Synthesis of 4-octuloses, V. - 4-Octulose derivatives as key intermediates in a new and short synthesis of polyhydroxyindolizidines

Article abstract of DOI:10.1002/(SICI)1099-0690(199906)1999:6<1269::AID-EJOC1269>3.0.CO;2-H

Reaction of 3 with (cyanomethylene)triphenylphosphorane in refluxing dichloromethane or methanol gave mixtures of 4a and 4b in ratios of about 3:1 and 1:3, respectively. The same reaction performed with the furanoid isomer 5 afforded 6a and 6b in (E)/(Z)

Full text of DOI:10.1002/(SICI)1099-0690(199906)1999:6<1269::AID-EJOC1269>3.0.CO;2-H

FULL PAPER
Synthesis of 4-Octuloses, V[°]
4-Octulose Derivatives as Key Intermediates in a New and Short Synthesis of
Polyhydroxyindolizidines
[a]
[a]
[a]
[a]
´
´
´
Isidoro Izquierdo,* Marıa T. Plaza, Rafael Robles, Concepcion Rodrıguez,
[a]
[a]
´
Antonio Ramırez, and Antonio J. Mota
Keywords: Asymmetric synthesis / 4-Octulose derivatives / Aminations / Double cyclization / Polyhydroxyindolizidines
Reaction of 3 with (cyanomethylene)triphenylphosphorane in
8,9,10-trihydroxy-1-aza-6-oxaspiro[4.5]decane, which was
refluxing dichloromethane or methanol gave mixtures of 4a identified as its peracylated derivative 16, was isolated.
and 4b in ratios of about 3:1 and 1:3, respectively. The same
reaction performed with the furanoid isomer 5 afforded 6a
and 6b in (E)/(Z) ratios of approximately 9:1 and 1:2,
Following an alternative synthetic strategy, partial hydrolysis
of compound 9 afforded 17 which was regioselectively
transformed into the corresponding derivative 22 via its 8-O-
respectively. Catalytic hydrogenation of the α,β-unsaturated p-toluenesulfonyl derivative 18. Removal of the 4,5-O-
nitriles 4 and 6 with either 10% Pd-C or Raney nickel isopropylidene group in 22 with aqueous trifluroacetic acid
afforded the saturated nitriles 7 and 9, or the 1-amino-1,2,3- gave the free octulose 23, which was hydrogenated in the
trideoxy-4-octulose derivatives 8 and 10, respectively. In an
attempt to transform 6a into the appropriate polyhy-
droxylated branched-chain pyrrolidine 15, (5R,8S,9R,10S)-
presence of 10% Pd-C, to afford the expected
(6S,7R,8R,8aR)-6,7,8-trihydroxyindolizidine (1-deoxycasta-
nospermine, 11).
Introduction
Potent glycosidase inhibitors such as polyhydroxyindoli-
zidines (1)[2] have received much attention in recent years
because of their potential as antitumour, anti-HIV, antidia-
betic agents, etc. Retrosynthesis of such molecules (see
Scheme 1) clearly demonstrates that 4-octulosononitriles (2)
could be excellent chiral synthetic intermediates, since all
that would be necessary would be the transformation of CN
to CH2NH2 to initially promote an internal reductive amin-
ation of the ketone at C-4 to give the required pyrrolidine,
and subsequently another cyclization by internal nucleo-
philic displacement of the appropriate derivative, to form
the indolizidine ring. Moreover, the cheap and readily avail-
able -fructose and -sorbose can be considered excellent
starting chiral templates for the enantioselective synthesis
of such 4-octulosononitriles en route to these inhibitors, de-
pending on the required stereoisomers. The necessary exten-
sion of the sugar chain by two more carbon atoms at C-1,
together with the introduction of a nitrogen function to af-
ford the 4-octulosononitrile, could be achieved by Wittig
methodology. Finally, the configurations of the stereogenic
centres at C-6,7,8 in 1 would be predetermined by the start-
ing hexulose.
Scheme 1. Retrosynthesis of 1
Results and Discussion
The reaction of 2,3:4,5-di-O-isopropylidene-β--arabino-
hexos-2-ulopyranose[4] (3) with (cyanomethylene)triphenyl-
phosphorane[5] in refluxing dichloromethane or methanol
gave mixtures of (E)-4a and (Z)-4b in the ratios 3:1 and 1:3
(GLC analysis), respectively. On the other hand, the reac-
tion of 2,3:4,6-di-O-isopropylidene-α--xylo-hexos-2-ulofu-
ranose[6] (5) with the above Wittig reagent afforded (E)-6a
and (Z)-6b in 9:1 and 1:2 ratios (GLC analysis), respec-
Recently, our group has described the use of 4-octulose
derivatives in the synthesis of tetra- and pentahydroxyindol-
izidines.[3]
1
tively. The H-NMR spectra of 4aϪ6a and 4bϪ6b showed
J2,3 values of ca. 16 and 12 Hz, respectively, as expected for
the (E) and (Z) configurations.
The above results were in agreement with those pre-
viously reported,[7] in which the stereoselectivity depended
on the polarity of the solvent.
[°] Part IV: Ref.[1]
[a]
Department of Organic Chemistry, Faculty of Pharmacy,
University of Granada,
E-18071 Granada, Spain
Catalytic hydrogenation of 4 and 6 in the presence of 10%
Pd-C did not affect the cyano group and gave the corre-
Fax: (internat.) ϩ 34-958/243845
E-Mail: isidoro@platon.ugr.es
Eur. J. Org. Chem. 1999, 1269Ϫ1274
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0606Ϫ1269 $ 17.50ϩ.50/0
1269

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I. Izquierdo, M. T. Plaza, R. Robles, C. Rodrıguez, A. Ramırez, A. J. Mota
FULL PAPER
oxycastanospermine (11) from 6a, was carried out. Thus,
compound 6a was deacetonated in an acid medium to give
the corresponding (E)-12, which was subsequently hydro-
genated to afford the intermediate 1-amino-1,2,3-trideoxy-
-xylo-4-octulose (13). Nucleophilic attack of the C-1 am-
ino group at the C-4 carbonyl group in 13 would give the
cyclic pyrroline intermediate 14, which after subsequent
hydrogenation, would produce the pyrrolidine 15 (see be-
low, Scheme 4). This, in turn, could be transformed in three
steps into the expected 11 according to our previous re-
sults.[3] However, the only compound obtained, which was
isolated in very low yield and identified from the reaction
mixture after peracetylation, was (5R,8S,9R,10S)-8,9,10-tri-
acetoxy-1-N-acetyl-1-aza-6-oxaspiro[4.5]decane (16). An
analogue of 16 has been described by Richardson et al.[8]
Scheme 2. Formation of 4-octulosononitrile derivatives by Wittig
methodology
as a byproduct in the synthesis of the corresponding trihy-
droxyindolizidine starting from an 1-azido-2,3-dideoxy-4-
octulose.
sponding saturated nitriles 7 and 9, whereas hydrogenation
in the presence of Raney nickel afforded the 1-amino de-
rivatives 8 and 10, respectively.
On the basis of the above results, a new synthetic strategy
was designed by introducing a good leaving group at C-8
that would be attacked by the nitrogen atom of the inter-
mediate pyrrolidine, to form the bicyclic indolizidine skel-
eton. Thus, compound 9 was partially hydrolyzed to 17,
which was then regioselectively transformed into its 8-O-
tosylate (18). When total deprotection of 18 occurred, an
internal cyclization by a nucleophilic attack of 5-OH to C-
8 took place (see Scheme 5) to give firstly 20, which in turn
epimerized to 21.
Scheme 3. Synthesis of 1-amino-1-deoxy-4-octulose derivatives
Treatment of 18 with sodium azide gave 22, and by total
As an example of the potential of the above 4-octulo- deacetonation, the free 4-octulosononitrile 23 was obtained
sononitriles as important key intermediates in the synthesis as a mixture of keto-, α- and β-furanose forms (13C-NMR
of polyhydroxyindolizidines, an attempt to synthesize 1-de- evidence). This was subjected to hydrogenation (Pd-C/H2/
Scheme 4. Cyclization of 12 to spiroaminoketal 16
1270
Eur. J. Org. Chem. 1999, 1269Ϫ1274

Synthesis of 4-Octuloses, V
FULL PAPER
authors[10] in which analogous polyhydroxypiperidines
were obtained.
Experimental Section
General Remarks: Melting points were determined with a Gallen-
kamp apparatus and are uncorrected. Solutions were dried with
MgSO4 before being concentrated under reduced pressure. The 1H-
and 13C-NMR spectra were recorded with Bruker AMX-300, AM-
300 and ARX-400 spectrometers for solutions in CDCl3 (internal
Me4Si). IR spectra were recorded with a PerkinϪElmer 782 instru-
ment and mass spectra with Fisons mod. Platform II and VG Auto-
specϪQ mass spectrometers. Optical rotations were measured for
solutions in CHCl3 (1-dm tube) with a Jasco DIP-370 polarimeter.
GLC was performed with a PerkinϪElmer 8410 gas chromatog-
raph equipped with a flame-ionisation detector and a steel column
(2 m ϫ 0.125 in i.d.) packed with 5% OV-17 on Chromosorb W
(100Ϫ120 mesh) at 200°C. 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 aluminium
sheets and the spots were detected by charring with H2SO4. Col-
umn chromatography was performed on silica gel (Merck, 7734).
Scheme 5. Formation of 5,8-anhydro-4-octulosononitrile derivati-
ves (20 and 21) from 18
(E)- and (Z)-2,3-Dideoxy-4,5:6,7-di-O-isopropylidene-β-D-arabino-
oct-2-ene-4-ulo-4,8-pyranosononitrile (4a and 4b): a) A solution of
3[4] (1.14 g, 4.4 mmol) and (cyanomethylene)triphenylphosphorane
(1.86 g, 6.2 mmol) in dry CH2Cl2 (30 mL) was refluxed for 1 h.
GLC showed that 3 had disappeared and that two new compounds
in a ca. 3:1 ratio were present. The mixture was concentrated and
the residue adsorbed onto silica gel and chromatographed (ether/
hexane, 1:5) to afford firstly crystalline 4a (710 mg, 57%), tR
ϭ
26
4.74 min. Ϫ M.p. 87Ϫ88°C. Ϫ [α]D ϭ Ϫ26.4 (c ϭ 1.14). Ϫ IR
(KBr): ν˜ ϭ 2232 cmϪ1 (CϵN), 1387 and 1379 (CMe2). Ϫ NMR
data, see Tables 1Ϫ3. Ϫ C14H19NO5 (281.30): calcd. C 59.77, H
6.81, N 4.98; found C 59.43, H 6.92, N 5.18. Ϫ Eluted secondly was
crystalline 4b (280 mg, 23%), tR ϭ 5.97 min. Ϫ M.p. 100Ϫ102°C. Ϫ
[α]D24 ϭ Ϫ52 (c ϭ 0.73). Ϫ IR (KBr): ν˜ ϭ 2226 cmϪ1 (CϵN), 1384
and 1374 (CMe2). Ϫ NMR data, see Tables 1Ϫ3. Ϫ C14H19NO5
(281.30): calcd. C 59.77, H 6.81, N 4.98; found C 59.51, H 7.28, N
4.62. Ϫ b) When reaction of 3 (970 mg, 3.8 mmol) with (cyano-
methylene)triphenylphosphorane (1.7 g, 5.6 mmol) was carried out
in refluxing dry methanol (30 mL) for 1.5 h, GLC also revealed the
presence of 4a and 4b in a ca. 1:3 ratio. Resolution of the reaction
mixture was performed as above to give 4a and 4b in a total yield
of 890 mg (84%).
Scheme 6. Double cyclization of 22 to 1-deoxycastanospermine
(11)
methanol) to afford, after 4 h, the intermediate piperidine
26 together with 1-deoxycastanospermine (11) (13C-NMR
measurement of an aliquot). The latter was probably
formed by a process similar to that found in the literature[9]
,
in which an intermediate similar to 27 was aminated, pre-
sumably to be formed by nucleophilic addition of a piperi-
dine moiety to the cyano group (see Scheme 6). Subsequent
catalytic reductive deamination of 27 would lead to the in-
dolizidine skeleton. When hydrogenation was carried out
over a 24 h period, only 11 could be detected by 13C-
NMR spectroscopy.
On the other hand, the highly stereoselective formation
of the new stereocentre (C-2) in the piperidine ring (only
one isomer for 26 and 11 could be observed in the 13C-
NMR spectrum) was crucial for the whole process and ac-
counted for the stereochemistry of the target molecule 11.
This result could be explained by a preferential attack of
hydrogen from the bottom face (see Figure 1) of the ∆1-
piperidine (25), in accordance with those reported by other
(E)- and (Z)-2,3-Dideoxy-4,5:6,8-di-O-isopropylidene-α-L-xylo-oct-
2-ene-4-ulo-4,7-furanosononitrile (6a and 6b): a) A solution of 5[6]
(750 mg, 2.9 mmol) and (cyanomethylene)triphenylphosphorane
(1.46 g, 4.85 mmol) in dry CH2Cl2 (30 mL) was refluxed for 1 h.
GLC showed that 5 had disappeared and that two new compounds
in a ca. 9:1 ratio were present. The mixture was concentrated and
the residue adsorbed onto silica gel and chromatographed (ether/
hexane, 1:4) to afford firstly syrupy 6a (585 mg, 72%), tR
ϭ
28
5.20 min. Ϫ [α]D ϭ ϩ26 (c ϭ 0.9).Ϫ IR (film): ν˜ ϭ 2231 cmϪ1
(CϵN), 1386 and 1377 (CMe2). Ϫ NMR data, see Tables 1Ϫ3. Ϫ
HRMS (LSIMS); m/z: found 304.11595 [Mϩ ϩ Na]; calcd.
304.11609. Ϫ Eluted secondly was syrupy 6b (70 mg, 8.6%), tR
ϭ
22
6.14 min. Ϫ [α]D ϭ Ϫ7 (c ϭ 1). Ϫ IR (film): ν˜ ϭ 2227 cmϪ1
(CϵN), 1387 and 1378 (CMe2). Ϫ NMR data, see Tables 1Ϫ3. Ϫ
HRMS (LSIMS); m/z: 304.11598 [Mϩ ϩ Na]; calcd. 304.11609. Ϫ
b) Reaction of 5 (810 mg, 3.14 mmol) with (cyanomethylene)tri-
phenylphosphorane (1.32 g, 4.39 mmol) was carried out under the
above conditions (dry methanol, 30 mL), and refluxed for 1.5 h.
Figure 1. Stereochemical course for the hydrogenation of 25
Eur. J. Org. Chem. 1999, 1269Ϫ1274
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I. Izquierdo, M. T. Plaza, R. Robles, C. Rodrıguez, A. Ramırez, A. J. Mota
FULL PAPER
GLC also revealed the presence of 6a and 6b in a ca. 1:2 ratio. Pd-C (66 mg) for 1 h. GLC then revealed the absence of 6 and the
Resolution of the reaction mixture was performed as above.
2,3-Dideoxy-4,5:6,7-di-O-isopropylidene-β- -arabino-oct-4-ulo-
presence of a new compound with tR ϭ 5.80 min. The catalyst was
collected and washed with methanol, and the combined filtrate and
washings were concentrated. Column chromatography (ether/hex-
ane, 2:1) of the residue gave crystalline 9 (141 mg, 88%). Ϫ M.p.
D
4,8-pyranosononitrile (7): A solution of 4 (145 mg, 0.52 mmol) in
dry methanol (10 mL) was hydrogenated at 1 atm in the presence
of 10% Pd-C (55 mg) for 1 h. GLC then revealed the absence of 4
and the presence of a new compound with tR ϭ 5.22 min. The
catalyst was collected, washed with methanol, and the combined
filtrate and washings were concentrated. Column chromatography
(ether/hexane, 2:1) of the residue gave syrupy 7 (126 mg, 86%). Ϫ
24
99Ϫ100°C.Ϫ [α]405 ϭ ϩ9.5 (c ϭ 1). Ϫ IR (KBr): ν˜ ϭ 2249 cmϪ1
(CϵN), 1383 and 1374 (CMe2). Ϫ NMR data, see Tables 1Ϫ3. Ϫ
C14H21NO5 (283.32): calcd. C 59.35, H 7.47, N 4.94; found C
59.41, H 7.59, N 4.73.
1-Amino-1,2,3-trideoxy-4,5:6,8-di-O-isopropylidene-α-
L-xylo-oct-
26
26
[α]D ϭ Ϫ10, [α]405 ϭ Ϫ15 (c ϭ 1). Ϫ IR (film): ν˜ ϭ 2249 cmϪ1
4-ulo-4,7-furanose (10): a) Compound 6 (1.17 g, 4.16 mmol) was
(CϵN), 1383 and 1374 (CMe2). Ϫ NMR data, see Tables 1Ϫ3. Ϫ hydogenated at 5 atm in methanol (30 mL) in the presence of Raney
HRMS (LSIMS); m/z: found 306.13171 [Mϩ ϩ Na]; calcd.
306.13174.
nickel (6 g) for 36 h, as above. TLC (ether/hexane, 3:2) then re-
vealed the presence of a non-mobile compound. The catalyst was
removed, washed with methanol and the filtrate and washings were
concentrated. Column chromatography (see above) afforded syrupy
10 (980 mg, 82%), Rf ϭ 0.20. Ϫ [α]D ϭ ϩ3, [α]405 ϭ ϩ7 (c ϭ
1.7). Ϫ IR (film): ν˜ ϭ 3376 cmϪ1 (NH2), 1384 and 1374 (CMe2).
Ϫ NMR data, see Tables 1Ϫ3. Ϫ HRMS (LSIMS); m/z: found
310.16307 [Mϩ ϩ Na]; calcd. 310.16304. Ϫ b) Compound 9 (73 mg,
0.26 mmol) was reduced with LiAlH4 (40 mg) in ether (5 mL) as
above. After 30 min, TLC (ether/methanol, 3:2 with a few drops of
triethylamine) showed the presence of 10. Work-up of the reaction
mixture as above, followed by column chromatography gave 10
(62 mg, 84%).
1-Amino-1,2,3-trideoxy-4,5:6,7-di-O-isopropylidene-β-D-arabino-
oct-4-ulo-4,8-pyranose (8): a) Compound 4 (3.18 g, 11.3 mmol) in
dry methanol (30 mL) containing ammonia was hydrogenated at 5
atm over Raney nickel (8 g) for 24 h. TLC (ether/hexane, 3:2) then
revealed the absence of 7 and the presence of a non-mobile com-
pound. The catalyst was filtered off, washed with methanol and the
filtrate and washings concentrated to a residue that was subjected
to column chromatography (ether/methanol, 5:1 with 0.15 mL of
triethylamine) to afford syrupy 8 (2.63 g, 81%), Rf ϭ 0.22 (ether/
24
25
24
methanol, 3:2 with 0.15 mL of triethylamine). Ϫ [α]D ϭ Ϫ9.5,
25
[α]405 ϭ Ϫ18 (c ϭ 1). Ϫ IR (film): ν˜ ϭ 3382 cmϪ1 (NH2), 1382
and 1373 (CMe2). Ϫ NMR data, see Tables 1Ϫ3. Ϫ HRMS
(LSIMS); m/z: found 310.16313 [Mϩ ϩ Na]; calcd. 310.16304. Ϫ
b) A stirred solution of 7 (120 mg, 0.42 mmol) in anhydrous ether
(5 mL) was treated with LiAlH4 (40 mg). After 30 min, TLC (ether/
methanol, 3:2 with 0.15 mL of triethylamine) then showed the pres-
ence of compound 8. The excess hydride was destroyed by the cau-
tious addition of aqueous 1  sodium hydroxide, the organic phase
was separated and the aqueous layer extracted with ether (5 mL).
(E)-2,3-Dideoxy-L-xylo-oct-2-ene-4-ulo-4,8-pyranosononitrile
(12): A solution of 6a (2 g, 7.1 mmol) in aqueous 70% trifluoro-
acetic acid (20 mL) was heated at 50°C for 1 h. TLC (chloroform/
methanol, 5:1) revealed the presence of a slower running com-
pound. The mixture was concentrated and repeatly codistilled with
water and then toluene. Column chromatography of the residue
(chloroform/methanol, 10:1) gave syrupy 12 (950 mg, 67%). Ϫ IR
(film): ν˜ ϭ 3445 cmϪ1 (OH) and 2235 (CϵN). Ϫ 1H NMR data
The combined extracts were concentrated to a residue that was ([D4]MeOH): δ ϭ 3.13 (d, 1 H, J5,6 ϭ 10.2 Hz, 5-H), 3.48 (dt, 1 H,
chromatographed as above to yield 8 (70 mg, 58%).
7-H), 3.58Ϫ3.72 (m, 3 H, 6,8,8Ј-H), 5.86 (d, 1 H, 2-H), 6.82 (d, 1
H, J2,3 ϭ 16.4 Hz, 3-H). Ϫ For 13C NMR data see Table 3.
2,3-Dideoxy-4,5:6,8-di-O-isopropylidene-α- -xylo-oct-4-ulo-4,7-
L
furanosononitrile (9): A solution of 6 (160 mg, 0.57 mmol) in dry
methanol (5 mL) was hydrogenated at 1 atm in the presence of 10%
(5R,8S,9R,10S)-1-N-Acetyl-8,9,10-triacetoxy-1-aza-6-oxaspiro-
[4.5]decane (16): A solution of 12 (750 mg, 3.73 mmol) in dry meth-
1
Table 1. H-NMR chemical shifts (δ) with multiplicities for compounds 4, 6Ϫ10, and 17Ϫ22
1-H
2-H
3-H
5-H
6-H
7-H
8-H
8Ј-H
CMe2
4a
4b
6a
6b
7
Ϫ
5.89 d
5.53 d
6.03 d
5.51 d
2.61 m
6.65 d
6.40 d
6.74 d
6.50 d
4.14 d
4.59 dd
4.66 dd
4.34 br. d
4.37 br. d
4.54 d
4.22 ddd
4.29 br. d
4.13 dd
4.80 dd
4.18 d
3.87 dd
3.96 dd
3.77 dd
3.86 d
1.54 s, 1.45 s, 1.34 s,
1.32 s
1.64 s, 1.53 s, 1.51 s,
1.38 s
1.51 s, 1.41 s, 1.34 s,
1.33 s
1.56 s, 1.48 s, 1.42 s,
1.36 s
1.49 s, 1.44 s, 1.32 s,
1.31 s
1.51 s, 1.47 s, 1.35 s,
1.33 s
1.47 s, 1.42 s, 1.36 s,
1.34 s
Ϫ
4.24 d
Ϫ
4.30 br. s
4.39 br. s
ǟ 4.06 d Ǟ
ǟ 4.06 d Ǟ
Ϫ
Ϫ
2.16 m, 2.02 m 4.06 s
3.77 d
3.67 d
3.71 d
3.99 d
8
2.83 br. t
Ϫ
ǟ 1.95Ϫ1.70 m Ǟ
4.09 d
4.29 s
4.56 dd
4.27 d
4.20 br. d
4.03 t
3.83 dd
4.06 dd
9
2.66 m
2.30 m
10
2.75 m
ǟ 2.05Ϫ1.71 2 m Ǟ
ǟ 4.25 br. s Ǟ
ǟ 4.04 m Ǟ
4.27 dd
1.47 s, 1.42 s, 1.36 s,
1.34 s
1.51 s, 1.37 s
1.46 s, 1.34 s
1.43 s, 1.32 s
17
18
19
20
21
22
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
2.69 t
2.34 br. t
2.21 m
2.15 t
3.02 dt, 2.90 dt 4.12 s
2.89 dt, 2.80 dt 4.40 d
4.32 s
4.48 s
4.22 s
4.39 br. d
4.10 d
4.12 dd
3.99 d
3.82 d
3.68 d
2.52 m
2.47 m
2.52 t
ǟ 4.40Ϫ4.29 m Ǟ
4.77 d
4.04 d
4.17 t
4.23 d
4.39 dt
4.03 dd
3.96 dd
4.06 dd
3.91 br. s
4.00 br. s
4.32 dt
2.55 t
2.62 m
2.25 t
4.31 s
ǟ 3.57 d Ǟ
1.48 s, 1.34 s
1272
Eur. J. Org. Chem. 1999, 1269Ϫ1274

Synthesis of 4-Octuloses, V
FULL PAPER
anol (20 mL) was hydrogenated at 5 atm in the presence of 10%
1.22). Ϫ IR (KBr): ν˜ ϭ 3430 cmϪ1 (OH) and 2249 (CϵN). Ϫ NMR
Pd-C (370 mg) overnight. The catalyst was collected and washed data, see Tables 1Ϫ3. Ϫ C18H23NO7S (397.43): calcd. C 54.39, H
with methanol, and the combined filtrate and washings were con- 5.83, N 3.53, S 8.07; found C 54.60, H 5.86, N 3.58, S 7.77. A small
centrated. Conventional acetylation of the residue in dry pyridine
(5 mL) with acetic anhydride (2.5 mL) followed by usual work-up
amount (300 mg) of the syrupy 6,8-di-O-p-toluenesulfonyl deriva-
24
tive (19) was also obtained. Ϫ [α]D ϭ ϩ16.3 (c ϭ 1.6). Ϫ IR
of the reaction mixture and column chromatography (ether/hexane,
(film): ν˜ ϭ 2251 cmϪ1 (CϵN), 1599 (aromatic), and 1373 (CMe2).
1
10:1) gave syrupy 16 (100 mg, 8%). Ϫ H NMR ([D4]MeOH): δ ϭ Ϫ NMR data, see Tables 1Ϫ3. Ϫ HRMS (LSIMS); m/z: found
1.97, 2.00 and 2.04 (3 s, 9 H, 3 OAc), 2.12 (s, 3 H, NAc), 2.00Ϫ2.20
(m, 4 H, 3,3Ј,4,4Ј-H), 2.46 (ddd, 1 H, J2Ј,3 ϭ 5.7, J2Ј,3Ј ϭ 8.5 Hz,
2Ј-H), 2.69 (dt, 1 H, J2,3 ϭ J2,3Ј ϭ 9.5, J2,2Ј ϭ 18 Hz, 2-H), 3.92
(dd, 1 H, 7e-H), 5.01 (ddd, 1 H, J7a,8 ϭ 10.8, J7e,8 ϭ 6 Hz, 8-H),
5.09 (d, 1 H, 10-H), 5.42 (t, 1 H, J8,9 ϭ J9,10 ϭ 9.8 Hz, 9-H). Ϫ
13C NMR ([D4] MeOH): δ ϭ 20.58, and 20.63 (3 MeCOO), 27.35
(2-C), 29.86 (3,4-C), 30.89 (MeCON), 61.37 (7-C), 68.62 (8-C),
70.85 (9-C), 71.04 (10-C), 106.11 (5-C),169.71, 169.90, 169.93 and
174.37 (4 Ac). Ϫ C16H23NO8 (357.35): calcd. C 53.77, H 6.49, N
3.92; found C 53.81, H 6.59, N 4.12.
574.11816 [Mϩ ϩ Na]; calcd. 574.11815.
Hydrolysis of 18: A solution of 18 (200 mg, 0.5 mmol) in aqueous
70% trifluoracetic acid (1 mL) was kept at room temperature for
60 h. TLC (ether) revealed a slower running compound. The mix-
ture was neutralized with Na2CO3, concentrated and the residue
was thoroughly extracted with ethyl acetate, then filtered, adsorbed
onto silica gel and chromatographed (ether/methanol, 20:1) to af-
ford firstly 5,8-anhydro-2,3-dideoxy--xylo-oct-4-ulosononitrile
26
24
(20) as a syrup. Ϫ [α]D ϭ ϩ3, [α]405 ϭ ϩ19 (c ϭ 0.4). Ϫ IR
(film): ν˜ ϭ 3459 and 3384 cmϪ1 (OH), 2252 (CϵN), and 1724 (Cϭ
O). Ϫ NMR data, see Tables 1Ϫ3. Ϫ HRMS (LSIMS); m/z: found
208.05859 [Mϩ ϩ Na]; calcd. 208.05858. Eluted secondly was sy-
rupy 5,8-anhydro-2,3-dideoxy--lyxo-oct-4-ulosononitrile (21). Ϫ
2,3-Dideoxy-4,5-O-isopropylidene-α-L-xylo-oct-4-ulo-4,7-furano-
sononitrile (17): A solution of 9 (3.73 g, 13.2 mmol) in 50% aqueous
acetic acid (20 mL) was stirred at room temperature for 24 h. TLC
(ether) then revealed the presence of a slower running product. The
mixture was neutralized with solid sodium carbonate, concentrated,
extracted with dichloromethane and the combined extracts were
concentrated. Column chromatography (ether/hexane, 4:1) of the
residue gave crystalline 17 (2.47 g, 77%). Ϫ M.p. 103Ϫ104°C (from
25
[α]D ϭ Ϫ61 (c ϭ 0.54). Ϫ IR (film): ν˜ ϭ 3446 and 3395 cmϪ1
(OH), 2251 (CϵN), 1733 and 1720 (CϭO). Ϫ NMR data, see
Tables 1Ϫ3. Ϫ HRMS (LSIMS); m/z: found 208.058557 [Mϩ
ϩ
Na]; calcd. 208.058578. Ϫ The same results were obtained when
hydrolysis was performed with 80% aqueous acetic acid at 80°C
for 13 h.
24
ether). Ϫ [α]D ϭ ϩ17 (c ϭ 1).Ϫ IR (KBr): ν˜ ϭ 3323 cmϪ1 (OH),
2251 (CϵN), 1383 and 1375 (CMe2). Ϫ NMR data, see Tables
1Ϫ3. Ϫ C11H17NO5 (243.26): calcd. C 54.31, H 7.04, N 5.76; found
C 54.20, H 7.17, N 5.86.
8-Azido-2,3,8-trideoxy-4,5-O-isopropylidene-α-L-xylo-oct-4-ulo-
4,7-furanosononitrile (22): To a stirred solution of 18 (2 g, 5 mmol)
in dry DMF (15 mL), NaN3 (1 g, 15.4 mmol) was added and the
mixture heated at 90°C for 5 h. TLC (ether) revealed the presence
of a faster running compound. The reaction mixture was concen-
trated, diluted with water (30 mL) and extracted with ether (4 ϫ
25 mL). The combined extracts were washed with brine, then water
and concentrated to a residue that was chromatographed (ether/
2,3-Dideoxy-4,5-O-isopropylidene-8-O-p-toluenesulfonyl-␣-L-xylo-
oct-4-ulo-4,7-furanosononitrile (18): To a stirred solution of 17
(2.34 g, 9.62 mmol), Et3N (3.2 mL, 23 mmol), and DMAP (50 mg),
in dry dichloromethane (40 mL), p-toluenesulfonyl chloride (2.75 g,
14.4 mmol) was added portionwise, and the mixture kept at room
temperature for 24 h. TLC (ether) revealed the presence of a faster
running product. Methanol (10 mL) was then added to the reaction
mixture and after 3 h, the mixture was concentrated. The residue
was partitioned in ether/water, the organic phase was separated and
the aqueous phase extracted with ether (3 ϫ 20 ml). Concentration
of the organic extracts followed by column chromatography (ether/
hexane, 1:2) of the residue gave crystalline 18 (3.16 g, 83%). Ϫ M.p.
24
hexane, 1:2) to afford syrupy 22 (1.19 g, 88%). Ϫ [α]D ϭ ϩ22.5
(c ϭ 1.5). Ϫ IR (KBr): ν˜ ϭ 3456 cmϪ1 (OH), 2252 (CϵN), and
2106 (N3). Ϫ NMR data, see Tables 1Ϫ3. Ϫ HRMS (LSIMS); m/z:
found 291.107085 [Mϩ ϩ Na]; calcd. 291.106925.
(6S,7R,8R,8aR)-6,7,8-Trihydroxyindolizidine (1-Deoxycastanosper-
mine) (11): A solution of 22 (1.1 g, 4.1 mmol) in aqueous 50% tri-
fluoroacetic acid (10 mL) was stirred at room temperature for 24 h.
TLC (ether) showed the presence of a slightly moving compound.
Work-up of the reaction mixture as above gave after column chro-
24
24
119Ϫ120°C (from ether). Ϫ [α]D ϭ ϩ0.6, [α]405 ϭ Ϫ6.5 (c ϭ
1
Table 2. H-NMR coupling consants (J) in Hz for compounds 4,
matography (chloroform/methanol, 35:1) 8-azido-2,3,8-trideoxy--
26
6Ϫ10, and 17Ϫ22
xylo-4-octulosononitrile (23, 805 mg, 86%) as a syrup. Ϫ [α]D
ϭ
Ϫ9.7 (c ϭ 0.45). Ϫ IR (film): ν˜ ϭ 3419 cmϪ1 (OH), 2254 (CϵN),
2109 (N3), and 1724 (CϭO). Ϫ 13C NMR ([D4]MeOH): δ ϭ 11.64
(2-C, α-f), 12.11 (2-C, β-f), 12.46 (2-C, keto form), 31.67 (3-C, keto
form), 35.26 (3-C, α-f), 35.94 (3-C, β-f), 52.01 (8-C, β-f), 52.45 (8-
C, α-f), 54.51 (8-C, keto form), 72.05, 73.92, 77.23, 77.81, 78.32,
80.77, 81.09 and 81.63 (5,6,7-C, α-f, β-f and keto form), 102.73 (4-
C, β-f), 107.62 (4-C, α-f), 120.82 (1-C, keto form), 121.40 and
121.46 (1-C, α-f and β-f), 210.39 (C-4, keto form). Ϫ HRMS
(LSIMS); m/z: found 251.075588 [Mϩ ϩ Na]; calcd. 251.075625.
Ϫ Compound 23 (650 mg, 2.85 mmol) in aqueous 20% acetic acid
(25 mL) containing NaOAc (1 g) was hydrogenated at 4 atm in the
presence of 10% Pd-C (100 mg) for 15 h to afford the title com-
pound (11, 285 mg, 58%) as white needles. Ϫ M.p. 179Ϫ180°C
(dec.) (ref.[11] m.p. 178Ϫ181°C). Ϫ [α]D29 ϭ ϩ50 (c ϭ 1.2, MeOH)
J1,2
J2,3
J5,6
J6,7
J7,8
J7,8Ј J8,8Ј
4a
4b
6a
6b
7
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
6.8
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
16.1 2.6
11.8 2.6
16.0 0.0
11.8 0.0
Ϫ
Ϫ
Ϫ
Ϫ
7.0
Ϫ
7.6
6.8
6.8
7.7
7.9
7.9
2.4
2.3
8.0
7.9
2.1
Ϫ
0.0
Ϫ
2.8
0.0
0.0
2.7
1.9
1.7
0.7
0.0
13
13
ǟ 1.8 Ǟ
ǟ 1.9 Ǟ
0.0
0.0
13
0.0
2.5
0.0
Ϫ
0.0
Ϫ
0.0
0.0
3.9
0.0
0.0
1.8
2.1
Ϫ
3.4
Ϫ
6.3
3.1
3.3
0.0
0.0
0.0
Ϫ
8
13
9
13.3
10
17
18
19
20[a]
21[b]
22
Ϫ
0.0
4.9
5.9
0.0
0.0
12
9.5
11
9.1
9.1
0.0
ǟ 6.1 Ǟ
29
{ref.[11] [α]D ϭ ϩ50.6 (c ϭ 0.2, MeOH)}. Ϫ IR (KBr): ν˜ ϭ 3379
and 3265 cmϪ1 (NH and OH). Ϫ 1H NMR ([D4]MeOH) (inter
alia): δ ϭ 2.01 (t, 1 H, J5α,5β ϭ J5α,6 ϭ 10.5 Hz, 5α-H), 2.23 (q, 1
[a] J
[b] J
ϭ 19, J6,OH ϭ 4, J7,OH ϭ 2.5 Hz. Ϫ
4.5, J7,OH ϭ 3.3 Hz.
ϭ 18.7, J6,OH ϭ
3,3Ј
3,3Ј
Eur. J. Org. Chem. 1999, 1269Ϫ1274
1273

´
´
I. Izquierdo, M. T. Plaza, R. Robles, C. Rodrıguez, A. Ramırez, A. J. Mota
FULL PAPER
Table 3. 13C-NMR data for compounds 4, 6Ϫ10, 12, and 17Ϫ22
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
CMe2
CMe2
4a
4b
6a
6b
7
116.60
115.16
116.64
115.17
120.03
42.36
101.86
99.80
102.93
100.28
11.60
27.38
12.50
35.07
151.93
148.95
150.47
147.95
36.80
100.59
100.67
113.23
114.04
102.11
103.96
113.33
115.49
73.18
73.31
87.72
88.27
73.62
73.70
86.60
86.53
69.80
69.72
73.40
73.54
70.22
70.51
73.47
73.67
70.21
70.20
73.05
73.22
70.51
70.73
72.29
71.95
61.50
61.34
60.21
60.17
61.05
60.84
60.30
60.48
109.43,
109.38
110.03,
109.24
111.18,
97.62
26.15, 25.91,
24.77, 24.11
26.66, 25.82,
24.61, 24.10
27.04, 26.16,
29.05, 18.59
27.25, 26.11,
28.94, 18.76
26.20, 25.83,
24.86, 23.98
26.34, 25.77,
25.08, 24.00
27.25, 26.46,
28.95, 18.67
27.52, 26.77,
28.99, 18.77
111.38,
97.56
108.98,
108.09
108.77,
107.35
111.58,
97.53
8
38.06
9
119.96
42.04
33.98
10
34.94
111.03,
97.35
12
17
18
19
20
21
22
118.04
120.91
119.86
119.18
120.26
120.30
119.96
102.15
12.45
12.16
11.97
10.52
10.36
12.26
154.82
33.81
33.56
33.66
33.78
35.40
33.87
96.93
75.58
87.51
86.84
84.83
89.79
85.81
87.15
71.18
79.44
78.42
81.25
80.63
78.02
79.32
75.52
77.23
74.16
76.80
74.95
76.24
75.16
63.54
61.43
66.53
65.80
74.17
74.20
49.28
113.21
113.33
113.11
209.02
207.07
113.17
111.57
111.97
112.91
27.21, 26.34
27.19, 26.36
26.94, 26.43
111.91
27.24, 26.42
Mason, P. C. Tyler, O. Hartley, B. G. Winchester, Tetrahedron
1997, 53, 245Ϫ268, and references therein.
H, J3α,3β ϭ J2α,3α ϭ J2β,3α ϭ 9 Hz, 3α-H), 3.02 (dt, 1 H, 3β-H),
3.12 (dd, 1 H, J5β,6 ϭ 5.2 Hz, 5β-H), 3.58 (ddd, 1 H, J6,7 ϭ 9.2 Hz,
6-H). Ϫ 13C NMR ([D4]MeOH): δ ϭ 22.67 (1-C), 29.14 (2-C),
54.51 (3-C), 57.40 (5-C), 69.24 (8a-C), 72.06 (6-C), 76.43 (8-C),
[3]
I. Izquierdo, M.-T. Plaza, R. Robles, A. J. Mota, Tetrahedron:
Asymmetry 1998, 9, 1015Ϫ1027.
[4]
[5]
[6]
I. Izquierdo, M.-T. Plaza, Carbohydr. Res. 1990, 205, 293Ϫ304.
G. P. Schiemenz, H. Engelhard, Chem. Ber. 1961, 94, 578Ϫ585.
I. Izquierdo, M.-T. Plaza, N. Kari, Carbohydr. Res. 1994, 261,
231Ϫ242.
80.81 (7-C). Ϫ HRMS (LSIMS); m/z: found 196.094987 [Mϩ
ϩ
Na]; calcd. 196.094963.
[7]
[8]
I. Izquierdo, M.-T. Plaza, Carbohydr. Res. 1988, 173, 41Ϫ52.
K. L. Aamlid, L. Hough, and A. C. Richardson, Carbohydr.
Res. 1990, 202, 117Ϫ129.
Acknowledgments
[9a] L. Mandell, J. U. Piper, K. P. Singh, J. Org. Chem. 1963, 28,
[9]
[9b]
3440Ϫ3442. Ϫ
L. Mandell, K. P. Singh, J. T. Greshem, W.
´
This work was supported by the Ministerio de Educacion y Cultura
J. Freeman, J. Am. Chem. Soc. 1965, 87, 5234Ϫ5236.
[10] [10a]
(Spain) (Project PB95-1157) and, in part, by a grant (to A. J. M.)
C. H. von der Osten, A. J. Sinskey, C. F. Barbas, III, R. L.
Pederson, Y.-F. Wang, C.-H. Wong, J. Am. Chem. Soc. 1989,
´
´
from the Fundacion Ramon Areces (Spain).
[10b]
111, 3924Ϫ3927. Ϫ
T. Kajimoto, L. Chen, K. K.-C. Liu,
C.-H. Wong, J. Am. Chem. Soc. 1991, 113, 6678Ϫ6680.
D. Hendry, L. Hough, A. C. Richardson, Tetrahedron 1988,
44, 6143Ϫ6152.
[1]
[11]
I. Izquierdo, M.-T. Plaza, R. Robles, A. J. Mota, Tetrahedron:
Asymmetry 1997, 8, 2597Ϫ2606.
[2]
For a review, see e. g.: J. Cossy, P. Vogel, Stud. Nat. Prod. Chem.
1993, 12, 275Ϫ363. Ϫ R. H. Furneaux, G. J. Gainsford, J. M.
Received October 9, 1998
[O98452]
1274
Eur. J. Org. Chem. 1999, 1269Ϫ1274