Complementary catalytic strategies to access α-chiral aldehydes

Article abstract of DOI:10.2533/chimia.2013.658

The present article summarizes the development of two novel and complementary catalytic methods to access α-chiral aldehydes. A C1-symmetric chiral (P,N) ligand with a structure derived from the ubiquitous binepine scaffold has been specifically designed for the Pd-catalyzed α arylation of aldehydes to access indane derivatives with a well-defined quaternary stereocenter in high yields and excellent enantioselectivities. In addition, a dinuclear palladium hydride catalyst has been synthesized for the isomerization of terminal and trisubstituted epoxides into aldehydes and ketones respectively. Combined experimental and theoretical investigations pointed to an unprecedented 'epoxide-opening/hydride-transfer' sequence. The mechanism also features two distinct enantio-determining steps in the kinetic resolution of racemic epoxides. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2013.658

658 CHIMIA 2013, 67, Nr. 9
doi:10.2533/chimia.2013.658
Werner Prize Winners
Chimia 67 (2013) 658–662 © Schweizerische Chemische Gesellschaft
Complementary Catalytic Strategies to
Access α-Chiral Aldehydes
Clément Mazet*
Werner Prize Winner 2013
Abstract: The present article summarizes the development of two novel and complementary catalytic methods
to access α-chiral aldehydes. A C1-symmetric chiral (P,N) ligand with a structure derived from the ubiquitous
binepine scaffold has been specifically designed for the Pd-catalyzed α-arylation of aldehydes to access indane
derivatives with a well-defined quaternary stereocenter in high yields and excellent enantioselectivities. In addition,
a dinuclear palladium hydride catalyst has been synthesized for the isomerization of terminal and trisubstituted
epoxides into aldehydes and ketones respectively. Combined experimental and theoretical investigations pointed
to an unprecedented ‘epoxide-opening/hydride-transfer’ sequence. The mechanism also features two distinct
enantio-determining steps in the kinetic resolution of racemic epoxides.
Keywords: Aldehydes · Catalysis · Cross-coupling · Isomerization · Palladium
After two years try with particular emphasis on asymmet- be worth deciphering using the most re-
of
ate studies in the Zasshikai Lectureship from the University physical-organic chemist.
laboratory of the of Tokyo (2012) and the Werner Prize Previous methods developed in our
late Professor from the Swiss Chemical Society (2013) grouptoaccesschiralaldehydesincludethe
undergradu- ric catalysis. He recently received the 1st cent practical and theoretical tools of the
John A. Osborn in recognition of his work in asymmetric iridium-catalyzed isomerization of prima-
at the University catalysis.
of Strasbourg
(France), Clément
ry allylic alcohols (β-chiral aldehydes),[2]
the sequential iridium/enamine catalysis
using the same substrates and diverse elec-
Mazet carried out 1. Introduction
trophiles (α,β-chiral aldehydes)[3] and the
his PhD research work under the guidance
of Professor Lutz H. Gade in the same
iridium catalyzed-hydroboration of termi-
Among other research activities, a large nal α-olefins followed by successive oxi-
University. In 2003, he moved to Basel part of our program is currently aimed at dations (α-chiral aldehydes).[4] These have
(Switzerland) where he worked as a post- developing innovative and complemen- already been discussed in a previous issue
doctoral fellow in the group of Professor tary catalytic methods using well-defined of this journal.[5] In the present article, we
Andreas Pfaltz. In 2006 he was awarded organometallic complexes to access chiral summarize the development of two addi-
a Marie Curie International Outgoing aldehydes. Our initial motivation stems tional and complementary methods that
Fellowship and spent nearly two years from the high prevalence of aldehydes as were specifically devised to gain access to
working with Professor Eric N. Jacobsen essential building blocks in synthesis and/ α-chiral aldehydes possessing either a ter-
at Harvard University (MA, USA).
or as a key function in biologically active tiary or a quaternary (stereo)center.
He joined the Organic Chemistry compounds. Although aldehydes are usu-
Department of the University of Geneva in ally associated with food additives and
November 2007 to build up his indepen- important fragrances, they are also often 2. Pd-Catalyzed α-Arylation of
dent research group as a Maître Assistant. found as pivotal intermediates in the syn- Aldehydes
In 2011, he was awarded a prestigious thesis of complex molecular architectures
Swiss National Foundation Professorship with applications in medicinal, pharma-
The palladium-catalyzed enantioselec-
(SNF Professorship). His research interests ceutical or even material sciences.[1] On tive α-arylation of carbonyl compounds
include mechanistic and synthetic chemis- the other hand, the versatile reactivity of has advanced at an impressive pace since
the aldehyde functionality is intimately the seminal report from Musco and Santi in
associated with its relative instability. 1992.[6] Challenges in this field are three-
Hence, at the outset of our investigations, fold.[7]
we postulated that devising catalytic meth-
i) Tertiary α-chiral carbonyls obtained
ods that would be tolerant to this peculiar from linear substrates tend to rapidly
oxidation state of the carbon atom may, in epimerize under the necessary basic con-
turn, be highly functional group tolerant as ditions. Advances in this direction have
they would be compatible with more ro- recently appeared in the literature for the
bust functional groups. Embarking in this α-arylation of pre-activated esters under
direction we also anticipated that we will mildly basic reaction conditions, though
certainly be confronted with more funda- ample room remains for further improve-
mental mechanistic questions that might ments.[8]
*Correspondence: Prof. Dr. C. Mazet
Department of Organic Chemistry
University of Geneva
30, quai Ernest Ansermet
CH-1211 Geneva 4
E-mail: clement.mazet@unige.ch

Werner Prize Winners
CHIMIA 2013, 67, Nr. 9 659
employed.[10] More importantly, at the difficult substrates as they lack a large vici-
beginning of our investigations, a single nal substituent (−H vs. −R, −OR or −N(R1)
example of Pd-catalyzed asymmetric R2) that may constructively interact with
α-arylation of α-branched aldehydes had the chiral catalyst during the enantioselec-
been reported.[11] In addition to the sen- tion process.
ii) α-Branched substrates are not con-
fronted with the issue of post-reaction
epimerization but instead face the inherent
difficulties associated with forging quater-
nary stereocenters.[9]
sitivity of the aldehyde functionality, the
The generic structure of the chiral (P,N)
iii) The nature of the carbonyl com-
basic conditions required for cross-cou- ligand we designed for the α-arylation of
pling may favor numerous undesired side- aldehydes is presented in Scheme 1.[13] It
reactions such as self-aldol condensations, distinguishes itself by a highly modular
pounds imparts an additional challenge
directly related to the reactivity and sta-
bility of the C=O double bond. Hence,
not surprisingly, examples of asymmetric
α-arylation of amides or esters are numer-
ous whereas ketones have been much less
Cannizzaro or Tishchenko disproportion-
scaffold possessing three elements of chi-
ations.[7,12] Furthermore, from a stereose- rality: i) the axial chirality of the elemen-
lective point of view, aldehydes are more tary binepine core;[14] ii) a central chirality
at a benzylic position; iii) a phosphorus
stereogenic center. The latter two elements
are stereoselectively installed by introduc-
tion of the methylpyridyl unit according to
Scheme 1. Novel
class of chiral (P,N)
ligands for the enan-
tioselective intramo-
lecular α-arylation of
aldehydes.
a strategy already employed by Wildhalm
generic structure
and Zhang.[15] Nine different ligands were
3
R
R
R
Br
initially synthesized in acceptable to good
overall yields. Substituents with various
steric and electronic demands were intro-
3
R
N
1
+
P R
2
P
R
N
1
R
duced at the phosphorus atom and the or-
tho position of the pyridyl ring.
2
R
R
R
♦ axial chirality
Optimizations of the reaction condi-
← central chirality @
←central chirality @P
C
tions (1.2 equiv. Cs CO3, 80 °C, DMF, 48 h)
were performed us2ing 4-(2-bromophenyl)-
2
1
R =H
(R,R,R )-1a R =Ph
(R ,R,R )-1b R =Ph
a
2-methylbutanal 2a as a model substrate
and ligand (Ra,R,RP)-1e (75% yield, 96%
ee) (Scheme 2, top). While bromoarenes
underwent cyclization, aryl chlorides and
iodides failed to react. Evaluation of all
other members of this new ligand class
indicated that (Ra,R,RP)-1i was clearly out-
standing in terms of reactivity and selectiv-
a
P
structure in this study
2
1
R =Me
P
2
1
R =H
(R ,R,R )-1c R =Et
a
P
2
1
R =H
(R ,R,S )-1d R =Cy
a
P
2
1
R =H
(R ,R,R )-1e R =t-Bu
a
P
N
2
1
2
R =Me
(R ,R,R )-1f R = t-Bu
P
R
a
P
1
R
2
1
R =Ph
(R ,R,R )-1g R = t-Bu
a
P
2
1
R =H
(R ,R,R )-1h R =2-MeO-C H
a
P
6 4
2
1
R =H
(R ,R,R )-1i R =2,4-(MeO) -C H
a
P
2
6 3
ity. With this candidate, a variety of indane
derivatives was obtained in consistently
high yield and enantioselectivity (9 exam-
ples, 51−99% yield, 35−99% ee). Primary
alkyl α-substituents were well tolerated
whereas secondary alkyls had a detrimen-
Scheme 2. Scope
for the enantiose-
lective α-arylation
of aldehydes using
ligand (Ra,R,RP)-1i.
Intramolecular ver-
sion: top; intermolec-
ular version: bottom.
3
R
5mol% Pd(OAc)
2
C
H
O
Br
1
0 mol% (R ,R,R )-1i
a P
CHO
1
R
tal effect on both the reactivity and the
1
1.2 e
quiv.Cs2CO3
R
n
n
2
3
R
R
2
DMF,80°C, 48 h
R
selectivity. The system proved insensitive
to variations of the electronic properties of
the bromoarenes moiety. More interesting-
n=1,2
2a-i
3a-i
Et
ly, the use of a dibrominated substrate 2h
Me
iPr
CHO
CHO
C
H
O
resulted in product formation in excellent
yield and nearly perfect enantioselectiv-
ity (87% yield, 99% ee) and, remarkably,
the second bromine atom remained intact
3
a: 7
5
% yield; 9
6
% e
e
3
b: 8
0
% yield; 9
4
% e
e
3
c: 5
1
% yield; 75% ee
in the cyclized product. This observation
is consistent with reversible oxidative
Me
Me
Me
CHO
C
H
O
C
H
O
addition of Pd(0) intermediates into the
carbon-halogen bond and was further sub-
F
MeO
F C
3
stantiated by engaging the product in other
3
d: 8
7
% yield; 9
4
% e
e
3
e: 8
4
% yield; 9
4
% e
e
3f: 77% yield; 91% ee
C−C bond forming processes using vari-
ous electrophiles under otherwise identical
reaction conditions. Such an observation is
Me
Me C
HO
Ph
CHO
CHO
rare in Pd-catalyzed cross-coupling reac-
tions and had not been documented in the
Br
context of asymmetric catalysis.[16]
3
g: 9
9
% yield; 2
0
% e
e
3
h: 8 % yield; 9
7
9
% e
e
3i: 99% yield; 35% ee
(11 C, 72
0
ϒ
h)
A real breakthrough in the enantio-
selective α-arylation of carbonyl com-
CHO
5mol% Pd(OAc)
2
Ph
pounds would consist in developing in-
1
0 mol% (R ,R,R )-1i
CHO
a P
Me
4-bromo
Cs2CO3 (1.1 e
MF,48h,110°C
a
nisole (1.0 e
quiv.)
termolecular variants of these transforma-
Me
tions.[17] Preliminary results obtained with
q
uiv.)
O
Me
D
(Ra,R,RP)-1i in the cross-coupling between
2j
3j: 2
0
%, 7% ee
2-methyl-3-phenylpropanal and 4-bro-

660 CHIMIA 2013, 67, Nr. 9
Werner Prize Winners
Scheme 3.
moanisole further highlight the difficulty
associated with this task (Scheme 2, bot-
tom).
not known
our work
Complementary
strategies to access
α-chiral aldehydes.
1
1
R
R
1
O
L*/cat
L*/cat
R
O
O
Ar
Ar
Ar-X
H
H
3. Isomerization of Terminal
Epoxides
linear
aldehydes
terminal
epoxides
α-chiral
aldehydes
As emphasized above, the enantiose-
lective α-arylation of linear carbonyl de-
rivatives in general and of aldehydes in
particular remains a formidable challenge.
Although work in this direction is current-
ly on-going in our laboratory, we have also
tackled this issue from a rather different
angle.[18]
We identified the isomerization of ter-
minal epoxides (Scheme 3) as a potentially
very attractive alternative method to access
α-chiral aldehydes with a tertiary stereo-
center. In principle, starting from readily
accessible substrates, the isomerization of
epoxides enables direct access to the corre-
sponding carbonyl derivatives. Despite its
occasional implementation in synthesis,
this reaction suffers from several limita-
tions.[19] Super-stoichiometric amounts of
reagents rather than well-defined catalysts,
unpredictable reaction outcome, plethora
of side-reactions, high substrate specific-
ity and an ill-defined mechanistic picture
have prevented widespread use of this
method. Examples of stereospecific isom-
erizations of epoxides are very rare and
have been described only for trisubstituted
epoxides.[20] Furthermore, although the
kinetic resolution of racemic 2,3-disubsti-
tuted and trisubstituted epoxides has been
documented, the main focus was to access
either enantioenriched epoxides or enan-
tioenriched allylic alcohols. In spite of the isomerization of terminal and trisubsti-
aforementioned shortcomings, we initially tuted epoxides into aldehydes and ke-
Scheme 4. Scope for the [Pd−H]-catalyzed isomerization of terminal and trisubstituted epoxides.
ating in sequence. A pathway that accounts
for partial racemization of the enantio-en-
riched aldehyde in presence of the Pd−H
catalyst and that lies off the productive
catalytic cycle was also identified.
set out to develop an asymmetric version tones respectively (1−6 mol% [Pd], THF,
of this transformation to access enantioen- 85−140 °C, 4−24 h). The functional group
riched α-chiral aldehydes.
tolerance of the method was delineated and
Although far from practicality, the pre-
liminary results obtained using commer-
cially available chiral bisphosphine ligands
clearly set a precedent that will serve as a
stepping-stone for further developments of
a more efficient asymmetric isomerization
of terminal epoxides to access chiral alde-
hydes with a α-tertiary stereocenter.
Our approach was inspired by the con- aryl halides (6k−n), alkoxy groups (6o,p)
tribution of Bunel and co-workers who ester (6s), cyano (6t), alkynes (6u), alkenes
had described the use of well-defined (6v), as well as ketones (6z) were all toler-
Pd−H catalysts for the related isomeriza- ated and the corresponding products were
tion of terminal olefins.[21] More impor- isolated in practical to excellent yields
tantly, Kulawiec and co-workers had also (Scheme 4). Although the method was
reported the highly selective isomerization initially designed as an alternative to the
of 2-methyl-2-(2-naphthyl)-oxirane with α-arylation of linear aldehydes, substrates
a combination of Pd(OAC)2 and PPh3.[22] containing two alkyl substituents in the
This precedent constituted a rare example
α-position were also isomerized efficiently
of a catalytic isomerization of terminal (6q, 6r, 6v, 6z).
epoxides, though it turned out to proceed A series of experimental investigations
4. Conclusions
The present article summarizes the de-
velopment of two novel and complemen-
exclusively for this substrate and required − which were further corroborated by DFT
the use of a protic solvent – a detrimental calculations − pointed to an unprecedent-
parameter in view of developing an asym- ed hydride-type mechanism (Scheme 5).
metric version of this reaction as it favors Preliminary results obtained in the kinetic
tary catalytic methods to access α-chiral
aldehydes. A novel C -symmetric chiral
(P,N) ligand with an ori1ginal structure de-
rapid enolization.
resolution of terminal epoxides (stereodi-
rived from the ubiquitous binepine scaf-
fold has been specifically designed for the
Pd-catalyzed α-arylation of aldehydes.
This reaction generates indane derivatives
with a well-defined quaternary stereocen-
During re-optimization of the condi- vergent) and in the isomerization of en-
tions initially reported by Kulawiec to antioenriched 2-methyl-2-phenyloxirane
develop a widely applicable protocol, we (94% ee) into racemic 2-phenylpropanal
identified a novel dinuclear Pd–H complex (stereoconvergent) revealed that two dis-
4 which proved competent in the selective tinct enantio-determining steps were oper-

Werner Prize Winners
CHIMIA 2013, 67, Nr. 9 661
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cals.
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enantio-determining steps were operating
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Acknowledgements
The results summarized in this article have
d) F. Bellina, R. Rossi, Chem. Rev. 2010, 110,
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of carbonyl compounds/amides has been
been carried out by a group of talented and
highly dedicated co-workers to whom I am
deeply indebted. Their names appear in the list
of references below. The author also thanks
the University of Geneva, the Swiss National
reported to date: A. M. Taylor, R. A. Altman,
S. L. Buchwald, J. Am. Chem. Soc. 2009, 131,
9900.
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