Application of the chiral base desymmetrisation of imides to the synthesis of the alkaloid jamtine and the antidepressant paroxetine

Tetrahedron 59 (2003) 9213–9230

Application of the chiral base desymmetrisation of

imides to the synthesis of the alkaloid jamtine

and the antidepressant paroxetine

*

Christopher D. Gill, Daniel A. Greenhalgh and Nigel S. Simpkins

School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK

Received 11 June 2003; revised 25 July 2003; accepted 21 August 2003

Abstract—The synthesis of the alkaloid jamtine and the antidepressant paroxetine have been addressed by a strategy involving asymmetric

desymmetrisation of prochiral imides by a chiral lithium amide base. A short reaction sequence, starting with a cyclohexane fused

succinimide, led to the structures originally reported for the alkaloid jamtine and its derived N-oxide. The structures synthesised are shown

not to correspond with those originally reported. A second sequence involves desymmetrisation of a 4-arylglutarimide, and provides a short

enantioselective synthesis of the drug substance paroxetine.

1. Introduction

be controlled by the trimethylsilyl substituent, for example

the highly regiocontrolled reduction of 3 (R¼Ph) to give

either hydroxylactam 4 or hydroxyamide 5. We have

subsequently applied this type of concept to the asymmetric

synthesis of speciﬁc target molecules, namely the drug

substance (2)-paroxetine 6,²and the unusual alkaloid jamtine

7,³and its N-oxide 8 that was reported as a natural product.

In previous studies we have demonstrated that the concept

of desymmetrisation by enolisation with a chiral lithium

amide base can be applied to certain types of cyclic imide.¹

For example, reaction of cyclopropane fused imide 1 with

chiral base 2 and chlorotrimethylsilane under in situ quench

conditions gave products 3 (with various groups R) in good

yield and high levels of enantioselectivity, Scheme 1.

These synthetic objectives required us to develop new

aspects of both the initial imide desymmetrisation reaction

and the subsequent regiocontrolled imide manipulation. In

We also showed that subsequent imide manipulation could

Scheme 1.

Keywords: asymmetric synthesis; enantioselective enolisation; chiral lithium amide base; imides; paroxetine; jamtine.

*

Corresponding author. Fax: þ44-115-9513564; e-mail: nigel.simpkins@nottingham.ac.uk

doi:10.1016/j.tet.2003.08.046

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C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

Scheme 2.

this paper, we describe this work in full detail, including the

new enantioselective route to 6, which utilises a simple

glutarimide starting material, and the ﬁrst asymmetric

syntheses of 7 and 8, which has established that these

structures do not correspond to the reported natural

products.

We ﬁrst established that effective asymmetric substitution

of imides of general structure 9 could be accomplished by

switching to mono-lithium amide base 11. The use of this

base enabled conversion of imide 10 into alkylated

derivatives 12 or 13 in reasonable yields and with excellent

levels of enantioselectivity in the latter case (we did not

determine the ee of 12), Scheme 3.⁸

It was also of interest to examine the regiochemistry of

subsequent reductions of these products to see if they

conformed to the trends identiﬁed previously. Reduction of

benzyl derivative 12 was poorly controlled, giving mixtures

of regioisomeric products 14 and 15 with either NaBH₄in

EtOH or DIBAL-H in CH₂Cl₂, Scheme 4.

2. Results and discussion

2.1. Chiral base reactions of cyclohexane fused imides: a

synthesis of jamtine

In seeking to apply our chiral base chemistry to interesting

alkaloid targets we were attracted to a report from the group

of Padwa,⁴describing the ﬁrst synthesis of an unusual

alkaloid called jamtine 7. This compound was originally

reported by Rahman and co-workers, in the form of an

N-oxide 8, as one of a small group of isoquinoline alkaloids

isolated from the climbing shrub Cocculus hirsutus.⁵This

plant is commonly found in parts of Pakistan and its various

parts are reputed to have therapeutic properties according to

local folk medicine.⁶

Although the ratios are not useful, they are in line with

previous observations that these two types of reduction tend

to give regiocomplementary results, with NaBH₄reducing

the apparently more hindered carbonyl function preferen-

tially.^7aSomewhat surprisingly, reduction of methyl

derivative 13 with either type of reagent led to the formation

of only the single regioisomeric product 16 in good yield.

Althoughtheproductratiosseeninthesepreliminaryreactions

were not encouraging, we were much more interested in the

reductions of imides bearing an a-substituent that incorpor-

ated functionality appropriate for our total synthesis of

jamtine. In the literature, the highly regioselective reduction

of imides derived from malic acid, e.g. 17, is very well known

to occur at the more electrophilic carbonyl (arrowed) using

NaBH₄,⁹and recently the reduction of sulfonyl imide 18 was

reported to follow the same trend.¹⁰

We were interested in the asymmetric synthesis of jamtine,

along the lines shown in Scheme 2, starting from a chiral

imide 9, in which the substituent X would be introduced by

the initial chiral base desymmetrisation of a simple

cyclohexane fused imide 10, and would ultimately become

the carbomethoxy substituent present in the natural product.

This idea presented two speciﬁc issues to be overcome.

First, in our previous work, succinimides having a fused

cyclohexane ring proved to be the sole substrates that did

not give good results on reaction with chiral base 2.

Secondly, the elaboration of 9 towards jamtine would

require regioselective reaction at the imide carbonyl

proximal to the installed group X. This complementary

mode of reaction, compared to that seen in reduction of 3 to

give 4 has limited precedent, but appeared viable through

electronic or chelation modes of activation.⁷

Based on this precedent we felt conﬁdent that the use of a

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

9215

Scheme 3.

Scheme 4.

carboxylic ester as the group X, in Scheme 2, would prove

viable, and would enable the most direct access to the

target alkaloids. This proved to be the case, with the

synthesis of jamtine and its N-oxide following exactly our

planned route, as summarised below.

With more than adequate supplies of essentially enantio-

merically pure imide 22 available, we were gratiﬁed to ﬁnd

that subsequent reduction was entirely regioselective to give

hydroxylactam 23, which then underwent stereoselective

cyclisation under typical N-acyliminium ion conditions to

give the complete alkaloid skeleton in the form of lactam

(þ)-24, Scheme 6.

Thus, efﬁcient and highly enantioselective introduction of

the required methoxycarbonyl function to imide 21, itself

easily available from commercial materials 19 and 20, was

effected using chiral base 11, by employing Mander’s

reagent as the electrophilic quench, Scheme 5.

Dehydrogenation using a selenoxide syn-elimination gave

25, which is an intermediate in the Padwa synthesis of

jamtine.⁴Finally, we used a method for selective lactam

reduction reported by Martin and co-workers to transform

unsaturated lactam 25 into jamtine 7.¹¹On exposure to

mCPBA in CH₂Cl₂at low temperature 7 was converted into

the corresponding N-oxide 8.

At present, our assignment of absolute stereochemistry of

these products (and those in Schemes 3 and 4) is based on

analogy with earlier examples.¹We anticipated further

clariﬁcation on completing the total synthesis, but this was

not forthcoming for reasons that will become clear (vide

infra).

At this stage, it became clear that there were substantial

differences between the NMR spectroscopic data for

Scheme 5.

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C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

Scheme 6.

synthetic 8 and those reported for the natural product

‘jamtine oxide’. That our synthesis had delivered the

structures 7 and 8 as shown became clear following our

communication with Professor Padwa, who had completed

the syntheses of these alkaloids by a different approach. Our

NMR spectroscopic data for these compounds, and for the

earlier intermediate 25, were practically identical to those of

Padwa and co-workers, and furthermore, this group had

secured the structure of 25 by X-ray crystallographic

analysis.¹²The contrast between the data from the two

independent syntheses of jamtine N-oxide and those

reported by Rahman and co-workers is perhaps best

highlighted by the ¹³C NMR data, Table 1.

2.2. Chiral base reactions of glutarimides: a synthesis of

paroxetine

In all of the chiral base desymmetrisation reactions of

imides demonstrated to this point, a ring-fused imide was

chosen so as to avoid issues of diastereoselectivity in either

the deprotonation or electrophilic quenching steps. How-

ever, this places limitations on the use of this desymme-

trisation approach, and we considered the more challenging

chiral base metallations of other types of imide an attractive

goal. Foremost amongst these was the transformation of

Table 1. Comparison of ¹³C NMR data for N-oxide 8 with literature

At present we have no explanation for the differences in the

data. That the natural product ‘jamtine oxide’ could be the

opposite N-oxide diastereomer to the one that we have

prepared appears a remote possibility. A more likely

explanation is that the original structural assignment

requires reassessment.

Isolation (Rahman)

Synthetic (Padwa)

Synthetic (this work)

172.6

158.8

135.2

134.6

134.4

131.1

124.4

112.4

80.7

73.9

62.2

56.4

56.3

55.9

52.3

31.2

27.1

172.1

148.7

148.0

131.1

127.7

125.1

121.9

111.6

110.2

90.3

76.5

64.1

58.0

56.3

56.2

52.2

33.0

25.8

171.9

148.6

147.8

130.8

127.1

124.9

121.7

110.6

109.4

90.0

75.9

63.8

57.7

56.1

55.8

52.0

32.8

25.6

Despite the remaining questions over the real identity of the

natural product from the C. hirsutus shrub we have

demonstrated the utility of the chiral base desymmetrisation

of imides in the synthesis of alkaloids having the distinctive

‘jamtine’ skeleton 7, and have also established the potential

of a methoxycarbonyl function to control the regiochemistry

of imide reduction. Our completely stereocontrolled route

delivers the tetracyclic isoquinoline structure 7 in six steps

from commercial materials and in an overall yield of around

20%. The approach has potential applications in the

synthesis of a number of other types of alkaloid system,

including erythrina and yohimbane types.

25.3

22.4

24.3

19.5

24.1

19.3

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

9217

alkylation to give compounds 31, but in reality the use of

bis-lithiated base proved essential for reasonable yields of

30. The trans arrangement of the newly installed sub-

stituent, relative to the ﬂuorophenyl group was evident from

the J values of associated ring protons (J_H3–J_H4

typically¼11–13 Hz). The absolute conﬁgurations shown

follow from the conversion of one adduct 30i into

paroxetine, as shown below.

Scheme 7.

The somewhat variable nature of the levels of ee attracted

our attention. Overall, the NBn series of compounds

appeared to give better levels of induction than the NMe

series, but in both cases the results were found to be

variable. We noticed a broad correlation between reactions

that gave signiﬁcant amounts of bis-substituted by-product

31 and those that gave the highest levels of asymmetric

induction. For example, in the reaction leading to 30i, high

levels of ee were found if the desired product was

accompanied by 10–20% of 31, whereas in reactions that

produced very little of 31 the ee could drop as low as 80%.

prochiral glutarimides, such as 26 into chiral products 27,

Scheme 7.

Such a transformation would signiﬁcantly expand the range

of target alkaloids potentially available by this approach,

and the synthesis of varied piperidines is especially

attractive because of their diverse biological activities. Of

the simpler systems that we considered, we identiﬁed the

commercial drug substance (2)-paroxetine 6 as a potential

candidate for asymmetric synthesis.¹³

These ﬁndings suggested that the observed ee for the

products 30 was the result of an initial asymmetric

enolisation of the starting imide 28, followed by an ee

enhancing kinetic resolution of 30, Scheme 8.

The literature concerning the reactions of metal enolates

derived from glutarimides is sparse.¹⁴In our hands enolate

alkylation reactions of glutarimides 26, with various Ar and

R substituents, were low yielding when using LDA as the

base, and some doubly substituted products were also

obtained. Mono-lithiated chiral bases, such as base 2 and

base 11 also gave rather disappointing yields, and we were

prompted to use the diamine system in the form of its bis-

lithium amide 29, which gave the results shown in Table 2.

This type of effect has been reported previously in diverse

types of transformation, including meso-diol esteriﬁca-

tion,¹⁵diester hydrolysis,¹⁶catalytic asymmetric desymme-

trisation processes involving coupling of prochiral bis

triﬂates or dihalides,^17,18and a chiral glycine synthesis

involving H to D exchange.¹⁹

The use of 29 in its bis-lithiated form enabled the formation

of the desired products 30 in good yields, with good to

excellent levels of ee, and as single diastereoisomers. The

use of a strongly dibasic system may seem to invite over-

In order to further verify this effect in our system we

exposed racemic 30a to an excess of bis-lithiated base 29

Table 2. Enantioselective substitution of glutarimides 28

Entry

R

Electrophile

Product 30 (%)

ee of 30

30/31^a

1

2

3

4

5

6

7

8

9

Me

Bn

MeI

BnBr

ArCH₂Br^b

MeO₂CCN

MeI

allylBr

BnBr

PhCHO^d

MeO₂CCN

30a (73)

30b (58)

30c (63)

30d (87)

30e (65)

30f (52)

30g (61)

30h (75)

30i (71)

86

74

77

75

97

90

97

3.5:1

2.5:1 (7)

3:1 (9)

20:1

3:1 (14)

(7)^c

2:1 (22)

(0)^e

6.5:1

a

Ratios estimated from ¹H NMR spectra of crude reaction mixture. Figures in brackets are isolated yields of 31.

b

c

d

e

Ar¼4-bromophenyl.

Ratio not determined.

Isolated as a ca. 1:1 mixture of diastereomers.

No doubly substituted product was detected.

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C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

The sense of enantioselectivity seen here, and also the high

level of diastereocontrol observed in all of the alkylations

deserves some further comment. In addressing the latter

issue we examined molecular models of the intermediate

enolate having the aromatic substituent in either a

pseudoequatorial or pseudoaxial orientation, i.e. 32 eq.

and 32 ax., as shown below (Scheme 9).

We could see little reason to invoke conformational

anchoring of the system, for example with the 4-phenyl

substituent pseudoequatorial (32 eq.), since the ﬂatness

of the imide portion of the ring means that the

alternative 32 ax. suffers no destabilising 1,3-diaxial

interactions. A certain degree of conformational mobil-

ity for phenyl substituted cyclohexenes and related

systems has been noted in the past, further supporting

the plausibility of conformation 32 ax.²⁰In the

equatorial conformer 32 eq. there is no obvious facial

bias to the system that would predict the high

diastereoselectivities that we observe, and in fact an

axial mode of alkylation would result in the unobserved

cis-isomer. Alkylation via 32 ax. appears attractive in

that a stereoelectronically preferred axial mode of

alkylation can occur on a very exposed face of the

enolate (from below as drawn), whereas the other (top)

face is clearly hindered by the aromatic substituent.

Scheme 8.

and then alkylated with MeI to generate 31a. When a 46%

conversion into 31a was achieved the remaining 30a

showed an ee of 13%. Although this level of enrichment

is rather low, representing a selectivity factor S below 2, our

ﬁndings broadly parallel the observations of Gotov and

Schmalz.¹⁸We also found that carboxymethyl derivative

30i could be enriched from ca. 44% ee to 81% ee by further

metallation with base 29 and reaction with MeO₂CCN.

These results support the picture of ‘constructive kinetic

If this explanation has some validity, and it is accepted that

the imide ring in 28 is also probably conformationally

mobile, then a model for deprotonation involving an imide

with an axially disposed aromatic substituent also appears

reasonable. In this model the base 29 would remove a

pseudoaxial hydrogen from the exposed face of the imide,

avoiding any interaction with the aromatic substituent—i.e.

the circled hydrogen in 33 is removed.

This idea gains some further credibility if the sense of

deprotonation in this compound is compared to that

assigned earlier in the deprotonation of imide 21 using

base 11 (the mono and bis-lithiated bases 11 and 29

have always displayed the same sense of selectivity),

illustrated as 34. An obvious similarity can be seen if in

both cases the base approaches from above (the most

accessible face) and removes the circled hydrogen,

which is in an analogous orientation in both structures

(i.e. on the left hand side when viewed from above).

Even a stereoelectronically dissimilar bridgehead depro-

tonation of imide 35, carried out using base 29, appears

to follow the same trend.²¹

resolution’ superimposed upon the initial asymmetric

enolisation, illustrated in Scheme 8. We assume that this

type of process may be operative in all of the asymmetric

substitutions described here, although the extent of kinetic

resolution may be dependent uponthe nature of the substituent

introduced as well as the extent to which ‘over-alkylation’ is

allowed to proceed. Therefore, we did not consider it

worthwhile to attempt to quantify the effect further.

The availability of highly enantioenriched glutarimides in

synthetically useful quantities via this method should be

useful for the preparation of a range of targets, including

biologically potent piperidines. To illustrate this point, and

to establish the sense of asymmetric induction in the chiral

base reactions shown in Table 2, we carried out the

conversion of imide 30i into the aforementioned drug

substance (2)-paroxetine, as shown in Scheme 10.

Reduction of imide 30i (97% ee) gave piperidine alcohol 36,

to which the appropriate sesamol side-chain 38 was

introduced by conventional means, via the intermediate

mesylate 37.²²Deprotection of the piperidine nitrogen then

Scheme 9.

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

9219

Scheme 10.

gave the desired drug substance (2)-6 as the free amine

after base treatment.²³

was subjected to standard reduction with DIBAL-H at low

temperature. As shown in Scheme 12, this reaction proved

very high yielding and entirely regioselective, giving

hydroxylactam 42.

The synthetic paroxetine prepared this way had [a]²_D⁰¼284

(c¼0.77, MeOH), which is comparable with reported

values, allowing us to assign the absolute stereochemistry

of intermediates as shown in Scheme 10 and Table 2.

Finally, two further aspects of the glutarimide chemistry

were brieﬂy explored. First, we were interested to see if

similar levels of diastereo- and enantioselectivity could be

achieved in chiral base reactions of a 4-alkyl (rather than

aryl) substituted glutarimide. Methyl substituted glutar-

imide 40 was therefore subjected to our typical deprotona-

tion conditions and alkylated with benzyl bromide, to give

41, Scheme 11.

Scheme 12.

Based on the scant evidence available in the literature,²⁴

regioselective reduction at the less substituted carbonyl

function is to be anticipated. Although we have not been

able to examine the generality of this result, the selectivity

observed in this example augurs well for synthetic

applications that require controlled reduction (e.g. lactam

synthesis) or substitution adjacent to the ring nitrogen.

3. Summary and conclusion

The imide desymmetrisation reactions described above

further expand the applications of chiral lithium amide

bases in organic synthesis. The initial asymmetric enolisa-

tion process can be usefully combined with a subsequent

regioselective imide transformation, as demonstrated in our

synthesis of jamtine, although simple removal of both imide

carbonyl functions can also be useful, as shown by our new

route to paroxetine. This type of stereo- and regiocontrolled

imide transformation appears to be a very powerful

approach to a wide range of alkaloid systems, and we

hope to further exemplify this strategy in the near future.

Scheme 11.

The product was obtained as a single diastereomer with an

enantiomeric excess of 67%. The absolute conﬁguration

shown for 41 is tentative at present and is assigned only by

analogy with reactions of imides 28. Although the

selectivity appears somewhat reduced from the levels

achieved in Table 2, we have not examined this process in

detail and consider this a promising indication that workable

levels of induction can indeed be achieved in the 4-alkyl

series.

Secondly, we were interested in the regioselectivity of imide

reduction in the chiral glutarimides, and therefore imide 30e

The synthesis of the proposed structures of jamtine, and its

corresponding oxide has demonstrated that the data for these

9220

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

compounds does not correspond to that for the originally

isolated natural products. Further study is required to

establish the true identities of these compounds.

leum ether 40/60–EtOAc) to give the title compound 13 as a

colourless oil (160 mg, 62%); [a]²_D³¼259 (c 1.0 in CHCl₃);

n_max(CHCl₃/cm²¹) 2941, 2862 (CH), 1772, 1704 (CvO),

1396, 1345, 1079; d_H(500 MHz, CDCl₃) 1.15–1.26 (1H,

m), 1.33 (3H, s, Me), 1.38–1.43 (2H, m), 1.45–1.50 (1H,

m), 1.51–1.71 (3H, m), 2.08 (1H, ddd, J¼4.4, 8.3, 14.2 Hz),

2.54 (1H, dd, J¼3.8, 6.4 Hz, CHCON), 4.63 (1H, d,

J¼14.3 Hz, NCH₂Ph), 4.67 (1H, d, J¼14.3 Hz, NCH₂Ph),

7.26–7.34 (3H, m, ArH), 7.36–7.40 (2H, m, ArH); d_C

(125 MHz, CDCl₃) 20.1 (CH₂), 21.3 (CH₂), 21.4 (CH₂),

21.5 (CH₃), 32.7 (CH₂), 42.1 (CH₂), 43.1 (C, CCH₃), 46.9

(CH, CHCON), 127.8 (CH, ArCH), 128.5 (CH, ArCH),

128.6 (CH, ArCH), 136.1 (C, ArC), 178.2 (CvO), 182.5

(CvO); MS (EI) m/z 257 (M^þ, 100%), 214 (11%), 106

(30%), 96 (46%) (HRMS: found M^þ257.1421. C₁₆H₁₉NO₂

requires M, 257.1416). The ee was determined as .98% by

HPLC (OD Column, 2% EtOH in hexane, 0.6 mL/min), the

retention times were 20 min (minor) and 22 min (major).

4. Experimental

4.1. General details

General experimental details can be found in our recent

paper.^1aStarting imides 10 and 28 were prepared by

condensation of the readily available anhydrides,^13dwith

the appropriate amine, according to the method of Garratt

and co-workers.^8bNote that all meso products 31 that we

isolated have the 3,4-anti, 4,5-anti conﬁguration and we

have not included stereochemical descriptors for the

pseudoasymmetric C-4 position.

4.2. Typical procedure for chiral base reactions of ring

fused imides using external quench

4.3. Imide reductions using NaBH₄or DIBAL-H

(Scheme 4)^1,9

4.2.1. (3aS,7aR)-2,3a-Dibenzyl-hexahydro-isoindole-1,3-

dione 12. A solution of mono-lithiated base 11 was prepared

by addition of a solution of n-BuLi (0.44 mL, 2.5 mol dm²³

solution in hexanes, 1.10 mmol) to a stirred solution of the

appropriate chiral diamine (462 mg, 1.10 mmol) in dry THF

(5 mL) at 2788C under N₂. The resulting dark pink solution

was allowed to warm to room temperature and stirred for

30 min, then cooled to 2788C and added, dropwise over

30 min, to a stirred solution of imide 10 (243 g, 1.00 mmol)

in dry THF (10 mL) under N₂at 2788C. Following

completion of addition the resulting orange solution was

stirred at 2788C for 1 h and then benzyl bromide (0.60 mL,

5.05 mmol) was added in one portion. The yellow solution

obtained was stirred at 2788C for 3 h then quenched with

saturated aqueous NH₄Cl solution and extracted with

CH₂Cl₂(3£50 mL). The organic phases were combined,

dried (MgSO₄) and concentrated in vacuo to give an oily

solid. Puriﬁcation by ﬂash silica chromatography (9:1

petroleum ether/EtOAc) gave the title compound 12 as a

white solid (225 mg, 68%); mp 70–728C; [a]²_D³¼þ30 (c 1.0

in CHCl₃); n_max(CHCl₃/cm²¹) 2941, 2860 (CH), 1770,

1698 (CvO), 1395, 1345, 1138, 1077, 959; d_H(500 MHz,

CDCl₃) 1.17–1.24 (1H, m), 1.43–1.64 (5H, m), 1.80–1.84

(1H, m), 2.10–2.14 (1H, m), 2.58 (1H, dd, J¼2.7, 6.1 Hz,

CHCON), 2.79 (1H, d, J¼13.8 Hz, CCH₂Ph), 3.34 (1H, d,

J¼13.8 Hz, CCH₂Ph), 4.56 (1H, d, J¼14.3 Hz, NCH₂Ph),

4.60 (1H, d, J¼14.3 Hz, NCH₂Ph), 7.10–7.12 (2H, m,

ArH), 7.20–7.30 (8H, m, ArH); d_C(125 MHz, CDCl₃) 20.2

(CH₂), 20.7 (CH₂), 21.4 (CH₂), 32.9 (CH₂), 39.2 (CH₂), 41.8

(CH, CHCON), 42.0 (CH₂), 48.4 (C, CCH₂Ph), 127.0 (CH,

ArCH), 127.6 (CH, ArCH), 128.2 (CH, ArCH), 128.5 (CH,

ArCH), 128.6 (CH, ArCH), 130.0 (CH, ArCH), 135.9 (C,

ArC), 136.6 (C, ArC), 178.3 (CvO), 181.7 (CvO); MS

(EI) m/z 333 (M^þ, 86%), 242 (12%), 91 (C₇H₇, 100%)

(HRMS: found M^þ333.1742. C₂₂H₂₃NO₂requires M,

333.1729).

4.3.1. (3aS,7aR)-2,3a-Dibenzyl-3-hydroxy-octahydro-

isoindol-1-one 14 and (3aS,7aR)-2,7a-dibenzyl-3-

hydroxy-octahydro-isoindol-1-one 15. To a stirred solu-

tion of mono-benzylated imide 12 (30 mg, 0.09 mmol) in

CH₂Cl₂(2 mL) at 2788C was added DIBAL-H (0.18 mL,

1.0 mol dm²³solution in CH₂Cl₂, 0.18 mmol). The reaction

mixture was then stirred at 2788C for 20 min before

quenching with water. The solution was ﬁltered to remove

the aluminium salts then diluted with CH₂Cl₂(25 mL) and

washed with water (25 mL). The organic phase was dried

(MgSO₄), ﬁltered and concentrated in vacuo to give a

yellow solid which consisted of a 1:2 mixture of the title

compounds 14 and 15, with 15 being a mixture of two

diastereomers. Puriﬁcation by ﬂash silica chromatography

(petroleum ether 40/60–Et₂O 2:1) allowed almost complete

separation of this mixture (combined yield 25 mg, 83%).

Data for (3aS,7aR)-2,3a-dibenzyl-3-hydroxy-octahydro-

isoindol-1-one 14. n_max(CHCl₃/cm²¹) 3586 (OH), 2931,

2859 (CH), 1688 (CvO), 1454, 1077; d_H(500 MHz,

CDCl₃) 1.29–1.54 (3H, m), 1.58–1.72 (3H, m), 2.11–

2.17 (2H, m), 2.21–2.24 (1H, m, CHCON), 2.78 (1H, d,

J¼13.8 Hz, CCH₂Ph), 2.85 (1H, d, J¼13.8 Hz, CCH₂Ph),

4.27 (1H, d, J¼14.5 Hz, NCH₂Ph), 4.61 (1H, d, J¼14.5 Hz,

NCH₂Ph), 4.93 (1H, d, J¼8.4 Hz, simpliﬁes to s on D₂O

shake, CHOH), 7.00–7.10 (2H, m, ArH), 7.18–7.31 (8H,

m, ArH); d_C(125 MHz, CDCl₃) 21.1 (CH₂), 21.5 (CH₂),

23.0 (CH₂), 29.8 (CH₂), 39.0 (CH₂), 43.4 (CH₂), 44.2 (C,

CCH₂Ph), 45.3 (CH, CHCON), 86.2 (CH, CHOH), 126.7

(CH, ArCH), 127.4 (CH, ArCH), 128.2 (CH, ArCH), 128.5

(CH, ArCH), 128.7 (CH, ArCH), 130.4 (CH, ArCH), 137.3

(C, ArC), 174.1 (CvO); MS (EI) m/z 335 (M^þ, 4%), 317

(M2H₂O, 25%), 226 (33%). 91 (C₇H₇, 49%), 51 (100%)

(HRMS: found M^þ335.1894. C₂₂H₂₅NO₂requires M,

335.1885).

Data for (3aS,7aR)-2,7a-dibenzyl-3-hydroxy-octahydro-

isoindol-1-one 15. Less polar diastereoisomer. n_max

(CHCl₃/cm²¹) 3569 (OH), 2932, 2859 (CH), 1723, 1688

(CvO), 1453, 1094, 972; d_H(500 MHz, CDCl₃) 1.09–1.16

(1H, m), 1.19 (1H, d, J¼10.5 Hz, disappears on D₂O shake,

4.2.2. (3aS,7aR)-2-Benzyl-3a-methyl-hexahydro-iso-

indole-1,3-dione 13. The above typical procedure was

followed using starting imide 10 (243 mg, 1.00 mmol) and

methyl iodide (0.31 mL, 5.0 mmol) and the resulting oily

solid puriﬁed by ﬂash silica chromatography (14:1 petro-

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

9221

CHOH), 1.36–1.41 (1H, m), 1.47–1.68 (5H, m), 1.66–1.70

(2H, m), 2.72 (1H, d, J¼13.5 Hz, CCH₂Ph), 3.34 (1H, d,

J¼13.5 Hz, CCH₂Ph), 4.08 (1H, d, J¼14.5 Hz, NCH₂Ph),

4.55 (1H, dd, J¼5.6, 10.4 Hz, simpliﬁes to d, J¼5.6 Hz, on

D₂O shake, CHOH), 4.80 (1H, d, J¼14.5 Hz, NCH₂Ph),

7.21–7.35 (10H, m, ArH); d_C(125 MHz, CDCl₃) 20.3

(CH₂), 20.9 (CH₂), 21.9 (CH₂), 31.5 (CH₂), 39.6 (CH₂), 43.4

(CH₂), 43.5 (CH, CHCHOH), 48.2 (C, CCH₂Ph), 83.5 (CH,

CHOH), 126.8 (CH, ArCH), 127.6 (CH, ArCH), 128.6 (CH,

ArCH), 128.7 (CH, ArCH), 130.5 (CH, ArCH), 136.7 (C,

ArC), 138.1 (C, ArC), 177.2 (CvO); MS (EI) m/z 335 (M^þ,

1%), 317 (M2H₂O, 14%), 227 (23%), 226 (88%), 91

(C₇H₇, 100%), 51 (18%) (HRMS: found M^þ335.1895.

C₂₂H₂₅NO₂requires M, 335.1885).

(63%), 91 (C₇H₇, 100%) (HRMS: found M^þ259.1575.

C₁₆H₂₁NO₂requires M, 259.1572).

Reduction of imide 13 using NaBH₄. The same procedure as

described above for reduction of 12 was followed using

methylated imide (100 mg, 0.39 mmol) 13 with a reaction

time of 5 h, to give the title compound 16 as a single isomer

as a white solid (100 mg, 99%) with data as described

above.

4.4. Synthesis of jamtine and jamtine N-oxide (Schemes 5

and 6)

4.4.1. (3aS,7aR)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-

hexahydro-isoindole-1,3-dione 21. To a stirred solution

of 1,2 cyclohexane carboxylic acid anhydride (6.16 g,

40 mmol) in glacial AcOH (80 mL) at room temperature

was added 2-(3,4-dimethoxyphenyl)-ethylamine (6.74 mL,

40 mmol) and the resulting mixture then heated at reﬂux for

18 h. Following cooling to room temperature water (80 mL)

and CH₂Cl₂(80 mL) were added. The organic phase was

separated and washed with 2 mol dm²³HCl (80 mL),

saturated aqueous NaHCO₃solution (80 mL) and water

(80 mL), then dried (MgSO₄), ﬁltered and concentrated in

vacuo to give a pale orange solid. Puriﬁcation by ﬂash silica

chromatography (3:1 petroleum ether 40/60–EtOAc) gave

the title compound 21 as a white solid (11.04 g, 87%); mp

87.5–89.58C; n_max(CHCl₃/cm²¹) 3034, 2942, 2860 (CH),

1701 (CvO), 1516, 1399, 1263, 1156, 1025, 797; d_H

(400 MHz, CDCl₃) 1.29 (2H, br. s), 1.38 (2H, br. s), 1.56

(2H, br. s), 1.76 (2H, br. s), 2.74 (2H, br. s), 2.85 (2H, app. t,

J¼7.4 Hz), 3.71 (2H, app. t, J¼7.4 Hz), 3.82 (3H, s, OMe),

3.85 (3H, s, OMe), 6.73–6.66 (3H, m, ArH); d_C(100 MHz)

21.6 (CH₂), 23.6 (CH₂), 32.9 (CH₂), 39.2 (CH₂), 39.6

(CH, CHCON), 55.8 (CH₃, OMe), 111.2 (CH, ArCH), 112.0

(CH, ArCH), 121.0 (CH, ArCH), 130.3 (C, ArC), 147.7 (C,

ArC), 148.8 (C, ArC), 179.7 (CvO); MS (EI) m/z 317 (M^þ,

28%), 164 (C₁₀H₁₂O₂, 100%), 151 (C₉H₁₁O₂, 28%)

(HRMS: found M^þ317.1634. C₁₈H₂₃NO₄requires M,

317.1627).

Data for (3aS,7aR)-2,7a-dibenzyl-3-hydroxy-octahydro-

isoindol-1-one 15. More polar diastereoisomer. n_max

(CHCl₃/cm²¹) 3616 (OH), 2932, 2862 (CH), 1724, 1692

(CvO), 1452, 1097, 969; d_H(500 MHz, CDCl₃) 1.50–1.75

(6H, m), 1.82–1.87 (1H, m), 1.88–1.92 (1H, m), 2.10 (1H,

d, J¼6.3 Hz), 2.83 (1H, d, J¼13.8 Hz, CCH₂Ph), 3.16 (1H,

d, J¼13.8 Hz, CCH₂Ph), 4.09 (1H, d, J¼15.3 Hz, NCH₂Ph),

4.55 (1H, app. dt, J¼6.3 Hz, CHOH), 4.80 (1H, d, J¼

14.5 Hz, NCH₂Ph), 6.92–7.01 (2H, m, ArH), 7.16–7.31

(8H, m, ArH); d_C(125 MHz, CDCl₃) 21.2 (CH₂), 21.5

(CH₂), 23.0 (CH₂), 33.3 (CH₂), 36.3 (CH, CHCHOH), 39.1

(CH₂), 43.4 (CH₂), 46.8 (C, CCH₂Ph), 83.4 (CH, CHOH),

126.5 (CH, ArCH), 127.3 (CH, ArCH), 127.7 (CH, ArCH),

128.3 (CH, ArCH), 128.6 (CH, ArCH), 130.5 (CH, ArCH),

136.8 (C, ArC), 138.2 (C, ArC), 179.3 (CvO).

Reduction of imide 12 using NaBH₄. To a stirred solution of

imide 12 (35 mg, 0.11 mmol) in EtOH (3 mL) at 258C

under N₂, was added, portionwise over 5 min, NaBH₄

(20 mg, 0.53 mmol). The reaction mixture was then stirred

at room temperature for 15 h and then carefully quenched

with 1% aq. HCl until a pH of 5/6 had been reached and then

extracted with CH₂Cl₂(3£50 mL). The organic phases were

combined then washed with saturated aqueous NaHCO₃

solution (10 mL), dried (MgSO₄), ﬁltered and concentrated

in vacuo to give a sticky solid that consisted of a 2:1 mixture

of products 14 and 15. Puriﬁcation by ﬂash silica

chromatography (petroleum ether 40/60–Et₂O 2:1) allowed

almost complete separation of this mixture (combined yield

24 mg, 68%) with data described as above.

4.4.2. (3aS,7aS)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-1,3-

dioxo-octahydro-isoindole-3a-carboxylic acid methyl

ester 22. The typical procedure for imide alkylation using

base 11 was followed using starting imide 21 (1.42 g,

4.48 mmol) and Mander’s reagent (0.71 mL, 8.96 mmol)

and the resulting oily solid puriﬁed by ﬂash silica

chromatography (9:1 petroleum ether 40/60–EtOAc then

4:1) to give the title compound 22 as a colourless oil (1.45 g,

4.3.2. (3aS,7aS)-2-Benzyl-3-hydroxy-3a-methyl-octa-

hydro-isoindole-1,3-dione 16. DIBAL-H reduction of meth-

ylated imide 13 (45 mg, 0.18 mmol), as described above for

12, gave the title compound 16 as a single isomer as a white

solid (37 mg, 82%); mp 150–1528C; [a]²_D³¼þ54 (c 1.0 in

CHCl₃); n_max(CHCl₃/cm²¹) 3585 (OH), 2935, 2861 (CH),

1688 (CvO), 1455, 1357, 1074; d_H(500 MHz, CDCl₃) 1.12

(3H, s, Me), 1.15–1.57 (6H, m), 1.59–1.66 (1H, m), 2.04–

2.12(2H,m), 3.30(1H,d,J¼8.3 Hz, disappearsonD₂Oshake,

CHOH), 4.22 (1H, d, J¼14.5 Hz, NCH₂Ph), 4.64 (1H, d,

J¼8.3 Hz, simpliﬁes to s on D₂O shake, CHOH), 4.79

(1H, d, J¼14.5 Hz, NCH₂Ph), 7.24–7.33 (5H, m, ArH); d_C

(125 MHz, CDCl₃) 21.2 (CH₂), 21.4 (CH₂), 21.9 (CH₃), 23.1

(CH₂), 28.2 (CH₂), 40.3 (C, CCH₃), 43.0 (CH₂), 47.9 (CH,

CHCON), 89.0 (CH, CHOH), 127.4 (CH, ArCH), 128.4 (CH,

ArCH), 128.6(CH, ArCH),137.1(C, ArC),174.6(CvO);MS

(EI)m/z 257 (M^þ, 64%), 241 (M2H₂O, 21%), 210 (23%), 136

86%); [a]²_D⁰¼261 (c 1.0 in CHCl₃); n_max(CHCl₃/cm²¹

)

2936 (CH), 1743 (CvO), 1707 (CvO), 1516, 1351, 1029,

801; d_H(500 MHz, CDCl₃) 1.06–1.08 (1H, m), 1.31–1.41

(3H, m), 1.50–1.65 (3H, m), 2.00 (1H, ddd, J¼4.7, 8.8,

13.9 Hz), 2.28–2.32 (1H, m), 2.90 (2H, app. dt, J¼2.8,

7.4 Hz), 3.22 (1H, dd, 3.7, 6.6, CHCON), 3.76 (3H,

CO₂Me), 3.77–3.81 (1H, m), 3.84 (3H, s, OMe), 3.87

(3H, s, OMe). 6.73–6.78 (3H, m, ArH); d_C(125 MHz,

CDCl₃) 20.0 (CH₂), 20.3 (CH₂), 21.0 (CH₂), 28.0 (CH₂),

32.2 (CH₂), 39.3 (CH₂), 43.3 (CH, CHCON), 52.8 (CH₃,

CO₂Me), 53.6 (C, CCO₂Me), 55.4 (CH₃, OMe), 55.5 (CH₃,

OMe), 110.9 (CH, ArCH), 111.6 (CH, ArCH), 120.7 (CH,

ArCH), 129.5 (C, ArC), 147.5 (C, ArC), 148.5 (C, ArC),

169.8 (CvO), 175.6 (CvO), 177.1 (CvO); MS (EI) m/z

9222

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

375 (M^þ, 50%), 164 (C₁₀H₁₂O₂, 100%), 151 (C₉H₁₁O₂,

45%) (HRMS: found M^þ375.1676. C₂₀H₂₅NO₆requires M,

375.16818). The ee was determined as 97% by HPLC (OD

Column, 3% EtOH in hexane, 0.6 mL/min), the retention

times were 50 min (major) and 70 min (minor).

25.5 (CH₂), 28.1 (CH₂), 28.5 (CH₂), 37.3 (CH₂), 46.3 (CH,

CHCON), 51.3 (CH₃, CO₂Me), 52.7 (C, CCO₂Me), 55.6

(CH₃, OMe), 55.9 (CH₃, OMe), 60.1 (CH, CHN), 108.9

(CH, ArCH), 111.6 (CH, ArCH), 124.2 (C, ArC), 127.7 (C,

ArC), 147.3 (C, ArC), 147.8 (C, ArC), 173.6 (CvO), 175.8

(CvO); MS (EI) m/z 359 (M^þ, 97%), 344 (M2CH₃, 79%),

191 (100%), 176 (31%) (HRMS: found M^þ359.1749.

C₂₀H₂₅NO₅requires M, 359.1733).

4.4.3. (3aS,7aS)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-3-

hydroxy-1-oxo-octahydro-isoindole-3a-carboxylic acid

methyl ester 23. To a stirred solution of carbomethoxy

imide 22 (1.00 g, 2.67 mmol) in EtOH (25 mL) at 258C

under N₂, was added, portionwise over 5 min, NaBH₄

(0.20 g, 5.28 mmol). The reaction mixture was stirred at

258C for 45 min, then carefully quenched with 1% aq. HCl

until a pH of 5/6 had been reached and then extracted with

CH₂Cl₂(3£50 mL). The organic phases were combined

then washed with saturated aqueous NaHCO₃solution

(100 mL), dried (MgSO₄), ﬁltered and concentrated in

vacuo to give the title compound 23 as a sticky solid (0.90 g,

90%); n_max(CHCl₃/cm²¹) 3607 (OH), 3030, 2929 (CH),

1697 (CvO), 1515, 1201, 797; d_H(500 MHz, CDCl₃/

DMSO-d₆) 1.01–1.13 (1H, m), 1.14–1.25 (1H, m), 1.28–

1.36 (1H, app. dt, J¼3.6, 13.4 Hz), 1.36–1.50 (2H, m),

1.52–1.60 (1H, m), 1.54–1.57 (1H, m), 1.95 (1H, br. d,

J¼14.3 Hz), 2.05 (1H, br. d, J¼14.3 Hz), 2.68–2.81 (3H,

m), 3.33 (1H, ddd, J¼5.5, 9.0, 14.1 Hz), 3.66 (3H, OMe),

3.76 (3H, OMe), 3.78 (3H, OMe), 5.09 (1H, d, J¼6.4 Hz,

disappears on D₂O shake, CHOH), 5.24 (1H, d, J¼6.4 Hz,

simpliﬁes to s on D₂O shake, CHOH), 6.65–6.70 (3H, m,

ArH); d_C(125 MHz, CDCl₃) 21.6 (CH₂), 21.7 (CH₂), 22.3

(CH₂), 24.8 (CH₂), 33.1 (CH₂), 40.7 (CH₂), 44.1 (CH,

CHCON), 52.0 (C, CCO₂Me), 52.4 (CH₃, CO₂Me), 55.8

(CH₃, OMe), 84.8 (CH, CHOH), 110.9 (CH, ArCH), 111.8

(CH, ArCH), 120.7 (CH, ArCH), 131.6 (C, ArC), 147.2 (C,

ArC), 148.5 (C, ArC), 172.6 (CvO), 174.6 (CvO); MS

(EI) m/z 377 (M^þ, 10%), 359 (M2H₂O, 69%), 344 (48%),

191 (53%), 164 (C₁₀H₁₂O₂, 100%) (HRMS: found M^þ

377.1830. C₂₀H₂₇NO₆requires M 375.1838).

4.4.5. (12aS,12bR)-8-Oxo-5,8,11,12,12b-hexahydro-6H-

isoindolo[1,2-a]isoquinoline-12a-carboxylic acid methyl

ester 25. To a stirred solution of lactam 24 (0.62 g,

1.73 mmol) and PhSeSePh (1.62 g, 5.18 mmol) in dry THF

(25 mL) under N₂at room temperature was added KH

(0.35 g, 8.75 mmol), portionwise over 5 min. After initial

effervescence had subsided the reaction mixture was heated

to 508C and stirred for 2 h. The mixture was then allowed to

cool to room temperature and quenched with saturated

aqueous NH₄Cl solution (2 mL), followed by dilution with

CH₂Cl₂(25 mL) and the addition of pyridine (1 mL) and

30% aqueous H₂O₂(10 mL). The resulting mixture was

stirred at room temperature for 15 h then carefully quenched

with saturated aqueous Na₂SO₃solution (20 mL). The

aqueous phase was further extracted with CH₂Cl₂

(2£50 mL). The organic phases were then combined,

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

concentrated in vacuo to give a brown oil. Puriﬁcation

by ﬂash silica chromatography gave the title compound 25

as a white solid (0.40 g, 65%); mp 153.9–155.88C (lit.^4,12

mp 155–1578C); [a]²_D⁰¼þ78 (c 1.0 in CHCl₃); n_max

(CHCl₃/cm²¹) 3011, 2940 (CH), 1731, 1681 (CvO),

1609 (CvC), 1234, 1200, 788; d_H(500 MHz, CDCl₃)

1.59–1.71 (2H, m), 1.94–1.96 (1H, m), 2.23–2.25 (1H, m),

2.29–2.35 (1H, m), 2.63 (1H, br. d, J¼15.3 Hz), 2.82 (1H,

app. dt, J¼5.0, 13.6 Hz), 2.91–2.95 (2H, m), 3.20 (3H, s,

CO₂Me), 3.86 (3H, s, OMe), 3.89 (3H, s, OMe), 4.50 (1H,

dd, J¼5.0, 12.6 Hz), 4.65 (1H, s, CHN), 6.59 (1H, s, ArH),

6.62 (1H, s, ArH) 6.67 (1H, app. t, J¼3.5 Hz, CvCH); d_C

(125 MHz, CDCl₃) 19.4 (CH₂), 24.3 (CH₂), 28.3 (CH₂),

30.1 (CH₂), 37.2 (CH₂), 51.5 (CH₃, CO₂Me), 53.9 (C,

CCO₂Me), 55.9 (CH₃, OMe), 56.1 (CH₃, OMe), 65.1 (CH,

CHN), 109.3 (CH, ArCH), 111.5 (CH, ArCH), 123.6 (C,

ArC), 127.4 (C, ArC), 130.4 (CH, CvCH), 134.5 (C,

CvCH), 147.7 (C, ArC), 148.3 (C, ArC), 166.9 (CvO),

171.1 (CvO); MS (EI) m/z 357 (M^þ, 58%), 192 (56%), 166

(100%) (HRMS: found M^þ357.1565. C₂₀H₂₃NO₅requires

M, 357.1576).

4.4.4. (8aS,12aS,12bR)-8-Oxo-5,8,8a,9,11,12,12b-octa-

hydro-6H-isoindolo[1,2-a]isoquinoline-12a-carboxylic

acid methyl ester 24. To a stirred solution of hydro-

xylactam 23 (0.90 g, 2.39 mmol) in toluene (25 mL) at 808C

under N₂was added camphor-sulfonic acid (0.90 g,

3.60 mmol), portionwise over 5 min. The reaction mixture

was stirred at 808C for 90 min then allowed to cool to room

temperature then quenched with saturated aqueous NaHCO₃

solution (50 mL) and extracted with CH₂Cl₂(3£50 mL).

The organic phases were combined, dried (MgSO₄), ﬁltered

and concentrated in vacuo to give a pale brown oil.

Puriﬁcation by ﬂash silica chromatography (petroleum

ether 40/60–EtOAc 1:2) gave the title compound 24 as a

white solid (0.75 g, 88%); mp 139.5–141.58C; [a]²_D⁰¼þ125

(c 1.0 in CHCl₃). (Found: C, 67.04; H, 7.02; N, 3.84.

C₂₀H₂₅NO₅requires C, 66.83; H, 7.01; N, 3.90%); n_max

(CHCl₃/cm²¹) 3017, 2929 (CH), 1729, 1684 (CvO), 1229,

1196, 791; d_H(500 MHz, CDCl₃) 1.34–1.42 (1H, m), 1.61

(1H, ddd, J¼3.9. 11.3, 25.4 Hz), 1.65–1.72 (1H, m), 1.79–

1.85 (2H, m), 2.15–2.24 (2H, m), 2.33 (1H, app. dt, J¼4.5,

14.6 Hz), 2.61 (1H, br. d, J¼13.0 Hz), 2.69 (1H, dd, J¼6.1,

11.3 Hz, CHCON), 2.87–2.95 (2H, m), 3.32 (3H, s,

CO₂Me), 3.92 (3H, s, OMe), 3.94 (3H, s, OMe), 4.45–

4.47 (1H, m), 4.98 (1H, s, CHN), 6.65 (1H, s, ArH), 6.72

(1H, s, ArH); d_C(125 MHz, CDCl₃) 21.1 (CH₂), 22.1 (CH₂),

4.4.6. Jamtine 7. To a stirred solution of enamide 25

(75 mg, 0.21 mmol) in dry CH₂Cl₂(2 mL) at room

temperature under N₂was added Me₃OBF₄(78 mg,

0.53 mmol) followed by 2,6-di-tert-butyl 4-methyl pyridine

(150 mg, 0.73 mmol). The resulting dark yellow solution

was stirred at room temperature for 22 h then cooled to 08C

and diluted with MeOH (2 mL) followed by the addition of

NaBH₄(48 mg, 1.27 mmol). The pale yellow solution

obtained was stirred at 08C for 10 min then quenched with

saturated aqueous NaHCO₃solution (5 mL) and extracted

with CH₂Cl₂(3£5 mL). The organic phases were combined,

dried (MgSO₄) and concentrated in vacuo to give a dark

yellow oil. Puriﬁcation by ﬂash silica chromatography

(CH₂Cl₂then 5% MeOH, then 10%) gave jamtine 7 as a

pale yellow solid (50 mg, 69%); [a]²_D⁰¼þ30 (c 1.0 in

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

9223

CHCl₃); n_max(CHCl₃/cm²¹) 2937, 2836 (CH), 1720

(CvO), 1612 (CvC), 1463, 1357, 1133, 864; d_H

(500 MHz, CDCl₃) 1.52–1.56 (2H, m), 1.83–1.91 (1H,

m), 2.12 (2H, br. s), 2.53 (1H, app. dt, J¼3.6, 15.3 Hz), 2.75

(1H, ddd, J¼3.6, 10.2, 11.8 Hz), 2.83 (1H, dd, J¼3.8,

9.0 Hz), 2.91 (1H, ddd, J¼4.9, 10.2, 15.3 Hz), 3.12 (1H,

ddd, J¼3.6, 4.9, 11.8 Hz), 3.30 (3H, s, CO₂Me), 3.42 (1H,

ddd, J¼1.7, 3.0, 12.0 Hz), 3.85 (4H, s, OMe and CHN), 3.89

(3H, s, OMe), 3.99 (1H, ddd, J¼3.0, 5.2, 12.0 Hz), 5.72 (1H,

br. s, CvCH), 6.58 (1H, s, ArH), 6.63 (1H, s, ArH); d_C

(125 MHz, CDCl₃) 19.9 (CH₂), 24.4 (CH₂), 27.3 (CH₂),

32.0 (CH₂), 47.9 (CH₂), 51.5 (CH₃, CO₂Me), 55.8 (CH₃,

OMe), 56.1 (CH₃, OMe), 56.9 (C, CCO₂Me), 57.1 (CH₂,

CH₂N), 71.4 (CH, CHN), 110.1 (CH, ArCH), 111.1 (CH,

ArCH), 121.1 (CH, CvCH), 127.1 (C, CvCH or ArC),

128.5 (C, CvCH or ArC), 138.0 (C, CvCH or ArC), 146.6

(C, ArC), 147.4 (C, ArC), 173.4 (CvO); MS (ES) m/z 344

([MþH]^þ, 100%), 340 (56%) (HRMS: found [MþH]^þ

344.1874. C₂₀H₂₅NO₄requires [MþH], 344.1862).

was diluted with further THF (14 mL) before addition of

methyl iodide (0.43 mL, 6.8 mmol). The reaction mixture

was then warmed to 2408C^1 and stirred at this

temperature for a further 4 h before quenching with

saturated aqueous NH₄Cl solution (10 mL) and extraction

into Et₂O (40 mL). The aqueous phase was separated and re-

extracted with Et₂O (2£20 mL). The organic extracts were

combined, washed with 2 M HCl (3£80 mL), followed by

saturated aqueous NaHCO₃(80 mL) then brine (80 mL),

dried (MgSO₄), ﬁltered and concentrated in vacuo to give a

3.5:1 mixture of mono-methylated glutarimide 30a and bis-

methylated glutarimide 31a. The products were puriﬁed via

ﬂash column chromatography on silica gel (40% Et₂O/

petroleum ether) to yield mono-methylated glutarimide 30a

as a pale yellow solid (117 mg, 73%). The minor component

was not isolated from this particular reaction, but the

presence of bis-methylated glutarimide 31a was veriﬁed by

comparison of the ¹H NMR spectrum of the crude reaction

mixture with data from a pure sample of bis-methylated

glutarimide from other reactions.

4.4.7. Jamtine N-oxide 8. To a stirred solution of jamtine 7

(30 mg, 0.09 mmol) in dry CH₂Cl₂under N₂at 2788C was

added mCPBA (70–75%, 35 mg, 0.14 mmol) in one

portion. The resulting solution was stirred at 278 to

2408C for 2 h, and then solid Na₂CO₃(50 mg) was added.

The reaction mixture was ﬁltered, then concentrated in

vacuo to give a yellow oil. Puriﬁcation by ﬂash silica

column chromatography (CH₂Cl₂–MeOH 95:5 then 9:1

then 1:1) gave jamtine N-oxide 8 as a colourless oil (22 mg,

Data for mono-methylated glutarimide 30a. Mp 121–

1238C; [a]²_D⁴¼232 (c 1.08 in CHCl₃): n_max(CHCl₃)/cm²¹

2961 and 2908 (C–H), 1725 and 1668 (CvO), 1607, and

1510 (Ar); d_H(400 MHz) 1.13 (3H, d, J¼6.8 Hz, CHCH₃),

2.72 (1H, dq, J¼11.4, 6.8 Hz, CHCH₃), 2.78 (1H, dd,

J¼17.7, 13.3 Hz, CH_axH_eqCHAr), 2.95 (1H, dd, J¼17.7,

4.1 Hz, CH_axH_eqCHAr), 2.98 (1H, m, CHAr), 3.21 (3H, s,

NCH₃), 7.07 (2H, m, ArH), 7.15 (2H, m, ArH); d_C

(100.6 MHz) 14.3 (CHCH₃), 27.0 (NCH₃), 40.7

70%); [a]²_D⁷¼þ12 (c 0.15 in CHCl₃); n_max(CHCl₃/cm²¹

)

2937 (CH), 1720 (CvO), 1602 (CvC), 1464, 1360, 1121,

1011, 864; d_H(500 MHz, CDCl₃) 1.46–1.59 (1H, m), 1.83

(1H, app. t, J¼13.3 Hz), 1.88–1.94 (1H, m), 2.12–2.34

(2H, m), 2.75–2.91 (2H, m), 3.23–3.28 (1H, m), 3.29 (3H,

s, CO₂Me), 3.74–3.84 (2H, m), 3.85 (3H, s, OMe), 3.86 (3H,

s, OMe), 4.40 (1H, d, J¼13.2 Hz), 4.81 (1H, s, CHN), 4.92

(1H, d, J¼13.2 Hz), 6.02 (1H, s, CvCH), 6.60 (1H, s, ArH),

6.64 (1H, s, ArH); d_C(125 MHz, CDCl₃) 19.3 (CH₂), 24.1

(CH₂), 25.6 (CH₂), 32.8 (CH₂), 52.0 (CH₃, CO₂Me), 55.8

(CH₃, OMe), 56.1 (CH₃, OMe), 57.7 (C, CCO₂Me), 63.8

(CH₂, CH₂N), 75.9 (CH₂, CH₂N), 90.0 (CH, CHN), 109.4

(CH, ArCH), 110.6 (CH, ArCH), 121.7 (C, CvCH or ArC),

124.9 (C, CvCH or ArC), 127.1 (CH, CvCH), 130.8 (C,

CvCH or ArC), 147.8 (C, ArC), 148.6 (C, ArC), 171.9

(CvO); MS (ES) m/z 360 ([MþH^þ], 100%) (HRMS: found

[MþH]^þ360.1806. C₂₀H₂₅NO₅requires [MþH], 360.1811).

(CH₂CHAr), 42.0 (CHAr), 43.3 (CHCH₃), 116.1 (J_C–F

22 Hz, ArCH), 128.6 (J_C–F¼8 Hz, ArCH), 136.4 (J_C–F

¼

3 Hz, ArC), 162.1 (J_C–F¼246 Hz, ArC), 171.3 (CvO),

174.8 (CvO); MS (EI) m/z 235 (M^þ, 100%), 220 (M2CH₃,

5), 149 (45), 136 (79), 122 (44), 113 (18), 109 (38), 86 (12)

(HRMS: found M^þ, 235.1008. C₁₃H₁₄NO₂F requires M,

235.1009). The ee was determined as 86% by HPLC (OD

column, 3% EtOH in hexane, 0.8 mL/min), the retention

times were 35.2 min (minor) and 38.1 min (major).

Data for bis-methylated glutarimide 31a. n_max(CHCl₃)/

cm²¹2978, 2938 and 2883 (C–H), 1723 and 1666 (CvO),

1606, and 1508 (Ar); d_H(400 MHz) 1.05 (6H, d, J¼6.7 Hz,

2£CHCH₃), 2.60 (1H, dd, J¼12.1, 12.1 Hz, CHAr), 2.74

(2H, dq, J¼12.1, 6.7 Hz, 2£CHCH₃), 3.21 (3H, s, NCH₃),

7.04–7.15 (4H, m, ArH); d_C(100.6 MHz) 14.5 (CHCH₃),

27.5 (NCH₃), 43.4 (CHCH₃), 49.5 (CHAr), 116.1 (J_C–F

¼

4.5. Typical procedure for chiral base reaction of

glutarimides 28 (Table 2)

21 Hz, ArCH), 129.1 (J_C–F¼8 Hz, ArCH), 136.0 (ArC),

162.0 (J_C–F¼246 Hz, ArC), 174.5 (CvO); MS (EI) m/z 250

([MþH]^þ, 14%), 249 (M^þ, 58), 234 (M2CH₃, 5), 206 (8),

195 (6), 163, (29), 149 (8), 137 (20), 136 (100), 135 (28),

121 (10), 113 (38), 109 (23), 96 (13), 85 (14), 58 (20), 51

(18) (HRMS found M^þ, 249.1161. C₁₄H₁₆NO₂F requires M,

249.1165).

4.5.1. (3S,4R)-1,3-Dimethyl-4-(4-ﬂuorophenyl)piperi-

dine-2,6-dione (2) 30a and (3R,5S)-4-(4-ﬂuorophenyl)-

1,3,5-trimethylpiperidine-2,6-dione 31a. A solution of

bis-lithium amide base 29 was prepared by treatment of the

corresponding chiral amine (342 mg, 0.81 mmol) in THF

(4.0 mL) with n-BuLi (1.02 mL of a 1.6 M solution in

hexanes, 1.63 mmol) at 2788C under N₂. The resulting

solution was allowed to warm to room temperature, stirred

for 30 min, and then cooled to 2788C before dropwise

addition, via cannula over 5 min, to a stirred solution of the

imide 28 (R¼Me) (150 mg, 0.68 mmol) in THF (10 mL),

maintaining a temperature of 2788C^1. The reaction

mixture was then stirred for 45 min after which the mixture

4.6. Typical procedure for synthesis of racemic

glutarimides using LDA–LiCl

4.6.1. trans-1,3-Dimethyl-4-(4-ﬂuorophenyl)piperidine-

2,6-dione (6) 30a. LDA was prepared by addition of

n-BuLi (1.08 mL of a 1.5 M solution in hexanes, 1.62 mmol)

i

to a solution of Pr₂NH–HCl (112 mg, 0.80 mmol) in

THF (4 mL) at 2788C, followed by warming to room

9224

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

temperature over 15 min. The resulting solution of LDA

and LiCl was then cooled to 2788C, before being added

dropwise via cannula over 5 min to a stirred solution of the

imide 28 (R¼Me) (150 mg, 0.68 mmol) in THF (10 mL),

maintaining a temperature of 2788C^1. The reaction

mixture was stirred for 45 min after which it was diluted

with further THF (14 mL) before addition of methyl iodide

(0.42 mL, 6.78 mmol). The reaction mixture was then

warmed to 2408C^1 and stirred for 4 h before quenching

with saturated aqueous NH₄Cl solution (20 mL) and

extraction into Et₂O (40 mL). The aqueous phase was

separated and re-extracted with Et₂O (2£20 mL). The

organic extracts were combined washed with brine

(80 mL), dried (MgSO₄), ﬁltered and concentrated in

vacuo. The product was puriﬁed via ﬂash column chroma-

tography on silica gel (40% EtOAc/petroleum ether) to yield

mono-methylated glutarimide 30a as a pale yellow solid

(48 mg, 30%). Spectroscopic data matched that of corre-

sponding chiral base reaction (HRMS [EI] found M^þ,

235.1006. C₁₃H₁₄NO₂F requires M, 235.1009).

128.3 (ArCH), 128.8 (ArCH), 129.3 (ArCH), 135.0 (ArC),

139.1 (ArC), 162.2 (J_C–F¼247 Hz, ArC), 173.8 (CvO);

MS (EI) m/z 401 (M^þ, 19%), 310 (M2C₇H₇, 14), 210 (91),

131 (23), 106 (97), 105 (100), 91 (C₇H₇, 64), 79 (13), 77

(C₆H₅, 18), 51 (14) (HRMS: found M^þ, 401.1802.

C₂₆H₂₄NO₂F requires M, 401.1791).

Glutarimide 30b was prepared in racemic form (24%) by

use of LDA–LiCl as base, according to the typical

procedure given above.

4.6.3. (3S,4R)-3-(4-Bromobenzyl)-4-(4-ﬂuorophenyl)-1-

methylpiperidine-2,6-dione (2) 30c and (3R,5S)-3,5-

bis(4-bromobenzyl)-4-(4-ﬂuorophenyl)-1-methylpiperi-

dine-2,6-dione 31c. A chiral base reaction, using the typical

procedure described above, employing imide 28 (R¼Me)

(150 mg, 0.68 mmol) and 4-bromobenzyl bromide (1.70 g,

6.78 mmol) gave a 3.0:1 mixture of mono-bromobenzylated

glutarimide 30c and bis-bromobenzylated glutarimide 31c.

The products were puriﬁed via ﬂash column chromatography

on silica gel (30% EtOAc/petroleum ether) to yield mono-

bromobenzylated glutarimide30c asanoil (115 mg, 63%)and

bis-bromobenzylated glutarimide 31c as an oil (33.3 mg, 9%).

4.6.2. (3S,4R)-3-Benzyl-4-(4-ﬂuorophenyl)-1-methyl-

piperidine-2,6-dione (2) 30b and (3R,5S)-3,5-dibenzyl-

4-(4-ﬂuorophenyl)-1-methylpiperidine-2,6-dione 31b. A

chiral base reaction, using the typical procedure described

above, employing imide 28 (R¼Me) (147 mg, 0.67 mmol)

and benzyl bromide (0.79 mL, 6.67 mmol) gave a 2.5:1

mixture of mono-benzylated glutarimide 30b and bis-

benzylated glutarimide 31b. The products were puriﬁed

via ﬂash column chromatography on silica gel (40% Et₂O/

petroleum ether) to yield mono-benzylated glutarimide 30b

as an oil (120 mg, 58%) and bis-benzylated glutarimide 31b

as an oil (19.9 mg, 7%).

Data for mono-bromobenzylated glutarimide 30c.

[a]²_D⁰¼225 (c 1.62 in CHCl₃): n_max(CHCl₃)/cm²¹2960

(C–H), 1726 and 1681 (CvO), 1606 and 1512 (Ar); d_H

(400 MHz) 2.70 (1H, dd, J¼17.2, 11.5 Hz, CH_axH_eqCHAr),

2.83 (1H, m, CHCH_AH_BAr), 2.91 (1H, dd, J¼17.2, 4.4 Hz,

CH_axH_eqCHAr), 2.99 (1H, ddd, J¼11.5, 11.0, 4.4 Hz,

CHAr), 3.13 (2H, m, CHCH₂Ar and CHCH_AH_BAr), 3.19

(3H, s, NCH₃), 6.86 (2H, m, ArH), 7.08 (4H, m, ArH), 7.33

(2H, m, ArH); d_C(125.8 MHz) 27.2 (NCH₃), 33.5 (CHCH₂

Ar), 38.3 (CHAr), 40.5 (CH₂CHAr), 49.6 (CHCH₂Ar),

Data for mono-benzylated glutarimide 30b. a]²_D⁰¼24.2 (c

1.05 in CHCl₃): n_max(CHCl₃)/cm²¹2935 and 2858 (C–H),

1727 and 1682 (CvO), 1607 and 1494 (Ar); d_H(400 MHz)

2.73 (1H, dd, J¼17.2, 10.7 Hz, CH_axH_eqCHAr), 2.92 (1H,

dd, J¼17.2, 4.5 Hz, CH_axH_eqCHAr), 2.92 (1H, m, CHCH_A-

H_BPh), 3.04 (1H, ddd, J¼10.7, 10.0, 4.5 Hz, CHAr), 3.13–

3.22 (2H, m, CHCH₂Ph and CHCH_AH_BPh), 3.21 (3H, s,

NCH₃), 7.00–7.12 (5H, m, ArH), 7.20–7.29 (4H, m, ArH);

d_C(125.8 MHz) 27.0 (NCH₃), 34.4 (CHCH₂Ph), 37.8

116.3 (J_C–F¼22 Hz, ArCH), 120.7 (ArC), 128.9 (J_C–F¼

8 Hz, ArCH), 131.3 (ArCH), 131.6 (ArCH), 136.1 (ArC),

137.3 (ArC), 162.2 (J_C–F¼247 Hz, ArC), 170.8 (CvO),

174.1 (CvO); MS (EI) m/z 392 ((C₁₉H₁₇NO₂F⁸¹BrþH)^þ,

30), 391 ((C₁₉H₁₇NO₂F⁸¹Br)^þ, 97), 390 ((C₁₉H₁₇NO₂

F⁷⁹BrþH)^þ, 30), 389 ((C₁₉H₁₇NO₂F⁷⁹Br)^þ, 100), 235

(18), 221 (21), 220 (91), 210 (56), 181 (31), 149 (64), 136

(19), 135 (19), 133 (21), 122 (59), 121 (21), 109 (36), 106

(40), 105 (70), 101 (19), 91 (31), 90 (24), 89 (22), 77 (22)

(HRMS: found M^þ, 389.0431. C₁₉H₁₇NO₂F⁷⁹Br requires

M, 389.0427). The ee was determined as 77% by HPLC (OJ

column, 2% IPA and 1% MeCN in hexane, 0.8 mL/min), the

retention times were 75.5 min (minor) and 90.9 min

(major).

(CHAr), 39.8 (CH₂CHAr), 49.4 (CHCH₂Ph), 116.1 (J_C–F

¼

22 Hz, ArCH), 126.7 (ArCH), 128.5 (ArCH), 128.8 (J_C–F

¼

7 Hz, ArCH), 129.4 (ArCH), 136.4 (ArC), 138.2 (ArC),

162.1 (J_C–F¼246 Hz, ArC), 171.0 (CvO), 174.0 (CvO);

MS (FAB) m/z 312 ([MþH]^þ, 8%), 176 (18), 154 (26), 136

(20), 123 (10), 109 (21), 95 (41), 81 (47) 69 (76), 57 (100)

(HRMS found [MþH]^þ, 312.1406. C₁₉H₁₈NO₂requires

[MþH], 312.1399). The ee was determined as 74% by

HPLC (OD column, 2% IPA in hexane, 0.8 mL/min), the

retention times were 56.4 min (minor) and 65.1 min (major).

Data for bis-bromobenzylated glutarimide 31c. n_max

(CHCl₃)/cm²¹2937 (C–H), 1723 and 1672 (CvO), 1606

and 1488 (Ar); d_H(400 MHz) 2.75 (2H, dd, J¼14.2, 6.4 Hz,

2£CHCH_AH_BAr), 2.79 (1H, dd, J¼12.2, 12.2 Hz, CHAr),

2.91 (2H, dd, J¼14.2, 3.1 Hz, 2£CHCH_AH_BAr), 3.00 (2H,

ddd, J¼12.2, 6.4, 3.1 Hz, 2£CHCH₂Ar), 3.21 (3H, s,

NCH₃), 6.76 (4H, m, ArH), 7.08 (4H, m, ArH), 7.29 (4H,

m, ArH); d_C(125.8 MHz) 27.8 (NCH₃), 33.3 (CHCH₂Ar),

43.8 (CHAr), 50.7 (CHCH₂Ar), 116.3 (J_{C – F}¼22 Hz,

ArCH), 120.3 (ArC), 130.0 (J_C–F¼8 Hz, ArCH), 131.0

(ArCH), 131.4 (ArCH), 134.8 (ArC), 138.0 (ArC), 162.2

(J_C–F¼248 Hz, ArC), 173.3 (CvO); MS (EI) m/z 561

((C₂₆H₂₂NO₂F⁸¹Br₂)^þ, 28%), 560 ((C₂₆H₂₂NO₂F⁷⁹Br⁸¹Brþ

H)^þ, 17), 559 ((C₂₆H₂₂NO₂F⁷⁹Br⁸¹Br)^þ, 55), 558

Data for bis-benzylated glutarimide 31b. n_max(CHCl₃)/

cm²¹2956, 2931 and 2871 (C–H), 1722 and 1667 (CvO),

1605 and 1495 (Ar); d_H(400 MHz) 2.79 (2H, dd, J¼14.2,

6.4 Hz, 2£CHCH_AH_BPh), 2.86 (1H, dd, J¼12.1, 12.1 Hz,

CHAr), 2.98 (2H, dd, J¼14.2, 3.2 Hz, 2£CHCH_AH_BPh),

3.06 (2H, ddd, J¼12.1, 6.4, 3.2 Hz, 2£CHCH₂Ph), 3.23

(3H, s, NCH₃), 6.89–7.32 (14H, m, ArH); d_C(125.8 MHz)

27.8 (NCH₃), 33.9 (CHCH₂Ph), 43.6 (CHAr), 50.8

(CHCH₂Ph), 116.1 (J_C–F¼22 Hz, ArCH), 126.4 (ArCH),

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

9225

((C₂₆H₂₂NO₂F⁷⁹Br₂þH)^þ, 9), 557 ((C₂₆H₂₂NO₂F⁷⁹Br₂)^þ,

36), 450 (9), 391 (12), 390 (58), 389 (10), 388 (58), 267

(19), 242 (18), 240 (36), 237 (18), 212 (9), 211 (40), 210

(97), 209 (46), 171 (C₇H⁸₆¹Br, 23), 170 (C₇H⁷₆⁹BrþH, 10),

169 (C₇H⁷₆⁹Br, 92), 148 (100), 109 (17), 106 (64), 105 (89),

91 (19), 90 (28), 51 (38) (HRMS: found M^þ, 557.0022.

C₂₆H₂₂NO₂F⁷⁹Br₂requires M, 557.0001).

Glutarimide 30d was prepared in racemic form (38%) by

use of LDA–LiCl as base, according to the typical

procedure given above.

4.6.5. (3S,4R)-1-Benzyl-4-(4-ﬂuorophenyl)-3-methyl-

piperidine-2,6-dione (2) 30e and (3R,5S)-1-benzyl-4-(4-

ﬂuorophenyl)-3,5-dimethylpiperidine-2,6-dione 31e. A

chiral base reaction, using the typical procedure described

above, employing imide 28 (R¼Bn) (202 mg, 0.68 mmol)

and methyl iodide (3.0 mL, 48.2 mmol) gave a 3:1 mixture

of mono-methylated glutarimide 30e and bis-methylated

glutarimide 31e. The products were puriﬁed via ﬂash

column chromatography on silica gel (40% Et₂O/petroleum

ether) to yield mono-methylated glutarimide 30e as a white

solid (137 mg, 65%) and bis-methylated glutarimide 31e as

a white solid (32 mg, 14%).

Glutarimide 30c was prepared in racemic form (12%) by use

of LDA–LiCl as base, according to the typical procedure

given above.

4.6.4. (3S,4R)-4-(4-Fluorophenyl)-1-methyl-2,6-dioxo-

piperidine-3-carboxylic acid methyl ester (2) 30d and

dimethyl (3R,5S)-4-(4-ﬂuorophenyl)-1-methyl-2,6-dioxo-

3,5-piperidinedicarboxylate 31d. A chiral base reaction,

using the typical procedure described above (but with

reaction time of only 30 min at 2788C after adding

MeO₂CCN), employing imide 28 (R¼Me) (150 mg,

0.68 mmol) and methyl cyanoformate (0.08 mL,

1.02 mmol) gave a 20:1 mixture of mono-methyl ester

glutarimide 30d and bis-methyl ester glutarimide 31d. The

crude product was puriﬁed via ﬂash column chromatography

on silica gel (80% Et₂O/petroleum ether) to yield mono-

methyl ester glutarimide 30d as a white solid (165 mg,

87%). The minor component was not isolated from this

particular reaction, but the presence of bis-methyl ester

glutarimide 30d was veriﬁed by comparison of the ¹H NMR

spectrum of the crude reaction mixture with data from a pure

sample of bis-methyl ester glutarimide from other reactions.

Data for mono-methylated glutarimide 30e. Mp 115–

1188C; [a]²_D²¼221 (c 1.02 in CHCl₃); n_max(CHCl₃)/cm²¹

3090–2881 (C–H), 1726 and 1681 (CvO), 1606 and 1512

(Ar); d_H(400 MHz) 1.11 (3H, d, J¼6.8 Hz, CHCH₃), 2.72

(1H, dq, J¼11.2, 6.8 Hz, CHCH₃), 2.78 (1H, dd, J¼17.7,

13.2 Hz, CH_axH_eqCHAr), 2.94 (1H, m, CHAr), 2.94 (1H,

dd, J¼17.7, 4.2 Hz, CH_axH_eqCHAr), 4.97 (1H, d, J¼

13.8 Hz, NCH_AH_BPh), 5.02 (1H, d, J¼13.8 Hz, NCH_AH_BPh),

7.02 (2H, m, ArH), 7.11 (2H, m, ArH), 7.29 (3H, m, ArH),

7.38 (2H, m, ArH); d_C(100.6 MHz) 14.4 (CHCH₃), 40.8

(CH₂CHAr), 41.9 (CHAr), 43.4 (NCH₂Ph), 43.5 (CHCH₃),

116.1 (J_C–F¼21 Hz, ArCH), 127.6 (ArCH), 128.5 (ArCH),

128.6 (ArCH), 128.9 (ArCH), 136.3 (ArC), 137.3 (ArC),

162.1 (J_C–F¼246 Hz, ArC), 171.0 (CvO), 174.5 (CvO);

MS (EI) m/z 311 (M^þ, 100%), 283 (M2CO, 14), 268 (10),

161 (25), 146 (48), 136 (25), 109 (25), 106 (36), 104 (39), 91

(C₇H₇, 43), 77 (C₆H₅, 11) (HRMS: found M^þ, 311.1334.

C₁₉H₁₈NO₂F requires M, 311.1322). The ee was determined

as 97% by HPLC (OD column 5% IPA in hexane, 0.8 mL/

min), the retention times were 49.8 min (minor) and

59.5 min (major).

Data for mono-methyl ester glutarimide 30d. Mp 80–838C;

[a]²_D⁴¼230 (c 1.81 in CHCl₃): n_max(CHCl₃)/cm²¹2956

(C–H), 1749, 1730 and 1681 (CvO), 1608 and 1512 (Ar);

d_H(400 MHz) 2.85 (1H, dd, J¼17.4, 11.9 Hz, CH_axH_eq-

CHAr), 2.99 (1H, dd, J¼17.4, 4.5 Hz, CH_axH_eqCHAr), 3.20

(3H, s, NCH₃), 3.64 (3H, s, OCH₃), 3.69 (1H, ddd, J¼11.9,

11.5, 4.5 Hz, CHAr), 3.82 (1H, d, J¼11.5 Hz, CHCO₂CH₃),

7.04 (2H, m, ArH), 7.19 (2H, m, ArH); d_C(125.8 MHz) 27.1

(NCH₃), 37.7 (CH₂CHAr), 38.9 (CHAr), 52.9 (CHCO₂CH₃),

Data for bis-methylated glutarimide 31e. Mp 124–1268C;

n_max(CHCl₃)/cm²¹3089–2881 (C–H), 1722 and 1682

(CvO), 1605 and 1512 (Ar); d_H(500 MHz) 1.04 (6H, d, J¼

6.8 Hz, 2£CHCH₃), 2.60 (1H, dd, J¼12.2, 12.2 Hz, CHAr),

2.74 (2H, dq, J¼12.2, 6.8 Hz, 2£CHCH₃), 5.01 (2H, s,

NCH₂Ph) 7.04–7.12 (3H, m, ArH), 7.26 (2H, m, ArH),

7.29–7.32 (2H, m, ArH), 7.41 (2H, m, ArH); d_C

(125.8 MHz) 14.4 (CHCH₃), 43.9 (NCH₂Ph), 44.0

(CHCH₃), 49.3 (CHAr), 116.1 (J_C–F¼21 Hz, ArCH), 127.5

(ArCH), 128.5 (ArCH), 129.0 (ArCH), 135.9 (ArCH), 137.5

(ArC), 162.0 (J_C–F¼247 Hz, ArC), 174.2 (CvO); MS (EI)

m/z 325 (M^þ, 100%), 282 (11), 161 (53), 136 (39), 133 (20),

106 (42), 91 (C₇H₇, 29), 77 (C₆H₅, 4) (HRMS found M^þ,

325.1486. C₂₀H₂₀NO₂F requires M, 325.1478).

56.4 (OCH₃), 116.3 (J_C–F¼22 Hz, ArCH), 128.5 (J_C–F

¼

8 Hz, ArCH), 134.5 (ArC), 162.3 (J_C–F¼247 Hz, ArC),

168.2 (CvO), 168.6 (CvO), 170.4 (CvO); MS (EI) m/z

279 (M^þ, 8%), 221 (16), 220 (M2CO₂CH₃, 100), 149 (17),

135 (9), 121 (7) (HRMS: found M^þ, 279.0909. C₁₄H₁₄NO₄F

requires M, 279.0907). The ee was determined as 75% by

HPLC (OD column, 3% EtOH in hexane, 0.8 mL/min), the

retention times were 83.4 min (minor) and 91.9 min (major).

Data for bis-methyl ester glutarimide 31d. n_max(CHCl₃)/

cm²¹2956 (C–H), 1749, 1730 and 1682 (CvO), 1607 and

1512 (Ar); d_H(500 MHz) 3.25 (3H, s, NCH₃), 3.62 (6H, s,

2£OCH₃), 3.83 (2H, d, J¼12.9 Hz, 2£CHCO₂CH₃), 4.04

(1H, dd, J¼12.9, 12.9 Hz, CHAr), 7.04 (2H, m, ArH), 7.19

(2H, m, ArH); d_C(125.8 MHz) 27.6 (NCH₃), 40.8 (CHAr),

52.9 (OCH₃), 55.8 (CHCO₂CH₃), 116.3 (J_C–F¼22 Hz,

ArCH), 129.1 (J_C–F¼8 Hz, ArCH), 131.9 (ArC), 162.6

(ArC), 167.5 (CvO), 170.4 (CvO); MS (EI) m/z 337 (M^þ,

13%), 279 (40), 278 (M2CO₂CH₃, 100), 277 (19), 247 (15),

246 (53), 234 (31), 221 (42), 220 (45), 219 (14), 189 (19),

181 (32), 133 (46), 121 (27), 101 (23), 59 (CO₂CH₃, 23)

(HRMS found M^þ, 337.0966. C₁₆H₁₆NO₆F requires M,

337.0962).

Glutarimide 30e was prepared in racemic form (34%) by use

of LDA–LiCl as base, according to the typical procedure

given above.

4.6.6. (3S,4R)-3-Allyl-1-benzyl-4-(4-ﬂuorophenyl)piperi-

dine-2,6-dione (2) 30f and (3R,5S)-1-benzyl-3,5-diallyl-

4-(4-ﬂuorophenyl)piperidine-2,6-dione 31f. A chiral base

reaction, using the typical procedure described above,

employing imide 28 (R¼Bn) (201 mg, 0.68 mmol) and

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C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

allyl bromide (2.0 mL, 23.1 mmol) gave a mixture of mono-

allylated glutarimide 30f and bis-allylated glutarimide 31f

(the ratio could not readily be determined from the ¹H NMR

spectrum of the crude material). The products were puriﬁed

via ﬂash column chromatography on silica gel (40% Et₂O/

petroleum ether) to yield mono-allylated glutarimide 30f as

an oil (118 mg, 52%) and bis-allylated glutarimide 31f as an

oil (19 mg, 7%).

dine-2,6-dione (1) -30g and (3R,5S)-4-(4-ﬂuorophenyl)-

1,3,5-tribenzylpiperidine-2,6-dione 31g. A chiral base

reaction, using the typical procedure described above,

employing imide 28 (R¼Bn) (201 mg, 0.68 mmol) and

benzyl bromide (2.0 mL, 16.7 mmol) gave a 2:1 mixture of

mono-benzylated glutarimide 30g and bis-benzylated

glutarimide 31g, respectively. The products were puriﬁed

via ﬂash column chromatography on silica gel (40% Et₂O/

petroleum ether) to yield mono-benzylated glutarimide 30g

as an oil (160 mg, 61%) and bis-benzylated glutarimide 31g

as an oil (72 mg, 22%).

Data for mono-allylated glutarimide 30f. [a]²_D⁷¼þ17 (c

1.27 in CHCl₃): n_max(CHCl₃)/cm²¹2961, 2927 and 2855

(C–H), 1725 and 1680 (CvO), 1605 and 1510 (Ar); d_H

(400 MHz) 2.14 (1H, ddd, J¼14.2, 8.2, 5.0 Hz, CH_AH_B-

CHvCH₂), 2.71 (1H, dddd, J¼14.2, 6.0, 5.0, 1.7 Hz,

CH_AH_BCHvCH₂), 2.77 (1H, dd, J¼17.2, 11.6 Hz, CH_ax-

H_eqCHAr), 2.88 (1H, dt, J¼10.9, 5.0 Hz, CHCH₂CHvCH₂),

2.94 (1H, dd, J¼17.2, 4.4 Hz, CH_axH_eqCHAr), 3.19, (1H, td,

J¼11.6, 4.4 Hz, CHAr), 4.91 (1H, ddd, J¼17.1, 3.0, 1.7 Hz,

CH_AvCH_BH_C), 4.98 (1H, d, J¼13.8 Hz, NCH_AH_BPh),

5.04 (1H, d, J¼13.8 Hz, NCH_AH_BPh), 5.04 (1H, m,

CH_AvCH_BH_C), 5.64 (1H, dddd, J¼17.1, 10.2, 8.2,

6.0 Hz, CH_AvCH_BH_C), 7.04 (2H, m, ArH), 7.11 (2H, m,

ArH), 7.25–7.33 (3H, m, ArH), 7.38 (2H, m, ArH); d_C

(125.8 MHz) 32.5 (CH₂CHvCH₂), 37.8 (CHAr), 40.2

(CH₂CHAr), 43.3 (NCH₂Ph), 47.8 (CHCH₂CHvCH₂),

116.0 (J_C–F¼21 Hz, ArCH), 118.7 (CHvCH₂), 127.6

(ArCH), 128.5 (ArCH), 128.8 (J_C–F¼8 Hz, ArCH), 128.9

(ArCH), 133.6 (CHvCH₂), 136.1 (ArC), 137.1 (ArC),

162.0 (J_C–F¼247 Hz, ArC), 170.8 (CvO), 173.3 (CvO);

MS (EI) m/z 338 ([MþH]^þ, 21%), 337 (M^þ, 100), 162 (23),

146 (20), 106 (18), 91 (C₇H₇, 31), 77 (C₆H₅, 3), 50 (26)

(HRMS: found M^þ, 337.1482. C₂₁H₂₀NO₂F requires M,

337.1478). The ee was determined as 90% by HPLC (OD

column, 5% IPA in hexane, 0.8 mL/min), the retention

times were 34.7 min (minor) and 38.4 min (major).

Data for mono-benzylated glutarimide 30g. [a]²_D⁷¼þ11 (c

1.15 in CHCl₃): n_max(CHCl₃)/cm²¹2931 and 2858 (C–H),

1725 and 1681 (CvO), 1606, 1585, 1495 and 1454 (Ar); d_H

(500 MHz) 2.64 (1H, dd, J¼17.2, 10.7 Hz, CH_axH_eqCHAr),

2.77 (1H, dd, J¼14.1, 5.3 Hz, CHCH_AH_BPh), 2.81 (1H, dd,

J¼17.2, 4.6 Hz, CH_axH_eqCHAr), 2.91 (1H, ddd, J¼10.7,

10.2, 4.6 Hz, CHAr), 3.07 (1H, dt, J¼10.2, 5.3 Hz,

CHCH₂Ph), 3.17, (1H, dd, J¼14.1, 5.3 Hz, CHCH_AH_BPh),

4.93 (2H, s, NCH₂Ph), 6.83 (2H, m, ArH), 6.91 (4H, m,

ArH), 7.06 (3H, m, ArH), 7.15–7.26 (5H, m, ArH); d_C

(125.8 MHz) 34.4 (CHCH₂Ph), 37.3 (CHAr), 39.8 (CH₂-

CHAr), 43.4 (NCH₂Ph), 49.3 (CHCH₂Ph), 116.1 (J_C–F

21 Hz, ArCH), 126.7 (ArCH), 127.6 (ArCH), 128.5 (ArCH),

128.8 (J_C–F¼8 Hz, ArCH), 129.0 (ArCH), 129.5 (ArCH),

¼

136.3 (ArC), 137.0 (ArC), 137.7 (ArC), 162.0 (J_C–F

¼

247 Hz, ArC), 170.8 (CvO), 173.7 (CvO); MS (EI) m/z

388 ([MþH]^þ, 36%), 387 (M^þ, 100), 296 (M2C₇H₇, 12),

268 (15), 256 (44), 169 (14), 147 (14), 106 (23), 91 (C₇H₇,

72), 77 (C₆H₅, 6) (HRMS: found M^þ, 387.1645.

C₂₅H₂₂NO₂F requires M, 387.1635). The ee was determined

as 97% by HPLC (OD column, 4% IPA and 1% MeCN in

hexane, 0.8 mL/min), the retention times were 23.5 min

(major) and 45.1 min (minor).

Data for bis-allylated glutarimide 31f. n_max(CHCl₃)/cm²¹

2925 and 2863 (C–H), 1723 and 1672 (CvO), 1606 and

1496 (Ar); d_H(400 MHz) 1.94 (2H, ddd, J¼14.2, 8.7,

4.6 Hz, 2£CH_AH_BCHvCH₂), 2.70 (2H, dm, J¼14.2 Hz,

2£CH_AH_BCHvCH₂), 2.84 (2H, dt, J¼12.4, 4.6 Hz, 2£

CHCH₂CHvCH₂), 3.04, (1H, dd, J¼12.4, 12.4 Hz, CHAr),

4.85 (2H, ddm, J¼17.0, 1.0 Hz, CH_AvCH_BH_C), 5.01 (2H,

dm, J¼10.2 Hz, CH_AvCH_BH_C), 5.04 (2H, s, NCH₂Ph),

5.59 (2H, dddd, J¼17.0, 10.2, 8.7, 5.5 Hz, CH_AvCH_BH_C),

7.05–7.15 (4H, m, ArH), 7.27–7.34 (3H, m, ArH), 7.40

(2H, m, ArH); d_C(125.8 MHz) 31.9 (CH₂CHvCH₂), 41.6

(CHAr), 43.8 (NCH₂Ph), 48.2 (CHCH₂CHvCH₂), 116.0

(J_C–F¼21 Hz, ArCH), 118.6 (HCvCH₂), 127.5 (ArCH),

128.4 (ArCH), 128.8 (ArCH), 129.6 (J_C–F¼7 Hz, ArCH),

162.0 Hz, ArC), 172.7 (CvO); MS (EI) m/z 378 ([MþH]^þ,

37%), 377 (M^þ, 100), 336 (M2C₃H₅, 20), 296 (12), 188

(45), 187 (20), 186 (35), 147 (21), 146 (16), 133 (13), 132

(14), 109 (20), 106 (24), 91 (C₇H₇, 85), 77 (C₆H₅, 4)

(HRMS: found M^þ, 377.1795. C₂₄H₂₄NO₂F requires M,

377.1791).

Data for bis-benzylated glutarimide 31g. n_max(CHCl₃)/

cm²¹3052, 2961, 2933 and 2857 (C–H), 1724 and 1678

(CvO), 1604 and 1512 (Ar); d_H(400 MHz) 2.75 (2H, dd,

J¼14.2, 6.2 Hz, 2£CHCH_AH_BPh), 2.82 (1H, dd, J¼12.1,

12.1 Hz, CHAr), 3.03 (2H, dd, J¼14.2, 3.3 Hz, 2£CHCH_A-

H_BPh), 3.07, (2H, ddd, J¼12.1, 6.2, 3.3 Hz, 2£CHCH₂Ph),

5.05 (2H, s, NCH₂Ph), 6.79 (4H, m, ArH), 6.99–7.17 (10H,

m, ArH), 7.30–7.36 (5H, m, ArH); d_C(125.8 MHz) 33.7

(CHCH₂Ph), 43.0 (CHAr), 44.3 (NCH₂Ph), 50.6 (CHCH₂Ph),

116.0 (J_C–F¼21 Hz, ArCH), 126.3 (ArCH), 127.5 (ArCH),

128.3 (ArCH), 128.5 (ArCH), 129.0 (ArCH), 129.3 (ArCH),

130.1 (J_C–F¼8 Hz, ArCH), 135.1 (ArC), 137.1 (ArC), 138.8

(ArC), 162.2 (J_C–F¼246 Hz, ArC), 173.3 (CvO); MS (EI)

m/z 478 ([MþH]^þ, 21%), 477 (M^þ, 53), 386 (M2C₇H₇,

29), 265 (22), 238 (21), 212 (17), 149 (31), 131 (56), 106

(15), 91 (C₇H₇, 100), 83 (23), 77 (C₆H₅, 6), 74 (22), 59 (31),

51 (42) (HRMS: found M^þ, 477.2120. C₃₂H₂₈NO₂F

requires M, 477.2104).

133.7 (HCvCH₂), 134.9 (ArC), 137.3 (ArC), 162.0 (J_C–F

¼

Glutarimide 30g was prepared in racemic form (31%) by

use of LDA–LiCl as base, according to the typical

procedure given above.

Glutarimide 30f was prepared in racemic form (28%) by use

of LDA–LiCl as base, according to the typical procedure

given above.

4.6.8. (3S,4R)-1-Benzyl-4-(4-ﬂuorophenyl)-3-(1-

hydroxy-1-phenylmethyl)piperidine-2,6-dione (1) 30h.

A chiral base reaction, using the typical procedure described

above, employing imide 28 (R¼Bn) (201 mg, 0.68 mmol)

4.6.7. (3S,4R)-1,3-Dibenzyl-4-(4-ﬂuorophenyl)piperi-

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

9227

and benzaldehyde (0.14 mL, 1.35 mmol) gave a crude

product 30h as a ca. 1:1 mixture of diastereomers.

Puriﬁcation by ﬂash column chromatography on silica gel

(40% Et₂O/petroleum ether) gave ﬁrstly the less polar

diastereomer of 30h as a pale yellow solid (110 mg, 40%):

[a]¹_D⁹¼þ11 (c 1.22 in CHCl₃): n_max(CHCl₃)/cm²¹3606

(OH), 3478 (br, OH), 3066, 3034, 2927 and 2890 (C–H),

1729 and 1681 (CvO), 1606, and 1514 (Ar); d_H(500 MHz)

2.69 (1H, dd, J¼18.4, 9.1 Hz, CH_axH_eqCHAr), 3.07 (2H, m,

CH_axH_eqCHAr and CHAr), 3.29 (1H, dd, J¼7.0, 4.1 Hz,

CHCH(OH)Ph), 4.07 (1H, d, J¼7.2 Hz, OH), 4.98 (1H, d,

J¼14.3 Hz, NCH_AH_BPh), 5.01 (1H, d, J¼14.3 Hz, NCH_A-

H_BPh), 5.08 (1H, dd, J¼7.2, 4.1 Hz, CH(OH)Ph), 6.84–

6.90 (4H, m, ArH), 7.05–7.14 (2H, m, ArH), 7.19–7.27

(8H, m, ArH); d_C(125.8 MHz) 34.8 (CHAr), 39.0 (CH₂-

CHAr), 43.2 (NCH₂Ph), 54.0 (CHCH(OH)Ph), 74.3

(CH(OH)Ph), 116.0 (J_C–F¼21 Hz, ArCH), 126.3 (ArCH),

127.6 (ArCH), 128.0 (ArCH), 128.4 (ArCH), 128.6 (ArCH),

reaction time of only 30 min at 2788C after adding

MeO₂CCN), employing imide 28 (R¼Bn) (199 mg,

0.67 mmol) and methyl cyanoformate (0.11 mL,

1.34 mmol) gave a 6.5:1 mixture of mono-methyl ester

glutarimide 30i and bis-methyl ester glutarimide 31i. The

products were puriﬁed via ﬂash column chromatography on

silica gel (30% EtOAc/petroleum ether followed by

dichloromethane) to yield mono-methyl ester glutarimide

30i as a white solid (168 mg, 71%) and bis-methyl ester

glutarimide 31i contaminated with 30i.

Data for mono-methyl ester glutarimide 30i. Mp 135–

1378C; [a]²_D⁸¼231 (c 0.74 in CHCl₃): n_max(CHCl₃)/cm²¹

2955 and 2902 (C–H), 1748, 1730 and 1680 (CvO), 1608,

and 1512 (Ar); d_H(400 MHz) 2.82 (1H, dd, J¼17.5,

11.2 Hz, CH_axH_eqCHAr), 3.02 (1H, dd, J¼17.5, 4.6 Hz,

CH_axH_eqCHAr), 3.65 (3H, s, OCH₃), 3.68 (1H, ddd, J¼11.2,

10.9, 4.6 Hz, CHAr), 3.81 (1H, d, J¼10.9 Hz, CHCO₂CH₃),

4.96 (1H, d, J¼13.8 Hz, NCH_AH_BPh), 5.03 (1H, d,

J¼13.8 Hz, NCH_AH_BPh), 7.01 (2H, m, ArH), 7.13 (2H,

m, ArH), 7.29 (3H, m, ArH), 7.37 (2H, m, ArH); d_C

(100.6 MHz) 37.5 (CHAr), 38.8 (CH₂CHAr), 43.5

128.7 (ArCH), 136.7 (ArC), 140.5 (ArC), 161.8 (J_C–F

¼

247 Hz, ArC), 171.1 (CvO), 174.1 (CvO); MS (FAB) m/z

404 ([MþH]^þ, 11%), 386 (M2OH, 12), 211 (23), 176 (10),

154 (19), 136 (81), 123 (15), 109 (30), 95 (50), 91 (C₇H₇,

40), 81 (53), 77 (C₆H₅, 17), 69 (80), 57 (89), 55 (100)

(HRMS: found [MþH]^þ404.1634. C₂₅H₂₂NO₃F requires

[MþH], 404.1662).

(NCH₂Ph), 52.9 (OCH₃), 56.4 (CHCO₂CH₃), 116.2 (J_C–F

21 Hz, ArCH), 127.8 (ArCH), 128.4 (ArCH), 128.6 (ArCH),

129.1 (ArCH), 134.4 (ArC), 136.5 (ArC), 162.3 (J_C–F

¼

247 Hz, ArC), 168.1 (CvO), 168.3 (CvO), 170.8 (CvO);

MS (FAB) m/z 356 ([MþH]^þ, 22%), 307 (32), 289 (15), 176

(13), 154 (100), 136 (73), 120 (13), 107 (22), 91 (C₇H₇, 25),

77 (C₆H₅, 20) (HRMS: found [MþH]^þ, 356.1299.

C₂₀H₁₈NO₄F requires [MþH], 356.1298). The ee was

determined as 97% by HPLC (OD column, 3% EtOH in

hexane, 0.8 mL/min), the retention times were 75.8 min

(minor) and 88.5 min (major).

The ee was determined as 97% by HPLC (OD column, 2%

IPA and 1% MeCN in hexane, 0.8 mL/min), the retention

times were 109.8 min (minor) and 121.5 min (major).

Further elution then gave the more polar diastereomer of

30h as a colourless oil (95 mg, 35%): [a]²_D⁴¼þ10 (c 1.51 in

CHCl₃); n_max(CHCl₃)/cm²¹3601 (OH), 3543 (br, OH),

3090 and 2923 (C–H), 1725 and 1681 (CvO), 1607, and

1494 (Ar); d_H(500 MHz) 2.79 (1H, dd, J¼17.6, 7.4 Hz,

CH_axH_eqCHAr), 2.87 (1H, dd, J¼17.6, 5.4 Hz, CH_axH_eq-

CHAr), 3.01 (1H, d, J¼6.0 Hz, OH), 3.26 (1H, m, CHAr),

3.31 (1H, dd, J¼7.0, 4.9 Hz, CHCH(OH)Ph), 4.97 (1H, dd,

J¼6.0, 4.9 Hz, CH(OH)Ph), 4.97 (1H, m, NCH_AH_BPh),

5.02 (1H, d, J¼13.8 Hz, NCH_AH_BPh), 6.93–7.01 (4H, m,

ArH), 7.24–7.35 (10H, m, ArH); d_C(125.8 MHz) 36.2

(CHAr), 37.8 (CH₂CHAr), 43.3 (NCH₂Ph), 55.5

(CHCH(OH)Ph), 73.4 (CH(OH)Ph), 116.1 (J_C–F¼21 Hz,

ArCH), 125.8 (ArCH), 127.7 (ArCH), 128.2 (ArCH), 128.5

(ArCH), 128.6 (J_C–F¼8 Hz, ArCH), 128.8 (ArCH), 129.0

(ArCH), 136.7 (ArC), 136.8 (ArC), 141.4 (ArC), 161.9

(J_C–F¼246 Hz, ArC), 170.8 (CvO), 172.6 (CvO); MS

(FAB) m/z 404 ([MþH]^þ, 4%), 386 (M2OH, 3), 307 (24),

289 (12), 176 (12), 155 (28), 154 (100), 139 (14), 138 (35),

137 (64), 136 (71), 120 (12), 107 (26), 105 (11), 95 (11), 91

(C₇H₇, 21), 90 (14), 89 (20), 77 (C₆H₅, 22), 69 (20), 57 (31),

55 (27) (HRMS found [MþH]^þ404.1646. C₂₅H₂₂NO₃FþH

requires [MþH], 404.1662).

Data for bis-methyl ester glutarimide 31i. n_max(CHCl₃)/

cm²¹3038, and 2956 (C–H), 1750, 1730 and 1682 (CvO),

1606, and 1513 (Ar);d_H(400 MHz) 3.62 (6H, s, 2£OCH₃),

3.83 (2H, d, J¼12.0 Hz, 2£CHCO₂CH₃), 4.06 (1H, dd,

J¼12.0, 12.0 Hz, CHAr), 5.01 (2H, s, NCH₂Ph), 7.02 (2H,

m, ArH), 7.12–7.20 (2H, m, ArH), 7.29–7.35 (3H, m,

ArH), 7.38–7.42 (2H, m, ArH); d_C(125.8 MHz) 40.7

(CHAr), 44.2 (NCH₂Ph), 53.0 (OCH₃), 55.8 (CHCO₂CH₃),

116.3 (J_C–F¼22 Hz, ArCH), 128.1 (ArCH), 128.5 (ArCH),

128.7 (ArCH), 129.3 (ArCH), 132.0 (ArC), 136.0 (ArC),

162.6 (J_C–F¼248 Hz, ArC), 167.4 (CvO), 170.8 (CvO);

MS (FAB) m/z 414 ([MþH]^þ, 3%), 319 (2), 369 (2), 329

(4), 307 (26), 289 (12), 176 (10), 154 (100), 136 (68), 120

(11), 107 (21), 91 (C₇H₇, 16), 77 (C₆H₅, 16), 69 (20), 57 (22)

(HRMS: found [MþH]^þ, 414.1359. C₂₂H₂₀NO₆F requires

[MþH], 414.1353).

Glutarimide 30i was prepared in racemic form (25%) by use

of LDA–LiCl as base, according to the typical procedure

given above.

Glutarimide 30h was prepared in racemic form as a ca. 1:1

ratio of diastereomers (50% yield) by use of LDA–LiCl as

base, according to the typical procedure given above.

4.6.10. Kinetic resolution of racemic trans-1,3-dimethyl-

4-(4-ﬂuorophenyl)piperidine-2,6-dione 30a. Chiral lithium

amide base 29 was prepared from the corresponding chiral

amine (304 mg, 0.72 mmol) in THF (4.0 mL) at 2788C

under an atmosphere of nitrogen, by addition of n-BuLi

(0.90 mL of a 1.6 M solution in hexanes, 1.44 mmol),

followed by warming to room temperature over 15 min. The

resulting solution of the chiral base 29 was then cooled to

4.6.9. (3S,4R)-1-Benzyl-4-(4-ﬂuorophenyl)-2,6-dioxo-

piperidine-3-carboxylic acid methyl ester (2) 30i and

dimethyl (3R,5S)-1-benzyl-4-(4-ﬂuorophenyl)-2,6-dioxo-

3,5-piperidinedicarboxylate 31i. A chiral base reaction,

using the typical procedure described above (but with

9228

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

2788C, before being added dropwise via cannula over

5 min to a stirred solution of racemic mono-methylated

glutarimide 30a (102 mg, 0.43 mmol) in THF (5 mL),

maintaining a temperature of 2788C^1. The reaction

mixture was then stirred for 45 min before dilution with

further THF (8 mL) followed by addition of methyl iodide

(0.27 mL, 4.35 mmol). The reaction mixture was then

warmed to 2408C^1 and stirred at this temperature for a

further 4 h before quenching with saturated aqueous NH₄Cl

solution (20 mL) and extraction into EtOAc (2£15 mL).

The organic extracts were combined, washed with 2 M HCl

(3£30 mL), followed by saturated aqueous NaHCO₃

(30 mL) then brine (30 mL), dried (MgSO₄), ﬁltered and

concentrated in vacuo to give a 1.2:1 mixture of mono-

methylated glutarimide 30a and bis-methylated glutarimide

31a, respectively. Chiral HPLC analysis of the crude

mixture established that 46% conversion of racemic

mono-methylated glutarimide 30a into bis-methylated

glutarimide 31a had occurred, and that the ee of recovered

mono-methylated glutarimide 30a had increased to 13%.

(3.0 mL) was then added and the reaction mixture was left

to stir for a further 10 min. The mixture was then poured

into saturated Rochelle’s salt solution (30 mL) and extracted

with EtOAc (4£20 mL). The organic extracts were

combined, washed with brine (3£20 mL), dried (MgSO₄),

ﬁltered and concentrated in vacuo to yield piperidine

alcohol 36 as a colourless oil (155 mg, 90%), which was

used without further puriﬁcation: n_max(CHCl₃)/cm²¹3626

(OH), 3085–2763 (C–H), 1604 and 1511 (Ar); d_H(400 MHz)

1.70–1.95 (2H, m, 5-CH₂), 2.05 (3H, m, 2-CH_AH_B, 3-CH

and 6-CH_AH_B), 2.35 (1H, ddd, J¼11.5, 11.5, 4.1 Hz, 4-CH),

3.00 (1H, dm, J¼11.5 Hz, 6-CH_AH_B), 3.23 (1H, dd, J¼10.9,

6.2 Hz, CH_AH_BOH), 3.23 (1H, m, 2-CH_AH_B), 3.38 (1H, dd,

J¼10.9, 2.6 Hz, CH_AH_BOH), 3.58 (1H, d, J¼13.0 Hz,

NCH_AH_BPh), 3.65 (1H, d, J¼13.0 Hz, NCH_AH_BPh), 6.95–

7.01 (2H, m, ArH), 7.14–7.37 (7H, m, ArH); d_C

(125.8 MHz) 34.5 (5-CH₂), 44.2 (4-CH), 44.3 (3-CH),

54.0 (6-CH₂), 57.4 (2-CH₂), 63.6 (NCH₂Ph), 64.0

(CH₂OH), 115.4 (J_C–F¼21 Hz, ArCH), 127.1 (ArCH),

128.3 (ArCH), 128.9 (J_C–F¼8 Hz, ArCH), 129.4 (ArCH),

138.1 (ArC), 140.2 (ArC), 161.5 (J_C–F¼244 Hz, ArC); MS

(EI) m/z 299 (M^þ, 35%), 208 (M2C₇H₇, 15), 176 (20), 146

(15), 134 (11), 120 (46), 109 (12), 91 (C₇H₇, 100), 65 (12),

57 (17), 51 (27) (HRMS: found M^þ, 299.1682. C₁₉H₂₂NOF

requires M, 299.1686).

4.6.11. Enantiomeric enrichment of (3S,4R)-1-benzyl-4-

(4-ﬂuorophenyl)-2,6-dioxopiperidine-3-carboxylic acid

methyl ester (2) 30i by kinetic resolution. Chiral lithium

amide base 29 was prepared from the corresponding chiral

amine (118 mg, 0.28 mmol) in THF (1.5 mL) at 2788C

under an atmosphere of nitrogen, by addition of n-BuLi

(0.35 mL of a 1.6 M solution in hexanes, 0.56 mmol),

followed by warming to room temperature over 15 min. The

resulting solution of the chiral base 29 was then cooled to

2788C, before being added dropwise via cannula over

5 min to a stirred solution of mono-methyl ester glutarimide

30i (58 mg, 0.16 mmol, 44% ee) in THF (1 mL), maintain-

ing a temperature of 2788C^1. The reaction mixture was

then stirred for 45 min after which THF (1 mL) followed by

methyl cyanoformate (0.03 mL, 3.29 mmol) were added.

The reaction mixture was then stirred at 2788C^1 for a

further 1 h before quenching with saturated aqueous NH₄Cl

solution (20 mL) and extraction into Et₂O (2£30 mL). The

organic extracts were combined, washed with 2 M HCl

(3£60 mL), followed by saturated aqueous NaHCO₃

(60 mL) then brine (60 mL), dried (MgSO₄), ﬁltered and

concentrated in vacuo to give a 1.4:1 mixture of recovered

mono-methyl ester glutarimide 30i and bis-methyl ester

glutarimide 31i. Puriﬁcation via ﬂash column chromato-

graphy on silica gel (DCM) yielded a mixture of bis-methyl

ester glutarimide 31i and mono-methyl ester glutarimide 30i

(18 mg) as a colourless oil and recovered mono-methyl ester

glutarimide 30i (8 mg, 15%) as a white solid. Chiral HPLC

analysis of the recovered mono-methyl ester glutarimide 30i

established that the ee had increased from 44% to 81%.

4.7.2. (3S,4R)-1-Benzyl-4-(4-ﬂuorophenyl)-3-methyl-

sulfonatepiperidine 37. Mesyl Chloride (0.05 mL,

0.57 mmol) was added to a solution of piperidine alcohol

36 (155 mg, 0.52 mmol) in pyridine (1.6 mL) at 108C. The

reaction mixture was left to stir for 1 h after which the

reaction mixture was poured into a 10% solution of

NaHCO₃(10 mL) and extracted with Et₂O (3£20 mL).

The organic extracts were combined, dried (MgSO₄),

ﬁltered and concentrated in vacuo to give mesylate 37 as

an oil (141 mg, 72%), which was used without further

puriﬁcation: n_max(CHCl₃)/cm²¹2924 and 2767 (C–H),

1606, 1509 and 1404 (Ar), 1350 (OSO₂CH₃); d_H(400 MHz)

1.73 (2H, m, 5-CH₂), 1.97 (2H, m, 2-CH_AH_Band 3-CH),

2.16 (1H, m, 6-CH_AH_B), 2.31 (1H, m, 4-CH), 2.74 (3H, s,

OSO₂CH₃), 2.90 (1H, dm, J¼11.8 Hz, 6-CH_AH_B), 3.08 (1H,

dd, J¼9.3, 3.4 Hz, 2-CH_AH_B), 3.47 (1H, d, J¼13.1 Hz,

NCH_AH_BPh), 3.55 (1H, d, J¼13.1 Hz, NCH_AH_BPh), 3.72

(1H, dd, J¼9.9, 6.8 Hz, CH_AH_BOSO₂CH₃), 3.84 (1H, dd,

J¼9.9, 3.0 Hz, CH_AH_BOSO₂CH₃), 6.93 (2H, m, ArH), 7.10

(2H, m, ArH), 7.17–7.27 (5H, m, ArH); d_C(125.8 MHz)

34.4 (5-CH₂), 36.9 (OSO₂CH₃), 41.5 (4-CH), 43.8 (3-CH),

53.6 (6-CH₂), 56.6 (2-CH₂), 63.3 (NCH₂Ph), 70.8 (CH_2-

OSO₂CH₃), 115.7 (J_C–F¼21 Hz, ArCH), 127.3 (ArCH),

128.4 (ArCH), 128.9 (ArCH), 129.3 (ArCH), 137.8 (ArC),

138.7 (ArC), 161.7 (J_C–F¼245 Hz, ArC); MS (EI) m/z 378

([MþH]^þ, 16%), 337 (M^þ, 58), 300 ((M2C₆H₅)^þ, 14), 298

(21), 282 (50), 267 (48), 146 (21), 134 (53), 120 (24), 109

(16), 91 (C₇H₇, 100), 77 (C₆H₅, 5), 65 (17), 57 (22), 50 (27)

(HRMS: found M^þ, 377.1452. C₂₀H₂₄NO₃SF requires M,

377.1461).

4.7. Total synthesis of paroxetine (2)-6 (Scheme 10)

4.7.1. (3S,4R)-1-Benzyl-4-(4-ﬂuorophenyl)-3-piperidine-

methanol 36. Imide 30i (97% ee) (204 mg, 0.57 mmol)

dissolved in THF (2.1 mL) was added dropwise to a stirred

solution of LiAlH₄(2.9 mL of a 1 M solution in THF,

2.9 mmol) whilst being cooled by an ice bath. The reaction

mixture was then warmed to room temperature and then

heated at reﬂux overnight. After this time the ﬂask was

cooled to room temperature, water (1.0 mL) was added

dropwise and the mixture was stirred for 10 min. 2 M NaOH

4.7.3. (3S,4R)-1-Benzyl-4-(4-ﬂuorophenyl)-3-[3,4-

(methylenedioxy)-phenoxymethyl] piperidine 39. Sesa-

mol 38 (245 mg, 1.77 mmol) was added to a suspension of

NaOMe (97 mg, 1.80 mmol) in MeOH (2 mL) at room

temperature and left to stir for 30 min. Mesylate 37

(134 mg) was then added and the reaction mixture was

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

9229

heated at reﬂux overnight. The reaction mixture was cooled

to room temperature and the solvent removed in vacuo. The

residue was diluted with EtOAc (60 mL), washed with 2 M

NaOH (3£60 mL), dried (MgSO₄), ﬁltered and concentrated

in vacuo. The product was puriﬁed via ﬂash column

chromatography using silica gel (40% EtOAc/petroleum

ether) to give piperidine 39 as an oil (81 mg, 55%): n_max

(CHCl₃)/cm²¹3085–2766 (C–H), 1605 and 1511 (Ar); d_H

(400 MHz) 1.75–1.92 (2H, m, 5-CH₂), 2.00–2.14 (2H, m,

2-CH_AH_Band 3-CH), 2.23 (1H, m, 6-CH_AH_B), 2.50 (1H,

ddd, J¼11.5, 11.5, 4.5 Hz, 4-CH), 3.00 (1H, dm, J¼

11.5 Hz, 6-CH_AH_B), 3.26 (1H, dd, J¼11.1, 1.6 Hz, 2-

CH_AH_B), 3.45 (1H, dd, J¼9.3, 6.8 Hz, CH_AH_BOAr), 3.56

(1H, d, J¼13.1 Hz, NCH_AH_BPh), 3.56 (1H, m, CH_AH_B-

OAr), 3.66 (1H, d, J¼13.1 Hz, NCH_AH_BPh), 5.89 (2H, s,

OCH₂O), 6.12 (1H, dd, J¼8.5, 2.5 Hz, 6⁰-ArCH), 6.34 (1H,

d, J¼2.5 Hz, 2⁰-ArCH), 6.63 (1H, d, J¼8.5 Hz, 5⁰-ArCH),

6.96–7.05 (2H, m, ArH), 7.14–7.19 (2H, m, ArH), 7.21–

7.39 (5H, m, ArCH); d_C(100.6 MHz) 34.4 (5-CH₂), 42.2

(4-CH), 44.2 (3-CH), 53.9 (6-CH₂), 57.7 (2-CH₂), 63.5

(NCH₂Ph), 69.7 (CH₂OAr), 98.1 (2⁰-ArCH), 101.1 (OCH₂O),

105.3 (6⁰-ArCH), 107.9, (5⁰-ArCH), 115.4 (J_C–F¼21 Hz,

ArCH), 127.1 (ArCH), 128.3 (ArCH), 128.9 (J_C–F¼8 Hz,

ArCH), 129.3 (ArCH), 138.2 (ArC), 139.9 (ArC), 141.6

69.4 (CH₂OAr), 98.0 (2⁰-ArCH), 101.1 (OCH₂O), 105.6 (6⁰-

ArCH), 107.9, (5⁰-ArCH), 115.5 (J_C–F¼21 Hz, ArCH),

128.9 (J_C–F¼8 Hz, ArCH), 139.8 (ArC), 141.6 (3⁰-ArC),

148.2 (4⁰-ArC), 154.4 (1⁰-ArC), 161.6 (J_C–F¼244 Hz, ArC);

MS (EI) m/z 330 ([MþH]^þ, 18%), 329 (M^þ, 78), 192

((M2C₇H₅O₃), 100), 138 (60), 135 (18), 109 (24), 70 (53)

(HRMS: found M^þ, 329.1430. C₁₉H₂₀NO₃F requires M,

329.1427).

4.7.5. Asymmetric benzylation of 40 to give (3R,4S)-1,3-

dibenzyl-4-methylpiperidine-2,6-dione (1) 41. A chiral

base reaction, using the typical procedure described above

for glutarimide alkylation, employing imide 40 (201 mg,

0.92 mmol) and benzyl bromide (1.1 mL, 9.24 mmol) gave

a crude product that was puriﬁed via ﬂash column

chromatography on silica gel (gradient elution, petroleum

ether to 40% Et₂O/petroleum ether) to yield mono-

benzylated glutarimide 41 as an oil (164 mg, 58%):

[a]²_D¹¼þ34 (c 1.25 in CHCl₃); n_max(CHCl₃)/cm²¹2961,

2932 and 2875 (C–H), 1723 and 1681 (CvO), 1604 and

1495 (Ar); d_H(400 MHz) 1.12 (3H, d, J¼6.7 Hz, CHCH₃),

1.99 (1H, m, CHCH₃), 2.43 (1H, dd, J¼17.2, 8.3 Hz,

CH_axH_eqCHCH₃), 2.70 (1H, dd, J¼12.8, 6.6 Hz, CHCH_2-

Ph), 2.83 (1H, dd, J¼17.2, 4.7 Hz, CH_axH_eqCHCH₃), 3.12

(1H, dd, J¼14.1, 5.4 Hz, CH_AH_BPh), 3.29 (1H, dd, J¼14.1,

6.6 Hz, CH_AH_BPh), 5.03 (1H, d, J¼14.4 Hz, NCH_AH_BPh),

5.06 (1H, d, J¼14.4 Hz, NCH_AH_BPh), 7.17 (2H, m, ArH),

7.23–7.39 (8H, m, ArH); d_C(125.8 MHz) 19.8 (CHCH₃),

26.1 (CHCH₃), 34.9 (CHCH₂Ph), 38.3 (CH₂CHCH₃), 43.0

(NCH₂Ph), 50.5 (CHCH₂Ph), 126.7 (ArCH), 127.3 (ArCH),

128.4 (ArCH), 128.6 (ArCH), 128.7 (ArCH), 129.2 (ArCH),

137.3 (ArC), 137.9 (ArC), 171.4 (CvO), 174.2 (CvO); MS

(EI) m/z 307 (M^þ, 75%), 265 (13), 231 (13), 216

(M2C₇H₇,17), 189 (17), 188 (70), 160 (11), 146 (40), 131

(42), 106 (56), 105 (28), 104 (35), 91 (C₇H₇, 100), 77 (C₆H₅,

16), 65 (22), 57 (19) (HRMS: found M^þ, 307.1572.

C₂₀H₂₁NO₂requires M, 307.1572). The ee was determined

as 67% by HPLC (OJ column, 3% EtOH in hexane, 1.0 mL/

min), the retention times were 43.6 min (major) and

51.6 min (minor).

(3⁰-ArC), 148.2 (4⁰-ArC), 154.5 (1⁰-ArC), 161.5 (J_C–F

¼

244 Hz, ArC); MS (EI) m/z 419 (M^þ, 21%), 282

((M2C₇H₅O₃)^þ, 48), 267 (58), 134 (36), 91 (C₇H₇, 100)

(HRMS: found M^þ, 419.1898. C₂₆H₂₆NO₃F requires M,

419.1897).

4.7.4. (3S,4R)-4-(4-Fluorophenyl)-3-[(3,4-(methylene-

dioxy)-phenoxymethyl]piperidine (paroxetine) (2)-6.

1-Chloroethyl chloroformate (0.03 mL, 0.27 mmol) was

added to a solution of piperidine 39 (73 mg, 0.17 mmol)

dissolved in dichloroethane (1.5 mL) at 08C. The reaction

mixture was then allowed to warm to room temperature and

was then heated at reﬂux for 3 h. After this time the reaction

mixture was allowed to cool to room temperature and the

solvent evaporated in vacuo. The residue was then dissolved

in MeOH (1 mL) and the solution heated at reﬂux for a

further 2 h. The reaction mixture was then allowed to cool to

room temperature, before the solvent was evaporated and

the product triturated with Et₂O. The product was then

washed with 2 M NaOH solution and extracted into EtOAc,

dried (MgSO₄), ﬁltered and concentrated in vacuo. The

product was puriﬁed via ﬂash column chromatography

using silica gel (7% MeOH/dichloromethane) to yield the

free amine (2)-6 as a white solid (31 mg, 54%): [a]²_D¹¼284

(c 0.77 in MeOH) (lit. [a]²_D¹¼275.5 (c 1.2, MeOH) for

.97:3 er,^13cand [a]²_D¹¼280.8 (c 1.25, MeOH) via

enantiopure intermediates^13e); n_max(CHCl₃)/cm²¹2923

and 2884 (C–H), 1631, 1606 and 1510 (Ar); d_H(400 MHz)

1.75 (1H, ddm, J¼12.4, 3.8 Hz, 5-CH₂), 1.81 (1H, m, 5-

CH_AH_B), 2.09 (1H, m, 3-CH), 2.60 (1H, ddd, J¼11.6, 11.6,

3.8 Hz, 4-CH), 2.70 (1H, dd, J¼11.7, 11.4 Hz, 2-CH_AH_B),

2.76 (1H, ddd, J¼12.1, 11.8, 2.4 Hz, 6-CH_AH_B), 3.20 (1H,

dm, J¼12.0 Hz, 6-CH_AH_B), 3.44 (2H, m, 2-CH_AH_Band

CH_AH_BOAr), 3.57 (1H, dd, J¼9.3, 2.7 Hz, CH_AH_BOAr),

5.88 (2H, s, OCH₂O), 6.13 (1H, dd, J¼8.4, 2.3 Hz, 6⁰-

ArCH), 6.34 (1H, d, J¼2.3 Hz, 2⁰-ArCH), 6.62 (1H, d,

J¼8.4 Hz, 5⁰-ArCH), 6.98 (2H, t, J¼8.6 Hz, ArH), 7.17 (2H,

dd, J¼8.3, 5.6 Hz, ArH); d_C(125.8 MHz) 35.0 (5-CH₂),

42.7 (4-CH), 44.4 (3-CH), 46.8 (6-CH₂), 50.1 (2-CH₂),

Glutarimide 41 was prepared in racemic form (21%) by use

of LDA–LiCl as base, according to the typical procedure

given above.

4.7.6. 1-Benzyl-4-(4-ﬂuorophenyl)-6-hydroxy-3-methyl-

piperidine-2-one 42. To a solution of imide 30e (39 mg,

0.12 mmol) in dichloromethane (1 mL) at 2788C was added

DIBAL-H (0.25 mL of a 1.0 M solution in dichloromethane,

0.25 mmol). The reaction mixture was then stirred at this

temperature for 3 h before water (1 mL) was added and the

resulting mixture allowed to warm to room temperature.

The product was extracted with dichloromethane (3£10 mL),

the organic extracts combined, dried (MgSO₄), ﬁltered and

concentrated in vacuo to give hydroxy lactam 42 as a

colourless oil (37 mg, 94%): n_max(CHCl₃)/cm²¹3579

(OH), 2929 (C–H), 1644 (CvO), 1606 and 1510 (Ar); d_H

(400 MHz) 1.01 (3H, d, J¼6.5 Hz, CHCH₃), 1.92 (1H, ddd,

J¼13.6, 11.7, 7.8 Hz, CH_AH_BCHAr), 2.31 (1H, ddd,

J¼13.6, 5.6, 3.3 Hz, CH_AH_BCHAr), 2.52 (2H, m, CHAr

and CHCH₃), 2.85 (1H, br s, OH), 4.47 (1H, d, J¼14.6 Hz,

NCH_AH_BPh), 4.86 (1H, dd, J¼7.8, 5.6 Hz, CHOH), 5.01

(1H, d, J¼14.6 Hz, NCH_AH_BPh), 6.96 (2H, t, J¼8.7 Hz,

9230

C. D. Gill et al. / Tetrahedron 59 (2003) 9213–9230

Chem. 1996, 61, 3187. (b) Marson, C. M.; Pink, J. H.; Hall, D.;

Hursthouse, M. B.; Malik, A.; Smith, C. J. Org. Chem. 2003,

68, 792.

ArH), 7.07 (2H, dd, J¼8.7, 5.3 Hz, ArH), 7.20–7.30 (5H,

m, ArH); d_C(100.6 MHz) 15.3 (CHCH₃), 40.2 (CH₂), 42.7

(CHAr), 43.1 (CHCH₃), 46.0 (CH₂), 79.4 (CHOH), 115.8

(J_C–F¼21 Hz, ArCH), 127.5 (ArCH), 128.3 (ArCH), 128.7

(J_C–F¼8 Hz, ArCH), 128.8 (ArCH), 137.8 (ArC), 138.6

(ArC), 162.0 (J_C–F¼247 Hz, ArC), 173.3 (CvO); MS (EI)

m/z 313 (M^þ, 7%), 295 (M2H₂O, 72), 283 (54), 238 (41),

227 (19), 186 (60), 163 (23), 147 (22), 133 (26), 109 (24), 91

(C₇H₇, 100), 65 (34) (HRMS: found M^þ, 313.1478.

C₁₉H₂₀NO₂F requires M, 313.1463).

10. Hsu, R.-T.; Cheng, L.-M.; Chang, N.-C.; Tai, H.-M. J. Org.

Chem. 2002, 67, 5044. See also references therein for further

examples of regioselective imide reactions.

11. Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am.

Chem. Soc. 1996, 118, 9805.

12. Padwa, A.; Danca, M. D.; Hardcastle, K. I.; McClure, M. S.

J. Org. Chem. 2003, 68, 929.

13. For recent asymmetric syntheses of paroxetine, see: (a) de

Gonzalo, G.; Brieva, R.; Sanchez, V. M.; Bayod, M.; Gotor, V.

J. Org. Chem. 2001, 66, 8947. (b) Cossy, J.; Mirguet, O.;

Gomez Pardo, D.; Desmurs, J.-R. Tetrahedron Lett. 2001, 42,

7805. (c) Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem.

Soc. 2001, 123, 1004. (d) Liu, L. T.; Hong, P-C.; Huang, H-L.;

Chen, S-F.; Wang, C-L. W.; Wen, Y-S. Tetrahedron:

Asymmetry 2001, 12, 419. (e) Amat, M.; Bosch, J.; Hidalgo,

J.; Canto, M.; Perez, M.; Llor, N.; Molins, E.; Miravitlles, C.;

Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074.

14. (a) Rama Rao, R.; Singh, A. K.; Varaprasad, C. V. N. S.

Tetrahedron Lett. 1991, 32, 4393. (b) Goehring, R. R.;

Greenwood, T. D.; Nwokogu, G. C.; Pisipati, J. S.; Rogers,

T. G.; Wolfe, J. F. J. Med. Chem. 1990, 33, 926.

15. Kawabata, T.; Stragies, R.; Fukaya, T.; Nagaoka, Y.; Schedel,

H.; Fuji, K. Tetrahedron Lett. 2003, 44, 1545.

Acknowledgements

We thank the Engineering and Physical Sciences Research

Council (EPSRC) for support of CDG, and we thank the

University of Nottingham for support of DAG. We would

also like to thank Professor Albert Padwa of Emory

University for very helpful exchange of information and

spectral data, and Dr William Jackson for his interest in this

project, and for initial supplies of glutarimides.

References

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would certainly expect A^1,2strain to destabilise 32 eq.

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Tetrahedron Lett. 2000, 41, 5647. See also Ref. 13 and

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23. Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195. and

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8. For previous examples of alkylations of this imide system, see:

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Article Doi

Application of the chiral base desymmetrisation of imides to the synthesis of the alkaloid jamtine and the antidepressant paroxetine

DOI: 10.1016/j.tet.2003.08.046

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Article abstract of DOI:10.1016/j.tet.2003.08.046

Full text of DOI:10.1016/j.tet.2003.08.046

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