Synthesis and glycosidase inhibitory activity of enantiopure polyhydroxylated octahydroindoles and decahydroquinolines, analogs to castanospermine

Article abstract of DOI:10.1016/j.tet.2003.09.044

The synthesis of new enantiopure polyhydroxylated octahydroindoles and decahydroquinolines, analogs to castanospermine, via a double reductive amination of enantiopure cyclic ketoaldehyde, and their inhibitory activity against α- or β-D-glucosidases, α-D-

Full text of DOI:10.1016/j.tet.2003.09.044

Tetrahedron 59 (2003) 8721–8730
Synthesis and glycosidase inhibitory activity of enantiopure
polyhydroxylated octahydroindoles and decahydroquinolines,
analogs to castanospermine
*
Christine Gravier-Pelletier, William Maton, Gildas Bertho and Yves Le Merrer
´ ´
Universite Rene Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS,
`
45 rue des Saints-Peres, 75270 Paris Cedex 06, France
Received 8 July 2003; revised 3 September 2003; accepted 15 September 2003
Abstract—The synthesis of new enantiopure polyhydroxylated octahydroindoles and decahydroquinolines, analogs to castanospermine, via
a double reductive amination of enantiopure cyclic ketoaldehyde, and their inhibitory activity against a- or b-D-glucosidases,
a-D-mannosidase and a-L-fucosidase are described.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Polyhydroxylated indolizidine alkaloids are widespread in
nature and possess very diverse and important physiological
properties.1 For example, castanospermine 1 (Fig. 1) is a
competitive inhibitor of a-D-glucosidase which blocks the
processing of N-linked glycoproteins.2 Consequently, this
compound and its derivatives have been extensively studied
as potential therapeutic agents to treat various diseases such
as diabetes,3 cancer4 and HIV.5 Unfortunately many of these
compounds are also toxic to human cells, and the use of
castanospermine as a clinical therapeutic has been with-
drawn. Nevertheless, there is a need to prepare new
polyhydroxylated alkaloid analogs to allow a better under-
standing of the structural requirements for glycosidase
Figure 1.
inhibition and to develop more potent, selective and less
toxic drugs. In that context, we embarked on the synthesis of
of intestinal digestive enzymes and which have been
new compounds with an octahydroindole skeleton, which is
approved to treat diabetes.
the N-atom position isomer of the indolizidine structure
encountered in the castanospermine; furthermore, com-
We report here full results concerning the synthesis of these
pounds displaying a decahydroquinoline skeleton, homolog
new compounds and their evaluation as glycosidase
to the previous one, were also targeted. In an effort to
inhibitors.8 Recently, we have delineated a convenient
produce new inhibitors of glycosidases with a good
access to a polyhydroxylated cycloalkanone (Fig. 2),
specificity, we wished to explore the N-substitution by an
protected as its dithioketal, involving a one-pot domino
aglycon part. The choice of the aglycon moiety was directed
alkylation–cyclization reaction of bis-epoxides derived
by careful examination of known inhibitors, such as
from D-mannitol.9 Herein, we further demonstrate the
miglitol6 (R¼CH2–CH2OH), and voglibose7 (R¼CH(CH2-
utility of this enantiopure polyhydroxylated cycloalkanone
OH)2) which have already been demonstrated as inhibitors
which has the same absolute configuration at the asym-
metric carbon atoms as castanospermine 1. To access to the
target molecules, our retrosynthetic analysis involves a
Keywords: alkaloid; azasaccharide; bicyclic compounds; castanospermine;
glycosidase; octahydroindole; decahydroquinoline; reductive amination.
formal homologation with one or two carbon moieties of the
hydroxymethyl side chain to give the corresponding
*
Corresponding author. Tel.: þ33-142-862-176; fax: þ33-142-868-387;
e-mail: yves.le-merrer@univ-paris5.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.044

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C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
Figure 2. Retrosynthetic analysis.
ketoaldehyde, and a subsequent cyclizing double reductive
amination with various primary amines.
Scheme 2. Reagents and conditions: (a) SO3/pyridine, DMSO, Et3N,
CH2Cl2, rt, 93%; (b) Ph3PCHCHO, PhCH3, 558C, 40% or (EtO)2POCH2-
CO2Et, t-BuOK, THF, 2788C, 85%; (c) TsNH-NH2, NaOAc, THF, H2O,
788C, 94% from 9; (d) DIBAL-H, PhCH3, 2788C, 58%; (e) NBS, acetone,
H2O, 2508C, 75%.
2. Results and discussion
The preparation of the indolizidine analogs of castano-
spermine requires, at first, elongation of the hydroxymethyl
side chain of the dithioketal polyhydroxylated cyclo-
alkanone 2 by one carbon atom to reach the ketoaldehyde
6 (Scheme 1).
Wittig olefination of the aldehyde 7 by treatment with the
formylmethylene triphenylphosphorane in toluene at 558C
gave the pure trans-a,b-ethylenic aldehyde 8 in 40% yield
(Jtrans¼15.8 Hz). Attempts to complete this reaction were
unsuccessful. Thus, increasing the reaction time or the
temperature did not improve the yield, and increasing the
equivalent of the ylide gave the corresponding a,b,g,d-
diethylenic aldehyde. To overcome this difficulty, we used a
Horner–Wadsworth–Emmons reaction with the anion of
triethylphosphonoacetate, generated in situ by potassium
tert-butoxide,13 to afford the a,b-ethylenic ester 9 in 85%
yield. Nevertheless, a second difficulty was encountered
during the double bond reduction of the a,b-ethylenic ester
9 which proved troublesome again because of the presence
of the dithioketal function. Thus, neither the hetereogeneous
hydrogenation in the presence of palladium on charcoal, or
palladium black, or rhodium on alumina in ethanol, or in the
presence of platinium (IV) oxide in ethyl acetate,14 nor
reduction in the presence of the copper (I) hydride cluster
{((Ph3P)CuH(6, PhCH3, 08C}15 or K-selectridew (THF,
2788C)16 or magnesium turnings (MeOH, reflux)17 gave
any expected product. Sodium borohydride reduction in the
presence of lithium iodide (MeOH, reflux)18 only afforded
the a,b-ethylenic methyl ester resulting from trans-
esterification. Hydrogenation (P¼6 bar) in the presence of
Wilkinson’s catalyst19 in benzene or toluene at 808C gave
no expected product, while in benzene–EtOH an
unexpected lactone 11, probably resulting from double
bond reduction followed by transketalisation and sub-
sequent lactonization, was isolated in a non-reproducible
63% yield. Fortunately, the double bond reduction
performed with tosyl hydrazide20 in aqueous THF at 788C
followed by slow addition of sodium acetate in H2O
afforded the desired saturated ethyl ester 10 (94%). Then,
reduction of the ester21 10 was achieved using DIBAL-H in
toluene at 2788C giving the corresponding aldehyde 12 in
58% yield. Finally, removal of the dithioketal group, as
above, with N-bromosuccinimide at 2508C gave the
ketoaldehyde 13 (75%). During the chemical modifications
Scheme 1. Reagents and conditions: (a) TsCl, Et3N, DMAP, CH2Cl2, rt,
98%; (b) NaCN, DMSO, 908C, 92%; (c) DIBAL-H, PhCH3, 2788C, 77%;
(d) NBS, acetone, H2O, 2508C, 75%.
This was easily accomplished by activation of the free
primary alcohol function as tosylate (98%) followed by
nucleophilic substitution with sodium cyanide in DMSO10
at 908C to afford the nitrile 4 (92%). Subsequent reduction
by di-iso-butylaluminium hydride (DIBAL-H) in toluene at
2788C led to the expected aldehyde 5 (77%). Finally,
hydrolysis of the dithioketal function with N-bromo-
succinimide in aqueous acetone at 2508C11 gave the
ketoaldehyde 6 (75%). No epimerization adjacent to the
ketone was observed by 1H and 13C NMR.
On the other hand, the preparation of the quinolizidine
analogs of castanospermine requires elongation of hydroxy-
methyl side chain of the dithioketal polyhydroxylated
cycloalkanone 2 by two carbon atoms to reach the
ketoaldehyde 13 (Scheme 2). Oxidation of the primary
free alcohol function of 2 was achieved by SO3-pyridine12
in the presence of triethylamine at 208C to afford the
corresponding aldehyde 7 (93%). No trace of epimerization
could be detected by 13C and 1H NMR analysis. It should be
noted that Swern’s oxidation ((COCl)2, DMSO, Et3N,
2788C) of 2, only afforded full degradation of the starting
material, probably because of the sulphur participation.
1
of 2 in 13, no epimerization was observed by H and 13C
NMR.
We next turned our attention to the double reductive
amination22 of the ketoaldehyde 6 or 13 with various

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
8723
Scheme 3. Reagents and conditions: (a) RNH2, NaBH3CN, MeOH, AcOH,
50–75%; (b) TFA, H2O, or H2, Pd(OH)2, EtOH then TFA, H2O, 50–90%.
primary amines as the origin of the octahydroindole or
decahydroquinoline skeleton. Based on diversity, hydro-
philicity and expected further reactivity of amino-building
blocks, three primary amines were selected: benzylamine,
2-ethanolamine, and bis-O-tert-butyldimethylsilylserinol,
chosen to afford, the N-unsubstituted derivative analog of
castanospermine, as a reference in the inhibition studies, and
the aglycon part of miglitol and voglibose, respectively. For
example, treatment of the ketoaldehyde 6 (Scheme 3) with
either benzylamine, 2-ethanolamine, or bis-O-tert-butyl-
dimethylsilylserinol in the presence of acetic acid and
sodium borohydride in methanol at 208C afforded the
expected octahydroindole 14a, 14b, or 14c, isolated as a
single product in 50, 62 or 75% yield, respectively. 1H and
13C NMR analysis established without ambiguity firstly, the
absence of epimerization during the reaction, and secondly a
cis relationship at the ring junction (14a, for example:
J3a,7a¼ca. 4.4 Hz). Finally, hydrogenolysis of the N-benzyl
bond of 14a in the presence of catalytic palladium
hydroxide (46%), followed by acidic hydrolysis of both
acetonide and silylether and subsequent purification by ion
exchange chromatography led to the desired analog of
castanospermine 16a (66%). For compounds 14b and 14c,
deprotections were achieved in a single step by acidic
hydrolysis (TFA-H2O) to give after purification, as above,
the N-substituted analogs 16b and 16c in 98 and 92% yield,
respectively.
Scheme 4. Reagents and conditions: (a) RNH2, NaBH3CN, MeOH, AcOH;
(b) TFA, H2O, or H2, Pd(OH)2, EtOH then TFA, H2O, 50–92%.
NMR spectrum (J4a,8a¼ca. 12.8 and 3.2 Hz, respectively) of
the crude mixture 17/18. Then, complete deprotection was
carried out under similar conditions as in the octahydro-
indole series to afford after purification by ion exchange
chromatography the targeted pure decahydroquinolines 21a,
21b, 21c, 22a, 22b, and 22c.
3. Inhibition studies23
The new polyhydroxylated alkaloids 16, 21 and 22 were
screened against four common glycosidases (a-D-gluco-
sidase from Bacillus stearothermophilus, b-D-glucosidase
from almonds, a-D-mannosidase from Jack beans and a-L-
fucosidase from bovine kidney). The data are summarized
in the Table 1 and compared with the reported activity of the
castanospermine 1. The polyhydroxylated octahydroindoles
16a, 16b and 16c whose structure is closely related to that of
indolizidine moiety encountered in the castanospermine are
weakly or no-potent on the four commercially available
enzymes. The same behavior was observed for the homo-
analogs, with a polyhydroxylated decahydroquinoline
skeleton 21 and 22, except for the N-substituted derivatives
by the aglycon part of the voglibose. In the later case,
interestingly both epimers at the ring junction competitively
and almost exclusively inhibit the a-L-fucosidase (Ki¼70
and 18 mM for 21c and 22c, respectively).
In a similar manner, access to the decahydroquinoline
analogs has been carried out from the ketoaldehyde 13
(Scheme 4).
Nevertheless, it should be noted that the reductive amination
led to a mixture of the two epimers 17 and 18 at the ring
junction which could be easily separated by flash chroma-
tography. The trans/cis ratio, 75/25, 60/40 and 40/60,
1
respectively for a, b and c has been evaluated by the H
Table 1. Comparison of inhibitory activities for castanospermine 1, polyhydroxylated octahydroindoles 16 and decahydroquinolines 21, 22. Percentage of
inhibitions at 1 mM and Ki in mM (in bold) when measured
Enzyme
1
16a (%)
16b (%)
16c (%)
21a (%)
21b (%)
21c (%)
22b (%)
22c (%)
a-D-Glu
b-D-Glu
a-D-Man
a-L-Fuc
8 mM
12
9
25
11
10
15
25
13
29
23
29
8
5
26
17
14
2
18
14
4
70 mM
12
5
11
19
14
18 mM
n.i.a
24
n.i.a
7
39
a
No inhibition detected.

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C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
These Ki values, in the low micromolar range, show that the
polyhydroxylated decahydroquinoline skeleton can fit in the
active site of the a-L-fucosidase, on one hand and revealed
the importance of the aglycon part of voglibose, on the other
hand.
chloride (949 mg, 4.98 mmol, 3 equiv.). After stirring for
14 h, an HCl aqueous solution (1 M, 2 mL) was added and
the resulting mixture was extracted with CH2Cl2. The
combined organic layers were then washed with a saturated
aqueous NH4Cl solution, dried (MgSO4) filtered and
concentrated in vacuo. Flash chromatography of the residue
(cyclohexane/EtOAc 97:3) afforded the pure tosylate 3
(939.5 mg) as a white solid, in 98% yield. Rf 0.49
(cyclohexane/EtOAc 8:2); mp 1128C; [a]D¼þ7 (c 1.0,
CH2Cl2); 1H NMR d 7.85 (dd, 2H, Ja,b¼8.2 Hz, Hara), 7.30
(dd, 2H, Jb,a¼8.2 Hz, Harb), 4.68 (dd, 1H, J7a,7b¼10.3 Hz,
The biological activity of the synthesized compounds was
further evaluated towards a-D-galactosidase from green
coffee beans, b-D-galactosidase from Thermus thermophilus
and pancreatic porcine a-amylase. However, none of them
exhibited significant activity against these enzymes.
J7a,6¼3.9 Hz, H7a), 4.32 (dd, 1H, J7b,7a¼10.3 Hz, J7b,6
¼
5.2 Hz, H7b), 3.92 (ddd, 1H, J3,2b¼10.2 Hz, J3,4¼9.1 Hz,
J3,2a¼4.2 Hz, H3), 3.53 (dd, 1H, J5,6¼11.5 Hz, J5,4¼9.1 Hz,
H5), 3.27 (dd, 1H, J4,5¼J4,3¼9.1 Hz, H4), 3.17–3.00 (m,
4. Conclusion
0
0
1H, H1 a), 3.06–2.98 (m, 2H, H3 a,2a), 2.70–2.53 (m, 2H,
The present work outlined an efficient synthetic pathway to
build various enantiopure polyhydroxylated octahydro-
indoles and decahydroquinolines. Biological studies
indicate, notably, that the polyhydroxylated decahydro-
quinoline for which the N-atom was substituted by the
aglycon part of voglibose is an inhibitor of a-L-fucosidase
with Ki in the low micromolar range. This skeleton
constitutes a new lead for selective inhibition of this
enzyme.
0
0
H1 b,3 b), 2.43 (s, 3H, Me), 2.13–1.98 (m, 1H, H2 a,6), 1.85–
0
0
1.70 (m, 1H, H2 b), 1.78 (dd, 1H, J2b,2a¼14.3 Hz, J2b,3
¼
10.2 Hz, H2b), 1.33, 1.29 (2s, 6H, CMe2), 0.88 (s, 9H, tBu),
0.08 (s, 6H, SiMe2); 13C NMR d 144.4, 133.2, 129.5, 128.3
(Car), 110.3 (CMe2), 84.4 (C4), 74.9 (C5), 68.8 (C3), 68.6
(C7), 52.0 (C1), 49.2 (C6), 46.0 (C2), 26.8 (CMe2), 26.6,
0
0
0
25.8, 25.1 (C1 ,2 ,3 ), 25.8, 18.3 (tBu), 24.6, 24.8 (SiMe2).
5.1.2. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-
cyanomethyl-4,5-O-methylethylidene-3,4,5-trihydroxy-
cyclohexan-1-one 1,3-propanedithioketal (4). To a sus-
pension of the tosylate 3 (707.6 mg, 1.23 mmol) in dimethyl
sulfoxide (16 mL) was added sodium cyanide (185.6 mg,
3.79 mmol, 3.1 equiv.). The resulting mixture was heated to
808C for 4 h and then cooled to 208C, prior to H2O (10 mL)
addition. After 5 or 6 extractions with ether, the combined
organic layers were dried (MgSO4), filtered and concen-
trated in vacuo. Flash chromatography of the residue
(cyclohexane/CH2Cl2 7:3) gave the nitrile 4 (487.7 mg) as
a white solid in 92% yield. Rf 0.1 (cyclohexane/CH2Cl2
7:3); mp 1298C; [a]D¼þ7 (c 1.1, CH2Cl2); IR (KBr):
5. Experimental
1H NMR (250 MHz) and 13C NMR (63 MHz) spectra were
recorded on a Bruker AM250 in CDCl3 (unless indicated).
Chemical shifts (d) are reported in ppm and coupling
constants are given in Hz. IR spectra were recorded on a
Perkin–Elmer 783 Infrared Spectrophotometer. Optical
rotations were measured on a Perkin–Elmer 241C polari-
meter with sodium (589 nm) or mercury (365 nm) lamp.
Mass spectra, chemical ionization (CI), and high resolution
´
(HRMS) were recorded by the Service de Spectrometrie de
Masse, Ecole Normale Superieure, Paris. All reactions were
2254 cm21
;
1H NMR d 3.99 (ddd, 1H, J3,2b¼10.1 Hz,
´
J3,4¼9.0 Hz, J3,2a¼4.2 Hz, H3), 3.64 (dd, 1H, J5,6¼11.4 Hz,
J5,4¼9.0 Hz, H5), 3.36 (dd, 1H, J4,3¼J4,5¼9.0 Hz, H4),
carried out under an argon atmosphere, and were monitored
by thin-layer chromatography with Merck 60F-254 pre-
coated silica (0.2 mm) on glass. Flash chromatography was
performed with Merck Kieselgel 60 (200–500 mm); the
0
3.23–3.06 (m, 1H, H1 a), 3.07 (dd, 1H, J7a,b¼17.3 Hz,
0
J7a,6¼5.0 Hz, H7a), 3.02–2.86 (m, 1H, H3 a), 2.97 (dd, 1H,
J2a,b¼14.3 Hz, J2a,3¼4.3 Hz, H2a), 2.77 (dd, 1H, J7b,a
¼
solvent systems were given v/v. Spectroscopic (1H and 13
C
0
0
17.3 Hz, J7b,6¼5.9 Hz, H7b), 2.78–2.62 (m, 2H, H1 b,3 b),
NMR, MS) and/or analytical data were obtained using
chromatography homogeneous samples. To simplify the
description of NMR-spectroscopic data, N-substituents
[(CH2CH2OH and CH(CH2OH)2] of octahydroindoles and
decahydroquinolines have been named A, B, C:
0
0
2.19–2.01 (m, 2H, H6,2 a), 1.93–1.72 (m, 1H, H2 b), 1.84
(dd, 1H, J2b,a¼14.3 Hz, J2b,3¼10.1 Hz, H2b), 1.39 (s, 6H,
CMe2), 0.90 (s, 9H, tBu), 0.10 (s, 6H, SiMe2); 13C NMR d
118.8 (C8), 110.8 (CMe2), 82.3 (C4), 75.8 (C5), 68.8 (C3),
53.3 (C1), 46.6 (C6), 45.9 (C2), 26.8 (CMe2), 26.8, 25.8, 25.1
0
(C1 ,2 ,3 ), 25.8, 18.3 (tBu), 16.7 (C7), 24.6, 24.8 (SiMe2).
0
0
5.1.3. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-
formylmethyl-4,5-O-methylethylidene-3,4,5-trihydroxy-
cyclohexan-1-one 1,3-propanedithioketal (5). To
a
2788C cooled solution of the nitrile 4 (473.8 mg,
1.10 mmol) in toluene (14 mL) was added dropwise a
solution of di-iso-butylaluminium hydride in toluene
(1.42 M, 1.55 mL, 2.20 mmol, 2 equiv.). After stirring for
1 h while progressively raising the temperature to 208C,
acetone (510 mL), EtOAc (510 mL) and phosphate buffer
(pH 7.2, 510 mL) were successively added and the resulting
mixture was vigorously stirred for 20 min prior to the
further addition of anhydrous sodium sulfate. After stirring
5.1. To the ketoaldehyde 6
5.1.1. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-tosyl-
oxymethyl-4,5-O-methylethylidene-3,4,5-trihydroxy-
cyclohexan-1-one 1,3-propanedithioketal (3). To
solution of the alcohol 2 (700 mg, 1.66 mmol) in dichloro-
methane (4 mL) at 08C were successively added 4,4-
dimethylaminopyridine (27 mg, 0.225 mmol, 0.1 equiv.),
triethylamine (700 mL, 5.02 mmol, 3 equiv.) and tosyl
a

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
8725
for 20 min, the suspension was filtered through a silica gel
pad, the salts were washed with CH2Cl2 and the resulting
filtrate was concentrated in vacuo. Flash chromatography of
the residue (cyclohexane/EtOAc 99:1) led to the aldehyde 5
(372.5 mg) as a white solid in 77% yield. Rf 0.1
(cyclohexane/CH2Cl2 7:3); [a]D¼þ10 (c 1.1, CH2Cl2);
mp 828C; 1H NMR d 9.78 (t, 1H, JCHO,7a¼JCHO,7b¼1.8 Hz,
brine, dried (Na2SO4), filtered and concentrated in vacuo.
The residue was then purified by flash chromatography
(cyclohexane/EtOAc 97:3) to give the pure aldehyde 7
(919.4 mg) as a white solid in 93% yield. Rf 0.57
(cyclohexane/EtOAc 8:2); mp 1128C; [a]D¼þ33 (c 1.0,
1
CH2Cl2); H NMR d 9.99 (d, 1H, JCHO,6¼2.8 Hz, HCHO),
4.04 (dd, 1H, J5,6¼11.4 Hz, J5,4¼9.1 Hz, H5), 4.03 (ddd,
CHO), 4.00 (ddd, 1H, J3,2b¼10.3 Hz, J3,4¼9.1 Hz, J3,2a
¼
1H, J3,2b¼10.1 Hz, J3,4¼9.1 Hz, J3,2a¼4.3 Hz, H3), 3.36
0
4.3 Hz, H3), 3.60 (dd, 1H, J5,6¼11.3 Hz, J5,4¼9.1 Hz, H5),
3.38 (dd, 1H, J4,3¼J4,5¼9.1 Hz, H4), 3.24–3.05 (m, 1H,
(dd, 1H, J4,3¼J4,5¼9.1 Hz, H4), 3.15 (ddd, 1H, J1 a,b
¼
0
0
0
0
0
14.7 Hz, J1 a,2 b¼12.1 Hz, J1 a,2 a¼2.7 Hz, H1 a), 3.07–2.89
0
0
H1 a), 3.15 (ddd, 1H, J7a,b¼17.6 Hz, J7a,6¼4.9 Hz,
(m, 1H, H3 a), 2.98 (dd, 1H, J2a,b¼14.1 Hz, J2a,3¼4.3 Hz,
0
0
H2a), 2.78–2.64 (m, 2H, H1 b,3 b), 2.62 (dd, 1H, J6,5
0
J7a,CHO¼1.8 Hz, H7a), 3.04–2.86 (m, 1H, H3 a), 2.98 (dd,
¼
0
1H, J2a,b¼14.2 Hz, J2a,3¼4.3 Hz, H2a), 2.77–2.57 (m, 3H,
11.4 Hz, J6,CHO¼2.8 Hz, H6), 2.12–2.04 (m, 1H, H2 a),
0
0
0
H7b,1 b,3 b), 2.48 (ddd, 1H, J6,5¼11.3 Hz, J6,7b¼6.9 Hz,
1.95–1.78 (m, 1H, H2 b), 1.86 (dd, 1H, J2b,a¼14.2 Hz,
0
J6,7a¼4.9 Hz, H6), 2.19–1.99 (m, 1H, H2 a), 1.94–1.69
J2b,3¼10.1 Hz, H2b), 1.39, 1.38 (s, 6H, CMe2), 0.91 (s, 9H,
tBu), 0.11 (s, 6H, SiMe2); 13C d 198.6 (C7), 111.1 (CMe2),
84.4 (C4), 72.4 (C5), 68.7 (C3), 60.7 (C6), 49.7 (C1), 46.2
0
(m, 1H, H2 b), 1.87 (dd, 1H, J2b,a¼14.2 Hz, J2b,3¼10.3 Hz,
H2b), 1.34 (s, 6H, CMe2), 0.90 (s, 9H, tBu), 0.11 (s, 6H,
SiMe2); 13C NMR d 200.8 (C8), 110.3 (CMe2), 84.5 (C4),
76.6 (C5), 69.0 (C3), 53.6 (C1), 46.0 (C7), 44.4 (C6), 42.9
0
0
0
(C2), 26.9 (CMe2), 26.6, 26.2, 25.0 (C1 ,2 ,3 ), 25.8, 18.3
(tBu), 24.6, 24.8 (SiMe2); Anal. calcd for C19H34O4S2Si:
C, 54.50; H, 8.19; found: C, 54.44; H, 8.23.
0
(C2), 26.9, 26.8 (CMe2), 26.6, 25.3 (C1 ,2 ,3 ), 25.9, 18.3
0
0
(tBu), 24.5, 24.8 (SiMe2).
5.2.2. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-
formylethylene-4,5-O-methylethylidene-3,4,5-tri-
hydroxycyclohexan-1-one 1,3-propanedithioketal (8). To
a solution of the aldehyde 7 (83.9 mg, 0.2 mmol) in toluene
(1 mL) was added formylmethylene triphenyl-phosphorane
(67 mg, 0.22 mmol, 1.1 equiv.) and the mixture was stirred
at 558C for 48 h prior to the addition of H2O. After ether
extractions, the combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. Flash
chromatography of the residue (toluene/CH2Cl2 9:1) led to
the unsaturated aldehyde 8 (28.2 mg) as a white solid in
40% yield. Rf 0.1 (toluene/CH2Cl2 9:1; [a]D¼þ39 (c 1.0,
5.1.4. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-
formylmethyl-4,5-O-methylethylidene-3,4,5-trihydroxy-
cyclohexan-1-one (6). To a 2508C cooled solution of
N-bromosuccinimide (1.02 g, 5.75 mmol, 8 equiv.) in a 98:2
mixture of acetone/H2O (33 mL) was added a solution of the
dithioketal 5 (311.3 mg, 0.719 mmol) in acetone (11 mL).
The mixture was then stirred for 30 min at 2508C prior to
the addition of a saturated Na2S2O3 aqueous solution
(10 mL). After increasing the temperature to 208C and
evaporating the acetone, the resulting residue was extracted
with ether and the combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. The crude
ketoaldehyde was then purified by flash chromatography
(cyclohexane/EtOAc 9:1) to afford 6 (185.4 mg) as a
colorless oil in 75% yield. Rf 0.35 (cyclohexane/EtOAc
8:2); [a]Hg¼þ40 (c 0.95, CH2Cl2); 1H NMR d 9.79 (s, 1H,
CHO), 3.96 (ddd, 1H, J3,2b¼9.6 Hz, J3,4¼8.9 Hz,
J3,2a¼5.6 Hz, H3), 3.82 (dd, 1H, J4,3¼J4,5¼8.9 Hz, H4),
3.36 (dd, 1H, J5,6¼12.7 Hz, J5,4¼8.9 Hz, H5), 3.07 (ddd,
1H, J6,5¼12.7 Hz, J6,7b¼7.4 Hz, J6,7a¼4.0 Hz, H6), 2.82
(dd, 1H, J7b,a¼18.0 Hz, J7b,6¼7.4 Hz, H7b), 2.76 (dd, 1H,
1
CH2Cl2); H NMR d 9.60 (d, 1H, JCHO,8¼7.9 Hz, HCHO),
7.14 (dd, 1H, J7,8¼15.8 Hz, J7,6¼6.9 Hz, H7), 6.38 (ddd,
1H, J8,7¼15.8 Hz, J8,CHO¼7.9 Hz, J8,6¼0.9 Hz, H8), 4.04
(ddd, 1H, J3,2b¼10.2 Hz, J3,4¼9.1 Hz, J3,2a¼4.3 Hz, H3),
3.80 (dd, 1H, J5,6¼11.1 Hz, J5,4¼9.1 Hz, H5), 3.36 (dd, 1H,
0
J4,3¼J4,5¼9.1 Hz, H4), 3.14 (ddd, 1H, J1 a,b¼14.7 Hz,
0
0
0
0
0
J1 a,2 b¼12.2 Hz, J1 a,2 a¼2.8 Hz, H1 a), 3.00 (dd, 1H,
J2a,b¼14.2 Hz, J2a,3¼4.3 Hz, H2a), 3.06–2.88 (m, 1H,
0
H3 a), 2.78–2.59 (m, 3H, H1 b,3 b,6), 2.18–2.02 (m, 1H,
0
0
0
0
H2 a), 1.95–1.73 (m, 1H, H2 b), 1.87 (dd, 1H, J2b,a¼14.2 Hz,
J2b,3¼10.2 Hz, H2b), 1.38 (s, 6H, CMe2), 0.91 (s, 9H, tBu),
0.11 (s, 6H, SiMe2); 13C NMR d 193.9 (C9), 152.4 (C8),
136.1 (C7), 110.5 (CMe2), 84.6 (C4), 74.9 (C5), 68.7 (C3),
52.9 (C6), 52.8 (C1), 45.8 (C2), 26.7 (CMe2), 26.9, 26.1, 25.1
J2a,b¼15.8 Hz, J2a,3¼5.8 Hz, H2a), 2.64 (dd, 1H, J7a,b
¼
18.0 Hz, J7a,6¼4.0 Hz, H7a), 2.46 (dd, 1H, J2b,a¼15.8 Hz,
J2b,3¼9.6 Hz, H2b), 1.44, 1.39 (2s, 6H, (CH3)2C), 0.87 (s,
9H, tBu), 0.09, 0.07 (s, 6H, SiMe2); 13C NMR d 204.5 (C1),
199.5 (C8), 112.2 (CMe2), 83.9 (C4), 76.4 (C5), 67.6 (C3),
48.7 (C2), 48.3 (C6), 40.0 (C7), 30.2, 29.7 (CMe2), 26.9, 18.1
(tBu), 24.6, 25.0 (SiMe2).
0
(C1 ,2 ,3 ), 25.8, 18.3 (tBu), 24.6, 24.8 (SiMe2).
0
0
5.2.3. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-ethyl-
acrylate-4,5-O-methylethylidene-3,4,5-trihydroxycyclo-
hexan-1-one 1,3-propanedithioketal (9). To a suspension
of potassium tert-butoxide (958 mg, 8.54 mmol,
4.01 equiv.) in THF (13 mL), at 08C, was added triethyl-
phosphonoacetate (1.7 mL, 8.57 mmol, 4.02 equiv.). After
stirring for 20 min, the mixture was cooled to 2788C and a
solution of the aldehyde 8 (894.3 mg, 2.13 mmol) in THF
(1.1 mL) was added dropwise. The resulting mixture was
stirred for 3 h at 2788C and a saturated NH4Cl aqueous
solution was added. After ether extraction, the combined
organic layers were dried (MgSO4), filtered and concen-
trated in vacuo. Flash chromatography of the residue
(cyclohexane/EtOAc 98:2) afforded the unsaturated ester 9
5.2. To the ketoaldehyde 13
5.2.1. [3S,4S,5R,6S]-3-O-tert-Butyldimethylsilyl-6-
formyl-4,5-O-methylethylidene-3,4,5-trihydroxycyclo-
hexan-1-one 1,3-propanedithioketal (7). To a solution of
the alcohol 2 (1.04 g, 2.47 mmol) in CH2Cl2 (4.5 mL) were
successively added dimethyl sulfoxide (1.7 mL, 23.9 mmol,
9.7 equiv.), then triethylamine (3.6 mL, 25.6 mmol,
10.4 equiv.) and SO3/pyridine (1.79 g, 12.9 mmol,
5.2 equiv.) and the resulting mixture was stirred for 2 h at
208C. After the addition of ether (50 mL) and H2O (50 mL)
followed by decantation, the organic layer was washed with

8726
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
(919.4 mg) as a white solid in 85% yield. Rf 0.33
1
hexane, 1.54 mL, 1.54 mmol). After stirring for 1 h at
2788C, a saturated sodium tartrate aqueous solution
(4.2 mL), brine (2.1 mL), H2O (2.1 mL) and ether
(8.4 mL) were successively added and the resulting mixture
was stirred at 208C for 2 h. After decantation, the aqueous
layer was extracted with ether and the combined organic
layers were dried (MgSO4), filtered and concentrated in
vacuo. Flash chromatography of the residue (cyclohexane/
EtOAc 9:1) afforded the expected aldehyde 12 (359.6 mg)
as a white solid in 58% yield. Rf 0.32 (cyclohexane/EtOAc
(cyclohexane/EtOAc 9:1); [a]D¼þ27 (c 1.0, CH2Cl2); H
NMR d 7.19 (dd, 1H, J7,8¼15.7 Hz, J7,6¼7.8 Hz, H7), 6.07
(dd, 1H, J8,7¼15.7 Hz, J8,6¼0.8 Hz, H8), 4.18 (q, 2H,
J¼7.1 Hz, OCH2CH3), 4.02 (ddd, 1H, J3,2b¼10.2 Hz,
J3,4¼9.0 Hz, J3,2a¼4.2 Hz, H3), 3.78 (dd, 1H, J5,6¼11 Hz,
J5,4¼9.0 Hz, H5), 3.35 (dd, 1H, J4,3¼J4,5¼9 Hz, H4), 3.06
0
0
0
0
0
(ddd, 1H, J1 a,b¼14.4 Hz, J1 a,2 b¼11.3 Hz, J1 a,2 a¼3.1 Hz,
0
0
H1 a), 2.99–2.83 (m, 1H, H3 a), 2.93 (dd, 1H, J2a,b¼14.1 Hz,
0
0
J2a,3¼4.2 Hz, H2a), 2.77–2.64 (m, 2H, H1 b,3 b,), 2.56 (dd,
1
1H, J6,5¼11.0 Hz, J6,7¼7.8 Hz, H6), 2.11–1.97 (m, 1H,
9:1); mp 878C; [a]D¼þ3 (c 1.0, CH2Cl2); H NMR d 9.74
0
0
H2 a), 1.96–1.74 (m, 1H, H2 b), 1.82 (dd, 1H, J2b,a¼14.1 Hz,
J2b,3¼10.2 Hz, H2b), 1.37 (s, 6H, CMe2), 1.28 (t, 3H,
J¼7.1 Hz, OCH2CH3), 0.90 (s, 9H, tBu), 0.10 (s, 6H,
SiMe2); 13C NMR d 166.1 (C9), 143.7 (C8), 125.3 (C7),
110.3 (CMe2), 84.5 (C4), 75.2 (C5), 68.7 (C3), 60.3
(OCH2CH3), 53.3 (C6), 52.8 (C1), 46.2 (C2), 26.8 (CMe2),
(t, 1H, JCHO,8¼1.1 Hz, HCHO), 3.96 (ddd, 1H, J3,2b¼
10.3 Hz, J3,4¼9.1 Hz, J3,2a¼4.2 Hz, H3), 3.57 (dd, 1H,
J5,6¼11.0 Hz, J5,4¼9.1 Hz, H5), 3.29 (dd, 1H, J4,3¼J4,5
¼
0
0
0
9.1 Hz, H4), 3.14 (ddd, 1H, J1 a,b¼14.8 Hz, J1 a,2 b¼12.5 Hz,
0
0
0
0
J1 a,2 a¼2.7 Hz, H1 a), 3.04–2.87 (m, 1H, H3 a), 2.95 (dd, 1H,
J2a,b¼14.2 Hz, J2a,3¼4.2 Hz, H2a), 2.86–2.43 (m, 5H,
0
0
0
0
H1 b,3 b,8a,8b,7a), 2.16–2.00 (m, 1H, H2 a), 1.99–1.53 (m,
0
0
26.2, 25.0 (C1 ,2 ,3 ), 25.8, 18.3 (tBu), 14.3 (OCH2CH3),
24.6, 24.8 (SiMe2); Anal. calcd for C23H40O5S2Si: C,
56.52; H, 8.25; found: C, 56.48; H, 8.42.
0
3H, H2 b,7b,6), 1.80 (dd, 1H, J2b,a¼14.2 Hz, J2b,3¼10.3 Hz,
H2b), 1.33 (s, 6H, CMe2), 0.89 (s, 9H, tBu), 0.09 (s, 6H,
SiMe2); 13C NMR d 202.7 (C9), 109.9 (CMe2), 84.6
(C4), 78.1 (C5), 69.0 (C3), 54.5 (C1), 49.0 (C6), 45.7
5.2.4. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-ethyl-
carboxyethyl-4,5-O-methylethylidene-3,4,5-trihydroxy-
cyclohexan-1-one 1,3-propanedithioketal (10). To a
0
0
0
(C2), 43.1 (C8), 26.9 (CMe2), 26.7, 25.9, 25.6 (C1 ,2 ,3 ),
25.9, 18.3 (tBu), 22.2 (C7), 24.5, 24.8 (SiMe2); Anal. calcd
for C21H38O4S2Si: C, 56.46; H, 8.57; found: C, 56.70; H,
8.99.
suspension of the unsaturated ester
9
(526.8 mg,
1.08 mmol) and tosyl hydrazide (2.44 g, 13.1 mmol,
12.1 equiv.) in a 1:1 mixture of THF/H2O (30 mL) heated
at 788C was added dropwise a solution of sodium acetate
(1.79 g, 21.8 mmol, 20.2 equiv.) in H2O (8 mL). After
stirring for 8 h at 788C, the mixture was concentrated to a
final volume of 10 mL and a saturated NH4Cl aqueous
solution (30 mL) and pure H2O (10 mL) were added. After
CH2Cl2 extractions, the combined organic layers were
washed with a NaOH aqueous solution (2N), dried
(Na2SO4), filtered and concentrated in vacuo. Flash
chromatography (cyclohexane/EtOAc 9:1) of the residue
gave the saturated ester 10 (494.9 mg) as a white solid in
94% yield. Rf 0.45 (cyclohexane/EtOAc 9:1); mp 1158C;
[a]Hg¼þ13 (c 1.1, CH2Cl2); 1H NMR d 4.12 (q, 2H,
J¼7.1 Hz, OCH2CH3), 3.26 (ddd, 1H, J3,2b¼10.3 Hz,
5.2.6. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-
formylethyl-4,5-O-methylethylidene-3,4,5-trihydroxy-
cyclohexan-1-one (13). The dithioketal hydrolysis of the
aldehyde 12 (353.1 mg, 0.792 mmol) was carried out under
the same conditions as above for the transformation 5!6,
and led to the ketoaldehyde 13 (209.2 mg) as a solid in 75%
yield, after flash chromatographic purification (cyclo-
hexane/EtOAc 9:1). Rf 0.46 (cyclohexane/EtOAc 8:2); mp
1
628C; [a]D¼þ9 (c 1.0, CH2Cl2); H NMR d 9.79 (t, 1H,
JCHO,8a¼JCHO,8b¼1.1 Hz, HCHO), 3.91 (ddd, 1H, J3,2b
¼
9.9 Hz, J3,4¼8.9 Hz, J3,2a¼5.8 Hz, H3), 3.77 (dd, 1H,
J4,3¼J4,5¼8.9 Hz, H4), 3.23 (dd, 1H, J5,6¼12.5 Hz, J5,4
8.9 Hz, H5), 2.79 (dd, 1H, J2a,b¼15.5 Hz, J2a,3¼5.8 Hz,
H2a), 2.66–2.45 (m, 3H, H6,8a,8b), 2.42 (dd, 1H, J2b,a
¼
J3,4¼9.1 Hz, J3,2a¼4.3 Hz, H3), 3.58 (dd, 1H, J5,6
11.0 Hz, J5,4¼9.1 Hz, H5), 3.35 (dd, 1H, J4,3¼J4,5
¼
¼
¼
15.5 Hz, J2b,3¼9.9 Hz, H2b), 2.17–1.94 (m, 1H, H7a), 1.92–
1.72 (m, 1H, H7b), 1.43, 1.38 (2s, 6H, CMe2), 0.86 (s, 9H,
tBu), 0.08, 0.06 (2s, 6H, SiMe2); 13C NMR d 205.9 (C1),
201.9 (C9), 112.0 (CMe2), 83.8 (C4), 77.7 (C5), 67.6 (C3),
51.9 (C6), 49.2 (C2), 41.1 (C8), 30.2 (C7), 27.0 (CMe2), 25.8,
18.2 (tBu), 24.6, 25.0 (SiMe2); Anal. calcd for
C18H32O4Si: C, 60.64; H, 9.05; found: C, 60.48; H, 9.19.
0
0
0
9.1 Hz, H4), 3.14 (ddd, 1H, J1 a,b¼14.7 Hz, J1 a,2 b¼12.5
0
0
0
0
Hz, J1 a,2 a¼2.8 Hz, H1 a), 3.01–2.85 (m, 1H, H3 a), 2.99 (dd,
1H, J2a,b¼14.1 Hz, J2a,3¼4.3 Hz, H2a), 2.73–2.58 (m, 3H,
0
0
H1 b,3 b,8a), 2.57–2.35 (m, 2H, H8b,7a), 2.14–2.00 (m, 1H,
0
0
H2 a), 1.96–1.60 (m, 3H, H2 b,7b,6), 1.81 (dd, 1H,
J2b,a¼14.2 Hz, J2b,3¼10.3 Hz, H2b), 1.33 (s, 6H, CMe2),
1.24 (t, 3H, J¼7.1 Hz, OCH2CH3), 0.89 (s, 9H, tBu),
0.10 (s, 6H, SiMe2); 13C NMR d 173.6 (C9), 109.8 (CMe2),
84.6 (C4), 78.2 (C5), 69.1 (C3), 60.1 (OCH2CH3), 54.4
(C1), 49.8 (C6), 45.7 (C2), 33.8 (C8), 26.9 (CMe2),
5.3. To the octahydroindoles (16)
To a solution of the ketoaldehyde 6 (0.387 mmol) in
methanol (1 mL) cooled to 08C, were successively added
sodium cyanoborohydride (0.753 mmol, 1.9 equiv.) and a
mixture of a primary amine (387 mmol, 1 equiv.) and acetic
acid (0.387 mmol, 1 equiv.) in methanol (0.4 mL). After
stirring for 24 h at 208C, the mixture was concentrated in
vacuo, and a 10% aqueous solution of NaOH was added and
was followed by CH2Cl2 extractions. The combined organic
layers were dried (Na2SO4), filtered and concentrated in
vacuo. Flash chromatographic purification (cyclohexane/
EtOAc/Et3N 97:3:0.03) afforded the corresponding pure
octahydroindole 14.
0
0
0
26.7, 25.6, 25.0 (C1 ,2 ,3 ,7), 25.9, 18.3 (tBu), 14.3
(OCH2CH3), 24.5, 24.8 (SiMe2); Anal. calcd for
C23H42O5S2Si: C, 56.29; H, 8.63; found: C, 56.28; H,
8.65.
5.2.5. [3S,4S,5R,6R]-3-O-tert-Butyldimethylsilyl-6-
formylethyl-4,5-O-methylethylidene-3,4,5-trihydroxy-
cyclohexan-1-one 1,3-propanedithioketal (12). To a
2788C cooled solution of the ester 10 (685.9 mg,
1.40 mmol) in a 8:2 mixture of hexane/CH2Cl2 (9 mL)
was added dropwise di-iso-butylaluminium hydride (1 M in

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
8727
5.3.1. [3aS,4R,5S,6S,7aS]-1-Benzyl-6-O-tert-butyl-
dimethylsilyl-4,5-O-methylethylidene-4,5,6-trihydroxy-
octahydroindole (14a). 50% yield from 6 (132.4 mg,
0.387 mmol); Rf 0.3 (cyclohexane/EtOAc 95:5);
5.3.4. [3aS,4R,5S,6S,7aS]-6-O-tert-Butyldimethylsilyl-
4,5-O-methylethylidene-4,5,6-trihydroxyoctahydro-1H-
indole (15a). To a suspension of palladium hydroxide
(80 mg) in absolute EtOH (0.5 mL), saturated with
dihydrogen, was added a solution of the N-benzylamine
14a (90.5 mg, 0.217 mmol) in a mixture of absolute EtOH
(0.5 mL) and EtOAc (0.4 mL). After stirring for 4 days at
208C, the catalyst was removed by filtration through a Celite
pad and the filtrate was concentrated in vacuo. Flash
chromatography (CH2Cl2/MeOH 99:1) gave the pure amine
15 (32.1 mg) as an oil in 45% yield. Rf 0.2 (CH2Cl2/MeOH
98:2); [a]D¼þ49 (c 1.0, CH2Cl2); 1H NMR d 3.94 (ddd, 1H,
0
1
[a]D¼þ56 (c 1.0, CH2Cl2); H NMR d 7.35–7.20 (m, 5H,
Har), 4.07–3.94 (m, 1H, H6), 4.01, 3.08 (AB, 2H,
JAB¼13.1 Hz, NCH2Ph), 3.54 (dd, 1H, J4,3a¼10.3 Hz,
J4,5¼9.2 Hz, H4), 3.30 (dd, 1H, J5,6¼J5,4¼9.2 Hz, H5),
0
0
2.99 (ddd, 1H, J2,2 ¼13.7 Hz, J2,3 ¼9.0 Hz, J2,3¼4.4 Hz,
0
H2b), 2.74–2.68 (m, 1H, H7a), 2.30–2.07 (m, 3H, H7,3a,2 ),
0
0
1.94–1.62 (m, 2H, H3,3 ), 1.54 (ddd, 1H, J7 ,7¼14.7 Hz,
0
0
0
J7 ,6¼10.0 Hz, J7 ,7a¼4.5 Hz, H7 ), 1.40 (s, 6H, CMe2), 0.89
(s, 9H, tBu), 0.09, 0.08 (s, 6H, SiMe2); 13C NMR d 140.7,
128.5, 128.2, 126.8 (Car), 109.1 (CMe2), 83.7 (C5), 80.1
(C4), 69.5 (C6), 64.4 (C7a), 58.1 (NCH2Ph), 52.8 (C2),
42.3 (C3a), 35.0 (C7), 27.0 (CMe2), 25.9, 18.2 (tBu),
24.8 (C3), 24.5 (SiMe2); MS (CI, CH4) 418 (Mþþ1);
HMRS for C24H40NO3Si (Mþþ1): calcd 418.2777; found:
418.2769.
J6,7 ¼J6,5¼9.2 Hz, J6,7¼5.1 Hz, H6), 3.46 (dd, 1H, J4,3a
¼
10.1 Hz, J4,5¼9.2 Hz, H4), 3.25 (dd, 1H, J5,6¼J5,4¼9.2 Hz,
0
0
H5), 2.99 (ddd, 1H, J2,2 ¼13.1 Hz, J2,3 ¼8.8 Hz,
J2,7a¼4.0 Hz, H2), 2.60–2.47 (m, 1H, H7a), 2.25–1.74 (m,
0
0
0
0
5H, H7,3a,3,3 ,2 ), 1.47 (ddd, 1H, J7 ,7¼14.6 Hz, J7 ,6¼9.2 Hz,
0
0
J7 ,7a¼4.8 Hz, H7 ), 1.38, 1.37 (2s, 6H, CMe2), 0.89 (s, 9H,
tBu), 0.08 (s, 6H, SiMe2); 13C NMR d 109.8 (CMe2), 83.8
(C5), 79.9 (C4), 69.0 (C6), 64.6 (C7a), 51.9 (C2), 42.1 (C3a),
34.2 (C7), 27.0 (CMe2), 25.9, 18.2 (tBu), 25.4 (C3), 24.5
(SiMe2).
5.3.2. [3aS,4R,5S,6S,7aS]-1-(20-Hydroxyethyl)-6-O-tert-
butyldimethylsilyl-4,5-O-methylethylidene-4,5,6-tri-
hydroxyoctahydroindole (14b). 62% yield from
(70.8 mg, 0.207 mmol); Rf 0.33 (cyclohexane/EtOAc 9:1);
6
5.3.5. [3aS,4R,5R,6S,7aS]-Octahydro-1H-indole-4,5,6-
triol (16a). The protected derivative 15a (31.6 mg,
97 mmol) in a 9:1 solution of trifluoroacetic acid/H2O
(2 mL) was stirred at 208C for 14 h. After concentration in
vacuo, the resulting oil was triturated in dry ether and the
supernatant was discarded to afford a brownish solid which
was purified by ion-exchange chromatography (Dowexw
50X8-100, 3% aqueous ammonium hydroxide) to give the
octahydroindole 16a (11.1 mg) as a solid in 66% yield.
1
[a]D¼þ63 (c 1.0, CH2Cl2); H NMR d 3.88 (ddd, 1H,
0
J6,7 ¼J6,5¼9.3 Hz, J6,7¼4.6 Hz, H6), 3.72–3.49 (m, 2H,
0
HB,B ), 3.40 (dd, 1H, J4,3a¼10.3 Hz, J4,5¼9.3 Hz, H4), 3.27
(dd, 1H, J5,6¼J5,4¼9.3 Hz, H5), 3.33–3.20 (m, 1H, HA),
0
0
2.99 (ddd, 1H, J2,2 ¼12.2 Hz, J2,3 ¼9.8 Hz, J2,3¼5.7 Hz,
0
0
H2), 2.80–2.65 (m, 1H, H7a), 2.34–2.09 (m, 4H, H3a,2 ,7,A ),
0
0
2.02–1.74 (m, 2H, H3,3 ), 1.50 (ddd, 1H, J7 ,7¼14.6 Hz,
0
0
0
J7 ,6¼9.3 Hz, J7 ,7a¼4.6 Hz, H7 ), 1.38, 1.37 (2s, 6H, CMe2),
0.88 (s, 9H, tBu), 0.08 (s, 6H, SiMe2); 13C NMR d 109.3
(CMe2), 85.6 (C5), 79.5 (C4), 69.2 (C6), 64.4 (C7a), 59.6
(CB), 55.6 (CA), 52.2 (C2), 42.2 (C3a), 35.0 (C7), 27.0
(CMe2), 25.9, 18.3 (tBu), 25.2 (C3), 24.6, 24.9 (SiMe2);
MS (CI, CH4) 372 (Mþþ1); HMRS for C19H38NO4Si2
(Mþþ1): calcd 372.2570; found: 372.2570.
1
[a]D¼þ49 (c 1.0, H2O); H NMR (D2O) d 3.95–3.77 (m,
1H, H6), 3.42–3.26 (m, 2H, H4,5), 3.23 (ddd, 1H,
0
0
J2,2 ¼13.2 Hz, J2,3 ¼9.4 Hz, J2,3¼3.4 Hz, H2), 2.72–2.54
0
(m, 1H, H7a), 2.40–1.94 (m, 4H, H3a,7,2 ,3), 1.88–1.58 (m,
0
2H, H7 ,3 ); 13C NMR (D2O) d 81.1 (C5), 77.9 (C4), 71.5
(C6), 65.5 (C7a), 53.8 (C2), 46.5 (C3a), 33.4 (C7), 28.0 (C3).
0
5.3.3. [3aS,4R,5S,6S,7aS]-1-(10,30-Di-tert-butyldimethyl-
silyloxy-20-propyl)-6-O-tert-butyldimethylsilyl-4,5-O-
methylethylidene-4,5,6-trihydroxyoctahydroindole
5.3.6. [3aS,4R,5R,6S,7aS]-1-(20-Hydroxyethyl)-octa-
hydroindole-4,5,6-triol (16b). The octahydroindole 16b
was obtained from the protected derivative 14b (47.1 mg,
0.128 mmol) under the same conditions as above for 16a
and was isolated (27.6 mg) as a solid in 98% yield.
(14c). 75% yield from
6
(60.9 mg, 0.178 mmol);
1
[a]D¼þ24.5 (c 1.1, CH2Cl2); H NMR (500 MHz) d 3.89
1
0
(ddd, 1H, J6,7 ¼9.5 Hz, J6,5¼9.2 Hz, J6,7¼5.0 Hz, H6), 3.75
[a]D¼þ37 (c 1.0, H2O); H NMR (D2O) d 3.99 (t, 2H,
0
(dd, 1H, JA,A ¼10.4 Hz, JA,B¼6.2 Hz, HA), 3.72 (dd, 1H,
JB,A¼5.3 Hz, HB), 3.95–3.77 (m, 3H, H6, 7a,2), 3.61 (dt, 1H,
0
0
0
0
0
JA ,A¼10.4 Hz, JA ,B¼5.0 Hz, HA ), 3.60 (dd, 1H, JC,C
¼
JA,A ¼13.4 Hz, JA,B¼5.3 Hz, HA), 3.51–3.36 (m, 3H,
0
0
0
0
0
10.0 Hz, JC,B¼5.9 Hz, HC), 3.57 (dd, 1H, JC ,C¼10.0 Hz,
H4,5,2 ), 3.30 (dt, 1H, JA ,A¼13.4 Hz, JA ,B¼5.3 Hz, HA ),
0
0
0
2.63–2.32 (m, 3H, H3a,7,3), 2.27–2.15 (m, 1H, H3 ), 2.07
JC ,B¼6.4 Hz, HC ), 3.44 (dd, 1H, J4,3a¼10.0 Hz,
0
0
0
0
0
J4,5¼9.2 Hz, H4), 3.36 (ddd, 1H, J7a,7 ¼J7a,3a¼4.4 Hz,
(ddd, 1H, J7 ,7¼16.0 Hz, J7 ,6¼10.9 Hz, J7 ,7a¼5.6 Hz, H7 );
13C NMR (D2O) d 80.5 (C5), 75.8 (C4), 71.1 (C6), 68.4
(C7a), 60.0 (CB), 59.1 (CA), 56.0 (C2), 45.9 (C3a), 32.3 (C7),
28.4 (C3); MS (FABþ) 218 (Mþþ1); HMRS for
C10H20NO4 (Mþþ1): calcd 218.1392; found: 218.1395.
J7a,7¼2.9 Hz, H7a), 3.26 (dd, 1H, J5,6¼J5,4¼9.2 Hz, H5),
0
0
2.97–2.87 (m, 2H, HB,2 ), 2.83 (ddd, 1H, J2,2 ¼14.8 Hz,
0
0
J2,3 ¼9.4 Hz, J2,3¼5.6 Hz, H2), 2.15 (ddd, 1H, J7,7
¼
14.2 Hz, J7,6¼5.0 Hz, J7,7a¼2.9 Hz, H7), 2.13–2.06 (m,
0
1H, H3a), 1.86–1.73 (m, 2H, H3,3 ), 1.42 (ddd, 1H,
0
0
0
0
J7 ,7¼14.2 Hz, J7 ,6¼9.5 Hz, J7 ,7a¼4.4 Hz, H7 ), 1.38, 1.36
(2s, 6H, CMe2), 0.88 (s, 27H, tBu), 0.05 (s, 18H, SiMe2);
13C NMR d 109.1 (CMe2), 83.9 (C5), 79.1 (C4), 69.4 (C6),
63.3, 59.3 (CA,C), 60.7, 59.4 (C7a,B), 44.9 (C2), 41.9 (C3a),
35.3 (C7), 29.7 (C3), 27.0 (CMe2), 25.9, 18.3, 18.2 (tBu),
24.5, 24.8, 25.4 (SiMe2); MS (CI, CH4) 630 (Mþþ1);
HMRS for C32H68NO5Si3 (Mþþ1): calcd 630.4405; found:
630.4393.
5.3.7. [3aS,4R,5R,6S,7aS]-1-(10,30-Dihydroxy-20-N-pro-
pyl)octahydroindole-4,5,6-triol (16c). The octahydro-
indole 16c was obtained from the protected derivative 14c
(80.2 mg, 0.128 mmol) under the same conditions as above
for 16a and was isolated (29 mg) as a solid in 92% yield.
1
[a]D¼þ65 (c 1.0, H2O); H NMR (500 MHz, D2O) d 3.86
0
(dd, 1H, JA,A ¼11.7 Hz, JA,B¼5.0 Hz, HA), 3.80–3.64 (m,
0
0
4H, HA ,C,C ,6), 3.67 (dd, 1H, J4,3a¼10.6 Hz, J5,4¼9.3 Hz,

8728
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
H4), 3.48–3.42 (m, 1H, H7a), 3.33 (dd, 1H, J5,6
0
¼
17b (41%) from 13 (82.2 mg, 0.232 mmol) after separation
by chromatography (cyclohexane/EtOAc 8:2); Rf 0.1
(cyclohexane/EtOAc 8:2); [a]Hg¼218 (c 1.0, CH2Cl2);
J5,4¼9.3 Hz, H5), 3.11–3.00 (m, 2H, H2,2 ), 2.90–2.79 (m,
0
1H, HB), 2.23 (ddd, 1H, J7,7 ¼14.4 Hz, J7,6¼J7,7a¼3.4 Hz,
1H NMR d 3.74 (ddd, 1H, J7,8 ¼10.0 Hz, J7,6¼9.1 Hz,
0
H7), 2.16–2.06 (m, 1H, H3a), 2.03–1.92 (m, 1H, H3), 1.90–
0
0
1.80 (m, 1H, H3 ), 1.42 (ddd, 1H, J7 ,7¼14.4 Hz,
J7,8¼4.2 Hz, H7), 3.67–3.44 (m, 2H, HB), 3.31 (dd, 1H,
J7 ,6¼11.0 Hz, J7 ,7a¼3.9 Hz, H7 ); 13C NMR (D2O) d 81.5
(C5), 76.8 (C4), 71.7 (C6), 63.3, 60.3 (CA,C), 62.5, 61.4
(C7a,B), 47.3 (C2), 47.2 (C3a), 34.2 (C7), 28.8 (C3); MS
(FABþ) 248 (Mþþ1); HMRS for C11H22NO5 (Mþþ1):
calcd 248.1498; found: 248.1493.
J6,7¼J6,5¼9.1 Hz, H6), 3.11–2.87 (m, 3H, H5,A ,2), 2.96
0
0
0
0
0
0
(ddd, 1H, JA,A ¼13.0 Hz, JA,B¼JA,B ¼4.3 Hz, HA), 2.24–
0
1.92 (m, 4H, H2 ,8,8a,4), 1.69–1.45 (m, 3H, H3,4a,3 ), 1.43–
0
0
1.28 (m, 1H, H8 ), 1.40, 1.38 (2s, 6H, CMe2), 1.17–0.97 (m,
0
1H, H4 ), 0.87 (s, 9H, tBu), 0.07, 0.06 (2s, 6H, SiMe2); 13C
NMR d 110.5 (CMe2), 84.1 (C6), 79.8 (C5), 69.8 (C7), 62.4
(C8a), 58.7 (CB), 53.6 (CA), 53.2 (C2), 42.4 (C4a), 38.9 (C8),
27.9 (C3), 26.9 (CMe2), 25.8, 18.3 (tBu), 23.7 (C4), 24.5,
24.9 (SiMe2); MS (CI, CH4) 386 (Mþþ1); HRMS for
C20H40NO4Si (Mþþ1): calcd 386.2727; found: 386.2726.
5.4. To the decahydroquinolines 21 and 22
The reductive amination of the ketoaldehyde 13 was
accomplished under the same experimental conditions as
for 6.
18b (29%); Rf 0.1 (cyclohexane/EtOAc 6:4); [a]D¼þ29 (c
1.0, CH2Cl2); 1H NMR d 4.03–3.88 (m, 1H, H7), 3.96 (dd,
1H, J5,4a¼11.5 Hz, J5,6¼9.0 Hz, H5), 3.69 (ddd, 1H,
5.4.1. [4aS,5R,6S,7S,8aR]-1-Benzyl-7-O-tert-butyl-
dimethylsilyl-5,6-O-methylethylidene-5,6,7-trihydroxy-
decahydroquinoline (17a), and its 8a epimer (18a).
0
0
JB,B ¼10.7 Hz, JB,A¼6.5 Hz, JB,A ¼4.1 Hz, HB), 3.54
1
0
0
0
0
17a/18a¼75:25 determined by the H NMR spectrum of
(ddd, 1H, JB ,B¼10.7 Hz, JB ,A ¼5.2 Hz, JB ,A¼3.8 Hz,
0
the crude.
HB ), 3.38 (dd, 1H, J6,5¼J6,7¼9.0 Hz, H6), 3.14–2.93 (m,
2H, H2,A), 2.60–2.52 (m, 1H, H8a), 2.24 (ddd, 1H,
0
17a (31%) from 13 (120.4 mg, 0.34 mmol) after separation
by chromatography (cyclohexane/EtOAc 95:5); Rf 0.39
(cyclohexane/EtOAc 8:2); [a]D¼222.5 (c 1.0, CH2Cl2); 1H
NMR d 7.33–7.16 (m, 5H, Har), 4.04, 3.20 (AB, 2H,
J8,8 ¼14.2 Hz, J8,7¼J8,8a¼3.3 Hz, H8), 2.18–1.81 (m, 3H,
0
HA ,2 ,4a), 1.79–1.56 (m, 3H, H4,3,3 ), 1.53–1.44 (m, 1H,
0
0
0
0
H4 ), 1.39 (s, 6H, CMe2), 1.29–1.17 (m, 1H, H8 ), 0.89 (s,
9H, tBu), 0.09, 0.08 (s, 6H, SiMe2); 13C NMR d 109.1
(CMe2), 85.1 (C6), 74.5 (C5), 68.4 (C7), 61.5 (C8a), 58.3
(CB), 54.4 (CA), 54.0 (C2), 39.5 (C4a), 37.3 (C8), 30.2 (C3),
27.0 (CMe2), 25.8, 18.2 (tBu), 25.0 (C4), 24.6, 24.9
(SiMe2), MS (CI, CH4) 386 (Mþþ1); HRMS for
C20H40NO4Si (Mþþ1): calcd 386.2727; found: 386.2719.
0
JA,B¼13.4 Hz, NCH2Ph), 3.79 (ddd, 1H, J7,8 ¼10.3 Hz,
J7,6¼9.1 Hz, J7,8¼4.8 Hz, H7), 3.38 (dd, 1H, J6,7
J6,5¼9.1 Hz, H6), 3.04 (dd, 1H, J5,4a¼10.8 Hz, J5,6
¼
¼
9.1 Hz, H5), 2.91–2.74 (m, 1H, H2), 2.33 (ddd, 1H,
0
J8,8 ¼12.8 Hz, J8,7¼J8,8a¼4.8 Hz, H8), 2.25–2.04 (m, 3H,
0
H2 ,4,8a), 1.70–1.45 (m, 4H, H3,3 ,8 ,4a), 1.40, 1.38 (2s, 6H,
0
0
0
CMe2), 1.16–0.92 (m, 1H, H4 ), 0.88 (s, 9H, tBu), 0.09,
5.4.3. [4aS,5R,6S,7S,8aR]-1-(10,30-Di-tert-butyldimethyl-
silyloxy-20-propyl)-7-O-tert-butyldimethylsilyl-5,6-O-
methylethylidene-5,6,7-trihydroxydecahydroquinoline
(17c) and its 8a epimer (18c). 17c/18c¼40:60 determined
0.08 (s, 6H, SiMe2); 13C NMR d 139.3, 128.9, 128.2, 126.8
(Car), 110.4 (CMe2), 84.2 (C6), 80.0 (C5), 70.1 (C7),
62.7 (C8a), 57.8 (NCH2Ph), 53.7 (C2), 42.8 (C4a), 39.0
(C8), 28.0 (C3), 27.0 (CMe2), 25.9, 18.3 (tBu), 24.1 (C4),
24.5, 24.8 (SiMe2); MS (CI, CH4) 432 (Mþþ1); HRMS
for C25H42NO3Si (Mþþ1): calcd 432.2934; found:
432.2934.
1
on the H NMR spectrum of the crude.
17c (20%) from 13 (42.3 mg, 0.119 mmol) after separation
by chromatography (cyclohexane/EtOAc 8:2); Rf 0.42
1
(cyclohexane/EtOAc 9:1); [a]Hg¼þ5 (c 1.0, CH2Cl2); H
0
0
0
18a (16%); Rf 0.70 (cyclohexane/EtOAc 8:2); [a]D¼þ40 (c
1.0, CH2Cl2); 1H NMR d 7.35–7.20 (m, 5H, Har), 4.17 (dd,
1H, J5,4a¼11.3 Hz, J5,6¼9.0 Hz, H5), 4.10–4.00 (m, 1H,
H7), 4.09, 2.97 (AB, 2H, JAB¼13.5 Hz, NCH2Ph), 3.31 (dd,
1H, J6,7¼J6,5¼9.0 Hz, H6), 2.84–2.69 (m, 1H, H2), 2.58–
NMR d 3.75 (dd, 1H, JA ,A¼10.4 Hz, JA ,B¼8.2 Hz, HA ),
0
3.71 (dd, 1H, JA,A ¼10.4 Hz, JA,B¼4.6 Hz, HA), 3.81–3.66
0
(m, 1H, H7), 3.59 (dd, 1H, JC,C ¼10.0 Hz, JC,B¼5.3 Hz,
0
0
0
HC), 3.53 (dd, 1H, JC ,C¼10.0 Hz, JC ,B¼7.4 Hz, HC ), 3.32
(dd, 1H, J6,7¼J6,5¼9.1 Hz, H6), 3.27–3.14 (m, 1H, HB),
2.97 (dd, 1H, J5,6¼10.8 Hz, J5,4a¼9.1 Hz, H5), 2.91–2.80
0
2.47 (m, 1H, H8a), 2.38 (ddd, 1H, J8,8 ¼14.8 Hz,
0
0
J8,7¼J8,8a¼3.4 Hz, H8), 2.03–1.80 (m, 3H, H4,2 ,4a), 1.79–
(m, 1H, H2), 2.48 (dd, 1H, J8a,4a¼12.8 Hz, J8a,8 ¼9.0 Hz,
0
0
0
0
1.56 (m, 2H, H3,3 ), 1.53–1.29 (m, 2H, H4 ,8 ), 1.43, 1.41 (2s,
C
J8a,8¼4.0 Hz, H8a), 2.45–2.31 (m, 2H, H2 ,8), 2.04–1.90 (m,
6H, CMe2), 0.86 (s, 9H, tBu), 0.06, 0.03 (s, 6H, SiMe2); 13
0
1H, H4), 1.69–1.54 (m, 1H, H3), 1.50–1.39 (m, 2H, H4a,3 ),
0
1.37, 1.36 (2s, 6H, CMe2), 1.31–1.20 (m, 1H, H8 ), 1.07–
NMR d 139.4, 128.6, 128.3, 126.8 (Car), 109.0 (CMe2), 85.3
(C6), 74.6 (C5), 68.7 (C7), 61.5 (C8a), 57.9 (NCH2Ph), 54.1
(C2), 39.6 (C4a), 37.5 (C8), 27.0 (CMe2), 25.9, 18.2 (tBu),
25.4 (C3), 21.2 (C4), 24.5, 24.8 (SiMe2); MS (CI, CH4) 432
(Mþþ1); HRMS for C25H42NO3Si (Mþþ1): calcd
432.2934; found: 432.2929.
0
0.93 (m, 1H, H4 ), 0.88, 0.87 (2s, 27H, tBu), 0.08, 0.07, 0.03,
0.02 (s, 18H, SiMe2); 13C NMR d 111.3 (CMe2), 84.2 (C6),
79.9 (C5), 70.3 (C7), 64.2 (CA), 61.4 (CB), 60.6 (CC), 59.2
(C8a), 48.1 (C2), 44.5 (C4a), 38.6 (C8), 28.5 (C3), 27.0
(CMe2), 25.9, 18.2 (tBu), 25.6 (C4), 24.4, 24.9, 25.3,
25.4, 25.6 (SiMe2); MS (CI, CH4) 644 (Mþþ1); HRMS
for C33H70NO5Si3 (Mþþ1): calcd 644.4562; found:
644.4570.
5.4.2. [4aS,5R,6S,7S,8aR]-1-(20-Hydroxyethyl)-7-O-tert-
butyldimethylsilyl-5,6-O-methylethylidene-5,6,7-tri-
hydroxydecahydroquinoline (17b) and its 8a epimer
(18b). 17b/18b¼60:40 determined on the 1H NMR
spectrum of the crude.
18c (35%); Rf 0.78 (cyclohexane/EtOAc 9:1); [a]D¼þ14 (c
1.0, CH2Cl2); 1H NMR d 4.12 (dd, 1H, J5,4a¼11.1 Hz,

C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
8729
0
J5,6¼9.1 Hz, H5), 3.95 (ddd, 1H, J7,8 ¼11.0 Hz,
5.4.6. [4aS,5R,6R,7S,8aR]-Decahydro-1H-quinoline-
5,6,7-triol (21a). The decahydroquinoline 21a was obtained
from the protected derivative 19a (28.8 mg, 84 mmol) under
the same conditions as above for 16a and was isolated
(14.9 mg) as a solid in 94% yield. [a]D¼þ65 (c 1.0, H2O);
1H NMR (D2O) d 3.68–3.50 (m, 1H, H7), 3.32 (dd, 1H,
J6,7¼J6,5¼9.1 Hz, H6), 3.25–3.10 (m, 1H, H2), 3.17 (dd,
1H, J5,4a¼10.2 Hz, J5,6¼9.1 Hz, H5), 2.82–2.67 (m, 1H,
0
J7,6¼9.0 Hz, J7,8¼3.2 Hz, H7), 3.72 (dd, 1H, JA ,A¼10.3
0
0
0
Hz, JA ,B¼6.9 Hz, HA ), 3.56 (dd, 1H, JA,A ¼10.3 Hz,
0
JA,B¼4.6 Hz, HA), 3.60–3.49 (m, 2H, HC,C ), 3.24 (dd,
1H, J6,7¼J6,5¼9.0 Hz, H6), 3.20–3.10 (m, 1H, HB), 3.06
0
(ddd, 1H, J8a,4a¼J8a,8¼J8a,8 <3.2 Hz, H8a), 2.93–2.77 (m,
0
1H, H2), 2.39 (ddd, 1H, J8,8 ¼14.7 Hz, J8,7¼J8,8a¼3.2 Hz,
0
0
0
0
0
H8), 2.26 (ddd, 1H, J2 ,2¼J2 ,3 ¼11.5 Hz, J2 ,3¼1.9 Hz, H2 ),
0
2.04–1.85 (m, 1H, H4), 1.81–1.53 (m, 3H, H4a,3,3 ), 1.52–
0
0
H2 ), 2.56 (ddd, 1H, J8a,4a¼J8a,8 ¼11.8 Hz, J8a,8¼3.0 Hz,
0
0
1.40 (m, 1H, H4 ), 1.40–1.34 (m, 1H, H8 ), 1.38 (s, 6H,
CMe2), 0.88, 0.87 (2s, 27H, tBu), 0.09, 0.08, 0.06, 0.04,
0.02 (s, 18H, SiMe2); 13C NMR d 108.7 (CMe2), 85.4 (C6),
74.9 (C5), 68.6 (C7), 62.9 (CA), 59.8 (CB), 59.4 (CC),
58.8 (C8a), 47.8 (C2), 40.0 (C4a), 37.5 (C8), 30.2 (C3),
27.1, 26.9 (CMe2), 25.9, 18.2 (tBu), 22.0 (C4), 24.4, 24.7,
25.4, 25.6 (SiMe2); MS (CI, CH4) 644 (Mþþ1); HRMS
for C33H70NO5Si3 (Mþþ1): calcd 644.4562; found:
644.4556.
H8a), 2.25–2.04 (m, 2H, H8,4), 1.95–1.77 (m, 1H, H3),
1.75–1.15 (m, 4H, H8 ,4a,4 ,3 ); 13C NMR (D2O) d 81.2 (C6),
76.9 (C5), 72.1 (C7), 56.3 (C8a), 47.5 (C2), 46.9 (C4a), 39.6
(C8), 28.5 (C3), 25.9 (C4).
0
0
0
5.4.7. [4aS,5R,6R,7S,8aR]-1-(20-Hydroxyethyl) deca-
hydroquinoline-5,6,7-triol (21b). The decahydroquinoline
21b was obtained from the protected derivative 17b
(35.1 mg, 91 mmol) under the same conditions as above
for 16a and was isolated (16.9 mg) as a solid in 80% yield.
1
5.4.4. [4aS,5R,6S,7S,8aR]-7-O-tert-Butyldimethylsilyl-
5,6-O-methylethylidene-5,6,7-trihydroxydecahydro-1-
H-quinoline (19a). To a suspension of palladium hydroxide
(44.6 mg) in absolute EtOH (1 mL), saturated with
dihydrogen, was added a solution of the N-benzylamine
17a (44.6 mg, 0.103 mmol) in absolute EtOH (0.5 mL).
After stirring for 14 h at 208C, the catalyst was removed by
filtration through a Celite pad and the filtrate was
concentrated in vacuo. Flash chromatography (CH2Cl2/
MeOH 98:2) gave the pure amine 19a (29.6 mg) as an oil in
84% yield. Rf 0.1 (CH2Cl2/MeOH 98:2); [a]D¼þ19 (c 1.0,
CH2Cl2); 1H NMR d 3.86–3.69 (m, 1H, H7), 3.35 (dd, 1H,
J6,7¼J6,5¼9.0 Hz, H6), 3.14–3.04 (m, 1H, H2), 3.01 (dd,
1H, J5,4a¼10.0 Hz, J5,6¼9.0 Hz, H5), 2.70–2.53 (m, 1H,
[a]D¼217 (c 1.0, H2O); H NMR (D2O) d 3.81 (t, 2H,
JB,A¼6.5 Hz, HB), 3.65–3.47 (m, 1H, H7), 3.31 (dd, 1H,
J6,7¼J6,5¼9.2 Hz, H6), 3.14 (dd, 1H, J5,4a¼10.0 Hz,
J5,6¼9.2 Hz, H5), 3.07–2.94 (m, 1H, H2), 2.96 (td, 1H,
0
0
JA,A ¼13.8 Hz, JA,B¼JA,B ¼6.5 Hz, HA), 2.69 (td, 1H,
0
0
0
0
0
JA ,A¼13.8 Hz, JA ,B¼JA ,B ¼6.5 Hz, HA ), 2.50–2.32 (m,
0
0
2H, H2 ,8), 2.21 (ddd, 1H, J8a,4a¼J8a,8 ¼11.7 Hz,
J8a,8¼2.6 Hz, H8a), 1.87–1.69 (m, 1H, H4), 1.87–1.69 (m,
0
1H, H3), 1.66–1.45 (m, 1H, H3 ), 1.44–1.21 (m, 2H, H4a,8 ),
0
0
0
0
0
0
1.08 (dddd, 1H, J4 ,4¼J4 ,4a¼J4 ,3 ¼12.6 Hz, J4 ,3¼3.6 Hz,
H4 ); 13C NMR (D2O) d 81.1 (C6), 77.4 (C5), 72.6 (C7),
0
61.3 (C8a), 60.3 (CB), 56.1 (CA), 55.6 (C2), 47.4 (C4a), 38.2
(C8), 29.2 (C3), 26.2 (C4); MS (CI, NH3) 232 (Mþþ1);
HRMS for C11H22NO4 (Mþþ1): calcd 232.1549; found:
232.1446.
0
0
H2 ), 2.27 (ddd, 1H, J8a,4a¼12.4 Hz, J8a,8 ¼9.1 Hz,
J8a,8¼4.0 Hz, H8a), 2.13–2.01 (m, 1H, H4), 1.95 (ddd, 1H,
J8,8 ¼13.2 Hz, J8,7¼4.7 Hz, J8,8a¼4.0 Hz, H8), 1.72–1.59
5.4.8. [4aS,5R,6R,7S,8aR]-1-(10,30-Dihydroxy-20-N-pro-
pyl)-decahydroquinoline-5,6,7-triol (21c). The deca-
hydroquinoline 21c was obtained from the protected
derivative 17c (33 mg, 51 mmol) under the same conditions
as above for 16a and was isolated (11.4 mg) as a solid in
86% yield. [a]D¼217 (c 1.0, H2O); 1H NMR (D2O) d 3.95
0
0
(m, 2H, H3,3 ), 1.51–1.29 (m, 2H, H4a,8 ), 1.39, 1.37 (2s, 6H,
0
0
CMe2), 1.18–1.07 (m, 1H, H4 ), 0.88 (s, 9H, tBu), 0.07
(s, 6H, SiMe2); 13C NMR d 110.4 (CMe2), 84.6 (C6),
79.6 (C5), 69.6 (C7), 57.5 (C8a), 47.1 (C2), 43.9 (C4a), 41.3
(C8), 27.9 (C3), 26.9 (CMe2), 25.8, 18.3 (tBu), 25.6 (C4),
24.5, 24.9 (SiMe2); MS (CI, CH4) 342 (Mþþ1); HRMS
for C18H36NO3Si (Mþþ1): calcd 342.2464; found:
342.2462.
0
(dd, 1H, JA,A ¼12.0 Hz, JA,B¼5.2 Hz, HA), 3.84–3.67 (m,
0
0
3H, HA ,C,C ), 3.65–3.50 (m, 1H, H7), 3.42–3.23 (m, 1H,
HB), 3.33 (dd, 1H, J6,7¼J6,5¼9.7 Hz, H6), 3.15 (dd, 1H,
J5,6¼J5,4a¼9.7 Hz, H5), 3.11–3.00 (m, 1H, H2), 2.67–2.33
0
(m, 3H, H2 ,8,8a), 2.20–2.01 (m, 1H, H4), 1.89–1.70 (m, 1H,
5.4.5. [4aS,5R,6S,7S,8aS]-7-O-tert-Butyldimethylsilyl-
5,6-O-methylethylidene-5,6,7-trihydroxydecahydro-1-
H-quinoline (20a). The decahydroquinoline 20a was
obtained from the protected derivative 18a (144 mg,
0.269 mmol) under the same conditions as above for the
compound 19a except that the reaction was carried out in
EtOAc and that the crude product 20a (71.9 mg) was
submitted to further reaction without purification. Rf 0.3
(CH2Cl2/MeOH 98:2); [a]D¼þ24 (c 1.0, CH2Cl2); 1H
0
0
0
H3), 1.62–1.20 (m, 3H, H3 ,4a,8 ), 1.08 (dddd, 1H, J4,4
¼
J4 ,4a¼J4 ,3 ¼12.2 Hz, J4 ,3¼3.2 Hz, H4 ); 13C NMR (D2O) d
81.4 (C6), 77.8 (C5), 73.0 (C7), 63.5 (CA), 62.1 (CB), 60.2
(C8a), 60.1 (CC), 49.6 (C2), 48.4 (C4a), 38.1 (C8), 29.7 (C3),
27.2 (C4); MS (CI, NH3) 262 (Mþþ1); HRMS for
C12H24NO5 (Mþþ1): calcd 262.1654; found: 262.1653.
0
0
0
0
0
5.4.9. [4aS,5R,6R,7S,8aS]-Decahydro-1H-quinoline-
5,6,7-triol (22a). The decahydroquinoline 22a was obtained
from the protected derivative 20a (20 mg, 56 mmol) under
the same conditions as above for 16a and was isolated
(9 mg) as a solid in 92% yield. [a]D¼þ65 (c 1.0, H2O); 1H
NMR (D2O) d 3.87–3.68 (m, 1H, H7,5), 3.40–3.21 (m, 1H,
0
NMR d 4.10 (ddd, 1H, J7,8 ¼J7,6¼9.1 Hz, J7,8¼5.2 Hz, H7),
4.01 (dd, 1H, J5,4a¼11.1 Hz, J5,6¼9.1 Hz, H5), 3.01 (dd, 1H,
J6,7¼J6,5¼9.1 Hz, H6), 3.12–2.95 (m, 2H, H2,8a), 2.69–2.51
0
(m, 1H, H2 ), 2.08–1.90 (m, 1H, H4), 1.83–1.34 (m, 6H,
0
0
0
H4a,8,8 ,3,4 ,3 ), 1.39 (s, 6H, CMe2), 0.88 (s, 9H, tBu), 0.08 (s,
6H, SiMe2); 13C NMR d 108.9 (CMe2), 85.2 (C6), 74.8 (C5),
68.8 (C7), 58.8 (C8a), 56.1 (C2), 52.9 (C4a), 47.0 (C8), 39.2
(C3), 27.0 (CMe2), 25.9, 18.3 (tBu), 25.4 (C4), 24.5, 24.8
(SiMe2).
0
H2), 3.16–2.97 (m, 2H, H6,8a), 2.77–2.58 (m, 1H, H2 ),
0
0
0
2.16–1.87 (m, 2H, H8,4), 1.80–1.42 (m, 5H, H4A,8 ,4 ,3,3 );
13C NMR (D2O) d 79.8 (C4), 74.7 (C5), 70.5 (C3), 67.8 (C1),
54.1 (C8), 45.7 (C6), 31.3 (C2), 27.3 (C7); MS (CI, NH3) 188

8730
C. Gravier-Pelletier et al. / Tetrahedron 59 (2003) 8721–8730
(Mþþ1); HRMS for C9H18NO3 (Mþþ1): calcd 188.1287;
References
found: 188.1286.
1. (a) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675. (b) Michael,
J. P. In Iminosugars as Glycosidases Inhibitors; Stu¨tz, A. E.,
Ed.; Wiley: Weiheim, 1999; pp 1–397.
5.4.10. [4aS,5R,6R,7S,8aS]-1-(20-Hydroxyethyl)-deca-
hydroquinoline-5,6,7-triol (22b). The decahydroquinoline
22b was obtained from the protected derivative 18b
(24.7 mg, 64 mmol) under the same conditions as above
for 16a and was isolated (10.2 mg) as a solid in 92% yield.
[a]D¼þ27 (c 0.93, H2O); 1H NMR (D2O) d 3.93–3.74 (m,
2. Kang, M. S.; Liu, P. S.; Bernotas, R. C.; Harry, B. S.; Sunkara,
P. S. Glycobiology 1995, 5, 147.
3. Platt, F. M.; Neises, G. R.; Reinkensmeier, G.; Townsend,
M. J.; Perry, V. H.; Proia, R. L.; Winchester, B.; Dwek, R. A.;
Butters, T. D. Science 1997, 276, 428.
0
0
3H, H5,B,B ), 3.71 (ddd, 1H, J7,8 ¼12.2 Hz, J7,6¼9.0 Hz,
J7,8¼2.6 Hz, H7), 3.35 (dd, 1H, J6,5¼J6,7¼9.0 Hz, H6),
4. For a review, see: Gross, P. E.; Baker, M. A.; Carver, J. P.;
Dennis, J. W. Clin. Cancer Res. 1995, 1, 935.
0
3.15–3.02 (m, 1H, H2), 3.01–2.73 (m, 3H, H8a,A,A ), 2.67–
2.49 (m, 1H, H2), 2.46–2.30 (m, 1H, H8), 2.13–1.97 (m,
1H, H4), 1.92–1.78 (m, 1H, H4a), 1.77–1.43 (m, 4H,
5. Ratner, L.; Heyden, N. V.; Dedera, D. Virology 1991, 181,
180.
H8 ,4 ,3,3 ); 13C NMR (D2O) d 82.3 (C6), 72.3 (C5), 70.8 (C7),
61.4 (C8a), 58.8 (CB), 56.8 (CA), 56.5 (C2), 43.6 (C4a), 35.9
(C8), 25.9 (C3), 22.5 (C4); MS (CI, NH3) 232 (Mþþ1);
HRMS for C11H22NO4 (Mþþ1): calcd 232.1549; found:
232.1546.
0
0
0
6. Johnson, P. S.; Coniff, R. F.; Hoogwerf, B. J.; Santiago, J. V.;
Pi-Sunyer, F. X.; Krol, A. Diabetes Care 1994, 17, 2029.
7. Matsumoto, K.; Yano, M.; Miyake, S.; Ueki, Y.; Yamaguchi,
Y.; Akazawa, S.; Tominaga, Y. Diabetes Care 1998, 21, 256.
8. Preliminary report: Gravier-Pelletier, C.; Maton, W.; Le
Merrer, Y. Synlett 2003, 333.
5.4.11. [4aS,5R,6R,7S,8aS]-1-(10,30-Dihydroxy-20-N-pro-
pyl)-decahydroquinoline-5,6,7-triol (22c). The deca-
hydroquinoline 22c was obtained from the protected
derivative 18c (59 mg, 92 mmol) under the same conditions
as above for 16a and was isolated (16.5 mg) as a solid in
69% yield. [a]D¼þ35 (c 1.0, H2O); 1H NMR (D2O) d 4.04
(dd, 1H, J5,4a¼10.6 Hz, J5,6¼9.0 Hz, H5), 3.89 (dd, 1H,
9. Le Merrer, Y.; Gravier-Pelletier, C.; Maton, W.; Numa, M.;
Depezay, J.-C. Synlett 1999, 1322.
10. Fall, Y.; Torneiro, M.; Castedo, L.; Mourino, A. Tetrahedron
1997, 54, 4703.
11. (a) Gravier-Pelletier, C.; Maton, W.; Le Merrer, Y.
Tetrahedron Lett. 2002, 43, 8285. (b) Corey, E. J.; Erickson,
B. W. J. Org. Chem. 1971, 36, 3553.
0
JA,A ¼11.7 Hz, JA,B¼5.3 Hz, HA), 3.83–3.62 (m, 3H,
12. Toshima, H.; Aramaki, H.; Furumoto, Y.; Inamura, S.; Ichiara,
A. Tetrahedron Lett. 1998, 54, 5531.
0
0
0
0
HC,C ,7), 3.56 (dd, 1H, JA ,A¼11.7 Hz, JA ,B¼6.9 Hz, HA ),
3.35 (dd, 1H, J6,7¼J6,5¼9.0 Hz, H6), 3.29–3.17 (m, 1H,
HB), 3.16–3.08 (m, 1H, H8a), 3.06–2.94 (m, 1H, H2), 2.51–
13. Shimizu, S.; Nakamura, S.-I.; Nakada, M.; Shibasaki, M.
Tetrahedron 1996, 52, 13363.
0
2.36 (m, 1H, H8), 2.35–2.18 (m, 1H, H2 ), 2.10–1.94 (m,
1H, H4), 1.84–1.69 (m, 1H, H4a), 1.62–1.20 (m, 4H,
14. (a) Suenega, K.; Araki, K.; Sengoku, T.; Uemura, D. Org. Lett.
2001, 3, 527. (b) Marshall, J. A.; Yannick, M. M. J. Org.
Chem. 2001, 66, 1373.
H8 ,3,3 ,4 ); 13C NMR (D2O) d 83.1 (C6), 73.0 (C5), 71.3 (C7),
62.0 (CA), 60.1 (CB), 60.0 (C8a,C), 49.0 (C2), 45.0 (C4a), 36.8
(C8), 27.2 (C3), 23.7 (C4); MS (CI, NH3) 262 (Mþþ1);
HRMS for C12H24NO5 (Mþþ1): calcd 262.1654; found:
262.1656.
0
0
0
15. Chiu, P.; Szeto, C. P.; Geng, Z.; Cheng, K. F. Tetrahedron
Lett. 2001, 42, 4091.
16. Midland, M. M.; Brown, H. C. J. Org. Chem. 1975, 40, 2846.
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5.5. Inhibition studies
The inhibition studies against a-D-glucosidase from
Bacillus stearothermophilus (EC 3.2.1.20), b-D-glucosidase
from almonds (EC 3.2.1.21), a-D-mannosidase from Jack
beans (EC 3.2.1.24), a-L-fucosidase from bovine kidney
(EC 3.2.1.51), a-D-galactosidase from green coffee bean
(EC 3.2.1.22), b-D-galactosidase from Thermus thermo-
philus and pancreatic porcine a-amylase (EC 3.2.1.1) were
performed according to the procedure previously
described.23
21. Marshall, J. A.; Yanick, M. M. J. Org. Chem. 2001, 66, 1373.
22. (a) Manescalchi, F.; Nardi, A. R.; Savoia, D. Tetrahedron Lett.
1994, 35, 2575. (b) Reitz, A. B.; Baxter, E. W. J. Org. Chem.
1994, 59, 3175.
Acknowledgements
23. Gravier-Pelletier, C.; Maton, W.; Dintinger, T.; Tellier, C.; Le
Merrer, Y. Tetrahedron 2003, 59, 8705.
The authors are grateful to Dr T. Dintinger and to Professor
C. Tellier for fruitful discussions on inhibition studies.