An unexpected inversion of enantioselectivity in the proline catalyzed intramolecular Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tetlet.2005.10.072

A highly enantioselective proline catalyzed intramolecular Baylis-Hillman reaction of hept-2-enedial is reported. Addition of imidazole to the mixture results in an unusual inversion of enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2005.10.072

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8899–8903
An unexpected inversion of enantioselectivity in the
proline catalyzed intramolecular Baylis–Hillman reaction
Shang-Hung Chen,a Bor-Cherng Hong,a,* Cheng-Feng Sua and Sepehr Sarsharb
aDepartment of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 621, Taiwan, ROC
bAuspex Pharmaceuticals, Inc. 1261 Liberty Way, Suite C, Vista, CA 92081-8356, USA
Received 27 June 2005; revised 17 October 2005; accepted 18 October 2005
Available online 4 November 2005
Abstract—A highly enantioselective proline catalyzed intramolecular Baylis–Hillman reaction of hept-2-enedial is reported. Addi-
tion of imidazole to the mixture results in an unusual inversion of enantioselectivity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The recent advent of enantioselective organocatalysis
has opened new doors in asymmetric chemistry.1 These
processes eliminate the need to carry out reactions under
an inert atmosphere and do not require the use of anhy-
drous solvents or low temperatures. In certain instances,
organocatalysis provides results that heretofore could
not be achieved with the use of inorganic metals. Organo-
catalysts such as proline,2 imidazolidinone3 and their
derivatives have found wide applications in asymmetric
Mannich,4 Michael,5 aldol,6 and Diels–Alder reactions,7
as well as a-amination,8 a-alkylations,9 and a-selenenyl-
ation of aldehydes.10
yls and aldehydes. Applications to total synthesis12 and
mechanistic studies13 of this reaction are also well docu-
mented. Surprisingly, relatively few examples of the
intramolecular B–H reaction have been reported so
far.14 Certain studies15 revealed that the use of dual cat-
alyst systems can increase the enantioselectivity of the
asymmetric intermolecular B–H reaction.16 Yet, to the
best of our knowledge, there have been no reports of
an enantioselective intramolecular B–H reaction. Herein,
we disclose our recent attempts at achieving the first
enantioselective intramolecular B–H reaction.
Hept-2-enedial (4a) was synthesized from tetrahydro-
pyran-2-one in four steps and 53% total yield (Scheme
1). Reduction of tetrahydropyran-2-one with DIBAL-
H afforded pyranol 1 in 91% yield. Wittig reaction of
The Baylis–Hillmann (B–H) reaction11 allows the direct
preparation of a-methylene-b-hydroxyl carbonyl com-
pounds from the corresponding a,b-unsaturated carbon-
OH
O
DIBAL-H
Ph3P=CHCO2Et
88% yield
DIBAL-H, CH2Cl2
HO
HO
OH
O
O
CO2Et
91% yield
92% yield
3
2
1
PCC, CH2Cl2
72% yield
acrolein,
Grubbs cat.
CH2Cl2
O
O
H
OHC
n
n
n=1, 2, 0
H
4a. n=1; 55% yield
4b. n=2; 51% yield
4c. n=0; 47% yield
Scheme 1. Synthesis of dialdehydes 4a–c.
Keywords: Baylis–Hillman; Proline; Intramolecular; Inversion.
*
Corresponding author. Tel.: +886 5 2428174; fax: +886 5 2721040; e-mail: chebch@ccu.edu.tw
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.072

8900
S.-H. Chen et al. / Tetrahedron Letters 46 (2005) 8899–8903
1 with Ph3P@CHCO2Et in CH2Cl2 afforded ester 2 (88%
yield), which was reduced with DIBAL-H and oxidized
with PCC to give dialdehyde 4a in 92% and 72% yield,
respectively. Alternatively, 4a–c can be prepared by
cross-metathesis of the corresponding olefinic aldehydes
and acrolein in the presence of GrubbsÕ catalyst. The
B–H reaction of 4a with L-(S)-proline was examined
in various solvents at ambient temperature (Table 1,
entries 1–11). Most reactions gave rise to the corre-
sponding (S)-6-hydroxy-cyclohex-1-enecarbaldehyde (5)
albeit with variable yield and enantioselectivities. Reac-
tions in DMF and CH3CN gave the highest yields,
enantioselectivities and reaction rates. Reactions in non-
polar solvents such as toluene were slower, and gave
lower yield and ee values. No reaction took place in
Et2O, THF, or MeOH after two days at ambient tem-
perature. Reaction with D-(R)-proline in DMF at
15 ꢁC afforded (R)-5 (entry 12). When the temperature
increased to 70 ꢁC, the reaction went to completion in
1 h and the ee value of the product increased from
45% to 60% (entries 11 and 13).
Recent reports have shown that the use of a Lewis
base such as imidazole, quinuclidine, DABCO, or Ph3P
facilitate the B–H reaction.17 In our hands, addition of
0.1 equiv of imidazole to the reaction of 4a and L-proline
(0.1 equiv) resulted in an increased reaction rate and a
higher yield of 5 at ambient temperature (entries 10, 11,
Table 1. Baylis–Hillman reaction of 4a–c
OH
O
CH2CHO
CO2Et
O
O
OH
OHC
H
R
N
n
H
H
H
n
6. R = CO2Et
7. R = CH2OH
4a. n = 1
4b. n = 2
4c. n = 0
9
8
5. n = 1
10. n = 0
Entry Compound, Catalyst (equiv) Additive (equiv) T (ꢁC) Solvent
Time (h) Product Yielda (%) eeb (%) Conf.c
1
2
3
4
5
6
7
8
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, D-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (0.1)
4a, L-Pro (1)
4a, D-Pro (0.1)
4a, D-Pro (0.1)
4a, D-Pro (1)
4a, L-Pro (1)
4a
25
25
25
25
25
25
25
25
25
25
25
15
70
25
25
0
CH2Cl2
Toluene
CHCl3
Et2O48
THF
MeOH
Dioxane
Dioxane–H2O48
DMSO6
CH3CN
DMF
8
96
9
5
47
31
41
ꢀ0d
ꢀ0d
ꢀ0d
5e
68
54
67
73
75
69
79
71
73
72
76
77
10
5
13
0
0
0
N.A
30
7
15
45
41
60
24
59
80
93
77
96
98
82
0
0
0
4
5
N.A
31
48
43
54
24
S
S
S
5
5
5
48
48
6
5
5
5
5
S
S
S
S
R
S
R
R
R
R
S
S
S
R
9
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
24
5
5
1
4
6
14
7
5
15
8
72
48
48
48
24
24
3
5
3
2
3
5
5
DMF
DMF
DMF
5
5
Imid. (0.1)
Imid. (0.1)
Imid. (0.1)
Imid. (1)
Imid. (0.1)
Imid. (0.1)
Imid. (1)
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
5
5
0
15
0
5
5
5
0
5
74
68
Imid. (1)
Imid. (0.1)
ꢁ30
25
25
25
25
25
25
25
25
0
5
5
ꢀ0d
ꢀ0e
ꢀ0e
20e
23e
ꢀ0e
20e
65g
47g
62g
46g
4a, 6 (0.1)
4a, 7 (0.1)
4a, 7 (0.1)
4a, 7 (0.1)
4b, L-Pro (0.1)
4b, L-Pro (0.1)
4c, L-Pro (0.1)
4c, L-Pro (0.1)
4c, D-Pro (0.1)
4c, D-Pro (0.1)
5
5
HOAc (0.1)
HFIP (0.1)
Imid. (0.1)
5
S
S
5
9
9
antif
S
10
10
10
10
Imid. (0.1)
Imid. (0.1)
CH3CN
DMF
CH3CN
S
25
0
R
2
R
a Isolated yield.
b Enantiomeric excesses (ee) were measured by GC–MS (Shimadzu QP 5000, chiral capillary column, gamma-cyclodextrin trifluoroacetyl, Astec Type
G-TA, size 30 m · 0.25 mm, flow rate 24 mL/min, temperature range: 60–120 ꢁC, gradient: 3 ꢁC/min).
c Absolute configuration of the major isomer assigned by comparison of [a]D values with the literature.18
d No reaction.
e Complex mixture of by-products.
f anti:syn > 99.5:1.
g 4c was completely consumed.

S.-H. Chen et al. / Tetrahedron Letters 46 (2005) 8899–8903
8901
14, and 15). Surprisingly, we found that in the presence of
imidazole, the enantioselectivity of the reaction was com-
pletely reversed.19 This selectivity is highly sensitive to the
nature of the solvent and temperature. We found that the
reaction in the presence of L-proline and imidazole was
more selective in CH3CN than in DMF (entries 14 and
15). However, this was reversed in the absence of imidaz-
ole (entries 10 and 11). This unprecedented and striking
inversion of selectivity is most likely due to the formation
of a new reactive intermediate (Schemes 2 and 3).
O
O
4a
H
H
(S)
CO2H
OH
(R)
H
H
N
H
CHO
O
O
H
N
OH
CO2
(S)
H
CO2H
O
OH
(S)
N
CHO
H
H
OH
H
5
O
N
H2O
CO2H
H
H
H
H
H
H
H
H
H
N
O
N
N
N
O
O
OH
H
H
O
OH
H
H
O
H
O
O
H
O
O
H
H
O
A
B
Scheme 2. Proposed mechanism for the L-proline-catalyzed formation of (S)-5.
HN
H
N
O
(S)
N
O
N
si face
CO2H
N
N
H
O
H
O
N
O
O
CO2H
H
H
H
H
H
H
re face
4a
N
HN
(S)
O
N
N
CO2H
CO2H
H
H
+
N
N
N
H
H
HN
H2O
H
H
H
H
OH
NH
N
H
O
H
(s)
H
N
N
(R)
H
CHO
N
H
O
OH
N
OH
O
5
H
H
O
O
O
B'
H
H
OH
H
O
H
(S)
(s)
N
CHO
N
H2O
OH
H
OH
O
H
O
H
O
O
N
H
O
5
N
H
H
H
N
HN
A'
N
CO2H
+
N
N
H
H
Scheme 3. Proposed mechanism for the L-proline-imidazole co-catalyzed formation of (R)-5.

8902
S.-H. Chen et al. / Tetrahedron Letters 46 (2005) 8899–8903
Lowering the reaction temperature drastically increased
the selectivity (entries 15–21). In fact, addition of D-pro-
line and imidazole at 0 ꢁC gave (S)-5 in 98% ee (entry
20). However, lowering the temperature to ꢁ30 ꢁC
caused a slight loss of selectivity (entry 21). This is most
likely due to the low solubility of proline in CH3CN at
this temperature.
Financial support from the National Science Council
is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2005.
10.072.
Enal 4a is most likely activated by L-proline to give the
corresponding iminium ion, which isomerizes to afford
the enamine intermediate (Scheme 2). The enamine–
aldol reaction proceeds preferentially through a Zimmer-
man–Traxler transition state (A), instead of transition
state (B), to afford (S)-5 and to regenerate the proline
catalyst. The alternative transition state (B) is higher in
energy and less favorable.20
References and notes
1. For reviews, see: (a) Rouhi, A. M. Chem. Eng. News 2004,
41; (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138; (c) Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719; (d) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis: From Biomimetic Concepts to Applica-
tions in Asymmetric Synthesis; Wiley: New York, 2005.
2. (a) For the recent reviews, see: (i) List, B. Tetrahedron
2002, 58, 5573; (ii) Notz, W.; Tanaka, F.; Barbas, C. F.
Acc. Chem. Res. 2004, 37, 580; (b) Mans, D. M.; Pearson,
W. H. Org. Lett. 2004, 6, 3305; (c) Thayumanavan, R.;
Tanaka, F.; Barbas, C. F. Org. Lett. 2004, 6, 3541; (d) For
a two-step proline catalyzed synthesis of carbohydrates,
see: (i) Northrup, A. B.; Mangion, I. K.; Hettche, F. H.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43,
2152; (ii) Northrup, A. B.; MacMillan, D. W. C. Science
2004, 305, 1752.
Addition of imidazole facilitates the reaction and
reverses the stereoselectivity (Scheme 3). It is likely that
an intramolecular H-bond facilitates the addition of
imidazole from the Si-face of the iminium ion21 to afford
the (S)-imidazolium. The resulting transition state A0
suffers from an axial imidazonium group and would pre-
fer to rearrange to the alternative transition state B0
which would lead to the formation of (R)-5.
When compared to other amines, the pyrrolidine por-
tion of proline displays enhanced nucleophilic activity
in the B–H reaction. This can be contributed to the pres-
ence of the a-carboxyl group, which acts as a Brønsted
co-catalyst during the formation of the enamine.22 Such
behavior is similar to the catalytic activity of an enzyme.
In fact, the B–H reaction of 4a in the presence of 6 or 7
gave none of the desired product 5 (entries 23 and 24).
Product 5 was isolated, albeit in lower yield than with
proline, when a Brønsted acid was added to the above
mixtures (entries 25 and 26). Reaction of 4b with proline
gave the intramolecular Michael addition product 9 with
high diastereoselectivity.23 Addition of imidazole gave a
complicated mixture (entries 27 and 28). Reaction of 4c
gave the Baylis–Hillman product 10, albeit with lower
enantioselectivity (entry 29). This erosion in selectivity
may be a result of the small energy difference between
the five-membered transition states (i.e., pseudo-axial
vs pseudo-equatorial imidazole). Similarly, addition of
imidazole in the reaction of 4c did not invert the enantio-
selectivity (entry 30).
3. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2000, 122, 4243.
4. (a) Chowdari, N. S.; Suri, J. T.; Barbas, C. F. Org. Lett.
2004, 6, 2507; (b) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
5. (a) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C.
F. Org. Lett. 2004, 6, 2527; (b) Fronseca, M. T. H.; List,
B. Angew. Chem., Int. Ed. 2004, 43, 3958; (c) Andrey, O.;
Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559.
6. (a) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew.
Chem., Int. Ed. 2003, 42, 2785; (b) Chandrasekhar, S.;
Narsihmulu, C.; Reddy, N. R.; Sultana, S. S. Chem.
Commun. 2004, 2450; (c) Pan, Q.; Zou, B.; Wang, Y.; Ma,
D. Org. Lett. 2004, 6, 1009.
´
7. (a) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2003, 42, 1498; (b) Ramchary, D. B.; Chowdari, N. S.;
Barbas, C. F. Angew. Chem., Int. Ed. 2003, 42, 4233; (c)
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 2458.
8. (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656; (b)
Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.;
Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254; (c)
Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790.
9. Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 125, 450.
10. Wang, W.; Wang, J.; Li, H. Org. Lett. 2004, 6, 2817.
11. For reviews, see: (a) Basavaiah, D.; Rao, A. J.; Satya-
narayana, T. Chem. Rev. 2003, 103, 811; (b) Langer, P.
Angew. Chem., Int. Ed. 2000, 39, 3049; (c) Basavaiah, D.;
Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 24, 8001.
12. (a) Mergott, D. J.; Frank, S. A.; Roush, W. R. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11955; (b) Krishna, P. R.;
Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45,
4773; (c) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am.
Chem. Soc. 2003, 125, 13155; (d) Almeida, W. P.; Coelho,
F. Tetrahedron Lett. 2003, 44, 937; (e) Trost, B. M.; Thiel,
O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124, 11616; (f)
Mateus, C. R.; Feltrin, M. P.; Costa, A. M.; Coelho, F.;
Almeida, W. P. Tetrahedron 2001, 57, 6901; (g) Wang, B.;
Yu, X.-M.; Lin, G.-Q. Synlett 2001(Spec. issue), 904; (h)
In summary, an efficient proline catalyzed enantioselec-
tive intramolecular Baylis–Hillman reaction is reported.
Addition of imidazole to the mixture resulted in an
inversion of selectivity. This unprecedented and novel
inversion methodology provides an opportunity to
explore a new concept in asymmetric synthesis. Further
mechanistic studies and synthetic applications of this
system are currently under active investigation in our
laboratories.
Acknowledgements
We thank Mr. Chun-Yao Yang and Dr. Mahanandee-
sha Siddappa Hallur for their assistance in this study.

S.-H. Chen et al. / Tetrahedron Letters 46 (2005) 8899–8903
8903
Jauch, J. Eur. J. Org. Chem. 2001, 3, 473; (i) Iwabuchi, Y.;
Furukawa, M.; Esumi, T.; Hatakeyama, S. Chem. Com-
mun. 2001, 2030; (j) Jauch, J. Angew. Chem., Int. Ed. 2000,
39, 2764.
18. (a) The absolute configurations of (+)-5 and (ꢁ)-5 were
assigned by comparison of their specific rotations with
reported data for 8. Compound 8 was prepared by
oxidation of 5 with NaClO2 (NaClO2, t-BuOH, 2-
13. (a) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade,
D. T. Org. Lett. 2005, 7, 147; (b) Bode, M. L.; Kaye, P. T.
Tetrahedron Lett. 1991, 32, 5611.
14. (a) Krishna, P. R.; Kannan, V.; Sharma, G. V. M. J. Org.
Chem. 2004, 69, 6467; (b) Yeo, J. E.; Yang, X.; Kim, H. J.;
Koo, S. Chem. Commun. 2004, 236; (c) Keck, G. E.;
Welch, D. S. Org. Lett. 2002, 4, 3687; (d) Frank, S. A.;
Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002,
124, 2404; (e) Black, G. F.; Dinos, F.; Fratuccello, S.;
Murphy, F. J.; Nielsen, M.; Williams, H. L. Tetrahedron
methyl-2-butene, NaH2PO4, 23 ꢁC) followed by esterifica-
28
tion (cat. HCl, EtOH). ½aꢂ2D5 +57.4 (c 0.25, CHCl3); lit. ½aꢂ
D
+57.9 (c 0.99, CHCl3), see: (a) Takano, S.; Yamane, T.;
Takahashi, M.; Ogasawara, K. Tetrahedron: Asymmetry
1992, 3, 837; (b) The absolute configuration of (S)-10 was
assigned by comparison of its specific rotation with
reported data for 2-hydroxymethyl-cyclopentanol (12).
Compound 12 was prepared by reduction of (S)-10, 48%
ee, with NaBH4 followed by hydrogenation (cat. Pt/C,
MeOH), see: (i) Buisson, D.; Azerad, R. Tetrahedron Lett.
1986, 27, 2631–2634; (ii) Weidner, J.; Theil, F.; Schick, H.
Tetrahedron: Asymmetry 1994, 5, 751–754; (iii) Inoguchi,
K.; Fujie, N.; Yoshikawa, K.; Achiwa, K. Chem. Pharm.
Bull. 1992, 40, 2921–2926.
´
Lett. 1997, 38, 8561; (f) Roth, F.; Gygax, P.; Frater, G.
Tetrahedron Lett. 1992, 33, 1045.
15. (a) Shi, M.; Jiang, J.-K.; Li, C.-Q. Tetrahedron Lett. 2002,
43, 127; (b) Imbriglio, J. E.; Vasbinder, M. M.; Miller, S.
J. Org. Lett. 2003, 5, 3741.
19. To the best of our knowledge, such an inversion of
enantioselectivity is unprecedented. For an example of
solvent mediated inversion of enzymatic enantioselectivity,
see: (a) Tawaki, S.; Klibanov, A. J. Am. Chem. Soc. 1992,
114, 1882; (b) For an example of solvent mediated
inversion of enantioselectivity in platinum-catalyzed
hydrogenation, see: (i) Hess, R.; Vargas, A.; Mallat, T.;
16. For recent examples in asymmetric intermolecular B–H
reaction, see: (a) Barrett, A. G. M.; Cook, A. S.;
Kamimura, A. Chem. Commun. 1998, 2533; (b) Shi, M.;
Jiang, J.-K. Tetrahedron: Asymmetry 2002, 13, 1941; (c)
Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521;
(d) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc.
2003, 125, 12094; (e) Hayashi, Y.; Tamura, T.; Shoji, M.
Adv. Synth. Catal. 2004, 346, 1106; (f) Pegot, B.; Vo-
Thanh, G.; Gori, D.; Loupy, A. Tetrahedron Lett. 2004,
45, 6425; (g) Krishna, P. R.; Kannan, V.; Reddy, P. V. N.
Adv. Synth. Catal. 2004, 346, 603; (h) Sohtome, Y.;
Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron
Lett. 2004, 45, 5589; (i) Mocquet, C. M.; Warriner, S. L.
Synlett 2004, 2, 356; (j) Kawahara, S.; Nakano, A.; Esumi,
T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103;
(k) Yang, K.-S.; Lee, W.-D.; Pan, J.-F.; Chen, K. J. Org.
Chem. 2003, 68, 915; (l) Shi, M.; Xu, Y.-M. Angew. Chem.,
Int. Ed. 2002, 41, 4507; (m) Aggarwal, V. K.; Castro, A.
M.; Mereu, A.; Adams, H. Tetrahedron Lett. 2002, 43,
1577; (n) Iwabuchi, Y.; Furukawa, M.; Esumi, T.;
Hatakeyama, S. Chem. Commun. 2001, 19, 2030; (o)
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatake-
yama, S. J. Am. Chem. Soc. 1999, 121, 10219; (p) Hayase,
T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem. Commun.
1998, 12, 1271; (q) Mark, I. E.; Giles, P. R.; Hindley, N. J.
Tetrahedron Lett. 1997, 53, 1015.
Burgi, T.; Baiker, A. J. Catal. 2004, 222, 117; (ii) Arx, M.;
¨
Mallat, T.; Baiker, A. Angew. Chem., Int. Ed. 2001, 40,
2302.
20. TS A was reported to be more stable than B. For
calculations and discussions on the transition states of
proline-catalyzed aldol reactions, see: (a) Bahmanyar, S.;
Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273; (b)
Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
12911; (c) Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J.
Phys. Chem. A 2002, 106, 5155; (d) Bahmanyar, S.; Houk,
K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125,
2475; (e) Hoanh, L.; Bahmanyar, S.; Houk, K. N.; List, B.
J. Am. Chem. Soc. 2003, 125, 16.
21. The combination of the Lewis base and proline is
necessary to achieve the increased reaction rates and
inversion of stereoselectivity. In contrast to other nucleo-
philes such as DABCO, imidazole alone does not catalyze
the B–H reaction (Table 1, entry 22). For discussion, see
Ref. 15a.
22. List, B. Synlett 2001, 1675.
17. (a) Shi, M.; Xu, Y.-M.; Zhao, G.-L.; Wu, X.-F. Eur. J.
Org. Chem. 2002, 3666–3679; (b) Shi, M.; Xu, Y.-M. Eur.
J. Org. Chem. 2002, 696–701.
23. For the same reaction with proline derivatives, see:
Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed. 2004,
43, 3958.