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. Author manuscript; available in PMC: 2009 Jun 30.
Published in final edited form as: Tetrahedron. 2008 Jun 30;64(27):6434–6439. doi: 10.1016/j.tet.2008.04.073

Diastereoselective Synthesis of a Highly Substituted cis-Decahydroquinoline via a Knoevenagel Condensation

Junfeng Huang 1, Stephen C Bergmeier 1,*
PMCID: PMC2597876  NIHMSID: NIHMS54068  PMID: 19572008

Abstract

A diastereoselective approach to 3,7,8-trisubstituted cis-decahydroquinolines is described. This ring system forms the core of rings B and E of the norditerpenoid alkaloid methyllycaconitine. This approach starts with a known disubsituted cyclohexene. The remaining carbons are attached via a Knoevenagel condensation followed by an intramolecular lactam formation. The stereochemistry of the substituents is controlled by the cis-substitution of the starting cyclohexene ring.

1. Introduction

Methyllycaconitine (MLA), a norditerpenoid alkaloid isolated from plants of the genera Aconitum and Delphinium,1,2 is the most potent nonpeptide antagonist at the α7 nicotinic acetylcholine receptors (nAChRs).3,4 The interesting structure and biological activities of methyllycaconitine have stimulated numerous synthetic efforts in the past decades.5–26 In our efforts to identify structure activity relationships of methyllycaconitine, we have synthesized numerous simple analogues of methyllycaconitine which contain only the E ring and the succinimidoylanthranilate ester.27–30 All of the simple E ring analogues have been shown to be noncompetitive antagonists to the α3β4* nAChR, with no affinity to the agonist binding sites of either α7, α4β2, or α3β4* nAChRs.31 We hoped that introducing a more rigid conformation to our previous E-ring analogues might provide a selective and competitive ligand to the α7 nAChR. A simple removal of the A, C, D and F rings of MLA provides a BE ring analog. This analog should thus be available from the cis-decahydroquinoline core structure (Figure 1).

Figure 1.

Figure 1

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Methyllycaconitine and necessary decahydroquinoline core structure

In addition, the cis-decahydroquinoline ring system is an essential component of many interesting and pharmacologically useful compounds. These include amphibian alkaloids such as cis-195A, isolated from the skin extract of the Panamanian frog Dendrobates pumilio in 1969.32 Since that time, over 50 cis-decahydroquinoline alkaloids have been isolated from amphibian sources.33 Moreover, this cis-fused heterocyclic ring system frequently occurs as a subunit of many polycyclic natural alkaloids, such as huperzine B34 and cylindricine A–K.35,36

Much of the methodology for the synthesis of the cis-decahydroquinoline ring system has focused on the synthesis of the 2,5-disubstituted ring system (e.g. cis-195A, Lepadins).37–39 These methods are not well suited for the synthesis of the desired 3,7,8-trisubstituted ring system 1. Many of these methods are focused on carbon substitution at the 2- and 5-positions as are seen in natural products such as cis-195A, and Lepadin A. For the synthesis of our required bicyclic amine 1, we need a carbon substituent at position 3 and the ability to introduce hydroxyl groups at positions 7 and 8. Perhaps just as important is the ability to control the relative stereochemistry at position 3. While some of the known methods for the synthesis of the cis-decahydroquinoline ring system might be adapted by omitting a carbon chain or two, they lack a method to control the newly instituted stereocenter a position 3. Herein we wish to describe a diastereoselective route to this cis-decahydroquinoline ring core, which includes five stereocenters. The cis-decahydroquinoline system 1 can be obtained via the reduction of the lactam-ester 2. This bicycle can be formed from an intramolecular cyclization reaction of diester-amine 3. The diester compound 3 can be obtained from aldehyde 4 via a Knoevenagel condensation. The starting aldehyde 4 is known40 and can be readily prepared via a Diels-Alder cycloaddition.41–45

2. Results and discussion

As outlined in Scheme 2, our synthesis of aldehyde 4 follows the previously published method of Overman and co-workers. We have made slight changes in the procedure that have improved the yield of diene 7.45–47 Reaction of acid 6 with diphenylphosphoryl azide48 provides the intermediate acylazide. In the original procedure46,47 the acylazide was prepared in situ by using ethyl chloroformate and sodium azide. Our modification avoids any formation of ethanol, a good nucleophile that can react with the acylazide in the work-up process and lower the overall yield. The acylazide was sufficiently stable at room temperature that it was quickly chromatographed to remove the very polar by-product formed in the reaction. Curtius rearrangement of the acylazide in the presence of benzyl alcohol provides diene 7 in 70% yield from acid 6.

Scheme 2.

Scheme 2

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a) acrolein, pyridine, rt, 3 h, 50% (b) Et3N, (PhO)2P(O)N3, CH2Cl2, rt, 1 h (c) PhCH2OH, toluene, 0.5 h, 110 °C, 70% over 2 steps (d) acrolein, toluene, 110 °C, 90 min 80%

The Diels-Alder reaction of 7 with acrolein was carried out in a sealed tube, and provided an 80 % yield of predominantly cis compound 4 (cis:trans = 10:1). The cis-compound can be further purified via recrystallization from 20% EtOAc-hexanes solution.

The synthetic approach was designed to use the Knoevenagel condensation for the installation of the remaining carbons of the decahydroquinoline ring system. The Knoevenagel condensation is a well known method for the synthesis of alkylidine malonates.49,50 As shown in Table 1, the use of standard reaction conditions provides the expected product and its diastereomer in a 1:1 ratio. While the yield of the product was excellent, the large amount of epimerization was unacceptable for preparation of our target compounds. Adding 4 Å molecular sieves to the reaction and decreasing the reaction temperature to 0 °C reduces the amount of trans-product 9, giving a cis:trans ratio of 4:1. In considering the reaction mechanism, we hypothesized that the piperidine first reacted with aldehyde 4 to form an iminium salt.50 This iminium salt can subsequently tautomerize to form an enamine,51 and then tautomerization again provides the more stable trans-isomer. To avoid this epimerization, we changed the secondary amine catalyst to 3° amine such Et3N or pyridine to preclude iminium ion formation (and the subsequent epimerization). We believe that the change in base from piperidine to Et3N may shift the mechanism from the Knoevenagel mechanism (iminium formation) to the Hann-Lapworth mechanism (β-hydroxy ester formation).50 This shift in mechanistic pathway should eliminate the possibility for enamine formation and consequently epimerization. We were pleased to see that reaction using either pyridine or Et3N provided solely the cis-diastereomer. Decreasing the amount of Et3N and adding molecular sieves decreases the reaction time while retaining the good yields and excellent diastereoselectivity. Decreasing the amount of Et3N to 10 mol% did provide similar levels of diastereoselectivity, however, the reaction took over 24 hours to provide an 80% yield. Compared with the only 2 hours required with 20 mol% of Et3N, this seemed to be as low as was practical for this transformation.

Table 1.

Comparison of Knoevenagel reaction conditions

graphic file with name nihms54068t1.jpg
Entry Conditions Product ratio (8:9)a
(% Yield)b
1 10 mol% piperidine, 10 mol% HOAc, rt, 8 h 1:1, (95)
2 10 mol% piperidine, 10 mol% HOAc, 4Å MS, 0 °C, 4 h 4:1 (90)
3 Pyridine (solvent), 100 mol% HOAc, rt, 20 h 1:0 (80)
4 200 mol% Et3N, 200 mol%, HOAc, rt, 8 h 1:0 (70)
5 20 mol% Et3N, 20 mol% HOAc, 4Å MS, rt, 4 h 1:0 (80)
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a

Determined by 1H NMR.

b

isolated yield of an inseperable mixture of 8 and 9.

The next step was to carry out a selective dihydroxylation of the cyclohexene double bond. The use of catalytic OsO4/NMO provided an excellent yield of diol 10.52 Our expectation was that diol 10 would be the preferred product with osmylation occurring from the least hindered face of the molecule. An examination of the coupling constants between Hb and Hc showed the expected large diaxial coupling constant (Scheme 3 inset). The corresponding all cis product would not have any diaxial couplings. The relatively polar diol was converted to the acetonide in 85% yield by treatment with 2,2-dimethoxypropane. The relative stereochemistry of 10 was further confirmed by single crystal x-ray of acetonide 11 as shown in Figure 2.53.

Scheme 3.

Scheme 3

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(a) 5 mol% OsO4, NMO, Acetone-H2O (3:1), 8 h, rt, 85% (b) (CH3)2C(OCH3)2, 2 mol% p TSA, 6 h, rt, 95%

Figure 2.

Figure 2

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Perspective view of the molecular structure of 11 with the atom labeling scheme. The thermal ellipsoids are scaled to enclose 30% probability.

Our plan for the conversion of 11 to 2 required the selective removal of the carbobenzyloxy group followed by an intramolecular cyclization to lactam 2. Reduction of the double bond at this stage would generate a 1,3-dicarbonyl compound (12) which would likely readily epimerize. As shown in Table 2, the use of standard deprotection conditions provided over-reduced compound 12 as the sole product in excellent yield. The use of different hydrogen sources (Table 1, entries 2 and 3) such as cyclohexadiene or ammonium formate also provided only the over-reduced product 12. Interestingly, decreasing the amount of catalyst and reducing the reaction time (entry 4) provided 13 as the major product. Sakaitani and Ohfune described the conversion of a Cbz group into a triethylsilyl carbamate (NH-CO2SiEt3) which is converted to the corresponding carbamic acid in situ and decarboxylated to give the free amine.54 Applying these conditions to our substrate provided no product at all (entry 5). Using the Coleman modification of a stoichiometric amount of Pd salt to significantly increase the reaction rate,55,56 (entry 6) provided some of the desired product. We thus increased the loading of Pd(OAc)2 to 300 mol% and found the deprotection and cyclization reaction occurred in only 30 minutes (entry 7). In addition to the changes in catalyst loading we also changed the solvent to the more polar EtOAc:EtOH mixture.57 We were then able to decrease the Pd(OAc)2 to only 30 mol% which provided the desired product in acceptable yield without using a large excess of the palladium salt (entry 8).

Table 2.

Conditions for selective removal of a Cbz group from 11

graphic file with name nihms54068t2.jpg
Entry Conditions Product Yield (%)
1 10 mol % of 10% Pd/C, H2, MeOH, 8 h 12 90
2 10 mol% of 10% Pd/C, 1,4-cyclohexadiene, solvent, 8 h 12 80
3 10 mol% of 10% Pd/C, HCO2NH4, solvent, 8 h 12 70
4 3 mol% of 10% Pd/C, H2, MeOH, solvent, 2 h 13 50 (+ 20% of 11)a
5 400 mol% Et3SiH, 10 mol% Pd(OAc)2, 100 mol% Et3N, CH2Cl2, rt, 16 h NR
6 120 mol% Et3SiH, 100 mol% Pd(OAc)2, 120 mol% Et3N, EtOAc, rt, 6 h 2 10
7 120 mol% Et3SiH, 300 mol% Pd(OAc)2, 120 mol% Et3N, EtOAc:EtOH (1:1), rt, 0.5 h 2 50
8 120 mol% Et3SiH, 30 mol% Pd(OAc)2, 120 mol% Et3N, EtOAc:EtOH (1:1), rt, 4 h 2 50 (+ 10% of 11)
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a

Isolated yield of an inseperable mixture of 13 and 11, ratio of 13 to 11 determined by 1H NMR

With lactam 2 in hand we needed to reduce either the lactam or ester without reducing the double bond. Upon reduction of one of these carbonyl moieties, the double bond can be stereoselectively reduced and the final stereocenter introduced into the molecule. The reaction of 2 with a slight excess of DIBAL cleanly provided the alcohol with no concomitant 1,4 reduction of the double bond. The double bond was then stereoselectively reduced with 10% Pd/C and H2 to provide 14 as a single diastereomer. Compound 14 was unfortunately too polar to readily purify and we thus converted it directly to the target compound 1. The lactam of 14 was reduced with LiAlH4 to the amine and then alkylated with ethyl iodide to provide 1 in 45% overall yield from 2. With compound 1 in hand we were now able to confirm the relative stereochemistry that was set in the hydrogenation of 2. A NOESY experiment with compound 1 clearly showed NOE crosspeaks between H-3 and H-9 as well as between H-9 and H-10 (Scheme 4, inset). This confirms the hydrogenation occurring from the less hindered face of the bicycle 2 as one would predict.

Scheme 4.

Scheme 4

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(a) DIBAL-H, THF, 0 °C, 4 h (b) 10 mol% of 10% Pd/C, H2 (1 atm), MeOH, rt, 4 h (c) LiAlH4, THF, rt, 24 h (d) Iodoethane, K2CO3, acetone, rt, 16 h, 45% over four steps. Inset: Observed NOE crosspeaks from NOESY spectra of 1.

In summary, we have developed an efficient and highly diasteroselective approach to the cis-fused 3,7,8-trisubstituted decahydroquinoline 1. The epimerization in the Knoevenagel condensation was prevented by using a tertiary amine catalyst. The removal of the Cbz group and subsequent intramolecular cyclization was accomplished using catalytic Pd(OAc)2 and triethylsilane. This methodology provides synthetic flexibility and opens the door for the controlled construction of more complex alkaloids with cis-decahydroquinoline subunits. The conversion of 1 to MLA analogues and subsequent pharmacological assays are underway and will be reported in due course.

3. Experimental

General

All reagents used were purchased from commercial sources or prepared according to standard literature methods using references given in the text and purified as necessary prior to use by standard literature procedures. THF and CH2Cl2 were dried using a Solv-Tek solvent purification system. Dry DMF was distilled from calcium hydride and degassed for 10 min prior to use. Dry toluene was distilled from calcium hydride prior to use. Column chromatography was performed using ICN silica gel 60A. Proton (1H) and carbon (13C) magnetic resonance spectra (NMR) were recorded on a Bruker 300 MHz spectrometer, and chemical shift values are expressed in parts per million (δ) relative to tetramethylsilane (TMS, 0 ppm) as an internal reference. All High Resolution Mass Spectra (HRMS) were acquired using positive electrospray ionization (ESI) at the Mass Spectrometry Center of the University of Tennessee. The relative stereochemistry of all compounds are noted using the R* or S* notation.58

Benzyl trans-1,3-Butadiene-l-carbamate (7)

To a solution of trans-2,4-pentadienoic acid 6 (2.45 g, 25 mmol) in Et2O (50 mL) at 0 °C was added Et3N (3.8 mL, 27.5 mmol) followed by diphenyl phosphoryl azide (6.0 mL, 27.5 mmol). The reaction was warmed to rt and stirred for 30 min. The mixture was cooled to 0 °C, and saturated aqueous NaHCO3 and Et2O were added. The aqueous layer was separated and extracted with Et2O, and the combined organic layers were dried over MgSO4, filtered and concentrated. Chromatography (15% EtOAc in hexane) of the residue with a short column to remove the polar impurity provided 3.0 g of the acylazide as a brown oil. The acylazide was diluted with dry toluene (10 mL), and was then added over 30 min to a vigorously stirred solution of benzyl alcohol (2.4 mL, 23 mmol) and 2,6-di-tert-butyl-4-methylphenol (20 mg) in dry toluene (30 mL) while a rapid reflux was maintained. Reflux was continued for an additional 30 min, then the reaction mixture was cooled to rt and concentrated to afford a brown semisolid residue which was purified immediately by chromatography (10% EtOAc in hexanes) to give 4 g (79%) of 7 as a white solid, mp 70–73 °C. Rf 0.7 (20% EtOAc in hexanes) which matched the reported analytical data.46

Carbamic acid, [(1R*,6S*)-6-formyl-2-cyclohexen-1-yl]-, phenylmethyl ester (4)

A solution of 7 (3 g, 14.8 mmol), acrolein (1.1 mL, 14.8 mmol), and 2,6-di-tert-butyl-4-methylphenol (10 mg) in toluene (10 mL) was placed in an Ace glassware resealable sealed tube (Cat. # 8648-86). The tube was degassed with 3 freeze/thaw cycles and then filled with Ar. The tube was heated to 110 °C for 90 min, then cooled, concentrated, and chromatographed (15% EtOAc in hexanes) to give 2.9 g (80% considering recovered 7) of 4 as a white solid, mp 80–82 °C. Rf 0.4 (20% EtOAc in hexanes); 1H NMR (CDCl3, 300 MHz) δ 9.80 (s, 1H), 7.35 (m, 5H), 5.90 (m, 1H), 5.72 (d, J = 9.8 Hz, 1H), 5.12 (m, 3H), 4.75 (bs, 1H), 2.80 (bs, 1H), 1.92–2.15 (m, 3H), 1.58–1.80 (m, 1H); 13C NMR (CDCl3, 70 MHz) δ 202.7, 136.2, 135.8, 130.7, 128.6, 128.2, 128.1, 126.3, 67.0, 51.0, 45.6, 23.4, 18.6; HRMS calcd for C15H17NO3Na+ 282.1101, found 282.1105 (1.4 ppm).

Benzyl (1R*,6R*)-6-(2,2-di(methoxycarbonyl)vinyl)cyclohex-2-enylcarbamate (8)

Et3N (0.43 mL, 3.1 mmol) and HOAc (0.18 mL, 3.1 mmol) were simultaneously added by syringe to a vigorously stirred EtOH (50 mL) solution of methyl malonate (1.94 mL, 17.0 mmol), aldehyde 4 (4.0 g, 15.4 mmol), and 4 Å molecular sieves (5.0 g). After stirring for 6 h at room temperature, the solvent was removed by rotary evaporator at room temperature. The resulting slurry was diluted with Et2O and filtered. The filtrate was washed with 1 N HCl, saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, concentrated, and chromatographed (20% EtOAc in hexanes) to provide 4.6 g (80%) of 8 as a white solid, mp 92–94 °C; Rf 0.3 (20% EtOAc in hexanes); 1H NMR (CDCl3, 300 MHz) δ 7.36 (m, 5H), 7.04 (d, J = 10.8, 1H), 5.89 (m, 1H), 5.62 (d, J = 9.6 Hz, 1 H), 5.12 (m, 2H), 4.75 (d, J = 8.9 Hz, 1H), 4.46 (bs, 1H), 3.83(s, 3H), 3.79 (s, 3H), 3.05 (bs, 1H), 2.12 (bs, 2H), 1.60–1.92 (m, 2H); 13C NMR (CDCl3, 70 MHz) δ 165.7, 164.1, 155.8, 148.5, 136.4, 130.2, 129.6, 128.5, 128.1, 127.9, 126.4, 66.9, 52.4, 48.7, 38.1, 24.8, 22.6; HRMS calcd for C20H23NO3Na+ 396.1418, found 396.1408 (2.3 ppm).

Benzyl (1S*,2R*,3S*,4R*)-4-(2,2-di(methoxycarbonyl)vinyl)cyclohexyl-1,2-diol-3-enylcarbamate (10)

To a 0 °C solution of 8 (5.7 g, 15.2 mmol) and NMO (3.6 g, 30.7 mmol) in acetone-water (3:1, 100 mL). was added OsO4 (7.0 mL of a 2.5% solution in H2O, 0.7 mmol). The reaction was warmed to rt and stirred for 8 h. A solution of Na2S2O4 (1 g) in H2O (10 mL) was added to the reaction and stirred for 20 min. The reaction was extracted with EtOAc (3 × 50 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and chromatographed (50% EtOAc in hexanes) to provide 5.3 g (85%) of 10 as a colorless oil, Rf 0.3 (50% EtOAc in hexanes), 1H NMR (CDCl3, 500 MHz) δ 7.35 (m, 5H), 7.05 (d, J = 11.5 Hz, 1H), 5.30 (d, J = 9.6 Hz, 1H), 5.11 (m, 2H), 4.10 (ddd, J = 12.2, 9.5 Hz, 3.5, 1H), 4.04 (bs, 1H), 3.79 (s, 6H), 3.72 (dd, J = 12.2, 4.5 Hz, 1H), 3.10 (m, 1H), 2.05 (bs, 1H), 1.84 (bs, 1H), 1.75 (t, J = 12.5 Hz, 1H), 1.46 (dd, J = 14.0, 4.5 Hz, 1H); 13C NMR (CDCl3, 70 MHz) δ 165.7, 163.8, 157.7, 145.9, 136.1, 130.8, 128.6, 128.3, 71.7, 68.8, 67.3, 53.5, 52.7, 38.5, 25.8, 23.5; HRMS calcd for C20H23NO8Na+ 430.1472, found 430.1476 (1.0 ppm).

Benzyl (1S*,2R*,3S*,4R*)-4-(2,2-di(methoxycarbonyl)vinyl)cyclohexyl-1,2-diol-1,2-O-isopropylidine-3-enylcarbamate (11)

The diol 10 (5.0 g, 12.3 mmol) was dissolved in a 2,2-dimethoxypropane:acetone (2:1) solution (60 mL), then TsOH•H2O (25 mg, 0.13 mmol) and MgSO4 (5.0 g) were added. The reaction was stirred for 6 hr at rt, filtered, concentrated, and chromatographed (30% EtOAc in hexane) to provide 5.2 g of 11 (95%) as a white solid, mp 143–146 °C; Rf 0.7 (50% EtOAc in hexanes). 1H NMR (CDCl3, 300 MHz) δ 7.35 (m, 5H), 6.94 (d, J = 11.5 Hz, 1H), 5.15 (m, 2H), 4.98 (d, J = 7.9 Hz, 1H), 4.33 (bs, 1H), 3.95 (m, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 3.15 (dd, J = 11.1, 3.4 Hz, 1H), 2.05 (m, 3H), 1.54 (m, 4H), 1.36 (s, 3H); 13C NMR (CDCl3, 70 MHz) δ 166.0, 164.5, 156.7, 145.8, 136.9, 131.8, 129.1, 128.9, 128.8, 109.5, 76.2, 73.9, 67.6, 54.4, 53.4, 53.3, 39.0, 28.8, 26.8, 23.1, 21.7; HRMS calcd for C23H29NO8Na+ 470.1785, found 470.1788 (1.0 ppm).

(4aR*,7S*,8R*,8aR*)-methyl 1,2,4a,5,6,7,8,8a-octahydro-2-oxoquinoline-7,8-diol-7,8-O-isopropylidine-3-carboxylate (2)

Pd(OAc)2 (68 mg, 0.3 mmol) was added to a solution of 11 (450 mg, 1.0 mmol) in dry EtOAc (6 mL). Dry EtOH (6 mL) was then added and the reaction stirred for 5 min, and then freshly distilled triethylsilane (0.19 mL, 1.2 mmol) was added, immediately followed by the addition of dry Et3N (0.17 mL, 1.2 mmol). The reaction was stirred for an additional 30 min (until TLC indicated the starting material wsa consumed) and the reaction was diluted with CH2Cl2, filtered through a Celite pad, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, concentrated, and chromatographed (5% MeOH in CH2Cl2) to provide 140 mg (50%) of 2 as a brown oil, Rf 0.2 (50% EtOAc in hexanes). 1H NMR (CDCl3, 300 MHz) δ 6.90 (d, J = 11.5 Hz, 1H), 6.45 (d, J = 10.5 Hz, 1H), 4.09 (m, 1H), 3.85 (s, 3H), 3.78 (m, 2H), 3.50 (m, 1H), 1.98 (m, 3H), 1.36 (m, 4H), 1,20 (m, 3H); 13C NMR (CDCl3, 70 MHz) δ 166.7, 160.5, 143.8, 131.0, 109.5, 75.5, 73.6, 54.4, 52.5, 38.4, 28.2, 26.2, 22.4, 21.1; HRMS (ESI) C14H19NO5 m/z calculated M + H+ 282.1341, measured M + H+ 282.1346 (1.8 ppm).

((3S*,4aR*,7S*,8R*,8aR*)-1-ethyl-decahydroquinolin-7,8-diol-7,8-O-isopropylidine-3-yl)methanol (1)

Compound 2 (310 mg, 1.1 mmol) was dissolved in THF (20 mL) and cooled to 0 °C. DIBAL-H (1.3 mL of a 1.0 M solution in hexane, 1.3 mmol) was added and the reaction stirred for 4 hr. The reaction was quenched with MeOH until no additional gas (H2) release was observed, then NaF (50 mg, 1.19 mmol) was added. The mixture was stirred for 2 h at rt, filtered, concentrated to provide the crude allylic alcohol. The crude alcohol was dissolved in MeOH (20 mL), then 10% Pd/C (106 mg) was added. The reaction was then stirred under an H2 atmosphere (balloon) for 4 hr. The reaction was filtered through a Celite pad, and concentrated to give 216 mg (77%) of crude 14, which was used directly in next step. Crude compound 14 (216 mg, 0.85 mmol) was dissolved in THF (10 mL) and cooled to 0 °C, followed by the addition of LiAlH4 (100 mg, 2.6 mmol). The reaction was warmed to rt and stirred for 24 h. The reaction was then diluted with Et2O. To this mixture was sequentially added H2O (0.11 mL), 15 % aqueous NaOH (0.11 mL), and H2O (2.6 mL). The reaction was stirred for an additional 30 min at rt, filtered, and concentrated to give 144 mg (0.6 mmol, 70% yield) crude 15 as a colorless oil. Amine 15 was dissolved in acetone (8 mL), then iodoethane (0.06 mL, 0.72 mmol) and K2CO3 (332 mg, 2.4 mmol) were added and the reaction was stirred for 16 h at room temperature. The reaction was then filtered, concentrated, and chromatographed (5% MeOH in CH2Cl2) to provide 133 mg (81%, 45% from compound 2) of 1 as a yellow oil, Rf 0.35 (10% MeOH in CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 4.21 (m, 2H), 3.38 (m, 2H), 2.82 (m, 3H), 2.53 (m, 1H), 2.17 (m, 1H), 1.80 (m, 6H), 1.44 (m, 4H), 1.25 (m, 5H), 1.02 (t, J = 14.2 Hz, 3H); 13C NMR (CDCl3, 70 MHz) δ 107.4, 74.2, 71.7, 68.0, 60.1, 49.2, 48.8, 38.1, 33.6, 28.3, 28.2, 28.1, 24.9, 13.4; HRMS (ESI) C15H27NO3 m/z calculated M + H+ 270.2069, measured M + H+ 270.2067 (0.7 ppm).

Scheme 1.

Scheme 1

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Retrosynthesis of the cis-decahydroquinoline core structure 1.

Acknowledgments

This work was supported by grant DA13939 (SCB) from the National Institutes on Drug Abuse at the National Institutes of Health. We would also like to acknowledge support of the NanoBioTechnology Initiative funded by the office of the Vice President for Research at Ohio University. We thank Judith Galluci (Ohio State University Crystallography Laboratory) for the x-ray structural determination of compound 11.

Footnotes

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