Total synthesis of a piperidine alkaloid, microcosamine A

Article abstract of DOI:10.1039/c5ob02085a

The first asymmetric total synthesis of a new natural piperidine alkaloid, microcosamine A, has been accomplished from d-serine and d-methyl lactate as chiral pool starting materials. Key features of the strategy include the utility of Horner-Wadsworth-Emmons reaction, Luche reduction, intramolecular carbamate N-alkylation to form the piperidine framework and Julia-Kocienski olefination to install the triene side-chain.

Full text of DOI:10.1039/c5ob02085a

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Total synthesis of a piperidine alkaloid,
Microcosamine A
Cite this: DOI: 10.1039/x0xx00000x
Chada Raji Reddy,*, a Bellamkonda Latha,a Kamalkishor Warudikara and Kiran Kumar
Singarapub
Received 00th October 2015,
Accepted 00th October 2015
The first asymmetric total synthesis of a new natural piperidine alkaloid, microcosamine A, has
been accomplished from D-Serine and D-methyl lactate as chiral pool starting materials. Key
features of the strategy include the utility of Horner-Wadsworth-Emmons reaction, Luche
reduction, intramolecular carbamate N-alkylation to form the piperidine framework and Julia-
Kocienski olefination to install the triene side-chain.
DOI: 10.1039/x0xx00000x
www.rsc.org/
roots, stem bark, leaves and fruits are being used traditionally to
treat diarrhea and fever, as herbal tea to treat cold, enteritis, and
Introduction
skin rash and as insecticides.9 There is a good number of 2,3,6-
trisubstituted piperidine alkaloids which have been isolated
from this species.10 Later, in 2013, it was again isolated from
the same plant along with some other piperidine alkaloids by
Kinghorn et al and examined for their effects on neuronal
nicotinic acetylcholine receptors (nAChRs).5 Microcosamine A
2-Methyl-3-hydroxy-6-alkylated piperidines constitute an
important class of natural alkaloids due to their interesting
biological and pharmacological properties (anaesthetic,
analgesic, antitumor, antibiotic, CNS stimulating biological
properties, antihypertensive and antifungal activities etc.).1-6
These molecules possess in different stereochemical pattern and
C6 side chain with either saturated or unsaturated alkyl group.
Up to date three types of 2-methyl-3-hydroxy natural
piperidines having different unsaturated side chain at C6
(
2a) exhibited approximately 53.7% and 59% h34 and
h32 nAChR activity, respectively Herein, we presented the
first total synthesis of microcosamine A (2a).
carbon, such as corydendramines
A
&
B
(
1a, 1b),4
6
microgrewiapine A (1c)5 and microcosamines A & B (2a
, 2b)
have been isolated. However, there is no synthesis reported for
any of these molecules. The interesting structural feature of
these molecules is the presence of a chiral hydroxy group at
C3-position of piperidine ring with trans stereochemistry with
respect to the C2 and C6 carbons, which is a rare substructure
in piperidine alkaloids. Structurally, these compounds possess a
polar head group with hydroxyl and amine functionalities and a
hydrophobic aliphatic tail, which can be considered as cyclic
analogues of the lipid sphingosine membrane.7 The above
observations combined with our interest in the synthesis of
alkaloids8 have driven us for the synthesis of microcosamine A
(
2a).
Microcosamine A (2a), was first isolated by Lin and co-
workers in 2008, from the chloroform extraction of the leaves
of Microcos paniculata along with microcosamine B (2b) and
found their insecticidal activity against the larvae of Culex
quinquefasciatus with LC50 value of 5.2 and 17.0 µg/mL,
respectively.6 Microcos paniculata, a large shrub or small tree
that grows in South and Southeast Asia countries, is found to be
a rich source of bio-active compounds and several parts such as
Figure 1. Structures of corydendramines A & B, microgrewiapine A
and microcosamines A & B
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Journal Name
Results and discussion
was protected as methoxy methyl (MOM) ether 13 using
MOMCl/diisopropylethyl amine in CH2Cl2 (89%). To obtain
Scheme 1 outlines the retrosynthetic strategy of 2a. We planned the
installation of triene-side chain at C6 position of hydroxy piperidine
ring 4 by using 3 via oxidation followed by Julia-Kocienski
olefination.11 Synthesis of the sulfone fragment 3 was projected from
1-octyne (8) by way of a known conjugated alcohol 5.12 The
construction of piperidine 4 was designed through the intramolecular
carbamate N-alkylation of its precursor which could be obtained
from N,O-protected D-serine ester 6 and -keto phosphonate 7 using
Horner-Wadsworth-Emmons (HWE) olefination13 as the key
reaction. Ester 6 and phosphonate 7 inturn could be prepared from
the chiral starting materials, D-serine (9) and D-methyl lactate (10),
respectively. The C2 and C6 stereochemistry is expected to arise
from 9 and C3-hydroxyl stereochemistry envisaged from 10 using
diastereoselective Luche reduction14 of keto functionality.
Scheme 2. Synthesis of 4 from 6 and 7
free secondary hydroxyl group, a two-step protecting group
manipulation was chosen. Deprotection of both the tert-
butyldimethyl silyl groups of 13 under HF (40% in water) in
CH3CN followed by selective protection of the resulting
primary hydroxyl group as a TBS ether produced the required
alcohol 14 in 81% yield over two steps. After the oxidation of
alcohol 14 to the corresponding ketone 14-I, the attempt to
form the piperidine ring 14-II through hydrogenation was
unsuccessful.17
Scheme 1. Retrosynthetic analysis of 2a
The ester intermediate
D-serine (
) following the reported procedure.15 The desired -
keto phosphonate
6 was prepared in three steps from
9
7
was also smoothly obtained in two steps
Thus, an alternative sequence was followed. Hydrogenation
reaction of 14 using 10% Pd/C in EtOH involves the olefin
reduction as well as Cbz-deprotection to free amine, which was
from D-methyl lactate (10) using literature protocol.16 The
synthesis of piperidine fragment is outlined in scheme 2.
Initially, the ester
aldehyde followed by HWE olefination with -keto
phosphonate under Ba(OH)2 8H2O in THF/H2O condition to
afford the enone 11 in 87% yield, precursor for
diastereoselective Luche reduction. Exposure of 11 to NaBH4
6 was subjected to DIBAL-H reduction to
subsequently
treated
with
di-tert-butyl-dicarbonate
(Boc2O)/Et3N to get Boc-protected amino alcohol 15 in 88%
yield. Treatment of 15 with methanesulfonyl chloride in
presence of triethyl amine in CH2Cl2 gave the mesylate 16 in
85% yield. Compound 16 was successfully converted into
2,3,6-trisubstituted piperidine via intramolecular carbamate N-
alkylation (SN reaction) using potassium tert-butoxide in THF
(88%).18 At this point, the diastereomers formed during the
Luche reduction of 11 were seperated by column
chromatography (dr 92:8). The major isomer 17 was found to
the desired one and the minor isomer 17a was undesired, which
were characterized by 2D COSY and NOESY experiments.19
The nOe cross correlations between H8(Me)/H7(H7'), H2/H9
and H3/H8(Me) for 17 (Figure 2) support the desired
7

a
o
in MeOH in the presence of CeCl3
allylic alcohol 12 along with its minor diastereomer in 85%
yield [dr >9:1, based on the diastereomers 17 17a, seperated
H2O at -78 C provided the
&
in the cyclization step]. At this stage, we were unable to
separate these diastereomers either by column or by HPLC (In
1H NMR spectra, the signals were not seperated to verify the
diasrereomeric ratio) and hence, moved for further
transformations as a mixture. Thus, the hydroxyl group of 12
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diastereomer. In case of 17a the nOe cross correlations for natural product (see Table S1 in supplementary
observed between H8(Me)/H7(H7'), H7/H9, H8/H9, H2/H3 information). The specific rotation of synthetic 2a {[α]D20 : +5.6
support the undesired diastereomer (Figure 2). Next, TBS (c 1.00, CH3OH)} was also comparable to the natural product
20
group of 17 was deprotected using HF (40% in water) in {[α]D : +4.0 (c 1.00, CH3OH)}. These results confirm the
CH3CN to give the piperidinol
4
in 80% yield.
structure and absolute configuration of the natural product 2a.
Conclusions
In summary, The first asymmetric total synthesis of natural
piperidine alkaloid, microcosamine A, was accomplished using
commercially available D-serine, D-methyl lactate (for
piperidine unit) and 1-octyne (for triene-side chain) as starting
materials. The key features of the strategy are the successful
Figure
2: The characteristic nOe cross correlations of utilization of HWE-olefination and intramolecular carbamate
compound 17 and 17a
.
N-cyclization for piperidine ring construction and Julia-
Kocienski olefination for the installation of side chain in the
The sulfone
from dienol
3
5
required for Julia olefination was synthesised natural product synthesis. The approach is handy for the
, obtained from 1-octyne (
).12 Mitsunobu synthesis of other natural products and their analogues having
with 1-phenyl-1H-tetrazole-5-thiol to different side chains.
8
reaction20 of the alcohol
5
thio-tetrazole 18 (95% yield) followed by ammonium
molybdate catalyzed oxidation21 using hydrogen peroxide in Experimental
EtOH provided the sulfone
3 in 82% yield (Scheme 3).
General
Melting points were determined on a POLMON melting point
apparatus and are uncorrected. NMR spectra were recorded in
CDCl3 on 300 MHz, 400 MHz or 500 MHz spectrometers at
ambient temperature. Chemical shifts δ were denoted with
reference to TMS or solvent residual (CDCl3: δ 7.26 ppm for 1H
and 77.0 ppm for 13C) peak given in ppm (parts per million)
and coupling constants J are measured in Hz (hertz). FTIR
spectra were recorded on
a Perkin-Elmer 683 infrared
Scheme 3. Synthesis of sulfone 3
spectrophotometer in KBr or as neat. Optical rotations were
measured on an Anton Paar MLP 200 modular circular digital
polarimeter by using a 2 mL cell with a path length of 1 dm
with MeOH or CHCl3 as solvent. Low-resolution MS were
collected on an Agilent Technologies LC-MSD trap SL
spectrometer in positive ion mode. Technical-grade EtOAc and
hexanes used for column chromatography were distilled before
use. All the reagents and solvents were of reagent grade and
used without further purification unless otherwise stated. THF,
when used as solvent for reactions, was freshly distilled from
sodium benzophenone ketyl radical. Progress of the reactions
was monitored by thin-layer chromatography using silica plates
(UV254, glass backed; Merk KGaA) and the spots were
visualized under UV-light and/or after charring with nihydrin or
potassium permanganate or β-naphthol stain solutions. Column
chromatography was performed over silica gel (60–120 mesh)
or on alumina (aluminium oxide activated, neutral, 150 mesh)
packed in glass columns, eluted with gradients of petroleum
ether and ethyl acetate. Column fractions were concentrated
under reduced pressure at temperatures not more than 40 °C.
All the reactions were performed under N2 in ovendried
glassware with magnetic stirring.
The stage was set for the conversion of
4 to microcosamine A
(
2a) by connecting the side chain (Scheme 4). Accordingly, the
alcohol
4 was oxidized with IBX (2-iodoxybenzoic acid) to the
corresponding aldehyde followed by Julia-Kocienski
olefination with the trienyl sulfone by treating with KHDMS
3
in the presence of 18-crown-6 in DME provided the trienyl-
piperidine 19 exclusively as Z-isomer in 72% yield over two
steps.22 Removal of MOM and Boc groups was accomplished
in one step by the treatment of 19 with 3N HCl in MeOH to
give the desired microcosamine A (2a) in 78% yield.
Scheme 4. Synthesis of 2a from
4
The spectral data (1H, 13C NMR and mass) of our synthetic
microcosamine A (2a) were in full agreement to those reported
Benzyl (6
S
,10
R,
E)-2,2,3,3,10,12,12,13,13-nonamethyl-9-oxo-
4,11-dioxa-3,12-disilatetradec-7-en-6-ylcarbamate
(11):
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Methyl N-((benzyloxy)carbonyl)-O-(tert-butyldimethylsilyl)-D- hexanes/EtOAc 8:2) to furnish 12 (2.1 g, 85%) as a colorless
20
serinate.15
6 (2.2 g, 5.99 mmol) was taken in a round bottemed oil. Rf = 0.2 (petroleum ether : EtOAc = 9:1); [α]D = −6.6 (c
flask and added anhydrous toluene (20 mL). The mixture was 1.10, CHCl3); IR (neat): νmax 3446, 2953, 2930, 1714, 1253,
1
cooled to -78 °C before adding DIBAL-H (25% w/v in toluene, 773 cm-1; H NMR (500 MHz, CDCl3): δ 7.41-7.28 (m, 5H,
5.1 mL, 7.18 mmol) drop wise under N2 and stirred at the same Ph), 5.79 (dd, J = 15.6, 5.7 Hz, 1H, CH=CH), 5.65 (dd, J =
temperature for 10 min. The mixture was quenched with 15.6, 5.9 Hz, 1H, CH=CH), 5.15-5.04 (m, 1H, -NH), 5.11 (s,
aqueous saturated sodium potassium tartrate (20 mL), diluted 2H, CH2−Ph), 4.32-4.20 (br m, 1H, CH−N), 3.84-3.76 (m, 1H,
with DCM (20 mL), stirred for 3 h at rt for the separation of CH−OH), 3.72 (dd, J = 10.1, 4.1 Hz, 1H, CH2−OTBS), 3.67-
two layers. The organic layers were separated and the aqueous 3.58 (m, 2H, CH2−OTBS, CH−OTBS), 1.10 (d, J = 5.8 Hz,
layer was extracted with DCM (2 x 20 mL). The combined 3H, CH3), 0.91 (s, 9H, tBu-Si), 0.89 (s, 9H, tBu-Si), 0.09 (s, 3H,
organic layers were washed with brine (20 mL), dried over Si(CH3)2), 0.08 (s, 3H, Si(CH3)2), 0.05 (s, 6H, Si(CH3)2); 13C
Na2SO4, filtered and concentrated under reduced pressure. The NMR (125 MHz, CDCl3): δ 155.7, 136.5, 131.2, 130.9, 130.4,
aldehyde was used for the next step without further purification. 128.4, 128.0, 76.5, 71.9, 66.6, 65.2, 53.7, 25.7, 25.8, 19.8, 18.2,
To
butyldimethylsilyl)oxy)-2-oxobutyl)phosphonate16
7.19 mmol) in THF (30 mL), was added Ba(OH)2
8.99 mmol) at rt and stirred vigorously for 45 min. The reaction Benzyl
a
stirred solution of (R)-dimethyl (3-((tert- 17.9, -4.2, -4.8, -5.4; MS (ESI): m/z 524 (M+H)+; HRMS (ESI):
(2.2 g, m/z calcd for C27H50NO5Si2 (M+H)+, 524.3222; found
8H2O (2.8 g, 524.3228.
7

(6S,9R,10R,E)-9-(methoxymethoxy)-
mixture was cooled to 0 oC before adding above crude aldehyde 2,2,3,3,10,12,12,13,13-nonamethyl-4,11-dioxa-3,12-
in 15 mL of THF/H2O (20:1) and the mixture was allowed to disilatetradec-7-en-6-ylcarbamate (13): To the compound 12
warm to rt. After completion of reaction (4 h), the reaction (2 g, 3.82 mmol) in dry dichloromethane (40 mL) was added
mixture was diluted with EtOAc (30 mL), organic layer was iPr2EtN (1.98 mL, 11.47 mmol) and methoxymethyl chloride
washed with water (30 mL), brine (30 mL), dried over Na2SO4 chloride (MOMCl) (0.92 mL, 11.47 mmol) at 0 oC. The
and concentrated under reduced pressure. The crude product solution was stirred at rt for 12 h and quenched by the addition
was purified by flash column chromatography (neutral alumina, of saturated aqueous NaHCO3 solution (30 mL). The aqueous
hexanes/EtOAc 9:1) to afford enone 11 (2.7 g, 87%) as a layer was separated and extracted with DCM (2 x 25 mL). The
20
colorless oil. Rf = 0.4 (petroleum ether : EtOAc = 9:1); [α]D
=
combined organic layers were dried over Na2SO4 and volatiles
+ 9.5 (c 1.50, CHCl3); IR (neat): νmax 3446, 2954, 2931, 2858, were removed under reduced pressure. The crude product was
1705, 1631, 1255, 1116, 837 cm-1; 1H NMR (400 MHz, purified by column chromatography (neutral alumina,
CDCl3): δ 7.41-7.28 (m, 5H, Ph), 6.93 (dd, J = 15.8, 4.7 Hz, hexanes/EtOAc 9:1) to get compound 13 as a colourless liquid
20
1H, CH=CH), 6.73 (d, J = 15.8 Hz, 1H, CH=CH), 5.22-5.06 (1.9 g, 89%). Rf = 0.4 (petroleum ether : EtOAc = 9:1); [α]D
=
(m, 3H, CH2−Ph, -NH), 4.52-4.43 (br m, 1H, CH−N), 4.25 (q, −15.4 (c 1.00, CHCl3); IR (neat): νmax 3446, 2954, 2857, 1725,
J = 13.6, 6.8 Hz, 1H, CH−CH3), 3.76 (d, J = 3.7 Hz, 2H, 1254, 1106, 836 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.43-7.27
t
CH2−O), 1.29 (d, J = 6.8 Hz, 3H, CH−CH3), 0.90 (s, 9H, Bu- (m, 5H, Ph), 5.71 (dd, J = 15.8, 5.6 Hz, 1H, CH=CH), 5.57 (dd,
t
Si), 0.85 (s, 9H, Bu-Si), 0.06 (s, 3H, Si(CH3)2), 0.05 (s, 3H, J = 15.7, 6.9 Hz, 1H, CH=CH), 5.16-5.03 (m, 3H, CH2−Ph, -
Si(CH3)2), 0.03 (s, 3H, Si(CH3)2), 0.02 (s, 3H, Si(CH3)2); 13C NH), 4.64 (A of AB q, J = 6.5 Hz, 1H, OCH2O), 4.57 (B of AB
NMR (100 MHz, CDCl3): δ 201.0, 155.7, 145.2, 136.3, 128.5, q, J = 6.6 Hz, 1H, OCH2O), 4.35-4.21 (m, 1H, CH−N), 3.89 (t,
128.1, 128.0, 124.2, 74.3, 66.9, 64.6, 53.7, 25.7, 25.7, 20.8, J = 6.4 Hz, 1H, CHOMOM), 3.85-3.76 (m, 1H, CH−OTBS),
18.2, 18.0, -4.8, -4.9, -5.5, -5.5; MS (ESI): m/z 544 (M+Na)+; 3.70 (dd, J = 10.0, 4.3 Hz, 1H, CH2−OTBS), 3.64 (dd, J = 9.6,
HRMS (ESI): m/z calcd for C27H47NO5Si2Na (M+Na)+, 3.5 Hz, 1H, CH2−OTBS), 3.34 (s, 3H, OCH3), 1.06 (d, J = 6.1
544.2885; found 544.2890.
Benzyl (6 ,9 ,10
nonamethyl-4,11-dioxa-3,12-disilatetradec-7-en-6-
Hz, 3H, CH3), 0.89 (s, 9H, tBu-Si), 0.87 (s, 9H, tBu-Si), 0.06 (s,
S
R
R
,
E
)-9-hydroxy-2,2,3,3,10,12,12,13,13- 6H, Si(CH3)2), 0.03 (s, 3H, Si(CH3)2), 0.03 (s, 3H, Si(CH3)2).
13C NMR (100 MHz, CDCl3): δ 155.7, 136.5, 131.8, 128.5,
ylcarbamate (12): To a stirred solution of 11 (2.5 g, 4.79 128.4, 128.0, 94.4, 80.3, 70.4, 66.6, 65.2, 55.3, 53.7, 25.8, 25.8,
.
mmol) in MeOH (30 mL) was added CeCl3 7H2O (3.5 g, 9.59 19.4, 18.2, 18.1, -4.6, -4.7, -5.5, -5.5; MS (ESI): m/z 590
mmol) and was allowed to stir for 45 min at room temperature. (M+Na)+; HRMS (ESI): m/z calcd for C29H53NO6Si2Na (M+
It was cooled to -78 °C and NaBH4 (265 mg, 7.18 mmol) was Na)+, 590.3303; found 590.3304.
added portion wise for over 10 min and stirred for an additional Benzyl
(5R,8S,E)-5-((R)-1-hydroxyethyl)-11,11,12,12-
1 h at the same temperature. After completion of the reaction tetramethyl-2,4,10-trioxa-11-silatridec-6-en-8-ylcarbamate
(10 min), it was quenched by addition of ice pieces/ice cold (14): To a stirred solution of 13 (1.9 g, 3.35 mmol) in CH3CN
o
water (2 mL) at -78 °C and slowly allowed to warm to room (20 mL) at 0 C was added HF (40% in water, 0.29 mL, 6.70
temperature. After stirring at room temperature for further 30 mmol) drop wise and allowed to rt over 30 min. After
min, it was poured into water (20 mL) and extracted with completion of the reaction, saturated aqueous NaHCO3 (20 mL)
diethyl ether (3 x 25 mL). Combined organic layers were was added dropwise and the aqueous layer was extracted with
washed with brine (20 mL), dried over Na2SO4 and EtOAc (2 x 25 mL). The combined organic extracts were
concentrated under reduced pressure. The crude product was washed with brine (20 mL), dried over Na2SO4 and evaporated
purified by column chromatography (neutral alumina, under reduced pressure. To the residue in DCM (30 mL) was
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added imidazole (296 mg, 4.35 mmol) and t-BuMe2SiCl (502 the heterogeneous mixture was stirred for 12 h under hydrogen
o
mg, 3.35 mmol) at 0 C and warmed to rt. The reaction mixture atmosphere at rt. The reaction mixture was filtered over celite,
was diluted with water (20 mL) at the point all the starting the volatiles removed under reduced pressure. To the residue
materials consumed and extracted with DCM (2 x 20 mL). The and triethyl amine (0.62 ml, 4.41 mmol) in THF (20 ml), di-
combined organic extracts were washed with brine (20 mL), tert-butyl-dicarbonate (Boc2O) (0.5 mL, 2.20 mmol) was added
dried over Na2SO4 and evaporated. Flash chromatography of at 0 °C. The reaction mixture was warmed to rt and stirred for 4
the residue over neutral alumina (hexanes/EtOAc 7:3), gave 14 h. The reaction mixture was diluted with water after the
(1.23 g, 81%) as a colorless oil. Rf = 0.3 (petroleum ether : completion of reaction and extracted with EtOAc (2 x 20 mL).
20
EtOAc = 7:3); [α]D = −46.2 (c 1.70, CHCl3); IR (neat): νmax The combined organic layer was washed with brine (20 mL),
1
3445, 3332, 2953, 2931, 1716, 1255, 1102, 838 cm-1; H NMR dried over Na2SO4 and concentrated under reduced pressure.
(400 MHz, CDCl3) δ 7.39-7.30 (m, 5H, Ph), 5.75 (dd, J = 15.7, Flash chromatography of the residue over neutral alumina
5.5 Hz, 1H, CH=CH), 5.49 (dd, J = 15.6, 8.0 Hz, 1H, CH=CH), (hexanes/EtOAc 7:3), gave 15 (817 mg, 88%) as a colorless oil.
20
5.11 (s, 2H, CH2−Ph), 4.70 (d, J = 6.1 Hz, 1H, OCH2O), 4.55 Rf = 0.5 (petroleum ether : EtOAc = 7:3); [α]D = −19.5 (c
(d, J = 6.4 Hz, 1H, OCH2O), 4.28 (m, 1H, CH−N), 3.79 (t, J = 1.00, CHCl3); IR (neat): νmax 3451, 2955, 2932, 1709, 1103,
1
7.6 Hz, 1H, CHOMOM), 3.74-3.62 (m, 3H, CH2−OTBS, 838 cm-1; H NMR (400 MHz, CDCl3) δ 4.71-4.66 (m, 2H,
CH−OH), 3.38 (s, 3H, OCH3), 2.03 (br s, 1H, OH), 1.12 (d, J = OCH2O), 3.71-3.63 (m, 1H, CH−OH), 3.59-3.52 (m, 2H,
t
6.0 Hz, 3H, CH3), 0.88 (s, 9H, Bu-Si), 0.04 (s, 3H, Si(CH3)2), CH2−OTBS), 3.40 (s, 3H, OCH3), 3.29-3.22 (m, 1H, CH−N),
0.04 (s, 3H, Si(CH3)2). 13C NMR (100 MHz, CDCl3) δ 155.7, 3.05-3.14 (m, 1H, CHOMOM), 1.70-1.57 (m, 2H, CH2−CH2),
136.4, 134.0, 128.5, 128.1, 93.9, 81.7, 69.5, 66.7, 65.0, 55.6, 1.50-1.38 (m, 11H, tBu in Boc, CH2−CH2), 1.13 (d, J = 6.4 Hz,
t
53.7, 25.8, 18.4, 18.2, -5.5, -5.5; MS (ESI): m/z 476 (M+Na)+; 3H, CH3), 0.87 (s, 9H, Bu-Si), 0.03 (s, 6H, Si(CH3)2). 13C
HRMS (ESI): m/z calcd for C23H39NO6SiNa (M+Na)+, NMR (100 MHz, CDCl3) δ 155.5, 97.4, 85.4, 79.0, 69.1, 64.6,
476.2438; found 476.2445.
Benzyl ((5 ,8
)-5-acetyl-11,11,12,12-tetramethyl-2,4,10- m/z 444 (M+Na)+; HRMS (ESI): m/z calcd for C20H44NO6Si
trioxa-11-silatridec-6-en-8-yl)carbamate (14-I)
2- (M+H)+, 422.2751; found 422.2761.
Iodoxybenzoic acid (IBX) (185 mg, 0.66 mmol) was taken in a (2 ,3 ,6 )-6-(tert-Butoxycarbonylamino)-7-(tert-butyldi-
55.7, 52.0, 28.3, 27.7, 27.1, 25.8, 18.8, 18.2, -5.4; MS (ESI):
R
S,E
:
R
R S
round bottomed flask, added DMSO (0.5 mL) and stirred at rt methylsilyloxy)-3-(methoxymethoxy)heptan-2-yl
under nitrogen atmosphere for 10 min to get a clear solution. To methanesulfonate (16): To a stirred solution of compound 13
the clear solution, at the same temperature, added compound 14 (1.0 g, 2.37 mmol), triethyl amine (0.66 mL, 4.75 mmol) in
(200 mg, 0.44 mmol) in EtOAc (2 mL) dropwise. The reaction dichloromethane (20 mL) at 0 °C, was added methane sulfonyl
mixture was heated to 70 oC and stirred for 30 min. After chloride (0.27 mL, 3.56 mmol) dropwise. The mixture was
completion of reaction, the mixture was diluted with EtOAc (10 allowed to warm to rt and stirred for a further 1 hour. After
mL). The precipitate was filtered and washed with EtOAc (10 completion of reaction, it was diluted with water (20 mL) and
mL). The filtrate was washed with aqueous saturated NaHCO3 the aqueous layer was extracted with DCM (2 x 15 mL). The
solution (15 mL), brine (15 mL), dried over Na2SO4 and combined organic layer was washed with brine (20 mL), dried
concentrated under reduced pressure. The residue was purified over Na2SO4. Volatiles were removed under reduced pressure
by flash column chromatography (neutral alumina, and the residue was purified by flash column chromatography
hexanes/EtOAc 8:2) to yield ketone 14-I as the product (175 (neutral alumina, hexanes/EtOAc 7:3) to yield pale yellow oil
20
mg, 88%). Rf = 0.7 (petroleum ether : EtOAc = 7:3); [α]D
=
16 as the product (1 g, 85%). Rf = 0.6 (petroleum ether : EtOAc
20
−28.8 (c 1.57, CHCl3); IR (neat): νmax 3441, 2940, 1716, 766 = 7:3); [α]D = −6.9 (c 1.20, CHCl3); IR (neat): νmax 3392,
cm-1; H NMR (500 MHz, CDCl3): δ 7.38-7.29 (m, 5H, Ph), 2933, 1712, 1361, 1176, 837 cm-1; 1H NMR (400 MHz, CDCl3)
1
5.91 (dd, J = 15.6, 5.5 Hz, 1H,CH=CH), 5.61 (dd, J = 15.6, 6.6 δ 4.87-4.59 (m, 3H, OCH2O, CHOMs), 3.69-3.49 (m, 4H,
Hz, 1H, CH=CH), 5.15-5.07 (m, 1H, -NH), 5.09 (s, 2H, CH2−OTBS, CH−N, CHOMOM), 3.39 (s, 3H, OCH3), 3.02 (s,
CH2−Ph), 4.68 (d, J = 6.4 Hz, 1H, OCH2O), 4.61 (d, J = 6.6 3H, CH3 in Ms), 1.80-1.60 (m, 2H, CH2−CH2), 1.56-1.47 (m,
Hz, 1H, OCH2O), 4.52 (d, J = 6.6 Hz, 1H, CHOMOM), 4.34- 2H, CH2−CH2), 1.47-1.38 (m, 12H, tBu in Boc, CH3), 0.88 (s,
4.26 (br m, 1H, CH−N), 3.70 (dd, J = 10.0, 4.3 Hz, 1H, 9H, tBu-Si), 0.04 (s, 6H, Si(CH3)2). 13C NMR (100 MHz,
CH2−OTBS), 3.65 (d, J = 7.2 Hz, 1H, CH2−OTBS), 3.35 (s, CDCl3) δ 155.6, 96.9, 79.6, 79.2, 79.1, 64.8, 55.9, 51.9, 38.4,
3H, OCH3 ), 2.15 (s, 3H, COCH3 ), 0.86 (s, 9H, tBu-Si), 0.03 (s, 28.3, 26.9, 26.6, 25.8, 18.2, 16.8, -5.4; MS (ESI): m/z 522
3H, Si(CH3)2), 0.02 (s, 3H, Si(CH3)2); 13C NMR (125 MHz, (M+Na)+; HRMS (ESI): m/z calcd for C21H45NO8SSiNa
CDCl3) δ 206.1, 155.7, 136.3, 133.9, 128.4, 128.1, 125.7, 94.7, (M+Na)+, 522.2527; found 522.2560.
82.0, 66.8, 64.9, 55.8, 53.6, 25.7, 18.2, -5.5; MS (ESI): m/z 452 (2
S,3R,6S)-tert-Butyl 6-((tert-butyldimethylsilyloxy)methyl)-
(M+H)+; HRMS (ESI): m/z calcd for C23H37NO6SiNa (M+ 3-(methoxymethoxy)-2-methylpiperidine-1-carboxylate
Na)+, 474.2282; found 474.2286.
tert-Butyl (5 ,8 )-5-((
(17): The mesylated compound 16 (650 mg, 1.30 mmol) was
)-1-hydroxyethyl)-11,11,12,12- dissolved in dry THF (20 mL) under nitrogen atmosphere and
R
S
R
tetramethyl-2,4,10-trioxa-11-silatridecan-8-ylcarbamate
added potassium tert-butoxide (1.16 g, 10.4 mmol) dropwise as
(15): 10% Pd on C (5 mol %) was added to a degassed solution a solution in dry THF (10 mL). The reaction was stirred at rt for
of the compound 14 (1.0 g, 2.20 mmol) in EtOH (0.5 M) and 2 h then quenched with water (30 mL) and extracted with
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EtOAc (3 x 20 mL). The combined organic layers were washed h. After completion of the reaction, solvent was evaporated
with brine (1 x 20 mL), dried over Na2SO4, filtered and under reduced pressure and the residue was purified by flash
concentrated. The residue was purified by flash column column chromatography (silica gel, hexanes/EtOAc 9:1) to give
chromatography (neutral alumina, 2% EtOAc in hexanes) to 18 (1.01 g, 94%) as a colorless oil. Rf = 0.4 (petroleum ether :
give 17 (425 mg, 81%) and 17a (37 mg, 7%) as a separable EtOAc = 9:1); 1H NMR (300 MHz, CDCl3) δ 7.68-7.43 (m, 5H,
mixture (92:8) of diastereomers. Rf = 0.4 (petroleum ether : Ar), 6.31 (dd, J = 15.0, 10.4 Hz, 1H, 3-CH), 5.97 (dd, J = 15.2,
EtOAc = 9:1); 17: [α]D20 = −8.7 (c 0.90, CHCl3); IR (neat): νmax 10.4 Hz, 1H, 4-CH), 5.81-5.55 (m, 2H, 2-CH, 5-CH), 4.06 (d, J
1
2954, 2932, 1691, 1367, 1099, 838 cm-1; H NMR (400 MHz, = 7.6 Hz, 2H, 1-CH2), 2.05 (q, J = 6.7 Hz, 2H, 6-CH2), 1.43-
CDCl3) δ 4.70-4.61 (m, 2H, OCH2O), 4.25 (q, J = 6.8 Hz, 1H, 1.20 (m, 4H, CH2−CH2), 0.87 (t, J = 7.0 Hz, 3H, −CH3); 13C
2-CH−N), 4.17-4.06 (m, 1H, 6-CH−N), 3.61-3.50 (m, 2H, NMR (75 MHz, CDCl3) δ 153.8, 137.0, 135.8, 133.6, 130.0,
CH2−OTBS, CHOMOM), 3.46 (dd, J = 9.3, 4.7 Hz, 1H, 129.6, 128.7, 123.7, 122.8, 35.7, 32.2, 31.1, 22.1, 13.8; MS
CH2−OTBS), 3.36 (s, 3H, OCH3), 1.97-1.56 (m, 4H, (ESI): m/z 323 (M+Na)+; HRMS (ESI): m/z calcd for
t
CH2−CH2), 1.45 (s, 9H, Bu in Boc), 1.07 (d, J = 7.1 Hz, 3H, C16H21N4S (M+H)+, 301.1481; found 301.1482.
CH3), 0.89 (s, 9H, tBu-Si), 0.06 (s, 3H, Si(CH3)2), 0.05 (s, 3H, 5-((2E,4E)-Nona-2,4-dien-1-ylsulfonyl)-1-phenyl-1H-
Si(CH3)2). 13C NMR (100 MHz, CDCl3) δ 155.4, 94.7, 79.3, tetrazole (3): To the solid (NH4)6Mo7O24·4H2O (1.03 g, 0.834
o
73.5, 63.1, 55.3, 51.2, 50.0, 28.4, 25.8, 19.6, 19.3, 18.2, 17.3, - mmol) in a round bottemed flask at 0 C was added aq. H2O2
o
5.2, -5.4; MS (ESI): m/z 426 (M+Na)+; HRMS (ESI): m/z calcd (30% w/w, 4 mL) and stirred for 15 min at 0 C before it was
for C20H42NO5Si (M+H)+, 404.2827; found 404.2858.
added to a solution of 18 (0.5 g, 1.66 mmol) in EtOH (17 mL)
17a: [α]D = −26.2 (c 1.01, CHCl3); 1H NMR (300 MHz, at 0°C. The mixture was allowed to warm up to room
CDCl3) δ 4.62 (q, J = 7.0 Hz, 2H, OCH2O), 4.11 (qd, J = 7.0, temperature and stirred overnight. After completion of the
3.1 Hz, 1H, 2-CH−N), 3.87 (t, J = 9.5 Hz, 1H, CH2−OTBS), reaction, it was diluted with water (20 mL) and extracted with
3.75 (dd, J = 9.6, 4.2 Hz, 1H, CH2−OTBS), 3.69-3.55 (m, 2H, EtOAc (2 x 20 mL). The combined organic extracts were
6-CH−N, CHOMOM), 3.34 (s, 3H, OCH3), 2.00-1.83 (m, 2H, washed with saturated aqueous Na2S2O3 (20 mL), brine (20
CH2−CH2), 1.81-1.69 (m, 2H, CH2−CH2), 1.44 (s, 9H, tBu in mL), dried over Na2SO4 and concentrated under reduced
20
t
Boc), 1.22 (d, J = 7.1 Hz, 3H, CH3), 0.88 (s, 9H, Bu-Si), 0.04 pressure. Flash column chromatography of the residue (silica
(s, 6H, Si(CH3)2). 13C NMR (75 MHz, CDCl3) δ 155.7, 94.5, gel, hexanes/EtOAc 9:1) gave
3 (453 mg, 82 %) as a colorless
79.2, 73.9, 62.9, 55.3, 53.3, 51.3, 28.4, 25.9, 22.9, 20.2, 18.2, oil. Rf = 0.4 (petroleum ether : EtOAc = 9:1); IR (neat): νmax
1
17.9, -5.2, -5.3.
(2 ,3 ,6 )-tert-Butyl
2958, 2930, 2871, 1723, 1498, 1349, 1153, 763 cm-1; H NMR
S
R
S
6-(hydroxymethyl)-3-(methoxy- (500 MHz, CDCl3) δ 7.69-7.50 (m, 5H, Ar), 6.35 (dd, J = 15.2,
methoxy)-2-methylpiperidine-1-carboxylate (4): HF (40% in 10.5 Hz, 1H, 3-CH), 6.01 (dd, J = 15.2, 10.5 Hz, 1H, 4-CH),
water, 0.04 mL, 0.99 mmol) was added to a stirred solution of 5.86-5.78 (m, 1H, 2-CH), 5.48 (dt, J = 15.3, 7.6 Hz, 1H, 5-CH),
17 (400 mg, 0.99 mmol) in CH3CN (10 mL) at 0 oC. The 4.41 (d, J = 7.6 Hz, 2H, 1-CH2), 2.09 (q, J = 7.0 Hz, 2H, 6-
reaction mixture was allowed to warm to rt slowly over 30 min CH2), 1.40-1.24 (m, 4H, CH2−CH2), 0.89 (t, J = 7.2 Hz, 3H,
and added saturated aqueous NaHCO3 (10 mL) dropwise. The −CH3); 13C NMR (125 MHz, CDCl3) δ 153.0, 142.4, 139.9,
reaction mixture was extracted with EtOAc (2 x 10 mL). The 132.9, 131.3, 129.5, 128.3, 125.2, 111.8, 60.0, 32.2, 30.9, 22.1,
combined organic extracts were washed with brine (10 mL), 13.8; MS (ESI): m/z 355 (M+Na)+; HRMS (ESI): m/z calcd for
dried over Na2SO4 and concentrated under reduced pressure. C16H21N4O2S (M+H)+, 333.1380; found 333.1404.
Flash chromatography of the residue over neutral alumina (2
S
,3
R
,6
S
)-tert-Butyl
6-((1E,3E,5E)-deca-1,3,5-trienyl)-3-
(hexanes/EtOAc 1:1) gave
4
(229 mg, 80%) as a colorless oil. (methoxymethoxy)-2-methylpiperidine-1-carboxylate (19)
:
Rf = 0.2 (petroleum ether : EtOAc = 6:4); [α]D20 = −5.4 (c 1.10, A round bottomed flask charged with 2-iodoxybenzoic acid
CHCl3); IR (neat): νmax 3444, 2973, 2936, 1667, 1686, 1369, (IBX) (116 mg, 0.41 mmol), DMSO (0.2 mL) was stirred under
1042 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.67 (s, 2H, nitrogen atmosphere for 10 min at rt to get a clear solution. To
OCH2O), 4.29 (q, J = 6.9 Hz, 2H, CH−N), 3.68-3.52 (m, 3H, this solution was then added compound
4 (60 mg, 0.20 mmol)
CH2−OH, CHOMOM), 3.37 (s, 3H, OCH3), 2.06-1.94 (m, 1H, in EtOAc (1 mL) dropwise at room temperature. The reaction
CH2−CH2), 1.84-1.49 (m, 3H, CH2−CH2), 1.46 (s, 9H, tBu in mixture was heated to 70 oC and stirred for 30 min. After
Boc), 1.15 (d, J = 7.2 Hz, 3H, CH3). 13C NMR (75 MHz, completion of the reaction, the reaction mixture was cooled to
CDCl3) δ 156.9, 94.9, 80.0, 73.5, 65.6, 55.4, 51.1, 50.5, 28.4, room temperature and diluting with EtOAc (5 mL). The
19.7, 19.5, 18.4; MS (ESI): m/z 312 (M+Na)+; HRMS (ESI): precipitate was filtered and washed with EtOAc (5 mL). The
m/z calcd for C14H27NO5Na (M+Na)+, 312.1781; found filtrate was washed with aqueous saturated NaHCO3 solution
312.1808.
5-((2 ,4
(18): To a solution of (2E,4E)-nona-2,4-dien-1-ol12
3.57 mmol) in THF (30 mL) was added PPh3 (1.12 g, 4.28
mmol) and 1-phenyl-1H-tetrazole-5-thiol (762 mg, 4.28 mmol). 6 (64 mg, 0.24 mmol) in dry DME (5 mL) was added dropwise
(10 mL), brine (10 mL), dried over Na2SO4 and concentrated
E
E)-Nona-2,4-dien-1-ylthio)-1-phenyl-1H-tetrazole
under reduced pressure to get aldehyde which was used for the
5
(500 mg, next step without further purification.
To a solution of sulfone (82 mg, 0.24 mmol) and 18-crown-
3
o
o
The reaction mixture was cooled to 0 C, DIAD (0.9 mL, 4.64 KHMDS (1 M in THF, 0.2 mL, 0.2 mmol) at -78 C under
mmol) was slowly added and stirred at room temperature for 1 nitrogen atmosphere. After being stirred for 30 min, a solution
6 | J. Name., 2012, 00, 1-3
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ARTICLE
of above prepared aldehyde in dry DME (3 mL) was added
o
slowly to the reaction mixture and stirred for 2 h at -78 C Notes and references
before warming to rt and stirred over night. The reaction
mixture was poured into aqueous saturated NH4Cl solution (5
aDivision of Natural Products Chemistry,
CSIR-Indian Institute of Chemical Technology,
Hyderabad, India 500 007
E-mail: rajireddy@iict.res.in
bCentre for NMR & Structural Chemistry
CSIR-Indian Institute of Chemical Technology
Hyderabad, 500 007, India
mL) and extracted with ethyl acetate (2 x 5 mL). The combined
organic layer was washed with brine (5 mL), dried over
Na2SO4, and solvent was removed under reduced pressure.
Flash chromatography of the crude over neutral alumina (5%
EtOAc in hexanes) gave 19 (58 mg, 72%) as a colorless oil. Rf
= 0.3 (petroleum ether : EtOAc = 9:1); [α]D20 = −18.6 (c =1.30,
1
CHCl3); IR (neat): νmax 2930, 1688, 1365, 1038 cm-1; H NMR
(300 MHz, CDCl3) δ 6.20-5.98 (m, 4H, =CH−CH=CH−CH=), †Electronic Supplementary Information (ESI) available: See
5.76-5.62 (m, 2H, −CH2−CH=, =CH−CHN), 4.77 (br t, J = 5.1 DOI: 10.1039/b000000x/
Hz, 1H, 6-CH−N), 4.66 (q, J = 7.0 Hz, 2H, OCH2O), 4.31 (q, J
= 7.0 Hz, 1H, 2-CH−N), 3.64-3.55 (m, 1H, CHOMOM), 3.36
(s, 3H, OCH3), 2.19-2.00 (m, 2H, =CH−CH2), 1.90-1.54 (m,
3H, CH2−CH2), 1.45 (s, 9H, Bu in Boc), 1.50-1.22 (m, 5H,
CH2−CH2), 1.11 (d, J = 7.2 Hz, 3H, CH−CH3), 0.88 (t, J = 7.0
Hz, 3H, CH2−CH3). 13C NMR (75 MHz, CDCl3) δ 155.4,
135.4, 134.7, 132.5, 130.3, 130.1, 130.1, 94.7, 79.4, 73.3, 55.3,
50.5, 50.4, 32.4, 31.4, 28.4, 22.1, 21.6, 19.8, 19.3, 13.8; MS
(ESI): m/z 416 (M+Na)+; HRMS (ESI): m/z calcd for
C23H40NO4 (M+H)+, 394.2952; found 394.2976.
1. For selected reviews of piperidine alkaloids, see; (a) Makabe, H.
Stud. Nat. Prod. Chem. 2014, 42, 353 371; (b) Ojima, I.; Iula, D. M.
Alkaloids: Chemical and Biological Perspectives; Elsevier: Oxford,
UK, 1999; Vol. 13, p 371 412; (c) Plunkett, O.; Sainsbury, M. In
Rodd’s Chemistry of Carbon Compounds, 2nd ed.; Sainsbury, M.,
Ed.; Elsevier: Amsterdam, 1998, Part F/Part G (partial), pp 365 421;
(d) Schneider, M. J. Alkaloids: Chemical and Biological
Perspectives; Elsevier: Oxford, UK, 1996; Vol. 10, p 155 299; (e)
Angle, S. R.; Breitenbucher, J. G. Stud. Nat. Prod. Chem. 1995, 16,
453 502; (f) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi,
A., Ed.; Academic: New York, NY, 1985, Vol. 26, pp 89 183; (g)
−
t
−
−
−
Microcosamine A (2a): To the compound 19 (100 mg, 2.18
mmol) was added 3N HCl in methanol (2 mL) and stirred for
12 h at rt. After completion of the reaction, methanol was
evaporated to dryness under reduced pressure and 6N HCl (5
mL) was added. The aqueous layer was washed with diethyl
ether (2 x 10 mL), basified with 2 N NaOH solution and
extracted with diethyl ether (3 x 15 mL), dried over Na2SO4 and
concentrated under reduced pressure to furnish the desired
compound 2a (49 mg, 78%) as a pale yellow solid. . Mp: 107-
109 oC; Rf = 0.2 (EtOAc : MeOH = 95:5); [α]D20 = +5.6 (c 1.00,
−
−
Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, NY, 1985, Vol.
3, pp 1
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York,
1983; Vol. 1, Chapter 2, pp. 33 84.
−90; (h) Jones, T. H.; Blum, M. S. In Alkaloids: Chemical and
−
2. Representative references, for isolation, see: (a) Viegas Jr., C.;
Bolzani, V. da S.; Furlan, M.; Barreiro, E. J.; Young, M. C. M.;
Tomazela, D.; Eberlin, M. N. J. Nat. Prod. 2004, 67, 908
Kusano, G.; Orihara, S.; Tsukamoto, D.; Shibano, M.; Coskun, M.;
Guvenc, A.; Erdurak, C. S. Chem. Pharm. Bull. 2002, 50, 185 192;
(c) Highet, R. J. J. Org. Chem. 1964, 29, 471 474; (d) Rice, W. Y.;
Coke, J. L. J. Org. Chem. 1966, 31, 1010 1012; For activity, see: (e)
Sansores-Peraza, P.; Rosado-allado, M.; Brito-Loeza, W.; Mena-
Rejon, G. J.; Quijano, L. Fitoterapia 2000, 71, 690 692; (f)
Astudillo, S. L.; Jurgens, S. K.; SchmedaHirschmann, G.; Griffith, G.
A.; Holt, D. H.; Jenkins, P. R. Planta Med. 1999, 65, 161 162; (g)
Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59,
3575 3584; (h) Aguinaldo, A. M.; Read, R. W. Phytochemistry 1990
29, 2309 2313; (i) Ahmad, A.; Khan, K. A.; Ahmad, V. U.; Qazi, S.
Planta Med. 1986, 4, 285 288; (j) Fodor, G. B.; Colasanti, B. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; Wiley: New York, 1985; Vol. 3, Chapter 1, pp. 1 90; (k) Fodor,
G.; Fumeaux, J.-P.; Sankaran, V. Synthesis 1972, 464 472; (l)
Bourinet, P.; Quevauviller, A. Compt. Rend. Soc. Biol. 1968, 162,
1138 1140; (m) Bourinet, P.; Quevauviller, A. Ann. Pharm. Fr.
1968, 26, 787 796.
3. Selected recent references for synthesis, see: (a) Pijl, F. V. D.; Delft,
F. L. V.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2015, 4811 4829; (b)
Xiao, K.-J.; Wang, Y.; Huang, Y.-H.; Wang, X.-G.; Huang, P.-Q. J.
Org. Chem. 2013, 78, 8305 8311; (c) Wijdeven, M. A.; Willemsen,
J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2010, 2831 2844; (d)
−910; (b)
CH3OH); IR (neat): νmax 3445, 2924, 2854, 1660, 1127, 473 cm-
1
;
1H NMR (500 MHz, CDCl3) δ 6.22-6.11 (m, 2H,
−
=CH−CH=CH−CH=),
6.11-5.98
(m,
2H,
−
=CH−CH=CH−CH=), 5.73-5.66 (m, 1H, −CH2−CH=), 5.60
(dd, J = 15.2, 7.1 Hz, 1H, =CH−CHN), 3.23-3.14 (m, 2H, 6-
CH−N, CHOH), 2.57-2.50 (m, 1H, 2-CH−N), 2.25 (br s, 1H,
OH), 2.11-2.04 (m, 3H, =CH−CH2, CH2−CH2), 1.77-1.71 (m,
1H, CH2−CH2), 1.40-1.28 (m, 6H, CH2−CH2), 1.20 (d, J = 6.1
Hz, 3H, CH−CH3), 0.89 (t, J = 7.1 Hz, 3H, CH2−CH3); 13C
NMR (125 MHz, CDCl3) δ 135.6, 135.0, 132.9, 130.4, 130.1,
129.8, 73.6, 58.6, 58.3, 33.9, 32.4, 31.9, 31.4, 22.2, 18.9, 13.9;
MS (ESI): m/z 250 (M+H)+; HRMS (ESI): m/z calcd for
C16H28NO (M+H)+, 250.2165; found 250.2180.
−
−
−
−
,
−
−
−
−
Acknowledgements
−
The authors thank Council of Scientific and Industrial Research
(CSIR)-New Delhi for the award of research fellowship to BL
and KW, and for financial support as part of XII-five year plan
project under title ORIGIN (CSC-0108).
−
−
−
−
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DOI: 10.1039/C5OB02P08a5gAe 8 of 9
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Journal Name
829
4833
Huang, P.-Q. J. Org. Chem. 2004, 69, 6001; (f) Maa, D.; Ma, N. 12. Experimental procedures for preparation of the conjugated alcohol
−
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8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

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DOI: 10.1039/C5OB02085A
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Journal Name
Organic & Biomolecular Chemistry
ARTICLE
Graphical Abstract
Total synthesis of a piperidine alkaloid, Microcosamine A
Chada Raji Reddy* and Bellamkonda Latha, Kamalkishore Warudikar and Kiran Kumar Singarapu
The first total synthesis of a novel piperidine alkaloid, microcosamine A, is achieved from commercially available D-serine, D-methyl lactate
and 1-octyne as starting materials.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9