Synthesis of AE and BE ming analogues of the alkaloid methyllycaconitine

FULL PAPER

DOI: 10.1002/ejoc.200900030

Synthesis of AE and BE Ring Analogues of the Alkaloid Methyllycaconitine

Holger Guthmann,^[a]Daniel Conole,^[a]Emma Wright,^[a]Karsten Körber,^[b]David Barker,^[a]

and Margaret A. Brimble*^[a]

Keywords: Alkaloids / Olefination / Hydrogenation / Nicotinic acetylcholine receptors

The synthesis of AE and BE analogues of the alkaloid meth-

yllycaconitine is reported. The analogues contain two key

cyclohexanone leading to an efficient assembly of an octahy-

droquinoline ring system that mimics the BE-rings of methyl-

lycaconitine. In both the AE and BE analogues, the key 2-(2-

methylsuccinimido)benzoate ester pharmacophore is intro-

duced by esterification of the alcohol precursors with 2-(2-

methylmaleimido)benzoic acid (10) under Steglich conditions

followed by hydrogenation over palladium on charcoal.

pharmacophores:

and a homocholine motif formed from a tertiary N-(3-phen-

ylpropyl)amine incorporated into either 3-azabicyclo-

a 2-(2-methylmaleimido)benzoate ester

a

[3.3.1]nonane (AE) or octahydroquinoline (BE) ring system.

An additional aromatic group is introduced into the AE bicy-

clic system using a Horner–Wadsworth–Emmons reaction.

The BE analogues are synthesised by a one-pot cyclisation

using ethyl α-(bromomethyl)acrylate, a primary amine and

Germany, 2009)

Introduction

Methyllycaconitine (1) is the major toxic component in

Delphinium brownii and was first discovered by Manske in

1938.^[1]Goodson later determined the formula of methyl-

lycaconitine (1) to be the 2-[2-(S)-methylsuccinimido]benzo-

ate ester of the norditerpenoid alkaloid lycoctonine (2).^[2]

The methyllycaconitine (1) core structure contains a piperi-

dine (E) ring and a cyclohexane (A) ring embedded in an

azabicyclo[3.3.1]nonane framework. The primary mode of

action of methyllycaconitine (1) is via competitive blockade

at the nicotinic acetylcholine receptors (nAChRs). Struc-

ture–activity studies on methyllycaconitine (1) have shown

that the N-substituted anthranilate ester moiety is essential

for potent pharmacological activity.^[3]Comparison of the

neuronal activity of methyllycaconitine (1) and lycoctonine

(2), established that lycoctonine (2) exhibits 2000 times less

affinity for rat neuronal α7 nAChRs than its N-substituted

anthranilate ester methyllycaconitine (1) (Figure 1).^[4,5]

nAChRs are a family of ligand-gated ion channels

formed by the association of five subunits, involving homo-

meric and heteromeric structures, which are widely distrib-

uted in the human brain.^[6]The α7 nAChR subtype is

amongst the most common in the brain and has been linked

to pain, neurodegenerative diseases such as Alzheimer’s dis-

ease and Parkinson’s disease, and psychiatric disorders such

as schizophrenia and depression.^[7]Only a few compounds

Figure 1. Methyllycaconitine and lycoctonine.

like methyllycaconitine (1) such as the poison frog alkaloid

235B^[8]or the peptide toxins α-bungarotoxin and α-con-

otoxin ImI bind with high affinity and selectivity to the α7

nAChR.^[9]Methyllycaconitine (1) is reported to be the most

potent non-protein competitive α7 nAChR antagonist pres-

ently available.

An essential structural feature of methyllycaconitine (1)

is the N-substituted anthranilate ester which is postulated

to be the key pharmacophore of the molecule.^[3,4,10]It has

been proposed that at physiological pH the tertiary amine

in the AE ring system of methyllycaconitine (1) is proton-

ated. Both the ester and the protonated amine form a

homocholine motif that mimics acetylcholine. The (S)-

methylsuccinimido moiety may help to maintain the correct

geometry between the tertiary nitrogen atom of the piper-

idine E ring in the alkaloid with the carbonyl oxygen of

the ester bond.^[11]A structure–activity relationship study of

simple E ring analogues 3 by Bergmeier et al.^[12,13]demon-

strated that the N-3-phenylpropyl moiety in comparison to

the natural N-Et group resulted in a significant increase in

binding affinity. Biological evaluation determined that all

[a] Department of Chemistry, The University of Auckland,

23 Symonds Street, Auckland 1142, New Zealand

Fax: +64-9-373-7422

E-mail: m.brimble@auckland.ac.nz

[b] BASF SE, Crop Protection Global Research Insecticides,

67056 Ludwigshafen, Germany

1944

Eur. J. Org. Chem. 2009, 1944–1960

Synthesis of Analogues of the Alkaloid Methyllycaconitine

four diastereomers of 3 showed the same potency, indicat- is shown in Scheme 1. The initial step was the synthesis of

ing that the binding to nAChRs is not stereospecific for the AE bicyclic framework system using a double Mannich

these analogues (Figure 2).^[14]

reaction (Scheme 1). Our group has previously reported a

high yielding double Mannich reaction using bis(aminol)

ethers.^[19]However, in the present work a simpler acid-cata-

lysed double Mannich reaction using formaldehyde and 3-

phenylpropylamine proved more reliable on a larger scale.

Treatment of 3-phenylpropylamine and β-keto ester 6 with

a catalytic quantity of acetic acid under reflux gave the ra-

cemic bicycle 7 in 49% yield. This acid-catalysed double

Mannich reaction^[20]proceeded in much higher yield than

carrying out the reaction using standard Mannich condi-

tions.^[21]Nevertheless, the moderate yield obtained for this

reaction is consistent with literature examples of double

Mannich reactions using cyclohexanones such as 6 that

only contain one α-carboxylate group. Better yields have

been reported for analogous reactions using cyclohexa-

nones substituted with electron-withdrawing groups at both

the α- and αЈ-positions.^[22]

Figure 2. Simple methyllycaconitine analogues.

A total synthesis of methyllycaconitine (1) has not been

reported to date, however, semi-syntheses of methyllycacon-

itine (1) from its parent alkaloid lycoctonine have been re-

ported by Blagborough^[15]and Carrol.^[16]A number of sim-

pler analogues of MLA incorporating the putative pharma-

cophore have been reported.^[17]

We herein report the full details of the synthesis of sev-

eral AE and BE analogues (4 and 5) of methyllycaconitine

(1). The AE analogues 4 contain the key 2-(2-methylsuc-

cinimido)benzoate ester, in which an additional styrene

(part of the B ring) is appended to the azabicyclo[3.3.1]-

nonane core structure (AE rings). An additional aryl moi-

ety is included in the AE analogues to raise the binding

affinity, due to increased interactions in a reported hydro-

phobic pocket.^[18]In order to enhance the selectivity and

potency of previously reported methyllycaconitine E ring

analogues we also synthesized BE ring analogues 5 in which

the cyclohexyl E ring was embedded in a more rigid cis-

fused octahydroquinoline framework (Figure 2). Incorpora-

tion of the N-substituted anthranilate ester and the N-3-

phenylpropyl moiety within a conformationally restricted

framework was envisaged to enhance the biostability, selec-

tivity and potency of previously reported analogues.

Scheme 1. (a) 3-phenylpropylamine, paraformaldehyde, AcOH,

EtOH, H₂O (49%); (b) ArCH₂PO(OEt)₂, nBuLi, THF, room temp.,

ovn or, for 8f, reflux ovn, 8a (84%), 8b (99%), 8c (31%), 8d (76%),

8e (68%), 8f (15%), 8g (10%), 8h (42%); (c) LiAlH₄, THF, 9a

(99%), 9b (98%), 9c (74%), 9d (61%), 9e (95%), 9f (91%), 9g

(95%), 9h (79%); (d) 10, DCC, DMAP, CH₂Cl₂, 11a (76%), 11b

(57%), 11c (58%), 11d (53%), 11e (60%), 11f (82%), 11g (63%),

11h (63%); (e) H₂, Pd/C, EtOAc, 4a (88%), 4b (73%), 4c (68%),

Results and Discussion

The strategy devised for the synthesis of AE bicyclic

methyllycaconitine analogues, represented by compound 4, 4d (47%), 4e (55%), 4f (57%), 4g (71%), 4h (79%).

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1945

M. A. Brimble et al.

FULL PAPER

With the synthesis of the azabicycle 7 in hand, attention

focused on the introduction of the styrene group by Wittig

olefination. Wittig olefination of azabicyclic ketones similar

to 6 has been reported using methyl^[23]and meth-

oxymethyl^[21]phosphonium salts. When Wittig olefination

of the azabicycle 6 was attempted using the benzyl phos-

phonium salt with nBuLi as the base, the reaction did not

proceed and only starting material was recovered. However

using a Horner–Wadsworth–Emmons modification^[24,25]

with benzyl diethyl phosphonate and nBuLi as base gave

the required styrene 8a in good yield (84%). Due to the

steric hindrance of the ester group only the (E)-substituted

olefin 8a was formed. The reaction was also carried out

using para-methoxybenzyl diethylphosphonate and para-

chlorobenzyl diethylphosphonate to afford olefins 8b and

8c in 31% and 99% yield, respectively. It is postulated that

neutral and electron-withdrawing aryl rings, which form

stable phosphonate anions, afford higher yields of the

Horner–Wadsworth–Emmons products than when using

phosphonate anions that bear electron-donating aryl com-

ponents. Our experimental observations are consistent with

these literature reports.^[21,23]

With the styrene unit appended to the key azabicyclic

scaffold, attention turned to appendage of the 2-(2-methyl-

succinimido)benzoate ester via the neopentyl alcohols 9.

Lithium aluminium hydride reduction of ethyl ester 8a af-

forded neopentyl alcohol 9a in good yield facilitating the

use of an efficient two-step procedure to introduce the 2-

(2-methyl maleimido)benzoate ester. Firstly, the key 2-(2-

methylsuccinimido)benzoate group was introduced by di-

rect coupling with 2-(2-methylmaleimido)benzoic acid (10)

under Steglich conditions to afford ester 11a. The double

bond of the maleimide 11a was then hydrogenated over

10% palladium on charcoal in ethyl acetate. Surprisingly,

hydrogenation effected conversion of the maleimido moiety

to a succinimido ring leaving the styrene double bond in-

tact. Usually styrene double bonds are hydrogenated under

Scheme 2. (a) 0 °C, 15 min, toluene, then add cyclohexanone, re-

flux, 18 h 14a (60%), 14b (47%), 14c (72%), 14d (50%); (b) H₂,

PtO₂, EtOAc, 18 h, 15a (41%), 15b (54%), 15c (54%), 15d (72%);

(c) LiAlH₄, THF, 1 h, 16a (100%), 16b (100%), 16c (100%), 16d

(100%); (d) 10, DCC, DMAP, CH₂Cl₂, 17a (95%), 17b (53%), 17c

(53%), 17d (70%); (e) H₂, 10% Pd/C, EtOAc, 18 h, 5a (95%), 5b

mild conditions however, in the present case the double (97%), 5c (99%), 5d (95%) all as 1:1 mixtures of diastereomers.

bond of the styrene is sterically hindered. Overall use of this

four-step sequence afforded racemic ester 4a in 56% overall

yield, starting from azabicycle 7.

none to assemble an octahydroquinoline ring system that

With a reliable synthesis of 4a in hand, the remaining mimics the BE-rings of methyllycaconitine. Moreover, the

analogues, 4b–h were synthesized uneventfully in a similar nature of the alkaloid substituent on the E-ring nitrogen is

fashion starting from the appropriate ketone 7. All reac- also probed in the present work.

tions proceeded in reliable yields affording the AE ana-

The synthetic strategy hinges on a successful one-pot

logues 4b–h of methyllycaconitine.

cyclisation to set up an octahydroquinoline core using ethyl

We next proceeded to synthesize a series of BE analogues α-(bromomethyl)acrylate (12), cyclohexanone and various

of MLA (1). The strategy for the synthesis of the BE ana- primary amines 13 to vary the substitution on the alkaloid

logues, represented by compound 5, is shown in Scheme 2. nitrogen. The strategy is based on a method used by both

During the course of this work the first synthesis of a BE- Horii et al.^[27]and Cassady et al.^[28]who constructed a

ring analogue of methyllycaconitine was reported^[26]how- tetracyclic ergot alkaloid core by reaction of a highly substi-

ever, no data on this analogue’s ability to bind to α7 tuted cyclohexanone with ethyl α-(bromomethyl)acrylate

nAChRs was included. Importantly, this BE analogue did (12) and methylamine. The present work tests the generality

not contain the critical 2-(2Ј-methylsuccinimido)benzoate of this one-pot cyclisation as a method to afford an octahy-

pharmacophore.

droquinoline core by reaction of simple cyclohexanone with

The aim was to prepare BE-ring analogues of methyl- a range of primary amines (Scheme 1).

lycaconitine (1) by efficient one-pot cyclisation of ethyl α-

Ethyl α-(bromomethyl)acrylate (12) was prepared by bro-

(bromomethyl)acrylate, a primary amine and cyclohexa- mination of ethyl α-(hydroxymethyl)acrylate using phos-

1946

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Eur. J. Org. Chem. 2009, 1944–1960

Synthesis of Analogues of the Alkaloid Methyllycaconitine

phorus tribromide. as previously reported by Villieras and

Rambaud.^[29]In our case an alternative route to ethyl α-

(hydroxymethyl)acrylate was used wherein 1,4-diazabicy-

clo[2.2.2]octane (DABCO) was an effective catalyst to effect

union of formaldehyde with ethyl acrylate.^[30]

With ethyl α-(bromomethyl)acrylate (12) in hand, atten-

tion turned to the synthesis of the octahydroquinoline ring

system. The first amine to be investigated was 3-phenylpro-

pylamine 13a, as the 3-phenylpropyl substituent had pre-

viously been shown to exhibit increased binding affinity to

α₃β₄nAChRs.^[14]Thus, ethyl α-(bromomethyl)acrylate (12)

(1.0 equiv.) in dry toluene was added dropwise to 3-phenyl-

propylamine (13a) (2.0 equiv.) at 0 °C, the mixture stirred

for 15 min then ice-cold cyclohexanone (1.0 equiv.) in tolu-

ene added and the resultant mixture heated at reflux for

18 h. Work-up and purification by flash chromatography

gave octahydroquinoline 14a in 60% yield (Scheme 2).

Pleasingly, the literature yields for construction of related

octahydroquinolines were similar.^[28,31]

Having successfully synthesized octahydroquinoline

14a, the next step was to investigate this one-pot reaction

varying the nature of the amine thus providing different

substituents on the E-ring nitrogen. Using the exact condi-

tions described above, the one-pot reaction was investi-

gated with benzylamine 13b, butylamine 13c and (R)-1-

phenylethanamine (13d) affording octahydroquinolines

14b, 14c and 14d in 47%, 72% and 50% yield, respectively.

Interestingly, use of ethylamine and isopropylamine as the

amine component only afforded low yields of the desired

octahydroquinolines, which was attributed to the volatile

nature of these amines. In addition, in these cases the

crude octahydroquinoline products were unstable decom-

posing upon attempted purification by flash chromatog-

raphy.

Figure 3. Stereochemistry of decahydroquinoline 15a determined

by nOe interactions between 8a-H and 4a-H and between 4a-H and

3-H.

In a similar fashion to the synthesis of other analogues

of methyllycaconitine (1), the 2-(2-methylsuccinimido)ben-

zoate ester was next appended to the BE ring system

(Scheme 2). Prior to this esterification step the ethyl esters

15a–d were reduced to a primary alcohol. Reduction of the

ethyl esters 15a–d using lithium aluminium hydride in THF

at room temperature for 1.0 h afforded alcohols 16a–d in

quantitative yield in preparation for appendage of the key

2-(2-methylsuccinimido)benzoate pharmacophore.

Having synthesised decahydroquinoline alcohols 16a–d

the final step was to install the anthranilate ester pharmaco-

phore of methyllycaconitine (1). The direct coupling of 2-

(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic

acid (10, 2.0 equiv.) with neopentyl-type alcohols in dry

acetonitrile using 10 mol-% of DMAP and 2 equiv. of DCC

for 6 h has been reported.^[32]In the present work however,

these conditions failed to effect conversion of alcohol 16a

to anthranilate ester 17a. The use of DIC/HOBt and EDCI

were also ineffective. Fortunately, simply changing the sol-

vent to dichloromethane using DCC and DMAP (cat.) ef-

fected smooth conversion of alcohol 16a to anthranilate es-

ter 17a in 95% yield after 18 h. Similar conversion of

alcohols 16b, 16c and 16d to anthranilates 17b, 17c and 17d

proceeded uneventfully in moderate yield.

With the BE framework in hand, attention focused on

hydrogenation to establish the cis stereochemistry of the

bridgehead protons in decahydroquinolines 14 thus retain-

ing the natural stereochemistry of the BE-rings in methylly-

caconitine (1). Precedent for the use of a similar catalytic

hydrogenation to prepare a cis-decahydroquinoline was re-

ported by Cassady et al. using Adam’s catalyst (PtO₂).^[28]

Octahydroquinoline 14a was therefore subjected to hydro-

genation (1 atm) over Adam’s catalyst in ethyl acetate for

18 h to afford cis-decahydroquinoline 15a in 41% yield after

flash chromatography. cis-Decahydroquinoline 15a was es-

Finally the maleimide unit in anthranilates 17a–d under-

went smooth hydrogenation over 10% palladium on char-

coal (1 atm H₂) for 18 h to yield the desired succinimide

anthranilates 5a–d as 1:1 mixtures of diastereomers in 95–

99% yield.

Conclusions

In summary, the successful syntheses of eight AE bicyclic

tablished to exhibit cis-syn stereochemistry as confirmed by analogues 4a–h and four BE-ring analogues 5a–d of methyl-

the observation of an nOe interaction (Figure 3) between lycaconitine (1) have been achieved. Both AE and BE ana-

4a-H and 3-H thus establishing the relative stereochemistry logues contain the key structural features that contribute to

to be (3S*,4aR*,8aR*) which is the same as that found in the observed bioactivity, namely the presence of a homo-

methyllycaconitine (1).

choline motif derived from a tertiary N-3-phenylpropyl-

Reduction of octahydroquinolines 14b and 14c pro- amine embedded in either a 3-azabicyclo[3.3.1]nonane (AE)

ceeded in a similar manner affording the desired cis-syn de- or piperidine (BE) ring system together with a 2-(2-methyl-

cahydroquinolines 15b and 14c both in 54% yield. In the succinimido)benzoate ester side chain.

case of octahydroquinoline 14d, which already contained a

The key steps in the synthesis of AE analogues 4a–h in-

stereogenic centre of fixed configuration in the amine side volved a double Mannich cyclisation to assemble the 3-aza-

chain, only one diastereomer of the decahydroquinoline bicyclo[3.3.1]nonane AE ring system in combination with

was obtained from the hydrogenation step, however, the ste- use of a Horner–Wadsworth–Emmons reaction to further

reochemistry was not determined.

functionalize the B ring.

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M. A. Brimble et al.

FULL PAPER

3

H), 2.36 (t, J = 7.2 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.44–2.49 (m, 1

The BE analogues 5a–d were constructed using an ef-

ficient one pot annelation of ethyl α-(bromomethyl)acrylate

with a primary amine and cyclohexanone followed by cis-

hydrogenation of the resultant octahydroquinoline ring sys-

tem. Appendage of the key 2-(2-methylsuccinimido)benzo-

ate pharmacophore required the use of dichloromethane as

the solvent to effect coupling of benzoic acid 9 with

alcohols 16a–d.

3

H, 5-H), 2.49–2.61 (m, 2 H, 4-H and 8-H), 2.69 (t, J = 7.2 Hz, 2

H, NCH₂CH₂CH₂Ph), 2.81–2.99 (m, 1 H, 7-H), 2.94 (dd, ²J = 11.4,

⁴J = 1.7 Hz, 1 H, 2-H), 3.14 (dt, J = 11.0, J = 2.0 Hz, 1 H, 4-H),

2

3

2

4

3

3.21 (dd, J = 11.4, J = 2.0 Hz, 1 H, 2-H), 4.21 (q, J = 7.1 Hz,

2 H, OCH₂CH₃), 7.16–7.32 (m, 5 H, ArH) ppm. ¹³C NMR

(75.5 MHz, CDCl₃): δ = 14.1 (OCH₂CH₃), 20.6 (C-7), 29.0

(NCH₂CH₂CH₂Ph), 33.5 (NCH₂CH₂CH₂Ph), 34.2 (C-6), 36.8 (C-

8), 47.2 (C-5), 56.4 (NCH₂CH₂CH₂Ph), 58.8 (C-1), 60.4 (C-4), 61.1

(OCH₂CH₃), 62.0 (C-2), 125.8, 128.4 (ϫ2), 142.0 (Ph), 171.1 (CO-

The synthesis of AE 4a–h and BE 5a–d ring analogues of

methyllycaconitine (1) may provide access to more effective OEt), 212.5 (C-9) ppm. This data was in agreement with that re-

ported in the literature.^[19]

inhibitors of the α7 nAChR sub-type.

General Procedure for the Synthesis of Styrenes 7: n-Butyllithium

in hexane (1.4 equiv.) was added to a solution of benzyl diethyl-

phosphonates (1.4 equiv.) in THF (0.9 ) at –78 °C and the mixture

Experimental Section

stirred for 30 min. The mixture was warmed to room temperature,

General Methods: Analytical thin layer chromatography (TLC) was

left to stand for 30 min, recooled to –78 °C, and a solution of ethyl

performed using 0.2 mm thick precoated silica gel plates (Merck

9-oxo-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]nonane-1-carboxylate

Kieselgel 60 F254). Compounds were visualized by ultraviolet fluo-

(6, 1.0 equiv.) in THF (0.6 ) was added. The resulting mixture was

rescence or by staining with potassium permanganate in aqueous

stirred overnight at room temperature. The reaction mixture was

sodium hydroxide. Flash chromatography was performed using

diluted with brine and extracted with EtOAc. The combined or-

Riedel-de Haën silica gel (0.032–0.063 mm) with the indicated sol-

ganic layers were dried (MgSO₄) and solvent was evaporated in

vacuo to give the crude product which was purified by flash

chromatography to yield desired styrenes 7a–h.

vents. ¹H NMR spectra were recorded with a Bruker DRX 300

(300 MHz) or a Bruker DRX 400 (400 MHz) spectrometer at ambi-

ent temperature using CDCl₃as a solvent. Chemical shifts are given

Ethyl (E)-9-Benzylidene-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]non-

ane-1-carboxylate (7a): Using benzyl diethylphosphonate (970 mg,

4.26 mmol) and ketone 6 (1.00 g, 3.04 mmol); purified by column

chromatography (hexane/EtOAc, 95:5), to give the olefin 7a as a

pale yellow oil (1.03 g, 84%). R_f= 0.44 (hexane/EtOAc, 9:1). ¹H

NMR (300 MHz, CDCl₃): δ = 1.33 (t, ³J = 7.1 Hz, 3 H,

OCH₂CH₃), 1.56–1.68 (m, 1 H, 7-H), 1.81 (t, ³J = 7.6 Hz, 2 H,

in parts per million (ppm) downfield shift from tetramethylsilane

as an internal standard, and reported as position (δ), multiplicity

(s = singlet, d = doublet, dd = double doublet, t = triplet, dt =

double triplet, q = quartet, m = multiplet), relative integral, assign-

ment and coupling constant (J in Hz). ¹³C NMR spectra were re-

corded with a Bruker DRX 300 (75 MHz) or a Bruker DRX 400

(100 MHz) spectrometer at ambient temperature with complete

proton decoupling. Chemical shifts are expressed in parts per mil-

lion referenced to the residual chloroform peak (δ = 77.0 ppm),

and reported as position (δ) and assignment, aided by DEPT 135

experiments ppm. In addition, ¹H-¹H-COSY and ¹H-¹³C-HSQC

correlation spectra were used for the complete assignment of the

proton and carbon resonances. ¹H-¹H-NOESY NMR spectra were

recorded in special cases. The NMR spectroscopic data for the bi-

cyclic analogues of methyllycaconitine were assigned using the fol-

lowing descriptors: bicyclic ring system (no primes), anthranilate

ester (one prime Ј) and methylsuccinimide (two primes ЈЈ). High

resolution mass spectra were recorded with a VG-70SE mass spec-

trometer. Ionisation method employed was electron impact (EI).

Melting points were determined on a Kofler hot-stage apparatus

and are uncorrected. 2-(3-methyl-2,5-dioxo-2,5-dihydropyrrol-1-yl)-

benzoic acid (10)^[33]and the diethylphosphonates^[25]were prepared

as reported.

2

NCH₂CH₂CH₂Ph), 1.85–1.92 (m, 2 H, 6-H), 2.05 (ddd, J = 13.3,

³J = 6.5, ⁴J = 1.8 Hz, 1 H, 8-H), 2.21–2.32 (m, 3 H, 4-H and

NCH₂CH₂CH₂Ph), 2.39 (ddt, ²J = 13.3, ³J = 6.5, ⁴J = 1.8 Hz, 1

H, 8-H), 2.65–2.76 (m, 2 H, NCH₂CH₂CH₂Ph), 2.72 (dd, ²J = 10.5,

⁴J = 1.8 Hz, 1 H, 2-H), 2.80–2.98 (m, 2 H, 4-H and 7-H), 3.04–

3.09 (m, 1 H, 5-H), 3.12 (dd, ²J = 10.5, ⁴J = 0.9 Hz, 1 H, 2-H),

4.25 (qd, ³J = 7.1, J = 1.8 Hz, 2 H, OCH₂CH₃), 6.08 (s, 1 H,

CHAr), 7.15–7.15 (m, 10 H, ArH) ppm. ¹³C NMR (75.5 MHz,

CDCl₃): δ = 14.3 (OCH₂CH₃), 21.4 (C-7), 28.9 (NCH₂CH₂CH₂Ph),

33.1 (C-6), 33.5 (C-5 and NCH₂CH₂CH₂Ph), 36.2 (C-8), 51.3 (C-

1), 57.4 (NCH₂CH₂H₂CPh), 60.5 (C-4), 60.6 (OCH₂CH₃), 62.7 (C-

2), 119.1 (CHAr), 125.7, 126.3, 128.1, 128.3, 128.5, 128.7 (CH_arom.),

137.6, 142.5 (C_arom.), 145.7 (C-9), 174.6 (COOEt) ppm. IR (film):

ν = 3024 (w), 2936 (s), 1724 (vs), 1650 (w), 1599 (w), 1494 (w),

˜

1453 (s), 1260 (s), 1244 (s), 1112 (s), 1052 (s), 746 (w), 699 (s) cm^–1.

MS (EI, 70 eV): m/z (%) = 403 (16) [³⁵Cl, M⁺] 298 (100) [M⁺

–

C₆H₅CH₂CH₂], 148 (14), 91 (25) [C₆H₅CH₂]; found (M⁺,

403.25186); C₂₇H₃₃NO₂calcd. 403.25113.

Ethyl 9-Oxo-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]nonane-1-carbox-

ylate (6): AcOH (1 mL) was added to a solution of 3-phenylpropyl-

amine (13.3 mL, 12.6 g, 74.1 mmol), ethyl-2-oxocyclohexanecar-

boxylate 5 (9.40 mL, 10.0 g, 74.1 mmol) and paraformaldehyde

(4.44 g, 148 mmol) in EtOH/H₂O (60 mL, v/v = 1:1). The mixture

was stirred under reflux overnight and then concentrated under

reduced pressure. To crude residue was added water (100 mL) and

the aqueous mixture was extracted with EtOAc (3ϫ75 mL). The

combined organic layers were dried (Na₂SO₄) and solvent removed

in vacuo to give the crude product, which was purified by flash

chromatography (5% ethyl acetate in hexane) to give 6 as a pale

Ethyl (E)-9-(4-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo-

[3.3.1]nonane-1-carboxylate (7b): Using 4-chlorobenzyl diethyl-

phosphonate (1.04 g, 3.95 mmol) and ketone 6 (1.00 g, 3.04 mmol);

purified by column chromatography (hexane/EtOAc, 95:5), to give

the olefin 7b as an oil (1.33 g, 100%). R_f= 0.43 (hexane/EtOAc,

1

3

9:1). H NMR (300 MHz, CDCl₃): δ = 1.31 (t, J = 7.2 Hz, 3 H,

OCH₂CH₃), 1.54–1.66 (m, 1 H, 7-H_A), 1.72–1.94 (m, 4 H, 6-H and

2

3

NCH₂CH₂CH₂Ph), 2.04 (dd, J = 13.3, J = 5.3 Hz, 1 H, 8-H_A),

2

4

3

2.20 (dd, J = 10.0, J = 1.8 Hz, 1 H, 4-H_A), 2.27 (td, J = 7.0, J

1

3

yellow oil (12.0 g, 49%). R_f= 0.26 (hexane/EtOAc, 9:1). H NMR

= 2.2 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.36 (ddt, ²J = 13.3, J = 6.5, J

(300 MHz, CDCl₃): δ = 1.28 (t, ³J = 7.1 Hz, 3 H, OCH₂CH₃), 1.52–

=

2.0 Hz,

1 H, 8-H_B), 2.63–2.73 (m, 3 H, 2-H_Aand

1.63 (m,

NCH₂CH₂CH₂Ph), 2.06–2.19 (m, 2 H, 6-H), 2.21–2.29 (m, 1 H, 8- (d, J = 11.0 Hz, 1 H, 2-H_B), 4.23 (td, J = 7.2, J = 1.7 Hz, 2 H,

1 = 7.2 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.79–3.01 (m, 3 H, 4-H_B, 5-H and 7-H_B), 3.10

H, 7-H), 1.83 (quintet, ³J

2

3

1948

www.eurjoc.org

Eur. J. Org. Chem. 2009, 1944–1960

Synthesis of Analogues of the Alkaloid Methyllycaconitine

OCH₂CH₃), 6.00 (s, 1 H, CHAr), 7.07–7.31 (m, 9 H, ArH) ppm.

¹³C NMR (75.5 MHz, CDCl₃): δ = 14.3 (OCH₂CH₃), 21.3 (C-7),

M⁺– C₆H₅CH₂CH₂], 91 (25) [C₆H₅CH₂]; found (M⁺, 437.21325),

C₂₇H₃₂³⁵ClNO calcd. 437.21216; found (M⁺, 439.20863),

28.9 (NCH₂CH₂CH₂Ph), 33.1 (C-6), 33.5 (C-5), 33.6 (NCH₂- C₂₇H₃₂³⁷ClNO calcd. 439.20921.

CH₂CH₂Ph), 36.2 (C-8), 51.3 (C-1), 57.3 (NCH₂CH₂H₂CPh), 60.4

Ethyl (E)-9-(3-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo-

(C-4), 60.6 (OCH₂CH₃), 62.6 (C-2), 117.9 (CHAr), 125.7, 128.3

(ϫ2), 128.4, 130.0 (CH_arom.), 132.0, 135.9, 142.4 (C_arom.), 146.5 (C-

[3.3.1]nonane-1-carboxylate (7e): Using 3-chlorobenzyl diethylphos-

phonate (1.12 g, 4.25 mmol) and ketone 6 (1.00 g, 3.04 mmol);

purified by column chromatography (hexane/EtOAc, 95:5), to give

the olefin 7e as an oil (906 mg, 68%). R_f= 0.71 (hexane/EtOAc,

9), 174.4 (COOEt) ppm. IR (film): ν = 3025 (w), 2937 (s), 1724 (vs,

˜

C=O), 1489 (s), 1372 (w), 1259 (s), 1244 (s), 1111 (s), 1091 (s), 854

(m), 747 (m), 699 (m) cm^–1. MS (EI, 70 eV): m/z (%) = 439 (7)

[³⁷Cl, M⁺], 437 (15) [³⁵Cl, M⁺], 332 (100) [M⁺– C₆H₅CH₂CH₂],

148 (21), 91 (25) [C₆H₅CH₂]. found (M⁺, 437.21248),

C₂₇H₃₂³⁵ClNO calcd. 437.21216; found (M⁺, 439.20744),

C₂₇H₃₂³⁷ClNO calcd. 439.20921.

1

3

9:1). H NMR (300 MHz, CDCl₃): δ = 1.33 (t, J = 7.2 Hz, 3 H,

OCH₂CH₃), 1.59–1.64 (m, 1 H, 7-H_A), 1.79–1.85 (m, 4 H, 6-H and

2

3

NCH₂CH₂CH₂Ph), 2.06 (dd, J = 13.6, J = 4.4 Hz, 1 H, 8-H_A),

2

4

3

2.24 (dd, J = 11.2, J = 2.0 Hz, 1 H, 4-H_A), 2.28 (td, J = 6.8, J

= 2.5 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.39 (ddt, ²J = 11.5, J = 5.7, J

3

Ethyl (E)-9-(4-Methoxybenzylidene)-3-(3-phenylpropyl)-3-azabicy-

clo[3.3.1]nonane-1-carboxylate (7c): Using 4-methoxybenzyl dieth-

=

2.8 Hz,

1 H, 8-H_B), 2.65–2.69 (m, 3 H, 2-H_Aand

NCH₂CH₂CH₂Ph), 2.75–2.94 (m, 3 H, 4-H_B, 5-H and 7-H_B), 3.14

2

3

ylphosphonate (1.10 g, 4.26 mmol) and ketone

6

(1.00 g,

(d, J = 10.4 Hz, 1 H, 2-H_B), 4.24 (td, J = 4.0, J = 2.0 Hz, 2 H,

OCH₂CH₃), 6.08 (s, 1 H, CHAr), 7.13–7.37 (m, 9 H, ArH) ppm.

¹³C NMR (75.5 MHz, CDCl₃): δ = 14.2 (OCH₂CH₃), 21.3 (C-7),

28.8 (NCH₂CH₂CH₂Ph), 32.9 (C-6), 33.4 (C-5), 33.9 (NCH₂CH₂-

CH₂Ph), 36.1 (C-8), 51.2 (C-1), 57.2 (NCH₂CH₂H₂CPh), 60.4 (C-

4), 60.6 (OCH₂CH₃), 62.6 (C-2), 116.9 (CHAr), 125.6, 126.2, 127.8,

128.2, 128.4, 129.2, 130.3 (CH_arom.), 134.0, 135.8, 142.3 (C_arom.),

3.04 mmol); purified by column chromatography (hexane/EtOAc,

95:5), to give the olefin 7c as a pale yellow oil (402 mg, 31%). R_f

= 0.50 (hexane/EtOAc, 9:1). ¹H NMR (300 MHz, CDCl₃): δ = 1.31

3

(t, J = 7.2 Hz, 3 H, OCH₂CH₃), 1.54–1.65 (m, 1 H, 7-H_A), 1.81

3

(t, J = 7.6 Hz, 2 H, NCH₂CH₂CH₂Ph), 1.83–1.93 (m, 2 H, 6-H),

1.89–2.07 (m,

1 H, 8-H_A), 2.18–2.30 (m, 3 H, 4-H_Aand

NCH₂CH₂CH₂Ph), 2.36 (ddt, ²J = 13.0, ³J = 6.2, ⁴J = 1.9 Hz, 1

H, 8-H_B), 2.63–2.72 (m, 3 H, 2-H_Aand NCH₂CH₂CH₂Ph), 2.79–

2.96 (m, 2 H, 4-H_Band 7-H_B), 3.03–3.06 (m, 1 H, 5-H), 3.09 (d,

146.5 (C-9), 174.3 (COOEt) ppm. IR (film): ν = 2978 (s), 1722 (vs,

˜

C=O), 1651 (s), 1467 (s), 1245 (s), 1111 (s), 1091 (s), 740 (m), 698

(m) cm^–1. MS (EI, 70 eV): m/z (%) = 439 (7 ) [³⁷Cl, M⁺], 437 (15)

[³⁵Cl, M⁺], 332 (100) ) [³⁵Cl, M⁺– C₆H₅CH₂CH₂], and 91 (25)

[C₆H₅CH₂]; found (M⁺, 437.21216), C₂₇H₃₂³⁵ClNO calcd.

437.21216; found (M⁺, 439.20876), C₂₇H₃₂³⁷ClNO calcd.

439.20921.

²J = 11.0 Hz, 1 H, 2-H_B), 3.08 (s, 3 H, OCH₃), 4.23 (td, J = 7.2,

3

J = 1.8 Hz, 2 H, OCH₂CH₃), 6.00 (s, 1 H, CHAr), 6.84 (dt, J =

3

8.6, J = 2.0 Hz, 2 H, m-ArH), 6.84 (dt, J = 8.6, J = 2.0 Hz, 2

H, o-ArH), 7.16–7.31 (m, 5 H, ArH) ppm. ¹³C NMR (75.5 MHz,

CDCl₃): δ = 14.3 (OCH₂CH₃), 21.4 (C-7), 28.9 (NCH₂CH₂CH₂Ph),

33.1 (C-6), 33.4 (C-5), 33.5 (NCH₂CH₂CH₂Ph), 36.2 (C-8), 51.3

(C-1), 55.2 (OCH₃), 57.4 (NCH₂CH₂CH₂Ph), 60.5 (C-4), 60.6

(OCH₂CH₃), 62.7 (C-2), 113.5 (m-ArC), 118.5 (CHAr), 125.7,

128.3, 128.5 (CH_arom.), 129.8 (o-ArC), 129.9, 142.5 (C_arom.), 144.6

Ethyl (E)-9-(3-Methoxybenzylidene)-3-(3-phenylpropyl)-3-azabicy-

clo[3.3.1]nonane-1-carboxylate (7f): Using 3-methoxybenzyl dieth-

ylphosphonate (1.03 g, 4.25 mmol) and ketone

6

(1.00 g,

3.04 mmol); purified by column chromatography (hexane/EtOAc,

95:5), to give the olefin 7f as a pale yellow oil (197 mg, 15%). R_f

= 0.48 (hexane/EtOAc, 95:5). ¹H NMR (300 MHz, CDCl₃): δ =

(C-9), 158.0 (ArC-OMe) 174.7 (COOEt) ppm. IR (film): ν = 3026

˜

(w), 2933 (br), 1723 (vs, C=O), 1607 (s), 1510 (vs), 1454 (s), 1247

(vs), 1175 (s), 1111 (s), 1037 (s), 851 (w), 819 (w), 746 (w), 699 (s)

3

1.30 (t, J = 7.0 Hz, 3 H, OCH₂CH₃), 1.58–1.63 (m, 1 H, 7-H_A),

2

cm^–1. MS (EI, 70 eV): m/z (%) = 433 (33) [M⁺], 328 (100) [M⁺

–

1.75–1.88 (m, 4 H, 6-H, NCH₂CH₂CH₂Ph), 2.04 (dd, J = 13.2, J

=

5.0 Hz, 1 H, 8-H_A), 2.21–2.30 (m, 3 H, 4-H_Aand

C₆H₅CH₂CH₂], 148 (48), 121 (27), 91 (23) [C₆H₅CH₂], 44 (16);

NCH₂CH₂CH₂Ph), 2.38 (td, ²J = 9.8, J = 5.6 Hz, 1 H, 8-H_B), 2.64–

2.73 (m, 3 H, 2-H_Aand NCH₂CH₂CH₂Ph), 2.85–2.94 (m, 2 H, 4-

H_Band 7-H_B), 3.07–3.12 (m, 2 H, 5-H and 2-H_B), 3.77 (s, 3 H,

found (M⁺, 433.2614), C₂₈H₃₅NO₃calcd. 433.2617.

Ethyl (E)-9-(2-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo-

[3.3.1]nonane-1-carboxylate (7d): Using 2-chlorobenzyl diethyl-

phosphonate (1.12 g, 4.25 mmol) and ketone 6 (1.00 g, 3.04 mmol);

purified by column chromatography (hexane/EtOAc, 95:5), to give

the olefin 7d as an oil (1.01 g, 76%). R_f= 0.72 (hexane/EtOAc,

2

OCH₃), 4.22 (dd, J = 6.8, J = 1.8 Hz, 2 H, OCH₂CH₃), 6.06 (s, 1

H, CHAr), 6.73–6.82 (m, 3 H, ArH), 7.04–7.29 (m, 6 H, ArH)

ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 14.2 (OCH₂CH₃), 21.3

(C-7), 28.8 (NCH₂CH₂CH₂Ph), 33.0 (C-6), 33.4 (C-5), 33.6

(NCH₂CH₂CH₂Ph), 36.2 (C-8), 51.2 (C-1), 55.1 (OCH₃), 57.3

(NCH₂CH₂CH₂Ph), 60.4 (C-4), 60.5 (OCH₂CH₃), 62.6 (C-2),

111.7, 114.2 (CH_arom.), 118.9 (CHAr), 121.6, 125.6, 128.2 (2ϫ),

128.4 (2ϫ), 129.0 (CH_arom.), 138.9, 142.5 (C_arom.), 145.8 (C-9),

1

3

9:1). H NMR (300 MHz, CDCl₃): δ = 1.29 (t, J = 6.2 Hz, 3 H,

OCH₂CH₃), 1.58–1.64 (m, 1 H, 7-H_A), 1.75–1.92 (m, 4 H, 6-H and

NCH₂CH₂CH₂Ph), 2.04 (dd, ²J = 8.7, ³J = 6.0 Hz, 1 H, 8-H_A),

2

4

3

2.20 (dd, J = 10.0, J = 1.8 Hz, 1 H, 4-H_A), 2.28 (td, J = 6.9, J

= 2.4 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.33 (ddt, ²J = 13.1, J = 6.2, J

3

159.3 (ArC-OMe) 174.5 (COOEt) ppm. IR (film): ν = 2921 (br),

˜

=

2.2 Hz,

1 H, 8-H_B), 2.64–2.71 (m, 3 H, 2-H_Aand

1721 (vs, C=O), 1598 (s), 1452 (s), 1257 (vs), 1110 (s), 1047 (s), 735

(w), 694 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 433 (30) [M⁺], 328

(100) [M⁺– C₆H₅CH₂CH₂], 148 (21), (91) [C₆H₅CH₂]; found (M⁺,

433.26169), C₂₈H₃₅NO₃calcd. 433.26152.

NCH₂CH₂CH₂Ph), 2.79–3.02 (m, 3 H, 4-H_B, 5-H and 7-H_B), 3.10

2

3

(d, J = 11.7 Hz, 1 H, 2-H_B), 4.23 (td, J = 6.4, J = 1.5 Hz, 2 H,

OCH₂CH₃), 6.01 (s, 1 H, CHAr), 7.03–7.31 (m, 9 H, ArH) ppm.

¹³C NMR (75.5 MHz, CDCl₃): δ = 14.2 (OCH₂CH₃), 21.2 (C-7),

28.7 (NCH₂CH₂CH₂Ph), 33.0 (C-6), 33.4 (C-5), 33.5 (NCH₂- Ethyl (E)-9-(3-Methylbenzylidene)-3-(3-phenylpropyl)-3-azabicyclo-

CH₂CH₂Ph), 36.2 (C-8), 51.2 (C-1), 57.4 (NCH₂CH₂H₂CPh), 60.3 [3.3.1]nonane-1-carboxylate (7g): Using 3-methylbenzyl diethyl-

(C-4), 60.7 (OCH₂CH₃), 62.5 (C-2), 118.1 (CHAr), 125.7, 126.4, phosphonate (1.03 g, 4.25 mmol) and ketone 6 (1.00 g, 3.04 mmol);

126.8, 128.3 (2ϫ), 128.4 (2ϫ, CH_arom.) 128.5 (C_arom.), 128.6, 129.4

(CH_arom.), 134.0, 139.3, 142.3 (C_arom.), 146.6 (C-9), 174.2 (COOEt) the olefin 7g as a pale yellow oil (123 mg, 10%). R_f= 0.35 (hexane/

ppm. IR (film): ν = 2978 (s), 1722 (vs, C=O), 1651 (s), 1495 (s),

EtOAc, 95:5). ¹H NMR (300 MHz, CDCl₃): δ = 1.30 (t, ³J =

1245 (s), 1111 (s), 1050 (s), 740 (m), 699 (m) cm^–1. MS (EI, 70 eV): 7.0 Hz, 3 H, OCH₂CH₃), 1.59–1.63 (m, 1 H, 7-H_A), 1.76–1.87 (m,

m/z (%) = 439 (7) [³⁷Cl, M⁺], 437 (15) [³⁵Cl, M⁺], 332 (100) [³⁵Cl, 4 H, 6-H, NCH₂CH₂CH₂Ph), 2.03 (dd, J = 13.6, ²J = 5.2 Hz, 1 H,

purified by column chromatography (hexane/EtOAc, 95:5), to give

˜

Eur. J. Org. Chem. 2009, 1944–1960

www.eurjoc.org

1949

M. A. Brimble et al.

FULL PAPER

8-H_A), 2.21–2.42 (m, 4 H, 4-H_A, 8-H_Band NCH₂CH₂CH₂Ph), 2.32

(s, 3 H, ArCH₃), 2.65–2.72 (m, 3 H, 2-H_Aand NCH₂CH₂CH₂Ph),

2.83–2.94 (m, 2 H, 4-H_Band 7-H_B), 3.06–3.12 (m, 2 H, 5-H and 2-

ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.5 (C-7), 28.9

(NCH₂CH₂CH₂Ph), 33.5 (NCH₂CH₂CH₂Ph), 33.7 (C-6), 34.1 (C-

5), 36.7 (C-8), 42.4 (C-1), 57.6 (NCH₂CH₂CH₂Ph), 60.7 (C-4), 63.1

(C-2), 69.1 (CH₂OH), 117.0 (CHAr), 125.6, 126.1, 128.1, 128.3,

2

H_B), 4.22 (dd, J = 6.8, J = 1.7 Hz, 2 H, OCH₂CH₃), 6.05 (s, 1 H,

CHAr), 6.97–7.32 (m, 9 H, ArH) ppm. ¹³C NMR (75.5 MHz, 128.5, 128.6 (CH_arom.), 138.0, 142.6 (C_arom.), 148.3 (C-9) ppm. IR

CDCl₃): δ = 14.2 (OCH₂CH₃), 21.4 (ArCH₃), 21.4 (C-7), 28.9 (film): ν = 3368 (br., O-H), 3023 (w), 2920 (w), 2799 (w), 1648 (s),

˜

(NCH₂CH₂CH₂Ph), 33.1 (C-6), 33.5 (C-5), 33.5 (NCH₂CH₂-

1599 (s), 1494 (vs), 1452 (vs), 1372 (s), 1256 (s), 1029 (vs), 915 (w),

CH₂Ph), 36.2 (C-8), 51.3 (C-1), 57.3 (NCH₂CH₂CH₂Ph), 60.5 (C- 841 (w), 759 (s), 698 (m) cm^–1. MS (EI, 70 eV): m/z (%) = 361 (20)

4), 60.5 (OCH₂CH₃), 62.7 (C-2), 119.1 (CHAr), 123.6, 125.6, 127.0,

127.9, 128.2 (2ϫ), 128.4 (2ϫ), 129.4 (CH_arom.), 137.4, 137.6, 142.4

[M⁺], 256 (100) [M⁺– C₆H₅CH₂CH₂], 148 (12), 91 (24) [C₆H₅CH₂],

44 (24); found (M⁺, 361.2400), C₂₅H₃₁NO calcd. 361.2406.

(C_arom.), 145.4 (C-9), 174.5 (COOEt) ppm. IR (film): ν = 2921 (br),

˜

(E)-{9-(4-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methanol (8b): According to the general LiAlH₄re-

duction procedure, ester 7b (1.18 g, 2.69 mmol) gives the desired

alcohol 8b (1.04 g, 98%) as a colourless oil. R_f= 0.18 (hexane/

1722 (vs, C=O), 1602 (s), 1453 (s), 1241 (vs), 1111 (s), 784 (w), 744

(w), 696 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 417 (30) [M⁺], 312

(100) [M⁺– C₆H₅CH₂CH₂], 148 (19), 91 (11) [C₆H₅CH₂], 44 (8);

found (M⁺, 417.26678), C₂₈H₃₅NO₂calcd. 417.26588.

1

EtOAc, 8:2). H NMR (300 MHz, CDCl₃): δ = 1.50–1.65 (m, 3 H,

Ethyl (E)-9-(4-Methylbenzylidene)-3-(3-phenylpropyl)-3-azabicyclo- OH, 7-H_Aand 8-H_A), 1.66–2.00 (m, 5 H, 6-H, 8-H_Band

[3.3.1]nonane-1-carboxylate (7h): Using 4-methylbenzyl diethyl-

phosphonate (1.03 g, 5.46 mmol) and ketone 6 (1.00 g, 3.04 mmol);

purified by column chromatography (hexane/EtOAc, 9:1), to give

the olefin 7h as a pale yellow oil (538 mg, 42%). R_f= 0.70 (hexane/

NCH₂CH₂CH₂Ph), 2.07–2.20 (m, 2 H, 2-H_Aand 4-H_A), 2.24 (t,

³J = 6.6 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.67 (t, ³J = 7.7 Hz, 2 H,

NCH₂CH₂CH₂Ph), 2.77–3.07 (m, 4 H, 2-H_B, 4-H_B, 5-H and 7-H_B),

2

3.62 (d, J = 10.9 Hz, 1 H, CH_AH_BOH), 3.69 (d, J = 10.9 Hz, 1

EtOAc, 9:1). ¹H NMR (300 MHz, CDCl₃): δ = 1.30 (t, ³J = 7.4 Hz, H, CH_AH_BOH), 6.11 (s, 1 H, CHAr), 7.11 (d, ³J = 8.3 Hz, 2 H,

3 H, OCH₂CH₃), 1.58–1.61 (m, 1 H, 7-H_A), 1.75–1.86 (m, 4 H, 6- ArH), 7.14–7.32 (m, 7 H, ArH) ppm. ¹³C NMR (75.5 MHz,

H, NCH₂CH₂CH₂Ph), 2.03 (dd, J = 13.2, ²J = 5.2 Hz, 1 H, 8-H_A),

2.21–2.41 (m, 4 H, 4-H_A, 8-H_Band NCH₂CH₂CH₂Ph), 2.32 (s, 3

CDCl₃): δ = 21.4 (C-7), 28.9 (NCH₂CH₂CH₂Ph), 33.5

(NCH₂CH₂CH₂Ph), 33.7 (C-6), 34.0 (C-5), 36.6 (C-8), 42.4 (C-1),

H, ArCH₃), 2.64–2.71 (m, 3 H, 2-H_Aand NCH₂CH₂CH₂Ph), 2.83– 57.5 (NCH₂CH₂CH₂Ph), 60.5 (C-4), 62.9 (C-2), 68.9 (CH₂OH),

2.93 (m, 2 H, 4-H_Band 7-H_B), 3.06–3.11 (m, 2 H, 5-H and 2-H_B),

116.0 (CHAr), 125.7, 128.2, 128.3, 128.4, 130.0 (CH_arom.), 131.8,

4.22 (dd, ²J = 6.8, J = 1.8 Hz, 2 H, OCH₂CH₃), 6.04 (s, 1 H,

136.4, 142.5 (C_arom.), 149.2 (C-9) ppm. IR (film): ν = 3368 (br., O-

˜

CHAr), 7.03–7.29 (m, 9 H, ArH) ppm. ¹³C NMR (75.5 MHz, H), 3025 (s), 2918 (vs), 1646 (m), 1489 (vs), 1453 (s), 1372 (m),

CDCl₃): δ = 14.2 (OCH₂CH₃), 21.3 (ArCH₃), 21.3 (C-7), 28.9 1157 (m), 1089 (s), 1037 (m), 1014 (s), 872 (m), 811 (m), 751 (m),

(NCH₂CH₂CH₂Ph), 33.1 (C-6), 33.5 (C-5), 33.5 (NCH₂CH₂-

699 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 397 (5) [³⁷Cl, M⁺], 395

CH₂Ph), 36.2 (C-8), 51.3 (C-1), 57.4 (NCH₂CH₂CH₂Ph), 60.5 (C- (7) [³⁵Cl, M⁺], 290 (100) [M⁺– C₆H₅CH₂CH₂], 148 (16), 91 (24)

4), 60.7 (OCH₂CH₃), 62.7 (C-2), 118.9 (CHAr), 125.6, 128.3 (2ϫ), [C₆H₅CH₂]; found (M⁺, 395.20160), C₂₅H₃₀³⁵ClNO calcd.

128.4 (2ϫ), 128.6 (2ϫ), 128.8 (2ϫ, CH_arom.), 134.6, 135.8, 142.5

395.20159; found (M⁺, 397.19763), C₂₅H₃₀³⁷ClNO 397.19864.

(C_arom.), 145.6 (C-9), 174.6 (COOEt) ppm. IR (film): ν = 2920 (br),

˜

(E)-{9-(4-Methoxybenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methanol (8c): According to the general LiAlH₄re-

duction procedure, ester 7c (280 mg, 647 µmol) gives the desired

alcohol 8c (186 mg, 74%) as a colourless oil. R_f= 0.21 (hexane/

1722 (vs, C=O), 1652 (s), 1453 (s), 1239 (vs), 1110 (s), 1084 (s), 804

(s), 784 (w), 744 (w), 698 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 417

(8) [M⁺], 312 (90) [M⁺– C₆H₅CH₂CH₂], 148 (28), 105 (44), 91 (100)

[C₆H₅CH₂], 57 (27), 42 (44); found (M⁺, 417.26678), C₂₈H₃₅NO₂

calcd. 417.26673.

1

EtOAc, 8:2). H NMR (400 MHz, CDCl₃): δ = 1.50–1.62 (m, 3 H,

O H , 7 - H _Aa n d 8 - H _A) , 1 . 7 0 – 1 . 8 5 ( m , 3 H , 6 - H _Aa n d

General Procedure for the Synthesis of Alcohols 8: Lithium alumin-

ium hydride (2.0 equiv.) was added to a solution of the esters 7a–h

(1.0 equiv.) in dry THF (0.2 ), and the mixture was stirred for

30 min at room temperature. Excess LiAlH₄was decomposed by

cautiously adding a solution of KOH or NaOH in water (4.0–4.5 ,

ca. 6.0 equiv.) until aluminium hydroxide precipitates. After stirring

for 15 min the mixture was filtered through Celite and the remain-

ing salts were further washed with EtOAc. The combined organic

filtrates were dried (MgSO₄) and evaporated in vacuo to give the

crude product which was purified by flash chromatography (in all

cases using hexane/EtOAc, 8:2) to yield the desired alcohols 8a–h.

NCH₂CH₂CH₂Ph), 1.86–1.99 (m, 2 H, 6-H_Band 8-H_B), 2.10 (d, ²J

2

= 10.1 Hz, 1 H, 2-H_A), 2.17 (d, J = 10.5 Hz, 1 H, 4-H_A), 2.23 (t,

³J = 6.3 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.67 (t, ³J = 7.9 Hz, 2 H,

NCH₂CH₂CH₂Ph), 2.79–2.91 (m, 1 H, 7-H_B), 2.93 (d, ²J =

2

10.5 Hz, 1 H, 4-H_B), 3.01 (d, J = 10.1 Hz, 1 H, 2-H_B), 3.05 (br. s,

2

1 H, 5-H), 3.61 (d, J = 10.9 Hz, 1 H, CH_AH_BOH), 3.69 (d, J =

10.9 Hz, 1 H, CH_AH_BOH), 3.79 (s, 3 H, OCH₃), 6.10 (s, 1 H,

3

4

3

CHAr), 6.85 (dd, J = 8.7, J = 2.0 Hz, 2 H, m-ArH), 7.11 (dd, J

= 8.7, ⁴J = 2.0 Hz, 2 H, o-ArH), 7.15–7.30 (m, 5 H, ArH) ppm.

^{1 3}C N M R ( 1 0 0 M H z , C D C l ₃) : δ = 2 1 . 6 ( C - 7 ) , 2 8 . 9

(NCH₂CH₂CH₂Ph), 33.5 (NCH₂CH₂CH₂Ph), 33.7 (C-6), 34.0 (C-

5), 36.7 (C-8), 42.3 (C-1), 55.2 (OCH₃), 57.6 (NCH₂CH₂CH₂Ph),

60.6 (C-4), 63.1 (C-2), 69.1 (CH₂OH), 113.5, 116.4, 125.6, 128.3,

128.5, 129.8 (CH_arom.), 130.4, 142.6 (C_arom.), 147.2 (C-9), 159.8

(E)-{9-Benzylidene-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]nonan-1-yl}-

methanol (8a): According to the general LiAlH₄reduction pro-

cedure, ester 7a (895 mg, 2.22 mmol) gives the desired alcohol 8a

(790 mg, 99%) as a colourless oil. R_f= 0.64 (hexane/EtOAc, 8:2).

¹H NMR (300 MHz, CDCl₃): δ = 1.46 (br. s, 1 H, OH), 1.51–

1.65 (m, 2 H, 7-H_Aand 8-H_A), 1.70–2.01 (m, 5 H, 6-H, 8-H_Band

(ArC-OMe) ppm. IR (film): ν = 3400 (br., O-H), 3025 (w), 2931

˜

(s), 1606 (s), 1509 (vs), 1453 (s), 1246 (vs), 1176 (s), 1035 (s), 748

(w), 699 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 391 (29) [M⁺], 286

(100) [M⁺– C₆H₅CH₂CH₂], 148 (19), 121 (31) [C₇H₆OMe], 91 (14)

[C₆H₅CH₂]; found (M⁺, 391.2508), C₂₆H₃₃NO₂calcd. 391.2511.

2

4

NCH₂CH₂CH₂Ph), 2.12 (dd, J = 10.5, J = 1.9 Hz, 1 H, 2-H_A),

2 . 1 4 – 2 . 2 0 ( m , 1 H , 4 - H _A) , 2 . 2 3 ( t , ³J = 7 . 0 Hz , 2 H,

3

NCH₂CH₂CH₂Ph), 2.67 (t, J = 7.7 Hz, 2 H, NCH₂CH₂CH₂Ph), (E)-{9-(2-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

2.79–2.98 (m, 2 H, 4-H_Band 7-H_B), 2.99–3.09 (m, 2 H, 2-H_Band 5- nonan-1-yl}methanol (8d): According to the general LiAlH₄re-

H), 3.63 (d, ²J = 10.9 Hz, 1 H, CH_AH_BOH), 3.70 (d, ²J = 10.9 Hz, 1

H, CH_AH_BOH), 6.16 (s, 1 H, CHAr), 7.13–7.34 (m, 10 H, ArH)

duction procedure, ester 7d (1.40 g, 3.20 mmol) gives the desired

alcohol 8d (1.15 g, 90%) as a colourless oil. R_f= 0.20 (hexane/

1950

www.eurjoc.org

Eur. J. Org. Chem. 2009, 1944–1960

Synthesis of Analogues of the Alkaloid Methyllycaconitine

1

EtOAc, 8:2). H NMR (300 MHz, CDCl₃): δ = 1.56–1.62 (m, 3 H, (E)-{9-(3-Methylbenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

OH, 7-H_Aand 8-H_A), 1.67–1.99 (m, 5 H, 6-H, 8-H_Band nonan-1-yl}methanol (8 g): According to the general LiAlH₄re-

NCH₂CH₂CH₂Ph), 2.04–2.18 (m, 2 H, 2-H_Aand 4-H_A), 2.24 (t, duction procedure, ester 7g (100 mg, 240 µmol) gives the desired

³J = 6.9 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.67 (t, ³J = 7.7 Hz, 2 H,

alcohol 8g (82 mg, 91%) as a colourless oil. R_f= 0.19 (hexane/

NCH₂CH₂CH₂Ph), 2.81–3.05 (m, 4 H, 2-H_B, 4-H_B, 5-H and 7-H_B), EtOAc, 8:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.55–1.61 (m, 3 H,

2

3.70 (d, J = 10.8 Hz, 2 H, CH₂OH), 6.13 (s, 1 H, CHAr), 7.14–

OH, 7-H_Aand 8-H_A), 1.73–1.98 (m, 5 H, 6-H_B, 8-H_B, 6-H_Aand

NCH₂CH₂CH₂Ph), 2.10–2.25 (m, 4 H, 2-H_A, 4-H_Aand

7.38 (m, 9 H, ArH) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.1

(C-7), 28.6 (NCH₂CH₂CH₂Ph), 33.5 (NCH₂CH₂CH₂Ph), 33.6 (C- NCH₂CH₂CH₂Ph), 2.33 (s, 3 H, ArCH₃), 2.67 (t, ³J = 7.6 Hz, 2

6), 34.3 (C-5), 36.6 (C-8), 42.4 (C-1), 57.6 (NCH₂CH₂CH₂Ph), 60.3

(C-4), 62.6 (C-2), 68.8 (CH₂OH), 115.2 (CHAr), 125.7, 126.3,

H, NCH₂CH₂CH₂Ph), 2.84–2.94 (m, 2 H, 7-H_Band 4-H_B), 3.01–

2

3.06 (m, 2 H, 2-H_Band 5-H), 3.66 (d, J = 8.9 Hz, 2 H, CH₂OH),

127.8, 128.3 (2ϫ), 128.4 (2ϫ), 129.4, 130.4 (CH_arom.), 133.9, 139.9, 6.12 (s, 1 H, CHAr), 6.98–7.32 (m, 9 H, ArH) ppm. ¹³C NMR

142.5 (C_arom.), 148.8 (C-9) ppm. IR (film): ν = 3387 (br., O-H), (100 MHz, CDCl₃): δ = 21.4 (ArCH₃), 21.5 (C-7), 28.9

˜

2920 (vs), 1649 (m), 1467 (vs), 1452 (s), 1255 (m), 1052 (m), 1038 (NCH₂CH₂CH₂Ph), 33.5 (NCH₂CH₂CH₂Ph), 33.7 (C-6), 34.0 (C-

(s), 1032 (m), 908 (m), 731 (m), 698 (s) cm^–1. MS (EI, 70 eV): m/z

5), 36.7 (C-8), 42.3 (C-1), 57.6 (NCH₂CH₂CH₂Ph), 60.6 (C-4), 63.0

(C-2), 69.0 (CH₂OH), 117.0 (CHAr), 125.6, 125.7, 126.8, 128.0,

128.3 (2ϫ), 128.4 (2ϫ), 129.5 (CH_arom.), 137.6, 137.9, 142.5 (C_a-

(%) = 397 (6) [³⁷Cl, M⁺], 395 (15) [³⁵Cl, M⁺], 290 (100) [³⁵Cl, M⁺

–

C₆H₅CH₂CH₂], 91 (35) [C₆H₅CH₂] and 44 (28); found (M⁺,

395.20075), C₂₅H₃₀³⁵ClNO calcd. 395.20159; found (M⁺,

397.19960), C₂₅H₃₀³⁷ClNO calcd. 397.19864.

), 148.0 (C-9) ppm. IR (film): ν = 3383 (br., O-H), 2920 (s),

˜

rom.

1651 (s), 1597 (vs), 1452 (s), 1259 (vs), 1157 (s), 1040 (s), 779 (w),

746 (w), 694 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 392 (16) [MH⁺],

307 (18) [MH⁺– C₆H₅CH₂CH₂], 154 (100), 136 (70), 107 (24), 89

(22), 77 (24); found (MH⁺, 392.25895), C₂₆H₃₄NO₂calcd.

392.25917.

(E)-{9-(3-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methanol (8e): According to the general LiAlH₄re-

duction procedure, ester 7e (500 mg, 1.14 mmol) gives the desired

alcohol 8e (430 mg, 95%) as a colourless oil. R_f= 0.21 (hexane/

(E)-{9-(4-Methylbenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methanol (8h): According to the general LiAlH₄re-

duction procedure, ester 7g (600 mg, 1.44 mmol) gives the desired

alcohol 8h (407 mg, 75%) as a colourless oil. R_f= 0.20 (hexane/

1

EtOAc, 8:2). H NMR (300 MHz, CDCl₃): δ = 1.56–1.68 (m, 3 H,

OH, 7-H_Aand 8-H_A), 1.72–2.04 (m, 5 H, 6-H, 8-H_Band

NCH₂CH₂CH₂Ph), 2.04–2.26 (m, 4 H, 2-H_A, 4-H_Aand

3

NCH₂CH₂CH₂Ph), 2.67 (t, J = 7.7 Hz, 2 H, NCH₂CH₂CH₂Ph),

1

EtOAc, 8:2). H NMR (400 MHz, CDCl₃): δ = 1.52–1.59 (m, 3 H,

2.75–3.08 (m, 4 H, 2-H_B, 4-H_B, 5-H and 7-H_B), 3.65 (d, ²J =

10.8 Hz, 2 H, CH₂OH), 6.11 (s, 1 H, CHAr), 7.11 (d, J = 7.6 Hz,

1 H, ArH), 7.16–7.30 (m, 8 H, ArH) ppm. ¹³C NMR (75.5 MHz,

CDCl₃): δ = 21.5 (C-7), 28.9 (NCH₂CH₂CH₂Ph), 33.5

(NCH₂CH₂CH₂Ph), 33.7 (C-6), 34.2 (C-5), 36.6 (C-8), 42.4 (C-1),

57.5 (NCH₂CH₂CH₂Ph), 60.6 (C-4), 63.0 (C-2), 69.0 (CH₂OH),

115.9 (CHAr), 125.7, 126.2, 126.9, 128.3 (2ϫ), 128.5 (2ϫ), 128.8,

129.3 (CH_arom.), 133.9, 139.9, 142.5 (C_arom.), 148.9 (C-9) ppm. IR

OH, 7-H_Aand 8-H_A), 1.72–1.95 (m, 5 H, 6-H_B, 8-H_B, 6-H_Aand

NCH₂CH₂CH₂Ph), 2.12–2.29 (m, 4 H, 2-H_A, 4-H_Aand

NCH₂CH₂CH₂Ph), 2.34 (s, 3 H, ArCH₃), 2.67 (t, ³J = 7.6 Hz, 2

H, NCH₂CH₂CH₂Ph), 2.77–3.09 (m, 4 H, 7-H_B, 4-H_B, 2-H_Band

5-H), 3.66 (d, ²J = 8.9 Hz, 2 H, CH₂OH), 6.15 (s, 1 H, CHAr),

7.05–7.29 (m, 9 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

21.1 (ArCH₃), 21.3 (C-7), 28.6 (NCH₂CH₂CH₂Ph), 33.4

(NCH₂CH₂CH₂Ph), 33.4 (C-6), 33.5 (C-5), 36.6 (C-8), 42.2 (C-1),

57.7 (NCH₂CH₂CH₂Ph), 60.4 (C-4), 62.7 (C-2), 68.8 (CH₂OH),

116.9 (CHAr), 125.7, 128.3 (2ϫ), 128.4 (2ϫ), 128.6 (2ϫ), 128.8

(2ϫ, CH_arom.), 134.9, 135.8, 142.5 (C_arom.), 149.8 (C-9) ppm. IR

(film): ν = 3347 (br., O-H), 2977 (vs), 1649 (m), 1471 (vs), 1263

˜

(m), 1157 (m), 1077 (s), 1038 (m), 782 (m), 736 (m), 697 (s) cm^–1.

MS (EI, 70 eV): m/z (%) = 397 (5) [³⁷Cl, M⁺], 395 (15) [³⁵Cl, M⁺],

290 (100) [³⁵Cl, M⁺– C₆H₅CH₂CH₂], 91 (29) [C₆H₅CH₂], 44 (33);

found (M⁺, 395.20129), C₂₅H₃₀³⁵ClNO calcd. 395.20159; found

(M⁺, 397.19849), C₂₅H₃₀³⁷ClNO calcd. 397.19864.

(film): ν = 3336 (br., O-H), 2922 (s), 1646 (s), 1452 (s), 1253 (vs),

˜

1043 (s), 908 (w), 728 (w), 698 (s) cm^–1. MS (EI, 70 eV): m/z (%) =

375 (17%) [M⁺], 270 (100) [M⁺– C₆H₅CH₂CH₂], 148 (16), 105

(32), 91 (45) [C₆H₅CH₂], 44 (46); found (M⁺, 375.25621),

C₂₈H₃₃NO calcd. 375.25593.

(E)-{9-(3-Methoxybenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methanol (8f): According to the general LiAlH₄re-

duction procedure, ester 7f (170 mg, 390 µmol) gives the desired

alcohol 8f (146 mg, 95%) as a colourless oil. R_f= 0.21 (hexane/

General Procedure for the Synthesis of Esters 10: To a solution of

alcohols 8a–h (1.0 equiv.) in dichloromethane (0.1 ) were added

benzoic acid 9 (2.0 equiv.) and 4-(dimethylamino)pyridine

(0.1 equiv.) and the solution placed under nitrogen. Dicyclohex-

ylcarbodiimide (2.0 equiv.) was added, and the mixture stirred un-

der nitrogen at room temperature overnight. The mixture was fil-

tered through Celite and the solvent removed in vacuo. The residue

was dissolved in ethyl acetate, washed with saturated NaHCO₃and

brine, dried (Na₂SO₄), filtered and the solvent removed in vacuo.

The crude product was purified by flash chromatography to yield

the desired esters 10a–e.

1

EtOAc, 8:2). H NMR (400 MHz, CDCl₃): δ = 1.53–1.59 (m, 3 H,

O H , 7 - H _Aa n d 8 - H _A) , 1 . 7 3 – 1 . 8 1 ( m , 3 H , 6 - H _Aa n d

NCH₂CH₂CH₂Ph), 1.87–1.98 (m, 2 H, 6-H_Band 8-H_B), 2.11–2.24

3

(m, 4 H, 2-H_A, 4-H_Aand NCH₂CH₂CH₂Ph), 2.66 (t, J = 7.8 Hz,

2 H, NCH₂CH₂CH₂Ph), 2.83–2.94 (m, 2 H, 7-H_Band 4-H_B), 3.01–

2

3.06 (m, 2 H, 2-H_Band 5-H), 3.62 (d, J = 8.9 Hz, 2 H, CH₂OH),

3.77 (s, 3 H, OCH₃), 6.12 (s, 1 H, CHAr), 6.73–6.82 (m, 3 H, ArH),

7.04–7.28 (m, 6 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

21.4 (C-7), 28.8 (NCH₂CH₂CH₂Ph), 33.4 (NCH₂CH₂CH₂Ph), 33.7

(C-6), 34.1 (C-5), 36.6 (C-8), 42.2 (C-1), 55.1 (OCH₃), 57.5

(NCH₂CH₂CH₂Ph), 60.6 (C-4), 63.0 (C-2), 68.9 (CH₂OH), 111.7, (E)-{9-Benzylidene-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]nonan-1-

114.3 (CH_arom.), 116.9 (CHAr), 121.2, 125.6, 128.3 (2ϫ), 128.4 yl}methyl 2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzo-

(2 ϫ), 129.5 (CH_arom.), 139.4, 142.5 (C_arom.), 148.4 (C-9) 159.3 ate (10a): According to the general esterification procedure, alcohol

(ArC-OMe) ppm. IR (film): ν = 3383 (br., O-H), 2920 (s), 1651 (s), 8a (361 mg, 1.00 mmol) gives the desired ester 10a (436 mg, 76%)

˜

1597 (vs), 1452 (s), 1259 (vs), 1157 (s), 1040 (s), 779 (w), 746 (w),

as an oil. R_f= 0.29 (hexane/EtOAc, 8:2). ¹H NMR (400 MHz,

CDCl₃): δ = 1.53–1.69 (m, 2 H, 7-H_Aand 8-H_A), 1.74–1.85 (m, 3

694 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 392 (16) [MH⁺], 307 (18)

[MH⁺– C₆H₅CH₂CH₂], 154 (100), 136 (70), 107 (24), 89 (22), 77 H, 6-H_Aand NCH₂CH₂CH₂Ph), 1.87–1.95 (m, 1 H, 6-H_B), 2.05–

(24); found (MH⁺, 392.25895), C₂₆H₃₄NO₂calcd. 392.25917.

2.30 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band NCH₂CH₂CH₂Ph), 2.17 (d,

Eur. J. Org. Chem. 2009, 1944–1960

www.eurjoc.org

1951

M. A. Brimble et al.

FULL PAPER

4

3

4

⁴J = 2 . 0 H z , 3 H , M e ) , 2 . 6 8 ( t , ³J = 7 . 9 H z , 2 H , 7.9, J = 1.5 Hz, 1 H, 5Ј-H), 7.66 (td, J = 7.9, J = 1.5 Hz, 1 H,

NCH₂CH₂CH₂Ph), 2.82–2.98 (m, 1 H, 7-H_B), 2.96 (d, ²J = 4Ј-H), 8.11 (dd, J = 7.9, J = 1.5 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR

3

4

10.6 Hz, 1 H, 4-H_B), 3.06–3.12 (m, 2 H, 2-H_Band 5-H), 4.28 (s, 2

( 1 0 0 M H z , C D C l ₃) : δ = 1 1 . 2 ( M e ) , 2 1 . 4 ( C - 7 ) , 2 8 . 9

(NCH₂CH₂CH₂Ph), 33.4 (C-6), 33.5 (NCH₂CH₂CH₂Ph), 33.8 (C-

4

H, CH₂O), 6.14 (s, 1 H, CHAr), 6.49 (q, J = 2.0 Hz, 1 H, 4ЈЈ-H),

7.15–7.36 (m, 11 H, 6Ј-H and CH_arom.), 7.52 (td, ³J = 7.5, ⁴J = 5), 36.8 (C-8), 41.1 (C-1), 55.2 (OCH₃), 57.4 (NCH₂CH₂CH₂Ph),

3

4

1.5 Hz,1 H, 5Ј-H), 7.66 (td, J = 7.5, J = 1.5 Hz,1 H, 4Ј-H), 8.11

60.3 (C-4), 63.3 (C-2), 70.9 (CH₂O), 113.5 (m-Ar), 116.8 (CHAr),

125.6 (p-Ph), 127.9 (C-4ЈЈ), 128.0 (C-1Ј), 128.2, 128.4, 129.0, 129.8

(dd, J = 7.5, J = 1.5 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR (100 MHz,

3

4

CDCl₃): δ = 11.2 (Me), 21.4 (C-7), 28.9 (NCH₂CH₂CH₂Ph), 33.5 (CH_arom.), 130.2 (C_arom.), 130.4, 131.4 (CH_arom.), 131.9 (C-2Ј),

(C-6 and NCH₂CH₂CH₂Ph), 33.9 (C-5), 36.9 (C-8), 41.2 (C-1), 57.4 133.3 (CH_arom.), 142.5 (C_arom.), 146.0 (C-3ЈЈ), 146.2 (C-9), 157.9

(NCH₂CH₂CH₂Ph), 60.4 (C-4), 63.4 (C-2), 70.9 (CH₂O), 117.4 (ArC-OMe), 164.8 (COO), 169.7 (C-5ЈЈ), 170.7 (C-2ЈЈ) ppm. IR

(CHAr), 125.7, 126.2, 128.0 (ϫ2), 128.1 (CH_arom.), 128.3 (C-4ЈЈ), (film): ν = 3026 (w), 2933 (s), 1713 (vs, C=O), 1605 (w), 1509 (s),

˜

128.5 (CH_arom.), 128.7 (C-1Ј), 129.0, 130.5, 131.4 (CH_arom.), 131.9 1453 (w), 1395 (s), 1249 (s), 1108 (s), 1034 (w), 910 (s), 732 (s) cm^–1.

(C-2Ј), 133.3 (CH_arom.), 137.8, 142.6 (C_arom.), 146.2 (C-3ЈЈ), 147.1 MS (FAB): m/ z ( % ) = 6 0 5 ( 2 1) [ M H ⁺] , 4 9 9 ( 5 ) [ M ⁺

–

(C-9), 164.8 (COO), 169.7 (C-5ЈЈ), 170.8 (C-2ЈЈ) ppm. IR (film): ν C₆H₅CH₂CH₂], 307 (23), 154 (100), 136 (67), 107 (21) [C₆H₇OMe],

˜

= 3024 (w), 2922 (m), 1713 (vs, C=O), 1644 (w), 1601 (w), 1494 77 (22) [C₆H₅]; found (MH⁺, 605.3023) C₃₈H₄₁N₂O₅calcd.

(m), 1454 (m), 1394 (s), 1261 (s), 1108 (s), 1086 (m), 857 (w), 736

605.3016.

(m), 699 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 574 (22) [M⁺], 469

(E)-{9-(2-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-

yl)benzoate (10d): According to the general esterification pro-

cedure, alcohol 8d (1.1 g, 2.778 mmol) gives the desired ester 10d

(901 mg, 53%) as a pale yellow oil. R_f= 0.29 (hexane/EtOAc, 8:2).

¹H NMR (300 MHz, CDCl₃): δ = 1.57–1.62 (m, 2 H, 7-H_Aand 8-

H_A), 1.67–1.83 (m, 3 H, 6-H_Aand NCH₂CH₂CH₂Ph), 1.86–1.91

(m, 1 H, 6-H_B), 2.04–2.30 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band

NCH₂CH₂CH₂Ph), 2.17 (d, ⁴J = 1.9 Hz, 3 H, Me), 2.69 (t, ³J =

(100) [M⁺– C₆H₅CH₂CH₂], 382 (13), 344 (24), 214 (23) [M⁺

–

C_{1 2}H₈NO₃], 91 (36) [C₆H₅CH₂]; found (M⁺, 574.2832),

C₃₇H₃₈N₂O₄calcd. 574.2832.

(E)-{9-(4-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-

yl)benzoate (10b): According to the general esterification pro-

cedure, alcohol 8b (913 mg, 2.31 mmol) gives the desired ester 10b

(795 mg, 57%) as a pale yellow oil. R_f= 0.29 (hexane/EtOAc, 8:2).

¹H NMR (300 MHz, CDCl₃): δ = 1.55–1.75 (m, 2 H, 7-H_Aand 8- 7.7 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.84–2.93 (m, 2 H, 5-H and 7-

2

H_A), 1.75–1.88 (m, 3 H, 6-H_Aand NCH₂CH₂CH₂Ph), 1.89–2.00 H_B), 2.94 (d, J = 10.8 Hz, 1 H, 4-H_B), 3.08 (d, J = 10.5 Hz, 1 H,

(m, 1 H, 6-H_B), 2.05–2.35 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band 2-H_B), 4.31 (s, 2 H, CH₂O), 6.14 (s, 1 H, CHAr), 6.50 (q, ⁴J =

NCH₂CH₂CH₂Ph), 2.18 (d, ⁴J = 1.8 Hz, 3 H, Me), 2.70 (t, ³J =

1.8 Hz, 1 H, 4ЈЈ-H), 7.13–7.39 (m, 10 H, 6Ј-H and ArH), 7.50 (td,

7.9 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.82–3.07 (m, 2 H, 5-H and 7- ²J = 7.5, J = 1.2 Hz, 1 H, 5Ј-H), 7.66 (td, ²J = 7.5, J = 1.5 Hz, 1

4

2

H_B), 2.99 (d, J = 11.4 Hz, 1 H, 4-H_B), 3.11 (d, J = 10.6 Hz, 1 H,

H, 4Ј-H), 8.19 (dd, ²J = 8.4, ⁴J = 1.5 Hz, 1 H, 3Ј-H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃): δ = 11.2 (Me), 21.3 (C-7), 28.8

(NCH₂CH₂CH₂Ph), 33.3 (C-6), 33.4 (NCH₂CH₂CH₂Ph), 34.4 (C-

5), 36.7 (C-8), 41.4 (C-1), 57.5 (NCH₂CH₂CH₂Ph), 60.3 (C-4), 63.1

(C-2), 70.3 (CH₂O), 114.4 (CHAr), 125.7 126.3 (CH_arom.), 127.7

2-H_B), 4.29 (s, 2 H, CH₂O), 6.11 (s, 1 H, CHAr), 6.51 (q, ⁴J =

3

1.8 Hz, 1 H, 4ЈЈ-H), 7.12 (d, J = 8.4 Hz, 2 H, m-ArH), 7.16–7.39

(m, 8 H, 6Ј-H, o-ArH and Ph), 7.53 (td, ²J = 7.7, J = 1.7 Hz, 1

4

2

4

2

H, 5-H), 7.68 (td, J = 7.7, J = 1.7 Hz, 1 H, 4Ј-H), 8.13 (dd, J =

7.7, J = 1.7 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): (C-1Ј), 127.8, 127.9, 128.3 (2ϫ), 128.4 (2ϫ, CH_arom.), 128.4 (C-

4

δ = 11.2 (Me), 21.3 (C-7), 28.8 (NCH₂CH₂CH₂Ph), 33.4 (C-6), 33.5

(NCH₂CH₂CH₂Ph), 33.9 (C-5), 36.8 (C-8), 41.2 (C-1), 57.3

4ЈЈ), 128.9, 129.3, 130.4, 131.6 (CH_arom.), 131.9 (C-2Ј), 133.3

(CH_arom.), 134.0, 136.3, 142.4 (C_arom.), 146.2 (C-3ЈЈ), 148.0 (C-9),

(NCH₂CH₂CH₂Ph), 60.3 (C-4), 63.2 (C-2), 70.6 (CH₂O), 116.3 164.6 (COO), 169.7 (C-5ЈЈ), 170.8 (C-2ЈЈ) ppm. IR (film): ν = 2978

˜

(CHAr), 125.6 (p-Ph), 127.9, 128.3 (CH_arom.), 128.4 (C-4ЈЈ), 128.9

(CH_arom.), 129.0 (C-1Ј), 130.0, 130.4 131.3 (CH_arom.), 131.9 (C-2Ј),

133.3 (CH_arom.), 136.2, 142.4 (C_arom.), 146.2 (C-3ЈЈ), 148.0 (C-9),

(w), 2921 (s), 1709 (s), 1494 (s), 1452 (s), 1393 (s), 1255 (s), 1106

(s), 1083 (s), 755 (s), 735 (s), 698 (vs) cm^–1. MS (EI, 70 eV): m/z

(%) = 610 (8) [³⁷Cl, M⁺] 608 (16) [³⁵Cl, M⁺] 503 (82) [³⁵Cl, M⁺

–

164.7 (COO), 169.7 (C-5ЈЈ), 170.7 (C-2ЈЈ) ppm. IR (film): ν = 3015 C₆H₅CH₂CH₂], 378 (25), 214 (100) [M⁺– C₁₂H₈NO₃], 91 (74)

˜

(w), 2923 (s), 1713 (vs, C=O), 1490 (s), 1452 (s), 1395 (s), 1259 (s),

[C₆H₅CH₂]; found (M⁺, 608.24204), C₃₇H₃₇³⁵ClN₂O₄calcd.

608.24419; found (M⁺, 610.23934), C₃₇H₃₇³⁷ClN₂O₄610.24124.

1108 (s), 909 (s), 732 (vs) cm^–1. MS (FAB): m/z (%) = 609 (65) [M⁺

+ H], 503 (47) [M⁺– C₆H₅CH₂CH₂], 378 (29), 214 (64) [M⁺

–

(E)-{9-(3-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-

yl)benzoate (10e): According to the general esterification procedure,

alcohol 8d (169 mg, 430 µmol) gives the desired ester 10e (156 mg,

C₁₂H₈NO₃], 125 (22), 91 (100) [C₆H₅CH₂]; found (MH⁺, 609.2519)

C₃₇H₃₈³⁵ClN₂O₄calcd. 609.2520.

(E)-{9-(4-Methoxybenzylidene)-3-(3-phenylpropyl)-3-azabicyclo-

[3.3.1]nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyr- 60%) as a pale yellow oil. R_f= 0.40 (hexane/EtOAc, 8:2). ¹H NMR

rol-1-yl)benzoate (10c): According to the general esterification pro-

cedure, alcohol 8c (174 mg, 445 µmol) gives the desired ester 10c

(157 mg, 58%) as a pale yellow oil. R_f= 0.23 (hexane/EtOAc, 8:2).

(300 MHz, CDCl₃): δ = 1.56–1.66 (m, 2 H, 7-H_Aand 8-H_A), 1.75–

1.82 (m, 3 H, 6-H_Aand NCH₂CH₂CH₂Ph), 1.90–1.95 (m, 1 H, 6-

H_B), 2.03–2.30 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band NCH₂CH₂CH₂Ph),

¹H NMR (400 MHz, CDCl₃): δ = 1.52–1.67 (m, 2 H, 7-H_Aand 8- 2.16 (d, ⁴J = 1.8 Hz, 3 H, Me), 2.67 (t, ³J = 7.6 Hz, 2 H,

H_A), 1.74–1.84 (m, 3 H, 6-H_Aand NCH₂CH₂CH₂Ph), 1.87–1.95 NCH₂CH₂CH₂Ph), 2.83–2.96 (m, 2 H, 4-H_Band 7-H_B), 3.08 (d, ²J

4

(m, 1 H, 6-H_B), 2.05–2.13 (m, 2 H, 2-H_Aand 8-H_B), 2.16 (d, J = = 8.4 Hz, 2 H, 5-H and 2-H_B), 4.25 (s, 2 H, CH₂O), 6.08 (s, 1 H,

4

1.9 Hz, 3 H, Me), 2.16–2.30 (m, 3 H, 4-H_Aand NCH₂CH₂CH₂Ph),

CHAr), 6.49 (q, J = 1.8 Hz, 1 H, 4ЈЈ-H), 7.04 (d, J = 7.6 Hz, 1

2.67 (t, ³J = 7.9 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.82–2.97 (m, 1 H, H, ArH), 7.16–7.36 (m, 9 H, 6Ј-H and ArH), 7.51 (td, J = 5.6, J

2

4

2

7-H_B), 2.96 (d, J = 10.4 Hz, 1 H, 4-H_B), 3.06–3.11 (m, 2 H, 2-H_B

= 1.0 Hz, 1 H, 5-H), 7.65 (td, ²J = 7.6, ⁴J = 1.6 Hz, 1 H, 4Ј-H),

and 5-H), 3.79 (s, 3 H, OCH₃), 4.27 (s, 2 H, CH₂O), 6.07 (s, 1 H,

8.19 (dd, ²J = 8.0, ⁴J = 1.2 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR

4

3

CHAr), 6.49 (q, J = 1.9 Hz, 1 H, 4ЈЈ-H), 6.85 (d, J = 8.8 Hz, 2 ( 7 5 . 4 M H z , C D C l ₃) : δ = 1 1 . 1 ( M e ) , 2 0 . 9 ( C - 7 ) , 28 . 8

3

H, m-ArH), 7.10 (d, J = 8.8 Hz, 2 H, o-ArH), 7.15–7.30 (m, 5 H, (NCH₂CH₂CH₂Ph), 33.4 (C-6), 33.4 (NCH₂CH₂CH₂Ph), 33.9 (C-

ArH), 7.12 (dd, ³J = 7.9, ⁴J = 1.5 Hz, 1 H, 6Ј-H), 7.51 (td, ³J =

5), 36.8 (C-8), 41.2 (C-1), 57.3 (NCH₂CH₂CH₂Ph), 60.3 (C-4), 63.2

1952

www.eurjoc.org

Eur. J. Org. Chem. 2009, 1944–1960

Synthesis of Analogues of the Alkaloid Methyllycaconitine

(C-2), 70.6 (CH₂O), 116.2 (CHAr), 125.6, 126.2 (CH_arom.), 126.9

(%) = 588 (3) [M⁺], 483 (15) [M⁺– C₆H₅CH₂CH₂], 214 (85), 158

(C-1Ј), 127.9, 128.3 (2ϫ), 128.4 (2ϫ, CH_arom.), 128.5 (C-4ЈЈ), 128.9, (29), 146 (32), 105 (30), 91 (100) [C₆H₅CH₂], 77 (23), 39 (44); found

129.3, 130.4, 131.2 (CH_arom.), 131.9 (C-2Ј), 133.3 (CH_arom.), 133.9, (M⁺, 588.29881), C₃₈H₄₀N₂O₄calcd. 588.29826.

139.6, 142.4 (C_arom.), 146.2 (C-3ЈЈ), 148.6 (C-9), 164.7 (COO), 169.6

(E)-{9-(4-Methylbenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

(C-5ЈЈ), 171.0 (C-2ЈЈ) ppm. IR (film): ν = 2921 (s), 1709 (s), 1391

˜

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-

yl)benzoate (10h): According to the general esterification pro-

cedure, alcohol 8g (350 mg, 930 µmol) gives the desired ester 10h

(344 mg, 63%) as a white foam. R_f= 0.31 (hexane/EtOAc, 8:2). ¹H

NMR (300 MHz, CDCl₃): δ = 1.56–1.64 (m, 2 H, 7-H_Aand 8-H_A),

1.77–1.82 (m, 3 H, 6-H_Aand NCH₂CH₂CH₂Ph), 1.89–1.91 (m, 1

H , 6 - H_B) , 2 . 0 8– 2 . 2 9 ( m , 5 H , 2 - H_A, 4 - H_A, 8 - H _Ba n d

NCH₂CH₂CH₂Ph), 2.16 (d, ⁴J = 1.6 Hz, 3 H, Me), 2.32 (s, 3 H,

ArCH₃), 2.67 (t, ³J = 7.0 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.83–2.96

(s), 1254 (s), 1105 (s), 754 (s), 697 (vs) cm^–1. MS (FAB): m/z (%) =

611 (3) [³⁷Cl, MH⁺] 609 (5) [³⁵Cl, MH⁺], 307 (21), 154 (100), 136

(70), 107 (25), 89 (22), 77 (22); found (MH⁺, 609.25201),

C₃₇H₃₇³⁵ClN₂O₄calcd. 609.25197; found (MH⁺, 611.25089),

C₃₇H₃₇³⁷ClN₂O₄requires 611.25004.

(E)-{9-(3-Methoxybenzylidene)-3-(3-phenylpropyl)-3-azabicyclo-

[3.3.1]nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyr-

rol-1-yl)benzoate (10f): According to the general esterification pro-

cedure, alcohol 8f (130 mg, 330 µmol) gives the desired ester 10f

(165 mg, 82%) as a white foam. R_f= 0.25 (hexane/EtOAc, 8:2). ¹H

NMR (300 MHz, CDCl₃): δ = 1.53–1.67 (m, 2 H, 7-H_Aand 8-H_A),

1.75–1.82 (m, 3 H, 6-H_Aand NCH₂CH₂CH₂Ph), 1.89–1.92 (m, 1

H, 6 -H_B), 2 . 07– 2 . 2 8 ( m , 5 H , 2 - H_A, 4 - H_A, 8 - H _Ba n d

NCH₂CH₂CH₂Ph), 2.16 (d, ⁴J = 1.6 Hz, 3 H, Me), 2.67 (t, ³J =

7.8 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.86–2.97 (m, 2 H, 4-H_Band 7-

H_B), 3.09 (d, ²J = 10.4 Hz, 2 H, 5-H and 2-H_B), 3.78 (s, 3 H,

OCH₃), 4.32 (s, 2 H, CH₂O), 6.11 (s, 1 H, CHAr), 6.48 (q, ⁴J =

1.6 Hz, 1 H, 4ЈЈ-H), 6.72–6.78 (m, 3 H, ArH), 7.15–7.33 (m, 7 H,

6Ј-H and ArH), 7.51 (td, ²J = 7.6, ⁴J = 0.4 Hz, 1 H, 5-H), 7.65 (td,

2

(m, 2 H, 4-H_Band 7-H_B), 3.08 (d, J = 10.4 Hz, 2 H, 5-H and 2-

H_B), 4.27 (s, 2 H, CH₂O), 6.10 (s, 1 H, CHAr), 6.47 (q, ⁴J = 1.8 Hz,

1 H, 4ЈЈ-H), 7.06–7.34 (m, 10 H, 6Ј-H and ArH), 7.49 (td, ²J = 6.8,

2

4

⁴J = 1.2 Hz, 1 H, 5-H), 7.65 (td, J = 7.6, J = 1.6 Hz, 1 H, 4Ј-H),

8.11 (dd, ²J = 7.6, ⁴J = 0.4 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 11.1 (Me), 21.1 (C-7), 21.4 (ArCH₃), 28.9

(NCH₂CH₂CH₂Ph), 33.4 (C-6), 33.5 (NCH₂CH₂CH₂Ph), 33.8 (C-

5), 36.8 (C-8), 41.1 (C-1), 57.4 (NCH₂CH₂CH₂Ph), 60.3 (C-4), 63.3

(C-2), 70.9 (CH₂O), 117.2 (CHAr), 125.6, 127.6, 128.2 (2ϫ), 128.4

(2ϫ), 128.6 (2ϫ), 128.8 (2ϫ, CH_arom.), 129.0 (C-4ЈЈ), 129.0 (C-1Ј),

130.4, 131.2 (CH_arom.), 131.9 (C-2Ј), 133.2 (CH_arom.), 134.8, 135.7,

142.5 (C_arom.), 146.2 (C-3ЈЈ), 146.5 (C-9), 164.8 (COO), 169.7 (C-

4

2

4

²J = 7.6, J = 1.6 Hz, 1 H, 4Ј-H), 8.11 (dd, J = 8.8, J = 1.2 Hz,

1 H, 3Ј-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 11.2 (Me),

21. 4 (C-7), 28.8 (NCH₂CH₂CH₂Ph), 33. 4 (C-6), 33.4

(NCH₂CH₂CH₂Ph), 33.9 (C-5), 36.8 (C-8), 41.1 (C-1), 55.1

(OCH₃), 57.3 (NCH₂CH₂CH₂Ph), 60.3 (C-4), 63.3 (C-2), 70.8

(CH₂O), 111.7, 114.3 (CH_arom.), 117.2 (CHAr), 121.2, 125.6, 127.9

(CH_arom.), 127.9 (C-1Ј), 128.2 (2ϫ), 128.4 (2ϫ), 128.9 (CH_arom.),

129.0 (C-4ЈЈ), 130.4, 131.3 (CH_arom.), 131.9 (C-2Ј), 133.2 (CH_arom.),

139.2, 142.5 (C_arom.), 146.2 (C-3ЈЈ), 147.3 (C-9), 159.3 (ArC-OMe),

5ЈЈ), 170.7 (C-2ЈЈ) ppm. IR (film): ν = 2920 (s), 1709 (s), 1391 (s),

˜

1254 (s), 1105 (s), 1084 (s), 725 (s), 697 (vs) cm^–1. MS (EI, 70 eV):

m/z (%) = 588 (15) [M⁺], 483 (100) [M⁺– C₆H₅CH₂CH₂], 358 (23),

214 (45), 105 (34), 91 (46) [C₆H₅CH₂], 44 (21); found (M⁺,

588.29881), C₃₈H₄₀N₂O₄calcd. 588.29891.

General Hydrogenation Procedure for the Synthesis of Compound 4:

To a solution of the maleimido esters 10a–h (1.0 equiv.) in ethyl

acetate (0.2 ) was added 10% palladium on carbon (10%w/w) and

the mixture stirred under hydrogen for 3 h. After this time the mix-

ture was filtered through Celite, washed with EtOAc, and the sol-

vent removed in vacuo. The crude product was purified by flash

chromatography to afford the desired succinimide anthranilate es-

ters 4a–h.

164.8 (COO), 169.7 (C-5ЈЈ), 170.7 (C-2ЈЈ) ppm. IR (film): ν = 2925

˜

(s), 1708 (s), 1392 (s), 1254 (s), 1105 (s), 1083 (s), 754 (s), 728 (s),

695 (vs) cm^–1. MS (FAB): m/z (%) = 605 (15) [MH⁺], 307 (20), 154

(100), 136 (70), 107 (22), 91 (21) [C₆H₅CH₂], 77 (22); found (MH⁺,

605.30155), C₃₈H₄₁N₂O₅calcd. 605.30101.

(E)-{9-(3-Methylbenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-

yl)benzoate (10g): According to the general esterification pro-

cedure, alcohol 8g (80 mg, 200 µmol) gives the desired ester 10g

(76 mg, 63%) as a pale yellow oil. R_f= 0.28 (hexane/EtOAc, 8:2).

(E)-{9-Benzylidene-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]nonan-1-

yl}methyl 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoate (4a): Ac-

cording to the general hydrogenation procedure, maleimide 10a

(200 mg, 350 µmol) gives the product 4a (178 mg, 88%) purified by

¹H NMR (300 MHz, CDCl₃): δ = 1.56–1.66 (m, 2 H, 7-H_Aand 8- column chromatography (hexane/EtOAc, 6:4) as a pale yellow oil

H_A), 1.75–1.82 (m, 3 H, 6-H_Aand NCH₂CH₂CH₂Ph), 1.89–1.92 and as a 1:1 mixture of diastereomers. R_f= 0.43 (hexane/EtOAc,

(m, 1 H, 6-H_B), 2.07–2.31 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band 6:4). H NMR (300 MHz, CDCl₃): δ = 1.45 (d, J = 13.3 Hz, 3 H,

NCH₂CH₂CH₂Ph), 2.16 (d, ⁴J = 1.6 Hz, 3 H, Me), 2.33 (s, 3 H,

Me), 1.55–1.71 (m, 2 H, 7-H_Aand 8-H_A), 1.74–1.86 (m, 1 H, 6-

ArCH₃), 2.68 (t, ³J = 7.6 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.85–2.97 H_A), 1.79 (t, J = 7.7 Hz, 2 H, NCH₂CH₂CH₂Ph), 1.88–1.96 (m, 1

1

4

3

(m, 2 H, 4-H_Band 7-H_B), 3.08–3.10 (m, 2 H, 5-H and 2-H_B), 4.27

H , 6 - H_B) , 2 . 0 8– 2 . 3 2 ( m , 5 H , 2 - H_A, 4 - H_A, 8 - H _Ba n d

NCH₂CH₂CH₂Ph), 2.44–2.62 (m, 2 H, 4ЈЈ-H), 2.68 (t, J = 7.7 Hz,

3

(s, 2 H, CH₂O), 6.11 (s, 1 H, CHAr), 6.47 (q, ⁴J = 1.6 Hz, 1 H,

4ЈЈ-H), 6.97–7.02 (m, 3 H, ArH), 7.14–7.35 (m, 7 H, 6Ј-H and 2 H, NCH₂CH₂CH₂Ph), 2.84–3.16 (m, 4 H, 2-H_B, 3ЈЈ-H, 5-H and

4

2

ArH), 7.51 (td, ²J = 7.6, J = 1.0 Hz, 1 H, 5-H), 7.66 (td, J = 7.6,

7-H_B), 2.96 (d, ²J = 11.2 Hz, 1 H, 4-H_B), 4.28 (s, 2 H, CH₂O), 6.16

⁴J = 1.2 Hz, 1 H, 4Ј-H), 8.12 (dd, J = 7.6, J = 1.4 Hz, 1 H, 3Ј- (s, 1 H, CHAr), 7.12–7.34 (m, 11 H, 6Ј-H and CH_arom.), 7.51 (td,

2

4

H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 11.2 (Me), 21.4 (C-7),

21.4 (ArCH₃), 28.9 (NCH₂CH₂CH₂Ph), 33.5 (C-6), 33.5 H, 4Ј-H), 8.14 (d, ³J = 7.8 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR

(NCH₂CH₂CH₂Ph), 33.9 (C-5), 36.9 (C-8), 41.1 (C-1), 57.4 (75.4 MHz, CDCl₃): δ = 16.2 (Me), 16.4 (Me), 21.3 (C-7), 28.8

³J = 7.8, J = 1.5 Hz, 1 H, 5Ј-H), 7.65 (td, ³J = 7.8, J = 1.5 Hz, 1

4

(NCH₂CH₂CH₂Ph), 60.4 (C-4), 63.3 (C-2), 70.9 (CH₂O), 117.4 (NCH₂CH₂CH₂Ph), 33.4 (C-6 and NCH₂CH₂CH₂Ph), 33.8 (C-5),

(CHAr), 125.6, 125.7 (CH_arom.), 126.9 (C-1Ј), 127.9, 128.0, 128.3 35.1 (C-3ЈЈ), 35.3 (C-3ЈЈ), 36.8 (C-8), 36.9 (C-4ЈЈ), 41.1 (C-1), 57.3

(2 ϫ), 128.4 (2 ϫ), 129.0 (CH_arom.), 129.0 (C-4ЈЈ), 129.4, 130.4,

(NCH₂CH₂CH₂Ph), 60.3 (C-4), 63.2 (C-2), 70.6 (CH₂O), 117.3

131.4 (CH_arom.), 131.9 (C-2Ј), 133.3 (CH_arom.), 136.7, 137.7, 142.5 (CHAr), 125.6, 125.7, 126.1, 126.3 (CH_arom.), 127.2 (C-1Ј), 128.0,

(C_arom.), 146.2 (C-3ЈЈ), 146.9 (C-9), 164.8 (COO), 169.7 (C-5ЈЈ), 128.2, 128.4, 128.6, 128.9 (ϫ2), 129.0, 129.3, 129.6, 129.8, 131.3

170.8 (C-2ЈЈ) ppm. IR (film): ν = 2920 (s), 1709 (s), 1392 (s), 1253

(CH_arom.), 132.9 (C-2Ј), 133.4 (CH_arom.),137.7, 142.4 (C_arom.), 147.1

(C-9), 164.1 (CO), 164.3 (CO), 175.7 (C-5ЈЈ), 179.8 (C-2ЈЈ) ppm. IR

˜

(s), 1105 (s), 1083 (s), 725 (s), 696 (vs) cm^–1. MS (EI, 70 eV): m/z

Eur. J. Org. Chem. 2009, 1944–1960

www.eurjoc.org

1953

M. A. Brimble et al.

FULL PAPER

(film): ν = 3024 (m), 2934 (s), 1738 (vs, C=O), 1732 (vs, C=O),

(E)-{9-(2-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

˜

1714 (vs, C=O), 1602 (m), 1494 (s), 1454 (s), 1392 (vs), 1257 (s),

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoate

1190 (s), 1083 (m), 1045 (m), 910 (w), 761 (m), 699 (s) cm^–1. MS (4d): According to the general hydrogenation procedure, maleimide

(EI, 70 eV): m/z (%) = 576 (2) [M⁺], 471 (13) [M⁺– C₆H₅CH₂CH₂],

10d (800 mg, 1.31 mmol) gives the product 4d (380 mg, 47%) puri-

358 (14), 216 (100) [M⁺– C₁₂H₁₀NO₃], 146 (14), 98 (17), 91 (15) fied by column chromatography (hexane/EtOAc, 7:3) as a pale yel-

[C₆H₅CH₂], 41 (17); found (M⁺, 576.2999), C₃₇H₄₀N₂O₄calcd.

576.2988.

low oil and as a 1:1 mixture of diastereomers. R_f= 0.12 (hexane/

EtOAc, 8:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.45–1.49 (m, 3 H,

Me), 1.55–1.65 (m, 2 H, 7-H_Aand 8-H_A), 1.65–1.93 (m, 4 H, 6-H

and NCH₂CH₂CH₂Ph), 2.04–2.32 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band

NCH₂CH₂CH₂Ph), 2.42–2.62 (m, 1 H, 4ЈЈ-H_A), 2.68 (t, ³J =

7.6 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.81–2.92 (m, 1 H, 7-H_B), 2.92–

3.21 (m, 5 H, 2-H_B, 3ЈЈ-H, 4-H_B, 4ЈЈ-H_Aand 5-H), 4.31 (s, 2 H,

CH₂O), 6.16 (s, 1 H, CHAr), 7.12–7.30 (m, 9 H, CH_arom.), 7.37 (t,

(E)-{9-(4-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoate

(4b): According to the general hydrogenation procedure, maleimide

10b (615 mg, 1.01 mmol) gives the product 4b (445 mg, 73%) puri-

fied by column chromatography (hexane/EtOAc, 8:2) as a pale yel-

low oil and as a 1:1 mixture of diastereomers. R_f= 0.11 (hexane/

EtOAc, 8:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.40–1.51 (m, 3 H,

Me), 1.55–1.70 (m, 2 H, 7-H_Aand 8-H_A), 1.72–1.99 (m, 4 H, 6-H

and NCH₂CH₂CH₂Ph), 2.07–2.40 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band

NCH₂CH₂CH₂Ph), 2.42–2.62 (m, 1 H, 4ЈЈ-H_A), 2.67 (t, ³J =

7.7 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.81–2.92 (m, 1 H, 7-H_B), 2.92–

3.21 (m, 5 H, 2-H_B, 3ЈЈ-H, 4-H_B, 4ЈЈ-H_Aand 5-H), 4.26 (s, 2 H,

CH₂O), 6.13 (s, 1 H, CHAr), 7.08–7.30 (m, 9 H, CH_arom.), 7.52 (t,

3

³J = 7.6 Hz, 1 H, 3Ј-H), 7.53 (t, J = 7.6 Hz, 1 H, 5Ј-H), 7.67 (t,

3

³J = 7.6 Hz, 1 H, 4Ј-H), 8.22 (d, J = 7.6 Hz, 1 H, 6Ј-H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 16.2 (Me), 21.1 (C-7), 28.5

(NCH₂CH₂CH₂Ph), 33.1 (C-5), 33.3 (NCH₂CH₂CH₂Ph), 34.2 (C-

6), 35.0 (C-3ЈЈ), 36.4 (C-4ЈЈ), 36.8 (C-8), 41.2 (C-1), 57.3

(NCH₂CH₂CH₂Ph), 60.0 (C-4), 62.7 (C-2), 70.0 (CH₂O), 115.4

(CHAr), 125.5, 126.1 (CH_arom.), 127.7 (C-1Ј), 128.1, 128.2, 129.1,

129.7, 130.2, 131.4 (CH_arom.), 132.8 (C-2Ј), 133.3 (CH_arom.), 133.8,

136.0, 142.1 (C_arom.), 147.8 (C-9), 164.0 (CO), 175.6 (C-5ЈЈ), 179.7

3

³J = 7.7 Hz, 1 H, 5Ј-H), 7.66 (t, J = 7.7 Hz, 1 H, 4Ј-H), 8.12 (d,

³J = 7.7 Hz, 1 H, 6Ј-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

16.3 (Me), 21.1 (C-7), 28.4 (NCH₂CH₂CH₂Ph), 33.1 (C-5), 33.4

(NCH₂CH₂CH₂Ph), 33.6 (C-6), 34.7 (C-3ЈЈ), 36.6 (C-4ЈЈ), 36.9 (C-

8), 41.1 (C-1), 57.5 (NCH₂CH₂CH₂Ph), 59.9 (C-4), 62.7 (C-2), 70.2

(CH₂O), 116.6 (CHAr), 125.6, 126.3 (CH_arom.), 127.1 (C-1Ј), 128.2,

128.3, 129.3, 129.8, 129.9 (CH_arom.), 131.2, 131.9 (C_arom.), 132.8 (C-

2Ј), 133.4 (CH_arom.), 135.9, 142.1 (C_arom.), 147.2 (C-9), 164.0 (CO),

(C-2ЈЈ) ppm. IR (film): ν = 2970 (w), 2941 (m), 1720 (vs, C=O),

˜

1602 (w), 1493 (m), 1453 (m), 1371 (m), 1257 (s), 1229 (m), 1135

(m), 1082 (m), 734 (s), 699 (w) cm^–1. MS (EI, 70 eV): m/z (%) =

612 (7) [³⁷Cl, M⁺], 610 (17) [³⁵Cl, M⁺], 505 (82) [³⁵Cl, M⁺

–

C₆H₅CH₂CH₂], 378 (25), 216 (46) [M⁺– C₁₂H₁₀NO₃], 91 (56)

[C₆H₅CH₂], 40 (82); found (M⁺, 610.25750), C₃₇H₃₉³⁵ClN₂O₄

calcd. 610.25984; found (M⁺, 612.25461), C₃₉H₃₇³⁷ClN₂O₄calcd.

612.25689.

175.8 (C-5ЈЈ), 179.7 (C-2ЈЈ) ppm. IR (film): ν = 3059 (w), 2934 (m),

˜

1714 (vs, C=O), 1602 (w), 1491 (m), 1454 (m), 1392 (m), 1264 (s),

1187 (m), 1086 (m), 736 (s), 700 (w) cm^–1. MS (FAB): m/z (%) =

611 (23) [MH⁺], 307 (21), 154 (100), 136 (69), 107, (24), 91 (23)

[C₆H₅CH₂] , 7 7 (24 ) [ C₆H₅]; found (MH ⁺, 61 1. 26 84 ),

C₃₇H₄₀³⁵ClN₂O₄calcd. 611.2677.

(E)-{9-(3-Chlorobenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoate

(4e): According to the general hydrogenation procedure, maleimide

10d (150 mg, 240 µmol) gives the product 4e (83 mg, 55%) purified

by column chromatography (hexane/EtOAc, 7:3) as a pale yellow

oil and as a 1:1 mixture of diastereomers. R_f= 0.15 (hexane/EtOAc,

8:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.43–1.47 (m, 3 H, Me),

1.57–1.70 (m, 2 H, 7-H_Aand 8-H_A), 1.74–1.94 (m, 4 H, 6-H and

NCH₂CH₂CH₂Ph), 2.09–2.37 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band

NCH₂CH₂CH₂Ph), 2.46–2.55 (m, 1 H, 4ЈЈ-H_A), 2.68 (t, ³J =

7.7 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.87–3.14 (m, 6 H, 7-H_B, 2-H_B,

3ЈЈ-H, 4-H_B, 4ЈЈ-H_Aand 5-H), 4.25 (s, 2 H, CH₂O), 6.10 (s, 1 H,

(E)-{9-(4-Methoxybenzylidene)-3-(3-phenylpropyl)-3-azabicyclo-

[3.3.1]nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)ben-

zoate (4c): According to the general hydrogenation procedure, ma-

leimide 10c (80 mg, 132 µmol) gives the product 4c (54 mg, 68%)

purified by column chromatography (hexane/EtOAC, 7:3) as an oil

and as a 1:1 mixture of diastereomers. R_f= 0.11 (EtOAc/hexane,

2:8). ¹H NMR (300 MHz, CDCl₃): δ = 1.40–1.54 (m, 3 H, Me),

1.55–1.72 (m, 2 H, 7-H_Aand 8-H_A), 1.72–1.98 (m, 4 H, 6-H and

NCH₂CH₂CH₂Ph), 2.05–2.33 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band

3

CHAr), 7.05 (d, J = 7.5 Hz, ArH), 7.15–7.30 (m, 9 H, 3Ј-H and

2

4

2

CH_arom.), 7.53 (td, J = 7.8, J = 1.5 Hz, 1 H, 5Ј-H), 7.66 (td, J =

4

2

4

7.5, J = 1.5 Hz, 1 H, 4Ј-H), 8.12 (dd, J = 7.8, J = 1.2 Hz, 1 H,

3Ј-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.3 (Me), 21.3 (C-

7), 28.9 (NCH₂CH₂CH₂Ph), 33.5 (C-5), 33.5 (NCH₂CH₂CH₂Ph),

34.0 (C-6), 35.2 (C-3ЈЈ), 36.9 (C-4ЈЈ), 37.0 (C-8), 41.3 (C-1), 57.4

(NCH₂CH₂CH₂Ph), 60.3 (C-4), 62.3 (C-2), 70.5 (CH₂O), 116.2

(CHAr), 125.7 (CH_arom.), 126.3 (C-1Ј), 127.2, 128.3 (2ϫ), 128.4

(2ϫ), 128.7, 129.1, 129.1, 129.3, 129.4, 129.9, 131.4 (CH_arom.),

133.0 (C-2Ј), 133.5 (CH_arom.), 133.9, 139.6, 142.5 (C_arom.), 148.6 (C-

3

NCH₂CH₂CH₂Ph), 2.44–2.65 (m, 1 H, 3ЈЈ-H), 2.68 (t, J = 7.7 Hz,

2 H, NCH₂CH₂CH₂Ph), 2.82–3.18 (m, 6 H, 2-H_B, 4-H_B, 5-H and

4ЈЈ-H), 3.79 (s, 3 H, OCH₃), 4.26 (s, 2 H, CH₂O), 6.09 (s, 1 H,

3

CHAr), 6.85 (d, J = 8.7 Hz, 2 H, m-ArH), 7.11 (d, J = 8.7 Hz, 2

3

4

H, o-ArH), 7.16–7.32 (m, 6 H, 6Ј-H and Ph), 7.53 (td, J = 7.6, J

3

4

= 1.3 Hz, 1 H, 5Ј-H), 7.67 (td, J = 7.6, J = 1.3 Hz, 1 H, 4Ј-H),

8.15 (d, ³J = 7.6 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR (75.4 MHz,

C D C l ₃) : δ = 1 6 . 3 ( M e ) , 1 6 . 5 ( M e ) , 2 1 . 4 ( C - 7 ) , 2 8 . 9

(NCH₂CH₂CH₂Ph), 33.4 (C-6), 33.5 (NCH₂CH₂CH₂Ph), 33.7 (C-

5), 35.2 (C-3ЈЈ), 36.8 (C-4ЈЈ), 36.9 (C-8), 41.1 (C-1), 55.2 (OCH₃),

57.4 (NCH₂CH₂CH₂Ph), 60.3 (C-4), 63.3 (C-2) 70.8 (CH₂O), 113.5

(CH_arom.), 116.7 (CHAr), 125.6, 128.2, 128.4, 129.4 (CH_arom.),

129.8 (C-1Ј), 129.9, 131.4 (CH_arom.), 132.9 (C-2Ј), 133.4 (CH_arom.),

142.5 (C_arom.), 146.0 (C-9), 157.9 (ArC-OMe), 164.3 (CO), 175.9

9), 164.2 (CO), 176.0 (C-5ЈЈ), 179.9 (C-2ЈЈ) ppm. IR (film): ν =

˜

2924 (m), 1711 (vs, C=O), 1602 (w), 1453 (m), 1390 (m), 1258 (s),

1184 (m), 1136 (m), 1079 (m), 908 (m), 728 (s), 698 (w) cm^–1. MS

(FAB): m/z (%) = 613 (7) [³⁷Cl, MH⁺] 611 (20) [³⁵Cl, MH⁺] 307

(16), 154 (100), 136 (68), 107 (26), 91 (22) [C₆H₅CH₂], 77 (25);

found (MH⁺, 611.26766), C₃₇H₃₉³⁵ClN₂O₄calcd. 611.26732; found

(MH⁺, 613.26654), C₃₉H₃₇³⁷ClN₂O₄calcd. 613.26593.

(C-5ЈЈ), 179.9 (C-2ЈЈ) ppm. IR (film): ν = 3027 (w), 2934 (s), 1714

˜

(vs, C=O), 1604 (m), 1510 (m), 1454 (m), 1392 (m), 1250 (s), 1181

(E)-{9-(3-Methoxybenzylidene)-3-(3-phenylpropyl)-3-azabicyclo-

(m), 1083 (m), 910 (m), 732 (m) cm^–1. MS (FAB): m/z (%) = 607 [3.3.1]nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)ben-

(6) [MH⁺], 307 (24), 154 (100), 136 (67), 107 (20), 89 (20), 77 (19)

[C₆H₅]; found (MH⁺, 607.3177), C₃₈H₄₃N₂O₅calcd. 607.3172.

zoate (4f): According to the general hydrogenation procedure, ma-

leimide 10f (58 mg, 100 µmol) gives the product 4f (41 mg, 71%)

1954

www.eurjoc.org

Eur. J. Org. Chem. 2009, 1944–1960

Synthesis of Analogues of the Alkaloid Methyllycaconitine

purified by column chromatography (hexane/EtOAc, 7:3) as a pale

NCH₂CH₂CH₂Ph), 2.32 (s, 3 H, ArCH₃), 2.46–2.58 (m, 1 H, 4ЈЈ-

H_A), 2.67 (t, J = 7.2 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.89–3.10 (m, 6

3

yellow oil and as a 1:1 mixture of diastereomers. R_f= 0.17 (hexane/

EtOAc, 8:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.45–1.49 (m, 3 H, H, 7-H_B, 2-H_B, 3ЈЈ-H, 4-H_B, 4ЈЈ-H_Aand 5-H), 4.27 (s, 2 H, CH₂O),

Me), 1.55–1.69 (m, 2 H, 7-H_Aand 8-H_A), 1.75–1.93 (m, 4 H, 6-H

and NCH₂CH₂CH₂Ph), 2.09–2.34 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band

6.12 (s, 1 H, CHAr), 7.09–7.26 (m, 8 H, 3Ј-H and CH_arom.), 7.50

(td, ²J = 7.2, ⁴J = 1.2 Hz, 1 H, 5Ј-H), 7.64 (td, ²J = 7.2, ⁴J =

NCH₂CH₂CH₂Ph), 2.52–2.62 (m, 1 H, 4ЈЈ-H_A), 2.68 (t, ³J = 1.2 Hz, 1 H, 4Ј-H), 8.13 (dd, ²J = 7.2, ³J = 1.2 Hz, 1 H, 3Ј-H)

7.6 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.87–3.12 (m, 6 H, 7-H_B, 2-H_B,

3ЈЈ-H, 4-H_B, 4ЈЈ-H_Aand 5-H), 3.80 (s, 3 H, OCH₃), 4.25 (s, 2 H,

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.2 (Me), 21.0 (C-7), 21.4

( A r C H ₃) , 2 8 . 8 ( N C H ₂C H ₂C H ₂P h ) , 3 3 . 4 ( C - 5 ) , 3 3 . 4

(NCH₂CH₂CH₂Ph), 33.7 (C-6), 35.1 (C-3ЈЈ), 36.8 (C-4ЈЈ), 36.8 (C-

8), 41.1 (C-1), 57.3 (NCH₂CH₂CH₂Ph), 60.3 (C-4), 62.2 (C-2), 70.7

(CH₂O), 117.1 (CHAr), 125.5 (CH_arom.), 127.2 (C-1Ј), 128.2 (2ϫ),

128.3 (2ϫ), 128.5 (2ϫ), 128.7 (2ϫ), 129.3, 129.8 (CH_arom.), 131.9

3

CH₂O), 6.13 (s, 1 H, CHAr), 6.75 (dd, J = 10.8, J = 1.2 Hz, 2 H,

2

4

ArH), 7.16–7.30 (m, 8 H, 3Ј-H and CH_arom.), 7.53 (td, J = 8.0, J

2

4

= 0.8 Hz, 1 H, 5Ј-H), 7.67 (td, J = 7.6, J = 1.2 Hz, 1 H, 4Ј-H),

8.14 (d, ²J = 7.6 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 16.4 (Me), 21.4 (C-7), 28.9 (NCH₂CH₂CH₂Ph), 33.5 (C-2Ј), 132.9, 133.3 (CH_arom.), 134.7, 135.6, 142.4 (C_arom.), 146.5

(C-5), 33.5 (NCH₂CH₂CH₂Ph), 34.0 (C-6), 35.3 (C-3ЈЈ), 36.9 (C-

4ЈЈ), 37.0 (C-8), 41.2 (C-1), 55.1 (OCH₃), 57.4 (NCH₂CH₂CH₂Ph),

(C-9), 164.1 (CO), 175.9 (C-5ЈЈ), 179.8 (C-2ЈЈ) ppm. IR (film): ν =

2925 (m), 1710 (vs, C=O), 1602 (w), 1453 (m), 1388 (m), 1257 (s),

˜

60.4 (C-4), 63.3 (C-2), 70.8 (CH₂O), 111.7, 114.3 (CH_arom.), 117.3 1181 (m), 1135 (m), 731 (s), 698 (w) cm^–1. MS (EI, 70 eV): m/z (%)

(CHAr), 121.2, 123.5, 125.6 (CH_arom.), 127.3 (C-1Ј), 128.3 (2ϫ), = 590 (12) [M⁺] 485 (100) [M⁺– C₆H₅CH₂CH₂], 358 (16), 216

128.5 (2ϫ), 129.1, 129.4, 129.9 (CH_arom.), 131.4 (C-2Ј), 133.0, 133.5

(CH_arom.), 139.2, 142.5 (C_arom.), 147.4 (C-9), 159.4 (ArC-OMe),

(28), 105 (27), 91 (36) [C₆H₅CH₂], 41 (29); found (M⁺, 590.31446),

C₃₈H₄₂N₂O₄calcd. 590.31475.

164.8 (CO), 175.8 (C-5ЈЈ), 179.9 (C-2ЈЈ) ppm. IR (film): ν = 2934

˜

Ethyl 2-(Hydroxymethyl)acrylate:^[30]Phosphoric acid (1 , 0.4 mL,

0.4 mmol) was added to a stirred solution of paraformaldehyde

(3.3 g, 110 mmol) in water (10 mL) was added. The resulting mix-

ture was heated at 90 °C for 2.5 h then cooled to room temperature.

A solution of ethyl acrylate (10.9 mL, 100 mmol) and 1,4-diazobi-

cyclo[2.2.2]octane (DABCO) (1.13 g, 10.1 mmol) in THF (10 mL),

was added and the mixture heated at reflux for 20 h. The mixture

was cooled to room temperature and sodium chloride (3.0 g) and

diethyl ether (10 mL) added. The organic layer was separated and

further product was extracted from the aqueous layer with diethyl

ether (3ϫ10 mL). The combined organic layers were washed with

brine (2 ϫ 10 mL), dried (MgSO₄) and the solvent removed in

vacuo to give the crude product which was distilled under vacuum

to give the title compound (5.9 g, 45%); b.p. 65–82 °C/1 Torr. ¹H

NMR (300 MHz, CDCl₃): δ = 1.32 (t, J = 4.0 Hz, 3 H, OCH₂CH₃),

2.68 (s, 1 H, OH), 4.25 (q, J = 7.2 Hz, 2 H, OCH₂CH₃), 4.33 (s, 2

(m), 1716 (vs, C=O), 1602 (w), 1453 (m), 1390 (m), 1261 (s), 1187

(m), 1135 (m), 910 (m), 731 (s), 698 (w) cm^–1. MS (EI, 70 eV): m/z

(%) = 606 (5) [M⁺] 501 (33) [M⁺– C₆H₅CH₂CH₂], 216 (73), 188

(31), 146 (53), 91 (100) [C₆H₅CH₂], 77 (23), 69 (26), 41 (77); found

(M⁺, 606.30937), C₃₈H₄₂N₂O₄calcd. 606.30838.

(E)-{9-(3-Methylbenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoate

(4g): According to the general hydrogenation procedure, maleimide

10g (37 mg, 62 µmol) gives the product 4g (20 mg, 55%) purified

by column chromatography (hexane/EtOAc, 7:3) as a pale yellow

oil and as a 1:1 mixture of diastereomers. R_f= 0.14 (hexane/EtOAc,

8:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.43–1.47 (m, 3 H, Me),

1.56–1.70 (m, 2 H, 7-H_Aand 8-H_A), 1.74–1.94 (m, 4 H, 6-H and

NCH₂CH₂CH₂Ph), 2.07–2.29 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band

NCH₂CH₂CH₂Ph), 2.33 (s, 3 H, ArCH₃), 2.48–2.61 (m, 1 H, 4ЈЈ-

3

1

H_A), 2.68 (t, J = 6.3 Hz, 2 H, NCH₂CH₂CH₂Ph), 2.86–3.14 (m, 6

H, CH₂OH), 5.38 (m, 1 H, =CH₂), 6.26 (m, 1 H, =CH₂) The H

H, 7-H_B, 2-H_B, 3ЈЈ-H, 4-H_B, 4ЈЈ-H_Aand 5-H), 4.27 (s, 2 H, CH₂O),

NMR spectroscopic data was in agreement with the literature val-

6.13 (s, 1 H, CHAr), 7.00 (t, ³J = 7.7 Hz, 2 H, ArH), 7.03–7.30 (m,

ues.^[34]

2

4

8 H, 3Ј-H and CH_arom.), 7.53 (td, J = 7.8, J = 1.2 Hz, 1 H, 5Ј-

Ethyl 2-(Bromomethyl)acrylate (12):^[29]Phosphorus tribromide

(1.4 mL, 15.4 mmol) was slowly added to a stirred solution of ethyl

2-(hydroxymethyl)acrylate (5.9 g, 45 mmol) in diethyl ether (45 mL)

at –10 °C. The mixture was stirred for 3 h during which time the

temperature was warmed to room temperature. The mixture was

then cooled to –10 °C and water (3 mL) added. The mixture was

extracted with hexanes (3ϫ20 mL). The combined organic layers

were washed with brine (2ϫ20 mL), dried (MgSO₄) and the sol-

vent removed in vacuo to give the crude product which was distilled

under vacuum to give the title compound 12 (6.82 g, 78%) for

which the spectroscopic data was consistent with the literature val-

ues.^[29]

2

4

2

H), 7.67 (td, J = 7.5, J = 1.5 Hz, 1 H, 4Ј-H), 8.14 (dd, J = 7.8,

³J = 1.2 Hz, 1 H, 3Ј-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

16.4 (Me), 21.5 (C-7), 21.5 (ArCH₃), 28.9 (NCH₂CH₂CH₂Ph), 33.5

(C-5), 33.5 (NCH₂CH₂CH₂Ph), 33.9 (C-6), 35.3 (C-3ЈЈ), 36.9 (C-

4ЈЈ), 37.0 (C-8), 41.2 (C-1), 57.5 (NCH₂CH₂CH₂Ph), 60.4 (C-4),

63.4 (C-2), 70.8 (CH₂O), 117.4 (CHAr), 125.7, 126.4, 127.0

(CH_arom.), 127.7 (C-1Ј), 128.0, 128.3 (2 ϫ), 128.5 (2 ϫ), 129.1,

129.4, 129.9 (CH_arom.), 130.8 (C-2Ј), 131.4 (CH_arom.), 133.0

(C_arom.), 133.5 (CH_arom.), 137.7, 142.5 (C_arom.), 146.9 (C-9), 164.1

(CO), 175.9 (C-5ЈЈ), 179.9 (C-2ЈЈ) ppm. IR (film): ν = 2924 (m),

˜

1714 (vs, C=O), 1602 (w), 1454 (m), 1392 (m), 1260 (s), 1187 (m),

1137 (m), 1084 (m), 910 (m), 731 (s), 698 (w) cm^–1. MS (EI, 70 eV):

m/z (%) = 590 (6) [M⁺] 485 (48) [M⁺– C₆H₅CH₂CH₂], 216 (100),

91 (26) [C₆H₅CH₂], 41 (23); found (M⁺, 590.31446), C₃₈H₄₂N₂O₄

calcd. 590.31406.

Ethyl 1-(3-Phenylpropyl)-1,2,3,4,5,6,7,8-octahydroquinoline-3-car-

boxylate (14a): To 3-phenylpropylamine 13a (0.85 mL, 6.0 mmol)

in toluene (32 mL) was added dropwise ethyl 2-(bromomethyl)acry-

(E)-{9-(4-Methylbenzylidene)-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]- late (12, 580 mg, 3.00 mmol) in toluene (5 mL) at 0 °C. After

nonan-1-yl}methyl 2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoate 15 min a solution of cyclohexanone (0.31 mL, 3.00 mmol) in tolu-

(4h): According to the general hydrogenation procedure, maleimide

10h (250 mg, 420 µmol) gives the product 4h (198 mg, 79%) puri-

fied by column chromatography (hexane/EtOAc, 7:3) as a pale yel-

low oil and as a 1:1 mixture of diastereomers. R_f= 0.21 (hexane/

ene (5 mL) was added and the reaction mixture was heated under

reflux under N₂for 18 h using a Dean–Stark trap containing 5-Å

molecular sieves. The mixture was cooled and extracted with 1 

HCl (2ϫ100 mL). The combined aqueous layers were washed with

EtOAc, 8:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.43–1.46 (m, 3 H, EtOAc (100 mL), basified with solid Na₂CO₃and then extracted

Me), 1.61–1.63 (m, 2 H, 7-H_Aand 8-H_A), 1.77–1.89 (m, 4 H, 6-H

and NCH₂CH₂CH₂Ph), 2.12–2.28 (m, 5 H, 2-H_A, 4-H_A, 8-H_Band

with CH₂Cl₂(3ϫ75 mL). The extract was dried Na₂SO₄and con-

centrated in vacuo. The crude product was purified by column

Eur. J. Org. Chem. 2009, 1944–1960

www.eurjoc.org

1955

M. A. Brimble et al.

FULL PAPER

chromatography on silica gel (hexane/EtOAc, 8:2) to give 14a

(589 mg, 60%) as a pale yellow oil. R_f= 0.22 (hexane/EtOAc, 8:2).

¹H NMR (300 MHz, CDCl₃): δ = 1.25 (t, J = 6.8 Hz, 3 H,

OCH₂CH₃), 1.43–1.79 (m, 4 H, 6-CH₂and 7-CH₂), 1.72–1.79 (m

2 H, NCH₂CH₂CH₂Ph), 1.82–1.90 (m, 4 H, 5-CH₂and 8-CH₂),

1.97–2.03 (m, 2 H, 4-CH₂), 2.59 (td, J = 8.3, J = 2.7 Hz, 2 H,

NCH₂CH₂CH₂Ph), 2.71 (tdd, J = 11.8, J = 3.3, J = 5.7 Hz, 1 H,

3-H), 2.86–2.99 (m, 3 H, 2-H_A, NCH₂CH₂CH₂Ph), 3.20 (ddd, J =

11.9, J = 3.3, J = 1.8 Hz, 1 H, 2-H_B), 4.13, (m, 2 H, OCH₂CH₃),

7.12–7.31 (m, 5 H, Ph) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ =

14.2 (OCH₂CH₃), 22.9, 23.6, (CH₂), 26.4 (NCH₂CH₂CH₂Ph), 29.7

(C-8), 29.9 (C-5), 31.2 (C-4), 33.4 (NCH₂CH₂CH₂Ph), 38.1 (C-3),

50.0 (NCH₂CH₂CH₂Ph), 50.2 (C-2), 60.3 (OCH₂CH₃), 106.1 (C-

4a), 125.7 (p-Ph), 128.3 (o- and m-Ph), 135.8 (C-8a), 142.0 (Ph),

222 (36), 86 (100); found [M]⁺265.20370. C₁₆H₂₇NO₂requires

265.20418.

(R)-Ethyl 1-[(R)-1-Phenylethyl]-1,2,3,4,5,6,7,8-octahydroquinoline-

3-carboxylate (14d): Following a similar procedure to that de-

scribed above for the preparation of 14a, (R)-1-phenylethanamine

13d (0.73 mL, 6.0 mmol) was treated with ethyl 2-(bromomethyl)-

acrylate (12, 579 mg, 3.0 mmol) and cyclohexanone (0.31 mL,

3.0 mmol). The crude product was purified by column chromatog-

raphy on silica gel (hexane/EtOAc, 8:2) to give 14d (472 mg, 50%)

as a bright yellow oil. R_f= 0.24 (hexane/EtOAc, 8:2). [α]²_D⁰= +39

1

(c = 0.89, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 1.94 (t, J =

7.1 Hz, 3 H, OCH₂CH₃), 1.43 [d, J = 7.0 Hz, 3 H, NCH(CH₃)Ph],

1.60–1.77 (m, 4 H, 6-CH₂and 7-CH₂), 1.85–2.08 (m, 3 H, 5-CH₂

and 8-H_A), 2.13–2.36 (m, 3 H, 4-CH₂and 8-H_B), 2.61–2.70 (m, 2

H, 2-H_Aand 3-H), 2.98–3.10 (m, 1 H, 2-H_B), 3.99–4.17 (m, 2 H,

OCH₂CH₃), 4.73–4.81 [m, 1 H, NCH(CH₃)Ph], 7.23–7.40 (m, 5 H,

Ph) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 14.1 (OCH₂CH₃),

15.5 [NCH(CH₃)Ph], 23.1 (C-7), 23.9 (C-6), 26.7 (C-5), 30.1 (C-

8), 30.3 (C-4), 38.1 (C-3), 44.9 (C-2), 53.3 [NCH(CH₃)Ph], 60.1

(OCH₂CH₃), 105.6 (C-4a), 126.5, 127.2, 128.6 (Ph), 134.5 (C-8a),

174.6 (COO) ppm. IR (film): ν = 3025 (w), 2930 (m), 1729 (vs,

˜

C=O), 1637 (w), 1453 (w), 1184 (m), 1029 (w) cm^–1. MS (EI,

70 eV): m/z (%) = 327 (88) [M⁺], 222 (100) [M⁺– EtPh], 91 (45)

[Bn⁺]; found [M]⁺327.2195. C₂₁H₂₉NO₂requires 327.2198.

Ethyl 1-Benzyl-1,2,3,4,5,6,7,8-octahydroquinoline-3-carboxylate

(14b): Following a similar procedure to that described above for

the preparation of 14a, benzylamine 13b (0.66 mL, 6.0 mmol) was

treated with ethyl 2-(bromomethyl)acrylate 12 (579 mg, 3.0 mmol)

and cyclohexanone (0.31 mL, 3.0 mmol). The crude product was

purified by column chromatography on silica gel (hexane/EtOAc,

8:2) to give 14b (440 mg, 47%) as a pale yellow oil. R_f= 0.24 (hex-

ane/EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 1.21 (t, J =

7.0 Hz, 3 H, OCH₂CH₃), 1.55–1.73 (m, 4 H, 6-CH₂and 7-CH₂),

1.81–2.14 (m, 3 H, 5-CH₂and 8-H_A), 2.15–2.26 (m, 3 H, 4-CH₂

and 8-H_B), 2.61–2.75 (m, 1 H, 3-H), 2.91 (t, J = 11.3 Hz, 1 H, 2-

H_A), 3.14 (ddd, J = 11.4, J = 3.3, J = 1.9 Hz, 1 H, 2-H_B), 3.96–

4.06 (m, 2 H, NCH₂Ph), 4.07–4.13, (m, 2 H, OCH₂CH₃), 7.22–

7.33 (m, 5 H, Ph) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 14.1

(OCH₂CH₃), 23.0, 23.6, (CH₂), 26.7 (C-5), 29.9 (C-8), 31.2 (C-4),

37.6 (C-3), 50.2 (C-2), 53.8 (NCH₂Ph), 60.2 (OCH₂CH₃), 106.3 (C-

4a), 126.7, 128.3 (Ph), 135.9 (C-8a), 140.1 (Ph), 174.5 (COO) ppm.

143.3 (Ph), 174.7 (COO) ppm. IR (film): ν = 3021 (w), 2930 (w),

˜

2846 (w), 1727 (vs, C=O), 1446 (m), 1371 (m), 1176 (w), 1026 (m)

cm^–1. MS (EI, 70 eV): m/z (%) = 313 (56) [M⁺], 209 (35), 136 (24),

105 (100), 77 (27); found [M]⁺313.20420. C₂₀H₂₇NO₂requires

313.20418.

Ethyl (3S*,4aR*,8aR*)-1-(3-Phenylpropyl)decahydroquinoline-3-

carboxylate (15a): Olefin 14a (350 mg, 1.07 mmol) and PtO₂

(40 mg, ca. 10 mol-%) in EtOAc (5 mL) were stirred under H₂for

18 h. The mixture was filtered through a Celite pad. The filtrate

was concentrated in vacuo and the crude product was purified by

column chromatography on silica (hexane/EtOAc, 8:2) to give 15a

(149 mg, 41%) as a pale yellow oil. R_f= 0.21 (hexane/EtOAc, 8:2).

¹H NMR (300 MHz, CDCl₃): δ = 1.10–1.97 (m, 1 H, 8-H_A), 1.20

(t, J = 7.1 Hz, 3 H, OCH₂CH₃), 1.28–1.41 (m, 2 H, 6-CH₂), 1.43–

1.50 (m, 2 H, 7-CH₂), 1.51–1.58 (m, 2 H, 5-CH₂), 1.61–1.73 (m, 2

H, 4-CH₂), 1.74–1.76 (m, 1 H, 8-H_B), 1.79–1.87 (m, 2 H,

NCH₂CH₂CH₂Ph), 1.94–2.01 (m, 1 H, 4a-H), 2.45–2.53 (m, 3 H,

2-H_A, and NCH₂CH₂CH₂Ph), 2.65 (t, J = 7.6 Hz, 2 H,

NCH₂CH₂CH₂Ph), 2.55–2.67 (m, 1 H, 3-H), 2.68–2.73 (m, 1 H,

8a-H), 2.78 (dd, J = 11.2, J = 2.7 Hz, 1 H, 2-H_B), 4.11 (q, J =

7.1 Hz, 2 H, OCH₂CH₃), 7.14–7.29 (m, 5 H, Ph) ppm. ¹³C NMR

(75.5 MHz, CDCl₃): δ = 14.0 (OCH₂CH₃), 17.3 (C-7), 20.2 (C-6),

25.3 (C-8), 26.9 (C-4), 29.3 (NCH₂CH₂CH₂Ph), 31.2 (C-5), 33.4

(NCH₂CH₂CH₂Ph), 34.5 (C-4a), 42.0 (C-3), 47.2 (C-2), 53.1

(NCH₂CH₂CH₂Ph), 58.4 (C-8a), 59.9 (OCH₂CH₃), 125.4 (p-Ph),

128.0 (o-Ph), 128.1 (m-Ph), 142.1 (Ph), 174.2 (COO) ppm. IR

IR (film): ν = 3025 (w), 2927 (m), 2836 (w), 1727 (vs, C=O), 1176

˜

(m), 1027 (w) cm^–1. MS (EI, 70 eV): m/z (%) = 299 (76) [M⁺], 226

(25), 208 (75), 91 (100) [Bn⁺]; found [M]⁺299.18853. C₁₉H₂₅NO₂

requires 299.18823.

Ethyl 1-Butyl-1,2,3,4,5,6,7,8-octahydroquinoline-3-carboxylate

(14c): Following a similar procedure to that described above for the

preparation of 14a, butylamine 13c (0.51 mL, 5.2 mmol) was

treated with ethyl 2-(bromomethyl)acrylate 12 (500 mg, 2.6 mmol)

and cyclohexanone (0.27 mL, 2.6 mmol). The crude product was

purified by column chromatography on silica gel (hexane/EtOAc,

8:2) to give 14c (496 mg, 72%) as a dark yellow oil. R_f= 0.29

(hexane/EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (t,

J = 7.0 Hz, 3 H, NCH₂CH₂CH₂CH₃), 1.23 (t, J = 6.3 Hz, 3 H,

OCH₂CH₃), 1.20–1.30 (m, 2 H, NCH₂CH₂CH₂CH₃), 1.31–1.39 (m,

2 H, 6-CH₂), 1.41–1.54 (m, 2 H, NCH₂CH₂CH₂CH₃), 1.55–1.72

(m, 2 H, 7-CH₂), 1.81–2.05 (m, 3 H, 5-CH₂and 8-H_A), 2.08–2.11

(m, 1 H, 8-H_B), 2.13–2.22 (m, 2 H, 4-CH₂), 2.66 (ddt, J = 3.1, 5.6

(film): ν = 3025 (w), 2931 (vs), 2864 (s), 1730 (vs, C=O), 1602 (w),

˜

1496 (m), 1453 (m), 1370 (m), 1320 (w), 1261 (m), 1248 (m), 1157

(s), 1032 (m), 746 (m), 699 (m) cm^–1. MS (EI, 70 eV): m/z (%) =

329 (38) [M⁺], 286 (92), 224 (100) [M⁺– EtPh], 91 (22) [Bn⁺]; found

[M]⁺329.2360. C₂₁H₃₁NO₂requires 329.2355.

Ethyl (3S*,4aR*,8aR*)-1-Benzyldecahydroquinoline-3-carboxylate

and 10.8 Hz, 1 H, 3-H), 2.73–2.86 (m, 2 H, NCH₂CH₂CH₂CH₃), (15b): Following a similar procedure to that described above for the

2.91 (t, J = 10.9 Hz, 1 H, 2-H_A), 3.16 (ddd, J = 2.0, 3.2 and preparation of 15a, olefin 14b (415 mg, 1.4 mmol) was subjected to

12.0 Hz, 1 H, 2-H_B) and 4.07–4.14 (m, 2 H, OCH₂CH₃) ppm. ¹³C

NMR (75.5 MHz, CDCl₃): δ = 14.1 (NCH₂CH₂CH₂CH₃), 14.2

( O C H ₂C H ₃) , 2 0 . 6 ( N C H ₂C H ₂C H ₂C H ₃) , 2 3 . 0

(NCH₂CH₂CH₂CH₃), 23.6 (C-7), 26.4 (C-8), 30.0 (C-6), 30.2 (C-

5), 31.3 (C-4), 38.1 (C-3), 50.2 (C-2 and NCH₂CH₂CH₂CH₃), 60.3

(OCH₂CH₃), 105.8 (C-4a), 136.0 (C-8a), 174.7 (COO) ppm. IR

hydrogenation over platinum oxide (50 mg) to give 15b (227 mg,

54%) as a pale yellow oil. H NMR (300 MHz, CDCl₃): δ = 1.08–

1.14 (m, 1 H, 8-H_A), 1.21 (t, J = 10.3 Hz, 3 H, OCH₂CH₃), 1.31–

1.39 (m, 2 H, 6-CH₂), 1.45–1.71 (m, 5 H, 4-H_A, 5-CH₂and 7-CH₂),

1.72–1.92 (m, 2 H, 4-H_Band 8-H_B), 1.94–2.10 (m, 1 H, 4a-H),

2.51–2.66 (m, 2 H, 2-H_Aand 3-H), 2.67–2.80 (m, 2 H, 2-H_Band

1

(film): ν = 2955 (w), 2927 (m), 2859 (w), 1729 (vs, C=O), 1659 (m), 8a-H), 3.57–3.62 (m, 1 H, NCH_ACH_BPh), 3.71–3.76 (m, 1 H,

˜

1176 (m), 1160 (w) cm^–1. MS (EI, 70 eV): m/z (%) = 265 (14) [M⁺], NCH_ACH_BPh), 4.10 (q, J = 7.0 Hz, 2 H, OCH₂CH₃), 7.16–7.31

1956

www.eurjoc.org

Eur. J. Org. Chem. 2009, 1944–1960

Synthesis of Analogues of the Alkaloid Methyllycaconitine

(m, 5 H, Ph) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 14.2 1.93 (m, 3 H, 3-H and NCH₂CH₂CH₂Ph), 1.94–2.08 (m, 1 H, 4a-

(OCH₂CH₃), 18.1 (C-7), 21.0 (C-6), 25.5 (C-8), 27.3 (C-4), 31.4 (C-

5), 34.7 (C-4a), 42.3 (C-3), 47.0 (C-2), 58.4 (NCH₂Ph), 58.9 (C-8a), NCH₂CH₂CH₂Ph), 2.55–2.71 (m, 2 H, NCH₂CH₂CH₂Ph), 2.74–

60.1 (OCH₂CH₃), 126.7, 128.1, 128.4 (Ph), 139.8 (Ph), 174.7 (COO) 2.76 (m, 1 H, 2-H_B), 2.79–2.81 (m, 1 H, 8a-H), 3.41–3.55 (m, 2 H,

H ) , 2 . 1 2 – 2 . 1 9 ( m , 1 H , 2 - H _A) , 2 . 4 0 – 2 . 5 4 ( m , 2 H ,

ppm. IR (film): ν = 2927 (vs), 2836 (s), 1727 (vs, C=O), 1660 (w), CH₂OH), 7.14–7.30 (m, 5 H, Ph) ppm. ¹³C NMR (100 MHz,

˜

1176 (s), 1027 (m) cm^–1. MS (EI, 70 eV): m/z (%) = 301 (35) [M⁺],

258 (100), 149 (27), 91 (73); found [M]⁺301.20339. C₁₉H₂₇NO₂

requires 301.20418.

CDCl₃): δ = 17.0 (C-8), 21.0 (C-6), 25.6 (C-7), 27.2 (C-4), 29.5

(NCH₂CH₂CH₂Ph), 31.7 (C-5), 33.8 (NCH₂CH₂CH₂Ph), 35.2 (C-

4a), 39.4 (C-3), 49.4 (C-2), 53.7 (NCH₂CH₂CH₂Ph), 58.9 (C-8a),

66.6 (CH₂OH), 125.6 (p-Ph), 128.2 (o-Ph), 128.4 (m-Ph), 142.3 (Ph)

Ethyl (3S*,4aR*,8aR*)-1-Butyldecahydroquinoline-3-carboxylate

(15c): Following a similar procedure to that described above for the

preparation of 15a, olefin 14c (466 mg, 1.8 mmol) was subjected to

hydrogenation over platinum oxide (68 mg) to give 15c (255 mg,

ppm. IR (film): ν = 3369 (br., O–H), 3025 (m), 2928 (vs), 2860 (s),

˜

1495 (m), 1466 (m), 1452 (s), 1372 (m), 1081 (s), 1039 (s), 738 (s),

699 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 287 (28) [M⁺], 244 (100),

182 (87), 91 (26) [Bn⁺], 44 (26); found [M]⁺287.2246. C₁₉H₂₉NO

requires 287.2249.

1

54%) as a pale yellow oil. IR (film): H NMR (400 MHz, CDCl₃):

δ = 0.91 (t, J = 7.3 Hz, 3 H, NCH₂CH₂CH₂CH₃), 1.12–1.19 (m, 1

H, 8-H_A), 1.26 (t, J = 7.2 Hz, 3 H, OCH₂CH₃), 1.12–1.41 (m, 4 H, [(3S*,4aR*,8aR*)-1-Benzyldecahydroquinolin-3-yl]methanol (16b):

7-CH₂and NCH₂CH₂CH₂CH₃), 1.43–1.50 (m, 4 H, 6-CH₂and Following a similar procedure to that described above for the prep-

NCH₂CH₂CH₂CH₃), 1.52–1.62 (m, 3 H, 4-H_Aand 5-CH₂), 1.76– aration of 16a, ester 15b (277 mg, 0.96 mmol) was reduced with

1.85 (m, 2 H, 4-H_Band 8-H_B), 1.95–1.99 (m, 1 H, 3-H), 2.41–2.54

lithium aluminium hydride (37 mg, 0.97 mmol) to give 16b

(m, 3 H, 2-H_Aand NCH₂CH₂CH₂CH₃), 2.58–2.65 (m, 1 H, 4a-H), (195 mg, 100%) as a pale yellow oil, which was used without fur-

2.72–2.75 (m, 1 H, 8a-H), 2.76–2.81 (m, 1 H, 2-H_B), 4.12 (q, J = ther purification. ¹H NMR (400 MHz, CDCl₃): δ = (CDCl₃) 1.02–

7.1 Hz, 2 H, OCH₂CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

1.18 (m, 1 H, 7-H_A), 1.23–1.29 (m, 2 H, 6-CH₂), 1.29–1.39 (m, 2

1 4 . 0 ( N C H ₂C H ₂C H ₂C H ₃) , 1 4 . 1 ( O C H ₂C H ₃) , 1 7 . 2 9 H, 4-CH₂), 1.48–1.64 (m, 4 H, 5-CH₂and 8-CH₂), 1.70–1.77 (m, 1

(NCH₂CH₂CH₂CH₃), 20.7 (NCH₂CH₂CH₂CH₃), 20.9 (C-7), 25.5 H, 7-H_B), 1.81–1.92 (m, 1 H, 3-H), 2.01–2.08 (m, 1 H, 4a-H), 2.15–

(C-8), 27.1 (C-4), 30.1 (C-6), 31.4 (C-5), 34.6 (C-3), 42.1 (C-4a),

47.5 (C-2), 53.8 (NCH₂CH₂CH₂CH₃), 58.5 (C-8a), 60.1 (m, 1 H, 8a-H), 3.42–3.45 (m, 2 H, CH₂OH), 3.58 (dd, J = 2.6,

(OCH CH ), 174.58 (COO) ppm. ν = 2929 (vs), 2863 (s), 1729 (vs, 13.6 Hz, 1 H, NCH_ACH_BPh), 3.73 (dd, J = 2.6, 13.6 Hz, 1 H,

2.21 (m, 1 H, 2-H_A), 2.63 (d, J = 11.4 Hz, 1 H, 2-H_B), 2.72–2.82

˜

2

3

C=O), 1448 (w), 1260 (m), 1176 (s), 1160 (m) cm^–1. MS (EI, 70 eV): NCH_ACH_BPh), 7.20–7.34 (m, 5 H, Ph) ppm. ¹³C NMR (100 MHz,

m/z (%) = 267 (13) [M⁺], 224 (100), 41 (7); found [M]⁺267.22008.

C₁₆H₂₉NO₂requires 267.21983.

CDCl₃): δ = 17.5 (C-8), 20.8 (C-6), 25.4 (C-7), 27.0 (C-4), 31.5 (C-

5), 34.9 (C-4a), 39.0 (C-3), 48.6 (C-2), 58.4 (NCH₂Ph), 59.1 (C-8a),

66.1 (CH₂OH), 126.5, 128.1, 128.4 (Ph), 139.6 (Ph) ppm. IR (film):

Ethyl (3R,4aS,8aS)-1-[(R)-1-Phenylethyl]decahydroquinoline-3-car-

boxylate (15d): Following a similar procedure to that described

above for the preparation of 15a, olefin 14d (323 mg, 1.0 mmol)

was subjected to hydrogenation over platinum oxide (60 mg) to give

15d (235 mg, 72%) as a yellow oil. [α]²_D⁰= +45 (c = 0.90, CHCl₃).

ν = 3352 (br., O–H), 3027 (m), 2920 (vs), 2852 (s), 1494 (m), 1451

˜

(s), 1369 (m), 1069 (s), 1036 (s), 735 (s), 700 (s) cm^–1. MS (EI,

70 eV): m/z (%) = 258 (40) [M⁺], 214 (95), 153 (100), 91 (31); found

[M]⁺258.20298. C₁₇H₂₅NO requires 258.20275.

¹H NMR (400 MHz, CDCl₃): δ = 1.14–1.22 (m, 1 H, 8-H_A), 1.9 (t, [(3S*,4aR*,8aR*)-1-Butyldecahydroquinolin-3-yl]methanol (16c):

J = 7.2 Hz, 3 H, OCH₂CH₃), 1.27–1.30 [m, 3 H, NCH(CH₃)Ph],

1.32–1.46 (m, 2 H, 6-CH₂), 1.43–1.77 (m, 6 H, 4-CH₂, 5-CH₂and

Following a similar procedure to that described above for the prep-

aration of 16a, ester 15c (220 mg, 0.82 mmol) was reduced with

7-CH₂), 1.79–1.86 (m, 1 H, 4a-H), 2.00–2.08 (m, 1 H, 8-H_B), 2.40– lithium aluminium hydride (31 mg, 0.82 mmol) to give 16c (185 mg,

2.53 (m, 2 H, 2-H_Aand 3-H), 2.64 (d, J = 5.6 Hz, 1 H, 2-H_B), 3.05 100%) as a pale yellow oil, which was used without further purifi-

1

(dt, J = 3.5, 12 Hz, 1 H, 8a-H), 3.66 [q, J = 6.4 Hz, 1 H,

NCH(CH₃)Ph], 4.01–4.05 (m, 2 H, OCH₂CH₃), 7.21–7.35 (m, 5 H,

Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (OCH₂CH₃), 18.0

cation. H NMR (400 MHz, CDCl₃): δ = 0.83 (t, J = 7.3 Hz, 3 H,

NCH₂CH₂CH₂CH₃), 1.02–1.08 (m, 1 H, 7-H_A), 1.14–1.31 (m, 6 H,

4-CH₂, 8-CH₂and NCH₂CH₂CH₂CH₃), 1.32–1.42 (m, 4 H, 6-CH₂

[NCH(CH₃)Ph], 21.0 (C-7), 22.2 (C-6), 25.6 (C-8), 27.6 (C-4), 31.6 and NCH₂CH₂CH₂CH₃), 1.43–1.51 (m, 2 H, 5-CH₂), 1.67 (d, J =

(C-5), 34.7 (C-4a), 42.3 (C-3), 45.4 (C-2), 55.1 [NCH(CH₃)Ph], 60.0 12.8 Hz, 1 H, 7-H_B), 1.74–1.80 (m, 1 H, 3-H), 1.89–1.95 (m, 1 H,

(C-8a), 60.4 (OCH₂CH₃), 126.5, 126.9, 128.3 (Ph), 147.1 (Ph), 4a-H), 1.99 (t, J = 11.5 Hz, 1 H, 2-H_A), 2.26–2.33 (m, 1 H,

174.8 (COO) ppm. IR (film): ν = 2973 (s), 2930 (vs), 2870 (s), 1720

N C H

H

C H C H ₂C H ) , 2 . 3 6 – 2 . 4 3 ( m , 1 H ,

B 2 3

˜

A

(vs, C=O), 1449 (w), 1367 (m), 1324 (m), 1186 (m), 1153 (s), 1029 NCH_AH_BCH₂CH₂CH₃), 2.66 (dd, J = 3.5, 11.7 Hz, 1 H, 2-H_B),

(m) cm^–1. MS (EI, 70 eV): m/z (%) = 315 (79) [M⁺], 300 (42), 272

2.69–2.74 (m, 1 H, 8a-H), 3.26–3.30 (m, 1 H, CH_AH_BOH), 3.37–

(74), 210 (18), 168 (63), 105 (100), 91 (12); found [M]⁺315.21981. 3.41 (m, 1 H, CH_AH_BOH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

C₂₀H₂₉NO₂requires 315.21983.

= 13.9 (NCH₂CH₂CH₂CH₃), 16.6 (NCH₂CH₂CH₂CH₃), 20.8 (C-8

and NCH₂CH₂CH₂CH₃), 25.5 (C-7), 27.1 (C-4), 29.5 (C-6), 31.5

( C - 5 ) , 3 4 . 9 ( C - 4 a ) , 3 9 . 1 ( C - 3 ) , 4 9 . 7 ( C - 2 ) , 5 4 . 1

(NCH₂CH₂CH₂CH₃), 58.6 (C-8a), 65.8 (CH₂OH) ppm. IR (film):

[(3S*,4aR*,8aR*)-1-(3-Phenylpropyl)decahydroquinolin-3-yl]meth-

anol (16a): A solution of ester 15a (350 mg, 1.07 mmol) in dry THF

(4.5 mL) was added dropwise to a suspension of LiAlH₄(40 mg,

1.06 mmol) in dry THF (1.5 mL) and the mixture was stirred under

nitrogen for 1 h. The reaction was quenched cautiously with 5.2 

aq. KOH (0.7 mL) and the mixture stirred for 15 min. The mixture

was filtered through a pad of Celite and washed with EtOAc. The

filtrate was concentrated to yield 16a (130 mg, 100%) as a pale

yellow oil that was used without further purification. ¹H NMR

(300 MHz, CDCl₃): δ = 1.10–1.20 (m, 1 H, 7-H_A), 1.29–1.37 (m,

2 H, 4-CH₂), 1.39–1.42 (m, 2 H, 6-CH₂), 1.43–1.50 (m, 2 H, 8-

CH₂), 1.58–1.62 (m, 2 H, 5-CH₂), 1.78–1.82 (m, 1 H, 7-H_B), 1.85–

ν = 3367 (br., O–H), 2927 (vs), 2861 (s), 1448 (m), 1374 (m), 1079

˜

(s), 1037 (s), 735 (s), 702 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 225

(60) [M⁺], 41 (32); found [M]⁺225.21248. C₁₄H₂₇NO requires

225.21305.

{(3R,4aS,8aS)-1-[(R)-1-Phenylethyl]decahydroquinolin-3-

yl}methanol (16d): Following a similar procedure to that described

above for the preparation of 16a, ester 15d (235 mg, 0.74 mmol)

was reduced with lithium aluminium hydride (28 mg, 0.74 mmol)

to give 16d (202 mg, 100%) as a pale yellow oil, which was used

Eur. J. Org. Chem. 2009, 1944–1960

www.eurjoc.org

1957

M. A. Brimble et al.

FULL PAPER

without further purification. [α]²_D⁰= +44 (c = 0.75, CHCl₃). ¹H

NMR (300 MHz, CDCl₃): δ = 1.11–1.22 (m, 1 H, 7-H_A), 1.27 [t, J

= 7.4 Hz, 3 H, NCH(CH₃)Ph], 1.30–1.43 (m, 4 H, 4-CH₂and 6-

CH₂), 1.46–1.63 (m, 4 H, 5-CH₂and 8-CH₂), 1.65–1.78 (m, 1 H,

Ph), 7.44 (t, J = 8.0 Hz, 1 H, 5-H), 7.61 (t, J = 8.0 Hz, 1 H, 4-H),

7.95 (d, J = 8.0 Hz, 1 H, 3-H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 11.1 (3Ј-CH₃), 17.6 (C-8ЈЈ), 20.94 (C-6ЈЈ), 25.4 (C-7ЈЈ), 27.3

(C-4ЈЈ), 31.5 (C-5ЈЈ), 35.0 (C-4aЈЈ), 36.1 (C-3ЈЈ), 48.4 (C-2ЈЈ), 58.4

7-H_B), 1.95–2.08 (m, 3 H, 2-H_A, 3-H and 4a-H), 2.46 (dd, J = 3.8, (NCH₂Ph), 58.9 (C-8aЈЈ), 68.3 (CH₂O), 126.6 (Ph), 127.8 (C-4Ј),

11.6 Hz, 1 H, 2-H_B), 3.08–3.12 (m, 1 H, 8a-H), 3.35 (d, J = 6.0 Hz, 128.0 (C-1), 128.1 (Ph), 128.5 (Ph), 128.8 (C-5), 130.2 (C-6), 131.4

2 H, CH₂OH), 3.61 [q, J = 6.5 Hz, 1 H, NCH(CH₃)Ph], 7.17–7.31

(C-3), 131.6 (C-2), 133.1 (C-4), 139.7 (Ph), 146.1 (C-3Ј), 164.7

(m, 5 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 17.6 (C-8),

(COO), 169.64 (CO), 170.7 (CO) ppm. IR (film): ν = 3025 (w),

˜

21.1 [NCH(CH₃)Ph], 22.1 (C-6), 25.9 (C-7), 27.5 (C-4), 31.9 (C-5), 2929 (vs), 1727 (vs, C=O), 1714 (vs, C=O), 1602 (m), 1494 (s), 1454

35.2 (C-4a), 39.3 (C-3), 47.1 (C-2), 55.6 [NCH(CH₃)Ph], 60.7 (C- (s), 1393 (s), 1292 (s), 1259 (s), 1108 (s) cm^–1. MS (EI, 70 eV): m/z

8a), 66.6 (CH₂OH), 126.5, 127.0, 128.3 (Ph), 147.4 (Ph) ppm. IR

(%) = 427 (26) [M⁺], 429 (46), 224 (26), 91 (87), 56 (100), 41 (65);

found [M]⁺427.23547. C₂₉H₃₂N₂O₄requires 427.23621.

(film): ν = 3285 (br., O–H), 3027 (w), 2920 (vs), 2871 (s), 1450 (m),

˜

1368 (m), 1070 (s), 1040 (s), 761 (s), 701 (s) cm^–1. MS (EI, 70 eV):

m/z (%) = 273 (47) [M⁺], 229 (80), 168 (100), 91 (32); found [M]⁺

273.21513. C₁₈H₂₇NO₂requires 273.21533.

[(3S*,4aR*,8aR*)-1-Butyldecahydroquinolin-3-yl]methyl 2-(3-

Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate (17c): Fol-

lowing a similar procedure to that described above for the prepara-

tion of 17a, alcohol 16c (100 mg, 0.39 mmol) was treated with 2-

[(3S*,4aR*,8aR*)-1-(3-Phenylpropyl)decahydroquinolin-3-yl]methyl

2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate (17a): 2-(3- (3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acid 10

Methyl-2,5-dioxo-2,5-dihydropyrrol-1-yl)benzoic acid 10^[33]

(180 mg, 0.78 mmol), DCC (160 mg, 0.78 mmol) and DMAP

(143 mg, 0.62 mmol), DMAP (5 mg) and DCC (161 mg,

0.78 mmol). The crude product was purified by flash chromatog-

(4.00 mg, 0.04 mmol) was added to alcohol 16a (112 mg, raphy (20% hexanes in ethyl acetate) to give 17c (91 mg, 53%) as

1

0.39 mmol) in CH₂Cl₂(7 mL). The reaction was stirred for 18 h at

room temperature, then filtered through Celite, washed with EtOAc

and the filtrate concentrated in vacuo. The crude product was puri-

fied by column chromatography on silica (hexane/EtOAc, 8:2) to

give 17a (180 mg, 95%) as an oil. R_f= 0.32 (hexane/EtOAc, 8:2).

an oil. H NMR (400 MHz, CDCl₃): δ = 0.98 (t, J = 14.8 Hz, 3 H,

NCH₂CH₂CH₂CH₃), 1.03–1.19 (m, 1 H, 7ЈЈ-H_A), 1.21–1.36 (m, 4

H, 8ЈЈ-CH₂and NCH₂CH₂CH₂CH₃), 1.39–1.48 (m, 6 H, 4ЈЈ-CH₂,

6ЈЈ-CH₂and NCH₂CH₂CH₂CH₃), 1.51–1.59 (m, 2 H, 5ЈЈ-CH₂),

1.67–1.81 (m, 1 H, 7ЈЈ-H_B), 1.98–2.10 (m, 4 H, 4aЈЈ-H and 3Ј-CH₃),

¹H NMR (400 MHz, CDCl₃): δ = 1.03–1.17 (m, 1 H, 7ЈЈ-H_A), 1.29– 2.12–2.18 (m, 2 H, 2ЈЈ-H_Aand 3ЈЈ-H), 2.41–2.60 (m, 2 H,

1.40 (m, 4-H, 4ЈЈ-CH₂and 6ЈЈ-CH₂), 1.41–1.50 (m, 2 H, 8ЈЈ-CH₂), NCH₂CH₂CH₂CH₃), 2.62–2.69 (m, 1 H, 2ЈЈ-H_B), 2.78–2.85 (m, 1

1.54–1.59 (m, 2 H, 5ЈЈ-CH₂), 1.68–1.84 (m, 3 H, 7ЈЈ-H_Band H, 8aЈЈ-H), 3.96–4.27 (m, 2 H, CH₂O), 6.50 (t, J = 1.8 Hz, 1 H, 4-

NCH₂CH₂CH₂Ph), 1.98–2.09 (m, 2 H, 3ЈЈ-H and 4aЈЈ-H), 2.10–

H), 7.28 (dd, J = 1.8, 10 Hz, 1 H, 6-H), 7.49 (dt, J = 1.9, 10.2 Hz,

2.20 (m, 4 H, 2ЈЈ-H_Aand 3Ј-CH₃), 2.44–2.57 (m, 2 H, 1 H, 5-H), 7.63 (dt, J = 2.4, 10 Hz, 1 H, 4-H), 8.07 (dd, J = 2.0,

N C H ₂C H ₂C H ₂P h ) , 2 . 6 1 – 2 . 6 5 ( m , 3 H , 2 Ј Ј - H _B, a n d 10.4 Hz, 1 H, 3-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 11.1

NCH₂CH₂CH₂Ph), 2.76–2.80 (m, 1 H, 8aЈЈ-H), 4.04–4.21 (m, 2 H, (3Ј-CH₃), 14.0 (NCH₂CH₂CH₂CH₃), 16.8 (NCH₂CH₂CH₂CH₃),

CH₂O), 6.48 (t, J = 1.7 Hz, 1 H, 4Ј-H), 7.15–7.30 (m, 6 H, 6-H and

Ph), 7.49 (td, J = 7.8, J = 1.2 Hz, 1 H, 5-H), 7.61 (td, J = 7.7, J =

1.4 Hz, 1 H, 4-H), 8.07 (dd, J = 7.8, J = 1.5 Hz, 1 H, 3-H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 11.1 (Me), 16.9 (C-8ЈЈ), 20.9 (C-

20.7 (C-8ЈЈ), 20.8 (CH₂, NCH₂CH₂CH₂CH₃), 25.5 (C-7ЈЈ), 27.2 (C-

4ЈЈ), 29.6 (C-6ЈЈ), 31.4 (C-5ЈЈ), 34.9 (C-4aЈЈ), 38.1 (C-3ЈЈ), 49.1 (C-

2ЈЈ), 53.8 (NCH₂CH₂CH₂CH₃), 58.4 (C-8aЈЈ), 65.4 (CH₂O), 127.8

(C-4Ј), 128.1 (C-1), 128.8 (C-5), 130.2 (C-6), 131.4 (C-3), 131.6 (C-

6ЈЈ), 25.4 (C-7ЈЈ), 27.3 (C-4ЈЈ), 29.4 (NCH₂CH₂CH₂Ph), 31.5 (C- 2), 133.1 (C-4), 146.1 (C-3Ј), 164.8 (COO), 169.6 (CO), 170.6 (CO)

5ЈЈ), 33.7 (NCH₂CH₂CH₂Ph), 35.1 (C-4aЈЈ), 36.1 (C-3ЈЈ), 49.0 (C-

2ЈЈ), 53.4 (NCH₂CH₂CH₂Ph), 58.4 (C-8aЈЈ), 68.3 (CH₂O), 125.6 (p-

Ph), 127.9 (C-4Ј), 128.0 (C-1), 128.1 (m-Ph), 128.3 (o-Ph), 128.8

ppm. IR (film): ν = 2926 (w), 2849 (vs), 1715 (vs, C=O), 1449 (s),

˜

1390 (s), 1372 (s), 1292 (s), 1241 (s), 1085 (s) cm^–1. MS (EI, 70 eV):

m/z (%) = 438 (8) [M⁺], 395 (48), 224 (26), 143 (20), 99 (33), 56

(C-5), 130.2 (C-6), 131.4 (C-3), 131.5 (C-2), 133.1 (C-4), 142.2 (Ph), (100), 41 (20); found [M]⁺438.25122. C₂₆H₃₄N₂O₄requires

146.1 (C-3Ј), 164.8 (COO), 169.6 (CO), 170.6 (CO) ppm. IR (film):

438.25186.

ν = 3025 (w), 2929 (vs), 1727 (vs, C=O), 1714 (vs, C=O), 1602 (m),

˜

{(3R,4aS,8aS)-1-[(R)-1-Phenylethyl]decahydroquinolin-3-yl}methyl

2-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate (17d):

Following a similar procedure to that described above for the prep-

aration of 17a, alcohol 16d (100 mg, 0.36 mmol) was treated with

2-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acid 10

(169 mg, 0.73 mmol), DMAP (5 mg) and DCC (151 mg,

0.73 mmol). The crude product was purified by flash chromatog-

raphy (20% hexanes in ethyl acetate) to give 17d (121 mg, 70%) as

an oil. [α]²_D⁰= +46 (c = 0.84, CHCl₃). ¹H NMR (400 MHz, CDCl₃):

δ = 1.01–1.19 (m, 1 H, 7ЈЈ-H_A), 1.22–1.26 [m, 3 H, NCH(CH₃)Ph],

1.29–1.44 (m, 4 H, 4ЈЈ-CH₂and 6ЈЈ-CH₂), 1.52–1.63 (m, 4 H, 5ЈЈ-

CH₂and 8ЈЈ-CH₂), 1.71–1.80 (m, 1 H, 7ЈЈ-H_B), 1.89–2.08 (m, 3 H,

2ЈЈ-H_A, 3ЈЈ-H and 4aЈЈ-H), 2.13 (s, 3 H, 3Ј-CH₃), 2.52 (d, J =

1494 (s), 1454 (s), 1393 (s), 1292 (s), 1259 (s), 1108 (s), 910 (m),

855 (m), 756 (m), 732 (s), 699 (s) cm^–1. MS (EI, 70 eV): m/z (%) =

500 (45) [M⁺], 457 (68), 395 (100), 308 (14), 214 (40), 91 (35) [Bn⁺],

41 (15); found [M]⁺500.2670. C₃₁H₃₆N₂O₄requires 500.2675.

[(3S*,4aR*,8aR*)-1-Benzyldecahydroquinolin-3-yl]methyl 2-(3-

Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate (17b): Fol-

lowing a similar procedure to that described above for the prepara-

tion of 17a, alcohol 16b (80 mg, 0.31 mmol) was treated with 2-(3-

methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acid 10

(143 mg, 0.62 mmol), DMAP (3 mg) and DCC (128 mg,

0.62 mmol). The crude product was purified by flash chromatog-

raphy (20% hexanes in ethyl acetate) to give 17b (0.077 g, 53%) as

1

an oil. H NMR (400 MHz, CDCl₃): δ = 1.04–1.14 (m, 1 H, 7ЈЈ- 9.2 Hz, 1 H, 2ЈЈ-H_B), 3.10–3.17 (m, 1 H, 8aЈЈ-H), 3.61 [q, J =

H_A), 1.26–1.31 (m, 2 H, 6ЈЈ-CH₂), 1.34–1.43 (m, 2 H, 4ЈЈ-CH₂),

1.46–1.61 (m, 4 H, 5ЈЈ-CH₂and 8ЈЈ-CH₂), 1.69–1.79 (m, 1 H, 7ЈЈ- 4.01 (m, 1 H, CH_AH_BO), 6.45–6.46 (m, 1 H, 4Ј-H), 7.21–7.39 (m,

H_B), 1.87–1.94 (m, 1 H, 3ЈЈ-H), 1.97–2.10 (m, 4 H, 4aЈЈ-H, 3Ј-CH₃), 7 H, 5-H, 6-H and Ph), 7.56–7.65 (m, 2 H, 3-H and 4-H) ppm. ¹³

6.5 Hz, 1 H, NCH(CH₃)Ph], 3.82–2.87 (m, 1 H, CH_AH_BO), 3.96–

C

2.22 (t, J = 11.2 Hz, 1 H, 2ЈЈ-H_A), 2.58 (dd, J = 3.2, 1 H, 11.2 Hz,

2ЈЈ-H_B), 2.73–2.78 (m, 1 H, 8aЈЈ-H), 3.58 (d, J = 13.6 Hz, 1 H,

NCH_AH_BPh), 3.73 (d, J = 13.6 Hz, 1 H, NCH_AH_BPh), 4.01–4.14

(m, 2 H, CH₂O), 6.45 (s, 1 H, 4Ј-H), 7.21–7.34 (m, 6 H, 2-H and

NMR (100 MHz, CDCl₃): δ = 11.0 (3Ј-CH₃), 17.4 (C-8ЈЈ), 20.9 (C-

6ЈЈ), 21.0 [NCH(CH₃)Ph], 25.5 (C-7ЈЈ), 27.4 (C-4ЈЈ), 31.7 (C-5ЈЈ),

35.2 (4aЈЈ-H), 36.2 (C-3ЈЈ), 47.0 (C-2ЈЈ), 55.3 [NCH(CH₃)Ph], 60.5

(C-8aЈЈ), 70.0 (CH₂O), 126.5 (Ph), 127.0 (C-4Ј), 127.8 (C-1), 127.9,

1958

www.eurjoc.org

Eur. J. Org. Chem. 2009, 1944–1960

Synthesis of Analogues of the Alkaloid Methyllycaconitine

128.2 (Ph), 128.8 (C-5), 130.1 (C-6), 131.2 (C-3), 131.6 (C-2), 132.9

(C-4), 146.0 (C-3Ј and Ph), 164.44 (COO), 169.4 (CO), 170.7 (CO)

[(3S*,4aR*,8aR*)-1-Butyldecahydroquinolin-3-yl]methyl 2-(3-

Methyl-2,5-dioxopyrrolidin-1-yl)benzoate (5c): Following a similar

ppm. IR (film): ν = 2931 (w), 2852 (vs), 1710 (vs, C=O), 1602 (s), procedure to that described above for the preparation of 5a, olefin

˜

1492 (s), 1452 (s), 1394 (s), 1244 (s), 1208 (s), 1109 (s), 1108 (s)

17c (91 mg, 0.21 mmol) was subjected to hydrogenation over 10%

cm^–1. MS (EI, 70 eV): m/z (%) = 486 (73) [M⁺], 471 (31), 443 (56),

palladium on carbon (5 mg) to give 5c (90 mg, 99%) as an oil and

339 (63), 214 (43), 105 (100); found [M]⁺486.25221. C₃₀H₃₄N₂O₄as a 1:1 mixture of diastereomers. H NMR (400 MHz, CDCl₃): δ

1

requires 486.25186.

= 0.92 (t, J = 7.4 Hz, 3 H, NCH₂CH₂CH₂CH₃), 1.16–1.19 (m, 1

H, 7ЈЈ-H_A), 1.30–1.37 (m, 4 H, 8ЈЈ-CH₂and NCH₂CH₂CH₂CH₃),

1.40–1.50 (m, 9 H, 4ЈЈ-CH₂, 6ЈЈ-CH₂, NCH₂CH₂CH₂CH₃and 3Ј-

CH₃), 1.52–1.60 (m, 2 H, 5ЈЈ-CH₂), 1.71–1.82 (m, 1 H, 7ЈЈ-H_B),

2.04–2.16 (m, 1 H, 4aЈЈ-H), 2.21–2.33 (m, 2 H, 3Ј-H and 2ЈЈ-H_A),

2.47–2.52 (m, 4 H, 4Ј-CH₂and NCH₂CH₂CH₂CH₃), 2.78–2.83 (m,

1 H, 2ЈЈ-H_B), 2.87–2.91 (m, 1 H, 8aЈЈ-H), 2.95–3.05 (m, 1 H, 3Ј-

H), 4.06–4.15 (m, 2 H, CH₂O), 7.26 (d, J = 7.6 Hz, 1 H, 6-H), 7.53

(t, J = 7.6 Hz, 1 H, 5-H), 7.66 (t, J = 7.2 Hz, 1 H, 4-H), 8.10 (d, J

= 7.6 Hz, 1 H, 3-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.1

(NCH₂CH₂CH₂CH₃), 16.4 (3Ј-CH₃), 16.5 (3Ј-CH₃), 17.0

(NCH₂CH₂CH₂CH₃), 20.7 (C-8ЈЈ), 20.8 (NCH₂CH₂CH₂CH₃), 25.5

(C-7ЈЈ), 26.9 (C-4ЈЈ), 29.6 (C-6ЈЈ), 31.2 (C-5ЈЈ), 34.5 (C-4aЈЈ), 35.3

(C-3Ј), 35.5 (C-3Ј), 36.9 (C-3ЈЈ), 38.1 (C-4Ј), 49.0 (C-2ЈЈ), 53.7

(NCH₂CH₂CH₂CH₃), 58.4 (C-4aЈЈ), 67.9 (CH₂O), 127.2 (C-1),

129.2 (C-5), 129.7 (C-6), 131.3 (C-3), 132.6 (C-2), 133.3 (C-4), 167.2

[(3S*,4aR*,8aR*)-1-(3-Phenylpropyl)decahydroquinolin-3-yl]methyl

2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoate (5a): 10% Palladium

on carbon (10 mg) was added to a solution of maleimide 17a

(180 mg, 0.36 mmol) in EtOAc (2 mL) and the mixture stirred un-

der hydrogen for 18 h. The mixture was filtered through Celite that

was washed with EtOAc. The solvent was removed in vacuo to give

5a (172 mg, 95%) as an oil and as a 1:1 mixture of diastereomers.

1

R_f= 0.43 (CH₂Cl₂/MeOH, 9:1). H NMR (400 MHz, CDCl₃): δ =

1.02–1.98 (m, 1 H, 7ЈЈ-H_A), 1.23–1.52 (m, 9 H, 4ЈЈ-H, 6ЈЈ-H, 8ЈЈ-H

and 3Ј-CH₃), 1.57–1.62 (m, 2 H, 5ЈЈ-H), 1.72–1.80 (m, 1 H, 7ЈЈ-H_B),

1.81–1.92 (m, 2 H, NCH₂CH₂CH₂Ph), 2.02–2.07 (m, 1 H, 4aЈЈ-H),

2.14–2.20 (m, 2 H, 2ЈЈ-H_Aand 3Ј-H), 2.47–2.59 (m, 3 H, 4Ј-H_Aand

NCH₂CH₂CH₂Ph), 2.61–2.65 (m, 2 H, NCH₂CH₂CH₂Ph), 2.71–

2.80 (m, 1 H, 2ЈЈ-H_B), 2.82–2.91 (m, 1 H, 8aЈЈ-H), 2.95–3.14 (m,

2 H, 3Ј-H and 4Ј-H_B), 4.06–4.13 (m, 2 H, CH₂O), 7.14–7.28 (m,

6 H, 6-H and Ph), 7.50 (td, J = 7.7, J = 1.1 Hz, 1 H, 5-H), 7.64

(dt, J = 7.7, J = 1.4 Hz, 1 H, 4-H), 8.07 (d, J = 7.5 Hz, 1 H, 3-H)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.1 (Me), 16.4 (Me), 16.4

(C-8), 17.0 (C-8ЈЈ), 20.9 (C-6ЈЈ), 25.3 (C-7ЈЈ), 26.9 (C-4ЈЈ), 28.7

(NCH₂CH₂CH₂Ph), 31.3 (C-5ЈЈ), 33.4 (NCH₂CH₂CH₂Ph), 34.6

(C-4aЈЈ), 35.0 (C-3Ј), 35.2 (C-3Ј), 35.7 (C-3ЈЈ), 36.8 (C-4Ј), 49.0 (C-

2ЈЈ), 53.2 (NCH₂CH₂CH₂Ph), 58.4 (C-8aЈЈ), 67.8 (CH₂O), 125.6 (p-

Ph), 127.2 (C-1), 128.1 (m-Ph), 128.2 (o-Ph), 129.2 (C-5), 129.6 (C-

6), 131.3 (C-3), 132.6 (C-2), 133.2 (C-4), 141.8 (Ph), 164.1 (COO),

(COO), 175.9 (CO), 179.7 (CO) ppm. IR (film): ν = 3323 (br), 2926

˜

(vs), 2849 (s), 1715 (s), 1570 (m), 1449 (m), 1389 (s), 1241 (m), 1185

(s), 1135 (s), 1085 (s), 1045 (s), 1045 (s) cm^–1. MS (EI, 70 eV): m/z

(%) = 440 (16) [M⁺], 397 (100), 224 (14), 99 (16), 56 (41), 41 (16);

found [M]⁺440.26751. C₂₆H₃₆N₂O₄requires 440.26751.

{(3R,4aS,8aS)-1-[(R)-1-Phenylethyl]decahydroquinolin-3-yl}methyl

2-(3-Methyl-2,5-dioxopyrrolidin-1-yl)benzoate (5d): Following

a

similar procedure to that described above for the preparation of

5a, olefin 17d (100 mg, 0.20 mmol) was subjected to hydrogenation

over 10% palladium on carbon (5 mg) to give 5c (95 mg, 95%) as

a yellow oil and as a 1:1 mixture of diastereomers. [α]²_D⁰= +30 (c

175.8 (CO), 179.7 (CO) ppm. IR (film): ν = 3025 (w), 2931 (vs),

˜

1713 (vs, C=O), 1602 (m), 1494 (m), 1454 (m), 1391 (s), 1291 (m),

1261 (s), 1187 (s), 1137 (m), 1084 (m), 910 (m), 745 (m), 700 (m)

cm^–1. MS (EI, 70 eV): m/z (%) = 502 (46) [M⁺], 459 (67), 397 (100),

216 (18), 146 (15), 91 (24) [Bn⁺], 41 (16); found [M]⁺502.2833.

C₃₁H₃₈N₂O₄requires 502.2832.

1

= 0.90, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 1.01–1.13 (m, 1

H, 7ЈЈ-H_A), 1.17–1.33 [m, 5 H, 6ЈЈ-CH₂and NCH(CH₃)Ph], 1.35–

1.46 (m, 5 H, 4ЈЈ-CH₂and 3Ј-CH₃), 1.51–1.71 (m, 4 H, 5ЈЈ-CH₂

and 8ЈЈ-CH₂), 1.75–1.83 (m, 1 H, 7ЈЈ-H_B), 1.89–1.92 (m, 1 H, 3ЈЈ-

H), 1.95–2.10 (m, 2 H, 2ЈЈ-H_Aand 4aЈЈ-H), 2.44–2.50 (m, 2 H, 4Ј-

CH₂), 2.55 (d, J = 8.8 Hz, 1 H, 2-H_B), 2.95–3.14 (m, 1 H, 3Ј-H),

3.18–3.21 (m, 1 H, 8aЈЈ-H), 3.57–3.68 [q, J = 6.8 Hz, 1 H,

NCH(CH₃)Ph], 3.83–3.90 (m, 1 H, CH_AH_BO), 4.00–4.07 (m, 1 H,

CH_AH_BO), 7.19–1.40 (m, 7 H, 5-H, 6-H and Ph), 7.58–7.62 (m, 2

H, 3-H and 4-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.2 (3Ј-

CH₃), 16.4 (3Ј-CH₃), 17.3 (C-8ЈЈ), 21.0 [NCH(CH₃)Ph], 21.1 (C-

6ЈЈ), 25.5 (C-7ЈЈ), 27.3 (C-4ЈЈ), 30.8 (C-5ЈЈ), 35.1 (C-3ЈЈ), 35.3 (C-

4aЈЈ), 36.3 (C-3Ј), 36.9 (C-4Ј), 48.8 (C-2ЈЈ), 55.3 [NCH(CH₃)Ph],

60.5 (C-8aЈЈ), 67.9 (CH₂O), 126.4 (Ph), 127.0 (C-1), 128.2 (Ph),

129.2 (C-5), 129.6 (C-6), 131.3 (C-3), 132.6 (C-2), 133.1 (C-4), 147.0

[(3S*,4aR*,8aR*)-1-Benzyldecahydroquinolin-3-yl]methyl 2-(3-

Methyl-2,5-dioxopyrrolidin-1-yl)benzoate (5b): Following a similar

procedure to that described above for the preparation of 5a, olefin

17b (77 mg, 0.16 mmol) was subjected to hydrogenation over 10%

palladium on carbon (7 mg) to give 5b (75 mg, 97%) as an oil and

1

as a 1:1 mixture of diastereomers. H NMR (400 MHz, CDCl₃): δ

= 1.05–1.14 (m, 1 H, 7ЈЈ-H_A), 1.26–1.34 (m, 2 H, 6ЈЈ-CH₂), 1.36–

1.49 (m, 5 H, 4ЈЈ-CH₂and 3Ј-CH₃), 1.50–1.61 (m, 4 H, 5ЈЈ-CH₂

and 8ЈЈ-CH₂), 1.69–1.77 (m, 1 H, 7ЈЈ-H_B), 1.83–1.97 (m, 1 H, 3ЈЈ-

H), 2.00–2.12 (m, 1 H, 4aЈЈ-H), 2.24 (t, J = 11.3 Hz, 1 H, 2ЈЈ-H_A),

2.42–2.60 (m, 2 H, 4Ј-CH₂), 2.62–2.65 (m, 1 H, 2ЈЈ-H_B), 2.72–2.81

(m, 1 H, 8aЈЈ-H), 2.98–3.13 (m, 1 H, 3Ј-H), 3.60 (d, J = 13.1 Hz, 1

H, NCH_AH_BPh), 3.74 (d, J = 13.6 Hz, 1 H, NCH_AH_BPh), 3.98–

4.25 (m, 2 H, CH₂O), 7.21–7.36 (m, 6 H, 2-H, Ph), 7.46 (dt, J =

1.1, 7.7 Hz, 1 H, 5-H), 7.63 (dt, J = 1.5, 7.7 Hz, 1 H, 4-H), 7.96

(d, J = 10 Hz, 1 H, 3-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

16.2 (3Ј-CH₃), 16.4 (3Ј-CH₃), 17.7 (C-8ЈЈ), 20.9 (C-6ЈЈ), 25.4 (C-

7ЈЈ), 27.3 (C-4ЈЈ), 31.5 (C-5ЈЈ), 33.9 (C-4-aЈЈ), 35.2 (C-3Ј), 36.1 (C-

3ЈЈ), 36.9 (C-4Ј), 48.4 (C-2ЈЈ), 58.4 (NCH₂Ph), 59.0 (C-8aЈЈ), 68.1

(CH₂O), 122.7 (Ph), 127.3 (C-1), 128.1, 128.5 (Ph), 129.2 (C-5),

129.7 (C-6), 131.4 (C-3), 132.6 (C-2), 133.2 (C-4), 139.6 (Ph), 164.1

(Ph), 163.9 (COO), 171.0 (CO), 179.8 (CO) ppm. IR (film): ν =

˜

2927 (vs), 2840 (s), 1720 (s), 1605 (m), 1494 (m), 1452 (m), 1393

(s), 1245 (m), 1205 (s), 1110 (s), 1108 (s) cm^–1. MS (EI, 70 eV): m/z

(%) = 488 (48) [M⁺], 473 (34), 445 (58), 341 (63), 216 (100), 149

(55), 105 (98), 71 (43), 57 (71), 41 (64); found [M]⁺488.26769.

C₃₀H₃₆N₂O₄requires 488.26751.

Acknowledgments

We would like to acknowledge BASF SE for supporting this re-

search.

(COO), 171.0 (CO), 179.8 (CO) ppm. IR (film): ν = 2926 (vs), 2853

˜

(s), 1713 (s), 1493 (m), 1389 (s), 1290 (m), 1259 (s), 1184 (s), 1036

(s), 1082 (s), 1044 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 474 (47)

[M⁺], 431 (100), 258 (24), 149 (22), 91 (87), 71 (22), 57 (33), 43

(22); found [M]⁺474.25225. C₂₉H₃₄N₂O₄requires 474.25186.

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Received: January 13, 2009

Published Online: February 26, 2009

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Article Doi

Synthesis of AE and BE ming analogues of the alkaloid methyllycaconitine

DOI: 10.1002/ejoc.200900030

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