Total synthesis of the 2,6-disubstituted piperidine alkaloid (-)-andrachcinidine

Article abstract of DOI:10.1016/j.tetasy.2013.05.004

The total synthesis of the 2,6-disubstituted piperidine alkaloid (-)-andrachcinidine is reported using Keck's asymmetric allylation, Sharpless epoxidation, nucleophilic substitution, and intramolecular aza-Michael addition as the key steps.

Full text of DOI:10.1016/j.tetasy.2013.05.004

Tetrahedron: Asymmetry 24 (2013) 758–763
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of the 2,6-disubstituted piperidine alkaloid (ꢀ)-
andrachcinidine
⇑
Palakodety Radha Krishna , Bonepally Karunakar Reddy
D-211, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of the 2,6-disubstituted piperidine alkaloid (ꢀ)-andrachcinidine is reported using
Keck’s asymmetric allylation, Sharpless epoxidation, nucleophilic substitution, and intramolecular aza-
Michael addition as the key steps.
Received 15 April 2013
Accepted 10 May 2013
Available online 6 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
ring. An asymmetric allylation, Sharpless epoxidation and nucleo-
philic substitution were the other key reactions employed to build
Natural alkaloid products, which contain a piperidine ring skel-
eton, are of great importance due to their potential biological activ-
ities.1 Some piperidine derivatives are in clinical and preclinical
studies.2 The development of new methods for the synthesis of
the piperidine ring skeleton is also important due to it being pres-
ent in a large number of alkaloid natural products.3
the requisite carbon chain as well as the stereogenic centers.
2. Results and discussions
Retrosynthetic analysis (Scheme 1) revealed that the synthesis
of target compound (ꢀ)-andrachcinidine 1 could be obtained from
(ꢀ)-Andrachcinidine 1 is a 2,6-disubstituted piperidine alkaloid
that is isolated from Andrachne aspera spreng along with other
piperidine alkaloids.4 The plant Andrachne aspera spreng is a small
perennial commonly found under shrubs in Karachi. The crude
alkaloidal mixture showed activity in various biological tests with
predominant antibacterial activity.5 Chutian et al. reported on the
first total synthesis of 1 by employing the desymmetrization of a
a
,b-unsaturated ketone 14 via an intramolecular aza-Michael addi-
tion reaction9,10 and hydrogenation reactions;
a,b-unsaturated ke-
tone 14 could be obtained from alcohol 10 using an oxidation/
Wittig olefination/saturation/reduction reaction set, followed by
oxidation and Wittig olefination reactions; alcohol 10 was synthe-
sized from compound 9 by a reduction and benzyl carbamate pro-
tection, compound 9 could be generated from compound 6
followed by regioselective 1,3-epoxide ring opening reaction and
general functional group transformations. Epoxy alcohol 6 could
be generated from homoallylic alcohol 2 by a one-pot dihydroxyla-
tion, oxidative cleavage followed by Wittig olefination, reduction,
and Sharpless asymmetric epoxidation reactions, and the homoal-
lylic alcohol 2 could be synthesized from n-butyraldehyde using
Keck’s asymmetric allylation reaction.11
meso-g
-(3,4,5)-dihydropyridinylmolybdenum complex,6 Hyung
et al. reported on (+)-andrachcinidine using gold-catalyzed synthe-
sis from alkynyl ethers.7 Recently we reported on its synthesis
using cross-metathesis and nucleophilic substitution reactions as
the key steps.8
OH
O
Our envisaged synthetic strategy (Scheme 2) started from com-
mercially available n-butyraldehyde, which upon Keck’s asymmet-
ric allylation11 {(R,R)-BINOL, 4 Å MS, Ti(OiPr)4, allyltri-n-butyltin,
CH2Cl2, ꢀ78 to ꢀ20 °C, 24 h} gave homoallylic alcohol 2 (82%);
its ee was found to be 97% (as determined by chiral HPLC: Chiralcel
N
H
(-)-andrachcinidine 1
However, due to its potent biological activity and interesting
cis-2,6-disubstituted piperidine core skeleton, we revisited the
synthesis of 1, by using a linear synthetic strategy wherein a highly
diastereoselective intramolecular aza-Michael addition strategy
was used as the crucial reaction for construction of the piperidine
i
OBH; PrOH/hexane, 1:99).11 Homoallylic alcohol 211b,c was pro-
tected as its benzyl ether (BnBr, NaH, THF, 0 °C to rt, 4 h) to yield
compound 3 (93%).11b,c Compound 3 upon one-pot dihydroxylation
and oxidative cleavage {OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane:H2O
(3:1), rt, 4.5 h}, followed by Wittig olefination (Ph3P@CHCO2Et,
CH2Cl2, 0 °C to rt, 5 h) furnished the
a,b-unsaturated ester 4 (75%
yield over two steps). Ester 4 was further reduced (DIBAL-H,
CH2Cl2, 0 °C, 2 h) to allylic alcohol 5 (82%). Allylic alcohol 5 was
⇑
Corresponding author. Tel.: +91 4027193158; fax: +91 4027160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.004

P. Radha Krishna, B. K. Reddy / Tetrahedron: Asymmetry 24 (2013) 758–763
759
OH
O
OBn NHCbz
OBn NHCbz
O
N
H
1
OH
14
10
OH
2
OBn N3
OBn
O
OBz
OH
6
9
Scheme 1. Retrosynthetic analysis of (ꢀ)-andrachcinidine.
OBn
OH
OBn
O
a
b
c
f
n-Butyraldehyde
OEt
OH
2
3
4
OBn
OBn
OBn OH
O
e
d
OH
OH
5
6
7
OBn N3
OBn NHCbz
OBn OH
g
h
i
OBz
OH
OBz
10
8
9
OBn NHCbz
O
OBn NHCbz
O
k
j
l
OEt
OEt
11
12
OBn NHCbz
OBn
O
OBn NHCbz
O
m
n
OH
N
Cbz
13
15
14
OH
O
o
N
H
1
Scheme 2. (a) (R,R)-BINOL, 4 Å MS, Ti(OiPr)4, allyltri-n-butyltin, CH2Cl2, ꢀ78 to ꢀ20 °C, 24 h, 82%; (b) BnBr, NaH, THF, 0 °C to rt, 4 h, 93%; (c) (i) OsO4, NaIO4, 2,6-lutidine, 1,4-
dioxane:H2O (3:1), rt, 4.5 h; (ii) Ph3P@CHCO2Et, CH2Cl2, 0 °C to rt, 5 h, 75% (over two steps); (d) DIBAL-H, CH2Cl2, 0 °C, 2 h, 82%; (e) (ꢀ)-DIPT, Ti(OiPr)4, CHP, CH2Cl2, ꢀ20 °C,
12 h, 84%; (f) Red-Al, THF, 0 °C, 5 h, 80%; (g) Bz-Cl, Et3N, CH2Cl2, 0 °C to rt, 6 h, 92%; (h) (i) Mesyl chloride, Et3N, 0 °C, 1 h; (ii) NaN3, DMF, 50 °C, 5 h, 78%, (over two steps); (i) (i)
LiAlH4, THF, 0 °C, 2 h; (ii) Cbz-Cl, NaHCO3, EtOAc:H2O (1:1), 0 °C to rt, 5 h, 72% (over two steps); (j) (i) IBX, DMSO, CH2Cl2, rt, 8 h; (ii) Ph3P@CHCO2Et, CH2Cl2, 0 °C to rt, 5 h, 85%;
(k) NiCl2ꢁ6H2O, NaBH4, MeOH, 0 °C, 1 h, 92%; (l) DIBAL-H, CH2Cl2, 0 °C, 2 h, 76%; (m) IBX, DMSO, CH2Cl2, rt, 6 h; (ii) 1-(Triphenylphosphoranylidene)-2-propanone, THF, 65 °C,
i
12 h, 72% (over two steps); (n) (i) TFA, PrOH, 65 °C, 6 h; (ii) Cbz-Cl, NaHCO3, EtOAc:H2O (1:1), 0 °C to rt, 6 h, 60% (over two steps); (o) Pd/C, H2, MeOH, 12 h, 89%
converted into epoxy alcohol 6 under Sharpless asymmetric epox-
idation conditions {(ꢀ)-DIPT, Ti(OiPr)4, CHP, CH2Cl2, ꢀ20 °C, 12 h}
to give 6 in 84% yield; its diastereoselectivity was measured by
LCMS (dr, 95.414:4.586) {Column: XDB-C18, acetonitrile/water
(80:20)}. Next, epoxy alcohol 6 was subjected to a regioselective
ring opening reaction using Red-Al (Red-Al, THF, 0 °C, 5 h) to afford
1,3-diol 7 in 80% yield. The thus obtained 1, 3-diol 7 was then sub-
jected to a selective primary benzoylation reaction (Bz-Cl, Et3N,
CH2Cl2, 0 °C to rt, 6 h, 92%) to afford hydroxy benzoyl ester 8. Com-
pound 8 upon mesylation (mesyl chloride, Et3N, 0 °C, 1 h) followed
by nucleophilic substitution with azide (NaN3, DMF, 50 °C, 5 h, 78%,
over two steps) in an SN2 fashion gave azide 9. In order to obtain

760
P. Radha Krishna, B. K. Reddy / Tetrahedron: Asymmetry 24 (2013) 758–763
the hydroxy benzyl carbamate functionality, we planned to reduce
both the ester and azide functional groups in one-pot under LAH
reaction conditions (LiAlH4, THF, 0 °C, 2 h) to give the
aminoalcohol, which could then be transformed into a carbamate
{Cbz-Cl, NaHCO3, EtOAc:H2O (1:1), 0 °C to rt, 5 h} with protection
of the amine functionality to selectively furnish the hydroxy benzyl
carbamate 10 (72% yield over two steps). The hydroxy carbamate
10 was subjected to oxidation (IBX, DMSO, CH2Cl2, rt, 8 h) followed
by Wittig olefination (Ph3P@CHCO2Et, CH2Cl2, 0 °C to rt, 5 h) to
4.1.1. (S)-Hept-1-en-4-ol 2
A mixture of (R,R)-BINOL (5.04 g, 16.56 mmol) and Ti(OiPr)4
(5.04 mL, 16.56 mmol) in CH2Cl2 (120.0 mL) in the presence of
4 Å molecular sieves (12.0 g) was stirred at reflux. After 1 h, the
reaction mixture was cooled to room temperature and the com-
mercially available butyraldehyde (12.0 g, 165.6 mmol) in CH2Cl2
(60.0 mL) was added and stirred for a further 10 min. The reaction
mixture was then cooled to ꢀ78 °C, allyltri-n-butyltin (56.88 mL,
183.36 mmol) was added and the stirring continued at ꢀ20 °C for
24 h. Next, satd aq NaHCO3 solution (180.0 mL) was added to
quench the reaction mixture, which was then stirred for an addi-
tional 30 min and then extracted with CH2Cl2 (2 ꢂ 200.0 mL). The
organic phase was washed with water (100.0 mL), dried (Na2SO4),
and the solvent was evaporated and the residue was purified by
column chromatography (Silica gel, 60–120 mesh, Rf 0.75, EtOAc/
n-hexane 1:9) to give 2 (15.6 g, 82%) as a clear oil (ee was found
afford
a,b-unsaturated ester 11 (85% yield over two steps). The
olefin in compound 11 was saturated by selective reduction
(NiCl2ꢁ6H2O, NaBH4, MeOH, 0 °C, 1 h) to furnish ester 12 (92%).
The ester was reduced to alcohol 13 (DIBAL-H, CH2Cl2, 0 °C, 2 h,
76%), followed by oxidation (IBX, DMSO, CH2Cl2, rt, 6 h) and Wittig
olefination [1-(triphenyl phosphoronylidene)-2-propanone/THF/
reflux] to give the
over two steps).
a,b-unsaturated keto carbamate 14 (72% yield
i
to be 97%, determined by chiral HPLC: Chiralcel OBH; PrOH/hex-
With the
a
,b-unsaturated keto carbamate 14 in hand, our next
ane, 1:99).
½
a 2D5
ꢃ
¼ þ22:8 (c 0.65, CHCl3); 1H NMR (CDCl3,
step was to synthesize the piperidine ring skeleton using an intra-
molecular aza-Mchael addition reaction.9 Accordingly, the key step
was attempted under acidic conditions in a protic solvent (TFA, iso-
propanol, 65 °C, 6 h) to produce the piperidine derivative, which
was reprotected as its benzyl carbamate {Cbz-Cl, NaHCO3, EtOAc/
H2O (1:1), 0 °C to rt, 5 h} to afford the 2,6-disubstituted derivative
exclusively as the cis-isomer 15 (69%), whose diastereoselectivity
was measured by LCMS {Column: XDB-C18, acetonitrile/water
(70:30)}. Its structure was confirmed by 1H NMR, 13C NMR and
NOE experiments. Global deprotection of the benzylether group
and benzyl carbamate under hydrogenation reaction conditions
(Pd/C, H2, MeOH, 12 h) on compound 15 furnished the target com-
pound (ꢀ)-andrachcinidine 1 (89%) whose data matched with the
data of natural4 as well as the reported data.6–8
300 MHz): d 5.87–5.72 (m, 1H), 5.14–5.08 (m, 2H), 3.66–3.58 (m,
1H), 2.32–2.23 (m, 1H), 2.16–2.06 (m, 1H), 1.51–1.33 (m, 4H),
0.94 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): 134.9, 118.1,
70.4, 42.2, 38.9, 18.7 14.1; IR (Neat) tmax 3330, 3055, 1620, 1497,
1208, 769, 732 cmꢀ1; EIMS (m/z): [M]+ 114.
4.1.2. (S)-((Hept-1-en-4-yloxy)methyl)benzene 3
To a cooled (0 °C) suspension of NaH (5.89 g, 147.37 mmol, 60%
w/w dispersion in paraffin oil) in THF (100.0 mL), a solution of (S)-
hept-1-en-4-ol 2 (14.0 g, 122.8 mmol) in THF (20.0 mL) was added
dropwise. After 15 min. BnBr (16.04 mL, 135.09 mmol) was added
dropwise at 0 °C and stirred for 4 h. at room temperature. The reac-
tion mixture was quenched with satd aq NH4Cl solution (120.0 mL)
and extracted with EtOAc (2 ꢂ 200.0 mL). The combined organic
layers were washed with water (100.0 mL), brine (80.0 mL), dried
(Na2SO4), and evaporated. The crude product was purified by col-
umn chromatography (Silica gel 60–120 mesh, Rf 0.90, EtOAc/n-
hexane, 1:19) to afford 3 (21.46 g, 93%) as a colorless liquid.
3. Conclusion
In conclusion, we have reported on the total synthesis of (ꢀ)-
andrachcinidine 1 via a linear strategy using asymmetric allylation,
Sharpless epoxidation, regioselective epoxide opening, nucleo-
philic substitution reaction and intramolecular aza-Michael addi-
tion reaction as the key steps. This strategy is general and
amenable for the synthesis of related aza-analogues by changing
the Michael acceptor moiety of the skeleton via the Wittig olefin-
ation reaction.
½
a 2D5
ꢃ
¼ ꢀ15:8 (c 0.59, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.32–
7.31 (m, 5H), 5.88–5.74 (m, 1H), 5.09–5.00 (m, 2H), 4.50 (dd,
J = 11.5 Hz, 2H), 3.44–3.37 (m, 1H), 2.30 (br s, 2H), 1.54–1.24 (m,
4H), 0.90 (t, J = 6.9 Hz, 3H); 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;
IR (Neat) tmax 3060, 2890, 1610, 1475, 1160, 810, 735 cmꢀ1
.
4.1.3. (S,E)-Ethyl 5-(benzyloxy)oct-2-enoate 4
To a stirred solution of 3 (20.0 g, 106.38 mmol) in 1,4-dioxane/
H2O (3:1, 150.0 mL) at 0 °C was added OsO4 (15.0 mL, 0.5 M in tol-
uene) drop wise. After 5 min. 2,6-lutidine (14.71 mL, 127.66 mmol)
and NaIO4 (34.13 g, 159.57 mmol) were added at 0 °C and stirred
for 4.5 h at rt. The reaction mixture was quenched with Na2SO3
(15.0 g) and extracted with EtOAc (2 ꢂ 100.0 mL). The combined
organic layers were washed with water (80.0 mL), brine
(50.0 mL), dried, (Na2SO4) and evaporated. The obtained crude
aldehyde was used directly for the next reaction.
4. Experimental
4.1. General
Column chromatography was performed on silica gel, Acme
grade 60–120 mesh. 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, optical rotations were measured with a
JASCO P-1020 instrument at 25 °C. 1H NMR and 13C NMR spectra
were recorded either on a Bruker 300 in CDCl3 as solvent with
TMS as reference unless otherwise indicated. Unless stated other-
wise, HRMS spectra were recorded on a QTOF analyser (QSTAR
XL, Applied Biosystems/MDS Sciex) at NCMS-IICT, Hyderabad. Un-
less stated otherwise, Elemental Analysis was carried on a Vario
Micro Cube Elementar at the Analytical Chemistry Division CSIR-
IICT, Hyderabad. The software ACD/Name Version 1.0, developed
by M/s Advanced Chemistry Development Inc., Toronto, Canada,
assisted nomenclature was used in the experimental section. Un-
less stated otherwise, all reactions were performed under an inert
atmosphere.
To a solution of aldehyde (16.5 g, 88.71 mmol) in CH2Cl2 was
added
(ethoxycarbonylmethylene)
triphenyl
phosphorane
(Ph3P@CHCO2Et) (37.04 g, 106.45 mmol) at 0 °C and allowed to stir
at room temperature for approximately 5 h, after which the solvent
was evaporated and adsorbed on silica, purified by column chro-
matography (Silica gel 60–120, Rf 0.8, EtOAc/n-hexane 1:9) to af-
ford the
a,b-unsaturated ester 4 (22.0 g, 75%) over two steps as a
colorless syrup. ½a D25
ꢃ
¼ ꢀ10:1 (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz): d 7.24–7.37 (m, 5H), 6.99 (dt, J = 7.2, 15.1 Hz, 1H),
5.88 (d, J = 15.5 Hz, 1H), 4.52 (dd, J = 6.8, 11.3 Hz, 2H), 4.19 (q,
J = 7.2 Hz, 2H), 3.52 (qt, J = 5.3 Hz, 1H), 2.45 (t, J = 6.4 Hz, 2H),
1.26–1.77 (m, 7H), 0.90 (t, J = 6.4 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 166.4, 145.4, 138.5, 128.3, 127.7, 127.5, 123.4, 77.6,

P. Radha Krishna, B. K. Reddy / Tetrahedron: Asymmetry 24 (2013) 758–763
761
71.1, 60.2, 36.8, 36.3, 18.6, 14.2, 14.1; IR (Neat) tmax 3035, 1720,
1630, 1210 cmꢀ1; HRESIMS (m/z): Calcd for C17H25O3 [M+H]+
277.1798, found 277.1797, Calcd for C17H29NO3 [M+NH4]+
294.2064. Found: 294.2060.
(dd, J = 11.3, 17.7 Hz, 2H), 4.19 (td, J = 2.3, 8.9 Hz, 1H), 3.83 (q,
J = 4.5 Hz, 2H), 3.69–3.77 (m, 1H), 3.51 (d, J = 2.1 Hz, 1H), 2.76–
2.84 (br s, 1H), 1.47–1.89 (m, 6H), 1.29–1.43 (m, 2H), 0.93 (t,
J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 138.1, 128.5, 127.9,
127.8, 77.0, 71.2, 69.2, 61.8, 39.6, 38.7, 35.5, 18.7, 14.2; IR (Neat)
tmax 3500, 3400, 3050, 1590, 1250 cmꢀ1; HRESIMS (m/z): Calcd
for C15H25O3 [M+H]+ 253.1798. Found: 253.1794.
4.1.4. (S,E)-5-(Benzyloxy)oct-2-en-1-ol 5
To a stirred solution of ester 4 (18.0 g, 65.22 mmol) in dry
CH2Cl2 (150.0 mL), DIBAL-H (102.0 mL, 143.48 mmol, 20% solution
in hexane) was added at 0 °C and stirred at the same temperature
for 2 h. Methanol (12.0 mL) was then added to the reaction mixture
at 0 °C and stirred for 10 min. Next, a satd aq solution of sodium
potassium tartrate (30.0 mL) was added and after 10 min methanol
was evaporated. The reaction mixture was diluted with water
(80.0 mL) and extracted with dichloromethane (2 ꢂ 100.0 mL).
The combined organic layers were washed with brine (40.0 mL),
dried (Na2SO4), concentrated, and the residue purified by column
chromatography (Silica gel 60–120, Rf 0.50, EtOAc/n-hexane 2:8)
to afford allylic alcohol 5 (12.5 g, 82%) as a colorless syrup.
4.1.7. (3S,5S)-5-(Benzyloxy)-3-hydroxyoctyl benzoate 8
To
a well stirred and cooled (0 °C) solution of 7 (6.0 g,
23.8 mmol) and Et3N (6.59 mL, 47.62 mmol) in CH2Cl2 (120.0 mL)
was added benzoyl chloride (2.77 mL, 23.80 mmol) over 40 min.
After the completion of the reaction, the reaction mixture was
poured into water, the organic layer was separated and the aque-
ous layer was extracted with CHCl3 (2 ꢂ 50.0 mL). The combined
organic extracts were washed with water (2 ꢂ 20.0 mL), brine
(50.0 mL), dried, and evaporated. The crude product was purified
by column chromatography (Silica gel 60–120 mesh, Rf 0.70,
EtOAc/n-hexane, 1.5:8.5) to obtain hydroxyl benzoate 8 (7.80 g,
½
a 2D5
ꢃ
¼ þ3:2 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.26–
7.38 (m, 5H), 5.68–5.73 (m, 2H), 4.52 (dd, J = 7.9, 11.3 Hz, 2H),
4.07 (d, J = 3.0 Hz, 2H), 3.44 (qt, J = 5.3 Hz, 1H), 2.31 (t, J = 5.3 Hz,
2H), 1.68–1.83 (br s, 1H), 1.25–1.60 (m, 4H), 0.90 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 138.8, 131.4, 128.9, 128.3,
127.7, 127.4, 78.3, 70.9, 63.5, 36.5, 36.0, 18.6, 14.1; IR (Neat) tmax
92%) as a colorless liquid. ½a D25
ꢃ
¼ þ8:6 (c 0.5, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 8.03–8.05 (m, 2H), 7.54–7.60 (m, 1H), 7.41–
7.50 (m, 2H), 7.25–7.30 (m, 5H), 4.36–4.61 (m, 4H), 4.09 (tt,
J = 2.8, 8.5 Hz, 1H), 3.74 (tt, J = 3.4, 6.6 Hz, 1H), 1.61–1.91 (m, 5H),
1.31–1.58 (m, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 166.8, 138.2, 132.9, 129.5, 128.4, 128.3, 127.9, 127.7,
76.4, 71.2, 65.2, 62.0, 40.1, 36.6, 35.6, 18.6, 14.2; IR (Neat) tmax
3500, 3040, 1740, 1610, 1550, 1240 cmꢀ1; HRESIMS (m/z): Calcd
3450, 3020, 1590, 1560 cmꢀ1
15H26NO2 [M+NH4]+ 252.1958. Found 252.1958.
; HRESIMS (m/z): Calcd for
C
4.1.5. ((2R,3R)-3-((S)-2-(Benzyloxy)pentyl)oxiran-2-yl)methanol
6
for
C
C
22H29O4 [M+H]+ 357.2060, found 357.2055, Calcd for
22H28O4Na[M+Na]+ 378.1879. Found: 378.1874.
To a suspension of thoroughly dried molecular sieves 4 Å (4.8 g)
in dry CH2Cl2 (80.0 mL) was added (ꢀ)-DIPT (2.4 g, 10.26 mmol),
followed by the slow addition of Ti(OiPr)4 (1.5 mL, 5.1 mmol) at
ꢀ20 °C. After stirring for 30 min, cumene hydroperoxide
(10.7 mL, 56.4 mmol, 80% in cumene) was added slowly and the
resulting solution was stirred at ꢀ20 °C for a further 30 min. Allylic
alcohol 5 (12.0 g, 51.2 mmol) in CH2Cl2 (30.0 mL) was then added
and the reaction mixture was stirred at ꢀ20 °C for 12 h, then
warmed up to 0 °C, and quenched with an aq. basic solution
(6.0 g NaOH in 60.0 mL of brine). After stirring for 1 h, the reaction
mixture was filtered through a pad of Celite and the pad was fur-
ther washed with CH2Cl2. The filtrate was concentrated and puri-
fied by column chromatography (Silica gel 60–120 mesh, Rf 0.30,
EtOAc/n-hexane 3:7) to afford hydroxy epoxide 6 (10.76 g, 84%)
as a colorless oil (diastereoselectivity was measured by LCMS (dr,
95.414:4.586) {Column: XDB-C18, acetonitrile/water (80:20)}.
4.1.8. (3R,5S)-3-Azido-5-(benzyloxy)octyl benzoate 9
To a stirred solution of alcohol 8 (5.1 g, 14.33 mmol) in CH2Cl2
(55.0 mL), were added Et3N (3.96 mL, 28.66 mmol) and methane-
sulfonyl chloride (1.11 mL, 15.76 mmol) at 0 °C after which the
mixture was allowed to stir at 0 °C for 1 h. After completion of
reaction, the reaction mixture was diluted with CH2Cl2 (20.0 mL),
washed with satd NaHCO3 (1 ꢂ 15.0 mL), 1 M HCl (1 ꢂ 15.0 mL),
and water (2 ꢂ 20.0 mL) and brine solution (1 ꢂ 16.0 mL). The
CH2Cl2 layer was dried over anhydrous Na2SO4. The reaction mix-
ture was then concentrated under reduced pressure and the crude
mesylate was used as such without further purification.
To a stirred solution of the above mesylate in dry DMF
(25.0 mL), was added NaN3 (1.40 g, 21.49 mmol) after which the
mixture was heated to 55 °C and stirring continued for 5 h. After
completion of the reaction, the reaction mixture was extracted
with EtOAc/n-hexane (6:4) (2 ꢂ 35.0 mL), the organic phase was
washed with brine (20.0 mL), dried (Na2SO4), the solvent was
evaporated, and the residue was purified by column chromatogra-
phy (Silica gel, 60–120 mesh, Rf 0.90, EtOAc/n-hexane 1:19) to af-
½
a 2D5
ꢃ
¼ þ43:5 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.25–
7.34 (m, 5H), 4.55 (dd, J = 11.3, 15.5 Hz, 2H), 3.86 (d, J = 12.1 Hz,
1H), 3.54–3.66 (m, 2H), 3.07–3.12 (m, 1H), 2.90–2.95 (m, 1H),
2.11–2.26 (br s, 1H), 1.26–1.98 (m, 6H), 0.92 (t, J = 7.2 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d 138.5, 128.3, 127.7, 127.5, 76.6, 71.3,
61.7, 59.0, 53.5, 36.6, 36.5, 18.3, 14.1; IR (Neat) tmax 3500, 3025,
1610, 1580 cmꢀ1; HRESIMS (m/z): Calcd for C15H23O3 [M+H]+
251.1642, found 251.1640, Calcd for C15H26NO3 [M + NH4]+
268.1913. Found: 268.1906.
ford
9 (4.26 g, 78% over two steps) as a colorless syrup.
½
a 2D5
ꢃ
¼ þ31:4 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 8.05
(dd, J = 1.2, 7.1 Hz, 2H), 7.6 (tt, J = 1.2, 8.6 Hz, 1H), 7.41–7.46 (m,
2H), 7.27–7.34 (m, 5H), 4.37–4.60 (m, 4H), 3.72 (tt, J = 4.2,
11.0 Hz, 1H), 3.57 (qt, J = 5.4 Hz, 1H), 1.97–2.09 (m, 2H), 1.82–
1.90 (m, 1H), 1.53–1.77 (m, 3H), 1.38–1.48 (m, 2H), 0.95 (t,
J = 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 166.3, 138.3, 132.9,
133.0, 129.5, 128.3, 127.7, 127.6, 75.4, 70.8, 61.6, 56.7, 38.5, 35.8,
33.1, 18.2, 14.2; IR (Neat) tmax 3040, 3010, 2150, 1730, 1640,
1580, 1090 cmꢀ1; HRESIMS (m/z): Calcd for C22H28N3O3 [M+H]+
382.2125. Found: 382.2127. Calcd for C22H31N4O3 [M+NH4]+
399.2396. Found: 399.2388.
4.1.6. (3S,5S)-5-(Benzyloxy)octane-1,3-diol 7
To a stirred solution of epoxide 6 (9.0 g, 36.0 mmol) in dry THF
(90.0 mL) was added Red-Al (18.2 mL, 54.0 mmol, 60 wt % in tolu-
ene) at 0 °C. After 5 h the reaction mixture was quenched with sat.
Na2SO4 solution (15 mL) and filtered through a Celite pad. The res-
idue was washed with EtOAc (2 ꢂ 150 mL) and the combined or-
ganic layers were dried over anhydrous Na2SO4 and
concentrated. The crude product was purified by column chroma-
tography (Silica gel 60–120 mesh, Rf 0.2, EtOAc/n-hexane, 4:6) to
4.1.9. Benzyl (3R,5S)-5-(benzyloxy)-1-hydroxyoctan-3-ylcarb-
amate 10
To a stirred solution of LAH (0.39 g, 11.14 mmol) in dry THF
(35.0 mL) at 0 °C was added compound 9 (4.2 g, 11.02 mmol) in
obtain 1,3-diol 7 (7.2 g, 80%) as a colorless liquid. ½a D25
ꢃ
¼ þ27:4 (c
0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.29–7.37 (m, 5H), 4.56

762
P. Radha Krishna, B. K. Reddy / Tetrahedron: Asymmetry 24 (2013) 758–763
THF (10.0 mL) and the reaction allowed to stir at rt for 2 h. The
reaction mixture was then quenched with satd aq Na2SO4
(10.0 mL) at 0 °C, filtered through a Celite pad, and the Celite pad
was washed with ethyl acetate (30.0 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated. The crude product
was used for the next reaction without further purification.
To the above compound (2.5 g, 9.96 mmol) was added EtOAc/
water (1:1, 20.0 mL), followed by Cbz-Cl (1.49 mL, 10.49 mmol)
at 0 °C and stirred for 5 h. at room temperature. After completion
of the reaction, the reaction mixture was diluted with ethyl acetate
(20.0 mL) and extracted with ethyl acetate (2 ꢂ 10.0 mL). The com-
bined organic layers were washed with brine (15.0 mL), dried
(Na2SO4), and the solvent was evaporated under reduced pressure.
The residue was purified by column chromatography (Silica gel,
60–120 mesh, Rf 0.60, EtOAc/n-hexane 3:7) to afford 10 (3.05 g,
60–120 mesh, Rf 0.8, EtOAc:n-hexane, 1:9) to obtain 12 (2.31 g,
92%) as a colorless liquid. ½a D25
ꢃ
¼ þ14:7 (c 1.0, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 7.24–7.36 (m, 10H), 5.06 (s, 2H), 4.89 (d,
J = 7.93 Hz, 1H), 4.42 (2 ꢂ d, AB pattern, J = 11.1 Hz, 2H), 4.10 (q,
J = 7.0 Hz, 2H), 3.65–3.78 (m, 1H), 3.45 (qt, J = 5.7 Hz, 1H), 2.19–
2.35 (m, 2H), 1.31–1.71 (m, 10H), 1.24 (t, J = 7.2 Hz, 3H), 0.91 (t,
J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 173.2, 156.1, 138.4,
136.5, 128.4, 128.3, 128.0, 127.9, 127.5, 76.9, 70.6, 66.5, 60.3,
49.6, 39.2, 35.6, 35.1, 34.0, 20.9, 18.1, 14.2; IR (Neat) tmax 3600,
3030, 1750, 1640, 1610, 1070 cmꢀ1; HRESIMS (m/z): Calcd for
C
27H38NO5 [M+H]+ 456.2745. Found: 456.2728.
4.1.12. Benzyl (5R,7S)-7-(benzyloxy)-1-hydroxydecan-5-ylcarb-
amate 13
To a solution of 12 (2.0 g, 4.39 mmol) in dry CH2Cl2 (20.0 mL) at
0 °C, DIBAL-H (7.1 mL, 9.67 mmol, 20% solution in hexane) was
slowly added for 15 min. The reaction mixture was stirred at the
same temperature for 2 h, quenched with methanol (10.0 mL)
and sodium potassium tartrate solution (5.0 mL), after which it
was diluted with water (10.0 mL) and extracted with dichloro-
methane (2.0 ꢂ 25 mL). The combined organic layers were washed
with brine (10.0 mL), dried (Na2SO4), concentrated, and the residue
purified by column chromatography (Silica gel 60–120, Rf 0.40,
EtOAc/n-hexane, 2:8) to afford alcohol 13 (1.37 g, 76%) as a color-
72% over two steps) as a viscous liquid. ½a D25
¼ þ30:7 (c 1.0, CHCl3);
ꢃ
1H NMR (CDCl3, 300 MHz): d 7.26–7.34 (m, 10H), 5.06–5.18 (m,
3H), 4.43 (2 ꢂ d, AB pattern, J = 10.9 Hz, 2H), 3.87–4.03 (m, 1H),
3.31–3.71 (m, 4H), 1.22–1.90 (m, 8H), 0.92 (t, J = 7.0 Hz, 3H); 13C
NMR (CDCl3, 75 MHz): d 157.5, 138.2, 136.3, 128.5, 128.3, 128.2,
128.1, 128.0, 127.6, 70.8, 67.0, 58.6, 47.1, 39.6, 39.5, 35.9, 18.1,
14.2; IR (Neat) t
max 3650, 3480, 3020, 1640, 1590, 980 cmꢀ1; HRE-
SIMS (m/z): Calcd for C23H32NO4 [M+H]+ 386.2326. Found:
386.2327. Calcd for C23H31NO3Na [M + Na]+ 408.2145. Found:
408.2137.
less syrup. ½a 2D5
ꢃ
¼ þ20:7 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz):
d 7.25–7.35 (m, 10H), 5.07 (s, 2H), 4.85 (d, J = 7.9 Hz, 1H), 4.43
(2 ꢂ d, AB pattern, J = 11.1 Hz, 2H), 3.66–3.76 (m, 1H), 3.60 (t,
J = 5.9 Hz, 2H), 3.45 (qt, J = 5.7 Hz, 1H), 1.26–1.67 (m, 12H), 0.91
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 156.2, 138.5,
136.6, 128.5, 128.3, 128.1, 128.0, 127.9, 127.5, 70.6, 66.6, 62.7,
49.8, 39.3, 35.9, 35.7, 32.5, 21.8, 18.1, 14.2; IR (Neat) tmax 3650,
4.1.10. (5R,7S,E)-Ethyl 7-(benzyloxy)-5-(benzyloxycarbonylamino)
dec-2-enoate 11
To a stirred solution of compound 10 (3.0 g, 7.79 mmol), in
CH2Cl2 (30.0 mL) and dimethyl sulfoxide (1.0 mL, 12.82 mmol)
was added 2-iodoxy benzoic acid (2.62 g, 9.35 mmol) at 0 °C, and
stirred for 8 h. After completion of the reaction, the reaction mix-
ture was filtered through a Celite pad and washed with CH2Cl2
(30.0 mL). The organic layer was washed with satd aq NaHCO3
(15.0 mL). The organic layers were dried (Na2SO4) and concen-
trated under reduced pressure. The crude aldehyde was used for
the next reaction without further purification.
3400, 2990, 1650, 1610 cmꢀ1
25H36NO4 [M+H]+ 414.2639. Found: 414.2633.
; HRESIMS (m/z): Calcd for
C
4.1.13. Benzyl (4S,6R,E)-4-(benzyloxy)-12-oxotridec-10-en-6-
ylcarbamate 14
To a stirred solution of alcohol 13 (0.5 g, 1.21 mmol), in CH2Cl2
(0.5 mL) and dimethyl sulfoxide (0.38 mL, 19.38 mmol), was added
2-iodoxybenzoic acid (0.41 g, 1.45 mmol) at 0 °C and stirred for
6 h. After completion of the reaction, the reaction mixture was fil-
tered through a Celite pad and washed with CH2Cl2 (2 ꢂ 5.0 mL).
The organic layer was washed with satd aq NaHCO3 (1 ꢂ 5.0 mL).
The organic layers were dried (Na2SO4) and concentrated under re-
duced pressure. The crude aldehyde was used for the next reaction
without further purification.
To a solution of above obtained aldehyde (2.80 g, 7.31 mmol) in
CH2Cl2 (30.0 mL) was added (ethoxycarbonylmethylene)triphenyl
phosphorane (Ph3P@CHCO2Et) (3.25 g, 9.35 mmol) at 0 °C and al-
lowed to stir at room temperature for approximately 5 h. After
completion of the reaction, the solvent was evaporated, adsorbed
on silica, and purified by column chromatography (Silica gel 60–
120, Rf 0.70, EtOAc/n-hexane 1:9) to afford the a,b-unsaturated es-
ter 11 (2.99 g, 85% over two steps) as a pale yellow syrup.
½
a 2D5
ꢃ
¼ þ1:2 (c 0.33, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.25–
To a stirred solution of the above obtained aldehyde (0.47 g,
1.14 mmol) in dry THF (6.0 mL), was added 1-(triphenylphosphor-
anylidene)-2-propanone ylide (0.47 g, 1.49 mmol) and stirred at
reflux for 12 h. After completion of the reaction, the solvent was
evaporated under reduced pressure and the crude residue was
purified by column chromatography (Silica gel, 60–120 mesh, Rf
0.60, EtOAc/n-hexane, 2:8) to furnish compound 14 (0.40 g, 72%)
7.37 (m, 10H), 6.79–6.92 (m, 1H), 5.82 (d, J = 15.7 Hz, 1H), 5.04–
5.13 (m, 3H), 4.43, (2 ꢂ d AB pattern, J = 11.1 Hz, 2H), 4.18 (q,
J = 7.2 Hz, 2H), 3.86 (m, 1H), 3.47 (qt, J = 5.5 Hz, 1H), 2.36–2.50
(m, 2H), 1.53–1.71 (m, 5H), 1.25–1.41 (m, 4H), 0.92 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 166.5, 155.7, 144.2, 138.1,
128.6, 128.4, 128.1, 127.7, 124.3, 70.7, 66.5, 60.2, 49.2, 38.1, 37.8,
35.7, 17.9, 14.2; IR (Neat) tmax 3650, 3035, 1730, 1650, 1610,
as a colorless thick liquid. ½a D25
¼ þ13:6 (c 1.0, CHCl3); (two rota-
ꢃ
;
1080 cmꢀ1 HRESIMS (m/z): Calcd for C27H36NO5 [M + H]+
mers), 1H NMR (CDCl3, 300 MHz): d 7.28–7.40 (m, 10H), 6.70–
6.80 (m, 1H), 5.99–6.11 (m, 1H), 4.86–5.22 (m, 3H), 4.44 (2 ꢂ d,
AB pattern, J = 11.3 Hz, 2H), 3.66–3.85 (m, 1H), 3.46 (t, J = 6.6 Hz,
1H), 2.10–2.28 (m, 5H), 1.25–1.88 (m, 10H), 0.92 (t, J = 7.9 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 198.7, 166.4, 156.1, 147.8,
147.6, 138.5, 136.4, 136.3, 133.3, 132.9, 131.5, 130.1, 129.5,
128.5, 128.3, 128.0, 127.9, 127.5, 127.4, 72.3, 70.6, 69.9, 66.8,
66.5, 53.4, 49.6, 48.6, 39.6, 39.3, 36.3, 35.9, 35.4, 35.1, 32.2, 32.1,
29.7, 26.8, 24.2, 18.5, 18.1, 14.2, 13.6; IR (Neat) tmax 3680, 3040,
454.2588. Found: 454.2587.
4.1.11. (5R,7S)-Ethyl 7-(benzyloxy)-5-(benzyloxycarbonylamino)
decanoate 12
To a stirred solution of 11 (2.5 g, 5.52 mmol) and NiCl2ꢁ6H2O
(0.37 g, 1.10 mmol) in MeOH (30.0 mL) under an H2 atmosphere
at 0 °C, NaBH4 (0.20 g, 5.52 mmol) was added in small portions
(the solution turned black). After the addition was complete, the
reaction mixture was stirred at room temperature for 1 h. The
black precipitate formed was filtered through a Celite pad and
washed with EtOAc (3 ꢂ 20.0 mL). The solvent was evaporated
and the residue purified by column chromatography (silica gel,
1740, 1660, 1620, 1070 cmꢀ1
C
C
;
HRESIMS (m/z): Calcd for
28H38NO4 [M+H]+ 452.2795. Found: 452.2795, Calcd for
28H41N2O4 [M + NH4]+ 469.3061. Found: 469.3059.

P. Radha Krishna, B. K. Reddy / Tetrahedron: Asymmetry 24 (2013) 758–763
763
4.1.14. (2R,6S)-Benzyl 2-((S)-2-(benzyloxy)pentyl)-6-(2-oxopropyl)
piperidine-1-carboxylate 15
NH4OH) to obtain
1
(0.016 g, 89%) as
a
colorless liquid.
½
a 2D5
ꢃ
¼ ꢀ21:4 (c 0.5, CHCl3), lit.4
½
a 2D5
ꢃ
¼ ꢀ20:0 (c 1.6, CHCl3); 1H
To a stirred solution of compound 14 (0.20 g, 0.44 mmol) in iso-
propanol (2.0 mL) was added TFA (5.0 mL) and then heated at re-
flux for 6 h. at 65 °C. The solvent and TFA were then removed
under reduced pressure, the crude TFA salt was used as such in
the next step without further purification.
After 5 h, the reaction was brought to pH 8–9 using aq satd
NaHCO3 and the compound was extracted with CH2Cl2
(3 ꢂ 3.0 mL). The organic layer was dried over Na2SO4 and concen-
trated in vacuo to obtain a crude compound, which was used for
the next step without further purification.
NMR (CDCl3, 300 MHz): d 3.80–3.83 (m, 1H), 3.10–3.18 (m, 2H),
2.99–3.07 (m, 1H), 2.66 (m, 1H), 2.19 (m, 4H), 1.10–1.89 (m,
13H), 0.92 (t, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 207.0,
72.8, 58.9, 53.0, 49.1, 43.5, 39.7, 33.5, 32.2, 30.0, 24.0, 18.6, 14.1;
IR (Neat) tmax 3450, 3310, 2900, 1730, 1640 cmꢀ1; HRESIMS (m/
z): Calcd for C13H26NO2 [M+H]+ 228.1963. Found: 228.1972.
Acknowledgments
One of the authors (B.K.R) thanks the CSIR, New Delhi, for finan-
cial support in the form of a fellowship.
To the above obtained crude amine (0.095 g, 0.30 mmol) were
added EtOAc/water (1:1, 2.0 mL), then Cbz-Cl (0.05 mL, 0.33 mmol)
at 0 °C and stirred for 6 h at room temperature. After completion of
the reaction, the reaction mixture was diluted with ethyl acetate
and the combined organic layers were washed with brine
(5.0 mL), dried (Na2SO4), and the organic solvent was evaporated
under reduced pressure. The residue was purified by column chro-
matography (Silica gel, 60–120 mesh, Rf 0.95, EtOAc/n-hexane, 1:9)
to afford 15 (0.138 g, 69% over two steps) as a thick liquid {diaste-
reoselectivity was measured by LCMS, Column: XDB-C18, acetoni-
References
1. (a) Jones, T. H.; Blum, M. S. Alkaloids: Chemical and Biological Perspectives In
In Pelletier, S. W., Ed.; Wiley: New York, 1983; Vol. 1, pp 33–84. Chapter 2; (b)
Fodor, G. B.; Colasanti, B. Alkaloids: Chemical and Biological Perspectives In In
Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp 1–90. Chapter 1; (c)
Schneider, M. J. Alkaloids: Chemical and Biological Perspectives In In Pelletier,
S. W., Ed.; Wiley: New York, 1996; Vol. 10, pp 155–315. Chapter 3; (d) Strunz,
G. M.; Findlay, J. A. The Alkaloids In In Brossi, A., Ed.; Academic Press: London,
UK, 1985; Vol. 26, pp 89–183. Chapter 3; (e) Numata, A.; Ibuka, I. The Alkaloids
In In Brossi, A., Ed.; Academic Press: New York, 1987; Vol. 31, pp 193–315; (f)
Angle, R. S.; Breitenbucher, J. G. Studies in Natural Products Chemistry,
Stereoselective Synthesis (Part J) In In Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, The Netherlands, 1995; Vol. 16, pp 453–502.
2. (a) Felpin, F. X.; Lebreton, J. Curr. Org. Synth. 2004, 1, 83–109; (b) Lebrum, S.;
Couture, A.; Deniau, E.; Grandclaydon, P. Org. Lett. 2007, 9, 2473–2476.
3. O’Hagen, D. Nat. Prod. Rep. 1997, 14, 637–651.
4. Mill, S.; Hootele, C. J. Nat. Prod. 2000, 63, 762–764.
5. (a) Ahmed, V. Q.; Nasir, M. A. Phytochemistry 1986, 24, 2841–2844; (b) Ahmed,
V. Q.; Nasir, M. A. Phytochemistry 1987, 26, 585–586.
trile/water (70:30)}. ½a D25
ꢃ
¼ þ6:3 (c 0.5, CHCl3); 1H NMR (CDCl3,
300 MHz): d 7.23–7.35 (m, 10H), 5.09 (s, 2H), 4.49 (2 ꢂ d, AB pat-
tern, J = 11.6 Hz, 2H), 4.25–4.31 (br s, 1H), 4.06–4.13 (br s, 1H),
3.46 (qt, J = 6.1 Hz, 1H), 3.06–3.15 (m, 1H), 2.61 (dd, J = 7.9 Hz,
16.7, 1H), 2.35 (t, J = 7.2 Hz, 1H), 2.05–2.12 (m, 4H), 1.28–1.72
(m, 10H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d
206.8, 155.6, 138.9, 136.7, 128.4, 128.2, 127.9, 127.8, 127.7,
127.3, 76.2, 70.3, 66.7, 50.1, 48.2, 48.0, 36.4, 35.9, 30.1, 27.9,
26.1, 18.4, 16.7, 14.2; IR (Neat) tmax 3040, 2950, 1730, 1640,
6. Chutian, S.; Lanny, S. L. J. Am. Chem. Soc. 2003, 125, 2878–2879.
7. Jung, H. H.; Floreancig, P. E. J. Org. Chem. 2007, 72, 7359–7366.
8. Radha Krishna, P.; Dayaker, G. Tetrahedron Lett. 2007, 48, 7279–7282.
9. (a) Felpin, F. X.; Libreton, J. J. Org. Chem. 2002, 67, 9192; (b) Chandrasekhar, S.;
Babu, G. S. K.; Reddy, C. R. Tetrahedron: Asymmetry 2009, 20, 2216–2219; (c)
Chandrasekhar, S.; Murali, R. V. N. S.; Reddy, C. R. Tetrahedron Lett. 2009, 50,
5686–5688.
1580 cmꢀ1
;
HRESIMS (m/z): Calcd for C28H38NO4 [M+H]+
452.2795, found 452.2789. Calcd for C28H37NO4Na [M+Na]+
474.2615. Found: 474.2611.
10. Radha Krishna, P.; Sreeshailam, A.; Srinivas, R. Tetrahedron 2009, 65, 9657–
9672.
4.1.15. (ꢀ)-Andrachcinidine 1
To a stirred solution of compound 15 (0.035 g, 0.07 mmol) in
methanol (0.50 mL), 10.0 mg of 10% Pd/C was added and stirred
under an H2 atmosphere for 12 h. The reaction mixture was filtered
through a Celite pad and the filtrate was concentrated under re-
duced pressure, adsorbed onto silica, and purified by column chro-
matography (Silica gel 60–120 mesh, Rf 0.40, MeOH: CHCl3 1:9, 5%
11. (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467–
8468; (b) Radha Krishna, P.; Reddy, B. K. Tetrahedron 2012, 68, 841–845; (c)
Grove, C. I.; Maso, M. J. D.; Jaipuri, F. A.; Kim, M. B.; Shaw, J. T. Org. Lett. 2012,
14, 4338–4341; (d) Sabitha, G.; Yadagiri, K.; Swapna, R.; Yadav, J. S. Tetrahedron
Lett. 2009, 50, 5417–5419.