Synthesis of 4-octuloses, VI([≠]) - 4-Octulose derivatives, prepared from 1-sorbose, as key intermediates in the stereoselective synthesis of C- glycoside and polyhydroxyindolizidine analogues

Article abstract of DOI:10.1002/1099-0690(200006)2000:11<2071::AID-EJOC2071>3.0.CO;2-A

Reactions of 1 and 12 with p-toluenesulfonyl chloride in pyridine gave the corresponding 1-O-p-toluenesulfonyl derivatives 2 and 13 in yields of 91% and 60%, respectively. Compound 12 was also transformed into 14 by treatment with I₂/Ph₃

Full text of DOI:10.1002/1099-0690(200006)2000:11<2071::AID-EJOC2071>3.0.CO;2-A

FULL PAPER
Synthesis of 4-Octuloses, VI[°]
4-Octulose Derivatives, Prepared from -Sorbose, as Key Intermediates in the
l
Stereoselective Synthesis of C-Glycoside and Polyhydroxyindolizidine
Analogues
Isidoro Izquierdo,*[a] Maria T. Plaza,[a] Rafael Robles,[a] and Antonio J. Mota[a]
Keywords: Asymmetric synthesis / Carbohydrates / C-Glycosides / 4-Octulose derivatives / Reductive amination /
Indolizidines
Reactions of 1 and 12 with p-toluenesulfonyl chloride in pyr-
OMes transformation at C-8 in the N−Cbz-protected pyrroli-
idine gave the corresponding 1-O-p-toluenesulfonyl derivat- dines 7 and 19 was unsuccessful and an internal anhydration
ives 2 and 13 in yields of 91% and 60%, respectively. Com- process took place to yield the corresponding C-glycoside-
pound 12 was also transformed into 14 by treatment with I2/
Ph3P/imidazole in anhydrous dichloromethane. Treatment of
like furanoses 9 and 20. On the other hand, 23 was trans-
formed into the -ribo analogue 25 through reduction of the
D
compounds 12 and 13/14 with NaN3 in DMF furnished the intermediate 4,6-diulose 24. Finally, deprotection of 25 in
respective 1-azido-1-deoxy derivatives 3 and 15, which were
then deacetonated to give the free 4-octuloses 4 and 16.
These were subsequently hydrogenated in the presence of
acid medium to give the free 4-ulose 26, followed by hydro-
genation of the latter in the presence of 10% Pd/C in meth-
anol, allowed the preparation of (6S,7S,8S,8aS)-6,7,8-trihyd-
10% Pd/C to afford the expected polyhydroxylated roxy-8a-methoxyindolizidin-3-one (27).
branched-chain pyrrolidines 5 and 17. Attempted OH Ǟ
Introduction
The bicyclic skeleton of indolizidine occurs extensively in
Nature since a high proportion of alkaloids incorporate this
moiety. Polyhydroxyindolizidines are important inhibitors
of glycosidases, enzymes that are essential in the biosyn-
thetic processing of polysaccharides and glycoproteins, and
thus may be considered as potential chemotherapeutic
agents against viral infections, cancer, malaria, and dia-
betes.[2] Given that the activity of such compounds as glyco-
sidase inhibitors cannot reliably be predicted, the synthesis
of their natural and nonnatural analogues is of great im-
portance for establishing structureϪactivity relationships.[3]
Our group has recently reported on the highly stereose-
lective synthesis of some derivatives of 4-octulose, 2-deoxy-
Scheme 1. Retrosynthetic analysis
4-octulose,[4] and 2,3-dideoxy-4-octulosononitriles,[1] using
common hexuloses (-fructose and -sorbose) as chiral
sible synthetic routes are outlined in Scheme1, involving
starting materials for the synthesis of polyhydroxyindolizid-
ines.[1,5] Moreover, from the retrosynthetic analysis shown
in Scheme 1, it can be seen that 4-octuloses, due to the di-
versity of their functional groups, may be considered as ex-
cellent intermediates for the stereoselective synthesis of the
aforementioned polyhydroxyindolizidines, as these groups
can easily be transformed into appropriate functionalities
allowing construction of the indolizidine skeleton. Two pos-
construction of either a polyhydroxylated branched-chain
pyrrolidine (A) (route a) or a suitably functionalized 4-octu-
losononitrile (B) (route b) as an intermediate. Intermediates
of type A are cyclized to the bicyclic indolizidine system in
two steps, whereas for intermediates of type B only one step
is required. In the present study, both routes were used ac-
cording to the natures of the starting 4-octulose derivatives.
Results and Discussion
[°]
Part V: Ref.[1]
[a]
Department of Organic Chemistry, Faculty of Pharmacy,
University of Granada,
On the basis of previous reports and in accordance with
route a in Scheme 1, our first objective was a ϪCH2OH Ǟ
ϪCH2N3 modification at C-1 of the protected 4-octuloses
18071 Granada, Spain
Fax: (internat.) ϩ 34-958/243845
E-mail: isidoro@platon.ugr.es
Eur. J. Org. Chem. 2000, 2071Ϫ2078
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0611Ϫ2071 $ 17.50ϩ.50/0
2071

I. Izquierdo, M. T. Plaza, R. Robles, A. J. Mota
FULL PAPER
1 and 12 by introducing a good leaving group (e.g. iodide
or p-toluenesulfonyloxy) and then displacing this with az-
ide. Thus, 2,3:4,5:6,8-tri-O-isopropylidene-α--glycero--ga-
lacto-oct-4-ulofuranose (1)[4c] was transformed into the cor-
responding 1-O-p-toluenesulfonyl derivative 2 in 91% yield.
When the same reaction was performed on the related 2-
deoxy--gulo-oct-4-ulofuranose (12),[4d] only a moderate
yield (60%) of the corresponding 1-O-p-toluenesulfonyl de-
rivative 13 was obtained. In this case, it proved preferable
to proceed via the 1-deoxy-1-iodo derivative 14, which was
prepared in 90% yield by reaction of 12 with I2/Ph3P/imida-
zole. It was found that the iodide leaving group could not
be introduced into compound 1 in this way. These results
reveal that both steric effects and the presence of a free
hydroxyl at C-3 are important factors in determining the
yields of the above transformations.
Scheme 3. Synthesis of polyhydroxylated branched-chain pyrrolid-
ines 5 and 17 with indication of the stereochemistry
Compounds 2 and 13/14 were allowed to react with so-
dium azide in DMF to afford the corresponding 1-azido-1-
deoxy derivatives 3 and 15, respectively. Deacetonation of
3 and 15 in acid media then gave the free octuloses 4 and 3-H and 4-H, in accordance with the proposed configura-
16, respectively (Scheme 2), mainly in their α-pyranoid tions.
forms, as evidenced by 13C-NMR spectroscopy.
The high stereoselectivity observed for the hydrogenation
of the ∆1-pyrroline intermediates B is in accordance with
that previously reported by our group[5] and other au-
thors.[6] The hydrogen molecule approaches the same face
as occupied by the substituent at C-3, resulting in a product
with a trans relationship between C-3 and C-4. The pres-
ence of the hydroxy group at C-3 seems to be crucial for
the stereocontrol of the hydrogenation; in the absence of
such a substituent the stereoselectivity is reduced and a
mixture of two diastereomeric pyrrolidines is obtained.[7]
Our next objective was to construct the indolizidine sys-
tem through the application of a well-established synthetic
protocol.[5] This involved selective NϪCbz protection,
chemoselective transformation of 8-OH into a mesitylenes-
ulfonyloxy group, and finally hydrogenolysis of the NϪCbz
group in order to promote further cyclization to the bicyclic
system. Thus, compounds 5 and 17 were selectively N-pro-
tected as benzyloxycarbonyl derivatives 7 and 19, respect-
ively. However, attempts to prepare the corresponding 8-O-
mesitylenesulfonyloxy derivatives were partly unsuccessful.
Scheme 2. N-Functionalization of 4-octuloses at C-1
Catalytic hydrogenations of 4 and 16 in the presence of Instead of the desired derivatization, an internal anhydriz-
10% Pd/C gave a single product in each case, which were ation process took place, presumably involving attack of the
identified as 1,4-dideoxy-1,4-imino--threo--altro-octitol 5-OH group at C-8, with formation of the corresponding
(5) and 1,2,4-trideoxy-1,4-imino--glycero--talo-octitol C-glycoside-like furanoses
9
and 20, respectively
(17), respectively. The formation of 5 and 17 can be envis- (Scheme 4). This unexpected cyclization seems to be general
aged as proceeding by reduction of N3 to NH2 to produce and is apparently favoured with a xylo[1] configuration at
the corresponding 1-amino-1-deoxy-4-octuloses (interme- C-5 to C-8 of the polyhydroxy chain. It is not observed with
diates A, not isolated), nucleophilic attack of the newly an arabino[5] configuration of the chain. A similar process
formed C-1 amino group on the carbonyl group at C-4 to in analogous compounds has previously been reported by
give the cyclic pyrrolinic intermediate B, and finally hydro- other authors,[8] where it was attributed to steric factors.
genation to give the observed products (Scheme 3).
Compounds 9 and 20 were deprotected to give 10 and 21,
The structures of 5 and 17, and hence the stereochemistr- which were characterized as their acetyl derivatives 11 and
ies at the newly formed stereogenic centres (C-4), were de- 22, respectively.
termined on the basis of their analytical and spectroscopic
Finally, on the basis of the above results we envisaged a
data, as well as those of their peracetylated derivatives (6 new strategy for preparing novel indolizidines that avoids
and 18). Thus, the small J3,4 values for 6 and 18 (3.9 and the aforementioned undesirable cyclization. This involves
ca. 0 Hz, respectively) indicate a trans relationship between inversion of the configuration at C-6 of a 4-octulose and the
2072
Eur. J. Org. Chem. 2000, 2071Ϫ2078

Synthesis of 4-Octuloses, VI
FULL PAPER
Scheme 4. Formation of either 5,8-anhydro-1,4-dideoxy- or -1,2,4-trideoxy-1,4-iminooctitols
Scheme 5. Synthetic route for polyhydroxyindolizidin-3-one 27
application of the protocol[1] (route b) outlined in Scheme 1, The formation of 27 may be rationalized in terms of fast
where the indolizidine skeleton is formed by a double cyc- reduction of the 8-azido function to an amino group with
lization with the participation of three functional groups, subsequent formation of a ∆1-piperidine intermediate,
specifically nitrile at C-1, keto at C-4, and azido at C-8. which then undergoes addition of a solvent molecule (meth-
Thus,
8-azido-2,3,8-trideoxy-4,5-O-isopropylidene-α-- anol) to give the corresponding piperidine (Scheme 5). In-
xylo-oct-4-ulofuranose (23)[1] was oxidized with PCC in tramolecular addition of the piperidine NH to the cyano
dichloromethane to give the corresponding 4,6-diulofur- group presumably then afforded a cyclic amidine-like inter-
anose 24 and its hydrated form (see Experimental Section). mediate, which, instead of undergoing hydrogenolytic de-
Reduction of 24 with sodium tetrahydroborate in methanol amination to give the indolizidine skeleton,[1,10] was hy-
proceeded with high stereofacial control in favour of the β- drolyzed to give the indolizidin-3-one 27. This type of solv-
face, presumably owing to the presence of the 4,5-O-isopro- ent addition has previously been observed by other au-
pylidene group, which blocks approach of the hydride at the thors.[11]
α-face. Consequently, solely 8-azido-2,3,8-trideoxy-4,5-O-
isopropylidene-α--ribo-oct-4-ulofuranose (25) was ob-
tained, which was subsequently deacetonated to give the in-
Experimental Section
termediate free 4-octulose derivative 26. The final step in-
General Remarks: Melting points were determined with a Gallenk-
volved hydrogenation of 26 in the hope of obtaining the
required indolizidine, but (6S,7S,8S,8aS)-6,7,8-trihydroxy-
8a-methoxyindolizidin-3-one (27) was produced instead.[9]
amp apparatus and are uncorrected. Ϫ Organic solutions were
dried with MgSO4 prior to concentration under reduced pressure.
Ϫ
1H- and 13C-NMR spectra were recorded with Bruker AMX-
Eur. J. Org. Chem. 2000, 2071Ϫ2078
2073

I. Izquierdo, M. T. Plaza, R. Robles, A. J. Mota
FULL PAPER
1
Table 1. H NMR spectroscopic data; chemical shifts (δ) with multiplicities
1-H
1Ј-H
2-H
2Ј-H
3-H
4-H
5-H
6-H
7-H
8-H
8Ј-H
CMe2
2
3
4.43 dd
3.77 dd
4.11 dd 4.42 m
Ϫ
Ϫ
4.04 br. d
4.10 d
Ϫ
Ϫ
4.41 s 4.28 d
4.44 s 4.30 d
4.04 m
4.06 dd
3.98 dd
4.02 dd
4.22 dd
3.82 d 1.47 s, 1.39 s, 1.36 s,
1.35 s, 1.33 s
3.92 d 1.49 s, 1.47 s, 1.41 s,
1.39 s, 1.38 s, 1.35 s
3.97 dd Ϫ
3.37 dd 4.43 ddd
6[a]
9
4.05 dd 3.28 dd 5.19 ddd Ϫ
3.83 dd 3.39 d 4.11 br. d Ϫ
5.44 br. dd 4.26 br. t 5.65 dd 5.45 dd 5.26 m
4.38 s
5.69 d
3.92 d 4.23 dd 3.87 br. d 4.19 br. d 4.11 br. dd 3.63 d Ϫ
11[b] 3.99 dd 3.66 d 5.20 br. d Ϫ
3.81 dd 4.33 d 3.98 s
5.20 br. d 4.26 dd
3.74 d Ϫ
13 4.32Ϫ
2.26 dddd 1.80 dddd 3.90 dd
Ϫ
4.42 s 4.27 br. d 4.07 br. dd 4.03 dd
3.97 d 1.47 s, 1.40 s, 1.36 s,
4.20 m
1.32 s
14 3.42 ddd 3.32 dt 2.41 ddt 1.98 dddd 3.93 br. d Ϫ
4.46 s 4.30 d
4.47 s 4.30 d
4.11 br. d 4.06 dd
4.11 br. d 4.06 dd
4.01 d 1.49 s, 1.41 s, 1.39 s,
1.38 s
15 3.53 m
2.18 ddt 1.76 ddt 3.93 dd
Ϫ
4.01 d 1.49 s, 1.41 s, 1.39 s,
1.35 s
18[c] 3.52 dt 3.44 dt 2.26 m
20 3.67Ϫ
2.10 m
3.48 t 2.16 ddt 1.91 dd
5.36 d
4.50 d
4.10 br. s 5.69 dd 5.53 dd 5.42 br. ddd 4.24 dd
3.91 d 3.67Ϫ 3.85 br. s 4.17 d
4.01 dd Ϫ
4.10 dd
3.67Ϫ Ϫ
3.59 m
3.59 m
3.59 m
22[d] 4.30 br. d 3.48 dd 2.37 m
25
2.12 m
5.54 d
2.19 m
3.62 d 3.61 dd 3.97 d
Ϫ
5.17 d
4.28 dd
3.69 dd
3.72 d Ϫ
Ϫ
Ϫ
2.59 m
4.43 d 3.95 m
3.34 dd 1.55 s, 1.41 s
[a]
[b]
[c]
AcO and AcN groups at δ ϭ 2.17, 2.10, 2.09, 2.07, 2.03, 2.0. Ϫ AcO and AcN groups at δ ϭ 2.12, 2.11, 2.07, 2.05. Ϫ AcO and
[d]
AcN groups at δ ϭ 2.18, 2.05, 2.03, 2.02, 2.00. Ϫ AcO and AcN groups at δ ϭ 2.14, 2.05, 2.04.
1
300, AM-300, ARX-400, and AMX-500 spectrometers with
samples in CDCl3 solution (Me4Si as internal reference). Ϫ IR
spectra were recorded with a PerkinϪElmer 782 instrument. Ϫ
Mass spectra were obtained with Hewlett-Packard HP-5988A, Fi-
sons model Platform II, and VG Autospec-Q mass spectrometers.
Ϫ Optical rotations were measured for solutions in CHCl3 (1-dm
tube) with a Jasco DIP-370 polarimeter. Ϫ TLC was performed on
precoated silica gel 60 F254 aluminium-backed sheets with detection
by charring with H2SO4 (A) or by treatment with phosphomolybdic
acid (B) or ninhydrin (C). Ϫ Column chromatography was per-
formed on silica gel (Merck, 7734).
Table 2. H-NMR-spectroscopic data, coupling constants (Hz)
J1,1Ј J1,2 J1Ј,2 J1,2Ј J1Ј,2Ј J2,2Ј J2,3 J2Ј,3 J3,4 J4,5 J5,6 J6,7 J7,8 J7,8Ј J8,8Ј
2
3
6
9
11.1 1.9 6.1
13.1 2.4 5.4
11.8 7.6 5.1
12.0 5.2 0.0
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
8.1 Ϫ
8.3 Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
0.0 2.3 2.4 0.0 13.2
0.0 2.3 2.2 0.0 13.2
2.7 Ϫ 3.9 4.0 7.2 3.9 5.1 6.7 11.6
0.0 Ϫ 0.0 9.9 2.3 0.0 4.1 0.0 9.4
0.0 Ϫ 2.4 10.5 0.0 0.0 4.2 0.0 10.4
11 12.6 5.7 0.0
13 Ϫ 9.5 6.9 5.6 4.6 14.7 2.7 10.3 Ϫ
14 7.4 9.7 9.6 4.5 7.3 14.5 2.7 10.0 Ϫ
Ϫ
Ϫ
Ϫ
0.0 3.6 2.3 0.0 13.4
0.0 2.2 2.1 0.0 13.5
0.0 2.2 2.0 0.0 13.5
15 Ϫ 8.0 8.0 6.0 6.0 14.2 2.7 9.8
Ϫ
18 10.0 10.0 10.0 7.7 2.3
Ϫ
5.0 0.0 0.0 1.9 8.0 3.6 5.4 6.6 11.5
9.7 7.1 0.0 13.6 3.8 0.0 0.0 9.8 0.0 0.0 4.0 0.0 9.4
20 9.7
22 10.0 Ϫ 2.4
25 Ϫ
Ϫ
2,3:4,5:6,8-Tri-O-isopropylidene-1-O-p-toluenesulfonyl-α-
L-glycero-
Ϫ
Ϫ
0.0
Ϫ
Ϫ
Ϫ
3.9 0.0 0.0 10.3 1.6 0.0 4.2 0.0 10.4
4.1 Ϫ 2.4 3.7 13.6
D-galacto-oct-4-ulofuranose (2): To an ice/water-cooled solution of
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ Ϫ
2,3:4,5:6,8-tri-O-isopropylidene-α--glycero--galacto-oct-4-ulo-
furanose (1,[4c] 5.26 g, 14.6 mmol) in dry dichloromethane (50 mL)
containing triethylamine (6 mL, 43.3 mmol), p-toluenesulfonyl
chloride (3.0 g, 15.73 mmol) was added portionwise with stirring
and then the mixture was set aside at room temperature for 24 h.
Subsequent TLC analysis (diethyl ether/hexane, 2:1; detection by
method A) revealed the presence of a main faster moving com-
pound. The mixture was poured into ice/water and the resulting
solution was left for 1 h. It was then extracted with diethyl ether
(3 ϫ 50 mL) and the combined extracts were washed with 10% aq.
hydrochloric acid, water, saturated NaHCO3 solution, and further
water. After concentration to dryness, the residue was subjected to
column chromatography (diethyl ether/hexane, 1:2) to afford pure
2 (6.8 g, 91%) as a syrup. Ϫ [α]2D5 ϭ Ϫ18 (c ϭ 1.2). Ϫ IR (film):
ane). Ϫ [α]2D5 ϭ Ϫ47 (c ϭ 1.1). Ϫ IR (KBr): ν˜ ϭ 2101 (N3); 1385,
1373 cmϪ1 (CMe2). Ϫ NMR: See Table 1, Table 2 and Table 3. Ϫ
C17H27N3O7 (385.4): calcd. C 52.98, H 7.06, N 10.90; found C
52.86, H 7.41, N 11.04.
1,4-Dideoxy-1,4-imino-L-threo-L-altro-octitol (5): A suspension of 3
(4.0 g, 10.4 mmol) in 50% aq. trifluoroacetic acid (20 mL) was
stirred at room temperature for 24 h, in the course of which it be-
came a clear solution. Subsequent TLC analysis (chloroform/meth-
anol, 5:2; detection by method A) showed the presence of only one
product of lower mobility. The mixture was concentrated and the
remaining trifluoroacetic acid was removed by repeated co-distilla-
ν˜ ϭ 1601, 1385, 1373 (CMe2), 666 cmϪ1 (aromatic). Ϫ NMR: See tion with water. The residue was chromatographed (chloroform/
Table 1, Table 2 and Table 3. Ϫ C24H34O10S (514.6): calcd. C 56.02,
H 6.66, S 6.23; found C 55.85, H 6.81, S 6.13.
methanol, 10:1) to yield 1-azido-1-deoxy--glycero--galacto-4-oc-
tulose (4, 2.63 g, quantitative) as a syrup. Ϫ IR (film): ν˜ ϭ 3372
(OH), 2112 cmϪ1 (N3). Ϫ 13C NMR ([D4]MeOH): δ (inter alia) ϭ
104.4 (C-4, α-Fu), 99.3 (C-4, α-Pyr), 63.2 (C-8, α-Pyr), 62.2 (C-8,
α-Fu), 58.3 (C-1, α-Fu), 55.0 (C-1, α-Pyr). Ϫ HRMS (LSIMS); m/z:
288.08077 [Mϩ ϩ Na] (calcd. 288.08077).
1-Azido-1-deoxy-2,3:4,5:6,8-tri-O-isopropylidene-α-
L-
glycero- -galacto-oct-4-ulofuranose (3): To a stirred solution of 2
D
(6.7 g, 13 mmol) in dry DMF (35 mL), NaN3 (2.55 g, 39.2 mmol)
was added and the mixture was heated at 100 °C for 15 h. There-
after, TLC analysis (diethyl ether/hexane, 2:1; detection by method
A) revealed the presence of a new compound of higher mobility.
The reaction mixture was concentrated, diluted with water, and ex-
tracted with diethyl ether (4 ϫ 50 mL). The combined extracts were
washed with brine and water, concentrated to dryness, and the res-
idue was chromatographed (diethyl ether/hexane, 1:3) to afford
crystalline 3 (4.52 g, 90%); m.p. 62Ϫ64 °C (from diethyl ether/hex-
Compound 4 (2.6 g, 9.80 mmol) in water (100 mL) was hydrogen-
ated at 4 atm in the presence of 10% Pd/C (500 mg) for 13 h. Sub-
sequent TLC analysis (chloroform/methanol, 5:2; detection by
method B) revealed that 4 had been completely consumed and
showed the presence of a nonmobile compound. Further TLC (2-
propanol/methanol/aq. ammonia, 2:1:1) showed the presence of
one major product. The catalyst was filtered off and washed with
2074
Eur. J. Org. Chem. 2000, 2071Ϫ2078

Synthesis of 4-Octuloses, VI
FULL PAPER
Table 3. 13C-NMR-spectroscopic data
C-1
C-2
C-3
C-5
C-6
C-7
C-8
C-4
CMe2
CMe2
2
3
70.4
53.0
ǟ
85.4, 76.1, 75.2, 73.2, and 72.8
85.5, 76.9, 76.5, 73.2, and 72.7
Ǟ
Ǟ
60.1
60.2
113.0 112.9, 110.8, 97.4 29.0, 27.6, 27.3, 26.6,
26.4, 18.8
113.2 113.0, 110.6, 97.4 29.0, 27.6, 27.4, 26.7,
26.5, 18.7
ǟ
5
50.9
51.8
54.9
53.4
68.1
3.21
48.8
45.9
46.0
46.4
77.7
78.9
71.2
ǟ 69.7, 69.6, and 68.5 Ǟ
81.2 77.2 77.6
72.5
71.8
62.7
65.6
61.9
65.6
60.9
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
6[a]
9[b]
11[c]
13
ǟ 75.9, 75.8 Ǟ
61.7
76.6
ǟ
78.6
74.5
79.7, 79.4, 77.0, 75.2, and 73.6
Ǟ
Ǟ
Ǟ
Ǟ
Ǟ
Ǟ
Ǟ
71.7
31.1
35.7
31.0
31.4
32.2
29.6
84.7
84.8
84.7
ǟ
ǟ
ǟ
ǟ
ǟ
ǟ
73.2, 72.6, 68.7
73.1, 72.6, 72.2
73.2, 72.6, 69.8
60.4
115.7 112.6, 97.5
115.8 112.6, 97.5
116.0 112.6, 97.5
63.7
66.1
61.3
113.2 111.6
Ϫ
28.9, 27.8, 27.0, 18.7
14
60.4
29.0, 27.8, 27.1, 18.8
15
60.4
28.9, 27.9, 27.1, 18.7
18[d]
20[e]
22[f]
25
73.7, 70.3, 70.0, 68.4
82.1, 77.4, 77.3, 73.7
80.8, 79.1, 75.5, 73.6
61.6
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
74.9
72.0
119.3 12.0
26.1 30.1
34.0
81.2
37.0
80.3
66.4
71.9
72.9
50.5
27.0, 26.8
Ϫ
27
170.6
72.8, 96.9 (8a)
Ϫ
[a]
[b]
AcO and AcN groups at δ ϭ 170.5, 170.1, 169.8, 22.3, 20.9, 20.8, 20.7, 20.6. Ϫ Cbz group at δ ϭ 158.9 (CϭO) and 68.7 (PhCH2).
[c]
[d]
Ϫ
AcO and AcN groups at δ ϭ 172.0, 169.8, 169.6, 169.2, 22.7, 21.1, 21.0. Ϫ
AcO and AcN groups at δ ϭ 170.5, 170.4, 170.1,
169.9, 169.3, 22.5, 21.0, 20.9, 20.8, 20.7, 20.6. Ϫ [e] Cbz group at δ ϭ 158.8 (CϭO) and 68.6 (PhCH2). Ϫ [f] AcO and AcN groups at δ ϭ
172.2, 170.2, 169.9, 22.6, 21.2, 21.1.
water and the combined filtrate and washings were concentrated.
Column chromatography (2-propanol/methanol/aq. ammonia,
2:1:1) of the residue afforded the title compound 5 (2.02 g, 91%) as
a colourless solid foam, which was characterized as its peracetyl
derivative (see below). Ϫ NMR: See Table 3. Ϫ HRMS (LSIMS);
m/z: 246.09533 [Mϩ ϩ Na] (calcd. 246.09536).
was left at room temperature for 1 h and then concentrated. Col-
umn chromatography (dichloromethane Ǟ dichloromethane/meth-
anol, 20:1) of the residue afforded first syrupy N-benzyloxycarb-
onyl-1,4-dideoxy-1,4-imino-8-O-mesitylenesulfonyl--threo--
altro-octitol (8, 80 mg, 5%). Ϫ [α]2D5 ϭ ϩ29 (c ϭ 0.9). Ϫ IR (film):
1
ν˜ ϭ 3396 (OH), 1681 cmϪ1 (NCbz). Ϫ H NMR: δ (inter alia) ϭ
7.40Ϫ7.30 (m, 5 H, PhCH2), 6.97 (s, 2 H, Mes), 5.14 and 5.10 (2
Conventional acetylation of 5 (50 mg, 0.22 mmol) in dry pyridine
(2 mL) by overnight treatment with acetic anhydride (1 mL) and a
catalytic amount of DMAP gave, after the usual workup and col-
umn chromatography (diethyl ether/acetone, 10:1), the correspond-
ing N-acetyl-2,3,5,6,7,8-hexa-O-acetyl derivative 6 (91 mg, 85%) as
a colourless syrup. Ϫ [α]2D5 ϭ ϩ10 (c ϭ 0.7). Ϫ IR (film): ν˜ ϭ 1762,
1757, 1748 (MeCOO), 1661 cmϪ1 (MeCON). Ϫ NMR: See Table 1,
d, 2 H, J ϭ 12.3 Hz, PhCH2), 4.16 (dd, 1 H, J7,8 ϭ 4.2 Hz, J8,8Ј
ϭ
9.7 Hz, 8-H), 4.02 (dd, 1 H, J1,2 ϭ 5.9 Hz, J1,1Ј ϭ 13 Hz, 1-H), 3.62
(d, 1 H, 8Ј-H), 3.59 (dd, 1 H, J1Ј,2 ϭ 2.6 Hz, 1Ј-H), 2.61 and 2.30
(2 s, 9 H, Mes). Ϫ 13C NMR: δ ϭ 156.7 (CϭO), 143.9, 140.1,
135.7, 132.0, 128.7, 128.5, 128.0 (Mes and PhCH2), 81.4, 80.2, 77.1,
76.2, 73.8 (C-2,3,5,6,7), 73.8 (C-8), 68.1 (PhCH2), 63.2 (C-4), 51.2
(C-1), 22.8, 22.6, 21.1 (Mes). Ϫ HRMS (LSIMS); m/z: 562.17247
[Mϩ ϩ Na] (calcd. 562.17229).
Table 2 and Table 3. Ϫ HRMS (LSIMS); m/z: 540.16814 [Mϩ
ϩ
Na] (calcd. 540.16931).
Syrupy 9 was eluted subsequently and was crystallized from dichlo-
romethane (645 mg, 68%); m.p. 193Ϫ194 °C. Ϫ [α]2D7 ϭ ϩ23 (c ϭ
0.9, MeOH). Ϫ IR (KBr): ν˜ ϭ 3413, 3339 (OH), 1675, 1670 cmϪ1
(NCbz). Ϫ C16H21NO7 (339.3): calcd. C 56.63, H 6.24, N 4.13;
found C 56.96, H 6.07, N 4.16.
N-Benzyloxycarbonyl-1,4-dideoxy-1,4-imino-L-threo-L-altro-
octitol(7): To an ice/water-cooled solution of 5 (1.95 g, 8.8 mmol)
in water (15 mL) containing sodium hydrogen carbonate (1 g) and
sodium carbonate (1 g), benzyl chloroformate (2 mL, 14 mmol) was
added dropwise with stirring. After 24 h, TLC analysis (2-pro-
panol/methanol/aq. ammonia, 6:2:1; detection by method B) re-
vealed the presence of a faster moving compound. The mixture was
acidified (to pH ϭ 4Ϫ5) with 1  aq. hydrochloric acid and then
extracted with diethyl ether. The aqueous phase was concentrated
and the residue was applied to a silica gel column and chromato-
graphed (2-propanol/methanol/aq. ammonia, 15:2:1 Ǟ 6:2:1) to
give 7 (2.88 g, 92%) as a syrup. Ϫ [α]2D5 ϭ ϩ32 (c ϭ 0.3, MeOH).
Ϫ IR (film): ν˜ ϭ 3374 (OH); 1680, 1675 cmϪ1 (NCbz). Ϫ 1H NMR
([D4]MeOH): δ (inter alia) ϭ 7.45Ϫ7.35 (m, 5 H, PhCH2), 5.20 (s,
2 H, PhCH2). Ϫ 13C NMR: δ ϭ 158.4 (CϭO), 137.9, 129.5, 129.1,
128.9 (PhCH2), 77.5, 76.4, 74.3, 71.8, 71.5 (C-2,3,5,6,7), 69.2 (C-
4), 68.4 (PhCH2), 64.0 (C-8), 54.7 (C-1).
5,8-Anhydro-1,4-dideoxy-1,4-imino-L-threo-L-altro-octitol (10): A
solution of 9 (200 mg, 0.59 mmol) in dry methanol (25 mL) con-
taining 10% Pd/C (40 mg) was hydrogenated at 75 psi for 4 h. Sub-
sequent TLC analysis (chloroform/methanol, 7:1; detection by
method B) revealed that 9 had been completely consumed and that
a nonmobile product was present. Further TLC (2-propanol/meth-
anol/aq. ammonia, 2:1:0.5; detection by method C) revealed the
presence of only one product. The catalyst was filtered off, washed
with methanol, and the combined filtrate and washings were con-
centrated to dryness. Chromatographic workup of the residue (2-
propanol/methanol/aq. ammonia, 5:1:0.5) afforded crystalline 10
28
(110 mg, 91%); m.p. 153Ϫ154 °C (dec.). Ϫ [α]2D7 ϭ Ϫ2; [α]
ϭ
405
Ϫ18 (c ϭ 0.45, MeOH). Ϫ IR (KBr): ν˜ ϭ 3355, 3268 cmϪ1 (OH
5,8-Anhydro-N-benzyloxycarbonyl-1,4-dideoxy-1,4-imino-
and NH). Ϫ 1H NMR ([D4]MeOH): δ ϭ 4.15 (dd, 1 H, J7,8
ϭ
L-threo-L-altro-octitol (9): To an ice/water-cooled solution of 7
3.9 Hz, 8-H), 4.13Ϫ4.01 (m, 5 H, 2-,3-,5-,6-,7-H), 3.66 (dd, 1 H,
J7,8Ј ϭ 3.7 Hz, J8,8Ј ϭ 11.7 Hz, 8Ј-H), 3.28 (dd, 1 H, 4-H), 3.17 (br.
ddd, 1 H, J1,1Ј ϭ 11.4 Hz, 1-H), 2.85 (br. dt, 1 H, 1Ј-H). Ϫ 13C
NMR: δ ϭ 81.7, 80.9, 78.8, 78.6, 78.2 (C-2,3,5,6,7), 74.6 (C-8), 65.6
(C-4), 52.4 (C-1). Ϫ C8H15NO5 (205.2): calcd. C 46.82, H 7.37, N
6.83; found C 47.24, H 7.58, N 6.54.
(1.0 g, 2.8 mmol) in dry pyridine (15 mL), DMAP (50 mg) and me-
sitylenesulfonyl chloride (1.0 g, 4.57 mmol) were added portionwise
with stirring and then the mixture was set aside at room temper-
ature for 15 h. Subsequent TLC analysis (chloroform/methanol,
7:1; detection by method B) revealed the presence of two faster-
moving compounds. Methanol (5 mL) was added, and the mixture
Eur. J. Org. Chem. 2000, 2071Ϫ2078
2075

I. Izquierdo, M. T. Plaza, R. Robles, A. J. Mota
FULL PAPER
Conventional acetylation of 10 (50 mg, 0.24 mmol) in dry dichloro-
methane (5 mL) by overnight treatment with acetic anhydride
(0.2 mL) and triethylamine (0.5 mL) gave, after the usual workup
and column chromatography (diethyl ether), the corresponding N-
one product of lower mobility. The mixture was concentrated and
the remaining trifluoroacetic acid removed by repeated co-distilla-
tion with water. The residue was chromatographed (chloroform/
methanol, 10:1) to yield 1-azido-1,2-dideoxy--gulo-4-octulose (16,
acetyl-2,3,7-tri-O-acetyl derivative 11 (70 mg, 77%) as a colourless 1.31 g, 87%) as a syrup. Ϫ 13C NMR ([D4]MeOH): δ (inter alia) ϭ
syrup. Ϫ [α]2D7 ϭ ϩ12 (c ϭ 1.2). Ϫ IR (film): ν˜ ϭ 3284 (OH), 1748
98.9 (C-4, α-Pyr), 76.3, 73.4, 72.7, 71.4 (C-3,5,6,7, α-Pyr), 63.4 (C-
(MeCOO), 1635 cmϪ1 (MeCON). Ϫ NMR: See Table 1, Table 2 8, α-Pyr), 49.8 (C-1, α-Pyr), 31.1 (C-2, α-Pyr).
and Table 3. Ϫ HRMS (LSIMS): m/z ϭ 396.12704 [Mϩ ϩ Na]
(calcd. 396.12704).
Compound 16 (1.14 g, 4.57 mmol) in water (60 mL) and methanol
(20 mL) was hydrogenated at 4 atm in the presence of 10% Pd/C
(150 mg) for 18 h. Subsequent TLC analysis (chloroform/methanol,
5:2; detection by method B) revealed that 16 had been completely
consumed and showed the presence of a nonmobile compound.
Further TLC (2-propanol/methanol/aq. ammonia, 6:2:1; detection
by method B) showed the presence of one major product. The cata-
lyst was filtered off and washed with water, and the combined fil-
trate and washings were concentrated. Column chromatography (2-
propanol/methanol/aq. ammonia, 6:2:1) of the residue afforded the
title compound (17, 850 mg, 90%), which was characterized as its
peracetyl derivative (see below).
2-Deoxy-4,5:6,8-di-O-isopropylidene-1-O-p-toluenesulfonyl-α-L-
gulo-oct-4-ulofuranose (13): To an ice/water-cooled solution of 2-
deoxy-4,5:6,8-di-O-isopropylidene-α--gulo-oct-4-ulofuranose
(12,[4d] 3.0 g, 9.86 mmol) in dry dichloromethane (50 mL) and tri-
ethylamine (2.5 mL), p-toluenesulfonyl chloride (2.1 g, 11 mmol)
was added portionwise with stirring and then the mixture was set
aside at room temperature for 24 h. Subsequent TLC analysis (di-
ethyl ether; detection by method A) revealed the presence of a fas-
ter moving compound. The mixture was poured into ice/water and
the resulting solution was left for 1 h. It was then extracted with
diethyl ether (3 ϫ 50 mL) and the combined extracts were washed
with 10% aq. hydrochloric acid, water, saturated NaHCO3 solution,
and further water, and then concentrated to dryness. Chromato-
Conventional acetylation of 17 (93 mg, 0.45 mmol) in dry pyridine
(1 mL) by overnight treatment with acetic anhydride (1 mL) and a
catalytic amount of DMAP gave, after the usual workup and col-
umn chromatography (diethyl ether/acetone, 5:1) the corresponding
N-acetyl-3,5,6,7,8-penta-O-acetyl derivative 18 (150 mg, 73%),
which was crystallized from diethyl ether/hexane; m.p. 99Ϫ100 °C.
Ϫ [α]2D7 ϭ ϩ17 (c ϭ 1). Ϫ IR (KBr): ν˜ ϭ 1757, 1748, 1740 (Me-
COO), 1658 cmϪ1 (MeCON). Ϫ NMR: See Table 1, Table 2 and
Table 3. Ϫ C20H29NO11 (459.4): calcd. C 52.28, H 6.36, N 3.05;
found C 52.43, H 6.21, N 3.12.
graphic workup of the residue (diethyl ether/hexane, 1:1) afforded
26
13 (2.7 g, 60%) as a colourless syrup. Ϫ [α]2D5 ϭ ϩ13; [α] ϭ ϩ30
405
(c ϭ 1.2). Ϫ IR (film): ν˜ ϭ 3529 (OH), 1385, 1374, 1360 cmϪ1
(CMe2). Ϫ NMR: See Table 1, Table 2 and Table 3. Ϫ HRMS
(LSIMS): m/z ϭ 459.16787 [Mϩ ϩ 1] (calcd. 459.16888).
1,2-Dideoxy-1-iodo-4,5:6,8-di-O-isopropylidene-α-L-gulo-oct-4-
ulofuranose (14): To a stirred solution of 12 (1.56 g, 5.12 mmol) in
anhydrous dichloromethane (15 mL), a solution of iodine (1.42 g,
5.6 mmol), triphenylphosphane (1.47 g, 5.6 mmol), and imidazole
(694 mg, 10.2 mmol) in the same solvent (40 mL) was added at
room temperature. After 4 h, TLC analysis (diethyl ether/hexane,
3:2; detection by UV) revealed the presence of a faster moving com-
pound. The mixture was filtered and concentrated. Column chro-
matography (diethyl ether/hexane, 1:1) of the residue gave syrupy
14 (1.91 g, 90%), which was crystallized from hexane; m.p. 77Ϫ78
°C. Ϫ [α]2D8 ϭ ϩ28 (c ϭ 1). Ϫ IR (KBr): ν˜ ϭ 3520 (OH), 1388,
1374 cmϪ1 (CMe2). Ϫ NMR: See Table 1, Table 2 and Table 3. Ϫ
C14H23IO6 (414.2): calcd. C 40.59, H 5.60; found C 40.95, H 5.70.
N-Benzyloxycarbonyl-1,2,4-trideoxy-1,4-imino-L-glycero-D-talo-
octitol (19): To an ice/water-cooled solution of 17 (800 mg,
3.86 mmol) in water (10 mL) containing sodium hydrogen carbon-
ate (400 mg) and sodium carbonate (400 mg), benzyl chloroformate
(1.2 mL, 8.41 mmol) was added dropwise with stirring. After 30 h,
TLC analysis (2-propanol/methanol/ammonia, 6:2:1; detection by
method B) revealed the presence of a faster moving compound.
The mixture was acidified (to pH ϭ 4Ϫ5) with 1  aq. hydrochloric
acid and then extracted with diethyl ether. The aqueous phase was
concentrated and the residue was applied to a silica gel column and
chromatographed (2-propanol/methanol/aq. ammonia, 10:2:1 Ǟ
1-Azido-1,2-dideoxy-4,5:6,8-di-O-isopropylidene-α-L-gulo-oct-4-
ulofuranose (15): (a) To a stirred solution of 13 (2.95 g, 6.43 mmol)
in dry DMF (40 mL), sodium azide (1.05 g, 16 mmol) was added
and the mixture was heated at 80 °C for 15 h. Subsequent TLC
analysis (diethyl ether; detection by method A) revealed that 13
had been completely consumed and showed the presence of a faster
moving compound. The reaction mixture was concentrated, diluted
with water, and extracted with diethyl ether (4 ϫ 50 mL). The com-
bined extracts were washed with brine and water, and then concen-
trated to dryness. Chromatographic workup of the residue (diethyl
ether/hexane, 1:2) afforded crystalline 15 (2.0 g, 94%); m.p. 72Ϫ74
°C. Ϫ [α]2D4 ϭ ϩ20 (c ϭ 0.8). Ϫ IR (KBr): ν˜ ϭ 3538 (OH), 2104
(N3), 1387, 1376 cmϪ1 (CMe2). Ϫ NMR: See Table 1, Table 2 and
Table 3. Ϫ C14H23N3O6 (329.3): calcd. C 51.05, H 7.04, N 12.76;
found C 51.29, H 7.54, N 12.53.
6:2:1) to give 19 (980 mg, 74%) as a syrup. Ϫ [α]2D6 ϭ ϩ22 (c ϭ 0.3,
Ϫ1
˜
MeOH). Ϫ IR (film): ν ϭ 3169, 3157 (OH), 1680, 1675 cm
1
(NCbz). Ϫ H NMR ([D4]MeOH): δ (inter alia) ϭ 7.42Ϫ7.25 (m,
5 H, PhCH2), 5.15 (s, 2 H, PhCH2), 4.52 (d, 1 H, 5-H), 2.19 (m, 1
H, 2-H), 1.89 (m, 1 H, 2Ј-H). Ϫ 13C NMR: δ ϭ 158.6 (CϭO),
138.0, 129.5, 129.1, 128.8 (PhCH2), 74.5, 73.0, 72.8, 71.4, 69.8 (C-
3,4,5,6,7), 68.4 (PhCH2), 64.0 (C-8), 46.0 (C-1), 32.8 (C-2).
5,8-Anhydro-N-benzyloxycarbonyl-1,2,4-trideoxy-1,4-imino-
L-
glycero- -talo-octitol (20): To an ice/water-cooled solution of 19
D
(220 mg, 0.65 mmol) in dry pyridine (5 mL), mesitylenesulfonyl
chloride (240 mg, 1.10 mmol) was added portionwise with stirring
and then the mixture was set aside at room temperature for 18 h.
Subsequent TLC analysis (chloroform/methanol, 10:1; detection by
method B) revealed the presence a faster moving compound. Meth-
anol (5 mL) was added, and the mixture was left at room temper-
ature for 1 h and then concentrated. Column chromatography
(dichloromethane Ǟ dichloromethane/methanol, 20:1) of the res-
(b) Treatment of compound 14 (1.47 g, 3.55 mmol) in dry DMF
(35 mL) with sodium azide (2.55 g, 39.2 mmol) as above gave 15
(1.11 g, 95%).
1,2,4-Trideoxy-1,4-imino-L-glycero-D-talo-octitol (17): A suspension
of 15 (2.0 g, 6.07 mmol) in 50% aq. trifluoroacetic acid (15 mL) idue afforded 20 (135 mg, 65%). Ϫ [α]2D3 ϭ ϩ27 (c ϭ 0.9, MeOH).
was stirred at room temperature for 24 h, in the course of which
it became a clear solution. Subsequent TLC analysis (chloroform/
Ϫ IR (film): ν˜ ϭ 3389 (OH), 1680, 1669 cmϪ1 (NCbz). Ϫ NMR:
See Table 1, Table 2 and Table3. HRMS (LSIMS); m/z:
Ϫ
methanol, 5:1; detection by method A) showed the presence of only 346.12711 [Mϩ ϩ Na] (calcd. 346.12666).
2076
Eur. J. Org. Chem. 2000, 2071Ϫ2078

Synthesis of 4-Octuloses, VI
FULL PAPER
detection by method A) revealed the presence of just one product
of lower mobility. The mixture was concentrated and the remaining
trifluoroacetic acid was removed by repeated co-distillation with
water. The residue was chromatographed (diethyl ether Ǟ diethyl
ether/methanol, 20:1) to yield 26 (550 mg, 83%) as a syrup. Ϫ
α]D25 ϭ Ϫ36 (c ϭ 1.2, methanol). Ϫ IR (film): ν˜ ϭ 3417 (OH), 2254
(CN), 2112 cmϪ1 (N3). Ϫ 13C NMR ([D4]MeOH): δ (inter alia) ϭ
209.7 (C-4, keto form), 121.4 and 121.3 (C-1, α,β-Fu), 120.5 (C-1,
keto form), 82.9 and 82.7 (C-5, α,β-Fu), 80.0 (C-5, keto form),
75.6, 74.6, 74.0, 72.7 (C-6,7, α,β-Fu), 75.4 (C-6, keto form), 70.8
(C-7, keto form), 55.6 (C-8, keto form), 55.1 and 53.3 (C-8, α,β-
Fu), 35.8 (C-3, keto form), 35.4 and 32.6 (C-3, α,β-Fu), 12.4 and
12.1 (C-2, α,β-Fu), 11.7 (C-2, keto form). Ϫ HRMS (LSIMS); m/z:
251.07490 [Mϩ ϩ Na] (calcd. 251.07563).
5,8-Anhydro-1,2,4-trideoxy-1,4-imino-L-glycero-D-talo-octitol (21):
A solution of 20 (100 mg, 0.31 mmol) in dry methanol (15 mL)
containing 10% Pd/C (40 mg) was hydrogenated at 75 psi for 6 h.
Subsequent TLC analysis (chloroform/methanol, 7:1; detection by
method B) revealed that 20 had been completely consumed and
that a nonmobile product was present. Further TLC (2-propanol/
methanol/aq. ammonia, 6:1:0.5; detection by method C) revealed
the presence of only one product. The catalyst was filtered off,
washed with methanol, and the combined filtrate and washings
were concentrated to dryness. Chromatographic workup of the res-
idue (2-propanol/methanol/aq. ammonia, 5:1:0.5) afforded 21
(52 mg, 89%), which was characterized as its triacetyl derivative.
Conventional acetylation of 21 (35 mg, 0.11 mmol) in dry dichloro-
methane (4 mL) by overnight treatment with acetic anhydride
(0.1 mL) and triethylamine (0.3 mL) gave, after the usual workup
and column chromatography (diethyl ether/hexane, 1:1), the corres-
ponding N-acetyl-3,7-di-O-acetyl derivative (22, 35 mg, 79%) as a
colourless syrup. Ϫ [α]2D4 ϭ Ϫ14 (c ϭ 1). Ϫ IR (film): ν˜ ϭ 3270
(OH), 1748, 1740 (MeCOO), 1628 cmϪ1 (MeCON). Ϫ NMR: See
Table 1, Table 2and Table 3. Ϫ C14H21NO7 (315.3): calcd. C 53.32,
H 6.71, N 4.44; found C 53.43, H 6.57, N 4.32.
(6S,7S,8S,8aS)-6,7,8-Trihydroxy-8a-methoxyindolizidin-3-one
(27): Compound 26 (240 mg, 1.05 mmol), dissolved in methanol/
water (7:1; 25 mL) containing triethylamine (0.3 mL) and 10% Pd/
C (50 mg), was hydrogenated at 4 atm for 48 h. Subsequent TLC
analysis (2-propanol/methanol/aq. ammonia, 6:2:1; detection by
method C) revealed that 26 had been completely consumed and
showed the presence of a nonmobile compound. The catalyst was
filtered off, washed with water, and the combined filtrate and wash-
ings were concentrated to dryness. Chromatographic workup of the
residue (2-propanol/methanol/aq. ammonia, 6:2:1 Ǟ methanol/
water, 1:1) afforded crystalline 27 (210 mg, 92%); m.p. 146Ϫ147 °C
(dec.). Ϫ [α]2D7 ϩ22.4 (c ϭ 0.8, water). Ϫ IR (KBr): ν˜ ϭ 3486, 3437,
8-Azido-2,3,8-trideoxy-4,5-O-isopropylidene-α-L-ribo-oct-4-ulo-
furanosononitrile (25): To a stirred solution of 8-azido-2,3,8-trid-
eoxy-4,5-O-isopropylidene-α--xylo-oct-4-ulofuranosononitrile
(23,[1] 970 mg, 3.62 mmol) in anhydrous dichloromethane (20 mL)
˚
were added 4-A molecular sieves (2 g) and pyridinium chlorochro-
1
3305 (OH); 1676, 1661 cmϪ1 (CO). Ϫ H NMR (D2O, 500 MHz):
mate (2.0 g, 9 mmol). Stirring was continued for 4 h at room tem-
perature, whereupon TLC analysis (diethyl ether) showed the pres-
ence of a new product of slightly lower mobility. The mixture was
diluted with diethyl ether (40 mL), filtered through silica gel, and
concentrated. Column chromatography (diethyl ether/hexane, 1:1
Ǟ 3:1) of the residue gave syrupy 8-azido-2,3,8-trideoxy-4,5-O-iso-
δ ϭ 4.10 (br. t, 1 H, J6,7 ϭ 2.8 Hz, 7-H), 3.94 (br. dd, 1 H, 5β-H),
3.77 (m, 1 H, 6-H), 3.73 (d, 1 H, J7,8 ϭ 3.1 Hz, 8-H), 3.21 (s, 3 H,
OMe), 2.88 (br. t, 1 H, J5α,5β ഠ J5α,6 ϭ 11.4 Hz, 5α-H), 2.80Ϫ2.50
(2 m, 2 H, 2α-,2β-H), 2.40Ϫ2.20 (2 m, 2 H, 1α-,1β-H). Ϫ 13C NMR
(D2O/[D6]acetone): δ ϭ 170.6 (C-3), 96.9 (C-8a), 72.9 (C-7), 72.8
(C-8), 66.4 (C-6), 48.6 (OMe), 37.0 (C-5), 30.1 (C-2), 26.1 (C-1). Ϫ
MS (CI, CH4): m/z (%) ϭ 218 [Mϩ ϩ 1] (13.6), 201 [Mϩ ϩ 1 Ϫ
propylidene-α--erythro-oct-4,6-diulofuranosononitrile
(24,
860 mg, 89%) and its hydrated form in a ratio of ca. 3:4, as evid-
enced by 1H NMR. Ϫ [α]2D8 ϭ Ϫ67 (c ϭ 1.2). Ϫ IR (film): ν˜ ϭ
3439 (OH), 2252 (CN), 2114 (N3), 1779 (CO), 1386, 1377 cmϪ1
OH] (3.5), 186 [Mϩ ϩ 1 Ϫ MeOH] (18.4), 170 (3.0), 167 [Mϩ
Ϫ
MeOH Ϫ H2O] (100). Ϫ C9H15NO5 (217.2): calcd. C 49.76, H 6.96,
N 6.45; found C 49.62, H 7.27, N 6.59.
1
(CMe2). Ϫ H NMR: δ (inter alia) ϭ 4.52 (dt, 1 H, J5,7 ϭ 1.1 Hz,
7-H), 4.28 (s, 1 H, OH, hydrated form), 4.21 (d, 1 H, 5-H), 4.06 (s,
1 H, 5-H, hydrated form), 4.04 (dd, 1 H, 7-H, hydrated form), 3.82
(s, 1 H, OH, hydrated form), 3.70 (dd, 1 H, J7,8 ϭ 3.2 Hz, 8-H),
3.65 (dd, 1 H, J7,8 ϭ 4.3 Hz, 8-H, hydrated form), 3.60 (dd, 1 H,
J7,8Ј ϭ 3.1 Hz, J8,8Ј ϭ 13.2 Hz, 8Ј-H), 3.54 (dd, 1 H, J7,8Ј ϭ 5.3,
J8,8Ј ϭ 13.4 Hz, 8Ј-H, hydrated form), 1.54 and 1.38 (2 s, 6 H,
CMe2, hydrated form), 1.44 and 1.42 (2 s, 6 H, CMe2). Ϫ 13C
NMR: δ ϭ 208.7 (C-6), 119.8 (C-1, hydrated form), 119.2 (C-1),
114.8 (C-4), 113.0 (C-4, hydrated form), 111.8 (CMe2, hydrated
form), 110.4 (CMe2), 100.5 (C-6, hydrated form), 85.1 and 79.0 (C-
5,7, hydrated form), 78.9 and 78.7 (C-5,7), 51.2 (C-8), 48.4 (C-8,
hydrated form), 33.8 (C-3, hydrated form), 33.3 (C-3), 27.9, 27.8,
23.3, and 26.8 (CMe2), 12.0 (C-2, hydrated form), 11.8 (C-2).
Acknowledgments
This work was supported by the Ministerio de Educacion y Cultura
(Spain) (Project PB95Ϫ1157) and, in part, by a grant (to A. J.
Mota) from the Fundacion Ramon Areces (Spain).
´
´
´
[1]
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[2]
To a cooled (Ϫ20 °C) solution of 24 (820 mg, 3.1 mmol) in anhyd-
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3.2 mmol) was added portionwise with stirring. After 10 min, the
mixture was neutralized with acetic acid and then concentrated.
Chromatographic workup of the residue (diethyl ether/hexane, 3:1)
afforded 25 (780 mg, quantitative) as a syrup. Ϫ [α]2D5 ϭ Ϫ76 (c ϭ
2.7). Ϫ IR (film): ν˜ ϭ 3462 (OH), 2251 (CN), 2107 (N3), 1386,
1373 cmϪ1 (CMe2). Ϫ NMR: See Table 1, Table 2 and Table 3. Ϫ
HRMS (LSIMS): m/z ϭ 291.10685 [Mϩ ϩ Na] (calcd. 291.10693).
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I. Izquierdo, M.-T. Plaza, R. Robles, A. J. Mota, Tetrahedron:
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Eur. J. Org. Chem. 2000, 2071Ϫ2078
2077

I. Izquierdo, M. T. Plaza, R. Robles, A. J. Mota
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M.-J. Domınguez, M.-T. Garcıa Lopez, R. Gonzalez Mun˜iz,
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´
´
´
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´
Compound 27 could not be transformed into the correspond-
Garcıa Lopez, R. Herranz, M. Martın Martınez, R. Gonzalez
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Received October 1, 1999
ing indolizidine owing to its insolubility in the organic solvents
typically used for the relevant reducing agents. It is also note-
worthy that previous enzymatic assays have revealed 27 to be
an excellent inhibitor (Ki ϭ 32 µ, IC50 ϭ 35 µ) versus α-
[O99549]
2078
Eur. J. Org. Chem. 2000, 2071Ϫ2078