Synthetic entry to functionalised morpholines and [1,4]-oxazepanes via reductive amination reactions of carbohydrate derived dialdehydes

Article abstract of DOI:10.1016/j.tetasy.2004.10.002

Synthetic entry to functionalised morpholines and [1,4]-oxazepanes by reductive amination reactions between amines and carbohydrate derived dialdehydes is described. The rapid synthesis of functionalised morpholines and [1,4]-oxazepanes displaying up to three stereocentres, by reductive amination reactions between carbohydrate derived dialdehydes and a range of amines, is described.

Full text of DOI:10.1016/j.tetasy.2004.10.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3643–3652
Synthetic entry to functionalised morpholines and
[1,4]-oxazepanes via reductive amination reactions of
carbohydrate derived dialdehydes
Stuart M. Clark and Helen M. I. Osborn*
School of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK
Received 13 September 2004;accepted 1 October 2004
Abstract—The rapid synthesis of functionalised morpholines and [1,4]-oxazepanes displaying up to three stereocentres, by reductive
amination reactions between carbohydrate derived dialdehydes and a range of amines, is described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
3-oxagranatane skeleton,4 the methyl ester of leukotri-
ene A4,5 and substituted tetrahydrofurans.6 As part of
a programme directed towards the synthesis of novel
carbohydrate-based therapeutics,7 we were interested
in developing methodology that would allow rapid entry
to functionalised [1,4] oxazepanes and morpholines.8
Recent literature reports have suggested that such tar-
gets may offer potential as anti-fungal9 and anti-viral10
agents and as inhibitors of the glycosidase enzymes.11
[1,4] Oxazepanes are also important components of
skeleta of interesting natural products, such as the
neurotoxin batrachotoxin.12 The work reported herein
details strategies that have allowed selective entry to
either morpholines, 7-hydroxymethyl-[1,4]-oxazepanes
or 7-alkoxy-[1,4]-oxazepanes, via reductive amination
reactions13 of dialdehydes generated from methyl a-D-
glucopyranosides. This has proved possible via control
of the oxidative cleavage of the diol pairs within the
glucopyranoside starting material.
The synthetic utility of carbohydrates as inexpensive
and readily available, stereodefined starting materials
for syntheses programmes has been well recognised
and exploited in the chemical literature.1 In particular,
carbohydrates have been utilised for the generation of
dialdehydes, via oxidative cleavage of 1,2-diol pairs
using NaIO4.2 If a carbohydrate contains a C-2,3-4 triol
moiety, as found within methyl a-D-glucopyranoside 1,
it is recognised that oxidation occurs twice in the pres-
ence of excess NaIO4 to yield dialdehyde 4 via dialde-
hydes 2 and 3 (Scheme 1).
The oxidative cleavage reactions generally occur readily
at room temperature and the dialdehydes thus formed
are believed to exist in equilibrium in aqueous solution
as a number of cyclic and acyclic species.2 The synthetic
versatility of this transformation is reflected by its incor-
poration within a range of synthetic pathways that have
allowed entry to a variety of targets including an anti-
herpetic agent,3 a glycosidase inhibitor containing the
Of particular relevance to this work is the report that
morpholino glycopeptides can be prepared via reductive
HO
HO
HO
HO
HO
NaIO4
HO
O
NaIO4
HO
O
O
O
O
O
+
O
O
HO
O
HO
O
OMe
OMe
OMe
1
OMe
4
2
3
Scheme 1.
*
Corresponding author. Tel.: +44 0118 987 5123;fax: +44 0118 931 6331;e-mail: h.m.i.osborn@rdg.ac.uk
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.002

3644
S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
HO
HO
HO
HO
HO
HO
O
HO
O
O
O
O
O
NaIO4
+
NaIO4
OMe
O
O
HO
O
HO
O
OMe
OMe
1
OMe
2
3
4
RNH2,
NaBH3CN
RNH2,
NaBH3CN
RNH2,
NaBH3CN
OH
OH
OH
R
N
OH
O
R
N
O
O
N
R
OMe
HO
OMe
5
OMe
7
6
Scheme 2.
amination reactions between carbohydrate derived
dialdehydes and amines.14 Herein we report an investi-
gation into a modification of this procedure, which has
probed the efficiency of this reaction for entry to stereo-
defined, functionalised [1,4]-oxazepanes 6 and 7 by care-
ful control of the sodium periodate ring cleavage
reaction of methyl a-D-glucopyranoside, as illustrated
in Scheme 2.
For initial studies, methyl a-D-glucopyranoside was
treated with NaIO4 (2molar equivalents) in methanol
at 0ꢁC and then at room temperature for 3h to effect
dialdehyde formation. Although purification of the
intermediate dialdehyde was attempted using C18
reverse phase chromatography, as described by Hinds-
gaul14 for the purification of the analogous dialdehyde
derived from octyl b-D-glucopyranoside, complete sepa-
ration of the dialdehyde from the inorganic impurities
proved unsuccessful. Therefore, subsequent work-up of
the dialdehyde involved concentration of the reaction
mixture in vacuo followed by suspension of the resulting
colourless solid in ethyl acetate. The suspension was
then filtered through Celite and the filtrate concentrated
in vacuo to yield the crude dialdehyde as a clear oil.
Amine (1equiv) and sodium cyanoborohydride (5equiv)
were then added to the crude dialdehyde (3equiv) in
2. Results and discussion
Before selective formation of dialdehydes 2 and 3 was
attempted, synthetic entry to a range of morpholines 5
was investigated. In particular, the reaction of dialde-
hyde 4 with the carbohydrate derived amine 10 was
investigated to potentially allow access to a morpholino
pseudo-disaccharide. Pseudo-disaccharides have proved
to be of interest as glycosidase inhibitors with enhanced
specificities compared with monosaccharide inhibitors
due to their rich display of hydroxyl functionalities.15
Carbohydrate amine 10 was prepared in 95% yield by
treatment of triflate 9 with ammonia gas in dichloro-
methane at ꢀ15ꢁC. Triflate 9 was itself prepared in
85% yield by reaction of alcohol 8 with triflic anhydride
and pyridine (Scheme 3).16
˚
methanol containing 10A powdered molecular sieves
and the reaction stirred at room temperature for 4h.
Interestingly, work-up of the reaction mixture illustrated
that both morpholine 5a and 7-methoxy-[1,4]-oxazepane
6a had been formed in a 1:1 ratio in 58%, suggesting that
incomplete formation of dialdehyde 4 had occurred
(Scheme 4). This was despite the reaction conditions
that should effect further cleavage of the 1,2-diol within
intermediate dialdehyde 3.
H2N
TfO
NH3,
95%
O
Tf2O,
85%
HO
BnO
BnO
O
BnO
BnO
O
BnO
10
BnO
BnO
BnO
BnO
OMe
OMe
OMe
9
8
Scheme 3.
OH
OH
O
OH
OMe
N
O
O
+
N
O
i) NaIO4;
ii) Amine 10, NaBH3CN
O
HO
HO
BnO
BnO
OMe
OH
6a
BnO
BnO
HO
OMe
BnO
1
BnO
OMe
5a
OMe
Scheme 4.

S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
Table 1. Selective entry to functionalised morpholines 5
3645
with ozone in methanol at ꢀ78ꢁC to allow in situ
generation of aldehyde 11. The subsequent reductive
amination reaction then afforded the morpholine 12
in 33% (Scheme 5);this yield compares closely with
that obtained for the synthesis of morpholines 5 from
dialdehyde 4. It was, therefore, concluded that the
generation of dialdehyde 4 was unlikely to be the limit-
ing step in the synthetic process.
Primary amine
Morpholine
5, %
7-Methoxy-[1,4]-oxazepane
6, %
Glucose amine 10
Benzylamine
5a, 32
5b, 33
5c, 29
6a, 7
6b, —
6c, —
L-Phenylalanine
methyl ester
Since the formation of small quantities of 7-methoxy-
[1,4]-oxazepanes 6 had occurred in the strategy above,
we next sought to investigate whether conditions could
be found that favoured formation of the latter. Thus
limited equivalents of NaIO4 (1.2molar equivalents)
were utilised for effecting diol cleavage and the reaction
time decreased from 24h to 4h, in an attempt to favour
formation of dialdehyde 3 over dialdehyde 4. This in-
deed proved successful and subsequent reductive amina-
tion reactions with the same range of amines as
described for entry to morpholines 5, in the presence
of sodium cyanoborohydride, allowed entry to the
desired 7-alkoxy-oxazepanes 6 with good selectivities
(Scheme 6, Table 2). Again, although the reactions pro-
ceeded in only moderate yield, entry to single isomers of
the highly substituted, polyfunctionalised 7-methoxy-
[1,4]-oxazepanes 6 proved possible in a concise fashion
from commercially available starting materials.
Attempts were also made to bias the reaction to allow
formation of dialdehyde 2, and thus allow eventual ac-
cess to the isomeric 7-hydroxymethyl-[1,4]-oxazepanes
7. Thus a bulky silyl ether protecting group was incorpo-
rated at the C-6 hydroxyl group of methyl a-D-glucopyr-
anoside19 to potentially minimise sodium periodate
mediated cleavage of the C-3, C-4 hydroxyl pair. How-
ever, when triol 13 was treated with 1.2molar equiva-
lents of NaIO4 in water/methanol for 4h, and the
resulting dialdehydes treated with the amine and 5molar
equivalents of sodium cyanoborohydride, the 7-meth-
oxy-[1,4]-oxazepane isomers 6 were still formed in
preference to the isomeric 7-hydroxymethyl-[1,4]-
oxazepanes 7 (Scheme 6, Table 2). The selectivity of
the reaction to form the 7-methoxy-[1,4]-oxazepanes 6
was particularly prominent when the sterically hindered
amines L-phenylalanine methyl ester and glucose amine
10 were utilised in the reaction.
Moreover, since isomeric 7-hydroxymethyl-[1,4]-oxaze-
pane 7 had not been isolated, formation of dialdehyde
2 could not be considered to be a competing reaction.
However, increasing the molar equivalents of NaIO4
to 5 and extending the duration of the dialdehyde form-
ing reaction to 15h biased the reaction to the formation
of the morpholine product 5a in 32%, with only 7% of
the oxazepane product 6a resulting. These conditions
were then extended to investigate the reaction of two
other amines, namely benzylamine and L-phenylalanine
methyl ester with the dialdehyde, to form morpholines
5b and c. The latter was selected for incorporation
within the methodology to potentially allow access to
analogues of glycosyl amino acids.17 Pleasingly, in all
cases it proved possible to isolate the morpholines in
preference to the 7-methoxy-[1,4]-oxazepane products
6b and c, albeit in moderate yields, after work-up and
careful purification by column chromatography on silica
gel (Table 1). It should be noted that the morpholines
were formed as single isomers in one synthetic step from
commercially available starting material without the
need for any hydroxyl protecting groups.
As there was no evidence for the formation of by-prod-
ucts or recovery of methyl a-D-glucopyranoside from
the reaction mixtures, the aqueous phase collected dur-
ing the extraction procedure was analysed, after lyophi-
lisation. This again failed to afford any useful
information as to why the yields of the reactions were
moderate. Attempts were made to further improve the
yield of this reaction but this proved particularly diffi-
cult—analysis of the crude dialdehyde mixture to ascer-
tain the exact proportion of dialdehydes present is
difficult due to the complex equilibrium that exists
between the cyclic and acyclic forms of the dialdehydes
under aqueous conditions. Model studies were, therefore,
performed that involved the sodium cyanoborohydride
mediated reductive amination reaction between a less
functionalised glutaric dialdehyde 1118 (formed under
nonaqueous conditions) and glucose amine 10 to ascer-
tain whether the formation and stability of dialdehyde 4
was a limiting factor. Thus 2,5-dihydrofuran was treated
An alternative approach that proved successful for entry
to the 7-hydroxymethyl-[1,4]-oxazepanes 7 involved
dialdehyde formation from triol 14 via NaIO4 mediated
oxidative cleavage of the C-2, C-3 diol pair. Thus when
methyl pyranoside 1420 was treated with 1.2molar
equivalents of NaIO4 for 1.5h and the dialdehyde thus
O
N
O3, MeOH,
-78 ºC
O
O
(10), NaCNBH3,
O
O
BnO
BnO
O
11
BnO
MeOH, 33% over
2 steps
OMe
12
Scheme 5.

3646
S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
OH
OR'
R
OR'
O
OR'
N
OR'
i) NaIO4;
HO
HO
O
R
N
O
+
+
O
N
R
ii) RNH2, NaBH3CN
HO
OMe
OMe
HO
OMe
OMe
R' = H 1
5
6
7
R' = TBDPS 13
Scheme 6.
Table 2. Selective entry to functionalised 7-methoxy-[1,4]-oxazepanes 6
Primary amine
Methyl a-D-
glucopyranoside
Morpholine 5, %
7-Methoxy-[1,4]-
oxazepane 6, %
7-Hydroxymethyl-[1,4]-
oxazepane 7, %
Glucose amine 10
Benzylamine
1
5a, —
5b, 4
6a, 31
6b, 21
6c, 26
6d, 30
6e, 25
6f, 20
7a, —
7b, —
7c, —
7d, —
7e, 7
1
L-Phenylalanine methyl ester
Glucose amine 10
Benzylamine
1
5c, 14
5d, —
5e, 25
5f, 1
13
13
13
L-Phenylalanine methyl ester
7f, —
OBn
apparatus and are uncorrected. Infrared spectra were
recorded on a Perkin–Elmer Paragon 1000 FT-IR spec-
trometer. Liquid samples were placed between sodium
chloride plates as thin films. Frequencies of absorption
maxima are reported in wave numbers (cmꢀ1). The fol-
lowing abbreviations are used for the degree of absorp-
OH
OH
i) NaIO4;
ii) RNH2, NaBH3CN
O
BnO
HO
O
N
R
HO
OMe
14
Scheme 7.
OMe
7
1
tion: s (strong), m (medium), w (weak), br (broad). H
NMR spectra were recorded at 250MHz on a Bruker
DPX-250 FT-NMR spectrometer or at 400MHz on a
Bruker AMX-400 FT-NMR spectrometer, using CDCl3
or CD3OD as an internal standard unless stated other-
wise. Multiplicities of carbon atoms (methyl, methylene,
methine or quaternary) were determined using broad-
band decoupled carbon spectra and distortionless
enhancement by polarisation transfer (DEPT) carbon
spectra. All chemical shifts (dH and dC values) are
quoted in units of parts per million (ppm). The follow-
ing abbreviations are used: s (singlet), d (doublet), t (tri-
plet), dd (double doublet), app. t (apparent triplet), m
(multiplet). All coupling constants (J values) are ex-
pressed in hertz to the nearest 0.5Hz. 13C NMR spectra
were recorded on the spectrometers described above at
63MHz and 101MHz and the external reference pro-
vided by the solvents CDCl3 or CD3OD. Low and high
resolution mass spectrometry data were recorded using a
Fisons VG Autospec, a Micromass Platform LC/MS or
a Finnigan MAT900XLT. Molecular ions and fractions
from molecular ions are reported as mass/charge (m/z)
ratios. Optical activities were determined using a Per-
kin–Elmer 341 polarimeter at a wavelength of 589nm
and specific rotations are quoted in units of
10ꢀ1 degcm2 gꢀ1. Flash chromatography was performed
using silica gel 60 (Merck) using head pressure by means
of bellows. TLC analysis was performed using Merck
aluminium backed plates, coated with 0.2mm silica 60
F254. Visualisation of the compounds on the TLC plates
was achieved using 254nm UV light or by using an acid
dip (EtOH–H2SO4, 25:1). All chemicals were obtained
from Sigma–Aldrich, BDH, Fluka or Lancaster chemi-
cal suppliers and were used as received, unless stated
otherwise. For reactions requiring anhydrous condi-
Table 3. Selective entry to functionalised 7-hydroxymethyl-[1,4]-oxa-
zepanes 7
Primary amine
7-Hydroxymethyl-[1,4]-
oxazepane 7, %
Glucose amine 10
Benzylamine
L-Phenylalanine methyl ester
7g, 46
7h, 23
7i, 53
formed reacted with amines and sodium cyanoborohy-
dride, the desired 7-hydroxymethyl-[1,4]-oxazepanes 7
were isolated as the only products (Scheme 7, Table 3).
3. Conclusion
In summary, conditions have been described that allow
synthetic entry to highly substituted, polyfunctionalised
morpholines 5, 7-methoxy-[1,4]-oxazepanes 6 and 7-
hydroxymethyl-[1,4]-oxazepanes
7 from inexpensive
and readily available methyl a-D-glucopyranosides.
These intermediates may be of use for access to a range
of functionalised targets. Chemical elaboration of the
targets to allow access to carbohydrate analogues of
therapeutic interest is currently being pursued within
our laboratories.
4. Experimental procedures
The melting points of all solid products were determined
using an Electrothermal digital heated metal block

S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
3647
tions, anhydrous solvents were used with glassware
oven-dried prior to use and procedures carried out
under a nitrogen atmosphere. Elemental analyses were
performed by MEDAC Ltd, Brunel Science Centre,
CooperÕs Hill Lane, Egham, Surrey.
138.6 (ArC), 128.9 (ArC), 128.8 (ArC), 128.6 (ArC),
128.4 (ArC), 128.2 (ArC), 128.1 (ArC), 98.4 (C1), 97.7
(C6a), 82.5 (C3), 80.4 (C2), 79.9 (C4), 76.3 (PhCH2O),
75.4 (PhCH2O), 73.7 (PhCH2O), 69.9 (C5), 69.4 (C2a),
64.6 (C7a), 58.9 (C6), 56.8 (C5a), 56.1 (OCH3), 55.4
(OCH3), 55.0 (C3a); m/z (CI) 594 (37%, [M+H]+), 502
(32%, [MꢀPhCH2]+), 380 (26%, [MꢀPhCH2–PhCH2–
OCH3]+), found [M+H]+ 594.3066, C34H44NO8 requires
594.3067.
4.1. General method for access to morpholines 5
4.1.1. Step 1: Synthesis of dialdehyde 4. A solution of
sodium periodate (5equiv) in distilled water was added
dropwise to a stirred solution of methyl a-D-glucopyr-
anoside (1equiv) in methanol at 0ꢁC, and the reaction
mixture stirred at room temperature for 15h. The reac-
tion mixture was concentrated in vacuo and the result-
ing colourless solid suspended in ethyl acetate, filtered
through Celiteꢂ and concentrated in vacuo to yield the
crude dialdehyde 4 as a clear oil.
4.3. (2S,6S)-4-Benzyl-6-methoxy-morpholin-2-yl-metha-
nol 5b
By following the general procedure above, sodium cya-
noborohydride (668mg, 10.6mmol) was added to a stir-
red solution of benzylamine (0.23mL, 2.11mmol),
˚
dialdehyde 4 (1.02g, 6.33mmol) and 10A molecular
sieves in methanol (20mL). Work-up and purification
by flash column chromatography (96:4 CH2Cl2–MeOH)
afforded 5b as a clear oil (163mg, 0.69mmol, 33%).
4.1.2. Step 2: Reductive amination reaction to afford
morpholines 5. Sodium cyanoborohydride (5equiv)
was added to a stirred solution of benzylamine (1equiv),
20
½aŠ ¼ þ91:5 (c 1.0, CHCl3); mmax (NaCl disc)/cmꢀ1
D
˚
dialdehyde 4 (3equiv) and 10A molecular sieves in
3422 (br s, OH), 2972 (s, CH), 2850 (s, CH), 1636 (w,
C@C), 1317 (s, C–O), 1287 (s, C–O), 1262 (s, C–O);
1H NMR (250MHz;CDCl 3) 7.25–7.14 (5H, m, Ph),
4.62–4.61 (1H, m, C(6)H), 3.99–3.95 (1H, m, C(2)H),
3.57–3.42 (4H, m, C(7,70)H, PhCH2), 3.32 (3H, s,
methanol. The pH of the reaction mixture was adjusted
to 7 with 2M HCl (soln Et2O). After stirring for 24h at
room temperature, the reaction mixture was concen-
trated in vacuo. The residue was partitioned between
H2O and dichloromethane and the organic phase dried
over MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography
(96:4 CH2Cl2–MeOH) to yield the morpholines 5.
0
OCH3), 2.76 (1H, dd, J5,5 11.0 J5,6 1.0, C(5)H), 2.62
0
0
(1H, dd, J3,3 11.0 J2,3 2.0, C(3)H), 2.16 (1H, dd, J5,5
11.0 J5 ,6 3.0, C(50)H), 1.98 (1H, at J3,3 J2,3 11.0,
C(30)H); 13C NMR (63MHz;CDCl 3) 136.9 (ArC),
129.9 (ArC), 128.5 (ArC), 127.7 (ArC), 97.7 (C6), 69.4
(C2), 64.4 (PhCH2), 63.6 (C7), 56.0 (C5), 55.5 (OCH3),
54.0 (C3); m/z (CI) 238 (100%, [M+H]+), 206 (30%,
[MꢀOCH3]+), 91 (51%, [PhCH2]+), found 238.1445,
C13H20O3N requires 238.1443.
0
0
0
4.2. Methyl 2,3,4-tri-O-benzyl-6-deoxy-6-((2S,6S)-2-
hydroxymethyl-6-methoxy-morpholin-4-yl)-a-D-glucopyr-
anoside 5a
By following the general procedure above, sodium
cyanoborohydride (30mg, 0.50mmol) was added to a
stirred solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-6-
amino-a-D-glucopyranoside 10 (50mg, 0.10mmol),
4.4. (2R)-((2S,6S)-2-Hydroxymethyl-6-methoxy-morpho-
lin-4-yl)-3-phenyl-propionic acid methyl ester 5c
˚
dialdehyde 4 (49mg, ꢁ0.30mmol) and 10A molecular
By following the general procedure above, sodium
cyanoborohydride (63mg, 1.00mmol) was added to a
stirred solution of L-phenylalanine methyl ester
(43mg, 0.20mmol), dialdehyde (97mg, 0.6mmol) and
sieves in methanol (10mL). Work-up and purification
of the residue by flash column chromatography (95:5
CH2Cl2–MeOH) afforded morpholine 5a (19mg,
20
˚
0.032mmol, 32%) as a clear oil; ½aŠ ¼ þ61:5 (c 1.0,
10A molecular sieves in methanol (20mL). Work-up
and purification of the crude residue by flash column
D
CHCl3); mmax (NaCl disc)/cmꢀ1 3454 (br s, OH), 2927
(s, CH), 1116 (s, C–O), 1054 (s, C–O); 1H NMR
(250MHz;CDCl ) 7.31–7.15 (15H, m, Ph), 4.90 (1H,
chromatography (6:4 hexane–EtOAc) afforded 5c
20
D
(18mg, 0.058mmol, 29%) as a clear oil; ½aŠ ¼ þ39:7 (c
3
d, J 11.0, PhCH2), 4.85 (1H, d, J 11.0, PhCH2), 4.84
(1H, d, J 10.0, PhCH2), 4.79 (1H, d, J 10.0, PhCH2),
4.67 (1H, d, J 11.0, PhCH2), 4.66 (1H, d, J 11.0,
0.9, CHCl3); mmax (NaCl disc)/cmꢀ1 3436 (br s, OH),
2929 (s, CH), 1731 (s, C@O), 1604 (w, C@C), 1161 (s,
C–O), 1058 (s, C–O); 1H NMR (250MHz;CDCl
)
3
0
PhCH2), 4.58 (1H, dd, J5a,6a 11.0 J5a ,6a 1.5, C(6a)H),
4.46 (1H, d, J1,2 3.5, C(1)H), 3.99–3.94 (1H, m,
C(2a)H), 3.90 (1H, app. t, J2,3 J3,4 9.5, C(3)H), 3.80
7.20–7.09 (5H, m, Ph), 4.68–4.66 (1H, m, C(6)H), 4.06–
4.01 (1H, m, C(2)H), 3.59–3.52 (1H, m, C(7,70)H), 3.49
(3H, s, OCH3), 3.40 (1H, dd, J 4.5 J 11.0, PhCH2CH),
3.37 (3H, s, OCH3), 3.07–2.94 (3H, m, PhCH2CH,
0
(1H, ddd, J4,5 8.5 J5,6 1.0 J5, 6 7.5, C(5)H), 3.57 (1H,
0
0
0
dd, J2a, 7a 1.0 J7a,7a 12.0, C(7a)H), 3.47 (1H, dd, J2a,7a
0
C(3)H), 2.71 (1H, app. d, J5,5 11.0, C(5)H), 2.57 (1H,
0
7.5 J7a,7a 12.0, C(7a0)H), 3.39 (1H, d, J1,2 3.5 J2,2
10.0, C(2)H), 3.32 (3H, s, OCH3), 3.29 (3H, s, OCH3),
3.26–3.20 (1H, m, C(4)H), 2.76 (1H, app. t, J5a,6a
dd, J2,3 3.0 J3,3 12.0, C(30)H), 2.36 (1H, app. t, J5 ,6
0
0
0
J5,5 11.0, C(50)H); 13C NMR (63MHz;CDCl ) 171.7
(CO), 137.8 (ArC), 129.6 (ArC), 128.8 (ArC), 127.0
0
3
0
J5a,5a ) 11.0, C(5a), 2.74 (1H, m, C(3a)H), 2.62 (1H,
(ArC), 97.6 (C6), 70.0 (PhCH2CH), 69.5 (C2), 64.3
(C7), 55.6 (OCH3), 53.3 (C5), 51.5 (OCH3), 50.6 (C3),
36.3 (PhCH2CH); m/z (CI) 310 (100%, [M+H]+), 278
(28%, [MꢀOCH3]+), 218 (83%, [MꢀPhCH2]+), found
[M+H]+ 310.1641, C16H24NO5 requires 310.1654.
0
0
dd, J5,6 1.0 J6, 6 14.0, C(6)H), 2.43 (1H, dd, J5,6 7.5
J6,6 14.0, C(60)H), 2.31 (1H, dd, J5a ,6a 1.5 J5a,5a 11.0,
0
0
0
C(5a0)H), 2.15 (1H, app. t, J3a,3a J2a,3a 11.0, C(3a0)H);
0
0
13C NMR (63MHz;CDCl ) 139.1 (ArC), 138.7 (ArC),
3

3648
S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
4.5. General method for access to 7-hydroxymethyl-[1,4]-
oxazepanes 6
4.7. (2S,6R,7S)-4-Benzyl-2-hydroxymethyl-7-methoxy-
[1,4]-oxazepan-6-ol 6b
4.5.1. Step 1: Synthesis of dialdehyde 2. A solution of
sodium periodate (1.2equiv) in distilled water was added
dropwise to a stirred solution of methyl a-D-glucopyr-
anoside (1equiv) in methanol at 0ꢁC. The reaction mix-
ture was stirred at room temperature for 4h and then
concentrated in vacuo with the resulting colourless solid
dissolved in ethyl acetate (100mL), filtered through
Celiteꢂ and concentrated in vacuo to yield the crude
dialdehyde 2 as a clear oil.
By following the general procedure described above, so-
dium cyanoborohydride (630mg, 10.0mmol) was added
to
a stirring solution of benzylamine (0.22mL,
˚
2.00mmol), dialdehyde (1.16g, 6mmol) and 10A mole-
cular sieves in methanol (40mL). Work-up and purifica-
tion by flash column chromatography (96:4 CH2Cl2–
MeOH) afforded[1,4]-oxazepane 6b as a clear oil
20
(111mg, 0.42mmol, 21%); ½aŠ ¼ þ66:0 (c 0.7, CHCl3);
D
mmax (NaCl disc)/cmꢀ1 3402 (br s, OH), 2924 (s, CH),
1172 (s, C–O), 1058 (s, C–O); 1H NMR (250MHz;
CDCl3) 7.40–7.28 (5H, m, Ph), 4.55 (1H, d, J6,7 4.0,
C(7)H), 4.23 (1H, m, C(2)H), 4.00 (1H, app. dd, J6,7
4.0 J5.6 6.5, C(6)H), 3.76 (2H, s, PhCH2N), 3.57 (1H,
4.5.2. Step 2: Reductive amination reactions to afford 7-
hydroxymethyl-[1,4]-oxazepanes 6. Sodium cyanoboro-
hydride (5equiv) was added to a stirring solution of
˚
0
dd, J2,8 4.5 J8,8 11.0, C(8)H), 3.51 (3H, s, OCH3), 3.49
amine (1equiv), dialdehyde (3equiv) and 10A molecular
(1H, dd, J2,8 6.0 J8,8 11.0, C(80)H), 3.05 (1H, dd, J5,6
0
0
sieves in methanol (40mL). The pH of the reaction mix-
ture was adjusted to 7 with 2M HCl (soln Et2O). After
stirring for 18h at room temperature, the reaction mix-
ture was concentrated in vacuo, partitioned between
H2O and dichloromethane (3 · 100mL) and the organic
phase dried over MgSO4, filtered and concentrated in
vacuo to yield the [1,4]-oxazepanes 6.
0
0
6.5 J5,5 12.5, C(5)H), 2.90 (1H, app. d, J3,3 12.5,
0
C(30)H), 2.72 (1H, app. d, J5,5 12.5, C(50)H), 2.44
(1H, dd, J2,3 10.0 J2,3 12.5, C(3)H); 13C NMR
0
(63MHz;CDCl 3) 137.6 (ArC), 129.5 (ArC), 128.8
(ArC), 128.1 (ArC), 102.5 (C7), 72.4 (C2), 69.4
(C6), 64.9 (C8), 63.5 (PhCH2), 58.6 (C3), 56.5
(OCH3), 54.8 (C5); m/z (CI) 268 (37%, [M+H]+), 236
(14%, [MꢀOCH3]+), 120 (66%, [PhCHNCH2]+),
found [M+H]+ 268.1542, C14H22NO4 requires
268.1549.
4.6. Methyl 2,3,4-tri-O-benzyl-6-deoxy-6-((2S,6R,7S)-6-
hydroxy-2-hydroxymethyl-7-methoxy-[1,4]-oxazepan-4-
yl)-a-D-glucopyranoside 6a
By following the general procedure detailed above, so-
dium cyanoborohydride (198mg, 3.15mmol) was added
to a stirred solution of methyl 2,3,4-tri-O-benzyl-6-
4.8. (2R)-[(2S,6R,7S)-6-Hydroxy-2-(hydroxymethyl)-7-
methoxy-[1,4]-oxazepan-4-yl]-3-phenyl-propionic acid
methyl ester 6c
deoxy-6-amino-a-D-glucopyranoside
0.63mmol), dialdehyde (362mg, 1.89mmol) and
10
(374mg,
˚
10A molecular sieves in methanol (40mL). Work-up and
By following the general procedure above, sodium
cyanoborohydride (630mg, 10.0mmol) was added to a
stirred solution of L-phenylalanine methyl ester
(432mg, 2.00mmol), dialdehyde (1.16g, 6mmol) and
purification of the residue by flash column chromatogra-
phy (99:1 CH2Cl2–MeOH) afforded [1,4]-oxazepane 6a
20
D
(122mg, 0.19mmol, 31%) as a clear oil; ½aŠ ¼ þ21:0
(c 1.0, CHCl3); mmax (NaCl disc)/cmꢀ1 3452 (br s, OH),
2918 (s, CH), 1178 (s, C–O), 1070 (s, C–O); H NMR
10A molecular sieves in methanol (40mL). The reaction
˚
1
mixture was stirred for 19h at room temperature, then
concentrated in vacuo, partitioned between 1M HCl
(100mL) and dichloromethane (3 · 100mL), and the
organic phase dried over MgSO4, filtered and concen-
trated in vacuo. Flash column chromatography (94:6
(250MHz;CDCl ) 7.30–7.16 (15H, m, Ph), 4.92 (1H,
3
d, J 11.0, PhCH2), 4.83 (1H, d, J 11.0, PhCH2), 4.71
(2H, d, J 10.0, PhCH2), 4.57 (1H, d, J 11.0, PhCH2),
4.48 (1H, d, J1,2 3.0, C(1)H), 4.47 (1H, d, J 11.0,
PhCH2), 4.44 (1H, d, J6a,7a 4.0, C(7a)H), 4.05 (1H, dd,
CH2Cl2–MeOH) of the residue yielded 6c (173mg,
20
D
0
J6a,7a J5a,6a 4.0 J5a 6a 9.0, C(6a)H), 3.91 (1H, app. t,
0.52mmol, 26%) as a clear oil; ½aŠ ¼ þ23:7 (c 1.0,
J2,3 J3,4 9.5, C(3)H), 3.88–3.85 (1H, m, C(2a)H), 3.71
(1H, app. t, J4,5 J5,6 9.0, C(5)H), 3.47–3.38 (3H, m,
C(2,8a,8a0)H), 3.40 (3H, s, OCH3), 3.32 (3H, s,
OCH3), 3.08 (1H, app. t, J3,4 J4,5 9.0, C(4)H), 2.91
CHCl3); mmax (NaCl disc)/cmꢀ1 3412 (br s, OH), 2949
(s, CH), 1732 (s, C@O), 1604 (w, C@C), 1173 (s,
C–O), 1068 (s, C–O); 1H NMR (250MHz;CDCl
)
3
7.34–7.17 (5H, m, Ph), 4.52 (1H, d, J6,7 4.0, C(7)H),
4.19–4.12 (1H, m, C(2)H), 3.97 (1H, app. dd, J5,6 J6,7
0
4.0 J5 ,6 7.0, C(6)H), 3.72 (1H, dd, J 8.0 J 12.0,
(2H, dd, J5,6 J5,6 1.5, J6,6 14.0, C(6,60)H), 2.85–2.76
0
0
(3H, m, C(3a,3a0,5a)H), 2.47 (1H, dd, J5a 6a 9.0 J5a,5a
0
0
0
13.0, C(5a0)H); 13C NMR (63MHz;CDCl 3) 139.0
(ArC), 138.6 (ArC), 138.4 (ArC), 128.9 (ArC), 128.7
(ArC), 128.6 (ArC), 128.4 (ArC), 128.2 (ArC),
128.1 (ArC), 102.8 (C7a), 98.4 (C1), 82.4 (C3), 80.3
(C2, C4), 76.2 (PhCH2O), 75.5 (PhCH2O), 73.8
(PhCH2O), 72.7 (C6a), 69.8 (C5), 69.6 (C2a), 65.1
(C8a), 60.6 (C6), 58.9 (C5a), 56.7 (C3a), 56.6 (OCH3),
56.1 (OCH3); m/z (CI) 624 (100%, [M+H]+), 533 (6%,
PhCH2CH), 3.70 (3H, s, OCH3), 3.61–3.49 (2H, m,
C(8,80)H), 3.48 (3H, s, OCH3), 3.21–3.15 (2H, m,
C(5)H, PhCH2CH), 2.96–2.74 (4H, m, C(50,3,30)H,
PhCH2CH); 13C NMR (63MHz;CDCl ) 172.6 (CO),
3
137.7 (ArC), 129.6 (ArC), 128.8 (ArC), 127.2 (ArC),
102.4 (C7), 72.6 (C2), 69.7 (PhCH2CH), 69.4 (C6),
64.7 (C8), 58.2 (C3), 56.4 (OCH3), 52.2 (OCH3), 50.5
(C5), 36.5 (PhCH2CH); m/z (CI) 340 (91%, [M+H]+),
308 (11%, [MꢀOCH3]+), 248 (83%, [MꢀPhCH2]+),
found [M+H]+ 340.1769, C17H26NO6 requires
340.1760.
[MꢀPhCH2]+),
410
(6%,
[MꢀPhCH2–PhCH2–
OCH3]+), 91 (38%, [PhCH2]+), found [M+H]+
624.3170, C35H46NO6 requires [M+H]+ 624.3167.

S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
3649
4.9. Synthesis of glutaric dialdehyde 11
tion of amine (1.1equiv), the dialdehydes (3equiv) and
˚
10A molecular sieves in methanol. The pH was adjusted
Ozone was bubbled through a stirred solution of 2,5-
dihydrofuran (0.17mL, 2.24mmol) in anhydrous metha-
nol (40mL) at ꢀ78ꢁC, which had been previously
flushed with nitrogen. Upon the formation of a blue col-
our, the reaction mixture was flushed with nitrogen until
the blue colour disappeared. Dialdehyde 11 was used
immediately in situ in subsequent reactions after allow-
ing the solution to warm to room temperature.
to 7 by the addition of 5M HCl in methanol. The reac-
tion mixture was stirred for 41h at room temperature
and then concentrated in vacuo. The residue was parti-
tioned between H2O and dichloromethane and the
organic phase dried over MgSO4, filtered and concen-
trated in vacuo.
4.12. Methyl 2,3,4-tri-O-benzyl-6-deoxy-6-[(2S,6R,7S)-2-
(tertbutyldiphenylsilanyloxymethyl)-6-hydroxy-7-meth-
oxy-[1,4]-oxazepan-4-yl]-a-D-glucopyranoside 6d
4.10. Methyl 6-deoxy-6-(morpholin-4-yl)-2,3,4-tri-O-benz-
yl-a-D-glucopyranoside 12
By following the general procedure above, sodium
cyanoborohydride (55mg, 1.05mmol) was added to a
stirred solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-6-
amino-a-D-glucopyranoside 10 (0.10g, 0.21mmol), the
A stirred solution of glutaric dialdehyde 11 (50mg,
0.50mmol) in methanol (50mL) was synthesised using
the above method, to which methyl 2,3,4-tri-O-benzyl-
˚
6-deoxy-6-amino-a-D-glucopyranoside
10
(0.10g,
dialdehydes (234mg, 0.63mmol) and 10A molecular
˚
0.21mmol) and powdered 4A molecular sieves (10mg)
were added. After 10min, sodium cyanoborohydride
(0.04g, 0.63mmol) was added and the reaction mixture
stirred for a further 48h. Upon completion, the reaction
mixture was concentrated in vacuo and partitioned
between 1M HCl (50mL) and dichloromethane
(4 · 50mL). The organic phase was dried over MgSO4,
filtered and concentrated in vacuo. Purification of the
residue by flash column chromatography (98:2–9:1
sieves in methanol (30mL). Work-up and purification
of the residue by flash column chromatography (8:2 hex-
ane–EtOAc) yielded [1,4]-oxazepane 6d as a clear oil
20
(52mg, 0.06mmol, 30%); ½aŠ ¼ þ21:0 (c 1.0, CHCl3);
D
mmax (NaCl disc)/cmꢀ1 1654 (w, C@C), 1454 (w, C@C),
1428 (w, C@C), 1071 (s, C–O); 1H NMR (400MHz;
CDCl3) 7.68–7.13 (25H, m, Ph), 5.00–4.53 (7H, m,
C(1)H, 3(PhCH2)), 4.42 (1H, d, J6a,7a 2.5, C(7a)H),
4.19–4.12 (1H, m, C(6a)H), 3.98 (1H, app. t, J2,3 J3,4
5.0, C(3)H), 4.00–3.95 (1H, m, C(2a)H), 3.80–3.73
CH2Cl2–MeOH) yielded 12 as a clear oil (38mg,
20
D
0
(1H, m, C(5)H), 3.58 (1H, dd, J2a,8a 2.5 J8a,8a 5.0,
C(8a)H), 3.47 (1H, dd, J1,2 2.5 J2,3 5.0, C(2)H), 3.42–
3.39 (1H, m, C(8a0)H), 3.32 (6H, s, OCH3), 3.15 (1H,
0.071mmol, 33%); ½aŠ ¼ þ25:0 (c 1.0, CHCl3); mmax
(NaCl disc)/cmꢀ1 2917 (s, CH), 1646 (w, C@C), 1497
1
(w, C@C), 1454 (w, C@C), 1071 (s, C–O); H NMR
0
(250MHz;CDCl ) 7.28–7.18 (15H, m, Ph), 4.93–4.53
app. t, J3,4 J4,5 5.0, C(4)H), 3.09 (1H, app. d, J3a,3a
0
3
(6H, m, PhCH2), 4.48 (1H, d, J1,2 5.0, C(1)H), 3.88
(1H, app. t, J2,3 J3,4 7.5, C(3)H), 3.84–3.70 (1H, m,
C(5)H), 3.66–3.58 (2H, m, C(6,60)H), 3.41 (1H, dd, J1,2
2.5 J2,3 10.0, C(2)H), 3.32–3.25 (4H, m, C(4)H,
OCH3), 2.50–2.33 (8H, m, CH2); 13C NMR (63MHz;
CDCl3) 139.1 (ArC), 138.9 (ArC), 138.6 (ArC), 128.9
(ArC), 128.8 (ArC), 128.7 (ArC), 128.5 (ArC), 128.4
(ArC), 128.2 (ArC), 128.0 (ArC), 98.3 (C1), 82.5 (C3),
80.4 (C2), 80.3 (C4), 76.3 (PhCH2), 75.5 (PhCH2), 73.8
(PhCH2), 69.1 (C5), 59.8 (C6), 55.8 (OCH3), 55 (CH2);
m/z (CI) 534 (82%, [M+H]+), 442 (23%, [MꢀPhCH2]+),
321 (18%, [MꢀOCH3–2PhCH2]+), 91 (100%, [PhCH2]+),
found: [M+H]+ 534.2852, C32H40NO6 requires [M+H]+
534.2856.
5.0, C(3a)H), 2.99 (1H, app. d, J6,6 7.5, C(6)H), 2.89–
0
2.82 (2H, m, C(5a,5a0)H), 2.53 (1H, dd, J6,6 ) 7.5,
J5,6 5.0, C(60)H, 2.41 (1H, dd, J3a,3a 5.0, J3a ,2a 7.5,
C(3a0)H, 1.05–1.01 (9H, m, (C(CH3)3)); 13C NMR
(101MHz;CDCl 3) 138.6 (ArC), 137.8 (ArC), 137.0
(ArC), 136.4 (ArC), 135.5 (ArC), 129.7–126.3 (Ph),
102.0 (C7a), 97.9 (C1), 82.0 (C3), 80.0 (C2), 80 (C4),
75.8 (PhCH2), 75.0 (PhCH2), 73.4 (PhCH2), 72.3
(C6a), 69.5 (C5), 69.2 (C2a), 65.5 (C8a), 60.3 (C6),
58.9 (C3a), 56.6 (C5a), 55.9 (OCH3), 55.6 (OCH3),
26.8 (C(CH3)3), 19.2 (C(CH3)3); m/z (CI) 862 (24%,
[M+H]+), 196 (66%, [CH2OSiPh2]+), 91 (100%,
[PhCH2]+), found: [M+H]+ 862.4372, C51H64NO9 Si
requires [M+H]+ 862.4350.
0
0
0
4.11. General method for reductive amination of O-
TBDPS methyl pyranoside 13
4.13. (2S,6S)-4-Benzyl-2-(tertbutyldiphenylsilanyloxy-
methyl)-6-methoxy-morpholine 5e, (2S,6R,7S)-4-benzyl-
2-(tertbutyldiphenylsilanyloxymethyl)-7-methoxy-[1,4]-
oxazepan-6-ol 6e and (2S,6S,7R)-4-benzyl-7-(tertbutyldi-
phenylsilanyloxymethyl)-2-methoxy-[1,4]-oxazepan-6-ol
7e
4.11.1. Step 1: Synthesis of dialdehydes. A solution of
sodium periodate (1.2equiv) in distilled water (20mL)
was added dropwise to a stirred solution of methyl
6-O tert butyldiphenylsilyl-a-D-glucopyranoside 13
(1equiv) in methanol at 0ꢁC, and the reaction mixture
stirred at room temperature for 4h. The reaction mix-
ture was concentrated in vacuo and the resulting colour-
less solid dissolved in ethanol (20mL), filtered through
Celiteꢂ and concentrated in vacuo to yield a mixture
of crude dialdehydes as a clear oil.
By following the general procedure above, sodium
cyanoborohydride (255mg, 4.05mmol) was added to a
stirred solution of benzylamine (0.09mL, 0.81mmol),
˚
the dialdehydes (1.05g, 2.43mmol) and 10A molecular
sieves in methanol (40mL). Work-up and purification
of the residue by flash column chromatography (9:1–
6:4 hexane–EtOAc) yielded 5e (95mg, 0.29mmol,
25%), 6e (101mg, 0.20mmol, 25%) and 7e (28mg,
0.056mmol, 7%) as clear oils.
4.11.2. Step 2: Reductive amination reaction. Sodium
cyanoborohydride (5equiv) was added to a stirred solu-

3650
S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
20
Compound 5e: ½aŠ ¼ þ72:0 (c 1.0, CHCl3); mmax (NaCl
4.14. (2R)-[(2S,6S)-2-(tertButyldiphenylsilanyloxy-
methyl)-6-methoxy-morpholin-4-yl]-3-phenyl-propionic
acid methyl ester 5f and (2R)-[(2S,6R,7S)-2-(tertbutyldi-
phenylsilanyloxymethyl)-6-hydroxy-7-methoxy-[1,4]-oxa-
zepan-4-yl]-3-phenyl-propionic acid methyl ester 6f
D
disc)/cmꢀ1 2924 (s, CH), 1611 (w, C@C), 1114 (s, C–O),
1
1047 (s, C–O); H NMR (400MHz;CDCl ) 7.59–7.54
3
(5H, m, Ph), 7.37–7.16 (10H, m, Ph), 4.65–4.64 (1H,
m, C(6)H), 4.12–4.09 (1H, m, C(2)H), 3.70 (1H, dd,
0
0
0
J2,7 5.0 J7,7 10.0, C(7)H), 3.58 (1H, dd, J2,7 5.0 J7,7
10.0, C(70)H), 3.53 (2H, s, PhCH2N), 3.38 (3H, s,
By following the general procedure above, sodium cya-
noborohydride (1.6g, 1.7mmol) was added to a stirred
solution of L-phenylalanine methyl ester (73mg,
0.34mmol), the dialdehydes (0.44g, 1.02mmol) and
0
OCH3), 2.89–2.83 (2H, m, C(3,5)H), 2.20 (1H, dd, J5,5
0
11.0 J5 ,6 3.0, C(50)H), 1.93 (1H, app. t, J2,3 J3,3 11.0,
0
0
C(30)H), 1.02 (9H, s, C(CH3)3); 13C NMR (101
MHz;CDCl ) 136.7 (ArC), 135.8 (ArC), 134.3 (ArC),
˚
10A molecular sieves in methanol (40mL). Work-up
3
129.7 (ArC), 129.1 (ArC), 128.7 (ArC), 128.2 (ArC),
127.9 (ArC), 127.7 (ArC), 127.2 (ArC), 97.2 (C6), 69.1
(C2), 65.2 (C7), 63.4 (PhCH2N), 55.7 (C5), 55.0 (C3),
54.8 (OCH3), 26.8 (C(CH3)3), 19.2 (C(CH3)3); m/z (CI)
476 (65%, [M+H]+), 446 (42%, [MꢀOCH3]+), 220
and purification of the residue by flash column chroma-
tography (8:2 Et2O–hexane) afforded morpholine 5f
(2mg, 0.0036mmol, 1%) and [1,4]-oxazepane 6f (39mg,
0.068mmol, 20%) as clear oils.
(41%,
[MꢀOSi(Ph2)C(CH3)3]+),
found
[M+H]+
20
476.2633, C29H38NO3Si requires 476.2621.
Compound 5f: ½aŠ ¼ þ18:8 (c 0.4, CHCl3); mmax (NaCl
D
disc)/cmꢀ1 2926 (s, CH), 2854 (s, CH), 1732 (s, C@O),
1113 (s, C–O), 1058 (s, C–O); 1H NMR (400MHz;
CDCl3) 7.74–7.18 (15H, m, Ph), 4.71–4.70 (1H, m,
C(6)H), 4.17–4.11 (1H, m, C(2)H), 3.70 (1H, dd,
20
Compound 6e: ½aŠ ¼ þ71:0 (c 1.0, CHCl3); mmax (NaCl
D
disc)/cmꢀ1 3325 (br s, OH), 2930 (s, CH), 1173 (s, C–O),
1063 (s, C–O); H NMR (250MHz;CDCl ) 7.53–7.17
1
0
0
0
J2,7 5.0 J7,7 11.0, C(7)H), 3.59 (1H, dd, J2,7 5.0 J7,7
3
11.0, C(70)H), 3.54 (3H, s, OCH3), 3.49 (1H, dd, J 3.0
J 11.0, PhCH2CH), 3.41 (3H, s, OCH3), 3.11 (2H, m,
(15H, m, Ph), 4.37 (1H, d, J6,7 4.0, C(7)H), 4.15–4.05
(1H, m, C(2)H), 3.88 (1H, app. dd, J6,7 4.0 J5,6 7.0,
C(6)H), 3.69 (1H, d, J 13.0, PhCH2N), 3.60 (1H, d, J
0
PhCH2CH), 2.99 (1H, dd, J2,3 18.0 J3,3 12.0, C(3)H),
0
0
2.95 (1H, app. d, J5,5 11.0, C(5)H), 2.61 (1H, dd, J2,3
0
0
13.0, PhCH2N), 4.52 (1H, dd, J2,8 5.0 J8,8 10.0,
0
2.5 J3,3 12.0, C(30)H), 2.29 (1H, app. t, J5 ,6 J5,5 11.0,
C(8)H), 3.31 (1H, dd, J2,8 7.0 J8,8 10.0, C(80)H), 3.29
0
0
0
C(50)H), 1.06 (9H, s, C(CH3)3); 13C NMR (101
MHz;CDCl ) 171.2 (CO), 137.6 (ArC), 136.6 (ArC),
0
(3H, s, OCH3), 3.01 (1H, dd, J2,3 5.0 J3,3 12.0,
0
C(3)H), 2.96 (1H, dd, J5,6 7.0 J5,5 12.0, C(5)H), 2.62
0
3
(1H, app. d, J5,5 12.0, C(50)H), 2.12 (1H, dd, J2,3 10.0
136.2 (ArC), 129.8 (ArC), 129.2 (ArC), 128.8 (ArC),
128.2 (ArC), 127.8 (ArC), 127.1 (ArC), 126.6
(ArC), 97.1 (C6), 69.8 (PhCH2CH), 69.3 (C2), 65.1
(C7), 55.1 (OCH3), 54.2 (C5), 51.0 (OCH3), 50.3 (C3),
36.0 (PhCH2CH), 26.8 (C(CH3)3), 19.2 (C(CH3)3); m/z
(EI) 547 (13%, [M]+), 488 (82%, [MꢀCO2CH3]+),
456 (100%, [MꢀPhCH2]+), found [M]+ 547.2742,
C32H41NO5Si requires 547.2754.
0
J3,3 12.0, C(30)H), 0.87 (9H, s, C(CH3)3); 13C NMR
0
(63MHz;CDCl 3) 138.2 (ArC), 137.7 (ArC), 135.9
(ArC), 130.1 (ArC), 129.7 (ArC), 128.9 (ArC), 128.2
(ArC), 128.0 (ArC), 127.9 (ArC), 102.3 (C7), 72.2
(C2), 69.6 (C6), 65.7 (C8), 63.8 (PhCH2N), 58.9 (C3),
55.5 (OCH3), 53.8 (C5), 27.1 (C(CH3)3), 19.5
(C(CH3)3); m/z (CI) 506 (10%, [M+H]+), 218 (12%,
[MꢀOCH3–OSi(Ph2)C(CH3)3]+), 120 (37%, [PhCH2N-
CH2]+), found [M+H]+ 506.2713, C30H40NO4Si
requires 506.2727.
20
Compound 6f: ½aŠ ¼ þ1:7 (c 1.9, CHCl3); mmax (NaCl
D
disc)/cmꢀ1 3382 (br s, OH), 2930 (s, CH), 1736 (s,
C@O), 1113 (s, C–O), 1069 (s, C–O); 1H NMR
(400MHz;CDCl 3) 7.60–7.54 (5H, m, Ph), 7.36–7.15
(10H, m, Ph), 4.43 (1H, d, J6,7 6.0, C(7)H), 4.12–4.05
(1H, m, C(2)H), 3.95–3.88 (1H, m, C(6)H), 3.68 (3H,
s, OCH3), 3.61 (1H, dd, J 10.0 J 5.0, PhCH2CH), 3.49
20
Compound 7e: ½aŠ ¼ þ79:0 (c 1.0, CHCl3); mmax (NaCl
D
disc)/cmꢀ1 3357 (br s, OH), 2915 (s, CH), 1113 (s, C–O),
1040 (s, C–O); H NMR (250MHz;CDCl ) 7.76–7.28
1
3
0
(15H, m, Ph), 4.62 (1H, dd, J2,3 9.0 J2,3 5.0, C(2)H),
0
0
(1H, dd, J2,8 6.0 J8,8 10.0 C(8)H), 3.39 (1H, dd, J2,8
0
4.02–3.97 (1H, m, C(7)H), 3.91–3.89 (3H, m,
C(6,8,80)H), 3.84 (1H, d, J 13.5, PhCH2N), 3.74 (1H,
d, J 13.5, PhCH2N), 3.22 (3H, s, OCH3), 3.19 (1H,
6.0 J8,8 10.0 C(80)H), 3.35 (3H, s, OCH3), 3.16 (1H,
0
dd, J 14.0 J 5.0, PhCH2H), 3.13 (1H, dd, J5,6 7.0 J5,5
0
12.5 C(5)H), 2.99 (1H, app. d, J3,3 12.0 C(3)H), 2.90
0
0
0
app. d, J5,5 5.0, C(5)H), 2.94 (1H, dd, J3,3 14.5 J2,3
5.0, C(30)H), 2.59 (1H, dd, J3,3 ) 14.5 (J2,3 9.0, C(3)H),
2.56–2.54 (1H, m, C(50)H), 1.10 (9H, s, C(CH3)3); 13C
NMR (63MHz;CDCl 3) 139.1 (ArC), 136.0 (ArC),
135.4 (ArC), 129.90 (ArC), 128.7 (ArC), 128.5 (ArC),
127.9 (ArC), 127.6 (ArC), 100.7 (C2), 72.6 (C6), 71.7
(C7), 67.3 (C8), 63.1 (C5), 61.8 (PhCH2N), 58.8 (C3),
55.8 (OCH3), 27.2 (C(CH3)3), 19.6 (C(CH3)3); m/z (CI)
506 (16%, [M+H]+), 274 (14%, [MꢀOSi(Ph2)-
C(CH3)2]+), 218 (43%, [MꢀOCH3–OSi(Ph2)C(CH3)3]+),
found [M+H]+ 506.2727, C30H40NO4Si requires
506.2727.
(1H, dd, J 14.0 J 10.0, PhCH2CH), 2.76–2.69 (2H, m,
C(50,30)H), 1.03 (9H, s, C(CH3)3); 13C NMR (63MHz;
CDCl3) 172.7 (CO), 137.9 (ArC), 136.8 (ArC), 135.0
(ArC), 129.9 (ArC), 129.3 (ArC), 128.7 (ArC), 128.2
(ArC), 127.9 (ArC), 127.6 (ArC), 127.1 (ArC), 102.1
(C7), 72.5 (C2), 69.9 (PhCH2CH), 69.5 (C6), 65.6 (C8),
58.6 (C3), 56.3 (OCH3), 52.0 (OCH3), 51.0 (C5), 36.3
(PhCH2CH), 27.2 (C(CH3)3), 19.6 (C(CH3)3); m/z (CI)
578 (63%, [M+H]+), 486 (82%, [MꢀPhCH2]+), 454
(10%, [MꢀOCH3–PhCH2]+), found [M+H]+ 578.2939,
C33H44NO6Si requires 578.2938.
0

S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
3651
4.15. General method for entry to [1,4]-oxazepanes 7
4.17. ((2S,6S,7R)-4-Benzyl-6-benzyloxy-2-methoxy-[1,4]-
oxazepan-7-yl)-methanol 7h
4.15.1. Step 1: Synthesis of dialdehyde. A solution of
sodium periodate (1.2equiv) in distilled water was added
dropwise to a stirred solution of methyl 4-O-benzyl-a-D-
glucopyranoside 14 (1equiv) in methanol at 0ꢁC and
then the reaction mixture stirred at room temperature for
1.5h. The reaction mixture was concentrated in vacuo
and the resulting colourless solid dissolved in ethanol,
filtered through Celiteꢂ and concentrated in vacuo to
yield the crude dialdehyde 14 as a colourless foam.
By following the general procedure above, sodium cya-
noborohydride (527mg, 8.35mmol) was added to a stir-
red solution of benzylamine (0.18mL, 1.67mmol),
˚
dialdehyde (1.4g, 5.01mmol) and 10A molecular sieves
in methanol (20mL). Work-up and purification of the
residue by flash column chromatography (2:8 hexane–
Et2O) afforded 7h as a clear oil (136mg, 0.38mmol,
20
23%); ½aŠ ¼ þ91:5 (c 1.0, CHCl3); 1H NMR
D
(250MHz;CDCl ) 7.29–6.91 (10H, m, Ph), 4.69 (1H,
3
0
dd, J2,3 13.0 J2,3 8.0, C(2)H), 4.54 (1H, d, J 12.5,
PhCH2O), 4.46 (1H, d, J 12.5, PhCH2O), 3.95 (1H,
4.15.2. Step 2: Reductive amination reaction. Sodium
cyanoborohydride (5equiv) was added to a stirred solu-
tion of the amine (1equiv), the dialdehyde (3equiv) and
0
ddd, J6,7 13.0 J7,8 9.0 J7,8 4.0, C(7)H), 3.88–3.79 (4H,
m, C(8,80)H, PhCH2N), 3.60 (1H, ddd, J5,6 9.0 J5 ,6 5.0
J6,7 13.0, C(6)H), 3.39 (3H, s, OCH3), 3.28 (1H, dd,
˚
0
10A molecular sieves in methanol. After stirring for 24h
at room temperature, the reaction mixture was concen-
trated in vacuo. The residue was partitioned between
H2O and dichloromethane and the organic phase dried
over MgSO4, filtered and concentrated in vacuo.
0
0
J5,5 5.0 J5,6 9.0, C(5)H), 3.02 (1H, dd, J2,3 13.0 J3,3
5.0, C(3)H), 2.64–2.50 (2H, m, C(30,50)H); 13C NMR
(63MHz;CDCl 3) 139.1 (ArC), 138.3 (ArC), 129.1
(ArC), 128.8 (ArC), 128.2 (ArC), 127.9 (ArC), 127.6
(ArC), 100.9 (C2), 76.5 (C6), 72.8 (C7), 72.6 (PhCH2O),
64.4 (C8), 61.4 (PhCH2N), 60.4 (C5), 58.4 (C3), 55.9
(OCH3); m/z (CI) 358 (58%, [M+H]+), 328 (14%,
[MꢀOCH3]+), 266 (13%, [MꢀPhCH2]+), found:
[M+H]+ 358.2002, C21H28NO4 requires [M+H]+
358.2018.
4.16. Methyl 2,3,4-tri-O-benzyl-6-deoxy-6-((2S,6S,7R)-6-
benzyloxy-7-hydroxymethyl-2-methoxy-[1,4]-oxazepan-4-
yl)-a-D-glucopyranoside 7g
By following the general procedure above, sodium
cyanoborohydride (28mg, 0.45mmol) was added to a
stirred solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-6-
amino-a-D-glucopyranoside 10 (45mg, 0.09mmol), dial-
4.18. (2R)-((2S,6S,7R)-6-Benzyloxy-7-hydroxymethyl-2-
methoxy-[1,4]-oxazepan-4-yl)-3-phenyl-propionic acid
methyl ester 7i
˚
dehyde (84mg, 0.27mmol) and 10A molecular sieves in
methanol (25mL) and the pH of the reaction mixture
adjusted to 7 using HCl (0.20mL, 2M soln in Et2O).
Work-up and purification of the residue by flash column
By following the general procedure above, sodium
cyanoborohydride (747mg, 11.9mmol) was added to
a stirred solution of L-phenylalanine methyl ester
(512mg, 2.37mmol), dialdehyde (2.22g, 7.11mmol)
chromatography (97:3 CH2Cl2–MeOH) afforded 7g
20
D
(31mg, 4.14mmol, 46%) as a clear oil; ½aŠ ¼ þ53:5 (c
0.2, CHCl3); mmax (NaCl disc)/cmꢀ1 3503 (br s, OH),
2924 (s, CH), 1496 (w, C@C), 1070 (s, C–O); 1H
and 10A molecular sieves in methanol (100mL). The
˚
NMR (400MHz;CDCl ) 7.39–7.15 (20H, m, Ph), 5.00
reaction mixture was stirred for 2h at room temperature
and then concentrated in vacuo. The residue was parti-
tioned between 1M HCl (200mL) and dichloromethane
(3200mL) and the organic phase dried over MgSO4, fil-
tered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (8:2 Et2O–
3
(1H, d, J 11.0, PhCH2O), 4.93 (1H, d, J 11.0, PhCH2O),
4.81 (1H, d, J 10.5, PhCH2O), 4.78 (1H, d, J 10.5,
PhCH2O), 4.65–4.61 (2H, m, C(2a)H, PhCH2O), 4.51
(1H, d, J1,2 3.5, C(1)H), 4.48 (1H, d, J 11.0, PhCH2O),
4.40 (1H, d, J 11.0, PhCH2O), 4.14 (1H, d, J 11.0,
PhCH2O), 3.99 (1H, app. t, J2,3 J3,4 9.0, C(3)H), 3.85
hexane) to yield 7i (545mg, 1.26mmol, 53%) as a clear
20
0
(1H, ddd, J4,5 12.0 J5,6 1.0 J5,6 9.0, C(5)H), 3.80 (3H,
0
oil; ½aŠ ¼ þ64:3 (c 1.0, CHCl3); mmax (NaCl disc)/
D
m, C(7a,8a,8a0)H), 3.56 (1H, ddd, J5a,6a 5.0 J5a ,6a 9.0
J6a,7a 12.0, C(6a)H), 3.45 (1H, dd, J1,2 3.5 J2,3 10.0,
cmꢀ1 3479 (br s, OH), 2905 (s, CH), 1732 (s, C@O),
1604 (w, C@C), 1070 (s, C–O); 1H NMR (250MHz;
CDCl3) 7.35–7.18 (10H, m, Ph), 4.63 (1H, dd, J2,3 5.0
C(2)H), 3.38 (3H, s, OCH3), 3.36 (3H, s, OCH3), 3.35–
0
0
J2,3 3.0, C(2)H), 4.59 (1H, d, J 11.5, PhCH2O), 4.53
3.31 (1H, m, C(4)H), 3.25 (1H, dd, J5a,6a 5.0 J5a,5a
0
13.0, C(5a)H), 3.18 (1H, dd, J2a,3a 5.0 J3a,3a 15.0,
(1H, d, J 11.5, PhCH2O), 3.89 (1H, ddd, J6,7 13.0 J7,8
0
0
C(3a)H), 3.02 (1H, dd, J5,6 1.0 J6, 6 14.0, C(6)H), 2.72
9.0 J7,8 3.0, C(7)H), 3.70 (2H, m, C(8,80)H), 3.64 (3H,
s, OCH3), 3.52 (2H, m, C(6)H, PhCH2CH), 3.39 (3H,
(1H, dd, J5, 6 7.5 J6,6 14.0, C(60)H), 2.64–2.59 (2H, m,
C(3a0,5a0)H); 13C NMR (101MHz;CDCl 3) 138.7
(ArC), 138.4 (ArC), 138.1 (ArC), 137.9 (ArC), 128.5–
127.7 (ArC), 100.5 (C2a), 98.0 (C1), 82.1 (C3), 80.1
(C2), 79.5 (C4), 76.1 (C6a), 75.8 (PhCH2O), 75.1
(PhCH2O), 73.4 (PhCH2O), 72.5 (PhCH2O), 72.0 (C5),
70.1 (C7a), 64.0 (C8a), 60.6 (C5a), 59.6 (C6), 57.0
(C3a), 55.6 (OCH3, OCH3); m/z (CI) 714 (100%,
[M+H]+), 578 (22%, [MꢀPhCH2–OCH3]+), 548 (8%,
0
0
0
s, OCH3), 3.30 (1H, dd, J5,5 13.0 J5,6 5.0, C(5)H), 3.11
0
(1H, dd, J2,3 5.0 J3,3 15.0, C(3)H), 3.05 (1H, dd, J
13.5 J 8.0, PhCH2CH), 2.88 (1H, dd, J 13.5 J 8.0,
PhCH2CH), 2.73 (1H, dd, J2,3 8.0 J3,3 15.0, C(30)H),
0
0
2.52 (1H, dd, J5,5 13.0 J5 ,6 9.0, C(50)H) ; 13C NMR
(63MHz;CDCl ) 172.9 (COCH3), 138.4 (ArC), 138.2
0
0
3
(ArC), 129.6 (ArC), 129.0 (ArC), 128.8 (ArC), 128.1
(ArC), 127.5 (ArC), 126.9 (Ph), 100.7 (C2), 77.2 (C6),
72.8 (PhCH2O), 72.2 (C7), 70.5 (PhCH2CH), 64.3
(C8), 58.7 (C3), 57.4 (C5), 55.8 (OCH3), 51.9 (OCH3),
[MꢀPhCH2–OCH3–OCH3]+),
found:
[M+H]+
714.3643, C42H52NO9 requires [M+H]+ 714.3637.

3652
S. M. Clark, H. M. I. Osborn / Tetrahedron: Asymmetry 15 (2004) 3643–3652
36.7 (PhCH2CH); m/z (CI) 430 (7%, [M+H]+), 338 (18%,
9. Herreros, E.;Almela, M. J.;Lozano, S.;De Las Heras, F.
G.;Gargallo-Viola, D. Antimicrob. Agents Chemother.
2001, 45, 3132.
10. Okazaki, S.;Shirai, N.;Sato, Y. J. Org. Chem. 1990, 55,
334.
[MꢀPhCH2]+),
454
(10%,
[MꢀOCH3–PhCH2–
PhCH2]+), found [M+H]+ 430.2224, C24H32NO6 re-
quires 430.2230.
11. (a) El Ashry, E. S. H.;Abdel-Rahman, A. A. H.;Kattab,
M.;Shobier, A. H.;Schmidt, R. R. J. Carbohydr. Chem.
2000, 19, 345;(b) Alper, J. Science 2001, 291, 2338;(c) Li,
Acknowledgements
´
H.;Ble riot, Y.;Chanterau, C.;Mallet, J.-M.;Sollogoub,
M.;Zhang, Y.;Rodriguez-Garcia
Barbero, J.;Sinay , P. Org. Biochem. 2004, 2, 1492, and
¨
references cited therein.
We gratefully acknowledge the EPSRC for their finan-
cial support of this work.
´
´
Vogel, P.;Jime nez-
12. (a) Grinsteiner, T. J.;Kishi, Y. Tetrahedron Lett. 1994, 45,
8333;(b) Grinsteiner, T. J.;Kishi, Y. Tetrahedron Lett.
1994, 45, 8337.
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