Aldol reactions of 2-thioxotetrahydropyrimidin-4(1H)-ones: stereoregulations from endo- and exocyclic chiral centres

Tetrahedron 69 (2013) 1747e1754

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Aldol reactions of 2-thioxotetrahydropyrimidin-4(1H)-ones: stereoregulations from endo- and exocyclic chiral centres Varun Kumar, Kapil Kumar, Anang Pal, Gopal Lal Khatik, Vipin A. Nair * Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 4 September 2012 Received in revised form 4 December 2012 Accepted 10 December 2012 Available online 19 December 2012

The steric regulations imparted by the substituent at N1 in lithium mediated asymmetric aldol reactions of conformationally restricted 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones governed the formation of anti aldol adducts, by a kinetic reaction pathway. The preferential formation of the anti aldol diastereomers was also assisted by the steric effects of the electrophile through diastereofacial selection while the electronic effects of the aryl group at N3 remained subtle. Incorporation of an endocyclic methyl group at C6 witnessed the diastereoselective formation of an anti aldol adduct by regulation of p-facial selectivity. The absolute configurations of the aldol adducts were determined by computational calculations and NMR experiments, and confirmed by single crystal X-ray analysis. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Aldol Cyclic enolate 2-Thioxotetrahydropyrimidin-4(1H)-one Chiral induction Diastereoselectivity

1. Introduction The origin of chirality in stereoselective carbonecarbon bond forming reactions facilitated the synthesis of numerous natural products and chiral building blocks in optically pure forms.1,2 The aldol reactions of acyclic chiral enolates are well understood where the stereochemical outcomes are often explained on the basis of highly organized transition states.3 However the aldol reactions of cyclic chiral enolates are rather complex due to stereoregulations originating from the substrate conformation. To gain more insights into the factors influencing the stereochemical outcome in aldol reactions of cyclic enolates, a conformationally rigid heterocyclic enolate of 2-thioxotetrahydropyrimidin-4(1H)-one was considered. The scaffold is associated with various applications and diverse biological properties (Fig. 1). The pyrimidinone core is an integral part of many drugs, such as 5-fluorouracil, uramustine and floxuridine (anticancer); zidovudine, stavudine and 1[(2-hydroxyethoxy)methyl]-6-(phenyl thio)thymine (antiHIV); lamivudine and telbivudine (treatment of chronic hepatitis B); sorivudine and trifluridine (antiviral); alogliptin (antidiabetic) and aminometradine (diuretic).4 The present work discusses about the asymmetric aldol reactions of 2-thioxotetrahydropyrimidin4(1H)-ones, and illustrates how the steric constraints and stereoregulations lead to diastereoselectivity. Our earlier studies in

* Corresponding author. Tel.: þ91 172 229 2045; fax: þ91 172 221 4692; e-mail addresses: [email protected], [email protected] (V.A. Nair). 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.12.020

Fig. 1. A few biologically active pyrimidinones.

this direction have demonstrated that the stereoselective alkylation of 3-aryl-1-alkyl-2-thioxotetrahydropyrimidin-4(1H)one can be achieved by regulating the reaction kinetics using HMPA as an additive and chiral ethyl lactate as a quencher.5a Stereochemical outcome of the alkylation reactions can also be governed by incorporating suitably positioned exocyclic and endocyclic groups, as illustrated in the case of 3-aryl-(S/R)6-methyl-1-[((S/R)-1-phenylethyl)]-2-thioxotetrahydropyrimidin4(1H)-ones.5b Similarly, in the aldol reactions of 3-aryl-1-alkyl-2thioxotetrahydropyrimidin-4(1H)-ones, the exocyclic group at N1,

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electronic effects of the aryl substituent at N3 and steric demands of the electrophile have been found to influence the stereoselectivity.5c 2. Results and discussion Based on our previous works on heterocyclic scaffolds,5 a one-pot synthesis of optically pure 3-aryl-1-alkyl-2-thioxotetrahydropyrimidin4(1H)-ones was achieved by the condensation of aryl isothiocyanates with chiral b-aminoesters.5b As a model reaction, the lithium enolate of 3-(4-chlorophenyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 1 was treated with 4-chlorobenzaldehyde. Incorporation of a chiral a-methyl benzyl group at N1 imparted steric biasness and chiral features to the substrate leading to an asymmetric aldol reaction. The reaction afforded diastereoselectivity forming only two isomers 5a and 5b out of the four possible aldol diastereomers (Scheme 1). The protons at C5 and C7 showed coupling constants of 8.8 and 8.0 Hz for 5a and 5b, respectively, indicating an anti orientation for both of the aldol diastereomers formed.5c The dihedral angles obtained by ab initio calculations6 from the energy optimized structures of 5a and 5b were also in agreement with the observed coupling constants.

Fig. 3. Ortep diagram of the acetate derivative of 5b.

1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones gave similar diastereoselectivity with 4-halo benzaldehydes (Table 1). Further the steric effects of the electrophiles were explored in the aldol reactions of 3-(4-chlorophenyl)-1-((S)-1-phenylethyl)-2thioxotetrahydropyrimidin-4(1H)-ones by varying the aldehydes (Scheme 2). Reactions with benzaldehydes containing electron withdrawing substituents afforded good yields and moderate diastereoselectivity whereas electron donating groups retarded the reaction giving poor yields. The diastereoselectivity of the reaction increased with increasing size of the electrophile, as observed with furfural, N-benzyl-indole-3-carboxaldehyde and 2naphthaldehyde, while the reaction with 9-anthraldehyde afforded only one anti aldol diastereomer (Table 2). Reactions with aliphatic aldehydes afforded inseparable mixture of diastereomers. Table 1 Aldol reactions of 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)ones: effect of substituents

Scheme 1. Aldol reactions pyrimdin-4(1H)-ones.

of

3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydro-

The energy minimized structure for the diastereomer 5b with R configuration at C5 indicated that the proton at C5 has to be shielded because of the anisotropy of the adjacent carbonyl carbon (Fig. 2). 1H NMR spectra of 5b indicated a d value of 2.78 ppm for the C5 proton confirming that it was shielded while the corresponding proton for 5a resonated at 3.12 ppm. Hence S and R configurations can be fairly assigned at C5 for 5a and 5b, respectively. Since the protons at C5 and C7 have an anti relation, R and S configurations were assigned, respectively, for 5a and 5b, at C7. Thus an overall configuration of SSR was assigned at Ca, C5 and C7 for the anti aldol diastereomer 5a and an SRS configuration for the anti aldol diastereomer 5b. The configuration of 5b was finally confirmed by single crystal X-ray diffraction analysis of the corresponding acetate derivative 5b0 (Fig. 3). The aldol reactions of different 3-aryl-1-((S)-

Entry

R1

R2

R

Yield (%)

Product

anti:syn

b:aa

1 2 3 4 5 6 7 8

Cl CN F Cl Cl CN F Cl

H Cl Cl CF3 H Cl Cl CF3

Cl Cl Cl Cl F F F F

82 78 80 84 81 79 82 85

5a, 5b 6a, 6b 7a, 7b 8a, 8b 9a, 9b 10a, 10b 11a, 11b 12a, 12b

100:0 100:0 100:0 100:0 100:0 100:0 100:0 100:0

67:33 64:36 62:38 65:35 64:36 62:38 66:34 63:37

a

Ratio determined from 1H NMR spectrum of the crude product.

Scheme 2. Aldol reactions of 3-(4-chlorophenyl)-1-((S)-1-phenylethyl)-2thioxotetrahydropyrimidin-4(1H)-ones with different aldehydes.

Fig. 2. Configuration determination from the energy minimized structures of 5a and 5b.

Based on the conformation adopted by the 2-thioxotetrahydropyrimidin-4(1H)-one ring, the orientation of the substituents and the stereoregulations posed by the electrophile, transition state models were proposed (Scheme 3). The transition states TS-1 and TS-2 correspond to anti aldol diastereomers a and b, whereas the transition states TS-3 and TS-4 correspond to the syn aldol diastereomers c and d, respectively. A careful consideration of the stereoelectronic effects indicate that the transition states TS-3 and TS-4 are highly unfavourable because of the steric interactions between the aldehyde and the substituent at N1 and hence the reaction is anti specific. However, with increasing steric constraints, the preferred formation of the anti aldol diastereomer b can be explained on the basis of 1,2-interaction between the electrophile and the 2-thioxotetrahydropyrimidin-4(1H)-

V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754

1749

Table 2 Steric effects of electrophiles on aldol reactions of 3-(4-chlorophenyl)-1-((S)-1phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one Yield (%)

Product

anti:syn

b:aa

1

82

5a, 5b

100:0

65:35

2

81

9a, 9b

100:0

64:36

3

80

13a, 13b

100:0

65:35

4

78

14a, 14b

100:0

58:42

5

72

15a, 15b

100:0

82:18

6

84

16a, 16b

100:0

85:15

7

86

17a, 17b

100:0

>99

8

70

18a, 18b

100:0

70:30

Entry

a

RCHO

Scheme 4. Diastereoselective aldol reaction of 3-aryl-(S)-6-methyl-1-((S)-1phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.

coupling constant of 6.8 Hz was observed for the protons at C5 and C7 for 23b confirming an anti orientation. The decoupled spectra obtained by irradiating the methyl protons at C6, revealed no interaction between the protons at C5 and C6, confirming an orthogonal relation. Therefore with the configuration at C6 known, an R configuration can be assigned at C5. Since the protons at C5 and C7 also have an anti relation, configuration at C7 was assigned S, leading to an overall configuration of SRSS at Ca, C5, C6 and C7, respectively. This was further confirmed by single crystal X-ray diffraction analysis of 23b (Fig. 4). The transition state TS-6 is preferred over TS-5 (Scheme 5) because of the steric constraints arising from an unfavourable coplanar relation between the C5eC6eMe and the aldehyde. Transition state TS-6 is free from such an interaction as C5eC6eMe and the aldehyde are in opposite planes and this leads to the diastereoselective formation of anti aldol diastereomers 23be30b (Table 3).

Ratio determined from 1H NMR spectra of the crude product.

Fig. 4. Ortep diagram of 23b.

Scheme 3. Transition state models for aldol reactions of 3-aryl-1-((S)-1-phenylethyl)-2thioxotetrahydropyrimidin-4(1H)-ones.

one ring. For the transition state TS-1 leading to the anti aldol diastereomer a, attack of the enolate occurs on the re face of the aldehyde and this brings the electrophile and the heterocyclic ring in same plane. Therefore with increasing size of the aldehyde substituent Rz, steric interaction becomes prominent and hence the formation of anti aldol diastereomer a is disfavoured. The transition state TS-2 is freefrom such interactions as the aldehyde and 2-thioxotetrahydropyrimidin-4(1H)-one ring are in opposite planes leading to the preferential formation of anti aldol diastereomer b. From the transition state models, we speculated that the approach of the electrophile can be controlled by incorporating an endocyclic methyl group at the C6 position of 2-thioxotetrahydropyrimidin-4(1H)-ones. Thus the aldol reaction of 3-(4-chlorophenyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2thioxotetrahydropyrimdin-4(1H)-one 19, where the two methyl groups at Ca and C6 are in syn orientation (Scheme 4), led to the stereoselective formation of the anti aldol diastereomer 23b. A vicinal

Scheme 5. Transition state models for the diastereoselective aldol reaction of 3-aryl(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.

Table 3 Aldol reactions of 3-aryl-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones Entry

R1

R2

R

Yield (%)

Product

anti:syn

de

1 2 3 4 5 6 7 8

Cl CN F Cl Cl CN F Cl

H Cl Cl CF3 H Cl Cl CF3

Cl Cl Cl Cl F F F F

81 88 85 84 82 86 82 85

23b 24b 25b 26b 27b 28b 29b 30b

100:0 100:0 100:0 100:0 100:0 100:0 100:0 100:0

>99 >99 >99 >99 >99 >99 >99 >99

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The aldol reaction of 3-(4-chlorophenyl)-(R)-6-methyl-1-((S)-1phenylethyl)-2-thioxotetrahydropyrimdin-4(1H)-one 31, where the two methyl groups at Ca and C6 are anti oriented (Scheme 6), also afforded only one anti aldol diastereomer 35a. The configuration of the product 35a was concluded anti based on the vicinal coupling constant of 8.2 Hz between the protons at C5 and C7. The methyl group at C6 was irradiated to decouple and the decoupled spectra showed that the protons at C5 and C6 are orthogonal to each other. Thus with the configuration at C6 known, an S configuration was assigned at C5. Since the protons at C5 and C7 share an anti relation, an R configuration was assigned at C7 with an overall configuration of SSRR at Ca, C5, C6 and C7, respectively. The steric effects imparted by the methyl group at C6 disfavours the transition state TS-8 (Scheme 7) and hence the only possibility left is the formation of anti aldol diastereomers 35ae42a (Table 4) through TS-7, resulting in a diastereoselective reaction.

4. Experimental 4.1. General The 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively, in CDCl3 using TMS as an internal standard. The chemical shifts (d) for 1H and 13C are given in parts per million relative to residual signals of the solvent. Coupling constants are given in Hertz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad signal. HRMS were recorded using TOF mass analyzer. All reactions were performed under nitrogen atmosphere. THF was freshly distilled from sodium benzophenone ketyl. Hexane was distilled before use for column chromatography. The reactions were monitored by TLC. Commercial grade reagents and solvents were used without further purification.

4.2. General procedure for the aldol reaction

Scheme 6. Diastereoselective aldol reaction of 3-aryl-(R)-6-methyl-1-((S)-1phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.

Scheme 7. Transition state models for the diastereoselective aldol reaction of 3-aryl(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.

Table 4 Aldol reactions of 3-aryl-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones Entry

R1

R2

R

Yield (%)

Product

anti:syn

de

1 2 3 4 5 6 7 8

Cl CN F Cl Cl CN F Cl

H Cl Cl CF3 H Cl Cl CF3

Cl Cl Cl Cl F F F F

83 81 84 82 86 80 80 85

35a 36a 37a 38a 39a 40a 41a 42a

100:0 100:0 100:0 100:0 100:0 100:0 100:0 100:0

>99 >99 >99 >99 >99 >99 >99 >99

3. Conclusions Aldol reactions of 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones afforded stereoselectivity towards anti aldol diastereomers. Incorporation of a methyl group at the C6 position of 2-thioxotetrahydropyrimidin-4(1H)-one dictated the diastereoselectivity, forming one of the anti aldol diastereomers exclusively. The combined effects exerted by the endo- and exocyclic groups at C6 and N1 provide convincing evidence for the stereoelectronic influences of the cyclic substrate and the substituents in governing the stereoselectivity of aldol reactions.

In a typical experiment, 1-alkyl-3-aryl-2-thioxotetrahyd ropyrimidin-4(1H)-one (1.5 mmol), dissolved in anhydrous THF (10 mL) and cooled to 78  C was treated with LHMDS (1.8 mL, 1 M solution) under nitrogen atmosphere and stirred for 30 min. Aldehyde (1.65 mmol) was introduced into the reaction mixture, stirred for another 30 min, then quenched with saturated aq NH4Cl and extracted with ethyl acetate. The organic layer was dried and concentrated to provide a gummy compound. The crude product was purified by column chromatography on silica gel (230e400 mesh) using ethyl acetate/hexane mixture (15:85) as the eluent. 4.2.1. 3-(4-Chlorophenyl)-(S)-5-((R)-(4-chlorophenyl)(hydroxy) methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)one, 5a. Rf (30% EtOAc/Hexane) 0.32; white solid; mp 160e162  C; yield 29% (0.21 g); 1H NMR (400 MHz, CDCl3): d 1.47 (d, 3H, J¼7.0 Hz), 2.56e2.69 (m, 2H), 3.12 (m, 1H), 4.29 (s, 1H), 4.75 (d, 1H, J¼8.8 Hz), 6.72 (q, 1H, J¼7.0 Hz), 6.87 (d, 2H, J¼8.9 Hz), 7.15e7.47 (m, 11H); 13C NMR (100 MHz, CDCl3): d 13.8, 40.8, 47.1, 59.5, 71.9, 127.0, 127.7, 128.4, 128.8, 129.0, 129.4, 134.4, 134.6, 136.9, 137.5, 138.4, 170.5, 180.3; HRMS (ESI): m/z [MþNa]þ calcd for C25H22Cl2N2NaO2S: 507.0677, found: 507.0674; [a]25 D 117.18 (c 1.0, CHCl3). 4.2.2. 3-(4-Chlorophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy) methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)one, 5b. Rf (30% EtOAc/Hexane) 0.22; white solid; mp 219e221  C; yield 53% (0.38 g); 1H NMR (400 MHz, CDCl3): d 1.43 (d, 3H, J¼7.0 Hz), 2.78e2.82 (m, 1H), 2.88e2.96 (m, 2H), 4.09 (s, 1H), 4.76 (d, 1H, J¼8.4 Hz), 6.87 (q, 1H, J¼7.0 Hz), 6.99e7.04 (m, 2H), 7.10e7.14 (m, 4H), 7.22e2.26 (m, 2H), 7.35e7.45 (m, 5H); 13C NMR (100 MHz, CDCl3): d 14.9, 41.1, 47.8, 59.2, 71.9, 115.7, 115.9, 127.3, 128.2, 128.3, 128.5, 128.9, 129.4, 130.6, 134.5, 135.2, 137.6, 169.5, 180.4; HRMS (ESI): m/z [MþNa]þ calcd for C25H22Cl2N2NaO2S: 507.0677, found: 507.0672; [a]25 D 253.74 (c 1.0, CHCl3). 4.2.3. 3-(3-Chloro-4-cyanophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)one, 6b. Rf (30% EtOAc/Hexane) 0.25; white solid; mp 220e222  C; yield 50% (0.38 g); 1H NMR (400 MHz, CDCl3): d 1.49 (d, 3H, J¼7.0 Hz), 2.81e2.91 (m, 1H), 2.98e3.09 (m, 2H), 3.63 (s, 1H), 4.76 (d, 1H, J¼7.4 Hz), 6.85 (q, 1H, J¼6.9 Hz), 7.03 (d, 2H, J¼8.4 Hz), 7.23e7.43 (m, 8H), 7.77 (d, 2H, J¼8.2 Hz); 13C NMR (100 MHz, CDCl3): d 14.9, 41.1, 47.7, 59.2, 71.7, 113.4, 115.5, 127.4, 127.8, 128.7, 128.8, 129.1, 131.5, 134.1, 134.7, 137.3, 137.4, 137.8, 143.9, 168.5, 179.3; HRMS (ESI): m/z [MþNa]þ

V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754

calcd for C26H21Cl2N3NaO2S: 532.0629, found: 532.0628; [a]25 D 73.40 (c 1.0, CHCl3). 4.2.4. 3-(3-Chloro-4-fluorophenyl)-(S)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)one, 7a. Rf (30% EtOAc/Hexane) 0.35; white solid; mp 166e168  C; yield 28% (0.20 g); 1H NMR (400 MHz, CDCl3): d 1.47 (d, 3H, J¼6.88 Hz), 2.60e2.71 (m, 2H), 3.01e3.14 (m, 1H), 4.23 (s, 1H), 4.76 (d, 1H, J¼8.4 Hz), 6.73 (q, 1H, J¼6.8 Hz), 6.88e6.91 (m, 4H), 7.19e7.36 (m, 8H); 13C NMR (100 MHz, CDCl3): d 13.8, 40.9, 47.1, 59.5, 71.9, 115.6, 115.9, 116.9, 127.0, 128.1, 128.2, 128.4, 128.9, 134.2, 138.4, 170.6, 180.2; HRMS (ESI): m/z [MþNa]þ calcd for C25H21Cl2FN2NaO2S: 525.0583, found: 525.0587; [a]25 D þ114.11 (c 0.5, CHCl3). 4.2.5. 3-(3-Chloro-4-fluorophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy) methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)one, 7b. Rf (30% EtOAc/Hexane) 0.25; white solid; mp 216e218  C; yield 50% (0.37 g); 1H NMR (400 MHz, CDCl3): d 1.45 (d, 3H, J¼7.0 Hz), 2.77e2.84 (m, 1H), 2.93e3.00 (m, 2H), 3.89 (s, 1H), 4.76 (d, 1H, J¼7.7 Hz), 6.85 (q, 1H, J¼7.0 Hz), 7.05 (d, 2H, J¼8.4 Hz), 7.19e7.39 (m, 10H); 13C NMR (100 MHz, CDCl3): d 14.9, 41.1, 47.7, 59.3, 71.8, 113.4, 115.5, 127.4, 127.8, 128.7, 128.8, 129.1, 131.5, 134.1, 134.7, 137.3, 137.4, 137.8, 143.9, 168.5, 179.3; HRMS (ESI): m/z [MþNa]þ calcd for C25H21Cl2FN2NaO2S: 525.0583, found: 525.0583; [a]25 D 195.87 (c 1.0, CHCl3). 4.2.6. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(S)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 8a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 203e206  C; yield 34% (0.25 g); 1H NMR (400 MHz, CDCl3): d 1.57 (d, 3H, J¼7.0 Hz), 2.58e2.65 (m, 2H), 2.96e3.00 (m, 1H), 3.55e3.62 (m, 1H), 5.43 (s, 1H), 6.74 (q, 1H, J¼7.0 Hz), 6.93 (d, 2H, J¼8.5 Hz), 7.18e7.24 (m, 5H), 7.26e7.40 (m, 3H), 7.54 (s, 1H), 7.62 (d, 1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3): d 13.9, 29.7, 31.9, 38.3, 47.9, 59.6, 68.1, 126.1, 127.0, 127.6, 128.4, 128.8, 128.8, 128.9, 129.1, 132.0, 132.4, 133.4, 134.0, 137.6, 138.0, 138.4, 168.3, 179.9; HRMS (ESI): m/z [MþNa]þ calcd for C26H21Cl2F3N2NaO2S: 575.0551, found: 575.0551; [a]25 D þ75.54 (c 0.5, CHCl3). 4.2.7. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(R)-5-((S)-(4chlorophenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 8b. Rf (30% EtOAc/Hexane) 0.31; white solid; mp 202e204  C; yield 54% (0.45 g); 1H NMR (400 MHz, CDCl3): d 1.48 (d, 3H, J¼7.0 Hz), 2.80e2.88 (m, 1H), 2.96e3.03 (m, 2H), 3.80 (s, 1H), 4.76 (d, 1H, J¼7.7 Hz), 6.85 (q, 1H, J¼7.0 Hz), 7.05 (d, 2H, J¼8.4 Hz), 7.25e7.35 (m, 5H), 7.37e7.44 (m, 3H), 7.49 (s, 1H), 7.59 (d, 1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3): d 14.9, 41.1, 47.8, 59.3, 71.8, 121.0, 123.7, 127.4, 127.8, 128.6, 129.0, 129.3, 132.1, 132.5, 134.0, 134.7, 137.5, 137.8, 137.9, 169.0, 179.9; HRMS (ESI): m/z [MþNa]þ calcd for C26H21Cl2F3N2NaO2S: 575.0551, found: 575.0551; [a]25 D 238.26 (c 1.0, CHCl3). 4.2.8. 3-(4-Chlorophenyl)-(S)-5-((R)-(4-fluorophenyl)(hydroxy) methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 9a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 186e189  C; yield 29% (0.20 g); 1H NMR (400 MHz, CDCl3): d 1.47 (d, 3H, J¼7.0 Hz), 2.57e2.69 (m, 2H), 3.08e3.16 (m, 1H), 4.29 (s, 1H), 4.74 (d, 1H, J¼7.0 Hz), 6.72 (q, 1H, J¼7.0 Hz), 6.87e6.90 (m, 2H), 7.13e7.20 (m, 5H), 7.29e7.38 (m, 4H), 7.46 (d, 2H, J¼4.3 Hz); 13C NMR (100 MHz, CDCl3): d 13.8, 40.8, 47.1, 59.5, 71.9, 126.0, 126.8, 127.0, 127.6, 128.4,128.9, 129.0, 129.4, 130.4, 136.9, 137.5, 138.4, 170.5, 180.3; HRMS (ESI): m/z [MþNa]þ calcd for C25H22ClFN2NaO2S: 491.0972, found: 491.0972; [a]25 D þ170.76 (c 1.0, CHCl3). 4.2.9. 3-(4-Chlorophenyl)-(R)-5-((S)-(4-fluorophenyl)(hydroxy) methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one,

1751

9b. Rf (30% EtOAc/Hexane) 0.25; white solid; mp 226e228  C; yield 52% (0.36 g); 1H NMR (400 MHz, CDCl3): d 1.45 (d, 3H, J¼7.1 Hz), 2.75e2.82 (m, 1H), 2.87e2.99 (m, 2H), 4.11 (s, 1H), 4.77 (d, 1H, J¼8.3 Hz), 6.87 (q,1H, J¼7.2 Hz), 7.00e7.04 (m, 2H), 7.11e7.15 (m, 4H), 7.22e2.26 (m, 2H), 7.32e7.50 (m, 5H); 13C NMR (100 MHz, CDCl3): d 14.9, 41.1, 47.8, 59.2, 72.0, 115.7, 115.9, 127.3, 128.2, 128.3, 128.5, 128.9, 129.4, 130.6, 134.5, 135.2, 137.6, 169.5, 180.4; HRMS (ESI): m/z [MþNa]þ calcd for C25H22ClFN2NaO2S: 491.0972, found: 491.0971; [a]25 D 297.00 (c 1.0, CHCl3). 4.2.10. 3-(3-Chloro-4-cyanophenyl)-(R)-5-((S)-(4-fluorophenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)one, 10b. Rf (30% EtOAc/Hexane) 0.25; white solid; mp 168e170  C; yield 49% (0.36 g); 1H NMR (400 MHz, CDCl3): d 1.46 (d, 3H, J¼7.0 Hz), 2.80e2.87 (m, 1H), 2.96e3.03 (m, 2H), 3.68 (s, 1H), 4.76 (d, 1H, J¼7.7 Hz), 6.85 (q, 1H, J¼7.0 Hz), 7.01e7.09 (m, 4H), 7.20e7.29 (m, 3H), 7.32e7.42 (m, 4H), 7.76 (d, 1H, J¼8.3 Hz); 13C NMR (100 MHz, CDCl3): d 14.9, 41.2, 47.9, 59.2, 71.8, 113.4, 115.5, 115.7, 127.4, 128.1, 128.7, 128.8, 129.0, 131.5, 134.1, 135.1, 137.3, 143.9, 161.6, 164.0, 168.7, 179.3; HRMS (ESI): m/z [MþNa]þ calcd for C26H21ClFN3NaO2S: 516.0925, found: 516.0921; [a]25 D 289.20 (c 1.0, CHCl3). 4.2.11. 3-(3-Chloro-4-fluorophenyl)-(S)-5-((R)-(4-fluorophenyl)hydroxy)methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin4(1H)-one, 11a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 175e178  C; yield 28% (0.20 g); 1H NMR (400 MHz, CDCl3): d 1.50 (d, 3H, J¼6.9 Hz), 2.63e2.74 (m, 2H), 3.01e3.17 (m, 1H), 4.26 (s, 1H), 4.78 (d, 1H, J¼8.2 Hz), 6.75 (q, 1H, J¼6.8 Hz), 6.89e6.94 (m, 4H), 7.22e7.28 (m, 4H), 7.33e7.39 (m, 4H); 13C NMR (100 MHz, CDCl3): d 13.8, 28.2, 40.9, 47.1, 59.5, 71.9, 115.7, 115.9, 116.7, 116.9, 127.0, 128.1, 128.2, 128.5, 129.0, 134.2, 138.4, 170.6, 180.2; HRMS (ESI): m/z [MþNa]þ calcd for C25H21ClF2N2NaO2S: 509.0878, found: 509.0878; [a]25 D þ139.88 (c 0.5, CHCl3). 4.2.12. 3-(3-Chloro-4-fluorophenyl)-(R)-5-((S)-(4-fluorophenyl)hydroxy) methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 11b. Rf (30% EtOAc/Hexane) 0.28; white solid; mp 197e198  C; yield 54% (0.39 g); 1H NMR (400 MHz, CDCl3): d 1.46 (d, 3H, J¼7.0 Hz), 2.75e2.83 (m, 1H), 2.88e3.00 (m, 2H), 3.96 (s, 1H), 4.76 (d, 1H, J¼8.2 Hz), 6.86 (q, 1H, J¼7.0 Hz), 6.99e7.04 (m, 2H), 7.08e7.13 (m, 3H), 7.15e7.25 (m, 4H), 7.30e7.42 (m, 3H); 13C NMR (100 MHz, CDCl3): d 14.9, 41.1, 47.8, 59.3, 71.9, 115.5, 116.7, 121.4, 127.0, 127.1, 128.2, 128.8, 135.2, 135.5, 137.6, 156.7, 159.2, 161.5, 164.0, 169.4, 180.2; HRMS (ESI): m/ z [MþNa]þ calcd for C25H21ClF2N2NaO2S: 509.0878, found: 509.0878; [a]25 D 280.02 (c 1.0, CHCl3). 4.2.13. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(S)-5-((R)-(4-fluorophenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 12a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 210e213  C; yield 32% (0.25 g); 1H NMR (400 MHz, CDCl3): d 1.58 (d, 3H, J¼7.2 Hz), 2.60e2.66 (m, 2H), 2.99e3.04 (m, 1H), 3.57e3.63 (m, 1H), 5.44 (s, 1H), 6.77 (q, 1H, J¼6.9 Hz), 6.90e7.00 (m, 4H), 7.24e7.37 (m, 6H), 7.54 (s, 1H), 7.62 (d, 1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3): d 14.0, 38.5, 47.9, 59.5, 68.1,115.4,115.6,126.4,126.5,127.0,128.33,128.8, 132.1, 132.0, 134.7, 138.0, 138.5, 168.4, 179.9; HRMS (ESI): m/z [MþNa]þ calcd for C26H21ClF4N2NaO2S: 559.0846, found: 559.0840; [a]25 D þ146.48 (c 1.0, CHCl3). 4.2.14. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(R)-5-((S)-(4-fluorophenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin4(1H)-one, 12b. Rf (30% EtOAc/Hexane) 0.31; white solid; mp 192e194  C; yield 53% (0.43 g); 1H NMR (400 MHz, CDCl3): d 1.48 (d, 3H, J¼7.2 Hz), 2.79e2.86 (m, 1H), 2.94e3.02 (m, 2H), 3.87 (s, 1H), 4.76 (d, 1H, J¼7.8 Hz), 6.85 (q, 1H, J¼7.0 Hz), 7.00e7.12 (m, 4H), 7.25e7.43 (m, 6H), 7.50 (s, 1H), 7.60 (d, 1H, J¼8.5 Hz); 13C NMR (100 MHz, CDCl3):

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d 14.9, 41.2, 47.9, 59.3, 71.9, 115.7, 115.9, 127.4, 128.1, 128.2, 128.6, 129.0, 132.0, 132.5, 135.2, 137.5, 137.9, 161.6, 169.4, 179.9; HRMS (ESI): m/z [MþNa]þ calcd for C26H21ClF4N2NaO2S: 559.0846, found: 559.0846; [a]25 D 284.02 (c 1.0, CHCl3). 4.2.15. 3-(4-Chlorophenyl)-(S)-5-((R)-(hydroxy)(phenyl)methyl)-1((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 13a. Rf (30% EtOAc/Hexane) 0.26; white solid; mp 216e219  C; yield 28% (0.17 g); 1H NMR (400 MHz, CDCl3): d 1.43 (d, 3H, J¼7.0 Hz), 1.57 (s, 1H), 2.78e2.85 (m, 1H), 2.89e2.96 (m, 1H), 2.98e3.05 (m, 1H), 4.80 (d, 1H, J¼8.3 Hz), 6.89 (q, 1H, J¼7.0 Hz), 7.15e7.20 (m, 4H), 7.23e7.24 (m, 2H), 7.34e7.38 (m, 6H), 7.48 (d, 2H, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3): d 15.0, 41.3, 47.8, 59.2, 72.7, 126.4, 127.3, 128.4, 128.9, 129.3, 129.3, 130.6, 134.5, 137.6, 137.8, 139.3, 169.8, 180.4; HRMS (ESI): m/z [MþNa]þ calcd for C25H23ClN2NaO2S: 473.1066, found: 473.1060; [a]25 D 153.82 (c 1.0, CHCl3). 4.2.16. 3-(4-Chlorophenyl)-(R)-5-((S)-(hydroxy)(phenyl)methyl)-1((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 13b. Rf (30% EtOAc/Hexane) 0.35; white solid; mp 175e178  C; yield 52% (0.32 g); 1H NMR (400 MHz, CDCl3): d 1.48 (d, 3H, J¼7.0 Hz), 1.60 (s, 1H), 2.70e2.74 (m, 1H), 2.75e2.79 (m, 1H), 3.15 (m, 1H), 4.80 (d, 1H, J¼1.5 Hz), 6.78 (q, 1H, J¼7.0 Hz), 6.96e6.98 (m, 2H), 7.21e7.26 (m, 5H), 7.28e7.39 (m, 5H), 7.49 (d, 2H, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3): d 13.9, 41.0, 46.9, 59.4, 72.7, 126.4, 126.9, 128.3, 128.7, 128.9, 128.9, 129.4, 134.5, 137.7, 138.3, 138.5, 170.7, 180.4; HRMS (ESI): m/z [MþNa]þ calcd for C25H23ClN2NaO2S: 473.1066, found: 473.1061; [a]25 D 62.65 (c 0.5, CHCl3 ). 4.2.17. 3-(4-Chlorophenyl)-(S)-5-((R)-(furan-2-yl(hydroxy)methyl))-1((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 14a. Rf (30% EtOAc/Hexane) 0.26; white solid; mp 148e151  C; yield 24% (0.16 g); 1H NMR (400 MHz, CDCl3): d 1.56 (d, 3H, J¼7.0 Hz), 1.94 (d, 1H, J¼6.9 Hz), 2.94 (d, 1H, J¼5.2 Hz), 3.02e3.09 (m, 1H), 3.19e3.26 (m, 1H), 4.90 (d, 1H, J¼8.6 Hz), 6.07 (d, 1H, J¼3.1 Hz), 6.24e6.25 (m, 1H), 6.85 (q, 1H, J¼6.9 Hz), 7.07e7.16 (m, 2H), 7.32e7.48 (m, 8H); 13C NMR (100 MHz, CDCl3): d 14.0, 40.8, 45.0, 59.5, 65.8, 108.7, 110.1, 127.1, 128.3, 129.0, 129.3, 134.5, 137.7, 138.6, 142.9, 147.3, 151.1, 169.9, 180.5; HRMS (ESI): m/z [MþNa]þ calcd for C23H21ClN2NaO3S: 463.0859, found: 463.0852; [a]25 D 130.29 (c 0.5, CHCl3).

calcd for C34H30ClN3NaO2S: 602.1645, found: 602.1645; [a]25 D þ150.67 (c 1.0, CHCl3). 4.2.20. 3-(4-Chlorophenyl)-(R)-5-(S)-(naphthalen-2-yl(hydroxy) methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)one, 16b. Rf (30% EtOAc/Hexane) 0.28; white solid; mp 209e211  C; yield 72% (0.53 g); 1H NMR (400 MHz, CDCl3): d 1.37 (d, 3H, J¼7.0 Hz), 2.82e2.93 (m, 1H), 2.95e3.12 (m, 2H), 4.95 (d, 1H, J¼8.4 Hz), 6.84 (q, 1H, J¼7.0 Hz), 7.12e7.15 (m, 4H), 7.22e7.54 (m, 9H), 7.73e7.88 (m, 3H), 13C NMR (100 MHz, CDCl3): d 15.0, 41.3, 47.6, 59.2, 72.7, 123.4, 126.1, 126.6, 127.4, 127.8, 128.1, 128.4, 128.8, 129.0, 129.4, 130.6, 133.0, 133.4, 134.5, 136.6, 137.6, 137.8, 169.6, 180.4; HRMS (ESI): m/z [MþNa]þ calcd for C29H25ClN2NaO2S: 523.1223, found: 523.1223; [a]25 D 245.88 (c 1.0, CHCl3). 4.2.21. 3-(4-Chlorophenyl)-(R)-5-(S)-(anthracen-9-yl(hydroxy) methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)one, 17b. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 162e164  C; yield 86% (0.71 g); 1H NMR (400 MHz, CDCl3): d 1.09 (d, 3H, J¼7.2 Hz), 2.12e2.15 (m, 1H), 3.03e3.10 (m, 1H), 3.50e3.58 (m, 1H), 6.47e6.81 (m, 5H), 7.20e7.52 (m, 12H), 7.80e7.81 (m, 2H), 8.40 (s, 1H); 13C NMR (100 MHz, CDCl3): d 13.7, 40.9, 45.9, 59.2, 68.0, 125.9, 126.6, 126.9, 127.2, 127.8, 128.0, 128.1, 128.4, 128.5, 129.3, 129.4, 129.5, 129.8, 134.5, 137.5, 137.8, 171.7, 180.2; HRMS (ESI): m/z [MþNa]þ calcd for C33H27ClN2NaO2S: 573.1379, found: 573.1379; [a]25 D 167.35 (c 1.0, CHCl3). 4.2.22. 3-(4-Chlorophenyl)-(S)-5-((E,R)-1-hydroxy-3-phenylallyl)-1((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 18a. Rf (30% EtOAc/Hexane) 0.16; white solid; mp 218e221  C; yield 49% (0.23 g); 1H NMR (400 MHz, CDCl3): d 1.68 (d, 3H, J¼7.0 Hz), 2.92e2.97 (m, 1H), 3.05 (d, 1H, J¼3.7 Hz), 3.14e3.20 (m, 1H), 3.50e3.55 (m, 1H), 4.48 (s, 1H), 5.99e6.05 (m, 1H), 6.38 (d, 1H, J¼15.9 Hz), 7.03 (q, 1H, J¼7.0 Hz), 7.14 (d, 2H, J¼8.0 Hz), 7.28e7.34 (m, 6H), 7.37e7.48 (m, 6H); 13C NMR (100 MHz, CDCl3): d 14.9, 41.0, 46.6, 59.3, 71.0, 126.7, 127.0, 127.5, 128.3, 128.5, 128.6, 129.0, 129.3, 130.7, 133.5, 134.4, 135.7, 137.9, 138.0, 168.3, 180.6; HRMS (ESI): m/z [MþNa]þ calcd for C27H25ClN2NaO2S: 499.1226, found: 499.1226; [a]25 D 93.54 (c 0.5, CHCl3).

4.2.18. 3-(4-Chlorophenyl)-(R)-5-((S)-(furan-2-yl(hydroxy)methyl))-1((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 14b. Rf (30% EtOAc/Hexane) 0.16; white solid; mp 219e221  C; yield 44% (0.30 g); 1H NMR (400 MHz, CDCl3): d 1.60 (d, 3H, J¼7.0 Hz), 2.89e2.95 (m, 1H), 3.08e3.12 (m, 2H), 3.30e3.36 (m, 1H), 4.85 (d, 1H, J¼8.3 Hz), 6.13 (d, 1H, J¼3.1 Hz), 6.34e6.35 (m, 1H), 6.95 (q, 1H, J¼7.0 Hz), 7.14e7.16 (m, 2H), 7.32e7.48 (m, 8H); 13C NMR (100 MHz, CDCl3): d 15.0, 39.7, 46.0, 59.1, 64.7, 107.7, 110.6, 127.3, 127.4, 128.4, 129.0, 129.3, 130.7, 134.3, 138.1, 142.4, 152.6, 167.4, 180.6; HRMS (ESI): m/z [MþNa]þ calcd for C23H21ClN2NaO3S: 463.0859, found: 463.0859; [a]25 D 308.22 (c 1.0, CHCl3).

4.2.23. 3-(4-Chlorophenyl)-(R)-5-((E,S)-1-hydroxy-3-phenylallyl)-1((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 18b. Rf (30% EtOAc/Hexane) 0.22; white solid; mp 185e189  C; yield 21% (0.14 g); 1H NMR (400 MHz, CDCl3): d 1.64 (d, 3H, J¼7.0 Hz), 2.61e2.68 (m, 1H), 3.29e3.40 (m, 2H), 3.48e3.63 (m, 1H), 4.49e4.53 (s, 1H), 5.83 (q, 1H, J¼8.1 Hz), 6.56 (d, 1H, J¼15.9 Hz), 6.86e6.94 (m, 1H), 7.16 (s, 2H), 7.24e7.26 (m, 2H), 7.32e7.42 (m, 8H), 7.47 (d, 2H, J¼8.7 Hz); 13C NMR (100 MHz, CDCl3): d 14.1, 40.9, 46.0, 59.6, 71.2, 126.6, 126.7, 127.2, 128.4, 128.5, 128.6, 129.0, 129.3, 130.7, 134.0, 134.5, 135.6, 137.8, 138.7, 169.5, 180.6; HRMS (ESI): m/z [MþNa]þ calcd for C27H25ClN2NaO2S: 499.1223, found: 499.1226; [a]25 D 161.27 (c 1.0, CHCl3).

4.2.19. 3-(4-Chlorophenyl)-(R)-5-((S)-(1-benzyl-1H-indol-3-yl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin4(1H)-one, 15b. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 231e233  C; yield 51% (0.46 g); 1H NMR (400 MHz, CDCl3): d 1.38 (d, 3H, J¼7.0 Hz), 2.86e2.93 (m, 1H), 3.15e3.21 (m, 1H), 3.47e3.50 (m, 1H), 3.63 (d, 1H, J¼2.8 Hz), 5.05 (m, 1H), 5.23 (m, 2H), 6.64 (s, 1H), 6.88 (q, 1H, J¼7.0 Hz), 7.04e7.32 (m, 15H), 7.44 (d, 2H, J¼8.8 Hz), 7.66 (d, 1H, J¼8.0 Hz), 13C NMR (100 MHz, CDCl3): d 14.9, 41.7, 47.0, 50.0, 59.1, 66.8, 110.2, 113.6, 119.7, 120.2, 122.6, 125.7, 126.7, 127.0, 127.5, 127.9, 128.2, 128.8, 128.9, 129.3, 130.7, 134.4, 137.0, 137.1, 138.0, 138.1, 169.6, 180.6; HRMS (ESI): m/z [MþNa]þ

4.2.24. 3-(4-Chlorophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy) methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 23b. Rf (30% EtOAc/Hexane) 0.37; white solid; mp 188e190  C; yield 81% (0.60 g); 1H NMR (400 MHz, CDCl3): d 1.49 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.18 (d, 1H, J¼4.9 Hz), 2.79 (d, 1H, J¼6.6 Hz), 3.60 (q, 1H, J¼6.6 Hz), 3.94 (dd, 1H, J¼5.0 Hz, J¼6.5 Hz), 6.50e6.53 (m, 2H), 7.08e7.16 (m, 3H), 7.29e7.35 (q, 1H, J¼7.3 Hz), 7.43e7.51 (m, 6H), 7.64 (m, 2H); 13C NMR (100 MHz, CDCl3): d 16.1, 21.0, 49.3, 53.3, 59.2, 71.7, 127.7, 128.5, 128.8, 129.1, 129.2, 129.3, 134.1, 134.2, 138.8, 139.1, 140.1, calcd for 165.7, 180.5; HRMS (ESI): m/z [MþNa]þ

V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754

C26H24Cl2N2NaO2S: 521.0833, found: 521.0833; [a]25 D 186.51 (c 1.0, CHCl3). 4.2.25. 3-(3-Chloro-4-cyanophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 24b. Rf (30% EtOAc/Hexane) 0.32; white solid; mp 192e193  C; yield 88% (0.69 g); 1H NMR (400 MHz, CDCl3): d 1.50 (d, 3H, J¼6.3 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.01 (s, 1H), 2.79 (d, 1H, J¼5.8 Hz), 3.67 (q, 1H, J¼6.6 Hz), 3.87 (m, 1H), 6.57 (d, 2H, J¼8.4 Hz), 7.16 (d, 2H, J¼8.4 Hz), 7.22e7.27 (m, 1H), 7.37e7.50 (m, 4H), 7.63e7.66 (m, 2H). 7.75 (d, 2H, J¼8.2 Hz); 13C NMR (100 MHz, CDCl3): d 16.1, 21.0, 49.7, 55.1, 59.2, 72.0, 113.0, 115.7, 127.0, 127.5, 128.5, 129.0, 129.3, 129.4, 134.1, 134.4, 137.0, 138.5, 140.0, 145.0, 165.0, 179.5; HRMS (ESI): m/z [MþNa]þ calcd for C27H23Cl2N3NaO2S: 546.0786, found: 546.0781; [a]25 D 208.19 (c 1.0, CHCl3). 4.2.26. 3-(3-Chloro-4-fluorophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 25b. Rf (30% EtOAc/Hexane) 0.32; white solid; mp 225e226  C; yield 85% (0.65 g); 1H NMR (400 MHz, CDCl3): d 1.49 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.08 (s, 1H), 2.79 (d, 1H, J¼6.3 Hz), 3.62 (q, 1H, J¼6.6 Hz), 3.90 (m, 1H), 6.54 (d, 2H, J¼8.4 Hz), 7.13e7.34 (m, 6H), 7.47e7.52 (m, 3H), 7.62e7.66 (m, 2H); 13C NMR (100 MHz, CDCl3): d 16.1, 21.0, 49.4, 55.3, 59.3, 71.8, 116.6, 121.3, 127.6, 128.6, 128.9, 129.2, 129.2, 134.3, 136.5, 136.6, 139.1, 140.2, 156.5, 159.0, 165.3, 180.4; HRMS (ESI): m/z [MþNa]þ calcd for C26H23Cl2FN2NaO2S: 539.0739, found: 539.0739; [a]25 D 182.91 (c 1.0, CHCl3).

1753

163.8, 165.3, 179.5; HRMS (ESI): m/z [MþNa]þ calcd for C27H23ClFN3NaO2S: 530.1081, found: 530.1081; [a]25 D 207.19 (c 1.0, CHCl3). 4.2.30. 3-(3-Chloro-4-fluorophenyl)-(R)-5-((S)-(4-fluorophenyl)(hydroxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 29b. Rf (30% EtOAc/Hexane) 0.31; white solid; mp 204e205  C; yield 82% (0.61 g); 1H NMR (400 MHz, CDCl3): d 1.48 (d, 3H, J¼6.7 Hz), 1.72 (d, 3H, J¼7.3 Hz), 2.00 (d, 1H, J¼4.6 Hz), 2.79 (d, 1H, J¼6.2 Hz), 3.62 (q, 1H, J¼6.7 Hz), 3.87e3.90 (m, 1H), 6.57e6.61 (m, 2H), 6.83e6.88 (m, 2H), 7.09e7.38 (m, 4H), 7.46e7.48 (m, 3H), 7.62e7.65 (m, 2H); 13C NMR (100 MHz, CDCl3): d 16.1, 21.0, 49.4, 55.2, 59.3, 71.9, 115.5, 115.7, 116.6, 116.9, 128.1, 128.2, 128.6, 129.1, 129.2, 136.6, 139.1, 161.3, 163.8, 165.6, 180.4; HRMS (ESI): m/z [MþNa]þ calcd for C26H23ClF2N2NaO2S: 523.1035, found: 523.1033; [a]25 D 186.31 (c 1.0, CHCl3). 4.2.31. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(R)-5-((S)-(4fluorophenyl)(hydroxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)2-thioxotetrahydropyrimidin-4(1H)-one, 30b. Rf (30% EtOAc/Hexane) 0.31; white solid; mp 224e225  C; yield 85% (0.70 g); 1H NMR (400 MHz, CDCl3): d 1.51 (d, 3H, J¼6.6 Hz), 1.73 (d, 3H, J¼7.1 Hz), 2.05 (s, 1H), 2.82 (d, 1H, J¼6.0 Hz), 3.62 (q, 1H, J¼6.4 Hz), 3.90 (d, 1H, J¼5.5 Hz), 6.59e6.63 (m, 2H), 6.85e6.89 (m, 2H), 7.17e7.48 (m, 6H), 7.59 (d, 1H, J¼8.2 Hz), 7.64e7.66 (m, 2H); 13C NMR (100 MHz, CDCl3): 14.1, 16.1, 49.5, 55.3, 59.3, 71.9, 115.5, 115.7, 127.0, 128.0, 128.1, 128.6, 129.0, 129.1, 129.2, 132.0, 137.5, 139.0, 161.3, 163.8, calcd for 165.6, 180.0; HRMS (ESI): m/z [MþNa]þ C27H23ClF4N2NaO2S: 573.1003, found: 573.1002; [a]25 D 182.32 (c 1.0, CHCl3).

4.2.27. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(R)-5-((S)-(4chlorophenyl)(hydroxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)2-thioxotetrahydropyrimidin-4(1H)-one, 26b. Rf (30% EtOAc/Hexane) 0.37; white solid; mp 118e120  C; yield 84% (0.71 g); 1H NMR (400 MHz, CDCl3): d 1.49 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.07 (s, 1H), 2.79 (d, 1H, J¼6.2 Hz), 3.62 (q, 1H, J¼6.9 Hz), 3.89 (s, 1H), 6.52 (d, 2H, J¼8.4 Hz), 7.13e7.16 (m, 2H), 7.24e7.30 (m, 2H), 7.42e7.65 (m, 7H); 13C NMR (100 MHz, CDCl3): d 16.1, 21.1, 49.5, 55.2, 59.3, 71.9, 121.1, 123.8, 127.6, 128.6, 128.9, 129.2, 129.3, 132.0, 134.4, 138.9, 139.0, 140.1, 165.5, 180.1; HRMS (ESI): m/z [MþNa]þ calcd for C27H23Cl2F3N2NaO2S: 589.0707, found: 589.0708; [a]25 D 166.03 (c 1.0, CHCl3).

4.2.32. 3-(4-Chlorophenyl)-(S)-5-((R)-(4-chlorophenyl)(hydroxy) methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 35a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 203e204  C; yield 83% (0.62 g); 1H NMR (400 MHz, CDCl3): d 0.58 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.1 Hz), 2.75 (s, 1H), 2.79 (d, 1H, J¼7.9 Hz), 3.48 (q, 1H, J¼6.7 Hz), 4.85 (d, 1H, J¼5.0 Hz, J¼5.5 Hz), 7.09e7.15 (m, 2H), 7.25e7.40 (m, 8H), 7.41e7.43 (m, 4H); 13C NMR (100 MHz, CDCl3): d 15.6, 19.6, 49.3, 54.1, 59.0, 72.3, 128.4, 128.6, 128.9, 129.3, 129.5, 130.3, 134.2, 135.1, 137.9, 138.6, 139.0, 166.1, 179.6; HRMS (ESI): m/z [MþNa]þ calcd for C26H24Cl2N2NaO2S: 521.0833, found: 521.0833; [a]25 D 229.57 (c 1.0, CHCl3).

4.2.28. 3-(4-Chlorophenyl)-(R)-5-((S)-(4-fluorophenyl)(hydroxy) methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 27b. Rf (30% EtOAc/Hexane) 0.28; white solid; mp 169e170  C; yield 82% (0.59 g); 1H NMR (400 MHz, CDCl3): d 1.50 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.12 (d, 1H, J¼4.8 Hz), 2.81 (d, 1H, J¼6.5 Hz), 3.60 (q, 1H, J¼6.6 Hz), 3.94 (m, 1H), 6.58 (m, 2H), 6.86 (m, 2H), 7.20e7.30 (m, 2H), 7.31 (q, 1H, J¼7.3 Hz), 7.43e7.51 (m, 5H), 7.63e7.65 (m, 2H); 13C NMR (100 MHz, CDCl3): d 16.1, 21.0, 49.3, 55.4, 59.3, 71.7, 115.5, 128.1, 128.2, 128.6, 129.1, 129.2, 129.9, 131.3, 134.1, 137.5, 138.8, 139.1, 161.3, 163.7, 165.7, 180.5; HRMS (ESI): m/z [MþNa]þ calcd for C26H24ClFN2NaO2S: 505.1129, found: 505.1129; [a]25 D 185.31 (c 1.0, CHCl3).

4.2.33. 3-(3-Chloro-4-cyanophenyl)-(S)-5-(R)-(4-chlorophenyl(hydroxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 36a. Rf (30% EtOAc/Hexane) 0.22; white solid; mp 188e190  C; yield 81% (0.63 g); 1H NMR (400 MHz, CDCl3): d 0.61 (d, 3H, J¼6.7 Hz), 1.61 (d, 3H, J¼7.1 Hz), 2.45 (s, 1H), 2.97 (d, 1H, J¼7.1 Hz), 3.44e3.49 (m, 1H), 3.59 (d, 1H, J¼6.7 Hz), 4.91 (d, 1H, J¼7.0 Hz), 7.09 (q, 1H, J¼7.0 Hz), 7.35e7.46 (m, 11H), 7.82 (d, 1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3): d 15.5, 19.7, 49.8, 55.2, 58.93, 72.8, 115.1, 115.7, 128.3, 128.4, 128.7, 129.0, 129.1, 129.3, 129.6, 134.1, 135.3, 137.2, 137.6, 139.0, 144.8, 165.6, 178.6; HRMS (ESI): m/z [MþNa]þ calcd for C27H23Cl2N3NaO2S: 546.0786, found: 546.0786; [a]25 D 217.88 (c 1.0, CHCl3).

4.2.29. 3-(3-Chloro-4-cyanophenyl)-(R)-5-((S)-(4-fluorophenyl)(hydroxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 28b. Rf (30% EtOAc/Hexane) 0.19; white solid; mp 177e178  C; yield 86% (0.65 g); 1H NMR (400 MHz, CDCl3): d 1.50 (d, 3H, J¼6.7 Hz), 1.75 (d, 3H, J¼7.3 Hz), 1.94 (d, 1H, J¼4.4 Hz), 2.81 (d, 1H, J¼5.8 Hz), 3.62 (q, 1H, J¼6.8 Hz), 3.86 (m, 1H), 6.61e6.65 (m, 2H), 6.88 (t, 2H, J¼8.6 Hz), 7.23e7.28 (m, 2H), 7.42e7.50 (m, 4H), 7.64e7.66 (m, 2H), 7.74e7.77 (m, 1H); 13C NMR (100 MHz, CDCl3): d 16.1, 21.0, 49.7, 55.2, 59.2, 72.1, 113.1, 115.7, 128.0, 128.1, 128.5, 129.2, 134.1, 137.2, 137.5, 137.6, 138.9, 145.0, 161.4,

4.2.34. 3-(3-Chloro-4-fluorophenyl)-(S)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 37a. Rf (30% EtOAc/Hexane) 0.32; white solid; mp 179e180  C; yield 84% (0.62 g); 1H NMR (400 MHz, CDCl3): d 0.61 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.08 (s, 1H), 2.79 (d, 1H, J¼6.3 Hz), 3.62 (q, 1H, J¼6.6 Hz), 3.90 (m, 1H), 6.54 (d, 2H, J¼8.4 Hz), 7.13e7.34 (m, 6H), 7.47e7.52 (m, 3H), 7.62e7.66 (m, 2H); 13C NMR (100 MHz, CDCl3): d 16.1, 21.0, 49.4, 55.3, 59.3, 71.8, 116.6, 121.3, 127.6, 128.6, 128.9, 129.2, 129.3, 134.3, 136.5, 136.6, 139.1, 140.2, 156.5, 159.0, 165.3, 180.4; HRMS (ESI): m/z [MþNa]þ

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V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754

calcd for C26H23Cl2FN2NaO2S: 539.0739, found: 539.0739; [a]25 D 206.89 (c 1.0, CHCl3). 4.2.35. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(S)-5-((R)-(4chlorophenyl)(hydroxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)2-thioxotetrahydropyrimidin-4(1H)-one, 38a. Rf (30% EtOAc/Hexane) 0.35; white solid; mp 146e148  C; yield 82% (0.69 g); 1H NMR (400 MHz, CDCl3): d 0.63 (d, 3H, J¼6.6 Hz), 1.61 (d, 3H, J¼7.1 Hz), 2.47 (d, 1H, J¼4.0 Hz), 3.00 (d, 1H, J¼7.4 Hz), 3.57 (q, 1H, J¼6.5 Hz), 4.90e4.93 (m, 1H), 7.11 (q, 1H, J¼7.0 Hz), 7.30e7.48 (m, 11H), 7.59 (d, 1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3): d 15.6, 19.7, 49.5, 54.2, 59.1, 72.6, 128.1, 128.4, 128.9, 129.0, 129.2, 129.4, 129.6, 132.0, 132.2, 135.3, 135.5, 137.7, 138.7, 139.0, 166.0, 179.1; HRMS (ESI): m/z [MþNa]þ calcd for C27H23Cl2F3N2NaO2S: 589.0707, found: 589.0707; [a]25 D 195.20 (c 1.0, CHCl3). 4.2.36. 3-(4-Chlorophenyl)-(S)-5-((R)-(4-fluorophenyl)(hydroxy) methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 39a. Rf (30% EtOAc/Hexane) 0.32; white solid; mp 175e176  C; yield 86% (0.62 g); 1H NMR (400 MHz, CDCl3): d 0.60 (d, 3H, J¼6.7 Hz), 1.55 (d, 3H, J¼7.1 Hz), 2.52 (s, 1H), 2.99 (d, 1H, J¼8.1 Hz), 3.50 (q, 1H, J¼6.8 Hz), 4.88 (d, 1H, J¼8.0 Hz), 7.05e7.17 (m, 4H), 7.32e7.43 (m, 10H); 13C NMR (100 MHz, CDCl3): d 15.7, 19.6, 49.2, 54.2, 59.0, 72.3, 116.1, 128.4, 128.8, 129.0, 129.1, 129.3, 134.2, 136.3, 138.0, 138.6, 161.8, 164.3, 166.2, 179.5; HRMS (ESI): m/z [MþNa]þ calcd for C26H24ClFN2NaO2S: 505.1129, found: 505.1129; [a]25 D 151.12 (c 1.0, CHCl3). 4.2.37. 3-(3-Chloro-4-cyanophenyl)-(S)-5-((R)-(4-fluorophenyl)(hydroxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 40a. Rf (30% EtOAc/Hexane) 0.19; white solid; mp 134e135  C; yield 80% (0.61 g); 1H NMR (400 MHz, CDCl3): d 0.61 (d, 3H, J¼6.7 Hz), 1.60 (d, 3H, J¼7.3 Hz), 2.34 (s, 1H), 2.99 (d, 1H, J¼7.3 Hz), 3.58 (q, 1H, J¼6.7 Hz), 4.91 (d, 1H, J¼7.3 Hz), 7.07e7.18 (m, 4H), 7.35e7.45 (m, 8H), 7.74 (d, 1H, J¼8.3 Hz); 13C NMR (100 MHz, CDCl3): d 15.5, 19.7, 49.7, 54.3, 58.9, 72.7, 113.1, 115.7, 116.3, 116.5, 128.4, 128.8, 128.8, 128.9, 129.0, 134.1, 134.4, 137.2, 144.8, 161.8, 165.7, 178.6; HRMS (ESI): m/z [MþNa]þ calcd for C27H23ClFN3NaO2S: 530.1081, found: 530.1081; [a]25 D 253.44 (c 1.0, CHCl3). 4.2.38. 3-(3-Chloro-4-fluorophenyl)-(S)-5-((R)-(4-fluorophenyl)(hydroxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 41a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 171e172  C; yield 80% (0.60 g); 1H NMR (400 MHz, CDCl3): d 0.62 (d, 3H, J¼6.7 Hz), 1.58 (d, 3H, J¼7.1 Hz), 2.39 (s, 1H), 3.01 (d, 1H, J¼7.7 Hz), 3.46e3.56 (m, 1H), 4.91 (d, 1H, J¼5.3 Hz), 7.11e7.25 (m, 5H), 7.30e7.45 (m, 8H); 13C NMR (100 MHz, CDCl3): d 15.6, 19.7, 49.3, 54.3, 59.1, 72.4, 116.3, 116.4, 116.7, 116.9, 128.4, 128.9, 129.0, 129.1, 136.3, 136.4, 137.8, 166.1, 179.4; HRMS (ESI): m/z [MþNa]þ calcd for C26H23ClF2N2NaO2S: 523.1035, found: 523.1035; [a]25 D 236.56 (c 1.0, CHCl3). 4.2.39. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(S)-5-((R)-(4-fluoro phenyl)(hydroxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 42a. Rf (30% EtOAc/Hexane) 0.32; white solid; mp 174e175  C; yield 85% (0.66 g); 1H NMR (400 MHz, CDCl3): d 0.62 (d, 3H, J¼6.6 Hz), 1.59 (d, 3H, J¼7.1 Hz), 2.35 (s, 1H), 2.99 (d, 1H, J¼7.6 Hz), 3.55 (q, 1H, J¼6.6 Hz), 4.91 (d, 1H, J¼7.6 Hz), 7.07e7.19 (m, 4H), 7.34e7.439 (m, 8H), 7.58 (d, 1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3): d 15.6, 19.7, 49.5, 54.3, 59.1, 75.26, 116.3, 116.5,

128.4, 128.9, 129.0, 129.1, 132.0, 136.3, 136.4, 137.7, 138.7, 164.3, 166.1, 179.1; HRMS (ESI): m/z [MþNa]þ calcd for C27H23ClF4N2NaO2S: 573.1003, found: 573.1003; [a]25 D 235.97 (c 1.0, CHCl3). Acknowledgements The research funding from the Department of Science and Technology, Government of India, and the National Single Crystal Xray Diffractometer facility at the Indian Institute of Technology Bombay are gratefully acknowledged. Supplementary data Crystallographic data for the compounds 5b0 and 23b have been deposited with the Cambridge Crystallographic Data Centre, CCDC No. 881433 and 881434, respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail: [email protected]). Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2012.12.020. References and notes 1. For a comprehensive discussion on aldol reactions see: (a) Heathcock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Elmsford, New York, 1991; Vol. 2, pp 133e238; (b) Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Elmsford, New York, 1991; Vol. 2, pp 239e275. 2. Selected references (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127; (b) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493; (c) Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem. Soc. 1990, 112, 2767; (d) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506. 3. (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995, 117, 9073; (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113, 1047; (c) Baldwin, S. W.; Chen, P.; Nikolic, N.; Weinseimer, D. C. Org. Lett. 2000, 2, 1193. 4. (a) Elokdah, H.; Sulkowski, T. S.; Abou-Gharbia, M.; Butera, J. A.; Chai, S.-Y.; McFarlane, G. R.; McKean, M.-L.; Babiak, J. L.; Adelman, S. J.; Quinet, E. M. J. Med. Chem. 2004, 47, 681; (b) Mijasaka, T. H.; Tanaka, M.; Baba, H.; Hayakawa, R. T.; Walker; Balzarini, J. E. J. Med. Chem. 1989, 32, 2507; (c) Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249, 1533; (d) Rahlan, R.; Kaur, J. Expert Opin. Ther. Pat. 2007, 17, 1061; (e) Baraldi, P. G.; Romagnoli, R.; Guadix, A. E.; de las Infantas, M. J. P.; Gallo, M. A.; Espinosa, A.; Martinez, A.; Bingham, J. P.; Hartley, J. A. J. Med. Chem. 2002, 45, 3630; (f) Yutaka, S.; Fujita, T.; Hiroi, S.; Hirayama, M.; Kaku, K. Curr. Med. Res. Opin. 2012, 27, 1781. 5. (a) Kumar, V.; Pal, A.; Khatik, G. L.; Nair, V. A. Tetrahedron: Asymmetry 2012, 23, 434; (b) Kumar, V.; Raghavaiah, P.; Mobin, S. M.; Nair, V. A. Org. Biomol. Chem. 2010, 8, 4960; (c) Kumar, V.; Khatik, G. L.; Nair, V. A. Synlett 2011, 2997; (d) Kumar, V.; Nair, V. A. Tetrahedron Lett. 2010, 51, 966; (e) Khatik, G. L.; Pal, A.; Mobin, S. M.; Nair, V. A. Tetrahedron Lett. 2010, 51, 3654; (f) Khatik, G. L.; Khurana, R.; Kumar, V.; Nair, V. A. Synthesis 2011, 3123; (g) Kumar, V.; Khatik, G. L.; Pal, A.; Praneeth, M. R.; Bhattarai, S.; Nair, V. A. Synlett 2012, 2357; (h) Khatik, G. L.; Kumar, V.; Nair, V. A. Org. Lett. 2012, 14, 2442; (i) Chauhan, M.; Sharma, R.; Nair, V. A. Org. Lett. 2012, 14, 5672. 6. Energy calculations were performed using the Gaussian 03 program package: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision E.01; Gaussian: Wallingford CT, 2004.