Carbohydrate-derived aminoalcohol ligands for asymmetric Reformatsky reactions

Article abstract of DOI:10.1016/j.tetasy.2004.11.049

Members of a family of functionally and stereochemically diverse d-glucosamine-derived tertiary aminoalcohol ligands have been used to promote the asymmetric Reformatsky reaction. The β-hydroxyester product tert-butyl 3-phenyl-3-hydroxy-propanoate was obt

Full text of DOI:10.1016/j.tetasy.2004.11.049

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 213–221
Carbohydrate-derived aminoalcohol ligands for asymmetric
Reformatsky reactions
Daniel P. G. Emmerson,a William P. Hemsb and Benjamin G. Davisa,*
aDepartment of Organic Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
bJohnson Matthey Catalysis and Chiral Technologies, 28, Cambridge Science Park, Milton Road, Cambridge CB4 0FP, UK
Received 1 November 2004; accepted 19 November 2004
Available online 5 January 2005
Abstract—Members of a family of functionally and stereochemically diverse D-glucosamine-derived tertiary aminoalcohol ligands
have been used to promote the asymmetric Reformatsky reaction. The b-hydroxyester product tert-butyl 3-phenyl-3-hydroxy-pro-
panoate was obtained enriched in either the (+)-(R) (upto 74% ee) or ( ꢀ)-(S) (upto 42% ee) enantiomer depending on the choice of
ligand. Although the selectivities are modest in absolute terms they represent some the better selectivities obtained to date for this
reaction. A 1H NMR study was conducted to investigate this selectivity and suggested a secondary binding mode between ligand and
zinc in addition to the expected N-2, O-3 coordination.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
part of our ongoing studies7 into the application of glu-
cosamine-derived, aminoalcohol ligands to promote
asymmetric transformations we report here results using
a small family of carbohydrate tertiary aminoalcohol
ligands 4f–k, in the Reformatsky reaction.
The Reformatsky reaction is one of the most syntheti-
cally useful methods for the preparation of b-hydroxy-
esters.1 Since the first example of an enantioselective
version of the reaction in 1973 using (ꢀ)-sparteine,2 a
wide range of chiral ligands, most notably tertiary amino-
alcohols 4a–d, has been applied to this reaction using
bromoacetate-3 and difluorobromoacetate4-derived
Reformatsky reagents 2a–c (Scheme 1). A general, enan-
tioselective method affording b-hydroxyesters 3a–c in
high yield and ee, however, remains elusive and selectiv-
ities above 70% ee are rare. Compound 4a-promoted
reaction of ethyl bromoacetate-derived Reformatsky re-
agent 2b with benzaldehyde in 68% yield and 90% ee has
given the most highly enantioenriched products.3a The
greatest selectivity achieved using tert-butyl bromoace-
tate-derived 2a was 78% ee (56% yield) and was achieved
using ligand 4d.3b
2. Results and discussion
2.1. Preliminary ligand screening and optimisation
We synthesised a family of stereochemically and func-
tionally diverse 1,2-aminoalcohol ligands based on a
4-6-O-benzylidene-D-glucosamine scaffold. Based on ini-
tial screening of primary and secondary amines and con-
sistent with the nature of the Reformatsky reaction as
determined by previous studies,3a,e we selected tertiary
amine ligands as a preferred motif. Functional diversity
was introduced through alkylation of the key, primary
amine intermediate 8 by heating with the appropriate
alkyl iodides and potassium carbonate in acetonitrile
(Scheme 2). Using ethyl iodide, 1,5-diiodopentane and
di(2-iodoethyl)ether, acyclic and cyclic tertiary amines
4f–h were prepared in 84–91%, with little or no associ-
ated quaternisation.
Carbohydrates have recently received much attention as
sources of chiral ligands for asymmetric catalysis,5 how-
ever to our knowledge there is only one example6 of a
carbohydrate-derived ligand for the Reformatsky reac-
tion, open chain D-mannitol derived 4e, which afforded
the desired product in 58% yield and only 30% ee. As
We used the Reformatsky reaction of benzaldehyde with
tert-butyl bromoacetate-derived 2a (Scheme 1) as a stan-
dard method to test the effects of changing reaction con-
ditions and ligands. Reformatsky reactions of 2a have
*
Corresponding author. Tel.: +44 (0) 1865 275652; fax: +44 (0) 1865
275674; e-mail: ben.davis@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.049

214
D. P. G. Emmerson et al. / Tetrahedron: Asymmetry 16 (2005) 213–221
X X
X X
X X
Br
R'CHO
4a-k
Zn-Cu
THF, reflux
O
O
R'
O
Br
R
Zn
R
R
O
1
O
OH O
2
3
1-3a: X = H, R = t-Bu
1-3b: X = H, R = Et
1-3c: X = F, R = Me
OH
O
Me
N
Ph
O
Ph
OH
O
Ph
N
N
N
N
OH
O
OH
F3C
OH
Ph OH
HO Ph
4c (ref. 3e, 4)
4a (ref. 3a)
4b (S)-(+)-DPMPM
4e (ref. 6)
(ref. 3c)
4d (ref. 3b)
O
N
O
O
O
O
HO
O
O
O
O
O
O
HO
O
N
O
N
HO
N
O
O
O
HO
4k
O
O
4f
N = NEt2
O
4i
4j
N
N =
4g
4h
N = N
O
Scheme 1.
Ph
O
Ph
O
O
NH2
O
N
O
iii.
iv.
O
OMe
HO
OMe
HO
7
HO
HO
HO
Ph
O
O
4i
O
ii.
O
i.
+
HO
O
O
N
AcHN
AcHN
OMe
O
OH
Ph
O
5
Ph
O
O
6
O
O
HO
HO
H2N
OMe
OMe
8
iii.
v.
Ph
O
Ph
O
O
viii
O
O
4f
HO
vi.
O
OMe
OMe
N
N
Ph
O
Ph
O
O
N
O
N
O
O
HO
HO
11
ix
O
O
4h
OMe
OH
OMe
4g
9
vii.
NH2
O
Ph
O
O
O
N
O
iii
Ph
O
Ph
O
O
O
O
OMe
OH
4j
HO
HO
N
OMe
OMe
4k
10
O
Scheme 2. Reagents and conditions: (i) MeOH, AcCl, 100%, then PhCH(OMe)2, p-TsOH, DMF, 70 ꢁC, 69%; (ii) KOH (4 M) EtOH, reflux, 70%,
then chromatography; (iii) I(CH2)2O(CH2)2I (3 equiv), K2CO3, MeCN, reflux, 91% for 4h, 66% for 4k, 74% for 4i; (iv) EtI (2.1 equiv), K2CO3,
MeCN, reflux, 84%; (v) I(CH2)5I (3 equiv), K2CO3, MeCN, reflux, 85%; (vi) H2O2, NaWO4, NaHCO3, H2O–MeOH, 46%; (vii) LiAlH4, H2SO4,
THF, 36%; (viii) DMSO, (COCl)2, Et3N, DCM, ꢀ78 ꢁC, 82%; (ix) K-Selectride, THF, ꢀ78 ꢁC, 62%.
proven to be the most testing both in terms of yield and
selectivity and we felt that this would provide the more
rigorous trial of our methodology. In this initial screen
of a-glucosamine-derived ligands 4f–h, the 2-diethyl-
amino ligand 4f gave desired b-hydroxyester 3a in 25%
yield and 15% ee; the piperidinyl ligand 4g, an analogue
of 4f in which the amine alkyl substituents are cyclically
constrained, failed to promote the reaction at all; while
the 2-morpholinyl ligand 4h gave the most promising re-
sult, a yield of 20% but with better selectivity (42% ee)
than 4f (Table 1).
Based on this lead result we sought to optimise yield and
selectivity. Studies using ligand 4h (Table 1) suggested

D. P. G. Emmerson et al. / Tetrahedron: Asymmetry 16 (2005) 213–221
215
Table 1. Reformatsky reaction of benzaldehyde with 2a accelerated by
ligands 4f–k
4j showed both a remarkable reversal of the sense of
induction (S ! R) as well as much higher selectivity
(74% ee); unfortunately the efficiency was greatly re-
duced (10%).
Ligand Temp/ꢁC Time/h Ratio; 4:2aa: Yield/%b Ee/%c
PhCHO
3a
(config.)d
4f
0
20
0
24
24
24
1:3:1
1:3:1
1:3:1
25
15 (S)
—
42 (S)
2.3. NMR studies
4g
4h
Nil
20
Although the yields and enantioselectivities obtained
were disappointing in absolute terms, they compare rea-
sonably well with other systems and only two exam-
ples3b,c report enantioselectivities higher than 65% ee
for addition of benzaldehyde to tert-butyl bromoacetate.
In order to obtain a better insight into the mode of bind-
ing of the Reformatsky reagent to the ligand and to bet-
ter understand the role of the ligand, an NMR study was
undertaken, using mixtures of the Reformatsky reagent
and representative ligand, 4h in variable ratios. THF-d8
was used as solvent since all reactions were performed in
THF.
4h
4h
4h
4h
20
20
0
24
24
24
48
1:3:1
1:6:1
1:6:1
2:6:1
20
57
30
44
35 (S)
16 (S)
19 (S)
42 (S)
0
4i
20
20
20
48
48
48
2:6:1
2:6:1
2:6:1
21
10
33 (S)
74 (R)
—
4j
4k
Nil
a Assuming 100% conversion of bromoacetate 1a to enolate 2a.
b After isolation by column chromatography.
c Ee determined by chiral GC analysis (C-DEX-b).
d Configuration determined by sign of specific rotation previously
assigned.22
Reformatsky reagent 2a was generated and isolated by
heating zinc dust and copper(I) chloride in dry THF
for half an hour, then adding tert-butyl bromoacetate
dropwise and heating at reflux for a further hour, before
cooling and allowing to settle. A sample of the superna-
tant liquid was then removed from the reaction and con-
centrated. Its NMR spectrum in THF-d8 showed
expected10 resonances for methylene (d = 1.81) and
tert-butyl protons (d = 1.36) as well as those for unre-
acted bromoacetate 1a (d = 3.75, 1.23) (Fig. 1).11
that there was a minimal temperature effect; a small de-
crease in ee occurred (42–35%) when the temperature
was changed from 0 to 20 ꢁC. However the ratio of
ligand: Reformatsky reagent: aldehyde was more impor-
tant and the yield was improved from 20% to 57% when
a 1:6:1, rather than a 1:3:1 ratio was used, but with a
consequent halving of selectivity (ee change from 35%
to 16%). The optimal results in combined terms of both
ee (42%) and yield (44%) were achieved when a 2:6:1
ratio of ligand: Reformatsky reagent: aldehyde was used.
1
Next, the H NMR spectrum of ligand 4h was recorded
2.2. Effects of ligand stereochemistry
in THF-d8, and portions of Reformatsky reagent 2a were
added to the sample. The chemical shifts of the reso-
nances due to H-1, H-2, H-3 and PhCH were monitored
(Fig. 2), and in all cases steady increases in chemical shift
as well as general broadening of peaks were observed as
the ratio 2a:4h was increased to 1:1 (Fig. 2). These
changes are consistent with binding of zinc by the amino
alcohol function at O-3 and N-2 and appear to show the
formation of a single species, but may represent several
rapidly exchanging, bidentate and monodentate species.
These results contrast with the findings of previous
NMR studies of the asymmetric Reformatsky reaction
To explore the effects of ligand stereochemistry we next
prepared three further diastereomers of a-gluco ligand
4h arising from inversion of configuration at C-1, C-2
and C-3. The b-gluco ligand, 4i (C-1 inversion) was pre-
pared from 7 through dialkylation with di(2-iodo-
ethyl)ether in 74% yield, which in turn was isolated by
chromatography of an anomeric mixture of 7 and 8.
The ligand with a-allo stereochemistry 4j (C-3 inversion)
was prepared from 4h via Swern oxidation followed by
reduction using K-Selectride in 51% yield over two
steps. C-2 epimerisation was performed via an analo-
gous oxidation/selective reduction strategy: primary
amine 8 was converted to oxime 9 in 46% yield using so-
dium tungstate and hydrogen peroxide.8 Reduction of
oxime 9 using AlH3, prepared by reaction of LiAlH4
with H2SO4,9 afforded a 58% yield of a 3:2 mixture of
the desired primary amine with a-manno configuration
10, and a-gluco 8; alkylation of 10 with di(2-iodo-
ethyl)ether gave 4k in 66%.
1
in which H NMR revealed resonances due to several
new species in a 1:1 mixture of a less rigid, chiral ligand
and Reformatsky reagent.10 This might therefore reflect
a less dynamic nature of the reaction mixture obtained
from 4h with Reformatsky regent 2a.
Interestingly, when the ratio of Reformatsky reagent to
ligand was increased beyond 1:1 to 2:1, a second peak
due to PhCH was observed at d = 5.65, while little or
no notable change was observed in other peaks. This
second distinct shift is suggestive of a second zinc in
proximity to the 4,6-oxygen system, and was further
supported by an additional signal for ortho-Ph benzylid-
ene protons; a new peak emerging at d = 7.65. When the
ratio was increased to 5:1 these two new peaks increased
in intensity so that the original peaks (d = 5.58 (PhCH),
7.47 (ortho-Ph)) all but disappeared (Fig. 2). Together
this is suggestive of a secondary binding mode between
the zinc species and the ligand, to give a Ôdoubly boundÕ
These three new diastereomeric ligands 4i–k were then
tested in the Reformatsky reaction, using the previously
determined 2:6:1 ratio of ligand: Reformatsky reagent:
aldehyde. In all cases a temperature of 20 C was re-
quired for reaction. When the b-gluco ligand 4i was used
in the Reformatsky reaction, slightly diminished reactiv-
ity and selectivity (21% yield, 33% ee) were observed
compared to a-gluco 4h. The a-manno C-2 epimer 4k
failed to promote the reaction but the a-allo C-3 epimer

216
D. P. G. Emmerson et al. / Tetrahedron: Asymmetry 16 (2005) 213–221
Figure 1. 1H NMR spectrum of Reformatsky reagent, 2a in THF-d8 at 400 MHz and 293 K.
Figure 2. Variable-ratio NMR study of ligand 4h and Reformatsky reagent 2a in THF-d8 at 400 MHz and 293 K and plot of Dd versus ratio 2a:4h.

D. P. G. Emmerson et al. / Tetrahedron: Asymmetry 16 (2005) 213–221
217
ligand species, the second binding mode possibly being
4. Experimental methods
4.1. General methods
through the oxygen atoms at the 4- and 6-positions of
ligand 4h. These distinct changes in d (Dd) are plotted
in Figure 2, which highlights this biphasic shift.
Ether, DCM and THF were distilled; dry toluene, other
dry solvents were Fluka ÔpurissÕ solvents. Silica gel
(Merck, 400 mesh) was used for column chromatogra-
phy. TLC was performed on Merck F254 silica gel pre-
coated, aluminium backed sheets. Melting points were
determined on a Leica Galen III melting point appara-
tus. Optical rotations were measured on a Perkin–Elmer
241 polarimeter. IR spectra were recorded on a Perkin–
Elmer 1000 FT-IR spectrometer. NMR spectra were
recorded on a Bruker 400 or 200 MHz spectrometer,
assignments of peaks are made by means of COSY,
HMQC and APT experiments. High resolution mass
spectra were measured on Waters 2790 Micromass
LCT electrospray ionisation mass spectrometer using
chemical ionisation (NH3, Cl). Gas Chromatograms
were measured using a b-CD chir-DEX, 25 m column.
1
The predominant species observed in these H NMR
spectra may not be the reactive one; indeed theoretical
studies12 and crystallographic evidence13 suggest that
although a dimeric species of 2a predominates in solu-
tion, the reactive species is monomeric. It may be that
this additional putative O-4, O-6 binding mode between
the zinc and ligand is detrimental to the enantioselectiv-
ity and reactivity in this reaction. The secondary binding
mode that we have observed may be due to the ligand
coordinating dimeric Reformatsky reagent in which
the second zinc is close to O-4, O-6 and the first held
1
by N-2 and O-3. Indeed, qualitative H NMR analysis
of the nonreactive complex formed between 4k and 2a
appear to show a higher proportion of shifted and
broadened benzylidene peak indicative of this secondary
mode. This proposal raises the question of the nature of
the Reformatsky reagent when ligand is in excess: is it di-
meric or monomeric? The lack of a signal due to second-
ary binding of zinc to the ligand suggests that either it is
monomeric or, more likely, that a second ligand coordi-
nates the dimer. Reactions using a 1:1 ratio of ligand 4h:
Reformatsky reagent 2a in an attempt to reduce this
putative secondary binding mode failed to afford any
of the desired product.
4.2. Methyl N-acetyl-D-glucosamine, 5
N-Acetyl-D-glucosamine (36 g, 162.7 mmol) was dis-
solved in dried methanol (700 mL) and acetyl chloride
(57.5 g, 732 mmol) was added slowly. The resulting mix-
ture was stirred for 23 h and the solvent was evaporated
affording crude methyl N-acetyl-D-glucosamine,
in quantitative yield, as
a
3/2 a/b anomeric
mixture; mp181 ꢁC (MeOH/AcOEt); {lit.,14 mp
Although the secondary binding mode by ligand may
helpto explain the generally low reactivity it cannot
account for the differences observed. The remarkable
change in the sense selectivity on changing from a-gluco
4h to a-allo 4i (S ! R) may be explained by considering
that, in the latter case, the zinc is forced bellow the ring,
exposing it to steric bulk on one face only, whereas in
the case of 4h the zinc is held more distantly from the
sugar ring by the equatorial coordinating 3-OH.
166 ꢁC; lit.,15 mpaanom.(EtOH) 195 ꢁC; lit.,16 mpbanom.
-
24
(EtOH) 200 ꢁC}; ½aŠ ¼ þ83 (c 1.0, H2O); {lit.,17
D
25
25
½aŠ
¼ ꢀ46:9 (c 2.0, H2O); lit.,18 ½aŠ
¼ þ127
D banom:
D aanom:
(c 1.0, H2O)}; mmax/cmꢀ1 (KBr): 3382 (O–H), 2934
(N–H), 1651 (amide I), 1573 (amide II); dH (400 MHz,
CD3OD) 4.73 (0.6H, d, J 3.5, H-1a), 4.38 (0.4H, d, J
8.3, H-1b), 3.96 (0.6H, dd, J 10.6 and 3.4), 3.90 (0.4H,
dd, J 12.0 and 1.8), 3.84 (0.6H, J 11.9 and 3.8), 3.76–
3.69 (2H, m), 3.59–3.45 (1.4H, m), 3.40 (1.2H, s,
CH3O), 3.36 (1.8H, s, CH3O), 3.33 (1H m,), 2.23
(1.2H, s, Ac), 2.20 (1.8H, s, Ac); dC (100 MHz, CD3OD)
101.8, 98.12 (2 · C-1), 77.1, 74.6, 72.7, 71.5, 71.1, 70.9,
61.6, 61.5 (2 · C-6), 57.6, 56.2, 55.62, 55.56, 54.5, 48.9
(2 · OCH3), 20.5, 20.3 (2 · COCH3); m/z (APCI+)
236.18 ([M+H]+), (APCIꢀ) 234.37 ([MꢀH]+).
3. Conclusions
In conclusion we have demonstrated that fine-tuning of
functionality and stereochemistry in D-glucosamine-
derived aminoalcohol ligands can give rise to a diverse
family of ligands, all members of which may be prepared
from a key intermediate in three steps or fewer. The
Reformatsky reaction was promoted by these ligands
and the resulting b-hydroxyesters were enriched in either
enantiomer, depending on the choice of ligand. Some of
the selectivities (upto 74% ee for 2a) are amongst the
best seen for the reaction (678% for 2a); although effi-
ciencies are generally poor. The ability to access both
enantiomers in this way also demonstrates the utility
of fine-tuning in ligand design.
4.3. Methyl 2-N-acetylamido-4,6-O-benzylidene-
2-deoxy-D-glucopyranoside, 6
Methyl N-acetyl-D-glucosamine, (162.7 mmol) was dis-
solved in DMF (400 mL); benzaldehyde dimethyl acetal
(48.8 mL, 325.4 mmol) and para-toluenesulfonic acid
(0.62 g, 3.25 mmol) were added and the mixture stirred
at 70 ꢁC for 2.5 h. The product was identified by mass
spectrometry (m/z (APCI+) 324.27, [M+H]+) and the
solvent was evaporated under reduced pressure. The res-
idue was partitioned between CHCl3 (1.0 L) and satu-
rated sodium hydrogen carbonate solution (500 mL).
Undissolved material was removed by filtration, dis-
solved in hot chloroform (700 mL) and recrystallised
to give methyl 2-N-acetylamido-4,6-O-benzylidene-2-
deoxy-D-glucopyranoside. The organic layer from the
partition was separated, washed with brine (100 mL),
1
We have presented H NMR evidence suggesting a sec-
ondary ligand–zinc binding mode in addition to the ex-
pected N,O-coordination of zinc and we have postulated
an intermediate in which ligand coordinates dimeric
Reformatsky reagent through the 4,6-oxygen system as
well as the N-2, O-3 aminoalcohol.

218
D. P. G. Emmerson et al. / Tetrahedron: Asymmetry 16 (2005) 213–221
dried over MgSO4 and evaporated, recrystallisation
from ethyl acetate (700 mL) gave methyl 2-N-acetyl-
amido-4,6-O-benzylidene-2-deoxy-D-glucopyranoside (to-
tal yield, 36 g, 69%, overall anomeric ratio, 4/1, a/b).
H-1), 4.26 (1H, dd, J 9.3 and 4.0, H-6), 3.82–3.70 (2H,
m, H-4, H-60), 3.65 (1H, pt, J 9.1, H-3), 3.43 (1H, pt,
J 9.3, H-5), 3.39 (3H, s, OCH3), 2.74 (1H, dd, J 9.6
and 3.5, H-2); dC (50 MHz, CDCl3) 137.3, 129.2,
128.3, 126.4, (4 · Ph), 101.9 (CHPh), 101.2 (C-1), 82.1
(C-5), 76.0 (C-3), 69.1 (C-6), 62.6 (C-4), 56.6 (C-2),
55.4 (OCH3); m/z (TOF, ES+) 282.1350 ([M+H]+,
C14H20NO6 requires 282.1341).
4.3.1. Methyl 2-N-acetylamido-4,6-O-benzylidene-2-
deoxy-a-D-glucopyranoside. White solid; Rf 0.4 (9/1,
24
CHCl3/MeOH); mp298 ꢁC (EtOAc); ½aŠ ¼ þ90 (c
D
0.11, MeOH); mmax/cmꢀ1 (KBr) 3436 (OH), 3294 (NH),
3090 (CH, aromatic) 2990, 2946, 2912, 2872, 2834
(CH, aliphatic), 1653 (amide I), 1555 (amide II); dH
(400 MHz, CDCl3) 7.52–7.35 (5H, m, Ph), 5.93 (1H, d,
J 8.6, NH), 5.57 (1H, s, CHPh), 4.73 (1H, d, J 3.8, H-
1), 4.29 (1H, dd, J 3.2 and 8.3, H-6), 4.23 (1H, ddd, J
3.8, 8.9 and 10.2, H-2), 3.91 (1H, t, J 9.5, H-3), 3.83–
3.75 (2H, m, H-5, H-60), 3.59 (1H, m, H-4), 3.41 (3H,
s, OCH3), 3.24 (1H, s, OH), 2.06 (3H, s, Ac); dC
(100 MHz, CDCl3) 171.5 (CH3CO), 137.0, 129.2,
128.3, 126.3 (Ph), 102.0 (CHPh), 98.8 (C-1), 82.0 (C-
4), 70.7 (C-3), 68.8 (C-6), 62.3 (C-5), 55.3 (OCH3),
54.0 (C-2), 23.3 (CH3CO); m/z (TOF, ES+) 324.1447
([M+H]+, C16H22NO6 requires 324.1442).
4.4.2. Methyl 2-amino-4,6-O-benzylidene-2-deoxy-b-D-
25
D
glucopyranoside, 7. ½aŠ ¼ ꢀ55:6 (c 0.90, CHCl3); mp
(MeOH/EtOAc): 159.5–160.5 ꢁC;
m
max/cmꢀ1 (KBr)
3435 (NH2), 3174 (OH), 2938, 2879 (CH, aliphatic),
1600, (CC, aromatic); dH (400 MHz, CDCl3) 7.48–7.31
(5H, m, Ph), 5.51 (1H, s, CHPh), 4.31 (1H, dd, J 10.4
and 4.9, H-6), 4.15 (1H, d, J 7.94, H-1), 3.76 (1H, pt,
J 10.4, H-60), 3.56 (1H, pt, J 9.1, H-3), 3.49 (1H, pt, J
9.0, H-4), 3.48 (3H, s, OCH3), 3.35–3.42 (1H, m, H-5),
2.75 (1H, dd, J 8.4 and 8.5, H-2); dC (50 MHz, CDCl3)
137.2, 129.3, 128.4, 126.3 (4 · Ph), 105.3 (C-1), 102.0
(CHPh), 81.5 (C-4), 72.8 (C-3), 68.7 (C-6), 66.5 (C-5),
57.8 (C-2), 57.4 (OCH3); m/z (TOF, ES+) 282.1351
([M+H]+, C14H20NO6 requires 282.1341).
4.3.2. Methyl 2-N-acetylamido-4,6-O-benzylidene-2-
deoxy-b-D-glucopyranoside. White solid; Rf 0.3 (9/1,
4.5. Methyl 4,6-O-benzylidene-2-deoxy-2-N,N-diethyl-
amino-a-D-glucopyranoside, 4f
24
CHCl3/MeOH); mp292 ꢁC (MeOH); ½aŠ ¼ ꢀ57 (c
D
25
D
0.21, MeOH) {lit.19 ½aŠ ¼ ꢀ59:3 (c 0.56, MeOH)}; dH
(400 MHz, CDCl3) 7.45 (2H, m, Ph), 7.23 (3H, m, Ph),
6.08 (1H, d, J 6.5, NH), 5.53 (1H, s, CHPh), 4.57 (1H,
d, J 8.9, H-1), 4.27 (1H, dd, J 3.5 and 10.4, H-6), 4.25
(1H, ddd, J 6.5, 8.9 and 9.8, H-2), 4.06 (1H, pt, J 9.4,
H-4), 3.91 (1H, pt, J 9.6, H-3), 3.83–3.75 (2H, m, H-5,
H-60), 3.60–3.54 (1H, m, OH), 3.50 (3H, s, OMe), 2.04
(3H, s, C(O)CH3); dC (100 MHz, CD3OD) 171.5
(CH3CO), 137.0, 129.1, 128.3, 126.3 (4 · Ph), 102.0
(PhCH), 101.7 (C-1), 81.6 (C-4), 71.3 (C-3), 68.0 (C-6),
58.5 (C-5), 57.0 (OMe), 54.1 (C-2), 23.6 (CH3CO).
Ethyl iodide (120 lL, 2.1 mmol), potassium carbonate
(206 mg, 1.50 mmol) and 8 (200 mg, 0.78 mmol) were
added to acetonitrile and heated at 60 ꢁC for a total of
60 h, further portions of ethyl iodide were added after
10 h (85 lL, 1.07 mmol), 22 h (58 lL, 0.71 mmol), 30 h
(58 lL) and 54 h (29 lL, 0.34 mmol). The reaction was
filtered, concentrated under reduced pressure and purifi-
cation by column chromatography (0–10% MeOH/
EtOAc) afforded 4f (201 mg, 84%) as a colourless syrup;
24
D
Rf 0.4 (10% MeOH/EtOAc); ½aŠ ¼ þ113 (c 1.23,
CHCl3); (found: C 63.65, H 8.4, N 4.1. C18H27NO5 re-
quires C 64.1, H 8.1, N 4.15%); mmax/cmꢀ1 (CHCl3)
3431br (OH), 2969, 2928, 2858 (CH, aliphatic), 1459w
(CC, aromatic); dH (400 MHz, CDCl3) 7.54–7.51 (2H,
m, Ph), 7.38–7.33 (3H, m, Ph), 5.59 (1H, s, CHPh),
4.83 (1H, d, J 2.5, H-1), 4.27 (1H, dd, J 9.8 and 4.5,
H-6), 4.08 (1H, dd, J 10.5 and 8.8, H-3), 3.85 (1H,
ddd, J 10.4, 9.2 and 4.5, H-5), 3.77 (1H, pt, J 10.1, H-
60), 3.61 (1H, pt, J 9.0, H-4), 3.47 (1H, s, OH), 3.38
(3H, s, OCH3), 2.90 (2H, dq, J 13.7 and 7.4, NCH2),
2.84 (1H, dd, J 10.5 and 3.0, H-2), 2.62 (2H, dq, J
13.7 and 7.0, NCH2), 1.06 (3H, pt, J 7.6, CH2CH3);
dC (100 MHz, CDCl3) 137.3, 129.0, 128.2, 126.4 (Ph),
101.7 (CHPh), 99.2 (C-1), 83.3 (C-4), 69.1 (C-6), 65.4
(C-3), 64.8 (C-2), 62.2 (C-5), 55.9 (OCH3), 44.4
(NCH2), 14.8 (CH2CH3); m/z (TOF, ES+) 338.1974
([M+H]+, C18H28NO5 requires 338.1967).
4.4. Methyl 2-amino-4,6-O-benzylidene-2-deoxy-D-
glucopyranoside, 7/8
Methyl 2-N-acetylamido-4,6-O-benzylidene-2-deoxy-D-
glucopyranoside (31.84 g, 99 mmol) was added to 4 M
KOH in ethanol (800 mL) and heated at reflux for 4 h.
TLC (9/1 HCCl3/MeOH) showed completion and the
reaction was concentrated to 600 mL and diluted with
DCM (1 L). This mixture was washed twice with water
(2 · 1.5 L), dried (MgSO4) and concentrated under re-
duced pressure to give crude product as an orange solid
(23.1 g). Column chromatography (9/1–5/1 CHCl3/
MeOH) allowed separation of the anomers, affording
methyl 2-amino-4,6-O-benzylidene-2-deoxy-D-glucopyr-
anoside as a white solid (19.5 g, 70%).
4.4.1. Methyl 2-amino-4,6-O-benzylidene-2-deoxy-a-D-
25
D
glucopyranoside, 8. ½aŠ ¼ þ103:1 (c 0.905, CHCl3);
4.6. Methyl 4-6-O-benzylidene-2-deoxy-2-
(1-piperidinyl)-a-D-glucopyranoside, 4g
mp(MeOH/EtOAc) 135 ꢁC (dec), 172 ꢁC (melt);
m
max/cmꢀ1 (KBr) 3376, 3300 (OH, NH2), 3068, 3036
(CH, aromatic), 2993, 2966, 2872, 2835 (CH, aliphatic),
1576, 1455 (CC, aromatic); dH (400 MHz, CDCl3) 7.50–
7.36 (5H, m, Ph), 5.52 (1H, s, CHPh), 4.65 (1H, d, J 3.5,
1,5-Diiodopentane (116 lL, 0.78 mmol), potassium car-
bonate (108 mg, 0.78 mmol) and 8 (200 mg, 0.78 mmol)
were added to acetonitrile and the reaction was heated

D. P. G. Emmerson et al. / Tetrahedron: Asymmetry 16 (2005) 213–221
219
at 60 ꢁC for 12 h, then at 78 ꢁC for 8 h. A further por-
4.8. Methyl 4,6-O-benzylidene-a-D-arabino-hexopyrano-
side-2-ulose Z-oxime, 9
tion of 1,5-diiodopentane (53 lL) was then added and
the reaction was heated at reflux for 15 h. The reaction
was filtered, concentrated under reduced pressure and
purification by column chromatography (2.5–15%
MeOH/DCM) afforded 4g (210 mg, 85%) as an amor-
Hydrogen peroxide (35% (aq v/v), 1.38 mL, 7.12 mmol)
was added dropwise to a solution of 2-amino-4,6-O-benz-
ylidene-2-deoxy-a-D-glucopyranoside
8
(200 mg,
phous, white solid; Rf 0.4 (10% MeOH/EtOAc);
½aŠ ¼ þ106 (c 1.63, CHCl3) (found: C 65.00, H 7.70,
0.71 mmol), sodium tungstate dihydrate (23.8 mg,
0.071 mmol) and sodium hydrogen carbonate
(72 mg, 0.86 mmol) in methanol/water (1:1, 10 mL).
The reaction was stirred at room temperature for 34 h
during which time further portions of methanol (total
10 m) were added to partially dissolve the precipitate
that formed. TLC (10% MeOH/EtOAc) indicated com-
pletion and the methanol was evaporated under reduced
pressure. Water was added to the aqueous residue and
this was extracted three times with ethyl acetate; the
combined organic extracts were washed with brine and
dried (MgSO4). Evaporation of the solvent under re-
duced pressure and purification of the residue by column
chromatography (5–15% MeOH/DCM) afforded methyl
4,6-O-benzylidene-a-D-arabino-hexopyranoside-2-ulose
Z-oxime (97 mg, 46%) as a white solid; Rf 0.7 (10%
24
D
N 4.00. C19H27NO5 requires C 65.30, H 7.80, N
4.00%); mmax/cmꢀ1 (KBr) 3454br (OH), 2929, 2852
(CH, aliphatic), 1455 (CC, aromatic); dH (400 MHz,
CDCl3) 7.53–7.51 (2H, m, Ph), 7.38–7.33 (3H, m, Ph),
5.58 (1H, s, CHPh), 4.85 (1H, d, J 3.0, H-1), 4.26 (1H,
dd, J 9.6 and 4.3, H-6), 4.13 (1H, dd, J 10.6 and 8.8,
H-3), 3.84 (1H, ddd, J 10.3, 9.1 and 4.4, H-5), 3.77
(1H, pt, J 10.0, H-60), 3.59 (1H, pt, J 9.0, H-4), 3.39
(3H, s, OCH3), 2.83–2.78 (2H, m, NCH2), 2.67 (1H,
dd, J 10.6 and 3.0, H-2), 2.67–2.63 (2H, m, NCH2),
1.63–1.46 (6H, m, NCH2CH2, NCH2CH2CH2); dC
(100 MHz, CDCl3) 137.3, 129.0, 128.1, 126.4 (Ph),
101.7 (CHPh), 98.8 (C-1), 83.4 (C-4), 69.4 (C-2), 69.1
(C-6), 64.8 (C-3), 62.3 (C-5), 54.6 (OCH3), 51.0
(NCH2), 27.0 (NCH2CH2), 24.7 (NCH2CH2CH2); m/z
(TOF, ES+) 350.1971 ([M+H]+, C19H28NO5 requires
350.1967).
MeOH/EtOAc); mp140 ꢁC, crystal form change,
24
D
196–197 ꢁC, melts; ½aŠ ¼ þ40 (c 1.16, CHCl3); mmax
/
cmꢀ1 (KBr) 3510, 3392br (OH), 2973, 2947, 2920,
2878 (CH aliphatic), 1642 (C@N); dH (400 MHz,
DMSO-d6) 11.39 (1H, s, N–OH), 7.54–7.43 (2H, m,
Ph), 7.40–7.37 (3H, m, Ph), 5.77 (1H, s, H-1), 5.64
(1H, s, PhCH), 5.31 (1H, d, J 6.1, OH), 4.35 (1H, dd,
J 9.7 and 5.9, H-3), 4.23 (1H, dd, J 8.8 and 3.8, H-6),
3.78 (1H, ptd, J 9.9 and 4.5, H-5), 3.74 (1H, pt, J
10.4, H-60), 3.59 (1H, pt, J 9.5, H-4), 3.36 (3H, s,
OCH3); dC (100 MHz, DMSO-d6) 152.9 (C-2), 138.5,
129.8, 128.9, 127.2 (Ph), 101.5 (CHPh), 92.7 (C-1),
83.2 (C-4), 69.1 (C-3), 68.6 (C-6), 63.7 (C-5), 55.7
(OCH3); m/z (TOF, ESꢀ) 294.0970 ([MꢀH]ꢀ,
C14H16NO6 requires 294.0978). The oxime was assigned
as the Z-isomer on the basis of a strong NOE enhance-
ment between H-1 and NOH but not between H-3 or C-
3-OH and NOH.
4.7. Methyl 4-6-O-benzylidene-2-deoxy-2-(4-morpholin-
yl)-a-D-glucopyranoside, 4h
Di(2-iodoethyl)ether20 (255 mg, 0.78 mmol), potassium
carbonate (108 mg, 0.78 mmol) and
8
(200 mg,
0.78 mmol) were added to acetonitrile and heated at
70 ꢁC for 24 h a further portion of di(2-iodoethyl)ether
(70 mg) was then added and the reaction was heated at
reflux for 6 h. Removal of solvent under reduced pres-
sure and purification by column chromatography (2.5–
5% MeOH/DCM) afforded 4h (226 mg, 0.64 mmol,
91%) as a white solid; Rf 0.4 (5% MeOH/CHCl3); mp
24
D
155–157.5 ꢁC (DCM); ½aŠ ¼ þ92 (c 1.97, CHCl3);
(found: C 61.50, H 7.20, N 4.00. C18H25NO6 req-
uires C 61.50, H 7.15, N 4.00%); mmax/cmꢀ1 (KBr)
3440 (OH), 3067w (CH, aromatic), 2975, 2928, 2863
(CH, aliphatic), 1458 (CC, aromatic); dH (400 MHz,
CDCl3) 7.52–7.49 (2H, m, Ph), 7.39–7.34 (3H, m, Ph),
5.57 (1H, s, CHPh), 4.85 (1H, d, J 3.1, H-1), 4.27 (1H,
dd, J 9.6 and 4.2, H-6), 4.18 (1H, dd, J 10.3 and 9.1,
H-3), 3.83 (1H, ddd, J 10.3, 9.0 and 4.3, H-5), 3.76
(1H, pt, J 9.6, H-60), 3.71 (2H, ddd, J 11.1, 5.7 and
3.4, CH2O), 3.66 (2H, ddd, J 11.1, 5.7 and 3.4,
CH2O), 3.57 (1H, pt, J 9.1, H-4), 3.40 (3H, s, OCH3),
3.15 (1H, s, OH), 2.84 (4H, m, CH2N), 2.70 (1H, dd,
J 10.6 and 3.1, H-2); dH (400 MHz, THF-d8) 7.48–7.46
(2H, m, Ph), 7.32–7.28 (3H, m, Ph), 5.51 (1H, s, CHPh),
4.67 (1H, d, J 3.8, H-1), 4.46 (1H, d, J 3.1, OH), 4.16–
4.09 (2H, m, H-3, H-6), 3.66–3.64 (2H, m, H-5, H-6),
3.54 (4H, pt, J 4.7·, OCH2), 3.41 (1H, m, H-4), 3.34
(3H, s, OCH3), 3.12 (2H, m, NCH2), 2.69 (2H, m,
NCH2), 2.57 (1H, dd, J 10.6, 3.4, H-2); dC (100 MHz,
CDCl3) 137.2, 129.1, 128.2, 126.3 (4 · Ph), 101.8
(PhCH), 99.3 (C-1), 83.2 (C-4), 69.1 (C-6), 68.6 (C-2),
67.8 (CH2O), 65.4 (C-3), 62.2 (C-5), 54.7 (OCH3), 50.3
(CH2N); m/z (TOF, ES+) 352.1772 ([M+H]+,
C18H26NO6 requires 352.1760).
4.9. Methyl 2-amino-4,6-O-benzylidene-2-deoxy-a-D-
mannopyranoside, 1021
H2SO4 (concd, 91 lL) was added dropwise, with vigor-
ous stirring, over 5 min to LiAlH4 (1 N, THF,
3.39 mL) in THF (1.7 mL) in a two-necked flask
equipped with a reflux condenser and cooled in a water
bath. After 1 h stirring at room temperature, 9 (100 mg,
0.34 mmol) was added dropwise as a solution in THF
(2 mL) over 10 min. TLC indicated completion after
5 h whereupon the reaction was quenched by the drop-
wise addition of water, and NaHCO3. The solvents were
evaporated under reduced pressure and the residue
taken upin methanol and filtered over Celite. The filtrate
was concentrated under reduced pressure and purified
by column chromatography affording methyl 2-
amino-4,6-O-benzylidene-2-deoxy-a-D-glucopyranoside,
8 (27 mg, 22%) and methyl 2-amino-4,6-O-benzylidene-
2-deoxy-a-D-mannopyranoside, 10 (35 mg, 36%) as a
white solid; Rf 0.1 (5% MeOH/CHCl3); mp102–
24
105 ꢁC; ½aŠ ¼ þ26 (c 1.24, CHCl3); mmax/cmꢀ1 3414
D
(O–H), 2931 (C–H aliphatic); dH (400 MHz, CDCl3)

220
D. P. G. Emmerson et al. / Tetrahedron: Asymmetry 16 (2005) 213–221
7.52–7.49 (2H, m, Ph), 7.39–7.35 (3H, m, Ph), 5.57 (1H,
s, CHPh), 4.66 (1H, s, H-1), 4.27 (1H, dd, J 8.5 and 3.2,
H-6), 4.03 (1H, dd, J 9.7 and 4.7, H-3) 3.82–3.77 (2H, m,
H-5, H-60), 3.69 (1H, pt, J 9.3, H-4), 3.38 (3H, s, OCH3),
3.28 (1H, d, J 4.5, H-2); dC (100 MHz, CDCl3) 137.3,
129.2, 128.3, 126.3 (4 · Ph), 103.3 (C-1), 102.3 (CHPh),
79.6 (C-4), 68.9 (C-6), 67.5 (C-3), 62.9 (C-5), 55.0
(OCH3), 54.4 (C-2); m/z (TOF, ES+) 282.1347
([M+H]+, C14H20NO5 requires 282.1341).
H-1), 4.40 (1H, dd, J 10.3 and 4.6, H-6), 4.24 (1H, d,
J 10.3, H-4), 4.09 (1H, ptd, J 9.9 and 4.6, H-5), 3.92
(1H, pt, J 10.2, H-60), 3.76 (4H, m, OCH2), 3.44 (3H,
s, OCH3), 3.42 (1H, d, J 4.0, H-2), 2.89 (2H, m,
NCH2), 2.74 (2H, m, NCH2); dC (100 MHz, CDCl3)
196.4 (s, C-3), 136.4 (s, Ph), 129.3, 128.3, 126.4 (3 · d,
Ph), 102.4 (d, C-1), 101.9 (d, CHPh), 82.6 (d, C-4),
73.3 (d, C-2), 69.5 (t, C-6), 67.1 (t, OCH2), 65.7 (d, C-
5), 55.0 (q, OCH3), 50.1 (t, NCH2); m/z (TOF, ES+)
350.1611 ([M+H]+, C18H24NO6 requires 350.1604).
4.10. Methyl 4,6-O-benzylidene-2-deoxy-2-(4-morpholin-
yl)-a-D-mannopyranoside, 4k
4.12. Methyl 4,6-O-benzylidene-2-deoxy-2-(4-morpholin-
yl)-a-D-allopyranoside, 4j
Methyl 2-amino-4,6-O-benzylidene-2-deoxy-2-a-D-man-
nopyranoside (188 mg, 0.67 mmol) and potassium
carbonate (102 mg, 0.74 mmol) were dissolved in aceto-
nitrile (50 mL) and di(2-iodoethyl)ether (306 mg,
0.94 mmol) was added; the reaction was heated at reflux
for 56 h. The solvent was removed under reduced pres-
sure and the residue was purified by column chromato-
graphy to give 4k (155 mg, 66%) as a white solid; Rf 0.43
Methyl 4,6-O-benzylidene-2-deoxy-2-(4-morpholinyl)-a-
D-ribo-hexopyranoside-3-ulose 11 (520 mg, 1.49 mmol)
was dissolved in THF and cooled to ꢀ78 ꢁC. K-Select-
ride, (3.6 mL, 1 M, THF) was added and the reaction
stirred for 8 h. The reaction was quenched with water
and diluted with ethyl acetate, the aqueous layer was ex-
tracted with ethyl acetate and the combined organic lay-
ers was washed with NaOH (1 M) and brine, then dried
(MgSO4) and purified by column chromatography
(EtOAc ! 20% MeOH/EtOAc) to give 4j (320 mg,
(1:1 petrol/ethyl acetate); mp 168–170 ꢁC (EtOAc);
24
½aŠ ¼ ꢀ3:8 (c 0.95, CHCl3); mmax/cmꢀ1 3316 (O–H),
D
2972, 2906, 2836 (C–H, aliphatic); dH (400 MHz,
CDCl3) 7.53–7.51 (2H, m, Ph), 7.38–7.34 (3H, m, Ph),
5.60 (1H, s, PhCH), 4.91 (1H, s, H-1), 4.27 (1H, dd, J
9.6 and 4.2, H-6), 4.04 (1H, dd, J 9.8 and 6.9, H-3),
3.82 (1H, ptd, J 9.3 and 4.4, H-5), 3.77–3.69 (5H, m,
OCH2, H-60), 3.67 (1H, pt, J 9.5, H-4), 3.38 (3H, s,
OCH3), 3.00 (1H, d, J 6.8, H-2), 2.92 (2H, ddd, J 11.2,
6.2 and 3.1, NCH2), 2.67 (2H, ddd, J 11.5, 5.9 and
3.1, NCH2); dC (100 MHz, CDCl3) 137.2 (s, Ph),
129.1, 128.2, 126.3 (3 · d, Ph), 102.1 (CHPh), 97.2 (C-
1), 81.1 (d, C-4), 69.0 (t, C-6), 67.3 (t, OCH2), 66.8 (d,
C-2), 66.0 (d, C-3), 62.2 (d, C-5), 54.7 (q, OCH3), 52.2
(t, NCH2); m/z (TOF, ES+) 352.1753 ([M+H]+,
C18H26NO6 requires 352.1760).
62%) as a white solid; Rf 0.15 (EtOAc); mp134–
24
D
136 ꢁC (EtOAc); ½aŠ ¼ þ59 (c 1.02, CHCl3); mmax
/
cmꢀ1 3484 (O–H), 2927, 2856 (C–H aliphatic); dH
(400 MHz, CDCl3) 7.53–7.50 (2H, m, Ph), 7.38–7.33
(3H, m, Ph), 5.59 (1H, s, PhCH), 4.87 (1H, d, J 3.3,
H-1), 4.40 (1H, br s, H-3), 4.38 (1H, dd, J 10.2 and
5.1, H-6), 4.21 (1H, ptd, J 10.0 and 5.1, H-5), 3.79
(4H, pt, J 4.7, OCH2), 3.76 (1H, pt, J 10.4, H-60), 3.50
(1H, dd, J 9.7 and 2.6, H-4), 3.43 (3H, s, OCH3), 3.21
(1H, s, OH), 2.73 (2H, m, NCH2), 2.53 (2H, m,
NCH2), 2.38 (1H, pt, J 3.1, H-2); dC (100 MHz, CDCl3)
139 (s, Ph), 129.1, 128.2, 126.3 (3 · d, Ph), 102.1 (d,
CHPh), 98.4 (d, H-1), 79.6 (d, C-4), 69.2 (t, C-6), 66.7
(t, OCH2), 65.8 (d, C-2), 64.6 (d, C-3), 57.8 (d, C-5),
55.4 (q, OCH2), 50.4 (t, NCH2); m/z (TOF, ES+)
352.1759 ([M+H]+, C18H26NO6 requires 352.1760).
4.11. Methyl 4,6-O-benzylidene-2-deoxy-2-(4-morpholin-
yl)-a-D-ribo-hexopyranoside-3-ulose, 11
Oxalyl chloride (249 lL, 2.85 mmol) and DMSO
(405 lL, 5.70 mmol) were added to DCM (8 mL) at
ꢀ78 ꢁC and the reaction was stirred for 45 min. A solu-
tion of 4h (0.5 g, 1.42 mmol) in DCM (2 mL) was then
added dropwise via syringe. After 2 h triethylamine
(2.00 mL, 14.2 mmol) was added and the reaction was
allowed to reach room temperature. After a further
2 h brine was added, followed by a few drops of water;
the layers were separated and the aqueous layer ex-
tracted three times with DCM. The combined organic
extracts were dried (MgSO4) and concentrated under re-
duced pressure; purification of the resulting residue by
column chromatography (gradient: neat ethyl ace-
tate ! 5% methanol/ethyl acetate) afforded methyl
4,6-O-benzylidene-2-deoxy-2-(4-morpholinyl)-a-D-ribo-
hexopyranoside-3-ulose 11 (405 mg, 82%) as a white
4.13. Methyl 4-6-O-benzylidene-2-deoxy-2-(4-morpholin-
yl)-b-D-glucopyranoside, 4i
Di(2-iodoethyl)ether (255 mg, 0.78 mmol), potassium
carbonate (108 mg, 0.78 mmol) and
7
(200 mg,
0.78 mmol) were added to acetonitrile and heated at
70 ꢁC for 24 h; a further portion of di(2-iodoethyl)ether
(70 mg) was added after 24 h. Purification by column
chromatography (1–4% MeOH/DCM) afforded 4i
(188 mg, 75%) as a white solid; Rf 0.6 (5% MeOH/
24
D
CHCl3); mp148–150 ꢁC (DCM); ½aŠ ¼ ꢀ24 (c 1.73,
CHCl3); dH (400 MHz, CDCl3) 7.52–7.50 (2H, m, Ph),
7.39–7.34 (3H, m, Ph), 5.57 (2H, s, CHPh), 4.54 (1H,
d, J 8.5, H-1), 4.33 (1H, dd, J 10.4 and 4.9, H-6), 3.82
(1H, pt, J 10.2, H-60), 3.76 (1H, dd, J 10.1 and 9.0, H-
3), 3.72, 3.67 (4H, 2 · ddd, J 8.0, 6.3 and 2.9, CH2O),
3.61 (1H, pt, J 9.0, H-4), 3.56 (3H, s, OCH3), 3.40
(1H, ddd, J 10.1, 9.3 and 5.0, H-5), 3.06 (2H, br m,
CH2N), 2.63 (2H, ddd, J 11.3, 6.1 and 3.2, CH2N),
2.43 (1H, dd, J 10.2 and 8.5, H-2); dC (100 MHz,
CDCl3) 137.1, 129.1, 128.2, 126.3 (4 · Ph), 102.5 (C-1),
101.6 (CHPh), 81.5 (C-4), 70.3 (C-2), 68.7 (C-6), 67.74
solid; mp148–155 ꢁC crystal form change, 162–163,
23
D
melts (EtOAc); ½aŠ ¼ þ105 (c 0.88, CHCl3); mmax
/
cmꢀ1 3058, 3032 (C–H aromatic), 2979, 2955, 2927,
2913, 2861, 2833 (C–H aliphatic), 1737 (C@O); dH
(400 MHz, CDCl3) 7.56–7.50 (2H, m, Ph), 7.37–7.36
(3H, m, Ph), 5.56 (1H, s, CHPh), 5.25 (1H, d, J 3.8,

D. P. G. Emmerson et al. / Tetrahedron: Asymmetry 16 (2005) 213–221
221
3787–3794; (c) Soai, K.; Kawase, Y. Tetrahedron: Asym-
metry 1991, 2, 781–784; (d) Pini, D.; Mastantuono, A.;
Salvadori, P. Tetrahedron: Asymmetry 1994, 5, 1875–1876;
(e) Mi, A.; Wang, Z.; Chen, Z.; Jiang, Y.; Chan, A. S. C.;
Yang, T.-K. Tetrahedron: Asymmetry 1995, 6, 2641–2642;
(CH2O), 67.71 (C-3), 66.7 (C-5), 56.6 (OCH3), 50.2 (br,
CH2N); mmax/cmꢀ1 (KBr) 3460 (OH), 3032w (CH, aro-
matic), 2994, 2968, 2907, 2874, 2814 (CH, aliphatic),
1471, 1455 (CC, aromatic); m/z (TOF, ES+) 352.1760
([M+H]+, C18H26NO6 requires 352.1760).
´
(f) Andres, J. M.; Pedrosa, R.; Perez-Encabo, A. Tetra-
hedron 2000, 56, 1217–1223.
´
4.14. Reformatsky reactions
4. (a) Braun, M.; Vonderhagen, A.; Waldmuller, D. Liebigs
¨
Ann. 1995, 1447–1450; (b) Andres, J. M.; Martınez, M. A.;
´
´
Pedrosa, R.; Perez-Encabo, A. Synthesis 1996, 1070–1072.
4.14.1. Preparation of Reformatsky reagent. A flame
dried two-necked flask fitted with a reflux condenser
and septum was charged with zinc dust (392 mg,
6 mmol), CuCl (59.4 mg, 0.6 mmol) and THF (6 mL),
then heated to reflux with stirring under nitrogen for
30 min. The flask was then removed from the heat and
tert-butyl bromoacetate (969 lL, 6 mmol) was added
via syringe at such a rate as to maintain gentle reflux.
Heating was then resumed for 1 h. Stirring was then
stopped and the suspension allowed to settle leaving a
green solution of the Reformatsky reagent, Rf 0.7 (3:1
40–60 petroleum spirit/ether).
´
5. (a) Kunz, H.; Ruck, K. Angew. Chem., Int. Ed. 1997, 32,
336–358; (b) Park, H.; RajanBabu, T. V. J. Am. Chem.
Soc. 2002, 124, 734–735; (c) Bauer, T.; Tarasiuk, J.;
Pasniczek, K. Tetrahedron: Asymmetry 2002, 13, 77–82;
(d) Selke, R.; Ohff, M.; Riepe, A. Tetrahedron 1996, 52,
15079–15102; (e) Matsumoto, S.; Usada, H.; Suzuki, M.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
5634–5635.
6. Ribeiro, C. M. R.; Santos, E. de S.; Jardim, A. H. de O.;
Maia, M. P.; da Silva, F. C.; Moreira, A. P. D.; Ferreira,
V. F. Tetrahedron: Asymmetry 2002, 13, 1703–
1706.
7. Emmerson, D. P. G.; Villard, R.; Mugnaini, C.; Batsanov,
A.; Howard, J. A. K.; Hems, W. P.; Tooze, R. P.; Davis,
B. G. Org. Biomol. Chem. 2003, 1, 3826–3838.
8. (a) Kahr, K.; Berther, C. Chem. Ber. 1960, 93, 132–136; (b)
Salituro, G. M.; Townsend, C. A. J. Am. Chem. Soc. 1990,
112, 760–770.
9. Herscovici, J.; Egron, M. J.; Antonakis, K. J. Chem. Soc.,
Perkin Trans. 1 1988, 1219–1226.
10. Pini, D.; Uccello-Barretta, G.; Mastantuono, A.; Salva-
dori, P. Tetrahedron 1997, 53, 6065–6072.
4.14.2. Reformatsky reaction, representative proce-
dure. The ligand 4h (210 mg, 0.6 mmol) was dissolved
in THF (1.25 mL) and stirred under nitrogen at 0 ꢁC.
A solution of the Reformatsky reagent (1.8 mL,
1.8 mmol) was added by syringe and stirred for 5 min.
Benzaldehyde (30.3 lL, 0.3 mmol) was then added in
one portion and the reaction was stirred for 48 h. The
reaction was quenched by the addition of saturated,
aqueous NH4Cl (2 mL) and extracted three times with
ethyl acetate; the combined organic layers were then
washed with saturated sodium bicarbonate solution
and brine, and dried over MgSO4. The solvents were re-
moved under reduced pressure and the residue purified
by column chromatography (gradient: 4:1, petroleum
sprit (40–60 ꢁC): ether ! neat ether; then 4:1, ethyl ace-
tate: methanol) affording (S)-(ꢀ)-tert-butyl 3-hydroxy-
11. Note also the small impurity peaks in the 1H NMR
spectrum of the Reformatsky reagent at d = 4.97 and
d = 2.2–2.8; the peak at d = 4.97 could be assigned to the
methylene protons of a zinc enolate, which has been
proposed previously; see: Vaughan, W. R.; Bernstein, S.
C.; Lorber, M. E. J. Org. Chem. 1965, 30, 1790–1795.
12. Dewar, M. J. S.; Mertz, K. M., Jr. J. Am. Chem. Soc.
1987, 109, 6553–6554.
13. (a) Dekker, J.; Boersma, J.; van der Kerk, G. M. J. J.
Chem. Soc., Chem. Commun. 1983, 553–555; (b) Dekker,
J.; Budzelaar, P. H. M.; Boersma, J.; van der Kerk, G. M.
J. Organometallics 1984, 3, 1403–1407.
14. Bragiswar, P.; Bernaki, R. J.; Korytnyk, W. Carbohydr.
Res. 1980, 80, 99–116.
3-phenylpropanoate (29 mg, 44%) as a colourless oil;
23
½aŠ ¼ ꢀ10:5 (c 2.4, CHCl3); mmax/cmꢀ1 3454 (O–H),
D
2979 (C–H, aliphatic), 1728 (C@O); dH (400 MHz,
CDCl3) 7.40–7.27 (5H, m, Ph), 5.09 (1H, dd, J 8.3 and
4.4, CHOH), 3.48 (1H, br s, OH), 2.67 (2H, m, CH2),
1.46 (9H, s, C(CH3)3); dC (100 MHz, CDCl3) 171.9
(C@O), 142.6, 128.4, 127.6, 125.7 (4 · Ph), 81.5
(C(CH3)3), 70.4 (CHOH), 44.2 (CH2), 28.1 (CH3); and
recovered ligand (199 mg, 95%) as a white solid.
15. Yoshikawa, M.; Kamigaushi, I.; Isao, K. Chem. Pharm.
Bull. 1981, 29, 2582–2586.
16. Leeback, K. J. Org. Chem. 1973, 38, 1190–1193.
17. Nagabushan, T. L. Can. J. Chem. 1980, 58, 2720–2723.
18. Kovac, P.; Edgar, K. J. J. Org. Chem. 1992, 2455–2467.
19. Falcone, H.; Margaret, L.; Davis, J. T. J. Org. Chem.
1998, 63, 5555–5561.
References
20. Di(2-iodoethylether) was prepared according to the pro-
cedure of Gibson, C. S.; Johnson, J. D. A. J. Chem. Soc.
1930, 2525–2530, the crude product was distilled at 108 ꢁC
(4 mbar).
1. (a) Furstner, A. Synthesis 1989, 571–590; (b) Rathke, M.
¨
W. Org. React. 1975, 22, 423.
´ ´
2. Guette, M.; Capillon, J.; Guette, J. P. Tetrahedron 1973,
29, 3659–3667.
3. (a) Fujiwara, Y.; Katagiri, T.; Uneyama, K. Tetrahedron
21. Tsuda, Y.; Okundo, Y.; Iwaki, M.; Kanemitsu, K. Chem.
Pharm. Bull. 1989, 37, 2673–2678.
22. Butlin, R. J.; Linney, I. D.; Critcher, D. J.; Mahon, M. F.;
Molley, K. C.; Wills, M. J. Chem. Soc., Perkin Trans. 1
1993, 1581–1589.
´
Lett. 2003, 44, 6161–6163; (b) Andres, J. M.; Martın, Y.;
Pedrosa, R.; Perez-Encabo, A. Tetrahedron 1997, 53,
´
´