Asymmetric Mannich reaction of dicarbonyl compounds with α-amido sulfones catalyzed by cinchona alkaloids and synthesis of chiral dihydropyrimidones

Article abstract of DOI:10.1021/jo701777g

(Chemical Equation Presented) The highly enantioselective cinchona alkaloid-catalyzed Mannich reaction of dicarbonyl compounds with α-amido sulfones as acyl imine precursors is described. The reaction requires 10 mol % of the cinchona alkaloid catalyst, w

Full text of DOI:10.1021/jo701777g

Asymmetric Mannich Reaction of Dicarbonyl Compounds with
r-Amido Sulfones Catalyzed by Cinchona Alkaloids and Synthesis
of Chiral Dihydropyrimidones
Sha Lou, Peng Dai, and Scott E. Schaus*
Department of Chemistry, Center for Chemical Methodology and Library DeVelopment, Life Science and
Engineering Building, Boston UniVersity, 24 Cummington Street, Boston, Massachusetts 02215
seschaus@bu.edu
ReceiVed August 21, 2007
The highly enantioselective cinchona alkaloid-catalyzed Mannich reaction of dicarbonyl compounds with
R-amido sulfones as acyl imine precursors is described. The reaction requires 10 mol % of the cinchona
alkaloid catalyst, which serves as a general base to generate acyl imines in situ, and aqueous Na2CO3 to
maintain the concentration of free alkaloid catalyst. The reaction products are obtained in good yields
and high enantioselectivities, and in diastereoselectivities that range from 1:1 to >95:5. The cinchonine-
catalyzed reactions provide practical access to highly functionalized building blocks which have been
employed in the synthesis of chiral dihydropyrimidones, a class of compounds rich in diverse biological
activity. Dihydropyrimidone modifications include a highly diastereoselective hydrogenation of the enamide
moiety, using an H-Cube flow hydrogenator and a Rh(II)-mediated 1,3-dipolar cycloaddition to afford
highly functionalized complex heterocycles.
Introduction
such highly functionalized blocks.3 A class of compounds
readily accessed with these building blocks are 4-aryl-3,4-
dihydropyrimidin-2(1H)-ones, compounds which possess wide-
ranging pharmacological properties.4 They have served as
calcium channel modulators,5 antihypertensive agents,6 R-1a-
antagonists,7 mitotic kinesin Eg5 inhibitors,8 neuropeptide
Y(NPY) antagonists,9 and melanin concentrating hormone
receptor antagonists (Figure 1).10 In most cases only one
enantiomer was found to be biologically active.11 Although the
racemic form of dihyropyrimidinones is easily afforded Via
Biginelli reaction,12 there are only a few procedures to synthesize
this heterocyclic system in enantioenriched form, including
chemical resolution,13 enzymatic synthesis,14 and Yb-15 or chiral
phosphoric acid-catalyzed16 Biginelli reaction. The asymmetric
addition of â-dicarbonyls to acyl imines17 affords multifunctional
chiral amines which can serve as starting materials for dihy-
dropyrimidones and other pharmaceutically active hetero-
Amine-containing building blocks in optically enriched form
are valuable synthons for organic synthesis.1 A direct asym-
metric Mannich reaction2 provides practical methods to access
* Author to whom correspondence should be addressed. Phone: 01-617-353-
2489. Fax: 01-617-353-6466.
(1) Reviews: (a) Kleinmann, E. F. In Comprehensive Organic Synthesis;
Trost, B. M., Flemming I., Eds.; Pergamon Press: New York, 1991; Vol.
2, Chapter 4.1. (b) EnantioselectiVe Synthesis of a-Amino Acids; Juaristi,
E., Ed.; Wiley-VCH: New York, 1997. (c) Magriotis, P. A. Angew. Chem.,
Int. Ed. 2001, 40, 4377-4379. (d) Liu, M.; Sibi, M. P. Tetrahedron 2002,
58, 7991. (e) Sewald, N. Angew. Chem., Int. Ed. 2003, 42, 5794-5795. (f)
Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290-4299.
(2) For reviews: (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99,
1069-1094. (b) Denmark, S.; Nicaise, J.-C. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Germany, 1999; Vol. 2, p 954. (c) Benaglia, M.; Cinquini, M.; Cozzi, F.
Eur. J. Org. Chem. 2000, 4, 563-572. (d) Co´rdova, A. Acc. Chem. Res.
2004, 37, 102-112.
10.1021/jo701777g CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/30/2007
9998
J. Org. Chem. 2007, 72, 9998-10008

Asymmetric Mannich Reaction and Chiral Dihydropyrimidone
alkylations,21 and aldehyde-imine cross-coupling reactions.22
Under basic conditions, R-amido sulfones are readily converted
to the corresponding acyl imine.23 We recently described the
asymmetric Mannich reactions of â-keto esters to acyl imines
catalyzed by the cinchona alkaloids.24 In an effort to create a
more general Mannich reaction methodology for the practical
synthesis of chiral dihydropyrimidones that includes a broader
range of â-dicarbonyl nucleophiles and aliphatic acyl imine
electrophiles, we have developed a biphasic cinchona alkaloid-
catalyzed Mannich reaction utilizing R-amido sulfones as acyl
imine precursors (Scheme 1). A diverse chiral pilot dihydro-
pyrimidones library containing over 200 compounds was
generated with use of asymmetric Mannich reaction products
as scaffolds.
Results and Discussion
Asymmetric Mannich Reactions of R-Amido Sulfones. We
began our investigation with the addition of methyl acetoacetate
3 to the R-amido sulfones 4 using cinchonine 1 as the catalyst
(Table 1). Aqueous Na2CO3 in a saturated solution of NaCl was
used to consume the sulfinic acid produced during the course
of the reaction and maintain the basic reaction conditions for
imine formation. Saturation of the aqueous layer with NaCl
prevented the aqueous phase from freezing at -15 °C, the
temperature required for optimal enantioselectivities. Other bases
FIGURE 1. Representative bioactive dihydropyrimidones.
cycles.18 Although aryl acyl imines and R,â-unsaturated imines
are easily accessed, aliphatic acyl imines are difficult to isolate
because reactive imine functionality tends to tautomerize to
enamine under normal conditions.
R-Amido sulfones19 are bench-stable precursors to N-
acylimines that have proven useful in a wide range of enanti-
oselective reactions including aza-Henry reactions,20 imine
(3) For recent examples: (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin,
H. J. J. Am. Chem. Soc. 2002, 124, 827-833. (b) Co´rdova, A.; Notz, W.;
Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem. Soc. 2002,
124, 1842-1843. (c) Zhuang, W.; Sabby, S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2004, 43, 4476-4478. (d) Marigo, M.; Kjaersgaard, A.;
Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359-
2367. (e) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338-
339. (f) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J.
Org. Chem. 2003, 68, 2583-2599. (g) Hayashi, Y.; Tsuboi, W.; Ashimine,
I.; Urushima, T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42,
3677-3680. (h) Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8777-8785. (i) Kano, T.;
Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005, 127,
16408-16409. (j) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2005, 44, 4365-4368. (k) Okada, A.; Shibuguchi,
T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4564-4567. (l) Trost, B. M.; Jaratjaroonphong, J.;
Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778-2779. (m) Mitsumori,
S.; Zhang, H.; Cheong, P.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III J.
Am. Chem. Soc. 2006, 128, 1040-1041. (n) Zhang, H. L.; Mifsud, M.;
Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 9630-9631.
(o) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am. Chem.
Soc. 2006, 128, 14010-14011. (p) Ramasastry, S. S. V.; Zhang, H.; Tanaka,
F.; Barbas, C. F., III J. Am. Chem. Soc. 2007, 129, 288-289. (q) Suto, Y.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 500-501. (r) Guo,
Q-X.; Liu, H.; Guo, C.; Luo, S-W.; Gu, Y.; Gong, L.-Z. J. Am. Chem. Soc.
2007, 129, 3790-3791.
(8) (a) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. L.; Mitchison, T. J. Science 1999, 286, 971-974. (b) Haggarty,
S. J.; Mayer, T. U.; Miyamoto, D. T.; Fathi, R.; King, R. W.; Mitchison,
T. J.; Schreiber, S. L. Chem. Biol. 2000, 7, 275-286. (c) Barrow, J. C.;
Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle, K. E.; Gilbert, K. F.;
Steele, T. G.; Homnick, C. F.; Freidinger, R. M.; Ransom, R. W.; Kling,
P.; Reiss, D.; Broten, T. P.; Schorn, T. W.; Chang, R. S. L.; O’Malley, S.
S.; Olah, T. V.; Ellis, J. D.; Barrish, A.; Kassahun, K.; Leppert, P.;
Nagarathnam, D.; Forray, C. J. Med. Chem. 2000, 43, 2703-2718.
(9) Bristol-Myers Squibb Co.: Expert Opin. Ther. Pat. 1999, 9, 321-
325.
(10) Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.;
Deleon, J.; Lagu, B.; Heurich, R.; Lichtblau, H.; Shaposhnik, Z.; Daniewska,
I.; Blackburn, T. P.; Branchek, T. A.; Gerald, C.; Vaysse, P. H. J.; Forray,
C. Nat. Med. 2002, 8, 825-830.
(11) (a) Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1-116. (b)
Kappe, C. O. QSAR Comb. Sci. 2003, 22, 630-645.
(12) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360-416. (b) Kappe,
C. O. Tetrahedron 1993, 49, 6937-6963.
(13) (a) Kleidernigg, O. P.; Kappe, C. O. Tetrahedron: Asymmetry 1997,
8, 2057-2067. (b) Lewandowske, K.; Murer, P.; Svec, F.; Frechet, J. M.
J. J. Comb. Chem. 1999, 1, 105-112. (c) Kappe, C. O.; Uray, G.; Roschger,
P.; Lindner, W.; Kratky, C.; Keller, W. Tetrahedron 1992, 48, 5473-5480.
(d) Kontrec, D.; Vinkovic, V.; Sunjic, V.; Schuiki, B.; Fabian, W. M.;
Kappe, C. O. Chirality 2003, 15, 550-557.
(14) Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.; Kappe, C. O.
Tetrahedron: Asymmetry 2000, 11, 1449-1453.
(15) Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386-
16387.
(4) For reviews on dihydropyrimidones, see: (a) Kappe, C. O. Acc. Chem.
Res. 2000, 33, 879-888. (b) Kappe, C. O. Eur. J. Med. Chem. 2000, 35,
1043-1058.
(16) Chen, X.; Yu, X.; Liu, H.; Chun, L.; Gong, L. J. Am. Chem. Soc.
2006, 128, 14802-14803.
(5) (a) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.;
Moreland, S.; Gougoutas, J. Z.; O’ Reilly, B. C.; Schwart, J.; Malley, M.
J. Med. Chem. 1992, 35, 3254-3263. (b) Rovnyak, G. C.; Kimball, S. D.;
Beyer, B.; Cucinotta, G.; Dimarco, J. D.; Gougoutas, J.; Hedberg, A.;
Malley, M.; McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med Chem. 1995,
38, 119-129. (c) Grover, G. J.; Dzwonczyk, S.; McMullen, D. M.;
Normandin, D. E.; Parham, C. S.; Sleph, P. G.; Moreland, S. J. CardioVasc.
Pharmacol. 1995, 26, 289-294.
(6) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland,
S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem. 1991, 34, 806-811.
(7) (a) Nagarathnam, D.; Miao, S. W.; Lagu, B.; Chiu, G.; Fang, J.; Dhar,
T. G. M.; Zhang, J.; Tyagarajan, S.; Marzabadi, M. R.; Zhang, F. Q.; Wong,
W. C.; Sun, W. Y.; Tian, D.; Wetzel, J. M.; Forray, C.; Chang, R. S. L.;
Broten, T. P.; Ransom, R. W.; Schorn, T. W.; Chen, T. B.; O’Malley, S.;
Kling, P.; Schneck, K.; Benedesky, R.; Harrell, C. M.; Vyas, K. P.;
Gluchowski, C. J. Med. Chem. 1999, 42, 4764-4777.
(17) (a) Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Chem. Eur. J. 2003, 9, 2359-2367. (b) Uraguchi, D.; Terada, M. J.
Am. Chem. Soc. 2004, 126, 5356-5357. (c) Hamashima, Y.; Sasamoto,
N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem.,
Int. Ed. 2005, 44, 1525-1529. (d) Poulsen, T. B.; Alemparte, C.; Saaby,
S.; Bella, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896-
2899. (e) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 11,
1191-1193. (f) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006,
128, 6048-6049.
(18) (a) Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348-352.
(b) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He,
H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.;
McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Roy, R.
S.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.; Thornberry, N. A.;
Weber, A. E. J. Med. Chem. 2005, 48, 141-151.
J. Org. Chem, Vol. 72, No. 26, 2007 9999

Lou et al.
SCHEME 2. Role of Cinchonine in the Mannich Reaction
SCHEME 1. Synthesis of Dihydropyrimidones via
Asymmetric Mannich Reaction Catalyzed by Cinchona
Alkaloids
with r-Amido Sufones
10 enantiomeric ratio (er), respectively (Table 1, entries 1 and
2). Higher enantioselectivity was obtained in the reaction of 3
with methyl carbamate sulfone 4c (85% yield, 95:5 er) (entry
3). When cinchonidine 2 was used as catalyst, similar enantio-
meric excess was attained with the opposite sense of enanti-
oselectivity (entry 6). Other commercially available cinchona
alkaloids such as quinine, quinidine, and hydroquinidine were
not as effective as cinchonine in promoting enantioselective
Mannich reactions.
TABLE 1. Asymmetric Mannich Reactions of r-Amido Sulfonesa
Interestingly, the reaction did not proceed in the absence of
water (Table 1, entry 4). Aqueous Na2CO3 alone was capable
of promoting the reaction, albeit very slowly; only 15%
conversion was observed in the absence of cinchonine after 48
h (entry 5). The reaction with phase transfer reagent benzyl
cinchonium chloride as the catalyst did not give any desired
product under biphasic conditions. These experiments strongly
suggested that cinchonine acts primarily as a chiral base that
promotes the generation of acyl imines from R-amido sulfones
under biphasic reaction conditions. In addition, aqueous base
sodium carbonate helps to maintain the basic reaction environ-
ment and regenerate active cinchonine to subsequently catalyze
the addition of methyl acetate 3 to the acyl imines (Scheme 2).
Reaction Scope. The optimal reaction conditions for the
reaction of 3 with 4c proved general for a variety of N-methyl
carbamate sulfones (Table 2). Nonsubstituted alkyl amido
sulfone cleanly underwent the Mannich reaction to afford the
desired Mannich product in greater than 85% isolated yields
(Table 2 entries 1 and 2). Subsequent condensation with benzyl
amine gave Z-enamines in high yields (>71%) and high er (95:
5). R-Substituted (entries 3 and 4) and â-substituted (entry 5)
alkyl amido sulfones reacted with 3 under the general conditions,
although at a slower rate, to give the Mannich adduct in
comparable yields and enantioselectivity. The substrates bearing
benzyl-protected alcohol (entry 6) and double bond (entry 7)
were also tolerated under optimized conditions. Aromatic
N-methyl carbamate sulfones proved to be more reactive than
aliphatic derivatives. The addition of 3 to phenyl amido sulfone
(entry 8) took only 15 h to generate the Mannich product in
quantitative yield and excellent er (98:2). Electron withdrawing
(entries 9, 10, and 11) and electron donating (entries 12-14)
substitution on the aromatic ring did not affect the reaction rate
or enantioselectivity. Heteroaromatic amido sulfones (entries
15 and 16) were also tolerated under these conditions. The
reaction rate and enantioselectivities were sensitive to the type
of amido sulfone employed in the reaction. For slow reactions
or reactions that resulted in lower enantioselectivities, we
hypothesized that p-chlorophenyl sulfones used in the reaction
would more readily eliminate to form the acyl imine. Allyl
carbamate p-chlorophenyl sulfones were used in the Mannich
reaction to achieve a higher reaction rate and higher enantiose-
lectivity for aliphatic derivatives (entries 17-20), although
R-amido
entry
catalyst
sulfone
% yieldb
erc
1
2
3
4d
5
6
7
8
9
1
1
1
1
4a
4b
4c
4c
4c
4c
4c
4c
4c
81
88
85
0
15
90
81
62
75
91.5:8.5
90:10
95:5
2
5:95e
16:84e
86:14
quinine
quinidine
hydroquinidine
85.5:14.5
a Reactions were run with amido sulfone 4a-c (0.5 mmol), ester 3 (1.5
mmol), and catalyst (0.05 mmol) in CH2Cl2 (5 mL) and Na2CO3 in brine
(5 mL) at -15 °C for 48 h, followed by flash chromatography on silica
gel. b Yield of isolated product. c Determined by chiral HPLC analysis.d The
reaction was run without water, using 10 mol % Na2CO3. e Opposite sense
of enantioselectivity.
were tested in the reaction, including KOH, DBU, and proton
sponge, all of which resulted in lower enentioselectivities. The
reaction of N-Boc sulfone 4a and N-Cbz sulfone 4b with 3
catalyzed afforded the corresponding â-amino esters in 81%
and 88% yields, 1:1 diastereoselectivity, and 91.5:8.5 and 90:
(19) (a) Review: Petrini, M. Chem. ReV. 2005, 105, 3949-3977. (b)
Messinger, P. Pharmazie 1976, 31, 16-18.
(20) (a) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R. J. Am. Chem.
Soc. 2005, 127, 17622-17623. (b) Fini, F.; Sgarzani, V.; Pettersen, D.;
Herrera, R. P.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44,
7975-7978.
(21) (a) Dahmen, S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940-
5941. (b) Zhang, H.-L.; Liu, H.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong,
L.-Z. Synlett 2005, 615-618. (c) Hermanns, N.; Dahmen, S.; Bolm, C.;
Bra¨se, S. Angew. Chem., Int. Ed. 2002, 41, 3692-3694.
(22) (a) Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J. J. Am.
Chem. Soc. 2005, 127, 1654-1655. (b) Murry, J. A.; Frantz, D. E.; Soheili,
A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001,
123, 9696-9697.
(23) (a) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75-77.
(b) Kanazawa, S. M.; Denis, J.-N.; Greene, S. E. J. Org. Chem. 1994, 59,
1238-1240. (c) Zawadzki, S.; Zwierzak, A. Tetrahedron Lett. 2004, 45,
8505-8506. (d) Morton, J.; Rahim, A.; Walker, E. R. H. Tetrahedron Lett.
1982, 23, 4123-4126.
(24) (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem.
Soc. 2005, 127, 11256-11257. (b) Ting, A.; Lou, S.; Schaus, S. E. Org.
Lett. 2006, 8, 2003-2006.
10000 J. Org. Chem., Vol. 72, No. 26, 2007

Asymmetric Mannich Reaction and Chiral Dihydropyrimidone
TABLE 2. Asymmetric Mannich Reactions of â-Keto Ester 3a
TABLE 3. Asymmetric Mannich Reactions of â-Keto Ester 10a
% yieldb yield (%)c
erd
entry
dicarbonyls
yield (%)b
drc
erd
entry
R1
R2
1
2
3
10a
10b
10c
12a (86)
12b (96)
12c (85)
1:1
1:1
1:1
96:4
92.5:7.5
95:5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17e
18e
19e
20e
21
22
23
24
25
26
27
28
CH3 PhCH2CH2
CH3 PhCH2
CH3 (CH3)2CH
CH3 c-C6H11
CH3 (CH3)2CHCH2
CH3 BnOCH2
CH3 (s)-citronellyl
CH3 Ph
CH3 4-Br-C6H4
CH3 3-F-C6H4
CH3 3-CF3-C6H4
CH3 4-CH3-C6H4
CH3 3-CH3O-C6H4
CH3 3,4-(OCH2O)- C6H4
CH3 2-C4H3O
CH3 2-C4H3S
allyl PhCH2CH2
allyl PhCH2
allyl BnOCH2
allyl (CH3)2CHCH2
allyl Ph
allyl 4-Br-C6H4
allyl 3-F-C6H4
allyl 3-CF3-C6H4
allyl 4-CH3-C6H4
allyl 3-CH3O-C6H4
allyl 3,4-(OCH2O)-C6H4
allyl 2-C4H3O
85
87
84
85
87
92
86
99
93
98
96
92
93
97
90
92
91
81
90
88
95
90
88
91
94
86
82
88
8a (84)
8b (71)
8c (73)
8d (83)
8e (75)
8f (78)
8g (81)
8h (95)
8i (83)
8j (82)
8k (84)
8l (96)
8m (86)
8n (82)
8o (84)
8p (88)
9a (81)
9b (78)
9c (76)
9d (73)
9e (81)
9f (80)
9g (83)
9h (82)
9i (84)
9j (80)
9k (81)
9l (81)
95:5
95:5
96.5:3.5
92:8
93.5:6.5
97.5:2.5
97:3
98.5:1.5
95:5
97.5:2.5
95.5:4.5
95:5
95.5:4.5
95.5:4.5
96:4
95.5:4.5
95:5
94.5:5.5
95:5
94:6
95.5:4.5
95:5
95:5
95.5:4.5
95:5
94:6
93:7
95:5
a Reactions were run with R-amido sulfones (0.5 mmol), dicarbonyls 10
(1.5 mmol), and catalyst (0.05 mmol) in CH2Cl2 (5 mL) and aqueous
Na2CO3 in brine (5 mL) at -15 °C for 48 h, followed by flash
chromatography on silica gel. b Yields of isolated products. c Determined
by H NMR. d Determined by chiral HPLC analysis.
TABLE 4. Asymmetric Mannich Reactions of Diketone 13a
entry
R
yield (%)b
erc
1
2
3
4
5
6
PhCH2CH2
Ph
4-Br-C6H4
3-CF3-C6H4
2-C4H3O
2-C4H3S
14a (88)
14b (91)
14c (90)
14d (87)
14e (88)
14f (86)
95:5
96.5:3.5
95.5:4.5
96:4
95.5:4.5
96.5:3.5
a Reactions were run with R-amido sulfones (4.0 mmol), diketone 13
(12.0 mmol), and catalyst (0.40 mmol) in CH2Cl2 (5 mL) and aqueous
Na2CO3 in brine (5 mL) at -15 °C for 48 h, followed by flash
chromatography on silica gel. b Isolated yield. c Determined by chiral HPLC
analysis.
a Reactions were run with R-amido sulfone (0.5 mmol), ester 3 (1.5
mmol), and catalyst (0.05 mmol) in CH2Cl2 (5 mL) and aqueous Na2CO3
in brine (5 mL) at -15 °C for 48 h, followed by flash chromatography on
silica gel. b Yield of isolated Mannich reaction product. c Yields of isolated
enamine 8 and 9. d Determined by chiral HPLC analysis. e p-Cl-Ph sulfones
were used in the Mannich reactions.
proved to be less reactive under standard conditions than â-keto
ester 3 and diketone 13. When aliphatic phenyl sulfone 4c was
used, the reaction afforded the Mannich adduct in less than 50%
yield. p-Chlorophenyl sulfones were successfully utilized to
increase the reaction rate (Table 5). Nonsubstituted aliphatic
and aromatic R-amido sulfones (entry 1-6) reacted with
dimethyl malonate smoothly to afford â-amino esters in good
yield and high er (>95:5). However, the R-substituted substrate
was less reactive, probably because of steric hindrance (entry
7). Low yields of the desired Mannich product were the result
of an undesired reaction pathway to form the ene-amide (entry
8). R-Formamido sulfones were successfully used as a solution
for the two problematic substrates. In both cases, the yields were
higher than 70% and er values were higher than 95:5 (entries 9
and 10). When phenyl formamido sulfone was used in the
Mannich reaction, quantitative yield and 99:1 er were observed
(entry 11). Similar work was reported by Deng and co-workers
using 9-thiourea cinchona alkaloid derivatives in the asymmetric
aromatic and heteroaromatic allyl carbamate phenyl sulfones
worked just as well as methyl carbamate sulfones to afford
Mannich adducts with high yield and high enantioselectivity
(entries 21-28).
The reaction conditions proved to be general for the â-keto
esters we surveyed in the reaction (Table 3). p-Chlorophenyl
sulfones were used to achieve the best reaction rates and
enantioselectivities. 3-Oxopentanoate (entry 1), benzoylacetate
(entry 2), and 4-methoxy-3-oxobutanoate (entry 3) afforded the
corresponding Mannich addition products in high er but with
no diastereoselectivity.
The reaction conditions also proved to be highly effective in
the Mannich reaction with 2,4-pentanedione 13 as the nucleo-
phile (Table 4). Aliphatic and aromatic amido sulfones were
examined in the reaction with 13 to afford the Mannich product
with a similar level of selectivity. Cinchonidine was also
successfully used to promote the Mannich reaction of 13 with
a variety of R-amido sulfones to afford opposite enantiomers.
In all cases the reaction proceeded cleanly with greater than
85% yields and excellent er (>95:5).
The malonates represent an important substrate for investiga-
tion in the asymmetric direct Mannich reaction because the
products of the malonate Mannich reaction provide direct access
to chiral â-amino acids.25 However, dimethyl malonate 15
(25) (a) Myers, J.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-
8960. (b) Sibi, M. P.; Asano, Y. J. Am Chem. Soc. 2001, 123, 9708-9709.
(c) Zhou, Y.; Tang, W.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002, 124,
4952-4953. (d) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito,
E.; Wang, F.; Sun, Y.; Armstrong, J. D.; Grabowske, E. J.; Tillyer, R. D.;
Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918-9919. (e)
Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew. Chem., Int. Ed. 2005,
44, 7466-7469. (f) Liu, T-Y.; Cui, H.-L.; Long, J.; Li, B.-J.; Wu, Y.; Ding,
L.-S.; Chen, Y.-C. J. Am. Chem. Soc. 2007, 129, 1878-1879.
J. Org. Chem, Vol. 72, No. 26, 2007 10001

Lou et al.
TABLE 5. Asymmetric Mannich Reactions of Methyl Malonate
15a
TABLE 7. Asymmetric Mannich Reactions of N-Boc Sulfones 22a
entry
dicarbonyls
R-amido sulfones
yield (%)b
erc
entry
R1
R2
yield (%)b
erc
1
3
22a
22a
22a
22b
22b
23a (93)
23b (97)
23c (81)
23d (84)
23e (90)
97.5:2.5
97.5:2.5
95:5
95:5
96:4
2
15
20
3
1
2
3
4
5
6
7
8
9
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
PhCH2CH2
CH3(CH2)7CH2
BnOCH2
18a (86)
18b (71)
18c (82)
18d (83)
18e (91)
18f (84)
18g(58)
18h (56)
19a (72)
19b (73)
19c (95)
96:4
95:5
97.5:2.5
95:5
95:5
95.5:4.5
95:5
85:15
95.5:4.5
97.5:2.5
99:1
3d
4
5
15
Ph
4-Br-C6H4
3,4-(OCH2O)-C6H4
(CH3)2CH
2,4,5-F-C6H4CH2
(CH3)2CH
a Reactions were run with R-amido sulfones 22 (0.5 mmol), dicarbonyls
(1.5 mmol), and catalyst (0.05 mmol) in CH2Cl2 (5 mL) and aqueous
Na2CO3 in brine (5 mL) at -15 °C for 48 h, followed by flash
chromatography on silica gel. b Yields of isolated products. c Determined
by chiral HPLC analysis. d Reaction was run in acetonitrile (2.5 mL), CH2Cl2
(2.5 mL), and aqueous Na2CO3 in brine at -30 °C (2.5 mL).
10
11
H
H
2,4,5-F-C6H4CH2
Ph
a Reactions were run with R-amido sulfones (0.5 mmol), methyl malonate
15 (1.5 mmol), and catalyst (0.05 mmol) in CH2Cl2 (5 mL) and aqueous
Na2CO3 in brine (5 mL) at -15 °C for 48 h, followed by flash
chromatography on silica gel. b Yields of isolated products. c Determined
by chiral HPLC analysis.
Finally, we used N-Boc R-amido sulfones 22a and 22b in
the Mannich reaction (Table 7). The reactions of methyl
acetoacetate 3 and 2,4-pentanedione 15 to 22a or 22b afforded
the desired product in high yield. Reactions involving dimethyl
malonate 20 as the nucleophile required lower temperatures to
achieve good enantioselectivities. Acetonitrile was added to run
the reaction at -30 °C without freezing the aqueous layer. We
were able to isolate the malonate adduct 23c in 81% yield and
95:5 er. Subsequent decarboxylation under modified microwave
conditions29 furnished the â-amino ester in 82% yield while
maintaining the enantiopurity (eq 1).
TABLE 6. Asymmetric Mannich Reactions of Cyclic Dicarbonyls
20a
entry
dicarbonyls
yield (%)b
drc
erd
1
2
3
20a
20b
20c
21a (91)
21b (95)
21c (84)
99:1
99:1
99:1
95:5
98.5:1.5
99.5:0.5
a Reactions were run with R-amido sulfones (0.5 mmol), dicarbonyls 20
(1.5 mmol), and catalyst (0.05 mmol) in CH2Cl2 (5 mL) and aqueous
Na2CO3 in brine (5 mL) at -15 °C for 48 h, followed by flash
chromatography on silica gel. b Yields of isolated products. c Determined
by H NMR. d Determined by chiral HPLC analysis.
Dihydropyrimidone Library Synthesis. Having established
a practical method to both aliphatic and aromatic Mannich
adducts with high er, we next carried out synthesis of a
diversified 1,2-dihydropyrimidone library based on our previ-
ously reported methodology.24
addition of benzyl malonate to R-amido sulfones employing
aqueous solutions of Cs2CO3 and CsOH for in situ generation
of the imine.26 Alternative approaches include using the cinchona
alkaloid-derived phase transfer reagents to promote asymmetric
Mannich reaction of R-amido sulfones.27 In this case, p-anisyl
malonate and aqueous K2CO3 were applied under the optimal
reaction conditions to achieve high enantioselectivities.
We have also expanded the scope of this reaction to include
cyclic R-substituted â-keto ester 20a, â-diketones 20b, and
â-keto lactone 20c (Table 6). Treatment of R-amido sulfone
with these dicarbonyls catalyzed by 10 mol % cinchonine 1
under biphasic conditions afforded the corresponding products
in high yield (84-95%), high diastereroselectivity (99:1 dr),
and high enantioselectivity (>95:5 er) (Table 6, entries 1-3).
The reaction provides a catalytic route toward the construction
of cyclic â-amino esters with R-quaternary carbon centers as a
supplement to our recent study.11b,28
The library contains three points of diversity. As illustrated
in Scheme 3, two dicarbonyls and six R-amido sulfones were
utilized to produce 12 scaffolds in both enantiomeric senses
(>95:5 er). Eight different isocyanates either from commercial
sources or derived from primary amines were utilized for the
R3 diversity element.30 The synthesis of dihydropyrimidone is
a two-step process: first, treatment of the Mannich product with
catalytic Pd(PPh3)4 and dimethyl barbituric acid as the allyl
scavenger in the presence of isocyanate afforded the corre-
sponding unsymmetrical urea in 75-88% isolated yield; second,
ring closure to the dihydropyrimidone was promoted by AcOH
in EtOH under microwave conditions in 72-85% yield.
Analysis by chiral HPLC revealed that there is no significant
loss of enantiomeric excess in this procedure.
(28) Cinchonine-catalyzed addition of â-keto esters to azodicarboxylates
proceeds with a similar sense of stereochemical induction. Pihko, P. M.;
Pohjakallio, A. Synlett 2004, 2115-2118.
(26) Song, J.; Shih, H.-W.; Deng, L. Org. Lett. 2007, 9, 603-606.
(27) Fini, F.; Bernardi, L.; Pettersen, D.; Ricci, A.; Sagarzabu, V. AdV.
Synth. Catal. 2006, 348, 2043-2046.
(29) Krapcho, A. P. Synthesis, 1982, 805-822.
(30) Nowick, J. S.; Holmes, D. L.; Noronha, G.; Smith, E. M.; Nguyen,
T. M.; Huang S.-L. J. Org. Chem. 1996, 61, 3929-3934.
10002 J. Org. Chem., Vol. 72, No. 26, 2007

Asymmetric Mannich Reaction and Chiral Dihydropyrimidone
SCHEME 3. Synthesis of Dihydropyrimidone Library
SCHEME 4. Hydrogenation of Dihydropyrimidone with H-Cube
A library containing 110 compounds has been synthesized.
Scheme 4 illustrated some representative structures of this
library. We performed an analysis of trace palladium content
to ensure the palladium content was within a suitable range for
biological assays. The result from our inductively coupled
plasma mass spectrometry (ICP-MS) test revealed that, after
flash chromatography, the palladium content was 12 ppm. The
dihydropyrimidones were then treated with macroporous poly-
styrene-bound trimercaptotriazine (MP-TMT resin) to scavenge
trace palladium. After the treatment, the palladium content was
reduced to 0.9 ppm, which was comparable to negative controls.
The library was next purified by reverse-phase HPLC. Samples
were collected automatically based on the desired exact mass.
Immediately following the purification process, each compound
was evaluated for purity with analytical LC/MS/UV/ELSD
(Evaporative Light Scattering Detector). The purified com-
pounds were found to have purity higher than 98% (by both
ELSD and UV).
the corresponding tetrahydropyrimidone. Our strategy employed
a flow hydrogenation reactor (H-Cube) due to faster catalyst
screening capabilities, easier reaction optimization, and facili-
tated library synthesis.31 Several catalysts, including Pd/C, Pt/
Al2O3, Pt/C, and Raney-Ni, were initially screened. The initial
results indicated that Raney-Ni provided the best conversion
with fewer side reactions. Further optimization of the reaction
conditions focused on reaction pressure, temperature, and
solvent. After considerable experimentation, the best conditions
were determined to be 90 bar of pressure at 45 °C, which
provided complete conversion of most of the substrates inves-
tigated with the highest selectivities. It is interesting to note
that subjecting 25 to comparable hydrogenation conditions (10%
Pd/C or Raney Nickel) under benchtop conditions resulted in
multiple hydrogenation products with little to no chemoselec-
tivity or stereoselectivity.
Illustrated in Scheme 4, the tetrahydropyrimidones were
(31) (a) Jones, R.; Godorhazy, L.; Varga, N.; Szalay, D.; Urge, L.; Darvas,
F. J. Comb. Chem. 2006, 8, 110-116. (b) Franckevicius, V.; Knudsen, K.
R.; Ladlow, M.; Longbottom, D. A.; Ley, S. V. Synlett 2006, 6, 889-892.
(c) Desai, B.; Kappe, C. O. J. Comb. Chem. 2005, 7, 641-643.
Synthesis of Tetrahydropyrimidones by Flow Hydrogena-
tion. The first approach toward modification of the dihydro-
pyrimidone core was hydrogenation of the enamide to produce
J. Org. Chem, Vol. 72, No. 26, 2007 10003

Lou et al.
FIGURE 2. Representative structures of the dihydropyrimidone library (yield, purity by UV/ELSD).
produced as the result of syn addition of dihydrogen from the
opposite face of the R2 substituent. The diastereoselectivity was
found to be greater than 20:1 (by LC-MS with ELSD detector).
The stereochemistry was established by NOE experiments and
coupling constants of C3 hydrogen with C2 and C4 hydrogens.
We observed that the ketone-bearing tetrahydropyrimidone 29
underwent epimerization at the C3 position upon storage to form
the more stable isomer 30, while epimerization of the ester
tetrahydropyrimidone 27 did not occur upon storage. Both
compounds can be readily epimerized to the thermodynamically
more stable isomer via treatment in MeOH with a catalytic
amount of K2CO3.
We initially investigated the intermolecular 1,3-dipolar cy-
cloaddition reactions using dihydropyrimidone 31a (Scheme 5).
Acylation of 32a with methyl chlorocarbonyl acetate in benzene
followed by diazo-transfer with p-acetamidobenzene sulfony-
lazide (p-ABSA) and DBU afforded diazo amide 32 in 83%
yield. The isomu¨nchnone dipole was formed in situ upon
treatment with rhodium(II) acetate dimer and refluxed in
benzene. In the presence of maleimide as a dipolarophile, the
dipole intermediate underwent 1,3-dipolar cycloaddition to
generate adduct 34a in 91% yield. Only one diastereomer was
isolated and the relative stereochemistry was determined by
NOESY experiments. According to recent computational studies,
the dihydropyrimidone ring has a boat-like conformation with
the 4-aryl substituent in the pseudoaxial position.36 This
geometric arrangement probably resulted in the attack of the
Dihydropyrimidones containing heteroaromatic or cyclopro-
pane moieties decomposed under the hydrogenation reaction
conditions with no desired product isolated. These starting
materials were excluded from further modification by hydro-
genation. Figure 3 illustrates several representative structures
afforded by the hydrogenation procedure.
(32) Review: (a) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91,
263-309. (b) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223-
270. (c) Jorgensen, K. A.; Gothelf, K. V. Chem. ReV. 1998, 98, 863-909.
(d) Padwa, A. HelV. Chim. Acta 2005, 88, 1357-1374.
Cycloaddition Reactions. In recent years, [3+2] cycload-
dition has proven to be an effective strategy to rapidly build
molecular complexity.32 Padwa33 and others34 have pioneered
this class of reactions using mesomeric betains, especially
isomu¨nchnones, in cycloaddition reactions. On the basis of this
work and preliminary work by Kappe,35 we investigated the
possibility of using dihydropyrimidone-fused mesomeric betaine
in the [3+2] cycloaddition to diversify the dihydropyrimidone
core structure in order to synthesize highly complex bicyclic
angular compounds.
(33) (a) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60, 6258-6259.
(b) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556-565. (c) Padwa,
A.; Lynch, S. M.; Mej´ıa-Oneto, J. M.; Zhang, H. J. Org. Chem. 2005, 70,
2206-2218. (d) Mej´ıa-Oneto, J. M.; Padwa, A. Org. Lett. 2006, 8, 3275-
3278. (e) England, D. B.; Padwa, A. Org. Lett. 2007, 9, 3249-3252.
(34) (a) Hodgson, D. M.; Lestrat, F.; Avery, T. D.; Donohue, A. C.;
Bru¨kl, T. J. Org. Chem. 2004, 69, 8796-8803. (b) Chen, B.; Ko, R. Y. Y.;
Yuen, M. S. M.; Cheng, K.-F.; Chiu, P. J. Org. Chem. 2003, 68, 4195-
4205. (c) Graening, T.; Bette, V.; Neudo¨rfl, J.; Lex, J.; Schmalz, H. G.
Org. Lett. 2005, 7, 4317-4320.
(35) Kappe, C. O.; Peters, K.; Peters, E.-M. J. Org. Chem. 1997, 62,
3109-3118.
10004 J. Org. Chem., Vol. 72, No. 26, 2007

Asymmetric Mannich Reaction and Chiral Dihydropyrimidone
FIGURE 3. Representative structures of tetrahydropyrimidones (isolate yield, dr by LC/MS/ELSD, purity after preparative RP-HPLC purification
by LC/MS/UV/ELSD).
SCHEME 5. Dipolar Cycloaddition Sequence
bridged bicycle product in high yield (entries 1-3). High
regioselectivity was obtained when cyclohexenone, 5,6-dihy-
dropyran-2-one, vinylnitrile, and chalcone were used as dipo-
larophiles (entries 4-7). The regioselectivity and facial selec-
tivity were established by NMR experiments. Only one
diastereomer was isolated from exo-addition of the dipolarophile.
Dimethylacetylene dicarboxylate also readily underwent cy-
cloaddition to afford the desired product in 2:1 diastereomeric
ratio (entry 8).
The use of methyl vinyl ketone as the dipolarophile resulted
in the isolation of tertiary alcohol 36a after silica gel column
purification. Exposure of the crude cycloadduct to catalytic
amounts of p-toluenesulfonic acid in CH2Cl2 resulted in the
exclusive formation of tertiary alcohol 36a in high yield (Table
9, entry 1). Dehydration for tertiary alcohols 36a did not occur
under acid-mediated condition possibly because it is difficult
to build up the positive charge on the tertiary carbon attached
with two electron withdrawing groups, ester and amide. The
regioselectivity was confirmed Via comparison of spectra data
with similar compounds derived from dihydropyrimidone be-
taines.35 This two-step sequence was successfully applied to
other dipolarophiles. Methyl acrylate and acrylonitrile underwent
cycloaddition smoothly and gave similar regioselectivities and
high yields (entries 2 and 3). Benzalacetone and chalcone also
yielded the corresponding tertiary alcohols in high diastereo-
selectivity (>20:1) (entries 4 and 5). The acid-catalyzed ring-
opening conditions could also effect the ring opening of more
stable bicyclic adducts derived from maleimide, cyclohexenone,
and dihydropyranone (entries 6-9). In all cases, the tertiary
alcohols were isolated in good yields (>73%).
dipolarophile from the anti-face of the phenyl group. Similar
results for related structures were obtained by Kappe and co-
workers where the exo-cycloadduct was verified by X-ray crystal
structure analysis. The stability of the cycloadduct was tested
by stirring in pH 4, 7, and 10 aqueous buffers overnight at room
temperature. No decomposition was observed under these
conditions.
The substrate scope of [3+2] intermolecular cycloaddition
was expanded by employing a variety of dipolarophiles in the
reaction (Table 8). Dihydropyrimidones 32a and 32b derived
from benzyl isocynate and ethyl isocynate were chosen as
scaffolds for the cycloadditions. N-Methyl-N-phenyl maleimide
and dimethyl maleate underwent cycloaddition cleanly under
Rh(II)-catalyzed conditions to afford the corresponding oxygen-
We next investigated the feasibility of intramolecular cy-
cloaddition based on a dihydropyrimidone skeleton (Scheme
6). A â-methyl-substituted homoallylic alcohol 40 was synthe-
(36) (a) Kappe, C. O.; Fabian, W. M. F. Tetrahedron 1997, 53, 2803-
2816. (b) Kappe, C. O.; Shishkin, O. V.; Uray, G.; Verdino, P. Tetrahedron
2000, 56, 1859-1862.
J. Org. Chem, Vol. 72, No. 26, 2007 10005

Lou et al.
TABLE 9. Cycloaddition and Oxo-Bridge Ring Openinga
TABLE 8. Intermolecurlar Dipolar Cycloaddition Reactionsa
a Reactions were run with 32a or 32b (0.10 mmol) and Rh2(OAc)4 (2.5
mg) in benzene (2.0 mL) and reflux for 1 h, followed by flash chroma-
tography on silica gel. b Yields of isolated products. c Determined by 1H
NMR.
sized in two steps according to a reported procedure.37 Selective
condensation of 1,3,5-trioxane with chiral silane 38 provided
tetrahydropyran 39 in 90% yield. Upon treatment with SbCl5,
tetrahydrofuran 39 underwent E2-type elimination, providing
homoallylic alcohol 40. Subsequent formation of the tosylate
followed by displacement with sodium azide afforded the
corresponding homoallylic azide. The primary amine was
obtained via a Staudinger reaction with use of a polymer
supported triphenylphosphine in THF/H2O. The isocyanate was
a Cycloaddition reaction crude mixture was filtered though a silica plug,
concentrated in Vacuo, and treated with TsOH (10 mol %) in CH2Cl2 (2.0
mL). The reaction solution was stirred overnight followed by flash
chromatography on silica gel. b Yields of isolated products.
obtained by treatment with phosgene under basic conditions.
Dihydropyrimidone synthesis proceeded accordingly and con-
struction of the dihydropyrimidone diazo amide 43 was obtained
in reasonable yield after four steps. Finally, the cycloaddition
(37) Beresis, R.; Panek, J. S. Bio. Med. Chem. Lett. 1993, 3, 1609-
1614.
10006 J. Org. Chem., Vol. 72, No. 26, 2007

Asymmetric Mannich Reaction and Chiral Dihydropyrimidone
SCHEME 6. Intramolecular Cycloaddition
resulting biphasic solution was stirred at -15 °C for 48 h and diluted
with CH2Cl2 (10 mL) and H2O (10 mL). The organic layer was
quickly separated and the aqueous phase was extracted with CH2-
Cl2 (2 × 10 mL). The combined organic layers were dried over
sodium sulfate, filtered, and concentrated under reduced pressure.
The resulting residue was purified by flash chromatography over
silica gel (elution with 15% to 40% EtOAc in hexanes) to afford
the Mannich reaction products.
General Procedure for the Preparation of (Z)-Enamines (8a-
p, 9a-l). An oven-dried 10-mL round-bottomed flask was charged
with Yb(OTf)3 (2.0 mg, 0.003 mmol), flamed dried under high
vacuum, and purged with nitrogen. The flask was cooled to room
temperature and charged with the â-ketone ester Mannich addition
product (0.30 mmol). Trimethyl orthoformate (1 mL) and benzy-
lamine (0.070 mL, 0.60 mmol) were sequentially added. The
solution was stirred at room temperature under nitrogen for 4.0 h.
The reaction mixture was subjected directly to flash chromatography
over silica gel (elution with 15-20% ethyl acetate in hexanes) to
give the enamines 8a-p and 9a-l.
Characterization Data for Selected Compounds. (a) Methyl
(S,Z)-4-(methoxycarbonyl)-5-(benzylamino)-1-phenylhex-4-en-
3-ylcarbamate (8a): white solid; [R]23 -33.7 (c 1.0, CHCl3); er
D
95:5; HPLC analysis, tr major 14.5 min, tr minor 18.0 min
1
(ChiralcelOD-H column, hexanes:IPA ) 98:2, 1.0 mL/min); H
NMR (400 MHz, CDCl3) δ 9.81 (t, J ) 6.0 Hz, 1H), 7.34 (m,
2H), 7.24 (m, 5H), 7.15 (m, 3H), 5.58 (d, J ) 9.6 Hz, 1H), 4.46
(dd, J ) 15.2, 9.6 Hz, 1H), 4.39 (d, J ) 6.0 Hz, 2H), 3.69 (s, 3H),
3.63 (s, 3H), 2.56 (t, J ) 7.6 Hz, 2H), 2.14 (m, 1H), 1.95 (m, 1H),
1.93 (s, 3H). 13C NMR (75.0 MHz, CDCl3) δ 166.7, 157.8, 152.9,
142.1, 134.7, 125.1, 124.8, 124.7, 124.6, 123.7, 123.2, 122.0, 90.1,
48.1, 46.5, 45.7, 43.6, 33.4, 31.0, 18.9; IR (thin film, cm-1) 3333,
3050, 2953, 1720, 1657, 1580, 1498, 1230, 1081; HRMS
(CI/NH3) m/z calcd for (M + H)+ C23H29N2O4 397.2049, found
397.2081.
reaction afforded the desired bicyclic adduct 44 in 80% yield
and as a single diastereomer.
(b) (S)-Allyl 4-acetyl-5-oxo-1-phenylhexan-3-ylcarbamate (14a):
white crystals; [R]23D -56.2 (c 1.0, CHCl3); er 95:5; HPLC analysis,
tr minor 9.4 min, tr major 12.3 min (ChiralPakAD-H Column,
Conclusion
1
hexane:IPA ) 95:5, 1.0 mL/min); H NMR (400 MHz, CDCl3) δ
In summary, we have developed a general enantioselective
Mannich reaction of â-dicarbonyls with R-amido sulfones as
acyl imine precursors. The reactions were run under biphasic
conditions requiring 10 mol % of the cinchona alkaloid catalyst
and aqueous Na2CO3. We have obtained the reaction products
in good yields and high enantioselectivities, and in diastereo-
selectivities that range from 1:1 to >99:1. A library of
dihydropyrimidones was synthesized based on the cinchonine
and cinchonidine-catalyzed Mannich reaction. Dipolar cycload-
dition reactions were used to modify the dihydropyrimidone core
and afforded highly functionalized complex, polycyclic struc-
tures. The use of the cinchona alkaloids as catalysts for the
asymmetric Mannich reaction has proven effective at providing
chiral building blocks for synthesis. As development of this
asymmetric Mannich reaction continues, emphasis will be placed
on the synthetic utility of the products obtained from the
reaction. Ongoing investigations include the expansion of the
current methodology and the use of chiral dihydropyrimidones
in synthesis.
7.16-7.32 (5H), 5.90 (m, 1H), 5.61 (d, J ) 10.2 Hz, 1H), 5.25
(m, 2H), 4.54 (m, 2H), 4.35 (m, 1H), 3.88 (d, J ) 4.7 Hz, 1H),
2.74 (m, 1H), 2.61 (m, 1H), 2.24 (s, 3H), 2.10 (s, 3H), 1.96 (m,
1H), 1.74 (m, 1H); 13C NMR (75.0 MHz, CDCl3) δ 205.2, 203.8,
156.3, 141.1, 132.8, 128.8, 128.6, 126.4, 117.9, 69.6, 65.9, 50.8,
35.9, 33.0, 31.1, 30.1; IR (thin film, cm-1) 3323, 1720, 1694, 1536,
1363, 1278, 1149, 1060, 700.
(c) Methyl (R)-2,2-di(methoxycarbonyl)-1-phenylethylcar-
bamate (18e): white solid; [R]23 -15.3 (c 1.0, CHCl3); er 95:5;
D
HPLC analysis, tr major 9.2 min, tr minor 12.7 min (ChiralcelOD-H
1
column, hexanes:IPA ) 95:5, 1.0 mL/min); H NMR (400 MHz,
CDCl3) δ 7.33-7.22 (m, 5H), 6.39 (d, J ) 8.4 Hz, 1H), 5.51 (dd,
J ) 8.4, 4.0 Hz, 1H), 3.92 (d, J ) 4.0 Hz, 1H), 3.73 (s, 3H), 3.65
(s, 3H), 3.63 (s, 3H); 13C NMR (75.0 MHz, CDCl3) δ 168.6, 167.6,
156.6, 139.3, 128.9, 128.1, 126.4, 56.7, 54.2, 53.2, 52.8, 52.5; IR
(thin film, cm-1) 3387, 1720, 1500, 1220, 1130; HRMS (CI/NH3)
m/z calcd for (M + H)+ C14H18NO6 396.1056, found 296.1065.
(d) tert-Butyl (S)-5-oxo-4-acyl-1-phenylhexan-3-ylcarbamate
(23e): white solids; [R]23 -19.3 (c 1.0, CHCl3); er 95:5; HPLC
D
analysis, tr major 8.5 min, tr minor 6.1 min [(R,R)-Whelk-O 1
1
column, hexanes:IPA 85:15, 1.0 mL/min ]; H NMR (400 MHz,
CDCl3) δ 7.30-7.15 (m, 5H), 5.40 (d, J ) 10 Hz, 1H), 4.32 (br,
1H), 3.83 (d, J ) 4.4 Hz, 1H), 2.81-2.55 (m, 2H), 2.22 (s, 3H),
2.09(s, 3H), 1.42 (s, 9H); 13C NMR (75.0 MHz, CDCl3) δ 205.3,
204.0, 155.9, 141.3, 128.8, 128.5, 126.3, 79.8, 70.0, 50.3, 36.0,
32.9, 30.9, 30.2, 28.5; IR (thin film, cm-1) 3446, 3390, 2951, 1720,
1650, 1591, 1499, 1453, 1253, 1193, 1090; HRMS (CI/NH3) m/z
calcd for (M + H)+ C19H27NO4 334.1940, found 334.1973.
Experimental Section
General Procedure for Asymmetric Mannich Reaction of
Dicarbonyls with R-Amido sulfones. A 25-mL one-necked round-
bottomed flask equipped with a stir bar was charged with (+)-
cinchonine (16.0 mg, 0.05 mmol), R-amido sulfone (0.50 mmol),
and CH2Cl2 (5.0 mL). The solution was cooled to -15 °C.
Dicarbonyl compound (1.50 mmol) and aqueous Na2CO3/NaCl (5.0
mL, 5 wt % Na Na2CO3 in deionized water saturated with NaCl)
were sequentially added to the reaction mixture dropwise. The
Acknowledgment. The authors acknowledge ThalesNano
Nanotechnology, Inc. (Budapest, Hungary) for H-Cube instru-
J. Org. Chem, Vol. 72, No. 26, 2007 10007

Lou et al.
Supporting Information Available: Experimental procedures
for synthesis of chiral dihydropyrimidones, flow hydrogenation, and
[3+2] dipolar cycloadditions, characterization data for compounds
8a-p, 9a-l, 12a-c, 14a-f, 18a-g, 19a-c, 21a-c, 23a-e,
dihydropyrimidone library members, tetrahydropyrimidones library
members, 34a-h and 36a-i, chiral HPLC analysis for the Mannich
reaction products, and HPLC/UV/ELSD/MS data for the represen-
tative library members. This material is available free of charge
via the Internet at http://pubs.acs.org.
mentation support. Assistance was provided by CEM Corpora-
tion (Matthew, NC) with microwave instrumentation and
Symyx, Inc. (Santa Clara, CA) with chemical reaction planning
software. The authors thank ChemAxon (Budapest, Hungary),
Molinspiration Cheminformatics (Slovak Republic), and Open-
Eye Scientific Software (Santa Fe, NM) for academic software
support. S.L. gratefully acknowledges a graduate research
fellowship from Merck Research Laboratories-Boston. This
research was supported by a gift from Amgen, Inc., an NSF
CAREER grant (CHE-0349206), and the NIH (P50 GM067041
and P41 GM076263).
JO701777G
10008 J. Org. Chem., Vol. 72, No. 26, 2007