Trimethylsilyltriflate-promoted addition of 2-trimethylsilyloxyfuran to a chiral cyclic nitrone; a short synthesis of [1S(1α,2β,7β,8α,8aα)]-1,2- di(t-butyldiphenylsilyloxy)-indolizidine-7,8-diol

Article abstract of DOI:10.1016/S0040-4020(99)01001-7

The trimethylsilyl triflate promoted addition of 2- trimethylsilyloxyfuran to (3S,4S)-3,4-dihydro-3,4-di(t- butyldiphenylsilyloxy)2H-pyrrole 1-oxide, derived from (R,R)-tartaric acid, displays complete facial selectivity, affording two diastereomeric butenolides in excellent overall yield. The major adduct undergoes silica-gel induced ring-closure to give in almost quantitative yield [4S(4α,5β,5aβ,5bα,8aα)]-hexahydro-4,5-di(t-butyldiphenylsilyloxy)- pyrrolo [1,2-b]furo[2,3d] isoxazol-7(3H)one; reduction with DIBAH followed by hydrogenolysis on Pd(OH)₂/C affords the partially protected 1,2,7,8- indolizidinetetrol.

Full text of DOI:10.1016/S0040-4020(99)01001-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 323–326
Trimethylsilyltriflate-Promoted Addition of
2-Trimethylsilyloxyfuran to a Chiral Cyclic Nitrone;
a Short Synthesis of [1S(1a,2b,7b,8a,8aa)]-
1,2-Di(t-butyldiphenylsilyloxy)-indolizidine-7,8-diol
*
*
Marco Lombardo and Claudio Trombini
`
Dipartimento di Chimica ‘G. Ciamician’, Universita di Bologna, via Selmi 2, I-40126 Bologna, Italy
Received 7 September 1999; revised 15 October 1999; accepted 4 November 1999
Abstract—The trimethylsilyl triflate promoted addition of 2-trimethylsilyloxyfuran to (3S,4S)-3,4-dihydro-3,4-di(t-butyldiphenylsilyloxy)-
2H-pyrrole 1-oxide, derived from (R,R)-tartaric acid, displays complete facial selectivity, affording two diastereomeric butenolides in
excellent overall yield. The major adduct undergoes silica-gel induced ring-closure to give in almost quantitative yield [4S(4a,5b,5ab,5-
ba,8aa)]-hexahydro-4,5-di(t-butyldiphenylsilyloxy)-pyrrolo [1,2-b]furo[2,3d] isoxazol-7(3H)one; reduction with DIBAH followed by
hydrogenolysis on Pd(OH)2/C affords the partially protected 1,2,7,8-indolizidinetetrol. ᭧ 1999 Elsevier Science Ltd. All rights reserved.
Glycosidases and glycosyltransferases are widespread
enzymes present in almost all organisms. They are essential
for the processing of oligo- and polysaccharides and
complex carbohydrates such as glycolipids and glyco-
proteins.1 The inhibition of this family of hydrolases repre-
sents a powerful solution on the one hand to control obesity,
diabetes and other metabolic disorders,2 and on the other
hand to block infection, inflammation and metastasis by
preventing the biogenesis of membrane glycoproteins in
fungi, bacteria and viruses.3 A number of polyhydroxylated
piperidines, pyrrolidines, indolizidines and pyrrolizidines,
isolated from natural sources, are powerful and specific
inhibitors of a- and b-glycosidases, and an even larger
number of isomers and congeners have been synthesised
and assayed for biological activity. A few of them display
outstanding inhibition levels.4 Among polyhydroxylated
indolizidine alkaloids, besides naturally occurring lentigino-
sine, swainsonine and castanospermine (Fig. 1), a number of
stereoisomers and analogues have been synthesised and
tested in order to get information on structure–activity rela-
tionships.5 For example, among 1,2,7,8-indolizidinetetrols,
the stereoisomers 1a,6 1b7 and 1c7 have been synthesised
and tested for biological activity.
Here we propose
a
route to the skeleton of
[1S(1a,2b,7b,8a,8aa)]-1,2,7,8-indolizidinetetrol (1d) and
of ent-1d by applying to a chiral cyclic five-membered
ring nitrone deriving from tartaric acid, an efficient
protocol previously developed by us for the synthesis
of 2-substituted 3,4-piperidinediols starting from aldoni-
trones (Scheme 1).8
The key reaction is the trimethylsilyl triflate (TMSOTf)-
catalysed condensation of 2-trimethylsilyloxyfuran with
an aldonitrone 2 to give an intermediate butenolide 3,
which, in the presence of fluoride, undergoes cyclisation
to 4.9 These bicyclic compounds are successfully
transformed into piperidines 6 in a two-reductive step
sequence involving DIBAH reduction to lactol 5 and,
finally, hydrogenolysis to the target piperidine.8
Five-membered cyclic nitrones derived from tartaric acid10
have been successfully manipulated to indolizidines by
Brandi11 and Wightman12 exploiting 1,3-dipolar cyclo-
addition reactions. The results obtained by applying our
preceding protocol to nitrone 2a are summarised in
Scheme 2.
Condensation of 2a and 2-trimethylsilyloxyfuran in the
presence of TMSOTf (10%) in dichloromethane at Ϫ20ЊC
displayed complete facial selectivity and afforded buteno-
lides 3a and 3b possessing the 20S,5S and 20S,5R absolute
stereochemistry, respectively, in 82/18 ratio and in 71%
overall yield. Bulky t-butyldiphenylsilyl protecting group
(TBDPS) in 2a proved to be an optimum choice forcing
the nucleophilic attack of 2-trimethylsilyloxyfuran only on
Keywords: 2-trimethylsilyloxyfuran; (3S,4S)-3,4-dihydro-3,4-di(t-butyldi-
phenylsilyloxy)-2H-pyrrole 1-oxide; [4S(4a,5b,5ab,5ba,8aa)]-hexa-
hydro-4,5-di(t-butyldiphenylsilyloxy)-pyrrolo [1,2-b]furo[2,3-d] isoxazol-
7(3H)one.
* Corresponding authors. Tel.: ϩ51-2099513; fax: ϩ51-2099456; e-mail:
marlom@ciam.unibo.it; trombini@ciam.unibo.it
0040–4020/00/$ - see front matter ᭧ 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01001-7

324
M. Lombardo, C. Trombini / Tetrahedron 56 (2000) 323–326
Figure 1.
Figure 2.
the less encumbered si face of the nitrone 2a. Formation of
the 20S,5S relationship is favoured (d.e. 64%) according to
synclinal approach A in Fig. 2, which involves the re face of
2-trimethylsilyloxyfuran. Anti approach B is disfavoured
both by unfavourable dipolar interactions and by oxygen
atoms lone pairs repulsion. Butenolides 3a and 3b were
easily separated by silica-gel flash-chromatography and
treated with diluted trifluoroacetic acid (TFA) in order to
remove the trimethylsilyl group chemoselectively. Silica-
gel chromatographic purification of the crude residue led,
in one case, to complete cyclisation to 4a, as we observed
previously on simple aldonitrones,9a in the other case to the
almost quantitative recovery of 7b. The absence of the
corresponding tricyclic product deriving from 3b was
probably due to steric compression in the cis–syn–cis
triquinane-type nucleus. Such a dramatically different
behaviour allowed us to develop a shorter and more efficient
procedure for the synthesis of 4a; after condensation of
2-trimethylsilyloxyfuran with 2a, the crude reaction mixture
was directly treated with dilute aqueous TFA, then, after
water extraction and solvent concentration, the residue
was eluted through a silica-gel column affording 4a (56%)
and 7b (12%).
Scheme 1.
Transformation of the hexahydropyrrolo[1,2-b]furo[2,3-d]-
isoxazol-7(3H)one ring system of 4a into an indolizidine
was easily accomplished via DIBAH reduction of 4a to 5a
followed by hydrogenolysis of 5a in the presence
of Pd(OH)2. The N–O bond cleavage was followed
by spontaneous intramolecular reductive amination
to [1S(1a,2b,7b,8a,8aa)]-1,2-di(t-butyldiphenylsilyloxy)-
indolizidine-7,8-diol (6a).
Regioselectively protected 6a offers interesting opportu-
nities since it allows the hydroxyl groups to be orthogonally
manipulated to generate further stereoisomers.
Scheme 2.

M. Lombardo, C. Trombini / Tetrahedron 56 (2000) 323–326
325
Experimental
[4S(4a,5b,5ab,5ba,8aa)]-Hexahydro-4,5-di(t-butyl-
diphenylsilyloxy)-pyrrolo[1,2-b]furo[2,3-d] isoxazol-
7(3H)one (4a). 0.65 M Trifluoroacetic acid in H2O
(0.23 mL, 0.15 mmol) was added to a solution of 3a
(0.18 g, 0.23 mmol) in CH2Cl2 (2 mL). The reaction mixture
was stirred at room temperature for 45 min, then quenched
with aq. NaHCO3 and extracted with CH2Cl2 ꢀ3×5 mL†: The
combined organic layers were dried (Na2SO4) and solvent
was evaporated to dryness. Chromatography of the residue
on silica gel using cyclohexane/ethyl acetate (95/5) yielded
0.144 g (92%) of pure 4a: [a]2D2ˆϩ46.0 (cˆ0.20 in CHCl3);
1H NMR (CDCl3) d 0.93 (s, 9H, SitBu), 0.96 (s, 9H, SitBu),
2.58 (dd, Jˆ4.8/18.6 Hz, 1H, H-8), 2.66 (br dd, JϷ0.9/
18.6 Hz, 1H, H-8), 3.11 (br dd, JϷ0.6/14.7 Hz, 1H, H-3),
3.66 (dd, Jˆ4.2/14.7 Hz, 1H, H-3), 3.86 (br s, 1H, H-5a),
4.22–4.28 (m, 2H, H-4ϩH-5), 4.77 (br dd, JϷ1.6/4.5 Hz,
1H, H-5b), 4.92 (m, 1H, H-8a; upon irradiation of H-8 the
signal collapses into a doublet with Jˆ4.5 Hz), 7.22–7.58
(m, 20H, ArH); 13C NMR (CDCl3) d14.2 (C-8), 19.1
(SiCMe3), 26.8 (SiCMe3), 27.0 (SiCMe3), 34.0 (C-3), 63.9
(C-5a), 78.2, 78.3, 79.1, 81.3, (C-4, C-5, C-5b, C-8a), 127.8,
127.9, 128.0, 130.0 (Cquat), 130.2 (Cquat), 131.9 (Cquat),
132.3 (Cquat), 135.5, 135.6, 173.5 (CyO). Anal. Calcd. for
C40H47NO5Si2: C, 70.86; H, 6.99; N, 2.07. Found: C, 70.95;
H, 6.91; N, 2.16.
General
1H NMR and 13C NMR spectra in deuterated solvents
were recorded at 300 and 75 MHz, respectively, using a
Varian Gemini 300 spectrometer. Chemical shifts are
reported in ppm relative to internal standard Me4Si.
Optical rotations were measured on a Perkin–Elmer
241 polarimeter. Water content of anhydrous solvents
used was measured with a Karl-Fisher titrator Mettler
DL18. Reactions were performed in oven-dried glass-
ware under argon. Hydrogenations were performed at
45 psi on a Parr apparatus. 2-Trimethylsilyloxyfuran
and moist 20% Pd(OH)2 on carbon (Degussa type
E101) were purchased from Aldrich. Nitrone 2a was
synthesised from (R,R)-tartaric acid diethyl ester accord-
ing to the procedure reported by Brandi et al.11 Melting
points are uncorrected.
5-[10-Trimethylsilyloxy-30,40-di(t-butyldiphenylsilyloxy)-
20-pyrrolidinyl]-2(5H)-furanones (3a, 3b). 2-Trimethyl-
silyloxyfuran (0.19 mL, 1.1 mmol) was added to a solution
of 2a (0.6 g, 1 mmol) in CH2Cl2 (2 mL) and the solution was
cooled to Ϫ20ЊC. TMSOTf (0.018 mL, 0.1 mmol) was
added and the reaction mixture was stirred at Ϫ20ЊC for
1.5 h. The reaction was quenched with aq. NaHCO3 and
extracted with CH2Cl2 ꢀ3×5 mL†: Silica gel was directly
added to the combined organic layers and the solvent was
evaporated at reduced pressure. The solid residue was
loaded on a silica gel column. Elution with cyclohexane/
ethyl acetate (95/5) afforded 0.43 g (58%) of 3a as a white
solid and 0.1 g (13%) of 3b as an oil.
H-5a/H-5b trans and a H-5a/H-5 trans stereorelationships
were assigned on the basis of n.O.e. measurements. Upon
irradiation of H-5a, similar enhancements for both H-5b
(3.0%) and H-5 (4.6%) were observed; moreover, irradia-
tion of H-5b caused a strong enhancement of H-5 (10.5%)
and a smaller response of H-5a (4.7%).
[20,S-[20a,30a,40b(5S*)]]-5-[10-Hydroxy-30,40-di(t-butyl-
diphenylsilyloxy)-20-pyrrolidinyl]-2(5H)-furanone (7b).
TFA treatment of 3b followed by silica gel chromatography
brought about the chemoselective deprotection of the
trimethylsilyl group affording 7b in almost quantitative
[20S-[20a,30a,40b(5Rء)]]-3a: m.p. 98–100ЊC; [a]2D2ˆ
1
Ϫ11.0 (cˆ0.21 in CHCl3); H NMR (CDCl3) d 0.07 (s,
9H, SiMe3), 0.93 (s, 9H, SitBu), 0.97 (s, 9H, SitBu), 2.95
(dd, Jˆ4.2/11.0 Hz, 1H, H-50), 3.01 (br d, Jˆ11.0 Hz, 1H,
H-50), 3.19 (br dd, JϷ1.5/6.0 Hz, 1H, H-20), 4.20–4.30 (m,
2H, H-30ϩH-40), 4.99 (dt, Jˆ2.0/6.0 Hz, 1H, H-5), 5.87 (dd,
Jˆ2.0/5.5 Hz, 1H, H-3), 7.20–7.62 (m, 21H, ArHϩH-4);
13C NMR (CDCl3) d Ϫ0.3 (SiCH3), 19.0 (SiCMe3), 19.1
(SiCMe3), 26.7 (SiCMe3), 26.8 (SiCMe3), 64.8 (C-50),
78.4, 78.9, 79.5, 81.9 (C-5, C-20, C-30, C-40), 121.7 (C-3),
127.6, 127.7, 128.0, 129.6, 129.7, 129.8, 129.9, 132.8
(Cquat), 133.0 (Cquat), 133.1 (Cquat), 133.6 (Cquat),
135.7, 135.8, 154.7 (C-4), 172.6 (CyO). Anal. Calcd. for
C43H55NO5Si3: C, 68.85; H, 7.39; N, 1.87. Found: C, 68.53;
H, 7.42; N, 1.85.
1
yield. [a]2D2ˆϩ21.9 (cˆ0.62 in CHCl3); H NMR (CDCl3)
d 0.93 (s, 9H, SitBu), 0.97 (s, 9H, SitBu), 3.12 (dd, Jˆ3.6/
10.5 Hz, 1H, H-50), 3.16-3.26 (m, 2H, H-50ϩH-20), 3.98–
4.05 (m, 1H, H-40), 4.20 (dd, Jˆ1.5/3.0 Hz, 1H, H-30), 4.83
(ddd, Jˆ1.5/2.1/6.6 Hz, 1H, H-5), 5.86 (dd, Jˆ2.1/5.7 Hz,
1H, H-3), 6.81 (dd, Jˆ1.5/5.7 Hz, 1H, H-4), 7.20–7.70 (m,
20H, ArH); 13C NMR (CDCl3) d 19.0 (SiCMe3), 19.1
(SiCMe3), 26.8 (SiCMe3), 62.8 (C-50), 77.8, 78.4, 78.8,
83.1 (C-5, C-20, C-30, C-40), 121.8 (C-3), 127.6, 127.7,
127.8, 127.9, 129.8, 129.9, 130.0, 132.6 (Cquat), 132.7
(Cquat), 132.9 (Cquat), 133.4 (Cquat), 135.58, 135.63,
135.9, 154.2 (C-4), 172.7 (CyO). Anal. Calcd. for
C40H47NO5Si2: C, 70.86; H, 6.99; N, 2.07. Found: C,
70.94; H, 7.10; N, 2.11.
[20S-[20a,30a,40b(5Sء)]]-3b: [a]2D2ˆϩ2.0 (cˆ0.11 in
1
CHCl3); H NMR (CDCl3) d 0.13 (s, 9H, SiMe3), 0.87
(s, 9H, SitBu), 0.97 (s, 9H, SitBu), 2.99–3.03 (m, 2H,
H-50), 3.58–3.64 (m, 1H, H-20), 3.80–3.97 (m, 1H,
CHOSi), 4.02–4.08 (m, 1H, CHOSi), 5.06 (dt, Jˆ2.0/
5.1 Hz, 1H, H-5), 5.92 (dd, Jˆ2.0/7.8 Hz, 1H, H-3), 7.10–
7.70 (m, 21H, ArHϩH-4); 13C NMR (CDCl3) d Ϫ0.17
(SiCH3), 19.0 (SiCMe3), 19.1 (SiCMe3), 26.8 (SiCMe3),
63.7 (C-50), 77.6, 77.9, 78.1, 82.1 (C-5, C-20, C-30, C-40),
122.0 (C-3), 127.7, 127.9, 129.6, 129.8, 129.9, 132.1, 132.2,
133.2, 133.9, 135.5, 135.7, 135.9, 155.5 (C-4), 172.5
(CyO). Anal. Calcd. for C43H55NO5Si3: C, 68.85; H, 7.39;
N, 1.87. Found: C, 68.66; H, 7.44; N, 1.83.
[1S(1a,2b,7b,8a,8aa)]-1,2-di(t-butyldiphenylsilyloxy)-
indolizidine-7,8-diol (6a). 1 M DIBAH in hexane
(0.55 mL, 0.55 mmol) was added dropwise at Ϫ78ЊC to a
solution of 4a (0.24 g, 0.35 mmol) in anhydrous diethyl
ether (8 mL). The reaction mixture was stirred for 4 h at
Ϫ78ЊC and then quenched with ice. Seignette salt was
added in order to dissolve aluminum salts and, after stirring
for 1 h, the solution was carefully extracted with Et2O. The
combined organic layers were dried (Na2SO4) and evapo-
rated under reduced pressure. The residue was filtered

326
M. Lombardo, C. Trombini / Tetrahedron 56 (2000) 323–326
W.; Ducep, J.-B.; Kastner, P. R.; Marshall, F. N.; Danzin, C.
Diabetes 1991, 40, 825.
affording 0.16 g (67%) of crude 5a as a mixture of epimers
at C-7: 1H NMR (CDCl3) two broad triplets at d 5.63 and d
4.90 with JϷ4.0 Hz, due to H-7; 13C NMR (CDCl3) d 89.9
and 98.9 (C-7).
3. (a) Elbein, A. D. Ann. Rev. Biochem. 1987, 56, 497. (b) Taylor,
D. L.; Nash, R.; Fellows, L. E.; Kang, M. S.; Tyms, A. S. Antiviral
Chem. Chemother. 1992, 3, 273. (c) Taylor, D. L.; Kang, M. S.;
Brennan, T. M.; Bridges, C. G.; Sunkara, P. S.; Tyms, A. S.
Antimicrob. Agents Chemother. 1994, 38, 1780. (d) Gross, P. E.;
Baker, M. A.; Carver, J. P.; Dennis, J. W. Clinical Cancer Res.
1995, 1, 935.
4. (a) Wong, C.-H.; Halcomb, R. L.; Ichihawa, Y.; Kajimoto, T.
Angew. Chem. Int. Ed. Engl. 1995, 34, 521. (b) Bols, M. Acc.
Chem. Res. 1998, 31, 1.
Crude lactol 5a (0.16 g, 0.24 mmol) and 20% Pd(OH)2 on
carbon (0.035 g) in anhydrous methanol (10 mL) was
hydrogenated for 12 h at 45 psi. The solution was filtered
over Celite and the solvent was removed at reduced pres-
sure. The residue was purified by flash-chromatography on
silica gel using cyclohexane/ethyl acetate (95/5) yielding 6a
(0.106 g, 66%) as a viscous oil: [a]2D2ˆϩ8.4 (cˆ0.62 in
1
´
5. (a) Carretero, J. C.; Arrayas, R. G. J. Org. Chem. 1998, 63, 2993
CHCl3); H NMR (CDCl3) d 0.89 (s, 9H, SitBu), 1.06
and references quoted therein. (b) Burgess, K.; Henderson, I.
Tetrahedron 1992, 48, 4045.
(s, 9H, SitBu), 1.61 (br dq, JϷ5.1/12.6 Hz, 1H, H-6),
1.78–1.86 (m, 1H, H-6), 1.97–2.11 (m, 2H, H-5ϩH-8a),
2.18 (dd, Jˆ5.4/9.9 Hz, 1H, H-3), 2.56–2.62 (m, 1H,
H-5), 2.63 (d, Jˆ9.9 Hz, 1H, H-3), 3.24–3.35 (m, 2H,
H-7ϩH-8), 4.29 (d, Jˆ5.1 Hz, 1H, CHOSi), 4.39 (d,
Jˆ5.1 Hz, 1H, CHOSi), 7.27–7.78 (m, 20H, ArH); 13C
NMR (CDCl3, APT) d 19.1 (SiCMe3), 19.2 (SiCMe3),
26.7 (SiCMe3), 27.0 (SiCMe3), 31.0 (C-6), 47.9 (C-5),
59.0 (C-3), 73.5, 74.8, 76.4, 81.0, 85.8, (C-1, C-2, C-7,
C-8, C-8a), 127.2, 127.5, 127.6, 127.7, 129.3, 129.5,
129.7, 129.8, 133.4 (Cquat), 133.5 (Cquat), 133.6 (Cquat),
134.7 (Cquat), 135.6, 135.9. Anal. Calcd. for C40H51NO4Si2:
C, 72.14; H, 7.72; N, 2.10. Found: C, 72.18; H, 7.65; N,
2.13.
6. Furneaux, R. H.; Gainsford, G. J.; Mason, J. M.; Tyler, P. C.;
Hartley, O.; Winchester, B. G. Tetrahedron 1995, 51, 12611.
7. Davis, B.; Bell, A. A.; Nash, R. J.; Watson, A. A.; Griffiths, R.
C.; Jones, M. G.; Smith, C.; Fleet, G. W. J. Tetrahedron Lett. 1996,
37, 8565.
8. Degiorgis, F.; Lombardo, M.; Trombini, C. Synthesis 1997,
1243. See also Degiorgis, F.; Lombardo, M.; Trombini, C. Org.
Prep. Proced. Int. 1997, 29, 485.
9. (a) Camiletti, C.; Poletti, L.; Trombini, C. J. Org. Chem. 1994,
59, 6843. (b) Castellari, C.; Lombardo, M.; Pietropaolo, G.; Trom-
bini, C. Tetrahedron: Asymmetry 1996, 7, 1059. (c) Degiorgis, F.;
Lombardo, M.; Trombini, C. Tetrahedron 1997, 53, 11721.
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57, 1316. (b) Cicchi, S.; Hold, I.; Brandi, A. J. Org. Chem. 1993,
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Acknowledgements
11. (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti,
A.; Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806. (b) Goti,
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A. Tetrahedron Lett. 1997, 38, 8097. (e) Cicchi, S.; Numes, Jr., J.;
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Valenza, S.; Picasso, S.; Goti, A.; Brandi, A. J. Org. Chem. 1998,
63, 7311.
The authors thank M.U.R.S.T.—Rome (National Project
‘Stereoselezione in Sintesi Organica. Metodologie
e
Applicazioni’) and University of Bologna (funds for
selected topics) for financial support.
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