Enantioselective access to (-)-indolizidines 167B, 209D, 239AB, 195B and (-)-monomorine from a common chiral synthon

Article abstract of DOI:10.1016/j.tet.2011.10.076

An enantioselective access to (-)-indolizidine alkaloids 167B, 209D, 239AB, 195B and (-)-monomorine from a new chiral synthon is described. The use of (S)-3-(Cbz-amino)-4-(tert-butyldimethylsilyloxy)butanal, obtained from l-aspartic acid, has provided eff

Full text of DOI:10.1016/j.tet.2011.10.076

Tetrahedron 68 (2012) 145e151
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Tetrahedron
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Enantioselective access to (ꢀ)-indolizidines 167B, 209D, 239AB, 195B
and (ꢀ)-monomorine from a common chiral synthon
*
Chada Raji Reddy , Bellamkonda Latha, Nagavaram Narsimha Rao
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 18 July 2011
Received in revised form 20 October 2011
Accepted 22 October 2011
Available online 29 October 2011
An enantioselective access to (ꢀ)-indolizidine alkaloids 167B, 209D, 239AB, 195B and (ꢀ)-monomorine
from a new chiral synthon is described. The use of (S)-3-(Cbz-amino)-4-(tert-butyldimethylsilyloxy)
butanal, obtained from
L-aspartic acid, has provided efficient access of the indolizidine frame work
through a HornereWadswortheEmmons reaction and reductive cyclization as the key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indolizidine alkaloid
Chiral synthon
HornereWadswortheEmmons reaction
Reductive cyclization
1. Introduction
The synthesis of indolizidine alkaloids has stimulated consid-
erable efforts due to the frequent presence of indolizidine ring
system in naturally occurring bio-active molecules.1 Of particular
interest are 5-substituted and 3,5-disubstituted indolizidines due
to their biological activities.2 Although numerous enantioselective
syntheses are known for these indolizidines,3 the development of
new strategies using a common chiral synthon having distinct ab-
solute stereochemistry and functional attributes for structural
elaboration is of interest. In continuation of our work on the syn-
thesis of bio-active molecules,4 we wish to report an expedient
general strategy toward the synthesis of (ꢀ)-indolizidines 167B,5
209D,6 239AB,7 195B3b,8 and (ꢀ)-monomorine9 (Fig. 1) using
Fig. 1. Structures of (ꢀ)-indolizidines 167B, 209D, 239AB, 195B and (ꢀ)-monomorine.
a new chiral synthon,10 derived from
L-aspartic acid.
We hypothesized that (S)-3-(Cbz-amino)-4-(tert-butyldime-
thylsilyloxy)butanal (7) would be a suitable chiral synthon having
an aldehyde functionality for accessing 5-substituted and 3,5-di-
removal during the reductive cyclization step and the tert-butyl-
dimethyl silyl (TBS) group was expected to be stable throughout the
sequence of reactions and can then be removed after the con-
struction of indolizidine frame work for further structural
elaboration.
substituted indolizidines via
a HornereWadswortheEmmons
(HWE) reaction followed by reductive cyclization as the key steps
(Scheme 1). The desired stereocenters in indolizidine scaffold can
be created as follows: (i) C-5 stereocenter from the chirality of the
synthon (ii) the C-9 configuration through reductive amination (iii)
the C-3 chirality via proline-catalyzed a-hydroxylation. Further, the
2. Results and discussion
choice of benzyloxy carbonyl (Cbz) protection would allow its
In order to verify the hypothesis, initially chiral synthon 7 was
prepared from a known ester 6, obtained in four steps from L-
aspartic acid.11 Reduction of compound 6 using DIBAL-H delivered
the requisite aldehyde 7 in 90% yield. The aldehyde was prepared
* Corresponding author. Tel.: þ91 040 27191885; fax: þ91 040 27160512; e-mail
address: rajireddy@iict.res.in (C.R. Reddy).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.076

146
C.R. Reddy et al. / Tetrahedron 68 (2012) 145e151
Scheme 1. Proposed strategy for (ꢀ)-indolizidines 167B, 209D, 239AB, 195B and
(ꢀ)-monomorine.
on a several-gram scale without any difficulty and found to be
stable at rt for several months (Scheme 2).
Scheme 3. Formal total synthesis of (ꢀ)-indolizidine 167B and 209D.
dimethyl methylphosphonate in the presence of n-BuLi in THF
afforded the b
-keto phosphonate 16 in 63% yield.12 Phosphonate 16
was used for the HWE olefination with chiral synthon 7 to provide
enone 17 in 87% yield. The concomitant one-pot hydro-
genationecyclization reaction (H2/PdeC, rt) of 17 gave 2,6-
disubstituted piperidine 18 in 83% yield. Compound 18 un-
derwent a second cyclization in the presence of Et3N/MsCl followed
by TBS deprotection to afford 3,5-disubstituted indolizidine 19
in 78% yield (over two steps) with excellent stereoselectivity
(Scheme 4).
Scheme 2. Synthesis of chiral synthon 7.
Having the desired new chiral synthon in hand, next the con-
struction of indolizidine ring was studied with the syntheses of
(ꢀ)-indolizidine 167B and 209D in mind. The other subunit needed
for HWE olefination, 5-hydroxy-2-oxo-pentylphosphonic acid di-
methyl ester (9),12 was easily prepared from
g
-butyrolactone (8) in
one-step.13 Now, the chiral synthon 7 was subjected to HWE ole-
fination with -keto phosphonate 9 to afford the key enone 10 in
b
89% yield, a precursor for reductive cyclization. Exposure of 10 to
10% Pd/CeH2 (gas) in EtOH provided piperidine 11 in 90% yield.
This hydrogenation reaction involves four transformations in sin-
gle step: (a) olefin reduction, (b) Cbz-removal, (c) intramolecular
cyclic imine formation, and (d) stereoselective reduction of the
imine to give piperidine 11 exclusively as cis-isomer. The formation
of cis-11 was confirmed at later stage (converting alcohol 13 to
known acetyl derivative)5f by NOE experiments.14 Further, to ach-
ieve the indolizidine scaffold, compound 11 was treated with Et3N/
MsCl at 0 ꢁC under which the free hydroxyl group was mesylated
followed by in situ cyclization furnishing the indolizidine 12 in 92%
yield. TBS deprotection of 12 using 0.1 M HCl in EtOH provided
compound 13 in 85% yield, which has previously been converted to
(ꢀ)-indolizidine 167B and 209D in a known two step sequence
(Scheme 3).5f
After the above success, we decided to apply a similar strategy
for the synthesis of 3,5-disubstituted indolizidine alkaloids,
(ꢀ)-indolizidine 239AB, 195B and (ꢀ)-monomorine from chiral
synthon 7. Following the retrosynthetic approach depicted in
Scheme 1, the desired phosphonate partner for the HWE reaction
was accessed from n-hexanal 14. Compound 14 was subjected to
Scheme 4. Synthesis of 3,5-disubstituted indolizidine 19.
The key indolizidine subunit 19 was further utilized to complete
the synthesis of (ꢀ)-indolizidine 239AB and 195B. Thus, alcohol 19
was oxidized to the corresponding aldehyde using ParikheDoering
conditions, which upon exposure to (ethoxycarbonylmethylene)
asymmetric
HWE reaction with ethyl 2-(diethoxyphosphoryl)acetate (DBU/LiCl/
CH3CN) in one-pot to obtain -aminoxy -unsaturated ester,
a-aminoxylation (PhNO/D-proline/DMSO) followed by
triphenyl phosphorane gave the a,b-unsaturated ester 20 in 74%
g
a
,b
yield over two steps. Saturation of olefin 20 under atmospheric
pressure of H2 in the presence of 10% Pd/C and subsequent re-
duction of the ester using LiAlH4 in THF completed the total syn-
which was subsequently exposed to hydrogenation conditions (10%
Pd/CeH2 in EtOAc) to provide 3-hydroxy ethyl octanoate 15 (94%
ee)15 in 62% yield (over three operations).16a The reaction of 15 with
thesis of (ꢀ)-indolizidine 239AB (½a D30
ꢂ
ꢀ92, c 0.4, MeOH)7 (3) in 85%

C.R. Reddy et al. / Tetrahedron 68 (2012) 145e151
147
yield (Scheme 5). Similarly, compound 19 was subjected to a two
using a stable and scalable new chiral synthon, obtained from L-
step sequence of transformations involving (i) conversion of alco-
aspartic acid. The formal synthesis of (ꢀ)-indolizidine 167B, 209D
and total synthesis of (ꢀ)-indolizidine 239AB, 195B and (ꢀ)-mon-
omorine have been successfully accomplished in good yield. Fur-
ther, applications of this strategy using a new chiral synthon in the
synthesis of indolizidine as well as piperidine alkaloids are cur-
rently underway.
hol 19 to chloride 21 (ii) reduction of chloro methyl to methyl
group, to obtain (ꢀ)-indolizidine 195B (½a D27
ꢂ
ꢀ61, c 0.5, MeOH)3b,8
(4) in 64% yield (over two steps) (Scheme 6).
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were recorded in CDCl3 solvent on
300 MHz or 75 MHz spectrometer at ambient temperature.
Scheme 5. Synthesis of (ꢀ)-indolizidine 239AB (3).
Chemical shifts
d are given in parts per million, coupling constant J
are in hertz. The chemical shifts are reported in ppm on scale
downfield from TMS as internal standard and signal patterns are
indicated as follows: s, singlet; d, doublet; dd, doublet of doublet, t,
triplet; td, triplet of doublets; m, multiplet; br, broad peak. FTIR
spectra were recorded as KBr thin films or neat. Optical rotations
were measured on digital polarimeter using a 1 mL cell with a 1 dm
path length. For low (MS) and High (HRMS) resolution, m/z ratios
are reported as values in atomic mass units. All the reagents and
solvents were reagent grade and used without further purification
unless specified otherwise. Technical grade ethyl acetate and pe-
troleum ether used for column chromatography were distilled prior
to use. Tetrahydrofuran (THF) when used as solvent for the re-
actions was freshly distilled from sodium benzophenone ketyl and
the solvents acetonitrile and dichloromethane prior to use were
dried using CaH2. Column chromatography was carried out using
silica gel (60e120 mesh and 100e200 mesh) or neutral Al2O3
packed in glass columns. All the reactions were performed under an
atmosphere of nitrogen in flame-dried or oven-dried glassware
with magnetic stirring.
Scheme 6. Synthesis of (ꢀ)-indolizidine 195B (4).
With the efficient routes established for enantioselective syn-
thesis of (ꢀ)-indolizidine 167B, 209D, 239AB, and 195B from
a common chiral synthon, the stereoselective synthesis of un-
natural (ꢀ)-monomorine, C3-epimer of (ꢀ)-indolizidine 195B, was
also pursued. The desired g-hydroxy ester 15a was obtained from
n-hexanal 14 using
-proline (94% ee).16b,17 The ester 15a was then
L
converted to (ꢀ)-monomorine 5 (½a D28
ꢂ
ꢀ30.5, c 0.9, n-hexane)9
following the same sequence of reactions carried out for
(ꢀ)-indolizidine 195B (4) (Scheme 7).
4.1.1. (S)-Benzyl 1-(tert-butyldimethylsilyloxy)-4-oxobutan-2-
ylcarbamate (7). To a mixture of 6 (2.0 g, 5.25 mmol) in anhy-
drous toluene (20 mL), DIBAL-H (7.8 mL, 1 M in toluene, 7.8 mmol)
was added slowly at ꢀ78 ꢁC under N2. The mixture was stirred at
ꢀ78 ꢁC for 10 min. After completion of the reaction (monitored by
TLC) the mixture was quenched with aqueous saturated sodium
potassium tartrate (20 mL), diluted with ethyl acetate (20 mL),
stirred for 3 h at rt by which time two layers formed. The organic
layers were separated and the aqueous layer was extracted with
ethyl acetate (2ꢃ30 mL). The combined organic extracts were
washed with brine (20 mL), dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was purified
by column chromatography (silica gel, hexanes/EtOAc 7:3) to afford
pure 7 (1.65 g, 90%) as a white solid. Rf (30% EtOAc/hexanes) 0.6;
mp: 58e60 ꢁC; ½a 2D7
ꢂ
ꢀ10.3 (c 1.0, CHCl3); IR (KBr): vmax 3442, 2928,
2855, 2738, 1723, 1253, 1512, 1064, 837 cmꢀ1
;
1H NMR (300 MHz,
CDCl3)
d 9.75 (s, 1H, HCO), 7.38e7.25 (m, 5H, Ph), 5.17 (br d,
J¼7.9 Hz, 1H, HN), 5.06 (s, 2H, CH2ePh), 4.20e4.06 (br m, 1H,
HCeN), 3.74e3.60 (m, 2H, CH2eOSi), 2.73e2.63 (br m, 2H,
CH2eCO), 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 (2ꢃC), 128.1, 128.0
(2ꢃC), 66.8, 64.3, 48.2, 45.4, 25.8 (3ꢃC), 18.2, -5.6 (2ꢃC); MS (ESI):
m/z 352 (MþH)þ; HRMS (ESI): (m/z) calcd for C18H30NO4Si [MþH]þ,
352.1939; found 352.1940.
Scheme 7. Synthesis of (ꢀ)-monomorine (5).
4.1.2. Dimethyl 5-hydroxy-2-oxopentylphosphonate (9)13. n-Butyl
lithium (14 mL, 2.5 M in hexanes, 35 mmol) was added to a solution
of dimethyl methylphosphonate (4.7 g, 38.3 mmol) in tetrahydro-
3. Conclusion
furan (60 mL) at ꢀ78 ꢁC. The mixture was stirred for 1 h and the
g-
In summary, an efficient and general route for the stereo-
selective synthesis of indolizidine alkaloids has been developed
butyrolactone 8 (1 g, 11.6 mmol) in tetrahydrofuran (10 mL) was
added drop wise. After 1 h, water (20 mL) was added, slowly

148
C.R. Reddy et al. / Tetrahedron 68 (2012) 145e151
warmed to rt and the mixture poured into dichloromethane
(100 mL). The aqueous layer was extracted with dichloromethane
(3ꢃ20 mL). The combined organic extracts were washed with
water (40 mL), dried over Na2SO4, and concentrated under reduced
pressure. Flash column chromatography of the residue using hex-
1H NMR (300 MHz, CDCl3):
3.38 (dd, J¼6.7, 9.8 Hz, 1H, CH2eOSi), 3.19 (td, J¼2.2, 9.0 Hz, 1H,
eqeC(3)), 2.10e1.99 (m, 2H, HaxeC(3), H-C(5)) 1.91e1.55 (m, 7H,
CeCH2eC, including HeC(9)), 1.46e0.99 (m, 4H, CeCH2eC), 0.89 (s,
9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3):
66.8,
d
3.78 (dd, J¼5.2, 9.8 Hz, 1H, CH2eOSi),
H
d
ane/ethyl acetate/methanol (10:2:1) as eluent gave the
phosphonate 9 (1.9 g, 80%), as a colorless oil, which present as the
mixture of ketoelactol form. Rf (10% MeOH/CH2Cl2) 0.5.
b
-keto
65.3, 65.0, 51.9, 30.9, 29.9, 29.0, 25.9 (3ꢃC), 24.2, 20.8, 18.2, ꢀ5.4
(2ꢃC); MS (ESI): m/z 270 (MþH)þ; HRMS (ESI): (m/z) calcd for
C15H32NOSi [MþH]þ, 270.2253; found 270.2258.
4.1.3. (S,E)-Benzyl 1-(tert-butyldimethylsilyloxy)-9-hydroxy-6-
oxonon-4-en-2-ylcarbamate (10). To a solution of keto phospho-
nate 9 (1.08 g, 5.17 mmol) in THF (50 mL) was added Ba(OH)2$8H2O
(3.5 g, 20.6 mmol) under N2 and stirred for 45 min at rt. The re-
action mixture was cooled to 0 ꢁC, added aldehyde 7 (1.6 g,
4.7 mmol) in 20 mL of THF/H2O (40:1) slowly and mixture was
allowed to warm to rt and stirring continued for 4 h. The reaction
mixture was diluted with CH2Cl2 (50 mL), organic layer was washed
with aqueous saturated NaHCO3 (50 mL), brine (50 mL), dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (silica gel,
hexanes/EtOAc 1:1) afforded enone 10 (1.8 g, 89%) as a colorless oil.
4.1.6. ((5S,8aR)-Octahydroindolizin-5-yl)methanol
(13). To the
compound 12 (930 mg, 3.4 mmol) was added 0.1 M concd HCl
(17.2 mL) in ethanol and stirred for 4 h at rt. After the completion of
reaction (monitored by TLC) ethanol was evaporated to dryness
under reduced pressure and added 5% HCl (10 mL). The aqueous
layer was washed with diethyl ether (3ꢃ10 mL) and then basified
with 2 N NaOH solution. The aqueous layer was extracted with
diethyl ether (2ꢃ15 mL), dried over Na2SO4, and evaporated the
solvent at <20 ꢁC under reduced pressure to furnish the desired
compound 13 (445 mg, 85%) as yellow oil. Rf (10% MeOH/CH2Cl2)
0.1; ½a 2D3
ꢂ
ꢀ13.2 (c 1.1, CHCl3); IR (KBr): vmax 3364, 2927, 2861, 1726,
1459, 1280, 1055, 745 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
3.72 (dd,
a 23
Rf (50% EtOAc/hexanes) 0.3; ½ ꢂD ꢀ8.43 (c 1.6, CHCl3); IR (KBr): vmax
J¼3.9, 10.7 Hz, 1H, CH2eOH), 3.43 (dd, J¼2.2, 10.7 Hz, 1H, CH2eOH),
3.21 (td, J¼2.0, 8.6 Hz, 1H, HeqeC(3)), 2.66e2.51 (br s, 1H, OH),
2.12e2.00 (m, 2H, HaxeC(3), HeC(5)), 2.00e1.52 (m, 6H, CeCH2eC,
including HeC(9)), 1.47e1.07 (m, 5H, CeCH2eC); 13C NMR (75 MHz,
3441, 3332, 2931, 2859, 1699, 1531, 1251, 838 cmꢀ1 1H NMR
;
(300 MHz, CDCl3):
d 7.40e7.27 (m, 5H, Ph), 6.90e6.95 (m, 1H,
CH2eCH]C), 6.12 (d, J¼15.8 Hz, 1H, C]CHeCO), 5.14e5.01 (m, 3H,
CH2ePh, eNH), 3.94e3.79 (br m, 1H, CHeN), 3.69e3.56 (m, 4H,
CH2eOSi, CH2eOH), 2.70e2.60 (br t, J¼6.7 Hz, 2H, COeCH2),
2.52e2.40 (m, 2H, CH2eC]C), 1.84 (m, 2H, CH2eCH2eCH2), 0.89 (s,
CDCl3):
d 68.0, 64.6, 64.1, 51.1, 30.3, 30.1, 27.9, 24.1, 20.4; MS (ESI):
m/z 156 (MþH)þ; HRMS (ESI): (m/z) calcd for C9H18NO [MþH]þ,
156.1388; found 156.1382.
9H, tBu-Si), 0.05 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3):
d 200.6,
155.9, 143.4, 136.3, 132.5, 128.5 (2ꢃC), 128.1, 128.0 (2ꢃC), 66.7, 64.3,
62.0, 51.5, 36.4, 35.1, 26.9, 25.8 (3ꢃC),18.2, -5.5 (2ꢃC); MS (ESI): m/z
458 (MþNa)þ; HRMS (ESI): (m/z) calcd for C23H37NO5SiNa
[MþNa]þ, 458.2338; found 458.2342.
4.1.7. (S)-Ethyl 4-hydroxyoctanoate (15)16a. To a solution of hexanal
(1.2 g, 8.67 mmol) and nitroso benzene (0.93 g, 8.67 mmol) in an-
hydrous DMSO (20 mL) was added D-proline (0.4 g, 3.5 mmol) at
20 ꢁC. The mixture was vigorously stirred for 25 min under nitrogen
atmosphere. The reaction mixture was cooled to 0 ꢁC and was
quickly added a premixed and cooled (0 ꢁC) solution of triethyl-
phosphonoacetate (5.2 mL, 26.1 mmol), DBU (3.9 mL, 26.1 mmol),
and LiCl (1.1 g, 26.1 mmol) in CH3CN (20 mL) at 0 ꢁC. The resulting
mixture was allowed to warm to rt over 1 h, and quenched by
addition of ice pieces. The acetonitrile was evaporated under re-
duced pressure. The reaction mixture then poured into water
(60 mL) and was extracted with Et2O (5ꢃ50 mL). The combined
organic layers were washed with water (30 mL), brine (30 mL),
dried over Na2SO4, and concentrated in vacuo to give crude prod-
uct, which was directly subjected to hydrogenation. To the crude
product was added 10% Pd on C (5 mol %) in ethyl acetate (0.5 M)
and the heterogeneous mixture was stirred for 12 h under hydro-
gen atmosphere at rt. The mixture was filtered through a pad of
Celite and evaporated the solvent in vacuo. The crude product was
then purified by using flash column chromatography (silica gel,
4.1.4. 3-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piperidin-2-
yl)propan-1-ol (11). 10% Pd on
C (5 mol %) was added to
a degassed solution of the carbamate 10 (1.8 g, 4.18 mmol) in EtOH
(0.5 M) and the heterogeneous mixture was stirred for 12 h under
hydrogen atmosphere at rt. After filtration over Celite, the solvent
was evaporated under reduced pressure and the crude product was
purified by flash chromatography (silica gel, EtOAc) to obtain 11
(1.0 g, 90%). Rf (10% MeOH/CH2Cl2) 0.5; ½a D23
þ0.39 (c 1.2, CHCl3); IR
ꢂ
(KBr): vmax 3620, 2931, 2858, 2362, 1693, 1516, 839 cmꢀ1; 1H NMR
(300 MHz, CDCl3):
d 3.91e3.70 (br s, 1H, OH), 3.59e3.40 (m, 4H,
CH2eOSi, CH2eOH), 2.70e2.53 (m, 2H, CHeNH, CHeNH), 1.89e1.78
(m, 1H, CeCH2eC), 1.78e1.44 (m, 6H, CeCH2eC), 1.44e1.01 (m, 3H,
CeCH2eC), 0.88 (s, 9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2); 13C NMR
(75 MHz, CDCl3):
d 67.0, 62.5, 58.0, 56.1, 35.5, 31.7, 29.6, 27.7, 25.8
(3ꢃC), 24.1, 18.2, ꢀ5.4 (2ꢃC); MS (ESI): m/z 288 (MþH)þ; HRMS
(ESI): (m/z) calcd for C15H34NO2Si [MþH]þ, 288.2358; found
288.2347.
hexanes/EtOAc 9.5:0.5) to obtain g-hydroxy ester 15 as a colorless
liquid (1.0 g, 62%). Rf (20% EtOAc/hexanes) 0.3; ½a D27
ꢀ1.2 (c 2.24,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3):
d
4.12 (q, J¼7.5 Hz, 2H, OCH2),
4.1.5. (5S,8aR)-5-((tert-Butyldimethylsilyloxy)methyl)
octahy-
3.62e3.52 (m, 1H, OCH), 2.41 (t, J¼7.5 Hz, 2H, CH2eCO), 1.99e1.57
(m, 3H, CH2eCH2eCO, CHeOH), 1.50e1.21 (m, 6H, CeCH2eC), 1.26
(t, J¼7.5 Hz, 3H, OCH2eCH3), 0.95e0.86 (m, 3H, CH3eCH2); 13C
droindolizine (12). To a solution of 11 (1.0 g, 3.76 mmol) in
dichloromethane (30 mL) at ꢀ20 ꢁC were added Et3N (2.41 g,
3.4 mL, 23.9 mmol) and MsCl (0.45 mL, 5.64 mmol) in dichloro-
methane (10 mL) successively. The reaction mixture was continued
to stir at 0 ꢁC for 3 h and quenched by adding water (20 mL), the
layers were separated and aqueous layer was extracted with
dichloromethane (2ꢃ30 mL). The dichloromethane extracts were
washed with 1 M HCl (20 mL), water (20 mL), aqueous saturated
NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, and evaporated
under reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexanes/EtOAc 7:3) to obtain
NMR (75 MHz, CDCl3):
13.8, 13.7.
d 174.0, 70.8, 60.1, 36.9, 31.8, 30.4, 27.5, 22.3,
4.1.8. (S)-Dimethyl 5-hydroxy-2-oxononylphosphonate (16). n-Butyl
lithium (9 mL, 2.5 M in hexane, 23 mmol) was added to a solution of
dimethyl methylphosphonate (3.0 g, 25 mmol) in tetrahydrofuran
(50 mL) at ꢀ78 ꢁC. The mixture was stirred for 1 h and the hydroxy
ester 15 (1.4 g, 7.5 mmol) in tetrahydrofuran (10 mL) was added
drop wise. After 1 h, water (10 mL) was added, slowly warmed to rt
and the mixture poured into dichloromethane (100 mL). The
aqueous layer was extracted with dichloromethane (3ꢃ20 mL). The
compound 12 (0.93 g, 92%). Rf (100% EtOAc) 0.4; ½a D23
ꢀ42.6 (c 1.4,
ꢂ
CHCl3); IR (KBr): vmax 2929, 2857, 1464, 1253, 1102, 837, 775 cmꢀ1
;

C.R. Reddy et al. / Tetrahedron 68 (2012) 145e151
149
combined organic extracts were washed with water (30 mL), dried
over Na2SO4, and concentrated under reduced pressure. Flash col-
umn chromatography of the residue using hexanes/ethyl acetate/
methanol (10:2:1) as eluent gave the b-keto phosphonate 16 (1.2 g,
63%), as a yellow oil, which present as the mixture of ketoelactol
form. Rf (100% EtOAc/hexanes) 0.4.
30 min at rt, added (ethoxycarbonylmethylene)triphenyl phos-
phorane (0.5 g, 1.53 mmol) to the reaction mixture at 0 ꢁC and
stirred at rt for 5 h. The reaction mixture was quenched with water
(10 mL) and extracted with ethyl acetate (2ꢃ15 mL). The combined
organic layers were washed with brine (10 mL) and dried over
Na2SO4. The solvent was removed under reduced pressure and
crude was purified by column chromatography (silica gel, hexanes/
EtOAc 8:2) to get 20 (0.24 g, 74%) as colorless oil. Rf (100% EtOAc)
4.1.9. Benzyl (2S,9S,E)-1-(tert-butyldimethylsilyloxy)-9-hydroxy-6-
oxotridec-4-en-2-ylcarbamate (17). The reaction was carried out
according to the representative procedure described for the prep-
aration of compound 10. Aldehyde 7 (2 g, 5.69 mmol) was treated
0.57; ½a 2D6
ꢀ46.6 (c 1.4, CHCl3); IR (KBr): vmax 2957, 2924, 2854,
ꢂ
1731, 1639, 1464, 1285, 1074, 721 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
6.89 (dd, J¼15.8, 9.0 Hz, 1H, C]CHeCH), 5.91 (d, J¼15.8 Hz, 1H,
with
b
-keto phosphonate 16 (1.6 g, 6.2 mmol), to obtain 17 (2.4 g) in
COeCH]C), 4.18 (q, J¼7.5 Hz, 2H, CH2eCH3), 3.25e3.09 (m, 2H,
HeC(3), HeC(5)), 2.49e2.33 (m, 1H, HeC(9)), 2.4e1.73 (m, 4H,
CeCH2eC), 1.68e1.51 (m, 1H, CeCH2eC), 1.51e1.35 (m, 2H,
CeCH2eC), 1.36e1.10 (m, 8H, CeCH2eC), 1.30 (t, J¼7.5 Hz, 3H,
OCH2eCH3), 1.11e0.93 (m, 1H, CeCH2eC), 0.87 (t, J¼6.8 Hz, 3H,
87% yield as colorless oil. Rf (20% EtOAc/hexanes) 0.32; ½a D27
ꢀ6.9 (c
ꢂ
1.0, CHCl3); IR (KBr): vmax 3441, 3332, 2932, 1697, 1531, 1252, 838,
777 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 7.40e7.28 (m, 5H, Ph),
6.91e6.76 (m, 1H, CH2eCH]C), 6.14 (d, J¼16.0 Hz, 1H, C]CHeCO),
5.09 (s, 2H, CH2ePh), 5.02 (br d, J¼8.8 Hz, 1H, NH), 3.92e3.79 (br m,
1H, CHeNH), 3.63 (br d, J¼2.8 Hz, 2H, CH2eOSi), 3.67e3.51 (m, 1H,
CHeOH), 2.69 (t, J¼6.9 Hz, 2H, COeCH2), 2.54e2.41 (m, 2H,
CH2eC]C), 1.89e1.57 (br m, 4H, CeCH2eC), 1.51e1.39 (m, 2H,
CeCH2eC), 1.39e1.27 (m, 2H, CeCH2eC), 0.95e0.85 (m, 3H,
CH2eCH3), 0.89 (s, 9H, tBu-Si), 0.05 (s, 6H, Si(CH3)2); 13C NMR
CH2eCH3); 13C NMR (75 MHz, CDCl3):
d 166.6, 151.1, 120.9, 60.2,
59.7, 59.1, 58.1, 32.6, 31.8, 29.8, 28.7, 26.3, 25.5, 24.1, 22.8, 14.2, 14.0;
MS (ESI): m/z 280 (MþH)þ; HRMS (ESI): (m/z) calcd for C17H30NO2
[MþH]þ, 280.2276; found 280.2288.
4.1.13. (ꢀ)-Indolizidine 239AB (3). To a solution of compound 20
(240 mg, 0.86 mmol) in ethyl acetate (4 mL), 10% PdeC (5 mol %)
was added and stirred for 12 h under hydrogen atmosphere. The
mixture was filtered through a plug of Celite, washed with diethyl
ether (10 mL), and concentrated at <20 ꢁC under reduced pressure
to give saturated ester as yellow oil (228 mg, 95%), which was used
for the next step without further purification.
(75 MHz, CDCl3):
d
200.9, 155.9, 143.2, 136.3, 132.5, 128.5 (2ꢃC),
128.1, 128.0 (2ꢃC), 71.3, 66.8, 64.2, 51.5, 37.4, 36.2, 35.1, 31.3, 27.8,
25.8 (3ꢃC), 22.7, 18.2, 14.0, ꢀ5.5 (2ꢃC); MS (ESI): m/z 514 (MþNa)þ;
HRMS (ESI): (m/z) calcd for C27H45NO5SiNa [MþNa]þ, 514.2964;
found 514.2983.
4.1.10. (S)-1-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piper-
idin-2-yl) heptan-3-ol (18). Preparation of compound 18 from
compound 17 (2.4 g, 4.94 mmol) was accomplished following the
procedure used for compound 11 in 83% yield (1.4 g) as colorless oil.
The above compound (228 mg, 0.81 mmol) in THF (2 mL) was
added to a suspension of LiAlH4 (62 mg,1.63 mmol) in THF (5 mL) at
0 ꢁC, warmed to rt slowly and continued stirring for 1 h at rt. After
the completion of reaction (monitored by TLC), the mixture was
cooled to 0 ꢁC, quenched slowly by adding few drops of 10%
aqueous NaOH solution. The reaction mixture was stirred for 2 h
and filtered through a small pad of Celite, washed with diethyl
ether (10 mL), dried over Na2SO4, and concentrated under reduced
pressure at <20 ꢁC. The residue was purified by column chroma-
tography (neutral alumina, hexanes/diethyl ether 9:1) to get 3
Rf (5% MeOH/CH2Cl2) 0.5; ½a D28
ꢂ
þ0.06 (c 1.0, CHCl3); IR (KBr): vmax
2927, 2857, 1649, 1460, 1255, 1092, 836 cmꢀ1
;
1H NMR (300 MHz,
CDCl3):
d
4.32e4.19 (br s, 1H, NH), 3.63 (dd, J¼10.0, 3.9 Hz, 1H,
CH2eOSi), 3.54e3.46 (m, 1H, CHeOH), 3.50 (dd, J¼9.8, 6.9 Hz, 1H,
CH2eOSi), 2.81e2.69 (m, 2H, CHeNH, CHeNH), 1.92e1.09 (m, 16H,
CeCH2eC), 0.93e0.86 (m, 12H, CH2eCH3, tBu-Si), 0.07 (s, 6H,
Si(CH3)2); 13C NMR (75 MHz, CDCl3):
d
71.3, 66.4, 58.1, 55.7, 37.4,
(164 mg, 85%) as pale yellow oil. Rf (5% MeOH/EtOAc) 0.1; ½a D30
ꢀ92
ꢂ
33.3, 32.9, 30.3, 28.1, 27.2, 25.9 (2ꢃC), 23.9, 22.8, 18.3, 14.1, ꢀ5.4
(2ꢃC); MS (ESI): m/z 344 (MþH)þ; HRMS (ESI): (m/z) calcd for
C19H42NO2Si [MþH]þ, 344.2984; found 344.2977.
(c 0.4, MeOH); IR (KBr): vmax 3459, 2924, 2852, 1639, 1463, 1378,
697 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 3.63e3.53 (m, 1H,
CH2eOH), 3.52e3.39 (m, 1H, CH2eOH), 3.35e3.26 (m, 1H, HeC(3)),
2.64e2.55 (m, 1H, HeC(5)), 2.49e2.39 (m, 1H, HeC(9)), 1.99e1.41
(m, 9H, CeCH2eC), 1.39e0.98 (m, 12H, CeCH2eC), 0.90 (t, J¼5.8 Hz,
4.1.11. ((3R,5S,8aR)-3-Butyl-octahydroindolizin-5-yl)methanol
(19). The reaction was carried out using the procedure described
for the preparation of compound 12 starting from 18 (1.4 g, 4 mmol)
to obtain TBS protected bicyclic compound. The crude TBS ether
product underwent deprotection of TBS group as described for the
compound 13 to provide compound 19 (0.68 g, 78% over two steps)
3H, CH2eCH3); 13C NMR (75 MHz, CDCl3):
d 62.6, 60.3, 58.9, 56.3,
30.3, 29.7, 29.6, 29.0, 28.5, 28.4, 27.8, 25.7, 23.9, 22.7, 14.0; MS (ESI):
m/z 240 (MþH)þ; HRMS (ESI): (m/z) calcd for C15H31NO [MþH]þ,
240.2322; found 240.2329.
as colorless oil. Rf (10% MeOH/CH2Cl2) 0.1; ½a D29
ꢂ
ꢀ34.3 (c 0.5, CHCl3);
4.1.14. (3R,5S,8aR)-3-Butyl-5-(chloromethyl)-octahydroindolizine
(21). To the compound 19 (0.25 g, 1.18 mmol) in THF (5 mL) was
added SOCl2 (0.12 mL, 1.77 mmol) at 0 ꢁC under nitrogen atmo-
sphere. The reaction mixture was allowed to rt and heated for
20 min at 50 ꢁC. The mixture was cooled to 0 ꢁC and quenched with
saturated aqueous NH4Cl (5 mL) and extracted with diethyl ether
(2ꢃ10 mL). The organic layer was dried over Na2SO4 and concen-
trated at <20 ꢁC under reduced pressure. The residue was purified
by flash column chromatography (silica gel, hexanes/EtOAc 8:2) to
get the compound 21 (0.21 g, 78%) as a colorless oil. Rf (30% EtOAc/
IR (KBr): vmax 3355, 2927, 2861, 1649, 1458, 1052 cmꢀ1
;
1H NMR
(300 MHz, CDCl3):
d
3.78 (dd, J¼11.3, 3.7 Hz, 1H, CH2eOH), 3.50 (dd,
J¼11.3, 2.2 Hz, 1H, CH2eOH), 3.36 (br t, J¼8.3 Hz, 1H, HeC(3)),
2.79e2.66 (m, 1H, HeC(5)), 2.66e2.51 (m, 1H, HeC(9)), 2.04e1.88
(m, 1H, CeCH2eC), 1.88e1.77 (m, 1H, CeCH2eC), 1.71e1.62 (m, 1H,
CeCH2eC), 1.60e1.41 (m, 2H, CeCH2eC), 1.39e1.02 (m, 11H,
CeCH2eC), 0.91 (t, J¼6.8 Hz, 3H, CH2eCH3); 13C NMR (75 MHz,
CDCl3):
d 63.2, 59.1, 58.6, 57.1, 31.3, 29.5, 28.8, 27.8, 26.4, 25.9, 23.9,
22.9, 14.1; MS (ESI): m/z 212 (MþH)þ; HRMS (ESI): (m/z) calcd for
C13H26NO [MþH]þ, 212.2014; found 212.2021.
hexanes) 0.43; ½a D26
ꢀ47.2 (c 0.5, CHCl3); IR (KBr): vmax 2952, 2854,
ꢂ
1644, 1463, 1379, 1274, 1083, 739 cmꢀ1; 1H NMR (300 MHz, CDCl3):
4.1.12. (E)-Ethyl 3-((3R,5S,8aR)-3-butyl-octahydroindolizin-5-yl)ac-
rylate (20). To the compound 19 (0.25 g, 1.18 mmol) in dichloro-
methane (2 mL), Et3N (2 mL, 14.1 mmol), and DMSO (2 mL,
28.2 mmol) was added SO3$Py (0.93 g, 5.9 mmol) at 0 ꢁC, stirred for
1 h at 0 ꢁC and slowly warmed to rt. Continued stirring for another
d
3.64 (dd, J¼3.0, 10.5 Hz, 1H, CH2eCl), 3.34 (dd, J¼7.5, 10.5 Hz, 1H,
CH2eCl), 3.21 (br t, J¼9.1 Hz, 1H, HeC(3)), 2.74e2.65 (m, 1H,
HeC(5)), 2.48e2.37 (m, 1H, HeC(9)), 1.99e1.73 (m, 4H, CeCH2eC),
1.52e1.00 (m, 12H, CeCH2eC), 0.91 (t, J¼6.8 Hz, 3H, CH2eCH3); 13
C
NMR (75 MHz, CDCl3):
d 59.0, 58.5, 57.5, 47.1, 31.8, 29.7, 29.6, 28.9,

150
C.R. Reddy et al. / Tetrahedron 68 (2012) 145e151
26.5, 25.2, 24.0, 22.9, 14.1; MS (ESI): m/z 230 (MþH)þ; HRMS (ESI):
(m/z) calcd for C13H25ClN [MþH]þ, 230.1670; found 230.1671.
2.59e2.46 (m, 1H, CHeNH),1.93e1.81 (br d, J¼13.6 Hz, 1H, CHeOH),
t
1.72e1.04 (br m, 16H, CeCH2eC), 0.90 (s, 12H, Bu-Si), 0.06 (s, 6H,
Si(CH3)2); 13C NMR (75 MHz, CDCl3):
d 71.6, 67.1, 58.4, 57.8, 37.3,
4.1.15. (ꢀ)-Indolizidine 195B (4). Compound 21 (200 mg,
0.87 mmol) in dry THF (2 mL) was added to the suspension of
LiAlH4 (70 mg, 1.84 mmol) in THF (3 mL) at 0 ꢁC, allowed to rt and it
was refluxed for 12 h. After the completion of reaction (monitored
by TLC), the mixture was cooled to 0 ꢁC, quenched with aqueous
10% NaOH, stirred for 2 h and filtered through a pad of Celite,
washed with diethyl ether (10 mL). The organic solvent was
evaporated under reduced pressure at <20 ꢁC and the residue was
purified by flash column chromatography (neutral alumina, hex-
anes/diethyl ether 9:1) to get compound 4 as a pale yellow oil
34.8, 33.6, 31.8, 27.9, 26.7, 25.8 (3ꢃC), 23.7, 22.6, 18.2, 13.9, ꢀ5.5,
ꢀ5.4; MS (ESI): m/z 344 (MþH)þ; HRMS (ESI): (m/z) calcd for
C19H42NO2Si [MþH]þ, 344.2979; found 344.3000.
4.1.20. ((3S,5S,8aR)-3-Butyl-octahydroindolizin-5-yl)
methanol
(24). Compound 23 (700 mg, 2 mmol) was transformed to com-
pound 24 (337 mg) according to the representative procedure de-
scribed for the preparation of compound 19 in 78% yield as colorless
oil. Rf (10% MeOH/CH2Cl2) 0.1. ½a D26
ꢂ
þ6.75 (c 1.5, CH2Cl2); 1H NMR
(300 MHz, CDCl3):
d
3.73 (dd, J¼11.3, 4.5 Hz, 1H, CH2eOH), 3.50 (dd,
(139 mg, 82%). Rf (50% MeOH/CH2Cl2) 0.1; ½a D27
ꢂ
ꢀ61 (c 0.5, MeOH);
J¼11.3, 3.0 Hz, 1H, CH2eOH), 2.56 (br t, J¼9.0 Hz, 1H, HeC(3)),
2.29e2.18 (m, 1H, HeC(5)), 2.18e2.06 (m, 1H, HeC(9)), 1.91e1.54
(m, 6H, CeCH2eC), 1.49e1.15 (m, 10H, CeCH2eC), 0.89 (t, J¼6.7 Hz,
IR (KBr): vmax 2956, 2923, 2852, 1637, 1463, 1377, 1248, 772 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
3.24 (br t, J¼7.9 Hz, 1H, HeC(3)),
2.57e2.44 (m, 1H, HeC(5)), 2.43e2.31 (m, 1H, HeC(9)), 1.94e1.65
(m, 4H, CeCH2eC), 1.62e1.15 (m, 12H, CeCH2eC), 1.08 (d, J¼6.2 Hz,
3H, CHeCH3), 0.90 (t, J¼6.9 Hz, 3H, CH2eCH3); 13C NMR (75 MHz,
3H, CH2eCH3); 13C NMR (75 MHz, CDCl3):
d 67.4, 65.9, 65.1, 62.9,
38.3, 30.4, 29.9, 29.6, 29.5, 29.3, 24.4, 22.9, 14.2; MS (ESI): m/z 212
(MþH)þ; HRMS (ESI): (m/z) calcd for C13H26NO [MþH]þ, 212.2009;
found 212.2024.
CDCl3): d 60.0, 59.3, 53.2, 33.2, 30.8, 29.6, 29.2, 28.7, 25.9, 24.2, 22.8,
19.5, 14.1; MS (ESI): m/z 196 (MþH)þ; HRMS (ESI): (m/z) calcd for
C13H26N [MþH]þ, 196.2065; found 196.2058.
4.1.21. (3S,5S,8aR)-3-Butyl-5-(chloromethyl)octahydroindolizine
(25). The reaction was carried out according to the representative
procedure described for the preparation of compound 21. Com-
pound 24 (300 mg, 1.42 mmol) was treated with SOCl2 (0.15 mL,
2.1 mmol) to obtain 25 (244 mg, 75%) as pale yellow color oil. Rf
4.1.16. (R)-Ethyl 4-hydroxyoctanoate (15a)16b. Preparation of com-
pound 15a (ent-15) from compound 14 (2 g, 19.9 mmol) was ac-
complished following the procedure used for compound 15 (by
using
L
-proline, 40 mol %) in 61% yield (2.2 g) as colorless oil. ½a D27
ꢂ
(30% EtOAc/hexanes) 0.45; ½a D27
ꢂ
ꢀ24.1 (c 1.4, CHCl3); 1H NMR
þ1.0 (c 2.24, CHCl3); 1H NMR (300 MHz, CDCl3):
d
4.12 (q, J¼7.5 Hz,
(300 MHz, CDCl3):
d
3.66 (d, J¼10.3 Hz, 1H, CH2eCl), 3.41 (dd,
2H, OCH2), 3.62e3.52 (m, 1H, OCH), 2.41 (t, J¼7.5 Hz, 2H, CH2eCO),
1.99e1.57 (m, 3H, CH2eCH2eCO, CHeOH), 1.50e1.21 (m, 6H,
CeCH2eC), 1.26 (t, J¼7.5 Hz, 3H, OCH2eCH3), 0.95e0.86 (m, 3H,
J¼10.3, 7.5 Hz, 1H, CH2eCl), 2.50e2.33 (m, 1H, HeC(3)), 2.74e2.65
(m, 1H, HeC(5)), 2.23e2.06 (m, 1H, HeC(9)), 1.99e1.58 (m, 4H,
CeCH2eC), 1.57e1.12 (m, 12H, CeCH2eC), 0.90 (t, J¼6.9 Hz, 3H,
CH3eCH2); 13C NMR (75 MHz, CDCl3):
d
174.0, 70.8, 60.1, 36.9, 31.8,
CH2eCH3); 13C NMR (75 MHz, CDCl3):
d 67.4, 65.4, 62.2, 48.6, 39.3,
30.4, 27.5, 22.3, 13.8, 13.7.
30.7, 29.9, 29.7, 29.5, 29.1, 24.2, 22.8, 14.0; MS (ESI): m/z 230
(MþH)þ; HRMS (ESI): (m/z) calcd for C13H25ClN [MþH]þ, 230.1670;
found 230.1687.
4.1.17. (R)-Dimethyl 5-hydroxy-2-oxononylphosphonate (16a). The
reaction was carried out according to the representative procedure
described for the preparation of compound 16. (R)-Hydroxy ester
15a (2 g, 10.6 mmol) was treated with (dimethoxyphosphoryl)
methanide (3 equiv) to obtain 16a (ent-16) as a pale yellow oil
(1.8 g, 65%), which present as the mixture of ketoelactol form.
4.1.22. (ꢀ)-Monomorine (5). Compound 25 (100 mg, 0.43 mmol)
was treated with LiAlH4 (35 mg, 0.92 mmol) as described in the
procedure for the preparation of compound 4 to obtain (ꢀ)-mon-
omorine 5 (65 mg, 80%). Rf (50% MeOH/CH2Cl2) 0.1; ½a D28
ꢀ30.5 (c
ꢂ
0.9, n-hexane); IR (KBr): vmax 2925, 2860, 1733, 1516, 1458, 1271,
4.1.18. Benzyl (2S,9R,E)-1-(tert-butyldimethylsilyloxy)-9-hydroxy-6-
oxotridec-4-en-2-ylcarbamate (22). The reaction was carried out
according to the representative procedure described for the prep-
aration of compound 10. Aldehyde 7 (1 g, 2.87 mmol) was treated
1066 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
2.47 (br t, J¼9.4 Hz, 1H,
HeC(3)), 2.29e2.15 (m, 1H, HeC(5)), 2.13e1.99 (m,1H, HeC(9)),
1.91e1.49 (br m, 6H, CeCH2eC), 1.49e1.15 (br m, 10H, CeCH2eC),
1.13 (d, J¼6.4 Hz, 3H, CHeCH3), 0.89 (t, J¼6.9 Hz, 3H, CH2eCH3); 13
C
with
b
-keto phosphonate 16a (840 mg, 3.15mmol), to obtain 22
NMR (75 MHz, CDCl3): d 67.1, 62.9, 60.2, 39.6, 35.8, 30.8, 30.3, 29.7,
(1.2 g) in 86% yield as colorless oil. Rf (20% EtOAc/hexanes) 0.32.
29.4, 24.8, 22.9, 22.8, 14.1; MS (ESI): m/z 196 (MþH)þ; HRMS (ESI):
½
a 2D4
ꢂ
ꢀ13.5 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.42e7.27 (m,
(m/z) calcd for C13H26N [MþH]þ, 196.2065; found 196.2067.
5H, Ph), 6.91e6.71 (m, 1H, CH2eCH]C), 6.13 (d, J¼15.8 Hz, 1H, C]
CHeCO), 5.22e4.98 (m, 3H, CH2ePh, NH), 3.97e3.78 (br m, 1H,
CHeNH), 3.74e3.48 (br m, 3H, CH2eOSi, CHeOH), 2.76e2.60 (m,
2H, COeCH2), 2.56e2.36 (m, 2H, CH2eC]C), 1.89e1.58 (m, 3H,
Acknowledgements
B.L. and N.N.R. thank Council of Scientific and Industrial Re-
search (CSIR), New Delhi for research fellowships. The authors are
thankful to the reviewers for their valuable suggestions in im-
proving the quality of the manuscript.
t
CeCH2eC), 1.50e1.19 (m, 5H, CeCH2eC), 0.88 (s, 12H, Bu-Si), 0.04
(s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3):
d 200.9, 155.8, 143.3,
136.3, 132.6, 128.5 (2ꢃC), 128.2, 128.1, 128.0, 71.2, 66.7, 64.2, 51.5,
37.3, 35.2, 35.1, 31.3, 27.8, 25.8 (3ꢃC), 22.7, 18.2, 14.0, ꢀ5.5 (2ꢃC);
MS (ESI): m/z 514 (MþNa)þ; HRMS (ESI): (m/z) calcd for
C27H45NO5SiNa [MþNa]þ, 514.2959; found 514.2993.
Supplementary data
1H and 13C NMR spectra for all the new compounds. Supple-
mentary data associated with this article can be found, in the online
version, at doi:10.1016/j.tet.2011.10.076.
4.1.19. (R)-1-((2R,6S)-6-((tert-Butyldimethylsilyloxy)methyl) piper-
idin-2-yl)heptan-3-ol (23). Compound 22 (1.2 g, 2.46 mmol) on
hydrogenation according to procedure described for preparation of
compound 11 yields 23 (700 mg, 83%) as colorless oil. Rf (5% MeOH/
References and notes
CH2Cl2) 0.5; ½a 2D6
ꢂ
ꢀ5.61 (c 1.6, CHCl3); 1H NMR (300 MHz, CDCl3):
d
3.59 (dd, J¼9.8, 3.7 Hz, 1H, CH2eOSi), 3.51 (dd, J¼9.8, 6.0 Hz, 1H,
1. (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556e1575; (b)
Jones, T. H.; Voegtle, H. L.; Miras, H. M.; Weatherford, R. G.; Spande, T. F.;
CH2eOSi), 3.53e3.42 (m, 1H, CHeOH), 2.69e2.59 (m, 1H, CHeNH),

C.R. Reddy et al. / Tetrahedron 68 (2012) 145e151
151
Garraffo, H. M.; Daly, J. W.; Davidson, D. W.; Snelling, R. R. J. Nat. Prod. 2007, 70,
160e168; (c) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191e222; (d) Michael, J. P.
Nat. Prod. Rep. 2008, 25, 139e165; (e) Huang, P.-Q. In Asymmetric Synthesis of
Nitrogen Heterocycles; Royer, J., Ed.; Wiley: Weinheim, 2009.
11. Andres, J. M.; Munoz, E. M.; Pedrosa, R.; Perez-Encabo, A. Eur. J. Org. Chem. 2003,
3387e3397.
12. Compounds 9 and 16 exist as a mixture of keto and lactol forms, which was
confirmed by 1H NMR.
2. (a) Daly, J. W.; Brown, G. B.; Mensahdwumah, M.; Myers, C. W. Toxicon 1978, 16,
163e188; (b) Erspamer, V.; Melchiorri, P. Trends Pharmacol. Sci. 1980, 1,
391e395; (c) Daly, J. W.; Spande, T. F. Alkaloids: Chem. Biol. Perspect. 1986, 4,
1e274; (d) Elbein, A. D.; Molyneux, R. J. Alkaloids 1987, 5, Chapter 1; (e) Daly, J.
W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25, 1023e1095.
3. (a) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L. R.; Lidert, Z.; Swi-
thenbank, C. J. Org. Chem. 1991, 56, 1393e1405; (b) Machinaga, N.; Kibayashi, C.
J. Org. Chem. 1992, 57, 5178e5189; (c) Kiddle, J. J.; Green, D. L. C.; Thompson, C.
M. Tetrahedron 1995, 51, 2851e2864; (d) Celimene, C.; Dhimane, H.; Saboureau,
A.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 1585e1588; (e) Chenevert, R.;
Ziarani, G. M.; Dasser, M. Heterocycles 1999, 51, 593e598; (f) Back, T. G.; Na-
kajima, K. Org. Lett. 1999, 1, 261e263; (g) Back, T. G.; Nakajima, K. J. Org. Chem.
2000, 65, 4543e4552; (h) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J.
Org. Chem. 2003, 68, 1919e1928; (i) Varga, T. R.; Nemes, P.; Mucsi, Z.; Scheiber,
P. Tetrahedron Lett. 2007, 48, 1159e1161; (j) Barbe, G.; Pelletier, G.; Charette, A.
B. Org. Lett. 2009, 11, 3398e3401.
OH
O
O
P
O
P
R = H, 9
R = n-Bu,
R
O
16
O
O
O
O
OH
R
13. Folker, L. Ger. Offen. DE2711010, 1978.
14. NOE experiment has been carried out on known acetyl derivative of alcohol 13
and key NOE enhancements are shown below.
4. (a) Reddy, C. R.; Rao, N. N. Tetrahedron Lett. 2009, 50, 2478e2480; (b) Chan-
drasekhar, S.;Murali, R. V. N. S.;Reddy, C. R. TetrahedronLett. 2009, 50, 5686e5688;
(c) Reddy, C. R.; Rao, N. N.; Srikanth, B. Eur. J. Org. Chem. 2010, 345e351.
5. Representative references for synthesis of (ꢀ)-167B: (a) Polniaszek, R. P.; Bel-
mont, S. E. J. Org. Chem. 1990, 55, 4688e4693; (b) Lee, E.; Li, K. S.; Lim, J. Tet-
rahedron Lett. 1996, 37, 1445e1446; (c) Carbonnel, S.; Troin, Y. Heterocycles
2002, 57, 1807e1830; (d) Zaminer, J.; Stapper, C.; Blechert, S. Tetrahedron Lett.
2002, 43, 6739e6741; (e) Corvo, M. C.; Pereira, M. M. A. Tetrahedron Lett. 2002,
43, 455e458; (f) Reddy, P. G.; Baskaran, S. J. Org. Chem. 2004, 69, 3093e3101;
(g) Roa, L. F.; Gnecco, D.; Galindo, A.; Teran, J. L. Tetrahedron: Asymmetry 2004,
15, 3393e3395; (h) Guazzelli, G.; Lazzaroni, R.; Settambolo, R. Synthesis 2005,
3119e3123; (i) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129,
9300e9301; (j) Stead, D.; Obrien, P.; Sanderson, A. Org. Lett. 2008, 10,
1409e1412; (k) Kapat, A.; Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc.
2009, 131, 17746e17747; (l) Gracia, S.; Jerpan, R.; Pellet-Rostaing, S.; Popowycz,
F.; Lemaire, M. Tetrahedron Lett. 2010, 51, 6290e6293.
6. Representative references for synthesis of (ꢀ)-209D: (a) Takahata, H.; Kubota,
M.; Ihara, K.; Okamoto, N.; Momose, T.; Azer, N.; Eldefrawi, A. T.; Eldefrawi, M.
E. Tetrahedron: Asymmetry 1998, 9, 3289e3301; (b) Yamazaki, N.; Ito, T.; Ki-
bayashi, C. Org. Lett. 2000, 2, 465e467; (c) Kim, G.; Lee, E. J. Tetrahedron:
Asymmetry 2001, 12, 2073e2076; (d) Kim, G.; Jung, S.; Kim, W. Org. Lett. 2001, 3,
2985e2987; (e) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005,
46, 2101e2103; (f) Yu, R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem., Int. Ed.
2009, 48, 2379e2382; (g) Liu, H.; Su, D.; Cheng, G.; Xu, J.; Wang, X.; Hu, Y. Org.
Biomol. Chem. 2010, 8, 1899e1904.
15. To determine the enantiomeric excess of (S)-ethyl 4-hydroxyoctanoate 15 by
chiral HPLC, it was converted to p-nitro benzoate derivative under DCC/DMAP
reaction conditions using p-nitrobenzoic acid. Chiral HPLC: Chiralcel OD-H
column (250ꢃ4.6 mm, 5 ), isopropanol/hexanes¼7:93, flow rate 1.0 mL/min,
m
l
210 nm. Retention time (min): 7.32 (major) and 7.96 (minor); ee 94%; Rf (20%
EtOAc/hexanes) 0.55; ½a D20
ꢂ
þ12.3 (c 0.6, CHCl3); 1H NMR (300 MHz, CDCl3):
d 8.
29 (d, J¼8.7 Hz, 2H, CH(Ar)), 8.20 (d, J¼8.7 Hz, 2H, CH(Ar)), 5.23e5.17 (m, 1H,
OeCH), 4.14e4.02 (m, 2H, OCH2eCH3), 2.39 (t, J¼7.6 Hz, 2H, CH2eCO), 2.15e1.
97 (m, 2H, CH2eCH2eCO), 1.81e1.62 (m, 2H, CH2eCHeO), 1.44e1.27 (m, 4H,
CeCH2eC), 1.21 (t, J¼7.6 Hz, 3H, OCH2eCH3), 0.89 (t, J¼7.6 Hz, 3H, CH3eCH2);
13C NMR (75 MHz, CDCl3):
d 172.8, 164.2, 150.5, 135.7, 130.6, 123.5, 75.4, 60.5,
33.7, 30.3, 29.1, 27.3, 22.4, 14.1, 13.8.
7. For isolation of (ꢀ)-239AB see: (a) Skrinjar, M.; Wistrand, L. G. Tetrahedron Lett.
1990, 31, 1775e1778 For synthesis of (ꢀ)-239AB see: (b) Thanh, G. V.; Celerier,
J.-P.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 2211e2212; (c) Celimene, C.;
Dhimane, H.; Lhommet, G. Tetrahedron 1998, 54, 10457e10468; (d) Dhimane,
H.; Vanucci-Bacque, C.; Hamon, L.; Lhommet, G. Eur. J. Org. Chem. 1998, 9,
1955e1963.
8. For isolation of (ꢀ)-195B see: (a) Edwards, M. W.; Daly, J. W. J. Nat. Prod. 1988,
51, 1188e1197 Representative references for synthesis of (ꢀ)-195B: (b) Angle, S.
R.; Kim, M. J. Org. Chem. 2007, 72, 8791e8796; (c) Davis, F. A.; Zhang, J.; Wu, Y.
Tetrahedron Lett. 2011, 52, 2054e2057.
9. Representative references for synthesis of (ꢀ)-monomorine: (a) Royer, J.;
Husson, H. P. J. Org. Chem. 1985, 50, 670e673; (b) Jefford, C. W.; Sienkiewicz, K.;
Thornton, S. R. Tetrahedron Lett. 1994, 35, 4759e4762; (c) Zhang, S. H.; Xu, L.;
Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007, 72, 3133e3136; (d) Pattenden,
L. S.; Adams, H.; Smith, S. A.; Harrity, J. P. A. Tetrahedron 2008, 64, 2951e2961;
(e) Toyooka, N.; Zhou, D. J.; Nemoto, H. J. Org. Chem. 2008, 73, 4575e4577.
10. The similar aldehyde with different protecting groups is little explored. For
references see: (a) Ofuna, Y.; Hori, K. Jpn. Kokai Tokkyo Koho, JP 63063673 A
19880322, 1988. (b) Acharya, H. P.; Clive, D. L. J. J. Org. Chem. 2010, 75,
5223e5233; (c) Alvaro, G.; Amantini, D.; Castiglioni, E.; Fabio, R. D.; Pavone, F.
PCT Int. Appl. WO 2010063662 A1 2010610, 2010.
16. (a) Kondekar, N. B.; Kumar, P. Org. Lett. 2009, 11, 2611e2614; (b) Jha, V.; Kon-
dekar, N. B.; Kumar, P. Org. Lett. 2010, 12, 2762e2765.
17. The enantiomeric excess of (R)-ethyl 4-hydroxyoctanoate 15a was determined
by converting it to p-nitro benzoate derivative under DCC/DMAP reaction
conditions using p-nitrobenzoic acid. Chiral HPLC: Chiralcel OD-H column
(250ꢃ4.6 mm, 5
m
), isopropanol/hexanes¼7:93, flow rate 1.0 mL/min,
l 210 nm.
Retention time (min): 7.39 (minor) and 8.00 (major); ee 94%; Rf (20% EtOAc/
hexanes) 0.55; ½a D20
ꢀ12.9 (c 0.6, CHCl3).
ꢂ