Chiral primary-tertiary diamine-bronsted acid salt catalyzed syn-selective cross-aldol reaction of aldehydes

Article abstract of DOI:10.1021/jo100976e

(Figure presented) Highly syn-selective cross-aldol reaction of aldehydes has remained a challenging subject in the field of aminocatalysis. To achieve this end, chiral primary amines have been explored and the primary-tertiary diamine-Bronsted acid salts are found to promote the cross-aldol reactions of aldehydes with high activity and syn selectivity. Among various vicinal diamines screened, l-phenylalanine derived 2a/TfOH conjugate is identified as the optimal catalyst, showing good catalytic activity (up to 97% yield) and high syn selectivities (syn/anti up to 24:1, 87% ee). The current catalysis works selectively with small aliphatic aldehydes donors such as propionaldehyde and isobutyraldehyde, but not with aliphatic aldehydes bearing larger β-substitute (>Me). In addition, the use of 2a/TfOH conjugate has also enabled the first syn-selective cross-aldol reactions of glycoaldehyde donors.

Full text of DOI:10.1021/jo100976e

pubs.acs.org/joc
Chiral Primary-Tertiary Diamine-Brønsted Acid Salt Catalyzed
Syn-Selective Cross-Aldol Reaction of Aldehydes
Jiuyuan Li, Niankai Fu, Xin Li, Sanzhong Luo,* and Jin-Pei Cheng
Beijing National Laboratory for Molecule Sciences (BNLMS), CAS Key Laboratory for Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190 China
luosz@iccas.ac.cn
Received April 8, 2010
Highly syn-selective cross-aldol reaction of aldehydes has remained a challenging subject in the field
of aminocatalysis. To achieve this end, chiral primary amines have been explored and the
primary-tertiary diamine-Brønsted acid salts are found to promote the cross-aldol reactions of
aldehydes with high activity and syn selectivity. Among various vicinal diamines screened, L-pheny-
lalanine derived 2a/TfOH conjugate is identified as the optimal catalyst, showing good catalytic
activity (up to 97% yield) and high syn selectivities (syn/anti up to 24:1, 87% ee). The current catalysis
works selectively with small aliphatic aldehydes donors such as propionaldehyde and isobutyralde-
hyde, but not with aliphatic aldehydes bearing larger β-substitute (>Me). In addition, the use of 2a/
TfOH conjugate has also enabled the first syn-selective cross-aldol reactions of glycoaldehyde donors.
Introduction
pyrrolidines such as L-proline, have enabled a range of
asymmetric direct aldol reactions.2 In this area, cross-aldol
reactions of aldehydes have been known to be difficult because
of the various side products with enolizable aldehydes and the
accompanying uncontrolled self-aldolization.2f,3 With judi-
cious selection of coupling partners and strict control of
reaction conditions, chiral secondary amines such as L-proline
and MacMillan’s imidazoline catalyst have been shown to
catalyze cross-aldol reactions of aldehdyes. In most of the
secondary amine catalyses, the reactions mainly afford anti-
diastereoselctive aldol products.4 In contrast, syn-selective
cross-aldol reactions of aldehdyes have been much less ex-
plored. The development of syn-selective cross-aldol reactions
with a simple chiral catalyst is still highly desirable and has
remained an elusive goal until recently.
The aldol reaction, a fundamental C-C bond-forming
reaction, undergoes constant rebirth echoing the advances
in modern organic synthesis.1 In the past decade, enamine-
based organocatalysts, exemplified by the typical chiral
(1) For reviews on direct aldol reactions, see: (a) Modern Aldol Additions;
Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004. (b) Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352–1374. (c) Palomo, C.; Oiarbide,
M.; Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65–75. (d) Mukiyama, T. Angew.
Chem., Int. Ed. 2004, 43, 5590. (e) Denmark, S. E.; Stavenger, R. A. Acc. Chem.
Res. 2000, 33, 432–440. (f) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.;
Shibasaki, M. Angew. Chem., Int. Ed. 1997, 36, 1871. (g) Johnson, J. S.; Evans,
D. A. Acc. Chem. Res. 2000, 33, 325–335.
(2) For reviews on chiral amine catalyzed direct aldol reactions, see:
(a) Dalko, P. L.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5176.
(b) Berkessel, A.; Groger, H. Asymmetric Organocatalysis: Wiley-VCH:
Weinheim, 2005. (c) List, B. Acc. Chem. Res. 2004, 37, 548–557. (d) List, B.
Chem. Commun. 2006, 819–824. (e) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc.
Chem. Res. 2004, 37, 580–591. (f) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. Rev. 2007, 107, 5471–5569. (g) Guillena, G.; Najera, C.; Ramon, D. J.
Tetrahedron: Asymmetry 2007, 18, 2249–2293. (h) Geary, L. M.; Hultin, P. G.
Tetrahedron: Asymmetry 2007, 20, 131–173. For leading examples, see: (i) List,
B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395–2396.
(j) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001,
123, 5260–5267. (k) Torri, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983–1986. (l) Tang, Z.; Yang, Z.-H.; Chen,
X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005,
127, 9285–9289.
Maruoka and co-workers recently reported the first ex-
ample of syn-selective cross-aldol reaction of aldehydes
by an axially chiral secondary aminocatalyst. Good syn-
diastereoselectivity and enantioselectivity were obtained
with cross coupling of aliphatic aldehydes and aromatic
ꢀ
ꢀ
ꢀ
(3) (a) Cordova, A; Notz, W.; Barbas, C. F., III. J. Org. Chem. 2002, 67,
301. (b) Aratake, S.; Itoh, T.; Okano, T.; Usui, T.; Shoji, M.; Hayashi, Y.
Chem. Commun. 2007, 2524–2526.
DOI: 10.1021/jo100976e
r
Published on Web 06/03/2010
J. Org. Chem. 2010, 75, 4501–4507 4501
2010 American Chemical Society

Li et al.
JOCArticle
SCHEME 1. Primary Amines for syn-Aldol Reaction
FIGURE 1. Chiral primary amines in this study.
aldehydes.5 Previously, we and others have showed that
primary amines could promote syn-selective aldol reactions
of ketones via thermodynamically favored Z-type enamine
intermediates.6,7 Simple chiral primary-tertiary diamines
such as 1 and 2 (Figure 1) have been successfully applied to
catalyze a range of syn-selective aldol reactions of aliphatic
ketones such as R-hydroxy ketones,7d dihydroxyacetone,7b
pyruvic acetals,7c and acetoacetals.7e With the objective of
developing an effective and simple chiral aminocatalyst for
syn-selective cross-aldol reactions of aldehydes, we reasoned
that the application of chiral primary amine should enable
TABLE 1. Screening of Brønsted Acid in 1b Catalyzed Cross-Aldol
Reaction
entrya
acid
yieldb
syn:antic
eed (%)
1e
2
3
4
5
6
7
8
82
89
90
89
88
91
92
87
2:1
3:1
2:1
3:1
5:1
9:1
5:1
9:1
10:1
39
59
47
58
57
55
54
52
58
(4) For examples of organocatalytic cross-aldol reaction of aldehydes,
see: (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
m-NO2PhCOOH
salicylic acid
DBSA
TFA
PTSA
2,4-DNBS
phthalic acid
TfOH
€
6798–6799. (b) Pihko, P. M.; Erkkila, A. Tetrahedron Lett. 2003, 44, 7607–
7609. (c) Chowdari, N. S.; Ramachary, D. B.; Cordova, A. Tetrahedron Lett.
ꢀ
2002, 43, 9591–9595. (d) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
ꢀ
Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 1343–1345. (e) Storer, R. I.;
MacMillan, D. W. C. Tetrahedron 2004, 60, 7705–7714. (f) Thayumanavan,
R.; Tanaka, F.; Barbas, F. C., III. Org. Lett. 2004, 6, 3541–3544. (g) Hayashi,
Y.; Aratake, S.; Okano, T.; Takahashi, J.; Samiya, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 5527–5529. (h) Mangion, I, K.; Northrup, A. B.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 6722–6724. (i) Reyes,
9
90
<20
10f
TfOH
aUnless otherwise stated, the reaction was performed with 0.5 mmol
of p-nitrobenzaldehyde and 0.5 mL of propionaldehyde for 12 h.
bIsolated yield. cDetermined by 1H NMR. dDetermined by HPLC.
eNo acid was used. fAdditional 10 mol % of m-NO2PhCOOH was used.
DBSA: dodecylsulfonic acid. PTSA: p-toluenesulfonic acid. DNBS:
dinitrobenzenesulfonic acid.
ꢀ
E.; Cordova, A. Tetrahedron. Lett. 2005, 46, 6605–6609. (j) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2004, 43, 2152–2154. (k) Northrup, A. B.; Macmillan, D. W. C. Science 2004,
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305, 1752–1755. (l) Cordova, A.; Engqvist, M.; Ibrahem, I.; Casas, J.;
Sunden, H. Chem. Commun. 2005, 2047–2049. (m) Cordova, A.; Ibrahem,
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I.; Casas, J.; Sunden, H.; Engqvist, M.; Reyes, E. Chem.;Eur. J. 2005, 11,
4772–4784. (n) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa, H. Angew.
Chem., Int. Ed. 2008, 47, 2082–2084. (o) Mase, N.; Tanaka, F.; Barbas, C. F.,
III. Angew. Chem., Int. Ed. 2004, 43, 2420–2423. (p) Pidathala, C.; Hoang, L.;
Vignola, N.; List, B. Angew. Chem., Int. Ed. 2003, 42, 2785. (q) Mans, D. M.;
Pearson, W. H. Org. Lett. 2004, 6, 3305. (r) Mase, N.; Tanaka, F.; Barbas,
C. F., III. Org. Lett. 2003, 5, 4369–4372.
(5) (a) Kano, T.; Yamaguchi, Y.; Tanaka, Y.; Maruoka, K. Angew.
Chem.,Int. Ed. 2007, 46, 1738–1741. (b) Kano, T.; Yamaguchi, Y.; Maruoka,
K. Chem.;Eur. J. 2009, 15, 6678–6687.
(6) For recent reviews for primary amine catalysis, see: (a) Peng, F.; Shao,
Z. J. Mol. Catal. A: Chem. 2008, 285, 1–13. (b) Xu, L.-W.; Luo, J.; Lu, Y.
Chem. Commun. 2009, 1807–1821. (c) Xu, L.-W.; Lu, Y. Org. Biomol. Chem.
2008, 6, 2047–2053. (d) Chen, Y.-C. Synlett. 2008, 1919. For selected examples
syn-diastereoselectivity in this reaction via a Z-enamine
(Scheme 1). A recent report by Mahrwald and co-workers
has shown that chiral primary amine L-histidine was indeed a
viable catalyst for cross-aldol reactions of aldehydes, encoura-
gingly enolizable aldehydes, with good syn-diastereoselectivity
and moderate to good enantioselectivity.8 However, the reac-
tions were limited to R-substituted aliphatic aldehyde donors.
Herein, we report a simple chiral primary-tertiary diamine
derived from L-phenylalanine as a highly effective syn-selective
catalyst for cross-aldol reactions of both R-substituted and
unsubstituted aldehyde donors.
ꢀ
on primary amines catalyzed direct aldol reactions, see: (e) Cordova, A.; Zou,
W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem.;Eur. J. 2006, 12, 5383–
5397. (f) Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 17666–
17667. (g) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int. Ed.
2008, 47, 7656–7658. (h) Li, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen, X.; Liu,
X.; Feng, X.-M. J. Am. Chem. Soc. 2008, 130, 5654–5655. For selected
examples of primary amine catalyzed syn-aldol reaction of ketones, see:
(i) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. J. Am.
Chem. Soc. 2007, 129, 288–289. (j) Ramasastry, S. S. V.; Albertshofer, K.;
Utsumi, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2007, 46,
5572–5575. (k) Xu, X.-Y.; Wang, Y.-Z.; Gong, L.-Z. Org. Lett. 2007, 9, 4247–
4249. (l) Ramasastry, S. S. V.; Albershofer, K.; Utsumi, N.; Barbas, C. F., III.
Org. Lett. 2008, 10, 1621–1624. (m) Wu, X.; Ma, Z.; Ye, Z.; Qian, S.; Zhao, G.
Adv. Synth. Catal. 2009, 351, 158–162.
(7) (a) Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc.
2007, 129, 3074–3075. (b) Luo, S.; Xu, H.; Zhang, L.; Li, J.; Cheng, J.-P. Org.
Lett. 2008, 10, 653–656. (c) Luo, S.; Xu, H.; Chen, L.; Cheng, J.-P. Org. Lett.
2008, 10, 1775–1778. (d) Li, J.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2009, 74,
1747–1750. (e) Luo, S.; Qiao, Y.; Zhang, L.; Li, J.; Li, X.; Cheng, J.-P. J. Org.
Chem. 2009, 74, 9521–9523.
Results and Discussion
Screening of Acidic Additives. We started with our pre-
viously developed primary amine catalyst 1b/TfOH,7a and
the reaction between propionaldehyde and p-nitrobenzalde-
hyde was selected as the model reaction. To our delight, 1b/
TfOH was found to be an effective catalyst for the reaction,
showing good syn-diastereoselectivity (syn/anti 10:1, Table 1,
(8) Markert, M.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2009,
131, 16642–16643.
4502 J. Org. Chem. Vol. 75, No. 13, 2010

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TABLE 2. Solvent Screening for 1b/TfOH-Catalyzed Cross-Aldol
Reaction
TABLE 3. Catalyst Screening for the Cross-Aldol Reaction
entrya
catalyst
yieldb (%)
syn/antic
eed (%)
entrya
solvent
neat
n-hexane
CH2Cl2
DMF
THF
MeOH
toluene
NMP
[BIMB]BF4
H2O (30 equiv)
H2O (10 equiv)
H2O (4 equiv)
H2O (2 equiv)
H2O (1 equiv)
yieldb (%)
syn:antic
eed (%)
1
2
3
4
5
6
7
8
L-Phe-OH
L-His-OH
1a/TfOH
1b/TfOH
1c/TfOH
2a/TfOH
2b/TfOH
2c/TfOH
2d/TfOH
2e/TfOH
2f/TfOH
3/TfOH
trace
14
88
90
92
93
90
91
90
86
94
23
35
73
94
2:1
11:1
5:1
9:1
6:1
8:1
7:1
7:1
4:1
7:1
4:1
4:1
4:1
7:1
12
70
73
70
87
84
85
86
81
73
55
41
71
87
1
2
3
4
5
6
7
8
90
33
36
14
37
16
13
67
74
75
77
80
88
77
10:1
6:1
3:1
5:1
4:1
6:1
16:1
3:1
2:1
5:1
6:1
8:1
11:1
6:1
58
49
37
11
7
29
38
17
55
55
64
68
70
64
9
10
11
12
13
14
15e
9
10e
11e
12f
13f
14f
4/TfOH
5/TfOH
2a/TfOH
aUnless otherwise stated, the reaction was performed with 0.5 mmol
of p-nitrobenzaldehyde and 0.1 mL of propionaldehyde in 0.4 mL of
solvent for 12 h. bIsolated yield. cDetermined by 1H NMR. dDetermined
by HPLC. eThe reaction was performed in the presence of 3 mol % of
catalyst for 24 h at 4 °C.
aUnless otherwise stated, the reaction was performed with 0.5 mmol
of p-nitrobenzaldehyde and 0.1 mL of propionaldehyde in 0.4 mL of
solvent for 12 h. bIsolated yield. cDetermined by 1H NMR. dDetermined
by HPLC. 0.3 mL of propionaldehyde was used. 0.5 mL of propio-
naldehyde was used.
e
f
yield, 10:1 syn/anti, and 58% ee (Table 1, entry 9). The
further addition of a second weak acid such as m-nitroben-
zoic acid led to serious depletion of activity (Table 1, entry 10).
Screening of Solvents. With 1b/TfOH conjugate as the
catalyst, the reaction was next optimized by screening dif-
ferent solvents. Not quite unexpectedly, the reaction be-
comes sluggish in the dilute conditions in organic solvents,
and to make it even worse, the stereoselectivity is also
deteriorated under these conditions (Table 2, entries 2-8).
Neither the use of ionic liquid nor that of the large quantity
of water led to any improvements (Table 2, entries 9 and 10).
Finally, it was delightful to find out that the addition of
small amount of water results in marked improvements of
enantioselectivity (Table 2, entries 11-14). A similar water
effect has previously been observed in similar enamine-based
aldol reactions.10 The optimal quantity of water was then
determined to be 2 equiv (Table 2, entries 11-14). In the
presence of 2 equiv of water under neat conditions, the 1b/
TfOH (10 mol %)-catalyzed reaction afforded the optimal
70% ee and 11:1 syn/anti (Table 2, entry 13). These were then
selected as the optimal conditions for the subsequent studies.
Screening of Chiral Primary Amines. Under the optimized
conditions, a range of chiral primary amines were examined.
The natural primary amino acids such as L-phenylalanine
and L-histine are almost inactive for this reaction (Table 3,
entries 1 and 2). Primary-tertiary vicinal diamines were
again found to be the skeleton of choice for this cross-aldol
entry 9) and moderate enantioselectivity (58% ee). Bearing in
mind that acidic additives generally exhibit significant im-
pact on both activity and stereoselectivity in the catalysis of
1b,7 we next screened different acidic additives in order to
further improve the activity and stereoselectivity. Surpris-
ingly, the reaction proceeded equally well in the absence of
any acidic additives to give 82% yield, albeit with lower
stereoselectivity (2:1 syn/anti, 39% ee, Table 1, entry 1), to
note that similar aldol reaction of acetone barely occurred in
the presence of only 1b without any acidic additive.7a In a
separate experiment with (1R,2R)-N,N,N0,N0-tetramethylcy-
clohexane-1,2-diamine as the catalyst, the reaction afforded
only trace product (<5% yield) with virtually no enantios-
electivity (<2% ee). These observations together with the
obtained significant chiral induction in the catalysis of 1b
suggest that enol-based mechanism is insignificant in the
latter reaction and the catalysis of 1b would occur via
enamine intermediate even in the absence of acids.9
A survey of a range of acidic additives has also been
conducted. As shown in Table 1, both the product yields
and enantioselectivities are generally improved in the pre-
sence of acidic additives but maintain at a similar level re-
gardless of their varying acidity (Table 1, entries 2-9). On
the other hand, the acidity of the added acids was shown to
impact the diastereoselectivity considerably with more acidic
additive generally offering better syn diastereoselectivity.
Accordingly, the most acidic additive TfOH gave the optimal
syn diastereoselectivity (syn/anti 10:1, Table 1, entry 9).
Under this condition (1b/TfOH), the reaction gave 90%
(10) For discussions on water effect in enamine-based aldol reactions, see:
(a) Mlynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502–1511.
(b) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem.,
Int. Ed. 2007, 46, 3798–3800. (c) Brogan, A. P.; Dickerson, T. J.; Janda, K. D.
Angew. Chem., Int. Ed. 2006, 45, 8100–8102. For selected examples, see ref 3b
and: (d) Torri, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983–1986. (e) Zotova, N.; Franzke, A.;
Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2007, 129, 15100.
(9) The reason why acetone and propionaldehyde perform quite differ-
ently remains an intriguing problem. Presumably this may be rationalized by
considering the readily enolizable nature of propionaldehyde.
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Li et al.
JOCArticle
SCHEME 2
TABLE 4. 2a/TfOH-Catalyzed Cross-Aldol Reaction of Aldehydes
SCHEME 3. Determination of the Absolute Configuration
entry (X)a
R1, R2
Me, H
R
yieldb (%) syn/antic eed (%)
1 (3)
2 (3)
3 (3)
4 (3)
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-CNPh
3-Py
4-CF3Ph
2-ClPh
4-ClPh
94/6a
94/6b
93/6c
97/6d
87/6e
87/6f
64/6g
56/6h
75/6i
75/6j
h
7:1
10:1
8:1
13:1
10:1
6:1
6:1
6:1
7:1
2:1
87
84
87
84
84
82
87
81
87
83
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
H, H
attempted but without success, probably due to the low reac-
tivity of these acceptors.
5 (3)
6 (3)e
7 (10)e
8 (10)e
9 (10)e
10 (10)e
11 (10)
12 (10)
13 (10)
14 (10)f
15 (10)f
16 (10)f
17 (10)f
18 (10)f
19 (10)g
With respect to other aldehyde donors, branched aldehyde
such as isobutyraldehyde4o was also applicable in the cata-
lysis of 2d/TFA with moderate to excellent yields and
moderate enantioselectivity (Table 4, entries 14-18). Under
the present conditions, the reaction of acetaldehyde afforded
unfortunately no desired cross-aldol product (Table 4,
entry 11) with aldehyde donors larger than propionaldehyde
such as n-butyraldehyde and isovaleraldehyde in the cataly-
sis of 2a/TfOH (Table 4, entries 12 and 13). These results,
which on one hand clearly define the limitations of the
current reactions, may on the other hand set the basis for
further developing syn-selective cross-aldol reactions as the
primary amine catalyst demonstrates considerable differen-
tiation between enolizable aldehydes. In a competitive ex-
periment, the reaction was conducted in the presence of
equal amounts of propionaldehyde and n-butyralde-
hyde (Scheme 2). Only cross-aldol adduct 6a derived from
propionaldehyde was isolated with slightly lower stereose-
lectivity and yield (unreacted aldehyde recovered), and no
obvious aldol product of n-butyraldehyde was detected in the
reaction mixture (Scheme 2), highlighting the differentiation
power of the catalysis of 2a/TfOH. Concurrently, the origin
of this differentiating effect remains unclear, and a rough
analysis suggests that a larger β-substitute in the putative
Z-enamine (R1>Me, Figure 1; see also Scheme 3) would be
unfavored for the subsequent aldol coupling probably due to
steric hindrance of β-substitute. Further studies to rationa-
lize this phenomena are clearly warranted.
2,4-Cl2Ph
4-PhPh
4-NO2Ph
4-NO2Ph
4-NO2Ph
4-NO2Ph
3-NO2Ph
2-NO2Ph
1-Naph
Et, H
h
h
i-Pr, H
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
97/6k
96/6l
99/6m
45/6n
67/6o
42/6p
76
75
78
69
40
10
BnOCH2
-(CH2)5- 4-NO2Ph
aUnless otherwise stated, the reaction was performed with 0.5 mmol
of aromatic aldehyde and 0.5 mL of alkyl aldehyde in the presence of 1
mmol of H2O. bIsolated yield. cDetermined by 1H NMR. dDetermined
e
by HPLC. Datas for the acetylated 1,3-diol products after reduction
with NaBH4 by treatment with Ac2O/pyridine. f4 equiv of isobutyralde-
hyde was used as donor in toluene in the presence of 10 mol % of 2d/TFA
without H2O. g4 equiv of cyclohexanecarbaldehyde as aldol donor in
toluene in presence of 10 mol % 2d/TFA without H2O, and the product
was isolated directly without reduction with NaBH4. hNo desired cross-
aldol products were isolated.
reaction (Table 3, entries 3-5 and 7-13). Among different
vicinal diamines (3-5) screened, the L-phenylalanine-de-
rived 2a was found to be the optimal catalyst in terms of
both activity and stereoselectivity (Table 3, entry 6). In the
presence of 2a/TfOH (10 mol %), the reactions gave 93%
yield, 6:1 syn/anti, and 87% ee. Primary amine amide
catalyst with multihydrogen bonding 5 was also tested,
showing inferior activity and stereoselectivity. Further study
indicated that the catalyst loading amount could be reduced
to 3 mol % with still high yield and maintained selectivities in
24 h (Table 3, entry 15).
Substrate Scope. Under the optimal conditions, other
substrates including various aldehyde donors and acceptors
were next examined. The reactions between electron-poor
aromatic aldehydes including heteroaromatic aldehyde
such as nicotinaldehyde and propionaldehyde proceeded
smoothly to give the desired aldol products with up to 97%
yield, 13:1 syn/anti, and 87% ee (Table 4, entries 1-10). In all
these cases, only trace self-aldol product of propionaldehyde
was detected. In addition, no further aldolization of the cross-
aldol products was observed. The reactions of electron-rich
aromatic aldehydes or aliphatic aldehyde have also been
Glycol aldehyde and its derivatives are versatile building
blocks in chemical and enzymatic synthesis of carbo-
hydrates.4h,k,m,11 Though the parent glycol aldehyde was
totally inactive in the current catalysis (Table 5, entry 1),
2-benzyloxyacetaldehyde, a protected glycol aldehyde, could
react with p-nitrobenzaldehyde smoothly to afford the de-
sired syn-selective cross-aldol products with DMF as the
optimal solvent (Table 5, entries 2-5). Other aromatic
(11) For selected examples on direct aldol reaction of glycol aldehyde, see:
ꢀ
(a) Garrabou, X.; Castillo, J. A.; Guerard-Helaine, C.; Parella, T.; Joglar, J.;
Lemaire, M.; Clapes, P. Angew. Chem., Int. Ed. 2009, 48, 5521–5525.
ꢀ
ꢀ
(b) Pizzarello, S.; Weber, A. L. Science 2004, 303, 1151. (c) Kofoed, J.;
Machuqueiro, M.; Reymond, J. L.; Barbre, T. Chem. Commun. 2004, 1540–
1541.
4504 J. Org. Chem. Vol. 75, No. 13, 2010

Li et al.
JOCArticle
TABLE 5. 2a/TfOH-Catalyzed Cross-Aldol Reaction of 2-Benzyloxy-
acetaldehyde
In particular, the catalysis of 2a/TfOH has enabled the
first syn-selective aldol reactions of glycoaldehyde donors.
Though the substrate scope is still limited, this study presents
a simple catalyst for the syn-selective cross-aldol reactions of
aldehydes and sets the basis for future development along
this line.
entrya R1
R2
solvent yieldb (%) syn/antic eed (%)
Experimental Section
1
H
4-NO2Ph
DMF
DMF
NMP
CH2Cl2
DMF
DMF
DMF
DMF
trace
71/6q
70/6q
20/6q
90/6q
83/6r
87/6s
74/6t
65/6u
2e
3e
4e
5
Bn 4-NO2Ph
Bn 4-NO2Ph
Bn 4-NO2Ph
Bn 4-NO2Ph
Bn 3-NO2Ph
Bn 2-NO2Ph
Bn 4-CNPh
13:1
13:1
16:1
16:1
24:1
24:1
7:1
80
77
70
79
80
78
85
46
General Information. Commercial reagents were used as
received, unless otherwise indicated. H NMR and 13C NMR
1
were recorded on a 300 MHz instruments, as noted, and are
internally referenced to the residual protic solvent signals.
Chemical shifts are reported in ppm from tetramethylsilane
with the solvent resonance as the internal standard. The fol-
lowing abbreviations were used to designate chemical shift
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
h = heptet, m = multiplet, br = broad. All first-order splitting
patterns were assigned on the basis of the appearance of the
multiplet. Splitting patterns that could not easily interpreted are
designated as multiplet (m) or broad (br). HPLC analysis was
performed using Chiralcel columns purchased. Absolute config-
urations were determined by correlation to literature reported
results.5
6
7
8
9f
Bn BnOCH2- DMF
2:1d
aUnless otherwise stated, the reaction was performed with 0.25 mmol
of aromatic aldehyde and 1 mmol of 2-benzyloxyacetaldehyde in the
presence of 0.5 mmol of H2O in 0.2 mL of solvent. bIsolated yield.
cDetermined by 1H NMR. dDetermined by HPLC. eNo H2O was added.
fThe reaction was performed with 1.0 mmol of 2-benzyloxyacetaldehyde
and 0.1 mmol of 2a/TfOH in 0.2 mL of DMF in the presence of 1 mmol
of H2O, and the product was isolated directly without acetylation after
reduction with NaBH4.
General Procedure for the Cross-Aldol Reaction between
Propionaldehyde and p-Nitrobenzaldehyde. Catalyst 2a/TfOH
(5.4 mg, 0.015 mmol), H2O (18 mg, 1 mmol), propionaldehyde
(0.5 mL), and p-nitrobenzaldehyde (76 mg, 0.5 mmol) were
mixed together and stirred at 4 °C for 24 h. Then the mixture
was concentrated and diluted with 20 mL of CH2Cl2/MeOH
(5:1, v/v) mixed solvent. NaBH4 (76 mg, 2 mmol) was added and
reacted for 10 min, followed by the addition of 20 mL of 3%
NaHCO3 aqueous solution. After 15 min, the organic phase was
separated, and the aqueous phase was extracted with 10 mL of
CH2Cl2. The organics was combined, dried over anhydrous
Na2SO4, and concentrated. The residue was directly purified
by flash column chromatography carefully to afford the aldol
adducts 6a (99 mg, yield 94%).12 1H NMR (CDCl3, 300 MHz): δ
0.80-0.83 (3 H, d, J = 7.2 Hz), 2.07 (1 H, m), 2.19 (1 H, br), 3.35
(1 H, br), 3.72 (1 H, m), 3.85 (1 H, m), 5.14 (1 H, d, J = 2.7 Hz),
7.51-7.54 (2 H, d, J = 8.7 Hz), 8.18-8.22 (2 H, m). 13C NMR
(CDCl3, 75 MHz): δ 9.9, 41.2, 66.4, 75.4, 123.4, 126.8, 147.1,
150.6. HRMS for C10H13NO4 (M): calcd 211.0845, found
211.0843. The enantiomeric excess was determined by HPLC
(AD-H column, 254 nm, 2-propanol/n-hexane = 1:9 as eluent,
25 °C, 1.0 mL/min), tR = 13.9 min (major syn isomer), tR = 15.0
min (minor syn isomer), 87% ee (1R,2S). Aldol products 6a,5a
the anti isomers of 6b-d,f-j had been previously reported,4g
and 6e is a new compound.
SCHEME 4. Proposed Transition States of syn-Aldol Reactions
aldehydes with strong electron-withdrawn groups could also
react with 2-benzyloxyacetaldehyde to afford syn-aldol pro-
ducts in high yield and good stereoselectivities (Table 5,
entries 6-8). However, less active aldehydes as acceptors
gave complicated product mixtures because 2-benzyloxya-
cetaldehyde itself acted as an acceptor4h in the primary amine
catalysis to afford moderate stereoselectivities (Table 5,
entry 9).
Proposed Transition State. The absolute configurations of
the syn-aldol products were determined by comparison of the
optical rotation value with the known compounds and
determined as (1R,2S) for the reduced 1,3-diol products
(Scheme 4).5 Consistent with previous reports, the high syn
selectivity could be reasoned by a Z-enamine transition state.
Cross-aldol products of isobutyraldehydes 6k-n,4o 6o,13 and
6p4r were known compounds.
(1R,2S)-2-Methyl-1-(3-nitrophenyl)propane-1,3-diol (6b). 1H
NMR (CDCl3, 300 MHz): δ 0.73 (3 H, d, J = 7.2 Hz), 1.99 (1 H,
m), 2.95 (2 H, br), 3.60-3.75 (2 H, m), 5.04 (1 H, d, J = 3.6 Hz),
7.42 (1 H, m), 7.60 (1 H, d, J = 7.8 Hz), 8.03 (1 H, d, J = 8.1 Hz),
8.13 (1 H, s). 13C NMR (CDCl3, 75 MHz): δ 9.9, 41.2, 66.3, 75.0,
121.0, 122.1, 129.0, 132.2, 145.3, 148.2. HRMS for C10H13NO4
(M): calcd 211.0845, found 211.0843.
Following this model, the N-H O hydrogen bond was
3
assumed to play a critical role for stabilizing the Z-enamine
in the cases of 2-(benzyloxy)acetaldehyde to achieve high
distereocontrol (Scheme 4).
(1R,2S)-2-Methyl-1-(2-nitrophenyl)propane-1,3-diol (6c). 1H
NMR (CDCl3, 300 MHz): δ 0.88 (3 H, d, J = 6.7 Hz), 2.09 (1 H,
m), 2.64 (2 H, br), 3.72-3.94 (2 H, m), 5.69 (1 H, d, J = 2.7 Hz),
7.42 (1 H, m), 7.64 (1 H, m), 7.87-7.96 (2 H, m). 13C NMR
(CDCl3, 75 MHz): δ 9.3, 39.8, 67.4, 70.9, 124.6, 127.8, 129.0,
Conclusions
To conclude, the simple primary amine catalysts such as
2a/TfOH could catalyze syn-selective cross-aldol reaction of
aldehydes to afford the desired products with up to 97%
yield, 24:1 syn/anti, and 87% ee for a range of substrates.
(12) In several cases, the reduced aldol products were acetylated for
purification.
(13) Matsuno, J.; Iida, D.; Yamanaka, H.; Mukaiyama, T. Tetrahedron
2003, 59, 6739–6750.
J. Org. Chem. Vol. 75, No. 13, 2010 4505

Li et al.
JOCArticle
133.0, 138.7, 147.4. HRMS for C10H13NO4 (M): calcd 211.0845,
found 211.0844.
1.24-1.30 (3 H, m), 1.48-1.58 (5 H, m), 1.66-1.79 (1 H, m),
3.62-3.65 (2 H, m), 4.01-4.03 (1 H, d, J = 5.7 Hz), 4.76-4.77
(1 H, d, J = 5.4 Hz), 7.51-7.53 (2 H, d, J = 8.7 Hz), 8.18-8.20
(2 H, d, J = 8.7 Hz). 13C NMR (CDCl3, 75 MHz): δ 21.3, 21.4,
26.0, 28.7, 30.3, 41.0, 66.0, 81.7, 122.9, 128.6, 147.3, 149.0.
HRMS for C14H19NO4 (M): calcd 265.1314, found 265.1315.
General Procedure for the Cross-Aldol Reaction of 2-Benzy-
loxyacetaldehyde. Catalyst 2a/TfOH (9 mg, 0.025 mmol), H2O
(9 mg, 0.5 mmol), 2-benzyloxyacetaldehyde (150 mg, 1 mmol),
and p-nitrobenzaldehyde (38 mg, 0.25 mmol) were mixed to-
gether and stirred at 4 °C for 24 h. Then the mixture was diluted
with 10 mL of CH2Cl2/MeOH (5:1, v/v) mixed solvent. NaBH4
(76 mg, 2 mmol) was added and reacted for 10 min, followed by
the addition of 10 mL of 3% NaHCO3 aqueous solution. After
15 min, the organic phase was separated, and the aqueous phase
was extracted with 10 mL of CH2Cl2. The organics were com-
bined, dried over anhydrous Na2SO4, and concentrated. The
residue was dissolved in 1 mL of CH2Cl2. To the solution were
added Ac2O (0.2 mL) and pyridine (0.5 mL). After 24 h of
stirring, the reaction was quenched with 1 M HCl and extracted
with ethyl acetate. The combined organics were washed with
brine, dried over anhydrous Na2SO4, and concentrated. The
residue was purified by flash column chromatography on silica
gel to afford (1S,2S)-2-(benzyloxy)-1-(4-nitrophenyl)propane-
1,3-diyl diacetate (6q, 87 mg, 90% yield). 1H NMR (CDCl3, 300
MHz): δ 2.02 (3 H, s), 2.15 (3 H, s), 3.90-3.95 (2 H, m),
4.24-4.26 (1 H, m), 4.46-4.62 (2 H, m), 5.98 (1 H, d, J = 2.1
Hz), 7.15 (2 H, m), 7.24 (3 H, m), 7.49 (2 H, d, J = 8.7 Hz), 8.16
(2 H, dd, J = 6.9 Hz, 1.7 Hz). 13C NMR (CDCl3, 75 MHz): δ
20.7, 20.9, 62.6, 73.4, 76.7, 123.5, 127.8, 128.1, 128.3, 128.4,
137.1, 144.3, 147.8, 169.7, 170.5. HRMS for C20H21NO7 (M):
calcd 387.1318, found 387.1316. The enantiomeric excess was
determined by HPLC (OJ-H column, 254 nm, 2-propanol/
-zhexane =15:85 as eluent, 25 °C, 1.0 mL/min), tR = 40.7
min (minor syn isomer), tR = 47.2 min (major syn isomer), 79%
ee (1S, 2S). Aldol products 6q-t were all new compounds, and
the anti isomer of 6u was a known compound.4h
(1S,2S)-2-(Benzyloxy)-1-(3-nitrophenyl)propane-1,3-diyl Dia-
cetate (6r). 1H NMR (CDCl3, 300 MHz): δ 2.03-2.15 (6 H, m),
3.87-3.98 (2 H, m), 4.22-4.27 (1 H, m), 4.47-4.64 (2 H, m),
5.99 (1 H, d, J = 4.5 Hz), 7.15-7.18 (2 H, m), 7.28-7.31 (3 H,
m), 7.47-7.52 (1 H, m), 7.65-7.67 (1 H, d, J = 7.8 Hz), 8.14-
8.17 (2 H, m). 13C NMR (CDCl3, 75 MHz): δ 20.7, 20.9, 62.5,
73.4, 73.6, 77.8, 122.0, 123.2, 128.1, 128.4, 129.4, 133.0, 137.0,
139.3, 148.3, 169.7, 170.5. HRMS for C20H21NO7 (M): calcd
387.1318, found 387.1316.
(1S,2S)-2-(Benzyloxy)-1-(2-nitrophenyl)propane-1,3-diyl Dia-
cetate (6s). 1H NMR (CDCl3, 300 MHz): δ 1.99 (3 H, s), 2.04 (3
H, s), 4.07-4.13 (2 H, m), 4.16-4.25 (2 H, m), 4.37-4.40 (1 H,
m), 6.39 (1 H, d, J = 2.4 Hz), 6.96-6.99 (2 H, m), 7.11-7.18 (3
H, m), 7.37-7.39 (1 H, m), 7.50-7.55 (1 H, m), 7.60-7.63 (1 H,
m), 7.86-7.88 (1 H, m). 13C NMR (CDCl3, 75 MHz): δ 20.8,
20.9, 62.5, 70.1, 73.8, 76.6, 124.7, 127.9, 128.2, 128.3, 128.7,
129.7, 133.1, 133.4, 137.0, 147.7, 169.7, 170.7. HRMS for
C20H21NO7 (M): calcd 387.1318, found 387.1317.
(1R,2S)-2-Methyl-1-(4-cyanophenyl)propane-1,3-diol (6d). 1H
NMR (CDCl3, 300 MHz): δ 0.72 (3 H, d, J = 7.4 Hz), 1.96 (1 H,
m), 2.63 (2 H, br), 3.59-3.75 (2 H, m), 5.00 (1 H, d, J = 2.9 Hz),
7.39 (2 H, d, J = 8.4 Hz), 7.55-7.58 (2 H, d, 8.4 Hz). 13C NMR
(CDCl3, 75 MHz): δ 9.9, 41.2, 66.5, 75.5, 110.8, 118.9, 126.8,
132.0, 148.6. HRMS for C11H13NO2 (M): calcd 191.0946, found
191.0945.
(1R,2S)-2-Methyl-1-(pyridin-3-yl)propane-1,3-diol (6e). 1H
NMR (CDCl3, 300 MHz): δ 1.87 (3 H, s), 3.79 (1 H, br), 4.21 (2 H,
s), 6.51 (1 H, s), 7.25 (1 H, m), 7.58 (1 H, m), 8.40 (1 H, dd,
J = 4.8 Hz, 1.5 Hz), 8.49 (1 H, d, J = 1.8 Hz). 13C NMR (CDCl3,
75 MHz): δ15.2, 67.9, 120.4, 123.2, 133.7, 136.0, 141.0, 147.0, 149.7.
HRMS for C9H13NO2 (M): calcd 167.0946, found 167.0942.
(1R,2S)-2-Methyl-1-(4-trifluoromethylphenyl)propane-1,3-diol
(6f). The acetylated product was obtained by treated of the
1,3-diols after reduction with Ac2O and pyridine. 1H NMR
(CDCl3, 300 MHz): δ 0.96 (3 H, d, J = 6.9 Hz), 2.03 (3 H, s),
2.12 (3 H, s), 2.32 (1 H, m), 3.79-4.07 (2 H, m), 5.84 (1 H, d, J =
5.7 Hz), 7.38 (2 H, d, J = 8.1 Hz), 7.60 (2 H, d, 8.1 Hz). 13C NMR
(CDCl3, 75 MHz): δ 11.9, 20.7, 20.9, 38.3, 65.4, 75.3, 122.2, 125.3,
125.5, 125.8, 127.4, 129.9, 130.2, 143.2, 169.9, 170.8. HRMS for
C15H17F3O4 (M): calcd 318.1079, found 318.1080.
(1R,2S)-2-Methyl-1-(2-chlorophenyl)propane-1,3-diol (6g).
1H NMR (CDCl3, 300 MHz): δ 0.81-0.87 (3 H, m), 1.94 (3
H, s), 2.05 (3 H, s), 2.35 (1 H, m), 3.93 (2 H, m), 6.11 (1 H, d, J =
4.2 Hz), 7.02-7.08 (1 H, m), 7.18-7.23 (2 H, m), 7.44 (1 H, d,
7.8 Hz). 13C NMR (CDCl3, 75 MHz): δ 10.8, 20.8, 36.4, 65.7,
74.0, 122.0, 127.3, 127.8, 129.1, 133.1, 138.6, 169.6, 170.9.
HRMS for C14H17ClO4 (M): calcd 284.0815, found 284.0814.
(1R,2S)-2-Methyl-1-(4-chlorophenyl)propane-1,3-diol (6h).
1H NMR (CDCl3, 300 MHz): δ 0.97 (3 H, d, J = 0.9 Hz),
2.00-2.10 (6 H, m), 2.33 (1 H, m), 3.76-4.12 (2 H, m), 5.75
(1 H, d, J = 6.0 Hz), 7.19-7.32 (4 H, m). 13C NMR (CDCl3, 75
MHz): δ 12.2, 20.7, 38.3, 65.6, 75.4, 127.8, 128.6, 133.7, 137.6,
169.9, 170.8. HRMS for C14H17ClO4 (M): calcd 284.0815,
found 284.0813.
(1R,2S)-2-Methyl-1-(2,4-dichlorophenyl)propane-1,3-diol (6i). 1H
NMR (CDCl3, 300 MHz): δ 0.85 (3 H, m), 1.95 (3 H, s), 2.03 (3 H,
s), 2.29 (1 H, m), 3.90-3.93 (2 H, m), 6.10 (1 H, d, J = 4.4 Hz),
7.18 (2 H, m), 7.30 (1 H, s). 13C NMR (CDCl3, 75 MHz): δ 11.0,
20.7, 20.8, 65.5, 71.7, 127.1, 128.4, 129.6, 132.8, 134.0, 135.8, 169.6,
170.9. HRMS for C14H16Cl2O4 (M): calcd 318.0426, found
318.0423.
(1R,2S)-2-Methyl-1-(4-phenylphenyl)propane-1,3-diol (6j). 1H
NMR (CDCl3, 300 MHz): δ 0.86-1.02 (3 H, m), 2.02-2.11 (6
H, m), 2.31-2.37 (1 H, m), 3.80-4.15 (2 H, m), 5.69-5.85 (1 H,
m), 7.24-7.57 (9 H, m). 13C NMR (CDCl3, 75 MHz): δ 12.4,
13.6, 20.8, 21.1, 65.5, 65.8, 76.0, 76.6, 126.9, 127.1, 127.2, 127.4,
127.8, 128.9, 137.7, 138.0, 140.7, 140.9, 141.0, 170.1, 171.0.
HRMS for C20H22O4 (M): calcd 326.1518, found 326.1516.
(S)-2,2-Dimethyl-1-(naphthalen-1-yl)propane-1,3-diol (6n). 1H
NMR (CDCl3, 300 MHz): δ 0.82 (3 H, s), 0.86 (3 H, s), 3.33-
3.40 (2 H, m), 3.55-3.67 (2 H, m), 5.64 (1 H, s), 7.42-7.52 (3 H, m),
7.70-7.86 (3 H, m), 8.06 (1 H, d, J = 2.7 Hz). 13C NMR (CDCl3,
75 MHz): δ 19.2, 23.3, 40.3, 72.4, 123.7, 125.1, 125.3, 125.7, 128.1,
128.9, 131.7, 133.4, 137.9. HRMS for C15H18O2 (M): calcd
230.1307, found 230.1309.
(1S,2S)-2-(Benzyloxy)-1-(4-cyanophenyl)propane-1,3-diyl dia-
1
cetate (6t). H NMR (CDCl3, 300 MHz): δ 2.02 (3 H, S), 2.14
(3 H, s), 3.86-3.94 (2 H, m), 4.20-4.24 (1 H, m), 4.45-4.61 (2 H,
m), 5.93 (1 H, d, J = 4.2 Hz), 7.14-7.18 (2 H, m), 7.27-7.31 (3 H,
m), 7.44 (2 H, d, J = 8.4 Hz), 7.62 (2 H, d, J = 8.4 Hz). 13C NMR
(CDCl3, 75 MHz): δ 20.8, 20.9, 62.6, 73.4, 73.9, 77.8, 112.1, 118.5,
127.6, 128.0, 128.4, 132.2, 137.1, 142.3, 160.7, 170.5, 193.2. HRMS
for C21H21NO5 (M): calcd 367.1420, found 367.1421.
(R)-4-(Benzyloxy)-2,2-dimethylbutane-1,3-diol (6o). 1H NMR
(CDCl3, 300 MHz): δ 0.90 (3 H, s), 0.91 (3 H, s), 3.00 (1 H, br),
3.12 (1 H, t), 3.44-3.51 (3 H, m), 3.59-3.63 (1 H, m), 3.73-3.76
(1 H, d, J = 8.4 Hz), 4.56 (2 H, s), 7.30-7.36 (5 H, m). 13C NMR
(CDCl3, 75 MHz): δ 19.4, 22.5, 37.4, 71.2, 71.7, 73.5, 76.6, 127.8,
127.9, 128.5, 137.7. HRMS for C13H20O3 (M): calcd 224.1412,
found 224.1415.
(2S,3S)-2,4-Bis(benzyloxy)butane-1,3-diol (6u). 1H NMR
(CDCl3, 300 MHz): δ 2.43 (1 H, br), 2.74 (1 H, br), 3.51-3.67
(3 H, m), 3.63-3.67 (2 H, m), 3.94-3.97 (1 H, m), 4.48-4.70
(4 H, m), 7.27-7.37 (10 H, m). 13C NMR (CDCl3, 75 MHz): δ
61.5, 70.8, 70.9, 72.3, 73.5, 76.6, 127.9, 128.0, 128.1, 128.5, 128.6,
(S)-(1-(Bydroxymethyl)cyclohexyl)(4-nitrophenyl)methanol
(6p). 1H NMR (CDCl3, 300 MHz): δ 1.11-1.19 (1 H, m),
4506 J. Org. Chem. Vol. 75, No. 13, 2010

Li et al.
JOCArticle
137.7, 137.9. HRMS for C18H23O4 (M þ H): calcd 303.1596,
found 303.1592.
(CDCl3, 300 MHz): δ 0.77 (3 H, s), 0.82-0.84 (3 H, d, J = 7.2
Hz), 1.24 (3 H, s), 2.00-2.04 (1 H, m), 3.44-3.53 (2 H, m),
3.67-3.73 (3 H, m), 4.59 (1 H, d, J = 2.4 Hz), 5.40 (1 H, s),
7.52-7.55 (2 H, d, J = 8.4 Hz), 8.18-8.20 (2 H, d, J = 8.7 Hz).
13C NMR (CDCl3, 75 MHz): δ 7.1, 21.0, 21.8, 30.3, 43.8, 71.8,
77.2, 77.8, 104.0, 123.1, 126.5, 146.3, 150.7. HRMS for C15H21-
NO5 (M): calcd 295.1420, found 295.1422. The absolute con-
figuration of 7 was determined as (1R,2R), and the reduced
cross-aldol product 6a was thus determined as (1R,2S).
Typical Procedure for Determining the Absolute Configura-
tion. After the reaction between propional and p-nitrobenzal-
dehyde (0.5 mmol) catalyzed by 2a/TfOH was finished, the
mixture was diluted with 5 mL of aqueous NaCl solution
(2 M) and extracted with CH2Cl2 (3 mL) three times. The
organics were combined and dried with anhydrous Na2SO4.
After concentration in vacuo, the residue was dissolved in 2 mL
of CH2Cl2. To the solution were added 2,2-dimethyl-1,3-propa-
nediol (62 mg, 0.6 mmol), triethyl orthoformate (0.091 mL, 0.55
mmol), and p-toluenesulfonic acid (9 mg, 0.05 mmol) sequen-
tially at room temperature. After 4 h of stirring, the reaction was
quenched with water and extracted with ethyl acetate. The
combined organics were washed with brine, dried over anhy-
drous Na2SO4, and concentrated. The residue was purified by
flash column chromatography on silica gel to afford (1R,2R)-
2-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-nitrophenyl)propan-1-ol
(7, 93 mg, 63% yield). [R]25D -8.9 (CHCl3, c = 1.0). 1H NMR
Acknowledgment. This project was supported by the Natural
Science Foundation of China (NSFC 20702052 and 20972163),
the Ministry of Science and Technology (2009ZX09501-018),
and the Chinese Academy of Sciences.
Supporting Information Available: NMR spectra and HPLC
traces for aldol products. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 13, 2010 4507