Ring expansion: Synthesis of the velbanamine piperidine core

Article abstract of DOI:10.1055/s-2001-17454

A ring expansion reaction applied to a substituted prolinol has been used in order to obtain the piperidine core of (-)-velbanamine, an alkaloid extracted from Tabernaemontana eglandulosa.

Full text of DOI:10.1055/s-2001-17454

LETTER
1575
Ring Expansion: Synthesis of the Velbanamine Piperidine Core
R
ing Expa
a
nsion: Syn
nthesis of the
i
V
elban
n
a
mine Piperi
e
dine
C
ore Cossy,* Olivier Mirguet, Domingo Gomez Pardo*
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Received 13 June 2001
O
Abstract: A ring expansion reaction applied to a substituted proli-
nol has been used in order to obtain the piperidine core of (-)-velba-
namine, an alkaloid extracted from Tabernaemontana eglandulosa.
OH
OTBS
Cl
N
N
Key words: (-)-velbanamine, alkaloid, ring expansion, piperidines,
trans-4-hydroxy-(L)-proline
H
H
N
N
H
H
(–)-Velbanamine
B
Of the numerous alkaloids isolated from the pantropical
plant Catharanthus roseus, vinblastine and vincristine
have antitumor activity and are used in the treatment of
Hodgkin’s disease and leukemia.1 Reductive cleavage of
both alkaloids gave the indole derivative (+)-velban-
amine.2 On the other hand, (–)-velbanamine was extracted
from leaves and twigs of Tabernaemontana eglandulosa
in 1984.3 Five racemic syntheses of velbanamine and two
chiral non-racemic syntheses of (+)-velbanamine and (–)-
velbanamine have been achieved previously.4–6 For our
part, we have envisaged the synthesis of (–)-velbanamine
by photochemical cyclization7 of -chloroacetamide B to
built up the 9-membered ring, and enantioselective ring
expansion of prolinol to piperidin-3-ol8 to afford the
3,3,5-trisubstituted piperidine ring present in (–)-velban-
amine. The precursor of the -chloroacetamide B could be
obtained by condensation of the phosphonium methyl in-
dole bromide9 with piperidinoaldehyde A. Here, we
would like to report the synthesis of alcohol 9 from trans-
4-hydroxy-(L)-proline, which is the precursor of aldehyde
A (Scheme 1).
O
OTBS
PPh3, Br
N
+
N
CO2i-Bu
CO2Me
A
OH
HO
OTBS
CO2H
N
H
N
CO2i-Bu
trans-4-hydroxy-(L)-proline, 1
9
Scheme 1 Retrosynthetic Scheme
R3O
TBDPSO
TBDPSO
+
CO2Me
d
CO2R1
100%
N
R2
N
N
CO2Me
Boc
Boc
3'
1 (R1, R2, R3= H)
The enantiomerically pure commercially available trans-
4-hydroxy-(L)-proline 1 was transformed, in quantitative
yield, to the corresponding methylester carbamate by
treatment with SOCl2 in the presence of methanol, fol-
lowed by the nitrogen protection as a tert-butyl carbam-
ate. After protection of the hydroxy group at C-4
(TBDPSCl, imidazole, DMF, r.t., 88%), the correspond-
ing silyl-ether 210 was treated with LDA at –78 °C and the
enolate was quenched with ethyl iodide (7.5 equiv) in the
presence of HMPA (7.0 equiv)10 to afford two inseparable
alkylated compounds 3 and 3’ in a 78:22 ratio and in quan-
titative yield (Scheme 2).
3
a-c
88%
2 (R1= Me, R2= Boc,
R3= TBDPS)
Scheme 2 (a) SOCl2 (1.2 equiv), MeOH, 0 °C to r.t., 1 day; (b)
Boc2O (1.1 equiv), Et3N (2.2 equiv), dioxane–H2O, 2:1, r.t., 1 day; (c)
TBDPSCl (1.0 equiv), imidazole (2.5 equiv), DMF, r.t., 2 days; (d)
LDA (2.0 equiv), THF, –78 °C, 1 h then HMPA (7.0 equiv), EtI (7.5
equiv), –78 °C, 20 min.
responding lactone. After deprotection of the hydroxy
groups at C-4 in 3 and 3’, using TBAF (MS 4 Å, THF,
r.t.), the hydroxyesters 10 and 10’ were isolated in 87%
yield and separated by chromatography. Compound 10’
was treated with LiOH and transformed to the hydroxy
acid 11 (89%) which, after treatment with diphenylphos-
phorylazide (DPPA) in the presence of Et3N in DMF,10
led to lactone 1211 in 44% yield (Scheme 3).
To determine the relative stereochemistry between the hy-
droxy group at C-4 and the ester group at C-2, the minor
isomer 3’ was transformed to the corresponding hydroxy
acid, as the cis isomer should cyclize to produce the cor-
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1575,1577,ftx,en;G11901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
As the minor diastereomer 3’ clearly has the cis relation-
ship between the hydroxy group at C-4 and the ester at

1576
J. Cossy et al.
LETTER
HO
HO
TBDPSO
HO
CO2Me
OH
a
87%
a
3
3'
+
+
+
3
3'
+
93%
N
N
N
N
CO2Me
Boc
10
Boc
10'
OH
4'
4
93%
b
b
89%
OTBS
OH
O
O
N
HO
TBDPSO
TBDPSO
c, d
CO2H
c
92%
N
N
44%
N
CO2i-Bu
6
Boc
Boc
12
5
11
f, e 92%
Scheme 3 (a) TBAF (2.0 equiv), powdered MS 4 Å, THF, r.t., 2.5
days; (b) LiOH (2.8 equiv), THF–H2O, 1:1, 0 °C to r.t., 17 h; (c)
DPPA (1.2 equiv), Et3N (2.3 equiv), DMF, 0 °C to r.t., 5 h.
OTBS
OTBS
O
g
98%
N
N
C-2, the major isomer 3 has the desired trans relative ster-
eochemistry required for our synthesis. The mixture of
compounds 3 and 3’ was reduced with LiAlH4 in reflux-
ing THF to afford the corresponding prolinols 412 and 4’
(ratio 4/4’ = 78/22) in 93% yield, which could be separat-
ed by flash chromatography. It is worth noting that the si-
lylether group of the cis diastereomer was deprotected
under these conditions.13 Ring expansion conditions8g ap-
plied to 4, using trifluoroacetic anhydride (TFAA) in THF
at r.t. followed by addition of Et3N and NaOH, led to pip-
eridinol 514 in 93% yield and with a diastereomeric excess
of >98%. After protection of the tertiary alcohol at C-3
(TBSOTf, 2,6-lutidine, CH2Cl2, r.t.) followed by the N-
demethylation and carboxylation of the piperidine using
isobutyl chloroformate in presence of K2CO3 in refluxing
toluene,15 the 3,3,5-trisubstituted piperidine 6 was isolat-
ed in 92% yield. Selective deprotection of the C-5 silyl-
ether was achieved with TBAF (1.0 equiv) and PCC oxi-
dation afforded the aminoketone 7 in 92% yield. Transfor-
mation of 7 to the desired alcohol 9 was achieved in two
steps via the methylene piperidine 8. Treatment of ketone
7 with Cp2TiMe2, in THF in the dark16 afforded the meth-
ylene piperidine 8 (98%), which was then transformed to
the primary alcohols 9 and 9’ in 94% yield and in a ratio
of 61:39 with BH3 THF/NaOH, H2O2. Remarkably, the
ratio in 9/9’ was not improved when a hindered borane
such as t-hexylborane was used (Scheme 4).
CO2i-Bu
7
CO2i-Bu
8
h
94%
OH
OH
OTBS
OTBS
+
N
N
CO2i-Bu
CO2i-Bu
9
9'
Scheme 4 (a) LiAlH4 (4.8 equiv), THF, 0 °C to reflux, 2 h; (b)
TFAA (1.2 equiv), THF, 0 °C, 1.2 h then Et3N (4.0 equiv), 0 °C to r.t.,
2 days then 3.75 N NaOH (20.0 equiv), r.t., 2 h; (c) TBSOTf (1.2
equiv), 2,6-lutidine (3.0 equiv), CH2Cl2, r.t., 1 h; (d) ClCO2i-Bu (1.0
equiv), K2CO3 (0.6 equiv), toluene, reflux, 3 h; (e) TBAF (1.0 equiv),
powdered MS 4 Å , THF, r.t., 3.5 h; (f) PCC (2.5 equiv), powdered
MS 4 Å , CH2Cl2, r.t., 2.5 h; (g) Cp2TiMe2 (3.2 equiv), THF, dark, re-
flux, 4 h; (h) BH3 THF (1.1 equiv), THF, 0 °C, 50 min then 3.75 N
NaOH (4.0 equiv), 30 % H2O2 (8.0 equiv), 0 °C to r.t., 1.5 h.
OH
OH
OH
OH
a
9
+ 9'
+
100%
N
N
CO2i-Bu
CO2i-Bu
13'
13
b
HO
O
O
O
OH
OH
To determine the relative stereochemistry between the hy-
droxy at C-3 and the hydroxymethyl at C-5 in compounds
9/9’, the alcohol at C-3 was deprotected (TBAF, THF, re-
flux, 100% yield) and the diol was oxidized (TPAP,
NMO, MS 4 Å, CH2Cl2/CH3CN). Under these conditions,
lactone 16 was the only compound isolated. The monitor-
ing of this reaction by GC/MS shows us that lactone 16
was obtained via the hydroxyaldehyde-lactol 14-15. The
minor compound 13’ was transformed to hydroxyalde-
hyde 14’,17 which decomposed very rapidly under these
conditions (Scheme 5).
+
N
N
N
CO2i-Bu
14
CO2i-Bu
14'
CO2i-Bu
15
51%
O
O
decomposition
N
CO2i-Bu
16
Scheme 5 (a) TBAF (5.0 equiv), THF, reflux, 17 h; (b) TPAP
(0.04 equiv), NMO (3.0 equiv), powdered MS 4 Å , CH2Cl2/CH3CN
= 10/1, r.t., 1.5 h.
Synlett 2001, No. 10, 1575–1577 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Ring Expansion: Synthesis of the Velbanamine Piperidine Core
1577
J = 11.8 Hz), 2.50 (m, 1 H), 2.16-1.94 (3 H), 1.44 (s, 9 H),
1.00 (t, 3 H, J = 7.3 Hz). 13C NMR (75 MHz, CDCl3) 172.1
(s), 154.8 (s), 81.2 (s), 74.9 (d), 68.3 (s), 53.3 (t), 42.9 (t),
28.2 (q,), 20.1 (t), 9.0 (q). EI MS m/z (relative intensity): 241
(M+, 0.06), 197 (15), 168 (11), 141 (62), 112 (15), 97 (22),
96 (25), 84 (13), 68 (10), 57 (100), 56 (13), 55 (11).
Elemental analysis: calcd. for C12H19NO4: C, 59.73; H, 7.94;
N, 5.80. Found: C, 59.92; H, 8.04; N, 5.55.
By employing a ring expansion of the 2,2,4-trisubstituted
prolinol 4, we were able to obtain the 3,3,5-trisubstituted
piperidine 5 with excellent diastereoselectivity. This latter
compound can be transformed in four additional steps to
piperidine 9, which will be utilized in the synthesis of (–)-
velbanamine.
(12) 4: [ ]20D = +2.4 (c 1.36, CHCl3). IR(neat): 3416, 1472, 1428,
1111 cm-1. 1H NMR (300 MHz, CDCl3) 7.75–7.54 (4 H),
7.48–7.30 (6 H), 4.32 (m, 1 H), 3.26 (d, 1 H, J = 10.3 Hz),
3.14 (d, 1 H, J = 10.3 Hz), 3.12 (br s, 1 H), 3.11 (dd, 1 H,
J = 9.2 and 6.6 Hz), 2.68 (m, 1 H), 2.18 (s, 3 H), 2.03 (dd, 1
H, J = 13.6 and 8.5 Hz), 1.81 (dd, 1 H, J = 13.6 and 4.4 Hz),
1.71 (dq, 1 H, J = 13.2 and 7.7 Hz), 1.42 (m, 1 H), 1.07 (s, 9
H), 0.91 (t, 3 H, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3)
135.6 (d), 134.1 (s), 134.0 (s), 129.6 (d), 127.6 (d), 127.5 (d),
70.3 (d), 65.7 (s), 62.9 (t), 62.7 (t), 40.8 (t), 32.8 (q), 26.8 (q),
23.3 (t), 19.0 (s), 8.7 (q). EI MS m/z (relative intensity): 397
(M+, 0.1), 368 (11), 367 (32), 366 (100), 254 (4), 199 (10),
183 (5), 154 (10), 135 (4), 110 (20), 82 (6). MS (CI+, CH4)
m/z (relative intensity): 398 (M+H+, 100), 396 (28), 380
(17), 366(16), 320(17), 179(19), 154(47). HRMS (CI+,
CH4): calcd. for C24H35NO2Si (M+H+): 398.2515. Found:
398.2519.
References and Notes
(1) Noble, R. N. Can. Cancer Conf. 1961, 4, 333.
(2) Neuss, N. Bull. Soc. Chim. Fr. 1962, 1509.
(3) Van Beck, T. A.; Verpoorte, R.; Baerheim Svendsen, A.
Tetrahedron 1984, 40, 737.
(4) Racemic syntheses: (a) Büchi, G.; Kulsa, P.; Rosati, R. L. J.
Am. Chem. Soc. 1968, 90, 2448. (b) Büchi, G.; Kulsa, P.;
Ogasawara, K.; Rosati, R. L. J. Am. Chem. Soc. 1970, 92,
999. (c) Narisada, M.; Watanabe, F.; Nagata, W.
Tetrahedron Lett. 1971, 12, 3681. (d) Takano, S.; Hirama,
M.; Ogasawara, K. J. Org. Chem. 1980, 45, 3729.
(5) Chiral syntheses for (-)-velbanamine: Takano, S.; Yonaga,
M.; Chiba, K.; Ogasawara, K. Tetrahedron Lett. 1980, 21,
3697.
(6) Chiral syntheses for (+)-velbanamine: (a) Kutney, J. P.;
Bylsma, F. J. Am. Chem. Soc. 1970, 92, 6090. (b) Kutney,
J. P.; Bylsma, F. Helv. Chim. Acta 1975, 58, 1672.
(c) Takano, S.; Uchida, W.; Hatakeyama, S.; Ogasawara, K.
Chem. Lett. 1982, 733.
(7) For the synthesis of a 9-membered ring by photochemical
cyclization see: Amat, M.; Coll, M.-D.; Bosch, J.; Espinosa,
E.; Molins, E. Tetrahedron: Asymmetry 1997, 8, 935.
(8) (a) Cossy, J.; Dumas, C.; Michel, P.; Gomez Pardo, D.
Tetrahedron Lett. 1995, 36, 549. (b) Cossy, J.; Dumas, C.;
Gomez Pardo, D. Synlett 1997, 905. (c) Cossy, J.; Dumas,
C.; Gomez Pardo, D. Bioorg. Med. Chem. Lett. 1997, 7,
1343. (d) Wilken, J.; Kossenjans, M.; Saak, W.; Haase, D.;
Pohl, S.; Martens, J. Liebigs Ann. 1997, 573. (e) Langlois,
N.; Calvez, O. Synth. Commun. 1998, 28, 4471. (f) Davis,
P. W.; Osgood, S. A.; Hébert, N.; Sprankle, K. G.; Swayze,
E. E. Biotechnol. Bioeng. 1999, 61, 143. (g) Cossy, J.;
Dumas, C.; Gomez Pardo, D. Eur. J. Org. Chem. 1999,
1693. (h) Michel, P.; Rassat, A. J. Org. Chem. 2000, 65,
2572.
(13) de Vries, E. F. J.; Brussee, J.; van der Gen, A. J. Org. Chem.
1994, 59, 7133.
(14) 5: [ ]20D = +18.2 (c 1, CHCl3). IR(neat): 3442, 1461, 1428,
1136, 1111 cm-1. 1H NMR (300 MHz, CDCl3) 7.81–7.61
(4 H), 7.52–7.31 (6 H), 4.08 (dddd, 1 H, J = 10.2, 10.2, 5.1
and 5.1 Hz), 2.81 (ddm, 1 H, J = 10.5 and 5.0 Hz), 2.71 (m,
1 H), 2.45 (dm, 1 H, J = 11.4 Hz), 2.21 (s, 3 H), 1.97 (dm, 1
H, J = 12.7 Hz), 1.90-1.80 (2 H), 1.47 (m, 2 H), 1.26 (dd, 1
H, J = 12.7 and 10.8 Hz), 1.11 (s, 9 H), 0.91 (t, 3 H, J = 7.4
Hz). 13C NMR (75 MHz, CDCl3) 135.7 (d), 135.6 (d),
134.3 (s), 134.1 (s), 129.6 (d), 129.5 (d), 127.5 (d), 71.0 (s),
67.0 (d), 64.5 (t), 62.8 (t), 45.7 (q), 43.6 (t), 32.3 (t), 26.9 (q),
19.1 (s), 7.1 (q). EI MS m/z (relative intensity): 397 (M+, 7),
379 (24), 340 (79), 263 (22), 262 (100), 261 (12), 225 (10),
199 (23), 197 (12), 183 (25), 181 (13), 142 (12), 135 (14),
124 (19), 84 (12), 58 (38). MS (CI+, CH4) m/z (relative
intensity): 398 (M+H+, 100), 380 (19), 340 (7), 321 (9), 320
(39), 302 (5), 179 (2), 142 (8). HRMS (CI+, CH4): calcd. for
C24H36NO2Si (M+H+): 398.2515. Found: 398.2521.
(15) Kratzel, M.; Weigl, A. J. Chem. Soc., Perkin Trans. 1 1997,
1009.
(9) Nagarathnam, D. Synthesis 1992, 743.
(10) Nagumo, S.; Mizukami, M.; Akutsu, N.; Nishida, A.;
Kawahara, N. Tetrahedron Lett. 1999, 40, 3209.
(11) 12: [ ]20D = –98.9 (c 1.8, CHCl3). Mp: 63 °C. IR (KBr):
1781, 1697, 1366, 1331 cm-1. 1H NMR (300 MHz, CDCl3)
4.92 (m, 1 H), 3.59 (d, 1 H, J = 11.8 Hz), 3.54 (d, 1 H,
(16) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392.
(17) The minor diastereomer 14’ was only detected by GC/MS.
Synlett 2001, No. 10, 1575–1577 ISSN 0936-5214 © Thieme Stuttgart · New York