Evolution of pyrrolidine-type asymmetric organocatalysts by "click" chemistry

Article abstract of DOI:10.1021/jo061657r

(Chemical Equation Presented) Click chemistry has been employed to construct a library of the pyrrolidine-type asymmetric organocatalysts. The clicked organocatalysts were evaluated in asymmetric Michael addition of ketones to nitroolefins, showing good c

Full text of DOI:10.1021/jo061657r

SCHEME 1. Clicking Strategy for Asymmetric
Organocatalysts
Evolution of Pyrrolidine-Type Asymmetric
Organocatalysts by “Click” Chemistry
Sanzhong Luo,*,† Hui Xu,† Xueling Mi,‡ Jiuyuan Li,†
Xiaoxi Zheng,† and Jin-Pei Cheng*,†,‡
Beijing National Laboratory for Molecular Sciences, Center for
Chemical Biology, Institute of Chemistry, Chinese Academy of
Science, Beijing, 100080 China, and Department of Chemistry
and State Key Laboratory of Elemento-organic Chemistry,
Nankai UniVersity, Tianjin, 300071 China
luosz@iccas.ac.cn; chengjp@mail.most.goV.cn
ReceiVed August 9, 2006
therefore have to be prepared by multistep synthesis. In this
context, a modular and more efficient approach for constructing
a chiral pyrrolidine library with structural diversity to speed up
the catalyst finding process is undoubtedly most desirable.6
Because of its modularity, fidelity, and wide scopes, the so-
called “click” chemistry has recently emerged as a powerful
strategy for rapid assembly of organic molecules with diverse
functionality.7 Currently, click chemistry, represented by the 1,3-
dipolar cycloaddition between azides and alkynes,7b has been
applied in drug discovery for generating a drug-like library via
the diversity-oriented approach,8 in biological study as ligation
chemistry, in material science, and so on.9 In this work, we
explored the utility of click chemistry as a modular approach
for the construction of an organocatalyst-like library on the basis
of the “privileged” chiral pyrrolidine skeletons (Scheme 1).
Asymmetric Michael addition was selected as the targeted
model reaction for the clicked pyrrolidine library. Michael
reaction is one of the basic C-C bond-forming reactions, and
its versatile utility in organic synthesis has stimulated tremen-
dous research interests in the development of asymmetric
Click chemistry has been employed to construct a library of
the pyrrolidine-type asymmetric organocatalysts. The clicked
organocatalysts were evaluated in asymmetric Michael
addition of ketones to nitroolefins, showing good catalytic
activity and stereoselectivity (up to 100% yield, syn:anti )
99:1, 96% ee).
Ever since Gilbert Stork et al.’s seminal work in 1954,1
enamine has become one of the most useful synthons in many
organic transformations, and recently the enamine-based mech-
anism has also found many successful applications in a number
of organocatalytic reactions.2 Chiral pyrrolidine is now regarded
as one of the best asymmetric organocatalysts of the type.3 In
2000, List and co-workers reported that L-proline could catalyze
an enantioselective direct Aldol reaction.4 Later, many applica-
tions of the L-proline-catalyzed asymmetric organic synthesis
were soon accumulated.2 In some of the reactions, the natural
catalysts such as L-proline failed to demonstrate good enantio-
selectivity and worked normally only for limited substrates.5
Consequently, considerable efforts have been directed toward
the development of a new type of asymmetric organocatalysts.
Now, a sound improvement has already been achieved with
chiral pyrrolidine-based catalytic systems. However, these
pyrrolidine-type organocatalysts are generally more complex and
Michael catalysts, especially metal-free organocatalysts.10
A
variety of asymmetric organocatalysts have been explored for
the Michael addition of ketones or aldehydes to nitroolefins, of
which a few chiral pyrrolidinyl derivatives show high enantio-
selectivity.11 In general, the pyrrolidine-catalyzed Michael
addition occurs via an enamine intermediate, wherein efficient
space shielding would be a key factor for stereo-control as
suggested by literature12 and our recent studies13 (Scheme 1).
On the basis of these observations, we envisioned that elabora-
tion of chiral azido pyrrolidines (like that in pyrrolidine CP-1)
into their triazole derivatives by click chemistry would provide
a viable strategy for the discovery of better catalysts because
the polar and planar triazole ring should be more efficient for
space shielding than the small azido group (Scheme 1).
(6) (a) Fonseca, M. H.; List, B. Curr. Opin. Chem. Biol. 2004, 8, 319-
326. (b) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrehedron 2002, 58, 8167-
8177. (c) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5, 4369-
4372.
(7) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004-2021. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V.
V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
(8) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128-
1137.
(9) For a review, see: Hawker, C. J.; Wooley, K. L. Science 2005, 309,
1200-1205.
(10) For a review, see: Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J.
Org. Chem. 2002, 1877-1894.
† Chinese Academy of Sciences.
‡ Nankai University.
(1) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76,
2029.
(2) For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138-5175. (b) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005.
(3) List, B. Chem. Commun. 2006, 819-824.
(4) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395-2396.
(5) (a) List, B. Tetrahedron 2002, 58, 5573-5590. (b) Notz, W.; Tanaka,
F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580-591.
10.1021/jo061657r CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/04/2006
9244
J. Org. Chem. 2006, 71, 9244-9247

TABLE 1. Screening of Clicked Catalysts
entry
catalyst (mol %)
time (h)
yielda (%)
drb
eec (%)
entry
catalyst (mol %)
time (h)
yielda (%)
drb
eec (%)
Initial Catalyst Discovery
12
13
CP-10
CP-11
18
18
74
92
9:1
19:1
33
40
1d
2
L-proline
L-prolinol
CP-1
24
24
24
18
94
23
34
99
>20:1
20:1
20:1
23
78
80
92
3
Clicked Library II
4
CP-2
49:1
14
15
16
17
18
19
20
21
22
CP-12
18
20
18
18
18
18
18
18
24
99
56
97
95
99
99
90
87
90
49:1
49:1
19:1
49:1
49:1
49:1
49:1
49:1
49:1
91
91
90
90
89
92
90
91
87
Clicked Library I
CP-13
CP-14
CP-15
CP-16
CP-17
CP-18
CP-19
CP-20
5
6
7
8
9
CP-3
CP-4
CP-5
CP-6
CP-7
CP-8
CP-9
24
36
70
24
18
18
24
25
7
10:1
n.d.e
n.d.
17:1
24:1
19:1
49:1
87
n.d.
n.d.
79
93
92
trace
44
95
51
59
10
11
94
1
a Isolated yields. b Syn/anti as determined by H NMR. c Determined by HPLC (chiral pak AD-H column). d 15 mol % of L-proline was employed, see
ref 14a. e Abbreviation n.d.) not determined.
Previously, L-proline has been shown to be a viable catalyst
for Michael addition of ketones to nitroolefins but with low
enantioselectivity (Table 1, entry 1).14 We found that simple
proline derivatives such as L-prolinol and azido-pyrrolidine CP-1
were able to promote the same reaction with improved enan-
tioselectivity, albeit in low yields (Table 1, entries 2 and 3).
On the basis of these observations, we thought to further
improve the catalyst by click chemistry based on the clicking
hypothesis (Scheme 1). The pyrrolidine-triazole conjugate
CP-2 was easily accessed by reaction of azido-pyrrolidine CP-1
or Boc-protected CP-1 with phenylacetylene in high yields
(Scheme 2).
SCHEME 2. Synthesis of CP-2 by Click Reaction
49:1, 92% ee). The Michael adduct obtained has the (1′S,2R)
absolute stereochemistry by optical comparison with published
results.12,13 Therefore, the stereoselectivity can be explained by
the transition state shown in Scheme 1, which is consistent with
our initial hypothesis (Scheme 1). Next, libraries of the clicked
pyrrolidines were successively constructed using the clicking
protocol (see Supporting Information for details)15 from the
corresponding azido cores in order to identify more potent
catalysts and to better understand the structure-activity relation-
ships (Figure 1).
First, we explored clicked catalysts with different chiral
skeletons (Clicked Library I). As shown in Table 1, the
performance of clicked catalysts vary dramatically with different
skeletons where several features are evident: (1) The thiozo-
lidine-type catalysts (CP-3-5) are ineffective in catalyzing the
reaction (Table 1, entries 5-7). The reason for the failure of
this type of catalysts is unclear presently, but warrants further
theoretical study. (2) 4-cis-Substituted pyrrolidines (CP-6-9,
Table 1, entries 8-11) showed better enantioselectivity than
the 4-trans-substituted catalysts (CP-10 and CP-11, Table 1,
entries 12 and 13). The clicked catalyst CP-10 with a bulky
4-trans-BnO group gave lower activity and enantioselectivity
than its analogue CP-11 (bearing a less bulky 4-OH group),
suggesting the space-shielding effect is working in the reaction.
To our delight, CP-2 demonstrated high activity (18 h, 99%
yield) and high stereoselectivity (Table 1, entry 4, syn/anti )
(11) For examples, see: (a) Betancort, J. M.; Barbas, C. F., III. Org.
Lett. 2001, 3, 3737-3740. (b) Mase, N.; Thayumanavan, R.; Tanaka, F.;
Barbas, C. F., III. Org. Lett. 2004, 6, 2527. (c) Cobb, A. J. A.; Longbottom,
D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808-1809. (d)
Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V.
Org. Biomol. Chem. 2005, 3, 84-96. (e) Alexakis, A.; Andrey, O. Org.
Lett. 2002, 4, 3611-3614. (f) Andrey, O.; Alexakis, A.; Bernardinelli, G.
Org. Lett. 2003, 5, 2559-2561. (g) Mosse, S.; Laars, M.; Kriis, K.; Kanger,
T.; Alexakis, A. Org. Lett. 2006, 8, 2559-2562. (h) Wang, W.; Wang, J.;
Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (i) Wang, J.; Li, H.; Lou,
B.; Zu, L.; Guo, H.; Wang, W. Chem.sEur. J. 2006, 12, 4321-4332. (j)
Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077-3079. (k)
Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901-
2904. (l) Xu, Y.; Cordova, A. Chem. Commun. 2006, 1451-1453. (m) Xu,
Y.; Zou, W.; Sunden, H.; Ibrahem, I.; Cordova, A. AdV. Synth. Catal. 2006,
348, 418-424. (n) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451-
1453. (o) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170-
7171. (p) Zhu, M.-L.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z.
Tetrahedron: Asymmetry 2006, 17, 491-493. (q) Mase, N.; Watanabe, K.;
Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 128, 4966-4967. (r) Terakado, D.; Takano, M.; Oriyama, T. Chem.
Lett. 2005, 34, 962-963. (s) Enders, D.; Huttl, M. R. M.; Grondal, C.;
Raabe, G. Nature 2006, 441, 861-863.
(12) (a) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem.
Soc. 2004, 126, 9558-9559. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji,
M. Angew. Chem., Int. Ed. 2005, 44, 4212-4215. (c) Andrey, O.; Alexakis,
A.; Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147-
1168. (d) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005, 611-
614. (e) Betancort, J. M.; Sakthivel, K.; Thayumanava, R.; Tanaka, F.;
Barbas, C. F., III. Synthesis 2004, 1509-1521.
(13) (a) Luo, S. Z.; Mi, X. L.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P.
Angew. Chem., Int. Ed. 2006, 45, 3093-3097. (b) Luo, S. Z.; Mi, X. L.;
Liu, S.; Xu, H.; Cheng, J.-P. Chem. Commun. 2006, 3687.
(15) For “click” reaction, that is, 1,3-dipolar cycloaddition between azides
and alkynes with 1,4-regioselectivity, see ref 7b and (a) Tornoe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. For 1,5-
regioselectivity, see (b) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.;
Williams, I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc.
2005, 127, 15998-15999. (c) Krasinski, A.; Fokin, V. V.; Sharpless, K. B.
Org. Lett. 2004, 6, 1237.
(14) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423-
2425. (b) Enders, D.; Seki, A. Synlett 2002, 26.
J. Org. Chem, Vol. 71, No. 24, 2006 9245

FIGURE 1. Library of clicked organocatalysts.
TABLE 2. Substrate Scope of the Clicked Catalysts
(3) And again, the clicked catalysts were found to exhibit
superior performance to their azido precursors (CP-7-9 vs CP-
6, Table 1, entries 9-11 vs entry 8), validating our clicking
strategy.
With the identified chiral pyrrolidinyl core, we next examined
the substitute effect of the triazole rings. The Clicked Library
II with variations on triazole rings were readily constructed by
click reactions between CP-1 and a variety of alkynes (Table
1). As revealed in Table 1, there is only a modest influence of
the substitute patterns of triazole rings on the reaction (Table
1, entries 14-22). Most of the clicked catalysts demonstrated
a similar performance to CP-2, but none of them were found
to exceed the level of CP-2 (9 representative catalysts out of
30 were shown in Figure 1). For example, clicked catalysts CP-
12-20 with varied substituents on the triazole rings gave
comparable stereoselectivities (syn/anti ) 19:1-49:1, 87%-
92% ee) in the reactions (Table 1, entries 14-22). Both the
position (CP-2 vs CP-19, CP-13 vs CP-20) and the nature of
the substituents (CP-12-18) were shown to have little impact
on the stereoselectivities. These results suggest that the sub-
stituents on the triazole rings might be oriented too far from
the enamine intermediate to affect stereocontrol in the reaction.
Overall, several clicked catalysts such as CP-2, CP-7, and CP-
17 gave the best outcomes in terms of both the activity and the
selectivity. CP-2 and CP-7 were selected for further experiments
since they were easily accessible.
entry
Ar
catalyst time (h) yielda (%) drb eec (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
CP-2
CP-7
CP-2
CP-7
CP-2
CP-7
CP-2
CP-2
CP-7
CP-2
CP-2
CP-2
18
17
18
18
16
19
16
22
38
24
24
22
99
95
93
>99
98
97
99
99
95
49:1
24:1
49:1
99:1
49:1
49:1
99:1
49:1
49:1
49:1
99:1
99:1
92
93
93
94
95
96
94
93
90
94
93
93
4-ClPh
4-ClPh
2-ClPh
2-ClPh
2-BrPh
4-MePh
4-MeOPh
Piperal
2,4-(MeO)2Ph
2-Naphth
10
11
12
98
93
99
a Isolated yields. b Syn/anti as determined by 1H NMR. c Determined by
HPLC (chiral pak AD-H column).
SCHEME 3. CP-2 Catalyzed Michael Addition to
Nitrostyrene
With CP-2 and CP-7 as the selected catalysts, the scope of
the Michael reaction was briefly explored (Table 2). In general,
the reaction worked quite well with cyclohexanone to give the
desired Michael adducts in high yields and excellent diaselec-
tivity and enantioselectivity. Both electron-rich and electron-
deficient nitrostyrenes were excellent Michael acceptors for
cyclohexanone. A value of 10 mol % of the clicked catalyst
was sufficient to promote the reactions, giving the desired
Michael adducts in nearly quantitative yields. It was found that
catalyst CP-7 and CP-2 worked equally well for the cases
examined (Table 2, entries 1-6). The reactions of other Michael
donors such as cyclopentanone, acetone, and iso-valeraldehyde
were also attempted with CP-2 (20 mol %) as the catalyst
(Scheme 3). The reactions gave the desired Michael adducts in
high yields but low enantioselectivities. The absolute configura-
tions of the Michael adducts obtained were determined to be
(1′S,2R) by comparison with the known products.12,13 Therefore,
the transition state shown in Scheme 1 should be applicable to
all of these cases except to the reaction of iso-valeraldehyde.16
9246 J. Org. Chem., Vol. 71, No. 24, 2006

SCHEME 4. Gram-Scale Synthesis Catalyzed by CP-2
[R]Drt +41° (c 1.0, CH3OH); 1H NMR (300 MHz, CDCl3) δ 1.35-
1.52 (1H, m), 1.58-1.83 (3H, m), 1.85-1.99 (1H, m), 2.89 (2H,
t, J ) 6.6 Hz), 3.51-3.64 (1H, m), 4.11-4.21 (1H, dd, J ) 7.9
Hz, 7.7 Hz, 13.8 Hz), 4.35-4.44 (1H, dd, J ) 4.5 Hz, 4.3 Hz,
13.4 Hz), 7.21-7.30 (1H, t, J ) 7.5 Hz), 7.35 (2H, t, J ) 7.4 Hz),
7.77 (2H, t, J ) 7.3), 7.86 (1H, s); 13C NMR (CDCl3, 75 MHz) δ
25.5, 29.1, 46.6, 55.5, 58.0, 120.5, 125.7, 128.0, 128.8, 130.7, 147.5;
HRMS for C13H17N4+ (M + 1+) calcd, 229.1448; found, 229.1446.
Method B. To a solution of Boc-protected CP-1 (452 mg, 2
mmol) in CH2Cl2 (5 mL) was added dropwise TFA (5 mL) at 0
°C. The mixture was warmed to room temperature and stirred
overnight. After removal of the organic solvents under vacuo, the
residue was dissolved in CH2Cl2 (5 mL) and then treated with a
saturated NaHCO3 solution (15 mL) for 1 h at rt. The aqueous layer
was extracted with CH2Cl2 three times (5 mL × 3), and the
combined extracts were dried over anhydrous Na2SO4. Concentra-
tion in vacuo after filtration gave CP-1 as yellow oil (438 mg, 97%).
[R]Drt -32° (c 0.75, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.35-
1.50 (1H, m), 1.66-2.00 (3H, m), 2.44-2.61 (1H, m), 2.86-3.04
(2H, m), 3.17-3.39 (3H, m); 13C NMR (CDCl3, 75 MHz) δ 25.5,
Finally, the practical application of clicked asymmetric
organocatalyst was demonstrated in a gram-scale synthesis using
only 5 mol % of CP-2 as the catalyst (Scheme 4). The reaction
afforded the chiral Michael product in a nearly quantitative yield
and high stereoselectivity.
In conclusion, we have developed a clicking strategy for the
discovery of new asymmetric organocatalysts. The modular and
versatile nature of the click chemistry allows for a rapid
synthesis of a library of organocatalysts that should largely
facilitate catalyst discovery and structure-activity study. Using
the clicking strategy, we proved pyrrolidine-triazole conjugates
to be a modular skeleton for the asymmetric Michael addition
of cyclohexanone to nitrostyrenes. CP-2 and CP-7 were found
to catalyze the reaction with high reactivity (up to 100% yield)
and excellent stereoselectivity (syn/anti up to 99:1, ee up to
96%). Works are currently underway to further optimize the
current clicked asymmetric organocatalysts and to apply the
clicking strategy to other asymmetric organocatalytic processes.
29.0, 46.6, 56.2, 57.7; HRMS for C5H11N4 (M + 1+) calcd,
+
127.0984; found, 127.0982.
To a solution of CP-1 (438 mg) and phenylacetylene (245 mg,
2.4 mmol) in a mixed solvent of toluene (8 mL) and tert-butanol
(2 mL) were added CuI (20 mg, 10 mmol) and DIPEA (500 µL, 6
mmol). The reaction mixture was stirred at room temperature
overnight. After removal of the solvents, the resulting residue was
purified by flash chromatography on silica gel to give CP-2 as a
yellow solid (365 mg, 83%).
Procedure for the Michael Reaction. Nitrostyrene (37 mg, 0.25
mmol) and CP-2 (12 mg, 10 mol %) were mixed with cyclohex-
anone (0.5 mL, 5 mmol) in the presence of TFA (0.00625 mmol)
at room temperature (bulk solution of TFA in cyclohexanone was
freshly prepared and employed in the reaction, 20 µL of TFA in
50 mL of cyclohexanone). The homogeneous reaction mixture was
stirred at room temperature for 18 h. The reaction mixture was
directly loaded onto a silica gel column to afford the Michael adduct
Experimental Section
Representative Procedure for the Click Reaction (Scheme 2):
Method A. To a solution of Boc-protected CP-1 (226 mg, 1 mmol)
in toluene and tert-butanol (4 mL and 1 mL, respectively) were
added phenylacetylene (122 mg, 1.2 mmol), CuI (10 mg, 0.05
mmol), and N,N′-diisopropylethylamine (DIPEA) (170 µL, 2 mmol).
The reaction mixture was stirred at rt overnight. After removal of
the solvent under vacuo, the residue was purified by flash
chromatography on silica gel to afford a Boc-protected product as
a white solid (314 mg, yield of 96%). 1H NMR (300 MHz,
CDCl3): δ 1.37-1.65 (10H, m), 1.67-1.83 (1H, m), 1.89-2.07
(2H, m), 3.08-3.50 (2H, m), 4.15 (1H, s), 4.37-4.79 (2H, m),
7.29-7.38 (1H, m), 7.38-7.48 (2H, m), 7.62-7.90 (3H, m). The
clicked product was deprotected in 5 M HCl in ethanol to give the
hydrogen chloride salts and was subsequently dissolved in CH2Cl2
(5 mL) and then treated with a saturated NaHCO3 solution (15 mL).
This mixture was stirred for 1 h. The aqueous layer was extracted
with CH2Cl2 (5 mL × 3). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo after filtration
to give essentially pure CP-2 as pale yellow solid (301 mg, 96%).
rt
1 (61 mg, 99%) as a white solid:11-13 [R]D -15.2° (c 0.5, CH3-
OH), syn/anti ) 49:1 (by 1H NMR), 92% ee (by HPLC on a chiral
phase chiralpak AD-H column, λ ) 254 nm, iPrOH/hexane 10:90,
20 °C, 0.5 mL min-1; tR ) 22.7 min (minor), 29.4 min (major)).
Acknowledgment. This work was supported by the Natural
Science Foundation of China (NSFC 20452001, 20421202, and
20542007), the Ministry of Science and Technology (MoST),
and the Institute of Chemistry, Chinese Academy of Sciences
(ICCAS). We thank Prof. Mei-Xiang Wang and Prof. Dong
Wang for HPLC analysis.
Supporting Information Available: Synthesis of CP-1-20,
general experimental procedures, and NMR spectra for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
(16) The Michael adduct of iso-valeraldehyde has (1′R,2S) absolute
configuration, and an anti-enamine intermediate would be formed in the
reaction.
JO061657R
J. Org. Chem, Vol. 71, No. 24, 2006 9247