Concise synthesis of novel practical sulfamide-amine alcohols for the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1021/jo048520q

Novel sulfamide-amine alcohol ligands were designed using a grafting strategy and synthesized from readily available starting materials via a simple, efficient method. The key features of these ligands for the asymmetric addition of diethylzinc to aldehydes included stability, enhanced effectiveness without using Ti(OⁱPr)₄, suitability for a variety of aldehydes, the ability to operate at room temperature, and selectability to afford either absolute configuration products with enantiomeric excess up to >99%.

Full text of DOI:10.1021/jo048520q

Concise Synthesis of Novel Practical Sulfamide-Amine Alcohols
for the Enantioselective Addition of Diethylzinc to Aldehydes
Jincheng Mao, Boshun Wan,* Rongliang Wang, Fan Wu, and Shiwei Lu*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China, and
Graduate School of Chinese Academy of Sciences, Beijing, China
bswan@dicp.ac.cn
Received August 23, 2004
Novel sulfamide-amine alcohol ligands were designed using a grafting strategy and synthesized
from readily available starting materials via a simple, efficient method. The key features of these
ligands for the asymmetric addition of diethylzinc to aldehydes included stability, enhanced
i
effectiveness without using Ti(O Pr)
4
, suitability for a variety of aldehydes, the ability to operate
at room temperature, and selectability to afford either absolute configuration products with
enantiomeric excess up to >99%.
Introduction
for the addition reactions of both aromatic and aliphatic
or R,â-unsaturated aldehydes are rare. Therefore, stable,
easily accessible, operationally simple, and general ligands
are still desirable. Recently, many reports showed that
Great efforts have been devoted to the development of
various types of chiral ligands for the asymmetric addi-
tion of diorganozinc to aldehydes. Either amino alcohols,
amino thiols, disulfides, diselenides, and amines with Zn
systems or Ti with diols, phosphoramides, and sulfona-
mide ligands such as bistriflamide, bissulfonamide, and
sulfonamide alcohol could provide high yields and excel-
lent enantioselectivities for the asymmetric addition of
diethylzinc to aldehydes. However, Zn with sulfonamide
ligand systems were not good catalysts for this reaction.1
To our knowledge, no highly efficient chiral sulfonamide
ligand has been reported for the asymmetric addition
a chiral ligand L
achiral ligand L
1
in combination with another chiral or
as an activator could exhibit enhanced
efficiency and enantioselectivity in many asymmetric
2
reactions.5 Herein, using grafting strategy we designed
-10
a new type of ligand L
3 2
by grafting activator L into the
chiral ligand L , which led to more rigid structures that
1
might better discriminate between the two enantiotopic
faces of benzaldehyde within the transition state complex.
Thus, an activated catalyst is generated that could
accelerate the reaction and afford higher enantiomeric
excesses of the carbinol product (Figure 1). Recognizing
-3
i
4
4
reaction without the addition of Ti(O Pr) . On the other
hand, of approximately 600 chiral ligands for the asym-
metric addition reactions shown in recent reviews, only
1
a small number of effective ligands were obtained by
simple synthetic methods. Furthermore, ligands suitable
(
1) For reviews see: (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757-
8
24. (b) Soai, K.; Shibata, T. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
pp 911-922. (c) Noyori, R. Asymmetric Catalysis in Organic Synthe-
sis: Wiley: New York, 1994.
(
2) For recently selected reports on ligands without using Ti, see:
(
(
a) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2001, 3, 3053-3056.
b) Liu, D.-X.; Zhang, L.-C.; Wang, Q.; Da, C.-S.; Xin, Z.-Q.; Wang, R.;
Chol, M. C. K.; Chan, A. S. C. Org. Lett. 2001, 3, 2733-2735. (c)
Nugent, W. A. Org. Lett. 2002, 4, 2133-2136. (d) Ko, D.-H.; Kim, K.
H.; Ha, D.-C. Org. Lett. 2002, 4, 3759-3762. (e) Wipf, P.; Wang, X.
Org. Lett. 2002, 4, 1197-1200. (f) Dahmen, S.; Br a¨ se, S. Chem.
Commun. 2002, 26-27. (g) Fontes, M.; Verdaguer, X.; Sola, L.; Vidal-
Ferran, A.; Reddy, K. S.; Riera, A.; Peric a` s, M. A. Org. Lett. 2002, 4,
FIGURE 1. Design of novel sulfamide-amine alcohol ligands.
2
381-2383. (h) Bringmann, G.; Pfeifer, R.-M.; Rummey, C.; Hartner,
K.; Breuning, M. J. Org. Chem. 2003, 68, 6859-6863. (i) Braga, A. L.;
Paixao, M. W.; Ludtka, D. S.; Silveira, C. C.; Rodrigues, O. E. D. Org.
Lett. 2003, 5, 2635-2638. (j) Richmond, M. L.; Seto, C. T. J. Org. Chem.
that achiral bissulfonamides are known to increase
2
003, 68, 7505-7508. (k) Spout, C. M.; Seto, C. T. J. Org. Chem. 2003,
(5) (a) Hashihayata, T.; Ito, Y.; Katsuki, T. Synlett 1996, 11, 1079-
1081. (b) Hashihayata, T.; Ito, Y.; Katsuki, T. Tetrahedron 1997, 53,
9541-9552. (c) Miuka, K.; Katsuki, T. Synlett 1999, 6, 783-785.
(6) (a) Mikami, K.; Matsukawa, S. Nature 1997, 385, 613-615. (b)
Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.; Korenaga, T.; Terada,
M.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 1086-1087. (c) Mat-
sukawa, S.; Mikami, K. Tetrahedron: Asymmetry 1997, 8, 815-816.
(d) Ding, K.; Ishii, A.; Mikami, K. Angew. Chem., Int. Ed. 1999, 38,
497-501. (e) Mikami, K.; Angelaud, R.; Ding, K. L.; Ishii, A.; Tanaka,
A.; Sawada, N.; Kudo, K.; Senda, M. Chem. Eur. J. 2001, 7, 730-737.
(7) Kobayashi, S.; Ishitani, J. J. Am. Chem. Soc. 1994, 116, 4083-
4084.
6
8, 7788-7794.
(3) For recently selected reports on ligands using Ti, see: (a) Lake,
F.; Moberg, C. Tetrahedron: Asymmetry 2001, 12, 755-760. (b) Lake,
F.; Moberg, C. Eur. J. Org. Chem. 2002, 18, 3179-3188. (c) Yus, M.;
Ram o´ n, D. J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103-
1
114. (d) You, J.-S. Shao, M.-Y.; Gau, H.-M. Tetrahedron: Asymmetry
001, 12, 2971-2975. (e) Kang, S.-W.; Ko, D.-H.; Kim, K. H.; Ha, D.-
2
C. Org. Lett. 2003, 5, 4517-4519.
(
4) (a) Cho, B. T.; Chun, Y. S. Synth. Commun. 1999, 29, 521-531.
b) Fonseca, M. H.; Eibler, E.; Zabel, M.; K o¨ nig, B. Tetrahedron:
Asymmetry 2003, 14, 1989-1994.
(
1
0.1021/jo048520q CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/18/2004
J. Org. Chem. 2004, 69, 9123-9127
9123

Mao et al.
SCHEME 1. Evaluated Ligands
enantioselectivity in the addition of diethylzinc to ben-
or commercially available L-prolinol 8 and the corre-
1
0
12
zaldehyde, we chose sulfonamide as the activator.
Herein, we report a new class of sulfamide-amine alcohol
ligands (Scheme 1) obtained by introducing another
nitrogen from sulfonamide to a chiral amino alcohol using
the grafting strategy for asymmetric addition reactions.
The key features of these ligands include (a) ease of
sponding aziridines 12 in one step in an atom-economi-
cal synthesis (Scheme 2).13 Pure products were obtained
SCHEME 2. Synthesis of Sulfamide-Amine
Alcohols
preparation and high stability, (b) enhanced effectiveness
i
without using Ti(O Pr)
4
, (c) suitability for a variety of
aldehydes, (d) the ability to operate at room temperature,
and (e) selectability to afford the high ee products with
either absolute configurations. Based on the mechanistic
consideration of titanium-catalyzed asymmetric additions
of organozinc to aldehydes,11 we expected that the sul-
famide-amine alcohol ligands where the oxygen, nitro-
gen from the tertiary amine, and nitrogen from the
sulfonamide could bind zinc in a tridentate fashion would
by recrystallization rather than using complex column
chromatography. Moreover, these ligands are stable for
several months in air.
be efficient catalysts for the addition reaction of Et
2
Zn
to aldehydes without addition of the moisture sensitive
i
4
Ti(O Pr) .
To investigate the catalytic properties of these ligands,
2
the asymmetric addition of Et Zn to benzaldehyde was
Results and Discussion
first carried out in hexane using ligands 1a and 1b (Table
1). Poor enantioselectivities were observed with 1a and
1b (entries 1 and 2). Therewith, ligands 2a-d were
evaluated in this reaction (entries 3-6). Ligand 2c
showed 99% yield and 86% ee (entry 5). Finally, by
changing the substituent of the backbone of 2c, an
effective ligand 4 with a benzyl group was obtained and
provided the product with 92% ee and 91% yield (entry
8). Obviously, the third suitable sterogenic center was
necessary to achieve high enantioselectivities, and the
Sulfamide-amine alcohol ligands 1-4 and 9-11 were
successfully prepared via reactions between natural
chiral resources (-)-ephedrine 5, (+)-pseudoephedrine 6,
(
8) (a) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802-
1
2
803. (b) Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett.
001, 3, 2161-2164. (c) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carrol,
P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929-6941.
(9) (a) Chavarot, M.; Byrne, J. J.; Chavant, P. Y.; Guindet, P.; Vallee,
Y. Tetrahedron: Asymmetry 1998, 9, 3889-3894. (b) Reetz, M. T.;
Neugebauer, T. Angew. Chem., Int. Ed. 1999, 38, 179-181. (c) Vogl,
E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38,
1
2
570-1577. (d)Mun n˜ iz, K.; Bolm, C. Chem. Eur. J. 2000, 6, 2309-
(12) Chiral aziridines 12 were easily synthesized from corresponding
commercially available R-amino alcohols in one step: L. W. Bieber,
M. C. F. de Ara u´ jo, Molecules 2002, 7, 902-906.
(13) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B.
M.; Jiang, C. H. J. Am. Chem. Soc. 2001, 123, 12907-12908. (c) Trost,
B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
316.
(
10) Mu n˜ oz-Mu n˜ iz, O.; Juaristi, E. J. Org. Chem. 2003, 68, 3781-
3
785.
11) (a) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739-749. (b) Wu,
(
K.-H.; Gau, H.-M. Organometallics 2004, 23, 580-588.
9124 J. Org. Chem., Vol. 69, No. 26, 2004

Synthesis of Novel Practical Sulfamide-Amine Alcohols
TABLE 1. Addition of Diethylzinc to Benzaldehyde
TABLE 2. Addition of Diethylzinc to Various Aromatic,
Using Sulfamide-Amine Alcoholsa
Aliphatic, and r,â-Unsaturated Aldehydes Using 4 and
a
11b
entry
ligand
% isolated yield
% eeb
entry
ligand
R
% isolated yield
% eeb
1
2
3
4
5
6
7
8
9
1a
1b
2a
2b
2c
2d
3
87
96
99
61
99
99
87
91
86
29
68
32
84
53
89
86
42 (S)
28 (S)
81 (S)
26 (S)
86 (R)
25 (S)
84 (S)
92 (S)
72 (R)
35 (S)
77 (R)
29 (R)
66 (R)
59 (R)
87 (R)
>99 (R)
1
2
4
p-Cl-Ph
p-Me-Ph
p-F-Ph
p-MeO-Ph
p-Br-Ph
o-MeO-Ph
o-Cl-Ph
1-naphthyl
p-Cl-Ph
p-Me-Ph
p-F-Ph
p-Br-Ph
o-Cl-Ph
1-naphthyl
i-C4H9
PhCH2CH2
c-C6H11
(E)-PhCHdCH
i-C4H9
PhCH2CH2
(E)-PhCHdCH
c-C6H11
92
67
91
76
81
99
74
90
97
99
93
98
92
88
38
66
51
99
36
50
99
63
89 (S)
85 (S)
4
3
4
88 (S)
4
4
87 (S)
5
4
88 (S)
6
4
90 (S)
4
7
4
>99 (S)
>99 (S)
94 (R)
83 (R)
86 (R)
93 (R)
>99 (R)
>99 (R)
92 (S)
5
8
4
1
1
1
1
1
1
1
0
1
2
3
4
5
6
6
9
11b
11b
11b
11b
11b
11b
4
7
10
11
12
13
14
15
8
9
10
11a
11b
16
17
18
19
20
21
22
4
75 (S)
>99 (S)
54 (S)
>99 (R)
89 (R)
81 (R)
46 (R)
a
Et2Zn/aldehyde/ligand ) 2.2:1:0.1, hexane, rt, 24 h. b The ee
4
values were determined by GC, and the absolute configuration was
assigned by comparison to literature values.
4
11b
11b
11b
11b
stereogenic centers of the ligand derived from (-)-
ephedrine and (R)-aziridine matched well. To our sur-
prise, ligand 2c induced (R)-enriched product the opposite
chirality to other ligands. It was probably related to the
conformationally more restricted phenyl group in 2c.14
For comparison, the chiral sources 5 and 6 and the chiral
aziridines 12 with various substituents were used in the
reaction under the same conditions. Expectedly, ligands
a
b
Et2Zn/aldehyde/ligand ) 2.2:1:0.1, hexane, rt, 24 h The ee
values were determined by GC or HPLC, and the absolute
configuration was assigned by comparison to literature values.
used in the asymmetric addition of diethylzinc to other
aromatic aldehydes (Table 2, entries 1-14). Using 4, the
catalytic diethylzinc addition to the aldehyde possessing
an electron-withdrawing group in the para position of the
aromatic ring proceeded with higher enantioselectivity
than that in the ortho position of the aromatic ring
(entries 1-7). Employing 11b, high yields and enantio-
selectivities were observed for various tested aldehydes
(entries 9-14). Fortunately, both 4 and 11b showed
excellent optical activity of >99% ee with opposite
absolute configuration products for 2-chlorobenzaldehdye
and 1-naphthylaldehdye (entries 7, 8, 13, and 14). It is
known that in the diethylzinc addition reaction the
enantioselectivity is usually much lower with aliphatic
and R,â-unsaturated aldehydes than the identical reac-
tion with aromatic aldehydes. Compounds 4 and 11b
5
and 6 afforded poor enantioselectivities, and chiral
aziridines gave no enantioselectivity. On the other hand,
the literature known (-)-N-methylephedrine 71 was also
used in the reaction but afforded inferior result to that
of ligand 4. So, it is demonstrated that the suitable and
weak coordination of the additional sulfonamide frag-
ment is necessary for further acceleration and stereo-
control in the addition reaction compared to the classic
amino alcohols.
5
To further verify the effectiveness of the weak coordi-
nation of the additional sulfonamide, ligands 9-11,
derived from inexpensive chiral source L-prolinol 816 by
the route shown in Scheme 2, and 8 were next examined.
Ligand 8 only provided 32% yield and 29% enantioselec-
tivities (entry 12). Unexpectedly, both 9 with benzyl and
2
were next examined in the addition of Et Zn to these
1
0 with methyl afforded low yields and enantioselectivi-
more challenging substrates (Table 2, entries 15-22).
Apparently, good to excellent reactivity and enantiose-
lectivity were observed with both primary and secondary
aliphatic aldehydes. The best results of up to >99% ee
were obtained using both 4 and 11b (entries 17 and 19).
Possible binding models of Zn with 4 and 11b are
ties (entries 13 and 14). However, by changing the
substituent from a benzyl or methyl group to phenyl with
R configuration, ligand 11b provided excellent enantio-
selectivity of >99% (entry 16) with yield and facial
selectivity complementary to that afforded by the (-)-
ephedrine-derived ligand 4 (entry 8).
i
depicted in Figure 2. In the absence of Ti(O Pr) , the
4
With the above-mentioned optimal result, (-)-ephe-
drine-derived 4 and L-prolinol-derived 11b were further
sulfamide-amine alcohol ligand binds with Zn in a
tridentate fashion. Comparing to the inferior results of
ligands 5, 6, 7, and 8, we can reason that the nitrogen
atom from the sulfonamide serves as another weakly
coordinative site in the cycle because it is a poor electron
donor.17 Thus, this tridentate binding can reduce the
number of possible diastereomeric intermediates or
(
14) Sibi, M. P.; Chen, J. X.; Cook, G. R. Tetrahedron Lett. 1999,
0, 3301-3304.
15) Bernardi, L.; Bonini, B. F.; Comes-Franchini, M.; Forchi, M.;
Mazzanti, G.; Ricci, A.; Varchi, G. Eur. J. Org. Chem. 2002, 16, 2776-
784.
4
(
2
(
16) The pioneering report of ephedrine and proline derived triden-
tate ligand systems in the enantioselective addition of diethylzinc to
aldehydes: Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28,
233-5236.
(17) Pritchett, S.; Gantzel, P.; Walsh, P. J. Organometallics 1997,
16, 5130-5132.
5
J. Org. Chem, Vol. 69, No. 26, 2004 9125

Mao et al.
31 2 3
29.9, 137.1, 141.8, 143.5; HRMS (APCI) calcd for C25H N O S
1
+
(
M + H ) 363.1737, found 363.1744.
Characterization of 2a: white solid (1.12 g); 70% yield;
2
0
1
mp 36-38 °C; [R]
D 3 3
) -38.21 (c 0.62, CHCl ); H NMR (CDCl )
δ 0.74 (d, J ) 6.8 Hz, 3H), 1.85 (s, 3H), 2.41 (s, 3H), 2.86-
2
.91 (m, 1H), 3.04 (t, J ) 6.8 Hz, 1H), 3.24 (t, J ) 11.4 Hz,
H), 3.54-3.57 (m, 1H), 4.52 (d, J ) 6.8 Hz, 1H), 7.01-7.03
1
(
m, 2H), 7.25-7.27 (m, 5H), 7.32-7.37 (m, 3H), 7.40-7.44 (m,
1
3
2
2
1
3
H), 7.59 (d, J ) 8.4 Hz, 2H); C NMR (CDCl ) δ 12.7, 22.2,
FIGURE 2. Proposed trivalent binding modes of the Zn with
and 11b, respectively.
9.5, 43.9, 64.4, 67.8, 77.0, 126.9, 127.7, 128.6, 128.8, 129.0,
4
29.2, 130.2, 137.4, 137.9, 143.8; HRMS (APCI) calcd for
+
25
C H
29
N
2
O
3
S (M - H ) 437.1904, found 437.1887.
transition states, strongly increasing the probability of
an efficient chirality transfer.18
Characterization of 2b: white solid; 75% yield (1.20 g);
20
1
mp 188-189 °C; [R]
D 3
) +30.23 (c 0.63, CHCl ); H NMR
(
3
CDCl ) δ 0.52 (d, J ) 4.0 Hz, 3H), 2.04 (s, 3H), 2.44 (s, 3H),
2
)
.85-2.89 (m, 1H), 3.16-3.21 (m, 1H), 3.54 (s, 1H), 3.71 (t, J
Conclusion
6 Hz, 1H), 4.23 (d, J ) 8.0 Hz, 1H), 4.48 (br, 1H), 5.05 (br,
In summary, we have successfully prepared a new class
of stable sulfamide-amine alcohol ligands from (-)-
ephedrine, (+)-pseuoephedrine, and L-prolinol, which
were designed using a grafting strategy, for the enantio-
selective addition of diethylzinc to a wide range of
aldehydes at room temperature. These ligands provide
high yields and excellent enantioselectivities for both
1H), 7.13 (t, J ) 4.0 Hz, 2H), 7.26-7.35 (m, 10H), 7.72 (d, J )
1
3
8
6
1
4
.0 Hz, 2H); C NMR (CDCl
3
) δ 10.8, 22.2, 30.1, 45.4, 64.5,
8.1, 75.8, 127.8, 128.0, 128.5, 129.0, 129.4, 130.4, 137.6, 138.6,
+
42.5, 144.1; HRMS (APCI) calcd for C25
29 2 3
H N O S (M - H )
37.1904, found 437.1876.
Characterization of 2c: white solid; 78% yield; mp 118-
25
1
1
(
D 3 3
19 °C; [R] ) +21.67 (c 0.5, CHCl ); H NMR (CDCl ) δ 0.63
d, J ) 6.4 Hz, 3H), 2.13 (s, 3H), 2.42 (s, 3H), 2.88-2.91 (m,
aromatic and aliphatic or R,â-unsaturated aldehydes in
1H), 3.10-3.20 (m, 1H), 3.58 (s, 1H), 4.56-4.57 (d, J ) 5.2
Hz, 1H), 6.97-6.98 (d, J ) 3.6 Hz, 2H), 7.23-7.34 (m, 10H),
i
the absence of Ti(O Pr)
4
. The products with enantiomeric
1
3
7
3
1
3
.64-7.66 (d, J ) 8.0 Hz, 2H); C NMR (CDCl ) δ 10.6, 21.7,
excess up to >99% and either absolute configuration were
obtained by using ligands 4 and 11b, respectively. The
preparation of the ligands and their use in the asym-
metric addition of diethylzinc to aldehydes is practical
and could be amenable to scale-up.19 Further work is in
progress in this laboratory with the aim of expanding
applications of these inexpensive chiral ligands to other
enantioselective catalytic processes.
5.3, 44.3, 58.6, 65.8, 76.4, 126.5, 127.3, 127.88, 128.0, 128.3,
28.4, 128.7, 129.7, 137.5, 138.2, 143.1, 143.3; HRMS (APCI)
+
calcd for C25
H
31 2
N O
3
S (M + H ) 439.2050, found 439.2074.
Characterization of 2d: white solid; 60% yield; mp 150-
25
1
1
(
D 3 3
51 °C; [R] ) +67.98 (c 0.5, CHCl ); H NMR (CDCl ) δ 0.44
d, J ) 6.0 Hz, 3H), 2.17-2.43 (m, 6H), 2.64 (s, 1H), 3.17-
3.21 (m, 1H), 3.62 (d, J ) 45.6 Hz, 2H), 4.22 (d, J ) 9.2 Hz,
1H), 5.02 (br, 1H), 7.09-7.29 (m, 13H), 7.67 (d, J ) 7.2 Hz,
1
3
1
1
1
3
H); C NMR (CDCl ) δ 8.7, 21.7, 33.1, 45.8, 59.8, 66.6, 74.8,
27.3, 127.4, 127.9, 128.4, 128.5, 129.2, 129.5, 129.9, 137.0,
38.2, 143.1, 143.6; HRMS (APCI) calcd for C25 S (M
Experimental Section
31 2 3
H N O
+
+
H ) 439.2050, found 439.2030.
Characterization of 3: white solid; 90% yield; mp 75-76
General Procedure for Preparation of Sulfamide-
Amine Alcohols 1-4 and 9-11. (-)-Ephedrine 5 ((+)-
pseudoephedrine 6 or L-prolinol 8) (3.80 mmol) and the
2
5
1
°
C; [R]
1.08 (m, 6H), 1.60 (d, J ) 6.0 Hz, 3H), 2.21 (d, J ) 11.6 Hz,
H), 2.33-2.37 (m, 4H), 2.76-2.85 (m, 2H), 4.52 (d, J ) 7.2
Hz, 1H), 7.19 (d, J ) 8.0 Hz, 2H), 7.29-7.31 (m, 2H), 7.36 (d,
D 3 3
) -48.15 (c 0.5, CHCl ); H NMR (CDCl ) δ 1.02-
12
corresponding aziridine 12 (3.66 mmol) were dissolved in dry
acetonitrile (30 mL), and the mixture was stirred under reflux
for 40 h. The solvent was evaporated under reduced pressure.
The residue was recrystallized with dichloromethane and
petroleum ether and gave the pure ligand.
2
1
3
J ) 4.4 Hz, 7H), 7.38-7.46 (m, 1H), 7.40-7.45 (m, 4H);
NMR (CDCl ) δ 9.9, 19.4, 21.6, 34.5, 46.6, 61.7, 65.1, 76.1,
126.4, 127.4, 128.2, 128.9, 129.5, 136.9, 143.2; HRMS (APCI)
C
3
2
5
Characterization of 1a: sticky oil (0.93 g), 70% yield; [R]
D
+
1
calcd for C20
29 2 3
H N O S (M + H ) 377.1893, found 377.1908.
)
3 3
-10.85 (c 0.5, CHCl ); H NMR (CDCl ) δ 1.00 (d, J ) 6.8
Characterization of 4: white solid; 80% yield; mp 39-40
Hz, 3H), 1.95 (s, 3H), 2.40 (s, 3H), 2.46 (d, J ) 15.2 Hz, 2H),
2
5
1
°
D 3 3
C; [R] ) -59.48 (c 0.5, CHCl ); H NMR (CDCl ) δ 0.95 (d,
2
.70-2.73 (m, 1H), 2.80-2.82 (t, J ) 5.6 Hz, 2H), 4.58 (d, J )
J ) 6.4 Hz, 3H), 1.60 (s, 3H), 2.28-2.35 (m, 2H), 2.38 (m, 3H),
2.60-2.72 (m, 2H), 3.03-3.07 (t, J ) 8.2 Hz, 2H), 4.50 (d, J )
6
.8 Hz, 1H), 7.23-7.31 (m, 4H), 7.33-7.37 (m, 2H), 7.55 (d, J
1
3
)
3
8.0 Hz, 2H); C NMR (CDCl ) δ 9.3, 21.6, 36.3, 40.2, 53.4,
6
.8 Hz, 1H), 7.06 (d, J ) 6.8 Hz, 2H), 7.17-7.27 (m, 7H), 7.35
6
1
4.3, 75.7, 126.3, 127.1, 127.9, 128.57, 128.61, 136.9, 143.2,
13
+
(d, J ) 7.2 Hz, 1H), 7.40-7.45 (m, 4H); C NMR (CDCl ) δ
43.3; HRMS (APCI) calcd for C25
H
27
N
2
O
3
S (M + H ) 363.1737,
3
9
1
.9, 21.6, 35.2, 39.8, 52.4, 59.0, 64.8, 75.8, 126.4, 126.5, 127.4,
found 363.1718.
28.1, 128.5, 128.8, 129.6, 129.6, 136.8, 137.6, 143.2; HRMS
Characterization of 1b: white solid; 85% yield; mp 117-
+
2
5
1
(APCI) calcd for C26
53.2220.
H
33
N
O
2 3
S (M + H ) 453.2206, found
1
18 °C; [R]
D 3 3
) +56.37 (c 0.5, CHCl ); H NMR (CDCl ) δ
4
0
.63-0.66 (m, 3H), 2.16 (s, 3H), 2.43-2.48 (m, 4H), 2.53-2.55
Characterization of 9: white solid; 97% yield. mp 109-
(
m, 1H), 2.61-2.66 (m, 1H), 3.07-3.09 (s, 2H), 4.17-4.21 (m,
2
6
1
1
3
110 °C; [R]
D 3 3
) -79.30 (c 0.5, CHCl ); H NMR (CDCl ) δ
1
H), 7.26-7.33 (m, 7H), 7.77-7.80 (m, 2H); C NMR (CDCl
3
)δ
1
.30-1.44 (m, 1H), 1.53 (d, J ) 4.0 Hz, 2H), 1.71 (d, J ) 8.0
7
.8, 21.7, 36.1, 41.1, 52.8, 65.4, 75.0, 127.4, 127.5, 128.1, 128.5,
Hz, 1H), 1.76-1.87 (m, 1H), 2.29-2.35 (m, 2H), 2.40 (s, 3H),
2
1
.58-2.63 (m, 2H), 2.73 (d, J ) 4.0 Hz, 1H), 3.06-3.10 (m,
H), 3.33-3.36 (m, 3H), 3.52-3.56 (m, 1H), 7.12 (d, J ) 8.0
(
18) (a) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
6
327-6335. (b) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am.
13
Hz, 2H), 7.18-7.27 (m, 5H), 7.75 (d, J ) 8.0 Hz, 2H); C NMR
Chem. Soc. 1998, 120, 9800-9809. (c) Rasmussen, T.; Norrby, P.-O.
J. Am. Chem. Soc. 2003, 125, 5130-5138. (d) Goldfuss, B.; Houk, K.
N. J. Org. Chem. 1998, 63, 8998-9006. (e) Goldfuss, B.; Steigelmann,
M.; Khan, S. I.; Houk, K. N. J. Org. Chem. 2000, 65, 77-82.
(CDCl
3
) δ 21.6, 23.8, 27.3, 40.6, 54.1, 54.3, 58.0, 63.7, 64.7,
126.5, 127.4, 128.5, 129.6, 137.4, 137.7, 143.2; HRMS (APCI)
+
calcd for C21
29 2 3
H N O S (M + H ) 389.1893, found 389.1880.
(19) For a current state of the art catalyst for the addition of
2
6
Characterization of 10: sticky oil; 90% yield; [R]
D
)
diethylzinc to benzaldehyde with excellent yield and enantiomeric
excess on scale, see: Kitamura, M.; Oka, H.; Suga, S.; Noyori, R. Org.
Synth. 2003, 79, 139-145.
1
-67.85 (c 0.5, CHCl
3 3
); H NMR (CDCl ) δ 1.14 (d, J ) 6.4 Hz,
3H), 1.38-1.55 (m, 1H), 1.57-1.61 (m, 2H), 1.77 (d, J ) 8.8
9126 J. Org. Chem., Vol. 69, No. 26, 2004

Synthesis of Novel Practical Sulfamide-Amine Alcohols
Hz, 1H), 1.94 (d, J ) 6.4 Hz, 1H), 2.23-2.27 (m, 1H), 2.40 (d,
J ) 14.4 Hz, 4H), 2.59-2.62 (m, 1H), 2.67 (d, J ) 12.4 Hz,
phase was extracted with ethyl acetate (3 × 5 mL). The
combined organic phase was washed with a small amount of
1H), 3.12 (s, 1H), 3.40-3.44 (m, 1H), 3.59-3.63 (m, 1H), 7.29
2 4
brine, dried with anhydrous Na SO , filtered, and concen-
1
3
(
d, J ) 8.0 Hz, 2H), 7.79 (d, J ) 8.4 Hz, 2H); C NMR (CDCl
3
)
trated. The residue was purified by flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate ) 12:1) to
give the carbinol. The enantiomeric purity of the product was
determined by HPLC. The absolute configurations of the
products were assigned by comparison to literature values.
Conditions for the Analysis of Chiral Secondary Al-
cohols. Chiral capillary GC: Chiral cyclodex capillary column
δ 19.9, 21.6, 23.8, 27.3, 48.8, 54.0, 60.4, 63.7, 64.7, 127.4, 129.6,
+
1
3
37.4, 143.2; HRMS (APCI) calcd for C15
13.1580, found 313.1565.
25 2 3
H N O S (M + H )
Characterization of 11a: white solid; 60% yield; mp 94-
26
1
9
5 °C; [R]
.64 (m, 4H), 2.21 (d, J ) 7.6 Hz, 1H), 2.42 (s, 3H), 2.62 (d, J
6.0 Hz, 1H), 2.83 (s, 1H), 3.19-3.22 (m, 1H), 3.36-3.48
m,2H), 3.66-3.70 (m, 1H), 3.89-3.93 (m, 1H), 7.06 (d, J )
.2 Hz, 2H), 7.29 (d, J ) 9.2 Hz, 5H), 7.76 (d, J ) 8.4 Hz, 2H);
D 3 3
) -56.51 (c 0.5, CHCl ); H NMR (CDCl ) δ 1.47-
1
)
â-2, 3, 6-M, 30 m × 0.32 mm. Carrier gas: N (1.67 mL/min).
2
(
Detector: FID, 250 °C. Injector: 220 °C.
7
Chiral HPLC: Chiralcel OD-H column; flow rate 1 mL.min-1
;
1
3
C NMR (CDCl
3
) δ 21.7, 23.4, 27.6, 45.0, 46.8, 60.2, 61.8, 63.4,
219 nm UV detection.
1
27.3, 128.1, 128.5, 129.0, 130.0, 135.8, 137.1, 143.5; HRMS
The racemic alcohol products were obtained by addition of
EtMgBr to aldehydes. The conditions of analysis and retention
times of the R and S isomers have been reported elsewhere.
+
(
27 2 3
APCI) calcd for C20H N O S (M + H ) 375.1737, found
3
75.1726.
Characterization of 11b: white solid; 65% yield; mp 113-
25
1
1
14 °C; [R]
.69 (m, 4H), 2.44 (s, 3H), 2.62 (d, J ) 6.8 Hz, 1H), 2.87 (t, J
8.0 Hz, 2H), 3.03-3.06 (m, 2H), 3.17-3.22 (m, 1H), 3.49-
.54 (m, 1H), 3.63-3.66 (m, 1H), 7.14-7.16 (m, 2H), 7.29 (t, J
D 3 3
) +1.33 (c 0.5, CHCl ); H NMR (CDCl ) δ 1.61-
Acknowledgment. Financial support from the
Knowledge Innovation Program of the Chinese Academy
of Sciences (Grant No. DICP Y200201) is gratefully
acknowledged. We thank Dr. Chunqing Liu at the
University of Illinois at Urbana-Champaign for helpful
discussions and Prof. Xiuwen Han at the Dalian Insti-
tute of Chemical Physics, Chinese Academy of Sciences
for discussion assistance of NMR spectra analyses.
1
)
3
5.2 Hz, 5H), 7.68 (d, J ) 8.0 Hz, 2H); 1 C NMR (CDCl
3
)
3
) δ
2
1.7, 24.5, 29.1, 45.7, 52.8, 61.5, 64.6, 66.6, 127.3, 128.6, 129.0,
1
27 2 3
29.9, 137.0, 138.9, 143.6; HRMS (APCI) calcd for C20H N O S
+
(
M + H ) 375.1737, found 375.1710.
2
General Procedure for the Addition of Et Zn to Alde-
hydes. Under a dry argon atmosphere, chiral ligand (10 mol
%
, 0.05 mmol) in dry hexane (4 mL) was cooled to 0 °C, and a
Supporting Information Available: General experimen-
solution of Et Zn (1.0 M in hexane, 1.1 mmol) was added
2
1
13
tal methods and H and C NMR and HRMS spectra for
characterization compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
slowly. After the mixture was stirred for 30 min at 0 °C, freshly
distilled aldehyde (0.5 mmol) was added, and the reaction was
stirred for 20-24 h at room temperature. The reaction mixture
was quenched with 1 M aqueous HCl at 0 °C. The aqueous
JO048520Q
J. Org. Chem, Vol. 69, No. 26, 2004 9127