Doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to enantiopure ε-O-protected α,β-unsaturated esters derived from d-ribose

Article abstract of DOI:10.1016/j.tetasy.2014.02.004

Enantiopure ε-O-silyloxy- and ε-O-benzyloxy-α,β- unsaturated esters derived from d-ribose, each containing a cis-dioxolane unit, display excellent (≥95:5 dr) levels of diastereofacial directing ability upon conjugate addition of achiral lithium N-benzyl-N-isopropylamide. In contrast to the corresponding enantiopure ε-O-silyloxy-α,β-unsaturated ester derived from l-tartaric acid, which contains a trans-dioxolane unit, the conjugate additions of the antipodes of lithium N-benzyl-N-(α- methylbenzyl)amide to its cis-configured counterpart result in doubly diastereoselective 'matched' and 'mismatched' reaction pairings in which the inherent reagent control serves to augment or oppose, respectively, the established substrate diastereocontrol.

Full text of DOI:10.1016/j.tetasy.2014.02.004

Tetrahedron: Asymmetry 25 (2014) 534–546
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Doubly diastereoselective conjugate additions of the antipodes
of lithium N-benzyl-N-(a-methylbenzyl)amide to enantiopure
e
-O-protected ,b-unsaturated esters derived from D-ribose
a
⇑
Stephen G. Davies , Emma M. Foster, James A. Lee, Paul M. Roberts, James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiopure
e-O-silyloxy- and e-O-benzyloxy-a,b-unsaturated esters derived from D-ribose, each
Received 22 January 2014
Accepted 6 February 2014
Available online 22 March 2014
containing a cis-dioxolane unit, display excellent (P95:5 dr) levels of diastereofacial directing ability
upon conjugate addition of achiral lithium N-benzyl-N-isopropylamide. In contrast to the corresponding
enantiopure
e
-O-silyloxy-
a,b-unsaturated ester derived from
L
-tartaric acid, which contains a trans-
-methylbenzyl)amide
dioxolane unit, the conjugate additions of the antipodes of lithium N-benzyl-N-(
a
to its cis-configured counterpart result in doubly diastereoselective ‘matched’ and ‘mismatched’ reaction
pairings in which the inherent reagent control serves to augment or oppose, respectively, the established
substrate diastereocontrol.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
systems where the two controlling elements do not act indepen-
dently, as in these cases it is often possible to extract useful mech-
The interaction of any two chiral species (e.g., a reagent and a
substrate) results in the phenomenon of double asymmetric induc-
tion to form one or more new stereogenic centres. Masamune et al.
qualified double asymmetric induction for the interaction of two
enantiopure species in terms of ‘matched’ and ‘mismatched’
reaction pairings. In these scenarios, the individual stereocontrol-
ling preferences of the reagent and substrate may either promote
formation of the same or different diastereoisomers of the product.
If the stereocontrolling ability of the two reacting species are able
to operate independently of each other, then their use in combina-
tion results in either (i) an augmentation of diastereocontrol in the
‘matched’ reaction pairing, often producing synthetically useful
levels of selectivity; or (ii) opposition of diastereocontrol in the
‘mismatched’ reaction pairing, often resulting in low diastereose-
lectivity. In the latter case, the element (reagent or substrate) with
the dominant stereodirecting ability dictates the identity of the
major diastereoisomeric product, although mixtures are often
produced.1 Thus, when planning deployment of double asymmet-
ric induction as a synthetic strategy, it is often therefore desirable
to first garner an understanding of the inherent reagent and
substrate control independently, before their use in combination.
This approach has the benefit of allowing ready identification of
anistic information from the results.
As part of an ongoing research programme directed towards the
development of de novo asymmetric syntheses of imino2 and
amino3 sugars, we have investigated double asymmetric induction
upon conjugate addition of the antipodes of lithium N-benzyl-N-
(a a,b-unsatu-
-methylbenzyl)amide 24 to a range of enantiopure
rated esters containing cis- and trans-dioxolane units.5–7 We have
optimised a strategy to independently evaluate the levels of
diastereocontrol offered by the enantiopure a,b-unsaturated ester
alone by employing the conjugate addition reaction of an achiral
lithium amide that closely mimics the reactivity of 2, viz. lithium
N-benzyl-N-isopropylamide 1,5 before determining the nature of
the ‘matched’ and ‘mismatched’ reaction pairings of the enantio-
pure
a
,b-unsaturated ester with the antipodes of 2. When this
,b-unsaturated ester 3
strategy was applied to enantiopure
a
(containing a trans-dioxolane unit), the (singly) diastereoselective,
substrate directed conjugate addition of 1 gave 4 as the major dia-
stereoisomer (75:25 dr), which was isolated in 48% yield and >99:1
dr. From this substrate control, combined with the known diaste-
reofacial preferences of the antipodes of 2,4 it was anticipated that
the conjugate addition of (R)-2 to 3 would represent the doubly
diastereoselective ‘matched’ case. However, this reaction resulted
in the production of a 70:30 mixture of diastereoisomers 6 and 7
which were isolated in 60% and 8% yield, respectively, as single
diastereoisomers (>99:1 dr) in each case. Meanwhile, conjugate
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
http://dx.doi.org/10.1016/j.tetasy.2014.02.004
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
535
addition of (S)-2 to 3 gave 8 in >99:1 dr, which was isolated in 69%
yield. Thus, whilst significant levels of enantiorecognition between
the antipodes of 2 and 3 are observed, these empirically ‘matched’
and ‘mismatched’ reaction pairings are in contravention to those
anticipated from the substrate control elicited upon conjugate
addition of 1 to 3, demonstrating that the established, individual
stereocontrolling preferences of the reagent and substrate do not
act independently in these cases (Scheme 1).
isolated yield) was low and unreacted tert-butyl diethylphospho-
noacetate was present in the crude reaction mixture, indicating
that the reaction was not proceeding to full conversion. A stepwise
protocol was therefore examined. Reduction of lactone 12 with
DIBAL-H gave lactol 1310 (79:21 anomeric mixture) in 84% yield.
Unfortunately, olefination of lactol 13 under a range of literature
conditions11–15 resulted either in low mass return/isolated yield
of the desired olefin product, or in production of a mixture of
olefinic products within which the (E)-isomer 14 was the minor
t
component. For example, treatment of 13 with Ph3P@CHCO2 Bu
in 1,4-dioxane13 proceeded to full conversion to give a 42:58
mixture of (E)-14 and (Z)-15, respectively, which were isolated in
42% and 58% yield after chromatography (Scheme 2).
Ph
Ph
N
N
CO2tBu
CO2tBu
+
[Si]O
[Si]O
O
O
O
O
HO
O
O
O
(i)
O
HO
4, 48%, >99: 1 dr
5, 15%, >99:1 dr
HO
OH
Ph
(i)
1
HO
OH
75:25 dr
[4:5]
substrate
control
D-isoascorbic acid 10
11
N
Li
(ii)
CO2tBu
[Si]O
Ph
O
O
OH
Ph
O
O
O
(iii)
3, >99:1 dr
Ph
N
Li
(R)-2
Ph
N
Li
(S)-2
O
O
O
O
(ii)
(iii)
>99:1 dr
[8:9]
empirically
70:30 dr
empirically
"matched"
"mismatched"
[6:7]
13, 84%
12, 43% (2 steps)
79:21 dr
>99:1 dr
Ph
Ph
(iv)
(v)
42:58
88:12
Ph
N
Ph
N
[(E)-14:(Z)-15]
[(E)-14:(Z)-15]
CO2tBu
CO2tBu
CO2tBu
[Si]O
O
[Si]O
HO
HO
CO2tBu
O
O
O
+
O
O
O
O
6, 60%, >99:1 dr
8, 69%, >99:1 dr
(E)-14
(Z)-15
+
+
(iv). 42%, >99:1 dr
(v). 27%, >99:1 dr
(iv). 58%, >99:1 dr
Ph
Ph
Ph
N
Ph
N
Scheme 2. Reagents and conditions: (i) H2O2 (31.3% w/w aq), H2O, Na2CO3, 0 °C,
30 min, then 40 °C, 1 h; (ii) Me2C(OMe)2, Me2CO, TsOH, MgSO4, rt, 16 h; (iii) DIBAL-
H, CH2Cl2, ꢀ78 °C, 3 h; (iv) Ph3P@CHCO2tBu, 1,4-dioxane, 90 °C, 6 h, then
50 °C, 12 h; (v) DIBAL-H, THF, ꢀ78 °C to rt, 30 min, then ꢀ78 °C, then add
(EtO)2P(O)CH2CO2tBu, BuLi, THF, ꢀ78 °C to rt, 16 h.
CO2tBu
CO2tBu
[Si]O
[Si]O
O
O
O
O
7, 8%, >99:1 dr
9, notisolated
Independent treatment of lactol 13 (79:21 anomeric mixture)
with Ph3P@CHCO2 Bu and Ph3P@CHCO2Me in CH2Cl2 at reflux,
Scheme 1. Reagents and conditions: (i) 1, THF, ꢀ78 °C, 2 h; (ii) (R)-2, THF, ꢀ78 °C,
2 h; (iii) (S)-2, THF, ꢀ78 °C, 2 h. [Si] = TBDMS.
t
according to the procedure of Scharf et al.11 gave mixtures of chro-
matographically separable olefin products (E)-14 and (Z)-15
(R = tBu) in a 25:75 ratio, and (E)-16 and (Z)-17 (R = Me) in a
28:72 ratio, respectively (Scheme 3). Conversion of both (E)-16
and (Z)-17 to their corresponding p-nitrobenzoate esters (E)-18
and (Z)-19 allowed unambiguous determination of the (E)-olefin
geometry within 18 by single crystal X-ray diffraction analysis
(Fig. 1).16 Hence, the olefin geometries within 16, 17 and 19 were
also unambiguously confirmed. The values of the 1H NMR 3J2,3 cou-
pling constants of 14–19 were also diagnostic of the olefin geome-
tries (Scheme 3). This stereochemical outcome is, however, in
contrast to that of Scharf et al.11 who report that treatment of lactol
13 with Ph3P@CHCO2Me under identical conditions gives exclu-
sively (E)-16 (in 60% isolated yield). Comparison of spectroscopic
data reveals that the product obtained by Scharf et al. is (Z)-17,
and thus that their stereochemical assignment is in error. This er-
ror has previously been corrected by Gallos et al.17 who reported
that treatment of lactol 13 with Ph3P@CHCO2Me and PhCO2H in
THF at reflux gives a 29:71 mixture of (E)-16 and (Z)-17.18
In order to probe this behaviour further, we proposed to evalu-
ate double asymmetric induction upon conjugate addition of the
antipodes of 2 to the corresponding enantiopure
and -O-benzyloxy- ,b-unsaturated esters containing cis-dioxo-
lane units, to determine the effects of the -O-protecting group
e-O-silyloxy-
e
a
e
and configuration of the dioxolane moiety on the diastereoselectiv-
ity of this reaction, and report herein the results of our investiga-
tions within this area.
2. Results and discussion
The preparation of the requisite cis-dioxolane containing (E)-
a,b-unsaturated esters from commercially available D-isoascorbic
acid 10 was initially evaluated. Treatment of 10 with basic aqueous
H2O2 gave 11 and subsequent protection gave 12 in 43% isolated
yield over the 2 steps.8 Reduction of lactone 12 with DIBAL-H
and in situ reaction of lactol 13 with the lithium anion of tert-butyl
diethylphosphonoacetate in THF9 gave an 88:12 mixture of (E)-13
and (Z)-14, respectively, although the mass return (and hence the
Given the problems encountered with this approach, an alterna-
tive strategy was envisaged. Alcohol 23 was prepared from

536
S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
O
I
OH
OH
O
MeO
O
(i), (ii)
HO
O
O
O
O
HO
OH
13
D-ribose 20
21, 64%, >99:1 dr
79:21 anomeric mixture
(i)
(iii)
R = tBu, 25:75 dr [14:15]
R = Me, 28:72 dr [16:17]
CO2R
HO
O
HO
HO
O
O
O
O
+
O
O
CO2R
O
O
23, 84%, >99:1 dr
22
(
)-14, R = tBu, 25%
(
)-15, R = tBu, 44%
Z
E
>99:1 dr, J2,3 = 15.6 Hz
(E)-16, R = Me, 23%
>99:1 dr, J2,3 = 11.6 Hz
(Z)-17, R = Me, 56%
(iv) or (v)
94:6 dr,
= 15.7 Hz
>99:1 dr,
= 11.6 Hz
J2,3
J2,3
CO2tBu
RO
(ii)
(ii)
RO
(vi)
R = Me
R = Me
O
O
O
O
O
O
O
CO2Me
Ar
Ar
O
(iv). 24, R = TBDMS98%, >99:1 dr
(v). 25, R = Bn, 95%, >99:1 dr
26, R = TBDMS, 68%, >99:1 dr
27, R = Bn, 78%, >99:1 dr
+
O
O
CO2Me
O
O
Scheme 4. Reagents and conditions: (i) acetone/MeOH (v/v, 1:1), conc HCl (a few
drops), 60 °C, 1 h; (ii) imidazole, PPh3, I2, PhMe/MeCN (v/v, 5:1), 60 °C, 1 h; (iii) BuLi,
THF, ꢀ78 °C, 2 h, then DIBAL-H, ꢀ78 °C to rt, 16 h; (iv) TBDMSCl, imidazole, DMAP,
CH2Cl2, rt, 16 h; (v) NaH, THF, 0 °C, 45 min, then BnBr, rt, 16 h; (vi) Hoveyda–Grubbs
II (10 mol%), tert-butyl acrylate, CH2Cl2, reflux, 24 h.
(E)-18, 66%
>99:1 dr, = 15.4 Hz
(Z)-19, 68%
>99:1 dr, = 11.6 Hz
J2,3
J2,3
Scheme 3. Reagents and conditions: (i) Ph3P@CHCO2R, CH2Cl2, reflux, 3 days; (ii)
ArCOCl, pyridine, rt, 28 h. [Ar@p-C6H4NO2].
The inherent levels of substrate control offered by the enantio-
pure a,b-unsaturated esters 26 and 27 were initially evaluated by
reaction with achiral lithium N-benzyl-N-isopropylamide 1. When
the reactions were run in THF at ꢀ78 °C, these (singly) diastereose-
lective reactions proceeded under the control of the substrate to
give the corresponding b-amino esters 29 and 32 as the exclusive
products of conjugate addition. However, in these cases the
conjugate addition was accompanied by a competing
tion reaction, resulting in formation of the corresponding (Z)-b,
-unsaturated esters 28 and 31 after work-up. The configurations
c-deprotona-
c
of the newly formed C@C double bonds within 28 and 31 were
assigned by analogy to other reports concerning the kinetic
deprotonation/reprotonation of conjugated enones,20–25 and to
our observations in a very closely related system.5 Sewald et al.
noted a difference in the reactivity of lithium N-trimethylsilyl-
N-(
studies into its conjugate addition to enantiopure
b-unsaturated esters,26 and we have noted that competing
-deprotonation may be effectively suppressed when the reaction
a-methylbenzyl)amide in Et2O as compared to THF during
c
-alkoxy-
a,
c
solvent is changed from THF to Et2O.5 The conjugate additions of 1
to 26 and 27 were conducted in Et2O at ꢀ20 °C and gave b-amino
ester 29 in >99:1 dr (isolated in 82% yield, >99:1 dr) in the former
case, and b-amino ester 32 in 95:5 dr (isolated in 64% yield, >99:1
dr) in the latter case. The absolute configurations within b-amino
esters 29, 30, 32 and 33 were subsequently established unambigu-
ously via chemical correlation to a derivative of known absolute
configuration (vide infra). The competing production of (Z)-config-
Figure 1. X-ray crystal structure of (4S,5R,E)-18 (selected H atoms are omitted for
clarity).
-ribose 20 following our previously established route.6 Treatment
of -ribose 20 with acetone and MeOH in the presence of conc HCl,
ured b,c
-unsaturated esters in this type of reaction5 is consistent
D
D
with reactive conformation A, with the C(4)-hydrogen atom being
well placed to undergo deprotonation; kinetic protonation of the
resultant dienolate then gives 28 or 31.5,20–25 The substrate control
in THF is also consistent with reactive conformation A (in which
approach of the lithium amide reagent to C(3) from the 2Re,3Re
face27 would be expected to be favoured) [i.e., approach syn to
the C(4)-hydrogen atom and opposite the bulky C(4)-alkoxyalkyl
substituent, which provides significant shielding of the 2Si,3Si
face27]. Although the origin of the difference in reactivity upon
switching the reaction solvent to Et2O is unclear, it could result
from either a change of aggregation state of the lithium amide with
followed by reaction with I2 and PPh3 gave iodide 21 in 64% yield. A
one-pot transmetallation/ring-opening/reduction19 was next per-
formed upon treatment of 21 with BuLi (to give aldehyde 22), fol-
lowed by subsequent addition of DIBAL-H to the reaction flask to give
alcohol 23 in 84% isolated yield. O-Silyl and O-benzyl protection of 23
gave 24 and 25, respectively, with cross-metathesis mediated by
Hoveyda–Grubbs II catalyst (optimised conditions) giving the cor-
responding (E)-configured
and 27 (3J2,3 = 15.5 Hz) as single diastereoisomers, in 36% and 40%
overall yield from -ribose 20, respectively (Scheme 4).
a
,b-unsaturated esters 26 (3J2,3 = 15.5 Hz)
D

S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
537
solvent,28–30 or a subtle change in the reactive conformation of the
,b-unsaturated ester, for example to conformations B (identical to
the preferred solid-state conformation of ,b-unsaturated ester 18)
or C,6 in which the C(4)-alkoxyalkyl substituent is still able to
shield the 2Si,3Si face27 of the
,b-unsaturated system but the
configuration (vide infra) and are in accord with those predicted
by the transition state mnemonic that we have previously devel-
oped to rationalise the exceptional inherent diastereofacial bias
of this class of lithium amide.31 This is consistent with reaction
a
a
a
of the a,b-unsaturated ester substrate in conformation A in THF,
C(4)-hydrogen atom is no longer ideally placed for deprotonation
by the lithium amide. It is interesting to note that conformation
D (an expected, favourable ground-state conformation due to min-
imisation of allylic 1,3-strain) can be excluded as a reactive confor-
mation by these data, as in this conformation the C(4)-alkoxyalkyl
substituent provides shielding of the 2Re,3Re face27 (Scheme 5).
As 26 and 27 both display an inherent facial bias for conjugate
addition of 1 to C(3) on the 2Re,3Re face27 of the olefin, the conju-
gate additions of lithium amide (S)-2 to 26 and 27 were anticipated
to represent the doubly diastereoselective ‘matched’ reaction pair-
ings, given the well established facial bias of (S)-2 in its conjugate
with independent substrate control and reagent control4,31 in the
case of 26 resulting in a highly selective reaction (Scheme 6).
We have previously observed very high levels of substrate con-
trol in closely related systems: in these cases it is the a,b-unsatu-
rated ester and not the lithium amide reagent 2 which has the
dominant stereocontrolling influence in the ‘mismatched’ reac-
tion.5–7 When reaction of (R)-2 with 26 was run in THF at
ꢀ78 °C, this gave (Z)-b,
only product32 which was isolated in 72% yield, whilst (Z)-b,
-unsaturated ester 31 was formed as the major product of the
reaction of (R)-2 with 27. These observations are consistent with
-deprotonation being preferred over conjugate addition. Perform-
ing both the reactions in Et2O at ꢀ20 °C led to suppression of the
undesired -deprotonation pathway and gave an approximate
c-unsaturated ester 28 as essentially the
c
addition reactions to achiral
a
,b-unsaturated esters.4 In accordance
c
with this prediction, reaction of (S)-2 with 26 gave b-amino ester
34 in >99:1 dr, whilst reaction with 27 gave b-amino ester 36 in
93:7 dr. It is noteworthy, however, that the level of diastereoselec-
tivity observed for the addition of lithium amide (S)-2 to 27 (i.e.,
93:7 dr) is not as high as would be expected for a doubly diastereo-
selective ‘matched’ reaction when considering the very high levels
of stereocontrol exerted by (S)-2.4 This observation implies that the
stereocontrol of the lithium amide 2 does not operate indepen-
c
4:1 mixture of b-amino ester diastereoisomers 38 and 39, and 40
and 41, respectively, which proved separable by chromatography
in both cases (Scheme 7). The relative configuration within 41
was unambiguously assigned by single crystal X-ray diffraction
analysis (Fig. 2),16 with the absolute (3S,4R,5S,
a
R)-configuration
being assigned from the known configurations of the -methyl-
benzyl stereocentre, and the C(4) and C(5)-stereogenic centres
which were derived from -ribose 20. This analysis also allowed
the unambiguous assignment of the absolute (3R,4R,5S, R)-config-
a
dently of the stereocontrol of the
a,b-unsaturated ester 27, with
its normal mode of action being disrupted to some degree in this
instance, potentially due to chelation of lithium by the polyoxy-
D
a
genated
was again accompanied by
although in Et2O at ꢀ20 °C this reaction was completely
suppressed, allowing the isolation of 34 in 90% yield (>99:1 dr)
and 36 in 79% yield (93:7 dr). The absolute configurations
within 34 and 36 were subsequently established unambiguously
a
,b-unsaturated ester 27. The conjugate addition reaction
uration within 40. The absolute configurations within 38 and 39
were subsequently unambiguously established by chemical
correlation to those within 40 and 41 (vide infra). With the lithium
amide reagent (R)-2 known to exhibit very high diastereocontrol
c-deprotonation in THF at ꢀ78 °C,
upon conjugate addition to a range of achiral
a,b-unsaturated esters
(i.e., high reagent control)4,31 and the enantiopure
a,b-unsaturated
by chemical correlation to
a
derivative of known absolute
esters 26 and 27 exhibiting very high diastereocontrol upon
substrate
control
CO2tBu
H
RO
O
tBuO2C
O
H
H
O
OR
O
26, R = TBDMS
27, R = Bn
Ph
26A, R = TBDMS; 27A, R = Bn
N
Li
(i) or (ii)
1
Ph
N
Ph
N
CO2tBu
CO2tBu
CO2tBu
+
+
RO
RO
RO
O
O
O
O
O
O
MAJOR product
of conjugate addition
29, R = TBDMS; 32, R = Bn
MINOR product
of conjugate addition
30, R = TBDMS; 33, R = Bn
(Z)-β,γ-unsaturated ester
28, R = TBDMS; 31, R = Bn
product ratio
dra
R
TBDMS
TBDMS
Bn
conditions
yield (dr) %
28:29:30, 12:88:0 >99:1
28:29:30, 0:100:0 >99:1
31:32:33, 15:85:0 >99:1
31:32:33, 0:95:5 95:5
(i)
(ii)
(i)
-
29, 82 (>99:1)
-
32, 64 (>99:1)
Bn
(ii)
H
tBuO2C
H
H
H
OR
H
tBuO2C
tBuO2C
H
O
O
O
H
H
H
O
O
OR
tBuO2C
O
H
O
O
H
H
OR
RO
26D, 27D
26A, 27A
26B, 27B
26C, 27C
Scheme 5. Reagents and conditions: (i) 1, THF, ꢀ78 °C, 2 h; (ii) 1, Et2O, ꢀ20 °C, 5 h. aDiastereoisomeric ratio of b-amino ester products.

538
S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
reagent
control
substrate
control
CO2tBu
H
RO
tBuO2C
H
O
O
H
O
OR
O
26, R = TBDMS
27, R = Bn
Ph
26A, R = TBDMS; 27A, R = Bn
Ph
N
Li
(i) or (ii)
(S)-2
Ph
Ph
Ph
N
Ph
N
CO2tBu
CO2tBu
CO2tBu
+
+
RO
RO
RO
O
O
O
O
O
O
MAJOR product
MINOR product
(Z)-β,γ-unsaturated ester
28, R = TBDMS; 31, R = Bn
of conjugate addition
of conjugate addition
34, R = TBDMS; 36, R = Bn
35, R = TBDMS; 37, R = Bn
product ratio
dra
R
TBDMS
TBDMS
Bn
conditions
yield (dr) %
28:34:35, 25:75:0 >99:1
28:34:35, 0:100:0 >99:1
31:36:37, 14:80:6 93:7
31:36:37, 0:93:7 93:7
(i)
(ii)
(i)
-
34, 90 (>99:1)
-
36, 79 ( 93:7)
Bn
(ii)
Scheme 6. Reagents and conditions: (i) (S)-2, THF, ꢀ78 °C, 2 h; (ii) (S)-2, Et2O, ꢀ20 °C, 5 h. aDiastereoisomeric ratio of b-amino ester products.
substrate
Dominant
control
CO2tBu
H
RO
tBuO2C
H
O
O
H
O
OR
O
26, R = TBDMS
27, R = Bn
Ph
reagent
control
Ph
N
Li
(i) or (ii)
26A, R = TBDMS; 27A, R = Bn
(R)-2
Ph
Ph
Ph
N
Ph
O
N
CO2tBu
CO2tBu
CO2tBu
+
+
RO
RO
RO
O
O
O
O
O
MAJOR product
MINOR product
of conjugate addition
of conjugate addition
(Z)-β,γ-unsaturated ester
28, R = TBDMS; 31, R = Bn
38, R = TBDMS; 40, R = Bn
39, R = TBDMS; 41, R = Bn
product ratio
dra
R
TBDMS
TBDMS
Bn
conditions
yield (dr) %
28:38:39, 100:0:0
-
(i)
(ii)
(i)
28, 72 (>99:1)
28:38:39, 0:82:18 82:18
31:40:41, 46:37:17 69:31
31:40:41, 0:83:17 83:17
38, 58 (>99:1), 39, 12 (>99:1)
40, 29 (>99:1)
Bn
(ii)
40, 44 (>99:1), 41, 7 (>99:1)
Scheme 7. Reagents and conditions: (i) (R)-2, THF, ꢀ78 °C, 2 h; (ii) (R)-2, Et2O, ꢀ20 °C, 5 h. aDiastereoisomeric ratio of b-amino ester products.
conjugate addition of achiral lithium amide 1 (i.e., high substrate
control), it is impossible to predict a priori which will exert the
dominant controlling influence in the ‘mismatched’ reaction pair-
ings. However, the stereochemical outcomes from these conjugate
addition reactions have shown that the stereocontrol of substrates
26 and 27 is dominant over the stereocontrol of the reagent (R)-2,
consistent with our previous observations.5–7
In order to unambiguously establish the configurations within
b-amino esters 29, 30 and 32–39, a series of hydrogenolytic
N-debenzylation and reductive N-alkylation chemical correlation
93:7 dr (the major diastereoisomer being identical by 1H and
13C NMR spectroscopic analysis to the authentic sample). Next,
reductive alkylation of 42 (>99:1 dr) using NaBH3CN and acetone
gave an authentic sample of 43 in 61% yield and >99:1 dr. Finally,
hydrogenolysis of 32 gave a sample of 43 in quantitative yield and
>99:1 dr, identical by 1H and 13C NMR spectroscopic analysis to the
authentic sample. Thus, from the known absolute (3R,4R,5S,
configuration of 40, the known absolute configurations of the
C(4) and C(5) stereogenic centres (derived from -ribose 20)
within 32 and 36, and the known absolute configuration of the
(S)- -methylbenzyl stereocentre within 36, the absolute configu-
rations (3R,4R,5S)-32 and (3R,4R,5S, S)-36 were unambiguously
assigned, as well as the absolute configurations (3S,4R,5S)-33 and
(3S,4R,5S, S)-37 for the C(3)-epimers of 32 and 36, respectively
(Scheme 8).
aR)-
D
experiments was performed. For the
series, initial hydrogenolytic N-debenzylation of 40 [of known
absolute (3R,4R,5S, R)-configuration] gave an authentic sample of
e-O-benzyl protected
a
a
a
primary b-amino ester 42 in 42% yield and >99:1 dr. Similar
treatment of 36 (93:7 dr) gave a sample of 42 in 81% yield and
a

S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
539
Figure 2. Chem 3D representation of the single crystal X-ray diffraction structure of (3S,4R,5S,
aR)-41 (selected H atoms are omitted for clarity).
Ph
Ph
Ph
N
Ph
NH
N
CO2tBu
CO2tBu
CO2tBu
BnO
[Si]O
HO
O
O
O
O
O
O
40, >99:1 dr
38, >99:1 dr
43, >99:1 dr
(iii)
(i)
(i)
NH2
NH
(ii)
CO2tBu
CO2tBu
NH2
NH
HO
HO
(ii)
CO2tBu
CO2tBu
O
O
O
O
[Si]O
[Si]O
O
O
O
O
42, 81% from 36, 93:7 dr
42% from 40, >99:1 dr
43, >99:1 dr
quant from 32, 61% from 42
44, >99:1 dr
45, >99:1 dr, 65% from 29,
58% from 43, 62% from 44
64% from 34, 89% from 38
(i)
(i)
Ph
Ph
(i)
(i)
Ph
Ph
Ph
N
N
CO2tBu
CO2tBu
Ph
N
N
BnO
BnO
CO2tBu
CO2tBu
O
O
O
O
[Si]O
[Si]O
O
O
O
O
36, 93:7 dr
32, >99:1 dr
34, >99:1 dr
29, >99:1 dr
Scheme 8. Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), EtOAc, 18 h, rt; (ii)
NaBH3CN, acetone, MeOH, rt, 18 h.
Scheme 9. Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), EtOAc, 18 h, rt. (ii)
NaBH3CN, acetone, MeOH, rt, 18 h; (iii) TBDMSCl, DMAP, imidazole, CH2Cl2, rt, 16 h.
[Si] = TBDMS.
In order to unambiguously establish the absolute configurations
within the e-O-tert-butyldimethylsilyl protected series of b-amino
configurations (3S,4R,5S)-30, (3S,4R,5S,aS)-35 and (3S,4R,5S,aR)-
39 within the C(3)-epimeric series (Scheme 9).
esters, initial preparation of an authentic sample of 45 was
achieved via treatment of 43 [of known absolute (3R,4R,5S)-config-
uration] with TBDMSCl, imidazole and catalytic DMAP. Subse-
quently, N-debenzylation of 29 gave a sample of 45 which was
identical by 1H and 13C NMR spectroscopic analysis to the authen-
tic sample. Meanwhile, hydrogenolysis of 34 and 38 gave the same
primary b-amino ester 44 in 64 and 89% yield, respectively, and
reductive alkylation of 44 using NaBH3CN and acetone gave a
sample of 45, which was again identical by 1H and 13C NMR spec-
troscopic analysis to the authentic sample. Thus, the absolute con-
3. Conclusion
In conclusion, the singly diastereoselective conjugate additions
of achiral lithium N-benzyl-N-isopropylamide and the doubly
diastereoselective conjugate additions of both antipodes of lithium
N-benzyl-N-(
and -benzyloxy-
cis-dioxolane units (derived from
Both of these substrates display excellent (P95:5 dr) levels of
a
-methylbenzyl)amide to enantiopure
,b-unsaturated ester substrates containing
-ribose) have been evaluated.
e-silyloxy-
e
a
figurations (3R,4R,5S)-29, (3R,4R,5S,aS)-34 and (3R,4R,5S,aR)-38
D
were unambiguously assigned, as well as the absolute

540
S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
diastereofacial directing ability (substrate control) for attack at C(3)
on the 2Re,3Re face upon conjugate addition of lithium N-benzyl-
N-isopropylamide. Conjugate additions of the antipodes of lithium
by the addition of 6 M aq. HCl and then concentrated in vacuo. Ace-
tone (175 mL) and MgSO4 (50 g) were added to the residue and the
resultant mixture was stirred as 2,2-dimethoxypropane (350 mL,
2.85 mol) and TsOHꢁH2O (420 mg, 2.21 mmol) were added sequen-
tially at rt. The reaction mixture was stirred at rt for 16 h then
concd aq NH4OH (20 mL) was added. The resultant mixture was
stirred for a further 10 min then diluted with Et2O (500 mL) and
filtered. The filter cake was washed with Et2O (300 mL) and the
filtrate was concentrated in vacuo. The residue was dissolved in
Et2O, then MgSO4 (10 g) was added. The mixture was filtered
through CeliteÒ (eluent Et2O) and the filtrate was concentrated in
N-benzyl-N-(a-methylbenzyl)amide to the e-silyloxy-a,b-unsatu-
rated ester result in classical, doubly diastereoselective ‘matched’
and ‘mismatched’ reaction pairings in which the inherent reagent
control serves to augment (favour attack on the 2Re,3Re face) or
oppose (favour attack on the 2Si,3Si face), respectively, the estab-
lished substrate diastereocontrol, in contrast to the corresponding
enantiopure
e-silyloxy-a,b-unsaturated ester derived from
L-tartaric acid, which contains a trans-dioxolane unit. The applica-
tion of this methodology to the synthesis of a range of 1-deoxyimino
and 1-deoxyamino sugars will be reported in due course.
vacuo. Purification via recrystallisation (Et2O/30–40 °C petrol) gave
a 2D5
ꢂ
¼ ꢀ113
8
12 as a pale yellow solid (13.5 g, 43%, >99:1 dr);
½
(c 1.0 in H2O); {lit.8
½
a 2D5
ꢂ
¼ ꢀ120 (c 1.0 in H2O)}; mp 55–58 °C;
{lit.8 mp 64–65 °C}; dH (400 MHz, CDCl3) 1.41 (3H, s, MeCMe),
1.49 (3H, s, MeCMe), 4.39–4.50 (2H, m, C(5)H2), 4.76 (1H, d, J 5.7,
C(3)H), 4.89 (1H, dd, J 5.7, 3.8, C(4)H).
4. Experimental section
4.1. General experimental details
4.4. (R,R)-3,4-Dihydroxy-3,4-O-isopropylidenetetrahydrofuran-
2-ol 13
All reactions involving organometallic or other moisture-sensi-
tive reagents were carried out under a nitrogen or argon atmo-
sphere using standard vacuum line techniques and glassware
that was flame dried and cooled under nitrogen before use. Sol-
vents were dried according to the procedure outlined by Grubbs
and co-workers.33 Water was purified by an ElixÒ UV-10 system.
Organic layers were dried over MgSO4. Thin layer chromatography
was performed on aluminium plates coated with 60 F254 silica.
Plates were visualised using UV light (254 nm), iodine, 1% aq
KMnO4 or 10% ethanolic phosphomolybdic acid. Flash column
chromatography was performed on Kieselgel 60 silica or on an
automated flash column chromatography platform.
DIBAL-H (1.0 M in CH2Cl2, 10 mL, 10 mmol) was added drop-
wise to a solution of 12 (1.00 g, 6.32 mmol) in CH2Cl2 (20 mL) at
ꢀ78 °C and stirring was continued at ꢀ78 °C for 3 h. MeOH
(3.2 mL) was then slowly added and the reaction mixture was al-
lowed to warm to rt over 1 h. The resultant mixture was poured
into a mixture of EtOAc/H2O (v/v, 1:1, 100 mL). The resultant mix-
ture was then acidified to pH 3 with 1 M aq H2SO4 and the aqueous
layer was extracted with EtOAc (3 ꢃ 20 mL). The combined organic
extracts were then dried and concentrated in vacuo to give 13 as a
yellow oil (851 mg, 84%, 79:21 dr);10 dH (400 MHz, CDCl3) 1.33 (3H,
s, MeCMe), 1.48 (3H, s, MeCMe), 2.45 (1H, br s, OH), 4.04 (1H, d, J
10.2, C(5)HA), 4.09 (1H, dd, J 10.2, 3.4, C(5)HB), 4.59 (1H, d, J 5.8,
C(3)H), 4.85 (1H, dd, J 5.8, 3.4, C(4)H), 5.44 (1H, br s, C(2)H).
Melting points are uncorrected. Specific rotations are reported
in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL. IR spectra
were recorded as a thin film on NaCl plates (film), as a KBr disc
(KBr), or using an ATR module (ATR), as stated. Selected character-
istic peaks are reported in cm–1. NMR spectra were recorded in the
deuterated solvent stated. The field was locked by external
referencing to the relevant deuteron resonance. 1H–1H COSY
4.5. tert-Butyl (4S,5R,E)- and (4S,5R,Z)-4,5,6-trihydroxy-4,5-O-
isopropylidenehex-2-enoate (E)-14 and (Z)-15
and 1H–13
connectivity.
C HMQC analyses were used to establish atom
Method A: tert-Butyl (triphenylphosphoranylidene)acetate
(3.04 g, 8.08 mmol) was added to
a stirred solution of 13
4.2. General procedure for lithium amide conjugate addition
(851 mg, 5.31 mmol) in CH2Cl2 (17 mL) at rt. The resultant mixture
was heated at reflux for 3 days then concentrated in vacuo to give a
25:75 mixture of (E)-14:(Z)-15. Purification via flash column chro-
matography (eluent 30–40 °C petrol/EtOAc, 3:1) gave (Z)-15 as a
pale yellow oil (602 mg, 44%, >99:1 dr); C13H22O5 requires C,
BuLi was added dropwise to a stirred solution of the requisite
amine in either THF or Et2O (as stated) at ꢀ78 °C or ꢀ20 °C, respec-
tively, and stirring was continued for 30 min. A solution of the
60.45; H, 8.6%; found C, 60.4; H, 8.4%; ½a D25
ꢂ
¼ þ127:6 (c 1.0 in
requisite
a,b-unsaturated ester in either THF or Et2O (as stated)
was then added via cannula and the reaction mixture was stirred
for 2 h (for THF) or 5 h (for Et2O). The reaction mixture was
quenched with satd aq NH4Cl and then diluted with Et2O and
H2O. The layers were separated and the aqueous layer was
extracted three times with Et2O. The combined organic extracts
were washed sequentially with 10% aq citric acid, satd aq NaHCO3
and brine, then dried and concentrated in vacuo.
CHCl3); mmax (film) 3483 (O–H), 2982, 2936, 2877 (C–H), 1710
(C@O); dH (400 MHz, CDCl3) 1.41 (3H, s, MeCMe), 1.48 (9H, s,
CMe3), 1.53 (3H, s, MeCMe), 2.14 (1H, br s, OH), 3.44–3.53 (1H,
m, C(6)HA), 3.56–3.64 (1H, m, C(6)HB), 4.54–4.59 (1H, m, C(5)H),
5.55–5.61 (1H, m, C(4)H), 5.85 (1H, dd, J 11.6, 1.7, C(2)H), 6.27
(1H, dd, J 11.6, 6.8, C(3)H); dC (100 MHz, CDCl3) 24.7, 27.4
(CMe2), 28.0 (CMe3), 61.45 (C(6)), 74.55 (C(4)), 78.8 (C(5)), 81.0.
(CMe3), 108.7 (CMe2), 122.9 (C(2)), 145.6 (C(3)), 165.3 (C(1)); m/z
(ESI+) 281 ([M+Na]+, 100%); HRMS (ESI+) C13H22NaOþ ([M+Na]+)
4.3. (R,R)-3,4-Dihydroxy-O-isopropylidenedihydrofuran-2(3H)-
5
one 12
requires 281.1359; found 281.1357. Further elution gave (E)-14
as a pale yellow oil (343 mg, 25%, >99:1 dr); ½a D25
¼ þ30:6 (c 1.0
ꢂ
Na2CO3 (42.4 g, 0.400 mol) was added portionwise to a solution
in CHCl3); mmax (film) 3462 (O–H), 2983, 2936, 2888 (C–H), 1715
(C@O); dH (400 MHz, CDCl3) 1.38 (3H, s, MeCMe), 1.47 (9H, s,
CMe3), 1.51 (3H, s, MeCMe), 2.25 (1H, br s, OH), 3.55 (2H, app d, J
6.1, C(6)H2), 4.31–4.37 (1H, m, C(5)H), 4.74–4.79 (1H, m, C(4)H),
6.03 (1H, dd, J 15.6, 1.0, C(2)H), 6.76 (1H, dd, J 15.6, 5.8, C(3)H);
dC (100 MHz, CDCl3) 25.2, 27.7 (CMe2), 28.1 (CMe3), 61.9 (C(6)),
76.0 (C(4)), 78.3 (C(5)), 80.8 (CMe3), 109.4 (CMe2), 125.0 (C(2)),
140.7 (C(3)), 165.2 (C(1)); m/z (ESI+) 281 ([M+Na]+, 100%); HRMS
of -isoascorbic acid 10 (35.2 g, 0.200 mol) in H2O (500 mL) at 0 °C.
D
H2O2 (31.3% w/w, 44.0 mL, 0.450 mol) was then added dropwise
over 30 min. The resultant solution was stirred at 0 °C for 30 min
then heated at 40 °C for 1 h. Decolourising carbon (Norit AÒ,
8.0 g) was then added to decompose any excess peroxide and the
reaction mixture was stirred until a negative starch-iodide test
was observed (ca. 30 min). The reaction mixture was filtered
through CeliteÒ (eluent H2O). The filtrate was acidified to pH 1
(ESI+) C13H22NaOþ ([M+Na]+) requires 281.1359; found 281.1359.
5

S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
541
Method B: Dioxane (1.31 mL) was added to a mixture of 13
(84 mg, 0.52 mmol) and tert-butyl (triphenylphosphoranylid-
ene)acetate (237 mg, 0.63 mmol) and the resultant solution was
stirred at 90 °C for 6 h. The reaction mixture was allowed to cool
to 50 °C and stirring was continued at this temperature for a fur-
ther 12 h. The reaction mixture was then concentrated in vacuo
to give a 42:58 mixture of (E)-14:(Z)-15. Purification via flash
column chromatography (eluent 30–40 °C petrol/EtOAc, 3:2) gave
(Z)-15 as a pale yellow oil (80 mg, 58%, >99:1 dr). Further elution
gave (E)-14 as a pale yellow oil (56 mg, 42%, >99:1 dr).
Method C: BuLi (2.35 M in hexanes, 0.30 mL, 0.70 mmol) was
added dropwise to a stirred solution of tert-butyl diethylphospho-
noacetate (175 mg, 0.70 mmol) in THF (0.5 mL) at ꢀ78 °C and stir-
ring was continued at this temperature for 30 min. A solution of 12
(100 mg, 0.63 mmol) in THF (0.5 mL) at ꢀ78 °C was then added via
cannula. DIBAL-H (1.0 M in THF, 0.63 mL, 0.63 mmol) was then
added dropwise and the reaction mixture was allowed to warm
to rt over 16 h. Satd aq sodium potassium tartrate was then added
and the reaction mixture was partitioned between EtOAc (10 mL)
and 0.5 M aq HCl (10 mL). The organic layer was washed with
1 M aq K2CO3 (20 mL) and brine (20 mL), then dried and concen-
trated in vacuo to give an 88:12 mixture of (E)-14:(Z)-15;
unreacted tert-butyl diethylphosphonoacetate was also present in
the crude reaction mixture. Purification via flash column chroma-
tography (eluent 30–40 °C petrol/EtOAc, 3:1) gave (E)-14 as a pale
yellow oil (44 mg, 27%, >99:1 dr).
(20 mL) was then added and the reaction mixture was extracted
with CH2Cl2 (3 ꢃ 20 mL). The combined organic extracts were
washed sequentially with 1 M aq HCl (20 mL), H2O (20 mL) and
satd aq NaHCO3 (20 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C
petrol/EtOAc, 4:1) gave 18 as a pale yellow solid (96 mg, 66%,
>99:1 dr); C17H19NO8 requires C, 55.9; H, 5.2; N, 3.8%; found C,
56.0; H, 5.1; N, 3.75%; mp 90–94 °C; ½a D25
¼ þ3:6 (c 1.0 in CHCl3);
ꢂ
mmax (film) 2990, 2953 (C–H), 1728, 1663 (C@O), 1530 (N@O); dH
(400 MHz, CDCl3) 1.42 (3H, s, MeCMe), 1.53 (3H, s, MeCMe), 3.70
(3H, s, OMe), 4.30 (1H, dd, J 11.7, 6.4, C(6)HA), 4.35 (1H, dd, J
11.7, 5.7, C(6)HB), 4.56–4.62 (1H, m, C(5)H), 4.88–4.95 (1H, m,
C(4)H), 6.21 (1H, d, J 15.4, C(2)H), 6.94 (1H, dd, J 15.4, 5.3, C(3)H),
8.17–8.22 (2H, m, Ar), 8.26–8.31 (2H, m, Ar); dC (100 MHz, CDCl3)
25.3, 27.7 (CMe2), 51.8 (OMe), 63.9 (C(6)), 75.5 (C(5)), 75.9 (C(4)),
110.1 (CMe2), 123.0 (C(2)), 123.6, 130.9, 135.0 (Ar), 141.3 (C(3)),
150.7 (Ar), 164.2 (OCOAr), 166.0 (C(1)); m/z (ESI+) 388 ([M+Na]+,
100%); HRMS (ESI+) C17H19NNaOþ ([M+Na]+) requires 388.1003;
8
found 388.1002.
4.8. Methyl (4S,5R,Z)-4,5-dihydroxy-4,5-O-isopropylidene-6-(p-
nitrobenzoyloxy)hex-2-enoate 19
p-Nitrobenzoyl chloride (76 mg, 0.41 mmol) was added to a
solution of 17 (80 mg, 0.37 mmol) in pyridine (4 mL) at rt and
the resultant mixture was stirred at rt for 28 h. 1 M aq HCl
(20 mL) was then added and the reaction mixture was extracted
with CH2Cl2 (3 ꢃ 20 mL). The combined organic extracts were
washed sequentially with 1 M aq HCl (20 mL), H2O (20 mL) and
satd aq NaHCO3 (20 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C
petrol/EtOAc, 7:1) gave 19 as a pale yellow oil (92 mg, 68%, >99:1
4.6. Methyl (4S,5R,E)- and (4S,5R,Z)-4,5,6-trihydroxy-4,5-O-
isopropylidenehex-2-enoate (E)-16 and (Z)-17
Methyl (triphenylphosphoranylidene)acetate (933 mg, 2.79 mmol)
was added to a solution of 13 (294 mg, 1.84 mmol, 79:21 anomeric
mixture) in CH2Cl2 (6 mL) at rt. The resultant mixture was
heated at reflux for 3 days then concentrated in vacuo to give a
28:72 mixture of (E)-16:(Z)-17. Purification via flash column
chromatography (eluent 30–40 °C petrol/EtOAc, 3:2) gave (Z)-17
as a pale yellow oil (223 mg, 56%, >99:1 dr); C10H16O5 requires C,
dr); ½a 2D5
¼ þ176:5 (c 1.0 in CHCl3); mmax (film) 2990, 2954 (C–H),
ꢂ
1727, 1650 (C@O), 1530 (N@O); dH (400 MHz, CDCl3) 1.42 (3H, s,
MeCMe), 1.52 (3H, s, MeCMe), 3.72 (3H, s, OMe), 4.18 (1H, dd, J
11.7, 5.4, C(6)HA), 4.39 (1H, dd, J 11.7, 3.2, C(6)HB), 4.83–4.89
(1H, m, C(5)H), 5.66–5.71 (1H, m, C(4)H), 5.95 (1H, dd, J 11.6, 1.3,
C(2)H), 6.39 (1H, dd, J 11.6, 6.6, C(3)H), 8.18–8.23 (2H, m, Ar),
8.26–8.31 (2H, m, Ar); dC (100 MHz, CDCl3) 24.8, 27.4 (CMe2),
51.7 (OMe), 64.6 (C(6)), 74.8 (C(4)), 75.8 (C(5)), 109.4 (CMe2),
121.5 (C(2)), 123.6, 130.8, 135.3 (Ar), 146.2 (C(3)), 150.6 (Ar),
164.3 (OCOAr), 166.0 (C(1)); m/z (ESI+) 388 ([M+Na]+, 100%); HRMS
55.55; H, 7.5%; found C, 55.4; H, 7.4%; ½a D25
¼ þ144:6 (c 1.0 in
ꢂ
CHCl3); mmax (film) 3475 (O–H), 2988, 2953, 2978 (C–H), 1719
(C@O), 1647 (C@C); dH (400 MHz, CDCl3) 1.40 (3H, s, MeCMe),
1.53 (3H, s, MeCMe), 2.10 (1H, br s, OH), 3.40–3.50 (1H, m,
C(6)HA), 3.55–3.64 (1H, m, C(6)HB), 3.73 (3H, s, OMe), 4.54–4.60
(1H, m, C(5)H), 5.60 (1H, td, J 7.0, 1.6, C(4)H), 5.93 (1H, dd, J 11.6,
1.6, C(2)H), 6.40 (1H, dd, J 11.6, 7.0, C(3)H); dC (100 MHz, CDCl3)
24.6, 27.4 (CMe2), 51.7 (OMe), 61.5 (C(6)), 74.8 (C(4)), 78.8 (C(5)),
108.9 (CMe2), 120.5 (C(2)), 147.6 (C(3)), 166.4 (C(1)); m/z (ESI+)
(ESI+) C17H19NNaOþ ([M+Na]+) requires 388.1003; found 388.1003.
8
4.9. (2R,3R,4S,5S)-2-Methoxy-3,4-dihydroxy-3,4-O-isopropylidene-
5-iodomethyltetrahydrofuran 21
239 ([M+Na]+, 100%); HRMS (ESI+) C10H16NaOþ ([M+Na]+) requires
5
239.0890; found 239.0891. Further elution gave (E)-16 as a pale
Concd aq HCl (2.0 mL) was added to a solution of D-ribose 20
yellow oil (92 mg, 23%, 94:6 dr); C10H16O5 requires C, 55.55; H,
7.5%; found C, 55.7; H, 7.2%; ½a D21
¼ þ17:1 (c 1.0 in CHCl3); mmax
ꢂ
(50.0 g, 333 mmol) in acetone (350 mL) and MeOH (350 mL) and
the resultant solution was heated at 60 °C for 1 h. The reaction
mixture was allowed to cool to rt and was then neutralised by
addition of solid Na2CO3 (ꢄ10 g). The resultant mixture was then
filtered through CeliteÒ (eluent EtOAc) and the filtrate was concen-
trated in vacuo. The residue was dissolved in EtOAc (300 mL) and
was washed with H2O (300 mL). The aqueous layer was extracted
with EtOAc (2 ꢃ 300 mL) and the combined organic extracts were
dried and concentrated in vacuo. Imidazole (34.0 g, 500 mmol)
and PPh3 (105 g, 400 mmol) were added to the residue, and the
mixture was dissolved in PhMe/MeCN (v/v, 5:1, 1.05 L). I2 (101 g,
400 mmol) was then added and the resultant mixture was heated
at 60 °C for 1 h. The reaction mixture was then allowed to cool to
rt, diluted with Et2O (500 mL) and the resultant mixture was
washed sequentially with 10% aq Na2S2O3 (1 L), H2O (1 L) and brine
(1 L), then dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30–40 °C petrol/Et2O, 50:1) gave
(film) 3472 (O–H), 2989, 2952, 2938, 2890 (C–H), 1725 (C@O),
1662 (C@C); dH (400 MHz, CDCl3) 1.37 (3H, s, MeCMe), 1.50 (3H,
s, MeCMe), 2.37 (1H, br s, OH), 3.54 (2H, d, J 5.6, C(6)H2), 3.72
(3H, s, OMe), 4.31–4.38 (1H, m, C(5)H), 4.75–4.81 (1H, m, C(4)H),
6.11 (1H, dd, J 15.7, 1.5, C(2)H), 6.88 (1H, dd, J 15.7, 5.3,
C(3)H); dC (100 MHz, CDCl3) 25.2, 27.6 (CMe2), 51.7 (OMe), 61.7
(C(6)), 75.9 (C(4)), 78.2 (C(5)), 109.5 (CMe2), 122.5 (C(2)), 142.65
(C(3)), 166.3 (C(1)); m/z (ESI+) 239 ([M+Na]+, 100%); HRMS (ESI+)
C
10H16NaOþ ([M+Na]+) requires 239.0890; found 239.0890.
5
4.7. Methyl (4S,5R,E)-4,5-dihydroxy-4,5-O-isopropylidene-6-(p-
nitrobenzoyloxy)hex-2-enoate 18
p-Nitrobenzoyl chloride (82 mg, 0.44 mmol) was added to a
solution of 16 (87 mg, 0.40 mmol) in pyridine (5 mL) at rt and
the resultant mixture was stirred at rt for 28 h. 1 M aq HCl

542
S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
21 as a pale yellow oil (67.2 g, 64%, >99:1 dr);
1.0 in CHCl3); {lit.34
½
a 2D5
ꢂ
¼ ꢀ65:3 (c
(3.38 mL, 28.4 mmol) was then added at rt and stirring was contin-
ued at rt for 16 h. The solution was diluted with Et2O (50 mL) and
washed with satd aq NaHCO3 (2 ꢃ 50 mL). The aqueous layer was
extracted with Et2O (2 ꢃ 50 mL) and the combined organic extracts
were dried and concentrated in vacuo. Purification via flash col-
umn chromatography (eluent 30–40 °C petrol/EtOAc, 20:1) gave
34
½ ꢂ ¼ ꢀ67:8 (c 3.2 in CHCl3)}; dH (400 MHz,
a D
CDCl3) 1.33 (3H, s, MeCMe), 1.49 (3H, s, MeCMe), 3.17 (1H, app t,
J 9.9, CHAHBI), 3.29 (1H, dd, J 9.9, 6.1, CHAHBI), 3.38 (3H, s, OMe),
4.45 (1H, app dd, J 9.9, 6.1, C(5)H), 4.63 (1H, app d, J 6.1, C(4)H),
4.77 (1H, app d, J 6.1, C(3)H), 5.06 (1H, app s, C(2)H).
25 as a pale yellow oil (4.49 g, 95%, >99:1 dr); ½a D25
¼ þ1:7 (c 1.0
ꢂ
in CHCl3); mmax (film) 3030, 2987, 2934, 2865 (C–H), 1644 (C@C);
dH (400 MHz, CDCl3) 1.40 (3H, s, MeCMe), 1.52 (3H, s, MeCMe),
3.46 (1H, dd, J 9.9, 5.4, C(4)CHAHBOBn), 3.48 (1H, dd, J 9.9, 6.3,
C(4)CHAHBOBn), 4.37–4.43 (1H, m, C(4)H), 4.52 (1H, d, J 12.0,
OCHAHBPh), 4.60 (1H, d, J 12.0, OCHAHBPh), 4.60–4.65 (1H, m,
C(5)H), 5.23 (1H, d, J 10.4, C(5)CH@CHAHB), 5.36 (1H, d, J 17.4,
C(5)CH@CHAHB), 5.82 (1H, ddd, J 17.4, 10.4, 7.3, C(5)CH@CH2),
7.27–7.38 (5H, m, Ph); dC (100 MHz, CDCl3) 25.4, 27.9 (CMe2),
69.5 (C(4)CH2OBn), 73.5 (OCH2Ph), 76.9 (C(4)), 78.5 (C(5)), 108.9
(CMe2), 118.2 (C(5)CH@CH2), 127.7 (p-Ph), 127.8, 128.4 (o,m-Ph),
133.5 (C(5)CH@CH2), 138.0 (i-Ph); m/z (ESI+) 271 ([M+Na]+,
4.10. (4S,5R)-2,2-Dimethyl-4-hydroxymethyl-5-vinyl-1,3-dioxo-
lane 23
BuLi (2.5 M in hexanes, 23.4 mL, 58.4 mmol) was added to a
solution of 21 (18.35 g, 58.4 mmol) in THF (300 mL) at ꢀ78 °C
and the resultant solution was stirred at ꢀ78 °C for 2 h. DIBAL-H
(1.0 M in THF, 87.6 mL, 87.6 mmol) was then added and the reac-
tion mixture was allowed to warm to rt over 16 h. Acetone
(100 mL) and satd aq sodium potassium tartrate (150 mL) were
then added sequentially and stirring was continued at rt for
30 min. The reaction mixture was partitioned between brine
(300 mL) and EtOAc (300 mL) and the aqueous layer was extracted
with EtOAc (3 ꢃ 200 mL). The combined organic extracts were
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/EtOAc, 3:1) gave 23 as a
100%); HRMS (ESI+) C15H20NaOþ ([M+Na]+) requires 271.1305;
3
found 271.1305.
4.13. tert-Butyl (4R,5S,E)-4,5-dihydroxy-4,5-O-isopropylidene-6-
(tert-butyldimethylsilyloxy)hex-2-enoate 26
yellow oil (7.74 g, 84%, >99:1 dr);35,36
CHCl3); {lit.35
½
a 2D5
ꢂ
¼ ꢀ40:0 (c 1.0 in
½ ꢂ
a 2D5
¼ ꢀ44:0 (c 4.9 in CHCl3)}; dH (400 MHz, CDCl3)
Hoveyda-Grubbs II (23 mg, 36.7 lmol) was added to a degassed
1.40 (3H, s, MeCMe), 1.52 (3H, s, MeCMe), 1.86 (1H, br s, OH),
3.59 (2H, d, J 5.5, C(4)CH2OH), 4.25–4.31 (1H, m, C(4)H), 4.66
(1H, app t, J 7.2, C(5)H), 5.29 (1H, dd, J 10.5, 2.6, C(5)CH@CHAHB),
5.41 (1H, dd, J 17.1, 2.6, C(5)CH=CHAHB), 5.88 (1H, ddd, J 17.1,
10.5, 7.2, C(5)CH@CH2).
solution of 24 (100 mg, 0.367 mmol) and tert-butyl acrylate
(0.16 mL, 1.10 mmol) in CH2Cl2 (2 mL) and the resultant mixture
was heated at reflux for 22 h. The reaction mixture was then con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petrol/Et2O, 20:1) gave 26 as a colourless oil
(93 mg, 68%, >99:1 dr); ½a D25
¼ þ9:4 (c 1.0 in CHCl3); mmax (film)
ꢂ
4.11. (4S,5R)-2,2-Dimethyl-4-(tert-butyldimethylsilyloxymethyl)-
2981, 2956, 2932, 2859 (C–H), 1717 (C@O), 1660 (C@C); dH
(400 MHz, CDCl3) 0.04 (6H, s, SiMe2), 0.87 (9H, s, SiCMe3), 1.37
(3H, s, MeCMe), 1.48 (12H, s, MeCMe, OCMe3), 3.54 (1H, dd, J
10.1, 8.1, C(6)HA), 3.62 (1H, dd, J 10.1, 4.6, C(6)HB), 4.24–4.30
(1H, m, C(5)H), 4.78 (1H, app dt, J 5.4, 1.3, C(4)H), 6.02 (1H, dd, J
15.5, 1.3, C(2)H), 6.85 (1H, dd, J 15.5, 5.4, C(3)H); dC (100 MHz,
CDCl3) –5.6, –5.5 (SiMe2), 18.2 (SiCMe3), 25.2 (MeCMe), 25.9
(SiCMe3), 27.7 (MeCMe), 28.1 (OCMe3), 61.8 (C(6)), 76.7 (C(4)),
78.3 (C(5)), 80.4 (OCMe3), 109.6 (CMe2), 124.3 (C(2)), 141.6
(C(3)), 165.3 (C(1)); m/z (ESI+) 395 ([M+Na]+, 100%); HRMS (ESI+)
5-vinyl-1,3-dioxolane 24
Imidazole (3.87 g, 56.9 mmol), DMAP (93 mg, 0.76 mmol) and
TBDMSCl (3.43 g, 19.0 mmol) were sequentially added to a solution
of 23 (3.00 g, 19.0 mmol) in CH2Cl2 (135 mL) at rt and the resultant
solution was stirred at rt for 16 h. The reaction mixture was then
concentrated in vacuo. The residue was dissolved in Et2O (20 mL)
and the resultant solution was washed with 1 M aq HCl (20 mL),
then dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/EtOAc, 20:1) gave 24 as a
C
19H36NaO5Siþ ([M+Na]+) requires 395.2224; found 295.2221.
pale yellow oil (5.06 g, 98%, >99:1 dr); ½a D25
¼ þ1:6(c 1.0 in CHCl3);
ꢂ
mmax (film) 2988, 2956, 2931, 2858 (C–H), 1645 (C@C); dH
(400 MHz, CDCl3) 0.03 (3H, s, MeSiMe), 0.04 (3H, s, MeSiMe), 0.87
(9H, s, CMe3), 1.35 (3H, s, MeCMe), 1.45 (3H, s, MeCMe), 3.58 (1H,
dd, J 10.7, 6.1, C(4)CHAHBOSi), 3.61 (1H, dd, J 10.7, 6.1, C(4)CHAHB-
OSi), 4.18 (1H, app q, J 6.1, C(4)H), 4.60 (1H, app t, J 6.8, C(5)H), 5.19
(1H, d, J 10.4, C(5)CH@CHAHB), 5.33 (1H, d, J 17.2, C(5)CH@CHAHB),
5.87 (1H, ddd, J 17.2, 10.4, 6.8, C(5)CH@CH2); dC (100 MHz, CDCl3)
ꢀ5.5, ꢀ5.4 (SiMe2), 18.2 (CMe3), 25.3 (MeCMe), 25.9 (CMe3), 27.8
(MeCMe), 62.3 (C(4)CH2OSi), 78.5, 78.6 (C(4), C(5)), 108.5 (CMe2),
117.6 (C(5)CH@CH2), 133.7 (C(5)CH@CH2); m/z (ESI+) 295
([M+Na]+, 100%); HRMS (ESI+) C14H28NaO3Si+ ([M+Na]+) requires
295.1700; found 295.1699.
4.14. tert-Butyl (4R,5S,E)-4,5-dihydroxy-4,5-O-isopropylidene-6-
benzyloxyhex-2-enoate 27
Hoveyda–Grubbs II (25 mg, 39.9 lmol) was added to a degassed
solution of 25 (100 mg, 0.40 mmol) and tert-butyl acrylate
(0.18 mL, 1.21 mmol) in CH2Cl2 (2 mL) and the resultant mixture
was heated at reflux for 22 h. The reaction mixture was then con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petrol/EtOAc, 10:1) gave 27 as a colourless oil
(109 mg, 78%, >99:1 dr); ½a D25
¼ þ19:7 (c 1.0 in CHCl3); mmax (film)
ꢂ
2982, 2934, 2867 (C–H), 1714 (C@O), 1658 (C@C); dH (400 MHz,
CDCl3) 1.39 (3H, s, MeCMe), 1.48 (9H, s, CMe3), 1.51 (3H, s, MeCMe),
3.40 (1H, dd, J 9.6, 6.3, C(6)HA), 3.49 (1H, dd, J 9.6, 6.8, C(6)HB),
4.41–4.48 (1H, m, C(5)H), 4.48 (1H, d, J 12.0, OCHAHBPh), 4.52
(1H, d, J 12.0, OCHAHBPh), 4.77 (1H, dt, J 5.6, 1.4, C(4)H), 6.05
(1H, dd, J 15.5, 1.5, C(2)H), 6.82 (1H, dd, J 15.5, 5.6, C(3)H), 7.25–
7.37 (5H, m, Ph); dC (100 MHz, CDCl3) 25.3, 27.7 (CMe2), 28.1
(CMe3), 69.1 (C(6)), 73.5 (OCH2Ph), 76.3 (C(4)), 76.8 (C(5)), 80.6
(CMe3), 109.4 (CMe2), 124.6 (C(2)), 127.8 (p-Ph), 127.8, 128.4
(o,m-Ph), 137.7 (i-Ph), 141.3 (C(3)), 165.3 (C(1)); m/z (ESI+) 371
4.12. (4S,5R)-2,2-Dimethyl-4-(benzyloxymethyl)-5-vinyl-1,3-
dioxolane 25
NaH (60% dispersion in mineral oil, 1.89 g, 47.4 mmol) was stir-
red vigorously in 30–40 °C petrol (20 mL) at rt for 10 min and then
the solvent was decanted via cannula. THF (30 mL) was then added
and the suspension was cooled to 0 °C. A solution of 23 (3.00 g,
19.0 mmol) in THF (30 mL) was then added dropwise via cannula
and the reaction mixture was stirred at rt for 45 min. BnBr
([M+Na]+, 100%); HRMS (ESI+) C20H28NaOþ ([M+Na]+) requires
5
371.1829; found 371.1828.

S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
543
4.15. tert-Butyl (S,Z)-4,5-dihydroxy-4,5-O-isopropylidene-6-(tert-
butyldimethylsilyloxy)hex-3-enoate 28
CMe3), 2.33 (1H, dd, J 15.1, 5.1, C(2)HA), 2.64 (1H, dd, J 15.1, 7.3,
C(2)HB), 2.96 (1H, septet, J 6.6, NCHMe2), 3.53 (1H, dd, J 9.6, 7.1,
C(6)HA), 3.58–3.65 (2H, m, C(3)H, C(6)HB), 3.67 (1H, d, J 14.9,
NCHAHBPh), 3.85 (1H, d, J 14.9, NCHAHBPh), 4.29 (1H, dd, J 7.1,
5.1, C(4)H), 4.36 (1H, td, J 7.1, 4.8, C(5)H), 4.57 (1H, d, J 12.4,
OCHAHBPh), 4.60 (1H, d, J 12.4, OCHAHBPh), 7.21–7.43 (10H,
m, Ph); dC (100 MHz, CDCl3) 19.7, 21.3 (NCHMe2), 25.1, 27.2
(MeCMe), 28.3 (CMe3), 37.2 (C(2)), 49.6 (NCH2Ph), 50.1 (NCHMe2),
53.9 (C(3)), 68.7 (C(6)), 73.5 (OCH2Ph), 76.5 (CMe3), 78.2 (C(5)),
80.0 (C(4)), 108.1 (CMe2), 126.6, 127.6 (p-Ph), 127.9, 128.1, 128.3,
128.5 (o,m-Ph), 138.2, 141.6 (i-Ph), 172.1 (C(1)); m/z (ESI+) 498
Following the general procedure, (R)-N-benzyl-N-(a-methyl-
benzyl)amine (114 mg, 0.540 mmol) in THF (4 mL), BuLi (2.50 M
in hexanes, 0.21 mL, 0.521 mmol) and 26 (100 mg, 0.268 mmol)
in THF (4 mL) at ꢀ78 °C gave a mixture of products, of which the
major component was 28. Purification via flash column chroma-
tography (eluent 30–40 °C petrol/Et2O, 30:1) gave 28 as a colour-
less oil (72 mg, 72%, >99:1 dr); ½a D25
¼ ꢀ24:4 (c 1.0 in CHCl3);
ꢂ
mmax (film) 2980, 2956, 2931, 2859 (C–H), 1735 (C@O); dH
(400 MHz, CDCl3) 0.08 (6H, s, SiMe2), 0.91 (9H, s, SiCMe3), 1.40
(3H, s, MeCMe), 1.45 (9H, s, OCMe3), 1.50 (3H, s, MeCMe), 2.99
(1H, ddd, J 17.7, 6.4, 1.4, C(2)HA), 3.10 (1H, ddd, J 17.7, 7.3, 1.3,
C(2)HB), 3.70 (1H, dd, J 10.9, 5.6, C(6)HA), 3.74 (1H, dd, J 10.9, 4.6,
C(6)HB), 4.40–4.45 (1H, m, C(3)H), 4.60–4.65 (1H, m, C(5)H); dC
(100 MHz, CDCl3) ꢀ5.3 (SiMe2), 18.4 (SiCMe3), 25.6 (MeCMe),
25.9 (SiCMe3), 26.8 (MeCMe), 28.1 (OCMe3), 32.1 (C(2)), 66.0
(C(6)), 78.1 (C(5)), 80.3 (OCMe3), 87.8 (C(3)), 111.1 (CMe2), 151.8
(C(4)), 171.7 (C(1)); m/z (ESI+) 395 ([M+Na]+, 100%); HRMS (ESI+)
([M+H]+, 100%); HRMS (ESI+) C30H44NOþ ([M+H]+) requires
5
498.3214; found 498.3213.
Method B: Following the general procedure, N-benzyl-N-isopro-
pylamine (86 mg, 0.58 mmol) in THF (4 mL), BuLi (2.50 M in
hexanes, 0.21 mL, 0.56 mmol) and 27 (100 mg, 0.287 mmol) in
THF (4 mL) at ꢀ78 °C gave an 15:85 mixture of 31:32.
4.18. tert-Butyl (3R,4R,5S,aS)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-4,5-dihydroxy-4,5-O-isopropylidene-6-(tert-butyldimeth-
ylsilyloxy)hexanoate 34
C
19H36O5Siþ requires 395.2224; found 395.2222.
4.16. tert-Butyl (3R,4R,5S)-3-(N-benzyl-N-isopropylamino)-4,5-
dihydroxy-4,5-O-isopropylidene-6-(tert-butyldimethylsilyloxy)-
hexanoate 29
Method A: Following the general procedure, (S)-N-benzyl-N-(a-
methylbenzyl)amine (657 mg, 3.11 mmol) in Et2O (23 mL), BuLi
(2.50 M in hexanes, 1.21 mL, 3.02 mmol) and 26 (579 mg,
1.56 mmol) in Et2O (23 mL) at ꢀ20 °C gave 34 in >99:1 dr. Purifica-
tion via flash column chromatography (eluent 30–40 °C petrol/
Et2O, 30:1) gave 34 as a colourless oil (821 mg, 90%, >99:1 dr);
Method A: Following the general procedure, N-benzyl-N-isopro-
pylamine (481 mg, 3.22 mmol) in Et2O (24 mL), BuLi (2.50 M in
hexanes, 1.25 mL, 3.13 mmol) and 26 (600 mg, 1.61 mmol) in
Et2O (24 mL) at ꢀ20 °C gave 29 in >99:1 dr. Purification via flash
column chromatography (eluent 30–40 °C petrol/Et2O, 30:1) gave
29 as a colourless oil (687 mg, 82%, >99:1 dr); C29H51NO5Si re-
quires C, 66.75; H, 9.85; N, 2.7%; found C, 66.9; H, 9.8; N, 2.6%;
½
a 2D5
ꢂ
¼ þ13:8 (c 1.0 in CHCl3); mmax (film) 3063, 3028, 2932, 2857
(C–H), 1731 (C@O); dH (400 MHz, CDCl3) 0.14 (6H, s, SiMe2), 0.98
(9H, s, SiCMe3), 1.30 (3H, s, MeCMe), 1.41 (3H, s, MeCMe), 1.43
(3H, d, J 6.8, C(a)Me), 1.48 (9H, s, OCMe3), 2.25 (1H, dd, J 15.7,
5.1, C(2)HA), 2.43 (1H, dd, J 15.7, 7.3, C(2)HB), 3.69 (1H, dd, J 10.9,
6.6, C(6)HA), 3.78 (1H, d, J 15.2, NCHAHBPh), 3.80–3.84 (2H, m,
C(3)H, C(6)HB), 3.86 (1H, d, J 15.2, NCHAHBPh), 4.07 (1H, q, J 6.8,
½
a 2D5
ꢂ
¼ þ36:0 (c 1.0 in CHCl3); mmax (film) 2960, 2932, 2884, 2858
(C–H), 1730 (C@O); dH (400 MHz, CDCl3) 0.13 (6H, s, SiMe2), 0.95
(9H, s, SiCMe3), 1.03 (6H, d, J 6.8, NCHMe2), 1.34 (3H, s, MeCMe),
1.42 (3H, s, MeCMe), 1.52 (9H, s, OCMe3), 2.22 (1H, dd, J 15.1, 3.8,
C(2)HA), 2.60 (1H, dd, J 15.1, 8.8, C(2)HB) 2.88–3.00 (1H, m, CHMe2),
3.67 (1H, d, J 14.9, NCHAHBPh), 3.74 (1H, app td, J 8.8, 3.5, C(3)H),
3.78 (1H, dd, J 10.6, 6.3, C(6)HA), 3.91 (1H, dd, J 10.6, 6.1, C(6)HB),
3.99 (1H, d, J 14.9, NCHAHBPh), 4.20–4.27 (1H, m, C(5)H), 4.35
(1H, dd, J 7.0, 3.2, C(4)H), 7.18–7.43 (5H, m, Ph); dC (100 MHz,
CDCl3) ꢀ5.2, ꢀ5.1 (SiMe2), 18.5 (SiCMe3), 18.6, 21.7 (NCHMe2),
24.9 (MeCMe), 26.1 (SiCMe3), 26.9 (MeCMe), 28.2 (OCMe3), 37.6
(C(2)), 49.8 (NCH2Ph), 50.1 (NCHMe2), 53.2 (C(3)), 62.0 (C(6)),
78.2, 78.3 (C(4), C(5)), 79.8 (CMe3), 107.8 (CMe2), 126.4 (p-Ph),
128.0, 128.3 (o,m-Ph), 142.0 (i-Ph), 172.0 (C(1)); m/z (ESI+) 522
([M+H]+, 100%); HRMS (ESI+) C29H52NO5Si+ ([M+H]+) requires
522.3609; found 522.3602.
C(
dC (100 MHz, CDCl3) ꢀ5.1, ꢀ5.0 (SiMe2), 18.6 (SiCMe3), 18.9
(C( )Me), 25.0 (MeCMe), 26.1 (SiCMe3), 27.3 (MeCMe), 28.2
(OCMe3), 36.7 (C(2)), 45.8 (C(3)), 50.1 (NCH2Ph), 60.0 (C( )), 62.5
a)H), 4.18–4.26 (2H, m, C(4)H, C(5)H), 7.20–7.40 (10H, m, Ph);
a
a
(C(6)), 77.5, 78.5 (C(4), C(5)), 79.8 (OCMe3), 107.7 (CMe2), 126.5,
127.0 (p-Ph), 128.0, 128.1, 128.3 (o,m-Ph), 141.8, 143.5 (i-Ph),
171.5 (C(1)); m/z (ESI+) 584 ([M+H]+, 100%); HRMS (ESI+)
C34H54NO5Si+ ([M+H]+) requires 584.3766; found 584.3763.
Method B: Following the general procedure, (S)-N-benzyl-N-(a-
methylbenzyl)amine (114 mg, 0.540 mmol) in THF (4 mL), BuLi
(2.50 M in hexanes, 0.21 mL, 0.52 mmol) and 26 (100 mg,
0.268 mmol) in THF (4 mL) at ꢀ78 °C gave a 25:75 mixture of 28:34.
4.19. tert-Butyl (3R,4R,5S,aS)-3-[N-benzyl-N-(a-methylbenzyl)-
Method B: Following the general procedure, N-benzyl-N-isopro-
pylamine (80 mg, 0.54 mmol) in THF (4 mL), BuLi (2.50 M in
hexanes, 0.21 mL, 0.52 mmol) and 26 (100 mg, 0.268 mmol) in
THF (4 mL) at ꢀ78 °C gave a 12:88 mixture of 28:29.
amino]-4,5-dihydroxy-4,5-O-isopropylidene-6-benzyloxyhex-
anoate 36
Method A: Following the general procedure, (S)-N-benzyl-N-(a-
methylbenzyl)amine (784 mg, 3.71 mmol) in Et2O (28 mL), BuLi
(2.50 M in hexanes, 1.44 mL, 3.60 mmol) and 27 (646 mg,
1.86 mmol) in Et2O (28 mL) at ꢀ20 °C gave a 93:7 mixture of
36:37 respectively. Purification via flash column chromatography
(eluent 30-40 °C petrol/Et2O, 10:1) gave a 36 as a pale yellow oil
4.17. tert-Butyl (3R,4R,5S)-3-(N-benzyl-N-isopropylamino)-4,5-
dihydroxy-4,5-O-isopropylidene-6-benzyloxyhexanoate 32
Method A: Following the general procedure, N-benzyl-N-isopro-
pylamine (290 mg, 1.94 mmol) in Et2O (15 mL), BuLi (2.50 M in
hexanes, 0.75 mL, 1.88 mmol) and 27 (338 mg, 0.970 mmol) in
Et2O (15 mL) at ꢀ20 °C gave a 95:5 mixture of 32:33 respectively.
Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O, 15:1) gave 32 as a colourless oil (309 mg, 64%, >99:1
(820 mg, 79%, 93:7 dr); ½a D25
¼ þ3:3 (c 1.0 in CHCl3); mmax (film)
ꢂ
3062, 3029, 2979, 2933, 2877 (C–H), 1728 (C@O); dH (400 MHz,
CDCl3) 1.32 (3H, s, MeCMe), 1.36 (3H, d, J 7.0, C(a)Me), 1.42 (3H,
s, MeCMe), 1.47 (9H, s, CMe3), 2.25 (1H, dd, J 15.5, 5.9, C(2)HA),
2.42 (1H, dd, J 15.5, 5.9, C(2)HB), 3.48 (1H, dd, J 9.9, 8.1, C(6)HA),
3.56 (1H, dd, J 9.9, 4.3, C(6)HB), 3.69 (1H, app q, J 5.9, C(3)H),
3.77 (1H, d, J 15.4, NCHAHBPh), 3.82 (1H, d, J 15.4, NCHAHBPh),
dr); ½a 2D5
¼ þ10:6 (c 1.0 in CHCl3); mmax (film) 3029, 2978, 2934,
ꢂ
2873 (C–H), 1726 (C@O); dH (400 MHz, CDCl3) 1.01 (6H, d, J 6.6,
NCHMe2), 1.33 (3H, s, MeCMe), 1.42 (3H, s, MeCMe), 1.52 (9H, s,
4.00 (1H, q, J 7.0, C(a)H), 4.27 (1H, dd, J 6.3, 5.9, C(4)H),

544
S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
4.38–4.44 (1H, m, C(5)H), 4.56 (1H, d, J 12.6, OCHAHBPh), 4.60 (1H,
d, J 12.6, OCHAHBPh), 7.22–7.44 (15H, m, Ph); dC (100 MHz, CDCl3)
40:41. Purification via flash column chromatography (eluent 30–
40 °C petrol/Et2O, 15:1) gave 40 as a colourless oil (257 mg, 44%,
18.8 (C(a)Me), 25.1, 27.4 (CMe2), 28.2 (CMe3), 36.4 (C(2)), 50.4
>99:1 dr); ½a 2D5
¼ þ25:8 (c 1.0 in CHCl3); mmax (film) 3062, 3028,
ꢂ
(NCH2Ph), 54.6 (C(3)), 59.4 (C(a)), 68.7 (C(6)), 73.3 (OCH2Ph),
2978, 2933, 2872 (C–H), 1726 (C@O); dH (400 MHz, CDCl3) 1.18
76.6 (C(5)), 77.7 (C(4)), 79.9 (CMe3), 108.0 (CMe2), 126.7, 127.1
(p-Ph), 127.9, 128.1, 128.2, 128.3, 128.4 (o,m-Ph), 138.3, 141.5,
143.4 (i-Ph), 171.5 (C(1)); m/z (ESI+) 560 ([M+H]+, 100%); HRMS
(3H, s, MeCMe), 1.34 (3H, d, J 7.1, C(a)Me), 1.38 (3H, s, MeCMe),
1.57 (9H, s, CMe3), 2.29 (1H, dd, J 15.2, 4.6, C(2)HA), 2.57 (1H, dd,
J 15.2, 7.6, C(2)HB), 3.44–3.54 (2H, m, C(6)H2), 3.61 (1H, d, J 15.0,
NCHAHBPh), 3.62 (1H, dd, J 7.3, 4.0, C(4)H), 3.78–3.86 (1H, m,
(ESI+) C35H46NOþ ([M+H]+) requires 560.3371; found 560.3370.
5
Method B: Following the general procedure, (S)-N-benzyl-N-(
a
-
C(3)H) overlapping 3.81 (1H, q, J 7.1, C(a)H), 4.00 (1H, d, J 15.0,
methylbenzyl)amine (121 mg, 0.573 mmol) in THF (4 mL), BuLi
(2.50 M in hexanes, 0.21 mL, 0.56 mmol) and 27 (100 mg,
0.287 mmol) in THF (4 mL) at ꢀ78 °C gave a 14:80:6 mixture of
31:36:37.
NCHAHBPh), 4.06 (1H, app dt, J 7.2, 5.1, C(5)H), 4.59 (1H, d, J 12.3,
OCHAHBPh), 4.63 (1H, d, J 12.3, OCHAHBPh), 7.22–7.49 (15H, m,
Ph); dC (100 MHz, CDCl3) 18.8 (C(a)Me), 24.7, 27.0 (CMe2), 28.3
(CMe3), 37.3 (C(2)), 50.5 (NCH2Ph), 53.2 (C(3)), 58.2 (C(
a
)), 68.7
(C(6)), 73.4 (OCH2Ph), 76.4 (C(5)), 77.1 (C(4)), 80.1 (CMe3), 107.9
(CMe2), 126.8, 127.2, 127.7 (p-Ph), 128.0, 128.1, 128.2, 128.4,
128.6 (o,m-Ph), 138.3, 141.4, 142.2 (i-Ph), 172.1 (C(1)); m/z (ESI+)
4.20. tert-Butyl (3R,4R,5S,
aR)- and (3S,4R,5S,aR)-3-[N-benzyl-N-
(
a
-methylbenzyl)amino]-4,5-dihydroxy-4,5-O-isopropylidene-
6-(tert-butyldimethylsilyloxy)hexanoate 38 and 39
560 ([M+H]+, 100%); HRMS (ESI+) C35H46NOþ ([M+H]+) requires
5
560.3371; found 560.3367. Further elution gave 41 as a pale yellow
Following the general procedure, (R)-N-benzyl-N-(
a
-methyl-
oil (41 mg, 7%, >99:1 dr); ½a D25
ꢂ
¼ ꢀ26:5 (c 1.0 in CHCl3);
mmax (film)
benzyl)amine (641 mg, 3.04 mmol) in Et2O (23 mL), BuLi (2.50 M
in hexanes, 1.18 mL, 2.94 mmol) and 26 (565 mg, 1.52 mmol) in
Et2O (23 mL) at ꢀ20 °C gave an 82:18 mixture of 38:39. Purifica-
tion via flash column chromatography (eluent 30-40 °C petrol/
Et2O, 30:1) gave 38 as a colourless oil (513 mg, 58%, >99:1 dr);
3062, 3028, 2980, 2933, 2864 (C–H), 1730 (C@O); dH (400 MHz,
CDCl3) 1.43 (3H, s, MeCMe), 1.46 (9H, s, CMe3), 1.49 (3H, s, MeCMe),
1.51 (3H, d, J 6.8, C(a)Me), 2.14 (1H, dd, J 15.3, 2.9, C(2)HA), 2.26
(1H, dd, J 15.3, 10.1, C(2)HB), 3.43 (1H, dd, J 9.9, 5.6, C(6)HA), 3.52
(1H, dd, J 9.9, 6.1, C(6)HB), 3.72–3.80 (1H, m, C(3)H), 3.78 (1H, d,
J 14.2, NCHAHBPh), 3.93 (1H, d, J 14.2, NCHAHBPh), 4.12–4.17 (1H,
½
a 2D5
ꢂ
¼ þ34:7 (c 1.0 in CHCl3); mmax (film) 2978, 2955, 2932, 2884,
2857 (C–H), 1729 (C@O); dH (400 MHz, CDCl3) 0.16 (6H, s, SiMe2),
m, C(5)H), 4.21 (1H, q, J 6.8, C(
C(4)H), 4.39 (1H, d, J 12.1, OCHAHBPh), 4.53 (1H, d, J 12.1, OCHAHBPh),
7.13–7.47 (15H, m, Ph); dC (100 MHz, CDCl3) 20.0 (C( )Me), 25.6
(MeCMe), 28.1 (CMe3), 28.4 (MeCMe), 37.6 (C(2)), 51.3 (NCH2Ph),
52.9 (C(3)), 59.6 (C( )), 69.4 (C(6)), 73.5 (OCH2Ph), 76.7 (C(5)),
a)H), 4.35 (1H, dd, J 10.4, 5.1,
0.98 (9H, s, SiCMe3), 1.12 (3H, s, MeCMe), 1.34 (3H, s, MeCMe),
1.39 (3H, d, J 7.1, C(a)Me), 1.56 (9H, s, OCMe3), 2.27 (1H, dd, J
a
15.4, 3.8, C(2)HA), 2.55 (1H, dd, J 15.4, 9.1, C(2)HB), 3.54 (1H, dd,
J 6.7, 2.7, C(4)H), 3.56 (1H, d, J 15.2, NCHAHBPh), 3.68 (1H, dd, J
10.7, 6.7, C(6)HA), 3.74 (1H, dd, J 10.7, 5.3, C(6)HB), 3.82 (1H, q, J
a
79.0 (C(4)), 80.2 (CMe3), 108.2 (CMe2), 126.4, 127.6, 127.7 (p-Ph),
127.8, 128.0, 128.3, 129.1 (o,m-Ph), 138.0, 141.6, 146.3 (i-Ph),
170.7 (C(1)); m/z (ESI+) 560 ([M+H]+, 100%); HRMS (ESI+)
7.1, C(
(1H, d, J 15.2, NCHAHBPh), 7.23–7.50 (10H, m, Ph); dC (100 MHz,
CDCl3) –5.1 (SiMe2), 18.7 (SiCMe3), 19.4 (C( )Me), 24.5 (MeCMe),
26.2 (SiCMe3), 27.0 (MeCMe), 28.3 (OCMe3), 37.2 (C(2)), 50.3
(NCH2Ph), 52.5 (C(3)), 58.0 (C( )), 62.5 (C(6)), 76.9 (C(4)), 78.2
a)H), 3.82–3.88 (1H, m, C(5)H), 3.95 (1H, m, C(3)H), 4.05
a
C
35H46NOþ ([M+H]+) requires 560.3371; found 560.3373.
5
Method B: Following the general procedure, (R)-N-benzyl-N-(a-
a
methylbenzyl)amine (121 mg, 0.573 mmol) in THF (4 mL), BuLi
(2.50 M in hexanes, 0.21 mL, 0.56 mmol) and 27 (100 mg,
0.287 mmol) in THF (4 mL) at ꢀ78 °C gave a 46:37:17 mixture of
31:40:41. Purification via flash column chromatography (eluent
30-40 °C petrol/Et2O, 10:1) gave 40 as a colourless oil (46 mg,
29%, >99:1 dr). Further elution gave a 70:30 mixture of 31:41 as
a pale yellow oil (38 mg). Data for 31: dH (400 MHz, CDCl3) 1.43
(3H, s, MeCMe), 1.45 (9H, s, CMe3), 1.54 (3H, s, MeCMe), 3.01 (1H,
ddd, J 17.8, 6.7, 1.3, C(2)HA), 3.09 (1H, ddd, J 17.8, 7.2, 1.0,
C(2)HB), 3.56 (1H, dd, J 10.4, 7.3, C(6)HA), 3.62 (1H, dd, J 10.4, 3.5,
C(6)HB), 4.35–4.40 (1H, m, C(3)H), 4.59 (1H, d, J 12.3, OCHAHBPh),
4.67 (1H, d, J 12.3, OCHAHBPh), 4.82 (1H, ddd, J 7.3, 3.5, 1.5,
C(5)H), 7.12–7.46 (5H, m, Ph); dC (100 MHz, CDCl3) 25.4, 26.8
(CMe2), 28.1 (CMe3), 32.0 (C(2)), 72.4 (C(6)), 73.5 (OCH2Ph), 76.5
(C(5)), 80.3 (CMe3), 87.8 (C(3)), 111.4 (CMe2), 126.4 (p-Ph), 127.8,
128.4 (o,m-Ph), 137.9 (i-Ph), 151.2 (C(4)), 171.6 (C(1)).
(C(5)), 79.9 (OCMe3), 107.5 (CMe2), 126.6, 127.2 (p-Ph), 128.1,
128.6 (o,m-Ph), 141.5, 141.9 (i-Ph), 171.8 (C(1)); m/z (ESI+) 584
([M+H]+, 100%); HRMS (ESI+) C34H54NO5Si+ ([M+H]+) requires
584.3766; found 584.3769. Further elution gave 39 as a colourless
oil (109 mg, 12%, >99:1 dr); ½a D25
¼ ꢀ10:0 (c 1.0 in CHCl3); mmax
ꢂ
(film) 2980, 2955, 2931, 2858 (C–H), 1732 (C@O); dH (400 MHz,
CDCl3) 0.04 (3H, s, MeSiMe), 0.05 (3H, s, MeSiMe), 0.87 (9H,
s, SiCMe3), 1.42 (3H, s, MeCMe), 1.48 (3H, s, MeCMe), 1.49 (9H, s,
OCMe3), 1.51 (3H, d, J 6.8, C(a)Me), 2.19 (1H, dd, J 15.4, 9.85,
C(2)HA), 2.28 (1H, dd, J 15.4, 3.5, C(2)HB), 3.50 (1H, dd, J 10.6, 4.8,
C(6)HA), 3.75 (1H, dd, J 10.6, 7.3, C(6)HB), 3.81 (1H, d, J 14.4,
NCHAHBPh), 3.84–3.89 (1H, m, C(3)H), 3.88 (1H, d, J 14.4, NCHAHBPh),
3.95–4.01 (1H, m, C(5)H), 4.19 (1H, q, J 6.8, C(
J 10.6, 5.1, C(4)H), 7.10–7.47 (10H, m, Ph); dC (100 MHz, CDCl3)
ꢀ5.5, –5.4 (SiMe2), 18.4 (SiCMe3), 20.5 (C( )Me), 25.5 (MeCMe),
26.1 (SiCMe3), 28.2 (OCMe3), 28.5 (MeCMe), 37.7 (C(2)), 51.4
(NCH2Ph), 52.6 (C(3)), 60.9 (C( )), 62.7 (C(6)), 78.5 (C(5)), 78.9
a)H), 4.37 (1H, dd,
a
a
4.22. tert-Butyl (3R,4R,5S)-3-amino-4,5,6-trihydroxy-4,5-O-isopro-
(C(4)), 79.9 (OCMe3), 107.7 (CMe2), 126.3 (p-Ph), 127.7, 127.8,
128.0, 129.0 (o,m-Ph), 141.9, 146.7 (i-Ph), 170.7 (C(1)); m/z (ESI+)
584 ([M+H]+, 100%); HRMS (ESI+) C34H54NO5Si+ ([M+H]+) requires
584.3766; found 584.3766.
pylidenehexanoate 42
Method A (From 36): Pd(OH)2/C (50% w/w of substrate, 155 mg)
was added to a stirred solution of 36 (310 mg, 0.55 mmol, 93:7 dr)
in EtOAc (5 mL) at rt. The solution was degassed and saturated
with H2 before being left to stir under an atmosphere of H2
(1 atm) for 18 h. The reaction mixture was then filtered through
a short plug of CeliteÒ (eluent EtOAc) and the filtrate was concen-
trated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petrol/EtOAc, 1:2) gave 42 as a pale yellow oil
(124 mg, 81%, 93:7 dr).
4.21. tert-Butyl (3R,4R,5S,
-methylbenzyl)amino]-4,5-dihydroxy-4,5-O-isopropylidene-
6-benzyloxyhexanoate 40 and 41
aR)- and (3S,4R,5S,aR)-3-[N-benzyl-N-
(
a
Method A: Following the general procedure, (R)-N-benzyl-N-(a-
methylbenzyl)amine (437 mg, 2.07 mmol) in Et2O (15 mL), BuLi
(2.50 M in hexanes, 0.80 mL, 2.01 mmol) and 27 (360 mg,
1.03 mmol) in Et2O (15 mL) at ꢀ20 °C gave an 83:17 mixture of
Method B (From 40): Pd(OH)2/C (50% w/w of substrate, 63 mg)
was added to a stirred solution of 40 (126 mg, 0.23 mmol) EtOAc

S. G. Davies et al. / Tetrahedron: Asymmetry 25 (2014) 534–546
545
(5 mL) at rt. The solution was degassed and saturated with H2 be-
fore being left to stir under an atmosphere of H2 (1 atm) for 18 h.
The reaction mixture was then filtered through a short plug of Cel-
iteÒ (eluent EtOAc) and the filtrate was concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C
petrol/EtOAc, 1:2) gave 42 as a pale yellow oil (26 mg, 42%, >99:1
3.3, C(3)H), 3.53 (1H, dd, J 10.2, 3.4, C(6)HA), 3.75–3.82 (1H, m,
C(6)HB), 3.92 (1H, dd, J 9.1, 5.1, C(4)H), 4.14–4.20 (1H, m, C(5)H);
dC (100 MHz, CDCl3) ꢀ5.6 (SiMe2), 18.2 (SiCMe3), 25.5 (MeCMe),
25.9 (SiCMe3), 28.1 (MeCMe), 28.2 (OCMe3), 40.8 (C(2)), 47.4
(C(3)), 62.0 (C(6)), 77.6 (C(5)), 80.4 (OCMe3), 81.3 (C(4)), 107.8
(CMe2), 171.7 (C(1)); m/z (ESI+) 390 ([M+H]+, 100%); HRMS (ESI+)
dr); ½a 2D5
ꢂ
¼ þ20:7 (c 1.0 in CHCl3); mmax (film) 3367, 3288 (N–H,
C
19H40NO5Si+ ([M+H]+) requires 390.2670; found 390.2665.
O–H), 2983, 2935 (C–H), 1723 (C@O); dH (400 MHz, CDCl3) 1.29
(3H, s, MeCMe), 1.35 (3H, s, MeCMe), 1.43 (9H, s, CMe3), 2.29 (1H,
dd, J 16.8, 9.4, C(2)HA), 2.75 (1H, dd, J 16.8, 2.8, C(2)HB), 3.36 (1H,
app td, J 9.4, 2.8, C(3)H), 3.53 (3H, br s, NH2, OH), 3.63 (1H, dd, J
11.5, 3.9, C(6)HA), 3.73 (1H, dd, J 11.5, 9.9, C(6)HB), 3.97 (1H, dd, J
9.4, 5.8, C(4)H), 4.32–4.39 (1H, m, C(5)H); dC (100 MHz, CDCl3)
25.1, 27.7 (CMe2), 28.1 (CMe3), 41.0 (C(2)), 48.1 (C(3)), 60.3 (C(6)),
77.6 (C(5)), 79.3 (C(4)), 81.2 (CMe3), 108.2 (CMe2), 171.5 (C(1));
m/z (ESI+) 276 ([M+H]+, 100%); HRMS (ESI+) C13H26NO+5 ([M+H]+)
requires 276.1805; found 276.1799.
Method B (From 38): Pd(OH)2/C (50% w/w of substrate, 70 mg)
was added to a stirred solution of 38 (140 mg, 0.24 mmol) in EtOAc
(5 mL) at rt. The solution was degassed and saturated with H2
before being left to stir under an atmosphere of H2 (1 atm) for
18 h. The reaction mixture was then filtered through a short plug
of CeliteÒ (eluent EtOAc) and the filtrate was concentrated in vacuo
to give 44 as a pale yellow oil (83 mg, 89%, >99:1 dr).
4.25. tert-Butyl (3R,4R,5S)-3-N-isopropylamino-4,5-dihydroxy-
4,5-O-isopropylidene-6-(tert-butyldimethylsilyloxy)hexanoate
45
4.23. tert-Butyl (3R,4R,5S)-3-N-isopropylamino-4,5,6-trihydroxy-
4,5-O-isopropylidenehexanoate 43
Method A (From 29): Pd(OH)2/C (50% w/w of substrate, 67 mg)
was added to a stirred solution of 29 (133 mg, 0.26 mmol) in EtOAc
(5 mL) at rt. The solution was degassed and saturated with H2
before being left to stir under an atmosphere of H2 (1 atm) for
18 h. The reaction mixture was then filtered through a short plug
of CeliteÒ (eluent EtOAc) and the filtrate was concentrated in vacuo
Method A (From 32): Pd(OH)2/C (50% w/w of substrate, 93 mg)
was added to a stirred solution of 32 (185 mg, 0.37 mmol) EtOAc
(5 mL) at rt. The solution was degassed and saturated with H2
before being left to stir under an atmosphere of H2 (1 atm) for
18 h. The reaction mixture was then filtered through a short plug
of CeliteÒ (eluent EtOAc) and the filtrate was concentrated in vacuo
to give 43 as a pale yellow oil (118 mg, quant, >99:1 dr);
to give 45 as a pale yellow oil (72 mg, 65%, >99:1 dr); ½a D25
¼ ꢀ8:1
ꢂ
(c 1.0 in CHCl3); mmax (film) 3330 (N–H), 2960, 2932, 2858 (C–H),
1726 (C@O); dH (400 MHz, CDCl3) 0.07 (6H, app s, SiMe2), 0.89
(9H, s, SiCMe3), 0.99 (3H, d, J 5.8, MeCHMe), 1.01 (3H, d, J 6.1,
MeCHMe), 1.31 (3H, s, MeCMe), 1.41 (3H, s, MeCMe), 1.44 (9H, s,
OCMe3), 2.38 (1H, dd, J 15.4, 5.6, C(2)HA), 2.53 (1H, dd, J 15.4, 4.0,
C(2)HB), 2.86–2.97 (1H, m, CHMe2), 3.18–3.25 (1H, m, C(3)H),
3.72 (1H, dd, J 10.7, 6.4, C(6)HA), 3.95 (1H, dd, J 10.7, 4.9, C(6)HB),
4.05–4.11 (1H, m, C(4)H), 4.15–4.22 (1H, m, C(5)H); dC (100 MHz,
CDCl3) ꢀ5.3, ꢀ5.2 (SiMe2), 18.5 (SiCMe3), 22.3, 24.2 (CHMe2), 25.3
(MeCMe), 26.0 (SiCMe3), 27.5 (MeCMe), 28.1 (OCMe3), 37.2 (C(2)),
44.9 (CHMe2), 51.2 (C(3)), 62.3 (C(6)), 78.4, 78.5 (C(4), C(5)), 80.2
(OCMe3), 107.8 (CMe2), 171.7 (C(1)); m/z (ESI+) 432 ([M+H]+,
100%); HRMS (ESI+) C22H46NO5Si+ ([M+H]+) requires 432.3140;
found 432.3134.
½
a 2D5
ꢂ
¼ ꢀ4:5 (c 1.0 in CHCl3); mmax (film) 3261 (N–H, O–H), 2978,
2935, 2876 (C–H), 1726 (C@O); dH (400 MHz, CDCl3) 1.10 (6H, d,
J 6.1, CHMe2), 1.30 (3H, s, MeCMe), 1.35 (3H, s, MeCMe), 1.43
(9H, s, CMe3), 2.56 (1H, dd, J 16.5, 3.9, C(2)HA), 2.69 (1H, dd, J
16.5, 4.6, C(2)HB), 2.99–3.09 (1H, m, CHMe2), 3.33 (1H, app dt, J
9.9, 4.4, C(3)H), 3.66 (1H, dd, J 11.6, 9.1, C(6)HA), 3.69 (1H, dd,
J 11.6, 5.1, C(6)HB), 4.18 (1H, dd, J 9.9, 5.7, C(4)H), 4.40 (1H, app
dt, J 9.1, 5.7, C(5)H); dC (100 MHz, CDCl3) 20.0, 23.9 (CHMe2),
25.1, 27.7 (CMe2), 28.1 (CMe3), 34.1 (C(2)), 44.9 (CHMe2), 50.9
(C(3)), 60.0 (C(6)), 77.4 (C(5)), 78.1 (C(4)), 81.0 (CMe3), 108.1
(CMe2), 171.1 (C(1)); m/z (ESI+) 318 ([M+H]+, 100%); HRMS (ESI+)
C
16H32NOþ ([M+H]+) requires 318.2275; found 318.2270.
5
Method B (From 42): Acetone (51
l
L, 0.69 mmol) and NaBH3CN
Method B (From 43): Imidazole (37 mg, 0.54 mmol), DMAP
(1 mg, cat.) and TBDMSCl (27 mg, 0.18 mmol) were sequentially
added to a solution of 43 (57 mg, 0.18 mmol) in CH2Cl2 (1.5 mL)
at rt and the resultant solution was stirred at rt for 16 h. The reac-
tion mixture was then concentrated in vacuo. The residue was dis-
solved in Et2O (10 mL) and the resultant solution was washed with
1.0 M aq HCl (10 mL), then dried and concentrated in vacuo. Purifi-
cation via flash column chromatography (eluent 30–40 °C petrol/
Et2O, 2:1) gave 45 as a pale yellow oil (45 mg, 58%, >99:1 dr).
(87 mg, 1.4 mmol) were added sequentially to a solution of 42
(95 mg, 0.35 mmol) in MeOH (3 mL) at rt. The resultant solution
was stirred at rt for 18 h and then concentrated in vacuo. The res-
idue was partitioned between CH2Cl2 (5 mL) and H2O (5 mL) and
the aqueous layer was extracted with CH2Cl2 (2 ꢃ 5 mL). The com-
bined organic extracts were then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C
petrol/EtOAc, 3:1) gave 43 as a pale yellow oil (67 mg, 61%, >99:1
dr).
Method C (From 44): Acetone (25 lL, 0.33 mmol) and NaBH3CN
(42 mg, 0.67 mmol) were added sequentially to a solution of 44
(65 mg, 0.17 mmol) in MeOH (3 mL) at rt. The resultant solution
was stirred at rt for 18 h and then concentrated in vacuo. The res-
idue was partitioned between CH2Cl2 (5 mL) and H2O (5 mL) and
the aqueous layer was extracted with CH2Cl2 (2 ꢃ 5 mL). The com-
bined organic extracts were then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C
petrol/Et2O) gave 45 as a pale yellow oil (45 mg, 62%, >99:1 dr).
4.24. tert-Butyl (3R,4R,5S)-3-amino-4,5-dihydroxy-4,5-O-isopro-
pylidene-6-(tert-butyldimethylsilyloxy)hexanoate 44
Method A (From 34): Pd(OH)2/C (50% w/w of substrate, 45 mg)
was added to a stirred solution of 34 (89 mg, 0.15 mmol) in EtOAc
(5 mL) at rt. The solution was degassed and saturated with H2 be-
fore being left to stir under an atmosphere of H2 (1 atm) for 18 h.
The reaction mixture was then filtered through a short plug of Cel-
iteÒ (eluent EtOAc) and the filtrate was concentrated in vacuo to
References
give 44 as a pale yellow oil (38 mg, 64%, >99:1 dr); ½a D25
¼ ꢀ6:7
ꢂ
(c 1.0 in CHCl3); mmax (film) 3320 (N–H), 2982, 2956, 2933, 2859
(C–H), 1728 (C@O); dH (400 MHz, CDCl3) 0.08 (6H, app s, SiMe2),
0.89 (9H, s, SiCMe3), 1.29 (3H, s, MeCMe), 1.34 (3H, s, MeCMe),
1.45 (9H, s, OCMe3), 1.81 (2H, br s, NH2), 2.27 (1H, dd, J 15.9, 9.1,
C(2)HA), 2.72 (1H, dd, J 15.9, 3.3, C(2)HB), 3.40 (1H, app td, J 9.1,
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