Enantioselective synthesis of chiral sulfones by ir-catalyzed asymmetric hydrogenation: A facile approach to the preparation of chiral allylic and homoallylic compounds

Article abstract of DOI:10.1021/ja306731u

A highly efficient and enantioselective Ir-catalyzed hydrogenation of unsaturated sulfones was developed. Chiral cyclic and acyclic sulfones were produced in excellent enantioselectivities (up to 98% ee). Coupled with the Ramberg-Baecklund rearrangement, this reaction offers a novel route to chiral allylic and homoallylic compounds in excellent enantioselectivities (up to 97% ee) and high yields (up to 94%).

Full text of DOI:10.1021/ja306731u

Communication
pubs.acs.org/JACS
Enantioselective Synthesis of Chiral Sulfones by Ir-Catalyzed
Asymmetric Hydrogenation: A Facile Approach to the Preparation of
Chiral Allylic and Homoallylic Compounds
Taigang Zhou,† Byron Peters,† Matías F. Maldonado,† Thavendran Govender,‡
and Pher G. Andersson*,†,‡
†Department of Chemistry-BMC, Uppsala University, Box 576, S-75123 Uppsala, Sweden
‡Department of Pharmacy, University of KwaZulu-Natal, Durban 4000, South Africa
S
* Supporting Information
producing chiral allylic entities,5 but it cannot be applied in
homoallylic chiral induction. Conversely, methods that
selectively introduce homoallylic chirality cannot be used to
synthesize chiral allylic compounds.6
ABSTRACT: A highly efficient and enantioselective Ir-
catalyzed hydrogenation of unsaturated sulfones was
developed. Chiral cyclic and acyclic sulfones were
produced in excellent enantioselectivities (up to 98%
Transition-metal-catalyzed asymmetric hydrogenation is one
of the most efficient, straightforward, and well-established
methods for preparing enantiomericially enriched compounds.7
In recent decades, the transition-metal-catalyzed hydrogena-
tions using Ir, Ru, and Rh compounds have proven effective in
the asymmetric reduction of many types of olefins, such as α,β-
unsaturated acids, ketones, imines, phosphonates, and hetero-
cyclic compounds.8 However, to our knowledge, the asym-
metric hydrogenation of unsaturated cyclic sulfones is still
unknown in the literature, and only a few examples involving
unsaturated acyclic sulfones have been reported. Paul and
Palmer have reported the rhodium-catalyzed asymmetric
hydrogenation of acyclic β,β-disubstituted vinyl phenyl sulfones
in high enantioselectivities.9a Unfortunately, the reaction
required the substrate to have a coordinating group, e.g. an
ester or amide, next to the CC bond. Yuasa et al.
hydrogenated an acyclic allyl sulfone in 84% ee using a Ru-
BINAP catalyst.9b
ee). Coupled with the Ramberg−Backlund rearrangement,
̈
this reaction offers a novel route to chiral allylic and
homoallylic compounds in excellent enantioselectivities
(up to 97% ee) and high yields (up to 94%).
hiral sulfones are present in, and can be used as synthetic
C
intermediates for the preparation of, many biologically
active compounds and natural products, such as those shown in
Figure 1.1,2 Furthermore, one of their most important
Over the past few years, our group has developed several
classes of chiral N,P-ligated iridium complexes that are efficient
catalysts for the asymmetric hydrogenation of various
substrates.8d,g,i,10 We tested these catalysts in the asymmetric
hydrogenation of prochiral unsaturated sulfones and converted
the resulting chiral sulfones into chiral allylic and homoallylic
compounds via the Ramberg−Backlund rearrangement
̈
(Scheme 1). Herein we report the first examples of the Ir-
catalyzed asymmetric hydrogenation of acyclic sulfones, as well
as the first asymmetric hydrogenation of cyclic sulfones with
varying substitution patterns, in excellent enantioselectivities
Figure 1. Biologically active compounds with chiral sulfone moieties.
applications is their conversion to chiral olefins through the
(up to 98% ee). When coupled with the Ramberg−Backlund
̈
rearrangement, this method constitutes a novel approach to
both chiral allylic and homoallylic compounds in high yield and
excellent enantioselectivities.
Ramberg−Backlund rearrangement.3 Chiral olefins, especially
̈
chiral allylic and homoallylic compounds, are common
structural moieties in natural products and pharmaceutical
compounds.4 Thus the production of chiral sulfones is key to
numerous organic syntheses. Despite the well-known impor-
tance of chiral allylic and homoallylic compounds in organic
synthesis, no single, facile preparation of both chiral allylic and
homoallylic compounds has been developed. Asymmetric allylic
substitution is one of the most widely used methods of
We chose two model substrates to hydrogenate, the seven-
membered cyclic sulfone 1 and the acyclic β,β-disubstituted
vinyl sulfone 2 (Table 1) with Ir complexes bearing our chiral
ligands A−F (Scheme 2).10 [(C)Ir(COD)]+[BArF]− (COD =
Received: July 10, 2012
Published: July 26, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
chiral products using [(C)Ir(COD)]+[BArF]−. Excellent
enantioselectivities (90−98% ee, Table 2, entries 1−8) were
Scheme 1. Strategy for Asymmetric Synthesis of Chiral
Sulfone and Chiral Allylic, Homoallylic Compounds
Table 2. Asymmetric Hydrogenation of β-Substituted β,γ-
a
Unsaturated Seven-Membered Cyclic Sulfones
b
cd
,
entry
substrate
Ph
ligand
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
C
C
C
C
C
C
C
C
E
>99
23
98 (−)(R)
93 (−)
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
CH2OH
Table 1. Catalyst Screening for Asymmetric Hydrogenation
>99
>99
>99
91
98 (−)
a
of Cyclic and Acyclic Unsaturated Sulfones
96 (−)(R)
97 (−)
95 (−)
90 (−)
92 (−)
>99
>99
>99
e
Me
96 (−)(S)
a
Reaction conditions: 0.25 mmol of substrate, 0.5 mol % catalyst, 2
b
mL of CH2Cl2, 50 bar of H2, 17 h, rt. Conversion, determined by 1H
NMR spectroscopy. No side products were detected. Determined by
chiral HPLC or GC analyses. Absolute configuration determined by
c
d
b
cd
,
entry
1
ligand
substrate
conv. (%)
ee (%)
analogy with corresponding alkenes obtained from Ramberg−
A
1
2
1
2
1
2
1
2
1
2
1
2
25
45
14 (S)
76 (S)
97 (S)
50 (R)
96 (R)
96 (S)
83 (S)
27 (R)
87 (R)
41 (S)
96 (S)
74 (R)
e
Backlund rearrangement. Determined by chiral GC after conversion
̈
to 1-(2-cyclohexenyl)methanol and then into its acetate, 1-(2-
cyclohexenyl)methyl ethanoate.
2
3
4
5
6
B
C
D
E
F
42
27
>99
>99
>99
>99
30
obtained. When the substituent was an aryl ring, para
substituents on the ring had little influence on hydrogenation
selectivity (entries 1−7). However, an o-methyl substituent on
the aryl ring (entry 2) gave poorer conversion, likely due to the
steric bulk of the substrate. Despite the fact that [(C)Ir-
(COD)]+[BArF]− hydrogenated the hydroxymethyl-substituted
compound in 92% ee (entry 8), it gave only moderate
selectivity (41% ee) for the methyl-substituted variant.
However, [(E)Ir(COD)]+[BArF]− hydrogenated this com-
pound in 96% ee (entry 9).
Next, we evaluated substrates with different substitution
patterns and ring sizes (Table 3). Six-membered cyclic sulfones
(Table 3, entries 1−3) were hydrogenated in good to excellent
enantioselectivities (85−93% ee) using [(C)Ir-
(COD)]+[BArF]−. Substrates with seven-membered rings
were hydrogenated in good to excellent enantioselectivities
and full conversions (89−93%; entries 4−8) using the same
catalyst that was effective for their isomers in Table 2. Most
substrates gave excellent results with [(C)Ir(COD)]+[BArF]−
(entries 4−7), but the 4-methyl-4-5-unsaturated seven-mem-
bered ring was hydrogenated most selectively with [(E)Ir-
(COD)]+[BArF]− (entry 8) and [(A)Ir(COD)]+[BArF]− was
the best catalyst for the five-membered cyclic sulfone, giving
good enantioselectivity (87% ee, entry 9).
24
49
90
a
Reaction conditions: 0.25 mmol of substrate, 0.5 mol % catalyst, 2
b
mL of CH2Cl2, 50 bar of H2, 17 h, rt. Conversion, determined by 1H
NMR spectroscopy. No side products were detected. Determined by
chiral HPLC or GC analyses. Absolute configuration determined by
analogy with corresponding alkenes obtained from Ramberg−
Backlund rearrangement.
c
d
̈
Scheme 2. Ligands Tested in Asymmetric Hydrogenation of
Unsaturated Sulfones
a
We carried out the asymmetric reduction of several acyclic,
E-β,β-disubstituted vinyl sulfones (Table 4, entries 1−7). Full
conversions and high enantioselectivities (90−96% ee) were
achieved for all vinyl sulfones with [(C)Ir(COD)]+[BArF]−,
demonstrating the utility of the reaction for a series of different
aryl substitutions as well as a dialkyl substrate. An allylic sulfone
was also reduced in full conversion and excellent enantiose-
lectivity (97% ee, entry 8) with the same catalyst. These results
complement those obtained with the cyclic substrates,
demonstrating the utility of our N,P-ligated iridium catalysts
in the asymmetric hydrogenation of prochiral sulfones.
a
o-tol = 2-methylphenyl.
−
1,4-cyclooctadiene; BArF = tetrakis(3,5-bis-trifluoromethyl-
phenyl)borate) performed best, hydrogenating both 1 and 2
to full conversion and in 96% ee.
In light of this success, β-substituted β,γ-unsaturated seven-
membered cyclic sulfones bearing various aliphatic and
aromatic substituents were hydrogenated to the corresponding
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Communication
Table 3. Asymmetric Hydrogenations of Cyclic Unsaturated
Sulfones Having Five-, Six-, and Seven-Membered Rings by
Table 5. Transformation of Chiral Sulfones to Chiral Allylic
and Homoallylic Compounds by the Ramberg−Backlund
̈
a
−
[Ir(COD)L*]+BArF Catalysts
Rearrangement
a
Reaction conditions: 0.25 mmol of substrate, 0.5 mol % catalyst, 2
b
mL of CH2Cl2, 50 bar of H2, 17 h, rt. Conversion, determined by 1H
NMR spectroscopy. No side products were detected. Determined by
chiral HPLC or GC analyses. Absolute configuration determined by
c
d
analogy with corresponding alkenes obtained from Ramberg−
e
Backlund rearrangement. Determined by comparing optical rotation
̈
with a literature value.11 Determined by GC after conversion to
corresponding acetate. Determined by GC after conversion to 1-(3-
f
g
cyclohexenyl)methanol.
a
Table 4. Asymmetric Hydrogenation of Acyclic Sulfones
a
b
Isolated yields. Determined by chiral HPLC or GC analyses.
c
Absolute configuration determined by comparing optical rotation
d
with a literature value. Not an isolated yield but a conversion
determined by GC. Ee determined from the chiral sulfone. See
Supporting Information for reaction conditions. Only the trans (E)
e
f
isomer was observed.
corresponding cyclic alkenes, and the acyclic substrates
underwent rearrangement with complete trans selectivity.
Inherent ring strain was likely a factor in the poor conversion
obtained for the rearrangement of the six-membered cyclic
sulfone to the five-membered cyclic alkene (entry 1). No
erosion of enantiometric excess was observed during the
Ramberg−Backlund rearrangement of the substrates tested.
̈
We developed a Selectivity Model to explain the stereo-
selectivity of our catalysts in the hydrogenation (Figure 2).10b,12
The catalyst is drawn in its Ir3+ form, which is present after H2
and the substrate have been added,12 from the perspective of
the olefin. This is superimposed on a two-by-two grid to
separate the environment around Ir into four quadrants, as
shown in Figure 2. In this orientation, three of the quadrants
are occupied by the steric bulk of the ligand; quadrant 2 is fully
encumbered, and quadrants 1 and 4 are partially occupied.
Quadrant 3 is relatively free. In the most stable configuration,
the substrate will be oriented to have its least bulky substituent
(in the substrates described here, a proton) in the most
hindered quadrant (2, Figure 2).12 Thus the stereochemical
outcome of hydrogenation can be predicted assuming that
hydride is delivered from the iridium center. Little information
on the absolute configurations of the saturated sulfones
described here exists in the literature; however, absolute
a
Reaction conditions: 0.25 mmol of substrate, 0.5 mol % catalyst, 2
b
mL of CH2Cl2, 50 bar of H2, 17 h, rt. Conversion, determined by 1H
NMR spectroscopy. No side products were detected. Determined by
chiral HPLC analyses. Absolute configuration determined by analogy
with corresponding alkenes obtained from Ramberg−Backlund
rearrangement.
c
d
̈
By coupling asymmetric hydrogenation with Ramberg−
̈
Backlund rearrangement, we converted the chiral sulfone into
chiral allylic and homoallylic compounds. As shown in Table 5,
the Ramberg−Backlund rearrangements of the chiral acyclic
̈
and seven-membered cyclic sulfones produced here afforded
the corresponding alkenes in good to excellent yields (75−94%,
entries 2−14). The cyclic substrates ring-contracted to the
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Journal of the American Chemical Society
Communication
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Ramberg−Backlund rearrangement (Tables 2−4).
̈
The stereochemical outcomes of the hydrogenations shown
in Tables 2−4 conformed to those predicted by the Selectivity
Model in cases where absolute stereochemistry could be
assigned. Thus the model proved to be a useful and convenient
method for predicting the stereoselectivity of the hydro-
genation of an unsaturated sulfone by [Ir(COD) L*]+[BArF]−.
In conclusion, we have developed a highly efficient and
enantioselective hydrogenation of both cyclic and acyclic
unsaturated sulfones; the reaction was catalyzed by N,P-ligated
iridium catalysts. When coupled with the Ramberg−Backlund
̈
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rearrangement, this method constitutes a novel approach to
both chiral allylic and homoallylic compounds in high yield and
excellent enantioselectivities. We are currently exploring this
method as a route to chiral drug intermediates for biologically
active target molecules.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(9) (a) Paul, J. M.; Palmer, C. US Patent 6,274,758, 2001. (b) Yuasa,
Y.; Yuasa, Y.; Tsuruta, H. Can. J. Chem. 1998, 76, 1304.
AUTHOR INFORMATION
Corresponding Author
Pher.Andersson@biorg.uu.se
■
(10) Ligands were synthesized according to published procedures:
(a) Trifonova, A.; Diesen, J. S.; Andersson, P. G. Chem.Eur. J. 2006,
12, 2318. (b) Hedberg, C.; Kallstrom, K.; Brandt, P.; Hansen, L. K.;
̈
̈
Notes
Andersson, P. G. J. Am. Chem. Soc. 2006, 128, 2995. (c) Engman, M.;
Diesen, J. S.; Paptchikhine, A.; Andersson, P. G. J. Am. Chem. Soc.
2007, 129, 4536. (d) Kaukoranta, P.; Engman, M.; Hedberg, C.;
Bergquist, J.; Andersson, P. G. Adv. Synth. Catal. 2008, 350, 1168.
(e) Li, J.-Q.; Paptchikhine, A.; Govender, T.; Andersson, P. G.
Tetrahedron: Asymmetry 2010, 21, 1328. (f) Li, J.-Q.; Quan, X.;
Andersson, P. G. Chem.Eur. J. 2012, DOI: 10.1002/
chem.201200907.
(11) Sliwka, H.-R.; Hansen, H.-J. Helv. Chim. Acta 1984, 67, 434.
(12) (a) Brandt, P.; Hedberg, C.; Andersson, P. G. Chem.Eur. J.
2003, 9, 339. (b) Church, T. L; Rasmussen, T.; Andersson, P. G.
Organometallics 2010, 29, 6769. (c) Hopmann, K. H.; Bayer, A.
Organometallics 2011, 30, 2483.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Swedish Research Council
(VR), The Knut and Alice Wallenberg Foundation, AstraZe-
neca, VR/SIDA, Nordic Energy Research (N-INNER II), and
Energimyndigheten (The Swedish Energy Agency). We also
thank Dr. Tamara L. Church for careful reading of the
manuscript. T.Z. thanks the China Scholarship Council for a
fellowship.
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