Stereochemical and skeletal diversity employing pipecolate ester scaffolds

Article abstract of DOI:10.1021/ol070321g

Equation presented The stereocontrolled synthesis of pyridooxazinones by Mg(OTf)₂-promoted epoxide ring-opening with use of chiral pipecolates as nucleophiles is described. Pyridooxazinone products derived from azido-epoxides can be further rea

Full text of DOI:10.1021/ol070321g

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1529-1532
Stereochemical and Skeletal Diversity
Employing Pipecolate Ester Scaffolds
Yu Chen, John A. Porco, Jr.,* and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment (CMLD-BU), Metcalf Center for Science and Engineering,
590 Commonwealth AVenue, Boston UniVersity, Boston, Massachusetts 02215
porco@bu.edu; panek@bu.edu
Received February 7, 2007
ABSTRACT
The stereocontrolled synthesis of pyridooxazinones by Mg(OTf)2-promoted epoxide ring-opening with use of chiral pipecolates as nucleophiles
is described. Pyridooxazinone products derived from azido-epoxides can be further rearranged to seven-membered pyridodiazepinones by
azide reduction. The sequence of functional group interconversions generates diversity through topological and stereochemical variation.
The development of reaction methodology that allows rapid
access to structurally and stereochemically diverse frame-
works and scaffolds plays an important role in diversity-
oriented synthesis (DOS).1 Accordingly, methodology to
access new chemotypes in a stereocontrolled manner would
be a useful contribution to this area.2 Bicyclic alkaloids such
as quinolizidines and indolizidines incorporating a nitrogen
at the ring junction have a rich and diverse history as
pharmacological agents, and present an opportunity to create
DOS strategies loosely based on the natural product scaf-
folds.3
This Letter describes the assembly of stereochemically and
topologically diverse six- and seven-membered pyridoox-
azinones and pyridodiazepinones, respectively. The work also
illustrates the use of our amino-functionalized silane reagents4a
in the context of DOS. The approach makes efficient use of
our annulation strategy that provides enantioenriched pipe-
colates 3 and 6 as stereochemically diverse building blocks.4
An epoxide opening, lactonization, and ring expansion
sequence highlight a series of functional group interconver-
(2) (a) Wipf, P.; Stephenson, C. R. J.; Walczak, M. A. A. Org. Lett.
2004, 6, 3009-3012. (b) Gan, Z.; Reddy, P. T.; Quevillon, S.; Couve-
Bonnaire, S.; Arya, P. Angew. Chem., Int. Ed. 2005, 44, 1366-1368. (c)
Kesavan, S.; Su, Q.; Shao, J.; Porco, J. A., Jr.; Panek, J. S. Org. Lett.,
2005, 7, 4435-4438. (d) Beeler, A. B.; Acquilano, D. E.; Su, Q.; Yan, F.;
Roth, B. L.; Panek, J. S.; Porco, J. A., Jr. J. Comb. Chem. 2005, 7, 673-
681. (e) Adriaenssens, L. V.; Austin, C. A.; Gibson, M.; Smith, D.; Hartley,
R. C. Eur. J. Org. Chem. 2006, 22, 4998-5001. (f) Dandapani, S.; Lan,
P.; Beeler, A. B.; Beischel, S.; Abbas, A.; Roth, B. L.; Porco, J. A., Jr.;
Panek, J. S. J. Org. Chem. 2006, 71, 8934-8945. (g) Fitzmaurice, R. J.;
Etheridge, Z. C.; Jumel, E.; Woolfson, D. N.; Caddick, S. Chem. Commun.
2006, 46, 4814-4816. (h) Freifeld, L.; Holtz, E.; Dahmann, G.; Langer, P.
Eur. J. Org. Chem. 2006, 14, 3251-3258. (i) Beeler, A. B.; Su, S.;
Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 1413-
1419. (j) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc.
2007, 129, 1020-1021.
(1) For lead references on DOS, see: (a) Schreiber, S. L. Science 2000,
287, 1964-1969. (b) Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.;
Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 11577-11585. (c)
Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46-58.
(d) Arya, P.; Joseph, R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163-
180.
(3) (a) Garraffo, H. M.; Caceres, J.; Daly, J. W.; Spande, T. F. J. Nat.
Prod. 1993, 56, 1016-1038. (b) Fantauzzi, P. P.; Yager, K. M. Tetrahedron
Lett. 1998, 39, 1291-1294. (c) Jiang, W.; Alford, V. C.; Qiu, Y.;
Bhattacharjee, S.; John, T. M.; Haynes-Johnson, D.; Kraft, P. J.; Lundeen,
S. G.; Sui, Z. Bioorg. Med. Chem. 2004, 12, 1505-1515. (d) Daly, J. W.;
Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556-1575.
10.1021/ol070321g CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/17/2007

sions developed to access the target pyridooxazinone and
pyridodiazepinone ring systems.
The pipecolate scaffolds were constructed by using [4+2]-
annulation of aminosilanes syn-1 and anti-4 with m- or
p-bromobenzaldehyde providing both 2,6-cis- and 2,6-trans-
tetrahydropyridines 2 and 5 (Scheme 1).4a Diversification is
pipecolate ester 3b and epoxide (1.2 equiv) to provide the
2,6-cis-pyridooxazinone 7 in 16-20 h in good to excellent
yields (Table 1). To our knowledge, the use of Mg(OTf)2 to
promote epoxide-ring opening has not been reported.10
Table 1. Mg(OTf)2-Catalyzed Epoxide Ring-Opening of
cis-Pipecolates
Scheme 1. Preparation of Building Blocks
entry
R
isolate yielda
1
2
(R)-N3-CH2-
(S)-N3-CH2-
7a, 90%
7b, 92%
a Isolated yield after purification by SiO2 chromatography.
These conditions were then applied to 2,6-trans-6b with
mixed results; in comparison to reactions of 2,6-cis-pipeco-
lates, longer reaction time was required to achieve full
conversion for epoxide opening. Furthermore, cyclization was
not observed and only hydroxy-ester 8 was obtained illustrat-
ing a stereochemical dependency on the lactone formation
step (Table 2). The acyclic intermediate 8 was isolated and
established through variation in stereochemistry as well as
positional variation of the aryl bromide. To avoid epimer-
ization of the C6 stereocenter,5 annulation products 2 and 5
(bearing a vinyl glycine-like moiety) were protected as
trifluoroacetamides before hydrogenation of the tetrahydro-
pyridine ring. Removal of the acetamide afforded the free
secondary amines 2,6-cis-3 and 2,6-trans-6.4a
Table 2. Mg(OTf)2-Catalyzed Epoxide Ring-Opening of
trans-Pipecolates
Initial experiments concerning epoxide ring-opening were
carried out with 2,6-cis-pipecolate 3b in an effort to prepare
pyridooxazinone 7.6,7 Following literature precedent, a
number of different Lewis acid8 catalysts were evaluated for
the ring-opening of both racemic and enantioenriched ep-
oxides including 2-azidomethyl oxirane.9 Best results were
obtained by using a catalytic amount of Mg(OTf)2 with
(4) (a) Huang, H.; Spande, T. F.; Panek, J. S. J. Am. Chem. Soc. 2003,
125, 626-627. (b) See ref 2f.
(5) (a) Agami, C.; Couty, F.; Daran, J.; Prince, B.; Puchot, C. Tetrahedron
Lett. 1990, 31, 2889-2892. (b) Berkowitz, D. B.; McFadden, J. M.;
Chisowa, E.; Semerad, C. L. J. Am. Chem. Soc. 2000, 122, 11031-11032.
(6) Representative literature on similar bicyclic lactones: (a) Kim, Y.
B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.; Koh, H. Y.; Kim, Y.
Org. Lett. 2001, 3, 4149-4152. (b) Agami, C.; Comesse, S.; Kadouri-
Puchot, C. J. Org. Chem. 2002, 67, 2424-2428. (c) Pave, G.; Leger, J.-
M.; Jarry, C.; Viaud-Massuard, M.-C.; Guillaumet, G. J. Org. Chem. 2003,
68, 1401-1408.
entry
R
isolate yielda
1
2
(S)-N3-CH2-
(R)-N3-CH2-
9a, 80%
9b, 73%
a Isolated yield after purification by SiO2 chromatography.
(7) For epoxide opening of amino esters: (a) Lee, S.; Yi, K. Y.; Kim,
S.-K.; Suh, J.; Kim, N. J.; Yoo, S.-E.; Lee, B. H.; Seo, H. W.; Kim, S.-O.;
Lim, H. Eur. J. Med. Chem. 2003, 38, 459-471. (b) Babic, A.; Sova, M.;
Gobec, S.; Pecar, S. Tetrahedron Lett. 2006, 47, 1733-1735.
(8) (a) For activity and selectivity classification of Lewis acids, see:
Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Eur. J. 2000, 19, 3491-
3494.
cyclized with PPTS11 (6 mol %) at 100 °C for 10 h to give
2,6-trans-pyridooxazinone 9 as the major product with less
than 5% of the C6 epimer as determined by 1H NMR analysis
of the crude reaction mixture. The lower reactivity observed
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Org. Lett., Vol. 9, No. 8, 2007

opening with 2,6-cis- and 2,6-trans-methyl pipecolates, we
next focused on the lactone-to-lactam ring expansion via
azide reduction (Scheme 2).12 Conversion of pyridooxazi-
Scheme 2. Pyridodiazepinone Formation via Ring Expansion
of Aza-Pyridooxazinonesa
aIsolated yields after purification by SiO2 chromatography are
given.
Figure 1. Pyridooxazinones from cis-pipecolates. Isolated yields
after purification by SiO2 chromatography are given.
nones to the ring-expanded pyridodiazepinones was achieved
by using the venerable Staudinger reaction.13 Accordingly,
treatment of (S)-azido 2,6-cis-pyridooxazinone 7a with PS-
TPP (polystyryl triphenylphosphine)14 in methanol at 80 °C
(sealed tube, 12 h) provided the ring expansion product 2,6-
cis-pyridodiazepinone 10a in one pot via the intermediate
lactone amine.15,16 At temperatures exceeding 60 °C, 2,6-
trans-9a and 2,6-trans-9b epimerized at C6 to afford
enantiomers of 2,6-cis-10b and 2,6-cis-10a. We have not
established whether epimerization occurs during lactone or
lactam formation. In contrast to PS-TPP, use of Ph3P (1.5
equiv) in the solution phase allowed complete conversion
to 11a and 11b without epimerization at temperatures below
60 °C. The sequences in Table 1 and Scheme 2 illustrate
how subtle changes in the stereochemistry of the pipecolate
ester building block provide the basis for variation of
in the conversion of 8 to 9 may be a result of destablizing
1,3-diaxial interactions during the formation of the tetrahedral
intermediate leading to pyridooxazinone 9. Using this
strategy, we have created a small array of 2,6-cis- and 2,6-
trans-pyridooxazinones depicted in Figures 1 and 2, respec-
(9) For the synthesis of enantioenriched 2-azidomethyloxirane, see:
Spelberg, J. H. L.; Tang, L.; Kellogg, R. M.; Janssen, D. B. Tetrahedron:
Asymmetry 2004, 15, 1095-1102.
(10) Other less effective Lewis acids surveyed for epoxide ring opening
include: Yb(OTf)3, Yb(O-iPr)3, Sc(OTf)3, LiClO4, ZrCl4, Zr(O-iPr)4, Mg-
(ClO4)2, (R,R)-Co(Salen), B(C6F5)3, LiNTf2, NaH, [Rh(CO)2Cl]2, SmI2-
(THF)2, Aliquat R336, Sm(O-iPr)3, La(O-iPr)3, Bi(OTf)3‚nH2O, NaOMe,
NaI, ZnCl2.
(11) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
42, 3772-3774.
(12) (a) Nyffeler, P. T.; Liang, C.; Koeller, K. M.; Wong, C. J. Am.
Chem. Soc. 2002, 124, 10773-10778. (b) Pal, B.; Jaisankar, P.; Giri, V. S.
Synth. Commun. 2004, 34, 1317-1323.
(13) (a) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635-644.
(b) Staudinger, H.; Hauser, E. HelV. Chim. Acta 1921, 4, 861-868.
(14) Tunoori, A. R.; Dutta, D.; Georg, G. I. T. Tetrahedron Lett. 1998,
39, 8751-8754.
(15) Azido lactones 7a and 7b were initially obtained from the reaction
of (R)- and (S)-tosyl lactones with use of sodium azide. However, use of
(R)- and (S)-2-azidomethyloxirane in ring openings provided both cis and
trans lactones 7 and 9 in excellent yields.
(16) (a) Zhang, W.; Mayer, J. P.; Hall, S. E.; Weigel, J. A. J. Comb.
Chem. 2001, 3, 255-256. (b) Charette, A. B.; Boezio, A. A.; Janes, M. K.
Org. Lett. 2000, 24, 3777-3779.
Figure 2. Pyridooxazinones from trans-pipecolates. Isolated yields
after purification by SiO2 chromatography are given.
tively. Making use of a range of chiral epoxides, both 2,6-
cis- and 2,6-trans-tetrahydropyridine afforded the desired
pyridooxazinones 7c-p (Figure 1) and 9c-k (Figure 2) in
good to excellent yield.
Having succeeded in developing conditions to obtain
pyridooxazinones via Mg(OTf)2-catalyzed epoxide ring
Org. Lett., Vol. 9, No. 8, 2007
1531

topology (trans and cis ring fusion) of pyridooxazinones 7
and 9 and pyridodiazepinones 10 and 11.
The efficiency of the ring expansion prompted us to
investigate a one-pot synthesis of N-substituted pyridodiaz-
epinones via Staudinger13a reaction promoted with triphen-
ylphosphine with the intent of expanding scaffold diversity.
Unfortunately, a one-pot approach to N-substituted pyridodi-
azepinones was unsuccessful with use of the conditions
optimized for pyridodiazepinones 10 and 11. The desired
N-substituted pyridodiazepinones were not observed during
attempted one-pot addition of NaBH4 or NaBH3CN in MeOH
to a THF solution of the crude imine 12. However, the
N-substituted pyridodiazepinone 14 could be prepared by
using a two-step process that included isolation of the
intermediate imine 12 and treatment with NaBH3CN in
MeOH at rt to give 14 in 90% yield (Scheme 3).
Scheme 3. N-Substituted Pyridodiazepinone Formation
Figure 3. N-Substituted pyridodiazepinone scaffolds. Isolated
yields after purification by SiO2 chromatography are given.
studies concerning use of the pipecolate esters in library
synthesis as well as biological evaluation of the pyridoox-
azinone/pyridodiazepinone scaffolds are in progress and will
be reported in due course.
Acknowledgment. Financial support was obtained from
the NIGMS CMLD initiative (P50 GM067041, J.A.P., Jr.)
and RO1 GM55740 (J.S.P.). The authors are grateful to
Drs. Ping Lan, Sarathy Kesavan, and Aaron Beeler (Bos-
ton University) for helpful discussions. The authors also
thank Dr. Christopher Singleton (CMLD-BU) for 2D NMR
analysis.
Finally, a collection of pyridodiazepinones 14-22 bearing
substitution of the lactam nitrogen was prepared. This series
of scaffolds is shown in Figure 3, illustrating the versatility
of the overall functional group interconversion sequence.
In conclusion, a reaction sequence employing Mg(OTf)2-
catalyzed epoxide opening with 2,6-cis- and 2,6-trans-methyl
pipecolates, followed by lactone formation, has been devel-
oped to prepare functionalized pyridooxazinones. Azide
reduction enabled ring expansion to seven-membered pyri-
dodiazepinones. Further diversification was achieved by
converting the intermediate aza-pyridooxazinones to second-
ary amines prior to pyridodiazepinone formation.17 Further
Supporting Information Available: General experimen-
tal data and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL070321G
(17) The ultility of the arylbromide functionality in building blocks 3
and 6 has been established earlier on our studies of diketopiperazines; see
ref 1f.
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Org. Lett., Vol. 9, No. 8, 2007