Published on Web 12/29/2007
Catalysis of 3-Pyrrolidinecarboxylic Acid and
Related Pyrrolidine Derivatives in Enantioselective
anti-Mannich-Type Reactions: Importance of the 3-Acid
Group on Pyrrolidine for Stereocontrol
Haile Zhang,† Susumu Mitsumori,† Naoto Utsumi,† Masanori Imai,†
Noemi Garcia-Delgado,† Maria Mifsud,† Klaus Albertshofer,†
Paul Ha-Yeon Cheong,§ K. N. Houk,§ Fujie Tanaka,*,† and Carlos F. Barbas, III*,†
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
Received July 3, 2007; E-mail: ftanaka@scripps.edu; carlos@scripps.edu
Abstract: The development of enantioselective anti-selective Mannich-type reactions of aldehydes and
ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported
in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently
catalyzed the reactions of aldehydes with R-imino esters under mild conditions and afforded anti-Mannich
products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions
of ketones with R-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to
>99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at
the β-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carboncarbon bond formation and in directing anti-selectivity and enantioselectivity.
Introduction
Mannich and Mannich-type reactions are important carboncarbon bond-forming reactions for the synthesis of amino acids,
amino alcohols, amino carbonyls, and their derivatives that
contain two adjacent stereocenters; accordingly there is a
demand for the direct catalytic reactions that afford syn- or antiMannich products with high diastereo- and enantioselectivities.1-5
Because reactions that use unmodified carbonyl compounds as
nucleophile sources are more atom economical than those that
use preactivated carbonyl compounds, such as silyl enol ethers
or preformed enamines, development of the reactions that use
unmodified carbonyl compounds has been of interest. syn- or
anti-Selective Mannich-type reactions of unmodified carbonyl
†
§
The Scripps Research Institute.
University of California, Los Angeles.
(1) Enantioselective syn- or anti-selective Mannich-type reactions that use
silyl enolates or glycine imines as nucleophiles: (a) Ferraris, D.; Young,
B.; Dudding, T.; Lectka, T. J. Org. Chem. 1998, 63, 4584. (b) Ferraris, D.;
Young, B.; Cox, C.; Drury, W. J., III; Dudding, T.; Lectka, T. J. Org.
Chem. 1998, 63, 6090. (c) Ferraris, D.; Young, B.; Cox, C.; Dudding, T.;
Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc.
2002, 124, 67. (d) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem.
Soc. 1998, 120, 431. (e) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am.
Chem. Soc. 2002, 124, 5640. (f) Kobayashi, S.; Matsubara, R.; Nakamura,
Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507. (g)
Nakamura, Y.; Matsubara, R.; Kiyohara, H.; Kobayashi, S. Org. Lett. 2003,
5, 2481. (h) Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc.
2004, 7768. (i) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int. Ed. 2004, 43, 1566. (j) Ooi, T.; Kameda, M.; Fujii, J.; Maruoka,
K. Org. Lett. 2004, 6, 2397. (k) Okada, A.; Shibuguchi, T.; Ohshima, T.;
Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem., Int. Ed. 2005,
44, 4564. (l) Salter, M. M.; Kobayashi, J.; Shimizu, Y.; Kobayashi, S. Org.
Lett. 2006, 8, 3533. (m) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2006, 45, 7230.
10.1021/ja074907+ CCC: $40.75 © 2008 American Chemical Society
compounds that afford products with high enantioselectivities
have been performed using Zn-catalysts,2a-e Y-catalysts,2f Cucatalysts,2g,h Pd-catalysts,2i cinchona alkaloids,2j,k and proline
and related amine-based organocatalysts.3 In Mannich-type
reactions of R-hydroxyketones, Zn-catalysts selectively afforded
anti- or syn-products depending on the protecting group on the
reactant imine nitrogen.2a-e Cu-catalysts,2g,h Pd-catalysts,2i and
cinchona alkaloids2j,k have been used for Mannich-type reactions
of β-ketoesters. Proline and related amine-based enamine
catalysis have been used for enantioselective Mannich-type
reactions of aldehydes and ketones including simple alkylaldehydes and alkanones, in which in situ-formed enamine intermediates act as nucleophiles. When proline and related pyrrolidine derivatives that possess acidic groups at the R-position
of pyrrolidine are used as catalysts for these Mannich-type
reactions, typically syn-isomers are obtained as the major
products.3 Development of enamine-based Mannich-type reactions of aldehydes and of ketones that afford anti-products with
high diastereo- and enantioselectivities is a current challenge.4,5
Since Mannich-type reactions with R-imino esters are especially
useful for syntheses of a variety of amino acid derivatives
(Scheme 1),1a-c,2g,3a-g,j-l,q,r-t development of anti-Mannich-type
reactions with R-imino esters is considerably important.4,5a-c
We have recently reported in communications that pyrrolidine
derivatives (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and
(R)-3-pyrrolidinecarboxylic acid catalyze anti-Mannich-type
reactions of aldehydes4a and of ketones,4b respectively. To
provide information for the further development of efficient,
J. AM. CHEM. SOC. 2008, 130, 875-886
9
875
Zhang et al.
ARTICLES
Scheme 1
Scheme 2
highly diastereo- and enantioselective organocatalytic methods
of chemical transformations, here we report the details of the
design of pyrrolidine-derived catalysts bearing acid groups at
the 3-position of pyrrolidine for anti-Mannich-type reactions
and the scope of the catalyzed anti-Mannich-type reactions,
including reactions with R-imino esters.
Results and Discussion
Design and Evaluation of Catalysts for anti-Mannich-Type
Reactions of Aldehydes. (S)-Proline catalyzes Mannich-type
reactions between unmodified aldehydes and N-p-methoxyphenyl (PMP)-protected imine of ethyl glyoxylate and affords
(2S,3S)-syn-products with high enantioselectivities.3b,c The stereochemical outcome of the proline-catalyzed reactions can been
explained by the mechanism shown in Scheme 2a.3c,6 With
proline, (E)-enamines predominate. The s-trans-enamine conformation (A) of the (E)-enamine is used for the C-C bondforming transition state (C); the re face of the enamine reacts
with the si face of the imine. The C-C bond-forming transition
(2) Enantioselective syn- or anti-selective Mannich-type reactions of hydroxyketones, β-ketoesters, a trichloromethyl ketone, or an imide that use other
than enamine catalysis: (a) Matsunaga, S.; Kumagai, N.; Harada, S.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712. (b) Matsunaga, S.;
Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 8777. (c) Yoshida, T.; Morimoto, H.; Kumagai, N.; Matsunaga,
S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 3470. (d) Trost, B.;
Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. (e) Trost, B. M.;
Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778. (f)
Sugita, M.; Yamaguchi, A.; Yamagawa, N.; Handa, S.; Matsunaga, S.;
Shibasaki, M. Org. Lett. 2005, 7, 5339. (g) Juhl, K.; Gathergood, N.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995. (h) Foltz, C.;
Stecker, B.; Marconi, G.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L.
H. Chem. Commun. 2005, 5115. (i) Hamashima, Y.; Sasamoto, N.; Hotta,
D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005,
44, 1525. (j) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem.
Soc. 2005, 127, 11256. (k) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006,
8, 2003. (l) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006,
1191. (m) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2007, 129, 9588. (n) Cutting, G. A.; Stainforth, N.
E.; John, M. P.; Kociok-Kohn, G.; Willis, M. C. J. Am. Chem. Soc. 2007,
129, 10632.
(3) Enamine-based enantioselective syn-selective Mannich or Mannich-type
reactions that use aldehydes or ketones as nucleophiles: (a) Cordova, A.;
Notz, W.; Zhong, G.; Betancort, J.; Barbas, C. F., III. J. Am. Chem. Soc.
2002, 124, 1842. (b) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.;
Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866. (c) Notz, W.; Tanaka,
F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanuvan, R.;
Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624. (d) Chowdari, N. S.;
Ramachary, D. B.; Barbas, C. F., III. Synlett 2003, 1906. (e) Notz, W.;
Watanabe, S.; Chowdari, N. S.; Zhong, G.; Betancort, J. M.; Tanaka, F.;
Barbas, C. F., III. AdV. Synth. Catal. 2004, 346, 1131. (f) Chowdari, N.;
Suri, J.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507. (g) Chowdari, N.;
Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III. Org. Lett.
2006, 8, 2839. (h) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (i) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124,
827. (j) Zhuang, W.; Saaby, S.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2004, 43, 4476. (k) Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed.
2005, 44, 4077. (l) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew.
Chem., Int. Ed. 2005, 44, 4079. (m) Enders, D.; Vrettou, M. Synthesis 2006,
2155. (n) Enders, D.; Grondal, C.; Vrettou, M. Synthesis 2006, 3597. (o)
Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609.
(p) Fustero, S.; Jimenez, D.; Sanz-Cervera, J. F.; Sanchez-Rosello, M.;
Esteban, E.; Simon-Fuentes, A. Org. Lett. 2005, 7, 3433. (q) Janey, J. M.;
Hsiao, Y.; Armstrong, J. D., III. J. Org. Chem. 2006, 71, 390. (r) Cobb, A.
J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558. (s) Cobb, A. J. A.; Shaw,
D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem.
2005, 3, 84. (t) Wang, W.; Wang, J.; Li, H. Tetrahedron Lett. 2004, 45,
7243.
876 J. AM. CHEM. SOC.
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VOL. 130, NO. 3, 2008
state involving s-cis-enamine conformation B is disfavored
compared to transition state C. There are two main possiblities
for the predominant contribution of conformation A over B in
the C-C bond-forming transition state. One is position matching
between the nucleophilic carbon of the enamine and the
electrophilic carbon of the imine in A: When the imine is
protonated by the carboxylic acid, the enamine nucleophilic
carbon of conformation A is positioned within a suitable reaction
distance from the electrophilic carbon of the imine. The position
of the enamine nucleophilic carbon of conformation B, however,
(4) (a) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1040. (b) Zhang, H.;
Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128,
9630. (c) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III.
J. Am. Chem. Soc. 2007, 129, 288. (d) Cheong, P. H.-Y.; Zhang, H.;
Thayumanavan, R.; Tanaka, F.; Houk, K. N.; Barbas, C. F., III. Org. Lett.
2006, 8, 811. (e) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002,
43, 7749.
(5) (a) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc.
2005, 127, 16408. (b) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz,
T. C.; Kjaersgaard, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127,
18296. (c) Kano, T.; Hato, Y.; Maruoka, K. Tetrahedron Lett. 2006, 47,
8467. (d) Guo, Q.-X.; Liu, H.; Guo, C.; Luo, S.-W.; Gu, Y.; Gong, L.-Z.
J. Am. Chem. Soc. 2007, 129, 3790. (e) Cheng, L.; Wu, X.; Lu, Y. Org.
Biomol. Chem. 2007, 5, 1018.
(6) Bahmanyar, S.; Houk, K. N. Org. Lett. 2003, 5, 1249.
anti-Mannich-Type Reactions
Chart 1
is not correctly positioned near the electrophilic carbon of the
imine for bond formation under the proton transfer from the
carboxylic acid to the imine. The other possibility is that
conformation B has unfavorable steric interactions between the
carboxylic acid and the enamine, and thus conformation A,
which does not have such unfavorable interactions, predominates
over conformation B. Although computational analysis of the
transition state of the C-C bond-forming step suggests transition
state C,6 it has not been clearly explained why enamine
conformation A is used more favorably than conformation B
in the C-C bond-forming step. Therefore, in the design of
catalysts of anti-selective Mannich-type reactions, we considered
both possibilities.
To alter the selectivity from syn to anti, the reaction face of
the enamine or imine must be reversed from that of the prolinecatalyzed reactions. Since the 2-carboxylic acid of proline
controls both enamine conformation and reaction faces of the
enamine and the imine, we reasoned that separation of the steric
and the acid roles of this group into two groups and placing of
the groups at appropriate positions on a pyrrolidine ring should
result anti-selectivity. We reasoned that a pyrrolidine derivative
bearing substituents at 2- and 4-positions (or at 3- and
5-positions) should afford anti-products in the Mannich-type
reactions: The acid group at the 3-position of pyrrolidine can
be any acid functional group that engages the proton transfer
to the imine in the transition state and the substituent at
5-position can be any functional group that cannot initiate proton
transfer. Based on these considerations, we designed (3R,5R)5-methyl-3-pyrrolidinecarboxylic acid (1) (Chart 1) as an antiselective catalyst for the Mannich-type reactions of aldehydes
(Scheme 2b). We hypothesized that the 5-methyl group of
catalyst 1 controlled the enamine conformation to be present
as s-trans conformation D rather than s-cis conformation E
because of unfavorable steric interactions between the 5-methyl
group and the enamine in conformation E. We reasoned that
the 3-carboxylic acid of catalyst 1 should control the reaction
faces of the enamine and the imine through the proton transfer
from the carboxylic acid to the imine nitrogen. The proton
transfer from the carboxylic acid to the imine nitrogen should
also accelerate the reaction by increasing the imine electrophilicity. The 3-carboxylic acid and the 5-methyl group should be
ARTICLES
trans to avoid steric interactions between the 5-methyl group
of catalyst 1 and the imine in the C-C bond-forming transition
state. The trans-relationship between the 3-carboxylic acid and
5-methyl group should also block the approach of the imine to
the enamine from the undesired reaction face. Thus, catalyst 1
should catalyze the Mannich-type reactions via transition state
F that use s-trans-enamine conformation D of the (E)-enamine
intermediate (Scheme 2b). In this transition state, si-face of the
enamine reacts with the si-face of the imine. As we have
preliminary reported4a and further describe below, amino acid
1 is an excellent catalyst for the anti-selective Mannich-type
reactions of aldehydes and the product stereochemistry of the
1-catalyzed reaction accords with the C-C bond formation
through transition state F.
The acid group at the 3-position of 1 can be any functional
group that engages the proton transfer to the imine in the
transition state. The tetrazole derivative of (S)-proline, (S)-5pyrrolidine-2-yl-1H-tetrazole, has been used as an efficient
catalyst for Mannich reactions that can be catalyzed by proline,
and the reactions catalyzed by this catalyst affords Mannich
products with stereoselectivities similar to that obtained from
proline catalysis;3r therefore, we reasoned that ent-2 (Chart 1)
should also be an excellent anti-Mannich catalyst.
The 5-methyl group of catalysts 1 and ent-2 can be altered
upon the degrees of its contribution to the stereoselectivities of
the reactions. To determine the contribution of the carboxylic
acid at the 3-position and of the methyl group at the 5-position
of 1 to directing the stereochemical outcome of the reaction,
we reasoned to evaluate (2S,3R)-2-methyl-3-pyrrolidinecarboxylic acid (3), which has a methyl group at the 2-position on
the pyrrolidine, the unmethylated derivative (R)-3-pyrrolidinecarboxylic acid (4), and the pyrrolidine derivative without
3-carboxylic acid, (R)-2-methylpyrrolidine (5). If the acid group
at the 3-position is the group that predominantly directs the
stereochemical outcome, the use of unmethylated derivative 4
should also afford anti-products with high diastereo- and
enantioselectivities. Because catalyst 4 is more readily accessed
than catalyst 1, this catalyst would be useful for anti-selective
Mannich-type reactions if this catalyst provide reactivities and
selectivities similar to catalyst 1. As described below, reactions
of many aldehyde nucleophiles catalyzed by 4 afforded antiMannich products with high diastereo- and enantioselectivities.
With catalyst 4, both enamine conformations G and H may be
similarly present; that is, conformations G and H may have
similar free energies (Scheme 2c). However, only conformation
G should advance the C-C bond formation through transition
state I (Scheme 2c). The nucleophilic carbon of enamine G
should be properly positioned for the reaction with the electrophilic carbon of the imine, whereas the nucleophilic carbon
of enamine H should be too far from the imine electrophilic
carbon to form a bond.
Catalysts 1-14 were evaluated in the Mannich-type reaction
of isovaleraldehyde and N-PMP-protected ethyl glyoxylate imine
(Table 1). The reaction catalyzed by (3R,5R)-5-methyl-3pyrrolidinecarboxylic acid (1) afforded (2S,3R)-anti-157 in a
good yield with excellent diastereo- and enantioselectivities
(7) Determination of the absolute stereochemistry of 15 generated by the
1-catalyzed reaction has been reported in our communication (ref 4a).
J. AM. CHEM. SOC.
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VOL. 130, NO. 3, 2008 877
Zhang et al.
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Table 1. Evaluation of Catalysts for the anti-Selective Mannich-Type Reaction of Isovaleraldehyde to Afford 15a
entry
catalyst
catalyst load
(equiv)
time
(h)
yieldb
(%)
drc
anti/syn
major
anti-enantiomer
1
2
3
4
5
6e
7e
8e
9e
10e
11e
12
13
14
15
16e
17f
18
1
ent-2
3
4
ent-4
ent-5
ent-5 + CF3CO2H
ent-5 + 6
ent-5 + 7
7
pyrrolidine
ent-8
9
10
11
12
13
14
0.05
0.05
0.05
0.05
0.05
0.2
0.2
0.2
0.2
0.2
0.2
0.05
0.05
0.3
0.3
0.3
0.3
0.3
3
3
6
4
3
72
72
72
72
72
72
2.5
4
24
14
30
14
4
85
87
75
81
87
16
20
21
19
9
20
83
93
35
<20
51
82
62
98:2
98:2
97:3
99:1
99:1
75:25
80:20
67:33
64:36
63:37
89:11
94:6
87:13
93:7
75:25
78:22
1:1.4
10:90
(2S,3R)
(2R,3S)
(2S,3R)
(2S,3R)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
(2R,3S)
99
99
91
94
93
29 (19)
40 (18)
54 (40)
36 (46)
(2R,3S)
(2S,3R)
(2S,3R)
85
94 (95)
20
<5 (20)
36 (12)
98 (>99)
76 (80)
(2S,3R)
(2S,3R)
(2S,3R)
eed
(%)
a Typical reaction conditions: To a solution of N-PMP-protected R-imino ester (0.25 mmol, 1.0 equiv) and aldehyde (0.5 mmol, 2.0 equiv) in anhydrous
DMSO (2.5 mL), catalyst (0.0125 mmol, 0.05 equiv, 5 mol % to the imine) was added, and the mixture was stirred at room temperature (25 °C). b Isolated
yield containing anti- and syn-15. c The diastereomeric ratio (dr) was determined by 1H NMR or HPLC. d The ee of anti-15 was determined by chiral-phase
HPLC analysis. The ee of syn-15 is indicated in parenthesis. e When catalyst 0.05 equiv was used, no product formation was detected on TLC after 3 h.
f Taken from ref 4d.
(anti/syn 98:2, 99% ee, entry 1).8 The reaction using tetrazole
derivative ent-2 afforded the corresponding product enantiomer,
(2R,3S)-anti-15, with the same degree of diastereo- and enantioselectivities as the reaction using catalyst 1. Catalysts 1 and
ent-2 showed essentially the same level of catalytic efficiency.
Reactions catalyzed by 1- and by ent-2 were approximately 2to 3-fold faster than the corresponding proline-catalyzed reaction
that afforded the syn-product. These results indicate that the
tetrazole group at the 3-position of catalyst ent-2 functions as
efficiently as the carboxylic acid at the 3-position of catalyst 1.
Although the reaction catalyzed by 3, which has a methyl
group at the 2-position on the pyrrolidine, was slightly slower
than the reaction catalyzed by 1, there was not a significant
difference in rates of the reactions (entry 3 versus entry 1). The
reaction catalyzed by 3 afforded the same anti-product (2S,3R)15 as that by catalyst 1 with the same degree of diastereoselectivity and slightly lower enantioselectivity (91% ee, entry 3)
compared to the reaction catalyzed by 1 (99% ee, entry 1). These
results suggest that both s-trans and s-cis-enamine conformations
are present in the reaction catalyzed by 3 and that the C-C
bond formation is controlled by proton transfer from the
3-carboxylic acid group to the imine (Scheme 2d). Regardless
of the position of the methyl group of the catalysts, either at
the 5-position or at the 2-position, the reaction faces of the
enamine and the imine were the same in the formation of the
major product. These results indicate that a methyl group at
either the 5-position or the 2-position of the pyrrolidine ring of
the catalyst does not significantly effect the enamine conforma(8) To obtain the Mannich products generated from the reactions of aldehyde
nucleophiles in an excellent dr, quick and careful workup and purification
procedures were required. For example, the dr values of the products slightly
(up to 4% variation) changed during silica gel flash column chromatography.
Diastereomers of 15 were inseparable by typical silica gel flash column
chromatography (see Supporting Information).
878 J. AM. CHEM. SOC.
9
VOL. 130, NO. 3, 2008
tion. Although the 5-methyl group of catalyst 1 contributes to
afford almost perfect anti-selectivity and enantioselectivity in
the 1-catalyzed reaction, no significant steric interaction is
present between the enamine moiety and the methyl group at
either the 5-position or the 2-position. On the other hand, the
results indicate that the 3-acid group of the catalysts plays an
important role in directing the stereochemical outcome. Significant contribution of the 3-acid group on the pyrrolidine ring
of the catalysts in the stereocontrol of the reaction was also
supported from results of the reaction catalyzed by unmethylated
catalyst (R)-3-pyrrolidinecarboxylic acid (4). The reaction with
catalyst 4 afforded the same anti-product (2S,3R)-15 as did the
reaction with 1, and the enantiomeric excess of the anti-product
(2S,3R)-15 obtained using catalyst 4 was only slightly lower
(94% ee, entry 4) than that with catalyst 1. The major product
obtained from the 4-catalyzed reaction was in accord with a
mechanism of C-C bond formation through transition state I
(Scheme 2c).
The 3-acid group was essential not only for directing the
product stereochemistry, but also for reaction progress: The
reaction using (S)-2-methylpyrrolidine (ent-5), which lacked an
acid group, did not afford the Mannich product after 3 h when
0.05 equiv (i.e., 5 mol %) of catalyst to the imine was used.
Note that the reaction with 5 mol % of either 1 or ent-2 afforded
the anti-Mannich product in a good yield within a few hours.
Reaction with a higher loading of ent-5 (0.2 equiv) afforded
the Mannich product, but the diastereo- and enantioselectivities
were moderate (entry 6). The low yield of the reaction with
ent-5 was not improved by longer reaction time: A longer
reaction time resulted in decomposition of the imine and
Mannich product and formation of byproducts. Addition of acid
(equivalent to the catalyst), such as CF3CO2H, methyltetrazole
(6), or cyclopentanecarboxylic acid (7), to the ent-5-catalyzed
anti-Mannich-Type Reactions
Scheme 3
reaction did not meaningfully enhance the reaction rate; the
diastereo- and enantioselectivities of the reactions with these
acids were also moderate (entries 7-9). Reaction catalyzed by
cyclopentanecarboxylic acid (7) or by pyrrolidine also afforded
the anti-product as the major isomer (entries 10 and 11,
respectively). Since enantioselectivity was observed (although
low) in the ent-5-catalyzed reactions, the 2-methyl group plays
some role in the stereocontrol. The stereodirecting effect of the
2-methyl group of ent-5 was in accord with that of the 3-acid
group of catalyst 4. A pyrrolidine derivative with a bulky
2-substituent has been demonstrated as an anti-selective catalyst
in Mannich-type reactions of aldehydes,5b but catalyst ent-5,
pyrrolidine with a 2-methyl group alone, did not provide high
levels of stereocontrolling effects. These results indicate that
the 3-acid group of 1 plays a significant role in directing the
stereochemistry and in efficient reaction progress through proton
transfer to the imine intramolecularly. The 5-methyl group of
catalyst 1 cooperates with the stereodirecting effect of the 3-acid
group to provide perfect anti-selectivity and enantioselectivity.
The anti-product can be generated by isomerization of the
syn-product at the R-position of the aldehyde group (the
3-position of 15). To test whether the isomerization of the
product occurs under the Mannich-type reaction conditions, synrich 15 generated by the (S)-proline-catalyzed reaction was
treated with catalysts. First, syn-rich 15 was treated with
pyrrolidine under conditions similar to the catalyzed reactions
in Table 1, entry 11, and the ratios of the diastereomers and
enantiomers were analyzed. After 1 day, the anti-isomer became
the major isomer (anti/syn ) 1.6:1) as shown in Scheme 3;
(2S,3S)-syn-15 was converted to (2S,3R)-anti-15 in the presence
of pyrrolidine. Pyrrolidine isomerized the Mannich products
either through enamine formation with the product and/or by
acting as a base for enolization. This result indicates that the
anti-isomer is more thermodynamically stable than the synisomer. The anti-isomer was also more thermodynamically
favored in imidazole isomerization:4a,9 In the presence of
imidazole, the isomerization rate of 15 from syn to anti was
faster than that from anti to syn. The ratio of the diastereomers
obtained from the pyrrolidine-catalyzed reaction that afforded
the anti-isomer as the major product may reflect the consequences of isomerization; the pyrrolidine-catalyzed reaction may
not form the anti-product by kinetic control in the C-C bondforming step.
Next, isomerization of syn-15 to anti-15 in the presence of
pyrrolidine, ent-5, or 4 in CDCl3 or in DMSO-d6 was analyzed
by 1H NMR (Table 2). The isomerization rate with ent-5, which
possesses 2-methyl group, was slower than that with pyrrolidine
but the anti-isomer became the major isomer after 1 day.
(9) Ward, D. E.; Sales, M.; Sasmal, P. J. Org. Chem. 2004, 69, 4808.
ARTICLES
Table 2. Isomerization of syn-15 to anti-15 Catalyzed by
Pyrrolidinesa
catalyst
catalyst load
(equiv)
pyrrolidine
0.2
CDCl3
ent-5
0.2
CDCl3
4
0.1
CDCl3
4
0.1
DMSO-d6
solvent
time
syn-15/anti-15b
0 min
4h
24 h
0 min
4h
24 h
0 min
3h
24 h
0 min
2h
7h
96:4c
1:1
1:2.5d
96:4c
2:1
1:2d
96:4c
95:5
83:17e
96:4c
96:4
95:5
a Conditions: Mannich product 15 (0.1 M) and catalyst (0.2 or 0.1 equiv
to 15 as indicated). b The ratio of syn-15/anti-15 was determined by 1H
NMR. c Before addition of catalyst. d Includes decomposed products ∼20%.
e Includes decomposed products ∼5%.
Diastereomeric ratio of 15 obtained from the ent-5-catalyzed
reaction may also reflect the result of isomerization of the
kinetically formed product. On the other hand, isomerization
with 4, which possesses 3-carboxylic acid, was significantly
slower than that with pyrrolidine or with ent-5. Isomerization
with 4 was negligible over the time range of the 4-catalyzed
Mannich-type reaction. The negligible isomerization of the
Mannich product in the presence of 4 also supports that the
anti-selectivity of the 1- or 4-catalyzed reaction is the result of
the kinetic control at the C-C bond-forming step. In the
isomerization with pyrrolidine or with ent-5, basic environs may
contribute to acceleration of the isomerization rates.
To further understand the contribution of the 3-acid group
of the catalysts, 3-substituted pyrrolidines, including ent-8 and
9, 3-hydroxypyrrolidine (10), and 3-pyrrolidinecarboxylic acid
methyl ester (11), were also evaluated. The sulfonamide group
that is present in catalysts ent-8 and 9 has been used as an acid
functionality in the enamine-based catalysts for Mannich
reactions.3t,5a,c Catalysts ent-8 and 9 (entries 12 and 13) had
catalytic activity similar to 1, 2, 3, and 4, indicating that the
sulfonamide group is also a good acid for catalysis in the antiselective Mannich-type reaction. Since the anti-selectivity and
enantioselectivity varied depending on the catalyst, the results
also indicate that the distance and orientation between the 3-acid
group of a catalyst, enamine nucleophilic carbon, and imine
electrophilic carbon in the transition state affect to the antiselectivity and enantioselectivity. 3-Hydroxypyrrolidine (10) was
not a good catalyst (entry 14), indicating that hydroxyl group
at the 3-position was not an efficient acid for this reaction.
Reaction with methyl ester 11 was slow (entry 15), also
supporting the importance of the acid group on pyrrolidine for
catalysis.
Reaction catalyzed by 3-piperidinecarboxylic acid (12), a sixmembered ring catalyst, was slow and afforded the product with
moderate anti-selectivity and enantioselectivity (entry 16),
indicating the importance of the five-membered pyrrolidine ring
structure for efficient catalysis and high selectivity. We previously reported the (S)-pipecolic acid (13)-catalyzed reaction that
afforded both anti- and syn-isomers (2S,3R)-15 and (2S,3S)-15
(anti/syn 1:1.4) with high enantioselectivities (entry 17).4d
Computational analysis of the transition states of the C-C bond
formation step of the 13-catalyzed reaction suggested that the
both s-cis- and s-trans-enamines were similarly used for the
J. AM. CHEM. SOC.
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VOL. 130, NO. 3, 2008 879
Zhang et al.
ARTICLES
Table 3. Evaluation of Catalysts for the anti-Selective
Mannich-Type Reaction of 3-Pentanonea
entry
catalyst
time
(h)
yieldb
(%)
drc
anti/syn
major
anti−enantiomer
1
2
3
4
1
4
ent-8
9
72
29
72
17
<10
75
83
98
94:6
94:6
75:25
(2S,3R)-16
(2R,3S)-16
(2S,3R)-16
Scheme 4
eed
(%)
97
85
97 (syn 97)
a To a solution of N-PMP-protected R-imino ester (0.5 mmol, 1.0 equiv)
and 3-pentanone (2.0 mL, 19 mmol, 38 equiv) in anhydrous DMSO (3.0
mL), catalyst (0.1 mmol, 0.2 equiv, 20 mol % to the imine) was added,
and the mixture was stirred at room temperature (25 °C). b Isolated yield
containing anti- and syn-16. c Determined by HPLC before purification.
d Determined by chiral-phase HPLC for anti-16.
C-C bond formation in the 13-catalyzed reaction and that thus
both syn and anti products formed.4d Reaction catalyzed by
2-azetidinecarboxylic acid (14), a four-membered ring catalyst,
afforded syn-products as the major product. Stereoselectivity
of the product depended on the ring size of the amine catalyst
and on the position of the acid.
The results of the catalyst evaluation indicate that the acid
group at the 3-position of catalyst 1 plays a dominant role in
forwarding reaction (efficient catalysis) and in directing stereochemistry through proton transfer to the imine. The 5-methyl
group of catalyst 1 cooperatively contributes to the stereocontrolling effect of the 3-acid group to provide anti-products with
excellent enantioselectivity as almost single enantiomer. The
5-methyl group of catalyst 1 has little effect on controlling the
enamine conformation: There is no significant steric role of
R-methyl group on pyrrolidine to control enamine conformation.
The (E)-enamine of 1 (or 4) is present as either s-trans D or
s-cis E (or s-trans G or s-cis H), but only D (or G) advances
to the C-C bond formation through F (or I). The preference
of conformation D over E in the transition state of the C-C
bond-forming step originates mainly from the proton transfer
from the 3-acid group to the imine. Proper positioning of the
enamine and the imine for efficient catalytic activity, high antiselectivity, and high enantioselectivity is achieved by the proton
transfer from the 3-carboxylic acid to the imine nitrogen.
Of the catalysts evaluated, catalysts 1 and ent-2 were the most
efficient catalysts for the anti-Mannich-type reactions of aldehydes with respect to the catalytic efficiency, anti-selectivity,
and enantiostereoselectivity. When accessibility of catalysts was
also considered, 4 had advantages. Therefore, catalysts 1 and 4
were further studied for the anti-Mannich-type reactions of
aldehydes.
Design and Evaluation of Catalysts for anti-Mannich-Type
Reactions of Ketones. Compared to the reactions of aldehydes,
the reactions of ketones require additional consideration of steric
interactions in formation of enamine intermediates. Although
amino acid 1 was an excellent anti-selective catalyst for the
Mannich-type reactions of aldehydes, the reaction of 3-pentanone in the presence of catalyst 1 was very slow (Table 3,
entry 1). Whereas the R-methyl group on pyrrolidine did
not hinder the formation of enamine intermediates with aldehydes, we reasoned that the low efficiency of catalyst 1 in the
880 J. AM. CHEM. SOC.
9
VOL. 130, NO. 3, 2008
ketone reaction originated from relatively slow formation of
the enamine intermediates due to steric interactions with the
methyl group of the catalyst (Scheme 4a). We reasoned that
unmethylated catalyst 4 should afford anti-Mannich products
in the ketone reactions. Although enamine conformations J and
K may have similar free energies, only J should advance to
the C-C bond formation via transition state L (Scheme 4b).
When proton transfer occurs from the acid at the 3-position of
the catalyst to the imine nitrogen, the nucleophilic carbon of
enamine J should be properly positioned to react with the imine,
whereas the nucleophilic carbon of enamine K should be too
far from the imine electrophilic carbon to form a bond. Since 4
does not have an R-substituent on the pyrrolidine, neither
enamine J nor K has a disfavored steric interaction like the
one shown in Scheme 4a and enamine formation of ketones
with 4 should be faster than that with 1.
In fact, the reaction catalyzed by 4 was significantly faster
than the 1-catalyzed reaction and afforded anti-Mannich product
(2S,3R)-1610 in good yield with high diastereo- and enantioselectivities (entry 2, anti/syn 94:6, anti 97% ee). Catalyst ent-8,
which possesses a sulfonamide group, also catalyzed the
formation of the anti-product (entry 3), but the reaction catalyzed
by 4 was faster and showed higher enantioselectivity than the
ent-8-catalyzed reaction. Catalyst 9, which also has a sulfonamide group, catalyzed the reaction more efficiently than ent-8
did, and the ee of the product anti-16 obtained from the
9-catalyzed reaction was excellent (entry 4). These results
indicate that the acid functionality at the 3-position on the
pyrrolidine ring plays an important role in directing stereochemistry in the reactions of ketones as it did in the reactions
of aldehydes. The acid group contributes to proper positioning
of the imine for efficient catalytic activity and high antiselectivity and enantioselectivity. Because catalyst 4 afforded
the best results with respect to anti-selectivity and enantioselectivity, this catalyst was further investigated for the antiMannich-type reactions of ketones.
Mannich-Type Reactions of Aldehyde Donors Catalyzed
by 1. Solvents were evaluated for the 1-catalyzed Mannich
reaction to afford (2S,3R)-anti-15 in a good yield with high
diastereo- and enantioselectivities in a short reaction time (Table
(10) Determination of the absolute stereochemistry of 16 generated by the
4-catalyzed reaction has been reported in our communication (ref 4b).
anti-Mannich-Type Reactions
ARTICLES
Table 4. Solvent Effects on the anti-Mannich-Type Reaction of an
Aldehyde Catalyzed by 1a
Table 5. anti-Mannich-Type Reactions of Aldehydes Catalyzed
by 1a
entry
entry
solvent
time
(h)
yieldb
(%)
drc
anti/syn
eed
(%)
1
2
3
4
5
6
7
8
9
DMSO
DMF
CH3CN
EtOAc
dioxane
CH2Cl2
THF
Et2O
[bmim]BF4
3
3
3
6
5
3
20
20
5
85
78
76
80
77
85
45
40
35
98:2
97:3
96:4
94:6
97:3
91:9
91:9
90:10
94:6
99
98
96
96
95
93
83
84
77
a Typical reaction conditions: To a solution of N-PMP-protected R-imino
ester (0.125 mmol, 1.0 equiv) and aldehyde (0.5 mmol, 4.0 equiv) in
anhydrous solvent (1.25 mL), catalyst (0.0063 mmol, 0.05 equiv, 5 mol %
to the imine) was added, and the mixture was stirred at room temperature.
b Isolated yield containing anti- and syn-diastereomers. c The dr was
determined by 1H NMR. d The ee of (2S,3R)-anti-15 was determined by
chiral-phase HPLC analysis.
4). The reaction in DMSO provided the best anti-selectivity and
enantioselectivity among those solvents tested (entry 1). Reactions in DMF, CH3CN, EtOAc, and dioxane were as efficient
with respect to reaction rate as that in DMSO and afforded high
anti-selectivity and enantioselectivity (anti/syn 94:6-97:3, 9597% ee, entries 2-5). Although ionic liquids were good solvents
for the proline-catalyzed Mannich reaction affording syn-15,3d
the 1-catalyzed reaction in ionic liquid [bmim]BF4 (bmim )
1-butyl-3-methylimidazolium) was slow (entry 9).
The scope of the 1-catalyzed Mannich-type reaction with ethyl
glyoxylate imine was examined using a series of aldehydes
(Table 5). The reactions catalyzed by 1 afforded a series of antiMannich products (2S,3R)-15 and (2S,3R)-17-21 with excellent
diastereo- and enantioselectivities (anti/syn 94:6-99:1, anti
>97->99% ee).8 With 5 mol % catalyst loading, the reaction
rates with catalyst 1 were approximately 2- to 3-fold faster than
the corresponding proline-catalyzed reactions that afford the synproducts. Because of the high catalytic efficiency of 1, the
reactions catalyzed by only 1 or 2 mol % of 1 afforded the
desired products in reasonable yields within a few hours (entries
5, 6, 8, and 9). For the reaction of a bulky aldehyde 3,3dimethylbutanal, a higher loading of catalyst and a longer
reaction time were required to afford the Mannich product anti22 (entry 10) than for the reactions of R-unbranched aldehydes.
These anti-Mannich products were generally more resistant
to the isomerization at the R-position of the aldehyde carbonyl
group than corresponding syn-Mannich products, which were
often isomerized to anti-isomer3b,c or to R,β-unsaturated carbonyl
compounds11 (if applicable) during purification.8 Thus, formation of highly enantiomerically enriched Mannich products in
an anti-selective fashion was beneficial to access to amino acid
derivatives in more pure forms than formation of corresponding
syn-Mannich products.
(11) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int.
Ed. 2007, 46, 1878.
R
yieldb
drc
(%) anti/syn
eed
(%)
catalyst load
(equiv)
time
(h)
product
0.05
0.05
0.3
0.05
0.02
0.01
0.05
0.02
0.02
1
3
1
0.5
1
2
3
3
3
(2S,3R)-17
(2S,3R)-15
(2S,3R)-15
(2S,3R)-18
(2S,3R)-18
(2S,3R)-18
(2S,3R)-19
(2S,3R)-20
(2S,3R)-21
70
85
86
54
71
57
80
72
84
94:6
98:2
93:7
97:3
97:3
97:3
97:3
96:4
99:1
>99e
99
>99
99
99
>99
>99
>97
>99
(2S,3R)-22
57
86:14
77
1
2
3
4
5f
6f
7
8f
9
Me
i-Pr
i-Pr
n-Bu
n-Bu
n-Bu
n-Pent
CH2CHdCH2
CH2CH
CH(CH2)4CH3
10 t-Bu
0.1
48
a Typical reaction conditions: To a solution of N-PMP-protected R-imino
ester (0.25 mmol, 1.0 equiv) and aldehyde (0.5-1.0 mmol, 2-4 equiv) in
anhydrous DMSO (2.5 mL), catalyst 1 (0.0125 mmol, 0.05 equiv, 5 mol %
to the imine) was added, and the mixture was stirred at room temperature.
b Isolated yield containing anti- and syn-diastereomers. c The dr was
determined by 1H NMR or HPLC. d The ee of anti-product was determined
by chiral-phase HPLC analysis. e The ee was determined by HPLC analysis
of the corresponding oxime prepared with O-benzylhydroxylamine. f The
reaction was performed in a doubled scale.
Table 6. anti-Mannich-Type Reactions of Aldehydes Catalyzed by
1: Variation of R-Imino Glyoxylatesa
entry
R1
R2
time
(h)
product
yieldb
(%)
drc
anti/syn
eed
(%)
1
2
3
4
i-Pr
n-Pent
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
CH2CHdCH2
1
1
2.5
3
(2S,3R)-23
(2S,3R)-24
(2S,3R)-25
(2S,3R)-26
92
85
85
87
97:3
96:4
>99:1
98:2
98
>99
98
97
a Reaction conditions: To a solution of N-PMP-protected R-imino ester
(0.25 mmol, 1.0 equiv) and aldehyde (0.5-1.0 mmol, 2-4 equiv) in
anhydrous DMSO (2.5 mL), catalyst 1 (0.0125 mmol, 0.05 equiv, 5 mol %
to the imine) was added, and the mixture was stirred at room temperature.
b Isolated yield containing anti- and syn-diastereomers. c The dr was
determined by 1H NMR or HPLC. d The ee of anti-product was determined
by chiral-phase HPLC analysis.
The use of catalyst 1 was also examined in anti-selective
Mannich-type reactions of a series of N-PMP-protected glyoxylate imines to afford anti-products 23-26 (Table 6). The
anti-products were obtained in good yields and excellent
diastereo- and enantioselectivities. The reaction with a glyoxylate imine possessing a bulky group, tert-butyl, also proceeded
smoothly and afforded the Mannich product with excellent antiselectivity and enantioselectivity (entry 3).
Mannich-Type Reactions of Aldehyde Donors Using
Catalysts 4 and ent-4. Evaluation of solvents for the 4-catalyzed
Mannich-type reaction that affords (2S,3R)-anti-15 showed that
DMSO was the best among solvents tested with respect to yield,
anti-selectivity, and enantiomeric excess of the anti-Mannich
product (Table 7). Whereas the reaction in aprotic solvents
J. AM. CHEM. SOC.
9
VOL. 130, NO. 3, 2008 881
Zhang et al.
ARTICLES
Table 7. Solvent Effects on the anti-Mannich-Type Reaction of an
Aldehyde Using Catalyst 4a
entry
solvent
time
(h)
yieldb
(%)
drc
anti/syn
eed
(%)
1
2
3
4
5
6
7
8
9
10
DMSO
DMF
CH3CN
N-methylpyrrolidone (NMP)
EtOAc
dioxane
CHCl3
toluene
2-PrOH
[bmim]BF4
2.5
3.5
4.5
8
8
7
6
8
2
10
87
84
81
65
72
78
68
68
52
70
95:5
95:5
92:8
93:7
91:9
92:8
88:12
93:7
90:10
92:8
93
91
88
87
82
79
78
83
53
86
a Reaction conditions: To a solution of N-PMP-protected R-imino ester
(0.125 mmol, 1.0 equiv) and aldehyde (0.25 mmol, 2.0 equiv) in anhydrous
solvent (1.25 mL), catalyst 4 (0.0125 mmol, 0.1 equiv, 10 mol % to the
imine) was added, and the mixture was stirred at room temperature. bIsolated
yield containing anti- and syn-diastereomers. c The dr was determined by
HPLC. d The ee of (2S,3R)-anti-15 was determined by chiral-phase HPLC
analysis.
afforded the anti-Mannich product with good enantioselectivity,
the reaction in 2-PrOH provided the anti-product with moderate
ee. When the reactions in entry 1 (in DMSO) and in entry 9 (in
2-PrOH) were performed in the absence the catalyst, no
formation of Mannich product 15 was detected after 2.5 h in
either reaction. After 6.5 h, in 2-PrOH, formation of trace
amounts of 15 (<5%, anti/syn ) 4:1) was detected by 1H NMR
of the crude mixture. Formation of 15 in the absence of a catalyst
was negligible for the time range of the catalyzed reaction shown
in Table 7. When purified syn-15 (syn/anti 96:4) in 2-PrOH
(0.1 M) was treated with catalyst 4 (0.1 equiv to 15), the syn/
anti ratio of 15 was 95:5 at 3 h and 87:13 at 6 h. Although the
isomerization rate in 2-PrOH was faster than that in CDCl3 or
in DMSO-d6 (see Table 2), changes in the dr in 2-PrOH were
negligible for the time range of the 4-catalyzed Mannich
reaction. These results suggested that background reaction
(product formation without involving the catalyst) and isomerization of syn-15 with low ee (if any) to anti-15 were not main
reasons for the moderate ee of anti-15 obtained by the
4-catalyzed reaction in 2-PrOH and that anti-15 with moderate
ee in 2-PrOH was formed at the C-C bond-forming step. The
4-catalyzed reaction of isovaleraldehyde in 2-PrOH may partly
proceed without desired stereocontrolling participation of the
catalyst.
The scope of the Mannich-type reactions between aldehydes
and glyoxylate imines catalyzed by 4 and ent-4 was examined
in reactions that afforded products 15 and 17-27 (Table 8).
The anti-products were obtained with high diastereo- and
enantioselectivities in most cases (anti/syn 93:7-99:1, anti 9099% ee). In some cases, the enantioselectivity of the 4-catalyzed
reaction was slightly lower than that of the 1-catalyzed reaction.
However, reactions of aldehydes with a longer alkyl chain using
catalyst 4 afforded anti-Mannich products with excellent enantioselectivities (entries 5-8). Reaction with a bulky aldehyde,
3,3-dimethylbutanal, proceeded efficiently in the presence of
882 J. AM. CHEM. SOC.
9
VOL. 130, NO. 3, 2008
catalyst 4, although the ee of the anti-product was moderate
(entry 9). By using 4 or its enantiomer ent-4, both enantiomers
of the anti-Mannich products were obtained in good yields with
high enantioselectivities.
Mannich-type reactions of R,R-disubstituted aldehydes catalyzed by 4 afforded products 28 and 29 in good yields (Table
9), although the diastereo- and enantioselectivities were low to
moderate and the syn-product was the major diastereomer in
both cases. For the 4-catalyzed Mannich reactions of R-branched
aldehydes, use of 2-PrOH as the solvent provided good results
with respect to reaction rate and yield. These 4-catalyzed
Mannich-type reactions of R,R-disubstituted aldehydes were
significantly faster than the corresponding proline-catalyzed
reactions.3f
Enantioselective and asymmetric Mannich-type reactions
constitute key steps for simple access to enantiomerically
enriched β-lactams.3b,c,12 Using Mannich product (2R,3S)-anti15 obtained by the ent-4-catalyzed reaction, trans-β-lactam
(3S,4R)-30 was synthesized via 31 (Scheme 5). We previously
demonstrated that the corresponding syn-Mannich products
generated from (S)-proline-catalyzed reactions were easily
transformed to cis-β-lactams.3b,c With use of anti- or synMannich-type reactions, highly enantiomerically enriched β-lactams with desired stereochemistries, either trans or cis, respectively, can be readily obtained.
Mannich-Type Reaction of Ketone Donors Using Catalysts
4 and ent-4. Evaluation of solvents for the 4-catalyzed Mannichtype of reactions between 3-pentanone and N-PMP-protected
ethyl glyoxylate imine showed that 2-PrOH was the best solvent
tested to afford (2S,3R)-anti-16 in good yield with high antiselectivity and enantioselectivity within a short reaction time
(Table 10, entry 9). The reactions in DMSO, DMF, and
N-methylpyrrolidone (NMP) also proceeded well and afforded
the anti-product with high selectivities. Whereas catalyst 4 was
soluble in DMSO, DMF, and NMP, catalyst 4 was not
completely soluble in CHCl3, CH3CN, dioxane, THF, and
EtOAc in the presence of excess 3-pentanone under conditions
of Table 10. Catalyst 4 was even less soluble in THF and EtOAc
(or THF-3-pentanone or EtOAc-3-pentanone). The slow reaction
rate and low yield in these solvents may originate from the low
solubility of the catalyst. Catalyst 4 was also not completely
soluble in alcohols, including 2-PrOH, but the reaction in
alcohols proceeded well. The reaction rate in 2-PrOH was
approximately 2-fold faster than that in DMSO and the reaction
in 2-PrOH provided less byproducts than that in DMSO. The
reaction in EtOH was also efficient, although the ee of the antiMannich product was slightly lower than that in 2-PrOH. When
the reaction in MeOH (entry 11) was performed in the absence
of catalyst 4, no formation of the Mannich product was detected
after 48 h, indicating that the catalyst is necessary for the
reaction to proceed even in MeOH. Note that for the 4-catalyzed
reactions of aldehydes, 2-PrOH was not a good solvent; the ee
of the anti-Mannich product of the aldehyde reaction was
moderate in 2-PrOH (see Table 7).
The reactions of aldehydes in 2-PrOH may proceed without
desired stereocontrolling participation of catalysts in the C-C
bond-forming transition state. Enamine formation with ketones
(12) (a) Kobayashi, S.; Kobayashi, J.; Ishiani, H.; Ueno, M. Chem. Eur. J. 2002,
8, 4185. (b) Hata, S.; Iwasawa, T.; Iguchi, M.; Yamada, K.; Tomioka, K.
Synthesis 2004, 1471. (c) Iza, A.; Vicario, J. L.; Carrillo, L.; Badia, D.
Synthesis 2006, 4065.
anti-Mannich-Type Reactions
ARTICLES
Table 8. anti-Mannich-Type Reactions of Aldehydes Catalyzed by 4 and ent-4a
R1
R2
catalyst
time
(h)
product
Me
i-Pr
i-Pr
n-Bu
n-Pent
CH2CHdCH2
CH2CHdCH(CH2)4CH3
CH2Ph
t-Bu
i-Pr
i-Pr
i-Pr
i-Pr
Et
Et
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
t-Bu
CH2CHdCH2
4
4
ent-4
4
4
4
4
4
4
4
ent-4
4
4
4
4
3
2
3
3
3
1
16
3
3
2.5
3
(2S,3R)-17
(2S,3R)-15
(2R,3S)-15
(2S,3R)-18
(2S,3R)-19
(2S,3R)-20
(2S,3R)-21
(2S,3R)-27
(2S,3R)-22
(2S,3R)-23
(2R,3S)-23
(2S,3R)-25
(2S,3R)-26
entry
1
2
3
4
5
6
7
8
9e
10
11
12
13
yieldb
(%)
drc
anti/syn
eed
(%)
75
81
79
60
80
78
83
87
88
82
78
82
85
93:7
99:1
99:1
99:1
99:1
99:1
98:2
96:4
95:5
98:2
98:2
99:1
98:2
96
94
93
95
>97
>97
99
99
63
91
90
94
95
a Typical reaction conditions: To a solution of N-PMP-protected R-imino ester (0.25 mmol, 1.0 equiv) and aldehyde (0.5 mmol, 2.0 equiv) in anhydrous
DMSO (2.5 mL), catalyst 4 or ent-4 (0.0125 mmol, 0.05 equiv, 5 mol % to the imine) was added, and the mixture was stirred at room temperature. b Isolated
yield containing anti- and syn-diastereomers. c The dr was determined by 1H NMR or HPLC. d The ee of anti-product was determined by chiral-phase HPLC
analysis. e Catalyst 4 (0.1 equiv) and DMSO (0.5 mL) were used.
Table 9. Mannich-Type Reactions of R,R-Disubstituted Aldehydes
Catalyzed by 4a
entry
1
2
3
R
Ph
n-Pr
n-Pr
solvent
2-PrOH
2-PrOH
DMSO
time
(h)
1
28
72
product
28
29
29
yieldb
(%)
99
95
90
drc
anti/syn
36:64
37:63
45:55
anti eed
(%)
24
34
29
Table 10. Solvent Effects on the anti-Mannich-Type Reaction of
3-Pentanone Using Catalyst 4a
syn eed
(%)
37
9
14
a To a solution of N-PMP-protected R-imino ester (0.25 mmol, 1.0 equiv)
and aldehyde (0.5 mmol, 2.0 equiv) in solvent (2.5 mL), catalyst 4 (0.025
mmol, 0.1 equiv, 10 mol % to the imine) was added, and the mixture was
stirred at room temperature. b Isolated yield containing anti- and syndiastereomers. c The dr was determined by 1H NMR. d The ee was
determined by chiral-phase HPLC analysis.
Scheme 5 a
entry
solvent
time
yieldb
(%)
drc
anti/syn
eed
(%)
1
2
3
4
5
6
7
8
9
10
11
DMSO
DMF
NMP
CHCl3
CH3CN
dioxane
THF
EtOAc
2-PrOH
EtOH
MeOH
29 h
38 h
40 h
3d
3d
3d
3d
3d
18 h
18 h
32 h
75
74
65
46
51
30
<10
<10
90
91
79
94:6
87:13
93:7
95:5
97:3
74:26
ND
ND
97:3
95:5
96:4
97
97
96
97
95
71
ND
ND
98
92
87
a Typical reaction conditions: To a solution of N-PMP-protected R-imino
ester (0.1 mmol, 1.0 equiv) and 3-pentanone (0.4 mL, 3.8 mmol, 38 equiv)
in anhydrous solvent (0.6 mL), catalyst 4 (0.02 mmol, 0.2 equiv, 20 mol %
to the imine) was added, and the mixture was stirred at room temperature.
b Isolated yield containing anti- and syn-diastereomers. c The dr of the
isolated product was determined by HPLC analysis. d The ee of (2S,3R)anti-16 was determined by chiral-phase HPLC analysis.
a Conditions: (a) (i) NaClO , KH PO , 2-methyl-2-butene, t-BuOH/H O;
2
2
4
2
(ii) TMSCHN2; (b) LHMDS; (c) previously reported, see ref 3b,c.
is difficult compared to that with aldehydes and the reactions
of ketones do not proceed without proper catalyst participation
even in alcohol solvents. As a result, the reactions of ketones
occur in 2-PrOH through the transition state that affords the
anti-Mannich product in a highly stereocontrolled manner. That
is, 2-PrOH does not interrupt the proton transfer from the
carboxylic acid of the catalysts to the imine in the C-C bondforming transition state of the reactions of ketones. 2-PrOH may
stabilize the charged transition states of enamine formation of
ketones and the transition state of the C-C bond formation of
the Mannich-type reactions of ketones, resulting in the faster
reaction rate in this solvent than in other non-alcohol solvents
tested.
The scope of 4-catalyzed Mannich-type reactions between a
variety of ketones and R-imino esters was examined in the
formation of anti-products 16 and 32-55 (Tables 11-13). In
most cases, anti-Mannich products were obtained in good yields
J. AM. CHEM. SOC.
9
VOL. 130, NO. 3, 2008 883
Zhang et al.
ARTICLES
Table 11. anti-Mannich-Type Reactions of Acyclic Ketones Catalyzed by 4a
entry
R1
R2
R3
time (h)
product
yieldb (%)
drc anti/syn
eed (%)
1
2e
3
4
5
6h
7
8
9
10
11
Et
Et
Et
n-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Et
CH2CHdCH2
(CH2)3Cl
(CH2)2CO2Et
(CH2)2CN
Et
Et
t-Bu
Et
Et
Et
Et
Et
Et
Et
Et
20
48
20
96
5
5
10
14
14
24
24
16
16
32
33
34
ent-34
35
36
37
38
39
91
77
93
76
85f
81f
81f
85
68
80
78
97:3
97:3
>99:1
>99:1
∼10:1 (>99:1)g
∼10:1 (>99:1)g
∼10:1
>95:5
>95:5
∼9:1
∼9:1
97
98
95
82
90 (>99)g
88 (99)g
92
91
84
93
90
a Typical conditions: To a solution of imine (0.5 mmol, 1.0 equiv) and ketone (5.0 mmol, 10 equiv) in 2-PrOH (1.0 mL), 4 (0.05 mmol, 0.1 equiv) was
added, and the mixture was stirred at 25 °C. b Isolated yield containing anti- and syn-diastereomers. c Determined by 1H NMR of isolated products. d Determined
by chiral-phase HPLC for the anti-product. e Ketone (4 equiv), 4 (0.05 equiv), at 4 °C. f Containing regioisomer (∼5-10%). g Data after crystallization are
shown in parentheses. The dr was determined by HPLC. h Catalyst ent-4 was used.
Table 12. anti-Mannich-Type Reactions of R-Functionalized
Acyclic Ketones Catalyzed by 4a
entry
R1
R2
time
(h)
product
yieldb
(%)
drc
anti/syn
eed
(%)
1
2e,f
3
4g
5h
6i
7f
8h,j,k
9f
10f,l
Me
Me
Me
Me
Me
Me
Me
Et
CH2OBn
CH2OH
OMe
OBn
OH
OH
OH
OH
SMe
N3
OBn
OH
3
16
1
1
1
6
4
24
5
24
40
41
42
42
42
42
43
44
45
46
78
91
71
62
53
60
78
58
69
41
∼5:1
∼4:1
∼1:1
∼1:1
∼2:1
∼2:1
∼1:1
1.3:1
1.4:1
∼3:1
86
90
80 (10)
84 (8)
90 (12)
78 (55)
48
69 (54)
45 (9)
8
a Typical conditions: To a solution of imine (0.25 mmol, 1.0 equiv)
and ketone (0.5 mmol, 2.0 equiv) in 2-PrOH (1.25 mL), 4 (0.025 mmol,
0.1 equiv) was added, and the mixture was stirred at 25 °C. b Isolated yield
containing anti- and syn-diastereomers. c Determined by 1H NMR of isolated
products. d Determined by chiral-phase HPLC for the anti-product. The ee
of syn-product is indicated in parenthesis. e Catalyst ent-4 was used. f 2PrOH (0.5 mL). g Ketone (10 equiv). h Reaction at 4 °C. i Catalyst 9 was
used. j Catalyst 4 (0.2 equiv). k imine (0.2 mmol), ketone (0.4 mmol), 4
(0.02 mmol), and 2-PrOH (2.0 mL). l Ketone (1.0 equiv).
with high diastereo- and enantioselectivities. For the reactions
of unsymmetrical methyl alkyl ketones, the reaction occurred
predominantly at the more substituted R-position of the ketones
(Table 11, entries 5-11). The regio-, diastereo-, and/or enantiomeric purities of the anti-products were readily improved by
crystallization (Table 11, entries 5, 6; Table 13, entry 3). Catalyst
4 was also useful to catalyze the reactions of ketones bearing
functional groups, such as halide, ester, and cyano groups, in
their alkyl chains. The 4-catalyzed reactions of these functionalized ketones afforded desired anti-Mannich products without
special reaction conditions (Table 11, entries 9-11).
Reactions of R-heteroatom-bearing ketones were also catalyzed by 4 (Table 12). In all cases, C-C bond formation
selectively occurred at the carbon bearing the heteroatom. The
884 J. AM. CHEM. SOC.
9
VOL. 130, NO. 3, 2008
diastereo- and enantioselectivities of these products varied. Rates
of the 4-catalyzed reactions of these R-heteroatom-bearing
ketones were generally faster than those of the 4-catalyzed
reactions of alkylketones and than those of the (S)-prolinecatalyzed reactions of the same R-heteroatom-bearing ketones.
The 4-catalyzed reactions of methoxyacetone, benzyloxyacetone,
and hydroxyactone afforded anti-Mannich products as the major
products with high enantiomeric excess (entries 1, 2, and 5).
The diastereoselectivity of the reaction of hydroxyacetone was
poor compared to those of the reactions of alkylketones
catalyzed by 4. Use of DMSO as solvent for the reaction of
hydroxyacetone did not improve the result: When the reaction
was performed using the imine (1.0 mmol) and hydroxyacetone
(10 mmol) in the presence of catalyst 4 (0.2 mmol) in DMSO
(2.0 mL) at 25 °C, after 7 h product 42 was obtained in 67%
yield (anti/syn ) 1:2, anti-42 62% ee, syn-42 <5% ee).
To analyze the product formation in the absence of the
catalyst, the reactions of Table 12, entry 1 (the reaction of
methoxyacetone) and entry 3 (the reaction of hydroxyacetone)
were performed under the conditions of this table but in the
absence of the catalyst. After 2.5 h, no formation of the Mannich
product was detected for either reaction. When a mixture of
the imine (0.1 mmol) and hydroxyacetone (0.45 mmol) in
2-PrOH (0.2 mL), which was more concentrated than the
reaction in Table 12, entry 3, was stirred at room temperature
for 6.5 h, formation of a small amount of Mannich product 42
(∼10%, anti/syn ) 1:4) was observed by 1H NMR of the crude
mixture. Although the Mannich-type reaction of hydroxyacetone
proceeded in 2-PrOH without a catalyst, the reaction rate in
the absence of the catalyst was much slower than the rate of
the 4-catalyzed reaction. These results indicate that the stereoselectivities of 40 and 42 obtained in the 4-catalyzed reactions
shown in Table 12 were not affected by the background reaction
(product formation without involving the catalyst).
Isomerization of Mannich product 42 in the reaction mixture
was not also the reason for the low dr of this product: When a
mixture of purified product 42 (0.2 mmol; anti/syn ) 1:2, anti42 62% ee, syn-42 <5% ee) and catalyst 4 (0.02 mmol) in
2-PrOH (0.4 mL) was stirred at 25 °C, the dr and ee values of
anti-Mannich-Type Reactions
ARTICLES
Table 13. anti-Mannich-Type Reactions of Cyclic Ketones Catalyzed by 4a
entry
1e
2
3
4
5
6
7
8
9
10
11
X
R
CH2
CH2
CH2
CH2
S
S
O
C(OCH2)2
C(OCH2)2
(CH2)2
(CH2)3
Et
i-Pr
t-Bu
CH2CHdCH2
Et
Et
Et
Et
Et
Et
Et
catalyst (equiv)
product
yieldb (%)
drc anti/syn
eed (%)
0.1
0.05
0.05
0.05
0.1
0.05
0.1
0.1
0.05
0.1
0.1
47
48
49
50
51
51
52
53
53
54
55
96
94
92
95
78
71
82
87
80
80
65
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>95:5
>99:1
>99:1
>95:5
>95:5
96
94
95 (99)f
95
99
97
86
97
96
84
18
a Typical conditions: Imine (0.5 mmol, 1.0 equiv), ketone (1.0 mmol, 2.0 equiv), 4 (0.05 mmol, 0.1 equiv or 0.025 mmol, 0.05 equiv), 2-PrOH (1.0 mL),
25 °C. b Isolated yield. c Determined by 1H NMR of isolated products. d Determined by chiral-phase HPLC of the anti-product. e Ketone (5.0 mmol, 10
equiv). f Data after crystallization.
42 were unchanged at 1.5 and 4 h. Decomposition of 42 in this
mixture was approximately <2% at 1 h and <5% at 4 h as
estimated by 1H NMR of the crude mixtures. The decomposition
rate of 42 in the presence of catalyst 4 was similar to that in
the absence of the catalyst, and these rates were faster than the
decomposition rate of the Mannich product of 3-pentanone, 16.
However, the dr of 42 was not affected by the decomposition
for the time range used for the catalyzed reaction. When a
mixture of ethyl glyoxylate imine (0.1 mmol), hydroxyacetone
(0.2 mmol), and Mannich product 42 (0.1 mmol; anti/syn )
1:2) in 2-PrOH (0.4 mL) was stirred at 25 °C for 4 h, the imine
remained and the dr of 42 was not altered although some
decomposed products formed (∼10%). These results indicate
that Mannich product 42 did not facilitate isomerization of 42
or equilibrium/exchange between 42 and the starting materials
and did not act as a catalyst to form 42 for the time range of
the 4-catalyzed reaction.
In the 4-catalyzed reaction of hydroxyacetone, formation of
(Z)-enamine intermediate4c may be possible, because catalyst 4
does not have R-substituent on the pyrrolidine ring and because
the hydroxy group is not a bulky group. Contributions of the
(Z)-enamine and the (E)-enamine and/or contributions of
enamine conformations K and J (Scheme 4) to the C-C bondforming transition state may cause the low diastereoseoectivity
of the 4-catalyzed reaction of hydroxyacetone.
The 4-catalyzed reactions of (methylthio)acetone, 1-azido2-butanone, and R,R′-dibenzyloxyacetone also afforded Mannich
products, although diastereo- and enantioselectivities were
moderate (entries 7-9). For the reaction of dihydroxyacetone,
although 4 catalyzed the reaction with much faster rate than
proline did, the anti-product of the 4-catalyzed reaction was
almost racemic (entry 10). For highly enantioselective antiMannich-type reactions of R-azide ketones, R,R′-dibenzyloxyacetone, and dihydroxyacetone, we are developing other catalyst
systems that will be reported separately.
For the reactions of six-membered cyclic ketones, use of only
5 mol % of catalyst 4 and 2 equiv of ketone to the imine afforded
anti-Mannich products in good yields with high diastereo- and
enantioselectivities within approximately 12 h (Table 13). The
reaction of a seven-membered cyclic ketone was also efficiently
Scheme 6
Scheme 7
catalyzed by 4 and afforded anti-Mannich product with high
diastereoselectivity and good enantioselectivity (entry 10). For
the reaction between 2,2-dimethyl-1,3-dioxan-5-one3k,l and
N-PMP-protected R-imino ethyl glyoxylate, however, use of
catalyst 4 afforded the Mannich product with moderate diastereoselectivity as almost racemic form (Scheme 6).
Structural differences in enamine intermediates with catalyst
4 may cause deviation of positioning of reacting carbons of
enamine and imine from those of the most stable, desired
transition state that affords anti-Mannich products as a single
enantiomer, resulting in less differentiation of energies between
transition states that afford different diastereomers and enantiomers.
Reactions with Imines Other Than r-Imino Esters Catalyzed by 4. As described above, pyrrolidine derivative 4 is useful
for catalyzing enantioselective, anti-selective Mannich-type
reactions between many of enolizable aldehydes or ketones and
N-PMP-protected R-imino esters. To further explore the applicability of this catalyst, Mannich reactions with imines other
than R-imino esters were performed.
As shown in Scheme 7, amino acid 4 efficiently catalyzed
the reaction between 3-pentanone and an R-imino amide that
was generated from glyoxyamide13 and p-anisidine in situ; anti(13) Evans, D. A.; Aye, Y.; Wu, J. Org. Lett. 2006, 8, 2071.
J. AM. CHEM. SOC.
9
VOL. 130, NO. 3, 2008 885
Zhang et al.
ARTICLES
Scheme 8
Mannich product 56 was obtained in 93% ee. Note that when
(S)-proline was used as catalyst for this reaction, the reaction
rate was very slow (<10% after 4 days).
Whereas 4-catalyzed reactions of R-imino esters generally
afforded anti-Mannich products with high diastereo- and enantioselectivities, catalyst 4 was less optimal for reactions of imines
of arylaldehydes with respect to enantioselectivities as shown
in Scheme 8: The anti-Mannich products, 57, 58, and 59, were
obtained with high diastereoselectivities but ee values were
moderate (reaction conditions were not optimized for these
reactions). In the previously reported (S)-proline-catalyzed
reaction, 57 was obtained with anti/syn ) 1:2 (syn 84% ee).3h
The absolute stereochemistry of the major enantiomer of anti57 generated by the 4-catalyzed reaction was the same as that
of the isomerized (at the carbonyl R-position)9 product of major
enantiomer of syn-57 generated by (S)-proline-catalyzed reaction.3h
This suggested that the configuration of the carbon bearing the
amino group of the major enantiomer of anti-product 57
generated by the 4-catalyzed reaction was S as shown in Scheme
8 (absolute configuration of syn-57 generated by (S)-prolinecatalyzed reaction was assumed by analogy). Formation of this
major enantiomer is also in accord with transition state shown
in Scheme 4b when the ester group is altered to p-nitrophenyl
group. For imine that did not lead to high stereoselectivities,
bond lengths and angles of the imines may differ from those of
the glyoxylate imines, which lead to high anti-selectivity and
enantioselectivity. As a result, transition states other than the
most favored one may be involved in the C-C bond-forming
step, leading to a mixture of enantiomers.
Conclusion
We have developed enantioselective anti-selective Mannichtype reactions of enolizable aldehydes and ketones with imines
catalyzed by designed pyrrolidine derivatives bearing acid
functional groups at the 3-position of the pyrrolidine.
For reactions between aldehydes and N-PMP-protected
R-imino esters, catalysts 1 and 4 were efficient catalysts to afford
Mannich products with high anti-selectivity and enantioselectivity. Catalyst 2 was also an efficient catalyst for the reaction
as catalyst 1. For the 1- and 4-catalyzed Mannich reactions of
aldehydes, the 3-acid group on pyrrolidine was essential for
886 J. AM. CHEM. SOC.
9
VOL. 130, NO. 3, 2008
efficient acceleration of the C-C bond formation and for
stereocontrol as it engages proton transfer to the imine nitrogen
at the C-C bond-forming step. In the reactions of aldehydes,
the 5-methyl group of catalyst 1 cooperatively contributed to
the stereodirecting effect of the 3-acid group to provide perfect
anti-selectivity and enantioselectivity. Catalysis and stereocontrolling function provided by 1 and 4 originated in favored
positioning of the nucleophilic carbon of the enamine and the
electrophilic carbon of the imine under proton transfer from
the 3-acid group of the catalyst to the imine nitrogen.
For reactions between ketones and N-PMP-protected R-imino
esters or R-imino amide, catalyst 4 was useful to afford Mannich
products with high anti-selectivity and enantioselectivity. Ketones applicable to the 4-catalyzed reactions included acyclic
and cyclic ketones and functionalized ketones, although antiselectivity and enantioselectivity varied. Catalyst 4 also efficiently catalyzed the reactions of hindered ketones; these
reactions are generally difficult with catalysis of pyrrolidine
derivatives possessing R-substituents, such as proline.
In the 1- or 4-catalyzed reactions of reactants that did not
provide products with high stereoselectivities, bond lengths and
angles of the enamines and imines may vary from those of the
best reactants; causing deviations from the perfect positioning
of the reacting carbons. As a result, several transition states may
be used in the bond formation, leading reduced selectivities.
Importantly, our designed catalysts were useful for the reactions
with R-imino esters and amide to provide highly diastereomerically and enantiomerically enriched amino acid derivatives
containing two stereocenters.
Catalysts 1 and 4 are the smallest known catalysts for
enantioselective anti-selective Mannich reactions of enolizable
aldehydes and ketones. Compared to other larger catalysts
containing binaphthyl groups5a,d or metal-coordinating groups,2a-c,e
our catalyst designs are atom-economical. Our catalysts catalyze
enantioselective anti-selective Mannich reactions under mild
conditions using a low catalyst load. As we have shown here
and in previous reports, anti- or syn-Mannich products can be
enantioselectively generated by using catalysts that have an acid
group at the 3-position or 2-position on a pyrrolidine ring.
Further fine-tuning of the acid group at the 2- or 3-position of
pyrrolidine and attachment of substituents at remaining positions
of the acid-containing pyrrolidines should provide useful, highly
diastereoselective and enantioselective catalysts for other Mannich and Mannich-type reactions and for reactions other than
Mannich reactions, such as aldol and Michael reactions.
Computational studies concerning Mannich-type reactions catalyzed by the series of pyrrolidine derivatives described here are
currently under investigation by the Houk laboratory4a and will
be reported in due course.
Acknowledgment. This study was supported in part by The
Skaggs Institute for Chemical Biology.
Supporting Information Available: Detailed experimental
procedures and product characterization, including synthesis of
catalysts ent-2, 3, and 9, Mannich-type reactions, and synthesis
of β-lactams. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA074907+
Supporting Information
Catalysis of 3-Pyrrolidinecarboxylic Acid and Related Pyrrolidine Derivatives in
Enantioselective anti-Mannich-Type Reactions: Importance of the 3-Acid Group on
Pyrrolidine for Stereocontrol
Haile Zhang, Susumu Mitsumori, Naoto Utsumi, Masanori Imai, Noemi Garcia-Delgado, Maria Mifsud,
Klaus Albertshofer, Fujie Tanaka,* and Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
1. Synthesis of catalysts……………………………………………………………………………......S2
2. anti-Mannich-type reactions and products……………………………..............................................S6
3. Synthesis of β-lactams……………………………………………………………………………...S19
4. Additional Mannich-Type reactions and products….........................................................................S23
5. NMR spectra ………………………………………………….........................................................S25
General: For thin layer chromatography (TLC), silica gel plates VWR GL60 F254 were used and
compounds were visualized by irradiation with UV light and/or by treatment with a solution of
phosphomolybdic acid (25 g), Ce(SO4)2•H2O (10 g), and conc. H2SO4 (60 mL) in H2O (940 mL)
followed by heating or by treatment with a solution of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL),
and acetic acid (10 mL) in ethanol (900 mL) followed by heating. Flash column chromatography was
performed using Bodman silica gel 32-63, 60Å. 1H NMR and
13
C NMR spectra were recorded on
Bruker DRX-500, Varian INOVA-400, or Varian Mercury-300. Proton chemical shifts are given in
relative to tetramethylsilane (0.00 ppm) in CDCl3 or to the residual proton signals of the deuterated
solvent in CD3OD (3.31 ppm). Carbon chemical shifts were internally referenced to the deuterated
solvent signals in CDCl3 (77.00 ppm) or CD3OD (49.00 ppm). High-resolution mass spectra were
recorded on an Agilent ESI-TOF mass spectrometer. Enantiomeric excesses were determined by
chiral-phase HPLC using a Hitachi instrument. Optical rotations were measured on a Perkin-Elmer 241
polarimeter.
S1
1. Synthesis of catalysts
1.1. Synthesis of catalyst ent-2 (Scheme S1)
Scheme S1
HO
HO
TBSO
(1) SOCl2, MeOH
(1) TBSCl, imidazole
CO2 H (2) Boc 2O, Na2CO3
1,4-dioxane, H 2 O
N
H
60
y. quant.
(1) MsCl, Et3N
NC
HO
(2) LiBHEt3 , THF
(3) TBAF, THF
y. 72%
(1) TFA, CH 2Cl2
(2) Dowex 50WX8
y. 72%
OH
CO2 Me (2) LiBH
N
4
Boc
y. 76%
61
(1) MsCl, Et 3N
DMF,2days
y. 39%
Me
N
Boc
65
N
NH
N
N
N
H
62
N
NH
N
NaN 3 (1.1 eq.), ZnCl2 N
Me
N
Boc
64
Me (2) NaCN, DMSO
N
Boc
y. 30%
63
N
Boc
Me
ent -2
(2S,4S)-tert-Butyl 2-methyl-4-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylate (65)
N
NH
N
N
Me
N
Boc
Compound 63 was synthesized form cis-4-hydroxy-D-proline (60) by the reported procedures.1
Compound 63 was transformed to 64 by the procedures used for synthesis of the enantiomer of 64.2 To a
mixture of compound 64 (0.10g, 0.476 mmol) and ZnCl2 (77.8 mg, 0.571 mmol) in DMF (1.0 mL),
NaN3 (34.0 mg, 0.523 mmol) was added and the mixture was stirred at 130 ℃ for 48 h. The mixture
was poured into water and extracted with EtOAc. The organic layers were combined, washed with
brine, dried over Na2SO4, and concentrated. The residue was purified by flashing column
chromatography to give 65 (47.3 mg, 39%). 1H NMR (400MHz, CDCl3) : δ 1.31 (d, J = 6.4 Hz, 3H),
1.48 (s, 9H), 1.71 (m, 1H), 2.44 (m, 1H), 2.57 (m, 1H), 3.74 (m, 1H), 3.88-3.4.00 (m, 2H), 4.14 (m,
1H).
S2
5-((3S,5S)-5-Methylpyrrolidin-3-yl)-1H-tetrazole (ent-2)
N
HN
N
N
N
H
Me
To a solution of compound 65 (47.3 mg, 0.187 mmol) in CH2Cl2 (1.0 mL) was added trifluoroacetic
acid (1.0 mL) at 4ºC. The mixture was stirred at the same temperature for 1 h and concentrated in
vacuo. The resulting colorless solid was dissolved in 0.01 M HCl and loaded to Dowex 50WX8-100
ion-exchange resin (H+ form, activated with 0.01 M HCl). The resin was washed with water then eluted
with 1 M ammonium hydroxide. The eluted fractions were lyophilized to afford ent-2 (20.6 mg, 72.0%)
as a colorless solid.
1
H NMR (400 MHz, CD3OD): δ 1.42 (d, J = 6.4Hz, 3H), 2.14 (m, 1H), 2.47 (m, 1H), 3.53 (dd, J = 6.4
Hz, 11.6 Hz, 1H), 3.75 (dd, J = 6.0 Hz, 12.0 Hz, 1H), 3.85-3.98 (m, 2H).
13
C NMR (100 MHz,
CD3OD): δ 18.2, 35.6, 39.3, 51.5, 56.8, 163.7. HRMS: calcd for C6H12N5 (MH+), 154.1087, found
154.1085. [α]25D +5.4 (c = 0.46, MeOH).
S3
1.2. Synthesis of catalyst 3 (Scheme S2)
Scheme S2
O
K2 CO 3
acetone
O
+
OMe
Br
Br
CO2 Me
O
(S)-1-phenylethylamine
OMe
reflux
16 h
57%
CO 2Me
NaBH(OAc) 3
AcOH
O
CO2 Me
+
N
Ph
N
Ph
( 81
CO 2Me
:
19 )
Ph
( 83
:
N
Ph
47% f rom 66
17 )
66
MeOH, rt, 4 h
61%
67
1) LiOH, MeOH-H 2O (3:1)
4 o C, 23 h
2) Dowex 50WX8
67%
Ph
neat
100 o C
24 h
CO2 Me
10% Pd/C, H2
silica gel column
chromatography
Ph
N
CO 2Me
Separation
N
Ph
DBU
recrystallization
in hexane
55%
CO2 Me
+
N
CO2 Me
Separation
MeCN
0 oC, 3 h
86%
N
toluene
reflux, 22 h
70%
N
H
68
CO2 H
N
H
3
Methyl (2S,3R)-2-methyl-1-[(S)-1-phenylethyl]pyrrolidine-3-carboxylate (67)
CO2 Me
N
Ph
Compound 66 was synthesized from methyl 3-oxobutanonate and 1,2-dibromoethane by the reported
procedures.3 A mixture of 66 (550 mg, 2.22 mmol, 1 equiv) and DBU (1.01 mL, 6.67 mmol, 3 equiv)
was stirred at for 24 h at 100 oC under Ar atmosphere. The reaction mixture was cooled to room
temperature, worked up by addition of water, and extracted with ether (3 times). The organic layers
were combined, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by
flash column chromatography (5-10% EtOAc/hexane) to afford 67 as a colorless oil (261 mg, 47%).
S4
1
H NMR (500 MHz, CDCl3) : δ 1.00 (d, 3H, J = 6.2 Hz), 1.34 (d, 3H, J = 6.7 Hz), 1.94-2.01 (m, 1H),
2.53-2.58 (m, 1H), 2.58-2.65 (m, 1H), 2.74-2.79 (m, 1H), 3.03 (p, 1H, J = 6.2 Hz), 3.70 (s, 3H), 3.81 (q,
1H, J = 6.7 Hz), 7.19-7.24 (m, 1H), 7.28-7.33 (m, 2H), 7.35-7.39 (m, 2H).
Methyl (2S,3R)-2-methyl-3-pyrrolidinecarboxylate (68)
CO 2Me
N
H
To a solution of 67 (130 mg, 0.526 mmol) in MeOH (2.6 mL), 10 wt% Pd/C (39 mg) was added under
Ar atmosphere at room temperature, and the flask was purged by hydrogen (1 atm). After stirring for 3
h at the same temperature under hydrogen, the reaction mixture was filtered and washed with ether.
The filtrate was concentrated in vacuo to afford 68 as colorless oil (46.1 mg, 61%).
1
H NMR (400
MHz, CD3OD): δ 1.24 (d, 3H, J = 6.4 Hz), 1.98-2.15 (m, 2H), 2.42-2.50 (m, 1H), 2.83-2.92 (m, 1H),
2.98-3.06 (m, 1H), 3.10-3.19 (m, 1H), 3.68 (s, 3H).
(2S,3R)-2-Methyl-3-pyrrolidinecarboxylic acid (3)
CO 2H
N
H
To a solution of 68 (46.1 mg, 0.322 mmol) in MeOH/H2O (0.75 mL/0.25 mL), LiOH·H2O (67.6 mg, 5
equiv) was added at 0 oC. After stirring for 23 h at 4 oC, the reaction mixture was worked up by
addition of 1 M HCl until pH = 7, and concentrated in vacuo. The resulting colorless solid was
dissolved in 0.1 M HCl and loaded to Dowex 50WX8-100 ion-exchange resin (H+ form, activated with
0.1 M HCl). The resin was washed with water then eluted with 15% ammonium hydroxide. The eluted
fractions were lyophilized to afford catalyst 3 as a pale brown solid (28 mg, 67%).
1
H NMR (500
MHz, CD3OD) : δ 1.43 (d, 3H, J = 6.7 Hz), 2.20 (dddd, 1H, J = 7.4 Hz, 8.2 Hz, 8.8 Hz, 13.7 Hz), 2.35
(ddt, 1H, J = 6.1 Hz, 13.7 Hz, 8.2 Hz), 2.62 (q, 1H, J = 8.2 Hz), 3.29-3.40 (m, 2H), 3.78 (dq, 1H, J =
8.2 Hz, 6.7 Hz). 13C NMR (100 MHz, CD3OD): δ 17.9, 30.6, 46.2, 54.7, 61.4, 179.4. HRMS: calcd for
C6H12NO2 (MH+) 130.0863, found 130.0862. [α]25D –46.2 (c = 0.3, MeOH).
S5
1.3. Synthesis of catalyst 9 (Scheme S3)
Scheme S3
NH2
N
Boc
O O O O
S
S
F 3C
O
CF3
H
N
CF3
S
TFA, CH2 Cl2
O O
N
Boc
70
Et3N, CH 2Cl2
69
H
N
CF3
S
O O
Dowex 50WX8
RT
N
H
9
(R)-1-N-Boc-3-(trifluoromethylsulfonamido)pyrrolidine (70)
H
N
CF3
S
O O
N
Boc
Catalyst 9 was prepared from (R)-(+)-N-Boc-3-aminopyrrolidine (69) purchased from Aldrich. To a
solution of (R)-(+)-N-Boc-3-aminopyrrolidine (69) (96% purity, 1.0 g, 5.15 mmol) and triethylamine
(2.15 mL, 15.45 mmol) in anhydrous CH2Cl2 (50 mL) was slowly added trifluoromethanesulfonic
anhydride (1.04 mL, 6.18 mmol) in anhydrous CH2Cl2 (1.0 mL) using a syringe pump over 2 h at 0 °C
under N2.4,5 The resulting mixture was stirred over night at room temperature. The mixture was
concentrated in vacuo and purified by flash column chromatography (EtOAc/hexane = 1/3–1/1) to
afford 70 (1.30 g, 79%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 1.43 (s, 9H), 2.02 (m, 1H),
2.19 (m, 1H), 3.38-3.47 (m, 3H), 3.61 (dd, 1H, J = 6.4 Hz, 11.6 Hz), 4.18 (m, 1H), 6.94 (brs, 1/2H,
NH), 7.19 (brs, 1/2H, NH).
13
C NMR (125 MHz, CDCl3): δ 28.4, 31.8, 32.8, 43.3, 43.7, 51.0, 52.0,
53.8, 54.4, 80.4, 119.5 (q, J = 321 Hz), 154.5.
(R)-3-(Trifluoromethylsulfonamido)pyrrolidine (9)
H
N
CF3
S
O O
N
H
To a solution of 70 (800 mg, 2.51 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (5 mL) at 0
o
C and the resulting mixture was stirred at room temperature for 5 h. The mixture was concentrated in
vacuo, dissolved in water, and loaded to Dowex 50WX8-100 ion-exchange resin (H+ form, activated
S6
with 0.1 M HCl). The resin was washed with water then eluted with 15% ammonium hydroxide. The
eluted fractions were lyophilized to afford 9 (520 mg, 95%) as a colorless solid. 1H NMR (400 MHz,
CD3OD): δ 1.87 (m, 1H), 2.11 (m, 1H), 2.97 (dd, 1H, J = 5.2 Hz, 11.6 Hz), 3.20-3.41 (m, 3H), 4.11 (m,
1H).
13
C NMR (125 MHz, CD3OD): δ 34.7, 45.3, 54.0, 56.0, 123.2 (q, J = 327.0 Hz). HRMS: calcd
for C5H10F3N2O2S (MH+) 219.041, found 219.0403. [α]25 D +21.60 (c = 0.67, MeOH).
2. anti-Mannich-type reactions and products
The Mannich–type reactions were performed in a closed system (a vial with a cap). An inert
atmosphere of nitrogen or argon was not used for the reactions.
General procedure for the Mannich-type reactions between N-PMP protected α-imino esters and
aldehyde donors (Tables 5, 6 and 8). N-PMP-protected α-imino ester (0.25 mmol, 1 equiv) was
dissolved in anhydrous DMSO (2.5 mL) and aldehyde (0.5 mmol, 2 equiv) was added, followed by
catalyst 1 or 4 (0.0125 mmol, 0.05 equiv). After stirring at room temperature (25 oC) for the indicated
time in the Table, the mixture was worked up by addition of aqueous saturated ammonium chloride
solution and extracted with EtOAc. The organic layers were combined, washed with brine, dried over
MgSO4, filtered, concentrated in vacuo, and purified by flash column chromatography (10-15%
EtOAc/hexane) to afford the Mannich addition product. When the catalyst loading was 1 or 2 mol%,
the reaction was performed using N-PMP-protected α-imino ethyl glyoxylate (0.5 mmol, 1 equiv),
aldehyde (1.0 mmol, 2 equiv), and catalyst 1 (0.005 or 0.01 mmol, 0.01 or 0.02 equiv) in DMSO (5
mL).
The diastereomeric ratio was determined by 1H NMR or HPLC as indicated. The dr values of
the products changed with silica gel. To obtain excellent dr, flash chromatography was performed
quickly.
General procedure for the 4-catalyzed Mannich-type reactions between N-PMP protected
α-imino esters and acyclic ketones donors (Tables 11 and 12). N-PMP-protected α-imino ester (0.5
mmol, 1.0 equiv) was dissolved in 2-PrOH (1.0 mL) and ketone (1.0 mmol, 2 equiv for
α-functionalized ketones (Table 12) or 5.0 mmol, 10 equiv for Table 11) was added to the solution,
followed by catalyst 4 (0.05 mmol, 0.1 equiv).
After stirring at room temperature (25 oC) for the
indicated time in the Table, the reaction mixture was concentrated in vacuo and purified by flash
column chromatography.
The diastereomeric ratio was determined by 1H NMR of the isolated
S7
product.
The enantiomeric excess of the anti-product was determined by chiral-phase HPLC analysis.
The chiral-phase HPLC analysis was also used for the determination of the diastereomeric ratio as
indicated.
General procedure for the 4-catalyzed Mannich-type reactions between between N-PMP
protected α-imino esters and cyclic ketones (Table 13). N-PMP-protected α-imino ester (0.5 mmol,
1.0 equiv) was dissolved in 2-PrOH (1.0 mL) and ketone (1.0 mmol, 2.0 equiv) was added to the
solution, followed by catalyst 4 (0.05 mmol, 0.1 equiv or 0.025 mmol, 0.05 equiv). After stirring at
room temperature (25 oC) for 10–16 h, the reaction mixture was concentrated in vacuo and purified by
flash column chromatography. The diastereomeric ratio was determined by 1H NMR of the isolated
product.
The enantiomeric excess of the anti-product was determined by chiral-phase HPLC analysis.
N-PMP protected α-imino esters were prepared as previously reported. See Supporting Information of
ref. 5.
Racemic standards of the Mannich products were synthesized using (±)-pipecolic acid6,
(±)-pyrrolidine-3-carboxylic acid,2,5 (±)-proline, and/or pyrrolidine-CF3COOH. See Supporting
Information of refs. 2 and 5.
Characterizations of following anti-Mannich products were previously reported:
anti-Mannich products 15, 17-21, 23 and 24; ref. 2.
anti-Mannich products 16, 32-37 and 47-53; ref. 5.
anti-Mannich product 28; ref. 7.
anti-Mannich product 42; ref. 8.
anti Mannich product 27; ref. 9.
Ethyl (2S,3R)- 3-formyl-2-(p-methoxyphenylamino)-4,4-dimethylpentanoate (22)9-11
OMe
O
H
HN
CO2 Et
S8
1
H NMR (500 MHz, CDCl3): δ 1.14 (s, 9H, CH(CH3)3), 1.17 (t, 3H, J = 7.0 Hz, OCH2CH3), 2.76 (dd,
1H, J = 3.0 Hz, 6.5 Hz, CHCHO), 3.73 (s, 3H, OCH3), 3.97 (brd, 1H, J = 10.5 Hz, NHPMP), 4.06-4.13
(m, 2H, OCH2CH3), 4.30-4.34 (brdd, 1H, J = 6.5 Hz, 10.0 Hz, CHNHPMP), 6.65 (d, 2H, J = 9.0 Hz,
ArH), 6.76 (d, 2H, J = 9.0 Hz, ArH), 9.76 (d, 1H, J = 3.0 Hz, CHO). 13C NMR (125 MHz, CDCl3): δ
14.0, 28.9, 33.1, 55.6, 56.2, 61.2, 62.5, 114.7, 115.8, 140.4, 153.1, 173.2, 202.9. HRMS: calcd for
C17H26NO4 (MH+) 308.1856, found 308.1857. HPLC (Daicel Chiralpak AS-H, hexane/i-PrOH = 99:1,
flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer, (2R,3S)-22) = 17.4 min, tR (anti minor
enantiomer, (2S,3R)-22) = 52.1 min, tR (syn enantiomer, (2S,3S)-22) = 37.8 min, tR (syn enantiomer,
(2R,3R)-22) = 23.8 min.
syn-22. 1H NMR (300 MHz, CDCl3): δ 9.92 (d, 1H, J = 3.0 Hz, CHO), 2.41 (1H, dd, J = 3.9 Hz, 5.4 Hz,
CHCHO).
tert-Butyl (2S,3R)-3-formyl-2-(4-methoxyphenylamino)-4-methylpentanoate (25)9
OMe
O
HN
O
H
O
1
H NMR (400 MHz, CDCl3): δ 1.06 (d, 3H, J = 6.8 Hz), 1.12 (d, 3H, J = 6.8 Hz), 1.37 (s, 9H), 2.11 (m,
1H), 2.52 (m, 1H), 3.74 (s, 3H), 3.86 (s, 1H), 4.25 (d, 1H, J = 7.6 Hz), 6.66 (d, 2H, J = 9.2 Hz), 6.76 (d,
2H, J = 9.2 Hz), 9.73 (d, 1H, J = 3.6 Hz). 13C NMR (100 MHz, CDCl3): 19.1, 21.3, 27.5, 27.9, 55.6,
58.0, 59.6, 82.2, 114.7, 115.9, 140.6, 153.1, 171.9, 203.4. HRMS: calcd for C18H28NO4 (MH+)
322.2013, found. 322.2016. HPLC (Daicel Chiralpak AS-H, hexane/i-PrOH = 99:1, flow rate 1.0
mL/min, λ = 254 nm): tR (anti major enantiomer, (2R,3S)-25) = 13.0 min, tR (anti minor enantiomer,
(2S,3S)-25) = 40.7 min, tR (syn enantiomer, (2S,3S)-25) = 15.3 min, tR (syn enantiomer, (2R,3R)-25) =
29.8 min.
syn-25 was synthesized by using proline. 1H NMR (300 MHz, CDCl3): δ 1.03 (d, 3H, J = 6.8 Hz), 1.15
(d, 3H, J = 6.8 Hz), 1.39 (s, 9H), 2.30 (m, 1H), 2.46 (m, 1H), 3.74 (s, 3H), 3.88 (brd, 1H), 4.22 (brt, 1H,
J = 6.3 Hz), 6.66 (d, 2H, J = 9.0 Hz), 6.76 (d, 2H, J = 9.0 Hz), 9.76 (d, 1H, J = 3.3 Hz). 13C NMR (75
MHz, CDCl3): 19.9, 20.8, 26.3, 27.9, 55.6, 57.7, 59.5, 82.4, 114.7, 115.7, 140.3, 153.0, 171.6, 203.8.
S9
Allyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)-4-methylpentanoate (26)9
OMe
O
HN
O
H
O
1
H NMR (300 MHz, CDCl3): δ 1.07 (d, 3H, J = 6.6 Hz, CH(CH3)CH3), 1.13 (d, 3H, J = 6.9 Hz,
CH(CH3)CH3), 2.11 (m, 1H, CH(CH3)2), 2.63 (m, 1H, CHCHO), 3.74 (s, 3H, OCH3), 3.96 (brs, 1H,
NHPMP), 4.39 (d, 1H, J = 7.5 Hz, CHNHPMP), 4.58 (dt, 2H, J = 5.7 Hz, 1.5 Hz, OCH2CH=CH2),
5.18-5.27 (m, 2H, OCH2CH=CH2), 5.83 (m, 1H, OCH2CH=CH2), 6.66 (d, 2H , J = 9.0 Hz, ArH), 6.77
(d, 2H, J = 9.0 Hz, ArH), 9.75 (d, 1H, J = 3.3 Hz, CHO).
13
C NMR (75 MHz, CDCl3): δ 19.2, 21.3,
27.5, 55.6, 57.1, 59.6, 65.9, 114.8, 115.8, 118.9, 131.4, 140.4, 153.2, 172.6, 203.2. HRMS: calcd for
C17H24NO4 (MH+) 306.1700, found. 306.1697. HPLC (Daicel Chiralpak AS-H, hexane/i-PrOH = 99:1,
flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer, (2S,3R)-26) = 28.0 min, tR (anti minor
enantiomer, (2R,3S)-26) = 62.3 min, tR (syn enantiomer, (2S,3S)-26) = 39.5 min, tR (syn enantiomer,
(2R,3R)-26) = 81.3 min.
syn-26 was synthesized by using proline. 1H NMR (300 MHz, CDCl3): δ 1.02 (d, 3H, J = 6.9 Hz,
CH(CH3)CH3), 1.17 (d, 3H, J = 6.9 Hz, CH(CH3)CH3), 2.32 (m, 1H, CH(CH3)2), 2.59 (dt, 1H, J = 6.9
Hz, 2.9 Hz, CHCHO), 3.74 (s, 3H, OCH3), 3.85 (brd, 1H, J = 8.4 Hz, NHPMP), 4.39 (t, 1H, J = 8.4 Hz,
CHNHPMP), 4.58 (dt, 2H, J = 5.7 Hz, 1.5 Hz, OCH2CH=CH2), 5.19-5.29 (m, 2H, OCH2CH=CH2),
5.83 (m, 1H, OCH2CH=CH2), 6.66 (d, 2H, J = 9.0 Hz, ArH), 6.77 (d, 2H, J = 9.0 Hz, ArH),9.78 (d, 1H,
J = 2.9 Hz, CHO). 13C NMR (75 MHz, CDCl3): 19.7, 20.9, 26.3, 55.6, 56.9, 59.5, 65.9, 114.8, 115.7,
118.9, 131.4, 140.1, 153.1, 172.4, 203.6.
Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)-4-phenylbutanoate (27) 9
OMe
O
H
HN
CO2 Et
Ph
HPLC (Daicel Chiralpak AS-H, hexane/i-PrOH = 98:2, flow rate 1.0 mL/min, λ = 254 nm): tR (anti
major enantiomer, (2S,3R)-27) = 35.4 min, tR (anti minor enantiomer, (2R,3S)-27) = 41.6 min.
S10
Ethyl 2-(p-methoxyphenylamino)-3-methyl-4-oxo-3-phenylbutanoate (28) 7
OMe
O
HN
H
CO2 Et
Ph
HPLC (Daicel Chiralpak OJ-H, hexane/i-PrOH = 75:25, flow rate 0.8 mL/min, λ = 254 nm): tR (anti
major enantiomer) = 35.1 min, tR (anti minor enantiomer) = 57.6 min, tR (syn major enantiomer) = 62.8
min, tR (syn minor enantiomer) = 51.9 min.
Ethyl 3-formyl-2-(p-methoxyphenylamino)-3-methylhexanoate (29)
OMe
O
H
HN
CO2Et
anti- and syn-Diasteromers of 29 were assigned by comparison with the (S)-proline-catalyzed reaction
that afforded syn-29 (syn:anti = 3.3:1 by 1H NMR). It was assumed that the proline catalysis afforded
syn-29 as the major diastereomer by analogy.7
anti-29. 1H NMR (500 MHz, CDCl3): δ 0.92 (t, 3H, J = 7.2 Hz, CH2CH2CH3), 1.09 (s, 3H,
CH3C(CHO)), 1.20 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.29-1.36 (m, 2H, CH2CH2CH3), 1.70-1.75 (m, 2H,
CH2CH2CH3), 3.74 (s, 3H, OCH3), 3.92 (brs, 1H, NHPMP), 4.09-4.21 (m, 3H, OCH2CH3,
CHNHPMP), 6.68 (d, J = 9.0 Hz, ArH), 6.77 (d, J = 9.0 Hz, ArH), 9.67 (s, 1H, CHO).
13
C NMR (125
MHz, CDCl3): δ 14.10, 14.58, 14.66, 17.15, 35.55, 52.62, 55.66, 61.49, 63.28, 114.83, 116.13, 141.14,
153.33, 171.95, 203.68.
syn-29. 1H NMR (500 MHz, CDCl3): δ 0.91 (t, 3H, J = 7.2 Hz, CH2CH2CH3), 1.18 (s, 3H,
CH3C(CHO)), 1.22 (t, J = 7.2 Hz, OCH2CH3), 1.25-1.32 (m, 2H, CH2CH2CH3), 1.52-1.71 (m, 2H,
CH2CH2CH3), 3.73 (s, 3H, OCH3), 3.94 (brs, 1H, NHPMP), 4.09-4.21 (m, 3H, OCH2CH3,
CHNHPMP), 6.67 (d, J = 9.0 Hz, ArH), 6.76 (d, J = 9.0 Hz, ArH), 9.55 (s, 1H, CHO).
13
C NMR (125
MHz, CDCl3): δ 14.22, 14.63, 14.87, 17.13, 36.51, 51.64, 55.62, 61.26, 62.68, 114.76, 116.37, 140.54,
153.51, 171.76, 203.37. HRMS: calcd for C17H26NO4 (MH+) 308.1856, found 308.1863.
HPLC (Daicel Chiralpak OJ-H, hexane/i-PrOH = 97:3, flow rate 1.0 mL/min, λ = 254 nm): tR (anti
S11
major enantiomer) = 29.5 min, tR (anti minor enantiomer) = 27.9 min, tR (syn major enantiomer) = 40.6
min, tR (syn minor enantiomer) = 34.1 min.
Diethyl (2S,3R)-3-acetyl-2-(p-methoxyphenylamino)hexanedioate (38)
OMe
O HN
CO2Et
CO2Et
1
H NMR (500 MHz, CDCl3): δ 1.19 (t, 3H, J = 7.0 Hz, OCH2CH3), 1.23 (t, 3H, J = 7.0 Hz, OCH2CH3),
1.86-1.93 (m, 1H, CHHCH2CO2Et), 1.98-2.06 (m, 1H, CHHCH2CO2Et), 2.24 (s, 3H, CH3CO),
2.26-2.39 (m, 2H, CH2CO2Et), 3.02-3.10 (m, 1H, CH3COCH), 3.72 (s, 1H, OCH3), 4.09-4.17 (m, 6H,
NHPMP, OCH2CH3, OCH2CH3, CHNHPMP), 6.62 (d, 2H, J = 9.0 Hz, ArH), 6.75 (d, 2H, J = 9.0 Hz,
ArH). 13C NMR (125 MHz, CDCl3): δ 14.1, 14.2, 23.2, 30.1, 31.7, 53.5, 55.6, 59.2, 60.6, 61.4, 114.8,
115.7, 140.6, 153.1, 172.5, 209.2. HRMS: calcd for C19H28NO6 (MH+) 366.1911, found 366.1916.
HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 90:10, flow rate 1.0 mL/min, λ = 254 nm): tR (anti
major enantiomer, (2S,3R)-38) = 55.1 min, tR (anti minor enantiomer, (2R,3S)-38) = 41.7 min.
syn-38. 1H NMR (500 MHz, CDCl3): δ 1.21 (t, 3H, J = 7.5 Hz, OCH2CH3), 1.24 (t, 3H, J = 7.5 Hz,
OCH2CH3).
Ethyl (2S,3R)-3-acetyl-6-cyano-2-(p-methoxyphenylamino)pentanoate (39)
OMe
O
HN
CO2Et
CN
1
H NMR (500 MHz, CDCl3): δ 1.21 (t, J = 7.0 Hz, OCH2CH3), 1.83-1.92 (m, 1H CHHCH2CN),
2.02-2.09 (m, 1H CHHCH2CN), 2.31 (s, 3H, CH3CO), 2.28-2.35 (m, 1H, CHHCN), 2.40-2.45 (m, 1H,
CHHCN), 3.17-3.23 (m, 1H, CH3COCH), 4.09-4.23 (m, 4H, NHPMP, OCH2CH3, CHNHPMP), 6.62 (d,
2H, J = 9.0 Hz, ArH), 6.75 (d, 2H, J = 9.0 Hz, ArH). 13C NMR (125 MHz, CDCl3): δ 14.1, 15.3, 23.3,
S12
30.6, 52.6, 55.6, 58.9, 61.7, 114.9, 115.7, 118.6, 139.9, 153.3, 171.6, 207.8. HRMS: calcd for
C17H23N2O4 (MH+) 319.1652, found 319.1654. HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 90:10,
flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer, (2S,3R)-39) = 32.8 min, tR (anti minor
enantiomer, (2R,3S)-39) = 22.1 min.
syn-39. 1H NMR (500 MHz, CDCl3): δ 1.24 (t, 3H, J = 7.5 Hz, OCH2CH3).
Ethyl (2S,3R)-2-(p-methoxyphenylamino)-3-methoxy-4-oxopentanoate (40)
OMe
O
HN
CO2 Et
OMe
1
H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H, J = 6.8 Hz, OCH2CH3), 2.26 (s, 3H, CH3CO), 3.48 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3), 3.95 (d, 1H, J = 3.2 Hz, CH3COCH), 4.20 (q, 2H, J = 7.2 Hz, OCH2CH3),
4.30 (brd, 1H, J = 8.8 Hz, CHNHPMP), 4.49 (dd, 1H, J = 8.8 Hz, 3.2 Hz, OCH2CH3), 6.69 (d, 2H, J =
9.2 Hz, ArH), 6.79 (d, 2H, J = 9.2 Hz, ArH). 13C NMR (125 MHz, CDCl3): δ 14.1, 26.6, 55.7, 60.3,
60.6, 61.7, 87.1, 115.0, 115.4, 139.7, 153.1, 170.0, 209.2. HRMS: calcd for C15H22NO5 (MH+)
296.1492, found 296.1496. HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 95:5, flow rate 1.0 mL/min,
λ = 254 nm): tR (anti major enantiomer, (2S,3R)-40) = 27.4 min, tR (anti minor enantiomer, (2R,3S)-40)
= 40.4 min.
syn-40. 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H, CH3CO).
Ethyl (2R,3S) -2-(p-methoxyphenylamino)-3-benzyloxy-4-oxopentanoate (41)
OMe
O
HN
CO2 Et
O
Reaction using catalyst ent-4.
1
H NMR (400 MHz, CDCl3): δ 1.24 (t, 3H, J = 7.2 Hz, OCH2CH3),
2.25 (s, 3H, CH3CO), 3.74 (s, OCH3), 4.19-4.24 (m, 4H, NHPMP, OCH2CH3, CHNHPMP), 4.49-4.75
S13
(m, 3H, CH3COCHOCH2Ph), 6.62 (d, 2H, J = 9.2 Hz, ArH), 6.77 (d, 2H, J = 9.2 Hz, ArH), 7.28-7.34
(m, 5H, ArH). 13C NMR: δ 14.1, 26.9, 55.7, 60.7, 61.7, 74.2, 84.4, 115.0, 115.2, 127.9, 128.1, 128.5,
137.0, 139.6, 152.9, 170.1, 209.4. HRMS: calcd for C21H26NO5 (MH+) 372.1805, found 372.1817.
HPLC (Daicel Chiralpak OJ-H, hexane/i-PrOH = 75:25, flow rate 1.0 mL/min, λ = 254 nm): tR (anti
major enantiomer, (2R,3S)-41) = 29.2 min, tR (anti minor enantiomer, (2S,3R)-41) = 44.3 min, tR (syn
major enantiomer) = 26.9 min, tR (syn minor enantiomer) = 57.0 min.
Ethyl 2-(p-methoxyphenylamino)-3-(methylthio)-4-oxopentanoate (43)
OMe
O
HN
CO2 Et
SMe
anti- and syn-Diasteromers of 43 were assigned by comparison with the (S)-proline-catalyzed reaction
that afforded syn-43 (syn:anti = 9:1 by 1H NMR). It was assumed that the proline catalysis afforded
syn-43 as the major diastereomer by analogy.
1
H NMR (500 MHz, CDCl3): Mixture of diastereomers (anti:syn = 1:1), * denotes syn diastereomer δ
1.23 (t, 3H x 1/2, J = 7.2 Hz), 1.24 (t, 3H* x 1/2, J = 7.2 Hz), 1.90 (s, 3H x 1/2, SCH3), 2.08 (s, 3H* x
1/2, SCH3), 2.34 (s, 3H* x 1/2, COCH3), 2.39 (s, 3H x 1/2, COCH3), 3.52 (d, 1H x 1/2, J = 9.6 Hz,
CHSCH3), 3.73 (d, 1H*, J = 9.6 Hz, CHSCH3), 3.74 (s, 3H* x 1/2, OCH3), 3.75 (s, 3H x 1/2, OCH3),
3.96 (brs, 1H, NHPMP), 4.12-4.25 (m, 2H, OCH2CH3), 4.28 (d, 1H* x 1/2, J = 9.0 Hz), 4.39 (d, 1H x
1/2, J = 9.5 Hz), 6.77-6.79 (m, 4H, ArH). 13C NMR (125 MHz, CDCl3): (anti:syn = 1:1) δ 12.51, 13.19,
14.07, 14.16, 27.73, 28.08, 54.68, 55.63, 55.67, 55.73, 56.63, 59.71, 61.40, 61.67, 114.73, 114.76,
115.82, 116.77, 140.24, 140.80, 153.23, 153.69, 172.20, 172.47, 201.28, 201.98. HRMS: calcd for
C15H22NO4S (MH+), 312.1264, found 312.1269. HPLC (Daicel Chiralcel AS-H, hexane/i-PrOH = 96:4,
flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer) = 20.6 min; tR (anti minor enantiomer)
= 26.0 min, tR (syn major enantiomer) = 26.0 min, tR (syn minor enantiomer) = 44.4 min. Based on the
dr determined by 1HNMR, area of tR 26.0 min was corrected to give ee value.
S14
Ethyl (2S,3R)-3-azido-2-(p-methoxyphenylamino)-4-oxohexanoate (44)12
OMe
O
HN
CO 2Et
N3
1
H NMR (500 MHz, CDCl3): Mixture of diastereomers (anti:syn = 1.3:1), * denotes syn diastereomer δ
1.06 (t, 3H* x 1/2.3, J = 7.2 Hz), 1.12 (t, 3H x 1.3/2.3, J = 7.2 Hz), 1.26 (t, 3H x 1.3/2.3, J = 7.2 Hz),
1.27 (t, 3H* x 1/2.3, J = 7.2 Hz), 2.60-2.73 (m, 2H), 3.73 (s, 3H* x 1/2.3), 3.75 (s, 3H x 1.3/2.3), 4.03
(d, 1H* x 1/2.3, J = 10.8 Hz), 4.15-4.26 (m, 2H), 4.33 (brd, 1H x 1.3/2.3, J = 8.0 Hz), 4.34 (d, 1H x
1.3/2.3, J = 3.6 Hz), 4.49 (d, 1H* x 1/2.3, J = 3.2 Hz), 4.53 (dd, 1H* x 1/2.3, J = 10.8 Hz, 3.2 Hz), 4.67
(dd, 1H x 1.3/2.3, J = 8.0 Hz, 3.6 Hz), 6.63 (d, 2H* x 1/2.3, J = 8.8 Hz), 6.72 (d, 2H x 1.3/2.3, J = 8.8
Hz), 6.76 (d, 2H* x 1/2.3, J = 8.8 Hz), 6.81 (d, 2H x 1.3/2.3, J = 8.8 Hz). HPLC (Daicel Chiralpak
OJ-H, hexane/i-PrOH = 85:15, flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer) = 51.2
min, tR (anti minor enantiomer) = 85.7 min, tR (syn major enantiomer) = 27.1 min, tR (syn minor
enantiomer) = 37.7 min.
Ethyl (2S,3R)-2-(p-methoxyphenylamino)-3,5-bis(benzyloxy)-4-oxopentanoate (45)
OMe
O HN
CO2Et
O
1
O
H NMR (400 MHz, CDCl3): δ 1.19 (t, 3H, J = 7.2 Hz, COCH2CH3), 3.73 (s, 3H, OCH3), 4.16 (q, 2H,
J = 7.2 Hz, COCH2CH3), 4.20-4.70 (m, 9H, CH2Ph, CH2Ph, CH2OBn, CHOBn, CHNHPMP, NHPMP),
6.59 (d, 2H, J = 9.2 Hz, ArH), 6.70 (d, 2H, J = 9.2 Hz, ArH), 7.16-7.38 (m, 10H, Ph). 13C NMR (100
MHz, CDCl3): δ 14.0, 55.6, 60.3, 61.8, 73.4, 74.1, 74.3, 82.6, 114.9, 115.2, 128.0, 128.1, 128.4, 128.5,
136.8, 137.0, 139.4, 152.9, 169.8, 206.5.
HRMS: calcd for C28H32NO6 (MH+) 478.2224, found
478.2228. HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 95:5, flow rate 1.0 mL/min, λ = 254 nm): tR
(anti major enantiomer) = 92.2 min, tR (anti minor enantiomer) = 79.7 min, tR (syn major enantiomer) =
S15
48.1 min, tR (syn minor enantiomer) = 72.6 min.
syn-45. 1H NMR (400 MHz, CDCl3): δ 1.16 (t, 3H, J = 7.2 Hz, COCH2CH3), 3.72 (s, 3H, OCH3).
Ethyl (2S*,3R*)-3,5-dihydroxy-2-(p-methoxyphenylamino)-4-oxopentanoate (46)
OMe
O HN
CO2Et
OH OH
1
H NMR (500 MHz, CDCl3): δ 1.26 (t, 3H, J = 7.2 Hz), 2.83 (brs, 1H), 3.52 (brs, 1H), 3.73 (s, 3H),
4.22 (q, 2H, J = 7.5 Hz), 4.43 (d, 1H, J = 2.0 Hz), 4.49 (d, 1H, J = 19.5 Hz), 4.56 (d, 1H, J = 19.5 Hz),
4.74 (s, 1H), 6.64 (d, 2H, J = 9.0 Hz), 6.77 (d, 2H, J = 9.0 Hz). 13C NMR (100 MHz, CDCl3): δ 14.07,
55.6, 60.2, 62.0, 66.5, 76.0, 114.8, 116.4, 139.9, 153.6, 171.1, 209.5. HRMS: calcd for C14H20NO6
(MH+) 298.1285, found 298.1287. HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 95:5, flow rate 1.0
mL/min, λ = 254 nm): tR (anti major enantiomer) = 70.9 min, tR (anti minor enantiomer) = 63.1 min, tR
(syn enantiomers) = 93.7 min.
syn-46. 1H NMR (500 MHz, CDCl3): 3.75 (s, 3H), 6.72 (d, 2H, J = 9.0 Hz), 6.80 (d, 2H, J = 9.0 Hz).
Ethyl (2S,1′R)-2-(p-methoxyphenylamino)-2-(2′-oxocycloheptyl)acetate (54)
OMe
O
1'
1
HN
2 CO2 Et
H NMR (400 MHz, CDCl3): δ 1.21 (t, 3H, J = 7.2 Hz), 1.27-1.41 (m, 2H), 1.48-1.59 (m, 2H),
1.84-2.00 (m, 4H), 2.45-2.58 (m, 2H), 3.00 (dt, 1H, J = 11.2 Hz, 3.2 Hz), 3.73 (s, 3H), 4.22-4.32 (m,
4H), 6.65 (d, 2H, J = 8.8 Hz), 6.75 (d, 2H, J = 8.8 Hz). 13C NMR (100 MHz, CDCl3): δ 14.1, 24.2, 27.1,
29.0, 29.9, 43.9, 54.3, 55.7, 60.6, 61.3, 114.8, 115.2, 140.9, 152.7, 172.5, 214.2. HRMS: calcd for
C18H26NO4 (MH+) 320.1856, found 320.1864. HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 90:10,
flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer) = 23.0 min, tR (anti minor enantiomer)
= 17.5 min.
syn-54. 1H NMR (500 MHz, CDCl3): 1.20 (t, 3H, J = 7.2 Hz).
S16
Ethyl (2S*,1′R*)-2-(p-methoxyphenylamino)-2-(2′-oxocyclooctyl)acetate (55)
OMe
O
HN
CO2Et
1
H NMR (400 MHz, CDCl3): δ 1.20 (t, 3H, J = 7.2 Hz), 1.26-2.11 (m, 10H), 2.38-2.49 (m, 2H), 3.13
(m, 1H), 3.72 (s, 3H), 4.10-4.18 (m, 4H), 6.64 (d, 2H, J = 9.0 Hz), 6.74 (d, 2H, J = 9.0 Hz). 13C NMR
(100 MHz, CDCl3): δ 14.2, 23.8, 24.8, 25.2, 28.0, 30.7, 44.1, 51.6, 55.7, 61.1, 61.6, 114.8, 116.0, 140.8
153.1, 173.4, 217.2. HRMS: calcd for C19H28NO4 (MH+) 334.2013, found 334.2023. HPLC (Daicel
Chiralpak AD, hexane/i-PrOH = 97:3, flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer) =
23.5 min, tR (anti minor enantiomer) = 38.2 min, tR (syn enantiomer) = 46.8 min, tR (syn enantiomer) =
30.0 min.
(2S,3R)-2-(p-Methoxyphenylamino)-3-methyl-4-oxo-N-phenylhexanamide (56)
OMe
O
H
N
H
O
O
Ph
+
NH 2 PMP
HN
H
N
4 (0.2 equiv)
+
DMSO/2-PrOH
O
Ph
O
56
2-oxo-N-phenylacetamide
2-Oxo-N-phenylacetamide monhydride13 (55.5 mg, 0.3 mmol, 1.2 equiv) and p-anisidine (30.8 mg,
0.25 mmol, 1.0 equiv) were dissolved in 2-PrOH (1.0 mL)-DMSO (1.0 mL) and the resulting solution
was stirred at room temperature (25 oC) for 1 h. 3-Pentanone (264 μL, 2.5 mmol, 10 equiv) and catalyst
4 (5.8 mg, 0.05 mmol, 0.2 equiv) were added to the solution and the mixture was stirred at room
temperature for 3 d. The reaction mixture was concentrated in vacuo, worked up by addition of
saturated ammonium chloride solution and extracted with AcOEt. The organic layers were combined,
dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography
(EtOAc/hexanes = 1/4) to afford 56 (62.1 mg, 73%, anti : syn = 83:17, anti 93% ee).
1
H NMR (400 MHz, CDCl3): δ 1.01 (t, 3H, J = 7.2 Hz), 1.23 (d, 3H, J = 7.2 Hz), 2.54 (m, 2H), 3.63 (m,
1H), 3.75 (s, 3H), 3.94 (m, 1H), 4.84 (brd, 1H, J = 6.4 Hz), 6.66 (d, 2H, J = 8.8 Hz), 6.80 (d, 2H, J =
S17
8.8 Hz), 7.08-7.51 (m, 5H), 8.99 (s,1H). 13C NMR (100 MHz, CDCl3): δ
7.4, 14.8, 36.0, 46.5, 55.7,
63.1, 115.0, 115.1, 119.8, 124.5, 128.9, 137.2, 141.3, 153.2, 170.6, 215.9. HRMS: calcd for
C20H25N2O3 (MH+) 341.186 found 341.1858. HPLC (Daicel Chiralpak OD-H, hexane/i-PrOH = 96:4,
flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer) = 13.2 min, tR (anti minor enantiomer)
= 11.3 min.
(2R,1′S)-2-[(p-Methoxyphenylamino)(p-nitrophenyl)methyl]cyclohexanone (57)14
OMe
O
HN
1'
2
NO2
Preformed imine was used for the reaction to afford 57. 1H NMR (400 MHz, CDCl3): δ 1. 61-2.45 (m,
8H), 2.81 (m, 1H), 3.68 (s, 3H), 4.58 (brs, 1H), 4.64 (d, 1H, J = 5.6 Hz), 6.45 (d, 2H, J = 8.8 Hz), 6.67
(d, 2H, J = 8.8 Hz), 7.56 (d, 2H, J = 8.8 Hz), 8.14 (d, 2H, J = 8.8 Hz). 13C NMR (100 MHz, CDCl3): δ
24.4, 27.7, 31.8, 42.4, 55.6, 57.0, 58.7, 114.8, 115.1, 123.6, 128.3, 140.7, 147.0, 150.0, 152.5, 211.8.
HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 85:15, flow rate 1.0 mL/min, λ = 254 nm), tR (anti
major enantiomer, (2R,1’S)-57) = 21.6 min, tR (anti minor enantiomer, (2S,1’R)-57) = 18.2 min, tR (syn
major enantiomer, (2S,1’S)-57) = 26.1 min, tR (syn minor enantiomer, (2R,1’R)-57) = 23.5 min.
(2R,1′S)-2-[(p-Methoxyphenylamino)(thiophen-2-yl)methyl]cyclohexanone (58)
OMe
O
HN
1'
2
S
Preformed imine was used for the reaction to afford 58. 1H NMR (500 MHz, CDCl3): δ 1.60-2.03 (m,
6H), 2.32-2.47 (m, 2H), 2.82 (m, 1H), 3.70 (s, 3H), 4.36 (brs, 1H), 4.87 (d, 1H, J = 6.0 Hz, CH), 6.59
(d, 2H, J = 9.0 Hz), 6.71 (d, 2H, J = 9.0 Hz), 6.90 (dd, 1H, J = 3.5 Hz, 5.0 Hz), 6.94 (d, 1H, J = 3.5 Hz),
7.15 (dd, 1H, J = 1.0Hz, 5.0 Hz). 13C NMR (100 MHz, CDCl3): δ
24.0, 27.6, 30.9, 42.0, 55.3, 55.6,
57.4, 114.6, 115.5, 124.1, 124.8, 126.5, 141.2, 146.8, 152.5, 212.0. HRMS: calcd for
S18
C18H22NO2S
(MH+) 316.1366, found 316.1377. HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 95:5, flow rate 1.0
mL/min, λ = 254 nm): tR (anti major enantiomer) = 20.8 min, tR (anti minor enantiomer) = 18.0 min.
(2R,1′S)-2-[(tert-Butoxycarbonylamino)(furan-2-yl)methyl]cyclohexanone (59)
O
NHBoc
1'
2
1
O
H NMR (500 MHz, CDCl3): δ 1.43 (s, 9H), 1.63-2.10 (m, 6H), 2.30-2.40 (m, 2H), 3.03 (m, 1H), 4.92
(m, 1H), 5.62 (brs, 1H), 6.15 (1H, d, J = 3.5 Hz), 6.28 (dd, 1H, J =1.8 Hz, 3.5 Hz), 7.29 (d, 1H, J = 1.8
Hz). 13C NMR (125 MHz, CDCl3): δ 24.5, 27.8, 28.3, 31.4, 42.4, 49.7, 53.4, 79.6, 105.7, 110.3, 141.2,
154.2, 155.7, 211.9. HRMS: calcd for C16H24NO4 (MH+) 294.17, found 294.1701.
HPLC (Daicel
Chiralpak As-H, hexane/i-PrOH = 95:5, flow rate 1.0 mL/min, λ = 220 nm): tR (anti major enantiomer)
= 9.5 min, tR (anti minor enantiomer) = 12.5 min.
syn-59 was synthesized by using proline (syn:anti = 95:5). 1H NMR (500 MHz, CDCl3): δ 1.41 (s, 9H),
1.45-2.09 (m, 6H), 2.26 (m, 1H), 2.39 (m, 1H), 2.81 (m, 1H), 4.97 (dd, 1H, J = 6.0 Hz, 10.0 Hz), 5.63
(brd, 1H, J = 8.0 Hz), 6.18 (d, 1H, J = 3.3 Hz), 6.26 (dd, 1H, J = 1.7 Hz, 3.3 Hz), 7.27 (d, 1H, J = 1.7
Hz). 13C NMR (125 MHz, CDCl3): δ
24.5, 26.9, 28.3, 30.4, 42.1, 48.9, 53.9, 79.5, 107.3, 110.2, 141.2,
153.6, 155.1, 211.0.
3. Synthesis of β-lactams
OMe
OMe
OMe
CO2 R
O
H
HN
3
2
CO 2Et
NaClO 2, K 2H2 PO4 ,
2-methyl-2-butene
O
HN
HO
CO2 Et
t-BuOH/H2 O/THF
(2R,3S)-15
(93% ee)
O
71
TMSCHN2
MeOH
toluene
S19
HN
MeO
3
CO2 Et
LHMDS
THF
31
4
N
O
OMe
R = Et: (3S,4R)-30a
(93% ee)
R = Me: (3S,4R)-30b
(94% ee)
Compound 71
OMe
O
HO
HN
CO2 Et
β-Amino aldehyde (2R,3S)-15 (anti:syn = 99:1, anti 93% ee) was synthesized by the ent-4-catalyzed
reaction as described above.
This compound (724.0 mg, 2.5 mmol) was oxidized with NaClO2
according to the reported procedures15 and the product acid was purified by flash chromatography
(EtOAc/hexanes = 3:1) to afford 71 (503.7 mg, 66%) as a pale yellow solid. 1H NMR (400 MHz,
CDCl3) δ 1.02 (d, 3H, J = 6.8 Hz), 1.05 (d, 3H, J = 6.8 Hz), 1.20 (t, 3H, J = 7.2 Hz), 2.13 (m, 1H), 2.64
(m, 1H), 3.72 (s, 3H), 4.09-4.16 (m, 2H), 4.26 (d, 1H, J = 6.0 Hz), 6.64 (d, 2H, J = 8.8 Hz), 6.75 (d, 2H,
J = 8.8 Hz), 7.30-7.70 (br, 2H).
13
C NMR (100 MHz, CDCl3) δ 14.0, 19.9, 20.4, 27.6, 54.5, 55.6,
57.7, 61.3, 114.7, 115.5, 140.6, 152.9, 173.1, 178.1.
Ethyl (2R,3S)-3-methoxycarbonyl-2-(p-methoxyphenylamino)-4-methylpentanoate (31)
OMe
O
MeO
HN
CO2Et
To a solution of 71 (103.0 mg, 0.33 mmol) in toluene (2 mL)-MeOH (5 mL), TMSCHN2 (2M solution
in hexane) was added by dropwise at 0 °C until the yellow color persisted.
The solution was stirred
for additional 10 min and quenched with a drop of acetic acid. The solvents were removed in vacuo
and the residue was purified by flash column chromatography (EtOAc/hexanes = 1:4) to afford 31
(59.2 mg, 59.2 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 0.98 (d, 3H, J = 6.8 Hz), 0.99 (d, 3H, J = 6.8
Hz), 1.19 (t, 3H, J = 7.2 Hz), 2.16 (m, 1H), 2.61 (dd, 1H, J = 5.6 Hz, 8.8 Hz), 3.69 (s, 3H), 3.73 (s, 3H),
4.06-4.19 (m, 2H, J = 8.8 Hz), 4.24 (d, 1H, J = 5.6 Hz), 4.42 (brs, 1H), 6.62 (d, 2H, J = 8.8 Hz), 6.75 (d,
2H, J = 8.8 Hz).
13
C NMR (100 MHz, CDCl3): δ 14.1, 20.2, 20.3, 27.7, 51.7, 54.4, 55.6, 57.6, 61.1,
S20
114.8, 115.2, 140.8, 152.7, 173.1, 173.6. HRMS: calcd for C17H26NO5 (MH+) 324.1805, found
324.1802.
(3S,4R)-3-Isopropyl-1-(p-methoxyphenyl)-4-ethoxycarbonylazetidin-2-one
(30a)
and
(3S,4R)-3-isopropyl-1-(p-methoxyphenyl)-4-methoxycarbonylazetidin-2-one (30b).
To a solution of 31 (77.0 mg, 23.8 mmol) in THF (2.0 mL) was added lithium bis(trimethylsilyl)amide
(1.0 M in THF, 0.30 mL, 0.3 mmol) at 0 °C.
After stirring at the same temperature for 30 min, the
mixture was added to ice-cooled aqueous 5% HCl and extracted with AcOEt.
The combined organic
layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by flsh column
chromatography (EtOAc/hexanes = 1:4) to afford (3S,4R)-30a (16.8 mg, 24%, single diastereomer,
93% ee) and (3S,4R)-30b (4.9 mg, 7%, single diastereomer, 94% ee) as a colorless solid, respectively.
(3S,4R)-30a
CO 2Et
4
3
N
O
OMe
1
H NMR (400 MHz, CDCl3) δ 1.07 (d, 3H, J = 6.7 Hz, CH(CH3)CH3), 1.14 (d, 3H, J = 6.7 Hz,
CH(CH3)CH3), 1.26 (t, 3H, J = 7.2 Hz, OCH2CH3), 2.15 (m, 1H, CH(CH3)2), 3.13 (dd, 1H, J = 2.8 Hz,
8.1 Hz, COCHCH(CH3)2), 3.78 (s, 3H, OCH3), 4.19 (d, 1H, J = 2.8 Hz), 4.20-4.31 (m, 2H, OCH2CH3),
6.86 (d, 2H, J = 8.8 Hz, ArH), 7.25 (d, 2H, J = 8.8 Hz, ArH).
13
C NMR (100 MHz, CDCl3): δ 14.1,
19.9, 20.1, 28.2, 55.0, 55.5, 61.7, 62.3, 114.4, 117.7, 131.1, 156.2, 165.1, 170.3. HRMS: calcd for
C16H22NO4 (MH+) 292.1543, found 292.1542.
HPLC (Daicel Chiralpak AS, hexane/i-PrOH = 95:5,
flow rate 1.0 mL/min, λ = 254 nm): tR (major enantiomer) = 8.6 min, tR (minor enantiomer) = 21.9 min.
S21
(3S,4R)-30b
CO2 Me
3
4
N
O
OMe
1
H NMR (400 MHz, CDCl3) δ 1.07 (d, 3H, J = 6.7 Hz, CH(CH3)CH3), 1.14 (d, 3H, J = 6.7 Hz,
CH(CH3)CH3), 2.15 (m, 1H, CH(CH3)2), 3.14 (dd, 1H, J = 2.8 Hz, 8.0 Hz, COCHCH(CH3)2), 3.78 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 4.21 (d, 1H, J = 2.8 Hz, NCHCO2Et), 6.87 (d, 2H, J = 9.2 Hz, ArH),
7.25 (d, 2H, J = 9.2 Hz, ArH).
13
C NMR (100 MHz, CDCl3): δ 19.9, 20.1, 28.3, 52.7, 54.9, 55.5, 62.4,
114.4, 117.7, 131.0, 156.3, 165.0, 170.8. HRMS: calcd for C15H20NO4 (MH+) 278.1387, found
278.1381. HPLC (Daicel Chiralpak AS, hexane/i-PrOH = 95:5, flow rate 1.0 mL/min, λ = 254 nm):
tR (major) = 10.6 min, tR (minor) = 26.2 min.
S22
4. Additional Mannich-Type reactions and products
anti-tert-Butyl 2-formyl-3-methyl-1-phenylbutylcarbamate (anti-72)
O
NBoc
+
H
H
O
4 (0.1 equiv)
CHCl3 , 4 o C, 18 h
NHBoc
H
72
A mixture of the N-Boc-imine (102 mg, 0.5 mmol), isovaleraldehyde (108 µL, 1.0 mmol) and catalyst 4
(5.7 mg, 0.05 mmol) in anhydrous CHCl3 (5 mL) in a flame-dried Schlenk tube was stirred for 18 h
under Ar at 4 oC. Ethyl acetate (3 mL) and a scoop of silica gel were added to the reaction mixture and
the solvent was completely removed in vacuo. The mixture was purified by flash column
chromatography (EtOAc/hexane = 10:1) to afford product 72 (93 mg, 64% yield, anti:syn = 4:1,
anti-72, 79% ee). The diastereomer mixture was further purified by flash column chromatography to
afford anti-72.
1
H NMR (500 MHz, CDCl3): δ 1.02 (d, 3H, J = 7.0 Hz), 1.07 (d, 3H, J = 7. 0 Hz), 1.39 (s, 9H), 1.88 (m,
1H), 2.62 (m, 1H), 5.13 (s, 1H), 5.39 (s, 1H), 7.26-7.35 (m, 5H), 9.76 (d, 1H, J = 3.5 Hz). 13C NMR
(100 MHz, CDCl3): δ 18.9, 21.3, 28.2, 28.3, 53.0, 62.9, 79.8, 126.5, 127.5, 128.7, 140.8, 155.0, 206.1.
HRMS: calcd for C17H26NO3 (MH+) 292.1907, found 292.1907. HPLC (Daicel Chiralpak AS-H,
hexane/i-PrOH = 99:1, flow rate 0.5 mL/min, λ = 220 nm): tR (anti major enantiomer) = 20.9 min, tR
(anti minor enantiomer) = 17.5 min.
For (S,S)-syn-72, see ref. 16.
anti-tert-Butyl (2-oxocyclohexyl)(phenyl)methylcarbamate (anti-73)
O
NBoc
+
H
4 (0.1 equiv)
O
NHBoc
CH 2Cl2,rt, 48 h
73
A mixture of the N-Boc-imine (102 mg, 0.5 mmol), cyclohexanone (0.52 mL, 5 mmol), and catalyst 4
(5.7 mg, 0.05 mmol) in anhydrous dichloromethane (1 mL), was stirred at room temperature (25 oC)
for 48 h. Ethyl acetate (3 mL) and a scoop of silica gel were added to the reaction mixture and the
solvent was completely removed in vacuo. The mixture was purified by flash column chromatography
S23
(EtOAc/hexane = 8:1) to afford product 73 (101.6 mg, 67% yield, anti:syn = 4:1, anti-73, 80% ee). The
diastereomer mixture was further purified by flash column chromatography to afford anti-73.
1
H NMR (500 MHz, CDCl3): δ 1.41 (s, 9H), 1.66-1.85 (m, 3H), 1.89-1.96 (m, 1H), 1.96-2.03 (m, 1H),
2.08 (d, 1H, J = 10.68 Hz), 2.23-2.34 (m, 1H), 2.40 (td, 1H, J = 13.24, 4.81, 4.81 Hz), 2.88 (dd, 1H, J
= 9.28, 4.63 Hz), 4.92-4.76 (m, 1H), 5.76 (m, 1H), 7.21 (m, 1H), 7.28-7.32 (m, 4H).
13
C NMR (126
MHz, CDCl3): δ 24.2, 28.1, 28.3, 32.4, 42.4, 55.2, 56.1, 79.4, 126.6, 126.9, 128.3, 141.6, 155.7, 212.7.
HRMS: calcd for C18H26NO3 (MH+) 304.1907, found. 304.1907. HPLC (Daicel Chiralpak OD-H,
hexane/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 220 nm): tR (anti major enantiomer) = 11.2 min, tR
(anti minor enantiomer) = 14.2 min.
When the same reaction was performed using proline instead of catalyst 4, syn-73 was obtained.
References
(1) Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet,
A. G. J. Med. Chem. 1988, 31, 1598.
(2) Mitsumori, S.; Zhang, H.; H.-Y. Cheong, P.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2006, 128, 1040.
(3) a) Haviari, G.; Celerier, J. P.; Petit, H.; Lhommet, G.; Gardette, D.; Gramain, J. C. Tetrahedron
Lett. 1992, 33, 4311. b) Cimarelli, C.; Palmieri, G..; Volpini, E. Synth. Commun. 2001, 31, 2943. c)
Celerier, J. P.; Haddad, M.; Jacoby, D.; Lhommet, G. Tetrahedron Lett. 1987, 28, 6597.
(4) Wang, W.; Wang J.; Lia H.; Liao L. Tetrahedron Lett. 2004, 45, 7235.
(5) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 9630.
(6) Cheong, P. H.-Y.; Zhang, H.; Thayumanavan, R.; Tanaka, F.; Houk, K. N.; Barbas, C. F., III. Org.
Lett. 2006, 8, 811.
(7) Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507.
(8) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2007, 129, 288.
(9) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 16408.
(10) Kano, T.; Hato Y.; Maruoka, K. Tetrahedron Lett. 2006, 47, 8467.
(11) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 7749.
(12) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2006, 8,
2839.
(13) Evans, D. A.; Aye, Y.; Wu, J. Org. Lett. 2004, 8, 2071.
(14) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(15) a) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002,
124, 1866. b) Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 3541.
(16) a) Yang, J. W.; Stadler M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609. b) Yang, J. W.; Stadler
M.; List, B. Nat. Protocols 2007, 2, 1937.
S24
2.503
2.490
2.485
2.470
2.457
2.452
2.439
2.182
2.161
2.149
2.140
2.128
2
455
1 106
439
3.314
3.310
3.306
3.556
3.540
3.527
3.510
3.770
3.750
3.740
3.721
3.964
3.951
3.948
3.944
3.935
3.931
3.927
3.921
3.915
3.904
3.900
3.887
3.882
3.865
4.909
Date:
31 Aug 2006
Document's Title:
PROTON.fid
Spectrum Title:
susumub3-02_07Oct2005
N N
Frequency (MHz):
(f1) 399.740
Original Points Count:
(f1) 17959
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 12.000
Pulse Program:
Unknown
Temperature:
29
N
N
H
Me
N
H
ent-2
Number of Scans:
128
Acq. Date:
Oct 7 2005
3.00
1.09
1.08
4.05
1.04
1.15
2.10
5.0
ppm (f1)
0.0
S25
18.132
35.524
39.257
49.640
49.213
49.000
48.788
56.772
51.469
163.650
Date:
31 Aug 2006
Document's Title:
methyl-tetrazole-CNMR.mrc
Spectrum Title:
susumub3-01_18Oct2005
N N
Frequency (MHz):
(f1) 100.524
Original Points Count:
(f1) 25317
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 1.1994
Spectral Width (ppm):
(f1) 209.982
Pulse Program:
Unknown
Temperature:
29
N
N
H
Me
Number of Scans:
2000
N
H
Acq. Date:
Oct 18 2005
ent-2
150
ppm (t1)
100
50
0
S26
0.000000
0.803
0.790
2.535
2.516
1.356
1.343
2.706
2.698
3.497
3.483
3.482
3.481
3.468
3.105
3.085
3.592
3.579
3.671
7.234
7.220
7.350
7.336
7.309
7.294
7.279
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
16
Acq. Date:
Tue Mar 14 11:09:49 AM
CO 2Me
N
66
Ph
3.20
3.00
1.02
1.04
1.06
1.04
5.0
0.98
1.10
1.04
2.76
0.79
3.46
10.0
ppm (t1)
Date:
14 Sep 2006
Document's Title:
nu1-205-6
0.0
S27
67
Ph
-0.0000000
0.11
3.16
3.27
2.11
0.10
2.15
1.09
5.0
1.08
0.10
3.00
1.08
1.04
4.19
10.0
ppm (t1)
1.007
0.995
1.343
1.330
1.989
1.985
1.982
1.974
1.969
1.958
2.564
2.548
2.621
2.603
3.038
3.026
3.014
3.695
3.818
3.804
7.372
7.358
7.312
7.298
7.282
7.260
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
16
Acq. Date:
Tue Mar 21 10:25:05 AM
CO 2Me
N
Date:
14 Sep 2006
Document's Title:
1
0.0
S28
1.230
1.246
2.075
2.067
2.061
2.056
2.042
2.451
2.447
2.091
2.471
2.862
2.883
2.879
3.023
3.010
3.003
2.990
3.121
3.141
3.137
3.157
3.683
4.867
Date:
14 Sep 2006
Document's Title:
1
Spectrum Title:
None
Frequency (MHz):
(f1) 400.138
Original Points Count:
(f1) 8192
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 1.7039
Spectral Width (ppm):
(f1) 12.015
Pulse Program:
ZG30
Temperature:
300
Number of Scans:
16
Acq. Date:
Wed Mar 22 11:20:48 AM
CO 2Me
68
N
H
2.0
3.05
2.09
3.0
0.95
4.0
0.96
ppm (t1)
5.0
1.01
1.00
3.26
6.0
1.0
0.0
S29
1.408
1.394
2.212
2.198
2.196
2.180
2.178
2.171
2.170
2.164
2.155
2.338
2.328
2.316
2.312
2.300
2.583
2.600
3.765
3.752
3.749
3.736
3.313
3.310
3.307
Date:
14 Sep 2006
Document's Title:
nu1-233-1
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
32
Acq. Date:
Mon Mar 27 10:35:36 PM
CO 2H
3
N
H
3.16
3.0
1.04
4.0
1.00
5.0
1.00
1.01
6.0
ppm (t1)
2.0
1.0
0.0
S30
17.952
30.596
46.200
50.371
50.201
50.029
49.860
49.691
49.518
49.349
61.357
54.662
179.391
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
298.16
Number of Scans:
9223
Acq. Date:
Mon Mar 27 11:17:19 PM
CO 2H
3
N
H
200
ppm (t1)
150
Date:
14 Sep 2006
Document's Title:
4
100
50
0
S31
H b , Hc
e
f
H,H
Hd
Hg
H
Ha
Hc Hb
H e,
1.00
Ha
1.50
2.00
b
H
Hc
2.50
Hd
3.00
He, Hf
3.50
Hf
H
H
H
CO 2H
Hd
Hg
N CHa
3
H
3
Date:
14 Sep 2006
Document's Title:
nu1-233-1
Spectrum Title:
COSY (magnitude mode) using Gradient Pulse, DRX-500, BBO Probe
Frequency (MHz):
(f2) 500.133 (f1) 500.133
Original Points Count:
(f2) 1024 (f1) 256
Actual Points Count:
(f2) 1024 (f1) 1024
Acquisition Time (sec):
(f2) 0.1704 (f1) 0.0426
Spectral Width (ppm):
(f2) 12.016 (f1) 12.016
Pulse Program:
COSYGPQF
Temperature:
298.16
Number of Scans:
1
Acq. Date:
Mon Mar 27 10:39:12 PM
Hg
4.00
ppm (t1)
4.00
ppm (t2)
3.50
3.00
2.50
2.00
1.50
1.00
S32
2.054
2.050
2.048
2.042
2.036
2.020
2.017
2.011
2.007
2.005
446
1 430
991
2.234
2.217
2.202
2.185
2.169
2.151
3.376
3.471
3.470
3.468
3.634
3.618
3.605
3.589
4.175
7.260
7.192
6.935
Date:
18 Sep 2006
Document's Title:
ZHL-2217H.mrc
Spectrum Title:
ZHL-2217H_17Sep2006
Frequency (MHz):
(f1) 399.739
Original Points Count:
(f1) 23946
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
29
H
N
N
Boc
CF3
S
O O
70
Number of Scans:
8
Acq. Date:
Sep 17 2006
9.00
1.12
1.07
5.0
3.15
1.05
1.06
0.79
10.0
ppm (t1)
0.0
S33
32.786
31.755
28.374
43.700
43.317
51.989
51.048
54.448
53.798
80.444
77.254
77.000
76.745
118.319
120.871
123.424
154.467
115.766
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
300.16
Number of Scans:
12425
Acq. Date:
Tue Sep 19 01:48:54 AM
H
N
N
Boc
200
ppm (f1)
CF3
S
O O
70
150
Date:
18 Sep 2006
Document's Title:
2
100
50
0
S34
2.147
2.131
2.127
2.113
2 108
903
1 889
2.997
2.984
2.968
2.956
4.137
4.123
4.110
4.095
4.083
3.410
3.391
3.381
3.372
3.362
3.343
3.334
3.329
3.325
3.318
3.314
3.310
3.306
3.302
3.285
3.270
3.264
3.260
3.256
3.245
3.240
3.231
3.225
3.216
3.211
3.196
Date:
18 Sep 2006
Document's Title:
PROTON.fid
Spectrum Title:
ZHL-2219H-MeODag_17Sep2006
Frequency (MHz):
(f1) 399.740
Original Points Count:
(f1) 23946
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
29
H
N
N
H
CF3
S
O O
9
Number of Scans:
64
Acq. Date:
Sep 17 2006
1.00
1.02
5.0
1.01
2.14
1.11
0.94
10.0
ppm (f1)
0.0
S35
34.683
49.511
49.342
49.170
49.000
48.831
48.659
48.489
45.257
54.025
56.006
119.357
121.952
124.548
127.143
Date:
15 Sep 2006
Document's Title:
ZHL-2219H.mrc
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
298.16
Number of Scans:
1960
Acq. Date:
Sat Jun 03 06:42:57 PM
H
N
N
H
200
ppm (f1)
150
CF3
S
O O
9
100
50
0
S36
2.769
2.763
2.756
2.750
1.205
1.182
1.168
1.153
1.139
1 122
3.730
3.986
3.965
6.662
6.644
6.770
6.752
7.260
9.922
9.915
9.760
9.754
4.337
4.323
4.316
4.303
4.133
4.125
4.118
4.111
4.097
4.083
4.076
4.068
4.061
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
8
Acq. Date:
Fri May 19 11:13:34 AM
OMe
O
H
22
13.76
5.0
1.02
3.28
1.00
2.19
1.10
4.38
1.00
0.04
10.0
ppm (t1)
HN
CO 2Et
Date:
16 Apr 2007
Document's Title:
ZHL-2210-t-bu.mrc
0.0
S37
13.981
33.073
28.857
56.185
55.600
62.495
61.251
77.254
77.000
76.746
115.807
114.722
140.374
153.114
173.222
202.944
Date:
12 Mar 2007
Document's Title:
ZHL-2210.mrc
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
298.16
Number of Scans:
256
Acq. Date:
Fri May 19 11:19:51 AM
OMe
O
H
200
ppm (t1)
HN
CO 2Et
150
22
100
50
0
S38
2.424
2 172
411
1
143
1 125
3.986
3.947
3.927
3.890
3.737
2.783
2.772
2.761
2.750
4.184
4.172
4.160
4.148
4.137
4.130
4.125
4.117
4.113
4.107
4.101
4.093
4.083
4.070
4.059
4.047
6.690
6.670
6.661
6.640
4.386
4.369
4.351
4.332
4.314
4.292
6.782
6.762
6.753
9.766
9.755
7.260
Date:
25 Apr 2007
Document's Title:
PROTON.fid
Spectrum Title:
mm24-12-18_31Oct2005
Frequency (MHz):
(f1) 300.143
Original Points Count:
(f1) 7197
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 1.9979
Spectral Width (ppm):
(f1) 12.002
Pulse Program:
Unknown
Temperature:
25
OMe
O
HN
anti : sy n = 2:1
H
CO2Et
Number of Scans:
32
22
Acq. Date:
Oct 31 2005
22.90
0.59
5.0
1.09
5.34
1.68
3.47
1.83
3.58
3.52
1.00
0.57
10.0
ppm (f1)
0.0
S39
1.126
1.109
1.076
1.059
2.156
2.139
2.122
2.105
2.089
2.072
1.373
2.545
2.535
2.529
2.525
2.520
2.516
2.509
2.500
3.738
3.864
4.261
4.242
6.670
6.647
6.776
6.753
7.260
9.730
9.721
Date:
24 Apr 2007
Document's Title:
ZHL-2015A.mrc
Spectrum Title:
ZHL-2015A_07Dec2005
Frequency (MHz):
(f1) 399.739
Original Points Count:
(f1) 23946
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
29
OMe
O
H
HN
O
O
25
Number of Scans:
8
Acq. Date:
Dec 7 2005
3.35
3.28
9.94
0.98
1.01
5.0
3.27
0.02
0.99
1.03
2.13
2.14
1.00
10.0
ppm (t1)
0.0
S40
19.131
27.898
27.499
21.270
55.620
57.953
77.318
77.000
76.682
59.584
82.215
115.902
114.651
140.574
153.141
171.862
203.367
Date:
30 Mar 2007
Document's Title:
ZHL-3015B-CNMR.mrc
Spectrum Title:
ZHL-2015B-car_07Dec2005
Frequency (MHz):
(f1) 100.525
Original Points Count:
(f1) 30135
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 1.1994
Spectral Width (ppm):
(f1) 249.945
OMe
O
H
Pulse Program:
Unknown
Temperature:
29
HN
O
Number of Scans:
1000
O
25
Acq. Date:
Dec 7 2005
200
150
100
50
0
ppm (f1)
S41
1.164
1.141
2.357
2.334
2.311
2.287
2.264
2.241
1.386
3.879
3.737
2.495
2.483
2.470
2.459
2.447
2.436
4.241
4.220
4.198
6.659
6.629
6.784
6.755
7.260
9.767
9.756
Date:
24 Apr 2007
Document's Title:
ZHL-mm62h.mrc
Spectrum Title:
mm62h_07Dec2005
Frequency (MHz):
(f1) 300.143
Original Points Count:
(f1) 7197
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 1.9979
Spectral Width (ppm):
(f1) 12.002
Pulse Program:
Unknown
Temperature:
25
OMe
O
HN
O
H
O
sy n- 25
Number of Scans:
8
Acq. Date:
Dec 7 2005
3.00
2.93
9.18
0.89
0.91
5.0
2.91
0.91
0.93
1.97
1.85
0.80
10.0
ppm (t1)
0.0
S42
26.3
20.8
19.9
27.9
55.6
57.7
77.4
77.0
76.6
59.5
82.4
115.7
114.7
140.3
153.0
171.6
203.8
Date:
30 Mar 2007
Document's Title:
CARBON.fid
Spectrum Title:
mm62c_07Dec2005
Frequency (MHz):
(f1) 75.479
Original Points Count:
(f1) 34246
Actual Points Count:
(f1) 131072
Acquisition Time (sec):
(f1) 1.8150
Spectral Width (ppm):
(f1) 249.976
OMe
O
HN
Pulse Program:
Unknown
Temperature:
25
O
H
O
Number of Scans:
256
sy n- 25
Acq. Date:
Dec 7 2005
200
150
100
50
0
ppm (f1)
S43
2.164
2.142
2.119
2 114
096
137
074
1
2
052
083
3.733
2.656
2.645
2.636
2.631
2.625
2.620
2.611
2.600
4.398
4.373
3.970
4.592
4.573
5.887
5.867
5.852
5.848
5.833
5.831
5.810
5.795
5.791
5.775
5.756
5.265
5.260
5.222
5.220
5.217
5.207
5.202
5.187
5.185
5.183
6.674
7.260
6.753
9.754
9.743
Date:
24 Apr 2007
Document's Title:
ZHL-2011C.mrc
Spectrum Title:
ZHL-2011-C_06Dec2005
Frequency (MHz):
(f1) 300.143
Original Points Count:
(f1) 9596
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 1.9979
Spectral Width (ppm):
(f1) 16.003
Pulse Program:
Unknown
Temperature:
25
OMe
O
Number of Scans:
16
HN
O
H
Acq. Date:
Dec 6 2005
O
26
3.57
3.56
1.06
1.09
5.0
3.38
1.03
1.12
2.20
1.94
0.82
2.28
2.20
1.00
10.0
ppm (t1)
0.0
S44
19.184
27.547
21.255
55.608
57.130
65.858
59.559
77.424
77.000
76.577
118.823
115.796
114.771
131.377
140.369
153.240
172.553
203.217
Date:
17 Apr 2007
Document's Title:
MestReC1
Spectrum Title:
ZHL-2011B-car_06Dec2005
Frequency (MHz):
(f1) 75.479
Original Points Count:
(f1) 34246
Actual Points Count:
(f1) 131072
Acquisition Time (sec):
(f1) 1.8150
Spectral Width (ppm):
(f1) 249.976
Pulse Program:
Unknown
Temperature:
25
OMe
O
HN
O
H
Number of Scans:
8000
O
26
200
150
Acq. Date:
Dec 6 2005
100
50
0
ppm (t1)
S45
2.614
2.605
2.591
2
283
1
353
581
155
033
2 178
567
330
3.738
3.876
3.849
3.845
3.838
4.381
4.353
4.329
4.602
4.597
4.593
4.583
4.578
4.574
6.790
7.260
6.760
6.674
6.644
5.896
5.877
5.861
5.857
5.842
5.839
5.823
5.819
5.804
5.800
5.785
5.765
5.287
5.282
5.277
5.235
5.230
5.225
5.200
5.196
5.192
5.188
Date:
24 Apr 2007
Document's Title:
ZHL-mm60h.fid.mrc
Spectrum Title:
mm60-h_02Dec2005
Frequency (MHz):
(f1) 300.143
Original Points Count:
(f1) 7197
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 1.9979
Spectral Width (ppm):
(f1) 12.002
Pulse Program:
Unknown
Temperature:
25
OMe
O
HN
O
H
Number of Scans:
8
O
sy n-26
3.98
3.82
1.26
1.24
5.0
4.25
1.32
1.40
2.69
2.34
0.98
2.72
2.76
1.00
10.0
ppm (t1)
Acq. Date:
Dec 2 2005
0.0
S46
20.9
19.7
26.3
56.9
55.6
65.9
59.5
77.4
77.0
76.6
118.9
115.7
114.8
131.4
140.1
153.1
172.4
203.6
Date:
30 Mar 2007
Document's Title:
CARBON.fid
Spectrum Title:
mm60-c_02Dec2005
Frequency (MHz):
(f1) 75.479
Original Points Count:
(f1) 34246
Actual Points Count:
(f1) 131072
Acquisition Time (sec):
(f1) 1.8150
Spectral Width (ppm):
(f1) 249.976
OMe
O
HN
Pulse Program:
Unknown
Temperature:
25
O
H
O
sy n-26
Number of Scans:
256
Acq. Date:
Dec 2 2005
200
150
100
50
0
ppm (f1)
S47
1.602
1.299
1.274
1.236
1.222
1.216
1.207
1.202
1.187
1.177
1
906
00089
892
001
6.682
6.676
6.671
6.664
6.658
7.260
6.785
6.769
6.756
6.751
4.213
4.206
4.199
4.192
4.185
4.178
4.174
4.163
4.159
4.151
4.145
4.137
4.129
4.123
4.115
4.108
4.100
4.093
3.937
3.919
3.740
3.734
1.731
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
8
Acq. Date:
Mon Jul 17 05:43:26 PM
OMe
O
H
HN
syn : anti = 2:1
CO2Et
29
5.0
5.04
1.56
8.66
3.22
1.15
1.16
2.28
4.81
1.56
4.73
6.42
1.00
0.49
10.0
ppm (t1)
Date:
24 Apr 2007
Document's Title:
ZHL-2271C.mrc
0.0
S48
14.872
14.663
14.632
14.578
14.221
14 099
17.127
35.547
77.254
77.000
76.745
116.373
116.125
114.829
114.754
153.508
153.330
141.143
140.541
171.953
171.758
203.668
203.364
63.283
62.678
61.485
61.260
55.662
55.622
52.617
51.635
36.509
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
298.16
Number of Scans:
413
Acq. Date:
Mon Jul 17 05:54:40 PM
OMe
O
H
HN
CO2Et
syn : anti = 2:1
29
200
150
100
Date:
5 Mar 2007
Document's Title:
1
50
0
ppm (f1)
S49
2.373
2.354
2.340
2.337
2.324
2.307
2.292
2.277
2.259
2.240
2.029
2.013
2
1 000
250
236
221
208
911
1
193
897
179
883
3.729
3.725
6.745
7.260
6.632
6.614
4.168
4.161
4.154
4.150
4.147
4.135
4.132
4.128
4.121
4.114
4.108
4.100
4.085
3.096
3.086
3.082
3.078
3.073
3.069
3.064
3.055
3.044
3.038
3.033
3.028
3.017
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
16
Acq. Date:
Mon May 01 07:17:55 PM
OMe
O
Date:
29 Jun 2006
Document's Title:
ZHL-2170B.mrc
HN
CO2 Et
38
CO2 Et
5.90
1.80
4.86
0.92
5.0
2.99
5.32
2.04
2.00
10.0
ppm (t1)
0.0
S50
31.69
30.06
23.16
14.15
14.09
53.51
59.25
55.63
77.26
77.00
76.75
61.37
60.58
140.56
153.10
172.49
209.16
115.70
114.80
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
298.16
Number of Scans:
608
Acq. Date:
Mon May 01 07:29:51 PM
OMe
O
Date:
1 Mar 2007
Document's Title:
ZHL-2170BCaragain.mrc
HN
CO2 Et
38
CO2 Et
200
ppm (t1)
150
100
50
0
S51
HN
CO 2Et
39
CN
2.82
0.54
0.16
1.20
1.13
0.13
0.55
2.83
0.49
1.11
1.01
3.10
4.12
2.09
2.00
5.0
ppm (t1)
1.647
1.244
1 200
2.345
2.330
2.311
2.297
2.061
2.044
2.036
1.898
1.888
1.870
3.194
3.176
2.425
2.413
2.410
2.397
3.735
6.785
6.767
6.638
6.620
7.260
4.202
4.183
4.169
4.160
4.154
4.146
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
8
Acq. Date:
Tue May 02 12:04:24 AM
OMe
O
Date:
16 Apr 2007
Document's Title:
ZHL-2168B.mrc
0.0
S52
15.3
14.1
30.6
23.3
58.9
55.6
52.6
77.3
77.0
76.7
61.7
115.8
115.7
114.9
118.6
139.9
153.4
171.6
207.8
Date:
2 Mar 2007
Document's Title:
ZHL-2168BCaragain.mrc
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
298.16
Number of Scans:
588
Acq. Date:
Tue May 02 12:40:43 AM
OMe
O
HN
CO 2Et
39
CN
200
ppm (t1)
150
100
50
0
S53
1.269
1.251
1.246
1.233
3.745
3.475
3.470
2.261
2.250
3.955
3.947
4.234
4.216
4.198
4.180
4.487
6.614
6.807
6.790
6.784
6.731
6.704
6.698
6.681
7.260
Date:
16 Apr 2007
Document's Title:
ZHL-2105recolumn.fid.mrc
Spectrum Title:
ZHL-2105recolumn_06Aug2006
Frequency (MHz):
(f1) 399.739
Original Points Count:
(f1) 23946
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
40
CO2 Et
Number of Scans:
64
OMe
Acq. Date:
Aug 6 2006
4.21
0.68
2.60
0.69
2.56
3.00
0.91
2.32
0.90
1.82
1.81
0.71
5.0
ppm (t1)
0.0
S54
14.074
26.605
55.669
87.086
77.317
77.000
76.682
61.748
60.587
60.300
115.448
114.975
139.706
153.052
170.012
209.254
Date:
16 Apr 2007
Document's Title:
ZHL-2105recolumn-cnmr.mrc
Spectrum Title:
ZHL-2105recolumn-CNMR_06Aug2006
Frequency (MHz):
(f1) 100.525
Original Points Count:
(f1) 30135
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 1.1994
Spectral Width (ppm):
(f1) 249.945
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
CO2 Et
40
OMe
Number of Scans:
16000
Acq. Date:
Aug 6 2006
200
ppm (t1)
150
100
50
0
S55
2.045
1.595
1.263
1.259
1.245
1.227
0 000
2.263
2.248
3.742
3.722
4.608
4.578
4.241
4.236
4.232
4.223
4.219
4.205
4.201
4.192
4.184
4.697
4.668
6.630
6.607
7.336
7.332
7.317
7.311
7.281
7.276
7.260
6.781
6.759
Date:
28 Jun 2006
Document's Title:
ZHL-NGB-1008B.mrc
Spectrum Title:
NGB-1008B-2_15May2006
Frequency (MHz):
(f 1) 399.739
Original Points Count:
(f 1) 23946
Actual Points Count:
(f 1) 32768
Acquisition Time (sec):
(f 1) 3.7440
Spectral Width (ppm):
(f 1) 16.000
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
CO2 Et
O
41
Number of Scans:
8
Acq. Date:
May 15 2006
0.60
3.13
2.28
0.52
0.47
2.39
5.0
3.93
2.71
3.96
5.20
10.0
ppm (t1)
0.0
S56
14.086
26.931
55.686
74.239
61.725
60.707
77.318
77.000
76.682
128.504
128.113
127.921
115.229
114.961
84.416
136.957
139.577
152.949
170.082
209.395
Date:
28 Jun 2006
Document's Title:
ZHL-NGB-1008B.mrc
Spectrum Title:
NGB-1008B-2_15May2006-17:13:58
Frequency (MHz):
(f1) 100.525
Original Points Count:
(f1) 30135
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 1.1994
Spectral Width (ppm):
(f1) 249.945
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
CO2 Et
O
41
Number of Scans:
256
Acq. Date:
May 15 2006
200
ppm (f1)
150
100
50
0
S57
1.255
1.248
1.240
1.233
1.226
1.219
1.896
2.387
2.341
2.082
3.526
3.507
3.753
3.747
3.736
3.958
4.401
4.382
7.260
6.791
6.773
6.767
6.762
6.754
6.740
6.722
4.291
4.273
4.246
4.123
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
64
Acq. Date:
Tue Mar 14 06:21:55 PM
OMe
O
HN
Date:
16 Apr 2007
Document's Title:
ZHL-2146.mrc
43
CO2 Et anti : sy n = 1:1
SMe
5.0
4.0
3.0
2.0
3.23
6.0
1.43
1.52
1.49
1.44
7.0
0.52
3.52
0.94
2.12
1.04
4.00
8.0
ppm (t1)
1.0
0.0
S58
56.626
55.727
55.665
55.630
54.684
28.077
27.730
14.155
14.073
13.185
12.514
59.710
61.670
61.396
77.254
77.000
76.746
140.804
140.238
172.466
172.197
154.662
153.693
153.234
201.977
201.283
10000
OMe
O
HN
43
5000
CO2 Et anti : sy n = 1:1
SMe
Date:
5 Mar 2007
Document's Title:
ZHL-2196CNMR.mrc
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pul se Program:
ZGPG45
Temperature:
298.16
Number of Scans:
476
Acq. Date:
Tue Mar 14 06:54:11 PM
0
200
ppm (t1)
150
100
50
0
S59
3.754
3.733
2.701
2.688
2.683
2.671
2.665
2.653
2.647
636
2
619
1 633
119
615
101
285
1
083
275
4.265
4.256
4.246
4.240
4.238
4.228
4.222
4.220
4.210
4.201
4.192
4.183
4.173
4.060
4.041
4.027
4.014
4.000
6.772
6.750
6.646
6.729
6.828
6.624
4.688
4.679
4.668
4.659
4.550
4.542
4.523
4.515
4.494
4.486
4.346
4.337
Date:
25 Apr 2007
Document's Title:
ZHL-2081.mrc
Spectrum Title:
ZHL-2081B_02Feb2006
Frequency (MHz):
(f1) 399.739
Original Points Count:
(f1) 23946
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
anti : sy n = 1.3 :1
CO2 Et
N3
Number of Scans:
8
44
Acq. Date:
Feb 2 2006
4.0
3.0
1.34
1.69
3.27
5.0
2.00
6.0
1.26
1.66
0.46
2.08
1.01
0.41
0.22
0.20
0.56
0.89
2.05
1.13
7.0
ppm (t1)
2.0
1.0
0.0
S60
4.630
4.601
4.577
4.570
4.564
4.558
4.547
4.529
4.484
4.477
4.474
4.472
4.467
4.464
4.447
4.432
4.429
4.402
325
213
212
193
195
1
4 194
175
157
176
269
139
267
6.603
6.586
6.580
6.575
6.553
4.701
4.694
7.329
7.326
7.302
7.300
7.299
7.294
7.291
7.288
7.283
7.277
7.273
7.254
7.253
7.200
7.191
7.183
6.741
6.718
6.700
6.695
Date:
16 Apr 2007
Document's Title:
NGB-1025HNMR.fid.mrc
Spectrum Title:
NGB-1025_12Jun2006
Frequency (MHz):
(f1) 399.738
Original Points Count:
(f1) 17959
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 12.000
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
CO 2Et
O
O
45
Number of Scans:
8
Acq. Date:
Jun 12 2006
2.37
5.0
3.00
1.63
8.66
1.95
1.93
9.97
10.0
ppm (t1)
0.0
S61
74.274
74.106
73.983
73.424
73.200
61.804
61.543
60.472
60.357
14 046
77.318
77.000
76.682
83.699
82.615
137.023
136.772
128.552
128.502
128.464
128.438
128.357
128.253
128.121
128.100
128.031
127.941
116.332
115.224
114.904
114.665
169.763
152.886
139.384
206.516
Date:
16 Apr 2007
Document's Title:
NGB-1025B-CNMR.fid.mrc
Spectrum Title:
NGB-1025-13C_12Jun2006
Frequency (MHz):
(f1) 100.525
Original Points Count:
(f1) 30135
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 1.1994
Spectral Width (ppm):
(f1) 249.945
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
CO 2Et
O
O
45
Number of Scans:
256
Acq. Date:
Jun 12 2006
200
150
100
50
0
ppm (t1)
S62
2.863
2.856
2.853
2.848
1.267
1.253
1.239
4.436
4.431
4.243
4.229
4.214
4.200
3.751
3.736
3.544
3.541
6.644
6.626
6.776
6.758
7.260
4.737
4.578
4.539
4.506
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
8
Acq. Date:
Wed Jun 07 06:34:57 PM
OMe
O
HN
46
CO2Et
OH
OH
4.29
1.24
1.19
3.00
1.12
5.0
3.65
5.94
2.37
3.47
10.0
ppm (t1)
Date:
16 Apr 2007
Document's Title:
ZHL-2230A-b4.mrc
0.0
S63
14.069
55.603
62.009
60.236
77.255
77.000
76.746
75.975
66.520
116.381
115.913
114.991
114.797
139.900
153.641
171.132
209.468
Date:
5 Mar 2007
Document's Title:
ZHL-3020-CNMR.mrc
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
297.16
Number of Scans:
1372
Acq. Date:
Sun Aug 27 05: 01:49 PM
OMe
O
HN
46
CO2Et
OH
200
ppm (t1)
OH
150
100
50
0
S64
1.679
1.562
1.558
1.535
1.528
1.384
1.376
1.359
245
227
1 220
1.914
1.907
1.898
1.890
1.878
1.875
1.863
1.989
2.559
2.550
2.541
2.532
2.513
2.505
3.731
3.044
3.036
3.027
3.016
3.008
2.999
4.185
4.167
4.149
4.132
4.295
6.678
6.758
7.260
Date:
23 Apr 2007
Document's Title:
ZHL-2199forpaper.mrc
Spectrum Title:
ZHL-2199-all_10May2006
Frequency (MHz):
(f1) 399.739
Original Points Count:
(f1) 23946
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
CO 2Et
54
Number of Scans:
8
Acq. Date:
May 10 2006
3.33
2.17
2.09
4.24
2.12
0.93
3.00
2.10
1.90
2.08
2.05
S65
8.0
ppm (t1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
27.141
24.205
14.136
29.883
28.996
43.855
55.675
54.326
77.317
77.000
76.682
61.266
60.644
115.166
114.815
140.923
152.666
172.533
214.165
Date:
6 Mar 2007
Document's Title:
ZHL-2199CNMR.mrc
Spectrum Title:
ZHL-2199CNMR_10May2006
Frequency (MHz):
(f1) 100.525
Original Points Count:
(f1) 30135
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 1.1994
Spectral Width (ppm):
(f1) 249.945
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
CO 2Et
54
Number of Scans:
512
Acq. Date:
May 10 2006
200
ppm (t1)
150
100
50
0
S66
3.287
4.118
3.283
3.282
3.279
3.278
3.277
3.275
3.272
3.270
3.268
3.265
3.263
3.260
3.259
3.257
3.255
3.253
3.252
3.250
3.249
3.247
3.244
3.242
3.240
3.239
3.237
3.236
3.233
3.232
3.230
3.229
3.228
3.226
3.224
3.223
3.222
3.221
3.220
3.218
3.217
3.216
3.214
3.210
3.209
3.208
3.206
3.205
3.203
3.201
3.200
177
176
2
967
029
174
070
171
170
168
065
063
061
1
593
155
426
3
048
422
146
416
142
136
135
127
003
118
013
30180
008
112
10
Date:
16 Apr 2007
Document's Title:
PROTON.fid
Spectrum Title:
ZHL-2205A-2_15May2006
Frequency (MHz):
(f1) 399.739
Original Points Count:
(f1) 23946
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
CO 2Et
55
Number of Scans:
8
Acq. Date:
May 15 2006
3.44
2.0
12.61
3.0
0.89
4.0
1.93
5.0
0.90
6.0
2.73
7.0
3.92
2.00
1.80
8.0
1.0
0.0
ppm (f1)
S67
14 200
25.231
24.825
23.810
27.952
55.656
51.570
44.121
30.740
61.591
61.111
77.318
77.000
76.683
115.959
114.702
140.795
153.069
173.359
217.205
2500
Date:
6 Mar 2007
Document's Title:
ZHL-2205A-CNMR.mrc
Spectrum Title:
ZHL-2205A-2_15May2006-18:06:38
2000
1500
OMe
O
HN
CO 2Et
55
1000
Frequency (MHz):
(f1) 100.525
Original Points Count:
(f1) 30135
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 1.1994
Spectral Width (ppm):
(f1) 249.945
Pul se Program:
Unknown
Temperature:
29
Number of Scans:
256
Acq. Date:
May 15 2006
500
0
200
ppm (t1)
150
100
50
0
S68
3.648
3.639
3.630
3.620
2.567
2.549
2.541
2.522
1.605
1.240
1.221
031
1 995
013
0
4.841
4.825
3.952
3.943
3.939
3.928
3.751
3.744
6.676
6.654
6.814
6.792
7.118
7.100
7.081
7.511
7.492
7.305
7.260
8.994
Date:
16 Apr 2007
Document's Title:
ZHL-3106B-1HNMR_01.fid.mrc
Spectrum Title:
Std proton
Frequency (MHz):
(f1) 399.735
Original Points Count:
(f1) 13103
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.0487
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
25
OMe
O
HN
H
N
Ph
56
O
Number of Scans:
8
Acq. Date:
Dec 11 2006
3.00
3.33
1.96
5.0
0.97
3.20
1.00
0.82
2.10
1.98
0.90
2.50
1.96
0.87
10.0
0.0
ppm (t1)
S69
7.399
14.769
35.950
46.548
55.709
77.318
77.000
76.682
63.124
115.120
115.025
119.802
124.466
137.246
128.951
141.299
153.201
170.635
215.877
Date:
16 Apr 2007
Document's Title:
ZHL-3106B-1CNMR_01.fid.mrc
Spectrum Title:
Std proton
Frequency (MHz):
(f1) 100.523
Original Points Count:
(f1) 31375
Actual Points Count:
(f1) 65536
Acquisition Time (sec):
(f1) 1.3005
Spectral Width (ppm):
(f1) 239.998
Pulse Program:
Unknown
Temperature:
25
OMe
O
HN
H
N
Ph
56
Number of Scans:
500
O
Acq. Date:
Dec 11 2006
200
150
100
50
0
ppm (t1)
S70
2.448
2.438
2.426
2.416
2.404
2.392
2.365
2.353
2.351
2.339
2.324
2.317
2.306
2.304
2.289
2.044
2.035
2.030
2.019
2.012
1.993
633
629
1
973
967
776
960
767
955
764
949
944
749
937
747
1 612
744
932
925
913
723
911
902
02
2.835
2.823
2.810
2.797
2.784
3.742
3.677
4.148
4.130
4.112
4.094
4.082
4.065
4.048
6.659
6.466
6.650
6.637
8.156
7.569
8.134
7.547
6.443
4.794
4.783
4.645
4.631
Date:
24 Aug 2006
Document's Title:
ZHL-2127C.mrc
Spectrum Title:
ZHL-2119C-H_25Feb2006
Frequency (MHz):
(f1) 399.739
Original Points Count:
(f1) 23946
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 3.7440
Spectral Width (ppm):
(f1) 16.000
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
57
NO 2
Number of Scans:
8
Acq. Date:
Feb 25 2006
4.02
3.54
2.17
1.06
5.0
3.00
0.32
1.08
0.07
2.06
2.15
2.03
2.01
10.0
ppm (t1)
0.0
S71
27.736
24.439
31.853
42.351
55.630
55.599
57.038
77.317
77.000
76.682
58.697
115.064
114.768
123.609
150.008
146.980
140.676
128.331
152.463
211.800
Date:
24 Aug 2006
Document's Title:
ZHL-2127C-Car.mrc
Spectrum Title:
ZHL-2127C-car_25Feb2006
Frequency (MHz):
(f 1) 100.525
Original Points Count:
(f 1) 30135
Actual Points Count:
(f 1) 32768
Acquisition Time (sec):
(f 1) 1.1994
Spectral Width (ppm):
(f 1) 249.945
Pulse Program:
Unknown
Temperature:
29
OMe
O
HN
57
NO 2
Number of Scans:
1000
Acq. Date:
Feb 25 2006
200
ppm (t1)
150
100
50
0
S72
4.365
4.878
4.866
6.608
6.590
6.945
6.938
6.912
6.905
6.902
6.895
6.719
6.701
7.260
7.157
7.147
3.701
2.837
2.827
2.817
2.807
2.796
2.465
2.453
2.446
2.437
2.427
2.377
2.366
2.358
2.347
2.331
2.320
1.987
1.980
1.976
1.970
1.959
1.951
1.941
1.899
1 855
757
752
1 737
31
Spectrum Title:
None
Frequency (MHz):
(f 1) 500.133
Original Points Count:
(f 1) 16384
Actual Points Count:
(f 1) 16384
Acquisition Time (sec):
(f 1) 2.7263
Spectral Width (ppm):
(f 1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
8
Acq. Date:
Thu Jul 13 12:02:17 AM
OMe
O
HN
S
58
7.13
1.09
1.05
1.04
3.00
5.0
0.85
1.03
2.03
2.06
1.01
1.05
0.99
10.0
ppm (f1)
Date:
15 Sep 2006
Document's Title:
1
0.0
S73
30.947
27.641
24.044
42.019
55.585
55.310
57.370
77.255
77.000
76.746
115.521
114.623
124.806
124.135
126.469
141.160
146.784
152.526
212.044
Date:
15 Sep 2006
Document's Title:
ZHL-2263-2-NMR.mrc
Spectrum Title:
None
Frequency (MHz):
(f 1) 125.770
Original Points Count:
(f 1) 16384
Actual Points Count:
(f 1) 32768
Acquisition Time (sec):
(f 1) 0.5210
Spectral Width (ppm):
(f 1) 250.031
Pulse Program:
ZGPG45
Temperature:
298.16
Number of Scans:
256
Acq. Date:
Thu Jul 13 12:17:55 AM
OMe
O
HN
S
200
ppm (f1)
150
58
100
50
0
S74
1.909
1.900
1.747
1.731
1.710
1.694
1.685
1
414
10428
661
013
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
297.16
Number of Scans:
8
Acq. Date:
Thu Aug 31 06:54:04 PM
NHBoc
O
ant i-59
9.00
3.33
2.97
1.95
5.0
0.91
0.92
0.90
0.89
0.94
1.02
10.0
ppm (t1)
2.403
2.393
2.375
2.367
2.358
2.344
2.334
2.323
2.307
2.296
2.101
2.095
2.080
2.032
2.023
2.019
2.012
3.042
3.029
3.021
4.926
4.913
5.623
5.619
6.154
6.147
7.265
7.260
6.282
6.278
6.275
6.272
O
Date:
16 Apr 2007
Document's Title:
ZHL-2280B-2.mrc
0.0
S75
200
150
31.432
28.306
27.830
24.522
77.255
77.000
76.746
79.565
53.388
49.686
42.414
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
297.16
Number of Scans:
161
Acq. Date :
Thu Aug 31 07:04:06 PM
NHBoc
O
ppm (t1)
105.745
110.327
141.184
155.661
154.249
211.947
O
Date:
1 Mar 2007
Document's Title:
ZHL-2280B-2CNMR.mrc
ant i-59
100
50
0
S76
1.781
1.663
1.657
1.639
597
482
475
017
10457
33
1.897
1.888
1.880
1.873
2.008
2.000
1.989
1.977
2.088
2.077
2.069
2.064
2.292
2.279
2.267
2.255
2.239
2.410
2.403
2.381
2.376
6.186
6.180
5.644
5.628
4.978
4.966
4.958
4.946
2.832
2.820
2.808
2.796
2.785
7.274
7.260
6.267
6.264
6.260
O
Spectrum Title:
None
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 16384
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
297.16
Number of Scans:
8
Acq. Date:
Fri Sep 01 07:04:21 PM
NHBoc
O
2.0
9.14
1.20
3.0
5.93
4.0
1.03
1.07
5.0
1.01
6.0
1.00
7.0
0.85
1.94
0.88
8.0
ppm (t1)
Date:
16 Apr 2007
Document's Title:
ZHL-2280Anew.mrc
1.0
0.0
S77
24.477
28.307
28.239
26.864
48.925
42.134
42.112
30.354
53.932
77.255
77.000
76.746
79.515
107.305
110.213
110.190
155.075
153.612
141.246
211.001
210.973
O
Spectrum Title:
None
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
297.16
Number of Scans:
157
Acq. Date:
Fri Sep 01 07:09:22 PM
NHBoc
O
200
ppm (t1)
150
Date:
1 Mar 2007
Document's Title:
ZHL-2280A- CNMR.mrc
100
50
0
S78
OMe
O
MeO
2.0
6.29
3.09
3.0
1.05
4.0
1.03
5.0
2.86
2.91
6.0
2.02
1.04
7.0
0.88
2.05
2.00
ppm (t1)
HN
CO2 Et
31
1.0
0.0
S79
-0.003
1.208
1.190
1.173
1.000
0.987
0.983
0.971
2.167
2.145
2.626
2.612
2.604
2.590
3.691
3.726
4.415
4.413
4.411
4.242
4.228
4.138
4.120
4.118
4.100
6.625
6.603
6.762
6.740
7.260
OMe
O
ppm (t1)
HN
MeO
CO2 Et
31
150
100
50
0
S80
20,284
20,230
14,119
27,722
54,447
51,662
55,644
57,558
61,132
77,318
77,000
76,682
115,163
114,758
140,832
152,745
173,594
173,128
3
3.0
2.0
3.10
3.04
3.42
4.0
1.06
5.0
0.98
6.0
3.01
7.0
0.99
2.02
2.00
2.42
ppm (t1)
4
CO2Et
O
N
30a
OMe
1.0
0.0
S81
1,078
1,061
1,276
1,258
1,240
1,151
1,135
2,177
2,160
2,143
2,140
2,124
3,141
3,135
3,121
3,114
4,195
4,189
3,781
4,268
4,256
4,250
4,239
6,871
6,866
6,854
6,849
7,263
7,258
7,247
7,241
3
ppm (t1)
4
CO2Et
O
N
30a
OMe
150
100
50
0
S82
20,056
19,948
14,104
28,239
62,337
61,716
55,482
55,027
77,318
77,204
77,000
76,682
114,356
117,739
131,066
156,249
165,121
170,258
3
30b
OMe
4.0
3.0
3.13
3.11
5.0
1.09
6.0
0.99
7.0
6,875
6,852
7,263
7,258
7,235
2.0
1.0
1,078
1,061
1,149
1,133
1,587
1,576
2,159
2,157
2,142
2,140
3,154
3,148
3,134
3,128
3,792
3,782
N
4,215
4,208
O
2.97
2.89
CO2Me
1.01
2.00
2.68
ppm (t1)
4
0.0
S83
3
ppm (t1)
4
CO2Me
O
N
30b
OMe
150
100
50
0
S84
20,066
19,913
28,270
55,495
54,857
52,718
62,369
77,318
77,204
77,000
76,682
114,417
117,711
131,017
156,295
165,049
170,786
O
N
2.0
1.0
0,000
1,217
1,200
0,940
0,924
1,565
1,300
1,282
1,264
2,151
2,125
3,779
4,282
4,273
4,264
4,255
4,554
4,539
7,262
7,238
7,215
6,865
6,842
3,295
3,280
3,268
3,253
3.06
3.0
3.57
4.44
4.0
1.13
5.0
3.08
6.0
2.07
7.0
0.99
8.0
2.05
2.00
ppm (t1)
PMP
1.10
CO2Et
0.0
S85
1.913
1.899
1.886
1.873
1.859
1.845
1.394
1.078
1.064
1.024
1 010
2.641
2.628
2.623
2.609
2.167
5.133
5.387
7.272
7.263
7.258
7.350
7.335
7.333
7.320
9.762
9.755
Date:
15 Oct 2007
Document's Title:
MestReC1
Spectrum Title:
O
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
298.16
Number of Scans:
16
Acq. Date:
Wed Sep 19 06:42:43 PM
NHBoc
H
anti-72
Acetone
3.36
3.25
9.95
1.16
5.0
1.11
0.99
5.86
1.00
10.0
ppm (t1)
0.0
S86
-0.029
18.872
28.285
21.313
62.961
53.048
77.255
77.000
76.746
79.796
127.504
126.542
128.738
140.849
155.043
206.059
Date:
10 Oct 2007
Document's Title:
ZHL-4095anti-CNMR.mrc
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-135 pulse, 5-2-05
O
Frequency (MHz):
(f1) 125.770
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 0.5210
Spectral Width (ppm):
(f1) 250.031
Pulse Program:
ZGPG45
Temperature:
299.16
Number of Scans:
626
Acq. Date:
Thu Sep 20 06:50:56 PM
NHBoc
H
anti-72
Acetone
200
150
100
50
0
ppm (t1)
S87
1.927
1.774
1.754
1.748
1.727
706
1
1 408
632
1.977
2.095
2.074
2.041
2.311
2.289
2.877
2.414
2.387
2.377
5.757
5.755
5.753
4.864
4.862
4.855
4.847
4.838
7.306
7.297
7.261
7.229
7.221
7.212
7.205
7.203
7.195
Date:
15 Oct 2007
Document's Title:
ZHL-4109-b7b8.mrc
Spectrum Title:
C-13-APT, BBO Probe, DRX-500, using deptq-13
O
Frequency (MHz):
(f1) 500.133
Original Points Count:
(f1) 16384
Actual Points Count:
(f1) 32768
Acquisition Time (sec):
(f1) 2.7263
Spectral Width (ppm):
(f1) 12.016
Pulse Program:
ZG30
Temperature:
299.16
Number of Scans:
8
Acq. Date:
Mon Oct 01 05:42:27 PM
NHBoc
anti -73
9.65
3.44
3.57
1.19
1.15
1.10
1.08
1.00
S88
10.0
ppm (t1)
5.0
0.0
28.320
28.053
24.213
56.144
55.200
42.397
32.360
77.254
77.000
76.746
79.397
126.919
126.587
128.337
128.285
128.205
141.646
155.674
212.744
O
Date:
10 Oct 2007
Document's Title:
ZHL-2269A-CNMR.mrc
Spectrum Title:
None
Frequency (MHz):
(f 1) 125.770
Original Points Count:
(f 1) 16384
Actual Points Count:
(f 1) 32768
Acquisition Time (sec):
(f 1) 0.5210
Spectral Width (ppm):
(f 1) 250.031
Pulse Program:
ZGPG45
Temperature:
297.16
Number of Scans:
256
Acq. Date:
Fri Sep 01 04:47:58 PM
NHBoc
anti -73
200
150
100
50
0
ppm (t1)
S89