Asymmetric syntheses of methyl N-Boc-2-deoxy-2-amino-l-erythroside, methyl N-Boc-2-deoxy-2-amino-d-threoside and methyl N-Boc-2,3-dideoxy-3-amino-l- arabinopyranoside

Article abstract of DOI:10.1016/j.tet.2014.03.055

The asymmetric syntheses of methyl N-Boc-2-deoxy-2-amino-l-erythroside and methyl N-Boc-2-deoxy-2-amino-d-threoside have been achieved from sorbic acid, in six and eight steps, and in 35 and 13% overall yield, respectively. Diastereoselective aminohydroxy

Full text of DOI:10.1016/j.tet.2014.03.055

Tetrahedron 70 (2014) 3491e3501
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric syntheses of methyl N-Boc-2-deoxy-2-amino- -
L
erythroside, methyl N-Boc-2-deoxy-2-amino-
D-threoside
and methyl N-Boc-2,3-dideoxy-3-amino-
L
-arabinopyranoside
*
Marta Brambilla, Stephen G. Davies , Ai M. Fletcher, Li Hao, Linlu Lv, Paul M. Roberts,
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric syntheses of methyl N-Boc-2-deoxy-2-amino-L-erythroside and methyl N-Boc-2-deoxy-
Received 13 January 2014
Received in revised form 3 March 2014
Accepted 17 March 2014
2-amino-
overall yield, respectively. Diastereoselective aminohydroxylation of tert-butyl sorbate gives access to
two diastereoisomeric -hydroxy- -amino- -unsaturated esters. Reduction of the ester functionality
and ozonolysis of the double bond gives the corresponding aldehyde, which exists exclusively in the
ring-closed (furanose) form. An alternative synthesis of methyl N-Boc-2-deoxy-2-amino- -erythroside
was also developed, reliant on aminohydroxylation of an -unsaturated ester bearing an acetal func-
tionality at the -position, and this synthesis proceeded in five steps and 54% overall yield from acrolein
diethyl acetal. This approach was extended to permit the synthesis of methyl N-Boc-2,3-dideoxy-3-
D-threoside have been achieved from sorbic acid, in six and eight steps, and in 35 and 13%
a
b
g,d
Available online 22 March 2014
L
Keywords:
Amino sugar
Asymmetric synthesis
Conjugate addition
Lithium amide
a,b
g
amino-L-arabinopyranoside in six steps and 58% overall yield from ethyl 3,3-diethoxypropanote.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
diastereoselective ammonium-directed epoxidation9e12 of 5 gave
epoxide 6, which upon regioselective ring-opening, lactonisation,
Amino sugar moieties (analogues of monosaccharides in which
one of the hydroxyl functionalities has been formally exchanged for
an amino functionality) are prevalent as the glycosidic fragments in
both naturally occurring and synthetic molecules with highly de-
sirable biological activity, for example, antibacterial, antiviral and
anticancer.1 As such, there have been significant efforts from the
synthetic community directed towards the development of effi-
cient approaches to this class of compound.2 Within this area, we
have explored the oxidative functionalisation of the olefin within
reduction and deprotection gave D-3-epi-daunosamine, isolated as
its N,O-diacetyl protected methyl glycoside 10 (Scheme 1).6
We envisaged that this concept could be adapted to enable the
preparation of the 2-deoxy-2-aminotetroses (2-deoxy-2-amino-
L-
erythrose 19 and 2-deoxy-2-amino- -threose 20) using ozonolysis
D
(rather than dihydroxylation or epoxidation) of the C]C bond.
Thus, it was anticipated that reduction of the ester functionality
within either the anti- or syn-diastereoisomer of an alkyl 2-
hydroxy-3-[N-benzyl-N-(a-methylbenzyl)amino]hex-4-enoate 12
a
range of alkyl 3-[N-benzyl-N-(
a
-methylbenzyl)amino]hex-4-
would permit subsequent oxidative cleavage of the C]C bond
within 13 to give the corresponding aldehyde 17, which should
undergo spontaneous cyclisation to the corresponding furanoside
enoates as an efficient method for the preparation of a range of
amino hexoses.3e6 The requisite substrates for these studies are
readily accessible via our conjugate addition methodology, using
18. Alternatively, we anticipated
approach to these compounds involving conjugate addition of
enantiopure lithium N-benzyl-N-( -methylbenzyl)amide to an
unsaturated ester 14 (bearing an acetal functionality at the
sition), with enolate oxidation using CSO as one of the key steps to
give access to the anti- and syn- -hydroxy- -amino ester di-
a complementary synthetic
either antipode of lithium N-benzyl-N-(a-methylbenzyl)amide as
an enantiopure ammonia equivalent.7 Subsequently, for example,
treatment of 1 with OsO4 under Upjohn conditions8 proceeded
under steric control to give diol 2, which upon lactonisation, re-
a
a,b-
g
-po-
duction and deprotection gave
L-ristosamine, isolated as its
a
b
N,O-diacetyl protected methyl glycoside 4. Meanwhile,
astereoisomers 15, with subsequent hydrolysis giving the corre-
sponding furanoside 18 directly (Fig. 1). We report herein the
results of our investigations into the development of these two
approaches, which culminate in the formation of 2-deoxy-2-
amino-
L
-erythrose 19 and 2-deoxy-2-amino- -threose 20 in
D
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.055

3492
M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
Scheme 1. Reagents and conditions: (i) OsO4, NMO, THF, H2O, rt, 16 h; (ii) F3CCO2H, CH2Cl2, rt, 12 h; (iii) F3CCO2H, F3CCO3H, CH2Cl2, rt, 16 h; (iv) H2SO4 (concd aq), 1,4-dioxane, H2O,
rt, 12 h; (v) Boc2O, H2, Pd(OH)2/C, MeOH, rt, 48 h; (vi) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 30 min; (vii) HCl, MeOH, rt, 16 h; (viii) Ac2O, pyridine, DMAP, rt, 12 h.
Fig. 1. Proposed synthesis of the 2-deoxy-2-aminotetroses 2-deoxy-2-amino-L-erythrose 19 and 2-deoxy-2-amino-D-threose 20.
protected form.13 The extension of this methodology to enable an
Conjugate addition of lithium (R)-N-benzyl-N-(a-methylbenzyl)-
asymmetric synthesis of 2,3-dideoxy-3-amino-
tected form is also delineated.
L-arabinose in pro-
amide to 22 and either in situ enolate protonation [using NH4Cl
(satd aq)]7 or oxidation [using (ꢀ)-camphorsulfonyloxaziridine,
(ꢀ)-CSO]7,15 gave the known
b-amino ester (3S,a
R)-233e5,16,17 and
2. Results and discussion
the known anti-a-hydroxy-b
-amino ester (R,R,R)-244,18 in 80% iso-
lated yield and 98:2 dr, and 69% isolated yield and >99:1 dr, re-
spectively. Reduction of the ester functionalities within both 23 and
24 using LiAlH4 delivered the corresponding primary alcohols 2516
and 2618 in 90% isolated yield in both cases, and in 98:2 dr and
>99:1 dr, respectively (Scheme 2).
The requisite a-hydroxy-b-amino ester substrates for these in-
vestigations were first prepared. Esterification of commercially
available sorbic acid 21 was achieved under standard conditions
(isobutylene/H2SO4)14 to give tert-butyl sorbate 22 in 81% yield.

M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
3493
complete conversion to methyl glycoside 35 (95:5 anomeric mix-
ture), which was isolated in 85% yield. The relative configuration at
the anomeric stereocentre within methyl glycoside 35 was assigned
on the basis of 1H NMR NOE analysis (Scheme 4).
Scheme 2. Reagents and conditions: (i) isobutylene, H2SO4 (concd aq), CH2Cl2, 0 ꢁC,
1 h, then rt, 48 h; (ii) lithium (R)-N-benzyl-N-(
a
-methylbenzyl)amide, THF, ꢀ78 ꢁC, 2 h,
then NH4Cl (satd aq), ꢀ78 ꢁC to rt, 15 min; (iii) lithium (R)-N-benzyl-N-(
a-methyl-
benzyl)amide, THF, ꢀ78 ꢁC, 2 h, then (ꢀ)-CSO, ꢀ78 ꢁC to rt, 12 h; (iv) LiAlH4, THF, 0 ꢁ
C
to rt, 16 h.
Cross-metathesis of acrolein diethyl acetal 27 with tert-butyl
acrylate gave 28 (3J2,3¼15.9 Hz) as a single diastereoisomer, which
was isolated in 90% yield. Conjugate addition of lithium (R)-N-
benzyl-N-(
ester 29 in 99:1 dr, which was isolated in 87% yield. The amino-
hydroxylation of 28 was performed, which gave -hydroxy-
amino ester 30 in 68% isolated yield and >99:1 dr. The absolute
(3S, R)-configuration within 29 and the absolute (2R,3S, R)-con-
a-methylbenzyl)amide to 28 proceeded to give b-amino
Scheme 4. Reagents and conditions: (i) HCl (2.0 M in Et2O), rt, 5 min, then evaporate
solvent; (ii) O3, CH2Cl2, MeOH, ꢀ78 ꢁC, then Me2S, ꢀ78 ꢁC to rt, 16 h; (iii) HCl (1.25 M in
MeOH), MeOH, 50 ꢁC, 16 h.
a
b-
a
a
In order to access methyl glycoside 35 from 25 directly, the
crude reaction mixture from the ozonolysis reaction was treated
with HCl in MeOH, which allowed isolation of 35 in 80% yield
(>95:5 anomeric mixture), representing an overall yield of 47% in
five steps from sorbic acid 21. However, heating 31 with HCl in
MeOH gave 35 in 97% isolated yield, representing an overall yield of
73% in four steps from acrolein diethyl acetal 27. Attempted
hydrogenolysis of 35 (>95:5 anomeric mixture) in the presence of
Pd(OH)2/C followed by filtration of the crude reaction mixture
through CeliteÒ resulted in only low mass return of a species, which
produced a broad and unintelligible 1H NMR spectrum. However,
repetition of the hydrogenolysis experiment but in the presence of
Boc2O gave the corresponding N-Boc protected methyl glycoside 36
(>95:5 anomeric mixture) in 90% yield (Scheme 5).
figuration within 30 were assigned from the established
stereochemical outcomes of these hydroamination7,19 and amino-
hydroxylation7,15 reactions applied to a range of achiral
a,b-un-
saturated esters. Reduction of 29 and 30 using LiAlH4 gave the
corresponding primary alcohols 31 and 32 in 96 and 98% isolated
yield, and in 96:4 dr and >99:1 dr, respectively (Scheme 3).
Scheme 3. Reagents and conditions: (i) tert-butyl acrylate, HoveydaeGrubbs II, CH2Cl2,
reflux, 22 h; (ii) lithium (R)-N-benzyl-N-(
a
-methylbenzyl)amide, THF, ꢀ78 ꢁC, 2 h, then
NH4Cl (satd aq), ꢀ78 ꢁC to rt, 15 min; (iii) lithium (R)-N-benzyl-N-(
a-methylbenzyl)-
amide, THF, ꢀ78 ꢁC, 2 h, then (ꢀ)-CSO, ꢀ78 ꢁC to rt, 12 h; (iv) LiAlH4, THF, 0 ꢁC to rt, 16 h.
The behaviour of substrates 25 and 31 (lacking the hydroxyl
group) towards the proposed oxidation and hydrolysis procedures,
respectively, was examined to delineate efficient experimental
protocols. Ozonolysis of 25 was investigated first. In order to pre-
vent competing oxidation of the nitrogen atom, 25 was initially
converted to the corresponding HCl salt upon treatment with 2.0 M
HCl in Et2O, and a solution of 25$HCl in MeOH was then subjected
to O3 then Me2S to give an 85:15 mixture of furanoside 34 (64:36
anomeric mixture) and the corresponding methyl glycoside 35
(95:5 anomeric mixture). Purification allowed isolation of 34 in 45%
yield and 35 in 8% yield. Methyl glycoside 35 presumably arises
from interception of the intermediate aldehyde 33$HCl and/or fu-
ranoside 34$HCl by the methanol solvent. Heating 34 (64:36
anomeric mixture) with HCl in MeOH at 50 ꢁC for 16 h gave
Scheme 5. Reagents and conditions: (i) HCl (2.0 M in Et2O), rt, 5 min, then evaporate
solvent; (ii) O3, CH2Cl2, MeOH, ꢀ78 ꢁC, then Me2S, ꢀ78 ꢁC to rt, 16 h; (iii) HCl (1.25 M in
MeOH), 50 ꢁC, 16 h; (iv) Boc2O, H2 (5 atm), Pd(OH)2/C, MeOH, 24 h, rt.
These conditions were next applied to the synthesis of 2-deoxy-
2-amino- -erythrose 19 (in protected form). This amino sugar has
L
previously been isolated from Agaricus biosporus (the common
mushroom).13,20 Reaction of 26 under the optimised conditions for

3494
M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
ozonolysis and methyl glycoside formation delivered 37 (87:13
anomeric mixture), which was isolated in 76% yield. Meanwhile,
methanolysis of 32 gave 37 (87:13 anomeric mixture) in 97% yield.
Subsequent hydrogenolysis of 37 in the presence of Boc2O gave
Reduction of syn-a-hydroxy-b-amino ester 40 with LiAlH4 gave
primary alcohol 43 in 75% yield and >99:1 dr, with ozonolysis and
methanolysis giving methyl glycoside 44 (92:8 anomeric mixture)
in 91% yield. Subsequent hydrogenolysis of 44 in the presence of
methyl
N-Boc-2-deoxy-2-amino-
b-
L-erythroside
38
(87:13
Boc2O gave methyl N-Boc-2-deoxy-2-amino-a-D-threoside 45 (92:8
anomeric mixture), which was isolated in 92% yield (>95:5
anomeric mixture). The relative configurations at the anomeric
stereocentres within methyl glycosides 37 and 38 were assigned on
the basis of 1H NMR NOE analyses (Scheme 6).
anomeric mixture), which was isolated in 54% yield (>95:5
anomeric mixture). The relative configurations at the anomeric
stereocentres within methyl glycosides 44 and 45 were assigned on
the basis of 1H NMR NOE analyses (Scheme 8).
Scheme 6. Reagents and conditions: (i) HCl (2.0 M in Et2O), rt, 5 min, then evaporate
solvent; (ii) O3, CH2Cl2, MeOH, ꢀ78 ꢁC, then Me2S, ꢀ78 ꢁC to rt, 16 h; (iii) HCl (1.25 M in
MeOH), 50 ꢁC, 16 h; (iv) Boc2O, H2 (5 atm), Pd(OH)2/C, MeOH, 24 h, rt.
Scheme 8. Reagents and conditions: (i) LiAlH4, THF, 0 ꢁC to rt, 16 h; (ii) HCl (2.0 M in
Et2O), rt, 5 min, then evaporate solvent; (iii) O3, CH2Cl2, MeOH, ꢀ78 ꢁC, then Me2S,
ꢀ78 ꢁC to rt, 16 h; (iv) HCl (1.25 M in MeOH), 50 ꢁC, 16 h; (v) Boc2O, H2 (5 atm),
Pd(OH)2/C, MeOH, 24 h, rt.
With an efficient synthesis of 38 (a protected form of 2-deoxy-2-
amino-
development of a synthesis of the diastereoisomer, 2-deoxy-2-
amino- -threose 20. An oxidation/diastereoselective reduction
protocol was investigated to effect epimerisation of the hydroxyl-
L
-erythrose 19) in hand, investigations turned towards the
This methodology was next extended to facilitate the asym-
metric synthesis of a representative 2,3-dideoxy-3-aminopentose.
Reduction of ethyl 3,3-diethoxypropanoate 46 with DIBAL-H gave
the corresponding aldehyde, which was olefinated using
D
bearing stereocentre within anti-a-hydroxy-b
-amino ester 24.21,22
Ph3P]CHCO2tBu to give
a
,b
-unsaturated ester 47 (3J2,3¼15.7 Hz) in
Following our previously reported protocol,21,22 Swern oxidation
91% yield and >99:1 dr. Conjugate addition of lithium (R)-N-ben-
zyl-N-(a-methylbenzyl)amide to 47 gave b-amino ester 48 in 99:1
dr, isolated in 91% yield. The absolute (R,R)-configuration within 48
was assigned from the well-established stereochemical outcome of
this type of conjugate addition reaction.7,19 Aminohydroxylation of
of 24 gave complete conversion to the corresponding ketone 39,
with treatment of 39 with NaBH4 in MeOH at ꢀ20 ꢁC giving syn-
a
-
hydroxy-b-amino ester 40 in >99:1 dr and 65% isolated yield. In-
terestingly, under identical conditions, Swern oxidation of 30 pro-
ceeded to give ketone 41 in complete conversion, although
subsequent reduction with NaBH4 gave a 77:23 mixture of 30
and 42, respectively. A brief screen of a range of reducing agents
[DIBAL-H, LiAlH4, LiBH4, LiAl(OtBu)3H] resulted in analogous dia-
47 upon conjugate addition of lithium (R)-N-benzyl-N-(
benzyl)amide followed by in situ enolate oxidation using (ꢀ)-CSO
gave -hydroxy- -amino ester 49 in 77% yield and 92:8 dr. The
a-methyl-
a
b
absolute (R,R,R)-configuration within 49 was assigned by analogy to
the well-established stereochemical outcome of this amino-
hydroxylation procedure.7,15 Given that the lithium amide exerts
stereoselectivity, and anti-a-hydroxy-b-amino ester 30 was formed
either preferentially or exclusively [82:18 dr using DIBAL-H; >99:1
dr using LiAlH4,23 LiBH4 and LiAl(OtBu)3H] (Scheme 7).
Scheme 7. Reagents and conditions: (i) (COCl)2, DMSO, CH2Cl2, ꢀ78 ꢁC, 35 min, then Et3N, ꢀ78 ꢁC to rt, 30 min; (ii) NaBH4, MeOH, ꢀ20 ꢁC, 2 h.

M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
3495
total control upon formation of the C(3)-stereogenic centre within
48, and that 48 and 49 are formed from protonation or oxidation,
respectively, of the same intermediate lithium -amino enolate, the
Boc-2-deoxy-2-amino-
b
-
L
-erythroside was also prepared from
acrolein diethyl acetal, employing hydrolysis of the acetal func-
tionality, in five steps and 54% overall yield. This approach also
proved amenable to the synthesis of methyl N-Boc-2,3-dideoxy-3-
amino-b-L-arabinopyranoside from ethyl 3,3-diethoxypropanote,
in six steps and 58% overall yield.
b
minor diastereoisomer resulting from the aminohydroxylation re-
action was assigned as being epimeric at C(2). Reduction of 49 with
LiAlH4 gave primary alcohol 50 in 98% yield and 92:8 dr, and
methanolysis of 50 gave methyl glycoside 51 in 94% yield and 92:8
dr. The identical diastereoisomeric ratios of the primary alcohol
starting material 50 and methyl glycoside product 51 of this
transformation indicate that the anomeric stereocentre is formed
with total control for both the major and minor diastereoisomers in
this system. The relative configuration at the anomeric stereocentre
within the major diastereoisomer 51 was assigned with the aid of
1H NMR 3J coupling constant analysis. Subsequent hydrogenolysis
of 51 in the presence of Boc2O gave methyl N-Boc-2,3-dideoxy-3-
4. Experimental section
4.1. General experimental details
All reactions involving organometallic or other moisture-
sensitive reagents were carried out under a nitrogen or argon
atmosphere using standard vacuum line techniques and glassware
that was flame dried and cooled under nitrogen before use. Sol-
vents were dried according to the procedure outlined by Grubbs
and co-workers.24 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.
amino-b-L-arabinopyranoside 52 in 90% yield and >95:5 dr
(Scheme 9).
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 charac-
teristic peaks are reported in cmꢀ1. NMR spectra were recorded in
the deuterated solvent stated. The field was locked by external
referencing to the relevant deuteron resonance. 1He1H COSY and
1He13C HSQC analyses were used to establish atom connectivity.
4.2. tert-Butyl (E,E)-hexa-2,4-dienoate [tert-butyl sorbate] 22
Condensed isobutylene (60 mL) at ꢀ78 ꢁC was added to a stirred
solution of sorbic acid 21 (10.0 g, 89.3 mmol) and concd aq H2SO4
(1.00 mL) in CH2Cl2 (200 mL) at 0 ꢁC and the resultant mixture was
stirred at 0 ꢁC for 1 h. The reaction mixture was then allowed to
warm to rt and stirred at rt for 48 h. The reaction mixture was
washed with satd aq NaHCO3 (5ꢂ100 mL) and the combined
aqueous washings were extracted with CH2Cl2 (2ꢂ100 mL). The
combined organic extracts were washed with brine (100 mL), then
dried and concentrated in vacuo to give 22 as a colourless oil
(12.0 g, 81%);3e5,16,17 dH (400 MHz, CDCl3) 1.44 (9H, s, CMe3), 1.80
(3H, d, J 6.0, C(6)H3), 5.66 (1H, d, J 15.4, C(2)H), 6.01e6.16 (2H, m,
C(4)H, C(5)H), 7.14 (1H, dd, J 15.4, 10.2, C(3)H).
Scheme 9. Reagents and conditions: (i) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 50 min; (ii)
Ph3P]CHCO2tBu; rt, 16 h; (iii) lithium (R)-N-benzyl-N-(
a-methylbenzyl)amide, THF,
ꢀ78 ꢁC, 2 h, then NH4Cl (satd aq), ꢀ78 ꢁC to rt, 15 min; (iv) lithium (R)-N-benzyl-N-(
a-
methylbenzyl)amide, THF, ꢀ78 ꢁC, 2 h, then (ꢀ)-CSO, ꢀ78 ꢁC to rt, 12 h; (v) LiAlH4,
THF, 0 ꢁC to rt, 16 h; (vi) HCl (1.25 M in MeOH), 50 ꢁC, 16 h; (vii) Boc2O, H2 (5 atm),
Pd(OH)2/C, MeOH, 24 h, rt.
4.3. tert-Butyl (3S,
aR,E)-3-[N-benzyl-N-(a-methylbenzyl)
amino]hex-4-enoate 23
n-BuLi (2.5 M in hexanes, 15.0 mL, 37.5 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)-
3. Conclusion
a
amine (8.04 g, 38.1 mmol) in THF (120 mL) at ꢀ78 ꢁC, and the
resultant mixture was stirred at ꢀ78 ꢁC for 30 min. A solution of 22
(4.00 g, 23.8 mmol) in THF (80 mL) was then added via cannula and
the resultant mixture was stirred at ꢀ78 ꢁC for 2 h. Satd aq NH4Cl
(20 mL) was then added and the reaction mixture was allowed to
warm to rt over 15 min, then partitioned between Et2O (100 mL)
and H2O (100 mL). The aqueous layer was extracted with Et2O
(3ꢂ100 mL) and the combined organic extracts were washed se-
quentially with 10% aq citric acid (500 mL), satd aq NaHCO3
(500 mL) and brine (500 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 20:1) gave 23 as a pale yellow oil (7.22 g, 80%, 98:2
In conclusion, efficient asymmetric syntheses of the di-
astereoisomeric 2-deoxy-2-aminotetroses and a representative
2,3-dideoxy-3-aminopentose (in protected form) have been rapidly
achieved from
our diastereoselective procedure for aminohydroxylation of an
unsaturated ester) bearing either a -C]C bond or an acetal
functionality at the -position. In both cases these functionalities
a-hydroxy-b-amino esters (readily prepared using
a,b-
g,d
g
can be used to generate an aldehyde functional group, via either
ozonolysis in the former case or hydrolysis in the latter case. Thus,
methyl N-Boc-2-deoxy-2-amino-
Boc-2-deoxy-2-amino- -threoside were both prepared from
sorbic acid, employing ozonolysis of the -C]C bond, in six and
eight steps, and in 35 and 13% overall yield, respectively. Methyl N-
b-L-erythroside and methyl N-
a-D
25
24
g
,d
dr);3e5,16,17
[
a
]
D
ꢀ22.2 (c 2.0 in CHCl3); {lit. [
a
]
D
ꢀ23.3 (c 2.04 in
CHCl3)}; dH (400 MHz, CDCl3) 1.37 (9H, s, CMe3), 1.38 (3H, d, J 6.8,

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M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
C(
a
)Me), 1.70 (3H, d, J 4.6, C(6)H3), 2.22 (1H, dd, J 14.2, 9.2, C(2)HA),
chromatography (eluent 30e40 ꢁC petrol/Et2O, 2:1) gave 26 as
2.35 (1H, dd, J 14.2, 5.5, C(2)HB), 3.66 (2H, app s, NCH2Ph),
3.73e3.78 (1H, m, C(3)H), 4.01 (1H, q, J 6.8, C(
m, C(4)H, C(5)H), 7.17e7.39 (10H, m, Ph).
a colourless oil (1.10 g, 90%, >99:1 dr);18
[
a]
25 ꢀ49.4 (c 1.0 in CHCl3);
D
a
)H), 5.52e5.54 (2H,
{lit.18
6.7, C(
[
a
a
]
22 ꢀ48.7 (c 1.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.42 (3H, d, J
D
)Me), 1.83 (3H, d, J 4.8, C(6)H3), 3.20 (1H, br s, C(3)H), 3.44
(2H, app d, J 5.0, C(1)H2), 3.60 (1H, ddd, J 9.9, 5.4, 4.5, C(2)H), 3.62
(1H, br s, OH), 3.70 (1H, d, J 13.7, NCHAHBPh), 3.93 (1H, d, J 13.7,
4.4. tert-Butyl (R,R,R,E)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]hex-4-enoate 24
NCHAHBPh), 4.04e4.13 (1H, m, C(
C(4)H), 7.26e7.36 (10H, m, Ph).
a)H), 5.67e5.79 (2H, m, C(5)H,
n-BuLi (2.5 M in hexanes, 9.22 mL, 23.1 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)
a
4.7. tert-Butyl (E)-4,4-diethoxybut-2-enoate 28
amine (5.03 g, 23.8 mmol) in THF (60 mL) at ꢀ78 ꢁC, and the re-
sultant mixture was stirred at ꢀ78 ꢁC for 30 min. A solution of 22
(2.50 g, 14.9 mmol) in THF (30 mL) was then added via cannula and
the resultant mixture was stirred at ꢀ78 ꢁC for 2 h. (ꢀ)-CSO (5.80 g,
25.3 mmol) was then added and the reaction mixture was allowed
to warm to rt over 12 h. Satd aq NH4Cl (10 mL) was then added, and
the resultant mixture was concentrated in vacuo. The residue was
dissolved in CH2Cl2 (200 mL) and the resultant solution was
washed sequentially with 10% aq citric acid (200 mL), satd aq
NaHCO3 (200 mL) and brine (200 mL), then dried and concentrated
in vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 20:1) gave 24 as a pale yellow oil (4.06 g, 69%,
HoveydaeGrubbs II catalyst (482 mg, 0.77 mmol) was added to
a degassed solution of acrolein diethyl acetal 27 (1.00 g, 7.68 mmol)
and tert-butyl acrylate (3.37 mL, 23.0 mmol) in CH2Cl2 (38 mL) and
the resultant mixture was heated at reflux for 22 h. The reaction
mixture was then concentrated in vacuo. Purification via flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 35:1) gave
28 as a colourless oil (1.59 g, 90%, >99:1 dr); nmax (ATR) 1716 (C]O),
1664 (C]C); dH (400 MHz, CDCl3) 1.23 (6H, t, J 7.2, O(CH2Me)2), 1.49
(9H, s, CMe3), 3.49e3.56 (2H, m, O(CHAHBMe)2), 3.62e3.69 (2H, m,
O(CHAHBMe)2), 5.03 (1H, dd, J 4.4, 1.4, C(4)H), 6.05 (1H, dd, J 15.9,
1.4, C(2)H), 6.72 (1H, dd, J 15.9, 4.4, C(3)H); dC (100 MHz, CDCl3) 15.1
(O(CH2Me)2), 27.9 (CMe3), 61.2 (O(CH2Me)2), 80.6 (CMe3), 99.2
(C(4)), 125.7 (C(2)), 142.2 (C(3)), 165.2 (Cþ(1)); m/z (ESIþ) 253
([MþNa]þ, 100%); HRMS (ESIþ) C12H22NaO4 ([MþNa]þ) requires
253.1410; found 253.1401.
>99:1 dr);4,18
[
a]
25 ꢀ63.1 (c 1.0 in CHCl3); {lit. [
a
]
25 ꢀ62.6 (c 1.0 in
D
D
CHCl3)}; dH (400 MHz, CDCl3) 1.34 (9H, s, CMe3), 1.37 (3H, d, J 6.8,
C(
9.1, 2.6, C(3)H), 3.76 (1H, d, J 14.4, NCHAHBPh), 3.97 (1H, d, J 14.4,
NCHAHBPh), 4.08 (1H, br s, C(2)H), 4.23 (1H, q, J 6.8, C( )H), 5.55
a)Me), 1.71 (3H, d, J 6.3, C(6)H3), 2.94 (1H, br s, OH), 3.54 (1H, dd, J
a
(1H, dq, J 15.4, 6.3, C(5)H), 5.66e5.72 (1H, m, C(4)H), 7.19e7.42
(10H, m, Ph).
4.8. tert-Butyl (3S,
amino]-4,4-diethoxybutanoate 29
aR)-3-[N-benzyl-N-(a-methylbenzyl)
4.5. (3S,
en-1-ol 25
a
R,E)-3-[N-Benzyl-N-(
a
-methylbenzyl)amino]hex-4-
n-BuLi (2.5 M in hexanes, 0.35 mL, 0.86 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)
a
amine (188 mg, 0.89 mmol) in THF (5 mL) at ꢀ78 ꢁC, and the re-
sultant mixture was stirred at ꢀ78 ꢁC for 30 min. A solution of 28
(128 mg, 0.56 mmol, >99:1 dr) in THF (5 mL) was then added via
cannula and the resultant mixture was stirred at ꢀ78 ꢁC for 2 h.
Satd aq NH4Cl (5 mL) was then added and the resultant mixture
was allowed to warm to rt over 15 min, then partitioned between
Et2O (10 mL) and H2O (10 mL). The aqueous layer was extracted
with Et2O (3ꢂ25 mL) and the combined organic extracts were
washed sequentially with 10% aq citric acid (50 mL), satd aq
NaHCO3 (50 mL) and brine (50 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent
LiAlH4 (1.0 M in THF, 7.65 mL, 7.65 mmol) was added to a stirred
solution of 23 (2.90 g, 7.65 mmol, 98:2 dr) in THF (30 mL) at 0 ꢁC,
and the resultant mixture was stirred at rt for 16 h. The reaction
mixture was then cooled to 0 ꢁC and lumps of ice (w2 g), and then
2.0 M aq NaOH solution (15 mL), were added cautiously with vig-
orous stirring being maintained throughout. The resultant mixture
was then allowed to warm to rt over 15 min, diluted with EtOAc
(90 mL), and the resultant mixture was stirred for 30 min before
being filtered through CeliteÒ (eluent EtOAc). The filtrate was then
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O, 2:1) gave 25 as
30e40 ꢁC petrol/Et2O,15:1) gave 29 as a colourless oil (214 mg, 87%,
25
a colourless oil (2.14 g, 90%, 98:2 dr);16
[a
]
25 ꢀ65.6 (c 2.7 in CHCl3);
99:1 dr); [
a
]
ꢀ33.6 (c 1.0 in CHCl3); nmax (ATR) 1724 (C]O); dH
D
D
{lit.16
[
a
]
D
24 ꢀ62.3 (c 2.73 in CHCl3)}; dH (400 MHz, CDCl3) 1.40e1.47
(400 MHz, CDCl3) 1.12 (3H, t, J 7.1, OCH2Me), 1.22 (3H, t, J 7.1,
OCH2Me), 1.41 (3H, d, J 7.1, C( )Me), 1.46 (9H, s, CMe3), 1.99 (1H, dd, J
(1H, m, C(2)HA), 1.42 (3H, d, J 7.0, C(
a
)Me), 1.75 (3H, d, J 5.9, C(6)H3),
a
1.81e1.90 (1H, m, C(2)HB), 2.73 (1H, br s, OH), 3.28e3.41 and
3.55e3.60 (3H, m, C(1)H2, C(3)H), 3.64 (1H, d, J 13.7, NCHAHBPh),
15.7, 4.3, C(2)HA), 2.33 (1H, dd, J 15.7, 7.8, C(2)HB), 3.42e3.58 (3H, m,
OCH2Me, OCHAHBMe), 3.63 (1H, d, J 14.9, NCHAHBPh), 3.72e3.80
3.90 (1H, d, J 13.7, NCHAHBPh), 4.06 (1H, q, J 7.0, C(
J 15.0, 5.9, C(5)H), 5.67 (1H, dd, J 15.0, 9.1, C(4)H), 7.22e7.37 (10H, m,
Ph).
a
)H), 5.55 (1H, dq,
(2H, m, C(3)H, OCHAHBMe), 3.93 (1H, q, J 7.1, C(
14.9, NCHAHBPh), 4.45 (1H, d, J 4.8, C(4)H), 7.22e7.44 (10H, m, Ph);
dC (100 MHz, CDCl3) 15.1, 15.4 (C(OCH2Me)2), 19.9 (C( )Me), 28.1
(CMe3), 33.5 (C(2)), 51.2 (NCH2Ph), 55.0 (C(3)), 58.6 (C( )), 62.7, 63.8
a)H), 3.99 (1H, d, J
a
a
4.6. (R,R,R,E)-3-[N-Benzyl-N-(
en-1,2-diol 26
a
-methylbenzyl)amino]hex-4-
(C(OCH2Me)2), 79.7 (CMe3), 105.8 (C(4)), 126.4, 126.8, 127.9, 128.0,
128.1, 128.2 (o,m,p-Ph), 141.9, 143.2 (i-Ph), 171.8 (C(1)); m/z (ESIþ)
442 ([MþH]þ,100%); HRMS (ESIþ) C27H40NaO4þ ([MþH]þ) requires
442.2952; found 442.2948.
LiAlH4 (1.0 M in THF, 3.80 mL, 3.80 mmol) was added to a stirred
solution of 24 (1.50 g, 3.80 mmol, >99:1 dr) in THF (15 mL) at 0 ꢁC,
and the resultant mixture was stirred at rt for 16 h. The reaction
mixture was then cooled to 0 ꢁC and lumps of ice (w1 g), and then
2.0 M aq NaOH solution (8 mL), were added cautiously with vig-
orous stirring being maintained throughout. The resultant mixture
was then allowed to warm to rt over 15 min, diluted with EtOAc
(45 mL) and the resultant mixture was stirred for a further 30 min
before being filtered through CeliteÒ (eluent EtOAc). The filtrate
was dried and concentrated in vacuo. Purification via flash column
4.9. tert-Butyl (2R,3S,
aR)-2-hydroxy-3-[N-benzyl-
N-( -methylbenzyl)amino]-4,4-diethoxybutanoate 30
a
n-BuLi (2.5 M in hexanes, 0.96 mL, 2.40 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-(a-methylbenzyl)
amine (524 mg, 2.48 mmol) in THF (10 mL) at ꢀ78 ꢁC, and the re-
sultant mixture was stirred at ꢀ78 ꢁC for 30 min. A solution of 28
(357 mg, 1.55 mmol, >99:1 dr) in THF (8 mL) was then added via

M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
3497
cannula and the resultant mixture was stirred at ꢀ78 ꢁC for 2 h.
(ꢀ)-CSO (605 mg, 2.64 mmol) was then added and the reaction
mixture was allowed to warm to rt over 12 h. Satd aq NH4Cl (5 mL)
was then added, and the resultant mixture was concentrated in
vacuo. The residue was dissolved in CH2Cl2 (20 mL) and the re-
sultant solution was washed sequentially with 10% aq citric acid
(20 mL), satd aq NaHCO3 (20 mL) and brine (20 mL), then dried and
concentrated in vacuo. Purification via flash column chromatogra-
oil (137 mg, 98%, >99:1 dr); [
3424 (OeH); dH (400 MHz, CDCl3) 1.12e1.18 (6H, m, C(OCH2Me)2),
1.31 (3H, d, J 6.9, C(a)Me), 2.87 (1H, dd, J 7.6, 2.5, C(3)H), 3.22 (1H,
dd, J 11.4, 6.1, C(1)HA), 3.39 (1H, dd, J 11.4, 3.7, C(1)HB), 3.44e3.83
(4H, m, C(OCH2Me)2), 3.84e3.87 (1H, m, C(2)H), 3.90 (1H, d, J 14.4,
a
]
25 ꢀ39.3 (c 1.0 in CHCl3); nmax (ATR)
D
NCHAHBPh), 3.98 (1H, d, J 14.4, NCHAHBPh), 4.02 (1H, q, J 6.9, C(
4.71 (1H, d, J 2.5, C(4)H), 7.14e7.29 (10H, m, Ph); dC (400 MHz,
CDCl3) 15.3, 15.4 (C(OCH2Me)2), 16.7 (C( )Me), 51.7 (NCH2Ph), 57.7
(C( )), 59.1 (C(3)), 64.5, 64.6 (C(OCH2Me)2), 65.1 (C(1)), 71.1 (C(2)),
a)H),
a
phy (eluent 30e40 ꢁC petrol/Et2O, 20:1) gave 30 as a colourless
a
25
solid (482 mg, 68%, >99:1 dr); mp 51e52 ꢁC; [
a]
ꢀ41.2 (c 1.0 in
106.1 (C(4)), 126.9, 127.2, 127.9, 128.3, 128.4, 128.6 (o,m,p-Ph), 141.2,
D
CHCl3); nmax (ATR) 1724 (C]O); dH (400 MHz, CDCl3) 1.13 (3H, t, J
7.1, OCH2Me), 1.35 (3H, t, J 7.1, OCH2Me), 1.44 (3H, d, J 6.8, C( )Me),
143.7 (i-Ph); þm/z (ESIþ) 388 ([MþH]þ, 100%); HRMS (ESIþ)
a
C
23H33NNaO4 ([MþNa]þ) requires 410.2302; found 410.2295.
1.49 (9H, s, CMe3), 3.12 (1H, d, J 4.0, OH), 3.47e3.77 (6H, m, C(2)H,
C(3)H, C(OCH2Me)2), 3.80 (1H, d, J 15.6, NCHAHBPh), 4.08 (1H, q, J
4.12. (2R,3S,
a
R)- and (2S,3S,
a
R)-3-[N-Benzyl-N-(
a
-methyl-
R)-2-
a-methylbenzyl)amino]tetrahydro-
6.8, C(
7.22e7.53 (10H, m, Ph); dC (100 MHz, CDCl3) 15.1, 15.6
(C(OCH2Me)2), 19.3 (C( )Me), 28.0 (CMe3), 51.7 (NCH2Ph), 57.6
(C( )), 60.1 (C(3)), 62.5, 65.1 (C(OCH2Me)2), 71.5 (C(2)), 82.0 (CMe3),
a)H), 4.37 (1H, d, J 15.6, NCHAHBPh), 4.71 (1H, d, J 8.1, C(4)H),
benzyl)amino]tetrahydrofuran-2-ol 34, and (2S,3S,a
methoxy-3-[N-benzyl-N-(
a
furan 35
a
102.0 (C(4)), 126.4, 126.9, 127.9, 128.0, 128.1, 128.2 (o,m,p-Ph), 141.9,
HCl (2.0 M in Et2O, 6.50 mL, 13.0 mmol) was added to a stirred
solution of 25 (570 mg, 1.84 mmol, 98:2 dr) in Et2O (14 mL) and the
resultant mixture was stirred at rt for 5 min, then concentrated in
vacuo. The residue of 25$HCl was dissolved in CH2Cl2/MeOH (v/v,
1:1, 80 mL), the resultant solution was cooled to ꢀ78 ꢁC, and O3 was
bubbled through the solution until it turned blue. O2 was then
bubbled through the solution until it turned colourless, after which
Me2S (5 mL) was added dropwise. The reaction mixture was
allowed to warm to rt over 16 h, then concentrated in vacuo. The
residue was dissolved in CH2Cl2 (50 mL) and the resultant solution
was washed with satd aq NaHCO3 (30 mL), then dried and con-
centrated in vacuo to give an 85:15 mixture of 34 (64:36 dr) and 35
(95:5 dr). Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 2:1) gave 34 as a colourless oil (247 mg, 45%,
64:36 dr); nmax (ATR) 3394 (OeH); m/z (ESIþ) 320 ([MþNa]þ, 92%),
142.5 (i-Ph), 173.7 (C(1)); m/z (ESIþ) 458 ([MþH]þ, 100%); HRMS
þ
(ESIþ) C27H39NNaO5
480.2728.
([MþNa]þ) requires 480.2720; found
4.10. (3S,aR)-3-[N-Benzyl-N-(a-methylbenzyl)amino]-
4,4-diethoxybutan-1-ol 31
LiAlH4 (1.0 M in THF, 2.72 mL, 2.72 mmol) was added to a solu-
tion of 29 (1.00 g, 2.27 mmol, >99:1 dr) in THF (10 mL) at 0 ꢁC, and
the resultant mixture was stirred at rt for 16 h. The reaction mixture
was then cooled to 0 ꢁC and lumps of ice (w1 g), and then 2.0 M aq
NaOH solution (6 mL), were added cautiously with vigorous stirring
being maintained throughout. The resultant mixture was then
allowed to warm to rt over 15 min, diluted with EtOAc (30 mL), and
the resultant mixture was stirred for a further 30 min before being
filtered through CeliteÒ (eluent EtOAc). The filtrate was then dried
and concentrated in vacuo. Purification via flash column chroma-
þ
298 ([MþH]þ, 69%); HRMS (ESIþ) C19H24NO2 ([MþH]þ) requires
298.1802; found 298.1790. Data for major anomer:25 dH (400 MHz,
CDCl3) 1.48 (3H, d, J 6.8, C(
1.89e1.97 (1H, m, C(4)HB), 3.50e3.99 (6H, m, C(3)H, C(5)H2, C(
NCH2Ph),* 5.51 (1H, d, J 1.8, C(2)H), 7.27e7.50 (10H, m, Ph);* dC
(100 MHz, CDCl3) 15.9 (C( )Me), 29.1 (C(4)), 50.8 (NCH2Ph), 57.5
(C( )), 65.5 (C(3)), 66.4 (C(5)), 100.8 (C(2)), 126.7e128.5 (o,m,p-Ph),*
141.3, 143.4 (i-Ph). Data for minor anomer:26 dH (400 MHz, CDCl3)
1.53 (3H, d, J 7.1, C( )Me),1.59e1.77 (2H, m, C(4)H2),* 3.50e3.99 (5H,
m, C(3)H, C(5)H2, NCH2Ph),* 4.17 (1H, q, J 7.1, C( )H), 5.37 (1H, d,
J 4.3, C(2)H), 7.27e7.50 (10H, m, Ph);* dC (100 MHz, CDCl3) 13.5
(C( )Me), 26.9 (C(4)), 52.9 (NCH2Ph), 57.2 (C( )),63.1 (C(3)), 65.9
a
)Me), 1.59e1.77 (1H, m, C(4)HA),*
tography (eluent 30e40 ꢁC petrol/Et2O, 2:1) gave 31 as a colourless
a
)H,
25
oil (808 mg, 96%, 96:4 dr); [
a]
ꢀ28.8 (c 1.0 in CHCl3); nmax (ATR)
D
3427 (OeH); dH (400 MHz, CDCl3) 1.16 (3H, t, J 7.1, OCH2Me), 1.24
(3H, t, J 7.1, OCH2Me), 1.39 (3H, d, J 6.8, C( )Me), 1.50e1.58 (1H, m,
a
a
a
C(2)HA), 1.74e1.82 (1H, m, C(2)HB), 2.57 (1H, br s, OH), 2.99e3.03
(1H, m, C(3)H), 3.45e3.53 (2H, m, C(1)H2), 3.61e3.68 (2H, m,
O(CHAHBMe)2), 3.75e3.82 (2H, m, O(CHAHBMe)2), 3.86 (1H, d, J
14.6, NCHAHBPh), 3.98 (1H, d, J 14.6, NCHAHBPh), 4.03 (1H, q, J 6.8,
a
a
C(
(100 MHz, CDCl3) 15.2, 15.4 (C(OCH2Me)2), 18.2 (C(
(C(2)), 51.0 (NCH2Ph), 57.3, 57.6 (C(3), C( )), 61.6 (C(1)), 63.7, 63.9
a
)H), 4.59 (1H, d, J 3.5, C(4)H), 7.23e7.39 (10H, m, Ph); dC
a
a
a)Me), 29.0
(C(5)), 96.5 (C(2)), 126.7e128.5 (o,m,p-Ph),* 140.6, 142.2 (i-Ph).
a
Further elution gave 35 as a colourless oil (46 mg, 8%, 95:5 dr);
25
(C(OCH2Me)2), 106.3 (C(4)), 126.6, 126.9, 127.7, 128.2, 128.4 (o,m,p-
[a
]
ꢀ55.7 (c 2.0 in CHCl3); nmax (ATR) 1097, 1041; dH (500 MHz,
D
Ph), 141.8, 144.2 (i-Ph); m/z (ESIþ) 394 ([MþNa]þ, 19%), 372
CDCl3) 1.41 (3H, d, J 6.9, C(a)Me), 1.63e1.70 (1H, m, C(4)HA),
þ
([MþH]þ, 100%); HRMS (ESIþ) C23H33NNaO3 ([MþNa]þ) requires
1.84e1.90 (1H, m, C(4)HB), 3.32 (3H, s, OMe), 3.47e3.51 (1H, m, C(3)
H), 3.66e3.71 (1H, m, C(5)HA), 3.79 (2H, app d, J 15.1, NCH2Ph),
394.2353; found 394.2350.
3.85e3.91 (2H, m, C(5)HB, C(
7.21e7.44 (10H, m, Ph); dC (500 MHz, CDCl3) 15.5 (C(
(C(4)), 50.6 (NCH2Ph), 54.7 (OMe), 57.5 (C( )), 64.6 (C(3)), 66.0
a
)H), 4.93 (1H, d, J 2.0, C(2)H),
4.11. (2R,3S,
4,4-diethoxybutan-1,2-diol 32
a
R)-3-[N-Benzyl-N-(
a
-methylbenzyl)amino]-
a
)Me), 29.2
a
(C(5)), 107.2 (C(2)), 126.8, 127.7, 128.0, 128.1, 128.2 (o,m,p-Ph), 141.4,
LiAlH4 (1.0 M in THF, 0.36 mL, 0.36 mmol) was added to a solu-
tion 30 (164 mg, 0.36 mmol, >99:1 dr) in THF (4 mL) at 0 ꢁC, and the
resultant mixture was stirred at rt for 16 h. The reaction mixture
was then cooled to 0 ꢁC and lumps of ice (w1 g), and then 2.0 M aq
NaOH solution (3 mL), were added cautiously with vigorous stirring
being maintained throughout. The resultant mixture was then
allowed to warm to rt over 15 min, diluted with EtOAc (10 mL), and
the resultant mixture was stirred for a further 30 min before being
filtered through CeliteÒ (eluent EtOAc). The filtrate was then dried
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/Et2O, 1:2) gave 32 as a colourless
143.3 (i-Ph); m/z (ESIþ) 312 ([MþH]þ, 81%); HRMS (ESIþ)
þ
C
20H26NO2 ([MþH]þ) requires 312.1958; found 312.1955.
4.13. (2S,3S,aR)-2-Methoxy-3-[N-benzyl-N-(a-methylbenzyl)
amino]tetrahydrofuran 35
Method A: Step 1: HCl (2.0 M in Et2O, 3.40 mL, 6.80 mmol) was
added to a stirred solution of 25 (298 mg, 0.96 mmol, 98:2 dr) in
Et2O (10 mL) and the resultant mixture was stirred at rt for 5 min,
then concentrated in vacuo. The residue of 25$HCl was dissolved in
CH2Cl2/MeOH (v/v, 1:1, 40 mL), the resultant solution was cooled to

3498
M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
ꢀ78 ꢁC, and O3 was bubbled through the solution until it turned
blue. O2 was then bubbled through the solution until it turned
colourless, after which Me2S (3 mL) was added dropwise. The re-
action mixture was allowed to warm to rt over 16 h, then concen-
trated in vacuo. The residue was dissolved in CH2Cl2 (25 mL) and
the resultant solution was washed with satd aq NaHCO3 (15 mL),
dried and concentrated in vacuo to give an 85:15 mixture of 34
(64:36 dr) and 35 (95:5 dr).
colourless, after which Me2S (3 mL) was added dropwise. The
reaction mixture was allowed to warm to rt over 16 h, then con-
centrated in vacuo. The residue was dissolved in CH2Cl2 (25 mL) and
the resultant solution was washed with satd aq NaHCO3 (15 mL),
then dried and concentrated in vacuo.
Step 2: HCl (1.25 M in MeOH, 6.00 mL, 7.50 mmol) was added to
a stirred solution of the residue from the previous step in MeOH
(5 mL), and the resultant mixture was heated at 50 ꢁC for 16 h,
before being allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in CH2Cl2 (5 mL) and the resultant solution
was washed with satd aq NaHCO3 (5 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography (el-
uent 30e40 ꢁC petrol/Et2O, 4:1) gave 37 as a colourless oil (268 mg,
76%, 87:13 dr); nmax (ATR) 3440 (OeH); m/z (ESIþ) 350 ([MþNa]þ,
Step 2: HCl (1.25 M in MeOH, 2.00 mL, 2.50 mmol) was added to
a stirred solution of the residue of 34 and 35 (179 mg) in MeOH
(5 mL), and the resultant mixture was heated at 50 ꢁC for 16 h,
before being allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in CH2Cl2 (5 mL) and the resultant solution
was washed with satd aq NaHCO3 (5 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 15:1) gave 35 as a colourless oil
þ
100%), 328 ([MþH]þ, 94%); HRMS (ESIþ) C20H26NO3 ([MþH]þ)
requires 328.1907; found 328.1900. Data for major anomer: dH
(149 mg, 80%, >95:5 dr); [
a
]
25 ꢀ56.4 (c 2.0 in CHCl3).
(400 MHz, CDCl3) 1.43 (3H, d, J 6.8, C(
C(3)H), 3.32 (3H, s, OMe), 3.83e3.97 (5H, m, C(4)H, C(5)H2,
NCH2Ph),* 4.12 (1H, q, J 6.8, C( )H), 5.12 (1H, d, J 2.2, C(2)H),
7.24e7.44 (10H, m, Ph);* dC (100 MHz, CDCl3) 12.7 (C( )Me), 51.9
(NCH2Ph), 55.1 (OMe), 56.3 (C( )), 66.6 (C(3)), 69.8, 73.1 (C(4), C(5)),
a)Me), 3.30 (1H, dd, J 5.6, 2.1,
D
Method B: HCl (1.25 M in MeOH, 0.26 mL, 0.32 mmol) was added
to a stirred solution of 31 (30 mg, 0.08 mmol, 96:4 dr) in MeOH
(1.6 mL), and the resultant mixture was heated at 50 ꢁC for 16 h,
before being allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in CH2Cl2 (3 mL) and the resultant solution
was washed with satd aq NaHCO3 (3 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography
a
a
a
104.8 (C(2)), 127.3, 127.4, 127.8, 128.4, 128.7 (o,m,p-Ph), 139.6, 141.8
(i-Ph). Data for minor anomer: dH (400 MHz, CDCl3) 1.48 (3H, d, J 7.0,
C(
m, C(4)H, C(5)H2, NCH2Ph),* 4.43 (1H, q, J 7.0, C(
3.9, C(2)H), 7.24e7.44 (10H, m, Ph);* dC (100 MHz, CDCl3) 15.2
(C( )Me), 53.3 (NCH2Ph), 54.8 (OMe), 57.6 (C( )), 68.7 (C(3)),
a
)Me), 3.00e3.02 (1H, m, C(3)H), 3.17 (3H, s, OMe), 3.83e3.97 (5H,
(eluent 30e40 ꢁC petrol/Et2O, 15:1) gave 35 as a colourless oil
a
)H), 4.81 (1H, d, J
25
(24 mg, 97%, >95:5 dr); [
a]
ꢀ58.9 (c 2.0 in CHCl3).
D
Method C: HCl (1.25 M in MeOH, 2.00 mL, 2.50 mmol) was added
to a stirred solution of 34 (200 mg, 0.67 mmol, 64:36 dr) in MeOH
(3 mL), and the resultant mixture was heated at 50 ꢁC for 16 h,
before being allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in CH2Cl2 (4 mL) and the resultant solution
was washed with satd aq NaHCO3 (4 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography
a
a
69.6, 75.3 (C(4), C(5)), 103.7 (C(2)), 126.8, 127.1, 128.0, 128.2, 128.3
(o,m,p-Ph), 141.3, 142.0 (i-Ph).
Method B: HCl (1.25 M in MeOH, 0.72 mL, 0.90 mmol) was added
to a stirred solution of 32 (87 mg, 0.22 mmol, >99:1 dr) in MeOH
(4 mL), and the resultant mixture was heated at 50 ꢁC for 16 h,
before being allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in CH2Cl2 (4 mL) and the resultant solution
was washed with satd aq NaHCO3 (3 mL), dried and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 4:1) gave 37 as a colourless oil (70 mg, 97%,
87:13 dr).
(eluent 30e40 ꢁC petrol/Et2O, 15:1) gave 35 as a colourless oil
25
(178 mg, 85%, 95:5 dr); [
a]
ꢀ56.7 (c 2.0 in CHCl3).
D
4.14. tert-Butyl (S,S)-(2-methoxytetrahydrofuran-3-yl)carba-
mate 36
A stirred solution of 35 (200 mg, 0.64 mmol, >95:5 dr) and
Boc2O (435 mg, 1.28 mmol) in MeOH (2 mL) was purged with N2 for
15 min. After this time, Pd(OH)2/C (50% w/w of 35, 100 mg) was
added and the resultant suspension was placed under H2 (5 atm),
and stirring was continued for 24 h. The resultant suspension was
filtered through CeliteÒ (eluent MeOH) and the filtrate was con-
centrated in vacuo. Purification via flash column chromatography
4.16. tert-Butyl (2S,3S,4R)-(2-methoxy-4-
hydroxytetrahydrofuran-3-yl)carbamate [methyl N-Boc-2-
deoxy-2-amino-b-L-erythroside] 38
A stirred solution of 37 (209 mg, 0.64 mmol, 87:13 dr) and Boc2O
(435 mg, 1.28 mmol) in MeOH (2 mL) was purged with N2 for
15 min. After this time, Pd(OH)2/C (50% w/w of 37, 105 mg) was
added and the resultant suspension was placed under H2 (5 atm),
and stirring was continued for 24 h. The resultant suspension was
filtered through CeliteÒ (eluent MeOH) and the filtrate was con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/EtOAc, 10:1) gave 36 as a colourless oil
25
(125 mg, 90%, >95:5 dr); [
a
]
ꢀ34.8 (c 2.1 in CHCl3); nmax (ATR)
D
3329 (NeH), 1690 (C]O); dH (500 MHz, CDCl3) 1.44 (9H, s, CMe3),
1.66e1.72 (1H, m, C(4)HA), 2.32e2.39 (1H, m, C(4)HB), 3.32 (3H, s,
OMe), 3.90e4.00 (2H, m, C(5)H2), 4.08 (1H, br s, C(3)H), 4.62 (1H, br
s, NH), 4.78 (1H, m, C(2)H); dC (125 MHz, CDCl3) 28.3 (CMe3), 30.2
(C(4)), 54.4 (OMe), 55.8 (C(3)), 65.7 (C(5)), 79.6 (CMe3), 107.8 (C(2)),
(eluent 30e40 ꢁC petrol/EtOAc, 10:1) gave 38 as a colourless oil
25
(137 mg, 92%, >95:5 dr); [
a]
ꢀ31.8 (c 2.0 in CHCl3); nmax (ATR)
D
3442 (OeH), 3329 (NeH), 1688 (C]O); dH (500 MHz, CDCl3) 1.39
(9H, s, CMe3), 3.51 (3H, s, OMe), 3.58 (1H, br s, OH), 3.59e4.22 (3H,
m, C(4)H, C(5)H2), 4.33 (1H, dd, J 5.8, 2.3, C(3)H), 5.71 (1H, d, J 2.3,
C(2)H), 8.01 (1H, br s, NH); dC (125 MHz, CDCl3) 28.3 (CMe3), 54.8
(OMe), 67.9 (C(3)), 69.0 (C(4)), 71.3 (C(5)), 79.6 (CMe3), 114.2 (C(2)),
155.0 (NCO); m/z (ESIþ) 240 ([MþNa]þ, 100%); HRMS (ESIþ)
þ
C
10H19NNaO4 ([MþNa]þ) requires 240.1206; found 240.1214.
4.15. (2S,3S,4R,aR)-2-Methoxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]tetrahydrofuran-4-ol 37
155.7 (NCO); m/z (ESIþ) 256 ([MþNa]þ, 100%); HRMS (ESIþ)
þ
C
10H19NNaO5 ([MþNa]þ) requires 256.1155; found 256.1158.
Method A: Step 1: HCl (2.0 M in Et2O, 3.77 mL, 7.53 mmol) was
added to a stirred solution of 26 (350 mg, 1.08 mmol, >99:1 dr) in
Et2O (10 mL) and the resultant mixture was stirred at rt for 5 min,
then concentrated in vacuo. The residue of 26$HCl was dissolved in
CH2Cl2/MeOH (v/v, 1:1, 40 mL), the resultant solution was cooled to
ꢀ78 ꢁC, and O3 was bubbled through the solution until it turned
blue. O2 was then bubbled through the solution until it turned
4.17. tert-Butyl (2S,3R,
methylbenzyl)amino]hex-4-enoate 40
aR,E)-2-hydroxy-3-[N-benzyl-N-(a-
Step 1: DMSO (575
mL, 8.10 mmol) was added dropwise to
a stirred solution of (COCl)2 (685 mL, 8.10 mmol) in CH2Cl2 (50 mL)
at ꢀ78 ꢁC and the resultant mixture was stirred at ꢀ78 ꢁC for 5 min.

M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
3499
A solution of 24 (1.60 g, 4.05 mmol, >99:1 dr) in CH2Cl2 (50 mL) was
(C(OCH2Me)2) 18.7 (C(
a
)Me), 28.0 (CMe3), 52.1 (NCH2Ph), 59.5
then added via cannula and the reaction mixture was stirred at
ꢀ78 ꢁC for 30 min. Et3N (2.3 mL, 16.20 mmol) was then added and
stirring was continued at ꢀ78 ꢁC for 10 min. The reaction mixture
was then allowed to warm to rt over 20 min. H2O (25 mL) was then
added and the resultant mixture was extracted with CH2Cl2
(3ꢂ30 mL). The combined organic extracts were then dried and
concentrated in vacuo to give 39 as a yellow oil (1.60 g); dH
(C(a)), 61.0 (C(3)), 63.5, 64.3 (C(OCH2Me)2), 71.4 (C(2)), 81.6 (CMe3),
103.8 (C(4)), 126.6, 126.8, 128.0, 128.9 (o,m,p-Ph), 141.0, 144.4 (i-Ph),
172.6 (C(1)).
4.19. (2S,3R,aR,E)-3-[N-Benzyl-N-(a-methylbenzyl)amino]-
hex-4-en-1,2-diol 43
(200 MHz, CDCl3) 1.38 (3H, d, J 6.9, C(
(3H, d, J 4.9, C(6)H3), 3.85 (2H, A2, NCH2Ph), 4.01 (1H, q, J 6.9, C(
4.58 (1H, d, J 7.4, C(3)H), 5.51e5.75 (2H, m, C(4)H, C(5)H), 7.15e7.45
(10H, m, Ph).
a
)Me), 1.47 (9H, s, CMe3), 1.74
LiAlH4 (1.0 M in THF, 2.53 mL, 2.53 mmol) was added to a solu-
tion 40 (1.00 g, 2.53 mmol, >99:1 dr) in THF (10 mL) at 0 ꢁC, and the
resultant mixture was allowed to warm to rt and stirred at rt for
16 h. The reaction mixture was then cooled to 0 ꢁC and lumps of ice
(w1 g), and then 2.0 M aq NaOH solution (5 mL), were added
cautiously with vigorous stirring being maintained throughout. The
resultant mixture was then allowed to warm to rt over 15 min,
diluted with EtOAc (30 mL) and the resultant mixture was stirred
for a further 30 min before being filtered through CeliteÒ (eluent
EtOAc). The filtrate was then dried and concentrated in vacuo. Pu-
rification via flash column chromatography (eluent 30e40 ꢁC pet-
a
)H),
Step 2: NaBH4 (152 mg, 4.00 mmol) was added portionwise to
a stirred solution of the residue of 39 (1.60 g) in MeOH (8 mL) at
ꢀ20 ꢁC and the resultant mixture was stirred at ꢀ20 ꢁC for 2 h. The
reaction mixture was then allowed to warm to rt and concentrated
in vacuo. The residue was partitioned between H2O (20 mL) and
Et2O (20 mL), and the aqueous layer was extracted with Et2O
(3ꢂ20 mL). The combined organic extracts were then dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/Et2O, 20:1) gave 40 as a colourless oil
rol/Et2O, 2:1) gave 43 as a colourless oil (0.62 g, 75%, >99:1 dr);
25
[a
]
ꢀ43.0 (c 1.3 in CHCl3); nmax (ATR) 3410 (OeH); dH (400 MHz,
D
(2.14 g, 65%, >99:1 dr); [
(OeH), 1728 (C]O); dH (500 MHz, CDCl3) 1.36 (9H, s, CMe3), 1.46
a
]
25 ꢀ73.0 (c 1.0 in CHCl3); nmax (ATR) 3496
D
CDCl3) 1.37 (3H, d, J 6.9, C(a)Me), 1.71 (3H, dd, J 6.5, 1.6, C(6)H3), 3.16
(2H, m, C(1)HA, C(3)H), 3.40 (1H, dt, J 9.5, 3.0, C(2)H), 3.53 (1H, app
dd, J 11.4, 3.0, C(1)HB), 3.57 (1H, d, J 13.3, NCHAHBPh), 3.81 (1H, d, J
(3H, d, J 6.9, C(
4.4, C(3)H), 3.66 (1H, d, J 13.6, NCHAHBPh), 3.75 (1H, d, J 9.4, C(2)H),
3.86 (1H, d, J 13.6, NCHAHBPh), 4.08 (1H, q, J 6.9, C( )H), 5.62e5.63
(2H, m, C(4)H, C(5)H), 7.24e7.32 (10H, m, Ph); dC (125 MHz, CDCl3)
14.4 (C( )Me), 18.2 (C(6)), 27.9 (CMe3), 50.2 (NCH2Ph), 56.3 (C( )),
a)Me), 1.76 (3H, d, J 4.4, C(6)H3), 3.33 (1H, dd, J 9.4,
13.3, NCHAHBPh), 3.98 (1H, q, J 6.9, C(
1.6, C(4)H), 5.66 (1H, dq, J 15.2, 6.5, C(5)H), 7.13e7.29 (10H, m, Ph);
dC (100 MHz, CDCl3) 13.6 (C( )Me), 18.4 (C(6)), 50.4 (NCH2Ph), 55.9
(C( )), 59.7 (C(3)), 62.7 (C(1)), 69.2 (C(2)), 127.2, 127.3, 127.4, 127.9,
a)H), 5.48 (1H, ddd, J 15.2, 9.5,
a
a
a
a
a
62.7 (C(3)), 71.7 (C(2)), 81.1 (CMe3), 126.7, 127.2, 127.3, 127.8, 128.4,
128.6, 129.1, 131.3 (C(4), C(5), o,m,p-Ph), 139.5, 143.7 (i-Ph), 171.þ5
(C(1)); m/z (ESIþ) 396 ([MþH]þ, 100%); HRMS (ESIþ) C25H34NO3
([MþH]þ) requires 396.2533; found 396.2529.
128.4, 128.6, 129.2, 131.9 (C(4), C(5), o,m,p-Ph), 139.4, 143.4 (i-Ph);
þ
m/z (ESIþ) 326 ([MþH]þ, 100%); HRMS (ESIþ) C21H28NO2
([MþH]þ) requires 326.2115; found 326.2118.
4.18. tert-Butyl (2S,3S,
a
R)-2-hydroxy-3-[N-benzyl-N-(
a
-meth-
4.20. (2S,3S,4S,aR)-2-Methoxy-3-[N-benzyl-N-(a-methyl-
ylbenzyl)amino]-4,4-diethoxybutanoate 42
benzyl)amino]tetrahydrofuran-4-ol 44
Step 1: DMSO (125
a stirred solution of (COCl)2 (152
m
L, 1.79 mmol) was added dropwise to
Step 1: HCl (2.0 M in Et2O, 6.45 mL, 12.9 mmol) was added to
a stirred solution of 43 (600 mg, 1.85 mmol, >99:1 dr) in Et2O
(5 mL) and the resultant mixture was stirred at rt for 5 min, then
concentrated in vacuo. The residue of 43$HCl was dissolved in
CH2Cl2/MeOH (v/v, 1:1, 80 mL), the resultant solution was cooled to
ꢀ78 ꢁC, and O3 was bubbled through the solution until it turned
blue. O2 was then bubbled through the solution until it turned
colourless, after which Me2S (6 mL) was added dropwise. The re-
sultant solution reaction was allowed to warm to rt over 16 h, then
concentrated in vacuo. The residue was dissolved in CH2Cl2 (40 mL)
and the resultant solution was washed with satd aq NaHCO3
(20 mL), then dried and concentrated in vacuo.
mL, 1.79 mmol) in CH2Cl2 (6 mL) at
ꢀ78 ꢁC and the resultant mixture was stirred at ꢀ78 ꢁC for 5 min. A
solution of 30 (410 mg, 0.90 mmol) in CH2Cl2 (6 mL) was then
added via cannula and the reaction mixture was stirred at ꢀ78 ꢁC
for 30 min. Et3N (520 mL, 3.59 mmol) was then added and stirring
was continued at ꢀ78 ꢁC for 10 min. The reaction mixture was then
allowed to warm to rt over 20 min. H2O (5 mL) was then added and
the resultant mixture was extracted with CH2Cl2 (3ꢂ10 mL). The
combined organic extracts were then dried and concentrated in
vacuo to give 41 as a yellow oil (400 mg); dH (200 MHz, CDCl3) 1.08
(3H, t, J 7.1, OCH2Me), 1.30 (3H, t, J 7.1, OCH2Me), 1.41 (3H, d, J 6.9,
C(
a
)Me), 1.49 (9H, s, CMe3), 3.35e3.80 (4H, m, (OCH2Me)2),
)H), 4.64 (1H, d, J 7.3, C(3)H), 4.80
Step 2: HCl (1.25 M in MeOH, 5.2 mL, 6.50 mmol) was added to
a stirred solution of the residue from the previous step in MeOH
(10 mL), and the resultant mixture was heated at 50 ꢁC for 16 h,
before being allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in CH2Cl2 (5 mL) and the resultant solution
was washed with satd aq NaHCO3 (5 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography (el-
uent 30e40 ꢁC petrol/Et2O, 10:1) gave 44 as a colourless oil
3.93e4.22 (3H, m, NCH2Ph, C(
(1H, d, J 7.3, C(4)H), 7.11e7.42 (10H, m, Ph).
a
Step 2: NaBH4 (34 mg, 0.90 mmol) was added to a stirred solu-
tion of the residue 41 (400 mg) in MeOH (8 mL) at ꢀ20 ꢁC and the
resultant mixture was stirred at ꢀ20 ꢁC for 2 h. The reaction mix-
ture was then allowed to warm to rt and concentrated in vacuo. The
residue was partitioned between H2O (20 mL) and Et2O (20 mL),
and the aqueous layer was extracted with Et2O (3ꢂ20 mL). The
combined organic extracts were then dried and concentrated in
vacuo to give a 77:23 mixture of 30 and 42, respectively. Data for
42: dH (400 MHz, CDCl3) 1.14 (3H, t, J 7.1, OCH2Me), 1.21 (3H, t, J 7.1,
(493 mg, 91%, 92:8 dr); [
a
]
25 þ10.3 (c 0.6 in CHCl3); nmax (ATR) 3430
D
(OeH); dH (400 MHz, CDCl3) 1.35 (3H, d, J 6.8, C(a)Me), 3.26 (1H,
app dd, J 3.8, 1.0, C(3)H), 3.29 (3H, s, OMe), 3.52 (1H, dd, J 9.3, 6.4,
C(5)HA), 3.74 (2H, A2, NCH2Ph), 3.88 (2H, m, C(4)H, C(5)HB), 4.00
OCH2Me), 1.36 (9H, s, CMe3), 1.38 (3H, d, J 6.9, C(
a
)Me), 3.35 (1H, t, J
(1H, q, J 6.8, C(
a)H), 4.86 (1H, d, J 1.0, C(2)H), 7.14e7.37 (10H, m, Ph);
6.1, C(3)H), 3.42 (1H, dq, J 8.8, 7.1, C(OCHAHBMe)A), 3.54 (1H, dq, J
9.3, 7.1, C(OCHAHBMe)B), 3.64e3.70 (2H, m, C(OCHAHBMe)2), 3.83
(1H, d, J 14.2, NCHAHBPh), 3.96 (1H, d, J 14.2, NCHAHBPh), 4.05 (1H,
dC (100 MHz, CDCl3) 14.3 (C(
a
)Me), 51.4 (NCH2Ph), 55.0 (OMe), 57.1
(C(4)), 71.8 (C(5)), 72.3 (C(3)), 74.6 (C(a)), 106.3 (C(2)), 126.7, 127.0,
127.7, 127.9, 128.1, 128.3 (o,m,p-Ph), 140.7, 143.4 (i-Ph); m/z (ESIþ)
þ
d, J 5.4, C(2)H), 4.22 (1H, q, J 6.9, C(
a
)H), 4.72 (1H, d, J 6.4, C(4)H),
328 ([MþH]þ, 100%); HRMS (ESIþ) C20H26NO3 ([MþH]þ) requires
7.04e7.23 (10H, m, Ph); dC (100 MHz, CDCl3) 15.4, 15.5
328.1907; found 328.1911.

3500
M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
4.21. tert-Butyl (S,S,S)-(2-methoxy-4-
OCHAHBMe), 3.47e3.62 (4H, m, C(3)H, OCH2Me, NCHAHBPh),
3.67e3.75 (1H, m, OCHAHBMe), 3.78e3.85 (2H, m, C( )H,
NCHAHBPh), 4.87 (1H, dd, J 8.1, 3.0, C(5)H), 7.23e7.44 (10H, m, Ph);
dC (100 MHz, CDCl3) 15.2, 15.4 (C(OCH2Me)2), 19.9 (C( )Me), 28.0
(CMe3), 37.1 (C(4)), 37.8 (C(2)), 50.0 (NCH2), 50.5 (C(3)), 58.0 (C( )),
hydroxytetrahydrofuran-3-yl)carbamate [methyl N-Boc-2-
deoxy-2-amino- -threoside] 45
a
a-D
a
A stirred solution of 44 (190 mg, 0.58 mmol, 92:8 dr) and Boc2O
(253 mg, 1.16 mmol) in MeOH (1.8 mL) was purged with N2 for
15 min. After this time, Pd(OH)2/C (50% w/w of 44, 95 mg) was
added and the resultant suspension was placed under H2 (5 atm),
and stirring was continued for 24 h. The resultant suspension was
filtered through CeliteÒ (eluent MeOH) and the filtrate was con-
centrated in vacuo. Purification via flash column chromatography
a
60.4, 61.0 (C(OCH2Me)2), 80.1 (CMe3), 100.9 (C(5)), 126.7, 127.0,
128.0, 128.1, 128.2, 128.3 (o,m,p-Ph), 141.5, 142.4 (i-Ph), 171.7 (C(1));
þ
m/z (ESIþ) 456 ([MþH]þ, 100%); HRMS (ESIþ) C28H41NNaO4
([MþNa]þ) requires 478.2928; found 478.2931.
4.24. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methyl-
benzyl)amino]-5,5-diethoxypentanoate 49
(eluent 30e40 ꢁC petrol/EtOAc, 4:1) gave 45 as a colourless oil
25
(72 mg, 54%, >95:5 dr); [
a]
þ45.0 (c 0.4 in CHCl3); nmax (ATR)
D
3309 (OeH), 1682 (C]O); dH (500 MHz, CDCl3) 1.38 (9H, s, CMe3),
3.32 (3H, s, OMe), 3.34 (1H, br s, OH), 3.82 (1H, dd, J 9.8, 3.4, C(5)HA),
3.90 (1H, d, J 6.0, C(4)H), 4.06 (1H, br s, C(3)H), 4.14 (1H, dd, J 9.8, 6.0,
C(5)HB), 4.58 (1H, br s, NH), 4.76 (1H, app s, C(2)H); dC (125 MHz,
CDCl3) 27.3 (CMe3), 54.0 (OMe), 62.0 (C(4)), 72.9 (C(5)), 75.0 (C(3)),
79.4 (CMe3), 106.4 (C(2)), 154.4 (NCO); m/z (ESIþ) 489 ([2MþNa]þ,
n-BuLi (2.5 M in hexanes, 7.80 mL, 19.5 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)
a
amine (4.26 g, 20.1 mmol) in THF (60 mL) at ꢀ78 ꢁC, and the re-
sultant mixture was stirred at ꢀ78 ꢁC for 30 min. A solution of 47
(3.50 g, 12.6 mmol, >99:1 dr) in THF (50 mL) was then added via
cannula and the resultant mixture was stirred at ꢀ78 ꢁC for 2 h.
(ꢀ)-CSO (4.90 g, 21.4 mmol) was then added and the reaction
mixture was allowed to warm to rt over 12 h. Satd aq NH4Cl (10 mL)
was then added, and the resultant mixture was concentrated in
vacuo. The residue was dissolved in CH2Cl2 (200 mL) and the re-
sultant solution was washed sequentially with 10% aq citric acid
(200 mL), satd aq NaHCO3 (200 mL) and brine (200 mL), then dried
and concentrated in vacuo. Purification via flash column chroma-
100%), 256 ([MþNa]þ, 55%); HRMS (ESIþ) C10H19NNaO5
þ
([MþNa]þ) requires 256.1155; found 256.1155.
4.22. tert-Butyl (E)-5,5-diethoxypent-2-enoate 47
DIBAL-H (1.0 M in PhMe, 23.7 mL, 23.7 mmol) was added
dropwise to a stirred solution of ethyl 3,3-diethoxypropanoate 46
(3.00 g, 15.8 mmol) in CH2Cl2 (160 mL) at ꢀ78 ꢁC. The resultant
solution was stirred at ꢀ78 ꢁC for 50 min, then MeOH (40 mL) was
added and the resultant solution was allowed to warm to rt over
15 min. CeliteÒ (w50 g) and H2O (50 mL) were added, the resultant
mixture was stirred vigorously for 15 min and then filtered.
Ph3P]CHCO2tBu (5.93 g, 15.8 mmol) was added to the filtrate, and
the resultant mixture was stirred at rt for 16 h, then concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 7:1) gave 47 as a colourless oil (3.50 g, 91%,
>99:1 dr); nmax (ATR) 1714 (C]O), 1655 (C]C); dH (400 MHz,
CDCl3) 1.20 (6H, t, J 7.1, C(OCH2Me)2), 1.47 (9H, s, CMe3), 2.48e2.52
(2H, m, C(4)H2), 3.47e3.54 (2H, m, OCH2Me), 3.61e3.69 (2H, m,
OCH2Me), 4.55e4.58 (1H, m, C(5)H), 5.82 (1H, d, J 15.7, C(2)H), 6.80
(1H, dt, J 15.7, 7.1, C(3)H); dC (100 MHz, CDCl3) 15.2 (C(OCH2Me)2),
28.1 (CMe3), 36.8 (C(4)), 61.2 (C(OCH2Me)2), 80.1 (CMe3), 101.4
(C(5)), 125.4 (C(2)), 142.2 (C(3)), 165.7 (Cþ(1)); m/z (ESIþ) 267
([MþNa]þ, 100%); HRMS (ESIþ) C13H24NaO4 ([MþNa]þ) requires
267.1567; found 267.1570.
tography (eluent 30e40 ꢁC petrol/Et2O, 8:1) gave 49 as a colourless
25
oil (4.57 g, 77%, 92:8 dr); [
a]
ꢀ33.6 (c 1.0 in CHCl3); nmax (ATR)
D
3495 (OeH), 1719 (C]O); dH (400 MHz, CDCl3) 1.05e1.12 (6H, m,
C(OCH2Me)2), 1.24 (3H, d, J 6.9, C( )Me), 1.27e1.32 (1H, m, C(4)HA),
a
1.40 (9H, s, CMe3), 1.76e1.83 (1H, m, C(4)HB), 2.88 (1H, d, J 5.6, OH),
3.21e3.50 (4H, m, C(3)H, OCH2Me, OCHAHBMe), 3.58 (1H, d, J 15.7,
NCHAHBPh), 3.62e3.70 (2H, m, C(2)H, OCHAHBMe), 3.84 (1H, q, J 6.9,
C(
7.14e7.40 (10H, m, Ph); dC (100 MHz, CDCl3) 15.4, 15.5
(C(OCH2Me)2), 19.7 (C( )Me), 27.9 (CMe3), 32.3 (C(4)), 50.9
(NCH2Ph), 55.4 (C(3)), 58.3 (C( )), 60.3, 62.3 (C(OCH2Me)2), 71.1
a)H), 4.27 (1H, d, J 15.7, NCHAHBPh), 4.75 (1H, dd, J 8.3, 2.5, C(5)H),
a
a
(C(2)), 82.7 (CMe3), 101.6 (C(5)), 126.5, 127.1, 128.0, 128.1, 128.2,
128.3 (o,m,p-Ph), 142.4, 142.6 (i-Ph), 174.3 (þC(1)); m/z (ESIþ) 472
([MþH]þ, 100%); HRMS (ESIþ) C28H42NO5 ([MþH]þ) requires
472.3057; found 472.3066.
4.25. (R,R,R)-3-[N-Benzyl-N-(a-methylbenzyl)amino]-5,5-
diethoxypentane-1,2-diol 50
4.23. tert-Butyl (R,R)-3-[N-benzyl-N-(
amino]-5,5-diethoxypentanoate 48
a
-methylbenzyl)
LiAlH4 (1.0 M in THF, 1.78 mL, 1.78 mmol) was added to a solu-
tion 49 (840 mg, 1.78 mmol, 92:8 dr) in THF (20 mL) at 0 ꢁC, and the
resultant mixture was stirred at rt for 16 h. The reaction mixture
was then cooled to 0 ꢁC and lumps of ice (w1 g), and then 2.0 M aq
NaOH solution (8 mL), were added cautiously with vigorous stirring
being maintained throughout. The resultant mixture was then
allowed to warm to rt over 15 min, diluted with EtOAc (30 mL) and
the resultant mixture was stirred for a further 30 min before being
filtered through CeliteÒ (eluent EtOAc). The filtrate was then dried
and concentrated in vacuo. Purification via flash column chroma-
n-BuLi (2.5 M in hexanes, 1.90 mL, 4.82 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-( -methylbenzyl)
a
amine (1.05 g, 4.98 mmol) in THF (25 mL) at ꢀ78 ꢁC, and the re-
sultant mixture was stirred at ꢀ78 ꢁC for 30 min. A solution of 47
(865 mg, 3.11 mmol, >99:1 dr) in THF (10 mL) was then added via
cannula and the resultant mixture was stirred at ꢀ78 ꢁC for 2 h.
Satd aq NH4Cl (20 mL) was then added and the resultant mixture
was allowed to warm to rt over 15 min, then partitioned between
Et2O (100 mL) and H2O (100 mL). The aqueous layer was extracted
with Et2O (3ꢂ100 mL) and the combined organic extracts were
washed sequentially with 10% aq citric acid (500 mL), satd aq
NaHCO3 (500 mL) and brine (500 mL), then dried and concentrated
in vacuo. Purification via flash column chromatography (eluent
tography (eluent 30e40 ꢁC petrol/Et2O, 1:2) gave 50 as a colourless
25
oil (699 mg, 98%, 92:8 dr); [
a
]
ꢀ41.4 (c 1.0 in CHCl3); nmax (ATR)
D
3417 (OeH); dH (400 MHz, CDCl3) 1.22 (3H, t, J 7.1, OCH2Me), 1.27
(3H, t, J 7.1, OCH2Me), 1.43 (3H, d, J 6.8, C( )Me), 1.95e2.02 (1H, m,
a
C(4)HA), 2.09e2.14 (1H, m, C(4)HB), 2.97 (1H, br s, C(3)H), 3.28 (1H,
dd, J 11.0, 5.8, C(1)HA), 3.38 (1H, dd, J 11.0, 4.0, C(1)HB), 3.47e3.58
30e40 ꢁC petrol/Et2O, 10:1) gave 48 as a colourless oil (1.29 g, 91%,
(3H, m, C(2)H, O(CHAHBMe)2), 3.69e3.93 (5H, m, C(
O(CHAHBMe)2, NCH2Ph), 4.71e4.74 (1H, m, C(5)H), 7.25e7.41 (10H,
m, Ph); dC (100 MHz, CDCl3) 14.0 (C( )Me), 15.2, 15.4 (C(OCH2Me)2),
34.2 (C(4)), 51.5 (NCH2), 53.4 (C(3)), 57.3 (C( )), 62.2, 63.1
(C(OCH2Me)2), 65.2 (C(1)), 72.9 (C(2)), 102.9 (C(5)), 127.1, 127.2,
a)H,
25
99:1 dr); [
a
]
ꢀ42.2 (c 1.0 in CHCl3); nmax (ATR) 1722 (C]O); dH
D
(400 MHz, CDCl3) 1.17e1.25 (6H, m, C(OCH2Me)2), 1.37 (3H, d, J 7.1,
C( )Me), 1.42 (9H, s, CMe3), 1.64e1.70 (1H, m, C(4)HA), 1.73e1.79
(1H, m, C(4)HB), 1.89e1.91 (2H, m, C(2)H2), 3.35e3.42 (1H, m,
a
a
a

M. Brambilla et al. / Tetrahedron 70 (2014) 3491e3501
3501
128.2, 128.3, 128.4, 128.8 (o,m,p-Ph), 140.5, 143.6 (i-Ph); m/z (ESIþ)
3. Davies, S. G.; Smyth, G. D.; Chippindale, A. M. J. Chem. Soc., Perkin Trans. 1 1999,
þ
3089.
402 ([MþH]þ, 100%); HRMS (ESIþ) C24H36NO4 ([MþH]þ) requires
ꢀ
4. Csatayova, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.;
402.2639; found 402.2641.
Wilson, D. L. Org. Lett. 2011, 13, 2606.
5. Bagal, S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.;
Thomson, J. E. Tetrahedron Lett. 2011, 52, 2216.
6. Csatayova, K.; Davies, S. G.; Ford, J. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. J.
Org. Chem. 2013, 78, 12397.
4.26. (2S,4R,5R,
benzyl)amino]tetrahydro-2H-pyran-5-ol 51
aR)-2-Methoxy-4-[N-benzyl-N-(a-methyl-
ꢀ
7. For reviews concerning the conjugate addition of this class of lithium amide,
see: (a) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16,
2833; (b) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron:
Asymmetry 2012, 23, 1111.
8. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973.
9. Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson,
J. E. Org. Biomol. Chem. 2008, 6, 3751.
10. Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.
Org. Biomol. Chem. 2008, 6, 3762.
11. Bond, C. W.; Cresswell, A. J.; Davies, S. G.; Kurosawa, W.; Lee, J. A.; Fletcher, A.
M.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org. Chem. 2009,
74, 6735.
12. Brennan, M. B.; Claridge, T. D. W.; Compton, R. G.; Davies, S. G.; Fletcher, A. M.;
Henstridge, M. C.; Hewings, D. S.; Kurosawa, W.; Lee, J. A.; Roberts, P. M.;
Russell, A. J.; Schoonen, A. K.; Thomson, J. E. J. Org. Chem. 2012, 77, 7241.
13. For previous synthetic endeavours towards the 2-deoxy-2-aminotetroses, see:
(a) Yoshimura, J.; Ohgo, Y.; Sara, T. Bull. Chem. Soc. Jpn. 1961, 34, 1197; (b) Kuhn,
R.; Fischer, H. Justus Liebigs Ann. Chem. 1961, 152; (c) Wade, P. A.; D’Ambrosio, S.
G. J. Carbohydr. Chem. 1995, 14, 1329; (d) Wade, P. A.; D’Ambrosio, S. G.; Price, D.
T. J. Org. Chem. 1995, 60, 6302.
HCl (1.25 M in MeOH, 8.78 mL,11.0 mmol) was added to a stirred
solution of 50 (1.10 g, 2.74 mmol, 92:8 dr) in MeOH (30 mL), and the
resultant mixture was heated at 50 ꢁC for 16 h, before being allowed
to cool to rt and concentrated in vacuo. The residue was dissolved in
CH2Cl2 (15 mL) and the resultant solution was washed with satd aq
NaHCO3 (10 mL), then dried and concentrated in vacuo. Purification
via flash column chromatography (eluent 30e40 ꢁC petrol/Et2O,
1:1) gave 51 as a colourless oil (878 mg, 94%, 92:8 dr); [
a]
25 ꢀ37.8
D
(c 2.0 in CHCl3); nmax (ATR) 3419 (OeH); dH (400 MHz, CDCl3) 1.48
(3H, d, J 6.8, C(a)Me), 1.82 (1H, dd, J 12.6, 4.3, C(3)HA), 2.03 (1H, td, J
12.6, 3.5, C(3)HB), 2.64 (1H, br s, OH), 3.25 (1H, dt, J 12.6, 3.8, C(4)H),
3.34 (3H, s, OMe), 3.51 (1H, br s, C(5)H), 3.60e3.70 (3H, m, C(6)H2,
NCHAHBPh), 3.91 (1H, d, J 15.4, NCHAHBPh), 4.26 (1H, q, J 6.8, C(
4.77 (1H, d, J 2.0, C(2)H), 7.17e7.48 (10H, m, Ph); dC (100 MHz,
CDCl3) 13.9 (C( )Me), 30.1 (C(3)), 51.8 (NCH2Ph), 54.8 (OMe), 54.9
(C(4)), 55.5 (C(
a)H),
a
14. Smith, M. B.; March, J. March’s Advanced Organic ChemistrydReactions, Mech-
anisms, and Structure, 5th ed.; John Wiley & Sons: New York, NY, 2001.
15. For the development of this methodology, see: (a) Bunnage, M. E.; Davies, S. G.;
Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1993, 1375; (b) Bunnage, M. E.; Da-
vies, S. G.; Goodwin, C. J. Synlett 1993, 731; (c) Bunnage, M. E.; Davies, S. G.;
Goodwin, C. J.; Ichihara, O. Tetrahedron 1994, 50, 3975; (d) Bunnage, M. E.;
Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1994,
2373. For selected synthetic applications, see: (e) Bunnage, M. E.; Burke, A. J.;
Davies, S. G.; Goodwin, C. J. Tetrahedron: Asymmetry 1994, 5, 203; (f) Bunnage,
M. E.; Burke, A. J.; Davies, S. G.; Goodwin, C. J. Tetrahedron: Asymmetry 1995, 6,
165; (g) Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.;
Rodríguez-Solla, H.; Smith, A. D. Chem. Commun. 2006, 2664; (h) Davies, S. G.;
Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Smith, A. D.;
Rodríguez-Solla, H.; Thomson, J. E.; Toms, S. M. Org. Biomol. Chem. 2007, 5, 1961;
(i) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;
a
)), 62.3 (C(6)), 66.1 (C(5)), 98.3 (C(2)), 126.8, 127.0,
127.3, 128.0, 128.3, 128.4 (o,m,p-Ph), 142.3, 142.9 (i-Ph); m/z (ESIþ)
þ
342 ([MþH]þ, 100%); HRMS (ESIþ) C21H28NO3 ([MþH]þ) requires
342.2064; found 342.2056.
4.27. tert-Butyl (2S,4R,5R)-(2-methoxy-5-hydroxytetrahydro-
2H-pyran-4-yl)carbamate [methyl N-Boc-2,3-dideoxy-3-
amino-b-L-arabinopyranoside] 52
A stirred solution of 51 (218 mg, 0.64 mmol, 92:8 dr) and Boc2O
(435 mg, 1.28 mmol) in MeOH (2 mL) was purged with N2 for
15 min. After this time, Pd(OH)2/C (50% w/w of 51, 109 mg) was
added and the resultant suspension was placed under H2 (5 atm),
and stirring was continued for 24 h. The resultant suspension was
filtered through CeliteÒ (eluent MeOH) and the filtrate was con-
centrated in vacuo. Purification via flash column chromatography
ꢀ
ꢀ
Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J.
E. Tetrahedron: Asymmetry 2007, 18, 2510; (j) Abraham, E.; Davies, S. G.; Milli-
can, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008,
6, 1655; (k) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
ꢀ
M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sanchez-
ꢀ
Fernandez, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2008, 6, 1665.
(eluent 30e40 ꢁC petrol/EtOAc, 11:1) gave 52 as a colourless oil
16. Davies, S. G.; Smyth, G. D. J. Chem. Soc., Perkin Trans. 1 1996, 2467.
17. Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.; Zammit, C. M. Chem.
Commun. 2013, 49, 7037.
25
(142 mg, 90%, >95:5 dr); [
a
]
D
ꢀ23.8 (c 2.0 in CHCl3); nmax (ATR)
3441 (OeH), 3328 (NeH), 1687 (C]O); dH (500 MHz, CDCl3) 1.39
(3H, d, J 6.8, C( )Me), 1.83e2.08 (3H, m, C(3)H2), 3.51 (3H, s, OMe),
18. Davies, S. G.; Epstein, S. W.; Garner, A. C.; Ichihara, O.; Smith, A. D. Tetrahedron:
a
Asymmetry 2002, 13, 1555.
19. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 5, 1999.
20. Fujii, S.; Maruoka, M. Biochim. Biophys. Acta 1982, 717, 486.
21. Davies, S. G.; Fletcher, A. M.; Foster, E. M.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.
J. Org. Chem. 2013, 78, 2500.
22. Davies, S. G.; Fletcher, A. M.; Frost, A. B.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.
Tetrahedron 2013, 69, 8885.
3.58e3.86 (5H, m, C(4)H, C(5)H, C(6)H2, OH), 4.97 (1H, d, J 2.3,
C(2)H), 8.01 (1H, br s, NH); dC (125 MHz, CDCl3) 28.3 (CMe3), 32.4
(C(3)), 53.2 (C(4)), 54.9 (OMe), 66.1 (C(5)), 67.5 (C(6)), 79.6 (CMe3),
112.7 (C(2)), 155.7 (NCO); m/z (ESIþ) 270 ([MþNa]þ, 100%); HRMS
(ESIþ) C11H21NNaO5þ ([MþNa]þ) requires 270.1312; found 270.1311.
23. Use of LiAlH4 also resulted in reduction of the ester: the product of the reaction
in this case was 32.
24. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
References and notes
25. Resonances overlapping with those associated with the minor anomer are
indicated with an asterisk.
26. Resonances overlapping with those associated with the major anomer are in-
dicated with an asterisk.
1. For example, see: Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99.
2. For reviews of the synthesis of the 2,3,6-trideoxy-3-aminohexose family, for
example, see: (a) Hauser, F. M.; Ellenberger, S. R. Chem. Rev. 1986, 86, 35; (b)
Ding, F.; Cai, S.; William, R.; Liu, X.-W. RSC Adv. 2013, 3, 13594.