Alkylation and aldol reactions of acyl derivatives of N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine: asymmetric synthesis of α-alkoxy-, α-substituted-β-alkoxy- and α,β-dialkoxyaldehydes

Tetrahedron 66 (2010) 4167–4194

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Tetrahedron

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Alkylation and aldol reactions of acyl derivatives of N-1-(1⁰-naphthyl)ethyl-

O-tert-butylhydroxylamine: asymmetric synthesis of

a-alkoxy-,

a

-substituted-

b-alkoxy- and

a

,b

-dialkoxyaldehydes

,

a

b

Alexander N. Chernega ^a, Stephen G. Davies ^a, Ai M. Fletcher , Christopher J. Goodwin ,

*

David Hepworth ^{a y}, R. Shyam Prasad ^a, Paul M. Roberts ^a, Edward D. Savory ^a, Andrew D. Smith ^a,

,

James E. Thomson ^a

^aDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansﬁeld Road, Oxford OX1 3TA, UK

^bAstraZeneca R&D Charnwood, Process R&D, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK

a r t i c l e i n f o

a b s t r a c t

Treatment of a range of O-protected glycolate derivatives of the chiral auxiliary N-1-(1⁰-naphthyl)ethyl-

O-tert-butylhydroxylamine with KHMDS in the presence of 18-crown-6 followed by addition of an alkyl

Article history:

Received 11 January 2010

Received in revised form 11 March 2010

Accepted 29 March 2010

Available online 2 April 2010

halide generates

a-substituted derivatives with very high levels of diastereoselectivity. Alternatively,

reaction of the potassium enolate of a propanoate or O-protected glycolate derivative of N-1-(1⁰-naph-

thyl)ethyl-O-tert-butylhydroxylamine with a range of aldehydes gives syn-aldol products with high levels

of diastereoselectivity. These adducts may be reductively cleaved with LiAlH₄to give enantiopure

Keywords:

Weinreb amide

Glycolate enolate

Diastereoselective alkylation

Aldol reaction

a

-alkoxy-,

a-substituted-

b

-alkoxy- and

a

,b

-dialkoxyaldehydes in good yield.

1. Introduction

As part of our ongoing exploitation of this auxiliary for the

synthesis of enantiopure building blocks,⁵we examined the prep-

aration of glycolate derivatives of 1 and their subsequent stereo-

selective alkylation and aldol reactions, followed by reductive

Chiral glycolate enolates are useful synthetic intermediates for

the preparation of -hydroxy carbonyl compounds through ster-

eoselective alkylation reactions, and -dihydroxy carbonyl com-

a

a,

b

cleavage to facilitate the preparation of a-hydroxy- and a,b-dihy-

pounds through stereoselective aldol reactions, as demonstrated by

the application of both these approaches to the synthesis of

complex natural product targets.¹We have recently reported that

N-acyl derivatives of N-1-(1⁰-naphthyl)ethyl-O-tert-butylhydroxyl-

amine 1 are able to act as chiral Weinreb amide equivalents.^2,3

Treatment of N-acyl derivatives 2 with KHMDS followed by an al-

kyl halide proceeds with high levels of diastereoselectivity (>95:5

droxyaldehydes. The results of these investigations are delineated

herein.

dr) to give the corresponding a-substituted derivatives 3 in good

yield and as single diastereoisomers (>99:1 dr) after puriﬁcation.

We have rationalized the stereochemical outcome of these alkyl-

ation reactions by invoking a chiral relay mechanism.⁴Treatment of

3 with LiAlH₄or MeLi gives direct access to the corresponding

a

-stereogenic aldehyde or ketone 4 (Fig. 1).

Figure 1. Alkylation of chiral Weinreb amide equivalents 2, derived from N-1-(1⁰-

naphthyl)ethyl-O-tert-butylhydroxylamine 1, and cleavage to give homochiral carbonyl

compounds 4. [1-Nap¼1-naphthyl.].

* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).

Present address: Pﬁzer Groton Laboratories, Eastern Point Road, Groton,

CT 06340, USA.

y

doi:10.1016/j.tet.2010.03.105

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A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

2. Results and discussion

allyl alcohol and 3,4-dimethoxybenzyl alcohol in an analogous

reaction protocol, respectively (Scheme 3).

2.1. Synthesis of

naphthyl)ethyl-O-tert-butylhydroxylamine

a

-alkoxyacetyl derivatives of N-1-(1⁰-

O

(ii)

Br

OR

a-Alkoxy hydroxamates 5–7 were prepared upon treatment of the

1-Nap

N

1-Nap

N

diastereoisomerically pure camphorsulfonic acid (CSA) salt (R)-

1$(ꢀ)-CSA [or (S)-1$(þ)-CSA]²with the requisite O-protected glycolic

acid chloride under Schotten–Baumann⁶conditions (Scheme 1).

O^tBu

8

O^tBu

6, R = allyl, 75%

7, R = PMB, 61%

9, R = DMB, 74%

(i)

O

(i)

OR

OPMB

O^tBu

1-Nap

NH•(−)-CSA

O^tBu

+

1-Nap

N

O^tBu

1-Nap

N

1-Nap

N

H

O^tBu

7, 24%

(R)-1•(−)-CSA

5, R = Bn, 93%^†

6, R = allyl, 55%^†

7, R = PMB, 78%

10 and 11

10, 32%,>99:1 dr

Scheme 3. Reagents and conditions: (i) NaH (1.5 equiv), PMBOH (2.0 equiv), THF, 0 ^ꢁ

C

Scheme 1. Reagents and conditions: (i) ROCH₂COCl, NaOH (2 M aq), CH₂Cl₂, 0 ^ꢁC to rt.

[1-Nap¼1-naphthyl. PMB¼4-methoxybenzyl. ^yReaction performed in both enantio-

meric series].

to rt, 6 h; (ii) NaOR (1.05 equiv), 15-crown-5, Bu₄N^{þ ꢀ}(cat), THF, 0 ^ꢁC to rt, 2 h.

I

[1-Nap¼1-naphthyl. PMB¼4-methoxybenzyl. DMB¼3,4-dimethoxybenzyl. ^yReaction

performed in the opposite enantiomeric series].

Although this method was generally high yielding, preparation

of some of the O-protected glycolic acid chlorides required multi-

step syntheses. We have previously shown that acylation of 4-al-

kyl-5,5-dimethyloxazolidin-2-one (SuperQuat) chiral auxiliaries⁷

with bromoacetyl bromide can be followed by displacement of

The production of the diastereoisomeric acetals 10 and 11 in

these reactions was unexpected. The corresponding O-benzyl and

O-allyl compounds 13–16 were also produced as the major prod-

ucts when (R)-8 was treated with an excess of the corresponding

alkoxide ion in the absence of tetrabutylammonium iodide. There

appear to be two plausible mechanisms for this interesting rear-

rangement. Displacement of bromide by alkoxide gives the cor-

responding alkoxyacetyl adduct; in the presence of excess

alkoxide, this species may be deprotonated to give an enolate 12,

which may rearrange by two possible pathways. Homolytic ﬁssion

of the weak NꢀO bond leads to a radical pair 19, contained in

a solvent cage.⁹The electrophilic tert-butoxy radical attacks the

enolate radical anion to give 21, which gives the diastereoisomeric

acetal products upon work-up. This mechanism is analogous to

that of the well-known [1,2]-Wittig rearrangement of ethers¹⁰and

the Stevens rearrangement of quaternary ammonium salts.¹¹Al-

ternatively, heterolytic ﬁssion of the NꢀO bond, assisted by the

oxygen lone pair, results in an ion pair 20 conﬁned within a sol-

vent cage.⁹The tert-butoxide anion attacks the oxonium moiety to

form 21, leading to the acetals upon work-up. This mechanism also

bromide ion with a secondary amine to give

a-aminoacetyl

SuperQuat derivatives for use in aldol reactions,⁸and it was

anticipated that a similar approach could be employed for the

preparation of the desired glycolate derivatives of 1. Acylation of

(R)-1$(ꢀ)-CSA with bromoacetyl bromide and K₂CO₃in CH₂Cl₂gave

N-bromoacetyl hydroxamate 8 in quantitative yield after chroma-

tography (Scheme 2).

O

(i)

Br

1-Nap

NH•(−)-CSA

O^tBu

N

1-Nap

O^tBu

(R)-1•(−)-CSA

8, quant

Scheme 2. Reagents and conditions: (i) BrCH₂COBr, K₂CO₃, CH₂Cl₂, 0 ^ꢁC. [1-Nap¼1-

naphthyl.].

has a close relative in

b

-lactam chemistry¹²where it is possible to

-carbon of the enolate of a -lactam

Attempted preparation of 4-methoxybenzyloxyacetyl adduct 7

add nucleophiles to the

a

b

from bromide

8

by displacement with sodium 4-methoxy-

derivative bearing a good leaving group on the nitrogen atom. In

order to probe these mechanistic hypotheses (i.e., that the dia-

stereoisomeric acetals result from an enolate decomposition

pathway), hydroxamate (S)-9 was treated with KHMDS; the so-

lution turned pale yellow, consistent with the presence of the

enolate, and was held at ꢀ78 ^ꢁC for 1 h. After aqueous work-up ¹H

NMR spectroscopic analysis revealed only the presence of starting

material (quantitative mass return), indicating that the potassium

enolate of (S)-9 is stable at ꢀ78 ^ꢁC. However, when the experiment

was repeated and the mixture was allowed to warm to 0 ^ꢁC over

30 min, an 80:20 mixture of the diastereoisomeric acetals 17 and

18 was produced. Chromatography allowed partial separation,

giving a sample enriched in the major diastereoisomer in 86:14 dr

benzyloxide (prepared by treatment of 4-methoxybenzylalcohol

with NaH) gave 50% conversion to 7. An attempt to drive the

reaction to completion by increasing the number of equivalents of

alkoxide resulted in >90% consumption of starting material to

give a mixture of the required product and the diastereoisomeric

acetals 10 and 11 [whose absolute C(2)-conﬁgurations were not

assigned]. Chromatography allowed isolation of the desired

product 7 and the less polar acetal 10 in 24 and 32% yield,

respectively. Repeated column chromatography failed to afford

a pure sample of the more polar acetal diastereoisomer 11. Op-

timisation of this reaction to favour the production of 7 revealed

that long reaction times and the use of excess alkoxide were

deleterious, and resulted in decomposition of required product 7

to acetals 10 and 11. However, when the displacement reaction

was conducted with 1.05 equiv of sodium 4-methoxybenzyloxide

in the presence of 15-crown-5 and catalytic tetrabutylammonium

iodide in THF, a 90:5:5 mixture of 7:10:11 (along with trace

amounts of other unknown impurities) was produced, from which

7 was isolated in 61% yield after chromatography. This procedure

is readily applicable to gram-scale synthesis, and enabled the

synthesis of glycolate derivatives 6 and 9 in good yield by use of

and 73% yield, and

a sample enriched in the minor di-

astereoisomer in 58:42 dr and 17% yield. An analogous procedure

applied to (S)-5 gave an 80:20 mixture of acetals 13 and 14.

Chromatography allowed the isolation of the major di-

astereoisomer in 53% yield and >95:5 dr, and the minor di-

astereoisomer in 10% yield and 93:7 dr, after further puriﬁcation

by crystallisation. Similar treatment of (R)-6 resulted in the for-

mation of 15 and 16 (80:20 dr) as the only products; no trace of

any products resulting from a [2,3]-Wittig rearrangement were

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4169

O

(i)

Br

OR

O^tBu

OR

1-Nap

N

1-Nap

N

H

1-Nap

N

O^tBu

8

O^tBu

12

13 and 14, R = Bn, 79%*

15 and 16, R = allyl, 34%*

O

(ii)

O

OR

O^tBu

1-Nap

N

1-Nap

N

Me

H

O^tBu

5, R = Bn

6, R = allyl

9, R = DMB

1-Nap

N

O^tBu

22

13 and 14, R = Bn, 63%*

15 and 16, R = allyl, 64%*

17 and 18, R = DMB, 90%*

O

homolytic

O

N−O fission

OR

1-Nap

N

1-Nap

N

O^tBu

solvent cage

19

12

heterolytic

N O fission

−

O

OR

1-Nap

N

1-Nap

O^tBu

solvent cage

20

21

Scheme 4. Reagents and conditions: (i) NaH, ROH, THF, 0 ^ꢁC to rt, 2 h; (ii) KHMDS, THF, ꢀ78 ^ꢁC to 0 ^ꢁC, 1 h. [1-Nap¼1-naphthyl. PMB¼4-methoxybenzyl. DMB¼3,4-dimethox-

ybenzyl. *Combined yield for both diastereoisomers].

noted. In contrast to these observations, we have previously

reported that the potassium enolate of (RS)-22 does not fragment

or rearrange upon warming,²which suggests that the presence of

the oxygen atom within 5–7 and 9 is important in promoting this

enolate fragmentation reaction (Scheme 4).

O

(ii)

OBn

O^tBu

1-Nap

N

1-Nap

N

H

13:14

O^tBu

5

80:20

13 and 14

50%, >99:1 dr

(i)

23:24

98:2

2.2. Alkylation reactions of

a

-alkoxyacetyl hydroxamates

-alkoxyacetate derivatives

O

OBn

+

With an efﬁcient route to a range of

a

1-Nap

N

1-Nap

N

5–7 and 9 in hand, attention focused on their diastereoselective

elaboration by enolate alkylation. Having established that the

potassium enolate derived from the O-DMB glyoxalate derivative 9

was stable at ꢀ78 ^ꢁC but rearranged upon warming to rt, it was

hoped that enolate alkylation reactions of 5–7 and 9 could be

carried out at ꢀ78 ^ꢁC as our previous studies in this area have

revealed enolates derived from hydroxamates such as 22 are

highly reactive, even at ꢀ78 ^ꢁC, and undergo efﬁcient alkylation

reactions with less reactive alkyl halides such as ethyl iodide.²

Under our previously reported conditions,^2,4treatment of 5 with

KHMDS in THF at ꢀ78 ^ꢁC followed by addition of MeI gave 23 in

98:2 dr. Chromatographic puriﬁcation gave (2R,1⁰S)-23 in 74% yield

and >99:1 dr. The relative conﬁguration within 23 was assigned

by analogy to the alkylation reactions of the simple acyl de-

rivatives (e.g., 22),^2,4with the absolute conﬁguration being

assigned from the known (S)-stereocentre within the chiral aux-

iliary. Encouraged by this initial result, alkylation with less reactive

electrophiles was investigated. Unfortunately, treatment of 5 with

KHMDS followed by ethyl iodide or pentyl iodide returned only

staring material in both cases. When the alkylation reaction with

pentyl iodide was allowed to warm slowly to rt, an 80:20 mixture

of the diastereoisomeric acetals 13 and 14 was produced, in-

dicating that enolate fragmentation, rather than alkylation, was

the favoured pathway (Scheme 5).

O^tBu Me

23, 74%, >99:1 dr

O^tBu Me

24

Scheme 5. Reagents and conditions: (i) KHMDS, THF, ꢀ78 ^ꢁC, 30 min, then MeI,

ꢀ78 ^ꢁC, 8 h; (ii) KHMDS, THF, ꢀ78 ^ꢁC, 30 min, then C₅H₁₁I, ꢀ78 ^ꢁ

[1-Nap¼1-naphthyl.].

C to rt, 24 h.

These results suggest that the enolate derived from 5 is less

nucleophilic than those of the standard acyl derivatives of the chiral

auxiliary 1 (e.g., the enolate derived from 22). It was therefore

reasoned that the reactivity of the enolate needed to be increased to

allow efﬁcient alkylation by a range of unactivated electrophiles.

We have previously demonstrated that benzylation of the potas-

sium enolate derived from hydroxamate 22 proceeds with high

levels of diastereoselectivity at ꢀ78 ^ꢁC both in the absence and

presence of 18-crown-6.⁴It was hoped that employing this additive

with hydroxamate 5 would generate the corresponding (more re-

active) ‘naked’ enolate, which may undergo alkylation at ꢀ78 ^ꢁC.

Deprotonation of 5 in the presence of 18-crown-6 followed by ad-

dition of pentyl iodide at ꢀ78 ^ꢁC gave >90% conversion to a single

diastereoisomer (>95:5 dr) of alkylated product. Puriﬁcation gave

28 in 63% yield and >99:1 dr. Encouraged by these results, a range

of alkylation reactions of hydroxamates 5–7 and 9 were performed.

In each case, excellent levels of diastereoselectivity were noted and

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A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

O

(i) or (ii)

OR

1-Nap

N

1-Nap

N

O^tBu

O^tBu R'

5-7 and 9

23 and 25-35

Scheme 6. Reagents and conditions: (i) KHMDS, THF, ꢀ78 ^ꢁC, 30 min, then R⁰X, ꢀ78 ^ꢁC, 8 h; (ii) KHMDS, 18-crown-6, THF, ꢀ78 ^ꢁC, 30 min, then R⁰X, ꢀ78 ^ꢁC, 8 h. [1-Nap¼1-

naphthyl. PMB¼4-methoxybenzyl. DMB¼3,4-dimethoxybenzyl. Ar¼2-bromophenyl. ^aCrude. ^bIsolated yield of major diastereoisomer (>99:1 dr). ^yReaction performed in the

opposite enantiomeric series. ^zReaction performed in both enantiomeric series].

the alkylated products 23 and 25–35 were isolated as single di-

astereoisomers (>99:1 dr) after puriﬁcation by column chroma-

tography. In each case, the conﬁguration of the newly formed

stereocentre within the major diastereoisomeric product was

assigned by analogy to the simple alkyl systems and in the case of

29 was proven unambiguously by independent synthesis from

methyl (S)-lactate (Scheme 6).

Rather than isolate the aldehyde directly, it could be readily

trapped by treatment of the crude reaction mixture with an ylide.

Reduction of hydroxamate (2R,1⁰S)-23 with LiAlH₄and treatment of

the crude product mixture with Ph₃P]CHCO₂Me gave a 30:20:50

3

mixture of oleﬁn isomers (R,E)-42 (for which J_2,3¼15.8 Hz) and

(R,Z)-43 (for which ³J_2,3¼11.8 Hz), and auxiliary 1, which were iso-

lated in 49, 32 and 95% yield, respectively, from 23. Despite their

relatively frequent occurrence in the literature¹⁹there appears to

be some discrepancy concerning the speciﬁc rotations of 42 and 43.

23

For (R,E)-42, we obtained [

a

]

þ67.0 (c 1.2 in CHCl₃); cf. lit. for

2.3. Cleavage of

a-alkoxyacetyl hydroxamates: synthesis of

D

enantiomer^19a

[

a

]

D

ꢀ44 (c 0.2 in CHCl₃); lit. for enantiomer^19g

[a]

D

20

23

a

-alkoxyacetyl aldehydes, ketones and iodolactones

23

ꢀ34.8 (c 1.2 in CHCl₃). For (R,Z)-43 we obtained [

a

]

ꢀ55.9 (c 0.7 in

D

CHCl₃); cf. lit. for enantiomer^19a

[a

]

þ36 (c 0.6 in CHCl₃); lit. for

20

Reduction of hydroxamate (2S,1⁰R)-23 with LiAlH₄gave the

D

22

25

enantiomer^19b

[

a]

þ25.5 (c 1.0 in CHCl₃); lit.^19j

[

a

]

ꢀ49.2 (c 0.5 in

known aldehyde (S)-36¹³and auxiliary (R)-1. Separation was ach-

ieved by precipitation of (R)-1$(ꢀ)-CSA from pentane, which

allowed isolation of (S)-36 in quantitative yield and 97:3 er, and (R)-

1 in 87% yield and >99:1 er¹⁴after basiﬁcation and extraction. The

enantiomeric purity of 36 was determined by reduction to the

D

CHCl₃). However, the previously reported preparative routes to

these compounds either perform a Wittig reaction in protic sol-

vents or a Wadsworth–Emmons-type oleﬁnation reaction using

a Group I metal hydride as the base. Either of these conditions could

easily cause racemisation of the stereochemically labile aldehyde

36.²⁰It is notable that the speciﬁc rotations obtained by Valverde

et al.^19aand Annunziata et al.^19b,19g(who report values for both

isomers) are smaller than the values obtained by us by factors of

approximately 0.5 and 0.65, respectively, for both isomers, sug-

gesting that that the aldehyde starting material 36 may have been

racemised at some stage. In order to determine the enantiomeric

purity of (R,E)-42 and (R,Z)-43, the racemates were prepared by an

identical route, starting from (2RS,1⁰SR)-23, and analysis of these

samples by chiral HPLC showed (R,E)-42 and (R,Z)-43 to be of 99:1

er and 98:2 er, respectively. Thus, little or no racemisation occurs

during the Wittig reaction under our conditions and, therefore, the

speciﬁc rotations determined here are reliable (Scheme 8).

known alcohol 39^13,15and conversion to the corresponding

21

Mosher’s ester.¹⁶The speciﬁc rotation of 39 {[

a

]

þ40.0 (c 0.1 in

D

CHCl₃); lit.¹³

[

a]

þ45.9 (c 6.4 in CHCl₃); lit.¹⁵

[

]

þ44.7 (c 3.5 in

20

D

CHCl₃)} conﬁrmed the absolute (S)-conﬁguration, and with it the

absolute (2S,1⁰R)-conﬁguration within hydroxamate 23, since the

auxiliary was known to have the (R)-conﬁguration. This analysis

also established that the facial selectivity observed in the enolate

alkylation of a-benzyloxyacetate derivative 5 was identical to that

previously reported for standard acyl derivatives such as 22.^2,4An

analogous procedure applied to hydroxamates 25 and 26 gave al-

dehydes 37¹⁷and 38,¹⁸which were assessed to be 98:2 er in both

cases by reduction to alcohols 40¹⁷and 41,^18cand subsequent

conversion to the corresponding Mosher’s esters¹⁶(Scheme 7).

O

OH

(i), (ii)

OBn

(i)

OBn

+

1-Nap

NH

O^tBu

1-Nap

N

H

O^tBu

R

(S)-1, >99:1 er

87% from 23

85% from 25

85% from 26

23, R = Me

36, R = Me, quant

37, R = allyl, 93%

38, R = Et, 98%

39, R = Me, 97:3 er

40, R = allyl, 98:2 er

41, R = Et, 98:2 er

25, R = allyl

26, R = Et

Scheme 7. Reagents and conditions: (i) LiAlH₄, THF, ꢀ10 ^ꢁC; (ii) (þ)-CSA, pentane. [^yReaction performed in the opposite enantiomeric series].

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4171

MeO₂C

CO₂Me

OBn

O

(i), (ii)

OBn

+

OBn

1-Nap

NH

1-Nap

N

O^tBu

O^tBu Me

Me

23

(S)-1, 95%

>99:1 er

(R,E)-42, 49%

>99:1 dr

(R,Z)-43, 32%

>99:1 dr

99:1 er

98:2 er

Scheme 8. Reagents and conditions: (i) LiAlH₄, THF, ꢀ10 ^ꢁC; (ii) Ph₃P]CHCO₂Me, CH₂Cl₂, ꢀ10 ^ꢁC to rt.

The reduction/Wittig oleﬁnation procedure was repeated for 23

using Ph₃P]CHCON(Me)(OMe). This afforded -unsaturated

Weinreb amide 44 in a much improved (E)/(Z) ratio of 90:10. The

C]C bond geometry within 44 was readily assigned from the

coupling constant of 15.9 Hz between the vinylic protons in the ¹H

NMR spectrum. This reaction sequence was also applied to

27 gave indanone 50 and auxiliary (S)-1, which were separated by

precipitation of (S)-1$(þ)-CSA from pentane, followed by distillation

of the residue to afford 50 in 89% yield and >99:1 er.²²Auxiliary (S)-1

was recovered in 74% yield and >99:1 er¹⁴upon basiﬁcation of the

precipitate and basic aqueous extraction (Scheme 11).

a,b

hydroxamates 31 and 33 to produce the a,b-unsaturated Weinreb

O

amides 45 and 46 as the major products [(E)/(Z) ꢂ93:7 in each

case], which were isolated in good yield as single diastereoisomers

after chromatographic separation from auxiliary 1. The vinylic

coupling constants in the ¹H NMR spectra of 45 and 46 (15.7 Hz for

45, 15.4 Hz for 46) were indicative of a trans-conﬁgured oleﬁn

(Scheme 9).

(i)

OBn

+

1-Nap

NH

O^tBu

1-Nap

N

Me

O^tBu Me

23

Me

(S)-1, 82%

>99:1 er

49, 84%

>99:1 er

O

N

O^tBu

27

(ii)

OBn

O

+

1-Nap

NH

O^tBu

(S)-1, 74%

OBn

1-Nap

O

Me

(i), (ii)

N

OBn

+

1-Nap

NH

O^tBu

50, 89%

1-Nap

N

MeO

OBn

>99:1 er

O^tBu Me

Br

Me

(

)-1, 95%

S

Scheme 11. Reagents and conditions: (i) MeLi, Et₂O, ꢀ15 ^ꢁC; (ii) ^tBuLi (2 equiv), Et₂O,

ꢀ78 ^ꢁC.

23

>99:1 er

(R,E)-44, 82%, >99:1 dr

O

N

O^tBu C₅H₁₁

Me

N

Reaction of 25 with I₂in THF/H₂O required eight days before the

starting material was consumed; failure to let the reaction proceed

to completion caused problems in the puriﬁcation of the products.

The reaction produced a number of by-products, and the trans/cis

ratio was tentatively assigned as 85:15. Nevertheless, 51 was iso-

lated in 46% yield and >99:1 dr after ﬂash column chromatography.

The trans relative conﬁguration within 51 was assigned on the basis

of a ¹H NMR NOE difference experiment (Scheme 12).

(i), (ii)

OR

1-Nap

NH

O^tBu

1-Nap

MeO

OR

C₅H₁₁

(R)-1, >99:1 er

96% from 31

quant from 33

31, R = allyl

33, R = PMB

(S,E)-45, R = allyl

77%, >99:1 dr

(S,E)-46, R = PMB

89%, >99:1 dr

Scheme 9. Reagentsandconditions:(i)LiAlH₄,THF, ꢀ10 ^ꢁC;(ii) Ph₃P]CHCON(Me)(OMe),

CH₂Cl₂, ꢀ10 ^ꢁC to rt.

O

(i)

Weinreb amide 46 was oxidatively debenzylated by treatment

with CAN to provide 47 in 90% yield, which has been used for the

synthesis of the fatty-acid metabolite Coriolic acid 48 reported by

Bennani and Sharpless²¹(Scheme 10).

OBn

O

1-Nap

N

O^tBu

I

25

51, 46%

>99:1 dr

Scheme 12. Reagents and conditions: (i) I₂, THF/H₂O (3:1).

CO₂H

O

( )₆

Me

(i)

N

2.4. Aldol reactions of a-alkyl and a-alkoxy hydroxamates

MeO

OPMB

MeO

OH

Having developed efﬁcient methodology for the asymmetric

synthesis of -alkoxy substituted compounds, attention was turned

to the production of -alkoxy- and -dialkoxy substituted de-

C₅H₁₁

)-46

C₅H₁₁

a

(

E

(E)-47, 90%

coriolic acid 48

b

a,b

rivatives. It was hoped that this goal could be achieved by

employing an asymmetric aldol reaction. Enolate aldol reactions of

hydroxamate 22 were ﬁrst investigated. Treatment of 22 with

KHMDS in THF at ꢀ78 ^ꢁC gave a bright yellow solution, consistent

with enolate formation. Addition of benzaldehyde followed by

aqueous work-up after 5 min gave >90% conversion to 52 in >95:5

dr. Puriﬁcation gave 52 in 72% yield and >99:1 dr. The relative

conﬁguration within 52 was unambiguously established by single-

Scheme 10. Reagents and conditions: (i) CAN, MeCN, H₂O.

Treatment of (2R,1⁰S)-23 with methyllithiumgave a 50:50 mixture

ofmethylketone49andauxiliary(S)-1, whichwereseparatedbyﬂash

column chromatography to give 49 in 84% yield and >99:1 er,²²and

auxiliary 1 in 82% yield and >99:1 er.¹⁴A halogen-metal exchange

cyclisationprocedure using 2-bromobenzyl substituted hydroxamate

4172

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

crystal X-ray analysis, with the absolute (2S,3S,1⁰R)-conﬁguration

being assigned from the known (R)-conﬁguration of the auxiliary

(Fig. 2); furthermore the determination of a Flack parameter²³for

the structure of þ0.17(1), which satisﬁes the criterion for a reliable

assignment of absolute conﬁguration of a material known to be

homochiral,²⁴allowed the absolute (2S,3S,1⁰R)-conﬁguration to be

conﬁrmed. Further analysis of the X-ray crystal structure of 52

revealed that the relative conﬁguration of the nitrogen atom in-

duced by the adjacent stereogenic carbon centre is in contrast to

that in the X-ray structure of the alkylated hydroxamate derivative

3 (R¼Bn, R⁰¼Me) previously reported by us,²and that a hydrogen-

bond is present between the C(3)-hydroxyl and carbonyl group. The

hydrogen-bonded chelate has a ﬂattened chair-type conformation,

minor isomer 53 observed in the crude reaction mixture was

assigned a syn-relative conﬁguration based upon the ³J_2,3coupling

constant of 3.2 Hz²⁶(Scheme 13).

In order to test the generality of this asymmetric aldol reaction,

the reaction was performed using a variety of aldehydes. Reaction

of the potassium (Z)-enolate of 22 with pivalaldehyde gave 54 in

98:2 dr. Three diastereoisomeric products were noted in the re-

action with cinnamaldehyde, with the ratio of the major di-

astereoisomer to the sum of the others being conservatively

assigned as >95:5. Aldol reaction with isobutyraldehyde resulted in

incomplete conversion to 56 as the major diastereoisomeric prod-

uct and was accompanied by the formation of signiﬁcant quantities

of side products, thought to be aldehyde self-condensation prod-

ucts. Both these observations are consistent with the relatively high

basicity of the potassium enolate promoting proton transfer from

the enolisable aldehyde to the enolate; the resultant aldehyde

enolate presumably then undergoes self-aldol reaction. When the

reaction was run at ꢀ95 ^ꢁC, the diastereoselectivity of the reaction

remained the same although 56 was isolated in an improved 61%

yield and 97:3 dr. Finally, the aldol methodology was tested using

acetaldehyde, which gave 57 in 95:5 dr, which was isolated in 60%

yield and 95:5 dr. In each case, the absolute conﬁguration within

the major diastereoisomeric product was assigned by analogy to

that unambiguously established for the reaction with benzaldehyde

3

to give 52; in some cases the value of the J_2,3coupling constant

could be obtained (3.0–3.5 Hz) and was also supportive of these

assignments (Scheme 14).

The stereochemical outcome of these enolate aldol reactions

demonstrates that the facial selectivity observed is identical to that

noted upon enolate alkylation. Furthermore the high level of dia-

stereoselectivity observed here is notable, given that Group I metal

enolates usually show low levels of selectivity in their enolate re-

Figure 2. Chem3D representation of the single-crystal X-ray structure of 52 (some H

atoms omitted for clarity).

O

OH

O

OH

(i)

Me

+

1-Nap

N

1-Nap

N

Ph

1-Nap

N

Ph

52:53

O^tBu

22

O^tBu Me

52, 72%, >99:1 dr

O^tBu Me

53

>95:5 dr

H

^tBu

H

Ph

Me

H

O

Ph

O

1-Nap

H

O

H

O

N

H

1-Nap

N

O

^tBu

O

Me

52B favoured

52A disfavoured

Scheme 13. Reagents and conditions: (i) KHMDS, THF, ꢀ78 ^ꢁC, 30 min, then PhCHO, THF, ꢀ78 ^ꢁC, 5 min.

in which the C(2)-methyl group adopts a pseudo-axial position.

O

OH

(i)

Adoption of the usual auxiliary conformation would result in

a rather severe steric interaction between the tert-butyl group and

the pseudo-axial C(2)-methyl group (conformation 52A). In order

to avoid this unfavourable structure, the tert-butyl group prefers to

occupy the opposite face (conformation 52B), with the nitrogen

lone-pair syn-periplanar to it, i.e., a conformation about the N–O

bond in accordance with the preferred conformation for hydrox-

ylamine itself,²⁵in which lone pairs and bonds are eclipsed to

minimise lone pair–lone pair interactions. It is interesting to note

that an intramolecular hydrogen bond is formed, rather than the

putative preferred auxiliary conformation at nitrogen:⁴this sug-

gests that more energy is gained from the former than is lost by

adoption of an alternative conformation by the hydroxamate frag-

ment, although this may be a result of crystal packing effects. In

solution, it was noted that the ³J_2,3coupling constant of 2.1 Hz was

diagnostic of a syn-relationship.²⁶Following this analysis, the

Me

1-Nap

N

1-Nap

N

R

O^tBu

22

O^tBu Me

54-57

a

R

product

dr

yield % (dr)^b

^tBu

54

55

56

57

98:2

>95:5

92:8

60 (>99:1)

78 (>99:1)

42 (97:3)

60 (95:5)

(E)-CH=CHPh

ⁱPr

Me

95:5

Scheme 14. Reagents and conditions: (i) KHMDS, THF, ꢀ78 ^ꢁC, 30 min, then RCHO,

THF, ꢀ78 ^ꢁC, 2 h. [^aCrude. ^bPuriﬁed].

actions. Although the relative syn-conﬁgurations within 52 and

54–57 would be consistent with that predicted by reaction of the

intermediate potassium (Z)-enolate through a chelated, Zimmer-

man–Traxler,²⁷chair-like transition state, this seems unlikely due

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4173

H

K

O

Me

R

Me

O

N

O

OH

KHMDS

Me

H

1-Nap

N

O

1-Nap

N

R

then RCHO

1-Nap

O^tBu

O^tBu Me

^tBu

58

22

52 and 54-57

Figure 3. Postulated transition state 58 for aldol reaction of the potassium (Z)-enolate derived from hydroxamate 22.

to the known, low Lewis acidity of potassium ions. In order to probe

the role of the potassium counter-ion, reaction with benzaldehyde

was repeated but in the presence of 18-crown-6. The diaster-

eoselectivity of the reaction and yield of aldol products remained

unaffected, which may therefore suggest that the reaction proceeds

through reaction of the potassium (Z)-enolate [or ‘naked’ (Z)-eno-

late] through an open transition state²⁸such as 58, with enolate

diastereofacial selectivity consistent with our proposed chiral relay

model, which accounts for the high diastereofacial selectivity of

alkylation⁴(Fig. 3).

Reaction of the potassium (Z)-enolate of N-allyloxyacetyl

hydroxamate 6 with benzaldehyde was next investigated,²⁹which

gave aldol product 61 in 96:4 dr. Puriﬁcation gave 61 in 92% yield

and >99:1 dr. When the reaction was repeated in the presence of

18-crown-6, the diastereoselectivity and yield of the reaction

remained high. Application to a range of aldehydes (acetaldehyde,

butyraldehyde and pyridine-2-carboxaldehyde) gave similarly high

levels of selectivity with the major products being isolated in

modest to good yield after chromatography. The relative conﬁgu-

ration within the pyridine-2-carboxaldehyde adduct 64 was

established unambiguously by single-crystal X-ray analysis, with

the absolute (2S,3R,1⁰R)-conﬁguration being assigned from the

known (R)-conﬁguration within the auxiliary (Fig. 4). Therefore, the

absolute conﬁgurations within the other aldol products 61–63 were

assigned by analogy, with this analysis suggesting that the facial

selectivities in the propanoate and glycolate aldol reactions are the

same in this case.³⁰The similar levels of selectivity observed when

the reaction with benzaldehyde was performed either in the

presence or absence of 18-crown-6 underscores the insigniﬁcant

role of the potassium counterion in these reactions and is in ac-

cordance with an open transition state²⁸analogous to 58. In

a similar manner, aldol reactions of the O-benzyl, O-PMB and O-

DMB hydroxamates 5, 7 and 9 with a range of aliphatic, aromatic

and heteroaromatic aldehydes were performed and proceeded

with modest to good levels of diastereoselectivity. On occasion, the

presence of impurities in the ¹H NMR spectra of the crude reaction

mixtures prevented the determination of the reaction diaster-

eoselectivity. Reactions with acetaldehyde and 1-decanal pro-

ceeded to incomplete conversion, consistent with deprotonation of

the aldehyde by the basic enolate; these transenolisation processes

Figure 4. Chem3D representation of the single-crystal X-ray structure of 64 (some H

atoms omitted for clarity).

O

OH

(i) or (ii)

OR

1-Nap

N

1-Nap

N

R'

O^tBu

O^tBu OR

5-7 and 9

59-76

Scheme 15. Reagents and conditions: (i) KHMDS, THF, ꢀ78 ^ꢁC, 30 min, then R⁰CHO, ꢀ78 ^ꢁC, 8 h; (ii) KHMDS, 18-crown-6, THF, ꢀ78 ^ꢁC, 30 min, then R⁰CHO, ꢀ78 ^ꢁC, 8 h. [1-Nap¼1-

naphthyl. PMB¼4-methoxybenzyl. DMB¼3,4-dimethoxybenzyl. ^yReaction performed in the opposite enantiomeric series. ^aCrude. ^bPuriﬁed].

4174

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

also resulted in the production of large amounts of impurities de-

rived from polymerisation of the aldehyde. Chromatography gave

the desired aldol products 59, 60 and 65–76 in modest to good

yield. In all cases, the relative conﬁgurations within the products

were assigned by analogy to those proven unambiguously for 52

O

OH

O

OR'

(i) or (ii)

R’

1-Nap

N

R

1-Nap

N

R

O^tBu Me

52 and 55

O^tBu Me

79-81

3

and 64 and, in several cases, measurement of the ¹H NMR J_2,3

R

Ph

product

yield %

52

55

TBDMS

79

80

81

80

94

coupling constants were possible; the small values recorded

(J_2,3¼1.0–3.0 Hz) are consistent with the assigned syn-conﬁgura-

tions within these aldol adducts²⁶(Scheme 15).

BOM

(E)-CH=CHPh

BOM

Scheme 17. Reagents and conditions: (i) TBDMSCl, imidazole, DMF; (ii) BOMCl, ⁱPr₂NEt,

CH₂Cl₂, Bu₄NI, 48 h.

2.5. Cleavage of

b-alkoxy hydroxamates: synthesis of a,b-

dialkoxyaldehydes

BOM protected adducts 80 and 81 with LiAlH₄under the standard

conditions allowed exclusive production of the corresponding alde-

hydes (as single diastereoisomers, indicating that no epimerisation

was occurring during the cleavage step) and auxiliary (R)-1. Attempts

to isolate the aldehydes by ﬂash column chromatography on silica gel

were unsuccessful due to partial decomposition. Instead, the alde-

hydes were trapped by performing a Wittig reaction on the crude

reduction mixture to produce unsaturated esters 82 and 83, which

were obtained as single diastereoisomers after ﬂash column chro-

matography. The (E)-geometry of the oleﬁns was determined from

the characteristic ¹H NMR ³J coupling constants of 15.9 Hz in both 82

and 83. In both cases auxiliary (R)-1 was recovered in high yield and

>99:1 er¹⁴(Scheme 18).

Having obtained a number of aldol products with high di-

astereoisomeric purity, attention was turned to their trans-

formation into enantiomerically enriched products. Reductive

cleavage of the propanoate adducts with LiAlH₄to produce

a

-alkyl-

b-hydroxy-aldehydes was ﬁrst examined. Prior to this, it was

deemed prudent to protect the b-hydroxy group, in order to pre-

vent problems of retro-aldol reaction during cleavage or isolation of

the aldehyde products: benzyl, tert-butyldimethylsilyl (TBDMS)

and benzyloxymethyl (BOM) were investigated for this purpose.

Initially, it was hoped that a one-pot aldol reaction/O-protection

sequence may be developed, making use of the high nucleophilic-

ity of the intermediate potassium aldolate by its interception with

benzyl bromide. Aldol reaction of the enolate derived from 22 with

benzaldehyde was performed at ꢀ78 ^ꢁC before the addition of

benzyl bromide, and then the reaction mixture was allowed to

warm to 0 ^ꢁC. Analysis of the crude reaction product showed the

production of several diastereoisomeric products 77, consistent

with a reduction in selectivity occurring through a retro-aldol/re-

aldol process as the temperature was allowed to rise. This pre-

diction was reinforced by treatment of the diastereoisomerically

pure aldol product 52 with KHMDS and benzyl bromide at 0 ^ꢁC,

which gave the same mixture of O-benzylated products 77 ob-

served previously and the C-benzylated product 78,²which pre-

sumably arises from a retro-aldol fragmentation of the potassium

aldolate followed by trapping of the so-formed potassium enolate

by benzyl bromide²(Scheme 16).

Attempted application of an analogous procedure to facilitate

the preparation of a,b-dihydroxyaldehydes unfortunately met with

i

failure: treatment of 59 with BOMCl, Pr₂NEt and TBAI in CH₂Cl₂

returned a complex mixture of unidentiﬁed products. However,

when the aldol reaction of 5 with benzaldehyde was performed and

quenched with an excess of methyl iodide at low temperature, it

proved possible to trap the intermediate potassium aldolate to give

an 83:17 mixture of the diastereoisomeric products 84 and 88, re-

spectively. The absence of acetals 13 and 14 and starting material 5

suggests rapid, complete alkylation of the potassium aldolate anion

occurs at a temperature which is sufﬁciently low such that the

enolate decomposition pathway does not compete at an apprecia-

ble rate; the observation that the diastereoselectivities are slightly

lower than those of the aldol reactions themselves is consistent

O

OBn

Ph

(i)

Me

1-Nap

N

1-Nap

N

O^tBu

22

O^tBu Me

77

O

OH

O

N

OBn

Ph

(ii)

Me

Ph

+

1-Nap

N

O^tBu

1-Nap

N

Ph

O^tBu Me

52

O^tBu Me

77

78

Scheme 16. Reagents and conditions: (i) KHMDS, THF, ꢀ78 ^ꢁC, 30 min, then PhCHO, ꢀ78 ^ꢁC, 8 h, then BnBr, ꢀ78 ^ꢁC to rt; (ii) KHMDS, THF, 0 ^ꢁC, 30 min, then BnBr.

Protection of the hydroxyl group within 52 and 55 without re-

course to the formation of an intermediate aldolate was in-

vestigated. Thus, O-protection upon treatment with TBDMSCl and

BOMCl was achieved in high yield under mild conditions to give

79–81 in good yield (Scheme 17).

Attempts to cleave the auxiliary within O-silyl protected 79 with

LiAlH₄failed: at ꢀ10 ^ꢁC the reaction was prohibitively slow, and

allowing it to warm to rt led to a complex mixture of products, pos-

sibly due to over-reduction and/or protecting group loss. Presumably,

the bulkyprotecting grouphindersnucleophilicattackatthecarbonyl

with a degree of reversibility at the temperature of aldolate alkyl-

ation. Application to reaction of 6 and 9 with benzaldehyde, and 6

with acetaldehyde, gave mixtures of the corresponding di-

astereoisomeric products 85–87 (major products) and 89–91 (mi-

nor products). In each case, chromatographic puriﬁcation gave

samples of the major diastereoisomers 84–87 and in two cases it

was possible to isolate and fully characterise samples of the minor

diastereoisomers (88 and 91), for which the alternative relative syn-

conﬁguration was tentatively assigned (Scheme 19).

Treatment of 85 with LiAlH₄resulted in the exclusive production

of a 50:50 mixture of the corresponding aldehyde and auxiliary (R)-

1. The crude mixture was treated with Ph₃P]CHCO₂Me in the

group;itmayalsopreventchelationtothe

b-oxygenatom, whichmay

otherwise assist the cleavage reaction. However, treatment of both O-

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

OBOM

4175

O

OBOM

R

(i)

MeO₂C

+

1-Nap

NH

O^tBu

1-Nap

N

R

O^tBu Me

Me

82, R = Ph, 96%, >99:1 dr

E

(R)-1, >99:1 er

91% from 80

93% from 81

80, R = Ph

E

83, R = ( )-CH=CHPh, 93%, >99:1 dr

81, R = ( )-CH=CHPh

Scheme 18. Reagents and conditions: (i) LiAlH₄, THF, ꢀ10 ^ꢁC; (ii) Ph₃P]CHCO₂Me, CH₂Cl₂, ꢀ10 ^ꢁC to rt.

O

OMe

R'

O

OMe

R'

(i)

OR

+

1-Nap

N

1-Nap

N

1-Nap

N

O^tBu

5, 6 and 9

O^tBu OR

84-87, major

O^tBu OR

88-91, minor

yield of

a

R

R′

products

dr

major % (dr)^b

minor % (dr)^b

5

6

Bn

allyl

DMB

Ph

Me

Ph

84:88

83:17

88:12

-

72 (96:4)

73 (>99:1)

56 (>99:1)

63 (96:4)

10 (>99:1)

85:89

-

†

6_†

86:90_†

-

9

87:91

83:17

5 (>99:1)

Scheme 19. Reagents and conditions: (i) KHMDS, THF, ꢀ78 ^ꢁC, then RCHO, then MeI (15 equiv), ꢀ78 ^ꢁC to rt. [^yReaction performed in the opposite enantiomeric series. ^acrude.

^bpuriﬁed].

presence of powdered 3 Å molecular sieves to give 92

OH

OMe

Ph

OH

OMe

Ph

OH

OMe

Ph

(³J_2,3¼15.7 Hz) in 95:5 dr. Puriﬁcation gave auxiliary (R)-1 in 86%

yield and >99:1 er¹⁴and oleﬁn 92 in 59% yield and 95:5 dr from 85

(Scheme 20).

(i)

ODMB

93

OH

95

94, 87%

>99:1 dr

MeO₂C

O

OMe

Ph (i), (ii)

OMe

Ph

Scheme 22. Reagents and conditions: (i) DDQ, CH₂Cl₂/H₂O (5:1).

1-Nap

N

+

1-Nap

NH

O^tBu

O

butanol for 18 h³³gave the required product 97 as a 75:25 mixture of

diastereoisomers. Chromatography gave 97 in 47% yield, as an 88:12

mixture of diastereoisomers. The reaction of 61 with 0.1 equiv of

trans-Pd(NH₃)₂Cl₂gave 96 as an 86:14 mixture of diastereoisomers,

in 72% isolated yield (and 86:14 dr) after chromatography. The

palladium-catalysed procedure provided high yields of O-protected

aldol adducts in a single, experimentally simple synthetic step, and

the low diastereoselectivity of cyclisation is not believed to be

a drawback of this approach since the diastereoisomerism is only

a feature of the protecting group (Scheme 23).

O^tBu

85

(R)-1, 86%

>99:1 er

(E)-92, 59%

95:5 dr

Scheme 20. Reagents and conditions: (i) LiAlH₄, THF, ꢀ15 ^ꢁC; (ii) Ph₃P]CHCO₂Me, 3 Å

MS, CH₂Cl₂, 0 ^ꢁC to rt.

Reductive cleavage of 87 gave a 50:50 mixture of the corre-

sponding aldehyde and auxiliary (S)-1, which was treated, without

puriﬁcation, with LiAlH₄. Chromatographic puriﬁcation of the

crude reaction product gave auxiliary (S)-1 in 91% yield and >99:1

er¹⁴and alcohol 93 in 98% yield and >99:1 dr from 87 (Scheme 21).

O

OH

O

R

(i), (ii),

(i), (ii)

O

OMe

Ph

OH

OMe

Ph

1-Nap

N

R

(i)

1-Nap

N

O

+

1-Nap

N

O^tBu

O

1-Nap

NH

O^tBu

O

O^tBu ODMB

ODMB

Et

87

(S)-1, 91%

>99:1 er

93, 98%

61, R = Ph, >99:1 dr

62, R = Me, >99:1 dr

96, R = Ph, 72%, 86:14 dr

97, R = Me, 47%, 88:12 dr

>99:1 dr

Scheme 21. Reagents and conditions: (i) LiAlH₄, THF, ꢀ15 ^ꢁC; (ii) pH7 phosphate

Scheme 23. Reagents and conditions: (i) trans-Pd(NH₃)₂Cl₂, ^tBuOH, reﬂux.

buffer, pentane, 0 ^ꢁC.

Reductive cleavage of 96 using LiAlH₄, to give a 50:50 mixture of

auxiliary (S)-1 and the corresponding aldehyde, which was treated

with LiAlH₄without further puriﬁcation to give a mixture of (S)-1

and alcohol 98. Puriﬁcation by column chromatography afforded

auxiliary (S)-1 in 89% yield and >99:1 er¹⁴and alcohol 98 as a single

diastereoisomer (of unknown conﬁguration at the acetal stereo-

genic centre) in 53% yield from 96 (Scheme 24).

Similarly, sequential treatment of 96 with LiAlH₄followed by

Ph₃P]CHCO₂Me gave a mixture of auxiliary (S)-1, and (E)-oleﬁn

99 in 95:5 dr. Puriﬁcation by chromatography gave (S)-1 in 80%

yield and >99:1 er¹⁴and (E)-99 in 80% yield and 95:5 dr

(Scheme 25).

Alcohol 93 was subsequently debenzylated using DDQ to give

syn-94.³¹The anti-alcohol 95³²was absent by ¹H NMR spectro-

scopic analysis of the crude reaction mixture. Column chromatog-

raphy and recrystallisation from pentane afforded 94 in 87% yield

and >99:1 dr. The syn-conﬁguration within 94 further conﬁrms the

syn-diastereoselectivity of the aldol reactions (Scheme 22).

Analternative strategyfor protection of the O-allylglycolate aldol

adducts was also devised via formation of an acetal through allyl

isomerisation. Although reﬂuxing 61 or 62 with Wilkinson’s catalyst

for 3 h returned starting material, and reaction for extended periods

(>24 h) resulted in extensive decomposition to unknown product

mixtures, reﬂuxing 62 with trans-Pd(NH₃)₂Cl₂(0.33 equiv) in tert-

4176

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

OH Ph

O

Ph

points were recorded on a Gallenkamp Hot Stage apparatus and are

uncorrected. Optical rotations were recorded on a Perkin-Elmer 241

polarimeter with a water-jacketed 10 cm cell. Speciﬁc rotations are

reported in 10^ꢀ1deg cm²g^ꢀ1and concentrations in g/100 mL. IR

spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer as

either a thin ﬁlm on NaCl plates (ﬁlm) or a KBr disc (KBr), as stated.

Selected characteristic peaks are reported in cm^ꢀ1. NMR spectra

were recorded on Bruker Avance spectrometers in the deuterated

solvent stated. Spectra were recorded at rt unless otherwise stated.

The ﬁeld was locked by external referencing to the relevant deu-

teron resonance. The ¹³C NMR spectra of many of hydroxamate

derivatives contained peaks that were very broad (and in some

cases absent). Low-resolution mass spectra were recorded on either

a VG MassLab 20–250 or a Micromass Platform 1 spectrometer.

Accurate mass measurements were run on either a Bruker Micro-

TOF internally calibrated with polyalanine, or a Micromass GCT

instrument ﬁtted with a Scientiﬁc Glass Instruments BPX5 column

(15 mꢃ0.25 mm) using amyl acetate as a lock mass.

(i), (ii),

(i), (ii)

1-Nap

N

+

O

1-Nap

NH

O^tBu

O

O^tBu

Et

96, 86:14 dr

(

)-1, 89%

98, 53%

S

>99:1 er

>99:1 dr

Scheme 24. Reagents and conditions: (i) LiAlH₄, THF, ꢀ15 ^ꢁC; (ii) pH7 phosphate

buffer, pentane, 0 ^ꢁC.

Scheme 25. Reagents and conditions: (i) LiAlH₄, THF, ꢀ15 ^ꢁC; (ii) Ph₃P]CHCO₂Me, 3 Å

MS, CH₂Cl₂, 0 ^ꢁC to rt.

4.1.1. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl 2-benzyloxyacetamide

3. Conclusion

(R)-5.

The chiral auxiliary N-1-(1⁰-naphthyl)ethyl-O-tert-butylhy-

droxylamine has been used to promote highly diastereoselective

alkylation reactions on an

a-alkoxyacetate side chain. These

reactions generally require the addition of 18-crown-6 to en-

hance the rate of alkylation and suppress the enolate rear-

rangement which occurs at temperatures above ꢀ78 ^ꢁC. The

2-Benzyloxyacetyl chloride (4.50 g, 24.4 mmol) was added

dropwise to a vigorously stirred mixture of 2 M aq NaOH (20 mL,

40 mmol) and (R)-1$(ꢀ)-CSA (5.78 g, 12.2 mmol) in CH₂Cl₂

(30 mL) at 0 ^ꢁC. After 48 h, the reaction mixture was partitioned

between 1 M aq NaOH (100 mL) and CH₂Cl₂(100 mL), the layers

were separated and the aqueous layer was extracted with CH₂Cl₂

(3ꢃ100 mL). The combined organic extracts were dried and

concentrated in vacuo. Puriﬁcation via ﬂash column chroma-

tography (gradient elution, pentane/Et₂O, 19:1; increased to

pentane/Et₂O, 4:1) gave (R)-5 as a colourless oil (4.44 g, 93%); R_f

alkylated

into

enantiomeric purity. A number of O-protected

a-alkoxyacetate derivatives are readily transformed

a

-alkoxy aldehydes, ketones and iodolactones with high

-hydroxy-a,b-

g

unsaturated carbonyl compounds were also produced by a se-

quential reductive cleavage/Wittig reaction procedure. Alterna-

tively, aldol reaction of the potassium enolate gave syn-aldol

products upon reaction with an aldehyde. Good diastereocontrol

over both newly generated stereogenic centres was observed.

After suitable protection of the

b-hydroxyl group, the aldol

0.35 (pentane/Et₂O, 9:1); found C, 76.9; H, 7.6; N, 3.3%;

23

products may be reductively cleaved with LiAlH₄to afford al-

dehydes with high diastereoisomeric and enantiomeric purity.

Thus, the chiral auxiliary N-1-(1⁰-naphthyl)ethyl-O-tert-butylhy-

droxylamine has been shown to be effective for the synthesis of

a range of chiral oxygen-containing molecules in high enantio-

meric purity.

C₂₅H₂₉NO₃requires C, 76.7; H, 7.5; N, 3.6%; [

a]

þ28.6 (c 1.1 in

D

CHCl₃); n_max(ﬁlm) 1683 (C]O), 1600 (C]C); d_H(500 MHz,

PhMe-d₈, 70 ^ꢁC) 0.64 (9H, br s, CMe₃), 1.63 (3H, d, J 6.8, C(1⁰)Me),

4.22 (1H, d, J 16.6, C(2)H_A), 4.34 (1H, d, J 16.6, C(2)H_B), 4.63 (1H,

d, J 11.8, OCH_AH_BPh), 4.68 (1H, d, J 11.8, OCH_AH_BPh), 6.25 (1H, q,

J 6.8, C(1⁰)H), 6.98–7.67 (11H, m, Ar, Ph), 8.42–8.46 (1H, br m,

Ar); d_C(50 MHz, CDCl₃) 27.7, 55.0, 69.0, 73.3, 82.6, 124.9, 125.7,

126.1, 126.6, 127.9, 128.3, 128.5, 133.6, 137.5; m/z (APCI^þ) 392

([MþH]^þ, 100%).

4. Experimental

Analogous treatment of (S)-1$(þ)-CSA gave (S)-5 as a colourless

23

4.1. General experimental

oil; [

a]

ꢀ28.9 (c 1.6 in CHCl₃).

D

4.1.2. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl 2-allyloxyacetamide 6.

All reactions involving organometallic or other moisture-

sensitive reagents were carried out under a nitrogen or argon at-

mosphere using standard vacuum line techniques and glassware

that was ﬂame dried and cooled under nitrogen before use. Sol-

vents were dried according to the procedure outlined by Grubbs

et al.,³⁴or by distillation from sodium benzophenone ketyl (THF).

KHMDS was titrated according to an amalgamation of the pro-

cedures reported by Duhamel and Plaquevent,³⁵and Lin and

Paquette.³⁶Other solvents and reagents were used as supplied

(analytical or HPLC grade) without prior puriﬁcation. Organic layers

were dried over MgSO₄. Thin layer chromatography was performed

on aluminium plates coated with 60 F₂₅₄silica. Plates were

visualised using UV light (254 nm), iodine, 1% aq KMnO₄, or 10%

ethanolic phosphomolybdic acid. Flash column chromatography

was performed on Kieselgel 60 silica.

O

1-Nap

N

O^tBu

2-Allyloxyacetyl chloride (4.39 g, 23.8 mmol) was added drop-

wise to a vigorously stirred mixture of 2 M aq NaOH (10 mL,

20 mmol) and (R)-1$(ꢀ)-CSA (3.03 g, 6.4 mmol) in CH₂Cl₂(30 mL)

at 0 ^ꢁC. After 48 h, the reaction mixture was partitioned between

1 M aq NaOH (100 mL) and CH₂Cl₂(100 mL), the layers were sep-

arated and the aqueous layer was extracted with CH₂Cl₂

(3ꢃ100 mL). The combined organic extracts were dried and con-

centrated in vacuo. Puriﬁcation via ﬂash column chromatography

(eluent 30–40 ^ꢁC petrol/Et₂O, 10:1) gave 6 as a colourless oil (1.19 g,

Elemental analyses were recorded by the microanalysis service

of the Dyson Perrins Laboratory, University of Oxford, UK, or the

Inorganic Chemistry Laboratory, University of Oxford, UK. Melting

55%); found C, 73.4; H, 7.9; N, 4.4%; C₂₁H₂₇NO₃requires C, 73.9; H,

23

8.0; N, 4.1%; [

a

]

þ33.9 (c 1.2 in CHCl₃); n_max(ﬁlm) 1686 (C]O),

D

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4177

1600 (C]C); d_H(300 MHz, CDCl₃) 0.66 (9H, s, CMe₃), 1.60 (3H, d, J

6.9, C(1⁰)Me), 4.03–4.17 (2H, m, OCH₂CH]CH₂), 4.21 (1H, d, J 16.0,

4.1.5. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl 2-(4^%-methoxyben-

zyloxy)acetamide 7 and (R)-N-1⁰-(1⁰⁰-naphthyl)ethyl (

oxybenzyloxy)-2-tert-butoxyacetamide 10 from 8.

x

)-2-(4^%-meth-

C(2)H_A), 4.28 (1H, d,

J 16.0, C(2)H_B), 5.01–5.05 (1H, m,

CH₂CH]CH_AH_B), 5.10–5.14 (1H, m, CH]CH_AH_B), 5.89 (1H, ddt, J

17.3, 10.5, 5.5, CH]CH₂), 6.20 (1H, q, J 6.9, C(1⁰)H), 7.16–7.37 (3H, m,

Ar), 7.50–7.61 (3H, m, Ar), 8.37 (1H, d, J 8.4, Ar); d_C(50 MHz, CDCl₃)

15.0, 27.7, 55.0, 69.0, 72.4, 82.6, 118.0, 124.9, 125.7, 126.1, 126.5,

128.6, 133.6, 134.3, 135.5, 176.0; m/z (APCI^þ) 342 ([MþH]^þ, 100%).

O

OPMB

+

1-Nap

N

1-Nap

N

H

O^tBu

7

O^tBu

10

4.1.3. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl 2-(4^%-methoxyben-

zyloxy)acetamide 7.

p-Methoxybenzyl alcohol (0.13 mL, 1.13 mmol) was added

dropwise over 10 min to a stirred slurry of NaH (34 mg, 0.85 mmol)

in THF (2 mL) at 0 ^ꢁC and the resulting mixture was allowed to

warm to rt over 1 h. A solution of 8 (206 mg, 0.56 mmol) in THF

(5 mL) was added dropwise. After 6 h, the reaction was quenched

by addition of satd aq NH₄Cl (10 mL) and extracted with Et₂O

(3ꢃ10 mL). The combined organic extracts were dried and con-

centrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, pentane/Et₂O, 9:1; increased to Et₂O) gave 7 as

a colourless oil (56 mg, 24%). Further elution gave 10 [of unknown

2-(4⁰-Methoxybenzyloxy)acetyl chloride (3.10 g, 14.5 mmol)

was added dropwise to a vigorously stirred mixture of 2 M aq

NaOH (11 mL, 22 mmol) and (R)-1$(ꢀ)-CSA (3.44 g, 7.24 mmol) in

CH₂Cl₂(15 mL) at 0 ^ꢁC. After 48 h, the reaction mixture was par-

titioned between 1 M aq NaOH (100 mL) and CH₂Cl₂(100 mL), the

layers were separated and the aqueous layer was extracted with

CH₂Cl₂(3ꢃ100 mL). The combined organic extracts were dried and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatog-

raphy (eluent 30–40 ^ꢁC petrol/Et₂O, 3:1) gave 7 as a colourless oil

conﬁguration at C(2⁰)] as a colourless oil (76 mg, 32%, >99:1 dr); R_f

23

0.20 (pentane/Et₂O,1:1); [

a

]

ꢀ7.1 (c 0.2 in CHCl₃); n_max(ﬁlm) 3418

D

(N–H), 2962 (C–H), 1683 (C]O), 1515, 1260, 1099, 1024; d_H

(500 MHz, CDCl₃) 1.19 (9H, s, CMe₃), 1.69 (3H, d, J 6.8, C(1⁰)Me), 3.81

(3H, s, OMe), 4.51 (1H, d, J 10.9, OCH_AH_BAr), 4.61 (1H, d, J 10.9,

OCH_AH_BAr), 5.09 (1H, s, C(2)H), 5.90–5.93 (1H, m, C(1⁰)H), 6.87 (2H,

d, J 8.6, Ar), 6.93 (1H, br d, J 8.5, NH), 7.28–7.90 (8H, m, Ar), 8.11 (1H,

d, J 8.3, Ar); d_C(125 MHz, CDCl₃), 21.0, 28.4, 44.4, 55.2, 67.0, 76.1,

93.6, 113.7, 122.3, 123.3, 125.1, 125.7, 126.3, 128.2, 128.6, 129.4, 129.5,

130.8,133.8,138.1,159.1,167.8; m/z (ESI^þ) 444 ([MþNa]^þ,100%), 422

([MþH]^þ, 11%); HRMS (ESI^þ) found 444.2151; C₂₆H₃₁NNaO^þ₄

([MþNa]^þ) requires 444.2145.

(2.39 g, 78%); found C, 73.7; H, 7.5; N, 3.4%; C₂₆H₃₁NO₄requires C,

21

74.1; H, 7.4; N, 3.3%; [

a

]

þ28.9 (c 1.2 in CHCl₃); n_max(ﬁlm) 1682

D

(C]O), 1613 (C]C), 1587 (C]C); d_H(250 MHz, PhMe-d₈, 70 ^ꢁC)

0.65 (9H, s, CMe₃), 1.64 (3H, d, J 6.9, C(1⁰)Me), 3.37 (3H, s, OMe),

4.26 (1H, d, J 16.1, C(2)H_A), 4.33 (1H, d, J 16.1, C(2)H_B), 4.60 (1H, d, J

11.4, OCH_AH_BAr), 4.67 (1H, d, J 11.4, OCH_AH_BAr), 6.24 (1H, q, J 6.9,

C(1⁰)H), 6.71–6.76 (4H, m, Ar), 7.18–7.39 (4H, m, Ar), 7.54–7.62 (2H,

m, Ar), 8.41 (1H, d, J 8.5, Ar); d_C(50 MHz, CDCl₃) 16.0, 27.6, 55.1,

68.6, 72.9, 82.5, 113.8, 124.1, 124.9, 125.7, 126.1, 126.5, 128.7, 129.6,

129.9, 132.0, 133.6, 136.0, 159.4, 176.0; m/z (APCI^þ) 444 ([MþNa]^þ,

100%); HRMS (CI^þ) found 422.2325; C₂₆H₃₂NO^þ₄([MþH]^þ) requires

422.2326.

4.1.6. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl 2-allyloxyacetamide

6 from 8.

4.1.4. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl 2-bromoacetamide 8.

Allyl alcohol (0.74 mL, 10.9 mmol) was added dropwise over

10 min to a stirred slurry of NaH (414 mg,10.4 mmol) in THF (10 mL)

at 0 ^ꢁC and the resulting mixture was allowed to warm to rt over 1 h.

15-Crown-5 (2.15 mL, 10.9 mmol) and tetrabutylammonium iodide

(100 mg) were added, and stirring was continued at rt while a so-

lution of 8 (3.61 g, 9.9 mmol) in THF (20 mL) was added dropwise.

After 2 h, the reaction was quenched by addition of satd aq NH₄Cl

(30 mL) and extracted with Et₂O (3ꢃ30 mL). The combined organic

extracts were dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (gradient elution, pentane/Et₂O, 19:1; in-

creased to Et₂O) gave 6 as a colourless oil (2.5 g, 75%).

K₂CO₃(12.0 g, 86.9 mmol) was added to a vigorously stirred

solution of (R)-1$(ꢀ)-CSA (6.87 g, 14.5 mmol) in CH₂Cl₂(300 mL).

The resulting slurry was cooled to 0 ^ꢁC and bromoacetyl bromide

(6.30 mL, 72.3 mmol) was added dropwise. The mixture was left to

stir for 2 h, before the addition of H₂O (200 mL) and the addition of

K₂CO₃until pH >11 was achieved. The resultant mixture was stirred

for a further 10 min (to ensure consumption of any unreacted

bromoacetyl bromide). The layers were separated and the aqueous

layer was extracted with CH₂Cl₂(2ꢃ50 mL). The combined organic

extracts were dried and concentrated in vacuo. Puriﬁcation via ﬂash

4.1.7. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl 2-(4^%-methoxyben-

zyloxy)acetamide 7 from 8.

column chromatography (eluent pentane/Et₂O, 9:1) gave 8 as

23

a colourless oil (5.3 g, 100%); R_f0.30 (pentane/Et₂O, 9:1); [a]

D

þ16.7 (c 4.1 in CHCl₃); n_max(ﬁlm) 2977 (C–H), 1666 (C]O), 1368,

1093; d_H(200 MHz, CDCl₃) 0.89 (9H, s, CMe₃), 1.82 (3H, d, J 7.0,

C(1⁰)Me), 4.12–4.18 (2H, m, C(2)H₂), 6.10–6.30 (1H, br m, C(1⁰)H),

7.40–7.90 (6H, m, Ar), 8.20–8.23 (1H, br m, Ar); d_C(50 MHz, CDCl₃)

16.3, 27.6, 28.9, 56.6, 83.5, 123.8, 123.9, 125.2, 125.9, 126.3, 126.8,

129.0, 133.8, 173.1; m/z (ESI^þ) 366 ([MþH]^þ, ⁸¹Br, 96%), 364

([MþH]^þ, ⁷⁹Br,100%); HRMS (ESI^þ) found 364.0906; C₁₈H₂₃⁷⁹BrNO^þ₂

([MþH]^þ) requires 364.0912.

4-Methoxybenzylalcohol (2.03 mL, 16.3 mmol) was added

dropwise over 10 min to

a stirred slurry of NaH (623 mg,

15.6 mmol) in THF (20 mL) at 0 ^ꢁC and the resulting mixture was

allowed to warm to rt over 1 h. 15-Crown-5 (3.12 mL, 15.6 mmol)

and tetrabutylammonium iodide (100 mg) were added, and stirring

was continued at rt while a solution of 8 (5.41 g, 14.8 mmol) in THF

(20 mL) was added dropwise. After 2 h, the reaction was quenched

4178

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

by addition of satd aq NH₄Cl (30 mL) and extracted with Et₂O

(3ꢃ30 mL). The combined organic extracts were dried and con-

centrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, pentane/Et₂O, 9:1; increased to Et₂O) gave 7 as

a colourless oil (3.80 g, 61%).

4.1.10. (R)-N-1⁰-(1⁰⁰-Naphthyl)ethyl

(S)-2-benzyloxy-2-tert-butox-

yacetamide and (R)-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-benzyloxy-2-tert-

butoxyacetamide 13 and 14.

4.1.8. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl 2-(3^%,4^%-dimethoxy-

benzyloxy)acetamide 9 from 8.

From (R)-8: Benzyl alcohol (0.79 mL, 7.60 mmol) was added

dropwise over 10 min to

a stirred slurry of NaH (292 mg,

7.30 mmol) in THF (5 mL) at 0 ^ꢁC and the resulting mixture was

allowed to warm to rt over 20 min. A solution of 8 (2.22 g,

6.08 mmol) in THF (10 mL) was added dropwise. After 2 h, the

reaction was quenched by addition of satd aq NH₄Cl (20 mL) and

extracted with Et₂O (3ꢃ30 mL). The combined organic extracts

were dried and concentrated in vacuo. Puriﬁcation via ﬂash col-

umn chromatography (gradient elution, pentane/Et₂O, 19:1; in-

3,4-Dimethoxybenzyl alcohol (2.25 mL, 15.5 mmol) was added

dropwise over 10 min to a stirred slurry of NaH (592 mg,14.8 mmol)

in THF (20 mL) at 0 ^ꢁC and the resulting mixture was allowed to

warm to rt over 1 h. 15-Crown-5 (2.96 mL, 14.8 mmol) and tetra-

butylammonium iodide (100 mg) were added, and stirring was

continued at rt while a solution of 8 (5.15 g, 14.1 mmol) in THF

(20 mL) was added dropwise. After 2 h, the reaction was quenched

by addition of satd aq NH₄Cl (20 mL) and extracted with Et₂O

(3ꢃ30 mL). The combined organic extracts were dried and concen-

trated in vacuo. Puriﬁcation via ﬂash column chromatography (el-

creased to Et₂O) gave 13 as a colourless oil (876 mg, 37%, 92:8 dr);

23

[a

]

ꢀ7.1 (c 0.9 in CHCl₃). Further elution gave 14 as a colourless

D

oil (989 mg, 42%, 86:14 dr); R_f0.15 (pentane/Et₂O, 4:1); d_H

(400 MHz, CDCl₃), 1.31 (9H, s, CMe₃), 1.71 (3H, d, J 7.0, C(1⁰)Me),

4.44 (2H, ABq, OCH₂Ph), 5.18 (1H, s, C(2)H), 5.97 (1H, q, J 7.0,

C(1⁰)H), 6.95 (1H, br d, J 8.5, NH), 7.20–8.20 (12H, m, Ar, Ph); d_C

(100 MHz, CDCl₃) 20.8, 28.6, 44.3, 66.8, 76.4, 93.9, 122.5, 123.3,

125.2, 125.9, 126.5, 127.5, 127.9, 128.1, 128.4, 128.5, 128.8, 131.0,

133.9, 137.4, 138.0, 167.7.

uentpentane/Et₂O,1:1) gave 9 as acolourlessoil (4.73 g, 74%); R_f0.20

23

(pentane/Et₂O,1:1); [

a

]

ꢀ21.4 (c 2.0 in CHCl₃); n_max(ﬁlm) 2975 (C–

D

H), 1684 (C]O), 1594, 1516, 1464, 1419, 1368; d_H(400 MHz, CDCl₃)

0.72 (9H, s, CMe₃), 1.77 (3H, d, J 6.5, C(1⁰)Me), 3.88 (3H, s, OMe), 3.90

(3H, s, OMe), 4.29–4.31 (2H, m, C(2)H₂), 4.60 (1H, d, J 11.3, OCH_AH-

_BAr), 4.67 (1H, d, J 11.3, OCH_AH_BAr), 6.35–6.37 (1H, br m, C(1⁰)H), 6.82

(1H, d, J 8.1, Ar), 6.90 (1H, dd, J 8.1, 1.8, Ar), 7.01 (1H, d, J 1.8, Ar), 7.41–

7.88 (6H, m, Ar), 8.33–8.35 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 15.9,

27.6, 55.3, 55.8, 55.9, 68.6, 73.2, 82.6, 110.7, 111.4, 120.9, 124.2, 124.8,

125.6, 126.1, 126.5, 128.5, 128.6, 130.0, 133.5, 148.7, 149.0, 177.5; m/z

(ESI^þ) 474 ([MþNa]^þ,100%), 452 ([MþH]^þ,13%); HRMS (ESI^þ) found

474.2256; C₂₇H₃₃NNaO₅^þ([MþNa]^þ) requires 474.2251.

4.1.11. (R)-N-1⁰-(1⁰⁰-Naphthyl)ethyl (S)-2-allyloxy-2-tert-butoxyacet-

amide and (R)-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-allyloxy-2-tert-butoxy-

acetamide 15 and 16.

4.1.9. (S)-N-1⁰-(1⁰⁰-Naphthyl)ethyl (R)-2-benzyloxy-2-tert-butoxyacet-

amide and (S)-N-1⁰-(1⁰⁰-naphthyl)ethyl (S)-2-benzyloxy-2-tert-butoxy-

acetamide 13 and 14.

Allyl alcohol (70 mL, 1.07 mmol) was added dropwise over

10 min to a stirred slurry of NaH (39 mg, 1.07 mmol) in THF

(2 mL) at 0 ^ꢁC and the resulting mixture was allowed to warm to

rt over 1 h. A solution of 8 (300 mg, 0.82 mmol) in THF (5 mL)

was added dropwise. After 2 h, the reaction was quenched by

addition of satd aq NH₄Cl (10 mL) and extracted with Et₂O

(3ꢃ10 mL). The combined organic extracts were dried and con-

centrated in vacuo. Puriﬁcation via ﬂash column chromatography

(gradient elution, pentane/Et₂O, 10:1; increased to Et₂O) gave

a mixture of 15 and 16. Recrystallisation from pentane gave 15 as

colourless needles (105 mg, 28%, >99:1 dr); R_f0.20 (pentane/

From (S)-5: KHMDS (1.38 mmol) was added to a solution of 5

(279 mg, 0.71 mmol) in THF (2 mL) at ꢀ78 ^ꢁC. The resulting solution

was stirred at this temperature for 10 min, then allowed to warm to

0 ^ꢁC over 30 min and stirred for a further 1 h. The reaction was

quenched by addition of pH 7 phosphate buffer (2 mL) and the

mixture was concentrated in vacuo to give an 80:20 mixture of

13:14. Puriﬁcation via ﬂash chromatography (eluent 30–40 ^ꢁC

petrol/Et₂O, 2:1) gave the major diastereoisomer 13 as a colourless

oil, which was crystallised from pentane to give a cream powder

(147 mg, 50%, >99:1 dr); found C, 76.75; H, 7.55; N, 3.4%;

Et₂O, 4:1); found C, 73.6; H, 8.3; N, 4.0%; C₂₁H₂₇NO₃requires C,

24

73.9; H, 8.0; N, 4.1%; mp 56–58 ^ꢁC; [

a]

ꢀ1.0 (c 0.9 in CHCl₃);

D

n_max(KBr) 3264 (N–H), 1688 (C]O), 1647 (C]O), 1600 (C]C); d_H

(300 MHz, CDCl₃) 1.18 (9H, s, CMe₃), 1.69 (3H, d, J 6.8, C(1⁰)Me),

4.06–4.18 (2H, m, CH₂CH]CH₂), 5.04 (1H, s, C(2)H), 5.15–5.33

(2H, m CH]CH₂), 5.90–5.94 (1H, m, C(1⁰)H), 5.95 (1H, ddt, J 11.2,

10.4, 5.6, CH₂CH]CH₂), 6.92 (1H, br d, J 8.4, NH), 7.54–7.45 (5H,

m, Ar), 7.87 (1H, dd, J 8.5, 1.4, Ar), 8.10 (1H, d, J 8.4, Ar); d_C

(50 MHz, CDCl₃) 21.0, 28.4, 44.4, 66.2, 76.1, 93.6, 117.2, 122.3,

123.3, 125.1, 125.7, 126.3, 128.7, 130.9, 133.8, 134.0, 138.1, 167.8;

m/z (APCI^þ) 342 ([MþH]^þ, 100%). Concentration of the mother

liquors gave 16 as a colourless oil (17 mg, 6%, >99:1 dr); R_f0.20

(Et₂O:pentane 1:4); n_max(KBr) 3303, 3242 (N–H), 1686, 1654

(C]O), 1599 (C]C); d_H(300 MHz, CDCl₃) 1.18 (9H, s, CMe₃), 1.69

(3H, d, J 6.8, C(1⁰)Me), 3.90–3.97 (2H, m, CH₂CH]CH₂), 5.08 (1H,

s, C(2)H), 5.09 (1H, dd, J 10.5, 1.4, CH₂CH]CH_AH_B), 5.16 (1H, dd, J

C₂₅H₂₉NO₃requires C, 76.7; H, 7.5; N, 3.6%; R_f0.20 (pentane/Et₂O,

23

4:1); mp 67–68 ^ꢁC; [

a]

þ8.0 (c 1.1 in CHCl₃); n_max(KBr) 3255 (N–

D

H), 1685 (C]O), 1638 (C]O), 1599 (C]C); d_H(400 MHz, CDCl₃) 1.21

(9H, s, CMe₃), 1.71 (3H, d, J 7.0, C(1⁰)Me), 4.60 (1H, d, J 11.2,

OCH_AH_BPh), 4.70 (1H, d, J 11.2, OCH_AH_BPh), 5.15 (1H, s, C(2)H), 5.96

(1H, q, J 7.0, C(1⁰)H), 6.98 (1H, br d, J 8.4, NH), 7.30–8.15 (12H, m, Ar,

Ph); d_C(100 MHz, CDCl₃) 21.1, 28.5, 44.5, 67.2, 76.3, 93.8, 122.4,

123.4, 125.2, 125.8, 126.5, 127.7, 128.0, 128.3, 128.4, 128.8, 130.9,

133.9, 137.4, 138.1, 167.8; m/z (CI^þ) 414 ([MþNa]^þ, 100%), 392

([MþH]^þ, 30%); HRMS (CI^þ) found 392.2219; C₂₅H₃₀NO^þ₃([MþH]^þ)

requires 392.2220.

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4179

17.2, 1.4, CH₂CH]CH_AH_B), 5.82 (1H, ddt,

J

17.2, 10.5, 5.3,

4.2.1. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-benzyloxypro-

CH₂CH]CH₂), 5.91–5.95 (1H, m, C(1⁰)H), 6.90 (1H, br d, J 8.4, NH),

7.45–7.55 (4H, m, Ar), 7.81 (1H, d, J 8.1, Ar), 7.87–7.89 (1H, m, Ar),

8.11 (1H, d, J 8.3, Ar); d_C(50 MHz, CDCl₃) 20.9, 28.5, 44.3, 65.8,

76.3, 93.7, 117.0, 122.4, 123.4, 125.2, 125.8, 126.4, 128.3, 128.8,

131.0, 133.9, 138.0, 167.8; m/z (APCI^þ) 364 ([MþNa]^þ), 342

([MþH]^þ, 40%); HRMS (CI^þ) found 342.2071; C₂₁H₂₈NO^þ₃

([MþH]^þ) requires 342.2064.

panamide 23.

Compound (S)-5 (97 mg, 0.25 mmol) in THF (2 mL) was treated

with KHMDS (0.28 mmol) and 18-crown-6 (280 mg, 1.06 mmol) in

THF (2 mL) and MeI (0.47 mL, 0.75 mmol) according to the general

procedure. The reaction was held at ꢀ78 ^ꢁC for 1 h before being

quenched. ¹H NMR spectroscopic analysis of the crude reaction

mixture showed the presence of 23 in >95:5 dr. Puriﬁcation via

ﬂash column chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1)

gave 23 as a colourless oil, which crystallised upon prolonged

4.1.12. (S)-N-1⁰-(1⁰⁰-Naphthyl)ethyl (R)-2-(3^%,4^%-dimethoxybenzyl)-

2-tert-butoxyacetamide and (S)-N-1⁰-(1⁰⁰-naphthyl)ethyl (S)-2-

(3^%,4^%-dimethoxybenzyl)-2-tert-butoxyacetamide 17 and 18.

O

ODMB

1-Nap

N

H

O^tBu

standing (82 mg, 81%, >99:1 dr); found C, 77.3; H, 8.0; N, 3.3%;

C₂₆H₃₁NO₃requires C, 77.0; H, 7.7; N, 3.45%; mp 63–65 ^ꢁC; [

17 and 18

23

a]

D

ꢀ41.8 (c 1.0 in CHCl₃); n_max(ﬁlm) 1683 (C]O), 1600 (C]C); d_H

(250 MHz, PhMe-d₈, 70 ^ꢁC) 0.64 (9H, s, CMe₃), 1.39 (3H, d, J 6.7,

C(3)H₃), 1.62 (3H, d, J 6.9, C(1⁰)Me), 4.45 (1H, d, J 12.0, OCH_AH_BPh),

4.57 (1H, q, J 6.7, C(2)H), 4.80 (1H, d, J 12.0, OCH_AH_BPh), 6.36 (1H, q, J

6.9, C(1⁰)H), 6.96–7.62 (11H, m, Ar, Ph), 8.55 (1H, br d, J 8.5, Ar); d_C

(50 MHz, CDCl₃) 16.0, 16.3, 27.6, 55.8, 70.9, 73.0, 82.6, 124.7, 125.1,

125.9, 126.5, 126.6, 127.9, 128.0, 128.6, 128.9, 129.0, 132.5, 133.9,

135.8, 138.4, 180.2; m/z (CI^þ) 406 ([MþH]^þ, 100%).

KHMDS (0.70 mmol) was added to a solution of 9 (227 mg,

0.50 mmol) in THF (6 mL) at ꢀ78 ^ꢁC. The resulting solution was

stirred at this temperature for 20 min, then allowed to warm to rt

over 30 min and stirred for a further 30 min. The reaction was

quenched by addition of pH 7 phosphate buffer (0.4 mL) and the

mixture was concentrated in vacuo. The residue was redissolved in

Et₂O (100 mL) and ﬁltered through a silica gel/MgSO₄plug (eluent

Et₂O, 200 mL). The ﬁltrate was concentrated in vacuo. Exhaustive

ﬂash column chromatography (gradient elution, pentane/Et₂O, 1:1;

Analogous treatment of (R)-5 gave (2S,1⁰R)-23 as a colourless oil;

23

[a

]

þ42.1 (c 1.0 in CHCl₃).

D

increased to Et₂O) gave 17 as a colourless oil (166 mg, 73%, 86:14

23

dr); R_f0.60 (Et₂O); [

a

]

ꢀ4.1 (c 1.2 in CHCl₃); n_max(ﬁlm) 3417 (N–

D

4.2.2. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-benzyloxypent-

H), 2974 (C–H), 1682 (C]O), 1516, 1264, 1159, 1138; d_H(400 MHz,

CDCl₃) 1.19 (9H, s, CMe₃), 1.69 (3H, d, J 6.8, C(1⁰)Me), 3.87 (3H, s,

OMe), 3.88 (3H, s, OMe), 4.54 (1H, d, J 11.0, OCH_AH_BAr), 4.62 (1H, d, J

11.0, OCH_AH_BAr), 5.11 (1H, s, C(2)H), 5.91–5.94 (1H, m, C(1⁰)H),

6.81–6.96 (4H, m, NH, Ar), 7.43–7.52 (4H, m, Ar), 7.80 (1H, d, J 7.8,

Ar), 7.87 (1H, d, J 7.5, Ar), 8.11 (1H, d, J 8.3, Ar); d_C(100 MHz, CDCl₃)

21.1, 28.5, 44.5, 55.8, 55.9, 67.2, 76.3, 93.6, 110.8, 111.4, 120.5, 122.4,

123.4, 125.2, 125.8, 126.4, 128.3, 128.8, 130.0, 130.9, 133.9, 138.1,

148.6, 148.9, 167.9; m/z (ESI^þ) 474 ([MþNa]^þ, 100%), 452 ([MþH]^þ,

5%); HRMS (ESI^þ) found 474.2263; C₂₇H₃₃NNaO^þ₅([MþNa]^þ) re-

quires 474.2251. Further elution gave 18 (39 mg, 17%, 61:39 dr); R_f

0.50 (Et₂O); d_H(400 MHz, CDCl₃) [selected peaks] 1.30 (9H, s, CMe₃),

1.69 (3H, d, J 6.8, C(1⁰)Me), 3.78 (3H, s, OMe), 3.86 (3H, s, OMe), 4.38

(2H, A₂, OCH₂Ar), 5.16 (1H, s, C(2)H); d_C(100 MHz, CDCl₃) 20.9, 28.6,

44.3, 55.7, 55.8, 66.9, 76.4, 93.8, 110.7, 111.2, 120.3, 122.5, 123.4,

125.2, 125.9, 126.4, 128.4, 128.8, 129.9, 131.0, 138.0, 148.5, 148.8,

167.8.

4-enamide 25.

Compound (S)-5 (491 mg, 1.25 mmol) in THF (5 mL) was treated

with KHMDS (1.38 mmol) and 18-crown-6 (687 mg, 2.6 mmol) in

THF (5 mL) and allyl bromide (324 mL, 3.75 mmol) according to the

general procedure. The reaction was held at ꢀ78 ^ꢁC for 1.5 h before

being quenched. ¹H NMR spectroscopic analysis of the crude re-

action mixture showed the presence of 25 in >95:5 dr. Puriﬁcation

via ﬂash column chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1)

gave 25 as a colourless oil (511 mg, 95%, >99:1 dr); found C, 78.0; H,

7.95; N, 3.35%; C₂₈H₃₃NO₃requires C, 77.9; H, 7.7; N, 3.25%; [a]

D

21

þ56.4 (c 1.7 in CHCl₃); n_max(ﬁlm) 1680 (C]O), 1600 (C]C); d_H

(250 MHz, PhMe-d₈, 70 ^ꢁC) 0.64 (9H, s, CMe₃), 1.63 (3H, d, J 6.9,

C(1⁰)Me), 2.39–2.64 (2H, m, C(3)H₂), 4.47 (1H, d, J 11.8, OCH_AH_BPh),

4.56 (1H, dd, J 8.0, 4.0, C(2)H), 4.84 (1H, d, J 11.8, OCH_AH_BPh), 4.95–

5.08 (2H, m, C(5)H₂), 5.99 (1H, ddt, J 17.1,10.2, 6.9, C(4)H), 6.38 (1H, q,

J 6.9, C(1⁰)H), 6.97–7.62 (11H, m, Ar, Ph), 8.54 (1H, d, J 8.5, Ar); d_C

(50 MHz, CDCl₃) 16.3, 27.7, 35.0, 55.8, 71.2, 76.8, 82.8, 117.5, 124.6,

125.1,125.9,126.6,127.9,128.6,128.9,129.0,132.5,133.9,134.5,135.7,

138.4, 178.6; m/z (APCI^þ) 454 ([MþNa]^þ, 100%), 432 ([MþH]^þ, 20%).

4.2. General procedure for enolate alkylations

Titration procedure: KHMDS in PhMe solution (ca. 0.5 M) was

added dropwise to a solution of an accurately weighed sample of

menthol (ca. 150 mg in 3 mL of PhMe), containing a trace of (E)-N-

benzylidenebiphenyl-4-amine as an indicator, at 0 ^ꢁC. A single drop

of excess KHMDS caused the formation of an intense blue colour-

ation.³⁷The titration was repeated twice more by the addition of

a further aliquot of menthol.

Freshly titrated KHMDS (ca. 0.5 M in PhMe) was added dropwise

to a degassed solution of the substrate and 18-crown-6 in THF at

ꢀ78 ^ꢁC. After stirring for 30 min at this temperature, the requisite

alkylating agent was added dropwise and stirring was continued at

ꢀ78 ^ꢁC for the time stated. The reaction was then quenched by the

dropwise addition of pH 7 phosphate buffer and allowed to warm

to rt. The mixture was concentrated in vacuo, the residue was

dissolved in Et₂O and ﬁltered through a short, silica/MgSO₄plug

(eluent Et₂O). The ﬁltrate was concentrated in vacuo and puriﬁed as

described.

4.2.3. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-benzyloxybutan-

amide 26.

Compound (S)-5 (670 mg, 1.71 mmol) in THF (6 mL) was treated

with KHMDS (1.38 mmol) and 18-crown-6 (700 mg, 2.65 mmol) in

THF (5 mL) and EtI (410 mL, 5.13 mmol) according to the general

4180

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

procedure. The reaction was held at ꢀ78 ^ꢁC for 6 h before being

quenched. ¹H NMR spectroscopic analysis of the crude reaction

mixture showed the presence of 26 in >95:5 dr. Puriﬁcation via ﬂash

column chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 4:1) gave 26

(3H, d, J 7.0, C(1⁰)Me), 4.45 (1H, d, J 11.8, OCH_AH_BPh), 4.51 (1H, dd, J 7.7,

4.1, C(2)H), 4.82 (1H, d, J 11.8, OCH_AH_BPh), 6.29 (1H, q, J 7.0, C(1⁰)H),

6.97–7.63 (11H, m, Ar, Ph), 8.55 (1H, d, J 8.5, Ar); d_C(50 MHz, CDCl₃)

13.9, 16.4, 22.3, 25.0, 27.7, 30.3, 31.5, 56.4, 71.2, 82.5, 124.7, 125.0,

125.8,126.5,126.7,127.7,127.8,128.2,128.5,128.8,128.9,132.5,133.9,

135.7, 138.6, 179.5; m/z (CI^þ) 462 ([MþH]^þ, 100%). Further elution

gave returned starting material (S)-5 (462 mg, 31%).

as a colourless oil (567 mg, 79%, >99:1 dr); found C, 77.5; H, 8.1; N,

21

3.6%; C₂₇H₃₃NO₃requires C, 77.3; H, 7.9; N, 3.3%; [

a

]

þ50.1 (c 1.0 in

D

CHCl₃); n_max(ﬁlm) 1676 (C]O), 1600 (C]C); d_H(250 MHz, PhMe-d₈,

70 ^ꢁC) 0.64 (9H, s, CMe₃), 0.64 (3H, t, J 7.4, C(4)H₃), 1.63 (3H, d, J 6.9,

C(1⁰)Me),1.68–1.92 (2H, m, C(3)H₂), 4.45 (1H, dd, J 7.6, 3.9, C(2)H), 4.45

(1H, d, J 12.0, OCH_AH_BPh), 4.85 (1H, d, J 12.0, OCH_AH_BPh), 6.39 (1H, q, J

6.9, C(1⁰)H), 6.97–7.63 (11H, m, Ar, Ph), 8.58 (1H, d, J 8.5, Ar); d_C

(50 MHz, CDCl₃) 10.1,16.3, 23.7, 27.7, 55.7, 71.2, 78.3, 82.5,124.7,125.0,

125.9, 126.6, 127.8, 127.9, 128.3, 128.5, 128.9, 129.0, 132.5, 133.9, 135.8,

138.6, 179.4; m/z (CI^þ) 442 ([MþNa]^þ, 100%), 420 ([MþH]^þ, 50%).

4.2.6. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S)-2-allyloxypro-

panamide 29.

4.2.4. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-benzyloxy-3-

(2^%-bromophenyl)propanamide 27.

Compound (R)-6 (200 mg, 0.59 mmol) in THF (4 mL) was treated

with KHMDS (0.70 mmol) and 18-crown-6 (400 mg,1.52 mmol) inTHF

(4 mL) and MeI (0.15 mL, 2.43 mmol) according to the general pro-

cedure. The reactionwas held at ꢀ78 ^ꢁC for 5 h before being quenched.

¹H NMR spectroscopic analysis of the crude reaction mixture showed

the presence of 29 in >95:5 dr. Puriﬁcation via ﬂash column chroma-

tography (gradient elution, 30–40 ^ꢁC petrol/Et₂O, 19:1; increased to

30–40 ^ꢁCpetrol/Et₂O, 2:1) gave 29 as a colourless oil, which crystallised

upon prolonged standing to yield colourless needles (200 mg, 96%,

23

>99:1 dr); R_f0.30 (30–40 ^ꢁC petrol/Et₂O, 2:1); [

a]

D

þ29.0 (c 1.0 in

Compound (S)-5 (517 mg, 1.32 mmol) in THF (10 mL) was

treated with KHMDS (1.45 mmol) and 18-crown-6 (700 mg,

2.65 mmol) in THF (10 mL) and 2-bromobenzylbromide (990 mg,

3.96 mmol) according to the general procedure. The reaction was

held at ꢀ78 ^ꢁC for 6 h before being quenched. ¹H NMR spectro-

scopic analysis of the crude reaction mixture (250 MHz, PhMe-d₈,

70 ^ꢁC) showed the presence of 27 in >95:5 dr. Puriﬁcation via ﬂash

column chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 4:1) gave 27

CHCl₃); n_max(ﬁlm) 2978 (C–H), 1681 (C]O), 1512, 1371, 1238, 1109; d_H

(400 MHz, CDCl₃) 0.82 (9H, s, CMe₃),1.23 (3H, d, J 6.2, C(3)H₃),1.77 (3H,

d, J 6.9, C(1⁰)Me), 3.93 (1H, dd, J 12.6, 6.0, OCH_AH_BCH]CH₂), 4.22 (1H,

dd, J12.6, 4.7, OCH_AH_BCH]CH₂), 4.49(1H, q, J6.2, C(2)H), 5.17–5.33(2H,

m, OCH₂CH]CH₂), 5.96–5.99 (1H, m, OCH₂CH]CH₂), 6.29–6.32 (1H,

br m, C(1⁰)H), 7.41–7.87 (6H, m, Ar), 8.38–8.41 (1H, br m, Ar); d_C

(50 MHz, CDCl₃) 16.3,16.4, 27.8, 56.0, 70.1, 73.3, 82.5,117.1,124.3,124.8,

125.6,126.3,128.6,128.7,132.1,133.6,134.8,135.5,179.8; m/z (ESI^þ) 378

([MþNa]^þ, 100%), 356 ([MþH]^þ, 91%); HRMS (ESI^þ) found 356.2216;

C₂₂H₃₀NO^þ₃([MþH]^þ) requires 356.2220.

as a colourless glass (595 mg, 81%, >99:1 dr); found C, 68.3; H, 6.1;

21

N, 2.5%; C₃₂H₃₄BrNO₃requires C, 68.6; H, 6.1; N, 2.5%; [

a

]

þ44.7 (c

D

1.1 in CHCl₃); n_max(KBr) 1673 (C]O), 1599 (C]C); d_H(250 MHz,

PhMe-d₈, 70 ^ꢁC) 0.76 (9H, s, CMe₃), 1.69 (3H, d, J 6.8, C(1⁰)Me), 3.15

(1H, dd, J 13.7, 7.8, C(3)H_A), 3.33 (1H, dd, J 13.7, 5.5, C(3)H_B), 4.49

(1H, d, J 11.8, OCH_AH_BPh), 4.76 (1H, d, J 11.8, OCH_AH_BPh), 4.95 (1H,

dd, J 7.8, 5.5, C(2)H), 6.12 (1H, br q, J 6.8, C(1⁰)H), 6.67 (1H, dt, J 7.7,

1.7, Ar), 6.86 (1H, dt, J 7.5, 1.2, Ar), 6.97–7.61 (13H, m, Ar, Ph), 8.36

(1H, br s, Ar); d_C(125 MHz, CDCl₃) 17.3, 27.7, 36.9, 58.0, 71.3, 75.6,

83.1, 124.5, 125.1, 125.2, 125.8, 126.6, 126.8, 127.3, 127.7, 128.4, 128.9,

132.5, 132.7, 133.9, 137.3, 138.2; m/z (CI^þ) 562 ([MþH]^þ, ⁸¹Br, 100%),

560 ([MþH]^þ, ⁷⁹Br, 100%).

4.2.7. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-allyloxypent-

4-enamide 30.

Compound (S)-6 (200 mg, 0.59 mmol) in THF (4 mL) was treated

with KHMDS (0.70 mmol) and 18-crown-6 (400 mg, 1.52 mmol) in

THF (4 mL) and allyl bromide (0.12 mL, 1.36 mmol) according to the

generalprocedure. Thereactionwasheldatꢀ78 ^ꢁCfor5 hbeforebeing

quenched. ¹H NMR spectroscopic analysis of the crude reaction

mixture showed the presence of 30 in >95:5 dr. Puriﬁcation via ﬂash

columnchromatography(gradientelution, 30–40 ^ꢁC petrol/Et₂O, 9:1;

increased to 30–40 ^ꢁC petrol/Et₂O, 3:2) gave 30 as a colourless oil,

which crystallised upon prolonged standing to yield colourless nee-

4.2.5. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-benzyloxyhep-

tanamide 28.

Compound (S)-5 (1.42 g, 3.61 mmol) in THF (20 mL) was treated

with KHMDS (10.6 mmol) and 18-crown-6 (2.80 g, 10.6 mmol) in

THF (20 mL) and 1-iodopentane (1.41 mL, 10.8 mmol) according to

the general procedure. The reaction was held at ꢀ78 ^ꢁC for 5 h before

being quenched. ¹H NMR spectroscopic analysis of the crude re-

action mixture showed the presence of 28 in >95:5 dr. Puriﬁcation

via ﬂash column chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1)

dles (170 mg, 76%, >99:1 dr); R_f0.65 (pentane/Et₂O, 3:2); mp 74–

23

76 ^ꢁC;[

a]

D

þ41.7(c0.5 inCHCl₃); n_max(ﬁlm) 2978(C–H),1682(C]O),

1370, 1170, 1100, 1092; d_H(400 MHz, CDCl₃) 0.83 (9H, s, CMe₃), 1.78

(3H, d, J 7.0, C(1⁰)Me), 2.19–2.21 (1H, br m, C(3)H_A), 2.41–2.44 (1H, br

m, C(3)H_B), 3.90 (1H, dd, J 13.0, 6.0, OCH_AH_BCH]CH₂), 4.26 (1H, dd, J

13.0, 4.7, OCH_AH_BCH]CH₂), 4.42 (1H, dd, J 8.6, 3.0, C(2)H), 4.99–5.01

(2H, br m, C(5)H₂), 5.18 (1H, app dq, J 10.4, 1.4, OCH₂CH]CH_AH_B), 5.30

(1H, app dq, J 17.3, 1.5, OCH₂CH]CH_AH_B), 5.81–5.84 (1H, m,

CH₂CH]CH₂), 5.92–5.96 (1H, m, CH₂CH]CH₂), 6.31–6.34 (1H, br m,

C(1⁰)H), 7.41–7.88 (6H, m, Ar), 8.38–8.41 (1H, br m, Ar); d_C(100 MHz,

CDCl₃) 16.3, 27.8, 55.7, 70.4, 77.2, 82.7, 117.0, 117.1, 124.4, 124.8, 125.6,

126.3, 126.4, 128.6, 128.7, 132.2, 133.6, 134.2, 134.8, 135.5, 178.3; m/z

gave 28 as a colourless oil (1.05 g, 63%, >99:1 dr); found C, 78.1; H,

22

8.6; N, 3.3%; C₃₀H₃₉NO₃requires C, 78.05; H, 8.5; N, 3.0%; [

a

]

þ60.5

D

(c 1.0 in CHCl₃); n_max(ﬁlm) 1676 (C]O), 1600 (C]C); d_H(250 MHz,

PhMe-d₈, 70 ^ꢁC) 0.74 (9H, s, CMe₃), 0.82 (3H, t, J 6.7, C(7)H₃),1.11–1.51

(6H, m, C(4)H₂–C(6)H₂), 1.58–1.83 (2H, m, C(3)H₂) overlapping 1.69

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4181

(ESI^þ) 404 ([MþNa]^þ, 100%), 382 ([MþH]^þ, 80%); HRMS (ESI^þ) found

404.2194; C₂₄H₃₁NNaO₃^þ([MþNa]^þ) requires 404.2196.

4.2.10. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S)-2-(4^%-methoxy-

benzyloxy)heptanamide 33.

4.2.8. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S)-2-allyloxypen-

tanamide 31.

Compound (S)-7 (2.20 g, 5.22 mmol) in THF (20 mL) was treated

with KHMDS (11.7 mmol) and 18-crown-6 (2.50 g, 9.46 mmol) in

THF (20 mL) and 1-iodopentane (2.04 mL, 10.8 mmol) according to

the general procedure. The reaction was held at ꢀ78 ^ꢁC for 4 h before

being quenched. ¹H NMR spectroscopic analysis of the crude re-

action mixture showed the presence of 33 in >95:5 dr. Puriﬁcation

via ﬂash column chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1)

Compound (R)-6 (311 mg, 0.91 mmol) in THF (8 mL) was treated

with KHMDS (1.19 mmol) and 18-crown-6 (470 mg, 1.78 mmol) in

THF (8 mL) and 1-iodopropane (0.18 mL, 1.82 mmol) according to

the general procedure. The reaction was held at ꢀ78 ^ꢁC for 5 h be-

fore being quenched. ¹H NMR spectroscopic analysis of the crude

reaction mixture showed the presence of 31 in >95:5 dr. Puriﬁca-

tion via ﬂash column chromatography (gradient elution, 30–40 ^ꢁC

petrol/Et₂O, 19:1; increased to 30–40 ^ꢁC petrol/Et₂O, 2:1) gave 31 as

a colourless oil, which crystallised upon prolonged standing to yield

gave 33 as a colourless oil (2.23 g, 87%, >99:1 dr); found C, 75.5; H,

23

8.6; N, 2.7%; C₃₁H₄₁NO₄requires C, 75.7; H, 8.4; N, 2.85%; [

a

]

ꢀ53.1

D

(c 1.7 in CHCl₃); n_max(ﬁlm) 1675 (C]O), 1614, 1587 (C]C); d_H

(250 MHz, PhMe-d₈, 70 ^ꢁC) 0.72 (9H, s, CMe₃), 0.84 (3H, t, J 7.4,

C(7)H₃),1.10–1.59 (6H, m, C(4)H₂–C(6)H₂),1.61–1.86 (2H, m, C(3)H₂)

overlapping 1.68 (3H, d, J 7.0, C(1⁰)Me), 3.36 (3H, s, OMe), 4.42 (1H,

dd, J 11.8, OCH_AH_BAr), 4.52 (1H, dd, J 7.8, 3.8, C(2)H), 4.82 (1H, d, J 11.8,

OCH_AH_BAr), 6.35 (1H, q, J 7.0, C(1⁰)H), 6.74 (2H, app d, J 8.6, Ar), 7.64–

7.18 (8H, m, Ar), 8.61 (1H, d, J 8.5, Ar); d_C(50 MHz, CDCl₃) 14.1, 16.4,

22.4, 25.1, 27.8, 30.3, 31.5, 55.1, 55.3, 70.8, 76.8, 82.4, 113.7, 124.5,

124.8,125.6,126.2,126.5,128.7,129.2,130.4,132.3,133.7,135.4,159.2,

179.2; m/z (APCI^þ) 514 ([MþNa]^þ,100%), 492 ([MþH]^þ, 50%). Further

elution gave returned starting material (R)-7 (181 mg, 8%).

colourless needles (215 mg, 62%, >99:1 dr); mp 64 ^ꢁC; R_f0.30

23

(pentane/Et₂O, 9:1); [

a

]

ꢀ40.7 (c 2.2, CHCl₃); n_max(ﬁlm) 2963 (C–

D

H), 1678 (C]O), 1456, 1368, 1238, 1170, 1144, 1111, 1092; d_H

(400 MHz, CDCl₃) 0.78 (3H, br t, J 6.8, C(5)H₃), 0.86 (9H, s, CMe₃),

1.28–1.35 (3H, br m, C(3)H_A, C(4)H₂), 1.55–1.58 (1H, br m, C(3)H_B),

1.79 (3H, d,

J J 12.7, 6.0,

7.0, C(1⁰)Me), 3.86 (1H, dd,

OCH_AH_BCH]CH₂), 4.24 (1H, dd, J 12.7, 4.3, OCH_AH_BCH]CH₂), 4.34–

4.38 (1H, br m, C(2)H), 5.16–5.33 (2H, m OCH₂CH]CH₂), 5.95–5.99

(1H, m, OCH₂CH]CH₂) 6.25–6.28 (1H, br m, C(1⁰)H), 7.41–7.86 (6H,

m, Ar), 8.40–8.43 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 13.8, 16.3, 18.7,

27.8, 32.4, 56.1, 70.4, 77.2, 82.4, 116.8, 124.5, 124.7, 125.6, 126.2,

126.4, 128.5, 128.6, 132.2, 133.6, 135.0, 135.4, 179.2; m/z (ESI^þ) 406

([MþNa]^þ, 100%), 384 ([MþH]^þ, 96%); HRMS (ESI^þ) found

384.2556; C₂₄H₃₄NO₃^þ([MþH]^þ) requires 384.2533.

4.2.11. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-(3^%,4^%-dimeth-

oxybenzyloxy)propanamide 34.

4.2.9. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-allyloxy-3-

phenylpropanamide 32.

Compound (S)-9 (161 mg, 0.36 mmol) in THF (4 mL) was treated

with KHMDS (0.50 mmol) and 18-crown-6 (200 mg, 0.76 mmol) in

THF (4 mL) and MeI (0.13 mL, 2.09 mmol) according to the general

procedure. The reaction was held at ꢀ78 ^ꢁC for 4 h before being

quenched. ¹H NMR spectroscopic analysis of the crude reaction

mixture showed the presence of 34 in >95:5 dr. Puriﬁcation via ﬂash

columnchromatography(gradientelution, 30–40 ^ꢁC petrol/Et₂O, 4:1;

increased to 30–40 ^ꢁC petrol/Et₂O, 1:1) gave 34 as a white foam

23

Compound (S)-6 (200 mg, 0.59 mmol) in THF (4 mL) was treated

with KHMDS (0.70 mmol) and 18-crown-6 (400 mg, 1.52 mmol) in

THF (4 mL) and benzyl bromide (0.14 mL, 1.17 mmol) according to

the general procedure. The reaction was held at ꢀ78 ^ꢁC for 5 h be-

fore being quenched. ¹H NMR spectroscopic analysis of the crude

reaction mixture showed the presence of 32 in >95:5 dr. Puriﬁca-

tion via ﬂash column chromatography (gradient elution, 30–40 ^ꢁC

petrol/Et₂O,19:1; increased to 30–40 ^ꢁC petrol/Et₂O, 4:1) gave 32 as

a colourless oil, which crystallised upon prolonged standing to yield

(84 mg, 51%, >99:1 dr); [

a

]

þ28.6 (c 3.3 in CHCl₃); n_max(ﬁlm) 2977

D

(C–H), 1678 (C]O), 1594 (C]C); d_H(400 MHz, CDCl₃) 0.67 (9H, br s,

CMe₃),1.26 (3H, d, J 6.5, C(3)H₃),1.75 (3H, d, J 6.9, C(1⁰)Me), 3.83 (3H, s,

OMe), 3.86 (3H, s, OMe), 4.42 (1H, d, J 11.6, OCH_AH_BAr), 4.49 (1H, q, J

6.5,C(2)H),4.69(1H, d,J11.6, OCH_AH_BAr), 6.30–6.34(1H,brm, C(1⁰)H),

6.79 (1H, d, J 8.2, Ar), 6.90 (1H, dd, J 8.1, 1.6, Ar), 6.99 (1H, s, Ar), 7.30–

7.89 (6H, m, Ar), 8.39–8.41 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 16.0,

16.3, 27.6, 55.8, 55.9, 70.7, 72.7, 82.5, 110.8, 111.1, 120.3, 124.4, 124.8,

125.6,126.3,128.6,128.7,130.6,132.2,133.6,135.5,148.6,149.0,179.8;

m/z (ESI^þ) 488 ([MþNa]^þ, 100%), 466 ([MþH]^þ, 16%); HRMS (ESI^þ)

found 488.2419; C₂₈H₃₅NNaO^þ₅([MþNa]^þ) requires 488.2402.

colourless needles (222 mg, 88%, >99:1 dr); mp 79–82 ^ꢁC; R_f0.40

23

(30–40 ^ꢁC petrol/Et₂O, 9:1); [

a]

ꢀ3.2 (c 0.9 in CHCl₃); n_max(ﬁlm)

D

2973 (C–H), 1678 (C]O), 1453, 1091; d_H(400 MHz, CDCl₃) 0.92 (9H,

s, CMe₃), 1.85 (3H, d, J 7.0, C(1⁰)Me), 2.51 (1H, br m C(3)H_A), 2.77–

2.80 (1H, br m, C(3)H_B), 3.75–3.78 (1H, m, OCH_AH_BCH]CH₂), 4.16

(1H, app dd, J 13.1, 4.6, OCH_AH_BCH]CH₂), 4.49–4.52 (1H, m, C(2)H),

5.02–5.06 (2H, m, OCH₂CH]CH₂), 5.69–5.72 (1H, m,

OCH₂CH]CH₂), 6.23–6.27 (1H, br m, C(1⁰)H), 7.18–7.29 (5H, m, Ar),

7.32–7.87 (6H, m, Ar), 8.42–8.45 (1H, m, Ar); d_C(50 MHz, CDCl₃)

16.7, 27.9, 56.6, 70.4, 78.3, 82.9, 116.5, 124.3, 124.9, 125.6, 126.3,

126.5, 128.0, 128.6, 128.7, 129.6, 133.6, 134.6, 138.4, 175.8; m/z (CI^þ)

432 ([MþH]^þ, 46%); HRMS (CI^þ) found 432.2528; C₂₈H₃₄NO^þ₃

([MþH]^þ) requires 432.2533.

4.2.12. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (R)-2-(3^%,4^%-di-

methoxybenzyloxy)pentanamide 35.

Compound (S)-9 (272 mg, 0.60 mmol) in THF (8 mL) was treated

with KHMDS (0.78 mmol) and 18-crown-6 (300 mg, 1.14 mmol) in

4182

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

THF (8 mL) and 1-iodopropane (0.12 mL, 1.21 mmol) according to

the general procedure. The reaction was held at ꢀ78 ^ꢁC for 4 h be-

fore being quenched. ¹H NMR spectroscopic analysis of the crude

reaction mixture showed the presence of 35 in >95:5 dr. Puriﬁca-

tion via ﬂash column chromatography (gradient elution, 30–40 ^ꢁC

petrol/Et₂O, 9:1; increased to 30–40 ^ꢁC petrol/Et₂O, 2:1) gave 35 as

a colourless oil, which solidiﬁed upon prolonged standing to yield

7 phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was

extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined organic

extracts were dried (Na₂SO₄) and concentrated in vacuo to give an

approximate 50:50 mixture of auxiliary (S)-1 and aldehyde (R)-37.

The crude mixture of auxiliary (S)-1 and aldehyde (R)-37 was

dissolved in pentane (2.5 mL), the solution was stirred and (þ)-CSA

(321 mg, 1.38 mmol) was added. After 1 h a white precipitate had

formed, which was collected by ﬁltration. The ﬁltrate was passed

an amorphous solid (274 mg, 92%, >99:1 dr); R_f0.15 (30–40 ^ꢁC

23

petrol/Et₂O, 5:1); [

a]

þ50.9 (c 1.4 in CHCl₃); n_max(ﬁlm) 2961 (C–

through a short plug of silica gel (eluent Et₂O) and concentrated in

D

23

H), 1675 (C]O); d_H(400 MHz, CDCl₃) 0.74 (9H, s, CMe₃), 0.78 (3H, t,

J 7.0, C(5)H₃), 1.35–1.43 (3H, br m, C(3)H_A, C(4)H₂), 1.58–1.65 (1H, br

m, C(3)H_B) 1.78 (3H, d, J 6.9, C(1⁰)Me), 3.85 (3H, s, OMe), 3.87 (3H, s,

OMe), 4.34 (1H, d, J 11.9, OCH_AH_BAr), 4.35–4.40 (1H, br m, C(2)H),

4.74 (1H, d, J 11.9, OCH_AH_BAr), 6.29–6.34 (1H, br m, C(1⁰)H), 6.79

(1H, d, J 8.2, Ar), 6.88 (1H, dd, J 8.2, 1.7, Ar), 6.99 (1H, s, Ar), 7.41–7.87

(6H, m, Ar), 8.42–8.46 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 13.8, 16.2,

18.9, 27.8, 32.4, 55.7, 55.9, 56.0, 71.0, 77.2, 82.4, 110.7, 110.9, 120.1,

124.5, 124.7, 125.6, 126.2, 126.4, 128.6, 128.7, 130.9, 132.3, 133.6,

135.4, 148.4, 149.9, 179.4; m/z (ESI^þ) 516 ([MþNa]^þ, 100%), 494

([MþH]^þ, 45%); HRMS (ESI^þ) found 494.2907; C₃₀H₄₀NO^þ₅

([MþH]^þ) requires 494.2896.

vacuo to give (R)-37 as a colourless oil (130 mg, 93%);¹⁷

[

a

]

þ68.6

D

25

(c 2.0 in CHCl₃); {lit. for enantiomer ca. 82% ee¹⁷

[

a

]

D

ꢀ46.4 (c 2.5 in

CHCl₃)}; d_H(300 MHz, CDCl₃) 2.54–2.48 (2H, m, C(3)H₂), 3.85 (1H,

dt, J 6.4, 1.9, C(2)H), 4.61 (1H, d, J 11.8, OCH_AH_BPh), 4.70 (1H, d, J 11.8,

OCH_AH_BPh), 5.12–5.21 (2H, m, C(5)H₂), 5.83 (1H, ddt, J 17.1, 10.1, 6.9,

C(4)H), 7.27–7.38 (5H, m, Ph), 9.67 (1H, d, J 1.9, C(1)H). The pre-

cipitate was basiﬁed by the addition of satd aq NaHCO₃(20 mL) and

the mixture was extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL). The

combined organic extracts were dried and concentrated in vacuo to

give (S)-1 as a colourless oil (142 mg, 85%, >99:1 er).

4.2.15. (R)-2-Benzyloxybutanal 38.

4.2.13. (S)-2-Benzyloxypropanal 36.

Compound (2R,1⁰S)-26 (275 mg, 0.66 mmol) was dissolved in THF

(4 mL) and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice

bath. LiAlH₄(1 M in THF, 2 mL, 2 mmol) was added dropwise via sy-

ringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The re-

action mixture was transferred dropwise via cannula to stirred pH 7

phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was extracted

with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo to give an approxi-

mate 50:50 mixture of auxiliary (S)-1 and aldehyde (R)-38.

The crude mixture of auxiliary (S)-1 and aldehyde (R)-38 was

dissolved in pentane (2.5 mL), the solution was stirred and (þ)-CSA

(307 mg, 1.32 mmol) was added. After 1 h a white precipitate had

formed, which was collected by ﬁltration. The ﬁltrate was passed

Compound (2S,1⁰R)-23 (130 mg, 0.32 mmol) was dissolved in

THF (2 mL) and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/

ice bath. LiAlH₄(1 M in THF, 1 mL, 1 mmol) was added dropwise via

syringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixture was transferred dropwise via cannula to stirred

pH 7 phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was

extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined or-

ganic extracts were dried (Na₂SO₄) and concentrated in vacuo to

give an approximate 50:50 mixture of auxiliary (R)-1 and aldehyde

(S)-36.

The crude mixture of auxiliary (R)-1 and aldehyde (S)-36 was

dissolved in pentane (2.5 mL), the solution was stirred and (ꢀ)-CSA

(149 mg, 0.64 mmol) was added. After 1 h a white precipitate had

formed, which was collected by ﬁltration. The ﬁltrate was passed

through a short plug of silica gel (eluent Et₂O) and concentrated in

vacuo to give (R)-38 as a colourless oil (115 mg, 98%);¹⁸

[

a]

þ93.6

23

D

20

(c 1.0 in CHCl₃); {lit. for enantiomer^18a

[a

]

ꢀ95 (c 1.0 in CHCl₃); lit.

D

for enantiomer^18b

[

a]

ꢀ98.3 (c 0.95 in CHCl₃)}; d_H(200 MHz,

23

D

through a short plug of silica gel (eluent Et₂O) and concentrated in

23

vacuo to give (S)-36 as a colourless oil (53 mg, quant);¹³

[

a]

ꢀ50.2

CDCl₃) 1.02 (3H, t, J 7.2, C(4)H₃), 1.77 (2H, q, J 7.2, C(3)H₂), 3.73 (1H,

dt, J 7.2, 2.1, C(2)H), 4.58 (1H, d, J 11.7, OCH_AH_BPh), 4.71 (1H, d, J 11.7,

OCH_AH_BPh), 7.22–7.39 (5H, m, Ph), 9.69 (1H, d, J 2.1, C(1)H). The

precipitate was basiﬁed by the addition of satd aq NaHCO₃(20 mL)

and the mixture was extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL).

The combined organic extracts were dried and concentrated in

vacuo to give (S)-1 as a colourless oil (65 mg, 85%, >99:1 er).

D

(c 1.0 in CHCl₃); {lit.¹³

[

a]

ꢀ52.2 (c 6.5 in CHCl₃);}; d_H(200 MHz,

D

CDCl₃) 1.35 (3H, d, J 6.9, C(3)H₃), 3.91 (1H, dq, J 6.9, 1.7, C(2)H), 4.60

(1H, d, J 11.7, OCH_AH_BPh), 4.68 (1H, d, J 11.7, CH_AH_BPh), 7.63–7.35

(5H, m, Ph), 9.68 (1H, d, J 1.7, C(1)H). The precipitate was basiﬁed by

the addition of satd aq NaHCO₃(20 mL) and the mixture was

extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL). The combined organic

extracts were dried and concentrated in vacuo to give (R)-1 as

a colourless oil (68 mg, 87%, >99:1 er).

4.2.16. (S)-2-Benzyloxypropan-1-ol 39.

4.2.14. (R)-2-Benzyloxypent-4-enal 37.

Compound (S)-36 (10 mg, 0.06 mmol) was dissolved in THF

(1 mL) and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice

bath. LiAlH₄(1 M in THF, 2 mL, 2 mmol) was added dropwise via

syringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 10 min.

The reaction mixture was quenched with solid Na₂SO₄$10H₂O. The

mixture was diluted with Et₂O (50 mL) and ﬁltered through a short

Compound (2R,1⁰S)-25 (297 mg, 0.69 mmol) was dissolved in THF

(4 mL) and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice

bath. LiAlH₄(1 M in THF, 2 mL, 2 mmol) was added dropwise via

syringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixture was transferred dropwise via cannula to stirred pH

plug of MgSO₄(eluent Et₂O). The ﬁltrate was concentrated in vacuo

21

to give (S)-39 as a colourless oil (8 mg, 80%, 97:3 er);^13,15

[

a]

þ40.0

D

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4183

20

(c 0.1 in CHCl₃); {lit.¹³

[a

]

_Dþ45.9 (c 6.4 in CHCl₃); lit.¹⁵

[

a]

þ44.7 (c

vacuo. Puriﬁcation via ﬂash column chromatography (eluent 30–

D

3.5 in CHCl₃)}; d_H(200 MHz, CDCl₃) 1.19 (3H, d, J 6.2, C(3)H₃), 2.13

(1H, br s, OH), 3.50–3.74 (3H, m, C(1)H₂, C(2)H), 4.50 (1H, d, J 11.6,

CH_AH_BPh), 4.67 (1H, d, J 11.6, CH_AH_BPh), 7.27–7.36 (5H, m, Ph).

40 ^ꢁC petrol/Et₂O, 10:1) gave auxiliary (S)-1 (143 mg, 95%, >99:1 er).

21

Further elution gave (R,E)-44 as a colourless oil (125 mg, 82%); [a]

D

þ39.8 (c 1.0 in CHCl₃); n_max(ﬁlm) 1666 (C]O), 1638 (C]C); d_H

(300 MHz,CDCl₃)1.32(3H, d,J6.6,C(5)H₃), 3.23(3H, s,NMe), 3.66(3H,

s, OMe), 4.15 (1H, app quintet d, J 6.2, 1.0, C(4)H), 4.42 (1H, d, J 11.9,

CH_AH_BPh), 4.57 (1H, d, J 11.9, CH_AH_BPh), 6.60 (1H, d, J 15.9, C(2)H), 6.91

(1H, dd, J 15.9, 6.2, C(3)H), 7.23–7.32 (5H, m, Ph); d_C(50 MHz, CDCl₃)

20.8, 32.3, 61.7, 70.7, 74.3, 118.7, 127.8, 128.6, 138.5, 148.0, 166.7; m/z

(CI^þ) 250 ([MþH]^þ, 100%); HRMS (CI^þ) found 250.1445; C₁₄H₂₀NO^þ₃

([MþH]^þ) requires 250.1438.

4.2.17. Methyl (R,E)-4-benzyloxypent-2-enoate 42 and methyl (R,Z)-

4-benzyloxypent-2-enoate 43.

4.2.19. N-Methoxy-N-methyl (S,E)-4-allyloxynona-2-enamide 45.

Compound (2R,1⁰S)-23 (302 mg, 0.75 mmol) was dissolved in THF

(4 mL) and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice

bath. LiAlH₄(1 M in THF, 2.2 mL, 2.2 mmol) was added dropwise via

syringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixture was transferred dropwise viacannula to stirred pH 7

phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was extracted

with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo to give an approxi-

mate 50:50 mixture of auxiliary (S)-1 and aldehyde (R)-36.

The crude mixture of auxiliary (S)-1 and aldehyde (R)-36 was

dissolved in CH₂Cl₂(1 mL) and cooled to 0 ^ꢁC. Ph₃P]CHCO₂Me

(513 mg, 1.49 mmol) was added. The reaction mixture was allowed

to warm to rt over 16 h before being concentrated in vacuo. Puri-

ﬁcation via ﬂash column chromatography (eluent 30–40 ^ꢁC petrol/

Et₂O, 10:1) gave auxiliary (S)-1 (173 mg, 95%, >99:1 er). Further

elution gave (R,Z)-43 as a colourless oil (53 mg, 32%, >99:1 dr, 98:2

Compound (2S,1⁰R)-31 (271 mg, 0.66 mmol) was dissolved in

THF (20 mL) and the resultant solution was cooled to ꢀ15 ^ꢁC in

a salt/ice bath. LiAlH₄(1 M in THF, 2 mL, 2 mmol) was added

dropwise via syringe, and the reaction mixture was stirred at

ꢀ15 ^ꢁC for 1 h. The reaction mixture was transferred dropwise via

cannula to stirred pH 7 phosphate buffer solution (25 mL) at 0 ^ꢁC.

The mixture was extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the

combined organic extracts were dried (Na₂SO₄) and concentrated

in vacuo. The residue was dissolved in CH₂Cl₂(1 mL) and cooled to

0 ^ꢁC, then Ph₃P]CHCON(Me)(OMe) (478 mg, 5.26 mmol) was

added. The reaction mixture was allowed to warm to rt over 16 h

before being concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30–40 ^ꢁC petrol/EtOAc, 2:1) gave auxiliary

23

20

er);¹⁹

[

a

]

ꢀ55.9 (c 0.7 in CHCl₃); {lit. for enantiomer^19a

[

a]

þ36

D

25

(c 0.6 in CHCl₃); lit. for enantiomer^19b

[

a

]

þ25.5 (c 1.0 in CHCl₃);

D

25

lit.^19j

[

a

]

ꢀ49.2 (c 0.5 in CHCl₃)}; d_H(300 MHz, CDCl₃) 1.33 (3H, d, J

D

(R)-1 (154 mg, 96%, >99:1 er). Further elution gave (S,E)-45 as

6.5, C(5)H₃), 3.72 (3H, s, OMe), 4.44 (1H, d, J 11.6, CH_AH_BPh), 4.52

(1H, d, J 11.6, CH_AH_BPh), 5.15–5.19 (1H, m, C(4)H), 5.87 (1H, app dd, J

11.8, C(2)H), 6.25 (1H, dd, J 11.8, 8.4, C(3)H), 7.24–7.36 (5H, m, Ph).

Further elution gave (R,E)-42 as a colourless oil (81 mg, 49%);¹⁹

21

a colourless oil (130 mg, 77%, >99:1 dr); [

a

]

ꢀ22.7 (c 1.1 in CHCl₃);

D

n_max(ﬁlm) 1667 (C]O), 1639 (C]C); d_H(300 MHz, CDCl₃) 0.82 (3H,

t, J 6.8, C(9)H₃), 1.14–1.59 (8H, m, C(5)H₂–C(8)H₂), 3.20 (3H, s, NMe),

3.65 (3H, s, OMe), 3.81 (1H, app ddt, J 12.7, 5.7, 1.4, CH_AH_BCH]CH₂),

3.89 (1H, app q, J 6.3, C(4)H), 3.89 (1H, app ddt, J 12.7, 5.7, 1.4,

CH_AH_BCH]CH₂), 5.11 (1H, dq, J 10.5, 1.4, CH₂CH]CH_AH_B), 5.21 (1H,

dq, J 17.2, 1.4, CH₂CH]CH_AH_B), 5.84 (1H, ddt, J 17.2, 10.5, 5.7,

CH₂CH]CH₂), 6.50 (1H, d, J 15.7, C(2)H), 6.78 (1H, dd, J 15.7, 6.3,

C(3)H); d_C(50 MHz, CDCl₃) 13.8, 22.4, 24.7, 31.6, 32.2, 34.9, 61.7,

69.9, 78.5, 117.0, 119.2, 135.0, 147.3, 166.6; m/z (CI^þ) 256 ([MþH]^þ,

100%); HRMS (CI^þ) found 256.1913; C₁₄H₂₆NO^þ₃([MþH]^þ) requires

256.1907. Further elution gave an impure sample of the (S,Z)-isomer

(9 mg, w5%); d_H(300 MHz, CDCl₃) 0.87 (3H, t, J 6.8, C(9)H₃), 1.19–

1.68 (8H, m, C(5)H₂–C(8)H₂), 3.23 (3H, s, NMe), 3.70 (3H, s, OMe),

3.91 (1H, app ddt, J 12.8, 5.6, 1.2, CH_AH_BCH]CH₂), 4.02 (1H, app ddt,

J 12.8, 5.6, 1.2, CH_AH_BCH]CH₂), 4.92–4.96 (1H, m, C(4)H), 5.15 (1H,

app dt, J 10.4, 1.2, CH₂CH]CH_AH_B), 5.26 (1H, dq, J 17.2, 1.2,

CH₂CH]CH_AH_B), 5.92 (1H, app ddt, J 17.2, 10.4, 5.6, CH₂CH]CH₂),

6.03 (1H, dd, J 11.8, 8.7, C(3)H), 6.38 (1H, d, J 11.8, C(2)H).

23

20

[

a]

þ67.0 (c 1.2 in CHCl₃); {lit. for enantiomer^19a

[

a

]

ꢀ44 (c

D

23

0.2 in CHCl₃); lit. for enantiomer^19g

[

a]

ꢀ34.8 (c 1.2 in CHCl₃)}; d_H

D

(300 MHz, CDCl₃) 1.33 (3H, d, J 6.5, C(5)H₃), 3.77 (3H, s, OMe), 4.10–

4.14 (1H, m, C(4)H), 4.43 (1H, d, J 11.9, CH_AH_BPh), 4.58 (1H, d, J 11.9,

CH_AH_BPh), 6.04 (1H, dd, J 15.8, 1.5, C(2)H), 6.91 (1H, dd, J 15.8, 6.1,

C(3)H), 7.26–7.36 (5H, m, Ph).

4.2.18. N-Methoxy-N-methyl (R,E)-4-benzyloxypent-2-enamide 44.

Compound (2R,1⁰S)-23 (250 mg, 0.62 mmol) was dissolved in THF

(4 mL) and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice

bath. LiAlH₄(1 M in THF, 2 mL, 2 mmol) was added dropwise via sy-

ringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The re-

action mixture was transferred dropwise via cannula to stirred pH 7

phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was extracted

with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo to give an approxi-

mate 50:50 mixture of auxiliary (S)-1 and aldehyde (R)-36.

4.2.20. N-Methoxy-N-methyl (S,E)-4-(4⁰-methoxybenzyloxy)nona-2-

enamide 46.

The crude mixture of auxiliary (S)-1 and aldehyde (R)-36 was

dissolved in CH₂Cl₂(1 mL) and cooled to 0 ^ꢁC, then Ph₃P]CHCON

(Me)(OMe) (447 mg, 1.23 mmol) was added. The reaction mixture

was allowed to warm to rt over 16 h before being concentrated in

Compound (2S,1⁰R)-33 (1.3 g, 2.63 mmol) was dissolved in THF

(20 mL) and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice

bath. LiAlH₄(1 M in THF, 7.9 mL, 7.9 mmol) was added dropwise via

4184

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

syringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixture was transferred dropwise via cannula to stirred pH

7 phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was

extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined or-

ganic extracts were dried (Na₂SO₄) and concentrated in vacuo. The

residue was dissolved in CH₂Cl₂(10 mL) and cooled to 0 ^ꢁC, then

Ph₃P]CHCON(Me)(OMe) (1.90 g, 5.26 mmol) was added. The re-

action mixture was allowed to warm to rt over 16 h before being

concentrated in vacuo. Puriﬁcation via ﬂash column chromatogra-

phy (eluent 30–40 ^ꢁC petrol/EtOAc, 10:1) gave auxiliary (R)-1

was extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined

extracts were dried (Na₂SO₄) and concentrated in vacuo to give an

approximate 50:50 mixture of auxiliary (S)-1 and ketone 49. Puri-

ﬁcation via ﬂash column chromatography (eluent 30–40 ^ꢁC petrol/

Et₂O, 4:1) gave (S)-1 as a colourless oil (122 mg, 82%, >99:1 er).

Further elution gave (R)-49 as a colourless oil (92 mg, 84%); found C,

23

74.2; H, 8.0%; C₁₁H₁₄O₂requires C, 74.1; H, 7.9%; [

a

]

þ47.9 (c 1.0 in

D

CHCl₃); n_max(ﬁlm) 1719 (C]O); d_H(200 MHz, CDCl₃) 1.36 (3H, d, J

6.9, C(4)H₃), 2.21 (3H, s, C(1)H₃), 3.93 (1H, q, J 6.9, C(3)H), 4.50 (1H, d,

J 11.7, CH_AH_BPh), 4.59 (1H, d, J 11.7, CH_AH_BPh), 7.28–7.39 (5H, m, Ph);

d_C(125 MHz, CDCl₃) 17.1, 24.9, 71.9, 80.9, 128.0, 128.1, 128.7, 137.8,

211.8; m/z (CI^þ) 196 ([MþNH₄]^þ, 100%), 179 ([MþH]^þ, 45%).

(649 mg, quant, >99:1 er). Further elution gave (S,E)-46 as a col-

21

ourless oil (783 mg, 89%, >99:1 dr); [

a

]

ꢀ50.8 (c 1.0 in CHCl₃); n_max

D

(ﬁlm) 1666 (C]O), 1637, 1614, 1587 (C]C); d_H(300 MHz, CDCl₃)

0.83–0.90 (3H, m, C(9)H₃), 1.22–1.68 (8H, m, C(5)H_2–C(8)H₂), 3.27

(3H, s, NMe), 3.71 (3H, s, OMe), 3.81 (3H, s, OMe), 3.98 (1H, app q, J 6.2,

C(4)H), 4.32 (1H, d, J 11.4, CH_AH_BAr), 4.54 (1H, d, J 11.4, CH_AH_BAr), 6.60

(1H, d J 15.4, C(2)H), 6.87–6.94 (1H, dd, J 15.4, 6.2, C(3)H) overlapping

6.88 (2H, d, J 8.6, Ar), 7.27 (2H, d, J 8.6, Ar); d_C(50 MHz, CDCl₃) 14.0,

22.5, 24.9, 31.6, 32.3, 35.1, 55.2, 61.7, 70.5, 78.0, 113.7, 119.2, 129.3,

130.4, 147.2, 159.1, 166.4; m/z (APCI^þ) 336 ([MþH]^þ, 100%); HRMS

(CI^þ) found 336.2170; C₁₉H₃₀NO^þ₄([MþH]^þ) requires 336.2169.

Further elution gave an impure sample of the (S,Z)-isomer (53 mg,

w6%); d_H(300 MHz, CDCl₃) 0.86 (3H, t, J 6.8, C(9)H₃), 1.20–1.69 (8H,

m, C(5)H₂–C(8)H₂), 3.22 (3H, s, NMe), 3.69 (3H, s, OMe), 3.78 (3H, s,

OMe), 4.36 (1H, d, J 11.2, CH_AH_BAr), 4.46(1H, d, J 11.2, CH_AH_BAr), 4.99–

5.02 (1H, m, C(4)H), 6.07 (1H, dd, J 11.9, 8.6, C(3)H), 6.38 (1H, d, J 11.9,

C(2)H), 6.85 (2H, d, J 8.6, Ar), 7.25 (2H, d, J 8.6, Ar).

4.2.23. (R)-2-Benzyloxyindan-1-one 50.

Compound (2R,1⁰S)-27 (221 mg, 0.39 mmol) was dissolved in

Et₂O (3 mL) and the resultant solution was cooled to ꢀ78 ^ꢁC in

a

dry-ice/acetone bath. ^tBuLi (1.5 M in pentane, 0.53 mL,

0.79 mmol) was added dropwise via syringe, and the reaction

mixture was stirred at ꢀ78 ^ꢁC for 1 h. The reaction mixture was

transferred dropwise via cannula to a stirred solution pH 7 phos-

phate buffer solution (25 mL) at 0 ^ꢁC. The mixture was extracted

with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo to give an ap-

proximate 50:50 mixture of auxiliary (S)-1 and indanone (R)-50.

The crude mixture of auxiliary (S)-1 and indanone (R)-50 was

dissolved in pentane (2.5 mL), the solution was stirred and (þ)-CSA

(181 mg, 0.78 mmol) was added. After 1 h a white precipitate had

formed, which was collected by ﬁltration. The ﬁltrate was passed

through a short plug of silica gel (eluent Et₂O) and concentrated in

vacuo to give an oil, which was further puriﬁed by vacuum distil-

lation (bp ca. 200 ^ꢁC, 0.1 mmHg) to give (R)-50 as a colourless oil

4.2.21. N-Methoxy-N-methyl (S,E)-4-hydroxynona-2-enamide 47.

Compound 46 (203 mg, 0.61 mmol) was dissolved in MeCN

(4 mL) and the resultant solution was cooled to 0 ^ꢁC. A solution of

CAN (995 mg, 1.82 mmol) in H₂O (2 mL) was added dropwise and

stirring was maintained at 0 ^ꢁC for 2 h. The solution was allowed to

warm to rt over a further 1 h. The reaction mixture was then diluted

with brine (20 mL) and extracted with CH₂Cl₂(3ꢃ20 mL). The

combined organic extracts were dried and concentrated in vacuo.

(84 mg, 89%); found C, 80.55; H, 6.0%; C₁₆H₁₄O₂requires C, 80.65; H,

24

5.9%; [

a

]

þ46.1 (c 1.05 in CHCl₃); n_max(ﬁlm) 1722 (C]O); d_H

D

(200 MHz, CDCl₃) 3.01 (1H, dd, J 17.0, 4.5, C(3)H_A), 3.46 (1H, dd, J

17.0, 7.6, C(3)H_B), 4.34 (1H, dd, J 7.6, 4.5, C(2)H), 4.86 (1H, d, J 11.8,

CH_AH_BPh), 5.64 (1H, d, J 11.8, CH_AH_BPh), 7.45–7.32 (7H, m, Ar), 7.61

(1H, dt, J 6.6, 1.2, Ar), 7.78 (1H, d, J 7.4, Ar); d_C(50 MHz, CDCl₃) 33.8,

72.4, 79.0, 124.4, 126.9, 128.1, 128.3, 128.7, 135.1, 135.8, 137.9, 151.1,

204.3; m/z (CI^þ) 256 ([MþNH₄]^þ, 100%), 239 ([MþH]^þ, 60%). The

precipitate was basiﬁed by the addition of satd aq NaHCO₃(20 mL)

and the mixture was extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL).

The combined organic extracts were dried and concentrated in

vacuo to give (S)-1 as a colourless oil (71 mg, 74%, >99:1 er).

Puriﬁcation via ﬂash column chromatography (eluent 30–40 ^ꢁC

21

petrol/EtOAc, 3:2) gave 47 as a colourless oil (118 mg, 90%);²¹

[a]

D

þ26.1 (c 0.4 in CHCl₃); n_max(ﬁlm) 3414 (O–H), 1661, 1621 (C]C); d_H

(300 MHz, CDCl₃) 0.87–0.90 (3H, m, C(9)H₃), 1.20–1.63 (8H, m,

C(5)H₂–C(8)H₂), 3.25 (3H, s, NMe), 3.71 (3H, s, OMe), 4.34 (1H, app

dq, J 5.9,1.3, C(4)H), 6.61 (1H, d, J 15.3, C(2)H), 6.97 (1H, dd, J 15.3, 4.9,

C(3)H); d_C(125 MHz, CDCl₃) 13.9, 22.4, 24.8, 31.6, 32.3, 36.7, 61.7, 71.3,

117.2, 149.3, 166.7; m/z (APCI^þ) 216 ([MþH]^þ, 100%); HRMS (CI^þ)

found 216.1600; C₁₁H₂₂NO^þ₃([MþH]^þ) requires 216.1594.

4.2.24. (3R,5S)-3-Benzyloxy-5-iodomethyltetrahydrofuran-2-one 51.

4.2.22. (R)-3-Benzyloxybutanone 49.

Compound (2R,1⁰S)-25 (215 mg, 0.5 mmol) was dissolved in

THF/H₂O (v/v 3:1, 2.5 mL) and iodine (379 mg, 1.5 mmol) was

added. The reaction mixture was stirred at rt for eight days. The

reaction was quenched by the addition of 1 M aq Na₂S₂O₃(15 mL).

Satd aq NaHCO₃(15 mL) was added and the mixture was extracted

with 30–40 ^ꢁC petrol (3ꢃ30 mL). The combined organic extracts

were dried and concentrated in vacuo to give 51 in 85:15 dr. Puri-

ﬁcation via ﬂash column chromatography (eluent 30–40 ^ꢁC petrol/

Et₂O, 2:1) gave a white powder, which was further puriﬁed by

Compound (2R,1⁰S)-23 (248 mg, 0.61 mmol) was dissolved in

Et₂O (2 mL) and the resultant solution was cooled to ꢀ10 ^ꢁC in a salt/

ice bath. MeLi (1.6 M in Et₂O, 1.15 mL, 1.84 mmol) was added drop-

wise via syringe, and the reaction mixture was stirred at ꢀ10 ^ꢁC for

1 h. The reaction mixture was transferred dropwise via cannula to

stirred pH 7 phosphate buffer solution (12 mL) at 0 ^ꢁC. The mixture

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4185

recrystallisation from pentane to give 51 as a colourless solid

data can be obtained, free of charge, on application to CCDC, 12

Union Road, Cambridge CB2 1EZ, UK [fax: þ44(0) 1223 336033 or e-

mail: deposit@ccdc.cam.ac.uk].

(76 mg, 46%, >99:1 dr); found C, 43.5; H, 3.8%; C₁₂H₁₃IO₃requires C,

24

43.4; H, 3.95%; [

a

]

þ53.1 (c 0.5 in CHCl₃); n_max(KBr) 1773 (C]O);

D

d_H(300 MHz, CDCl₃) 2.19 (1H, app dt, J 14.0, 7.3, C(4)H_A), 2.48 (1H,

ddd, J 14.0, 6.8, 4.0, C(4)H_B), 3.30 (1H, dd, J 10.6, 7.1, CH_AH_BI), 3.40

(1H, dd, J 10.6, 4.3, CH_AH_BI), 4.26 (1H, dd, J 7.3, 4.0, C(3)H), 4.69 (1H,

d, J 11.6, CH_AH_BPh), 4.67–4.74 (1H, m, C(5)H), 4.91 (1H, d, J 11.6,

CH_AH_BPh), 7.32–7.38 (5H, m, Ph); d_C(125 MHz, CDCl₃) 7.4, 36.2, 72.2,

73.5, 77.0, 128.3, 128.6, 136.8, 173.7; m/z (CI^þ) 350 ([MþNH₄]^þ,

100%).

4.3.3. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S,S)-2,4,4-trimethyl-

3-hydroxypentanamide 54.

4.3. General procedure for enolate aldol reactions

Compound (R)-22 (194 mg, 0.65 mmol) in THF (2 mL) was

treated with KHMDS (0.71 mmol) in THF (2 mL) and pivalaldehyde

(211 m

L, 1.95 mmol) according to the general procedure. ¹H NMR

Freshly titrated KHMDS (ca. 0.5 M in PhMe) was added dropwise

to a degassed solution of the substrate and in THF at ꢀ78 ^ꢁC. After

stirring for 30 min at this temperature, the requisite aldehyde

(freshly distilled or dried) was added dropwise (neat or as a solu-

tion in THF) and stirring was continued at ꢀ78 ^ꢁC for 2 h. The re-

action was then quenched by the dropwise addition of pH 7

phosphate buffer and allowed to warm to rt. The mixture was

concentrated in vacuo, the residue was dissolved in Et₂O and ﬁl-

tered through a short, silica/MgSO₄plug (eluent Et₂O). The ﬁltrate

was concentrated in vacuo and puriﬁed as described.

spectroscopic analysis of the crude reaction mixture showed the

presence of 52 in 98:2 dr. Puriﬁcation via ﬂash column chroma-

tography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1) gave 54 as a colourless

21

oil (151 mg, 60%, >99:1 dr); [

a

]

D

ꢀ22.5 (c. 0.9 in CHCl₃); n_max(KBr)

3468 (O–H), 1646 (C]O); d_H(250 MHz, toluene-d₈, 90 ^ꢁC) 0.85 (9H,

s, CMe₃), 0.92 (9H, s, CMe₃), 1.22 (3H, d, J 6.9, C(2)Me), 1.69 (3H, d, J

7.0, C(1⁰)Me), 3.22–3.26 (2H, br m, C(3)H, OH), 3.36 (1H, dq, J 6.9, 1.1,

C(2)H), 6.02 (1H, q, J 7.0, C(1⁰)H), 7.19–7.37 (3H, m, Ar), 7.53–7.63

(3H, m, Ar), 8.23 (1H, d, J 8.3, Ar); d_C(125 MHz, CDCl₃) 10.4, 17.0,

27.0, 27.6, 35.2, 37.0, 57.0, 76.0, 82.9, 124.0, 125.2, 125.8, 126.4, 126.5,

128.7, 129.0, 133.9, 184.0; m/z (CI^þ) 386 ([MþH]^þ, 100%); HRMS

(CI^þ) found 386.2683; C₂₄H₃₆NO^þ₃([MþH]^þ) requires 386.2690.

4.3.1. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S,S)-2-methyl-3-

hydroxy-3-phenylpropanamide 52.

4.3.4. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R,E)-2-methyl-

3-hydroxy-5-phenylpent-4-enamide 55.

Compound (R)-22 (501 mg, 2.31 mmol) in THF (6 mL) was

treated with KHMDS (1.84 mmol) in THF (6 mL) and benzaldehyde

(508 m

L, 6.93 mmol) according to the general procedure. ¹H NMR

Compound (R)-22 (504 mg, 1.68 mmol) in THF (6 mL) was

spectroscopic analysis of the crude reaction mixture showed the

presence of 52 in 98:2 dr. Puriﬁcation via ﬂash column chromatog-

raphy (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1) gave a white solid, which

was recrystallised from pentane to give 52 as colourless crystals

treated with KHMDS (1.85 mmol) in THF (6 mL) and cinnamalde-

hyde (636 m

L, 5.04 mmol) according to the general procedure. ¹H

NMR spectroscopic analysis of the crude reaction mixture showed

the presence of 55 in >95:5 dr. Puriﬁcation via ﬂash column

chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1) gave 55 as

(485 mg, 72%, >99:1 dr); found C, 77.0; H, 7.7; N, 3.4%; C₂₆H₃₁NO₃

21

requires C, 77.0; H, 7.7; N, 3.45%; mp 137–138 ^ꢁC; [

a]

þ22.8 (c.1.1 in

D

a colourless glass (565 mg, 78%, >99:1 dr); found C, 78.0; H, 7.7; N,

CHCl₃); n_max(KBr) 3448 (O–H), 1639 (C]O), 1597 (C]C); d_H

(250 MHz, PhMe-d₈, 70 ^ꢁC) 0.81 (9H, s, CMe₃), 1.31 (3H, d, J 6.9,

C(2)Me),1.61 (3H, d, J 6.9, C(1⁰)Me), 3.37 (1H, dq, J 6.9, 2.7, C(2)H), 3.81

(1H, br s, OH), 4.97 (1H, br d, J 2.7, C(3)H), 6.08 (1H, q, J 6.9, C(1⁰)H),

6.96–7.64 (11H, m, Ar, Ph), 8.17 (1H, d, J 8.4, Ar); d_C(125 MHz, CDCl₃)

9.0, 27.7, 42.8, 75.2, 83.2,124.0,125.4,125.8,126.1,126.7,127.3,128.3,

128.7, 129.1, 133.9, 141.8, 183.1; m/z (CI^þ) 406 ([MþH]^þ, 100%).

21

3.0%; C₂₈H₃₃NO₃requires C, 77.9; H, 7.7; N, 3.25%; [

a

]

þ27.8 (c 1.0

D

in CHCl₃); n_max(KBr) 3436 (O–H), 1651 (C]O), 1600 (C]C); d_H

(250 MHz, PhMe-d₈, 90 ^ꢁC) 0.79 (9H, s, CMe₃), 1.30 (3H, d, J 6.9,

C(2)Me), 1.67 (3H, d, J 7.0, C(1⁰)Me), 3.24–3.34 (1H, br s, OH), 3.29

(1H, dq, J 6.9, 3.8, C(2)H), 4.50–4.53 (1H, m, C(3)H), 6.12–6.21 (1H,

m, C(1⁰)H) overlapping 6.16 (1H, dd, J 15.9, 5.5, C(4)H), 6.70 (1H, d, J

15.9, C(5)H), 6.97–7.62 (11H, m, Ar, Ph), 8.21 (1H, d, J 8.3, Ar); d_C

(125 MHz, CDCl₃) 10.0, 27.8, 41.8, 72.3, 83.1, 125.2, 125.7, 126.6,

127.6, 128.6, 129.0, 131.0, 133.7, 136.9, 182.2; m/z (ESI^þ) 449

([MþNH₄]^þ, 20%), 432 ([MþH]^þ, 100%).

4.3.2. X-ray crystal structure determination for 52. Data were col-

lected using an Enraf-Nonius MACH3 diffractometer with graphite

monochromated Cu Ka radiation using standard procedures at

190 K. The structure was solved by direct methods (SIR92); all non-

hydrogen atoms were reﬁned with anisotropic thermal parameters.

Hydrogen atoms were added at idealised positions. The structure

was reﬁned using CRYSTALS.³⁸

4.3.5. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2,4-dimethyl-

3-hydroxypentanamide 56.

X-ray crystal structure data for 52 [C₂₆H₃₁NO₃]: M¼405.54, or-

thorhombic, space group P 2₁2₁2₁, a¼9.0403(5) Å, b¼11.4794(4) Å,

c¼22.682(2) Å, V¼2353.8(2) Å³, Z¼4,

m

¼0.553 mm^ꢀ1, colourless

plate, crystal dimensions¼0.13ꢃ0.32ꢃ0.58 mm³. A total of 2494

unique reﬂections were measured for 5<

q

<27 and 2160 reﬂections

Compound (R)-22 (287 mg, 0.96 mmol) in THF (4 mL) was

were used in the reﬁnement. The ﬁnal parameters were wR₂¼0.046

treated with KHMDS (1.05 mmol) in THF (4 mL) and iso-

and R₁¼0.041 [I>3.0

s

(I)], Flack enantiopole¼0.17(1).

butyraldehyde (261 mL, 3.0 mmol) according to the general pro-

Crystallographic data (excluding structure factors) has been

deposited with the Cambridge Crystallographic Data Centre as

supplementary publication number CCDC 745789. Copies of the

cedure. ¹H NMR spectroscopic analysis of the crude reaction

mixture showed the presence of 56 in 92:8 dr. Puriﬁcation via ﬂash

column chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1) gave

4186

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

a colourless oil, which was crystallised from pentane at ꢀ30 ^ꢁC to

give 56 as colourless blocks (151 mg, 42%, 97:3 dr); found C, 74.1; H,

4.3.8. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-benzy-

loxy-3-hydroxybutanamide 60.

9.2; N, 3.7%; C₂₃H₃₃NO₃requires C, 74.4; H, 8.95; N, 3.8%; mp 63–

21

64 ^ꢁC; [

a

]

ꢀ6.4 (c 0.8 in CHCl₃); n_max(KBr) 3488 (O–H), 1641

D

(C]O),1600 (C]C); d_H(250 MHz, PhMe-d₈, 90 ^ꢁC) 0.71 (3H, d, J 6.8,

Me), 0.81 (9H, s, CMe₃), 1.04 (3H, d, J 6.8, Me), 1.17 (3H, d, J 6.8, Me),

1.67 (3H, d, J 7.0, C(1⁰)Me), 1.61–1.73 (1H, m, C(4)H), 3.22–3.29 (2H,

m, C(2)H, C(3)H), 3.32 (1H, br s, OH), 6.07 (1H, q, J 7.0, C(1⁰)H), 7.19–

7.37 (3H, m, Ar), 7.53–7.62 (3H, m, Ar), 8.21 (1H, d, J 8.3, Ar); d_C

(125 MHz, CDCl₃) 9.1, 17.5, 18.8, 19.4, 27.7, 30.4, 37.3, 56.5, 76.0, 82.8,

123.7, 125.0, 125.5, 125.5, 126.3, 128.8, 133.6, 136.1, 183.4; m/z

(APCI^þ) 394 ([MþNa]^þ, 30%), 372 ([MþH]^þ, 100%).

Compound (R)-5 (217 mg, 0.56 mmol) in THF (8 mL) was treated

with KHMDS (0.78 mmol) in THF (8 mL) and acetaldehyde (244 mg,

5.55 mmol) according to the general procedure.¹H NMR spectroscopic

analysis of the crude reaction mixture showed the presence of 60 in

80:20 dr. Puriﬁcation via ﬂash column chromatography (eluent 30–

40 ^ꢁC petrol/Et₂O,1:1) gave 60 as a colourless oil (180 mg, 75%, 80:20

4.3.6. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-methyl-

3-hydroxybutanamide 57.

23

dr); R_f0.25 (30–40 ^ꢁC petrol/Et₂O, 1:1); [

a]

D

ꢀ38.3 (c 1.6 in CHCl₃);

n_max(ﬁlm) 3467 (O–H), 2976 (C–H), 1674 (C]O), 1600 (C]C); d_H

(400 MHz, CDCl₃)0.67(9H, s,CMe₃),1.27(3H, d,J6.5,C(4)H₃),1.82 (3H,

d,J6.9,C(1⁰)Me),2.44–2.48(1H,brm, OH),4.18–4.22(1H, brm, C(3)H),

4.42(1H,d,J2.1, C(2)H),4.51(1H,d,J12.0, CH_AH_BPh), 4.94(1H,d,J12.0,

CH_AH_BPh), 6.41–6.46 (1H, br m, C(1⁰)H), 7.26–7.90 (11H, m, Ar, Ph),

8.41–8.45 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 15.9, 20.2, 27.8, 55.9,

66.6, 71.6, 79.6, 82.8,124.2,124.8,125.2,125.5,125.7,126.3,127.7,127.9,

128.3, 128.4, 128.7, 128.8, 132.2, 133.6, 135.5, 137.7, 177.0; m/z (ESI^þ)

458 ([MþNa]^þ, 100%), 436 ([MþH]^þ, 33%); HRMS (ESI^þ) found

458.2316; C₂₇H₃₃NNaO₄^þ([MþNa]^þ) requires 458.2302.

Compound (S)-22 (288 mg, 0.96 mmol) in THF (4 mL) was

treated with KHMDS (1.06 mmol) in THF (4 mL) and propanal

(161 m

L, 2.89 mmol) according to the general procedure. ¹H NMR

spectroscopic analysis of the crude reaction mixture showed the

presence of 57 in 95:5 dr. Puriﬁcation via ﬂash column chroma-

tography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1) gave a colourless oil,

which was crystallised from pentane at ꢀ30 ^ꢁC to give 57 as col-

ourless blocks (197 mg, 60%, 95:5 dr); found C, 73.6; H, 8.65; N,

4.3.9. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-allyloxy-

3-hydroxy-3-phenylpropanamide 61.

4.0%; C₂₁H₂₉NO₃requires C, 73.4; H, 8.5; N, 4.1%; mp 105–107 ^ꢁC;

21

[

a]

þ5.5 (c 1.45 in CHCl₃); n_max(KBr) 3420 (O–H), 1636 (C]O); d_H

D

(250 MHz, PhMe-d₈, 90 ^ꢁC) 0.77 (9H, s, CMe₃), 1.08 (3H, d, J 6.4,

C(4)H₃), 1.20 (3H, d, J 7.0, C(2)Me), 1.67 (3H, d, J 7.0, C(1⁰)Me), 2.98–

3.08 (1H, br s, OH) overlapping 3.03 (1H, dq, J 7.0, 3.5, C(2)H), 3.99

(1H, dq, J 6.4, 3.5, C(3)H), 6.14 (1H, q, J 7.0, C(1⁰)H), 7.22 (1H, app t, J

7.9, Ar), 7.29–7.36 (2H, m, Ar), 7.55 (1H, app d, J 8.2, Ar), 7.61 (2H,

app d, J 7.3, Ar), 8.21 (1H, d, J 8.4, Ar); d_C(125 MHz, CDCl₃) 9.6, 18.0,

19.9, 27.7, 41.6, 55.5, 67.1, 82.9, 123.5, 125.0, 126.1, 126.4, 128.5,

128.8, 136.2, 133.6, 182.8; m/z (APCI^þ) 366 ([MþNa]^þ, 100%), 344

([MþH]^þ, 50%).

Compound (S)-6 (593 mg, 1.74 mmol) in THF (15 mL) was treated

withKHMDS(2.61 mmol)inTHF(15 mL)andbenzaldehyde(0.53 mL,

5.22 mmol) according to the general procedure.¹H NMR spectroscopic

analysis of the crude reaction mixture showed the presence of 61 in

96:4 dr. Puriﬁcation via ﬂash column chromatography (eluent 30–

40 ^ꢁC petrol/Et₂O, 5:1) gave 61 as a colourless oil (720 mg, 92%, >99:1

23

dr);R_f0.20(30–40 ^ꢁCpetrol/Et₂O,5:1);[

a]

þ8.5 (c1.1 in CHCl₃);n_max

4.3.7. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-benzyloxy-

3-hydroxy-3-phenylpropanamide 59.

D

(ﬁlm) 3400 (O–H), 2976 (C–H),1666 (C]O); d_H(400 MHz, CDCl₃) 0.85

(9H, s, CMe₃), 1.84 (3H, d, J 6.9, C(1⁰)Me), 2.92 (1H, br s, OH) 3.84 (1H,

app dd, J 12.9, 4.8, CH_AH_BCH]CH₂), 4.22 (1H, app dd, J 12.9, 4.4,

CH_AH_BCH]CH₂), 4.65–4.68 (1H, br m, C(2)H), 5.01–5.06 (3H, br m,

OCH₂CH]CH₂, C(3)H), 5.69–5.73 (1H, m, CH₂CH]CH₂), 6.32–6.36

(1H, br m, C(1⁰)H), 7.25–7.88 (11H, m, Ar, Ph), 8.41–8.46 (1H, br m, Ar);

d_C(100 MHz, CDCl₃) 16.2, 27.9, 56.8, 70.8, 71.8, 79.4, 83.2, 117.1, 124.1,

124.4, 124.9, 125.2, 125.6, 125.7, 126.4, 126.6, 127.5, 128.0, 128.7, 128.8,

133.6,134.1,135.4,136.6,141.0,176.8; m/z (ESI^þ) 470 ([MþNa]^þ,100%),

448 ([MþH]^þ, 57%); HRMS (ESI^þ) found 448.2497; C₂₈H₃₄NO^þ₄

([MþH]^þ) requires 448.2482.

Compound (R)-5 (175 mg, 0.45 mmol) in THF (8 mL) was treated

with KHMDS (0.63 mmol) in THF (8 mL) and benzaldehyde

(0.14 mL, 1.34 mmol) according to the general procedure. ¹H NMR

spectroscopic analysis of the crude reaction mixture showed the

presence of 59 in 86:14 dr. Puriﬁcation via ﬂash column chroma-

tography (gradient elution, 30–40 ^ꢁC petrol/Et₂O, 3:1; increased to

4.3.10. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-allyloxy-

3-hydroxybutanamide 62.

Et₂O) gave 59 as a colourless oil (167 mg, 75%, 95:5 dr); R_f0.35 (30–

23

40 ^ꢁC petrol/Et₂O, 1:1); [

a

]

ꢀ25.7 (c 1.3 in CHCl₃); n_max(ﬁlm) 3459

D

(O–H), 2977 (C–H),1674 (C]O),1600 (C]C), 1512, 1495, 1454,1393,

1368; d_H(400 MHz, CDCl₃) 0.73 (9H, s, CMe₃), 1.87 (3H, d, J 7.0,

C(1⁰)Me), 2.94 (1H, br s, OH), 4.39 (1H, d, J 12.4, CH_AH_BPh), 4.68 (1H,

d, J 1.7, C(2)H), 4.77 (1H, d, J 12.4, CH_AH_BPh), 5.01–5.05 (1H, br m,

C(3)H), 6.34–6.37 (1H, br m, C(1⁰)H), 6.96–7.69 (16H, m, Ar, Ph),

8.46–8.49 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 16.2, 27.8, 57.2, 71.5,

71.7, 79.3, 83.1, 124.1, 124.9, 125.7, 126.4, 127.5, 127.6, 128.1, 128.2,

128.7, 132.1, 133.6, 135.4, 137.3, 141.1, 176.7; m/z (ESI^þ) 520

([MþNa]^þ, 100%), 498 ([MþH]^þ, 18%); HRMS (ESI^þ) found

520.2456; C₃₂H₃₅NNaO₄^þ([MþNa]^þ) requires 520.2458.

Compound (S)-6 (540 mg, 1.58 mmol) in THF (20 mL) was treated

with KHMDS (1.85 mmol) inTHF (20 mL) and acetaldehyde (0.44 mL,

7.92 mmol) according to the general procedure. Puriﬁcation via ﬂash

column chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 2:1) gave

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4187

a white solid, which was further puriﬁed by recrystallisation from

J 10.5, CH₂CH]CH_AH_B), 5.17–5.20 (1H, br m, C(2)H), 5.24–5.27 (1H,

br m, C(3)H), 5.56–5.60 (1H, m, OCH₂CH]CH₂) 6.42–6.48 (1H, br m,

C(1⁰)H), 7.13–7.88 (9H, m, Ar), 8.46–8.50 (1H, br m, Ar), 8.52 (1H, d, J

4.6, Ar); d_C(100 MHz, CDCl₃) 15.9, 27.9, 56.5, 70.9, 72.0, 79.2, 83.1,

116.9,120.7,121.5,122.0,124.3,124.9,125.7,125.9,126.5,128.8,132.3,

133.6, 134.4, 135.7, 136.2, 136.7, 148.4, 160.1, 176.8; m/z (ESI^þ) 471

([MþNa]^þ,100%), 449 ([MþH]^þ, 32%); HRMS (ESI^þ) found 449.2440;

C₂₇H₃₃N₂O^þ₄([MþH]^þ) requires 449.2435.

pentane to give 62 as colourless blocks (548 mg, 90%, >95:5 dr); R_f

23

0.15 (30–40 ^ꢁC petrol/Et₂O, 2:1); mp 92–93 ^ꢁC; [

a]

þ25.1 (c 1.1 in

D

CHCl₃); n_max(ﬁlm) 3460 (O–H), 2978 (C–H), 1672 (C]O), 1371, 1093;

d_H(400 MHz, CDCl₃) 0.78 (9H, s, CMe₃),1.23, (3H, d, J 6.3, C(4)H₃),1.81

(3H, d, J 6.9, C(1⁰)Me), 2.38 (1H, br s, OH) 3.95 (1H, app dd, J 12.7, 6.2,

CH_AH_BCH]CH₂), 4.11–4.15 (1H, br m, C(3)H), 4.32–4.36 (2H, br m,

C(2)H, CH_AH_BCH]CH₂), 5.22 (1H, dd, J 10.5, 1.1, CH₂CH]CH_AH_B), 5.31

(1H, dd, J 17.3, 1.1, CH₂CH]CH_AH_B), 5.95–5.99 (1H, m, CH₂CH]CH₂)

6.38–6.41 (1H, br m, C(1⁰)H), 7.42–7.88 (6H, m, Ar), 8.37–8.41 (1H, br

m, Ar); d_C(100 MHz, CDCl₃) 15.9, 20.1, 27.8, 56.1, 66.6, 70.8, 79.7, 82.8,

117.4, 124.2, 124.8, 125.7, 126.4, 128.7, 128.8, 132.1, 133.6, 134.5, 135.4,

177.0; m/z (ESI^þ) 408 ([MþNa]^þ, 100%), 386 ([MþH]^þ, 40%); HRMS

(ESI^þ) found 386.2341; C₂₃H₃₂NO^þ₄([MþH]^þ) requires 386.2326.

4.3.13. X-ray crystal structure determination for 64. Data were col-

lected using an Enraf-Nonius

k-CCD diffractometer with graphite

monochromated Mo K radiation using standard procedures at

a

190 K. The structure was solved by direct methods (SIR92); all non-

hydrogen atoms were reﬁned with anisotropic thermal parameters.

Hydrogen atoms were added at idealised positions. The structure

was reﬁned using CRYSTALS.³⁸

4.3.11. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-allyloxy-

3-hydroxyhexanamide 63.

X-ray crystal structure data for 64 [C₂₇H₂₇N₂O₄]: M¼443.52,

monoclinic, space group C 2, a¼25.6677(9) Å, b¼8.0723(3) Å,

c¼12.5059(4) Å,

b

¼108.6000(17)^ꢁ, V¼2455.85(15) Å³, Z¼4,

m

¼

0.081 mm^ꢀ1, colourless block, crystal dimensions¼0.20ꢃ0.20ꢃ

0.20 mm³. A total of 2970 unique reﬂections were measured for

5<

q

<27 and 2670 reﬂections were used in the reﬁnement. The

(I)].

ﬁnal parameters were wR₂¼0.059 and R₁¼0.054 [I>1.0

s

Crystallographic data (excluding structure factors) has been

deposited with the Cambridge Crystallographic Data Centre as

supplementary publication number CCDC 745790. Copies of the

data can be obtained, free of charge, on application to CCDC, 12

Union Road, Cambridge CB2 1EZ, UK [fax: þ44(0) 1223 336033 or

e-mail: deposit@ccdc.cam.ac.uk].

Compound (S)-6 (250 mg, 0.73 mmol) in THF (9 mL) was treated

with KHMDS (0.95 mmol) in THF (9 mL) and butyraldehyde

(158 mg, 2.20 mmol) according to the general procedure. Puriﬁca-

tion via ﬂash column chromatography (eluent 30–40 ^ꢁC petrol/

Et₂O, 4:1) gave 63 as a colourless oil (166 mg, 55%, 95:5 dr); R_f0.20

23

(30–40 ^ꢁC petrol/Et₂O, 4:1); [

a]

þ22.7 (c 1.0 in CHCl₃); n_max(ﬁlm)

D

4.3.14. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-(4^%-meth-

3472 (O–H), 2993 (C–H), 1682 (C]O), 1600 (C]C); d_H(400 MHz,

CDCl₃) 0.82 (9H, s, CMe₃), 0.87 (3H, t, J 7.1, C(6)H₃), 1.25–1.65 (4H, m,

C(4)H₂, C(5)H₂), 1.83 (3H, d, J 7.0, C(1⁰)Me), 2.07–2.10 (1H, br m, OH),

3.89–3.92 (2H, br m, C(3)H, CH_AH_BCH]CH₂), 4.35 (1H, app dd, J

12.8, 4.5, CH_AH_BCH]CH₂), 4.42 (1H, app s, C(2)H), 5.21 (1H, dd, J

10.8, 1.2, CH₂CH]CH_AH_B), 5.30 (1H, dd, J 17.3, 1.2, CH₂CH]CH_AH_B),

5.93–5.96 (1H, m, CH₂CH]CH₂), 6.32–6.35 (1H, br m, C(1⁰)H), 7.42–

7.88 (6H, m, Ar), 8.40–8.43 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 13.9,

16.0, 18.9, 27.9, 36.4, 56.4, 69.8, 70.8, 78.9, 82.7, 117.4, 125.2, 125.5,

125.6, 125.8, 126.4, 128.3, 128.6, 128.8, 133.6, 135.4, 134.6, 177.4; m/z

(ESI^þ) 436 ([MþNa]^þ, 100%), 414 ([MþH]^þ,18%); HRMS (ESI^þ) found

436.2451; C₂₅H₃₅NNaO₄^þ([MþNa]^þ) requires 436.2458.

oxybenzyloxy)-3-hydroxy-3-phenylpropanamide 65.

Compound (R)-7 (103 mg, 0.25 mmol) in THF (4 mL) was treated

with KHMDS (0.37 mmol) inTHF (4 mL) and benzaldehyde (0.08 mL,

0.74 mmol) according to the general procedure. ¹H NMR spectro-

scopic analysis of the crude reaction mixtureshowed the presence of

65 in 87:13 dr. Puriﬁcation via ﬂash column chromatography (gra-

dient elution, pentane; increased to Et₂O) gave 65 as a colourless oil

(112 mg, 87%, 87:13 dr); R_f0.20 (pentane/Et₂O 4:1); [

23

a

]

ꢀ14.3 (c 1.5

D

4.3.12. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-allyloxy-

in CHCl₃); n_max(ﬁlm) 3420 (O–H), 2974 (C–H), 1674 (C]O), 1613

(C]C); d_H(400 MHz, CDCl₃) 0.74 (9H, s, CMe₃), 1.86 (3H, d, J 6.9,

C(1⁰)Me) 3.76 (3H, s, OMe), 4.32 (1H, d, J 11.9, OCH_AH_BAr), 4.65–4.67

(2H, br m, C(2)H, OCH_AH_BAr), 5.04 (1H, br d, J 3.2, C(3)H), 6.34–6.36

(1H, br m, C(1⁰)H), 6.72 (2H, d, J 8.4, Ar), 7.34 (2H, d, J 8.0, Ar), 7.28–

7.89 (11H, m, Ar), 8.45–8.48 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 16.2,

27.8, 55.3, 56.9, 71.3, 71.7, 79.1, 83.1, 113.6, 122.4, 123.4, 124.9, 125.3,

125.7,126.4,126.5,127.4,128.2,128.3,128.8,129.1,129.3,130.9,132.1,

133.5, 133.6, 135.4, 138.4, 159.2, 176.9; m/z (ESI^þ) 550 ([MþNa]^þ,

100%), 528 ([MþH]^þ, 5%); HRMS (ESI^þ) found 550.2579;

C₃₃H₃₇NNaO^þ₅([MþNa]^þ) requires 550.2564.

3-hydroxy-3-(2^%-pyridyl)propanamide 64.

Compound (R)-6 (461 mg,1.35 mmol) inTHF (10 mL) was treated

with KHMDS (1.89 mmol) in THF (10 mL) and pyridine-2-carbox-

aldehyde (0.26 mL, 2.70 mmol) according to the general procedure.

¹H NMR spectroscopic analysis of the crude reaction mixture

showed the presence of 64 in 94:6 dr. Puriﬁcation via ﬂash column

chromatography (gradient elution, 30–40 ^ꢁC petrol/Et₂O, 2:1; in-

creased to30–40 ^ꢁC petrol/Et₂O,1:1) gavea colourlessoil, whichwas

crystallised from pentane at ꢀ30 ^ꢁC to give 64 as colourless blocks

4.3.15. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-(4^%-meth-

oxybenzyloxy)-3-hydroxybutanamide 66.

(402 mg, 66%, >99:1 dr); R_f0.40 (30–40 ^ꢁC petrol/Et₂O,1:1); mp 98–

23

100 ^ꢁC; [

a

]

ꢀ3.5 (c 1.1 in CHCl₃); n_max(ﬁlm) 3460 (O–H), 2977 (C–

D

H), 1674, (C]O), 1591, 1369, 1112, 1070; d_H(400 MHz, CDCl₃) 0.87

(9H, s, CMe₃), 1.87 (3H, d, J 6.9, C(1⁰)Me), 3.51 (1H, br s, OH) 3.80 (1H,

app dd, J 13.3, 6.0, CH_AH_BCH]CH₂), 4.16 (1H, dd, J 13.3, 4.7,

CH_AH_BCH]CH₂), 4.94 (1H, app d, J 17.5, CH₂CH]CH_AH_B), 4.99 (1H, d,

Compound (R)-7 (111 mg, 0.26 mmol) in THF (4 mL) was treated

with KHMDS (0.40 mmol) in THF (4 mL) and acetaldehyde (0.15 mL,

4188

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

2.63 mmol) according to the general procedure.¹H NMR spectroscopic

analysis of the crude reaction mixture showed the presence of 66 in

69:31 dr. Puriﬁcation via ﬂash column chromatography (eluent pen-

529 ([MþH]^þ, 100%); HRMS (ESI^þ) found 529.2712; C₃₂H₃₇N₂O₅^þ

([MþH]^þ) requires 529.2697.

tane/Et₂O, 4:1) gave 66 as a colourless oil (84 mg, 69%, 87:13 dr); R_f

4.3.18. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-(4^%-meth-

oxybenzyloxy)-3-hydroxy-4,4-dimethylpentanamide 69.

23

0.15 (pentane/Et₂O, 4:1); [

a

]

ꢀ30.5 (c 0.8 in CHCl₃); n_max(ﬁlm) 3462

D

(O–H), 2975 (C–H), 1674 (C]O), 1613 (C]C); d_H(500 MHz, CDCl₃)

0.69 (9H, s, CMe₃),1.24 (3H, d, J 6.3, C(4)H₃),1.82 (3H, d, J 6.9, C(1⁰)Me),

2.49–2.51 (1H, br m, OH), 3.80 (3H, s, OMe), 4.17–4.20 (1H, br m,

C(3)H), 4.37–4.41 (1H, br m, C(2)H), 4.43 (1H, d, J 11.5, CH_AH_BAr), 4.85

(1H, d, J 11.5, CH_AH_BAr), 6.42–6.45 (1H, br m, C(1⁰)H), 6.88 (2H, d, J 8.5,

Ar), 7.34 (2H, d, J 8.5, Ar), 7.43–7.88 (6H, m, Ar), 8.41–8.44 (1H, br m,

Ar); d_C(125 MHz, CDCl₃) 15.8, 20.1, 27.8, 55.2, 55.9, 66.5, 71.3, 79.4,

82.7, 113.6, 124.2, 124.7, 125.4, 125.6, 126.3, 128.6, 128.7, 129.2, 129.3,

129.4,129.6,133.5,133.6,135.4,159.3,177.0; m/z (ESI^þ) 488 ([MþNa]^þ,

100%), 466 ([MþH]^þ, 4%); HRMS (ESI^þ) found 488.2424;

C₂₈H₃₅NNaO^þ₅([MþNa]^þ) requires 488.2407.

Compound (R)-7 (90 mg, 0.21 mmol) in THF (5 mL) was treated

with KHMDS (0.32 mmol) in THF (5 mL) and pivalaldehyde (74 mL,

0.86 mmol) according to the general procedure. Puriﬁcation via ﬂash

column chromatography (eluent pentane/Et₂O, 4:1) gave 68 as

a colourless oil (103 mg, 95%, 90:10 dr); R_f0.25 (pentane/Et₂O, 4:1);

23

[a

]

ꢀ34.1 (c 0.9 in CHCl₃); n_max(ﬁlm) 3566 (O–H), 2958 (C–H),

D

1682 (C]O), 1614 (C]C), 1515, 1249, 1110, 1037; d_H(400 MHz,

CDCl₃) 0.86 (9H, s, CMe₃), 0.93 (9H, s, CMe₃), 1.93 (3H, d, J 7.0,

C(1⁰)Me), 2.05–2.07 (1H, br m, OH), 3.09 (1H, br d, J 8.2, C(3)H), 3.81

(3H, s, OMe), 4.28 (1H, d, J 10.7, CH_AH_BAr), 4.66 (1H, d, J 10.7,

CH_AH_BAr), 4.74 (1H, app s, C(2)H), 6.19 (1H, q, J 7.0, C(1⁰)H) 6.87 (2H,

d, J 8.6, Ar), 7.33 (2H, d, J 8.5, Ar), 7.45–7.88 (6H, m, Ar), 8.54 (1H, d, J

8.3, Ar); d_C(100 MHz, CDCl₃) 16.4, 26.8, 27.9, 35.6, 55.2, 58.3, 68.0,

71.2, 75.3, 82.9, 113.6, 124.4, 124.8, 125.5, 126.2, 126.5, 128.7, 128.8,

129.6, 129.8, 132.2, 133.7, 135.2, 159.2, 178.4; m/z (ESI^þ) 530

([MþNa]^þ, 100%), 508 ([MþH]^þ, 16%); HRMS (ESI^þ) found

508.3069; C₃₁H₄₂NO₅^þ([MþH]^þ) requires 508.3057.

4.3.16. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-(4^%-meth-

oxybenzyloxy)-3-hydroxy-3-(4^&-nitrophenyl)propanamide 67.

Compound (R)-7 (100 mg, 0.24 mmol) in THF (5 mL) was treated

with KHMDS (0.36 mmol) in THF (5 mL) and 4-nitrobenzaldehyde

(112 mg, 0.74 mmol) inTHF (1 mL) according tothe general procedure.

Puriﬁcation via exhaustive ﬂash column chromatography (eluent

4.3.19. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S,S)-2-(4^%-meth-

oxybenzyloxy)-3-hydroxy-3-(thiophen-2^&-yl)propanamide 70.

pentane/Et₂O,1:1) gave 67 as a colourless oil (66 mg, 49%, >95:5 dr);

23

R_f0.20 (pentane/Et₂O, 1:1); [

a

]

ꢀ11.9 (c 0.6 in CHCl₃); n_max(ﬁlm)

D

3440 (O–H), 2976 (C–H), 1668 (C]O), 1610 (C]C) 1515, 1346 (NO₂),

1249, 1109, 1092, 1069; d_H(400 MHz, CDCl₃) 0.87 (9H, s, CMe₃), 1.92

(3H, d, J 6.9, C(1⁰)Me) 3.75 (3H, s, OMe), 4.24 (1H, d, J 12.0, CH_AH_BAr),

4.61(1H, d, J1.5, C(2)H), 4.68(1H, d, J12.0, CH_AH_BAr), 4.97–5.01 (1H, br

m, C(3)H), 6.23–6.25 (1H, br m, C(1⁰)H), 6.70 (2H, d, J 8.5, Ar), 6.91 (2H,

d, J 8.5, Ar), 7.33–8.41 (10H, m, Ar), 8.39–8.41 (1H, br m, Ar); d_C

(100 MHz, CDCl₃) 16.6, 27.9, 55.2, 57.6, 71.3, 72.5, 78.3, 83.6, 113.6,

122.9, 123.2, 123.3, 123.7, 123.9, 124.9, 125.5, 125.6, 125.8, 126.4, 126.9,

127.3, 128.5, 128.7, 129.2, 130.9, 133.7, 134.9, 135.7, 147.3, 159.3, 175.7;

m/z (ESI^þ) 595 ([MþNa]^þ, 100%), 573 ([MþH]^þ, 7%); HRMS (ESI^þ)

found 595.2441; C₃₃H₃₆N₂NaO^þ₇([MþNa]^þ) requires 595.2415.

Compound (R)-7 (112 mg, 0.27 mmol) in THF (5 mL) was treated

with KHMDS (0.40 mmol) in THF (5 mL) and thiophene 2-carbox-

aldehyde (0.74 mL, 0.80 mmol) according to the general procedure.

Puriﬁcationvia ﬂash column chromatography (eluent pentane/Et₂O,

5:1) gave 70 as a colourless oil (115 mg, 81%, 90:10 dr); R_f0.50

23

(Et₂O:pentane 1:1); [

a

]

ꢀ19.1 (c 0.9 in CHCl₃); n_max(ﬁlm) 3422 (O–

D

H), 2973 (C–H), 1679 (C]O), 1613 (C]C), 1514, 1463, 1393, 1368,

1250,1174,1110; d_H(400 MHz, CDCl₃) 0.69 (9H, s, CMe₃),1.85 (3H, d, J

6.9, C(1⁰)Me), 3.02–3.06 (1H, br m, OH), 3.79 (3H, s, OMe), 4.46 (1H, d,

J11.3, CH_AH_BAr), 4.70(1H, d, J 2.3, C(2)H), 4.76 (1H, d, J 11.3, CH_AH_BAr),

5.37 (1H, br d, J 2.3, C(3)H), 6.39–6.42 (1H, br m, C(1⁰)H), 6.82 (2H, d, J

8.5, Ar), 6.95–6.98 (2H, m, Ar), 7.20 (2H, d, J 8.5, Ar), 7.25–7.89 (7H, m,

Ar), 8.41–8.45 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 16.1, 27.8, 55.2,

56.6, 68.4, 71.7, 79.4, 83.1,113.7,122.4,123.4,124.1,124.6,124.9,125.2,

125.7, 126.3, 128.3, 128.7, 128.8, 129.3, 129.6, 133.6, 135.4, 159.3,

176.2; m/z (ESI^þ) 556 ([MþNa]^þ, 100%); HRMS (ESI^þ) found

556.2123; C₃₁H₃₅NNaO₅S^þ([MþNa]^þ) requires 556.2128.

4.3.17. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-(4^%-meth-

oxybenzyloxy)-3-hydroxy-3-(pyridin-2^&-yl)propanamide 68.

Compound (R)-7 (120 mg, 0.29 mmol) in THF (6 mL) was treated

with KHMDS (0.43 mmol) in THF (6 mL) and pyridine-2-carbox-

aldehyde (91 mg, 0.86 mmol) according to the general procedure.

Puriﬁcation via ﬂash column chromatography (eluent pentane/

4.3.20. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S,S)-2-(4^%-meth-

oxybenzyloxy)-3-hydroxy-3-(furan-2^&-yl)propanamide 71.

Et₂O, 4:1) gave 68 as a colourless oil (109 mg, 72%, >99:1 dr); R_f0.15

23

(pentane/Et₂O, 1:1); [

a]

ꢀ26.8 (c 1.1 in CHCl₃); n_max(ﬁlm) 3460

D

(O–H), 2975 (C–H), 1682 (C]O), 1613 (C]C); d_H(400 MHz, CDCl₃)

0.76 (9H, s, CMe₃), 1.88 (3H, d, J 6.9, C(1⁰)Me), 3.49–3.51 (1H, br m,

OH), 3.75 (3H, s, OMe), 4.27 (1H, d, J 11.9, CH_AH_BAr), 4.64 (1H, d, J

11.9, CH_AH_BAr), 5.13 (1H, d, J 2.0, C(2)H), 5.26 (1H, d, J 2.0, C(3)H),

6.45–6.47 (1H, br m, C(1⁰)H) 6.68 (2H, d, J 8.6, Ar), 6.83 (2H, d, J 8.4,

Ar), 7.18–7.89 (9H, m, Ar), 8.49–8.51 (1H, br m, Ar); d_C(100 MHz,

CDCl₃) 15.9, 27.8, 55.2, 56.6, 71.3, 72.0, 78.9, 83.0, 113.4, 120.8, 122.0,

122.4, 124.3, 124.9, 125.7, 126.5, 127.9, 128.7, 129.0, 129.6, 133.6,

135.7,136.2,148.4,159.0,160.2,177.6; m/z (ESI^þ) 551 ([MþNa]^þ, 8%),

Compound (R)-7 (99 mg, 0.24 mmol) in THF (4 mL) was treated

with KHMDS (0.35 mmol) in THF (4 mL) and 2-furan 2-carbox-

aldehyde (0.58 mL, 0.71 mmol) according to the general procedure.

Puriﬁcation via ﬂash column chromatography (eluent pentane/

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4189

23

Et₂O, 9:1) gave 71 as a colourless oil (87 mg, 71%, 88:12 dr); [

a

]

([MþNa]^þ, 100%), 558 ([MþH]^þ, 5%); HRMS (ESI^þ) found 580.2693;

C₃₄H₃₉NNaO^þ₆([MþNa]^þ) requires 580.2670.

D

ꢀ24.8 (c 0.9 in CHCl₃); n_max(ﬁlm) 3455 (O–H), 2976 (C–H), 1682

(C]O), 1613 (C]C), 1514, 1369, 1248, 1112, 1081; d_H(400 MHz,

CDCl₃) 0.66 (9H, s, CMe₃), 1.83 (3H, d, J 6.9, C(1⁰)Me), 2.98 (1H, br s,

OH), 3.77 (3H, s, OMe), 4.43 (1H, d, J 11.9, CH_AH_BAr), 4.72 (1H, d, J

11.9, CH_AH_BAr), 4.86 (1H, d, J 2.9, C(2)H), 5.19 (1H, d, J 2.9, C(3)H),

6.35–6.38 (2H, m, Ar), 6.41–6.45 (1H, br m, C(1⁰)H) 6.79 (2H, d, J 8.6,

Ar), 7.08 (2H, d, J 8.6, Ar), 7.35–7.89 (7H, m, Ar), 8.40–8.44 (1H, br m,

Ar); d_C(100 MHz, CDCl₃) 15.9, 27.7, 55.2, 56.2, 67.0, 71.4, 77.2, 83.1,

106.8, 110.4, 113.7, 124.2, 124.8, 125.5, 125.7, 126.3, 126.4, 128.7,

128.8, 129.3, 129.4, 132.2, 133.6, 135.5, 141.5, 154.3, 159.2, 176.4; m/z

(ESI^þ) 540 ([MþNa]^þ, 100%), 518 ([MþH]^þ, 9%); HRMS (ESI^þ) found

518.2531; C₃₁H₃₆NO₆^þ([MþH]^þ) requires 518.2537.

4.3.23. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-(3^%,4^%-

dimethoxybenzloxy)-3-hydroxybutanamide 74.

Compound (S)-8 (510 mg,1.13 mmol) in THF (10 mL) was treated

with KHMDS (1.58 mmol) in THF (10 mL) and acetaldehyde

(0.45 mL, 7.96 mmol) according to the general procedure. ¹H NMR

spectroscopic analysis of the crude reaction mixture showed the

presence of 74 in 80:20 dr. Puriﬁcation via ﬂash column chroma-

4.3.21. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-(4^%-meth-

oxybenzyloxy)-3-hydroxy-3-(3^&,4^&-methylenedioxyphenyl)pro-

panamide 72.

tography (eluent pentane/Et₂O, 1:1) gave 74 as a white foam

23

(252 mg, 45%, 80:20 dr); R_f0.50 (Et₂O); [

a

]

þ41.4 (c 1.2 in CHCl₃);

D

n_max(ﬁlm) 3482 (O–H), 2973 (C–H), 1674 (C]O), 1515, 1464, 1369,

1263, 1158, 1091, 1029; d_H(400 MHz, CDCl₃) 0.65 (9H, s, CMe₃), 1.24

(3H, d, J 6.6, C(4)H₃), 1.80 (3H, d, J 6.9, C(1⁰)Me), 2.44 (1H, br s, OH),

3.85 (3H, s, OMe), 3.88 (3H, s, OMe), 4.16–4.20 (1H, br m, C(3)H),

4.37 (1H, d, J 2.1, C(2)H), 4.44 (1H, d, J 11.8, CH_AH_BAr), 4.85 (1H, d, J

11.8, CH_AH_BAr), 6.41–6.44 (1H, br m, C(1⁰)H), 6.77–7.89 (9H, m, Ar),

8.40–8.43 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 15.8, 20.2, 27.8, 55.8,

55.9, 66.5, 71.6, 79.3, 82.7, 110.7, 111.1, 120.4, 124.2, 124.8, 125.5,

125.7, 126.4, 128.7, 128.8, 130.2, 132.2, 133.6, 135.4, 148.7, 149.0,

177.1; m/z (ESI^þ) 518 ([MþNa]^þ, 100%), 496 ([MþH]^þ, 6%); HRMS

(ESI^þ) found 518.2518; C₂₉H₃₇NNaO^þ₆([MþNa]^þ) requires 518.2513.

Compound (R)-7 (100 mg, 0.24 mmol) in THF (5 mL) was treated

with KHMDS (0.36 mmol) in THF (5 mL) and piperonal (112 mg,

0.74 mmol) according to the general procedure. ¹H NMR spectro-

scopic analysis of the crude reaction mixture showed the presence

of 72 in 81:19 dr. Puriﬁcation via ﬂash column chromatography

4.3.24. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-(3^%,4^%-

(eluent pentane/Et₂O, 4:1) gave 72 as a colourless oil (89 mg, 66%,

23

dimethoxybenzloxy)-3-hydroxy-3-(pyridin-2^&-yl)propanamide 75.

82:18 dr); R_f0.30 (pentane/Et₂O, 1:1); [

a

]

D

ꢀ6.8 (c 0.6 in CHCl₃);

n_max(ﬁlm) 3466 (O–H), 2975 (C–H), 1669 (C]O), 1613 (C]C), 1513,

1247, 1093, 1038; d_H(400 MHz, CDCl₃) 0.75 (9H, s, CMe₃), 1.85 (3H,

d, J 6.9, C(1⁰)Me), 2.86–2.90 (1H, br m, OH), 3.75 (3H, s, OMe), 4.35

(1H, d, J 11.7, CH_AH_BAr), 4.61 (1H, d, J 2.0, C(2)H), 4.70 (1H, d, J 11.7,

CH_AH_BAr), 4.90–4.93 (1H, br m, C(3)H), 5.92–5.98 (2H, m, OCH₂O),

6.30–6.35 (1H, br m, C(1⁰)H), 6.73–7.89 (13H, m, Ar), 8.42–8.45 (1H,

br m, Ar); d_C(100 MHz, CDCl₃) 16.3, 27.8, 55.2, 57.0, 71.4, 71.6, 79.2,

83.2, 100.9, 107.4, 107.8, 107.9, 113.6, 119.9, 123.4, 124.1, 124.9, 125.2,

125.5, 126.1, 128.3, 129.3, 132.1, 133.6, 135.4, 146.8, 147.4, 159.2,

176.6; m/z (ESI^þ) 594 ([MþNa]^þ, 100%); HRMS (ESI^þ) found

594.2460; C₃₄H₃₇NNaO₇^þ([MþNa]^þ) requires 594.2462.

Compound (S)-8 (247 mg, 0.55 mmol) in THF (6 mL) was treated

with KHMDS (0.77 mmol) in THF (6 mL) and pyridine-2-carbox-

aldehyde (0.10 mL,1.09 mmol) according tothe general procedure.¹H

NMR spectroscopic analysis of the crude reaction mixture showed

the presence of 75 in 80:20 dr. Puriﬁcation via ﬂash column chro-

matography (gradient elution, pentane/Et₂O,1:1; increased to Et₂O)

gave 75 as a colourless foam (97 mg, 32%, >99:1 dr); R_f0.2 (Et₂O);

4.3.22. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-(3^%,4^%-

dimethoxybenzloxy)-3-hydroxy-3-phenylpropanamide 73.

23

[a

]

þ25.0 (c 0.9 in CHCl₃); n_max(ﬁlm) 3501 (O–H), 2973 (C–H),1683

D

(C]O),1591 (C]C),1516,1464,1263,1158,1138,1029; d_H(400 MHz,

CDCl₃)0.76 (9H, s, CMe₃),1.88 (3H, d, J 6.9, C(1⁰)Me), 3.48–3.53 (1H, br

m, OH), 3.70 (3H, s, OMe), 3.82 (3H, s, OMe), 4.30 (1H, d, J 11.9,

CH_AH_BAr), 4.62 (1H, d, J 11.9, CH_AH_BAr), 5.19 (1H, app s, C(2)H), 5.24–

5.27 (1H, br m, C(3)H), 6.44–6.46 (1H, br m, C(1⁰)H), 6.50–6.53 (1H,

m, Ar), 6.65 (1H, d, J 8.7, Ar), 7.15–7.89 (10H, m, Ar), 8.48–8.51 (2H, br

m, Ar); d_C(100 MHz, CDCl₃) 15.9, 27.8, 55.7, 55.8, 56.5, 71.7, 72.0, 79.0,

83.1, 110.4, 110.9, 120.1, 120.7, 121.9, 124.3, 124.9, 125.5, 125.7, 126.3,

128.2,128.6,130.1,132.3,133.6,135.7,136.2,148.5,148.7,160.3,177.5;

m/z (ESI^þ) 581 ([MþNa]^þ, 26%), 559 ([MþH]^þ, 100%); HRMS (ESI^þ)

found 559.2805; C₃₃H₃₉N₂O^þ₆requires ([MþH]^þ) 559.2803.

Compound (S)-8 (589 mg, 1.31 mmol) in THF (15 mL) was

treated with KHMDS (1.96 mmol) in THF (15 mL) and benzaldehyde

(0.40 mL, 3.92 mmol) according to the general procedure. ¹H NMR

spectroscopic analysis of the crude reaction mixture showed the

presence of 73 in 83:17 dr. Puriﬁcation via ﬂash column chroma-

tography (eluent pentane/Et₂O, 1:1) gave 73 as a white foam

23

(556 mg, 77%, 85:15 dr); R_f0.60 (Et₂O); [

a

]

þ21.9 (c 1.7 in CHCl₃);

4.3.25. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-(3^%,4^%-

D

n_max(ﬁlm) 3454 (O–H), 2975 (C–H), 1674 (C]O), 1594 (C]C), 1515,

1435, 1368, 1264, 1239, 1158, 1112, 1029; d_H(400 MHz, CDCl₃) 0.72

(9H, s, CMe₃), 1.86 (3H, d, J 6.9, C(1⁰)Me), 2.95–2.98 (1H, br m, OH),

3.66 (3H, s, OMe), 3.81 (3H, s, OMe), 4.38 (1H, d, J 12.1, CH_AH_BAr),

4.69 (1H, d, J 12.0, CH_AH_BAr), 4.69 (1H, d, J 1.6, C(2)H), 5.02–5.06

(1H, br m, C(3)H), 6.34–6.38 (1H, br m, C(1⁰)H), 6.55–7.90 (14H, m,

Ar, Ph), 8.46–8.50 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 16.2, 27.8,

55.7, 55.8, 57.1, 71.4, 71.6, 79.0, 83.1, 110.5, 110.6, 120.0, 120.2, 122.4,

123.4, 124.1, 124.9, 125.5, 125.8, 126.4, 127.4, 128.2, 128.7, 129.3,

129.9, 130.9, 133.9, 135.4, 141.4, 148.5, 148.9, 176.8; m/z (ESI^þ) 580

dimethoxybenzloxy)-3-hydroxy-4,4-dimethylpentanamide 76.

Compound (S)-8 (180 mg, 0.40 mmol) in THF (15 mL) was

treated with KHMDS (0.60 mmol) in THF (15 mL) and pivalaldehyde

(0.95 mL, 0.86 mmol) according to the general procedure. ¹H NMR

4190

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

spectroscopic analysis of the crude reaction mixture showed the

presence of 76 in 85:15 dr. Puriﬁcation via ﬂash column chroma-

(1H, q, J 6.8, C(1⁰)H), 6.97–7.61 (16H, m, Ar), 8.30 (1H, d, J 8.3, Ar); d_C

(125 MHz, CDCl₃) 15.1, 27.9, 42.0, 54.0, 69.8, 80.9, 82.5, 92.6, 124.5,

125.1, 125.8, 126.5, 126.6, 127.9, 128.2, 128.6, 128.9, 133.8, 136.8,

138.0, 140.0, 180.0; m/z (APCI^þ) 526 ([MþH]^þ, 100%).

tography (eluent pentane/Et₂O, 3:1) gave 76 as a colourless oil

23

(155 mg, 72%, 86:14 dr); R_f0.30 (pentane/Et₂O, 3:1); [

a]

þ38.6 (c

D

1.0 in CHCl₃); n_max(ﬁlm) 3566 (O–H), 2956 (C–H),1674 (C]O), 1516,

1465, 1393, 1369, 1263, 1240, 1160, 1111, 1029; d_H(400 MHz, CDCl₃)

0.87 (9H, s, CMe₃), 0.95 (9H, s, CMe₃), 1.93 (3H, d, J 7.0, C(1⁰)Me),

2.00–2.05 (1H, br m, OH), 3.08–3.10 (1H, br m, C(3)H), 3.87 (3H, s,

OMe), 3.88 (3H, s, OMe), 4.30 (1H, d, J 11.1, CH_AH_BAr), 4.70 (1H, d, J

11.1, CH_AH_BAr), 4.71–4.74 (1H, br m, C(2)H), 6.18 (1H, d, J 7.0, C(1⁰)H),

6.79–7.88 (9H, m, Ar), 8.53 (1H, br d, J 8.4, Ar); d_C(100 MHz, CDCl₃)

16.6, 26.8, 27.9, 35.5, 55.7, 55.9, 58.4, 71.4, 75.3, 77.3, 82.9, 110.6,

111.4, 120.4, 124.4, 124.8, 125.5, 126.2, 126.5, 128.7, 128.8, 130.2,

132.2, 133.7, 135.1, 148.6, 148.8, 178.3; m/z (ESI^þ) 560 ([MþNa]^þ,

100%), 538 ([MþH]^þ, 4%); HRMS (ESI^þ) found 538.3176; C₃₂H₄₄NO^þ₆

([MþH]^þ) requires 538.3163.

4.3.28. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R,E)-2-methyl-

3-benzyloxymethoxy-5-phenylpent-4-enoate 81.

Compound 55 (552 mg, 1.02 mmol) was dissolved in CH₂Cl₂

(1 mL) and Bu₄NI (100 mg, 0.3 mmol) was added. Di-iso-propyle-

thylamine (1.12 mL, 6.4 mmol) and BOMCl (ca. 80% pure, 1.1 mL,

4.1 mmol) were then added sequentially. The reaction mixture was

stirred at rt for two days. H₂O (10 mL) was added and the mixture

was stirred for a further 6 h. The mixture was extracted with CH₂Cl₂

(3ꢃ10 mL) and the combined organic extracts were dried, ﬁltered

through a short plug of alumina (grade V, eluent CH₂Cl₂), then

concentrated in vacuo. Puriﬁcation via ﬂash column chromatogra-

phy (eluent 30–40 ^ꢁC petrol/Et₂O, 4:1) gave 81 as a colourless oil

4.3.26. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S,S)-2-methyl-3-

tert-butyldimethylsilyloxy-3-phenylpropanamide 79.

(677 mg, 94%); found C, 78.2; H, 7.75; N, 2.9%; C₃₆H₄₁NO₄requires

21

C, 78.4; H, 7.5; N, 2.5%; [

a

]

ꢀ75.4 (c 0.9 in CHCl₃); n_max(KBr) 1654

D

(C]O), 1599 (C]C); d_H(250 MHz, PhMe-d₈, 90 ^ꢁC) 0.75 (9H, s,

CMe₃), 1.46 (3H, d, J 6.9, C(2)Me), 1.61 (3H, d, J 6.9, C(1⁰)Me), 3.57

TBDMSCl (40 mg, 0.27 mmol) and imidazole (37 mg, 0.54 mmol)

were added sequentially to a stirred solution of 52 (88 mg,

0.22 mmol) in DMF (1 mL). After stirring for two days, H₂O (10 mL)

was added and the mixture was extracted with 30–40 ^ꢁC petrol

(3ꢃ10 mL). The combined organic extracts were dried (Na₂SO₄) and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatogra-

(1H, app quintet,

J 6.9, C(2)H), 4.45–4.82 (5H, m, C(3)H,

OCH₂OCH₂Ph), 6.28–6.37 (1H, m, C(1⁰)H) overlapping 6.33 (1H, dd, J

16.0, 7.9, C(4)H), 6.62 (1H, d, J 16.0, C(5)H), 6.97–7.53 (15H, m, Ar,

Ph), 7.59 (1H, J 8.1, Ar), 8.37 (1H, d, J 8.3, Ar); d_C(125 MHz, CDCl₃)

14.1, 16.0, 27.9, 41.0, 54.0, 69.6, 79.5, 82.4, 91.6, 124.4, 124.8, 125.5,

126.6, 127.6, 127.7, 127.9, 128.3, 128.5, 133.5, 134.2, 136.4, 137.8,

180.0; m/z (CI^þ) 552 ([MþH]^þ, 100%).

phy (eluent 30–40 ^ꢁC petrol/Et₂O, 4:1) gave 79 as a colourless oil

21

(90 mg, 80%); [

a

]

ꢀ19.4 (c 1.9 in CHCl₃); n_max(KBr) 1654 (C]O); d_H

D

(250 MHz, PhMe-d₈, 90 ^ꢁC) ꢀ0.16 (3H, s, SiMe), 0.09 (3H, s, SiMe),

0.63 (9H, s, SiCMe₃), 0.93 (9H, s, OCMe₃), 1.26 (3H, br d, J 6.7,

C(2)Me), 1.52 (3H, d, J 6.8, C(1⁰)Me), 3.57 (1H, dq, J 8.5, 6.7, C(2)H),

5.04 (1H, d, J 8.5, C(3)H), 6.10 (1H, q, J 6.8, C(1⁰)H), 6.97–7.60 (11H,

m, Ar, Ph), 8.23 (1H, d, J 8.3, Ar); d_C(50 MHz, CDCl₃) ꢀ5.1, ꢀ4.7, 15.9,

18.1, 25.7, 27.7, 82.2, 125.0, 125.6, 126.4, 126.4, 127.6, 127.9, 128.0,

128.8, 133.7, 137.0, 143.0; m/z (APCI^þ) 542 ([MþNa]^þ, 40%), 520

([MþH]^þ, 100%); HRMS (CI^þ) found 520.3247; C₃₂H₄₆NO₃Si^þ

([MþH]^þ) requires 520.3241.

4.3.29. Methyl (4R,5S,E)-4-methyl-5-benzyloxymethoxy-5-phenylpent-

2-enoate 82.

Compound 80 (160 mg, 0.3 mmol) was dissolved in THF (2 mL)

and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice bath.

LiAlH₄(1 M in THF, 0.9 mL, 0.9 mmol) was added dropwise via sy-

ringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixture was transferred dropwise via cannula to stirred

pH 7 phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was

extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined or-

ganic extracts were dried (Na₂SO₄) and concentrated in vacuo. The

residue was dissolved in CH₂Cl₂(1 mL) and cooled to 0 ^ꢁC, then

Ph₃P]CHCO₂Me (203 mg, 0.61 mmol) was added. The reaction

mixture was allowed to warm to rt over 16 h before being con-

centrated in vacuo. Puriﬁcation via ﬂash column chromatography

(eluent 30–40 ^ꢁC petrol/Et₂O, 6:1) gave auxiliary (R)-1 (67 mg, 91%,

>99:1 er). Further elution gave a colourless oil, which was crys-

tallised from pentane to give 82 as yellow needles (99 mg, 96%,

4.3.27. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (S,S)-2-methyl-3-

benzyloxymethoxy-3-phenylpropanamide 80.

Compound 52 (415 mg, 1.02 mmol) was dissolved in CH₂Cl₂

(1 mL) and Bu₄NI (100 mg, 0.3 mmol) was added. Di-iso-propyle-

thylamine (1.07 mL, 6.1 mmol) and BOMCl (ca. 90% pure, 810 mL,

4.1 mmol) were then added sequentially. The reaction mixture was

stirred at rt for 2 days. H₂O (10 mL) was added and the mixture was

stirred for a further 6 h. The mixture was extracted with CH₂Cl₂

(3ꢃ10 mL) and the combined organic extracts were dried, ﬁltered

through a short plug of alumina (grade V, eluent CH₂Cl₂), then

concentrated in vacuo. Puriﬁcation via ﬂash column chromatogra-

phy (eluent 30–40 ^ꢁC petrol/Et₂O, 4:1) gave 80 as a colourless oil

>99:1 dr); found C, 74.1; H, 7.3%; C₂₁H₂₄O₄requires C, 74.1; H, 7.1%;

23

mp 53–54 ^ꢁC; [

a

]

ꢀ105.8 (c 1.0 in CHCl₃); n_max(KBr) 1724 (C]O),

D

1657 (C]C); d_H(300 MHz, CDCl₃) 1.14 (3H, d, J 6.9, C(4)Me), 2.76

(1H, app d sextet, J 6.6, 1.1, C(4)H), 3.69 (3H, s, OMe), 4.51 (1H, d, J

11.6, CH_AH_BPh), 4.66 (1H, d, J 7.1, OCH_AH_BO), 4.73 (1H, d, J 11.6,

CH_AH_BPh), 4.75 (1H, d, J 7.1, OCH_AH_BO), 5.76 (1H, dd, J 15.8, 1.1,

C(2)H), 6.99 (1H, dd, J 15.8, 7.7, C(3)H), 7.26–7.38 (10H, m, Ph); d_C

(50 MHz, CDCl₃) 14.6, 43.0, 51.4, 69.9, 80.9, 92.5, 121.3, 127.7, 127.9,

128.1, 128.5, 128.6, 138.0, 139.6, 150.9, 167.2; m/z (ESI^þ) 358

([MþNH₄]^þ, 100%).

(503 mg, 94%); found C, 77.6; H, 7.6; N, 2.7%; C₃₄H₃₉NO₄requires C,

21

77.7; H, 7.5; N, 2.7%; [

a]

ꢀ63.0 (c 1.0 in CHCl₃); n_max(KBr) 1653

D

(C]O), 1600 (C]C); d_H(250 MHz, PhMe-d₈, 90 ^ꢁC) 0.66 (9H, s,

CMe₃), 1.24 (3H, d, J 6.8, C(2)Me), 1.55 (3H, d, J 6.8, C(1⁰)Me), 3.68

(1H, dq, J 8.5, 6.8, C(2)H), 4.40 (1H, d, J 12.0, OCH_AH_BO), 4.58 (2H, A₂,

CH₂Ph), 4.60 (1H, d, J 12.0, OCH_AH_BO), 5.01 (1H, d, J 8.5, C(3)H), 6.14

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4191

4.3.30. Methyl (4R,5S,E,E)-4-methyl-5-benzyloxymethoxy-7-phenyl-

hept-2,6-dienoate 83.

7.0, C(1⁰)Me), 2.81 (1H, br s, OMe), 4.42 (1H, br d, J 12.8, OCH_AH_BPh),

4.47 (1H, br d, J 2.6, C(2)H), 4.64–4.69 (1H, br m, C(3)H), 4.81 (1H, d, J

12.9, OCH_AH_BPh), 6.19–6.22 (1H, br m, C(1⁰)H), 6.80–7.89 (16H, m, Ar,

Ph), 8.47–8.50 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 16.5, 27.8, 56.5,

57.2, 71.4, 79.4, 81.0, 83.1,124.4,125.0,125.5,126.3,126.8,127.2,127.3,

127.7, 128.0, 128.1, 128.5, 128.6, 133.7, 135.4, 137.8, 138.1, 175.2; m/z

(ESI^þ) 534 ([MþNa]^þ,100%), 512 ([MþH]^þ, 25%); HRMS (ESI^þ) found

512.2787; C₃₃H₃₈NO^þ₄([MþH]^þ) requires 512.2801. Further elution

Compound 81 (252 mg, 0.46 mmol) was dissolved in THF (4 mL)

and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice bath.

LiAlH₄(1 M in THF, 1.0 mL, 1.0 mmol) was added dropwise via sy-

ringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixture was transferred dropwise via cannula to stirred pH

7 phosphate buffer solution (50 mL) at 0 ^ꢁC. The mixture was

extracted with 30–40 ^ꢁC petrol (3ꢃ50 mL) and the combined organic

extracts were dried (Na₂SO₄) and concentrated in vacuo. The residue

was dissolved in CH₂Cl₂(2 mL) and cooled to 0 ^ꢁC, then

Ph₃P]CHCO₂Me (306 mg, 0.61 mmol) was added. The reaction

mixture was allowed to warm to rt over 16 h before being concen-

trated in vacuo. Puriﬁcation via ﬂash column chromatography (elu-

ent 30–40 ^ꢁC petrol/Et₂O, 4:1) gave auxiliary (R)-1 (103 mg, 93%,

>99:1 er). Further elution gave 83 as a colourless oil (131 mg, 93%,

gave 88 as a colourless oil (24 mg, 10%, >99:1 dr); R_f0.65 (pentane/

23

Et₂O, 1:1); [

a]

ꢀ27.5 (c 1.1 in CHCl₃); n_max(ﬁlm) 2976 (C–H), 1668

D

(C]O),1513,1454,1368,1247,1092; d_H(400 MHz, CDCl₃) 0.88 (9H, s,

CMe₃), 1.78 (3H, br d, J 6.5, C(1⁰)Me), 3.27 (1H, br s, OMe), 4.55–4.59

(2H, br m, C(2)H, OCH_AH_BPh), 4.84 (1H, br d, J 12.1, OCH_AH_BPh), 4.93–

4.96 (1H, br m, C(3)H), 5.55–6.05 (1H, br m, C(1⁰)H), 6.85–7.90 (16H,

m, Ar, Ph), 7.98 (1H, brd, J 7.9, Ar); d_C(100 MHz, CDCl₃) 18.5, 27.3, 57.3,

72.1, 79.8, 82.3, 82.9, 123.0, 125.3, 125.6, 126.3, 127.2, 127.5, 127.8,

128.0, 128.1, 128.9, 133.5, 138.2, 174.2; m/z (ESI^þ) 534 ([MþNa]^þ,

100%), 512 ([MþH]^þ, 53%); HRMS (ESI^þ) found 534.2621;

C₃₃H₃₇NNaO^þ₄([MþNa]^þ) requires 534.2620.

4.4.2. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-allyloxy-

3-methoxy-3-phenylpropanamide 85.

>99:1 dr); found C, 75.2; H, 7.1%; C₂₃H₂₆O₄requires C, 75.4; H, 7.15%;

21

[a]

ꢀ122.4 (c 1.0 in CHCl₃); n_max(ﬁlm) 1723 (C]O), 1657 (C]C),

D

1600 (C]C); d_H(300 MHz, CDCl₃) 1.20 (3H, d, J 6.8, C(4)Me), 2.72 (1H,

app d sextet, J 6.8, 1.0, C(4)H), 3.75 (3H, s, OMe), 4.29 (1H, dd, J 8.3,

5.5, C(5)H), 4.66 (1H, d, J 11.8, OCH_AH_BO), 4.77 (1H, d, J 11.8,

OCH_AH_BO), 4.79 (1H, d, J 7.0, CH_AH_BPh), 4.90 (1H, d, J 7.0, CH_AH_BPh),

5.95 (1H, dd, J 15.9, 1.1, CH, oleﬁn), 6.08 (1H, dd, J 15.9, 8.3, CH, oleﬁn),

6.62 (1H, d, J 15.9, CH, oleﬁn), 7.16 (1H, dd, J 15.9, 7.3, CH, oleﬁn),

7.26–7.43 (10H, m, Ar); d_C(50 MHz, CDCl₃) 14.9, 41.4, 51.5, 69.8, 79.8,

91.8, 121.3, 126.4, 126.7, 127.8, 127.8, 128.0, 128.5, 128.6, 136.2, 137.9,

150.6, 167.0; m/z (ES^þ) 384 ([MþNH₄]^þ, 100%), 367 ([MþH]^þ, 5%).

Compound (R)-6 (200 mg, 0.59 mmol) in THF (5 mL) was treated

with KHMDS (0.75 mmol) in THF (5 mL), benzaldehyde (0.15 mL,

1.47 mmol) and then MeI (0.36 mL, 5.87 mmol) according to the

general procedure. ¹H NMR spectroscopic analysis of the crude re-

action mixture showed the presence of 85:89 in 88:12 dr. Puriﬁcation

via ﬂash column chromatography (gradient elution, pentane/Et₂O,

9:1; increased to pentane/Et₂O,1:1) gave 85 as a colourless oil, which

4.4. General procedure for enolate aldol reactions and

tandem O-methylation

solidiﬁed upon prolonged standing to give a pale yellow amorphous

23

Freshly titrated KHMDS (ca. 0.5 M in PhMe) was added dropwise

to a degassed solution of the substrate and in THF at ꢀ78 ^ꢁC. After

stirring for 30 min at this temperature, the requisite aldehyde (freshly

distilled or dried) was added dropwise (neat or as a solution in THF)

and stirring was continued at ꢀ78 ^ꢁC for 2 h. MeI was then added

dropwise and the mixture was stirred at ꢀ78 ^ꢁC for a further 10 min

before being allowed to warm to rt over 12 h. The reaction was then

quenched by the dropwise addition of pH 7 phosphate buffer. The

mixture was concentrated in vacuo, the residue was dissolved in Et₂O

and ﬁltered through a short, silica/MgSO₄plug (eluent Et₂O). The

ﬁltrate was concentrated in vacuo and puriﬁed as described.

solid (195 mg, 73%, >99:1 dr), R_f0.30 (pentane/Et₂O, 2:1); [

a

]

þ52.5

D

(c 1.0 in CHCl₃); n_max(ﬁlm) 2978 (C–H), 1683 (C]O), 1369, 1091; d_H

(400 MHz, CDCl₃) 0.93 (9H, s, CMe₃), 1.75 (3H, d, J 7.0, C(1⁰)Me), 2.81

(3H, br s, OMe) 3.82–3.85 (1H, br m, OCH_AH_BCH]CH₂), 4.23 (1H, dd, J

13.3, 4.5, OCH_AH_BCH]CH₂), 4.51 (1H, d, J 3.1, C(2)H), 4.61 (1H, d, J 3.0,

C(3)H), 4.92–4.97 (2H, m, CH₂CH]CH₂), 5.60–5.63 (1H, br m,

OCH₂CH]CH₂)6.17–6.21(1H, brm, C(1⁰)H), 7.25–7.85(11H, m, Ar, Ph),

8.45–8.48(1H, brm,Ar);d_C(100 MHz,CDCl₃)16.4,27.9, 56.5, 57.1, 71.0,

79.8, 81.2, 83.1, 116.4, 124.4 125.0, 125.5, 126.3, 126.8, 127.8, 128.2,

128.5, 128.6, 128.9, 129.4, 132.2, 133.5, 134.7, 135.4, 138.0, 175.4; m/z

(ESI^þ) 462 ([MþH]^þ, 10%); HRMS (ESI^þ) found 462.2650; C₂₉H₃₆NO^þ₄

([MþH]^þ) requires 462.2644.

4.4.1. (R)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2S,3R)-2-benzyloxy-

4.4.3. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-allyloxy-

3-methoxy-3-phenylpropanamide 84.

3-methoxybutanamide 86.

Compound (R)-5 (187 mg, 0.48 mmol) in THF (6 mL) was treated

with KHMDS (0.67 mmol) in THF (6 mL), benzaldehyde (0.15 mL,

1.43 mmol) and then MeI (0.45 mL, 7.17 mmol) according to the

general procedure. ¹H NMR spectroscopic analysis of the crude re-

action mixture showed the presence of 84:88 in 83:17 dr. Puriﬁca-

tion via ﬂash column chromatography (gradient elution, pentane;

Compound (S)-6 (380 mg, 1.11 mmol) in THF (9 mL) was treated

with KHMDS (1.50 mmol) in THF (9 mL), acetaldehyde (0.15 mL,

2.61 mmol) and then MeI (1.00 mL, 16.2 mmol) according to the

general procedure. Puriﬁcation via ﬂash column chromatography

(gradient elution, pentane/Et₂O, 19:1; increased to Et₂O) gave 86 as

increased to Et₂O) gave 84 as a colourless oil (176 mg, 72%, 96:4 dr);

23

R_f0.50 (pentane/Et₂O, 1:1); [

a

]

ꢀ74.5 (c 2.2 in CHCl₃); n_max(ﬁlm)

D

2978 (C–H), 1682 (C]O), 1600 (C]C), 1512, 1495, 1454, 1393, 1369,

1239,1173,1092; d_H(400 MHz, CDCl₃) 0.79 (9H, s, CMe₃),1.80 (3H, d, J

a colourless oil (248 mg, 56%, >99:1 dr), R_f0.20 (pentane/Et₂O, 3:1);

23

[a]

þ40.8 (c 2.0 in CHCl₃); n_max(ﬁlm) 2976 (C–H),1678 (C]O),1370,

D

4192

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

1093; d_H(400 MHz,CDCl₃)0.85(9H,s,CMe₃),1.15,(3H,d,J6.3,C(4)H₃),

1.81 (3H, d, J 7.0, NapCHMe), 3.10 (3H, brs, OMe), 3.85(1H, dq, J 6.3, 3.5,

C(3)H), 3.91–3.94 (1H, br m, OCH_AH_BCH]CH₂), 4.32 (1H, d, J 3.3,

C(2)H), 4.36 (1H, dd, J 13.1, 4.3, OCH_AH_BCH]CH₂), 5.17 (1H, dd, J 10.4,

0.8, OCH₂CH]CH_AH_B), 5.28 (1H, dd, J 17.3, 1.5, OCH₂CH]CH_AH_B),

5.92–5.96 (1H, br m, OCH₂CH]CH₂) 6.30–6.33 (1H, br m, C(1⁰)H),

7.41–7.85 (6H, m, Ar), 8.45–8.48 (1H, br m, Ar); d_C(100 MHz, CDCl₃)

15.3,16.3, 27.9, 56.0, 56.4, 71.1, 74.9, 80.1, 82.7,117.0,124.5,124.8,125.6,

126.3, 126.6, 128.5, 128.6, 132.3, 133.6, 135.1, 135.5, 175.0; m/z (ESI^þ)

422 ([MþNa]^þ, 100%), 400 ([MþH]^þ, 40%); HRMS (ESI^þ) found

400.2487; C₂₄H₃₄NO₄^þ([MþH]^þ) requires 400.2488.

phosphate buffer solution (15 mL) at 0 ^ꢁC. The mixture was extracted

with 30–40 ^ꢁC petrol (3ꢃ15 mL) and the combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo. The residue was

dissolved in CH₂Cl₂(5 mL) and 3 Å powdered molecular sieves

(w50 mg) were added. The resultant slurry was cooled to 0 ^ꢁC.

Ph₃P]CHCO₂Me (189 mg, 0.57 mmol) was added. The reaction mix-

ture was allowed to warm to rt over 16 h before being concentrated in

vacuo. Puriﬁcationviaﬂashcolumnchromatography(eluent30–40 ^ꢁC

petrol/EtOAc, 9:1)gave auxiliary (R)-1(118 mg, 86%,>99:1er). Further

elution gave 92 as a colourless oil (93 mg, 59%, 95:5 dr); R_f0.30

23

(Et₂O:pentane1:9);[

a

]

þ38.9(c1.1 in CHCl₃); n_max(ﬁlm)2970(C–H),

D

1724 (C]O), 1436, 1273, 1168, 1102; d_H(400 MHz, CDCl₃) 3.27 (3H, s,

OMe), 3.70(3H, s,OMe), 3.95(1H, ddt, J13.0, 5.9,1.3, OCH_AH_BCH]CH₂),

4.06 (1H, ddt, J 13.1, 5.3, 1.4, OCH_AH_BCH]CH₂), 4.15 (1H, td, J 5.8, 1.4,

C(4)H), 4.24 (1H, d, J 5.8, C(5)H), 5.14 (1H, ddd, J 10.5, 2.9, 1.4,

OCH₂CH]CH_AH_B), 5.21 (1H, ddd, J 17.3, 3.2, 1.5, OCH₂CH]CH_AH_B),

5.78–5.83 (1H, m, OCH₂CH]CH₂), 5.92 (1H, dd, J 15.7,1.4, C(2)H), 6.68

(1H, dd, J 15.7, 5.8, C(3)H), 7.26–7.37 (5H, m, Ph); d_C(100 MHz, CDCl₃)

51.5, 57.2, 71.1, 81.0, 85.6, 117.2, 122.6, 127.6, 128.1, 128.2, 134.3, 137.6,

145.1, 166.4; m/z (ESI^þ) 299 ([MþNa]^þ, 100%); HRMS (ESI^þ) found

299.1253; C₁₆H₂₀NaO₄^þ([MþNa]^þ) requires 299.1259.

4.4.4. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2R,3S)-2-(3^%,4^%-

dimethoxybenzyloxy)-3-methoxy-3-phenylpropanamide 87.

Compound (S)-9 (540 mg, 1.20 mmol) in THF (8 mL) was treated

with KHMDS (1.55 mmol) in THF (8 mL), benzaldehyde (0.24 mL,

2.39 mmol) and then MeI (0.99 mL, 16.0 mmol) according to the

general procedure. ¹H NMR spectroscopic analysis of the crude re-

action mixture showed the presence of 87:91 in 88:12 dr. Puriﬁcation

via ﬂash column chromatography (gradient elution, pentane/Et₂O,

4.4.6. (2R,3S)-2-(3⁰,4⁰-Dimethoxybenzloxy)-3-methoxy-3-phenyl-

propan-1-ol 93.

3:2; increased to pentane/Et₂O, 2:3) gave 87 as a colourless oil

23

(433 mg, 63%, 96:4 dr); R_f0.25 (pentane/Et₂O); [

a

]

þ52.8 (c 2.8 in

D

CHCl₃); n_max(ﬁlm) 2976, 2936 (C–H), 1680 (C]O), 1594 (C]C), 1515,

1465, 1370, 1264, 1237, 1092, 1029; d_H(400 MHz, CDCl₃) 0.79 (9H, s,

CMe₃), 1.80 (3H, d, J 7.0, C(1⁰)Me), 2.77 (3H, br s, OMe), 3.60 (3H, s,

OMe), 3.79 (3H, s, OMe), 4.42 (1H, brd, J 12.6, OCH_AH_BAr), 4.49 (1H, d, J

2.7, C(2)H), 4.64 (1H, app br s, C(3)H), 4.71 (1H, d, J 12.6, OCH_AH_BAr),

6.19–6.22 (1H, br m, C(1⁰)H), 6.52–6.55 (3H, br m, Ar), 7.26–7.85 (11H,

m, Ar, Ph), 8.46–8.49 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 16.5, 27.8,

55.6, 55.8, 56.5, 57.1, 71.4, 79.1, 80.9, 83.1, 110.4, 110.4, 119.8, 124.4,

125.0, 125.5, 126.2, 126.5, 126.8, 127.7, 128.0, 128.3, 128.5, 128.6, 130.4,

132.2,133.7,135.3,138.2,148.2,148.7,175.2; m/z (ESI^þ) 594 ([MþNa]^þ,

100%), 572 ([MþH]^þ, 3%); HRMS (ESI^þ) found 572.3013; C₃₅H₄₂NO^þ₆

Compound 87 (383 mg, 0.67 mmol) was dissolved in THF (5 mL)

and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice bath.

LiAlH₄(1 M in THF, 2.01 mL, 2.01 mmol) was added dropwise via

syringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixturewastransferred dropwise via cannula to stirred pH7

phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was extracted

with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo. The residue was

dissolved in THF (1 mL) and the resultant solution was cooled to

ꢀ15 ^ꢁC in a salt/ice bath. LiAlH₄(1 M in THF, 1.34 mL, 1.34 mmol) was

added dropwise via syringe, and the reaction mixture was stirred at

ꢀ15 ^ꢁC for 1 h. The reaction mixture was transferred dropwise via

cannula to stirred pH 7 phosphate buffer solution (25 mL) at 0 ^ꢁC. The

mixture was extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the

combined organic extracts were dried (Na₂SO₄) and concentrated in

vacuo. Puriﬁcation via ﬂash column chromatography (eluent 30–

40 ^ꢁC petrol/Et₂O, 6:1) gave auxiliary (S)-1 (149 mg, 91%, >99:1 er).

([MþH]^þ) requires 572.3012. Further elution gave 91 as a colourless

23

oil (36 mg, 5%, >99:1 dr); R_f0.35 (pentane/Et₂O,1:1); [

a

]

þ17.0 (c 1.3

D

in CHCl₃); n_max(ﬁlm) 2927 (C–H), 1668 (C]O), 1594, 1515 (C]C),

1368, 1264, 1238, 1158, 1138, 1090, 1029; d_H(400 MHz, CDCl₃) 0.88

(9H, br s, CMe₃),1.79 (3H, brd, J 6.4, C(1⁰)Me), 3.25 (3H, br s, OMe), 3.72

(3H, br s, OMe), 3.84 (3H, br s, OMe), 4.52–4.57 (2H, br m, C(2)H,

OCH_AH_BAr), 4.74 (1H, d, J 11.9, OCH_AH_BAr), 4.95 (1H, app br s, C(3)H),

5.78–5.81 (1H, br m, C(1⁰)H), 6.62–6.66 (3H, br m, Ar), 7.28–7.90 (12H,

m, Ar, Ph); d_C(100 MHz, CDCl₃) 18.5, 27.3, 55.7, 55.8, 57.2, 72.2, 79.6,

81.9, 82.9, 110.4, 110.8, 120.0, 123.0, 125.3, 125.6, 126.3, 126.9, 127.8,

127.9, 128.1, 128.2, 128.6, 128.9, 130.6, 133.5, 138.3, 148.2, 148.7, 174.1;

m/z (ESI^þ) 594 ([MþNa]^þ, 100%), 572 ([MþH]^þ, 39%); HRMS (ESI^þ)

found 572.3010; C₃₅H₄₂NO^þ₆([MþH]^þ) requires 572.3012.

Further elution gave 93 as a colourless oil (233 mg, 98%); R_f0.10

23

(pentane/Et₂O,1:1); [

a

]

þ32.2 (c 2.4 in CHCl₃); n_max(ﬁlm) 3458 (O–

D

H), 2935 (C–H), 1593 (C]C), 1516, 1454, 1264, 1237, 1028; d_H

(400 MHz, CDCl₃) 2.16 (1H, t, J 5.9, OH), 3.28 (3H, s, OMe), 3.35–3.38

(1H, m, C(1)H_A), 3.48–3.52 (1H, m, C(1)H_B), 3.64–3.67 (1H, m, C(2)H),

3.86 (3H, s, OMe), 3.87 (3H, s, OMe), 4.36 (1H, d, J 6.2, C(3)H), 4.54 (1H,

d, J 11.4, OCH_AH_BAr), 4.71 (1H, d, J 11.4, OCH_AH_BAr), 6.82–6.92 (3H, m,

Ar), 7.19–7.43 (5H, m, Ph); d_C(100 MHz, CDCl₃) 55.8, 55.9, 57.1, 62.0,

73.5, 82.2, 85.2, 110.8, 111.2, 120.5, 127.4, 128.1, 128.4, 130.9, 138.3,

148.6, 148.9; m/z (ESI^þ) 355 ([MþNa]^þ, 100%); HRMS (ESI^þ) found

355.1515; C₁₉H₂₄NaO₅^þ([MþNa]^þ) requires 355.1521.

4.4.5. Methyl (R,R,E)-4-allyloxy-5-methoxy-5-phenylpenten-2-eno-

ate 92.

4.4.7. (2R,3S)-3-Methoxy-3-phenyl-propane-1,2-diol 94.

Compound 85 (261 mg, 0.57 mmol) was dissolved in THF (3 mL)

and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice bath.

LiAlH₄(1 M in THF,1.7 mL,1.7 mmol) was added dropwise via syringe,

and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The reaction

mixture was transferred dropwise via cannula to stirred pH 7

DDQ (110 mg, 0.49 mmol) was added to a solution of 93 (164 mg,

0.49 mmol) in CH₂Cl₂:H₂O (v/v 5:1, 5 mL) and the mixture was stirred

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

4193

at rt for 18 h and then concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent CHCl₃/MeOH, 9:1) and recrystalli-

4.4.10. (2x,4S,5S)-2-(Ethyl-5-phenyl-1,3-dioxolan-4-yl)methanol 98.

sationfrompentanegave94asﬁnecolourlessneedles(78 mg,87%);³¹

23

mp 71 ^ꢁC; [

a]

þ102.9 (c 1.2 in CHCl₃); n_max(ﬁlm) 3370 (O–H), 2881

D

(C–H), 1461, 1310, 1264, 1119, 1038; d_H(400 MHz, CDCl₃) 2.36–2.39

(1H, br m, OH), 3.27 (3H, s, OMe), 3.35 (1H, dd, J 11.8, 4.7, C(1)H_A), 3.55

(1H, dd, J 11.8, 3.1, C(1)H_A), 3.75 (1H, ddd, J 8.1, 4.7, 3.1, C(2)H), 4.21 (1H,

d, J 8.1, C(3)H), 7.30–7.42 (5H, m, Ph); d_C(50 MHz, CDCl₃) 56.8, 62.4,

75.7, 84.6, 127.7, 128.6, 128.8, 137.9; HRMS (CI^þ) found 200.1289;

C₁₀H₁₈NO^þ₃([MþNH₄]^þ) requires 200.1287.

Compound 96 (200 mg, 0.45 mmol) was dissolved in THF (3 mL)

and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice bath.

LiAlH₄(1 M in THF, 1.34 mL, 1.34 mmol) was added dropwise via

syringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixture was transferred dropwise via cannula to stirred

pH 7 phosphate buffer solution (25 mL) at 0 ^ꢁC. The mixture was

extracted with 30–40 ^ꢁC petrol (3ꢃ20 mL) and the combined or-

ganic extracts were dried (Na₂SO₄) and concentrated in vacuo. The

residue was dissolved in THF (1 mL) and the resultant solution was

cooled to ꢀ15 ^ꢁC in a salt/ice bath. LiAlH₄(1 M in THF, 1.34 mL,

1.34 mmol) was added dropwise via syringe, and the reaction

mixture was stirred at ꢀ15 ^ꢁC for 1 h. The reaction mixture was

transferred dropwise via cannula to stirred pH 7 phosphate buffer

solution (25 mL) at 0 ^ꢁC. The mixture was extracted with 30–40 ^ꢁC

petrol (3ꢃ20 mL) and the combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30–40 ^ꢁC petrol/Et₂O, 4:1) gave auxiliary

4.4.8. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2

x,4R,5S)-2-ethyl-

5-phenyl-1,3-dioxolane-4-carboxamide 96.

trans-Pd(NH₃)₂Cl₂(16 mg, 0.08 mmol) was added to a solution of

61 (340 mg, 0.76 mmol) in degassed ^tBuOH (9 mL). The resultant so-

lution was heated at reﬂux for 18 h, cooled to rt and diluted with

MeOH (10 mL). The reaction mixture was then ﬁltered through Cel-

ite^Ò(eluent MeOH) and the ﬁltrate was concentrated in vacuo. Puri-

ﬁcation via ﬂash column chromatography (gradient elution, pentane/

(S)-1 (96 mg, 89%, >99:1 er). Further elution gave 98 as a colourless

23

oil (49 mg, 53%); R_f0.55 (pentane/Et₂O, 1:1); [

a

]

þ3.2 (c 1.7 in

Et₂O,19:1; increased to pentane/Et₂O, 4:1) gave 96 as a colourless oil

D

23

CHCl₃); n_max(ﬁlm) 3437 (O–H), 2931, 2889 (C–H), 1455, 1119, 1045;

d_H(400 MHz, CDCl₃) 1.04 (3H, t, J 7.6, C(3)CH₂CH₃), 1.80 (2H, app.

dq, J 7.6, 4.6, C(3)CH₂CH₃), 2.25–2.28 (1H, br m, OH), 3.72–3.75 (1H,

br m, CH_AH_BOH), 3.93 (1H, br app d, J 12.5, CH_AH_BOH), 3.98–4.01

(1H, m, C(4)H), 4.86 (1H, d, J 7.6, C(5)H), 5.33 (1H, t, J 4.6, C(2)H),

7.30–7.40 (5H, m, Ph); d_C(100 MHz, CDCl₃) 7.9, 27.5, 61.3, 78.4, 84.7,

106.2, 126.1, 128.1, 128.7, 139.4; m/z (CI^þ) 208 ([M]^þ, 39%), 191

(100%); HRMS (CI^þ) found 226.1440; C₁₂H₂₀NO₃^þ([MþNH₄]^þ) re-

quires 226.1443.

(246 mg, 72%); R_f0.25 (pentane/Et₂O, 19:1); [

a

]

þ10.4 (c 1.8 in

D

CHCl₃); n_max(ﬁlm) 2976 (C–H), 1682 (C]O), 1600 (C]C), 1455, 1369,

1265, 1169; d_H(400 MHz, CDCl₃) 0.75 (9H, s, CMe₃), 1.06 (3H, t, J 7.0,

C(2)CH₂CH₃), 1.86 (3H, d,

J

7.0, C(1⁰)Me), 1.90–1.93 (2H, m,

C(2)CH₂CH₃), 4.87–4.90(1H,brm,C(4)H), 5.01–5.04(1H, brm, C(5)H),

5.36 (1H, t, J 5.0, C(2)H), 6.21 (1H, brq, J 6.8, C(1⁰)H), 7.10–7.90 (11H, m,

Ar, Ph), 8.35–8.37 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 8.4, 16.9, 27.5,

27.7, 56.9, 79.5, 81.0, 83.4,108.0,124.3,124.8,125.4,125.6,126.4,127.2,

128.1, 128.4, 128.6, 128.8, 129.1, 132.0, 133.6, 135.1, 138.8, 175.6; m/z

(ESI^þ) 470 ([MþNa]^þ, 100%), 448 ([MþH]^þ, 82%); HRMS (ESI^þ) found

470.2316; C₂₈H₃₃NNaO₄^þ([MþNa]^þ) requires 470.2307.

4.4.11. Methyl (2⁰,4⁰S,5⁰S,E)-3-(2⁰-ethyl-5⁰-phenyl-1⁰,3⁰-dioxolan-4⁰-yl)-

x

propenoate 99.

4.4.9. (S)-N-tert-Butoxy-N-1⁰-(1⁰⁰-naphthyl)ethyl (2

x,4R,5S)-2-ethyl-

5-methyl-1,3-dioxolane-4-carboxamide 97.

Compound 96 (220 mg, 0.49 mmol) was dissolved in THF (3 mL)

and the resultant solution was cooled to ꢀ15 ^ꢁC in a salt/ice bath.

LiAlH₄(1 M in THF, 1.48 mL, 1.48 mmol) was added dropwise via

syringe, and the reaction mixture was stirred at ꢀ15 ^ꢁC for 1 h. The

reaction mixture was transferred dropwise via cannula to stirred pH

7 phosphate buffer solution (15 mL) at 0 ^ꢁC. The mixture was

extractedwith 30–40 ^ꢁC petrol (3ꢃ15 mL) andthe combined organic

extracts were dried (Na₂SO₄) and concentrated in vacuo. The residue

was dissolved in CH₂Cl₂(5 mL) and 3 Å powdered molecular sieves

(w50 mg) were added. The resultant slurry was cooled to 0 ^ꢁC.

Ph₃P]CHCO₂Me (164 mg, 0.49 mmol) was added. The reaction

mixture was allowed to warm to rt over 16 h before being concen-

trated in vacuo. Puriﬁcation via ﬂash column chromatography (el-

uent 30–40 ^ꢁC petrol/Et₂O, 9:1) gave auxiliary (S)-1 (96 mg, 80%,

trans-Pd(NH₃)₂Cl₂(37 mg, 0.17 mmol) was added to a solution of

62 (200 mg, 0.52 mmol) in degassed BuOH (8 mL). The resultant

solution was heated at reﬂux for 18 h, cooled to rt and diluted with

MeOH (10 mL). The reaction mixture was then ﬁltered through

Celite^Ò(eluent MeOH) and the ﬁltrate was concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (gradient elution,

t

pentane; increased to pentane/Et₂O, 9:1) gave 97 as a colourless oil

23

(94 mg, 47%); R_f0.35 (pentane/Et₂O, 4:1); [

a

]

ꢀ37.6 (c 0.9 in CHCl₃);

D

n_max(ﬁlm) 2976 (C–H), 1683 (C]O), 1456, 1371, 1239, 1166; d_H

(400 MHz, CDCl₃) 0.83 (9H, s, CMe₃), 1.04 (3H, t, J 7.6, C(2)CH₂CH₃),

1.29 (3H, d, J 6.4, C(5)Me), 1.79 (3H, d, J 6.9, C(1⁰)Me), 1.85–1.89 (2H,

m, C(2)CH₂CH₃), 4.10–4.13 (1H, br m, C(5)H), 4.71–4.75 (1H, br m,

C(4)H), 5.18 (1H, t, J 5.0, C(2)H), 6.34 (1H, br q, J 6.9, C(1⁰)H), 7.41–7.88

(6H, m, Ar), 8.38–8.42 (1H, br m, Ar); d_C(100 MHz, CDCl₃) 8.4, 16.4,

18.3, 27.4, 27.9, 56.3, 75.7, 79.4, 83.4, 106.3, 124.3, 124.7, 125.7, 126.2,

126.5, 128.5, 128.9, 132.1, 133.6, 135.2, 176.7; m/z (ESI^þ) 408

([MþNa]^þ, 100%), 386 ([MþH]^þ, 67%); HRMS (ESI^þ) found 408.2149;

C₂₃H₃₁NNaO^þ₄([MþNa]^þ) requires 408.2151.

>99:1 er). Further elution gave 99 as a colourless oil (104 mg, 80%,

23

95:5 dr); R_f0.25 (pentane/Et₂O, 9:1); [

a

]

þ2.9 (c 1.7 in CHCl₃); n_max

D

(ﬁlm) 2973, 2881 (C–H),1728 (C]O),1456,1199,1031; d_H(400 MHz,

CDCl₃) 1.05 (3H, t,

J

7.5, C(2⁰)CH₂CH₃), 1.79–1.82 (2H, m,

C(2⁰)CH₂CH₃), 3.76 (3H, s, OMe), 4.40 (1H, ddd, J 7.9, 5.6,1.4, C(5⁰)H_A),

4.66 (1H, d, J 7.9, C(4⁰)H), 5.40 (1H, t, J 4.6, C(2⁰)H), 6.12 (1H, dd, J 15.7,

4194

A.N. Chernega et al. / Tetrahedron 66 (2010) 4167–4194

18. (a) Bernardi, R.; Fuganti, C.; Grasselli, P. Tetrahedron Lett. 1981, 22, 4021; (b)

Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.; Springer, J. P. J. Am.

Chem. Soc. 1985, 101, 1256; (c) Aoyagi, S.; Hirashima, S.; Saito, K.; Kibayashi, C.

J. Org. Chem. 2002, 67, 5517.

1.4, C(2)H), 6.97 (1H, dd, J 15.7, 5.6, C(3)H), 7.30–7.40 (5H, m, Ph); d_C

(100 MHz, CDCl₃) 7.7, 27.7, 51.8, 82.4, 83.4, 106.8, 122.8, 126.1, 128.0,

128.7, 137.9, 142.3, 166.2; m/z (CI^þ) 263 ([MþH]^þ, 47%), 205 (100%);

HRMS (CI^þ) found 263.1283; C₁₅H₁₉O^þ₄([MþH]^þ) requires 263.1283.

19. (a) Valverde, S.; Martin-Lomas, M.; Herradon, B.; Garcia-Ochoa, S. Tetrahedron

1987, 43, 1895; (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Dondio, G.; Raimondi,

L. Tetrahedron 1987, 43, 2369; (c) Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R.

Tetrahedron 1988, 44, 491; (d) Mortlock, S. V.; Thomas, E. J. Tetrahedron Lett.

1988, 29, 2479; (e) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. J. Org.

Chem. 1990, 55, 1901; (f) Gung, B. W.; Peat, A. J. Synth. Commun. 1991, 21, 1797;

(g) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Pilati, T. Tetrahedron:

Asymmetry 1991, 2, 1329; (h) De´sert, S.; Metzner, P. Tetrahedron 1992, 48, 10327;

(i) Enders, D.; Finkam, M. Synlett 1993, 401; (j) Kan, T.; Oikawa, M.; Hosokawa,

S.; Yanagiya, M.; Matsuda, F.; Shirahama, H. Synlett 1994, 801; (k) Kan, T.; Oi-

kawa, M.; Hosokawa, S.; Yanagiya, M.; Matsuda, F.; Shirahama, H. Synlett 1994,

805; (l) Enders, D.; Jandeleit, B. Acros Organics Acta 1995, 1, 59; (m) Annunziata,

R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L. Eur. J. Org. Chem. 1998,

1823; (n) Enders, D.; Jandeleit, B.; von Berg, S.; Raabe, G.; Runsink, J. Organo-

metallics 2001, 20, 4312; (o) Kireev, A. S.; Manpadi, M.; Kornienko, A. J. Org.

Chem. 2006, 71, 2630.

References and notes

1. For instance, see: (a) Andrus, M. B.; Soma Sekhar, B. B. V.; Turner, T. M.; Mer-

edith, E. L. Tetrahedron Lett. 2001, 42, 7197; (b) Dixon, D. J.; Guarna, A.; Ley, S. V.;

Polara, A.; Rodriguez, F. Synthesis 2002, 1973; (c) Andrus, M. B.; Meredith, E. L.;

Simmons, B. L.; Soma Sekhar, B. B. V.; Hicken, E. J. Org. Lett. 2002, 4, 3549; (d)

Andrus, M. B.; Meredith, E. L.; Hicken, E. J.; Simmons, B. L.; Glancey, R. R.; Ma, W.

J. Org. Chem. 2003, 68, 8162.

2. Chernega, A. N.; Davies, S. G.; Goodwin, C. J.; Hepworth, D.; Kurosawa, W.;

Roberts, P. M.; Thomson, J. E. Org. Lett. 2009, 11, 3254.

3. Masamune has also reported a benzopyranoisoxazolidine auxiliary which is

capable of acting as a chiral Weinreb amide equivalent; see: Abiko, A.; Moriya,

O.; Filla, S. A.; Masamune, S. Angew. Chem., Int. Ed. Engl. 1995, 34, 793; Abiko, A.;

Masamune, S. Tetrahedron Lett. 1996, 37, 1081.

20. We have recently reported a variant of the Wadsworth–Emmons oleﬁnation

using MeMgBr as the base, which is amenable to the oleﬁnation of stereo-

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Article Doi

Alkylation and aldol reactions of acyl derivatives of N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine: asymmetric synthesis of α-alkoxy-, α-substituted-β-alkoxy- and α,β-dialkoxyaldehydes

DOI: 10.1016/j.tet.2010.03.105

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