Stereoselective synthesis of 2,3,6-trisubstituted tetrahydropyridines via Tf2O-mediated Grob fragmentation: Access to indolizidines (-)-209I and (-)-223J

Article abstract of DOI:10.1021/jo1015344

Herein we describe the γ-amino hydroxide Grob fragmentation of the aza-bicyclo[2.2.2]octene 1 using triflic anhydride as the activating agent. The resulting dihydropyridinium ion can react with a wide variety of Grignard reagents, giving access to 2,3,6-t

Full text of DOI:10.1021/jo1015344

pubs.acs.org/joc
studied,3 but stereoselective synthesis of variously substi-
Stereoselective Synthesis of 2,3,6-Trisubstituted
Tetrahydropyridines via Tf2O-Mediated Grob
Fragmentation: Access to Indolizidines (-)-209I
and (-)-223J
tuted rings still remains a contemporary area of research.4
Recently, as part of our program to develop new stereo-
selective access to nitrogen-containing heterocycles,5 our
group reported an original synthesis of 2,3,6-trisubstituted
dihydropyridines based on a silver ion-induced Grob frag-
mentation of γ-amino iodides.5c,6 Since this method displayed
high efficiency and stereoselectivity, we were interested in
employing it in the synthesis of naturally occurring nitrogen-
containing heterocycles. However, this process required the
use of a stoichiometric amount of an expensive silver salt.
Hence, in this note, we describe our efforts toward the elabo-
ration of a silver-free Grob fragmentation and its application
to the enantioselective synthesis of dendrobatid indolizidine
alkaloids (-)-209I and (-)-223J.
ꢀ
Gerald Lemonnier and Andre B. Charette*
ꢀ
ꢀ
ꢀ
Departement de Chimie, Universite de Montreal, P.O. Box
6128, Station Downtown, Montreꢀal, Queꢀbec, Canada H3C 3J7
ꢀ
andre.charette@umontreal.ca
Received August 4, 2010
To overcome the use of the silver salt, we envisioned that
the alcohol functionality of the aza-bicyclo[2.2.2]octene 17
could be activated via its corresponding O-triflyl intermediate
I.8 A thermal Grob fragmentation could then occur, leading to
the dihydropyridinium salt II that would then be trapped in situ
by a nucleophile such as a Grignard reagent (Scheme 1).
SCHEME 1. Silver-Free Grob Fragmentation
Herein we describe the γ-amino hydroxide Grob frag-
mentation of the aza-bicyclo[2.2.2]octene 1 using triflic
anhydride as the activating agent. The resulting dihydro-
pyridinium ion can react with a wide variety of Grignard
reagents, giving access to 2,3,6-trisubstituted tetrahydro-
pyridines (2) with high regio- and stereoselectivities. This
methodology has been applied to the short synthesis of
natural indolizidines (-)-209I (3) and (-)-223J (4).
Piperidine and indolizidine subunits are found in numer-
ous biologically active natural products1 and medicinal
drugs.2 For the past 10 years, their synthesis has been widely
(1) For reviews, see: (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M.
J. Nat. Prod. 2005, 68, 1556. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(c) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 6, 633.
(d) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139.
(2) For examples, see: (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett.
2000, 2, 3679. (b) Vazzana, I.; Budriesi, R.; Terranova, E.; Ioan, P.; Ugenti,
M. P.; Tasso, B.; Chiarini, A.; Sparatore, F. J. Med. Chem. 2007, 50, 334.
(c) Satoh, A.; Sagara, T.; Sakoh, H.; Hashimoto, M.; Nakashima, H.; Kato,
T.; Goto, Y.; Mizutani, S.; Azuma-Kanoh, T.; Tani, T.; Okuda, S.; Okamoto,
O.; Osaki, S.; Iwasawa, Y.; Ohta, H.; Kawamoto, H. J. Med. Chem. 2009, 52,
During the optimization process, using the bicyclo[2.2.2]-
octene 1a (R1 = Me) as a test substrate, triflic anhydride
proved to be the most efficient electrophile for the in situ
transformation of the alcohol function into a suitable leav-
ing group.9 To examine the intermediates involved in this
€
€
4091. (d) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601.
(3) For recent reviews, see: (a) Escolano, C.; Amat, M.; Bosch, J. Chem.;
Eur. J. 2006, 12, 8198. (b) Cossy, J. Chem. Rec. 2005, 5, 70.
(c) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (d) Weintraub, P. M.; Sabol,
J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953.
(e) Laschat, S.; Dickner, T. Synthesis 2000, 1781. (f) Felpin, F.-X.; Lebreton,
J. Eur. J. Org. Chem. 2003, 3693.
(5) (a) Lemire, A.; Charette, A. B. J. Org. Chem. 2010, 75, 2077. (b) Barbe,
G.; Pelletier, G.; Charette, A. B. Org. Lett. 2009, 11, 3398. (c) Barbe, G.;
St-Onge, M.; Charette, A. B. Org. Lett. 2008, 10, 5497.
(6) For examples of stereoselective synthesis of 2,3,6-trisubstituted piper-
idines, see: (a) Takahashi, M.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129,
7514. (b) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.
(c) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747.
ꢀ
ꢀ~
ꢀ
(4) (a) Fernandez-Ibanez, M. A.; Macia, B.; Pizzuti, M. G.; Minnaard,
A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2009, 48, 9339. (b) McLaughlin,
N. P.; Evans, P. J. Org. Chem. 2010, 75, 518. (c) Chen, M. Z.; Micalizio, G. C.
Org. Lett. 2009, 11, 4982. (d) Chen, Y.; Zhong, C.; Petersen, J. L.; Akhmedov,
N. G.; Shi, X. Org. Lett. 2009, 11, 2333. (e) Ahari, M.; Perez, A.; Menant, C.;
Vasse, J.-L.; Szymoniak, J. Org. Lett. 2008, 10, 2473. (f) Hayashi, Y.; Gotoh,
H.; Masui, R.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4012.
(g) Sarkar, N.; Banerjee, A.; Nelson, S. G. J. Am. Chem. Soc. 2008, 130,
9222. (h) Terada, M.; Machioka, K.; Sorimachi, K. J. Am. Chem. Soc.
2007, 129, 10336. (i) Legault, C.; Charette, A. B. J. Am. Chem. Soc. 2005, 127,
8966.
(7) The enantiopure aza-bicyclo[2.2.2]octene 1 was prepared by reduction
of the corresponding N-benzoyl compound which can be prepared on
multigram scale via a three-step sequence, see Supporting Information and
see: (a) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 13873.
(b) Sales, M.; Charette, A. B. Org. Lett. 2005, 7, 5773.
(8) For review on nucleofugality and for examples of fragmentation
involving triflate leaving group, see: (a) Lepore, S. D.; Mondal, D. Tetra-
hedron 2007, 63, 5103. (b) Murphy, J. A.; Mahesh, M.; McPheators, G.;
Anand, R. V.; McGuire, T. M.; Carling, R.; Kennedy, A. R. Org. Lett. 2007,
9, 3233. (c) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128, 6499.
(9) See Supporting Information for detailed optimization data.
DOI: 10.1021/jo1015344
r
Published on Web 10/14/2010
J. Org. Chem. 2010, 75, 7465–7467 7465
2010 American Chemical Society

Lemonnier and Charette
JOCNote
TABLE 1. Scope of the Silver-Free Grob Fragmentation
SCHEME 2. Synthesis of Indolizidines (-)-209I and (-)-223J
entry
RM
product
dra
yield (%)
1
2
3
4
5
6
MeMgBr
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
6.3:1
>19:1
>19:1
>19:1
10:1
>19:1
>19:1
>19:1
>19:1
b
92
92
95
99
92
94
77
78
72
88
91
94
86
77
97
83
82
78
n-PrMgCl
n-BuMgBrb
n-OctylMgBr
2-(1,3-dioxan-2-yl)ethylMgBr
i-PrMgCl
CpMgCl
7
8c
9
CyMgCl
(1,3-dithiane-2-yl)MgBrd
(1,3-dithiane-2-phenyl-2-yl)MgBrd
allylMgBr
10
11
12
13
vinylMgBr
phenylMgBr
14e furylMgBr
15
16
17
18
HCꢀCMgBr
C3H7CtCMgBrf
TMSCtCMgBrf
LiAlH4
aDetermined from H NMR of the crude material. Prepared from
1
nBuLi and MgBr2 OEt2. cGrignard reagent was added at -20 °C.
3
dPrepared from corresponding dithiane, nBuLi and MgBr2 OEt2. eTHF
(0.1 N) was added before nucleophile addition. Prepared from corre-
sponding terminal alkynes and EtMgBr.
3
f
transformation, the fragmentation reaction was performed
in deuterated chloroform. The γ-amino alcohol 1a was
dissolved in CDCl3, and 1 equiv of Tf2O was added. Within
10 min, the formation of the triflate and the subsequent
trapping of the triflic acid byproduct by the amine were
1
apparent by H NMR, as indicated by the expected slight
shifts of all signals. After the addition of Et3N, the char-
acteristic allylic signals of the Grob product were immedi-
ately observed. This indicates that the γ-amino triflate I
undergoes rapid Grob fragmentation to form the dihydro-
pyridinium salt II.
Our optimized conditions were tested with a wide variety
of Grignard reagents, providing an array of substituted
tetrahydropyridines in high yields and with high stereoselec-
tivities (Table 1). Primary (entries 1-5 and 11), secondary
(entries 6-9), and tertiary (entry 10) sp3, as well as sp2
(entries 12-14) and sp (entries 15-17) hybridized carbon
nucleophiles are well tolerated in this process. The dihydro-
pyridinium intermediate II can also be reduced using LiAlH4
(entry 18).
It is noteworthy that unusual Grignard reagents derived
from dithiane compounds can be used, even though a moderate
selectivity (6.3:1) is obtained for the 2-phenyl-1,3-dithiane
magnesium bromide addition (entry 10). Furthermore, in the
case of the cyclohexylmagnesium chloride addition (entry 8),
the temperature had to be lowered to -20 °C to avoid a
β-hydride elimination that would lead to the reduced tetrahy-
dropyridine 2r.
The 1,2-dihydropyridine 6 was prepared as a single regio-
and diastereoisomer11 from valinol derivative 5, pyridine,
and the appropriate Grignard reagent.12 A subsequent endo-
selective Diels-Alder condensation gave the bicyclic com-
pound 7.7b In the next step, the amidine and ester function-
alities were reduced using aluminum(III) hydride followed
by an in situ N-benzoylation7a,13 to give the γ-amido alcohol
8 in 37% overall yield from 5 and with 95% ee.14 The amide
was reduced with LiAlH4 in 93% yield, providing the
(10) (a) Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J. W.; Garraffo,
H. M. Tetrahedron 1997, 53, 9553. (b) Enders, D.; Thiebes, C. Synthesis 2000,
1745. (c) Michel, P.; Rassat, A.; Daly, J. W.; Spande, T. F. J. Org. Chem.
2000, 65, 8908. (d) Yu, S.; Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 7364.
(e) De Koning, C. B.; Michael, J. P.; Riley, D. L. Heterocycles 2009, 79, 935.
(11) Determined from the crude product, for other examples, see: Charette,
A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc.
2001, 123, 11829.
(12) Prepared from 1,3-propanediol in a three-step sequence of alcohol
monoprotection/bromination/oxidative addition; see: (a) Frankowski, K. J.;
ꢀ
Golden, J. E.; Zeng, Y.; Lei, Y.; Aube, J. J. Am. Chem. Soc. 2008, 130, 6018.
(b) Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410. (c) Kende,
A. S.; Hernando, J. I. N.; Milbank, J. B. J. Tetrahedron 2002, 58, 61.
(13) Lemire, A.; Beaudoin, D.; Grenon, M.; Charette, A. B. J. Org. Chem.
2005, 70, 2368.
As depicted in Scheme 2, our strategy has been applied to
the expedient stereoselective synthesis of two alkaloids found
in poison frog skin: indolizidines (-)-209I and (-)-223J.10
(14) Determined by chiral SFC, see Supporting Information.
7466 J. Org. Chem. Vol. 75, No. 21, 2010

Lemonnier and Charette
JOCNote
γ-amino alcohol precursor 9; the latter underwent fragmen-
tation and subsequent reaction with Grignard reagents, thus
producing tetrahydropyridines 10 and 11 in 90% and 78%
yield, respectively. SFC analysis on chiral stationary phase
indicated that the enantiomeric excess remained unchanged
after this transformation. The alkenes were hydrogenated
using PtO2 catalysis under 400 psi of H2; the use of other
metal catalysts, such as Pd(OH)2/C, Rh/C, or Pt/C, resulted
in a mixture of the corresponding C6-epimerized piperidine.
The benzyl protecting groups were then removed using
catalytic Pd(OH)2/C and trifluoroacetic acid under 400 psi
of H2. Finally, the resulting piperidines 12 and 13 were
converted into the corresponding indolizidines (-)-209I 3
([R]20 = -143.4 (c 0.99, acetone), lit. [R]29 = -123.4 (c
mixture was stirred at rt for 5 min. Triethylamine (69 μL, 0.493
mmol, 1.2 equiv) was then added (reaction mixture color turned
to red, indicating the formation of the dihydropyridinium
intermediate). After 5 min, the Grignard reagent (2.2 equiv)
was added dropwise; the reaction was stirred for 20 min at rt and
was then quenched by the addition of a saturated aqueous
solution of sodium bicarbonate (2 mL). Et2O (10 mL) was
added; the resulting mixture was transferred into a separation
funnel. The organic layer was separated, and the aqueous layer
was washed with EtOAc. Organic layers were combined, dried
over Na2SO4, and concentrated under reduced pressure to give a
crude residue that was purified by flash chromatography using
triethylamine neutralized silica gel (2% EtOAc/hexanes).
(2S,3R,6R)-3-Allyl-1-benzyl-6-butyl-2-methyl-1,2,3,6-tetra-
hydropyridine (2c): 95% yield; yellowish oil; Rf (10% EtOAc/
hexanes) = 0.55; 1H NMR (CDCl3, 400 MHz), δ 7.39 (d, J =
7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H),
5.80-5.67 (m, 3H), 4.99-4.87 (m, 2H), 3.80 (s, 2H), 3.23-3.15
(m, 1H), 2.75 (dq, J = 4.7, 6.6 Hz, 1H), 2.29-2.20 (m, 1H),
2.14-2.05 (m, 1H), 1.98-1.91 (m, 1H), 1.76-1.65 (m, 1H),
1.41-1.10 (m, 5H), 1.06 (d, J = 6.6 Hz, 3H), 0.86 (t, J = 7.1,
3H); 13C NMR (CDCl3, 100 MHz), δ 141.9 (C), 137.2 (CH),
129.2 (CH), 128.5 (2xCH), 128.1 (2 ꢁ CH), 127.5 (CH), 126.5
(CH), 116.0 (CH2), 59.3 (CH), 55.4 (CH), 54.5 (CH2), 41.3 (CH),
38.4 (CH2), 32.6 (CH2), 29.2 (CH2), 23.1 (CH2), 18.2 (CH3), 14.2
(CH3); FTIR (cm-1) (neat) 3746, 2929, 909, 726, 696; HRMS
(ESI, Pos) calcd for C20H30N [M þ H]þ: 284.2373, found 284.2378.
D
D
0.71, acetone),10b [R]24D = -126.5 (c 0.19, acetone)10d) and
(-)-223J 4 ([R]20D = -105.0 (c 1.02, acetone), lit. [R]26
=
D
-90.5 (c 0.70, acetone)10b) through a one-pot chlorination/
cyclization procedure15 with 59% and 60% yield respectively.
In conclusion, we have developed an improved procedure
for the synthesis of 2,3,6-trisubstituted dihydropyridines
based on the Grob fragmentation of a γ-amino hydroxide
containing bicyclo[2.2.2]octene scaffold. We have also
characterized by proton, carbon, and two-dimensional
NMR analysis the triflate dihydropyridinium intermediate.
Finally, this methodology has been applied to an expedient
total stereoselective synthesis of two frog skin alkaloids:
indolizidines (-)-209I (3) and (-)-223J (4).
Acknowledgment. This work was supported by the Natural
Science and Engineering Research Council of Canada (NSERC),
the Canada Research Chairs Program, the Canada Foundation
Experimental Section
ꢀ
for Innovation, and the Universite de Montreal.
ꢀ
General Procedure for the Grob Fragmentation. To a solution
of 1a (100 mg, 0.411 mmol) in CH2Cl2 (0.1 N) was added triflic
anhydride (76 μL, 0.452 mmol, 1.1 equiv), and the reaction
Supporting Information Available: Experimental procedure
for the preparation of compounds and spectroscopic data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(15) Xu, F.; Simmons, B.; Reamer, R. A.; Corley, E.; Murry, J.; Tschaen,
D. J. Org. Chem. 2008, 73, 312.
J. Org. Chem. Vol. 75, No. 21, 2010 7467