Synthesis of polyfunctional quinolizidine alkaloids: Development towards selective glycosidase inhibitors

Article abstract of DOI:10.1039/b907007a

A highly divergent route to a variety of quinolizidine alkaloids is described. The enantiomeric precursors 22a and 22b utilized for the synthesis of these alkaloids were constructed stereospecifically from the PET cyclization of the corresponding acetylen

Full text of DOI:10.1039/b907007a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of polyfunctional quinolizidine alkaloids: development towards
selective glycosidase inhibitors†
Ganesh Pandey,*a Debasish Grahacharya,a K. S. Shashidhara,b M. Islam Khanb and Vedavati G. Puranikc
Received 9th April 2009, Accepted 18th May 2009
First published as an Advance Article on the web 19th June 2009
DOI: 10.1039/b907007a
A highly divergent route to a variety of quinolizidine alkaloids is described. The enantiomeric
precursors 22a and 22b utilized for the synthesis of these alkaloids were constructed stereospecifically
from the PET cyclization of the corresponding acetylene tethered a-trimethylsilyl amine moieties 21a
and 21b, respectively, both of which were synthesised from D-ribose. The polyhydroxy quinolizidine
alkaloid 7 was found to be a selective inhibitor of a-galactosidase with Ki 83.9 mM. The amine analogs
18, 12 and 10 are found to be selective and potent inhibitors of a-glucosidase with Ki 28, 120 and
140 mM, respectively.
Introduction
Polyhydroxy azabicyclic alkaloids like castanospermine1 (1) and
swainsonine2 (2) have emerged as an important family of glycosi-
dase inhibitors having chemotherapeutic potential3 for a variety
of diseases such as HIV,4 cancer5 and several viral infections
such as influenza (Fig. 1).6 Despite their therapeutic potential,
these molecules have not had a full clinical evaluation, largely
due to their low natural abundance and the difficulty in prepar-
ing a comprehensive array of variant structures. In addition,
many of these molecules exhibit superfluous toxic effects e.g.
castanospermine, although known to display potent inhibitory
activity against glucosidases and antiviral properties against a
Fig. 1
number of viruses6, is also found to inhibit intestinal sucrases
causing osmic diarrhea7 resulting in its withdrawal from use as a
clinical therapeutic. Thus, there is a need to synthesize a palette
of polyhydroxylated analogs of these molecules to allow a better
sualized as a bicyclic analog of the potent glycosidase inhibitor
understanding of the structural requirements for a glycosidase
1-deoxynojirimycine (3), are scarce in literature.10
inhibitor and to develop more potent, selective and less toxic
In connection with this, intense research has also been done
drugs.
on changing the lipophilicity of 3 by attaching a hydrophobic
As a result, considerable efforts have been directed towards
group to its nitrogen atom, resulting in interesting inhibitory
the development of ring expansion analogs8 and stereoisomers9
activities.11 All these facts, coupled with our continuing interest
of 1 and 2. By contrast, examples involving ring expansion
in this area,12 spurred us to synthesize azasugars of general
analogs of 1-deoxycastanospermine (4), which can also be vi-
structure 4. The known synthetic efforts towards molecules of type
4 have involved a chiron approach with long reaction sequences
producing a maximum of two analogs. In some cases, a key
reaction produces two diastereomers which were further reacted
to get different analogs indicating a difficulty in getting a single
required product in an appreciable yield.10b,c Recently, we have
aDivision of Organic Chemistry, National Chemical Laboratory, Pune,
411008, India. E-mail: gp.pandey@ncl.res.in; Fax: +91-20-25902628;
Tel: +91-20-25902627
bDivision of Biochemical Sciences, National Chemical Laboratory, Pune,
demonstrated the construction of azabicyclic system 5 where the
bridge head stereocentre is constructed in a stereospecific manner
along with subsequent application to the syntheses of various
classes of azasugars.12e–g Thus, we envisaged the synthesis of
azasugars 6–12 from a common intermediate 22a and similarly
azasugars 13–18 from 22b. Both 22a and 22b were traced back
to a common starting material, D-ribose, through 21a and 21b,
respectively (Scheme 1). We wish to report herein the synthesis
of a variety of quinolizidine alkaloids having general structure 4
along with their enzyme inhibition study.
411008, India
cCenter for Material characterization, National Chemical Laboratory, Pune,
411008, India
† Electronic supplementary information (ESI) available: Experimental
and spectroscopic data of compounds 7·HCl, 8·HCl, 9·2HCl, 10·2HCl,
11·2HCl, 12·2HCl and 29, X-ray crystal structure analysis of 23 and 25,
optical rotation data for all enantiomeric compounds, copies of 1H and 13C-
NMR spectra for compounds 6–12, 21a, 22a and 23–31, C O S Y, N O E S Y,
HETCOR spectra for 22a, 23, 25 and 28, general procedure for the enzyme
inhibition assay, Lineweaver–Burke plots for selected compounds. CCDC
reference numbers 726211 and 726212. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b907007a
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Transformation of 22a to various polyhydroxy quinolizidine
alkaloids 6, 7 and 8
The olefinic moiety of 22a upon dihydroxylation with OsO4 in
the presence of 50% aqueous NMO using acetone as a s◦olvent
produced 23 in 90% yield (crystalline solid, m.p. 135–136 C) as
a single diastereomer. X-Ray diffraction analysis unambiguously
confirmed the relative stereochemistry of the newly generated
stereocentre (Fig. 2).18 Acetonide deprotection from 23 using
1 N HCl gave 6·HCl in quantitative yield.
Scheme 1 Retrosynthetic plan.
Results and discussion
Fig. 2 ORTEP diagram of 23.18 Ellipsoids are drawn at 50% probability.
Stereospecific synthesis of azabicyclic template 22a
The synthesis of azasugars 6–12 began with the preparation
of the key precursor 21a (72% yield), which was achieved by
the reductive amination13 of aldehyde 20 in the presence of
2-(trimethylsilyl)piperidine.14 The aldehyde 20 was obtained by
the IBX oxidation15 of 19 (85% yield) synthesized from D-ribose
by following literature procedures.12h,16 The photoinduced elec-
tron transfer (PET) mediated cyclization17 of 21a (3.38 mmol)
was carried out by irradiating its dilute solution containing
1,4-dicyanonaphthalene (DCN) (0.67 mmol) in isopropanol
(200 ml) in a pyrex vessel using a 450 W Honovia medium
pressure lamp as the light source. Usual workup and purification
of the photolysate by column chromatography gave 22a as a single
diastereomer in 65% yield (Scheme 2).
NaIO4 cleavage of 23 afforded the corresponding ketone 24,
which on sodium borohydride reduction provided 25 in 82% yield
as an exclusive diastereomer (Scheme 3). The stereochemistry
1
of 25 was ascertained from its H NMR coupling constants, in
addition to COSY, NOESY and HETCOR spectral analyses. The
relative stereochemical outcome was further confirmed by X-ray
crystallography (Fig. 3).18 The acetonide moiety was removed to
give 7·HCl in quantitative yield.
Fig. 3 ORTEP diagram of 25.18 Ellipsoids are drawn at 50% probability.
At this stage, we also synthesized 1-deoxy-8-methylhomo-
castanospermine (8) from 23 and studied its potential as a
glycosidase inhibitor. In this context, the diol 23 was converted
to the corresponding epoxide 26 (via its primary mesylate) in
90% yield using mesylchloride and triethylamine. The regioselec-
tive reductive opening of the epoxide ring using LiAlH4 gave 27 as
an exclusive product in 90% yield, which upon acetonide removal
furnished 8·HCl quantitatively.
Scheme 2 Reagents and conditions: (a) Ref. 12h; (b) IBX, EtOAc, reflux,
8 h, 85%; (c) 2-(trimethylsilyl)piperidine, NaBH(OAc)3, 1,2-dichloroethane
(DCE), rt, 3 h, 72%; (d) hn, DCN, 2-PrOH, 1 h, 60%.
The cyclized product 22a was fully characterized by extensive
1H NMR, 13C NMR, COSY, NOESY and HETCOR spectral
analyses.
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Scheme 4 Reagents and conditions: (a) (i) MeSO2Cl, Et3N, DCM, 0 ◦C
to rt, 6 h, (ii) LiN3, DMF, 110 ◦C, 20 h, 72% over two steps; (b) H2, 10%
Pd/C, MeOH, 2 h, 85%; (d) 1 N HCl, rt, 4 h, 100%; (d) (i) C14H29Br,
K2CO3, CH3CN–THF (3:1), reflux, 6 h, 65%, (ii) 1 N HCl, rt, 4 h, 100%.
it would not be a disadvantage to make two other new analogs 11
and 12. In this regard, ketone 24, upon reductive amination with
benzyl amine, furnished 28 as a single diastereomer in 75% yield.
The stereochemistry at C-10 of 28 was ascertained by analyzing
coupling constants for 3a-H (dH 3.98, dt, J = 10.07, 4.10 Hz),
10a-H (dH 3.38, dd, J = 9.45, 3.63 Hz), 10-H (dH 3.04, t, J =
2.91 Hz) and 9a-H (dH 1.97, td, J = 11.14, 2.34 Hz) suggesting
the orientations for 3a-H-axial, 10a-H-axial, 10-H-equatorial and
9a-H-axial, respectively. This stereochemical outcome was further
confirmed from COSY, NOESY and HETCOR experiments.
Amine 28 upon acetonide deprotection gave 11·2 HCl in quan-
titative yield.
Similarly, 12·2 HCl was obtained as a single diastereomer by
reductive amination of keto 24 with dodecyl amine (65% yield)
followed by acetonide removal (Scheme 3).
Scheme 3 Reagents and conditions: (a) OsO4, NMO (50% aq. solution),
acetone, rt, 12 h, 90%; (b) 1 N HCl, rt, 4 h, 100%; (c) NaIO4, silica
gel, DCM, 10 min; (d) NaBH4, MeOH, rt, 6 h, 80% over two steps;
(e) MeSO2Cl, Et3N, DCM, 0 ◦C to rt, 12 h, 90%; (f) LiAlH4, THF, 12 h,
90%; (g) NaB(OAc)3H, EDC, R NH2, rt, 3 h, 65–75%.
Synthesis of enantiomers 13–18. The syntheses of 13–18 were
envisaged from synthon 22b which in turn we planned to obtain
from 21b in a similar manner to that discussed in Scheme 2. Syn-
thon 21b was obtained by the reductive amination of aldehyde12h
32 with 2-(trimethylsilyl)piperidine14 in 65% yield.
Synthesis of amine analogs 9, 10, 11 and 12
At this juncture, we also visualized the creation of another class
of azasugars with an additional basic site12h,19 for binding to the
enzyme. In this regard, a hydroxyl moiety at C-10 was converted
to corresponding amine functionality. The mesylate obtained
from alcohol 25 was directly subjected to SN2 displacement
with LiN3 to produce azide 30 in 72% yield, which on catalytic
hydrogenation over 10% Pd/C furnished the corresponding free
amine in 85% yield. Removal of the acetonide group gave 9·2 HCl
in quantitative yield (Scheme 4).
Following similar steps as described above, the enantiomeric
template 22b was obtained (Scheme 5), which was transformed to
hydrochloride salts of 13–18 (Scheme 6) in a parallel manner as
described for 6–12.
Based on our previous research experiences regarding struc-
ture activity relationships among glycosidase inhibitors,12e–h we
intended to increase the lipophilicity of amine functionalities
by attaching a long hydrocarbon chain20 and evaluating its role
in enzyme inhibition. Towards this end, N-alkylation of 31 was
carried out by refluxing with tetradecyl bromide in the presence
of K2CO3 in CH3CN–THF (3:1) to furnish the corresponding
alkylated product in 65% yield which, upon acetonide removal,
produced 10·2 HCl quantitatively (Scheme 4).
Scheme 5 Reagents and conditions: (a) Ref. 12h; (b) 2-(trimethylsilyl)-
piperidine, NaBH(OAc)3, 1,2-dichloroethane, rt, 3 h; (c) hn, DCN,
2-PrOH, 1 h, 60%.
Since it was not possible at this stage to predict which
diastereomer would be the most biologically active, we felt that
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inhibitory activity against a-glucosidase in general compared with
their polyhydroxy analogs. An increase in the inhibitory activity
was successfully accomplished by increasing the lipophilicity. For
example, 10 (Ki = 140 mM) was found to be 5 times more potent
against a-glucosidase compared to its free amine counterpart 9
(Ki = 675 mM). This increased lipophilicity in compound 10 also
exhibited better activity against b-glucosidase, a-mannosidase and
b-mannosidase with Ki values (in mM) of 524, 805 and 830,
respectively, in comparison to no inhibition shown by 9 against
these enzymes up to 1 mM concentration. A similar observation
was found in the case of alkylated amine 17 with respect to free
amine 16. To our pleasant surprise, the exploratory work to make
another diastereomeric amine analog was also fruitful as 12 (Ki =
293 mM) was not only anomer specific for a-mannosidase but
was also found to be an inhibitor 3 fold stronger than 10 (Ki =
805 mM).
Conclusions
Scheme 6 Syntheses of 13–18.
Enzyme inhibition studies
In summary, we present a general synthetic route for a variety of
enantiopure polyhydoxy quinolizidine alkaloids and some of their
amine analogs. Thirteen new azasugars are synthesized and tested
against six different enzymes. The simplicity of the steps involved
in their syntheses make the route attractive for their preparation.
As many of these compounds are selective inhibitors, efficient drug
delivery may make them useful therapeutics. Moreover, the enzyme
inhibitory study can provide an insight into structure activity
relationships for the development of newer analogs as drugs. All
the free and alkylated amine analogs produced promising activity,
demanding more research in this area.
The enzyme inhibitory activities of all the final molecules 6–18
were tested against various enzymes and the results are summa-
rized in Table 1. Compound 12 and 17 were found to be anomer
specific inhibitors of a-mannosidase (Ki = 293 mM and 650 mM,
respectively). The other compounds 9, 11, 14, 16 and 18 were
found to be anomer specific inhibitors of a-glucosidase with Ki
values (in mM) of 675, 278, 450, 258 and 28, respectively.
Compound 18 in particular was found to be a very selective
potent inhibitor of a-glucosidase (Ki = 28 mM) as it did not show
any inhibition against other enzymes under investigation.
Among the polyhydroxy quinolizidine alkaloids, 7 was found
to be a competitive inhibitor for a as well as b-galactosidase
with Ki values 83.9 mM and 591 mM, respectively, whereas 14
was showing selective inhibitory activity for a-glucosidase, Ki =
450 mM. Barring these two cases, none of the polyhydroxy analogs
exhibited any significant inhibitions towards the enzymes under
study. Introduction of an additional amine functionality was found
to be advantageous as all the amine analogs afforded better
Experimental section
General experimental methods
Unless mentioned, all reactions were performed under an argon
atmosphere. All commercially available reagents were used with-
out further purification unless otherwise noted. Enzymes were
purchased from commercial sources. Tetrahydrofuran was freshly
distilled from benzophenone ketyl radical under argon prior to
Table 1 Inhibition of glycosidases (Ki in mM)a: a comparative study
Inhibitorb
Enzyme (source)
b-Gal. (Aspergills oryzaie) a-Gal. (Green coffee beans) b-Man. (Snail) a-Man. (Jack Beans) b-Glu. (Almond) a-Glu. (Yeast)
6
7
8
33%c
591
NI
NI
NI
11%c
18%c
22%c
NI
NI
NI
83.9
NI
NI
NI
830
NI
NI
NI
NI
NI
NI
NI
9
NI
NI
NI
NI
11%c
NI
675
140
278
120
42%c
450
39%c
258
235
28
10
11
12
13
14
15
16
17
18
805
524
31%c
NI
NI
NI
NI
NI
293
NI
46%c
NI
NI
NI
28%c
NI
13%c
NI
18%c
14%c
13%c
NI
NI
NI
NI
29%c
22%c
650
NI
NI
NI
NI
NI
NI
NI
NI
43%c
NI
NI
a Ki in mM (in italics). b Hydrochloride salts of the compounds 6–18 were used for inhibitory activity tests. c Percent inhibition at 1 mM; NI, no inhibition
up to 1 mM.
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use. Column chromatography was performed with silica gel (100–
200 and 230–400 mesh). The combined organic layers were dried
over NaSO4. Solvents were evaporated under reduced pressure.
All yields given refer to isolated yields. Melting points are reported
uncorrected. Optical rotations were measured on a precision auto-
mated polarimeter JASCO P-1030. NMR spectra were recorded
on 200, 400, and 500 MHz spectrometers. Chemical shifts are
reported in ppm. Coupling constants (J values) are reported in
Hertz. 13C peak multiplicity assignments were made based on
DEPT data. IR spectra were recorded on a FT-IR spectrometer.
MS experiments were performed on a low resolution magnetic
sector mass spectrometer. GC analysis was performed on a Varian
CP 3800 GC using a CP-Sil 5CB column. Microanalysis data
were obtained using a Carlo-Erba CHNS-O EA 1108 Elemental
Analyser. The optical density measurements were carried out on
a Varian CARY-50 BIO UV-vis spectrophotometer. The crystal
data for compounds 23 and 25 were collected at T = 296 K, on
SMART APEX CCD Single Crystal X-ray diffractometer using
0.67 mmol) in 2-propanol (250 ml) was irradiated in an open vessel
using a 450 W Hanovia medium pressure mercury vapor lamp.
The lamp was immersed in a Pyrex water-jacketed immersion well
to allow only wavelengths greater than 280 nm to pass through.
After about 1 h of irradiation, the consumption of the starting
material was found to be almost complete (monitored by GC)
and at this stage the irradiation was discontinued. The solvent
was removed under reduced pressure and the residue was column
chromatographed (silica, pet. ether–acetone, 6:1) to afford cyclized
product 22a (0.453 g, 60%) as a yellow liquid. [a]2D9 = +55.80 (c 0.85,
CH2Cl2). Anal. calcd. for C13H21NO2: C, 69.92; H, 9.48; N, 6.27;
Found: C, 69.98; H, 9.51; N, 6.25%. IR (neat) nmax cm-1 2985(=C–
=
H), 2858, 1806, 1667(C C), 1370, 1226. dH (400 MHz, CDCl3)
1.24–1.33 (1H, m, 8ax-H), 1.44, 1.47 (3H each, 2 s, C(CH3)2),
1.48–1.65 (3H, m, 7ax-H, 7eq-H, 9ax-H), 1.82–1.92 (2H, m, 8eq-
3
3
H, 9eq-H), 2.27 (1H, dt, J6ax,7ax = 11.79, J6ax,7eq = 3.01, 6ax-H),
2.33 (1H, d, 3J9ax,9a-ax = 11.70, 9a-ax-H), 2.38 (1H, t, 3J4ax,3ax = 10.29,
4ax-H), 2.93 (1H, d, 2JH,H = 11.54, 6eq-H), 3.23 (1H, dd, J4eq,3ax
=
◦
Mo-Ka radiation (l = 0.7107 A) to a maximum q range of 25.00 .
3.97, 4eq-H), 3.48 (1H, dt, 3J3a-ax,10a-ax = 10.02, 3a-ax-H), 3.74 (1H,
˚
4
=
dt, JH,H = 1.79, 10a-ax-H), 4.89, 5.06 (1H each, 2 s, C CH2).
dC (100 MHz, CDCl3) 24.0 (C-8), 25.7 (C-7), 26.7, 26.9 C(CH3)2,
27.8 (C-9), 56.8 (C-6), 57.7 (C-4), 61.9 (C-9a), 77.1 (C-3a), 82.2
(C10a), 103.2 (C=CH2), 111.0 (C(CH3)2), 144.2 (C=CH2). Mass
(ESI): m/z 224 (M+ + H).
General procedure for the enzyme inhibition assays
Inhibition assays to determine the inhibitory potencies of the
azasugars were carried out spectrophotometrically measuring the
residual hydrolytic activities of the glycosidases on the correspond-
ing p-nitrophenyl glycosides in the presence of the azasugars. The
absorbance of the resulting solution was read at 405 nm.
(3aS,9aR,10S,10aR)-10-(Hydroxymethyl)-2,2-dimethylocta-
hydro-3aH-[1,3]dioxolo[4,5-b]quinolizin-10-ol (23). To a solution
of 22a (0.45 g, 2.02 mmol) in acetone (5 ml) was added N-
methylmorpholine-N-oxide (50% aq so◦lution, 1.41 g, 6.06 mmol).
The reaction mixture was cooled to 0 C and to that was added
a catalytic amount of osmium tetroxide (1 mL of 1% solution of
OsO4 in t-BuOH). The reaction mixture was allowed to come to
rt and stirred for 10 h. Solid Na2SO3 was added to this reaction
mixture. Stirring was continued for 30 min to quench excess N-
methylmorpholine-N-oxide and OsO4. The mixture was filtered
through a short pad of celite and the solvent was evaporated
off. The crude reaction mixture upon column chromatography
(silica, pet ether–ethyl acetate, 3:2) afforded 23 (0.466 g, 90%) as
1-(((4S,5S)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-
2-(trimethylsilyl)piperidine (21a). To a solution of crude aldehyde
20 (5.76 g, 31.82 mmol) (>85% pure by GC) in DCE (90 ml),
was added 2-(trimethylsilyl)piperidine (5.24 g, 33.41 mmol) and
NaB(OAc)3H (8.77 g, 41.36 mmol) under argon atmosphere and
the mixture was stirred for 3 h. The reaction mixture was cooled
in an ice bath and quenched by adding 2 N NaOH until the
aqueous layer was basic. After stirring for 0.5 h, the reaction
mixture was extracted in DCM. The solvent was removed under
reduced pressure and the crude product was purified by column
chromatography (pet ether/ethyl acetate, 6:1) to furnish 21a
(6.77 g, 72%). [a]2D6 = -17.20 (c 1.25, CHCl3). Anal. Calcd. for
C16H29NO2Si: C, 65.03; H, 9.89; N, 4.74; Si, 9.50; Found: C, 65.12;
H, 9.86; N, 4.76, Si, 9.44%. IR nmax cm-1 in CHCl3 3311 (∫C–H),
◦
a colorless solid (mp. 135–136 C (from ethyl acetate/hexanes)).
[a]2D9 = +27.7(c 1.2, DCM). Anal. Calcd. for C13H23NO4: C, 60.68;
H, 9.01; N, 5.44; Found: C, 60.51; H, 9.05; N, 5.45%. IR nmax cm-1
in CHCl3 3432 (OH), 2938, 2306, 2232, 1654, 1265. dH (400 MHz,
CDCl3, D2O exchange) 1.13–1.19 (2H, m, 8ax-H, 9ax-H), 1.44
(3H, s, C(CH3)2), 1.44 (4H, apparent s, C(CH3)2, 7ax-H), 1.59–
≡
2933, 2120 (C C), 1441, 1381, 1250, 1055. dH (400 MHz, CDCl3)
0.6, 0.7 (4.5 H each, 2 s, Si(CH3)3), 1.21–1.29 (1H, m, 4ax-H), 1.40,
1.41, 1.46 1.46 (1.5H each, 4 s, C(CH3)2), 1.50–1.63 (4H, m, 3ax-
1.62 (1H, m, 7eq-H), 1.79–1.80 (1H, m, 8eq-H), 1.93–1.95 (1H,
2
3
3
H, 3eq-H, 4eq-H, 5ax-H), 1.71 (1H, dt, JH,H= 12.51, J5eq,6ax
=
m, 9a-ax-H), 2.01–2.03 (1H, m, 9eq-H), 2.13 (1H, dt, J9ax,8ax
=
3
3
12.55,3J9ax,8eq = 2.76, 9ax-H), 2.21 (1H, t, J4ax,3a-ax = 10.04, 4ax-
H), 2.92 (1H, d, 2JH,H = 11.50, 6eq-H), 3.14 (1H, dd, 2JH,H = 9.88,
3J4eq,3a-ax = 4.28, 4eq-H), 3.43 (1H, d, 3J10a-ax,3a-ax = 9.54, 10a-ax-H),
3.73 (1H, d, 2JH,H = 11.54,CH2OH), 3.80 (1H, dt, 3a-ax-H), 3.97
(1H, d, CH2OH). dC (50 MHz, CDCl3) 24.2 (C-8), 24.9 (C-9),
25.7 (C-7), 26.6 C(CH3)2, 56.7 (C-4), 57.9 (C-6), 62.9 (CH2OH),
68.4 (C-9a), 71.9 (C-3a), 72.4 (C-10), 86.9 (C-10a), 110.6 C(CH3)2.
Mass (ESI): m/z 257 (M+ + H), 280 (M+ + Na).
3
3.76, 5eq-H), 1.87 (1H, dt, J2ax,3ax = 11.54, J2ax,3eq = 3.76, 2ax-
H), 2.03–2.14 (1H, m, 6ax-H), 2.40–2.46 (1H, m, NCH2CH), 2.51
4
≡
(1H, t, JH,H = 2.14, C CH), 2.92–2.97 (1H, m, 6eq-H), 3.12–
3.18 (1H, m, NCH2CH), 4.22–4.32 (2H, m, H-4 dioxolane, H-5
dioxolane). dC (50 MHz, CDCl3) -1.1, -1.0 (Si(CH3)3), 23.8, 24.2
(C-4), 25.7 (C-5), 26.0, 26.09 (C(CH3)2), 26.03, 26.6 (C-3), 27.06,
27.11 (C(CH3)2), 54.7, 55.0 (NCH2CH), 56.0, 56.1 (C-2), 58.1,
58.2 (C-6), 68.6, 68.8 (C-5, dioxolane), 74.4, 74.5 (C∫CH), 80.3,
80.9 (C-4, dioxolane), 81.0, 81.1 (C∫CH), 110.5, 110.7 (C(CH3)2).
Mass (ESI): m/z 296 (M+ + H).
(1S,2R,3S,9aR)-1,2,3-Trihydroxy-1-(hydroxymethyl) decahy-
droquinolizinium chloride (6·HCl). Compound 23a (0.025 g,
0.097 mmol) was subjected to acetonide deprotection using
aqueous 1 N HCl (1 ml) to provide the hydrochloride salt of 6
quantitatively. [a]2D3 = +24.1 (c 0.95, MeOH). Anal. Calcd. for
(3aS,9aR,10aS)-2,2-Dimethyl-10-methyleneoctahydro-3aH-
[1,3]dioxolo[4,5-b]quinolizine (22a). A solution containing 21a
(1.0 g, 3.38 mmol) and 1,4-dicyanonaphthalene (0.12 g,
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C10H20ClNO4: C, 47.34; H, 7.95; N, 5.52; Found: C, 47.44; H,
7.99; N, 5.63%. dH (400 MHz, D2O) 1.36–1.47 (1H, m, 8ax-H),
1.53–1.70 (2H, m, 7ax-H, 9ax-H), 1.82–1.90 (2H, m, 7eq-H,
CDCl3) 1.01 (1H, ddd, 2JH,H = 15.96,3J8ax,9ax 3 = 12.66, 3J7eq,8ax
=
3
3
3.31, 8ax-H), 1.18 (1H, tq, J9ax,9a-ax = 12.9, J8eq,9ax = 3.58, 9ax),
1.39, 1.43 (3H each, 2 s, C(CH3)2), 1.50 (1H, tq, 3J7ax,8ax = 12.93,
3J6eq,7ax = 3.85, 7ax), 1.63–1.69 (2H, m, 7eq, 8eq), 1.77 (1H, d,
2
3
8eq-H), 2.18 (1H, dt, JH,H = 14.38, J9eq,8ax = 2.81, 9eq-H),
3
3
2.82–2.90 (2H, m, 4ax-H, 6ax-H), 3.01 (1H, dd, J9a-ax,9ax
=
2JH,H = 13.2, 9eq), 2.26 (1H, dt, J6ax,7ax = 11.83,3J6ax,7eq = 2.48,
3
12.28, J9a-ax,9eq = 2.03, 9a-ax-H), 3.36–3.41 (2H, m, 4eq-H,
6eq-H), 3.47, 3.52 (1H each, d,2JH,H = 10.55, CH2OH), 3.98
6ax-H), 2.31 (1H, dd, 3J9ax,9a-ax = 11.22,3J9eq,9a-ax = 1.54, 9a-ax-H),
3
2
2.37 (1H, t, J4ax,3a-ax = 10.18, 4ax-H), 2.92 (1H, d, JH,H = 4.67,
3
3
2
(1H, d, J2ax,3ax = 10.80, 2ax-H), 4.17 (1H, ddd, J4ax,3ax = 10.25,
3J4eq,3ax = 5.30, 3ax-H). dC (100 MHz, D2O) 21.3, 22.9, 23.0
(C-7, C-8, C-9), 56.3, 56.8 (C-4, C-6), 58.7 (CH2-OH), 64.2
(C-3), 67.9 (C-9a), 72.6 (C-1), 78.0 (C-2). Mass (ESI): m/z
218 (M+ + H).
3¢-H), 2.99 (1H, br d, JH,H = 11.56, 6eq-H), 3.03 (1H, d, 3¢-H),
2
3
3.23 (1H, dd, JH,H = 9.90, J4eq, 3a-ax = 3.85, 4eq-H), 3.63 (1H, d,
3J10a-ax,3a-ax = 9.08, 10a-H), 3.72 (1H, dt, 3a-ax-H). dC (50 MHz,
CDCl3) 23.6 (C-8), 24.6 (C-7), 25.8 (C-9), 26.5, 26.7 (C(CH3)2),
45.2 (C-3¢), 56.7 (C-6), 57.2 (C-4), 60.3 (C-2¢), 62.3 (C-9a), 75.2
(C-3a), 78.4 (C-10a), 111.5 (C(CH3)2). Mass (ESI): m/z 240 (M+ +
H), 262 (M+ + Na).
(3aS,9aR,10S,10aS)-2,2-Dimethyloctahydro-3aH-[1,3]dioxolo-
[4,5-b]quinolizin-10-ol (25). A solution of 23 (0.45 g, 1.75 mmol)
in DCM (5 ml) was added to a suspension of silica gel sup-
ported sodium periodate [prepared by dissolving NaIO4 (0.53 g,
2.62 mmol) in 1 mL water and 2.77 g of flash silica gel] in DCM
(5 ml). The suspension was stirred for 10 min. and filtered. The
solvent was evaporated off and the brownish pasty mass was
extracted with ethyl acetate (3 ¥ 10 ml). The combined organic
extracts were dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure. To the solution of that crude
ketone (24) (0.35 g, 1.55 mmol) in methanol (5 ml) was added
NaBH4 (0.118 g, 3.10 mmol). The resulting mixture was stirred at
rt for 6 h and then quenched by adding an excess of the saturated
solution of NaCl. This brownish suspension was stirred overnight
and extracted with ethyl acetate (4 ¥ 5 ml). The combined organic
extracts were dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure. The residue was purified by
column chromatography (silica, pet ether–ethyl acetate, 1:9) to
afford 25 (0.282 g, 80%) as a colorless solid (mp 133–134 ◦C
(from ethyl acetate/hexanes)). [a]2D9 = +16.77 (c 1.2, DCM). Anal.
Calcd. for C12H21NO3: C, 63.41; H, 9.31; N, 6.16; Found: C, 63.44;
H, 9.29; N, 6.19%. IR nmax cm-1 in CHCl3 3436 (OH), 2940, 1653,
1265. dH (400 MHz, CDCl3, D2O exchange) 1.23–1.29 (1H, m,
8ax-H), 1.43, 1.43 (3H each, 2 s, C(CH3)2, 1.56–1.58 (3H, m, 7ax-
H, 7eq-H, 9ax-H), 1.77–1.80 (2H, m, 8eq-H, 9eq-H), 1.98 (1H,
(3aS,9aR,10R,10aR)-2,2,10-Trimethyloctahydro-3aH-[1,3]dio-
xolo[4,5-b]quinolizin-10-ol (27). To a solution of 26 (0.1 g,
0.42 mmol) in dry THF (2 ml) at 0 ◦C was added LiAlH4 (0.031 g,
0.84 mmol), which was allowed to come to rt and stirred overnight.
After recooling to 0 ◦C the reaction mixture was quenched by drop
wise addition of 2 N NaOH solution. It was dried with Na2SO4
and was filtered through a short celite pad. The reaction mixture
was concentrated and purified by column chromatography (pet.
ether/ethyl acetate, 3:2) to give corresponding alcohol 27 (0.091 g,
90%) as a white solid. [a]2D5 = +38.1 (c 1.0, CHCl3). Anal. Calcd. for
C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C, 64.75; H, 9.63;
N, 5.75%. IR nmax cm-1 in CHCl3 3442 (OH), 2366, 1631, 1259.
dH (500 MHz, CDCl3, D2O exchange) 1.15–1.21 (1H, m, 8ax-H),
1.23 (3H, s, 10-Me), 1.24–1.27 (1H, m, 9ax-H), 1.42, 1.44 (3H each,
2 s, C(CH3)2), 1.46–1.52 (1H, m, 7ax-H), 1.61 (1H, br d, 2JH,H
13.07, 7eq-H), 1.76–1.81 (2H, m, 8eq-H, 9eq-H), 1.89–1.91 (1H,
=
3
3
m, 9a-ax), 2.18 (1H, dt, J6ax,7ax = 12.38, J6ax,7eq = 2.89, 6ax-H),
2.21 (1H, t, 3J4ax,3a-ax = 10.18, 4ax-H), 2.93 (1H, br d, 2JH,H = 11.50,
6eq-H), 3.12 (1H, dd, 2JH,H = 9.81, 3J3a-ax,4eq = 3.96, 4eq-H), 3.28
(1H, d, 3J3a-ax,10a-ax = 9.43, 10a-ax-H), 3.53 (1H, ddd, 3a-ax-H). dC
(125 MHz, CDCl3) 16.2 (10-Me), 24.0, 24.3, 25.8 (C-7, C-8, C-9),
26.5, 26.8 (C(CH3)2), 56.8 (C-6), 58.1 (C-4), 69.4 (C-9a), 72.3
(C-10), 72.5 (C-3a), 86.9 (C-10a), 110.4 (C(CH3)2). Mass (ESI):
m/z 242 (M+ + H).
3
d, J9ax,9a-ax = 11.04, 9a-ax-H), 2.14–2.23 (2H, m, 6ax-H, 4ax-H),
2
2
2.92 (1H, d, JH,H = 11.04, 6eq-H), 3.17 (1H, dd, JH,H = 9.79,
(3aS,9aR,10S,10aS)-N -Benzyl-2,2-dimethyloctahydro-3aH-
[1,3]dioxolo[4,5-b]quinolizin-10-amine (28). The reductive ami-
nation procedure used for synthesizing 21a was applied to ketone
24 (0.078 g, 0.345 mmol) in the presence of benzyl amine (0.045 g,
0.415 mmol) to produce 28 (0.082 g, 75%) as a faint yellow solid.
[a]2D6 = +18.41 (c 1.2, CHCl3). Anal. Calcd. for C19H28N2O2: C,
72.12; H, 8.92; N, 8.85; Found: C, 71.99; H, 8.97; N, 8.81%. IR
3J4eq,3a-ax = 4.02, 4eq-H), 3.29 (1H, dd, 3J3a-ax,10a-ax = 9.28, 3J10eq,10a-ax
=
2.51, 10a-ax-H), 3.96 (1H, t, 10-H), 4.00 (1H, dt, 3a-ax-H). dC
(100 MHz, CDCl3) 24.1 (C-8), 25.4 (C-7), 26.5, 26.8 C(CH3)2, 28.4
(C-9), 56.4 (C-6), 57.8 (C-4), 63.8 (C-9a), 69.2 (C-10), 70.2 (C-3a),
82.1 (C-10a), 110.2 (C(CH3)2). Mass (ESI): m/z 228 (M+ + H),
250 (M+ + Na).
nmax cm-1 in CHCl3 3351 (NH), 2984 (C–H arom), 1604 (C C
=
(2¢S,3aS,9aR,10aR)-2,2-Dimethyloctahydrospiro[[1,3]dioxolo-
[4,5-b]quinolizine-10,2¢-oxirane] (26). To a solution of 23 (0.2 g,
0.777 mmol) in dry DCM (3 ml) at 0 ◦C under argon atmosphere
was added triethyl amine (0.22 ml, 1.554 mmol) and methane-
sulfonyl chloride (0.066 mL, 0.855 mmol). The reaction mixture
was stirred at room temperature for 12 h; water was added and
extracted with DCM (2 ¥ 5 ml). The combined organic extracts
were dried over anhydrous Na2SO4, concentrated under reduced
pressure and purified by column chromatography (silica, pet.
ether/ethyl acetate, 4:1) to get 26 (0.168 g, 90%) as a white solid.
[a]2D6 = +49.16 (c 1.05, CHCl3). Anal. Calcd. for C13H21NO3: C,
65.25; H, 8.84; N, 5.85 Found: C, 65.34; H, 8.87; N, 5.83%. IR
arom), 1453, 1370, 1235. dH (500 MHz, CDCl3) 1.20–1.27 (1H, m,
8ax-H), 1.44, 1.45 (3H, 2 s, C(CH3)2), 1.48–1.59 (3H, m, 7ax-H,
7eq-H, 9ax-H), 1.76–1.84 (2H, m, 8eq-H, 9eq-H), 1.97 (1H, td,
3J9ax,9a-ax = 11.14, 3J9eq,9a-ax = 2.38, 9a-ax-H), 2.11 (1H, dt, 2JH,H
=
3
3
11.72, J6ax,7eq = 3.53, 6ax-H), 2.14 (1H, t, J3a-ax,4ax = 10.24 Hz,
3
4ax-H), 2.91 (1H, d, 6eq-H), 3.04 (1H, t, 3J10eq,10a-ax = J10eq,9a-ax
=
3
2.91 Hz, 10eq-H), 3.17 (1H, dd, J3a-ax,4eq = 4.10, 4eq-H), 3.38
(1H, dd, 3J10a-ax,3a-ax = 9.45, 3J10a-ax,10eq = 3.63, 10a-ax-H), 3.88 (1H,
2
d, JH,H = 13.11, CH2Ph), 3.98 (1H, dt, 3a-ax-H), 4.01 (1H, d,
CH2Ph), 7.19–7.22 (1H, m, H-arom), 7.27–7.30 (2H, m, H-arom),
7.35–7.36 (2H, m, H-arom). dC (125 MHz, CDCl3) 24.3 (C-8),
25.4 (C-7), 26.6, 26.9 (C(CH3)2), 29.5 (C-9), 54.4 (CH2Ph), 56.8
n
max cm-1 in CHCl3 3054 (C–O epoxide), 1421, 1265. dH (500 MHz,
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Org. Biomol. Chem., 2009, 7, 3300–3307 | 3305
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(C-6), 58.3 (C-10), 58.4 (C-4), 64.9 (C-9a), 70.8 (C-3a), 82.9 (C-
10a), 109.8 (C(CH3)2), 126.7, 128.1, 128.1, 140.9 (4 C-arom). Mass
(ESI): m/z 317 (M+ + H), 339 (M+ + Na).
Crystal structure determination of compound 23
Crystal data
C13H23NO4, M = 257.32, orthorhombic, a = 5.3743(4), b =
3
˚
˚
10.2506 (7), c = 24.311(2) A, V = 1339.27(16) A , space group
P212121, Z = 4, Dc = 1.276 g/cc, m (Mo–Ka) = 0.094 mm-1, 12741
reflections measured, 2369 unique (Rint = 0.0398) [I>2s(I)], R
value 0.0358, the final wR(F2) = 0.0823 [I>2s(I)].
(3aS,9aR,10R,10aS)-10-Azido-2,2-dimethyloctahydro-3aH-
[1,3]dioxolo[4,5-b]quinolizine (30). To a solution of 26 (70 mg,
0.309 mmol) in pyridine (2 ml) at 0 ◦C was added mesyl chloride
(42 mg, 0.371 mmol, in 1 mL DCM). The reaction mixture was
stirred at room temperature for 6 h. When TLC revealed no
starting material, the solution was diluted with dichloromethane
(10 ml) and washed with water (3 ¥ 5 ml) followed by brine solution
(5 ml). It was then dried over anhydrous Na2SO4. After removal of
solvent the crude mesylate (77 mg, 0.251 mmol) was taken up in
DMF (2 ml). LiN3 (123 mg, 2.51 mmol) was added and the mixture
Crystal structure determination of compound 25
Crystal data
C12H21NO3, M = 227.30, orthorhombic, a = 9.725 (1), b =
3
˚
˚
6.4790(7), c = 20.325(2) A, V = 1280.6(2) A , space group P212121,
Z = 4, Dc = 1.179 g/cc, m (Mo–Ka) = 0.084 mm-1, 10685
reflections measured, 2250 unique (Rint = 0.0745) [I>2s(I)], R
value 0.0480, the final wR(F2) = 0.0864 [I>2s(I)].
◦
was heated at 110 C for 12 h. The reaction mixture was diluted
with water (10 ml) and extracted with ethyl acetate (3 ¥ 10 ml). The
ethylacetate layer was washed with water and dried over anhydrous
Na2SO4. Solvent removal followed by column chromatography
(silica, pet. ether/ethyl acetate, 6:1) gave 30 (56 mg, 72%) as a
colorless liquid. [a]2D5 = +60.19 (c 1.1, CHCl3). Anal. Calcd. for
C12H20N4O2: C, 57.12; H, 7.99; N, 22.21; Found: C, 57.01; H, 7.90;
N, 22.05%. IR nmax cm-1 in CHCl3 2936, 2208 (N3), 2107, 1654,
1446, 1229. dH (400 MHz, CDCl3) 1.19–1.25 (2H, m, 8ax-H, 9ax-
H), 1.44, 1.45 (3H each, 2 s, C(CH3)2), 1.48–1.54 (1H, m, 7ax-H),
1.61–1.64 (1H, m, 8eq-H), 1.74–1.81 (2H, m, 7eq-H, 9eq-H), 2.07–
2.11 (1H, m, 9a-ax-H), 2.22 (1H, dt, 3J6ax,7ax = 11.83, 3J6ax,7eq = 2.76,
Acknowledgements
We thank Dr P. R. Rajmohan for special NMR experiments.
D. G. and K. S. S. thank CSIR, New Delhi for the award of
Research Fellowships. Financial support by the DBT, New Delhi
is gratefully acknowledged.
6ax-H), 2.25 (1H, t, 3J3a-ax,4ax = 10.17, 4ax-H), 2.90 (1H, d, 2JH,H
=
References
11.28, 6eq-H), 3.10 (1H, dd, 2JH,H = 9.90, 3J3a-ax,4eq = 3.85, 4eq-H),
3.20–3.28 (2H, m, 10ax-H, 10a-ax-H), 3.58 (1H, ddd, 3a-ax-H).
dC (50 MHz, CDCl3) 23.8 (C-8), 25.6 (C-7), 26.7 (C(CH3)2), 29.4
(C-9), 56.0 (C-6), 56.9 (C-4), 64.6, 65.2 (C-9a, C-10), 74.2 (C-3a),
81.9 (C-10a), 111.1 (C(CH3)2). Mass (ESI): m/z 253 (M+ + H),
275 (M+ + Na).
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3
3
3J6ax,7ax = 11.83, J6ax,7eq = 3.03, 6ax-H), 2.27 (1H, t, J3a-ax,4ax
=
=
3
3
10.18, 4ax-H), 2.66 (1H, dd, J10ax,10a-ax = 10.18, J10ax,9a-ax
2
8.53, 10ax-H), 2.89 (1H, br d, JH,H = 11.56, 6eq-H), 3.10
3
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(1H, dd, J3a-ax,10a-ax = 9.07, 10a-ax-H), 3.13 (1H, dd, J4eq,3a-ax
=
4.01, 4eq-H), 3.58 (1H, ddd, 3a-H). dC (100 MHz, CDCl3)
24.1 (C-8), 25.8 (C-7), 26.7, 26.8 (C(CH3)2), 28.6 (C-9), 55.7
(C-9a), 56.2 (C-6), 57.5 (C-4), 67.6 (C-10), 74.3 (C-3a), 84.4
(C-10a), 110.4 (C(CH3)2). Mass (ESI): m/z 227 (M+ + H),
249 (M+ + Na).
3306 | Org. Biomol. Chem., 2009, 7, 3300–3307
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The Royal Society of Chemistry 2009
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