A stereoselective total synthesis of (-)-andrachcinidine via an olefin cross-metathesis protocol

Article abstract of DOI:10.1016/j.tetlet.2007.08.053

A stereoselective total synthesis of 1-(2S,6R)-6-[(2S)-2-hydroxypentyl]-hexahydro-2-pyridinylacetone, (-)-andrachcinidine is reported. The strategy utilizes olefin cross-metathesis and intramolecular S_N2 cyclization as the key steps.

Full text of DOI:10.1016/j.tetlet.2007.08.053

Tetrahedron Letters 48 (2007) 7279–7282
A stereoselective total synthesis of (ꢀ)-andrachcinidine via an
olefin cross-metathesis protocol
Palakodety Radha Krishna* and G. Dayaker
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 11 July 2007; revised 8 August 2007; accepted 13 August 2007
Available online 16 August 2007
Abstract—A stereoselective total synthesis of 1-(2S,6R)-6-[(2S)-2-hydroxypentyl]-hexahydro-2-pyridinylacetone, (ꢀ)-andrachcini-
dine is reported. The strategy utilizes olefin cross-metathesis and intramolecular SN2 cyclization as the key steps.
ꢀ 2007 Published by Elsevier Ltd.
The piperidine ring is a common structural feature
of numerous naturally occurring alkaloids and can be
frequently recognized in the structure of drug candi-
dates.1 Substituted five- or six-membered N-hetero-
cycles are found in numerous natural products and
pharmaceutical compounds and they continue to
attract considerable attention, due to their broad
and important biological activities. It is interesting to
note that over 12,000 piperidine derivatives have been
reported in clinical or preclinical studies in the last
decade.2
to chiral derivatives. Lanny and Chutian6 reported the
first synthesis of 1 using chiral auxiliary-induced pseu-
do-desymmetrization in the presence of molybdenum
complexes. In continuation of our interest in the synthe-
sis of piperidine-containing bioactive natural products,7
we report herein the stereoselective total synthesis of 1
using olefin cross-metathesis to prepare the requisite car-
bon chain with correctly disposed stereogenic centers
and functional groups and an intramolecular nucleo-
philic cyclization to construct the piperidine ring system
as the key step.
The plant Andrachne aspera spreng is a small perennial
undershrub commonly found in Karachi and is used in
the local system of medicine for the treatment of eye
sores and eye sight improvement. The crude alkaloidal
mixture was found to be biologically potent with pre-
dominantly antibacterial activity.3 A. aspera spreng
was previously shown to contain the piperidine alkaloids
andrachamine and andrachcine.3,4 Recently, two new
2,6-disubstituted piperidine alkaloids, namely, andra-
chcinine and (ꢀ)-andrachcinidine 1 have been isolated
from A. aspera spreng.5
Retrosynthetic analysis suggested that 1 could be ob-
tained from 2 by intramolecular SN2 cyclization and
functional group transformations. Compound 2 in turn
could be formed from 3 and 4 by olefin cross-metathesis,
hydrogenation, and mesylation reactions. Fragment 3
can be visualized from 5 by a regioselective ring opening
reaction of an epoxide and 1,3-anti chiral allylation.
Alkene 4 was conceived from Garner’s aldehyde by
Wittig olefination and hydroboration reactions.
The synthesis of fragment 3 began from known epoxide
5 (Scheme 1), which was readily obtained from trans-2-
hexenol.8 Regioselective ring-opening of 5 with Red-Al
in dry THF gave the corresponding 1,3-diol9 (80%),
which was converted into a benzylidene derivative with
benzaldehyde dimethyl acetal in CH2Cl2 using PTSA
(cat) to afford an acetal (95%), selective opening of
which with LAH–AlCl3 furnished benzyl protected pri-
mary alcohol 7 (90%). Alcohol 7 was oxidized under
Swern conditions and then allylated10 (TiCl4/allyltri-
methylsilane) to afford fragment 3 (de 90%, 80% yield
over the two steps) in favor of the 1,3-anti isomer.
The development of new methods for the synthesis of
pyrrolidine- or piperidine-based compounds is of con-
siderable importance, particularly approaches leading
Keywords: Garner’s aldehyde; Hydroboration; 1,3-anti Chiral allyla-
tion; Sharpless asymmetric epoxidation; Grubbs’ catalyst; Olefin cross-
metathesis; Intramolecular SN2 cyclization.
*
Corresponding author. Tel.: +91 40 27160123x2651; fax: +91 40
27160387; e-mail: prkgenius@iict.res.in
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.08.053

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P. Radha Krishna, G. Dayaker / Tetrahedron Letters 48 (2007) 7279–7282
Retrosynthetic route
NHBoc
OBn OMs
OH
O
OTBDPS
N
H
2
1
OBn OH
OTBDPS
NH-Boc
4
3
CHO
O
OH
O
N-Boc
5
6
Synthesis of fragment 3
OBn
OBn OH
O
a
b
OH
HO
OH
5
7
3
Synthesis of fragment 4
OH
CHO
c
NBoc
OTBDPS
OTBDPS
d
e
O
NBoc
O
NHBoc
NHBoc
9
4
8
6
Scheme 1. Reagents and conditions: (a) (i) Red-Al, THF, 0 ꢁC to rt, 80%, (ii) PhCH(OMe)2, CH2Cl2, PTSA (cat), rt, 95%, (iii) LAH–AlCl3, ether,
0 ꢁC, 90%; (b) (i) (COCl)2, DMSO, Et3N, ꢀ78 ꢁC, (ii) TiCl4, allyltrimethylsilane, CH2Cl2, ꢀ78 ꢁC, (80% over two steps); (c) (i) CH3 +PPh3Iꢀ, KOtBu,
THF, 0 ꢁC, 78%, (ii) (Cy)2BH, THF, 0 ꢁC, 95%; (d) (i) TBDPSCl, imidazole, CH2Cl2, rt, 95%, (ii) CuCl2Æ2H2O, CH3CN, 90%; (e) (i) (COCl)2,
DMSO, Et3N, ꢀ78 ꢁC, 95%, (ii) CH3 +PPh3Iꢀ, KOtBu, THF, 0 ꢁC, THF, 0 ꢁC, 66%.
The synthesis of fragment 4 started from Garner’s alde-
hyde11 6, which on Wittig olefination and hydroboration
with dicyclohexylborane [(Cy)2BH] afforded homolo-
gated primary alcohol 8 (95%) as the exclusive product.
Next, alcohol 8 was silylated (TBDPSCl/imidazole/
CH2Cl2/rt) and then exposed to CuCl2Æ2H2O12 in aceto-
nitrile to give the free alcohol 9 (90%). Oxidation of 9
under Swern conditions followed by Wittig olefination
furnished fragment 4.
15% to 80% (Table 1, Scheme 2). However, 11 could
be recycled effectively to the desired olefin 10 (75%) by
utilizing a cross-metathesis reaction with 4 under stan-
dardized reaction conditions (4:11 in a 2:1 ratio, Grub-
bs’ 2nd generation catalyst). Hydrogenation of 10
(PtO2–NaHCO3/H2) and subsequent mesylation of
resulting 2a [MsCl/Et3N/DMAP (cat)/ꢀ15 to 0 ꢁC]
afforded mesylate 2 in 80% yield. Boc deprotection
(TFA/CH2Cl2/0 ꢁC to rt) of 2 followed by intramole-
cular SN2 cyclization14 (K2CO3/CH3CN/rt) and Boc pro-
tection of the ensuing secondary amine [(Boc)2O/Et3N/
CH2Cl2/0 ꢁC to rt] afforded 2,6-disubstituted piperidine
derivative 12.
In order to access intermediate 10 (Scheme 2) we
adopted the olefin cross-metathesis strategy through
the coupling of fragments 3 and 4 using Grubbs’ cata-
lyst.13 Initially we attempted the reaction in CH2Cl2 or
toluene as the solvent in combination with Grubbs’ 1st
generation (A) or 2nd generation (B) catalysts. The best
yield of 10 (60%), was obtained when olefin cross-
metathesis was performed using 3 and 4 in 1:2 ratio with
Grubbs’ 2nd generation catalyst in toluene (Table 1,
entry 5). All the other results are tabulated.
Silyl deprotection of 12 (TBAF/THF/0 ꢁC to rt) and
Dess–Martin periodinane oxidation (DMP/CH2Cl2/
0 ꢁC to rt) followed by Grignard reaction (MeMgI/
ether) gave the corresponding secondary alcohol, which
on further oxidation with Dess–Martin periodinane
gave methyl ketone15 13 (80%). Hydrogenation (10%
Pd–C/MeOH) of 13 and Boc deprotection (TFA/
CH2Cl2/0 ꢁC to rt) gave target compound 1 (50%),
During the cross-metathesis reaction we observed the
formation of homo-coupled 11 in yields ranging from
25
25
½aꢁD ꢀ23.0 (c 0.25, CHCl3) {natural 1; ½aꢁD ꢀ20.0 (c

P. Radha Krishna, G. Dayaker / Tetrahedron Letters 48 (2007) 7279–7282
7281
g
OBn OH
NHBoc
OBn OH
a
3 + 4
OTBDPS +
OH OBn
OTBDPS
10
11
OBn
OBn
b
d
10
OTBDPS
N
OR
NHBoc
Boc
R = H
2a
12
c
2
R = Ms
OBn
O
OH
O
e
f
N
N
H
Boc
13
1
Scheme 2. Reagents and conditions: (a) Grubbs’ 2nd generation catalyst (B, 10 mol %), toluene, 110 ꢁC, 18 h, 60%; (b) PtO2–NaHCO3/H2, EtOAc,
rt, 95%; (c) Et3N, MsCl, DMAP (cat), ꢀ15 to 0 ꢁC, 80%; (d) (i) TFA, CH2Cl2, 0 ꢁC to rt, 2M K2CO3, (ii) K2CO3, CH3CN, rt, (iii) Et3N, (Boc)2O,
CH2Cl2, 0 ꢁC to rt; (e) (i) TBAF, THF, 0 ꢁC to rt, 80%, (ii) DMP, CH2Cl2, 0 ꢁC to rt, 80%, (iii) CH3MgI, ether, 0 ꢁC to rt, 60%, (iv) DMP, CH2Cl2,
0 ꢁC to rt, 80%; (f) (i) 10% Pd–C/H2, MeOH, rt, 90%, (ii) TFA, 0 ꢁC to rt, CH2Cl2, 2M K2CO3, 50%; (g) 4, Grubbs’ 2nd generation catalyst (B,
10 mol %), toluene, 110 ꢁC, 24 h, 75%.
Table 1. Study of the olefin cross-metathesis reaction of 3 and 4 under
2. Felpin, F.-X.; Lebreton, J. Curr. Org. Synth. 2004, 1, 83–
various reaction conditions
109.
3. Ahmed, V. Q.; Nasir, M. A. Phytochemistry 1986, 24,
Entry
3:4
(equiv)
Catalyst
(10 mol %)
Solvent
Time
(h)
Yield
(%)
2841–2844.
4. Ahmed, V. Q.; Nasir, M. A. Phytochemistry 1987, 26, 585–
10
11
586.
´
5. Mill, S.; Hootele, C. J. Nat. Prod. 2000, 63, 762–764.
1
2
3
4
5
2:1
1:1
1:2
1:2
1:2
A
A
A
B
B
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
24
24
24
24
18
5
10
10
20
60
80
70
70
50
15
6. Chutian, S.; Lanny, S. L. J. Am. Chem. Soc. 2003, 125,
2878–2879.
7. (a) Radha Krishna, P.; Krishnarao, L. Synlett 2007, 1742–
1745; (b) Radha Krishna, P.; Sreeshailam, A. Tetrahedron
Lett. 2007 48, in press.
8. (a) Gao, Y.; Hanson, R. M.; Kluder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780; (b) Brunner, H.; Sicheneder, A. Angew.
Chem., Int. Ed. Engl. 1988, 27, 718–719.
1.6, CHCl3)}.5 The physical and spectroscopic data of
synthetic sample 116 were identical to those of the natu-
ral product.5
9. Steven, M. V. Tetrahedron Lett. 1982, 23, 4541–4544.
10. Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833–
4835.
11. Garner, P.; Ramakanth, S. J. Org. Chem. 1986, 51, 2609–
2912.
12. Chandrasekhar, M.; Chandra, K. L.; Singh, V. K. J. Org.
Chem. 2003, 68, 4039–4045.
13. (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140; (b)
Nolen, E. G.; Kurish, A. J.; Wong, K. A.; Orlando, M. D.
Tetrahedron Lett. 2003, 44, 2449–2453.
In conclusion, the stereoselective synthesis of 1 has been
accomplished by an olefin cross-metathesis approach to
access the requisite cyclization precursor, which was
elaborated to the target compound. The synthesis re-
ported herein is general and could be adopted for access-
ing related natural products.
14. Takashi, L. S.; Gerwick, H. Org. Lett. 2006, 8, 4541–4543.
15. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7278.
Acknowledgment
One of the authors (G.D.) thanks the UGC, New Delhi,
for financial support in the form of a fellowship.
16. Spectral data for selected compounds. Compound 3: light
25
yellow liquid; ½aꢁD +52.89 (c 0.55, CHCl3): 1H NMR
(200 MHz, CDCl3): d 7.35–7.20 (m, 5H, Ar-H), 5.91–5.66
(m, 1H, CH), 5.03 (d, 2H, J = 13.2 Hz, CH2), 4.52 (d, 2H,
J = 2.3 Hz, CH2–Ph), 3.98–3.82 (m, 1H, CH), 3.75–3.60
(m, 1H, CH), 2.58 (br s, 1H, OH), 2.18 (t, 2H, J = 6.2 Hz,
CH2), 1.76–1.25 (m, 6H, 3 · CH2), 0.92 (t, 3H, J = 7.8 Hz,
CH3); 13C NMR (75 MHz, CDCl3): d 138.3, 134.8, 128.3,
References and notes
1. Lebrum, S.; Couture, A.; Deniau, E.; Grandclaydon, P.
Org. Lett. 2007, 9, 2473–2476.

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P. Radha Krishna, G. Dayaker / Tetrahedron Letters 48 (2007) 7279–7282
127.8, 127.6, 117.3, 76.8, 71.1, 67.7, 42.1, 39.3, 35.7, 18.6,
Calcd for C40H59NO5Si: C, 72.57; H, 8.98; N, 2.12.
14.1; IR (neat) 3400, 3050, 2950, 1590 cmꢀ1; ESI-MS; 271
[M+Na]+, 249 [M+H]+. Anal. Calcd for C16H24O2: C,
77.38; H, 9.74. Found: C, 77.33; H, 9.78. Compound 4:
Found: C, 72.54; H, 9.00; N, 2.14. Compound 13:
25
Colorless syrupy liquid;½aꢁD ꢀ4.56 (c 0.66, CHCl3): 1H
NMR (300 MHz, CDCl3): d 7.39–7.22 (m, 5H, Ar-H), 4.54
(dd, 2H, J = 11.7, 19.2 Hz, CH2–Ph), 4.19–4.09 (m, 1H,
CH), 4.09–3.99 (m, 1H, CH), 3.46 (p, 1H, J = 5.8 Hz,
CH), 3.04 (dd, 1H, J = 5.2, 16.6 Hz, CH), 2.62 (dd, 1H,
J = 8.4, 16.6 Hz, CH), 2.14 (s, 3H, CH3), 2.06 (dd, 1H,
J = 7.1, 16.0 Hz, CH), 1.73–1.49 (m, 8H), 1.43 (s + m,
12H), 0.91 (t, 3H, J = 7.3 Hz, CH3); 13C NMR (75 MHz,
CDCl3): d 206.9, 155.3, 139.1, 128.1, 127.6, 127.2, 79.3,
76.4, 70.5, 49.9, 48.2, 47.9, 36.7, 35.9, 30.1, 28.4, 27.0, 26.0,
25
1
light yellow liquid; ½aꢁ +8.13 (c 0.30, CHCl3): H NMR
(200 MHz, CDCl3): d D7.69–7.57 (m, 4H, Ar-H), 7.38–7.29
(m, 6H, Ar-H), 5.84–5.65 (m, 1H, CH), 5.50–5.37 (m, 1H,
NH–Boc), 5.31–5.05 (m, 2H, CH2), 4.39–4.23 (m, 1H,
CH), 3.86–3.58 (m, 2H, CH2), 1.99–1.79 (m, 1H, CH),
1.72–1.51 (m, 1H, CH), 1.43 (s, 9H), 1.05 (s, 9H); 13C
NMR (75 MHz, CDCl3): d 155.4, 138.3, 135.6, 134.7,
133.2, 129.6, 127.5, 114.3, 61.0, 51.3, 28.3, 26.7, 26.5, 19.0;
IR (neat) 3300, 3015, 2900, 1690, 1580 cmꢀ1; ESI-MS; 440
[M+H]+. Anal. Calcd for C26H37NO3Si: C, 71.03; H, 8.48;
N, 3.19. Found: C, 71.10; H, 8.44; N, 3.23. Compound 2a:
18.5, 16.6, 14.2; IR (neat) 3030, 2900, 1740, 1580 cmꢀ1
;
ESI-MS; 440 [M+Na]+, 418 [M+H]+. Anal. Calcd for
C25H39NO4: C, 71.91; H, 9.41; N, 3.35. Found: C, 71.93;
25
25
Syrupy liquid; ½aꢁD +32.53 (c 0.30, CHCl3): 1H NMR
H, 9.39; N, 3.31. Compound 1: Yellow oil; ½aꢁD ꢀ23.0 (c
1
(300 MHz, CDCl3): d 7.64–7.59 (m, 4H, Ar-H), 7.41–7.20
(m, 11H, Ar-H), 4.97 (t, 1H, J = 9.8 Hz, NH–Boc), 4.52
(d, 2H, J = 2.2 Hz, CH2–Ph), 3.89–3.63 (m, 5H), 1.86–1.74
(m, 1H), 1.56–1.28 (m, 22H), 1.04 (s, 9H), 0.92 (t, 3H,
J = 6.7 Hz, CH3); 13C NMR (75 MHz, CDCl3): d 155.7,
138.4, 135.5, 133.4, 129.6, 128.3, 127.8, 127.6, 78.63, 71.1,
68.3, 61.2, 48.8, 39.9, 39.6, 37.6, 35.7, 28.4, 26.8, 22.0, 21.8,
19.0, 18.7, 14.1; IR (neat) 3400, 3015, 2940, 1670,
1550 cmꢀ1; ESI-MS; 684 [M+Na]+, 662 [M+H]+. Anal.
0.25, CHCl3): H NMR (400 MHz, CDCl3): d 3.84–3.80
(m, 1H, CH), 3.18–3.11 (m, 2H, CH and NH), 3.07–2.99
(m, 1H, CH), 2.65 (m, 1H, CH), 2.19 (s + m, 4H, CH3 and
CH), 1.90–1.00 (m, 13H), 0.91 (t, 3H, J = 6.7 Hz,
CH3);13C NMR (150 MHz, CDCl3): d 207.0, 72.9, 58.9,
53.0, 49.0, 43.5, 39.7, 33.4, 32.2, 30.0, 24.0, 18.6, 14.0; IR
(neat) 3300, 2900, 1740 cmꢀ1; ESI-MS; 228 [M+H]+.
Anal. Calcd for C13H25NO2: C, 68.68; H, 11.08; N, 6.16.
Found: C, 68.63; H, 11.12; N, 6.15.