5 days (Table 2), the difference in the reactivity of 2r and 5r
with pyrrolidine was examined computationally. The con-
certed transition state geometries were obtained for 2r
and 5r with two pyrrolidines for the equatorial approach
(Figure 4); however, such transition states for the axial
(14) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chem-
istry; University Science Books: Mill Valley, CA, 2006; p 380.
J. Org. Chem. Vol. 75, No. 2, 2010 309

Bhattacharya et al.
JOCArticle
FIGURE 3. RHF/6-31G* optimized transition state geometries (distances in A) and activation barriers (kcal mol-1) for 5r and 2r with two
isopropylamines. B3LYP/6-31þG*//RHF/6-31G* calculated activation barriers in the gas phase and in THF are given in parentheses and
square brackets, respectively (gray = carbon; blue = nitrogen; red = oxygen; yellow = sulfur; white = hydrogen).
˚
FIGURE 4. RHF/6-31G* optimized transition state geometries (distances in A) and activation barriers (kcal mol-1) for 5r and 2r with two
˚
pyrrolidine. B3LYP/6-31þG*//RHF/6-31G* calculated activation barriers in the gas phase and in THF are given in parentheses and square
brackets, respectively (gray = carbon; blue = nitrogen; red = oxygen; yellow = sulfur; white = hydrogen).
approach of the amines were not found. The N-H proton
transfer to olefinic carbon via proton relay mechanism in the
axial approach is not concerted with the formation of the
N-C bond. Experimental results suggested that the equa-
torial approach of pyrrolidine leads to the formation of 17e-e
as a major product for 2r, but 5r did not afford desired
products with this amine (Table 2). The computed activation
barriers suggest that the transition state (17e-e-TS2) ob-
tained for 2r with two pyrrolidine is much lower in energy
(∼4-6 kcal mol-1) than the corresponding 5r transition
state (28e-e-TS2) (Figure 4). Therefore, these results indicate
that the formation of aminosugars with secondary amine for
310 J. Org. Chem. Vol. 75, No. 2, 2010

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JOCArticle
TABLE 5. B3LYP/6-31+G* Calculated Strain Energy Derived from
Transition State Geometries by Removing the Amines and Their Corre-
sponding Parent Systems
entry
strain energy
13e-e-TS2
14e-e-TS2
28e-e-TS2
17e-e-TS2
50.1
46.6
56.4
53.9
unprotected VSM carbohydrate 5r is more difficult than the
protected VSM carbohydrate 2r. The experimental findings
corroborate the calculated results.
The observed differences in the activation barriers for 5r
and 2r with isopropylamine (Figure 3) and pyrrolidine
(Figure 4) can be rationalized with the strain induced in
VSM carbohydrates upon reaction with such amines. We
have calculated the strain energies in VSM carbohydrate
systems by removing the amines from the transition state
geometries and computing the energies for those carbohy-
drates without perturbing their structures at the B3LYP/6-
31þG* level. The energy difference between the parent VSM
carbohydrates and their corresponding geometries derived
from the transition state structures without amines yields the
strain developed with different amines (Table 5). These
results clearly show that the strain energies are higher for
VSM carbohydrate with pyrrolidine than that of isopropy-
lamine in both cases of 5r and 2r, which presumably leads
toward the relatively higher activation barrier with the
former amine. Further, strain energy data also rationalize
the higher activation barriers for 5r compared to 2r with
respective amines (Table 5).
It should be noted that pyrrolidine on reaction with 2r
afforded 17a-e as a minor product, but the addition of
pyrrolidine and proton transfer is not concerted in nature.
The amine residue and proton come from the opposite side of
the olefinic carbons (Scheme 6). Therefore, the formation of
17a-e seems to be a stepwise process, as shown in Figure 5.
The transition state 17a-e-Ts1 forms via the abstraction of
pyrrolidine proton by the second pyrrolidine ring and goes to
17a-e-complex for the antiface proton transfer to the olefinic
double bond. The protonated pyrrolidine in 17a-e-complex
interacts with sulfone oxygen near the newly formed carba-
nion, which eventually leads toward the formation of second
transition state 17a-e-TS2 with the transfer of proton from
the amine to VSM carbohydrate. 17a-e-TS2 is slightly lower
in energy compared to the complex, which suggests that the
proton transfer process from the protonated pyrrolidine
could take place instantaneously without involving these
steps. It is known that the proton transfer processes from
cationic systems could be spontaneous or barrierless.15 The
influence of solvent seems to be larger in the stepwise process
as the gas phase activation barrier for the formation of the
17a-e-Ts1 transition state is stabilized by ∼6.0 kcal mol-1 in
THF. The calculated energy indicates that the reaction is
exothermic by 8.8 kcal mol-1 in THF. Higher activation
barrier (29.5 kcal mol-1) for 17a-e-Ts1 (Figure 5) compared
to 17e-e-TS2 (22.7 kcal mol-1; Figure 4) suggests that the
latter should be the major product. The observed experi-
mental product ratios are qualitatively in agreement with the
calculated results.
FIGURE 5. Stepwise B3LYP/6-31þG*//RHF/6-31G* calculated
potential energy surface for the formation of 17a-e. Calculated
results in solvent (THF) are given in square brackets.
Conclusion
We have established that the protecting groups of VSM
hex-2-enopyranosides present at C-6 and C-4 play an im-
portant role in determining the rate and the selectivity of
addition of amines to these compounds. The absence of
protecting group at 6-OH of 5r adversely affects its reactiv-
ity even with primary amines. Tritylated VSM carbohydrate
4r is much less reactive toward primary amines and virtually
resistant toward Michael addition by secondary amines. We
presume that the rigid and more organized structural fea-
tures of 2r expose the electrophilic C-2 site toward attacking
nucleophiles. The conformational flexibilities of 4r/5r
makes the C-2 position of these compounds more hindered
toward incoming nucleophilic nitrogen. It is also clear from
our present study that primary amines under no circum-
stances could be delivered from a direction opposite to the
disposition of the anomeric methoxy group of 4r as was the
case for the addition of deuterides and carbon nucleophiles
to analogous flexible nitroolefin derivatives.16
Extensive computational study explains the experimental
observations appropriately and, for the first time, speculates
into the mechanistic aspects for the Michael addition reac-
tions of free amines to the VSM carbohydrates. In the
present investigation, quantum chemical calculations were
used to study the addition of the primary and secondary
amines to VSM carbohydrates 2r and 5r. The difference in
the activation barriers for VSM carbohydrates 2r and 5r
with pyrrolidine arises due to the strain induced on the
substrates while interacting with the amine. The calculated
activation barrier for the formation of 17a-e-TS1 from 2r
and pyrrolidine via stepwise mechanism was found to be
(16) (a) Seta, A.; Tokuda, K.; Kaiwa, M.; Sakakibara, T. Carbohydr. Res.
1996, 281, 129–142. (b) Sakakibara, T.; Tokuda, K.; Hayakawa, T.; Seta, A.
Carbohydr. Res. 2000, 327, 489–496.
(15) Zeng, K.; Cao, Z.-X. Chin. J. Chem. 2006, 24, 293–298.
J. Org. Chem. Vol. 75, No. 2, 2010 311

Bhattacharya et al.
JOCArticle
higher than that of concerted proton relay mechanism 17e-e-
TS2, which is in good agreement with the product ratios
obtained in this reaction. The selectivity of addition of
nucleophiles to vinyl nitro-modified hex-2-enopyranosides
was explained earlier in terms of electrostatic interaction,17a
stereoelectronic control17a steric hindrance,17a A(1,3) strain,17b
and also hydrogen bonding.17b The present study emphasizes
that, henceforth, any discussion on the selectivity of addition
of nucleophiles to electron-deficient hex-2-enopyranosyl sys-
tems would require the study of the influence of protecting
groups, as well.
137.5, 137.8, 143.8, 144.8. Anal. Calcd for C28H30O6-
S 0.5CH3OH: C, 67.04; H, 6.32. Found: C, 67.2; H, 6.75.
3
Methyl 2,3-dideoxy-3-C-p-tolylsulfonyl-r-D-erythro-hex-2-
enopyranoside 5r: Compound 2r (0.5 g, 1.24 mmol) was dis-
solved in dry methanol (20 mL) and cooled to 0 °C under
nitrogen. To this solution was added acetyl chloride (0.2 mL,
2.82 mmol) dropwise over a period of 0.5 h with continuous
stirring. After completion of addition, the reaction mixture was
warmed to room temperature and the stirring was continued for
another 2 h. The solution was then evaporated to dryness under
reduced pressure, and the residual liquid was coevaporated
twice with pyridine to get a syrupy compound. The compound
thus obtained was dissolved in EtOAc, and the organic layer
was washed thoroughly with aq saturated NaHCO3 solution.
The organic layer was then separated, dried over anhyd Na2SO4,
filtered, and evaporated to dryness. The residue was puri-
fied over silica gel to yield 5r (0.38 g, 96%): colorless jelly;
[R]28D -29.9 (c 0.11, CHCl3); 1H NMR (CDCl3) δ 2.30 (s, 3H),
3.40 (s, 3H), 3.65-3.83 (m, 3H), 4.52-4.56 (m, 1H), 5.05 (d, J =
3.03 Hz, 1H), 6.81-6.84 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.76
(d, J = 8.0 Hz, 2H); 13C NMR δ 21.6, 56.4, 61.5, 62.3 (CH2),
71.5, 94. 9, 128.3, 129.9, 134.8, 136.7. 144.9. Anal. Calcd for
C14H18O6S: C, 53.49; H, 5.77. Found: C, 53.66; H, 5.53.
Experimental Section
General Method: See Supporting Information
Methyl 3-C-p-tolylsulfonyl-4,6-di-O-(phenylmethylene)-r-D-
altro-pyranoside 8: To a solution of 6 (3.2 g, 8.99 mmol) in
DMF (15 mL) were added p-thiocresol (7.51 g, 60.6 mmol) and
TMG (4.56 g, 36.36 mmol). The reaction mixture was heated for
4 h at 80-90 °C, cooled to rt, and poured into saturated aq NaCl
solution (80 mL). The mixture was extracted with EtOAc (3 ꢀ 30
mL). The EtOAc layer was washed with saturated aq NaHCO3
(2 ꢀ 25 mL). EtOAc layers were pooled together, dried over
anhyd Na2SO4, and filtered, and the filtrate was evaporated
under reduced pressure. The resulting syrup was purified over
silica gel to yield 7 (3.84 g, 89%). To a solution of 7 (4.81 g, 10.0
mmol) in methanol (30 mL) was added MMPP (16.88 g, 34.17
mmol). The reaction mixture was stirred for 6 h at room
temperature and filtered, and the filtrate was neutralized with
saturated aq NaHCO3 (70 mL). The mixture was extracted with
EtOAc (3 ꢀ 30 mL). The organic layer was separated, dried over
anhyd Na2SO4, and filtered, and the filtrate was concentrated to
dryness under reduced pressure to yield 8 (5.1 g, 88%): colorless
jelly; [R]28D þ18.9 (c 0.75, CHCl3); 1H NMR (CDCl3) δ 2.32 (s,
3H), 3.42 (s, 3H), 3.54-3.63 (m, 2H), 3.73-3.77 (m, 1H),
4.14-4.16 (m, 1H), 4.18-4.22 (m, 1H), 4.37-4.39 (m, 1H),
4.47-4.55 (m, 4H), 4.62 (d, 1H, J = 5.2 Hz), 7.08 (d, 2H, J = 8.0
Hz), 7.24-7.39 (m, 10H), 7.75 (d, 2H, J = 8.0 Hz); 13C NMR δ
21.5, 56.3, 67.4, 67.5, 70.1 (CH2), 72.1 (CH2), 72.6, 73.5 (CH2),
74.0, 102.8, 127.5, 127.7, 127.8, 127.9, 128.1, 128.5, 129.0, 129.2,
137.4, 144.1. Anal. Calcd for C28H32O7SCH3OH: C, 63.95; H,
6.66. Found: C, 63.86; H, 7.03.
Methyl 2,3-dideoxy-3-C-p-tolylsulfonyl-4,6-di-O-(phenylme-
thylene)-r-D-erythro-hex-2-enopyranoside 3r: To a solution of
8 (5.12 g, 10.0 mmol) in dry pyridine (25 mL) was added a
solution of methanesulfonyl chloride (2.8 mL, 36.45 mmol) in
dry pyridine (15 mL) at 0 °C. The mixture was left overnight at
4 °C, poured into saturated aq NaHCO3 (70 mL), and the
aqueous phase was extracted with EtOAc (3 ꢀ 30 mL). Organic
layers were collected together, dried over anhyd Na2SO4, and
filtered, and the filtrate was evaporated. To the crude residue
thus obtained was added dry pyridine (20 mL), and the resulting
solution was heated under reflux for 2 h and cooled. Pyridine
was evaporated under reduced pressure to get an oily residue.
The resulting residue was purified over silica gel (eluent 33%
EtOAc/petroleum ether) to yield 3r (4.95 g, 86%): colorless
jelly; [R]28D -11.4 (c 0.65, CHCl3); 1H NMR (CDCl3) δ 2.31 (s,
3H), 3.47 (s, 3H), 3.64-3.71 (m, 2H), 3.94-3.96 (m, 1H), 4.40 (d,
1H, J = 11.2 Hz), 4.48 (d, 1H, J = 12.0 Hz), 4.64 (d, 1H, J =
12.0 Hz), 4.75 (d, 1H, J = 8.8 Hz), 4.84 (d, 1H, J = 11.2 Hz),
5.15 (d, 1H, J = 2.8 Hz), 6.93-6.95 (m, 3H), 7.04 (d, 2H, J = 8.0
Hz), 7.19-7.34 (m, 8H), 7.64 (d, 2H, J = 8.0 Hz); 13C NMR δ
21.5, 56.3, 68.1 (CH2), 70.2, 70.3, 73.5 (CH2), 73.9 (CH2), 95.0,
127.3, 127.4, 127.5, 127.8, 127.9, 128.0, 128.4, 129.3, 136.1,
Methyl 2,3-dideoxy-3-C-p-tolylsulfonyl-β-D-erythro-hex-2-
enopyranoside 5β: Compound 5β (0.69 g, 71%, colorless jelly)
was prepared from 2β (1.20 g, 2.98 mmol) following the same
procedure as described above for the preparation of 5r: [R]28
D
-10.2 (c 0.324, CHCl3); 1H NMR (CDCl3) δ 2.16-2.17 (m, 1H),
2.18 (s, 3H), 3.34 (m, 1H), 3.48 (s, 3H), 3.59-3.64 (m, 1H),
3.71-3.74 (m, 1H), 3.89-3.92 (m, 1H), 4.26 (br s, 1H), 5.21 (s,
1H), 6.69 (d, 1H, J = 2.0 Hz), 7.36 (d, 2H, J = 8.0 Hz), 7.78 (d,
2H, J = 8.0 Hz); 13C NMR δ 21.7, 56.5, 61.3, 62.71 (CH2), 77.8,
95.8, 128.4, 130.1, 135.2, 135.4, 143.3, 145.4; HRMS [ES, (M þ
Na)þ] calcd for C14H18O6NaS 337.0722, obsd 337.0724.
General Procedure for the Addition of Primary and Secondary
Amines to 2r, 2β, 3r, 4r, 4β, 5r, and 5β: To a solution of the
appropriate vinyl sulfone-modified carbohydrate in dry THF
(1 mL/mmol) was added an amine (5 equiv) and was either
stirred at room temperature or heated at 90-100 °C. After
completion of the reaction (TLC), THF was evaporated under
reduced pressure. The residue obtained was triturated with
EtOAc, and the organic layer was washed with saturated aq
solution of NaHCO3. The organic layer was separated, dried
over anhyd Na2SO4, and filtered, and the filtrate was evapo-
rated under reduced pressure. The residue was purified over
silica gel to afford the product.
Methyl 2,3-dideoxy-2-C-isopropylamino3-C-p-tolylsulfonyl-
4,6-di-O-(phenylmethylene)-r-D-glucopyranoside 9e-e: Follow-
ing the general procedure, isopropylamine was reacted with
3r (0.5 g, 1.01 mmol) at rt for 14 h to yield 9e-e (0.53 g, 93%):
hygroscopic solid; [R]28 þ26.8 (c 0.75, CHCl3); 1H NMR
D
(CDCl3) δ 0.9 (d, 3H, J = 6.3 Hz), 0.99 (d, 3H, J = 6.3 Hz),
2.36 (s, 3H), 2.84-2.91 (m, 1H), 3.33 (s, 3H), 3.35-3.38 (m, 5H),
4.20-4.31 (m, 2H), 4.52 (d, 1H, J = 12.0 Hz), 4.71-4.76 (m,
2H), 4.99 (d, 1H, J = 10.4 Hz), 7.11-7.36 (m, 12H), 7.83 (d, 2H,
J = 8.0 Hz); 13C NMR δ 21.5, 21.9, 24.4, 46.0, 54.4, 55.0, 68.5
(CH2), 69.1, 69.8, 71.2, 73.2 (CH2), 73.6 (CH2), 97.4, 127.4,
127.8, 127.9, 128.1, 128.4, 128.9, 137.5, 138.2, 140.5, 143.3.
Anal. Calcd for C31H39O6S 1CH3OH: C, 65.62; H, 7.40; N,
3
2.39. Found: C, 65.69; H, 7.57; N, 2.79.
Methyl 2,3-dideoxy-2-C-isopropylamino-3-C-p-tolylsulfonyl-
6-O-trityl-r-D-glucopyranoside 10e-e: Following the general
procedure, isopropylamine was reacted with 4r (0.15 g, 0.27
mmol) at rt for 12 h to yield 10e-e (0.158 g, 91%): white crystal;
mp 126-127 °C; [R]28 þ42.9 (c 0.366, CHCl3); 1H NMR
D
(CDCl3) δ 0.85-0.97 (m, 6H), 2.42 (s, 3H), 2.87 (m, 1H),
3.23-3.43 (m, 4H), 3.42 (s, 3H), 3.73-3.80 (m, 1H),
4.08-4.17 (m, 1H), 4.43 (br s, 1H), 4.79 (d, 1H, J = 3.0 Hz),
(17) (a) Sakakibara, T.; Sudoh, R. J. Org. Chem. 1977, 42, 1746–1750.
(b) Sakaibara, T.; Tachimori, Y.; Sudoh, R. Tetrahedron 1984, 40, 1533–1539.
312 J. Org. Chem. Vol. 75, No. 2, 2010

Bhattacharya et al.
JOCArticle
7.19-7.50 (m, 17H), 7.81 (d, 2H, J = 8.2 Hz); 13C NMR δ 21.6,
24.4, 30.9, 45.4, 53.9, 54.9, 63.3 (CH2), 64.7, 69.5, 70.2, 76.4,
86.5, 96.6, 126.9, 127.7, 128.7, 128.7, 128.9, 139.0, 144.0. Anal.
Calcd for C36H41NO6S 0.5CHCl3: C, 64.90; H, 6.19; N, 2.07.
Found: C, 64.90; H, 5.99; N, 1.95.
1.70-1.82 (m, 3H), 1.96-1.99 (m, 1H), 2.13 (s, 3H), 2.24-2.29
(m, 1H), 2.54-2.60 (m, 1H), 3.40 (s, 3H), 3.57-3.61 (dd, 1H, J =
3.6, 11.6 Hz), 3.64-3.72 (m, 2H), 3.74-3.87 (m, 2H), 4.14-4.17
(dd, 1H, J = 4.4, 10.4 Hz), 4.70 (d, 1H, J = 3.2 Hz), 5.20 (s, 1H),
6.95-7.00 (m, 4H), 7.18-7.29 (m, 3H), 7.61 (d, 2H, J = 8.4 Hz);
13C NMR δ 21.4, 24.8 (CH2), 24.9 (CH2), 25.9 (CH2), 32.7 (CH2),
34.9 (CH2), 54.6, 54.8, 55.3, 62.2, 64.9, 69.3 (CH2), 76.3, 98.9,
101.6, 126.1, 127.7, 128.0, 129.0, 136.4, 139.0, 144.0; HRMS (ES,
(M þ H)þ) calcd for C27H36NO6S 502.2263, obsd 502.2261.
Methyl 2,3-dideoxy-2-C-pyrrolidino-4,6-O-(phenylmethylene)-
3-C-p-tolylsulfonyl-r-D-glucopyranoside 17e-e and Methyl 2,3-di-
deoxy-2-C-pyrrolidino-4,6-O-(phenylmethylene)-3-C-p-tolylsulfo-
nyl-R-D-mannopyranoside 17a-e: Following the general procedure,
pyrrolidine was reactedwith2r(0.62 g, 1.54 mmol) at rt for 12 h to
yield a diastereomeric mixture from which 17e-e (0.41 g, 55%) was
isolated by column chromatography over silica gel: white crystal;
mp 89-92 °C; [R]28D þ 45.6 (c 0.71, CDCl3); 1H NMR (CDCl3) δ
1.25-1.58 (m, 4H), 2.16 (s, 3H), 2.69-2.74 (m, 2H), 2.91-2.94
(m, 2H), 3.43 (s, 3H), 3.66-3.74 (m, 2H), 3.80-3.93 (m, 2H),
3.97-4.03 (m, 1H), 4.18-4.22 (m, 1H), 4.83 (d, 1H, J = 3.2 Hz),
5.25 (s, 1H), 7.04-7.06 (d, 2H, J = 8.0 Hz), 7.16-7.17 (m, 2H),
7.28-7.31 (m, 3H), 7.68 (d, 2H, J = 8.0 Hz); 13C NMR δ 21.3,
24.1 (CH2), 47.9 (CH2), 54.6, 57.7, 62.4, 62.4, 69.4 (CH2), 76.4,
98.9, 101.4, 126.0, 127.8, 128.0, 128.8, 128.9, 136.6, 139.2, 143.7.
3
Methyl 2,3-dideoxy-2-C-benzylamino-3-C-p-tolylsulfonyl-6-
O-trityl-r-D-glucopyranoside 11e-e: Following the general pro-
cedure, benzylamine was reacted with 4r (0.15 g, 0.27 mmol) at
90-100 °C for 12 h to yield 11e-e (0.163 g, 91%): hygroscopic
solid; [R]28D þ41.2 (c 0.315, CHCl3); 1H NMR (CDCl3) δ 2.41 (s,
3H), 3.05-3.33 (m, 2H), 3.41 (s, 3H), 3.45-3.63 (m, 2H),
3.70-3.79 (m, 2H), 4.05-4.15 (m, 1H), 4.34 (br s, 1H), 4.56
(d, 1H, J = 3.1 Hz), 7.07-7.34 (m, 17H), 7.44-7.49 (m, 5H),
7.78 (d, 2H, J = 8.1 Hz); 13C NMR 22.0, 52.0 (CH2), 55.3, 57.3,
63.7 (CH2), 65.2, 70.2, 70.6, 87.0, 96.9, 127.4, 127.5, 128.2, 128.8,
128.9, 129.2, 129.7, 138.7, 140.6, 144.5, 144.7; HRMS (ES, (M þ
H)þ) calcd for C40H42NO6S 664.2733, obsd 664.2715.
Methyl 2,3-dideoxy-2-C-cyclohexylamino-3-C-p-tolylsulfonyl-
6-O-trityl-r-D-glucopyranoside 12e-e: Following the general pro-
cedure, cyclohexylamine was reacted with 4r (0.15 g, 0.27 mmol)
at 90-100 °C for 12 h to yield 12e-e (0.168 g, 93%): glassy solid;
[R]28D þ24.8 (c 0.716, CHCl3); 1H NMR(CDCl3) δ 0.84-1.81 (m,
10H), 2.43 (s, 3H), 3.21-3.41 (m, 4H), 3.44 (s, 3H), 3.50-3.78 (m,
1H), 4.09-4.15 (m, 1H), 4.43 (br s, 1H), 4.77 (d, 1H, J = 3.1 Hz),
7.17-7.34 (m, 12H), 7.40-7.59 (m, 5H), 7.79 (d, 2H, J = 8.2 Hz);
13C NMR δ 22.0, 25.3 (CH2), 25.4 (CH2), 26.5 (CH2), 54.0, 54.5,
55.3, 63.7 (CH2), 65.2, 70.1, 70.6, 86.9, 97.5, 127.3, 128.2, 129.0,
129.2, 129.4, 139.6, 144.5; HRMS (ES, (M þ H)þ) calcd for
C39H46NO6S 656.3046, obsd 656.3071.
Synthesis of 10e-e from 13e-e: Following the general proce-
dure, isopropylamine was reacted with 5r (0.15 g, 0.27 mmol) at
rt for 10 h to yield a mixture from which 13e-e was separated
(0.09 g, 53%). Compound 13e-e was tritylated using tritylchlor-
ide in pyridine under standard conditions afforded the trityl
analogue 10e-e in 45% overall yield.
Methyl 2,3-dideoxy-2-C-isopropylamino-4,6-O-(phenylmethy-
lene)-3-C-p-tolylsulfonyl-r-D-glucopyranoside 14e-e: Following
the general procedure, isopropylamine was reacted with 2r (0.74
g, 1.84 mmol) at rt for 8 h to yield 14e-e (0.73 g, 90%): white
crystal; mp 99-101 °C; [R]28D þ34.6 (c 0.625, CDCl3); 1H NMR
(CDCl3) δ 1.06-1.16 (m, 6H), 2.17 (s, 3H), 2.95-3.01 (m, 1H),
3.43 (s, 3H), 3.48-3.58 (m, 1H), 3.69-3.89 (m, 4H), 4.15-4.21
(m, 1H), 4.73 (d, 1H, J = 3.3 Hz), 5.24 (s, 1H), 6.97-7.01 (m,
4H), 7.19-7.30 (m, 3H), 7.63 (d, 2H, J = 8.2 Hz); 13C NMR δ
21.1, 22.0, 23.9, 46.7, 54.7, 55.0, 61.8, 64.4, 68.9 (CH2), 76.0,
98.4, 101.3, 125.7, 127.4, 127.67, 128.6, 128.7, 136.0, 138.6,
143.7. Anal. Calcd for C24H31NO6S: C, 62.45; H, 6.77, N,
3.03. Found: C, 62.63; H, 6.60; N, 2.96.
Anal. Calcd for C25H31NO6S 1H2O: C, 61.08; H, 6.77; N, 2.85.
3
Found: C, 60.80; H, 6.51; N, 2.87. The slower moving compound
inTLC, 17a-e, was isolated by column chromatography over silica
gel (0.27 g, 37%): yellow jelly; [R]28D þ36.6 (c 0.71, CDCl3); 1H
NMR (CDCl3) δ 1.80-1.82 (m, 4H), 2.30 (s, 3H), 2.68-2.73 (m,
4H), 3.45 (s, 3H), 3.66-3.69 (m, 1H), 3.79-3.83 (m, 2H),
4.23-4.34 (m, 2H), 4.69-4.80 (m, 1H), 4.83 (s, 1H), 5.40 (s,
1H), 6.94 (d, 2H, J =8.0Hz), 7.33-7.39 (m, 5H), 7.67 (d, 2H, J =
8.0 Hz); 13C NMR δ 21.4, 23.4 (CH2), 51.6 (CH2), 54.4, 57.9, 61.2,
61.6, 69.4 (CH2), 75.3, 98.4, 102.2, 126.4, 127.9, 128.8, 128.9,
129.0, 136.8, 139.5, 143.5; HRMS (ES, (M þ H)þ) calcd for
C25H32NO6S 474.1950, obsd 474.1940.
(1R,3S,4R,7R,8S)-7-Benzyloxy-3-methoxy-8-[(4-methylphenyl)-
sulfonyl)]-2,5 dioxabicyclo[2.2.2]octane 20: A solution of compound
5r (1.57 g, 5.0 mmol) in neat morpholine (5 mL) was heated at
70-80 °C for 24 h under N2. Morpholine was evaporated under
reduced pressure, and the resulting residue was dissolved in EtOAc
(30 mL). The organic layer was washed with water (2 ꢀ 25 mL),
separated, and dried over anhyd Na2SO4. Organic layer was
filtered, and the filtrate was evaporated under reduced pressure.
The residue obtained was purified over silica gel to afford 19:
colorless jelly (0.91 g, 58%). To a suspension of 90% t-BuOK
(0.673 g, 6.0 mmol) in dry THF (10 mL/mmol) at 0 °C was added a
solution of 19 (0.785 g, 2.5 mmol) in dry THF (15 mL), and the
resulting solution was stirred for 15 min under N2. The reaction
mixture was alloewd to come to room temperature, and to this
reaction mixture was added benzylbromide (0.72 mL, 6.1 mmol)
under stirring; the reaction was continued for 2 h. The organic
solvent was evaporated, and the residue was dissolved in EtOAc
(25 mL), washed with saturated aq NH4Cl (70 mL), and separated.
Organic layer was dried over anhyd Na2SO4 and filtered, and the
filtrate was evaporated. The resulting residue was purified over
silica gel to yield 20 (0.82 g, 81%): white crystal; mp 131-133 °C;
[R]28D þ15.2 (c 0.6, CHCl3); 1H NMR (CDCl3) δ 2.44 (s, 3H), 3.43
(s, 3H), 3.53-3.58 (m, 1H), 3.80-3.83 (m, 1H), 3.87-3.94 (m, 1H),
4.05-4.13 (m, 3H), 4.60 (dd, 2H, J = 12.2, 14.6 Hz), 7.22-7.38 (m,
7H), 7.77 (d, 2H, J = 8.2 Hz); 13C NMR δ 21.6, 55.2, 65.1 (CH and
CH2), 65.4, 67.5, 70.6, 72.2 (CH2), 98.9, 127.7, 127.8, 128.3, 129.0,
134.7, 137.4. 145.0; HRMS (ESþ), m/z calcd for (M þ Na)þ
C21H24O6SNa 427.1191, found 427.1187.
Methyl 2,3-dideoxy-2-C-benzylamino-4,6-O-(phenylmethy-
lene)-3-C-p-tolylsulfonyl-r-D-glucopyranoside 15e-e: Following
the general procedure, benzylamine was reacted with 2β (0.21 g,
0.52 mmol) at room temperature for 12 h to yield 15e-e (0.21 g,
80%): yellowish solid; mp 126-128 °C; [R]28 þ42.2 (c 0.856,
D
CHCl3); 1H NMR (CDCl3) δ 2.19 (s, 3H), 3.35 (s, 3H),
3.50-3.54 (dd, 1H, J = 3.2, 10.0 Hz), 3.64-3.69 (m, 1H),
3.74-3.86 (m, 3H), 3.92 (s, 2H), 4.14-4.17 (dd, 1H, J = 3.6,
10.0 Hz), 4.59 (d, 1H, J = 3.2 Hz), 5.23 (s, 1H), 7.00 (d, 2H, J =
8.0 Hz), 7.04-7.06 (m, 2H), 7.22-7.43 (m, 8H), 7.64 (d, 2H, J =
8.0 Hz); 13C NMR δ 21.4, 51.5 (CH2), 55.3, 56.1, 62.0, 64.8, 69.2
(CH2), 76.2, 98.1, 101.6, 126.1, 127.1, 127.8, 128.1, 128.3, 128.5,
128.9, 129.1, 136.4, 138.6, 140.0, 144.2; HRMS (ES, (M þ H)þ)
calcd for C28H32NO6S 510.1950, obsd 510.1946.
Methyl 2,3-dideoxy-2-C-cyclohexylamino-4,6-O-(phenylmethy-
lene)-3-C-p-tolylsulfonyl-r-D-glucopyranoside 16e-e: Following
the general procedure, cyclohexylamine was reacted with 2β
(0.25 g, 0.62 mmol) at room temperature for 12 h to yield 16e-e
(0.24 g, 78%): dark brownish jelly; [R]28D þ39.7 (c 0.625, CHCl3);
1H NMR (CDCl3) δ 0.86-1.32 (m, 2H), 1.55-1.59 (m, 1H),
Methyl 2,3-dideoxy-2-C-isopropylamino-3-C-p-tolylsulfonyl-
6-O-trityl-β-D-glucopyranoside 21e-e: Following the general
procedure, isopropylamine was reacted with 4β (0.21 g,
0.37 mmol) at room temperature for 12 h to yield 21e-e
J. Org. Chem. Vol. 75, No. 2, 2010 313

Bhattacharya et al.
JOCArticle
(0.22 g, 93%): colorless jelly; [R]28D -18.7 (c 0.856, CHCl3); 1H
NMR (CDCl3) δ 0.93-1.26 (m, 6H), 2.47 (s, 3H), 2.92-3.02 (m,
1H), 3.11-3.40 (m, 4H), 3.48 (s, 3H), 4.02-4.11 (m, 2H), 4.19 (d,
1H, J = 6.9 Hz), 7.18-7.48 (m, 17H), 7.81 (d, 2H, J = 8.2 Hz);
13C NMR δ 21.6, 22.0, 24.5, 46.1, 54.6, 56.1, 63.1 (CH2), 64.9,
72.3, 75.9, 86.4, 106.4, 126.9, 127.7, 128.7, 129.1, 129.6, 135.3,
143.9, 145.1. Anal. Calcd for C36H41NO6S: C, 70.22; H, 6.71; N,
2.27. Found: C, 70.17; H, 6.47; N, 2.33.
TABLE 6. B3LYP/6-31þG*//RHF/6-31G* and B3LYP/6-31þG*
Calculated Activation Barriers (kcal mol-1) for 5r and 2r with Single
Isopropylamine
B3LYP/6-31þG* //RHF/6-31G*
B3LYP/6-31þG*
13e-e-TS1
13a-a-TS1
14e-e-TS1
14a-a-TS1
36.4
41.3
36.0
41.6
36.3
41.2
35.9
41.8
Methyl 2,3-dideoxy-2-C-pyrrolidino-3-C-p-tolylsulfonyl-6-O-
trityl-β-D-glucopyranoside 22e-e: Following the general proce-
dure, pyrrolidine was reacted with 4β (0.30 g, 0.54 mmol) at
rt for 36 h to yield 22e-e (0.32 g, 93%): brown solid; mp 119-
B3LYP/6-31þG*//RHF/6-31G* calculated results, full optimi-
zation of transition state geometries of VSM carbohydrates 2r
and 5r was performed with single isopropylamine. The calcu-
lated activation barriers with B3LYP/6-31þG* level are similar
to that of B3LYP/6-31þG*//RHF/6-31G* calculated results
(Table 6). Therefore, further calculations were carried out with
the B3LYP/6-31þG*//RHF/6-31G* level of theory, which
would be economical with similar accuracy for the studied
systems herein. The optimized transition state structures with
B3LYP/6-31þG* and RHF/6-31G* are quite similar in nature,
and no significant deviations were observed (Figure S2, Sup-
porting Information). To account for the solvation effect, single
point calculations were performed at the B3LYP/6-31þG* level
in solvent THF (ε = 7.58) using the polarizable continuum
solvation model (PCM)19 and UFF topological radii.20 Com-
plete vibrational analyses were performed to characterize the
transition states and ground state geometries. All calculations
were performed with the Gaussian 03 suite program on Win-
dows-based dual core Intel xeon machines.21
121 °C; [R]28 -10.4 (c 0.35, CHCl3); 1H NMR (CDCl3) δ
D
1.08-1.39 (m, 4H), 2.35 (s, 3H), 2.42-2.53 (m, 4H), 3.15-3.46
(m, 4H), 3.49 (s, 3H), 4.16-4.25 (m, 1H), 4.34 (d, 1H, J = 1.7
Hz), 4.47 (d, 1H, J = 8.0 Hz), 7.18-7.40 (m, 11H), 7.46-7.52
(m, 6H), 7.72 (d, 2H, J = 8.2 Hz); 13C NMR δ 21.5, 23.2 (CH2),
47.1 (CH2), 55.7, 58.4, 63.2 (CH2), 65.1, 69.4, 76.8, 86.4, 102.3,
126.9, 127.4, 127.7, 128.7, 129.0, 138.6, 144.0. Anal. Calcd for
C37H41NO6S 0.5CH2Cl2: C, 67.2; H, 6.32; N, 2.09. Found: C,
3
67.54; H, 6.29; N, 1.92.
Methyl 2,3-dideoxy-2-C-piperidino-3-C-p-tolylsulfonyl-6-O-
trityl-β-D-glucopyranoside 23e-e. Following the general proce-
dure, pyrrolidine was reacted with 4β (0.30 g, 0.54 mmol) at rt
for 38 h to yield 23e-e (0.30 g, 87%): brownish solid; mp
1
103-104 °C (decomposed); [R]28 -16.3 (c 0.35, CHCl3); H
D
NMR (CDCl3) δ 0.73 (br m, 2H), 1.17-1.25 (m, 4H), 2.28-2.36
(m, 2H), 2.43 (s, 3H), 2.61-2.79 (m, 3H), 3.29-3.48 (m, 4H),
3.55 (s, 3H), 4.14-4.16 (m, 1H), 4.33 (d, 1H, J = 1.8 Hz),
4.40-4.45 (m, 1H), 7.10-7.30 (m, 11H), 7.47-7.51 (m, 6H),
7.77 (d, 2H, J = 8.0 Hz); 13C NMR δ 21.5, 24.2 (CH2), 25.1, 50.1
(CH2), 55.6, 63.3 (CH2), 64.0, 65.3, 68.6, 76.7, 86.4, 102.6, 126.9,
127.7, 127.9, 128.8, 129.3, 138.5, 144.1; HRMS (ES, (M þ H)þ)
calcd for C38H44NO6S 642.2878, obsd 642.2889.
Acknowledgment. T.P. thanks the Department of Science
and Technology (DST), New Delhi, for financial support.
R.B. and C.M. thank CSIR, New Delhi, for a fellowship.
D.S.T. is also thanked for the creation of 400 MHz facility
under IRPHA program and DST-FIST for single crystal
X-ray facility. M.K.K. thanks UGC, New Delhi. for a fellowship.
Methyl 2,3-dideoxy-2-C-isopropylamino-4,6-O-(phenylmethy-
lene)-3-C-p-tolylsulfonyl-β-D-glucopyranoside 24e-e: Following
the general procedure, isopropylamine was reacted with 2β (0.30
g, 0.75 mmol) at rt for 12 h to yield 24e-e (0.31 g, 89%):
brownish-yellow solid; mp 112-115 °C; [R]28 þ40.5 (c 0.71,
D
CDCl3); 1H NMR (CDCl3) δ 1.06-1.24 (m, 6H), 2.20 (s, 3H),
3.15-3.21 (m, 1H), 3.44-3.51 (m, 2H), 3.53 (s, 3H), 3.55-3.58
(m, 1H), 3.65-3.70 (m, 1H), 3.98-4.03 (m, 1H), 4.22-4.26 (m,
1H), 4.43 (d, 1H, J = 5.6 Hz), 5.23 (s, 1H), 6.96-7.05 (m, 4H),
7.20-7.31 (m, 3H), 7.65 (d, 2H, J = 8.0 Hz); 13C NMR δ 21.5,
22.1, 24.3, 47.2, 54.3, 56.7, 66.7, 67.5, 69.2 (CH2), 75.6, 101.4,
106.1, 126.1, 127.9, 128.3, 129.0, 129.6, 136.3, 137.8, 144.5;
HRMS (ES, (M þ H)þ) calcd for C24H32NO6S 462.1950, obsd
462.1970.
Supporting Information Available: Experimental proce-
dures, full spectroscopic data of selected compounds. and CIF
files of compounds 10e-e, 20, and 22e-e. Supporting Informa-
tion also includes calculated total energies and Cartesian co-
ordinates of products and parent compounds along with the
calculated total energies, imaginary frequencies, and Cartesian
coordinates of transition states for 5r and 2r with two amines.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Methyl 2,3-dideoxy-2-C-pyrrolidino-4,6-O-(phenylmethylene)-
3-C-p-tolylsulfonyl-β-D-glucopyranoside 25e-e: Following the gen-
eral procedure, pyrrolidine was reacted with 2β (0.3 g, 0.75 mmol)
at rt for 15 h to yield 25e-e (0.30 g, 89%): brown solid; mp
108-110 °C; [R]28D -16.8 (c 0.327, CHCl3); 1H NMR (CDCl3) δ
1.39-1.66 (m, 4H), 2.33 (s, 3H), 2.66-2.72 (m, 4H), 3.43 (s, 3H),
3.57-3.64 (m, 2H), 3.67-3.77 (m, 2H), 4.29-4.31 (m, 1H),
4.41-4.46 (m, 1H), 4.71 (d, 1H, J = 3.6 Hz), 5.45 (s, 1H), 7.17
(d, 2H, J = 8.0 Hz), 7.24-7.35 (m, 5H), 7.73 (d, 2H, J = 8.0 Hz);
13C NMR δ 21.5, 23.3 (CH2), 49.6 (CH2), 55.6, 60.0, 65.1, 66.6,
69.7 (CH2), 75.0, 100.7, 101.0, 125.9, 128.1, 128.2, 128.8, 129.1,
136.7, 138.4, 144.0; HRMS (ES, (M þ H)þ) calcd for
C25H32NO6S 474.1950, obsd 474.1941.
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Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
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Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
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Computational Methods: All geometries were fully optimized
with restricted Hartree-Fock method18 using the 6-31G* basis
set. To calculate the energies with a higher basis set, single point
calculations were performed at the B3LYP/6-31þG* level11
using RHF/6-31G* optimized geometries. To validate the
(18) Roothaan, C. C. J. Rev. Mod. Phys. 1951, 23, 69–89.
314 J. Org. Chem. Vol. 75, No. 2, 2010