Catalytic asymmetric Stetter reaction onto vinylphosphine oxides and vinylphosphonates

Article abstract of DOI:10.1021/ol801047k

(Chemical Equation Presented) An intramolecular Stetter reaction of vinylphosphine oxides and vinylphosphonates has been developed. Treatment of an aldehyde with a nucleophilic N-heterocyclic carbene catalyst allows for addition of an acyl anion equivalent into a vinylphosphine oxide or vinylphosphonate Michael acceptor in yields up to 99% and ee values up to 96%.

Full text of DOI:10.1021/ol801047k

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3141-3144
Catalytic Asymmetric Stetter Reaction
Onto Vinylphosphine Oxides and
Vinylphosphonates
Steven C. Cullen and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
roVis@lamar.colostate.edu
Received May 6, 2008
ABSTRACT
An intramolecular Stetter reaction of vinylphosphine oxides and vinylphosphonates has been developed. Treatment of an aldehyde with a
nucleophilic N-heterocyclic carbene catalyst allows for addition of an acyl anion equivalent into a vinylphosphine oxide or vinylphosphonate
Michael acceptor in yields up to 99% and ee values up to 96%.
Organophosphorus compounds are abundant in many facets
of chemistry including agrochemistry1 and medicinal chem-
istry.2 They have also found much utility as ligands in
asymmetric catalysis.3 Owing to the multiple ways in which
they can be employed, the synthesis of small molecules
containing phosphorus has garnered significant attention.4
More importantly, the ability to generate phosphorus com-
pounds with chiral centers at or near phosphorus in an
asymmetric fashion is particularly attractive.5
Since the first report of N-heterocyclic carbenes in 1991,6
carbene catalysis has become a burgeoning field. NHCs have
been used to propagate Umpolung reactivity of aldehydes
to form new carbon-carbon bonds catalytically and enan-
tioselectively.7 Over the past several years, we have been
engaged in developing a family of chiral nucleophilic
carbenes (Figure 1)8 and applying them to a variety of
(1) (a) Kukhar, V. P.; Hudson, H. R. Aminophosphonic and Amino-
phosphinic Acids: Chemistry and Biological ActiVity; Wiley: New York,
2000. (b) Eto, M. Biosci. Biotechnol. Biochem. 1997, 61, 1.
(2) (a) Krise, J. P.; Stella, V. J. AdV. Drug DeliVery ReV. 1996, 19, 287.
(b) Hwang, J. T.; Choi, J. R. Drug Future 2004, 29, 163–177.
(3) (a) Tang, W. J.; Zhang, X. M. Chem. ReV. 2003, 103, 3029–3069.
(b) Zhou, Y. G. Acc. Chem. Res. 2007, 40, 1357–1366.
(4) (a) Mader, M. M.; Bartlett, P. A. Chem. ReV. 1997, 97, 1281. (b)
Hanessian, S.; Rogel, O. J. Org. Chem. 2000, 65, 2667. (c) Bricklebank,
N. Organophosphorus Chem. 2003, 33, 289. (d) McReynolds, M, D.;
Dougherty, J. M.; Hanson, P. R Chem. ReV. 2004, 104, 2239. (e)
Montchamp, J.-L. J. Organomet. Chem. 2005, 690, 2388. (f) Baumgartner,
T.; Re´au, R. Chem. ReV. 2006, 106, 4681.
Figure 1. Chiral triazolium salts.
(5) (a) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (b) Denmark,
S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825.
(6) (a) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem.
Soc. 1991, 113, 361. Also see: (b) Igau, A.; Grutzmacher, H.; Baceiredo,
A.; Bertrand, G. J. Am. Chem. Soc. 1988, 110, 6463.
transformations. These catalysts, in particular 1a-d and
2a-d, have proven especially useful in the catalytic asym-
10.1021/ol801047k CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

metric Stetter reaction providing ketoester products in
typically high yield and enantioselectivity.9
Scheme 1. Rhodium-Catalyzed Hydrophosphinylation
Although there are numerous examples that exploit the
nucleophilic nature of the acyl anion equivalent,10 the R,ꢀ-
unsaturated acceptors of the Stetter reaction11 have been
largely limited to simple enones and enoates. We envisaged
that vinylphosphine oxides and vinylphosphonates would
make excellent acceptors for the intramolecular Stetter
reaction due to their highly electrophilic nature at the
ꢀ-position.12
While many nucleophiles add readily to the ꢀ-position of
vinylphosphines and vinylphosphine oxides, few examples
have been shown to do so asymmetrically.13 Recently, the
first organocatalytic asymmetric transformation employing
highly activated bis-phosphonates as electrophilic acceptors
has been achieved by Alexakis and co-workers yielding chiral
bis-phosphonates in good yields and enantioselectivities.14
During the preparation of this manuscript, Jørgensen also
reported a method complementary to Alexakis’ work utilizing
cinchona alkaloid derived catalysts in an asymmetric Michael-
type addition affording high yields and enantioselectivities.15
We decided to employ a series of vinylphosphine oxides
and vinylphosphonates as electrophilic acceptors in the
intramolecular Stetter reaction. The vinylphosphine oxides
of type 4 were prepared by using a modified procedure
described by Tanaka and co-workers (Scheme 1).16 The use
of the bromide salt of Wilkinson’s catalyst17 on alkynes 3
provides a smooth transformation to the desired vinylphos-
phine oxides in good yields. Deprotection of the 1,3-dithiane
proved trivial and provided the desired aldehydes 4 in
excellent yields.
The requisite vinylphosphonates of type 6 were prepared
by treatment of the corresponding aldehyde 5 with a
preformed bis-phosphonate complex, as demonstrated by
Ojea and Ruiz (Scheme 2).18
Scheme 2. Aliphatic Vinylphosphonates
(7) For recent reviews see: (a) Zeitler, K. Angew. Chem., Int. Ed. 2005,
44, 7506. (b) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007,
107, 5606. (c) Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2007, 46, 2988. (d) Rovis, T. Chem. Lett. 2008, 37, 2.
(8) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70,
5725.
With a series of vinylphosphine oxides and vinylphos-
phonates prepared, we were able to test our hypothesis on
the viability of these Michael acceptors for the intramolecular
Stetter reaction.
(9) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298. (b) Kerr, M. S.; Rovis, T. Synlett 2003, 1934. (c) Kerr,
M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (d) Liu, Q.; Rovis, T.
J. Am. Chem. Soc. 2006, 128, 2552. (e) Moore, J. L.; Kerr, M. S.; Rovis,
T. Tetrahedron 2006, 62, 11477. (f) Read de Alaniz, J.; Kerr, M. S.; Moore,
J. L.; Rovis, T J. Org. Chem. 2008, 73, 2033. (g) Read de Alaniz, J.; Rovis,
T. J. Am. Chem. Soc. 2005, 127, 6284.
Structures with an aromatic backbone employing a vi-
nylphosphine oxide or vinylphosphonate as the electrophilic
acceptor afford the Stetter product in typically high yields
and enantioselectivities (Table 1). Vinylphosphine oxide 4a
provides higher yields than its vinylphosphonate congener
8 while enantioselectivities are increased as well (entries 1
and 9). The presence of halogen substituents on the aromatic
ring (entries 2-4) is well tolerated as long as reaction time
is limited to 30 min. When the reaction time is extended to
12 h, enantioselectivities drop significantly to 80% and 70%
ee, respectively, due to epimerization. Electron-donating
p-methoxy aldehyde 4e shows only a slight increase in
selectivity over σ withdrawing m-methoxy aldehyde 4d and
only a slight decrease in chemical yield.19 The presence of
sulfur in the tether (4f) leads to higher enantioselectivies,
albeit in lower chemical yields than when an oxygen is used
in the tether (e.g., 4a). Five-membered carbocycle 7g was
also obtained in excellent yield and high enantioselectiv-
ity.20,21
(10) (a) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew.
Chem., Int. Ed. 2006, 45, 3492. (b) Mattson, A. E.; Bharadwaj, A. R.; Zuhl,
A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71, 5715. (c) See ref 9f.
(11) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407.
(12) For 1,4-additions with amines, see: (a) Collins, D. J.; Rowley, L. E.;
Swan, J. M.; Rowley, L. E. Aust. J. Chem. 1974, 27, 841. (b) Pietrusiewicz,
K. J.; Zablocka, M. Tetrahedron Lett. 1988, 29, 1991. (c) Cavalla, D.;
Warren, S. Tetrahedron Lett. 1982, 23, 4505. For 1,4-additions with oxygen,
see: (d) Johnson, C. R.; Imamoto, T. J. J. Org. Chem. 1987, 52, 2170. (e)
Kawashima, T.; Nakamura, M.; Inamoto, N Heterocycles 1997, 44, 487.
For 1,4-additions with sulfur, see: (f) Pietrusiewicz, K. M.; Wisniewski,
W.; Zablocka, M. Tetrahedron 1989, 45, 337. For 1,4-additions with
carbanions, see: (g) Berlan, J.; Battioni, J. P.; Koosha, K. Tetrahedron Lett.
1976, 3351. (h) Pietrusiewicz, K. M.; Zablocka, M. Tetrahedron Lett. 1988,
29, 937.
(13) (a) Minowa, N.; Hirayama, M.; Fukatsu, S. Tetrahedron Lett. 1984,
25, 1147. (b) Ruiz, M.; Vicente, O.; Shapiro, G.; Weber, H. P. Tetrahedron
Lett. 1994, 35, 4551. (c) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara,
M. J. Am. Chem. Soc. 1999, 121, 11591. (d) Ferna´ndez, M. C.; Diaz, A.;
Guillin, J. J.; Blanco, O.; Ruiz, M.; Ojea, V. J. Org. Chem. 2006, 71, 6958.
(e) Kondoh, A.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129,
6996. (f) Nishida, G.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem.,
Int. Ed. 2008, 47, 3410.
Previously, we demonstrated that aliphatic aldehydes are
competent substrates to undergo the intramolecular Stetter
(14) Sulzer-Mosse´, S.; Tissot, M.; Alexakis, A. Org. Lett. 2007, 9, 3749.
(15) Capuzzi, M.; Perdicchia, D.; Jørgensen, K. A. Chem. Eur. J. 2008,
14, 128.
(16) Han, L.-B.; Zhao, C.-Q.; Tanaka, M. J. Org. Chem. 2001, 66, 5929.
(17) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G J. Chem.
Soc. (A) 1966, 1711. Also see ref 16.
(19) σ value for p-MeO ) -0.27, σ value for m-MeO ) 0.12: Carey,
F. A.; Sundberg, R. J. AdVanced Organic Chemistry Part A: Structure and
Mechanisms, 5th ed.; Springer: New York, 2007; p 339.
(18) Ruiz, M.; Fernandez, M. C.; Diaz, A.; Quintela, J. M.; Ojea, V. J.
Org. Chem. 2003, 68, 7634.
(20) Substrate 4g was also cyclized on 0.72 mmol scale with 20 mol %
of 1c to provide 7g in 95% yield and 89% ee
.
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Org. Lett., Vol. 10, No. 14, 2008

Table 1. Scope of Aromatic Aldehyde Substrates
Table 2. Scope of Aliphatic Aldehyde Substrates
a See footnote a in Table 1. b See footnote b in Table 1.
Phosphonate 11a was obtained in modest yield and
enantioselectivity. Gratifyingly, when the diethyl vinylphos-
phonate was switched to the diphenyl phosphonate 10b, the
yield and enantioselectivity of the desired product 11b were
both improved substantially (entry 2). This increase in ee is
most likely due to the increased steric demand of the
diaryloxy group, but indicates that tuning of selectivities is
possible with this approach.
Introduction of an oxygen in the aliphatic chain 10c gives
higher yields and enantioselectivities in the Stetter product
11c compared to its alkyl congener 11a (entry 3 vs entry 1).
It is also possible to form a carbocycle bearing a phosphine
oxide moiety 11d that proceeds in good yield and enanti-
oselectivity.22
Treatment of 11d under Luche-type conditions affords the
global reduction product 12 (Scheme 3) bearing a syn
relationship (>19:1), presumably due to the intervention of
a Lewis acid chelation during the reduction step.23,24
Hydrolysis of 11a with bromotrimethylsilane in DCM
overnight followed by a methanol quench affords phosphonic
a All reactions conducted in the presence of 20 mol % of catalyst 1c,
20 mol % of KHMDS (0.25 M in PhMe) in PhMe for 12 h at 23 °C.
b Determined by HPLC, using a chiral stationary phase; ee values in
parantheses were obtained with catalyst 2c. c With catalyst 1a, no reaction
was observed. d 10 mol % of 1c and 10 mol % of KHMDS.
reaction.9a,f By exchanging the acceptor to a vinylphospho-
nate or vinylphosphine oxide, the intramolecular Stetter
reaction proceeds smoothly to give the desired products in
high yields and enantioselectivities (Table 2).
(22) Six-membered aliphatic carbocycles bearing phosphonate Michael
acceptors were not competent substrates in this reaction.
(23) (a) Constantino, M. G.; Matias, L. G. D.; da Silva, G. V. J.; Barbieri,
E.; Gambardella, M. T. D. Quim. NoVa 1998, 21, 719. (b) Dalpozzo, R.;
Bartoli, G.; Bosco, M.; De Nino, A.; Procopio, A.; Sambri, L.; Tagarelli,
A. Eur. J. Org. Chem. 2001, 2971. (c) Kison, C.; Opatz, T. Eur. J. Org.
Chem. 2008, 2740.
(21) Absolute stereochemistry was unequivocally assigned for 7b and
7g by X-ray analysis; the rest were assigned by analogy to these products
(24) The use of NaBH4 provides the hydroxy phosphine oxide in lower
and those found in ref 9f. See the Supporting Information for details
.
diastereoselectivity (6:1).
Org. Lett., Vol. 10, No. 14, 2008
3143

aliphatic substrates are tolerated providing keto phosphonates
and phosphine oxides in good to excellent yields and
enantioselectivities. This extension of the Stetter reaction
leads to interesting new enantioenriched scaffolds of phos-
phorus-containing compounds not easily obtainable by other
methods.
Scheme 3. Elaboration of Substrates
Acknowledgment. We thank NIGMS (GM72586) and the
Herman Frasch Foundation for support of this research. We
acknowledge Eli Lilly, Johnson & Johnson, and Boehringer-
Ingelheim for additional support. T.R. thanks the Monfort
Family Foundation for a Monfort Professorship. We thank
Donald Gauthier (Merck) for a generous gift of aminoin-
danol. We thank Brian Newell and Professor Matthew P.
Shores (CSU) for X-ray analysis.
acid 13 in quantitative yield, which was then subjected to
esterification with (trimethylsilyl)diazomethane25 to generate
methyl ester 14 with no loss of ee.
In summary, we have developed an intramolecular Stetter
reaction employing vinylphosphine oxides and vinylphos-
phonates as electrophilic acceptors. Both aromatic and
Supporting Information Available: Experimental pro-
cedures, 1H, 13C, and 31P spectra, and chiral separations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Joly, G. D.; Jacobsen, N. E. J. Am. Chem. Soc. 2004, 126, 4102.
OL801047K
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