enantioselective synthesis of benzomorphan analogues by intramolecular oxa-pictet–spengler...

Tetrahedron: Asymmetry xxx (2014) xxx–xxx

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Tetrahedron: Asymmetry

journal homepage: www.elsevier .com/locate / tetasy

Enantioselective synthesis of benzomorphan analoguesby intramolecular oxa-Pictet–Spengler cyclization

http://dx.doi.org/10.1016/j.tetasy.2013.12.0160957-4166/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +91 20 2560 1394x585; fax: +91 20 25691728.E-mail address: [email protected] (S.B. Waghmode).

Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016

Viraj P. Patil a, Anirban Ghosh b, Uddhavesh Sonavane b, Rajendra Joshi b, Rajiv Sawant a, Satish Jadhav a,Suresh B. Waghmode a,⇑a Department of Chemistry, University of Pune, Ganeshkhind, Pune 411 007, Indiab Bioinformatics Group, Centre for Development of Advanced Computing, Pune 411 007, India

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

Article history:Received 26 October 2013Accepted 19 December 2013Available online xxxx

A new strategy toward biologically active enantiomerically pure benzomorphan analogues is described.The key steps in the synthesis are the L-proline catalyzed asymmetric a-aminooxylation of an aldehydeand the titanium tetrachloride promoted intramolecular oxa-Pictet–Spengler cyclization of (4R)-2-(bromomethyl)-4-(2,5-dimethoxybenzyl)-1,3-dioxolane. In the intramolecular oxa-Pictet–Spenglercyclization, cis-pyran 8a (71%) formed over the trans-pyran 8b (14%). Computational modeling studiesprovided an insight into the stereoselectivity of the products. Docking studies of benzomorphanderivatives indicated that compound 6c had the best binding efficiency, and that it formed extensivehydrogen bonding with TYR148 on transmembrane (TM) helix 3 and HIS297 on TM6 of the l-opioidreceptor, which belong to the G-protein coupled receptor super family.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction modifications include the synthesis of a simple tricyclic system,

Opioid alkaloids and related pharmaceuticals are the mosteffective analgesics for the treatment of acute and chronic pain.The active alkaloids in opium are morphine 1a and codeine 1b,which act on the central nervous system of humans to produce awide range of effects such as analgesia, euphoria, sedation, respira-tory depression, and cough suppression, and have peripheraleffects such as constipation. The management of pain, acutepulmonary edema, coughs, diarrhea, and shivering is mainlycontrolled by the l-opioid receptor (l-OR).1 It is one of the familymembers of the class A G-protein-coupled receptors (GPCRs)2 andthe most important signaling receptors of the central nervoussystem.3 The majority of opioid alkaloids, such as morphine andcodeine, function by binding to and activating l-OR. Dependingupon the substitution on N of the tricyclic ring system, it interactswith the l, j (Opioid), d receptor, and phenacyclidine binding siteof the NMDA (N-methyl-D-aspartate) receptor.4 These compoundsconsist of a basic skeleton of benzomorphan (2-phenyl ethylaminesubstructure Fig. 1, structures 1 to 5). However, the highlyaddictive nature of opioid drugs makes it necessary to developsome new forms of opioid drugs which might help in reducingdependence while increasing efficiency. Structural modificationcan reduce this problem to a considerable degree. These

ring size variation,5 nitrogen atom repositioning,6 and synthesisof the 5-arylmorphan skeleton.7 A substituted benzomorphanscaffold has potential as a lead structure in the search for new drugcandidates with selective activity on opioid receptors.

Since the stereochemistry of a drug strongly influencespharmacological activity, nowadays one of the major challengesorganic chemists face is, the synthesis of chiral molecules inefficient and economical ways. In this context, the organocatalyticL-proline catalyzed a-aminooxylation of an aldehyde8 and theoxa-Pictet–Spengler rearrangement of 6-aryl 1,3-dioxolaneprovide a means to improve the chemical transformations and thusthe synthetic efficiency for novel tricyclic benzomorphananalogues. A convenient, straightforward, and practical route tothe synthesis of benzomorphan analogues from prochiral startingmaterials is highly desirable. Since a part of our research programwas aimed toward the synthesis of biologically active compoundsand their key intermediates9 by using the proline-catalyzedasymmetric a-aminooxylation of aldehydes,8 we were encouragedto design a short and effective route for the synthesis ofbenzomorphan analogues. In order to search for a novel receptorof the benzomorphan analogues, tricyclic amines with a2-phenylethylamine substrate were envisaged. Herein we reporta novel enantioselective synthesis of benzomorphan analogues byemploying an L-proline-catalyzed asymmetric a-aminooxylationof an aldehyde and a titanium tetrachloride promoted intramolec-ular oxa-Pictet–Spengler cyclization10 as the key steps for chirality

http://dx.doi.org/10.1016/j.tetasy.2013.12.016

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ON

2

RN H

NH

HN

NMe

OHORO

3 4 51a: R = H1b: R = Me

Figure 1. Structure of benzomorphan with planned tricyclic amine and prominent analogues.

2 V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx

induction. In order to understand the stability of the isomers andbinding efficiency of benzomophan compounds with l-opioidreceptors, optimization by DFT calculations and docking studieswere carried out, respectively.

2. Results and discussion

2.1. Synthesis of benzomorphan analogues

Our plan for the synthesis of enantiomerically pure tricyclicbenzomorphan analogues is shown in Scheme 1. The retrosynthet-ic scheme is centered on the organocatalytic enantioselective syn-thesis of the cis-1,3-dimethylpyran containing key intermediatewhile its analogues were developed in our laboratory.9c The onestep nucleophilic substitution of tosylate by various benzyl aminesto deliver tricyclic benzomorphans has been envisaged. The tosyl-ate 7 itself can be obtained by tosylation of alcohol 8, formed viaintra-molecular pyran formation by the diastereoselective intra-molecular oxa-Pictet–Spengler cyclization of bromomethyl-1,3-dioxolane 9.

The synthesis of benzomorphan analogues started with (R)-diol10, which was prepared in 98% ee by following an organocatalyticapproach based on the L-proline catalyzed asymmetric a-amino-oxylation of aldehydes.9c,d Diol 10 was reacted with 2-bromo-1,1-diethoxyethane in the presence of p-toluenesulfonic acid inCH2Cl2 and gave bromomethyl-1,3-dioxolane 9 in excellent yield.Bromomethyl-1,3-dioxolane 9 was subjected to intramolecularoxa-Pictet–Spengler cyclization with TiCl4 (2 equiv) in dry CH2Cl2

at �30 �C to afford cis- and trans-pyran 8a and 8b. The TiCl4 pro-moted intramolecular oxa-Pictet–Spengler cyclization gave thecis-pyran (71%) as the major product over the trans-pyran (14%)(Scheme 2).

In Fig. 2, the cyclization of the acetals presumably starts by alk-oxide abstraction by the Lewis acid (TiCl4) from 9, leaving a stabi-lized oxocarbocation 12, which undergoes an electrophilic attackon the aromatic ring to afford intermediate species 13 and 14.The final elimination of a proton produces the isochroman nucleus

OMe

OMe

ON

ROMe

O

OTs

Br

6 7

OMe

Scheme 1. Retrosynthetic analysis

Please cite this article in press as: Patil, V. P.; et al. Tetrahedron: Asymm

8a and 8b. In this reaction, we presume that the Re and Si attack ofthe nucleophile gives the cis- and trans-pyran through transitionstate 15a and 15b, respectively. The product distribution may bedue to the fact that the cis-isomer 8a has both of its methyl alcoholand methyl bromide groups adopting a pseudoequatorial orienta-tion 15a, which minimizes the 1,3-diaxial interaction across theoxygen in the 6 membered oxonium transition state. The trans-isochroman would result from the oxonium transition state 15bwhere the methyl bromide group is in a pseudoaxial position, afeature already observed in other pyran derivatives.11

The relative stereochemistry of isochroman 8a was ascertainedby a 2D-NOE correlation experiment. The 1,3-trans pyran showed astrong NOE correlation between the proton H3 and the bromo-methyl protons (Fig. 3). The stereochemistry at the C1 positionwas further confirmed by carrying out the cyclization of isochro-mans 8a and 8b. The cis-isochroman cyclized to the tricyclic ben-zomorphan, while the trans-isochroman did not cyclize. Theseexperimental results helped to fix the stereochemistry of 8a and8b isochromans as (1S,3R) and (1R,3R), respectively.

The major cis-configured pyran was subjected to tosylation byusing p-toluenesulfonyl chloride, Et3N, and DMAP in CH2Cl2 toafford the desired 1,3-disubstituted bromotosylate 7a in 71% yield.The one step nucleophilic substitution of various benzyl aminederivatives 16a–i was performed using K2CO3 in CH3CN at 80 �C,to afford tricyclic benzomorphan derivatives. Benzyl amine gave81% yield, whereas halogen substituted benzyl amines gave yieldsbetween 71% and 85% (Table 1, entries 1–4). When electrondonating para-methoxy benzyl amine was subjected to nucleo-philic substitution, the desired product was obtained in 90% yield.Heterocyclic pyridin-4-ylmethanamine gave 77% yield (entry 6).Homobenzyl amines gave the desired product in 60–65% yield(Table 1, entries 7 and 8). This is due to the decrease in the nucleo-philic character of the amine. The same methodology was appliedfor the trans-isomer 8b, but we were unable to obtain the cyclizedproduct, since in structure 8b, the –CH2Br adopts a pseudoaxialposition 15b, so that the nucleophilic attack by an amine is notfeasible; this also reveals the trans-geometry of 8b.

OMe

OMe

O

OH

Br OMe

OMe

OO

Br

8 9

OMe

OMe

OHOH

10

of benzomorphan analogues.

etry (2014), http://dx.doi.org/10.1016/j.tetasy.2013.12.016


OMe

OMe

OO

BrOMe

OMe

OHOH

OMe

OMe

O

OH

Br

OMe

OMe

O

OH

Br

BrOEt

OEt

PTSA,CH2Cl2,0 °C rt,4h, 90%

TiCl4

CH2Cl2,-30 °C,3h.

OMe

OMe

O

OTs

Br

CH2Cl2,0 °C rt,12h, 71%

p-TsCl

OMe

OMe

ON

R

K2CO3, CH3CN,80 °C, 12h

RNH2

10 9

8b (14%)

8a (71%) 7a 6

OMe

OMe2,5-dimethoxybenzaldehyde

CHO

Ref. 9d

CH2Cl2,0 °C rt,12h, 72%

p-TsCl

OMe

OMe

O

OTs

Br

7b

K2CO3, CH3CN,80 °C, 12h

RNH2

OMe

OMe

ON

R

not formed

9 6'

Scheme 2. Synthesis of benzomorphan analogues.

OMe

OMe

OO

Br OMe

OMe

OO

Br

TiCl4 TiCl4

OMe

OMe

OO

CH2Br

TiCl4

OMe

OMe

O

CH2Br

TiCl4

O

OMe

OMe

O

CH2Br

TiCl4

O

H H

OMe

OMe

OH

CH2Br

O

OMe

OMe

OH

CH2Br

O

8b (14%) 8a (71%)

(Re attack) (Si attack)

(Si attack)

(Re attack)

9 12

1314

15b

15a

OOMe

MeO

Br

Cl4TiO

OOMe

MeO

Cl4TiO

Br

11

Figure 2. Plausible reaction mechanism for the oxa-Pictet–Spengler cyclization.

OMe

OMe

O

OHH

3

1

8b

HBr

H

H

2

OMe

OMe

O

OHH

3

1

8a

HBr

H

H

2

Figure 3. 2D-NOE correlation observed in cis-8a and trans-8b.

V. P. Patil et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx 3

2.2. DFT calculations

The oxa-Pictet–Spengler reaction of compound 9 gave twoisomers 8a and 8b in 71% and 14% yields, respectively. In orderto determine the reason for this, we performed an optimization


of these isomers by using DFT calculations. We observed thattrans-8b was more stable (0.66744 kcal/mol) compared to cis-8a.Experimentally obtained result suggested that the cis-isomer wasa kinetically controlled product. In this reaction, the transitionstate (Fig. 2) of the product formation played an important role,whereas the quasi 1,3-diaxial interactions were minimized (Fig. 4).

2.3. Docking studies

Using the recently solved crystal structure of l-OR (PDB ID:4DKL), bound to an irreversible benzomorphan antagonist, b-fun-altrexamine (b-FNA), docking studies were carried out. The bindingefficiencies of these new compounds were compared with those ofb-FNA, which was redocked to l-OR. The best docked conforma-tions based on the calculated binding energy for each of the com-pounds with l-OR are listed in Table 2. From Table 2, it can be



Table 1Summary of one step nucleophilic substitution of bromotosylate 7 with various benzyl amines

OMe

OMe

O

OTs

Br OMe

OMe

ON

R

K2CO3,CH3CN,80 °C,12 h

7 6a-i

RNH2

16a-i

Entry Benzyl amines Product Yield (%)

1

NH2

16a

OMe

OMe

ON

6a

81

2

NH2

Cl

Cl

16b

OMe

OMe

ON

Cl

Cl

6b

76

3

NH2

Cl16c

OMe

OMe

ON

Cl

6c

71

4

NH2

F16d

OMe

OMe

ON

F

6d

85

5

NH2

MeO16e

OMe

OMe

ON

OMe

6e

90

6N

NH2

16f

OMe

OMe

ON

N

6f

77

7NH

NH2

16g

OMe

OMe

ON

HN6g

60

8

MeO

MeO

NH2

16h

OMe

OMe

ON

OMe

OMe6h

65

9

NH2

16i

OMe

OMe

ON

6i

88


clearly seen that b-FNA, which was present in the crystal structure,has a minimum free energy of binding of �11.84 kcal/mol. It formsa hydrogen bond with LEU219 on extracellular loop 2 (ECL2).Among the synthesized compounds it was found that compound


6c had the best binding efficiency with a binding free energy of�8.30 kcal/mol. It formed extensive hydrogen bonding withTYR148 on transmembrane (TM) helix 3 and HIS297 on TM6 ofthe receptor (Fig. 5).



Table 2Binding free energies of the native ligands and the ligand derivatives with l-ORobtained after docking

Compound Binding energy (kcal/mol)

Crystal ligands b-FNA �11.84Morphine �10.55

Ligand derivatives 6a0 �8.116a �8.266b �7.896c �8.306d �7.946e �6.996f �8.166g �7.876h �6.996i �7.00

cis pyran 8a trans pyran 8b

Figure 4. DFT optimized structures of 8a and 8b.


3. Conclusion

In conclusion we have reported on a concise and easymethodology for the stereoselective synthesis of benzomorphananalogues through L-proline catalyzed a-aminooxylation of analdehyde and intramolecular oxa-Pictet–Spengler cyclization.The oxa-Pictet–Spengler reaction gave cis-pyran as the majorproduct. The versatility of our new approach is shown with the

Figure 5. l-OR-ligand interactions. (A) Shows the hydrogen bond network (seen from themolecule after re-docking. The higher number of hydrogen bonds formed explains thehydrogen bond network between the best ligand derivative 6c, with the lowest free enerthe hydrogen bonds with the ligands belong to TM3 and TM6 of the receptor.


synthesis of tricyclic benzomorphan derivatives using chiral diol10 as a building block. This route is practical since it uses the chi-ral diol 10, which can be readily synthesized by using an L-prolinecatalyzed asymmetric a-aminooxylation of aldehyde. The presentmethodology should gain importance, as it provides a route forthe synthesis of tricyclic benzomorphan derivatives, which areimportant moieties in medicinal chemistry and bioactive naturalproducts. The biological activity of synthesized compound is un-der investigation. The trend observed in the docking study ishelpful in designing and synthesizing new benzomorphan ana-logues, which have more binding efficiency with a receptor.

4. Experimental

4.1. General

Melting points were recorded with a Thomas Hoover Capillarymelting point apparatus. Thin-layer chromatography was per-formed on Merck 60F254 silica gel plates, and visualization wasaccomplished by irradiation with UV light and/or by treatmentwith a solution of phosphomolybdic acid (1.25 g) and Ce(SO4)2�H2O(0.5 g) in concentrated H2SO4/H2O (3.47 mL) followed by heating.Crude products were purified by column chromatography on silicagel of 100–200 mesh. IR spectra were recorded with a ShimadzuFTIR 8400 in CHCl3 or as KBr pellets. Optical rotations were ob-tained with Jasco P-1020 digital polarimeter. 1H and 13C NMR spec-tra were recorded with a Varian Mercury spectrometer at 300 and75 MHz, respectively, by using CDCl3 as a solvent. Chemical shiftsare reported in d units (ppm) with reference to TMS as an internalstandard. LC mass spectra were obtained with a Shimadzu LC–MS-2010ev spectrometer. All solvents were purified and dried by stan-dard procedures prior to use.

4.2. Methodology for the DFT calculations

We used the Gaussian0912,13 software packages for our calcula-tions. The computational studies of the benzomorphan isomerswere carried out using Density Functional Theory (DFT).12 TheDFT calculations were subjected to unrestricted energy optimiza-tion and single point energy calculations. Geometry optimizations

extracellular side of the receptor) formed by the native ligand b-FNA with the l-ORlowest free energy of binding (�11.84 kcal/mol) with the receptor. (B) Depicts thegy of binding (�8.30 kcal/mol) with l-OR. The residues involved in the formation of




were performed by using the hybrid-DFT B3LYP14 exchange corre-lation functionals and the double-f 6-311++G(d,p) basis set for allof the atoms. Normal self-consistent field (SCF) and geometry con-vergence criteria were employed throughout using C1 symmetry.The calculated geometries with all bond lengths and bond anglesare within the standard errors expected for geometry optimiza-tions using the B3LYP exchange correlation functionals and the6-311++G(d,p) basis set.

4.3. Methodology for the docking studies

Docking was carried out using the AutoDock (version 4.2.5.1)package.15 The receptors and ligands were initially prepared byadding hydrogen atoms, with partial charges being calculated withGasteiger’s method using the AutoDock software tools. The dockingprotocol was carried out, and the results were in good agreementwith the experimental results.16–21 The binding pocket was basedon the ligand binding site of receptor crystal structures. The ligandwas kept flexible along with some of the residues in the receptorbinding pocket based on the crystal structure. Auto Grid was usedfor generating the grid parameter files and atom-specific affinitymaps. While carrying out the docking of all of the compounds, 4 res-idues (ASP147, TYR148, LYS233, and HIS297) of lOR, which areknown to be present in the ligand binding pocket of the receptorand directly interact with b-FNA, were set as flexible residues whilethe rest of the protein was kept as rigid. The roots of the torsionwere selected individually for all of the ligands. AutoGrid 4.2 wasused to generate the grid parameter files and atom-specific affinitymaps. Grid points for the map files were generated with dimensionsof 48 � 48 � 48 (Å) with a grid spacing of 0.375 Å and centered atthe crystallographic binding site, which is conserved among allthe class A GPCR molecules. Docking simulations were carried outusing Lamarkian Genetic Algorithm with maximum number of iter-ations set to 10 and a population size of 150. Maximum number ofenergy evaluations was set to 2,500,000. Other AutoDock parame-ters were set to default values. Finally, ranked cluster analysiswas performed to sort out the docked poses.

4.4. (R)-4-(2,5-Dimethoxybenzyl)-2-(bromomethyl)-1,3-dioxo-lane 9

To a stirred solution of (R)-3-(2,5-dimethoxyphenyl) propane-1,2-diol 10 (500 mg, 2.358 mmol) and (2-bromo-1-ethoxy)ethane(1.064 ml 7.075 mmol) in 15 mL of CH2CI2 was added p-toluenesul-fonic acid (44 mg 0.235 mmol) at 0 �C and the mixture was stirredat room temperature for 4 h. The reaction was then quenched withsaturated aqueous NaHCO3 solution and extracted with CH2Cl2

(3 � 5 mL). The combined organic layer was washed with brine,dried over anhydrous Na2SO4, and concentrated under reducedpressure. The residue was purified by column chromatography(EtOAc/hexane, 2:8) to afford pure 9 (698 mg, 90%) as a brown li-quid. 1H NMR (300 MHz, CDCl3) d: 6.76 (m, 3H, ArH), 5.13 (t,J = 3.8 Hz, 1H, CH), 4.40 (quint, J = 6.7 Hz, 1H, CH), 3.94 (t,J = 6.7 Hz, 1H, CH), 3.77 (s, 3H, OCH3), 3.75 (br s, 4H, OCH3 andCH), 3.35–3.43 (m, 2H, CH), 3.00 (dd, J = 6.2 and 13.3 Hz, 1H, CH),2.86 (dd, J = 6.7 and 13.4 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3)d: 153.3, 151.6, 126.4, 117.3, 112.0, 111.0, 102.1, 76.5, 69.8, 55.7,55.6, 34.1, 32.6.

4.5. (R)- and (S)-1-(Bromomethyl)-3,4-dihydro-5,8-dimethoxy-1H-isochromen-3-yl)methanol 8a and 8b

To a stirred solution of (R)-4-(2,5-dimethoxybenzyl)-2-(bromo-methyl)-1,3-dioxolane 9 (200 mg 0.6079 mmol) in CH2Cl2 (30 mL)


under a nitrogen atmosphere, a TiCl4 solution (691.38 lL,6.329 mmol) was added dropwise in dry CH2Cl2 (4 mL) over5 min, and the mixture was stirred at the same temperature for3 h. The reaction was quenched with saturated aqueous NH4Clsolution and extracted with CH2Cl2 of (3 � 15 mL). The combinedorganic layer was washed with brine, dried with anhydrousNa2SO4, and concentrated under reduced pressure to afford a mix-ture of 8a and 8b, which was purified by column chromatography(EtOAc/hexane, 1.8:8.2) to give nonpolar trans-isomer 8b (28 mg,14%) as a white solid. ½a�23

D ¼ �23:4 (c 1, CHCl3); FTIR (KBr cm�1):788, 1062, 1084, 1128, 1257, 1481, 2929, 3265; 1H NMR(300 MHz, CDCl3) d: 6.72 (d, J = 9.1 Hz, ArH); 6.66 (d, J = 9.1 Hz,1H, ArH), 5.12 (dd, J = 10.9 and 3.2 Hz, 1H, CH), 3.91–3.98 (m, 2H,CH), 3.80 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.59–3.74 (m, 2H,CH), 2.66 (dd, J = 3.6 and 17.0 Hz, 1H, CH), 2.35–2.45 (m, 2H, CH),1.57 (s, 1H, OH), 13C NMR (75 MHz, CDCl3) d: 151.1, 149.5, 123.8,123.3, 108.9, 107.5, 71.3, 67.7, 65.7, 55.6, 55.4, 32.8, 23.9. Furtherelution (EtOAc/hexane, 1.8:8.2) gave 8a (142 mg 71%) as white so-lid. ½a�25

D ¼ þ185:4 (c 1, CHCl3); FTIR (KBr cm�1): 788, 1062, 1084,1128, 1257, 1481, 2929, 3265; 1H NMR (300 MHz, CDCl3) d:6.58–6.67 (m, 2H, ArH), 5.13 (br s, 1H, CH), 3.95 (dd, J = 8.5 and3.8 Hz, 1H, CH), 3.93 (dd, J = 6.5 and 3.0 Hz, 1H, CH), 3.80 (s, 3H,OCH3), 3.78 (s, 3H, OCH3), 3.73 (br d, J = 7.3 Hz, 1H, CH) 3.63 (t,J = 10.9 Hz, 1H, CH), 2.66 (dd, J = 17.0 and 3.6 Hz, 1H, CH), 2.40(dd, J = 17.3 and 11.4 Hz, 1H, CH), 2.34 (br s, 1H, OH); 13C NMR(75 MHz, CDCl3) d: 151.1, 149.5, 123.8, 123.3, 108.9, 107.5, 71.3,67.7, 65.7, 55.6, 55.4, 32.8, 23.9.

4.6. ((1S,3R)-1-(Bromomethyl)-5,8-dimethoxyisochroman-3-yl)methyl 4-methylbenzene-sulfonate 7a

To a stirred solution of alcohol 8a (123 mg, 0.3892 mmol) in dryCH2Cl2 (10 ml), under a nitrogen atmosphere were added Et3N(55.71 ll, 0.3971 mmol), p-toluene sulphonyl chloride (75.44 mg,0.3971 mmol), and DMAP at 0 �C, and mixture was stirred at roomtemperature for 12 h. The reaction mixture was then quenchedwith aq NH4Cl and extracted with CH2CI2 (3 � 25 ml). The com-bined organic layer was washed with brine, dried over anhydrousNa2SO4, filtered, and concentrated under reduced pressure, and theresidue was purified by column chromatography (EtOAc/hexane,0.5:9.5) to afford pure tosylate 7a, 187 mg (71.12%) as a white so-lid. FTIR (KBr cm�1): 790, 833, 977, 1084, 1130, 1180, 1255, 1356,1481, 1599, 2835, 2939; 1H NMR (300 MHz, CDCl3) d: 7.85 (d,J = 8.2 Hz, 2H, ArH), 7.36 (d, J = 8.2 Hz, 2H, ArH), 6.72 (q,J = 8.8 Hz, 1H, ArH), 6.66 (d, J = 8.8 Hz, 1H, ArH), 5.12 (br s, 1H,CH), 4.17 (m, 3H, CH), 3.88 (dd, J = 10.4 and 4.9 Hz, 1H, CH), 3.74(br d, J = 2.2 Hz, 1H, CH), 3.77 (br s, 6H, OCH3), 2.74 (dd, J = 17.6and 4.0 Hz, 1H, CH), 2.44 (s, 3H, CH3), 2.37 (dd, J = 17.2 and6.6 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3) d: 150.46, 149.72,144.75, 132.09, 129.82, 128.06, 124.78, 123.87, 108.88, 108.03,73.06, 71.87, 70.69, 55.63, 55.48, 37.04, 25.19, 21.62.

4.7. (1S,5R)-3-Aryl-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 6a–i

To a stirred solution of tosylate 7a (50 mg, 0.1036 mmol) inCH3CN (10 ml), benzyl amine 16a–i (0.1554 mmol) and K2CO3

(35.80 mg, 0.2590 mmol) were added at reflux, (reaction was mon-itored by TLC). The reaction mixture was quenched with aq NH4Cland extracted with EtOAc. The combined organic layer was washedwith brine solution, dried over anhydrous Na2SO4, filtered, andconcentrated under reduced pressure to afford a crude product,which was purified by column chromatography (EtOAc/hexane,0.2:9.8) to afford 6a–i (60–90%).




4.7.1. (+)-(1S,5R)-3-Benzyl-7,10-dimethoxy-1,2,3,4,5,6-hexahy-dro-1,5-epoxybenzo[d] azocine 6a

White solid (27.5 mg, 81%); ½a�26D ¼ þ37:5 (c 1, CHCl3); FTIR (KBr,

cm�1): 1074, 1251, 1481, 1600, 2798, 2928; 1H NMR (300 MHz,CDCl3) d: 7.06–7.08 (m, 3H, ArH), 6.8–6.9 (m, 2H, ArH), 6.35 (d,J = 8.8 Hz, 1H, ArH), 6.55 (d, J = 8.9 Hz, 1H, ArH), 5.01 (s, 1H, CH),4.23–4.26 (m, 1H, CH), 3.75 (s, 3H, OCH3), 3.61 (s, 3H, OCH3),3.34 (ABq, J = 13.7 Hz, 2H, CH2), 3.01 (dd, J = 8.0 and 17.7 Hz, 1H,CH), 2.70 (br d J = 11.3 Hz, 1H, CH), 2.62 (br d, J = 11.3 Hz, 1H,CH), 2.54 (br d, J = 4.8 Hz, 1H, CH), 2.49 (br d, J = 4.3 Hz, 1H, CH),2.42 (dd, J = 11.0 and 3.3 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3)d: 150.5, 148.6, 138.4, 128.2, 127.8, 127.9, 126.6, 125.3, 107.8,106.6, 67.6, 66.3, 62.1, 59.1, 56.1, 55.7, 55.5, 27.1; LC-MS (ESIM+1): 326.45.

4.7.2. (+)-(1S,5R)-3-(3,4-dichlorobenzyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d] azocine 6b

White solid (31.1 mg, 76%); ½a�22:3D ¼ þ29:4 (c 1, CHCl3); FTIR

(KBr, cm�1): 1075, 1254, 1473, 2891, 2944, 3004; 1H NMR(300 MHz, CDCl3) d: 7.19 (d, J = 8.2 Hz, 1H, ArH), 6.92 (d,J = 1.5 Hz, 1H, ArH), 6.70–6.77 (m, 2H, ArH), 6.63 (d, J = 8.8 Hz,1H, ArH), 5.07 (s, 1H, CH), 4.32 (d, J = 7.9 Hz, 1H, CH), 3.82 (s, 3H,OCH3), 3.68 (s, 3H, OCH3), 3.33 (ABq, J = 14.3 Hz, 2H, CH), 3.08(dd, J = 8 and 17.9 Hz, 1H, CH), 2.56–2.70 (m, 4H, CH), 2.48 (dd,J = 3.2 and 11.1 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3) d: 150.4,148.4, 139.1, 132.1, 130.2, 129.9, 129.8, 127.2, 127.1, 125.1,107.8, 106.8, 67.5, 66.3, 60.4, 59.2, 55.7, 55.6, 55.5, 27.1; LC–MS(ESI M+1): 395.15.

4.7.3. (+)-(1S,5R)-3-(2-Chlorobenzyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 6c

White solid (27.05 mg, 71%); ½a�26:4D ¼ þ26:5 (c 0.5, CHCl3); FTIR

(KBr, cm�1): 1078, 1256, 1483, 2802, 3004; 1H NMR (300 MHz,CDCl3) d: 7.22 (d, J = 7.9, 1H, ArH), 7.03 (t, J = 7.6 Hz, 1H, ArH),6.93 (t, J = 7.1 Hz, 1H, ArH), 6.76 (d, J = 6.6 Hz, 1H, ArH), 6.69 (d,J = 8.7 Hz, 1H, ArH), 6.62 (d, J = 8.8 Hz, 1H, ArH), 5.08 (s, 1H, CH),4.34 (br d, J = 7.5 Hz, 1H, CH), 3.8 (s, 3H, OCH3), 3.67 (s, 3H,OCH3), 3.49 (ABq, J = 15.4 Hz, 2H, CH), 3.09 (dd, J = 7.9 and17.6 Hz, 1H, CH), 2.71 (m, 4H, CH), 2.55 (dd, J = 12.9 and 5.4 Hz1H, CH); 13C NMR (75 MHz, CDCl3) d: 150.50, 148.6, 146.6, 136.0,133.5, 129.5, 128.9, 127.4, 126.2, 125.4, 107.8, 106.6, 67.6, 66.3,59.4, 58.3, 56.0, 55.6, 55.5, 27.1; LC–MS (ESI M+1): 360.10.

4.7.4. (+)-(1S,5R)-3-(4-Fluorobenzyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxy-benzo[d]azocine 6d

White solid (31 mg, 85%); ½a�26D ¼ þ22:8 (c 1, CHCl3); FTIR (KBr,

cm�1): 1150, 1257, 1494, 1603, 2932; 1H NMR (300 MHz, CDCl3) d:6.80–6.92 (m, 4H, ArH), 6.71 (d, J = 8.8 Hz, 1H, ArH), 6.62 (d,J = 9.1 Hz, 1H, ArH), 5.08 (s, 1H, CH), 4.33 (br d, J = 5.9 Hz, 1H,CH), 3.83 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.36 (s, 2H, CH), 3.09(dd, J = 8.2 and 18.1 Hz, 1H, CH), 2.45–2.75 (m, 5H, CH); 13C NMR(75 MHz, CDCl3) d: 150.5, 148.6, 134.1, 129.6, 129.5, 127.5, 125.3,114.8, 114.5, 107.7, 106.6, 67.5, 66.3, 61.2, 59.1, 56.0, 55.6, 55.5,29.6, 27.1; LC–MS (ESI M+1): 344.10.

4.7.5. (+)-(1S,5R)-7,10-Dimethoxy-3-(4-methoxybenzyl)-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 6e

White solid (34 mg, 90%); ½a�23D ¼ þ17:0 (c 1, CHCl3); FTIR (KBr)

cm�1: 1074, 1251, 1481, 1600, 2798, 2928; 1H NMR (300 MHz,CDCl3) d: 6.89 (d, J = 8.6 Hz, 2H, ArH), 6.68–6.72 (m, 3H, ArH),6.61 (d, J = 8.6 Hz, 1H, ArH), 5.08 (s, 1H, CH), 4.31 (dd, J = 1.9 and7.6 Hz, 1H, CH), 3.82 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.69 (s,3H, OCH3), 3.35 (q, J = 13.4 Hz, 2H, CH), 3.07 (dd, J = 8.1 and18.1 Hz, 1H, CH), 2.76 (d, J = 11 Hz, 1H, CH), 2.67 (d, J = 11 Hz, 1H,CH), 2.46–2.59 (m, 3H, CH); 13C NMR (75 MHz, CDCl3) d: 158.4,150.5, 148.7, 130.3, 129.4, 127.6, 125.4, 113.4, 107.8, 106.6, 67.6,


66.3, 61.5, 58.9, 56.1, 55.7, 55.5, 55.2, 29.7, 27.1; LC–MS (ESIM+1): 356.10.

4.7.6. (+)-(1S,5R)-7,10-Dimethoxy-3-(pyridin-4-ylmethyl)-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 9f

White solid (26.6 mg, 77%); ½a�26:3D ¼ þ32:2 (c 1, CHCl3); FTIR

(KBr, cm�1): 1072, 1256, 1485, 1602, 2799, 2927; 1H NMR(300 MHz, CDCl3) d: 8.28 (d, J = 4.6 Hz, 1H, ArH), 6.76 (d,J = 5.6 Hz, 1H, ArH), 6.66 (d, J = 8.8 Hz, 1H, ArH), 6.63 (d,J = 9.1 Hz, 1H, ArH), 5.02 (br d, J = 1.2 Hz, 1H, CH), 4.28 (dd, J = 2.4and 5.9 Hz, 1H, CH), 3.77 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 3.33(ABq, J = 14.5 Hz, 2H, CH2), 3.04 (dd, J = 7.9 and 17.8 Hz, 1H, CH),2.52–2.65 (m, 4H, CH), 2.43 (dd, J = 3.0 and 10.9 Hz 1H, CH); 13CNMR (75 MHz, CDCl3) d: 150.4, 149.3, 148.5, 148.1, 127.1, 125.1,123.1, 107.7, 106.6, 104.9, 67.4, 66.2, 60.7, 59.3, 55.8, 55.6, 55.5,27.1; LC–MS (ESI M+1): 327.10.

4.7.7. (+)-(1S,5R)-3-(2-(1H-Indol-3-yl)ethyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 6g

White solid (23.1 mg, 60%); ½a�24D ¼ þ15:8 (c 1.35, CHCl3); FTIR

(KBr, cm�1): 1078, 1258, 1485, 1605, 2851, 2923, 3215; 1H NMR(300 MHz, CDCl3) d: 7.8 (s, 1H, NH), 7.47 (d, J = 7.9 Hz, 1H, ArH),7.25 (d, J = 8.2 Hz, 1H, ArH), 7.01–7.14 (m, 2H, ArH), 6.56–6.68(m, 3H, ArH), 5.1 (s, 1H), 4.37 (br d, J = 5.6 Hz, 1H, CH), 3.77 (s,3H, OCH3), 3.72 (s, 3H, OCH3), 3.1 (dd, J = 7.9 and 17.9 Hz, 1H,CH), 2.91 (dd, J = 11.1 and 16.7 Hz, 2H, CH), 2.75 (t, 6.8 Hz, 2H,CH), 2.53–2.64 (m, 5H, CH); 13C NMR (75 MHz, CDCl3) d: 150.5,148.6, 135.8, 127.6, 127.5, 125.2, 122.0, 121.5, 118.9, 118.6,114.1, 110.8, 107.5, 106.7, 67.4, 66.1, 59.2, 58.6, 56.3, 55.5, 27.1,21.5; LC–MS (ESI M+1): 379.15.

4.7.8. (+)-(1S,5R)-3-(3,4-Dimethoxyphenethyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 6h

White solid (27.5 mg, 65%); ½a�23D ¼ þ3:8 (c 1, CHCl3); FTIR (KBr)

cm�1: 1078, 1258, 1484, 1605, 2852, 2924; 1H NMR (300 MHz,CDCl3) d: 6.61–6.68 (m, 4H, ArH), 6.53 (d, J = 7.9 Hz, 1H, ArH),5.10 (s, 1H, CH), 4.36 (m, 1H, CH), 3.82 (s, 3H, OCH3), 3.80 (s, 3H,OCH3), 3.76 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.10 (dd, J = 8.2 and17.9 Hz, 1H, CH), 2.84 (dd, J = 10.9 and 19.1 Hz, 2H, CH), 2.41–2.59 (m, 7H, CH); 13C NMR (75 MHz, CDCl3) d: 150.4, 148.6,148.5, 146.9, 133.2, 127.6, 125.0, 120.5, 111.8, 110.9, 107.4,106.5, 67.4, 66.0, 60.2, 59.4, 56.5, 55.7, 55.6, 55.5, 55.3, 32.1,27.0; LC–MS (ESI M+1): 400.19.

4.7.9. (+)-(1S,5R)-7,10-Dimethoxy-3-((S)-1-phenylethyl)-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocine 6i

White solid (32 mg, 88%); ½a�26:7D ¼ þ27:8 (c 1, CHCl3); FTIR (KBr)

cm�1: 1149, 1256, 1484, 1603, 2794, 2928; 1H NMR (300 MHz,CDCl3) d: 7.02 (t, J = 2.9 Hz, 3H, ArH), 6.76 (m, 2H, ArH), 6.64 (d,J = 8.8 Hz, 1H, ArH), 6.51 (d, J = 9.1 Hz, 1H, ArH), 4.92 (s, 1H, CH),4.29 (m, 1H, CH), 3.77 (s, 3H, OCH3), 3.49 (s, 3H, OCH3), 3.2 (q,J = 6.7 Hz, 1H, CH), 3.03 (dd, J = 8 and 17.9 Hz, 1H, CH), 2.81 (d,J = 10.8 Hz, 1H, CH), 2.51–2.58 (m, 3H, CH), 2.32 (dd, J = 2.9 and11.1 Hz, 1H, CH), 1.09 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (75 MHz,CDCl3) d: 150.4, 148.7, 145.5, 144.8, 127.8, 127.1, 126.3, 125.4,107.6, 106.6, 67.8, 66.6, 63.4, 55.6, 55.4, 54.5, 31.9, 29.6, 27.3,19.5, 14.1; GC–MS: m/z 339 (M+).

Acknowledgments

We are thankful to the Department of Science and Technology(DST) (Project No. SR/FT/CS-015/2010), UGC, New Delhi, for finan-cial support. V.P.P. is thankful to the Council of Scientific andIndustrial Research (CSIR), New Delhi, for a junior researchfellowship.




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enantioselective synthesis of benzomorphan analogues by intramolecular oxa-pictet–spengler...

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