Strategies for the Asymmetric Construction of Pelletierine and its Use in the Synthesis of Sedridine, Myrtine, and Lasubine

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Accepted Article

Title: Strategies for the asymmetric construction of pelletierine and its

use in the synthesis of sedridine, myrtine and lasubine

Authors: Raed K. Zaidan and Paul Evans

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900477

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Strategies for the asymmetric construction of pelletierine and its

use in the synthesis of sedridine, myrtine and lasubine

Raed K. Zaidan^[a,b]and Paul Evans*^[a]

^aSchool of Chemistry, Centre for Synthesis and Chemical Biology,

University College Dublin, Dublin D04, N2E5, Ireland.

Email: paul.evans@ucd.ie ; ORCID: 0000-0002-0584-876X; https://people.ucd.ie/paul.evans

^bDepartment of Chemistry, College of Science, University of Basra, Iraq; ORCID: 0000-0001-6000-6410

Abstract:

Three methods for the asymmetric synthesis of both enantiomers of

pelletierine 6 are reported. Bella’s proline-based Mannich process

gave (R)- and (S)-Cbz-protected 6 in good yields from Δ¹-piperideine

14 and in reasonable enantiomeric excess (74-80% e.e.). An

intramolecular aza-Michael, cinchona-based, organocatalytic method

is also reported and with commercially available 9-amino quinine

(24a) and quinidine (24b) catalysts Cbz-protected α,β-unstaturated

ketone 23 also gave (R)- and (S)-Cbz-protected 6 in good yields and

enantiomeric excess (90-99% e.e.). This material was used to

synthesise both optically active forms of deoxyhalofuginone (26), an

analogue of febrifugine which is of interest as an anti-fibrotic agent.

Finally, a resolution of racemic pelletierine using (R)- and (S)-

mandelic acid 27 is reported. This scalable method gave both

enantiomers of Cbz- and Boc-protected 6 in excellent enantiomeric

excess (≥ 99%). Both highly enantioenriched forms of 6 (obtained

from the resolution study) were used to synthesise several alkaloids.

Firstly, (–)-(S)-Cbz-protected pelletierine 17 was used to prepare

naturally occurring sedridine (32) and its epimer allosedridine (8).

Then the preparation of both enantiomers of the quinolizidine

myrtine (33) by an olefination-intramolecular aza-Michael sequence

is reported. Finally, the synthesis of the epimeric quinolizidine

alkaloids, lasubine I (34) and lasubine II (35), from (+)- and (–)-Boc-

protected pelletierine (29) respectively, is discussed.

Figure 1. Representative 2-substituted piperidine-containing pharmaceuticals.

Functionalised piperidine derivatives also feature in many

natural products.^[3]The breadth of structures and biological

activities presented by these compounds mean they are

attractive to both chemists and biologists. One large group of

biologically and structurally interesting piperidine alkaloids are

those presenting a 2-substituent, which, with and without

additional substituents, have been isolated from various different

plants (see Figure 2 for selected examples).^[2,4]

Introduction

Heterocycles are the most widespread recurring motif in

pharmaceuticals. In turn one of the most common of these

heterocyclic units is the piperidine ring^[1]which, possessing a

range of different substituent patterns, is found as a core

structural motif in various pharmaceuticals.^[2]One substantial

sub-group of these include a substituent in the 2-position of the

heterocycle and a selection of representative 2- and 1,2-

substitued piperidine-based pharmaceuticals are depicted in

Figure 1.^[2]These compounds possess a variety of biological

actions, for example methylphenidate (1), better known as ritalin,

is widely prescribed to treat hyperactivity and chronic sleep

disorders. Mefloquine (4), also known as lariam, is an anti-

malarial and racemic perhexiline (5) is an antifungal agent.

Figure 2. Representative 2-substituted piperidine containing natural products.

Pelletierine (6), a 2-acetyl substituted piperidine, was first

isolated in 1878 by Tanret from the root bark of the pomegranate

tree (Punica Granafum L.).^[5]Compound 6 has an interesting

history: it is isolated in an optically active form, however, it co-

occurs with a compound termed isopelletierine, which is simply

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racemic pelletierine (it is now appreciated that β-keto amines,

like 6, undergo isomerisation, see Scheme 3) and its exact

structure was not unequivocally confirmed until its first synthesis

in 1961.^[6]More recently several new methodologies have been

developed to obtain this and related molecules in optically active

form.^[7]Part of this interest stems from the fact that 6 represents

a

useful, functionalised building block to assemble more

complex structures.^[8]Coniine (7), a toxic substance from several

plants famously including poison hemlock (Conium maculatum),

contains an unfunctionalised n-propyl substituent.^[9]It is likely

that natural products like 6 are assembled biosynthetically from

a Mannich-type process, therefore, unsurprisingly the 1,3-amino

oxygenation pattern is frequently found in this class of

Scheme 1. Δ¹-Piperideine 14-based synthesis of (±)-pelletierine 6. Reagents

and conditions: (i) NCS, ether, rt; then KOH, EtOH, 0 °C to rt; (ii) NaOH_(aq)

reflux, 4 h, then rt, 18 h; (iii) reflux, 4 h, 40%.

,

compounds.^[10]

For example, amino alcohols such as

An asymmetric organocatalytic version of the intermolecular

Mannich reaction detailed in Scheme 1 has been reported by

Bella.^[7n]We have used this method to prepare both optically

active versions of pelletierine and in turn used this material to

prepare analogues of febrifugine (12).^[15]As summarised in

Scheme 2, use of L- or D-proline facilitated the enantioselective

intermolecular Mannich reaction of 14 with an excess of acetone

in a DMSO-water (9:1) solvent mixture. This led to a rapid and

reproducible reaction generating unnatural and natural

pelletierine respectively. In order to purify and characterise the

secondary amine adducts they were directly converted into their

Cbz-protected forms. Use of L-proline in this manner gave (–)-

17 in 72% yield from 14, whereas D-proline generated (+)-17 in

63% yield. Analysis by chiral HPLC demonstrated that (–)-17

was produced in 80% e.e., whereas the value for (+)-17 was

74%. It has been established that laevorotatory Cbz-pelletierine,

(–)-17, possesses a 2S configuration, whereas dextrotatory (+)-

17 possesses R-stereochemistry (Scheme 2).^[7n]

allosedridine 8 and sedamine 9 are representative members of

this piperidine family.^[11]Deoxynojirimycin 10 is an example of a

natural product which has additional oxidation within the

piperidine ring. This compound has disease relevant α-

glucosidase activity and two N-alkylated analogues of 10

(termed miglitol and miglustat) are clinically useful and an

epimer (migalastat) has just been given FDA approval for the

treatment of Anderson-Fabry disease.^[12]Lobeline 11, isolated

from plants of the Lobelia family, resembles 9 but has an

additional oxidised phenethyl substituent.^[13]Finally, febrifugine

(12) is a di-substituted piperidine-based natural product that has

potent biological activities and also includes

oxygenation pattern.^[14]

a 1,3-amino

As a consequence of their distribution and important activities

methods to prepare the types of compounds included in Figures

1 and 2 are of significance – particularly those able to introduce

the substituents in a stereocontrolled manner.

Results and Discussion

The Mannich and N-conjugate addition reactions represent two

of the most direct methods to prepare β-amino ketones.

Therefore, in our efforts to develop syntheses of 2-substituted

piperidines bearing a keto-side-chain, we focused on each of

these processes.

2.1 The Mannich reaction for the synthesis of pelletierine

Scheme 2. Proline-based asymmetric synthesis of Cbz-protected pelletierine

17. Reagents and conditions: (i) L-Pro (20 mol%), acetone, DMSO-H₂O (9:1),

rt, 1 h then CbzCl, Na₂CO₃, DCM-H₂O (3:2), 0 °C to rt, 72%, 80% e.e.; (ii) D-

Pro (20 mol%), acetone, DMSO-H₂O (9:1), rt, 1 h then CbzCl, Na₂CO₃, DCM-

H₂O (3:2), 0 °C to rt, 63%, 74% e.e.

Based on a reported procedure the synthesis of racemic

pelletierine 6 was achieved as shown in Scheme 1.^[7c]Piperidine

13 was initially N-halogenated and the intermediate N-chloro

compound was then immediately dehydrohalogenated. As

reported, the product from this process is

a mixture of

compounds which represent surrogates for imine 14. This

mixture was taken up in EtOH-Et₂O and was directly reacted

with the sodium salt of acetoacetic acid 16 (prepared by base

Although the yields for the two-step process were good and the

enantiomeric excesses obtained were reasonably high they did

prove to be slightly lower than those reported.^[7n]The reason for

this, we believe, is not solely due to the inherent selectivity of the

proline-mediated Mannich reaction. It is known^[16]that β-keto

amines, like 6, can undergo isomerisation and we believe, that in

this free-base form, isomerisation occurs during the course of

hydrolysis of ethyl acetoacetate 15) in

a decarboxylative

Mannich reaction. Following this procedure (±)-pelletierine 6 was

reproducibly produced in approximately 40% overall yield

(Scheme 1).

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the organocatalysed Mannich reaction and/or the work-up

procedure. As shown in Scheme 3 this isomerisation can occur

either via a retro-Mannich process, or via a retro-Michael

process and these reversible reactions lead to gradual erosion

of the optical purity of 6. In contrast, prolonged storage of

solutions of optically active 17 in organic solvents (chlorinated

solvents and alcohols) demonstrated no loss of enantiopurity.

deoxyhalofuginone 26, a compound of interest as an analogue

of the natural product febrifugine (12, Figure 2).^[15]The

enantioexcess recorded for Cbz-protected (R)- and (S)-

deoxyhalofuginone (25), derived from these sequences were

98% and 90% respectively and this high level of optical purity

enabled an X-ray crystal structure of (R)-25 to be obtained,

which confirmed the sense of selectivity for the stereoselective

IMAMR (Figure 3).

Scheme 3. Retro-Mannich and N-conjugate addition mechanisms for the

racemisation of 6.

2.2. Intramolecular aza-Michael-type reaction for the

synthesis of pelletierine

An alternative method to prepare pelletierine by an

intramolecular aza-Michael-type reaction (IMAMR)^[17]was also

considered. Racemic Cbz-protected pelletierine 17 was

prepared by a straight-forward four-step process from 5-amino

pentanol 21. This was first converted into its Cbz-protected form

before Swern oxidation generated 2-hydroxy Cbz-protected

piperidine (Scheme 4). The masked aldehyde was then reacted

with stabilised ylide 22 in order to form trans-enone 23, which,

upon treatment with a Lewis acid, underwent an intramolecular

aza-Michael reaction (IMAMR) to produce racemic 17.

Scheme 5. Cinchona-based asymmetric synthesis of (+)- and (–)-Cbz-

protected pelletierine 17 and their use in the synthesis of (–)- and (+)-

deoxyhalofuginone 26. Reagents and conditions: (i) 24a (20 mol%), TFA (40

mol%), THF, rt, 18 h, 91%, 98% e.e.; (ii) 24b (20 mol%), TFA (40 mol%), THF,

rt, 18 h, 90%, 90% e.e.; (iii) see ref. 15; (iv) HBr, AcOH, see ref. 15.

The comparatively better enantiomeric excess observed for the

formation of 17 with the cinchona catalysts must be factored with

their increased price in comparison to, particularly L- but also D-

proline.^[18]Therefore, a less costly alternative was considered for

the larger scale preparation of optically active (protected)

pelletierine.

C14

C13

Scheme 4. IMAMR for the synthesis of (±)-Cbz-protected pelletierine 17.

Reagents and conditions: (i) CbzCl, NaHCO₃, THF-H₂O (1:1); (ii) (COCl)₂,

DMSO, TEA, DCM, -78 °C; (iii) 22, PhMe, 110 °C, 44%; (iv) BF₃·OEt₂, MeCN,

rt, quant.

C12

C15

C11

O1

C10

N3

C17

C18

C9

C16

O3

C7

Following a two recent reports, the enantioselective version of

this type of IMAMR was also studied as a means to produce

enantioenriched 17.^[7o,p]Thus, under Sánchez-Roselló’s and

Fan’s conditions, treatment of 23 with quinine-based amine 24a

gave (+)-17 in good yield (Scheme 5). Importantly the pseudo-

enantiomer of 24a is commercially available, therefore, the

enantiomeric form of 17 was similarly accessed from quinidine-

based amine 24b in similar yield. Both (R)- and (S)-17 accessed

from this study were used to prepare (–)- and (+)-

O2

N1

O4

C4

C3

Cl1

C2

C1

C19

C8

C20

C21

C5

N2

C24

C23

C6

Br1

C22

Figure 3. Single X-ray crystal structure of (R)-Cbz-deoxyhalofuginone 25

(thermal ellipsoids drawn on the 50% probability level).^[19]

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(MeOH-Et₂O); then CbzCl, i-Pr₂NEt, DCM, 0 °C to rt, 18 h, 41%, >99% e.e.; or

Boc₂O, Et₃N, DCM, 0 °C to rt, 18 h, 90%.

2.3. Resolution of racemic pelletierine 6

The mixture was stored in the fridge (approx. 5 °C) for 22 h. It

was then filtered, to give the insoluble salt, which was further

Although direct enantioselective syntheses of 6 are elegant the

preparation of a racemic mixture followed by its resolution could

still be a straightforward, scalable alternative, and this is

particularly true in situations where both enantiomers might be of

value.^[20]A cheap and potentially very effective method for

obtaining enantioenriched amines is the use of a chiral acid and

the resolution of the resultant diastereomeric salt based on

solubility differences. The resolution of racemic pelletierine 6

was reported by Galinovsky, Bianchetti, and Vogl,^[21]and then

modified and extended by Beyerman and Maat.^[22]This was

achieved using non-commercially available, enantiomerically

pure 6,6’-dinitrobiphenyl-2,2’-dicarboxylic acid. It should be

noted that it was reported that the free base, obtained by

treating the ammonium salt with hydrochloric acid and then with

sodium carbonate, was observed to racemise in aqueous and in

ethanolic solution, and, in particular, in alkaline medium (see

Scheme 3).^[16]Beyerman’s development was to repeat the

resolution but to add picric acid directly to the reaction mixtures.

This produced a precipitate of crystalline R-(–)-pelletierine

picrate and thus avoided the racemisation of free-base

recrystallised using

a mixture of MeOH and Et₂O. The

recrystallised salt was converted into both Cbz-pelletierine 17, or

Boc pelletierine 29, for characterisation and storage. In this

manner (+)-17 was ultimately isolated from (±)-6 in 33% overall

yield and > 99% e.e. The mother liquors, containing mainly the

more soluble (S,R)-pelletierine mandelate salt 28b, were

collected, combined and in this way enantioenriched (S)-

pelletierine 6 was recovered by base treatment. Treatment of

this material with (S)-mandelic acid 27, in an otherwise identical

procedure to that described above for the production of (R)-17,

led to the isolation of (S)-17, which was produced in a 41%

overall yield and > 99% e.e. (Scheme 6).

The optical purity of protected pelletierine accessed by this route

was determined by the HPLC analysis of both enantiomeric

forms of Cbz-pelletierine 17. However, it also proved possible to

use ¹H-NMR spectroscopy of the insoluble, 28a and soluble

salts, 28b, to determine their diastereomeric ratio. This method

was used to determine how many recrystallisations were

required in order to ultimately obtain high optical purity of 17

(see ESI section). In terms of absolute stereochemistry, material

obtained from either salt 28a and 28b was compared to the

literature data^[15]and was also consistent with the previous work

discussed above in Schemes 2 and 5. In addition the absolute

stereochemistry of the insoluble salt 28a was further confirmed

by single crystal X-ray crystallography (Figure 4).^[25]

pelletierine.

In relation to the resolution of 2-substituted

piperidines, in 1999 an efficient procedure for the resolution of 2-

methylpiperidine was described by Sage et al. which used both

enantiomers of mandelic acid as the resolving agent.^[23]A similar

strategy was applied by Nanayakkara et al. in 2008 for the

resolution of racemic 2-undecylpiperidine. This enabled access

to enantiomers of the fire ant venom alkaloids solenopsin and

isosolenopsin A, B, and C.^[24]

O8

C8

Therefore, subsequent to the multi-gram preparation of racemic

6 (Scheme 1) the use of both enantiomers of mandelic acid 27

were considered as potential resolving agents. An equimolar

amount of (R)-mandelic acid 27 was added to a stirred solution

of (±)-6 in MeOH. Then Et₂O was added (MeOH-Et₂O; 1:2.5)

and gratifyingly it was found that (R,R)-pelletierine mandelate

28a readily crystallised from this mixture leaving the more

soluble diastereomeric (S,R)-pelletierine mandelate 28b in

solution (Scheme 6).

C32

O7

C31

C6

C1

C7

O1

C30

O6

C29

C25

N1

C5

C2

C28

C26

C3

C27

C4

Figure 4. Single X-ray crystal structure of (R,R)-pelletierine mandelate 28a

(thermal ellipsoids drawn on the 50% probability level).^[25]

With a reliable means to access multi-gram amounts of both

enantiomers of Cbz- and Boc-pelletierine, 17 and 29, in

excellent enantiomeric excess >99% e.e., we then sought to

investigate their use for the synthesis of other optically active

natural products bearing a substituted piperidine motif within

their structure.

2.4. Asymmetric synthesis of sedridine 32 and allosedridine

8

Scheme 6. Resolution of pelletierine 6 using mandelic acid 27: Synthesis of

enantioenriched protected pelletierine 17 and 29. Reagents and conditions: (i)

(±)-6, MeOH-Et₂O, 0 °C, 22 h; (ii) recrystallise (MeOH-Et₂O); then CbzCl, i-

Pr₂NEt, DCM, 0 °C to rt, 18 h, 33%, >99% e.e.; or Boc₂O, Et₃N, DCM, 0 °C to

rt, 18 h, quant.; (iii) KOH_(aq), then (S)-6, MeOH-Et₂O, 0 °C, 22 h, recrystallise

The most commonly occurring members of the sedum alkaloid

family are 2-substituted saturated nitrogen heterocycles

featuring a 1,3-amino alcohol moiety.^[11]Representative are

sedridine 32 and its diastereomer allosedridine 8 which differ in

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the stereogenic secondary alcohol unit in the side chain. These

two sedum alkaloids were prepared from (S)-Cbz-pelletierine 17,

prepared from the more soluble mandelate salt 28b (see

Scheme 6), using NaBH₄as the reducing agent.^[26]The non-

diastereoselective reduction produced both natural sedum

alkaloids which differ in polarity. This enabled their separation on

silica-gel by flash column chromatography. Both Cbz-sedridine

30 and allosedridine 31 were then deprotected by

hydrogenolysis of the carbamate group in the presence of

Pearlman's catalyst, which led to (+)-sedridine 32 and (–)-

allosedridine

8

in very good yield (Scheme 7).

The

spectroscopic data and optical behaviour of 32 and 8 prepared

via this sequence was consistent with the structure and

stereochemistry of the naturally occurring amino alcohols.^[11]

Figure 6. Indolizidine and quinolizidine alkaloids: Structures of (+)-myrtine

(33) and (–)-lasubine I (34) and (–)-lasubine II (35).

It was planned to use the resolved pelletierine in order to access

the core quinolizidine in compunds 33, 34 and 35 by an initial

olefination of the methyl ketone, followed by an intramolecular

aza-Michael-type reaction (IMAMR). In terms of 33, rather than

attempting a direct aldol-type reaction with acetaldehyde we

elected to make use of the regioselective bromination process

used in our deoxyfebrifugine syntheses.^[15]Thus, highly

enantioenriched (+)-Cbz-pelletierine 17 was introduced to an α-

bromination process, using TMSOTf as a Lewis acid and DIPEA

as a base, to produce a silyl enol ether intermediate which was

directly brominated with N-bromosuccinimide. After work-up the

protected α-bromopelletierine was then used, without purification,

to produce ylide 36 by the reaction with Ph₃P in toluene,

followed by base treatment (Scheme 8). In this manner, 36 was

produced in approximately 67% from (+)-Cbz-pelletierine 17.

Scheme 7. Asymmetric synthesis of sedridine 32 and allosedridine 8.

Reagents and conditions: (i) NaBH₄(2 eq.), MeOH, 0 °C, 3 h; (ii) H₂, Pd(OH)₂,

MeOH, rt, 18 h, 99%; (ii) H₂, Pd(OH)₂, MeOH, rt, 18 h, quant.

In addition, both (+)-32 and (–)-8 proved crystalline and single

crystal X-ray structures for both^[27]served to confirm the

structure of these alkaloids and were consistent with

stereochemical data reported by Beyerman and Fodor^[7b](Figure

5).

C3

C4

C5

C4

C5

C7

C6

C7

C2

O

C8

C6

C2

C1

N

C8

O

Figure 5. Single crystal X-ray structures of (+)-(S,S)-sedridine 32 and (–)-

(S,R)-allosedridine 8 (thermal ellipsoids drawn on the 50% probability level).^[27]

2.5. Synthesis of the quinolizidine alkaloids (+)- and (–)-

myrtine (33) and (–)-lasubine I (34) and II (35)

Scheme 8. Synthesis of (+)-myrtine 33. Reagents and conditions: (i) TMSOTf,

DIPEA, DCM, rt, 1 h; then NBS, 2 h; (ii) Ph₃P, toluene, rt, 18 h; then K₂CO₃in

MeOH-H₂O, 67%; (iii) MeCHO, THF, rt, 7 h, 70%; (iv) HBr-AcOH, rt, 4 h; then

K₂CO₃, MeOH, rt, 4 h, 40%.

Indolizidine and quinolizidine containing alkaloids feature a

bicyclic 4.3.0 and 4.4.0 ring structure respectively,

encompassing the nitrogen atom at a ring fusion point (Figure

6).^[28]Numerous examples of natural products containing this

The Wittig reaction of 36 with acetaldehyde in dry THF smoothly

afforded trans-enone (–)-37 in 70% yield. The Cbz group in

enone 37 was removed with HBr-AcOH and the intermediate

ammonium salt was converted to the secondary amine with

K₂CO₃. In turn this underwent an IMAMR process to give the

desired alkaloid, 33. Although the yield (40%) was moderate

complete diastereoselectivity was observed in the cyclisation

step, when K₂CO₃was employed as a base in MeOH. Data,

core structural motif exist.

Myrtine (33), from Vaccinium

myrtillus,^[29]and lasubine I and II (34 and 35) from Lagerstroemia

subcostata,^[30]are representative examples of quinolizidine

alkaloids. Both compounds include a 1,3-amino oxidation

pattern and over the years have proved popular synthetic

targets.^[29,30]

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including specific rotation, were in agreement with that reported

in the literature.^[29]In an identical manner to that described

above (–)-(S)-Cbz-pelletierine 17 gave enantiomeric (–)-myrtine

33 which was obtained in a 17% overall yield for the four-step

sequence (not shown).

retained during the course of the reaction sequence. There is a

reported HPLC method^[34]for 41 and using these conditions it

was clear that, unfortunately, competitive racemisation had

occurred during this sequence (enantiomeric ratio 70:30). Thus,

based on the low isolated yields of 40 and 41, and more

importantly the marked erosion of optical purity observed with

(–)-Lasubine I (34) and II (35) are examples of additional

quinolizidine alkaloids of interest.^[30]These natural products,

featuring a 2-substituted piperidine and a 3,4-dimethoxyphenyl

unit, attached to carbon-4 of the fused-bicyclic ring, differ in

terms of their stereochemistry at position 9a. In the case of

lasubine I (34) there is a cis-relationship between the 9a-

the direct aldol-IMAMR sequence, we next considered a

stepwise approach using protected 17 since this material does

not racemise (vide supra). A pyrrolidine catalysed Mannich-type

reaction converted (–)-(S)-Cbz-pelletierine 17 to trans-(S)-α,β-

unsaturated ketone 42. This process successfully occurred in

62% yield. Subsequent cleavage of the Cbz group in 42 and

hydrogen atom and the aryl unit (akin to myrtine (33), Scheme 8), treatment of the product with base over a prolonged reaction

whereas its diastereomer, lasubine II (35), has trans-

a

period afforded a mixture of the desired aryl quinolizidines, 40

and 41 (Scheme 9). The crude ratio for this mixture was

approximately 90:10 in favour of the trans-diastereomer 41,

which could be isolated in 48% yield from 42. More significantly,

and in contrast to the aldol-IMAMR method, only a moderate

loss of optical purity was detected by HPLC (80% e.e.). Although

this represented an advance, based on the moderate yields

encountered for the Cbz-removal-cyclisation sequence, and the

loss in overall optical purity, we felt that we might be able to

improve the overall efficiency of this sequence. Since the Cbz

group is not likely to be compatible with basic reaction conditions,

we felt that a change of the protecting group to a Boc group

might be a good way to produce the required enone by a direct

aldol reaction. This then might enable production of the

precursors 40, and 41 with better yields and with reduced loss of

enantiopurity (observed when the free-base was used, Scheme

9). Thus, (S)-Boc-pelletierine 29 was introduced to a cross aldol

condensation, promoted by NaOH in MeOH at 60 °C for 18 h.

This afforded (+)-(S)-enone-43 in 60% (Scheme 10).

relationship between the aryl group and the 9a-hydrogen.

Stereochemically, (–)-lasubine I (34) can be traced back to (R)-

pelletierine (6), whereas, synthetically, lasubine II (35) would

originate from (S)-pelletierine (6). These compounds have been

prepared from protected pelletierine previously^[28]and since we

had access to both enantiomeric forms of 17 in very high optical

purity, their synthesis was considered.

We initially decided to study

a

directed, cross-aldol

condensation-IMAMR cascade sequence^[31]between pelletierine

(6) and veratraldehyde (38). Deprotection of (–)-(S)-Cbz-

pelletierine (17) to ammonium salt 39 was achieved using HBr-

AcOH. Then, following

a

procedure adapted from the

literature,^[32]39 was directly treated with 38 and three

equivalents of NaOH in a mixture of H₂O-EtOH (1:6) for 3 h at

room temperature. Unlike the myrtine synthesis (Scheme 8) this

process is not diastereoselective and gave a mixture of the cis-

fused isomer 40 and the trans-fused isomer 41. These were

formed in a ratio of 1:4 (40:41).^[33]Pleasingly, the diastereomers

proved chromatographically separable, and this gave samples of

40 and 41 in 3% and 20% isolated yields respectively (Scheme

9).

Scheme 10. Synthesis of cis- and trans-arylquinolizidines 40 and 41 by a

cross-aldol-IMAMR sequence from (–)-(S)-Boc-pelletierine 29 and conversion

of 41 to (–)-lasubine II (35). Reagents and conditions: (i) 3,4-(MeO)₂C₆H₃CHO

38, NaOH, MeOH, 65 °C, 18 h, 60%; (ii) TFA, DCM, 0 °C to rt, 2 h, then NaOH,

H₂O-MeOH (1:1), rt, 2 days, 40: 37%, 41: 30%, 96% e.e.; (iii) L-selectride,

THF, -78 °C, 2 h, 69%.

Scheme 9. Synthesis of cis- and trans-arylquinolizidines 40 and 41. Reagents

and conditions: (i) HBr-AcOH, 0 °C to rt, 4 h, then 3,4-(MeO)₂C₆H₃CHO 38,

NaOH, EtOH-H₂O (2:3), 0 °C to rt, 3 h, 40: 20%, 41: 3%, 40% e.e.; (ii) 3,4-

(MeO)₂C₆H₃CHO 38, pyrrolidine (20 mol%), DCM, rt, 24 h, 62%; (iii) HBr-

AcOH, 0 °C to rt, 4 h, then NaOH_(aq), MeOH, rt, 2 days, 41: 48%, 80% e.e.

The penultimate part in the synthesis of the natural product (–)-

lasubine II (35) is a two-step process involving the removal of

Boc group followed immediately by cyclisation. This generates

arylquinolizidinone 40 and 41 and significantly the relative ratio

of these diastereomers can be adjusted depending on the

reaction time and conditions. For instance, on prolonged

Based on our experience with the racemisation of unprotected

pelletierine 6 (Scheme 3), we were keen to prove whether, or

not, the excellent optical purity of the starting material, 17, was

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reaction trans-arylquinolizidinone, 41, the direct precursor of

naturally occurring (–)-lasubine II (35), can be formed in

comparatively larger amounts.^[34]After Boc removal with TFA

IMAMR was achieved by treating a mixture of the intermediate

ammonium salt in methanol with NaOH at rt for 48 h. This

afforded 41 and its cis-diastereomer 40 in a ratio of 1:1.2

(determined by proton NMR spectroscopy performed on the

crude reaction mixture). This outcome is consistent with the

longer reaction time, which allows the reaction to come under

thermodynamic control, thereby forming comparatively more of

the trans-diastereomer. These isomers were separated and

pleasingly HPLC demonstrated that only minor epimerisation

had occurred during this sequence. The enantiopurity of the

resolution derived Boc-pelletierine 29 (>99% e.e.) was only

eroded slightly to 96% for compound 41 obtained in this manner.

The final step in this synthesis was the well-reported^[7f]

diastereoselective reduction of (–)-41 by L-selectride. Only (–)-

lasubine II 35 was isolated following this process in 69% yield.

we propose that the more favoured process, in this case, must

involve

a

chair-boat transition state. This enables the

nucleophilic addition to occur at the Re-face of the alkene

generating 33 (R = Me). It would appear that when R = Me this

process is either effectively irreversible - under the conditions

employed - or that this diastereomer is strongly favoured over its

counterpart. None of the diastereomer, termed epi-myritine was

detected during the synthesis of 33 (see Scheme 8). Moving to

lasubine, as discussed above, depending on the conditions

employed for the quinolizidine forming step the relative amounts

of the 2-ketoquinolizidines 40 and 41 alter. The lasubine I

precursor 40 can be produced in approximately a 3:1 ratio,

relative to 41, using ammonium hydroxide over a short (30 min)

reaction period. Whereas, 41 can be produced in larger relative

amounts (40:41; approx. 1:3) if the IMAMR is performed over a

longer period using sodium hydroxide as the base. In the latter

case it should be noted that the preferentially formed isomer (41)

has different relative stereochemistry to that observed in the

synthesis of myrtine. This finding suggests that 40 may be the

kinetic product and that, where R = aryl, epimerisation may

proceed selectively at the benzylic position (C-4) through a retro-

aza-Michael/aza-Michael sequence (or possibly Mannich, see

Scheme 3), in order to ultimately afford the thermodynamically

more favourable product 41. Further work aimed at explaining

these different outcomes is underway.

As shown in Scheme 11, under identical conditions to those

described above, (+)-(R)-29 gave enone (R)-43. The Boc group

in 43 was then removed and a modified IMAMR step was

performed. In this reaction the time for the cyclisation was

reduced to 30 min and the base used was ammonium

hydroxide.^[34]This gave a separable mixture of 40 and 41 in a

3:1 ratio. Enantiopurity for compound 41 was checked by the

chiral HPLC method and the main diastereomer, 40, isolated in

23% yield, was converted to (–)-lasubine

diastereoselective L-selectride reduction.

I (34) by a

Scheme 11. Synthesis of cis- and trans-arylquinolizidines 40 and 41 by a

cross-aldol-IMAMR sequence from (+)-(R)-pelletierine 29 and conversion of 40

to (–)-lasubine I (34). Reagents and conditions: (i) 3,4-(MeO)₂C₆H₃CHO 38,

Scheme 12. Proposed chair-chair and chair-boat conformations for the

IMAMR with α,β-unsaturated ketone 44 (Ar = aromatic ring).

NaOH, MeOH, 65 °C, 18 h, 45%; (ii) TFA, DCM, 0 °C to rt, 2 h, then NH_3(aq)

,

MeOH, rt, 0.5 h (40:41; 3:1, crude mixture), 40: 23%, 41: 8%, 96% e.e.; (iii) L-

selectride, THF, -78 °C, 2 h, 42%.

Conclusions

2.6. Stereoselectivity in the quinolizidine IMAMR

In summary, we have reported three methods for the synthesis

of both enantiomers of the β-amino ketone natural product

pelletierine (6). Two organocatalytic methods, using a proline-

The stereoselectivity of the intramolecular aza-Michael addition

in the syntheses of myrtine (33) and lasubine I (34) and II (35) is

of interest. Natural (+)-myrtine is formed from the Re-facial

attack of the nucleophilic piperidine nitrogen atom at the

electrophilic β-carbon. As shown in Scheme 12 consideration of

the possible transition state indicates that the chair-chair fused

trans-bicyclic quinolizidine will lead to preferential Si-facial attack,

even after flipping the ring to the cis-decalin form. Based on this

mediated Mannich reaction and

a

cinchona-mediated

intramolecular N-conjugate addition reaction of α,β-unsaturated

ketone 23, are detailed. The latter gives high enantiomeric

excess (90-98% e.e.), a fact at least partly attributed to the lack

of racemisation that can occur with unprotected 6. The third

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method relied on the differential solubilities of the diastereomeric

pelletierine-mandelate salts (28a and 28b) and by repeated

recrystallisation highly enantioenriched protected-pelletierine

can be readily obtained. To exemplify this resolution-based

method (S)-Cbz-protected pelletierine 17 was used to prepare

the sedum alkaloids sedridine 32, and allosedridine 8. (R)-Cbz-

Protected pelletierine 17 was used to prepare (+)-myrtine (33), a

naturally occurring quinolizidine, in an efficient sequence

featuring a novel Wittig olefination. Finally, (R)-Boc-protected

pelletierine 29 was used to prepare lasubine I (34) and its

enantiomer, (S)-29, was used to access lasubine II (35).

extracted with ether (2 X 100 mL). The combined organic

phases were washed with brine and dried with anhydrous

magnesium sulfate, filtered, and concentrated in vacuo to afford

14 (2.5 g, 60%) as yellowish oil, which gradually solidified. This

material was subsequently used without further purification and

could be stored indefinitely at low temperature.

(±)-1-(Piperidin-2-yl)propan-2-one

[(±)-Pelletierine]

6:^[7c]

Piperidine 13 (8.4 mL, 84 mmol) was added dropwise to a

rapidly stirred suspension of NCS (12.76 g, 94 mmol) in ether

(422 ml). After stirring for 4 h at room temperature, the mixture

was filtered and the filtrate concentrated to approx. 60 mL

behind a safety screen. The crude chloroamine solution was

then added dropwise into an ice-cold solution of KOH (4.7 g,

84.6 mmol) in absolute ethanol (42 ml). The mixture was allowed

to stir overnight. The white precipitate formed was removed by

filtration. In parallel, the sodium salt of ethyl acetoacetate was

prepared from NaOH (5.0 g, 127 mmol) and ethyl acetoacetate

(10.8 ml, 84.6 mmol) in water (170 mL), heating to 50 °C for 4 h

and then stirring overnight at room temperature. The crude

piperideine 14 and the sodium acetoacetate solutions were

combined and refluxed for 4h. The resulting yellow solution was

cooled to room temperature, and most of the organic solvent

(ether, EtOH) removed under reduced pressure. The aqueous

mixture was extracted with CH₂Cl₂(3 × 65 mL), dried over

MgSO₄and concentrated in vacuo. The resulting oil was purified

by adding ether and filtered; the solvent of filtrate was removed

Experimental Section

General experimental: Starting materials were supplied from

commercial sources and used without further purification. All

commercially available solvents were used as supplied unless

otherwise stated. All “dry” solvents were dried and distilled by

standard procedures or were processed through a Grubbs type

still. Oxygen free nitrogen was obtained from BOC gases and

was used without further drying. Infrared spectroscopy was

performed on a FT-IR spectrometer. Elemental analyses were

carried out by the UCD Microanalytical Laboratory. Routine

electrospray mass spectra and high-resolution mass spectra

were run on electrospray ionisation (ESI) with a time-of-flight

(TOF) analyser. Chiral HPLC was performed on Chiralpak IB, IC,

or AS-H columns as stated. The NMR spectra were recorded at

25 °C on 300, 400, 500 MHz spectrometers as indicated. All

peak assignments are confirmed by 2D experiments (¹H-¹H

gCOSY, ¹H-¹³C HSQC). TLC (thin layer chromatography) was

performed on 60F₂₅₄aluminium plates with realisation by UV

1

in vacuo, affording 6 (4.6 g, 39%) as yellow oil. H NMR (400

MHz, CDCl₃): δ 3.00-2.93 (m, 2H), 2.64 (td, J = 11.7, 2.7 Hz, 1H),

2.48 (d, J = 6.3 Hz, 2H), 2.34 (br s, 1H), 2.11 (s, 3H), 1.77-1.70

(m, 1H), 1.60-1.50 (m, 2H), 1.43-1.26 (m, 2H), 1.17-1.06 (m, 1H)

ppm.

irradiation

and/or

chemical

staining.

Flash

column

(–)-(2S)-(2-Oxopropyl)piperidine-1-carbamic acid benzyl

ester (Cbz-pelletierine) 17:^[7n]Δ¹-Piperideine 14 (670 mg, 8.06

mmol, 1 eq.), acetone (27 mL, 367.59 mmol, 46 eq.), DMSO (27

mL), water (3.4 mL), and L-proline (185 mg, 1.61 mmol, 0.2 eq.)

were mixed and stirred for one hour at room temperature. An

aqueous saturated solution of sodium bicarbonate (50 mL) was

added to the mixture, which was extracted with CH₂Cl₂(2 x 50

mL). The organic layer was washed with brine (50 mL), filtered

and dried over anhydrous magnesium sulfate. After filtration the

solvent was removed under reduced pressure and the crude

pelletierine was used immediately without purification. HRMS

(ES⁺) calcd for [(C₈H₁₅NO + H)]⁺142.1232, found 142.1232 (0.1

ppm). The residue obtained above was diluted in CH₂Cl₂(25

mL) and a 0.4 M solution of aqueous sodium carbonate (18 mL,

7.20 mmol, 0.9 eq.) was added. The mixture was cooled to 0 ^oC

and benzyl chloroformate (0.9 mL, 6.30 mmol, 0.8 eq.) was

added dropwise. The ice bath was removed and the solution

was stirred at room temperature overnight. The solution was

diluted with CH₂Cl₂(25 mL), and extracted. The organic layer

was washed with water (50 mL), and then with brine (50 mL),

dried over anhydrous magnesium sulfate, filtered and

concentrated in vacuo. This gave the crude product, which was

purified by flash column chromatography (CH₂Cl₂/EtOAc; 6:1),

which afforded the title compound 17 (1.25 g, 72 % yield over

two steps) as light yellow oil. R_f= 0.55 (EtOAc/CH₂Cl₂; 1:6);

chromatography was performed with silica, particle size 0.040-

0.063 mm.

Δ¹-Piperideine 14:^[7n]Piperidine 13 (5.17 g, 60.72 mmol) was

added to a solution of N-chlorosuccinimide (15.00 g, 112.33

mmol) in diethyl ether (400 mL). The solution was stirred at room

temp. for 1 h. After filtration and rinsing of the precipitate with

diethyl ether (40 mL), the diethyl ether solution was washed with

water (2 X 400 mL) and brine (200 mL) and then dried with

MgSO₄. The N-chloropiperidine solution was then filtered and

carefully concentrated under reduced pressure to roughly 80 mL

volume. CARE: Whilst we never experienced any issues, as a

precaution this procedure was conducted behind a blast shield

and the solutions were concentrated with the rotary evaporator’s

bath temperature set to < 40 °C and crude solutions were never

evaporated to dryness. The resultant solution was added

dropwise to a solution of KOH (4.00 g, 71.20 mmol) in absolute

ethanol (64 mL). During this process the temperature was

maintained between 5 and 10 °C. After addition, the mixture was

stirred at room temperature for 24 h and filtered. The precipitate

was rinsed with absolute ethanol (60 mL), and the combined

solution was concentrated to about 25 mL. Ether (200 mL) and

water (20 mL) were added and the mixture was extracted. The

phases were separated and the aqueous phase was then further

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20

28

[α]_D= –10.5 (c = 1.00, CHCl₃) {lit.,^[35][α]_D= –10.0 (c = 0.50,

CHCl₃)}; IR: 3032, 2938, 2862, 1688, 1497, 1353, 1258, 1165,

1049, 735, 697 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ 7.42-7.32 (m,

M.p 51-53 °C; R_f= 0.55 (EtOAc/c-Hex; 1:1); ¹H NMR (300 MHz,

CDCl₃): δ 7.40-7.28 (m, 5H), 5.84-5.78 (m, 1H), 5.17 (s, 2H),

3.91 (br. d, 1H), 3.19 (app. t, J = 12.6 Hz, 2H), 1.96-1.39 (m, 6H)

5H), 5.11 (d, J = 12.5 Hz, 1H), 5.08 (d, J = 12.5 Hz, 1H), 4.84 (br. ppm.

s, 1H), 4.07 (br. s, 1H), 2.87 (app. t, J = 12.8 Hz, 1H), 2.73-2.61

(m, 2H), 2.15 (s, 3H), 1.78-1.34 (m, 6H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ 206.9 (CO), 155.3 (CO), 136.7 (C), 128.4 (CH),

127.9 (CH), 127.8 (CH), 67.1 (CH₂), 47.5 (CH), 44.3 (CH₂), 39.8

(CH₂), 30.0 (CH₃), 28.3 (CH₂), 25.2 (CH₂), 18.8 (CH₂) ppm;

HPLC analysis (Chiralpak IB), heptane/EtOH; 98:2 (1mL/min): (–

)-17 tr = 12.1 min, (+)-17 tr = 13.6 min; e.r. 91:9.

(7-Oxooct-5-enyl)carbamic acid benzyl ester 23:^[7p]To a

solution of Cbz-protected 2-hydroxypiperidine (235 mg, 1.0

mmol, 1 eq.) in toluene (10 mL) was added (acetylmethylene)

triphenylphosphorane 22^[38](477 mg, 1.5 mmol, 1.5 eq.) at room

temperature. The resulting reaction mixture was stirred at reflux

overnight. After removal of the solvent the residue was purified

by flash column chromatography (EtOAc/c-Hex; 1:2) to give the

enone 23 (234 mg, 85%) as light yellow oil. R_f= 0.3 (EtOAc/c-

Hex; 1:2); ¹H NMR (300 MHz, CDCl₃): δ 7.40-7.29 (m, 5H), 6.78

(dt, J = 15.6 and 6.9 Hz, 1H), 6.09 (d, J = 15.6 Hz, 1H), 5.07 (s,

2H), 4.90 (br. s, 1H), 3.22 (m, 2H), 2.31-2.20 (m, 5H), 1.65-1.44

(m, 4H) ppm.

(+)-(2R)-(2-Oxopropyl)piperidine-1-carbamic acid benzyl

ester 17: In an identical procedure to that described above, Δ¹-

piperideine 14 (670 mg, 8.06 mmol, 1.0 eq.), acetone (27 mL,

367.59 mmol, 46 eq.), DMSO (27 mL), water (3.4 mL) and D-

proline (185 mg, 1.61 mmol, 0.2 eq.) gave pelletierine 6 which

was converted into its benzyloxycarbamate following the

procedure above which afforded the title compound (+)-17 (1.12

(±)-2-(2-Oxopropyl) piperidine-1-carbamic acid benzyl ester

(Cbz-pelletierine) 17: To a solution of enone 23 (137 mg, 0.50

mmol, 1 eq.) in acetonitrile (5 mL) was added borontrifluoride

diethyletherate (0.03 mL, 0.25 mmol, 0.5 eq.) at 0 °C. The

mixture was stirred at the same temperature for 10-15 min and

then 15 min at room temperature. The mixture was poured into

saturated aqueous NaHCO₃(25 mL) and extracted with EtOAc

(2 x 25 mL). The combined organic layers were dried over

anhydrous magnesium sulfate, filtered and the solvent was

removed by in vacuo. This afforded the title compound 17 (137

mg, 100 %) as light yellow oil. R_f= 0.35 (EtOAc/c-Hex; 1:2).

20

g, 63%) as a light yellow oil, with data as above. [α]_D= +9.0 (c

25

= 1.00, CHCl₃) {lit.,³⁶[α]_D= +10.1 (c = 0.90, CHCl₃)}; HPLC

analysis (Chiralpak IB) n-heptane/EtOH; 98:2 (1 mL/min): (–)-17

tr = 12.5 min, (+)-17 tr = 13.6 min; e.r. 13:87.

N-Benzyloxycarbonyl-5-aminopentan-1-ol:^[37]To a solution of

5-aminopentanol 21 (4.10 g, 40.00 mmol) and NaHCO₃(10.00 g,

120.00 mmol) in water (40 mL) was added a solution of

benzyloxycarbonyl chloride (9.10 g, 54.00 mmol) in THF (40 mL)

at 0 °C. The reaction mixture was warmed to room temperature

and stirred vigorously overnight. The mixture was extracted with

ethyl acetate (2 x 25 mL). The combined organic layers were

washed with brine (50 mL), dried over MgSO₄, filtered and

concentrated in vacuo to afford the crude product. This was

triturated with n-hexane. The resulting solid was collected by

filtration, washed with diethyl ether and dried under reduced

pressure to afford the title compound (9.00 g, 97%) as a

colourless low melting solid. M.p 42-43 °C (Lit.^[37]M.p 43-44 °C);

R_f= 0.2 (EtOAc/c-Hex; 1:1); ¹H NMR (300 MHz, CDCl₃): δ 7.40-

7.27 (m, 5H), 5.09 (s, 2H), 4.80 (s, 1H), 3.65 (t, J = 6.1 Hz, 2H),

3.29-3.12 (m, 2H), 1.70-1.48 (m, 4H), 1.47-1.33 (m, 2H) ppm.

(+)-(2R)-(2-Oxopropyl) piperidine-1-carbamic acid benzyl

ester [(+)-(R)-Cbz-pelletierine] 17: In an identical procedure to

that described above, solution of TFA (30 µl, 0.40 mmol) in THF

(6

mL)

was

sequentially

added

(8S,9S)-9-amino-9-

deoxyepiquinine 24a (51 mg, 0.20 mmol) and enone carbamate

23 (275 mg, 1.00 mmol) at room temperature. The reaction was

stirred for 8 h. After removal of the solvent, the residue was

purified by flash column chromatography on silica gel

(CH₂Cl₂/EtOAc; 10:1), affording (+)-17 (245 mg, 89%) as

colourless oil. [α]_D²⁰= +8.5 (c = 1.00, CHCl₃).

N-Benzyloxycarbonyl-2-hydroxypiperidine:^[7p]Under N₂, to a

solution of oxalyl chloride (0.61 ml, 6.95 mmol) in CH₂Cl₂(25

mL) at -78 °C was added anhydrous DMSO (0.90 mL, 12.60

mmol) dropwise over 5 min. The reaction mixture was stirred at -

78 °C for 10 min. N-Benzyloxycarbonyl-5-aminopentan-1-ol

(1.50 g, 6.32 mmol) in CH₂Cl₂(60 mL) was added dropwise over

5 min and a pale yellow precipitate formed. The reaction mixture

was warmed until the precipitate dissolved and then re-cooled to

-78 °C and stirred for 10 min. Triethylamine (4.41 mL, 31.60

mmol) was added, the reaction was warmed to room

temperature (approx. 0.5 h) before H₂O (15 mL) was added. The

organic layer was separated and the aqueous layer was

extracted with CH₂Cl₂(20 mL). The combined organic layers

were dried (MgSO₄), filtered, and concentrated in vacuo to afford

the crude product, which was purified by flash column

chromatography, (EtOAc/c-Hex; 2:3) affording the title

compound (0.80 g, 53%) as a clear oil which gradually solidified.

(+)-(2R)-2-[2-Oxo-3-(7-bromo-6-chloro-4-oxoquinazolin-

4(3H)-yl)propyl]piperidine-1-carbamic acid benzyl ester 25:

Following the published procedure^[15](+)-17 was converted into

(+)-25. HPLC analysis (Chiralpak A-SH), heptane/EtOH; 90:10

(1mL/min): (+)-25 tr = 18.2 min, (–)-25 tr = 20.7 min; e.r. 99:1.

Recrystallisation of this material (MeOH) led to crystals suitable

for X-ray diffraction.

(–)-(2S)-(2-Oxopropyl) piperidine-1-carbamic acid benzyl

ester [(–)-(S)-Cbz-pelletierine] 17: To a solution of TFA (30 µl,

0.40 mmol) in THF (6 mL) was sequentially added (9R)-9-amino-

9-deoxyquinidine 24b (51 mg, 0.20 mmol) and enone carbamate

23 (275 mg, 1.00 mmol) at room temperature. The reaction was

stirred for 8 h. After removal of the solvent, the residue was

purified by flash column chromatography on silica gel

(DCM/EtOAc; 10:1), affording 17 (224 mg, 81%) as colourless

oil. [α]_D²⁰= –8.0 (c = 1.00, CHCl₃).

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mmol, 1.0 eq.) was then added and the suspension became

homogenous. The reaction mixture was stirred at rt overnight.

The solvent was removed and the residue was purified by flash

column chromatography (CH₂Cl₂/EtOAc, 6:1) to afford (+)-17 as

(–)-(2S)-2-[2-Oxo-3-(7-bromo-6-chloro-4-oxoquinazolin-

4(3H)-yl)propyl]piperidine-1-carbamic acid benzyl ester 25:

Following the reported procedure^[15](–)-17 was converted into (–

)-25. HPLC analysis (Chiralpak A-SH), heptane/EtOH; 90:10

(1mL/min): (+)-25 tr = 18.3 min, (–)-25 tr = 20.8 min; e.r. 5:95.

20

a transparent oil (2.64 g, 9.6 mmol, 94%). [α]_D= +10.6 (c =

1.00, CHCl₃); HPLC analysis (Chiralpak IB) n-heptane/EtOH;

98:2 (1 mL/min): (–)-17 tr = 11.7 min, (+)-17 tr = 12.5 min; e.r.

0.1:99.9.

(2R)-(2-Oxopropyl)piperidin-1-ium·(2R)-2-hydroxy-2-

phenylacetate salt 28a and (2S)-(2-oxopropyl)piperidin-1-

ium·(2R)-2-hydroxy-2-phenylacetate salt 28b: Isopelletierine

6 (racemic pelletierine) (4.60 g, 32.57 mmol) and (–)-mandelic

acid 27 (4.95 g, 32.57 mmol) were mixed with cooling, and

methanol (13 mL) was added. The mixture was warmed to affect

solution, cooled, and then treated with anhydrous ether (32 mL).

After a few minutes crystals began to form. After 22 h at 0 °C,

the crystals were collected and dried in vacuo (4.40 g).

Recrystallisation was performed by dissolving the salt (4.40 g) in

methanol (11 mL) and adding ether (22 mL). After 22 h at 0 °C

the insoluble pelletierine mandelate 28a was collected and dried

in vacuo, (3.37 g). A third recrystallisation was performed by

dissolving the salt (3.37 g) in methanol (11 mL) and adding ether

(23 mL). After 22 h at 0 °C feathery white needles 28a (3.15 g,

33% - after three recrystallisations) were collected by filtration;

(–)-(2S)-(2-Oxopropyl) piperidine-1-carbamic acid benzyl

ester [(–)-(S)-Cbz-pelletierine] 17: In an identical procedure to

that described above, N,N-diisporopylethyl amine (2.5 mL, 15.0

mmol, 3.4 eq.) was added at 0 °C to a solution of the salt (S,S)-

pelletierine mandelate ent-28a (1.30 g, 4.4 mmol, 1.0 eq.) in

CH₂Cl₂(50.0 ml), benzylchloroformate (0.7 ml, 5.1 mmol, 1.16

eq.) which after work-up and purification afforded (–)-17 as a

20

transparent oil (1.20 g, 15.0 mmol, 100%). [α]_D= –11.0 (c =

1.00, CHCl₃); HPLC analysis (Chiralpak IB), heptane/EtOH; 98:2

(1 mL/min): (–)-17 tr = 11.7 min, (+)-17 tr = 12.5 min; e.r.

99.9:0.1.

(+)-(2R)-(2-Oxopropyl) piperidine-1-carbamic acid tert-butyl

ester [(+)-(R)-Boc-pelletierine] 29: Triethylamine (1.35 mL,

9.68 mmol) was added at 0 °C to a solution of the salt (R,R)-

pelletierine mandelate 28a (925 mg, 3.15 mmol) in CH₂Cl₂(7.5

ml), di-tert-butyl dicarbonate (760 mg, 3.48 mmol) was then

added and the reaction mixture was stirred at rt overnight. The

solvent was removed and the residue was purified by flash

column chromatography (CH₂Cl₂/EtOAc, 6:1) to afford (R)-29 as

a transparent oil (780 mg, 0.57 mmol, 100%). ¹H NMR (400 MHz,

CDCl₃): δ 4.78-4.66 (m, 1H), 3.96 (d, J = 13.2 Hz, 1H), 2.77 (t, J

= 12.8 Hz, 1H), 2.67-2.60 (m, 2H), 2.18 (s, 3H), 1.71-1.48 (m,

6H), 1.44 (s, 9H) ppm.

20

M.p = 138-139 °C; [α]_D= –59 (c = 1.00, CHCl₃); HRMS (ESI)

calcd for [(C₈H₁₅NO + H)]⁺142.1232, found 142.1226 (-4.1 ppm);

IR 3300-3000 broad, 2958, 1714, 1639, 1582, 1368, 1166, 1063,

732, 683 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ 7.48 (d, J = 7.3 Hz,

2H), 7.29 (t, J = 7.3 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 4.9 (s, 1H),

3.20-3.09 (m, 2H), 2.79 (dd, J = 18.5, 6.2 Hz, 1H), 2.51-2.41 (m,

2H), 2.06 (s, 3H), 1.80-1.56 (m, 4H), 1.41-1.31 (m, 2H) ppm; ¹³

C

NMR (100 MHz, CDCl₃): δ 206.4 (C=O), 178.5 (C=O), 142.4 (C),

128.1 (CH), 127.1 (CH), 126.5 (CH), 74.3 (CH), 52.3 (CH), 45.7

(CH₂), 44.3 (CH₂), 30.3 (CH₃), 28.2 (CH₂), 22.4 (CH₂), 22.2

(CH₂) ppm; Anal. Calcd for C₁₆H₂₃NO₄: C, 65.51; H, 7.90; N,

4.77%. Found C, 65.58; H, 7.90; N, 4.77%. The soluble salt 28b

from above filtrate was collected and solvent removed under

reduced pressure. The resultant viscous yellow oil (4.50 g, 15.3

mmol) in water (40 mL) was cooled with ice-water and basified

slowly with solid potassium hydroxide (1.70 g, 30.6 mmol). The

liberated, optically active (+)-pelletierine 6 was extracted with

DCM (3 x 50 mL) and the combined extracts were dried over

MgSO₄. The DCM was evaporated in vacuo at room

temperature. The residual (+)-pelletierine was purified by adding

ether (yield 1.80 g, 12.7 mmol, 83% based on salt). In an

identical procedure to that described above, a mixture of the

resultant enantioenriched (+)-pelletierine 6 (1.80 g, 12.7 mmol),

(+)-mandelic acid 27 (1.93 g, 12.7 mmol), MeOH (5.0 mL), and

(–)-(2S)-(2-Oxopropyl) piperidine-1-carbamic acid tert-butyl

ester [(–)-(S)-Boc-pelletierine] 29: In an identical procedure to

that described above, triethylamine (0.27 mL, 1.89 mmol, 3.0

eq.) was added at 0 °C to a solution of the salt (S,S)-pelletierine

mandelate ent-28a (185 mg, 0.63 mmol, 1.0 eq.) in CH₂Cl₂(1.5

ml), di-tert-butyl dicarbonate (152 mg, 0.63 mmol, 1.0 eq.) was

then added and the reaction mixture was stirred at rt overnight.

The solvent was removed and the residue was purified by flash

column chromatography (CH₂Cl₂/EtOAc, 6:1) to afford (S)-29 as

a transparent oil (137 mg, 0.57 mmol, 90%).

(–)-Benzyl

carboxylate [(–)-Cbz-sedridine] 30 and (–)-benzyl (S)-2-[(R)-

ether (12.6 mL) gave ent-28a (2.17 g). A second recrystallisation, 2-hydroxypropyl]piperidine-1-carboxylate [(–)-Cbz-

(S)-2-[(S)-2-hydroxypropyl]piperidine-1-

using MeOH (5.4 mL), and ether (10.8 mL) gave ent-28a (1.80

allosedridine] 31: NaBH₄(76 mg, 2.00 mmol) was added to a

stirred solution of ketone 17 (275 mg, 1.00 mmol) in methanol

(10 mL) at 0 °C and the reaction was left at room temperature

for 4 h. Excess sodium borohydride were quenched with water

(15 mL) and extracted with CH₂Cl₂(2 x 20 mL). The organic

layer was dried with anhydrous MgSO₄and the solvent removed

under reduced pressure. The diastereomers were purified by

flash column chromatography (CH₂Cl₂/EtOAc; 10:1). (–)-30:

clear oil (103 mg, 37%); R_f= 0.2 (CH₂Cl₂/EtOAc; 10:1 to EtOAc);

g). The final recrystallisation, using MeOH (5.0 mL), and ether

20

(10.0 mL) gave ent-28a (1.36 g, 37%). [α]_D= +60.9 (c = 1.00,

CHCl₃).

(+)-(2R)-(2-Oxopropyl) piperidine-1-carbamic acid benzyl

ester [(+)-(R)-Cbz-pelletierine] 17: N,N-Diispropylethyl amine

o

(5.0 mL, 30.0 mmol, 3.0 eq.) was added at 0 C to a solution of

the salt (R,R)-pelletierine mandelate 28a (3.00 g, 10.2 mmol, 1.0

eq.) in CH₂Cl₂(100 mL), benzylchloroformate (1.4 mL, 10.2

20

28

[α]_D= –29.2 (c = 1.00, CHCl₃) {lit.,^[26][α]_D= –25.8 (c = 0.1,

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European Journal of Organic Chemistry

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1

CHCl₃)}; H NMR (500 MHz, CDCl₃): δ 7.40-7.30 (m, 5H), 5.17

2.0 mmol) was added and stirred at rt for 16 h. Ether (40 mL)

(d, J = 12.3 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 4.58-4.45 (m, 1H), was added, and the yellow precipitate was collected by filtration,

4.14-4.04 (m, 1H), 3.60-3.47(m, 1H), 2.76 (td, J = 13.2, 2.6 Hz,

1H), 1.99 (t, J = 13.3 Hz, 1H), 1.80-1.68 (m, 1H), 1.67-1.37 (m,

5H), 1.37-1.29 (m, 1H), 1.18 (d, J = 6.0 Hz, 3H) ppm; ¹³C NMR

(120 MHz, CDCl₃): δ 156.9, 136.5, 128.5, 128.1, 127.9, 67.5,

63.3, 47.4, 39.4, 39.3, 29.3, 25.4, 22.5, 19.1 ppm. (–)-32: clear

dissolved in MeOH-CH₃CN (10:10 mL), the solvents was

removed by vacuum. Solid was triturated with ether, dried and

kept in desiccator. The phosphonium salt then was dissolved in

MeOH (20 mL), aqueous Na₂CO₃(230 mg, 2.0 mmol) in water

(6 mL) was added; white suspension was diluted with water (20

mL) and stirred for 2 h. The solution was extracted with EtOAc

(2 x 30 mL) and the organic layer washed with water (20 mL),

and brine (20 mL), then dried over MgSO₄. The solvent was

removed in vacuo to afford ylide 36 (480 mg, 0.89 mmol, 45%).

R_f= 0.15 (EtOAc); HRMS (ESI) calcd for [(C₃₄H₃₅NO₃P + H)]⁺

536.2355, found 536.2353 (-0.3 ppm); ¹H NMR (400 MHz,

CDCl₃): δ 7.66-7.58 (m, 6H), 7.56-7.50 (m, 3H), 7.47-7.39 (m,

6H), 7.34-7.19 (m, 5H), 5.14-4.97 (m, 2H), 4.86-4.77 (m, 1H),

4.10 (app. d, J = 13.0 Hz, 1H), 3.83-3.60 (m, 1H), 2.96 (app. t, J

= 13.0 Hz, 1H), 2.60 (d, J = 6.5 Hz, 2H), 1.86-1.53 (m, 5H), 1.49-

1.32 (m, 1H) ppm; ¹³C NMR* (100 MHz, CDCl₃): δ 190.6 (CO),

20

oil (152 mg, 55%); R_f= 0.1 (CH₂Cl₂/EtOAc; 10:1); [α]_D= –52.8

(c = 1.00, CHCl₃) {lit.,^[26][α]_D²⁸= –50.6 (c = 0.1, CHCl₃)}; ¹H NMR

(400 MHz, CDCl₃): δ 7.38-7.28 (m, 5H), 5.15 (d, J = 12.4 Hz,

1H), 5.10 (d, J = 12.4 Hz, 1H), 4.45-4.37 (m, 1H), 4.04 (d, J =

13.5 Hz, 1H), 3.81 (br s, 1H), 2.90 (t, J = 12.8 Hz, 1H), 1.84 (dt,

J = 14.3, 7.9 Hz, 1H), 1.68-1.36 (m, 7H), 1.18 (d, J = 6.0 Hz, 3H)

ppm; ¹³C NMR (100 MHz, CDCl₃): δ 157.0, 136.8, 128.5, 128.0,

127.9, 67.2, 66.3, 49.0, 40.1, 39.5, 29.5, 25.5, 23.6, 19.0 ppm.

(+)-(S)-1-[(S)-Piperidin-2-yl]propan-2-ol [(+)-Sedridine] 32: A

suspension of Cbz-sedridine 30 (100 mg, 0.36 mmol) and

3

Pd(OH)₂(30 mg) in MeOH (2.5 mL) under

a

hydrogen

155.5 (CO), 137.3 (C), 133.0 (d, J_C–P= 10.0 Hz, CH), 131.9 (d,

2

atmosphere was stirred overnight. The mixture was filtered

through a Celite pad, and the filtrate was evaporated to give 32

(51 mg, 99%) as a solid. M.p 80-82 °C (lit.,^[39]M.p 84-85 °C);

⁴J_C–P= 2.7 Hz, CH), 128.7 (d, J_C–P= 12.2 Hz, CH), 128.3 (CH),

127.5 (CH), 127.4 (CH), 127.2 (s, ¹J_C–P= 90.7 Hz, C), 66.6 (CH₂),

50.4 (CH), 42.1 (d, ³J_C–P= 15.0 Hz, CH₂), 39.7 (CH₂), 27.9 (CH₂),

25.6 (CH₂), 19.0 (CH₂) ppm; ³¹P NMR (160 MHz, CDCl₃): δ

14.87 ppm. *Signal for ylide CHP was not observed.

20

28

[α]_D= +22.0 (c = 1.00, MeOH) {lit.,^[26][α]_D= +27.5 (c = 0.07,

EtOH)}; ¹H NMR (400 MHz, CDCl₃): δ 4.10 (dqd, J = 9.4, 6.2, 3.5

Hz, 1H), 3.23 (br s, 2H), 3.06 (d, J = 10.6 Hz, 1H), 2.88 (ddt, J =

9.7, 6.6, 3.1 Hz, 1H), 2.57 (td, J = 11.8, 2.7 Hz, 1H), 1.84-1.75

(m, 1H), 1.61-1.54 (m, 3H), 1.48-1.34 (m, 4H), 1.17 (d, J = 6.3

Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 65.1, 54.8, 46.8,

43.6, 31.2, 25.9, 24.6, 23.6 ppm.

Benzyl

(R)-2-(2-oxo-3-(triphenyl-λ⁵-phosphaneylidene)

propyl)piperidine-1-carboxylate 36: In an identical procedure

to that described above, (+)-Cbz-pelleteirine 17 (550 mg, 2.0

mmol, 1.00 eq.) in dry CH₂Cl₂(15 mL) was cooled to 0 °C and

left for 30 min, DIPEA (0.56 mL, 3.2 mmol, 1.48 eq.) and

TMSOTf (0.54 mL, 3.0 mmol, 1.37 eq.) were added, and the

mixture was stirred at room temperature for 1 h. NBS (496 mg,

2.8 mmol, 1.28 eq.) was then added in one portion. The mixture

was stirred at room temperature for 2 h, then poured into water

(40 mL) and extracted with EtOAc (2 x 60 mL). The combined

organic layers were washed with saturated aqueous NaHCO₃

(60 mL) and brine (60 mL), dried over anhydrous MgSO₄, filtered,

(–)-(R)-1-[(S)-piperidin-2-yl]propan-2-ol [(–)-Allosedridine] 8:

A suspension of Cbz-allosedridine 31 (150 mg, 0.54 mmol) and

Pd(OH)₂(40 mg) in MeOH (3.5 mL) under

a hydrogen

atmosphere was stirred overinght. The mixture was filtered

through a Celite pad, and the filtrate was evaporated to give 8

(119 mg, 100%) as a solid. M.p 60-62 °C, (lit.,^[39]M.p 60-61 °C);

20

28

[α]_D= –16.0 (c = 1.00, MeOH) {lit.,^[26][α]_D= –15.6 (c = 0.05,

1

MeOH)}; H NMR (400 MHz, CDCl₃): δ 4.00 (dqd, J = 10.4, 6.2,

and concentrated. To

a

solution of crude Cbz-α-

2.2 Hz, 1H), 3.04 (dp, J = 14.1, 1.9 Hz, 1H), 2.72 (tt, J = 10.8,

2.5 Hz, 1H), 2.58 (ddd, J = 13.6, 12.1, 3.0 Hz, 1H), 1.85-1.77 (m,

1H), 1.66-1.56 (m, 2H), 1.53-1.45 (m, 2H), 1.35-1.20 (m, 2H),

1.13 (d, J = 6.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ

69.2, 58.3, 46.0, 44.2, 34.3, 27.2, 24.4, 23.9 ppm.

bromopelletierine in toluene (20 mL), Ph₃P (534 mg, 2.0 mmol)

was added and stirred at rt for 16 h, ether (40 mL) was added,

and the yellow precipitate was collected by filtration, dissolved in

MeOH-CH₃CN (10:10 mL), the solvents was removed in vacuo.

Solid was triturated with ether, dried and kept in desiccator. The

phosphonium salt than was dissolved in MeOH (20 mL),

aqueous Na₂CO₃(230 mg, 2.0 mmol) in water (6 mL) was

added; white suspension was diluted with water (20 mL) and

stirred for 2 h. The solution was extracted with EtOAc (2 x 30

mL) and the resultant organic layer washed with water (20 mL),

and brine (20 mL), and dried over MgSO₄. After filtration the

solvent was removed under reduced pressure to afford ylide 36

(720 mg, 1.34 mmol, 67%) with data as above.

Benzyl

(S)-2-(2-oxo-3-(triphenyl-λ⁵-phosphaneylidene)

propyl)piperidine-1-carboxylate 36: A mixture of (–)-Cbz-

pelleteirine 17 (550 mg, 2.0 mmol, 1.00 eq.) in dry CH₂Cl₂(15

mL) was cooled to 0 °C and left for 30 min, DIPEA (0.56 mL, 3.2

mmol, 1.48 eq.) and TMSOTf (0.54 mL, 3.0 mmol, 1.37 eq.)

were added, and the mixture was stirred at room temperature for

1 h. NBS (496 mg, 2.8 mmol, 1.28 eq.) was then added in one

portion. The mixture was stirred at room temperature for 2 h,

then poured into water (40 mL) and extracted with EtOAc (2 x 60

mL). The combined organic layers were washed with saturated

aqueous NaHCO₃(60 mL) and brine (60 mL), dried over

anhydrous MgSO₄, filtered, and concentrated. To a solution of

(S,E)-Benzyl-2-(2-oxopent-3-en-1-yl)piperidine-1-carboxylate

37: To a solution of ylide 36 (107 mg, 0.20 mmol, 1.0 eq.) in

anhydrous THF (2 mL) was added acetaldehyde (0.11 mL, 2.00

mmol, 10.0 eq.). The reaction was stirred at rt for 7 h, the

crude Cbz-α-bromopelletierine in toluene (20 mL), Ph₃P (534 mg, solvent was removed in vacuo. This gave the crude product,

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European Journal of Organic Chemistry

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which was purified by flash column chromatography (c-

Hex/EtOAc; 3:1), which afforded the enone 37 (43 mg, 0.143

mmol, 71%) as light yellow oil. R_f= 0.3 (c-Hex/EtOAc; 3:1); [α]_D

chromatography on silica to afford 33 (20 mg, 40%) as a yellow

20

25

viscous oil [α]_D= + 11.0 (c = 0.2, CHCl₃) {lit.,^[40][α]_D= +10.1

20

(c = 1.5, CHCl₃)}.

= +15.5 (c = 1.00, CHCl₃); HRMS (ESI) calcd for [(C₁₈H₂₃NO₃+

1

H)]⁺302.1756, found 302.1751 (-1.7 ppm); H NMR (400 MHz,

(S,E)-Benzyl-2-(4-(3,4-dimethoxyphenyl)-2-oxobut-3-

CDCl₃): δ 7.41-7.25 (m, 5H), 6.84 (br s, 1H), 6.08 (d, J = 17.1 Hz, enyl)piperidine-1-carboxylate 42: To a solution of (–)-Cbz-

1H), 4.82-4.70 (m, 1H), 5.12 (d, J = 12.2 Hz, 1H), 5.09 (d, J =

12.2 Hz, 1H), 2.96-2.67 (m, 3H), 1.83 (d, J = 5.4 Hz, 3H), 1.71-

1.35 (m, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 198.2 (CO),

155.3 (CO), 143.51 (CH), 136.8 (C), 131.8 (CH), 128.5 (CH),

127.9 (CH), 127.8 (CH), 67.1 (CH₂), 48.1 (CH), 40.6 (CH₂), 39.8

(CH₂), 27.8 (CH₂), 25.2 (CH₂), 18.7 (CH₂), 18.3 (CH₃) ppm.

pelletierine 17 (138 mg, 0.50 mmol, 1.0 eq.) in dry CH₂Cl₂(3 mL)

was added 3,4-dimethoxybenzaldehyde 38 (83 mg, 0.5 mmol,

1.0 eq.) and pyrrolidine (8 µL, 0.1 mmol, 0.2 eq.). The reaction

was stirred at room temperature until the starting material was

consumed as evidenced by TLC (24 h). The reaction mixture

was concentrated and the residue diluted in ethyl acetate (2 mL)

and washed with water (3 x 3 mL). The aqueous extracts were

combined and back extracted with ethyl acetate (5 mL). The

organic extracts were combined, dried over MgSO₄, filtered and

evaporated. The product was purified by flash column

chromatography (c-Hex/EtOAc, 2:1) to give compound 42 (129

mg, 0.31 mmol, 62%) as yellow oil. R_f= 0.25 (c-Hex/EtOAc; 2:1);

LRMS (ESI) calcd for [(C₂₅H₂₉NO₅+ Na)]⁺446.5, found 446.7;

¹H NMR (400 MHz, CDCl₃): δ 7.52 (d, J = 16.0 Hz, 1H), 7.36-

7.22 (m, 5H), 7.14-6.99 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.61 (d,

J = 16.0 Hz, 1H), 5.11 (d, J = 12.5 Hz, 1H), 5.07 (d, J = 12.5 Hz,

1H), 4.92-4.84 (m, 1H), 4.16-4.03 (m, 3H), 3.89 (s, 3H), 3.87 (s,

3H), 2.99-2.84 (m, 3H), 1.72-1.54 (m, 5H), 1.51-1.37 (m, 1H)

ppm.

(R,E)-Benzyl-2-(2-oxopent-3-en-1-yl)

piperidine-1-

carboxylate 37: In an identical to that described above, to ylide

ent-36 (214 mg, 0.40 mmol, 1.0 eq.) in anhydrous THF (4 mL)

was added acetaldehyde (0.22 mL, 4.00 mmol, 10.0 eq.). The

reaction was stirred at rt for 7 h, the solvent was removed in

vacuo. This gave the crude product, which was purified by flash

column chromatography (c-Hex/EtOAc; 3:1), which afforded the

title compound 37 (84 mg, 0.28 mmol, 70%) as light yellow oil;

[α]_D²⁰= –16.3 (c = 1.00, CHCl₃).

(–)-(4S,9aR)-4-Methyloctahydro-2H-quinolizin-2-one

[(–)-

myrtine] 33: To a solution of 37 (115 mg, 0.38 mmol) in CH₂Cl₂

(3 mL) was added HBr-AcOH (33%, 0.32 mL, 1.8 mmol) at 0 °C,

the mixture was stirred at rt for 4 h. The solvent and excess of

acid was removed in vacuo, and the residue was dissolved in

MeOH (5 mL), and K₂CO₃(415 mg, 3.00 mmol) was added at

0 °C. The reaction mixture was stirred for 3 h and then

concentrated to dryness. A saturated aqueous ammonium

chloride solution (5 mL) was added, the quenched reaction

mixture was extracted with CH₂Cl₂(3 x 7 ml), and the combined

organic layers were dried over anhydrous MgSO₄. Solvents were

removed under reduced pressure and the crude myrtine was

purified by flash column chromatography (CH₂Cl₂/MeOH, 95:5)

to afford 33 (34 mg, 53%) as a yellow viscous oil. R_f= 0.25

(R,E)-Benzyl-2-(4-(3,4-dimethoxyphenyl)-2-oxobut-3-

enyl)piperidine-1-carboxylate 42: In an identical procedure

that described above (+)-Cbz-pelletierine 17 (138 mg, 0.50 mmol,

1.0 eq.) in dry CH₂Cl₂(3 mL) was added 3,4-

dimethoxybenzaldehyde 38 (83 mg, 0.50 mmol, 1.0 eq.) and

pyrrolidine (8 µL, 0.1 mmol, 0.2 eq.), affording compound 42

(125 mg, 0.30 mmol, 60%) with data as above.

(4S,9aR)-4-(3,4-Dimethoxyphenyl)octahydro-2H-quinolizin-2-

one 40 and (4R,9aR)-4-(3,4-dimethoxyphenyl)octahydro-2H-

quinolizin-2-one 41 via a direct aldol-IMAMR: A solution of

HBr-HOAc (33%, 1.1 mL, 6.00 mmol) was added to (+)-17 (275

mg, 1.00 mmol) under ice cooling and the solution was stirred at

room temperature for 4 h. The reaction mixture was evaporated

under reduced pressure and the crude pelletierine hydrobromide

39 was mixed with an equimolar quantity of the veratraldehyde

38 (166 mg, 1.00 mmol) in water (1 mL) and EtOH (0.6 mL). The

mixture was cooled at ice-bath temp. granular NaOH (120 mg,

3.00 mmol) was added. After dissolution of the base the reaction

mixture was allowed to stir at rt for 3 h and at 65 °C for 3 h. The

solution was diluted with ice water (5 mL) and extracted with

chloroform (3 x 5 mL). The combined organic fractions were

washed with water (5 mL) and dried over MgSO₄. The solvent

was removed in vacuo to provide orange oil, which was purified

by flash column chromatography to afford trans-fused isomer 41

(84 mg, 0.29 mmol, 29%) and cis-fused isomer 40 (45 mg, 0.16

mmol, 16 %). HPLC analysis (Chiralpak IC), n-heptane/EtOH;

80:20 (1 mL/min): (–)-41 tr = 15 min, (+)-41 tr = 17 min; e.r.

45:55.

20

(CH₂Cl₂/MeOH; 95:5); [α]_D= – 13.6 (c = 1.0, CHCl₃) {lit.,^[40]

[α]_D²⁵= +10.1 (c = 1.5, CHCl₃) for (4R,10R)-enantiomer} ; HRMS

1

calcd for [(C₁₀H₁₇NO + H)]⁺168.1311, found 168.1307; H NMR

(400 MHz, CDCl₃): δ 3.44-3.32 (m, 1H), 2.90-2.74 (m, 2H), 2.71-

2.58 (m, 1H), 2.47 (td, J = 11.4, 2.9 Hz, 1H), 2.30-2.13 (m, 3H),

1.76- 1.53 (m, 4H), 1.38-1.10 (m, 2H), 0.96 (d, J = 6.8 Hz, 3H)

ppm.

(+)-(4R,9aR)-4-Methyloctahydro-2H-quinolizin-2-one

[(+)-

myrtine] 33: In an identical to that described above, enone 37

(90 mg, 0.30 mmol, 1.0 eq.) in CH₂Cl₂(2.5 mL) was treated with

o

HBr-AcOH (33%, 0.25 mL, 1.41 mmol) at 0 C, the mixture was

stirred at rt for 4 h. The solvent and excess of acid was removed

in vacuo, and the residue was dissolved in MeOH (4 mL), and

0

K₂CO₃(325 mg, 2.35 mmol) was added at 0 C. The reaction

mixture was stirred for 3 h and then concentrated to dryness. A

saturated aqueous ammonium chloride solution (4 mL) was

added, the quenched reaction mixture was extracted with

CH₂Cl₂(3 x 6 mL), the combined organic layers were dried over

anhydrous MgSO₄. Solvents were removed under reduced

pressure and the crude was purified by flash column

(4R,9aS)-4-(3,4-Dimethoxyphenyl)octahydro-2H-quinolizin-2-

one 40 and (4S,9aS)-4-(3,4-dimethoxyphenyl)octahydro-2H-

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quinolizin-2-one 41 via a direct aldol-IMAMR: The reaction

was repeated with an identical procedure above using (–)-17 at

rt for 3 h afford trans-fused isomer 41 (3%) and cis-fused isomer

40 (20%). HPLC analysis (Chiralpak IC), n-heptane/EtOH; 80:20

(1 mL/min): (–)-41 tr = 15 min, (+)-41 tr = 17 min; e.r. 70:30.

(m, 1H), 3.92 (s, 6H), 2.90-2.80 (m, 3H), 1.70-1.55 (m, 6H), 1.42

(s, 10H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 198.3, 154.8, 151.3,

149.2, 143.1, 127.4, 124.1, 123.2, 111.0, 109.8, 79.6, 56.0, 55.9,

44.0, 41.5, 39.3, 28.4, 28.1, 25.3, 18.9 ppm.

(R,E)-tert-Butyl-2-[4-(3,4-dimethoxyphenyl)-2-oxobut-3-

enyl]piperidine-1-carboxylate 43: In an identical procedure

that described above a solution of compound (R)-Boc-29 (780

mg, 3.25 mmol), veratraldehyde 38 (620 mg, 3.75 mmol) and 6

M NaOH (0.7 mL, 4.9 mmol) in MeOH (5 mL) was heated at

55 °C for 16 h which afforded (R)-43 (560 mg, 1.44 mmol, 45%)

as a yellow oil. [α]_D²⁰= –42.0 (c = 1.0, CHCl₃).

(4R,9aS)-4-(3,4-Dimethoxyphenyl)octahydro-2H-quinolizin-2-

one 40 and (4S,9aS)-4-(3,4-dimethoxyphenyl)octahydro-2H-

quinolizin-2-one 41 via (S)-Cbz-42: A solution of HBr-HOAc

(33%, 0.15 mL, 0.84 mmol) was added to (S)-42 (65 mg, 0.14

mmol) under ice cooling and the solution was stirred at room

temperature for 4 h. The reaction mixture was evaporated under

reduced pressure and the residue was treated with saturated

NaHCO₃solution (6 mL) for 28 h at rt. The products were

extracted with CH₂Cl₂(2 x 7 mL). The combined organic layers

were dried and concentrated after filtration to afford a crude

mixture (40/41), which was dissolved in MeOH (0.8 mL) and

treated with 2 M NaOH (0.8 mL) for 48 h at rt. The reaction

mixture was diluted with H₂O, and products were extracted with

CH₂Cl₂(2 x 5 mL). After concentration, the crude diastereomeric

compounds were isolated by flash column chromatography

(EtOAc) to afford 41 (19 mg, 48% yield) as a yellow viscous oil.

(R,E)-tert-Butyl-2-[4-(3,4-dimethoxyphenyl)-2-oxobut-3-

enyl]piperidine-1-carboxylate 43: In an identical procedure

that described above a solution of compound (R)-Boc-29 (780

mg, 3.25 mmol), veratraldehyde 38 (620 mg, 3.75 mmol) and 6

M NaOH (0.7 mL, 4.9 mmol) in MeOH (5 mL) was heated at

55 °C for 16 h which afforded (R)-43 (560 mg, 1.44 mmol, 45%)

as a yellow oil. [α]_D²⁰= –42.0 (c = 1.0, CHCl₃).

(4R,9aS)-4-(3,4-Dimethoxyphenyl)octahydro-2H-quinolizin-2-

one 40 and (4S,9aS)-4-(3,4-dimethoxyphenyl)octahydro-2H-

quinolizin-2-one 41 via (S)-Boc-43:^[34]TFA (1.3 mL, 17.3

mmol, 54 eq.) was added dropwise to a solution of (S)-43 (100

mg, 0.25 mmol, 1.0 eq.) in dry CH₂Cl₂(1.0 mL) under N₂at 0 °C.

The resulting mixture was stirred at 0 °C for 2 h and then the

reaction was quenched by adding saturated NaHCO₃solution

(15 mL) and the products were extracted with CH₂Cl₂(2 x 4 mL).

The combined organic layers were concentrated in vacuo giving

a yellowish oil. The resulting yellowish oil was dissolved in

MeOH (1.3 mL) and treated with 2 M NaOH (1.3 mL) for 48 h at

rt. The reaction mixture was diluted with H₂O (10 mL), and

R_f

= 0.5 (EtOAc)). Then the column was eluted with

(CH₂Cl₂/MeOH; 15:1) affording 40 (2 mg, 5%). R_f= 0.3 (EtOAc))

and HPLC analysis (Chiralpak IC), n-heptane/EtOH; 80:20 (1

mL/min): (–)-41 tr = 14.38 min, (+)-41 tr = 16.48 min; e.r. 90:10;

Data for 41: IR: 3079, 2955, 2850, 2808, 2750, 1711, 1594,

1509, 1383, 1258, 1148, 1023, 877, 764 cm^-1; ¹H NMR (400

MHz, CDCl₃): δ 6.90 (d, J = 1.5 Hz, 1H), 6.75 (m, 2H), 3.89 (s,

3H), 3.87 (s, 3H), 3.20 (dd, J = 12.1, 3.2 Hz, 1H), 2.78 (d, J =

11.4 Hz, 1H), 2.67 (t, J = 12.8 Hz, 1H), 2.54–2.22 (m, 4H), 1.78–

1.42 (m, 6H), 1.42-1.23 (m, 1H) ppm; ¹³C NMR (100 MHz,

CDCl₃): δ 207.9, 149.3, 148.3, 135.1, 119.5, 111.0, 109.8, 70.0,

62.5, 56.0, 55.9, 52.8, 50.9, 48.7, 34.3, 25.8, 24.2 ppm. Data for

40: IR: 3070, 2929, 2853, 1712, 1591, 1512, 1320, 1256, 1142,

1025, 914, 808, 730 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ 6.80 (d,

products were extracted with CH₂Cl₂(2

x 4 mL). After

concentration, the diastereomeric ratio was determined by ¹H

NMR spectroscopy at this stage (40:41; 1.2:1). The crude

J = 8.7 Hz, 1H), 6.70-6.64 (m, 2H), 4.23 (dd, J = 6.1, 4.0 Hz, 1H), mixture was then isolated by flash column chromatography

3.87 (s, 3H), 3.85 (s, 3H), 2.83-2.96 (m, 3H), 2.51–2.66 (m, 2H),

2.37 (dd, J = 14.8, 8.9 Hz, 1H), 2.19 (td, J = 11.7, 3.2 Hz, 1H),

1.35–1.74 (m, 6H), 1.14-1.28 (m, 1H) ppm; ¹³C NMR (100 MHz,

CDCl₃): δ 209.6, 148.5, 148.2, 131.3, 120.7, 111.5, 110.4, 63.7,

55.7, 55.6, 54.0, 51.2, 47.4, 46.7, 31.7, 23.9, 23.2 ppm.

(EtOAc) to afford 41 as (22 mg, 30%) as a yellow viscous oil. R_f

= 0.5 (EtOAc)). Then the column was further eluted with

(CH₂Cl₂/MeOH; 150:10) affording 40 (27 mg, 37%) as a yellow

oil. R_f= 0.3 (EtOAc)); [α]_D²⁰of 41 = –60.0 (c = 1.0, CHCl₃) {lit.,^[34]

24

20

[α]_D= –78.2 (c = 1.5, CHCl₃)}, [α]_Dof 40 = –11.6 (c = 1.0,

24

CHCl₃) {lit.,^[34][α]_D= –10.8 (c =0.26, CHCl₃)}; HPLC analysis

(S,E)-tert-Butyl-2-[4-(3,4-dimethoxyphenyl)-2-oxobut-3-

enyl]piperidine-1-carboxylate 43: A solution of compound (S)-

Boc-29 (130 mg, 0.54 mmol), veratraldehyde 38 (104 mg, 0.62

mmol) and 6 M NaOH (0.14 mL, 0.81 mmol) in MeOH (9 mL)

was heated at 55 °C for 16 h. The reaction mixture was cooled

down and evaporated in vacuo. Water was added (3 mL) then

the aq. layer was extracted with CH₂Cl₂(3 x 5 mL). The

combined organic layers were dried over MgSO₄and

evaporated in vacuo. The residue was then purified by flash

chromatography (CH₂Cl₂:EtOAc; 10:1) to yield colourless oil

(Chiralpak IC), heptane/EtOH; 80:20 (1 mL/min): (–)-41 tr = 14.0

min, (+)-41 tr = 16.0 min; e.r. 98:2.

(2S,4S,9aS)-4-(3,4-Dimethoxyphenyl)octahydro-2H-

quinolizin-2-ol [(–)-lasubine II] 35: To a flame-dried 5 mL vial

was added 41 (15 mg, 0.05 mmol, 1.0 eq.) and THF (0.3 mL).

The solution was cooled to -78 °C before dropwise addition of L-

selectride (1.0 M in THF, 0.1 mL, 0.10 mmol, 2.0 eq.). The

o

reaction was allowed to stir at -78 C for 2 h before warming up

to 0 °C and quenching with saturated aq. NaHCO₃(0.3 mL). The

resulting mixture was warmed to rt and stirred for 30 min before

extracting with EtOAc (5 x 2 mL). The combined organic phases

20

(126 mg, 0.32 mmol, 60%). [α]_D= +45.3 (c = 1.0, CHCl₃);

LRMS (ESI) calcd for [(C₂₂H₃₁NO₅+ Na)]⁺412.5, found 412.7;

¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, J = 16.0 Hz, 1H), 7.13 (dd, were dried over MgSO₄, filtered, and concentrated in vacuo to

J = 8.3 and 1.7 Hz, 1H), 7.09 (d, J = 1.7 Hz, 1H), 6.86 (d, J = 8.3

Hz, 1H), 6.65 (d, J = 16.0 Hz, 1H), 4.80-4.71 (m, 1H), 4.00-3.94

yield a yellow residue. The crude product was purified by flash

column chromatography (CH₂Cl₂/MeOH; 80:20) affording 35 (10

10.1002/ejoc.201900477

European Journal of Organic Chemistry

FULL PAPER

mg, 69%) as a colourless oil. R_f= 0.2 (CH₂Cl₂/MeOH; 80:20).

Keywords:

20

25

[α]_D= –60.7 (c = 0.32, CHCl₃) {lit.,^[41][α]_D= –56 (c = 0.32,

MeOH)}; HRMS (ESI) calcd for [(C₁₇H₂₅NO₃+ H)]⁺292.1913,

Pelletierine

•

quinolizidine alkaloids

•

sedum alkaloids

•

1

found 292.1903 (-3.3 ppm); H NMR (400 MHz, CDCl₃): δ 6.96-

diastereomeric salt resolution

reaction (IMAMR)

• intramolecular aza-Michael

6.78 (m, 3H), 4.14 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.31 (dd, J

= 11.3, 2.9 Hz, 1H), 2.68 (d, J = 11.3 Hz, 1H), 2.44-2.32 (m, 1H),

1.93–1.21 (m, 12H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 149.0,

147.8, 137.3, 119.6, 110.9, 110.5, 65.0, 63.4, 56.4, 55.9, 55.8,

53.2, 42.8, 40.4, 33.7, 26.2, 24.9 ppm.

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Chattopadhyay, S. Hanessian, Chem. Commun. 2015, 51, 16450-16467.

[3] S. Funayama, G. A. Cordell, Alkaloids: A Treasury of Poisons and

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Foubelo, M. Yus, J. Org. Chem. 2012, 77, 780-789; (b) V. G. Lisnyak, T.

Lynch-Colameta, S. A. Snyder, Angew. Chem. Int. Ed. 2018, 57, 15162-15166

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6833-6841.

[5] C. Tanret, Compt. Rend. Acad. Sci. 1878, 86, 1270-1272.

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1039; (b) H. C. Beyerman, L. Maat, A. V. Veen, A. Zweistra, Recl. Trav. Chim.

Pays-Bas 1965, 84, 1367-1379, (c) J. Quick, R. Oterson, Synthesis 1976, 745-

746; (d) C. Louis, S. Mill, V. Mancuso, C. Hootelé, Can. J. Chem. 1994, 72,

1347-1350; (e) H. Takahata, M. Kubota, S. Takahashi, T. Momose,

Tetrahedron: Asymmetry 1996, 7, 3047-3054; (f) G. Cheng, X. Wang, D. Su, H.

Liu, F. Liu, Y. Hu, J. Org. Chem. 2010, 75, 1911-1916; (g) T. K. Beng, R. E.

Gawley, J. Am. Chem. Soc. 2010, 132, 12216-12217; (h) I. Coldham, D.

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Gallagher, Y. S. Park, S. Thayumanavan, Acc. Chem. Res. 1996, 29, 552-560;

(j) D. Hoppe, T. Hense, Angew. Chem., Int. Ed. 1997, 36, 2282-2316; (k) M. C.

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Chem. Soc. 2001, 123, 5132-5133; (n) M. R. Monaco, P. Renzi, D. M.

Scarpino Schietroma, M. Bella, Org. Lett. 2011, 13, 4546-4549; (o) S. Fustero,

C. del Pozo, C. Mulet, R. Lazaro, M. Sánchez-Roselló, Chem. Eur. J. 2011, 17,

14267-14272; (p) J. -D. Liu, Y. -C. Chen, G. -B. Zhang, Z. -Q. Li, P. Chen, J. -

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2518-2520.

(4S,9aR)-4-(3,4-Dimethoxyphenyl)octahydro-2H-quinolizin-2-

one 40 via (R)-Boc-43:^[34]TFA (4.0 mL, 52.00 mmol, 67 eq.)

was added dropwise to a solution of (R)-Boc-43 (300 mg, 0.77

mmol, 1 eq.) in dry CH₂Cl₂(4 mL) at 0 °C. The mixture was

stirred at 0 °C for 2 h and the reaction was quenched by adding

saturated NaHCO₃solution (15 mL). The mixture was basified to

pH 6.5 and the combined organic layers were dried over MgSO₄

and concentrated in vacuo to give a yellowish oil. The oil was

dissolved in MeOH (1.5 mL) and treated with NH₄OH (1.5 mL)

for 30 min at room temperature. The reaction mixture was

extracted with CH₂Cl₂(4 x 5 mL). The combined organic layers

were dried over MgSO₄, filtered and evaporated in vacuo. The

diastereomeric ratio was determined by ¹H NMR spectroscopy at

this stage (40:41; 3:1). The crude product was purified by

column chromatography (EtOAc to CH₂Cl₂:MeOH; 80:20)

affording 40 (50.4 mg, 23%) as a colourless oil. R_f= 0.2

(EtOAc); [α]_D²⁰= +14.4 (c = 1, CHCl₃).

(2S,4S,9aR)-4-(3,4-Dimethoxyphenyl)octahydro-2H-

quinolizin-2-ol [(–)-lasubine I] 34: L-Selectride (1 M in THF,

0.32 mL, 0.32 mmol) was added to a solution of (+)-40 (50.4 mg,

0.17 mmol) in THF (0.6 mL) at –78 °C. The mixture was stirred

for 2 h, then warmed to 0 °C and quenched with saturated

NaHCO₃(1.00 mL). The mixture was warmed to room

temperature and stirred for 30 min. The product was extracted

with EtOAc (5 x 4 mL) and purified by column chromatography

(CH₂Cl₂:MeOH 90:10 to 70:30) affording (–)-34 (20.5 mg, 42%)

20

as a yellow oil. R_f= 0.35 (CH₂Cl₂:MeOH; 70:30) [α]_D= –8.4 (c

20

= 1.0, CHCl₃) {lit.,^[42][α]_D= -7.9 (c 0.2, CHCl₃); HRMS (EI)

calcd for [C₁₇H₂₅NO₃]⁺291.1834, found 291.1843 (+3.1 ppm); ¹H

NMR (400 MHz, CDCl₃): δ 6.87 (d, J = 8.1 Hz, 2H), 6.80 (d, J =

8.3 Hz, 1H), 4.18 (septet, 1H), 4.12 (s, 1H), 3.87 (d, J = 5.7 Hz,

6H), 3.00 (s, 1H), 2.72 (d, J = 12.1 Hz, 1H), 2.29 (s, 1H), 1.18–

2.12 (series of m, 11H) ppm; ¹³C NMR (100 MHz; CDCl₃) δ 24.1,

24.5, 32.4, 40.2, 40.3, 51.2, 54.0, 55.8, 55.9, 61.9, 65.0, 110.7,

111.9, 120.6, 135.3, 147.8, 148.7 ppm.

[8] L. Chausset-Boissaire, R. Àrvai, G. R. Cumming, L. Guénée, E. P. Kündig,

Org. Biomol. Chem. 2012, 10, 6473-6479.

[9] H. Hotti, H. Rischer, Molecules 2017, 22, 1962-1986.

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2018, 54, 11316-11319; (b) G. W. Morrow, Bioorganic Synthesis: An

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2009, 65, 10192-10213; (b) H. Ren, W. D. Wulff, Org. Lett. 2013, 15, 242-245.

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Chen, Y. Zhou, W. Wang, Molecules 2016, 21, 1600-1614.

[13] G. Zheng, P. A. Crooks, Org. Prep. Proced. Int. 2015, 47, 317-337.

[14] S. Smullen, N. P. McLaughlin, P. Evans, Bioorg. Med. Chem. 2018, 26,

Acknowledgments

We thank Dr. Helge Müller-Bunz, University College Dublin for

X-ray crystallography and the Ministry of Higher Education Iraq

for a postgraduate scholarship (R.K.Z). We would also like to

thank Prof. Nick Greeves, University of Liverpool for helpful

advice and Mr. Conor Lennon, University College Dublin for

input during his BSc research project.

2199-2220.

[15] R. K. Zaidan, S. Smullen, P. Evans, Tetrahedron Lett. 2015, 56, 6433-

6453.

[16] See for example: (a) F. Galinovsky, R. Hollinger, Monatsh. 1954, 85,

1012-1014; (b) A. Durant, C. Hootelé, Can. J. Chem. 1992, 70, 2722-2725; (c)

J. R. Harrison, P. O’Brien, D. W. Porter, N. M. Smith, J. Chem. Soc., Perkin

Trans. 1 1999, 3623-3631; (d) E.Akiyama, M. Hirama, Synlett 1996, 100-102;

(e) L. -H. Yan, F. Dagorn, E. Gravel, B. Séon-Méniel, E. Poupon, Tetrahedron,

2012, 68, 6276-6283; (f) Z. Amara, G. Bernadat, P. -E. Venot, P. Retailleau, C.

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Troufflard, E. Drège, F. Le Bideau, D. Joseph, Org. Biomol. Chem. 2014, 12,

9797-9810.

[17] For a review, see: (a) M. Saha, R. G. Carter, Synlett 2017, 2212-2229; (b)

M. Sánchez-Roselló, J. L. Acena, A. Simon-Fuentes, C. del Pozo, Chem. Soc.

Rev. 2014, 43, 7430-7453.

[18] Approximate comparative costs of organocatalysts used (Sigma-Aldrich):

L-Pro: 100 g = € 112; D-Pro: 5 g = € 114; 24a: 0.25 g = € 140; 24b: 0.25 g = €

132.

Brown, M. A. Foley, D. L. Comins, J. Am. Chem. Soc. 1988, 110, 7445-7447;

(b) D. L. Comins, D. H. LaMunyon, J. Org. Chem. 1992, 57, 5807-5809; (c) B.

M. Trost, C. -I. Jung, J. Am. Chem. Soc. 2015, 137, 15940-15946; (d) N. V. G.

Moorthy, R. Dyapa, S. V. Pansare, Org. Lett. 2015, 17, 5312-5315; (e) M. J.

James, N. D. Grant, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Org. Lett.

2016, 18, 6256-6529; (f) N. F. bte Mohamed Aslam, O. Simon, R. W. Bates,

Tetrahedron 2018, 74, 5032-5039.

[31] Note: this reaction could theoretically proceed via iminium ion formation

followed by an intramolecular Mannich reaction. Under the basic reaction

conditions we feel that the chalcone formation-IMAMR sequence alluded to is

more likely.

[19] Compound R-25, CCDC code: 1898957; Formula: C₂₄H₂₃BrClN₃O₄; Unit

Cell Parameters: a: 20.02860(14), b: 5.58301(4), c: 20.29450(14); P21.

[20] (a) D. Kozma, Handbook of optical resolutions via diastereomeric salt

formation, CRC Press, Florida, 2002; (b) R. A. Scheldon, Chirotechnology,

Marcel Dekker, US, 1993.

[21] F. Galinovsky, G. Bianchetti, O. Vogl, Monatsh. 1953, 84, 1221-1227.

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1747-1756.

[32] H. Iida, M. Tanaka, C. Kibayashi, J. Org. Chem. 1984, 49, 1909-1912.

[33] This ratio was readily determined by ¹H NMR spectroscopy. The

characteristic doublet of doublets for 40 at δ = 4.23 ppm was compared with

corresponding doublet of doublets at δ = 3.20 ppm for 41.

[34] S. -L. Shi, X. -F. Wei, Y. Shimizu, M. Kanai, J. Am. Chem. Soc. 2012, 134,

17019-17022.

[35] A. – E. Al-Sarabi, A. Bariau, M. Gabant, J. -C. Wypych, P. Chalard, Y.

Troin, Arkivoc 2007, (i), 119-133.

[36] E. C. Carlson, L. K. Rathbone, H. Yang, N. D. Collett, R. G. Carter, J. Org.

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4058-4073.

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[39] H. Takahata, M. Kubota, N. Ikota, J. Org. Chem. 1999, 64, 8594-8601.

[40] S. Fustero, J. Moscardo, M. S. Rosello, S. Flores, M. Guerola, C. Pozo,

Tetrahedron 2011, 67, 7412-7414.

[41] J. M. M. Verkade, F. van der Pijl, M. M. J. H. P. Willems, P. J. L. M.

Quaedflieg, F. L. van Delft, F. P. J. T. Rutjes, J. Org. Chem. 2009, 74, 3207-

3210.

[24] H. M. T. B. Herath, N. P. D. Nanayakkara, J. Heterocycl. Chem. 2008, 45,

129-136.

[25] Compound 28a, CCDC code 1898966; Formula: [C₈H₁₆NO]⁺·[C₈H₇O₃]^-;

Unit Cell Parameters: a: 7.2941(3), b: 8.1026(4), c: 13.2522(5); P1

[26] C. Bhat, S. G. Tilve, Tetrahedron 2013, 69, 6129-6143.

[27] Compound 32, CCDC code 1898968; Formula: C₈H₁₇NO; Unit Cell

Parameters: a: 5.1920(1), b: 9.1464(2), c: 9.0122(2); P21. Compound 8,

CCDC code 1898967; Formula: C₈H₁₇NO; Unit Cell Parameters: a: 9.069(1),

b: 5.1647(7), c: 9.539(2); P21.

[28] For a detailed recent review, see: J. P. Michael, The Alkaloids: Chemistry

and Biology, 2016, 75, 1-498.

[29] P. Slosse, C. Hootelé, Tetrahedron 1981, 37, 4287-4294. For a recent

synthesis of myrtine, see: J. D. Bell, A. H. Harkiss, C. R. Wellaway, A.

Sutherland, Org. Biomol. Chem. 2018, 16, 6410-6422.

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2515-2521. For representative syntheses of lasubine I and II, see: (a) J. D.

10.1002/ejoc.201900477

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Entry for the Table of Contents (Please choose one layout)

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Key Topic* Stereocontrolled

synthesis of saturated N-heterocycles

Raed K. Zaidan and Paul Evans*

Page No. – Page No.

Strategies for the asymmetric

construction of pelletierine and its

use in the synthesis of sedridine,

myrtine and lasubine

Three methods are described for the synthesis of both enantiomers of optically active pelletierine. The usefulness of these

compounds as building blocks is demonstrated in the asymmetric syntheses of several piperidine-based compounds of

interest.

*Asymmetric synthesis of piperidines

Article Doi

Strategies for the Asymmetric Construction of Pelletierine and its Use in the Synthesis of Sedridine, Myrtine, and Lasubine

DOI: 10.1002/ejoc.201900477

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