Palladium-catalyzed asymmetric allylic alkylation of electron-deficient pyrroles with meso electrophiles

Article abstract of DOI:10.1021/ol3006584

Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd-catalyzed asymmetric allylic alkylation. The products from this transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole

Full text of DOI:10.1021/ol3006584

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2254–2257
Palladium-Catalyzed Asymmetric Allylic
Alkylation of Electron-Deficient Pyrroles
with Meso Electrophiles
Barry M. Trost,* Maksim Osipov, and Guangbin Dong
Department of Chemistry, Stanford University, Stanford, California 94305,
United States
bmtrost@stanford.edu
Received March 14, 2012
ABSTRACT
Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd-catalyzed asymmetric allylic alkylation. The products from this
transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole-containing nucleoside analogue
was synthesized in seven steps to demonstrate the synthetic utility of this transformation.
The assembly oforganicmoleculesin anenantioselective
fashion remains an important synthetic challenge. The Pd-
catalyzed asymmetric allylic alkylation (Pd-AAA) is a
powerful method for the construction of several different
bond types, including CÀC, CÀN, CÀO, and CÀS
bonds.1 Typically, the Pd-AAA requires the use of soft,
stabilized nucleophiles, such as malonates or imides. Re-
cently, less stabilized nucleophiles have been successfully
employed in the Pd-AAA.2
have been shown to act as universal nucleosides in PCR
amplification of DNA.3 This activity has been attributed
to the electronic distribution of the pyrrole nucleus, which
interacts equally well with all four natural nucleoside
bases. Further, due to the broad-spectrum antiviral activity
observed in the drug ribavirin, pyrrole-containing nucleo-
side analogues have been studied as isosteres for their
potential antiviral properties and other useful biological
activities (Figure 1).3 Likewise, these nucleoside analo-
gues have been used to study the mechanism of action
of ribavirin.4
The importance of nitrogen-containing compounds makes
the stereoselective construction of CÀN bonds an important
synthetic endeavor. Pyrrole-substituted nucleoside analogues
(1) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (c) Trost,
B. M. J. Org. Chem. 2004, 69, 5813. (d) Trost, B. M.; Machacek, M. R.;
Aponick, A. Acc. Chem. Res. 2006, 39, 747. (e) Trost, B. M.; Fandrick,
D. R. Aldrichimica Acta 2007, 40, 59.
(2) For some examples, see: (a) Trost, B. M.; Schroeder, G. M. J. Am.
Chem. Soc. 1999, 121, 6759. (b) Trost, B. M.; Zhang, T. Org. Lett. 2006,
8, 6007. (c) Trost, B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2008,
130, 14092. (d) Trost, B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc.
2009, 131, 12056. Trost, B. M.; Thaisrivongs, D. A.; Hartwig, J. J. Am.
Chem. Soc. 2011, 133, 12439.
(3) (a) Nichols, R.; Andrews, P. C.; Zhang, P.; Bergstrom, D. E.
Nature 1994, 369, 492. (b) Bergstrom, D. E.; Zhang, P.; Toma, P. H.;
Andrews, P. C.; Nichols, R. J. Am. Chem. Soc. 1995, 117, 1201.
(c) Klewer, D. A.; Hoskins, A.; Zhang, P.; Davisson, V. J.; Bergstrom,
D. E.; LiWang, A. C. Nucleic Acids Res. 2000, 28, 4514. (d) Harki, D. A.;
Graci, J. D.; Korneeva, V. S.; Ghosh, S. K. B.; Hong, Z.; Cameron,
C. E.; Peterson, B. R. Biochemistry 2002, 41, 9026.
Figure 1. Representative compounds.
(4) Sanghvi, Y. S.; Bhattacharya, B. K.; Kini, G. D.; Matsumoto,
S. S.; Larson, S. B.; Jolley, W. B.; Robins, R. K.; Revanker, G. R.
J. Med. Chem. 1990, 33, 336.
r
10.1021/ol3006584
Published on Web 04/16/2012
2012 American Chemical Society

While nucleoside analogues have a wealth of applica-
tions, traditional syntheses of these compounds are limited
by their reliance on chiral pool strategies. These strategies
only provide access to the natural enantiomer of ribose.
Recently, some L-nucleoside analogues have been shown
to have higher potency and lower toxicity when compared
to their D-enantiomer.5 As a result, processes that provide
access to both enantiomers are desirable. Inspired by the
wealth of biological activity present in pyrrole-substituted
nucleoside analogues, we sought to develop a general
method to utilize these nitrogen heterocycles as nucleo-
philes in the Pd-AAA. While pyrroles have been shown to
act as competent nucleophiles in the Pd-AAA with vinyl
aziridines,6 and in the context of a total synthesis,7 the
generality of utilizing meso electrophiles with pyrroles has
not been studied. By employing a meso starting material,
both D- and L-enantiomers of ribose can be accessed simply
by switching the chiral ligand used in the enantiodetermin-
ing Pd-AAA.
chiral ligand (Table 1). Employing (R,R)-L1 as the ligand
facilitated the desired alkylation reaction in a promising
53% yield and 83% enantiomeric excess (entry 1). Switch-
ing to (R,R)-L2, which contains a bulkier naphthyl phos-
phine, improved the reaction yield to 80% and the
enantiomeric excess to 98% (entry 2). Employing (R,R)-
L3 providedthe alkylated pyrrole3ain 78% yield and 90%
enantiomeric excess (entry 3). Finally, using (R,R)-L4 as
the chiral ligand delivered the product in 62% yield and an
82% enantiomeric excess (entry 4). With an optimal ligand
in hand, the effects of various additives were studied to
further improve the reactivity (entries 5À8). The addition
of acetic acid had a detrimental effect on the reaction, and
none of the desired product could be observed. In general,
adding base tothe reaction medium had a positiveeffecton
the reactivity. Triethylamine (entry 6) showed comparable
results to the case with no additives; however, potassium
carbonate improved the reaction to afford the product 3a
in 94% with >98% enantiomeric excess (entry 7). Chang-
ing to the softer cesium counterion delivered the product
3b in 90% yield as a single observable enantiomer by chiral
HPLC (entry 8).
Table 1. Selected Optimization Studiesa
Scheme 1. Scope of Pd-AAA of Pyrroles with Cyclopentene
Dicarbonate 2a
entry
ligand
additive
% yieldb
% eec
1
2
3
4
5
6
7
8
(R,R)-L1
(R,R)-L2
(R,R)-L3
(R,R)-L4
(R,R)-L2
(R,R)-L2
(R,R)-L2
(R,R)-L2
none
55
80
78
62
À
83
98
90
82
À
none
none
none
HOAc
NEt3
75
94
90
97
98
>99
K2CO3
Cs2CO3
a All reactions were performed with 1.0 equiv of 1a, 1.1 equiv of 2,
and 1.1 equiv of the indicated additive at ambient temperature, 0.25 M in
DCE for 24 h. b Isolated yield. c % ee determined by chiral HPLC.
a All reactions were performed with 1.0 equiv of pyrrole nucleophile
(1), 1.1 equiv of meso electrophile 2, and 1.1 equiv of Cs2CO3 at ambient
temperature, 0.25 M in DCE for 24 h. Yield refers to isolated yield. % ee
determined by chiral HPLC. b(R,R)-L1 was used.
Our initial studies examined the reaction between 2-ni-
tro-1H-pyrrole (1a) and meso-cyclopentene dicarbonate 2
in the presence of 2 mol % Pd2(dba)3•CHCl3 and 6 mol %
With the optimized conditions in hand, the scope of the
desymmetrization was explored by varying the pyrrole
nucleophile (Scheme 1). A number of functional groups
were tolerated at either the 2- or 3-position of the pyrrole
nucleus, including nitro groups (3a and 3c), nitriles (3b),
aldehydes (3d), ketones (3e), esters (3f), and halides (3f).
The reaction also proceeded smoothly using a six-
membered cyclohexyl dicarbonate, providing the desired
(5) (a) Jahnke, T. S.; Nair, V. Antimicrob. Agents Chemother. 1995,
ꢀ
39, 1017. (b) Gosselin, G.; Mathe, C. Antiviral Res. 2006, 71, 276.
(6) Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem. Soc. 2010, 132,
15800.
(7) (a) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
(b) Trost, B. M.; Dong, G. Org. Lett. 2007, 9, 2357. (c) Trost, B. M.;
Dong, G. Chem.;Eur. J. 2009, 15, 6910.
Org. Lett., Vol. 14, No. 9, 2012
2255

cyclohexyl-substituted pyrrole 3g in quantitative yield as a
single observed enantiomer. The presence of an electron-
withdrawing group was necessary to facilitate the trans-
formation, and only starting materials were observed after
24 h when electron-rich or -neutral pyrroles were used (3h
and 3i). Employment of a weaker electron-withdrawing
group, such as an aldehyde or ester, led to diminished
yields while retaining high levels of enantioselectivity. The
presence of an electron-withdrawing group was likely
needed to increase the acidity of the pyrrole NÀH as well
as to make the anionic nucleophile softer and more
compatible with the soft π-allyl Pd electrophile. In all cases
examined, the desymmetrized product was observed as a
single regio- and diastereomer, and only unreacted starting
materials were isolated in cases where lower yields were
observed.
To introduce the hydroxymethylene functionality, benzo-
ate 5c was substituted with acetoxy Meldrum’s acid (6) using
a Pd-catalyzed diastereoselective substitution, which af-
forded dihydrofuran 7in 95% yield as a single diastereomer.8
Being substrate controlled, this reaction was conducted
using (Rac.)-L1, which is far more cost-effective than the
chiral variant of the same ligand. Previous work has demon-
strated that using (Rac.)-L1 in place of an achiral ligand
can improve the outcome of a diastereoselective allylic
substitution.7c Os-catalyzed dihydroxylation of dihydrofur-
an 7 provided diol 8 as a >20:1 mixture of diastereomers in
72% yield. Conversion of the free diol to the subsequent
acetonide 9 proceeded in 84% yield. Without isolation or
purification, acetonide 9was converted to primary alcohol 10.
First, acetonide 9 was treated with LiOH in THF/H2O,
which chemoselectively hydrolyzed the Meldrum’s acid
acetonide in the presence of the diol acetonide and furnished
a dicarboxylic acid intermediate. This dicarboxylic acid was
treated with lead(IV) acetate in acetone to effect the oxida-
tive double decarboxylation and unmask the monocar-
boxylic acid. This monocarboxylic acid was then reduced
using BH3•DMS providing the primary alcohol 10 in 67%
yield. Finally, removal of the acetonide in methanolic HCl
afforded the desired nucleoside analogue (11) in >99% yield
without the need for purification. Characterization data for
11 were in agreement with previous reports.3d,9
Scheme 2. Scope of Pd-AAA of Pyrroles with Dihydrofuran 4a
Scheme 3. Synthesis of Pyrrole-Substituted Ribonucleoside
Analogue 11
a All reactions were performed with 1.0 equiv of pyrrole nucleophile
(1), 1.1 equiv of 4, and 1.1 equiv Cs2CO3 at ambient temperature, 0.25 M
in DCE for 24 h. Yield refers to isolated yield. % ee determined by chiral
HPLC.
To expand the scope of this transformation, meso dihy-
drofuran 4 was utilized as an electrophile in the transforma-
tion (Scheme 2). Dihydrofuran 4 is a more challenging
system due to its high propensity to undergo elimination/
aromatization under basic conditions leading to the unde-
sired, achiral furan product. To our delight, dihydrofuran 4
could serve as an electrophile to afford the alkylated product
without any observed aromatization of the product to the
undesired furan. Electron-deficient pyrroles substituted at
either the 2- or 3-position served as nucleophiles to provide
chiral dihydrofurans 5aÀd in good yield and with excellent
levels of enantioselectivity. These products were observed
exclusively with recovered starting materials accounting for
the remainder of the mass balance.
To demonstrate the synthetic utility of this process,
dihydrofuran 5c was elaborated into a pyrrole-substituted
nucleoside analogue 11 (Scheme 3). Previously, nitropyr-
role-substituted nucleoside analogues were reported to act
as universal bases in DNA transcription.3 Unfortunately,
prior syntheses of these compounds started from carbohy-
drate precursors, which are available only as the natural
D-enantiomer, and require extensive use of protecting
groups.
(8) Previous studies showed that acetoxyMeldrum’s acid is a versatile
acyl anion equivalent in the Pd-AAA: Trost, B. M.; Osipov, M.; Kaib,
P. S. J.; Sorum, M. T. Org. Lett. 2011, 13, 3222.
(9) Absolute configuration was assigned by analogy to previous
reports. See ref 7a, 7b.
2256
Org. Lett., Vol. 14, No. 9, 2012

proceeds in a matched manner under the flap of the
(R,R)-Pd-ligand complex 14 with another inversion, on the
same face that ionization occurred delivering product 15.
The absolute configuration of 11 as well as other systems
are in agreement with this model.
Scheme 4. Mechanistic Rationale for Observed Stereochemistry
In conclusion, we have demonstrated that pyrroles can act
as nucleophiles in the Pd-AAA with meso electrophiles. Both
cyclopentene dicarbonates and dihydrofuran dibenzoates
were used as electrophiles in the transformation. The reac-
tion proceeded with high chemoselectivity and tolerated a
variety of functional groups on the pyrrole nucleus. The
products of this transformation were obtained in high yield
and enantiomeric excess, as single regio- and diastereomers.
To demonstrate the synthetic utility, a pyrrole-containing
ribonuceloside analogue was synthesized in eight steps and
30% overall yield using minimal protecting groups. Unlike
other strategies, both natural and unnatural enantiomers of
the nucleoside analogues could be readily accessed.
Acknowledgment. We thank the National Science Foun-
dation and National Institutes of Health (GM33049) for
their generous support of our programs. M.O. is a John
Stauffer Memorial Fellow. M.O. and G.D. are Stanford
Graduate Fellows. Palladium salts were generously supplied
by Johnson-Matthey.
To rationalize the observed absolute configuration of
the products obtained from the Pd-AAA of pyrrole with
meso electrophiles, we propose the following explanation
based on the wall-and-flap model we have previously
disclosed (Scheme 4).1d,10 Matched ionization from one
of the prochiral faces of the meso electrophile 12 proceeds
as the enantiodetermining step with inversion such that the
leaving group (OR) departs from underneath the “flap” of
the (R,R)-Pd-ligand complex 13. Nucleophilic attack
Supporting Information Available. Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(10) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(b) Butts, C. P.; Filali, E.; Lloyd-Jones, G. C.; Norrby, P.-O.; Sale, D. A.;
Schramm, Y. J. Am. Chem. Soc. 2009, 131, 9945.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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