Asymmetric syntheses of dihydroxyhomoprolines via doubly diastereoselective lithium amide conjugate addition reactions

Tetrahedron 69 (2013) 8680e8704

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Tetrahedron

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Asymmetric syntheses of dihydroxyhomoprolines via doubly

diastereoselective lithium amide conjugate addition reactions

*

Stephen G. Davies , Emma M. Foster, James A. Lee, Paul M. Roberts, James E. Thomson

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

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 6 June 2013

Received in revised form 17 July 2013

Accepted 30 July 2013

Available online 5 August 2013

The asymmetric syntheses of novel dihydroxyhomoprolines have been achieved using the doubly dia-

stereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(a-methylbenzyl)amide to

a set of four chiral -unsaturated esters (derived from -pentoses) as one of the key steps. A full account

a,

b

D

of the diastereoselectivity observed in these conjugate additions is presented and the stereochemical

outcomes of these reactions have been established unambiguously via a combination of hydrogenolytic

chemical correlation and single crystal X-ray diffraction analyses. A tandem hydrogenolysis/intra-

molecular reductive amination reaction was then used to create the corresponding enantiopure pyrro-

lidines, providing access to (2⁰S,3⁰S,4⁰R)-dihydroxyhomoproline and (2⁰S,3⁰R,4⁰S)-dihydroxyhomoproline

after deprotection.

Keywords:

Lithium amide

Conjugate addition

Asymmetric synthesis

Doubly diastereoselective

Homoprolines

1. Introduction

the interesting features of this class of cyclic b-amino acids, the

dihydroxy analogues 6 have not previously been the targets of any

Polyhydroxylated pyrrolidines are challenging targets for

synthetic chemists due to the presence of dense oxygen function-

ality and multiple contiguous stereogenic centres within these

molecular scaffolds. Of the eight possible stereoisomers of 3,4-

dihydroxyproline, only three have been isolated from natural

sources:¹in 1969 (S,S,S)-1 was isolated from the cell wall hydro-

lysates of the diatom Navicula pelicullosa,²in 1980 (2S,3R,4R)-2 was

isolated from the acid hydrolysates of the toxic mushroom Amanita

virosa,³and in 1994 (2S,3R,4S)-3 was identiﬁed as the sixth residue

in the repeating decapeptide sequence of Mefp1, an adhesive pro-

tein produced by the marine mussel Mytilus edulis.⁴These com-

pounds have been shown to display potent activity as glycosidase

inhibitors,⁵and are also of interest due to their roles in peptide

structure and function.⁶Many elegant syntheses of the 3,4-

dihydroxyproline motif have been reported,⁷although relatively

synthetic endeavours (Fig. 1).

Fig. 1. The structures of naturally occurring dihydroxyprolines 1e3,

tetrazole derivative 5 and dihydroxyhomoprolines 6.

b-homoproline 4,

As part of our long-term goal directed towards the ab initio

asymmetric syntheses of pyrrolidines and piperidines (including

unnatural aminosugars and amino acids),¹⁵we envisaged that

few investigations have focussed on the

The parent -amino acid, -homoproline 4, and derivatives such as

tetrazole 5, have shown utility as effective organocatalysts.¹⁰The

b

-amino acid congeners.^8,9

b

-amino esters 9, derived from conjugate addition of an enantio-

conformational behaviour¹¹of

b-homoproline 4 and the secondary

pure lithium amide reagent 7^16e20to enantiopure

a,b

-unsaturated

structure of its oligomers¹²has also been studied, and a range of

derivatives of 4 have been found to display signiﬁcant biological

activity¹³including in peptidomimetic studies.¹⁴However, despite

esters 8, would be useful templates for elaboration to a range of

densely functionalised azacycles, including dihydroxyhomopro-

lines 6. It was anticipated that selective deprotection of the primary

acetonide functionality within 9 followed by oxidative cleavage of

the C(6)eC(7) bond within the resultant diol would then give the

corresponding aldehyde 10. Application of a tandem hydro-

genolysis/intramolecular reductive amination protocol²¹would

* Corresponding

author.

E-mail

address:

steve.davies@chem.ox.ac.uk

(S.G. Davies).

http://dx.doi.org/10.1016/j.tet.2013.07.096

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8681

then effect both the removal of the N-benzyl and N-a-methylbenzyl

groups within 10, as well as reduction of the intermediate imine

resulting from cyclisation of the C(3)-amino group onto the alde-

hyde functionality to give the corresponding pyrrolidines 11. Global

deprotection of 11 upon treatment with acid would then ﬁnally

reveal the target dihydroxyhomoproline 6 (Fig. 2).

–78

Fig. 3. Models to account for the diastereoselectivity observed upon conjugate addi-

Fig. 2. Proposed synthetic strategy towards dihydroxyhomoprolines 6.

tion of lithium amides to trans- and cis-dioxolane containing

and 14.

a,b-unsaturated esters 12

2. Results and discussion

We have previously investigated the effects of double asym-

metric induction²²upon conjugate addition of enantiopure lithium

diastereoselective conjugate additions of the antipodes of lithium

N-benzyl-N-( -methylbenzyl)amide 7 could then be predicted

amides to some enantiopure a,b

-unsaturated esters.¹⁸These stud-

a

prior to their investigation (Fig. 4). The stereochemical outcomes of

these conjugate addition reactions were, in each case, established

unambiguously by a series of hydrogenolytic/reductive alkylation

experiments and single crystal X-ray diffraction analyses.

ies prompted us to investigate further the origin of diaster-

eoselectivity in these systems and we have recently reported a full

account of the effects of double asymmetric induction upon con-

jugate addition of the antipodes of lithium N-benzyl-N-(

a-meth-

ylbenzyl)amide 7^20,23to trans- and cis-dioxolane containing

a,b-

unsaturated esters 12 and 14, which culminated in the production

of models to rationalise the outcomes of these reactions.²⁴In the

case of trans-dioxolane containing a,b-unsaturated esters, such as

12, reactive conformations similar to 12A were proposed to account

for the observed diastereoselectivity where the lithium amide re-

agent approaches the Si face²⁵of the

a

,

b

-unsaturated ester. In the

-unsaturated esters, such as 14,

-unsaturated esters (such as 16),

due to deprotonation of the substrate at the -position by the basic

lithium amide reagent, complicates the assessment of the reaction

diastereoselectivity. We therefore reasoned that this -deprotona-

case of cis-dioxolane containing

a,b

the competitive formation of b,g

g

tion pathway proceeds via a similar reactive conformation to that of

conjugate addition and considered the ‘facial selectivity’ of both

Fig. 4. Investigations into the doubly diastereoselective conjugate additions of the

antipodes of lithium amide 7 to a,b-unsaturated esters 8.

conjugate addition and

be consistent with approach of the lithium amide reagent on the Re

face²⁵of the

-unsaturated ester in conformations similar to 14A,

g-deprotonation. These data were found to

a

,b

2.1. Doubly diastereoselective conjugate additions to

tose derived -unsaturated esters

D-pen-

14B or 14C (Fig. 3).

a,b

Given this precedent, we proposed to investigate fully the

effects of double asymmetric induction upon the conjugate addi-

a

,

b

-Unsaturated esters 20e23 were synthesised from the nat-

urally occurring pentose sugars -arabinose, -xylose, -ribose and

-lyxose. Wittig reaction of the requisite (unprotected) pentose

tion of the antipodes of 7 to a range of four

unsaturated esters 8. In order to determine the inherent substrate

control provided by the -unsaturated esters 8, the conjugate

D-pentose derived

a

,b

-

D

a

,b

with tert-butyl 2-(triphenylphosphoranylidene)acetate was ex-

pected to provide the corresponding tetraols,²⁶within which the

free hydroxyl groups could easily be protected with isopropylidene

additions of the achiral lithium amides lithium N-isopropyl-N-

benzylamide 17 and lithium N,N-dibenzylamide 18 were performed

ﬁrst. The stereochemical outcomes of the corresponding doubly

groups. Thus, in the case of a,b-unsaturated ester 20, subjection of

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S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

D-arabinose to the Wittig reaction gave the corresponding tetraol as

Upon treatment of a,b-unsaturated ester 20 with lithium

a single diastereoisomer (>99:1 dr); the crude reaction mixture

was then treated with DMP and TsOH, which, after puriﬁcation via

N-isopropyl-N-benzylamide 17 under our standard reaction con-

ditions (in THF at ꢀ78 ^ꢁC),²⁰an 88:12 mixture of

b-amino esters 24

ﬂash column chromatography, gave

yield and >99:1 dr. Repetition of this procedure using

-ribose and -lyxose resulted in the production of the remaining

-unsaturated esters 21, 22 and 23, respectively, in 37e62%

a

,b

-unsaturated ester 20 in 78%

and 25, respectively, was produced. Puriﬁcation of the crude re-

action mixture via ﬂash column chromatography allowed isolation

of an 88:12 mixture of 24 and 25 in 85% combined yield. The

conjugate addition of lithium N,N-dibenzylamide 18 to 20 in THF at

ꢀ78 ^ꢁC proceeded with lower diastereocontrol, giving a 67:33

mixture of 26 and 27, respectively, which was isolated in 86%

combined yield (Scheme 2). An aliquot of 26 was subsequently

recrystallised to homogeneity (>99:1 dr) and the relative conﬁg-

uration within 26 was then unambiguously established via single

crystal X-ray diffraction analysis,²⁷with the absolute (3R,4R,5S,6R)-

conﬁguration within 26 being assigned relative to the known

D

-xylose,

D

a,b

overall yield and in >99:1 dr [(E):(Z)] in each case after puriﬁcation

(Scheme 1). The conﬁgurations of the newly formed CeC double

conﬁgurations of the D-arabinose derived dioxolane units (Fig. 6).

This analysis therefore also allowed the unambiguous de-

termination of the absolute conﬁguration within 27. These data

therefore enabled the sense of substrate control, whereby the

lithium amide reagent is directed to the Re face²⁵of the

a

,

b

-un-

saturated ester 20, to be established. Based on the known diaster-

eofacial preference of lithium N-benzyl-N-( -methylbenzyl)amide

7,²³it was therefore predicted that the conjugate addition of (S)-7

to -unsaturated ester 20 would represent the doubly diaster-

a

a,b

eoselective ‘matched’ reaction. As expected, conjugate addition of

(S)-7 to 20 proceeded to give 28 (>99:1 dr) as the sole reaction

product; after chromatographic puriﬁcation 28 was isolated in 73%

yield and >99:1 dr (Scheme 2). The relative conﬁguration within 28

was unambiguously established via single crystal X-ray diffraction

analysis,²⁷with the absolute (3R,4R,5S,6R,

a

S)-conﬁguration within

28 being assigned relative to the known conﬁgurations of the

arabinose derived dioxolane units and the -methylbenzyl frag-

D

-

a

ment (Fig. 6). The conjugate addition of (R)-7 to 20 (which was

predicted to be the doubly diastereoselective ‘mismatched’ re-

action) gave a 19:81 mixture of 30 and 31, respectively. Chro-

matographic puriﬁcation of the crude reaction mixture produced

a 15:85 mixture of 30 and 31, which was isolated in 60% combined

yield. These data therefore conﬁrm that upon conjugate addition to

the D-arabinose derived a,b-unsaturated ester 20, reaction with (S)-

Scheme 1. Reagents and conditions: (i) dioxane, Ph₃PCHCO₂^tBu; 90 ^ꢁC, 6 h, then

7 represents the doubly diastereoselective ‘matched’ pairing, and

reaction with (R)-7 represents the doubly diastereoselective ‘mis-

matched’ reaction. In the latter case, conjugate addition proceeds

under the dominant stereocontrol of the lithium amide reagent (R)-

7, giving 31 as the major product (Scheme 2).

As the absolute conﬁgurations within 26e29 had already been

unambiguously established via single crystal X-ray diffraction

analyses of 26 and 28, a series of hydrogenolytic/reductive alkyl-

ation experiments were next conducted to unambiguously estab-

50 ^ꢁC, 12 h; (ii) DMP, TsOH, 18 h, rt.

bonds within 20e23 were assigned based on the diagnostic values

of the ¹H NMR ³J coupling constants observed between the C(2)H

and C(3)H protons (³J_2,3¼15.4e15.7 Hz); in the case of the

D-xylose

derived a,b-unsaturated ester 21 this assignment was conﬁrmed by

single crystal X-ray diffraction analysis (Fig. 5).²⁷

lish the conﬁgurations within all the remaining

products of conjugate addition to the -arabinose derived

saturated ester 20. Firstly, an authentic sample of primary

b

-amino ester

-un-

-amino

D

a,b

b

ester 32 was synthesised via hydrogenolysis of 28 [>99:1 dr; ob-

tained as the major product in the conjugate addition of (S)-7 to 20]

in the presence of Pearlman’s catalyst [Pd(OH)₂/C], which gave 32

in quantitative yield and >99:1 dr. The ¹H NMR spectrum of this

sample of 32 was entirely consistent with a sample obtained via

hydrogenolysis of 26 [>99:1 dr; obtained as the major product in

the conjugate addition of 18 to 20], which gave 32 in 85% yield and

>99:1 dr. Subjection of 32 (>99:1 dr) to reductive alkylation con-

ditions (NaBH₃CN/acetone) gave an authentic sample of N-iso-

propyl substituted b-amino ester 33 in 93% yield and >99:1 dr.

Hydrogenolysis of 24 [88:12 dr; obtained as the major product in

the conjugate addition of 17 to 20] gave 33 in 96% yield and 88:12

dr; the ¹H NMR data for the major component of this mixture were

found to be in complete accord with those of the authentic sample

of 33 obtained from reductive alkylation of 32, therefore allowing

the absolute conﬁgurations within 24 and 25 to also be

Fig. 5. X-ray crystal structure of (4S,5R,6R,E)-21 (selected H atoms are omitted for

clarity).

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8683

Scheme 2. Reagents and conditions: (i) 17, THF, ꢀ78 ^ꢁC, 2 h; (ii) 18, THF, ꢀ78 ^ꢁC, 2 h; (iii) (S)-7, THF, ꢀ78 ^ꢁC, 2 h; (iv) (R)-7, THF, ꢀ78 ^ꢁC, 2 h.

Fig. 6. X-ray crystal structures of (3R,4R,5S,6R)-26 [left] and (3R,4R,5S,6R,aS)-28 [right] (selected H atoms are omitted for clarity).

unambiguously assigned. A sample of 31 [85:15 dr; obtained as the

major product in the conjugate addition of (R)-7 to 20] was also

mixture of b-amino esters 36 and 37, which were subsequently

isolated in 19 and 57% yield, respectively, and in >99:1 dr in each

case (Scheme 4). The relative conﬁguration within the major di-

astereoisomer 37 was unambiguously established via single crystal

X-ray diffraction analysis,²⁷with the absolute (3S,4S,5R,6R)-con-

ﬁguration within 37 being assigned relative to the known conﬁg-

subjected to the hydrogenolysis conditions, which gave

ester 34 in 87% yield and 85:15 dr. Subsequent reductive alkylation

of 34 gave N-isopropyl substituted -amino ester 35 in 72% yield

b-amino

b

and 85:15 dr. The ¹H NMR spectra of both 34 and 35 were found to

be markedly different to those of 32 and 33, conﬁrming their op-

posing conﬁgurations at C(3). In addition, the peaks for the minor

components in the ¹H NMR spectra of 34 (85:15 dr) and 35 (85:15

dr) were found to be consistent with those for the authentic sam-

ples of the epimeric compounds 32 and 33 (Scheme 3). This series

of correlation experiments therefore allowed the absolute conﬁg-

urations of the

D-xylose derived dioxolane units (Fig. 7). This

analysis therefore also allowed the unambiguous determination of

the absolute conﬁguration within 36. The conjugate addition of

lithium N,N-dibenzylamide 18 to 21 was found to proceed with

essentially no diastereofacial control, giving a 44:56 mixture of 38

and 39, respectively; after puriﬁcation 38 was isolated in 26% yield

and >99:1 dr, and 39 was isolated in 36% yield and 96:4 dr. Whilst

these reactions proceeded with only modest levels of diaster-

eocontrol, preferential attack of the lithium amide upon the Si

urations within all the

addition reactions of 17, 18, (R)-7 and (S)-7 to the

rived -unsaturated ester 20 to be established unambiguously.

The conjugate addition of lithium N-isopropyl-N-benzylamide

17 to the -xylose derived -unsaturated ester 21 gave a 28:72

b

-amino ester products from the conjugate

D

-arabinose de-

a,b

face²⁵of the

was therefore predicted that the conjugate addition of (R)-7 to 21

a,b-unsaturated ester 21 was observed in both cases. It

D

a,b

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S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

Scheme 3. Reagents and conditions: (i) Pd(OH)₂/C, H₂(1 atm), EtOAc, rt, 18 h; (ii) NaBH₃CN, acetone, MeOH, rt, 18 h. [the conﬁgurations within 26 and 28 (highlighted in red) have

been unambiguously assigned by single crystal X-ray diffraction analysis].

Scheme 4. Reagents and conditions: (i) 17, THF, ꢀ78 ^ꢁC, 2 h; (ii) 18, THF, ꢀ78 ^ꢁC, 2 h; (iii) (R)-7, THF, ꢀ78 ^ꢁC, 2 h; (iv) (S)-7, THF, ꢀ78 ^ꢁC, 2 h. [^aa 43:57 mixture of 38 and 39 was also

isolated in 12% combined].

would represent the doubly diastereoselective ‘matched’ reaction,

and reaction of (S)-7 with 21 would be the ‘mismatched’ pairing.

Conjugate addition of (R)-7 to 21 did not, however, proceed with

high diastereocontrol as expected: in this case a 35:65 mixture of

41 was isolated in 52% yield and 96:4 dr, and the minor di-

astereoisomer 40 was isolated in 33% yield and >99:1 dr (Scheme

4). The relative conﬁguration within 40 was unambiguously

established via single crystal X-ray diffraction analysis,²⁷with the

b

-amino esters 40 and 41, respectively, was observed. Upon puri-

absolute (3R,4S,5R,6R,

relative to the known conﬁgurations of the

a

R)-conﬁguration within 40 being assigned

-xylose derived

ﬁcation of the crude reaction mixture, the major diastereoisomer

D

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8685

Fig. 7. X-ray crystal structures of (3S,4S,5R,6R)-37 [left] and (3R,4S,5R,6R,aR)-40 [right] (selected H atoms are omitted for clarity).

dioxolane units and

therefore also allowed unambiguous assignment of the absolute

conﬁguration within 41. Conjugate addition of (S)-7 to -un-

saturated ester 21, however, proceeded with much higher diaster-

eocontrol than expected, giving a 90:10 mixture of 42 and 43,

a

-methylbenzyl fragment (Fig. 7). This analysis

ester 47 in quantitative yield and >99:1 dr. Hydrogenolysis of 39

(96:4 dr) and 41 (96:4 dr) gave 46 in 77 and 94% yield, respectively,

and in 96:4 dr in each case. Subsequent reductive alkylation of 46

(96:4 dr) gave 47 in 49% yield and 96:4 dr. The ¹H NMR spectro-

scopic data for the major diastereoisomer 47 were found to be

entirely consistent with those of the authentic sample of 47,

thereby serving to conﬁrm the assigned conﬁgurations within 39

and 41 (Scheme 5). This series of correlation experiments had

a,b

respectively. b-Amino ester 42 was subsequently isolated in 41%

yield and >99:1 dr after chromatographic puriﬁcation. These ob-

servations therefore resulted in the reaction between (S)-7 and 21

being assigned as the ‘empirically matched’ reagent/substrate

pairing and the reaction between (R)-7 and 21 being assigned as the

‘empirically mismatched’ reagent/substrate pairing. A reactive

conformation such as 21A (i.e., a similar conformation to that ob-

served for 21 in the solid state) is consistent with the stereo-

chemical outcome in the ‘empirically matched’ conjugate addition

of (S)-7 to 21 (Scheme 4).

therefore allowed the absolute conﬁgurations within all the

amino ester products from the conjugate addition reactions of 17,

18, (R)-7 and (S)-7, to the -xylose derived -unsaturated ester 21

to be established unambiguously.

The conjugate addition reactions of 17, 18, (R)-7 and (S)-7 to

the cis-dioxolane containing -unsaturated esters 22 and 23

were investigated next. When attempting conjugate additions to

b-

D

a,b

As the absolute conﬁgurations within 36, 37, 40 and 41 had al-

ready been unambiguously established via single crystal X-ray

diffraction analyses of 37 and 40, a series of hydrogenolytic corre-

lation experiments were next undertaken to secure the conﬁgu-

similar cis-dioxolane containing a,b-unsaturated esters under our

standard reaction conditions (i.e., in THF at ꢀ78 ^ꢁC), we have

previously observed competitive deprotonation of the substrate at

the

g-position by the basic lithium amide reagent, generating the

rations within the remaining

b

-amino ester products of conjugate

-unsaturated ester 21. Hydro-

corresponding b,g

-unsaturated ester; however, suppression of this

addition to the -xylose derived

D

a,

b

g-deprotonation pathway can be achieved when the reaction is

genolysis of 40 [>99:1 dr; obtained as the minor product in the

conjugate addition of (R)-7 to 21] gave an authentic sample of

carried out in Et₂O at ꢀ20 ^ꢁC.^18b,24In light of this differing re-

activity, the conjugate additions of 17, 18, (R)-7 and (S)-7 to a,b-

b

-amino ester 44 in 77% yield and >99:1 dr. Hydrogenolysis of 42

unsaturated esters 22 and 23 in both THF (at ꢀ78 ^ꢁC) and Et₂O (at

[>99:1 dr; obtained as the major product of conjugate addition of

(S)-7 to 21] and of 38 [>99:1 dr; obtained as the minor product in

the conjugate addition of 18 to 21] gave 44 in 83 and 73% yield,

respectively, and in >99:1 dr in both cases. Both samples of 44 were

found to display ¹H NMR spectra that were entirely consistent with

that of the authentic sample of 44, obtained upon hydrogenolysis of

40, thereby allowing the absolute conﬁgurations within 38 and 42

ꢀ20 ^ꢁC) were investigated. The substrate control provided by

D-

ribose derived a,b-unsaturated ester 22 was investigated ﬁrst via

the conjugate additions of achiral lithium amides 17 and 18. Under

the standard reaction conditions (in THF at ꢀ78 ^ꢁC), the conjugate

addition of lithium N-isopropyl-N-benzylamide 17 to

a,

b

-un-

-amino ester 49

b,g

-unsaturated ester 50,²⁸respectively, which represented

saturated ester 22 resulted in a 93:7 mixture of

and

b

to be unambiguously assigned. Treatment of a sample of

ester 44 (>99:1 dr) with NaBH₃CN and acetone then provided an

authentic sample of N-isopropyl substituted -amino ester 45 in

78% yield and >99:1 dr. Hydrogenolysis of 36 [>99:1 dr; obtained

as the minor product in the conjugate addition of 17 to 21] gave 45

in quantitative yield and >99:1 dr. The ¹H NMR spectrum of this

sample was found to be in complete agreement with that of the

authentic sample of 45, allowing the assigned absolute conﬁgura-

tion within 36 to also be conﬁrmed. Hydrogenolysis of 37 [>99:1

dr; obtained as the major product in the conjugate addition of 17 to

b

-amino

a diastereoselectivity of >99:1 dr for the conjugate addition re-

action alone. Subsequent puriﬁcation of the crude reaction mix-

ture gave 49 in 73% yield and >99:1 dr (Scheme 6). The relative

conﬁguration within 49 was unambiguously established via single

crystal X-ray diffraction analysis,²⁷with the absolute (3S,4S,5S,6R)-

conﬁguration within 49 being assigned relative to the known

b

conﬁgurations of the

D-ribose derived dioxolane units (Fig. 8).

Interestingly, in contrast to our previous results,^18b,24repetition of

the reaction in Et₂O at ꢀ20 ^ꢁC did not suppress the

g-deproto-

nation pathway and instead served to enhance it: in this case an

21] gave an authentic sample of N-isopropyl substituted

b

-amino

80:20 mixture of 49 (>99:1 dr) and 50 was recovered. Conjugate

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S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

Scheme 5. Reagents and conditions: (i) Pd(OH)₂/C, H₂(1 atm), EtOAc, rt, 18 h; (ii) NaBH₃CN, acetone, MeOH, rt, 18 h. [the conﬁgurations within 37 and 40 (highlighted in red) have

been unambiguously assigned by single crystal X-ray diffraction analysis].

addition of lithium N,N-dibenzylamide 18 to 22 was found to

proceed with poorer diastereofacial control, producing a 10:90

mixture of 51 and 52, respectively, upon reaction in THF at ꢀ78 ^ꢁC;

this observation has previously been attributed to the greater re-

activity (and therefore faster conjugate addition reaction) of 18.^18b

therefore predicted that the conjugate addition of (R)-7 to 22

would represent the doubly diastereoselective ‘matched’ reaction

pairing, and reaction of (S)-7 with 22 was expected to represent

the doubly diastereoselective ‘mismatched’ case. Upon conjugate

addition of (R)-7 to 22 in THF at ꢀ78 ^ꢁC exclusive formation of 54

was observed; after chromatographic puriﬁcation, 54 was sub-

sequently isolated in 94% yield and >99:1 dr. The corresponding

conjugate addition reaction in Et₂O at ꢀ20 ^ꢁC gave a 97:3 mixture

No evidence of b,g-unsaturated ester 50 was observed in this case.

Repetition of the reaction in Et₂O at ꢀ20 ^ꢁC resulted in a 38:62

mixture of 51 and 52, respectively, and again 50 was absent from

the ¹H NMR spectrum of the crude reaction mixture (Scheme 6).

The exclusive (in the case of 49) or preferential (in the case of 52)

of b-amino ester 54 and b,g-unsaturated ester 50, respectively. The

formation of 54 as the sole product of conjugate addition served to

support the prediction that the conjugate addition of (R)-7 to 22

represents the doubly diastereoselective ‘matched’ reagent/sub-

strate combination. The conjugate addition of (S)-7 to 22 in THF at

production of the

b-amino esters 49 and 52 upon conjugate ad-

dition of 17 and 18 to

a,b-unsaturated ester 22 suggests that the

substrate control is extremely high and serves to direct conjugate

addition of the lithium amide reagent to the Si face.²⁵It was

ꢀ78 ^ꢁC gave a 24:76 mixture of

b-amino ester 56 and b,g-

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8687

Scheme 6. Reagents and conditions: (i) 17, THF, ꢀ78 ^ꢁC, 2 h; (ii) 17, Et₂O, ꢀ20 ^ꢁC, 5 h; (iii) 18, THF, ꢀ78 ^ꢁC, 2 h; (iv) 18, Et₂O, ꢀ20 ^ꢁC, 5 h; (v) (R)-7, THF, ꢀ78 ^ꢁC, 2 h; (vi) (R)-7,

Et₂O, ꢀ20 ^ꢁC, 5 h; (vii) (S)-7, THF, ꢀ78 ^ꢁC, 2 h; (viii) (S)-7, Et₂O, ꢀ20 ^ꢁC, 5 h. [^aa 31:69 mixture of 51 and 52 was isolated in 32% combined yield].

conjugate addition of (R)-7 to 22] gave b-amino ester 57 in 97%

yield and >99:1 dr. Similar treatment of a sample of 56 [>99:1 dr;

obtained as the sole product of conjugate addition of (S)-7 to 22]

gave 57 in quantitative yield and >99:1 dr, and hydrogenolysis of

52 [>99:1 dr; obtained as the major product of conjugate addition

of 18 to 22] gave 57 in 90% yield and >99:1 dr. The ¹H NMR spectra

of all samples of 57 were found to be in complete accord, thereby

conﬁrming the homochirality at C(3) between b-amino esters 52,

54 and 56. Hydrogenolysis of 49 [>99:1 dr; obtained as the major

product of conjugate addition of 17 to 22] gave an authentic sample

of N-isopropyl substituted

b-amino ester 58 in 99% yield and >99:1

dr. -Amino ester 57 (>99:1 dr) was then subjected to a reductive

b

alkylation reaction using NaBH₃CN and acetone to give 58 in 50%

yield and >99:1 dr. The ¹H NMR spectra of the two samples of 58

were also found to be identical, thus establishing the absolute

conﬁguration within 57 and therefore also those within 52, 54 and

56 (Scheme 7).

Conjugate addition of lithium N-isopropyl-N-benzylamide 17 to

Fig. 8. X-ray crystal structure of (3S,4S,5S,6R)-49 (selected H atoms are omitted for

clarity).

a,

b

-unsaturated ester 23 in THF at ꢀ78 ^ꢁC resulted in a 76:8:16

mixture of b-amino esters 59 and 60, and b,g-unsaturated ester 61,

unsaturated ester 50, respectively. Subsequent puriﬁcation via

ﬂash column chromatography gave 56 in 15% isolated yield and

>99:1 dr, whilst 50 was isolated in 75% yield and >99:1 dr. Upon

consideration of the conjugate addition reaction alone, the ob-

servation that only 56 is produced suggests that the reaction is

under the dominant control of the substrate 22, rather than the

lithium amide (S)-7. Repetition of the reaction in Et₂O at ꢀ20 ^ꢁC

gave a 70:30 mixture of 56 and 50, respectively, indicating that

these alternative conditions do not completely suppress the for-

mation of 50 (Scheme 6).

respectively; an 83:17 mixture of 59 (>99:1 dr) and b,g-un-

saturated ester 61²⁸(>99:1 dr) was subsequently isolated after

chromatographic puriﬁcation of the crude reaction mixture. Upon

changing the reaction conditions to Et₂O at ꢀ20 ^ꢁC, the pathway

resulting in the formation of 61 was found to be completely sup-

pressed, giving an 81:19 mixture of 59 and 60, respectively. No

evidence of b,g-unsaturated ester 61 was observed upon conjugate

addition of lithium N,N-dibenzylamide 18 in THF at ꢀ78 ^ꢁC, which

gave a 50:50 mixture of b-amino esters 62 and 63. b-Amino esters

62 and 63 were subsequently isolated in 40 and 33% yield, re-

spectively, and in >99:1 dr in each case. Repetition of the reaction

in Et₂O at ꢀ20 ^ꢁC also resulted in a 50:50 mixture of 62 and 63

(Scheme 8). The relative conﬁguration within 63 was un-

ambiguously established via single crystal X-ray diffraction analy-

sis,²⁷with the absolute (3S,4R,5R,6R)-conﬁguration within 63 being

As the absolute conﬁguration within 49 had already been un-

ambiguously established via single crystal X-ray diffraction analy-

sis, a series of hydrogenolytic/reductive alkylation experiments

were next conducted to unambiguously establish the conﬁgura-

tions within all the remaining

addition to -ribose derived

genolysis of 54 [>99:1 dr; obtained as the sole product in the

b

-amino ester products of conjugate

D

a

,

b-unsaturated ester 22. Hydro-

assigned relative to the known conﬁgurations of the

D-lyxose de-

rived dioxolane units (Fig. 9). This analysis also secured the absolute

8688

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

Scheme 7. Reagents and conditions: (i) Pd(OH)₂/C, H₂(1 atm), EtOAc, rt, 18 h; (ii) Pd(OH)₂/C, H₂(1 atm), MeOH, rt, 18 h; (iii) NaBH₃CN, acetone, MeOH, rt, 18 h. [the conﬁguration

within 49 (highlighted in red) has been unambiguously assigned by single crystal X-ray diffraction analysis].

Scheme 8. Reagents and conditions: (i) 17, THF, ꢀ78 ^ꢁC, 2 h; (ii) 17, Et₂O, ꢀ20 ^ꢁC, 5 h; (iii) 18, THF, ꢀ78 ^ꢁC, 2 h; (iv) 18, Et₂O, ꢀ20 ^ꢁC, 5 h; (v) (S)-7, THF, ꢀ78 ^ꢁC, 2 h; (vi) (S)-7, Et₂O,

ꢀ20 ^ꢁC, 5 h; (vii) (R)-7, THF, ꢀ78 ^ꢁC, 2 h; (viii) (R)-7, Et₂O, ꢀ20 ^ꢁC, 5 h. [^a59 (>99:1 dr) and 61 (>99:1 dr) were isolated as an 83:17 mixture; ^b64 (>99:1 dr) and 61 (>99:1 dr) were

isolated as an 86:14 mixture; ^c66 (>99:1 dr) and 61 (>99:1 dr) were isolated as a 12:88 mixture].

conﬁguration within 62. As the conjugate addition reaction of

18 to 23 resulted in a 50:50 mixture of the diastereoisomeric

18. However, as the conjugate addition of 17 to 23 resulted in

a strong preference for the formation of 59, this suggests that the

b

-amino esters 62 and 63, this indicates that no substrate control is

a,

b

-unsaturated ester 23 favours a conjugate addition pathway

provided by -unsaturated ester 23 upon conjugate addition of

a,b

involving attack of the lithium amide reagent 17 on the Re face.²⁵

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8689

this system and so the reactions cannot be classiﬁed according to

the classical ‘matched’ and ‘mismatched’ deﬁnitions of Masamune

et al.^22,24

As the absolute conﬁgurations within 62 and 63 had already

been unambiguously established via single crystal X-ray diffraction

analysis of 63, a series of hydrogenolytic/reductive alkylation ex-

periments were next conducted to unambiguously establish the

conﬁgurations within all the remaining -amino ester products of

b

conjugate addition to -lyxose derived a,b-unsaturated ester 23. In

D

the ﬁrst instance, hydrogenolysis of 62 [>99:1 dr; obtained from

the conjugate addition of 18 to 23 (crude ratio 50:50 dr)] gave an

authentic sample of primary b-amino ester 68 in 83% yield and

>99:1 dr. Hydrogenolysis of a sample of 64 [>99:1 dr; obtained as

the major product in the conjugate addition of (S)-7 to 23] then

gave 68 in 76% yield and >99:1 dr, whilst hydrogenolysis of

a sample of 66 [>99:1 dr; obtained as the major product in the

conjugate addition of (R)-7 to 23 in Et₂O at ꢀ20 ^ꢁC] also gave 68 in

62% yield and >99:1 dr. The ¹H NMR spectra of both samples of 68

were found to be in complete agreement with that of the authentic

sample of 68 (obtained upon hydrogenolysis of 62), thereby serving

to establish the absolute conﬁgurations within both 64 and 66.

Subjection of 68 (>99:1 dr) to the reductive alkylation conditions

Fig. 9. X-ray crystal structure of (3S,4R,5R,6R)-63 (selected H atoms are omitted for

clarity).

gave an authentic sample of N-isopropyl substituted b-amino ester

69 in 79% yield and >99:1 dr. Hydrogenolysis of 59 [>99:1 dr;

obtained as the major product in the conjugate addition of 17 to 23]

then gave 69 in 89% yield and >99:1 dr; this sample was found to

display an identical ¹H NMR spectrum to that of the authentic

sample of 69 and allowed the absolute conﬁguration within 59 to

be established. Hydrogenolysis of 63 gave an authentic sample of

Based upon the substrate control provided by 23 (during conjugate

addition of 17) it was predicted that reaction with (S)-7 would

represent the doubly diastereoselective ‘matched’ reaction. The

conjugate addition of (S)-7 to 23 was found to give a 71:21:8

mixture of

b

-amino esters 64 and 65, and

b

,

g

-unsaturated ester 61,

primary

this sample to the reductive alkylation conditions gave N-isopropyl

-amino ester 71 in 53% yield and >99:1 dr. The ¹H NMR spectra of

70 and 71 were found to be signiﬁcantly different to those of 68 and

69, respectively, thereby serving to conﬁrm further the assigned

b-amino ester 70 in 84% yield and >99:1 dr. Subjection of

respectively, which represented a 77:23 dr (in favour of 64) for the

conjugate addition reaction. Subsequent puriﬁcation via ﬂash col-

umn chromatography resulted in 65 being isolated in 21% yield and

>99:1 dr; an 86:14 mixture of 64 (>99:1 dr) and 61 (>99:1 dr),

respectively, was also isolated. The diastereoselectivity of this re-

action (77:23 dr) is not only lower than would be expected from the

known high diastereoselectivity of the conjugate addition of (S)-7

b

conﬁgurations within this series of

D

-lyxose derived

b-amino esters

(Scheme 9).

The lithium amide conjugate addition reactions to

a,b

-un-

to achiral

a,

b

-unsaturated esters,²⁰but it is also inferior to that

saturated esters 20 and 22 had conformed to the predicted out-

comes; the doubly diastereoselective ‘matched’ reactions had

proceeded with the same sense (and with an enhanced level) of

diastereocontrol as those suggested by the substrate control ex-

periments, resulting in the preferential formation of the corre-

observed under substrate control alone (90:10 dr for the conjugate

addition of 17). This suggests that some other effect may be in

operation to affect the normal mode of action of the lithium amide

and therefore result in a lower than expected diastereoselectivity

for the reaction. When the same reaction was performed in Et₂O at

ꢀ20 ^ꢁC, a 42:52:6 mixture of 64, 65 and 61 was produced, which

indicated that these conditions had resulted not only in a lower

level of diastereoselectivity but also a reversal in the sense of dia-

stereofacial control due to the slight preference for the formation of

65 (45:55 dr). The conjugate addition of (R)-7 to 23 in THF at ꢀ78 ^ꢁC

sponding 3,4-anti-b-amino ester products 28 and 54. These

stereochemical outcomes were found to be consistent with our

previous results concerning the conjugate addition of the antipodes

of 7 to analogous chiral

this, in the case of -unsaturated ester 23, an erosion in diaster-

a,b

-unsaturated esters.^18b,24In contrast to

a,b

eoselectivity was observed for the conjugate addition reactions of

both antipodes of 7 compared with the analogous reaction in-

volving substrate control alone (upon conjugate addition of lithium

N-isopropyl-N-benzylamide 17). Furthermore, in the case of 21, the

‘empirically matched’ conjugate addition reaction of (S)-7 had

produced a 15:23:62 mixture of b-amino esters 66 and 67, and b,g-

unsaturated ester 61, respectively, from which a 12:88 mixture of

66 and 61 was isolated after puriﬁcation of the crude reaction

mixture. Upon consideration of the products of conjugate addition

alone, 66 and 67 were produced in 40:60 dr, respectively. The

diastereoselectivity of this reaction is again inferior (and opposite)

to that observed under substrate control alone (90:10 dr for the

conjugate addition of 17). When the reaction was instead con-

proceeded to give the 3,4-syn-

whilst the substrate control experiments had indicated preferential

attack on the opposing face of the -unsaturated ester 21, giving

3,4-anti- -amino esters as the major products (Fig. 10). This

b-amino ester 42 preferentially,

a,b

b

ducted in Et₂O at ꢀ20 ^ꢁC, the

g-deprotonation pathway was found

therefore suggests an unusual reversal in the sense of diaster-

eocontrol in the two reactions [i.e., that conjugate addition of

lithium N-isopropyl-N-benzylamide 17 occurs on the Si face²⁵of

the substrate 21 whilst the ‘empirically matched’ conjugate addi-

tion of (S)-7 occurs on the Re face²⁵]. We have previously noted this

behaviour in related systems.^18bFor all the conjugate addition re-

actions of either (R)-7 or (S)-7 to either 21 or 23, in no case is the

diastereoselectivity of the conjugate addition as high as would be

expected from the reaction of lithium amide 7 with an achiral

substrate (>95:5 dr in >200 examples).²⁰According to the classical

to be completely suppressed and resulted in a 66:34 mixture of b-

amino esters 66 and 67, which were isolated in 42% yield and >99:1

dr, and 16% yield and 91:9 dr, respectively (Scheme 8). This set of

reactions therefore represents another example where a reversal in

diastereofacial selectivity is observed upon changing the reaction

conditions from THF at ꢀ78 ^ꢁC to Et₂O at ꢀ20 ^ꢁC and that the sense

of substrate control provided by 23 is not augmented upon con-

jugate addition of either antipode of 7. The factors that inﬂuence

the substrate and reagent control are therefore not independent in

8690

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

Scheme 9. Reagents and conditions: (i) Pd(OH)₂/C, H₂(1 atm), EtOAc, rt, 18 h; (ii) NaBH₃CN, acetone, MeOH, rt, 18 h. [^a86:14 mixture of 64 (>99:1 dr) and 61 (>99:1 dr); ^b83:17

mixture of 59 (>99:1 dr) and 61 (>99:1 dr); the conﬁguration within 63 (highlighted in red) has been unambiguously assigned by single crystal X-ray diffraction analysis].

deﬁnition by Masamune et al.,²²introduction of chirality into the

substrate should presumably work to enhance the stereoselectivity

of the conjugate addition reaction in the doubly diastereoselective

‘matched’ case (compared to the analogous reactions proceeding

under substrate control alone), although the results from these

experiments have shown this not to be the case. This observation

implies that the factors that inﬂuence the substrate and reagent

control in these two instances are not independent and therefore

that the usual mode of action of the antipodes of lithium amide 7

upon conjugate addition to these substrates must be disrupted in

therefore on the relative conﬁguration of the multiple stereogenic

centres within the -unsaturated ester.

a,b

2.2. Elaboration to dihydroxyhomoprolines

Effortswerenextturnedtotheelaborationoftheseenantiopureb-

amino esters 9 to the corresponding dihydroxyhomoprolines 6. We

havepreviouslyemployedacyclisationprocedureinvolvingatandem

hydrogenolysis/intramolecular reductive amination reaction: alde-

hydes 72 and 73 were subjected to high pressure hydrogenolysis

conditions using Pd(OH)₂/C to give pyrrolidine 74 and piperidine 75

in 87 and 91% yield, respectively.²¹These conditions were therefore

some way, possibly due to the polyoxygenated nature of the a,b-

unsaturated ester substrates: an abundance of oxygen atoms in the

substrate could potentially allow chelation to occur between the

substrate and the lithium amide, as this phenomenon has been

noted in similar systems.^20,29Such chelation could result in intra-

molecular delivery of the lithium amide via a substrate-lithium

amide chelate or, alternatively, in intermolecular delivery from

a substrateelithium amide chelate to another substrate molecule.

The ability of the substrate to chelate to the lithium amide would

depend on the spatial arrangement of the oxygen atoms, and

able to effectboth the removal of the N-benzyl andN-a-methylbenzyl

groups within 72 and 73, as well as the reduction of the intermediate

imines resulting from cyclisation of the C(3)-amino groups onto the

aldehyde functionalities. It was therefore envisaged that the elabo-

ration of cis-dioxolane containing

b-amino esters 9 to dihydrox-

yhomoprolines 6 could be achieved using a tandem hydrogenolysis/

reductive aminationprocedure as the key step. It was anticipated that

selectivedeprotectionoftheprimaryacetonidefunctionalitywithin9

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8691

Fig. 10. The doubly diastereoselective conjugate additions of the antipodes of lithium amide 7 to

dr) was also observed; ^b16% conversion to -unsaturated ester 61 (>99:1 dr) was also observed; ^c8% conversion to

83:17 mixture of 59 (>99:1 dr) and 61 (>99:1 dr) was isolated; ^ean 86:14 mixture of 64 (>99:1 dr) and 61 (>99:1 dr) was isolated].

a

,

b

-unsaturated esters 20e23. [^a7% conversion to

b,

g

-unsaturated ester 50 (>99:1

b,

g

b,g

-unsaturated ester 61 (>99:1 dr) was also observed; ^dan

followed by oxidative cleavage of the C(6)eC(7) bond within the re-

sultant diol would then give the corresponding aldehydes 10, which,

upon subjection to the established high pressure hydrogenolysis

conditions, was expected to give pyrrolidines 11. Global deprotection

of 11 upon treatment with acid would then ﬁnally reveal the target

dihydroxyhomoprolines 6 (Fig. 11).

b-Amino ester 54 [the sole diastereoisomeric product in the

doubly diastereoselective ‘matched’ reaction of (R)-7 and 22] was

selected as a model system with which to screen conditions for

selective primary acetonide deprotection. The deprotection of pri-

mary acetonides in the presence of secondary acetonides can be

a difﬁcult transformation due to the tendency for over-deprotection

to the corresponding tetraol, even under mild conditions.³⁰As such,

many procedures have been developed to achieve this sort of

transformation for a variety of different substrates. Following one

such literature procedure,³¹54 was treated with 5 mol % BiCl₃in

MeCN/H₂O (100:1), which, unfortunately, resulted in only returned

starting material despite further attempts involving extended re-

action times and increased catalyst loading. A second procedure

involved heating 54 in AcOH/H₂O (4:1) at 50 ^ꢁC; however, the levels

of conversion to diol 76 were variable and 76 was only isolated in

a maximum 21% yield. Finally, treatment of 54 with a catalytic

amount of concentrated HCl in EtOH/H₂O (v/v 7:3) at 60 ^ꢁ³²gave

C

a mixture of diol 76 and starting material 54, from which 76 was

isolated in 32% yield. The selective primary acetonide deprotection

of 65³³under identical reaction conditions was found to proceed in

a similar fashion, giving 77 in 31% yield and >99:1 dr. In both cases,

the starting materials 54 and 65 were easily recovered and recycled

(Scheme 10).

Oxidative cleavage of the 1,2-diol unit within 76 upon treatment

with NaIO₄in MeOH gave aldehyde 78, which was found to rapidly

decompose on standing and so the crude sample of 78 was im-

mediately subjected to a high pressure hydrogenolysis reaction

with Pd(OH)₂/C catalyst, which resulted in tandem hydrogenolysis/

intramolecular reductive amination to give pyrrolidine 79 in 60%

Fig. 11. Proposed synthetic strategy towards dihydroxyhomoprolines 6.

8692

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

3. Conclusion

In conclusion, the doubly diastereoselective conjugate addition

reactions of the antipodes of lithium N-benzyl-N-( -methyl-

benzyl)-amide to a range of chiral -unsaturated esters (derived

from naturally occurring -pentose sugars) have been investigated.

a

a,b

D

A full account of the diastereoselectivity observed in these conju-

gate additions is presented and the stereochemical outcomes of

these reactions have been established unambiguously via a com-

bination of hydrogenolytic chemical correlation and single

crystal X-ray diffraction analyses. Further elaboration of the cis-

dioxolane containing

addition reactions involved

molecular reductive amination procedure for the construction of

b-amino ester products from these conjugate

a

tandem hydrogenolysis/intra-

the corresponding pyrrolidines, providing access to the novel b-

amino acids (2⁰S,3⁰S,4⁰R)-dihydroxyhomoproline and (2⁰S,3⁰R,4⁰S)-

dihydroxyhomoproline as single diastereoisomers (>99:1 dr) in

seven steps from D-ribose and D-lyxose, respectively. Further ap-

Scheme 10. Reagents and conditions: (i) BiCl₃(5 mol %), MeCN/H₂O (v/v 100:1), rt,

16 h; (ii) AcOH/H₂O (v/v 4:1), 50 ^ꢁC, 16 h; (iii) HCl, EtOH/H₂O (v/v 7:3), 60 ^ꢁC, 6 h.

plications of this methodology, including the syntheses of highly

functionalised azacycles and aminosugars, will be reported in due

course.

yield and >99:1 dr over the two steps. Global deprotection of 79 by

treatment with 2.0 M aqueous HCl and subsequent puriﬁcation via

ion-exchange chromatography gave dihydroxyhomoproline 80 in

92% yield and >99:1 dr.³⁴Similarly, treatment of diol 77 with NaIO₄

resulted in successful cleavage to the corresponding aldehyde 81,

which was again immediately subjected to the tandem hydro-

genolysis/intramolecular reductive amination conditions to give

pyrrolidine 82 in 54% yield and >99:1 dr over the two steps.

Treatment of 82 with 2.0 M aqueous HCl under reﬂuxing conditions

resulted in global deprotection to give dihydroxyhomoproline 83 in

84% yield after puriﬁcation via ion-exchange chromatography

(Scheme 11).³⁴

4. Experimental

4.1. General experimental

Reactions involving organometallic or other moisture-sensitive

reagents were carried out under a nitrogen or argon atmosphere

using standard vacuum line techniques and glassware that was

ﬂame dried and cooled under nitrogen before use. BuLi was pur-

chased from SigmaeAldrich (as a solution in hexanes) and titrated

against diphenylacetic acid before use. Solvents were dried

according to the procedure outlined by Grubbs and co-workers.³⁵

Water was puriﬁed by an Elix^ÒUV-10 system. All other 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), io-

dine, 1% aq KMnO₄, or 10% ethanolic phosphomolybdic acid. Flash

column chromatography was performed on Kieselgel 60 silica.

Elemental analyses were recorded by the microanalysis

service of the London Metropolitan University, U.K. Melting points

were recorded on a Gallenkamp Hot Stage apparatus. Optical ro-

tations were recorded on a PerkineElmer 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. The ﬁeld was locked by external

referencing to the relevant deuteron resonance. ¹He¹H COSY,

¹He¹³C HMQC, and ¹He¹³C HMBC analyses were used to establish

atom connectivity. When the diastereotopic methyl groups of

acetonide and isopropyl functionalities could not be un-

ambiguously assigned, the descriptors MeCMe and MeCHMe were

employed, respectively. In the ¹H and ¹³C NMR spectra, these de-

scriptors are intended to convey neither that the resonances are

attributable to methyl groups that reside on the same, nor on dif-

ferent carbon atoms. Low-resolution mass spectra were recorded

on either a VG MassLab 20e250 or a Micromass Platform 1 spec-

trometer. Accurate mass measurements were run on either

a Bruker MicroTOF internally calibrated with polyalanine, or

a Micromass GCT instrument ﬁtted with a Scientiﬁc Glass In-

struments BPX5 column (15 mꢂ0.25 mm) using amyl acetate as

a lock mass.

Scheme 11. Reagents and conditions: (i) NaIO₄, MeOH, rt, 16 h; (ii) Pd(OH)₂/C, H₂

(5 atm), MeOH, rt, 18 h; (iii) HCl (2.0 M, aq), reﬂux, 8 h then DOWEX 50WX8-200.

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8693

4.2. General procedure 1: lithium amide conjugate addition

4.6. tert-Butyl (4S,5R,6R,E)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-

isopropylidenehept-2-enoate 21

BuLi was added dropwise to a stirred solution of the requisite

amine in either THF or Et₂O (as stated) at ꢀ78 ^ꢁC or ꢀ20 ^ꢁC, re-

spectively, and stirring was continued for 30 min. A solution of the

Step 1: Dioxane (20 mL) was added to a mixture of D-xylose

(1.00 g, 6.66 mmol) and tert-butyl 2-(triphenylphosphor-

anylidene)-acetate (3.00 g, 7.99 mmol) and the resultant solution

was stirred at 90 ^ꢁC for 6 h. The reaction mixture was then allowed

to cool to 50 ^ꢁC and stirred at 50 ^ꢁC for 12 h. The reaction mixture

was then concentrated in vacuo to give the corresponding tetraol in

85:15 dr; d_H(400 MHz, CDCl₃) [selected peaks] 6.09 (1H, d, J 15.7,

C(2)H), 6.85 (1H, dd, J 15.7, 4.8, C(3)H).

Step 2: The residue was dissolved in DMP (30 mL) and TsOH$H₂O

(500mg, 2.63mmol) was added. Theresultant mixturewasstirredat

rt for 18 h then satd aq NaHCO₃(10 mL) was added. The aqueous

layer was extracted with Et₂O (3ꢂ50 mL) and the combined organic

extracts were dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/EtOAc, 15:1) gave

requisite a,b-unsaturated ester in either THF or Et₂O (as stated) was

then added via cannula and the reaction mixture was stirred for 2 h

(for THF) or 5 h (for Et₂O). Satd aq NH₄Cl was then added to the

reaction mixture, which was then diluted with Et₂O and H₂O. The

aqueous layer was extracted with three portions of Et₂O and the

combined organic extracts were washed sequentially with 10% aq

citric acid, satd aq NaHCO₃and brine, then dried and concentrated

in vacuo.

4.3. General procedure 2: hydrogenolysis

Pd(OH)₂/C was added to a stirred solution of the requisite

amine in either MeOH or EtOAc (as stated) at rt. The resultant

mixture was degassed and saturated with H₂before being left to

stir under an atmosphere of H₂(1 atm) for 18 h. The reaction

mixture was then ﬁltered through a short plug of Celite^Ò(eluent

MeOH or EtOAc, as stated) and the ﬁltrate was concentrated in

vacuo.

21 as a white solid (1.36 g, 62% from D-xylose, >99:1 dr); C₁₇H₂₈O₆

requires C, 62.2; H, 8.6%; found C, 62.2; H, 8.5%; mp 74e78 ^ꢁC; ½a _D²⁵

ꢃ

ꢀ20.4 (c 1.0 in CHCl₃); n_max(KBr) 2985, 2936 (CeH), 1716 (C]O),

1661 (C]C); d_H(400 MHz, CDCl₃) 1.34 (3H, s, MeCMe),1.39 (6H, app

s, 2ꢂ MeCMe), 1.41 (3H, s, MeCMe), 1.44 (9H, s, CMe₃), 3.75e3.81

(2H, m, C(5)H, C(7)H_A), 3.96e4.02 (1H, m, C(7)H_B), 4.12e4.18 (1H, m,

C(6)H), 4.40e4.45 (1H, m, C(4)H), 6.01 (1H, d, J 15.7, C(2)H), 6.71 (1H,

dd, J 15.7, 6.0, C(3)H); d_C(100 MHz, CDCl₃) 25.4, 26.1, 26.7, 26.7 (4ꢂ

MeCMe), 28.1 (CMe₃), 65.5 (C(7)), 74.5 (C(6)), 76.5 (C(4)), 80.4 (C(5)),

80.8 (CMe₃),109.8,110.3 (2ꢂ MeCMe),125.1 (C(2)),142.4 (C(3)),165.0

(C(1)); m/z (ESI^þ) 679([2MþNa]^þ,100%), 351 ([MþNa]^þ, 40%); HRMS

(ESI^þ) C₁₇H₂₈NaO₆^þ([MþNa]^þ) requires 351.1778; found 351.1783.

4.4. General procedure 3: reductive alkylation with NaBH₃CN

Acetone and NaBH₃CN were added sequentially to a solution

of the requisite primary amine in MeOH at rt. The resultant so-

lution was stirred at rt for 18 h, then concentrated in vacuo. The

residue was partitioned between CH₂Cl₂and H₂O, and the

aqueous layer was extracted with two portions of CH₂Cl₂. The

combined organic extracts were then dried and concentrated in

vacuo.

4.7. tert-Butyl (4S,5S,6R,E)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-

isopropylidenehept-2-enoate 22

Step 1: Dioxane (20 mL) was added to a mixture of D-ribose

(2.00 g,13.3 mmol) and tert-butyl 2-(triphenylphosphoranylidene)-

acetate (6.02 g, 16.0 mmol) and the resultant solution was stirred at

90 ^ꢁC for 6 h. The reaction mixture was then allowed to cool to 50 ^ꢁC

and stirred at 50 ^ꢁC for 12 h. The reaction mixture was then con-

centrated in vacuo to give the corresponding tetraol in 72:28 dr;

d_H(400 MHz, MeOH-d₄) [selected peaks] 6.05 (1H, dd, J 15.7, 1.7,

C(2)H), 6.99 (1H, dd, J 15.7, 5.1, C(3)H).

Step 2: The residue was dissolved in DMP (50 mL) and TsOH$H₂O

(780 mg, 4.10 mmol) was added. The resultant mixture was stirred

at rt for 18 h then satd aq NaHCO₃(20 mL) was added. The aqueous

layer was extracted with Et₂O (3ꢂ50 mL) and the combined organic

extracts were dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 20:1) gave

4.5. tert-Butyl (4R,5S,6R,E)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-

isopropylidenehept-2-enoate 20

Step 1: Dioxane (167 mL) was added to a mixture of D-arabinose

(10.0 g, 66.6 mmol) and tert-butyl 2-(triphenylphosphor-

anylidene)-acetate (30.1 g, 79.9 mmol) and the resultant solution

was stirred at 90 ^ꢁC for 6 h. The reaction mixture was then allowed

to cool to 50 ^ꢁC and stirred at 50 ^ꢁC for 12 h. The reaction mixture

was then concentrated in vacuo to give the corresponding tetraol in

>99:1 dr; d_H(400 MHz, MeOH-d₄) [selected peaks] 6.07 (1H, d, J

15.7, C(2)H), 7.00 (1H, dd, J 15.7, 4.4, C(3)H).

Step 2: The residue was dissolved in DMP (300 mL) and

TsOH$H₂O (4.75 g, 25.0 mmol) was added. The resultant mixture

was stirred at rt for 18 h then satd aq NaHCO₃(100 mL) was

added. The aqueous layer was then extracted with Et₂O

(3ꢂ100 mL) and the combined organic extracts were dried and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatog-

raphy (eluent 30e40 ^ꢁC petrol/Et₂O, 10:1) gave 20 as a pale yel-

22 as a colourless oil (1.76 g, 40% from D-ribose, >99:1 dr); C₁₇H₂₈O₆

requires C, 62.2; H, 8.6%; found C, 62.2; H, 8.7%; ½a _D²⁵

ꢀ17.2 (c 1.0 in

ꢃ

CHCl₃); n_max(ﬁlm) 1660 (C]O), 1716 (C]C); d_H(400 MHz, CDCl₃)

1.32 (3H, s, MeCMe), 1.38 (3H, s, MeCMe), 1.41 (3H, s, MeCMe), 1.49

(12H, app s, CMe₃, MeCMe), 3.88 (1H, dd, J 8.2, 5.7, C(7)H_A), 3.97 (1H,

app dt, J 8.5, 5.7, C(6)H), 4.07 (1H, dd, J 8.2, 5.7, C(7)H_B), 4.16 (1H, dd,

J 8.5, 6.7, C(5)H), 4.83 (1H, ddd, J 6.7, 4.8, 1.7, C(4)H), 6.07 (1H, dd, J

15.4,1.7, C(2)H), 6.94 (1H, dd, J 15.4, 4.8, C(3)H); d_H(100 MHz, CDCl₃)

25.2, 25.3, 26.8, 27.5 (2ꢂ MeCMe), 28.1 (CMe₃), 67.5 (C(7)), 73.9

(C(6)), 76.6 (C(4)), 78.8 (C(5)), 80.3 (CMe₃), 109.5, 109.6 (4 ꢂ

MeCMe), 124.2 (C(2)), 142.0 (C(3)), 165.4 (C(1)); m/z (ESI^þ) 273

low oil (17.1 g, 78% from

D-arabinose, >99:1 dr); C₁₇H₂₈O₆

requires C, 62.2; H, 8.6%; found C, 62.2; H, 8.5%; ½a _D²⁵

ꢀ1.7 (c 1.0 in

ꢃ

CHCl₃); n_max(ﬁlm) 2986, 2936 (CeH), 1716 (C]O), 1661 (C]C); d_H

(400 MHz, CDCl₃) 1.34 (3H, s, MeCMe), 1.41 (6H, app s, 2ꢂ

MeCMe), 1.42 (3H, s, MeCMe), 1.48 (9H, s, CMe₃), 3.66e3.72 (1H,

m, C(5)H), 3.92e3.98 (1H, m, C(7)H_A), 4.09e4.15 (2H, m, C(6)H,

C(7)H_B), 4.51 (1H, ddd, J 7.9, 4.7, 1.7, C(4)H), 6.07 (1H, dd, J 15.7, 1.7,

C(2)H), 6.89 (1H, dd, J 15.7, 4.7, C(3)H); d_C(100 MHz, CDCl₃) 25.2,

26.7, 26.7, 27.0 (4ꢂ MeCMe), 28.1 (CMe₃), 67.5 (C(7)), 77.0 (C(6)),

78.9 (C(4)), 80.5 (CMe₃), 81.1 (C(5)), 109.8, 110.2 (2ꢂ MeCMe),

123.4 (C(2)), 143.7 (C(3)), 165.5 (C(1)); m/z (ESI^þ) 351 ([MþNa]^þ,

þ

([MꢀC₄H₈]^þ, 100%); HRMS (ESI^þ) C₁₇H₂₉O₆([MþH]^þ) requires

329.1959; found 329.1964.

4.8. tert-Butyl (R,R,R,E)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylidenehept-2-enoate 23

þ

100%); HRMS (ESI^þ) C₁₇H₂₈NaO₆([MþNa]^þ) requires 351.1778;

Step 1: Dioxane (167 mL) was added to a mixture of

D-lyxose

found 351.1779.

(10.0 g, 66.6 mmol) and tert-butyl 2-(triphenylphosphoranylidene)-

8694

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

acetate (30.1 g, 79.9 mmol) and the resultant solution was stirred at

90 ^ꢁC for 6 h. The reaction mixture was then allowed to cool to 50 ^ꢁC

and stirred at 50 ^ꢁC for 12 h. The reaction mixture was then con-

centrated in vacuo to give the corresponding tetraol in 76:24 dr; d_H

(400 MHz, CDCl₃) [selected peaks] 6.03 (1H, dd, J 15.7, 1.7, C(2)H),

7.12 (1H, dd, J 15.7, 4.8, C(3)H).

Step 2: The residue was dissolved in DMP (300 mL) and

TsOH$H₂O (4.75 g, 25.0 mmol) was added. The resultant mixture

was stirred at rt for 18 h then satd aq NaHCO₃(100 mL) was added.

The aqueous layer was extracted with Et₂O (3ꢂ100 mL) and the

combined organic extracts were dried and concentrated in vacuo.

Puriﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢁC

4.10. tert-Butyl (3R,4R,5S,6R)- and (3S,4R,5S,6R)-3-(N,N-di-

benzylamino)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 26 and 27

Following general procedure 1, a solution of N,N-dibenzylamine

(1.62 g, 8.22 mmol) in THF (60 mL) was reacted with BuLi (2.1 M,

3.80 mL, 7.98 mmol) and a solution of 20 (1.35 g, 4.11 mmol, >99:1

dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave a 67:33 mixture of 26

and 27, respectively. Puriﬁcation via ﬂash column chromatography

(eluent 30e40 ^ꢁC petrol/Et₂O, 6:1) gave a 67:33 mixture of 26 and

27, respectively, as a colourless oil (2.07 g, 86%). Recrystallisation

(30e40 ^ꢁC petrol) of an aliquot gave 26 as a white solid (>99:1

dr); C₃₁H₄₃NO₆requires C, 70.8; H, 8.2; N, 2.7%; found C, 70.9; H,

petrol/Et₂O, 6:1) gave 23 as a pale yellow solid (8.12 g, 37% from D-

lyxose, >99:1 dr); C₁₇H₂₈O₆requires C, 62.2; H, 8.6%; found C, 62.3;

8.3; N, 2.7%; mp 82e86 ^ꢁC; ½a _D²⁵

þ18.5 (c 1.0 in CHCl₃); n_max(ﬁlm)

ꢃ

H, 8.6%; mp 64e67 ^ꢁC; ½a _D²⁵

ꢃ

þ4.6 (c 1.0 in CHCl₃); n_max(ﬁlm) 2985,

2984, 2934, 2881 (CeH), 1729 (C]O); d_H(400 MHz, CDCl₃) 1.15

(3H, s, MeCMe), 1.31 (3H, s, MeCMe), 1.35 (3H, s, MeCMe), 1.38 (3H,

s, MeCMe), 1.45 (9H, s, CMe₃), 2.39 (1H, dd, J 14.8, 4.3, C(2)H_A), 2.69

(1H, dd, J 14.8, 8.8, C(2)H_B), 3.52e3.59 (2H, m, C(3)H, C(5)H), 3.62

(2H, d, J 14.2, N(CH_AH_BPh)₂), 3.77 (2H, d, J 14.2, N(CH_AH_BPh)₂),

3.86e3.93 (1H, m, C(7)H_A), 4.04e4.11 (2H, m, C(6)H, C(7)H_B), 4.37

(1H, dd, J 7.3, 2.0, C(4)H), 7.18e7.42 (10H, m, Ph); d_C(100 MHz,

CDCl₃) 25.4, 26.5, 27.2, 27.3 (4ꢂ MeCMe), 28.1 (CMe₃), 33.0 (C(2)),

54.5 (N(CH₂Ph)₂), 56.8 (C(3)), 67.5 (C(7)), 77.6 (C(6)), 79.0 (C(5)),

79.3 (C(4)), 80.2 (CMe₃), 109.7, 109.8 (2ꢂ MeCMe), 126.8 (p-Ph),

128.0, 129.2 (o,m-Ph), 139.9 (i-Ph), 172.1 (C(1)); m/z (ESI^þ) 526

2937, 2888 (CeH), 1716 (C]O), 1658 (C]C); d_H(400 MHz, CDCl₃)

1.34 (3H, s, MeCMe), 1.39 (3H, s, MeCMe), 1.44 (3H, s, MeCMe), 1.47

(9H, s, CMe₃), 1.55 (3H, s, MeCMe), 3.54e3.60 (1H, m, C(7)H_A),

3.94e3.99 (1H, m, C(7)H_B), 4.03e4.11 (1H, m, C(6)H), 4.18e4.24 (1H,

m, C(5)H), 4.64e4.69 (1H, m, C(4)H), 5.98 (1H, d, J 15.7, C(2)H), 6.67

(1H, dd, J 15.7, 7.1, C(3)H); d_C(100 MHz, CDCl₃) 25.2, 25.3, 26.6, 27.6

(4ꢂ MeCMe), 28.1 (CMe₃), 65.8 (C(7)), 75.0 (C(6)), 76.0 (C(4)), 80.0

(C(5)), 81.0 (CMe₃), 109.9, 110.3 (2ꢂ MeCMe), 126.1 (C(2)), 140.8

(C(3)), 164.8 (C(1)); m/z (ESI^þ) 351 ([MþNa]^þ, 100%); HRMS (ESI^þ)

C₁₇H₂₈NaO₆^þ([MþNa]^þ) requires 351.1778; found 351.1780.

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₃₁H₄₄NO₆([MþH]^þ) requires

4.9. tert-Butyl (3R,4R,5S,6R)- and (3S,4R,5S,6R)-3-(N-iso-

propyl-N-benzylamino)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 24 and 25

526.3163; found 526.3172. Data for 27: d_H(400 MHz, CDCl₃) 1.27

(3H, s, MeCMe), 1.28 (3H, s, MeCMe), 1.36 (3H, s, MeCMe), 1.37 (3H,

s, MeCMe), 1.50 (9H, s, CMe₃), 2.67 (1H, dd, J 14.3, 9.2, C(2)H_A), 2.75

(1H, dd, J 14.3, 4.4, C(2)H_B), 3.19e3.26 (1H, m, C(3)H), 3.38e3.44

(1H, m, C(7)H_A), 3.39 (2H, d, J 13.9, N(CH_AH_BPh)₂), 3.68e3.77 (2H,

m, C(6)H, C(7)H_B), 4.00 (1H, dd, J 7.6, 3.0, C(4)H), 4.10 (2H, d, J 13.9,

N(CH_AH_BPh)₂), 4.35e4.40 (1H, m, C(5)H), 7.18e7.42 (10H, m, Ph);

d_C(100 MHz, CDCl₃) 25.4, 26.3, 26.4, 27.2 (4ꢂ MeCMe), 28.1

(CMe₃), 32.8 (C(2)), 54.8 (C(3)), 55.8 (N(CH₂Ph)₂), 65.9 (C(7)), 76.2

(C(6)), 76.8 (C(5)), 80.6 (CMe₃), 80.8 (C(4)), 109.1, 109.8 (2ꢂ

MeCMe), 127.1 (p-Ph), 128.3, 129.3 (o,m-Ph), 139.8 (i-Ph), 171.9

(C(1)).

Following general procedure 1, a solution of N-isopropyl-N-

benzylamine (1.36 g, 9.14 mmol) in THF (60 mL) was reacted with

BuLi (2.1 M, 4.22 mL, 8.86 mmol) and a solution of 20 (1.50 g,

4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave an

88:12 mixture of 24 and 25, respectively. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 6:1) gave

an 88:12 mixture of 24 and 25, respectively, as a colourless oil

(1.86 g, 85%). Data for mixture: C₂₇H₄₃NO₆requires C, 67.9; H, 9.1;

N, 2.9%; found C, 67.8; H, 9.2; N, 2.9%; n_max(ﬁlm) 3027, 2982, 2934

(CeH), 1730 (C]O); m/z (ESI^þ) 478 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₂₇H₄₄NO₆^þ([MþH]^þ) requires 478.3163; found 478.3166. Data for

24: d_H(400 MHz, CDCl₃) 1.04 (3H, d, J 6.8, MeCHMe), 1.05 (3H, d, J

6.8, MeCHMe),1.35 (9H, app s, 3ꢂ MeCMe),1.41 (3H, s, MeCMe),1.48

(9H, s, CMe₃), 2.32 (1H, dd, J 14.9, 3.8, C(2)H_A), 2.60 (1H, dd, J 14.9,

9.5, C(2)H_B), 2.98 (1H, app septet, J 6.8, MeCHMe), 3.57e3.62 (1H,

m, C(5)H), 3.65 (1H, d, J 14.7, NCH_AH_BPh), 3.70 (1H, ddd, J 9.5, 3.8,

4.11. tert-Butyl (3R,4R,5S,6R,aS)-3-[N-benzyl-N-(a-methyl-

benzyl)amino]-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 28

Following general procedure 1, a solution of (S)-N-benzyl-N-

(a-methylbenzyl)amine (1.93 g, 9.14 mmol) in THF (60 mL) was

2.1, C(3)H), 3.91e3.95 (1H, m, C(7)H_A), 3.95 (1H, d,

J

14.7,

reacted with BuLi (2.1 M, 4.22 mL, 8.86 mmol) and a solution of 20

(1.50 g, 4.57mmol, >99:1 dr)inTHF (60 mL)at ꢀ78 ^ꢁC, which gave28

in >99:1 dr. Puriﬁcation via ﬂash column chromatography (eluent

30e40 ^ꢁC petrol/Et₂O, 10:1) gave 28 as a white solid (1.79 g, 73%,

>99:1 dr); C₃₂H₄₅NO₆requires C, 71.2; H, 8.4; N, 2.6%; found C, 71.1;

NCH_AH_BPh), 4.05e4.14 (2H, m, C(6)H, C(7)H_B), 4.20 (1H, dd, J 7.9, 2.1,

C(4)H), 7.18e7.41 (5H, m, Ph); d_C(100 MHz, CDCl₃) 18.5, 21.1 (2ꢂ

MeCHMe), 25.4, 26.8, 27.1, 27.2 (4ꢂ MeCMe), 28.2 (CMe₃), 34.8

(C(2)), 48.3 (MeCHMe), 50.0 (NCH₂Ph), 54.7 (C(3)), 67.7 (C(7)), 77.6

(C(6)), 79.4 (C(5)), 79.8 (CMe₃), 81.9 (C(4)), 109.5, 109.6 (2ꢂ

MeCMe), 126.4 (p-Ph), 127.9, 128.6 (o,m-Ph), 141.6 (i-Ph), 172.2

(C(1)). Data for 25: d_H(400 MHz, CDCl₃) 1.01 (3H, d, J 6.6, MeCHMe),

1.09 (3H, d, J 6.6, MeCHMe), 1.27 (3H, s, MeCMe), 1.31 (3H, s,

MeCMe), 1.38 (3H, s, MeCMe), 1.45 (3H, s, MeCMe), 1.49 (9H, s,

CMe₃), 2.67 (1H, dd, J 14.3, 3.8, C(2)H_A), 2.76 (1H, dd, J 14.3, 9.6, C(2)

H_B), 2.94e3.09 (1H, m, MeCHMe), 3.35e3.40 (1H, m, C(3)H), 3.57

(1H, d, J 14.9, NCH_AH_BPh), 3.78 (1H, app t, J 7.9, C(7)H_A), 3.90e3.96

(1H, m, C(6)H), 4.04 (1H, dd, J 7.9, 2.7, C(7)H_B), 4.08e4.12 (1H, m,

C(4)H), 4.19 (1H, d, J 14.9, NCH_AH_BPh), 4.30e4.35 (1H, m, C(5)H),

7.18e7.42 (5H, m, Ph); d_C(100 MHz, CDCl₃) 16.6, 22.6 (2ꢂ MeCHMe),

25.5, 26.3, 26.3, 26.9 (4ꢂ MeCMe), 28.1 (CMe₃), 36.5 (C(2)), 49.6

(MeCHMe), 52.0 (C(3)), 52.1 (NCH₂Ph), 67.7 (C(7)), 77.4, 77.5 (C(5),

C(6)), 80.2 (CMe₃), 82.9 (C(4)), 108.7, 109.3 (2ꢂ MeCMe), 126.5 (p-

Ph), 128.1, 128.2 (o,m-Ph), 141.6 (i-Ph), 171.9 (C(1)).

H, 8.3; N, 2.7%; mp 53e58 ^ꢁC; ½a _D²⁵

þ23.5 (c 1.0 in CHCl₃); n_max(ﬁlm)

ꢃ

3028, 2983, 2934 (CeH),1730 (C]O); d_H(400 MHz, CDCl₃) 1.36 (3H,

s, MeCMe),1.40 (3H, s, MeCMe),1.42 (6H, app s, 2ꢂ MeCMe),1.46 (9H,

s, CMe₃), 1.51 (3H, d, J 6.8, C(a)Me), 2.36 (1H, dd, J 15.4, 5.3, C(2)H_A),

2.43 (1H, dd, J 15.4, 7.1, C(2)H_B), 3.71e3.76 (1H, m, C(5)H), 3.79e3.83

(1H, m, C(3)H), 3.82 (1H, d, J 13.9, NCH_AH_BPh), 3.86 (1H, d, J 13.9,

NCH_AH_BPh), 3.96 (1H, dd, J 7.8, 5.6, C(7)H_A), 4.08e4.21 (3H, m, C(6)H,

C(7)H_B, C(

d_C(100 MHz, CDCl₃) 17.6 (C(

28.1 (CMe₃), 34.2 (C(2)), 50.8 (NCH₂Ph), 55.7 (C(3)), 57.2 (C(

a

)H), 4.32 (1H, dd, J 7.3,1.3, C(4)H), 7.21e7.47 (10H, m, Ph);

)Me), 25.6, 26.6, 27.1, 27.2 (4ꢂ MeCMe),

)), 67.4

a

(C(7)), 77.6 (C(6)), 79.4 (CMe₃), 79.9 (C(5)), 81.6 (C(4)), 109.6, 109.8

(2ꢂ MeCMe), 126.6, 126.7 (p-Ph), 127.9, 128.0, 128.3, 128.7 (o,m-Ph),

141.3, 143.9 (i-Ph), 171.8 (C(1)); m/z (ESI^þ) 540 ([MþH]^þ, 100%);

þ

HRMS (ESI^þ) C₃₂H₄₆NO₆([MþH]^þ) requires 540.3320; found

540.3320.

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8695

4.12. tert-Butyl (3R,4R,5S,6R,

a

R)- and (3S,4R,5S,6R,

a

R)-3-

which gave 33 in >99:1 dr. Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢁC petrol/Et₂O, 5:1) gave 33 as a colourless

oil (85 mg, 93%, >99:1 dr); C₂₀H₃₇NO₆requires C, 62.0; H, 9.6; N,

[N-benzyl-N-( -methylbenzyl)amino]-4,5,6,7-tetrahydroxy-

a

4,5,6,7-di-O-isopropylideneheptanoate 30 and 31

3.6%; found C, 62.1; H, 9.5; N, 3.45%; ½a _D²⁵

þ7.7 (c 1.0 in CHCl₃); n_max

ꢃ

Following general procedure 1, a solution of (R)-N-benzyl-N-(

a

-

(ﬁlm) 3326 (NeH), 2983, 2935, 2879 (CeH), 1730 (C]O); d_H

(400 MHz, CDCl₃) 1.02 (6H, d, J 6.3, 2ꢂ MeCHMe), 1.32 (3H, s,

MeCMe), 1.33 (3H, s, MeCMe), 1.36 (3H, s, MeCMe), 1.42 (3H, s,

MeCMe), 1.43 (9H, s, CMe₃), 2.31 (1H, dd, J 15.2, 7.3, C(2)H_A), 2.48

(1H, dd, J 15.2, 4.3, C(2)H_B), 2.87e2.98 (1H, m, MeCHMe), 3.21e3.26

(1H, m, C(3)H), 3.70e3.76 (1H, m, C(5)H), 3.91e4.00 (2H, m, C(4)H,

C(7)H_A), 4.06e4.12 (2H, m, C(6)H, C(7)H_B); d_C(100 MHz, CDCl₃) 23.1,

23.4 (2ꢂ MeCHMe), 25.2, 26.7, 27.1, 27.2 (4ꢂ MeCMe), 28.1 (CMe₃),

37.5 (C(2)), 45.7 (MeCHMe), 54.0 (C(3)), 67.4 (C(7)), 77.4 (C(6)), 79.4

(C(5)), 80.2 (CMe₃), 81.7 (C(4)), 109.5, 109.6 (2ꢂ MeCMe), 171.9

methylbenzyl)amine (1.93 g, 9.14 mmol) in THF (60 mL) was reac-

ted with BuLi (2.1 M, 4.22 mL, 8.86 mmol) and a solution of 20

(1.50 g, 4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave

a 19:81 mixture of 30 and 31, respectively. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 10:1) gave

a 15:85 mixture of 30 and 31, respectively, as a colourless oil (1.49 g,

60%). Data for mixture: n_max(ﬁlm) 3027, 2983, 2935 (CeH), 172_þ7

(C]O); m/z (ESI^þ) 540 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₂H₄₆NO₆

([MþH]^þ) requires 540.3320; found 540.3306. Data for 31: d_H

(400 MHz, CDCl₃) 1.30 (3H, s, MeCMe), 1.33 (3H, s, MeCMe), 1.42

þ

(C(1)); m/z (ESI^þ) 388 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₀H₃₈NO₆

(3H, d, J 7.1, C(

a)Me), 1.44 (3H, s, MeCMe), 1.49 (9H, s, CMe₃), 1.51

([MþH]^þ) requires 388.2694; found 388.2694.

(3H, s, MeCMe), 1.64 (1H, dd, J 14.8, 1.5, C(2)H_A), 2.46 (1H, dd,

J 14.8, 11.4, C(2)H_B), 3.56 (1H, d, J 14.5, NCH_AH_BPh), 3.69e3.76

(1H, m, C(3)H), 3.80 (1H, q, J 7.1, C(a)H), 3.91e3.96 (1H, m, C(7)H_A),

4.10 (1H, dd, J 7.3, 2.0, C(4)H), 4.11e4.16 (1H, m, C(5)H), 4.18e4.23

(1H, m, C(7)H_B), 4.38 (1H, d, J 14.5, NCH_AH_BPh), 4.52e4.58 (1H, m,

Method B (from 24): Following general procedure 2, a solution of

24 (218 mg, 0.456 mmol, 88:12 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 109 mg) and H₂(1 atm),

which gave 33 as a colourless oil (169 mg, 96%, 88:12 dr).

C(6)H), 7.22e7.58 (10H, m, Ph); d_C(100 MHz, CDCl₃) 20.0 (C(

25.6, 26.3, 26.5, 27.0 (4ꢂ MeCMe), 28.1 (CMe₃), 34.8 (C(2)), 50.9

(C(3)), 53.1 (NCH₂Ph), 57.3 (C( )), 68.0 (C(7)), 77.5, 77.7 (C(5), C(6)),

a

)Me),

4.15. tert-Butyl (3S,4R,5S,6R)-3-amino-4,5,6,7-tetrahydroxy-

4,5,6,7-di-O-isopropylideneheptanoate 34

a

80.1 (CMe₃), 83.0 (C(4)), 108.9, 109.6 (2ꢂ MeCMe), 126.6, 127.2 (p-

Ph), 128.1, 128.2, 128.2, 128.4 (o,m-Ph), 140.7, 141.4 (i-Ph), 171.5

(C(1)). Data for 30: d_H(400 MHz, CDCl₃) [selected peaks] 1.22 (3H, s,

MeCMe), 1.31 (3H, s, MeCMe), 1.39 (3H, s, MeCMe), 1.41 (3H, d, J 7.8,

Following general procedure 2, a solution of 31 (252 mg,

0.467 mmol, 85:15 dr) in EtOAc (5 mL) was reacted with Pd(OH)₂/C

(50% w/w of substrate, 126 mg) and H₂(1 atm), which gave 34 as

a pale yellow oil (140 mg, 87%, 85:15 dr); n_max(ﬁlm) 3329 (NeH),

2985, 2935, 2881 (CeH),1728 (C]O); d_H(400 MHz, CDCl₃) 1.27 (3H,

s, MeCMe), 1.29 (3H, s, MeCMe), 1.34 (3H, s, MeCMe), 1.35 (3H, s,

MeCMe), 1.40 (9H, s, CMe₃), 1.49 (2H, br s, NH₂), 2.29 (1H, dd, J 15.9,

9.6, C(2)H_A), 2.47 (1H, dd, J 15.9, 3.8, C(2)H_B), 3.23 (1H, app dt, J 9.6,

3.8, C(3)H), 3.80 (1H, dd, J 7.1, 3.8, C(4)H), 3.84e3.92 (2H, m, C(5)H,

C(7)H_A), 3.96e4.01 (1H, m, C(6)H), 4.07 (1H, dd, J 8.3, 6.1, C(7)H_B); d_C

(100 MHz, CDCl₃) 25.3, 26.6, 27.1, 27.2 (4ꢂ MeCMe), 28.1 (CMe₃),

41.9 (C(2)), 49.2 (C(3)), 67.8 (C(7)), 77.3 (C(6)), 78.0 (C(5)), 80.5

(CMe₃), 83.2 (C(4)), 109.2, 109.6 (2ꢂ MeCMe), 171.5 (C(1)); m/z

C(

C(2)H_A), 2.67 (1H, dd, J 15.4, 8.3, C(2)H_B), 7.22e7.58 (10H, m, Ph); d_C

(100 MHz, CDCl₃) [selected peaks] 17.5 (C( )Me), 25.5, 26.7, 27.0.

27.1 (4ꢂ MeCMe), 28.2 (CMe₃), 34.8 (C(2)), 50.9 (NCH₂Ph), 54.2

(C(3)), 57.1 (C( )), 67.2 (C(7)), 77.5 (C(6)), 79.0 (C(4)), 80.2 (CMe₃),

a)Me), 1.52 (3H, s, MeCMe), 1.56 (9H, s, CMe₃), 2.41e2.50 (1H, m,

a

81.7 (C(5)), 109.2, 109.6 (2ꢂ MeCMe), 126.6, 126.9 (p-Ph), 127.9,

128.4, 128.7 (o,m-Ph), 141.5, 143.2 (i-Ph), 172.2 (C(1)).

4.13. tert-Butyl (3R,4R,5S,6R)-3-amino-4,5,6,7-tetrahydroxy-

4,5,6,7-di-O-isopropylideneheptanoate 32

þ

(ESI^þ) 346 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₇H₃₂NO₆([MþH]^þ)

requires 346.2224; found 346.2224.

Method A (from 28): Following general procedure 2, a solution of

28 (200 mg, 0.371 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 100 mg) and H₂(1 atm),

4.16. tert-Butyl (3S,4R,5S,6R)-3-N-isopropylamino-4,5,6,7-

tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate 35

which gave 32 as a pale yellow oil (130 mg, quant, >99:1 dr); ½a _D²⁵

ꢃ

þ18.3 (c 1.0 in CHCl₃); n_max(ﬁlm) 3326 (NeH), 2985, 2935, 2884

(CeH), 1728 (C]O); d_H(400 MHz, CDCl₃) 1.28 (6H, app s, 2ꢂ

MeCMe), 1.31 (3H, s, MeCMe), 1.36 (3H, s, MeCMe), 1.40 (9H, s,

CMe₃), 1.70 (2H, br s, NH₂), 2.21 (1H, dd, J 16.2, 9.5, C(2)H_A), 2.57

(1H, dd, J 16.2, 3.3, C(2)H_B), 3.26 (1H, ddd, J 9.5, 6.3, 3.3, C(3)H),

3.69e3.74 (1H, m, C(5)H), 3.75e3.80 (1H, m, C(4)H), 3.90 (1H, dd, J

8.2, 5.6, C(7)H_A), 3.98e4.02 (1H, m, C(6)H), 4.09 (1H, dd, J 8.2, 6.1,

C(7)H_B); d_C(100 MHz, CDCl₃) 25.2, 26.5, 27.0, 27.1 (4ꢂ MeCMe), 28.1

(CMe₃), 39.7 (C(2)), 50.6 (C(3)), 67.8 (C(7)), 77.0 (C(6)), 80.1 (C(5)),

80.4 (CMe₃), 83.8 (C(4)), 109.1, 109.7 (2ꢂ MeCMe), 171.8 (C(1)); m/z

Following general procedure 3,

0.27 mmol, 85:15 dr) in MeOH (3 mL) was reacted with acetone

(40 L, 0.54 mmol) and NaBH₃CN (68 mg, 1.1 mmol), which gave 35

a solution of 34 (94 mg,

m

as a colourless oil (76 mg, 72%, 85:15 dr); n_max(ﬁlm) 3341 (NeH),

2983, 2935, 2878 (CeH), 1729 (C]O); d_H(400 MHz, CDCl₃) 0.96

(3H, d, J 5.8, MeCHMe), 1.02 (3H, d, J 6.1, MeCHMe), 1.31 (3H, s,

MeCMe), 1.32 (3H, s, MeCMe), 1.37 (3H, s, MeCMe), 1.38 (3H, s,

MeCMe), 1.43 (9H, s, CMe₃), 2.39 (1H, dd, J 14.5, 6.3, C(2)H_A), 2.44

(1H, dd, J 14.5, 6.0, C(2)H_B), 2.86e2.97 (1H, m, MeCHMe), 3.23e3.28

(1H, m, C(3)H), 3.88e3.93 (1H, m, C(7)H_A), 3.96e4.01 (3H, m, C(4)H,

C(5)H, C(6)H), 4.09e4.15 (1H, m, C(7)H_B); d_C(100 MHz, CDCl₃) 22.4,

24.0 (2ꢂ MeCHMe), 25.3, 26.6, 27.0, 27.1 (4ꢂ MeCMe), 28.6 (CMe₃),

40.0 (C(2)), 45.1 (MeCHMe), 51.6 (C(3)), 67.9 (C(7)), 77.4, 77.7, 82.5

(C(4), C(5), C(6)), 80.3 (CMe₃), 109.0, 109.6 (2ꢂ MeCMe), 171.6

(ESI^þ) 346 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₇H₃₂NO₆([MþH]^þ)

þ

requires 346.2224; found 346.2225.

Method B (from 26): Following general procedure 2, a solution of

26 (194 mg, 0.369 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 97 mg) and H₂(1 atm),

which gave 32 as a pale yellow oil (108 mg, 85%, >99:1 dr).

(C(1)); m/z (ESI^þ) 388 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₀H₃₈NO₆

þ

([MþH]^þ) requires 388.2694; found 388.2694.

4.14. tert-Butyl (3R,4R,5S,6R)-3-N-isopropylamino-4,5,6,7-

tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate 33

4.17. tert-Butyl (3R,4S,5R,6R)- and (3S,4S,5R,6R)-3-(N-iso-

propyl-N-benzylamino)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 36 and 37

Method A (from 32): Following general procedure 3, a solution of

32 (82 mg, 0.24 mmol, >99:1 dr) in MeOH (3 mL) was reacted with

Following general procedure 1, a solution of N-isopropyl-N-

acetone (35

mL, 0.47 mmol) and NaBH₃CN (60 mg, 0.95 mmol),

benzylamine (1.36 g, 9.14 mmol) in THF (60 mL) was reacted with

8696

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

BuLi (2.5 M, 3.54 mL, 8.86 mmol) and a solution of 21 (1.50 g,

4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave a 28:72

mixture of 36 and 37, respectively. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 10:1) gave 36 as

a white solid (412 mg, 19%, >99:1 dr); C₂₇H₄₃NO₆requires C, 67.9;

(866 mg, 36%, 96:4 dr); C₃₁H₄₃NO₆requires C, 70.8; H, 8.2; N, 2.7;

found C, 70.9; H, 8.15; N, 2.8%; ½a _D²⁵

ꢀ31.8 (c 1.0 in CHCl₃); n_max(ﬁlm)

ꢃ

3029, 2984, 2934, 2892 (CeH), 1728 (C]O); d_H(400 MHz, CDCl₃)

1.32 (3H, s, MeCMe),1.40 (6H, app s, 2ꢂ MeCMe),1.44 (3H, s, MeCMe),

1.48 (9H, s, CMe₃), 2.48 (1H, dd, J 15.4, 6.1, C(2)H_A), 2.69 (1H, dd, J 15.4,

6.1, C(2)H_B), 3.27 (1H, app td, J 6.1, 4.4, C(3)H), 3.30 (1H, dd, J 8.4, 3.3,

C(5)H), 3.55 (2H, d, J 13.5, N(CH_AH_BPh)₂), 3.61e3.74 (2H, m, C(7)H₂),

3.69 (2H, d, J 13.5, N(CH_AH_BPh)₂), 4.06 (1H, ddd, J 9.9, 6.8, 3.3, C(6)H),

4.31 (1H, dd, J 8.4, 4.4, C(4)H), 7.22e7.36 (10H, m, Ph); d_C(100 MHz,

CDCl₃) 26.2, 26.2, 26.9, 27.2 (4ꢂ MeCMe), 28.2 (CMe₃), 32.5 (C(2)),

54.6 (N(CH₂Ph)₂), 56.2 (C(3)), 65.7 (C(7)), 75.2 (C(6)), 76.9 (C(4)), 79.0

(C(5)), 80.3 (CMe₃), 109.3, 109.4 (2ꢂ MeCMe), 127.2 (p-Ph), 128.2,

128.3,129.3,129.5 (o,m-Ph),139.5 (i-Ph),172.2 (C(1)); m/z (ESI^þ) 526

H, 9.1; N, 2.9%; found C, 68.0; H, 9.1; N, 3.0%; mp 70e76 ^ꢁC; ½a _D²⁵

ꢃ

ꢀ10.4 (c 1.0 in CHCl₃); n_max(KBr) 2982, 2936 (CeH), 1727 (C]O); d_H

(400 MHz, CDCl₃) 1.02 (3H, d, J 6.8, MeCHMe), 1.11 (3H, d, J 6.5,

MeCHMe), 1.27 (3H, s, MeCMe), 1.30 (3H, s, MeCMe), 1.33 (3H, s,

MeCMe), 1.34 (3H, s, MeCMe), 1.47 (9H, s, CMe₃), 2.68 (1H, dd,

J 14.7, 9.2, C(2)H_A), 2.76 (1H, dd, J 14.7, 4.8, C(2)H_B), 3.08e3.15

(1H, m, C(3)H), 3.27e3.39 (2H, m, C(6)H, MeCHMe), 3.46 (1H, d, J

13.7, NCH_AH_BPh), 3.51e3.58 (1H, m, C(7)H_A), 3.71e3.77 (1H, m, C(7)

H_B), 3.92e4.00 (2H, m, C(4)H, NCH_AH_BPh), 4.03 (1H, dd, J 8.2, 3.1,

C(5)H), 7.19e7.38 (5H, m, Ph); d_C(100 MHz, CDCl₃) 17.6, 23.2 (2ꢂ

MeCHMe), 25.9, 26.1, 26.2, 27.2 (4ꢂ MeCMe), 28.0 (CMe₃), 35.9

(C(2)), 48.7 (MeCHMe), 50.9 (NCH₂Ph), 51.6 (C(3)), 65.8 (C(7)), 74.6

(C(6)), 76.1 (C(4)), 80.1 (C(5)), 80.7 (CMe₃),108.5,109.1 (2ꢂ MeCMe),

126.7 (p-Ph), 128.1, 129.2 (o,m-Ph), 141.1 (i-Ph), 172.0_þ(C(1)); m/z

(ESI^þ) 478 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₇H₄₄NO₆([MþH]^þ)

requires 478.3163; found 478.3158. Further elution gave 37 as

a white solid (1.24 g, 57%, >99:1 dr); C₂₇H₄₃NO₆requires C, 67.9; H,

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₃₁H₄₄NO₆([MþH]^þ) requires

526.3163; found 526.3165.

4.19. tert-Butyl (3R,4S,5R,6R,aR)- and (3S,4S,5R,6R,aR)-3-[N-

benzyl-N-( -methylbenzyl)amino]-4,5,6,7-tetrahydroxy-

a

4,5,6,7-di-O-isopropylideneheptanoate 40 and 41

Following general procedure 1, a solution of (R)-N-benzyl-N-(a-

methylbenzyl)amine (1.93 g, 9.14 mmol) in THF (60 mL) was reacted

with BuLi (2.5 M, 3.54 mL, 8.86 mmol) and a solution of 21 (1.50 g,

4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave a 35:65

mixture of 40 and 41, respectively. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 10:1) gave 40 as

a white solid (815 mg, 33%, >99:1 dr); C₃₂H₄₅NO₆requires C, 71.2; H,

9.1; N, 2.9%; found C, 68.0; H, 9.2; N, 2.9%; mp 94e100 ^ꢁC; ½a _D²⁵

ꢃ

ꢀ28.5 (c 1.0 in CHCl₃); n_max(KBr) 2982, 2935 (CeH), 1729 (C]O); d_H

(400 MHz, CDCl₃) 1.05 (3H, d, J 6.1, MeCHMe), 1.07 (3H, d, J 6.1,

MeCHMe), 1.34 (3H, s, MeCMe), 1.38 (3H, s, MeCMe), 1.41 (6H, app s,

2ꢂ MeCMe),1.48 (9H, s, CMe₃), 2.44 (1H, dd, J 15.4, 5.8, C(2)H_A), 2.61

(1H, dd, J 15.4, 6.1, C(2)H_B), 3.05 (1H, app septet, J 6.7, MeCHMe),

3.40 (1H, app q, J 5.6, C(3)H), 3.44 (1H, dd, J 8.1, 2.5, C(5)H), 3.67 (1H,

d, J 14.2, NCH_AH_BPh), 3.71 (1H, d, J 14.2, NCH_AH_BPh), 3.78e3.83 (1H,

m, C(7)H_A), 3.88e3.93 (1H, m, C(7)H_B), 4.15e4.23 (2H, m, C(4)H,

C(6)H), 7.20e7.37 (5H, m, Ph); d_C(100 MHz, CDCl₃) 19.3, 21.1 (2ꢂ

MeCHMe), 26.0, 26.1, 26.8, 27.3 (4ꢂ MeCMe), 28.2 (CMe₃), 35.2

(C(2)), 47.9 (MeCHMe), 50.1 (NCH₂Ph), 55.2 (C(3)), 65.9 (C(7)), 75.4

(C(6)), 78.4 (C(4)), 79.3 (C(5)), 80.2 (CMe₃), 109.1, 109.3 (2ꢂ

MeCMe), 126.8 (p-Ph), 128.0, 129.0 (o,m-Ph), 140.8 (i-Ph), 172.4

8.4; N, 2.6%; found C, 71.2; H, 8.45; N, 2.6%; mp 94e98 ^ꢁC; ½a _D²⁵

þ41.3

ꢃ

(c 1.0 in CHCl₃); n_max(KBr) 2983, 2935 (CeH), 1725 (C]O); d_H

(400 MHz, CDCl₃) 1.20 (3H, s, MeCMe), 1.28 (6H, app s, 2ꢂ MeCMe),

1.37 (3H, s, MeCMe), 1.40 (3H, d, J 7.1, C(a)Me), 1.49 (9H, s, CMe₃),

2.58e2.65 (1H, m, C(6)H), 2.76e2.90 (2H, m, C(2)H₂), 3.15e3.20 (1H,

m, C(3)H), 3.23e3.28 (1H, m, C(7)H_A), 3.40e3.45 (1H, m, C(7)H_B),

3.65 (1H, d, J 13.3, NCH_AH_BPh), 3.67 (1H, dd, J 8.6, 2.4, C(5)H), 3.90

(1H, dd, J 8.6, 2.0, C(4)H), 3.91e3.97 (1H, m, C(a)H), 4.39 (1H, d, J 13.3,

NCH_AH_BPh), 7.20e7.42 (8H, m, Ph), 7.47e7.52 (2H, m, Ph); d_C

(100 MHz, CDCl₃) 25.8, 25.9, 26.4, 27.2 (4ꢂ MeCMe), 28.0 (CMe₃), 31.0

þ

(C(1)); m/z (ESI^þ) 478 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₇H₄₄NO₆

([MþH]^þ) requires 478.3163; found 478.3158.

(C(a)Me), 37.0 (C(2)), 49.5 (C(3)), 53.0 (NCH₂Ph), 56.0 (C(a)), 65.8

(C(7)), 73.5 (C(6)), 75.5 (C(5)), 80.0 (C(4)), 80.8 (CMe₃), 108.8, 108.8

(2ꢂ MeCMe), 127.0, 127.1 (p-Ph), 128.0, 128.3, 128.7, 129.2 (o,m-Ph),

141.0,141.1 (i-Ph),171.8 (C(1)); m/z (ESI^þ) 540 ([MþH]^þ,100%); HRMS

4.18. tert-Butyl (3R,4S,5R,6R)- and (3S,4S,5R,6R)-3-(N,N-di-

benzylamino)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 38 and 39

þ

(ESI^þ) C₃₂H₄₆NO₆([MþH]^þ) requires 540.3320; found 540.3315.

Further elution gave 41 as a pale yellow oil (1.29 g, 52%, 96:4 dr);

Following general procedure 1, a solution of N,N-dibenzylamine

(1.62 g, 8.22 mmol) in THF (60 mL) was reacted with BuLi (2.1 M,

3.80 mL, 7.98 mmol) and a solution of 21 (1.35 g, 4.11 mmol, >99:1

dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave a 44:56 mixture of 38 and

39, respectively. Puriﬁcation via ﬂash column chromatography (el-

uent 30e40 ^ꢁC petrol/Et₂O, 6:1) gave 38 as a colourless oil (616 mg,

26%, >99:1 dr); C₃₁H₄₃NO₆requires C, 70.8; H, 8.2; N, 2.7%; found C,

C₃₂H₄₅NO₆requires C, 71.2; H, 8.4; N, 2.6%; found C, 71.2; H, 8.3; N,

2.55%; ½a ²_D⁵

ꢀ26.2 (c 1.0 in CHCl₃); n_max(ﬁlm) 2983, 2934 (CeH),1729

ꢃ

(C]O); d_H(400 MHz, CDCl₃) 1.37 (3H, s, MeCMe), 1.37 (3H, d, J 6.8,

C(a)Me), 1.39 (3H, s, MeCMe), 1.42 (12H, app s, MeCMe, CMe₃), 1.45

(3H, s, MeCMe), 2.14 (1H, dd, J 15.9, 4.3, C(2)H_A), 2.35 (1H, dd, J 15.9,

7.1, C(2)H_B), 3.54e3.62 (2H, m, C(3)H, C(5)H), 3.58 (1H, d, J 14.3,

NCH_AH_BPh), 3.77e3.83 (1H, m, C(7)H_A), 3.84e3.90 (1H, m, C(7)H_B),

70.8; H, 8.3; N, 2.7%; ½a _D²⁵

ꢃ

þ21.0 (c 1.0 in CHCl₃); n_max(ﬁlm) 3064,

3.88 (1H, d, J 14.3, NCH_AH_BPh), 3.95 (1H, q, J 6.8, C(

(1H, m, C(6)H), 4.30 (1H, dd, J 8.4, 4.6, C(4)H), 7.22e7.42 (10H, m, Ph);

d_C(100 MHz, CDCl₃) 19.4 (C(

)Me), 26.1, 26.2, 26.7, 27.2 (4ꢂ MeCMe),

28.1 (CMe₃), 33.6 (C(2)), 51.3 (NCH₂Ph), 54.8 (C(3)), 57.3 (C( )), 65.8

a)H), 4.17e4.23

3029, 2984, 2935 (CeH),1721 (C]O); d_H(400 MHz, CDCl₃) 1.25 (3H,

s, MeCMe), 1.30 (3H, s, MeCMe), 1.32 (3H, s, MeCMe), 1.36 (3H, s,

MeCMe).1.49 (9H, s, CMe₃), 2.66 (1H, dd, J 14.2, 9.9, C(2)H_A), 2.87 (1H,

dd, J 14.2, 4.1, C(2)H_B), 2.98e3.04 (1H, m, C(6)H), 3.04 (1H, ddd, J 9.9,

4.1, 2.1, C(3)H), 3.13e3.19 (1H, m, C(7)H_A), 3.28 (2H, d, J 13.0,

N(CH_AH_BPh)₂), 3.54 (1H, dd, J 7.9, 6.5, C(7)H_B), 3.92 (1H, dd, J 8.2, 2.1,

C(4)H), 4.08 (2H, app br s, N(CH_AH_BPh)₂), 4.09 (1H, dd, J 8.2, 4.1, C(5)

H), 7.23e7.39 (10H, m, Ph); d_C(100 MHz, CDCl₃) 26.0, 26.1, 26.3, 27.2

(4ꢂ MeCMe), 28.1 (CMe₃), 32.5 (C(2)), 52.3 (C(3)), 55.9 (N(CH₂Ph)₂),

65.5 (C(7)), 75.0 (C(6)), 76.2 (C(5)), 79.8 (C(4)), 80.7 (CMe₃), 108.9,

109.0 (2ꢂ MeCMe), 127.1 (p-Ph), 128.3, 129.5 (o,m-Ph), 139.9 (i-Ph),

171.9 (C(1)); m/z (ESI^þ) 526 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₃₁H₄₄NO₆^þ([MþH]^þ) requires 526.3163; found 526.3161. Further

elution gave a 43:57 mixture of 38 and 39, respectively, as a pale

yellow oil (286 mg, 12%). Further elution gave 39 as a colourless oil

a

(C(7)), 75.3 (C(6)), 78.7 (C(4)), 79.2 (C(5)), 80.1 (CMe₃), 109.2, 109.4

(2ꢂ MeCMe), 126.8, 127.0 (p-Ph), 128.0, 128.1, 128.2, 128.7 (o,m-Ph),

140.8, 143.1 (i-Ph), 171.9 (C(1)); m/z (ESI^þ) 540 ([MþH]^þ, 100%);

HRMS (ESI^þ) C₃₂H₄₆NO₆([MþH]^þ) requires 540.3320; found

þ

540.3309.

4.20. tert-Butyl (3R,4S,5R,6R,aS)-3-[N-benzyl-N-(a-methyl-

benzyl)amino]-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 42

Following general procedure 1, a solution of (S)-N-benzyl-N-

(a-methylbenzyl)amine (1.93 g, 9.14 mmol) in THF (60 mL) was

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8697

reacted with BuLi (2.1 M, 4.18 mL, 8.86 mmol) and a solution of 21

(1.50 g, 4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave

a 90:10 mixture of 42 and 43, respectively. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 10:1) gave

42 as a pale yellow oil (1.01 g, 41%, >99:1 dr); C₃₂H₄₅NO₆requires C,

65.8 (C(7)), 76.0, 76.8 (C(5), C(6)), 79.1 (C(4)), 80.5 (CMe₃), 109.2,

109.4 (2ꢂ MeCMe), 171.6 (C(1)); m/z (ESI^þ) 388 ([MþH]^þ, 100%);

þ

HRMS (ESI^þ) C₂₀H₃₈NO₆([MþH]^þ) requires 388.2694; found

388.2691.

Method B (from 36): Following general procedure 2, a solution of

36 (188 mg, 0.394 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 94 mg) and H₂(1 atm),

which gave 45 as a pale yellow oil (156 mg, quant, >99:1 dr).

71.2; H, 8.4; N, 2.6%; found C, 71.05; H, 8.4; N, 2.5%; ½a _D²⁵

þ4.7 (c 1.0

ꢃ

in CHCl₃); n_max(ﬁlm) 2983, 2935 (CeH), 1725 (C]O); d_H(400 MHz,

CDCl₃) 1.27 (3H, s, MeCMe), 1.29 (3H, d, J 7.1, C(a)Me), 1.33 (3H, s,

MeCMe), 1.37 (3H, s, MeCMe), 1.43 (3H, s, MeCMe), 1.44 (9H,

s, CMe₃), 1.92 (1H, dd, J 15.2, 2.3, C(2)H_A), 2.49 (1H, dd, J 15.2, 10.6,

C(2)H_B), 3.34e3.39 (1H, m, C(3)H), 3.52 (1H, d, J 14.7, NCH_AH_BPh),

4.23. tert-Butyl (3S,4S,5R,6R)-3-amino-4,5,6,7-tetrahydroxy-

4,5,6,7-di-O-isopropylideneheptanoate 46

3.72e3.88 (3H, m, C(a)H, C(6)H, C(7)H_A), 3.96e4.01 (1H, m, C(7)H_B),

4.03 (1H, dd, J 8.1, 1.8, C(4)H), 4.39e4.44 (1H, m, C(5)H), 4.40 (1H, d,

J 14.7, NCH_AH_BPh), 7.25e7.40 (8H, m, Ph), 7.48e7.54 (2H, m, Ph); d_C

Method A (from 39): Following general procedure 2, a solution of

39 (200 mg, 0.380 mmol, 96:4 dr) in EtOAc (5 mL) was reacted with

Pd(OH)₂/C (50% w/w of substrate, 100 mg) and H₂(1 atm), which

(100 MHz, CDCl₃) 20.7 (C(

28.0 (CMe₃), 34.2 (C(2)), 51.3 (C(3)), 53.2 (NCH₂Ph), 58.7 (C(6)), 65.8

(C(7)), 75.6 (C( )), 76.4 (C(5)), 79.9 (C(4)), 80.5 (CMe₃), 108.9, 109.3

a

)Me), 26.0, 26.1, 26.3, 27.0 (4ꢂ MeCMe),

gave 46 as a yellow oil (101 mg, 77%, 96:4 dr); ½a _D²⁵

ꢀ18.4 (c 1.0 in

ꢃ

a

CHCl₃); n_max(ﬁlm) 3322 (NeH), 2984, 2935 (CeH), 1726 (C]O); d_H

(400 MHz, CDCl₃) 1.35 (3H, s, MeCMe), 1.37 (3H, s, MeCMe), 1.38

(3H, s, MeCMe), 1.40 (3H, s, MeCMe), 1.43 (9H, s, CMe₃), 1.60 (2H,

br s, NH₂), 2.20 (1H, dd, J 16.2, 9.6, C(2)H_A), 2.62 (1H, dd, J 16.2, 3.0,

C(2)H_B), 3.18e3.26 (1H, m, C(3)H), 3.81e3.93 (2H, m, C(4)H, C(7)

H_A), 3.95 (1H, dd, J 7.1, 3.8, C(5)H), 3.99e4.04 (1H, m, C(7)H_B), 4.21

(1H, app td, J 7.1, 3.8, C(6)H); d_C(100 MHz, CDCl₃) 25.6, 26.2, 27.1,

27.4 (4ꢂ MeCMe), 28.1 (CMe₃), 40.5 (C(2)), 51.0 (C(3)), 66.0 (C(7)),

75.9 (C(6)), 78.7 (C(5)), 80.2 (C(4)), 80.8 (CMe₃), 109.4, 109.5 (2ꢂ

MeCMe), 171.6 (C(1)); m/z (ESI^þ) 346 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₁₇H₃₂NO₆^þ([MþH]^þ) requires 346.2224; found 346.2219.

Method B (from 41): Following general procedure 2, a solution of

41 (206 mg, 0.382 mmol, 96:4 dr) in EtOAc (5 mL) was reacted with

Pd(OH)₂/C (50% w/w of substrate, 103 mg) and H₂(1 atm), which

gave 46 as a yellow oil (124 mg, 94%, 96:4 dr).

(2ꢂ MeCMe), 126.5, 127.3 (p-Ph), 128.1, 128.2, 128.3, 128.4 (o,m-Ph),

141.8, 141.9 (i-Ph), 171.6 (C(1)); m/z (ESI^þ) 540 ([MþH]^þ, 100%);

þ

HRMS (ESI^þ) C₃₂H₄₆NO₆([MþH]^þ) requires 540.3320; found

540.3309.

4.21. tert-Butyl (3R,4S,5R,6R)-3-amino-4,5,6,7-tetrahydroxy-

4,5,6,7-di-O-isopropylideneheptanoate 44

Method A (from 40): Following general procedure 2, a solution of

40 (208 mg, 0.385 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 104 mg) and H₂(1 atm),

which gave 44 as a yellow oil (102 mg, 77%, >99:1 dr); ½a _D²⁵

ꢀ10.0

ꢃ

(c 1.0 in CHCl₃); n_max(ﬁlm) 3328 (NeH), 2985, 2935 (CeH), 1726

(C]O); d_H(400 MHz, CDCl₃) 1.35 (3H, s, MeCMe), 1.38 (3H, s,

MeCMe), 1.40 (6H, app s, 2ꢂ MeCMe), 1.43 (9H, s, CMe₃), 1.72 (2H,

br s, NH₂), 2.36 (1H, dd, J 15.9, 9.4, C(2)H_A), 2.47 (1H, dd, J 15.9, 4.3,

C(2)H_B), 3.11e3.18 (1H, m, C(3)H), 3.82e3.87 (1H, m, C(7)H_A), 3.88

(1H, dd, J 7.7, 2.8, C(4)H), 4.00e4.05 (1H, m, C(7)H_B), 4.08 (1H, dd, J

7.7, 3.8, C(5)H), 4.10e4.16 (1H, m, C(6)H); d_C(100 MHz, CDCl₃) 25.6,

26.2, 27.1, 27.2 (4ꢂ MeCMe), 28.1 (CMe₃), 42.2 (C(2)), 48.6 (C(3)),

65.8 (C(7)), 75.1 (C(6)), 76.8 (C(5)), 79.8 (C(4)), 80.8 (CMe₃), 109.4,

109.6 (2ꢂ MeCMe), 171.4 (C(1)); m/z (ESI^þ) 346 ([MþH]^þ, 100%);

4.24. tert-Butyl (3S,4S,5R,6R)-3-N-isopropylamino-4,5,6,7-

tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate 47

Method A (from 37): Following general procedure 2, a solution of

37 (188 mg, 0.394 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 94 mg) and H₂(1 atm),

which gave 47 as a pale yellow oil (157 mg, quant, >99:1 dr); ½a _D²⁵

ꢃ

þ

HRMS (ESI^þ) C₁₇H₃₂NO₆([MþH]^þ) requires 346.2224; found

ꢀ3.1 (c 1.0 in CHCl₃); n_max(ﬁlm) 3328 (NeH), 2985, 2935 (CeH),

1726 (C]O); d_H(400 MHz, CDCl₃) 0.91 (3H, d, J 6.1, MeCHMe), 0.95

(3H, d, J 6.3, MeCHMe), 1.29 (3H, s, MeCMe), 1.31 (3H, s, MeCMe),

1.33 (3H, s, MeCMe), 1.34 (3H, s, MeCMe), 1.37 (9H, s, CMe₃), 2.31

(1H, dd, J 15.4, 5.6, C(2)H_A), 2.47 (1H, dd, J 15.4, 4.8, C(2)H_B), 2.83

(1H, app septet, J 6.2, MeCHMe), 2.96 (1H, app q, J 5.6, C(3)H),

3.76e3.83 (2H, m, C(4)H, C(5)H), 3.84e3.94 (2H, m, C(7)H₂),

4.13e4.19 (1H, m, C(6)H); d_C(100 MHz, CDCl₃) 22.6, 23.9 (2ꢂ

MeCHMe), 25.7, 26.2, 27.1, 27.3 (4ꢂ MeCMe), 28.0 (CMe₃), 37.2

(C(2)), 45.4 (MeCHMe), 54.7 (C(3)), 66.0 (C(7)), 76.5 (C(6)), 79.2,

80.0 (C(4), C(5)), 80.4 (CMe₃), 109.3, 109.4 (2ꢂ MeCMe), 171.6 (C(1));

346.2215.

Method B (from 42): Following general procedure 2, a solution of

42 (205 mg, 0.380 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 103 mg) and H₂(1 atm),

which gave 44 as a yellow oil (109 mg, 83%, >99:1 dr).

Method C (from 38): Following general procedure 2, a solution of

38 (150 mg, 0.285 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 75 mg) and H₂(1 atm),

which gave 44 as a yellow oil (72 mg, 73%, >99:1 dr).

þ

4.22. tert-Butyl (3R,4S,5R,6R)-3-N-isopropylamino-4,5,6,7-

tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate 45

m/z (ESI^þ) 388 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₀H₃₈NO₆

([MþH]^þ) requires 388.2694; found 388.2688.

Method B (from 46): Following general procedure 3, a solution of

46 (97 mg, 0.28 mmol, 96:4 dr) in MeOH (3 mL) was reacted with

Method A (from 44): Following general procedure 3, a solution of

44 (82 mg, 0.24 mmol, >99:1 dr) in MeOH (3 mL) was reacted with

acetone (41 mL, 0.56 mmol) and NaBH₃CN (71 mg, 1.1 mmol), which

acetone (35

m

L, 0.47 mmol) and NaBH₃CN (60 mg, 0.95 mmol),

gave 47 as a pale yellow oil (53 mg, 49%, 96:4 dr).

which gave 45 as a pale yellow oil (71 mg, 78%, >99:1 dr); ½a _D²⁵

ꢃ

ꢀ32.6 (c 1.0 in CHCl₃); n_max(ﬁlm) 3344 (NeH), 2983, 2935 (CeH),

1726 (C]O); d_H(400 MHz, CDCl₃) 0.94 (3H, d, J 6.1, MeCHMe), 1.01

(3H, d, J 6.3, MeCHMe), 1.34 (3H, s, MeCMe), 1.37 (3H, s, MeCMe),

1.39 (6H, app s, 2ꢂ MeCMe), 1.42 (9H, s, CMe₃), 2.36e2.46 (2H, m,

C(2)H₂), 2.87 (1H, app septet, J 6.1, MeCHMe), 3.05 (1H, app td,

J 6.3, 2.3, C(3)H), 3.78e3.84 (1H, m, C(7)H_A), 3.98 (1H, dd, J 7.6, 2.3,

C(4)H), 4.00e4.05 (1H, m, C(7)H_B), 4.07e4.14 (2H, m, C(5)H, C(6)H);

d_C(100 MHz, CDCl₃) 22.5, 23.9 (2ꢂ MeCHMe), 25.7, 26.2, 27.0, 27.2

(4ꢂ MeCMe), 28.0 (CMe₃), 38.4 (C(2)), 45.2 (MeCHMe), 51.2 (C(3)),

4.25. tert-Butyl (3S,4S,5S,6R)-3-(N-isopropyl-N-benzylamino)-

4,5,6,7-tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate

49

Method A: Following general procedure 1, a solution of N-iso-

propyl-N-benzylamine (1.36 g, 9.14 mmol) in THF (60 mL) was

reacted with BuLi (2.5 M, 3.54 mL, 8.86 mmol) and a solution of 22

(1.50 g, 4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave

a 93:7 mixture of 49 and 50, respectively. Puriﬁcation via ﬂash

8698

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 10:1) gave

49 as a white solid (1.59 g, 73%, >99:1 dr); C₂₇H₄₃NO₆requires C,

67.9; H, 9.1; N, 2.9%; found C, 67.8; H, 9.15; N, 2.9%; mp 50e57 ^ꢁC;

Method B: Following general procedure 1, a solution of N,N-

dibenzylamine (120 mg, 0.608 mmol) in Et₂O (4 mL) was reacted

with BuLi (2.5 M, 0.24 mL, 0.59 mmol) and a solution of 22 (100 mg,

0.305 mmol, >99:1 dr) in Et₂O (4 mL) at ꢀ20 ^ꢁC, which gave a 38:62

mixture of 51 and 52, respectively.

½

a ²_D⁵

ꢃ

ꢀ43.2 (c 1.0 in CHCl₃); n_max(ﬁlm) 1729 (C]O); d_H(400 MHz,

CDCl₃) 1.02 (6H, d, J 6.8, 2ꢂ MeCHMe),1.31 (3H, s, MeCMe),1.38 (3H,

s, MeCMe), 1.39 (3H, s, MeCMe), 1.44 (3H, s, MeCMe), 1.50 (9H,

s, CMe₃), 2.21 (1H, dd, J 14.7, 3.4, C(2)H_A), 2.59 (1H, dd, J 14.7, 9.6,

C(2)H_B), 2.89 (1H, septet, J 6.8, MeCHMe), 3.63 (1H, d, J 14.9,

NCH_AH_BPh), 3.88 (1H, dd, J 8.5, 5.5, C(7)H_A), 3.96e4.00 (1H, m, C(3)

H), 4.00 (1H, d, J 14.9, NCH_AH_BPh), 4.06 (1H, dd, J 8.5, 6.1, C(7)H_B),

4.13 (1H, dd, J 8.7, 7.0, C(5)H), 4.28 (1H, app dt, J 8.7, 5.8, C(6)H), 4.41

(1H, dd, J 7.0, 2.2, C(4)H), 7.19e7.32 (3H, m, Ph), 7.39e7.43 (2H, m,

Ph); d_C(100 MHz, CDCl₃) 17.5, 21.8 (MeCHMe), 24.7, 25.5, 26.3, 26.8

(4 ꢂ MeCMe), 28.2 (CMe₃), 37.8 (C(2)), 49.4, 49.6 (NCH₂Ph,

MeCHMe), 52.8 (C(3)), 68.1 (C(7)), 73.4 (C(6)), 78.5, 78.6 (C(4), C(5)),

79.8 (CMe₃), 108.5, 109.5 (2ꢂ MeCMe), 126.4, 127.9, 128.5 (o,m,p-

Ph), 141.9 (i-Ph), 172.2 (C(1)); m/z (ESI^þ) 478 ([MþH]^þ, 100%); HRMS

4.27. tert-Butyl (3S,4S,5S,6R,aR)-3-[N-benzyl-N-(a-methyl-

benzyl)amino]-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 54

Method A: Following general procedure 1, a solution of (R)-N-

benzyl-N-(a-methylbenzyl)amine (129 mg, 0.611 mmol) in THF

(5 mL) was reacted with BuLi (2.4 M, 0.25 mL, 0.59 mmol) and

a solution of 22 (100 mg, 0.305 mmol, >99:1 dr) in THF (5 mL) at

ꢀ78 ^ꢁC, which gave 54 in >99:1 dr. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 10:1) gave 54 as

a white solid (155 mg, 94%, >99:1 dr); mp 65e75 ^ꢁC; ½a _D²⁵

ꢀ18.8 (c

ꢃ

þ

(ESI^þ) C₂₇H₄₄NO₆([MþH]^þ) requires 478.3163; found 478.3158.

1.0 in CHCl₃); n_max(ﬁlm) 1733 (C]O); d_H(400 MHz, CDCl₃) 1.25 (3H,

s, MeCMe), 1.35 (3H, s, MeCMe), 1.36 (3H, s, MeCMe), 1.41 (3H, d, J

Further elution gave an impure sample of 50 as a pale yellow oil

(267 mg, >99:1 dr).

6.8, C(a)Me), 1.41 (9H, s, CMe₃), 1.48 (3H, s, MeCMe), 2.19 (1H, dd, J

Method B: Following general procedure 1, a solution of N-iso-

propyl-N-benzylamine (91 mg, 0.61 mmol) in Et₂O (4 mL) was

reacted with BuLi (2.5 M, 0.24 mL, 0.59 mmol) and a solution of 22

(100 mg, 0.31 mmol, >99:1 dr) in Et₂O (4 mL) at ꢀ20 ^ꢁC, which gave

an 80:20 mixture of 49 and 50, respectively (160 mg).

15.4, 4.4, C(2)H_A), 2.47 (1H, dd, J 15.4, 8.2, C(2)H_B), 3.69 (1H, d, J 15.0,

NCH_AH_BPh), 3.85 (1H, dd, J 8.5, 6.1, C(7)H_A), 3.88 (1H, d, J 15.0,

NCH_AH_BPh), 3.99e4.05 (2H, m, C(5)H, C(7)H_B), 4.06e4.10 (1H, m,

C(

C(6)H), 4.31 (1H, dd, J 6.5, 3.1, C(4)H), 7.19e7.37 (10H, m, Ph); d_C

(100 MHz, CDCl₃) 17.2 (C(

)Me), 24.6, 25.5, 26.5, 26.8 (4 ꢂ MeCMe),

28.1 (CMe₃), 37.1 (C(2)), 50.0 (NCH₂Ph), 54.9 (C(3)), 59.4 (C( )), 67.9

a)H), 4.11 (1H, app dd, J 8.5, 6.8, C(3)H), 4.22 (1H, app dt, J 8.4, 6.1,

a

4.26. tert-Butyl (3R,4S,5S,6R)- and (3S,4S,5S,6R)-3-(N,N-di-

benzylamino)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 51 and 52

a

(C(7)), 73.3 (C(6)), 77.8 (C(4)), 78.7 (C(5)), 79.7 (CMe₃), 108.1, 109.5

(2ꢂ MeCMe),126.4,126.7,127.8,128.0,128.3,128.4 (o,m,p-Ph),141.9,

143.7 (i-Ph), 171.5 (C(1)); m/z (ESIþ) 540 ([MþH]^þ, 100%); HRMS

(ESI^þ) C₃₂H₄₆NO₆^þ([MþH]^þ) requires 540.3320; found 540.3309.

Method B: Following general procedure 1, a solution of (R)-N-

Method A: Following general procedure 1, a solution of N,N-

dibenzylamine (1.80 g, 9.14 mmol) in THF (60 mL) was reacted with

BuLi (2.2 M, 4.03 mL, 8.86 mmol) and a solution of 22 (1.50 g,

4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave a 10:90

mixture of 51 and 52, respectively. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 10:1) gave 52 as

a pale yellow oil (1.33 g, 55%, >99:1 dr); C₃₁H₄₃NO₆requires C, 70.8;

benzyl-N-(a-methylbenzyl)amine (129 mg, 0.611 mmol) in Et₂O

(4 mL) was reacted with BuLi (2.5 M, 0.24 mL, 0.59 mmol) and

a solution of 22 (100 mg, 0.305 mmol, >99:1 dr) in Et₂O (4 mL) at

ꢀ20 ^ꢁC, which gave a 97:3 mixture of 54 and 50, respectively

(170 mg).

H, 8.2; N, 2.7%; found C, 70.8; H, 8.3; N, 2.6%; ½a _D²⁵

ꢀ5.8 (c 1.7 in

ꢃ

CHCl₃); n_max(ﬁlm) 1732 (C]O); d_H(400 MHz, CDCl₃) 1.21 (3H, s,

MeCMe), 1.30 (3H, s, MeCMe), 1.39 (3H, s, MeCMe), 1.41 (3H, s,

MeCMe), 1.45 (9H, s, CMe₃), 2.26 (1H, dd, J 14.7, 5.5, C(2)H_A), 2.67

(1H, dd, J 14.7, 7.2, C(2)H_B), 3.61 (2H, d, J 13.8, N(CH_AH_BPh)₂),

3.68e3.74 (2H, m, C(3)H, C(7)H_A), 3.69 (2H, d, J 13.8, N(CH_AH_BPh)₂),

3.79 (1H, dd, J 8.2, 5.8, C(7)H_B), 4.04 (1H, app q, J 6.4, C(6)H), 4.18

(1H, app t, J 7.0, C(5)H), 4.41 (1H, dd, J 6.5, 5.3, C(4)H), 7.22e7.36

(10H, m, Ph) d_C(100 MHz, CDCl₃) 24.8, 25.3, 26.5, 26.6 (4 ꢂ MeCMe),

28.1 (CMe₃), 35.3 (C(2)), 54.5 (N(CH₂Ph)₂), 55.2 (C(3)), 67.1 (C(7)),

73.5 (C(6)), 76.4 (C(4)), 78.9 (C(5)), 80.0 (CMe₃), 108.3, 109.1 (2ꢂ

MeCMe), 127.0, 128.1, 129.5 (o,m,p-Ph), 139.4 (i-Ph), 171.5 (C(1)); m/z

4.28. tert-Butyl (3S,4S,5S,6R,aS)-3-[N-benzyl-N-(a-methyl-

benzyl)amino]-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 56 and tert-butyl (R,R,Z)-4,5,6,7-

tetrahydroxy-4,5,6,7-di-O-isopropylidenehept-3-enoate 50

Method A: Following general procedure 1, a solution of (S)-N-

benzyl-N-(a-methylbenzyl)amine (1.93 g, 9.14 mmol) in THF

(60 mL) was reacted with BuLi (2.0 M, 4.41 mL, 8.86 mmol) and

a solution of 22 (1.50 g, 4.57 mmol, >99:1 dr) in THF (60 mL) at

ꢀ78 ^ꢁC, which gave a 24:76 mixture of 56 and 50, respectively.

Puriﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢁC

petrol/Et₂O,10:1) gave 56 as a pale yellow solid (361 mg,15%, >99:1

þ

(ESI^þ) 526 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₁H₄₄NO₆([MþH]^þ)

requires 526.3163; found 526.3172. Further elution gave a 31:69

mixture of 51 and 52, respectively, as a pale yellow oil (777 mg,

32%). Data for mixture: n_max(ﬁlm) 3028, 2984, 2935, 2881 (CeH),

1729 (C]O); m/z (ESI^þ) 526 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₃₁H₄₄NO₆^þ([MþH]^þ) requires 526.3163; found 526.3165. Data for

51: d_H(400 MHz, CDCl₃) 1.18 (3H, s, MeCMe), 1.34 (3H, s, MeCMe),

1.45 (3H, s, MeCMe), 1.47 (9H, s, CMe₃), 1.53 (3H, s, MeCMe), 2.33

(1H, dd, J 14.4, 10.1, C(2)H_A), 2.46 (1H, dd, J 14.4, 3.5, C(2)H_B),

3.72e3.80 (1H, m, C(3)H), 3.80e3.85 (1H, m, C(6)H), 3.86 (2H, d, J

13.1, N(CH_AH_BPh)₂), 3.89e3.95 (1H, m, C(5)H), 3.92 (2H, d, J 13.1,

N(CH_AH_BPh)₂), 4.02e4.14 (2H, m, C(7)H₂), 4.37 (1H, dd, J 10.2, 5.2,

C(4)H), 7.19e7.43 (10H, m, Ph); d_C(100 MHz, CDCl₃) 25.3, 25.5, 26.6,

26.7 (4ꢂ MeCMe), 28.2 (CMe₃), 37.4 (C(2)), 55.6 (C(3)), 54.9

(N(CH₂Ph)₂), 68.0 (C(7)), 73.1 (C(6)), 78.5 (C(5)), 79.6 (C(4)), 79.8

(CMe₃), 108.2, 109.2 (2ꢂ MeCMe), 126.7, 127.9, 129.6 (o,m,p-Ph),

140.3 (i-Ph), 170.5 (C(1)).

dr); mp 110e118 ^ꢁC; ½a _D²⁵

ꢀ27.1 (c 1.0 in CHCl₃); n_max(ﬁlm) 1730

ꢃ

(C]O); d_H(400 MHz, CDCl₃) 1.08 (3H, s, MeCMe), 1.31 (3H, s,

MeCMe), 1.41 (3H, d, J 7.2, C(a)Me), 1.46 (3H, s, MeCMe), 1.56 (9H, s,

CMe₃), 1.59 (3H, s, MeCMe), 2.23 (1H, dd, J 15.0, 3.5, C(2)H_A), 2.55

(1H, dd, J 15.0, 9.4, C(2)H_B), 3.50 (1H, d, J 15.3, NCH_AH_BPh), 3.63 (1H,

dd, J 6.8, 2.3, C(4)H), 3.77e3.83 (2H, m, C(5)H, C(a)H), 3.85 (1H, dd, J

8.5, 6.4, C(7)H_A) 4.08 (1H, d, J 15.3, NCH_AH_BPh), 4.12 (1H, dd, J 8.5,

6.1, C(7)H_B), 4.19e4.26 (1H, m, C(6)H), 4.31e4.37 (1H, m, C(3)H),

7.23e7.39 (8H, m, Ph), 7.47e7.52 (2H, m, Ph); d_C(100 MHz, CDCl₃)

19.4 (C(

a

)Me), 24.2, 25.5, 26.5, 26.7 (4 ꢂ MeCMe), 28.2 (CMe₃), 37.4

(C(2)), 49.8 (NCH₂Ph), 52.3 (C(3)), 57.6 (C(

a

)), 68.3 (C(7)), 73.2

(C(6)), 77.3 (CMe₃), 78.8 (C(4)), 79.8 (C(5)), 107.8, 109.6 (2ꢂ

MeCMe), 126.4, 126.9, 127.8, 128.0, 128.3, 128.4 (o,m,p-Ph), 141.5,

141.6 (i-Ph), 171.8 (C(1)); m/z (ESI^þ) 540 ([MþH]^þ, 100%); HRMS

þ

(ESI^þ) C₃₂H₄₆NO₆([MþH]^þ) requires 540.3320; found 540.3330.

Further elution gave 50 as a pale yellow oil (1.13 g, 75%, >99:1 dr);

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8699

C₁₇H₂₈O₆requires C, 62.2; H, 8.6%; found C, 62.3; H, 8.5%; ½a _D²⁵

ꢃ

(2ꢂ MeCMe), 171.7 (C(1)); m/z (ESI^þ) 388 ([MþH]^þ, 100%); HRMS

(ESI^þ) C₂₀H₃₈NO₆^þ([MþH]^þ) requires 388.2694; found 388.2700.

Method B (from 57): Following general procedure 3, a solution of

57 (116 mg, 0.336 mmol, >99:1 dr) in MeOH (3 mL) was reacted

þ35.5 (c 1.0 in CHCl₃); n_max(ﬁlm) 1733 (C]O, C]C); d_H(400 MHz,

CDCl₃) 1.37 (3H, s, MeCMe), 1.40 (3H, s, MeCMe), 1.45 (9H, s, CMe₃),

1.46 (3H, s, MeCMe), 1.50 (3H, s, MeCMe), 2.96e3.04 (1H, m, C(2)

H_A), 3.06e3.13 (1H, m, C(2)H_B), 3.93 (1H, dd, J 8.5, 5.8, C(7)H_A), 4.06

(1H, dd, J 8.5, 6.5, C(7)H_B), 4.13 (1H, app q, J 6.1, C(6)H), 4.58e4.65

(2H, m, C(3)H, C(5)H); d_C(100 MHz, CDCl₃) 25.4, 25.5, 26.4, 26.6 (4 ꢂ

MeCMe), 28.1 (CMe₃), 32.1 (C(2)), 65.9 (C(7)), 76.3 (C(5)), 77.2 (C(6)),

80.3 (CMe₃), 89.1 (C(3)), 109.8, 111.2 (2ꢂ MeCMe), 151.4 (C(4)), 171.5

(C(1)); m/z (ESI^þ) 273 ([MꢀC₄H₈]^þ, 100%); HRMS (ESI^þ)

C₁₇H₂₈NaO₆^þ([MþNa]^þ) requires 351.1778; found 351.1776.

Method B: Following general procedure 1, a solution of (S)-N-

with acetone (49 mL, 0.67 mmol) and NaBH₃CN (84 mg, 1.3 mmol),

which gave a 16:84 mixture of 57 and 58, respectively. Puriﬁcation

via ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/EtOAc,

4:1) gave 58 as a colourless oil (65 mg, 50%, >99:1 dr).

4.31. tert-Butyl (R,R,R,R)- and (3S,4R,5R,6R)-3-(N-isopropyl-N-

benzylamino)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 59 and 60

benzyl-N-(a-methylbenzyl)amine (129 mg, 0.611 mmol) in Et₂O

(4 mL) was reacted with BuLi (2.5 M, 0.24 mL, 0.59 mmol) and

a solution of 22 (100 mg, 0.305 mmol, >99:1 dr) in Et₂O (4 mL) at

ꢀ20 ^ꢁC, which gave a 70:30 mixture of 56 and 50, respectively

(150 mg).

Method A: Following general procedure 1, a solution of N-iso-

propyl-N-benzylamine (1.36 g, 9.14 mmol) in THF (60 mL) was

reacted with BuLi (2.5 M, 3.54 mL, 8.86 mmol) and a solution of 23

(1.50 g, 4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave

a 76:8:16 mixture of 59, 60 and 61, respectively. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 4:1)

gave an 83:17 mixture of 59 and 61, respectively, as a pale yellow oil

(1.50 g). Data for mixture: n_max(ﬁlm) 2981, 2936, 2886 (CeH), 1730

(C]O). Data for 59: d_H(400 MHz, CDCl₃) 1.05 (6H, d, J 6.6, 2ꢂ

MeCHMe), 1.32 (3H, s, MeCMe), 1.33 (3H, s, MeCMe), 1.43 (3H, s,

MeCMe), 1.47 (3H, s, MeCMe), 1.49 (9H, s, CMe₃), 2.40 (1H, dd, J 15.4,

3.3, C(2)H_A), 2.59 (1H, dd, J 15.4, 8.6, C(2)H_B), 3.03e3.11 (1H, m,

MeCHMe), 3.33e3.40 (1H, m, C(3)H), 3.51e3.57 (1H, m, C(7)H_A),

3.65 (1H, d, J 15.1, NCH_AH_BPh), 3.89 (1H, d, J 15.1, NCH_AH_BPh),

3.93e3.99 (1H, m, C(7)H_B), 4.02e4.07 (1H, m, C(5)H), 4.28 (1H, dd, J

7.3, 2.5, C(4)H), 4.29e4.36 (1H, m, C(6)H), 7.18e7.36 (5H, m, Ph); d_C

(100 MHz, CDCl₃) 19.8, 21.6 (2ꢂ MeCHMe), 24.8, 25.3, 26.3, 26.6 (4ꢂ

MeCMe), 28.2 (CMe₃), 36.9 (C(2)), 49.2 (MeCHMe), 49.6 (NCH₂Ph),

54.7 (C(3)), 66.2 (C(7)), 73.9 (C(6)), 78.6, 78.7 (C(4), C(5)), 80.1

(CMe₃), 108.8, 109.6 (2ꢂ MeCMe), 126.7 (p-Ph), 128.1, 128.3 (o, m-

Ph), 141.6 (i-Ph), 172.1 (C(1)); m/z (ESI^þ) 478 ([MþH]^þ, 100%); HRMS

4.29. tert-Butyl (3S,4S,5S,6R)-3-amino-4,5,6,7-tetrahydroxy-

4,5,6,7-di-O-isopropylideneheptanoate 57

Method A (from 54): Following general procedure 2, a solution of

54 (270 mg, 0.500 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 135 mg) and H₂(1 atm),

which gave 57 as a pale yellow oil (167 mg, 97%, >99:1 dr);

C₁₇H₃₁NO₆requires C, 59.1; H, 9.05; N, 4.05%; found C, 59.2; H, 9.0;

N, 4.1%; ½a ²_D⁵

þ25.0 (c 1.0 in CHCl₃); n_max(ﬁlm) 3390 (NeH), 1728

ꢃ

(C]O, C]C); d_H(400 MHz, CDCl₃) 1.24 (3H, s, MeCMe), 1.29 (3H, s,

MeCMe), 1.30 (3H, s, MeCMe), 1.35 (3H, s, MeCMe), 1.41 (9H, s,

CMe₃), 1.94 (2H, br s, NH₂), 2.27 (1H, dd, J 16.2, 8.9, C(2)H_A), 2.67

(1H, dd, J 16.2, 3.4, C(2)H_B), 3.42 (1H, app td, J 9.2, 3.4, C(3)H),

3.84e3.92 (2H, m, C(4)H, C(7)H_A), 3.96 (1H, dd, J 9.2, 4.8, C(5)H),

4.03e4.14 (2H, m, C(6)H, C(7)H_B); d_C(100 MHz, CDCl₃) 25.4, 25.5,

26.6, 28.0 (4 ꢂ MeCMe), 28.1 (CMe₃), 40.1 (C(2)), 47.1 (C(3)), 68.0

(C(7)), 72.9 (C(6)), 78.8 (C(5)), 80.5 (CMe₃), 81.4 (C(4)), 108.1, 110.1

(2ꢂ MeCMe), 171.7 (C(1)); m/z (ESI^þ) 346 ([MþH]^þ, 100%); HRMS

(ESI^þ) C₁₇H₃₂NO₆^þ([MþH]^þ) requires 346.2224; found 346.2221.

Method B (from 56): Following general procedure 2, a solution of

56 (196 mg, 0.363 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 98 mg) and H₂(1 atm),

which gave 57 as a pale yellow oil (125 mg, quant, >99:1 dr).

Method C (from 52): Following general procedure 2, a solution of

52 (214 mg, 0.407 mmol, >99:1 dr) in MeOH (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 107 mg) and H₂(1 atm),

which gave 57 as a pale yellow oil (127 mg, 90%, >99:1 dr).

þ

(ESI^þ) C₂₇H₄₄NO₆([MþH]^þ) requires 478.3163; found 478.3164.

Further elution gave a complex mixture containing 60 as the major

product in >99:1 dr (164 mg). Data for mixture: n_max(ﬁlm) 2982,

2935, 2890 (CeH), 1731 (C]O). Data for 60: d_H(400 MHz, CDCl₃)

1.04 (3H, d, J 6.6, MeCHMe), 1.11 (3H, d, J 6.6, MeCHMe), 1.32 (3H, s,

MeCMe), 1.39 (3H, s, MeCMe), 1.45 (9H, s, CMe₃), 1.53 (3H, s,

MeCMe), 1.57 (3H, s, MeCMe), 1.89 (1H, dd, J 14.2, 2.5, C(2)H_A), 2.38

(1H, dd,

J 14.2, 10.4, C(2)H_B), 3.10e3.21 (1H, m, MeCHMe),

3.67e3.79 (2H, m, C(3)H, C(7)H_A), 3.84 (1H, d, J 14.8, NCH_AH_BPh),

3.85e3.96 (2H, m, C(5)H, C(7)H_B), 3.92 (1H, d, J 14.8, NCH_AH_BPh),

4.11e4.20 (2H, m, C(4)H, C(6)H), 7.17e7.44 (5H, m, Ph);

d

C (100 MHz, CDCl₃) 20.2, 22.6 (2ꢂ MeCHMe), 25.3, 25.7, 26.6, 26.8

(4ꢂ MeCMe), 28.2 (CMe₃), 39.0 (C(2)), 49.0 (MeCHMe), 49.5

(NCH₂Ph), 53.9 (C(3)), 66.2 (C(7)), 73.9 (C(4)), 75.8 (C(6)), 78.2

(C(5)), 80.4 (CMe₃), 108.8, 109.2 (2ꢂ MeCMe), 126.3 (p-Ph), 127.8,

129.0 (o,m-Ph), 142.2 (i-Ph), 170.6 (C(1)); m/z (ESI^þ) 478 ([MþH]^þ,

4.30. tert-Butyl (3S,4S,5S,6R)-3-N-isopropylamino-4,5,6,7-

tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate 58

þ

Method A (from 49): Following general procedure 2, a solution of

49 (200 mg, 0.418 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 100 mg) and H₂(1 atm),

which gave 58 as a colourless oil (161 mg, 99%, >99:1 dr);

C₂₀H₃₇NO₆requires C, 62.0; H, 9.6; N, 3.6%; found C, 62.1; H, 9.7;

100%); HRMS (ESI^þ) C₂₇H₄₄NO₆([MþH]^þ) requires 478.3163;

found 478.3163.

Method B: Following general procedure 1, a solution of N-iso-

propyl-N-benzylamine (91 mg, 0.61 mmol) in Et₂O (4 mL) was

reacted with BuLi (2.5 M, 0.24 mL, 0.59 mmol) and a solution of 23

(100 mg, 0.305 mmol, >99:1 dr) in Et₂O (4 mL) at ꢀ20 ^ꢁC, which

gave an 81:19 mixture of 59 and 60, respectively.

N, 3.7%; ½a ²_D⁵

þ22.7 (c 1.0 in CHCl₃); n_max(ﬁlm) 3325 (NeH), 1731

ꢃ

(C]O, C]C); d_H(400 MHz, CDCl₃) 1.05 (3H, d, J 6.1, MeCHMe), 1.06

(3H, d, J 6.1, MeCHMe), 1.32 (3H, s, MeCMe), 1.36 (3H, s, MeCMe),

1.38 (3H, s, MeCMe), 1.42 (3H, s, MeCMe), 1.46 (9H, s, CMe₃), 1.61

(1H, br s, NH), 2.45 (1H, dd, J 15.2, 5.1, C(2)H_A), 2.54 (1H, dd, J 15.2,

4.8, C(2)H_B), 2.96 (1H, app septet, J 6.1, MeCHMe), 3.42e3.49 (1H, m,

C(3)H), 3.90 (1H, dd, J 8.5, 6.5, C(7)H_A), 4.05e4.12 (2H, m, C(5)H,

C(7)H_B), 4.16e4.21 (1H, m, C(4)H), 4.22e4.29 (1H, m, C(6)H); d_C

(100 MHz, CDCl₃) 22.0, 24.3 (MeCHMe), 25.2, 25.6, 26.7, 27.4 (4 ꢂ

MeCMe) 28.1 (CMe₃), 38.1 (C(2)), 45.1 (MeCHMe), 51.0 (C(3)), 67.8

(C(7)), 73.0 (C(6)), 78.4 (C(5)), 79.7 (C(4)), 80.1 (CMe₃), 107.9, 109.7

4.32. tert-Butyl (R,R,R,R)- and (3S,4R,5R,6R)-3-(N,N-dibenzy-

lamino)-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-iso-

propylideneheptanoate 62 and 63

Method A: Following general procedure 1, a solution of N,N-

dibenzylamine (1.80 g, 9.14 mmol) in THF (60 mL) was reacted with

BuLi (2.5 M, 3.54 mL, 8.86 mmol) and a solution of 23 (1.50 g,

4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC, which gave a 50:50

8700

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

mixture of 62 and 63. Puriﬁcation via ﬂash column chromatography

(eluent 30e40 ^ꢁC petrol/Et₂O, 4:1) gave 62 as a white solid (964 mg,

(CeH), 1729 (C]O); d_H(400 MHz, CDCl₃) 1.20 (3H, s, MeCMe), 1.21

(3H, d, J 6.8, C( )Me), 1.37 (3H, s, MeCMe), 1.41 (3H, s, MeCMe), 1.51

a

40%, >99:1 dr); mp 55e62 ^ꢁC; ½a _D²⁵

ꢃ

þ26.9 (c 1.0 in CHCl₃); n_max

(9H, s, CMe₃), 1.57 (3H, s, MeCMe), 1.86 (1H, dd, J 14.9, 2.3, C(2)H_A),

2.38 (1H, dd, J 14.9, 9.9, C(2)H_B), 3.51e3.57 (1H, m, C(7)H_A),

3.61e3.67 (1H, m, C(7)H_B), 3.70 (1H, app dd, J 10.0, 2.3, C(3)H),

3.85e3.91 (1H, m, C(5)H), 3.88 (1H, d, J 15.5, NCH_AH_BPh), 3.96e4.02

(1H, m, C(6)H), 4.08 (1H, d, J 15.5, NCH_AH_BPh), 4.19 (1H, dd, J 10.0,

(ﬁlm) 3028, 2982, 2935, 2887 (CeH), 1728 (C]O); d_H(400 MHz,

CDCl₃) 1.26 (3H, s, MeCMe), 1.37 (3H, s, MeCMe), 1.43 (3H,

s, MeCMe), 1.51 (3H, s, MeCMe), 1.53 (9H, s, CMe₃), 2.43 (1H, dd,

J 15.4, 3.5, C(2)H_A), 2.70 (1H, dd, J 15.4, 8.3, C(2)H_B), 3.26e3.32 (1H,

m, C(3)H), 3.32e3.37 (1H, m, C(7)H_A), 3.54 (1H, dd, J 8.1, 6.3, C(7)

H_B), 3.62 (2H, d, J 14.2, N(CH_AH_BPh)₂), 3.79 (2H, d, J 14.2,

N(CH_AH_BPh)₂), 4.09e4.20 (2H, m, C(5)H, C(6)H), 4.45 (1H, dd, J 6.8,

2.8, C(4)H), 7.22e7.38 (10H, m, Ph); d_C(100 MHz, CDCl₃) 24.8, 25.2,

26.3, 26.7 (4ꢂ MeCMe), 28.2 (CMe₃), 35.0 (C(2)), 54.6 (N(CH₂Ph)₂),

55.7 (C(3)), 65.9 (C(7)), 73.8 (C(6)), 76.1 (C(4)), 79.1 (C(5)), 80.3

(CMe₃),109.1,109.6 (2ꢂ MeCMe),127.2 (p-Ph), 128.3, 129.0 (o,m-Ph),

139.6 (i-Ph), 171.8 (C(1)); m/z (ESI^þ) 526 ([MþH]^þ, 100%); HRMS

5.8, C(4)H), 4.40 (1H, q, J 6.8, C(

(100 MHz, CDCl₃) 21.9 (C(

)Me), 25.3, 25.5, 26.6, 27.2 (4ꢂ MeCMe),

28.2 (CMe₃), 38.8 (C(2)), 50.0 (NCH₂Ph), 54.5 (C(3)), 62.6 (C( )), 66.1

a)H), 7.19e7.43 (10H, m, Ph); d_C

a

(C(7)), 73.9 (C(6)), 76.8 (C(5)), 78.5 (C(4)), 80.6 (CMe₃), 108.8, 109.0

(2ꢂ MeCMe), 126.3, 126.6 (p-Ph), 127.9, 128.0, 128.1, 128.6 (o,m-Ph),

143.2, 145.4 (i-Ph), 170.4 (C(1)); m/z (ESI^þ) 540 ([MþH]^þ, 100%);

þ

HRMS (ESI^þ) C₃₂H₄₆NO₆([MþH]^þ) requires 540.3320; found

540.3313.

þ

(ESI^þ) C₃₁H₄₄NO₆([MþH]^þ) requires 526.3163; found 526.3163.

Method B: Following general procedure 1, a solution of (S)-N-

benzyl-N-(a-methylbenzyl)amine (129 mg, 0.611 mmol) in Et₂O

Further elution gave 63 as a white solid (799 mg, 33%, >99:1 dr);

C₃₁H₄₃NO₆requires C, 70.8; H, 8.2; N, 2.7%; found C, 70.9; H, 8.4; N,

(4 mL) was reacted with BuLi (2.5 M, 0.24 mL, 0.59 mmol) and

a solution of 23 (100 mg, 0.305 mmol, >99:1 dr) in Et₂O (4 mL) at

ꢀ20 ^ꢁC, which gave a 42:52:6 mixture of 64, 65 and 61, respectively.

2.45%; mp 122e124 ^ꢁC; ½a _D²⁵

ꢀ29.9 (c 1.0 in CHCl₃); n_max(ﬁlm)

ꢃ

3062, 3027, 2982, 2934, 2891 (CeH), 1730 (C]O); d_H(400 MHz,

CDCl₃) 1.22 (3H, s, MeCMe), 1.43 (9H, s, CMe₃), 1.44 (3H, s, MeCMe),

1.46 (3H, s, MeCMe), 1.61 (3H, s, MeCMe), 2.06 (1H, dd, J 14.4, 4.3,

C(2)H_A), 2.53 (1H, dd, J 14.4, 9.1, C(2)H_B), 3.51e3.56 (1H, m, C(7)H_A),

3.56e3.63 (2H, m, C(3)H, C(7)H_B), 3.72 (2H, d, J 13.3, N(CH_AH_BPh)₂),

3.95 (2H, d, J 13.3, N(CH_AH_BPh)₂), 4.00 (1H, dd, J 6.3, 4.6, C(5)H),

4.20e4.27 (1H, m, C(6)H), 4.32 (1H, dd, J 8.6, 6.3, C(4)H), 7.19e7.43

(10H, m, Ph); d_C(100 MHz, CDCl₃) 25.2, 25.5, 26.7, 26.8 (4ꢂ MeCMe),

28.1 (CMe₃), 36.6 (C(2)), 53.7 (C(3)), 54.7 (N(CH₂Ph)₂), 65.9 (C(7)),

73.8 (C(6)), 76.7 (C(5)), 79.0 (C(4)), 80.5 (CMe₃), 109.0, 109.3 (2ꢂ

MeCMe), 126.8 (p-Ph), 128.0, 129.7 (o,m-Ph), 140.0 (i-Ph), 170._þ5

(C(1)); m/z (ESI^þ) 526 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₁H₄₄NO₆

([MþH]^þ) requires 526.3163; found 526.3161.

4.34. tert-Butyl (R,R,R,R,R)- and (3S,4R,5R,6R,aR)-3-[N-benzyl-

N-( -methylbenzyl)amino]-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-

a

isopropylideneheptanoate 66 and 67, and (5S,6R,Z)-tert-butyl

4,5,6,7-tetrahydroxy-4,5,6,7-di-O-isopropylidenehept-3-

enoate 61

Method A: Following general procedure 1, a solution of (R)-N-

benzyl-N-(a-methylbenzyl)amine (1.93 g, 9.14 mmol) in Et₂O

(60 mL) was reacted with BuLi (2.5 M, 3.54 mL, 8.86 mmol) and

a solution of 23 (1.50 g, 4.57 mmol, >99:1 dr) in Et₂O (60 mL) at

ꢀ20 ^ꢁC, which gave a 66:34 mixture of 66 and 67, respectively.

Puriﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢁC

petrol/Et₂O, 4:1) gave 66 as a white solid (1.04 g, 42%, >99:1 dr);

C₃₂H₄₅NO₆requires C, 71.2; H, 8.4; N, 2.6%; found C, 71.2; H, 8.4; N,

Method B: Following general procedure 1, a solution of N,N-

dibenzylamine (120 mg, 0.608 mmol) in Et₂O (4 mL) was reacted

with BuLi (2.5 M, 0.24 mL, 0.59 mmol) and a solution of 23 (100 mg,

0.305 mmol, >99:1 dr) in Et₂O (4 mL) at ꢀ20 ^ꢁC, which gave

a complex mixture containing a 50:50 mixture of 62 and 63.

2.6%; ½a ²_D⁵

ꢃ

þ44.2 (c 1.0 in CHCl₃); mp 86e91 ^ꢁC; n_max(ﬁlm) 2981,

2934, 2888 (CeH), 1727 (C]O); d_H(400 MHz, CDCl₃) 1.22 (3H, s,

MeCMe), 1.34 (3H, s, MeCMe), 1.34 (3H, d, J 6.8, C(a)Me), 1.42 (3H, s,

4.33. tert-Butyl (3R,4R,5R,6R,

a

S)- and (3S,4R,5R,6R,

a

S)-3-[N-

MeCMe), 1.44 (3H, s, MeCMe), 1.56 (9H, s, CMe₃), 2.45e2.60 (2H, m,

C(2)H₂), 3.33 (1H, app t, J 7.8, C(7)H_A), 3.51e3.58 (1H, m, C(3)H),

3.69 (1H, d, J 15.2, NCH_AH_BPh), 3.71e3.80 (2H, m, C(5)H, C(7)H_B),

benzyl-N-( -methylbenzyl)amino]-4,5,6,7-tetrahydroxy-

a

4,5,6,7-di-O-isopropylideneheptanoate 64 and 65

3.89 (1H, dd, J 7.3, 2.3, C(4)H), 3.97 (1H, q, J 6.8, C(

15.2, NCH_AH_BPh), 4.16e4.23 (1H, m, C(6)H), 7.21e7.45 (10H, m, Ph);

d_C(100 MHz, CDCl₃) 19.6 (C(

)Me), 24.7, 25.5, 26.4, 26.6 (4ꢂ

MeCMe), 28.2 (CMe₃), 36.4 (C(2)), 50.9 (NCH₂Ph), 54.4 (C(3)), 58.9

(C( )), 66.0 (C(7)), 73.8 (C(6)), 77.9, 78.2 (C(4), C(5)), 80.2 (CMe₃),

a)H), 4.08 (1H, d, J

Method A: Following general procedure 1, a solution of (S)-N-

benzyl-N-(

a

-methylbenzyl)amine (1.93 g, 9.14 mmol) in THF

a

(60 mL) was reacted with BuLi (2.5 M, 3.54 mL, 8.86 mmol) and

a solution of 23 (1.50 g, 4.57 mmol, >99:1 dr) in THF (60 mL) at

ꢀ78 ^ꢁC, which gave a 71:21:8 mixture of 64, 65 and 61, respectively.

Puriﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢁC

petrol/Et₂O, 4:1) gave an 86:14 mixture of 64 and 61, respectively,

as a pale yellow oil (1.42 g). Data for mixture: n_max(ﬁlm) 3062, 3027,

2982, 2936, 2886 (CeH), 1728 (C]O). Data for 64: d_H(400 MHz,

CDCl₃) 1.30 (3H, s, MeCMe), 1.33 (3H, s, MeCMe), 1.40 (3H, d, J 6.6,

a

108.6, 109.5 (2ꢂ MeCMe), 126.7, 127.3 (p-Ph), 127.9, 128.2, 128.3,

128.4 (o,m-Ph), 141.9, 143.3 (i-Ph), 172.1 (C(1)); m/z (ESI^þ) 540

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₃₂H₄₅NNaO₆([MþNa]^þ) requires

562.3139; found 562.3137. Further elution gave 67 as a white solid

(384 mg,16%, 91:9 dr); mp 105e115 ^ꢁC; n_max(ﬁlm) 2982, 2935, 2891

(CeH), 1731 (C]O); d_H(400 MHz, CDCl₃) 1.33 (3H, s, MeCMe), 1.46

(3H, s, MeCMe), 1.48 (3H, s, MeCMe), 1.49 (9H, s, CMe₃), 1.55 (3H, d, J

C(a)Me), 1.43 (3H, s, MeCMe), 1.46 (3H, s, MeCMe), 1.48 (9H,

s, CMe₃), 2.41 (1H, dd, J 15.8, 2.8, C(2)H_A), 2.58 (1H, dd, J 15.8, 8.3,

C(2)H_B), 3.33e3.43 (2H, m, C(3)H, C(7)H_A), 3.63e3.69 (1H, m, C(7)

H_B), 3.80 (1H, d, J 15.8, NCH_AH_BPh), 3.85 (1H, d, J 15.8, NCH_AH_BPh),

6.7, C(a)Me), 1.64 (3H, s, MeCMe), 1.85 (1H, dd, J 14.9, 2.0, C(2)H_A),

2.34 (1H, dd, J 14.9, 10.1, C(2)H_B), 3.73e3.80 (1H, m, C(7)H_A), 3.81

(1H, d, J 14.2, NCH_AH_BPh), 3.89e3.93 (1H, m, C(7)H_B), 3.95 (1H, d, J

14.2, NCH_AH_BPh), 3.96e4.00 (1H, m, C(5)H), 4.07 (1H, app td, J 10.1,

4.04e4.11 (1H, m, C(5)H), 4.16 (1H, q, J 6.6, C(

m, C(6)H), 4.38e4.44 (1H, m, C(4)H), 7.17e7.44 (10H, m, Ph); d_C

(100 MHz, CDCl₃) 18.3 (C(

)Me), 24.6, 25.3, 26.3, 26.7 (4ꢂ MeCMe),

28.2 (CMe₃), 36.1 (C(2)), 50.3 (NCH₂Ph), 55.7 (C(3)), 58.0 (C( )), 65.9

a)H), 4.20e4.26 (1H,

2.0, C(3)H), 4.12e4.18 (1H, m, C(6)H), 4.25 (1H, q, J 6.7, C(

(1H, dd, J 10.1, 5.8, C(4)H), 7.11e7.49 (10H, m, Ph); d_C(100 MHz,

CDCl₃) 19.7 (C(

)Me), 25.5, 25.8, 26.7, 26.9 (4ꢂ MeCMe), 28.2

(CMe₃), 38.3 (C(2)), 51.4 (NCH₂Ph), 53.4 (C(3)), 65.9 (C( )), 66.2

a)H), 4.40

a

(C(7)), 73.8 (C(6)), 77.7 (C(4)), 78.9 (C(5)), 80.0 (CMe₃), 108.8, 109.5

(2ꢂ MeCMe), 126.8, 126.9 (p-Ph), 128.0, 128.1, 128.2, 128.3 (o,m-Ph),

141.4, 144.7 (i-Ph), 171.7 (C(1)); m/z (ESI^þ) 540 ([MþH]^þ, 100%);

a

(C(7)), 73.8 (C(6)), 75.7 (C(5)), 78.5 (C(4)), 80.4 (CMe₃), 108.9, 109.4

(2ꢂ MeCMe), 126.3, 126.3 (p-Ph), 127.7, 127.7, 128.1, 129.2 (o,m-Ph),

141.6, 146.5 (i-Ph), 170.5 (C(1)); m/z (ESI^þ) 540 ([MþH]^þ, 100%);

þ

HRMS (ESI^þ) C₃₂H₄₆NO₆([MþH]^þ) requires 540.3320; found

þ

540.3320. Further elution gave 65 as a pale yellow oil (527 mg, 21%,

HRMS (ESI^þ) C₃₂H₄₅NNaO₆([MþNa]^þ) requires 562.3139; found

>99:1 dr); ½a ²_D⁵

ꢃ

ꢀ27.1 (c 1.0 in CHCl₃); n_max(ﬁlm) 2982, 2933, 2889

562.3140.

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8701

Method B: Following general procedure 1, a solution of (R)-N-

benzyl-N-( -methylbenzyl)amine (1.93 g, 9.14 mmol) in THF (60 mL)

Method B (from 59): Following general procedure 2, a solution of

59 (205 mg, 0.429 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 103 mg) and H₂(1 atm),

which gave 69 as a pale yellow oil (148 mg, 89%, >99:1 dr).

a

was reacted with BuLi (2.5 M, 3.54 mL, 8.86 mmol) and a solution of

23 (1.50 g, 4.57 mmol, >99:1 dr) in THF (60 mL) at ꢀ78 ^ꢁC gave

a 15:23:62 mixture of 66, 67 and 61, respectively. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢁC petrol/Et₂O, 6:1)

gave a 12:88 mixture of 66 and 61, respectively, as a pale yellow oil

(746 mg). Data for mixture: n_max(ﬁlm) 2983, 2936, 2888 (CeH),1732

4.37. tert-Butyl (3S,4R,5R,6R)-3-amino-4,5,6,7-tetrahydroxy-

4,5,6,7-di-O-isopropylideneheptanoate 70

(C]O), 1642 (C]C); m/z (ESI^þ) 351 ([M(61)þNa]^þ, 100%); HRMS

Following general procedure 2, a solution of 63 (203 mg,

0.386 mmol, >99:1 dr) in EtOAc (5 mL) was reacted with Pd(OH)₂/C

(50% w/w of substrate, 102 mg) and H₂(1 atm), which gave 70 as

a pale yellow oil (112 mg, 84%, >99:1 dr); C₁₇H₃₁NO₆requires C,

þ

(ESI^þ) C₁₇H₂₈NaO₆

([M(61)þNa]^þ) requires 351.1778; found

351.1777. Data for 61: d_H(400 MHz, CDCl₃) 1.38 (3H, s, MeCMe), 1.40

(3H, s, MeCMe),1.44 (12H, app s, CMe₃, MeCMe),1.54 (3H, s, MeCMe),

3.02 (1H, dd, J 17.8, 6.6, C(2)H_A), 3.10 (1H, dd, J 17.8, 7.3, C(2)H_B),

3.80e3.85 (1H, m, C(7)H_A), 4.07e4.13 (1H, m, C(7)H_B), 4.16e4.22

(1H, m, C(6)H), 4.40e4.46 (1H, m, C(3)H), 4.60e4.64 (1H, m, C(5)H);

d_C(100 MHz, CDCl₃) 25.5, 25.6, 26.4, 26.6 (4ꢂ MeCMe), 28.1 (CMe₃),

32.2 (C(2)), 65.8 (C(7)), 77.0 (C(6)), 77.6 (C(5)), 80.4 (CMe₃), 89.3

(C(3)), 109.8, 111.5 (2ꢂ MeCMe), 150.4 (C(4)), 171.4 (C(1)).

59.1; H, 9.05; N, 4.05%; found C, 59.3; H, 8.9; N, 4.0%; ½a _D²⁵

þ1.6 (c 1.0

ꢃ

in CHCl₃); n_max(ﬁlm) 3389, 3322 (NeH), 2983, 2936, 2891 (CeH),

1726 (C]O); d_H(400 MHz, CDCl₃) 1.30 (6H, app s, 2ꢂ MeCMe), 1.38

(12H, app s, MeCMe, CMe₃), 1.46 (3H, s, MeCMe), 2.26 (1H, dd,

J 15.9, 8.1, C(2)H_A), 2.34 (1H, dd, J 15.9, 5.1, C(2)H_B), 3.10e3.17 (1H, m,

C(3)H), 3.64e3.70 (1H, m, C(7)H_A), 3.95 (1H, dd, J 6.8, 3.8, C(4)H),

4.03e4.08 (2H, m, C(5)H, C(7)H_B), 4.40e4.47 (1H, app q, J 6.6, C(6)

H); d_C(100 MHz, CDCl₃) 24.9, 25.3, 26.5, 26.6 (4ꢂ MeCMe), 28.1

(CMe₃), 42.2 (C(2)), 48.2 (C(3)), 66.3 (C(7)), 74.3 (C(6)), 78.0 (C(5)),

78.9 (C(4)), 80.7 (CMe₃), 108.7, 109.5 (2ꢂ MeCMe), 171.1 (C(1)); m/z

4.35. tert-Butyl (R,R,R,R)-3-amino-4,5,6,7-tetrahydroxy-

4,5,6,7-di-O-isopropylideneheptanoate 68

(ESI^þ) 346 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₇H₃₂NO₆([MþH]^þ)

þ

Method A (from 62): Following general procedure 2, a solution of

62 (199 mg, 0.379 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 100 mg) and H₂(1 atm),

requires 346.2224; found 346.2223.

which gave 68 as a pale yellow oil (109 mg, 83%, >99:1 dr); ½a _D²⁵

ꢃ

4.38. tert-Butyl (3S,4R,5R,6R)-3-N-isopropylamino-4,5,6,7-

tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate 71

þ1.4 (c 1.0 in CHCl₃); n_max(ﬁlm) 3388, 3319 (NeH), 2983, 2936

(CeH), 1725 (C]O); d_H(400 MHz, CDCl₃) 1.28 (3H, s, MeCMe), 1.30

(3H, s, MeCMe), 1.39 (12H, app s, MeCMe, CMe₃), 1.41 (3H,

s, MeCMe), 2.13 (1H, dd, J 16.2, 9.1, C(2)H_A), 2.72 (1H, dd, J 16.2, 2.8,

C(2)H_B), 3.17e3.27 (1H, m, C(3)H), 3.72e3.80 (2H, m, C(4)H,

C(7)H_A), 4.05e4.11 (2H, m, C(5)H, C(7)H_B), 4.32e4.39 (1H, m, C(6)

H); d_C(100 MHz, CDCl₃) 25.2, 25.5, 26.6, 27.3 (4ꢂ MeCMe), 28.1

(CMe₃), 42.0 (C(2)), 48.1 (C(3)), 67.0 (C(7)), 74.2 (C(6)), 78.0 (C(5)),

79.8 (C(4)), 80.6 (CMe₃), 108.6, 109.4 (2ꢂ MeCMe), 171.7 (C(1)); m/z

Following general procedure 3, a solution of 70 (106 mg,

0.307 mmol, >99:1 dr) in MeOH (3 mL) was reacted with acetone

(45 mL, 0.61 mmol) and NaBH₃CN (77 mg, 1.2 mmol), which gave 71

in >99:1 dr. Puriﬁcation via ﬂash column chromatography (eluent

30e40 ^ꢁC petrol/Et₂O, 2:1) gave 71 as a pale yellow oil (64 mg, 53%,

>99:1 dr); ½a ²_D⁵

þ35.7 (c 1.0 in CHCl₃); n_max(ﬁlm) 3347 (NeH),

ꢃ

2981, 2936, 2888 (CeH),1725 (C]O); d_H(400 MHz, CDCl₃) 0.97 (3H,

d, J 6.1, MeCHMe), 1.02 (3H, d, J 6.1, MeCHMe), 1.33 (6H, app s, 2ꢂ

MeCMe), 1.41 (9H, s, CMe₃), 1.44 (3H, s, MeCMe), 1.47 (3H, s,

MeCMe), 2.30 (1H, dd, J 15.4, 8.1, C(2)H_A), 2.48 (1H, dd, J 15.4, 4.0,

C(2)H_B), 2.85 (1H, app septet, J 6.1, MeCHMe), 2.96e3.03 (1H, m,

C(3)H), 3.64e3.70 (1H, m C(7)H_A), 4.08e4.15 (3H, m, C(4)H, C(5)H,

C(7)H_B), 4.75e4.84 (1H, m, C(6)H); d_C(100 MHz, CDCl₃) 21.6, 24.4

(2ꢂ MeCHMe), 24.5, 25.0, 26.6, 26.8 (4ꢂ MeCMe), 28.1 (CMe₃), 37.8

(C(2)), 44.4 (MeCHMe), 51.1 (C(3)), 66.1 (C(7)), 74.5 (C(6)), 78.3, 79.4

(C(4), C(5)), 80.5 (CMe₃), 108.6, 109.2 (2ꢂ MeCMe), 171.6 (C(1)); m/z

þ

(ESI^þ) 346 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₇H₃₂NO₆([MþH]^þ)

requires 346.2224; found 346.2231.

Method B (from 64): Following general procedure 2, a solution of

64 (188 mg, 0.348 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 94 mg) and H₂(1 atm),

which gave 68 as a pale yellow oil (92 mg, 76%, >99:1 dr).

Method C (from 66): Following general procedure 2, a solution of

66 (212 mg, 0.393 mmol, >99:1 dr) in EtOAc (5 mL) was reacted

with Pd(OH)₂/C (50% w/w of substrate, 106 mg) and H₂(1 atm),

which gave 68 as a pale yellow oil (84 mg, 62%, >99:1 dr).

þ

(ESI^þ) 388 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₀H₃₈NO₆([MþH]^þ)

requires 388.2694; found 388.2698.

4.36. tert-Butyl (R,R,R,R)-3-N-isopropylamino-4,5,6,7-

tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate 69

4.39. tert-Butyl (3S,4S,5R,6R,aR)-3-[N-benzyl-N-(a-methyl-

benzyl)amino]-4,5,6,7-tetrahydroxy-4,5-O-iso-

Method A (from 68): Following general procedure 3, a solution of

68 (102 mg, 0.295 mmol, >99:1 dr) in MeOH (3 mL) was reacted

propylideneheptanoate 76

with acetone (43

m

L, 0.59 mmol) and NaBH₃CN (74 mg, 1.2 mmol),

Method A: Concd HCl (1 drop) was added to a solution of 54

(50 mg, 93

mol, >99:1 dr) in 70% aq EtOH (1.1 mL) at 60 ^ꢁC and the

which gave 69 as a pale yellow oil (90 mg, 79%, >99:1 dr); ½a _D²⁵

ꢃ

e8.8

m

(c 1.0 in CHCl₃); n_max(ﬁlm) 2981, 2935, 2888 (CeH), 1720 (C]O); d_H

(400 MHz, CDCl₃) 0.99 (3H, d, J 6.1, MeCHMe), 1.01 (3H, d, J 6.5,

MeCHMe), 1.33 (6H, app s, 2ꢂ MeCMe), 1.42 (9H, s, CMe₃), 1.43 (3H,

s, MeCMe), 1.44 (3H, s, MeCMe), 2.47 (1H, dd, J 16.0, 4.1, C(2)H_A),

2.64 (1H, dd, J 16.0, 4.1, C(2)H_B), 2.89e3.01 (1H, m, MeCHMe),

3.15e3.24 (1H, m, C(3)H), 3.70e3.76 (1H, m, C(7)H_A), 3.99 (1H, dd,

J 8.9, 5.8, C(4)H), 4.06e4.11 (1H, m, C(5)H), 4.14 (1H, dd, J 8.2, 6.8,

C(7)H_B), 4.42 (1H, app q, J 6.5, C(6)H); d_C(100 MHz, CDCl₃) 21.4, 24.2

(2ꢂ MeCHMe), 25.2, 25.5, 26.7, 27.2 (4ꢂ MeCMe), 28.1 (CMe₃), 34.9

(C(2)), 44.9 (MeCHMe), 51.3 (C(3)), 67.1 (C(7)), 74.0 (C(6)), 77.7

(C(4)), 78.2 (C(5)), 80.6 (CMe₃), 108.5, 109.4 (2ꢂ MeCMe), 171.1

resultant mixture was heated at 60 ^ꢁC for 6 h. The reaction mixture

was then allowed to cooled to rt and ﬁltered through a short plug of

basic alumina (eluent EtOH), and the ﬁltrate was then concentrated

in vacuo. Puriﬁcation via ﬂash column chromatography (gradient

elution, 2:1/1:2 30e40 ^ꢁC petrol/Et₂O) gave 76 as a colourless oil

(15 mg, 32%, >99:1 dr); ½a _D²⁵

ꢀ7.9 (c 1.0 in CHCl₃); n_max(ATR) 3436

ꢃ

(OeH), 3086, 3062, 3028, 2980, 2935 (CeH), 1727 (C]O); d_H

(400 MHz, CDCl₃) 1.27 (3H, s, MeCMe), 1.33 (3H, s, MeCMe), 1.41

(9H, s, CMe₃), 1.57 (3H, d, J 6.8, C(a)Me), 2.21e2.28 (3H, m, C(2)H₂,

C(7)OH), 3.56e3.66 (2H, m, C(6)H, C(7)H_A), 3.62 (1H, d, J 14.2,

NCH_AH_BPh), 3.71e3.79 (1H, m, C(7)H_B), 3.86 (1H, d, J 14.2,

þ

(C(1)); m/z (ESI^þ) 388 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₀H₃₈NO₆

NCH_AH_BPh), 3.96e4.04 (2H, m, C(3)H, C(

a)H), 4.08 (1H, dd, J 8.9, 6.7,

([MþH]^þ) requires 388.2694; found 388.2695.

C(5)H), 4.41 (1H, dd, J 7.5, 6.7, C(4)H), 6.09 (1H, br s, C(6)OH),

8702

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

7.27e7.43 (10H, m, Ph); d_C(100 MHz, CDCl₃) 19.1 (C(

26.8 (2ꢂ MeCMe), 28.1 (CMe₃), 35.1 (C(2)), 51.7 (NCH₂Ph), 54.1, 59.3

(C(3), C( )), 64.8 (C(7)), 68.3 (C(6)), 78.0 (C(5)), 78.6 (C(4)), 80.3

(CMe₃), 108.1 (MeCMe), 127.5, 127.7 (p-Ph), 128.4, 128.5, 128.7, 129.4

(o,m-Ph), 138.4, 141.4 (i-Ph), 171.5 (C(1)); m/z (ESI^þ) 522 ([MþNa]^þ,

100%); HRMS (ESI^þ) C₂₉H₄₁NNaO₆^þ([MþNa]^þ) requires 522.2826;

found 522.2809.

a

)Me), 24.6,

128.3, 128.3, 128.4, 128.4 (o,m-Ph), 140.3, 141.9 (i-Ph), 170.8 (C(1)),

198.7 (C(6)); m/z (ESI^þ) 500 ([MþMeOHþH]^þ, 100%); HRMS (ESI^þ)

C₂₉H₄₂NO₆^þ([MþMeOHþH]^þ) requires 500.3007; found 500.3003.

Step 2: Pd(OH)₂/C (50% w/w of substrate, 29 mg) was added to

a stirred solution of the residue of 78 (57 mg) in MeOH (1 mL) at rt.

The resultant mixture was degassed and saturated with H₂before

being left to stir under an atmosphere of H₂(5 atm) for 18 h. The

reaction mixture was then ﬁltered through a short plug of Celite^Ò

(eluent MeOH) and the ﬁltrate was concentrated in vacuo. Puriﬁ-

cation via ﬂash column chromatography (gradient elution,

4:1/1:1 30e40 ^ꢁC petrol/EtOAc) gave 79 as a pale yellow oil

a

Method B: A solution of 54 (50 mg, 93 mmol, >99:1 dr) in 80% aq

AcOH (1.0 mL) was heated at 50 ^ꢁC for 16 h. The reaction mixture

was then cooled to 0 ^ꢁC and 5.0 M aq NaOH was added dropwise

until pH 14 was achieved. The resultant mixture was extracted with

CH₂Cl₂(3ꢂ10 mL) and the combined organic extracts were dried

and concentrated in vacuo. Puriﬁcation via ﬂash column chroma-

tography (gradient elution, 2:1/1:2 30e40 ^ꢁC petrol/Et₂O) gave 76

as a colourless oil (10 mg, 21%, >99:1 dr).

(20 mg, 60% from 76, >99:1 dr); ½a _D²⁵

ꢀ24.4 (c 1.0 in CHCl₃); n_max

ꢃ

(ATR) 3417 (NeH), 2979, 2934 (CeH), 1726 (C]O); d_H(400 MHz,

CDCl₃) 1.28 (3H, s, MeCMe), 1.44 (9H, s, CMe₃), 1.45 (3H, s, MeCMe),

2.24 (2H, app d, J 7.8, C(2)H₂). 2.53 (1H, br s, NH), 2.85 (1H, dd, J 13.5,

4.2, C(5⁰)H_A), 3.02 (1H, app d, J 13.5, C(5⁰)H_B), 3.50e3.56 (1H, m,

C(2⁰)H), 4.41 (1H, app d, J 5.6, C(3⁰)H), 4.65e4.70 (1H, m, C(4⁰)H); d_C

(100 MHz, CDCl₃) 24.0, 26.3 (2ꢂ MeCMe), 28.1 (CMe₃), 37.3 (C(2)),

51.9 (C(5⁰)), 61.9 (C(2⁰)), 80.7 (CMe₃), 81.7 (C(4⁰)), 85.4 (C(3⁰)), 111.1

(MeCMe),170.7 (C(1)); m/z (ESI^þ) 258 ([MþH]^þ,100%); HRMS (ESI^þ)

C₁₃H₂₄NO₄^þ([MþH]^þ) requires 258.1700; found 258.1699.

4.40. tert-Butyl (3S,4R,5S,6R,aS)-3-[N-benzyl-N-(a-methyl-

benzyl)amino]-4,5,6,7-tetrahydroxy-4,5-O-iso-

propylideneheptanoate 77

Concd HCl (1 drop) was added to a solution of 65 (50 mg,

mol, >99:1 dr) in 70% aq EtOH (1.1 mL) at 60 ^ꢁC and the re-

93

m

sultant mixture was heated at 60 ^ꢁC for 6 h. The reaction mixture

was then allowed to cool to rt and ﬁltered through a short plug of

basic alumina (eluent EtOH), and the ﬁltrate was then concentrated

in vacuo. Puriﬁcation via ﬂash column chromatography (gradient

elution, 2:1/1:2 30e40 ^ꢁC petrol/Et₂O) gave 77 as a colourless oil

4.42. (2⁰S,3⁰S,4⁰R)-2-[N(1⁰)-3⁰,4⁰-Dihydroxypyrrolidin-2⁰-yl]-

acetic acid 80

A solution of 79 (80 mg, 0.31 mmol, >99:1 dr) in 2.0 M aq HCl

(3 mL) was heated at reﬂux for 8 h. The reaction mixture was

allowed to cool to rt and was then concentrated in vacuo. Puriﬁ-

cation via ion-exchange chromatography (DOWEX 50WX8-200,

eluent 1.0 M aq NH₄OH) gave 80 as a pale orange solid (46 mg, 92%,

(14 mg, 31%, >99:1 dr); ½a _D²⁵

ꢀ29.3 (c 1.0 in CHCl₃); n_max(ATR) 3062,

ꢃ

3028, 2979, 2934, 2880 (CeH), 1724 (C]O); d_H(400 MHz, CDCl₃)

1.33 (3H, s, MeCMe), 1.35 (3H, d, J 7.1, C(a)Me), 1.51 (9H, s, CMe₃),

1.60 (3H, s, MeCMe), 2.07 (1H, br s, C(7)OH), 2.50 (1H, dd, J 15.7, 8.1,

C(2)H_A), 2.57e2.64 (2H, m, C(2)H_B, C(6)H), 3.36e3.44 (1H, m,

C(7)H_A), 3.50e3.56 (1H, m, C(7)H_B), 3.72 (1H, d, J 13.8, NCH_AH_BPh),

3.80e3.89 (2H, m, C(3)H, C(5)H), 4.12 (1H, dd, J 6.6, 3.8, C(4)H), 4.15

>99:1 dr); mp 219e223 ^ꢁC (dec); ½a _D²⁵

ꢀ43.5 (c 1.0 in H₂O); n_max

ꢃ

(ATR) 3338 (OeH), 3064, 2922, 2867 (CeH), 2246, 2139 (NH^þ₃),1537,

1397 (CO^ꢀ₂); d_H(500 MHz, D₂O) 2.50 (1H, dd, J 17.2, 8.5, C(2)H_A), 2.71

(1H, dd, J 17.2, 4.4, C(2)H_B), 3.24 (1H, dd, J 13.1, 2.1, C(5⁰)H_A), 3.45

(1H, dd, J 13.1, 4.4, C(5⁰)H_B), 3.64 (1H, app td, J 8.5, 4.4, C(2⁰)H), 4.00

(1H, dd, J 8.5, 4.4, C(3⁰)H), 4.29 (1H, app td, J 4.4, 2.1, C(4⁰)H); d_C

(125 MHz, D₂O) 36.6 (C(2)), 49.0 (C(5⁰)), 57.8 (C(2⁰)), 69.1 (C(3⁰)),

74.0 (C(4⁰)), 177.4 (C(1)); m/z (ESI^þ) 162 ([MþH]^þ, 100%); HRMS

(1H, q, J 7.1, C(

C(6)OH), 7.24e7.52 (10H, m, Ph); d_C(100 MHz, CDCl₃) 16.6 (C(

25.0, 26.4 (2ꢂ MeCMe), 28.2 (CMe₃), 37.5 (C(2)), 52.0 (NCH₂Ph), 52.1

(C(3)), 60.5 (C( )), 64.3 (C(7)), 68.8 (C(6)), 78.8 (C(5)), 80.3 (C(4)),

a)H), 4.31 (1H, d, J 13.8, NCH_AH_BPh), 5.00 (1H, br s,

a

)Me),

a

þ

81.2 (CMe₃), 108.4 (MeCMe), 127.1, 127.6 (p-Ph), 128.1, 128.5, 129.1,

(ESI^þ) C₆H₁₂NO₄([MþH]^þ) requires 162.0761; found 162.0767.

129.1 (o,m-Ph), 140.0, 141.8 (i-Ph), 171.3 (C(1)); m/z (ESI^þ) 500

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₄₂NO₆([MþH]^þ) requires

4.43. tert-Butyl (2⁰S,3⁰R,4⁰S)-2-[N(1⁰)-3⁰,4⁰-dihydroxy-3⁰,4⁰-O-

500.3007; found 500.3011.

isopropylidenepyrrolidin-2⁰-yl]acetate 82

4.41. tert-Butyl (2⁰S,3⁰S,4⁰R)-2-[N(1⁰)-3⁰,4⁰-dihydroxy-3⁰,4⁰-O-

Step 1: NaIO₄(321 mg, 1.50 mmol) was added to a solution of 77

(150 mg, 0.300 mmol, >99:1 dr) in MeOH (6 mL) at rt and the re-

sultant suspension was stirred at rt for 16 h. The reaction mixture

was then ﬁltered through a short plug of Celite^Ò(eluent MeOH) and

concentrated in vacuo. The residue was dissolved in Et₂O (6 mL)

and the resultant solution was ﬁltered through a short plug of

Celite^Ò(eluent Et₂O) and concentrated in vacuo to give 81 in >99:1

dr (134 mg).

isopropylidenepyrrolidin-2⁰-yl]acetate 79

Step 1: NaIO₄(139 mg, 0.650 mmol) was added to a solution of

76 (65 mg, 0.13 mmol, >99:1 dr) in MeOH (2.5 mL) at rt and the

resultant suspension was stirred at rt for 16 h. The reaction mixture

was then ﬁltered through a short plug of Celite^Ò(eluent MeOH) and

concentrated in vacuo. The residue was dissolved in Et₂O (5 mL)

and the resultant solution was ﬁltered through a short plug of

Celite^Ò(eluent Et₂O) and concentrated in vacuo to give 78 in >99:1

dr (57 mg). Puriﬁcation of an aliquot via ﬂash column chromatog-

raphy (gradient elution,10:1/5:130e40 ^ꢁC petrol/Et₂O) gave 78 as

Step 2: Pd(OH)₂/C (50% w/w of substrate, 67 mg) was added to

a stirred solution of the residue of 81 (134 mg) in MeOH (3 mL) at rt.

The resultant mixture was degassed and saturated with H₂before

being left to stir under an atmosphere of H₂(5 atm) for 18 h. The

reaction mixture was then ﬁltered through a short plug of Celite^Ò

(eluent MeOH) and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent EtOAc) gave 82 as a pale yellow oil

a white solid;³⁶mp 38e42 ^ꢁC; ½a ²_D⁵

þ3.0 (c 1.0 in CHCl₃); n_max(ATR)

ꢃ

2979, 2934 (CeH), 1730 (C]O); d_H(500 MHz, CDCl₃) 1.27 (3H, s,

MeCMe), 1.40 (3H, d, J 6.9, C(a)Me), 1.43 (9H, s, CMe₃), 1.46 (3H, s,

MeCMe), 2.13 (1H, dd, J 15.7, 7.9, C(2)H_A), 2.19 (1H, dd, J 15.7, 3.8,

C(2)H_B), 3.66 (1H, d, J 15.0, NCH_AH_BPh), 3.79 (1H, d, J 15.0,

NCH_AH_BPh), 3.91 (1H, ddd, J 14.2, 7.9, 3.8, C(3)H), 3.91 (1H, q,

(42 mg, 54% from 77, >99:1 dr); ½a _D²⁵

þ46.4 (c 1.0 in CHCl₃); n_max

ꢃ

(ATR) 3292 (NeH), 2979, 2934 (CeH), 1727 (C]O); d_H(400 MHz,

CDCl₃) 1.28 (3H, s, MeCMe), 1.41 (3H, s, MeCMe), 1.43 (9H, s, CMe₃),

2.28 (1H, br s, NH), 2.50 (1H, dd, J 16.5, 6.7, C(2)H_A), 2.59 (1H, dd, J

16.5, 7.1, C(2)H_B), 2.61 (1H, dd, J 13.1, 3.9, C(5⁰)H_A), 2.98 (1H, app td, J

6.8, 4.2, C(2⁰)H), 3.04 (1H, app d, J 13.1, C(5⁰)H_B), 4.56 (1H, dd, J 5.5,

4.2, C(3⁰)H), 4.65 (1H, app dd, J 5.5, 3.9, C(4⁰)H); d_C(100 MHz, CDCl₃)

23.9, 25.7 (2ꢂ MeCMe), 28.1 (CMe₃), 34.6 (C(2)), 52.8 (C(5⁰)), 59.7

J 6.9, C(

C(5)H), 7.23e7.36 (10H, m, Ph), 9.53 (1H, d, J 3.5, C(6)H); d_C

(125 MHz, CDCl₃) 18.9 (C(

)Me), 25.0, 27.3 (2ꢂ MeCMe), 28.0

(CMe₃), 35.9 (C(2)), 50.3 (NCH₂Ph), 53.8, 59.7 (C(3), C( )), 80.2

(C(4)), 80.6 (C(5)), 81.1 (CMe₃), 110.3 (MeCMe), 127.0, 127.4 (p-Ph),

a)H), 4.29 (1H, dd, J 14.2, 6.6, C(4)H), 4.31 (1H, dd, J 6.6, 3.5,

a

S.G. Davies et al. / Tetrahedron 69 (2013) 8680e8704

8703

(C(2⁰)), 80.6 (CMe₃), 81.3 (C(3⁰)), 81.6 (C(4⁰)), 110.5 (MeCMe), 171._þ1

(C(1)); m/z (ESI^þ) 258 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₃H₂₄NO₄

([MþH]^þ) requires 258.1700; found 258.1696.

13. (a) Zhu, S.; Zhang, Q.; Gudise, C.; Wei, L.; Smith, E.; Zeng, Y. Bioorg. Med. Chem.

€

2009 , 17 , 4496; (b) Fulep, G. H.; Hoesl, C. E.; Hofner, G.; Wanner, K. T. Eur. J. Med.

Chem. 2006 , 41 , 809.

14. (a) Aguilar, M.-I.; Pucell, A. W.; Devi, R.; Lew, R.; Rossjohn, J.; Smith, A. I.;

ꢀ

Perlmutter, P. Org. Biomol. Chem. 200 7 , 5 , 2884; (b) Katarzynska, J.; Mazur, A.;

Bilska, M.; Adamek, E.; Zimecki, M.; Jankowski, S.; Zabrocki, J. J. Pept. Sci. 2008 ,

14 , 1283.

4.44. (2⁰S,3⁰R,4⁰S)-2-[N(1⁰)-3⁰,4⁰-Dihydroxypyrrolidin-2⁰-yl]-

acetic acid 83

15. (a) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;

ꢀ

Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J.

E. Tetrahedron: Asymmetry 2007 , 18 , 2510; (b) Abraham, E.; Brock, E. A.; Can-

dela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.;

A solution of 82 (42 mg, 0.16 mmol, >99:1 dr) in 2.0 M aq HCl

(2 mL) was heated at reﬂux for 8 h. The reaction mixture was

allowed to cool to rt and was then concentrated in vacuo. Puriﬁ-

cation via ion-exchange chromatography (DOWEX 50WX8-200,

eluent 1.0 M aq NH₄OH) gave 83 as a pale orange solid (22 mg, 84%,

ꢀ

Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Scott, P. M.; Smith, A. D.;

Thomson, J. E. Org. Biomol. Chem. 2008 , 6 , 1665; (c) Davies, S. G.; Mujtaba, N.;

Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett. 2009 , 1 1 , 1959; (d) Davies, S.

G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D. Tetrahedron 2009 , 65 , 10192; (e)

Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Savory, E.

D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009 , 20 , 758; (f) Bagal,

S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.;

Thomson, J. E. Tetrahedron Lett. 2011 , 52 , 2216; (g) Brock, E. A.; Davies, S. G.; Lee,

J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 20 1 1 , 13 , 1594; (h) Davies, S. G.; Lee,

J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron Lett. 20 1 1 , 52 , 6477; (i)

Davies, S. G.; Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.; Roberts, P. M.;

Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Tetrahedron 2011 ,

67 , 9975; (j) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.

Org. Lett. 2011 , 13 , 2544; (k) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.;

Thomson, J. E. Org. Lett. 2012 , 14 , 4278; (l) Davies, S. G.; Lee, J. A.; Roberts, P. M.;

Thomson, J. E.; West, C. J. Tetrahedron 2012 , 68 , 4302; (m) Davies, S. G.; Fletcher,

A. M.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Taylor, R. J.; Thomson, A. D.;

Thomson, J. E. Org. Lett. 2012 , 14 , 1672; (n) Davies, S. G.; Huckvale, R.; Lee, J. A.;

Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2012 , 68 , 3263; (o)

>99:1 dr); mp 160e170 ^ꢁC (dec); ½a _D²⁵

ꢀ9.9 (c 1.0 in H₂O); n_max

ꢃ

(ATR) 3368 (OeH), 3085, 2932 (CeH), 2323, 2139 (NH^þ₃) 1526, 1396

(CO^ꢀ₂); d_H(500 MHz, D₂O) 2.58 (1H, dd, J 16.9, 8.5, C(2)H_A), 2.63 (1H,

dd, J 16.9, 6.0, C(2)H_B), 3.05 (1H, dd, J 12.0, 7.9, C(5⁰)H_A), 3.42 (1H, dd,

J 12.0, 7.9, C(5⁰)H_B), 3.75 (1H, ddd, J 8.5, 6.0, 4.0, C(2⁰)H), 4.15 (1H,

app t, J 4.0, C(3⁰)H), 4.42 (1H, app td, J 7.9, 4.0, C(4⁰)H); d_C(125 MHz,

D₂O) 34.0 (C(2)), 46.8 (C(5⁰)), 59.2 (C(2⁰)), 70.0 (C(4⁰)), 70.7 (C(3⁰)),

177.6 (C(1)); m/z (ESI^þ) 162 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₆H₁₂NO₄^þ([MþH]^þ) requires 162.0761; found 162.0765.

Supplementary data

ꢀ

Davies, S. G.; Fletcher, A. M.; Lebee, C.; Roberts, P. M.; Thomson, J. E.; Yin, J.

Tetrahedron 2013 , 69 , 1369.

Supplementary data related to this article can be found at http://

dx.doi.org/10.1016/j.tet.2013.07.096.

16. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991 , 2 , 183; (b) Davies, S.

G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price

Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006 , 17 ,

1 7 93; (c) Davies, S. G.; Garner, A. C.; Nicholson, R. L.; Osborne, J.; Roberts, P. M.;

Savory, E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2009 , 7 , 2604; (d)

Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.;

Toms, S. M. Tetrahedron 2010 , 66 , 4604; (e) Abraham, E.; Bailey, C. W.; Claridge,

T. D. W.; Davies, S. G.; Ling, K. B.; Odell, B.; Rees, T. L.; Roberts, P. M.; Russell, A.

J.; Smith, A. D.; Smith, L. J.; Storr, H. R.; Sweet, M. J.; Thompson, A. L.; Thomson,

J. E.; Tranter, G. E.; Watkin, D. J. Tetrahedron: Asymmetry 2010 , 21 , 1 7 97; (f)

Abraham, E.; Claridge, T. D. W.; Davies, S. G.; Odell, B.; Roberts, P. M.; Russell, A.

J.; Smith, A. D.; Smith, L. J.; Storr, H. R.; Sweet, M. J.; Thompson, A. L.; Thomson,

J. E.; Tranter, G. E.; Watkin, D. J. Tetrahedron: Asymmetry 2011 , 22 , 69; (g) Davies,

S. G.; Fletcher, A. M.; Lv, L.; Roberts, P. M.; Thomson, J. E. Tetrahedron Lett. 2012 ,

53 , 3052; (h) Davies, S. G.; Fletcher, A. M.; Lv, L.; Roberts, P. M.; Thomson, J. E.

Tetrahedron: Asymmetry 2012 , 23 , 910.

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Article Doi

Asymmetric syntheses of dihydroxyhomoprolines via doubly diastereoselective lithium amide conjugate addition reactions

DOI: 10.1016/j.tet.2013.07.096

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