The synthesis of carbohydrate α-amino acids utilizing the Corey-Link reaction

Article abstract of DOI:10.1071/CH04015

Various carbohydrate ketones (uloses) have been treated with chloroform under strongly basic conditions to yield trichloromethyl tertiary alcohols. These alcohols, when subjected to the conditions of the modified Corey-Link reaction (sodium azide and 1,8-

Full text of DOI:10.1071/CH04015

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 723–732
The Synthesis of Carbohydrate α-Amino Acids Utilizing
the Corey–Link Reaction
Adrian Scaffidi,A Brian W. Skelton,A Robert V. Stick,A,B and Allan H. WhiteA
A Chemistry, School of Biomedical and Chemical Sciences M313, University of Western Australia,
Crawley WA 6009, Australia.
B Author to whom correspondence should be addressed (e-mail: rvs@chem.uwa.edu.au).
Various carbohydrate ketones (uloses) have been treated with chloroform under strongly basic conditions to yield
trichloromethyl tertiary alcohols. These alcohols, when subjected to the conditions of the modified Corey–Link
reaction (sodium azide and 1,8-diazabicyclo[5.4.0]undec-7-ene in methanol), generally gave the expected azido
ester with complete stereocontrol. Subsequent transformations on these azido esters provided amino esters, azido
acids, and, in one case, the amino acid. A similar sequence applied to a protected d-glucono-1,5-lactone was only
partly successful.
Single-crystal X-ray structures are reported for 1,2:5,6-di-O-isopropylidene-3-C-trichloromethyl-α-d-
allose, (3S)-3-C-azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-α-d-ribo-hexose, 1,2:5,6-di-O-cyclo
hexylidene-3-C-trichloromethyl-α-d-gulose, (3S)-3-C-amino-1,2:5,6-di-O-cyclohexylidene-3-deoxy-3-C-methoxy
carbonyl-α-d-xylo-hexose, methyl 2-O-benzyl-4,6-O-benzylidene-3-C-trichloromethyl-α-d-alloside, methyl
(2S)-2-C-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-C-methoxycarbonyl-α-d-arabino-hexoside, methyl 2,3-
di-O-benzyl-6-deoxy-4-C-trichloromethyl-β-d-galactoside, 3,4,5,7-tetra-O-benzyl-1,1,1-trichloro-1-deoxy-α-d-
gluco-hept-2-ulose, and 5-O-benzyl-1,2-O-isopropylidene-3-C-trichloromethyl-α-d-ribose.
Manuscript received: 22 January 2004.
Final version: 26 March 2004.
NH2
O
HO2C
HO
HO
HO2C
Introduction
O
HO
HO
Proteins, nucleic acids, and polysaccharides are the three
classes of biopolymer that together are responsible for the
well being of most life forms. The monomers from which
these biopolymers are constituted are the amino acids, the
nucleotides, and the monosaccharides. It is obvious that a
change in the structure of each of these monomers could lead
to new sorts of polymers. We envisaged that a carbohydrate
α-amino acid, a monomer with the dual characteristics of
an amino acid and a monosaccharide, could lead to inter-
esting new polypeptides and polysaccharides. In addition, if
the carbohydrate α-amino acid also incorporated a purine
or pyrimidine base, there would be the chance to prepare
interesting mimics of nucleic acids.
NH2 OH
OH
1
2
O
O
HO2C
O
O
NH2
O
O
NH2
O
HO2C
O
3
4
Scheme 1.
Carbohydrate (or sugar) amino acids are not novel—
molecules such as 1[1] and 2[2] are components of polysac-
charides and various reviews have appeared on structural
variants thereof, for example, 3 (Scheme 1).[3–5] Not sur-
prisingly, some of these variants have been converted into
oligomers, generating both linear and cyclic oligopeptides of
interesting structure.[6] We decided to focus our attention on
carbohydrate α-amino acids, say of structure 4, for two rea-
sons: one, the amino acid is configurationally stable, having
no α-hydrogen, and two, there seemed a ready synthetic route
to such molecules.
One of the most reliable (and oldest) routes to α-amino
acids involves the treatment of a ketone (here) with ammo-
nium chloride and sodium cyanide, the so-called Strecker
synthesis.[7] A variation of such a process has been applied
to carbohydrate ketones (uloses), for example, the transfor-
mation of 5 into 6 (and thence potentially 7), but the presence
of a Lewis acid (titanium(iv) isopropoxide) was essential to
form the intermediate imine, and hence the amino nitrile
6 (Scheme 2).[8] The related Bucherer–Bergs reaction pro-
vides hydantoins that are direct precursors of α-amino acids
(Scheme 3).[8,9]
© CSIRO 2004
10.1071/CH04015
0004-9425/04/080723

724
A. Scaffidi et al.
Corey and Link have reported a novel method for the
the process (9 and 4) would be the opposite of that for the
Strecker and related reactions.
This paper describes our efforts towards the synthesis of
carbohydrate α-amino acids and their precursors, using the
modified Corey–Link reaction,[11,12] and is a full report on
our earlier communication.[13]
synthesis of α-amino acids, involving the treatment of a
trichloromethyl alcohol with sodium azide in aqueous base
(Scheme 4A); a subsequent reduction step then provides the
amino acid.[10] The whole process was improved somewhat
by Domínguez and coworkers who used sodium azide and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol to
provide the azido ester, a direct precursor of the α-amino
acid (Scheme 4B).[11]
We were attracted to this Corey–Link approach for two
reasons: one, the required trichloromethyl alcohols, such as 8
(Scheme 5), would be readily available from the correspond-
ing ketones,[11,12] and two, the stereochemical outcome of
Results and Discussion
As a logical starting point, the ketone 5[14] (Scheme 5) was
converted into the (3R)-configured alcohol 8 [the ideal base
was lithium bis(trimethylsilyl)amide[11]];[13] a single-crystal
X-ray structure determination confirmed both the absolute
O
O
O
O
O
O
O
O
CN
O
CO2H
(a)
hydrolysis
O
O
O
NH2
NH2
O
O
O
O
5
6
7
Scheme 2. (a) Ti(OPri)4, NH3, MeOH, followed by Me3SiCN.
H
N
O
O
O
CO2H
Bui
Bui
Bui
O
NH
NH2
O
(a)
(b)
O
O
OCH3
OCH3
OCH3
O
O
O
HO
OH
(mainly)
Scheme 3. (a) NaCN, (NH4)2CO3, EtOH, H2O; (b) CH3COOH, H2O, followed by Ba(OH)2 · 8H2O, H2O.
(a)
(b)
Cl3C
HO
N3
H2N
Cl2C
A
B
O
CO2H
CO2H
(a)
Cl3C
HO
N3
H2N
CO2Me
CO2H
Scheme 4. A, (a) NaN3, NaOH, H2O, 1,2-dimethoxyethane; (b) H2, Pd. B, (a) NaN3, DBU, [18]crown-6, MeOH.
O
O
O
O
O
O
O
O
CCl3
O
(a)
(b)
N3
O
O
O
OH
MeO2C
O
O
O
O
5
8
9
O
O
O
NH2
O
HO2C
O
4
Scheme 5. (a) CHCl3, base; (b) Corey–Link.

Synthesis of Carbohydrate α-Amino Acids
725
O
O
O
Ph
Ph
O
O
O
O
O
O
O
O
O
NH2
HO
N3
HO2C
BnO
BnO
O
OMe
OMe
O
O
O
MeO2C
O
20
21
22
10
11
Ph
Ph
O
O
O
O
O
O
BnO
Scheme 6.
BnO
O
HO
OMe
OMe
O
O
OH
23
O
O
Scheme 9.
O
O
O
O
O
O
O
24
26
27
28
X ϭ CCl3, Y ϭ OH
Ph
O
12
13
O
O
X ϭ N3, Y ϭ CO2Me
X ϭ N3, Y ϭ CO2H
X ϭ NH2, Y ϭ CO2Me
X
Scheme 7.
BnO
OMe
Y
O
O
OH
(a)
(b)
D-galactose
O
O
O
O
O
25
29
30
31
X ϭ CCl3, Y ϭ OH
X ϭ N3, Y ϭ CO2Me
X ϭ N3, Y ϭ CO2H
X ϭ NH2, Y ϭ CO2Me
Ph
O
X
O
O
O
O
O
O
BnO
Y
14
15
OMe
O
CCl3
O
N3
Scheme 10.
(c)
(d )
O
O
OH
O
O
O
CO2Me
O
we prepared the related acetal 14 (Scheme 8) in a slightly
improved manner[15] and oxidation gave the ketone 15, the
precursor of the alcohol 16. A modified Corey–Link reaction
on 16 gave the azido ester 17, and subsequent transforma-
tions gave the azido acid 18 and the amino ester 19. The
configuration of the newly formed stereocentres in 16 and
19 were again confirmed by single-crystal X-ray structure
determinations (Figs 3 and 4); in 16 alone, among the present
structure determinations, two (rather than one) independent
molecule(s) devoid of crystallographic symmetry comprise
the asymmetric unit of the structure. Here, the two differ only
trivially in geometrical descriptors.
With these successes in furanose examples we turned our
attentiontopyranoses—ourimprovedsynthesisofthealcohol
20[16] still provided amounts of the isomeric 21 (Scheme 9).
Oxidation of both alcohols gave the ketones 22 and 23
and the normal addition of chloroform gave the alcohols
24 and 25, respectively (Scheme 10). Only the alcohol 24 was
amenable to a single-crystal X-ray structure determination
(Fig. 5).
The submission of the alcohols 24 and 25 to the modified
Corey–Link reaction, followed by the usual transformations
as outlined in Scheme 8, gave the suites of compounds
26–28 and 29–31, respectively (Scheme 10). The structure
of 29 was confirmed from a single-crystal X-ray structure
determination (Fig. 6).
It seemed logical next to try the sequence on the alcohol
32[17] (Scheme 11). Oxidation of 32 gave the ketone 33 and
the normal addition of chloroform certainly gave an alcohol,
of suggested structure 34. However, all attempts to perform
O
O
17
16
O
X
(e)
(f )
18 X ϭ N3, Y ϭ CO2H
O
Y
O
19 X ϭ NH2, Y ϭ CO2Me
O
O
Scheme 8. (a) Cyclohexanone dimethyl acetal, pyridinium
p-toluenesulfonate, dimethylformamide, PhMe; (b) pyridinium dichro-
mate, Ac2O, CH2Cl2; (c) CHCl3, lithium bis(trimethylsilyl)amide,
tetrahydrofuran; (d) NaN3, DBU, [18]crown-6, MeOH; (e) KOH,
MeOH; (f) H2, Pd/C, MeOH.
and relative stereochemistries of 8. Along with the other
determinations presented in this paper, ring conformational
descriptors are presented in Tables 1, 2, and 3 and molecular
projections are given in Fig. 1.
The subsequent modified Corey–Link reaction gave an
azido ester, presumably of structure 9, and this was converted
into an azido acid 10 (saponification; Scheme 6), amino ester
11 (hydrogenolysis), and amino acid 4 (saponification and
hydrogenolysis; Scheme 5).[13] A single-crystal X-ray struc-
ture determination of 10 (Fig. 2) confirmed all of the assigned
stereochemistries and indicated that the Corey–Link reaction
had indeed proceeded with inversion of configuration (at C3).
Although we next wanted to repeat the above sequence on
the ketone 12 (Scheme 7), the synthetic routes to the pre-
requisite alcohol 13 are either long or unreliable. Therefore,

726
A. Scaffidi et al.
O(6)
the modified Corey–Link reaction on 34 failed to produce an
azido ester—the only isolated product was benzyl alcohol!
Also unsuccessful was the sequence starting with the methyl
β-d-glucoside 35 (Scheme 12)—although the ketone 36 and
N(33)
C(6)
N(31)
C(561)
C(56)
N(32)
O(4)
C(5)
C(562)
C(1)
Table 1. Ring torsion angles [◦] for five-membered mono-oxo rings
C(4)
O(5)
C(2)
O(1)
C(12)
C(122)
C(3)
Bond
Compound/molecule
8
10
16/1,2
19
46
O(31)
C(31)
O(4)–C(1) −32.1(1) −24.2(4) −39.7(6)
40.2(4) −32.3(8)
O(2)
C(1)–C(2)
C(2)–C(3)
11.4(1)
11.2(1)
0.0(4)
22.0(4)
21.5(6) −22.3(5)
−5.6(6) −2.3(5)
12.0(9)
10.8(8)
O(32)
C(3)–C(4) −29.8(1) −36.8(4) −11.3(6)
26.4(5) −30.0(9)
C(121)
C(4)–O(4) 39.4(1) 39.2(4)
26.2(6) −42.1(4)
37.2(9)
Table 2. Ring torsion angles [◦] for six-membered mono-oxo rings
Fig. 2. Molecular projection of 10.
Bond
Compound
Cl(132)
24A
29
39
42
O(5)–C(1)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–O(4)
C(5)–O(5)
−57.6(2)
40.2(2)
−56.8(2)
54.4(2)
38.0(3)
26.0(3)
−54.2(5)
54.2(5)
Cl(133)
Cl(131)
C(152)
C(153)
−35.4(2)
−54.8(2)
−61.0(3)
−56.1(6)
O(14)
47.1(2)
59.2(2)
33.5(4)
57.5(6)
C(14)
C(11)
−65.7(2)
71.3(2)
−62.0(2)
60.3(2)
24.8(3)
−65.7(5)
−54.4(5)
55.3(5)
C(154)
C(155)
O(15)
C(151)
C(16)
C(12)
C(13)
O(13)
O(11)
C(121)
C(156)
O(16)
A In the dioxo ring of 24, torsions in the bonds O(4)–C(4), C(4)–
C(5) and so forth are: −59.3(2), 55.1(3), −55.0(2), 59.2(2), −65.5(3),
65.5(2); those in 29 are: −60.7(2), 58.0(2), −55.3(2), 57.6(2), −61.6(2),
62.6(2)◦. In the carbocyclic rings of 19, torsions in C(n1)–C(n2), C(n2)–
C(n3) and so forth are: 50.0(6), −52.1(6), 55.7(6), −57.5(6), 55.7(5),
−51.9(6) (n = 1); 52.0(6), −54.7(7), 58.4(7), −57.2(7), 53.4(7),
−51.6(6)◦ (n = 5).
C(15)
C(122)
O(12)
C(123)
C(126)
C(124)
C(125)
Cl(72)
Fig. 3. Molecular projection of 16.
Cl(73)
Cl(71)
C(7)
C(55)
C(561)
C(54)
O(4)
C(5)
C(6)
C(1)
O(5)
C(56)
C(1)
N(3)
C(53)
C(52)
C(4)
C(2)
C(3)
C(56)
O(6)
C(6)
O(5)
C(5)
O(1)
C(4)
C(3)
O(6)
O(2)
C(2)
C(51)
O(3)
O(1)
C(12)
C(122)
C(562)
C(31)
O(32)
C(14)
C(15)
O(2)
C(13)
C(12)
O(31)
C(11)
C(16)
C(121)
C(32)
Fig. 1. Molecular projection of 8.
Fig. 4. Molecular projection of 19.
Table 3. Ring torsion angles [◦] for five-membered 1,3-dioxo ringsA
Bond
Compound (rings)
8 (1,5)
10 (1,5)
16 (1,5 (molecules 1; 2))
19 (1,5)
46 (1)
C–Cꢀ
C–O
−21.6(5); 36.1(5)
22.3(5); −34.4(5)
13.0(5); −25.2(5)
−14.3(5); 19.7(5)
−0.1(5); 4.5(5)
−2.7(4); 18.1(3)
−17.5(4); 1.6(4)
21.9(4); −31.5(4)
31.4(4); −20.9(4)
−32.8(4); 32.9(4)
23.1(5), 13.7(6); 19.1(6), 25.4(5)
−34.6(6), 6.7(6); −32.0(6), −7.4(6)
−3.8(6), −29.1(6); 0.6(6), −34.6(5)
33.0(6), −24.5(6); 33.1(6), −13.5(6)
−17.3(6), 33.5(6); −20.3(6), 30.4(6)
−21.6(5); 36.1(5)
−22.3(5); −34.4(5)
13.0(5); −25.2(5)
−14.3(5); 19.7(5)
−0.1(5); 4.5(5)
10.0(10)
−20.0(10)
3.3(11)
22.0(11)
−15.3(12)
Cꢀ–Oꢀ
O–Cꢀꢀ
Oꢀ–Cꢀꢀ
A In rings 1, C,Cꢀ,Cꢀꢀ are C(1,2,12), O,Oꢀ are O(1,2); in rings 5, counterparts are C(5,6,56), O(5,6).

Synthesis of Carbohydrate α-Amino Acids
727
OH
OBn
O
OBn
O
OBn
O
C(42)
C(43)
O
Cl(32)
Cl3C
BnO
HO
BnO
C(6)
C(44)
C(40)
C(41)
O(6)
BnO
O(5)
BnO
BnO
BnO
C(4)
OMe
OMe
OMe
O(4)
C(46)
C(5)
32
33
Scheme 11.
34
C(45)
C(1)
C(31)
C(101)
C(2)
O(1)
Cl(33)
C(3)
Cl(31)
O(3)
O(2)
C(10)
OBn
O
OBn
O
O
BnO
C(11)
HO
BnO
OMe
OH
OMe
C(12)
BnO
BnO
C(16)
35
36
C(15)
C(13)
OBn
C(14)
O
Cl3C
BnO
OMe
BnO
Fig. 5. Molecular projection of 24.
37
Scheme 12.
N(23)
N(22)
N(21)
C(60)
C(62)
O(6)
C(63)
C(61)
OH
C(6)
O(5)
C(1)
C(5)
O
O
C(66)
O(4)
C(36)
Cl3C
BnO
C(65)
HO
BnO
C(64)
C(4)
O(3)
OMe
OMe
C(2)
BnO
BnO
O(21)
C(3)
C(21)
38
39
C(33)
C(31)
C(32)
C(30)
O(1)
Scheme 13.
C(11)
O(22)
trichloromethyl alcohol 39 [which was, incidentally, crys-
talline and the subject of a single-crystal X-ray structure
determination(Fig. 7)]. Somewhattoourdismay, benzylalco-
hol was still formed when 39 was subjected to the modified
Corey–Link procedure. Our last effort was to record the 1H
NMR spectrum of 34 in [D4]ethanol immediately after the
addition of a few drops of DBU (Fig. 8b)—the result is, at
best, perplexing.
Although it is annoying and frustrating to yield to a chem-
ical problem, we decided that the preparation of a ‘mixed’
ether such as 40 (Scheme 14), which would surely cast
light on the untoward processes at hand, was not worth the
effort.
Our final effort in the pyranose series was to treat the
lactone 41[19] (Scheme 15) with chloroform and lithium
bis(trimethylsilyl)amide—although the desired ulose 42 was
the major product [with the structure being confirmed by
a single-crystal X-ray structure determination (Fig. 9)], the
unsaturated lactone 43 was a significant by-product. Unfor-
tunately, the treatment of 42 under modified Corey–Link
conditions (again) gave only benzyl alcohol.
C(22)
Fig. 6. Molecular projection of 29.
C(6)
O(4)
Cl(42)
C(5)
C(4)
O(1)
O(5)
C(41)
C(2)
Cl(43)
C(11)
C(33)
C(32)
C(3)
C(1)
O(3)
C(34)
C(35)
C(30)
C(20)
C(21)
C(31)
C(36)
C(26)
C(25)
C(22)
C(24)
C(23)
Fig. 7. Molecular projection of 39.
Our efforts so far had produced a variety of derivatives
of carbohydrate α-amino acids that would be suitable build-
ing blocks for the construction of novel oligopeptides and
oligosaccharides—what was still needed, for oligonucleotide
synthesis, was a nucleoside α-amino acid.
Towards this end, an improved synthesis of the alcohol
44 (Scheme 16) led to the ketone 45 and the alcohol 46,
the structure of which was confirmed from a single-crystal
theprobablealcohol 37couldbeeasilyproduced, benzylalco-
hol was again the only product isolated from the treatment of
37 under modified Corey–Link conditions.
We suspected (for no real reason) that the culprit
involved in the formation of benzyl alcohol from 34 and
37 was the 6-O-benzyl ether. Therefore, the 6-deoxy alco-
hol 38[18] (Scheme 13) was oxidized and converted into the

728
A. Scaffidi et al.
C(66)
C(61)
(a)
C(65)
C(64)
C(63)
C(60)
O(6)
C(62)
Cl(2)
Cl(1)
C(6)
C(4)
O(5)
C(40)
C(42)
C(1)
C(11)
C(5)
C(41)
C(46)
Cl(3)
O(4)
C(43)
C(44)
C(2)
C(3)
C(20)
O(3)
O(2)
O(1)
C(32)
C(31)
C(26)
C(25)
C(24)
C(21)
C(30)
C(45)
C(34)
C(22)
C(23)
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm
a
C(36)
C(35)
(b)
a
c
Fig. 9. Molecular projection of 42.
b
b
b
BnO
BnO
O
OH
O
ab
b
b
O
O
O
O
O
44
45
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm
BnO
BnO
O
O
CCl3
Fig. 8. (a) 1H NMR (300 MHz, CD3OD) spectrum of the alcohol 34.
(b) 1H NMR (300 MHz, CD3OD) spectrum of the same sample of the
alcohol 34 immediately after the addition of a few drops of DBU (the
labels a, b, and c indicate signals for benzyl alcohol, residual DBU, and
an unidentified product, respectively).
N3
O
O
OH
O
MeO2C
O
46
47
Scheme 16.
OCH2C6H4OEt-4
Cl(32)
O
HO
4-MeOC6H4CH2O
C(53)
BnO
OMe
C(31)
40
Cl(33)
C(5)
C(54)
C(56)
Cl(31)
C(55)
O(4)
Scheme 14.
C(50)
C(1)
O(5)
C(4)
C(3)
C(2)
OBn
O
OBn
O
O(1)
C(12)
OBn
O
O(3)
BnO
BnO
C(122)
O(2)
BnO
O
BnO
O
CCl3
BnO
BnO
OBn
OH
OBn
C(121)
41
42
43
Scheme 15.
Fig. 10. Molecular projection of 46.
X-ray structure determination (Fig. 10). A modified Corey–
Link reaction on 46 gave the azido ester, presumably of
structure 47.
For the introduction of a pyrimidine base at C1 of 47, we
first tried the procedure recommended by Vorbrüggen and
coworkers[20] (Scheme 17), which naturally first involved
the removal of the isopropylidene group, but this proce-
dure produced just the amide 48, the product of an obvious
Ritter reaction.[21] However, the required nucleoside α-amino
acid precursor 50 was obtained when the diacetate 49 was
treated with the pre-silylated pyrimidine base (uracil);[22]
deacetylation then gave the alcohol 51.
We had now completed our synthesis of the necessary
monomeric carbohydrate α-amino acid precursors and the
accompanying paper[26] describes our initial efforts into their
combination to form oligopeptides.

Synthesis of Carbohydrate α-Amino Acids
729
NHCOCH3
BnO
BnO
BnO
O
O
O
N3
(a)
(b)
(c)
N3
OAc
N3
OSiMe
N
3
O
MeO2C
OAc
MeO2C
O
MeO2C
OH
N
Me SiO
3
48
47
49
O
N
O
NH
NH
O
N
O
BnO
BnO
(d)
O
O
N3
N3
MeO2C
OAc
MeO2C
OH
50
51
Scheme 17. (a) 90% TFA/H2O, followed by uracil, bis(trimethylsilyl)amine, SnCl4, Me3SiCl, MeCN; (b) 90% TFA/H2O, followed by Ac2O,
pyridine; (c) Me3SiOTf, ClCH2CH2Cl; (d) Na, MeOH.
Experimental
Compound 24, C22H23Cl3O6, M 489.8. Monoclinic, space group
P21, a 11.7701(8), b 6.3566(4), c 14.873(1) Å, β 100.590(2)◦,
V 1094 Å3. Dc (Z 2) 1.482 g cm−3. µMo 0.46 mm−1; specimen:
0.25 × 0.15 × 0.10 mm3; ‘T’min/max 0.93. 2θmax 75◦; Nt 22368, N 6160
(Rint 0.035), No 5314; R 0.042, Rw 0.043. |ꢀρmax| 0.53(5) e Å−3. xabs
not refined.
Compound 29, C23H25N3O7, M 455.5. Orthorhombic, space group
P212121, a 9.1062(6), b 11.1661(7), c 22.368(2) Å,V 2274 Å3. Dc (Z 4)
1.330 g cm−3. µMo 0.10 mm−1; specimen: 0.38 × 0.20 × 0.08 mm3;
‘T’min/max 0.86. 2θmax 60◦; Nt 19670, N 3677 (Rint 0.055), No 3173;
R 0.040, Rw 0.043. |ꢀρmax| 0.34(3) e Å−3. xabs not refined.
Structure Determinations of 8, 10, 16, 19, 24, 29, 39, 42, and 46
Full spheres of ‘low’-temperature CCD area-detector diffractometer
data were measured (Bruker AXS instrument, ω-scans; monochromatic
MoKα radiation, λ 0.71073 Å; T ≈ 153 K) yielding N(total) reflections,
merging to N unique (Rint cited) after ‘empirical’/multiscan absorp-
tion correction, No with F > 4σ(F) considered ‘observed’ and used
in the full matrix least-squares refinements, refining anisotropic dis-
placement parameter forms for C, N, O, also (x, y, z, Uiso H unless
)
otherwise stated, in which case the latter were constrained at estimated
values. Conventional residuals R, Rw on |F| are cited at convergence
(weights: (σ2(F) + 0.000nwF2)−1). Neutral atom complex scattering
factors were employed within the context of the Xtal 3.7 program
system;[23] where ꢀf ꢀꢀ was significant, ‘Friedel’data were retained dis-
tinct and xabs refined unless otherwise stated. Pertinent results are given
below and in Tables 1, 2, and 3 and Figs 1, 2, 3, 4, 5, 6, 7, 9, and 10, the
figures showing 50% probability amplitude displacement ellipsoids for
the non-hydrogen atoms, hydrogen atoms having arbitrary radii of 0.1 Å.
Individual variations in procedure are cited as ‘variata’. CCDC nos
226185–226193.
Compound 39, C22H25Cl3O5, M 475.8. Orthorhombic, space group
P212121, a 9.792(3), b 10.507(3), c 21.995(6) Å, V 2263 Å3. Dc (Z 4)
1.396 g cm−3. µMo 0.44 mm−1; specimen: 0.35 × 0.22 × 0.15 mm3;
‘T’min/max 0.89. 2θmax 59◦; Nt 20548, N 3150 (Rint 0.020), No 2897;
R 0.031, Rw 0.037. |ꢀρmax| 0.31(2) e Å−3. (x, y, z, Uiso H
xabs 0.03(6).
Compound 42, C35H35Cl3O6, M 658.0. Monoclinic, space group
) not refined;
P21,
a 11.436(2), b 5.7208(8), c 24.457(2) Å, β
99.552(2)◦,
V 1578 Å3. Dc (Z 2) 1.385 g cm−3. µMo 0.34 mm−1; specimen:
0.13 × 0.05 × 0.04 mm3; ‘T’min/max 0.95. 2θmax 58◦; Nt 15422, N 4240
(Rint 0.033), No 3395; R 0.045, Rw 0.056. |ꢀρmax| 0.37(6) e Å−3. (x, y, z,
Crystal/Refinement Data
Uiso)H not refined; xabs 0.06(9).
Compound 46, C16H19Cl3O5, M 397.7. Monoclinic, space group
P21, a5.795(2), b9.808(4), c15.354(7) Å, β 92.982(3)◦,V872 Å3. Dc (Z
2) 1.515 g cm−3. µMo 0.55 mm−1; specimen: 0.22 × 0.07 × 0.04 mm3;
‘T’min/max 0.66. 2θmax 53◦; Nt 7349, N 1887 (Rint 0.082), No 1343;
R 0.069, Rw 0.073. |ꢀρmax| 0.5(1) e Å−3. (x, y, z, Uiso)H, xabs not refined.
Within the structures, bond lengths and angles are essentially as
expected and not commented on further, beyond noting that in 10 and
29, the C–N–N angles at the pendant azides are 114.5(4) and 114.5(2)◦.
Lattice interactions of interest are primarily concerned with hydrogen-
bonding interactions arising from any hydroxyl, carboxylic acid, or
amine groups present, as follows:
Compound 8, C13H19Cl3O6, M 377.7. Monoclinic, space group P21
(C22, no. 4), a 5.8235(4), b 9.8871(6), c 14.1337(9) Å, β 90.439(1)◦,
V 813.8 Å3. Dc(Z 2) 1.541 g cm−3. µMo 0.59 mm−1; specimen: 0.5 ×
0.4 × 0.35 mm3; ‘T’min/max 0.91. 2θmax 75◦; Nt 15888, N 4286 (Rint
0.014), No 4164; R 0.021, Rw 0.026. |ꢀρmax| 0.36(3) e Å−3. xabs
0.01(2).
Compound 10, C13H19N3O7, M 329.3. Monoclinic, space group
P21, a 6.374(3), b 8.855(3), c 13.932(5) Å, β 97.024(6)◦, V 780.4 Å3.
Dc (Z 2) 1.401 g cm−3. µMo 0.12 mm−1; specimen: 0.22 × 0.18 ×
0.08 mm3; ‘T’min/max 0.79. 2θmax 52.5◦; Nt 6959, N 1566 (Rint 0.053),
No 1427; R 0.045, Rw 0.051. |ꢀρmax| 0.20(4) e Å−3. (x, y, z, Uiso)H, xabs
not refined.
Compound 8, intramolecular: O,H(3)· · ·O(2) 2.605(2), 2.09(3) Å (inter-
molecular: O,H(3)· · ·O(4) (x−1, y, z) are 2.878(1) and 2.24(3) Å).
Compound 10, intermolecular: O,H(31)· · ·O(6) (x, 1+y, z) 2.709(5),
1.8 Å (est.).
Compound 16, intermolecular: O,H(13)· · ·O(16) (1−x, ½+y, 1−z)
2.748(6), 1.9 Å (est.). O,H(23)· · ·O(26) (2−x, ½+y, z) 2.757(6),
2.0 Å (est.).
Compound 16, C19H27Cl3O6, M 457.8. Monoclinic, space group
P21, a 9.625(1), b 12.164(2), c 17.454(2) Å, β 92.401(2)◦,V 2042 Å3. Dc
(Z4)1.489 g cm−3. µMo 0.48 mm−1;specimen:0.45 × 0.40 × 0.32 mm;
‘T’min/max 0.92. 2θmax 58◦; Nt 18911, N 5035 (Rint 0.039), No 4082; R
0.050, Rw 0.060. |ꢀρmax| 0.41(8) e Å−3. (x, y, z, Uiso H
xabs 0.06(8).
) not refined;
Compound 19, C20H31NO7, M 397.5. Orthorhombic, space group
P212121 (D24, no. 19), a 6.615(3), b 11.422(5), c 26.335(12) Å, V
1990 Å3. Dc (Z 4) 1.327 g cm−3. µMo 0.10 mm−1; specimen: 0.88 ×
0.05 × 0.03 mm3; ‘T’min/max 0.84. 2θmax 55◦; Nt 14952, N 2623 (Rint
0.10), No 1823; R 0.064, Rw 0.071. |ꢀρmax| 0.41(7) e Å−3. (x, y, z,
Uiso)H, xabs not refined.
Compound 19, ‘intramolecular’: N(3),H(3b)· · ·O(31) 2.736(6),
2.3 Å (est.).
Compound 24, intramolecular: O,H(3)· · ·O(2) 2.577(2), 2.13(3) Å.
Compound 39, intramolecular: O,H(4)· · ·O(3) 2.535(3), 2.00(3) Å.
Compound 42, intermolecular: O,H(1)· · ·O(6) (x, y−1, z) 2.795(5),
2.06(7) Å.

730
A. Scaffidi et al.
General
Methyl 2-O-Benzyl-4,6-O-benzylidene-3-C-trichloromethyl-
α-D-alloside 24
General experimental procedures have been given previously.[24] As
well, detailed procedures were given in our communication[13] for the
preparation of the various trichloromethyl alcohols, azido esters, azido
acids, and amino esters—only specific compound details are given here.
Notation such as A (AB) is used to describe the A part of an AB pattern.
The ketone 22 furnished (flash chromatography, EtOAc/petrol 1 : 4)
the alcohol 24 as needles (71%), mp 125–127◦C (Et2O), [α]D +3.8◦
(Found: C 53.7, H 4.7. C22H23Cl3O6 requires C 53.9, H 4.7%). δH
(300 MHz) 3.36 (s, OCH3), 3.70–3.80 (m, H5), 4.18, 4.50 (AB, J1,2 4.0,
H1, H2), 4.20–4.24 (2H, m, H4, H6), 4.25 (s, OH), 4.32–4.37 (m, H6),
4.62, 4.84 (AB, J 11.7, CH2Ph), 5.60 (s, CHPh), 7.25–7.32 (10H, m,
Ph). δC (75.5 MHz) 56.04 (OCH3), 59.74, 75.32, 77.93 (C2, C4, C5),
69.24 (C6), 74.15 (CH2Ph), 81.78 (C3), 98.23 (C1), 101.45 (CHPh),
103.54 (CCl3), 126.14–137.10 (Ph). m/z (FAB) 489.0605; [M + H]+
requires 489.0638.
General Procedure for the Swern Oxidation[25] of the Alcohols
20, 21, 32, 35, and 44
Dimethyl sulfoxide (3.0 equiv.) in CH2Cl2 was added dropwise to oxalyl
chloride (2.0 equiv.) in CH2Cl2 at −55◦C and the solution stirred (0.5 h).
The alcohol (1.0 equiv.) in CH2Cl2 was then added dropwise to the
solution and the resulting solution stirred at −55◦C (1.5 h).The solution
was then warmed to −30◦C, followed by the dropwise addition of Et3N
(3.0 equiv., 0.25 h). The solution was then warmed to room temperature
and a standard workup (CH2Cl2) yielded the ketone that was used in the
next step without any further purification.
Methyl 3-O-Benzyl-4,6-O-benzylidene-2-C-trichloromethyl-
α-D-glucoside 25
The ketone 23 yielded (flash chromatography, EtOAc/petrol 1 : 4) the
alcohol 25 as a yellow oil (85%), [α]D −6.4◦. δH (300 MHz) 3.53 (s,
OCH3), 3.83 (dd, J6,6 ≈ J5,6 10.1, H6), 3.94–4.02 (m, H5), 4.02 (s, OH),
4.21 (d, J3,4 8.7, H3), 4.33 (dd, J5,6 4.5, H6), 4.43 (dd, J4,5 9.3, H4), 4.85,
4.97 (AB, J 11.9, CH2Ph), 5.35 (s, H1), 5.60 (s, CHPh), 7.23–7.55 (10H,
m, Ph). δC (75.5 MHz) 55.90 (OCH3), 63.32, 79.57, 83.21 (C3, C4, C5),
69.06 (C6), 75.12 (CH2Ph), 82.54 (C2), 100.08 (C1), 101.62 (CHPh),
102.02 (CCl3), 126.11–137.72 (Ph). m/z (FAB) 489.0613; [M + H]+
requires 489.0638.
1,2:5,6-Di-O-cyclohexylidene-3-C-trichloromethyl-α-D-gulose 16
The ketone 15[13] afforded (flash chromatography, EtOAc/petrol 1 : 4)
the alcohol 16 as plates (75%), mp 126–128◦C (Et2O), [α]D −13.1◦
(Found: C 49.5, H 5.8%. C19H27Cl3O6 requires C 49.8, H 5.9%). δH
(300 MHz) 1.70–2.00 (20H, m, CH2), 3.98 (dd, J6,6 9.1, J5,6 6.4, H6),
4.13 (dd, J5,6 6.2, H6), 4.16 (s, OH), 4.36–4.45 (m, H5), 4.50 (d, J4,5 8.8,
H4), 4.77 (d, J1,2 4.4, H2), 6.05 (d, H1). δC (75.5 MHz) 23.28, 23.62,
23.77, 23.96, 24.63, 25.09, 34.76, 35.95, 36.00, 36.22 (10C, CH2), 65.91
(C6), 76.46, 80.59, 86.97 (C2, C4, C5), 87.15 (C3), 103.44 (CCl3),
Methyl (3S)-3-Azido-2-O-benzyl-4,6-O-benzylidene-3-deoxy-
3-C-methoxycarbonyl-α-D-ribo-hexoside 26
105.67 (C1), 109.60, 114.27 (2C, OCO). m/z (FAB) 455.0796; [M − H
The alcohol 24 furnished (flash chromatography, EtOAc/petrol 1 : 4)
the azido ester 26 as an oil (86%), [α]D −38.3◦. vmax/cm−1 (film)
2120 (N3), 1750 (OC=O). δH (300 MHz) 3.38 (s, OCH3), 3.62 (dd,
J6,6 ≈ J5,6 10.3, H6), 3.63 (d, J1,2 4.4, H2), 3.68 (d, J4,5 9.8, H4), 3.88 (s,
CO2CH3), 4.33 (dd, J5,6 5.2, H6), 4.53 (d, H1), 4.62–4.70 (m, H5), 4.75,
4.85 (AB, J 12.2, CH2Ph), 5.51 (s, CHPh), 7.30–7.45 (10H, m, Ph). δC
(75.5 MHz) 52.96 (CO2CH3), 55.68 (OCH3), 59.81, 79.20, 82.56 (C2,
C4, C5), 69.48 (C6), 70.56 (C3), 73.37 (CH2Ph), 98.12 (C1), 101.97
(CHPh), 126.13–136.98 (Ph), 166.32 (CO2CH3). m/z (FAB) 456.1777;
[M + H]+ requires 456.1771.
12
(
C
H2635Cl3O6)]+ requires 455.0795.
19
(3S)-3-Azido-1,2:5,6-di-O-cyclohexylidene-3-deoxy-
3-C-methoxycarbonyl-α-D-xylo-hexose 17
The alcohol 16 afforded (flash chromatography, EtOAc/petrol 1 : 4)
the azido ester 17 as needles (93%), mp 88–90◦C (EtOAc/petrol),
[α]D +49.2◦ (Found: C 56.7, H 7.1, N 9.8. C20H29N3O7 requires
C 56.7, H 6.9, N 9.9%). vmax/cm−1 (KBr) 2125 (N3), 1760 (OC=O).
δH (300 MHz) 1.51–2.00 (20H, m, CH2), 3.65 (dd, J6,6 8.6, J5,6 6.6,
H6), 3.74 (d, J4,5 8.7, H4), 3.84 (s, CO2CH3), 3.90 (dd, J5,6 6.4, H6),
4.67–4.77 (m, H5), 4.68 (d, J1,2 3.6, H2), 5.87 (d, H1). δC (75.5 MHz)
23.57, 23.67, 23.76, 23.89, 24.69, 25.04, 34.62, 36.19, 36.45, 36.55
(10C, CH2), 52.86 (CO2CH3), 65.30 (C6), 73.71 (C3), 74.49, 86.09,
86.47 (C2, C4, C5), 103.94 (C1), 110.21, 117.10 (2C, OCO), 166.87
(CO2CH3). m/z (FAB) 424.2072; [M + H]+ requires 424.2084.
Methyl (3S)-3-Azido-2-O-benzyl-4,6-O-benzylidene-
3-C-carboxy-3-deoxy-α-D-ribo-hexoside 27
The azido ester 26 afforded the azido acid 27 as a gum, [α]D +86.9◦. δH
(300 MHz) 3.45 (s, OCH3), 3.67 (dd, J6,6 ≈ J5,6 10.2, H6), 3.73 (d, J1,2
4.3, H2), 3.78 (d, J4,5 10.0, H4), 4.14 (ddd, J5,6 5.1, H5), 4.34 (dd, H6),
4.61 (d, H1), 4.68, 4.87 (AB, J 12.0, CH2Ph), 5.56 (s, CHPh), 7.30–7.48
(10H, m, Ph). δC (75.5 MHz) 55.87 (OCH3), 60.14, 78.35, 81.44 (C2,
C4, C5), 68.93 (C6), 74.02 (CH2Ph), 71.11 (C3), 97.20 (C1), 101.90
(CHPh), 126.09–136.41 (Ph), 164.94 (CO2H). m/z (FAB) 442.1613;
[M + H]+ requires 442.1614.
(3S)-3-Azido-3-C-carboxy-1,2:5,6-di-O-cyclohexylidene-
3-deoxy-α-D-xylo-hexose 18
The azido ester 17 furnished the azido acid 18 as an oil, [α]D +17.8◦.
δH (300 MHz) 1.35–1.94 (20H, m, CH2), 3.72 (dd, J6,6 8.6, J5,6 6.9,
H6), 3.88 (d, J4,5 8.5, H4), 4.01 (dd, J5,6 6.3, H6), 4.58–4.67 (m, H5),
4.65 (d, J1,2 3.6, H2), 5.41 (br s, OH), 5.93 (d, H1). δC (75.5 MHz)
23.45–36.21 (CH2), 65.70 (C6), 73.50 (C3), 74.28, 85.65, 86.22 (C2,
C4, C5), 104.25 (C1), 110.39, 116.98 (2C, OCO), 168.89 (CO2H). m/z
(FAB) 410.1933; [M + H]+ requires 410.1927.
Methyl (3S)-3-Amino-2-O-benzyl-4,6-O-benzylidene-3-deoxy-
3-C-methoxycarbonyl-α-D-ribo-hexoside 28
The azido ester 26 yielded (flash chromatography, Et3N/EtOAc/petrol
1 : 8 : 12) the amino ester 28 as an oil (96%), [α]D +50.1◦. vmax/cm−1
(film) 1750 (OC=O). δH (300 MHz) 2.25 (br s, NH2), 3.38 (s, OCH3),
3.55–3.64 (3H, m, H4, H5, H6), 3.79 (s, CO2CH3), 4.32 (dd, J6,6
10.3, J5,6 5.2, H6), 4.62–4.79 (4H, m, H1, H2, CH2Ph), 5.45 (s,
CHPh), 7.30–7.47 (10H, m, Ph). δC (75.5 MHz) 52.22 (CO2CH3),
55.35 (OCH3), 59.98, 82.20, 82.70 (C2, C4, C5), 61.58 (C3), 69.64
(C6), 73.25 (CH2Ph), 97.37 (C1), 102.25 (CHPh), 126.30–137.46 (Ph),
171.44 (CO2CH3). m/z (FAB) 430.1861; [M + H]+ requires 430.1866.
(3S)-3-Amino-1,2:5,6-di-O-cyclohexylidene-3-deoxy-
3-C-methoxycarbonyl-α-D-xylo-hexose 19
The azido ester 17 afforded (flash chromatography, Et3N/EtOAc/petrol
1 : 8 : 12) the amino ester 19 as prisms (97%), mp 163–165◦C
(EtOAc/pentane), [α]D +11.9◦ (Found: C 60.7, H 8.1, N 3.3.
C20H31NO7 requires C 60.4, H 7.9, N 3.5%). vmax/cm−1 (KBr) 1750
(OC=O). δH (300 MHz) 1.22–1.85 (20H, m, CH2), 3.68 (dd, J6,6 8.7,
J5,6 6.2, H6), 3.75(d, J4,5 10.1, H4), 3.78(s, CO2CH3), 3.95(dd, J5,6 6.4,
H6), 4.38 (d, J1,2 3.6, H2), 4.76 (ddd, H5), 5.90 (d, H1). δC (75.5 MHz)
23.64, 23.74, 23.83, 24.00, 24.85, 25.15, 34.49, 36.29, 36.42, 36.49
(10C, CH2), 52.34 (CO2CH3), 65.98 (C6), 68.11 (C3), 75.12, 88.88,
90.25 (C2, C4, C5), 104.23 (C1), 109.84, 115.81 (2C, OCO), 174.23
(CO2CH3). m/z (FAB) 398.2193; [M + H]+ requires 398.2179.
Methyl (2S)-2-Azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-
2-C-methoxycarbonyl-α-D-arabino-hexoside 29
The alcohol 25 afforded (flash chromatography, EtOAc/petrol 1 : 4)
the azido ester 29 as prisms (89%), mp 123–125◦C (EtOAc/pentane),
[α]D +23.5◦ (Found: C 60.7, H 5.6, N 9.1. C23H25N3O7 requires
C 60.7, H 5.5, N 9.2%). vmax/cm−1 (KBr) 2120 (N3), 1760 (OC=O).

Synthesis of Carbohydrate α-Amino Acids
731
δH (300 MHz) 3.37 (s, OCH3), 3.84 (s, CO2CH3), 3.80–3.94, 4.07–
4.15, 4.25–4.32 (4H, 3 m, H4, H5, H6), 4.56 (d, J3,4 9.6, H3), 4.70
(s, H1), 4.83, 4.95 (AB, J 11.0, CH2Ph), 5.64 (s, CHPh), 7.25–7.50
(10H, m, Ph). δC (75.5 MHz) 53.12 (CO2CH3), 55.61 (OCH3), 63.42,
76.58, 80.30 (C3, C4, C5), 68.54 (C6), 72.55 (C2), 75.67 (CH2Ph),
100.71 (C1), 101.59 (CHPh), 125.94–138.18 (Ph), 167.57 (CO2CH3).
m/z (FAB) 456.1765; [M + H]+ requires 456.1771.
3,4,5,7-Tetra-O-benzyl-1,1,1-trichloro-1-deoxy-α-D-gluco-
hept-2-ulose 42
The lactone 41[19] yielded (flash chromatography, EtOAc/petrol 1 : 4)
the hemiacetal 42 as prisms (42%), mp 90–92◦C (EtOAc/pentane), [α]D
+56.9◦ (Found: C 64.0, H 5.4. C35H35Cl3O6 requires C 63.9, H 5.4%).
δH (300 MHz) 3.76–4.10 (5H, m, H4, H5, H6, H7), 4.34 (br s, OH),
4.37 (d, J3,4 8.5, H3), 4.66, 4.76 (AB, J 12.3, CH2Ph), 4.76, 4.88 (AB,
J 10.9, CH2Ph), 4.89, 5.03 (AB, J 10.6, CH2Ph), 4.93, 5.03 (AB, J 10.6,
CH2Ph), 7.25–7.45 (20H, m, Ph). δC (75.5 MHz) 67.64 (C7), 73.29,
73.90, 74.92, 75.02 (4C, CH2Ph), 76.01, 77.16, 78.51, 85.00 (C3, C4,
C5, C6), 100.02 (C2), 103.21 (C1), 127.42–138.39 (Ph). m/z (FAB)
657.1529; [M + H]+ requires 657.1577.
Methyl (2S)-2-Azido-3-O-benzyl-4,6-O-benzylidene-
2-C-carboxy-2-deoxy-α-D-arabino-hexoside 30
The azido ester 29 yielded the azido acid 30 as a foam, [α]D +12.5◦. δH
(300 MHz) 3.40 (s, OCH3), 3.86–4.00, 4.12–4.20, 4.32–4.37 (4H, 3m,
H4, H5, H6), 4.58 (d, J3,4 9.6, H3), 4.78 (s, H1), 4.84, 4.98 (AB, J 10.9,
CH2Ph), 5.67 (s, CHPh), 7.20–7.55 (10H, m, Ph). δC (75.5 MHz) 55.68
(OCH3), 60.69 (C2), 63.49, 72.26, 80.26 (C3, C4, C5), 68.48 (C6), 75.72
(CH2Ph), 100.57 (C1), 101.66 (CHPh), 125.94–137.96 (Ph), 171.41
(CO2H). m/z (FAB) 442.1636; [M + H]+ requires 442.1614.
5-O-Benzyl-1,2-O-isopropylidene-3-C-trichloromethyl-α-D-ribose 46
The ketone 45 furnished (flash chromatography, EtOAc/petrol 1 : 4)
the alcohol 46 as plates (81%), mp 110–112◦C (EtOAc/pentane), [α]D
+14.2◦ (Found: C 48.4, H 4.6. C16H19Cl3O5 requires C 48.5, H 4.6%).
δH (300 MHz) 1.45, 1.64 (6H, 2 s, CH3), 3.90 (dd, J5,5 10.5, J4,5 8.6,
H5), 3.97 (br s, OH), 4.15 (dd, J4,5 3.3, H5), 4.42 (dd, H4), 4.56, 4.67
(AB, J 12.0, CH2Ph), 4.79 (d, J1,2 4.5, H2), 6.02 (d, H1), 7.23–7.38 (m,
Ph). δC (75.5 MHz) 26.34, 27.03 (2C, CH3), 67.33 (C5), 73.45 (CH2Ph),
81.67, 84.36 (C2, C4), 87.24 (C3), 100.72 (CCl3), 104.31 (C1), 113.48
(OCO), 127.62–137.64 (Ph). m/z (FAB) 395.0214; [M + H]+ requires
395.0220.
Methyl (2S)-2-Amino-3-O-benzyl-4,6-O-benzylidene-2-deoxy-
2-C-methoxycarbonyl-α-D-arabino-hexoside 31
The azido ester 29 furnished (flash chromatography, Et3N/EtOAc/petrol
1 : 8 : 12) the amino ester 31 as needles (95%), mp 133–135◦C
(EtOAc/pentane), [α]D +62.5◦ (Found: C 64.2, H 6.6, N 3.2.
C23H27NO7 requires C 64.3, H 6.3, N 3.3%). vmax/cm−1 (KBr) 1745
(OC=O). δH (300 MHz) 3.36 (s, OCH3), 3.75 (s, CO2CH3), 3.86–3.95,
4.25–4.35 (3H, 2 m, H4, H6), 4.10–4.20 (m, H5), 4.46 (d, J3,4 9.5, H3),
4.54 (s, H1), 4.80, 4.95 (AB, J 10.8, CH2Ph), 5.65 (s, CHPh), 7.25–7.53
(10H, m, Ph). δC (75.5 MHz) 52.53 (CO2CH3), 55.57 (OCH3), 63.48,
75.71, 80.27 (C3, C4, C5), 65.42 (C2), 68.76 (C6), 75.40 (CH2Ph),
101.49 (C1), 103.07 (CHPh), 125.97–138.56 (Ph), 173.64 (CO2CH3).
m/z (FAB) 430.1865; [M + H]+ requires 430.1866.
(3S)-3-Azido-5-O-benzyl-3-deoxy-1,2-O-isopropylidene-
3-C-methoxycarbonyl-α-D-erythro-pentose 47
The alcohol 46 afforded (flash chromatography, EtOAc/petrol 1 : 4) the
azido ester 47 as an oil (93%), [α]D +79.8◦. vmax/cm−1 (film) 2120
(N3), 1760 (OC=O). δH (300 MHz) 1.32, 1.53 (6H, 2 s, CH3), 3.67–3.71
(2H, m, H5), 3.81 (s, CO2CH3), 4.52, 4.61 (AB, J 12.0, CH2Ph), 4.68
(d, J1,2 4.7, H2), 4.85 (dd, J4,5 5.7, H4), 5.99 (d, H1), 7.25–7.38 (m, Ph).
δC (75.5 MHz) 26.35, 26.66 (2C, CH3), 52.97 (CO2CH3), 67.64 (C5),
73.30 (CH2Ph), 74.27 (C3), 78.78, 84.29 (C2, C4), 104.73 (C1), 113.25
(OCO), 127.55–137.74 (Ph), 166.65 (CO2CH3). m/z (FAB) 364.1524;
[M + H]+ requires 364.1509.
Methyl 2,3,6-Tri-O-benzyl-4-C-trichloromethyl-α-D-galactoside 34
The ketone 33 yielded (flash chromatography, EtOAc/petrol 1 : 4) the
alcohol 34 as a yellow oil (80%), [α]D +56.1◦. δH (300 MHz) 3.45
(s, OCH3), 3.85 (dd, J2,3 8.7, J1,2 3.3, H2), 3.90 (dd, J6,6 10.8, J5,6
5.6, H6), 4.30–4.37, 4.85–4.88 (2H, 2 m, H5, H6), 4.50 (d, H3),
4.51, 4.63 (AB, J 11.9, CH2Ph), 4.62, 4.74 (AB, J 11.9, CH2Ph),
4.68 (d, H1), 4.82, 5.10 (AB, J 10.7, CH2Ph), 7.25–7.37 (15H, m,
Ph). δC (75.5 MHz) 55.59 (OCH3), 70.72, 76.07, 79.62 (C2, C3, C5),
72.12 (C6), 73.35, 73.40, 74.98 (3C, CH2Ph), 83.81 (C4), 96.44 (C1),
N-Acetyl-3-azido-5-O-benzyl-3-deoxy-3-C-methoxycarbonyl-
β-D-erythro-pentofuranosylamine 48
Theazidoester 47(500 mg, 1.4 mmol)intrifluoroaceticacid(TFA)/H2O
(10 mL, 9 : 1) was stirred at room temperature (3 h). Concentration
of the mixture gave a yellow residue that was dissolved in CH3CN
(15 mL). SnCl4 (180 µL, 1.5 mmol) and uracil (200 mg, 1.8 mmol)
were added, followed by the dropwise addition of chlorotrimethylsilane
(TMSCl) (150 µL, 1.6 mmol) and 1,1,1,3,3,3-hexamethyldisilazane
(HMDS) (250 µL, 2.0 mmol), and the mixture stirred (2 h). Standard
workup (CH2Cl2) followed by flash chromatography (EtOAc/petrol,
7 : 3) afforded the acetamide 48 as an oil (409 mg, 82%). δH (300 MHz)
2.05 (s, COCH3), 3.70–3.80 (2H, m, H5), 3.78 (s, CO2CH3), 4.38
(dd, J4,5 6.1, H4), 4.50, 4.55 (AB, J 11.7, CH2Ph), 4.77 (d, J1,2 5.5,
H2), 6.15 (d, H1), 7.25–7.35 (m, Ph). δC (75.5 MHz) 13.65 (COCH3),
53.11 (CO2CH3), 66.89 (CH2Ph), 73.29 (C5), 74.11 (C3), 78.35, 84.74
(C2, C4) 100.87 (C1), 127.49–137.58 (Ph), 166.63, 168.29 (COCH3,
CO2CH3). m/z (FAB) 365.1466; [M + H]+ requires 365.1461.
104.69 (CCl3), 127.45–137.76 (Ph). m/z (FAB) 579.1111; [M − H
12
(
C
H2735Cl3O6)]+ requires 579.1108.
29
Methyl 2,3,6-Tri-O-benzyl-4-C-trichloromethyl-β-D-galactoside 37
The ketone 36 yielded (flash chromatography, EtOAc/petrol 1 : 4)
the alcohol 37 as a yellow oil (74%), [α]D +12.1◦. δH (300 MHz)
3.55 (s, OCH3), 3.85–3.98, 4.70–4.90 (8H, 2 m, H1, H2, H5, H6,
CH2Ph), 4.25 (d, J2,3 10.2, H3), 4.39 (br s, OH), 4.58, 4.66 (AB,
J 11.8, CH2Ph), 5.10 [A(AB), J 10.1, CH2Ph], 7.18–7.43 (15H, m,
Ph). δC (75.5 MHz) 55.55 (OCH3), 70.41 (C6), 73.08, 74.26, 74.98
(3C, CH2Ph), 75.82, 76.73, 80.47 (C2, C3, C5), 82.52 (C4), 104.50
(C1), 106.09 (CCl3), 125.26–138.18 (Ph). m/z (FAB) 579.1137; [M − H
12
(
C
H2735Cl3O6)]+ requires 579.1108.
29
Methyl 2,3-Di-O-benzyl-6-deoxy-4-C-trichloromethyl-
β-D-galactoside 39
(3S)-1,2-Di-O-acetyl-3-azido-5-O-benzyl-3-deoxy-
3-C-methoxycarbonyl-D-erythro-pentose 49
Methyl 2,3-di-O-benzyl-6-deoxy-β-d-xylo-hexopyranos-4-uloside fur-
nished (flash chromatography, EtOAc/petrol 1 : 4) the alcohol 39 as
needles (78%), mp 66–68◦C (EtOAc/pentane), [α]D +7.7◦ (Found: C
55.6, H 5.4. C22H25Cl3O5 requires C 55.5, H 5.3%). δH (300 MHz)
1.52 (3H, d, J5,6 7.2, H6), 3.50 (s, OCH3), 3.91 (dd, J2,3 10.1, J1,2
6.3, H2), 4.21 (d, H3), 4.47 (br s, OH), 4.62 (ddd, H5), 4.72, 4.85 (AB,
J 11.2, CH2Ph), 4.78, 5.11 (AB, J 10.2, CH2Ph), 4.78 (d, H1), 7.23–7.38
(10H, m, Ph). δC (75.5 MHz) 19.23 (C6), 54.95 (OCH3), 74.28, 74.95
(2C, CH2Ph), 74.65, 76.05, 80.29 (C2, C3, C5), 82.48 (C4), 104.48
The azido ester 47 (1.0 g, 2.8 mmol) in TFA/H2O (15 mL, 9 : 1) was
stirred at room temperature (3 h). The solvent was removed, followed by
the addition of Ac2O (1.2 mL, 11 mmol) in pyridine (15 mL). The solu-
tion was stirred at room temperature (3 h) before being quenched with
methanol. Standard workup (CH2Cl2) followed by flash chromotogra-
phy (EtOAc/toluene, 1 : 4) yielded the β-anomer of 49 as a gum (540 mg,
54%), [α]D +20.0◦. δH (300 MHz) 2.08, 2.10 (6H, 2 s, COCH3), 3.67–
3.73 (2H, m, H5), 3.75 (s, CO2CH3), 4.50, 4.55 (AB, J 11.9, CH2Ph),
4.85 (dd, J4,5 6.1, H4), 5.36 (s, H2), 6.16 (s, H1), 7.22–7.36 (m, Ph).
δC (75.5 MHz) 20.25, 20.73 (2C, COCH3), 53.18 (CO2CH3), 67.76
(C1), 106.63 (CCl3), 127.66–138.03 (Ph). m/z (FAB) 473.0718; [M − H
12
(
C
H2435Cl3O5)]+ requires 473.0689.
22

732
A. Scaffidi et al.
(C5), 71.48 (C3), 73.10 (CH2Ph), 79.42, 82.21 (C2, C4), 98.60 (C1),
127.39–137.51 (Ph), 166.50, (CO2CH3), 168.8, 168.93 (2C, COCH3).
m/z (FAB) 406.1263; [M − H]+ requires 406.1250.
[3] S. A. W. Gruner, V. Truffault, G. Voll, E. Locardi, M. Stöckle,
H. Kessler, Chem. Eur. J. 2002, 8, 4365. doi:10.1002/1521-
3765(20021004)8:19<4365::AID-CHEM4365>3.0.CO;2-U
[4] F. Schweizer, Angew. Chem. Int. Ed. 2002, 41, 230. doi:10.1002/
1521-3773(20020118)41:2<230::AID-ANIE230>3.0.CO;2-L
[5] S. A. W. Gruner, E. Locardi, E. Lohof, H. Kessler, Chem. Rev.
2002, 102, 491. doi:10.1021/CR0004409
[6] R. M. van Well, L. Marinelli, K. Erkelens, G. A. van der Marel,
A. Lavecchia, H. S. Overkleeft, J. H. van Boom, H. Kessler,
M. Overhand, Eur. J. Org. Chem. 2003, 2303. doi:10.1002/
EJOC.200300031
[7] A. Strecker, Liebigs Ann. Chem. 1850, 75, 27.
[8] D. Postel, A. Nguyen Van Nhien, P. Villa, G. Ronco, Tetrahedron
Lett. 2001, 42, 1499. doi:10.1016/S0040-4039(00)02294-2
[9] B. Steiner, J. Micˇová, M. Koóš, V. Langer, D. Gyepesová,
Carbohydr. Res. 2003, 338, 1349. doi:10.1016/S0008-6215(03)
00176-9
[10] E. J. Corey, J. O. Link, J. Am. Chem. Soc. 1992, 114, 1906.
[11] C. Domínguez, J. Ezquerra, S. R. Baker, S. Borrelly, L. Prieto,
M. Espada, C. Pedregal, Tetrahedron Lett. 1998, 39, 9305.
doi:10.1016/S0040-4039(98)02092-9
Next to elute was the α-anomer of 49 as a gum (380 mg, 38%),
[α]D +84.6◦. δH (300 MHz) 2.07 (6H, s, COCH3), 3.65–3.39 (2H, m,
H5), 3.78 (s, CO2CH3), 4.54 (s, CH2Ph), 4.93–4.98 (m, H4), 5.40 (d,
J1,2 4.6, H2), 6.47 (d, H1), 7.25–7.38 (m, Ph). δC (75.5 MHz) 20.08,
20.61 (2C, COCH3), 53.10 (CO2CH3), 67.28 (C5), 73.28 (CH2Ph),
73.42 (C3), 77.00, 80.67 (C2, C4), 94.16 (C1), 127.44–137.41 (Ph),
166.45 (CO2CH3), 168.60, 168.97 (2C, COCH3). m/z (FAB) 406.1260;
[M − H]+ requires 406.1250.
(3ꢀS)-2ꢀ-O-Acetyl-3ꢀ-azido-5ꢀ-O-benzyl-3ꢀ-deoxy-
3ꢀ-C-(methoxycarbonyl)uridine 50
Uracil (850 mg, 7.6 mmol) and (NH4)2SO4 (100 mg, 0.8 mmol) were
treated in HMDS (30 mL, 240 mmol) at reflux until a homogeneous
solutionresulted. Concentration ofthe mixture was followed by the addi-
tionofthediacetate49(1.0 g, 2.5 mmol)inClCH2CH2Cl(20 mL), along
with the dropwise addition of trimethylsilyl triflate (TMSOTf) (1.0 mL,
3.7 mmol). The mixture was refluxed (3 h) before being quenched with
sat. NaHCO3 solution. Standard workup (CH2Cl2) followed by flash
chromatography (EtOAc/toluene, 2 : 3) afforded the nucleoside 50 as
a gum (780 mg, 67%), [α]D +34.1◦. δH (300 MHz) 2.12 (s, COCH3),
3.73–3.77 (2H, m, H5ꢀ), 3.75 (s, CO2CH3), 4.51, 4.57 (AB, J 11.4,
[12] M. H. Sørensen, C. Nielsen, P. Nielsen, J. Org. Chem. 2001,
66, 4878. doi:10.1021/JO010299J
[13] G. S. Forman, A. Scaffidi, R. V. Stick, Aust. J. Chem. 2004, 57,
25. doi:10.1071/CH03214
[14] F. Andersson, B. Samuelsson, Carbohydr. Res. 1984, 129, C1.
doi:10.1016/0008-6215(84)85323-9
[15] I. Sakamoto, H. Ohrui, Biosci. Biotechnol. Biochem. 2000,
64, 1974.
CH2Ph), 4.73 (dd, J4 ,5 5.3, H4ꢀ), 5.42 (d, J1 ,2 3.4, H2ꢀ), 5.67 (d, J5,6
8.2, H5), 6.12 (d, H1ꢀ), 7.20–7.38 (m, Ph), 7.69 (d, H6), 10.04 (br s, NH).
δC (75.5 MHz) 20.22 (COCH3), 53.38 (CO2CH3), 66.94 (C5ꢀ), 72.09
(CH2Ph), 73.37 (C3ꢀ), 79.91, 81.23 (C2ꢀ, C4ꢀ), 87.51 (C1ꢀ), 102.68 (C5),
127.65–136.86 (Ph), 139.24 (C6), 150.23 (C2), 166.34 (C4), 166.34
(COCH3), 169.02 (CO2CH3). m/z (FAB) 460.1435; [M + H]+ requires
460.1468.
ꢀ
ꢀ
ꢀ
ꢀ
[16] J. K. Fairweather, M. J. McDonough, R. V. Stick,
D. M. G. Tilbrook, Aust. J. Chem. 2004, 57, 197. doi:10.1071/
CH03203
[17] M. P. DeNinno, J. B. Etienne, K. C. Duplantier, Tetrahedron
Lett. 1995, 36, 669. doi:10.1016/0040-4039(94)02348-F
[18] T. M. Weigel, H. W. Liu, Tetrahedron Lett. 1988, 29, 4221.
doi:10.1016/S0040-4039(00)80459-1
[19] H. Kuzuhara, H. G. Fletcher, J. Org. Chem. 1967, 32,
2531.
[20] B. Bennua-Skalmowski, K. Krolikiewicz, H. Vorbrüggen, Tetra-
hedron Lett. 1995, 36, 7845. doi:10.1016/0040-4039(95)01667-7
[21] J. J. Ritter, P. P. Minieri, J. Am. Chem. Soc. 1948, 70, 4045.
[22] Y. Saito, T. A. Zevaco, L. A. Agrofoglio, Tetrahedron 2002, 58,
9593. doi:10.1016/S0040-4020(02)01246-2
[23] The Xtal 3.7 System (Eds E. R. Hall, D. J. du Boulay,
R. Olthof-Hazekamp) 2002 (University of Western Australia:
Perth).
(3ꢀS)-3ꢀ-Azido-5ꢀ-O-benzyl-3ꢀ-deoxy-3ꢀ-C-
(methoxycarbonyl)uridine 51
A small piece of Na was added to the nucleoside 50 (200 mg,
0.40 mmol) in dry methanol (10 mL) and the mixture stirred at room
temperature (3 h). The reaction was neutralized by the addition of resin
(Dowex-50, H+). Filtration, evaporation, and flash chromatography
(EtOAc/toluene, 1 : 1) of the residue yielded the nucleoside 51 as an
oil (175 mg, 96%), [α]D +49.3◦. δH (300 MHz) 3.43 (br s, OH), 3.76–
3.85 (2H, m, H5ꢀ), 3.84 (s, CO2CH3), 4.53 (d, J1 ,2 1.6, H2ꢀ), 4.60 (s,
ꢀ
ꢀ
CH2Ph), 4.92 (dd, J4 ,5 5.6, 3.9, H4ꢀ), 5.62 (d, J5,6 8.2, H5), 5.85 (d,
H1ꢀ), 7.28–7.36 (m, Ph), 7.75 (d, H6), 10.66 (br s, NH). δC (75.5 MHz)
53.21 (CO2CH3), 67.65 (C5ꢀ), 73.18 (CH2Ph), 73.32 (C3ꢀ), 80.25, 81.29
(C2ꢀ, C4ꢀ), 91.50 (C1ꢀ), 101.83 (C5), 127.52–137.23 (Ph), 139.92 (C6),
150.93 (C2), 164.07 (C4), 167.00 (CO2CH3). m/z (FAB) 418.1372;
[M + H]+ requires 418.1363.
ꢀ
ꢀ
[24] J. C. McAuliffe, R. V. Stick, Aust. J. Chem. 1997, 50, 193.
[25] A. J. Mancuso, S. L. Huang, D. Swern, J. Org. Chem. 1978,
43, 2F480.
[26] A. Scaffidi, B. W. Skelton, R. V. Stick, A. H. White, Aust. J.
Chem. 2004, 57, 733. doi:10.1071/CH04014
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