Creation of quaternary stereocentres: Synthesis of new polyhydroxylated indolizidines

Article abstract of DOI:10.1016/j.tetasy.2005.11.017

(6R,7S,8aR)- and (6S,7R,8aR)-8a-tert-butyldimethylsilyloxymethyl-6,7- dihydroxy-indolizidin-3-ones 14 and 15 were synthesized from bicyclic silyloxypyrrole 2 by the selective formation of a quaternary stereogenic centre and a ring-closing metathesis as th

Full text of DOI:10.1016/j.tetasy.2005.11.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 53–60
Creation of quaternary stereocentres: synthesis of new
polyhydroxylated indolizidines
a,
a
a
b
*
Nicole Langlois, Bao Khanh Le Nguyen, Pascal Retailleau, C e´ line Tarnus and
b
Emmanuel Salomon
a
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Laboratoire de Chimie Organique et Bioorganique, Ecole Nationale Sup e´ rieure de Mulhouse, Universit e´ de Haute Alsace, 3,
rue Alfred Werner, F-68093 Mulhouse C e´ dex, France
b
Received 10 October 2005; accepted 17 November 2005
Abstract—(6R,7S,8aR)- and (6S,7R,8aR)-8a-tert-butyldimethylsilyloxymethyl-6,7-dihydroxy-indolizidin-3-ones 14 and 15 were syn-
thesized from bicyclic silyloxypyrrole 2 by the selective formation of a quaternary stereogenic centre and a ring-closing metathesis as
the main steps. They were converted into new polyhydroxyindolizidines 20 and 21 with high diastereoselectivity.
ꢀ
2005 Elsevier Ltd. All rights reserved.
1. Introduction
group at the ring junction, through ring-closure metath-
esis as the key step to form the six-membered ring.
The synthesis of several polyhydroxyindolizidine alkal-
oids has been the subject of intense investigation due
to their important biological properties and, particu-
2. Results and discussion
2.1. Synthesis
1
larly, their ability to inhibit glycosidases. Furthermore,
a wide range of structural analogues have also been syn-
thesized to be evaluated as selective inhibitors and
2
potential therapeutic agents. However, among these
(R)-Silyloxypyrrole 2 prepared from inexpensive (S)-
1
2
synthetic hydroxylated indolizidines, only a few struc-
pyroglutaminol, as previously described, was used as
starting material to investigate the validity of the retro-
synthetic route depicted in Scheme 1.
tures contain a quaternary carbon at the a-position to
3
–8
the nitrogen at the ring junction. The methodologies
developed for their construction include the creation
of the quaternary centre by C–C bond formation
It was envisaged that (8aR)-6,7-dihydroxy-8a-hydroxy-
methyl-indolizidines 1 was formed by the reduction of
the c-lactam carbonyl of 3, which could result from the
cis-dihydroxylation of 4. Compound 4 could be gener-
ated by the ring-closing metathesis of 1,5-diallyl-deriva-
tive 5. This intermediate could in turn be prepared from
bicyclic 5-allyl-lactam 6 derived from silyloxypyrrole 2.
3
4
through alkylation and aldol reactions of tert-butyl
a-aminoester derivatives, or through nucleophilic
6
–8
addition to N-acyliminium ions.
In the case invol-
ving a bicyclic tertiary iminium ion, its trapping has
been accomplished by an intramolecular nucleophilic
6
species.
In connection with our previous work using bicyclic
It is noteworthy that, in the literature, only a few exam-
ples of external C-nucleophile addition to tertiary
N-acyliminium ions at a ring junction have been
silyloxypyrrole 2 to stereoselectively introduce nucleo-
9
–12
philic species at C-5,
we here report the synthesis
1
3–15
of new indolizidines of type 1 bearing a hydroxymethyl
described.
Starting from 2, we developed a new
and simple access, in one step, to bicyclic 5-hydroxylac-
tam 7, which acts as a precursor to a trisubstituted acyl-
9
,12
iminium ion (Scheme 2).
The formation of 7 was the
*
0
Corresponding author. Fax: +33 1 69077247; e-mail: nicole.langlois@
icsn.cnrs-gif.fr
result of a double protonation at C-7 and C-6, followed
by trapping the N-acyliminium ion thus obtained by the
957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.017

54
N. Langlois et al. / Tetrahedron: Asymmetry 17 (2006) 53–60
OH
OP
OH
OP
O
O
N
N
N
OH
OH
OH
1
3
4
O
5
N
O
TBDMSO
N
N
OP
O
O
Ph
Ph
2
5
6
Scheme 1.
SnCl4, –35 °C
Me SiCH CH=CH
2
7
6
SnCl , –78 °C
4
OH
NaHCO
5
2
3
3
2
O
O
O
TBDMSO
N
N
N
+
N
(
78%)
O
O
O
O
Ph
Ph
Ph
Ph
2
7
6 (61%)
8
Scheme 2.
nucleophile. This probably occurred during the hydroly-
The oxazolidine ring of 6 was hydrolyzed in high yield
sis of the complex between silyloxypyrrole 2 and SnCl4
with trifluoroacetic acid in a mixture of THF–H O
2
with aqueous NaHCO . The configurations of 7 have
(1:1) at 45 ꢁC to furnish 9 (91%). Pyrrolidinone 9 was
then O-protected before the N-allylation. The first
attempts at preparing the corresponding benzoate led to
poor results, owing to the low reactivity of this primary
alcohol towards selective O-benzoylation, whereas the
tert-butyldimethylsilyl derivative 10 could be obtained
in 90% yield. A classical N-allylation (NaH–KI in
THF) gave rise to 11 (70%) and some recovered starting
material 10 (18%). A tri-allylated by-product 12 was also
isolated in small amounts (4%), probably as a result of
the desilylation of 10 by the sodium amide, followed
3
1
6a
been ascertained by X-ray analysis, and semiempirical
RHF/AM1 calculations have been performed to explain
the complete facial stereoselectivity of the hydroxide
anion addition to this flattened iminium ion: at the
approach of the nucleophile, the molecule becomes con-
vex and this conformation decreases the steric hindrance
1
6b
of the phenyl group.
In turn, starting from 7, the subsequent stereoselective
addition of C-nucleophiles at C-5, and particularly of
an allyl group, to form the quaternary centre of enantio-
merically pure bicyclic 5-allyllactam 6, was accomplished
as shown in Scheme 2, compared to the addition of tri-
1
9
by subsequent O-allylation.
Ring-closing metathesis reactions have been widely used
1
0–12
20,21
methylsilyl cyanide in several syntheses.
to prepare N-heterocycles,
including RCM of 5-
alkyl-1,5-diallylpyrrolidin-2-ones in the presence of first
Accordingly, the addition of allyltrimethylsilane to a
dichloromethane solution of (2R,5R)-5-hydroxy-2-phenyl-
generation Grubbsꢀ catalyst to form the six-membered
7
,8
ring of 8a-alkylindolizidinones. In our case, the more
active second generation Grubbsꢀ catalyst (4.5%) was
used in CH Cl at 40 ꢁC to perform a very efficient
3
-oxa-1-azabicyclo[3.3.0]octane-8-one
7
was per-
formed at ꢀ35 ꢁC in the presence of SnCl (2 equiv) to
4
2
2
2
2
give only one diastereomer 6 (61%), together with start-
ing 7 (12%) and b,c-unsaturated lactam 8 (ca. 10%). The
configuration of the newly created quaternary centre in
RCM of 1,5-diallyl-derivative 11. The ring closure
was complete after 2 h and indolizinone 13 isolated in
96% yield.
6
was postulated to be (5R) on the basis of the facial ste-
reoselectivity observed for 7, and of the high H-2 chem-
The cis-dihydroxylation of 13 using catalytic osmium
1
ical shift in the H NMR spectrum of 6 (CDCl ,
tetroxide (OsO ) and N-methylmorpholine N-oxide
3
4
6
.34 ppm). As observed by Nagasaka and Imai,17 exam-
(NMO) in acetone afforded the diastereomeric diols 14
and 15 (87%) in a 7:1 dr (Scheme 3).
ination of molecular models indicated that the aniso-
tropy of the lactam carbonyl deshields the endo C-2
proton and explained this high chemical shift. Further-
more, the stability of 6 supports this assignment. In
structurally related compounds, diastereomers with an
opposite configuration at C-5 are unstable, probably
due to steric congestion induced by the endo aromatic
As we anticipated, the facial selectivity in the osmylation
can be rationalized in terms of steric hindrance exerted
by the bulky tert-butyldimethylsilyloxymethyl group.
A NOESY study of the major diastereomer 14 indicated
correlations between one of the protons H-9 and Hb-5,
and between Hb-5 and the two protons H-6 and H-7.
These data are consistent with a trans relationship
1
7,18
group;
the configuration assigned to 6 was corrobo-
rated by the following synthesis.

N. Langlois et al. / Tetrahedron: Asymmetry 17 (2006) 53–60
55
7
9
2
O
a
c
O
O
O
+
N
N
N
N
H
6
O
OR
OTBDMS
O
Ph
6
9 R = H
0 R = TBDMS
b
11
12
1
9
2
1
OTBDMS
8a
OTBDMS
OTBDMS
OH
O
O
O
d
N
N
+
N
e
11
7
5
6
OH
1
4 : 15 = 7 : 1
OH
OH
13
14
15
Scheme 3. Reagents: (a) CF
CH Cl ; (e) OsO
3
CO
2
H, THF–H
2
O; (b) TBDMSCl, Im., DMF; (c) NaH–KI, allyl bromide, THF; (d) second Grubbsꢀ catalyst (4.5%),
2
2
4
, NMO, CH
3
COCH
3
–H O.
2
between the tert-butyldimethylsilyloxymethyl and the
The reduction was achieved with BH ÆDMS complex
3
two hydroxyl groups (Fig. 1).
in THF affording 18 and 19 in 82% and 84% yield,
respectively (Scheme 4).
H
TBDMSO
The corresponding indolizidines 20 and 21 were then
obtained as hydrochlorides in high yields after full depro-
tection with HCl (1 M) (98% and 93%, respectively).
9
H
H
H
7
OH
H
6
N
O
5
2.2. Evaluation of glycosidase inhibition
OH
Though the synthesized indolizidines 20 and 21 possess
Figure 1.
a CH OH group in the L-configuration, which is unfa-
2
vourable for enzyme recognition compared to the hex-
ose sugars, they were evaluated as inhibitors against
commercial glycosidases. The results are shown in
Table 1. They are essentially inactive, and only weakly
active against a-glucosidase and, for 20, against b-
galactosidase.
The X-ray analysis of 14 confirmed this attribution and
supported the (R)-configuration of the quaternary cen-
tre in precursor 6 (Fig. 2).
2
3
3. Conclusion
In conclusion, we herein report the unusual stereoselec-
tive addition of a C-nucleophile to tertiary N-acyl imin-
ium ions at a bicyclic ring junction. The synthetic
scheme presented constitutes as an efficient route to
new polyhydroxyindolizidines bearing a quaternary
hydroxymethyl group, compound 20 being diastereo-
selectively prepared in 20% overall yield from silyloxy-
pyrrole 2. This scheme, which could be applied to the
synthesis of the enantiomers as potential glycosidase
inhibitors, also involves lactam intermediates and, there-
fore, could lead to other analogues bearing hydroxyl
groups on the five membered ring.
Figure 2.
4. Experimental
The two hydroxyl groups of 14 and 15 were protected as
acetonides before the reduction of the lactam carbonyls.
The classical protocol for this (2,2-dimethoxypropane,
TsOH) led to partial deprotection of the primary alco-
hol. Thus, in order to overcome this drawback, aceto-
nides 16 and 17 were prepared, respectively, in 100%
4.1. General
Melting points were determined with a B u¨ chi B-540
apparatus and are uncorrected. Optical rotations were
measured on a Jasco P-1010 polarimeter and the con-
ꢀ
1
centrations given in g/100 mL. IR spectra (cm , film,
2
4
and 88% yield in the presence of powdered CuSO4.
CHCl ) were recorded on Perkin Elmer Spectrum BX
3

56
N. Langlois et al. / Tetrahedron: Asymmetry 17 (2006) 53–60
OTBDMS
OTBDMS
OH
+
O
a
N
b
N
c
N
14
H
Cl –
O
O
OH
1
0
O
O
OH
1
6
18
20
OTBDMS
OTBDMS
c
OH
+
O
a
N
b
H– N
N
15
Cl
O
O
OH
O
O
OH
17
19
21
3 3 2 3 4 3 3 3
Scheme 4. Reagents: (a) CH C(OCH ) CH , CuSO , CH COCH ; (b) BH ÆDMS, THF; (c) 1 M HCl.
Table 1. Inhibition data for indolizines 20 and 21 against commercial
glycosidases (IC50 in mM)
11,), 4.09 (d, 1H, J4a,4b = 8.3, Ha-4), 3.65 (d, 1H,
J4b,4a = 8.3, Hb-4), 2.87 (m, 1H, Ha-9), 2.54 (m, 1H,
Hb-9), 2.31 (m, 1H), 2.22 (m, 2H) and 2.06 (m, 1H):
a
Glycosidases Glucosidases Mannosidases
Galactosidases
1
3
H -7 and H -6. C NMR (CDCl ): 178.78 (CO),
2
2
3
a
b
a
b
a
b
1
39.23 (qC, Ar), 128.38 (CH, Ar, C-10), 125.88 (CH,
Ar), 119.87 (C-11), 87.63 (C-2), 76.42 (C-4), 69.35 (C-
), 42.11 (C-9), 33.90, 28.47 (C-6, C-7). Anal. Calcd
for C H NO (%): C, 74.05; H, 7.04; N, 5.76. Found
2
2
0
1
0.57
No inh. No inh. No inh. 0.56
0.59 No inh. No inh. No inh. No inh. No inh.
5
a
No inh.: no inhibition, IC50 > 1 mM.
1
5
19
2
(%): C, 73.46; H, 7.01; N, 5.64.
4
.3. (5R)-5-Allyl-5-hydroxymethyl-pyrrolidin-2-one 9
1
(
FT). H NMR spectra were obtained (CDCl , CHCl
3
3
d = 7.27 ppm, unless otherwise indicated) from Bruker
AM 300 (s, d, t, dd and m indicate singlet, doublet, trip-
let, doublet of doublets and multiplet, respectively).
Trifluoroacetic acid (0.3 mL, 4.04 mmol) was added
dropwise to a solution of bicyclic derivative 6 (0.49 g,
2.02 mmol) in a mixture of THF (2.0 mL) and H O
2
1
3
C NMR spectra were recorded on AM 300 (75.0
(2.0 mL) at rt. After being stirred at 45 ꢁC for 6 h, the
solvent and benzaldehyde were evaporated under
reduced pressure. EtOAc and Na CO were added to
MHz, CDCl centred at 77.14 ppm). Mass spectra and
3
high-resolution mass spectra were measured on a Navi-
gator (ESI), or a Micromass LC-TOF spectrometer.
Chromatography was performed on silica gel (SDS
2
3
the residue and the mixture was stirred at rt for
30 min, and filtered. The crude product obtained after
evaporation to dryness was purified by chromatography
(eluent: CH Cl –MeOH 95:5) to afford pyrrolidinone
2
30–400 mesh) and preparative thin layer chromatogra-
phy on silica gel (Merck HF 254+366). Usual workup
means that the organic layer was dried over magnesium
sulfate, filtered and evaporated under reduced pressure.
2
2
2
D
3
9 as a colourless oil (284.5 mg, 91%). ½aꢁ ¼ þ18 (c
1.8, CH OH). IR: 3276 (broad), 2938, 2876, 1676,
3
+
1
289. MS (ESI, CH CN+H O): 178 (MNa , 100%).
3
2
4
[
.2. (2R,5R)-5-Allyl-2-phenyl-3-oxa-1-azabicyclo-
3.3.0]octan-8-one 6
HRMS (ESI, CH CN+H O): calcd for C H NO Na
3
2
8
13
2
+
1
(MNa ): 178.0844, found: 178.0885.
H
NMR
(
CD OD, d = 3.34 ppm): 5.86 (m, 1H, H-8), 5.18 (m,
3
Allyltrimethylsilane (2.7 mL, 17.0 mmol) and SnCl4
2.0 mL, 17.1 mmol) were successively added under
argon to a stirred solution of (2R,5R)-5-hydroxy-2-
phenyl-3-oxa-1-azabicyclo[3.3.0]octan-8-one 7 (1.80 g,
2H, H -9), 3.50 (d, 1H, J
1H, J6b,6a = 11.4, Hb-6), 2.34 (m, 4H) and 2.01 (m,
= 11.4, Ha-6), 3.45 (d,
6a,6b
2
(
1
3
2H): H -7, H -3 and H -4.
C NMR (CD OD,
2
2
2
3
d = 49.00 ppm): 180.62 (CO), 133.98 (C-8), 119.69 (C-
9), 68.68 (C-6), 64.68 (C-5), 42.07 (C-7), 31.78, 27.98
(C-3, C-4).
8
.25 mmol) at ꢀ35 ꢁC. The mixture was stirred at the
same temperature for 5 h before the addition of a satu-
rated solution of NaHCO and extraction with CH Cl .
3
2
2
The crude product obtained after usual workup was
4.4. (5R)-5-Allyl-5-(tert-butyldimethylsilyloxymethyl)-
pyrrolidin-2-one 10
purified by chromatography (eluent: Et O) to afford
2
allyl-derivative 6 as a colourless oil (1.22 g, 61%) [together
with starting 7 (0.21 g, 12%) and b,c-unsaturated lactam
Imidazole (0.78 g, 11.5 mmol) and TBDMSCl (0.8 g,
5.25 mmol) were successively added under argon to a
stirred solution of pyrrolidinone 9 (0.38 g, 2.44 mmol)
in DMF (2.0 mL) at rt. After stirring for 26 h, the reac-
tion was quenched by the addition of cold water and
Et O. The product was extracted with Et O and the
23
8
(ca. 10%)]. Compound 6: ½aꢁ ¼ þ193 (c 1.15, CHCl ).
D
3
IR: 3065, 2978, 2875, 1704, 1641, 1493, 1451. MS (ESI,
MeOH): 244 (MH ). H NMR (CDCl ): 7.52 (m, 2H,
+
1
3
H–Ar), 7.36 (m, 3H, H–Ar), 6.34 (s, 1H, H-2), 5.69
(
m, 1H, H-10), 5.11 (m, 1H, Ha-11), 5.03 (m, 1H, Hb-
2
2

N. Langlois et al. / Tetrahedron: Asymmetry 17 (2006) 53–60
57
0
organic layers washed with cold water and brine, dried
3.91 (2H, H -13), 3.78 (dd, 1H, J = 15.6, J = 6.0, Hb-
2
over MgSO and concentrated under reduced pressure.
10), 3.37 (d, 1H, 1H, J6a,6b = 10, Ha-6), 3.30 (d, 1H,
4
The crude product (0.68 g) was purified by chromato-
J6b,6a = 10, Hb-6), 2.34 (m, 4H) and 1.91 (m, 2H): H -
2
1
3
graphy on silica gel (eluent: Et O) to afford silylether
3, H -4 and H -7. C NMR (CDCl ): 175.72 (CO),
2
2 2 3
1
0 as a white solid (589.2 mg, 90%). Mp = 53 ꢁC.
134.83, 134.40, 132.20 (C-8, C-11, C-14), 119.62,
117.07, 116.28 (C-9, C-12, C-15), 74.80 (C-6), 72.15
(C-13), 65.93 (C-5), 42.85 (C-10), 39.61 (C-7), 29.87,
26.76 (C-3, C-4).
23
½
aꢁ ¼ þ38 (c 1.98, CHCl ). IR: 3198, 2929, 2857,
D
3
1
698, 1463, 1362, 1255. MS (ESI, CH OH): 292
3
+
1
(
MNa , 100%). H NMR (CDCl ): 5.94 (s, 1H, NH),
3
5
.75 (m, 1H, H-8), 5.18, 5.13 (2H, H -9), 3.50 (d, 1H,
2
J6a,6b = 11.4, Ha-6), 3.45 (d, 1H, J6b,6a = 11.4, Hb-6),
4.7. 8aR-tert-Butyldimethylsilyloxymethyl-1,5,8,8a-tetra-
hydro-2H-indolizin-3-one 13
2
.37 (2 m, 3H, Ha-7 and H -3 or H -4), 2.27 (dd, 1H,
2 2
0
J = 13.8, J = 8.2, Hb-7), 1.86 (m, 2H, H -4 or H -3),
0
2
2
1
3
.90 (s, 9H, CH , t-Bu), 0.04 (2 s, 6H, Si(CH ) ).
C
3
3 2
A solution of diallyl-derivative 11 (99.4 mg, 0.32 mmol)
in anhydrous CH Cl (48.0 mL) and second Grubbsꢀ
NMR (CDCl ): 177.46 (CO), 132.72 (C-8), 119.56 (C-
3
2
2
9
), 68.79 (C-6), 62.58 (C-5), 41.41 (C-7), 30.36, 27.76
catalyst (12.5 mg, 4.5%) were stirred at 40 ꢁC for 2 h.
The solvent was evaporated at the same temperature
and the residue was purified by preparative TLC (eluent:
(
(
(
C-3, C-4), 25.89 (CH , t-Bu), 18.26 (qC, t-Bu), ꢀ5.45
3
SiCH ), ꢀ5.48 (SiCH ). Anal. Calcd for C H NO Si
3
3
14 27
2
%): C, 62.41; H, 10.10; N, 5.20; Found (%): C, 61.99;
Et O) to remove the catalyst. Bicyclic compound 13
2
H, 10.22; N, 5.26.
(
86.8 mg, 96%) was obtained as
a
white solid.
23
Mp = 40 ꢁC. ½aꢁ ¼ ꢀ27 (c 1.37, CHCl ). IR: 2948,
D
3
4.5. (5R)-1,5-Diallyl-5-(tert-butyldimethylsilyloxy-
methyl)-pyrrolidin-2-one 11
2
(
(
3
928, 2889, 2855, 1694, 1412. MS (ESI, CH OH): 585
3
+
+
+
2MNa ), 304 (MNa ), 282 (MH , 100%). HRMS
+
ESI, CH OH): calcd for C H NO SiNa (MNa ):
3
15 27
2
1
Potassium iodide (382.0 mg, 2.3 mmol) was added under
argon to a suspension of NaH (60% in oil, 92.0 mg,
04.1709, found: 304.1711. H NMR (CDCl ): 5.70
3
(
m, 2H, H-6, H-7), 4.29 (broad d, 1H, J = 18.5, Ha-5),
.58 (d, 1H, 1H, J9a,9b = 10, Ha-9), 3.43 (d, 1H,
J9b,9a = 10, Hb-9), 3.43 (masked d, 1H, Hb-5), 2.48
m, 1H), 2.30 (2 m, 3H), 2.11 (m, 1H) and 1.75 (m,
2
.3 mmol) in THF (4.0 mL) and stirred at rt. After cool-
ing at 0 ꢁC, a solution of silylether 10 (580 mg,
.2 mmol) in THF (4.0 mL) was added dropwise. The
3
2
(
mixture was stirred for 1.5 h at rt and cooled to 0 ꢁC.
Then, allylbromide (0.2 mL, 2.3 mmol) was added drop-
wise and the mixture was stirred at rt for additional
1
0
H): H -8, H -2 and H -1, 0.87 (s, 9H, CH , t-Bu),
2 2 2 3
1
3
.03 (s, 3H, SiCH ), 0.02 (s, 3H, SiCH ). C NMR
3
3
(
CDCl ): 174.63 (CO), 123.63, 122.53 (C-6, C-7), 65.30
3
2
4 h. After the addition of H O and Et O, the organic
2 2
(C-9), 61.16 (C-8a), 38.66 (C-5), 33.81 (C-8), 30.43,
0.14 (C-1, C-2), 25.86 (CH , t-Bu), 18.20 (qC, t-Bu),
layer was separated and the aqueous layer was extracted
3
3
twice more with Et O to give the crude product after
2
ꢀ5.48 (SiCH ), ꢀ5.86 (SiCH ).
3
3
usual workup. Purification by chromatography (eluent:
heptane–Et O 4:1) gave rise to diallyl-derivative 11
2
4.8. 8a-tert-Butyldimethylsilyloxymethyl-6,7-dihydroxy-
indolizidin-3-ones 14 and 15
(
475.7 mg, 70%) as a colourless oil, together with trial-
lyl-compound 12 (20.3 mg, 4%) and starting compound
2
D
3
1
0 (104 mg, 18%). Compound 11: ½aꢁ ¼ þ35 (c 0.60,
A solution of OsO in tert-butanol (0.1 M, 0.23 mL,
4
CHCl ). IR: 2954, 2928, 2857, 1695, 1462, 1403, 1255.
MS (ESI, CH OH): 310 (MH , 100%). HRMS (ESI,
CH OH): calcd for C H NO Si (MH ): 310.2202,
found: 310.2205. H NMR (CDCl ): 5.86 (m, 1H, H-
3
+
0.023 mmol) was added to a solution of N-methyl-
morpholine N-oxide (137.0 mg, 1.16 mmol) in a mix-
3
+
3
17 32
2
1
ture of acetone (0.50 mL) and H O (0.11 mL) at 0 ꢁC.
2
3
A solution of compound 13 (220.0 mg, 0.78 mmol) in
acetone (0.70 mL) was then added and the reaction mix-
ture stirred at 0 ꢁC for 6 h. An aqueous saturated solu-
1
9
1
1
1), 5.66 (m, 1H, H-8), 5.20–5.08 (4H, H -12 and H -
2 2
0
), 3.94 (dd, 1H, J = 15.5, J = 5.8, Ha-10), 3.82 (dd,
0
H, J = 15.5, J = 5.8, Hb-10), 3.56 (d, 1H, J
=
6
a,6b
tion of NaHSO was added and the products extracted
4
0.3, Ha-6), 3.46 (d, 1H, J6b,6a = 10.3, Hb-6), 2.34
with EtOAc. The usual workup gave rise to diastereo-
mers 14 and 15, which were separated by chromato-
(
2 m, 4H, H -7, H -3 or H -4), 1.87 (m, 2H, H -4 or
2 2 2 2
H -3), 0.88 (s, 9H, CH , t-Bu), 0.04 (2 s, 6H, Si(CH ) ).
2
3
3 2
1
3
graphy (eluent: CH
186.6 mg, 76%) and 15 (27.0 mg, 11%) as colourless
crystals.
2 2
Cl –MeOH 95:5) to afford 14
C NMR (CDCl ): 175.81 (CO), 134.99, 132.33 (C-11,
3
(
C-8), 119.49, 116.33 (C-9, C-12), 67.85 (C-6), 66.87
C-5), 42.81 (C-10), 39.31 (C-7), 30.03, 26.49 (C-3,
C-4), 25.87 (CH , t-Bu), 18.20 (qC, t-Bu), ꢀ5.54
(
3
(
2SiCH ).
4.9. (6R,7S,8aR)-8a-tert-Butyldimethylsilyloxymethyl-
,7-dihydroxy-indolizidin-3-one 14
3
6
4
.6. (5R)-1,5-Diallyl-5-allyloxymethyl-pyrolidin-2-one 12
23
Mp = 176–177 ꢁC. ½aꢁ ¼ ꢀ6:7 (c 0.65, CHCl ). IR:
D
3
2
D
3
½
aꢁ ¼ þ42 (c 1.47, CHCl ). IR: 2928, 1681, 1402, 1257.
3316 (broad), 2928, 2858, 1655, 1445, 1414. MS (ESI,
3
+
+
MS (ESI, CH OH): 258 (MNa , 100%). HRMS (ESI,
CH OH): calcd for C H NO Na (MNa ): 258.1470,
found: 258.1486. H NMR (CDCl ): 5.84 (m, 2H, H-
1, H-14), 5.67 (m, 1H, H-8), 5.26–5.05 (6H, H -9, H -
CH OH):
calcd for C15H29NO SiNa (MNa ): 338.1764, found:
4
3
OH): 338 (MNa , 100%). HRMS (ESI, CH
3
3
+
+
3
14 21
2
1
1
338.1772. H NMR (CDCl
J = 2.5, Ha-5), 3.98 (m, 1H, H-6), 3.86 (m, 1H, H-7),
): 4.20 (dd, 1H, J = 14.5,
3
3
0
1
1
2
2
0
2, H -15), 3.98 (dd, 1H, J = 15.6, J = 5.8, Ha-10),
3.65 (d, 1H, J9a,9b = 10.3, Ha-9), 3.48 (d, 1H,
2

58
N. Langlois et al. / Tetrahedron: Asymmetry 17 (2006) 53–60
J9b,9a = 10.3, Hb-9), 2.85 (broad d, 1H, J = 14.5,
4.11. (6S,7R,8aR)-8a-tert-Butyldimethylsilyloxymethyl-
6,7-dihydroxy-indolizidin-3-one 15
Hb-5), 2.46 (m, 1H), 2.36 (m, 1H) and 2.11 (m, 1H):
0
H -2 and Ha-1, 1.94 (dd, 1H, J = 12.9, J = 4.9, Ha-8),
2
23
1
0
.74 (m, 2H, Hb-8, Hb-1), 0.87 (s, 9H, CH , t-Bu),
Mp = 183 ꢁC. ½aꢁ ¼ ꢀ9:5 (c 0.78, CHCl ). IR: 3338
3
D
3
1
3
.04 (s, 3H, SiCH ), 0.03 (s, 3H, SiCH ). C NMR
(broad), 2950, 2858, 1640, 1462, 1414. MS (ESI,
3
3
+
1
(
(
CDCl ): 176.03 (CO), 67.49, 66.96 (C-6, C-7), 65.42
C-8a), 64.18 (C-9), 42.11 (C-5), 36.57 (C-8), 30.65,
CH OH): 338 (MNa , 100%). H NMR (C D , d =
3
3 6 6
0
7.15 ppm+D O): 4.39 (dd, 1H, J = 12, J = 5, Ha-5),
2
3
0.32 (C-1, C-2), 25.98 (CH , t-Bu), 18.19 (qC, t-Bu),
4.17 (d, 1H, J = 10, Ha-9), 3.88 (m, 1H, H-7), 3.50 (m,
1H, H-6), 3.36 (d, 1H, J = 10, Hb-9), 3.02 (dd, 1H,
3
ꢀ
5.47 (2SiCH ); NOESY: correlations were observed
3
0
between: Hb-5 and Ha-9, Hb-5, H-6 and H-7.
.10. Crystal structure determination of compound 14
J ꢂ J ꢂ 12, Hb-5), 2.43 (m, 1H), 2.11 (m, 1H) and
1
.91 (m, 1H): H -2 and Ha-1, 1.84 (dd, 1H, J = 15,
2
0
4
J = 3.0, Ha-8), 1.06 (m, 1H, Hb-1), 1.00 (dd, 1H, Hb-
8
), 0.91 (s, 9H, CH , t-Bu), 0.02 (s, 3H, SiCH ), 0.01
3
3
1
3
Suitable crystals for X-ray structure determination of
compound 14 were obtained from a dilute solution in
ethyl acetate at rt. X-ray diffraction data were recorded
from a single colourless plate, 0.6 · 0.4 · 0.2 mm, at
ambient temperature on an Enraf–Nonius Kappa-
CCD diffractometer, using graphite-monochromated
(s, 3H, SiCH3). C NMR (CDCl ): 174.33 (CO),
3
67.61, 67.48 (C-6, C-7), 67.49 (C-9), 61.74 (C-8a),
40.03 (C-5), 38.25 (C-8), 31.41, 31.22 (C-1 and C-2),
25.94 (CH , t-Bu), 18.29 (qC, t-Bu), ꢀ5.43 (2SiCH ).
3
3
Anal. Calcd for C H NO Si (%): C, 57.11; H, 9.27;
1
5
29
4
N, 4.44. Found (%): C, 57.01; H, 9.24; N, 4.33.
˚
Mo-Ka radiation (l = 0.71073 A). On a CAD4 diffracto-
meter, 244 Bijvoet pairs showing the strongest differ-
4.12. (6R,7S,8aR)-8a-tert-Butyldimethylsilyloxymethyl-
6,7-isopropylidendioxy-indolizidin-3-one 16
ences were later measured, using the Cu-Ka radiation
˚
(
l = 1.5418 A) to support the correct absolute structure
from weak Si anomalous signal. The structure was
solved by direct methods with the program SHELX-S97
Dimethoxypropane (0.5 mL) and dried powdered
CuSO (76.0 mg, 0.475 mmol) were successively added
4
(
Sheldrick, 1997)23a and all non-hydrogen atoms were
to a suspension of diol 14 (30.0 mg, 0.095 mmol) in
anhydrous acetone (0.5 mL) and the mixture was stirred
2
refined anisotropically on F values by full-matrix
least-square methods using SHELX-L97. All hydrogen
atoms were located on difference-Fourier syntheses
and were refined with a riding model and with Uiso set
to 1.15 time that of the carrier atom (or 1.2 in methyl
or hydroxyl groups, and waters). The asymmetric unit
of the crystal consists of one compound 14 molecule
and two waters involved in the hydrogen bonding
with the two hydroxyl groups and the carbonyl one.
Bijvoet-pair analysis as implemented within PLATON
at rt for 5 days. After filtration, CuSO was washed with
4
acetone. The solvent was evaporated to afford com-
pound 16 (34.0 mg, 100%) as colourless crystals.
23
Mp = 56 ꢁC. ½aꢁ ¼ þ47 (c 0.96, CHCl ). IR: 2928,
D
3
2855, 1682, 1412, 1380, 1368. MS (ESI, CH OH): 378
3
+
+
(MNa , 100%), 356 (MH ). HRMS (ESI, CH OH):
calcd for C H NO SiNa (MNa ): 378.2077, found:
378.2086. H NMR (CDCl ): 4.51 (m, 1H, H-7), 4.26
3
+
1
8
33
4
1
3
(masked d, 1H, J = 14.9, Ha-5), 4.23 (m, 1H, H-6),
2
3b
(
Spek, 2003), performed on the dataset using the cop-
3.51 (d, 1H, J9a,9b = 10.3, Ha-9), 3.49 (d, 1H, J
=
9b,9a
0
00
per radiation, supports the selected relative stereoche-
mistry of the asymmetric carbons, namely 6R,7S, and
10.3, Hb-9), 3.02 (ddd, 1H, J = 14.6, J = 3.0, J = 1.0,
Hb-5), 2.52 (m, 1H, Ha-2), 2.33 (m, 1H, Hb-2), 2.11
(m, 1H, Ha-1), 1.95 (m, 1H, Hb-1), 1.93 (masked dd,
8
aR. C H NO Si, 2(H O), M =351.51, monoclinic,
15 29 4 2 r
0
0
space group P21, a = 6.819(4), b = 7.304(3), c =
1H, J = 4.6, Ha-8), 1.88 (dd, 1H, J = 14.7, J = 5.5,
3
˚
3
˚
2
1
0.655(4) A, b = 99.43(2)ꢁ, V = 1014.8(8) A , r
=
Hb-8), 1.44 (s, 3H, CH -10), 1.32 (s, 3H, CH -10),
calcd
3
3
ꢀ1
13
.150 g/cm , F(000) = 384, l = 0.141 mm , no absorp-
0.91 (s, 9H, CH , t-Bu), 0.05 (s, 6H, 2SiCH ).
C
3
3
˚
tion correction, Z = 2, l = 0.71073 A, T = 293 K, j/w-
scans, 10328 measured reflections (ꢀ8 6 h 6 8, ꢀ9 6
k 6 9, ꢀ26 6 l 6 26), 4293 independent (1832 Friedel
pairs separated) and 3472 observed reflections with
I > 2s(I) (R = 0.0440), 215 parameters, 1 restraint, R =
NMR (CDCl ): 175.52 (CO), 108.32 (qC, C-10), 72.34,
3
71.10 (C-6, C-7), 68.27 (C-9), 61.61 (C-8a), 39.99 (C-
5), 32.63 (C-8), 30.54, 29.96 (C-1 and C-2), 27.14
(CH -10), 25.97 (CH , t-Bu), 24.75 (CH -10), 18.32
3
3
3
(qC, t-Bu), ꢀ5.41 (2SiCH3).
2
2
0
(
.0601, wR = 0.1184 for all reflections, w = 1/[s (F ) +
2
2
2
2
c
0.0536P) + 0.1441P], where P ¼ ðmaxðF ; 0Þ þ 2F Þ=3.
4.13. (6S,7R,8aR)-8a-tert-Butyldimethylsilyloxymethyl-
6,7-isopropylidendioxy-indolizidin-3-one 17
o
The largest difference peak and hole are meaningless,
3
˚
0
.256 and ꢀ0.174 e A , Flack parameter ꢀ0.19(14) (its
meaningfulness was confirmed by the good agreement
Minor diol 15 (33.2 mg, 0.105 mmol) was treated as its
diastereomer 14 in anhydrous acetone (0.2 mL) with
dimethoxypropane (0.2 mL) and CuSO4 (84.0 mg,
0.525 mmol) to afford the protected diol 17 (32.8 mg,
þ=ꢀ
þ=ꢀ
(
(
20 over 22) between the strongest DFobsd and DF
above one sigma) among 244 Bijvoet pairs measured
calcd
using Cu-Ka radiation).
2
D
3
8
8%) as a white solid. Mp = 55 ꢁC. ½aꢁ ¼ ꢀ27:5 (c
CCDC 280270 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retriev-
ing.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
2.55, CHCl ). IR: 2983, 2946, 2928, 2881, 2856, 1692,
1454, 1424, 1410. MS (ESI, CH OH): 733 [(2M+Na ),
100%], 378 (MNa ), 356 (MH ). HRMS (ESI,
CH OH): calcd for C H NO SiNa (MNa ):
3
+
3
+
+
+
3
18 33
1
4
378.2077, found: 378.2072. H NMR (CDCl ): 4.25
3
(
+44) 1223 336033; or deposit@ccdc.cam.uk).
(m, 2H, H-7, Ha-5), 4.10 (m, 2H, Ha-9, H-6), 3.42 (d,

N. Langlois et al. / Tetrahedron: Asymmetry 17 (2006) 53–60
59
1
H, J
= 10.5, Hb-9), 2.62 (dd, 1H, J = 13.3,
(CH -10), 18.35 (qC, t-Bu), ꢀ5.26 (SiCH ), ꢀ5.39
9
b,9a
3
3
0
J = 7.9, Hb-5), 2.51 and 2.30 (2 m, 2H, H -2 or H -
(SiCH ).
2
2
3
1
1
), 2.25 and 1.63 (2 m, 1H, H -1 or H -2), 2.18 (dd,
2 2
0
H, J = 15.3, J = 2.7, Ha-8), 1.75 (dd, 1H, J = 15.3,
4.16. (6R,7S,8aR)-6,7-Dihydroxy-8a-hydroxymethyl-
indolizidine hydrochloride 20
0
J = 4.6, Hb-8), 1.51 (s, 3H, CH -10), 1.34 (s, 3H,
CH -10), 0.87 (s, 9H, CH , t-Bu), 0.05 (s, 3H, SiCH ),
3
3
3
3
1
3
0
1
6
1
1
.03 (s, 3H, SiCH3). C NMR (CDCl ): 174.34 (CO),
3
A solution of HCl in H O (1 M, 1.88 mL) was added at
2
09.26 (C-10), 72.46, 70.15 (C-7, C-6), 65.23 (C-9),
1.21 (C-8a), 38.13 (C-5), 34.64 (C-8), 31.27, 30.49 (C-
, C-2), 28.54, 26.04 (2CH -10), 25.87 (CH , t-Bu),
8.18 (qC, t-Bu), ꢀ5.40 (SiCH ), ꢀ5.43 (SiCH ).
rt to a solution of the derivative 18 (69.1 mg, 0.16 mmol)
in THF (0.8 mL) and the mixture was stirred for 72 h at
the same temperature. The solvents were evaporated
under reduced pressure to give indolizidine hydrochloride
3
3
3
3
2
1
2
0 crystallized in MeOH–Et O (35.0 mg, 98%). Mp =
2
23
4
6
.14. (6R,7S,8aR)-8a-tert-Butyldimethylsilyloxymethyl-
,7-isopropylidendioxy-indolizidine 18
98 ꢁC. ½aꢁ ¼ ꢀ10 (c 2.95, H O). IR: 3291 (broad),
D
2
962, 2895, 1467, 1444, 1360. MS (ESI, CH OH): 188
3
+
(MH , 100%). HRMS (ESI, CH OH): calcd for C H -
3 9 18
1
+
A solution of BH ÆDMS (2 M in THF, 0.38 mL,
3
NO3 (MH ): 188.1287, found: 188.1295. H NMR
0
.76 mmol) was added under argon at rt to a solution
of compound 16 (90.0 mg, 0.25 mmol) in THF
1.25 mL). The mixture was heated at 60 ꢁC for 90 min
(
D O, d = 4.65 ppm): 3.90 (m, 1H, H-6), 3.86 (m, 1H,
2
H-7), 3.76 (m, 1H, Ha-3), 3.59 (d, 1H, J9a,9b = 12.3,
Ha-9), 3.50 (d, 1H, J9b,9a = 12.3, Hb-9), 3.43 (m, 1H,
(
and then cooled at 0 ꢁC before the addition of MeOH
0
Hb-3), 3.30 (dd, 1H, J = 14.3, J = 4.0, Ha-5), 3.13 (dd,
(
(
0.1 mL). After evaporation to dryness, methanol
2.0 mL) was added to the residue and the solution
0
1
H, J = 14.3, J = 2.7, Hb-5), 2.06–1.75 (m, 5H, H -2,
H -1, Ha-8), 1.70 (dd, 1H, J = 14.4, J = 4.4, Hb-8).
C NMR (D O, d CD OD = 49.00 ppm): 71.67 (C-8a),
2
0
2
1
3
was heated at 60 ꢁC for 14 h. The solvent was eliminated
under reduced pressure and indolizidine 18 (69.8 mg,
2
3
66.03, 65.12 (C-6, C-7), 61.46 (C-9), 54.91 (C-3), 48.83
8
2%) was obtained after purification by preparative
23
(C-5), 30.57 (C-8), 32.86, 20.30 (C-1, C-2).
TLC (eluent: EtOAc), as a colourless oil. ½aꢁ ¼ ꢀ5 (c
D
1
.19, CHCl ). IR: 2953, 2925, 2855, 1462, 1378, 1258.
3
+
4.17. (6S,7R,8aR)-6,7-Dihydroxy-8a-hydroxymethyl-
indolizidine hydrochloride 21
MS (ESI, CH OH): 342 (MH , 100%). HRMS (ESI,
CH OH): calcd for C H NO Si (MH ): 342.2464,
found: 342.2448. H NMR (C D , d = 7.15 ppm): 4.49
3
+
3
18 36
3
1
6
6
Compound 19 (18.7 mg, 0.055 mmol) in THF (0.3 mL)
was treated as its diastereomer 18 by an aqueous solu-
tion HCl (1 M, 0.6 mL) to afford indolizidine 21 hydro-
(
m, 1H, H-7), 4.30 (m, 1H, H-6), 3.16 (s, 2H, H -9),
2
0
3
.07 (dd, 1H, J = 10.8, J = 5.0, Ha-5), 2.96 (m, 1H,
0
Ha-3), 2.67 (dd, 1H, J = 10.8, J = 9.5, Hb-5), 2.53
23
0
chloride (11.4 mg, 93%). Mp = 196 ꢁC. ½aꢁ ¼ þ9:5 (c
D
(
dd, 1H, J = 13.3, J = 6.5, Ha-8), 2.42 (m, 1H, Hb-3),
0
.85, H O). IR: 3337, 3270, 3236, 3142, 1472, 1443,
2
1
3
1
.90 (m, 1H, Ha-1), 1.58–1.41 (2 m, 2H, H -2), 1.52 (s,
H, CH -10), 1.27 (s, 3H, CH -10), 1.19 (m, 1H, Hb-
), 0.92 (s, 9H, CH , t-Bu), 0.08 (s, 3H, SiCH ), 0.03
2
1
415, 1379, 1346, 1297, 1278. MS (ESI, H O): 210
2
3
3
+
+
(MNa) , 188 [(MH) , 100%]. HRMS (ESI, H O): calcd
2
3
3
+
1
1
3
for C H NO (MH ): 188.1287, found: 188.1287. H
9 18 3
(
s, 3H, SiCH3). C NMR (C D , d = 128.00 ppm):
6 6
NMR (D O, d = 4.65 ppm): 3.95 (m, 2H, H-6, H-7),
2
1
5
08.51 (C-10), 73.91, 71.91 (C-6, C-7), 68.62 (C-9),
5.79 (C-3), 52.25 (C-5), 35.91 (C-8), 32.90, 30.17 (C-1,
3
.49 (m, 3H, H -9, Ha-3), 3.28 (dd, 1H, J = 13.6,
2
0
J = 4.4, Ha-5), 3.15 (m, 2H, Hb-5, Hb-3), 2.03 (m,
C-2), 27.69 (CH -10), 26.05 (CH , t-Bu), 24.75 (CH -
1
3
3
3
13
4
H, H -1, Ha-8, Ha-2), 1.79 (m, 2H, Hb-8, Hb-2).
C
2
0), 18.38 (qC, t-Bu), ꢀ5.38 (SiCH ), ꢀ5.44 (SiCH ).
3
3
NMR (D O, d CD OD = 49.00 ppm): 72.75 (C-8a),
2
3
6
5.84, 65.06 (C-6, C-7), 63.75 (C-9), 52.99, 52.87 (C-3,
4.15. (6S,7R,8aR)-8a-tert-Butyldimethylsilyloxymethyl-
6,7-isopropylidendioxy-indolizidine 19
C-5), 28.29 (C-8), 30.18, 19.53 (C-1, C-2).
Compound 17 (24.8 mg, 0.07 mmol) was reduced with
BH ÆSMe as described for 16 to afford indolizidine 19
4.18. Enzyme inhibitions
3
2
23
(
2
(
19.9 mg, 84%). ½aꢁ ¼ þ3:6 (c 0.84, CHCl ). IR: 2929,
General conditions for the determination of glycosidase
D
3
2
5
855, 1462, 1378, 1253. MS (ESI, CH OH): 342
inhibitions:
3
+
MH , 100%). HRMS (ESI, CH OH): calcd for
3
+
1
C H NO Si (MH) : 342.2464, found: 342.2454.
H
Tested glycosidases: a-D-glucosidase (EC 3.2.1.20) from
bakerꢀs yeast (K = 0.21 mM, pH = 7.0), b-D-glucosi-
dase (EC 3.2.1.21) from almonds (K = 1.3 mM,
pH = 5.0), a-D-mannosidase (EC 3.2.1.24) from Jack
beans (K = 1.0 mM, pH = 4.5), b-D-mannosidase (EC
3.2.1.25) from snail, acetone powder (K = 1.3 mM,
pH = 4.0), a-D-galactosidase (EC 3.2.1.22) from
Aspergillus niger (K = 0.25 mM, pH = 6.5), and b-D-
galactosidase (EC 3.2.1.23) from Escherichia coli
(K = 0.2 mM, pH = 7.0). Used buffer: HPO
KH PO for pH 6.5 and 7.0, AcOH/AcOK for
pH 4.0–5.5.
1
8
36
3
NMR (CDCl ): 4.47 (m, 1H, H-6), 4.35 (m, 1H, H-7),
m
3
3
9
3
.44 (d, 1H, J9a,9b = 9.4, Ha-9), 3.35 (d, 1H, J
=
m
9b,9a
0
.4, Hb-9), 3.14 (dd, 1H, J = 13.7, J = 5.8, Ha-5),
0
.08 (m, 1H, Ha-3), 2.85 (dd, 1H, J = 13.7, J = 8.2,
m
Hb-5), 2.74 (m, 1H, Hb-3), 1.80 (m, 2H, H -8), 1.96
m
2
(
m, 1H), 1.69 (m, 2H) and 1.48 (m, 1H): H -1, H -2,
2 2
1
9
.49 (s, 3H, CH -10), 1.33 (s, 3H, CH -10), 0.89 (s,
m
3
3
1
3
H, CH , t-Bu), 0.04 (2 s, 6H, 2SiCH ). C NMR
3
3
(
(
CDCl ): 107.95 (C-10), 71.54, 69.88 (C-6, C-7), 68.61
C-9), 53.94 (C-3), 48.79 (C-5), 34.09, 33.19 (C-8, C-1),
m
K
2
/
4
3
2
4
3
0.02 (C-2), 27.35 (CH -10), 26.04 (CH , t-Bu), 24.78
3 3

60
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