Stereoselective synthesis of pyridinones: Application to the synthesis of (-)-barrenazines

Article abstract of DOI:10.1021/ol0609006

The stereoselective synthesis of pyridinones was accomplished by the nucleophilic addition of Grignard reagents to a chiral pyridinium salt derived from 4-methoxypyridine. This methodology was applied to an expedient synthesis of (-)-barrenazine A and B.

Full text of DOI:10.1021/ol0609006

ORGANIC
LETTERS
2006
Vol. 8, No. 14
2985-2988
Stereoselective Synthesis of
Pyridinones: Application to the
Synthesis of (−)-Barrenazines
Thilo Focken and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Quebec, H3C 3J7, Canada
andre.charette@umontreal.ca
Received April 13, 2006
ABSTRACT
The stereoselective synthesis of pyridinones was accomplished by the nucleophilic addition of Grignard reagents to a chiral pyridinium salt
derived from 4-methoxypyridine. This methodology was applied to an expedient synthesis of ( )-barrenazine A and B. After N-functionalization
−
and 1,4-reduction of the pyridinone system, the corresponding
pyridinopyrazine skeleton of the barrenazine alkaloids.
r
-amino piperidinones readily undergo dimerization to give the hexahydrodi-
In 2003, Kashman and co-workers isolated two novel
cytotoxic alkaloids, barrenazine A (1) and B (2), from
an unidentified tunicate collected at Barren Islands in
Madagascar.1 These two compounds have a unique 1,3,4,6,8,9-
hexahydrodipyridino[3,4-b:3′,4′-e]pyrazine skeleton. Re-
lated naturally occurring structures are rare, and among
those are the hexahydrodipyranopyrazines palythazin and
isopalythazine2c and the trihydropyranopyrazine clavulazine.2a
A synthesis of palythazine in six steps was reported starting
from tetra-O-benzoylated D-glucose.2b Herein, we report an
expedient, enantioselective synthesis of both barrenazines
from a common intermediate.
of the addition of a nucleophile to a chiral or achiral N-alkyl-
or N-acylpyridinium salt.4 As part of our ongoing research
program directed toward the expedient synthesis of enantio-
pure, polysubstituted piperidines from readily available
starting materials, we developed a new methodology for the
generation of pyridinium salts from pyridine, secondary
amide 5, and triflic anhydride.5 These salts undergo highly
diastereo- and regioselective addition of carbon nucleophiles
to produce dihydropyridines.
Our retrosynthetic analysis of barrenazines A and B is
depicted in Figure 1. It was envisioned that the pyrazine core
could be assembled through the dimerization of amino
pyridinone 3. Fragment 3 would be elaborated by the
stereoselective functionalization of 4-methoxypyridine (4).
A strategy that has been frequently used to prepare
substituted piperidine and piperidinone alkaloids3 consists
(1) Chill, L.; Aknin, M.; Kashman, Y. Org. Lett. 2003, 5, 2433-2435.
(2) (a) Watanabe, K.; Iguchi, K.; Fujimori, K. Heterocycles 1998, 49,
269-274. (b) Jarglis, P.; Lichtenthaler, F. W. Angew. Chem., Int. Ed. Engl.
1982, 21, 141-142. (c) Uemura, D.; Toya, Y.; Watanabe, I.; Hirata, Y.
Chem. Lett. 1979, 12, 1481-1482.
Figure 1. Retrosynthetic analysis of barrenazine A and B.
10.1021/ol0609006 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/10/2006

The addition of 4-methoxypyridine (4, 2.3 equiv) to a
mixture of amide 5 (1.0 equiv) and triflic anhydride (1.1
equiv) at -78 °C led to the formation of the desired
pyridinium salt (Table 1).
with simple alkylmagnesium reagents such as methyl-
magnesium bromide (entry 1) but also with bulkier nucleo-
philes such as tert-butylmagnesium bromide (entry 4).
Furthermore, the addition of vinyl-, aryl-, and furyl-
magnesium bromides led to adducts 6g, 6j, and 6k, respec-
tively, with excellent stereocontrol (entries 7, 10, and 11).
Only the addition of alkynylmagnesium reagents resulted in
a lower selectivity (entries 8 and 9).9
Table 1. Nucleophilic Addition to Pyridinium Salts Derived
from 4-Methoxypyridine (4) and Amide 5
The synthesis of (-)-barrenazines A and B started with
the introduction of the side chain using an appropriate
organomagnesium reagent (Scheme 1). Two approaches were
Scheme 1. Synthesis of R-Iodo Pyridinone 8 and Crystal
Structure of 7a
entry
RMgBr
product
yield (%)a
drb
1
2
3
4
5
6
7
8
9
Me
Et
n-Bu
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
76
71
61
70
84c
64
52 + 8
65
66
95:5
93:7
>95:5
93:7
>95:5
93:7
92:8
83:17
89:11
91:9
t-Bu
(CH2)6OTBS
(CH2)5CHdCH2
CHdCH2
CtCCH3
CtCPh
Ph
10
11
6j
6k
furanyl
65
95:5
1
a Products isolated as a single diastereomer. b Determined by H NMR
of the crude product. c Mixture of diastereomers (dr ) 13:1).
NMR monitoring of the pyridinium salt formation6 indi-
cated that the activation process was complete within 5 h at
room temperature. The pyridinium salt solution was then
cooled to -20 °C, and an ether solution of the Grignard
reagent was added. After acidic hydrolysis of the intermediate
methyl enol ethers, pyridinones 6a-k were obtained in
excellent diastereoselectivities and good yields.7 We found
that using THF as a cosolvent in the reaction led to a decrease
in diastereoselectivity.8 The addition proceeded well not only
pursued in parallel starting from 6e (Table 1, entry 5) and
from 6f (Table 1, entry 6).
The R-iodination of pyridinone 6e as well as that of ethyl
derivative 6b were efficiently performed using ICl in the
presence of Cs2CO3 to give 7a and 7b, respectively.10 The
generation of the unsaturated side chain of (-)-barrenazine
B (2) was completed by desilylation using TBAF, Swern
oxidation, and Wittig olefination to give 8.
Alternatively, the terminal olefin moiety of (-)-barren-
azine B (2) could be directly introduced when using the
organomagnesium reagent derived from 7-iodohept-1-ene.
Thus, the corresponding pyridinone 6f was obtained in high
diastereoselectivity (Table 1, entry 6). The chemoselective
(3) For recent reviews on the stereoselective synthesis of piperidines,
see: (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729. (b) Felpin,
F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712. (c) Weintraub,
P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953-2989.
(4) For selected, recent references on the syntheses of pyridinones by
addition of nucleophiles to pyridinium salts and the use of pyridinones in
synthesis, see: (a) Comins, D. L.; Sahn, J. J. Org. Lett. 2005, 7, 5227-
5228. (b) Comins, D. L.; King, L. S.; Smith, E. D.; Fe´vrier, F. C. Org.
Lett. 2005, 7, 5059-5062. (c) Knapp, S.; Yang, C.; Pabbaraja, S.; Rempel,
B.; Reid, S.; Withers, S. G. J. Org. Chem. 2005, 70, 7715-7720. (d) Kuethe,
J. T.; Comins, D. L. J. Org. Chem. 2004, 69, 5219-5231. (e) Ege, M.;
Wanner, K. T. Org. Lett. 2004, 6, 3553-3556. (f) Kuethe, J. T.; Comins,
D. L. J. Org. Chem. 2004, 69, 2863-2866.
(5) (a) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747-2750. (b)
Lemire, A.; Beaudoin, D.; Grenon, M.; Charette, A. B. J. Org. Chem. 2005,
70, 2368-2371. (c) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A.
B. Org. Lett. 2004, 6, 3517-3520. (d) Charette, A. B.; Grenon, M.; Lemire,
A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829-11830.
(6) Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694-1703.
(7) See Supporting Information for details.
(8) The organomagnesium reagents were either purchased as solutions
in Et2O or freshly prepared prior to use from the corresponding alkyl iodides,
vinyl, or phenyl bromides using t-BuLi or by deprotonation using n-BuLi,
followed by transmetalation to MgBr2‚OEt2. See Supporting Information
for details.
(9) THF had to be added in these reactions to solubilize the organo-
magnesium reagents.
(10) ICl for iodination of pyridinones: (a) Comins, D. L.; Hiebel, A.-
C.; Huang, S. Org. Lett. 2001, 3, 769-771. (b) See also: Comins, D. L.;
Joseph, S. P.; Chen, X. Tetrahedron Lett. 1995, 36, 9141-9144.
2986
Org. Lett., Vol. 8, No. 14, 2006

conversion of 6f to 8 was then accomplished using I2 in the
presence of pyridine.11
of the Boc derivatives 9 to the saturated piperidinone 10
would circumvent this problem. The construction of sym-
metrical pyrazines from R-amino aldehydes and ketones is
well-known, and condensation usually proceeds fairly eas-
ily.15 The 1,4-reduction of 9 using known procedures such
as L-selectride16 or Stryker’s reagent proved to be difficult.17
Poor selectivity of 1,4- vs 1,2-reduction and/or low yields
of the corresponding piperidinones were observed. The only
reagent that gave complete 1,4-selectivity and full conversion
was a combination of CuBr and LiAl(OtBu)3H.18 Thus, we
could obtain compounds 10a and 10b in excellent yields and
good diastereoselectivities. Although having diastereomeri-
cally enriched 10 is meaningless for the remainder of the
synthesis, as the stereogenic center is lost in the subsequent
step, the Boc-amino ketones 10 are interesting chiral building
blocks.
R-Iodo, R,â-unsaturated carbonyl compounds are valuable
intermediates in organic synthesis, especially in transition-
metal-mediated reactions.12 For the purpose of the synthesis
of 1 and 2, R-iodo 7a and 8 were transformed into the Boc-
amino enones 9a,b via a Buchwald’s Cu-catalyzed C-N
cross-coupling using tert-butyl carbamate13 (Scheme 2).
Scheme 2. Synthesis of Protected Barrenazine A and B
The configuration of piperidinone 10a was determined by
analyzing the coupling constants and by NOESY experi-
ments. Nitrogen heterocycles protected with acyl, carbamate,
or imidate groups are known to place substituents at the
2-position axially, to minimize A1,3 strain (Figure 2).19 NMR
Figure 2. Configuration of N-Boc-amino ketone 10.
analysis indicated that diastereomer 10 was the major product
arising from the reduction (Figure 2).
Having Boc-amino ketones 10 in hand, the next steps
consisted of the amine deprotection with TFA followed by
the oxidative cyclization under basic conditions in air to
afford 11.
The amidine auxiliary was then removed via an intra-
molecular, alkoxy-assisted strategy using BBr3 (Scheme 3).
Originally, we intended to use 9 directly in a reductive
cyclization to construct the pyrazine core of barrenazine.
However, the R-amino enone obtained from 9a upon TFA
deprotection did not undergo the desired reaction using Pd/C
and hydrogen gas.14 Presumably, the enone system is too
deactivated because of conjugation of the free amino group
with the amidine moiety. It was anticipated that reduction
(15) Selected examples: (a) Tonsiengsom, F.; Miyake, F. Y.; Yakushijin,
K.; Horne, D. A. Synthesis 2005, in print. (b) Gosh, U.; Ganessunker, D.;
Sattigeri, V. J.; Carlson, K. E.; Mortensen, D. J.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. Bioorg. Med. Chem. 2003, 11, 629-657. (c) Chiba,
T.; Sakagami, H.; Murata, M.; Okimoto, M. J. Org. Chem. 1995, 60, 6764-
6770.
(16) Selected examples: (a) Alcaide, B.; Almendros, P.; Alonso, J. M.;
Aly, M. F. Chem.-Eur. J. 2003, 9, 3415-3426. (b) Tasber, E. S.; Garbaccio,
R. M. Tetrahedron Lett. 2003, 44, 9185-9188. (c) Lim, S. H.; Curtis, M.
D.; Beak, P. Org. Lett. 2001, 3, 711-714. (d) Comins, D. L.; Libby, A.
H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem. 1999, 64, 2184-2185.
(17) Selected examples: (a) Lipshutz, B. H.; Chrisman, W.; Noson, K.;
Papa, P.; Sclafani, J. P.; Vivian, R. W.; Keith, J. M. Tetrahedron 2000, 56,
2779-2788. (b) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron
Lett. 1998, 39, 4627-4630. (c) Mahoney, W. S.; Brestensky, D. M.; Stryker,
J. M. J. Am. Chem. Soc. 1988, 110, 291-293.
(18) 1,4-Reduction of enones with CuX/LiAlH: (a) Comins, D. L.;
LaMunyon, D. H. Tetrahedron Lett. 1989, 30, 5053-5056. (b) Comins, D.
L.; Abdullah, A. H. J. Org. Chem. 1984, 49, 3392-3394. (c) Semmelhack,
M. F.; Stauffer, R. D.; Yamashita, A. J. Org. Chem. 1977, 42, 3180-3188.
(19) (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679-
3681. (b) Hoffmann, H. R. Chem. ReV. 1989, 89, 1841-1860. (c) Johnson,
F. Chem. ReV. 1968, 68, 375-413. See also the X-ray crystal structures in
the Supporting Information.
(11) I2/pyridine reagent: (a) Krafft, M. E.; Cran, J. W. Synlett 2005,
1263-1266. (b) Souza, F. E. S.; Sutherland, H. S.; Carlini, R.; Rodrigo, R.
J. Org. Chem. 2002, 67, 6568-6570. (c) Johnson, C. R.; Adam, J. P.; Braun,
M. P.; Senanayake, C. B. W.; Wovkulich, P. M.; Uskokovic, M. R.
Tetrahedron Lett. 1992, 33, 917-918.
(12) For review of â-iodo carbonyl compounds in Pd-catalyzed cross-
coupling reactions, see: Negishi, E. J. Organomet. Chem. 1999, 576, 179-
194.
(13) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003,
5, 3667-3669.
(14) For cyclizations of â-amino cyclohexenones, see: (a) Dro¨gemu¨ller,
M.; Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeldt, E. Eur. J. Org. Chem.
1998, 2811, 1-2831. (b) Kramer, A.; Ullmann, U.; Winterfeldt, E. J. Chem.
Soc., Perkin Trans. 1 1993, 2865-2867.
Org. Lett., Vol. 8, No. 14, 2006
2987

Pyrazine 11b is an interesting compound to apply ring-
closing metathesis conditions.21 Applying Grubbs’ second
generation catalyst, followed by hydrogenation of the double
bond and removal of the chiral auxiliary, allowed the
isolation of the cyclophane-type macrocycle 16 in 51% yield
(Scheme 4).22
Scheme 3. Amidine Group Cleavage and Isolation of
Barrenazine A (15a) and B (15b) Bis(trifluoroacetate)a
Scheme 4. RCM of 11b to Give Cyclophane 16a
a TFA salt was obtained after HPLC purification; see Supporting
Information for details.
In summary, an expedient synthesis of (-)-barrenazine A
and B was accomplished in 30% (eight steps) and 28%
(seven steps) overall yield, respectively, from 4-methoxy-
pyridine. The synthetic route allows for the preparation of
various analogues as exemplified by the synthesis of the ethyl
side chain analogue.
a TFA salts were obtained after HPLC purification; see Support-
ing Information for details.
Acknowledgment. This work was supported by the
National Science and Engineering Research of Canada
(NSERC), Merck Frosst Canada & Co., Boehringer
Ingelheim (Canada), Ltd., and the Universite´ de Montre´al.
We are also grateful to Professor Yoel Kashman from Tel
Aviv University for providing the spectra of the isolated
natural products. We also thank Dr. M. Sales for helpful
discussions.
After cleavage of the methoxy groups on the amidine moiety
of 11a, 12 spontaneously fragmented to afford oxazoline 14
and free hexahydrodipyridinopyrazine, which was isolated
as its Boc derivative 13. The same procedure applied to
pyrazine 11b, obtained after hydrogenation of the terminal
alkenes, produced barrenazine A bis(trifluoroacetate) (15a)
in 55% yield.
The amidine cleavage with the unsaturated side chain still
in place proved to be more challenging. A mixture with
varying amounts of brominated side chains was observed if
the same reaction conditions as before were used. Fortu-
nately, a combination of BBr3 and 2,6-lutidine turned out to
cleave the methoxy groups efficiently while leaving the
terminal olefin untouched. Thus, barrenazine B (15b) was
isolated as its bis(trifluoroacetate) salt in 51% yield.20 The
spectroscopic data for both 15a and 15b were identical to
those reported by Kashman.1 Neutralization upon treatment
with saturated aqueous NaHCO3 led to barrenazine A and
B.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds and crystal structure data for 6i and 7a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0609006
(21) For reviews on the olefin metathesis reaction, see: (a) Deiters, A.;
Martin, S. F. Chem. ReV. 2004, 104, 2199-2238. (b) Grubbs, R. H.
Tetrahedron 2004, 60, 7117-7140. (c) Connor, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900-1923. (d) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18-29. (e) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012-3043.
(20) The ratio of barrenazine/TFA was determined by NMR using R,R,R-
trifluorotoluene as the internal standard.
(22) A mixture of E/Z double-bond isomers in a ratio of 8:1 is isolated,
if the hydrogenation step is avoided.
2988
Org. Lett., Vol. 8, No. 14, 2006