Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)-Verapamil

Article abstract of DOI:10.1002/anie.201507927

We describe herein a highly regio- and enantioselective Pd-catalyzed Heck arylation of unactivated trisubstituted acyclic olefins to provide all-carbon quaternary stereogenic centers. Chiral N,N ligands of the pyrimidine- and pyrazino-oxazoline class were developed for that purpose, providing the desired products in good to high yields with enantiomeric ratios up to >99:1. Both linear and branched substituents on the olefins were well-tolerated. The potential of this new method is demonstrated by the straightforward synthesis of several O-methyl lactols and lactones containing quaternary stereocenters, together with a concise enantioselective total synthesis of the calcium channel blocker verapamil.

Full text of DOI:10.1002/anie.201507927

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International Edition: DOI: 10.1002/anie.201507927
German Edition: DOI: 10.1002/ange.201507927
Asymmetric Heck Reactions
Quaternary Stereogenic Centers through Enantioselective Heck
Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in
a Concise Synthesis of (R)-Verapamil
Caio C. Oliveira, Andreas Pfaltz,* and Carlos Roque Duarte Correia*
Abstract: We describe herein a highly regio- and enantiose-
lective Pd-catalyzed Heck arylation of unactivated trisubsti-
tuted acyclic olefins to provide all-carbon quaternary stereo-
genic centers. Chiral N,N ligands of the pyrimidine- and
pyrazino-oxazoline class were developed for that purpose,
providing the desired products in good to high yields with
enantiomeric ratios up to > 99:1. Both linear and branched
substituents on the olefins were well-tolerated. The potential of
this new method is demonstrated by the straightforward
synthesis of several O-methyl lactols and lactones containing
quaternary stereocenters, together with a concise enantioselec-
tive total synthesis of the calcium channel blocker verapamil.
E
nantioselective palladium-catalyzed Heck reactions have
a prominent position in modern chemical synthesis.[1]
A
À
pivotal aspect of these C C forming reactions is the precise
control of the carbopalladation and b-elimination steps in the
catalytic cycle. For these reasons, most applications in total
synthesis were based on intramolecular variants where the
substrate bias provides high level of regiocontrol (Sche-
me 1a).[2] In contrast, intermolecular enantioselective Heck
reactions have been mostly used for the evaluation of new
chiral ligands with only scattered applications in organic
synthesis (Scheme 1b).[3]
A new development in this field was the arylation of
acyclic alkenyl alcohols recently reported independently by
Sigman and Correia using aryldiazonium salts as electro-
philes.[4–6] The newly formed stereogenic centers in the
carbopalladation step were preserved owing to the high
preference of the palladium hydride species for migration
along the carbon chain followed by conversion of the alcohol
into an aldehyde group (Scheme 1c). Subsequently, Sigman
expanded the scope of the enantioselective Heck reaction for
the construction of both tertiary and quaternary stereocenters
using vinyl triflates and boronic acids as reactants.[7–9]
On the other hand, enantioselective intermolecular Heck
reactions with acyclic olefins are still in the early stage of
development. So far, only bisoxazoline L1 and pyridine-
Scheme 1. Overview of enantioselective Heck reactions.
oxazoline L2 were described as effective chiral ligands for this
important transformation (Scheme 2). While L1 shows high
efficiency for the desymmetrization alkenyl-diols,[6] L2 was
reported for the arylation of non-symmetrical alkenyl-alco-
hols bearing basically one free hydroxy group and linear
substituents on trisubstituted olefins (Scheme 1c).[5,7–9]
Herein, we describe chiral pyrimidine and pyrazine-
oxazolines as chiral N,N ligands for highly site and enantio-
selective palladium-catalyzed arylations of trisubstituted
olefins using aryldiazonium salts as aryl-transfer agents. The
unique reactivity of the newly developed catalytic systems
allowed the use of both branched and linear substituents in
the trisubstituted olefins at low catalyst loading. Furthermore,
a new route for the calcium channel blocker (R)-verapamil is
disclosed using the enantioselective Heck reaction of acyclic
olefins for the first time as a key step in total synthesis
(Scheme 1d).[9]
[*] Dr. C. C. Oliveira, Prof. Dr. C. R. D. Correia
Institute of Chemistry, State University of Campinas
JosuØ de Castro, 10384-612, S¼o Paulo (Brazil)
E-mail: roque@iqm.unicamp.br
Dr. C. C. Oliveira, Prof. Dr. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: andreas.pfaltz@unibas.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507927.
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Figure 1. a) Energy profile for complexes C1 and C2. b) X-ray structure
of C1. Ellipsoids set at 50% probability.
To circumvent the intrinsic formation of two isomeric
complexes from 2,3-disubstituted pyrazines, we synthesized
its 2,5 isomer (L5) and the 4,6-pyrimidine-bisoxazoline (L6).
Heck arylations with these ligands provided the Heck product
3a in good yields (82–83%), high regiocontrol (> 20:1), and
excellent enantiomeric ratios of 98:2, and 97:3, respectively
(Scheme 2). Further optimization enabled us to decrease the
loading of both Pd(TFA)2 and L5 or L6 to only 2 mol%, the
lowest reported catalyst loading for an intermolecular enan-
tioselective Heck reaction with acyclic olefins, without losses
in chemical yields or stereoselectivity.
Under the optimized conditions employing ligands L5 and
L6, we extended the application range of the intermolecular
Heck reaction to other olefins and aryldiazonium salts
(Scheme 3). To facilitate spectroscopic characterization and
also to increase the synthetic value of our Heck adducts, the
O-methyl lactols 3 were directly oxidized to the correspond-
ing lactones 4 with Jones reagent. Attractive features of the
new method include: i) high site selectivity for the migratory
insertion with the aryl group transferred to the more electron
poor olefinic carbon, regardless of the topology of the
hydroxy group, allowing the use of allylic and homoallylic
diols without protecting groups; ii) arylation of trisubstituted
olefins bearing branched substituents with high stereo- and
regiocontrol, using a slight increase in catalyst loading
(3 mol%) and temperature (508C); and iii) use of either
ligands L6 or L7 which proved equally efficient for the Heck
reactions leading to 4a,c, and d.
To obtain further information about the role of the second
chelation site of these new ligands, we synthesized the
pyridine-bisoxazoline ligand (L7) and the pyrazine-oxazoline
ligand (L8). Despite the high level of regiocontrol, these
ligands provided the Heck product 3a in only modest
chemical yields and slightly lower enantiomeric ratios than
those observed with L5 and L6. To evaluate the role of the
possible mono- and bis-chelated palladium pre-catalysts, we
synthesized complexes C3 and C4. While complex C3 gave
essentially the same results as the catalyst generated in situ,
the C2-symmetric binuclear complex C4 provided only
modest regiocontrol, suggesting that this type of complex is
not the major catalyst in our Heck arylations. However, the
good er indicated its potential use in other enantioselective
transformations, especially for those reactions where low
catalyst concentrations are required.[14] Although our
attempts to isolate the zinc complexes were unsuccessful,
we believe that the free chelation sites present in L5 and L6
might coordinate to zinc in the reaction medium leading to
Scheme 2. Ligand screening for the enantioselective Heck reactions.
As an extension of our interest in the stereoselective
arylation of allylic and homoallylic alcohols, we chose alkenol
1a as a model for our studies (Scheme 2).[5,10] We began the
investigation using our previously reported conditions of
Pd(TFA)2 (5 mol%), bisoxazoline L1 (10 mol%), and basic
zinc carbonate (0.1 equiv) in methanol at 608C, to obtain O-
methyl-lactol 3a in 77% yield with an enantiomeric ratio (er)
of 95:5. However, only moderate level of regiocontrol (9:1)
was observed in favor of the desired g-arylation.[5] Replace-
ment of ligand L1 by L2 provided higher regioselectivity
(14:1), but at the cost of a considerably lower yield (46%) of
the Heck product 3a. In view of the promising results with
these two ligands and the knowledge that electron with-
drawing groups in the ligand aromatic ring are beneficial to
achieve higher levels of enantiodifferentiation, we decided to
combine the C2-symmetry of L1 with the distinct donating
properties of the metal-binding nitrogen atoms present in the
pyridine-oxazoline L2 to access novel classes of N,N scaffolds.
Based on the seminal work of Brunner in the enantioselective
hydrosilylation of ketones,[11] we designed new pyrazine and
pyrimidine ligands decorated with two oxazolines L3–L6
(Scheme 2).
The new ligands L3 and L4 provided high levels of
regiocontrol (> 20:1), but only L3 was capable of producing
good er (94:6). Despite the lower er (36:64), an interesting
inversion of absolute configuration at the quaternary center
was observed with L4. This phenomenon can be rationalized
by the presence of the methyl groups at C5 and C6, thus
preventing the stabilizing C6-H-p interaction between the
pyridine a-hydrogen and the aryl group after the oxidative
addition and olefin coordination, as suggested by theoretical
mechanistic investigations for L2.[12,13] Furthermore, crystallo-
graphic analysis of the pre-catalyst obtained from L4 indi-
cated the preferred formation of the 7-membered ring
complex C1, where palladium is chelated by both oxazolines,
instead of the pyrazine-oxazoline complex C2. This unantici-
pated behavior was supported by DFTanalysis that predicted
the 7-membered Pd complex C1 to be 11.56 kcalmolÀ1 more
stable than complex C2 (Figure 1).
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Scheme 4. Rationale for the enantioinduction in the Heck reactions.
(CDI). It is worth mentioning that our 6-step synthesis with an
overall yield of 29% is the shortest and highest yielding
enantioselective route for verapamil (Scheme 5).[17]
Scheme 3. Enantioselective synthesis of lactones 4.
In conclusion, we described the development of novel
chiral pyrimidine and pyrazine-oxazoline ligands and their
effective application in the enantioselective palladium-cata-
lyzed Heck reaction of acyclic trisubstituted olefins bearing
linear or branched substituents. The Heck products were
a more electron-withdrawing portion on the ligand.[11] Finally,
we propose that at the carbopalladation step the aryl group is
placed trans to the oxazoline ring and is stabilized through the
C6-H-p interaction.[12,13] The enantioselectivity is controlled
by minimization of the repulsive interaction between the
bulkier substituent at the secondary olefinic carbon and the
tert-butyl substituent at the oxazoline (ET1 and ET2).
The structural complexity provided by our arylation
method allowed the development of a straightforward enan-
tioselective synthesis of the calcium channel blocker verapa-
mil.[15] Although this drug is commercialized in its racemic
form, the distinct pharmacological profiles of the enantiomers
makes an enantioselective synthesis highly desirable.[16,17] Our
synthetic route started with a gram scale Heck arylation of
diol 5 with aryldiazonium salt 6. The six-membered O-methyl
lactol 7 was obtained after filtration through a short pad of
silica-gel as a single regioisomer in 89% yield and 98:2 e.r.
(Scheme 4). After hydrolysis using aqueous HCl solution in
acetonitrile,[6,18] lactol 8 was directly used in a standard
reductive amination with the N-methyl homoveratrylamine 9
to provide the neo-pentylic alcohol 10 in 55% yield over two
steps.[19] Finally, (R)-verapamil 12 was obtained (0.98 g,
2.15 mmol) after three additional steps: i) Dess–Martin
oxidation of the 11, ii) oxime formation, and iii) oxime
decomposition after activation by 1,1’-carbonyldiimidazole
Scheme 5. Enantioselective synthesis of (R)-verapamil (12).
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6, 4807; h) Q.-S. Zhang, S.-L. Wan, D. Chen, C.-H. Ding, X.-L.
obtained in high enantiomeric ratios (up to 99:1) and
regioselectivities, even in gram scale reactions. Moreover,
we have successfully applied this enantioselective Heck-
Matsuda reaction of acyclic olefins as the key step in a concise,
highly enantioselective total synthesis of the calcium channel
blocker (R)-verapamil.
Hou, Chem. Commun. 2015, 51, 12235 – 12238.
[4] C. R. D. Correia, C. C. Oliveira, A. G. Salles Jr., E. A. F. Santos,
Tetrahedron Lett. 2012, 53, 3325 – 3328.
[5] E. W. Werner, T.-S. Mei, A. J. Burckle, M. S. Sigman, Science
2012, 338, 1455 – 1458.
[6] C. C. Oliveira, R. A. Angnes, C. R. D. Correia, J. Org. Chem.
2013, 78, 4373 – 4385.
[7] H. H. Patel, M. S. Sigman, J. Am. Chem. Soc. 2015, 137, 3462 –
3465.
[8] T.-S. Mei, E. W. Werner, A. J. Burckle, M. S. Sigman, J. Am.
Chem. Soc. 2013, 135, 6830 – 6833.
[9] T.-S. Mei, H. H. Patel, M. S. Sigman, Nature 2014, 508, 340 – 344;
For other catalytic approaches to quaternary stereocenters, see:
K. W. Quasdorf, L. E. Overman, Nature 2014, 516, 181 – 191.
[10] R. A. Angnes, J. M. Oliveira, C. C. Oliveira, N. C. Martins,
C. R. D. Correia, Chem. Eur. J. 2014, 20, 13117 – 13121.
[11] A similar compound to L5 was described for the hydrosilylation
of benzophenone in 65:35 e.r.: a) H. Brunner, R. Stçriko, F.
Rominger, Eur. J. Inorg. Chem. 1998, 771 – 781; b) H. Brunner,
R. Stçriko, Eur. J. Inorg. Chem. 1998, 783 – 788.
Acknowledgements
Financial support by the S¼o Paulo Research Foundation
(2013/07600-3, 2014/00588-0) and Swiss National Science
Foundation is gratefully acknowledged. Authors also thank
Dr. Jaroslav Padevet (University of Basel) and Dr. Alessan-
dro Prescimone (University of Basel) for performing the
calculation and X-ray analysis, as described in Figure 1.
Keywords: enantioselective Heck · N,N ligands · palladium ·
quaternary stereocenters · verapamil
[12] Y. Dang, S. Qu, Z.-X. Wang, X. Wang, J. Am. Chem. Soc. 2014,
136, 986 – 998.
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14036–14039
Angew. Chem. 2015, 127, 14242–14245
[13] L. Xu, M. J. Hilton, X. Zhang, P.-O. Norrby, Y.-D. Wu, M. S.
Sigman, O. Wiest, J. Am. Chem. Soc. 2014, 136, 1960 – 1967.
[14] a) T. Rosner, A. Pfaltz, D. G. Blackmond, J. Am. Chem. Soc.
2001, 123, 4621 – 4622; b) T. Rosner, J. Le Bars, A. Pfaltz, D. G.
Blackmond, J. Am. Chem. Soc. 2001, 123, 1848 – 1855; c) C.
Markert, M. Neuburger, K. Kulicke, M. Meuwly, A. Pfaltz,
Angew. Chem. Int. Ed. 2007, 46, 5892 – 5895; Angew. Chem.
2007, 119, 5996 – 5999; d) R. H. Crabtree, Chem. Rev. 2015, 115,
127 – 150.
[15] For enantioselective synthesis of verapamil, see: a) E. Brenna, C.
Fuganti, P. Grasselli, S. Serra, Eur. J. Org. Chem. 2001, 1349 –
1357; b) A. H. Mermerian, G. C. Fu, Angew. Chem. Int. Ed. 2005,
44, 949 – 952; Angew. Chem. 2005, 117, 971 – 974.
[1] a) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100,
3009 – 3066; b) F. Alonso, I. P. Beletskaya, M. Yus, Tetrahedron
2005, 61, 11771 – 11835; c) A. Roglans, A. Pla-Quintana, M.
Moreno-MaÇas, Chem. Rev. 2006, 106, 4622 – 4643; d) J. G.
Taylor, A. V. Moro, C. R. D. Correia, Eur. J. Org. Chem. 2011,
1403 – 1428; e) F.-X. Felpin, L. Nassar-Hardy, F. Le Callonnec, E.
Fouquet, Tetrahedron 2011, 67, 2815 – 2831; f) M. Oestreich,
Angew. Chem. Int. Ed. 2014, 53, 2282 – 2285; Angew. Chem.
2014, 126, 2314 – 2317.
[2] a) G. Yue, K. Lei, H. Hirao, J. Zhou, Angew. Chem. Int. Ed. 2015,
54, 6531 – 6535; Angew. Chem. 2015, 127, 6631 – 6635; b) A. B.
Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945 – 2964; c) C.
Zheng, I. Dubovyk, K. E. Lazarski, R. J. Thomson, J. Am. Chem.
Soc. 2014, 136, 17750 – 17756.
[3] a) D. Mc Cartney, P. J. Guiry, Chem. Soc. Rev. 2011, 40, 5122 –
5150; b) Z. S. Kean, S. Akbulatov, Y. Tian, R. A. Widenhoefer,
R. Boulatov, S. L. Craig, Angew. Chem. Int. Ed. 2014, 53, 14508 –
14511; Angew. Chem. 2014, 126, 14736 – 14739; c) T. H. Wçste,
M. Oestreich, Chem. Eur. J. 2011, 17, 11914 – 11918; d) J. Hu, Y.
Lu, Y. Li, J. Zhou, Chem. Commun. 2013, 49, 9425 – 9427; e) J.
Hu, H. Hirao, Y. Li, J. Zhou, Angew. Chem. Int. Ed. 2013, 52,
8676 – 8680; Angew. Chem. 2013, 125, 8838 – 8842; f) S. Liu, J.
Zhou, Chem. Commun. 2013, 49, 11758 – 11760; g) G. M.
Borrajo-Calleja, V. Bizet, T. Bürgi, C. Mazet, Chem. Sci. 2015,
[16] R. M. Bannister, M. H. Brookes, G. R. Evans, R. B. Katz, N. D.
Tyrrell, Org. Process Res. Dev. 2000, 4, 467 – 472.
[17] T. Kimura, N. Yamamoto, Y. Suzuki, K. Kawano, Y. Norimine,
K. Ito, S. Nagato, Y. Iimura, M. Yonaga, J. Org. Chem. 2002, 67,
6228 – 6231.
ˇ
´
[18] I. Coric, S. Müller, B. List, J. Am. Chem. Soc. 2010, 132, 17370 –
17373.
[19] K. M. Allan, K. Kobayashi, V. H. Rawal, J. Am. Chem. Soc. 2012,
134, 1392 – 1395.
Received: August 24, 2015
Published online: September 25, 2015
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