Alkyne-mediated domino hydroformylation/double cyclization: Mechanistic insight and synthesis of (±)-tashiromine

Article abstract of DOI:10.1039/c0cc05646d

A novel domino reaction, alkyne-mediated domino hydroformylation/double cyclization, has been developed for rapid preparation of indolizidine type alkaloids. DFT calculations were applied for rationales of reactivity and selectivity. A concise synthesis of tashiromine as the application of the methodology is also reported.

Full text of DOI:10.1039/c0cc05646d

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COMMUNICATION
Alkyne-mediated domino hydroformylation/double cyclization:
mechanistic insight and synthesis of (ꢀ)-tashirominew
Wen-Hua Chiou,* Yi-Huei Lin, Guei-Tang Chen, Yu-Kai Gao, Yu-Che Tseng, Chien-Lun Kao
and Jui-Chi Tsai
Received 17th December 2010, Accepted 1st February 2011
DOI: 10.1039/c0cc05646d
A novel domino reaction, alkyne-mediated domino hydroformyl-
ation/double cyclization, has been developed for rapid preparation
of indolizidine type alkaloids. DFT calculations were applied for
rationales of reactivity and selectivity. A concise synthesis of
tashiromine as the application of the methodology is also
reported.
The bicyclization process is initiated by Rh-catalyzed
hydroformylation4 of amide 1 using suitable ligands,5 affording
exclusively linear aldehyde 2 as the major product. The
resulting aldehyde 2 undergoes spontaneously intramolecular
cyclization to give hemiamidal 3. In the presence of an acid,
dehydration of hemiamidal 3 yields N-acyliminium 4.6 Sub-
sequent intramolecular cyclization of N-acyliminium 4 with
the alkyne moiety as a p carbon nucleophile leads to formation
of cation intermediate 5, followed by solvent addition to yield
bicyclo product 6, which completes the whole bicyclization
process.
Recently, applications of domino reactions have emerged as
efficient and economical strategies for the syntheses of com-
plex structures.1,2 A domino reaction is defined as a process
involving two or more consecutive bond formations, in which
the resulting functionalities obtained in the initial transformation
are utilized as the functionalities of reactants in the following
transformation.3 Such a process does not only allow rapid
increase in molecular complexity from simple starting materials,
but also includes many advantages such as reduction of
consumption of solvents, reagents, and energy. We describe
here a novel methodology, alkyne-mediated domino Rh-catalyzed
hydroformylation/double cyclization, for ready construction of
indolizidine derivatives (Scheme 1).
Our investigation commenced with hydroformylation on
N-allylamide 1a, readily available from coupling of the corres-
ponding acids and allylamine. Treatment of amide 1a under
the hydroformylation condition (Scheme 2)7,8 afforded a
mixture of cyclized product 6a and unidentified side products,
indicating the second cyclization with the acetylene nucleophile
proceeded incompletely. After purification, enol acetate 6a
was obtained in 32% isolated yield (Scheme 2). We envisioned
that an electron donating group on the phenyl moiety could
enhance the nucleophilicity of the triple bond moiety. Thus,
reaction of amide 1b, bearing a para-methoxyphenyl group,
was carried out to yield single E-enol acetate 6b in 83%
isolated yield.9 However, reaction of alkyne 1c, bearing a
benzyloxymethyl group, was examined but led to a messy
mixture. Obviously, the nature of the substituent next to the
alkyne group exerted a critical effect on the second cyclization.
Exposure of E-enol acetate 6b in a basic methanol solution
afforded only single anti-ketone 7b in 81% yield.10,11
Reaction of 1d, bearing a methyl group at the C-2 position
of the carboxylic moiety, was carried out to give only single
Scheme
1 Alkyne-mediated domino hydroformylation/double
cyclizations of N-allyl alkynamides 1.
Department of Chemistry, National Chung Hsing University,
Taichung, Taiwan, 402, ROC. E-mail: wchiou@dragon.nchu.edu.tw;
Fax: +886-4 22862547; Tel: +886-4-22840411-420
w Electronic supplementary information (ESI) available: Experimental
procedure, 1H, 13C NMR spectra, stereochemistry assignment and
calculated geometry coordinates. See DOI: 10.1039/c0cc05646d
Scheme 2 Reactions of amides 1a–1c.
c
3562 Chem. Commun., 2011, 47, 3562–3564
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highly diastereoselective for 1d but fairly low for 1e. Such
issues prompted us to perform ab initio calculations for
cyclization of N-acyliminium 4 to cation 5, the critical step
governing the formation of the second ring moiety and the
diastereoselectivity. Therefore, we carried out the corresponding
DFT calculations to obtain all optimized geometries and
reaction pathway profiles. The results are summarized in
Table 1.
The cyclization of 4b is favoured with a relatively lower
activation energy barrier of 1.6 Kcal/mol and a highly exergonic
reaction of 9.6 Kcal/mol; while the cyclization of 4a requires a
higher activation energy barrier of 5.1 Kcal/mol but a less
exergonic reaction of 0.9 Kcal/mol. However, the cyclization of
4c requires a large activation energy value of 14.4 Kcal/mol to
give an unstable alkenyl cation 5c. It is also a very endergonic
reaction with free energy change of 13.3 Kcal/mol. Both reasons
of the high activation energy and the instability of the adduct
keep 4c from cyclization. Compared to 4c, 4a can undergo
the intramolecular cyclization followed by solvent addition,
producing enol acetate 6a. Installation of a para-methoxy group
renders the N-acyliminium substrates more reactive by lowering
the activation energy (1.5–2.3 Kcal/mol) and increasing the free
energy difference (ꢁ7.6 to ꢁ10.2 Kcal/mol). The results
confirmed the presence of the para-methoxyphenyl group is
indispensable for the reaction.
In both cyclizations of 4d and 4e, the small differences in
activation barriers for two reactions (0.2 Kcal/mol for 4d and
0.1 Kcal/mol for 4e) suggested the activation energy barriers
should not be a critical factor. In the cyclization of 4d, one can
see both that the syn adduct is more stable than the anti isomer
by 2.7 Kcal/mol (i.e. thermodynamically favored), and the
syn reactant Rsyn is more stable than the anti isomer Ranti by
3.6 Kcal/mol (i.e. more populated) (Fig. 1). Moreover, the
difference in the two transition states is substantially large
enough (3.8 Kcal/mol) that the transition state TSsyn of the syn
approach is even lower than the reactant Ranti of the anti
approach. It suggested that the formation of TSsyn is easier
Scheme 3 Reactions of amides 1d–1f.
syn product 6d in 87% yield, indicating that the C-2 position
was a stereogenic center (Scheme 3). Subsequent methanolysis
of enol acetate 6d afforded single ketone 7d in 72% yield. In
the same manner, the reaction of 1e, bearing an n-propyl
group at the C-1 position of the amine moiety, afforded
(Z, anti)-enol acetate 6e (22%), (E, anti)-enol acetate 6e
(41%), (E, syn)-enol acetate 6e (14%). The results indicated
that the C-1 position was also a stereogenic center, but
obviously less efficient than the C-2 position in the carboxylic
moiety. Individual methanolysis for (Z, anti)-enol acetate 6e
and (E, anti)-enol acetate 6e led to the formation of the same
product, identified as anti-ketone 7e, while reaction of (E, syn)-
enol acetate 6e afforded syn-ketone 7e. Direct treatment of
the crude reaction product of 1e in the basic solution yielded
anti-ketone 7e (50%) and syn-ketone 7e (15%). These results
led us to conclude that methanolysis of enol acetates possessing
an indolizidine moiety proceeded diastereoselectively to give
only a single isomer with an anti configuration H-8 and H-8a.
We also examined the reaction of 1f bearing a hex-5-ynamide
moiety (m = 2), affording enol tosylate 8f and an inseparable
mixture of E and Z enol acetate 6f (B 1 : 1). Unlike the single
product formation of mentioned enol acetates in the basic
methanol condition, methanolysis of the E/Z enol acetate
mixture 6f yielded two ketones, identified as anti-ketone 7f
and syn-ketone 7f. We were able to treat the crude product
directly in the basic solution, yielding enol tosylate 8f (4%),
anti-ketone 7f (27%) and syn-ketone 7f (30%).
than conformation change to Ranti, from reactant Rsyn
.
Accordingly, only the syn approach proceeds to give product
6d. In the cyclization of 4e, although the anti product is more
stable than the syn isomer by 1.5 Kcal/mol and the anti
reactant Ranti is also more stable than the syn isomer Rsyn by
0.9 kcal molꢁ1, the difference is essentially too small to prevent
the syn approach completely (Fig. 2). Additionally, the difference
in the two transition states is not large enough (1.0 Kcal/mol)
Table 1 Relative energies and activation Gibbs energies for cyclization
of N-acyliminium 4 to cation 5a
Cyclization
R
m
DGz
DG
4a - 5a
4b - 5b
4c - 5c
4d - 5d (syn)
4e - 5e (anti)
4f - 5f
C6H5–
4-MeOC6H4–
BnOCH2–
4-MeOC6H4–
4-MeOC6H4–
4-MeOC6H4–
1
1
1
1
1
2
+5.1
+1.6
+14.4
+1.5
+2.1
+2.3
ꢁ0.9
ꢁ9.6
+13.3
ꢁ10.2
ꢁ8.4
ꢁ7.6
a
All of the geometries were obtained by DFT calculations at the level
of B3LYP/6-31G*, and verified by vibrational analysis. Thermal
corrections at 1 atm, 298.15 K for cyclizations of 4a–f in the gas
phase in Kcal/mol.
During the optimization of possible substrates, amide 1b
was more efficient than amide 1a, but amide 1c could not
undergo the bicyclization. In addition, the cyclizations were
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3562–3564 3563

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The research was supported by the National Science Council,
Taiwan (NSC98-2119-M-005-002-MY3). The authors are
grateful to Professor Fong-Yin Li and Mr Chen-Chang Wu
for useful discussions on theoretical calculations, and the
National Center for High-Performance Computing for
computation facilities.
Notes and references
1 For a leading reference, see: L. F. Tietze, G. Brasche and
K. M. Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH
Verlag GmbH & Co. KGaA, Weinheim, 2006.
2 For recent reviews of domino syntheses, see: (a) K. C. Nicolaou,
D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45,
7134; (b) A. Padwa and S. K. Bur, Tetrahedron, 2007, 63, 5341;
(c) A. K. Lawrence and K. Gademann, Synthesis, 2008, 331;
Fig. 1 Reaction pathway profile of diastereoselective cyclization of 4d.
(d) B. B. Toure and D. G. Hall, Chem. Rev., 2009, 109, 4439.
´
3 L. F. Tietze, Chem. Rev., 1996, 96, 115.
4 P. W. N. M. van Leeuwan and C. Claver, Rhodium Catalyzed
Hydroformylation, Kluwer Academic Publishers, Dordrecht, 2000.
5 For recent reviews of hydroformylation, see: (a) M. Beller,
J. Seayad, A. Tillack and H. Jiao, Angew. Chem., Int. Ed., 2004,
43, 3368; (b) B. Breit, Acc. Chem. Res., 2003, 36, 264; (c) B. Breit
and W. Seiche, Synthesis, 2001, 1.
6 W. N. Speckamp and M. J. Moolenaar, Tetrahedron, 2000, 56,
3817.
7 W.-H. Chiou, G.-H. Lin, C.-C. Hsu, S. J. Chaterpaul and I. Ojima,
Org. Lett., 2009, 11, 2659.
Fig. 2 Reaction pathway profile of diastereoselective cyclization of 4e.
8 (a) E. Billig, A. G. Abatjoglou and D. Bryant, BIPHEPHOS:
6,60-[(3,30-Di-tert-butyl-5,50-di-methoxy-1,10-biphenyl-2,20-diyl)bis-
(oxy)]-bis(dibenzo[d,f][1,3,2]dioxaphosphepin), Union Carbide, US,
1988; (b) G. D. Cuny and S. L. Buchwald, J. Am. Chem. Soc., 1993,
115, 2066.
so that the transition state TSanti in the anti approach is higher
than the reactant Rsyn in the syn approach. It shows both
approaches are allowed, and the anti addition appears as the
major approach, while the syn addition is the minor approach.
Calculation predictions are in good agreement with our experi-
mental results.
9 The ROESY analysis of enol acetate 6b showed a strong correlation
between the phenyl protons d 7.28 (H-20) and the bridgehead proton
d 4.18 (H-8a), and determined as an E arrangement.
10 A large 1H–1H coupling constant of 10.8 Hz was observed in both
peaks of d 3.30 (H-8) and d 3.83 (H-8a), indicating an anti
arrangement between H-8 and H-8a.
Finally, to demonstrate the ability of the novel methodology,
we report a facile synthesis of tashiromine (Scheme 4).12
Tashiromine (10) is a naturally occurring indolizidine alkaloid,
isolated from an Asian deciduous shrub Maackia tashiroi
(Leguminosae).13 Treatment of ketone 7b using Uneyama’s
protocol14 gave ester 9b in 66% yield. Reduction with LiAlH4
afforded tashiromine (10) in 73% yield.
11 Ketones 7a and 7b were able to be achieved by direct base-
catalyzed methanolysis of the crude product without purification,
in 30% (for 7a) and 71% (for 7b) combined yield.
12 For synthesis of tashiromine, see: (a) J. C. Conrad, J. Kong,
B. N. Laforteza and D. W. C. MacMillan, J. Am. Chem. Soc.,
2009, 131, 11640; (b) S. M. Amorde, I. T. Jewett and S. F. Martin,
Tetrahedron, 2009, 3222; (c) M. Pohmakotr, S. Prateeptongkum,
S. Chooprayoon, P. Tuchinda and V. Reutrakul, Tetrahedron,
´
2008, 64, 2339; (d) G. Belanger, R. Larouche-Gauthier, F. d.
r. Menard, M. Nantel and F. Barabe, J. Org. Chem., 2006, 71,
´
704; (e) R. K. Dieter, N. Chen and R. T. Watson, Tetrahedron,
2005, 61, 3221; (f) A. D. McElhinney and S. P. Marsden, Synlett,
2005, 16, 2528; (g) M. G. Banwell, D. A. S. Beck and J. A. Smith,
Org. Biomol. Chem., 2004, 2, 157; (h) R. K. Dieter and
R. T. Watson, Tetrahedron Lett., 2002, 43, 7725; (i) R. W. Bates
and J. Boonsombat, J. Chem. Soc., Perkin Trans. 1, 2001, 654;
(j) O. David, C. Bellec, M.-C. Fargeau-Bellassoued and
G. Lhommet, Heterocycles, 2001, 55, 1689; (k) S.-H. Kim,
S.-I. Kim, S. Lai and J. K. Cha, J. Org. Chem., 1999, 64, 6771;
(l) O. David, J. r. m. Blot, C. Bellec, M.-C. Fargeau-Bellassoued,
Scheme 4 Synthesis of tashiromine.
G. Haviari, J.-P. Celerier, G. Lhommet, J.-C. Gramain and
´ ´
D. Gardette, J. Org. Chem., 1999, 64, 3122; (m) D.-C. Ha,
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J. Org. Chem., 1994, 59, 1613; (p) A. L. J. Beckwith and
S. W. Westwood, Tetrahedron, 1989, 45, 5269.
In conclusion, a novel reaction, alkyne-mediated domino
hydroformylation/double cyclization, has been developed for
rapid preparation of indolizidine type alkaloids. The diastereo-
selectivity is rationalized in terms of the relative stability in the
potential energy profile. We used the novel methodology to
synthesize tashiromine in 33% yield over 4 steps. Extension of
this methodology toward other natural products of interest is
currently underway and will be reported shortly.
13 S. Ohmiya, H. Kubo, H. Otomasu, K. Saito and I. Murakoshi,
Heterocycles, 1990, 30, 537.
14 S. Kobayashi, H. Tanaka, H. Amii and K. Uneyama, Tetrahedron,
2003, 59, 1547.
c
3564 Chem. Commun., 2011, 47, 3562–3564
This journal is The Royal Society of Chemistry 2011