Diversity-based strategy for discovery of environmentally benign organocatalyst: Diamine-protonic acid catalysts for asymmetric direct aldol reaction

Article abstract of DOI:10.1016/S0040-4020(02)00965-1

Fifteen different diamines (4-18) and potonic acids have been screened in the catalytic asymmetric direct aldol reaction of three different aldehydes in acetone. These initial studies demonstrated that the secondary-tertiary diamine series is effective wi

Full text of DOI:10.1016/S0040-4020(02)00965-1

Tetrahedron 58 (2002) 8167–8177
Diversity-based strategy for discovery of environmentally benign
organocatalyst: diamine–protonic acid catalysts for asymmetric
direct aldol reaction
†
,
*
Masakazu Nakadai, Susumu Saito and Hisashi Yamamoto
Graduate School of Engineering, Nagoya University, SORST, Japan Science and Technology Corporation (JST), Chikusa,
Nagoya 464-8603, Japan
Received 22 March 2002; accepted 7 May 2002
Abstract—Fifteen different diamines (4–18) and potonic acids have been screened in the catalytic asymmetric direct aldol reaction of three
different aldehydes in acetone. These initial studies demonstrated that the secondary–tertiary diamine series is effective with regard to
reactivity. In contrast, the primary–tertiary diamines 13 and 14 were proved to be a superb structural module to avoid dehydration. Further
investigation led us to a new procedure for the preparation of diamine catalysts for synthetic convenience. This involves diamine–diacid salt
22, which acted not only as a catalyst backbone but also as a TfOH source. Salt 22–diamine 4 catalyst thus prepared was found to exhibit
higher reactivity and selectivity. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Aldol reaction is a useful method for preparing b-hydroxy
carbonyl compounds and has attracted a great deal of
attention from synthetic organic chemists.1 Over the last
decade, rapid progress in the development of enantio-
selective aldol reactions has been made;2 however, there are
only a few reports on the small molecular-catalyzed direct
aldol reactions.3 Watanabe,4a,b Shibasaki,4c,d,f,g Trost4e,h,i
and Noyori4j have reported several examples of direct
catalytic asymmetric aldol reactions using metal-based
catalysts4 while only a few examples of the reactions
using amines5,6 have been noted in the literature. Provoca-
tive and pioneering works7 by List,7a–c,e Lerner7a and
Barbas III7a,d involve proline8,9 and 5,5-dimethyl thiazoli-
dinium-4-carboxylate (DMTC) as a catalyst and the
subsequently occurring enamine10 as a key intermediate.
Each reported method has notable advantage, but problems
are frequently encountered enhancing the efficiency of the
aldol reaction and suppressing the dehydrated products.
We recently described that diamine–protonic acids11,12 are
effective catalysts for the direct asymmetric aldol reaction.13
This report details our full investigations of the diamine–
protonic acid catalysts and survey of a more efficient
catalyst.
2.1. Diamine–protonic acid catalysts for the asymmetric
aldol reaction
The most important aspect on which we focused our
attention at the first stage of our research was how to obtain
high catalytic efficiency in the direct aldol reaction. Several
diamines were screened with protonic and Lewis acids to
test their catalytic efficiency.‡ A protonic acid-1,2-diamino-
ethane module was found to be the best choice for the
efficiency and for ready accessibility to their chiral
derivatives from various a-amino acids (Scheme 1).
In a preliminary experiment, use of chiral diamine 4 gave
the aldol adduct with moderate enantioselectivity.
Sequential treatment of a DMF solution of p-nitrobenzalde-
hyde (1a) (1 equiv.) with p-TsOH·H2O (3 mol%), diamine 4
(3 mol%) and acetone (27 equiv.) at room temperature,
followed by stirring at 408C for 2 h, gave aldol adduct 2a in
19% yield with 83% ee, contaminated by dehydrated aldol
adduct 3a (4%). The use of p-TsOH·H2O or the diamine 4
‡
We initiated an investigation on direct aldol reaction using N,N-di-
methylethylenediamine–Lewis acid catalysts, acetone and p-nitro-
benzaldehyde in DMF. The rate enhancement was observed, though
moderate, with Eu(OTf)3 and Gd(OTf)3. To determine an essential
catalysis that leads to high productivity, an X-ray single crystallographic
study of the Gd(OTf)3–diamine 4 catalyst was undertaken. Interestingly,
single crystals of the Gd(III)-4 complex were not obtained but diprotonic
acid salt 22 was eventually grown at 2208C under a vapor of Et2O
(Fig. 4). This result implies that the protonic acid might play an important
role in even this Lewis acid–diamine system: triflate salts should work as
good TfOH sources.
Keywords: aldol reactions; asymmetric reactions; diamines; enamines.
*
Corresponding author. Tel.: þ81-52-789-3331; fax: þ81-52-789-3222;
e-mail: yamamoto@cc.nagoya-u.ac.jp; yamamoto@uchicago.edu
Present address: Department of Chemistry, University of Chicago, 5735
South Ellis Avenue, Chicago, 60637, USA.
†
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00965-1

8168
M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
Scheme 1.
Table 1. Protonic acid variations
Acid
TsOH·H2O
Tf3CH
19
20
21
% Yield
% ee
19
83
27
84
25
83
6
18
8
32
Reactions were performed using diamine 4 (3 mol%) and acid (3 mol%) in DMF at 408C for 2 h under air in a closed system.
alone led to negligible formation of 2a and 3a under similar
conditions. The most suitable acid–diamine ratio was found
to be 1:1 for effective rate acceleration; acid–diamine ratios
greater or less than 1:1 significantly reduced the reaction
rate.
was enhanced as the acidity14 of the protonic acid increased.
These acid variations affected the enantioselectivity
(18–84% ee). Both Tf3CH and acid 19 emerged as superior
protonic acids; we chose acid 19 for further survey due to
its commercial availability. In parallel with these investi-
gations, solvent effects were evaluated (THF: 7% yield,
79% ee; DMSO: 25%, 82% ee; MeOH: 6%, 75% ee;
CH3CN: 30%, 80% ee). Acetone was shown to be the best
solvent (63% yield, 83% ee).
Diamine 4 was evaluated for catalysis of the aldol reaction
with 1a in the presence of a series of different protonic acids
in DMF (Table 1). In general, the rate of the aldol reaction
Figure 1. Diamine ligand library.

M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
8169
Figure 2. Library 1: Aldol reaction of 1a–1c in acetone using chiral diamines and 19. (Yield% of 2a–2c (white bar); yield% of 3a–3c (black bar); ee% of 2a–
2c (gray bar)). For the details, Section 4.
Twelve different diamines15 (secondary–primary, secon-
dary–secondary and secondary–tertiary diamines) with
a consistent secondary amino structure derived from
(L)-proline, as well as three different diamines (primary–
tertiary diamines) derived from (D)-phenylalanine,
were synthesized (Fig. 1) and screened with a range of
aldehydes. Reactions were run at 23–408C in acetone under
conditions employing 1–20 mol% of catalyst relative to
substrate.
diamines (Fig. 3). After screening diamines 11–18, the
primary–tertiary diamines 13 and 14 were found to be a
superb structural module to avoid dehydration. Secondary–
primary diamine 11 was found to be ineffective with regard
to both productivity and efficiency. Secondary–secondary
diamine 15 gave the most optimal result, albeit with a
considerable amount of dehydrated products. The best result
afforded 2b in 58% yield with 74% ee and 2c in 64% yield
with 80% ee using 15. Unfortunately, the rate of the aldol
reaction with primary–tertiary and secondary–secondary
diamine modules§ was much slower than the rates with
secondary–tertiary diamines. The absolute configuration
of 2a–2c induced by a library of diamines derived from
(L)-proline was the opposite of those obtained by
(D)-phenylalanine-derived diamines.
Library 1. Based on these pioneering discoveries, our
design of diamines focused on the secondary–tertiary
diamine 4–10. The reaction with aldehyde 1a–1c was
carried out using seven different diamines (Fig. 2). When 1a
was used in the direct aldol reaction, diamine 6 was the best
choice for high ee (TON¼24), although the reaction rate
decreased in the order 4, 6.5.7.8–10 (Fig. 2) as the
tertiary amine moiety became bulkier. The turnover
numbers (TON) ranged from 73 to 20 using 1–3 mol% of
catalyst 4 under various conditions. 1b and 1c were reacted
in acetone using secondary–tertiary diamines. Unfortu-
nately, the formation of dehydrated product 3b and 3c posed
serious limitations.
2.2. Survey of more efficient catalyst: second generation
As demonstrated previously, the acidity14 of the protonic
acid appeared to be important to achieve high reactivity.
Due to the superior reactivity exhibited by the secondary–
tertiary diamine series, reinvestigation was initiated to
§
At present, we do not have a reasonable explanation for low
enantioselectivity using diamine 18 and the mechanism involving
secondary–secondary diamines.
Library 2. In an effort to expand the scope of acceptable
aldehyde, we examined the reaction using a number of

8170
M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
Figure 3. Library 2: Aldol reaction of 1a–1c in acetone using chiral diamines and 19. (Yield% of 2a–2c (white bar); yield% of 3a–3c (black bar); ee% of
2a–2c (gray bar)). For the details, see Experimental section.
Table 2. Sulfonic acid variations
Acid
19
MsOH
C8F17SO3H
TfOH
% Yield 2a (% ee)
% Yield 3a
37 (80)
18
23 (77)
17
49 (83)
16
51 (82)
13
Reactions were performed using diamine 4 (3 mol%) and acid (3 mol%) in acetone (27 equiv.) at 308C for 2 h under air in a closed system.
explore a more efficient catalyst involving 4 (Table 2). The
acid screening revealed that TfOH was the optimal acid (2a,
51%, 82% ee; 3a, 13%) with respect to both selectivity and
reactivity. It is interesting to note that dehydration was
relatively suppressed by using TfOH under otherwise
identical conditions.
Since TfOH is a corrosive and hygroscopic liquid that fumes
copiously on exposure to moist air,16 special care must be
taken regarding its handling especially in a small-scale
experiment. We thus developed a new method for the
preparation of a TfOH-4-like catalyst for further con-
venience: first, acid salt 22 was prepared by treatment of 4
with excess (.2 equiv.) TfOH (Scheme 2); second, salt 22
was exposed to 4 in a 1:1 ratio to give the catalyst 22–4.
This procedure enabled rather a large-scale preparation of
acid salt 22, which can be stored at a low temperature
without decomposition or any loss of catalytic activity over
a long period of time (more than 3 months). Subsequently,
an acetone solution of the 22–4 catalyst was easily prepared
Scheme 2. Salt 22 preparation.

M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
Table 3. Aldol reaction of 1a in acetone using diamine 4 and salt 22
8171
R
Time (h)
Aldol yield % (% ee)
Dehydrated product yield (%)
NO2 (1a)
H (1b)
2
48
60 (88)
37 (83)
7
32
Figure 4. X-ray crystal structure of 22.
even on a small scale (,1.0 mmol) just before use and
showed reactivity and reproducibility similar to the catalyst
generated by direct treatment of diamine 4 with TfOH.
Slight increase in enantioselectivity was observed using
the 22–4 catalyst compared with the 4–TfOH catalyst
(Table 3). Catalyst 22 alone had no catalytic activity.
protonic acid catalysts, attention was next directed to
the reaction of 1a with ketones less reactive than
acetone (Table 4).k Both cyclopentanone and cyclo-
hexanone exhibited good reactivity (88–97%). The cyclo-
hexanone provided the anti aldol product in moderate
diastereoselectivity with excellent enantioselectivity
(anti/syn¼74:26, ee (anti)¼96%). Among the least
reactive, diethylketone was also compatible with these
conditions to give a high level of enantioselectivity as
well as acceptable reactivity (81%, anti/syn¼54:46, ee
(anti)¼84%).
The X-ray single crystal structure of 2217 was established by
low temperature-measurement at 208 K and showed two
2.3. Plausible mechanism
˚
typical hydrogen bondings (1.925 and 1.910 A) between
Nþ–H and 2OTf (Fig. 4). Of interest for further research is
that 22 could be an attractive candidate as a di-protonic acid
catalyst in the termolecular double coordination system
involving spontaneous activation of two functional
groups by two acidic centers.18 Both older19 and modern
investigations also highlighted that carboxylate20 anions
or carbonyl compounds bearing oxazolidinones21 were
bimolecularly recognized and/or doubly activated by
guanidine derivatives.
The mechanism of the diamine–protonic acid-catalyzed
aldol addition is the subject of an extensive, ongoing
investigation but it remains unsolved. For the purposes of
the immediate discussion, we assume that the catalytic
cycle of the asymmetric aldol reaction is based on a
proline-catalyzed aldol reaction7,22 (Scheme 3) that was
discovered by List,7a–c,e Lerner,7a and Barbas III.7a,d At the
k
Diamine 6–TfOH was also a good catalyst to give comparable ees:
cyclopentanone, 93%, anti/syn¼55:45, ee (anti)¼85%, cyclohexanone,
With the highest catalytic activity found so far in diamine–
99%, anti/syn¼83:17, ee (anti)¼96%.

8172
M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
Table 4. Aldol reactions of 1a with ketones less reactive than acetone using 22–4 catalyst
Entry
1
Ketone
Time (h)
29
Yield (%)a
88
anti (% ee)/syn (% ee)b
43 (84)/57 (5)
2
29
97
81
74 (96)/26 (61)
54 (84)/46 (16)
3c
144
Unless otherwise noted, reaction were using 22 (5 mol%) and 4 (5 mol%) in a ketone solvent (18–22 equiv.)
Isolated yields.
a
b
anti/syn Ratios were determined by 1H NMR. Enantiomeric ratios were determined by chiral HPLC analysis.
10 mol% of 22 and 4 were used, respectively.
c
Scheme 3. Proposed mechanism of the diamine–protonic acid catalyzed aldol reaction with 1b and acetone.
current level of understanding, the dominant catalytic
pathway to aldol adducts likely involves the intermediacy
of an enamine derived from acetone. The reaction should
proceed through a six-membered chair-like transition
structure adopting the Ph-group of PhCHO at the
equatorial position. Furthermore, a pathway to dehydration
might involve an aldimine species, which undergoes
Mannich-type reaction with the acetone enamine to
give the b-aminoketone, followed by subsequent elimina-
tion.7c,11k
3. Conclusion
We demonstrated that a 1:1 mixture of chiral diamine–
protonic acid could be an alternative to previously reported

M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
8173
methods for the catalytic asymmetric aldol reaction.
Further, the diversity-based strategy was found to be of
potential importance for the discovery of an appropriate
catalyst for each carbonyl couple. Indeed, the screening
using diamine libraries facilitated the characterization of an
effective structure of diamine that leads to high catalytic
activity and efficiency. In addition, the use of salt 22 offers
the advantages of stability toward moisture and its handling.
These initial results will be helpful to design novel chiral
catalysts in the further improvement of the direct aldol
reaction. Studies toward this end are now in progress.
yield. After purification by column chromatography on
silica gel (EtOAc/hexane¼1/1 as the eluent), the enantio-
meric excess (ee) of 2a was determined to be 77% ee by
chiral HPLC analysis. The chiral HPLC analytical data
(column OB-H) of 2a: retention times: tR¼28.49 min
((R)-isomer: minor isomer using (D)-phenylalanine-derived
diamines; major isomer using (L)-proline-derived diamines)
and tR¼33.39 min ((S)-isomer: major isomer using
(D)-phenylalanine-derived diamines; minor isomer using
(L)-proline-derived diamines) using i-PrOH/hexane (1/6) as
eluent at a flow rate of 1.0 mL/min.
The ee of 2b was similarly determined by chiral HPLC
analysis. The chiral HPLC analytical data (column OB-H)
of 2b: retention times: tR¼37.32 min ((S)-isomer: major
isomer using (D)-phenylalanine-derived diamines; minor
isomer using (L)-proline-derived diamines) and tR¼
42.26 min ((R)-isomer: minor isomer using (D)-phenyl-
alanine-derived diamines; major isomer using (L)-proline-
derived diamines) using i-PrOH/hexane (1/40) as eluent at a
flow rate of 1.0 mL/min.
4. Experimental
4.1. General
1H NMR spectra were measured on a Varian Gemini-300
spectrometer (300 MHz) at ambient temperature. Data were
recorded as follows: chemical shift in ppm from internal
tetramethylsilane on the d scale, multiplicity (b¼broad, s¼
singlet, d¼doublet, t¼triplet, and m¼multiplet), coupling
constant (Hz), integration, and assignment. 13C NMR
spectra were recorded on a Varian Gemini-300 (75 MHz)
spectrometer at ambient temperature. Chemical shifts are
recorded in ppm from the solvent resonance employed as
the internal standard (deuterochloroform at 77.07 ppm). All
aldol reactions were carried out under an atmosphere of air
in a closed system. For thin-layer chromatography (TLC)
analysis throughout this work, Merck precoated TLC plates
(silica gel 60 GF254 0.25 mm) were used. In some
instances, the products were purified by preparative column
chromatography on silica gel (E. Merck Art. 9385).
The ee of 2c was determined by converting it to the
trifluoroacetate derivative (trifluoroacetic anhydride, Py,
cat. DMAP, ClCH2CH2Cl, rt) and subsequently by chiral
GC analysis using the chiral column g-TA (astec). The
chiral GC analytical data (column g-TA) of 2c: retention
times: tR¼33.26 min ((S)-isomer. major isomer using
(D)-phenylalanine-derived diamines; minor isomer using
(L)-proline-derived diamines) and tR¼36.07 min ((R)-isomer:
minor isomer using (D)-phenylalanine-derived diamines;
major isomer using (L)-proline-derived diamines) at the
column temperature of 928C (injection temperature: 1508C)
at a carrier gas (N2) pressure of 75 hPa.
Organic substrates p-nitrobenzaldehyde (1a), benzaldehyde
(1b), cyclohexanecaboxaldehyde (1c), cyclohexanone,
cyclopentanone, diethylketone, 3b, acids 19–21, diamines
4 and 11 were all commercially available. 1a was used
without any purification. 1b, 1c, cyclohexanone, cyclo-
pentanone and diethylketone were used after bulb-to-bulb
distillation. Acetone was purchased from Nacalai Tesque
(99% grade) and used without purification. Diamines 5–10
and 11–18 were prepared by the methods previously
described.15 Diamines 5,15g 8,15g 10,15g 13,23 1415a and
1515b, Tf3CH,24 aldol adducts 2a,7d 2b,7d 2c25 and aldol
adducts (Table 4, entries 17d and 27d), as well as dehydrated
products 3a26 are all known compounds.
4.2.1. 1-(2-Pyrrolidinylmethyl)hexamethyleneimine (6).
IR (neat) 3308, 2946, 1450, 1132, 1093, 804 cm21 1H
;
NMR (300 MHz, CDCl3) d 4 05 (bs, 1H), 3.32–3.20 (m,
1H), 3.10–2.87 (m, 2H), 2.75–2.35 (m, 6H), 1.93–1.30 (m,
12H); 13C NMR (75 MHz, CDCl3) d 62.3, 56.3, 55.7 (two
peaks are overlapped), 45.5, 29.4, 28.1 (two peaks are
overlapped), 27.0 (two peaks are overlapped), 24.7; HRMS
(FAB): exact mass calcd for C11H22N2þHþ: 183.1861.
Found: 183.1821. [a]2D5¼þ18.88 (c 2.00, CHCl3).
4.2.2. 1-(2-Pyrrolidinylmethyl)heptamethyleneimine (7).
IR (film) 3390, 2921, 2853, 1539, 1406, 1159, 1093, 1060,
1
814 cm21; H NMR (300 MHz, CDCl3) d 3.20–3.12 (m,
1H), 2.98–2.78 (m, 2H), 2.60–2.26 (m, 7H), 1.86–1.27 (m,
14H); 13C NMR (75 MHz, CDCl3) d 64.9, 56.6, 54.8 (two
peaks are overlapped), 45.7, 29.3, 28.1 (two peaks are
overlapped), 27.5, 26.1 (two peaks are overlapped), 24.8;
HRMS (EI): exact mass calcd for C12H24N2: 196.1939.
Found: 196.1982. [a]2D8¼þ12.58 (c 1.00, CHCl3).
4.2. Typical procedure for the aldol reaction using a
protonic acid and a diamine in acetone
The following procedure for the reaction of p-nitrobenz-
aldehyde (1a) in acetone using acid 19 and diamine 4 is
representative. To a mixture of diamine 4 (3.3 mL,
0.02 mmol) and acid 19 (5.4 mg, 0.02 mmol) in acetone
(4.0 mL) was added 1a (2.0 mmol) at 238C under air in a
closed system. The reaction mixture was stirred at 438C for
30 h. n-Oct3SiMe (47.1 mL, 0.1 mmol) was added as an
internal standard just before quenching. The reaction
mixture was quenched with aq. NaCl. The organic layer
was extracted with EtOAc, dried over Na2SO4, and
4.2.3. 2-(2-Pyrrolidinylmethyl)-1,2,3,4-tetrahydroiso-
quinoline (9). IR (film) 3330, 2951, 2788, 1399, 1093,
1
938, 810, 741 cm21; H NMR (300 MHz, CDCl3) d 7.13–
6.96 (m, 4H), 3.74 (d, 1H, J¼14.7 Hz), 3.59 (d, 1H, J¼
14.7 Hz), 3.42–3.33 (m, 1H), 3.02–2.40 (m, 9H), 1.90 (m,
1H), 1.75 (m, 2H), 1.38 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 134.8, 134.3, 128.6, 126.5, 126.0, 125.5, 63.6,
56.4, 55.5, 51.2, 45.9, 29.8, 29.0, 24.9; Anal. calcd for
1
concentrated. The residue was analyzed by H NMR to
give 2a in a NMR yield of 73%, together with 3a in 12%

8174
M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
C14H20N2: C, 77.73; H, 9.32; N, 12.95. Found: C, 77.62; H,
9.58; N, 12,83. [a]2D8¼þ27.48 (c 1.00, CHCl3).
2H), 1.94–0.97 (m, 16H); 13C NMR (75 MHz, CDCl3) d
58.5, 56.9, 52.2, 46.4, 33.55, 33.49, 29.7, 26.1, 25.6, 24.98,
24.95.
4.2.4. a-Phenylmethyl-1-trimethyleneimineethaneamine
(12). IR (neat) 3366, 2921, 2822, 1593, 1451, 1194, 905,
4.2.8. N-Cycloheptyl-N-(2-pyrrolidinylmethyl)amine
(16). IR (neat) 3293, 2924, 2857, 1646, 1460, 1116,
1
833, 747, 700 cm21; H NMR (300 MHz, CDCl3) d 7.25–
1
7.14 (m, 5H), 3.23–2.87 (m, 5H), 2.70 (dd, 1H, J¼4.5,
13.2 Hz), 2.44–2.32 (m, 3H), 2.02 (tt, 2H, J¼6.9, 6.9 Hz),
1.42 (bs, 2H); 13C NMR (75 MHz, CDCl3) d 139.2,
129.1 (two peaks are overlapped), 128.2 (two peaks are
overlapped), 126.0, 66.6, 55.7 (two peaks are overlapped),
50.8, 42.2, 17.8; HRMS (EI): exact mass calcd for
C12H18N2: 190.1470. Found: 190.1483. [a]2D7¼213.78
(c 1.14, CHCl3).
780 cm21; H NMR (300 MHz, CDCl3) d 3.36 (bs, 2H),
3.26–3.20 (m, 1H), 2.90 (t, 2H, J¼6.9 Hz), 2.66–2.42 (m,
3H), 1.93–1.33 (m, 16H); 13C NMR (75 MHz, CDCl3) d
59.2, 58.3, 51.9, 46.1, 34.6, 34.5, 29.5, 28.07, 28.04, 25.4,
24.28, 24.25; HRMS (FAB): exact mass calcd for
C12H25N2þHþ: 197.2018. Found: 197.1985. [a]2D5¼þ6.48
(c 1.00, CHCl3).
4.2.9. N-Cyclooctyl-N-(2-pyrrolidinylmethyl)amine (17).
IR (film) 3393, 2928, 1549, 1404, 752 cm21 1H NMR
;
4.2.5. a-Phenylmethyl-1-pyrrolidineethaneamine (13).
IR (film) 3300, 2965, 2803, 1580, 1455, 1308, 1144,
1078, 748, 702 cm21; 1H NMR (300 MHz, CDCl3) d 7.32–
7.20 (m, 5H), 3.16 (tt, 1H, J¼4.2, 8.7 Hz), 2.77 (dd, 1H,
J¼4.5, 13.2 Hz), 2.59–2.43 (m, 6H), 2.31 (dd, 1H, J¼4.2,
12.0 Hz), 1.99 (bs, 2H), 1.71–1.80 (m, 4H); 13C NMR
(75 MHz, CDCl3) d 139.4, 129.3 (two peaks are over-
lapped), 128.4 (two peaks are overlapped), 126.1, 63.2, 54.4
(two peaks are overlapped), 51.3, 42.5, 23.5 (two peaks are
overlapped); Anal. calcd for C13H20N2: C, 76.42; H, 9.87;
N, 13.71. Found: C, 76.3; H, 10.07; N, 13.59. [a]2D7¼214.18
(c 1.00, CHCl3).
(300 MHz, CDCl3) d 3.23–3.14 (m, 1H), 2.90 (td, 2H,
J¼2.7, 6.6 Hz), 2.63 (dd, 2H, J¼4.5, 11.1 Hz), 2.45 (dd, 1H,
J¼8.4, 11.1 Hz), 1.21–1.93 (m, 20H); 13C NMR (75 MHz,
CDCl3) d 58.6, 58.1, 53.0, 46.5, 33.0, 32.7, 29.8, 27.23,
27.19, 25.74, 25.73, 24.2, 24.1; HRMS (EI): exact mass
calcd for C13H26N2: 210.2096. Found: 210.2101.
[a]2D3¼þ10.28 (c 2.04, CHCl3).
4.2.10. N-t-Butyl-N-(2-pyrrolidinylmethyl)amine (18). IR
(neat) 3293, 2964, 2870, 1570, 1478, 1389, 1364, 1223,
1
1115, 797 cm21; H NMR (300 MHz, CDCl3) d 3.75 (bs,
2H), 3.25–3.16 (m, 1H), 2.90 (t, 2H, J¼6.9 Hz), 2.61–2.43
(m, 2H), 1.95–1.28 (m, 4H), 1.08 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 58.8, 50.5, 47.1, 46.1, 29.6, 28.7 (three
peaks are overlapped), 25.4; HRMS (FAB): exact mass
calcd for C9H20N2þHþ: 157.1705. Found: 157.1705.
[a]2D5¼þ12.08 (c 1.98, CHCl3).
4.2.6. a-Phenylmethyl-1-piperidineethaneamine (14). IR
(film) 3372, 2934, 1495, 1455, 1156, 1119, 779, 700 cm21
;
1H NMR (300 MHz, CDCl3) d 7.32–7.18 (m, 5H), 3.18 (tt,
1H, J¼4.8, 8.7 Hz), 2.71 (dd, 1H, J¼4.2, 13.2 Hz), 2.51–
2.43 (m, 3H), 2.27–2.16 (m, 4H), 1.79 (bs, 2H), 1.59–1.38
(m, 6H); 13C NMR (75 MHz, CDCl3) d 139.5, 129.3 (two
peaks are overlapped), 128.3 (two peaks are overlapped),
126.1, 65.8, 55.1 (two peaks are overlapped), 49.4, 42.4,
26.2 (two peaks are overlapped), 24.5; HRMS (FAB): exact
mass calcd for C14H22N2þHþ: 219.1861. Found: 219.1898.
[a]2D8¼223.58 (c 0.525, CHCl3).
4.2.11. 4-Cylohexyl-3-buten-2-one (3c). IR (neat) 2928,
2855, 1728, 1676, 1624, 1451, 1358, 1254, 980, 733 cm21
;
1H NMR (300 MHz, CDCl3) d 6.71 (dd, 1H, J¼6.9,
16.2 Hz), 6.48 (dd, 1H, J¼1.2, 16.2 Hz), 2.21 (s, 3H),
2.21–1.60 (m, 6H), 1.25–1.12 (m, 5H); 13C NMR (75 MHz,
CDCl3) d 199.1, 153.4, 128.7, 40.5, 31.7, 26.8, 25.8 (two
peaks are overlapped), 25.6 (two peaks are overlapped);
Anal. calcd for C10H16O: C, 78.90; H, 10.59. Found: C,
78.81; H, 10.77.
4.2.7. N-Cyclohexyl-N-(2-pyrrolidinylmethyl)amine
(15). 1H NMR (300 MHz, CDCl3) d 3.23–2.86 (m,
3H), 2.66 (dd, 1H, J¼4.8, 11.1 Hz), 2.52–2.35 (m,
4.2.12. Conditions of library 1 and 2.
Diamine
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
p-Nitrobenzaldehyde (3 mol% of a catalyst was used)
Temperature (8C)
Time (h)
23
10
23
10
23
10
23
111
40
2
40
2
23
72
23
72
23
72
23
72
23
36
23
36
23
36
23
36
23
24
Benzaldehyde
Cat. (mol%)
Temperature (8C)
Time (h)
10
40
2
3
23
120
10
23
33
10
23
111
3
23
84
3
23
84
10
23
24
10
23
72
10
23
72
10
23
84
10
23
60
10
23
144
10
30
72
10
30
96
3
23
120
Cyclohexacarboxaldehyde
Cat. (mol%)
Temperature (8C)
Time (h)
15
40
17
15
40
17
15
40
17
15
40
17
15
40
17
15
40
17
15
40
17
15
40
17
20
23
71
20
23
61
20
23
61
15
40
36
15
40
36
15
40
36
15
40
36

M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
8175
4.2.13. Results of library 1 and 2.
Diamine
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
p-Nitrobenzaldehyde
Yield (2a)
Yield (3a)
ee % (2a)
61
19
83
41
30
84
72
7
93
50
4
84
8
4
89
3
11
58
15
10
83
52
1
81
25
,1
66
71
,1
76
88
,1
63
81
5
81
84
,1
81
7
1
84
72
3
11
Benzaldehyde
Yield (2b)
Yield (3b)
ee % (2b)
6
64
80
2
72
69
13
25
91
7
23
76
1
23
74
,1
3
–
,1
23
–
3
8
78
27
5
68
56
4
72
69
7
45
58
19
74
16
57
54
39
34
52
12
69
15
Cyclohexacarboxaldehyde
Yield (2c)
Yield (3c)
ee % (2c)
,1
67
–
,1
82
–
,1
64
–
,1
1
–
,1
47
–
,1
1
–
,1
76
–
,1
,1
–
8
63
28
32
48
42
66
24
46
64
35
80
40
39
83
60
37
80
40
44
80
4.2.14. Preparation of salt 22. To a solution of diamine 4
(410 mL, 2.5 mmol) in Et2O (5 mL) was added trifluoro-
methanesulfonic acid (.443 mL, .5 mmol) with stirring.
The salt 22 was immediately precipitated then was filtered
and washed with Et2O. The salt 22 showed the following
data: IR (KBr) 3141, 3065, 2780, 2368, 1565, 1460, 1418,
1275, 1244, 1167, 1073, 1034, 841, 635, 577, 521 cm21; 1H
NMR (300 MHz, acetone-d6) d 8.74 (bs, 1H), 8.61 (bs, 1H),
8.35 (bs, 1H), 4.38 (bs, 1H), 4.08–3.64 (m, 4H), 3.64 (bs,
2H), 3.45 (bs, 2H), 2.59–1.94 (m, 8H); 13C NMR (75 MHz,
acetone-d6) d 121.4 (q, JCF¼317.3 Hz: two peaks are
overlapped), 58.1, 56.4, 56.0, 55.9, 47.7, 29.7, 23.7,
23.5 (two peaks are overlapped); Anal. calcd for
C13H24F6N2O6S2: C, 29.07; H, 4.44; N, 6.16. Found: C,
29.08; H, 4.41; N, 6.08. [a]2D5¼23.18 (c 1.03, EtOH).
overlapped), 75.6, 52.2, 36.4, 14.5, 7.4; HRMS (FAB):
exact mass calcd for C12H15NO4: 237.1001. Found:
237.0991. [a]2D5¼þ39.68 (c 0.22, CHCl3). Spectral data of
the syn isomer: IR (film) 3486, 2980, 2940, 2363, 1705,
1603, 1520, 1458, 1348, 1109, 1019, 978, 857, 820, 747,
704 cm21 1H NMR (300 MHz, CDCl3) d 8.22 (d, 2H,
;
J¼8.7 Hz), 7.52 (d, 2H, J¼8.7 Hz), 5.25 (dd, 1H, J¼3.0,
2.1 Hz), 3.60 (d, 1H, J¼2.1 Hz), 2.84 (qd, 1H, J¼7.2,
3.0 Hz), 2.63 (dq, 1H, J¼18.0, 7.2 Hz), 2.47 (dq, 1H, J¼
18.0, 7.2 Hz), 1.08 (t, 3H, J¼7.2 Hz), 1.04 (d, 3H, J¼
7.2 Hz); 13C NMR (75 MHz, CDCl3) d 216.3, 149.0,
147.1, 126.7 (two peaks are overlapped), 123.5 (two peaks
are overlapped), 71.9, 51.3, 35.1, 9.8, 7.5; HRMS (FAB):
exact mass calcd for C12H15NO4: 237.1001. Found:
237.0956.
4.2.15. Typical procedure for the aldol reaction using
salt 22 and diamine 4. The following procedure for the
reaction of p-nitrobenzaldehyde (1a) in diethylketone is
representative. To a mixture of diamine 4 (8.2 mL,
0.05 mmol) and salt 22 (22.7 mg, 0.05 mmol) in diethyl-
ketone (1.0 mL) was added 1a (0.5 mmol) at 238C under air
in a closed system. The reaction mixture was stirred at 308C
for 144 h, then was quenched with aq. NaCl. The organic
layer was extracted with EtOAc, dried over Na2SO4, and
concentrated. The residual crude product was purified by
column chromatography on silica gel to afford a mixture of
aldol adducts (96.4 mg, 81% yield). The anti/syn ratio27 was
determined to be 54/46 by 1H NMR analysis. The
enantioselectivities of the anti and syn isomers were
determined to be 84 and 16% ee by HPLC analysis. The
chiral HPLC analytical data (column AD-H) of aldol
adducts: retention times: tR¼92.8 (syn, minor), 98.6 (syn,
major), 105.7 (anti, major) and 115.6 (anti, minor) min
using hexane/i-PrOH (50/1) as the eluent at a flow rate of
1.0 mL/min. Spectral data of the anti isomer: IR (film) 3461,
2977, 2361, 1705, 1605, 1522, 1458, 1348, 1109, 1034, 853,
750, 702 cm21; 1H NMR (300 MHz, CDCl3) d 8.22 (d, 2H,
J¼8.7 Hz), 7.52 (d, 2H, J¼8.7 Hz), 4.89 (dd, 1H, J¼7.5,
5.7 Hz), 3.33 (d, 1H, J¼5.4 Hz), 2.93 (dq, 1H, J¼7.2,
7.5 Hz), 2.58 (dq, 1H, J¼18.0, 7.2 Hz), 2.38 (dq, 1H, J¼
18.0, 7.2 Hz), 1.04 (d, 3H, J¼7.2 Hz), 1.03 (t, 3H, J¼
7.2 Hz); 13C NMR (75 MHz, CDCl3) d 215.7, 149.5, 147.5,
127.3 (two peaks are overlapped), 123.7 (two peaks are
4.2.16. 2-[Hydroxy(4-nitrophenyl)methyl]-cycropenta-
none. Spectral data of the anti isomer: 1H NMR
(300 MHz, CDCl3) d 8.23 (d, 2H, J¼8.7 Hz), 7.54 (d, 2H,
J¼8.7 Hz), 4.85 (d, 1H, J¼9.3 Hz), 4.79 (s, 1H), 2.53–1.51
(m, 7H); 13C NMR (75 MHz, CDCl3) d 239.6, 148.6, 147.6,
127.3 (two peaks are overlapped), 123.7 (two peaks are
overlapped), 74.4, 55.1, 38.6, 26.9, 20.4; [a]2D9¼295.38
1
(c 0.73, CHCl3). Spectral data of the syn isomer: H NMR
(300 MHz, CDCl3) d 8.21 (d, 2H, J¼9.0 Hz), 7.53 (d, 2H,
J¼8.7 Hz), 5.43 (dd, 1H, J¼3.9, 3.6 Hz), 2.81 (d, 1H,
J¼4.8 Hz), 2.52–1.69 (m, 7H); 13C NMR (75 MHz, CDCl3)
d 219.6, 150.1, 147.1, 126.3 (two peaks are overlapped),
123.6 (two peaks are overlapped), 70.4, 56.1, 38.9, 22.4,
20.3; [a]2D7¼þ18.28 (c 0.66, CHCl3).
4.2.17. 2-[Hydroxy(4-nitrophenyl)methyl]-cycrohexa-
none. Spectral data of the anti isomer: 1H NMR
(300 MHz, CDCl3) d 8.22 (d, 2H, J¼8.7 Hz), 7.51 (d, 2H,
J¼8.7 Hz), 4.90 (dd, 1H, J¼8.4, 3.0 Hz), 4.10 (d, 1H, J¼
3.3 Hz), 2.64–1.35 (m, 9H); 13C NMR (75 MHz, CDCl3) d
214.8, 148.3, 147.5, 127.8 (two peaks are overlapped),
123.5 (two peaks are overlapped), 74.0, 57.1, 42.6, 30.7,
27.6, 24.6; [a]2D9¼þ12.08 (c 1.00, CHCl3). Spectral data of
the syn isomer: 1H NMR (300 MHz, CDCl3) d 8.21 (d, 2H,
J¼9.0 Hz), 7.49 (d, 2H, J¼9.0 Hz), 5.49 (dd, 1H, J¼2.4,
2.4 Hz), 3.20 (d, 1H, J¼3.3 Hz), 2.70–1.50 (m, 9H); 13C
NMR (75 MHz, CDCl3) d 214.2, 149.0, 147.0, 126.6 (two
peaks are overlapped), 123.4 (two peaks are overlapped),

8176
M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
70.7, 56.7, 42.6, 27.9, 25.9, 24.7; [a]2D6¼259.98 (c 1.00,
4. (a) Watanabe, K.; Yamada, Y.; Goto, K. Bull. Chem. Soc. Jpn
1985, 58, 1401. (b) Yamada, Y.; Watanabe, K.; Yasuda, H.
Kyoikugakubu Kiyo, Utsunomiya University, 1989; Vol. 2. p
25; and references cited therein. (c) Yamada, Y. M. A.;
Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int.
Ed. 1997, 36, 1871. (d) Yoshikawa, N.; Yamada, Y. M. A.;
Das, J.; Sasai, H.; Shibasaki, M. J. J. Am. Chem. Soc. 1999,
121, 4168. (e) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000,
122, 12003. (f) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.;
Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 2466; and references cited therein.
(g) Yoshikawa, N.; Kumagami, N.; Matsunaga, S.; Moll, G.;
Oshima, T.; Suzuki, T.; Shibasaki, M. Org. Lett. 2001, 3, 1539.
(h) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001,
123, 3367. (i) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett.
2001, 3, 2497; and references cited therein. (j) Suzuki, T.;
Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi, K.;
Shibasaki, M.; Noyori, R. Tetrahedron Lett. 2001, 42, 4669.
For other catalytic direct aldol reactions, see: (k) Mahrwald,
R.; Gundogan, B. J. Am. Chem. Soc. 1998, 120, 413.
(l) Mascarenhas, C. M.; Duffey, M. O.; Liu, S.-Y.; Morken,
J. P. Org. Lett. 1999, 1, 1427. (m) Loh, T.-P.; Wei, L.-L.; Feng,
L.-C. Synlett 1999, 1059. (n) Taylor, S. J.; Duffey, M. O.;
Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528. (o) Evans,
D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392.
CHCl3).
4.3. Preparation of a single crystal of salt 22 for X-ray
analysis
To a mixture of diamine 4 (2 equiv.) and Gd(OTf)3
(1 equiv.) was added acetone (453 equiv.) at 238C. The
crystal of salt 22 was grown at 2208C under Et2O vapor.
4.4. X-ray crystallographic determination of 22
A single crystal of the 22 complex suitable for X-ray
diffraction analysis was transferred to a glass capillary tube
as quickly as possible under air atmosphere, and the glass
capillary was mounted with a sticky compound on a
goniometer for measurement. Diffraction data were
obtained with graphite-monochromated Mo Ka radiation
on a MAC Science DIP2030 diffractometer at 208 K.
Standard reflections for each data set showed no significant
decrease in intensity throughout the acquisition. The
structure was solved by direct method and refined by full-
matrix least-squares on F. All non-hydrogen atoms were
refined anisotropically, and hydrogens were found by
Fourier synthesis, using isotropic temperature factors.
Crystallographic computations were performed on a Silicon
Graphics INDY computer using the maXus program for
data reduction, determining the structure, refining the
structure, and molecular graphics. MAC DENZO software
5. For a more recent review of enantioselective organocatalysis,
see: Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40,
3727.
was used for cell refinement. Crystal data: a¼8.3460 (5),
6. For selected early studies on amine catalysts, see: (a) Hine, J.;
Menson, B. C.; Jensen, J. H.; Mulders, J. Am. Chem. Soc.
1966, 88, 3367. (b) Tagaki, W.; Guthrie, J. P.; Westheimer,
F. H. Biochemistry 1968, 7, 905. (c) Coward, J. K.; Bruice,
T. C. J. Am. Chem. Soc. 1969, 91, 5329.
3
˚
˚
b¼11.0070 (8), c¼19.920 (2) A, V¼1829.90 (2) A ,
orthorhombic, P212121, Z¼4, m(Mo)¼0.0676 mm21, R¼
0.038, Rw¼0.040, GOF¼1.619, 2388 unique reflections
with I.3.0(I).
7. (a) List, B.; Lerner, R. A.; Barbas, III, C. F. J. Am. Chem. Soc.
2000, 122, 2395. (b) Notz, W.; List, B. J. Am. Chem. Soc.
2000, 122, 7386. (c) List, B.; Pojarliev, P.; Castello, C. Org.
Lett. 2001, 3, 573. (d) Sakthivel, K.; Notz, W.; Bui, T.; Barbas,
C. F.; III, J. Am. Chem. Soc. 2001, 123, 5260. (e) List, B.
Synlett 2001, 1675.
Acknowledgements
We are grateful to Mr S. Kitamura, S. Komai and H. Choshi
(Nagoya University) for performing high resolution mass
spectrometric and elemental analyses.
8. For recent examples of proline-catalyzed reactions, see:
(a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (b) Bui,
T.; Barbas, III, C. F. Tetrahedron Lett. 2000, 41, 6951. (c) List,
B. J. Am. Chem. Soc. 2000, 122, 9336. (d) Notz, W.; Sakthivel,
K.; Bui, T.; Zhong, G.; Barbas, III, C. F. Tetrahedron Lett.
2001, 42, 199. (e) Benaglia, M.; Celentano, G.; Cozzi, F. Adv.
Synth. Catal. 2001, 343, 171. (f) List, B.; Pojarliev, P.; Martin,
H. J. Org. Lett. 2001, 3, 2423. (g) List, B.; Castello, C. Synlett
References
1. For review: Heathcock, C. H. Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 2, p 133 and related
chapters.
´
2001, 1687. (h) Cordova, A.; Notz, W.; Barbas, III, C. F.
J. Org. Chem. 2002, 67, 301. (i) Enders, D.; Seki, A. Synlett
2002, 26. (j) List, B.; Pojarliev, P.; Biller, W. T.; Martin, J. Am.
´
Chem. Soc. 2002, 124, 827. (k) Cordova, A.; Notz, W.; Zhong,
G.; Betancort, J. M.; Barbas, III, C. F. J. Am. Chem. Soc. 2002,
2. For recent reviews of catalytic asymmetric aldol reactions,
see: (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int.
Ed. 2000, 39, 1352. (b) Arya, P.; Qin, H. Tetrahedron 2000,
56, 917. (c) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res.
2000, 33, 432.
´
124, 1842. (l) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz,
W.; Barbas, III, C. F. J. Am. Chem. Soc. 2002, 124, 1866.
9. For pioneering work of proline-catalyzed versions of enamine-
related reaction, see: (a) Yamada, S.; Hiroi, K.; Achiwa, K.
Tetrahedron Lett. 1969, 4233. (b) Eder, U.; Sauer, G.;
Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496. Angew.
Chem. 1971, 83, 492. (c) Hajos, Z. G.; Parrish, D. R. J. Org.
Chem. 1974, 39, 1615.
3. For a review of biological methods, see: class I aldolases and
catalytic antibodies which involve a protonic acid and two
(amino) basic groups are remarkably useful for the asymmetric
direct aldol reaction, see: (a) Hoffmann, T.; Zhong, G.; List,
B.; Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R. A.;
Barbas, III, C. F. J. Am. Chem. Soc. 1998, 120, 2768.
(b) Turner, J. M.; Bui, T.; Lerner, R. A.; Barbas, III, C. F.; List,
B. Chem. Eur. J. 2000, 2772; and references cited therein.
10. For reviews of enamine, see: (a) Cook, A. G. Enamines:
Synthesis, Structure, and Reactions; Marcel Dekker: New

M. Nakadai et al. / Tetrahedron 58 (2002) 8167–8177
8177
York/London, 1969. (b) Hickmott, P. W. Tetrahedron 1982,
38, 1975.
T. Tetrahedron 1981, 37, 4111. (e) Mukaiyama, T.; Iwasawa,
N.; Stevens, R. W.; Haga, T. Tetrahedron 1984, 40, 1381.
(f) Mukaiyama, T.; Kobayashi, S.; Sano, T. Tetrahedron 1984,
46, 4653. (g) Hendrie, T.; Kobayashi, S.; Sano, T. Tetrahedron
1984, 46, 4653. (h) Kobayashi, S.; Uchiro, H.; Fujishita, Y.;
Shiina, I.; Mukaiyama, T. J. J. Am. Chem. Soc. 1991, 113,
4247. (i) Yuste, F.; Ortiz, B.; Carrasco, A.; Peralta, M.;
Quintero, L.; Schez-Obregon, R.; Walls, F.; Ruano, J. L. G.
Tetrahedron: Asymmetry 2000, 11, 3079.
11. For selected early studies on diamine, see: (a) Kallen, R. G.;
Jecks, W. P. J. Biol. Chem. 1966, 241, 5845. (b) Benkovic,
S. J.; Benkovic, P. A.; Comfort, D. R. J. Am. Chem. Soc. 1969,
91, 5270. (c) Benkovic, S. J.; Benkovic, P. A.; Chrzanowski,
R. J. Am. Chem. Soc. 1970, 92, 523. (d) Koshechkina, L. P.;
Mel’nichenko, I. V. Ukr. Khim. Zhur. 1974, 40, 172; and
references cited therein. (e) Koshechkina, L. P.; Yasnikov,
A. A. Ukr. Khim. Zhur. 1974, 40, 948. (f) Tuszynski, G. P.;
Kallen, R. G. J. Am. Chem. Soc. 1975, 97, 2860. (g) Tobias,
P. S.; Kallen, R. G. J. Am. Chem. Soc. 1975, 97, 6530; and
references cited therein. For small diamine–protonic acid
modules directed to the effective formation of iminium-salts:
(h) Hine, J.; Chou, Y. J. Org. Chem. 1981, 46, 649; and
references cited therein. Diamines resulting mainly in the
formation of dehydration products, see: (i) Choudary, B. M.;
Kantam, M. L.; Sreekanth, P.; Bandopadhay, T.; Figueras, F.;
Tuel, A. J. J. Mol. Cat. A: Chem. 1999, 142, 361. (j) Sercheli,
R.; Vargas, R. M.; Sheldon, R. A.; Schechardt, U. J. Mol. Cat.
A: Chem. 1999, 148, 173. Dehydrated homo-aldol adducts
were formed in the presence of catalytic pyrrolidine and
PhCO2H, see: (k) Ishikawa, T.; Uedo, E.; Okada, S.; Saito, S.
Synlett 1999, 450.
´
16. Subramanian, L. R.; Garcıa, A. Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester,
1995; Vol. 7, pp 5142–5146.
17. Crystallographic data (excluding structure factors) for the
X-ray crystal structure analysis reported in this paper have
been deposited with Cambridge Crystallographic Data Center
(CCDC) as supplementary publication no. CCDC-184706.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ44-1223-336-033, e-mail: deposit@ccdc.cam.ac.uk).
18. Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157.
19. (a) von Heinzer, F.; Soukup, A.; Eschenmoser, A. Helv. Chim.
Acta 1978, 61, 2851. (b) Sternbach, D.; Shibuya, M.; Jaisli, F.;
Bonetti, M.; Eschenmoser, A. Angew. Chem., Int. Ed. 1979,
18, 634.
12. In the meanwhile, diamine 4-(1S)-camphorsulfonic acid
catalayst was reported to promote the direct aldol reaction
and the asymmetric three-component Mannich-type reaction
by Barbas, III, see Refs. 7d,8d. Diamine 4 alone tested for the
Mannich-type reaction by List, see Ref. 8j and: supporting
information of Ref. 8c. Diamine 4 alone tested for the direct
asymmetric Michael reaction and the asymmetric Robinson
annulation reaction by Barbas, III, see Ref. 8b and: (a)
Betancort, J. M.; Barbas, III, C. F. Org. Lett. 2001, 3, 3737.
(b) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.;
Barbas, III, C. F. Tetrahedron Lett. 2001, 42, 4441.
´ ´
20. Echavarren, A.; Galan, A.; Mendoza, J.; Salmeron, A.; Lehn,
J.-M. Helv. Chim. Acta 1988, 71, 685.
21. Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
22. (a) Sorensen, J. B.; Lewin, A. H.; Bowen, J. P. J. Org. Chem.
2001, 66, 4105. (b) Bahmanyar, S.; Houk, K. N. J. Am. Chem.
Soc. 2001, 123, 11273.
23. Novartis, A.-G. S.; Brundish, D. E.; Lyndon, N.; Le Grand,
D. M.; Menear, K. A.; Smith, G. P.; Allen, M. C.; Butler, P. T;
Cockroft, X.-L. GB Patent 9,746,553 1997. CAS Registry No.
200267-75-0.
24. Waller, F. J.; Barrett, G. M.; Braddock, D. C.; Ramprasad, D.;
McKinnell, R. M.; White, A. J. P.; Williams, D.; Ducray, R. J.
J. Org. Chem. 1999, 64, 2910.
13. Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245.
14. (a) Koppel, I. A.; Taft, R. W.; Anvia, F.; Zhu, S.-Z.; Hu, L.-Q.;
Sung, K.-S.; DesMarteau, D. D.; Yagupolskii, L. M.;
Yagupolskii, Y. L.; Ignat’ev, N. V.; Kondratenko, N. V.;
Volkonskii, A. Y.; Vlasov, V. M.; Notario, R.; Maria, P.-C.
J. Am. Chem. Soc. 1994, 116, 3047. (b) Homepage, D. A.
Evans group, http://daecrl.harvard.edu/
25. Boldrini, G. P.; Lodi, L.; Taglivavini, E.; Trombini, C.;
Umani-R, A. J. Organomet. Chem. 1987, 336, 23.
26. Shokat, K.; Uno, T.; Schultz, P. G. J. Am. Chem. Soc. 1994,
116, 2261.
27. The relative configuration (syn or anti) was determined by
the use of 1H NMR spectroscopy. (a) Heathcock, H. C.
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic:
Orland, 1984; Vol. 3, pp 111–212 Part B. (b) House, H. O.;
Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D. J. Am.
Chem. Soc. 1973, 95, 3310.
15. These diamines were prepared by the methods previously
described, see: (a) Saito, I.; Kikugawa, Y.; Yamada, S. Chem.
Pharm. Bull. 1970, 18, 1731. (b) Asami, M.; Ohno, H.;
Kobayashi, S.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1978, 51,
1869. (c) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.;
Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455. (d) Mukaiyama,