Trading N and O: Asymmetric syntheses of β-hydroxy-α-amino acids via α-hydroxy-β-amino esters

Article abstract of DOI:10.1016/j.tet.2013.08.007

Both diastereoisomers of 2-amino-3-hydroxybutanoic acid and 2-amino-3-hydroxy-3-phenylpropanoic acid have been prepared from enantiopure α-hydroxy-β-amino esters via the intermediacy of the corresponding cis- and trans-aziridines. Aminohydroxylation of two α,β-unsaturated esters produced enantiopure 2,3-anti-α-hydroxy-β-amino esters in >99:1 dr. Subsequent epimerisation at the C(2)-position via a sequential oxidation/diastereoselective reduction protocol gave the corresponding enantiopure 2,3-syn-α-hydroxy-β-amino esters in >99:1 dr. These syn- and anti-substrates were then converted into the corresponding N-Boc protected cis- and trans-aziridines, respectively, via a three step reaction sequence: (i) hydrogenolysis and in situ N-Boc protection; (ii) OH-activation; and (iii) aziridine formation. Subsequent regioselective ring-opening of the C(3)-methyl-aziridines with Cl₃CCO₂H proceeded with inversion of configuration to give the corresponding 2-amino-3-trichloroacetate esters, whereas the analogous reaction with the C(3)-phenyl-aziridines resulted in rearrangement to the corresponding oxazolidin-2-ones with retention of configuration. In each case, hydrolysis of the products from these ring-opening reactions produced the corresponding enantiopure β-hydroxy-α-amino acids as single diastereoisomers.

Full text of DOI:10.1016/j.tet.2013.08.007

Tetrahedron xxx (2013) 1e14
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Trading N and O: asymmetric syntheses of
via -hydroxy- -amino esters
b-hydroxy-a-amino acids
a
b
*
Stephen G. Davies , Ai M. Fletcher, Aileen B. Frost, 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:
Both diastereoisomers of 2-amino-3-hydroxybutanoic acid and 2-amino-3-hydroxy-3-phenylpropanoic
Received 31 May 2013
Received in revised form 23 July 2013
Accepted 5 August 2013
Available online xxx
acid have been prepared from enantiopure
responding cis- and trans-aziridines. Aminohydroxylation of two
tiopure 2,3-anti- -hydroxy- -amino esters in >99:1 dr. Subsequent epimerisation at the C(2)-position via
a sequential oxidation/diastereoselective reduction protocol gave the corresponding enantiopure 2,3-syn-
-hydroxy- -amino esters in >99:1 dr. These syn- and anti-substrates were then converted into the
corresponding N-Boc protected cis- and trans-aziridines, respectively, via a three step reaction sequence:
(i) hydrogenolysis and in situ N-Boc protection; (ii) OH-activation; and (iii) aziridine formation. Sub-
sequent regioselective ring-opening of the C(3)-methyl-aziridines with Cl3CCO2H proceeded with in-
version of configuration to give the corresponding 2-amino-3-trichloroacetate esters, whereas the
analogous reaction with the C(3)-phenyl-aziridines resulted in rearrangement to the corresponding
oxazolidin-2-ones with retention of configuration. In each case, hydrolysis of the products from these
a
-hydroxy-
b
-amino esters via the intermediacy of the cor-
a,b-unsaturated esters produced enan-
a
b
a
b
Keywords:
Aziridine
b
-Hydroxy-a-amino acids
Lithium amide
Conjugate addition
Asymmetric synthesis
ring-opening reactions produced the corresponding enantiopure
diastereoisomers.
b-hydroxy-a-amino acids as single
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
protection of 4 would then give the corresponding N-Boc protected
a-hydroxy-b-amino esters 5, which could be converted to the cor-
Enantiopure aziridines are important building blocks in synthetic
organic chemistry as they can be prepared readily from the corre-
sponding vicinal amino alcohols via a range of methods,1 and can be
used to access many chiral nitrogen containing compounds via regio-
and stereoselective ring-opening reactions.1,2 For example, Tomasini
and Vecchione have reported that the Lewis acid-promoted rear-
rangement of N(1)-tert-butoxycarbonyl-2-carboxymethyl aziridines
gives the corresponding 4-carboxymethyloxazolidin-2-ones, which
responding trans-aziridines 6 by conversion of the hydroxyl moiety
to a leaving group.12 Application of a sequential oxidation/re-
duction protocol to the 2,3-anti-a-hydroxy-b-amino esters 4 would
give the corresponding 2,3-syn-diastereoisomers 8 and therefore
allow access to the epimeric cis-aziridines 10 via an analogous re-
action sequence. Regioselective ring-opening of aziridines 6 and 10,
and subsequent global deprotection would then provide access to
the corresponding
b-hydroxy-a-amino acids 7 and 11 (Fig. 1).
can then be hydrolysed to give
In order to extend the scope and utility of our conjugate addition
methodology5e8 to include the preparation of enantiopure
-hy-
droxy-
-amino acids,9 it was envisaged that a range of enantiopure
b-hydroxy-a
-amino acids.3,4
2. Results and discussion
b
a
2.1. Preparation of enantiopure aziridines
trans-aziridines 6 could be accessed utilising our diastereoselective
aminohydroxylation protocol.8,10,11 This reliably yields the corre-
As many different methods are known for the formation of
enantiopure aziridines from the corresponding vicinal amino al-
cohols (or activated derivatives, such as mesylates),1 we set out to
sponding 2,3-anti-a-hydroxy-b-amino esters 4 [upon treatment of
a,b
-unsaturated esters 1 with enantiopure lithium amides, such
as 2, followed by oxidation of the intermediate enolate with cam-
phorsulfonyloxaziridine (CSO) 3] with a high and predictable sense
of diastereocontrol. Subsequent tandem hydrogenolysis and N-Boc
prepare a range of N-Boc protected a-hydroxy-b-amino esters and
the corresponding mesylates to screen the optimum conditions for
aziridine formation for this class of compounds. Conjugate addition
of lithium (R)-N-benzyl-N-(
butyl cinnamate 12 and tert-butyl crotonate 13, followed by in
situ oxidation of the intermediate lithium (Z)-
-amino enolates13
a-methylbenzyl)amide 2 to both tert-
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
b
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.007
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2
S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
consistent with its assigned absolute configuration (Fig. 2). An
analogous reaction sequence was then applied to 15, which gave
1916 in 75% overall yield for the two-step procedure (Scheme 1).
Fig. 2. X-ray crystal structures of 16 [left] and 18 [right] (selected H atoms are omitted
for clarity).
The corresponding 2,3-syn-configured mesylates were targeted
next. It was envisaged that epimerisation of 14 and 15 at the C(2)-
position could be achieved via a sequential Swern oxidation/dia-
stereoselective reduction protocol, which we have previously
employed to good effect to access a 2,3-syn-a-hydroxy-b-amino
ester in a related system.17 Swern oxidation of 15 (R¼Me) gave 21
and reduction of 21 with NaBH4 gave 23 as a single diastereoisomer
(>99:1 dr) in 95% isolated yield. Application of these conditions to
14 (R¼Ph) gave 20;18 however, poor diastereoselectivity was ob-
served upon reduction of 20 with NaBH4, which actually favoured
formation of the 2,3-anti-product 14 giving a mixture of 22 and 14
in 27:73 dr, respectively (Scheme 2).19
Fig. 1. Synthetic strategy to access b-hydroxy-a-amino acids 7 and 11.
with (ꢀ)-CSO 3 gave the known
a-hydroxy-b
-amino esters 1410a
and 1510a as single diastereoisomers (>99:1 dr), which were iso-
lated in 93 and 91% yield, respectively. Tandem hydrogenolysis/N-
Boc protection of 14 gave 16 in 99% yield and >99:1 dr, then
mesylation of the hydroxyl group within 16 gave 18 in 86% yield
and >99:1 dr (Scheme 1). Single crystal X-ray diffraction analyses14
of both 16 and 18 confirmed the assigned configurations within
these substrates. Furthermore, the determination of a Flack x pa-
rameter15 of 0.00(6) for the crystal structure of 18 was also
Scheme 2. Reagents and conditions: (i) (COCl)2, DMSO, CH2Cl2, ꢀ78 ꢁC, 30 min, then
Et3N, ꢀ78 ꢁC to rt, 30 min; (ii) NaBH4, MeOH, ꢀ20 ꢁC, 2 h.
A range of different reaction conditions was therefore screened
for the reduction of 20. The levels of diastereoselectivity were
found to be extremely variable with the 2,3-anti-diastereoisomer
14 predominating in most cases; however, it was found that re-
duction of 20 with DIBAL-H in THF at ꢀ20 ꢁC for 2 h gave exclusively
2,3-syn-22. Upon scale-up, application of these optimised condi-
tions gave 22 in >99:1 dr and 75% yield (from 14) after chro-
matographic purification (Scheme 3). Single crystal X-ray
Scheme 1. Reagents and conditions: (i) (R)-2, THF, ꢀ78 ꢁC, 2 h then (ꢀ)-CSO 3, ꢀ78 ꢁ
C
to rt, 15 h; (ii) Pd(OH)2/C, H2 (5 atm), Boc2O, EtOAc, rt, 15 h; (iii) MsCl, Et3N, DMAP,
CH2Cl2, rt, 15 h.
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S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
3
Ph
With samples of N-Boc protected amino alcohols 16,17, 24 and 25,
and the corresponding mesylates 18, 19, 26 and 27 in hand, in-
vestigations into aziridine formation from these substrates were
undertaken. It has been reported that some of the most successful
aziridine forming reactions from N-Boc protected vicinal amino al-
cohols use a strategy first published by Wessig et al.22 in which
Ph
(i) then
(ii) or (iii)
Ph
N
Ph
N
t
t
CO2 Bu
CO2 Bu
R
R
OH
OH
22, R = Ph, (ii). 75%, >99:1 dr
23, R = Me, (iii). 95%, >99:1 dr
14, R = Ph, >99:1 dr
15, R = Me, >99:1 dr
tosylation of the a-hydroxyl group is followed by in situ aziridine
formation in the presence of KOH. These conditions were first trialled
on 16 and resulted in a 61:34:5 mixture of three major products,
which were assigned as aziridines 28 and 29, and oxazolidin-2-one
30, respectively, from which only 28 and 29 were isolated in 34
and 28% yield (Scheme 4). The relative configurations within trans-28
and cis-29 were initially established by a combination of 1H NMR
NOE and 3J coupling constants analyses,23 and these assignments
were later confirmed by single crystal X-ray diffraction analyses of
both 28 and 29 (Fig. 5).24 Although the 1H NMR 3J coupling constants
observed between the C(4)H and C(5)H protons within 4,5-
disubstituted oxazolidin-2-ones are also diagnostic of their relative
configuration,25 the identity of oxazolidin-2-one 30 was established
unambiguously via the preparation of authentic samples of 30 and its
C(5)-epimer 32: hydrogenolysis of 14 and 22, and treatment of the
(iv)
NHBoc
NHBoc
(v)
t
t
CO2 Bu
CO2 Bu
R
R
OMs
OH
26, R = Ph, 95%, >99:1 dr
27, R = Me, 92%, >99:1 dr
24, R = Ph, 68%, >99:1 dr
25, R = Me, 70%, >99:1 dr
Scheme 3. Reagents and conditions: (i) (COCl)2, DMSO, CH2Cl2, ꢀ78 ꢁC, 30 min, then
Et3N, ꢀ78 ꢁC to rt, 30 min; (ii) DIBAL-H, THF, ꢀ20 ꢁC, 2 h; (iii) NaBH4, MeOH, ꢀ20 ꢁC,
2 h; (iv) Pd(OH)2/C, H2 (5 atm), Boc2O, EtOAc, rt, 15 h; (v) MsCl, Et3N, DMAP, CH2Cl2, rt,
15 h.
resultant b-amino esters 31 and 33 with CDI gave 32 and 30 in 22 and
diffraction analysis20 confirmed the assigned 2,3-syn-configuration
15% overall yield, respectively (Scheme 4). In this case, single crystal
X-ray diffraction analysis24 of 30 allowed its relative configuration to
be unambiguously confirmed (Fig. 5). The 1H NMR spectroscopic data
for this sample of 30 were found to be identical to those for the
sample prepared from 16 upon attempted aziridine formation and
distinctly different to those for 32. The formation of both 28 and 30 is
consistent with a mechanistic pathway in which intramolecular
displacement of the tosylate group within 16 by either the N or O
atom within the carbamate functionality proceeds with inversion of
configuration, and in the case of 30 this is followed by concomitant
loss of the tert-butyl group.26
within 22, with the absolute (2S,3R,
aR)-configuration within 22
being assigned relative to the known configuration of the N-
a
-
methylbenzyl fragment (Fig. 3). Subsequent tandem hydro-
genolysis and N-Boc protection of both 22 and 23, followed by
mesylation of the hydroxyl groups within 24 and 25 gave mesylates
26 and 27 in 65 and 64% overall yield, respectively, from 2,3-syn-b-
amino esters 22 and 23 (Scheme 3). Single crystal X-ray diffraction
analyses21 confirmed the assigned 2,3-syn-configurations within
24, 26 and 27 (Fig. 4).
Other attempts at the direct formation of aziridines from N-Boc
protected amino alcohols 16, 17, 24 and 25 were not successful,
therefore further studies were carried out on the corresponding
mesylates 18, 19, 26 and 27. Treatment of 18 with a variety of bases
under various reaction conditions revealed four main strategies,
which gave good conversion to trans-28. Heating a solution of 18 in
DMF at 50 ꢁC in the presence of Cs2CO3 gave an 81:10:9 ratio of 28,
29 and 30, respectively, from which 28 was isolated in 51% yield and
>99:1 dr. Improved selectivity was observed when 18 was treated
with NaH under the same reaction conditions, which gave a 98:2
mixture of 28 and 29, respectively, from which 28 was isolated in
72% yield and >99:1 dr. For the reactions in THF with NaH as the
base, the addition of 15-crown-5 greatly improved the reaction
selectivity in favour of the formation of 28. However, little differ-
ence was observed when 15-crown-5 ether was used in the cor-
responding reaction in DMF (Scheme 5).
Fig. 3. X-ray crystal structure of 22 (selected H atoms are omitted for clarity).
Fig. 4. X-ray crystal structures of 24 [left], 26 [centre] and 27 [right] (selected H atoms are omitted for clarity).
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4
S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
Scheme 4. Reagents and conditions: (i) KOH, TsCl, Et2O, 40 ꢁC, 15 h; (ii) H2 (5 atm), Pd(OH)2/C, MeOH, rt, 15 h; (iii) CDI, DMAP, THF, rt, 12 h.
Fig. 5. X-ray crystal structures of 28 [left], 29 [centre] and 30 [right] (selected H atoms are omitted for clarity).
Scheme 5. Reagents and conditions: (i) see table. [aIsolated yields correspond to single diastereoisomers (>99:1 dr)].
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S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
5
Subjecting 19 to Cs2CO3 in DMF gave a 66:14:20 mixture of
three major products: aziridines 34 and 35, and oxazolidin-2-one
36,10c which were isolated in 23, 8 and 20% yield, respectively
(Scheme 6). 1H NMR 3J coupling constant analysis enabled the
relative configurations within aziridines 34 (J2,3¼2.7 Hz) and 35
(J2,3¼6.8 Hz) to be assigned, although both 34 and 35 were found
to be crystalline and therefore subsequent single crystal X-ray
diffraction analyses27 enabled these assignments to be un-
ambiguously confirmed (Fig. 6). Furthermore, in the case of cis-35,
the determination of a Flack x parameter of ꢀ0.06(7) allowed the
assigned absolute (R,R)-configuration within 35 to be confirmed,
establishing that epimerisation at the a-centre was responsible for
the formation of cis-aziridine 35. The assigned relative configu-
ration within oxazolidin-2-one 36 was also confirmed un-
ambiguously via single crystal X-ray diffraction analysis (Fig. 6),27
and the absolute configuration within 36 was established by
comparison of the specific rotation of this sample with that of
a literature value for the antipode {½a D25
þ27.3 (c 1.0 in CHCl3);
ꢂ
lit.10c for ent-36: ½a 2D5
ꢀ22.6 (c 0.5 in CHCl3)}. Further optimisation
ꢂ
revealed that reaction with NaH in DMF produced trans-34 in 48%
isolated yield and >99:1 dr (Scheme 6).
Reaction of the corresponding syn-mesylates 26 and 27 under
the same conditions typically proceeded with higher diaster-
eoselectivity and gave cis-aziridines 29 and 35 in superior yields.
Under the optimal conditions treatment of 26 and 27 with Cs2CO3
in DMF at 50 ꢁC gave cis-aziridines 29 and 35 in >99:1 dr, and 99
and 73% isolated yield, respectively, and >99:1 dr after purification.
The corresponding oxazolidin-2-ones were not observed in any of
these reactions (Scheme 7).
Scheme 7. Reagents and conditions: (i) 50 ꢁC, 3 h, see table. [aIsolated as a single
diastereoisomers (>99:1 dr)].
Scheme 6. Reagents and conditions: (i) see table. [aIsolated as a single diastereoisomer (>99:1 dr); ban 84:16 mixture of 34 and 35 was also isolated in 20% combined yield].
Fig. 6. X-ray crystal structures of 34 [left], 35 [centre] and 36 [right] (selected H atoms are omitted for clarity).
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6
S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
2.2. Elaboration to
b
-hydroxy-
a
-amino acids
cases consistent with regioselective SN2-type ring-opening of the
aziridine at C(3) by the trichloroacetate ion, with inversion of
configuration. The formation of 38 and 41 is consistent with hy-
drolysis of the N-Boc group, under the acidic reaction conditions,
followed by O to N transfer of the trichloroacetyl group.30 In sup-
port of this hypothesis, a sample of 37 was re-subjected to the re-
action conditions for 15 h; this produced a 59:41 mixture of 37 and
38, respectively, confirming the intermediacy of 37 in the formation
of 38. For both 37 and 40, global deprotection upon treatment with
We have previously reported the ring-opening of a range of
epoxides with Cl3CCO2H in which regioselective attack of the tri-
chloroacetate ion occurs at the position distal to an electron
withdrawing ammonium group.28 It was therefore envisaged that
regioselective ring-opening of aziridines 28, 29, 34 and 35 with
Cl3CCO2H would occur selectively at the C(3)-position. Indeed,
treatment of trans-C(3)-methyl substituted aziridine 34 with
Cl3CCO2H gave rise to a 70:30 mixture of two products, which were
identified as 37 and 38, and isolated in 47 and 4% yield, respectively.
Likewise, reaction of cis-35 with Cl3CCO2H gave an 84:16 mixture of
40 and 41, which were isolated in 68 and 9% yield, respectively
(Scheme 8). The regiochemistries within 37, 38, 40 and 41 were
assigned via 1H NMR COSYanalyses (in which coupling between the
C(2)H and NH protons was observed) and 1He13C NMR HMBC
analyses. Furthermore, single crystal X-ray diffraction analyses29 of
37 and 41 enabled unambiguous confirmation of their relative
configurations, and the determination of Flack x parameters15 of
ꢀ0.017(15) and ꢀ0.023(13) for the crystal structures of 37 and 41,
respectively, allowed the assigned absolute (S,S)-configuration
within 37 and (2R,3S)-configuration within 41 to be confirmed
unambiguously (Fig. 7). The formation of these products is in both
6.0 M aq HCl at 60 ꢁC for 24 h gave
b-hydroxy-a-amino acids (S,S)-
allo-threonine 39 and (2R,3S)-threonine 42, respectively, which
were isolated in 72% yield and >99:1 dr, and 97% yield and 98:2 dr,
after purification on Dowex 50WX8 ion exchange resin (Scheme 8).
The spectroscopic data, including specific rotations, for the samples
of (S,S)-39 {mp 240e250 ꢁC (dec); ½a D20
ꢂ
þ7.5 (c 1.0 in H2O); lit.9c mp
264e266 ꢁC; lit.9c
½
a 2D0
ꢂ
þ8 (c 1.1 in H2O)} and (2R,3S)-42 {mp
250e260 ꢁC (dec); ½a 2D0
ꢂ
þ23.2 (c 1.0 in H2O); lit.31 mp 264 ꢁC; lit.32
½ ꢂ þ26.1 (c 1.0 in H2O)} were in excellent agreement with liter-
a D
ature values.9c,33,34
For the C(3)-phenyl substituted aziridines 28 and 29, however,
treatment with Cl3CCO2H induced rearrangement to give the cor-
responding oxazolidin-2-ones: upon treatment of cis-aziridine 29
with Cl3CCO2H a 92:8 mixture of cis- and trans-oxazolidin-2-ones
Scheme 8. Reagents and conditions: (i) Cl3CCO2H, CH2Cl2, rt, 15 h; (ii) HCl (6.0 M aq), 90 ꢁC, 24 h.
43 (J4,5¼9.2 Hz) and 44 (J4,5¼5.3 Hz) was produced, and 43 and
44 were subsequently isolated in 74 and 4% yield, respectively, after
purification of the crude reaction mixture. Identical treatment of
the epimeric trans-aziridine 28 produced trans-oxazolidin-2-one
ent-44 exclusively, which was isolated in 77% yield and >99:1 dr
(Scheme 9). For both 43 and ent-44 single crystal X-ray diffraction
analyses35 enabled unambiguous confirmation of the relative
configurations within these compounds, and the determination of
Flack x parameters15 of ꢀ0.03(19) and ꢀ0.08(16) for the crystal
structures of 43 and ent-44, respectively, allowed the absolute
(R,R)-configuration within 43 and (4S,5R)-configuration within ent-
44 to be assigned unambiguously (Fig. 8). These stereochemical
outcomes (i.e., retention of configuration) are consistent with
a mechanism whereby Cl3CCO2H promotes SN1-type ring-opening
of aziridines 28 and 29 to generate the corresponding benzylic
carbonium ions, which then undergo rapid intramolecular reaction
with the carbamate functionality to form the oxazolidin-2-one ring
Fig. 7. X-ray crystal structures of 37 [left] and 41 [right] (selected H atoms are omitted
for clarity).
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S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
7
OtBu
OtBu
Boc
N
slow
(i)
O
+
O
+
NH
H
NH
H
t
H
Ph
H
Ph
CO2 Bu
Ph
t
t
CO2 Bu
CO2 Bu
29, >99:1 dr
92:8
[43:44]
fast
O
O
O
NH
O
NH
+
t
t
Ph
CO2 Bu
Ph
CO2 Bu
43, 74%, >99:1 dr
44, 4%, >99:1 dr
(ii)
OH
CO2H
Ph
NH2
45, 76%, 96:4 dr
O
OH
OH
Boc
N
(i)
(ii)
O
NH
+
CO2H
CO2H
Ph
Ph
t
Ph
CO2 Bu
28, >99:1 dr
t
Ph
CO2 Bu
NH2
48
NH2
ent-45
ent-44, 77%, >99:1 dr
80:20 [48:ent-45]
52% mass return
(iii)
O
OH
OH
(iv)
(v)
O
NBoc
t
CO2 Bu
CO2H
Ph
Ph
t
Ph
CO2 Bu
NHBoc
47, 59%, 98:2 dr
NH2
48, quant, 98:2 dr
46, 92%, >99:1 dr
Scheme 9. Reagents and conditions: (i) Cl3CCO2H, CH2Cl2, rt, 15 h; (ii) HCl (6.0 M aq), 90 ꢁC, 24 h; (iii) Boc2O, Et3N, DMAP, THF, rt, 15 h; (iv) LiOH, dioxane/H2O (5:1), rt, 45 min; (v)
CH2Cl2/TFA (4:1), rt, 2 h.
Fig. 8. X-ray crystal structures of 43 [left], ent-44 [centre] and 47 [right] (selected H atoms are omitted for clarity).
with concomitant loss of the tert-butyl group; in the case of 29 the
corresponding benzylic carbonium ion presumably undergoes CeC
bond rotation (to minimise the interaction between the phenyl and
ester substituents) at a competitive rate, giving rise to the forma-
tion of the minor diastereoisomer 44.36 Hydrolysis of 43, upon
ent-44, application of identical hydrolysis conditions produced an
80:20 mixture of the epimeric -hydroxy- -amino acids 48 and
b
a
ent-45, respectively, in 52% mass return.37 Conversion of ent-44 to
the corresponding N(3)-Boc protected compound 46 followed
by hydrolysis with LiOH in dioxane38 gave 47 in 71% overall
yield and 98:2 dr after purification (Scheme 9). The relative con-
figuration within 47 was established unambiguously via single
crystal X-ray diffraction analysis,35 and the determination of a Flack
treatment with aqueous HCl, produced the corresponding
droxy- -amino acid 45 in 76% yield and 96:4 dr after purification
on Dowex 50WX8 ion exchange resin. However, in the case of
b-hy-
a
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8
S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
x parameter15 of ꢀ0.06(14) for the crystal structure of 47 allowed
the assigned absolute (2S,3R)-configuration within 47 to be con-
firmed (Fig. 8). Finally, hydrolysis of both the tert-butyl ester and N-
Boc groups within 47 was achieved upon treatment with TFA,
which gave 48 in quantitative yield and 98:2 dr after purification on
Dowex 50WX8 ion exchange resin (Scheme 9). The spectroscopic
data, including specific rotations, for both samples of (R,R)-45 {mp
resonance. 1He1H COSY, 1He13C HSQC 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.
189e192 ꢁC (dec); ½a 2D0
ꢂ
ꢀ2.4 (c 1.0 in H2O); lit.9a mp 174 ꢁC (dec);
lit.39
½
a D
ꢂ
ꢀ4.3 (c 1.1 in H2O)} and (2S,3R)-48 {mp 201e202 ꢁC; ½a D20
ꢂ
ꢀ28.9 (c 1.0 in H2O); lit.40 mp 192e195 ꢁC; lit.9c
½
a 2D0
ꢂ
ꢀ30 (c 1.0 in
4.2. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]-3-phenylpropanoate 14
H2O)} were in excellent agreement with literature values.41
BuLi (2.5 M in hexanes, 15.2 mL, 38.0 mmol) was added drop-
wise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)
3. Conclusion
a
amine43 (8.26 g, 39.1 mmol, >99:1 er) in THF (100 mL) at ꢀ78 ꢁC
and stirring was continued at ꢀ78 ꢁC for 30 min. A solution of 1244
(5.00 g, 24.5 mmol, >99:1 dr) in THF (100 mL) was then added via
cannula and the resultant mixture was stirred at ꢀ78 ꢁC for 2 h.
(ꢀ)-CSO 3 (8.97 g, 39.1 mmol) was then added and stirring was
continued as the reaction mixture was allowed to warm to rt over
15 h. Satd aq NH4Cl (5 mL) was added and the reaction mixture was
stirred at rt for 5 min then concentrated in vacuo. The residue was
partitioned between CH2Cl2 (100 mL) and 10% aq citric acid
(100 mL), and the aqueous layer was extracted with CH2Cl2
(3ꢃ40 mL). The combined organic extracts were washed sequen-
tially with satd aq NaHCO3 (100 mL) and brine (100 mL), then dried
and concentrated in vacuo. The residue was dissolved in Et2O
(100 mL), the insoluble CSO residues were filtered off, and the filter
cake was washed with Et2O (2ꢃ50 mL). The filtrate was concen-
trated in vacuo and the process was repeated. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 15:1) gave
14 as a pale yellow solid (9.77 g, 93%, >99:1 dr);30b mp 85e88 ꢁC;
In conclusion, a range of enantiopure
were converted into the corresponding N-Boc protected aziridines
and subsequently used in the syntheses of -hydroxy- -amino
acids. The -amino ester substrates were prepared upon conjugate
addition of lithium (R)-N-benzyl-N-( -methylbenzyl)amide to the
corresponding -unsaturated esters, followed by oxidation of the
intermediate lithium (Z)-
-amino enolate with (ꢀ)-CSO, which
a-hydroxy-b-amino esters
b
a
b
a
a,b
b
gave diastereoisomerically pure 2,3-anti-configured products. Epi-
merisation of these substrates was achieved using an oxidation/
diastereoselective reduction approach, which (under optimised
conditions) gave the corresponding 2,3-syn-configured products in
>99:1 dr. The syn- and anti-substrates were then converted into the
corresponding N-Boc protected mesylates followed by base-
promoted aziridine formation. Subsequent regioselective ring-
opening of the C(3)-methyl substituted aziridines with Cl3CCO2H
proceeded with inversion of configuration at C(3) (i.e., an SN2-type
process), and reaction of the analogous C(3)-phenyl substituted
aziridines with Cl3CCO2H produced the corresponding oxazolidin-
2-ones with retention of configuration (i.e., an SN1-type process). In
each case, hydrolysis of the products from these ring-opening re-
actions produced the corresponding diastereoisomerically pure
{lit.45 mp 87e88 ꢁC}; ½a 2D3
ꢂ
ꢀ26.7 (c 1.0 in CHCl3); {lit.45
½
a 2D5
ꢂ
ꢀ27.2
(c 1.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.26e1.29 (12H, m, C(
a
)Me,
CMe3), 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(
3.0, C(2)H), 7.21e7.61 (15H, m, Ph).
a)H, C(3)H), 4.49 (1H, d, J,
(>95:5 dr)
b-hydroxy-a-amino acids.
4. Experimental
4.3. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]butanoate 15
4.1. General experimental
BuLi (2.4 M in hexanes, 4.54 mL, 10.9 mmol) was added drop-
wise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)
Reactions involving organometallic or other moisture-
sensitive reagents were carried out under a nitrogen or argon
atmosphere using standard vacuum line techniques and glass-
ware that was flame dried and cooled under nitrogen before use.
BuLi was purchased from SigmaeAldrich (as a solution in hex-
anes) and titrated against diphenylacetic acid before use. Solvents
were dried according to the procedure outlined by Grubbs et al.42
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 phosphomo-
lybdic 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
a
amine43 (2.39 g, 11.3 mmol, >99:1 er) in THF (60 mL) at ꢀ78 ꢁC and
stirring was continued at ꢀ78 ꢁC for 30 min. A solution of 13 (1.00 g,
7.03 mmol, >99:1 dr) in THF (60 mL) was then added via cannula
and the resultant mixture was stirred at ꢀ78 ꢁC for 2 h. (ꢀ)-CSO 3
(2.59 g, 11.3 mmol) was then added and stirring was continued as
the reaction mixture was allowed to warm to rt over 15 h. Satd aq
NH4Cl (5 mL) was added and the reaction mixture was stirred at rt
for 5 min then concentrated in vacuo. The residue was partitioned
between CH2Cl2 (100 mL) and 10% aq citric acid (100 mL), and the
aqueous layer was extracted with CH2Cl2 (3ꢃ40 mL). The combined
organic extracts were washed sequentially with satd aq NaHCO3
(100 mL) and brine (100 mL), then dried and concentrated in vacuo.
The residue was dissolved in Et2O (100 mL), the insoluble CSO
residues were filtered off, and the filter cake was washed with Et2O
(2ꢃ50 mL). The filtrate was concentrated in vacuo and the process
was repeated. Purification via flash column chromatography (elu-
ent 30e40 ꢁC petrol/Et2O, 10:1) gave 15 as a yellow solid (2.29 g,
91%, >99:1 dr);45 mp 89e94 ꢁC; {lit.45 mp 88e89 ꢁC}; ½a 2D3
ꢀ35.5
ꢂ
(c 1.0 in CHCl3); {lit.45
½
a 2D5
ꢂ
ꢀ35.2 (c 1.0 in CHCl3)}; dH (400 MHz,
CDCl3) 1.08 (3H, d, J 7.0, C(4)H3), 1.32 (3H, d, J 6.8, C(
a)Me), 1.36 (9H,
s, CMe3), 2.92 (1H, app 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(
NCHAHBPh), 7.18e7.50 (10H, m, Ph).
a)H,
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.007

S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
9
4.4. tert-Butyl (R,R)-2-hydroxy-3-[N-(tert-butoxycarbonyl)-
amino]-3-phenylpropanoate 16
extracts were washed sequentially with 1.0 M aq HCl (100 mL), satd
aq NaHCO3 (100 mL) and brine (100 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography (el-
uent 30e40 ꢁC petrol/Et2O, 10:1) gave 19 a pale yellow oil (1.10 g,
Pd(OH)2/C (500 mg, 25% w/w) was added to a degassed solution
of 14 (2.00 g, 4.64 mmol, >99:1 dr) and Boc2O (1.11 g, 7.66 mmol) in
EtOAc (40 mL) and the resultant mixture was stirred under H2
(5 atm) at rt for 15 h. The reaction mixture was then filtered
through CeliteÒ (eluent EtOAc) and concentrated in vacuo. Purifi-
cation via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 20:1) gave 16 as a white solid (1.54 g, 99%, >99:1 dr); mp
85%, >99:1 dr);10c
½
a 2D3
ꢂ
þ35.5 (c 1.0 in CHCl3); {lit.10c for ent-19:
½
a 2D5
ꢂ
ꢀ38.4 (c 1.05 in CHCl3)}; dH (400 MHz, CDCl3) 1.13 (3H, d, J 7.0,
C(4)H3), 1.45 (9H, s, CMe3), 1.51 (9H, s, CMe3), 3.17 (3H, s, SO2Me),
4.23e4.34 (1H, m, C(3)H), 4.75 (1H, d, J 8.7, NH), 5.20 (1H, d, J 2.7,
C(2)H).
75e79 ꢁC; ½a 2D3
ꢂ
ꢀ25.8 (c 1.0 in CHCl3); nmax (ATR) 3400 (NeH), 3292
4.8. tert-Butyl (2S,3R,
aR)-2-hydroxy-3-[N-benzyl-N-(a-meth-
(OeH), 2976, 2933 (CeH), 1707, 1687 (2ꢃ C]O); dH (400 MHz,
CDCl3) 1.36 (9H, s, CMe3), 1.43 (9H, s, CMe3), 1.57 (1H, br s, OH),
4.44e4.51 (1H, m, C(2)H), 5.06 (1H, dd, J 8.9, 3.3, C(3)H), 5.60 (1H, d,
J 8.9, NH), 7.26e7.36 (5H, m, Ph); dC (100 MHz, CDCl3) 27.9, 28.4 (2ꢃ
CMe3), 56.3 (C(3)), 73.0 (C(2)), 79.8, 83.6 (2ꢃ CMe3), 127.9, 128.1,
128.2 (o,m,p-Ph), 137.2 (i-Ph), 155.0 (NCO), 171.0 (C(1)); m/z (ESIþ)
ylbenzyl)amino]-3-phenylpropanoate 22
Step 1: DMSO (0.17 mL, 2.32 mmol) was added to a stirred so-
lution of (COCl)2 (0.20 mL, 2.32 mmol) in CH2Cl2 (15 mL) at ꢀ78 ꢁC
and the resultant mixture was stirred at ꢀ78 ꢁC for 5 min. A solu-
tion of 14 (500 mg, 1.16 mmol, >99:1 dr) in CH2Cl2 (15 mL) was
added via cannula and the resultant mixture was stirred at ꢀ78 ꢁC
for 30 min. Et3N (0.62 mL, 4.64 mmol) was added and the reaction
mixture was allowed to warm to rt. H2O (20 mL) was then added,
the reaction mixture was extracted with CH2Cl2 (3ꢃ10 mL) and the
combined organic extracts were dried and concentrated in vacuo to
give 20 (498 mg, >99:1 dr).
þ
360 ([MþNa]þ, 100%); HRMS (ESIþ) C18H27NNaO5 ([MþNa]þ) re-
quires 360.1781; found 360.1767.
4.5. tert-Butyl (R,R)-2-hydroxy-3-[N-(tert-butoxycarbonyl)-
amino]butanoate 17
Pd(OH)2/C (1.00 g, 25% w/w) was added to a degassed solution of
15 (4.00 g, 10.8 mmol, >99:1 dr) and Boc2O (2.60 g, 11.9 mmol) in
EtOAc (50 mL) and the resultant mixture was stirred under H2
(5 atm) at rt for 15 h. The reaction mixture was then filtered
through CeliteÒ (eluent EtOAc) and concentrated in vacuo. Purifi-
cation via flash column chromatography (eluent 30e40 ꢁC petrol/
Step 2: DIBAL-H (1.0 M in THF, 1.16 mL, 1.16 mmol) was added to
a stirred solution of 20 (498 mg, >99:1 dr) in THF (13 mL) at ꢀ20 ꢁC
and the resultant mixture was stirred at ꢀ20 ꢁC for 2 h. MeOH
(1 mL) was added and the reaction mixture was then allowed to
warm to rt. Satd aq Rochelle’s salt (1 mL) was added and the re-
sultant suspension was stirred at rt for 15 h, then filtered through
CeliteÒ (eluent MeOH) and concentrated in vacuo to give 22 in
>99:1 dr. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 7:1) gave 22 as a white solid (375 mg, 75%,
Et2O, 5:1) gave 17 as a colourless oil (2.62 g, 88%, >99:1 dr);10c
½ ꢂ
a 2D3
ꢀ10.4 (c 1.0 in CHCl3); {lit.10c for ent-17: ½a 2D3
ꢂ
þ10.8 (c 2.4 in CHCl3)};
dH (400 MHz, CDCl3) 1.02 (3H, d, J 6.7, C(4)H3), 1.45 (9H, s, CMe3),
1.50 (9H, s, CMe3), 3.04 (1H, d, J 5.5, OH), 4.05e4.15 (1H, m, C(3)H),
4.21 (1H, m, C(2)H), 4.90 (1H, d, J 8.9, NH).
>99:1 dr); mp 110e114 ꢁC; ½a D23
ꢀ25.9 (c 1.0 in CHCl3); nmax (ATR)
ꢂ
3492 (OeH), 3085, 3062, 3028, 2976, 2934, 2879, 2842 (CeH),
1722 (C]O); dH (400 MHz, CDCl3) 1.08 (9H, s, CMe3), 1.10 (3H, d, J
4.6. tert-Butyl (R,R)-2-methanesulfonyloxy-3-[N-(tert-butox-
ycarbonyl)amino]-3-phenylpropanoate 18
6.9, C(
(1H, d, J 9.9, C(3)H), 4.07 (1H, d, J 13.3, NCHAHBPh), 4.21 (1H, q, J 6.9,
C( )H), 4.47 (1H, d, J 9.9, C(2)H), 7.24e7.42 (15H, m, Ph); dC
(100 MHz, CDCl3) 13.7 (C( )Me), 27.4 (CMe3), 50.4 (NCH2Ph), 56.0
(C( )), 64.4 (C(3)), 71.0 (C(2)), 81.0 (CMe3), 127.3, 127.4, 127.9, 128.1,
a)Me), 3.66 (1H, d, J 13.3, NCHAHBPh), 3.84 (1H, br s, OH), 3.90
a
MsCl (1.37 mL,17.8 mmol), Et3N (5.90 mL, 44.5 mmol) and DMAP
(5 mg, cat.) were added to a stirred solution of 16 (3.00 g,
8.89 mmol, >99:1 dr) in CH2Cl2 (270 mL) and the resultant solution
was stirred at rt for 15 h. H2O (180 mL) was then added and the
aqueous layer was extracted with CH2Cl2 (2ꢃ90 mL). The combined
organic extracts were washed sequentially with 1.0 M aq HCl
(200 mL), satd aq NaHCO3 (200 mL) and brine (200 mL), then dried
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/Et2O, 1:1) gave 18 as a yellow
a
a
128.2, 128.6, 128.7, 129.1, 130.0 (o,m,p-Ph), 136.7, 139.3, 143.2 (i-Ph),
171.2 (C(1)); m/z (ESIþ) 432 ([MþH]þ, 100%); HRMS (ESIþ)
C
28H34NO3þ ([MþH]þ) requires 432.2533; found 432.2518.
4.9. tert-Butyl (2S,3R,
aR)-2-hydroxy-3-[N-benzyl-N(a-meth-
ylbenzyl)amino]butanoate 23
solid (3.16 g, 86%, >99:1 dr); mp 113e116 ꢁC; ½a D23
ꢂ
ꢀ17.5 (c 1.0 in
Step 1: DMSO (0.58 mL, 8.13 mmol) was added to a stirred so-
lution of (COCl)2 (0.69 mL, 8.13 mmol) in CH2Cl2 (50 mL) at ꢀ78 ꢁC
and the resultant mixture was stirred at ꢀ78 ꢁC for 5 min. A solu-
tion of 15 (1.50 g, 4.06 mmol, >99:1 dr) in CH2Cl2 (50 mL) was
added via cannula and the resultant mixture was stirred at ꢀ78 ꢁC
for 30 min. Et3N (2.18 mL, 16.2 mmol) was added and the reaction
mixture was allowed to warm to rt. H2O (80 mL) was then added,
the reaction mixture was extracted with CH2Cl2 (3ꢃ50 mL) and
combined organic extracts were dried and concentrated in vacuo to
give 21 (1.49 g, >99:1 dr).
CHCl3); nmax (ATR) 3381 (NeH), 3064, 3034, 2974, 2936, 2872
(CeH), 1740, 1695 (2ꢃ C]O); dH (400 MHz, CDCl3) 1.32 (9H,
s, CMe3), 1.45 (9H, s, CMe3), 3.15 (3H, s, SO2Me), 5.22e5.32 (2H, m,
C(3)H, NH), 5.41e5.46 (1H, m, C(2)H), 7.31e7.39 (5H, m, Ph); dC
(100 MHz, CDCl3) 27.7, 28.3 (2ꢃ CMe3), 39.1 (SO2Me), 55.2 (C(3)),
79.0 (C(2)), 80.4, 83.9 (2ꢃ CMe3), 128.1, 128.6, 128.6 (o,m,p-Ph),
135.8 (i-Ph), 154.8 (NCO), 165.5 (C(1)); m/z (ESIþ) 438 ([MþNa]þ,
100%); HRMS (ESIþ) C19H29NNaO7Sþ ([MþNa]þ) requires 438.1557;
found 438.1574.
Step 2: NaBH4 (154 mg, 4.06 mmol) was added to a solution of 21
(1.49 g, >99:1 dr) in MeOH (105 mL) and the resultant solution was
cooled to ꢀ20 ꢁC and stirred at ꢀ20 ꢁC for 2 h, then allowed to
warm to rt and concentrated in vacuo. The reaction mixture was
then partitioned between Et2O (50 mL) and H2O (30 mL) and the
aqueous layer was extracted with Et2O (2ꢃ20 mL). The combined
organic extracts were then dried and concentrated in vacuo to give
4.7. tert-Butyl (R,R)-2-methanesulfonyloxy-3-[N-(tert-butox-
ycarbonyl)amino]butanoate 19
MsCl (0.56 mL, 7.26 mmol), Et3N (2.41 mL, 18.2 mmol) and
DMAP (3 mg, cat.) were added to a stirred solution of 17 (1.00 g,
3.63 mmol, >99:1 dr) in CH2Cl2 (110 mL) and the resultant solution
was stirred at rt for 15 h. H2O (60 mL) was added and the aqueous
layer was extracted with CH2Cl2 (2ꢃ40 mL). The combined organic
23 as a colourless oil (1.42 g, 95%, >99:1 dr); ½a D23
ꢀ68.0 (c 1.0 in
ꢂ
CHCl3); nmax (ATR) 3501 (OeH), 3086, 3062, 3028, 2975, 2935, 2881
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.007

10
S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
(CeH), 1724 (C]O); dH (400 MHz, CDCl3) 1.17 (3H, d, J 6.8, C(4)H3),
1.43 (9H, s, CMe3), 1.47 (3H, d, J 6.9, C( )Me), 3.07 (1H, dq, J 8.3,
6.8, C(3)H), 3.65e3.72 (2H, m, C(2)H, NCHAHBPh), 3.78 (1H, br s,
OH), 3.81 (1H, d, J 13.6, NCHAHBPh), 4.06 (1H, q, J 6.9, C( )H),
7.19e7.39 (10H, m, Ph); dC (100 MHz, CDCl3) 13.6 (C(4)), 14.4 (C(
Me), 27.9 (CMe3), 49.6 (NCH2Ph), 54.9 (C(3)), 57.1 (C( )), 73.5 (C(2)),
C(3)H), 7.28e7.42 (5H, m, Ph); dC (100 MHz, CDCl3) 27.8, 28.2 (2ꢃ
CMe3), 38.6 (SO2Me), 55.1 (C(3)), 81.5 (C(2)), 84.2 (2ꢃ CMe3), 126.4,
128.2, 128.8 (o,m,p-Ph), 137.7 (i-Ph), 154.6 (NCO), 165.6 (C(1)); m/z
(ESIþ) 438 ([MþNa]þ, 100%); HRMS (ESIþ) C19H29NNaO7Sþ
([MþNa]þ) requires 438.1557; found 438.1544.
a
a
a
)
a
81.3 (CMe3), 127.3, 127.3, 127.7, 128.4, 128.5, 129.1 (o,m,p-Ph), 139.8,
143.0 (i-Ph), 172.2 (C(1)); m/z (ESIþ) 370 ([MþH]þ, 100%); HRMS
(ESIþ) C23H32NO3þ ([MþH]þ) requires 370.2377; found 370.2364.
4.13. tert-Butyl (2S,3R)-2-methanesulfonyloxy-3-[(tert-butox-
ycarbonyl)amino]butanoate 27
MsCl (0.26 mL, 3.31 mmol), Et3N (1.10 mL, 8.30 mmol) and
DMAP (3 mg, cat.) were added to a stirred solution of 25 (456 mg,
1.66 mmol, >99:1 dr) in CH2Cl2 (50 mL) and the resultant solution
was stirred at rt for 16 h. H2O (40 mL) was added and the aqueous
layer was extracted with CH2Cl2 (2ꢃ25 mL). The combined organic
extracts were washed sequentially with 1.0 M aq HCl (50 mL), satd
aq NaHCO3 (50 mL) and brine (50 mL), then dried and concentrated
in vacuo to give 27 as a yellow solid (473 mg, 92%, >99:1); mp
4.10. tert-Butyl (2S,3R)-2-hydroxy-3-[N-(tert-butoxycarbonyl)-
amino]-3-phenylpropanoate 24
Pd(OH)2/C (150 mg, 40% w/w) was added to a degassed solution
of 22 (375 mg, 0.870 mmol, >99:1 dr) and Boc2O (189 mg,
0.870 mmol) in EtOAc (10 mL) and the resultant mixture was stirred
under H2 (5 atm) at rt for 15 h. The reaction mixture was then fil-
tered through CeliteÒ (eluent EtOAc) and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 10:1) gave 24 as a white solid (163 mg, 68%, >99:1
97e106 ꢁC; ½a 2D0
þ4.5 (c 1.0 in CHCl3); nmax (ATR) 3388 (NeH), 2981,
ꢂ
2966, 2935, 2866 (CeH),1750,1722 (2ꢃ C]O); dH (400 MHz, CDCl3)
1.28 (3H, d, J 6.8, C(4)H3), 1.42 (9H, s, CMe3), 1.49 (9H, s, CMe3), 3.19
(3H, s, SO2Me), 4.39e4.50 (1H, m, C(3)H), 4.65e4.75 (1H, m, C(2)H),
4.88 (1H, d, J 2.3, NH); dC (100 MHz, CDCl3) 18.3 (C(4)), 27.8, 28.3 (2ꢃ
CMe3), 39.3 (SO2Me), 47.6 (C(3)), 81.0 (C(2)), 79.7, 83.9 (2ꢃ CMe3),
154.6 (NCO), 166.2 (C(1)); m/z (ESIþ) 376 ([MþNa]þ, 100%); HRMS
(ESIþ) C14H27NNaO7Sþ ([MþNa]þ) requires 376.1400; found
376.1384.
dr);46 mp 106e107 ꢁC; ½a 2D3
ꢀ9.0 (c 1.0 in CHCl3); nmax (ATR) 3447
ꢂ
(NeH), 3392 (OeH), 3091, 3065, 3032, 2978, 2933 (CeH), 1716 (2ꢃ
C]O); dH (400 MHz, CDCl3) 1.42 (9H, s, CMe3), 1.52 (9H, s, CMe3),
3.27 (1H, br s, OH), 4.31e4.39 (1H, m, C(2)H), 5.20e5.26 (1H, m,
C(3)H), 5.41e5.49 (1H, m, NH), 7.22e7.43 (5H, m, Ph); dC (100 MHz,
CDCl3) 27.9, 28.3 (2ꢃ CMe3), 55.7 (C(3)), 73.7 (C(2)), 79.6, 83.7 (2ꢃ
CMe3), 126.7, 127.5, 128.5 (o,m,p-Ph), 139.7 (i-Ph), 155.0 (NCO), 172.1
(C(1)); m/z (ESIþ) 360 ([MþNa]þ, 100%); HRMS (ESIþ)
C
18H27NNaO5þ ([MþNa]þ) requires 360.1781; found 360.1769.
4.14. Di-tert-butyl (2S,3R)-3-phenylaziridine-N(1),2-
dicarboxylate 28
4.11. tert-Butyl (2S,3R)-2-hydroxy-3-[N-(tert-butoxycarbonyl)-
amino]butanoate 25
NaH (60% dispersion in mineral oil, 323 mg, 8.09 mmol) was
added to a stirred solution of 18 (2.80 g, 6.74 mmol, >99:1 dr) in
DMF (100 mL) and the resultant solution was heated at 50 ꢁC for
3 h. Et2O (60 mL) was then added and the resultant mixture was
washed with H2O (4ꢃ40 mL), then dried and concentrated in vacuo
to give a 98:2 mixture of 28 and 29, respectively. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 20:1)
gave 28 as a white solid (1.55 g, 72%, >99:1 dr); mp 120e128 ꢁC;
Pd(OH)2/C (78 mg, 25% w/w) was added to a degassed solution
of 23 (313 mg, 0.847 mmol, >99:1 dr) and Boc2O (203 mg,
0.932 mmol) in EtOAc (10 mL) and the resultant mixture was stirred
under H2 (5 atm) at rt for 15 h. The reaction mixture was then fil-
tered through CeliteÒ (eluent EtOAc) and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 5:1) gave 25 as a yellow solid (164 mg, 70%, >99:1 dr);
½
a 2D3
ꢂ
þ69.6 (c 1.0 in CHCl3); nmax (ATR) 3064, 3036, 2986, 2967, 2933
mp 65e80 ꢁC; ½a 2D3
þ17.7 (c 1.0 in CHCl3); nmax (ATR) 3449 (NeH),
ꢂ
(CeH), 1729, 1717 (2ꢃ C]O); dH (500 MHz, CDCl3) 1.48 (9H, s,
CMe3), 1.52 (9H, s, CMe3), 3.01 (1H, d, J 2.5, C(2)H), 3.74 (1H, d, J 2.5,
C(3)H), 7.27e7.37 (5H, m, Ph); dC (125 MHz, CDCl3) 27.9, 28.1 (2ꢃ
CMe3), 44.5 (C(3)), 45.1 (C(2)), 82.0, 82.7 (2ꢃ CMe3), 126.5, 128.2,
128.5 (o,m,p-Ph), 135.7 (i-Ph), 158.6 (NCO), 166.4 (CO2 tBu); m/þz
(ESIþ) 342 ([MþNa]þ, 100%); HRMS (ESIþ) C18H25NNaO4
([MþNa]þ) requires 342.1676; found 342.1674.
3391 (OeH), 2978, 2934 (CeH), 1714 (2ꢃ C]O); dH (400 MHz,
CDCl3) 1.24 (3H, d, J 7.1, C(4)H3), 1.40 (9H, s, CMe3), 1.49 (9H, s,
CMe3), 3.12e3.26 (1H, m, OH), 3.98 (1H, app br s, C(2)H), 4.13e4.24
(1H, m, C(3)H), 4.70e4.79 (1H, m, NH); dC (100 MHz, CDCl3) 18.5
(C(4)), 27.8, 28.3 (2ꢃ CMe3), 48.3 (C(3)), 73.4 (C(2)), 79.1, 83.3 (2ꢃ
CMe3), 154.9 (NCO), 172.6 (C(1)); m/z (ESIþ) 298 ([MþNa]þ, 100%);
HRMS (ESIþ) C13H25NNaO5 ([MþNa]þ) requires 298.1625; found
þ
298.1626.
4.15. Di-tert-butyl (R,R)-3-phenylaziridine-N(1),2-
4.12. tert-Butyl (2S,3R)-2-methanesulfonyloxy-3-[N-(tert-bu-
dicarboxylate 29
toxycarbonyl)amino]-3-phenylpropanoate 26
Cs2CO3 (299 mg, 0.918 mmol) was added to a stirred solution of
26 (127 mg, 0.306 mmol, >99:1 dr) in DMF (6.2 mL) and the re-
sultant mixture was heated at 50 ꢁC for 3 h. Et2O (5 mL) was then
added and the resultant mixture was washed with H2O (4ꢃ3 mL),
then dried and concentrated in vacuo to give 29 as a white solid
MsCl (34 mL, 0.45 mmol), Et3N (0.14 mL, 1.0 mmol) and DMAP
(1 mg, cat.) were added to a solution of 24 (30 mg, 0.09 mmol,
>99:1 dr) in CH2Cl2 (3 mL) and the resultant solution was stirred at
rt for 15 h. H2O (1.5 mL) was added and the aqueous layer was
extracted with CH2Cl2 (2ꢃ5 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 chromatography (eluent
30e40 ꢁC petrol/Et2O, 3:1 then increased to 1:1) gave 26 as a col-
(97 mg, 99%, >99:1 dr); mp 121e124 ꢁC; ½a D25
ꢂ ꢀ18.3 (c 1.0 in CHCl3);
nmax (ATR) 3065, 3034, 3007, 2976, 2959, 2926, 2853 (CeH), 1736,
1724 (2ꢃ C]O); dH (500 MHz, CDCl3); 1.16 (9H, s, CMe3), 1.49 (9H, s,
CMe3), 3.33 (1H, d, J 6.9, C(2)H), 3.77 (1H, d, J 6.9, C(3)H), 7.25e7.45
(5H, m, Ph); dC (125 MHz, CDCl3) 27.8, 27.9 (2ꢃ CMe3), 43.3 (C(2)),
44.2 (C(3)), 81.9, 82.2 (2ꢃ CMe3),127.6,127.9,128.5 (o,m,p-Ph),133.4
(i-Ph), 160.8 (NCO), 165.1 (CO2 tBu); m/z (ESIþ) 342 ([MþNa]þ,
ourless oil (35 mg, 95%, >99:1 dr); ½a D23
ꢀ5.8 (c 1.0 in CHCl3); nmax
ꢂ
(ATR) 3065, 2980, 2936 (CeH), 1749, 1717 (2ꢃ C]O); dH (400 MHz,
CDCl3) 1.42, (9H, s, CMe3), 1.51 (9H, s, CMe3), 2.72 (3H, s, SO2Me),
5.05e5.14 (1H, m, C(2)H), 5.35e5.44 (1H, m, NH), 5.46e5.53 (1H, m,
þ
100%); HRMS (ESIþ) C18H25NNaO4 ([MþNa]þ) requires 342.1676;
found 342.1661.
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.007

S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
11
4.16. (4R,5S)-4-Phenyl-5-(tert-butoxycarbonyl)oxazolidin-2-
one 30
127.0, 127.5, 128.4 (o,m,p-Ph), 142.2 (i-Ph), 172.6 (C(1)); m/z (ESIþ)
þ
260 ([MþNa]þ, 100%); HRMS (ESIþ) C13H19NNaO3 ([MþNa]þ) re-
quires 260.1257; found 260.1250.
CDI (73 mg, 0.449 mmol) and DMAP (3 mg, cat.) were added to
a stirred solution of 33 (77 mg, 0.299 mmol, >99:1 dr) in THF
(2.5 mL) and the resultant mixture was stirred at rt for 12 h. Satd aq
NH4Cl (2 mL) was added and the reaction mixture was extracted
with EtOAc (3ꢃ2 mL). The combined organic extracts were washed
with brine (5 mL), then dried and concentrated in vacuo. Purifica-
tion via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 2:1) gave 30 as a white solid (12 mg, 15%, >99:1 dr); mp
4.20. Di-tert-butyl (2S,3R)-3-methylaziridine-N(1),2-
dicarboxylate 34
Method A: NaH (60% dispersion in mineral oil, 68 mg,
1.69 mmol) was added to a stirred solution of 19 (459 mg,
1.41 mmol, >99:1 dr) in DMF (15 mL) and the resultant mixture
was heated at 50 ꢁC for 3 h. Et2O (15 mL) was then added and the
resultant mixture was washed with H2O (4ꢃ10 mL), then dried
and concentrated in vacuo to give a 93:7 mixture of 34 and 36,
respectively. Purification via flash column chromatography (elu-
ent 30e40 ꢁC petrol/Et2O, 15:1) gave 34 as a white solid (185 mg,
145e150 ꢁC; ½a 2D5
þ30.8 (c 1.0 in CHCl3); nmax (ATR) 3287 (NeH),
ꢂ
3037, 3004, 2981, 2932 (CeH), 1760, 1734 (2ꢃ C]O); dH (500 MHz,
CDCl3) 1.54 (9H, s, CMe3), 4.64 (1H, d, J 5.6, C(5)H), 4.93 (1H, d, J 5.6,
C(4)H), 5.78 (1H, br s, NH), 7.36e7.46 (5H, m, Ph); dC (125 MHz,
CDCl3) 28.0 (CMe3), 59.2 (C(4)), 80.8 (C(5)), 83.8 (CMe3),126.0,129.1,
48%, >99:1 dr); mp 69e71 ꢁC; ½a D25
ꢀ1.7 (c 1.0 in CHCl3); nmax
ꢂ
129.3 (o,m,p-Ph), 139.0 (i-Ph), 157.7 (C(2)), 167.1 (CO2 Bu); m/z (ESIþ)
(ATR) 3007, 2980, 2933, 2872 (CeH), 1728, 1718 (2ꢃ C]O); dH
(500 MHz, CDCl3) 1.31 (3H, d, J 5.5, C(3)Me), 1.46 (9H, s, CMe3),
1.49 (9H, s, CMe3), 2.68 (1H, d, J 2.7, C(2)H), 2.75 (1H, qd, J 5.5, 2.7,
C(3)H); dC (125 MHz, CDCl3) 16.5 (C(3)Me), 28.0, 28.0 (2ꢃ CMe3),
38.9 (C(3)), 42.4 (C(2)), 81.5, 82.3 (2ꢃ CMe3), 159.3 (NCO), 167.4
t
þ
286 ([MþNa]þ, 100%); HRMS (ESIþ) C14H17NNaO4 ([MþNa]þ) re-
quires 286.1050; found 286.1041.
4.17. tert-Butyl (R,R)-2-hydroxy-3-amino-3-phenylproanoate
31
t
(CO2 Bu); m/z (ESIþ) 280 ([MþNa]þ, 100%); HRMS (ESIþ)
þ
C
13H23NNaO4 ([MþNa]þ) requires 280.1519; found 280.1518.
Pd(OH)2/C (27 mg, 25% w/w) was added to a degassed solution
of 14 (108 mg, 0.292 mmol, >99:1 dr) in MeOH (5 mL) and the
resultant mixture was stirred under H2 (5 atm) at rt for 15 h. The
reaction mixture was then filtered through CeliteÒ (eluent MeOH)
and concentrated in vacuo to give 31 as a colourless oil (55 mg,
Method B: Cs2CO3 (4.85 g, 17.0 mmol) was added to a stirred
solution of 19 (1.76 g, 5.66 mmol, >99:1 dr) in DMF (110 mL) and
the resultant mixture was heated at 50 ꢁC for 3 h. Et2O (50 mL)
was added and the resultant mixture was washed with H2O
(4ꢃ70 mL), then dried and concentrated in vacuo to give
a 66:14:20 mixture of 34, 35 and 36, respectively. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/EtOAc,
30:1) gave 34 as a white solid (342 mg, 23%, >99:1 dr). Further
elution gave 35 as a white solid (88 mg, 8%, >99:1 dr). Further
elution gave 36 as a white solid (227 mg, 20%, >99:1 dr);10c mp
quant, >99:1 dr);10a
½
a 2D3
ꢂ
ꢀ27.7 (c 1.0 in CHCl3); {lit.10a
½
a 2D3
ꢂ
ꢀ29.0 (c
0.5 in CHCl3)}; dH (400 MHz, CDCl3) 1.33 (9H, s, CMe3), 3.42e3.47
(3H, br s, NH2, OH), 4.33e4.38 (2H, m, C(2)H, C(3)H), 7.21e7.36 (5H,
m, Ph).
4.18. (R,R)-4-Phenyl-5-(tert-butoxycarbonyl)oxazolidin-2-one
32
113e122 ꢁC; ½a 2D5
ꢂ
þ27.3 (c 1.0 in CHCl3); {lit.10c for ent-36 ½a D25
ꢂ
ꢀ22.6 (c 0.5 in CHCl3)}; dH (400 MHz, CDCl3) 1.40 (3H, d, J 6.1,
C(4)Me), 1.49 (9H, s, CMe3), 3.88e3.96 (1H, m, C(4)H), 4.39 (1H, d, J
5.8, C(5)H), 6.49e6.59 (1H, m, NH).
CDI (205 mg, 1.26 mmol) and DMAP (3 mg, cat.) were added to
a stirred solution of 31 (200 mg, 0.843 mmol, >99:1 dr) in THF
(7 mL) and the resultant mixture was stirred at rt for 12 h. Satd aq
NH4Cl (5 mL) was added and the reaction mixture was extracted
with EtOAc (3ꢃ3 mL). The combined organic extracts were washed
with brine (5 mL), then dried and concentrated in vacuo. Purifica-
tion via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 2:1) gave 32 as a white solid (49 mg, 22%, >99:1 dr); mp
4.21. Di-tert-butyl (R,R)-3-methylaziridine-N(1),2-
dicarboxylate 35
Cs2CO3 (974 mg, 2.99 mmol) was added to a stirred solution of
27 (352 mg, 0.997 mmol, >99:1 dr) in DMF (9 mL) and the re-
sultant mixture was heated at 50 ꢁC for 3 h. Et2O (15 mL) was
added and the resultant mixture was washed with H2O (4ꢃ10 mL),
then dried and concentrated in vacuo. Purification via flash col-
umn chromatography (eluent PhMe/Et2O, 80:1) gave 35 as a white
163e168 ꢁC; ½a 2D5
ꢀ63.2 (c 1.0 in CHCl3); nmax (ATR) 3288 (NeH),
ꢂ
3067, 3036, 2980, 2934 (CeH), 1735 (2ꢃ C]O); dH (400 MHz,
CDCl3) 1.04 (9H, s, CMe3), 5.16 (1H, d, J 9.2, C(5)H), 5.20 (1H, d, J 9.2,
C(4)H), 6.53 (1H, br s, NH), 7.23e7.39 (5H, m, Ph); dC (100 MHz,
CDCl3) 27.3 (CMe3), 58.4 (C(4)), 77.9 (C(5)), 83.0 (CMe3), 127.5, 128.7,
solid (187 mg, 73%, >99:1 dr); mp 61e63 ꢁC; ½a D25
þ68.0 (c 1.0 in
ꢂ
CHCl3); nmax (ATR) 3041, 2998, 2977, 2933, 2873, 2851 (CeH), 1740,
1712 (2ꢃ C]O), 1678 (CeN); dH (500 MHz, CDCl3) 1.31 (3H, d, J 5.6,
C(3)Me), 1.44 (9H, s, CMe3), 1.47 (9H, s, CMe3), 2.62e2.69 (1H, m,
C(3)H), 3.00 (1H, d, J 6.8, C(2)H); dC (125 MHz, CDCl3) 12.7
(C(3)Me), 27.8, 28.1 (2ꢃ CMe3), 38.5 (C(3)), 40.5 (C(2)), 81.7, 82.0
t
129.2 (o,m,p-Ph), 135.8 (i-Ph), 158.6 (C(2)), 165.0 (CO2 Bu); m/þz
(ESIþ) 286 ([MþNa]þ, 100%); HRMS (ESIþ) C14H17NNaO4
([MþNa]þ) requires 286.1050; found 286.1039.
t
4.19. tert-Butyl (2S,3R)-2-hydroxy-3-amino-3-
phenylproanoate 33
(2ꢃ CMe3), 161.0 (NCO), 166.5 (CO2 Bu); m/z (ESIþ) 280 ([MþNa]þ,
þ
100%); HRMS (ESIþ) C13H23NNaO4 ([MþNa]þ) requires 280.1519;
found 280.1519.
Pd(OH)2/C (35 mg, 25% w/w) was added to a degassed solution
of 22 (139 mg, 0.322 mmol, >99:1 dr) in MeOH (5 mL) and the
resultant mixture was stirred under H2 (5 atm) at rt for 15 h. The
reaction mixture was filtered through CeliteÒ (eluent MeOH) and
concentrated in vacuo to give 33 as a colourless oil (77 mg, quant,
4.22. tert-Butyl (S,S)-2-[N-(tert-butoxycarbonyl)amino]-3-
(trichloroacetoxy)butanoate 37 and tert-butyl (S,S)-2-(tri-
chloroacetamido)-3-hydroxybutanoate 38
>99:1 dr); ½a 2D3
ꢂ
þ11.4 (c 1.0 in CHCl3); nmax (ATR) 3363, 3298 (NeH),
Cl3CCO2H (1.19 g, 7.26 mmol) was added to a stirredsolution of 34
(400 mg, 1.45 mmol, >99:1 dr) in CH2Cl2 (9 mL) and the resultant
mixture was stirred at rt for 15 h. Satd aq NaHCO3 (5 mL) was then
added, the aqueous layer was extracted with CH2Cl2 (2ꢃ4 mL) and
the combined organic extracts were dried and concentrated in
3165 (OeH), 3086, 3063, 3030, 3003, 2978, 2932 (CeH), 1727
(C]O); dH (400 MHz, CDCl3) 1.41 (9H, s, CMe3), 2.59 (3H, br s, NH2,
OH), 4.15e4.20 (2H, m, C(2)H, C(3)H), 7.21e7.41 (5H, m, Ph); dC
(100 MHz, CDCl3) 27.9 (CMe3), 58.5, 75.3 (C(2), C(3)), 82.5 (CMe3),
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.007

12
S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
vacuo to give a 70:30 mixture of 37 and 38, respectively. Purification
via flash column chromatography (eluent 30e40 ꢁC petrol/Et2O,
10:1) gave 37 as a white solid (287 mg, 47%, >99:1 dr); mp 61e63 ꢁC;
4.25. (2R,3S)-2-Amino-3-hydroxybutanoic acid [(2R,3S)-thre-
onine] 42
½
a 2D5
ꢂ
þ36.4 (c 1.0 in CHCl3); nmax (ATR) 3440 (NeH), 2979, 2935
A stirred solution of 40 (160 mg, 0.382 mmol, >99:1 dr) in 6.0 M
aq HCl (4.8 mL) was heated at 90 ꢁC for 24 h. The reaction mixture
was then allowed to cool to rt and concentrated in vacuo. Purifi-
cation via ion exchange chromatography on Dowex-50WX8 resin
(hydrogen form,100e200 mesh, eluent 1.0 M aq NH4OH) gave 42 as
a white solid (44 mg, 98%, 98:2 dr);34 mp 250e260 ꢁC (dec); {lit.31
(CeH), 1763, 1743, 1707 (3ꢃ C]O); dH (400 MHz, C6D6) 1.17 (3H, d, J
6.6 C(4)H3), 1.31 (9H, s, CMe3), 1.47 (9H, s, CMe3), 4.77e4.84 (1H, m,
C(2)H), 5.39e5.47 (1H, m, C(3)H), 5.48e5.55 (1H, m, NH); dC
(100 MHz, C6D6) 15.3 (C(4)), 27.7, 28.2 (2ꢃ CMe3), 57.1 (C(2)), 77.0
(C(3)), 80.0, 82.7 (2ꢃ CMe3), 90.5 (CCl3),155.2 (NCO),161.4 (COCCl3),
167.6 (C(1));þm/z (FIþ) 419 ([M(35Cl3)]þ, 100%); HRMS (FIþ)
mp 264 ꢁC (dec)}; ½a 2D5
ꢂ
þ23.2 (c 1.0 in H2O); {lit.47
½
a 2D0
ꢂ
þ26.1 (c 1.0
35
C
H
Cl3NO6 ([M(35Cl3)]þ) requires 419.0664; found 419.0698.
in H2O)}; dH (400 MHz, D2O) 1.21 (3H, d, J 6.6, C(4)H3), 3.47 (1H, d, J
5.0, C(2)H), 4.13 (1H, qd, J 6.6, 5.0, C(3)H); dC (100 MHz, D2O) 19.4
(C(4)), 60.4 (C(2)), 65.8 (C(3)), 172.8 (C(1)).
15 24
Further elution gave 38 as a colourless oil (14 mg, 4%, >99:1 dr); ½a D25
ꢂ
þ4.8 (c 1.0 in CHCl3); nmax (ATR) 3413 (OeH), 2979, 2936 (CeH),1713
(2ꢃ C]O); dH (400 MHz, CDCl3) 1.28 (3H, d, J 6.6, C(4)H3),1.52 (9H, s,
CMe3), 2.76 (1H, br s, OH), 4.20e4.26 (1H, m, C(3)H), 4.48 (1H, dd, J
7.3, 3.5, C(2)H), 7.56e7.63 (1H, m, NH); dC (100 MHz, CDCl3) 18.9
(C(4)), 28.0 (CMe3), 60.0 (C(2)), 68.9 (C(3)), 84.0 (CMe3), 92.1 (CCl3),
4.26. (R,R)-5-Phenyl-4-(tert-butoxycarbonyl)oxazolidin-2-
one 43
162.3 (COCCl3), 168.0 (C(1)); m/z (ESIþ) 342 ([M(35Cl3)þNa]þ, 100%);
Cl3CCO2H (826 mg, 5.08 mmol) was added to a stirred solution
of 29 (323 mg, 1.01 mmol, >99:1 dr) in CH2Cl2 (6.5 mL) and the
resultant mixture was stirred at rt for 15 h. Satd aq NaHCO3 (5 mL)
was added, the aqueous layer was extracted with CH2Cl2
(2ꢃ3 mL) and the combined organic extracts were dried and con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 1:1) gave (4R,5S)-44 as a white solid
HRMS (ESIþ) C10H1635Cl3NNaO4
([M(35Cl3)þNa]þ) requires
þ
342.0037; found 342.0028.
4.23. (S,S)-2-Amino-3-hydroxybutanoic acid [(S,S)-allo-threo-
nine] 39
(10 mg, 4%, >99:1 dr); mp 113e127 ꢁC; ½a D25
ꢀ33.9 (c 1.0 in CHCl3);
ꢂ
A stirred solution of 37 (212 mg, 0.506 mmol, >99:1 dr) in 6.0 M
aq HCl (5.7 mL) was heated at 90 ꢁC for 24 h. The reaction mixture
was then allowed to cool to rt and concentrated in vacuo. Purifi-
cation via ion exchange chromatography on Dowex-50WX8 resin
(hydrogen form,100e200 mesh, eluent 1.0 M aq NH4OH) gave 39 as
a white solid (43 mg, 72%, >99:1 dr);9c mp 240e250 ꢁC (dec); {lit.9c
Further elution gave (R,R)-43 as a white solid (197 mg, 74%, >99:1
dr); mp 239e242 ꢁC (dec); ½a D25
ꢀ79.0 (c 0.5 in CHCl3); nmax (ATR)
ꢂ
3355 (NeH), 2989, 2937 (CeH), 1772, 1745 (2ꢃ C]O); dH (400 MHz,
CDCl3) 1.01 (9H, s, CMe3), 4.61 (1H, d, J 9.2, C(4)H), 5.80 (1H, d, J 9.2,
C(5)H), 6.14 (1H, br s, NH), 7.30e7.43 (5H, m, Ph); dC (100 MHz,
CDCl3) 27.3 (CMe3), 59.9 (C(4)), 79.2 (C(5)), 82.9 (CMe3), 126.8,
128.5, 129.2 (o,m,p-Ph), 134.5 (i-Ph), 158.9 (C(2)), 167.3 (COt2Bu); m/þz
(ESIþ) 286 ([MþNa]þ, 100%); HRMS (ESIþ) C14H17NNaO4
([MþNa]þ) requires 286.1050; found 286.1047.
mp 264e266 ꢁC}; ½a D20
ꢂ
þ7.5 (c 1.0 in H2O); {lit.9c
½
a 2D0
ꢂ
þ8.0 (c 1.1 in
H2O)}; dH (400 MHz, D2O) 1.11 (3H, d, J 6.6, C(4)H3), 3.75 (1H, d, J 4.1,
C(2)H), 4.27 (1H, qd, J 6.6, 4.1, C(3)H); dC (100 MHz, D2O) 16.2 (C(4)),
59.7 (C(2)), 65.3 (C(3)), 171.8 (C(1)).
4.27. (4S,5R)-5-Phenyl-4-(tert-butoxycarbonyl)oxazolidin-2-
one ent-44
4.24. tert-Butyl (2R,3S)-2-[N-(tert-butoxycarbonyl)amino]-3-
(trichloroacetoxy)butanoate 40 and tert-butyl (2R,3S)-2-(tri-
chloroacetamido)-3-hydroxybutanoate 41
Cl3CCO2H (2.14 g, 13.1 mmol) was added to a stirred solution of
28 (839 mg, 2.63 mmol, >99:1 dr) in CH2Cl2 (15 mL) and the re-
sultant mixture was stirred at rt for 15 h. Satd aq NaHCO3 (8 mL)
was added, the aqueous layer was extracted with CH2Cl2 (2ꢃ6 mL)
and the combined organic extracts were dried and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 3:1) gave (4S,5R)-44 (531 mg, 77%, >99:1
Cl3CCO2H (682 mg, 4.18 mmol) was added to a stirred solution of
35 (230 mg, 0.835 mmol, >99:1 dr) in CH2Cl2 (5 mL) and the re-
sultant solution was stirred at rt for 15 h. Satd aq NaHCO3 (4 mL)
was then added, the aqueous layer was extracted with CH2Cl2
(2ꢃ3 mL) and the combined organic extracts were dried and con-
centrated in vacuo to give an 84:16 mixture of 40 and 41, re-
spectively. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 5:1) gave 40 as a yellow oil (239 mg, 68%,
dr); mp 109e116 ꢁC; ½a D25
þ39.0 (c 1.0 in CHCl3); nmax (ATR) 3279
ꢂ
(NeH), 3067, 3036, 2980, 2934 (CeH), 1764 (2ꢃ C]O); dH
(400 MHz, CDCl3) 1.52 (9H, s, CMe3), 4.18 (1H, d, J 5.3, C(4)H), 5.58
(1H, d, J 5.3, C(5)H), 6.89 (1H, br s, NH), 7.33e7.45 (5H, m, Ph); dC
(100 MHz, CDCl3) 27.9 (CMe3), 62.1 (C(4)), 79.6 (C(5)), 83.7 (CMe3),
125.4, 128.9, 129.0 (o,m,p-Ph), 138.4 (i-Ph), 158.6 (C(2)), 168.7
(COt2Bu); m/z (ESIþ) 286 ([MþNa]þ, 100%); HRMS (ESIþ)
>99:1 dr); ½a 2D5
ꢀ17.8 (c 1.0 in CHCl3); nmax (ATR) 3441 (NeH), 2981,
ꢂ
2936 (CeH), 1767, 1741, 1717 (3ꢃ C]O); dH (400 MHz, CDCl3) 1.42
(3H, d, J 6.5, C(4)H3), 1.46 (9H, s, CMe3), 1.49 (9H, s, CMe3), 4.47 (1H,
dd, J 9.4, 2.2, C(2)H), 5.19 (1H, d, J 9.4, NH), 5.58 (1H, dq, J 6.5, 2.2,
C(3)H); dC (100 MHz, CDCl3) 16.0 (C(4)), 27.9, 28.2 (2ꢃ CMe3), 57.2
(C(2)), 76.7 (C(3)), 80.4, 83.2 (2ꢃ CMe3), 89.6 (CCl3), 155.9 (NCO),
160.8, 168.0 (C(1), COCCl3); m/z (FIþ) 419 ([M(35Cl3)]þ, 100%); HRMS
C
14H17NNaO4þ ([MþNa]þ) requires 286.1050; found 286.1048.
4.28. (R,R)-2-Amino-3-hydroxy-3-phenylpropanoic acid 45
(FIþ) C15H2435Cl3NO6 ([M(35Cl3)]þ) requires 419.0664; found
þ
419.0678. Further elution gave 41 as a brown solid (24 mg, 9%,
A stirred solution of 43 (50 mg, 0.190 mmol, >99:1 dr) in 6.0 M
aq HCl (4 mL) was heated at 90 ꢁC for 24 h. The reaction mixture
was then allowed to cool to rt and concentrated in vacuo. Purifi-
cation via ion exchange chromatography on Dowex-50WX8 resin
(hydrogen form,100e200 mesh, eluent 1.0 M aq NH4OH) gave 45 as
a white solid (26 mg, 76%, 96:4 dr);41 mp 189e192 ꢁC (dec); {lit.9a
>99:1 dr); mp 91e111 ꢁC; ½a D25
þ3.5 (c 1.0 in CHCl3); nmax (ATR)
ꢂ
3401 (OeH), 3420 (NeH), 2976, 2925, 2852 (CeH), 1737, 1698 (2ꢃ
C]O); dH (400 MHz, C6D6) 1.02 (3H, d, J 6.3, C(4)H3), 1.40 (9H, s,
CMe3), 2.32 (1H, br s, OH), 4.19 (1H, qd, J 6.3, 2.3, C(3)H), 4.48 (1H,
dd, J 8.6, 2.3, C(2)H), 7.54e7.60 (1H, m, NH); dC (100 MHz, C6D6) 20.0
(C(4)), 28.2 (CMe3), 59.5 (C(2)), 68.0 (C(3)), 82.5 (CMe3), 93.0 (CCl3),
mp 174 ꢁC (dec)}; ½a 2D0
ꢂ
ꢀ2.4 (c 1.0 in H2O); {lit.41
½
a 2D0
ꢂ
ꢀ4.3 (c 1.1
162.3 (COCCl3), 168.8 (C(1)); m/z (ESIþ) 342 ([M(35Cl3)þNa]þ, 100%);
in H2O)}; dH (400 MHz, D2O) 4.00 (1H, d, J 4.3, C(2)H), 5.28 (1H, d, J
4.3, C(3)H), 7.28e7.41 (5H, m, Ph); dC (100 MHz, D2O) 60.4 (C(2)),
71.1 (C(3)), 126.3, 128.8, 128.8 (o,m,p-Ph), 136.8 (i-Ph), 171.1 (C(1)).
þ
HRMS (ESIþ) C10H1635Cl3NNaO4
342.0037; found 342.0026.
([M(35Cl3)þNa]þ) requires
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.007

S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
13
3. Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153.
4. See also: (a) Cruz, D. C.; Sanchez-Murcia, P. A.; Jørgensen, K. A. Chem. Commun.
2012, 6112; (b) Lucarini, S.; Tomasini, C. J. Org. Chem. 2001, 66, 727.
4.29. (4S,5R)-5-Phenyl-4-(tert-butoxycarbonyl)-N(3)-(tert-bu-
toxycarbonyl)oxazolidin-2-one 46
ꢀ
5. (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.
Et3N (0.143 mL, 1.08 mmol), Boc2O (542 mg, 2.49 mmol) and
DMAP (20 mg, cat.) were added to a stirred solution of (4S,5R)-44
(142 mg, 0.540 mmol, >99:1 dr) in THF (7 mL) and the resultant
mixture was stirred at rt for 15 h, then concentrated in vacuo. The
residue was partitioned between CHCl3 (10 mL) and NaHCO3
(10 mL) and the organic layer was washed with brine (10 mL), then
dried over Na2SO4 and concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 3:1) gave
46 as a white solid (180 mg, 92%, >99:1 dr); mp 102e104 ꢁC; ½a D25
ꢂ
þ15.0 (c 1.0 in CHCl3); nmax (ATR) 2981, 2935 (CeH), 1827, 1747, 1730
(3ꢃ C]O); dH (400 MHz, CDCl3) 1.43 (9H, s, CMe3), 1.47 (9H, s,
CMe3), 4.42 (1H, d, J 4.1, C(5)H), 5.26 (1H, d, J 4.1, C(4)H), 7.28e7.40
(5H, m, Ph); dC (100 MHz, CDCl3) 27.8, 27.9 (CMe3), 64.3 (C(4)), 76.1
(C(5)), 83.8, 84.5 (CMe3), 124.9, 129.2, 129.3 (o,m,p-Ph), 137.5 (i-Ph),
6. 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.;
t
148.5, 151.0 (C(2), NCO), 167.5 (CO2 Bu); m/z (ESIþ) 386 ([MþNa]þ,
þ
100%); HRMS (ESIþ) C19H25NNaO6 ([MþNa]þ) requires 386.1574;
found 386.1578.
4.30. tert-Butyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-
hydroxy-3-phenylpropanoate 47
ꢀ
ꢀ
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.; Milli-
can, 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,
2.0 M aq LiOH (1.4 mL) was added to a stirred solution of 46
(100 mg, 0.275 mmol, >99:1 dr) in 1,4-dioxane (7 mL) and the
resultant mixture was stirred at rt for 45 min, then concentrated
in vacuo. The residue was dissolved in CHCl3 (15 mL) and the re-
sultant solution was filtered and concentrated in vacuo. Purifica-
tion via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 2:1) gave 47 as a white solid (55 mg, 59%, 98:2 dr); mp
ꢀ
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,
120e125 ꢁC; ½a 2D5
ꢀ8.7 (c 1.0 in CHCl3); nmax (ATR) 3457 (OeH),
ꢂ
ꢀ
6477; (m) Csatayova, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.;
2979 (NeH), 1721, 1695 (2ꢃ C]O); dH (400 MHz, CDCl3) 1.27 (9H,
s, CMe3), 1.34 (9H, s, CMe3), 3.00e3.18 (1H, m, OH), 4.28e4.39 (1H,
m, C(2)H), 4.99-5.04 (1H, m, C(3)H), 5.19-5.30 (1H, m, NH), 7.16-
7.32 (5H, m, Ph); dC (100 MHz, CDCl3) 27.9, 28.2 (2ꢃ CMe3), 59.9
(C(2)), 74.6 (C(3)), 79.9, 82.5 (2ꢃ CMe3), 126.3, 127.9, 128.3 (o,m,p-
Ph), 140.1 (i-Ph), 155.8 (NCO), 169.9 (C(1)); m/z (ESIþ) 360
([MþNa]þ, 100%); HRMS (ESIþ) C18H27NNaO5þ ([MþNa]þ) requires
360.1781; found 360.1785.
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.
7. 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.
8. 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.
4.31. (2S,3R)-2-Amino-3-hydroxy-3-phenylpropanoic acid 48
A solution of 47 (51 mg, 0.151 mmol, 98:2 dr) in CH2Cl2/TFA (4:1,
4 mL) was stirred at rt for 2 h, then concentrated in vacuo. 6.0 M aq
HCl (2 mL) was then added and the resultant solution was con-
centrated in vacuo. Purification via ion exchange chromatography
on Dowex-50WX8 resin (hydrogen form, 100e200 mesh, eluent
1.0 M aq NH4OH) gave 48 as a white solid (20 mg, quant, 98:2
dr);9c,40 mp 201e202 ꢁC; {lit.40 mp 192e195 ꢁC}; ½a 2D0
ꢀ28.9 (c 1.0
ꢂ
in H2O); {lit.9c
½
a 2D0
ꢂ
ꢀ30.0 (c 1.0 in H2O)}; dH (500 MHz, D2O) 3.83
(1H, d, J 4.1, C(2)H), 5.22 (1H, d, J 4.1, C(3)H), 7.28e7.45 (5H, m, Ph);
dC (125 MHz, D2O) 60.9 (C(2)), 71.3 (C(3)), 125.8, 128.5, 128.9 (o,m,p-
Ph), 139.1 (i-Ph), 172.0 (C(1)).
9. For examples of other approaches towards the synthesis of b-hydroxy-a-amino
acids, see: (a) Davis, F. A.; Srirajan, V.; Fanelli, D. L.; Portonovo, P. J. Org. Chem.
2000, 65, 7663; (b) Sladojevich, F.; Trabocchi, A.; Guarna, A.; Dixon, D. J. J. Am.
Chem. Soc. 2011, 133, 1710; (c) Li, Q.; Yang, S.-B.; Zhang, Z.; Li, L.; Xu, P.-F. J. Org.
Chem. 2009, 74, 1627; (d) Suga, H.; Ikai, K.; Ibata, T. J. Org. Chem. 1999, 64, 7040;
(e) Seashore-Ludlow, B.; Saint-Dizier, F.; Somfai, P. Org. Lett. 2012, 14, 6334; (f)
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.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.08.007.
10. (a) Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc.,
Perkin Trans. 1 1994, 2373; (b) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. J.
Chem. Soc., Perkin Trans. 1 1994, 2385; (c) Bunnage, M. E.; Burke, A. J.; Davies, S.
G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem.
2003, 1, 3708.
References and notes
11. For further applications of our aminohydroxylation procedure, see: (a) 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; (b) Brock, E.
A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 1594
See also Refs. 6e,f,g,m.
1. Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
2. (a) Stankovic, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Van Spey-
broeck, V.; De Kimpe, N.; Ha, H. J. Chem. Soc. Rev. 2012, 41, 643; (b) McCoull, W.;
Davis, F. A. Synthesis 2000, 10, 1347; (c) Hu, E. X. Tetrahedron 2004, 60, 2701; (d)
Lu, P. Tetrahedron 2010, 66, 2549.
ꢀ
Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.007

14
S.G. Davies et al. / Tetrahedron xxx (2013) 1e14
12. We have previously prepared a 5-(tert-butoxycarbonyl)oxazolidin-2-one upon
rearrangement of a N-Boc protected -amino ester by activation of an -hy-
Kurosawa, W.; Lee, J. A.; Poce, G.; Roberts, P. M.; Thomson, J. E.; Williamson, D.
M. J. Org. Chem. 2010, 75, 7745; (e) Brennan, M. B.; Claridge, T. D. W.; Compton,
R. G.; Davies, S. G.; Fletcher, A. M.; Henstridge, M. C.; Hewings, D. S.; Kurosawa,
W.; Lee, J. A.; Roberts, P. M.; Schoonen, A. K.; Thomson, J. E. J. Org. Chem. 2012,
77, 7241.
b
a
droxyl group as the corresponding mesylate; see: Davies, S. G.; Hughes, D. G.;
Nicholson, R. L.; Smith, A. D.; Wright, A. J. Org. Biomol. Chem. 2004, 2, 1549.
13. (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.
14. Crystallographic data (excluding structure factors) for 16 and 18 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 937109 and 937110, respectively.
29. Crystallographic data (excluding structure factors) for 37 and 41 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 937121 and 937122, respectively.
30. For analogous examples of the migration of a benzoyl group from O to N, see:
(a) Fodor, G.; Kiss, J. J. Am. Chem. Soc. 1950, 72, 3495; (b) Bunnage, M. E.; Davies,
S. G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1993, 1375.
31. Elliot, D. F. J. Chem. Soc. 1950, 62.
15. (a) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876; (b) Flack, H. D.; Bernar-
dinelli, G. Acta Crystallogr., Sect. A 1999, 55, 908; (c) Flack, H. D.; Bernardinelli, G.
J. Appl. Crystallogr. 2000, 33, 1143.
32. Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C. J. Org. Chem. 1998, 63,
3458.
33. Surprenant, H. L.; Sarneski, J. E.; Key, R. R.; Byrd, J. T.; Reilley, C. N. J. Magn.
16. For spectroscopic data for (S,S)-19, see Ref. 10c.
Reson. 1969, 40, 231.
17. Davies, S. G.; Fletcher, A. M.; Foster, E. M.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.
34. Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Helv. Chim. Acta 1987,
70, 237.
J. Org. Chem. 2013, 78, 2500.
18. 1H NMR spectroscopic analysis of intermediate 20 revealed that the oxidation
of 14 had proceeded to full conversion.
35. Crystallographic data (excluding structure factors) for 43, ent-44 and 47 have
been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 937123, 937124 and 937125, respectively.
36. A similar phenomenon was observed upon the BF3-mediated ring-opening
hydrofluorination of a range of aryl epoxides, which also proceeded with re-
tention of configuration, see: Cresswell, A. J.; Davies, S. G.; Lee, J. A.; Roberts, P.
M.; Russell, A. J.; Thomson, J. E.; Tyte, M. J. Org. Lett. 2010, 12, 2936.
37. The production of ent-45 upon hydrolysis of ent-44 may be due to the com-
petitive formation of the corresponding benzylic carbonium ion via cleavage of
the C(5)eO(1) bond, followed by reaction with H2O. It may be expected that
this process would be favoured in a conformation where the phenyl ring can
19. We have previously observed poor diastereoselectivity upon reduction of 20,
see: Ref. 10a.
20. Crystallographic data (excluding structure factors) for 22 have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 937111.
21. Crystallographic data (excluding structure factors) for 24, 26 and 27 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 937112, 937113 and 937114, respectively.
22. Wessig, P.; Schwarz, J. Synlett 1997, 893.
23. For trans-aziridines 1H NMR 3J coupling constants in the order of 2e4 Hz, and
for cis-aziridines 1H NMR 3J coupling constants in the order of 6e7 Hz, are
diagnostic of their relative configurations; for example, see: (a) Breuning, A.;
Vicik, R.; Schirmeister, T. Tetrahedron: Asymmetry 2003, 14, 3301; (b) Lu, Z.;
Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185; (c) Gandhi, S.; Bisai, A.;
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24. Crystallographic data (excluding structure factors) for 28, 29 and 30 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 937115, 937116 and 937117, respectively.
25. For trans-oxazolidin-2-ones 1H NMR 3J coupling constants in the order of
4e6 Hz, and for cis-oxazolidin-2-ones 1H NMR 3J coupling constants in the
order of 8e9 Hz, are diagnostic of their relative configurations; for example,
see: delle Monache, G.; Di Giovanni, M. C.; Misiti, D.; Zappia, G. Tetrahedron:
Asymmetry 1997, 8, 231 See also Refs. 4b,23b.
be perpendicular to the C(5)eO(1) bond due to overlap with the p system.
Such a conformation should be easily achievable for ent-44, and not possible
for 43: inspection of the X-ray crystal structure of 43 revealed that the dihedral
angle between the phenyl ring and the C(5)eO(1) bond is 57.1ꢁ and that fur-
ther bond rotation to place the phenyl ring at 90ꢁ to the C(5)eO(1) bond would
introduce a significant steric clash between the phenyl ring and the ester
substituent.
38. Moreno, M.; Murruzzu, C.; Riera, A. Org. Lett. 2011, 13, 5184; (b) Liu, G.-S.;
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26. For a related transformation, see Ref. 10b.
27. Crystallographic data (excluding structure factors) for 34, 35 and 36 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 937118, 937119 and 937120, respectively.
28. For example, see: (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.;
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Please cite this article in press as: Davies, S. G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.007