Asymmetric synthesis of α-amino carbonyl derivatives using lithium (R)-N-benzyl-N-α-methylbenzylamide

Article abstract of DOI:10.1016/S0957-4166(02)00406-8

An efficient protocol for the transformation of homochiral α-hydroxy-β-amino esters to their α-amino carbonyl components is presented. Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-α-methylbenzylamide to a range of α,β-unsaturated esters and subsequent enolate hydroxylation with (1R)-(-)-(camphorsulfonyl)oxaziridine, followed by LiAlH₄ reduction produces homochiral 3-amino 1,2-diols. Subsequent oxidative cleavage with H₅IO₆ provides N-benzyl-N-α-methylbenzyl protected α-amino aldehydes (96-98% d.e.) and ketones (88% d.e.). Further oxidation of the α-amino aldehydes with sodium chlorite and Pd-catalysed hydrogenation provides α-amino acids in 94-98% e.e.

Full text of DOI:10.1016/S0957-4166(02)00406-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1555–1565
Asymmetric synthesis of a-amino carbonyl derivatives using
lithium (R)-N-benzyl-N-a-methylbenzylamide
Stephen G. Davies,a,* Simon W. Epstein,a A. Christopher Garner,a Osamu Ichiharab and
Andrew D. Smitha
aThe Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
bEvotec OAI, 151 Milton Park, Abingdon, Oxon OX14 4SD, UK
Received 3 July 2002; accepted 16 July 2002
Abstract—An efficient protocol for the transformation of homochiral a-hydroxy-b-amino esters to their a-amino carbonyl
components is presented. Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-a-methylbenzylamide to a range of
a,b-unsaturated esters and subsequent enolate hydroxylation with (1R)-(−)-(camphorsulfonyl)oxaziridine, followed by LiAlH4
reduction produces homochiral 3-amino-1,2-diols. Subsequent oxidative cleavage with H5IO6 provides N-benzyl-N-a-methylben-
zyl protected a-amino aldehydes (96–98% d.e.) and ketones (88% d.e.). Further oxidation of the a-amino aldehydes with sodium
chlorite and Pd-catalysed hydrogenation provides a-amino acids in 94–98% e.e. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
of the potent anti-cancer agent Taxol6 and other natu-
ral products.7 We have previously shown that anti-a-
hydroxy-b-amino acids 4 may be prepared by the
conjugate addition of lithium (R)-N-benzyl-N-a-
methylbenzylamide 2 to a,b-unsaturated acceptors and
subsequent in situ diastereoselective enolate oxidation
with (1R)-(−)-(camphorsulfonyl)oxaziridine 3 (Scheme
1).8
The homologation of a-amino acids via the Arndt–
Eistert procedure1 is a routine method for the synthe-
sis of b-amino acids, while the reverse approach to
a-amino acids via degradation of homochiral b-amino
acids is not yet established. Previous work from our
laboratory has shown that the diastereoselective conju-
gate addition of homochiral lithium amides to a,b-
unsaturated esters provides an efficient route for the
asymmetric synthesis of homochiral b-amino acid
derivatives.2 Given the ready availability of struc-
turally diverse, homochiral b-amino esters available
from application of this chiral lithium amide method-
ology,3 we sought a degradative route from b- to a-
amino carbonyl derivatives to complement existing
methods for a-amino carbonyl syntheses.4 It was pro-
posed that this transformation could be achieved via
the oxidative cleavage of a-hydroxy-b-amino esters 1
(Fig. 1).
Figure 1.
The synthesis of the a-hydroxy-b-amino ester struc-
tural motif has been the subject of intense investiga-
tion,5 primarily due to its occurrence in the sidechain
We report herein how this approach may be utilised as
part of an efficient degradation protocol for the asym-
metric synthesis of N,N-protected a-amino aldehydes,
ketones and acids all of which have found extensive
use as homochiral building blocks in organic synthesis.
Part of this work has been communicated previously.9
* Corresponding author. E-mail: steve.davies@chemistry.ox.ac.uk
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00406-8

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S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
Initial attempts to oxidatively decarboxylate a-hydroxy-
Ph
N
b-amino esters 10–14 directly were unsatisfactory,
therefore degradation of a-hydroxy-b-amino esters 10–
14 via the related 1,2-diols was investigated. Thus,
LiAlH4 reduction of esters 10–14 afforded the N-ben-
zyl-N-a-methylbenzyl protected amino diols 15–19 as
single diastereoisomers in uniformly excellent yield (90–
98%) ready for oxidative cleavage to the N-benzyl-N-a-
methylbenzyl protected aldehydes (Scheme 3).
Li
Ph
O
(i)
t
CO2 Bu
R
R
OtBu
(ii)
3
N
Ph
O
S
O2
Ph
N
Li
Ph
(R)-2
Ph
N
t
CO2 Bu
R
OH
4
Scheme 1. Reagents and conditions: (i) lithium (R)-N-benzyl-
N-a-methylbenzylamide 2 (1.6 equiv.), THF, −78°C, 2 h then
(ii) (1R)-(−)-(camphorsulfonyl) oxaziridine, THF, −78°C to
rt.
Scheme 3. Reagents and conditions: (i) LiAlH4, THF, −78°C
to rt.
2. Results and discussion
2.1. Asymmetric synthesis of a-amino aldehydes
The inherent difficulties associated with the oxidation
of primary amino alcohols should not be relevant to
tertiary amines10 and accordingly H5IO6 oxidation of
amino diols 15–19 proceeded smoothly, furnishing the
N-benzyl-N-a-methylbenzyl protected a-amino alde-
hydes 20–24 in excellent yield (82–95%) and in high d.e.
(96–98%), as determined by 1H NMR spectroscopic
analysis. It is noteworthy that only minimal (1–2%)
epimerisation is seen upon oxidation to the aldehydes
(Scheme 4).
Following our established protocol, conjugate addition
of lithium (R)-N-benzyl-N-a-methylbenzylamide 2 to a
range of a,b-unsaturated tert-butyl esters 5–9 and sub-
sequent in situ enolate oxidation with (−)-(camphorsul-
fonyl) oxaziridine gave the anti-(2R,3R)-a-hydroxy-b-
amino esters 10–14 with high diastereoselectivity (crude
1
d.e. >88% by H NMR spectroscopic analysis). Purifi-
cation gave the required anti-a-hydroxy-b-amino esters
esters 10–14 as single diastereoisomers in good to excel-
lent yields. It should be noted that purification to
homogeneity at this stage is not strictly necessary as the
subsequent degredation protocol can be expected to be
equally applicable for the minor syn-(2S,3R)-a-
hydroxy-b-amino ester diastereoisomers arising from
enolate oxidation (Scheme 2).
2.2. Asymmetric synthesis of a-amino ketones
Having demonstrated the utility of this three-step pro-
tocol for the asymmetric synthesis of N-benzyl-N-a-
methylbenzyl protected a-amino aldehydes, extension
of this methodology to the preparation of both cyclic
Scheme 2. Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-methylbenzylamide (1.6 equiv.), THF, −78°C, 2 h then
(−)-(camphorsulfonyl) oxaziridine, THF, −78°C to rt.

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
1557
Scheme 4. Reagents and conditions: (i) H5IO6, DCM:H2O (1:1), 0°C, 30 min.
and acyclic a-amino ketones was investigated. Thus,
conjugate addition of lithium (R)-N-benzyl-N-a-
methylbenzylamide to either ethyl 1-cyclopentene-1-car-
boxylate 25 or tert-butyl tiglate 29 followed by
subsequent enolate oxidation gave a-hydroxy-b-amino
esters 26 and 30. Conjugate addition/hydroxylation of
ethyl 1-cyclopentene-1-carboxylate 25 proceeded with
facile, slight (6%) epimerisation upon oxidation to the
enolisable ketone is observed (Scheme 5).
2.3. Asymmetric synthesis of a-amino acids
With routes in hand for the synthesis of N-benzyl-N-a-
methylbenzyl protected a-amino aldehydes and ketones,
conversion of a-amino aldehydes 20–24 to their a-
amino acid hydrochloride salts was investigated. Meth-
ods for the chemoselective oxidation of aldehydes to
acids in the presence of an amine functionality are
comparatively rare,13 whilst similar oxidations of the
corresponding amides are plentiful.14 Jones’ reagent
was initially selected as the reagent for this oxidation,
with aldehyde 20 used as a model system, in anticipa-
tion of in situ protection of the amine from oxidation
by protonation under the reaction conditions. Exposure
of 20 to Jones’ reagent gave rise to the required acid 33
in 48% yield, but with 29% of N-benzyl-N-a-methyl-
benzylamine also recovered. Attempted oxidation of
aldehyde 20 through RuCl3 catalysed NaIO4 oxidation
1
high diastereoselectivity (crude d.e. >90% by H NMR
analysis), furnishing 26 as a single diastereoisomer in
62% yield after purification. Application of this proto-
col to tert-butyl tiglate 29 generated 30 in only 50%
crude d.e.,11 although purification to homogeneity led
to the isolation of 30 as a single diastereoisomer in 48%
yield.12 Subsequent LiAlH4 reduction to the amino
diols 27 and 31 (89 and 92% yield, respectively) and
oxidative cleavage furnished N-benzyl-N-a-methylben-
zyl protected a-amino ketones 28 and 32 in 85 and 79%
yields, respectively. 1H NMR spectroscopic analysis
allowed the d.e. of both ketones 28 and 32 to be
assessed as 88%, indicating that although the synthesis
of N-benzyl-N-a-methylbenzyl a-amino ketones is
Ph
Ph
Ph
N
Ph
N
t
CO2 Bu
t
(i)
(i)
CO2 Bu
CO2Et
OH
Me
CO2Et
Me
48%
62%
Me
29
OH
Me
30
26
25
(ii)
92%
Ph
(ii)
89%
Ph
Ph
Ph
(iii)
(iii)
Ph
N
Ph
N
Ph
N
Ph
N
Me
79%
85%
OH
OH
O
Me
Me
OH
OH
Me
31
O
32, 88% d.e.
28, 88% d.e.
27
Scheme 5. Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-methylbenzylamide (1.6 equiv.), THF, −78°C, 2 h then
(−)-(camphorsulfonyl) oxaziridine, THF, −78°C to rt; (ii) LiAlH4, THF, −78°C to rt; (iii) H5IO6, DCM:H2O (1:1), 0°C, 30 min.

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S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
furnished the correct carbonyl oxidation state, but con-
current benzylic oxidation was also noted, furnishing
the amide 34 in 63% yield (Scheme 6).15
Ph
Ph
Ph
Ph
N
(i)
Ph
N
Ph
N
H
+
OH
H
Me
Me
O
O
20
33, 48%
29%
(iI) 63%
Scheme 7. Reagents and conditions: (i) NaClO2, cyclohexene,
MeOH, 0°C.
Ph
alanine hydrochloride 38, (R)-leucine hydrochloride 39
and (R)-2-amino-nonanoic acid hydrochloride 40 were
shown to have been prepared in >98% e.e. and (R)-
phenylglycine hydrochloride 41 in 94% e.e. (Scheme 8).
Ph
N
O
OH
Me
O
34
3. Conclusion
Scheme 6. Reagents and conditions: (i) Jones’ reagent, acetone
0°C, 2 h; (ii) NaIO4, RuCl3, H2O–MeCN–CCl4 (1:3:2), 2 h, rt.
In conclusion, this methodology represents a novel
asymmetric synthesis of a-amino aldehydes, ketones
and acids via the diastereoselective conjugate addition
of lithium (R)-N-benzyl-N-a-methylbenzylamide 2 to
a,b-unsaturated esters with concomitant enolate
hydroxylation, followed by reduction and oxidative
cleavage. Further use of this protocol for the prepara-
tion of other a-amino carbonyl derivatives is currently
being investigated within our laboratory.
Efficient conversion to the required N-benzyl-N-a-
methylbenzyl amino acid was finally obtained using a
protocol involving sodium chlorite oxidation, with
cyclohexene as a chlorine trap, which afforded 33 in
54% yield after chromatography. This method was
therefore employed for oxidation of aldehydes 22–24 to
their acid counterparts, giving the N-benzyl-N-a-
methylbenzyl protected acids 35–37 in 64–68% yield
(Scheme 7).16
4. Experimental
The N-benzyl-N-a-methylbenzyl protected a-amino
acids 33, 35–37 were subjected to Pd-catalysed hydride
transfer deprotection, giving the a-amino acid hydro-
chloride salts 38–41 in excellent yield (91–96%) after
treatment with aqueous HCl. The e.e.s of 38–41 were
4.1. General experimental
All reactions involving organometallic or other mois-
ture sensitive reagents were performed under an atmo-
sphere of nitrogen via standard vacuum line techniques.
All glassware was flame-dried and allowed to cool
under vacuum. In all cases, the reaction diastereoselec-
tivity was assessed by peak integration of the H NMR
spectrum of the crude reaction mixture. Tetra-
1
unambiguously determined in each case by H NMR
spectroscopic analysis of the corresponding Mosher’s
amide derivatives of the derived methyl esters and
comparison to authentic racemic samples. Thus, (R)-
1
Scheme 8. Reagents and conditions: (i) 4.4% HCO2H, MeOH, Pd–C, 40°C, 2 h then HCl (aq.).

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
1559
hydrofuran was distilled under an atmosphere of dry
4.4. General procedure 3: oxidation of 1,2 diols with
H5IO6
nitrogen from sodium benzophenone ketyl. All other
solvents were used as supplied (analytical or HPLC
grade), without prior purification. Thin layer chro-
matography (TLC) was performed on aluminium or
plastic sheets coated with 60 F254 silica. Sheets were
visualised using iodine, UV light or 1% aqueous
KMnO4 solution. Flash chromatography was per-
formed on Kieselgel 60 silica. Melting points were
recorded on a Gallenkamp hot stage apparatus and are
uncorrected. Nuclear magnetic resonance (NMR) spec-
tra were recorded on a Bruker DPX 400 (1H: 400 MHz
and 13C: 100.6 MHz) or Bruker AMX 500 (1H: 500
MHz and 13C: 125 MHz) spectrometer in the deuter-
ated solvent stated. All chemical shifts (l) are quoted in
ppm and coupling constants (J) in Hz. Coupling con-
stants are quoted twice, each being recorded as
observed in the spectrum without averaging. Residual
signals from the solvents were used as an internal
reference. 13C multiplicities were assigned using a
DEPT sequence. Infrared spectra were recorded on a
Perkin–Elmer 1750 IR Fourier Transform spectropho-
tometer using either thin films on NaCl plates (film) or
KBr discs (KBr) as stated. Only the characteristic peaks
are quoted in cm−1. High resolution mass spectra
(HRMS) wee recorded on a Micromass Autospec 500
OAT spectrometer or on a Waters 2790 Micromass
LCT Exact Mass Electrospray Ionisation Mass Spec-
trometer. Techniques used were chemical ionisation
(CI, NH3) or atmospheric pressure chemical ionisation
(APCI). Optical rotations were recorded on a Perkin–
Elmer 241 polarimeter with a path length of 1 dm.
Concentrations are quoted in g/100 ml.
H5IO6 (1.1 equiv.) in H2O (1–5 ml) was added to a
stirred solution of the amino diol (1.0 equiv.) in DCM
(1–5 ml) at 0°C and stirred vigorously for 30 min before
extraction with Et2O (2×20 ml). The organic extracts
were washed with saturated sodium bicarbonate (20 ml)
and brine (20 ml) before concentration in vacuo to
afford the crude product.
4.5. General procedure 4: oxidation of aldehydes to
acids with NaClO2
Cyclohexene (1.0 ml) followed by NaClO2 (1.1 equiv.)
was added to the aldehyde (1.0 equiv.) in MeOH (1–5
ml) at 0°C and stirred for 4 h before extraction with
Et2O (2×20 ml). The organic extracts were washed with
saturated sodium bicarbonate (20 ml) and brine (20 ml)
before concentration in vacuo to afford the crude
product.
4.6. General procedure 5: Pd-catalysed debenzylation
The N-benzyl-N-a-methylbenzyl amino acid was dis-
solved in a solution of 4.4% formic acid in MeOH (10
ml) before the addition of Pd–C (10 mol%) and heated
at 40°C for 2 h. Upon cooling, the suspension was
filtered through a plug of Celite®, acidified (1 ml, 10 M
HCl) and concentrated in vacuo to afford the title
compound.
4.7. Preparation of (2R,3R,aR)-tert-butyl 2-hydroxy-3-
(N-benzyl-N-a-methylbenzylamino)butanoate 108
4.2. General procedure 1: conjugate addition/
hydroxylation
Following general procedure 1, tert-butyl crotonate17
5
(2.84 g, 20 mmol) in THF (40 ml), (R)-N-benzyl-N-a-
methylbenzylamine (6.8 g, 32 mmol) in THF (50 ml),
n-BuLi (2.5 M, 12.4 ml, 31 mmol) and (1R)-(−)-(10-
camphorsulfonyl)oxaziridine (9.2 g, 40 mmol) gave,
after chromatographic purification on silica (hexane–
ether, 10:1–5:1), 10 as a white solid (6.55 g, 89%);
[h]D25=−33.4 (c 1.0, CHCl3) {lit.8 [h]2D2=−35.2 (c 1.0,
CHCl3)}; mp 88°C (lit.8 88–89°C); lH (500 MHz,
n-BuLi (1.6 equiv.) was added to a solution of the
amine (2.0 equiv.) in THF at −78°C. After 30 min the
requisite a,b-unsaturated acceptor (1.0 equiv.) in THF
was added by cannula. After 2 h, (1R)-(−)-(10-cam-
phorsulfonyl)oxaziridine (2.0 equiv.) was added and the
reaction was stirred for 15 min at −78°C before warm-
ing to rt. After 12 h, saturated ammonium chloride
solution (1–2 ml) was added before concentration in
vacuo and the residue was extracted with Et2O. The
organic extracts were washed sequentially with 10%
citric acid solution (20 ml), saturated sodium bicarbon-
ate (20 ml) and brine (20 ml) before concentration in
vacuo to afford the crude product.
CDCl3) 7.47–7.18 (10H, m, Ph), 4.02 (1H, q, J6.8
,
C(a)H), 3.99 (1H, d, J2,3 10.0, C(2)H), 3.98 (1H, AB,
J14.9, NCHB), 3.88 (1H, AB, J14.9, NCHA), 3.26 (1H,
dq, J3,2 10.0, J3,4 7.0, C(3)H), 2.88 (1H, br s, OH), 1.36
(9H, s, OCMe3), 1.32 (3H, d, J6.8, C(a)Me), 1.07 (3H,
d, J7.0, C(4)H3).
4.8. Preparation of (4E,2R,3R,aR)-tert-butyl 2-hydroxy-
3-(N-benzyl-N-a-methylbenzylamino)hex-4-enoate 11
4.3. General procedure 2: LiAlH4 reduction of tert-
butyl esters to alcohols
Following general procedure 1, tert-butyl sorbate18
6
LiAlH4 (1.0 equiv., 1.0 M in THF) was added dropwise
to a solution of the b-amino ester (1.0 equiv.) THF
(5–20 ml) at −78°C before warming to rt. The reaction
was stirred for 24 h before cautious addition of 2 M
NaOH, then heated at reflux for 30 min before being
filtered through Celite®, washed with Et2O (2×20 ml)
and concentrated in vacuo to yield the crude product.
(1.68 g, 10 mmol) in THF (20 ml), (R)-N-benzyl-N-a-
methylbenzylamine (3.4 g, 16 mmol) in THF (25 ml),
and n-BuLi (2.5 M, 6.2 ml, 15.5 mmol) and (1R)-(−)-
(10-camphorsulfonyl)oxaziridine (4.6 g, 20 mmol) gave,
after chromatographic purification on silica (hexane–
ether, 10:1–5:1), 11 as a colourless oil (3.54 g, 89%);
[h]2D5=−64.8 (c 1.0, CHCl3); wmax (film) 3503 (O-H),

1560
S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
2977 (C-H), 1725 (CꢀO); lH (500 MHz, CDCl3) 7.42–
7.17 (10H, m, Ph), 5.69 (1H, m, C(4)H), 5.52 (1H, dq,
J5,4 15.3, J5,6 6.4, C(5)H), 4.24 (1H, q, J6.8, C(a)H),
4.11. Preparation of (2R,3R,aR)-tert-butyl 2-hydroxy-
3-phenyl-3-(N-benzyl-N-a-methylbenzylamino)prop-
anoate 148
4.09 (1H, d, J2,3 2.6, C(2)H), 3.98 (1H, AB, J14.5
,
Following general procedure 1, tert-butyl cinnamate 9
(4.1 g, 20 mmol) in THF (40 ml), (R)-N-benzyl-N-a-
methylbenzylamine (6.8 g, 32 mmol) in THF (50 ml),
n-BuLi (2.5 M, 12.4 ml, 31 mmol) and (1R)-(−)-(10-
camphorsulfonyl)oxaziridine (9.2 g, 40 mmol), gave,
after chromatographic purification on silica (hexane–
ether, 10:1–5:1), 14 as a white solid (6.00 g, 70%);
[h]D25=−23.4 (c 1.0, CHCl3), {lit.8 [h]2D0=−27.2 (c 1.0
CHCl3)}; mp 87°C (lit.8 mp 87–88°C); lH (500 MHz,
CDCl3) 7.49–7.17 (15H, m, Ph), 4.40 (1H, br s,
C(2)H), 4.22 (1H, q, J 6.9, C(a)H), 4.22 (1H, d, J3,2
3.2, C(3)H), 4.14 (1H, AB, J 15.0, NCHB), 3.83 (1H,
AB, J 15.0, NCHA), 2.77 (1H, d, J 3.7, OH), 1.21
(3H, d, J 6.9, C(a)Me), 1.20 (9H, s, OCMe3).
NCHB), 3.79 88 (1H, AB, J14.5, NCHA), 3.56 (1H, dd,
J3,4 9.7, J3,2 2.6, C(3)H), 2.87 (1H, br s, OH), 1.70
(3H, dd, J6,5 6.4, J6,4 1.3, C(6)H3), 1.36 (3H, d, J 6.8,
C(a)Me), 1.33 (9H, s, OCMe3); lC (100 MHz, CDCl3)
172.7 (CꢀO), 144.2, 141.6 (Phipso) 129.7, 128.4, 128.2,
128.0, 127.9 (Pho-,m-,p-), 126.7, 126.6 (C(4)ꢀC(5)), 81.8
(CMe3, 74.4 (C(2)H), 63.2 (C(h)H), 56.8 (C(3)H),
51.5 (NCH2), 27.9 (CMe3), 18.1 (C(6)Me), 14.8
(C(a)Me); HRMS (CI+) C25H34NO3 requires 396.2539;
found 396.2532.
4.9. Preparation of (2R,3R,aR)-tert-butyl 2-hydroxy-3-
(N-benzyl-N-a-methylbenzylamino)-5-methylhexanoate
12
4.12. Preparation of (2R,3R,aR)-2-hydroxy-3-(N-benz-
yl-N-a-methylbenzylamino)butanol 15
Following general procedure 1, (E)-tert-butyl 5-
methyl-hex-2-enoate19 7 (1.84 g, 10 mmol) in THF (20
ml), (R)-N-benzyl-N-a-methylbenzylamine (3.4 g, 16
mmol) in THF (25 ml), n-BuLi (2.5 M, 6.2 ml, 15.5
mmol) and (1R)-(−)-(10-camphorsulfonyl)oxaziridine
(4.6 g, 20 mmol) gave, after chromatographic purifica-
tion on silica (hexane–ether, 10:1–5:1), 12 as a colour-
less oil (3.74 g, 91%); [h]2D2=−18.9 (c 1.0, CHCl3); wmax
(film) 1722 (CꢀO); lH (500 MHz, CDCl3) 7.48–7.22
(10H, m, Ph), 4.35 (1H, AB, J 15.6, NCHB), 3.99 (1H,
d, J2,3 1.4, C(2)H), 3.95 (1H, q, J 7.0, C(a)H), 3.66
(1H, AB, J 15.6, NCHA), 3.26 (1H, m, C(3)H), 2.89
(1H, br d, J 1.9, OH), 1.94, (1H, m, C(5)H), 1.59 (2H,
m, C(4)H2), 1.45 (9H, s, OCMe3), 1.29 (3H, d, J 7.0,
C(a)Me), 0.90 (3H, d, J 6.8, C(5)CH3), 0.68 (3H, d, J
6.5, C(5)CH3); lC (50 MHz, CDCl3) 174.9 (CꢀO),
144.1, 143.5 (Phipso) 128.4, 128.2, 127.9, 127.2, 126.5
(Pho-,m-,p-), 82.5 (CMe3, 71.1 (C(2)H), 59.4 (C(h)H),
57.0 (C(3)H), 51.0 (NCH2), 36.9 (C(4)H2), 28.0
(CMe3), 24.1 (C(5)H), 23.6, 22.1 (C(5)(CH3)2), 20.4
(C(a)Me); HRMS (CI+) C26H38NO3 requires 412.2852;
found 412.2856.
Following general procedure 2, 10 (600 mg, 1.5 mmol)
and LiAlH4 (1.5 mmol) in THF (3 ml) gave, after
chromatographic purification (Et2O), 15 (427 mg, 95%)
as a colourless oil; [h]2D5=−22.8 (c 1.0, CHCl3); wmax
(film) 3391 (OH); lH (500 MHz, CDCl3) 7.40–7.23
(10H, m, Ph), 3.96 (1H, q, J 6.9, C(a)H), 3.82 (1H,
AB, J 13.6, NCHB), 3.74 (1H, AB, J 13.6, NCHA),
3.39 (3H, m, C(2)H(OH)C(1)H2), 2.87 (1H, m,
C(3)H), 1.43 (3H, d, J 6.9, C(a)Me), 1.27 (3H, d, J
6.9, C(4)H3); lC (125 MHz, CDCl3) 143.6, 140.3
(Phipso), 129.0, 128.5, 128.2, 128.1, 127.2, 127.1
(Pho-,m-,p-), 73.9 (C(2)H), 64.4 (C(1)H2OH), 56.4
(C(a)H), 52.3 (C(3)H), 51.1 (NCH2), 13.9 (C(a)Me),
12.8 (C(4)H3); HRMS (CI+) C19H26NO2 requires
300.1964; found 300.1978.
4.13. Preparation of (4E,2R,3R,aR)-2-hydroxy-3-(N-
benzyl-N-a-methylbenzylamino)hex-4-enol 16
Following general procedure 2, 11 (800 mg, 2.0 mmol)
and LiAlH4 (2.0 mmol) in THF (5 ml) gave, after
chromatographic purification (Et2O), 16 (593 mg, 90%)
as a colourless oil; [h]2D2=−48.7 (c 1.0, CHCl3); wmax
(film) 3393 (OH); lH (500 MHz, CDCl3) 7.36–7.24
(10H, m Ph), 5.72 (2H, m, C(4)HꢀC(5)H), 4.07 (1H,
q, J 6.9, C(a)H), 3.90 (1H, AB, J 13.7, NCHB), 3.68
(1H, AB, J 13.7, NCHA), 3.60 (1H, ddd, J 9.9, J 5.4,
J 4.5, C(2)H), 3.44 (2H, m, C(1)H2OH), 3.17 (1H,
ddd, J 8.1, J 5.4, J 2.7, C(3)H), 1.83 (3H, d, J 4.8,
C(6)H3), 1.41 (3H, d, J 6.9, C(a)Me); lC (125 MHz,
CDCl3) 143.6, 140.3 (Phipso), 131.5 (C(4)H), 128.8,
128.5, 128.4, 128.2, 128.1, 127.2, 127.1 (C(5)H,
Pho-,m-,p-), 71.3 (C(2)H), 64.9 (C(1)H2) 62.6 (C(3)H),
55.5 (C(a)H), 51.6 (NCH2), 18.3 (C(6)H3) 13.5
(C(a)Me); HRMS (CI+) C21H28NO2 requires 326.2120;
found 326.2128.
4.10. Preparation of (2R,3R,aR)-tert-butyl 2-hydroxy-
3-(N-benzyl-N-a-methylbenzylamino)decanoate 13
Following general procedure 1, (E)-tert-butyl dec-2-
enoate19 8 (2.3 g, 10 mmol) in THF (20 ml), (R)-N-
benzyl-N-a-methylbenzylamine (3.4 g, 16.0 mmol) in
THF (25 ml), n-BuLi (2.5 M, 6.2 ml, 15.5 mmol) and
(1R)-(−)-(10-camphorsulfonyl)oxaziridine (4.6 g, 20
mmol) gave, after chromatographic purification on sil-
ica (hexane–ether, 10:1–5:1), 13 as a colourless oil (3.2
g, 71%); [h]D22 −23.2 (c 1.0, CHCl3); {lit.,20 [h]2D2=−24.6
(c 1.02, CHCl3)}; lH (500 MHz, CDCl3) 7.48–7.18
(10H, m, Ph), 4.26 (1H, AB, J 15.4, NCHB), 3.99–3.92
(2H, m, C(2)H and C(a)H), 3.69 (1H, AB, J 15.6,
NCHA), 3.23–3.19 (1H, m, C(3)H), 2.89 (1H, d, J 6.0,
OH), 1.69–1.10 (12H, m, CH3(CH2)6), 1.45 (9H, s,
OCMe3), 1.29 (3H, d, J 7.0, C(a)Me), 0.90 (3H, d, J
6.8, C(10)H3), identical to that previously prepared in
the literature.20
4.14. Preparation of (2R,3R,aR)-2-hydroxy-3-(N-benz-
yl-N-a-methylbenzylamino)-5-methylhexanol 17
Following general procedure 2, 12 (2.23 g, 5.4 mmol)
and LiAlH4 (5.4 ml) in THF (10 ml) gave, after chro-

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
1561
matographic purification (Et2O), 17 (1.81 g, 98%) as a
colourless oil; [h]D25=−21.0 (c 1.0, CHCl3); wmax (film) 3401
(OH); lH (500 MHz, CDCl3) 7.47–7.26 (10H, m, Ph), 4.06
(1H, AB, J 14.6, NCHB), 3.97 (1H, q, J 6.9, C(a)H), 3.80
(1H, AB, J 14.6, NCHA), 3.57 (1H, m, C(2)H), 3.41 (2H,
m, C(1)H2), 2.90 (1H, m, C(3)H), 2.75 (2H, br s,
CH(OH)CH2OH), 1.90 (1H, m, (C(5)H), 1.59 (1H, m,
(C(4)HA), 1.39(3H, d, J6.9, C(a)Me), 1.36(1H, obscured,
(C(4)HB), 1.02 (3H, d, J 6.6, C(5)CH3), 0.87 (3H, d, J
6.5, C(5)CH3); lC (125 MHz, CDCl3) 144.0, 141.7 (Phipso),
128.5, 127.9, 127.2, 126.9 (Pho-,m-,p-), 72.0 (C(2)H), 64.5
(C(1)H2), 58.1 (C(h)H), 54.9 (C(3)H), 51.7 (NCH2) 37.9
(C(4)H2), 25.2 (C(5)H), 23.3, 22.9 (C(5)(CH3)2), 16.3
(C(a)Me); HRMS (CI+) C22H32NO2 requires 342.2433;
found 342.2436.
7.46–7.25 (10H, m, Ph), 4.05 (1H, q, J 6.8, C(a)H), 3.81
(1H, AB, J 14.0, NCHB), 3.76 (1H, AB, J 14.0, NCHA),
3.38 (1H, q, J 6.9, C(2)H), 1.46 (3H, d, J 6.8, C(a)Me),
1.23 (3H, d, J 6.9, C(3)H3); lC (125 MHz, CDCl3) 203.7
(CꢀO), 144.0, 140.0 (Phipso), 128.9, 128.3, 127.7, 127.3,
127.2 (Pho-,m-,p-), 61.5 (C(2)H), 58.1 (C(a)H), 51.6
(NCH2), 17.1 (C(a)Me), 13.3 (C(3)); HRMS (CI+)
C18H22NO requires 268.1701; found 268.1701.
4.18. Preparation of (3E,2R,aR)-2-(N-benzyl-N-a-
methylbenzylamino)pent-3-enal 21
Following general procedure 3, 16 (600 mg, 1.85 mmol)
and H5IO6 (463 mg, 2.0 mmol) gave 21 (441 mg, 82%)
as a colourless oil; [h]2D4=+14.6 (c 1.0, CHCl3); wmax (film)
1727 (CꢀO); lH (500 MHz, CDCl3) 9.32 (1H, d, J 1.2,
CHO), 7.49–7.20 (10H, m Ph), 5.70 (1H, dq, J4,3 15.5,
J4,5 6.2, C(4)H), 5.62 (1H, dd, J3,4 15.5, J3,2 8.1, C(3)H),
4.08 (1H, q, J 6.8, C(a)H), 3.85 (1H, AB, J 14.1, NCHB),
3.77 (1H, d, J 8.0, C(2)H), 3.73 (1H, AB, J 14.1, NCHA),
1.80 (3H, dd, J5,4 6.2, J5,3 1.0, C(5)H3), 1.44 (3H, d, J 6.8,
C(a)Me), lC (125 MHz, CDCl3) 201.3 (CꢀO), 143.6, 139.9
(Phipso), 132.7 (C(4)H), 129.3, 129.1, 128.8, 128.6, 128.3,
128.2, 127.8, 127.5 (Pho-,m-,p-), 124.4 (C(5)H), 70.5
(C(2)H), 57.5 (C(a)H), 51.9 (NCH2), 18.4 (C(5)H3), 16.0
(C(a)Me); HRMS (CI+) C20H24NO requires 294.1858;
found 294.1859.
4.15. Preparation of (2R,3R,aR)-2-hydroxy-3-(N-benz-
yl-N-a-methylbenzyl)aminodecanol 18
Following general procedure 2, 13 (45 mg, 0.1 mmol) and
LiAlH4 (0.1 ml) in THF (2 ml) gave, after chromato-
graphic purification (Et2O), 18 (35 g, 92%) as a colourless
oil; [h]2D5=−37.6 (c 1.1, CHCl3); wmax (film) 3368 (OH);
lH (500 MHz, CDCl3) 7.42–7.22 (10H, m, Ph), 3.93 (1H,
q, J 6.9, C(a)H), 3.89 (1H, AB, J 14.2, NCHB), 3.77 (1H,
AB, J 14.2, NCHA), 3.47 (3H, m, C(2)H(OH)C(1)H2),
2.77 (1H, dt, J 7.7, J 4.5, C(3)H), 1.71 (1H, m, C(4)HA),
1.51 (1H, m, C(4)HB), 1.39 (3H, d, J 6.9, C(a)Me),
1.37–1.27 (10H, m, CH3(CH2)5), 0.92 (3H, t, J 6.9,
C(10)H3); lC (125 MHz, CDCl3) 143.7, 140.7 (Phipso),
128.7, 128.5, 128.4, 127.9, 127.2, 127.1 (Pho-,m-,p-), 72.6
(C(2)H), 64.1 (C(1)H2), 51.8 {C(h)H), (C(3)H)}, 51.8
(NCH2), 31.9, 30.1, 29.2, 28.8, 28.1, 22.7, (CH3(CH2)6),
14.1 (C(a)Me), 13.9 (C(10)H3); HRMS (CI+) C25H38NO2
requires 384.2903; found 384.2900.
4.19. Preparation of (2R,aR)-2-(N-benzyl-N-a-methyl-
benzylamino)-4-methylpentanal 22
Following general procedure 3, 17 (363 mg, 1.07 mmol)
and H5IO6 (267 mg, 1.17 mmol) gave 22 (295mg, 90%)
as a colourless oil; [h]2D2=+1.3 (c 0.63, CHCl3); wmax
(film)/cm−1 1723 (CꢀO); lH (500 MHz, CDCl3) 9.42 (1H,
s, CHO), 7.51–7.27 (10H, m, Ph), 4.16 (1H, q, J 6.8,
C(a)H), 4.00 (1H, AB, J 14.7, NCHB), 3.96 (1H, AB, J
14.7, NCHA), 3.41 (1H, t, J 6.4, C(2)H), 1.82 (1H, app
sept, J 6.6, C(4)H), 1.77 (1H, m, C(3)H2), 1.51 (3H, d,
J 6.9, C(a)Me), 1.50 (1H, obscured, C(3)HA), 0.95 (3H,
d, J 6.8, C(4)CH3), 0.93 (3H, d, J 6.8, C(4)CH3); lC (125
MHz, CDCl3) 203.9 (CꢀO), 144.2, 141.3 (Phipso), 128.9,
128.8, 128.3, 127.8, 127.5 (Pho-,m-,p-), 64.2 (C(h)H), 58.9
(C(2)H), 51.1 (NCH2), 36.1 C(3)H2), 25.7 (C(4)H) 23.3,
23.2 (C(4)(CH3)2), 18.7 (C(a)Me); HRMS (CI+)
C21H28NO requires 310.2171; found 310.2177.
4.16. Preparation of (2R,3R,aR)-2-hydroxy-3-(N-benz-
yl-N-a-methylbenzylamino)-4-phenylbutanol 19
Following general procedure 2, 14 (2.0 g, 4.64 mmol) and
LiAlH4 (4.6 ml) in THF (10 ml) gave, after chromato-
graphic purification (Et2O), 19 (1.61 g, 96%) as a
colourless oil; [h]D22 −48.0 (c 0.5, CHCl3); wmax (film) 3400
(OH); lH (500 MHz, CDCl3) 7.47–7.25 (15H, m, Ph), 4.16
(1H, ddd, J 7.3, J 6.6, J 3.7, C(2)H(OH)), 4.21 (1H, q,
J 6.9, C(a)H), 4.02 (1H, AB, J 14.1, NCHB), 3.77 (1H,
d, J 7.5, C(3)H), 3.61 (1H, dd, J1A,1B 11.2, J1A,2 3.7,
C(1)HA), 3.57 (1H, AB, J 14.1, NCHA), 3.34 (1H, dd,
J1B,1A 11.2, J1B,2 6.5, C(1)HB), 1.84, 1.65 (2H, br s,
CH(OH)CH2OH), 1.08 (3H, d, J 6.9, C(a)Me); lC (125
MHz, CDCl3) 143.9, 140.6, 138.1 (Phipso), 129.7, 128.7,
128.5, 128.3, 128.0, 127.8, 127.2, 127.0 (Pho-,m-,p-), 71.0
(C(2)H), 65.5 (C(3)H), 64.9 (C(1)H2), 56.1 (C(h)H), 51.5
(NCH2), 12.2 (C(a)Me); HRMS (CI+) C24H28NO2
requires 362.2120; found 362.2122.
4.20. Preparation of (2R,aR)-2-(N-benzyl-N-a-methyl-
benzylamino)nonanal 23
Following general procedure 3, 18 (260 mg, 0.68 mmol)
and H5IO6 (170 mg, 0.75 mmol) gave 23 (220 mg, 92%)
as a colourless oil; [h]2D2=+1.1 (c 0.75, CHCl3); wmax (film)
1728 (CꢀO); lH (500 MHz, CDCl3) 9.30 (1H, s, CHO),
7.40–7.25 (10H, m, Ph), 4.06 (1H, q, J 6.9, C(a)H), 3.87
(2H, AB m, NCH2), 3.24 (1H, t, J 6.6, C(2)H), 1.78 (1H,
m, C(3)H), 1.54 (1H, m, C(3)H), 1.42 (3H, d, J 6.9,
C(a)Me), 1.40–1.27 (10H, m, (CH2)5), 0.90 (3H, t, J 6.8,
C(9)H3); lC (125 MHz, CDCl3) 203.3 (CꢀO), 143.7, 140.6
(Phipso), 128.5, 128.4, 128.3, 127.7, 127.3, 127.0 (Pho-,m-,p-),
65.9 (C(a)H), 58.3 (C(2)H), 51.6 (NCH2), 31.8, 29.7, 29.1,
27.1, 26.6, 22.6 ((CH2)6) 18.2 (C(h)Me), 14.1 (C(9)H3);
HRMS (CI+) C24H34NO requires 352.2640; found
352.2620.
4.17. Preparation of (2R,aR)-2-(N-benzyl-N-a-methyl-
benzylamino)propanal 20
Following general procedure 3, 15 (56 mg, 0.19 mmol)
and H5IO6 (47 mg, 0.21 mmol) gave 20 (48 g, 95%) as
acolourlessoil;[h]D22=+1.2(c1.0, CHCl3);wmax (film)1728
(CꢀO); lH (500 MHz, CDCl3) 9.41 (1H, s, CHCHO),

1562
S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
4.21. Preparation of (2R,aR)-2-phenyl-2-(N-benzyl-N-a-
methylbenzylamino)ethanal 24
4.24. Preparation of (2R,aR)-2-(N-benzyl-N-a-methyl-
benzylamino)cyclopentanone 28
Following general procedure 3, 19 (255 mg, 0.71 mmol)
and H5IO6 (229 mg, 1.00 mmol) gave 24 (221 mg, 95%)
as a colourless oil; [h]2D2=+1.1 (c 0.75, CHCl3); wmax (film)
1727 (CꢀO); lH (500 MHz, CDCl3) 9.13 (1H, d, J 3.8,
CHO), 7.52–7.14 (15H, m Ph), 4.40 (1H, d, J 3.7, C(2)H),
4.12 (1H, q, J 6.8, C(a)H), 3.92 (1H, AB, J 14.4, NCHB),
3.58 (1H, AB, J 14.4, NCHA), 1.34 (3H, d, J 6.8, C(a)Me);
lC (50 MHz, CDCl3) 199.2 (CꢀO), 143.3, 140.0, 135.4
(Phipso), 129.4, 129.2, 129.0, 128.6, 128.3, 128.2, 127.2
(Pho-,m-,p-), 76.5 (C(2)H), 56.3 (C(a)H), 52.4 (NCH2), 12.0
(C(a)Me); m/z (APCI+) 330 (MH+, 70%), 226 (MH+
−PhCHCH3).
Following general procedure 3, 27 (45 mg, 0.14 mmol)
and H5IO6 (35 mg, 0.15 mmol) gave 28 (35 mg, 85%) as
1
a colourless oil. This was shown by H 500 MHz NMR
spectroscopic analysis to contain two diastereoisomers in
88% d.e.; [h]2D4=−11.3 (c 0.75, CHCl3); wmax (film) 1743
(CꢀO); lH (500 MHz, CDCl3) 7.53–7.19 (10H, m, Ph),
4.15 (1H, q, J 6.8, C(a)H), 3.73 (2H, app s, NCH2), 3.18
(1H, dd, J 11.9, J 7.9, C(2)H), 2.19 (1H, m, C(5)HACO),
2.09 (1H, m, C(5)HBCO), 1.90 (2H, m, C(3)H2), 1.57 (2H,
m, C(4)H2), 1.32 (3H, d, J 6.8, C(a)Me); lC (125 MHz,
CDCl3) 219.4 (CꢀO), 141.1, 129.0 (Phipso), 128.5, 128.3,
128.1, 127.4, 126.7(Pho-,m-,p-), 66.5(C(h)H), 57.8(C(2)H),
52.2 (NCH2), 36.8 (C(5)H2), 27.4 (C(3)H2), 18.3
(C(4)H2), 17.6 (C(h)Me); m/z (APCI+) 294, (MH+, 10%);
HRMS (CI+, MH+) C20H24NO requires 294.1858; found
294.1852.
4.22. Preparation of (1R,2R,aR)-ethyl 1-hydroxy-2-(N-
benzyl-N-a-methylbenzylamino)cyclopentanecarboxylate
26
4.25. Preparation of (2R,3R,aR)- and (2S,3R,aR)-tert-
butyl 2-hydroxy-2-methyl-3-(N-benzyl-N-a-methylbenzyl-
amino)butanoate 30 and 42
Following general procedure 1, ethyl cyclopent-1-
enecarboxylate21 25 (1.40 g, 10.5 mmol) in THF (20 ml),
(R)-N-benzyl-N-a-methylbenzylamine (3.6 g, 16.8 mmol)
in THF (20 ml), n-BuLi (2.5 M, 6.5 ml, 16.3 mmol) and
(1R)-(−)-(10-camphorsulfonyl)oxaziridine (4.8 g, 21
mmol), gave, after chromatographic purification (hex-
ane:Et2O, 10:1–5:1), 26 (2.34 g, 62%) as a colourless oil;
C23H29NO3 requires C, 75.2; H, 7.95; N, 3.8; found C,
75.5; H, 7.9; N, 3.95%; [h]2D5=+11.0 (c 1.0, CHCl3); wmax
(film) 1714 (CꢀO); lH (500 MHz, CDCl3) 7.35–7.13 (10H,
m, Ph), 4.17 and 4.00 (2×1H, dq, J 7.0, J 3.5,
CO2CH2CH3), 3.84 (1H, q, J 6.6, C(a)H), 3.73 (1H, AB,
J 14.0, NCHB), 3.60 (1H, AB, J 14.0, NCHA), 3.10 (1H,
dd, J 12.0, J 7.3, C(2)H), 2.34 (1H, s, OH), 2.33–1.52 (6H,
m, CH(CH2)3), 1.21 (3H, d, J 6.6, C(a)Me), 1.14 (3H, t,
J 7.1, OCH2CH3); lC (125 MHz, CDCl3) 175.9 (CꢀO),
143.9, 140.7 (Phipso), 128.6, 128.3, 128.2, 128.1, 126.9,
126.8 (Pho-,m-,p-), 83.8 (C(1)), 70.8 (C(a)H), 61.4
(CO2CH2CH3), 55.4 (C(2)H), 52.0 (NCH2), 35.3, 28.2,
21.5 ((CH2)3), 13.9 (C(a)Me), 11.3 (CO2CH2CH3);
HRMS (CI+) C23H29NO3 requires 368.2230; found
368.2226.
Following general procedure 1, tert-butyl tiglate22 29
(0.78 g, 2.5 mmol) in THF (10 ml), (R)-N-benzyl-N-a-
methylbenzylamine (0.85 g, 4.0 mmol) in THF (10 ml),
n-BuLi (2.5 M, 1.6 ml, 3.9 mmol) and (1R)-(−)-(10-cam-
phorsulfonyl)oxaziridine (1.2 g, 5 mmol), gave, after
chromatographic purification (hexane:Et2O, 3:1) gave 30
(458 mg, 48%) and 42 (152 mg, 16%) as colourless oils.
Data for 30: [h]D22=−36.8 (c 2.0, CHCl3); wmax (film) 1716
(CꢀO); lH (400 MHz, CDCl3) 7.58–7.25 (10H, m, Ph),
4.23 (1H, AB, J 14.3, NCHB), 4.10 (1H, q, J6.7, C(a)H),
3.69 (1H, AB, J 14.3, NCHA), 3.67 (1H, s, OH), 3.09 (1H,
q, J 6.9, C(3)H), 1.47 (9H, s, OCMe3), 1.46 (3H, d, J 6.7,
C(a)Me), 1.27 (3H, d, J 6.9, C(4)H3), 1.00 (3H, s,
C(2)Me); lC (100 MHz, CDCl3) 176.1 (CꢀO), 143.4, 140.8
(Phipso), 129.2, 128.2, 128.0, 127.7, 126.7, 126.6 (Pho-,m-,p-),
81.4 (C(2)), 77.5 (OCMe3), 55.8 (C(a)H), 55.4 (C(3)), 51.2
(NCH2), 27.6 (OCMe3), 24.1 (C(2)Me), 12.1 (C(a)Me),
11.2 (C(4)H3); HRMS (CI+) C24H34NO3 requires
384.2539; found 384.2530.
4.23. Preparation of (1R,2R,aR)-1-hydroxymethyl-2-(N-
benzyl-N-a-methylbenzylamino)cyclopentanol 27
Data for 42: wmax (film) 1717 (CꢀO); lH (400 MHz, CDCl3)
7.47–7.09 (10H, m, Ph), 3.99 (1H, q, J 6.9, C(a)H), 3.95
(1H, AB, J 14.9, NCHB), 3.62 (1H, AB, J 14.9, NCHA),
3.28 (1H, q, J 7.0, C(3)H), 3.20 (1H, s, OH), 1.43 (9H,
s, OCMe3), 1.20 (3H, d, J 6.9, C(a)Me), 1.10 (3H, s,
C(2)Me); 0.88 (3H, d, J 6.9, C(4)H3); lC (100 MHz,
CDCl3) 179.4 (CꢀO), 142.6, 142.4 (Phipso), 128.3, 128.2,
128.1, 127.0, 126.5 (Pho-,m-,p-), 81.7 (C(2)), 78.8 (OCMe3),
59.6 (C(a)H, C(3)H), 50.0 (NCH2), 28.1 (OCMe3), 23.7
(C(2)Me), 17.8 (C(a)Me), 10.5 (C(4)H3); HRMS (CI+)
C24H34NO3 requires 384.2539; found 384.2532.
Following general procedure 2, 26 (1.10 g, 3.05 mmol)
and LiAlH4 (3.1 ml) in THF (8 ml) gave, after chromato-
graphic purification (Et2O), 27 (864 mg, 89%) as a
colourless oil; [h]D25=−69.0 (c 1.0, CHCl3); wmax (film) 3418
(OH); lH (500 MHz, CDCl3) 7.51–7.23 (10H, m, Ph), 4.26
(1H, br d, J 9.6, C(OH)CH2OH), 3.98 (1H, q, J 6.9,
C(a)H), 3.89 (1H, d, J 10.5, C(1%)HA), 3.79 (2H, app s,
NCH2), 3.40 (1H, br t, J 10.4, C(1%)HB), 3.26 (1H, t, J
8.3 C(2)H), 2.14 (1H, s, C(1)OH), 1.99–1.37 (6H, m,
(CH2)3), 1.35 (3H, d, J 6.9, C(a)Me); lC (125 MHz,
CDCl3) 142.8, 139.2 (Phipso), 129.1, 128.8, 128.5, 128.1,
127.5 (Pho-,m-,p-), 81.5 (C(1)), 67.5 (C(a)H), 67.3
(C(1%)H2OH), 53.8 (C(2)H), 53.2 (NCH2), 35.0, 28.0, 22.2
((CH2)3), 10.6 (C(h)Me); HRMS (CI+) C21H28N1O2
requires 326.2120; found 326.2123.
4.26. Preparation of (2R,3R,aR)-2-hydroxy-2-methyl-3-
(N-benzyl-N-a-methylbenzylamino)butanol 31
Following general procedure 2, 30 (192 mg, 0.5 mmol)
and LiAlH4 (0.5 ml) in THF (3 ml) gave, after chro-

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
1563
matographic purification (Et2O), 31 (144 mg, 92%) as a
colourless oil; [h]2D2=−14.5 (c 0.6, CHCl3); wmax (film)
3402 (OH); lH (500 MHz, CDCl3) 7.46–7.19 (10H, m,
Ph), 4.01 (1H, d, J 13.9, NCHA), 3.98 (1H, q, J 6.9,
C(a)H), 3.69 (1H, d, J 13.9, NCHB), 3.52, 3.17 (2×1H,
d, J 10.8, C(1)H2OH), 2.93 (1H, q, J 7.2, C(3)H), 1.42
(3H, d, J 6.9, C(a)Me), 1.27 (3H, d, J 7.2, C(4)H3), 0.96
(3H, s, C(2)Me); lC (125 MHz, CDCl3) 143.0, 140.2
(Phipso), 128.8, 128.6, 128.4, 128.2, 127.5, 127.4
(Pho-,m-,p-), 73.4 (C(2)), 67.1 (C(1)H2OH), 56.6 (C(a)H),
56.2 (C(3)H), 52.0 (NCH2), 21.7 (C(2)Me), 11.9
(C(4)H3), 10.7 (C(a)Me); HRMS (CI+) C20H28NO2
requires 314.2120; found 314.2130.
[h]2D4=+81.2 (c 1.0, CHCl3); wmax (film) 2992 (C-H),
1716 (CO2H), 1634 (COPh); lH (500 MHz, toluene,
85°C) 7.38–7.01 (10H, m, Ph), 5.00 (1H, q, J 6.8,
C(a)H), 3.59 (1H, q, J6.9, C(2)H), 1.62 (3H, d, J 6.9,
C(3)H3), 1.25 (3H, d, J 6.8, C(a)Me); lC (125 MHz,
CDCl3) 174.5 (CO2H), 172.9 (COPh) 136.3 (Phipso),
130.5, 129.3, 129.0, 128.6, 127.9 126.8 (Pho-,m-,p-), 58.1
(C(2)H), 54.1 (C(a)H), 18.5, 16.8 (C(a)Me, C(3)H3);
HRMS (CI+) C18H20NO3 requires 298.1443; found
298.1450.
4.30. Preparation B of (2R,aR)-2-(N-benzyl-N-a-methyl-
benzylamino)propanoic acid 33
4.27. Preparation of (3R,aR)-3-(N-benzyl-N-a-methyl-
Following general procedure 4, 20 (248 mg, 0.93 mmol)
and NaClO2 (92.5 mg, 1.0 mmol) gave, after purifica-
tion by chromatography on silica (hexane–Et2O, 3:1–
1:1), 33 (142 mg, 54%) as a colourless oil; [h]2D4=+27.7
(c 1.0, CHCl3); wmax (film) 1715 (CꢀO); lH (500 MHz,
CDCl3) 7.45–7.22 (10H, m, Ph), 4.15 (1H, q, J 6.8,
C(a)H), 3.91 (1H, AB, J 13.6, NCHB), 3.83 (1H, AB, J
14.3, NCHA), 3.56 (1H, q, J 7.3, C(2)H), 1.49 (3H, d, J
7.3, C(3)H3), 1.46 (3H, d, J 6.8, C(a)Me); lC (125
MHz, CDCl3) 174.7 (CO), 140.1, 137.4 (Phipso), 129.0,
128.8, 128.0, 127.9 127.5 (Pho-,m-,p-), 57.0 (C(2)H), 55.9
(C(a)H), 51.4 (NCH2), 13.9, 13.3 (C(a)Me, C(3)H3);
HRMS (CI+) C18H22NO2 requires 284.1651; found
284.1651.
benzylamino)butan-2-one 32
Following general procedure 3, 31 (27 mg, 0.1 mmol)
and H5IO6 (22 mg, 0.10 mmol) gave 32 (19 g, 79%) as
1
a colourless oil. This was shown by H 500 MHz NMR
spectroscopic analysis to contain two diastereoisomers
in 88% d.e.; [h]D21=−74.0 (c 0.5, CHCl3); wmax (film)
1713 (CꢀO); lH (500 MHz, CDCl3) 7.41–7.26 (10H, m,
Ph), 4.04 (1H, q, J 6.8, C(a)H), 3.82 (2H, app s,
NCH2), 3.46 (1H, q, J 6.9, C(2)H), 1.94 (3H, s,
COCH3), 1.42 (3H, d, J 6.8, C(a)Me); 1.25 (3H, d, J
6.9, C(3)H3); lC (125 MHz, CDCl3) 211.2 (CꢀO), 144.4,
141.1 (Phipso), 129.1, 128.7, 128.6, 128.3, 127.4 (Pho-,m-,p-),
61.8 (C(2)H), 58.2 (C(a)H), 51.5 (NCH2), 27.9
(COCH3), 16.7 (C(a)Me), 12.9 (C(3)H3); HRMS (CI+)
C19H24NO requires 282.1856; found 282.1850.
4.31. Preparation of (2R,aR)-2-(N-benzyl-N-a-methyl-
benzylamino)-4-methylpentanoic acid 35
4.28. Preparation A of (2R,aR)-2-(N-benzyl-N-a-
Following general procedure 4, 22 (295 mg, 0.96 mmol)
and NaClO2 (95 mg, 1.05 mmol) gave, after purification
by chromatography on silica (hexane–Et2O, 2:1–1:1), 35
(198 mg, 64%) as a colourless oil; [h]2D5=+28.9 (c 1.0,
CHCl3); wmax (film) 1704 (CꢀO); lH (500 MHz, CDCl3)
7.56–7.30 (10H, m, Ph), 4.17 (1H, q, J 6.8, C(a)H),
4.05 (1H, AB, J 15.1, NCHB), 3.99 (1H, AB, J 15.1,
NCHA), 3.50 (1H, dd, J2,3A 7.6, J2,3B 6.9, C(2)H), 2.00
(1H, app sept, J 6.7, (C(4)H), 1.76 (1H, m, C(4)H),
1.58 (1H, m, C(4)H), 1.41 (3H, d, J 6.8, C(a)Me), 0.92
(3H, d, J 6.7, C(4)CH3), 0.88 (3H, d, J 6.7, C(4)CH3);
lC (62.5 MHz, CDCl3) 178.3 (CꢀO), 143.3, 140.6
(Phipso), 129.4, 129.1, 129.0, 128.6, 128.2, 128.0, 127.6
(Pho-,m-,p-), 59.9, 59.3 (C(h)H, C(2)H), 52.1 (NCH2)
39.4 (C(3)H2), 26.0 (C(4)H), 22.8 (C(4)(CH3)2), 18.7
(C(a)Me); HRMS (CI+) C21H28NO2 requires 326.2120;
found 326.2123.
methylbenzylamino)propanoic acid 33
20 (81 mg, 0.30 mmol) was dissolved in acetone (10 ml)
and cooled to 0°C before the addition of Jones reagent
(0.13 ml, 0.33 mmol) and the solution stirred at 0°C for
2 h before the addition of isopropyl alcohol (1 ml).
Dissolution in ether (50 ml), filtration through Celite®
followed by concentration in vacuo afforded an oil
which was purified by chromatography on silica (hex-
ane–Et2O, 3:1–1:1) to afford 33 as a colourless oil (42
mg, 48%). The Celite® was washed with MeOH to
afford an oil, purified by chromatography (hexane–
ether, 1:1) to afford (R)-N-benzyl-N-a-methylbenzyl-
amine as an oil (19 mg, 29%).
4.29. Preparation of (2R,aR)-2-(N-benzoyl-N-a-methyl-
benzylamino)propanoic acid 34
NaIO4 (333 mg, 1.56 mmol) and RuCl3 (1.8 mg, 0.03
mmol) were dissolved in a mixture of CCl4 (2 ml),
MeCN (3 ml) and H2O (1 ml) before the addition of
121 (100 mg, 0.38 mmol) in CCl4 (0.5 ml) and stirred
for 2 h at rt. The crude reaction mixture was parti-
tioned between DCM (20 ml) and water (20 ml), the
organic phase was separated and the aqueous phase
extracted with CH2Cl2 (2×20 ml). The combined
organic extracts were dried (MgSO4) and concentrated
in vacuo to afford a brown oil which was purified by
chromatography on silica (Et2O to Et2O–methanol,
10:1) affording 34 as a colourless oil (70 mg, 63%);
4.32. Preparation of (2R,aR)-2-(N-benzyl-N-a-methyl-
benzylamino)nonanoic acid 36
Following general procedure 4, 23 (220 mg, 0.63 mmol)
and NaClO2 (62 mg, 0.69 mmol) gave, after purification
by chromatography on silica (hexane–Et2O, 2:1–1:1), 36
(156 mg, 68%) as a colourless oil; [h]2D5=+4.3 (c 1.0,
CHCl3); wmax (film) 1704 (CꢀO); lH (400 MHz, CDCl3)
7.47–7.25 (10H, m, Ph), 4.13 (1H, q, J 6.9, C(a)H),
4.02 (1H, AB, J 15.0, NCHB), 3.94 (1H, AB, J 15.0,
NCHA), 3.37 (1H, t, J 6.0, C(2)H), 1.84 (1H, m,
C(3)HA), 1.68 (1H, m, C(3)HB), 1.37 (3H, d, J 6.9,

1564
S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
C(a)Me), 1.34–1.21 (10H, m, ((CH2)5), 0.91 (3H, t, J
6.9, C(9)H3); lC (100 MHz, CDCl3) 177.5 (CꢀO), 142.7,
140.3 (Phipso), 128.5, 128.2, 127.7, 127.5, 127.2 (Pho-,m-,p-
), 60.9 (C(a)H), 59.3 (C(2)H), 51.7 (NCH2), 31.8, 29.7,
29.5, 29.1, 27.5, 22.6, ((CH2)6), 18.2 (C(a)Me), 14.1
(C(9)H3); HRMS (CI+) C24H34NO2 requires 368.2590;
found 368.2601.
Ph), 5.12 (1H, s, C(2)H), consistent with that recorded
in the literature.23
Acknowledgements
The authors wish to acknowledge the support of the
EPSRC and Oxford Asymmetry International plc for
providing a CASE award (S.W.E.) and to New College,
Oxford for a Junior Research Fellowship (A.D.S.).
4.33. Preparation of (2R,aR)-2-phenyl-2-(N-benzyl-N-
a-methylbenzylamino)ethanoic acid 37
Following general procedure 4, 24 (221 mg, 0.67 mmol)
and NaClO2 (70 mg, 0.77 mmol) gave, after purification
by chromatography on silica (hexane–Et2O, 3:1–2:1), 37
(156 mg, 64%) as a colourless oil; [h]2D5=−12.8 (c 1.0,
CHCl3); wmax (film) 1717 (CꢀO); lH (500 MHz, CDCl3)
7.44–7.24 (15H, m Ph), 4.75 (1H, s, C(2)H), 4.22 (1H,
q, J 6.9, C(a)H), 4.02 (1H, AB, J 14.4, NCHB), 3.78
(1H, AB, J 14.4, NCHA), 1.28 (3H, d, J 6.9, C(a)Me);
lC (50 MHz, CDCl3) 181.1 (CꢀO), 148.6, 145.9, 142.3
(Phipso), 137.4, 136.1, 135.9, 135.8, 135.7, 135.6, 135.3,
135.1, 134.8 (Pho-,m-,p-), 73.8 (C(2)H), 66.4 (C(a)H),
59.0 (NCH2), 23.6 (C(a)Me); HRMS (CI+) C23H24NO2
requires 346.1807; found 346.1812.
References
1. For examples, see: (a) Plucinska, K.; Liberek, B. Tetra-
hedron 1987, 43, 3509; (b) Grieco, P. A.; Hon, Y. S.;
Pedrez-Medrano, A. J. Am. Chem. Soc. 1988, 110,
1630.
2. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry
1991, 2, 183; (b) Davies, S. G.; Fenwick, D. R. J.
Chem. Soc., Chem. Commun. 1995, 1109.
3. For instance, see: (a) Davies, S. G.; Dixon, D. J.
Chem. Soc., Perkin Trans. 1 1998, 2635; (b) Bull, S. D.;
Davies, S. G.; Gianotti, M.; Kelly, P. J.; Smith, A. D.
J. Chem. Soc., Perkin Trans. 1 2001, 3106; (c) Bunnage,
M. E.; Burke, A. J.; Davies, S. G.; Goodwin, C. J.
Tetrahedron: Asymmetry 1995, 6, 165; (d) Davies, S. G.;
Smyth, G. D. Tetrahedron: Asymmetry 1996, 7, 1273;
(e) Davies, S. G.; Smyth, G. D. Tetrahedron: Asymme-
try 1996, 7, 1005; (f) Davies, S. G.; Ichihara, O. Tetra-
hedron Lett. 1999, 40, 9313.
4. a-Amino carbonyl compounds are widely used as
homochiral building blocks within organic synthesis.
For representative examples, see: (a) Golebiowski, A.;
Jacobsson, U.; Jurczak, J. Tetrahedron 1987, 43, 3063;
(b) Rittle, K. E.; Homnick, C. F.; Ponticello, G. S.;
Evans, B. E. J. Org. Chem. 1982, 47, 3016; (c) Hanson,
G. J.; Lindberg, T. J. Org. Chem. 1985, 50, 5399; (d)
Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979.
5. For instance, see: (a) Chuang, T.-H.; Sharpless, K. B.
Org. Lett. 2000, 2, 3555; (b) Chuang, T.-H.; Sharpless,
K. B. Helv. Chim. Acta 2000, 83, 1734; (c) Chuang,
T.-H.; Sharpless, K. B. Org. Lett. 1999, 1, 1435; (d)
Hennings, D. D.; Williams, R. M. Synthesis 2000, 1310;
(e) Ntirampebura, D.; Ghosez, L. Tetrahedron Lett.
1999, 40, 7079; (f) De, A.; Ghosh, S.; Iqbal, J. Tetra-
hedron Lett. 1997, 38, 8379; (g) Bhatia, B.; Jain, S.; De,
A.; Bagchi, I.; Iqbal, J. Tetrahedron Lett. 1996, 37,
7311; (h) Denis, J.-N.; Greene, A. E.; Guenard, D.;
Gueritte-Voegelein, F.; Mangatal, L.; Potier, P. J. Am.
Chem. Soc. 1988, 110, 5917.
4.34. Preparation of (R)-alanine hydrochloride 38
Following representative procedure 5, 33 (184 mg, 0.65
mmol) and Pd–C (184 mg, 10 mol%) gave 38 as a white
solid (79 mg, 92%); mp 202°C, {lit.23 207–209°C);
[h]D25=−8.2 (c 1.00, H2O), {lit.24 (ent) [h]2D0=+6.3 (c 1.2,
H2O)}; lH (250 MHz, D2O) 3.96 (1H, q, J 7.4, C(2)H),
1.42 (3H, d, J 7.4 Hz, C(3)H3), consistent with that
recorded in the literature.24
4.35. Preparation of (R)-leucine hydrochloride 39
Following representative procedure 5, 35 (77 mg, 0.24
mmol) and Pd–C (77 mg, 10 mol%) gave 39 as a white
solid (37 mg, 93%); mp 250°C dec.; [h]2D5=−3.2 (c 0.5,
H2O); {lit.24 (ent) [h]D20=+2.8 (c 0.61, H2O)}; lH (500
MHz, D2O) 3.97 (1H, m, C(2)H), 1.75 (1H, app quin-
tet, J 5.9, C(4)H), 1.64 (2H, m, C(3)H2), 0.87 (3H, d, J
6.2, (CH3)2CH), 0.85 (3H, d, J 6.2, (CH3)2CH); consis-
tent with that recorded in the literature.24
4.36. Preparation of (R)-2-amino-nonanoic acid
hydrochloride 4025
Following representative procedure 5, 36 (42 mg, 0.11
mmol) and Pd–C (42 mg, 10 mol%) gave 40 as a white
solid (23 mg, 96%); mp 251°C, dec.; [h]2D2=−25.0 (c 0.5,
AcOH); lH (500 MHz, D2O) 3.41 (1H, m, C(2)H), 1.71
(2H, m, C(3)H2), 1.17 (10H, m, (CH2)5), 0.73 (3H, t, J
7.1, C(9)H3).
6. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325.
7. For example consider: (a) phenylnorstatine, see: Izuka,
K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.;
Umeyama, H.; Ishido, T.; Kiso, Y. J. Med. Chem.
1990, 33, 2707; (b) bestatin, see: Nishizawa, R.; Saino,
T.; Takita, T.; Suda, H.; Aoyagi, T.; Umezawa, H. J.
Med. Chem. 1977, 20, 510; (c) microginin: Okino, T.;
Matsuda, H.; Murakami, M.; Yamaguchi, Y. Tetra-
hedron Lett. 1993, 34, 501.
4.37. Preparation of (R)-phenylglycine hydrochloride 41
Following representative procedure 5, 37 (69 mg, 0.2
mmol) and Pd–C (69 mg, 10 mol%) gave 41 as a white
solid (34 mg, 91%); mp 250°C dec., lit.23 254–256°C
dec.; [h]2D5=−105 (c 1.0, H2O), {lit.23 [h]2D5=−112.3 (c
0.98, H2O)}; lH (500 MHz, D2O) 7.49–7.45 (5H, m,

S. G. Da6ies et al. / Tetrahedron: Asymmetry 13 (2002) 1555–1565
1565
8. (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.
enoic acid; following general procedure 4, 21 (137.5 mg,
0.47 mmol) and NaClO2 (38 mg, 0.52 mmol) gave, after
purification by chromatography on silica (hexane–Et2O,
2:1–1:1), the title compound as a impure colourless oil (98
mg, 68%); [h]D25=+7.8 (c 0.5, CHCl3); wmax (film) 1716
(CꢀO); lH (500 MHz, CDCl3) 7.48–7.19 (10H, m, Ph),
5.91 (1H, dq, J4,3 15.3, J4,5 6.4, C(4)H), 5.69 (1H, ddd,
J3,4 15.3, J3,2 9.0, J3,5 1.2, C(3)H), 4.21 (1H, q, J 6.9,
C(a)H), 4.03 (1H, AB, J 13.5, NCHB), 4.02 (1H, d, J 9.0,
C(2)H), 3.89 (1H, AB, J 13.5, NCHA), 1.87 (3H, dd, J5,4
6.4, J5,3 1.2, C(5)H3), 1.54 (3H, d, J 6.9, C(a)Me); lC (125
MHz, CDCl3) 173.0 (CꢀO), 140.7, 137.3 (Phipso), 135.6
(C(3)H), 129.5, 129.4, 129.1, 128.7, 128.2 (Pho-,m-,p-),
124.4 (C(4)H), 64.5 (C(2)H), 58.0 (C(h)H), 52.4 (NCH2),
18.8 (C(5)H3) 14.4 (C(a)Me); HRMS (CI+) C20H24NO2
requires 310.1807; found 310.1814; salient impurity peaks
lH (500 MHz, CDCl3) 7.17 (1H, dd, J 10.0, 7.4,
C(3)HCHCO2), 6.24 (1H, d, J 7.0, CHC(2)HCO2), 4.55,
4.36 (2×1H, d, J17.8, NCH2), 1.87 (3H, obscured,
C(5)H3), 1.54 (3H, d, J6.9, C(a)Me).
9. Davies, S. G.; Epstein, S. W.; Ichihara, O.; Smith, A. D.
Synlett 2001, 1599.
10. Previous studies involving the oxidative cleavage of 1,2-
diols have shown that this transformation requires the
prior conversion of any amine functionality present to an
amide prior to oxidation, see: Czarnocki, Z.; Maclean, D.
B.; Szarek, W. A. Can. J. Chem. 1986, 64, 2205.
11. For previous studies concerning conjugate addition/
diastereoselective protonation and conjugate addition/
alkylation, see: (a) Davies, S. G.; Walters, I. A. S. J.
Chem. Soc., Perkin Trans. 1 1994, 1129; (b) Davies, S. G.;
Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1141; (c) Davies, S. G.; Edwards, A. J.;
Walters, I. A. S. Recl. Trav. Chim. Pays-Bas 1995, 114,
175.
12. The minor diastereoisomer was assumed to be the syn-a-
hydroxy-b-amino ester, and was isolated in 16% yield,
giving an overall yield of 64%.
17. Commercially available from Fluorochem Ltd.
18. Brackenridge, I.; Davies, S. G.; Fenwick, D. R.; Ichihara,
O.; Polywka, M. E. C. Tetrahedron 1999, 55, 533.
19. Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1992, 57,
2114.
20. Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Goodwin,
C. J. Tetrahedron: Asymmetry 1995, 6, 165.
21. Beagley, B.; Larsen, D. S.; Pritchard, R. G.; Stoodley, R.
J.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 1989, 6
1127.
22. (a) Lipshutz, B. H. Tetrahedron Lett. 1983, 24, 127; (b)
Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1994, 59,
649.
23. Camps, P.; Perez, F.; Soldevilla, N.; Borrego, M. A.
Tetrahedron: Asymmetry 1999, 10, 493.
24. Oppolzer, W.; Moretti, R. Tetrahedron 1988, 17, 5541.
25. (a) Scho¨llkopf, U.; Neubauer, H.-J. Synthesis 1982, 861;
(b) Albertson, N. F. J. Am. Chem. Soc. 1946, 68, 452.
13. Sanchez-Sancho, F. S.; Herradon, B. Tetrahedron: Asym-
metry 1998, 9, 1951.
14. Reginato, G.; Mordini, A.; Valacchi, M. Tetrahedron
Lett. 1998, 39, 9545.
15. Bettoni, G.; Carbonara, G.; Franchini, C.; Tortorella, V.
Tetrahedron 1981, 37, 4159.
16. Attempted oxidation of aldehyde 21 proceeded to good
conversion, but the crude reaction mixture was only
partially purified by chromatography, with the required
acid isolated containing a ꢀ10% impurity. This impurity
may arise from partial N-oxidation, followed by a [2,3]
sigmatropic rearrangement, a reaction which has been
synthetically exploited within our laboratory (see Davies,
S. G.; Smyth, G. D. Tetrahedron: Asymmetry 1996, 7,
1001; Davies, S. G.; Smyth, G. D. J. Chem. Soc., Perkin
Trans.
1
1996, 2467. Preparation and data for
(3E,2R,aR)-2-(N-benzyl-N-a-methylbenzylamino)pent-3-