Atropisomeric benzamides and naphthamides as chiral auxiliaries

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Atropisomeric benzamides and naphthamides as chiral auxiliaries†

Jonathan Clayden,* Madeleine Helliwell,‡ Catherine McCarthy and Neil Westlund

Department of Chemistry, University of Manchester, Oxford Road, Manchester,

UK M13 9PL. E-mail: j.p.clayden@man.ac.uk

1

Received (in Cambridge, UK) 13th June 2000, Accepted 1st August 2000

First published as an Advance Article on the web 14th September 2000

Atropisomeric compounds whose chirality resides in a rotationally restricted aryl–CONR₂bond may be employed as

chiral auxiliaries. The electron-withdrawing amide group causes problems in the diastereoselective functionalisation

of enolates derived from atropisomeric phenyl esters, but a strategy based on atroposelective nucleophilic addition

to a chiral aldehyde followed by stereospeciﬁc [3,3] sigmatropic rearrangement allows atropisomeric naphthamides

to be used as auxiliaries. The auxiliaries are resolved by dynamic resolution during aminal formation using a proline-

derived diamine.

one of the phenyl rings is made chiral by incorporating it into

the atropisomeric binaphthyl system. The philosophy of con-

Introduction

In a series of publications,^1–11we have demonstrated that the

structing chiral aryl groups by complexation to transition

stereogenic axis of hindered, atropisomeric tertiary aromatic

metals (principally chromium^17,18for benzenoid rings and

amides of general structure 1 is capable of controlling high

iron^19,20for cyclopentadienyl) has also been fruitful in the

invention of new chiral reagents, ligands and auxiliaries.

We were initially drawn to the idea of using atropisomeric

chiral auxiliaries for aldol chemistry by the work of Heath-

cock,^21,22who showed in 1980 that the propionate esters 3–5 of

heavily substituted phenols undergo highly anti-selective aldol

reactions with aldehydes (Scheme 1).

levels of stereoselectivity. We have also described two ways of

making this class of atropisomeric compounds as single enantio-

mers,^12,13both involving the control of axial stereochemistry by

the conformational inﬂuence of an adjacent stereogenic centre.

In this paper we describe our progress towards using atrop-

isomeric amides as a new class of chiral auxiliaries. We begin

with our attempts to design an auxiliary suitable for use in

asymmetric anti-aldol chemistry, before moving on to the asym-

metric synthesis of 2-substituted alcohols using a chiral, atrop-

isomeric, peri-substituted naphthamide chiral auxiliary.¹⁴We

found that the use of a hydrolysable ester linkage between the

auxiliary and the substrate led to many problems, and for our

successful development of the naphthamide auxiliary we use

the strategy of linking the auxiliary to the substrate via a C–C

bond, the auxiliary itself being an aldehyde. Our published¹⁵

use of 2-dibenzylamino-3-phenylpropanal as a chiral auxiliary

uses a similar strategy.

Scheme 1 anti-Aldol reactions with hindered phenyl esters.

Atropisomeric chiral auxiliaries

The DMP ester 3 gives ratios of 88:12 to 86:14 anti-6:syn-6

with aromatic aldehydes and α-unbranched aliphatic aldehydes,

and pure anti products with α-branched aliphatic aldehydes

(>98:<2). The BHT and BHA esters 4 and 5 give only anti-

aldols with all aldehydes. All are readily prepared from the

commercially available phenols. The products 6 from the less

selective DMP esters 3 may be hydrolysed; the BHT and BHA

esters from 4 and 5 resist hydrolysis, but the latter may be

cleaved oxidatively. The anti-selective aldol reactions of

hindered aryl esters appear as key steps in synthetic routes to

davanone,²³lankanolide,²⁴the pamamycins,²⁵erythronolides

A²⁶and B²⁷and the vitamin E side chain,²⁸among others.^29,30

Atropisomers which arise from restricted rotation in bonds

to aromatic rings—and the vast majority of atropisomeric

compounds fall into this category—can be seen as chiral

modiﬁcations of the aromatic rings themselves. The famous

and powerful atropisomeric phosphine ligands such as BINAP

2

¹⁶are in essence modiﬁcations to triphenylphosphine in which

† Further experimental details are available as supplementary data.

For direct electronic access see http://ww w .rsc.org/suppdata/p1/b0/

b004682p/

‡ Author to whom enquiries regarding the crystal structure should be

directed.

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This journal is © The Royal Society of Chemistry 2000

DOI: 10.1039/b004682p

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Table 1 Synthesis of the carbamoylphenols

R¹, R²

R³

H, H

11a

11b

11c

11d

11e

i-Pr

12a 92%

13a 94%

14a 95%

NH₂, H

NMe₂, H

–OCH₂O–

OMe, H

MeI, Na₂CO₃,

MeOH

i-Pr

Et

i-Pr

12c 68%

12d 92%

12e 85%

12f 90%

12g 88%

—

13c 81%

13d 71%

13e 91%

—

13g 60%

—

14c 82%

14d 93%

—

Me₂S:BBr₃

CH₂Cl₂

—

OH, H

OCOEt, H

OMOM, H

11g

—

14g 32%

14h 53%

14i 93%

NaI, HCl,

acetone

50 ЊC

NaH, MOMCl

THF, 0 ЊC

12i 93%

13i 45%

41%

Scheme 2 Fuji’s anti-aldol with an atropisomeric, hindered ester.

A chiral version of these hindered aryl groups oﬀers the

chance to achieve anti-diastereoselectivity in an enantioselective

fashion. Previous studies in this area include those of Fuji

and co-workers,³¹who have reported that the enolate of the

binaphthyl ester 7 reacts with aldehyde electrophiles to give the

anti-aldol products anti-8 with high diastereoselectivity and in

good yields (Scheme 2).

Our aim in the work described in this paper was to achieve

similar anti-selectivity in aldol reactions of esters derived from

hindered atropisomeric phenols bearing tertiary amide sub-

stituents. We hoped to exploit the Lewis-basicity of the amide

group to enhance the degree of chelation control in the aldol

transition state. We hoped then to develop an asymmetric anti-

aldol reaction by using enantiomerically pure atropisomeric

amides.

Our ﬁrst reactions were attempted using 2-hydroxybenz-

amide 13a. Phenol 11a and diisopropylcarbamoyl chloride in

reﬂuxing pyridine gave the carbamate 12a, which was converted

to the amide 13a using the “anionic ortho-Fries” rearrange-

ment developed by Snieckus⁴⁰—essentially an intramolecular

acyl transfer reaction of an ortholithiated carbamate. The

ortholithiated carbamate is stable at Ϫ78 ЊC, but undergoes

rearrangement to the phenoxide on warming and thence gives

13a on aqueous quench (Scheme 4). Esteriﬁcation with

propionyl chloride gave propionate 14a (Table 1).

Enantiomerically pure non-biaryl atropisomers have only

recently found uses in asymmetric synthesis, and the most well-

studied class to date are anilides related to 9 (Scheme 3). These

Scheme 3 syn-Aldol reaction of an atropisomeric anilide.

Scheme 4 Synthesis of propionate esters of 2-(N,N-dialkyl)carb-

have been obtained in enantiomerically enriched form^32–35

and employed as chiral auxiliaries to asymmetric enolate

alkylations and aldol reactions,^32,33cycloadditions³⁴and iodo-

lactonisations.³⁵Simpkins and co-workers achieved high syn-

diastereoselectivity in aldol reactions of atropisomeric anilide

9 derived from ortho-tert-butylaniline (Scheme 3).^36,33

amoylphenols.

An attempted aldol reaction between 14a and benzaldehyde

under standard conditions (Scheme 5) failed. Treatment of 14a

We ¹²and others³⁷have recently reported enantioselective

routes to atropisomeric benzamides 2 and the related naphth-

amides, but uses for enantiomerically enriched atropisomeric

benzamides have been conﬁned to NADH model studies³⁸and

components of tachykinin NK₁receptor agonists.³⁹

Scheme 5 Attempted aldol reactions of propionates 14.

Results

with LDA at Ϫ78 ЊC and quenching with benzaldehyde gave

only 2-hydroxybenzamide 13a and recovered starting material

14a: no aldol products 15 were observed (Table 2, entry 1). The

formation of 13a can be explained by decomposition of

the enolate according to Scheme 6. Compound 13a was also

Aldol reactions of N,N-dialkylcarbamoylphenyl esters

Our ﬁrst task was to establish whether aldol reactions of the

esters of amide-substituted phenols were even possible,

irrespective of stereochemistry.

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Table 2 Attempted aldol reactions of carbamoylaryl esters

Starting

material

Remaining starting

material

Decomposition

product

Entry

Conditions

Electrophile

Aldol product

1

2

3

4

5

6

7

14a

14c

14d

17

14g

LDA, Ϫ78 ЊC

2 × LDA, Ϫ78 ЊC

PhCHO

NH₄Cl

PhCHO

0

—

14a, n/d

14a, 67^a

14c, 58^a

14d, 68^a

17, 75^a

14e, 100^a

n/d

13a, n/d

13a, 33^a

13c, 42^a

13d, 32^a

16, 25^a

—

62% 18

n/d

(31:39 anti:syn)^b

—

8

9

25c

25f

LDA, Ϫ78 ЊC

2 × LDA, Ϫ78 ЊC

NH₄Cl

PhCHO

25c, 40^a

25f, 10

22c, 60^a

22f, 13

41% anti-26

32% syn-26

^aEstimated by NMR. ^bFrom ratio of reduction products 20.

we decided to attempt an aldol reaction on the enolate of esters

of the 8-hydroxynaphthamide 16. This type of compound was

Scheme 6 Decomposition of the enolate of 14a.

particularly attractive because it can be made from naphthalic

anhydride by a high-yielding route,⁴²and the peri-relationship

between the hydroxy group and the amide is expected to result

in good conformational stability. Esteriﬁcation of 16 and enolis-

ation of 17 with LDA however still led to decomposition by

elimination (Table 2, entry 5).

formed when the enolate was quenched at Ϫ78 ЊC with

ammonium chloride (entry 2).

We assume the problem arises from the stability of the

phenoxide, stabilised as it is by conjugation with the amide

carbonyl group. We therefore next made the amino-substituted

hydroxybenzamide 13c, hoping that destabilisation of the

phenoxide by the para-amino substituent would disfavour

the competing elimination. Compound 13c was made from

4-aminophenol 11b by methylation to give 11c, carbamate

formation to give 12c and anionic ortho-Fries rearrangement

to 13c. Unfortunately, formation of the lithium enolate of the

propionate ester 14c of the amino-substituted phenol 13c still

led to decomposition by elimination of 13c (entry 3).

A successful atropisomeric chiral auxiliary would necessarily

be a 2,6-disubstituted benzamide, or it would lack conform-

ational stability.⁴¹We wondered whether the enforced per-

pendicular conformation⁴of a 2,6-disubstituted amide would

furthermore lessen the ability of the amide group to stabilise

the phenoxide anion by conjugation. Both 2-substituted and

2,6-disubstituted benzamides adopt a perpendicular conform-

ation in the ground state,⁴but we expected rotation of the latter

into a conformation allowing some degree of conjugation to

incur a signiﬁcantly greater cost in steric strain. Our next target

phenol was therefore 13d, in which the methylenedioxy group

has a dual role: it increases the electron density on the ring,

and blocks any overlap of the amide π* with the conjugated

phenoxide orbitals. The synthesis of 13d was again straight-

forward: the only additional point of interest is the regio-

selectivity of the anionic ortho-Fries rearrangement of 12d,

which followed precedent:⁴⁰lithiation occurred in between the

two ortho-directors (carbamate and alkoxy) to give the 1,2,3,4-

tetrasubstituted phenol 13d. Esteriﬁcation gave 14d, but

unfortunately the lithium enolate of 14d was again unstable,

and collapsed to give signiﬁcant amounts of 13d at Ϫ78 ЊC

(Table 2, entry 4).

We ﬁnally concluded that to have any chance of preventing

the decomposition of the enolate, we would need to make it

a dianion. We therefore decided to try next the dihydroxy-

benzamide 13g. We expected problems with a dianionic

ortho-Fries rearrangement of 12g (which we required later in

the project), so we made 13g by demethylation of 13e using

boron tribromide–dimethyl sulﬁde complex. Compound 13e

was easily made by the usual route from 4-methoxyphenol 11e

(Table 1). Esteriﬁcation of the unsymmetrical diol 13g gave a

separable mixture of the desired monoester 14g and the diester

14h. Encouragingly, treatment of the monoester 14g with two

equivalents of LDA at Ϫ78 ЊC and quenching with saturated

aqueous ammonium chloride gave starting material only (no

decomposition products) by ¹H NMR (Table 2, entry 6).

Lack of regioselectivity in the esteriﬁcation of 13g hampered

further work with 14g, so we decided to turn to a protecting

group for the para-hydroxy group which we could retain until

after esteriﬁcation with propionyl chloride. Table 1 shows

how hydroquinone 11g, with one equivalent of diisopropyl-

carbamoyl chloride in pyridine, gave carbamate 12g in good

yield. The remaining hydroxy group of 12g was protected with

chloromethyl methyl ether to give carbamate 12i in excellent

yield. Anionic Fries rearrangement of 12i gave 13i, which was

esteriﬁed to give 14i and then selectively relieved of its MOM

group by sodium iodide in acetone in the presence of catalytic

conc. HCl, giving cleanly 14g.

The result of the aldol reaction of 14g is shown in Scheme 7

and Table 2, entry 7. Treatment of a solution of two equivalents

of LDA in THF at Ϫ78 ЊC with ester 14g and then benzalde-

hyde aﬀorded a mixture of aldol products 18 in 62% yield after

puriﬁcation. Evaluation of the diastereoisomeric ratio by NMR

was complicated by slow rotation about the amide Ar–CO and

C–N bonds. However, lithium aluminium hydride in reﬂuxing

THF gave a readily identiﬁable mixture of the diols 20 in a

diastereoisomeric ratio of 31 (anti):69 (syn) (identiﬁcation of

We brieﬂy investigated the possibility of “insulating” the

phenoxide from the electronic eﬀect of the amide by attaching

the two groups to the separate rings of a naphthalene system.

To maintain the stereochemical communication between the

two groups necessary for any successful asymmetric induction,

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Table 3 Ortholithiation, anionic ortho-Fries rearrangement and esteriﬁcation

R¹

R³

E

OMe

OMOM

OH

i-Pr

Et

i-Pr

Me

CD₃

SiMe₃

21a, 96%

21b, 95%

21c, 86%

21d, 70%

21e, 47%

—

22a, 18%

22b, 20%

22c, 86%

22d, 97%

22e, 82%

22f

23a, 26%

—

24b, 8%

—

25c, 72%

25d, 99%

25e, 89%

25f, 80%

23b, 13%

—

NaI, HCl

acetone

50 ЊC

Scheme 7 Aldol reaction of 14g.

Scheme 8 2,6-Disubstituted phenyl esters by regioselective anionic ortho-Fries rearrangement.

the diastereoisomers described below). These conditions also

reduced the amide to 19 in 22% yield.

Snieckus obtained ortho migration in 70% yield for a similar

ortho-methyl N,N-diethylcarbamate which diﬀered only by

lacking the para-methoxy substituent.⁴⁰Presumably this is

suﬃcient to disfavour metallation of the more electron-rich

ring.

Encouragingly, we had now conﬁrmed that the dianion

enolates were stable, and underwent clean aldol reactions. We

were, at this stage, hopeful that the 2:1 syn-selectivity would

be overturned by introduction of a second substituent ortho

to the ester linkage (in the manner of 5) so we decided to use

ortholithiation of the carbamate precursor to achieve this. We

took carbamates 12e and 12f, lithiated them with s-BuLi at

Ϫ78 ЊC, and added methyl iodide to give 21a and 21b in 95

and 96% yields respectively (Scheme 8). The anionic Fries

rearrangement of these compounds to 22a and 22b was sur-

prisingly complicated by a lack of regioselectivity in their

lithiation reactions. Although lateral lithiation (i.e. lithiation

at an ortho benzylic site) commonly dominates ortholithiation

in amides,^43,9,44even ortho-methyl substituted carbamates

typically undergo clean anionic ortho-Fries rearrangement.⁴⁰

Not so 21a and 21b: both showed evidence of consider-

able lateral lithiation and migration of the amide substituent

to the benzylic position (Table 3). Warming lithiated carb-

amate 21a to ambient temperature and quenching with water

aﬀorded a mixture of the desired 22a (18%), the product

of lateral lithiation and rearrangement 23a (26%) and

remaining 21a (24%). Judging the main diﬀerence between

our molecules and those of Snieckus to be the nitrogen sub-

stituents, we next tried rearranging 21b. The yield of the anionic

ortho-Fries product 22b (20%) was not increased by this

change, and the by-products included not only the laterally

rearranged 23b (13%) and remaining 21b (43%) but also its

acylated analogue 24b (8%), which presumably arises by inter-

molecular attack of lithiated 23b on remaining unreacted 21b.

Snieckus has demonstrated the use of trimethylsilyl as a tem-

porary blocking group for kinetically acidic sites, allowing

control over the regioselectivity of deprotonation.⁴⁵In our own

work we have found that the magnitude of the kinetic isotope

eﬀect for low-temperature lithiation,⁴⁶which has been shown

experimentally to exceed 50 at Ϫ78 ЊC,⁴⁷allows the use of

deuterium substituents as protecting groups for carbon atoms,

directing lithiation to other acidic sites in the molecule.⁴⁸

We decided to test both of these methods as a means of

encouraging the anionic ortho-Fries rearrangement to become

the major reaction pathway for compounds 21. We ortho-

lithiated carbamate 12e and quenched with d₃-methyl iodide

or chlorotrimethylsilane to give 21c and 21d in 86 and 70%

yields respectively (Table 3).

Under the usual conditions (sec-butyllithium at Ϫ78 ЊC,

followed by warming to 20 ЊC), both 21c and 21d underwent

clean anionic ortho-Fries rearrangement to give 22c and 22d

in excellent yield. The complete overturning of the regio-

selectivity of 21a’s rearrangement is a remarkable testimony to

the synthetic power of kinetic isotope eﬀects.⁴⁸

Esteriﬁcation of 22c and 22d with n-butyllithium and prop-

ionyl chloride gave the esters 25c and 25d in good to excellent

yield. Not surprisingly, a test exposure of the ester 25c to LDA

at Ϫ78 ЊC, quenching with saturated aqueous ammonium

chloride, returned a mixture of phenol 22c and recovered

starting material 25c in a ratio of 60:40 (Table 2, entry 8).

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Scheme 9 Aldol reaction of 25f.

In order to build on the encouraging results with enolate

dianions (Table 2, entries 6 and 7), attempts were made to

dealkylate the methyl ether 25c with BCl₃and TMSI which

are reportedly more selective than BBr₃.^49,50However BCl₃

(Ϫ78–0 ЊC) converted 31% of ester 25c to the phenol 22c.

Addition of BCl₃to ester 25c at 0 ЊC and stirring for 8

minutes before quenching with water converted 60% to 22c.

After 48 h at ambient temperature, 25c had not reacted with

TMSI.

We decided to revert to the more readily removed protecting

group, MOM, for protection of the second phenolic OH.

Ortholithiation with sec-butyllithium, quenching with chloro-

trimethylsilane, aﬀorded ortho-substituted carbamate 21e

(Table 3) in a low yield of 47%. Anionic ortho-Fries rearrange-

ment gave the phenol 22e in a yield of 82%, which was esteriﬁed

to give 25e and deprotected (using sodium iodide in acetone

with a catalytic amount of concentrated hydrochloric acid) to

the phenolic ester 25f in 80% yield.

Treatment of ester 25f with two equivalents of LDA at

Ϫ78 ЊC followed by benzaldehyde and work-up with saturated

aqueous ammonium chloride (Scheme 9 and Table 2, entry 9)

gave 73% combined yield (41% and 32%) of the two aldol

products 26, with only 13% of elimination product 22f. Deter-

mination of the sense of diastereoselectivity at this stage was

hampered by complex NMR data due to slow rotation in the

amides 26. The least polar diastereoisomer (32% yield) was

reduced with lithium aluminium hydride in reﬂuxing THF to

aﬀord the amine 27 and a single diol 20. To determine the

relative stereochemistry of 20, it was converted to its benzyl-

idene acetal 28, whose ³J_HH–CHMeCH(Ph)– coupling constant

of 2.5 Hz indicated axial–equatorial, and hence syn, stereo-

chemistry. The crude ratio of anti:syn aldol products from 25f

turned out to be 59:41.

We were pleased that the aldol reaction was now anti-

selective, though disappointed that the selectivity was not

higher, and that the phenol decomposition by-product was

again appearing in the product mixture. To facilitate further

studies, we decided to attempt to reduce the number of steps

required to reach the model auxiliaries. Snieckus⁵¹had made

compound 29a, and it was hoped that the analogue 29b (R =

i-Pr) would lead to ester 30 in three further steps (Scheme 10).

Ester 30 would have the oxy anion as well as the steric bulk

required for good diastereoselectivity when reacted with an

aldehyde. The dicarbamate 29b was made in 86% yield from the

phenol 12g and subsequent double ortholithiation with two

equivalents of sec-butyllithium, quenching with chlorotrimeth-

ylsilane, aﬀorded 31 in 84% yield. Treatment of 31 with two

equivalents of sec-butyllithium at Ϫ78 ЊC, warming to ambient

temperature and stirring overnight aﬀorded 32 in 44% yield

with other minor unidentiﬁable products. Presumably the tetra-

substituted benzene 31 is too hindered to undergo deproton-

ation: the sec-butyllithium removes a trimethylsilyl group to

Scheme 10 Attempted double anionic ortho-Fries rearrangement.

give an anion which undergoes an anionic ortho-Fries

rearrangement to give 32 after aqueous work-up.

At this point we decided to abandon this route to a potential

auxiliary. The problems posed by the phenyl ester linkage are

too great for us to have a reasonable expectation of success

in designing useful chiral auxiliaries. We decided to overcome

this lack of stability in the auxiliary–substrate linkage by con-

necting the two through a C–C bond.⁵²We had already

demonstrated the use of a phenylalanine-derived aldehyde 38

as a C–C bonded auxiliary in the synthesis of 2-substituted

primary alcohols,¹⁵and the strategy we used then is outlined in

Scheme 11. The auxiliary 33, an aldehyde, is chosen such that

nucleophilic additions of vinyl anion equivalents are highly

diastereoselective. This was true, as demonstrated by Reetz and

co-workers,^53–55for the phenylalanine-derived 38, but central

to our use of atropisomeric amides is our recent demon-

stration that 2-formylnaphthamides 39 also undergo extremely

diastereoselective nucleophilic additions.^5,7The addition of

a vinyl anion equivalent (in general, we have used alkynyl

nucleophiles followed by reduction) gives allylic alcohol 34.

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The enantiomerically and diastereoisomerically pure allylic

alcohol 34 is functionalised to give 35 in such a way that

stereospeciﬁc rearrangement (probably [3,3] sigmatropic)

can be induced to give 36. Finally, the auxiliary is recovered

by oxidative cleavage of the alkene to give a pair of alde-

hydes, the recyclable auxiliary 33 and the 2-substituted aldehyde

product 37.

A similar approach has been used by Spino and Beaulieu,^56,57

who employed a terpene-derived ketone as an auxiliary in a

similar route, by Thomas and co-workers, who have used lactic

acid as the source of chirality (not truly an auxiliary as it was

never recovered) in the synthesis of polyoxamic acid,⁵⁸and by

Larchevêque and co-workers in the synthesis of dipeptide

isosteres.⁵⁹

Fig. 1 X-Ray crystal structure of syn-46b.

We decided to use 39 as the basis of our design for a new

chiral auxiliary, aiming to introduce features which would lead

to total stability about the Ar–CO bond (and therefore resist-

ance to racemisation). We hoped to build on our understanding

of the stereoselective additions of nucleophiles to 39^5,7and to

exploit the shift of the double bond of 35 into conjugation

with the aromatic ring in 36. From previous work, we knew that

the 8-substituents of aldehydes 40, 41 and 42 led to much

increased conformational stability, with the greatest eﬀect being

exerted by the 8-MeO group of 42. A bonding interaction

between the 8-substituent and the amide carbonyl, evident

by X-ray crystallography, is responsible for this eﬀect.⁶⁰We

therefore decided to start by studying the stereoselectivity of

nucleophilic additions (Scheme 12) to 40, 41 and 42, which were

all available by our published route.⁴²

Table 4 summarises these results, and includes, for com-

parison, published results obtained with 39.

Aldehyde 39 and its analogues had generally showed moder-

ate anti-selectivity in additions of organolithiums such as BuLi

and MeLi,⁷and we were pleased to ﬁnd that BuLi added to 41

even more anti-selectively (entry 1). Unfortunately, the high

level of anti-selectivity was not displayed by the unsaturated

nucleophiles we need to use: both octynyllithium and ethynyl-

magnesium bromide gave only moderate anti-selectivity with 41

(entries 2 and 3). The anti-selective addition of octynyllithium

contrasts with the moderately syn-selective addition of this

nucleophile to 39, and when we tried this reaction with 42 we

again saw moderate syn-selectivity. The product of this reac-

Scheme 12 Nucleophilic additions to peri-substituted 2-formyl-1-

naphthamides.

tion, syn-46b, was characterised by X-ray crystallography

(Fig. 1), and allowed us continued conﬁdence in our provisional

assignment of anti-stereochemistry to the less polar diastereo-

isomer in all other cases.^4,6The amino group of 41 must be

playing a role in altering selectivity, perhaps by becoming

involved in coordination with the aggregated organolithium

nucleophile. With amino aldehyde 40, octynyllithium showed

no stereoselectivity at all.

Alkyltriisopropoxytitaniums, bulky nucleophiles which react

under non-chelation control,⁶¹had shown excellent anti-

selectivity with 39⁷(entries 4–6) but we found that with 40

this selectivity dropped substantially. With 41, no alcohol

products were observed—instead, the Lewis acidity of the titan-

ium species in the reaction mixture had promoted lactonisation

to 47, 48, or 49, and even some reduction to 50 (presumably by

hydride transfer from BuTi(Oi-Pr)₃). The other highly selective

additions observed with 39 had been those of organo-

lithiums in the presence of alkylaluminium reagents such as

DIBAL-H or Me₃Al (entries 7–9).⁷Adding DIBAL-H to the

reaction of octynyllithium with 40 increased the selectivity to

96:4, and extremely high levels of anti-selectivity resulted

from the addition of octynyllithium to 41 in the presence of

DIBAL-H. Not surprisingly, both reactions tended to be

accompanied by reduction of the aldehyde: the addition to 41

Scheme 11 Strategy for C–C bonded auxiliary control over new chiral centres.

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was quite capricious in this regard, and on one occasion

generated 88% of the alcohol 51.

At some small cost to selectivity, we found that the altern-

ative, to use Me₃Al as the additive,⁷reliably gave moderate to

good yield and good anti-selectivity. From the reaction of

octynyllithium with 41 in the presence of 0.1 equiv. Me₃Al,

for example, it was possible to isolate 51% yield of the anti

alcohol anti-46b. Replacing trimethylaluminium with triethyl-

aluminium led only to recovery of starting material.

Although we experimented with selective additions to all

three of 40–42, the ﬁnal decision to use 42 as the prospective

chiral auxiliary was based on the stability of its derivatives to

racemisation or epimerisation. We knew that 40 racemised con-

siderably faster than 41 or 42.⁶⁰Compound 41 has a half-life

for racemisation in dioxane solution of 6 days at 20 ЊC, even

though it bears only a –CHO substituent ortho to the amide.

(Trigonal substituents usually permit easy bond rotation.⁴¹) To

assess the stability to epimerisation of its addition products,

we took anti-45a and incubated it at 60 ЊC for 4 h. No sign of

epimerisation to syn-45a was evident, suggesting a rate constant

of <1.4 × 10^Ϫ6s^Ϫ1for this process, and hence a barrier to

epimerisation of >120 kJ mol^Ϫ1. Compound 42 racemises

almost 25 times more slowly than 41, and this informed our

ﬁnal choice of 42 as auxiliary.

The next challenge was to resolve 41 and 42. We decided to

convert them to pairs of diastereoisomeric aminals⁶²53 and 54

by reﬂuxing with the proline-derived diamine 52.⁶³We intended

to use 52 as a resolving agent, aiming to separate the diastereo-

isomeric aminals by column chromatography. In the event,

something more complex, and more useful, than a simple reso-

lution took place (Scheme 13). Instead of forming in a 1:1

ratio, as would be expected for a simple resolution, the product

aminals were formed with a signiﬁcant excess (4 or 5:1) of one

diastereoisomer over the other. We were unable to prove that

the minor diastereoisomer is an atropisomer of the major,

though this would account nicely for the enantiomeric excesses

obtained when the aminals were hydrolysed back to the alde-

hydes (see below). Aminals derived from 52 typically form with

high exo-selectivity for the new stereogenic centre.⁶⁴

The stereogenic axis of the amide is inverting during the

course of the aminal-forming reaction, though at this stage it

was not clear to us whether this inversion was a racemisation of

the starting material or an epimerisation of the product. The

two diastereoisomers of each pair of aminals were separable by

ﬂash chromatography on alumina (though the minor diastereo-

isomers 53b and 54b turned out to be very unstable), and we

were able to distinguish between these two possibilities by re-

subjecting puriﬁed 54a to the conditions of the reaction. No

54b was formed, suggesting that the inversion is a racemisation

of the starting material which occurs before aminal formation

takes place. The temperatures of the reactions (110–140 ЊC)

should racemise 41 and 42 in a matter of minutes.⁶⁰

The 4:1 mixture of aminals 54 was hydrolysed to the alde-

hyde (Ϫ)-42 in 92% yield. The aldehyde was formed in 62% ee

by HPLC on a chiral stationary phase. Alternatively, the

puriﬁed major aminal 54a could be hydrolysed to give (Ϫ)-42

with 99% ee.

Overall, the resolution has features of a dynamic resolution,

because the starting material racemises as the resolution takes

place. The dynamic resolution appears to be under kinetic con-

trol, since re-subjection of the puriﬁed product to the conditions

of the reaction does not regenerate the same ratio of products

as the reaction itself.⁶⁵We had previously noted a dynamic

thermodynamic resolution⁶⁶during similar aminal formation

from 39,¹²but in that case (where R = H), the barrier to epim-

erisation of the product is signiﬁcantly lower. Incidentally, that

dynamic thermodynamic resolution was apparently accom-

panied by an inconsequential dynamic kinetic resolution in the

opposite direction, which was overridden by the subsequent

equilibration of the product diastereoisomers. For 53 and

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J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

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Scheme 13 Dynamic resolution of 41 and 42.

54, our assignment of stereochemistry to 53a and 54a is not

proven, but we chose to follow the precedent of the proven

stereoselectivity of a similar reaction of 39, since the resulting

absolute axial chirality is consistent with the known absolute

stereochemistry of the ﬁnal product of the sequence, 61.

The remarkable and useful consequence of the dynamic

resolution is that it allows a simple two-step aminal form-

ation–hydrolysis sequence to generate material of 62% ee from

racemate in almost quantitative yield. We felt that 62% ee was

insuﬃcient for use as a chiral auxiliary, so we chose to work

with the 99% ee material available by aqueous hydrolysis of

puriﬁed 54a. Losses on puriﬁcation of the unstable aminal

meant that the overall yield of this essentially enantiomerically

pure material was, at 56%, just more than could be expected

from a simple, non-dynamic resolution.

The diamine 52, though recoverable, is made by a four-

step sequence from proline.⁶³Following some success with

ephedrine 55 as an agent of dynamic thermodynamic resolution

with atropisomeric amido-aldehydes,⁶⁷we attempted a similar

resolution with 42. Unfortunately, the products 56a and 56b

were formed in equal quantities, and after hydrolysis 42 was

recovered with only 5% ee (Scheme 14).

Scheme 14 Attempted dynamic resolution with ephedrine.

using the catalytic Me₃Al method (Table 4, entry 8). For the

auxiliary strategy, the alkyne required reduction to the allylic

alcohols 57, and we made both the E- and Z-isomers by reduc-

tion with RedAl or hydrogenation over Lindlar’s catalyst

(Scheme 15).

To recover the newly created stereogenic centre we decided to

use two variants of the [3,3] sigmatropic Claisen rearrangement

of known stereospeciﬁcity. Allylic alcohol (ϩ)-(Z)-57 was

heated with trimethyl orthoacetate to give the ketene acetal 63

which underwent a stereospeciﬁc Johnson–Claisen rearrange-

ment⁶⁸in 12 h at 110 ЊC (Scheme 16). The product ester (ϩ)-64

was isolated as a single diastereoisomer in 84% yield. By

With enantiomerically pure (Ϫ)-42 it was a straightforward

matter to make enantiomerically pure alkyne (ϩ)-anti-46b

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

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to epimerisation of the axis, preventing recovery of the

auxiliary in enantiomerically pure form even if the problem

of decomposition to 60 could be overcome. Other allylic

alcohol rearrangements⁷¹(preferably ones which occur at lower

temperatures) could be used to generate a variety of substituted

allylic products: in our previous work with a phenylalanine-

derived auxiliary¹⁵we demonstrated the use of a palladium()-

catalysed allylic transposition of allyl esters.

Scheme 15 Reduction to allylic alcohols 57 (R = n-hexyl).

contrast, Eschenmoser–Claisen rearrangement⁶⁹of (ϩ)-(Z)-57

with dimethylacetamide dimethoxy acetal in reﬂuxing xylene at

140 ЊC for 20 h gave a mixture of epimers of the product amide

(ϩ)-59. The most reasonable explanation for this is that the

higher temperature allows equilibration of the atropisomeric

epimers, particularly in the rearranged product which has a

small,⁴¹trigonal substituent (a trans double bond) adjacent to

the amide axis. The newly formed centre was nonetheless

evidently formed with high stereospeciﬁcity, because ozon-

olysis of 59 with reductive work-up yielded an optically active

alcohol (R)-(Ϫ)-61 whose Mosher ester⁷⁰62 (formed from

α-methoxy-α-(triﬂuoromethyl)phenylacetyl

chloride,

(ϩ)-

MTPACl) contained less than 5% of the diastereoisomer formed

from the known¹⁵(S)-(ϩ)-61. Fig. 2 compares the relevant

portions of the ¹H NMR spectra of the (ϩ)-MTPA esters of

(R)-(Ϫ)-61, (S)-(ϩ)-61 and the ( )-MTPA ester of (S)-(ϩ)-61.

Unfortunately, it proved impossible to recover the auxiliary

(in its reduced form) from the ozonolysis step: the only other

product turned out to be a benzamide 60 derived from further

oxidation of the naphthalene’s more electron-rich ring.

Although our route depends on resolution with naturally

derived proline, and hence is not viable in the enantiomeric

series, we demonstrated reduction to the (E)-, as well as

the (Z)-, allylic alcohol 57. Rearrangement chemistry from

(E)-57 should allow us to use the same strategy to make the

enantiomeric series of alcohol products. A trial reaction on

some racemic ( )-(E)-59 suggested that the longer reac-

tion times required to rearrange (E)-allylic alcohols would lead

Fig. 2 (a) Portion of the ¹H NMR spectrum of 62, the ester of

(R)-(Ϫ)-61 with (ϩ)-MTPA; (b) portion of the ¹H NMR spectrum

of the ester of (S)-(ϩ)-61 with (ϩ)-MTPA (from ref. 15); (c) portion of

the ¹H NMR spectrum of the ester of (S)-(ϩ)-61 with ( )-MTPA

(from ref. 15).

Scheme 16 Stereospeciﬁc rearrangements and cleavage (R = n-hexyl).

3240

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(1.34 ml, 17.67 mmol) was added dropwise. The mixture was

Summary

warmed to ambient temperature and stirred overnight. The

white precipitate was ﬁltered oﬀ and the solvent removed under

reduced pressure. The crude solid was dissolved in ether (50 ml)

and washed with water (50 ml), 10% aqueous sodium hydroxide

(2 × 50 ml) and water (50 ml), dried (MgSO₄), ﬁltered and con-

centrated under reduced pressure to give carbamate 12i (4.185 g,

93%) as a white solid which required no further puriﬁcation, mp

49–51 ЊC; R_f0.23 [5:1 petrol–EtOAc]; λ_max/nm (ε_max) (CH₂Cl₂)

230 (24430), 276 (9486); ν_max(ﬁlm)/cm^Ϫ12969, 2932, 1712;

δ_H(300 MHz, CDCl₃) 7.06 (4H, s, ArH), 5.17 (2H, s, CH₂), 4.10

(2H, br m, 2 × NCH), 3.50 (3H, s, OCH₃), 1.35 (12H, br m,

4 × NCHCH₃); δ_C(75 MHz, CDCl₃) 154.3, 145.8, 122.6, 122.3,

116.8, 94.7, 55.7, 46.8, 46.0, 21.4, 20.5; m/z (CI) 282 (100%,

M ϩ H^ϩ); m/z (EI) 281 (4%, M^ϩ), 128 (53, CONi-Pr₂) and 45

(100) (Found: M^ϩ, 281.1634. C₁₅H₂₃NO₄requires M, 281.1627).

The instability of amide-substituted phenyl esters poses severe

problems for the use of atropisomeric amides as chiral auxil-

iaries in a conventional sense—enolate chemistry of the esters

is made very diﬃcult. However, allowing the new stereogenic

centre to be formed by nucleophilic attack adjacent to the

aromatic ring allows a way round this problem, albeit at the

expense of a rather long synthetic sequence. Atropisomeric

auxiliaries have some nice features—not least their potential

for synthesis via dynamic resolution—but are evidently not a

realistic competitive alternative to the more widely used and

versatile alternatives.

Experimental

Flash chromatography refers to chromatography carried out by

the method of Still et al.⁷²Preparative HPLC was carried out

on a Dynamax-60A column at a pressure of 0.15 kPa at room

temperature using a Gilson 305 Pump with ﬂow rate at 15.0

ml min^Ϫ1. Analytical HPLC on a chiral stationary phase was

carried out using a Regis Whelk-O1 chiral column. Detection

was at 280 nm using a Gilson 115 UV Detector. Ether refers to

diethyl ether; petrol to the fraction of petroleum ether boiling

between 40 and 60 ЊC. J values are in Hz.

N,N-Diisopropyl-2-hydroxybenzamide 13a⁷³

sec-Butyllithium (1.84 ml, 2.39 mmol; 1.3 M solution in hex-

anes) was added dropwise over 10 minutes to a solution of

carbamate 12a (528 mg, 2.39 mmol) in THF (36 ml) at Ϫ78 ЊC

under an atmosphere of nitrogen. After 1 h, the resulting solu-

tion was warmed to ambient temperature, stirred for a further

12 hours and quenched with saturated aqueous ammonium

chloride (10 ml). The THF was removed under reduced pres-

sure and the aqueous residue was extracted with dichloro-

methane (4 × 20 ml). The combined organic extracts were dried

(MgSO₄), ﬁltered and concentrated under reduced pressure to

aﬀord the benzamide 13a⁷³(495 mg, 94%) as white needles

which required no further puriﬁcation, mp 159–160 ЊC

(EtOAc); ν_max(ﬁlm)/cm^Ϫ13206, 2998, 2969, 2934, 1611, 1590;

δ_H(300 MHz, CDCl₃) 9.28 (1H, br s, OH), 7.32 (1H, m, ArH),

7.22 (1H, dd, J 7.7 and 1.7, ArH), 7.03 (1H, dd, J 8.2 and 1.1,

ArH), 6.88 (1H, dt, J 7.5 and 1.1, ArH), 3.99 (2H, br m,

2 × NCH), 1.43 (12H, d, J 6.7, 4 × CH₃); δ_C(75 MHz, CDCl₃)

170.9, 157.7, 131.4, 126.6, 120.5, 118.5, 117.8, 48.9, 20.9; m/z

(CI) 222 (100%, M ϩ H^ϩ); m/z (EI) 221 (100%, M^ϩ), 178 (65,

M Ϫ i-Pr) and 121 (88, M Ϫ Ni-Pr₂).

Further experimental details are available as electronic

supplementary information.

Phenyl N,N-diisopropylcarbamate 12a⁷³

A solution of phenol (2.586 g, 27.47 mmol), N,N-diisopropyl-

carbamoyl chloride (4.496 g, 27.47 mmol) and anhydrous

pyridine (10 ml) was heated to reﬂux for 2 days. The mixture

was allowed to cool, poured onto ice-cooled water (50 ml) and

extracted with ether (4 × 40 ml). The combined ethereal

extracts were washed with aqueous 1 M hydrochloric acid

(4 × 20 ml) and saturated aqueous sodium hydrogen carbonate

(4 × 20 ml), dried (MgSO₄), ﬁltered and concentrated under

reduced pressure to give the crude carbamate. Puriﬁcation by

Kugelrohr distillation yielded the carbamate 12a⁷³as a colour-

less liquid (5.599 g, 92%) which crystallised on standing, bp

150–155 ЊC, 2.1 mmHg; ν_max(ﬁlm)/cm^Ϫ12996, 2971, 2935, 2876,

1710, 1692; δ_H(300 MHz, CDCl₃) 7.41 (2H, m, ArH), 7.23 (1H,

m, ArH), 7.18 (2H, m, ArH), 4.15 (1H, br m, NCH), 4.03 (1H,

br m, NCH), 1.38 (12H, br m, 4 × CH₃); δ_C(75 MHz, CDCl₃)

153.9, 151.3, 129.1, 124.9, 121.8, 46.8 (br), 21.5 (br), 20.5 (br);

m/z (CI) 222 (100%, M ϩ H^ϩ); m/z (EI) 221 (2%, M^ϩ) and

86 (100).

N,N-Diisopropyl-2-hydroxy-5-(methoxymethoxy)benzamide 13i

By the method used for 13a, a mixture of carbamate 12i (2.283

g, 8.13 mmol) and sec-butyllithium (7.50 ml, 9.75 mmol; 1.3 M

solution in hexanes) in THF (60 ml) gave, after ﬂash chrom-

atography on silica gel [3:2 petrol–EtOAc], benzamide 13i

(1.330 g, 58%) as white blades, mp 160–161 ЊC (EtOAc); ν_max

(ﬁlm)/cm^Ϫ13215–3101, 2996, 2965, 2935, 1589; δ_H(300 MHz,

CDCl₃) 8.70 (1H, s, OH), 7.01 (1H, dd, J 8.8 and 2.9, ArH),

6.95 (1H, d, J 2.6, ArH), 6.92 (1H, d, J 9.2, ArH), 5.10 (2H,

s, CH₂), 3.97 (2H, br m, 2 × NCH), 3.50 (3H, s, OCH₃), 1.42

(12H, d, J 6.7, 4 × NCHCH₃); δ_C(75 MHz, CDCl₃) 170.5,

152.4, 149.4, 120.4, 118.5, 114.6, 95.5, 55.7, 20.9; m/z (CI) 282

(100%, M ϩ H^ϩ); m/z (EI) 281 (7%, M^ϩ) and 49 (100) (Found:

M^ϩ, 281.1623. C₁₅H₂₃NO₄requires M, 281.1627).

4-Hydroxyphenyl N,N-diisopropylcarbamate 12g

In the same way, a solution of hydroquinone 11g (3.124 g, 28.37

mmol), N,N-diisopropylcarbamoyl chloride (4.643 g, 28.37

mmol) and anhydrous pyridine (10 ml) gave carbamate 12g

(5.908 g, 88%) as a white solid which required no further puriﬁ-

cation, mp 141–145 ЊC (EtOAc); R_f0.23 [5:1 petrol–EtOAc];

λ_max/nm (ε_max) (CH₂Cl₂) 230 (10630), 278 (5234); ν_max(ﬁlm)/

cm^Ϫ13287, 3277, 2970, 2934, 2874, 1672; δ_H(300 MHz, CDCl₃)

7.35 (1H, br s, OH), 6.84 (2H, d, J 8.8, ArH), 6.58 (2H, d, J 8.9,

ArH), 4.18 (1H, br m, NCH), 3.96 (1H, br m, NCH), 1.34

(12H, br m, 4 × CH₃); δ_C(75 MHz, CDCl₃) 153.8, 148.1, 143.8,

122.3, 116.3, 47.0, 46.0, 21.3, 20.4; m/z (CI) 238 (100%,

M ϩ H^ϩ) (Found: M^ϩ, 237.1362. C₁₃H₁₉NO₃requires M,

237.1365).

2-(Diisopropylcarbamoyl)phenyl propionate 14a

n-Butyllithium (1.31 ml, 2.09 mmol; 1.6 M solution in hexanes)

was added to a solution of benzamide 13a (462 mg, 2.09 mmol)

in THF (5.5 ml) at 0 ЊC under an atmosphere of nitrogen. After

10 minutes propionyl chloride (0.27 ml, 3.14 mmol) was added,

and the mixture was allowed to warm to ambient temper-

ature, stirred overnight, quenched with saturated aqueous

ammonium chloride (10 ml) and extracted with ether (4 × 15

ml). The combined ethereal extracts were washed with satur-

ated aqueous sodium hydrogen carbonate (3 × 10 ml) and brine

(20 ml), dried (MgSO₄), ﬁltered and concentrated under

reduced pressure to aﬀord the crude product. Puriﬁcation by

ﬂash chromatography on silica gel [2:1 petrol–EtOAc] aﬀorded

the ester 14a (549 mg, 95%) as a pale yellow oil, which crystal-

4-(Methoxymethoxy)phenyl N,N-diisopropylcarbamate 12i

Sodium hydride (0.707 g, 17.67 mmol, 60% dispersion) was

added in portions to a solution of carbamate 12g (3.807 g,

16.06 mmol) in THF (210 ml) at 0 ЊC and stirred for 2 hours 45

minutes to give a deep blue mixture. Chloromethyl methyl ether

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

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lised on standing; R_f0.44 [2:1 petrol–EtOAc]; λ_max/nm (ε_max

)

extracts were dried (MgSO₄), ﬁltered and concentrated under

(CH₂Cl₂) 232 (24530), 294 (1577); ν_max(ﬁlm)/cm^Ϫ13062, 2985,

2929, 2882, 1764, 1633; δ_H(300 MHz, CDCl₃) 7.42–7.33 (2H, m,

ArH), 7.24 (1H, m, ArH), 7.17 (1H, d, J 8.1, ArH), 3.77 (1H,

septet, J 6.7, NCH), 3.50 (1H, septet, J 6.7, NCH), 2.57 (2H, q,

J 7.6, CH₂), 1.54 (6H, m, 2 × NCHCH₃), 1.24 (3H, t, J 7.6,

CH₂CH₃), 1.12 (6H, br d, 2 × NCHCH₃); δ_C(75 MHz, CDCl₃)

172.3, 166.8, 146.6, 131.6, 129.2, 126.2, 125.7, 123.0, 50.8, 45.7,

27.4, 20.7, 20.4, 8.9; m/z (CI) 278 (100%, M ϩ H^ϩ); m/z (EI) 277

(17%, M^ϩ), 221 (77, M Ϫ C₃H₅O), 178 (78) and 121 (100)

(Found: M^ϩ, 277.1681. C₁₆H₂₃NO₃requires M, 277.1678).

reduced pressure to aﬀord carbamate 21a (568 mg, 96%) as a

colourless oil which required no further puriﬁcation; R_f0.53

[2:1 petrol–EtOAc]; ν_max(ﬁlm)/cm^Ϫ12996, 2969, 2934, 2876,

2836, 1712; δ_H(300 MHz, CDCl₃) 6.98 (1H, d, J 8.7, ArH), 6.78

(1H, d, J 2.9, ArH), 6.74 (1H, dd, J 8.7 and 3.0, ArH), 4.08 (2H,

br m, 2 × NCH), 3.81 (3H, s, OCH₃), 2.23 (3H, s, ArCH₃), 1.35

(12H, br m, 4 × NCHCH₃); δ_C(75 MHz, CDCl₃) 156.7, 153.8,

143.5, 131.5, 122.8, 116.0, 111.6, 55.5, 46.6, 46.1, 21.5, 20.5,

16.7, 16.6; m/z (CI) 266 (100%, M ϩ H^ϩ), 128 (18, CONi-Pr₂); EI

265 (9, M^ϩ), 86 (100) (Found: M^ϩ, 265.1675. C₁₅H₂₃NO₃

requires M, 265.1678).

2-(Diisopropylcarbamoyl)-4-(methoxymethoxy)phenyl

propionate 14i

4-Methoxy-2-(trideuteriomethyl)phenyl N,N-diisopropyl-

carbamate 21c

In the same way as for compound 14a, a mixture of benzamide

13i (1.330 g, 4.73 mmol) and n-butyllithium (3.55 ml, 5.68

mmol; 1.6 M solution in hexanes) in THF (60 ml) was treated

with propionyl chloride (0.62 ml, 7.10 mmol). After work-up

in the usual manner, ﬂash chromatography on silica gel [2:1

petrol–EtOAc] aﬀorded the ester 14i (1.487 g, 93%) as a colour-

less oil; R_f0.48 [1:1 petrol–EtOAc]; ν_max(ﬁlm)/cm^Ϫ12968, 2938,

1760, 1637; δ_H(300 MHz, CDCl₃) 7.15 (1H, d, J 8.9, ArH), 7.00

(1H, d, J 2.8, ArH), 6.88 (1H, d, J 2.6, ArH), 5.15 (1H, d, J 6.7,

OCH_AH_BOCH₃), 5.08 (1H, d, J 6.7, OCH_AH_BOCH₃), 3.77 (1H,

septet, J 6.7, NCH), 3.45 (1H, septet, NCH), 3.35 (3H, s,

OCH₃), 2.51 (2H, q, J 6.7, CH₃CH₂), 1.49 (6H, br m, 2 ×

NCHCH₃), 1.19 (3H, t, J 7.4, CH₃CH₂), 1.09 (6H, d, J 6.6,

2 × NCHCH₃); δ_C(75 MHz, CDCl₃) 172.6, 166.4, 154.6, 140.8,

132.2, 123.8, 116.8, 113.7, 94.6, 55.8, 50.8, 45.7, 27.3, 20.6, 20.3,

8.8; m/z (CI) 338 (100%, M ϩ H^ϩ); m/z (EI) 281 (82%), 337 (3,

M^ϩ) and 45 (100) (Found: M^ϩ, 337.1896. C₁₈H₂₇NO₅requires

M, 337.1889).

In a similar way, a mixture of carbamate 12e (800 mg, 3.19

mmol) in THF (10 ml) was added to a solution of sec-

butyllithium (2.70 ml, 3.51 mmol; 1.3 M solution in hexanes)

and TMEDA (0.53 ml, 3.51 mmol) in THF (20 ml) and treated

with methyl iodide-d₃(0.40 ml, 6.38 mmol). Work-up in the

usual manner aﬀorded carbamate 21c (737 mg, 86%) as a

colourless oil which required no further puriﬁcation; R_f0.50

[2:1 petrol–EtOAc]; ν_max(ﬁlm)/cm^Ϫ12997, 2970, 2936, 2875,

2836; δ_H(300 MHz, CDCl₃) 6.99 (1H, d, J 8.7, ArH), 6.79 (1H,

d, J 2.9, ArH), 6.76 (1H, dd, J 8.7 and 3.0, ArH), 4.08 (2H,

br m, 2 × NCH), 3.81 (3H, s, OMe), 1.37 (12H, br m, 4 ×

NCHCH₃); δ_C(75 MHz, CDCl₃) 156.7, 153.8, 143.6, 131.4,

122.8, 122.6, 116.0, 114.2, 111.6, 55.4, 46.6, 46.1, 21.5, 20.5; m/z

(CI) 269 (100%, M ϩ H^ϩ); m/z (EI) 268 (4%, M^ϩ), 86 (100)

(Found: M^ϩ, 268.1860. C₁₅H₂₀NO₃D₃requires M, 268.1866).

4-Methoxy-2-(trimethylsilyl)phenyl N,N-diisopropylcarbamate

21d

2-(Diisopropylcarbamoyl)-4-hydroxyphenyl propionate 14g

In the same way, a mixture of carbamate 12e (872 mg, 3.47

mmol) in THF (10 ml) was added to a solution of sec-

butyllithium (3.21 ml, 4.17 mmol; 1.3 M solution in hexanes)

and TMEDA (0.63 ml, 4.17 mmol) in THF (20 ml) and treated

with chlorotrimethylsilane (1.0 ml, 7.88 mmol). Work-up in the

usual manner followed by ﬂash chromatography on silica gel

[8:1 petrol–EtOAc] aﬀorded carbamate 21d (789 mg, 70%) as a

Concentrated hydrochloric acid (one drop) was added to a

stirred solution of ester 14i (1.487 g, 4.41 mmol) and sodium

iodide (1.981 mg, 13.24 mmol) in acetone (30 ml) at ambient

temperature. The pale green solution was stirred for 30 minutes,

by which time it had turned red–brown. The mixture was heated

to 50 ЊC for 4 hours, cooled to ambient temperature, treated

with water (5 ml) and extracted with dichloromethane (4 ×

10 ml). The combined organic extracts were dried (MgSO₄),

ﬁltered and concentrated under reduced pressure to give the

crude product as a brown oil. Puriﬁcation by ﬂash chromato-

graphy on silica gel [2:1 petrol–EtOAc] aﬀorded the ester 14g

(533 mg, 41%) as a sticky pale brown solid; R_f0.21 [1:1 petrol–

EtOAc]; ν_max(ﬁlm)/cm^Ϫ13223, 2972, 2939, 2881, 1759, 1612;

δ_H(300 MHz, CDCl₃) 8.90 (1H, br s, OH), 6.88 (1H, J 8.8,

ArH), 6.68 (1H, dd, J 8.7 and 2.6, ArH), 6.56 (1H, d, J 2.6,

ArH), 3.84 (1H, septet, J 6.6, NCH), 3.52 (1H, septet, J 6.6,

NCH), 2.52 (2H, q, J 7.6, CH₂), 1.54 (6H, br m, 2 × NCHCH₃),

1.22 (3H, t, J 7.6, CH₃CH₂), 1.10 (6H, br m, 2 × NCHCH₃);

δ_C(75 MHz, CDCl₃) 172.9, 168.1, 154.6, 138.8, 130.5, 123.5,

117.2, 113.1, 51.2, 45.9, 27.3, 20.5, 20.3, 8.9; m/z (CI) 294

(100%, M ϩ H^ϩ) (Found: M^ϩ, 293.1628. C₁₆H₂₃NO₄requires

M, 293.1627).

sticky white solid; R_f0.30 [8:1 petrol–EtOAc]; λ_max/nm (ε_max

)

(CH₂Cl₂) 232 (29980), 282 (5976); ν_max(ﬁlm)/cm^Ϫ12996, 2964,

2938, 2899, 1712; δ_H(300 MHz, CDCl₃) 6.96 (1H, d, J 2.9,

ArH), 6.92 (1H, d, J 8.8, ArH), 6.87 (1H, dd, J 8.8 and 2.9,

ArH), 4.34 (1H, septet, J 6.9, NCH), 3.78 (3H, s, OCH₃), 3.69

(1H, septet, J 6.7, NCH), 1.33 (6H, d, J 6.9, 2 × NCHCH₃),

1.28 (6H, d, J 6.7, 2 × NCHCH₃), 0.27 (9H, s, Si(CH₃)₃); δ_C(75

MHz, CDCl₃) 156.2, 153.5, 149.6, 132.9, 123.2, 119.9, 115.0,

55.5, 46.9, 45.8, 21.2, 20.5, 1.0; m/z (CI) 324 (100%, M ϩ H^ϩ),

128 (28, CONi-Pr₂); m/z (EI) 323 (3%, M^ϩ), 128 (72, CONi-Pr₂),

86 (100) (Found: M^ϩ, 323.1920. C₁₇H₂₉NO₃Si requires M,

323.1917).

N,N-Diisopropyl-2-hydroxy-5-methoxy-3-methylbenzamide 22a

By a method similar to that used for 13a, a solution of carb-

amate 21a (530 mg, 2.00 mmol) in THF (10 ml) was added to a

solution of sec-butyllithium (1.54 ml, 2.00 mmol; 1.3 M solu-

tion in hexanes) and TMEDA (0.30 ml, 2.00 mmol) in THF (20

ml), allowed to warm to ambient temperature and stirred over-

night. After work-up in the usual manner, puriﬁcation by ﬂash

chromatography on silica gel [5:1 petrol–EtOAc] aﬀorded the

4-Methoxy-2-methylphenyl N,N-diisopropylcarbamate 21a

sec-Butyllithium (2.07 ml, 2.69 mmol; 1.3 M solution in hex-

anes) was added dropwise to a solution of TMEDA (0.41 ml,

2.69 mmol) in THF (20 ml) at Ϫ78 ЊC under an atmosphere of

nitrogen. After 10 minutes a solution of carbamate 12e (562

mg, 2.24 mmol) in THF (10 ml) was added. After 1 h, methyl

iodide (0.70 ml, 11.24 mmol) was added. The mixture was

stirred for a further 60 minutes and allowed to warm to ambient

temperature. Water (10 ml) was added, the THF was removed

under reduced pressure, and the aqueous residue was extracted

with dichloromethane (4 × 20 ml). The combined organic

benzamide 22a (94 mg, 18%) as a colourless oil, λ_max/nm (ε_max

)

(CH₂Cl₂) 232 (14470), 318 (5533); ν_max(ﬁlm)/cm^Ϫ13108, 2968,

2934, 1601; δ_H(300 MHz, CDCl₃) 8.52 (1H, s, OH), 6.79 (1H,

d, J 3.0, ArH), 6.58 (1H, d, J 2.9, ArH), 3.98 (2H, br m,

2 × NCH), 3.78 (3H, s, OCH₃), 2.38 (3H, s, ArCH₃), 1.42 (12H,

d, J 6.7, 4 × NCHCH₃); δ_C(75 MHz, CDCl₃) 171.0, 151.2,

149.5, 128.0, 120.3, 118.7, 108.7, 55.7, 48.9, 20.9, 16.2; m/z (CI)

3242

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

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266 (100%, M ϩ H^ϩ); m/z (EI) 265 (21%, M^ϩ), 49 (100) (Found:

M^ϩ, 265.1674. C₁₅H₂₃NO₃requires M, 265.1678).

2-(Diisopropylcarbamoyl)-4-(methoxymethoxy)-6-(trimethyl-

silyl)phenyl propionate 25e

Also obtained was N,N-diisopropyl-2-(2-hydroxy-5-methoxy-

phenyl)acetamide 23a (140 mg, 26%) as a white solid; mp 154–

156 ЊC (EtOAc); λ_max/nm (ε_max) (CH₂Cl₂) 232 (21458), 296

(12870); ν_max(ﬁlm)/cm^Ϫ12963, 2932, 1613, 1596; δ_H(300 MHz,

CDCl₃) 6.91 (1H, d, J 8.7, ArH), 6.75 (1H, dd, J 8.7 and 2.8,

ArH), 6.61 (1H, d, J 2.8, ArH), 4.24 (1H, br septet, J 6.3,

NCH), 3.76 (3H, s, OMe), 3.70 (2H, s, CH₂), 3.63 (1H,

m, NCH), 1.36 (6H, d, J 6.7, 2 × NCHCH₃), 1.27 (6H, d,

J 6.7, 2 × NCHCH₃); δ_C(75 MHz, CDCl₃) 172.1, 152.9,

150.9, 122.2, 118.2, 116.0, 113.2, 55.7, 46.5, 38.7, 21.1,

20.9, 20.3; m/z (CI) 266 (100%, M ϩ H^ϩ); m/z (EI) 265 (8%,

M^ϩ), 86 (100) (Found: M^ϩ, 265.1679. C₁₅H₂₃NO₃requires M,

265.1678). Also obtained was recovered carbamate 21a (127

mg, 24%).

By the method used for 14a, benzamide 22e (167 mg, 0.47

mmol), n-butyllithium (0.33 ml, 0.52 mmol; 1.6 M solution in

hexanes) in THF (7 ml) and propionyl chloride (0.06 ml, 0.71

mmol) gave, after ﬂash chromatography on silica gel [5:1

petrol–EtOAc], ester 25e (173 mg, 89%) as a colourless oil; R_f

0.73 [2:1 petrol–EtOAc]; ν_max(ﬁlm)/cm^Ϫ12964, 2903, 1756,

1637; δ_H(300 MHz, CDCl₃) 7.07 (1H, d, J 3.0, ArH), 6.93 (1H,

d, J 2.9, ArH), 5.16 (1H, J 6.7, OCHaHbO), 5.07 (1H, d, J 6.7,

OCHaHbO), 3.90 (1H, septet, J 6.6, NCH), 3.44 (3H, s, OCH₃),

3.44 (1H, m, NCH), 2.52 (2H, m, CH₃CH₂), 1.49 (3H, d, J 7.3,

NCHCH₃), 1.45 (3H, d, J 7.3, NCHCH₃), 1.19 (3H, t, J 7.6,

CH₃CH₂), 1.13 (6H, d, J 6.5, 2 × NCHCH₃); δ_C(75 MHz,

CDCl₃) 173.0, 166.9, 154.0, 146.2, 135.0, 132.0, 123.0, 114.8,

94.8, 55.8, 55.8, 50.9, 45.7, 27.5, 20.7, 20.3, 20.2, 8.7, 1.0; m/z

(CI) 410 (65%, M ϩ H^ϩ), 74 (100) (Found: M ϩ H^ϩ, 410.2358.

C₂₁H₃₅NO₅Si requires M ϩ H, 410.2362).

N,N-Diisopropyl-2-hydroxy-5-methoxy-3-(trideuteriomethyl)-

benzamide 22c

2-(Diisopropylcarbamoyl)-4-hydroxy-6-(trimethylsilyl)phenyl

propionate 25f

In a similar way, a solution of carbamate 21c (629 mg, 2.35

mmol) in THF (10 ml), sec-butyllithium (1.81 ml, 2.35 mmol;

1.3 M solution in hexanes) and TMEDA (0.35 ml, 2.35 mmol)

in THF (20 ml) gave, after ﬂash chromatography on silica gel

[4:1 petrol–EtOAc], the benzamide 22c (542 mg, 86%) as a

white solid, mp 112–114 ЊC (EtOAc); R_f0.53 [2:1 petrol–

EtOAc]; ν_max(ﬁlm)/cm^Ϫ13066, 2996, 2969, 2937, 2836, 1599;

δ_H(300 MHz, CDCl₃) 8.55 (1H, s, OH), 6.79 (1H, d, J 3.0, ArH),

6.57 (1H, J 3.0, ArH), 3.97 (2H, br m, 2 × NCH), 3.78 (3H,

s, OCH₃), 1.42 (12H, d, J 6.7, 4 × NCHCH₃); δ_C(75 MHz,

CDCl₃) 171.0, 151.2, 149.5, 120.3, 118.7, 108.7, 55.7, 48.8,

20.9; m/z (CI) 269 (100%, M ϩ H^ϩ); m/z (EI) 268 (21%, M^ϩ),

167 (100) (Found: M^ϩ, 268.1863, C₁₅H₂₀NO₃D₃requires M,

268.1866).

By the method used to deprotect 14i, ester 25e (172 mg, 0.42

mmol) and sodium iodide (189 mg, 1.26 mmol) in acetone (5

ml) gave, after puriﬁcation by ﬂash chromatography on silica

gel [6:1 petrol–EtOAc], ester 25f (123 mg, 80%) as a white solid;

mp 178–179 ЊC; R_f0.24 [5:1 petrol–EtOAc]; λ_max/nm (ε_max

)

(CH₂Cl₂) 232 (24820), 292 (10790); ν_max(ﬁlm)/cm^Ϫ13386–3192,

2944, 2935, 2870, 1756; δ_H(300 MHz, CDCl₃) 8.90 (1H, br s,

OH), 6.77 (1H, d, J 2.8, ArH), 6.45 (1H, d, J 2.8, ArH), 3.93

(1H, septet, J 6.6, NCH), 3.46 (1H, septet, J 6.9, NCH), 2.49

(2H, m, CH₂), 1.51 (3H, d, J 7.0, NCHCH₃), 1.47 (3H, d, J 6.9,

NCHCH₃), 1.19 (3H, t, J 7.6, CH₂CH₃), 1.13 (3H, d, J 6.5,

NCHCH₃), 1.08 (3H, d, J 6.6, NCHCH₃), 0.20 (9H, s,

Si(CH₃)₃); δ_C(75 MHz, CDCl₃) 173.2, 168.7, 153.7, 144.1, 134.2,

129.9, 123.2, 115.0, 51.3, 45.9, 27.6, 20.7, 20.2, 20.1, 8.8, 1.0;

m/z (CI) 366 (100%, M ϩ H^ϩ); m/z (EI) 365 (M^ϩ), 309 (83,

M Ϫ C₃H₅O), 193 (100) (Found: C, 62.04; H, 8.61; N, 3.61%;

M^ϩ, 365.2022. C₁₉H₃₁NO₄Si requires C, 62.4; H, 8.5; N, 3.8%;

M, 365.2022).

N,N-Diisopropyl-2-hydroxy-5-methoxy-3-(trimethylsilyl)-

benzamide 22d

In the same way, a solution of carbamate 21d (716 mg, 2.22

mmol) in THF (10 ml), sec-butyllithium (1.71 ml, 2.22 mmol;

1.3 M solution in hexanes) and TMEDA (0.33 ml, 2.22 mmol)

in THF (20 ml) gave, after ﬂash chromatograhy on silica gel

[2:1 petrol–EtOAc], benzamide 22d (694 mg, 97%) as a pale

yellow oil; λ_max/nm (ε_max) (CH₂Cl₂) 234 (28412), 322 (12312);

ν_max(ﬁlm)/cm^Ϫ13240, 2996, 2964, 2902, 1612, 1584; δ_H(300

MHz, CDCl₃) 8.73 (1H, s, OH), 6.98 (1H, d, J 3.0, ArH), 6.70

(1H, d, J 3.0, ArH), 3.95 (2H, br m, 2 × NCH), 3.76 (3H,

s, OCH₃), 1.40 (12H, d, J 6.7, 4 × NCHCH₃), 0.30 (9H, s,

Si(CH₃)₃); δ_C(75 MHz, CDCl₃) 171.2, 156.3, 151.2, 129.7,

123.1, 119.3, 112.3, 55.8, 48.9, 20.9, 1.2; m/z (CI) 324 (100%,

M ϩ H^ϩ); m/z (EI) 323 (23%, M^ϩ), 207 (100) (Found: M^ϩ,

323.1921. C₁₇H₂₉NO₃Si requires M, 323.1917).

General procedure for assessment of enolate stability

A solution of n-butyllithium (0.5 mmol; 1.6 M solution in

hexanes) in THF (3 ml) at Ϫ78 ЊC was treated with diiso-

propylamine (0.075 ml, 0.55 mmol). After 10 min, a solution of

the ester 14a (0.5 mmol) in THF (2 ml) was added. After 60

minutes, saturated aqueous ammonium chloride (2 ml) was

added. The mixture was allowed to warm to ambient temper-

ature and extracted with dichloromethane (4 × 10 ml). The

combined organic extracts were dried (MgSO₄), ﬁltered and

concentrated under reduced pressure to aﬀord the crude

1

product, which was analysed by H NMR. Table 2 shows the

N,N-Diisopropyl-2-hydroxy-5-(methoxymethoxy)-3-(trimethyl-

results for esters 14a, 14c, 14d, 17, 14g, 25c and 25f.

silyl)benzamide 22e

(2S*,3S*)- and (2R*,3S*)-2-(Diisopropylcarbamoyl)-4-hydroxy-

6-(trimethylsilyl)phenyl 3-hydroxy-2-methyl-3-phenylpropano-

ate, syn-26 and anti-26

In the same way, a solution of carbamate 21e (813 mg, 2.30

mmol) in THF (15 ml), sec-butyllithium (2.13 ml, 2.76 mmol;

1.3 M solution in hexanes) and TMEDA (0.42 ml, 2.76 mmol)

in THF (30 ml) gave, after puriﬁcation by ﬂash chromatography

on silica gel [10:1 petrol–EtOAc], benzamide 22e (669 mg,

82%) as a pale yellow oil; R_f0.42 [5:1 petrol–EtOAc]; ν_max

(ﬁlm)/cm^Ϫ13224, 2967, 2936, 2899, 1612, 1581; δ_H(300 MHz,

CDCl₃) 9.07 (1H, s, OH), 7.08 (1H, d, J 2.9, ArH), 6.96 (1H,

d, J 2.9, ArH), 5.06 (2H, s, CH₂), 3.95 (2H, br m, 2 × NCH),

3.47 (3H, s, OCH₃), 1.39 (12H, d, J 6.6, 4 × NCHCH₃),

0.30 (9H, s, Si(CH₃)₃); δ_C(75 MHz, CDCl₃) 171.2, 157.6,

148.9, 129.7, 126.1, 118.9, 115.6, 95.6, 55.6, 48.8, 20.9, 1.2;

m/z (CI) 354 (100%, M ϩ H^ϩ); m/z (EI) 353 (15%, M^ϩ),

45 (100%) (Found: M^ϩ, 353.2021. C₁₈H₃₁NO₄Si requires M,

353.2022).

n-Butyllithium (0.237 ml, 0.318 mmol; 1.6 M solution in

hexanes) was added dropwise to a solution of diisopropylamine

(0.045 ml, 0.32 mmol) in THF (1 ml) at 0 ЊC under nitrogen.

After stirring for 10 minutes the solution was cooled to Ϫ78 ЊC

and a solution of ester 25f (58 mg, 0.16 mmol) in THF (2 ml)

was added dropwise over 3 minutes to give a yellow solution.

After 65 minutes, benzaldehyde (0.048 ml, 0.048 mmol) was

added, the mixture was stirred for a further 2 hours 20 minutes,

and saturated aqueous ammonium chloride (5 ml) was added

dropwise to give a solution that turned green, then pale yellow,

then colourless upon warming to ambient temperature. Water

(5 ml) was added, and the mixture was extracted with dichloro-

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

3243

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methane (5 × 5 ml). The combined organic extracts were dried

(MgSO₄), ﬁltered and concentrated under reduced pressure to

give an oil. Puriﬁcation by ﬂash chromatography on silica gel

[4:1 petrol–EtOAc] aﬀorded the syn aldol syn-26 (24 mg, 32%)

as a colourless oil; R_f0.52 [1:1 petrol–EtOAc]; ν_max(ﬁlm)/cm^Ϫ1

3307–3215, 2967, 2938, 1754, 1606, 1581; δ_H(300 MHz, 90 ЊC,

DMSO-d₆) 9.26 (1H, br s, ArOH), 7.67–7.20 (5H, m, Ph), 6.89

(1H, J 2.6, ArH), 6.63 (1H, d, J 2.8, ArH), 5.25 (1H, br s, OH),

4.89 (1H, br s, CHOH), 3.65 (2H, br m, 2 × NCH), 2.84 (1H, br

m, PhCH(OH)CHCH₃), 1.25 (12H, br m, 4 × NCHCH₃), 1.07

(3H, d, J 7.0, PhCH(OH)CHCH₃), 0.20 (9H, s, Si(CH₃)₃); δ_C(75

MHz, CDCl₃) 177.6, 172.2, 159.3, 149.1, 148.7, 139.6, 136.9,

133.0, 131.8, 131.0, 126.5, 119.2, 76.9, 76.7, 52.0, 51.8, 25.5,

14.3, 4.7, 4.5, 4.2, 4.0; m/z (CI) 472 (100%, M ϩ H^ϩ); m/z (EI)

105 (100%), 309 (29, M Ϫ PhC₄H₆O₂) (Found: M ϩ H^ϩ,

472.2526. C₂₆H₃₇NO₅Si requires M ϩ H, 472.2519).

Also obtained was the anti aldol anti-26 (31 mg, 41%) as a

colourless oil; R_f0.50 [1:1 petrol–EtOAc]; ν_max(ﬁlm)/cm^Ϫ1

3306, 2969, 2936, 1749, 1607, 1580; δ_H(300 MHz, 90 ЊC,

DMSO-d₆) 9.25 (1H, br s, ArOH), 7.37–7.22 (5H, m, Ph), 6.89

(1H, d, J 2.9, ArH), 6.62 (1H, d, J 2.9, ArH), 5.08 (1H, d, J 4.0,

OH), 4.74 (1H, dd, J 8.2 and 3.8, CHOH), 3.61 (2H, br m,

2 × NCH), 2.85 (1H, quintet, J 7.3, PhCH(OH)CH(CH₃)), 1.3

(12H, br m, 4 × NCHCH₃), 0.91 (3H, d, J 7.3, PhCH(OH)-

CH(CH₃)), 0.21 (9H, s, SiMe₃); δ_C(75 MHz, CDCl₃) 173.3,

154.3, 144.0, 142.9, 134.8, 132.2, 128.3, 127.5, 127.1, 121.9,

114.5, 114.3, 75.0, 47.7, 47.4, 20.5, 14.1, 13.8; m/z (CI) 472

(16%, M ϩ H^ϩ), 102 (100%) (Found: M ϩ H^ϩ, 472.2522.

C₂₆H₃₇NO₅Si requires M ϩ H, 472.2519).

2855; δ_H(300 MHz, CDCl₃) 6.45 (1H, s, ArH), 6.25 (1H, s,

ArH), 5.03 (2H, d, J 1.9, CH₂), 2.86 (2H, septet, J 6.7,

2 × NCH), 0.83 (12H, d, J 6.5, N(CH(CH₃)₂)₂), 0.01 (9H, s,

SiMe₃); δ_C(75 MHz, CDCl₃) 156.7, 148.1, 126.3, 122.5, 119.4,

116.7, 67.8, 47.6, 19.7, Ϫ1.1; m/z (CI) 296 (6%, M ϩ H^ϩ),

102 (100) (Found: M ϩ H^ϩ, 296.2043. C₁₆H₂₉NO₂Si requires

M ϩ H, 296.2046).

Also obtained was the diol syn-20 (17 mg, 100%) as a

colourless oil.

Diols 20 by reduction of esters syn- and anti-18

In the same way lithium aluminium hydride (17 mg, 0.45 mmol)

at 0 ЊC in THF (2 ml) and a solution of diastereoisomeric aldols

18 (123 mg, 0.308 mmol) in THF (4 ml) gave, after heating to

reﬂux for 3 hours and after puriﬁcation by ﬂash chromato-

graphy on silica gel [2:1 petrol–EtOAc ϩ 1% Et₃N], 2-(diiso-

propylcarbamoyl)benzene-1,4-diol 19 (14 mg, 22%) as a sticky

brown solid; ν_max(ﬁlm)/cm^Ϫ13260, 2964, 2928, 2871, 2855,

2751, 2732; δ_H(300 MHz, CDCl₃) 6.59 (2H, s, ArH), 6.48 (1H,

s, ArH), 3.74 (2H, s, CH₂), 3.12 (2H, septet, J 6.7, 2 × NCH),

1.10 (12H, d, J 6.6, N(CH(CH₃)₂)₂); δ_C(75 MHz, CDCl₃)

169.6, 151.7, 123.1, 116.0, 114.9, 114.5, 48.3, 47.6, 19.5;

m/z (CI) 224 (72%, M ϩ H^ϩ), 102 (100%); m/z (EI) 223 (1%,

M^ϩ), 49 (100) (Found: M^ϩ, 223.1568. C₁₃H₂₁NO₂requires M,

223.1572).

Also obtained was a mixture of (1S*,2S*)- and (1R*,2S*)-

2-methyl-1-phenylpropane-1,3-diol syn- and anti-20 (10 mg,

20%) in a ratio of 69:31.

Also recovered was N,N-diisopropyl-2,5-dihydroxy-3-(tri-

methylsilyl)benzamide 22f (5 mg, 13%) as a white solid; mp

182–185 ЊC (EtOAc); R_f0.56 [1:1 petrol–EtOAc]; ν_max(ﬁlm)/

cm^Ϫ13258, 2961, 2925, 2872, 2854, 1586; δ_H(300 MHz, CDCl₃)

6.86 (1H, d, J 2.9, ArH), 6.62 (1H, J 3.09, ArH), 3.94 (2H, br m,

2 × NCH), 1.38 (12H, d, J 6.7, 4 × NCHCH₃), 0.29 (9H, s,

Si(CH₃)₃); δ_C(75 MHz, CDCl₃) 170.9, 155.6, 147.2, 129.8, 123.9,

120.0, 114.1, 29.6, 20.9, Ϫ1.2; m/z (CI) 310 (100%, M ϩ H^ϩ);

m/z (EI) 309 (3%, M^ϩ), 49 (100) (Found: M^ϩ, 309.1759.

C₁₆H₂₇NO₃Si requires M, 309.1760). Also recovered was ester

25f (6 mg, 10%).

(2R*,4R*,5S*)-5-Methyl-2,4-diphenyl-1,3-dioxane 28

A mixture of diol syn-20 (17 mg, 0.10 mmol), benzaldehyde (0.5

ml, 4.9 mmol), toluene-p-sulfonic acid (a few crystals), 4 Å

molecular sieves and toluene (2 ml) was heated to reﬂux over-

night, cooled to ambient temperature, diluted with diethyl ether

(15 ml), washed with saturated aqueous sodium hydrogen

carbonate (2 × 10 ml) and brine (10 ml), dried (MgSO₄), ﬁltered

and concentrated under reduced pressure to aﬀord the crude

product. Puriﬁcation by ﬂash chromatography on neutral alu-

mina [5:1 petrol–EtOAc] aﬀorded dioxane 28 (26 mg, 100%)

as a colourless oil; ν_max(ﬁlm)/cm^Ϫ13305–2848, 1721; δ_H(300

MHz, CDCl₃) 7.54 (2H, dd, J 7.8 and 1.9, ArH), 7.38–7.16

(8H, m, ArH), 5.65 (1H, s, OCHOPh), 5.09 (1H, d, J 2.5,

PhCHOCHCH₃), 4.25 (1H, dd, J 11.1 and 2.2, CH_AH_B), 4.07

(1H, dd, J 11.1 and 1.2, CH_AH_B), 1.87 (1H, m, CHCH₃), 0.90

(3H, d, J 7.0, CHCH₃); δ_C(75 MHz, CDCl₃) 128.8, 128.2, 128.0,

126.9, 126.1, 125.2, 101.9, 80.7, 73.3, 34.0, 11.2; m/z (CI) 255

(82%, M ϩ H^ϩ), 106 (100) (Found: M^ϩ, 254.1302. C₁₇H₁₈O₂

requires M, 254.1307).

(2S*,3S*)- and (2R*,3S*)-2-(Diisopropylcarbamoyl)-4-hydroxy-

phenyl 3-hydroxy-2-methyl-3-phenylpropanoate syn- and anti-18

By the same method, a solution of LDA [from diisopropyl-

amine (0.14 ml, 0.99 mmol) and n-butyllithium (0.64 ml, 0.99

mmol; 1.54 M solution in hexanes) in THF (30 ml)] at Ϫ78 ЊC

was treated with a solution of ester 14g (145 mg, 0.50 ml) in

THF (25 ml). After 25 minutes, a solution of benzaldehyde

(0.13 ml, 1.24 mmol) in THF (5 ml) was added and the mixture

was stirred overnight. After work-up in the manner described

above, puriﬁcation by ﬂash chromatography on silica gel [4:1

petrol–EtOAc] aﬀorded a mixture of aldol products syn-18 and

anti-18 (123 mg, 62%) as a colourless oil.

(R*a,1ЈR*)- and (R*a,1ЈS*)-N,N-Diisopropyl-8-(dimethyl-

amino)-2-(1Ј-hydroxypentyl)-1-naphthamide anti-45a and

syn-45a

The aldehyde 41 (0.2 g, 0.6 mmol) in THF (50 ml) was added to

a stirred solution of n-butyllithium (0.38 ml; 1.6 M solution in

hexane) in THF (50 mL) under nitrogen at Ϫ78 ЊC. After 30

min the mixture was warmed to room temperature for 30 min.

Saturated NH₄Cl was added and the mixture was extracted with

dichloromethane (2 × 60 ml). The extracts were washed with

brine, dried (MgSO₄) and evaporated under reduced pressure.

Analytical HPLC of the crude mixture showed that the

atropisomers were present in a ratio of 15.5 (anti):1 (syn). Puri-

ﬁcation by ﬂash chromatography on SiO₂[1:5 EtOAc–petrol]

gave the anti alcohol anti-45a (0.12 g, 57%) as white plates, mp

124–128 ЊC; R_f[1:5 EtOAc–petrol] 0.37; ν_max(ﬁlm)/cm^Ϫ13422

(1R*,2S*)-2-Methyl-1-phenylpropane-1,3-diol syn-20 by

reduction of syn-26

A solution of ester syn-26 (43 mg, 0.09 mmol) in THF (4 ml)

was added to a stirred solution of lithium aluminium hydride

(17 mg, 0.45 mmol) at 0 ЊC in THF (2 ml). The mixture was

warmed to ambient temperature, stirred for 3 hours, heated to

reﬂux overnight, allowed to cool and treated successively with

water (0.5 ml), 15% aqueous sodium hydroxide (0.5 ml) and

water (1.5 ml). The mixture was extracted with diethyl ether

(3 × 10 ml), and the combined ethereal extracts were dried

(MgSO₄), ﬁltered and concentrated under reduced pressure to

aﬀord the crude product. Puriﬁcation by ﬂash chromatography

on silica gel [5:1 petrol–EtOAc] aﬀorded 2-(diisopropylamino-

methyl)-6-(trimethylsilyl)benzene-1,4-diol 27 (10 mg, 49%) as a

sticky brown oil, ν_max(ﬁlm)/cm^Ϫ13359, 2968, 2932, 2897, 2876,

(O–H), 1628 (C᎐O); δ (300 MHz, CDCl ) 7.86 (1H, d, J 8.5,

᎐

H

3

ArH), 7.70 (1H, d, J 8.5, ArH), 7.60 (1H, d, J 8, ArH), 7.44 (1H,

t, J 7.5, ArH), 7.28 (1H, d, J 7.5, ArH), 5.05 (1H, dt, J 3.5 and 9,

HCOH), 3.50 [1H, septet, J 6.5, NCH(CH₃)₂], 3.10 [1H, septet,

3244

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

View Article Online

J 6.5, NCH(CH₃)₂], 2.84 (3H, s, NMe), 2.56 (3H, s, NMe), 1.98

(2H, d, J 4, OH), 1.66 (3H, d, J 7, NCHCH₃), 1.65 (3H, d, J 7,

NCHCH₃), 1.60 [2H, m, CH₂(CH₂)₂CH₃], 1.50–1.30 [4H, m,

(CH₂)₂CH₃], 0.94 (3H, d, J 7, NCHCH₃), 0.92 (3H, d, J 7,

NCHCH₃), 0.94 (3H, t, J 7, CH₃); δ_C(75 MHz, CDCl₃) 169.1

aldehyde 40 (0.3 g, 0.8 mmol) was added and the mixture was

stirred for 6 h at 0 ЊC and room temperature for 30 min, poured

into aqueous HCl (1 M, 30 ml) and extracted with dichloro-

methane (2 × 30 ml). The extracts were washed with sodium

bicarbonate solution and brine, dried (MgSO₄) and evaporated

under reduced pressure. Analytical HPLC of the crude mixture

showed that the atropisomers were present in a ratio of 2

(anti):1 (syn). Puriﬁcation by ﬂash chromatography on SiO₂

(20:1 EtOAc–MeOH) gave the anti alcohol anti-44b (47 mg,

36%) as a yellow oil.

(C᎐O), 152.1, 139.8, 134.4, 130.5, 128.8, 126.3, 125.9, 124.3,

᎐

123.8, 117.0 (ArC), 71.6 (COH), 50.6, 49.7 (NMe₂), 45.6, 43.8

(NCH × 2), 39.3 (HOCHCH₂), 28.4, 22.5 ((CH₂) × 2), 20.7,

20.4, 20.3, 19.6 (CH₃× 4), 14.1 (CH₃); m/z (CI) 385 (100%,

(M ϩ H)^ϩ), (EI) 183 (52), 86 (80, 2 × i-Pr) (Found (EI): M^ϩ,

384.2787. C₂₄H₃₆N₂O₂requires M, 384.2777).

Also obtained was the syn alcohol syn-45a as white

plates; mp 125–128 ЊC; R_f[1:5 EtOAc–petrol] 0.25; ν_max(ﬁlm)/

cm^Ϫ11687 (C=O); δ_H(300 MHz, CDCl₃) 7.74 (1H, d, J 8.5,

ArH), 7.53 (1H, d, J 8.5, ArH), 7.48 (1H, d, J 8, ArH), 7.33

(1H, t, J 7.5, ArH), 7.14 (1H, d, 7.5, ArH), 4.80 (1H, m,

HCOH), 3.94 (1H, s, OH), 3.43 [1H, septet, J 7, NCH(CH₃)₂],

2.95 (1H, septet, J 7, NCH(CH₃)₂), 2.74 (3H, s, NMe), 2.45

(3H, s, NMe), 1.80 (3H, d, J 7, NCHCH₃), 1.75 (3H, d, J 7,

NCHCH₃), 1.35 [2H, m, CH₂(CH₂)CH₃], 1.30–1.10 [4H, m,

CH₂(CH₂)CH₃], 0.80 (3H, d, J 7, NCHCH₃), 0.75 (3H, d, J 7,

NCHCH₃), 0.80 (3H, m, CH₃); δ_C(75 MHz, CDCl₃) 170.9

(R*a,1ЈR*) and (R*a,1ЈS*)-N,N-Diisopropyl-8-(dimethyl-

amino)-2-[1Ј-hydroxynon-2Ј-ynyl]-1-naphthamide anti-45b and

syn-45b

By method A, n-butyllithium (0.43 ml; 1.6 M solution in

hexane), oct-1-yne (0.14 mL, 0.9 mmol) and aldehyde 41 (150

mg, 0.46 mmol) gave a crude product. Analytical HPLC of the

crude mixture showed that the atropisomers were present in a

ratio of 2 (anti):1 (syn). Puriﬁcation by ﬂash chromatography

on SiO₂(1:5 EtOAc–petrol) gave the anti alcohol anti-45b as a

yellow oil (69 mg, 35%); R_f[1:5 EtOAc–petrol] 0.23; ν_max(ﬁlm)/

cm^Ϫ13388 (OH), 1627 (C᎐O); δ (300 MHz, CDCl ) 7.74 (1H, d,

᎐

H

3

(C᎐O), 151.6, 138.8, 134.2, 132.6, 128.8, 126.2, 125.9, 123.9,

᎐

J 8.5, ArH), 7.74 (1H, d, J 8.5, ArH), 7.46 (1H, d, J 8, ArH),

7.34 (1H, t, J 7.5, ArH), 7.14 (1H, d, J 7.5, ArH), 5.70 (1H, m,

HCOH), 3.40 [1H, septet, J 7, NCH(CH₃)₂], 2.80 [1H, septet,

J 7, NCH(CH₃)₂], 2.72 (3H, s, NMe), 2.66 (1H, d, J 5.5, OH),

2.46 (3H, s, NMe), 2.15 [2H, m, CH₂(CH₂)₄CH₃], 1.60 (3H, d,

J 7, NCHCH₃), 1.55 (3H, d, J 7, NCHCH₃), 1.40–1.20 (8H, m,

(CH₂)₄), 0.84 (3H, t, J 7, CH₃), 0.78 [3H, d, J 7, NCH(CH₃)₂];

123.30, 116.2 (ArC), 69.5 (C-OH), 50.4, 49.8 (NMe₂), 45.7, 43.3

(NCH × 2), 33.3, 29.4, 28.8 [(CH₂)₃], 22.6, 22.3, 20.2, 19.3

(4 × CH₃), 13.9 (CH₃); m/z (CI) 385 (100%, (M ϩ H)^ϩ), (EI) 86

(80, 2 × i-Pr) (Found (EI): M^ϩ, 384.2783. C₂₄H₃₆N₂O₂requires

M, 384.2777).

(R*a,1ЈR*)-N,N-Diisopropyl-8-(dimethylaminomethyl)-2-

(1Ј-hydroxynon-2Ј-ynyl)-1-naphthamide anti-44b

δ (75 MHz, CDCl ) 170.7 (C᎐O), 151.6, 136.9, 134.8, 131.6,

᎐

C

3

129.0, 126.4, 126.1, 125.9, 124.2, 116.7 (ArC), 88.0 (COH),

78.4, 62.4 (alkyne C), 50.5, 50.2 (NMe₂), 45.9, 43.5 (NCH × 2),

31.2, 28.5, 28.4, 22.4, 20.5 (5 × CH₂), 20.4, 20.2, 19.4, 18.8

(4 × CH₃), 13.9 (CH₃); m/z (CI) 437 (100%, (M ϩ H)^ϩ), (EI)

226 (52), 86 (30, 2 × i-Pr) (Found: (M ϩ H)^ϩ, 437.3176.

C₂₈H₄₀N₂O₂requires M ϩ 1, 437.3168).

Method A. n-Butyllithium (0.83 ml; 1.6 M solution in

hexane) was added dropwise to a stirred solution of oct-1-yne

(0.20 ml, 1.3 mmol) in THF (30 ml) under nitrogen at 0 ЊC.

After 30 min at 0 ЊC, the aldehyde 40 (0.3 g, 0.8 mmol) was

added and the mixture was stirred for 30 min at Ϫ78 ЊC, 30

min at 0 ЊC and 30 min at room temperature. The mixture was

poured into aqueous HCl (1 M, 30 ml) and extracted with

dichloromethane (2 × 30 ml). The extracts were washed with

sodium bicarbonate solution and brine, dried (MgSO₄) and

evaporated under reduced pressure. Analytical HPLC of the

crude mixture showed that the atropisomers were present in a

ratio of 1 (anti):1 (syn). Puriﬁcation by ﬂash chromatography

on SiO₂(20:1 EtOAc–MeOH) gave the anti alcohol anti-44b

(0.26 g, 66%) as a yellow oil; R_f(20:1 EtOAc–MeOH) 0.33; ν_max

(ﬁlm)/cm^Ϫ13357 (OH), 2931 (CH), 1624 (C᎐O); δ (300 MHz,

Also obtained was the syn alcohol syn-45b as a yellow oil (35

mg, 18%); R_f[1:5 EtOAc–petrol] 0.14; ν_max(ﬁlm)/cm^Ϫ13388

(OH), 1627 (C᎐O); δ (300 MHz, CDCl ) 8.00 (1H, d, J 8.5,

᎐

H

3

ArH), 7.76 (1H, d, J 8.5, ArH), 7.50 (1H, d, J 8, ArH), 7.35

(1H, t, J 8, ArH), 7.16 (1H, d, J 7.5, ArH), 5.70 (1H, s, CHOH),

4.20 (1H, br, OH), 3.45 [1H, septet, J 7, NCH(CH₃)₂], 2.92 [1H,

septet, J 7, NCH(CH₃)₂], 2.72 (3H, s, NMe), 2.42 (3H, s, NMe),

2.25 (2H, m, alkyne-CH₂), 1.62 (3H, d, J 7 NCHCH₃), 1.60

(3H, d, J 7, NCHCH₃), 1.35 (2H, m, CH₂), 1.40–1.10 [6H,

m, (CH₂)₃], 0.85 (3H, t, J 7, CH₃), 0.80 (6H, d × 2, J 7,

᎐

H

NCH(CH ) ); δ (75 MHz, CDCl ) 170.7 (C᎐O), 151.6, 136.9,

᎐

3

2

C

3

CDCl₃) 7.94 (1H, d, J 7, ArH), 7.80 (1H, d, J 8, ArH), 7.65 (1H,

d, J 8, ArH), 7.42 (1H, t, J 8, ArH), 7.40 (1H, d, J 8, ArH),

5.60 (1H, s, CHOH), 4.14 (1H, d, J 15.5, Me₂NCH_AH_B),

3.88 (1H, d, J 15.5, Me₂NCH_AH_B), 3.52 [1H, septet, J 7,

NCH(CH₃)₂], 3.05 [1H, septet, J 7, NCH(CH₃)₂], 2.20 (6H,

s, NMe₂), 1.60 (3H, d, J 7, NCHCH₃), 1.55 (3H, d, J 7,

NCHCH₃), 1.50 [2H, m, CH₂(CH₂)₄CH₃], 1.40 [2H, m,

CH₂CH₂(CH₂)₃CH₃], 1.20 [6H, m, (CH₂)₃CH₃], 0.90 (3H, d,

J 7, NCHCH₃), 0.85 (3H, d, J 7, NCHCH₃), 0.85 (3H, t, J 7,

134.8, 131.6, 129.0, 126.4, 126.1, 125.5, 124.2, 116.7 (ArC), 88.0

(COH), 78.4, 62.4 (alkyne C), 50.5, 50.2 (NMe₂), 45.9, 43.5

(NCH × 2), 31.2, 28.5, 28.4, 22.4, 20.5 (5 × CH₂), 20.4,

20.2, 19.4, 18.9 (4 × CH₃), 13.9 (CH₃); m/z (CI) 437 (40%,

(M ϩ H)^ϩ), 419 (73), (EI) 226 (75), 210 (73) and 86 (47, 2 × i-Pr)

(Found: (M ϩ H)^ϩ, 437.3173. C₂₈H₄₀N₂O₂requires M ϩ 1,

437.3168).

9-(Dimethylamino)-3-(oct-1-ynyl)-1,3-dihydronaphtho[1,2-c]-

furan-1-one 47

CH ); δ (75 MHz, CDCl ) 170.0 (C᎐O), 138.3, 135.6, 134.2,

᎐

3

C

3

131.5, 130.2, 130.2, 127.8, 127.5, 126.3, 124.4 (ArH), 88.0

(COH), 80.1, 79.4 (alkyne C), 61.5 (Me₂NCH₂), 50.8

(NMe₂), 46.3, 45.6 (2 × NCH), 31.2, 28.4, 22.4, 20.3, 20.2

(5 × CH₂), 20.0, 19.8, 19.6, 18.8 (4 × CH₃), 13.9 (CH₃); m/z (CI)

451 (100%, (M ϩ H)^ϩ) (Found (EI): (M ϩ H)^ϩ, 451.3332.

C₂₉H₄₂N₂O₂requires M, 451.3246).

By method B, n-butyllithium (0.43 ml; 1.6 M solution in

hexane), oct-1-yne (0.14 m, 0.91 mmol), chlorotitanium triiso-

propoxide (0.30 ml; 1 M solution in hexane) and aldehyde 41

(150 mg, 0.46 mmol) gave, after puriﬁcation by ﬂash chromato-

graphy [1:6 EtOAc–petrol], the lactone 47 as a yellow oil (0.17

g, 83%); R_f[1:6 EtOAc–petrol] 0.2; δ_H(300 MHz, CDCl₃) 7.98

(1H, d, J 8, ArH), 7.80 (1H, d, J 8, ArH), 7.60 (1H, d, J 8,

ArH), 7.45 (1H, d, J 7, ArH), 7.10 (1H, t, J 7, ArH), 5.90 (1H, s,

COCH), 4.60 (1H, m, alkyne-CH_AH_B), 4.45 (1H, m, alkyne-

CH_AH_B), 2.90 (3H, s, NMe), 2.85 (3H, s, NMe), 1.65 (2H, t,

J 7, alkyne-CH₂CH₂), 1.28 (6H, m, (CH₂)₂CH₃), 0.90 (3H,

m, CH₃).

Method B. Alternatively, n-butyllithium (0.8 ml; 1.6 M solu-

tion in hexane) was added dropwise to a stirred solution of

oct-1-yne (0.20 ml, 1.3 mmol) in THF (30 ml) under nitrogen

at Ϫ78 ЊC. After 30 min at Ϫ78 ЊC, chlorotitanium triisoprop-

oxide (0.34 g, 1.3 mmol) was added dropwise and the mixture

warmed to 0 ЊC and stirred at this temperature for 45 min. The

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

3245

View Article Online

(R*a,1ЈS*) and (R*a,1ЈR*)-N,N-Diisopropyl-2-(1Ј-hydroxynon-

2Ј-ynyl)-8-methoxy-1-naphthamide anti-46b and syn-46b

102 (100), (EI) 199 (27), 86 (55, 2 × i-Pr), 84 (70) and 49 (100)

(Found (EI): M^ϩ, 315.1838. C₁₉H₂₅NO₃requires M, 315.1834).

By method A, n-butyllithium (1.1 ml; 1.6 M solution in

hexane), oct-1-yne (0.2 ml, 1.4 mmol) and aldehyde 42 (150 mg,

0.48 mmol) gave a crude product. Analytical HPLC of the

crude mixture showed that the atropisomers were present in a

ratio of 1 (anti):3 (syn). Puriﬁcation by column chromato-

graphy [1:2 EtOAc–petrol], gave the anti alcohol anti-46b (14

mg, 7%) as a pale yellow oil; R_f[1:2 EtOAc–petrol] 0.56; δ_H(300

MHz, CDCl₃) 7.74 (2H, d × 2, J 8.5, ArH), 7.34 (1H, t, J 7,

ArH), 7.30 (1H, d, J 8, ArH), 6.77 (1H, d, J 6.5, ArH), 5.60

(1H, s, HOCH), 3.80 (3H, s, OMe), 3.45 [1H, septet, J 7,

NCH(CH₃)₂], 3.35 [1H, septet, J 7, NCH(CH₃)₂], 2.6 (1H, br,

OH), 2.10 (CH₂, m, alkyne-CH₂), 1.60 (3H, d, J 7, NCHCH₃),

1.55 (3H, d, J 7, NCHCH₃), 1.30–1.10 [8H, m, (CH₂)₄], 1.0–0.8

[6H, d × 2, J 7, NCH(CH₃)₂], 0.80 (3H, t, J 7, CH₃); δ_C(75

Method D. Alternatively, n-butyllithium (1.1 ml; 1.6 M solu-

tion in hexane) was added dropwise to a stirred solution of

oct-1-yne (0.2 ml, 1.4 mmol) in THF (10 ml) under nitrogen at

Ϫ78 ЊC. After 30 min at Ϫ78 ЊC Me₃Al (24 µl; 2 M solution in

hexane) was added and the mixture stirred at this temperature

for 30 min. The aldehyde 42 (150 mg, 0.48 mmol) was added

and the mixture stirred for 30 min at Ϫ78 ЊC and the mixture

warmed to room temperature for 30 min. Saturated aqueous

NH₄Cl was added and the product extracted with dichloro-

methane (2 × 30 ml). The extracts were washed with brine (30

ml), dried (MgSO₄) and evaporated under reduced pressure.

Analytical HPLC of the crude mixture showed that the atrop-

isomers were present in a ratio of 21 (anti):1 (syn). Puriﬁcation

by column chromatography on SiO₂[1:2 EtOAc–petrol] gave

anti-46b (81 mg, 40%).

MHz, CDCl ) 169.4 (C᎐O), 155.8, 135.4, 134.7, 130.8, 128.5,

᎐

3

126.5, 125.6, 121.1, 120.8, 106.3 (ArC), 87.4 (COH), 80.8, 69.5

(alkyne), 61.5 (OMe), 50.9, 45.8 (NCH × 2), 31.2, 28.7, 28.3,

22.4, 20.4 (5 × CH₂), 20.1, 19.4, 18.8, 18.7 (4 × CH₃), 13.9

(CH₃); m/z (CI) 424 (100%, (M ϩ H)^ϩ), (EI) 86 (100, 2 × i-Pr),

43 (79, i-Pr) (Found (EI): M^ϩ, 423.2770. C₂₇H₃₇NO₃requires

M, 423.2773).

When Et₃Al was used in place of Me₃Al, only starting

material (97%) was recovered.

(S_a,1ЈR)-N,N-Diisopropyl-2-(1Ј-hydroxynon-2Ј-ynyl)-8-

methoxy-1-naphthamide (؉)-anti-46b

Also obtained was the syn alcohol syn-46b (73 mg, 37%) as a

pale yellow oil; R_f[1:2 EtOAc–petrol] 0.33; δ_H(300 MHz,

CDCl₃) 8.00 (1H, d, J 8.5, ArH), 7.75 (1H, d, J 8.5, ArH), 7.39

(1H, d, J 8, ArH), 7.34 (1H, t, J 8, ArH), 6.80 (1H, d, J 7, ArH),

5.70 (1H, s, HOCH), 3.85 (3H, s, OMe), 3.65 (1H, m, OH), 3.52

[1H, septet, J 7, NCH(CH₃)₂], 3.40 [1H, septet, J 7, NCH-

(CH₃)₂], 2.25 (2H, td, J 7 and 2, alkyne CH₂), 1.60 (3H, d,

J 7, NCHCH₃), 1.55 (3H, d, J 7, NCHCH₃), 1.35 [2H, m,

CH₂(CH₂)₃CH₃], 1.30–1.10 [6H, m, (CH₂)₃CH₃], 0.90 (3H, d,

J 7, NCHCH₃), 0.85 (3H, d, J 7, NCHCH₃), 0.80 (3H, t, J 7,

By method D, enantiomerically pure (Ϫ)-42 (0.37 g, 1.17 mmol)

gave optically active alcohol (ϩ)-anti-46b (0.20 g, 40%) as white

plates; mp 122–126 ЊC; [α]_D²³ϩ61 (c = 1, CH₂Cl₂).

(R_a,2ЈR,4ЈS)-N,N-Diisopropyl-8-(dimethylamino)-2-[2Ј-phenyl-

perhydropyrrolo[1,2-c]imidazol-3Ј-yl]-1-naphthamide 53a

The diamine 52⁶³(75 mg, 0.46 mmol) was added to a solution

of the aldehyde 41 (150 mg, 0.46 mmol) in toluene (20 ml). The

solution was heated to reﬂux in a Dean–Stark apparatus for

20 h, cooled and the toluene was removed under reduced pres-

sure. Puriﬁcation by ﬂash chromatography on alumina [1:20

EtOAc–petrol] gave the aminal 53a (170 mg, 79%) as colour-

less plates; R_f[1:20 EtOAc–petrol] 0.40; ν_max(ﬁlm)/cm^Ϫ12928

CH ); δ (75 MHz, CDCl ) 169.4 (C᎐O), 155.8, 135.4, 134.7,

᎐

3

C

3

130.8, 128.5, 126.2, 125.6, 121.1, 120.8, 106.3 (ArC), 87.4

(COH), 80.8, 69.5 (alkyne), 61.5 (OMe), 50.6, 45.8 (NCH × 2),

31.2, 28.4, 28.3, 22.4, 20.4 (5 × CH₂), 20.1, 19.4, 18.8, 18.7

(4 × CH₃), 13.9 (CH₃); m/z (CI) 424 (8%, (M ϩ H)^ϩ), (EI) 86

(98, 2 × i-Pr) (Found (EI): M^ϩ, 423.2770. C₂₇H₃₇NO₃requires

M, 423.2773).

(CH), 1618 (N–C᎐O); δ (300 MHz, CDCl ) 7.65 (1H, d, J 8,

᎐

H

3

ArH), 7.40 (1H, d, J 7, ArH), 7.35 (1H, t, J 8, ArH), 7.20 (1H,

d, J 8, ArH), 7.10 (1H, d, J 8, ArH), 7.10 (2H, 2 × t, J 7, ArH),

6.75 (2H, 2 × d, J 8, ArH), 6.60 (1H, t, J 7, ArH), 6.10 (1H,

s, NCHN), 4.1 (1H, t, J 7, NCHCH₂), 3.95 (1H, t, J 7, PhN-

CH_AH_B), 3.44 (1H, septet, J 7, NCHCH₃), 3.3 (2H, m, NCH₂-

CH₂and C), 2.80 (3H, s, NMe), 2.75 (2H, m, NCHCH₃and

PhNCH_AH_B), 2.60 (3H, s, NMe), 2.00–1.80 (4H, m, CH₂CH₂),

1.65 [6H, 2 × d, J 7, NCH(CH₃)₂], 0.90 (3H, d, J 7, NCHCH₃),

0.7 (3H, d, J 7, NCHCH₃); m/z (CI) 485 (50%, (M ϩ H)^ϩ), (EI)

86 (63, 2 × i-Pr) (Found (EI): (M ϩ H)^ϩ, 485.3278. C₃₁H₄₀N₄O

requires M ϩ 1, 485.3280).

Method C. Alternatively, n-butyllithium (1.1 ml of a 1.6 M

solution in hexane) was added dropwise to a stirred solution of

oct-1-yne (0.2 ml, 1.4 mmol) in THF (10 ml) under nitrogen at

Ϫ78 ЊC. After 30 min at Ϫ78 ЊC DIBAL-H (1.4 ml, 1.4 mmol)

was added and the mixture stirred at this temperature for 30

min. The aldehyde 42 (150 mg, 0.48 mmol) was added and the

mixture was stirred for 30 min at Ϫ78 ЊC and warmed to room

temperature. Saturated aqueous NH₄Cl was added and the

mixture was extracted with dichloromethane (2 × 30 ml). The

extracts were washed with brine (30 ml), dried (MgSO₄) and

evaporated under reduced pressure. Analytical HPLC of the

crude mixture showed that the atropisomers were present in a

ratio of >99 (anti):1 (syn). Puriﬁcation by column chromato-

graphy [1:2 EtOAc–petrol] gave only anti-46b (130 mg, 65%).

On one occasion, using an essentially identical method, alde-

hyde 42 (2.0 g, 6.4 mmol) gave N,N-diisopropyl-2-(hydroxy-

methyl)-8-methoxy-1-naphthamide 51 (1.8 g, 88%) as a white

solid; mp 205–207 ЊC; R_f[1:4 EtOAc–petrol] 0.45; δ_H(300 MHz,

CDCl₃) 7.60 (1H, d, J 8.5, ArH), 7.43 (1H, d, J 8, ArH), 7.28

(1H, d, J 8.5, ArH), 7.24 (1H, t, J 8, ArH), 6.73 (1H, d, J 6,

ArH), 4.76 (1H, d, J 12, CH_AH_BOH), 4.40 (1H, d, J 12, CH_A-

H_BOH), 3.78 (3H, s, OMe), 3.44 [1H, septet, J 7, NCH(CH₃)₂],

3.28 [1H, septet, J 7, NCH(CH₃)₂], 1.60 (3H, d, J 7, NCHCH₃),

1.55 (3H, d, J 7, NCHCH₃), 0.85 (3H, d, J 7, NCHCH₃), 0.80

(S_a,2ЈR,4ЈS)-N,N-Diisopropyl-8-methoxy-2-[2Ј-phenylperhydro-

pyrrolo[1,2-c]imidazol-3-yl]-1-naphthamide 54a

The diamine 52⁶³(470 mg, 2.9 mmol) was added to a solu-

tion of the aldehyde 42 (600 mg, 1.9 mmol) in xylene (50 ml).

The solution was heated to reﬂux in a Dean–Stark apparatus

for 3 days and cooled and the xylene was removed under

reduced pressure. Puriﬁcation of the crude product (obtained in

quantitative yield) by column chromatography on alumina [1:4

EtOAc–petrol] gave the aminal 54a (540 mg, 60%) as an

amorphous solid; mp 207–210 ЊC; R_f[1:4 EtOAc–petrol] 0.23;

ν_max(ﬁlm)/cm^Ϫ12968 (CH), 1623 (N–C᎐O); δ (300 MHz,

᎐

H

CDCl₃) 7.56 (1H, d, J 8.5, ArH), 7.27 (2H, 2 × d, J 7, ArH),

7.18 (1H, t, J 8.5, ArH), 7.06 (2H, t, J 7, ArH), 6.76 (1H, t, J 5,

ArH), 6.62 (2H, d, J 8, ArH), 6.49 (1H, t, J 7, ArH), 5.92 (1H,

s, NCHN), 4.08 (1H, m, NCHCH₂), 3.86 (3H, s, OMe), 3.74

(1H, t, J 8, PhNCH_AH_B), 3.52 (1H, septet, J 7, NCH(CH₂)₂),

3.30 [3H, m, NCH(CH₃)₂and NCH₂CH₂], 2.62 (1H, q, J 7,

PhNCH_AH_B), 2.00–1.80 (4H, m, CH₂CH₂), 1.70 [6H, 2 × d,

J 7, NCH(CH₃)₂], 1.14 (3H, d, J 7, NCHCH₃), 0.84 (3H, d, J 7,

(3H, d, J 7, NCHCH ); δ (75 MHz, CDCl ) 171.8 (C᎐O), 135.2,

᎐

3

C

3

134.4, 128.5, 128.4, 127.8, 126.4, 126.2, 125.7, 120.8, 120.8

(ArC), 105.9 (CH₂OH), 62.7 (OMe), 50.8, 45.9 (NCH × 2),

20.4, 20.3, 20.2, 19.4 (4 × CH₃); m/z (CI) 316 (32%, (M ϩ H)^ϩ),

3246

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

View Article Online

NCHCH ); δ (75 MHz, CDCl ) 170.3 (C᎐O), 155.8, 145.5,

d, J 8.5, ArH), 7.40 (2H, m, ArH), 6.90 (1H, dd, J 6.5, ArH),

᎐

3

C

3

137.0, 134.4, 131.9, 129.1, 128.2, 125.9, 124.7, 121.7, 120.8,

115.7, 112.2, 105.9 (ArC), 79.5 (ArCHR₂), 60.6 (OMe), 55.3,

53.6, 52.7 (ring C), 50.9, 46.0 (NCH × 2), 27.9, 23.4 (ring

C), 21.3, 20.4, 19.8, 19.7 (4 × CH₃); m/z (CI) 472 (100%,

(M ϩ H)^ϩ), (EI) 471 (17, M), 427 (100), 212 (100) and 86 (52,

2 × i-Pr) (Found (EI): M^ϩ, 471.2892. C₃₀H₃₇N₃O₂requires M,

471.2886).

5.76 (2H, m, RCHOH and alkene), 5.55 (1H, dd, J 9 and 7, cis

alkene), 3.94 (3H, s, OMe), 3.64 [1H, septet, J 7, NCH(CH₃)₂],

3.48 [1H, septet, J 7, NCH(CH₃)₂], 2.30 [2H, m, CH₂(CH₂)₄-

CH₃], 1.80 (3H, d, J 7, NCHCH₃), 1.75 (3H, d, J 7, NCHCH₃),

1.50–1.10 [8H, m, (CH₂)₄CH₃], 1.00 (3H, d, J 7, NCHCH₃), 0.95

(3H, d, J 7, NCHCH₃), 0.80 (3H, t, J 7, CH₃); δ_C(75 MHz,

CDCl ) 169.8 (C᎐O), 155.8 (alkene), 137.4, 133.3, 131.3, 130.5,

᎐

3

128.5, 126.2, 125.2, 121.2, 120.7, 106.2 (ArC), 66.6 (HCOH),

55.2 (OMe), 50.6, 45.8 (NCH × 2), 31.6, 29.4, 28.9, 27.6, 22.5,

21.0 (CH₂× 6), 20.3, 20.2, 20.1, 19.4 (4 × CH₃), 14.0 (CH₃);

m/z (CI) 426 (5%, (M ϩ H)^ϩ), 102 (100), (EI) 391 (52), 167 (65),

86 (42, 2 × i-Pr) and 74 (100) (Found (EI): M^ϩ, 425.2921.

C₂₇H₃₉NO₃requires M, 425.2929).

(R)-N,N-Diisopropyl-2-formyl-8-methoxy-1-naphthamide

(؊)-42

1 M aqueous HCl (50 ml) was added to a solution of the crude

mixture of diastereoisomers of aminal 54 (0.124 g, 0.27 mmol)

in methanol at 0 ЊC. After 30 min at room temperature the

mixture was extracted with dichloromethane (2 × 60 ml). The

extracts were washed with sodium bicarbonate solution and

with brine, dried (MgSO₄) and evaporated under reduced pres-

sure. The residue was recrystallised from ethyl acetate to give

the aldehyde (Ϫ)-42 (78 mg, 92%) as white prisms; mp 190–

192 ЊC; [α]_D²³Ϫ9.2 (c = 1, CH₂Cl₂). Analytical HPLC of the crude

reaction mixture on chiral stationary phase indicated 62% ee.

In the same way, hydrolysis of puriﬁed 54a (1.0 g, 2.12 mmol)

gave a residue which was recrystallised from ethyl acetate to

give the aldehyde (Ϫ)-42 (627 mg, 94%) as white prisms; mp

191–192 ЊC, [α]_D²³Ϫ15 (c = 1, CH₂Cl₂). Analytical HPLC of the

crude reaction mixture on chiral stationary phase indicated

99% ee. Evaporation of the mother liquors returned diamine 52

(270 mg, 80%).

(3ЈR)-N,N-Diisopropyl-2-[(E)-3Ј-(N,N-dimethylcarbamoyl-

methyl)non-1Ј-enyl]-8-methoxy-1-naphthamide 59

N,N-Dimethylacetamide dimethyl acetal (100 µl, 0.75 mmol)

was added to a solution of the cis alcohol (Z)-57 (64 mg, 0.15

mmol) in xylene (20 ml). The solution was heated to reﬂux for

20 h, cooled, and poured into dichloromethane (25 ml) and

saturated aqueous NH₄Cl (25 ml). The layers were separated,

and the aqueous layer extracted with dichloromethane (2 × 25

ml). The combined organic fractions were dried (MgSO₄), ﬁl-

tered, and concentrated under reduced pressure. Puriﬁcation

by column chromatography [1:1 EtOAc–petrol] gave one

diastereoisomer of the amide 59 as a pale yellow oil (20 mg,

27%); R_f(EtOAc) 0.40; [α]_D²³ϩ27.6 (c = 1, EtOH); ν_max(ﬁlm)/

cm^Ϫ12928 (CH), 1630 (C᎐O); δ (300 MHz, CDCl ) 7.70 (2H,

᎐

H

3

s, ArH), 7.35 (2H, m, ArH), 6.85 (1H, d, J 7, ArH), 6.80 (1H,

d, J 15.5, trans alkene), 6.40 (1H, dd, J 8 and 15.5, trans alkene),

3.95 (3H, s, OMe), 3.50 [2H, 2 × septet, J 7, NCH(CH₃)₂], 3.05

(3H, s, NMe), 2.95 (3H, s, NMe), 2.80 (1H, m, alkene-CHR₂),

2.45 (2H, 2 × d, J 7, NCHCH₃), 1.70 (3H, d, J 7, NCHCH₃),

1.65 (3H, d, J 7, NCHCH₃), 1.30 (3H, d, J 7, NCHCH₃), 1.40–

1.20 [10H, m, (CH₂)₅CH₃], 0.95 (3H, d, J 7, NCHCH₃), 0.85

(3H, t, J 7, CH₃); δ_C(75 MHz, CDCl₃) 171.7, 170.3, 155.7, 135.7,

134.2, 131.2, 130.9, 127.8, 126.8, 125.9, 123.7, 121.7, 120.8,

106.2, 55.2, 50.9, 45.7, 39.4, 38.7, 37.4, 35.4, 35.0, 31.7, 22.6,

20.5, 20.4, 20.3, 14.1 (Found (EI): M^ϩ, 494.3511. C₃₁H₄₆N₂O₃

requires M, 494.3508).

(S_a,1ЈS)-N,N-Diisopropyl-2-[(2E )-1Ј-hydroxynon-2-enyl]-8-

methoxy-1-naphthamide (E )-57

Red-Al^(0.17 ml, 0.87 mmol) was added dropwise over 20 min

to the alkyne (ϩ)-anti-46b (184 mg, 0.43 mmol) in ether (5 ml)

at 0 ЊC under nitrogen. After 1 h, water (2 ml) was added drop-

wise and the mixture, which was extracted into ether. The

extracts were washed with brine, dried (MgSO₄) and evaporated

under reduced pressure. Puriﬁcation by column chromato-

graphy on SiO₂[1:4 EtOAc–petrol] gave the alkene (E)-57

(183 mg, 99%) as a yellow oil; R_f[1:4 EtOAc–petrol] 0.26; [α]_D²³

ϩ130 (c = 1, EtOH); ν_max(ﬁlm)/cm^Ϫ13424 (OH), 2926 (CH),

1616 (C᎐O), 828 (alkene CH); δ (300 MHz, CDCl ) 7.72 (1H,

᎐

H

3

Also obtained was a second diastereoisomer of amide 59 as a

pale yellow oil (10 mg, 14%); R_f(EtOAc) 0.15; ν_max(ﬁlm)/cm^Ϫ1

d, J 8.5, ArH), 7.56 (1H, d, J 8.5, ArH), 7.34 (2H, m, ArH), 6.80

(1H, dd, J 7, ArH), 5.70 (2H, m, CH᎐CH), 5.43 [1H, ﬁne

᎐

2894 (CH), 1641 (C᎐O); δ (300 MHz, CDCl ) 7.70 (2H, m,

᎐

H

3

m, CHOH], 3.84 (3H, s, OMe), 3.50 [2H, septet × 2, J 7,

NCH(CH₃)₂], 1.90 [2H, m, CH₂(CH₂)₄CH₃], 1.60 (3H, d, J 7,

NCHCH₃), 1.55 (3H, d, J 7, NCHCH₃), 1.20 [8H, m, (CH₂)₄-

CH₃], 0.90 (3H, d, J 7, NCHCH₃), 0.85 (3H, d, J 7, NCHCH₃),

ArH), 7.35 (2H, m, ArH), 6.85 (1H, d, J 7, ArH), 6.80 (1H, d,

J 15.5, trans alkene), 6.25 (1H, dd, J 8, 15.5, trans alkene), 3.90

(3H, s, OMe), 3.50 [2H, 2 × septet, J 7, NCH(CH₃)₂], 3.00 (3H,

s, NMe), 2.95 (3H, s, NMe), 2.75 (1H, m, alkene-CHR₂), 2.45

(2H, 2 × d, J 7, NCH(CH₃)₂), 1.70 (3H, d, J 7, NCHCH₃), 1.65

(3H, d, J 7, NCHCH₃), 1.40–1.10 [10H, m, (CH₂)₅CH₃], 0.95

(3H, d, J 7, NCHCH₃), 0.90 (3H, d, J 7, NCHCH₃), 0.85 (3H, t,

J 7, CH₃); δ_C(75 MHz, CDCl₃) 171.6, 170.3, 155.7, 135.6, 134.2,

131.0, 131.0, 127.8, 127.0, 125.9, 123.5, 121.6, 120.8, 55.2, 50.9,

45.8, 39.2, 37.5, 35.4, 34.9, 31.8, 29.3, 27.7, 22.6, 20.8, 20.5, 14.0

(Found (EI): M^ϩ, 494.3513. C₃₁H₄₆N₂O₃requires M, 494.3508).

0.80 (3H, t, J 7, CH ); δ (75 MHz, CDCl ) 169.7 (C᎐O), 155.8,

᎐

3

C

3

136.8 (alkene), 134.5, 132.2, 131.2, 130.5, 128.5, 126.2, 124.7,

121.2, 120.8, 106.2 (ArC), 71.1 (RCH(OH)R), 55.2 (OMe),

50.6, 45.7 (CHN × 2), 32.1, 31.6, 28.9, 28.8, 22.5 (5 × CH₂),

20.5, 20.4, 20.3, 19.5 (4 × CH₃), 13.9 (CH₃); m/z (CI) 426 (18%,

(M ϩ H)^ϩ), 408 (80), 102 (100), (EI) 408 (50), 324 (52) and 86

(100, 2 × i-Pr) (Found (EI): M^ϩ, 425.2926. C₂₇H₃₉NO₃requires

M, 425.2929).

Ethyl (S_a,1R,E)-5-[1-(diisopropylcarbamoyl)-8-methoxy-2-

naphthyl]-3-hexylpent-4-enoate 64

(S_a,1ЈS) N,N-Diisopropyl-2-[(2Z )-1Ј-hydroxynon-2Ј-enyl]-8-

methoxy-1-naphthamide (Z )-57

Triethyl orthoacetate (26 µl, 0.14 mmol) and propionic acid

(1 µl, cat.) were added to a solution of the alcohol (Z)-57 (20

mg, 0.05 mmol) in toluene (20 ml). The solution was heated to

reﬂux for 12 h, cooled, and concentrated under reduced pres-

sure. Puriﬁcation by ﬂash chromatography [1:4 EtOAc–petrol]

gave a single diastereoisomer of the ester 64 as a pale yellow oil

(21 mg, 84%); R_f[1:4 EtOAc–petrol] 0.38; [α]_D²³ϩ20 (c = 1,

EtOH); δ_H(300 MHz, CDCl₃) 7.62 (2H, s, ArH), 7.28 (2H, m,

ArH), 6.78 (1H, d, J 7, ArH), 6.73 (1H, d, J 16, trans alkene),

6.08 (1H, dd, J 8 and 16, trans alkene), 4.05 (2H, m,

OCH₂CH₃), 3.83 (3H, s, OMe), 3.40 [2H, 2 × septet, J 7,

Alkyne (ϩ)-anti-46b (209 mg, 0.5 mmol) and Lindlar catalyst

(42 mg, cat.) were stirred in n-BuOH (50 ml) at room temper-

ature under 1 atm of hydrogen. After hydrogen uptake ceased

in 24 h, the mixture was ﬁltered through a thin pad of Celite,

washed with EtOAc, dried (MgSO₄) and the solvent removed

under reduced pressure. Puriﬁcation by column chromato-

graphy [1:4 EtOAc–petrol] gave the alkene (Z)-57 (180 mg,

85%) as a yellow oil; R_f[1:4 EtOAc–petrol] 0.44; [α]_D²³ϩ130

(c = 1, EtOH); ν_max(ﬁlm)/cm^Ϫ13424 (OH), 2928 (CH), 1617

(C᎐O); δ (300 MHz, CDCl ) 7.84 (1H, d, J 8.5, ArH), 7.72 (1H,

᎐

H

3

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

3247

View Article Online

N(CH(CH ) ) ], 2.65 (1H, m, CH ᎐CH CHR ), 2.38 (2H, 2 × d,

CCDC reference number 207/466. See http://ww w .rsc.org/

᎐

3

2

J 7, EtOCOCH₂R₂), 1.60 (3H, d, J 7, NCHCH₃), 1.55 (3H, d,

J 7, NCHCH₃), 1.40 [2H, m, CH₂(CH₂)₄CH₃], 1.30–1.10 [14H,

m, NCHCH₃, (CH₂)₄CH₃and OCH₂CH₃], 0.90 (3H, d, J 7,

NCHCH₃), 0.80 [3H, t, J 7, (CH₂)₅CH₃]; δ_C(75 MHz, CDCl₃)

172.4, 170.2, 155.7, 134.8, 134.3, 131.2, 131.1, 128.4, 127.7,

127.6, 125.9, 123.7, 120.8, 106.2, 60.1, 55.3, 50.9, 45.8, 40.1,

39.4, 34.9, 31.6, 29.8, 26.9, 22.6, 20.4, 20.3, 19.6, 14.2, 14.0.

(Found (EI): M^ϩ, 495.3343. C₃₁H₄₅NO₄requires M, 495.3348).

suppdata/p1/b0/b004682p/ for crystallographic ﬁle in .cif

format.

References

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2 J. Clayden, Angew. Chem., Int. Ed. Engl., 1997, 36, 949.

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36, 9219.

4 P. Bowles, J. Clayden, M. Helliwell, C. McCarthy, M. Tomkinson

and N. Westlund, J. Chem. Soc., Perkin Trans. 1, 1997, 2607.

5 J. Clayden, N. Westlund and F. X. Wilson, Tetrahedron Lett., 1996,

37, 5577.

6 J. Clayden, N. Westlund, R. L. Beddoes and M. Helliwell, J. Chem.

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13 J. Clayden, P. Johnson, J. H. Pink and M. Helliwell, J. Org. Chem.,

2000, in press.

(R)-3-(Hydroxymethyl)-N,N-dimethylnonamide (؊)-61¹⁵

A solution of naphthamide 59 (30 mg, 0.06 mmol) in MeOH at

0 ЊC was treated with a steady stream of ozone in oxygen for 60

min at 0 ЊC. Excess ozone was removed by passing a stream of

oxygen through the reaction mixture for 10 min, and the reac-

tion mixture was diluted with 50% aqueous ethanol (8 ml).

Sodium borohydride (23 mg, 0.6 mmol) was carefully added,

and the reaction mixture was allowed to warm to 23 ЊC and

stirred for a further 1 h. Concentrated hydrochloric acid (0.5

ml) and EtOAc (30 ml) were added. The solution was washed

with saturated aqueous NaHCO₃(10 ml), water (10 ml) and

brine (10 ml), dried (Na₂SO₄) and concentrated under reduced

pressure. Flash chromatography (1:1 MeOH–EtOAc) gave the

alcohol (Ϫ)-61¹⁵as a pale yellow oil (10 mg, 77%); R_f[1:1

EtOAc–petrol] 0.25; δ_H(300 MHz, CDCl₃) 3.70 (1H, dd, J 11

and 4, CH_AH_BOH), 3.50 (1H, dd, J 11 and 4, CH_AH_BOH), 3.08

(3H, s, NMe_AMe_B), 3.00 (3H, s, NMe_AMe_B), 2.53 (1H, dd, J 4

and 16, OCCH_AH_B), 2.40 (1H, dd, J 9 and 16, OCH_AH_B), 2.10

(1H, m, HOCH₂CH), 1.30 [10H, m, (CH₂)₅], 0.9 (3H, t, J 7,

CH₂Me).

14 Preliminary communication: J. Clayden, C. McCarthy and J. G.

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Asymmetry, 1998, 9, 1427.

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New York, 1994.

Also obtained was 2-(N,N-diisopropylcarbamoyl)-3,6-bis-

(hydroxymethyl)benzoic acid 60; δ_H(300 MHz, CDCl₃) 7.73

(1H, d, J 8, ArH), 7.40 (1H, d, J 8, ArH), 5.25 (2H, m,

ArCH₂OH), 4.73 (1H, dd, J 12.5 and 1.5, ArCH_AH_BOH),

4.46 (1H, dd, J 12.5 and 9, ArCH_AH_BOH), 3.6–3.4 (2H, m,

NCH × 2), 1.61 (3H, d, J 7, Me), 1.54 (3H, d, J 7, Me), 1.12

(3H, d, J 7, Me), 1.00 (3H, d, J 7, Me); m/z (CI) 292 (100%,

(M Ϫ OH)^ϩ).

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Determination of enantiomeric excess of (؊)-61. (ϩ)-MTPACl

(17 mg, 0.069 mmol) was added to a solution of alcohol (Ϫ)-61

(10 mg, 0.046 mmol), Et₃N (19 µl, 0.138 mmol), and DMAP

1

(3 mg) in CDCl₃(100 µl). After 1 h, H NMR of the mixture

revealed complete consumption of 61 and conversion into a

single diastereoisomer of 62. Comparison with the diastereo-

isomeric esters formed from (ϩ)- or ( )-MTPACl and (ϩ)-61¹⁵

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X-Ray crystallography

Crystal data for syn-46b: C₂₇H₃₇NO₃, M_r= 423.58. A colourless

block (ca. 0.50 × 0.37 × 0.35 mm³) was mounted on a glass

ﬁbre and analysed with a Rigaku AFC-5R diﬀractometer.

¯

Cu-Kα radiation (λ = 1.5418 Å), triclinic, space group P1,

a = 11.0048(15), b = 12.0970(18), c = 10.7206(16) Å, α =

103.229(13), β = 94.072(14), γ = 113.705(11)Њ, V = 1250.6(3) Å³,

Z = 2, ρ_calcd= 1.125 Mg m^Ϫ3, µ(Cu-Kα) = 0.566 mm^Ϫ1. Total

number of reﬂections measured = 5244 of which 4966 were

independent; R_int= 0.0154, 2850 reﬂections were observed,

(I > 2.0σ(I )). Hydrogen atoms were included in constrained

positions, except for H2, which was found by diﬀerence Fourier

techniques and reﬁned isotropically. Atoms of the C₆H₁₃group

showed high thermal motion, especially towards the end of the

chain. Reﬁnement on F²with 290 parameters gave R₁= 0.0728,

wR²= 0.2382 (all data), S = 1.048, ∆/σ_max= 0.003. Maximum

and minimum residual electron density = 0.271 and Ϫ0.217

e Å^Ϫ3respectively. Data collection: MSC/AFC Diﬀractometer

Control. Cell reﬁnement: MSC/AFC Diﬀractometer Control.

Data reduction: teXsan.⁷⁴Program used to solve structure:

SHELXS86. Program used to reﬁne structure: SHELXL97.⁷⁵

3248

J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

View Article Online

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J. Chem. Soc., Perkin Trans. 1, 2000, 3232–3249

3249

Article Doi

Atropisomeric benzamides and naphthamides as chiral auxiliaries

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