An expansion of the role of the coreylink reaction for the synthesis of α-substituted carboxylic acid esters

Article abstract of DOI:10.1071/CH06137

The treatment of 1,2:5,6-di-O-isopropylidene-?-d-ribo-hexos-3-ulose with chloroform under basic conditions has yielded the normal 3-C-trichloromethyl-?- d-allofuranose derivative. Under the conditions of the modified Corey?Link reaction but with a nucleophile different from the usual azide, a range of ?-substituted carboxylic acid esters (and one amide) has been obtained. A similar addition of bromoform to the ulose has formed the ?-bromo methyl ester. Two attempts at forming an ?inositol ?-amino acid' from a polyhydroxylated cyclohexanone failed. Single-crystal X-ray structure determinations are reported for (3S)-1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-3-S-phenyl-3-thio-?-d- ribo-hexose, (3S)-1,2:5,6-di-O-isopropylidene-3-S-phenyl-3-C-(phenylthio) carbonyl-3-thio-?-d-ribo-hexose, 3-deoxy-1,2:5,6-di-O-isopropylidene-3-C- methoxycarbonyl-?-d-erythro-hex-3-enofuranose, 4,6-di-O-benzyl-2-C- trichloromethyl-scyllo-inositol 1,3,5-orthoformate, 2,2'-anhydro-4,6-di-O- benzyl-2-C-dichlorohydroxymethyl-scyllo-inositol 1,3,5-orthoformate, 1,3,4,5,6-penta-O-benzyl-2-C-trichloromethyl-myo-inositol, and 2-amino-1,3,4,5,6-penta-O-benzyl-2-C-cyano-2-deoxy-myo-inositol. CSIRO 2006.

Full text of DOI:10.1071/CH06137

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2006, 59, 426–433
www.publish.csiro.au/journals/ajc
An Expansion of the Role of the Corey–Link Reaction for the Synthesis
of α-Substituted Carboxylic Acid Esters
Adrian Scaffidi,A Brian W. Skelton,A Robert V. Stick,A,B and Allan H. WhiteA
A Chemistry M313, School of Biomedical, Biomolecular and Chemical Sciences,
University of Western Australia, Crawley WA 6009, Australia.
B Corresponding author. Email: rvs@chem.uwa.edu.au
The treatment of 1,2:5,6-di-O-isopropylidene-α-d-ribo-hexos-3-ulose with chloroform under basic conditions has
yielded the normal 3-C-trichloromethyl-α-d-allofuranose derivative. Under the conditions of the modified Corey–
Link reaction but with a nucleophile different from the usual azide, a range of α-substituted carboxylic acid esters
(and one amide) has been obtained. A similar addition of bromoform to the ulose has formed the α-bromo methyl
ester. Two attempts at forming an ‘inositol α-amino acid’ from a polyhydroxylated cyclohexanone failed.
Single-crystal X-ray structure determinations are reported for (3S)-1,2:5,6-di-O-isopropylidene-3-C-meth-
oxycarbonyl-3-S-phenyl-3-thio-α-d-ribo-hexose, (3S)-1,2:5,6-di-O-isopropylidene-3-S-phenyl-3-C-(phenylthio)-
carbonyl-3-thio-α-d-ribo-hexose, 3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-α-d-erythro-hex-3-
enofuranose, 4,6-di-O-benzyl-2-C-trichloromethyl-scyllo-inositol 1,3,5-orthoformate, 2,2ꢀ-anhydro-4,6-di-O-
benzyl-2-C-dichlorohydroxymethyl-scyllo-inositol 1,3,5-orthoformate, 1,3,4,5,6-penta-O-benzyl-2-C-trichloro-
methyl-myo-inositol, and 2-amino-1,3,4,5,6-penta-O-benzyl-2-C-cyano-2-deoxy-myo-inositol.
Manuscript received: 26 April 2006.
Final version: 3 July 2006.
Introduction
acids could be coupled together to give a range of novel
carbohydrate oligopeptides.[4]
In 1992 Corey and Link reported a general procedure for
the synthesis of α-amino acids (Scheme 1A); the start-
ing optically active trichloromethyl alcohols were generally
obtained by the stereoselective reduction of a precursor
trichloromethyl ketone.[1] Some years later a modification
of the procedure was reported, resulting in the formation
of α-azido methyl esters, direct precursors of the α-amino
acids (Scheme 1B); this time, the starting optically active
trichloromethyl alcohols were obtained by the stereoselec-
tive addition of chloroform to a ketone.[2] We have applied
the modified Corey–Link sequence to a range of carbo-
hydrate ketones, resulting in the formation of intermediate
trichloromethyl alcohols that were transformed into α-azido
methyl esters, direct precursors of α-amino methyl esters and
α-azido acids (for example, Scheme 2).[3] These amines and
It occurred to us that other nucleophiles (apart from azide)
could be used to trap the accepted intermediate dichloro
epoxide (Scheme 1A). In the extreme, treatment of the alco-
hol 1 with just 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
methanol gave the chloro ester 2 (Scheme 3); the addition of
a source of bromide ion to the original reaction mixture failed
to yield the pure bromo ester 3, being contaminated with the
chloro ester 2. Treatment of 1 with a source of fluoride ion
in the normal reaction mixture gave the fluoro ester 4, prob-
ably owing to the fortuitous precipitation of the less-soluble
caesium chloride. Other nucleophiles, namely methoxide,
cyanide, and cyanate, provided the methoxy ester 5, the cyano
ester 6, and the carbamate 7. The carbamate was the obvious
product of methanolysis of an intermediate isocyanate. In an
(a)
(b)
Cl3C
HO
Cl2C
N3
H2N
A
O
CO2H
CO2H
(c)
N3
Cl3C
HO
B
H2N
CO2Me
CO2H
Scheme 1. (a) (i) NaN3, NaOH, H2O, 1,2-dimethoxyethane. (ii) H3O+. (b) H2, Pd/C, MeOH. (c) NaN3, DBU, [18]crown-6, MeOH.
© CSIRO 2006 10.1071/CH06137 0004-9425/06/070426

Corey–Link Reaction for the Synthesis of α-Substituted Carboxylic Acid Esters
427
O
O
O
O
O
O
O
O
(a)
(b)
(b)
(a)
O
CBr3
O
CCl3
O
O
O
O
O
O
O
O
O
OH
O
O
O
OH
11
1
O
O
O
O
O
O
(c)
O
O
(c) or (d)
O
O
X
Br
N3
O
O
O
O
O
O
O
MeO2C
O
MeO2C
O
O
MeO2C
RO2C
3
12
X ϭ NH2, R ϭ Me (c)
ϭ N3, ϭ H (d)
Scheme 6. (a) LiN(SiMe3)2, CHBr3, THF. (b) DBU, MeOH. (c) DMF,
NaN3.
Scheme 2. (a) LiN(SiMe3)2, CHCl3, THF. (b) NaN3, DBU,
[18]crown-6, MeOH. (c) H2, Pd/C, MeOH. (d) (i) KOH, MeOH.
(ii) H3O+.
O
O
O
O
(a)
O
O
1
Cl
Cl
O
O
O
Cl(O)C
O
O
BnNH(O)C
(a)
2
3
4
5
6
7
X ϭ Cl
ϭ Br
ϭ F
ϭ OMe
ϭ CN
O
(a), (b), (c), (d), or (e)
O
1
X
(b)
(c)
(d)
(e)
13
O
MeO2C
O
ϭ NHCO2Me
Scheme 7. (a) DBU, BnNH2, CH2Cl2.
Scheme 3. (a) DBU, MeOH. (b) CsF, DBU, MeOH. (c) NaOMe,
MeOH. (d) NaCN, DBU, MeOH. (e) KOCN, DBU, MeOH.
O
O
O
O
O
O
(b)
(a)
HO
O
BnO
BnO
O
O
OBn
OBn
O
15
14
(a)
O
1
Cl2C
7
O
O
O
O
O
O
O
O
3
(c)
Cl2C
Cl3C
1
8
BnO
BnO
O
OBn
OBn
OH
Scheme 4. (a) KOCN, KOBut, ButOH.
16
17
Scheme 8. (a) (i) (COCl)2, DMSO, CH2Cl2. (ii) Et3N. (b)
LiN(SiMe3)2, CHCl3, THF. (c) DBU, NaN3, [18]crown-6, MeOH.
O
O
O
O
O
(a)
O
SPh
ϩ
1
SPh
OH
O
O
OBn
O
OBn
MeO2C
O
(a)
(b)
PhS(O)C
10
O
OBn
OBn
OBn
OBn
BnO
BnO
OBn
9
OBn
18
19
OH
Scheme 5. (a) NaOMe, PhSH, MeOH.
OH
BnO
OBn
OBn
(c)
Cl3C
BnO
OBn
OBn
attempt to prepare the related tert-butyl carbamate (by replac-
ing methanol with tert-butanol and using tert-butoxide as the
base), only the dichloro epoxide 8 (Scheme 4) was isolated —
apparently, potassium cyanate in tert-butanol was not soluble
enough for a further reaction to occur.
The use of thiophenol in combination with sodium
methoxide gave a mixture of the phenylthio ethers 9 and 10
(Scheme 5), the structures being confirmed by single-crystal
X-ray structure investigations (Figs 1a and 1b). Further minor
experimentation indicated that the methyl ester 9 is first
formed, followed by a trans-esterification reaction with the
remaining thiophenol to form 10.
OBn
OBn
21
20
Scheme 9. (a) (i) (COCl)2, DMSO, CH2Cl2. (ii) Et3N. (b)
LiN(SiMe3)2, CHCl3, THF. (c) DBU, NaN3, [18]crown-6, MeOH.
NH2
OBn
(a)
NC
BnO
OBn
OBn
19
OBn
22
Some interesting observations were made during the
above investigations, one being the addition of bromoform to
Scheme 10. (a) (i) NH3, MeOH, Ti(OPri)4. (ii) Me3SiCN.

428
A. Scaffidi et al.
C305
C17
C306
O12
O6
O14
C14
C304
C301
O16
C13
C6
S3
C561
C303
C12
C56
Cl11
C302
O4
C5
(a)
C111
C1
C562
C16
C15
C130
C11
C4
Cl12
O5
C3
O13
O15
C2
O1
(e)
O11
O31
C12
C31
O32
C150
C151
C131
C136
C132
O2
C121
C32
C135
C152
C153
C122
C133
C134
C156
C303
C155
C154
C302
C301
C304
S3
O4
C305
C306
C6
C5
C1
C22
C21
O6
C561
C2
(b)
C56
C3
C4
O1
C32
C30
C121
O5
C31
S31
C311
C20
O2
C31
O32
O3
O2
C12
C562
C312
Cl3
C2
C3
C4
C316
Cl2
C122
O4
C313
C40
C41
(f)
C1
C11
Cl1
O1
C5
C314
C6
O6
C315
O5
C50
C60
C61
C52
C51
O6
C62
O6Ј
C6
O4
C1
C4
C5
C56
C562
C3
(c)
O1
O2
O31
C2
O32
O5
C562Ј
O5Ј
C31
C32
C12
C24
C121
C122
C23Ј
C22Ј
C23
C33
C32
C34
C35
C36
C25Ј
C26
C31
C26Ј
C21
C20
C30
C7
O6
C3
O2
O2
Cl3
O4
O3
C42
C2
N1
C3
C43
(g)
C1
C2
O4
C4
C11
C1
C41
N11
C11
C60
C4
Cl1
C40
C44
C45
C6
(d)
C5
C5
O5
C6
C46
O3
C30
Cl2
O6
O5
C50
O1
C56
C61
C66
C62Ј
C50
C31
C51
C52
C66Ј
C65Ј
C55
C54
C36
C32
C63Ј
C53
C56
C51
C35
C64
C52
C55
C53
C34
C54
Fig. 1. Molecular projections of (a) 9, (b) 10, (c) 12, (d) 16, (e) 17 (molecule 1), (f ) 20, and (g) 22.

Corey–Link Reaction for the Synthesis of α-Substituted Carboxylic Acid Esters
429
X-ray structure investigation (Fig. 1d). The treatment of 16
under the conditions of the modified Corey–Link reaction
failed to yield the desired azido ester — only the dichloro
epoxide 17 was (again) obtained, the structure of which was
confirmed by a single-crystal X-ray investigation (Fig. 1e).
It seems that the trajectory of approach for a successful dis-
placement by the azide ion is blocked in this rigid tricyclic
framework.
31
(a)
11
21
a sin b
b
An alternative approach was from the alcohol 18
(Scheme 9). Although oxidation to the ketone 19 and subse-
quent addition of chloroform yielded the alcohol 20, the basic
conditions of the modified Corey–Link reaction yielded only
the phenol 21. This sort of elimination process is not without
precedent.[5] We were ultimately able to form a precursor to
an inositol amino acid but not by the chosen route — treat-
ment of the ketone 19 under modern Strecker conditions gave
the amino nitrile 22, the hydrolysis of which proved impos-
sible in our hands (Scheme 10). The configuration of 20 and
22 were again confirmed by single-crystal X-ray structure
investigations (Figs 1f and 1g).
c
a
O5
O6
O4
O3
O1
O2
Cl1
(b)
Cl2
Cl3
The results described here show that the conditions of the
modifiedCorey–Linkreactioncanbeusedforthesynthesisof
a range of α-substituted carboxylic acid esters (and amides).
Structural Comment
c
The results of the seven single crystal X-ray studies are
consistent, in terms of stoichiometry, connectivity and stereo-
chemistry (Fig. 1), with those given above for 9, 10, 12, 16,
17, 20, and 22, the determinations being of diverse degrees
of precision; absolute configurations, where assignable (at
relatively low levels of confidence on the basis of the pres-
ence of Cl or S), are consistent with those expected. With the
exception of 17, one formula unit devoid of crystallographic
symmetry comprises the asymmetric unit of each structure; in
17, three similar molecules comprise the asymmetric unit, the
structure overall displaying an interesting packing as sheets
parallel to the ac-plane (Fig. 2). In both 20 and 22, the pack-
ing of the molecules is also of interest, in both cases, stacking
being found up the short (b) axes. The conformations of the
fused dioxolane rings of 9 and 10 (Table 1) are similar, as
are those of the parent furanoses, which are envelopes with
O4 the flaps; in 12 with the incorporation of the double bond,
the ring is flattened, while the dioxolane rings, also envelopes
with C12 the flaps, have the latter atoms directed ‘outwards’
in 9, and in 10 turned ‘inwards’, with methyl substituent C122
lying over the furanose ring. The conformations of the pen-
dant dioxolane rings are similar in 9 and 10; in 12, disorder is
resolved and refinable in the oxygen atoms, the minor com-
ponents conforming to the conformation found in 9 and 10,
while the major component now differs. A concomitant of
this is that in the major component H5 may lie marginally
more distant from O31 (with which it is ‘coplanar’) than H5ꢀ,
which lies at the van der Waals distance; there seems to be no
compelling intramolecular imperative why the disposition of
H5, H5ꢀ should be thus, relative to O31.
a
O6
O5
O2
O3
(c)
O4
Fig. 2. Unit cell projections of (a) 17 down the c-axis, (b) 20 down the
b-axis, and (c) 22 down the b-axis.
1,2:5,6-di-O-isopropylidene-α-d-ribo-hexos-3-ulose to pro-
vide the pure bromo ester 3 (Scheme 6), via the alcohol 11.An
attempt to replace the bromine atom in 3 with azide, hope-
fully with inversion of configuration, gave only the alkene
12, the structure of which was confirmed by a single crystal
X-ray structure investigation (Fig. 1c).
One final experiment, with benzylamine, converted the
alcohol 1 into the amide 13 (Scheme 7) — apparently, the
chloro acid chloride is formed and is subsequently trapped
by the (weakly nucleophilic) amine.
We were always interested in seeing if the Corey–Link
reaction could be used for the synthesis of ‘inositol α-amino
acids’; to the best of our knowledge this is a new class
of molecule. Therefore, the easily prepared ortho ester 14
was oxidized and the resulting ketone 15 converted into
the trichloromethyl alcohol 16 (Scheme 8), the expected
configuration of which was confirmed by a single-crystal
All six-membered rings in 16, 17, 20, and 22, are
‘chairs’ (Table 2), relatively undistorted by fusion into the

430
A. Scaffidi et al.
trioxaadamantane systems of 16 and 17, and by the epox-
ide in 17, although the rings in 20 and 22, are ‘flatter’ than
their counterparts in 16 and 17 (Table 2); in 16 and 17, ring
torsions involving the apical carbon, C7, are slightly greater
than elsewhere in the trioxaadamantane array.
Experimental
Structure Determinations of 9, 10, 12, 16, 17, 20, and 22
Full spheres of CCD area-detector diffractometer data were measured
(Bruker AXS instrument, ω-scans, monochromatic MoKα radiation,
λ 0.71073 Å; T ca. 153 or 298 K) yielding Nt(otal) reflections, these
merging to N unique (Rint cited) after ‘empirical’/multiscan absorption
correction (proprietary software), No with F > 4σ(F) being employed
in the full matrix least-squares refinements on |F2| (12, 17) or |F| (the
remainder), anisotropic displacement parameter forms being refined
Table 1. Five-membered ring conformational descriptors, torsion
angles
Compound
9
10
12
for the non-hydrogen atoms, (x,y,z,Uiso H being constrained at esti-
)
mates (hydroxylic hydrogens excepted, which were positioned from
difference maps). Conventional residuals R, Rw on |F| are cited at con-
vergence (weights: (σ2(F2) + nwF2)−1 or σ2(F) + 0.000nwF2)−1; for
the non-centrosymmetric structures containing Cl or S, Friedel data were
retained distinct and the absolute structure refined. Neutral atom com-
plex scattering factors were employed within the context of the Xtal 3.7
program system.[6] Pertinent results are given below and in the Table
and Figures, the latter showing 50% (153 K) or 20% (298 K) probabil-
ity amplitude envelopes for the non-hydrogen atoms, hydrogen atoms
having arbitrary radii of 0.1 Å. Individual variations in procedure are
cited under ‘variata’; data quality across this series of compounds was,
in general, quite poor in consequence of deficiencies in crystal quality
and/or size. Full CIF depositions, excluding structure factor amplitudes,
are deposited with the Cambridge Crystallographic Data Centre, CCDC
no. 603019–603025.
C5O rings
O4–C1–C2–C3
C1–C2–C3–C4
C2–C3–C4–O4
C3–C4–O4–C1
C4–O4–C1–C2
1,2-Fused dioxolane rings
O1–C1–C2–O2
C1–C2–O2–C12
−2.5(11)
22.8(10)
−35.8(9)
36.5(10)
−21.6(11) −26.6(9)
2.1(9)
20.3(8)
−5.8(7)
4.3(9)
−1.0(10)
−3.1(10)
5.6(8)
−36.0(7)
40.0(9)
−4.0(12)
−0.1(9)
−7.4(7)
−9.9(7)
22.6(7)
21.0(12)
19.5(9)
C2–O2–C12–O1 −30.2(12) −31.1(9)
O2–C12–O1–C1 28.3(13)
30.7(9) −27.8(6)
C12–O1–C1–C2 −14.9(12) −18.5(9)
21.9(6)
4-Pendant dioxolane ringsA
O5–C5–C6–O6
29.4(11)
38.9(10) −22.7(9), 37(2)
33.6(8), −43(1)
C5–C6–O6–C56 −34.3(11) −32.4(12)
C6–O6–C56–O5
O6–C56–O5–C5
26.0(12)
−6.1(12)
13.5(1) −31.9(9), 36(2)
Crystal/Refinement Data
12.3(12)
16.9(11), −12(3)
Compound 9, C20H26O7S, M 410.5. Monoclinic, space group C2
(C32, no. 5), a 21.566(7), b 7.077(2), c 14.873(4) Å, β 103.149(5)◦,
V 2210 Å3. Dc (Z 4) 1.233 g cm−3. µMo 0.18 mm−1; specimen:
0.54 × 0.23 × 0.18 mm3; ‘T’min/max 0.69. 2θmax 50◦; Nt 7993, N 2134
C56–O5–C5–C6 −14.5(11) −31.4(11)
A The two entries for 12 are for the major (unprimed) and minor (primed)
3.3(11), 15(3)
ring components of the disordered array, respectively (Fig. 1c).
Table 2. Six-membered ring conformational descriptors, torsion angles
Compound/mol.
16
17/1
17/2
17/3
20
22
Cyclohexane rings
C6–C1–C2–C3
C1–C2–C3–C4
C2–C3–C4–C5
C3–C4–C5–C6
C4–C5–C6–C1
C5–C6–C1–C2
62.4(1)
−60.1(1)
57.7(1)
57.3(6)
−55.0(9)
57.9(3)
58.1(5)
−56.3(5)
58.5(5)
58.6(5)
−54.9(5)
57.6(5)
48.0(5)
−45.7(6)
48.6(6)
−59(2)
50(2)
−45(2)
−56.8(1)
−58.8(6)
−59.3(5)
−59.6(5)
−57.1(6)
48(2)
59.1(1)
57.6(5)
58.0(5)
58.4(5)
63.1(6)
−55(2)
60(2)
−61.8(1)
−58.7(6)
−59.9(5)
−59.8(5)
−56.5(5)
16
17/1
17/2
17/3
Mean
1,3-Dioxane rings
(a) O2, O6 ring
C6–C1–C2–O2
C1–C2–O2–C7
C2–O2–C7–O6
O2–C7–O6–C6
C7–O6–C6–C1
O6–C6–C1–C2
−54.9(1)
59.5(1)
−58.5(6)
59.5(1)
−57.9(5)
59.6(5)
−58.1(5)
60.4(5)
−58.2(3)
59.8(5)
−61.5(1)
−63.9(6)
−63.9(5)
−65.2(5)
−64.3(8)
60.8(1)
62.7(6)
64.4(5)
63.2(5)
63.4(9)
−58.6(1)
54.6(1)
−58.9(6)
58.5(6)
−61.0(5)
59.1(5)
−58.7(5)
58.1(5)
−59.5(13)
58.6(5)
(b) O2, O4 ring
O2–C2–C3–C4
C2–C3–C4–O4
C3–C4–O4–C7
C4–O4–C7–O2
O4–C7–O2–C2
C7–O2–C2–C3
59.3(1)
−60.0(1)
61.4(1)
59.1(5)
−59.9(5)
61.3(6)
59.1(5)
−59.4(5)
60.4(6)
60.1(5)
−60.9(5)
62.4(6)
59.4(6)
−60.1(8)
61.4(10)
−61.7(9)
60.4(3)
−63.1(1)
−62.1(6)
−60.7(6)
−62.3(6)
63.2(1)
60.6(5)
60.6(5)
60.1(5)
−60.9(1)
−59.1(6)
−59.2(6)
−59.2(6)
−59.2(1)
(c) O4, O6 ring
O6–C6–C5–C4
C6–C5–C4–O4
C5–C4–O4–C7
C4–O4–C7–O6
O4–C7–O6–C6
C7–O6–C6–C5
−60.4(1)
60.5(1)
−58.6(6)
58.5(5)
−59.0(5)
59.1(6)
−58.8(5)
58.1(56)
−60.8(6)
63.0(6)
−58.8(2)
58.6(5)
−60.3(1)
−60.9(5)
−62.2(3)
−61.3(8)
61.7(1)
62.5(6)
63.0(6)
62.8(3)
−63.7(1)
61.8(1)
−62.0(5)
60.5(6)
−60.3(5)
59.3(5)
−62.5(5)
−61.6(12)
60.2(8)
60.7(5)

Corey–Link Reaction for the Synthesis of α-Substituted Carboxylic Acid Esters
431
(Rint 0.051), No 1546; R 0.072, Rw 0.094 (nw 7); |ꢀρmax| 0.40(4) e Å−3
xabs 0.1(3).
.
Percentage yields for chemical reactions as described are quoted
only for those compounds that were purified by recrystallization or by
column chromatography and the purity assessed by TLC or 1H NMR
spectroscopy.
All solvents except DMF and MeCN were distilled before use and
dried according to the methods of Burfield and Smithers.[7]
‘Usual workup’refers to dilution with water, repeated extraction into
an organic solvent, sequential washing of the combined extracts with
hydrochloric acid (1 M, where appropriate), saturated aqueous sodium
bicarbonate and brine solutions, followed by drying over anhydrous
magnesium sulfate, filtration, and evaporation of the solvent by means
of a rotary evaporator at reduced pressure.
Compound 10, C25H28O6S2, M 488.6. Monoclinic, space group P21
(C22, no. 4), a 6.973(2), b 17.219(5), c 10.756(2) Å, β 103.868(4)◦,
V 1254 Å3. Dc (Z 2) 1.294 g cm−3. µMo 0.25 mm−1; specimen:
0.54 × 0.20 × 0.15 mm3; ‘T’min/max 0.64. 2θmax 52.6◦; Nt 10852,
N 2652 (Rint 0.035), No 2014; R 0.070, Rw 0.086 (nw 3); |ꢀρmax| 0.50(3)
e Å−3. xabs 0.1(2).
Compound 12, C14H20O7, M 360.1. Monoclinic, space group P21, a
9.232(2), b 9.051(2), c 9.932(2) Å, β 113.019(3)◦, V 763.8 Å3. Dc (Z 2)
1.306 g cm−3. µMo 0.11 mm−1; specimen: 0.35 × 0.25 × 0.25 mm3;
‘T’min/max 0.82. 2θmax 58◦; Nt 7041, N 2012 (Rint 0.098), No 1422;
R 0.070, Rw 0.14 (nw 0.16); |ꢀρmax| 0.31(4) e Å−3. xabs not refined.
Variata. Atoms O5, O6, C561, C562 of the pendant ring were mod-
elled as disordered over pairs of sites, occupancies refining to 0.78(1)
and complement.
(3S)-3-Chloro-3-deoxy-1,2:5,6-di-O-isopropylidene-
3-C-methoxycarbonyl-α-D-arabino-hexose 2
DBU (0.90 mL, 6.0 mmol) was added to the alcohol 1 (200 mg,
0.53 mmol) in MeOH (10 mL) and the solution stirred at 50◦C (1 h)
before being diluted with saturated NH4Cl solution. A usual workup
(EtOAc) gave a yellow residue that was subjected to flash chromatog-
raphy (EtOAc/petrol 1/9) to yield the chloride 2 as a solid (148 mg,
83%), mp 68–70◦C, [α]D +54.4◦. δH (300 MHz) 1.23, 1.25, 1.35, 1.45
(12H, 4s, CH3), 3.75 (s, CO2CH3), 4.03 (2H, d, H6), 4.28 (ddd, J4,5
6.0, J5,6 5.6, 5.6, H5), 4.68 (d, J1,2 3.4, H2), 4.72 (d, H4), 5.88 (d, H1).
δC (75.5 MHz) 24.82, 25.91, 26.34, 26.67 (4C, CH3), 53.09 (CO2CH3),
66.13 (C6), 73.67 (C3), 74.26, 81.19, 88.15 (C2,C4,C5), 104.44 (C1),
109.19, 113.44 (2C, OCO), 165.39 (CO2CH3). m/z (HR-MS FAB)
337.1044; [M + H]+ requires 337.1054.
Compound 16, C22H21Cl3O6, M 487.8. Triclinic, space group P1
(C1i , no. 2), a 8.075(2), b 8.726(2), c 16.131(4) Å, α 85.438(5), β
89.692(5), γ 65.606(5)◦, V 1031 Å3. Dc (Z 2) 1.570 g cm−3. µMo
0.48 mm−1; specimen: 0.38 × 0.33 × 0.30 mm3; ‘T’min/max 0.89. 2θmax
75◦; Nt 20253, N 10562 (Rint 0.027), No 8337; R 0.044, Rw 0.069 (nw
3); |ꢀρmax| 1.07(5) e Å−3
.
Compound 17, C22H20Cl2O6, M 451.3. Monoclinic, space group
P21/c (C52h, no. 14), a 15.986(3), b 27.010(6), c 14.480(3) Å, β
104.217(4)◦,V 6060 Å3. Dc (Z 12) 1.484 g cm−3. µMo 0.36 mm−1; spec-
imen: 0.28 × 0.20 × 0.04 mm3; ‘T’min/max 0.81. 2θmax 50◦; Nt 55706,
N 10581 (Rint 0.13), No 6858; R 0.078, Rw 0.14 (nw 4.5); |ꢀρmax
|
1.0(2) e Å−3
Compound 20, C42
.
(3S)-3-Bromo-3-deoxy-1,2:5,6-di-O-isopropylidene-
3-C-methoxycarbonyl-α-D-arabino-hexose 3
H
41Cl3O6, M 748.2. Monoclinic, space group
Pn (C2s , no. 7 variant), a 13.623(2), b 5.7876(9), c 24.173(4) Å, β
103.529(2)◦, V 1853 Å3. Dc (Z 2) 1.145 g cm−3. µMo 0.30 mm−1; spec-
imen: 0.26 × 0.24 × 0.16 mm3; ‘T’min/max 0.93. 2θmax 56◦; Nt 17281,
DBU (1.0 mL, 6.7 mmol) was added to the alcohol 11 (1.1 g, 2.2 mmol)
in MeOH (30 mL) and the mixture stirred at 50◦C (1 h) before being
diluted with saturated NH4Cl solution. A usual workup (EtOAc)
gave a yellow residue that was subjected to flash chromatography
(EtOAc/petrol 1/9) to afford the bromide 3 as an oil (690 mg, 82%),
[α]D +57.7◦. δH (500 MHz) 1.26, 1.30, 1.40, 1.46 (12H, 4s, CH3), 3.79
(s, CO2CH3), 4.07 (dd, J6,6 8.7, J5,6 6.6, H6), 4.10 (dd, J5,6 5.0, H6), 4.33
(ddd, J4,5 5.1, H5), 4.55 (d, H4), 4.90 (d, J1,2 3.5, H2), 5.93 (d, H1). δC
(125.8 MHz) 24.95, 26.02, 26.50, 26.73 (4C, CH3), 53.23 (CO2CH3),
65.93 (C6), 66.10 (C3), 76.09, 81.20, 88.20 (C2,C4,C5), 104.34 (C1),
109.15, 113.54 (2C, OCO), 165.71 (CO2CH3). m/z (HR-MS FAB)
381.0536; [M + H]+ requires 381.0549.
N 4229 (Rint 0.027), No 3637; R 0.050, Rw 0.069 (nw 5); |ꢀρmax
0.37(5) e Å−3. xabs 0.30(8).
|
Compound 22, C42H42N2O5, M 654.9. Monoclinic, space group
P21/n (C52h, no. 14 variant), a 24.05(2), b 4.945(4), c 31.06(2) Å, β
109.13(1)◦, V 3490 Å3. Dc (Z 4) 1.246 g cm−3. µMo 0.08 mm−1; speci-
men: 0.68 × 0.04 × 0.02 mm3; ‘T’min/max 0.68. 2θmax 50◦; Nt 17850,
N 5946 (Rint 0.18), No 1885; R 0.17, Rw 0.25 (nw 0.042); |ꢀρmax
|
1.05(9) e Å−3
.
Variata. Weak and limited data would support meaningful displace-
ment parameter refinement for C,N,O only with the isotropic form;
phenyl rings 2,6 were modelled as disordered over pairs of sites,
rotationally related about the pendant axis, site occupancies set at 0.5
after trial refinement.
(3S)-3-Deoxy-3-fluoro-1,2:5,6-di-O-isopropylidene-
3-C-methoxycarbonyl-α-D-arabino-hexose 4
DBU (0.90 mL, 6.0 mmol) was added to the alcohol 1 (200 mg,
0.53 mmol) and CsF (400 mg, 2.6 mmol) in MeOH (10 mL) and the
mixture stirred at 50◦C (1 h) before being diluted with saturated NH4Cl
solution. A usual workup (EtOAc) gave a yellow residue that was
subjected to flash chromatography (EtOAc/petrol 1/9) to afford the flu-
oride 4 as fine needles (145 mg, 85%), mp 66–68◦C, [α]D +55.3◦. δH
(300 MHz) 1.26, 1.29, 1.35, 1.50 (4C, CH3), 3.80 (s, CO2CH3), 4.00–
4.10 (2H, m, H6), 4.16–4.25 (m, H5), 4.55–4.70 (m, H2,H4), 5.96 (d, J1,2
3.9, H1). δC (75.5 MHz) 24.84, 26.13, 26.43, 26.78 (4C, CH3), 53.00 (d,
JC,F 55.0, CO2CH3), 66.72 (C6), 72.03 (d, JC5,F 6.3, C5), 81.82 (d, JC2,F
20.5, C2), 84.81 (d, JC4,F 37.4, C4), 98.87 (d, JC3,F 196.7, C3), 105.36
(C1), 109.73, 113.63 (2C, OCO), 165.37 (d, JC,F 24.1, CO2CH3). m/z
(HR-MS FAB) 321.1383; [M + H]+ requires 321.1350.
General
1H and 13C NMR spectra were obtained on a Varian Gemini 200
(200 MHz for 1H), a BrukerAM 300 (300 MHz for 1H and 75.5 MHz for
13C), a Bruker ARX500 (500 MHz for 1H and 125.7 MHz for 13C), or a
Bruker AV600 (600 MHz for 1H and 150.8 MHz for 13C) spectrometer.
Unless stated otherwise, deuterated chloroform (CDCl3) was used as
the solvent with CHCl3 (δH 7.26) or CDCl3 (δC 77.0) being employed
as internal standards. NMR spectra run in D2O used internal CH3OH
(δH 3.34, δC 49.0) as the standard.
Melting points were determined on a Reichert hot stage melting
point apparatus. Optical rotations were performed with a Perkin–Elmer
141 Polarimeter in a microcell (1 mL, 10 cm path length) in CHCl3 at
room temperature, unless otherwise stated. Mass spectra were recorded
with a VG-Autospec spectrometer using the fast atom bombardment
(FAB) technique, with 3-nitrobenzyl alcohol as a matrix, unless other-
wise stated. Microanalyses were performed by the Microanalytical Unit,
Australian National University, Canberra.
1,2:5,6-Di-O-isopropylidene-3-C-methoxycarbonyl-
3-O-methyl-α-D-glucose 5
Sodium methoxide (560 mg, 10.6 mmol) in MeOH (5 mL) was added
to the alcohol 1 (200 mg, 0.53 mmol) in MeOH (5 mL) and the mixture
stirred at 50◦C (0.5 h) before being diluted with saturated NH4Cl solu-
tion. A usual workup (EtOAc) gave a yellow residue that was subjected
to flash chromatography (EtOAc/petrol 3/17) to afford the ether 5 as
an oil (95 mg, 54%), [α]D +55.1◦. δH (500 MHz) 1.32, 1.35, 1.43, 1.53
(12H, 4s, CH3), 3.58 (s, OCH3), 3.81 (s, CO2CH3), 4.03–4.07 (2H,
Flash chromatography was performed on BDH silica gel or Gedu-
ran silica gel 60 with the specified solvents. Thin-layer chromatography
(TLC) was effected on Merck silica gel 60 F254 aluminium-backed
plates that were stained by heating (>200◦C) with 5% sulfuric acid
in EtOH.

432
A. Scaffidi et al.
m, H6), 4.35 (ddd, J4,5 6.4, J5,6 6.1, 6.0, H5), 4.65 (d, H4), 4.72 (d,
J1,2 3.8, H2), 5.88 (d, H1). δC (125.8 MHz) 25.28, 26.26, 26.72, 26.74
(4C, CH3), 52.08 (CO2CH3), 54.93 (OCH3), 66.64 (C6), 72.98, 82.29,
82.96 (C2,C4,C5), 87.52 (C3), 104.61 (C1), 109.02, 112.82 (2C, OCO),
107.79 (CO2CH3). m/z (HR-MS FAB) 333.1559; [M + H]+ requires
333.1550.
26.13, 26.79, 26.89 (4C, CH3), 66.97 (C6), 71.92 (C3), 74.44, 82.05,
85.75 (C2,C4,C5), 104.38 (C1), 109.48, 113.18 (2C, OCO), 128.70–
136.88 (Ph), 192.20 (C=O). m/z (HR-MS FAB) 489.1393; [M + H]+
requires 489.1406.
Next to elute was the methyl ester 9 as plates (100 mg, 46%), mp
98–100◦C (EtOAc/pentane), [α]D +71.9◦. δH (500 MHz) 1.26, 1.40,
1.49 (12H, 3s, CH3), 3.62 (s, CO2CH3), 4.17 (dd, J6,6 8.4, J5,6 6.7,
H6), 4.24 (dd, J5,6 5.8, H6), 4.60 (d, J1,2 3.4, H2), 4.74 (ddd, J4,5 3.6,
H5), 4.86 (d, H4), 5.94 (d, H1), 7.36–7.59 (Ph). δC (125.8 MHz) 25.23,
26.21, 26.85, 26.94 (4C, CH3), 52.18 (CO2CH3), 64.22 (C3), 65.79
(C6), 74.71, 81.37, 84.81 (C2,C4,C5), 104.04 (C1), 108.79, 112.95
(2C, OCO), 128.45–137.51 (Ph), 167.89 (CO2CH3). m/z (HR-MS FAB)
411.1476; [M + H]+ requires 411.1478.
(3R)-3-C-Cyano-3-deoxy-1,2:5,6-di-O-isopropylidene-
3-C-methoxycarbonyl-α-D-arabino-hexose 6
DBU (0.90 mL, 6.0 mmol) was added to the alcohol 1 (200 mg,
0.53 mmol) and NaCN (130 mg, 2.6 mmol) in MeOH (10 mL) and the
mixture stirred at 50◦C (1 h) before being diluted with saturated NH4Cl
solution. A usual workup (EtOAc) gave a yellow residue that was sub-
jected to flash chromatography (EtOAc/petrol 1/9) to afford the nitrile
6 as fine needles (140 mg, 80%), mp 107–109◦C (EtOAc/pentane),
[α]D +75.5◦. δH (300 MHz) 1.30, 1.37, 1.50 (12H, 3s, CH3), 3.82 (s,
CO2CH3), 4.05 (dd, J6,6 9.0, J5,6 3.6, H6), 4.15 (dd, J5,6 6.2, H6), 4.25
(ddd, J4,5 8.7, H5), 4.57 (d, H4), 5.00 (d, J1,2 3.8, H2), 6.00 (d, H1).
δC (75.5 MHz) 24.75, 25.93, 25.95, 26.85 (4C, CH3), 53.61 (CO2CH3),
56.41 (C3), 67.13 (C6), 74.75, 80.79, 85.76 (C2,C4,C5), 105.11 (C1),
110.31, 113.98 (2C, OCO), 114.86 (CN), 161.99 (CO2CH3). m/z
(HR-MS FAB) 328.1391; [M + H]+ requires 328.1396.
1,2:5,6-Di-O-isopropylidene-3-C-tribromomethyl-α-D-allose 11
Lithiumbis(trimethylsilyl)amideinTHF(1.0 M, 14.0 mL, 14 mmol)was
added dropwise to 1,2:5,6-di-O-isopropylidene-α-d-ribo-hexofuran-3-
ulose (2.5 g, 8.9 mmol) and CHBr3 (1.3 mL, 15 mmol) in THF (50 mL)
at −78◦C.The resulting solution was stirred at −78◦C (1 h) before being
diluted with saturated NaHCO3 solution. A usual workup (EtOAc) fol-
lowed by flash chromatography (EtOAc/petrol 1/9) yielded the alcohol
11 as plates (4.0 g, 81%), mp 119–121◦C, [α]D +26.8◦. δH (500 MHz)
1.37, 1.47, 1.65 (12H, 3s, CH3), 3.91 (dd, J6,6 8.4, J5,6 7.4, H6), 4.00
(s, CO2CH3), 4.18 (dd, J5,6 5.8, H6), 4.23 (d, J4,5 8.1, H4), 4.77 (d, J1,2
4.5, H2), 4.81–4.86 (m, H5), 5.97 (d, H1). δC (125.8 MHz) 25.74, 26.38,
26.65, 27.11 (4C, CH3), 46.21 (CBr3), 68.06 (C6), 71.37, 83.05, 85.42
(C2,C4,C5), 86.30 (C3), 103.02 (C1), 110.02, 113.32 (2C, OCO). m/z
(HR-MS FAB) 508.8755; [M + H]+ requires 508.8810.
(3S)-3-Deoxy-1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-
3-methoxycarbonylamino-α-D-arabino-hexose 7
DBU (0.90 mL, 6.0 mmol) was added to the alcohol 1 (200 mg,
0.53 mmol) and KOCN (215 mg, 2.70 mmol) in MeOH (30 mL) and
the mixture stirred at 50◦C (1 h) before being diluted with saturated
NH4Cl solution. A usual workup (EtOAc) gave a yellow residue that
was subjected to flash chromatography (EtOAc/petrol 7/13) to afford
the carbamate 7 as an oil (100 mg, 50%), [α]D +56.8◦. δH (300 MHz)
1.26, 1.35, 1.50 (12H, 3s, CH3), 3.65, 3.75 (6H, 2s, CO2CH3), 3.97–
4.02 (2H, m, H6), 4.18–4.26 (m, H5), 4.74 (d, J4,5 6.7, H4), 5.09 (d,
J1,2 3.7, H1), 5.67 (bs, NH), 6.07 (d, H1). δC (75.5 MHz) 24.82, 25.98,
26.15, 26.52 (4C, CH3), 52.37, 52.77 (2C, CO2CH3), 66.11 (C6), 69.95
(C3), 73.47, 82.07, 85.47 (C2,C4,C5), 105.51 (C1), 109.22, 112.48
(2C, OCO), 155.79 (C(O)NH), 167.94 (CO2CH3). m/z (HR-MS FAB)
376.1610; [M + H]+ requires 376.1608.
3-Deoxy-1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-
α-D-erythro-hex-3-enofuranose 12
Sodium azide (34 mg, 0.52 mmol) was added to the bromo ester 3
(100 mg, 0.26 mmol) in DMF (1 mL) and the mixture heated at 70◦C
(24 h). A usual workup (CH2Cl2) gave a yellow residue that was
subjected to flash chromatography (EtOAc/petrol 3/17) to yield the
alkene 12 as plates (63 mg, 80%), mp 94–96◦C, [α]D +34.4◦. δH
(500 MHz) 1.40, 1.46, 1.48, 1.49 (12H, 4s, CH3), 3.78 (s, CO2CH3),
3.97 (dd, J6,6 8.6, J5,6 5.3, H6), 4.25 (dd, J5,6 7.0, H6), 5.42 (d, J1,2
5.2, H2), 5.62 (dd, H5), 6.16 (d, H1). δC (125.8 MHz) 25.47, 25.68,
27.71, 27.97 (4C, CH3), 51.63 (CO2CH3), 67.49 (C6), 69.76, 82.28
(C2,C5), 107.04 (C1), 107.19 (C3), 111.15, 113.82 (2C, OCO), 164.41
(CO2CH3), 170.32 (C4). m/z (HR-MS FAB) 301.1294; [M + H]+
requires 301.1287.
3,3ꢀ-Anhydro-1,2:5,6-di-O-isopropylidene-
3-C-dichlorohydroxymethyl-α-D-allose 8
The alcohol 1 (500 mg, 1.33 mmol) was added to KOCN (430 mg,
5.4 mmol) and KOBut (500 mg, 5.4 mmol) in tert-butanol (20 mL) and
the mixture stirred at 30◦C (0.5 h).The mixture was concentrated before
being diluted with EtOAc/petrol (1/4, 50 mL) and then filtered. Con-
centration of the filtrate gave a brown residue that was subjected to
flash chromatography (EtOAc/petrol 1/9) to afford 8 as a colourless
oil (350 mg, 77%), [α]D +109.8◦. δH (500 MHz) 1.36, 1.46, 1.53, 1.57
(12H, 4s, CH3), 4.05 (dd, J6,6 8.7, J5,6 6.1, H6), 4.13 (dd, J5,6 7.1, H6),
4.40 (d, J4,5 3.3, H4), 4.45 (ddd, H5), 4.92 (d, J1,2 4.5, H2), 6.04 (d,
H1). δC (125.8 MHz) 24.86, 26.19, 26.75, 27.85 (4C, CH3), 65.93 (C6),
75.33 (C3), 75.73, 79.07, 80.71 (C2,C4,C5), 87.60 (CCl2), 104.47 (C1),
110.53, 115.50 (2C, OCO). m/z (HR-MS FAB) 341.0541; [M + H]+
requires 341.0559.
(3S)-3-Chloro-3-deoxy-1,2:5,6-di-O-isopropylidene-
3-C-benzylaminocarbonyl-α-D-arabino-hexose 13
DBU (0.50 mL, 3.3 mmol) was added to the alcohol 1 (200 mg,
0.53 mmol) in a mixture of benzylamine/CH2Cl2 (1/2, 3 mL) and the
solution heated at 40◦C (0.5 h). A usual workup (EtOAc) followed
by flash chromatography (EtOAc/petrol 3/17) gave the amide 13 as a
colourless gum (80 mg, 37%), [α]D +32.9◦. δH (500 MHz) 1.07, 1.24,
1.38, 1.57 (12H, 4s, CH3), 4.04 (dd, J6,6 9.0, J5,6 5.5, H6), 4.19 (dd,
J5,6 6.2, H6), 4.38–4.43 (m, H5), 4.47 (d, J4,5 8.3, H4), 4.46–4.48
(2H, m, CH2Ph), 4.99 (d, J1,2 3.2, H2), 5.86 (d, H1), 7.27–7.38 (Ph),
7.94 (br t, NH). δC (125.8 MHz) 24.91, 25.59, 26.70, 26.91 (4C, CH3),
44.13 (CH2Ph), 67.84 (C6), 73.36, 80.27, 88.32 (C2,C4,C5), 75.92 (C3),
103.34 (C1), 110.57, 113.85 (2C, OCO), 127.63–137.24 (Ph), 164.35
(C=O). m/z (HR-MS FAB) 412.1519; [M + H]+ requires 412.1527.
(3S)-1,2:5,6-Di-O-isopropylidene-3-S-phenyl-
3-C-(phenylthio)carbonyl-3-thio-α-D-ribo-hexose 10 and
(3S)-1,2:5,6-Di-O-isopropylidene-3-C-methoxycarbonyl-
3-S-phenyl-3-thio-α-D-ribo-hexose 9
Sodium methoxide (560 mg, 10.6 mmol) and PhSH (0.12 mL, 1.1 mmol)
in MeOH (5 mL) were added to the alcohol 1 (200 mg, 0.53 mmol)
in MeOH (5 mL) and the mixture stirred at 50◦C (5 min) before
being diluted with saturated NH4Cl solution. A usual workup (EtOAc)
gave a yellow residue that was subjected to flash chromatography
(EtOAc/petrol 1/9) to afford the thio ester 10 as plates (90 mg, 31%),
mp 74–76◦C (EtOAc/pentane), [α]D +168.7◦. δH (500 MHz) 1.25, 1.33,
1.43, 1.53 (12H, 4s, CH3), 4.15 (dd, J6,6 8.6, J5,6 5.6, H6), 4.17 (dd, J5,6
6.4, H6), 4.59 (d, J1,2 4.6, H2), 4.66 (ddd, J4,5 6.2, H5), 4.92 (d, H4), 5.59
(d, H1), 7.38–7.48, 7.77–7.79 (10H, 2m, Ph). δC (125.8 MHz) 25.31,
4,6-Di-O-benzyl-2-C-trichloromethyl-scyllo-inositol
1,3,5-Orthoformate 16
(a) Dimethyl sulfoxide (1.7 mL, 24 mmol) in CH2Cl2 (5 mL) was added
dropwise to oxalyl chloride (1.0 mL, 11 mmol) in CH2Cl2 (20 mL) at
−55◦C and the solution stirred (0.5 h). The alcohol 14 (1.8 g, 4.9 mmol)
in CH2Cl2 (5 mL) was then added dropwise and the resulting solution
stirred at −55◦C (1.5 h). The solution was warmed to −30◦C, followed
by the dropwise addition of Et3N (8.0 mL, 57 mmol). The solution was

Corey–Link Reaction for the Synthesis of α-Substituted Carboxylic Acid Esters
433
then warmed to room temperature and a usual workup (CH2Cl2) pre-
sumably yielded the ketone 15 (1.7 g) that was used in the next step
without any purification.
(d, H1,H3), 4.61 (s, OH), 4.84 (s, CH2Ph), 4.86, 4.95 (4H, ABq, J 11.2,
CH2Ph), 4.96, 5.05 (4H, ABq, J 11.2, CH2Ph), 7.35–7.45 (25H, m, Ph).
δC (75.5 MHz) 73.54 (CH2Ph), 74.27 (CH2Ph), 74.38 (CH2Ph), 78.90
(2C, C1/6,C3/4), 81.09 (C2/5), 81.29 (2C, C6/1,C4/3), 82.93 (C5/2),
105.26 (CCl3), 127.43–137.92 (Ph). m/z (HR-MS FAB) 747.2076;
[M + H]+ requires 747.2047.
(b) Lithium bis(trimethylsilyl)amide in THF (1.0 M, 6.0 mL,
6.0 mmol) was added dropwise to the above ketone 15 (1.7 g) and
CHCl3 (1.0 mL, 12 mmol) in THF (30 mL) at −78◦C. The resulting
solution was stirred at −78◦C (1 h) before being diluted with satu-
rated NaHCO3 solution. A usual workup (EtOAc) followed by flash
chromatography (EtOAc/petrol 1/9) yielded the alcohol 16 as prisms
(1.4 g, 63%), mp 154–156◦C (EtOAc/pentane) (Found: C 54.1, H 4.5.
C22H21Cl3O6 requires C 54.2, H 4.3%). δH (300 MHz) 4.55–4.63, 4.93–
4.97 (2m, H1,H3,H4,H5,H6), 4.61, 4.76 (4H, ABq, J 10.8, CH2Ph),
5.55, 6.04 (2s, H7, OH), 7.24–7.35 (10H, m, Ph). δC (75.5 MHz) 67.65
(C2/C5), 69.07 (C1/4,C3/6), 71.80 (CH2Ph), 74.80 (C4/1,C6/3), 74.89
(C5/C2), 102.10 (C7), 103.78 (CCl3), 128.11–136.06 (Ph). m/z (HR-MS
FAB) 487.0488; [M + H]+ requires 487.0482.
2,4,6-Tri(phenylmethyloxy)phenol 21
DBU (0.10 mL, 0.66 mmol) was added to the alcohol 20 (100 mg,
0.13 mmol), NaN3 (25 mg, 0.38 mmol) and [18]crown-6 (1 mg) in
MeOH(10 mL) and the mixture stirred at 50◦C (1 h) before being diluted
with saturated NH4Cl solution. A usual workup (EtOAc) gave a yellow
residue that was subjected to flash chromatography (toluene) to afford
the phenol 21 as colourless needles (32 mg, 58%). The spectral data of
21 were consistent with those previously reported.[5]
2-Amino-1,3,4,5,6-penta-O-benzyl-2-C-cyano-2-deoxy-
myo-inositol 22
2,2ꢀ-Anhydro-4,6-di-O-benzyl-2-C-dichlorohydroxymethyl-
scyllo-inositol 1,3,5-Orthoformate 17
Titanium(iv) isopropoxide (0.30 mL, 1.0 mmol) was added to the ketone
19 (550 mg, 0.87 mmol) in NH3/MeOH (7 M, 15 mL) and the solu-
tion stirred at r.t. (5 h). Trimethylsilyl cyanide (0.12 mL, 0.90 mmol)
was added and the solution stirred (5 h) before being diluted with
H2O and concentrated, to leave a yellow residue. Flash chromatogra-
phy (toluene/Et3N 99/1) afforded the amine 22 as fine needles (480 mg,
82%), mp 135–138◦C (EtOAc/pentane). δH (300 MHz) 2.30 (br s, NH2),
3.68 (dd, J4,5 ≈ J5,6 9.5, H5), 3.82 (d, J1/3,6/4 9.5, H1,H3), 4.21 (dd,
H4,H6), 4.96, 5.03 (4H, ABq, J 10.8, CH2Ph), 5.04 (s, CH2Ph), 5.06,
5.11 (4H, ABq, J 10.3, CH2Ph) 7.40–7.55 (25H, m, Ph). δC (75.5 MHz)
57.09 (C5), 75.77 (CH2Ph), 75.84 (CH2Ph), 76.29 (CH2Ph), 80.99,
81.34 (C1,C3,C4,C6), 82.68 (C2), 122.40 (C≡N), 127.53–138.22 (Ph).
m/z (HR-MS FAB) 655.3132; [M + H]+ requires 655.3172.
DBU(0.90 mL, 6.0 mmol)wasaddedtothealcohol 16(1.0 g, 2.1mmol),
NaN3 (270 mg, 4.1 mmol) and [18]crown-6 (10 mg) in MeOH (30 mL)
and the mixture stirred at 50◦C (1 h) before being diluted with saturated
NH4Cl solution. A usual workup (EtOAc) gave a yellow residue that
was subjected to flash chromatography (EtOAc/petrol 1/9) to afford the
epoxide 17 as plates (860 mg, 93%), mp 80–82◦C (EtOAc/pentane). δH
(300 MHz) 4.44–4.48 (m, H1,H3,H4,H6), 4.60–4.63 (m, H5), 4.64–4.66
(4H, m, CH2Ph), 5.68 (s, H7), 7.32–7.40 (10H, m, Ph). δC (75.5 MHz)
63.21, 68.02 (C2,C5), 68.47, 72.47 (C1,C3,C4,C6), 71.30 (CH2Ph),
88.21 (CCl2), 102.87 (C7), 127.63–137.06 (Ph). m/z (HR-MS FAB)
451.0680; [M + H]+ requires 451.0715.
1,3,4,5,6-Penta-O-benzyl-2-C-trichloromethyl-myo-inositol 20
(a) Dimethyl sulfoxide (0.55 mL, 7.7 mmol) in CH2Cl2 (2 mL) was
added dropwise to oxalyl chloride (0.35 mL, 4.0 mmol) in CH2Cl2
(10 mL) at −55◦C and the solution stirred (0.5 h). The alcohol 18
(800 mg, 1.27 mmol)inCH2Cl2 (5 mL)wasthenaddeddropwiseandthe
resulting solution stirred at −55◦C (1.5 h). The solution was warmed to
−30◦C, followed by the dropwise addition of Et3N (2.5 mL, 18 mmol).
The solution was then warmed to room temperature and a usual workup
(CH2Cl2) presumably yielded the ketone 19 (780 mg) that was used in
the next step without any purification.
References
[1] E. J. Corey, J. O. Link, J. Am. Chem. Soc. 1992, 114, 1906.
doi:10.1021/JA00031A069
[2] 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
[3] A. Scaffidi, B. W. Skelton, R. V. Stick, A. H. White, Aust. J. Chem.
2004, 57, 723. doi:10.1071/CH04015
(b) Lithium bis(trimethylsilyl)amide in THF (1.0 M, 1.5 mL,
1.5 mmol) was added dropwise to the above ketone 19 (780 mg) and
CHCl3 (0.20 mL, 2.5 mmol) in THF (15 mL) at −78◦C. The resulting
solution was stirred at −78◦C (1 h) before being diluted with satu-
rated NaHCO3 solution. A usual workup (EtOAc) followed by flash
chromatography (EtOAc/petrol 1/9) afforded the alcohol 20 as plates
(810 mg, 86%), mp 128–130◦C (EtOAc/pentane). δH (300 MHz) 3.94
(dd, J4,5 ≈ J5,6 9.8, H5), 4.14 (dd, J1/3,6/4 ≈ J6/4,5 9.8, H4,H6), 4.44
[4] A. Scaffidi, B. W. Skelton, R. V. Stick, A. H. White, Aust. J. Chem.
2004, 57, 733. doi:10.1071/CH04014
[5] D. James, R. Massy, P. Wyss, Helv. Chim. Acta 1990, 73, 1037.
doi:10.1002/HLCA.19900730428
[6] The Xtal 3.7 System (Eds S. R. Hall, D. J. du Boulay, R. Olthof-
Hazekamp) 2002 (University of Western Australia: Perth).
[7] D. R. Burfield, R. H. Smithers, J. Org. Chem. 1983, 48, 2420.
doi:10.1021/JO00162A026