SmI2-mediated couplings of α-amino acid derivatives. Formal synthesis of (-)-pumiliotoxin 251D and (±)-epiquinamide

Article abstract of DOI:10.1021/ol400903n

The coupling between cyclic and acyclic α-amino acid derivatives and methyl acrylate, mediated by samarium diiodide, is described. The method constitutes a powerful tool to construct indolizidine, quinolizidine, and piperidine systems in a straightforward two-step fashion. The formal synthesis of (-)-pumiliotoxin 251D and (±)-epiquinamide is achieved after two or three steps from these amino acid derivatives.

Full text of DOI:10.1021/ol400903n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
SmI2‑Mediated Couplings of r‑Amino
Acid Derivatives. Formal Synthesis
of (À)-Pumiliotoxin 251D and
(()-Epiquinamide
Vagner D. Pinho,† David J. Procter,‡ and Antonio C. B. Burtoloso*,†
´
Instituto de Quımica de Sao Carlos, Universidade de Sao Paulo, CEP 13560-970,
Sao Carlos, SP, Brazil, and The School of Chemistry, University of Manchester,
~
~
~
Manchester, M13 9PL, U.K.
antonio@iqsc.usp.br
Received April 2, 2013
ABSTRACT
The coupling between cyclic and acyclic R-amino acid derivatives and methyl acrylate, mediated by samarium diiodide, is described. The method
constitutes a powerful tool to construct indolizidine, quinolizidine, and piperidine systems in a straightforward two-step fashion. The formal
synthesis of (À)-pumiliotoxin 251D and (()-epiquinamide is achieved after two or three steps from these amino acid derivatives.
N-Heterocycles are of remarkable importance in the fields
of asymmetric catalysis, chemical-biology, and medicinal
chemistry, and they continue to inspire the development of
new synthetic methodologies. Among them, indolizidine,
quinolizidine, and piperidine alkaloids play an important
role due to their interesting framework and biological
activities. These compounds are very widespread in nature
and are found in a myriad of organisms.1 Although the
literature describes plenty of methods to prepare these
heterocyclic systems, short, direct, and diversity-oriented
approaches are scarce.
Samarium(II) iodide (SmI2) is a powerful reagent in
organic synthesis2 and has been applied with success in the
synthesis of many nitrogen and oxygen heterocycles. Due
to its great potential asa one electron donor, it is capable of
mediating a wide range of transformations.2,3
The coupling between acrylates and aldehydes (or ketones)
mediated by SmI2 was first described by Fukuzawa4 and
Inanaga.5 This reaction has proven to be one of the most
(2) Procter, D. J.; Flowers, R. A.; Skrydstrup, T. Organic Synthesis
Using Samarium Diiodide: A Practical Guide; Royal Society of Chemistry:
Cambridge, 2010.
(3) (a) Soderquist, J. A. Aldrichimica Acta 1991, 24, 15. (b) Molander,
G. A. Chem. Rev. 1992, 92, 29. (c) Molander, G. A. Org. React. 1994, 46,
21. (d) Kagan, H. B. Tetrahedron 2003, 59, 10351. (e) Edmonds, D. J.;
Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371.
(4) (a) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem.
Soc., Chem. Commun. 1986, 624. (b) Fukuzawa, S.; Iida, M.; Nakanishi,
A.; Fujinami, T.; Sakai, S. J. Chem. Soc., Chem. Commun. 1987, 920.
(c) Fukuzawa, S.; Seki, K.; Tasuzawa, M.; Mutoh, K. J. Am. Chem. Soc.
1997, 119, 1482.
†
~
Universidade de Sao Paulo.
‡ University of Manchester.
(1) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (b) Michael, J. P.
Nat. Prod. Rep. 2007, 24, 191. (c) Michael, J. P. Nat. Prod. Rep. 2007, 25,
139. (d) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603. (e) Michael, J. P.
Nat. Prod. Rep. 2004, 21, 625. (f) Michael, J. P. Nat. Prod. Rep. 2003, 20,
458. (g) Michael, J. P. Nat. Prod. Rep. 2002, 19, 719. (h) Michael, J. P.
Nat. Prod. Rep. 2001, 18, 520. (i) Michael, J. P. Nat. Prod. Rep. 2000, 17,
579 and references therein cited.
(5) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986,
27, 5763.
r
10.1021/ol400903n
XXXX American Chemical Society

important transformations3e,6 in the chemistry of SmI2
and has been applied to the construction of a range of
carbon frameworks in recent years.7 However, a strong
limitation of this method arises when R-amino-aldehydes/
ketones are employed as substrates. As described by
Honda,8 the exposure of these aldehydes/ketones to SmI2
is typically accompanied by CÀN bond scission R to the
carbonyl group (Scheme 1). Herein, we describe for the
first time the Fukuzawa and Inanaga couplings of amino-
aldehydes/ketones and methyl acrylate, without CÀN
bond cleavage, and the application of such couplings
in the direct construction of functionalized indolizidine,
quinolizidine, and piperidine systems (Scheme 2). In just
two key transformations the method allows the synthesis
of indolizidine 1 and quinolizidine 2, advanced intermedi-
ates in the total syntheses of pumiliotoxin 251D9,10 and
epiquinamide,11 respectively.
Scheme 2. This Work: Sm(II)-Mediated Coupling Strategy for
the Construction ofPiperidines, Indolizidines, and Quinolizidines
Scheme 1. Honda’s Work on Reductive Deamination
Table 1. Optimizing the Sm(II)-Mediated Couplings
We started our study by investigating the coupling between
commercially and readily available (S)-N-Boc-prolinal or
(S)-N-Cbz-prolinal12 and methyl acrylate (Table 1).
As depicted in Table 1, the proton source, amount of
methyl acrylate, and order of addition were investigated
during the optimization of the reaction. The addition of
1À2 equiv of methyl acrylate in the presence of t-BuOH,
MeOH, or H2O as proton sources gave low yields of
lactone products (23À31%, entries 1À6). Using 10 equiv
acrylate
(equiv)
SmI2
proton source
(equiv)
yield
(%)
entry
PG
(equiv)
1
Cbz
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
Boc
Cbz
2
2
t-BuOH (1)
t-BuOH (1)
t-BuOH (5)
MeOH (5)
t-BuOH (1)
H2O (5)
23a
2
2
2
23a
3
2
2
31a
4
2
2
30a
(6) (a) Vogel, J. C.; Butler, R.; Procter, D. J. Tetrahedron 2008, 64,
11876. (b) Kerrigan, N. J.; Hutchison, P. C.; Heightman, T. D.; Procter,
D. J. Chem. Commun. 2003, 1402. (c) Kerrigan, N. J.; Hutchison, P. C.;
Heightman, T. D.; Procter, D. J. Org. Biomol. Chem. 2004, 2, 2476.
(d) Kawatsura, M.; Matsuda, F.; Shirahama, H. J. Org. Chem. 1994, 59,
6900. (e) Kerrigan, N. J.; Upadhyay, T.; Procter, D. J. Tetrahedron Lett.
2004, 45, 9087. (f) Xu, M.-H.; Wang, W.; Lin, G. Org. Lett. 2000, 2, 2229.
(g) Xu, M.-H.; Wang, W.; Xia, L.-J.; Lin, G. J. Org. Chem. 2001, 66,
3953. (h) Wang, W.; Zhong, Y.; Lin, G. Tetrahedron Lett. 2003, 44, 4613.
(i) Zhang, Y.; Wang, Y.; Dai, W.-M. J. Org. Chem. 2006, 71, 2445.
(7) (a) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int.
Ed. 2009, 48, 7140. (b) Kaname, M.; Yoshifuji, S. Tetrahedron Lett.
1992, 33, 8103. (c) Tadano, K.; Isshiki, Y.; Minami, M.; Ogawa, S. J.
Org. Chem. 1993, 58, 6266. (d) Molander, G. A.; Sono, M. Tetrahedron
1998, 54, 9289. (e) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron Lett.
1999, 40, 8859–8862. (f) Carroll, G. L.; Little, R. D. Org. Lett. 2000, 2,
2873. (g) Shirahama, H.; Kamabe, M.; Miyazaki, T.; Hashimoto, K.
Heterocycles 2002, 56, 105. (h) Suzuki, K.; Nakata, T. Org. Lett. 2002, 4,
3943. (i) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5,
4811.
5
1
3
27a
6
2
4
24c
7
10
10
10
10
10
2.5
2.5
2.5
2.5
2.5
MeOH (5)
H2O (5)
43bÀd
55b,c
48
8
9
MeOH (5)
H2O (5)
10
11
65bÀd
75bÀd
H2O (5)
a Recovery of starting aldehyde. b SmI2 added to starting material.
c H2O added to SmI2 before addition of starting material to SmI2.
d Syringe pump addition of SmI2.
of methyl acrylate, lactones 5 and 6 were provided in
43À75% yield (entries 7À11). For this case, the use of
H2O as the proton source13 seemed to be the best choice. It
is interesting to mention that lactones 5 and 6 were formed
as single diastereomers14 and that no products arising from
CÀN bond cleavage were observed.
(8) Honda, T.; Ishikawa, F. Chem. Commun. 1999, 1065.
(9) Fox, D. N. A.; Lathbury, D.; Mahon, M. F.; Molloy, K. C.;
Gallagher, T. J. Am. Chem. Soc. 1991, 113, 2652–2656.
€
(10) Sudau, A.; Munch, W.; Bats, J.-W.; Nubbemeyer, U. Eur. J.
Org. Chem. 2002, 2002, 3315.
(11) Wijdeven, M. A.; Wijtmans, R.; Vanden Berg, R. J. F.; Noorduin,
W.; Schoemaker, H. E.; Sonke, T.; Van Delft, F. L.; Blaauw, R. H.; Fitch,
R. W.; Spande, T. F. Org. Lett. 2008, 10, 4001.
(12) Prolinals 3 and 4 can also be prepared in multigram quantities
and in two or three steps from the cheap amino acid proline.
(13) Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem.
Commun. 2012, 48, 330.
(14) Due the presence of rotamers in the NMR spectra of lactones,
the diastereoselectivity was securely determined after the sequence of
deprotection and lactamization.
B
Org. Lett., Vol. XX, No. XX, XXXX

The conversion of lactone 6 to an indolizidine system, as
well as the proof of its stereochemistry, was accomplished
after a one-pot synthesis of the known octahydroindolizidin-
8-ol 7.15 Treatment of 6 with H2 and Pd/C in MeOH for 24 h
afforded indolizidine 7 in 97% yield after Cbz deprotection
and lactamization (Scheme 3).
Table 2. Extension of the Sm(II)-Mediated Coupling to Other
Amino Acids Derivatives
Scheme 3. Construction of an Indolizidine System from Lactone 6
Employing the optimized conditions described in entry 11
(Table 1), we then turned our attention to the Sm(II)-
mediated coupling reaction of other amino acid derivatives,
in order to access different indolizidine, quinolizidine,
and piperidine systems. Targeting the formal syntheses of
pumiliotoxin 251D and (()-epiquinamide, we first elected
(S)-proline-derived methyl ketone 8 and N-Cbz-(()-
pipecolinal 9, respectively, to study the Sm(II) reaction
(Table 2). Moreover, considering the importance of indole
moieties in natural products and medicinal chemistry16 we
also employed indoline-2-carboxylic acid derived aldehyde
10 as a substrate. Acyclic aldehydes 11À12 were also studied
in the Sm(II)-mediated coupling. After the coupling of
carbonyl compounds 8À12 with methyl acrylate, lactones
13À17 were obtained in 42À65% yields. Identical to what
was observed in the case of lactone 6, all these reactions
furnished the threo isomer with good to complete diaster-
eoselectivity. The stereochemistry of the coupling products
was assigned by comparison of the NMR data of the
lactones, and the stereochemistry of the corresponding
cyclized products, with those of known compounds, and
by crystallographic analysis of lactam 18, derived from
lactone 15 (Scheme 4).
a 0.25 mmol scale. b Yield based on two experiments each, with 0.25
and 4.0 mmol scale of starting material.
Scheme 4. X-ray Study of Lactam 20
To show the utility of the present method for the
expedited preparation of indolizidine and quinolizidine
systems, the formal syntheses of pumiliotoxin 251D and
epiquinamide were accomplished from lactones 13 and 14,
(15) Lee, H. K.; Chun, J. S.; Pak, C. S. J. Org. Chem. 2003, 68, 2471.
(16) (a) De Sa Alves, F. R.; Barreiro, E. J.; Manssour Fraga, C. A.
Mini-Rev. Med. Chem. 2009, 9, 782. (b) Joule, J. A. Science of Synthesis
(Houben-Weyl, Methods of Molecular Transformations); Georg Thieme
Verlag: Stuttgart, 2000; Vol.10, pp 361À652. (c) Bonjoch, J.; Bosch, J.
Alkaloids 1996, 48, 75. (d) Sundberg, R. J. Indoles; Academic Press:
London, 1996. (e) Saxton, J. E. The Chemistry of Heterocyclic Compounds;
Academic Press: New York, 1994; Vol. 25, Part IV. (f) Chadwick, D. J.; Jones,
R. A.; Sundberg, R. J. Comprehensive Heterocyclic Chemistry; Pergamon:
Oxford, 1984; Vol. 4, pp 155À376.
respectively, after Cbz removal and lactamization
(Scheme 5).17 Threo isomer 13, obtained as a single isomer
after the Sm(II)-mediated coupling, was converted to
lactam 1 in a quantitative yield. Compound 1 not only is
the key intermediate in the total synthesis of pumiliotoxin
251D described by Gallagher9 but also constitutes the
principal bicyclic core of the pumiliotoxins. Many addi-
tional routes to this intermediate have been published
to date,10,17b,18 but just a few of them provide compound
1 in a straighforward fashion. For the formal synthesis
(17) For a straightforward preparation of lactones similar to 13 and
14, employing the addition of silyloxyfurans to iminion ions, see:
(a) Martin, S. F.; Corbett, J. W. Synthesis 1992, 1, 55. (b) Martin,
S. F.; Bur, S. K. Tetrahedron 1999, 55, 8905. (c) Santos, L. S.; Pilli, R. A.
Tetrahedron Lett. 2001, 42, 6999. (d) de Oliveira, M. C.; Santos, L. S.;
Pilli, R. A. Tetrahedron Lett. 2001, 42, 6995.
Org. Lett., Vol. XX, No. XX, XXXX
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(Scheme 5) were in complete accordance with those de-
scribed in the literature.9À11
Scheme 5. Formal Syntheses of Pumiliotoxin (À)-251D and
(()-Epiquinamide
In summary, we have demonstrated a straight-
forward approach for the construction of hydroxylated
indolizidine, quinolizidine, and piperidine systems from
cyclic and acyclic R-amino acid derivatives. Key to the
approach is a highly diastereoselective SmI2-mediated
coupling of R-amino acid derivatives with methyl acrylate,
followed by protecting group removal and lactamization.
The approach has been used in the short formal syntheses
of pumiliotoxin 251D and epiquinamide. To our knowl-
edge, the new syntheses are among the shortest reported
to date.
Acknowledgment. We thank FAPESP (Research Sup-
porting Foundation of the State of Sao Paulo) for financial
support (2012/04685-5) and a fellowship to V.D.P. (2008/
09653-9). We also thank CNPq for a research fellowship to
A.C.B.B. (307905/2009-8) and the University of Manchester
for support.
of epiquinamide, racemic piperidine 14 was employed, in
an analogous sequence. The spectroscopic data of 1 and 2
(18) (a) Cossy, J.; Cases, M.; Gomez Pardo, D. Synlett 1996, 909.
(b) Cossy, J.; Cases, M.; Gomez Pardo, D. Bull. Soc. Chim. Fr. 1997, 134,
141. (c) Barrett, A. G. M.; Damiani, F. J. Org. Chem. 1999, 64, 1410.
(d) Ni, Y.; Zhao, G.; Ding, Y. J. Chem. Soc., Perkin Trans. 1 2000, 3264.
(e) Wang, B.; Fang, F.; Lin, G. Tetrahedron Lett. 2003, 44, 7981–7984.
(f) O’Mahony, G.; Nieuwenhuyzen, M.; Armstrong, P.; Stevenson, P. J.
J. Org. Chem. 2004, 69, 3968. (g) Wu, H.; Yu, M.; Zhang, Y.; Zhao, G.
Chin. J. Chem. 2009, 27, 183.
Supporting Information Available. NMR spectra of all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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