4-Octulose derivatives; part 8: Highly stereocontrolled synthesis of 2-deoxy-4-octulosononitriles by reformatsky-type reaction

Article abstract of DOI:10.1055/s-2004-822328

2-Deoxy-4,5:6,7-di-O-isopropylidene-β-D-manno-oct-4-ulo-4, 8-pyranosononitrile (3) and 2-deoxy-4,5:6,8-di-O-isopropylidene-α-L-gulo- oct-4-ulo-4,7-furanosononitrile (5) were prepared by a high stereocontrolled indium-mediated Reformatsky-type reaction of

Full text of DOI:10.1055/s-2004-822328

PAPER
1083
4-Octulose Derivatives; Part 8:1 Highly Stereocontrolled Synthesis of 2-Deoxy-
4-octulosononitriles by Reformatsky-Type Reaction
H
ighly S
s
tereocontr
i
olled
S
d
ynthesis of
2
o
-Deoxy-4-o
r
o
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Fax +34(958)243845; E-mail: isidoro@ugr.es
Received 4 February 2004
tween an a-halonitrile and a suitably protected ‘hexulose
Abstract: 2-Deoxy-4,5:6,7-di-O-isopropylidene-b-D-manno-oct-
4-ulo-4,8-pyranosononitrile (3) and 2-deoxy-4,5:6,8-di-O-isopro-
pylidene-a-L-gulo-oct-4-ulo-4,7-furanosononitrile (5) were pre-
pared by a high stereocontrolled indium-mediated Reformatsky-
aldehyde’. With this objective in mind, the influence of
the ring size, as well as the chirality at C(5,6,7), of the
starting aldehyde-sugar on the stereochemical control of
type reaction of 2,3:4,5-di-O-isopropylidene-b-D-arabino-hexos-2- the new stereogenic centre C(3) must be investigated, pri-
ulopyranose (1) and 2,3:4,6-di-O-isopropylidene-a-L-xylo-hexos-2-
ulofuranose (2) with bromoacetonitrile, repectively. The configura-
tions at C(3) in 3 and 5 were established by chemical correlation.
or to any other transformation leading to related azido
hexuloses C and D. Thus, two readily available ‘diacetone
hexulose aldehyde’, namely 2,3:4,5-di-O-isopropylidene-
b-D-arabino-hexos-2-ulopyranose3 (1) and 2,3:4,6-di-O-
isopropylidene-a-L-xylo-hexos-2-ulofuranose4 (2), were
chosen as models.
Key words: D-fructose, L-sorbose, stereoselective synthesis, 2-
deoxy-4-octulosononitriles, indium
Although a-halonitriles are less reactive under the Refor-
matsky conditions, recent modifications of this
metodology5 as well as the use of other metal promoter,6
have overcame this drawback. In the present paper, we
communicate the results from the above-mentioned reac-
tion under different conditions as well as those aspects
concerning the stereochemistry of the new products.
We have earlier reported the synthesis of 2,3-dideoxy-4-
octulosononitriles (A), from common hexuloses (D-fruc-
tose and L-sorbose), as well as their use for the preparation
of trihydroxylated indolizidines related with the potent
glycosidase inhibitor castanospermine2 (Scheme 1). The
key step of these syntheses was a tandem double cycliza-
tion process, involving an internal reductive amination,
followed by an addition-deamination reaction.
Aldehyde 1 reacted slowly with bromoacetonitrile in the
presence of Zn-Cu couple6a to yield a 4.5:1 mixture (GC
analysis) of 2-deoxy-4,5:6,7-di-O-isopropylidene-b-D-
manno-oct-4-ulo-4,8-pyranosononitrile (3) and probably
its 3-epimer, since the latter compound could not be iso-
lated after workup and column chromatography
(Scheme 2). When the same reaction was mediated by in-
dium/TMSCl6b an impressive increase in the reaction rate
as well as in the stereoselectivity was observed. Thus, the
corresponding 3-O-TMS derivatives of 3 (4) and that of
According to Scheme 1, 2-deoxy analogues B of the
above mentioned nitriles would be excellent chiral inter-
mediates for the preparation of tetrahydroxylated indoliz-
idines (route a) and pyrrolizidines (route b), depending on
the location of azide function [either C(8) or C(7), respec-
tively], whereas the stereochemistry would depend on the
starting hexulose. On the other hand, intermediate nitrile
B could be synthesized by a Reformatsky-like reaction be-
Scheme 1 Retrosynthesis of polyhydoxyindolizidines and pyrrolizidines from 2,3-dideoxy- (A) and 2-deoxy-4-octulosononitriles (B).
SYNTHESIS 2004, No. 7, pp 1083–1087
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x
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Advanced online publication: 02.04.2004
DOI: 10.1055/s-2004-822328; Art ID: P01504SS
© Georg Thieme Verlag Stuttgart · New York

1084
I. Izquierdo et al.
PAPER
Figure 1 Preparation of Amides 11 and 13. Reagents and conditi-
ons: a) H2O2/MeOH/aq NaOH; b) aq NH3/MeOH/D.
Organic solutions were dried over MgSO4 before concentration un-
1
der reduced pressure. H and 13C NMR spectra were recorded on
Scheme 2 Reagents and conditions: a) XCH2CN/Zn-Cu/I2 (cat.)/D;
Bruker AMX-300, AM-300, and ARX-400 spectrometers in CDCl3
(internal Me4Si). IR spectra were recorded with a Perkin-Elmer 782
instrument, and mass spectra with a Hewlett-Packard HP-5988-A
and Fisons mod. Platform II and VG Autospec-Q mass spectrome-
ters. Optical rotations were measured in CHCl3 (1 dm tube) with a
Jasco DIP-370 polarimeter. GC was performed on a Hewlett-Pack-
ard 6890 gas chromatograph equipped with split/splitless injector, a
flame-ionization detector, and a capillary HP-5 column (30
m × 0.25 mm i.d. × 0.25 mm film thickness) at: (A) 5 min at 200 °C,
program to 250 °C, 10 °C/min; (B) 5 min at 180 °C program to 250
°C, 10 °C/min. The He flow rate was 1.1 mL/min, the injection port
and the zone-detector temperatures were 275 °C. GC (conditions C)
was performed on a Perkin-Elmer 8410 gas chromatograph
b) BrCH2CN/TMSCl/THF/In/sonication.
its 3-epimer in a 19:1 ratio (GC evidence) was detected.
Compounds 4 and 3 were obtained after basic and acidic
workup of the reaction mixture, respectively. O-Desilyla-
tion of 4 gave 3, confirming the same configuration at
C(3) in both compounds.
In the same manner, reaction of aldehyde 2 with chloroac-
etonitrile mediated by the Zn-Cu couple (Scheme 2), gave
an unresolvable mixture of 2-deoxy-4,5:6,8-di-O-isopro-
pylidene-a-L-gulo-oct-4-ulo-4,7-furanosononitrile
(5) equipped with a flame-ionization detector, and a steel column (2
m × 3 mm i.d.) packed with 5% OV-17 on Chromosorb W (100–
120 mesh): 3 min at 200 °C, program to 230 °C, 15 °C/min. The He
flow rate was 30 mL/min, the injection port and the zone-detector
temperatures were 250 °C. TLC was performed on precoated silica
gel 60 F254 aluminum sheets and detection by charring with H2SO4.
Column chromatography was performed on silica gel (Merck,
7734). The noncrystalline compounds were shown to be homoge-
neous by chromatographic methods and characterized by NMR, MS
and HRMS.
and probably its 3-epimer 6. This mixture could partially
be resolved after its O-benzoylation to afford the 3-O-ben-
zoyl derivative of 5 (7). On the other hand, the indium/
TMSCl-mediated reaction gave an unexpected result,
since only 5 and its O-TMS derivative 8 was observed by
GC analysis. Compound 8 could be isolated when the re-
action was processed after 1 hour. Upon standing at room
temperature, the reaction mixture containing 8 was trans-
formed into the O-desilylated derivative 5. In order to
prove that 5 proceeding from latter reaction has the same
stereochemistry to that previously prepared, it was trans-
formed into the univocal benzoate 7. When the workup of
the reaction mixture was carried out with diethyl ether sat-
urated with aqueous 10% HCl, compound 5 and its 6,8-
deacetonated derivative 9 were obtained.
Reformatsky Reaction of Aldehyde 1 with Bromoacetonitrile;
2-Deoxy-4,5:6,7-di-O-isopropylidene-b-D-manno-oct-4-ulo-4,8-
pyranosononitrile (3) and its Trimethylsilyl Derivative 4; Typi-
cal Procedures
a) Zn-Cu Couple-Mediated: To a stirred solution of ‘diacetone alde-
hyde fructose’3 1 (400 mg, 1.55 mmol), in anhyd dioxane (20 mL)
was added Zn-Cu couple (460 mg), bromoacetonitrile (200 mL, 3
mmol), and I2 (108 mg, 0.43 mmol), and the mixture was heated at
80 °C for 40 h. GC (A) then revealed the presence of two new com-
pounds (tR 6.25 and 6.98 min, in a 4.5:1 ratio) and unreacted 1 (tR
2.78 min, 30%). Additional Zn-Cu couple (150 mg), bromoacetoni-
trile (70 mL, 1 mmol), and I2 (40 mg, 0.16 mmol) were needed in or-
der to complete the reaction. The reaction mixture was filtered and
concentrated to a residue that was dissolved in Et2O (30 mL). The
Et2O layer was washed with aq 10% HCl (10 mL), H2O, aq 10%
Attempts to synthesize 3 and 5 by the alkyllithium-medi-
ated reaction of 1 and 2 with acetonitrile6c were unsuc-
cessful.
The configurations at C(3) in 3 and 5 were determined as
follows: 3 and the 3-O-benzoyl derivative of 5 (7) were
transformed into the corresponding amides 11 and 13 by
conventional treatment with H2O2 in basic medium. On Na2S2O3 (10 mL), H2O, and concentrated. Column chromatography
(Et2O–hexane, 2:1) gave pure 3; yield: 150 mg (32%); tR 6.25;
the other hand, 11 and 13 were unequivocally obtained af-
25
white needles; mp 137–140 °C (Et2O–hexane); [a]D25 –1.5; [a]405
ter transamidation of the already known methyl esters 10
+6 (c = 1.2).
and 127 and hence an R configuration at C(3) was assigned
according to Figure 1.
3
IR (KBr): 3410 (OH), 2256 (C≡N), 1383 and 1378 cm–1 (CMe2).
We can conclude that indium is an excellent metal-pro-
1H NMR (400 MHz): d = 4.63 (dd, 1 H, J5,6 = 2.7 Hz, J6,7 = 7.9 Hz,
H-6), 4.51 (d, 1 H, H-5), 4.25 (br d, 1 H, H-7), 3.99 (dt, 1 H, H-3),
3.90 (dd, 1 H, J7,8ax = 1.8 Hz, J8ax,8eq = 13 Hz, H-8ax), 3.77 (d, 1 H,
H-8eq), 2.95 (dd, 1 H, J2,3 = 3.2 Hz, J2,2¢ = 17 Hz, H-2), 2.73 (d, 1
moter for the synthesis of chiral b-hydroxy nitriles by Re-
formatsky-type reaction not only for the high yielding, but
even for the high stereoselectivity of the procedure.
Synthesis 2004, No. 7, 1083–1087 © Thieme Stuttgart · New York

PAPER
Highly Stereocontrolled Synthesis of 2-Deoxy-4-octulosononitriles
1085
H, J3,HO = 8.9 Hz, OH), 2.66 (dd, 1 H, J2¢,3 = 9.3 Hz, H-2¢), 1.55,
1.48, 1.45 and 1.36 [4 s, 12 H, 2 C(CH3)2].
above gave an unresolvable mixture of 5 (tR 6.73 min) and its 3-
epimer 6 (tR 7.59 min); yield: 1.30 g (43%).
13C NMR (100 MHz): d = 118.49 (C-1), 109.28 and 109.18 (2
CMe2), 102.84 (C-4), 70.66 (C-7), 70.11 (C-6), 69.98 (C-5), 69.35
(C-3), 61.55 (C-8), 26.60, 25.91, 25.60 and 23.93 [2 C(CH3)2] and
21.15 (C-2).
Conventional benzoylation of above mixture (1 g, 3.3 mmol) in
CH2Cl2 (25 mL) with BzCl (0.5 mL, 4.3 mmol) and Et3N (1.2 mL,
8.7 mmol) for 6 h, gave after workup and column chromatography
(Et2O–hexane, 1:3) pure 7; yield: 1 g (72%); colorless syrup; [a]D
–22 (c = 1.2).
25
Anal. Calcd for C14H21NO6: C, 56.18; H, 7.07; N, 4.68. Found: C,
56.55; H, 6.85; N, 4.84.
7
IR (neat): 2255 (C≡N), 1733 (C=O benzoate), 1386 and 1376 cm–1
b) Indium/TMSCl-Mediated: To a suspension of indium powder
(220 mg, 1.9 mmol) in anhyd THF (2 mL), was added bromoaceto-
nitrile (360 mL, 5.2 mmol) and the mixture was stirred at 0 °C for 10
min, and then at r.t. for additional 10 min. The reaction mixture was
cooled at 0 °C and aldehyde 1 (310 mg, 1.2 mmol) dissolved in the
same solvent (3 mL), and Me3SiCl (460 mL, 3.8 mmol) were succes-
sively added and the whole mixture was stirred at 0 °C for 1 h. GC
(A) revealed two main compounds (tR 6.56 and 7.58 min, in a 19:1
ratio). The reaction mixture was diluted with Et2O (15 mL) and the
Et2O layer was washed with aq 10% NaHCO3. The organic phase
was separated and the aqueous phase was extracted with Et2O
(2 × 10 mL). The combined organic extracts were washed with
brine and concentrated to a residue that was submitted to column
chromatography (Et2O–hexane, 1:2) to afford 4; yield: 260 mg
(58%); tR 6.56 min; white needles mp 129–131 °C (Et2O–hexane);
[a]D26 –3, [a]40528 +2.5 (c = 1).
(CMe2).
1H NMR (400 MHz): d = 8.12 (d, 2 H-ortho, PhCO), 7.60 (t, 1 H-
para, PhCO), 7.46 (t, 2 H-meta, PhCO), 5.71 (dd, 1 H, J2,3 = 4.7 Hz,
J2¢,3 = 7.2 Hz, H-3), 4.38 (s, 1 H, H-5), 4.33 (d, 1 H, J6,7 = 2.3 Hz, H-
6), 4.17 (br dd, 1 H, H-7), 4.08 (dd, 1 H, J7,8 = 2.1 Hz, J8,8¢ = 13.6
Hz, H-8), 4.03 (br d, 1 H, H-8¢), 3.14 (dd, 1 H, J2,2¢ = 17.2 Hz, H-2),
3.09 (dd, 1 H, H-2¢), 1.52, 1.45, and 1.43 [3 s, 12 H, 2 C(CH3)2].
13C NMR (100 MHz): d = 165.01 (PhCO), 133.65, 130.10, 129.08
and 128.62 (C6H5CO), 116.81 (C-1), 113.43 and 113.30 (C-4 and
CMe2 dioxolane), 97.69 (CMe2 dioxane), 84.84 (C-5), 73.36 (C-6),
73.00 (C-7), 68.68 (C-3), 60.25 (C-8), 28.95 and 18.85 [C(CH3)2,
dioxane], 27.55 and 26.76 [C(CH3)2, dioxolane] and 18.90 (C-2).
HRMS (LSIMS): m/z calcd for C21H25NNaO7: 426.1529;
found: 426.1528 [M+ + Na] (deviation + 0.2 ppm).
A second fraction (200 mg) contained 7 slightly contaminated with
its 3-epimer.
4
IR (KBr): 2248 (C≡N), 1382 and 1372 cm–1 (CMe2).
1H NMR (400 MHz): d = 4.62 (dd, 1 H, J5,6 = 2.6 Hz, J6,7 = 7.9 Hz,
H-6), 4.42 (d, 1 H, H-5), 4.24 (br d, 1 H, H-7), 4.01 (dd, 1 H, J2,3 = 3
Hz, J2¢,3 = 8.2 Hz, H-3), 3.87 (dd, 1 H, J7,8ax = 1.7, J8ax,8eq = 12.9 Hz,
H-8ax), 3.74 (d, 1 H, H-8eq), 2.90 (dd, 1 H, J2,2¢ = 16.9 Hz, H-2),
2.68 (d, 1 H, H-2¢), 1.53, 1.49, 1.41 and 1.36 [4 s, 12 H, 2 C(CH3)2],
and 0.27 [s, 9 H, Si(CH3)3].
13C NMR (100 MHz): d = 119.16 (C-1), 109.04 and 108.83 (2
CMe2), 103.33 (C-4), 70.96, 70.81, 70.35, and 69.41 (C-3,5,6,7),
61.17 (C-8), 26.65, 26.58, 25.51 and 23.97 [2 C(CH3)2], 21.48 (C-
2), and 0.60 [Si(CH3)3].
b) Indium/TMSCl-Mediated: To a suspension of indium powder
(350 mg, 3 mmol) in anhyd THF (3 mL), was added bromoacetoni-
trile (480 mL, 6.9 mmol) and the mixture stirred at 0 °C for 10 min,
and then at r.t. for an additional 10 min. The reaction mixture was
cooled at 0 °C and aldehyde 2 (415 mg, 1.6 mmol), dissolved in the
same solvent (4 mL), and Me3SiCl (610 mL, 5.1 mmol) were succes-
sively added and the whole mixture was stirred at 0 °C for 4 h. GC
(B) revealed the presence of 2 (20%) and two new compounds (tR
8.96 and 9.66 min, in a 8:1 ratio). The reaction mixture was diluted
with Et2O (15 mL) and the Et2O layer was washed with aq 10%
NaHCO3. The organic phase was separated and the aqueous phase
was extracted with Et2O (2 × 10 mL). The combined organic ex-
tracts were washed with brine and concentrated to a residue that was
submitted to column chromatography (Et2O–hexane, 2:1) to afford
Anal. Calcd for C17H29NO6Si: C, 54.96; H, 7.87; N, 3.77. Found: C,
55.57; H, 8.10; N, 3.91.
When the reaction was carried out as above with indium powder
(350 mg, 3 mmol), bromoacetonitrile (600 mL, 8.6 mmol), aldehyde
1 (500 mg, 1.94 mmol), and Me3SiCl (740 mL, 6 mmol), but diluting
with Et2O saturated with aq 5% HCl and stirred for 10 min, fol-
lowed by the same workup, the O-desilylated compound 3 was ob-
tained; yield: 380 mg (66%).
28
5; yield: 300 mg (78%); tR 8.96 min; colorless thick syrup; [a]D
+7, [a]40528 +24.5 (c = 1).
5
IR (neat): 3445 (OH), 2253 (C≡N), 1385, 1380, and 1376 cm–1
(CMe2).
O-Desilylation of Compound 4
1H NMR (400 MHz): d = 4.55 (br s, 1 H, H-5), 4.36 (br d, 1 H,
J6,7 = 2.1 Hz, H-6), 4.17 (dt, 1 H, H-3), 4.14 (br t, 1 H, H-7), 4.08
(dd, 1 H, J7,8 = 2.1 Hz, J8,8¢ = 13.6 Hz, H-8), 4.02 (br d, 1 H, H-8¢),
2.97 (dd, 1 H, J2,3 = 3.4 Hz, J2,2¢ = 16.9 Hz, H-2), 2.75 (d, 1 H,
J3,OH = 8.8 Hz, HO-3), 2.73 (dd, 1 H, J2¢,3 = 8.9 Hz, H-2¢), 1.52,
1.45, 1.44, and 1.39 [4 s, 12 H, 2 C(CH3)2].
13C NMR (100 MHz): d = 118.15 (C-1), 114.47 and 113.23 (C-4 and
CMe2 dioxolane), 97.64 (CMe2 dioxane), 84.57 (C-5), 73.03 and
73.00 (C-6,7), 68.48 (C-3), 60.35 (C-8), 28.98 and 18.62 [C(CH3)2
dioxane], 27.69 and 26.85 [C(CH3)2 dioxolane], and 21.47 (C-2).
To a stirred solution of 4 (230 mg, 0.62 mmol) in THF (3 mL) was
added TBAF trihydrate (205 mg, 0.65 mmol) and the mixture was
left at r.t. for 1 h. TLC (Et2O–hexane, 2:1) then showed the presence
of 3. The reaction mixture was concentrated and the residue was
partitioned between Et2O (30 mL) and brine (10 mL). The organic
phase was separated and concentrated. Column chromatography
(Et2O–hexane, 2:3) of the residue afforded pure 3; yield: 170 mg
(quantitative).
Reformatsky Reaction of Aldehyde 2 with Haloacetonitriles
a) Zn-Cu Couple-Mediated: The above typical procedure was ap-
plied to ‘diacetone aldehyde L-sorbose’4 2 (2.6 g, 10.1 mmol), in an-
hyd dioxane (30 mL), with Zn-Cu couple (3 g), chloroacetonitrile
(1.25 mL, 20 mmol), and I2 (700 mg, 2.76 mmol) for 2 h at 80 °C.
GC (C) then revealed the presence of two new compounds (tR 6.73
and 7.59 min, in a 4:1 ratio). Workup of the reaction mixture as
HRMS (LSIMS): m/z calcd for C14H21NNaO6: 322.1267; found:
322.1270 [M+ + Na] (deviation –1.2 ppm).
When the reaction was processed after 1 h as above, a small sample
of the 3-O-trimethylsilyl derivative 8 was obtained; yield: 50 mg,
(11%); tR 9.66 min; [a]D25 +7, [a]40526 +24.3 (c = 1).
Synthesis 2004, No. 7, 1083–1087 © Thieme Stuttgart · New York

1086
8
I. Izquierdo et al.
PAPER
13C NMR (100 MHz): d = 175.85 (C-1), 108.99 and 108.72 (2
CMe2), 103.90 (C-4), 70.82, 70.32, 69.82, and 69.71 (C-3,5,6,7),
61.11 (C-8), 36.01 (C-2), 26.64, 25.87, 25.59, and 23.92 [2
C(CH3)2].
IR (neat): 2247 (C≡N), 1384 and 1376 cm–1 (CMe2).
1H NMR (400 MHz): d = 4.43 (br s, 1 H, H-5), 4.31 (d, 1 H,
J6,7 = 1.8 Hz, H-6), 4.20 (dd, 1 H, H-3), 4.12 (br s, 1 H, H-7), 4.06
(dd, 1 H, J7,8 = 1.8 Hz, J8,8¢ = 13.6 Hz, H-8), 3.99 (br d, 1 H, H-8¢),
2.90 (dd, 1 H, J2,3 = 2.9 Hz, J2,2¢ = 16.8 Hz, H-2), 2.74 (dd, 1 H,
HRMS (LSIMS): m/z calcd for C14H23NNaO7: 340.1372;
found: 340.1374 [M+ + Na] (deviation –0.6 ppm).
J
2¢,3 = 8.7 Hz, H-2¢), 1.50, 1.44, 1.40 and 1.39 [4 s, 12 H, 2 C(CH3)2],
b) From b-Hydroxy Nitrile 3: An ice-H2O cooled and stirred solu-
tion of 3 (350 mg, 1.2 mmol) in MeOH (5 mL) was treated with aq
30% H2O2 (0.5 mL) and aq 6 N NaOH (0.26 mL) and the mixture
was left at r.t. for 5 h. TLC (Et2O–hexane, 2:1) then revealed a not
mobile compound. The reaction mixture was neutralized with
AcOH, and chromatographed on silica gel (Et2O–MeOH, 20:1) to
afford pure 11; yield: 310 mg (84%).
and 0.27 [s, 9 H, Si(CH3)3].
13C NMR (100 MHz): d = 118.95 (C-1), 115.01 and 112.84 (C-4 and
CMe2 dioxolane), 97.47 (CMe2 dioxane), 84.40 (C-5), 73.12 and
73.05 (C-6,7), 70.08 (C-3), 60.36 (C-8), 28.03 and 18.57 [C(CH3)2
dioxane], 27.62 and 26.45 [C(CH3)2 dioxolane], 21.61 (C-2), and
0.56 [Si(CH3)3].
HRMS (LSIMS): m/z calcd for C17H29NNaO6Si: 394.1661; found
2-Deoxy-4,5:6,8-di-O-isopropylidene-a-L-gulo-oct-4-ulo-4,7-
furanosonamide (13)
394.1662 [M+ + Na] (deviation –0.1 ppm).
Conventional benzoylation of 5 (50 mg, 0.17 mmol) in anhyd
CH2Cl2 (2 mL) with Et3N (0.1 mL) and benzoyl chloride (0.1 mL)
gave after usual workup and column chromatography (Et2O–hex-
ane, 1:2 → 1:1) pure 7 (45 mg, 66%).
a) From b-Hydroxy Ester 12: A stirred solution of methyl 2-deoxy-
4,5:6,8-di-O-isopropylidene-a-L-gulo-oct-4-ulo-4,7-furanosonate7
(12; 190 mg, 0.59 mmol) in MeOH (10 mL) containing aq 30% NH3
(10 mL) was heated in a sealed tube at 100 °C for 4 h. TLC (Et2O–
hexane, 2:1) then revealed a not mobile compound. Workup of the
reaction mixture as for 10 afforded pure 13; yield: 170 mg (93%);
colorless thick syrup; [a]D25 +18 (c = 1.9).
When the reaction was carried out as above, but diluting with Et2O
saturated with aq 10% HCl and stirred for 5 min, followed by the
same workup, the O-desilylated compound 5 together with a more
polar compound were detected in TLC. Column chromatography of
the reaction mixture gave pure 5 as the first fraction; yield: 220 mg
(54%).
IR (neat): 3439 and 3362 (OH and NH2), 1675 and 1669 (CONH2),
1385 and 1376 cm–1 (CMe2).
1H NMR (400 MHz): d = 6.12 and 5.72 (2 br s, 2 H, CONH2), 4.56
(s, 1 H, H-5), 4.29 (br d, 1 H, J6,7 = 1.9 Hz, H-6), 4.19 (dd, 1 H, H-
3), 4.08 (br s, 1 H, H-7), 4.06 (dd, 1 H, J7,8 = 2.1 Hz, H-8), 3.99 (d,
1 H, J8,8¢ = 12.9 Hz, H-8¢) 2.78 (dd, 1 H, J2,3 = 2.9 Hz, J2,2¢ = 15.5
Hz, H-2), 2.55 (dd, 1 H, J2¢,3 = 9 Hz, H-2¢), 1.48, 1.41 and 1.34 [3 s,
12 H, 2 C(CH3)2].
13C NMR (100 MHz): d = 175.21 (C-1), 115.44 (C-4), 112.67
(CMe2 dioxolane), 97.54 (CMe2, dioxane), 84.46 (C-5), 73.28 (C-
6), 72.51 (C-7), 69.20 (C-3), 60.39 (C-8), 36.38 (C-2), 28.99 and
18.66 [C(CH3)2 dioxane], 27.76 and 26.73 [C(CH3)2 dioxolane].
The more polar compound was shown to be the 6,8-O-deacetonated
25
derivative of 5 (9; yield: 150 mg (45%); colorless thick syrup; [a]D
+4; [a]40525 +11 (c = 1, MeOH).
9
1H NMR (400 MHz): d = 4.44 (br s, 1 H, H-5), 4.26 (ddd, 1 H, H-
7), 4.12 (br d, 1 H, J6,7 = 2.8 Hz, H-6), 3.95 (dd, 1 H, J2,3 = 3 Hz,
J2¢3 = 9.7 Hz, H-3), 3.77 (dd, 1 H, J7,8 = 4.9 Hz, J8,8¢ = 11.7 Hz, H-
8), 3.71 (dd, 1 H, J7,8¢ = 6.4 Hz, H-8¢) 2.93 (dd, 1 H, J2,2¢ = 17 Hz, H-
2), 2.63 (dd, 1 H, J2¢,3 = 9.8 Hz, H-2¢), 1.44 and 1.36 [2 s, 6 H,
C(CH3)2].
13C NMR (100 MHz): d = 119.87 (C-1), 115.89 and 113.81 (C-4 and
CMe2), 86.65 (C-5), 83.71 (C-6), 75.59 (C-7), 69.51 (C-3), 61.24
(C-8), 27.96 and 27.01 [C(CH3)2], and 21.28 (C-2).
Anal. Calcd for C14H23NO7: C, 52.99; H, 7.31; N, 4.41. Found: C,
52.61; H, 6.96; N, 4.40.
b) From b-Benzoyloxy Nitrile 7: An ice-H2O cooled and stirred so-
lution of 7 (68 mg, 0.16 mmol) in MeOH (2 mL) was treated with
aq 30% H2O2 (0.1 mL) and aq 6 N NaOH (0.05 mL) and the mixture
was left at r.t. for 4 h. Workup of the reaction mixture as above gave
pure 13; yield: 36 mg (70%).
Anal. Calcd for C11H17NO6: C, 50.96; H, 6.61; N, 5.40. Found: C,
51.21; H, 6.56; N, 5.53.
2-Deoxy-4,5:6,7-di-O-isopropylidene-b-D-manno-oct-4-ulo-4,8-
pyranosonamide (11)
Acknowledgment
a) From b-Hydroxy Ester 10: A stirred solution of methyl 2-deoxy-
4,5:6,7-di-O-isopropylidene-b-D-manno-oct-4-ulo-4,8-pyranoson-
ate7 (10; 188 mg, 0.56 mmol) in MeOH (3 mL) containing aq 30%
NH3 (2 mL) was heated in a sealed tube at 100 °C for 3 h. TLC
(Et2O–hexane, 2:1) then revealed a not mobile compound. The re-
action mixture was chromatographed on silica gel (Et2O–MeOH,
20:1) to afford pure 11; yield: 150 mg (84%); colorless thick syrup;
[a]D26 –0.3; [a]40526 +10 (c = 1.3).
The authors are deeply grateful to Ministerio de Ciencia y Tecnolo-
gía (Spain) for financial support (Project PPQ2002-01303).
References
(1) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Mota, A.-J.
Tetrahedron: Asymmetry 2000, 11, 4509.
IR (neat): 3431 and 3356 (OH and NH2), 1675 (CONH2), 1384 and
1373 cm–1 (CMe2).
(2) (a) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Rodríguez, C.;
Ramírez, A.; Mota, A.-J. Eur. J. Org. Chem. 1999, 1269.
(b) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Mota, A.-J. Eur.
J. Org. Chem. 2000, 2071.
(3) Izquierdo, I.; Plaza, M.-T. Carbohydr. Res. 1990, 205, 293.
(4) Izquierdo, I.; Plaza, M.-T.; Kari, N. Carbohydr. Res. 1994,
261, 231.
1H NMR (400 MHz): d = 6.14 and 6.06 (2 br s, 2 H, CONH2), 4.60
(m, 2 H, H-6,7), 4.39 (br s, 1 H, OH), 4.22 (d, 1 H, J5,6 = 7.6 Hz, H-
5), 4.03 (dd, 1 H, H-3), 3.39 (d, 1 H, J8,8¢ = 12.9 Hz, H-8), 3.72 (d,
1 H, H-8¢), 2.76 (dd, 1 H, J2,3 = 2.6 Hz, J2,2¢ = 15.9 Hz, H-2), 2.55
(dd, 1 H, J2¢,3 = 9.2 Hz, H-2¢), 1.52, 1.46, 1.43 and 1.33 [4 s, 12 H,
2 C(CH3)2].
(5) Han, B.-H.; Boudjouk, P. J. Org. Chem. 1982, 47, 5030.
Synthesis 2004, No. 7, 1083–1087 © Thieme Stuttgart · New York

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Highly Stereocontrolled Synthesis of 2-Deoxy-4-octulosononitriles
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(6) (a) Zn/Cu-Mediated: Smith, R. D.; Simmons, H. E. Org.
Synth. 1961, 41, 72. (b) See also: Corbin, T. F.; Hahn, R. C.;
(7) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Mota, A.-J.
Tetrahedron: Asymmetry 1997, 8, 2597.
Shechter, H. Org. Synth. 1964, 44, 30. (c) See also: Chung,
W. J.; Higashiya, S.; Welch, J. T. J. Fluorine Chem. 2001,
112, 343. (d) Indium-Mediated: Araki, S.; Yamada, M.;
Butsugan, Y. Bull. Chem. Soc. Jpn. 1994, 67, 1126. (e) See
also: Podlech, J.; Maier, T. C. Synthesis 2003, 633.
(f) Alkyllithium-Mediated: Zhou, J. J. P.; Zhong, B.;
Silverman, R. B. J. Org. Chem. 1995, 60, 2261. (g) Tin-
Mediated: Sun, P.; Shi, B. J. Chem. Res., Synop. 1999, 318.
(h) Samarium-Mediated: Caracoti, A.; Flowers, R. A. II
Tetrahedron Lett. 2000, 41, 3039.
Synthesis 2004, No. 7, 1083–1087 © Thieme Stuttgart · New York