Trading N and O. Part 2: Exploiting aziridinium intermediates for the synthesis of β-hydroxy-α-amino acids

Article abstract of DOI:10.1016/j.tet.2014.06.057

The β-hydroxy-α-amino acids (S,S)-allo-threonine, (S,S)-β-hydroxyleucine and a range of aryl substituted (S,S)-β-hydroxyphenylalanines were prepared from the corresponding enantiopure anti-α-hydroxy-β-amino esters via a rearrangement protocol, which proceeds via the intermediacy of the corresponding aziridinium ions. The starting anti-α-hydroxy-β-amino esters were prepared in >99:1 dr using our diastereoselective aminohydroxylation procedure, whereby conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester is followed by oxidation of the resultant enolate with (-)-camphorsulfonyloxaziridine. Subsequent activation of the hydroxyl group within the anti-α-hydroxy-β-amino esters promoted aziridinium ion formation [which proceeds with inversion of configuration at C(2)], and regioselective ring-opening of the intermediate aziridinium ions with H₂O [which proceeds with inversion of configuration at C(3)] gave the corresponding anti-β-hydroxy-α-amino esters as single diastereoisomers (>99:1 dr). Deprotection of these substrates via sequential hydrogenolysis and ester hydrolysis gave the corresponding β-hydroxy-α-amino acids in good yield and high diastereoisomeric and enantiomeric purity.

Full text of DOI:10.1016/j.tet.2014.06.057

Tetrahedron xxx (2014) 1e14
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Trading N and O. Part 2: Exploiting aziridinium intermediates
for the synthesis of b-hydroxy-a-amino acids
*
Stephen G. Davies , Ai M. Fletcher, Aileen B. Frost, 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:
The
(S,S)-
amino esters via a rearrangement protocol, which proceeds via the intermediacy of the corresponding
aziridinium ions. The starting anti- -hydroxy- -amino esters were prepared in >99:1 dr using our di-
astereoselective aminohydroxylation procedure, whereby conjugate addition of lithium (R)-N-benzyl-N-
-methylbenzyl)amide to an -unsaturated ester is followed by oxidation of the resultant enolate with
(ꢀ)-camphorsulfonyloxaziridine. Subsequent activation of the hydroxyl group within the anti- -hy-
droxy- -amino esters promoted aziridinium ion formation [which proceeds with inversion of configu-
ration at C(2)], and regioselective ring-opening of the intermediate aziridinium ions with H2O
[which proceeds with inversion of configuration at C(3)] gave the corresponding anti- -hydroxy-
amino esters as single diastereoisomers (>99:1 dr). Deprotection of these substrates via sequential
b
b
-hydroxy-
a
-amino acids (S,S)-allo-threonine, (S,S)-
b
-hydroxyleucine and a range of aryl substituted
Received 21 March 2014
Received in revised form 26 May 2014
Accepted 10 June 2014
Available online xxx
-hydroxyphenylalanines were prepared from the corresponding enantiopure anti-
a
-hydroxy-
b-
a
b
(
a
a,b
Keywords:
a
Asymmetric synthesis
Lithium amide
Aziridinium
b
b
a-
b
-Hydroxy-a-amino acids
hydrogenolysis and ester hydrolysis gave the corresponding
high diastereoisomeric and enantiomeric purity.
b
-hydroxy-a-amino acids in good yield and
Ó 2014 Published by Elsevier Ltd.
1. Introduction
-Hydroxy- -amino acids are an important class of compounds
methodology)10e13 to the corresponding N-Boc protected aziridines
7 and 8, respectively, followed by regioselective ring-opening at the
C(3)-position. Aziridines 7 and 8 were therefore produced from
b
a
because they occur naturally (e.g., serine, threonine and
3-hydroxyproline) and are also present as components within an
array of more complex, biologically active natural products, such as
antibiotics (e.g., vancomycin) and immunosuppressants (e.g.,
ciclosporin).1 As a result of the impressive biological activity which
this class of compounds displays, a number of elegant strategies for
their synthesis in enantiopure form have been developed,2 in-
cluding several different aldol protocols,3 enzymatic methods,4
oxy-Michael reactions,5 organocatalytic systems,6 and dynamic
kinetic resolution processes,7 amongst other approaches.8
a-hydroxy-b-amino esters 5 and 6 via a three-step reaction
sequence of: (i) hydrogenolysis and in situ N-Boc protection;
(ii) OH-activation; and (iii) base-promoted aziridine formation.
Subsequent regioselective ring-opening of the C(3)-methyl
substituted aziridine 7 with Cl3CCO2H proceeded with inversion
of configuration at the C(3)-position to give the corresponding
2-amino-3-trichloroacetate ester 9, whereas the analogous re-
action with the C(3)-phenyl substituted aziridine 8 resulted in
rearrangement to the corresponding oxazolidin-2-one 11 with
retention of configuration at the C(3)-position. In each case,
hydrolysis of the products from these ring-opening reactions
We have recently described asymmetric syntheses of (S,S)-2-
amino-3-hydroxybutanoic acid [(S,S)-allo-threonine] 10 and
produced the corresponding enantiopure
b-hydroxy-a-amino
(2S,3R)-2-amino-3-hydroxy-3-phenylpropanoic
hydroxyphenylalanine] 13, and the corresponding C(2)-epimers in
both cases.9 Our synthetic strategy involved conversion of
-hy-
droxy- -amino esters 5 and 6 (which were obtained in >99:1 dr
upon aminohydroxylation of -unsaturated esters 1 and
acid
[(S,S)-
b
-
acids 10 and 13 in high diastereoisomeric purity (Scheme 1). The
analogous series of reactions was then conducted in the epimeric
a
series following C(2)-epimerisation of anti-
esters and via sequential oxidation/diastereoselective
reduction protocol.
Herein we report an extension of this methodology in which
OH-activation of -hydroxy- -amino esters 14 promotes migra-
a-hydroxy-b-amino
b
5
6
a
a
,b
2
using our established lithium amide conjugate addition
a
b
tion of the amino group to the C(2)-position via the intermediacy
DOI of original article: http://dx.doi.org/10.1016/j.tet.2013.08.007.
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G.
Davies).
of the corresponding aziridinium species 15,14 followed by
deprotection of the resultant
b-hydroxy-a-amino esters 16
http://dx.doi.org/10.1016/j.tet.2014.06.057
0040-4020/Ó 2014 Published by Elsevier Ltd.
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2
S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
a reduction in the number of reaction steps and increased overall
atom economy.
2. Results and discussion
2.1. Asymmetric synthesis of b-aryl-b-hydroxy-a-amino acids
Racemic
system to investigate this rearrangement process and optimise
procedures for the synthesis of -hydroxy- -amino esters. -Hy-
droxy- -amino ester 18 was prepared as a single diastereoisomer
(>99:1 dr) upon conjugate addition of lithium N,N-dibenzylamide
a-hydroxy-b-amino ester 18 was selected as a model
b
a
a
b
to
a,b-unsaturated ester 2, followed by oxidation of the in-
termediate lithium (Z)-
b
-amino enolate15 with (ꢀ)-CSO 4.16 Sub-
sequent activation of the hydroxyl group within 18 under either
Appel17 or mesylation14b conditions gave
20 as the sole reaction product in 75 or 80% yield, respectively
(Scheme 2). The relative anti-configuration within -chloro-
b-chloro-a-amino ester
b
a-
amino ester 20 was determined unambiguously via single crystal
X-ray diffraction analysis (Fig. 2).18 This stereochemical outcome is
Scheme 2.
Scheme 1.
(X¼OH) to give
b-hydroxy-a-amino acids 17. The stereochemical
outcome of this process would therefore constitute overall in-
version of configuration, as inversion of configuration occurs at
C(2) during the formation of aziridinium intermediate 15 and
inversion of configuration occurs at C(3) upon ring-opening of 15
(Fig. 1). This approach would therefore provide significant ad-
vantages over our first generation approach in terms of both
Fig. 1. Proposed second-generation synthesis of
b-hydroxy-a-amino acids 17.
Fig. 2. X-ray crystal structure of (RS,SR)-20 (selected H atoms are omitted for clarity).
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S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
3
entirely consistent with our proposed strategy, involving inversion
of configuration at C(2) during the formation of aziridinium in-
termediate 19 and inversion of configuration at C(3) upon ring-
opening of 19 with chloride.
aliquot was removed and worked-up 1 h after the H2O was added
and revealed the presence of only b-mesylate 22 (>99:1 dr). The
atom connectivity within 22 was established by 1H/13C NMR HMBC
analysis, confirming that this reaction must proceed via the in-
termediacy of aziridinium 19, followed by regioselective ring-
opening with mesylate (reversibly in the first instance) then ring-
opening of aziridinium 19 with H2O (Scheme 3).
b
-Chloro-
mixture of EtOAc/H2O, which promoted substitution of the chloro
group to give -hydroxy- -amino ester 21 in 89% yield and >99:1
a-amino ester 20 was then treated with AgOTf in a 4:1
b
a
dr (Scheme 3). The relative anti-configuration within 21 was de-
termined unambiguously via single crystal X-ray diffraction anal-
ysis (Fig. 3),18 establishing that the stereochemical outcome of this
reaction (i.e., retention of configuration) is consistent with an SN1-
type neighbouring group participation process proceeding again
via the intermediacy of aziridinium 19. However, it was also found
The optimised procedures for rearrangement of the racemic
model system were next applied to enantiopure
a
-hydroxy-
b-
amino ester 6,9 both via the corresponding
b-chloro-a-amino ester
23 and directly from 6.19 Activation of the hydroxyl group within 6
with MsCl gave 23 as a single diastereoisomer (>99:1 dr) in 81%
isolated yield (Scheme 4). The relative configuration within 23 was
determined unambiguously via single crystal X-ray diffraction
that
b
-hydroxy-a-amino ester 21 could be obtained directly from a-
hydroxy-
b
-amino ester 18 upon treatment with Ms2O and Et3N in
analysis, and the absolute (2R,3S,
assigned by reference to the known (R)-configuration of the
-methylbenzyl fragment (Fig. 4).18 Subsequent treatment of
23 with AgOTf in EtOAc/H2O (4:1) gave -hydroxy- -amino ester
aR)-configuration within 23 was
CH2Cl2, followed by the addition of H2O after 1 h; after a further
24 h stirring at rt, 21 was isolated in 54% yield as a single di-
astereoisomer (>99:1 dr). When this reaction was repeated, an
a
b
a
24 in 90% yield and >99:1 dr, and the relative anti-configuration
within 24 was assigned by analogy to that within 21. However,
a superior yield of
b-hydroxy-a-amino ester 24 was obtained
directly from -hydroxy-
a
b
-amino ester 6, giving 24 in 82% yield
and >99:1 dr. Hydrogenolytic deprotection of 24 gave 25 in 71%
yield and >99:1 dr, which was followed by hydrolysis of 25 to
20
give
b
-hydroxyphenylalanine 26 {mp 183e188 ꢁC (dec); [
a
]
D
þ1.9
20
(c 1.0, H2O); lit.8a mp 174 ꢁC (dec); lit.20
[
a
]
ꢀ4.3 (c 1.1, H2O)} in
D
quantitative yield and ꢂ96:4 dr, thereby confirming the assigned
configurations within 24 and 25 (Scheme 4).
Scheme 3.
Scheme 4.
The substrate scope of this methodology was demonstrated by
preparing a range of aryl substituted
52e56, incorporating both electron-donating and electron-
withdrawing groups. The requisite -hydroxy- -amino ester sub-
strates 32e36 were prepared, in 67e85% yield, and >99:1 dr in
each case, upon conjugate addition of lithium (R)-N-benzyl-N-(
methylbenzyl)amide 3 to
-unsaturated esters 27e31,21 followed
by reaction of the resultant lithium (Z)-
-amino enolates15 with
b-hydroxyphenylalanines
a
b
a
-
a,b
Fig. 3. X-ray crystal structure of (RS,RS)-21 (selected H atoms are omitted for clarity).
b
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4
S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
Fig. 4. X-ray crystal structure of (2R,3S,aR)-23 (selected H atoms are omitted for
clarity).
(ꢀ)-CSO 4. Under optimised conditions, treatment of this range of
substrates 32e36 with Ms2O and Et3N in CH2Cl2 promoted rear-
rangement to mesylates 37e41,22 which were then stirred with H2O
to give
(>99:1 dr) in 55e88% yield (Scheme 5). Single crystal X-ray dif-
fraction analysis of the p-fluoro substituted -hydroxy- -amino
ester 45 allowed the relative configuration within 45 to be de-
termined unambiguously (Fig. 5);18 the absolute (2S,3S,
R)-con-
figuration within 45 was then assigned by reference to the known
b-hydroxy-a-amino esters 42e46 as single diastereoisomers
Scheme 5. aAfter H2O was added the reaction mixture was heated at 40 ꢁC for 48 h.
bAfter H2O was added the reaction mixture was heated at 40 ꢁC for 24 h. cH2O was
added after only 1 min then the reaction mixture was stirred at rt for 24 h.
b
a
a
(R)-configuration of the a-methylbenzyl fragment, and the config-
conditions produced a 24:76 mixture of
a-hydroxy-b-amino ester
urations within 42e44 and 46 were assigned by analogy.23
Deprotection of 42e46 via hydrogenolysis in the presence of
Pearlman’s catalyst [Pd(OH)2/C] followed by hydrolysis of 47e51,
59 and -hydroxy- -amino ester 63, as single diastereoisomers
b
a
(>99:1 dr) in each case. These reaction outcomes are consistent
with poor regioselectivity upon ring-opening of the corresponding
aziridinium intermediates with H2O.26 Alternative reaction condi-
tions were therefore examined whereby Tf2O was used instead of
Ms2O and, after 3 h, H2O was added and the reaction mixture was
then allowed to stir at rt for 24 h. After work-up a 34:66 mixture of
gave aryl substituted
b-hydroxyphenylalanines 52e56 in good
overall yield and ꢂ93:7 dr in each case (Scheme 5).24
2.2. Asymmetric synthesis of
acids
b-alkyl-b-hydroxy-a-amino
a-hydroxy-b-amino ester 58 (>99:1 dr) and b-hydroxy-a-amino
ester 62 (>99:1 dr) was isolated. However, repeating this reaction
substituting 2,6-di-tert-butyl-4-methylpyridine 64 as the base was
The compatibility of this protocol with substrates bearing
b-al-
kyl substituents was examined next, and racemic
a
-hydroxy-
b
-
found to produce b-hydroxy-a-amino ester 62 exclusively, which
was then isolated in 54% yield and >99:1 dr after chromatographic
purification (Scheme 6).
amino alcohols 58 (R¼Me) and 59 (R¼iPr) were evaluated as model
systems in the first instance. Conjugate addition of lithium N,N-
dibenzylamide to
oxidation of the intermediate lithium (Z)-
a
,
b
-unsaturated esters 1 and 57, followed by
These optimised conditions were next applied to enantiopure
b
-amino enolate15 with
substrates 5 (R¼Me) and 65 (R¼iPr).
a-Hydroxy-b-amino esters 5
(ꢀ)-CSO 4, gave 58 and 59 in 50 and 52% yield, respectively, and
>99:1 dr in each case.25 Activation of the hydroxyl groups within
both 58 and 59, under our standard conditions, gave the corre-
and 65 were prepared in 91 and 56% yield, respectively, and in
>99:1 dr in each case, using our standard aminohydroxylation
procedure.10e13 Treatment of either 5 or 65 with Tf2O and 2,6-di-
tert-butyl-4-methylpyridine 64 followed, after 4e6 h, by the ad-
sponding b
-mesylates 60 and 61 (as determined by 1H/13C NMR
HMBC spectroscopic analysis of the crude reaction mixtures), in 90
and 60% conversion from 58 and 59, respectively. In an effort to
promote the hydrolysis of these mesylates, subsequent addition of
MeCN/H2O (2:1) to 60 and heating the resultant mixture at 50 ꢁC
dition of H2O gave b-hydroxy-a-amino esters 68 and 69, re-
spectively, in 68% yield and >99:1 dr in both cases (Scheme 7). The
relative configuration within 69 (R¼iPr) was determined un-
ambiguously via single crystal X-ray diffraction analysis (Fig. 6),18
produced a 41:59 mixture of
a
-hydroxy-b-amino ester 58 and
and the absolute (2S,3S,
aR)-configuration within 69 was assigned
b
-hydroxy- -amino ester 62, and treatment of 59 under identical
a
by reference to the known (R)-configuration of the a-methylbenzyl
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S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
5
Fig. 5. X-ray crystal structure of (2S,3S,aR)-45 (selected H atoms are omitted for
clarity).
Scheme 7.
Scheme 6. aProduced as single diastereoisomers (>99:1 dr).
fragment; the configuration within 68 was then assigned by anal-
ogy. Subsequent deprotection of both 68 and 69 via hydrogenolysis
in the presence of Pearlman’s catalyst gave 70 and 71 in 71% and
quantitative yield, respectively, as single diastereoisomers (>99:1
dr). Finally, hydrolysis of 70 and 71 in 6.0 M aq HCl gave (S,S)-allo-
threonine 10 in 64% yield and ꢂ97:3 dr, and (S,S)-
b-hydroxyleucine
72 in 69% yield and ꢂ96:4 dr, respectively (Scheme 7). The spec-
troscopic data, including specific rotations, for the samples of
Fig. 6. X-ray crystal structure of (2S,3S,aR)-69 (selected H atoms are omitted for
clarity).
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6
S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
(S,S)-10 {mp 215e225 ꢁC (dec); [
a]
20þ7.6 (c 1.0, H2O); lit.3e mp
and the resultant mixture was stirred at ꢀ78 ꢁC for 2 h. (ꢀ)-CSO 4
(1.60 equiv) was then added and the reaction mixture was allowed
to warm to rt over 14 h. Satd aq NH4Cl was then added and the
reaction mixture was stirred at rt for 5 min, then concentrated in
vacuo. The residue was partitioned between CH2Cl2 and 10% aq
citric acid and the aqueous layer was extracted with three portions
of CH2Cl2. The combined organic extracts were washed sequentially
with satd aq NaHCO3 and brine, then dried and concentrated in
vacuo. The residue was then dissolved in Et2O and the resultant
solution was filtered, then concentrated in vacuo.
D
20
264e266 ꢁC (dec); lit.3e
[
a
]
þ8 (c 1.1, H2O)} and (S,S)-72 {mp
D
20
220e226 ꢁC (dec); [
a]
þ17.6 (c 1.0, H2O); lit.3e mp 187 ꢁC (dec);
D
lit.3e
[
a
]
D
25 þ20 (c 1.1, H2O)} were in good agreement with literature
values, thereby confirming the assigned configurations within
68e71.
3. Conclusion
In conclusion, a range of enantiopure anti-a-hydroxy-b-amino
esters were prepared in >99:1 dr using our diastereoselective
aminohydroxylation procedure. In each case, activation of the hy-
droxyl group within these substrates promoted aziridinium for-
mation, and subsequent regioselective ring-opening of the
4.3. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]butanoate 5
intermediate aziridiniums with H2O gave the corresponding anti-
b
-
Following the general procedure, BuLi (2.4 M in hexanes, 4.54 mL,
10.9 mmol) and (R)-N-benzyl-N-( -methylbenzyl)amine (2.39 g,
hydroxy- -amino esters as single diastereoisomers (>99:1 dr). The
a
a
stereochemical outcomes of these reactions (i.e., overall inversion
of configuration) are entirely consistent with this proposed mech-
11.3 mmol, >99:1 er) were reacted with 1 (1.00 g, 7.03 mmol, >99:1
dr) and 4 (2.74 g, 12.0 mmol) in THF (120 mL) at ꢀ78 ꢁC to give 5 in
>99:1 dr. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 10:1) gave 5 as a yellow solid (2.29 g, 91%,
anism. Following deprotection of the anti-
ters, (S,S)-allo-threonine, (S,S)- -hydroxyleucine and a range of six
(S,S)- -hydroxyphenylalanines were prepared in good overall yield
b-hydroxy-a-amino es-
b
b
>99:1 dr);9,28 mp 89e94 ꢁC; {lit.28 mp 88e89 ꢁC}; [
a]
23 ꢀ35.5 (c 1.0,
D
and high diastereoisomeric purity.
CHCl3); {lit.28
[
a]
25 ꢀ35.2 (c 1.0, CHCl3)}; dH (400 MHz, CDCl3) 1.08
D
(3H, d, J 7.0, C(4)H3), 1.32 (3H, d, J 6.8, C(a)Me), 1.36 (9H, s, CMe3),
4. Experimental
2.92 (1H, d, J 6.5, OH), 3.25 (1H, qd, J 7.0, 2.6, C(3)H), 3.87 (1H, d, J
14.7, NCHAHBPh), 3.97e4.04 (3H, m, C(2)H, C(a)H, NCHAHBPh),
4.1. General experimental
7.18e7.50 (10H, m, Ph).
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.27
Water was purified by an ElixÒ UV-10 system. All other reagents
were used as supplied (analytical or HPLC grade) without prior
purification. Organic layers were dried over MgSO4 or NaSO4. Thin
layer chromatography was performed on aluminium plates coated
with 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq KMnO4, or 10% ethanolic phosphomolybdic acid. Flash
column chromatography was performed on Kieselgel 60 silica.
Melting points were recorded on a Gallenkamp Hot Stage ap-
paratus. Optical rotations were recorded on a PerkineElmer 241
polarimeter with a water-jacketed 10 cm cell. Specific rotations are
reported in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL. IR
spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer
using an ATR module. Selected characteristic peaks are reported in
cmꢀ1. 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. Low-resolution mass
spectra were recorded on either a VG MassLab 20e250 or
a Micromass Platform 1 spectrometer. Accurate mass measure-
ments were run on either a Bruker MicroTOF internally calibrated
with polyalanine, or a Micromass GCT instrument fitted with
a Scientific Glass Instruments BPX5 column (15 mꢃ0.25 mm) using
amyl acetate as a lock mass.
4.4. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]-3-phenylpropanoate 6
Following the general procedure, BuLi (2.5 M in hexanes, 15.2 mL,
38.01 mmol) and (R)-N-benzyl-N-( -methylbenzyl)amine (8.26 g,
a
39.1 mmol, >99:1 er) were reacted with 2 (5.00 g, 24.5 mmol,
>99:1 dr) and 4 (9.55 g, 41.7 mmol) in THF (200 mL) at ꢀ78 ꢁC to
give 6 in >99:1 dr. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 15:1) gave 6 as a pale yellow solid
23
(9.77 g, 93%, >99:1 dr);29 mp 85e88 ꢁC; {lit.28 mp 87e88 ꢁC}; [
a]
D
ꢀ26.7 (c 1.0, CHCl3); {lit.28
[
a
]
25 ꢀ27.2 (c 1.0, CHCl3)}; dH (400 MHz,
D
CDCl3) 1.20 (9H, s, CMe3), 1.18e1.22 (3H, obsc d, C(a)Me), 2.91 (1H,
br s, OH), 3.92 (1H, d, J 14.9, NCHAHBPh), 4.22 (1H, d, J 14.9,
NCHAHBPh), 4.27e4.33 (2H, m, C(
C(2)H), 7.21e7.61 (15H, m, Ph).
a)H, C(3)H), 4.49 (1H, d, J 3.0,
4.5. (S,S)-2-Amino-3-hydroxybutanoic acid [(S,S)-allo-threo-
nine] 10
A solution of 70 (21 mg, 0.12 mmol, >99:1 dr) in 6.0 M aq HCl
(1 mL) was stirred at rt for 3 h, then concentrated in vacuo. H2O
(4 mL) and CHCl3 (3 mL) were added and the aqueous layer was
washed with CHCl3 (2ꢃ3 mL) then concentrated in vacuo. Purifi-
cation via ion exchange chromatography (DOWEX 50WX8-200,
eluent 1.0 M aq NH4OH) gave 10 as a white solid (9 mg, 64%, 97:3
dr);9 mp 215e225 ꢁC (dec); {lit.3e mp 264e266 ꢁC}; [
a
]
20 þ7.6 (c 1.0,
D
H2O); {lit.3e
[
a]
25 þ8.0 (c 1.1, H2O)}; dH (500 MHz, D2O) 1.11 (3H, d, J
D
6.6, C(4)H3), 3.75 (1H, d, J 4.0, C(2)H), 4.27 (1H, dq, J 6.6, 4.0, C(3)H).
4.6. tert-Butyl (RS,RS)-2-hydroxy-3-(N,N-dibenzylamino)-3-
phenylpropanoate 18
4.2. General procedure for the diastereoselective amino-
hydroxylation of a,b-unsaturated esters
Following the general procedure, BuLi (2.2 M in hexanes, 6.9 mL,
15.2 mmol) and Bn2NH (3.01 mL, 15.7 mmol) were reacted with 2
(2.00 g, 9.79 mmol, >99:1 dr) and 4 (3.82 g, 16.6 mmol) in THF
(80 mL) at ꢀ78 ꢁC to give 18 in >99:1 dr. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/EtOAc, 20:1) gave
18 as a white solid (2.94 g, 72%, >99:1 dr); mp 79e81 ꢁC; nmax (ATR)
3501 (OeH), 1724 (C]O); dH (400 MHz, CDCl3) 1.30 (9H, s, CMe3),
BuLi (1.55 equiv) was added dropwise to a stirred solution of the
requisite amine (1.60 equiv) in THF at ꢀ78 ꢁC and the resultant
solution was stirred at ꢀ78 ꢁC for 30 min. A solution of the requisite
a,b-unsaturated ester (1.0 equiv) in THF was then added via cannula
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057

S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
7
2.85 (1H, br s, OH), 3.46 (2H, d, J 13.9, N(CHAHBPh)2), 3.98 (2H, d, J
4.9. tert-Butyl (RS,RS)-2-(N,N-dibenzylamino)-3-(meth-
13.9, N(CHAHBPh)2), 4.11 (1H, d, J 4.3, C(3)H), 4.74e4.81 (1H, m,
C(2)H), 7.19e7.42 (15H, m, Ph); dC (100 MHz, CDCl3) 27.8 (CMe3),
54.8 (N(CH2Ph)2), 64.5 (C(3)), 72.7 (C(2)), 82.6 (CMe3), 126.9, 127.6,
128.0, 128.2, 128.8, 130.0 (o,m,p-Ph), 135.9, 139.8 (i-Ph), 173.0 (C(1));
anesulfonyloxy)-3-phenylpropanoate 22
Ms2O (25 mg, 0.144 mmol) was added to a solution of 18 (20 mg,
mol, >99:1 dr) and Et3N (29 L, 0.216 mmol) in CH2Cl2 (0.2 mL)
48
m
m
þ
m/z (ESIþ) 418 ([MþH]þ, 100%); HRMS (ESIþ) C27H32NO3
and the resultant mixture was stirred at rt for 1 h. H2O (0.026 mL,
7.2 mmol) was then added and the reaction mixture was stirred at
rt for 1 h. H2O (1 mL) was then added and the resultant mixture was
extracted with CH2Cl2 (3ꢃ2 mL). The combined organic extracts
were washed sequentially with 1.0 M aq HCl (3 mL), satd aq
NaHCO3 (3 mL) and brine (3 mL), then dried and concentrated in
vacuo to give 22 as yellow oil (17 mg, >99:1 dr); dH (500 MHz,
CDCl3) 1.67 (9H, s, CMe3), 2.55 (3H, s, SO2Me), 3.41 (2H, d, J 13.6,
N(CHAHBPh)2), 3.75 (1H, d, J 10.7, C(2)H), 3.84 (2H, d, J 13.6,
N(CHAHBPh)2), 5.89 (1H, d, J 10.7, C(3)H), 6.88e7.52 (15H, m, Ph); dC
(125 MHz, CDCl3) 28.4 (CMe3), 39.2 (SO2Me), 54.8 (N(CH2Ph)2), 64.2
(C(2)), 82.6 (C(3)), 82.7 (CMe3), 127.2, 128.1, 128.5, 128.7, 129.1, 129.5
(o,m,p-Ph), 135.3, 137.9 (i-Ph), 168.3 (C(1)).
([MþH]þ) requires 418.2377; found 418.2379.
4.7. tert-Butyl (RS,SR)-2-(N,N-dibenzylamino)-3-chloro-3-
phenylpropanoate 20
Method A: MsCl (0.28 mL, 3.60 mmol), Et3N (1.10 mL,
8.27 mmol), and DMAP (5 mg) were added to a solution of 18
(300 mg, 0.719 mmol, >99:1 dr) in CH2Cl2 (20 mL) and the resultant
mixture was stirred at rt for 2 h. H2O (10 mL) was then added, the
aqueous layer was extracted with CH2Cl2 (3ꢃ10 mL) and the
combined organic extracts were washed sequentially with 1.0 M aq
HCl (20 mL), satd aq NaHCO3 (20 mL) and brine (20 mL), then dried
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/Et2O, 10:1) gave 20 as a white
solid (251 mg, 80%, >99:1 dr); mp 98e110 ꢁC; nmax (ATR) 1723
(C]O); dH (400 MHz, CDCl3) 1.66 (9H, s, CMe3), 3.35 (2H, d, J 13.4,
N(CHAHBPh)2), 3.72e3.86 (3H, m, C(2)H, N(CHAHBPh)2), 5.24 (1H, d,
J 11.1, C(3)H), 6.86e7.47 (15H, m, Ph); dC (400 MHz, CDCl3) 28.5
(CMe3), 54.5 (N(CH2Ph)2), 60.1 (C(3)), 66.9 (C(2)), 82.2 (CMe3), 127.2,
128.0, 128.3, 128.6, 128.7, 129.1 (o,m,p-Ph), 138.2, 138.2 (i-Ph), 168.6
(C(1)); m/z (ESIþ) 460 ([M(37Cl)þNa]þ, 30%), 458 ([M(35Cl)þNa]þ,
4.10. tert-Butyl (2R,3S,
aR)-2-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-chloro-3-phenylpropanoate 23
MsCl (0.179 mL, 2.32 mmol), Et3N (0.709 mL, 5.34 mmol) and
DMAP (5 mg) were added to a solution of 6 (200 mg, 0.464 mmol,
>99:1 dr) in CH2Cl2 (13 mL) and the resultant mixture was stirred
at rt for 2 h. H2O (10 mL) was then added and the aqueous layer was
extracted with CH2Cl2 (3ꢃ10 mL). The combined organic extracts
were washed sequentially with 1.0 M aq HCl (25 mL), satd aq
NaHCO3 (25 mL) and brine (25 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 20:1) gave 23 as a white solid (170 mg, 81%,
þ
100%); HRMS (ESIþ) C27H3035ClNNaO2 ([M(35Cl)þNa]þ) requires
458.1857; found 458.1865.
Method B: CCl4 (1.74 mL, 18.0 mmol) was added to a solution of
18 (500 mg, 1.20 mmol, >99:1 dr), PPh3 (630 mg, 2.40 mmol) in
PhMe (4 mL) and the resultant mixture was heated at 100 ꢁC for 2 h.
The reaction mixture was allowed to cool to rt and filtered, then
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/Et2O, 40:1) gave 20 as a white solid
(389 mg, 75%, >99:1 dr).
>99:1 dr); mp 90e93 ꢁC; [
(C]O); dH (400 MHz, CDCl3) 1.27 (3H, d, J 7.0, C(a)Me), 1.55 (9H, s,
a]
23 þ27.0 (c 1.0, CHCl3); nmax (ATR) 1723
D
CMe3), 3.70e3.82 (3H, m, C(2)H, C(
14.3, NCHAHBPh), 5.06 (1H, d, J 11.0, C(3)H), 7.24e7.42 (15H, m, Ph);
dC (100 MHz, CDCl3) 12.3 (C( )Me), 28.2 (CMe3), 50.7 (NCH2Ph), 55.8
(C( )), 61.5 (C(3)), 64.5 (C(2)), 82.0 (CMe3), 127.0, 127.1, 128.2, 128.4,
a)H, NCHAHBPh), 4.01 (1H, d, J
a
a
4.8. tert-Butyl (RS,RS)-2-(N,N-dibenzylamino)-3-hydroxy-3-
phenylpropanoate 21
128.4, 128.6, 128.7, 129.0 (o,m,p-Ph), 138.4, 139.3, 141.9 (i-Ph), 171.7
(C(1)); m/z (ESIþ) 474 ([M(37Cl)þNa]þ, 30%), 472 ([M(35Cl)þNa]þ,
þ
100%); HRMS (ESIþ) C28H3235ClNNaO2 ([M(35Cl)þNa]þ) requires
Method A (from 20): AgOTf (12 mg, 0.046 mmol) was added to
a solution of 20 (20 mg, 0.046 mmol, >99:1 dr) in EtOAc/H2O
(0.5 mL, 4:1) and the resultant mixture was stirred at rt for 16 h. The
reaction mixture was then filtered through alumina (eluent EtOAc)
and concentrated in vacuo to give 21 in >99:1 dr. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 5:1)
gave 21 as a white solid (17 mg, 89%, >99:1 dr); mp 133e136 ꢁC;
nmax (ATR) 3465 (OeH), 1722 (C]O); dH (500 MHz, CDCl3) 1.65 (9H,
s, CMe3), 2.74 (1H, d, J 4.1, OH), 3.43e3.54 (3H, m, C(2)H,
N(CHAHBPh)2), 3.90 (2H, d, J 13.9, N(CHAHBPh)2), 5.05 (1H, dd, J 9.4,
3.8, C(3)H), 6.94e7.41 (15H, m, Ph); dC (125 MHz, CDCl3) 28.6
(CMe3), 55.0 (N(CH2Ph)2), 66.5 (C(2)), 73.0 (C(3)), 82.2 (CMe3),
126.9, 127.8, 127.9, 128.1, 128.1, 128.8 (o,m,p-Ph), 138.6, 140.9 (i-Ph),
472.2014; found 472.2024.
4.11. tert-Butyl (2S,3S,aR)-2-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-hydroxy-3-phenylpropanoate 24
Method A (from 23): AgOTf (61 mg, 0.229 mmol) was added to
a solution of 23 (100 mg, 0.23 mmol, >99:1 dr) in EtOAc/H2O
(2.62 mL, v/v 4:1) and the resultant mixture was stirred at rt for
16 h, then filtered through alumina (eluent EtOAc) and concentrated
in vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 5:1) gave 24 as a white solid (89 mg,
90%, >99:1 dr); mp 78e85 ꢁC; [
3496 (CeO), 1722 (C]O); dH (400 MHz, CDCl3) 1.39 (3H, d, J 6.9,
a]
D
23 ꢀ22.7 (c 1.0, CHCl3); nmax (ATR)
171.6 (C(1)); m/z (ESIþ) 418 ([MþH]þ, 100%); HRMS (ESIþ)
C(
C(2)H), 3.94 (1H, d, J 14.2, NCHAHBPh), 4.01 (1H, q, J 6.9, C(
(1H, d, J 14.2, NCHAHBPh), 4.92 (1H, dd, J 8.0, 4.7, C(3)H), 6.86e7.39
(15H, m, Ph); dC (100 MHz, CDCl3) 13.4 (C( )Me), 28.2 (CMe3), 51.7
(NCH2Ph), 56.2 (C( )), 64.6 (C(2)), 74.6 (C(3)), 81.7 (CMe3), 126.7,
a)Me), 1.58 (9H, s, CMe3), 2.59 (1H, br s, OH), 3.60 (1H, d, J 8.0,
þ
C
27H32NO3 ([MþH]þ) requires 418.2377; found 418.2382.
a)H), 4.19
Method B (from 18): Ms2O (125 mg, 0.719 mmol) was added to
a solution of 18 (100 mg, 0.240 mmol >99:1 dr) and Et3N (0.14 mL,
1.1 mmol) in CH2Cl2 (1 mL) and the resultant solution was stirred at
a
a
rt for 1 h. H2O (26
m
L, 7.2 mmol) was added and the resultant
126.9, 127.5, 127.7, 127.9, 128.1, 128.1, 128.1, 129.0 (o,m,p-Ph), 139.9,
mixture was stirred at rt for 24 h. H2O (1 mL) was then added and
the resultant mixture was extracted with CH2Cl2 (3ꢃ2 mL). The
combined organic extracts were washed sequentially with 1.0 M aq
HCl (3 mL), satd aq NaHCO3 (3 mL) and brine (3 mL), then dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/Et2O, 5:1) gave 21 as a white solid
(54 mg, 54%, >99:1 dr).
141.2, 143.0 (i-Ph), 173.5 (C(1)); m/z (ESIþ) 432 ([MþH]þ, 100%);
þ
HRMS (ESIþ) C28H33NNaO3 ([MþNa]þ) requires 454.2353; found
454.2362.
Method B (from 6): Ms2O (121 mg, 0.695 mmol) was added to
a solution of 6 (100 mg, 0.23 mmol, >99:1 dr) and Et3N (0.139 mL,
1.04 mmol) in CH2Cl2 (1 mL) and the resultant mixture was stirred
at rt for 1 h, then H2O (0.125 mL, 6.96 mmol) was added and the
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057

8
S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
reaction mixture was stirred at rt for 24 h. H2O (1 mL) was then
added and the resultant mixture was extracted with CH2Cl2
(3ꢃ2 mL). The combined organic extracts were washed sequen-
tially with 1.0 M aq HCl (3 mL), satd aq NaHCO3 (3 mL) and brine
(3 mL), then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 4:1) gave
24 as a white solid (82 mg, 82%, >99:1 dr).
33 in >99:1 dr. Purification via flash column chromatography (el-
uent 30e40 ꢁC petrol/Et2O, 10:1) gave 33 as a pale yellow solid
20
(1.16 g, 82%, >99:1 dr); mp 73e79 ꢁC; [
a]
ꢀ34.6 (c 1.0, CHCl3);
D
nmax (ATR) 3485 (OeH), 1724 (C]O); dH (400 MHz, CDCl3) 1.39 (9H,
s, CMe3), 1.32e1.50 (3H, obsc d, C( )Me), 3.20 (1H, br s, OH), 4.13
(1H, d, J 15.0, NCHAHBPh), 4.37 (1H, d, J 15.0, NCHAHBPh), 4.41e4.50
(2H, m, C(3)H, C( )H), 4.61e4.70 (1H, m, C(2)H), 7.09e7.75 (14H, m,
Ar, Ph); dC (100 MHz, CDCl3) 14.8 (C( )Me) 27.4 (CMe3) 52.0
(NCH2Ph), 57.3 (C( )), 64.0 (C(3)), 73.1 (C(2)), 82.1 (CMe3), 114.4,
a
a
a
4.12. tert-Butyl (S,S)-2-amino-3-hydroxy-3-phenylpropanoate
a
25
116.8 (2ꢃd, J 21.5, C(20), C(40)), 125.5 (d, J 2.9, C(60)), 126.7, 127.0,
128.0, 128.0, 128.2, 128.3 (o,m,p-Ph), 129.4 (d, J 7.6, C(50)), 141.1 (d, J
6.7, C(10)), 143.9, 141.6 (i-Ph), 162.5 (d, J 245þ.1, C(30)), 172.0 (þC(1)); dF
(377 MHz, CDCl3) ꢀ112.9 (C(30)F); m/z (ESI ) 450 ([MþH] , 100%);
Pd(OH)2/C (22 mg, 25% w/w) was added to a degassed solution of
24 (89 mg, 0.21 mmol, >99:1 dr) in MeOH (1 mL) and the resultant
mixture was placed under an atmosphere of H2 (5 atm) and stirred
at rt for 16 h. The reaction mixture was then filtered through CeliteÒ
(eluent MeOH) and concentrated in vacuo to give 25 as a white solid
þ
HRMS (ESIþ) C28H33FNO3 ([MþH]þ) requires 450.2439; found
450.2439.
(35 mg, 71%, >99:1 dr); mp 151e154 ꢁC; [
a
]
20 þ44.7 (c 1.0, MeOH);
4.16. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(
a-methyl-
D
nmax (ATR) 3446 (OeH), 1732 (C]O); dH (400 MHz, CDCl3) 1.22 (9H,
s, CMe3), 4.07e4.15 (1H, m, C(2)H), 5.13e5.17 (1H, m, C(3)H),
7.19e7.36 (5H, m, Ph); dC (125 MHz, CDCl3) 26.8 (CMe3), 60.5 (C(2)),
74.6 (C(3)), 81.6 (CMe3), 126.4, 127.5, 127.8 (o,m,p-Ph), 140.3 (i-Ph),
benzyl)amino]-3-(30-methoxyphenyl)propanoate 34
Following the general procedure, BuLi (2.3 M in hexanes, 2.02 mL,
4.63 mmol) and (R)-N-benzyl-N-( -methylbenzyl)amine (1.15 g,
a
171.1 (C(1)); m/z (ESIþ) 260 ([MþNa]þ, 100%); HRMS (ESIþ)
4.78 mmol, >99:1 er) were reacted with 29 (700 mg, 2.99 mmol,
>99:1 dr) and 4 (1.17 g, 5.09 mmol) in THF (20 mL) at ꢀ78 ꢁC to give
34 in >99:1 dr. Purification via flash column chromatography (el-
þ
C
13H19NNaO3 ([MþNa]þ) requires 260.1257; found 260.1270.
4.13. (S,S)-2-Amino-3-hydroxy-3-phenyl propanoic acid 26
uent 30e40 ꢁC petrol/Et2O,10:1) gave 34 as a pale yellow oil (1.04 g,
20
75%, >99:1 dr); [
a
]
ꢀ30.8 (c 1.0, CHCl3); nmax (ATR) 3958 (OeH),
D
A solution of 25 (27 mg, 0.114 mmol, >99:1 dr) in 6.0 M aq HCl
(2 mL) was heated at 90 ꢁC for 18 h. The reaction mixture was then
allowed to cool to rt and concentrated in vacuo. Purification via ion
exchange chromatography (DOWEX 50WX8-200, eluent 1.0 M aq
NH4OH) gave 26 as a white solid (21 mg, quant, 96:4 dr);9 mp
1722 (C]O); dH (400 MHz, CDCl3) 1.23 (9H, s, CMe3), 1.17e1.26 (3H,
obsc d, C( )Me), 2.72 (1H, br s, OH), 3.79 (3H, s, OMe), 3.86 (1H, d, J
15.0, NCHAHBPh), 4.12 (1H, d, J 15.0, NCHAHBPh), 4.19 (1H, d, J 3.1,
C(3)H), 4.22 (1H, q, J 6.8, C( )H), 4.37 (1H, d, J, 3.1, C(2)H), 6.77e7.57
(14H, m, Ar, Ph); dC (100 MHz, CDCl3) 14.6 (C( )Me), 27.8 (CMe3),
52.4 (NCH2Ph), 55.2 (OMe), 57.4 (C( )), 65.4 (C(3)), 73.5 (C(2)), 82.2
a
a
a
183e188 ꢁC; {lit.30 mp 185e187 ꢁC}; [
ent-26 [
a
]
D
20 þ1.9 (c 1.0, H2O); {lit.9 for
a
20
a
]
ꢀ2.4 (c 1.0, H2O); nmax (ATR) 3135 (OeH, NeH), 1604
(CMe3), 112.9, 115.8, 122.4, 126.7 (C(20), C(40), C(50), C(60)), 126.7,
128.1, 128.1, 128.2, 128.3, 129.0 (o,m,p-Ph), 140.0 (C(10)), 141.9, 144.2
(i-Ph), 159.4 (C(30)), 172.3 (C(1)); m/z (ESIþ) 462 ([MþH]þ, 100%);
D
(C]O); dH (500 MHz, D2O) 4.01 (1H, d, J 4.1, C(2)H), 5.28 (1H, d, J 4.1,
C(3)H), 7.28e7.39 (5H, m, Ph).
þ
HRMS (ESIþ) C29H36NO4 ([MþH]þ) requires 462.2639; found
4.14. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(
a
-methyl-
462.2636.
benzyl)amino]-3-(40-trifluoromethylphenyl)propanoate 32
4.17. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(
a-methyl-
Following the general procedure, BuLi (2.5 M in hexanes, 1.73 mL,
3.98 mmol) and (R)-N-benzyl-N-(a-methylbenzyl)amine (993 mg,
benzyl)amino]-3-(40-fluorophenyl)propanoate 35
4.11 mmol, >99:1 er) were reacted with 27 (700 mg, 2.57 mmol,
>99:1 dr) and 4 (1.00 g, 4.37 mmol) in THF (20 mL) at ꢀ78 ꢁC to give
32 in >99:1 dr. Purification via flash column chromatography (el-
uent 30e40 ꢁC petrol/Et2O, 10:1) gave 32 as a pale yellow oil
Following the general procedure, BuLi (2.3 M in hexanes, 2.12 mL,
4.88 mmol) and (R)-N-benzyl-N-( -methylbenzyl)amine (1.22 g,
a
5.04 mmol, >99:1 er) were reacted with 30 (493 mg, 2.22 mmol,
>99:1 dr) and 4 (865 mg, 3.77 mmol) in THF (20 mL) at ꢀ78 ꢁC to
give 35 in >99:1 dr. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 10:1) gave 35 as a pale yellow oil
(865 mg, 67%, >99:1 dr); [
a
]
23 ꢀ27.5 (c 1.0, CHCl3); nmax (ATR) 3496
D
(OeH), 1722 (C]O); dH (400 MHz, CDCl3) 1.38 (9H, s, CMe3),
1.36e1.44 (3H, obsc d, C(
14.8, NCHAHBPh), 4.36 (1H, d, J 14.8, NCHAHBPh), 4.40e4.48 (1H, m,
C( )H), 4.54e4.59 (1H, m, C(3)H), 4.64e4.72 (1H, m, C(2)H),
7.34e7.89 (14H, m, Ar, Ph); dC (100 MHz, CDCl3) 15.5 (C( )Me), 27.7
(CMe3), 52.4 (NCH2Ph), 57.9 (C( )), 64.4 (C(3)), 73.2 (C(2)), 82.6
a
)Me), 3.24 (1H, br s, OH), 4.16 (1H, d, J
(819 mg, 82%, >99:1 dr); [
(OeH), 1723 (C]O); dH (400 MHz, CDCl3) 1.23 (9H, s, CMe3),
a
]
20 ꢀ26.7 (c 1.0, CHCl3); nmax (ATR) 3499
D
a
1.19e1.31 (3H, obsc d, C(
NCHAHBPh), 4.11 (1H, d, J 15.0, NCHAHBPh), 4.16e4.25 (2H, m, C(3)H,
C(
)H), 4.40e4.44 (1H, m, C(2)H), 7.01 (2H, app t, J 8.0, C(30)H,
C(50)H), 7.38 (2H, app t, J 8.0, C(20)H, C(60)H), 7.20e7.52 (10H, m, Ph);
dC (125 MHz, CDCl3) 14.7 (C( )Me) 27.8 (CMe3) 52.2 (NCH2Ph), 57.5
(C(
)), 64.7 (C(3)), 73.3 (C(2)), 82.4 (CMe3), 114.9 (d, J 21.5, C(30),
a)Me), 2.77 (1H, br s, OH), 3.85 (1H, d, J 15.0,
a
a
a
(CMe3), 124.5 (q, J 272.2, CF3), 124.9 (q, J 4.0, C(30), C(50)), 126.9,
127.2, 128.1, 128.1, 128.4, 128.5 (o,m,p-Ph), 129.7 (q, J 34.4, C(40)),
130.3 (C(20), C(60)), 143.1, 143.7 (i-Ph), 143.9 (C(10)), 172.4 (C(1)); dF
(377 MHz, CDCl3) ꢀ62.2 (CF3); m/z (ESIþ) 500 ([MþH]þ, 100%);
a
a
C(50)), 126.8, 127.0, 128.0, 128.0, 128.3, 128.4 (o,m,p-Ph), 131.6 (d, J
7.2, C(20), C(60)), 134.3 (C(10)), 141.9, 144.1 (i-Ph), 162.3 (d, J 246.þ4,
C(40)), 172.2 (C(1)); dF (377 MHz, CDCl3) ꢀ114.7 (C(40)F); m/z (ESI )
450 ([MþH]þ,100%); HRMS (ESIþ) C28H33FNO3þ ([MþH]þ) requires
450.2439; found 450.2435.
þ
HRMS (ESIþ) C29H33F3NO3 ([MþH]þ) requires 500.2407; found
500.2400.
4.15. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(
a-methyl-
benzyl)amino]-3-(30-fluorophenyl)propanoate 33
4.18. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(
a-methyl-
Following the general procedure, BuLi (2.3 M in hexanes, 2.12 mL,
4.88 mmol) and (R)-N-benzyl-N-( -methylbenzyl)amine (1.22 g,
benzyl)amino]-3-(40-methoxyphenyl)propanoate 36
a
5.04 mmol, >99:1 er) were reacted with 28 (700 mg, 3.15 mmol,
Following the general procedure, BuLi (2.3 M in hexanes, 2.02 mL,
4.63 mmol) and (R)-N-benzyl-N-( -methylbenzyl)amine (1.15 g,
>99:1 dr) and 4 (1.23 g, 5.36 mmol) in THF (20 mL) at ꢀ78 ꢁC to give
a
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057

S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
9
4.78 mmol, >99:1 er) were reacted with 31 (700 mg, 2.99 mmol,
>99:1 dr) and 4 (1.17 g, 5.08 mmol) in THF (20 mL) at ꢀ78 ꢁC to give
36 in >99:1 dr. Purification via flash column chromatography (el-
uent 30e40 ꢁC petrol/Et2O, 10:1) gave 36 as a yellow oil (1.18 g, 85%,
127.1, 128.0, 128.2, 128.9 (o,m,p-Ph), 129.4 (d, J 8.0, C(50)), 140.0,
142.9 (i-Ph),143.9 (d, J 7.2, C(10)),162.7 (d J 245.6, C(30)),173.2 (C(1)þ);
dF (377 MHz, CDCl3) ꢀ113.3 (C(30)F); m/z (ESIþ) 472 ([MþNa] ,
þ
100%); HRMS (ESIþ) C28H32FNNaO3
([MþNa]þ) requires
>99:1 dr); [
a
]
20 ꢀ24.5 (c 1.0, CHCl3); nmax (ATR) 3497 (OeH), 1722
472.2258; found 472.2247.
D
(C]O); dH (400 MHz, CDCl3) 1.26 (9H, s, CMe3), 1.22e1.37 (3H, obsc
d, C(
NCHAHBPh), 4.26 (1H, d, J 15.0, NCHAHBPh), 4.30e4.41 (2H, m,
C(3)H, C(
)H), 4.52e4.57 (1H, m, C(2)H), 6.96 (2H, d, J 7.8, C(30)H,
C(50)H), 7.45 (2H, d, J 7.8, C(20)H, C(60)H), 7.25e7.64 (10H, m, Ph); dC
(100 MHz, CDCl3) 14.6 (C( )Me), 27.8 (CMe3), 52.3 (NCH2Ph), 55.2
(OMe), 57.5 (C(
)), 64.8 (C(3)), 73.7 (C(2)), 82.0 (CMe3), 113.5 (C(30),
a
)Me), 3.16 (1H, br s, OH), 3.83 (3H, s, OMe), 3.97 (1H, d, J 15.0,
4.21. tert-Butyl (2S,3S,aR)-2-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-hydroxy-3-(30-methoxyphenyl)propanoate 44
a
Ms2O (227 mg, 1.30 mmol) was added to a solution of 34
(200 mg, 0.433 mmol, >99:1 dr) and Et3N (0.257 mL, 1.94 mmol) in
CH2Cl2 (1.72 mL) and the resultant mixture was stirred at rt for 1 h,
then H2O (0.240 mL, 13.3 mmol) was added and the resultant
mixture was stirred at rt for 24 h. H2O (3 mL) was then added and
the resultant mixture was extracted with CH2Cl2 (3ꢃ3 mL). The
combined organic extracts were washed sequentially with 1.0 M
aq HCl (4 mL), satd aq NaHCO3 (4 mL) and brine (4 mL), then dried
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/Et2O, 4:1) gave 44 as a yellow oil
a
a
C(50)), 128.2 (C(20), C(60)), 126.7, 126.9, 128.2, 128.2, 128.3, 131.2
(o,m,p-Ph), 130.5 (C(10)), 142.1, 144.5 (i-Ph), 159.1 (C(40)), 172.þ4
(C(1)); m/z (ESIþ) 462 ([MþH]þ, 100%); HRMS (ESIþ) C29H36NO4
([MþH]þ) requires 462.2639; found 462.2628.
4.19. tert-Butyl (2S,3S,aR)-2-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-hydroxy-3-(40-trifluoromethylphenyl)propanoate
42
(137 mg, 68%, >99:1 dr); [
(OeH), 1722 (C]O); dH (400 MHz, CDCl3) 1.38 (3H, d, J 6.9, C(a)Me),
a
]
20 ꢀ34.4 (c 1.0, CHCl3); nmax (ATR) 3502
D
Ms2O (52 mg, 0.30 mmol) was added to a solution of 32 (50 mg,
0.10 mmol, >99:1 dr) and Et3N (0.06 mL, 0.45 mmol) in CH2Cl2
(0.43 mL) and the resultant solution was stirred at rt for 1 h, then
H2O (0.054 mL, 3.00 mmol) was added and the resultant mixture
was stirred at 40 ꢁC for 48 h. H2O (1 mL) was added and the mixture
was extracted with CH2Cl2 (3ꢃ2 mL) and the combined organic
washed with 1.0 M aq HCl (3 mL), satd aq NaHCO3 (3 mL) and brine
(3 mL), then dried and concentrated in vacuo to give 42 in >99:1 dr.
Purification via flash column chromatography (eluent 30e40 ꢁC
1.58 (9H, s, CMe3), 2.77 (1H, br s, OH), 3.57 (1H, d, J 8.1, C(2)H), 3.66
(3H, s, OMe), 3.95 (1H, d, J 14.3, NCHAHBPh), 4.02 (1H, q, J 6.9,
C(a)H), 4.17 (1H, d, J 14.3, NCHAHBPh), 4.89 (1H, d, J 8.1, C(3)H),
6.37e6.40 (1H, m, C(20)H), 6.49 (1H, d, J 8.0, C(60)H), 6.74 (1H, app
dd, J 8.0, 2.5, C(40)H), 7.05 (1H, t, J 8.0, C(50)H), 6.95e7.22 (10H, m,
Ph); dC (100 MHz, CDCl3) 13.4 (C(
a
)Me), 28.2 (CMe3), 51.8
(NCH2Ph), 55.1 (OMe), 56.2 (C(
a
)), 64.9 (C(2)), 74.6 (C(3)), 81.7
(CMe3), 111.7 (C(20)), 114.3 (C(40)), 119.9 (C(60)), 129.0 (C(50)), 126.7,
126.9, 127.9, 128.1, 128.2, 129.0 (o,m,p-Ph), 139.9 (C(10)), 143.9, 143.1
(i-Ph), 159.4 (C(30)), 173.4 (C(1)); m/z (ESIþ) 462 ([MþH]þ, 100%);
petrol/Et2O, 5:1) gave 42 as a pale yellow oil (32 mg, 64%, >99:1 dr);
23
þ
[
a]
ꢀ30.5 (c 1.0, CHCl3); nmax (ATR) 3498 (OeH), 1722 (C]O); dH
HRMS (ESIþ) C29H36NO4 ([MþH]þ) requires 462.2639; found
D
(400 MHz, CDCl3) 1.39 (3H, d, J 6.9, C(
a
)Me), 1.59 (9H, s CMe3), 3.01
462.2640.
(1H, br s, OH), 3.60 (1H, d, J 8.3, C(2)H), 3.92 (1H, d, J 14.3,
NCHAHBPh), 4.02 (1H, q, J 6.9, C(
a
)H), 4.14 (1H, d, J 14.3, NCHAHBPh),
4.22. tert-Butyl (2S,3S,aR)-2-[N-benzyl-N-(a-methylbenzyl)-
4.90 (1H, d, J 8.3, C(3)H), 6.88 (2H, d, J 8.1, C(20)H, C(60)H), 6.90e7.22
amino]-3-hydroxy-3-(30-fluorophenyl)propanoate 45
(10H, m, Ph), 7.32 (2H, d, J 8.1, C(30)H, C(50)H); dC (100 MHz, CDCl3)
13.5 (C(
a
)Me), 28.1 (CMe3), 51.9 (NCH2Ph), 53.6 (C(
a
)), 64.8 (C(2)),
Ms2O (58 mg, 0.333 mmol) was added to a solution of 35
73.9 (C(3)), 82.1 (CMe3), 123.2 (q, J 271.8, CF3), 123.8 (q, J 3.8, C(30),
C(50)), 125.8, 126.1, 126.6, 126.9, 127.0, 127.9 (o,m,pPh), 127.2 (C(20),
C(60)), 128.7 (q, J 32.4, C(40)), 138.4, 141.8 (i-Ph), 144.3 (C(10)),
173.1 (C(1)); dF (377 MHz, CDCl3) ꢀ62.4 (CF3); m/z (ESIþ) 500
(50 mg, 0.11 mmol, >99:1 dr) and Et3N (66
CH2Cl2 (0.45 mL) and the resultant mixture was stirred at rt for 1 h,
then H2O (60 L, 3.3 mmol) was added and the resultant mixture
mL, 0.50 mmol) in
m
was stirred at rt for 24 h. H2O (1 mL) was then added and the re-
sultant mixture was extracted with CH2Cl2 (3ꢃ2 mL). The com-
bined organic extracts were washed sequentially with 1.0 M aq HCl
(3 mL), satd aq NaHCO3 (3 mL) and brine (3 mL), then dried and
concentrated in vacuo. Purification via flash column chromatog-
þ
([MþH]þ, 100%); HRMS (ESIþ) C29H32F3NNaO3 ([MþNa]þ) re-
quires 522.2226; found 522.2223.
4.20. tert-Butyl (2S,3S,aR)-2-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-hydroxy-3-(30-fluorophenyl)propanoate 43
raphy (eluent 30e40 ꢁC petrol/Et2O, 5:1) gave 45 as a pale yellow
20
oil (40 mg, 80%, >99:1 dr); [
a
]
ꢀ30.2 (c 1.0, CHCl3); nmax (ATR)
D
Ms2O (58 mg, 0.333 mmol) was added to a solution of 33 (50 mg,
3496 (OeH), 1722 (C]O); dH (400 MHz, CDCl3) 1.39 (3H, d, J 6.9,
C( )Me), 1.59 (9H, s, CMe3), 2.70 (1H, br s, OH), 3.56 (1H, d, J 8.4,
C(2)H), 3.92 (1H, d, J 14.2, NCHAHBPh), 4.01 (1H, q, J 6.9, C( )H), 4.11
(1H, d, J 14.2, NCHAHBPh), 4.87 (1H, d, J 8.4, C(3)H), 6.72e6.82 (4H,
m, Ar), 6.92e7.22 (10H, m, Ph); dC (100 MHz, CDCl3) 13.5 (C( )Me),
28.2 (CMe3), 51.7 (NCH2Ph), 56.3 (C( )), 64.7 (C(2)), 73.8 (C(3)), 81.9
0.111 mmol, >99:1 dr) and Et3N (66
(0.45 mL) and the resultant solution was stirred at rt for 1 h, then
H2O (60 L, 3.3 mmol) was added and the resultant mixture was
mL, 0.50 mmol) in CH2Cl2
a
a
m
stirred at 40 ꢁC for 24 h. H2O (1 mL) was added and the resultant
mixture was extracted with CH2Cl2 (3ꢃ2 mL). The combined or-
ganic extracts were washed sequentially with 1.0 M aq HCl (3 mL),
satd aq NaHCO3 (3 mL) and brine (3 mL), then dried and concen-
trated in vacuo to give 43 in >99:1 dr. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O, 5:1) gave 43 as
a
a
(CMe3), 114.9 (d, J 20.7, C(30), C(50)), 126.8, 127.0, 128.0, 128.1, 128.2,
129.0 (o,m,p-Ph), 129.1 (d, J 8.0, C(20), C(60)), 137.0 (d, J 2.4, C(10)),
143.0, 139.7 (i-Ph), 162.3 (d, J 244.8, C(40)), 173.4 (C(1)); dF
(377 MHz, CDCl3) ꢀ114.9 (C(40)F); m/z (ESIþ) 450 ([MþH]þ, 100%);
þ
a pale yellow oil (44 mg, 88%, >99:1 dr); [
nmax (ATR) 3498 (OeH), 1721 (C]O); dH (400 MHz, CDCl3) 1.39 (3H,
a
]
20 ꢀ29.0 (c 1.0, CHCl3);
HRMS (ESIþ) C28H33FNO3 ([MþH]þ) requires 450.2439; found
D
450.2442.
d, J 6.8, C(
8.0, C(2)H), 3.94 (1H, d, J 14.3, NCHAHBPh), 4.04 (1H, q, J 6.8, C(
4.14 (1H, d, J 14.3, NCHAHBPh), 4.87 (1H, d, J 8.0, C(3)H), 6.53e7.34
(14H, m, Ar, Ph); dC (100 MHz, CDCl3) 13.5 (C( )Me), 28.2 (CMe3),
a
)Me), 1.58 (9H, s, CMe3), 2.86 (1H, br s, OH), 3.56 (1H, d, J
a
)H),
4.23. tert-Butyl (2S,3S,aR)-2-[N-benzyl-N-(a-methylbenzyl)-
amino]-3-hydroxy-3-(40-methoxyphenyl)propanoate 46
a
51.9 (NCH2Ph), 56.3 (C(
a
)), 64.7 (C(2)), 74.1 (C(3)), 82.0 (CMe3), 114.1
Ms2O (114 mg, 0.65 mmol) was added to a solution of 36
(100 mg, 0.22 mmol, >99:1 dr) and Et3N (0.13 mL, 0.97 mmol) in
(2ꢃd, J 21.5, Ar), 114.6 (2ꢃd, J 21.5, Ar), 123.1 (d, J 2.4, C(60)), 126.9,
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057

10
S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
CH2Cl2 (0.86 mL) and the resultant solution was stirred at rt for
1 min, then H2O (0.12 mL, 6.66 mmol) was added and the resultant
mixture was stirred at rt for 24 h. H2O (2 mL) was then added and
the mixture was extracted with CH2Cl2 (3ꢃ4 mL). The combined
organic extracts were washed sequentially with 1.0 M aq HCl
(6 mL), satd aq NaHCO3 (6 mL) and brine (6 mL), then dried and
concentrated in vacuo to give 46 in >99:1 dr. Purification via flash
stirred at rt for 24 h. The reaction mixture was then filtered
through CeliteÒ (eluent MeOH) and concentrated in vacuo to give
20
49 as a colourless oil (36 mg, quant, >99:1 dr); [
a
]
þ21.4 (c 0.5,
D
MeOH); nmax (ATR) 3273 (OeH, NeH), 1733 (C]O); dH (400 MHz,
MeOH-d4) 1.22 (9H, s, CMe3), 3.71 (3H, s, OMe), 3.98 (1H, br s,
C(2)H), 5.06 (1H, br s, C(3)H), 6.78 (1H, dd, J 8.1, 2.2, C(50)H),
6.87e6.94 (2H, m, C(20)H, C(60)H), 7.19 (1H, t, J 8.1, C(40)H);
dC (100 MHz, MeOH-d4) 26.7 (CMe3), 54.4 (OMe), 58.9 (C(2)),
71.1 (C(3)), 83.3 (CMe3), 111.8, 118.2 (C(20), C(60)), 113.0 (C(50)),
129.1 (C(40)), 140.6 (C(10)), 159.9 (C(30)), 165.9 (C(1)); m/z (ESIþ)
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 4:1) gave
20
46 as a pale yellow oil (55 mg, 55%, >99:1 dr); [
a
]
ꢀ5.5 (c 1.0,
D
CHCl3); nmax (ATR) 3504 (OeH), 1722 (C]O); dH (400 MHz, CDCl3)
1.38 (3H, d, J 7.0, C( )Me), 1.59 (9H, s, CMe3), 2.52 (1H, br s, OH), 3.55
(1H, d, J 8.5, C(2)H), 3.84 (3H, s, OMe), 3.92 (1H, d, J 14.3,
þ
a
268 ([MþH]þ, 100%); HRMS (ESIþ) C14H21NNaO4 ([MþNa]þ)
requires 290.1363; found 290.1366.
NCHAHBPh), 3.98 (1H, q, J 7.0, C(a)H), 4.11 (1H, d, J 14.3, NCHAHBPh),
4.87 (1H, d, J 8.5, C(3)H), 6.66 (2H, d, J 8.6, C(30)H, C(50)H), 6.75 (2H,
d, J 8.6, C(20)H, C(60)H), 6.92e7.21 (10H, m, Ph); dC (100 MHz, CDCl3)
13.3 (C(a)Me), 28.2 (CMe3), 51.6 (NCH2Ph), 55.4 (OMe), 56.2 (C(a)),
4.27. tert-Butyl (S,S)-2-amino-3-hydroxy-3-(40-fluorophenyl)-
propanoate 50
64.5 (C(2)), 74.0 (C(3)), 81.6 (CMe3), 113.5 (C(30), C(50)), 128.1 (C(20),
C(60)), 126.7, 127.0, 127.9, 128.2, 128.7, 129.0 (o,m,p-Ph), 133.5þ(C(10)),
139.9, 143.0 (i-Ph), 159.2 (C(40)), 173.7 (Cþ(1)); m/z (ESI ) 462
([MþH]þ, 100%); HRMS (ESIþ) C29H36NO4 ([MþH]þ) requires
462.2639; found 462.2643.
Pd(OH)2/C (13 mg, 25% w/w) was added to a degassed solution
of 45 (65 mg, 0.15 mmol, >99:1 dr) in MeOH (3 mL) and the re-
sultant mixture was placed under an atmosphere of H2 (5 atm) and
stirred at rt for 16 h. The reaction mixture was then filtered through
CeliteÒ (eluent MeOH) and concentrated in vacuo to give 50 as
20
a colourless oil (30 mg, 81%, >99:1 dr); [
a]
þ21.2 (c 1.0, MeOH);
D
4.24. tert-Butyl (S,S)-2-amino-3-hydroxy-3-(40-trifluoromethyl-
phenyl)propanoate 47
nmax (ATR) 3281, 2980 (OeH, NeH), 1732 (C]O); dH (400 MHz,
MeOH-d4) 1.26 (9H, s, CMe3), 3.52 (1H, d, J 4.7, C(2)H), 4.77e4.81
(1H, m, C(3)H), 6.97 (2H, app t, J 8.7, C(30)H, C(50)H), 7.29 (2H, dd, J
8.7, 5.3, C(20)H, C(60)H); dC (100 MHz, MeOH-d4) 26.8 (CMe3), 60.6
(C(2)), 74.2 (C(3)), 81.3 (CMe3), 114.3 (d, J 21.5, C(30), C(50)),128.3 (d, J
7.8, C(20), C(60)), 136.7 (C(10)), 162.5 (d, J 244.8, C(40)), 171.4 (C(1));
Pd(OH)2/C (12 mg, 20% w/w) was added to a degassed solution
of 42 (60 mg, 0.12 mmol, >99:1 dr) in MeOH (1 mL) and the re-
sultant mixture was placed under an atmosphere of H2 (5 atm)
and stirred at rt for 24 h. The reaction mixture was then filtered
through CeliteÒ (eluent MeOH) and concentrated in vacuo to give
þ
m/z (ESIþ) 256 ([MþH]þ, 100%); HRMS (ESIþ) C13H18FNNaO3
([MþNa]þ) requires 278.1163; found 278.1167.
47 as an orange solid (30 mg, 81%, >99:1 dr); mp 164e172 ꢁC;
20
[
a
]
þ45.8 (c 1.0, MeOH); nmax (ATR) 3409 (OeH, NeH), 1734
D
4.28. tert-Butyl (S,S)-2-amino-3-hydroxy-3-(40-methoxyphenyl)-
propanoate 51
(C]O); dH (700 MHz, MeOH-d4) 1.18 (9H, s, CMe3), 4.07 (1H, br s,
C(2)H), 5.15 (1H, br s, C(3)H), 7.60 (2H, d, J 8.3, C(20)H, C(60)H), 7.55
(2H, d, J 8.3, C(30)H, C(50)H); dC (176 MHz, MeOH-d4) 26.6 (CMe3),
58.9 (C(2)), 71.4 (C(3)), 83.1 (CMe3), 124.3 (q, J 270.8, CF3), 124.8
(q, J 3.8, C(30), C(50)), 126.6 (C(20),þC(60)), 129.7 (q, J 31.8, C(40)),
144.5 (C(10)), 166.7 (C(1)); m/z (ESI ) 306 ([MþH]þ, 100%); HRMS
Pd(OH)2/C (15 mg, 20% w/w) was added to a degassed solution
of 46 (75 mg, 0.16 mmol, >99:1 dr) in MeOH (1 mL) and the re-
sultant mixture was placed under an atmosphere of H2 (5 atm) and
stirred at rt for 24 h. The reaction mixture was then filtered through
CeliteÒ (eluent MeOH) and concentrated in vacuo to give 51 as
þ
(ESIþ) C14H18F3NNaO3 ([MþNa]þ) requires 328.1131; found
328.1131.
a colourless oil (43 mg, quant, >99:1 dr); [
a
]
D
20 ꢀ4.0 (c 0.5, MeOH);
nmax (ATR) 3401 (OeH, NeH), 1728 (C]O); dH (400 MHz, MeOH-d4)
1.28 (9H, s, CMe3), 3.68 (3H, s, OMe), 3.63e3.72 (1H, m, C(2)H),
4.84e4.92 (1H, m, C(3)H), 6.81 (2H, d, J 8.7, C(30)H, C(50)H), 7.21 (2H,
d, J 8.5, C(20)H, C(60)H); dC (100 MHz, MeOH-d4) 26.8 (CMe3), 54.4
(OMe), 60.0 (C(2)), 73.1 (C(3)), 82.1 (CMe3), 113.3 (C(30), C(50)), 127.5
(C(20), C(60)), 131.7 (C(10)), 159.6 (C(40)), 169.5þ(C(1)); m/z (ESIþ) 268
([MþH]þ, 100%); HRMS (ESIþ) C14H21NNaO4 ([MþNa]þ) requires
290.1363; found 290.1364.
4.25. tert-Butyl (S,S)-2-amino-3-hydroxy-3-(30-fluorophenyl)-
propanoate 48
Pd(OH)2/C (15 mg, 20% w/w) was added to a degassed solution
of 43 (75 mg, 0.17 mmol, >99:1 dr) in MeOH (1 mL) and the re-
sultant mixture was placed under an atmosphere of H2 (5 atm) and
stirred at rt for 48 h. The reaction mixture was then filtered through
CeliteÒ (eluent MeOH) and concentrated in vacuo to give 48 as an
orange oil (43 mg, quant, >99:1 dr); [
a
]
20 þ32.7 (c 1.0, MeOH); nmax
D
(ATR) 3432 (OeH, NeH), 1734 (C]O); dH (500 MHz, MeOH-d4) 1.22
(9H, s, CMe3), 3.98 (1H, br s, C(2)H), 5.06 (1H, br s, C(3)H), 7.07 (1H,
dt, J 8.5, 2.4, C(40)H), 7.20e7.25 (1H, m, C(20)H), 7.25e7.30 (1H, m,
C(60)H), 7.39e7.45 (1H, m, C(50)H); dC (125 MHz, MeOH-d4) 26.7
(CMe3), 59.0 (C(2)), 71.2 (C(3)), 83.1 (CMe3), 112.9 (d, J 22.0, C(20)),
114.2 (d, J 22.0, C(40)), 121.8 (d, J 2.9, C(60)), 129.8 (d, J 7.6,þC(50)),
142.6 (C(10)), 162.9 (d, J 244.1, C(30)), 166.6 (C(1)); m/z (ESI ) 256
4.29. (S,S)-2-Amino-3-hydroxy-3-(40-trifluoromethylphenyl)-
propanoic acid 52
A solution of 47 (20 mg, 66 mmol, >99:1 dr) in 6.0 M aq HCl
(0.6 mL) was stirred at rt for 6 h. The reaction mixture was then
allowed to cool to rt and concentrated in vacuo. Purification via ion
exchange chromatography (DOWEX 50WX8-200, eluent 1.0 M aq
þ
([MþH]þ, 100%); HRMS (ESIþ) C13H18FNNaO3 ([MþNa]þ) requires
NH4OH) gave 52 as a white solid (17 mg, quant, 98:2 dr); mp
20
278.1163; found 278.1166.
172e180 ꢁC (dec); [
a
]
þ14.4 (c 0.5, H2O); nmax (ATR) 3508, 3364
D
(OeH, NeH), 1579 (C]O); dH (500 MHz, D2O) 4.04 (1H, d, J 4.0,
C(2)H), 5.33 (1H, d, J 4.0, C(3)H), 7.46 (2H, d, J 8.2, C(20)H, C(60)H),
7.65 (2H, d, J 8.2, C(30)H, C(50)H); dC (125 MHz, D2O) 60.3 (C(2)), 70.6
(C(3)), 124.0 (q, J 271.8, CF3), 125.6 (q, J 3.8, C(30), C(50)), 126.8 (C(20),
C(60)), 130.0 (q, J 31.8, C(40)), 141.4 (C(10)), 170.6 (C(1)); dF (377 MHz,
4.26. tert-Butyl (S,S)-2-amino-3-hydroxy-3-(30-methoxyphenyl)-
propanoate 49
Pd(OH)2/C (22 mg, 20% w/w) was added to a degassed solution
of 44 (58 mg, 0.13 mmol, >99:1 dr) in MeOH (1 mL) and the re-
sultant mixture was placed under an atmosphere of H2 (5 atm) and
CDCl3) ꢀ62.4 (CF3); m/z (ESIþ) 250 ([MþH]þ, 100%); HRMS (ESIþ)
þ
C
10H10F3NNaO3 ([MþNa]þ) requires 272.0505; found 272.0507.
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057

S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
11
4.30. (S,S)-2-Amino-3-hydroxy-3-(30-fluorophenyl)propanoic
acid 53
3503, 3238 (OeH, NeH), 1513 (C]O); dH (500 MHz, D2O) 3.75 (3H,
s, OMe), 3.97 (1H, d, J 4.1, C(2)H), 5.22 (1H, d, J 4.1, C(3)H), 6.94 (2H,
d, J 8.7, C(30)H, C(50)H), 7.25 (2H, d, J 8.7, C(20)H, C(60)H); dC
(125 MHz, D2O) 55.3 (OMe), 60.4 (C(2)), 71.1 (C(3)), 114.2 (C(30),
C(50)),127.7 (C(20), C(60)), 129.3 (C(10)), 159.1 (C(40)),171.1 (C(1)); m/z
A solution of 48 (44 mg, 0.172 mmol, >99:1 dr) in 6.0 M aq HCl
(1 mL) was stirred at rt for 3 h, then concentrated in vacuo. H2O
(4 mL) and CHCl3 (3 mL) were added and the aqueous layer was
washed with CHCl3 (2ꢃ3 mL) then concentrated in vacuo. Purifi-
cation via ion exchange chromatography (DOWEX 50WX8-200,
eluent 1.0 M aq NH4OH) gave 53 as a white solid (25 mg, 74%, 93:7
þ
(ESIþ) 212 ([MþH]þ, 100%); HRMS (ESIþ) C10H13NNaO4
([MþNa]þ) requires 234.0737; found 234.0737.
4.34. tert-Butyl (RS,RS)-2-hydroxy-3-(N,N-dibenzylamino)-
butanoate 58
dr); mp 197e199 ꢁC (dec); [
a
]
20 þ17.6 (c 0.5, H2O); nmax (ATR) 3059
D
(OeH, NeH), 1591 (C]O); dH (500 MHz, D2O) 4.00 (1H, d, J 3.9,
C(2)H), 5.28 (1H, d, J 3.9, C(3)H), 7.02e7.13 (3H, m, C(20)H, C(40)H,
C(60)H), 7.32e7.37 (1H, m, C(50)H); dC (125 MHz, D2O) 60.3 (C(2)),
70.5 (C(3)), 113.1 (d, J 22.5, C(20)), 115.5 (d, J 22.5, C(40)), 122.1 (d, J
2.9, C(60)), 130.5 (d, J 8.6, C(50)),140.0 (d, J 6.7, C(10)), 162.6 (d, J 244þ.1,
C(30)), 170.9 (C(1)); dF (377 MHz, CDCl3) ꢀ113.0 (C(30)F); m/z (ESI )
Following the general procedure, BuLi (2.2 M in hexanes, 9.9 mL,
21.9 mmol) and Bn2NH (4.44 g, 22.5 mmol) were reacted with 1
(2.00 g, 14.1 mmol, >99:1 dr) and 4 (5.50 g, 2.40 mmol) in THF
(80 mL) at ꢀ78 ꢁC to give 58 in >99:1 dr. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 10:1/8:1)
gave 58 as a white solid (2.51 g, 50%, >99:1 dr); mp 73e77 ꢁC; nmax
(ATR) 3468 (OeH), 1720 (C]O); dH (400 MHz, CDCl3) 1.04 (3H, d, J
7.0, C(4)H3), 1.38 (9H, s, CMe3), 2.97 (1H, br s, OH), 3.15 (1H, dq, J 7.0,
2.3, C(3)H), 3.66 (2H, d, J 14.0, N(CHAHBPh)2), 3.75 (2H, d, J 14.0,
N(CHAHBPh)2), 4.40 (1H, d, J 2.3, C(2)H), 7.18e7.41 (10H, m, Ph); dC
(100 MHz, CDCl3) 10.1 (C(4)), 28.0 (CMe3), 54.5 (N(CH2Ph)2), 55.5
(C(3)), 71.4 (C(2)), 82.3 (CMe3), 126.9, 128.2, 128.9 (o,m,p-Ph), 140.3
200 ([MþH]þ, 100%); HRMS (ESIþ) C9H10FNNaO3 ([MþNa]þ) re-
þ
quires 222.0537; found 222.0542.
4.31. (S,S)-2-Amino-3-hydroxy-3-(3-methoxy)phenylpropanoic
acid 54
A solution of 49 (45 mg, 0.17 mmol, >99:1 dr) in 6.0 M aq HCl
(1 mL) was stirred at rt for 3 h, then concentrated in vacuo. H2O
(4 mL) and CHCl3 (3 mL) were added and the aqueous layer was
washed with CHCl3 (2ꢃ3 mL) then concentrated in vacuo. Purifica-
tion via ion exchange chromatography (DOWEX 50WX8-200, eluent
(i-Ph), 174.3 (C(1)); m/z (ESIþ) 356 ([MþH]þ, 100%); HRMS (ESIþ)
þ
C
22H30NO3 ([MþH]þ) requires 356.2220; found 356.2216.
4.35. tert-Butyl (RS,RS)-2-hydroxy-3-(N,N-dibenzylamino)-4-
methylpentanoate 59
1.0 M aq NH4OH) gave 54 as a white solid (28 mg, 80%, 93:7 dr); mp
20
162e170 ꢁC (dec); [
a]
þ5.0 (c 1.0, H2O); nmax (ATR) 3137 (OeH,
D
NeH),1598 (C]O); dH (500 MHz, D2O) 3.76 (3H, s, OMe), 4.04 (1H, d,
J 4.1, C(2)H), 5.27 (1H, d, J 4.1, C(3)H), 6.85e6.95 (3H, m, C(20)H, C(40)
H, C(60)H) 7.31 (1H, appt, J 8.0, C(50)H); dC (125 MHz, D2O) 55.4 (OMe),
60.3 (C(2)), 70.9 (C(3)), 111.8, 119.0 (C(20), C(60)), 114.4 (C(50)), 130.1
(C(40)), 138.7 (C(10)), 159.0 (C(30)), 170.0 (C(1)); m/z (ESIþ) 212
Following the general procedure, BuLi (2.2 M in hexanes, 8.3 mL,
18.2 mmol) and Bn2NH (3.61 g, 18.8 mmol) were reacted with 57
(2.00 g, 11.8 mmol, >99:1 dr) and 4 (4.60 g, 2.01 mmol) in THF
(80 mL) at ꢀ78 ꢁC to give 59 in >99:1 dr. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 20:1) gave
59 as a white solid (2.32 g, 52%, >99:1 dr); mp 119e123 ꢁC; nmax
(ATR) 3468 (OeH), 1720 (C]O); dH (400 MHz, CDCl3) 0.70 (3H, d, J
6.6, C(4)MeA), 1.00 (3H, d, J 6.6, C(4)MeB), 1.42 (9H, s, CMe3), 2.23
(1H, d septet, J 10.4, 6.6, C(4)H), 2.71 (1H, app d, J 10.4, C(3)H), 3.12
(1H, d, J 3.1, OH), 3.34 (2H, d, J 13.9, N(CHAHBPh)2), 3.99 (2H, d, J 13.9,
N(CHAHBPh)2), 4.48 (1H, app d, J 3.1, C(2)H), 7.16e7.44 (10H, m, Ph);
dC (100 MHz, CDCl3) 20.0, 21.4 (C(4)Me2), 26.2 (C(4)), 28.0 (CMe3),
54.7 (N(CH2Ph)2), 66.1 (C(3)), 67.3 (C(2)), 82.9 (CMe3), 126.8, 128.1,
128.3 (o,m,p-Ph), 140.1 (i-Ph), 175.9 (C(1)); m/z (ESIþ) 384 ([MþH]þ,
þ
([MþH]þ, 100%); HRMS (ESIþ) C10H13NNaO4 ([MþNa]þ) requires
234.0737; found 234.0740.
4.32. (S,S)-2-Amino-3-hydroxy-3-(40-fluorophenyl)propanoic
acid 55
A solution of 50 (8 mg, 31 mmol, >99:1 dr) in 6.0 M aq HCl (1 mL)
was stirred at rt for 6 h, then concentrated in vacuo. H2O (2 mL) and
CHCl3 (3 mL) were added and the aqueous layer washed with CHCl3
(2ꢃ3 mL) then concentrated in vacuo. Purification via ion exchange
chromatography (DOWEX 50WX8-200, eluent 1.0 M aq NH4OH)
þ
100%); HRMS (ESIþ) C24H34NO3 ([MþH]þ) requires 384.2533;
found 384.2539.
gave 55 as a white solid (7 mg, quant, 97:3 dr); mp 161e168 ꢁC
20
(dec); [
a
]
D
þ9.0 (c 0.5, H2O); nmax (ATR) 3066 (OeH, NeH), 1602
(C]O); dH (500 MHz, D2O) 3.99 (1H, d, J 4.1, C(2)H), 5.27 (1H, d, J 4.1,
C(3)H), 7.08 (2H, app t, J 8.7, C(30)H, C(50)H), 7.31 (2H, dd, J 8.7, 5.5,
C(20)H, C(60)H); dC (125 MHz, D2O) 60.3 (C(2)), 70.5 (C(3)), 115.5 (d, J
21.9, C(30), C(50)), 128.2 (d, J 8.6, C(20), C(60)), 132.8 (C(10)), 162.5 (d, J
244.1, C(40)), 171.0 (C(1)); dF (377 MHz, CDCl3) ꢀ114.1 (C(40)F); m/z
4.36. tert-Butyl (RS,RS)-2-(N,N-dibenzylamino)-3-(meth-
anesulfonyloxy)butanoate 60
Ms2O (74 mg, 0.422 mmol) was added to a solution of 58 (50 mg,
0.141 mmol, >99:1 dr) and Et3N (84
(0.6 mL) and the resultant solution was stirred at rt for 1 h, then
H2O (76 L, 4.2 mmol) was then added and the resultant mixture
mL, 0.64 mmol) in CH2Cl2
þ
(ESIþ) 200 ([MþH]þ, 100%); HRMS (ESIþ) C9H10FNNaO3
([MþNa]þ) requires 222.0537; found 222.0537.
m
was stirred at rt for 24 h. H2O (1 mL) was then added and the re-
sultant mixture was extracted with CH2Cl2 (3ꢃ2 mL). The combined
organic extracts were washed sequentially with 1.0 M aq HCl
(3 mL), satd aq NaHCO3 (3 mL) and brine (3 mL), then dried and
concentrated in vacuo to give a 90:10 mixture of 60 and 58, re-
spectively, as a colourless oil. Data for 60: dH (400 MHz, CDCl3) 1.47
(3H, d, J 6.3, C(4)H3), 1.63 (9H, s, CMe3), 2.96 (3H, s, SO2Me), 3.24
(1H, d, J 10.4, C(2)H), 3.43 (2H, d, J 13.4, N(CHAHBPh)2), 3.92 (2H, d, J
13.4, N(CHAHBPh)2), 5.05 (1H, dq, J 10.1, 6.3, C(3)H), 7.22e7.40 (10H,
m, Ph); dC (100 MHz, CDCl3) 19.1 (C(4)), 28.5 (CMe3), 38.3 (SO2Me),
55.3 (N(CH2Ph)2), 64.4 (C(2)), 78.2 (C(3)), 82.3 (CMe3), 127.5, 128.4,
129.0 (o,m,p-Ph), 138.1 (i-Ph), 169.0 (C(1)).
4.33. (S,S)-2-Amino-3-hydroxy-3-(4-methoxy)phenylpropanoic
acid 56
A solution of 51 (43 mg, 0.16 mmol, >99:1 dr) in 6.0 M aq HCl
(1 mL) was stirred at rt for 3 h, then concentrated in vacuo. H2O
(4 mL) and CHCl3 (3 mL) were added and the aqueous layer washed
with CHCl3 (2ꢃ3 mL) then concentrated in vacuo. Purification via
ion exchange chromatography (DOWEX 50WX8-200, eluent 1.0 M
aq NH4OH) gave 56 as a white solid (21 mg, 62%, 93:7 dr); mp
20
20
176e181 ꢁC (dec); [
MeOH 1:1); {lit.24
a
]
þ8.0 (c 1.0, H2O); [
a
]
ꢀ2.4 (c 0.5, H2O/
D
[
a
]
D
20Dꢀ2.73 (c 0.586, H2O/MeOH 1:1)}; nmax (ATR)
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057

12
S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
4.37. tert-Butyl (RS,RS)-2-(N,N-dibenzylamino)-3-(meth-
4.40. tert-Butyl (2S,3S,aR)-2-[N-benzyl-N-(a-methylbenzyl)-
anesulfonyloxy)-4-methylpentanoate 61
amino]-3-hydroxybutanoate 68
Ms2O (68 mg, 0.391 mmol) was added to a solution of 59 (50 mg,
Tf2O (36 mL, 0.21 mmol) added to a solution of 5 (50 mg,
0.130 mmol, >99:1 dr) and Et3N (77
m
L, 0.59 mmol) in CH2Cl2
0.14 mmol, >99:1 dr) and 64 (87 mg, 0.42 mmol) in CH2Cl2 (0.6 mL)
at 0 ꢁC and the resultant solution was stirred at rt for 6 h. H2O
(0.026 mL, 7.2 mmol) was then added and the resultant mixture
was stirred at rt for 24 h. H2O (1 mL) was then added and the re-
sultant mixture was extracted with CH2Cl2 (3ꢃ2 mL). The combined
organic extracts were then dried and concentrated in vacuo. The
residue was dissolved in Et2O (10 mL), and the resultant solution
was filtered and concentrated in vacuo to give a 79:21 mixture of 68
and 5, respectively. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 5:1) gave 68 as a colourless oil
(0.55 mL) and the resultant solution was stirred at rt for 1 h. H2O
(0.070 mL, 3.90 mmol) was then added and the resultant mixture
was stirred at rt for 24 h. H2O (1 mL) was then added and the re-
sultant mixture was extracted with CH2Cl2 (3ꢃ2 mL). The combined
organic extracts were washed sequentially with 1.0 M aq HCl
(3 mL), satd aq NaHCO3 (3 mL) and brine (3 mL), then dried and
concentrated in vacuo to give a 60:40 mixture of 61 and 59, re-
spectively, as a colourless oil. Data for 61: dH (400 MHz, CDCl3) 0.35
(3H, d, J 6.8, C(4)MeA), 1.07 (3H, d, J 7.3, C(4)MeB), 1.68 (9H, s, CMe3),
2.40 (1H, app septet, J 6.9, C(4)H), 3.00 (3H, s, SO2Me), 3.39e3.49
(3H, m, C(2)H, N(CHAHBPh)2), 3.94 (2H, d, J 13.4, N(CHAHBPh)2), 5.03
(1H, d, J 10.6, C(3)H), 7.22e7.46 (10H, m, Ph); dC (100 MHz, CDCl3)
14.0, 20.4 (C(4)Me2), 27.5 (C(4)), 28.7 (CMe3), 38.9 (SO2Me), 55.2
(N(CH2Ph)2), 61.5 (C(2)), 82.4 (CMe3), 85.6 (C(3)), 127.5, 128.4, 129.3
(o,m,p-Ph), 138.3 (i-Ph), 169.0 (C(1)).
(34 mg, 68%, >99:1 dr); [
a
]
23 ꢀ52.6 (c 1.0, MeOH); nmax (ATR) 3475
D
(OeH), 1722 (C]O); dH (400 MHz, CDCl3) 0.97 (3H, d, J 6.4, C(4)H3),
1.38 (3H, d, J 6.9, C(
(1H, d, J 8.6, C(2)H), 3.82 (1H, d, J 14.2, NCHAHBPh), 3.85e3.94 (1H,
m, C(3)H), 4.99 (1H, d, J 14.2, NCHAHBPh), 4.04 (1H, q, J 6.9, C( )H),
7.14e7.31 (10H, m, Ph); dC (100 MHz, CDCl3) 14.3 (C( )Me), 20.3
(C(4)), 28.3 (CMe3), 52.3 (NCH2Ph), 57.1 (C( )), 65.7 (C(2)), 67.4
a)Me), 1.53 (9H, s, CMe3), 2.25 (1H, br s, OH), 3.06
a
a
a
4.38. tert-Butyl (RS,RS)-2-(N,N-dibenzylamino)-3-hydroxy-
butanoate 62
(C(3)), 81.6 (CMe3), 127.0, 127.0, 128.1, 128.1, 128.3, 129.1 (o,m,p-Ph),
140.2, 143.7 (i-Ph), 173.6 (C(1)); m/z (ESIþ) 370 ([MþH]þ, 100%);
þ
HRMS (ESIþ) C23H31NNaO3 ([MþNa]þ) requires 392.2196; found
Tf2O (35
m
L, 0.21 mmol) was added to a solution of 58 (50 mg,
392.2197.
0.141 mmol, >99:1 dr) and 64 (87 mg, 0.42 mmol) in CH2Cl2
(1.75 mL) at 0 ꢁC and the resultant solution was stirred at rt for 6 h.
H2O (26 mL, 7.2 mmol) was then added and the resultant mixture
4.41. tert-Butyl (2S,3S,
amino]-3-hydroxy-4-methylpentanoate 69
aR)-2-[N-benzyl-N-(a-methylbenzyl)-
was stirred at rt for 15 h. H2O (1 mL) was then added and the re-
sultant mixture was extracted with CH2Cl2 (3ꢃ2 mL). The combined
organic extracts were then dried and concentrated in vacuo. The
residue was dissolved in Et2O (10 mL), and the resultant solution
was filtered and concentrated in vacuo to give 62 in >99:1 dr. Pu-
rification via flash column chromatography (eluent 30e40 ꢁC pet-
rol/Et2O, 3:1) gave 62 as a white solid (27 mg, 54%, >99:1 dr); mp
98e101 ꢁC; nmax (ATR) 3461 (OeH), 1722 (C]O); dH (400 MHz,
CDCl3) 1.11 (3H, d, J 6.4, C(4)H3), 1.55 (9H, s, CMe3), 2.49 (1H, br s,
OH), 2.94 (1H, d, J 9.1, C(2)H), 3.45 (2H, d, J 13.4, N(CHAHBPh)2), 3.83
(2H, d, J 13.4, N(CHAHBPh)2), 4.01e4.11 (1H, m, C(3)H), 7.10e7.33
(10H, m, Ph); dC (100 MHz, CDCl3) 20.0 (C(4)), 28.7 (CMe3), 55.6
(N(CH2Ph)2), 66.2 (C(2)), 67.2 (C(3)), 82.1 (CMe3), 127.2, 128.3, 129.1
(o,m,p-Ph), 139.0 (i-Ph), 172.2 (C(1)); m/z (ESIþ) 378 ([MþNa]þ,
Tf2O (32 mL, 0.19 mmol) was added to a solution of 65 (50 mg,
0.13 mmol, >99:1 dr) and 64 (78 mg, 0.38 mmol) in CH2Cl2 (0.6 mL)
at 0 ꢁC and the resultant solution was stirred at rt for 6 h. H2O
(26 mL, 7.2 mmol) was then added and the resultant mixture was
stirred at rt for 24 h. H2O (1 mL) was then added and the resultant
mixture was extracted with CH2Cl2 (3ꢃ2 mL). The combined or-
ganic extracts were then dried and concentrated in vacuo. The
residue was dissolved in Et2O (10 mL), and the resultant solution
was filtered and concentrated in vacuo to give a 92:8 mixture of 65
and 69, respectively. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 5:1) gave 69 as a colourless oil
(34 mg, 68%, >99:1 dr); [
(OeH),1707 (C]O); dH (700 MHz, CDCl3) 0.18 (3H, d, J 7.0, C(4)MeA),
a
]
23 ꢀ38.3 (c 1.0, MeOH); nmax (ATR) 3540
D
þ
100%); HRMS (ESIþ) C22H29NNaO3 ([MþH]þ) requires 378.2040;
0.71 (3H, d, J 7.0, C(4)MeB), 1.35 (3H, d, J 6.9, C(a)Me), 1.50 (9H, s,
CMe3), 1.84 (1H, d septet, J 7.0, 2.6, C(4)H), 1.90 (1H, d, J 6.0, OH), 3.17
(1H, d, J 8.6, C(2)H), 3.53e3.58 (1H, m, C(3)H), 3.79 (1H, d, J 14.2,
found 378.2038.
4.39. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]-4-methylpentanoate 65
NCHAHBPh), 4.01 (1H, q, J 6.9, C(
7.11e7.27 (10H, m, Ph); dC (176 MHz, CDCl3) 12.6 (C(
(C(4)Me2), 27.2 (CMe3), 27.3 (C(4)), 50.9 (NCH2Ph), 55.9 (C(
a
)H), 4.05 (1H, d, J 14.2, NCHAHBPh),
)Me), 12.9, 19.2
)), 60.4
a
a
Following the general procedure, BuLi (2.3 M in hexanes, 1.98 mL,
4.56 mmol) and (R)-N-benzyl-N-( -methylbenzyl)amine (1.14 g,
(C(2)), 74.6 (C(3)), 80.4 (CMe3), 125.9, 125.9, 127.0, 127.2, 127.2, 128.1
a
(o,m,p-Ph), 139.4, 142.5 (i-Ph), 172.8 (C(1)); m/z (ESIþ) 398 ([MþH]þ,
4.70 mmol, >99:1 er) were reacted with 57 (500 mg, 2.94 mmol,
>99:1 dr) and 4 (1.15 mg, 5.00 mmol) in THF (20 mL) at ꢀ78 ꢁC to
give 65 in >99:1 dr. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 10:1) gave 65 as a white solid
þ
100%); HRMS (ESIþ) C25H35NNaO3 ([MþNa]þ) requires 420.2509;
found 420.2516.
(658 mg, 56%, >99:1 dr);28 mp 82e86 ꢁC; [
nmax (ATR) 3498 (OeH), 1716 (C]O); dH (400 MHz, CDCl3) 0.77 (3H,
d, J 6.7, C(4)MeA), 1.14 (3H, d, J 6.7, C(4)MeB), 1.35 (3H, d, J 7.0,
a
]
23 ꢀ32.2 (c 1.0, CHCl3);
4.42. tert-Butyl (S,S)-2-amino-3-hydroxybutanoate 70
D
Pd(OH)2/C (12 mg, 20% w/w) was added to a degassed solution
of 68 (60 mg, 0.162 mmol, >99:1 dr) in MeOH (1 mL) and the re-
sultant mixture was placed under an atmosphere of H2 (5 atm) and
stirred at rt for 16 h. The reaction mixture was then filtered through
C(
(1H, d, J 2.9, OH), 3.18 (1H, app d, J 9.8, C(3)H), 3.60 (1H, d, J 15.7,
NCHAHBPh), 3.68 (1H, app d, J 2.9, C(2)H), 3.91 (1H, q, J 7.0, C( )H),
4.32 (1H, d, J 15.7, NCHAHBPh), 7.18e7.57 (10H, m, Ph); dC (100 MHz,
CDCl3) 20.0, 22.3 (C(4)Me2), 20.9 (C( )Me), 27.8 (C(4)), 28.1 (CMe3),
52.0 (NCH2Ph), 58.1 (C( )), 64.1 (C(3)), 70.9 (C(2)), 82.8 (CMe3),
a)Me), 1.52 (9H, s, CMe3), 2.07 (1H, d septet, J 9.8, 6.7, C(4)H), 2.91
a
CeliteÒ (eluent MeOH) and concentrated in vacuo to give 70 as
23
a
a colourless oil (20 mg, 71%, >99:1 dr);9
[
a
]
D
þ7.1 (c 1.0, CHCl3);
a
nmax (ATR) 3368 (OeH, NeH), 1728 (C]O); dH (400 MHz, MeOH-d4)
1.03 (3H, d, J 6.4, C(4)H3),1.38 (9H, s, CMe3), 3.28 (1H, d, J 4.2, C(2)H),
3.88 (1H, dq, J 6.4, 4.2, C(3)H); dC (100 MHz, MeOH-d4) 16.8 (C(4)),
26.7 (CMe3), 60.0 (C(2)), 68.4 (C(3)), 81.2 (CMe3), 174.6 (C(1)); m/z
126.4, 127.1, 128.0, 128.4, 128.4, 128.6 (o,m,p-Ph), 142.5, 142.5 (i-Ph),
175.4 (C(1)); þm/z (ESIþ) 398 ([MþH]þ, 100%); HRMS (ESIþ)
C
25H35NNaO3 ([MþNa]þ) requires 420.2509; found 420.2513.
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057

S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
13
þ
(ESIþ) 176 ([MþH]þ, 100%); HRMS (ESIþ) C8H18NO3 ([MþH]þ)
(c) Lee, K.-D.; Suh, J.-M.; Park, J.-H.; Ha, H.-J.; Choi, H. G.; Park, C. S.; Chang, J. W.;
Lee, W. K.; Dong, Y.; Yun, H. Tetrahedron 2001, 57, 8267.
9. Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.
requires 176.1281; found 176.1285.
Tetrahedron 2013, 69, 8885.
10. (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,
1793; (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)
Davies, S. G.; Mujtaba, N.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett.
2009, 11, 1959; (e) 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; (f) 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, 1797; (g) 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. Tet-
rahedron: Asymmetry 2011, 22, 69; (h) 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; (i) Davies, S. G.; Huckvale, R.; Lee, J. A.; Lorkin, T. J. A.; Roberts, P. M.;
Thomson, J. E. Tetrahedron 2012, 68, 3263.
4.43. tert-Butyl (S,S)-2-amino-3-hydroxy-4-methylpentanoate
71
Pd(OH)2/C (9 mg, 20% w/w) was added to a degassed solution of
69 (43 mg, 0.11 mmol, >99:1 dr) in MeOH (1 mL) and the resultant
mixture was placed under an atmosphere of H2 (5 atm) and stirred
at rt for 16 h. The reaction mixture was then filtered through CeliteÒ
(eluent MeOH) and concentrated in vacuo to give 71 as a colourless
23
oil (22 mg, quant, >99:1 dr); mp 68e73 ꢁC; [
a
]
þ14.0 (c 1.0,
D
CHCl3); nmax (ATR) 3361 (OeH, NeH), 1729 (C]O); dH (500 MHz,
CDCl3) 0.97 (3H, d, J 6.7, C(4)MeA), 0.99 (3H, d, J 6.7, C(4)MeB), 1.49
(9H, s, CMe3), 1.80 (1H, app septet, J 6.7, C(4)H), 2.62 (3H, br s, NH2,
OH), 3.38e3.46 (1H, m, C(3)H), 3.49e3.59 (1H, m, C(2)H); dC
(125 MHz, CDCl3) 18.7, 19.9 (C(4)Me2), 28.5 (CMe3), 31.3 (C(4)), 57.5
(C(2)), 78.9 (C(3)), 82.5 (CMe3), 173.7 (C(1)); m/z (ESIþ) 204
11. For selected applications of this methodology in total synthesis, see: (a) Davies,
S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Synlett
2002, 1146; (b) Davies, S. G.; Kelly, R. J.; Price Mortimer, A. J. Chem. Commun.
2003, 2132; (c) Davies, S. G.; Burke, A. J.; Garner, A. C.; McCarthy, T. D.; Roberts,
P. M.; Smith, A. D.; Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem. 2004, 2,
1387; (d) Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price
Mortimer, A. J.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 2630; (e)
Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;
þ
([MþH]þ, 100%); HRMS (ESIþ) C10H21NNaO3 ([MþNa]þ) requires
226.1414; found 226.1420.
4.44. (S,S)-2-Amino-3-hydroxy-4-methylpentanoic acid [(S,S)-
b-hydroxyleucine] 72
ꢀ
ꢀ
Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J.
E. Tetrahedron: Asymmetry 2007, 18, 2510; (f) Abraham, E.; Davies, S. G.; Millican,
N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6,
1655; (g) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
A solution of 71 (22 mg, 0.11 mmol, >99:1 dr) in 6.0 M aq HCl
(1 mL) was stirred at rt for 3 h, then concentrated in vacuo. H2O
(4 mL) and CHCl3 (3 mL) were then added and the aqueous layer
was washed with CHCl3 (2ꢃ3 mL) then concentrated in vacuo.
Purification via ion exchange chromatography (DOWEX 50WX8-
ꢀ
M.; Nicholson, R. L.; Perkins, J. H.; 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; (h) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Tetrahedron 2009, 65, 10192; (i) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P.
M.; Thomson, J. E. Org. Lett. 2011, 13, 2544; (j) Davies, S. G.; Ichihara, O.; Roberts,
P. M.; Thomson, J. E. Tetrahedron 2011, 67, 216; (k) 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; (l) Davies, S. G.;
Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron Lett. 2011, 52,
200, eluent 1.0 M aq NH4OH) gave 72 as a white solid (11 mg, 69%,
96:4 dr);3e mp 220e226 ꢁC (dec); [
a]
þ17.6 (c 1.0, H2O); {lit.3e
20
D
25
[
a]
þ20 (c 1.1, H2O)}; nmax (ATR) 3449, 3058 (OeH, NeH), 1627
D
(C]O); dH (500 MHz, D2O) 0.89 (3H, d, J 6.7, C(4)MeA), 0.90 (3H, d, J
6.7, C(4)MeB), 1.87 (1H, d septet, J 9.1, 6.7, C(4)H), 3.46 (1H, dd, J 9.1,
3.2, C(3)H), 3.84 (1H, d, J 3.2, C(2)H); dC (125 MHz, CDCl3) 18.5, 18.5
(C(4)Me2), 30.2 (C(4)), 57.1 (C(2)), 76.1 (C(3)), 171.7þ(C(1)); m/z (ESIþ)
148 ([MþH]þ, 100%); HRMS (ESIþ) C6H13NNaO3 ([MþNa]þ) re-
quires 170.0788; found 170.0788.
ꢀ
6477; (m) Csatayova, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E.; Wilson, D. L. Org. Lett. 2011, 13, 2606; (n) Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Stonehouse, J. P.; Thomson, J. E. Tetrahedron Lett. 2012, 53, 1119;
(o) Davies, S. G.; Fletcher, A. M.; Lv, L.; Roberts, P. M.; Thomson, J. E. Tetrahedron
Lett. 2012, 53, 3052; (p) 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;
(q) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron
2012, 68, 4302.
12. For selected applications of this methodology in enantiorecognition phenom-
ena and resolution protocols, see: (a) Cailleau, T.; Cooke, J. W. B.; Davies, S. G.;
Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3922; (b) Davies, S. G.;
Durbin, M. J.; Goddard, E. C.; Kelly, P. M.; Kurosawa, W.; Lee, J. A.; Nicholson, R.
L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D. Org. Biomol.
Chem. 2009, 7, 761; (c) Davies, S. G.; Garner, A. C.; Long, M. J. C.; Morrison, R. M.;
Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2005,
3, 2762; (d) Aye, Y.; Davies, S. G.; Garner, A. C.; Roberts, P. M.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 2195; (e) Abraham, E.; Davies, S. G.;
Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S.
M. Tetrahedron: Asymmetry 2008, 19, 1356; (f) Davies, S. G.; Durbin, M. J.;
Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.;
Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 2870; (g) Davies,
S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; Yin, J. Org. Lett. 2012, 14, 218.
13. For reviews, see: (a) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asym-
metry 2005, 16, 2833; (b) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson,
J. E. Tetrahedron: Asymmetry 2012, 23, 1111.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.06.057.
References and notes
€
1. (a) Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N. Angew. Chem., Int. Ed.
1999, 38, 2096; (b) Boger, D. L. Med. Res. Rev. 2001, 21, 356; (c) Blaskovich, M. A.;
Evindar, G.; Rose, N. G. W.; Wilkinson, S.; Luo, Y.; Lajoie, G. A. J. Org. Chem. 1998,
63, 3631; (d) McDonald, L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.; Lotvin, J. J.
Am. Chem. Soc. 2002, 124, 10260; (e) Taniguchi, M.; Suzumura, K.; Nagai, K.;
Kawasaki, T.; Saito, T.; Takasaki, J.; Suzuki, K.; Fujita, S.; Tsukamoto, S. Tetra-
hedron 2003, 59, 4533; (f) Ford, P. W.; Gustafson, K. R.; McKee, T. C.; Shigematsu,
N.; Maurizi, L. K.; Pannell, L. K.; Williams, D. E.; de Silva, E. D.; Lassota, P.; Allen,
T. M.; Soest, R. V.; Andersen, R. J.; Boyd, M. R. J. Am. Chem. Soc. 1999, 121, 5899.
2. For a review, see: Genet, J.-P. Pure Appl. Chem. 1996, 68, 593.
3. (a) Caddick, S.; Parra, N. J.; Pritchard, M. C. Tetrahedron Lett. 2000, 41, 5963; (b)
Mettath, S.; Srikanth, G. S. C.; Dangerfield, B. S.; Castle, S. L. J. Org. Chem. 2004,
69, 6489; (c) Willis, M. C.; Cutting, G. A.; Piccio, V. J.-D.; Durbin, M. J.; John, M. P.
Angew. Chem., Int. Ed. 2005, 44, 1543; (d) Cremonesi, G.; Dalla Croce, P.; Fontana,
F.; Fornic, A.; La Rosaa, C. Tetrahedron: Asymmetry 2007, 18, 1667; (e) Li, Q.; Yang,
S.-B.; Zhang, Z.; Li, L.; Xu, P.-F. J. Org. Chem. 2009, 74, 1627; (f) Sladojevich, F.;
Trabocchi, A.; Guarna, A.; Dixon, D. J. J. Am. Chem. Soc. 2011, 133, 1710; (g)
Singjunla, Y.; Baudoux, J.; Rouden, J. Org. Lett. 2013, 15, 5770.
14. For examples of related studies concerning the regioselective ring-opening of
€
aziridinium intermediates, see: (a) Gmeiner, P.; Junge, D.; Kartner, A. J. Org.
Chem. 1994, 59, 6766; (b) Chuang, T. H.; Sharpless, K. B. Org. Lett. 2000, 2, 3555;
(c) O’Brien, P.; Towers, T. D. J. Org. Chem. 2002, 67, 304; (d) Couturier, C.;
ꢀ
Blanchet, J.; Schlama, T.; Zhu, J. Org. Lett. 2006, 8, 2183; (e) Metro, T.-X.; Ap-
penzeller, J.; Gomez Pardo, D.; Cossy, J. Org. Lett. 2006, 8, 3509.
15. (a) Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1129; (b)
Davies, S. G.; Fletcher, A. M.; Hermann, G. J.; Poce, G.; Roberts, P. M.; Smith, A.
D.; Sweet, M. J.; Thomson, J. E. Tetrahedron: Asymmetry 2010, 21, 6135; (c)
Davies, S. G.; Foster, E. M.; McIntosh, C. R.; Roberts, P. M.; Rosser, T. E.; Smith, A.
D.; Thomson, J. E. Tetrahedron: Asymmetry 2011, 22, 1035.
16. The assigned relative configuration within anti-20 was confirmed by chem-
ical correlation to tert-butyl (RS,RS)-2-hydroxy-3-amino-3-phenylpropa
noate in 96% yield upon hydrogenolytic N-debenzylation. For specroro-
scopic data for tert-butyl (R,R)-2-hydroxy-3-amino-3-phenylpropanoate,
see: Refs. 9 and 19.
4. (a) Kimura, T.; Vassilev, V. P.; Shen, G.; Wong, C. J. Am. Chem. Soc. 1997, 119,
11734; (b) Saeed, A.; Young, D. W. Tetrahedron 1992, 48, 2507.
5. Hernandez-Juan, F. A.; Richardson, R. D.; Dixon, D. J. Synlett 2006, 2673.
6. Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 3541.
7. (a) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew. Chem., Int. Ed. 2004, 43,
882; (b) Seashore-Ludlow, B.; Saint-Dizier, F.; Somfai, P. Org. Lett. 2012, 14, 6334.
8. For example, see: (a) Davis, F. A.; Srirajan, V.; Fanelli, D. L.; Portonovo, P. J. Org.
Chem. 2000, 65, 7663; (b) Suga, H.; Ikai, K.; Ibata, T. J. Org. Chem. 1999, 64, 7040;
17. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057

14
S.G. Davies et al. / Tetrahedron xxx (2014) 1e14
18. Crystallographic data (excluding structure factors) for compounds 20, 21, 23, 45
and 69 have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 992638e992642, respectively
19. Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin
Trans. 1 1994, 2373.
20. Toscano, M. D. Angew. Chem., Int. Ed. 2007, 46, 4468.
21. Claridge, T. D. W.; Davies, S. G.; Lee, J. A.; Nicholson, R. L.; Roberts, P. M.; Russell,
A. J.; Smith, A. D.; Toms, S. M. Org. Lett. 2008, 10, 5437.
sooner, which may be to prevent other reaction pathways, proceeding via the
benzylic carbonium ion, competing with the hydrolysis.
24. The specific rotation for 56 was in good agreement with the literature value
20
20
{[
a
]
ꢀ2.4 (c 0.5, H2O/MeOH 1:1); lit. [
a
]
ꢀ2.73 (c 0.586, H2O/MeOH 1:1)};
D
D
see: Inoue, H.; Matsuki, K.; Oh-ishi, T. Chem. Pharm. Bull. 1993, 41, 1521.
25. The relative anti-configurations within both 58 and 59 were assigned by
analogy to that within 18.
26. Resubjection of an authentic sample of b-hydroxy-a-amino ester 63 (>99:1 dr)
22. For 32 (R¼p-CF3), 33 (R¼m-F) and 36 (R¼p-OMe), the corresponding
b
-me-
to the reaction conditions returned a 32:68 mixture of 59 and 63, respectively.
27. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
sylates 37, 38 and 41 were also isolated under different reaction conditions. In
each case, the atom connectivity within 37, 38 and 41 was established by
1H/13C NMR HMBC analysis, and resubjection to the reaction conditions gave
28. Davies, S. G.; Epstein, S. W.; Garner, A. C.; Ichihara, O.; Smith, A. D. Tetrahedron:
the corresponding b-hydroxy-a-amino esters 42, 43 and 46.
Asymmetry 2002, 13, 1555.
23. Longer reaction times (after the addition of water) may be required for sub-
strates with strongly electron-withdrawing groups (i.e., p-CF3 and m-F) due to
slower SN1-type hydrolysis of the mesylates, whilst for substrates with strongly
electron-donating groups (i.e., p-OMe) the addition of water was required
29. Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1993,
1375.
30. Trincado, M.; Kuhlein, K.; Grutzmacher, H. Chem.dEur. J. 2011, 17, 11905.
€
€
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.057