Total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloids (-)-halosaline and (-)-8-epi-halosaline via iterative asymmetric allylation/RCM strategy

Article abstract of DOI:10.1016/j.tet.2011.11.045

Total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloids, (-)-halosaline and (-)-8-epi-halosaline is reported from n-butyraldehyde using iterative asymmetric allylation, nucleophilic substitution with an azide and ring-closing metathesis as the key reactions.

Full text of DOI:10.1016/j.tet.2011.11.045

Tetrahedron 68 (2012) 841e845
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloids (ꢀ)-halosaline and
(ꢀ)-8-epi-halosaline via iterative asymmetric allylation/RCM strategy
*
Palakodety Radha Krishna , Bonepally Karunakar Reddy, Palabindela Srinivas
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2011
Received in revised form 16 November 2011
Accepted 17 November 2011
Available online 25 November 2011
Total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloids, (ꢀ)-halosaline and (ꢀ)-8-epi-halosaline is
reported from n-butyraldehyde using iterative asymmetric allylation, nucleophilic substitution with an
azide and ring-closing metathesis as the key reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Piperidine alkaloids
2-(2-Hydroxy substituted)-piperidines
Iterative asymmetric allylation
Ring-closing metathesis (RCM)
1. Introduction
Andrachne aspera spreng is a small perennial under shrub com-
monly found in Karachi and is used in the local system of medicine
A wide range of piperidine alkaloid natural products shows
excellent biological activities.1 Many pharmaceutically active
compounds possess piperidine derivatives as part structures and
more are under clinical and preclinical studies.2 Due to their im-
portant biological activities, substituted piperidine ring containing
alkaloids have been the target of considerable synthetic efforts.3
Thus, construction of the 2-(2-hydroxy substituted)-piperidine
moiety is always a challenging task for synthetic chemists, more
so if the piperidine ring is decorated with substituents (Fig. 1).
for the treatment of eye sores and eye sight improvement. The
crude alkaloidal mixture was found to be biologically potent with
predominantly antibacterial activity. A. aspera spreng was shown to
contain piperidine alkaloids and the one 2-(2-hydroxyalkyl)-pi-
peridine alkaloid (ꢀ)-8-epi-halosaline was isolated from this spe-
cies,4 another alkaloid (ꢀ)-halosaline, a diastereomer of (ꢀ)-8-epi-
halosaline, was isolated from Haloxylon salicornicum (Fig. 1).5
As part of research program on the synthesis of natural prod-
ucts, we embarked on the synthesis of piperidine alkaloids that
have interesting biological properties. Earlier, we reported total
synthesis of some piperidine alkaloids.6 In continuation, herein we
describe the total synthesis of piperidine alkaloids (ꢀ)-halosaline 1
and (ꢀ)-8-epi-halosaline 1a. Although syntheses for 1 and 1a were
reported,7 the one described herein is strategically different, gen-
eral and amenable for accessing other 2-(2-hydroxyalkyl)-piperi-
dine natural products as well.8
OH
R = Alkyl or Aryl
2
RI = H or Methyl
2
R
N
RI
1
2-(2-hydroxy substituted)-piperidine moiety
Amongst all the reported syntheses, the most important ones
are: Posner et al. have used a cylcopentanone ring-expansion based
functionalized strategy,7f while Vincent et al.7g more recently have
used a nitroso DielseAlder cycloaddition/ring-rearrangement me-
tathesis sequence while yet another impressive synthesis reported
by Lesma et al.7e using a ruthenium catalyzed ring-opening/ring-
closing metathesis reaction set as the key step in the stereo-
selective synthesis of targets is worth mentioning. Keeping these
strategies in mind, herein we used an iterative Keck asymmetric
allylation to garner both the stereogenic centers of (ꢀ)-halosaline 1
and (ꢀ)-8-epi-halosaline 1a.9 The nitrogen functionality was
OH
OH
N
N
1a
H
1
H
(-)-8-epi-Halosaline
(-)-Halosaline
Fig. 1. 2-(2-Hydroxy substituted)-piperidine alkaloids.
* Corresponding author. Tel.: þ91 40 27193158; fax: þ91 40 27160387; e-mail
address: prkgenius@iict.res.in (P.R. Krishna).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.045

842
P.R. Krishna et al. / Tetrahedron 68 (2012) 841e845
introduced by an SN2 displacement of the appropriate hydroxyl
functionality with an azide group followed by its reduction, ally-
lation, and ring-closing metathesis to afford the piperidine ring-
skeleton, which upon further transformations led to the target
compounds. Thus the envisaged strategy is general, efficient and
applicable to the synthesis of many such 2-(2-hydroxyalkyl)-pi-
peridine ring containing alkaloids viz. (ꢀ)-halosaline, (ꢀ)-8-epi-
halosaline, (þ)-N-methylallosedridine,10a (þ)-8-ethylnorlebolol,10b
(þ)-sedridine,10c (þ)-allosedridine,10d (ꢀ)-allosedridine,10e and
(þ)-N-methylsedridine.10f
yield (82%, >95% ee).12 Data of alcohol 4 matched with the reported
values.12 Later, alcohol 4 was protected as its benzyl ether 5 (BnBr/
NaH/THF/0 ꢁC to room temperature, 86%).13 Benzyl ether 5 was
identified as the common intermediate for accessing both
(ꢀ)-halosaline 1 and (ꢀ)-8-epi-halosaline 1a. Consequently, com-
pound 5 was subjected to one pot dihydroxylation, oxidative
cleavage of diol (OsO4/NaIO4/2,6-lutidine/1,4-dioxane/H2O) to fur-
nish the corresponding aldehyde, which on second asymmetric
Keck allylation gave the homoallyl alcohols 3 and 3a6c,13b {for 3
(S,S)-BINOL; for 3a (R,R)-BINOL are the chiral ligands used} in 76%
(3), 80% (3a) with high diastereoselectivities (>94%). The di-
astereomeric ratio of 3 and 3a was measured using 1H NMR.
After having 3 and 3a in hand, these were protected as mesy-
lates under conventional conditions. The corresponding mesylates
were subjected to azidation (NaN3/DMF/50 ꢁC) to afford homoallyl
azides 6 (78% over two steps) and 6a (83% over two steps). These
azides were converted to the corresponding N-allyl benzylcarba-
mates 2 (68%) and 2a (65%) via a two-step process; firstly to their
amines using TPP in MeOH followed by allylation (allylbromide/
K2CO3/MeOH) and later the second derivatization {CbzeCl/EtOAc/
H2O(1:1)} to afford 2 and 2a that were subsequently cyclized via
ring-closing metathesis using Grubbs I catalyst (10 mol %) in
CH2Cl2 to furnish unsaturated piperidine carbamates 7 (92%) and
2. Results and discussion
Scheme 1 depicts the retrosynthetic analysis of (ꢀ)-halosaline 1
and (ꢀ)-8-epi-halosaline 1a from n-butyraldehyde using an itera-
tive asymmetric Keck allylation to garner the two stereogenic
centers to afford 3/3a followed by functional group transformation
of one of the hydroxyl groups into amine derivative through the SN2
displacement of the corresponding mesylate with an azide. Sub-
sequent conversions led to bis olefin 2/2a. Finally, the piperidine
ring formation was effected by the Grubbs’ I catalyst assisted ring-
closing metathesis protocol11 and further conversions gave the
target molecules.
OH
OH
CbzN
OBn
BnO
N
H
1
3
2
(-)-Halosaline
n-Butyraldehyde
OH
CbzN
BnO
OH
OBn
N
H
1a
3a
2a
(-)-8-epi -Halosaline
Scheme 1. Retrosynthetic analysis.
Accordingly, the synthesis (Schemes 2 and 3) began with n-
butyraldehyde being subjected to the first asymmetric Keck ally-
lation reaction {(S,S)-BINOL/Ti(OiPr)4/allyltri-n-butyltin/CH2Cl2/
ꢀ78 ꢁC to ꢀ20 ꢁC} to afford the known homoallyl alcohol 4 in good
7a (87%), respectively. Finally, natural products (ꢀ)-halosaline and
(ꢀ)-8-epi-halosaline were obtained by global deprotection of the
protecting groups like benzyl ether and benzylcarbamate with
simultaneous saturation of the double bond, all three
Synthesis of (-)-halosaline.
OBn
OH
c
b
a
n-Butyraldehyde
5
4
CbzN
BnO
OBn N3
OBn OH
d
e
2
6
3
OH
OBn
f
g
N
N
H
Cbz
1
7
(-)-Halosaline
i
Scheme 2. Reagents and conditions. (a) (S,S)-BINOL, 4 A MS, Ti(O Pr)4, allyltri-n-butyltin, CH2Cl2, ꢀ78 to ꢀ20 ꢁC, 24 h, 82%; (b) BnBr, NaH, THF, 0 ꢁC to rt, 4 h, 86%; (c) (i) OsO4, NaIO4,
ꢀ
i
2,6-lutidine, 1,4-dioxane:H2O (3:1), rt, 4.5 h; (ii) (S,S)-BINOL, 4 A MS, Ti(O Pr)4, allyltri-n-butyltin, CH2Cl2, ꢀ78 to ꢀ20 ꢁC, 36 h, 76%; (d) (i) Mesyl chloride, Et3N, 0 ꢁC, 1.5 h; (ii) NaN3,
ꢀ
DMF, 50 ꢁC, 3 h, (78% over two steps); (e) (i) TPP, MeOH, rt, 4 h; (ii) allylbromide, K2CO3, MeOH, 2 h; (iii) CbzeCl, EtOAc/H2O (1:1), rt, 5 h (68% over three steps); (f) G-I catalyst,
CH2Cl2, rt, 1.5 h, 92%; (g) H2/Pd/C, MeOH, rt, 12 h, 81%.

P.R. Krishna et al. / Tetrahedron 68 (2012) 841e845
843
Synthesis of (-)-8-epi - halosaline.
OBn OH
OBn
OBn N3
a
b
3a
5
6a
OBn
OH
BnO CbzN
c
d
e
N
N
H
Cbz
7a
1a
2a
(-)-8-ep i- halosaline
i
Scheme 3. Reagents and conditions. (a) (i) OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane/H2O (3:1), rt, 4.5 h; (ii) (R,R)-BINOL, 4 A MS, Ti(O Pr)4, allyltri-n-butyltin, CH2Cl2, ꢀ78 to ꢀ20 ꢁC,
24 h, 80%; (b) Mesyl chloride, Et3N, 0 ꢁC, 1.5 h; (ii) NaN3, DMF, 50 ꢁC, 3 h (83% over two steps); (c) (i) TPP, MeOH, rt, 5 h; (ii) allylbromide, K2CO3, MeOH, 3 h (iii) CbzeCl, EtOAc/H2O
(1:1), rt, 4 h (65% over three steps); (d) G-I catalyst, CH2Cl2, rt, 2 h, 87%; (e) H2/Pd/C, MeOH, rt, 8 h, 84%.
ꢀ
transformations were carried out under standard conditions (H2/
Pd/C/MeOH/room temperature/6 h) to afford 1 (81%) and 1a (84%),
respectively. The analytical data of synthetic compounds matched
with reported data in literature {(ꢀ)-halosaline: solid. Mp 82 ꢁC,
7.64 mmol) was added to it and the stirring continued at ꢀ20 ꢁC for
24 h. Later saturated aq NaHCO3 solution (15.0 mL) was added to
quench the reaction mixture, stirred for an additional 30 min and
was then extracted with CH2Cl2 (2ꢃ40.0 mL). The organic phase was
washed with water (10.0 mL), dried (Na2SO4), the solvent was
evaporated and the residue purified by column chromatography
(Silica gel, 60e120 mesh, Rf 0.75, EtOAc/n-hexane 1:9) gave 4 (0.65 g,
a 25
a 25
½ ꢂ ꢀ24.5 (c 0.86, EtOH), reported7b ½ ꢂD ꢀ19.5 (c 0.6, EtOH);
(ꢀD)-8-epi-halosaline: thick syrup, ½a 2D5
ꢀ12.1 (c 0.45, MeOH),
ꢂ
reported7c
½
a 2D2
ꢂ
ꢀ8.0 (c 3.7, MeOH)}.
82%) as a clear oil. ½a D25
ꢀ22.5 (c 0.65, CHCl3); IR (Neat) nmax 3330,
ꢂ
3. Conclusions
3055, 1620, 1497, 1208, 769, 732 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d
5.87e5.72 (1H, m, OlefiniceH), 5.14e5.08 (2H, m, OlefiniceH),
In conclusion we report a general strategy for the synthesis of
2-(2-hydroxyalkyl)-piperidines, whereby (ꢀ)-halosaline and
(ꢀ)-8-epi-halosaline were accomplished in an overall yield of
21.2% (1), 22.2% (1a), respectively, using iterative Keck’s asym-
metric allylation, nucleophilic substitution with an azide and ring-
closing metathesis. This strategy may be adopted for the synthesis
of similar 2-(2-hydroxy substituted)-piperidine moiety containing
alkaloids.
3.66e3.58 (1H, m, OCH), 2.32e2.23 (1H, m, AllyliceH), 2.16e2.06
(1H, m, AllyliceH), 1.51e1.33 (4H, m, eCH2), 0.94 (3H, t, J¼6.8 Hz,
eCH3); 13C NMR (CDCl3, 75 MHz): 134.9, 118.1, 70.4, 42.2, 38.9, 18.7
14.1; EIMS (m/z): [M]þ 114.
4.1.2. (R)-((Hept-1-en-4-yloxy)methyl)benzene (5). To
a cooled
(0 ꢁC) suspension of NaH (0.17 g, 6.94 mmol, 60% w/w dispersion in
paraffin oil) in THF (10 mL), a solution of (R)-hept-1-en-4-ol 4
(0.65 g, 5.7 mmol) in THF (8.0 mL) was added drop wise. After
15 min. BnBr (0.75 mL, 6.27 mmol) was added drop wise at 0 ꢁC and
stirred for 4 h at room temperature. The reaction mixture was
quenched with saturated aq NH4Cl solution (30.0 mL) and extracted
with EtOAc (2ꢃ100.0 mL). The combined organic layers were
washed with water (50.0 mL), brine (25.0 mL), dried (Na2SO4), and
evaporated. The crude product was purified by column chroma-
tography (Silica gel 60e120 mesh, EtOAc/n-hexane,1:19) to afford 5
4. Experimental section
4.1. General procedures
Column chromatography was performed on silica gel, Acme
grade 60e120 mesh. TLC plates were visualized either with UV, in
an iodine chamber, or with phosphomolybdic acid spray, charred
with
a
-napthol or ninhydrin charring solutions, unless noted oth-
(1.00 g, 86%) as colorless liquid. ½a D25
þ12.8 (c 0.89, CHCl3); IR (Neat)
ꢂ
erwise. Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification. THF
was freshly distilled over Na-benzophenoneketyl. Unless stated
otherwise, 1H NMR and 13C NMR spectra were recorded either on
a bruker 300 or Varian VXR 400 or Varian VXR 500 in CDCl3 as
solvent with TMS as reference unless otherwise indicated. Unless
stated otherwise, HRMS spectra were recorded on a QTOF analyser
(QSTAR XL, Applied Biosystems/MDS Sciex) at NCMS-IICT, Hyder-
abad. Unless stated otherwise, Elemental Analysis was carried on
a Vario Micro Cube Elementar at Analytical Chemistry Division IICT,
Hyderabad. Unless stated otherwise, all the reactions were per-
formed under inert atmosphere.
nmax 3060, 2890, 1610, 1475, 1160, 810, 735 cmꢀ1 1H NMR (CDCl3,
300 MHz):
d 7.32e7.31 (5H, m, AreH), 5.88e5.74 (1H, m,
OlefiniceH), 5.09e5.00 (2H, m, Olefinic), 4.50 (2H, dd, J¼11.5 Hz,
OCH2Ar), 3.44e3.37 (1H, m, eOCH), 2.30 (2H, br s, AllyliceH),
1.54e1.24 (4H, m, eCH2), 0.90 (3H, t, J¼6.9 Hz, eCH3); 13C NMR
(CDCl3, 75 MHz): 139.0, 135.1, 128.3, 127.7, 127.3, 116.8, 78.4, 70.9,
38.3, 36.1, 18.7, 14.2.
4.1.3. (4S,6R)-6-(Benzyloxy)non-1-en-4-ol (3). To a cool (0 ꢁC) stir-
red solution of 5 (0.4 g, 1.96 mmol) in 1,4-dioxane/H2O (3:1, 5.0 mL),
added OsO4 (0.4 mL, 0.5 M in toluene) drop wise. After 5 min. 2,6-
lutidine (0.27 mL, 2.35 mmol) and NaIO4 (0.5 g, 2.35 mmol) was
added at 0 ꢁC and stirred for 4.5 h at room temperature. The re-
action mixture was quenched with Na2SO3 (1.5 g) and extracted
with EtOAc (2ꢃ50.0 mL). The combined organic layers were
washed with water (40.0 mL), brine (30.0 mL), dried (Na2SO4), and
evaporated. The obtained crude aldehyde was directly used for the
next reaction.
4.1.1. (R)-Hept-1-en-4-ol (4). A mixture of (S,S)-BINOL (0.21 g,
0.69 mmol) and Ti(OiPr)4 (0.21 mL, 0.69 mmol) in CH2Cl2 (8.0 mL) in
ꢀ
the presence of 4 A molecular sieves (1.0 g) was stirred under reflux.
After 1 h, the reaction mixture was cooled to room temperature and
thecommerciallyavailable butyaldehyde (0.5 g, 6.9 mmol), in CH2Cl2
(4.0 mL) was added and further stirred for 10 min. The reaction
mixture was then cooled to ꢀ78 ꢁC and allyltri-n-butyltin (2.37 mL,
A mixture of (S,S)-BINOL (0.06 g, 0.2 mmol) and Ti(OiPr)4
ꢀ
(0.06 mL, 0.2 mmol) in CH2Cl2 (6.0 mL) in the presence of 4 A

844
P.R. Krishna et al. / Tetrahedron 68 (2012) 841e845
molecular sieves (0.6 g) was stirred under reflux. After 1 h, the
reaction mixture was cooled to room temperature and the obtained
aldehyde in above in CH2Cl2 (4.0 mL) was added and further stirred
for 10 min. The reaction mixture was then cooled to ꢀ78 ꢁC and
allyltri-n-butyltin (0.7 mL, 2.35 mmol) was added to it and the
stirring continued at ꢀ20 ꢁC for 16 h. Later saturated aq NaHCO3
solution (10.0 mL) was added to quench the reaction mixture,
stirred for an additional 30 min and was then extracted with CH2Cl2
(2ꢃ30.0 mL). The organic phase was washed with water (10.0 mL),
dried (Na2SO4), the solvent was evaporated and the residue purified
by column chromatography (Silica gel, 60e120 mesh, Rf 0.80,
EtOAc/n-hexane 1:15) to give 3 (0.37 g, 76%) as a yellow colorless
oil; [Found: C, 74.95; H, 9.40. C16H24O2 requires C, 77.38; H, 9.74%];
n-hexane 1:30) afforded 2 (0.26 g, 68% over three steps) as a thick
liquid. ½a 2D5
ꢂ
ꢀ83.7 (c 0.23, CHCl3); IR (Neat) nmax 3060, 1650, 1610,
1280, 695 cmꢀ1
;
1H NMR (CDCl3, 300 MHz):
d
7.36e7.15 (10H, m,
AreH), 5.94e5.52 (2H, m, OlefiniceH), 5.21e4.90 (6H, m,
OlefiniceH, OCH2Ar), 4.45e4.23 (3H, m, OCH2Ar, OH), 3.83 (1H, d,
J¼19.5 Hz, CHNH), 3.64e3.57 (1H, m, CHaHbNH), 3.32 (1H, br s,
CHaHbNH), 2.40e2.12 (2H, m, AllyliceH), 1.74e1.25 (6H, m, eCH2),
0.89 (3H, t, J¼7.2 Hz, eCH3); 13C NMR (CDCl3, 75 MHz): 163.9,
135.7, 135.5, 135.2, 128.4, 128.3, 128.1, 127.9, 127.8, 127.6, 127.4,
117.0, 116.6, 116.4, 76.2, 71.3, 67.1, 66.8, 38.8, 38.3, 37.9, 37.4, 36.2,
35.9, 29.7, 18.2, 14.4; HRESIMS (m/z): calcd for [MþNa]þ 444.2514,
found 444.2521.
½
a 2D5
1590, 715 cmꢀ1
ꢂ
ꢀ80.7 (c 0.22, CHCl3); IR (Neat) nmax 3470, 3051, 2950, 1635,
4.1.6. (R)-Benzyl 6-((R)-2-(benzyloxy)pentyl)-5,6-dihydropyridine-
1(2H)-carboxylate (7). Compound 2 (0.22 g, 0.5 mmol) was taken in
an oven dried round bottom flask, added CH2Cl2 (40.0 mL) under
nitrogen atmosphere, then added Grubbs I-generation catalyst
(0.04 g, 10 mol %) and stirred for 1.5 h. After completion of the
reaction CH2Cl2 was evaporated, the crude residue was purified by
column chromatography (Silica gel, 60e120 mesh, Rf 0.82 EtOAc/n-
;
1H NMR (CDCl3, 300 MHz):
d
7.33e7.23 (5H, m,
AreH), 5.86e5.71 (1H, m, OlefiniceH), 5.08e5.02 (2H, m,
OlefiniceH), 4.62 (1H, d, AB pattern, J¼11.2 Hz, OCH2Ar), 4.42 (1H,
d, AB pattern, J¼11.2 Hz, OCH2Ar), 3.80e3.60 (2H, m, OCH), 2.17 (2H,
qt, J¼6.4 Hz, AllyliceH), 1.64e1.24 (6H, m, eCH2), 0.94 (3H, t,
J¼7.2 Hz, eCH3); 13C NMR (CDCl3, 75 MHz): 138.0, 135.0, 128.5,
127.9, 127.7, 117.3, 79.7, 70.8, 70.6, 42.1, 40.3, 35.7, 17.9, 14.3; ESIMS
(m/z): [MþNa]þ 271.
hexane 1:25) afforded 7 (0.19 g, 92%) as a colorless syrup. ½a D25
ꢂ
ꢀ45.9 (c 0.15, CHCl3); IR (Neat) nmax 3060, 1655, 1620, 1405, 1280,
710 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d 7.39e7.12 (10H, m, AreH),
4.1.4. {(4R,6R)-6-(Azido)non-8-en-4-yloxymethyl}benzene
a stirred solution of alcohol 3 (0.33 g,1.33 mmol) in CH2Cl2 (4.0 mL),
(6). To
5.79e5.52 (2H, m, OlefiniceH), 5.19e4.90 (2H, m, OCH2Ar),
4.76e4.59 (1H, m, OCHAr), 4.48e4.21 (3H, m, OCHAr, CHOH,
CHNH), 3.49 (1H, tt, J¼3.8, 7.2, 17.7 Hz, CHaHbNH), 3.34e3.18 (1H,
m, CHaHbNH), 2.55e2.40 (1H, m, AllyliceH), 2.00e1.68 (2H, m,
AllyliceH), 1.54e1.25 (5H, m, eCH2), 0.90 (3H, t, J¼6.8 Hz, eCH3);
13C NMR (CDCl3, 75 MHz): 140.9, 138.9, 128.5, 128.4, 128.2, 127.9,
127.6, 127.4, 126.9, 123.3 (m), 76.7, 71.5, 71.0, 67.0, 65.3, 46.0, 39.9,
36.3, 29.6, 29.3, 22.7, 18.3, 14.3; HRESIMS (m/z): calcd for [MþNa]þ
416.2201, found 416.2204.
Et3N (0.37 mL, 2.66 mmol), and methanesulphonyl chloride
(0.12 mL, 1.46 mmol) was added at 0 ꢁC and allowed to stir at 0 ꢁ
C
for 1 h. After completion of reaction compound was diluted with
CH2Cl2 (8.0 mL), washed with sat NaHCO3 (1ꢃ5.0 mL), 1 N HCl
(1ꢃ5.0 mL), and water (2ꢃ5.0 mL), and brine solution (1ꢃ6.0 mL).
The CH2Cl2 layer was dried over anhydrous Na2SO4. The reaction
mixture was concentrated under reduced pressure and the crude
mesylate used as such without further purification.
To a stirred solution of above yielded mesylate in dry DMF
(4.0 mL), added NaN3 (0.11 g, 1.73 mmol) and heated to 50 ꢁC and
stirring continued for 3 h. After completion of the reaction, re-
action mixture was extracted with EtOAc/n-hexane (6:4)
(2ꢃ15.0 mL), organic phase was washed with brine (10.0 mL),
dried (Na2SO4), the solvent was evaporated and the residue pu-
rified by column chromatography (Silica gel, 60e120 mesh, Rf 0.90
EtOAc/n-hexane 1:19) afforded 6 (0.28 g, 78% over two steps) as
a yellow liquid; [Found: C, 70.17; H, 8.18; N, 14.93. C16H23N3O re-
4.1.7. (ꢀ)-Halosaline (1). To
a stirred solution of 7 (0.15 g,
0.35 mmol) in methanol (1 mL), 40 mg of 10% Pd/C was added and
stirred under H2 atmosphere for 12 h. The reaction mixture was
filtered through Celite and the filtrate was concentrated under
reduced pressure adsorbed on silica to do the column chroma-
tography (Silica gel 60e120 mesh, Rf 0.40, MeOH/CHCl3 5:95, 5%
NH4OH) to obtain 1 (0.049 g, 81%) as solid, mp 82 ꢁC ½a D25
ꢀ24.5 (c
ꢂ
0.86, EtOH); IR (Neat) nmax 3450, 2950, 2860, 1570, 1320,
760 cmꢀ1 1H NMR (CDCl3, 500 MHz):
; d 3.91e3.82 (1H, m, OCH),
quires C, 70.30; H, 8.48; N, 15.37%]; ½a D25
ꢂ
ꢀ183.5 (c 0.17, CHCl3); IR
3.12 (1H, d, J¼12.1 Hz, eCHNH), 2.97e2.87 (1H, m, CHaHbNH),
2.66e2.55 (1H, m, CHaHbNH), 1.88e1.80 (1H, m, eCHaCHbCH),
1.67e1.16 (11H, m, eCHaCHbCH, eCH2), 0.92 (3H, t, J¼6.9 Hz,
eCH3); 13C NMR (CDCl3, 75 MHz): 68.9, 54.8, 47.0, 42.2, 40.1, 31.7,
26.3, 24.9, 18.9, 14.2; HRESIMS: calcd for [MþH]þ 172.1701, found
172.1701.
(Neat) nmax 3080, 2985, 2190, 1595, 785, 580 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz):
d 7.34e7.22 (5H, m, AreH), 5.85e5.72 (1H, m,
OlefiniceH), 5.15e5.09 (2H, m, OlefiniceH), 4.49 (2H, dd,
J¼11.3 Hz, OCH2Ar), 3.65e3.54 (2H, m, OCH, N3CH), 2.29 (2H, t,
J¼6.4 Hz, AllyliceH), 1.65e1.35 (6H, m, eCH2), 0.94 (3H, t, J¼7.2 Hz,
eCH3); 13C NMR (CDCl3, 75 MHz): 138.6, 133.8, 128.4, 127.9, 118.2,
75.7, 71.3, 59.7, 39.6, 39.4, 36.1, 18.2, 14.3; ESIMS (m/z): [MþH]þ
274.
4.1.8. (4R,6R)-6-(Benzyloxy)non-1-en-4-ol (3a). It was prepared
using the same condition as described for compound 3, purified by
column chromatography (Silica gel, 60e120 mesh, Rf 0.80 EtOAc/n-
hexane 1:25) as a colorless liquid; [Found: C, 74.95; H, 9.40.
4.1.5. Benzyl
allyl((4R,6R)-6-(benzyloxy)non-1-en-4-yl)carbamate
(2). To a stirred solution of homoallyl azide 6 (0.23 g, 0.84 mmol)
in methanol added TPP (0.44 g, 1.68 mmol) at 0 ꢁC and stirred for
4 h at room temperature. After consuming azide into amine added
K2CO3 (0.23 g, 1.68 mmol) and allylbromide (0.09 mL, 1.01 mmol)
at 0 ꢁC and stirred for 2 h. After completion of the reaction
evaporated the methanol under reduced pressure. To this crude
mixture added EtOAc/water (1:1, 3.0 mL), then added CbzeCl
(0.14 mL, 1.01 mmol), at 0 ꢁC and stirred for 5 h at room tem-
perature. After completion of the reaction, diluted the reaction
mixture with ethyl acetate and the combined organic layers were
washed with brine (5.0 mL), dried (Na2SO4), organic solvent was
evaporated under reduced pressure and the residue purified by
column chromatography (Silica gel, 60e120 mesh, Rf 0.95, EtOAc/
C16H24O2 requires C, 77.38; H, 9.74%]; ½a D25
ꢂ
ꢀ48.7 (c 0.54, CHCl3); IR
(Neat) nmax 3450, 3050, 2890, 1605, 1490, 720 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz):
d 7.34e7.23 (5H, m, AreH), 5.85e5.71 (1H, m,
OlefiniceH), 5.10e5.04 (2H, m, OlefiniceH), 4.53 (2H, 2ꢃd, AB
pattern, J¼11.7 Hz, OCH2Ar), 3.95e3.87 (1H, m, OCH), 3.72e3.64
(1H, m, OCH), 2.54 (1H, br s, OH), 2.18 (2H, t, J¼6.4 Hz, AllyliceH),
1.73e1.26 (6H, m, eCH2), 0.93 (3H, t, J¼7.2 Hz, eCH3); 13C NMR
(CDCl3, 75 MHz): 138.4, 134.9, 128.4, 127.9, 127.7, 117.5, 76.9, 71.2,
67.7, 42.2, 39.3, 35.7, 18.7, 14.2; ESIMS (m/z): [MþNa]þ 271.
4.1.9. {(4R,6S)-6-(Azido)non-8-en-4-yloxymethyl}benzene (6a). It
was prepared using the same condition as described for com-
pound 6, purified by column chromatography (Silica gel,

P.R. Krishna et al. / Tetrahedron 68 (2012) 841e845
845
60e120 mesh, Rf 0.91, EtOAc/n-hexane 1:20) as a yellow oily liq-
42.4, 40.5, 33.9, 27.1, 24.4, 18.7, 14.1; HRESIMS (m/z): calcd for
[MþH]þ 172.1701, found 172.1693.
uid; [Found: C, 70.04; H, 8.27; N, 14.91. C16H23N3O requires C,
70.30; H, 8.48; N, 15.37%]; ½a D25
ꢂ
þ11.4 (c 0.63, CHCl3); IR (Neat) nmax
3045, 2210, 1610, 745, 590 cmꢀ1
;
1H NMR (CDCl3, 300 MHz):
Acknowledgements
d
7.35e7.23 (5H, m, AreH), 5.80e5.72 (1H, m, OlefiniceH),
5.14e5.09 (2H, m, OlefiniceH), 4.48 (2H, dd, J¼11.3 Hz, OCH2Ar),
3.46 (2H, sept, J¼5.9 Hz, OCH, N3CH), 2.31e2.19 (2H, m, AllyliceH),
1.82 (1H, qt, J¼6.9 Hz, eCHaHbCH), 1.64e1.35 (5H, m, eCHaHbCH,
eCH2), 0.93 (3H, t, J¼7.4 Hz, eCH3); 13C NMR (CDCl3, 75 MHz):
133.6, 130.2, 128.4, 127.8, 118.3, 75.7, 70.7, 58.9, 38.6, 37.9, 35.9,
18.3, 14.2; ESIMS (m/z): [MþH]þ 274.
Two of the authors (B.K.R. and P.S.) thank the Council of Scien-
tific and Industrial Research (CSIR), New Delhi for the senior re-
search fellowships.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.11.045.
4.1.10. Benzyl allyl((4S,6R)-6-(benzyloxy)non-1-en-4-yl)carbamate
(2a). It was prepared using the same condition as described for
compound 2, purified by column chromatography (Silica gel,
60e120 mesh, Rf 0.95, EtOAc/n-hexane 1:30) as a colorless liquid.
References and notes
a 2D5
1250, 680 cmꢀ1
ꢂ
ꢀ10.7 (c 0.78, CHCl3); IR (Neat) nmax 3050, 1640, 1620, 1580,
1. (a) Jones, T. H.; Blum, M. S. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, NY, 1983; Vol. 1; Chapter 2, pp 33e84; (b)
Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, NY, 1985; Vol. 3; Chapter 1, pp 1e90; (c)
Schneider, M. J. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; Wiley: New York, NY, 1996; Vol. 10; Chapter 3, pp 155e315; (d) Strunz, G.
M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic: London, UK, 1985;
Vol. 26; Chapter 3, pp 89e183; (e) Numata, A.; Ibuka, I. In The Alkaloids; Brossi,
A., Ed.; Academic: New York, NY, 1987; Vol. 31, pp 193e315; (f) Angle, R. S.;
Breitenbucher, J. G. In Studies in Natural Products Chemistry. Stereoselective
Synthesis (Part J); Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The Netherlands,
1995; Vol. 16, pp 453e502.
½
;
1H NMR (CDCl3, 300 MHz):
d
7.37e7.17 (10H, m,
AreH), 5.91e5.52 (2H, m, OlefiniceH), 5.16e4.94 (6H, m,
OlefiniceH, OCH2eAr), 4.49e4.32 (2H, m, OCH2eAr), 4.14e3.98
(1H, m, OCH), 3.77e3.67 (2H, m, CH2NH), 3.31 (1H, q, J¼7.9 Hz,
CHNH), 2.36e2.08 (2H, m, AllyliceH), 1.90e1.78 (1H, m,
CHaCHbCH2), 1.66e1.26 (6H, m, CHaCHbCH2, CH2), 0.90 (3H, t,
J¼6.4 Hz, eCH3); 13C NMR (CDCl3, 75 MHz): 135.7, 135.2, 128.5,
128.3, 127.7, 127.4, 126.9, 117.0, 116.4, 70.6, 67.2, 66.9, 37.9, 37.1, 29.7,
18.2, 14.2; HRESIMS (m/z): calcd for [MþNa]þ 444.2514, found
444.2521.
2. (a) Felpin, F. X.; Lebreton, J. Curr. Org. Synth. 2004, 1, 83e109; (b) Lebrum, S.;
Couture, A.; Deniau, E.; Grandclaydon, P. Org. Lett. 2007, 9, 2473e2476.
3. O’Hagen, D. Nat. Prod. Rep. 1997, 14, 637e651.
4. (a) Ahmed, V. Q.; Nasir, M. A. Phytochemistry 1986, 24, 2841e2844; (b) Ahmed,
V. Q.; Nasir, M. A. Phytochemistry 1987, 26, 585e586; (c) Mill, S.; Hootele, C. J.
Nat. Prod. 2000, 63, 762e764.
4.1.11. (S)-Benzyl 6-((R)-2-(benzyloxy)pentyl)-5,6-dihydropyridine-
1(2H)-carboxylate (7a). It was prepared using the same condition
as described for compound 7, purified by column chromatography
(Silica gel, 60e120 mesh, Rf 0.80, EtOAc/n-hexane 1:20) as a color-
5. Michel, K. H.; Sandberg, F.; Haglid, F.; Norin, T. Acta Pharm. Suec. 1967, 4, 97e116.
6. (a) Krishna, P. R.; Lopinti, K. Synlett 2007,1742e1744; (b) Krishna, P. R.; Srishailam,
A. Tetrahedron Lett. 2007, 48, 6924e6927; (c) Krishna, P. R.; Dayaker, G. Tetrahe-
dron Lett. 2007, 48, 7279e7282; (d) Krishna, P. R.; Reddy, P. S. J. Comb. Chem. 2008,
10, 426e435; (e) Krishna, P. R.; Reddy, B. K. Tetrahedron Lett. 2010, 51, 6262e6264.
7. (a) Takahata, H.; Kubota, M.; Momose, T. Tetrahedron Lett. 1997, 38, 3451e3454;
(b) Stragies, R.; Blechert, S. Tetrahedron 1999, 55, 8179e8188; (c) Takahata, H.;
Kubota, M.; Ikota, N. J. Org. Chem. 1999, 64, 8594e8601; (d) Kochi, T.; Tang, T. P.;
Ellmann. J. Am. Chem. Soc. 2003, 125, 11276e11282; (e) Lesma, G.; Crippa, S.;
Danieli, B.; Passarella, D.; Sacchetti, A.; Silvani, A.; Virdis, A. Tetrahedron 2004,
60, 6437e6442; (f) Maio, W. A.; Sinishtaj, S.; Posner, G. H. Org. Lett. 2007, 9,
2673e2676; (g) Sancibrao, P.; Karila, D.; Koulovsky, C.; Vincent, G. J. Org. Chem.
2010, 75, 4333e4336.
less syrup. ½a 2D5
ꢂ
þ79.4 (c 0.11, CHCl3); IR (Neat) nmax 3065, 2950,
1650, 1400, 1615, 720 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d
7.36e7.16
(10H, m, AreH), 5.75e5.54 (2H, m, OlefiniceH), 5.15e4.97 (2H, m,
CH2OAr), 4.66e4.17 (4H, m, OCH2eAr, CHNH, OCH), 3.54 (1H, t,
J¼17.7 Hz, CHaHbNH), 3.41e3.32 (1H, m, CHaHbNH), 2.39 (1H, t,
J¼14.3 Hz, AllyliceH), 2.03e1.78 (2H, m, AllyliceH, CHaHb),
1.62e1.25 (5H, m, eCH2), 0.89 (3H, t, J¼6.8 Hz, eCH3); 13C NMR
(CDCl3, 75 MHz): 136.8, 128.4, 128.3, 127.9, 127.7, 127.4, 70.5, 67.0,
46.1, 40.0, 36.0, 35.6, 29.7, 28.8, 22.6, 18.3, 14.2; HRESIMS (m/z):
calcd for [MþNa]þ 416.2201, found 416.2190.
8. Bisai, A.; Singh, V. K. Tetrahedron Lett. 2007, 48, 1907e1910.
9. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 125, 8467e8468.
10. (a) Kim, J. H.; T’Hart, H.; Stevens, J. F. Phytochemistry 1996, 41, 1319e1324; (b)
Mill, S.; Durant, A.; Hootele, C. Liebigs Ann. 1996, 2083e2086; (c) Beyerman, H.
C.; Maat, L.; Van Veen, A.; Zweistra, A.; Von Philipsborn, W. Recl. Trav. Chim.
Pays-Bas 1965, 84, 1367e1379; (d) Schopf, C.; Gams, E.; Koppernock, F.; Rausch,
R.; Wallbe, R. Liebigs Ann. Chem. 1970, 732, 181e194; (e) Stevens, J. F.; T’Hart, H.;
Hendriks, H.; Malingre, T. M. Phytochemistry 1992, 31, 3917e3924; (f) Schneider,
M. J.; Brendze, S.; Montali, J. A. Phytochemistry 1995, 39, 1387e1390.
11. (a) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 3171e3174; (b)
Grubbs, R. H. Tetrahedron 2004, 60, 7117e7140.
4.1.12. (ꢀ)-8-epi-Halosaline (1a). It was prepared using the same
condition as described for compound 1, purified by column chro-
matography (Silica gel 60e120 mesh, Rf 0.40, MeOH/CHCl3 5:95, 5%
NH4OH) as a colorless oil. ½a D25
ꢂ
ꢀ12.1 (c 0.45, MeOH); IR (Neat) nmax
3052, 2938, 1712, 1441, 1359, 1275, 740 cmꢀ1
;
1H NMR (CDCl3,
12. (a) Boruwa, J.; Gogoi, N.; Barua, N. C. Org. Biomol. Chem. 2006, 4, 3521e3525; (b)
Sabitha, G.; Yadagiri, K.; Swapna, R.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
5417e5419.
13. (a) Kobayashi, Y.; Czechtizky, W.; Kishi, Y. Org. Lett. 2003, 5, 93e96; (b) Mar-
tinez-Solorio, D.; Jennings, M. P. J. Org. Chem. 2010, 75, 4095e4104.
300 MHz):
d 3.85e3.71 (1H, m, CHOH), 3.18e3.05 (1H, m, CHNH),
2.75 (1H, t, J¼10.6 Hz, CHaHbNH), 2.63 (1H, dt, J¼2.6, 13.9 Hz,
CHaHbNH), 1.84 (1H, m, CHaHbCH), 1.68e1.28 (12H, m, CH2), 0.91
(3H, t, J¼6.4 Hz, CH3); 13C NMR (CDCl3, 75 MHz): 72.6, 58.3, 45.8,