Synthesis of (-)-dihydropinidine, (2S,6R)-isosolenopsin and (+)-monomorine via a chiral synthon from l-aspartic acid

Article abstract of DOI:10.1016/j.tetasy.2011.11.006

The use of a β-amino aldehyde derived from l-aspartic acid as a chiral synthon to construct 2,6-disubstituted piperidines is described. The synthesis of (-)-dihydropinidine·HCl, (2S,6R)-isosolenopsin·HCl and (+)-monomorine has been achieved from this chiral synthon using a Wittig reaction followed by hydrogenation (reductive cyclization) as the key steps.

Full text of DOI:10.1016/j.tetasy.2011.11.006

Tetrahedron: Asymmetry 22 (2011) 1849–1854
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Synthesis of (ꢀ)-dihydropinidine, (2S,6R)-isosolenopsin and
(+)-monomorine via a chiral synthon from L-aspartic acid
⇑
Chada Raji Reddy , Bellamkonda Latha
Organic Chemistry Division-I, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2011
Accepted 9 November 2011
The use of a b-amino aldehyde derived from L-aspartic acid asa chiralsynthon to construct 2,6-disubstituted
piperidines is described. The synthesis of (ꢀ)-dihydropinidineꢁHCl, (2S,6R)-isosolenopsinꢁHCl and
(+)-monomorine has been achieved from this chiral synthon using a Wittig reaction followed by hydroge-
nation (reductive cyclization) as the key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
8
Chiral synthons have received prominence in the synthesis of
enantiomerically pure complex bio-active natural products and
pharmaceutical agents via further structural and stereochemical
elaboration.1 Over the last few decades, natural amino acids which
are inexpensive, readily available, endowed with a wealth of chi-
rality and valuable features, have comprehensively served as ‘chi-
ral synthon’ resources to access a range of nitrogen containing
compounds including alkaloids.2 However, the scope of amino
acids as chiral synthons relies on the expansion of key intermedi-
ates desired for synthesis. For instance, Garner’s aldehyde, derived
1
9
4
7
6
2
5
3
N
3
5
6
2
N
H
C9H19
N
H
(-)-dihydropinidine 1
(2S,6R)-isosolenopsin 2
(+)-monomorine 3
Figure 1. Structures of (ꢀ)-dihydropinidine 1, (2S,6R)-isosolenopsin
(+)-monomorine 3.
2 and
from L-serine, has found tremendous applications as a chiral pool
reagent in the synthesis of various nitrogen-containing com-
pounds.3 Therefore, the search for efficient chiral synthons, which
are easily accessible and stable for longer periods of time is of great
importance in organic synthesis.
(i) SOCl2, MeOH
0
NH2
O
NHCbz
CO2Me
oC to rt, 30 min
HO
HO
OH
(ii) CbzCl, Na2CO3
H2O:dioxane (1:1)
0 oC to rt, 12 h
2,6-Dialkylated piperidines constitute a representative class of
several naturally occurring alkaloids4 displaying significant
pharmacological properties.5,6 In particular, cis-2-alkyl-6-methyl
piperidine is an important framework found in monocyclic piper-
idine alkaloids as well as bicyclic alkaloids such as indolizidines,7
decahydroquinolines,8 galbuliminas9 and histrionicotoxins.10
Consequently, this class of piperidines has elicited significant
synthetic studies and further development of new approaches
using chiral synthons with useful functionalities would be a
helpful addition to the literature. Herein, we report a facile access
to (ꢀ)-dihydropinidine11 1, (2S,6R)-isosolenopsin12,11k 2, and
(+)-monomorine13 3 (Fig. 1) through a chiral synthon obtained
O
O
4
L-aspartic acid
68% (over two steps)
ClCO2Et, NMM
NHCbz
THF, -10 °C, 20 min.
TBSCl, imidazole
DMF, rt, 12 h, 87%
HO
CO2Me
then NaBH4, MeOH,
0 °C, 15 min., 47%
5
NHCbz
DIBAL-H
NHCbz
from L-aspartic acid.
toluene, -78 o
10 min., 90%
C
TBSO
CO2Me
TBSO
CHO
6
7
⇑
Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512.
E-mail address: rajireddy@iict.res.in (C.R. Reddy).
Scheme 1. Synthesis of the chiral synthon 7 from
L-aspartic acid.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.006

1850
C. R. Reddy, B. Latha / Tetrahedron: Asymmetry 22 (2011) 1849–1854
O
Ph3P
8
NHCbz
CHO
NHCbz
O
TBSO
TBSO
toluene, reflux
6 h, 96%
7
9
BnBr, K2CO3
10% Pd/C-H2
TBSO
HO
TBSO
DMF, rt, 12 h,
89%
N
H
N
EtOH, rt, 12 h
90%
Bn
11
10
nOe enhancement
1% HCl, EtOH
rt, 4 h, 88%
H
H
N
HO
N
Bn
12
12
Bn
Scheme 2. Synthesis of the common intermediate 12.
i) SO3·Py, CH2Cl2, DMSO
Et3N, 0 oC, 30 min
(i) 20% Pd(OH)2/C-H2
MeOH, 12 h
1·
HCl
N
(ii) 2M HCl, 90%
(over two steps)
o
13
ii) , KHMDS, DME, -60 C
1 h, 72% (over two steps)
Bn
14
i) SO3·Py, CH2Cl2, DMSO
Et3N, 0 oC, 30 min
(i) 20% Pd(OH)2/C-H2
MeOH, 12 h
2·HCl
12
C7H15
N
(ii) 2M HCl, 86%
(over two steps)
o
15
ii) , KHMDS, DME, -60 C
Bn
1 h, 78% (over two steps)
16
20% Pd(OH)2/C-H2
MeOH, 12 h
i) SO3·Py, CH2Cl2, DMSO
Et3N, 0 oC, 30 min
O
N
3
Bn
ii) 17, Ba(OH)2·8H2O
THF:H2O (20:1), 5 h
88% (over two steps)
80%
18
Ph
O
Ph
O
O
C7H15
S
N
S
PO(OMe)2
N
O
N
N
O
C4H9
17
15
N
N
13
N
N
Scheme 3. Synthesis of (ꢀ)-dihydropinidine 1, (2S,6R)-isosolenopsin 2 and (+)-monomorine 3.
chiral synthon, b-amino aldehyde 7, was found to be a stable solid
2. Results and discussion
at room temperature for several months15 and easily accessible on
a multigram scale.16
With the chiral synthon in hand, the formation of the 2,6-
disubstituted piperidine ring was studied. A Wittig reaction of alde-
hyde with (acetylmethylene)triphenylphosphorane 8 in toluene
Our approach began with the preparation of a chiral synthon
starting from
-aspartic acid through a known ester 614 in four
steps (Scheme 1). Initially, esterification of the b-carboxylic acid
of -aspartic acid followed by protection of the amine using benzyl
L
L
under refluxing conditions gave
a,b-unsaturated-d-amino ketone
chloroformate/Na2CO3 provided 4 in a 68% yield over two steps.
Acid 4 was then subjected to reduction via a mixed anhydride pro-
cedure to give 5 in a 47% yield. The hydroxy functionality of 5 was
protected as tert-butyldimethylsilyl (TBS) ether with TBSCl/imid-
azole in DMF to obtain the fully protected compound 6 in an 87%
yield. The ester functionality in 6 was reduced to b-amino aldehyde
9, a key precursor for the reductive cyclization. Treatment of 9 with
10% Pd/C under hydrogen atmosphere in EtOH, gave 2-alkyl-6-
methyl piperidine 10 in a 90% yield. This hydrogenation involved
olefin reduction and intramolecular cyclic imine formation,
followed by stereoselective reduction of the imine. The cis-configu-
ration of the 2,6-substituents was confirmed at a later stage (com-
pound 12) by NOE studies. Next, the protection of the free NH in
piperidine 10 with a benzyl group to give 11 followed by TBS depro-
tection with 1% HCl/EtOH afforded piperidinol 12 in an 88% yield
7 in a 90% yield (5 g of 7 was prepared in a 25% overall yield from L-
aspartic acid). Aldehyde 7 would serve as a useful synthon for the
construction of a 2,6-disubstituted piperidine through a Wittig
reaction followed by reductive cyclization. Furthermore, this new

C. R. Reddy, B. Latha / Tetrahedron: Asymmetry 22 (2011) 1849–1854
1851
(Scheme 2), an advanced common intermediate for all three alka-
loid targets: (ꢀ)-dihydropinidine hydrochloride, (2S,6R)-isosole-
nopsin hydrochloride, and (+)-monomorine. An NOE experiment
on 2-alkyl-6-methyl piperidine 12 confirmed the cis-configuration
of the 2,6-substituents and key NOE enhancements are shown in
Scheme 2.
mixture was stirred for 25 min at room temperature, and diluted
with diethyl ether (50 mL), upon cooling and shaking, -aspartic
acid methyl ester precipitated as a colorless solid which was fil-
tered immediately. The solid was washed with ice cold diethyl
ether (20 mL) and collected as a colorless solid (75%). The crude
L
L-aspartic acid methyl ester (9.8 g, 53 mmol) was taken in water
As shown in Scheme 3, primary alcohol 12 was oxidized to an
aldehyde using Parikh–Doering oxidation (SO3ꢁPy, CH2Cl2, DMSO,
Et3N, 0 °C) followed by Julia olefination with 5-(ethylsulfonyl)-1-
phenyl-1H-tetrazole 1317 to give olefin 14 (72% yield over two
steps). Exposure of 14 to 20% Pd(OH)2/H2 (gas) in EtOH for saturation
of the olefin as well as debenzylation in a one-pot reaction and sub-
sequent treatment with 2 M HCl provided the desired (ꢀ)-dihydro-
(115 mL) and dioxane (53 mL), and cooled to 0 °C after which
was added Na2CO3 (5.6 g, 53 mmol), followed by benzyl chlorofor-
mate (9.1 g, 53.4 mmol) in dioxane (63 mL) dropwise over 3 h. The
reaction mixture was stirred at rt overnight. The solution was ex-
tracted with ethyl acetate (3 ꢃ 50 mL). The aqueous layer was acid-
ified to pH 2 with 6 M HCl. The product was extracted with ethyl
acetate (2 ꢃ 50 mL). The combined organic layer was washed with
brine (50 mL), dried over Na2SO4 and the solvent was evaporated
under reduced pressure. The crude compound was passed through
a short pad of silica gel (EtOAc) and concentrated to provide 4 (68%
pinidine hydrochloride 1 in a 90% yield, mp: 242–243 °C, ½a D28
¼ ꢀ9
ꢂ
(c 0.29, EtOH), {lit.: mp: 245–246 °C; ½a D25
ꢂ
¼ ꢀ9:1 (c 1.03, EtOH)}.11c
A similar sequence of reactions was carried out on alcohol 12
involving; (i) oxidation of alcohol 12 followed by Julia olefination
with 5-(octylsulfonyl)-1-phenyl-1H-tetrazole 1518 to olefin 16;
and (ii) hydrogenation of 16 followed by treatment with HCl, formed
(2S,6R)-isosolenopsin as its hydrochloride salt 2 in good yield, mp:
over two steps) as a semi-solid. ½a D29
ꢂ
¼ þ20:3 (c 0.5, CHCl3). 1H
NMR (300 MHz, CDCl3): 7.39–7.24 (m, 5H, H(Ph)), 5.96 (br d,
J = 9.0 Hz, 1H, NH), 5.10 (s, 2H, CH2-Ph), 4.72–4.59 (m, 1H, CHN),
3.64 (s, 3H, OCH3), 3.02 (dd, J = 17.3, 4.56 Hz, 1H, CH2–CO), 2.85
(dd, J = 17.3, 4.56 Hz, 1H, CH2–CO); 13C NMR (75 MHz, CDCl3): d
174.0, 171.5, 156.1, 135.9, 128.4, 128.1, 128.0, 67.2, 52.0, 50.1, 36.2.
173–175 °C, ½a 3D0
ꢂ
¼ ꢀ11 (c 0.5, CHCl3), {lit.: ½a D25
¼ ꢀ10:1 (c 1.0,
ꢂ
CHCl3)}.12c Having in hand the established routes for the synthesis
of (ꢀ)-dihydropinidine and (2S,6R)-isosolenopsin from 12, the syn-
thesis of an indolizidine alkaloid, (+)-monomorine was also pursued
(Scheme 3). Thus, alcohol 12 was oxidized to aldehyde, which upon
HWE olefination with b-keto phosphorane 1719 afforded enone 18 in
an 88% yield. Subjection of enone 18 to reductive cyclization involv-
ing four transformations in a one-pot reaction under hydrogenation
reaction conditions 20% Pd(OH)2 in MeOH gave the target indolizi-
4.1.2. (S)-Methyl 3-(benzyloxycarbonylamino)-4-
hydroxybutanoate 514c
The N-protected amino acid 4 (14.5 g, 51.6 mmol) was dissolved
in anhydrous THF (250 mL) and cooled to ꢀ10 °C (ice-salt bath). To
the reaction mixture was added N-methyl morpholine (NMM)
(5.6 mL, 51.6 mmol), followed by ethyl chloroformate (4.9 mL,
51.6 mmol) dropwise. After 10 min, NaBH4 (5.7 g, 154.8 mmol)
was added to the reaction mixture in one portion followed by
the dropwise addition of MeOH (532 mL). After the complete addi-
tion of MeOH, the solution was stirred for an additional 10 min,
and then neutralized slowly at 0 °C with 1 M HCl to pH 6. The or-
ganic solvents were evaporated under reduced pressure and the
product was extracted with EtOAc (3 ꢃ 50 mL). The combined or-
ganic layer was washed consecutively with 1 M HCl (50 mL), H2O
(50 mL), 5% aq NaHCO3 (50 mL), dried over Na2SO4 and the solvent
was evaporated under reduced pressure. The residue was purified
by flash chromatography (silica gel, hexanes/EtOAc, 1:1) to obtain
dine alkaloid, (+)-monomorine 3 in good yield, ½a D28
¼ þ30:5 (c 0.9,
ꢂ
hexanes), {lit.: ½a D24
ꢂ
¼ þ33:3 (c 0.39, hexanes)}.13d
3. Conclusion
In conclusion, we have developed a useful chiral synthon
from -aspartic acid that can be used to synthesize cis-2,6-disub-
stituted piperidines via Wittig followed by hydrogenation
L
a
reaction sequence. Using this strategy, we accomplished the
total syntheses of (ꢀ)-dihydropinidine, (2S,6R)-isosolenopsin
and (+)-monomorine. The scope and utility of this chiral synthon
will be further explored using other natural product (alkaloid)
targets.
5 (47%) as a colorless oil. ½a D27
ꢂ
¼ ꢀ10:5 (c 1.0, MeOH). 1H NMR
(300 MHz, CDCl3):
d 7.36–7.26 (m, 5H, H(Ph)), 5.52 (br d,
J = 6.9 Hz, 1H, NH), 5.07 (s, 2H, CH2-Ph), 4.07–3.96 (m, 1H, CHN),
3.72–3.63 (m, 2H, CH2-OH), 3.67 (s, 3H, OCH3), 2.63 (d, J = 5.6 Hz,
2H, CH2–CO); 13C NMR (75 MHz, CDCl3): d 172.0, 156.1, 136.0,
128.3, 128.0, 127.9, 66.7, 63.7, 51.7, 49.6, 35.4.
4. Experimental
4.1. General
4.1.3. (S)-Methyl 3-(benzyloxycarbonylamino)-4-(tert-
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel of 60–120 mesh. IR spectra were recorded on Perkin–Elmer 683
spectrometer. Optical rotations were obtained on Jasco Dip 360
digital polarimeter. 1H and 13C NMR spectra were recorded in
CDCl3 solution on a Varian Inova 500 and Brucker Avance 300.
Chemical shifts are reported in parts per million with respect to
internal TMS. Coupling constants (J) are quoted in Hz. Mass spectra
were recorded on CEC-21-11013 or Fannigan Mat 1210 double
focusing mass spectrometers operating at a direct inlet system or
LC/MSD Trap SL.
butyldimethyl-silyloxy)butanoate 614c
Alcohol 5 (6 g, 22.4 mmol) was dissolved in 50 mL of anhydrous
DMF to which imidazole (2.3 g, 33.7 mmol) was added at rt fol-
lowed by TBSCl (6.7 g, 44.8 mmol). The mixture was stirred at rt
under a nitrogen atmosphere for 12 h. The mixture was diluted
with Et2O and washed successively with H2O (2 ꢃ 50 mL) and
brine (50 mL). The aqueous solution was combined and extracted
with Et2O (3 ꢃ 50 mL). The organic phases were combined and
dried over Na2SO4. The solvent was evaporated under reduced
pressure and the residue was purified by flash column chromatog-
raphy (silica gel, hexane/EtOAc, 8:2) to obtain 6 (87%) as a colorless
oil. ½a 2D6
ꢂ
¼ ꢀ12:4 (c 0.6, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.35–
4.1.1. (S)-2-(Benzyloxycarbonylamino)-4-methoxy-4-
oxobutanoic acid 414a,14b
7.26 (m, 5H, H(Ph)), 5.33 (br d, J = 9.0 Hz, 1H, NH), 5.06 (s, 2H, CH2-
Ph), 4.08–3.98 (m, 1H, CHN), 3.75–3.59 (m, 2H, CH2–OH), 3.65 (s,
3H, OCH3), 2.68–2.50 (m, 2H, CH2–CO), 0.88 (s, 9H, tBu-Si), 0.03
(s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 171.1, 155.5, 136.3,
128.3, 127.9, 66.4, 63.7, 51.4, 49.1, 35.2, 25.6, 18.0, ꢀ5.7.
L-Aspartic acid (10.0 g, 75 mmol) was added to cold methanol
(50 mL) at ꢀ10 °C (ice-salt bath). To the mixture was added thionyl
chloride (7.7 mL) dropwise. The cooling bath (ice-salt) was then
removed and the solution was allowed to rt slowly. The reaction

1852
C. R. Reddy, B. Latha / Tetrahedron: Asymmetry 22 (2011) 1849–1854
4.1.4. (S)-Benzyl 1-(tert-butyldimethylsilyloxy)-4-oxobutan-2-
ylcarbamate 7
followed by benzyl bromide (0.4 mL, 3.27 mmol) at 0 °C. The reac-
tion mixture was stirred for 12 h at rt and then quenched by add-
ing ice. The reaction mixture was extracted with diethyl ether
(2 ꢃ 20 mL) and the ether extracts were washed with brine
(20 mL), dried over Na2SO4, and evaporated under reduced pres-
sure. Flash column chromatography (silica gel, hexanes/EtOAc
Ester 6 (1.2 g, 3.32 mmol) was dissolved in anhydrous toluene
(20 mL), after which DIBAL-H (5 mL, 1 M in THF, 5 mmol) was
added slowly at ꢀ78 °C under N2. The mixture was stirred at
ꢀ78 °C for 30 min and quenched with an aqueous saturated so-
dium potassium tartrate (20 mL). The reaction mixture was diluted
with ethyl acetate (20 mL) and stirred for 3 h at rt. The organic
layer was separated and the aqueous layer was extracted with
ethyl acetate (2 ꢃ 30 mL). The combined organic layer was washed
with brine (20 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (silica gel, hexanes/EtOAc 7:3) to give 7 as a col-
9:1) gave compound 11 (89%): ½a D23
ꢂ
¼ ꢀ13:9 (c 1.0, CHCl3); IR
(neat):
m
2925, 2855, 1461, 1253, 1089, 837 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 7.48–7.16 (m, 5H, H(Ph)), 3.90 (s, 2H, CH2-
Ph), 3.74 (dd, J = 10.2, 4.3 Hz, 1H, CH2–OSi), 3.34 (dd, J = 10.2,
6.5 Hz, 1H, CH2–OSi), 2.70–2.52 (m, 2H, H–C(2), H–C(6)) 2.01–
1.60 (m, 3H, C–CH2–C), 1.53–1.32 (m, 3H, C–CH2–C), 1.10 (d,
J = 5.8 Hz, 3H, CH3–C(2)), 0.92 (s, 9H, tBu-Si), 0.03 (s, 3H, Si(CH3)2),
0.01 (s, 3H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 127.9, 126.3,
66.6, 64.2, 57.5, 54.5, 33.6, 28.7, 25.8, 23.0, 21.4, 18.2, ꢀ5.4; MS
(ESI): m/z 334 (M+H)+; HRMS (ESI): m/z [M+H]+ calcd for
C20H36NOSi, 334.2566 [M+H]+; found, 334.2556.
ourless solid (90%): mp: 58–60 °C; ½a D27
¼ ꢀ10:3 (c 1.05, CHCl3);
ꢂ
IR (neat):
m 3332, 2928, 2855, 1720, 1512, 1463, 1252, 1084,
1064, 838, 778 cmꢀ1 1H NMR (300 MHz, CDCl3): d 9.75 (s, 1H),
;
7.38–7.25 (m, 5H, H(Ph)), 5.17 (br d, J = 7.9 Hz, 1H, HN), 5.06 (s,
2H, CH2-Ph), 4.20–4.06 (m, 1H, HC–N), 3.74–3.60 (m, 2H, CH2–
OSi), 2.73–2.63 (m, 2H, CH2–CO), 0.89 (s, 9H, tBu-Si), 0.04 (s, 6H,
Si(CH3)2); 13C NMR (75 MHz, CDCl3): d 200.6, 155.7, 136.2, 128.5,
128.1, 128.0, 66.8, 64.3, 48.2, 45.4, 25.8, 18.2, ꢀ5.6; MS (ESI): m/z
352 (M+H)+; HRMS (ESI): (m/z) calcd for C18H30NO4Si, 352.1939
[M+H]+; found, 352.1940.
4.1.8. ((2S,6S)-1-Benzyl-6-methylpiperidin-2-yl)methanol 12
To compound 11 (728 mg, 2.18 mmol) was added 1% concd HCl
in ethanol (15.3 mL) and stirred for 5 h at rt. After confirming the
completion of reaction by TLC, ethanol was evaporated to dryness
under reduced pressure and 5% HCl (10 mL) was added. The aque-
ous layer was washed with diethyl ether (3 ꢃ 10 mL) and the aque-
ous layer basified with a 2 M NaOH solution. The aqueous layer
was extracted with diethyl ether (2 ꢃ 15 mL), dried over Na2SO4
and concentrated at <20 °C under vacuum to furnish the desired
4.1.5. (S,E)-Benzyl 1-(tert-butyldimethylsilyloxy)-6-oxohept-4-
en-2-ylcarbamate 9
To a solution of aldehyde 7 (1.0 g, 2.85 mmol) in toluene
(20 mL) was added (acetylmethylene)triphenylphosphorane
8
compound 12 as a yellow oil (85%): ½a D20
¼ þ22:8 (c 0.8, CHCl3);
ꢂ
(1.3 g, 4.27 mmol) under an N2 atmosphere at rt and refluxed for
5 h. The reaction mixture was cooled to 0 °C and concentrated un-
der reduced pressure. Flash column chromatography (silica gel,
hexanes/EtOAc 7:3) afforded enone 9 as a colorless oil (96%):
IR (neat): m ;
3388, 2924, 2855, 1673, 1452, 1376, 1046, 728 cmꢀ1
1H NMR (500 MHz, CDCl3): d 7.30–7.18 (m, 4H, H(Ph)), 7.15–7.08
(m, 1H, H(Ph)), 3.79 (ABq, J = 16.4 Hz, 1H, A of AB, CH2-Ph), 3.62
(ABq, J = 16.4 Hz, 1H, B of AB, CH2-Ph), 3.55 (dd, J = 11.3, 3.9 Hz,
1H, CH2–OSi), 3.20 (dd, J = 11.3, 3.7 Hz, 1H, CH2–OSi), 2.62–2.52
(m, 1H, H–C(2)), 2.52–2.43 (m, 1H, H–C(6)), 2.17 (br s, 1H, OH),
1.72–1.42 (m, 3H, C–CH2–C), 1.34–1.16 (m, 3H, C–CH2–C), 1.11
(d, J = 6.2 Hz, 3H, CH3–C(2)); 13C NMR (75 MHz, CDCl3): d 140.9,
128.4, 127.6, 126.7, 63.7, 63.1, 56.7, 53.7, 32.8, 27.2, 23.0, 22.1;
MS (ESI): m/z 220 (M+H)+; HRMS (ESI): (m/z) calcd for C14H22NO,
220.1701 [M+H]+; found, 220.1695.
½
a 2D6
ꢂ
¼ ꢀ10:7 (c 1.34, CHCl3); IR (neat):
m 3448, 2953, 2924, 1721,
1673, 1463, 1253, 838 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.36–
;
7.24 (m, 5H, H(Ph)), 6.78–6.64 (m, 1H, CH2–CH@CH), 6.06 (d,
J = 15.8 Hz, 1H, CH@CH–CO), 5.13–4.99 (m, 2H, CH2-Ph), 4.92 (d,
J = 8.3 Hz, 1H, HN), 3.89–3.70 (m, 1H, CH–N), 3.63 (d, J = 3.7 Hz,
2H, CH2–OSi), 2.46 (m, 2H, CH2–CH@C), 2.18 (s, 3H, CO-CH3), 0.89
(s, 9H, tBu-Si), 0.05 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3): d
198.2, 155.8, 143.9, 136.3, 133.4, 128.4, 128.1, 128.0, 66.7, 64.2,
51.4, 35.0, 26.7, 25.7, 18.1, ꢀ5.5; MS (ESI): m/z 414 (M+Na)+ HRMS
(ESI): (m/z) calcd for C21H33NO4NaSi, 414.2076 [M+Na]+; found,
414.2071.
4.1.9. (2S,6S)-1-Benzyl-2-methyl-6-((E)-prop-1-enyl)piperidine
14
To compound 12 (100 mg, 0.45 mmol) in dichloromethane
(1 mL), Et3N (1 mL) and DMSO (1 mL) at 0 °C was added SO3ꢁPy
(290 mg, 1.8 mmol), stirred for 1 h at 0 °C and then slowly warmed
to room temperature. After completion of the reaction (by TLC), the
reaction mixture was quenched with cold water. The aqueous layer
was extracted with ether (2 ꢃ 10 mL). The combined organic layers
were washed with brine (10 mL) and dried over Na2SO4. The crude
residue was used immediately in the next step without further
purification.
4.1.6. (2S,6S)-2-((tert-Butyldimethylsilyloxy)methyl)-6-methyl-
piperidine 10
At first, 10% Pd/C (50 mg) was added to a degassed solution of
the carbamate 9 (1.06 g, 2.73 mmol) in EtOH (6 mL) under nitrogen
and the heterogeneous mixture was stirred for 12 h under a hydro-
gen atmosphere at rt. After filtration over Celite, the solvent was
evaporated under reduced pressure and purified on a column (sil-
ica gel, EtOAc) to give compound 10 as a colorless oil (90%);
Next, KHMDS 0.5 M (1.8 mL, 0.92 mmol) was slowly added to a
stirred solution of sulfone 13 (219 mg, 0.92 mmol) in dry DME
(2 mL) under a N2 atmosphere at ꢀ78 °C. After 20 min, a solution
of the above crude aldehyde (100 mg, 0.4 mmol) in dry DME
(2 mL) was slowly added. After 3 h at ꢀ78 °C, the reaction mixture
was further stirred at rt. for 15 h. Ether (20 mL) and water
(25 mL) were added and the organic phase was washed with brine
(20 mL), dried over Na2SO4, filtered and evaporated. Column chro-
matography of the crude product (silica gel, hexanes/EtOAc 9:1),
½
a 2D0
ꢂ
¼ ꢀ7:4 (c 1.0, CHCl3); IR (neat):
m 3374, 2924, 2854, 2362,
1660, 1461, 1100, 838 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.41
;
(br s, 1H, HN), 3.56–3.42 (m, 2H, CH2–OSi), 2.73–2.61 (m, 2H,
H–C(2), H–C(6)), 1.83–1.73 (m,1H, C–CH2–C), 1.64–1.48 (m, 2H,
C–CH2–C), 1.43–0.99 (m, 3H, C–CH2–C), 1.11 (d, J = 6.2 Hz, 3H,
CH3–C(2)), 0.87 (s, 9H, tBu-Si), 0.03 (s, 6H, Si(CH3)2); 13C NMR
(75 MHz, CDCl3): d 66.5, 58.5, 52.3, 33.4 27.3, 25.9, 23.9, 22.1,
18.3, ꢀ5.3; MS (ESI): m/z: 244 (M+H)+; HRMS (ESI): (m/z) calcd
for C13H30NOSi, 244.2091 [M+H]+; found, 244.2095.
afforded 14 as a colorless oil (72% over two steps): ½a D29
¼ ꢀ17:2
ꢂ
(c 0.9, CHCl3); IR (neat):
m 2924, 2853 1637, 1457, 1219,
4.1.7. (2S,6S)-1-Benzyl-2-((tert-butyldimethylsilyloxy)methyl)-
6-methylpiperidine 11
Piperidine compound 10 (600 mg, 2.45 mmol) was dissolved in
DMF (10 mL), after which was added K2CO3 (742 mg, 5.46 mmol)
772 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.35–7.06 (m, 5H, H(Ph)),
;
5.58–5.29 (m, 2H, HC@CH), 3.94 (ABq, J = 15.8 Hz, 1H, A of AB,
CH2-Ph), 3.58 (ABq, J = 15.8 Hz, 1H, B of AB, CH2-Ph), 2.86–2.77
(m, 1H, H–C(2)), 2.43–2.30 (m, 1H, H–C(6)), 1.71–1.50 (m, 3H,

C. R. Reddy, B. Latha / Tetrahedron: Asymmetry 22 (2011) 1849–1854
1853
C–CH2–C), 1.60 (d, J = 6.0 Hz, 3H, CH3–CH@C), 1.47–1.21 (m, 3H, C–
CH2–C), 0.98 (d, J = 6.7 Hz, 3H, CH3–C(2)); 13C NMR (75 MHz,
CDCl3): d 135.4, 128.8, 127.9, 126.4, 65.3, 56.9, 54.3, 34.0, 29.7,
23.7, 21.9, 17.8; MS (ESI): m/z 230 (M+H)+; HRMS (ESI): (m/z) calcd
for C16H24N, 230.1908 [M+H]+; found, 230.1897.
25.7, 22.8, 22.5, 19.6, 14.0; MS (ESI): m/z 226 (M+H)+; HRMS
(ESI): m/z [M+H]+ calcd for C15H32N, 226.2529 [M+H]+; found,
226.2533.
4.1.13. (E)-1-((2S,6S)-1-Benzyl-6-methylpiperidin-2-yl)hept-1-
en-3-one 18
4.1.10. (ꢀ)-Dihydropinidine hydrochloride 111
To a solution of ketophosphonate 17 (95 mg, 0.46 mmol) in THF
(5 mL) was added Ba(OH)2ꢁ8H2O (157 mg, 0.92 mmol) under N2
and stirred for 45 min at rt. The reaction mixture was cooled to
0 °C, after which was slowly added the crude aldehyde (106 mg,
0. 3 mmol) (obtained from 12 as described for the preparation of
14) in 2 mL of THF/H2O (20:1) and the mixture was allowed to
warm to rt and stirred for 1 h. The reaction mixture was diluted
with CH2Cl2 (10 mL), and the organic layer was washed with aque-
ous sat. NaHCO3 (10 mL), brine (10 mL), dried over Na2SO4, and
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography (silica gel, hexanes/EtOAc
To a solution of 14 (75 mg, 0.32 mmol) in MeOH (10 mL) was
added 20% Pd(OH)2/C (7 mg) and the mixture was hydrogenated
under an atmospheric pressure of hydrogen. After completion of
the reaction (12 h), the mixture was filtered through Celite and
washed with MeOH (10 mL). Hydrochloric acid (1 M, 2 mL) was
added to the combined methanol solution and concentrated under
reduced pressure to provide 1 as a white solid (90%): mp: 242–
243 °C;
½
a 2D8
ꢂ
¼ ꢀ9 (c 0.29, EtOH) {lit.:11c mp: 245–246 °C;
½
a 2D5
ꢂ
¼ ꢀ9:1 (c 1.03, EtOH)}; IR (neat):
m 3422, 2931, 2838, 2745,
2541, 2362, 1461 cmꢀ1 1H NMR (300 MHz, CDCl3)11g: d 9.49 (br
;
s, 1H, NHꢁHCl), 9.19 (br s, 1H, NHꢁHCl), 3.14–2.99 (m, 1H, H–
C(2)), 2.97–2.83 (m, 1H, H–C(6)), 2.17–2.04 (m, 1H, C–CH2–C),
1.99–1.19 (m, 10H, C–CH2–C), 1.57 (d, J = 6.0 Hz, 3H,CH3–C(2)),
0.94 (t, J = 7.5 Hz, 3H, CH3–CH2); 13C NMR (75 MHz, CDCl3): d
58.6, 54.7, 35.3, 30.9, 27.7, 22.9, 19.8, 18.9, 13.9; MS (EI): m/z
142 (M+H)+; HRMS (ESI): (m/z) calcd for C9H20N, 142.1595
[M+H]+; found, 142.1602.
9:1) to afford enone 18 as a colorless oil (88%): ½a D29
¼ þ11:1 (c
ꢂ
0.7, CHCl3); IR (neat):
m 2957, 2929, 2856, 1676, 1454, 1317,
727 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.29–7.01 (m, 5H, H(Ph)),
;
6.52 (dd, J = 16.2, 8.4 Hz, 1H, C@CH–C(6)), 5.98 (d, J = 16.2 Hz, 1H,
CO–CH@C), 3.80–3.61 (m, 2H, CH2-Ph), 3.20 (td, J = 18.1, 9.0,
3.9 Hz, 1H, H–C(6)), 2.49–2.37 (m, 1H, H–C(2)), 2.35–2.09 (m, 2H,
CH2–CO), 1.88–1.13 (m, 10H, C–CH2–C), 1.10 (d, J = 6.0 Hz, 3H,
CH3–C(2)), 0.85 (t, J = 7.3 Hz, 3H, CH3–CH2); 13C NMR (75 MHz,
CDCl3): d 201.5, 150.9, 130.1, 128.5, 128.0, 126.5, 65.5, 56.4, 56.1,
38.5, 34.6, 33.1, 26.3, 23.4, 22.3, 21.9, 13.8; MS (ESI): m/z 300
(M+H)+; HRMS (ESI): m/z [M+H]+ calcd for C20H30NO, 300.2327
[M+H]+; found, 300.2328.
4.1.11. (2S,6S)-1-Benzyl-2-methyl-6-((E)-non-1-enyl)piperidine
16
KHMDS 0.5 M (1.8 mL, 0.92 mmol) was slowly added to a stir-
red solution of sulfone 15 (296 mg, 0.92 mmol) in dry DME
(2 mL) under a N2 atmosphere at ꢀ78 °C. After 20 min, a solution
of crude aldehyde (obtained by oxidation of 12 as described for
the preparation of 14) (100 mg, 0.4 mmol) in dry DME (2 mL)
was added slowly. After 3 h at ꢀ78 °C, the reaction mixture was
stirred further at rt. for 15 h. Ether (20 mL) and water (25 mL) were
added and the organic phase was washed with brine (20 mL), dried
over Na2SO4, filtered, and evaporated. Column chromatography of
the crude product (silica gel, hexanes/EtOAc 9:1), afforded 16 as
4.1.14. (+)-Monomorine 313
To a solution of compound 18 (73 mg, 0.24 mmol) in ethanol
(2 mL), 20% Pd(OH)2/C (7 mg) was added and stirred for 12 h under
a hydrogen atmosphere. Filtration of the mixture through a plug of
Celite, which was washed with ether (10 mL), and then concen-
trated at <20 °C to give the title compound as a colorless oil
(80%): ½a 2D8
ꢂ
¼ þ30:5 (c 0.9, hexanes) {lit.13d: ½a D24
¼ þ33:3 (c 0.39,
ꢂ
a colorless oil (78% over two steps): ½a D27
ꢂ
¼ ꢀ15:5 (c 1.1, CHCl3);
hexanes)}; IR (neat):
m 2956, 2923, 2852, 1637, 1463, 1377, 1248,
2926, 2854, 1640, 1455, 971, 773 cmꢀ1 1H NMR
772 cmꢀ1 1H NMR (300 MHz, CDCl3): d 2.47 (m, 1H, H–C(3)),
;
IR (neat):
m ;
(300 MHz, CDCl3): d 7.34–7.05 (m, 5H, H(Ph)), 5.54–5.26 (m, 2H,
HC@CH), 3.97 (d, J = 15.8 Hz, 1H, CH2-Ph), 3.62 (d, J = 15.8 Hz, 1H,
CH2-Ph), 2.83 (br t, J = 10.5 Hz, 1H, H–C(2)), 2.46–2.31 (m, 1H, H–
C(6)), 1.92 (q, J = 6.7 Hz, 2H, CH2–CH@C), 1.71–1.45 (m, 2H, C–
CH2–C), 1.45–1.11 (m, 14H, C–CH2–C), 1.01 (d, J = 5.2 Hz, 3H,
CH3–C(2)), 0.86 (t, J = 6.7 Hz, 3H, CH3–CH2); 13C NMR (75 MHz,
CDCl3): d 141.2, 135.0, 131.3, 128.5, 127.6, 125.9, 65.3, 56.8, 54.7,
35.1, 34.5, 32.2, 31.8, 29.6, 29.1, 29.0, 23.9, 22.6, 22.3, 14.0; MS
(ESI): m/z 314 (M+H)+; HRMS (ESI): m/z [M+H]+ calcd for
2.29–2.15 (m, 1H, H–C(5)), 2.13–1.99 (m,1H, H–C(9)), 1.91–1.49
(m, 6H, C–CH2–C), 1.49–1.15 (m, 10H, C–CH2–C), 1.13 (d,
J = 6.4 Hz, 3H, CH3–C(5)), 0.89 (t, J = 6.9 Hz, 3H, CH2–CH3); 13C
NMR (75 MHz, CDCl3): d 67.3, 63.1, 60.4, 39.3, 35.5, 30.5, 30.1,
29.6, 29.4, 24.7, 22.8, 22.6, 14.1; MS (ESI): m/z 196 (M+H)+; HRMS
(ESI): m/z [M+H]+ calcd for C13H26N, 196.2065 [M+H]+; found,
196.2067.
Acknowledgement
C
22H36N, 314.2842 [M+H]+; found, 314.2840.
B.L. thanks CSIR, New Delhi for the research fellowship.
4.1.12. (2S,6R)-Isosolenopsin hydrocloride 212
To a solution of 16 (111 mg; 0.35 mmol) in MeOH (10 mL) was
added 20% Pd(OH)2/C (10 mg) and the mixture was hydrogenated
under atmospheric pressure of hydrogen. After completion of reac-
tion (12 h), the mixture was filtered through Celite and washed
with MeOH (10 mL). Hydrochloric acid (1 N, 2 mL) was added to
the combined methanol solution and concentrated under reduced
pressure to yield 2 as a white solid (86%): mp: 173–175 °C;
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