Organocatalytic activity of α,α-dipeptide derivatives of (S)-proline in the asymmetric aldol reaction in absence of solvent. Evidence for non-covalent π-π Interactions in the transition state

Article abstract of DOI:10.1016/j.tetlet.2015.01.079

The trend in the magnitude of stereoselectivities observed in the asymmetric aldol reaction between cyclohexanone and aromatic aldehydes with varying electron densities, catalyzed by dipeptidic organocatalyst (S,S)-1d, which contains an aromatic naphthyl substituent in the acyclic amino acid residue, is in line with expectation based on π-π stacking interactions between the aromatic ring on the organocatalyst and the aromatic aldehydes. Such non-covalent interactions are apparently enhanced under solvent-free mechanochemical activation in a ball mill.

Full text of DOI:10.1016/j.tetlet.2015.01.079

Tetrahedron Letters 56 (2015) 1144–1148
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic activity of
a,a-dipeptide derivatives of (S)-proline
in the asymmetric aldol reaction in absence of solvent. Evidence
for non-covalent
p–p
interactions in the transition state
⇑
Elizabeth Machuca, Eusebio Juaristi
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, 07000 México D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
The trend in the magnitude of stereoselectivities observed in the asymmetric aldol reaction between
cyclohexanone and aromatic aldehydes with varying electron densities, catalyzed by dipeptidic organo-
catalyst (S,S)-1d, which contains an aromatic naphthyl substituent in the acyclic amino acid residue, is in
Received 10 December 2014
Accepted 12 January 2015
Available online 20 January 2015
line with expectation based on p–p stacking interactions between the aromatic ring on the organocata-
lyst and the aromatic aldehydes. Such non-covalent interactions are apparently enhanced under solvent-
free mechanochemical activation in a ball mill.
Keywords:
Organocatalysis
Dipeptides
Ó 2015 Elsevier Ltd. All rights reserved.
Asymmetric aldol reaction
Ball milling
Solvent-free reactions
Introduction
Table 1
Direct asymmetric aldol reaction of cyclohexanone with 4-nitrobenzaldehyde cata-
lyzed by dipeptides (S,S)-1a–ca
The area of organocatalysis has grown exponentially since the
realization that small organic molecules can catalyze organic reac-
tions with efficiency comparable to that exhibited by enzymes.1 In
particular, proline and proline derivatives have been widely stud-
ied as chiral organocatalysts in asymmetric organic transforma-
tions.2 Application of these organocatalysts in asymmetric aldol
reactions is of great importance both in academics and in the phar-
maceutical industry.3 Several research groups have recently
reported the successful application of dipeptide and tripeptide
derivatives containing the proline residue as chiral organocatalysts
in asymmetric reactions.4
O
O
OH
O
1a-c
H
+
+
syn isomer
Ball-milling
2760 rpm
NO2
NO2
anti isomer
2
3
4
Cat.
O
O
O
N
H
N
H
N
H
HN
HN
HN
NH
OMe
OMe
OMe
O
O
O
In this context, we recently examined the aldol reaction
between representative ketones and various aromatic aldehydes
in the presence of organocatalysts (S,S)-1a–c.5 The reaction was
carried out at ꢀ20 °C in a ball mill at 2760 rpm, in the presence
of 1.1 equiv H2O, and PhCO2H (5 mol %) as additive. After 6 h of
milling, all six catalysts 1a–c afforded the aldol product in good
yields, high anti diastereoselectivity and high enantioselectivity
(Table 1).
1a
1b
(S,S)-
1c
(S,S)-
(S,S)-
Entry
Cat.
Yieldb (%)
dr (anti/syn)c
eed (%)
1
2
3
1a
1b
1c
89
79
88
93:7
91:9
92:8
94
85
>98
a
Reaction conditions: cyclohexanone (2, 0.22 mmol), 4-nitrobenzaldehyde (3,
Best results were generated with dipeptide (S,S)-1c as catalyst,
providing the aldol product in 88% yield, a diastereomeric ratio
0.20 mmol), catalyst 1a–c (3 mol %), ꢀ20 °C, 1.1 equiv H2O, PhCO2H (5 mol %), 6.0 h.
Best values are highlighted in bold.
b
Isolated yield.
c
Determined by 1H NMR of the crude product.
d
Determined by chiral HPLC.
⇑
Corresponding author. Tel.: +52 55 5747 3722; fax: +52 55 57473897.
E-mail addresses: juaristi@relaq.mx, ejuarist@cinvestav.mx (E. Juaristi).
http://dx.doi.org/10.1016/j.tetlet.2015.01.079
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

E. Machuca, E. Juaristi / Tetrahedron Letters 56 (2015) 1144–1148
1145
of 92:8 in favor of the anti isomer and higher than 98% ee of aldol
(2S,10R)-4.
H
O
H
H
H2O
CO2Me
O H
To account for the observed stereoselectivity, the transition
state presented in Figure 1 was suggested, which takes into
account previously advanced mechanistic proposals where cataly-
sis by dipeptides and prolinamides is operative.6 In particular, the
pyrrolidine functionality in (S,S)-1c activates the ketone through
the formation of a chiral enamine intermediate, while the aldehyde
is activated through the formation of a strong hydrogen bond
involving the amide N–H hydrogen atom.7 In addition, it was
(S)
O
N
H
O
HN
N
H
NO2
proposed that a non-covalent
p–p interaction between aromatic
rings of the catalyst and the aldehydes probably gives rise to a rigid
transition state that induces higher stereoselectivity in the aldol
reaction.8
H2O
Figure 1. Proposed transition state model of the aldol reaction catalyzed by (S,S)-
1c.
O
O
O
HCl-H2N
CO2Me
OMe
Cbz-Cl
OH
OH
N
H
NH
N
NH
O
NaOH ac
0°C to rt
1.- iBB-Cl
Cbz
NMM,THF,-10°C
2.- Pd/C H2
MeOH
1d
Scheme 1. Synthesis of organocatalyst (S,S)-1d.
Table 2
Efficiency of organocatalyst (S,S)-1d in the asymmetric aldol reaction of cyclohexanone as representative ketone with aromatic aldehydes of different electron densitiesa
Cat. 1d
O
O
O
OH
5 mol%
+
H
+
syn isomer
R2
HSBM
30´, 15Hz
R2
R1 R1
R1 R1
anti isomer
2
3
4
Entry
1
Product
Yieldb (%)
dr (anti/syn)c
erd (%)
O
O
O
O
OH
F
F
F
F
99
99:1
99:1
F
4a
OH NO2
2
3
4
94
98
98
96:4
95:5
98:2
95:5
4b
OH
NO2
NO2
89:11
4c
OH
95:5
4d
(continued on next page)

1146
E. Machuca, E. Juaristi / Tetrahedron Letters 56 (2015) 1144–1148
Table 2 (continued)
Entry
Product
Yieldb (%)
dr (anti/syn)c
erd (%)
95:5
O
OH Cl
5
84
94:6
4e
OH
O
O
O
Cl
6
7
8
9
46
97:3
93:7
93:7
96:4
94:6
94:6
92:8
93:7
4f
OH
72
Cl
4g
OH
Br
69
4h
OH
O
68
Br
4i
O
O
O
OH
10
11
99
94:6
94:6
91:9
90:10
93:7
92:8
CN
4j
OH
51
4k
OH
12
7
OMe
4l
a
Reaction conditions: ketone 2 (0.5 mmol), aldehyde 3 (0.25 mmol), catalyst 1d (5 mol %), H2O (2.5 equiv), benzoic acid (20 mol %), rt, 0.5 h, 15 Hz, MM200.
b
c
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by chiral HPLC.
d
H
O
catalyst and the substrate, which are probably responsible for the
high stereoselectivity in aldol product formation. Furthermore,
the absence of solvent under HSBM conditions might reduce
H2O
H
O
N
OMe
O H
O
H
molecular motion so that
p-stacking interactions become more
effective.8
H
O
F
N
F
Results and discussion
H
F
F
Dipeptide (S,S)-1d was prepared by the condensation of
N-Cbz-(S)-proline with the hydrochloride salt of the methyl ester
of (S)-naphthylalanine followed by N-deprotection with Pd/C and
hydrogen (Scheme 1).9
F
H2O
The efficiency of organocatalyst (S,S)-1d in the asymmetric aldol
reaction of cyclohexanone as representative ketone with aromatic
aldehydes of different electron densities was then examined. The
pentafluoro, nitro, chloro, bromo and cyano substituted benzalde-
hydes were chosen as electron-poor aldehydes, whereas
4-hydroxy- and 4-methoxybenzaldehydes were chosen as elec-
tron-rich aldehydes. The reactions were carried out in a ball mill
Figure 2. Proposed transition state model of the aldol reaction catalyzed by (S,S)-
1d.
The present work was undertaken to gather additional informa-
tion that could support the above evidence for the existence of
non-covalent
p–p interactions between aromatic rings of the

E. Machuca, E. Juaristi / Tetrahedron Letters 56 (2015) 1144–1148
1147
Angew. Chem., Int. Ed. 2005, 44, 4212–4215; (h) Enders, D.; Hüttl, M. R. M.;
Grondal, C.; Raabe, G. Nature 2006, 441, 861–863; (i) Palomo, C.; Landa, A.;
Mielgo, A.; Oiarbide, M.; Puente, Á.; Vera, S. Angew. Chem., Int. Ed. 2007, 46,
8431–8435; (j) Olivares-Romero, J. L.; Juaristi, E. Tetrahedron 2008, 64, 9992–
9998; (k) Almasßi, D.; Alonso, D. A.; Nájera, C. Adv. Synth. Catal. 2008, 350, 2467–
2472; (l) Gandhi, S.; Singh, V. K. J. Org. Chem. 2008, 73, 9411–9416; (m) Liu, X.
H.; Lin, L. L.; Feng, X. M. Chem. Commun. 2009, 6145–6158; (n) Chen, X H.; Yu,
J.; Gong, L. Z. Chem. Commun. 2010, 6437–6448; (o) Giacalone, F; Gruttadauria,
M.; Agrigento, P.; Meo, P. L.; Noto, R. Eur. J. Org. Chem. 2010, 5696–5704; (p) Xu,
J W.; Fu, X. K.; Wu, C. L.; Hu, X. Y. Tetrahedron: Asymmetry 2011, 22, 840–850;
(q) Montroni, E.; Sanap, S. P.; Lombardo, M.; Quintavalla, A.; Trombini, C.;
Dhavale, D. D. Adv. Synth. Catal. 2011, 353, 3234–3240; (r) Fotaras, S.; Kokotos,
C. G.; Tsandi, E.; Kokotos, G. Eur. J. Org. Chem. 2011, 1310–1317; (s)
Paradowska, J; Pasternak, M.; Gut, B.; Gryzło, B.; Mlynarski, J. J. Org. Chem.
2012, 77, 173–187; (t) Maycock, C. D.; Ventura, M. R. Tetrahedron: Asymmetry
2012, 23, 1262–1271; (u) Pandey, A. K.; Naduthambi, D.; Thomas, K. M.;
Zondlo, N. J. J. Am. Chem. Soc. 2013, 135, 4333–4363; (v) Nguyen, T.-H.; Toffano,
M.; Bournaud, C.; Vo-Thanh, G. Tetrahedron Lett. 2014, 55, 6377–6380; (w)
Vega-Peñaloza, A.; Sánchez-Antonio, O.; Ávila-Ortiz, C. G.; Escudero-Casao, M.;
Juaristi, E. Asian J. Org. Chem. 2014, 3, 487–496.
apparatus, at ambient temperature and in the presence of
5 mol % catalyst, 2.5 equiv of water, and 20 mol % benzoic acid as
additive.10,11
As shown in Table 2, aldehydes with electron-deficient
substituents on the aromatic ring led to aldol products in
higher stereoselectivity. Similarly, aldol products 4a–j containing
electron-withdrawing groups formed in better yields. (An excep-
tion was the 3-chloro substituted product 4f, that was produced
in a low 46% yield.) Furthermore, aldol products 4a–j were
obtained in very good diastereomeric ratios, in the order of 93:7
anti/syn ratios. Highest stereoselectivity was found in the forma-
tion of aldol product (2S,10R)-4a, which was obtained essentially
as the only stereoisomer, 99:1 anti/syn dr and 99:1 er.
On the other hand, aldol product-4k, which serves as a refer-
ence standard with medium electron density, was obtained with
a yield of 51%, 94:6 anti/syn diastereomeric ratio, and 93:7 enantio-
meric ratio in favor of (2S,10R)-4k. By contrast, aldol adduct 4l aris-
ing from an electron-rich aldehyde was obtained in lower yields, as
a consequence of its lower reactivity. Nevertheless, the diastereo-
meric ratio remained high, in the 90:10 anti/syn range.
3. For authoritative monographs and reviews of the aldol reaction, see: (a)
Mahrwald, R. In Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004; Vols. 1–
2,; (a) Trost, B M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–1632; (b) Bisai,
V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541–4580; (c)Modern Methods
in Stereoselective Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
2013.
4. For salient publications on the use of small peptides as organocatalysts, see: (a)
Oku, J.-I.; Inoue, S. J. Chem. Soc., Chem. Commun. 1981, 229–230; (a) Iyer, M S.;
Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910–
4911; (b) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901–4902;
These observations are in line with expectation based on the
transition state presented in Figure 1; that is, p-stacking between
the electron-rich naphthyl ring on the catalyst and the electron
poor aromatic aldehyde substrate leads to formation of a more
rigid transition state and therefore to a more stereoselective aldol
reaction (Fig. 2).
}
(c) Martin, H. J.; List, B. Synlett 2003, 1901–1902; (d) Szöllosi, G.; London, G.;
Baláspiri, L.; Somlai, C.; Bartók, M. Chirality 2003, 15, S90–S96; (e) Luppi, G.;
Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J. Org.
Chem. 2005, 70, 7418–7421; (f) Colby Davie, E. A.; Mennen, S. M.; Xu, Y.; Miller,
S. J. Chem. Rev. 2007, 107, 5759–5812; (g) Chen, F.; Huang, S.; Zhang, H.; Liu, F.;
Peng, Y. Tetrahedron 2008, 64, 9585–9591; (h) Freund, M.; Schenker, S.;
Tsogoeva, S. B. Org. Biomol. Chem. 2009, 7, 4279–4284; (i) Tsandi, E.; Kokotos, C.
G.; Kousidou, S.; Ragoussis, V.; Kokotos, G. Tetrahedron 2009, 65, 1444–1449; (j)
Wennemers, H. Chem. Commun. 2011, 12036–12041; (k) Kolundzic, F; Noshi,
M. N.; Tjandra, M.; Movassaghi, M.; Miller, S. J. J. Am. Chem. Soc. 2011, 133,
9104–9111; (l) Bayat, S.; Tejo, B. A.; Salleh, A. B.; Abdmalek, E.; Normi, Y. M.;
Rahman, M. B. A. Chirality 2013, 25, 726–734; (m) Yolacan, C.; Mavis, M. E.;
Aydogan, F. Tetrahedron 2014, 70, 3707–3713.
Conclusion
a,a-Dipeptide organocatalyst (S,S)-1d incorporating an elec-
tron-rich aromatic substituent is an efficient activator of the aldol
reaction between cyclohexanone as representative ketone and
substituted aldehydes. Higher stereoselectivity is found with elec-
tron-poor aldehydes, and this is in line with expectation in terms of
5. (a) Hernández, J. G.; Juaristi, E. J. Org. Chem. 2011, 76, 1464–1467; (b)
Hernández, J. G.; Juaristi, E. Tetrahedron 2011, 67, 6953–6959; (c) Hernández, J.
G.; García-López, V.; Juaristi, E. Tetrahedron 2012, 68, 92–97; See, also: (d)
Machuca, E.; Rojas, Y.; Juaristi, E. Asian J. Org. Chem. 2015, 4, 46–53.
6. (a) Dziedzic, P.; Zou, W.; Háfren, J.; Córdova, A. Org. Biomol. Chem. 2006, 4, 38–
40; (b) Fuentes de Arriba, A. L.; Simón, L.; Raposo, C.; Alcázar, V.; Sanz, F.;
Muñiz, F. M.; Morán, J. R. Org. Biomol. Chem. 2010, 8, 2979–2985.
p-stacking between the aromatic rings in the catalyst and in the
aldehyde leading to a more rigid transition state and resulting in
more stereoselective reactions.
7. See, for example: (a) Huang, X.-Y.; Wang, H.-J.; Shi, J. J. Phys. Chem. A 2010, 114,
1068–1081; (b) Gryko, D.; Zimnicka, M.; Lipin´ ski, R. J. Org. Chem. 2007, 72, 964–
970; (c) Wang, B.; Liu, X. W.; Liu, L. Y.; Chang, W. X.; Li, J. Eur. J. Org. Chem. 2010,
5951–5954; (d) Knowles, R R.; Jacobsen, E. N. PNAS 2010, 107, 20678–20685;
(e) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Çelebi-Ölçüm, N.; Houk, K. N.
Chem. Rev. 2011, 111, 5042–5137; (f) Jörres, M.; Schiffers, I.; Atodiresei, I.;
Bolm, C. Org. Lett. 2012, 14, 4518–4521.
Acknowledgments
The authors are indebted to Conacyt-México for financial sup-
port via grant 130826. We are also grateful to Conacyt-México
for a doctoral fellowship to E.M. (No. 245138).
8. (a) Jones, G. B.; Chapman, B. J. Synthesis 1995, 475–497; (b) Gruttadauria, M.;
Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33–57; (c) Hunter, C. A.;
Lawson, K. R.; Perkins, J.; Urch, C. J. Chem. Soc., Perkin Trans. 2 2001, 651–669;
(d) Rashkin, M. J.; Waters, M. L. J. Am. Chem. Soc. 2002, 124, 1860–1861; (e)
Wheeler, S. E. J. Am. Chem. Soc. 2011, 133, 10262–10274; (f) Snyder, S. E.;
Huang, B.-S.; Chu, Y. W.; Lin, H.-S.; Carey, J. R. Chem. Eur. J. 2012, 18, 12663–
12671; (g) Lima, C. F. R. A. C.; Rocha, M. A. A.; Gomes, L. R.; Low, J. N.; Silva, A.
M. S.; Santos, L. M. N. B. F. Chem. Eur. J. 2012, 18, 8934–8943; (h) Martinez, C. R.;
Iverson, B. L. Chem. Sci. 2012, 3, 2191–2201; (i) Hwang, J.; Li, P.; Carroll, W. R.;
Smith, M. D.; Pellechia, P. J.; Shimizu, K. D. J. Am. Chem. Soc. 2014, 136, 14060–
14067; (j) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801–2803;
(k) Giacalone, F; Gruttadauria, M.; Meo, P. L.; Riela, S.; Noto, R. Adv. Synth. Catal.
2008, 350, 2747–2760; (l) An, Y.-J.; Zhang, Y.-X.; Wu, Y.; Liu, Z.-M.; Pi, C.; Tao,
J.-C. Tetrahedron: Asymmetry 2010, 21, 688–694; (m) Saha, S.; Moorthy, J. N.
Tetrahedron Lett. 2010, 51, 912–916; (n) Yamada, S.; Fossey, J. S. Org. Biomol.
Chem. 2011, 9, 7275–7281; (o) Chauhan, P.; Chimni, S. S. Beilstein J. Org. Chem.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.01.
079.
References and notes
1. (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621; (b) Eder, U.;
Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496–497; (c) List, B.;
Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396; (d)
Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
4243–4244; (e) MacMillan, D. W. C. Nature 2008, 455, 304–308; (f) Scheffler,
U.; Mahrwald, R. Chem. Eur. J. 2013, 19, 14346–14396; (g)Stereoselective
Organocatalysis. Bond Formation Methodologies and Activation Modes; Ríos
Torres, R., Ed.; Wiley: New Jersey, 2013.
2. For the use of derivatives of (S)-proline in asymmetric organocatalysts see, for
example: (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc.
2001, 123, 5260–5267; (b) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi,
A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262–5263; (c) Torii,
H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2004, 43, 1983–1986; (d) Córdova, A.; Sundén, H.; Engqvist, M.; Ibrahem, I.;
Casas, J. J. Am. Chem. Soc. 2004, 126, 8914–8915; (e) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84–96; (f)
Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 6964–6965; (g) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M.
´
ˇ ´
2012, 8, 2132–2141; (p) Štrukil, V.; Igrc, M. D.; Eckert-Maksic, M.; Frišcic, T.
Chem. Eur. J. 2012, 18, 8464–8473; (q) Machuca, E.; Juaristi, E. Asymmetric
Organocatalytic Reactions under Ball-Milling. In Ball Milling Towards Green
Synthesis: Applications, Projects, Challenges, Brindaban, R.; Stolle, A., Eds.; Royal
Society of Chemistry, Cambridge, U.K., 2015, Chapter 4, pp. 81–95.
9. Preparation of the organocatalyst dipeptide (S,S)-1d. To a solution of N-Cbz-(S)-
proline (0.1452 g, 0.57 mmol) and NMM (0.07 mL, 0.62 mmol) in dry THF
under nitrogen at 0 °C was added a solution of isobutyl chloroformate (0.07 mL,
0.68 mmol). The resulting mixture was stirred at 0° to 10 °C for 30 min before a
solution of the corresponding
a-amino ester 2-(S)-naphthyl-alanine
hydrochloride (0.1819 g, 0.68 mmol) and NMM (0.08 mL, 0.81 mmol) in dry
THF. After 2 h at 0–10 °C, the reaction mixture was allowed to warm to room
temperature and further stirred overnight. The crude product was

1148
E. Machuca, E. Juaristi / Tetrahedron Letters 56 (2015) 1144–1148
concentrated and extracted with EtOAc. The organic phase was washed with
downfield from tetramethylsilane as an internal reference. Coupling constants
J are given in Hertz (Hz). Molecular weights were determined by means of
high-resolution mass spectrometry on an Agilent LC/MSD-TOF model 1069A.
Infrared spectra (IR) are reported in reciprocal centimeters and were recorded
satd 1 N HCl, satd NaHCO3 and brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by silica gel column chromatography
using CH2Cl2/MeOH (95:5 v/v) as eluent to afford the corresponding N(Cbz)-
(S)-Pro-(S)-2-Nal-CO2Me dipeptide. The dipeptide was then N-deprotected by
hydrogenolysis with hydrogen over 10% Pd/C (50 mg). The reaction mixture
was filtered and washed with methanol, and the filtrate was concentrated. The
crude product was purified by column chromatography using CH2Cl2/MeOH
(95:5 v/v) as eluent to afford the desired dipeptide, (S,S)-proline-2-
naphthylalanine ester 1d.
on
a
spectrophotometer Varian 640-IR FT-IR. Enantiomeric ratios were
Waters 600
measured by chiral HPLC at room temperature using
a
E
equipment fitted with a UV–Vis Waters 2487 detector at 210 or 254 nm,
with Chiralpak AD-H and Chiralcel OD-H columns. Reactions carried out under
ball-milling conditions were performed in a MM200 RETSCH mill, using 5-mL
grinding jars and 2 grinding balls of 7 mm of diameter, both of agate.
Rf = 0.34 [silica gel, DCM/MeOH 95:5], [
a
]
D
ꢀ14.98 (c 1.0, CH3Cl), (FT-IR/ATR,
11. General procedure for the intermolecular aldol reaction catalyzed by dipeptide 1d
cmꢀ1 3316, 2951, 1740, 1666. 1H NMR (500 MHz, CDCl3) d 8.43 (1H, br d,
)
m
under ball milling activation. A mixture of cyclohexanone 2 (0.5 mmol),
J = 7.3 Hz), 7.76 (3H, m), 7.65 (1H, br s), 7.42 (2H, m), 7.27 (2H, m), 4.82 (1H, dd,
J = 7.5, 13.7 Hz), 4.26 (1H, m), 3.65 (3H, s), 3.33–3.25 (2H, m), 3.14–3.09 (1H,
m), 3.03–2.98 (1H, m), 2.27–2.20 (1H, m), 1.90 (1H, m), 1.79–1.60 (2H, m) ppm.
13C NMR (125 MHz, CDCl3) d 171.7, 171.1, 133.7, 133.3, 132.3, 129.2, 128.5,
128.1, 127.6, 127.2, 126.1, 125.7, 59.8, 53.8, 52.3, 46.8, 37.5, 30.5, 24.8 ppm.
HR-ESI-TOF: calculated for C19H23N2O3 [M+H]+: 327.1703 found: 327.1711
(2.3 ppm error).
substituted benzaldehyde 3a–n (0.25 mmol) and catalyst 1d (10 mol %), was
milled for 0.5 h at 15 Hz at room temperature in a MM200 RETSCH mill, in a 5-
mL grinding jar and 2 grinding balls of 7 mm of diameter, both of agate.
Following reaction, the resulting mixture was extracted with EtOAc. The
organic phase was dried over an hour. MgSO4 and concentrated to give the
crude product, which was purified by flash chromatography (silica gel, hexane/
EtOAc, 10:1 to 3:1) to afford the aldol product as an anti/syn diastereomeric
mixture. Enantiomeric ratios in the major diastereomeric product were
determined by HPLC on a chiral column.
10. General information. 1H and 13C NMR spectra were recorded on a Jeol ECA-500
(500 MHz) spectrometer. Chemical shifts (d) are given in parts per million