Tetrahedron: Asymmetry 24 (2013) 883–893

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Tetrahedron: Asymmetry

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Highly stereoselective transformation of (1S,3S)-cis-1,3-disubstitutedtetrahydro-b-carbolines into (1S,3R)-trans-1,3-disubstitutedtetrahydro-b-carbolines: an improved asymmetric synthesis oftadalafil from L-tryptophan

0957-4166/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetasy.2013.06.006

⇑ Corresponding author. Tel.: +86 2164252052.E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).

Jing Dong, Tian-Zhuo Meng, Xiao-Xin Shi ⇑, Wen-Hui Zou, Xia LuDepartment of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, PR China

a r t i c l e i n f o a b s t r a c t

Article history:Received 29 April 2013Accepted 10 June 2013Available online 24 July 2013

An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubsti-tuted 1,2,3,4-tetrahydro-b-carbolines (THBCs) into (1S,3R)-trans-1,3-disubstituted THBCs is described.The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstitutedTHBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethyla-tion/benzylation; (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 were then converted into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerizationat C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (1S,3R)-trans-1,3-disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, asan application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tad-alafil (Cialis�) starting from natural and less expensive L-tryptophan was developed.

� 2013 Elsevier Ltd. All rights reserved.

1. Introduction

The 1,2,3,4-tetrahydro-b-carboline (THBC) nucleus exists in thestructures of a wide range of indole alkaloids and physiologicallyactive compounds.1 Recently, enantiomerically pure (1R,3R)-cis-1,3-disubstituted THBCs have been employed as key intermediatesfor the syntheses of tadalafil-like tetracyclic compounds,2 whichare an important type of cGMP specific phosphodiesterase-VPDE5 inhibitors.2d,e Moreover, enantiomerically pure (1R,3S)-trans-and (1R,3R)-cis-1,3-disubstituted THBCs have been employed askey intermediates for the syntheses of HR22C16 and its analogues,3

which are an important type of mitotic kinesin Eg5 inhibitors.4

Both cis- and trans-chiral 1,3-disubstituted THBCs can usually beobtained from stereoselective Pictet–Spengler reactions5 of trypto-phan esters with aldehydes; the cis-selectivity of 1,3-disubstitutedTHBCs has been particularly studied by several researchers.6 Wehave also reported on the synthesis of cis- and trans-enantiomeri-cally pure 1,3-disubstituted THBCs via highly stereoselective CIATprocesses.7 Herein we report an efficient and general method forthe highly stereoselective transformation of (1S,3S)-cis-1,3-disub-stituted THBCs into (1S,3R)-trans-1,3-disubstituted THBCs.

Tadalafil (Cialis�) can normally be synthesized from unnaturalD-tryptophan,2,8 but the synthesis of tadalafil from natural and less

expensive L-tryptophan, which could be more attractive, has re-ceived less attention. In 2009, we reported the first synthesis oftadalafil starting from L-tryptophan,9 but it suffered from loweroverall yield and the moderate stereoselectivity of the base-cata-lyzed 3-epimerization of an intermediate. Herein we report an im-proved and highly stereoselective synthesis of tadalafil fromnatural and less expensive L-tryptophan, in which the aforemen-tioned method for the highly stereoselective transformation of(1S,3S)-cis-1,3-disubstituted THBCs into (1S,3R)-trans-1,3-disubsti-tuted THBCs was successfully applied.

2. Results and discussion

As shown in Scheme 1, the enantiomerically pure (1S,3S)-cis-1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-alkylation with 1-naphthylmethylbromide or benzyl bromide (R3 = 1-NpCH2 or Bn) in the presenceof N,N-diisopropylethylamine (DIPEA) by means of Cook’smethod.10 The (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 were thentreated with base to undergo a base-catalyzed 3-epimerization(epimerization at the C-3 position) to furnish (1S,3R)-trans-1,2,3-trisubstituted THBCs 3. Subsequently, reductive removal of the R3

(Bn or 1-NpCH2) group from (1S,3R)-trans-1,2,3-trisubstitutedTHBCs 3 afforded the desired (1S,3R)-trans-1,3-disubstitutedTHBCs 4.

NH

CO2R1

NH

R2

(1S,3S)-cis-1,3-di-substituted THBCs 1

NH

CO2R1

N

R2

R31

3

NH

CO2R1

N

R2

R31

3

1

3

NH

CO2R1

NH

R2

1

3

a b

c

(1S,3S)-cis-1,2,3-tri-substituted THBCs 2

(1S,3R)-trans-1,3-di-substituted THBCs 4

(1S,3R)-trans-1,2,3-tri-substituted THBCs 3

Scheme 1. Transformation of (1S,3S)-cis-1,3-disubstituted THBCs 1 into (1S,3R)-trans-1,3-disubstituted THBCs 4 via base-catalyzed 3-epimerization of (1S,3S)-cis-1,2,3-trisubstituted THBCs 2. Reagents and conditions: (a) 1.1 equiv of benzyl bromide or 1-naphthylmethyl bromide, 1.5 equiv of DIPEA, reflux for 5 h in CH3CN; (b) 0.5–2.0 equivof DBU, reflux for 15–25 h in CH3CN under N2; (c) Pd/C (10%, w/w), 1.0–1.1 atm of H2, 60 �C for 8 h in CH3CN.

884 J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893

We first attempted the base-catalyzed 3-epimerization of(1S,3S)-cis-1,2,3-trisubstituted THBC 2a [R1 = Me, R2 = 3,4-(OCH2-

O)-Ph, R3 = 1-NpCH2] to (1S,3R)-trans-1,2,3-trisubstituted THBC3a [R1 = Me, R2 = 3,4-(OCH2O)-Ph, R3 = 1-NpCH2] under variousreaction conditions (Table 1). As can be seen from Table 1, five sol-vents such as methanol, dimethylsulfoxide (DMSO), 1,4-dioxane,toluene, and acetonitrile (CH3CN) were tested, and several bases,such as sodium methoxide, sodium carbonate, potassium carbon-ate, triethylamine, 1,8-diazabicyclo [5,4,0]undec-7-ene (DBU),and 4-N,N-dimethylaminopyridine (DMAP) were used as catalysts.It was found that the 3-epimerization of compound 2a in methanolor DMSO with DBU as the catalyst worked very well to afford com-pound 3a in high yields and with excellent stereoselectivities (Ta-ble 1, entries 2 and 7), but the reaction in CH3CN with 0.5 or1.0 equiv of DBU gave the best yield and stereoselectivity (entries14 and 15).

We then attempted the DBU-catalyzed 3-epimerization ofvarious (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 to (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 (Table 2). As can be seen from Table 2,a total of fourteen (1S,3S)-cis-1,2,3-trisubstituted THBCs 2a–2nwere examined, all of these cis-THBCs 2a–2n smoothly underwent

Table 1Base-catalyzed 3-epimerization of compound 2a to compound 3a under various condition

Entry Solvent Base (equiv) T (�C

1 MeOH CH3ONa (0.5) 652 MeOH DBUc (1.0) 653 MeOH Na2CO3(1.0) 654 MeOH K2CO3 (1.0) 655 DMSO Na2CO3 (1.0) 1106 DMSO K2CO3 (1.0) 1107 DMSO DBUc (0.5) 1108 1,4-Dioxane DBUc (1.0) 1019 Toluene DBUc (1.0) 11010 CH3CN Na2CO3 (1.0) 8111 CH3CN K2CO3(1.0) 8112 CH3CN DMAPd (1.0) 8113 CH3CN Et3N (1.0) 8114 CH3CN DBUc (1.0) 8115 CH3CN DBUc (0.5) 8116 CH3CN DBUc (0.25) 81

a Combined isolated yields of compounds 2a and 3a.b Refluxing under N2.c 1,8-Diazabicyclo[5,4,0]undec-7-ene.d 4-N,N-Dimethylaminopyridine.e Only the trans-isomer 3a was detected by HPLC.

DBU-catalyzed 3-epimerization in CH3CN at reflux to afford thecorresponding (1S,3R)-trans-1,2,3-trisubstituted THBCs 3a–3n inhigh yields. When the R2 substituents at the C-1 position were arylgroups (Table 2, entries 1–9), the stereoselectivities were excellent(P99:1). In some instances, almost only the trans-isomers could bedetected (entries 1, 3–5, 8, and 9). When the R2 substituents at theC-1 position were alkyl groups (entries 10–14), the 3-epimeriza-tion was hard to complete even after refluxing for a long periodof time. It should be noted that having 1-naphthylmethyl (R3 = 1-NpCH2) at the N-2 position gave better stereoselectivities thanbenzyl (entry 1 vs 2, and entry 10 vs 11) probably due to largerbulk of 1-NpCH2 versus a Bn. In addition, when the R2 substituentscontained a hydroxyl group in the aryl ring (entry 6), 2.0 equiv ofDBU should be used, because the phenol might consume 1 equivof DBU.

A plausible mechanism for the above base-catalyzed 3-epimer-ization is proposed in Figure 1.9 The cis-THBCs 2 were first reactedwith a base to form enolate intermediates, and then protonation ofthe enolates led to the formation of the trans-THBCs 3. The 3-epi-merization might be reversible, but when R2 is an aryl group,3-epimerization of cis-THBCs 2 to trans-THBCs 3 was almost

s with different bases as the catalyst

) t (h) Product (ratio) Yielda (%)

b 12 3a/2a (99:1) 8130 3a/2a (99:1) 9230 3a/2a (8:92) 8730 3a/2a (91:9) 8824 3a/2a (55:45) 9024 3a/2a (63:37) 9010 3a/2a (99:1) 93

b 24 3a/2a (62:38) 95b 30 3a/2a(77:23) 96b 24 3a/2a (5:95) 91

24 3a/2a (6:94) 9024 3a/2a (10:90) 9724 3a/2a (2:98) 9812 3a/2a (100:0)e 9618 3a/2a (100:0)e 9620 3a/2a (92:8) 96

Table 2DBU-catalyzed 3-epimerization of (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in CH3CNa

Entry 2 R1 R2 R3 DBU (equiv) Time (h) Product (ratio) Yieldb (%)

1 2a Me 3,4-(OCH2O)-Ph 1-NpCH2c 0.5 18 3a/2a (100:0)d 96

2 2b Me 3,4-(OCH2O)-Ph Bn 1.0 18 3b/2b (99:1) 943 2c Et 3,4-(OCH2O)-Ph 1-NpCH2 0.5 16 3c/2c (100:0)d 954 2d Me 4-F-Ph 1-NpCH2 0.5 18 3d/2d (100:0)d 945 2e Et 3,4,5-(MeO)3-Ph 1-NpCH2 0.5 16 3e/2e (100:0)d 986 2f Me 3-HO-Ph 1-NpCH2 2.0e 20 3f/2f (99:1) 917 2g Me Ph 1-NpCH2 1.0 15 3g/2g (99:1) 938 2h Me 3,4-(MeO)2-Ph 1-NpCH2 0.5 18 3h/2h (100:0)d 959 2i Me 3-MeO-4-EtO-Ph 1-NpCH2 1.0 15 3i/2i (100:0)d 9610 2j Me Me 1-NpCH2 1.0 25 3j/2j (95:5) 9511 2k Me Me Bn 1.0 26 3k/2k (86:14) 9412 2l Me Et 1-NpCH2 1.0 25 3l/2l (96:4) 9513 2m Me n-Pr 1-NpCH2 1.0 25 3m/2m (96:4) 9714 2n Me n-Hex 1-NpCH2 1.0 25 3n/2n (97:3) 92

a The reactions were performed at reflux in CH3CN under N2 with DBU as the catalyst.b Combined isolated yields of compounds 2 and 3.c 1-Naphthylmethyl.d Only trans-isomers were detected by HPLC.e Phenol might consume 1.0 equiv of DBU.

base

enolate intermediates

H+1 3

Twist-chair conformerof cis-THBCs 2

2

HN

N

R2

CO2R1

HR3

H

13

Twist-chair conformerof trans-THBCs 3

2

HN

N

R2

H

CO2R1

R3H

base

H+

12

HN

N

R2

R3H

OOR1

Figure 1. Possible mechanism for the base-catalyzed 3-epimerization of (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3.

J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893 885

complete (3/2 P99:1, Table 2, entries 1–9), implying that theremay be a large energy difference between cis-THBCs 2 and trans-THBCs 3, which is consistent with Cook’s reports.10,11 Since allthree substituents (CO2R1, R2, and R3) lie in equatorial positions,trans-THBCs 3 are thermodynamically more stable than cis-THBCs2, changes of enthalpies (4H) from cis-THBCs to trans-THBCs werereported to be approximately 150 KJ/mol.11

With (1S,3R)-trans-1,2,3-trisubstituted THBCs 3a–3n in hand,we next wanted to remove 1-naphthylmethyl or Bn group in orderto obtain the desired (1S,3R)-trans-1,3-disubstituted THBCs 4. Cooket al. have reported a method for the debenzylation of (1S,3R)-trans-1,2,3-trisubstituted THBCs via Pd/C-catalyzed hydrogenationunder a high pressure of H2 in a mixed solvent of methanol (or eth-anol) and acetic acid.12 However, when we applied Cook’s hydroge-nation method11 for the denaphthylmethylation (or debenzylation)of (1S,3R)-trans-1,2,3-trisubstituted THBCs 3a–3n, a significantamount (>25%) of the undesired over-hydrogenation products(R)-2-amino-3-(2-substituted-indol-3-yl) propanoates were alsoformed, especially when R2 was an aryl group.

In order to diminish the over-hydrogenation, we have at-tempted the hydrogenation of (1S,3R)-trans-1,2,3-trisubstitutedTHBCs 3a–3n under a normal pressure (1.0–1.1 atm) of H2 withPd/C (10%, w/w) as the catalyst in various solvents. Several solventssuch as methanol, isopropanol, tetrahydrofuran, ethyl acetate,dichloromethane, acetone, DMSO, and CH3CN were tested; CH3CNseemed to be the most appropriate solvent for hydrogenation.When the hydrogenation of (1S,3R)-trans-1,2,3-trisubstitutedTHBCs 3a–3n were performed in CH3CN at 60 �C under a normalpressure (1.0–1.1 atm) of H2 with Pd/C (10%, w/w) as the catalyst,the desired (1S,3R)-trans-1,3-disubstituted THBCs 4a–4l were ob-tained in excellent yields (95–99% yields, see Section 4), while only

low yields (<5%) of the undesired over-hydrogenation productscould be observed by HPLC.

It is worth noting that the stereochemistry of (1S,3R)-trans-1,3-disubstituted THBCs 4a–4l can be assigned by using 2D 1H NMRtechniques.7 In the 1H–1H NOESY spectra of (1S,3R)-trans-1,3-disubstituted THBCs 4a–4l, the proton at the C-3 position doesnot correlate with the proton at C-1 position, but correlates withthe neighboring protons on the substituent R2, meaning that theproton at the C-3 position and the substituent R2 are on the sameside of the piperidine ring. Moreover, in the structure of (1S,3R)-trans-1,2,3-trisubstituted THBCs 3a–3n, the proton at the C-3 posi-tion and the R2substituent at the C-1 position should also be on thesame side of the piperidine ring, since the Pd/C-catalyzed hydroge-nation does not change the stereochemistry of C-1 and C-3.

As an application of the aforementioned method for the highlystereoselective transformation of (1S,3S)-cis-1,3-disubstitutedTHBCs 2 into (1S,3R)-trans-1,3-disubstituted THBCs 4, we per-formed a novel, efficient, and highly stereoselective synthesis oftadalafil (Cialis�) starting from L-tryptophan methyl ester hydro-chloride through the synthetic route as depicted in Scheme 2.L-Tryptophan methyl ester hydrochloride was first converted into(1S,3S)-cis-disubstituted THBC 1a in 95% yield according to aknown procedure.9 Compound 1a then underwent a tandem N-naphthylmethylation and DBU-catalyzed 3-epimerization in aone-pot procedure to afford (1S,3S)-trans-trisubstituted THBC 3ain 96% yield. Next, compound 3a was converted into (1S,3R)-trans-disubstituted THBC 4a in 98% yield after Pd/C-catalyzeddenaphthylmethylation in CH3CN. Salt formation of compound 4awith HCl in CH3CN and the highly stereoselective simultaneous1-epimerization via a CIAT process8a furnished the hydrochloridesalt of (1R,3R)-cis-disubstituted THBC ent-1a-HCl in 91% yield.

NH

CO2Me

NH3Cl

1a

NH

CO2Me

NH

L-tryptophan methy esterhydrochloride

95%

OO

3a

NH

CO2Me

N

OO

Np

4a

NH

CO2Me

NH

OO

ent-1a-HCl

NH

CO2Me

NH2Cl

OO

Ref.9

2-steps89%

tadalafil

1

3

1

3

1

3

1

3

96%

a

98%

b

91%

c

Ref.9

Scheme 2. A novel asymmetric synthesis of tadalafil starting from L-tryptophan methyl ester hydrochloride. Reagents and conditions: (a) 1.1 equiv of 1-naphthylmethylbromide, 1.5 equiv of DIPEA, reflux for 5 h in CH3CN; then 1.3 equiv of K2CO3, 1.0 equiv of DBU, reflux for 18 h in CH3CN; (b) Pd/C (10%, w/w), 1.0–1.1 atm of H2, 60 �C for 8 h inCH3CN; (c) 1.2 equiv of HCl, azetropic distillation with CH3CN for 1 h; then reflux for 8 h in CH3CN.

886 J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893

Finally, ent-1a-HCl was converted into tadalafil in 89% yield viatwo steps as described previously.9

3. Conclusion

In conclusion, an efficient and general method for the highlystereoselective transformation of (1S,3S)-cis-1,3-disubstitutedTHBCs 2 into (1S,3R)-trans-1,3-disubstituted THBCs 4 has beendeveloped. The key point of this method, the base-catalyzed 3-epi-merization of 1,2,3-trisubstituted THBCs 3 was investigated in de-tail. Moreover, by applying this method, the synthesis of tadalafil(Cialis�) starting from less expensive L-tryptophan methyl esterhydrochloride was greatly improved. Compared with our previoussynthesis,9 the overall yield of tadalafil was increased from 42.3%9

to 72.4%.It is worth noting that this method for the highly stereoselective

transformation of (1S,3S)-cis-1,3-disubstituted THBCs into (1S,3R)-trans-1,3-disubstituted THBCs should also be applicable for thehighly stereoselective transformation of (1R,3R)-cis-1,3-disubsti-tuted THBCs into (1R,3S)-trans-1,3-disubstituted THBCs.

4. Experimental

4.1. General

1H NMR and 13C NMR spectra were acquired on Bruker AM-500,chemical shifts were given on the delta scale as parts per million(ppm) with tetramethylsilane (TMS) as the internal standard. IRspectra were recorded on Nicolet Magna IR-550. Mass spectra wererecorded on HP5989A. Optical rotations were measured on WZZ-1S automatic polarimeter at room temperature. Column chroma-tography was performed on silica gel (Qingdao Ocean ChemicalCorp.). All chemicals were analytically pure. Acetonitrile was driedby distillation over calcium hydride. L-Tryptophan methyl (orethyl) ester hydrochloride was prepared according to a known pro-cedure.13 The (1S,3S)-cis-1,3-disubstituted THBCs 1 were preparedfrom L-tryptophan methyl (or ethyl) ester hydrochloride and alde-hydes via CIAT process according to a previous report.7

4.2. General procedure for the preparation of (1S,3S)-cis-1,2,3-trisubstituted THBCs 2

To a solution of compounds 1 (4.000 mmol) in CH3CN (15 mL),were added DIPEA (0.776 g, 6.004 mmol) and 1-naphthylmethylbromide (0.975 g, 4.410 mmol). The resulting solution was heatedat reflux at 81 �C, and then stirred at this temperature for 5 h. Thereaction was monitored by TLC. After the reaction was complete,the solvent was removed by vacuum distillation. The residue waspartitioned between ethyl acetate (40 mL) and an aqueous solutionof potassium carbonate (10% w/w, 20 mL). The two phases wereseparated, and the aqueous solution was extracted twice withethyl acetate (2 � 20 mL). The extracts were combined and driedover anhydrous MgSO4, the organic solution was then concen-trated to give a crude product, which was purified by flash chroma-tography (eluent: EtOAc/hexane = 1:5) to afford compounds 2 in88–96% yields. Characterization data of compounds 2a–2n are asfollows:

4.2.1. (1S,3S)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthal-en-1-yl-methyl) -1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2a

95% Yield. White solid, mp 135–136 �C. ½a�20D ¼ �83:4 (c 1.00,

CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.67 (br s, 1H), 8.46 (d,J = 6.8 Hz, 1H), 7.89 (d, J = 6.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H),7.60 (d, J = 7.1 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.53–7.48 (m, 2H),7.42 (dd, J1 = 8.0 Hz, J2 = 7.1 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.09(dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 7.04 (dd, J1 = 7.7 Hz, J2 = 7.6 Hz,1H), 6.56 (d, J = 7.9 Hz, 1H), 6.50 (s, 1H), 6.47 (d, J = 7.9 Hz, 1H),5.85 (d, J = 12.2 Hz, 2H), 5.14 (s, 1H), 4.63 (d, J = 13.6 Hz, 1H),4.37 (d, J = 13.6 Hz, 1H), 3.93 (dd, J1 = 5.6 Hz, J2 = 4.2 Hz, 1H), 3.35(dd, J1 = 15.5 Hz, J2 = 4.2 Hz, 1H), 3.15 (s, 3H), 3.04 (dd,J1 = 15.5 Hz, J2 = 5.6 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d174.26, 148.07, 147.51, 137.87, 137.72, 135.67, 134.88, 133.85,133.70, 133.46, 129.20, 128.95, 128.69, 127.97, 126.56, 126.53,126.05, 126.06, 123.63, 122.23, 119.73, 118.97, 112.00, 110.57,107.83, 101.78, 61.58, 59.87, 57.97, 51.49, 22.54. HRMS (ESI) m/zcalcd for (C31H26N2O4+H)+ 491.1971; found 491.1974. IR (KBr film)3393, 2919, 2848, 1728, 1484, 1438, 1253, 1037, 796, 742 cm�1.

J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893 887

4.2.2. (1S,3S)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2b

92% Yield. White solid, mp 178–179 �C. ½a�20D ¼ �87:0 (c 1.60,

CHCl3). 1H NMR (400 MHz, acetone-d6) d 9.53 (br s, 1H), 7.51 (d,J = 7.3 Hz, 1H), 7.38 (d, J = 7.1 Hz, 2H), 7.34–7.18 (m, 4H), 7.10–6.98 (m, 2H), 6.82–6.72 (m, 3H), 5.94 (d, J = 1.9 Hz, 2H), 4.96 (s,1H), 4.05 (d, J = 14.6 Hz, 1H), 3.93 (d, J = 14.6 Hz, 1H), 3.82 (dd,J1 = 6.1 Hz, J2 = 5.2 Hz, 1H), 3.32 (s, 3H), 3.31 (dd, J1 = 15.2 Hz,J2 = 6.1 Hz, 1H), 3.03 (dd, J1 = 15.2 Hz, J2 = 5.2 Hz, 1H). 13C NMR(100 MHz, acetone-d6) d 174.07, 148.55, 147.97, 139.59, 137.85,135.77, 134.49, 130.01, 130.00, 128.90, 128.89, 127.83, 127.75,123.62, 122.10, 119.66, 118.81, 111.88, 110.25, 108.30, 107.15,101.96, 61.94, 61.13, 57.90, 51.65, 24.26. HRMS (ESI) m/z calcdfor (C27H24N2O4+H)+ 441.1814; found 441.1809. IR (KBr film)3324, 3054, 2896, 2850, 1728, 1488, 1439, 1255, 1174, 1071,1038, 938, 738 cm�1.

4.2.3. (1S,3S)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carb-oxylate 2c

91% Yield. White solid, mp 109–110 �C. ½a�20D ¼ �69:4 (c 1.00,

CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.67 (br s, 1H), 8.54–8.49 (m, 1H), 7.91–7.86 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.60–7.53 (m, 2H), 7.52–7.47 (m, 2H), 7.42 (dd, J1 = 8.0 Hz, J2 = 5.0 Hz,1H), 7.31 (d, J = 7.8 Hz, 1H), 7.14 (dd, J1 = 7.8 Hz, J2 = 7.9 Hz, 1H),7.06 (dd, J1 = 7.8 Hz, J2 = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.45(s, 1H), 6.43 (d, J = 8.0 Hz, 2H), 5.84 (d, J = 10.2 Hz, 2H), 5.11 (s,1H), 4.63 (d, J = 13.5 Hz, 1H), 4.36 (d, J = 13.5 Hz, 1H), 3.90 (dd,J1 = 5.9 Hz, J2 = 4.0 Hz, 1H), 3.69 (dq, J1 = 10.8 Hz, J2 = 7.1 Hz, 1H),3.37–3.32 (m, 2H), 3.01 (dd, J1 = 15.5 Hz, J2 = 5.9 Hz, 1H), 0.98 (t,J = 7.1 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 173.84, 148.02,147.50, 137.84, 135.76, 135.70, 134.91, 133.75, 133.49, 129.16,128.98, 128.72, 126.54, 126.49, 126.33, 126.02, 123.61, 122.21,119.70, 118.95, 111.96, 111.91, 110.64, 107.83, 107.73, 101.75,61.31, 60.95, 59.93, 58.37, 22.26, 14.15. HRMS (ESI) m/z calcd for(C32H28N2O4+H)+ 505.2127; found 505.2125. IR (KBr film) 3386,2921, 1731, 1485, 1442, 1305, 1239, 1191, 1103, 1037, 799,745 cm�1.

4.2.4. (1S,3S)-Methyl 1-(4-fluorophenyl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyl-ate 2d

95% Yield. White solid, mp 108–109 �C. ½a�20D ¼ �98:7 (c 1.00,

CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.74 (br s, 1H), 8.49 (d,J = 8.2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H),7.61–7.55 (m, 2H), 7.55–7.48 (m, 2H), 7.42 (dd, J1 = 8.0 Hz,J2 = 7.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.13–7.03 (m, 2H), 7.00–6.92 (m, 2H), 6.88–6.80 (m, 2H), 5.20 (s, 1H), 4.64 (d, J = 13.4 Hz,1H), 4.37 (d, J = 13.4 Hz, 1H), 3.96 (dd, J1 = 5.9 Hz, J2 = 3.4 Hz, 1H),3.35 (dd, J1 = 15.6 Hz, J2 = 3.4 Hz, 1H), 3.07 (s, 3H), 3.06 (dd,J1 = 15.6 Hz, J2 = 5.9 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d174.06, 137.85, 137.74, 137.71, 135.56, 134.94, 133.49, 133.16,132.10, 132.02, 129.21, 129.09, 128.81, 127.99, 126.59, 126.58,126.17, 126.04, 122.30, 119.75, 119.00, 114.93, 114.72, 111.97,107.98, 60.43, 59.38, 58.39, 51.37, 21.85. HRMS (ESI) m/z calcdfor (C30H25FN2O2+H)+ 465.1978; found 465.1981. IR (KBr film)3398, 3052, 2920, 2847, 1729, 1601, 1505, 1455, 1436, 1219,1156, 832, 796, 742 cm�1.

4.2.5. (1S,3S)-Ethyl 2-(naphthalen-1-ylmethyl)-1-(3,4,5-trimeth-oxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyl-ate 2e

96% Yield. White solid, mp 105–106 �C. ½a�20D ¼ �67:0 (c 1.05,

CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.65 (br s, 1H), 8.63 (d,J = 8.1 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H),7.60–7.47 (m, 4H), 7.43 (dd, J1 = 8.1 Hz, J2 = 7.4 Hz, 1H), 7.30 (d,

J = 7.4 Hz, 1H), 7.12–7.02 (m, 2H), 6.07 (s, 2H), 5.06 (s, 1H), 4.68(d, J = 13.3 Hz, 1H), 4.28 (d, J = 13.3 Hz, 1H), 4.04 (dd, J1 = 5.9 Hz,J2 = 3.9 Hz, 1H), 3.75 (dq, J1 = 10.7 Hz, J2 = 7.1 Hz, 1H), 3.55 (s,3H), 3.39 (s, 6H), 3.38 (dd, J1 = 15.6 Hz, J2 = 3.9 Hz, 1H), 3.28 (dq,J1 = 10.7 Hz, J2 = 7.1 Hz, 1H), 3.11 (dd, J1 = 15.6 Hz, J2 = 5.9 Hz, 1H),0.97 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 173.69,153.30, 153.29, 137.82, 137.65, 137.30, 136.04, 134.98, 133.65,133.16, 133.02, 129.10, 129.01, 127.94, 126.90, 126.52, 126.49,126.01, 122.14, 119.59, 118.94, 111.83, 107.71, 107.45, 107.44,60.89, 60.81, 60.75, 60.16, 59.35, 55.86, 55.85, 21.62, 14.24. HRMS(ESI) m/z calcd for (C34H34N2O5+H)+ 551.2546; found 551.2551. IR(KBr film) 3357, 2931, 2837, 1727, 1593, 1504, 1459, 1325, 1237,1125, 1037, 795, 742 cm�1.

4.2.6. (1S,3S)-Methyl 1-(3-hydroxyphenyl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyl-ate 2f

88% Yield. White solid, mp 121–122 �C. ½a�20D ¼ �77:3 (c 1.00,

CH3OH). 1H NMR (400 MHz, acetone-d6) d 9.69 (br s, 1H), 8.46–8.39 (m, 1H), 8.17 (s, 1H), 7.93–7.87 (m, 1H), 7.83 (d, J = 8.2 Hz,1H), 7.62 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.53–7.47 (m,2H), 7.43 (dd, J1 = 8.0 Hz, J2 = 7.2 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H),7.13–7.04 (m, 2H), 7.01 (dd, J1 = 8.0 Hz, J2 = 7.8 Hz, 1H), 6.63 (d,J = 7.8 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 6.48 (s, 1H), 5.18 (s, 1H),4.64 (d, J = 13.8 Hz, 1H), 4.45 (d, J = 13.8 Hz, 1H), 3.89 (dd,J1 = 6.0 Hz, J2 = 3.3 Hz, 1H), 3.35 (dd, J1 = 15.5 Hz, J2 = 3.2 Hz, 1H),3.04 (s, 3H), 2.99 (dd, J1 = 15.5 Hz, J2 = 6.0 Hz, 1H). 13C NMR(100 MHz, acetone-d6) d 174.26, 157.91, 142.79, 137.80, 135.65,134.93, 133.68, 133.50, 129.40, 129.21, 128.91, 128.64, 128.01,126.58, 126.52, 126.05, 125.97, 122.11, 121.86, 119.61, 118.87,117.13, 114.96, 111.94, 107.92, 61.52, 58.79, 57.78, 51.21, 22.19.HRMS (ESI) m/z calcd for (C30H26N2O3+H)+ 463.2022; found463.2022. IR (KBr film) 3366, 3053, 2940, 1704, 1599, 1454,1277, 1254, 1220, 1166, 792, 744 cm�1.

4.2.7. (1S,3S)-Methyl 1-phenyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2g

92% Yield. White solid, mp 89–90 �C, ½a�20D ¼ �43:9 (c 1.00,

CHCl3). 1H NMR (400 MHz, DMSO-d6) d 10.68 (br s, 1H), 8.45–8.38 (m, 1H), 7.96–7.90 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.58–7.50 (m, 4H), 7.45 (dd, J1 = 8.0, J2 = 7.8 Hz, 1H), 7.27 (d, J = 7.9 Hz,1H), 7.19–7.10 (m, 3H), 7.09 (dd, J1 = 7.8, J2 = 7.9 Hz, 1H), 7.02(dd, J1 = 7.8, J2 = 8.0 Hz, 1H), 6.89 (dd, J1 = 7.8, J2 = 1.7 Hz, 2H),5.16 (s, 1H), 4.58 (d, J = 13.5 Hz, 1H), 4.32 (d, J = 13.5 Hz, 1H),3.94 (dd, J1 = 6.0 Hz, J2 = 2.6 Hz, 1H), 3.34 (s, 3H), 3.21 (dd,J1 = 15.5 Hz, J2 = 2.6 Hz, 1H), 2.98 (dd, J1 = 15.5 Hz, J2 = 6.0 Hz, 1H).13C NMR (100 MHz, DMSO-d6) d 173.52, 140.80, 136.85, 134.94,134.00, 132.58, 129.54, 129.53, 128.74, 128.49, 128.48, 128.16,127.84, 127.83, 127.31, 127.01, 126.21, 126.20, 125.67, 125.50,121.40, 118.80, 118.36, 111.56, 106.66, 59.69, 57.72, 57.32, 51.11,20.76. HRMS (EI) m/z calcd for (C30H26N2O2)+ 446.1994; found446.1997. IR (KBr film) 3397, 2944, 2106, 1722, 1453, 1256,1174, 1100, 1009, 786, 741 cm�1.

4.2.8. (1S,3S)-Methyl 1-(3,4-dimethoxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carb-oxylate 2h

96% Yield. White solid, mp 207–208 �C, ½a�20D ¼ �77:2 (c 1.00,

CHCl3). 1H NMR (400 MHz, DMSO-d6) d 10.66 (br s, 1H), 8.52 (d,J = 8.1 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H),7.60–7.50 (m, 3H), 7.49–7.38 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H),7.08 (dd, J1 = 7.6 Hz, J2 = 7.8 Hz, 1H), 7.02 (dd, J1 = 7.6 Hz,J2 = 7.8 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 1.6 Hz, 1H),6.30 (dd, J = 8.4 Hz, J2 = 1.6 Hz, 1H), 5.02 (s, 1H), 4.57 (d,J = 13.5 Hz, 1H), 4.21 (d, J = 13.5 Hz, 1H), 4.03 (dd, J1 = 6.0 Hz,J2 = 2.6 Hz, 1H), 3.62 (s, 3H), 3.30 (s, 3H), 3.21 (dd, J = 15.6 Hz,

888 J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893

J2 = 2.6 Hz, 1H), 3.01 (dd, J = 15.6 Hz, J2 = 6.0 Hz, 1H), 2.91 (s, 3H).13C NMR (100 MHz, DMSO-d6) d 172.91, 147.94, 147.62, 136.11,134.66, 133.56, 132.91, 132.06, 131.83, 128.22, 128.05, 127.82,126.49, 125.71, 125.67, 125.38, 125.15, 120.88, 120.55, 118.27,117.87, 112.85, 110.96, 110.36, 105.89, 58.11, 57.90, 57.16, 55.42,54.69, 50.71, 19.82. HRMS (EI) m/z calcd for (C32H30N2O4)+

506.2206; found 506.2208. IR (KBr film) 3358, 2939, 2837, 1726,1512, 1450, 1265, 1230, 1139, 1028, 801, 743 cm�1.

4.2.9. (1S,3S)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-2-(naph-thalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]ind-ole-3-carboxylate 2i

91% Yield. White solid, mp 179–180 �C, ½a�20D ¼ �68:1 (c 3.00,

CHCl3). 1H NMR (400 MHz, DMSO-d6) d 10.67 (br s, 1H), 8.53(d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz,1H), 7.62–7.44 (m, 5H), 7.29 (d, J = 8.0 Hz, 1H), 7.08 (dd, J1 = 7.8HZ, J2 = 7.6 Hz, 1H), 7.02 (dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 6.66 (d,J = 8.2 Hz, 1H), 6.40 (s, 1H), 6.26 (d, J = 8.2 Hz, 1H), 5.03 (s, 1H),4.59 (d, J = 13.4 Hz, 1H), 4.22 (d, J = 13.4 Hz, 1H), 4.05 (dd,J1 = 4.2 Hz, J2 = 3.5 Hz, 1H), 3.87 (q, J = 6.8 Hz, 2H), 3.31 (s, 3H),3.20 (dd, J1 = 13.4 Hz, J2 = 3.5 Hz, 1H), 3.01 (dd, J1 = 13.4 Hz,J2 = 4.2 Hz, 1H), 2.92 (s, 3H), 1.24 (t, J = 6.8 Hz, 3H). 13C NMR(100 MHz, DMSO-d6) d 173.38, 148.68, 147.25, 136.75, 135.19,134.06, 133.43, 132.58, 132.47, 128.71, 128.54, 128.33, 127.04,126.19, 126.15, 125.90, 125.64, 121.33, 121.05, 118.72, 118.35,113.51, 112.10, 111.49, 106.41, 64.11, 58.62, 58.31, 57.67,55.17, 51.19, 20.30, 15.16. HRMS (EI): m/z calcd for(C33H32N2O4)+ 520.2362; found 520.2364. IR (KBr film) 3336,2972, 2941, 2883, 1734, 1512, 1452, 1271, 1284, 1138, 1033,796, 740 cm�1.

4.2.10. (1S,3S)-Methyl 1-methyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2j

94% Yield. White solid, mp 93–94 �C. ½a�20D ¼ �22:5 (c 1.10, CH3-

OH). 1H NMR (400 MHz, acetone-d6) d 9.86 (br s, 1H), 8.38 (dd,J1 = 6.5 Hz, J2 = 3.4 Hz, 1H), 7.90 (dd, J1 = 6.4 Hz, J2 = 3.4 Hz, 1H),7.84 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.52–7.44 (m, 4H),7.29 (d, J = 7.9 Hz, 1H), 7.06 (dd, J1 = 7.2 Hz, J2 = 7.0 Hz, 1H), 7.00(dd, J1 = 7.2 Hz, J2 = 7.1 Hz, 1H), 4.62 (s, 2H), 4.32 (q, J = 6.9 Hz,1H), 4.00 (dd, J1 = 6.2 Hz, J2 = 2.9 Hz, 1H), 3.60 (s, 3H), 3.25 (dd,J1 = 15.3 Hz, J2 = 2.9 Hz, 1H), 2.91 (dd, J1 = 15.3 Hz, J2 = 6.2 Hz, 1H),1.39 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 175.20,137.50, 137.07, 136.12, 135.00, 133.37, 129.29, 128.82, 128.24,128.21, 126.61, 126.53, 126.15, 125.59, 121.75, 119.53, 118.70,111.74, 106.25, 58.41, 55.83, 52.59, 51.68, 22.92, 18.15. HRMS(ESI) m/z calcd for (C25H24N2O2+H)+ 385.1916; found 385.1916.IR (KBr film) 3402, 3051, 2924, 2849, 1725, 1453, 1304, 1196,1163, 1016, 781, 743 cm�1.

4.2.11. (1S,3S)-Methyl 2-benzyl-1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylate 2k

90% Yield. White solid, mp 51–52 �C. ½a�20D ¼ �6:1 (c 2.6, CH3-

OH). 1H NMR (400 MHz, acetone-d6) d 9.85 (br s, 1H), 7.52–7.45(m, 3H), 7.35–7.28 (m, 3H), 7.24 (dd, J1 = 7.2 Hz, J2 = 7.3 Hz, 1H),7.05 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 7.00 (dd, J1 = 7.2 Hz,J2 = 7.6 Hz, 1H), 4.22 (q, J = 6.8 Hz, 1H), 4.11 (d, J = 1.7 Hz, 2H),3.91 (dd, J1 = 5.8, J2 = 4.4 Hz, 1H), 3.61 (s, 3H), 3.22 (dd,J1 = 15.3 Hz, J2 = 4.4 Hz, 1H), 2.95 (dd, J1 = 15.3 Hz, J2 = 5.8 Hz,1H), 1.35 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d174.95, 141.29, 137.53, 137.01, 129.36, 129.35, 129.07, 129.06,128.22, 127.73, 121.77, 119.59, 118.68, 111.79, 106.29, 59.83,56.77, 53.22, 51.77, 23.13, 18.49. HRMS (ESI) m/z calcd for(C21H22N2O2+H)+ 335.1760; found 335.1765. IR (KBr film) 3399,2922, 2849, 1730, 1453, 1356, 1320, 1269, 1219, 1172, 1142,739, 698 cm�1.

4.2.12. (1S,3S)-Methyl 1-ethyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2l

91% Yield. White solid, mp 82–84 �C. ½a�20D ¼ �42:2 (c 1.02, CH3-

OH). 1H NMR (400 MHz, acetone-d6): d = 9.81 (br s, 1H), 8.57 (d,J = 8.1 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H),7.62–7.48 (m, 4H), 7.45 (dd, J1 = 7.6 Hz, J2 = 7.9 Hz, 1H), 7.32 (d,J = 7.8 Hz, 1H), 7.07 (dd, J1 = 7.9 Hz, J2 = 7.6 Hz, 1H), 7.02 (dd,J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 4.51 (d, J = 13.5 Hz, 1H), 4.29 (d,J = 13.5 Hz, 1H), 4.05 (dd, J1 = 6.3 Hz, J2 = 2.9 Hz, 1H), 3.92 (dd,J1 = 8.2 Hz, J2 = 5.0 Hz, 1H), 3.56 (s, 3H), 3.25 (dd, J1 = 15.7 Hz,J2 = 2.9 Hz, 1H), 3.08 (dd, J1 = 15.7 Hz, J2 = 6.3 Hz, 1H), 1.62–1.42(m, 2H), 0.76 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d174.72, 137.53, 136.14, 135.56, 134.98, 133.65, 129.15, 128.99,128.50, 128.27, 126.56, 126.48, 126.42, 126.00, 121.80, 119.49,118.73, 111.75, 105.99, 59.42, 59.37, 58.98, 51.70, 28.32, 19.68,11.64. HRMS (ESI) m/z calcd for (C26H26N2O2+H)+ 399.2073; found399.2074. IR (KBr film) 3400, 2926, 1730, 1462, 1332, 1299, 1203,1159, 1052, 797, 742 cm�1.

4.2.13. (1S,3S)-Methyl 2-(naphthalen-1-ylmethyl)-1-propyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2m

93% Yield. Mp 73–74 �C, ½a�20D ¼ �33:2 (c 1.00, CHCl3). 1H NMR

(400 MHz, acetone-d6) d 9.82 (br s, 1H), 8.58 (d, J = 8.0 Hz, 1H),7.93 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.62–7.52 (m, 4H),7.48 (dd, J1 = 8.0 Hz, J2 = 7.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.09(dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 7.03 (dd, J1 = 7.9 Hz, J2 = 7.6 Hz,1H), 4.53 (d, J = 13.4 Hz, 1H), 4.30 (d, J = 13.4 Hz, 1H), 4.09 (dd,J1 = 6.3 Hz, J2 = 2.2 Hz, 1H), 4.04 (dd, J1 = 8.1 Hz, J2 = 6.7 Hz, 1H),3.60 (s, 3H), 3.28 (dd, J1 = 15.8 Hz, J2 = 2.2 Hz, 1H), 3.11 (dd,J1 = 15.8 Hz, J2 = 6.3 Hz, 1H), 1.54–1.38 (m, 3H), 1.25–1.16 (m,1H), 0.56 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d173.80, 136.62, 135.25, 134.71, 134.10, 132.75, 128.21, 128.11,127.60, 127.41, 125.65, 125.55, 125.50, 125.09, 120.86, 118.57,117.79, 110.82, 105.01, 58.52, 58.11, 56.25, 50.92, 36.77, 19.31,18.58, 13.14. HRMS (EI) m/z calcd for (C27H28N2O2)+ 412.2151;found 412.2153. IR (KBr film) 3403, 2953, 2926, 2853, 1734,1460, 1270, 1217, 1170, 793, 741 cm�1.

4.2.14. (1S,3S)-Methyl 1-hexyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 2n

92% Yield. White solid, mp 55–56 �C. ½a�20D ¼ �60:4 (c 1.10, CH3-

OH). 1H NMR (400 MHz, acetone-d6) d 9.81 (br s, 1H), 8.61 (d,J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H),7.59–7.48 (m, 4H), 7.44 (dd, J1 = 8.1 Hz, J2 = 7.6 Hz, 1H), 7.31 (d,J = 7.6 Hz, 1H), 7.07 (dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 7.02 (dd,J1 = 8.0 Hz, J2 = 7.6 Hz, 1H), 4.52 (d, J = 13.3 Hz, 1H), 4.24 (d,J = 13.3 Hz, 1H), 4.12 (dd, J1 = 6.3 Hz, J2 = 2.1 Hz, 1H), 3.98 (dd,J1 = 8.9 Hz, J2 = 5.5 Hz, 1H), 3.59 (s, 3H), 3.27 (dd, J1 = 15.7 Hz,J2 = 2.1 Hz, 1H), 3.10 (dd, J1 = 15.7 Hz, J2 = 6.3 Hz, 1H), 1.50–1.40(m, 2H), 1.36–1.25 (m, 1H), 1.12–0.99 (m, 3H), 0.96–0.78 (m,4H), 0.76 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d174.66, 137.53, 136.21, 135.59, 135.06, 133.77, 129.11, 129.10,128.62, 128.33, 126.69, 126.54, 126.43, 125.92, 121.73, 119.45,118.68, 111.70, 105.87, 59.76, 59.33, 56.80, 51.84, 35.57, 32.62,29.77, 27.00, 23.20, 19.35, 14.44. HRMS (ESI) m/z calcd for (C30H34-

N2O2+H)+ 455.2699; found 455.2704. IR (KBr film) 3394, 2924,2851, 1731, 1461, 1330, 1204, 1159, 796, 741 cm�1.

4.3. General procedure for the DBU-catalyzed 3-epimerizationof (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 to (1S,3R)-trans-1,2,3-trisubstituted THBCs 3

To a solution of compounds 2 (3.000 mmol) in anhydrous CH3-

CN (10 mL), added was DBU (0.5–2.0 equiv, see Table 2). The solu-tion was heated to reflux (81 �C), and stirred under N2 at thistemperature for 15–25 h. The reaction was monitored by HPLC.

J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893 889

After the reaction was complete, the solvent was removed by vac-uum distillation to give crude product, which was purified by flashchromatography to afford compounds 3 in 91–98% yields (see Ta-ble 2). Characterization data of compounds 3a–3n are as follows:

4.3.1. (1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphth-alen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3a

Mp 120–122 �C. ½a�20D ¼ þ67:3 (c 1.20, CH3OH). 1H NMR

(400 MHz, acetone-d6) d 9.62 (br s, 1H), 8.19 (d, J = 8.0 Hz, 1H),7.90 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.54–7.42 (m, 5H),7.26 (d, J = 7.9 Hz, 1H), 7.05 (dd, J1 = 7.9 Hz, J2 = 7.8 Hz, 1H), 7.01(dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.89 (s,1H), 6.80 (d, J = 7.9 Hz, 1H), 5.96 (d, J = 6.1 Hz, 2H), 5.42 (s, 1H),4.46 (d, J = 13.3 Hz, 1H), 4.30 (d, J = 13.3 Hz, 1H), 3.86 (dd,J1 = 5.6 Hz, J2 = 4.5 Hz, 1H), 3.64 (s, 3H), 3.22 (dd, J1 = 15.4 Hz,J2 = 4.5 Hz, 1H), 3.11 (dd, J1 = 15.4 Hz, J2 = 5.6 Hz, 1H). 13C NMR(100 MHz, acetone-d6) d 173.96, 148.86, 148.27, 137.89, 137.30,135.77, 135.46, 134.94, 133.37, 129.29, 128.95, 128.47, 127.83,126.66, 126.63, 126.27, 125.64, 123.61, 122.08, 119.69, 118.77,111.92, 109.94, 108.48, 106.64, 102.07, 61.86, 57.11, 53.17, 51.73,24.61. HRMS (ESI) m/z calcd for (C31H26N2O4+H)+ 491.1971; found491.1975. IR (KBr film) 3403, 2920, 2850, 1730, 1483, 1440, 1239,1174, 1038, 797, 742 cm�1.

4.3.2. (1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3b

White solid, mp 191–192 �C. ½a�20D ¼ þ91:4 (c 1.00, CHCl3). 1H

NMR (400 MHz, acetone-d6) d 9.58 (br s, 1H), 7.47 (d, J = 7.6 Hz,1H), 7.38–7.28 (m, 4H), 7.27–7.21 (m, 2H), 7.08–6.94 (m, 4H),6.80 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 7.6 Hz, 2H), 5.39 (s, 1H), 3.96–3.84 (m, 3H), 3.60 (s, 3H), 3.25–3.16 (m, 2H). 13C NMR (100 MHz,acetone-d6) d 173.80, 148.92, 148.23, 140.54, 137.97, 137.57,136.08, 129.39, 129.38, 129.26, 129.25, 127.97, 127.89, 123.32,121.99, 119.63, 118.71, 111.87, 109.47, 108.52, 106.27, 102.03,61.55, 56.97, 54.88, 51.61, 24.91. HRMS (ESI) m/z calcd for (C27H24-

N2O4+H)+ 441.1814; found 441.1811. IR (KBr film) 3418, 2915,2850, 1730, 1499, 1441, 1301, 1244, 1174, 1138, 1038, 925,747 cm�1.

4.3.3. (1S,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxy-late 3c

White solid, mp 140–141 �C. ½a�20D ¼ þ71:7 (c 1.00, CH3OH). 1H

NMR (400 MHz, acetone-d6) d 9.68 (br s, 1H), 8.21 (d, J = 8.0 Hz,1H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.52–7.40 (m,5H), 7.26 (d, J = 7.9 Hz, 1H), 7.06–6.93 (m, 3H), 6.89 (s, 1H), 6.81(d, J = 7.9 Hz, 1H), 5.96 (d, J = 5.6 Hz, 2H), 5.41 (s, 1H), 4.46 (d,J = 13.2 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H), 4.20–4.11 (m, 1H), 4.10–4.00 (m, 1H), 3.82 (dd, J1 = 5.7 Hz, J2 = 4.0 Hz, 1H), 3.22 (dd,J1 = 15.4 Hz, J2 = 4.0 Hz, 1H), 3.08 (dd, J1 = 15.4 Hz, J2 = 5.7 Hz, 1H),1.18 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 173.29,148.23, 147.58, 136.55, 135.98, 134.95, 134.59, 133.85, 132.46,128.43, 128.02, 127.34, 127.09, 125.77, 125.75, 125.41, 124.71,122.63, 121.68, 119.36, 118.28, 110.89, 109.15, 107.87, 106.74,101.14, 61.16, 60.31, 56.26, 52.61, 24.33, 14.30. HRMS (ESI) m/zcalcd for (C32H28N2O4+H)+ 505.2127; found 505.2124. IR (KBr film)3406, 2920, 2851, 1725, 1483, 1441, 1239, 1182, 1037, 796,741 cm�1.

4.3.4. (1S,3R)-Methyl 1-(4-fluorophenyl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxy-late 3d

White solid, mp 102–103 �C. ½a�20D ¼ þ67:5 (c 1.07, CH3OH). 1H

NMR (400 MHz, acetone-d6) d 9.69 (br s, 1H), 8.12 (d, J = 8.0 Hz,1H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.52–7.40 (m,

7H), 7.25 (d, J = 7.9 Hz, 1H), 7.15–6.95 (m, 4H), 5.48 (s, 1H), 4.45(d, J = 13.2 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 3.83 (dd, J1 = 5.7 Hz,J2 = 4.4 Hz, 1H), 3.64 (s, 3H), 3.23 (dd, J1 = 15.5 Hz, J2 = 4.4 Hz,1H), 3.09 (dd, J1 = 15.5 Hz, J2 = 5.7 Hz, 1H). 13C NMR (100 MHz, ace-tone-d6) d 173.86, 164.45, 162.02, 139.47, 139.44, 138.07, 135.28,134.93, 133.35, 132.09, 132.01, 129.28, 129.03, 128.61, 127.82,126.67, 126.62, 126.24, 125.58, 122.17, 119.76, 118.81, 115.93,115.72, 111.97, 106.88, 61.41, 57.07, 53.22, 51.75, 24.55. HRMS(ESI) m/z calcd for (C30H25FN2O2+H)+ 465.1978; found 465.1982.IR (KBr film) 3400, 3049, 2919, 2850, 1730, 1601, 1505, 1458,1221, 1193, 1014, 836, 795, 743 cm�1.

4.3.5. (1S,3R)-Ethyl 2-(naphthalen-1-ylmethyl)-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3e

White solid, mp 115–116 �C. ½a�20D ¼ þ44:3 (c 1.00, CH3OH). 1H

NMR (400 MHz, acetone-d6) d 9.68 (br s, 1H), 8.36 (d, J = 8.0 Hz,1H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.52–7.40 (m,5H), 7.25 (d, J = 7.8 Hz, 1H), 7.03 (dd, J1 = 7.8 Hz, J2 = 7.6 Hz, 1H),6.99 (dd, J1 = 7.8 Hz, J2 = 7.7 Hz, 1H), 6.81 (s, 2H), 5.42 (s, 1H),4.48 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.2 Hz, 1H), 4.20–4.02 (m,2H), 3.87 (dd, J1 = 5.8 Hz, J2 = 3.7 Hz, 1H 1H), 3.73 (s, 6H), 3.68 (s,3H), 3.23 (dd, J1 = 15.4 Hz, J2 = 3.7 Hz, 1H), 3.11 (dd, J1 = 15.4 Hz,J2 = 5.8 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, ace-tone-d6) d 173.46, 154.33, 138.91, 138.51, 137.97, 137.82, 135.75,135.52, 134.99, 133.41, 129.33, 129.03, 128.66, 127.96, 126.66,126.55, 126.26, 125.87, 122.01, 119.66, 118.73, 111.92, 111.87,106.89, 106.48, 62.35, 60.88, 60.53, 57.49, 56.33, 56.32, 53.84,24.46, 14.70. HRMS (ESI) m/z calcd for (C34H34N2O5+H)+

551.2546; found 551.2539. IR (KBr film) 3357, 2933, 2836, 1728,1592, 1504, 1459, 1418, 1328, 1232, 1182, 1126, 796, 742 cm�1.

4.3.6. (1S,3R)-Methyl 1-(3-hydroxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3f

White solid, mp 126–127 �C. ½a�20D ¼ þ67:1 (c 1.06, CH3OH). 1H

NMR (400 MHz, acetone-d6) d 9.66 (br s, 1H), 8.32 (s, 1H), 8.18(d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H),7.52–7.39 (m, 5H), 7.26 (d, J = 8.0 Hz, 1H), 7.18 (dd, J1 = 8.0 Hz,J2 = 7.8 Hz, 1H), 7.08–6.92 (m, 4H), 6.77 (dd, J1 = 8.0 Hz,J2 = 1.9 Hz, 1H), 5.40 (s, 1H), 4.43 (d, J = 13.1 Hz, 1H), 4.30 (d,J = 13.1 Hz, 1H), 3.82 (dd, J1 = 5.6 Hz, J2 = 4.3 Hz, 1H), 3.63 (s, 3H),3.21 (dd, J1 = 15.5 Hz, J2 = 4.3 Hz, 1H), 3.05 (dd, J1 = 15.4 Hz,J2 = 5.6 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d 173.94, 158.51,144.93, 138.01, 136.00, 135.43, 134.92, 133.43, 130.19, 129.21,128.97, 128.59, 127.83, 126.64, 126.63, 126.22, 125.80, 122.01,121.48, 119.66, 118.69, 116.95, 115.75, 111.95, 106.54, 62.23,56.93, 53.33, 51.69, 24.73. HRMS (ESI) m/z calcd for (C30H26N2O3+-H)+ 463.2022; found 463.2023. IR (KBr film) 3395, 3049, 2921,2849, 1717, 1595, 1455, 1271, 1225, 1140, 1013, 788, 742 cm�1.

4.3.7. (1S,3R)-Methyl 1-phenyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3g

White solid, mp 142–143 �C, ½a�20D ¼ þ127 (c 1.00, CHCl3). 1H

NMR (400 MHz, DMSO-d6) d 10.60 (br s, 1H), 8.07 (d, J = 8.0 Hz,1H), 7.92 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.54–7.40 (m,5H), 7.38–7.18 (m, 6H), 7.04 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 6.98(dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H), 5.29 (s, 1H), 4.37 (d, J = 13.3 Hz,1H), 4.12 (d, J = 13.3 Hz, 1H), 3.78 (dd, J1 = 4.8 Hz, J2 = 5.2 Hz, 1H),3.63 (s, 3H), 3.16 (dd, J1 = 15.5 Hz, J2 = 4.8 Hz, 1H), 3.04 (dd,J1 = 15.5 Hz, J2 = 5.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) d173.29, 142.63, 137.03, 134.81, 134.41, 133.90, 132.31, 129.37,129.36, 128.78, 128.68, 128.67, 128.45, 128.06, 127.94, 126.76,126.26, 126.25, 125.87, 124.83, 121.32, 118.89, 118.24, 111.60,105.53, 60.86, 56.22, 52.20, 51.95, 23.51. HRMS (EI) m/z calcd for(C30H26N2O2)+ 446.1994; found 446.2004. IR (KBr film) 3332,

890 J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893

3053, 3031, 2948, 2849, 1704, 1453, 1233, 1173, 1143, 783, 737,699 cm�1.

4.3.8. (1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3h

White solid, mp 185–186 �C, ½a�20D ¼ þ102 (c 1.00, CHCl3). 1H

NMR (400 MHz, DMSO-d6) d 10.56 (br s, 1H), 8.28 (d, J = 7.6 Hz,1H), 7.93 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.56–7.37 (m,5H), 7.26 (d, J = 8.0 Hz, 1H), 7.05 (dd, J1 = 7.6 Hz, J2 = 7.2 Hz, 1H),6.98 (dd, J1 = 7.6 Hz, J2 = 7.1 Hz, 1H), 6.92–6.78 (m, 3H), 5.19 (s,1H), 4.37 (d, J = 13.2 Hz, 1H), 4.12 (d, J = 13.2 Hz, 1H), 3.81 (dd,J1 = 5.3 Hz, J2 = 5.5 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.57 (s, 3H),3.16 (dd, J1 = 15.6 Hz, J2 = 5.3 Hz, 1H), 3.04 (dd, J1 = 15.6 Hz,J2 = 5.5 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) d 173.33, 149.10,148.72, 137.00, 134.84, 134.60, 133.98, 132.36, 128.80, 128.47,128.01, 126.86, 126.24, 126.19, 125.86, 125.11, 121.29, 121.28,118.87, 118.25, 112.35, 111.63, 111.59, 11.58, 105.50, 60.24,56.35, 55.91, 55.58, 52.36, 51.94, 23.15. HRMS (EI) m/z calcd for(C32H30N2O4)+ 506.2206; found 506.2207. IR (KBr film) 3360,2948, 2899, 2848, 1724, 1511, 1462, 1257, 1232, 1175, 1135,1022, 774, 740 cm�1.

4.3.9. (1S,3R)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3i

White solid, mp 165–166 �C, ½a�20D ¼ þ100 (c 1.50, CHCl3). 1H

NMR (400 MHz, DMSO-d6) d 10.57 (br s, 1H), 8.29 (d, J = 7.6 Hz,1H), 7.93 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.59–7.38 (m,5H), 7.26 (d, J = 8.0 Hz, 1H), 7.05 (dd, J1 = 7.6 Hz, J2 = 7.2 Hz, 1H),6.98 (dd, J1 = 7.5 Hz, J2 = 7.2 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.83(s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 5.17 (s, 1H), 4.37 (d, J = 13.2 Hz,1H), 4.12 (d, J = 13.2 Hz, 1H), 3.95 (q, J = 6.9 Hz, 2H), 3.81 (dd,J1 = 5.6 Hz, J2 = 5.5 Hz, 1H), 3.65 (s, 3H), 3.58 (s, 3H), 3.16 (dd,J1 = 15.5 Hz, J2 = 5.6 Hz, 1H), 3.03 (dd, J1 = 15.5 Hz, J2 = 5.5 Hz, 1H),1.28 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) d 173.32,149.23, 147.90, 136.99, 134.78, 134.77, 134.60, 133.98, 132.37,128.79, 128.48, 128.05, 126.86, 126.23, 126.16, 125.85, 125.14,121.28, 121.27, 118.86, 118.24, 112.65, 112.45, 111.58, 105.50,64.10, 60.20, 56.33, 55.54, 52.34, 51.94, 23.14, 15.21. HRMS (EI)m/z calcd for (C33H32N2O4)+ 520.2362; found 520.2365. IR (KBrfilm) 3353, 2950, 1733, 1509, 1464, 1255, 1255, 1134, 1036, 777,742 cm�1.

4.3.10. (1S,3R)-Methyl 1-methyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3j

White solid, mp 106–107 �C. ½a�20D ¼ �27:4 (c 1.00, CH3OH). 1H

NMR (400 MHz, acetone-d6) d 9.94 (br s, 1H), 8.52–8.45 (m, 1H),7.96–7.88 (m, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H),7.55–7.49 (m, 2H), 7.45 (dd, J1 = 8.1 Hz, J2 = 7.2 Hz, 2H), 7.32 (d,J = 7.9 Hz, 1H), 7.06 (dd, J1 = 7.9 Hz, J2 = 7.0 Hz, 1H), 7.01 (dd,J1 = 7.9 Hz, J2 = 7.0 Hz, 1H), 4.46 (d, J = 13.9 Hz, 1H), 4.38 (d,J = 13.9 Hz, 1H), 4.36 (q, J = 6.6 Hz, 1H), 4.00 (dd, J1 = 5.8 Hz,J2 = 5.4 Hz, 1H), 3.67 (s, 3H), 3.19 (dd, J1 = 15.5 Hz, J2 = 5.8 Hz,1H), 2.95 (dd, J1 = 15.5 Hz, J2 = 5.4 Hz, 1H), 1.53 (d, J = 6.6 Hz, 3H).13C NMR (100 MHz, acetone-d6) d 174.03, 137.69, 137.60, 136.05,134.95, 133.33, 129.28, 128.69, 128.15, 127.91, 126.61, 126.59,126.30, 125.52, 121.85, 119.67, 118.63, 111.81, 106.19, 57.76,53.02, 52.32, 51.83, 23.32, 21.23. HRMS (ESI) m/z calcd for (C25H24-

N2O2+H)+ 385.1916; found 385.1911. IR (KBr film) 3402, 2923,2850, 1731, 1454, 1318, 1269, 1220, 1171, 791, 743 cm�1.

4.3.11. (1S,3R)-Methyl 2-benzyl-1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylate 3k

White solid, mp 71–72 �C. ½a�20D ¼ �18:4 (c 1.10, CH3OH). 1H

NMR (400 MHz, acetone-d6) d 9.89 (br s, 1H), 7.46–7.40 (m, 3H),

7.37–7.28 (m, 3H), 7.25 (dd, J1 = 7.2 Hz, J2 = 7.5 Hz, 1H), 7.06 (dd,J1 = 7.6 Hz, J2 = 8.0 Hz, 1H), 7.00 (dd, J1 = 7.6 Hz, J2 = 7.8 Hz, 1H),4.24 (q, J = 6.6 Hz, 1H), 4.01 (dd, J1 = 6.7 Hz, J2 = 5.4 Hz, 1H), 3.91(d, J = 14.4 Hz, 1H), 3.89 (d, J = 14.4 Hz, 1H), 3.65 (s, 3H), 3.12 (dd,J1 = 15.5 Hz, J2 = 6.7 Hz, 1H), 2.98 (dd, J1 = 15.5 Hz, J2 = 5.4 Hz, 1H),1.48 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 174.02,141.42, 137.65, 137.57, 129.28, 129.27, 129.15, 129.14, 128.15,127.77, 121.85, 119.68, 118.62, 111.80, 106.21, 57.94, 54.78,52.20, 51.86, 23.32, 21.53. HRMS (ESI) m/z calcd for (C21H22N2O2+-H)+ 335.1760; found 335.1764. IR (KBr film) 3399, 2946, 2848,1725, 1453, 1322, 1304, 1272, 1196, 1163, 1018, 738, 698 cm�1.

4.3.12. (1S,3R)-Methyl 1-ethyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3l

White solid, mp 97–98 �C. ½a�20D ¼ �29:2 (c 1.60, CH3OH). 1H

NMR (400 MHz, acetone-d6) d 9.88 (br s, 1H), 8.58 (d, J = 7.8 Hz,1H), 7.91 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.56–7.48 (m,3H), 7.48–7.38 (m, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.06 (dd,J1 = 8.1 Hz, J2 = 7.6 Hz, 1H), 7.01 (dd, J1 = 8.0 Hz, J2 = 7.6 Hz, 1H),4.41 (d, J = 13.3 Hz, 1H), 4.20 (d, J = 13.3 Hz, 1H), 4.09 (dd,J1 = 8.0 Hz, J2 = 5.6 Hz, 1H), 4.01 (dd, J1 = 7.4 Hz, J2 = 4.8 Hz, 1H),3.75 (s, 3H), 3.26 (dd, J1 = 15.7 Hz, J2 = 7.4 Hz, 1H), 2.96 (dd,J1 = 15.7 Hz, J2 = 4.8 Hz, 1H), 1.92–1.75 (m, 2H), 0.66 (t, J = 7.3 Hz,3H). 13C NMR (100 MHz, acetone-d6) d 174.04, 137.67, 136.28,135.82, 134.92, 133.60, 129.13, 128.77, 128.61, 128.14, 126.52,126.43, 126.08, 126.07, 121.78, 119.60, 118.58, 111.80, 106.97,57.67, 57.49, 52.27, 51.94, 27.41, 21.93, 10.60. HRMS (ESI) m/zcalcd for (C26H26N2O2+H)+ 399.2073; found 399.2070. IR (KBr film)3401, 2925, 2852, 1732, 1459, 1268, 1218, 1170, 1142, 798, 789,741 cm�1.

4.3.13. (1S,3R)-Methyl 2-(naphthalen-1-ylmethyl)-1-propyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3m

White solid, mp 91–92 �C, ½a�20D ¼ �42:9 (c 1.30, CHCl3). 1H NMR

(400 MHz, acetone-d6) d 9.89 (br s, 1H), 8.65–8.58 (m, 1H), 7.96–7.90 (m, 1H), 7.89–7.82 (m, 1H), 7.60–7.52 (m, 3H), 7.48–7.42(m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.11 (dd, J1 = 8.0 Hz, J2 = 7.6 Hz,1H), 7.05 (dd, J1 = 8.0 Hz, J2 = 7.7 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H),4.20–4.10 (m, 2H), 4.03 (dd, J1 = 8.6 Hz, J2 = 4.9 Hz, 1H), 3.81 (s,3H), 3.29 (dd, J1 = 15.8 Hz, J2 = 8.6 Hz, 1H), 2.98 (dd, J1 = 15.8 Hz,J2 = 4.9 Hz, 1H), 1.88–1.63 (m, 2H), 1.32–1.04 (m, 2H), 0.49 (t,J = 7.4 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 173.13, 136.75,135.54, 134.92, 134.03, 132.82, 128.16, 127.93, 127.92, 127.30,125.61, 125.47, 125.33, 125.11, 120.87, 118.71, 117.68, 110.90,105.89, 56.50, 54.83, 51.18, 51.13, 36.05, 20.56, 18.50, 12.96. HRMS(EI) m/z calcd for (C27H28N2O2)+ 412.2151; found 412.2154. IR (KBrfilm) 3406, 2953, 2927, 1734, 1460, 1270, 1217, 1170, 793,741 cm�1.

4.3.14. (1S,3R)-Methyl 1-hexyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 3n

White solid, mp 69–70 �C. ½a�20D ¼ �34:7 (c 1.00, CH3OH). 1H

NMR (400 MHz, acetone-d6) d 9.88 (br s, 1H), 8.66 (d, J = 7.6 Hz,1H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.58–7.46 (m,3H), 7.44–7.35 (m, 2H), 7.32 (d, J = 7.7 Hz, 1H), 7.08 (dd,J1 = 7.6 Hz, J2 = 8.0 Hz, 1H), 7.03 (dd, J1 = 7.7 Hz, J2 = 8.0 Hz, 1H),4.43 (d, J = 12.9 Hz, 1H), 4.16 (dd, J1 = 9.6 Hz, J2 = 4.9 Hz, 1H), 4.09(d, J = 12.9 Hz, 1H), 4.00 (dd, J1 = 9.1 Hz, J2 = 3.8 Hz, 1H), 3.82 (s,3H), 3.27 (dd, J1 = 15.6 Hz, J2 = 9.6 Hz, 1H), 2.96 (dd, J1 = 15.6 Hz,J2 = 4.9 Hz, 1H), 1.82–1.74 (m, 1H), 1.74–1.64 (m, 1H), 1.16–1.05(m, 2H), 1.02–0.92 (m, 2H), 0.92–0.80 (m, 2H), 0.78–0.62 (m, 2H),0.73 (t, J = 7.4 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d 174.08,137.69, 136.50, 135.82, 135.00, 133.82, 129.09, 129.02, 128.93,128.22, 126.49, 126.46, 126.39, 125.95, 121.77, 119.61, 118.60, 111.83,106.80, 57.45, 55.56, 55.53, 52.19, 52.07, 34.72, 32.52, 26.19,23.24, 21.33, 14.42. HRMS (ESI) m/z calcd for (C30H34N2O2+H)+

J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893 891

455.2699; found 455.2704. IR (KBr film) 3392, 3050, 2924, 2851,1734, 1460, 1268, 1215, 1169, 1096, 780, 740 cm�1.

4.4. General procedure for the Pd/C-catalyzed hydrogenation of(1S,3R)-trans-1,2,3-trisubstituted THBCs 4

A solution of compounds 3 (3.000 mmol) in CH3CN (30 mL) wasplaced into a three-necked round flask (150 mL), which wasequipped with a magnetic stirring bar, an inlet, and an outlet ofhydrogen gas. Palladium on charcoal (10% w/w, 200 mg) wasadded in one portion, and then the flask was purged with H2 sev-eral times. The black suspension was heated to 60 �C, and stirredat this temperature under 1.05–1.10 atm of H2 for approximately8 h. After the reaction was complete (checked by TLC), the suspen-sion was cooled down to room temperature. Next, the Pd/C was re-moved by filtration. Evaporation of CH3CN produced a crude solidproduct, which was washed with a mixed solvent of hexane andethyl acetate (EtOAc/hexane = 1:9) to furnish compounds 4 in95–99% yields. Characterization data of compounds 4a–4l are asfollows:

4.4.1. (1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydro-9H-pyrido [3,4-b]indole-3-carboxylate 4a

98% and 95% Yields from compounds 3a and 3b, respectively.White solid, mp 187–188 �C. ½a�20

D ¼ þ33:0 (c 1.00, CHCl3). 1HNMR (acetone-d6) d 3.01 (dd, J1 = 15.2 Hz, J2 = 6.5 Hz, 1H), 3.16(dd, J1 = 15.2 Hz, J2 = 5.6 Hz, 1H), 3.66 (s, 3H), 3.93 (dd, J1 = 6.5 Hz,J2 = 5.6 Hz, 1H), 5.36 (s, 1H), 5.96 (d, J = 3.3 Hz, 2H), 6.75 (d,J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 7.03 (dd,J1 = 7.5 Hz, J2 = 7.8 Hz, 1H), 7.07 (dd, J1 = 8.0 Hz, J2 = 7.8 Hz, 1H),7.28 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 9.71 (br s, 1H). 13CNMR (acetone-d6) d 174.69, 148.66, 147.97, 138.02, 137.44,135.05, 127.98, 122.56, 122.08, 119.62, 118.66, 111.83, 109.56,108.50, 108.11, 101.99, 55.24, 53.15, 52.06, 25.46. HRMS (ESI) m/z calcd for (C20H18N2O4+H)+ 351.1345; found 351.1348. IR (KBrfilm) 3316, 2950, 2893, 1705, 1479, 1438, 1238, 1040, 744 cm�1.

4.4.2. (1S,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetra-hydro-9H-pyrido [3,4-b]indole-3-carboxylate 4b

98% Yield from compound 3c. White solid, mp 78–79 �C.½a�20

D ¼ þ33:2 (c 1.50, CH3OH). 1H NMR (400 MHz, acetone-d6) d9.71 (br s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H),7.06 (dd, J1 = 7.7 Hz, J2 = 7.2 Hz, 1H), 7.01 (dd, J1 = 7.8 Hz,J2 = 7.2 Hz, 1H), 6.82 (s, 1H), 6.80–6.72 (m, 2H), 5.96 (d, J = 3.4 Hz,2H), 5.36 (s, 1H), 4.18–4.05 (m, 2H), 3.90 (dd, J1 = 7.0 Hz,J2 = 5.4 Hz, 1H), 3.15 (dd, J1 = 15.2 Hz, J2 = 5.4 Hz, 1H), 3.00 (dd,J1 = 15.2 Hz, J2 = 7.0 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR(100 MHz, acetone-d6) d 174.28, 148.67, 147.96, 138.13, 137.58,135.23, 128.05, 122.56, 122.09, 119.65, 118.66, 111.92, 109.58,108.53, 108.29, 102.00, 61.21, 55.36, 53.21, 25.63, 14.57. HRMS(ESI) m/z calcd for (C21H20N2O4+H)+ 365.1501; found 365.1508. IR(KBr film) 3393, 2921, 1729, 1486, 1443, 1237, 1184, 1037,743 cm�1.

4.4.3. (1S,3R)-Methyl 1-(4-fluorophenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 4c

97% Yield from compound 3d. White solid, mp 173–174 �C.½a�20

D ¼ þ30:8 (c 1.05, CH3OH). 1H NMR (400 MHz, acetone-d6) d9.74 (br s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.38–7.24 (m, 3H), 7.12–6.98 (m, 4H), 5.44 (s, 1H), 3.89 (dd, J1 = 6.9 Hz, J2 = 5.5 Hz, 1H),3.65 (s, 3H), 3.15 (dd, J1 = 15.2 Hz, J2 = 5.5 Hz, 1H), 3.01 (dd,J1 = 15.2 Hz, J2 = 6.9 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d174.70, 164.27, 161.84, 140.23, 140.20, 137.62, 134.98, 131.24,131.16, 128.04, 122.18, 119.72, 118.71, 115.81, 115.59, 111.93,108.35, 54.85, 53.19, 52.08, 25.61. HRMS (ESI) m/z calcd for (C19-

H17FN2O2+H)+ 325.1352; found 325.1350. IR (KBr film) 3335,

2926, 2851, 1701, 1505, 1450, 1335, 1299, 1258, 1219, 1150,836, 746 cm�1.

4.4.4. (1S,3R)-Ethyl 1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetra-hydro-9H-pyrido[3,4-b]indole-3-carboxylate 4d

96% Yield from compound 3e. White solid, mp 96–97 �C.½a�20

D ¼ þ27:3 (c 1.60, CH3OH). 1H NMR (400 MHz, acetone-d6) d9.68 (br s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H),7.05 (dd, J1 = 7.5 Hz, J2 = 7.3 Hz, 1H), 7.00 (dd, J1 = 7.5 Hz,J2 = 7.3 Hz, 1H), 6.68 (s, 2H), 5.39 (s, 1H), 4.22–4.06 (m, 2H), 4.00(dd, J1 = 6.4 Hz, J2 = 5.4 Hz, 1H), 3.73 (s, 6H), 3.71 (s, 3H), 3.17(dd, J1 = 15.1 Hz, J2 = 5.4 Hz, 1H), 3.05 (dd, J1 = 15.1 Hz, J2 = 6.4 Hz,1H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d174.37, 154.31, 154.30, 139.62, 138.61, 137.61, 135.23, 128.11,122.06, 119.64, 118.67, 111.92, 108.04, 106.64, 106.63, 61.22,60.56, 56.41, 56.40, 55.87, 53.71, 25.45, 14.59. HRMS (ESI) m/zcalcd for (C23H26N2O5+H)+ 411.1920; found 411.1918. IR (KBr film)3347, 2935, 2837, 1731, 1592, 1505, 1459, 1419, 1326, 1234, 1185,1126, 1005, 743 cm�1.

4.4.5. (1S,3R)-Methyl 1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole-3-carboxylate 4e

98% Yield from compound 3f. White solid, mp 104–105 �C.½a�20

D ¼ þ35:5 (c 1.00, CH3OH). 1H NMR (400 MHz, acetone-d6) d9.75 (br s, 1H), 8.27 (br s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.30 (d,J = 7.8 Hz, 1H), 7.14 (dd, J1 = 7.8 Hz, J2 = 7.7 Hz, 1H), 7.11–6.98 (m,2H), 6.81 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.69 (s, 1H),5.34 (s, 1H), 3.90 (dd, J1 = 7.6 Hz, J2 = 5.2 Hz, 1H), 3.67 (s, 3H),3.14 (dd, J1 = 15.2 Hz, J2 = 5.2 Hz, 1H), 2.99 (dd, J1 = 15.2 Hz,J2 = 7.6 Hz, 1H). 13C NMR (100 MHz, acetone-d6) d 174.64, 158.29,145.50, 137.58, 135.08, 130.21, 128.02, 122.07, 120.45, 119.65,118.63, 116.12, 115.30, 111.93, 108.28, 55.60, 53.04, 52.09, 25.69.HRMS (ESI) m/z calcd for (C19H18N2O3+H)+ 323.1396; found323.1391. IR (KBr film) 3389, 2922, 2850, 1733, 1595, 1456,1352, 1272, 1221, 744 cm�1.

4.4.6. (1S,3R)-Methyl 1-phenyl-1,2,3,4-tetrahydro-9H-pyrido-[3,4-b]indole-3-carboxylate 4f

95% Yield from compound 3g. White solid, mp 220–221 �C.½a�20

D ¼ þ44:5 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.69(br s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.36–7.28 (m, 2H), 7.26–7.05(m, 6H), 5.34 (s, 1H), 3.94 (dd, J1 = 6.8 Hz, J2 = 5.5 Hz, 1H), 3.69 (s,3H), 3.25 (dd, J1 = 15.4 Hz, J2 = 5.5 Hz, 1H), 3.10 (dd, J1 = 15.4 Hz,J2 = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 174.14, 142.04,136.24, 133.21, 128.76, 128.75, 128.48, 128.47, 128.13, 126.97,121.95, 119.49, 118.24, 111.04, 108.44, 54.94, 52.39, 52.16, 24.82.HRMS (EI) m/z calcd for (C19H18N2O2)+ 306.1368; found306.1371. IR (KBr film) 3401, 3052, 2951, 1730, 1456, 1353,1329, 1206, 744, 701 cm�1.

4.4.7. (1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 4g

98% Yield from compound 3h. White solid, mp 191–192 �C.½a�20

D ¼ þ26:0 (c 1.90, CHCl3). 1H NMR (400 MHz, acetone-d6) d9.71 (br s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H),7.10–6.98 (m, 3H), 6.87 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H),5.38 (s, 1H), 3.96 (dd, J1 = 6.8 Hz, J2 = 5.4 Hz, 1H), 3.79 (s, 3H),3.75 (s, 3H), 3.68 (s, 3H), 3.17 (dd, J1 = 15.2 Hz, J2 = 5.4 Hz, 1H),3.03 (dd, J1 = 15.2 Hz, J2 = 6.8 Hz, 1H). 13C NMR (100 MHz, ace-tone-d6) d 173.84, 149.45, 149.00, 136.65, 135.65, 134.59, 127.18,121.05, 120.47, 118.66, 117.69, 112.35, 111.43, 110.94, 107.13,55.22, 55.18, 54.51, 52.41, 51.11, 24.64. HRMS (EI) m/z calcd for(C21H22N2O4)+ 366.1580; found 366.1581. IR (KBr film) 3362,2980, 1731, 1600, 1514, 1465, 1454, 1256, 1186, 1138, 1026,858, 743 cm�1.

892 J. Dong et al. / Tetrahedron: Asymmetry 24 (2013) 883–893

4.4.8. (1S,3R)-Methyl 1-(4-ethoxy-3-methoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 4h

97% Yield. White solid from compound 3i, mp 155–156 �C,½a�20

D ¼ þ17:9 (c 2.00, CHCl3). 1H NMR (400 MHz, acetone-d6) d9.72 (br s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H),7.12–6.96 (m, 3H), 6.86 (d, J = 8.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H),5.38 (s, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.96 (dd, J1 = 7.0 Hz,J2 = 5.4 Hz, 1H), 3.76 (s, 3H), 3.68 (s, 3H), 3.17 (dd, J1 = 15.2 Hz,J2 = 5.4 Hz, 1H), 3.02 (dd, J1 = 15.2 Hz, J2 = 7.0 Hz, 1H), 1.37 (t,J = 7.0 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d 174.79, 150.55,149.13, 137.57, 136.49, 135.48, 128.09, 122.01, 121.43, 119.61,118.64, 113.61, 113.39, 111.91, 108.07, 64.91, 56.09, 55.44, 53.28,52.09, 25.57, 15.31. HRMS (EI) m/z calcd for (C22H24N2O4)

+

380.1736; found 380.1735. IR (KBr film) 3355, 2931, 1735, 1512,1452, 1264, 1136, 1033, 743 cm�1.

4.4.9. (1S,3R)-Methyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido-[3,4-b]indole-3-carboxylate 4i

99% and 96% Yields from compounds 3j and 3k, respectively.White solid, mp 186–187 �C. ½a�20

D ¼ �16:4 (c 1.10, CH3OH). 1HNMR (400 MHz, acetone-d6) d 9.91 (br s, 1H), 7.42 (d, J = 7.8 Hz,1H), 7.29 (d, J = 7.9 Hz, 1H), 7.04 (dd, J1 = 7.8 Hz, J2 = 7.2 Hz, 1H),6.98 (dd, J1 = 7.9 Hz, J2 = 7.2 Hz, 1H), 4.41 (q, J = 6.7 Hz, 1H), 3.97(dd, J1 = 5.3 Hz, J2 = 6.7 Hz, 1H), 3.67 (s, 3H), 3.01 (dd, J1 = 15.0 Hz,J2 = 5.3 Hz, 1H), 2.91 (dd, J1 = 15.0 Hz, J2 = 6.7 Hz, 1H), 2.68 (br s,1H), 1.44 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, acetone-d6) d174.87, 138.08, 137.16, 128.23, 121.69, 119.49, 118.44, 111.64,106.44, 53.43, 51.97, 46.39, 25.72, 21.81. HRMS (ESI) m/z calcd for(C14H16N2O2+H)+ 245.1290; found 245.1296. IR (KBr film) 3155,3002, 2851, 1738, 1455, 1434, 1337, 1269, 1216, 1138, 747 cm�1.

4.4.10. (1S,3R)-Methyl 1-ethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 4j

98% Yield from compound 3l. White solid, mp 116–117 �C.½a�20

D ¼ �27:5 (c 1.00, CH3OH). 1H NMR (400 MHz, acetone-d6) d9.87 (br s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H),7.04 (dd, J1 = 7.7 Hz, J2 = 7.2 Hz, 1H), 6.98 (dd, J1 = 7.9 Hz,J2 = 7.2 Hz, 1H), 4.18 (dd, J1 = 8.7 Hz, J2 = 3.6 Hz, 1H), 3.94 (dd,J1 = 7.0 Hz, J2 = 5.3 Hz, 1H), 3.67 (s, 3H), 2.99 (dd, J1 = 15.0 Hz,J2 = 5.3 Hz, 1H), 2.89 (dd, J1 = 15.0 Hz, J2 = 7.0 Hz, 1H), 2.71 (br s,1H), 1.95–1.82 (m, 1H), 1.80–1.66 (m, 1H), 1.02 (d, J = 7.3 Hz,3H). 13C NMR (100 MHz, acetone-d6) d 175.01, 137.20, 137.12,128.19, 121.72, 119.49, 118.43, 111.70, 106.95, 53.41, 52.23,52.06, 28.73, 25.78, 10.88. HRMS (ESI) m/z calcd for (C15H18N2O2+-H)+ 259.1447; found 259.1444. IR (KBr film) 3390, 2957, 2921,2524, 1720, 1444, 1327, 1273, 1216, 1176, 1047, 743 cm�1.

4.4.11. (1S,3R)-Methyl 1-propyl-1,2,3,4-tetrahydro-9H-pyrido-[3,4-b]indole-3-carboxylate 4k

99% Yield from compound 3m. White solid, mp 112–113 �C.½a�20

D ¼ �4:5 (c 3.0, CHCl3). 1H NMR (400 MHz, acetone-d6) d 9.88(br s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.03 (dd,J1 = 7.7 Hz, J2 = 7.5 Hz, 1H), 6.96 (dd, J1 = 7.9 Hz, J2 = 7.5 Hz, 1H),4.25 (dd, J1 = 9.1 Hz, J2 = 3.7 Hz, 1H), 3.94 (dd, J1 = 7.3 Hz, J2 = 5.2H, 1H), 3.67 (s, 3H), 2.99 (dd, J1 = 15.0 Hz, J2 = 5.2 Hz, 1H), 2.87(dd, J1 = 15.0 Hz, J2 = 7.3 Hz, 1H), 1.82–1.64 (m, 2H), 1.60–1.44 (m,2H), 0.95 (t, J = 7.4, 3H). 13C NMR (100 MHz, acetone-d6) d 174.15,136.66, 136.45, 127.39, 120.85, 118.65, 117.54, 110.87, 106.03,52.54, 51.22, 49.94, 37.28, 25.08, 19.11, 13.62. HRMS (EI) m/z calcdfor (C16H20N2O2)+ 272.1525; found 272.1527. IR (KBr film) 3399,2955, 1733, 1452, 1329, 1271, 1218, 1174, 1027, 742 cm�1.

4.4.12. (1S,3R)-Methyl 1-hexyl-1,2,3,4-tetrahydro-9H-pyrido-[3,4-b]indole-3-carboxylate 4l

98% Yield from compound 3n. White solid, mp 75–76 �C.½a�20

D ¼ �21:6 (c 1.00, CH3OH). 1H NMR (400 MHz, acetone-d6) d

9.90 (br s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H),7.03 (dd, J1 = 7.9 Hz, J2 = 7.4 Hz, 1H), 6.97 (dd, J1 = 7.7 Hz,J2 = 7.4 Hz, 1H), 4.24 (dd, J1 = 9.1 Hz, J2 = 3.5 Hz, 1H), 3.94 (dd,J1 = 7.1 Hz, J2 = 5.2 Hz, 1H), 3.68 (s, 3H), 3.00 (dd, J1 = 14.9 Hz,J2 = 5.2 Hz, 1H), 2.89 (dd, J1 = 14.9 Hz, J2 = 7.1 Hz, 1H), 2.54 (br s,1H), 1.91–1.79 (m, 1H), 1.78–1.65 (m, 1H), 1.60–1.45 (m, 2H),1.42–1.25 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, ace-tone-d6) d 174.99, 137.41, 137.20, 128.23, 121.69, 119.48, 118.40,111.69, 106.82, 53.38, 52.06, 50.95, 36.00, 32.67, 30.15, 26.83,25.87, 23.40, 14.49. HRMS (ESI) m/z calcd for (C19H26N2O2+H)+

315.2073; found 315.2069. IR (KBr film) 3395, 2924, 2853, 1732,1453, 1332, 1453, 1332, 1269, 1218, 741 cm�1.

4.5. One-pot procedure for the conversion of compound 1a intocompound 3a (see also Scheme 2)

To a solution of compound 1a (1.460 g, 4.167 mmol) in CH3CN(16 mL), were added DIPEA (808.0 mg, 6.252 mmol) and 1-naph-thylmethyl bromide (1.015 g, 4.591 mmol). The resulting solutionwas heated at reflux at 81 �C, and then stirred at this temperaturefor 5 h. Potassium carbonate (752.0 mg, 5.441 mmol) and DBU(635.0 mg, 4.171 mmol) were then added, and the mixture wasfurther stirred under N2 at reflux for 18 h. When the reactionwas complete (checked by HPLC), the mixture was cooled downto room temperature. The mixture was filtered by suction, andthe cake was rinsed twice with CH3CN (2 � 5 mL). The organicsolution was concentrated under vacuum to give a crude solidproduct, which was purified by flash chromatography (eluent:EtOAc/hexane = 1:5) to afford compound 3a (1.961 g, 3.998 mmol)as a white solid in 96% yield.

4.6. Preparation of ent-1a-HCl from compound 4a

To a well-stirred solution of compound 4a (1.531 g,4.370 mmol) in CH3CN (25 mL), was added a concentrated aqueoussolution of HCl (0.45 mL, 12 M, 5.4 mmol). White crystals formedimmediately. The suspension was heated at reflux, and someamount of CH3CN (10–15 mL) was gradually removed by distilla-tion over 1 h, during which, water was also removed by azetropicdistillation. The remaining suspension was further stirred at refluxfor a further 8 h. After the reaction (CIAT) was complete (checkedby TLC), the mixture was cooled down to room temperature. Filtra-tion by suction and drying in warm air afforded the hydrochloridesalt ent-1a-HCl (1.540 g, 3.981 mmol) as pale yellow crystals in91% yield. Characterization data of compound ent-1a (after neu-tralization) are identical with the previously reported data.9

Acknowledgments

We thank the National Natural Science Foundation of China(No. 20972048) and the Shanghai Educational Development Foun-dation (The Dawn Program: No. 03SG27) for the financial supportof this work.

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