Scholarly article on (R,R)-(-)-bis(α-methylbenzyl)aminoacetaldehyde dimethyl acetal 573970-34-0 from Organic and Biomolecular Chemistry p. 834

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Studies on the Lewis acid mediated cleavage of ꢀ-aminoacetals:

synthesis of novel 1,2-aminoethers, and evidence for ꢀ-alkoxy

aziridinium ion intermediates†

Mark A. Graham,^aAlan H. Wadsworth,^bAbdul Zahid^aand Christopher M. Rayner*^a

^aSchool of Chemistry, University of Leeds, Leeds, UK LS2 9JT.

E-mail: C.M.Rayner@chem.leeds.ac.uk

^bGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts,

UK SG1 2NY

Received 18th October 2002, Accepted 9th January 2003

First published as an Advance Article on the web 5th February 2003

The nucleophilic cleavage of α-amino acetals induced by TMSOTf can be used to prepare a wide range of substituted

1,2-aminoethers. In particular, organometallic reagents, N-heterocycles, and enamines all react eﬃciently to give

products in good yield. In appropriate cases, good levels of stereocontrol are possible, but this is very dependent on

the nature of the nucleophile and the substrate, with diethylzinc proving particularly eﬀective across a range of

substrates. The degree of stereocontrol can be used to infer the nature of the reactive intermediates involved in the

reaction. With diethylzinc, it is most likely that the reaction proceeds by coordination of the nucleophile to the amino

group followed by transfer of an ethyl group to an α-oxocarbenium ion. With non-coordinating nucleophiles, the

stereochemical outcome can be rationalised in terms of addition to the possible α-alkoxy aziridinium ion

intermediates.

derivatives, are diﬃcult to isolate unless there are particular

stabilising inﬂuences, and are usually reacted further prior to

Introduction

The development of new chemistry based on reactive inter-

product isolation. It is thus unlikely that α-alkoxy aziridinium

mediates such as aziridinium ions (1) and episulfonium ions (2)

ions (5) would be isolable, but their presence as reactive inter-

continues to be an important area of research.^1,2These are

mediates is not unreasonable.

now well-established synthetic intermediates, allowing access to

highly functionalised products, often with a high degree of ster-

eochemical control. In the course of our own studies in this

area,³we have recently begun to investigate new methods for the

generation of related reactive intermediates containing further

heteroatom substituents, to investigate their reactivity and syn-

thetic utility. We have recently demonstrated the intermediacy

of α-thio episulfonium ions (3) by consideration of the stereo-

chemical outcome of the Lewis acid mediated cleavage of

α-acetoxy sulﬁdes, prepared in an enantiomerically enriched

form by enzymatic resolution.⁴Related intermediates have been

proposed during the preparation of α-sulfenyl dithioacetals,⁵

but have otherwise been little investigated. The related α-alkoxy

episulfonium ions (4) and related intermediates have been the

subject of more detailed investigations, although in some cases,

it would appear that the corresponding open chain α-oxocarb-

enium ion (cf. 8, Scheme 1) is a more likely intermediate.⁶In the

case of the corresponding nitrogen systems, α-alkoxy aziridin-

ium ions (5) are potentially very useful synthetic intermediates,

but appear not to have been investigated to a signiﬁcant degree.⁷

The related α-alkoxy aziridines (6) are better established, being

formed by the addition of alkoxides to azirines, or by aziridin-

ation of enol ethers.⁸However, even these species, which one

would expect to be relatively stable compared to the aziridinium

On reaction with appropriate nucleophiles, α-alkoxy aziridin-

ium ions would, in principle, allow access to 1,2-amino ethers

with a high degree of stereochemical control (Scheme 1). How-

ever, the reaction is more complex in that there is also the

potential for the α-alkoxy aziridinium ion (9) to be in equi-

librium with an open chain α-oxocarbenium ion (8) or various

intermediate forms. This could have important eﬀects on the

reactivity and stereochemical outcome of the reaction with

nucleophiles. We envisaged that such eﬀects would be import-

ant, and might allow us to be able to diﬀerentiate between the

possible reaction pathways to determine the nature of the

reactive intermediate involved. Hence this work is of mech-

anistic interest, particularly if reaction pathways involving

either 8 or 9 could be distinguished, but also synthetically

important due to the potential for the formation of a variety

of highly functionalised 1,2-amino alcohols and derivatives

thereof, which often show interesting biological activity.⁹

† Electronic supplementary information (ESI) available: correlation

of ¹H NMR spectra between the syn and anti diastereomeric series.

See http://ww w .rsc.org/suppdata/ob/b2/b210116e/

Scheme 1

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3

834

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Table 1 TMSOTf mediated nucleophilic cleavage of α-amino acetals

We thus embarked on a research programme to investigate

the reactivities of intermediates such as 8 and 9, and to exploit

them in the area of stereocontrolled synthesis. This paper

discusses the results of this study in detail.

Initial investigations

Entry

1

R

Nucleophile

Et₂Zn

Product

Yield (%)

86

In principle, α-alkoxy aziridinium ions (9) and related inter-

mediates can be generated by Lewis acid mediated cleavage of

α-amino acetals (7), and our initial goal was to demonstrate

feasibility of this process (Scheme 1).¹⁰Synthesis of substrates

for investigation was readily accomplished by reacting the

required secondary amine (diallylamine, dibenzylamine) with

bromoacetaldehyde diethyl acetal in DMF at 90–100 ЊC in the

presence of catalytic potassium iodide (Scheme 2). Substituents

on nitrogen were chosen such that they would allow subsequent

deprotection to the corresponding primary amine if required,

which we considered important to enhance the versatility of the

methodology.¹¹Interestingly, dibenzylamine was considerably

less reactive than diallylamine in this reaction, an observation

which would have implications for the synthesis of more substi-

tuted systems (vide infra).

Bn

2

3

4

Allyl

Bn

Et₂Zn

65

71

75

EtMgBr

Allyl

5

6

Bn

77

64

Allyl

7

8

Bn

84

86^a

9

Bn

13^ab

Scheme 2

^a78:22 mixture of isomers; ^bMajor product (57%) is enone from further

loss of EtOH.

We then investigated the Lewis acid mediated nucleophilic

cleavage of these simple acetals. Treatment of the substrates

with trimethylsilyl triﬂuoromethanesulfonate (TMSOTf ) at

Ϫ78 ЊC followed by addition of the nucleophile and slowly

warming to room temperature gave good yields of the acetal

substitution products 16–19 (Table 1).

Reaction with organometallic species such as dialkylzinc and

Grignard reagents proceeded eﬃciently, for both the N-allyl¹²

and N-benzyl substrates (entries 1–3 in Table 1). Similarly,

introduction of the uracil group and 2-pyridone was also eﬃ-

cient (entries 4–7). Enamines reacted smoothly to introduce

carbonyl functionality (entry 8), but with silyl enol ethers, the

Lewis acidic reaction conditions led to further loss of ethanol

to give the αβ-unsaturated ketone as the major product (entry

9).

formed in favour of 20, with the ester (21) presumably resulting

from 1,2-hydride migration in the iminium ion intermediate

(22) also being formed. This was readily removed however, by

basic hydrolysis and aqueous extraction, leaving a 55% isolated

yield of the desired acetal (20).

We believed the nature of the acetal group may be an import-

ant factor in inﬂuencing the stereocontrol in this reaction,

hence we also prepared both the ethyl acetal (23) and isopropyl

acetal (24) by acid catalysed exchange (Scheme 4). In the case of

the diethyl acetal, this was readily achieved using ethanol and

sulfuric acid, however in the case of the isopropyl system

analogous conditions led only to isolation of the original

amine, either by hydride migration and hydrolysis of the

intermediate iminium ion, or elimination of methanol and

hydrolysis of the resultant enamine. Fortunately the use of

tri(isopropyl)orthoformate and p-TsOH gave clean acetal

exchange with the desired product (24) isolated in 72% yield.

The nucleophilic cleavage of these acetals was then investi-

gated (Table 2). All nucleophiles reacted eﬃciently to give good

yields of products, however stereocontrol proved to be very

variable, depending on the nature of the nucleophile employed.

Diethylzinc showed the highest selectivity, giving 25 as an

85:15 ratio of diastereoisomers, irrespective of the nature of

the acetal (entries 1, 2 and 4). The more sterically demanding

diisopropylzinc aﬀorded the product 26 with low stereo-

selectivity (entry 5). Disappointingly, other organometallic

reagents such as Grignards and organocuprates also gave only

modest stereocontrol (entries 2, 6 and 7), as was also the case

for the heterocyclic nucleophiles bis(O-trimethylsilyl)uracil and

2-(trimethylsilyloxy)pyridine (entries 8, 9 and 10), and an enam-

ine (entry 11). With indole as nucleophile, the only acetal-

derived product (31) was that where two equivalents of the

Reactions of acetals derived from

(R,R)-(؊)-bis(ꢀ-methylbenzyl)amine

These encouraging preliminary results led us to consider

investigating more complex systems which had greater potential

for stereocontrolled synthesis. As a simple extension to the

above, we decided to synthesise the (R,R)-(Ϫ)-bis(α-methyl-

benzyl)amine derivative 20 which we reasoned may have the

potential for controlling the stereochemistry at the new chiral

centre, particularly if the reaction proceeded via the α-alkoxy

aziridinium ion. Use of the previous methodology (Scheme 2)

for the synthesis of 20 was unsuccessful (<5% yield) along-

side related alternative procedures, presumably due to the very

much greater steric hindrance around the amino group.

Instead, a reductive amination procedure was adopted utilising

commercially available glyoxal-1,1-dimethylacetal, (R,R)-(Ϫ)-

bis(α-methylbenzyl)amine, and sodium triacetoxyborohydride

(Scheme 3).¹³Even in this case, a 3:1 mixture of products was

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

835

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Scheme 3

immediate acetal formation from the crude aldehydes using

ethanol and triethylorthoformate under acid catalysis (Scheme

5). The stereochemical integrity of acetal (35 R = Bn) was con-

ﬁrmed by ¹H NMR using the chiral shift reagent Eu(hfc)₃which

showed that no appreciable racemisation of the intermediate

aldehyde (34 R = Bn) had occurred (e.e. >95%).¹⁸

Scheme 4

indole had added to the acetal (entry 12). This was not

unsurprising considering the known lability of related systems

under Lewis acidic conditions.¹⁴The yield for formation of 31

could be optimised to 64% if ﬁve equivalents of indole were

used. Also formed in this reaction was 2-(3-indolyl)indoline,¹⁵

known by-product of indole dimerisation under acidic reaction

conditions.

a

Scheme 5

These substrates were then subjected to the same reaction

conditions as before. The results of these reactions are shown

in Table 3 and show that all reactions proceed eﬃciently in

good to excellent yields. A number of interesting trends should

also be noted. Firstly, as previously observed, the use of di-

ethylzinc as nucleophile gave the product 36 with the highest

levels of diastereoselectivity; in this case this was the case

irrespective of size of the substituent R (entries 1, 2 and 3).

Secondly, when R is large (Bn, Prⁱ) high levels of selectivity are

obtained, irrespective of the nucleophile (entries 1, 2, 4, 5 and

7). Thirdly, low selectivity is observed with the heterocyclic

nucleophiles with a small R group (Me) in the substrate (entries

6 and 8).

Having obtained appreciable levels of stereocontrol, the

stereochemical assignments for the major products of the reac-

tion became of prime importance. The addition of diethyl zinc

to the aldehyde (34 R = Bn) is reported to give the syn dia-

stereomer 39 as the major product (Scheme 6) on the basis of ¹H

NMR coupling constants in the oxazolidinone product 40.¹⁹

Repeating the preparation of 39 and converting the major

product to the ethyl ether gives 41, which by comparison

of spectroscopic data, was shown to be the minor isomer

formed in our reactions. This leads to the anti assignment for

the major products for the addition of diethyl zinc to acetals 35

(Table 3, entries 1, 2 and 3). The stereochemistry of the uracil

derivative 37 (R = Bn) (Table 3, entry 4) was determined by

X-ray crystallography (Figure 1), which clearly shows the syn

stereochemistry.¹⁰

In the absence of nucleophiles, an interesting cyclisation is

observed, most likely originating from attack of an intermedi-

ate α-oxocarbenium ion (cf. 8) onto the adjacent aromatic

ring to form the tetrahydroisoquinoline 32.¹⁶Interestingly, this

reaction gave the highest diastereoselectivity (80% de) in this

series.

All of the above reactions were carried out at Ϫ78 ЊC; the

temperature was maintained at this level during the addition of

TMSOTf and the nucleophile, then for a further 2–3 h before

gradual warming to room temperature. Studies with the hetero-

cyclic nucleophiles to improve the stereochemical control in the

reaction by altering the length of time before or after the addi-

tion of the nucleophile, showed no signiﬁcant eﬀect. Attempted

initiation of the reaction using TBDMSOTf in place of

TMSOTf simply led to recovery of starting material.

Our results showed that the stereoselectivity of the acetal

cleavage reaction was dependent on the nature of the nucleo-

phile. It was however surprising that changing the nature of the

acetal resulted in no signiﬁcant improvement in selectivity for

either the organometallic (entries 1, 3 and 4) or heterocyclic

(entries 8 and 9) nucleophiles. This suggested a rethink of the

methodology was required if more useful levels of stereocontrol

were going to be realised.

Reaction of ꢀ-aminoacetals derived from chiral

1,2-amino alcohols

Although our early results demonstrated that some stereo-

chemical control was possible, with the exception of reactions

of diethyl zinc, these were generally modest at best. One pos-

sible reason for this may be that the stereocontrolling element is

too remote from the new chiral centre. A potentially more

promising system may be to have stereocontrolling element

adjacent to the developing chiral centre. Thus a further

series of α-aminoacetals were synthesised derived from chiral

1,2-amino alcohols.¹⁷The substrates were synthesised from

the corresponding optically active, commercially available

N,N-dibenzyl-1,2-amino alcohols (33) by Swern oxidation, and

Further evidence for stereochemical assignment comes from

comparison of a range of ¹H NMR chemical shifts of the

products. For all examples where comparative data is avail-

able,²⁰there is a good correlation between the syn and anti

diastereomeric series.

The most remarkable aspect of these stereochemical assign-

ments is that they show that for all the reactions investigated,

the sense of stereoselection is reversed when switching from

diethyl zinc to the nitrogen heterocycles. These intriguing

observations, in keeping with our original aims of the research

(vide supra), allow considerable insight into the nature of the

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

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Table 2 TMSOTf mediated nucleophilic cleavage of acetals derived from bis(α-methylbenzyl)amine

Entry

1

Nucleophile

Et₂

R

Major product

Diast. ratio^a

85 : 15

Yield (%)

67

Me

2

3

4

5

EtMgBr

Et₂Zn

Me

Et

64 : 36

85 : 15

55 : 45

87

73

72

53

Et₂Zn

Prⁱ

Me

Prⁱ₂Zn

6

7

PrⁱMgCl

Bu₂CuLi

Me

62 : 38

77

72

8

Me

55 : 45

85

9

10

Prⁱ

Me

55 : 45

70 : 30

76

82

11

12

Me

13 : 6 : 4 : 2

86

64^b

13

None^c

Me

90 : 10

69

^aConﬁguration of major isomer not determined. ^bFive equivalents of indole used. ^cReaction left for 3 d at rt.

reactive intermediates involved and are worthy of further

mechanistic discussion.

stereoselectivity consistently observed when using diethyl zinc

with a wide variety of acetals are particularly notable (Tables 2

and 3), and suggest that the mechanism of the reaction may

have signiﬁcant diﬀerences to that for other nucleophiles. For

example, it is well established that organozinc reagents are gen-

erally quite unreactive organometallic reagents towards carb-

onyl compounds unless activated by coordination to a tertiary

amine or alkoxide.²²In this case, although the α-oxocarbenium

ion would be expected to be signiﬁcantly more reactive than

simple aldehydes, the organozinc reagent may still require some

degree of activation. It is thus likely that the reaction proceeds

via pre-coordination of the diethyl zinc to the tertiary amine

group within the substrate (e.g. 46, Scheme 7). This leads to an

Mechanistic aspects

The Lewis acid mediated nucleophilic cleavage of acetals is a

reaction of considerable mechanistic and synthetic interest. The

nature of the reactive species involved is determined by an intri-

cate balance of electronic and steric eﬀects, and reaction condi-

tions.²¹Further evidence for this is provided by our own work

described here, where both the nature of the nucleophile and

the substrate substituents can have a signiﬁcant inﬂuence on the

stereochemical outcome of the reaction. The good levels of

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

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Table 3 TMSOTf mediated nucleophilic cleavage of chiral α-amino acetals

Entry

1

R

Nucleophile

Et₂Zn

Major product

Diast. ratio

95 : 5^a

Yield (%)

64

Bn

2

3

Prⁱ

Me

Et₂Zn

93 : 7

94 : 6

61

77

4

Bn

>95 : 5^b

70

5

6

7

Prⁱ

Me

Bn

89 : 11

55 : 45

95 : 5

78

71

89

8

Me

54 : 46

87

^aStereochemical assignment conﬁrmed by comparison with literature (Scheme 1).^{19 b}Stereochemical assignment conﬁrmed by X-ray crystallography

(Figure 1).¹⁰

Scheme 6

selectivity. Importantly, because the nitrogen atom is now

coordinated to zinc, it is no longer able to stabilise the adjacent

cationic centre, and so it would not be expected to be able to

form an α-alkoxy aziridinium ion intermediate (e.g. 45), and the

reaction proceeds via an α-oxocarbenium ion (44). In such a

case, the nature of the acetal groups would be expected to have

minimal eﬀect on selectivity, as they are remote from the react-

ing centre. This is consistent with the reactions of the various

acetals derived from bis(α-methylbenzyl)amine (Table 2) where

almost identical good levels of selectivity were observed with

Et₂Zn irrespective of the size of the acetal group (Me, Et and

Prⁱ). In such a case, an intermediate such as 47 may be expected,

where in addition, coordination of Et₂Zn helps relay the stereo-

chemical information from the otherwise remote chiral centres

on the α-methylbenzylamine moieties to the developing chiral

centre, leading to the reasonable selectivities observed. We have

so far been unable to establish the stereochemical outcome of

these particular reactions, however we do not believe this

detracts signiﬁcantly from the mechanistic discussion.

In the case of the nitrogen heterocycles, the situation would

appear to be signiﬁcantly more complex. Acetals derived from

α-methylbenzylamine (Table 2) show only low selectivity at

best. There are two possible explanations for this. Firstly, there

are two possible diastereomeric α-alkoxy aziridinium ions 48

and 50 (probably equilibrating via a low concentration of the

Fig. 1 X-Ray crystal structure of 37 (R = Bn).

exaggeration of steric eﬀects around the reacting centre and

could also lead to ‘intramolecular’ delivery of the ethyl group,

both of which would be expected to result in increased levels of

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

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Fig. 2 Felkin–Anh model predicts formation of 57 for addition to α-

oxocarbenium ion 54.

selectivity is predominant in the reaction of chiral α-amino

aldehydes with a variety of organometallic nucleophiles.¹⁷

Again, the relative stability of the various possible α-alkoxy

aziridinium ions can be invoked to explain the observations

(Scheme 9). There are two possible isomeric α-alkoxy aziridin-

ium intermediates we can form, the cis (53) and trans (55) iso-

mers, which may be in equilibrium via a small concentration of

the α-oxocarbenium ion (54). Extensive broadening observed

1

during variable temperature H NMR experiments on inter-

mediates derived from 35 (R = Bn) suggest this, but other pro-

cesses such as acetal exchange, which may also be expected to

lead to signiﬁcant broadening, cannot be discounted.

Scheme 7

α-oxocarbenium ion 49), which would, assuming a stereo-

controlled S_N2-like ring opening, each lead to the formation of

one of the possible diastereomeric products, 51 and 52 respect-

ively (Scheme 8). However, it would be expected that the energy

diﬀerence between these two possible intermediates would be

relatively small as the chiral centres in the α-methylbenzylamine

group are rather distant from the new aziridinium chiral centre.

Hence a mixture of the 2 isomeric α-alkoxy aziridinium ions 48

and 50 would be formed, leading to a corresponding mixture of

diastereomeric products 51 and 52. An alternative explanation

is that attack of the external nucleophile occurs directly on the

α-oxocarbenium ion intermediate 49. Such attack would be

remote to any stereocontrolling elements leading to formation

of a mixture of products.

Scheme 9

Similar considerations can be applied to rationalise the more

complex results obtained with the chiral amino acetals 35

described in Table 3. Although the variable levels of selectivity

observed may be expected and are consistent with the size of

the substituents R, the predominant syn stereoselectivity is

unlikely to originate from addition to the α-oxocarbenium ion

54. Indeed, the Felkin–Anh model (Fig. 2) would predict form-

ation of 57, the minor product in all cases, and this is usually

particularly strong for such heteroatom containing systems.²³

Detailed studies by Reetz and others have shown that anti

Stereocontrolled S_N2-like nucleophilic ring opening of the

trans isomer 55 would give the observed syn product, whereas

the cis isomer 53 would give the anti product. For large substi-

tuents (R = Bn, Prⁱ), the cis aziridinium ion 53 would be

expected to be signiﬁcantly less stable than the trans 55 due to a

steric clash between adjacent substituents on the three-mem-

bered ring. This leads to the high syn selectivity observed with

these substituents. The fact that little or no anti product is

formed suggests that direct addition to the α-oxocarbenium ion

Scheme 8

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

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54 does not occur. With smaller substituents (R = Me) there

would be much less diﬀerence in energy between the cis and

trans isomeric aziridinium ions 53 and 55, and hence both

would be present in similar concentrations leading to the

mixtures of products observed.

methylformamide (DMF) were distilled over calcium hydride

before use, and THF was distilled over sodium and benzo-

phenone. Bis(O-trimethylsilyl)uracil,²⁶2-(trimethylsilyloxy)-

pyridine,²⁷and 1-morpholinocyclohexane²⁸were prepared

according to literature procedures.

Although much of the evidence for α-alkoxy aziridinium ions

described here is circumstantial, their intermediacy, particularly

at low temperatures is not unrealistic, and provides what we

believe to be the ﬁrst real evidence for these potentially interest-

ing and useful reactive intermediates. We now aim to exploit

these results further in the stereocontrolled synthesis of

important biologically active molecules.

In summary, we have demonstrated that nucleophilic cleav-

age of acetals induced by TMSOTf can be used to prepare

a wide range of substituted 1,2-aminoethers. In particular,

organometallic reagents, N-heterocycles, and enamines all react

eﬃciently to give products in good yield. In appropriate cases,

good levels of stereocontrol are possible, but this is very

dependent on the nature of the nucleophile and the substrate,

with diethylzinc proving particularly eﬀective. The degree of

stereocontrol can be used to infer the nature of the reactive

intermediates involved in the reaction. With diethylzinc, it is

most likely that the reaction proceeds by addition of a coordin-

ated zinc species to an α-oxocarbenium ion, whereas with

non-coordinating nucleophiles, the stereochemical outcome is

consistent with addition to an α-alkoxy aziridinium ion.

Synthesis and reactions of achiral ꢀ-amino acetals (Scheme 2 and

Table 1)

N,N-Dibenzyl)aminoacetaldehyde diethyl acetal, 13. To a

solution of bromoacetaldehyde diethyl acetal (3.05 ml, 4.00 g,

20.3 mmol) in DMF (30 ml) was added dibenzylamine (3.90 ml,

4.00 g, 20.3 mmol), triethylamine (3.40 ml, 2.46 g, 24.3 mmol)

and potassium iodide (1.68 g, 10.2 mmol). The mixture was

heated at 100 ЊC for 2 d, then water (70 ml) was added, and the

product extracted with diethyl ether (3 × 80 ml), then dried

(Na₂SO₄) and concentrated in vacuo. The product was puriﬁed

by silica gel ﬂash chromatography (eluent: petroleum ether/

ethyl acetate/triethylamine 89 : 10 : 1) to yield the acetal 13 as a

pale yellow oil (3.69 g, 11.8 mmol, 58%). δ_H(400 MHz, CDCl₃),

1.20 (3H, t, J 7.0, OCH₂CH₃), 1.21 (3H, t, J 7.0, OCH₂CH₃),

2.70 (2H, d, J 4.9, NCH₂CH(OEt)₂), 3.48 (2H, dq, J 9.1, 7.0,

OCH₂CH₃), 3.60 (2H, dq, J 9.1, 7.0, OCH₂CH₃), 3.71 (4H, s,

NCH₂Ph), 4.62 (1H, t, J 4.9, CH(OEt)₂), 7.24–7.43 (10H, m,

Ph); δ_C(75 MHz, CDCl₃), 15.3 (OCH₂CH₃), 55.9 (NCH₂CH-

(OEt)₂), 59.0 (NCH₂Ph), 61.8 (OCH₂CH₃), 102.2 (CH(OEt)₂),

126.8 (Ph), 128.1 (Ph), 128.8 (Ph), 139.7 (Ph); IR (neat), ν_max

/

cm^Ϫ12970, 2880, 2791, 1444, 1375, 1112, 1060, 745, 695; MS

(FAB) m/z 313 (M ϩ 1, 15%), 312 (37), 268 (37), 210 (100), 91

(85); Microanalysis: found C 76.8, H 8.5, N 4.35; calculated for

C₂₀H₂₇NO₂: C 76.64, H 8.68, N 4.47.

Experimental section

General procedures and instrumentation

Nuclear magnetic resonance spectra were recorded at 500MHz

for ¹H or 125MHz for ¹³C on a Bruker DRX 500 spectrometer,

or at 300MHz for ¹H or 75MHz for ¹³C on a Bruker DPX 300

(N,N-Diallyl)aminoacetaldehyde diethyl acetal, 15. To a solu-

tion of bromoacetaldehyde diethyl acetal (15.3 ml, 20.0 g, 101

mmol) in DMF (100 ml) was added diallylamine (25.1 ml, 19.7

g, 203 mmol) and potassium iodide (8.47 g, 50.7 mmol). The

mixture was heated at 90 ЊC for 18 h, then water (120 ml) was

added, and the product extracted with diethyl ether (3 × 150

ml). The organic extracts were washed with brine (100 ml), then

dried (Na₂SO₄) and concentrated in vacuo. The product was

puriﬁed by silica gel ﬂash chromatography (eluent: petroleum

ether/ethyl acetate/triethylamine 89 : 10 : 1) to yield the acetal

15 as a pale yellow oil (15.3 g, 71.9 mmol, 71%). δ_H(300 MHz,

CDCl₃), 1.18 (6H, t, J 7.1, (OCH₂CH₃)₂), 2.58 (2H, d, J 5.3,

1

machine. H chemical shifts are expressed in parts per million

(ppm) downﬁeld of tetramethylsilane, and ¹³C chemical shifts

are expressed in ppm referenced to the central peak of the trip-

let of deuterated chloroform (77.0 ppm). All coupling constants

are quoted in hertz (Hz), (multiplicity: s, singlet; d, doublet; t,

triplet; q, quartet; quin, quintet; sept, septet; m, multiplet). 2D

1

COSY spectra were used to assign complex H NMR spectra,

and DEPT and HMQC techniques assisted in the assignment

of ¹³C spectra.

Infrared spectra were recorded on a Nicolet Avatar 360 FT-

IR ESP spectrometer. Only the most signiﬁcant absorptions are

listed. Mass spectra were recorded on a VG Autospec mass

spectrometer for electron impact (EI) and fast atom bombard-

ment (FAB) spectra. Electrospray (ES) spectra were recorded

on a Micromass LCT K111 spectrometer. Molecular ions

are reported as mass with percentage abundance quoted in

brackets. Optical rotations were recorded on an Optical Activ-

ity AA-100 polarimeter as a solution in chloroform with the

concentration quoted in brackets (g (100 ml)^Ϫ1). Melting points

were determined on a Reichert Hot Stage apparatus and are

uncorrected. Microanalyses were carried out at the University

of Leeds Microanalytical laboratory. All C, H and N analytical

ﬁgures are expressed in percentage values of total molecular

weight. HPLC was carried out on a Gynotek GINA50 machine.

Thin layer chromatography (tlc) was carried out using pre-

coated plastic backed silica plates, which were visualized using

ultraviolet light or potassium permanganate stain.²⁴Column

chromatography was carried out on Merck silica gel (230–

400 mesh) unless otherwise stated. Petroleum ether was distilled

in the range 40–60 ЊC.

NCH CH(OEt) ), 3.14 (4H, dt, J 6.5, 1.2, N(CH CH᎐CH ) ),

3.49 (2H, dq, J 9.3, 7.1, (OCH₂CH₃)₂), 3.64 (2H, dq, J 9.3, 7.1,

(OCH₂CH₃)₂), 4.48 (1H, t, J 5.3, CH(OEt)₂), 5.07–5.16 (4H, m,

᎐

2

2 2

N(CH CH᎐CH ) ), 5.77–5.87 (2H, m, N(CH CH᎐CH ) ); δ

᎐

2

C

(75 MHz, CDCl₃), 15.3 ((OCH₂CH₃)₂), 55.5 (NCH₂CH-

(OEt) ), 57.7 (N(CH CH᎐CH ) ), 61.9 (OCH CH ) ), 102.1

᎐

2

3 2

(CH(OEt) ), 117.3 (N(CH CH᎐CH ) ), 135.7 (N(CH CH᎐

᎐

2

CH₂)₂); IR (neat), ν_max/cm^Ϫ12961, 2910, 2880, 2790, 1441, 1418,

1369, 1128, 1057, 1021, 994, 912; MS (EI) m/z 213 (M^ϩ, 1%),

168 (17), 110 (100), 103 (21), 75 (15); Microanalysis: found C

67.4, H 11.0, N 6.6; calculated for C₁₂H₂₃NO₂: C 67.57, H

10.87, N 6.57.

Typical procedure A

(N,N-Dibenzyl)-1-amino-2-ethoxybutane, 16 (R

؍

Bn).

TMSOTf (521 µl, 640 mg, 2.88 mmol) was added to a stirred

solution of (N,N-dibenzyl)aminoacetaldehyde diethyl acetal

(301 mg, 960 µmol) in CH₂Cl₂(7 ml) at Ϫ78 ЊC. The temper-

ature was maintained at –78 ЊC for 30 min, then diethyl zinc

(1.1 M solution in toluene, 1.73 ml, 237 mg, 1.92 mmol) was

added. The mixture was stirred at Ϫ78 ЊC for a further 2 h, then

gradually warmed to room temperature. After 14 h, NaHCO₃

(sat. aq., 20 ml) was added, the product extracted with CH₂Cl₂

(3 × 25 ml), dried (Na₂SO₄) and concentrated in vacuo. The

product was puriﬁed by silica gel ﬂash chromatography (eluent:

petroleum ether/ethyl acetate/triethylamine 96 : 3 : 1), to yield

All reactions were carried out at atmospheric pressure under

a positive pressure of dry, oxygen-free nitrogen. Solvents were

removed under reduced pressure using a Büchi rotary evapor-

ator at water aspirator pressure, followed by drying under

high vacuum at 0.1 Torr. Solvents were puriﬁed before use

using established procedures.²⁵Dichloromethane and N,N-di-

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

840

View Article Online

the ether 16 (R = Bn) as a colourless oil (246 mg, 827 µmol,

86%). δ_H(300 MHz, CDCl₃), 0.75 (3H, t, J 7.4, CH(OEt)-

CH₂CH₃), 1.15 (3H, t, J 7.0, OCH₂CH₃), 1.38 (1H, quin, J 7.1,

CH(OEt)CH₂CH₃), 1.51–1.63 (1H, m, CH(OEt)CH₂CH₃), 2.49

(2H, app. t, J 5.9, NCH₂CH(OEt)Et), 3.29 (1H, quin, J 5.9,

NCH₂CH(OEt)Et), 3.40–3.53 (2H, m, CH(OCH₂CH₃)Et), 3.53

(2H, d, J 13.8, N(CH₂Ph)₂), 3.65 (2H, d, J 13.6, N(CH₂Ph)₂),

7.18–7.38 (10H, m, Ph); δ_C(75 MHz, CDCl₃), 9.9

(CH(OEt)CH₂CH₃), 16.1 (OCH₂CH₃), 25.9 (CH(OEt)CH₂-

CH₃), 57.5 (NCH₂CH(OEt)Et), 59.8 (N(CH₂Ph)₂), 65.1

(OCH₂CH₃), 79.7 (NCH₂CH(OEt)Et), 127.2 (Ph), 128.5 (Ph),

129.3 (Ph), 140.2 (Ph); IR (neat), ν_max/cm^Ϫ12971, 2928, 2874,

2795, 1495, 1453, 1110, 1072, 747, 698; MS (EI) m/z 297 (M^ϩ,

5%), 211 (19), 210 (83), 181 (8), 91 (100); Microanalysis: found

C 80.85, H 9.2, N 4.55; calculated for C₂₀H₂₇NO: C 80.76,

H 9.15, N 4.71.

(uracil–CO), 164.0 (uracil–CO); IR (neat), ν_max/cm^Ϫ12905, 2855,

1661, 1448, 1268, 1240, 1162, 1031; MS (EI) m/z 282 (M^ϩ3,

1%), 279 (0.2), 169 (26), 110 (100), 98 (15), 70 (49).

1-((N,N-Dibenzylamino)-ethoxyethyl)-1H-pyrimidine-2,4-

dione, 17 (R

؍

Bn). Typical procedure B was used with

TMSOTf (537 µl, 659 mg, 2.97 mmol), (N,N-dibenzyl)-

aminoacetaldehyde diethyl acetal (310 mg, 989 µmol) and

bis(O-trimethylsilyl)uracil (380 mg, 1.48 mmol). After 20 h at

ambient temperature, the reaction was worked up as described

and the product puriﬁed by silica gel ﬂash chromatography

(eluent: petroleum ether/ethyl acetate/triethylamine 50 : 49 : 1),

to yield the uracil derivative 17 (R = Bn) as colourless plates (288

mg, 759 µmol, 77%). M.p. 135–138 ЊC; δ_H(300 MHz, CDCl₃),

1.17 (3H, t, J 7.0, OCH₂CH₃), 2.72 (2H, d, J 6.0, NCH₂CH),

3.40 (2H, d, J 13.2, NCH₂Ph), 3.48 (2H, q, J 7.0, OCH₂CH₃),

3.78 (2H, d, J 13.2, NCH₂Ph), 5.49 (1H, d, J 8.1, uracil–CH ),

5.86 (1H, t, J 6.0, NCH₂CH(OEt)N), 6.88 (1H, d, J 8.1, uracil–

CH ), 7.21–7.28 (10H, m, Ph); δ_C(75 MHz, CDCl₃), 15.3

(OCH₂CH₃), 55.9 (NCH₂CH), 59.5 (NCH₂Ph), 65.3 (OCH₂-

CH₃), 83.1 (NCH₂CH(OEt)N), 102.7 (uracil–CH), 127.6 (Ph),

128.8 (Ph), 129.5 (Ph), 139.0 (Ph), 139.8 (uracil–CH), 151.7

(uracil–CO), 164.0 (uracil–CO); IR (nujol mull), ν_max/cm^Ϫ1

2919(s), 2852, 1697, 1683, 1448, 1383, 1257, 1081, 749, 698; MS

(EI) m/z 380 (M ϩ 1, 0.8%), 211 (49), 210 (100), 206 (22), 92

(38), 91 (95), 65 (36); Microanalysis: found C 69.45, H 6.65, N

11.1; calculated for C₂₂H₂₅N₃O₃: C 69.64, H 6.64, N 11.07.

(N,N-Diallyl)-1-amino-2-ethoxybutane 16 (R

؍

allyl). Typical

procedure A was used with TMSOTf (297 µl, 1.64 mmol),

(N,N-diallyl)-aminoacetaldehyde diethylacetal (100 mg, 469

mol) and diethylzinc (1.0 M solution in hexanes, 1.40 ml, 1.40

mmol). The product was puriﬁed by silica gel ﬂash chromato-

graphy (eluent: petroleum ether/ethyl acetate 98 : 2) to yield the

ether 16 (R = allyl) as a colourless oil (60 mg, 305 µmol, 65%);

δ_H(500 MHz, CDCl₃), 0.90 (3 H, t, J 7.2, CH(OEt)CH₂CH₃),

1.18 (3 H, t, J 7.2, OCH₂CH₃), 1.44 (1H, ddq, J 14.2, 7.1 and

7.1, CH(OEt)CH₂CH₃), 1.58 (1H, ddq, J 14.2, 5.1 and 7.1,

CH(OEt)CH₂CH₃), 2.44 (1 H, dd, J 13.3 and 5.8, NCH₂CH-

(OEt)Et), 2.50 (1 H, dd, J 13.3 and 5.8, NCH₂CH(OEt)Et), 3.08

1-((N,N-Diallylamino)ethoxyethyl)-1H-pyridin-2-one, 18 (R

؍

allyl). Typical procedure B was used with TMSOTf (207 µl,

254 mg, 1.14 mmol), (N,N-diallyl)aminoacetaldehyde diethyl

acetal (222 mg, 1.04 mmol), and 2-(trimethylsilyloxy)pyridine

(261 mg, 1.56 mmol). The product was puriﬁed by silica gel

ﬂash chromatography (eluent: petroleum ether/ethyl acetate/

triethylamine 50 : 49 : 1), to yield the pyridone 18 (R = allyl) as a

pale yellow oil (175 mg, 670 µmol, 64%). δ_H(300 MHz, CDCl₃),

1.19 (3H, t, J 7.0, OCH₂CH₃), 2.73 (1H, d, J 3.7, NCH₂CH-

(OEt)N), 2.75 (1H, d, J 4.5, NCH₂CH(OEt)N), 3.17 (4H, dt,

(2 H, dd, J 14.1 and 6.4, N(CH CH᎐CH ) ), 3.15 (2 H, dd,

᎐

2

2 2

J 14.1 and 6.4, N(CH CH᎐CH ) ), 3.28 (1 H, quin. J 5.8,

᎐

2

2 2

CH(OEt)Et), 3.50 (1 H, dq, J 9.3 and 7.0, OCH₂CH₃), 3.57

(1 H, dq, J 9.3 and 7.0, OCH₂CH₃), 5.11 (2 H, dd, J 10.2 and

1.5, N(CH₂CH=CH₂)₂), 5.16 (2 H, dd, J 17.0 and 1.5, N(CH₂-

CH=CH₂)₂), 5.85 (2 H, ddt, J 17.0, 10.2 and 6.4, N(CH₂-

CH=CH₂)₂); δ_C(75 MHz, CDCl₃), 10.1 (CH(OEt)CH₂CH₃),

16.1 (OCH₂CH₃), 26.1 (CH(OEt)CH₂CH₃), 57.1 (NCH₂-

CH(OEt)Et), 58.3 (N(CH CH᎐CH ) ), 65.2 (OCH₂CH₃),

᎐

2

2 2

J 6.4, 1.2, N(CH CH᎐CH ) ), 3.43 (1H, dq, J 9.5, 7.0,

᎐

2

2 2

79.7 (CH(OEt)Et), 117.6 (N(CH₂CH=CH₂)₂), 136.4 N(CH₂-

CH=CH₂)₂); IR (neat) ν_max/cm^Ϫ13079, 2929, 1643; MS (ES) m/z

(%) 198 (100, M^ϩϩ H); Microanalysis: found C 72.8, H 11.65,

N 7.2; calculated for C₁₂H₂₃NO: C 73.0, H 11.75, N 7.1.

OCH₂CH₃), 3.52 (1H, dq, J 9.6, 7.0, OCH₂CH₃), 5.07–5.18

(4H, m, N(CH₂CH=CH₂)₂), 5.66–5.80 (2H, m, N(CH₂-

CH=CH₂)₂), 6.16–6.20 (1H, m, NCH₂CH(OEt)N), 6.23 (1H,

dd, J 6.7, 1.2, py5–CH ), 6.52 (1H, ddd, J 9.1, 1.2, 0.7, py3–

CH ), 7.32 (1H, ddd, J 9.1, 6.5, 2.1, py4–CH ), 7.46 (1H, ddd,

Typical procedure B

J

7.0, 2.1, 0.6, py6–CH ); δ_C(75 MHz, CDCl₃), 15.3

1-((N,N-Diallylamino)ethoxyethyl)-1H-pyrimidine-2,4-dione,

17 (R

؍

allyl). TMSOTf (722 µl, 886 mg, 3.99 mmol) was added

to a stirred solution of (N,N-dibenzyl)aminoacetaldehyde di-

ethyl acetal (709 mg, 3.32 mmol) in CH₂Cl₂(7 ml) at Ϫ78 ЊC.

The temperature was maintained at Ϫ78 ЊC for 30 min, then

bis(O-trimethylsilyl)uracil (1.70g, 6.64 mmol) was added. The

mixture was stirred at Ϫ78 ЊC for a further 2 h, then warmed to

room temperature. After 20 h at ambient temperature, a satur-

ated solution of sodium hydrogen carbonate (20 ml) was added,

the product extracted with CH₂Cl₂(3 × 25 ml), dried (Na₂SO₄)

and concentrated in vacuo. The product was puriﬁed by silica

gel ﬂash chromatography (eluent: petroleum ether/ethyl acetate/

triethylamine 50 : 49 : 1 to ethyl acetate), to yield the uracil

derivative 17 (R = allyl) (696 mg, 2.49 mmol, 75%) as a colour-

less oil. δ_H(300 MHz, CDCl₃), 1.18 (3H, t, J 7.0, OCH₂CH₃),

2.69 (2H, d, J 5.9, NCH₂CH(OEt)N), 3.05 (2H, dd, J 13.9, 6.9,

(OCH₂CH₃), 56.5 (NCH₂CH(OEt)N), 57.9 (N(CH CH᎐

CH₂)₂), 65.3 (OCH₂CH₃), 83.7 (NCH₂CH(OEt)N), 106.1

᎐

2

(py5–CH), 118.0 (N(CH CH᎐CH ) ), 120.9 (py3–CH), 133.1

᎐

2

2 2

(py4–CH), 135.9 (N(CH CH᎐CH ) ), 139.7 (py6–CH), 163.2

᎐

2

2 2

(py2–CO); IR (neat), ν_max/ cm^Ϫ12972, 2895, 2805, 1636, 1579,

1554, 1528, 1250, 1236, 1148, 1135, 1101, 1084, 990, 916, 761;

MS (EI) m/z 262 (M^ϩ, 0.1%), 221 (2), 167 (22), 110 (100).

1-((N,N-Dibenzylamino)-ethoxyethyl)-1H-pyridin-2-one, 18

(R

؍

Bn). Typical procedure B was used with TMSOTf (330 µl,

406 mg, 1.83 mmol), (N,N-dibenzyl)aminoacetaldehyde diethyl

acetal (477 mg, 1.52 mmol), and 2-(trimethylsilyloxy)pyridine

(381 mg, 2.28 mmol). The product was puriﬁed by silica gel

ﬂash chromatography (eluent: petroleum ether/ethyl acetate/

triethylamine 50 : 49 : 1), to yield the pyridone 18 (R = Bn) as a

colourless oil (463 mg, 1.27 mmol, 84%). δ_H(300 MHz, CDCl₃),

1.16 (3H, t, J 7.0, CH₂CH₃), 2.77 (2H, d, J 5.9, 3.2, NCH₂CH),

3.48 (2H, dq, J 9.5, 7.0, CH₂CH₃), 3.55 (2H, d, J 13.6,

NCH₂Ph), 3.77 (2H, d, J 13.6, NCH₂Ph), 6.10 (1H, dt, J 1.1,

5.6, py5–CH ), 6.35 (1H, t, J 5.9, NCH₂CH ), 6.53 (1H, dt, J 9.2,

0.6, py3–CH ), 7.15–7.35 (12H, m, Ph, py4–CH, py6–CH );

δ_C(300 MHz, CDCl₃), 15.4 (OCH₂CH₃), 57.0 (NCH₂CH), 59.1

(NCH₂Ph), 65.2 (OCH₂CH₃), 82.7 (NCH₂CH(OEt)N), 106.3

(py5–CH), 120.9 (py3–CH), 127.3 (Ph), 128.6 (py4–CH),128.8

(Ph), 129.3 (Ph), 133.0 (py6–CH), 139.5 (Ph), 140.5 (py2–CO);

N(CH CH᎐CH ) ), 3.15 (2H, dd, J 13.9, 6.0, N(CH CH᎐

᎐

2

CH₂)₂), 3.51 (2H, q, J 7.0, OCH₂CH₃), 5.08–5.14 (4H, m,

(NCH₂CH=CH₂)₂), 5.63–5.66 (1H, m, NCH₂CH(OEt)N),

5.65–5.81 (2H, m, (NCH₂CH=CH₂)₂), 5.76 (1H, d, J 8.0, uracil–

CH ), 7.34 (1H, d, J 8.0, uracil–CH ), 9.35 (1H, s, br, uracil–

NH ); δ_C(75 MHz, CDCl₃), 15.2 (OCH₂CH₃), 55.6 (NCH₂-

CH(OEt)N), 58.1 (N(CH CH᎐CH ) ), 65.4 (OCH CH ), 83.4

᎐

2

3

(NCH CH(OEt)N), 102.4 (uracil–CH), 118.3 ((N(CH CH᎐

᎐

2

CH ) ), 135.6 (((N(CH CH᎐CH ) ), 140.5 (uracil–CH), 151.6

᎐

2

2 2

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

841

View Article Online

IR (neat), ν_max/cm^Ϫ13050, 3031, 2978, 2920(s), 2801, 1651, 1575,

1535, 1490, 1448, 1370, 1240, 1145, 1095, 1028, 748, 698; MS

(EI) m/z 362 (M^ϩ, 0.4%), 361 (1), 317 (2), 267 (45), 238 (10), 210

(75), 176 (12), 92 (25), 91 (100); Microanalysis: found C 75.5, H

6.95, N 7.3; calculated for C₂₃H₂₆N₂O₂: C 75.61, H 7.12, N 7.6.

(N(CH₂Ph)₂), 127.4 (Ph), 128.6 (Ph), 129.2 (Ph), 136.9 (NCH₂-

CH ), 138.2 (Ph), 139.6 (cyclohexyl–C2), 201.0 (CO); IR (liquid

ﬁlm), ν_max/cm^Ϫ11687, 1615, 1494, 1453, 1143, 1071, 1028, 739,

699; MS (FAB) m/z 320 (M^ϩ1, 78%), 319 (M^ϩ, 31%), 318 (40),

228 (18), 210 (21), 198 (5), 197 (21), 196 (25), 106 (24), 91 (100);

Microanalysis: found C 82.45, H 7.9, N 4.35; calculated for

C₂₂H₂₅NO: C 82.72, H 7.89, N 4.38. The ketone 19 (R = Bn)

(52 mg, 14 µmol, 13%) was also isolated as a colourless oil with

spectroscopic data identical to that reported above.

Typical procedure C

1-(N,N-Dibenzyl)amino-2-(2-oxocyclohexyl)-2-ethoxyethane,

19 (R

؍

Bn). TMSOTf (520 µl, 638 mg, 2.87 mmol) was added

to a stirred solution of (N,N-dibenzyl)aminoacetaldehyde di-

ethyl acetal (300 mg, 957 µmol) in CH₂Cl₂(7 ml) at Ϫ78 ЊC.

The temperature was maintained at Ϫ78 ЊC for 30 min, then

1-morpholinocyclohexene (160 mg, 957 µmol) was added. The

mixture was stirred at Ϫ78 ЊC for a further 2 h, then warmed to

room temperature. After 30 min, water (10 ml) was added and

the mixture stirred vigorously for 40 min, then a saturated solu-

tion of sodium hydrogen carbonate (20 ml) was added, the

product extracted with CH₂Cl₂(3 × 25 ml), dried (Na₂SO₄) and

concentrated in vacuo. The product was puriﬁed by silica gel

ﬂash chromatography (eluent: petroleum ether/ethyl acetate/

triethylamine 89 : 10 : 1), to yield the ketone 19 (R = Bn) as a

colourless oil and an inseparable mixture of two diastereo-

isomers (299 mg, 818 µmol, 86%). HPLC (eluent hexane/

2-propanol) indicated a 78 : 22 mixture of diastereoisomers.

Major diastereoisomer: δ_H(500 MHz, CDCl₃), 1.10 (3H, t,

J 7.0, OCH₂CH₃), 1.30–1.38 (1H, m, cyclohexyl–H6_ax), 1.35–

1.43 (1H, m, cyclohexyl–H5_ax), 1.46–1.50 (1H, m, cyclohexyl–

H6_eq), 1.53–1.63 (1H, m, cyclohexyl–H4_ax), 1.69–1.73 (1H, m,

cyclohexyl–H5_eq), 1.93–1.98 (1H, m, cyclohexyl–H4_eq), 2.22

(1H, dddd, J 14.2, 12.9, 6.1, 1.1, cyclohexyl–H3_ax), 2.36 (1H,

dddd, J 14.2, 4.8, 3.3, 1.6, cyclohexyl–H3_eq), 2.44 (1H, dd,

J 13.0, 5.5, NCH₂CH(OEt)), 2.47 (1H, dd, J 13.0, 7.9, NCH₂-

CH(OEt)), 2.52–2.57 (1H, m, cyclohexyl–H2_ax), 3.43 (2H, d,

J 13.4, N(CH₂Ph)₂), 3.48 (1H, dq, J 9.2, 7.0, OCH₂CH₃), 3.62

(1H, dq, J 9.2, 7.0, OCH₂CH₃), 3.68 (2H, d, J 13.4, N(CH₂-

Ph)₂), 4.07 (1H, ddd, J 8.1, 5.4, 3.4, NCH₂CH(OEt)), 7.20–7.32

(10H, m, N(CH₂Ph)₂); δ_C(125 MHz, CDCl₃), 15.6 (OCH₂CH₃),

24.7 (cyclohexyl–C5), 25.9 (cyclohexyl–C4), 26.8 (1H, m, cyclo-

hexyl–C6), 42.2 (cyclohexyl–C3), 52.0 (cyclohexyl–C1), 54.4

(NCH₂CH(OEt)), 59.3 (N(CH₂Ph)₂), 66.0 (OCH₂CH₃), 73.6

(NCH₂CH(OEt)), 127.0 (Ph), 128.2 (Ph), 129.1 (Ph), 139.5

(Ph), 212.1 (cyclohexyl–C2); Mixture of diastereoisomers: IR

(neat), ν_max/cm^Ϫ11706, 1445, 1266, 1103, 1072, 740, 700; MS

(FAB) m/z 366 (M ϩ 1, 23%), 365 (M^ϩ, 10%), 364 (32), 320 (7),

288 (4), 211 (17), 210 (98), 91 (100); Microanalysis: found C

78.6, H 8.5, N 3.9; calculated for C₂₄H₃₁NO₂: C 78.86, H 8.55,

N 3.83.

(R,R)-(؊)-Bis(ꢀ-methylbenzyl)aminoacetaldehyde dimethyl

acetal, 20. A solution of (R,R)-(Ϫ)-bis(α-methylbenzyl)amine

(4.46 g, 19.8 mmol), sodium triacetoxyborohydride (6.29 g, 29.7

mmol), acetic acid (1.25 ml, 1.31 g, 21.8 mmol) and glyoxal 1,1-

t

dimethyl acetal (45% solution in butylmethyl ether, 13.8 g of

solution, 59.4 mmol) was stirred at ambient temperature for

3 d. Sodium hydroxide solution (2 M, 100 ml) was added, and

the product extracted with CH₂Cl₂(3 × 100 ml), dried (MgSO₄)

and concentrated in vacuo. ¹H NMR indicated an approximate

75 : 25 mixture of ((R,R)-(Ϫ)-bis(α-methylbenzylaminoacet-

aldehyde dimethyl acetal (20) and ((R,R)-(Ϫ)-bis(α-methyl-

benzylaminoacetic acid methyl ester (21). The product was

dissolved in methanol (30 ml) and sodium hydroxide solution

(2M, 5 ml), and heated at 50 ЊC for 16h. The solution was then

concentrated in vacuo, water (10 ml) added, and the product

extracted with diethyl ether (3 × 30 ml), dried (MgSO₄) and

concentrated in vacuo. The product was puriﬁed by silica gel

ﬂash chromatography (eluent petroleum ether/ethyl acetate/

triethylamine 89.5 : 10 : 0.5) to yield the acetal (20) as a colour-

less oil (3.44 g, 11.0 mmol, 55%). [α]_DϪ41.7 (CHCl₃, c 1.2);

δ_H(400 MHz, CDCl₃), 1.39 (6H, d, J 6.9, N(CHCH₃Ph)₂), 2.62

(1H, dd, J 14.7, 4.0, NCH₂CH(OMe)₂), 2.86 (1H, dd, J 14.7,

6.0, NCH₂CH(OMe)₂), 3.10 (3H, s, CH(OCH₃)₂), 3.33 (3H, s,

CH(OCH₃)₂), 4.00 (2H, q, J 6.9, N(CHCH₃Ph)₂), 4.05 (1H, dd,

J 5.9, 4.0, NCH₂CH(OMe)₂), 7.20–7.31 (10H, m, N(CH-

CH₃Ph)₂); δ_C(100 MHz, CDCl₃), 18.3 (N(CHCH₃Ph)₂), 48.6

(NCH₂CH(OMe)₂), 53.3 (CH(OCH₃)₂), 55.1 (CH(OCH₃)₂),

58.1 (N(CHMePh)₂), 106.4 (CH(OCH₃)₂), 126.5 (Ph), 127.9

(Ph), 144.8 (Ph); IR (liquid ﬁlm), ν_max/cm^Ϫ12972, 2933, 2829,

1451, 1126, 1085, 700; HRMS (ES): 314.2113; calculated for

C₂₀H₂₈NO₂: 314.2120; Microanalysis: found C 76.9, H 8.95, N

4.7; calculated for C₂₀H₂₇NO₂: C 76.64, H 8.68, N 4.47.

(R,R)-(؊)-Bis(ꢀ-methylbenzyl)aminoacetaldehyde

diethyl

acetal, 23. A solution of (R,R)-(Ϫ)-bis(α-methylbenzyl) ami-

noacetaldehyde dimethyl acetal (20) (1.23 g, 3.92 mmol) and

conc. sulfuric acid (1 ml) in ethanol (40 ml) was heated at 65 ЊC

for 2 d. The solvent was removed in vacuo, sodium hydroxide

solution (2 M, 100 ml) added, and the product extracted with

diethyl ether (3 × 120 ml), dried (Na₂SO₄) and concentrated in

vacuo. Puriﬁcation by silica gel ﬂash chromatography (eluent:

petroleum ether/ethyl acetate/triethylamine 92.5 : 7 : 0.5) gave

the acetal (23) as a colourless oil (1.13g, 3.32 mmol, 85%). [α]_D

Ϫ40.0 (CHCl₃, c 1.1); δ_H(400 MHz, CDCl₃), 1.09 (3H, t, J 7.0,

OCH₂CH₃), 1.22 (3H, t, J 7.0, OCH₂CH₃), 1.39 (6H, d, J 6.9,

N(CHCH₃Ph)₂), 2.62 (1H, dd, J 14.7, 3.8, NCH₂CH(OEt)₂),

2.92 (1H, dd, J 14.7, 6.2, NCH₂CH(OEt)₂), 3.31 (1H, dq, J 9.1,

7.0, CH(OCH₂CH₃)₂), 3.40 (1H, dq, J 9.1, 7.0, CH(OCH₂-

CH₃)₂), 3.52 (1H, dq, J 9.1, 7.0, CH(OCH₂CH₃)₂), 3.66 (1H, dq,

J 9.1, 7.0, CH(OCH₂CH₃)₂), 3.98 (2H, q, J 6.9, N(CHCH₃Ph)₂),

4.22 (1H, dd, J 3.8, 6.2, NCH₂CH(OEt)₂), 7.18–7.32 (10H, m,

N(CHCH₃Ph); δ_C(100 MHz, CDCl₃), 15.7 (OCH₂CH₃), 15.9

(OCH₂CH₃), 19.1 (N(CHCH₃Ph)₂), 49.9 (NCH₂CH(OEt)₂),

58.6 (N(CHMePh)₂), 62.3 (OCH₂CH₃), 63.9 (OCH₂CH₃),

105.0 (NCH₂CH(OEt)₂), 126.9 (Ph), 128.3 (Ph), 145.3 (Ph); IR

(neat), ν_max/cm^Ϫ12972, 2930, 2886, 1452, 1118, 1070, 700; MS

(ES) m/z 342 (M^ϩ1, 100%), 296 (20), 192 (10); HRMS (ES):

342.2431; calculated for C₂₂H₃₂NO₂: 342.2433; Microanalysis:

found C 77.5, H 8.9, N 4.1; calculated for C₂₂H₃₁NO₂: C 77.38,

H 9.15, N 4.10.

(E )-2-(2-(N,N-Dibenzylamino)ethylidene)cyclohexanone

(Table 1, entry 9). TMSOTf (587 µl, 721 mg, 3.24 mmol) was

added to a stirred solution of (N,N-dibenzyl)aminoacetalde-

hyde diethyl acetal (339 mg, 1.018 mmol) in CH₂Cl₂(7 ml) at

Ϫ78 ЊC. The temperature was maintained at Ϫ78 ЊC for 30 min,

then 1-cyclohexenyloxytrimethylsilane (757 µl, 662 mg, 3.89

mmol) was added. The mixture was stirred at Ϫ78 ЊC for a

further 2 h, then ambient temperature for 3 h. A saturated solu-

tion of sodium hydrogen carbonate (20 ml) was added, and the

product extracted with CH₂Cl₂(3 × 25 ml), dried (Na₂SO₄) and

concentrated in vacuo. The product was puriﬁed by silica gel

ﬂash chromatography (eluent: petroleum ether/ethyl acetate/

triethylamine 92 : 7 : 1) to yield (E)-2-(2-(N,N-dibenzylamino)-

ethylidene)cyclohexanone as a colourless oil (192 mg, 6.01

µmol, 56%). δ_H(500 MHz, CDCl₃), 1.66–1.71 (2H, m, cyclo-

hexyl–H4), 1.80–1.85 (2H, m, cyclohexyl–H5), 2.33–2.36 (2H,

m, cyclohexyl–H3), 2.41 (2H, t, J 6.6, cyclohexyl–H6), 3.12 (2H,

d, J 6.5, NCH₂CH), 3.59 (4H, s, N(CH₂Ph)₂), 6.78 (1H, tt, J 6.5,

2.1, NCH₂CH ), 7.21–7.37 (10H, m, N(CH₂Ph)₂); δ_C(125 MHz,

CDCl₃), 23.7 (cyclohexyl–C4), 23.9 (cyclohexyl–C5), 27.5

(cyclohexyl–C3), 40.6 (cyclohexyl–C6), 51.0 (NCH₂CH), 58.9

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

842

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(R,R)-(؊)-Bis(ꢀ-methylbenzyl)aminoacetaldehyde diisopropyl

acetal, 24. A solution of (R,R)-(Ϫ)-bis(α-methylbenzyl)amino-

acetaldehyde dimethyl acetal (20) (420 mg, 1.34 mmol),

p-toluenesulfonic acid (765 mg, 4.02 mmol) and triisopropyl-

orthoformate (4.36 ml, 5.10 g, 26.8 mmol) in 2-propanol

(50 ml) was heated at 60 ЊC for 3 d. The solvent was removed

in vacuo, then a saturated solution of sodium hydrogen carbon-

ate (30 ml) was added added, and the product extracted with

diethyl ether (3 × 40 ml), dried (Na₂SO₄) and concentrated in

vacuo. The product was puriﬁed by silica gel ﬂash chromato-

graphy (eluent: petroleum ether/ethyl acetate/triethylamine

91.5 : 8 : 0.5) to yield the acetal (24) as a colourless oil (354 mg,

960 µmol, 72%). [α]_DϪ47.7 (CHCl₃, c 1.3); δ_H(500 MHz, CD-

Cl₃), 1.01 (3H, d, J 6.1, OCH(CH₃)₂), 1.08 (3H, d, J 6.1, OCH-

(CH₃)₂), 1.20 (6H, d, J 6.1, OCH(CH₃)₂), 1.38 (6H, d, J 6.9,

N(CH(CH₃)Ph)₂), 2.54 (1H, dd, J 14.8, 3.4, NCH₂CH(OPrⁱ)₂),

2.88 (1H, dd, J 14.8, 6.7, NCH₂CH(OPrⁱ)₂), 3.58 (1H, sept,

J 6.1, OCH(CH₃)₂), 3.83 (1H, sept, J 6.1, OCH(CH₃)₂), 3.98

(2H, q, J 6.9, N(CH(CH₃)Ph)₂), 4.31 (1H, dd, J 6.7, 3.4,

NCH₂CH(OPrⁱ)₂), 7.18–7.32 (10H, m, Ph); δ_C(125 MHz,

CDCl₃), 19.5 (N(CH(CH₃)Ph)₂), 22.9 (OCH(CH₃)₂), 23.1

((OCH(CH₃)₂), 23.5 ((OCH(CH₃)₂), 23.8 ((OCH(CH₃)₂), 51.2

(NCH₂CH(OPrⁱ)₂), 58.8 (N(CH(CH₃)Ph)₂), 68.6 ((OCH-

(CH₃)₂), 69.2 ((OCH(CH₃)₂), 101.7 (NCH₂CH(OPrⁱ)₂), 126.8

(Ph), 128.3 (Ph), 128.4 (Ph), 145.4 (Ph); IR (neat), ν_max/cm^Ϫ1

1452, 1379, 1161, 1130, 1030, 760, 748, 700; MS (FAB) m/z 369

(M^ϩ, 7%), 239 (10), 238 (59), 162 (10), 134 (13), 105 (100);

Microanalysis: found C 77.75, H 9.75, N 3.65; calculated for

C₂₄H₃₅NO₂: C 78.00, H 9.55, N 3.79.

2.72 (1H, dd, J 13.9, 5.8, NCH₂CH(OEt)Et), 2.77–2.83 (1H, m,

NCH₂CH(OEt)Et), 3.36 (1H, dq, J 9.2, 6.9, CH(Et)OCH₂-

CH₃), 3.52 (1H, dq, J 9.2, 6.9, CH(Et)OCH₂CH₃), 3.97 (2H, q,

J 6.9, N(CHCH₃Ph)₂), 7.16–7.30 (10H, m, Ph); δ_C(75 MHz,

CDCl₃), 9.9 (CH(OEt)CH₂CH₃), 16.1 (CH(Et)OCH₂CH₃),

18.1 (N(CHCH₃Ph)₂), 25.3 (CH(OEt)CH₂CH₃), 50.9 (NCH₂-

CH(OEt)Et), 58.7 (CH(OEt)Et), 65.8 (CH(OCH₂CH₃)Et),

81.4 (N(CHCH₃Ph)₂), 127.0 (Ph), 128.3 (Ph), 128.5 (Ph), 145.3

(Ph); Mixture of diastereoisomers: [α]_DϪ12.3 (CHCl₃, c 1.3);

MS (EI) m/z 325 (M^ϩ, 4%), 239 (8), 238 (38), 134 (33), 105

(100); Microanalysis: found C 81.3, H 9.5, N 4.2; calculated for

C₂₂H₃₁NO: C 81.18, H 9.60, N 4.30.

1-((R,R)-(؊)-Bis(ꢀ-methylbenzyl)amino)-2-isopropoxybu-

tane, 25 (R

؍

Prⁱ). Typical procedure A was used with TMSOTf

(395 µl, 485 mg, 2.18 mmol), (R,R)-(Ϫ)-bis(α-methylbenzyl)-

aminoacetaldehyde diisopropyl acetal (269 mg, 728 µmol), and

diethyl zinc (1.1 M solution in toluene, 1.31 ml of solution, 180

mg, 1.45 mmol). The product was puriﬁed by silica gel ﬂash

chromatography (eluent: petroleum ether/ethyl acetate/triethyl-

amine 96.5 : 3 : 0.5) to yield the ether 25 (R = Prⁱ) as a colourless

oil and an inseparable mixture of two diastereoisomers

(178 mg, 523 µmol, 72%, dr 85 : 15 by ¹H NMR). Major

diastereoisomer: δ_H(500 MHz, CDCl₃), 0.57 (3H, t, J 7.4,

CH(OPrⁱ)CH₂CH₃), 0.67–0.76 (1H, m, CH(OPrⁱ)CH₂CH₃),

0.96 (3H, d, J 6.1, OCH(CH₃)₂), 1.08 (3H, d, J 6.1, OCH-

(CH₃)₂), 1.26–1.32 (1H, m, CH(OPrⁱ)CH₂CH₃), 1.41 (6H, d,

J 6.8, N(CHCH₃Ph)₂), 2.33 (1H, dd, J 13.9, 7.7, NCH₂CH-

(OPrⁱ)Et), 2.62 (1H, dd, J 13.9, 5.1, NCH₂CH(OPrⁱ)Et), 2.76–

2.81 (1H, m, CH(OPrⁱ)Et), 3.47 (1H, hept, J 6.1, OCH(CH₃)₂),

3.98 (2H, q, J 6.8, N(CHCH₃Ph)₂), 7.17–7.30 (10H, m, Ph); δ_C

(75 MHz, CDCl₃), 9.6 (CH(OPrⁱ)CH₂CH₃), 17.3 (N(CH-

CH₃Ph)₂), 22.5 (OCH(CH₃)₂), 23.0 (OCH(CH₃)₂), 25.2

(CH(OPrⁱ)CH₂CH₃), 51.3 (NCH₂CH), 58.3 (CH(OPrⁱ)Et),

69.9 (OCH(CH₃)₂), 77.6 (N(CHCH₃Ph)₂), 126.5 (Ph), 127.8

(Ph), 128.1 (Ph), 144.9 (Ph); [α]_DϪ16.0 (CHCl₃, c 1.0); Mixture

of diastereoisomers: IR (neat), ν_max/cm^Ϫ12970, 1452, 1377,

1265, 741, 700; MS (EI) m/z 339 (M^ϩ, 0.4%), 239 (7), 238 (37),

134 (24), 105 (100); Microanalysis: found C 81.2, H 9.6, N 3.95;

calculated for C₂₃H₃₃NO: C 81.37, H 9.80, N 4.13.

((R,R)-(؊)-Bis(ꢀ-methylbenzyl)amino)-2-methoxybutane, 25

(R

؍

Me). Typical procedure A was used with TMSOTf (441

µl, 543 mg, 2.45 mmol), (R,R)-(Ϫ)-bis(α-methylbenzyl)amino-

acetaldehyde dimethyl acetal (20) (255 mg, 814 µmol), and di-

ethyl zinc (1.1 M solution in toluene, 1.61 ml, 1.79 mmol). The

product was puriﬁed by silica gel ﬂash chromatography (eluent:

petroleum ether/ethyl acetate/triethylamine 96.5 : 3 : 0.5), to

give the ether 25 (R = Me) as a colourless oil and an inseparable

mixture of two diastereoisomers (170 mg, 547 µmol, 67%, dr 85

: 15 by ¹H NMR). Major diastereoisomer: δ_H(400 MHz,

CDCl₃), 0.58 (3H, t, J 7.4, CH₂CH₃), 0.90–0.98 (1H, m,

CH(OMe)CH₂CH₃), 1.25–1.33 (1H, m, CH(OMe)CH₂CH₃),

1.41 (6H, d, 6.8, N(CHCH₃Ph)₂), 2.33–2.39 (1H, m, NCH₂-

CH(OMe)Et), 2.69–2.76 (2H, m, NCH₂CH(OMe)Et), 3.28

(3H, s, OCH₃), 3.99 (2H, q, J 6.8, N(CHCH₃Ph)₂), 7.19–

7.30 (10H, m, N(CHCH₃Ph)₂); δ_C(100 MHz, CDCl₃), 9.2

(CH₂CH₃), 17.5 (N(CHCH₃Ph)₂), 24.4 (CH(OMe)CH₂CH₃),

49.8 (NCH₂CH(OMe)Et), 57.8 (CH(OMe)Et), 58.2 (OCH₃),

82.7 (N(CHCH₃Ph)₂), 126.5 (Ph), 127.9 (Ph), 128.1 (Ph),

144.8 (Ph); Mixture of diastereoisomers: [α]_DϪ16.9 (CHCl₃,

c 1.3); IR (neat), ν_max/cm^Ϫ13026, 2969, 2930, 2874, 1494,

1453, 1117, 1088, 741, 698; HRMS (ES): 312.2335; calcu-

lated for C₂₁H₃₀NO: 312.2327; Microanalysis: found C 80.65,

H 9.35, N 4.6; calculated for C₂₁H₂₉NO: C 80.78, H 9.36,

N 4.49.

((R,R)-(؊)-Bis(ꢀ-methylbenzyl)amino)-2-methoxy-3-methyl-

butane, 26 (R

؍

Me). TMSOTf (612 µl, 751 mg, 3.38 mmol)

wasaddedtoastirredsolutionof(R,R)-(Ϫ)-bis(α-methylbenzyl)-

aminoacetaldehyde dimethyl acetal (353 mg, 1.13 mmol) in

CH₂Cl₂(7 ml) at Ϫ78 ЊC. The temperature was maintained at

Ϫ78 ЊC for 30 min. A solution of zinc chloride (45% solution in

CH₂Cl₂, 439 µl, 261 mg, 1.23 mmol) was added to isopropyl

magnesium chloride (2.0 M solution in diethyl ether, 1.24 ml,

2.48 mmol), in CH₂Cl₂(3 ml) at Ϫ78 ЊC and after 10 min was

allowed to warm to rt and stirred for 30 min. The solution of

organozinc reagent was re-cooled to Ϫ78 ЊC then added by

cannula to the above reaction mixture. The mixture was stirred

at Ϫ78 ЊC for a further 3 h, then allowed to warm to rt. After

14 h, a saturated solution of sodium hydrogen carbonate

(20 ml) was added, the product extracted with CH₂Cl₂(3 ×

25 ml), dried (Na₂SO₄) and concentrated in vacuo. The product

was puriﬁed by silica gel ﬂash chromatography (eluent: petrol-

eum ether/ethyl acetate/triethylamine 95.5 : 4 : 0.5), to give the

ether 26 (R = Me) as a colourless oil and an inseparable mixture

of two diastereoisomers (129 mg, 396 µmol, 53%, dr 55 : 45 by

¹H NMR). Major diastereoisomer: δ_H(500 MHz, CDCl₃), 0.45

(3H, d, J 6.8, CH(CH₃)CH₃), 0.77 (3H, d, J 5.2, CH(CH₃)CH₃),

1.41 (6H, d, J 6.8, N(CHCH₃Ph)₂), 1.60–1.64 (1H, m, CH(CH₃)-

CH₃), 2.38–2.43 (1H, m, NCH₂CH(OMe)), 2.70–2.75 (2H, m,

NCH₂CH(OMe)), 3.38 (3H, s, OCH₃), 3.98 (2H, q, J 6.8,

N(CHCH₃Ph)₂), 7.15–7.34 (10H, m, Ph); δ_C(125 MHz,

CDCl₃), 16.0 (CH(CH₃)CH₃), 18.1 (N(CHCH₃Ph)₂), 19.4

(CH(CH₃)CH₃), 29.6 (CH(CH₃)CH₃), 48.0 (NCH₂CH(OMe)),

58.4 (OCH₃), 59.3 (NCH₂CH(OCH₃)), 86.5 (N(CHCH₃Ph)₂),

1-((R,R)-(؊)-Bis(ꢀ-methylbenzyl)amino)-2-ethoxybutane, 25

(R

؍

Et). Typical procedure A was used with TMSOTf (474 µl,

582 mg, 2.62 mmol), (R,R)-(Ϫ)-bis(α-methylbenzyl)amino-

acetaldehyde diethyl acetal (298 mg, 876 µmol), and diethyl zinc

(1.1 M solution in toluene, 1.57 ml, 216 mg, 1.75 mmol). The

product was puriﬁed by silica gel ﬂash chromatography (eluent:

petroleum ether/ethyl acetate/triethylamine 95.5 : 4 : 0.5) to

yield the ether 25 (R = Et) as a colourless oil and an inseparable

mixture of two diastereoisomers (208 mg, 639 µmol, 73%, dr 85

: 15 by ¹H NMR). Major diastereoisomer: δ_H(300 MHz,

CDCl₃), 0.61 (3H, t, J 7.3, CH(OEt)CH₂CH₃), 0.84–0.93 (1H,

m, CH(OEt)CH₂CH₃), 1.13 (3H, t, J 6.9, CH(Et)OCH₂CH₃),

1.22–1.32 (1H, m, CH(OEt)CH₂CH₃), 1.40 (6H, d, J 6.9,

N(CHCH₃Ph)₂), 2.34 (1H, dd, J 13.9, 6.3, NCH₂CH(OEt)Et),

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

843

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126.5 (Ph), 127.9 (Ph), 128.1 (Ph), 145.0 (Ph); Minor diastereo-

isomer: δ_H(500 MHz, CDCl₃), 0.76 (6H, d, J 5.6, CH

(CH₃)CH₃), 1.41 (6H, d, J 6.8, N(CHCH₃Ph)₂), 1.83–1.90 (1H,

m, CH(CH₃)CH₃), 2.59 (1H, dd, J 14.2, 5.7, NCH₂CH(OMe)),

2.73–2.76 (1H, m, NCH₂CH(OMe)), 2.78–2.81 (1H, m, NCH₂-

CH(OMe)), 3.25 (3H, s, OCH₃), 3.95 (2H, q, J 6.8, N(CH-

CH₃Ph)₂), 7.15–7.34 (10H, m, Ph); δ_C(125 MHz, CDCl₃), 16.3

(CH(CH₃)CH₃), 18.2 (N(CHCH₃Ph)₂), 19.8 (CH(CH₃)CH₃),

29.3 (CH(CH₃)CH₃), 47.1 (NCH₂CH(OMe)), 58.4 (OCH₃),

58.8 (NCH₂CH(OCH₃)), 85.8 (N(CHCH₃Ph)₂), 126.4 (Ph),

127.9 (Ph), 128.2 (Ph), 145.0 (Ph); Mixture of diastereoisomers:

[α]_DϪ26.7 (CHCl₃, c 0.3); IR (neat), ν_max/cm^Ϫ12966, 2928,

2874, 1492, 1451, 1370, 1154, 1094, 1060, 1028, 760, 750, 700;

MS (FAB) m/z 326 (M^ϩ, 14%), 324 (8), 239 (16), 238 (87), 134

(20), 105 (100); Microanalysis: found C 80.95, H 9.65, N 4.1;

calculated for C₂₂H₃₁NO: C 81.18, H 9.60, N 4.30.

CH), 102.9 (NCH₂CH(N)OMe), 127.4 (Ph), 128.2 (Ph), 128.6

(Ph), 138.6 (uracil–CH), 143.9 (Ph), 151.6 (uracil–CO), 163.6

(uracil–CO). Minor diastereoisomer: δ_H(300 MHz, CDCl₃),

1.35 (6H, d, J 6.9, N(CHCH₃Ph)₂), 2.76 (1H, dd, J 15.1, 4.4,

NCH₂CH), 2.94 (1H, dd, J 15.1, 6.6, NCH₂CH), 3.17 (3H, s,

OCH₃), 3.97 (2H, q, J 6.9, N(CHCH₃Ph)₂), 5.63 (1H, d, J 8.1,

uracil–CH ), 5.32–5.35 (1H, m, NCH₂CH(N)OMe), 7.13 (1H,

d, J 8.1, uracil–CH ), 7.19–7.33 (10H, m, Ar); δ_C(75 MHz,

CDCl₃), 19.8 (N(CHCH₃Ph)₂), 50.4 (NCH₂CH), 57.1 (OCH₃),

59.4 (N(CHCH₃Ph)₂), 88.1 (uracil–CH), 102.9 (NCH₂CH-

(N)OMe), 127.4 (Ph), 128.2 (Ph), 128.6 (Ph), 139.7 (uracil–

CH), 144.2 (Ph), 151.4 (uracil–CO), 163.5 (uracil–CO). Mixture

of diastereoisomers: mp 50–52 ЊC; [α]_Dϩ23.3 (CHCl₃, c 1.2);

IR (neat), ν_max/cm^Ϫ11758, 1261, 1091, 723, 702; MS (EI) m/z

281 (5%), 239 (6), 238 (31), 105 (100).

1-[(R,R)-(؊)-Bis(ꢀ-methylbenzylamino)isopropoxy-ethyl]-

1H-pyrimidine-2,4-dione, 28 (R

؍

Prⁱ). Typical procedure B was

used with TMSOTf (395 µl, 485 mg, 2.18 mmol), (R,R)-(Ϫ)-

bis(α-methylbenzyl)aminoacetaldehyde dimethyl acetal (269

mg, 728 µmol), and bis(O-trimethylsilyl)uracil (373 mg, 1.46

mmol). The product was puriﬁed by silica gel ﬂash chromato-

graphy (eluent: gradient of petroleum ether/ethyl acetate/

triethylamine 69 : 30 : 1–49 : 50 : 1), to yield the uracil derivative

28 (R = Prⁱ) as an amorphous colourless solid and an insepar-

able mixture of two diastereoisomers (234 mg, 555 µmol, 76%,

dr 55 : 45 by ¹H NMR). Major diastereoisomer: δ_H(500 MHz,

CDCl₃), 0.97 (3H, d, J 6.1, OCH(CH₃)₂), 1.01 (3H, d, J 6.1,

OCH(CH₃)₂), 1.45 (6H, d, J 6.8, N(CHCH₃Ph)₂), 2.68 (1H, dd,

J 14.6, 7.9, NCH₂CH), 2.89 (1H, dd, J 14.6, 4.4, NCH₂CH),

3.41 (1H, hept, J 6.1, OCH(CH₃)₂), 4.04 (2H, q, J 6.8, N(CH-

CH₃Ph)₂), 5.22 (1H, d, J 8.1, uracil–CH ), 5.57 (1H, dd, J 7.8,

4.4, NCH₂CH(N)OPrⁱ), 6.63 (1H, d, J 8.1, uracil–CH ), 7.19–

7.32 (10H, m, Ar), 9.30 (1H, s, br, NH ); δ_C(125 MHz, CDCl₃),

16.4 (N(CHCH₃Ph)₂), 21.3 (OCH(CH₃)₂), 21.4 (OCH(CH₃)₂),

49.5 (NCH₂CH), 57.6 (N(CHCH₃Ph)₂), 70.6 (OCH(CH₃)₂),

81.6 (uracil–CH), 102.3 (NCH₂CH(N)OPrⁱ), 127.0 (Ph), 128.2

(Ph), 128.3 (Ph), 138.5 (uracil–CH), 143.5 (Ph), 151.2 (uracil–

CO), 163.5 (uracil–CO). Minor diastereoisomer: δ_H(500 MHz,

CDCl₃), 1.08 (3H, d, J 6.2, OCH(CH₃)₂), 1.14 (3H, d, J 6.1,

OCH(CH₃)₂), 1.34 (6H, d, J 6.9, N(CHCH₃Ph)₂), 2.71 (1H, dd,

J 15.1, 4.3, NCH₂CH), 2.97 (1H, dd, J 15.1, 7.0, NCH₂CH),

3.57 (1H, hept, J 6.1, OCH(CH₃)₂), 3.92 (2H, q, J 6.9, N(CH-

CH₃Ph)₂), 5.68 (1H, d, J 8.1, uracil–CH ), 5.69–5.73 (1H, m,

NCH₂CH(N)OPrⁱ), 7.20 (1H, d, J 8.1, uracil–CH ), 7.19–7.32

(10H, m, Ar), 9.25 (1H, s, br, NH ); δ_C(125 MHz, CDCl₃), 20.0

(N(CHCH₃Ph)₂), 22.7 (OCH(CH₃)₂), 22.8 (OCH(CH₃)₂), 50.4

(NCH₂CH), 59.1 (N(CHCH₃Ph)₂), 70.8 (OCH(CH₃)₂), 83.7

(uracil–CH), 102.3 (NCH₂CH(N)OPrⁱ), 126.9 (Ph), 127.8 (Ph),

128.3 (Ph), 138.8 (uracil–CH), 143.7 (Ph), 151.1 (uracil–CO),

163.6 (uracil–CO). Mixture of diastereoisomers: mp 50–52 ЊC;

[α]_DϪ16.7 (CHCl₃, c 1.2); IR (neat), ν_max/cm^Ϫ13060, 3029,

2975, 2935, 2873, 1717, 1463, 1071, 919, 762, 727, 701, 648; MS

(EI) m/z 422 (M^ϩ, 0.4%), 239 (37), 238 (86), 141 (17), 134 (64),

106 (38), 105 (100); HRMS (ES): 444.2255; calculated for

C₂₅H₃₁N₃O₃Na: 444.2263.

((R,R)-(؊)-Bis(ꢀ-methylbenzyl)amino)-2-methoxybutane, 27

(R

؍

Me). ⁿButyllithium (1.6M solution in hexanes, 1.7 ml, 270

mmol) was added to a solution of copper() iodide (257 mg,

1.35 mmol) in THF (5 ml), and the mixture was stirred at 0 ЊC

for 45 min. TMSOTf (489 µl, 600 mg, 2.70 mmol) was added to

a stirred solution of (R,R)-(Ϫ)-bis(α-methylbenzyl)amino-

acetaldehyde dimethyl acetal (282 mg, 900 µmol) in CH₂Cl₂

(7 ml) at Ϫ78 ЊC. After 30 min the solution of organocuprate

reagent was added via cannula. The mixture was stirred at

Ϫ78 ЊC for a further 3 h, then allowed to warm to rt. After 18h,

a saturated solution of sodium hydrogen carbonate (20 ml)

was added, the product extracted with CH₂Cl₂(3 × 25 ml),

dried (Na₂SO₄) and concentrated in vacuo. The product was

puriﬁed by silica gel ﬂash chromatography (eluent: petroleum

ether/ethyl acetate/triethylamine 96 : 3 : 1), to give the ether 27

(R = Me) as a colourless oil and an inseparable mixture of two

1

diastereoisomers (220 mg, 648 µmol, 72%, dr 62 : 38 by H

NMR). Major diastereoisomer: δ_H(500 MHz, CDCl₃), 0.89

(3H, t, J 7.2, CH₂CH₃), 1.07–1.17 (2H, m, CH₂CH₃), 1.22–1.30

(3H, m, CH₂CH₂CH₂CH₃), 1.34 (6H, d, 6.9, N(CHCH₃Ph)₂),

1.64–1.71 (1H, m, CH₂CH₂CH₂CH₃), 2.59 (1H, dd, J 14.2, 5.0,

NCH₂CH(OMe)Bu), 2.67 (1H, dd,

J 14.2, 7.4, NCH₂-

CH(OMe)Bu), 2.96–3.00 (1H, m, NCH₂CH(OMe)Bu), 3.24

(3H, s, OCH₃), 3.93 (2H, q, J 6.9, N(CHCH₃Ph)₂), 7.19–7.30

(10H, m, N(CHCH₃Ph)₂); δ_C(125 MHz, CDCl₃), 14.1 (CH₂-

CH₃), 19.2 (N(CHCH₃Ph)₂), 22.9 (CH₂CH₂CH₂CH₃), 27.9

(CH₂CH₂CH₂CH₃), 32.5 (CH₂CH₂CH₂CH₃), 49.2 (NCH₂-

CH(OMe)Bu), 57.4 (NCH₂CH(OMe)Bu), 58.9 (OCH₃), 82.7

(N(CHCH₃Ph)₂), 126.6 (Ph), 127.9 (Ph), 128.0 (Ph), 144.8 (Ph);

Mixture of diastereoisomers: [α]_DϪ66.7 (CHCl₃, c 1.2); IR

(neat), ν_max/cm^Ϫ12967, 2931, 1493, 1452, 1094, 760, 740, 701;

MS (ES) m/z 341 (M ϩ 2, 38%), 340 (M ϩ 1, 100%), 236 (90);

Microanalysis: found C 81.2, H 9.95, N 4.1; calculated for

C₂₃H₃₃NO: C 81.37, H 9.80, N 4.13.

1-[(R,R)-(؊)-Bis(ꢀ-methylbenzylamino)methoxyethyl]-1H-

pyrimidine-2,4-dione, 28 (R

؍

Me). Typical procedure B was

used with TMSOTf (288 µl, 353 mg, 1.59 mmol), (R,R)-(Ϫ)-

bis(α-methylbenzyl)aminoacetaldehyde dimethyl acetal (166

mg, 530 µmol), and bis(O-trimethylsilyl)uracil (272 mg, 1.06

mmol). The product was puriﬁed by silica gel ﬂash chromato-

graphy (eluent: gradient of petroleum ether/ethyl acetate/

triethylamine 69 : 30 : 1–49 : 50 : 1), to give the uracil derivative

28 (R = Me) as an amorphous colourless solid and an insepar-

able mixture of two diastereoisomers (178 mg, 452 µmol, 85%,

dr 55 : 45 by ¹H NMR). Major diastereoisomer: δ_H(300 MHz,

CDCl₃), 1.45 (6H, d, J 6.9, N(CHCH₃Ph)₂), 2.72 (1H, dd,

J 14.5, 8.0, NCH₂CH), 2.96 (1H, dd, J 14.5, 4.2, NCH₂CH),

3.08 (3H, s, OCH₃), 4.05 (2H, q, J 6.9, N(CHCH₃Ph)₂), 5.23

(1H, d, J 8.1, uracil–CH ), 5.35–5.38 (1H, m, NCH₂CH-

(N)OMe), 6.51 (1H, d, J 8.1, uracil–CH ), 7.19–7.33 (10H, m,

Ar); δ_C(75 MHz, CDCl₃), 16.1 (N(CHCH₃Ph)₂), 49.1

(NCH₂CH), 56.8 (OCH₃), 57.5 (N(CHCH₃Ph)₂), 85.6 (uracil–

1-[(R,R)-(؊)-Bis(ꢀ-methylbenzylamino)-methoxyethyl]-1H-

pyridine-2-one, 29 (R

؍

Me). Typical procedure B was used with

TMSOTf (471 µl, 579 mg, 2.60 mmol), (R,R)-(Ϫ)-bis(α-

methylbenzyl)aminoacetaldehyde dimethyl acetal (272 mg,

868 µmol), and 2-trimethylsilyloxypyridine (0.3 ml, 290 mg,

1.74 mmol). The product was puriﬁed by silica gel ﬂash chrom-

atography (eluent: petroleum ether/ethyl acetate/triethylamine

69 : 30 : 1), to give the pyridone 29 (R = Me) as a colourless

amorphous solid and an inseparable mixture of two diastereo-

1

isomers (268 mg, 713 µmol, 82%, dr 70 : 30 by H NMR).

Major diastereoisomer: δ_H(400 MHz, CDCl₃), 1.45 (6H, d,

J 6.9, N(CHCH₃Ph)₂), 2.76 (1H, dd, J 14.2, 6.2, NCH₂CH-

(py)OMe), 3.04 (1H, dd, J 14.2, 6.5, NCH₂CH(py)OMe), 3.17

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

844

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(3H, s, OCH₃), 4.03 (2H, q, J 6.9, N(CHCH₃Ph)₂), 5.94 (1H, t, J

6.2, NCH₂CH(py)OMe), 5.97 (1H, t, J 6.6, py5–CH ), 6.50 (1H,

d, J 9.1, py3–CH ), 6.97, (1H, d, J 6.9, py4–CH ), 7.16–7.19 (1H,

m, py6–CH ), 7.19–7.35 (10H, m, Ar); δ_C(100 MHz, CDCl₃),

18.0 (N(CHCH₃Ph)₂), 49.9 (NCH₂CH(py)OMe), 58.0 (OCH₃),

59.1 (N(CHCH₃Ph)₂), 85.9 (NCH₂CH(N)OMe), 106.4 (py5–

CH), 120.9 (py3–CH), 127.0 (Ph), 128.1 (Ph), 128.3 (Ph), 132.4

(py4–CH), 139.5 (py6–CH), 144.7 (Ph), 163.4 (py2–CO). Minor

diastereoisomer: δ_H(400 MHz, CDCl₃), 1.35 (6H, d, J 6.9,

N(CHCH₃Ph)₂), 2.74 (1H, dd, J 14.2, 6.2, NCH₂CH(N)OMe),

3.01 (1H, dd, J 14.2, 6.5, NCH₂CH(N)OMe), 3.23 (3H, s,

OCH₃), 3.96 (2H, q, J 6.9, N(CHCH₃Ph)₂), 5.94 (1H, t, J 6.2,

NCH₂CH(N)OMe), 6.18 (1H, t, J 6.7, py5–CH ), 6.56 (1H, d,

J 9.1, py3–CH ), 7.33, (1H, d, J 7.2, py4–CH ), 7.15–7.17 (1H,

m, py6–CH ), 7.19–7.35 (10H, m, Ar). δ_C(100 MHz, CDCl₃),

20.2 (N(CHCH₃Ph)₂), 51.0 (NCH₂CH(py)OMe), 57.2 (OCH₃),

59.1 (N(CHCH₃Ph)₂), 85.9 (NCH₂CH(N)OMe), 106.4 (py5–

CH), 121.3 (py3–CH), 127.0 (Ph), 128.1 (Ph), 128.3 (Ph), 132.5

(py4–CH), 139.5 (py6–CH), 144.8 (Ph), 163.4 (py2–CO). Mix-

ture of diastereoisomers: mp 107–110 ЊC; [α]_D–45.5 (CHCl₃, c

1.1); IR (neat), ν_max/cm^Ϫ12921, 2853, 1660, 1588, 1538, 1461,

1377; HRMS (ES): 377.2212; calculated for C₂₄H₂₉N₂O₂:

377.2229; Microanalysis: found C 76.6, H 7.5, N 7.5; calculated

for C₂₄H₂₈N₂O₂: C 76.56, H 7.50, N 7.44.

(Ar), 119.2 (Ar), 119.5 (Ar), 120.0 (Ar), 120.1 (Ar), 121.8 (Ar),

122.1 (Ar), 122.4 (Ar), 122.8 (Ar), 126.7 (Ar), 127.6 (Ar), 127.9

(Ar), 128.1 (Ar), 128.7 (Ar), 136.6 (Ar), 136.9 (Ar), 145.2 (Ar),

145.3(Ar); IR (neat), ν_max/cm^Ϫ13418, 1455, 740, 701; MS (ES)

m/z 485 (M ϩ 2, 12%), 484 (M ϩ 1, 100%).

3-(2-Indolyl)indole (174 mg, 744 µmol) was also isolated.²⁹

δ_H(300 MHz, CDCl₃), 3.21 (1H, dd, J 15.6, 8.3, NCHCH₂),

3.48 (1H, dd, J 15.6, 9.1, NCHCH₂), 5.26 (1H, t, J 8.6,

NCHCH₂), 6.67 (1H, d, J 7.7, indoleC2H ), 6.75 (1H, t, J 7.4,

Ar), 7.05–7.25 (5H, m, Ar), 7.36 (1H, d, J 8.1, Ar), 7.59 (1H,

dd, J 7.9, 0.5, Ar), 7.99 (1H, s, br, NH); δ_C(75 MHz, CDCl₃),

38.1 (NCHCH₂), 56.8 (NCHCH₂), 109.6 (Ar), 111.7 (Ar),

119.2 (Ar), 119.8 (Ar), 119.9 (Ar), 120.0 (Ar), 121.6 (Ar), 122.7

(Ar), 125.1 (Ar), 126.2 (Ar), 127.9 (Ar), 129.3 (Ar), 137.1 (Ar),

151.3 (Ar); IR (neat), ν_max/cm^Ϫ13413, 1607, 1484, 1463, 1422,

1245, 1229, 1152 (m), 1096, 1034, 1011, 905, 742, 701; MS (ES)

m/z 236 (M ϩ 2, 11%), 235 (M ϩ 1, 100%).

4-Methoxy-1R-methyl-2-((R)-ꢀ-methylbenzyl)-1,2,3,4-tetra-

hydroisoquinoline, 32 (R

؍

Me). TMSOTf (728 µl, 893 mg, 4.02

mmol) was added to a stirred solution of (R,R)-(Ϫ)-bis(α-

methylbenzyl)aminoacetaldehyde dimethyl acetal (252 mg, 804

µmol) in CH₂Cl₂(7 ml) at Ϫ78 ЊC. The mixture was stirred at

Ϫ78 ЊC for 3 h then rt for 3 d. After 14 h, a saturated solution of

sodium hydrogen carbonate (20 ml) was added, the product

extracted with CH₂Cl₂(3 × 25 ml), dried (Na₂SO₄) and concen-

trated. The product was puriﬁed by silica gel ﬂash chromato-

graphy (eluent: petroleum ether/ethyl acetate/triethylamine

92.5 : 7 : 0.5), to give the tetrahydroisoquinoline 32 (R = Me) as a

colourless oil and an inseparable mixture of two diastereo-

2-[2-(R,R)-(؊)-Bis(ꢀ-methylbenzylamino)-1-methoxyethyl]-

cyclohexanone, 30 (R

؍

Me). Typical procedure C was used

with TMSOTf (612 µl, 751 mg, 3.38 mmol), ((R,R)-(Ϫ)-bis(α-

methylbenzyl)aminoacetaldehyde dimethyl acetal (353 mg, 1.13

mmol), and 1-morpholinocyclohexene (283 mg, 1.70 mmol).

The product was puriﬁed by silica gel ﬂash chromatography

(eluent: petroleum ether/ethyl acetate/triethylamine 89.5 : 10 :

0.5), to give the ketone (30) R = Me as a colourless liquid (299

mg, 818 µmol, 86%) and a 13 : 6 : 4 : 2 mixture of diastereo-

isomers. Major diastereoisomer: δ_H(500 MHz, CDCl₃), 0.96–

0.99 (1H, m, cyclohexyl-H5_ax), 1.46 (6H, d, J 6.9, N(CH-

(CH₃)Ph)₂), 1.53–1.58 (1H, m, cyclohexyl-H6_ax), 1.81–1.88 (1H,

m, cyclohexyl-H5_eq), 1.91–1.97 (1H, m, cyclohexyl-H4_ax), 2.02–

2.08 (1H, m, cyclohexyl-H6_eq), 2.11–2.16 (1H, m, cyclohexyl-

H4_eq), 2.27–2.31 (1H, m, cyclohexyl-H3_ax), 2.30–2.35 (1H, m,

cyclohexyl-H3_eq), 2.53 (1H, dd, J 14.1, 4.9, NCH₂CH(OMe)),

2.73 (1H, dd, J 14.1, 8.5, NCH₂CH(OMe)), 2.59–2.63 (1H, m,

cyclohexyl-H2_ax), 3.73–3.76 (1H, m, NCH₂CH(OMe)), 3.25

(3H, s, OCH₃), 4.02 (2H, q, J 6.9, N(CHMePh)₂), 7.18–7.30

(10H, m, N(CHMePh)₂); Mixture of diastereoisomers: IR

(neat), ν_max/cm^Ϫ11708, 1450, 1101, 761(s), 752, 701; MS (FAB)

m/z 379 (M^ϩ, 31%), 378 (35), 302 (14), 238 (30), 105 (100).

1

isomers (156 mg, 556 µmol, 69%, dr 90 : 10 by H NMR).

Major diastereoisomer: δ_H(500 MHz, CDCl₃), 1.29 (3H, d, J

6.7, NCH(CH₃)Ph), 1.44 (3H, d, J 6.5, NCH(CH₃)Ar), 2.77

(1H, dd, J 13.5, 3.1, NCH₂CHOMe), 2.96 (1H, dd, J 13.5, 2.1,

NCH₂CHOMe), 3.20 (3H, s, OCH₃), 3.82 (1H, q, J 6.5, NCH-

(CH₃)Ar), 4.02 (1H, t, J 2.8, NCH₂CHOMe), 4.37 (1H, q, J 6.7,

NCH(CH₃)Ph), 7.08–7.46 (9H, m, Ar). δ_C(125 MHz, CDCl₃),

15.4 (NCH(CH₃)Ph), 20.6 (NCH(CH₃)Ar), 43.0 (NCH₂-

CHOMe), 53.1 (OCH₃), 56.6 (NCH(CH₃)Ar), 60.1 (NCH-

(CH₃)Ph), 75.7 (NCH₂CHOMe), 126.3 (Ar), 126.8 (Ar), 127.1

(Ar), 127.6 (Ar), 127.7 (Ar), 128.3 (Ar), 129.8 (Ar), 134.0 (Ar),

141.4 (Ar), 146.2 (Ar); Mixture of diastereoisomers: [α]_DϪ46.2

(CHCl₃, c 1.3); IR (neat), ν_max/cm^Ϫ11491, 1452, 1087, 1060, 757,

701; MS (FAB) m/z 282 (M^ϩ1, 41%), 239 (M^ϩ, 23%), 280 (56),

267 (21), 266 (100), 250 (20), 146 (25), 105 (88); Microanalysis:

found C 80.8, H 8.35, N 4.9; calculated for C₁₉H₂₃NO: C 81.10,

H 8.24, N 4.98.

[2,2-Bis-(1H-indol-3-yl)ethyl]-[(R,R)-(؊)-bis(ꢀ-methyl-

Typical procedure D

benzylamine] 31. TMSOTf (409 µl, 502 mg, 2.26 mmol) was

added to a stirred solution of (R,R)-(Ϫ)-bis(α-methylbenzyl)-

aminoacetaldehyde dimethyl acetal (236 mg, 753 µmol) in

CH₂Cl₂(7 ml) at Ϫ78 ЊC. The temperature was maintained at

Ϫ78 ЊC for 30 min, then indole (441 mg, 3.77 mmol) added. The

mixture was stirred at Ϫ78 ЊC for a further 3h, then allowed to

warm to rt. After 14 h, a saturated solution of sodium hydrogen

carbonate (20 ml) was added, the product extracted with

CH₂Cl₂(3 × 25 ml), dried (Na₂SO₄) and concentrated in vacuo.

The product was puriﬁed by silica gel ﬂash chromatography

(eluent: gradient of petroleum ether/ethyl acetate/triethylamine

79 : 20 : 1–69 : 30 : 1 to ethyl acetate), to give the bis-indole 31 as

colourless plates (234 mg, 483 µmol, 64%). M.p. 78–81 ЊC;

δ_H(300 MHz, CDCl₃), 1.37 (6H, d, J 6.9, N(CHCH₃Ph)₂), 3.21

(1H, dd, J 13.4, 8.3, NCH₂CH), 3.51 (1H, dd, J 13.4, 6.3,

NCH₂CH), 4.07 (2H, q, J 6.9, N(CHCH₃Ph)₂), 4.62–4.68 (1H,

m, NCH₂CH ), 6.40 (1H, d, J 2.2, indole-C2H), 6.76 (1H, d,

J 2.3, indole-C2H), 7.05–7.35 (18H, m, Ar), 7.68 (1H, s, indole-

NH), 7.78 (1H, s, indole-NH); δ_C(75 MHz, CDCl₃), 16.5

(N(CHCH₃Ph)₂), 34.2 (NCH₂CH), 51.0 (NCH₂CH), 56.6

(N(CHCH₃Ph)₂), 111.1 (indole-C2), 111.6 (indole-C2), 118.2

(S )-2-(N,N-Dibenzyl)amino-3-phenylpropanal diethyl acetal,

35 (R

؍

Bn).³⁰A solution of dimethyl sulfoxide (3.20 ml, 3.52g,

45.1 mmol) in CH₂Cl₂(10 ml) was added dropwise over 3 min to

a stirred solution of oxalyl chloride (1.97 ml, 2.86g, 22.6 mmol)

in CH₂Cl₂(50 ml) at Ϫ61ЊC (cardice/chloroform bath). After

5 min of stirring, a solution of-2-(N,N-dibenzylamino)-3-

phenyl-1-propanol (6.80g, 20.5 mmol) in CH₂Cl₂(25 ml) was

added dropwise over 5 min. After a further 30 min, triethyl-

amine (14.3 ml, 10.4g, 103 mmol) was added, and the mixture

stirred for 1 h at Ϫ61 ЊC, then 2 h at ambient temperature.

Water (120 ml) was added, and the aqueous layer extracted with

CH₂Cl₂(3 × 100 ml). Combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo, to yield-2-(N,N-dibenzyl-

amino)-3-phenylpropanal 34 (R = Bn) (6.15g, 18.7 mmol, 91%).

The crude aldehyde was added to a solution of triethyl ortho-

formate (34.1 ml, 30.4g, 205 mmol), HCl (1.0M solution in

diethyl ether, 45.1 ml, 45.1 mmol) and concentrated sulfuric

acid (0.5 ml) in ethanol (100 ml). The solution was stirred at

ambient temperature for 2 d. A saturated solution of sodium

hydrogen carbonate (150 ml) was added and the product

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

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extracted with diethyl ether (3 × 150 ml), dried (Na₂SO₄) and

concentrated in vacuo. The product was puriﬁed by silica gel

ﬂash chromatography chromatography (eluent: petroleum

ether/ethyl acetate/triethylamine 89.5 : 10 : 0.5) to give the

acetal³⁰35 (R = Bn) (7.11g, 17.6 mmol, 94%) as a colourless oil.

[α]_DϪ17.8 (CHCl₃, c 0.9); δ_H(400 MHz, CDCl₃), 1.20 (6H, t,

J 7.1, OCH₂CH₃), 2.88 (1H, dd, J 14.2, 9.3, NCH(CH₂Ph)),

2.93 (1H, dd, J 14.2, 4.7, NCH(CH₂Ph)), 3.10 (1H, quin, J 4.6,

NCH(CH₂Ph), 3.37 (1H, dq, J 9.2, 7.1, CH(OCH₂CH₃)₂), 3.50

(1H, dq, J 9.2, 7.1, CH(OCH₂CH₃)₂), 3.58 (1H, dq, J 9.2, 7.1,

CH(OCH₂CH₃)₂), 3.69 (1H, dq, J 9.2, 7.1, CH(OCH₂CH₃)₂),

3.74 (2H, d, J 13.9, N(CH₂Ph)₂), 3.78 (2H, d, J 13.9, N(CH₂-

Ph)₂), 4.58 (1H, d, J 4.3, CH(OEt)₂), 7.08–7.25 (15H, m, Ph); δ_C

(100 MHz, CDCl₃), 23.0 (OCH₂CH₃), 23.2 (OCH₂CH₃), 40.3

(NCH(CH₂Ph)), 62.1 (NCH(CH₂Ph)), 67.9 (N(CH₂Ph)₂), 70.7

(OCH₂CH₃), 70.8 (OCH₂CH₃), 112.6 (CH(OEt)₂), 133.2 (Ph),

134.2 (Ph), 135.6 (Ph), 136.4 (Ph), 137.3 (Ph), 148.1 (Ph), 148.7

(Ph); IR (neat), ν_max/cm^Ϫ13026, 2974, 2927, 2871, 1495, 1453,

1118, 1061, 744, 698; HRMS (ES): 404.2583; calculated for

C₂₇H₃₄NO₂: 404.2589; Microanalysis: found C 80.3, H 8.25, N

3.2; calculated for C₂₇H₃₃NO₂: C 80.36, H 8.24, N 3.47.

(CH(OEt)₂), 126.6 (Ph), 128.1 (Ph), 128.7 (Ph), 140.8 (Ph); IR

(neat), ν_max/cm^Ϫ12974, 1494, 1454, 1375, 1122, 1099, 1059,

1025, 747, 734, 699; MS (FAB) m/z 327 (M^ϩ, 6%), 326 (24), 282

(21), 225 (20), 224 (100), 91 (96); Microanalysis: found C 77.05,

H 8.9, N 4.25; calculated for C₂₁H₂₉NO₂: C 77.03, H 8.93, N

4.28.

(2S,3R)-2-(N,N-Dibenzyl)amino-3-ethoxy-1-phenylpentane,

36 (R

؍

Bn). Typical procedure A was used with TMSOTf (293

µl, 360 mg, 1.62 mmol), Ϫ2-(N,N-dibenzylamino)-3-phenyl-

propanal diethyl acetal (218 mg, 540 µmol), and diethyl zinc

(1.1M solution in toluene, 272 µl, 133 mg, 1.08 mmol). The

product was puriﬁed by silica gel ﬂash chromatography (eluent:

petroleum ether/ethyl acetate/triethylamine 96.5 : 3 : 0.5) to

yield the ether 36 (R = Bn) as a colourless oil and an inseparable

mixture of two diastereoisomers (134 mg, 346 µmol, 64%, dr 95

: 5 by ¹H NMR). Major diastereoisomer: δ_H(400 MHz, CDCl₃),

0.71 (3H, t, J 7.4, CH(OEt)CH₂CH₃), 1.17 (3H, t, J 7.2,

OCH₂CH₃), 1.43–1.55 (1H, m, CH(OEt)CH₂CH₃), 1.45–1.56

(1H, m, CH(OEt)CH₂CH₃), 2.89 (1H, dt, 2.7, 12.3, NCH-

BnCH), 2.95 (1H, dd, J 8.6, 5.2, NCH(CH₂Ph), 2.99 (1H, dd,

J 8.6, 12.3, NCH(CH₂Ph), 3.39–3.49 (2H, m, OCH₂CH₃), 3.57–

3.64 (1H, m, CH(OEt)Et), 3.56 (2H, d, J 14.1, N(CH₂Ph)₂),

3.79 (2H, d, J 14.1, N(CH₂Ph)₂), 7.11–7.34 (15H, m, Ph);

δ_C(100 MHz, CDCl₃), 10.1 (CH(OEt)CH₂CH₃), 15.8 (OCH₂-

CH₃), 24.7 (CH(OEt)CH₂CH₃), 32.3 (NCH(CH₂Ph), 54.3

(N(CH₂Ph)₂), 60.9 (NCHBnCH), 64.8 (OCH₂CH₃), 80.9

(CH(OEt)Et), 125.5 (Ph), 126.5 (Ph), 128.0 (Ph), 128.7 (Ph),

129.2 (Ph), 129.7 (Ph), 140.3 (Ph), 141.8 (Ph); mixture of

diastereoisomers (95 : 5): [α]_DϪ14.3 (CHCl₃, c 1.4); IR (neat),

ν_max/cm^Ϫ12970, 2933, 1452, 1101, 1088, 700; HRMS (ES):

388.2630; calculated for C₂₇H₃₄NO: 388.2640; Microanalysis:

found C 83.35, H 8.55, N 3.8; calculated for C₂₇H₃₃NO: C

83.74, H 8.59, N 3.62.

(S )-2-(N,N-Dibenzyl)amino-3-methylbutanal diethyl acetal,

35 (R

؍

Prⁱ). Typical procedure D was used with dimethyl

sulfoxide (2.70 ml, 2.96 g, 37.8 mmol), oxalyl chloride (1.65

ml, 2.40 g, 18.9 mmol),-2-(N,N-dibenzyl)amino-3-methyl-1-

butanol (4.89 g, 17.2 mmol), triethylamine (12.0 ml, 8.70 g, 86.0

mmol), triethyl orthoformate (28.6 ml, 25.5g, 172 mmol), and

concentrated sulfuric acid (2.8 ml). The product was puriﬁed by

silica gel ﬂash chromatography (eluent: petroleum ether/ethyl

acetate/triethylamine 89.5 : 10 : 0.5) to yield the acetal 35

(R = Prⁱ) as a colourless oil (4.55g, 12.8 mmol, 75%). [α]_DϪ42.7

(CHCl₃, c 1.5); δ_H(500 MHz, CDCl₃) 0.83 (3H, d, J 6.7, NCH-

CH(CH₃)₂), 0.98 (3H, d, J 6.8, NCHCH(CH₃)₂), 1.23 (3H, t,

J 7.0, OCH₂CH₃), 1.25 (3H, t, J 7.0, OCH₂CH₃), 1.99–2.07 (1H,

m, NCHCH(CH₃)₂), 2.45 (1H, dd, J 7.2, 4.5, NCHCH(CH₃)₂),

3.44 (1H, dq, J 9.2, 7.0, CH(OCH₂CH₃)₂), 3.53 (1H, dq, J 9.2,

7.0, CH(OCH₂CH₃)₂), 3.67 (1H, dq, J 9.2, 7.0, CH(OCH₂-

CH₃)₂), 3.69 (1H, dq, J 9.2, 7.0, CH(OCH₂CH₃)₂), 3.71 (2H, d,

J 13.7, N(CH₂Ph)₂), 3.91 (2H, d, J 13.7, N(CH₂Ph)₂), 4.69 (1H,

d, J 4.5, CH(OEt)₂), 7.18–7.38 (10H, m, Ph); δ_C(125 MHz,

CDCl₃), 15.5 (NCHCH(CH₃)₂), 15.6 (NCHCH(CH₃)₂) 20.8

(OCH₂CH₃), 20.9 (OCH₂CH₃), 27.4 (NCHCH(CH₃)₂), 55.7

(N(CH₂Ph)₂), 62.9 (OCH₂CH₃), 63.2 (NCHCH(CH₃)₂), 63.3

(OCH₂CH₃), 104.7 (CH(OEt)₂), 126.6 (Ph), 128.0 (Ph), 129.2

(Ph), 141.0 (Ph); IR (neat), ν_max/cm^Ϫ12974, 2924, 2870, 1494,

1454, 1373, 1165, 1123, 749, 698; MS (EI) m/z 355 (M^ϩ, 0.1%),

253 (26), 252 (100), 91 (98); Microanalysis: found C 77.45, H

9.4, N 3.65; calculated for C₂₃H₃₃NO₂: C 77.70, H 9.36, N 3.94.

(3S,4R)-3-(N,N-Dibenzyl)amino-4-ethoxy-1-methylhexane,

36 (R

؍

Prⁱ). Typical procedure A was used with TMSOTf

(501 µl, 615 mg, 2.77 mmol),-2-(N,N-dibenzyl)amino-3-methyl-

butanal diethyl acetal (328 mg, 922 µmol), and diethyl zinc

(1.1M solution in toluene, 1.7 ml, 228 mg, 1.84 mmol). The

product was puriﬁed by silica gel ﬂash chromatography (eluent:

petroleum ether/ethyl acetate/triethylamine 96.5 : 3 : 0.5) to

yield the ether 36 (R = Bn) as a colourless oil and an inseparable

mixture of two diastereoisomers (192 mg, 566 µmol, 61%,

1

dr 93 : 7 by H NMR). Major diastereoisomer: δ_H(500 MHz,

CDCl₃) 0.76 (3H, t, J 7.5, CH(OEt)CH₂CH₃), 0.95 (3H, d,

J 6.7, NCHCH(CH₃)₂), 1.07 (3H, d, J 6.8, NCHCH(CH₃)₂),

1.17 (3H, t, J 7.0, OCH₂CH₃), 1.54–1.61 (1H, m, CH(OEt)-

CH₂CH₃), 1.69–1.76 (1H, m, CH(OEt)CH₂CH₃), 2.15–2.23

(1H, m, NCHCH(CH₃)₂), 2.33 (1H, dd, J 6.3, 4.4, NCH-

CH(CH₃)₂), 3.37 (1H, dq, 8.8, 7.0, OCH₂CH₃), 3.47–3.50 (1H,

m, CH(OEt)Et), 3.50 (2H, d, J 13.8, N(CH₂Ph)₂), 3.57 (1H, dq,

8.7, 7.0, OCH₂CH₃), 3.80 (2H, d, J 13.8, N(CH₂Ph)₂), 7.17–7.38

(10H, m, Ph); δ_C(125 MHz, CDCl₃), 10.2 ((NCHCH(CH₃)₂),

15.8 (NCHCH(CH₃)₂), 20.9 (CH(OEt)CH₂CH₃), 22.7 (OCH₂-

CH₃), 25.1 (CH(OEt)CH₂CH₃), 26.6 (NCHCH(CH₃)₂), 54.8

(N(CH₂Ph)₂), 63.5 (NCHCH(CH₃)₂), 64.1 (OCH₂CH₃), 81.8

(CH(OEt)Et), 126.7 (Ph), 128.0 (Ph), 129.1 (Ph), 1406 (Ph);

Mixture of diastereoisomers (93 : 7): [α]_DϪ8.0 (CHCl₃, c 1.0);

IR (neat), ν_max/cm^Ϫ12971, 2932, 2874, 1494, 1453, 1115, 1074,

733, 698; MS (ES) m/z 341 (M^ϩ2, 15%), 340 (M^ϩ1, 100%).

(S )-2-(N,N-Dibenzyl)aminopropanal diethyl acetal, 35 (R

؍

Me).³⁰Typical procedure D was used with dimethyl sulfoxide

(2.47 ml, 2.72 g, 34.8 mmol), oxalyl chloride (1.52 ml, 2.21 g,

17.4 mmol),-2-(N,N-dibenzyl)amino-1-propanol (4.04 g, 15.8

mmol), triethylamine (11.0 ml, 8.00 g, 79.1 mmol), triethyl

orthoformate (26.3 ml, 23.4 g, 158 mmol), and concentrated

sulfuric acid (2.5 ml). The product was puriﬁed by silica gel

ﬂash chromatography (eluent: petroleum ether/ethyl acetate/

triethylamine 89.5 : 10 : 0.5) to yield the acetal³⁰35 (R = Me) as

a colourless oil (3.74 g, 11.4 mmol, 72%). [α]_DϪ11.7 (CHCl₃,

c 1.2); δ_H(500 MHz, CDCl₃), 1.09 (3H, d, J 6.8, NCHCH₃),

1.16 (3H, t, J 7.0, OCH₂CH₃), 1.17 (3H, t, J 7.0, OCH₂CH₃),

2.88 (1H, dq, J 5.3, 6.8, NCHCH₃), 3.33 (1H, dq, J 9.2, 7.0,

CH(OCH₂CH₃)₂), 3.46 (1H, dq, J 9.4, 7.0, CH(OCH₂CH₃)₂),

3.48 (1H, dq, J 9.2, 7.0, CH(OCH₂CH₃)₂), 3.53 (2H, d, J 13.8,

N(CH₂Ph)₂), 3.70 (1H, dq, J 9.4, 7.0, CH(OCH₂CH₃)₂), 3.83

(2H, d, J 13.8, N(CH₂Ph)₂), 4.49 (1H, d, J 5.3, CH(OEt)₂),

7.17–7.38 (10H, m, Ph); δ_C(125 MHz, CDCl₃), 9.1 (NCHCH₃),

15.3 (OCH₂CH₃), 15.4 (OCH₂CH₃), 54.2 (NCHCH₃), 54.4

(N(CH₂Ph)₂), 61.7 (OCH₂CH₃), 63.2 (OCH₂CH₃), 105.7

(2S,3R)-2-(N,N-Dibenzyl)amino-3-ethoxypentane, 36 (R

؍

Me). Typical procedure A was used with TMSOTf (474 µl, 582

mg, 2.62 mmol), Ϫ2-(N,N-dibenzyl)aminopropanal diethyl

acetal (286 mg, 873 µmol), and diethyl zinc (1.1M solution in

toluene, 1.6 ml, 216 mg, 1.75 mmol). The product was puriﬁed

by silica gel ﬂash chromatography (eluent: petroleum ether/

ethyl acetate/triethylamine 96.5 : 3 : 0.5) to yield the ether 36

(R = Me) as a colourless oil and an inseparable mixture of two

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

846

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diastereoisomers (210 mg, 674 µmol, 77%, dr 94 : 6 by ¹H

NMR). Major diastereoisomer: δ_H(500 MHz, CDCl₃), 0.66

(3H, t, J 7.4, CH(OEt)CH₂CH₃), 1.10 (3H, d, J 6.7, NCHCH₃),

1.14 (3H, t, J 7.0, OCH₂CH₃), 1.49–1.56 (1H, m, CH(OEt)-

CH₂CH₃), 1.68–1.75 (1H, m, CH(OEt)CH₂CH₃), 2.67 (1H,

quin, J 6.7, NCHCH₃), 3.20–3.26 (1H, m, CH(OEt)Et), 3.38–

3.43 (1H, m, OCH₂CH₃), 3.43 (2H, d, J 14.1, N(CH₂Ph)₂),

3.51–3.58 (1H, m, OCH₂CH₃), 3.72 (2H, d, J 13.8, N(CH₂Ph)₂),

7.13–7.38 (10H, m, Ph); δ_C(125 MHz, CDCl₃), 8.4 (CH-

(OEt)CH₂CH₃), 9.0 (NCHCH₃), 15.7 (OCH₂CH₃), 24.0

(CH(OEt)CH₂CH₃), 54.4 (N(CH₂Ph)₂), 54.9 (NCHCH₃), 65.5

(OCH₂CH₃), 83.1 (CH(OEt)Et), 126.7 (Ph), 128.1 (Ph), 128.8

(Ph), 140.4 (Ph); mixture of diastereoisomers (94 : 6): [α]_D

ϩ14.5 (CHCl₃, c 1.1); IR (neat), ν_max/cm^Ϫ12971, 2932, 2874,

1494, 1453, 1116, 1075, 909, 735, 698; MS (EI) m/z 311 (M^ϩ,

0.5%), 296 (1.4), 225 (20), 224 (100), 91 (94).

(89 : 11): mp 68–71 ЊC; [α]_Dϩ60.0 (CHCl₃, c 1.0); IR (neat),

ν_max/cm^Ϫ12976, 1698, 1455, 1266, 1153, 1093, 737, 701; MS (ES)

m/z 421 (M^ϩ, 0.1%), 309 (10), 280 (10), 253 (24), 252 (82), 92

(17), 91 (100).

1-((1R,2S )-2-(N,N-Dibenzylamino)-1-ethoxypropyl)-1H-pyr-

imidine-2,4-dione, 37 (R

؍

Me). Typical procedure B was used

with, TMSOTf (464 µl, 570 mg, 2.57 mmol), 2-(N,N-dibenzyl)-

aminopropanal diethyl acetal (286 mg, 873 µmol), and bis(O-

trimethylsilyl)uracil (438 mg, 1.71 mmol). The product was

puriﬁed by silica gel ﬂash chromatography (eluent: gradient of

petroleum ether/ethyl acetate/triethylamine 69.5 : 30 : 0.5 to

ethyl acetate) to yield the uracil derivative 37 (R = Me) as colour-

less needles and an inseparable mixture of two diastereoisomers

(240 mg, 610 µmol, 71%, dr 55 : 45 by ¹H NMR); major

diastereoisomer (1R,2S): δ_H(500 MHz, CDCl₃), 1.20 (3H, d,

J 7.0, NCHCH₃), 1.24 (3H, t, J 7.0, OCH₂CH₃), 2.96–3.02 (1H,

m, NCHCH₃), 3.41 (2H, d, J 13.8, N(CH₂Ph)₂), 3.48 (2H, q,

J 7.0, OCH₂CH₃), 4.01 (2H, d, J 13.8, N(CH₂Ph)₂), 5.41 (1H, d,

J 4.4, CH(OEt)N), 5.74 (1H, d, J 8.0, uracil-CH ), 7.18–7.31

(10H, m, Ph), 7.44 (1H, d, J 8.0, uracil-CH ); δ_C(125 MHz,

CDCl₃), 9.4 (NCHCH₃), 14.8 (OCH₂CH₃), 54.3 (NCHCH₃),

55.3 (N(CH₂Ph)₂), 66.0 (OCH₂CH₃), 89.1 (CH(OEt)N), 100.7

(uracil-CH), 127.0 (Ph), 128.4 (Ph), 128.5 (Ph), 139.5 (Ph),

141.1 (uracil-CH), 150.2 (uracil-CO), 163.2 (uracil-CO); minor

diastereoisomer (1S,2S): δ_H(500 MHz, CDCl₃), 1.13 (3H, t,

J 7.0, OCH₂CH₃), 1.26 (3H, d, J 6.5, NCHCH₃), 2.84–2.90

(1H, m, NCHCH₃), 3.28 (2H, d, J 13.2, N(CH₂Ph)₂), 3.45 (1H,

dq, J 9.2, 7.0, OCH₂CH₃), 3.52 (1H, dq, J 9.2, 7.0, OCH₂CH₃),

3.72 (2H, d, J 13.2, N(CH₂Ph)₂), 5.51 (1H, d, J 8.0, uracil-CH ),

5.73 (1H, d, J 9.1, CH(OEt)N), 6.58 (1H, d, J 8.0, uracil-CH ),

7.18–7.31 (10H, m, Ph); δ_C(125 MHz, CDCl₃), 8.4 (NCHCH₃),

14.8 (OCH₂CH₃), 53.9 (NCHCH₃), 55.1 (N(CH₂Ph)₂), 65.1

(OCH₂CH₃), 85.7 (CH(OEt)N), 102.3 (uracil-CH), 127.2

(Ph), 128.3 (Ph), 129.0 (Ph), 138.9 (Ph), 140.3 (uracil-CH),

151.4 (uracil-CO), 163.0(uracil-CO); mixture of diastereo-

isomers (55 : 45): mp 48–51 ЊC; [α]_Dϩ8.60 (CHCl₃, c 1.4);

IR (neat), ν_max/cm^Ϫ13190, 3061, 2977, 2937, 2808, 1699, 1495,

1452, 1385, 1265, 1151, 1085, 809, 743, 701; MS (EI) m/z

392 (M^ϩ, 0.2%), 281 (5), 225 (39), 224 (100), 181 (17),

91 (99); HRMS (ES): 416.1964; calculated for C₂₃H₂₇N₃O₃Na:

416.1950.

1-((1R,2S )-2-(N,N-Dibenzylamino)-1-ethoxy-3-phenyl-

propyl)-1H-pyrimidine-2,4-dione, 37 (R

؍

Bn). Typical pro-

cedure B was used with TMSOTf (179 µl, 220 mg, 989 µmol),-2-

(N,N-dibenzylamino)-3-phenylpropanal diethyl acetal (133 mg,

330 µmol), and bis(O-trimethylsilyl)uracil (169 mg, 660 µmol).

The product was puriﬁed by silica gel ﬂash chromatography

(eluent: gradient of petroleum ether/ethyl acetate/triethyl-

amine 79.5 : 20 : 0.5–59.5 : 40 : 0.5) to yield the uracil derivative

37 (R = Bn) as colourless plates and a single diastereoisomer

(109 mg, 232 µmol, 70%, de >98%). Mp 77–79 ЊC; [α]_Dϩ63.3

(CHCl₃, c 1.2); δ_H(500 MHz, CDCl₃), 1.24 (3H, J 7.0,

OCH₂CH₃), 2.91 (1H, dd, J 14.8, 11.2, NCHBn), 3.19–3.24

(2H, m, NCH(CH₂Ph)), 3.33 (1H, dq, J 9.5, 7.0, OCH₂CH₃),

3.45 (1H, dq, J 9.5, 7.0, OCH₂CH₃), 3.56 (2H, d, J 13.7,

N(CH₂Ph)₂), 4.14 (2H, d, J 13.7, N(CH₂Ph)₂), 5.32 (1H, d,

J 4.0, CH(uracil )OEt), 5.65 (1H, dd, J 8.0, 2.2, uracil-CH ),

7.11–7.34 (15H, m, Ph), 7.37 (1H, d, J 8.0, uracil-CH ); δ_C(125

MHz, CDCl₃), 15.0 (OCH₂CH₃), 31.1 (NCH(CH₂Ph)), 55.6

(N(CH₂Ph)₂), 60.1 (NCH(CH₂Ph)), 65.8 (OCH₂CH₃), 87.2

(CH(uracil )OEt), 100.4 (uracil-CH), 126.6 (Ph), 127.2 (Ph),

128.4 (Ph), 128.5 (Ph), 128.7 (Ph), 128.9 (Ph), 138.5 (Ph), 139.2

(Ph), 141.2 (uracil-CH), 149.8 (uracil-CO), 163.2 (uracil-CO);

IR (neat), ν_max/cm^Ϫ13060, 3029, 2977, 1699, 1495, 1456, 1102,

732, 699; MS (EI) m/z 469 (M^ϩ, 0.2%), 378 (17), 301 (56), 300

(93), 181 (13), 91 (100); HRMS (ES): 492.2273; calculated for

C₂₉H₃₁N₃O₃Na: 492.2263; structure conﬁrmed by X-ray crystal-

lographic analysis¹⁰and data has been deposited with the

Cambridge Crystallographic Data Centre as supplementary

publication number CCDC 153574.

1-((1R,2S )-2-(N,N-Dibenzylamino)-1-ethoxy-3-phenyl-

propyl)-1H-pyridin-2-one, 38 (R

؍

Bn). Typical procedure B was

used with TMSOTf (452 µl, 555 mg, 2.50 mmol), 2-(N,N-

dibenzylamino)-3-phenylpropanal diethyl acetal (336 mg, 833

µmol), and 2-trimethylsilyloxypyridine (279 mg, 1.67 mmol).

The product was puriﬁed by silica gel ﬂash chromatography

(eluent: gradient of petroleum ether/ethyl acetate/triethylamine

69 : 30 : 1–49 : 50 : 1) to yield 38 (R = Bn) as colourless plates

and an inseparable mixture of two diastereoisomers (340 mg,

715 µmol, 89%, dr 95 : 5 by ¹H NMR). Major diastereoisomer:

δ_H(500 MHz, CDCl₃), 1.23 (3H, J 7.0, OCH₂CH₃), 2.81 (1H,

dd, J 13.9, 8.4, NCH(CH₂Ph)), 3.11 (1H, dd, J 13.9, 6.3,

NCH(CH₂Ph)), 3.28 (1H, ddd, J 8.4, 6.3, 5.2, NCH(CH₂Ph)),

3.37 (1H, q, J 7.0, OCH₂CH₃), 3.38 (1H, q, J 7.0, OCH₂CH₃),

3.67 (2H, d, J 13.9, N(CH₂Ph)₂), 4.12 (2H, d, J 13.9,

N(CH₂Ph)₂), 5.92 (1H, d, J 5.2, CH(py)OEt), 6.17 (1H, dt,

J 1.3, 6.7, py5-CH ), 6.35 (1H, ddd, J 9.1, 1.3, 0.6, py3-CH ),

7.04 (1H, dd, J 6.8, 1.3, py4-CH ), 7.15–7.28 (15H, m, Ph), 7.46

(1H, ddd, J 7.0, 2.1, 0.6, py6-CH ); δ_C(125 MHz, CDCl₃), 15.2

(OCH₂CH₃), 31.8 (NCH(CH₂Ph)), 55.3 (N(CH₂Ph)₂), 60.4

(NCH(CH₂Ph)), 65.3 (OCH₂CH₃), 86.6 (CH(py)OEt), 105.0

(py5-CH), 120.6 (py3-CH), 126.1 (py4-CH), 126.8 (Ph), 128.2

(Ph), 128.3 (Ph), 128.4 (Ph), 129.1 (Ph), 133.8 (Ph), 138.9 (Ph),

139.1 (Ph), 139.6 (py6-CH), 162.5 (py2-CO); mixture of

diastereoisomers (95 : 5): [α]_Dϩ150.0 (CHCl₃, c 0.8); IR (neat),

ν_max/cm^Ϫ13063, 3027, 2977, 1660, 1587, 1538, 1495, 1454, 1139,

1103, 1077, 910, 734, 699; MS (EI) m/z 377 (M ϩ 1, 45%), 282

1-((1R,2S )-2-(N,N-Dibenzylamino)-1-ethoxy-3-methylbutyl)-

1H-pyrimidine-2,4-dione, 37 (R

؍

Prⁱ). Typical procedure B was

used with TMSOTf (505 µl, 621 mg, 2.79 mmol),-2-(N,N-

dibenzyl)amino-3-methylbutanal diethyl acetal (331 mg, 931

µmol), and bis(O-trimethylsilyl)uracil (477 mg, 1.86 mmol).

The product was puriﬁed by silica gel ﬂash chromatography

(eluent: gradient of petroleum ether/ethyl acetate/triethylamine

69.5 : 30 : 0.5 to ethyl acetate) to yield the uracil derivative 37 (R

= Prⁱ) as a colourless plates and an inseparable mixture of two

1

diastereoisomers (304 mg, 721 µmol, 76%, dr 89 : 11 by H

NMR); major diastereoisomer (1R,2S): δ_H(500 MHz, CDCl₃),

1.00 (3H, d, J 6.7, NCHCH(CH₃)₂), 1.17 (3H, d, J 6.8, NCH-

CH(CH₃)₂), 1.24 (3H, t, J 7.0, OCH₂CH₃), 2.16–2.23 (1H, m,

NCHCH(CH₃)₂), 2.68 (3H, dd, J 6.9, 4.2, NCHCH(CH₃)₂),

3.42–3.52 (2H, m, OCH₂CH₃), 3.74 (2H, d, J 13.1, N(CH₂Ph)₂),

4.07 (2H, d, J 13.1, N(CH₂Ph)₂), 5.66 (1H, d, J 8.0, uracil–CH ),

5.68 (1H, d, J 4.2, CH(OEt)N), 7.15–7.31 (10H, m, Ph), 7.40

(1H, d, J 8.0, uracil–CH ); δ_C(125 MHz, CDCl₃), 15.1 (NCH-

CH(CH₃)₂), 21.2 (NCHCH(CH₃)₂), 22.1 (OCH₂CH₃), 27.8

(NCHCH(CH₃)₂), 56.5 (N(CH₂Ph)₂), 63.2 (NCHⁱPr), 65.4

(OCH₂CH₃), 87.3 (CH(OEt)N), 100.9 (uracil–CH), 127.1 (Ph),

128.3 (Ph), 129.2 (Ph), 139.5 (Ph), 141.1 (uracil–CH), 150.2

(uracil–CO), 163.6 (uracil–CO); Mixture of diastereoisomers

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

847

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(100); microanalysis: found C 79.35, H 7.2, N 6.25; calculated

for C₃₀H₃₂N₂O₂: C 79.61, H 7.13, N 6.19.

(3H, t, J 7.3, CH₂CH₃), 1.06 (1H, m, CH₂CH₃), 1.46 (1H, m,

CH₂CH₃), 2.65 (1H, dd, J 14.3, 6.0, NCH(CH₂Ph)), 2.88 (1H,

m, NCH(CH₂Ph)), 3.07 (1H, dd, J 14.3, 6.5, NCH(CH₂Ph)),

3.35 (2H, d, J 13.2, N(CH₂Ph)₂), 3.52 (1H, m, CH(OH)Et), 3.89

(2H, d, J 13.2, N(CH₂Ph)₂), 4.47 (1H, s, OH ), 7.10–7.40 (15H,

m, Ph).

1-((1R,2S )-2-(N,N-Dibenzylamino)-1-ethoxypropyl)-1H-

pyridin-2-one, 38 (R

؍

Me). Typical procedure B was used with

TMSOTf (521 µl, 639 mg, 2.88 mmol), 2-(N,N-dibenzyl)-

aminopropanal diethyl acetal (314 mg, 959 µmol), and

2-trimethylsilyloxypyridine (321 mg, 1.92 mmol). Analysis

of crude ¹H NMR spectra indicated a 54 : 46 mixture of

diastereoisomers. The product was puriﬁed by silica gel ﬂash

chromatography (eluent: petroleum ether/ethyl acetate/

triethylamine 69 : 30 : 1) to yield the major diastereoisomer of

the pyridone derivative (1R,2S)-38 (R = Me) as a colourless oil

(185 mg, 491 µmol, 51%), and the minor diastereoisomer

(1S,2S)-38 (R = Me) as a colourless oil (130 mg, 345 µmol,

36%). Major diastereoisomer (1R,2S)-38 (R = Me) [α]_Dϩ187.4

(CHCl₃, c 1.9); δ_H(500 MHz, CDCl₃), 1.11 (3H, d, J 7.0,

NCHCH₃), 1.23 (3H, t, J 7.0, OCH₂CH₃), 3.03 (1H, ddd,

J 13.9, 7.0, 5.6, NCHCH₃), 3.45 (2H, q, J 7.0, OCH₂CH₃), 3.54

(2H, d, J 14.1, N(CH₂Ph)₂), 4.03 (2H, d, J 14.1, N(CH₂Ph)₂),

5.99 (1H, d, J 5.6, CH(OEt)N), 6.21 (1H, dt, J 1.3, 6.7, py5-

CH ), 6.41 (1H, ddd, J 9.2, 1.3, 0.7, py3-CH ), 7.17–7.32 (11H,

m, Ph, py4-CH ), 7.47 (1H, ddd, J 6.9, 2.1, 0.7, py6-CH );

δ_C(125 MHz, CDCl₃), 10.3 (NCHCH₃), 15.0 (OCH₂CH₃), 55.0

(N(CH₂Ph)₂), 55.2 (NCHCH₃), 65.4 (OCH₂CH₃), 87.7

(CH(OEt)N), 105.2 (py5-CH), 120.6 (py3-CH), 126.7 (Ph),

128.2 (Ph), 128.3 (Ph), 133.7 (py4-CH), 139.0 (Ph), 140.1 (py6-

CH), 162.6 (py2-CO); IR (neat), ν_max/cm^Ϫ12807, 1674, 1599,

1538, 1495, 1455, 1245, 1141, 1075, 1028, 910, 857, 840, 751,

699; MS (ES) m/z 454 (M^ϩ2, 32%), 453 (M^ϩ, 100%), 358 (60);

Microanalysis: found C 76.5, H 7.7, N 7.6; calculated for

C₂₄H₂₈N₂O₂: C 76.55, H 7.49, N 7.44. Minor diastereoisomer

(1S,2S)-38 (R = Me): [α]_DϪ123.1 (CHCl₃, c 1.3); δ_H(500 MHz,

CDCl₃), 1.10 (3H, t, J 7.0, OCH₂CH₃), 1.27 (3H, d, J 6.5,

NCHCH₃), 2.92 (1H, ddd, J 15.0, 8.5, 6.5, NCHCH₃), 3.31

(2H, d, J 13.3, N(CH₂Ph)₂), 3.41 (1H, dq, J 9.7, 7.0, OCH₂-

CH₃), 3.50 (1H, dq, J 9.7, 7.0, OCH₂CH₃), 3.74 (2H, d, J 13.3,

N(CH₂Ph)₂), 6.06 (1H, dt, J 1.2, 6.7, py5-CH ), 6.27 (1H, d,

J 8.5, CH(OEt)N), 6.54 (1H, ddd, J 9.2, 1.3, 0.7, py3-CH ), 6.81

(1H, ddd, J 7.0, 2.1, 0.6, py4-CH ), 7.09–7.26 (10H, m, Ph), 7.34

(1H, ddd, J 9.2, 6.5, 2.1, py6-CH ); δ_C(125 MHz, CDCl₃),

8.7 (NCHCH₃), 14.9 (OCH₂CH₃), 53.9 (N(CH₂Ph)₂), 55.7

(NCHCH₃), 64.8 (OCH₂CH₃), 84.8 (CH(OEt)N), 105.7 (py5-

CH), 120.4 (py3-CH), 126.8 (Ph), 128.1 (Ph), 129.1 (Ph), 133.9

(py4-CH), 139.1 (Ph), 139.5 (py6-CH), 163.2 (py-CO).

(2S,3S )-2-(N,N-dibenzyl)amino-3-ethoxy-1-phenylpentane,

41. To a solution of (2S,3S)-2-(N,N-dibenzyl)amino-1-phenyl-

3-pentanol (39) (93 mg, 259 µmol) in THF (5 ml) was added

sodium hydride (31 mg, 1.30 mmol), followed by ethyl iodide

(208 µl, 406 mg, 2.60 mmol), and the mixture heated under

reﬂux for 20 h. Wet THF (20 ml) was added, then the solvent

removed in vacuo. Water (20 ml) was added and the product

extracted with diethyl ether (3 × 25 ml), dried (Na₂SO₄) and

concentrated in vacuo. The product was puriﬁed by silica

gel ﬂash chromatography (eluent: hexane/ethyl acetate/triethyl-

amine 96.5 : 3 : 0.5) to yield the ether 41 as a colourless oil (64

mg, 166 µmol, 64%). δ_H(500 MHz, CDCl₃), 0.39 (3H, t, J 7.5,

CH₂CH₃), 1.17 (3H, t, J 7.0, OCH₂CH₃), 1.54–1.60 (1H, m,

CH₂CH₃), 1.69–1.74 (1H, m, CH₂CH₃), 2.82–2.85 (1H, m,

NCH(CH₂Ph)), 2.89 (1H, dt, J 7.8, 5.1, CH(OEt)Et), 2.96 (1H,

dd, J 13.1, 9.4, NCH(CH₂Ph)), 3.07 (1H, dd, J 13.1, 4.9,

NCH(CH₂Ph)), 3.19 (1H, dq, J 8.9, 7.0, OCH₂CH₃), 3.48 (2H,

d, J 13.5, N(CH₂Ph)₂), 3.50 (1H, dq, J 8.9, 7.0, OCH₂CH₃), 4.15

(2H, J 13.5, NCH₂Ph)₂), 7.10–7.35 (15H, m, Ph); δ_C(125 MHz,

CDCl₃), 10.0 (CH₂CH₃), 15.9 (OCH₂CH₃), 23.1 (CH₂CH₃),

30.1 (OCH₃CH₃), 55.5 (N(CH₂Ph)₂), 60.2 (NCH(CH₂Ph)),

65.4 (NCH(CH₂Ph)), 82.3 (CH(OEt)Et), 125.6 (Ph), 126.6

(Ph), 128.0 (Ph), 128.2 (Ph), 129.1 (Ph), 129.3 (Ph), 140.9 (Ph),

141.4 (Ph); MS (ES) m/z 388 (M ϩ 1).

Acknowledgements

We wish to thank the EPSRC and GlaxoSmithKline (Steve-

nage) for an Industrial CASE award (MAG), and the EPSRC

for research grant GR/N05222/01 (AZ).

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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 8 3 4 – 8 4 9

849

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Studies on the Lewis acid mediated cleavage of α-aminoacetals: Synthesis of novel 1,2-aminoethers, and evidence for α-alkoxy aziridinium ion intermediates

DOI: 10.1039/b210116e

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