Highly enantioselective Michael addition of malonates to nitroolefins catalyzed by chiral bifunctional tertiary amine-thioureas based on saccharides

Article abstract of DOI:10.1055/s-0028-1087370

A series of saccharide-derived bifunctional tertiary amine-thioureas for the asymmetric Michael addition reaction have been designed and synthesized. The addition products between malonates and various nitroolefins were obtained in high yields (up to 99%)

Full text of DOI:10.1055/s-0028-1087370

3242
LETTER
Highly Enantioselective Michael Addition of Malonates to Nitroolefins
Catalyzed by Chiral Bifunctional Tertiary Amine–Thioureas Based on
Saccharides
Enantioselective
M
i
ichae
l
a
A
ddition
o
o
f
Malonates
-
Jlefins uan Li, Kun Liu, Hai Ma, Jing Nie, Jun-An Ma*
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(022)27403475; E-mail: majun_an68@tju.edu.cn
Received 14 June 2008
enamine is the nucleophile, which attacks the Michael ac-
ceptor.9 In the second mechanism B, the tertiary amine
plays the role of chiral base which forms an ion pair be-
tween the enolate and the chiral ammonium. The enolate
is the nucleophilic species involved in this type of addi-
tion reactions.10 It should be noted that in the catalytic pro-
cedures both the amine and the thiourea functionalities are
required for the catalytic activity.
Abstract: A series of saccharide-derived bifunctional tertiary
amine-thioureas for the asymmetric Michael addition reaction have
been designed and synthesized. The addition products between
malonates and various nitroolefins were obtained in high yields (up
to 99%) and excellent enantioselectivities (up to 99% ee).
Key words: asymmetric catalysis, Michael addition, nitroolefins,
bifunctional thiourea, saccharides
As part of our ongoing effort in developing saccharide-
substituted thiourea catalysts,11,12 we realized that these
chiral molecules should be tunable and bifunctional orga-
nocatalysts. It is well known that the asymmetric Michael
addition of malonates to nitroolefins is an important C–C
bond-forming reaction that provides access to versatile
enantioenriched nitroalkanes.8m,13As mentioned above,
nitroolefin and malonate could be simultaneously activat-
ed by the thiourea-tertiary amine catalyst. Accordingly,
we designed and synthesized a series of saccharide-
substituted tertiary amine-thiourea compounds 2c–h
(Scheme 1),15 and their catalytic activities were evaluated
in the direct Michael addition reactions of malonates to
nitroolefins. In this letter, we wish to disclose the prelim-
inary results of this research.
Asymmetric Michael additions are one of the most valu-
able C–C bond-forming reactions because they give syn-
thetically useful chiral building blocks.1 Among the
variants of these reactions, Michael additions of carbonyl
compounds to nitroolefins normally generate versatile bi-
functionalized products.2 Recently, considerable research
efforts have been made toward developing environment-
friendly nonmetallic organocatalysts for these process-
es.3,4 In this vein, the utilization of chiral bifunctional thio-
ureas has emerged as a viable strategy in the design of
efficient organocatalysts.5 Notable examples include
Jacobsen’s peptide thioureas6 and Takemoto’s amine thio-
ureas.7 Following these pioneering work, a number of re-
search group have developed different bifunctional
thiourea catalysts for the Michael addition aimed to im-
proving reactivity, broadening substrate scope, and en-
hancing stereoselectivity.8
The Michael addition of methyl malonate to nitrostyrene
was selected as a model reaction (Scheme 2), and Table 1
summarizes the results. Bifunctional thioureas 2a and 2b,
which lack tertiary amine moiety, exhibited poor catalytic
activity for the addition reaction (entries 1 and 2). To our
delight, when the same reactions were carried out in the
presence of bifunctional thiourea-tertiary amines 2c,d–f,
Two catalytic approaches can be envisaged for organocat-
alyzed Michael addition to nitroolefins (Figure 1).2c,5d
Mechanism A involves the formation of an enamine inter-
mediate with a chiral primary or secondary amine. This
chiral
scaffold
S
chiral
scaffold
S
N
H
O
N
N
H
O
N
H
O–
H
O–
N
NH
Me
Me
+
+
+
N
H
N
R2
R1
O
O
RO
OR
R3
R3
A
B
Figure 1 Proposed dual functional activation mechanism
SYNLETT 2008, No. 20, pp 3242–3246
1
6
.1
2
.2
0
0
8
Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087370; Art ID: W09408ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Michael Addition of Malonates to Nitroolefins
3243
AcO
AcO
S
O
O
R1O
AcO
R1O
+
NCS
N
H
N
NR2
2
H
AcO
H2N
NR2
2
OAc
OAc
2
1
OAc
OAc
OAc
S
S
O
O
AcO
AcO
AcO
AcO
N
H
N
N
H
N
H
NH2
NH2
H
OAc
OAc
2a
2b
OAc
S
S
O
O
AcO
AcO
AcO
AcO
N
H
N
H
N
H
N
NMe2
NMe2
H
OAc
OAc
2c
2d
OAc
AcO
AcO
OAc
OAc
O
O
S
AcO
AcO
O
OAc
O
S
N
H
N
NMe2
O
OAc
H
AcO
AcO
O
OAc
N
H
N
H
NMe2
2f
AcO
OAc
2e
OAc
OAc
S
S
O
O
AcO
AcO
AcO
N
H
N
N
H
N
N(n-Bu)2
N(i-Bu)2
AcO
H
H
OAc
OAc
2g
2h
Scheme 1 Saccharide-substituted thiourea catalysts synthesized and evaluated in the direct Michael reaction
the adduct was produced in excellent yield with high
enantioselectivity (entries 3–6). Interestingly, the S,S-
configuration of 1,2-diamino-cyclohexane matched the
b-D-glucopyranose to enhance the stereochemical control
in this type of addition reaction. It is noteworthy that the
alkyl chain of the tertiary amine moiety could influence
the catalytic activity and enantioselectivity. The addition
reaction did not occur in the presence of organocatalyst 2g
(with i-Bu group), while excellent yield and enantioselec-
tivity were obtained by using thiourea 2h (with n-Bu sub-
stituent, entries 7 and 8). In addition, the catalyst loading
could be reduced to 10 mol% without compromising the
enantioselectivity, but the reaction must then be carried
out under a longer reaction time (entries 9–11).
Table 1 Enantioselective Michael Addition of Dimethyl Malonate
to Nitrostyrene Catalyzed by Organocatalysts 2a–fa
Entry
Cat. (mol%)
2a (15)
2b (15)
2c (15)
2d (15)
2e (15)
2f (15)
2g (15)
2h (15)
2h (10)
2c (10)
2c (5)
Time (h)
84
Yieldb (%) eec,d (%)
1
2
<5
<5
99
99
99
99
0
–
84
–
3
24
92 (S)
83 (R)
88 (S)
83 (S)
–
4
48
5
36
6
84
7
144
96
8
99
99
99
99
99 (S)
99 (S)
91 (S)
89 (S)
MeO2C
CO2Me
NO2
CO2Me
CO2Me
2
NO2
+
Ph
9
144
48
CH2Cl2, r.t.
Ph
10
11
Scheme 2 Model reaction for screening of organocatalysts
52
Subsequently, we investigated the temperature and the
solvent effect on the addition reaction. As show in
a Conditions: dimethyl malonate (1 mmol), nitrostyrene (0.2 mmol),
cat. 2, CH2Cl2 (1 mL), r.t.
Table 2, the change of temperature did not have a signifi- b Isolated yield.
c Determined by chiral HPLC analysis.
cant effect on the yield and stereoselection of the adduct,
but a prolonged reaction time was required at –20 °C (en-
tries 1–5). Notably, the yields and enantioselectivities
were highly solvent dependent (entries 1, 4, and 6–10).
The reaction proceeded with acceptable rates along with
d Absolute configuration as determined by comparison with literature
HPLC retention times and optical rotation data.8a
Synlett 2008, No. 20, 3242–3246 © Thieme Stuttgart · New York

3244
X.-J. Li et al.
LETTER
Table 3 Scope of the Enantioselective 2c- or 2h-Catalyzed Michael
Table 2 Optimizing Reaction Conditions in the Presence of Organo-
catalyst 2ca
Addition Reactiona
Entry
1
R
Time (h)
36 (144)
36 (108)
20 (60)
20 (108)
36 (60)
36 (60)
36
Yieldb (%) eec (%)
Entry Solvent/additive
Temp Time Yieldb eec
(°C)
25
0
(h)
24
48
84
16
36
24
36
36
48
48
36
40
84
16
(%)
99
99
99
99
99
99
86
98
–
(%)
92
93
94
92
94
92
80
88
–
Ph
99 (99)
99
94 (99)
94 (90)
97 (98)
93 (90)
95 (97)
92 (92)
95
1
2
CH2Cl2
2
4-BrC6H4
2-BrC6H4
4-ClC6H4
2-ClC6H4
4-FC6H4
CH2Cl2
3
99
3
CH2Cl2
–20
25
–20
25
25
25
25
25
25
25
25
25
4
98 (99)
99 (99)
97 (99)
99
4
toluene
5
5
toluene
6
6
Et2O
7
4-MeOC6H4
4-MeC6H4
2-naphthyl
3-PhOC6H4
2-furyl
7
THF
8
36
99
92
8
MeCN
9
36
99
96
9
DMF
10
11
12
13
14
15
16
17
36
99
91
10
11
12
13
14
DMSO
–
–
36
99
93
toluene/H2O (0.1 equiv)
toluene/AcOH (0.1 equiv)
toluene/BzOH (0.1 equiv)
toluene/4 Å MS (10 mg)
99
98
88
99
91
91
92
81
4-O2NC6H4
CH=CHPh
2-O2NC6H3CH=CH
4-MeOC6H4CH=CH
n-Pr
16 (60)
84
99 (99)
92
90 (91)
92
24
86
92
72
91
90
a Conditions (unless stated otherwise): dimethyl malonate (1 mmol),
nitrostyrene (0.2 mmol), catalyst 2c (10 mol%), solvent (1 mL).
b Isolated yield.
36
97
90
i-Bu
48
89
90
c Determined by chiral HPLC analysis.
a Conditions (unless stated otherwise): dimethyl malonate (1 mmol),
nitrostyrene (0.2 mmol), catalyst 2c (10 mol%), toluene (1 mL), –20
°C. The values in parentheses were obtained in the presence of cat. 2h
at r.t.
high enantioselectivity in less polar aprotic solvents.
However, no desired product was observed when more
polar DMF or DMSO was used. Among the solvents
tested, toluene was found to be the best with respect to
catalytic activity and asymmetric induction. The effect of
additives in toluene on enantioselectivity was also probed.
Water and acid additives neither retarded the process, nor
affected ee values (entries 11–13). Interestingly, it was
found that molecular sieves (4 Å) decreased the enantiose-
lectivity significantly (entry 14). The detailed mechanism
is not known at this moment.14
b Isolated yield.
c Determined by chiral HPLC analysis.
(Scheme 3) is summarized in Table 3. Both electron-rich
and electron-deficient nitrostyrenes were excellent
Michael acceptors for methyl malonate. The reactions
worked extremely well to afford Michael adducts in near-
ly quantitative yields and excellent enantioselectivities
(91–97% ee, entries 1–12). In addition, 1-nitro-4-phenyl
butadienes (R: C6H4CH=CH, 2-O2NC6H3CH=CH, 4-
MeOC6H3CH=CH) were also shown to be highly efficient
activated alkenes (entries 13–15). It is noteworthy that no
1,6-addition was observed. Moreover, it was found that
the 2c-catalyzed Michael addition processes were also ap-
plicable to the substrates possessing aliphatic-2-substitu-
ents in high yields with comparative enantioselectivities
(entries 16 and 17).
In the presence of catalyst 2c (or 2h), the scope of the
malonate addition under optimized reaction conditions
MeO2C
CO2Me
NO2
CO2Me
CO2Me
2c or 2h (10 mol%)
NO2
+
R
toluene, –20 °C
R
Scheme 3 The reaction of different nitroolefins with malonate cata-
lyzed by 2c or 2h
O
O
OEt
O
O
2c (10 mol%)
NO2
NO2
+
Ph
Ph
CH2Cl2, r.t., 16 h
OEt
99%, dr 90:10, 89% ee
Scheme 4 The Michael addition of b-keto ester to nitrostyrene
Synlett 2008, No. 20, 3242–3246 © Thieme Stuttgart · New York

LETTER
Enantioselective Michael Addition of Malonates to Nitroolefins
3245
Rev. 2002, 102, 2187. (b) Ma, J.-A.; Cahard, D. Angew.
Chem. Int. Ed. 2004, 43, 4566. For selected reviews
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organocatalysis, see: (c) Takemoto, Y. Org. Biomol. Chem.
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2008, 2499.
The scope of this reaction was also extended to the use of
b-keto ester (Scheme 4). When b-keto ester was em-
ployed, excellent yield with good diastereo- and enantio-
selectivity at the position b to the nitro group were
obtained.
In summary, we have successfully developed another type
of saccharide-substituted bifunctional tertiary amine-thio-
ureas, with the catalytic activity being easily tuned by
simply changing the amino moiety. These catalysts have
proven to be robust and can be efficiently used in the di-
rect Michael additions of malonate to various nitroolefins.
Excellent yields and enantioselectivities were obtained
under the optimized reaction conditions. Furthermore,
b-keto esters were also used as Michael donors to afford
adducts in high yield with good diastereo- and enantiose-
lectivity. A full scope of investigation of the strategy is
under way in our laboratory.
(6) For selected examples on Jacobsen’s urea and thiourea
catalysis, see: (a) Sigman, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 4901. (b) Sigman, M. S.; Vachal, P.;
Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279.
(c) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
10012. (d) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 10558. (e) Yoon, T. P.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2005, 44, 466. (f) Huang, H.; Jacobsen, E. N.
J. Am. Chem. Soc. 2006, 128, 7170. (g) Lalonde, M. P.;
Chen, Y.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45,
6366.
(7) For selected examples on Takemoto’s thiourea catalysis,
see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672. (b) Okino, T.; Nakamura, S.;
Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625.
(c) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119. (d) Hoashi, Y.;
Okino, T.; Takemoto, Y. Angew. Chem. Int. Ed. 2005, 44,
4032. (e) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.;
Takemoto, Y. Tetrahedron 2006, 62, 365. (f) Inokuma, T.;
Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128,
9413.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors are grateful to NFSC (No. 20772091), Tianjin Munici-
pal Science & Technology Commission (07JCZDJC04700), and
NCET from the Ministry of Education of China for financial sup-
port.
(8) For selected examples on other chiral thiourea-catalyzed
Michael addition reactions, see: (a) McCooey, S. H.;
Connon, S. J. Angew. Chem. Int. Ed. 2005, 44, 6367.
(b) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett.
2005, 7, 4713. (c) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem.
Commun. 2005, 4481. (d) McCooey, S. H.; McCabe, T.;
Connon, S. J. J. Org. Chem. 2006, 71, 7494. (e) Tsogoeva,
S. B.; Wei, S. Chem. Commun. 2006, 1451. (f) Yalalov,
D. A.; Tsogoeva, S. B.; Schmatz, S. Adv. Synth. Catal. 2006,
348, 826. (g) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y.
Org. Lett. 2006, 8, 2901. (h) Cao, Y.-Y.; Lu, H.-H.; Lai,
Y.-Y.; Lu, L.-Q.; Xiao, W.-J. Synthesis 2006, 3795.
(i) Hynes, P. S.; Stranges, D.; Stupple, P. A.; Guarna, A.;
Dixon, D. J. Org. Lett. 2007, 9, 2107. (j) Cao, Y.-J.; Lai,
Y.-Y.; Wang, X.; Li, Y.-J.; Xiao, W.-J. Tetrahedron Lett.
2007, 48, 21. (k) Jiang, L.; Zheng, H.-T.; Liu, T.-Y.; Yue,
L.; Chen, Y.-C. Tetrahedron 2007, 63, 5123. (l) Wang,
C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem.
Commun. 2008, 1431. (m) Hynes, P. S.; Stupple, P. A.;
Dixon, D. J. Org. Lett. 2008, 10, 1389.
References and Notes
(1) For reviews of asymmetric Michael addition reactions, see:
(a) Tomioka, K.; Nagaoka, Y.; Yamaguchi, M.
Comprehensive Asymmetric Catalysis, Vol. 3; Jacobsen
, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York,
1999, Chap. 31.1 and 31.2, 1105–1139. (b) Krause, N.;
Hoffmann-Röder, A. Synthesis 2001, 171. (c) Christoffers,
J.; Baro, A. Angew. Chem. Int. Ed. 2003, 42, 1688. (d)Guo,
H.-C.; Ma, J.-A. Angew. Chem. Int. Ed. 2006, 45, 354.
(e) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem.
Int. Ed. 2007, 46, 1570.
(2) For reviews on utility of nitro group, see: (a) Seebach, D.;
Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 33, 1.
(b) Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86,
751. (c) Rosini, G.; Ballini, R. Synthesis 1988, 833.
(d) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991,
423. (e) Fuji, K.; Node, M. Synlett 1991, 603. (f) Ono, N.
The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001.
(9) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3,
2423. (b) Enders, D.; Seki, A. Synlett 2002, 26.
(3) For selected reviews regarding organocatalysis, see:
(a) List, B. Acc. Chem. Res. 2004, 37, 548. (b) Dalko, P. I.;
Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138. (c)Notz,
W.; Tanaka, F.; Barbas, C. F. III. Acc. Chem. Res. 2004, 37,
580. (d) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3,
719. (e) Duthaler, R. O. Angew. Chem. Int. Ed. 2003, 42,
975.
(4) For a review on asymmetric Michael additions to
nitroalkenes, see: (a) Berner, O. M.; Tedeschi, L.; Enders,
D. Eur. J. Org. Chem. 2002, 1877. (b) Almasi, D.; Alonso,
D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299.
(c) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(5) For reviews concerning chiral bifunctional metal complexes
as catalysts, see: (a) Shibasaki, M.; Yoshikawa, N. Chem.
(10) (a) Herrman, K.; Wynberg, H. J. Org. Chem. 1979, 44,
2238. (b) Colonna, S.; Re, A.; Wynberg, H. J. Chem. Soc.,
Perkin Trans. 1 1981, 547. (c) Zhang, F.-Y.; Corey, E. J.
Org. Lett. 2000, 2, 1097.
(11) (a) Ma, J.-A.; Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li,
X.-J. CN Patent 1974009, 2006. (b) Liu, K.; Cui, H.-F.; Nie,
J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923.
(12) During the preparation of this manuscript, similar
organocatalysts were published by Zhou’s group: Wang, C.;
Zhou, Z.; Tang, C. Org. Lett. 2008, 10, 1707.
(13) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007,
129, 11583.
(14) Li, X.-J.; Zhang, G.-W.; Wang, L.; Hua, M.-Q.; Ma, J.-A.
Synlett 2008, 1255.
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3246
X.-J. Li et al.
LETTER
pyranose-H), 5.28–5.42 (m, 2 H, pyranose-H). 13C NMR
(125 MHz, DMSO): d = 171.00, 170.86, 170.72, 170.60,
170.04, 169.95, 169.65, 95.60, 82.72, 75.51, 73.77, 72.54,
71.86, 70.19, 69.44, 68.62, 68.13, 62.80, 61.55, 60.60,
56.70, 40.34, 32.76, 29.86, 29.53, 25.06, 24.57, 21.25,
21.08, 21.03, 20.89, 20.82, 20.80, 14.39. IR (KBr): 3354,
2938, 1757, 1542, 1372, 1226, 1046, 940, 906, 754, 601
cm–1. ESI-MS: m/z = 820.22 [M+ + 1].
(15) A Typical Procedure for the Preparation of
Organocatalyst
To a solution of 1, 2-cyclohexyldiamine (3.6 mmol) in
CH2Cl2 (20 mL) was added the corresponding saccharide-
derived isothiocyanates 1 (3 mmol). The mixture was stirred
at r.t. for 3–24 h (TLC) and concentrated. The resulting
residue was purified by flash column chromatography with
the eluent (EtOAc–Et3N, 100:1) to give the crude solid. The
crude solid was dissolved in a minimal amount of CH2Cl2
and slowly precipitated from solution by the addition of PE
at 0 °C. Filtration afforded the desired thiourea products 2.
Compound 2c: yield 55%; mp 90–92 °C; [a]D20 –0.5 (c 1.0,
CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 0.94–1.26 (m,
5 H, cyclohexane-H), 1.66–1.88 (m, 3 H, cyclohexane-H),
1.99 (s, 3 H, COCH3), 2.01 (s, 3 H, COCH3), 2.03 (s, 3 H,
COCH3), 2.05 (s, 3 H, COCH3), 2.24 (s, 6 H, 2 NCH3), 2.32
(m, 1 H, NCH), 3.45 (m, 1 H, NCH), 3.81–3.84 (m, 1 H,
pyranose-H), 4.09–4.12 (m, 1 H, pyranose-H), 4.27–4.31
(m, 1 H, pyranose-H), 4.93–4.97 (t, 1 H, CH2), 5.05–5.09 (t,
1 H, CH2), 5.29–5.33 (m, 2 H, pyranose-H), 5.58–5.60 (br,
1 H, NH), 6.20 (br, 1 H, NH). 13C NMR (125 MHz, CDCl3):
d = 170.85, 170.81, 170.07, 169.85, 83.30, 73.41, 73.5,
73.16, 71.22, 68.50, 61.88, 56.76, 40.46, 32.86, 24.96,
24.58, 22.76, 20.96, 20.94, 20.82, 20.81. IR (KBr): 3352,
2936, 1753, 1542, 1377, 1225, 1035, 910, 758, 601cm–1.
ESI-MS: m/z = 532.26 [M+ + 1].
Compound 2f: yield 24%; mp 92–94 °C; [a]D20 +14.1 (c 1.0,
CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 0.97–1.28 (m,
5 H, cyclohexane-H), 1.54–1.87 (m, 3 H, cyclohexane-H),
1.88–2.25 (m, 27 H, 7 CH3, 2 NCH3), 2.34–2.51 (m, 1 H,
NCH), 3.64–3.71 (m, 1 H, pyranose-H), 3.72–3.89 (m, 2 H,
pyranose-H), 4.00–4.17 (m, 4 H, OCH2), 4.27–4.48 (m, 2 H,
pyranose-H), 4.72–4.87 (m, 1 H, pyranose-H), 4.87–4.93
(m, 1 H, pyranose-H), 5.02–5.09 (m, 1 H, pyranose-H),
5.12–5.27 (m, 1 H, pyranose-H), 5.27–5.31 (m, 1 H,
pyranose-H), 5.42–5.65 (br, 1 H, NH). 13C NMR (125 MHz,
DMSO): d = 170.97, 170.65, 170.54, 170.34, 170.26,
169.29, 169.11, 100.99, 90.16, 74.00, 73.10, 72.34, 71.19,
70.81, 70.77, 69.29, 69.16, 66.89, 66.83, 61.01, 52.66,
40.15, 34.08, 25.44, 24.80, 24.55., 21.04, 21.02, 20.86,
20.83, 20.81, 20.70, 14.38; IR (KBr): 3357, 2938, 1757,
1542, 1372, 1225, 1046, 940, 906, 754, 602 cm–1. ESI-MS:
m/z = 820.19 [M+ + 1].
Compound 2g: yield 38%; mp 158–160 °C; [a]D20 +57.9 (c
1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 0.75–0.88 (t,
12 H, CH3), 0.89–1.72 (m, 8 H, cyclohexane-H), 1.72–2.38
(m, 20 H), 3.78–3.88 (m, 1 H, pyranose-H), 3.97–4.11 (m,
1 H, pyranose-H), 4.31–4.44 (m, 1 H, pyranose-H), 4.89–
5.12 (m, 2 H, CH2), 5.25–5.37 (m, 1 H, pyranose-H), 5.66–
5.83 (m, 1 H, NH), 6.08–6.23 (m, 1 H, pyranose-H), 6.33–
6.61 (m, 1 H, NH). 13C NMR (125 MHz, CDCl3): d = 183.17,
171.38, 170.92, 170.04, 169.89, 82.83, 73.37, 73.14, 70.72,
68.63, 63.84, 61.84, 58.91, 55.05, 32.48, 26.80, 25.85,
24.65, 23.09, 21.36, 20.99, 20.95, 20.83, 20.79. IR (KBr):
3371, 2951, 1751, 1511, 1369, 1232, 1038, 909, 759, 594
cm–1. ESI-MS: m/z = 616.4 [M+ + 1].
Compound 2d: yield 50%; mp 83–86 °C; [a]D20 +4.0 (c 1.0,
CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 1.03–1.30 (m,
4 H, cyclohexane-H), 1.62–1.91 (m, 4 H, cyclohexane-H),
1.99 (s, 3 H, COCH3), 2.01 (s, 3 H, COCH3), 2.03 (s, 3 H,
COCH3), 2.05 (s, 3 H, COCH3), 2.24 (s, 6 H, 2 NCH3), 2.33
(m, 1 H, NCH), 3.45 (m, 1 H, NCH), 3.81–3.84 (m, 1 H,
pyranose-H), 4.09–4.12 (m, 1 H, pyranose-H), 4.27–4.32
(m, 1 H, pyranose-H), 4.91–4.99 (t, 1 H, CH2), 5.04–5.09 (t,
1 H, CH2), 5.30–5.33 (m, 2 H, pyranose-H), 5.58–5.60 (br,
1 H, NH), 6.20 (br, 1 H NH). 13C NMR (125 MHz, CDCl3):
d = 170.86, 170.81, 170.07, 169.86, 83.30, 73.42, 73.16,
71.22, 68.50, 61.88, 56.76, 40.46, 32.86, 24.98, 24.58,
20.96, 20.94, 20.82, 20.81. IR (KBr): 3352, 2939, 1755,
1545, 1378, 1231, 1038, 907, 755, 602 cm–1. ESI-MS: m/z =
532.25 [M+ + 1].
Compound 2h: yield 35%; [a]D20 +23.3 (c 1.0, CH2Cl2).
1H NMR (500 MHz, CDCl3): d = 0.79–0.87 (t, 6 H, CH3),
0.87–1.20 (m, 8 H, CH2), 1.20–1.35 (7 H, cyclohexane-H),
1.63–1.84 (m, 3 H, cyclohexane-H), 1.94–2.08 (q, 12 H,
COCH3), 2.15–2.45 (m, 4 H, NCH2), 3.30–3.65 (m, 1 H,
NH), 3.72–4.34 (m, 3 H, pyranose-H), 4.90–5.71 (m, 4 H,
pyranose-H), 6.35–6.60 (m, 1 H, NH). 13C NMR (125 MHz,
CDCl3): d = 183.16, 171.59, 170.83, 170.0, 169.81, 90.11,
82.81, 73.35, 73.04, 71.08, 68.61, 63.63, 62.09, 55.53,
49.55, 32.79, 31.41, 25.75, 24.68, 23.64, 20.91, 20.90,
20.83, 20.78, 14.28. IR (KBr): 3362, 2933, 1758, 1543,
1377, 1232, 1039, 912, 751, 610 cm–1. ESI-MS: m/z = 616.5
[M+ + 1].
Comound 2e: yield 30%; mp 94–97 °C; [a]D20 +63.0 (c 1.0,
CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 1.15–1.29 (m,
5 H, cyclohexane-H), 1.64–1.84 (m, 3 H, cyclohexane-H),
1.96–2.01 (s, 12 H, 4 COCH3), 2.01–2.04 (s, 3 H, COCH3),
2.04–2.07 (s, 3 H, COCH3), 2.07–2.10 (s, 3 H, COCH3), 2.19
(s, 6 H, 2 NCH3), 2.24–2.38 (br, 1 H, NCH), 2.41–2.92 (br,
1 H, NCH), 3.76–3.82 (d, 1 H, OCH2, J = 7.0 Hz), 3.84–3.89
(d, 1 H, OCH2, J = 10.5 Hz), 3.98–4.04 (d, 2 H, OCH2,
J = 8.0 Hz), 4.04–4.10 (m, 1 H, pyranose-H), 4.16–4.27 (m,
3 H, pyranose-H), 4.42–4.46 (d, 1 H, pyranose-H, J = 12.5
Hz), 4.74–4.82 (m, 2 H, pyranose-H), 5.00–5.07 (m, 1 H,
Synlett 2008, No. 20, 3242–3246 © Thieme Stuttgart · New York

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