that our catalyst provided improved yield and ee at the low loading
of 5 mol% (R)-PicAm-2 (Scheme 2, product 9).
2 (13.8 mg, 0.025 mmol, 5.0 mol%, MW = 550.58) or (ii) the
1 : 1 salt of (S,S)-D-tartaric acid and (R)-PicAm-2 (11.3 mg,
0.025 mmol, 5.0 mol%, MW = 452.50) and the sodium salt of
dodecylbenzenesulfonate (NaDBSA) (8.7 mg, 0.025 mmol, 5.0
mol%, MW = 348.48), or (iii) the 1-naphthalenesulfonic acid (1-
NSA) salt of (S)-PicAm-2 (12.8 mg, 0.025 mmol, 5.0 mol%, MW
= 510.65). To this was added the ketone (1.65 mmol, 3.3 equiv)
and the aldehyde (0.5 mmol, 1.0 equiv). This mixture was stirred
and heated at 45 ◦C for the specified time. The reaction was
quenched by adding water (10 mL) and extracting with EtOAc
(10 mL ¥ 3). The combined organic extracts were dried (Na2SO4),
evaporated (Rot Vap), and high vacuum dried. The resulting
A similar trend was observed for aldol products 10 and 11.
Reaction of N–Boc-piperidone with 4-Cl-benzaldehyde in the
presence of 5 mol% (S)-PicAm-2 provided product 10 (55% yield,
66 : 1 dr, and >99% ee). Two other organocatalyst reports exist for
its synthesis, one uses a 10 mol% loading (40% yield, 4 : 1 dr, 74%
ee),26 while the other uses a 20 mol% loading (80% yield, 97 : 3 dr,
95% ee).8f
For the reaction of 4-ketalcyclohexanone with 4-
nitrobenzaldehyde we examined the effect of lowering the
ketone/aldehyde ratio to 2 : 1. Using 5 mol% (S)-PicAm-
2, product 11 (Scheme 2) was obtained in excellent yield
(91%), dr (65 : 1), and ee (98%). Five prior literature reports
are noted for product 11.9a,12,22b,27 One study was clearly
superior regarding catalyst loading, using 1 mol% of a trans-4-
silylhydroxyproline/amide-alcohol (four stereogenic centers), but
the yield (75%), dr (9 : 1), and ee (95%) are considerably lower and
the reaction time significantly longer (70 h vs. 21 h).9a In another
study, 5 mol% of a different trans-4-silylhydroxyproline/amide-
alcohol resulted in a 90% yield, 45 : 1 dr, and 94% ee.22b This result
was possible when using the ketone in solvent like volumes after
four days of reaction. Our final aldol product (12) is reported here
for the first time in the literature.
1
crude product was examined by H NMR to determine the dr.
The crude product was then purified by column chromatography
(EtOAc/petroleum ether). The chromatography purified aldol
products were then examined by HPLC to determine their ee.
The relative and absolute configurations of products 3–11 were
1
determined by comparison with the known H NMR data and
by direct comparison with the literature available HPLC data for
aldol products 3–11. Compound 12 is new and was identified as
the anti product based on its 1H NMR chemical shift data.
Notes and references
Although preliminary, a mechanism justifying the observed
diastereo- and enantiocontrol is offered in Fig. 2. Whether these
types of reactions are occuring in, on, or at the organic–water
interface is still a matter of intense discussion in the literature. For
now we can say that a concentrated organic phase is observed on
the water during our reactions.
1 B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000,
122, 2395–2396.
2 (a) For recent reviews, see: M. Raj and V. K. Singh, Chem. Commun.,
2009, 6687–6703; (b) J. Paradowska, M. Stodulski and J. Mlynarski,
Angew. Chem., Int. Ed., 2009, 48, 4288–4297; (c) L. M. Geary and P. G.
Hultin, Tetrahedron: Asymmetry, 2009, 20, 131–173; (d) J. Mlynarski
and J. Paradowska, Chem. Soc. Rev., 2008, 37, 1502–1511; (e) C.
Allemann, R. Gordillo, F. R. Clemente, P. H.-Y. Cheong and K. N.
Houk, Acc. Chem. Res., 2004, 37, 558–569.
3 To the best of our knowledge, Cinchona alkaloid template examples
have yet to be demonstrated with low catalyst loading, for a 10 mol%
loading example see: B.-L. Zheng, Q.-Z. Liu, C.-S. Guo, X.-L. Wang
and L. He, Org. Biomol. Chem., 2007, 5, 2913–2915.
4 S. Aratake, T. Itoh, T. Okano, N. Nagae, T. Sumiya, M. Shoji and Y.
Hayashi, Chem.–Eur. J., 2007, 13, 10246–10256.
5 J. Huang, X. Zhang and D. W. Armstrong, Angew. Chem., Int. Ed.,
2007, 46, 9073–9077.
6 F. Giacalone, M. Gruttadauria, P. L. Meo, S. Riela and R. Noto, Adv.
Synth. Catal., 2008, 350, 2747–2760.
Fig. 2 Proposed transition state model.
7 X. Wu, Z. Jiang, H.-M. Shen and Y. Lu, Adv. Synth. Catal., 2007, 349,
812–816.
8 Valuable proline-amide alcohols were first introduced by Gong in 2003
for acetone activation, see ref. 8g. By now, the development of proline-
amide alcohols, proline-bisamides, and proline-amides is extensive. The
following are not comprehensive but representative: (a) Y. Okuyama,
H. Nakano, Y. Watanabe, M. Makabe, M. Takeshita, K. Uwai, C.
Kabuto and E. Kwon, Tetrahedron Lett., 2009, 50, 193–197; (b) J. N.
Moorthy and S. Saha, Eur. J. Org. Chem., 2009, 739–748; (c) Y.-N. Jia,
F.-C. Wu, X. Ma, G.-J. Zhu and C.-S. Da, Tetrahedron Lett., 2009, 50,
3059–3062; (d) G. Guillena, M. C. Hita, C. Na´jera and D. F. Vio´zquez,
J. Org. Chem., 2008, 73, 5933–5943; (e) X.-H. Chen, S.-W. Luo, Z. Tang,
L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang and L.-Z. Gong, Chem.–Eur. J., 2007,
13, 689–701; (f) J.-R. Chen, X.-Y. Li, X.-N. Xing and W.-J. Xiao, J. Org.
Chem., 2006, 71, 8198–8202; (g) Z. Tang, F. Jiang, L.-T. Yu, X. Cui,
L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang and Y.-D. Wu, J. Am. Chem. Soc.,
2003, 125, 5262–5263.
Conclusions
In summary, the 2-picolylamine template has been established as a
promising new organocatalyst. A chiral version containing a single
stereogenic center, (R)- and (S)-PicAm (2), has been identified
as allowing fast and highly stereoselective anti-aldol product
formation at a low catalyst loading (5 mol%). Importantly, PicAm-
2 excelled when examining more functionalized ketone substrates.
The new template is likely to be amenable to mechanistically
related organocatalytic reactions.
Experimental
9 (a) J.-F. Zhao, L. He, J. Jiang, Z. Tang, L.-F. Cun and L.-Z. Gong,
Tetrahedron Lett., 2008, 49, 3372–3375; (b) Z. Tang, Z.-H. Yang, X.-H.
Chen, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang and L.-Z. Gong, J. Am. Chem.
Soc., 2005, 127, 9285–9289.
General procedure for enantioselective aldol reactions (compounds
3–12)
10 (a) M. R. Vishnumaya and V. K. Singh, J. Org. Chem., 2009, 74,
4289–4297; (b) S. Gandhi and V. K. Singh, J. Org. Chem., 2008, 73,
9411–9416.
To distilled water or brine (1.0 mL, 0.5 M) was added: (i) the
2,4-dinitrobenzenesulfonic acid (2,4-DNBSA) salt of (S)-PicAm-
4088 | Org. Biomol. Chem., 2010, 8, 4085–4089
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