Tandem asymmetric Michael reaction-intramolecular Michael addition. An easy entry to chiral fluorinated 1,4-dihydropyridines

Article abstract of DOI:10.1021/ol101318t

(Equation Presented). A novel one-pot tandem asymmetric Hantzsch-type process has been employed to generate fluorinated 1,4-dihydropyridines (1,4-DHPs) as single diastereoisomers. It involves the condensation of (R)-(+)-allyl p-tolyl sulfoxide, fluorinated nitriles, and alkyl propiolates, giving access to a new family of enantiomerically pure fluorine-containing 1,4-DHPs.

Full text of DOI:10.1021/ol101318t

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3484-3487
Tandem Asymmetric Michael
Reaction-Intramolecular Michael
Addition. An Easy Entry to Chiral
Fluorinated 1,4-Dihydropyridines
Santos Fustero,*,†,‡ Silvia Catala´n,† Mar´ıa Sa´nchez-Rosello´,‡
Antonio Simo´n-Fuentes,† and Carlos del Pozo†
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
E-46100 Burjassot, Spain, and Laboratorio de Mole´culas Orga´nicas, Centro de
InVestigacio´n Pr´ıncipe Felipe, E-46012 Valencia, Spain
santos.fustero@uV.es; sfustero@cipf.es
Received June 8, 2010
ABSTRACT
A novel one-pot tandem asymmetric Hantzsch-type process has been employed to generate fluorinated 1,4-dihydropyridines (1,4-DHPs) as
single diastereoisomers. It involves the condensation of (R)-(+)-allyl p-tolyl sulfoxide, fluorinated nitriles, and alkyl propiolates, giving access
to a new family of enantiomerically pure fluorine-containing 1,4-DHPs.
Dihydropyridines (DHPs) constitute an important class of
biologically active heterocycles. They can be considered
“privileged structures” in medicinal chemistry exhibiting a
wide range of pharmacological and biological activities.1
Probably, the best known family of 1,4-DHPs are calcium
blockers, compounds used routinely in the treatment of a
variety of vascular disorders.2 In addition, 1,4-DHPs are
NADH mimics and may be involved in hydrogen transfer
reactions. These bioinspired transformations are extensively
used in organocatalytic enantioselective hydrogenations,
reductive aminations, and other enantioselective reductions
of CdC, CdN, and CdO functionalities.3 1,4-DHPs have
also proven to be valuable synthetic intermediates in the
preparation of a large number of nitrogen heterocycles.4
One of the most straightforward routes to the synthesis of
1,4-DHPs is the Hantzsch condensation, which was first
developed in 1882.5 This process constitutes an emblematic
example of a multicomponent reaction, allowing for the creation
of molecular diversity and complexity and the synthesis of wide
libraries of such important compounds.6 The absolute config-
uration of the stereogenic center of chiral DHPs has a crucial
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893. (b) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
(2) (a) Wang, X. M.; Du, L.; Peterson, B. Z. Biochemistry 2007, 46,
7590. (b) Cosconati, S.; Marinelli, L.; Lavecchia, A.; Novellino, E. J. Med.
Chem. 2007, 50, 1504. (c) Ana, B. B.; Rosa, M. A.; Rosa, M. J.; Wolfgang,
W. Forensic Sci. Int. 2006, 156, 23. (d) Arun, K. H. S.; Ramarao, P.
CardioVasc. Drug ReV. 2005, 23, 99. (e) Catterall, W. A.; Striessnig, J.
Trends Pharmacol. Sci. 1992, 13, 256. (f) Bossert, F.; Vater, W. Med. Res.
ReV. 1989, 9, 291. (g) Janis, R. A.; Silver, P. J.; Triggle, D. J. AdV. Drug
Res. 1987, 16, 309.
(3) For recent reviews, see: (a) You, S.-L. Chem. Asian J. 2007, 2, 820.
(b) Ouellet, S. G.; Walji, A. M.; MacMillan, D. W. C. Acc. Chem. Res.
2007, 40, 1327. (c) Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407.
(4) For reviews of the chemistry of 1,4-DHPs, see: (a) Lavilla, R. J. Chem.
Soc., Perkin Trans. 1 2002, 1141. (b) Kumar, R.; Chandra, R. AdV.
Heterocycl. Chem. 2001, 78, 269. (c) Comins, D. L.; O’Connor, S. AdV.
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10.1021/ol101318t  2010 American Chemical Society
Published on Web 07/09/2010

influence on their biological activity.7 In this respect, a classical
example is compound (R)-(+)-Bay K 8644, which shows anti-
hypertensive activity due to its calcium antagonist effect,
whereas the S enantiomer induces the opposite response (Figure
1).
derived organocopper reagents15 have been used in diastereo-
selective additions to the 4-position of pyridines. To date, only
three examples of catalytic enantioselective syntheses of 1,4-
DHPs have been described, both in an organocatalytic fashion.16
Chiral sulfoxides are reliable chiral synthons able to bring
about important asymmetric transformations.17 In this context,
metalated allylic sulfoxides, despite the ambident reactivity of
the carbanion, have been used as chiral inducers in their addition
to conjugated enones.18 The reaction takes place almost
exclusively through the γ-position giving rise to the corre-
sponding vinyl sulfoxidessa successfully applied strategy for
the synthesis of natural products.19 As part of our continued
interest in the preparation of new fluorinated building blocks,20
and taking advantage of the enhanced electrophilicity of
fluorinated nitriles, we envisioned the possibility of using them
as reaction partners with metalated allyl sulfoxides. The attack
by the γ-position would provide enamino sulfoxides, which in
turn could be treated with alkyl propiolates to afford fluorinated
1,4-DHPs. Herein, we report the development of this closely
related asymmetric Hantzsch transformation by using allylic
sulfoxides, fluorinated nitriles, and alkyl propiolates as the three
components of the novel one-pot tandem reaction outlined in
Scheme 1. This methodology allows for the preparation of a
new family of enantiomerically pure fluorinated 1,4-DHPs.21
Figure 1. Influence of the chiral center on the biological activity of
DHPs.
Despite the biological importance of enantiomerically pure
DHPs, a general method for their asymmetric synthesis still
remains an important challenge. Traditional strategies make use
of either enzymatic8 or chemical9 resolutions of racemates or,
alternatively, chiral auxiliaries. In this context, sugar-derived
aldehydes,10 chiral acetoacetate esters,11 chiral amino alde-
hydes12 (derived from the corresponding R-amino acids), and
chiral sulfoxides13 have been reported as asymmetry inducers
for the synthesis of 1,4-DHPs in Hantzsch syntheses. Alterna-
tively, chiral oxazoline-derived aryl lithiums14 and chiral aminal-
Our synthetic strategy starts with the reaction of allyl
sulfoxide 1 through the γ-position with fluorinated nitriles 2 to
generate enamino sulfoxides 4. Upon treatment with alkyl
propiolates 3, a tandem intermolecular aza-Michael reaction
(AMR)-intramolecular Michael addition (IMA) (over the
previously formed vinyl sulfoxides 5)22 might render 1,4-DHPs
6 (Scheme 1).
We initially explored the preparation of enamino sulfoxides
4 to evaluate our synthetic proposal. After testing several bases
and temperatures, we found that optimal reaction conditions
involved the treatment of (R)-(+)-allyl p-tolyl sulfoxide 1 with
KN(SiMe3)2 at -78 °C, followed by addition of fluorinated
nitriles 2. The reaction took place exclusively over the γ-carbon
(6) For reviews of related multicomponent reactions, see: (a) Dondoni, A.;
Massi, A. Acc. Chem. Res. 2006, 39, 451. (b) Lie´by-Muller, F.; Simon, C.;
Constantieux, T.; Rodriguez, J. QSAR Combi. Sci. 2006, 25, 432. (c) Simon,
C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957.
(7) (a) Shan, R.; Howlett, S. E.; Knaus, E. E. J. Med. Chem. 2002, 45,
ˇ
955. (b) Marchal´ın, S.; Chud´ık, M.; Mastihuba, V.; Decroix, B. Heterocycles
1998, 48, 1943. (c) Vo, D.; Matowe, W. C.; Ramesh, M.; Iqbal, N.;
Wolowyk, M. W.; Howlett, S. E.; Knaus, E. E. J. Med. Chem. 1995, 38,
2851. (d) Goldmann, S.; Stoltefuss, J. Angew. Chem., Int. Ed. Engl. 1991,
30, 1559.
(8) Sobolev, A.; Franssen, M. C. R.; Makarova, N.; Duburs, G.; de Groot,
A. Tetrahedron: Asymmetry 2000, 11, 4559 and references cited therein.
(15) Mangeney, P.; Gosmini, R.; Raussou, S.; Commerc¸on, M.; Alexakis,
A. J. Org. Chem. 1994, 59, 1877.
ˇ
(9) By formation of diastereoisomeric salts: (a) Marchal´ın, S.; Cvopova´,
(16) (a) Evans, C. G.; Gestwicki, J. E. Org. Lett. 2009, 11, 2957. (b)
Franke, P. T.; Johansen, R. L.; Bertelsen, S.; Jørgensen, K. A. Chem. Asian
J. 2008, 3, 216. (c) Jiang, J.; Yu, J.; Sun, X.-X.; Rao, Q.-Q.; Gong, L.-Z.
Angew. Chem., Int. Ed. 2008, 47, 2458.
K.; Krizˇ, M.; Baran, P.; Oulyadi, H.; Da¨ıch, A. J. Org. Chem. 2004, 69, 4227
and the references cited therein. (b) Ashworth, I.; Hopes, P.; Levine, D.;
Patel, I.; Salloo, R. Tetrahedron Lett. 2002, 43, 4931. (c) Kosugi, Y.; Hori,
M.; Tatsuo, N. Heterocycles 1994, 39, 591. (d) Arrowsmiths, J. E.;
Campbell, S. F.; Cross, P. E.; Stubbs, J. K.; Burges, R. A.; Gardiner, D. G.;
Blackburn, K. J. J. Med. Chem. 1986, 29, 1696 By chiral HPLC separation:
(e) Kleidernigg, O. P.; Kappe, C. O. Tetrahedron: Asymmetry 1997, 7, 2057.
(10) (a) Ducatti, D. R. B.; Massi, A.; Noseda, M. D.; Duarte, M. E. R.;
Dondoni, A. Org. Biomol. Chem. 2009, 7, 1980. (b) Dondoni, A.; Massi,
A.; Minghini, E.; Bertolasi, V. HelV. Chim. Acta 2002, 85, 3331. (c)
Dondoni, A.; Massi, A.; Minghini, E. Synlett 2002, 89.
(17) For recent reviews about the use of chiral sulfoxides in asymmetric
synthesis, see: (a) Pellisier, H. Tetrahedron 2006, 62, 5559. (b) Ferna´ndez,
I.; Khiar, N. Chem. ReV. 2003, 103, 3651.
(18) (a) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.;
Vonwiller, S. C. J. Am. Chem. Soc. 1988, 110, 5411. (b) Hua, D. H.;
Venkataraman, S.; Coulter, M. J.; Sinai, G. Z. J. Org. Chem. 1987, 52,
719.
(19) (a) Hua, D. H.; Sinai, G. Z.; Venkataraman, S. J. Am. Chem. Soc.
1985, 107, 4088. (b) Hua, D. H. J. Am. Chem. Soc. 1986, 108, 3835. (c)
Hua, D. H.; Venkataraman, S.; Ostrander, R. A.; Sinai, G. Z.; McCann,
P. J.; Coulter, M. J.; Xu, M. R. J. Org. Chem. 1988, 53, 507. (d) Zeng, Z.;
Xu, X. Tetrahedron Lett. 2000, 41, 3459. (e) Jones, D. N.; Maybury,
M. W. J.; Swallow, S.; Tomkinson, N. C. O.; Wood, W. W. Tetrahedron
Lett. 2001, 42, 2193.
(11) (a) Rose, U.; Dra¨ger, M. J. Med. Chem. 1992, 35, 2238. (b) Enders,
D.; Mu¨ller, S.; Demir, A. S. Tetrahedron Lett. 1988, 29, 6437.
(12) (a) Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V. Tetrahedron
2004, 60, 2311. (b) Dondoni, A.; Massi, A.; Minghini, E.; Sabbatini, S.;
Bertolasi, V. J. Org. Chem. 2003, 68, 6172.
(13) (a) Imanishi, T.; Miyashita, K.; Nishimoto, M.; Murafuji, H.;
Obikka, S. Chem. Pharm. Bull. 1996, 44, 457. (b) Imanishi, T.; Miyashita,
K.; Nishimoto, M.; Murafuji, H.; Obikka, S. Chem. Pharm. Bull. 1995, 43,
711. (c) Davis, R.; Kern, J. R.; Kurz, L. J.; Pfister, J. R. J. Am. Chem. Soc.
1988, 110, 7873.
(20) For a recent review, see: Fustero, S.; Sanz-Cervera, J. F.; Acen˜a,
J. L.; Sa´nchez-Rosello´, M. Synlett 2009, 525.
(21) Despite the relevance of fluorine in medicinal chemistry, only a few
examples of fluorinated DHPs have been reported. In most of them, fluorine
atoms are present as substituents in the aromatic rings of 4-aryl-1,4-DHPs.
(22) The conjugate addition of carbon nucleophiles over R,ꢀ-unsaturated
sulfoxides has been extensively used in its intermolecular version, while
examples of its intramolecular counterpart are very scarce. See reference 18a.
(14) (a) Cheng, Y. C.; Chen, J. Y.; Lee, M. J. Heterocycles 1996, 43,
2425. (b) Meyers, A. I.; Oppenlaender, T. J. Am. Chem. Soc. 1986, 108,
1989. (c) Meyers, A. I.; Oppenlaender, T. J. Chem. Soc., Chem. Commun.
1986, 920.
Org. Lett., Vol. 12, No. 15, 2010
3485

Scheme 1
.
Synthetic Strategy
Scheme 2
.
Double Michael Reaction of 4a with Methyl
Propiolate 3a
3 to the reaction mixture led to the formation of the corre-
sponding 1,4-DHPs 6 in moderate isolated yields. In most cases,
a single diastereoisomer of 6 according to the 19F NMR of the
crude reaction mixtures (Table 2) was formed. This novel
methodology gives access to a new family of enantiomerically
pure fluorinated Hantzsch-type derivatives.
Table 2. One-Pot Tandem Process for the Synthesis of
Enantiomerically Pure DHPs 6
of 1 giving rise to dienic sulfoxides 4 after tautomerization of
the iminic double bond to the more conjugated enamine
tautomer.
In all cases studied, the 1H NMR spectra of the crude reaction
mixtures were very clean, indicating that the reaction took place
almost quantitatively. However, during the purification process,
compounds 4 appeared to be partially unstable, thus decreasing
the final isolated yields (Table 1).
entry
2
3
RF
R1
R2
6
% yielda
1
2
3
4
5
6
7
8
9
2a 3a PhCF2
2a 3b PhCF2
2a 3c PhCF2
2a 3d PhCF2
2b 3a allylCF2
2b 3b allylCF2
2b 3d allylCF2
2c 3a 2-Naph-CF2
2d 3a 1-Naph-CF2
H
Me 6a 60
CO2Et Et
Ph
H
6b 62
Et
Et
6c 35 (45)b
6d 48
H
Me 6e 53
6f 55
6g 57
Me 6h 60
Me 6i
52c
Table 1. Preparation of Enamino Sulfoxides 4
CO2Et Et
H
H
H
Et
a Isolated yields after flash column chromatography. b The conversion was
entry
2
RF
PhCF2
allylCF2
2-naphtylCF2
1-naphtylCF2
4
% yielda b
,
45%. c A 7:1 mixture of two diastereoisomers was obtained.
1
2
3
4
2a
2b
2c
2d
4a
4b
4c
4d
65 (98)
60 (95)
66 (99)
73 (99)
The absolute stereochemistry of the newly created stereo-
center was determined by means of X-ray analysis of derivative
8 (Scheme 3). Thus, N-allylation of 6e generated diene 7, which
smoothly cyclized in the presence of Hoveyda-Grubbs (II G)
catalyst [Cl2(IMes)RudCH(o-i-PrOC6H4)]. The bicyclic system
8 allowed us to prepare suitable crystals for X-ray diffraction.
The absolute configuration of the chiral center was found to be
S (Scheme 3),23 and an identical stereochemical outcome was
assumed for all examples in Table 2.
The stereochemical outcome of the overall process could be
rationalized as depicted in Scheme 4. After the initial aza-
Michael addition of the enaminic nitrogen to the propiolate, a
potassium enolate bearing an allene functionality would be
formed. Assuming that the S-lone pair should be coplanar to
the CdC bond,24 the most favored approach would be to the
Re face in a 1,3-like-type addition, since the p-tolyl substituent
would block the Si face.
a Isolated yields after flash column chromatography. b In parentheses, yield
determined by 1H NMR on the crude reaction mixture.
The next step in our synthetic plan was the double Michael
tandem sequence initiated by reaction of sulfoxides 4 with alkyl
propiolates 3. Again, KN(SiMe3)2 was chosen to generate the
amine anion. Thus, when compound 4a was treated with
KN(SiMe3)2 at -78 °C followed by addition of methyl
propiolate (3a), 1,4-DHP 6a was obtained as a single diaste-
reoisomer (determined by means of 19F NMR in the crude
reaction mixture) in 60% yield after flash chromatography
(Scheme 2). As for sulfoxides 4, 1H NMR of the crude mixture
was very clean. Most likely, the final compound 6a partially
decomposed under the purification conditions, thus diminishing
the final isolated yield.
Once it was demonstrated that both Michael processes took
place in a tandem manner, we decided to combine them with
the formation of sulfoxides 4 in a one-pot sequence. To our
delight, we found that after the initial reaction of the potassium
anion of 1 with fluorinated nitriles 2 the addition of propiolates
(23) For the X-ray structure of (+)-8, see Supporting Information.
(24) This coplanarity of the S-lone pair with aryl or dienic moieties was
previously described by several authors: (a) Clayden, J.; Fletcher, S. P.;
MacDouall, J. J. W.; RowBottom, S. J. M. J. Am. Chem. Soc. 2009,
131, 5331 and references cited therein. (b) Paley, R. S.; Berry, K. E.; Liu,
J. M.; Sanan, T. T. J. Org. Chem. 2009, 74, 1611.
3486
Org. Lett., Vol. 12, No. 15, 2010

Scheme 3
.
Determination of the Absolute Configuration of the
Newly Created Stereocenter
Table 3. N-Cbz Protection and Non-oxidative Pummerer
Reaction
entry
9
% yielda
RF
R2
10
% yielda (er)b
1
2
3
4
5
9a
9b
9c
9d
9e
76
72
60
73
63
PhCF2
PhCF2
allylCF2
allylCF2
2-naph-CF2 Me 10e
Me 10a
70 (88:12)
68 (86:14)
65 (83:17)
67 (76:24)
73 (85:15)
Et 10b
Me 10c
Et 10d
a Isolated yields after flash column chromatography. b Enantiomeric ratios
were determined by chiral HPLC analysis.
Scheme 4. Rationalization of the Stereochemical Outcome
Although several attempts directed toward avoiding the
erosive process of the ee in the NOPR reaction were performed
(by changing reaction conditions), they were unsuccessful.
However, we found that the protection of the hydroxyl group
of compounds 10 as tert-butyl dimethylsilyl ethers rendered
DHPs 11, which were susceptible to separation by means of
semipreparative chiral HPLC (Scheme 5). In this manner, it
was finally possible to access DHPs 11 in enantiomerically pure
form (see Supporting Information for details).
Scheme 5. Obtention of Enantiomerically Pure DHPs 11
The last step in our study was the removal of the chiral
auxiliary from the final products. To this end, Pummerer-type
reactions have been extensively used in synthesis.25,18a The non-
oxidative variant of the Pummerer reaction (NOPR) enables
the conversion of ꢀ-amino sulfoxides into the corresponding
ꢀ-amino alcohols by reaction with TFAA and sym-collidine
followed by NaBH4 reduction.26 In this context, when several
N-Cbz-protected DHPs 9 were subjected to NOPR condi-
tions, alcohols 10 were isolated in reasonable yields (Table
3).27 However, a partial erosion of the ee was observed
during the sulfoxide cleavage, as determined by means of
chiral HPLC analysis of the dihydropyridine alcohols 10
(Table 3) (see Supporting Information for details). This was
probably due to the acidity of the hydrogen present in the
stereocenter, since it is located in a double allylic position,
and therefore being susceptible to racemization under NOPR
conditions.
In conclusion, a novel asymmetric tandem aza-Michael
reaction (AMR)-intramolecular Michael addition (IMA) has
been described. It involves the reaction of (R)-(+)-allyl p-tolyl
sulfoxide, fluorinated nitriles, and alkyl propiolates. The reaction
took place with complete selectivity allowing for the preparation
of a new family of fluorinated 1,4-dihydropyridines (DHPs) as
single diastereoisomers in moderate yields. The elimination of
the sulfoxide group by means of a Pummerer-type process took
place with partial erosion of the ee. However, it was possible
to access the final DHPs in enantiomerically pure form after
semipreparative chiral HPLC separation.
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2007-61462) of Spain for their financial support.
S.C. expresses her thanks for a predoctoral fellowship, M.S.-
R. for a Juan de la CierVa contract, and C.P. for a Ramo´n y
Cajal contract.
(25) For a review of the applications of Pummerer reactions in total
synthesis, see: Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis 1997,
1353
.
(26) For recent examples of NOPRs, see: (a) Sa´nchez-Obrego´n, R.;
Salgado, F.; Ortiz, B.; D´ıaz, E.; Yuste, F.; Walls, F.; Garc´ıa-Ruano, J. L.
Tetrahedron 2007, 63, 10521. and references cited therein. (b) Pesenti, C.;
Arnone, A.; Arosio, P.; Frigerio, M.; Meille, S. V.; Panzeri, W.; Viani, F.;
Zanda, M. Tetrahedron Lett. 2004, 45, 5125.
Supporting Information Available: Experimental proce-
dures and NMR spectra for all new compounds, as well as
crystallographical data for compound 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
(27) A complex mixture was obtained when non-protected 1,4-DHPs 6 were
subjected to NOPR conditions.
OL101318T
Org. Lett., Vol. 12, No. 15, 2010
3487