3,3′-Bithiophene-Based Chiral Bisphosphine Oxides as Organocatalysts in Silicon-Derived Lewis Acid Mediated Reactions

Article abstract of DOI:10.1055/s-0039-1690777

This account summarizes the development of new biheteroaromatic chiral bisphosphine oxides. 3,3′-Bithiophene-based phosphine oxides (BITIOPOs) have been successfully used as organocatalysts to promote Lewis base catalyzed, Lewis acid mediated stereoselective transformations. These highly electron-rich compounds, in combination with trichorosilyl derivatives (allyltrichlorosilane and silicon tetrachloride), generate hypervalent silicon species that act as chiral Lewis acids in highly diastereo- and enantioselective organic reactions. Several relevant examples related to these applications are discussed in detail. 1 Introduction 2 The BITIOPO Family 3 Enantioselective Opening of Epoxides 4 Enantioselective Allylation of Aldehydes 5 Stereoselective Direct (Double) Aldol-Type Reaction with Ketones 6 Stereoselective Direct Aldol-Type Reaction with Ester Derivatives 7 Conclusions.

Full text of DOI:10.1055/s-0039-1690777

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© Georg Thieme Verlag Stuttgart · New York
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S. Rossi et al.
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3,3′-Bithiophene-Based Chiral Bisphosphine Oxides as Organo-
catalysts in Silicon-Derived Lewis Acid Mediated Reactions
Sergio Rossi*a
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Tiziana Benincorib
Laura Maria Raimondia
Maurizio Benaglia*a
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a Dipartimento di Chimica, Università degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
maurizio.benaglia@unimi.it
sergio.rossi@unimi.it
b Dipartimento di Scienza e Alta Tecnologia, Università degli
Studi Dell’Insubria, Via Valleggio 11, 22100 Como, Italy
Published as part of the ISySyCat2019 Special Issue
Received: 21.10.2019
Accepted after revision: 03.12.2019
Published online: 07.01.2020
Lewis acids to generate in situ penta- or hexa- coordinated
chiral hypervalent silicon species with enhanced reactivi-
ty.5 In 2004, Kobayashi demonstrated that a stoichiometric
amount of a chiral phosphine oxide could be used to per-
form the enantioselective allylation of hydrazones with all-
yltrichloro silane.6 However, it was only in 2005 that Nakajima
developed the first enantioselective allylation of aldehydes
promoted by a catalytic amount of 2,2′-bis(diphenylphos-
phanyl)-1,1′-binaphthyl dioxide (1; BINAPO).7
DOI: 10.1055/s-0039-1690777; Art ID: st-2019-a0576-a
Abstract This account summarizes the development of new bihet-
eroaromatic chiral bisphosphine oxides. 3,3′-Bithiophene-based phos-
phine oxides (BITIOPOs) have been successfully used as organocatalysts
to promote Lewis base catalyzed, Lewis acid mediated stereoselective
transformations. These highly electron-rich compounds, in combina-
tion with trichorosilyl derivatives (allyltrichlorosilane and silicon tetra-
chloride), generate hypervalent silicon species that act as chiral Lewis
acids in highly diastereo- and enantioselective organic reactions. Sever-
al relevant examples related to these applications are discussed in de-
tail.
The hypervalent silicon species generated by the coordi-
nation of a Lewis base with the silicon-derived Lewis acid
are not isolable,3,8,9 and their chemical behavior mainly de-
pends on two factors: (i) the type of ligand connected to the
silicon atom and (ii) the reaction partners present in the re-
action media.8 In Scheme 1 three of the possible pathways
related to the activation of SiCl4 and allyltrichlorosilane by
bisphosphine oxides are depicted. Since a complete and ex-
haustive treatment of all activation modes derived by the
coordination of a Lewis base to silicon Lewis acids was re-
cently reported,4,10 it will not be discussed here. Initially, a
Lewis base, such as a phosphine oxide, interacts with the
silicon-based Lewis acid, generating the pentacoordinate
silicon species i. This species is then coordinated by another
molecule of Lewis base to form the thermodynamically fa-
vored hypercoordinate silicon species ii, which intercon-
verts into the cationic pentacoordinate silicon species iii af-
ter the expulsion of a chloride ion. At this point, according
to pathway A, a coordination of the substrate (typically an
aldehyde) occurs and, in the absence of an external nucleo-
phile, one of the silicon substituents of species iv is trans-
ferred to the substrate in an intramolecular manner
through a chair-like six-membered-ring cationic transition
state. Lewis base catalyzed allylation of aromatic aldehydes
performed with allyltrichlorosilane and the Lewis base cat-
alyzed, SiCl4-mediated opening of epoxides operate accord-
ing to this pathway.
1
2
3
4
5
6
7
Introduction
The BITIOPO Family
Enantioselective Opening of Epoxides
Enantioselective Allylation of Aldehydes
Stereoselective Direct (Double) Aldol-Type Reaction with Ketones
Stereoselective Direct Aldol-Type Reaction with Ester Derivatives
Conclusions
Key words silicon hypercoordination, organocatalysis, Lewis bases,
aldol reactions, stereoselective reactions, chiral phosphine oxides
1 Introduction
Lewis base catalysis derived from the activation of tri-
chlorosilanes has been known since 1993, when Kobayashi
reported for the first time the allylation of aldehydes by the
in situ generation of a hypervalent silicon species derived
from the coordination of dimethylformamide with allyltri-
chlorosilane.1 Starting from that pioneering study, the de-
velopment of the ‘Lewis base catalyzed Lewis acid mediated
reactions’ concept has seen an explosive growth, and nowa-
days this approach is a well-established methodology for
the synthesis of functionalized compounds.2–4 Three years
after the discovery, Berrisford and co-workers reported that
phosphine oxides were able to coordinate silicon-derived
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–L
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B
S. Rossi et al.
Account
Synlett
If an external nucleophile is present instead, species iv
undergoes nucleophilic attack from the external nucleo-
phile through an intermolecular pathway (path B). This is
the case of Lewis base catalyzed allylation of aldehydes per-
formed with allyltributyltin and mediated by SiCl4. Howev-
er, when the nucleophile can also be coordinated to the sili-
con atom, species iii evolves into the neutral hexacoordi-
nate species v (path C). The expulsion of a silicon ligand
(typically a chloride anion) and the consequent coordina-
tion of the substrate leads to the formation of the hyperco-
ordinate silicon species vi. As before, also in this case, both
the substrate and the nucleophile are coordinated to the sil-
icon atom, and the new bond between them is formed
through an intramolecular approach. This pathway is ob-
Biographical Sketches
Maurizio Benaglia completed
his PhD with Prof. M. Cinquini
and F. Cozzi, then joined the
group of Prof. J. S. Siegel at
UCSD (USA) in 1995. He then
moved back to the University of
Milan, where, in 2015, he was
appointed as full professor of
organic chemistry. His research
activities focus on the develop-
ment of novel synthetic meth-
odologies, investigation of
reactions in alternative reaction
media, design of new chiral or-
ganocatalysts, study of stereo-
selective reactions in flow and
catalytic reactors, and synthesis
of pharmaceutical products. His
work also involves the use of
3D-printed devices and en-
abling technologies.
Sergio Rossi received his PhD
from University of Milan, Italy, in
2010. He joined the University
of Illinois at Urbana Champaign
(USA) in 2011 as a post-doctoral
fellow, in the group of Prof. S. E.
Denmark where he worked in
the development of new Lewis
base catalyzed reactions. In
2017 he obtained an assistant
professor position at the Univer-
sity of Milan, where he is cur-
ral pharmaceutical products
and in the development of new
catalytic stereoselective metal-
free methodologies, under con-
tinuous-flow conditions in mi-
rently
working
in
the
cro
and
3D
printed
stereoselective synthesis of chi-
mesoreactors.
Laura Raimondi received her
PhD in chemistry from the Uni-
versity of Milano in 1989, and
joined the group of Prof. K. N.
Houk at UCLA (Los Angeles,
USA). She became assistant pro-
fessor in the University of Milan
in 1990, and associate professor
in 1998. Experimental and theo-
retical studies on the origin of
stereoselection in organic reac-
tions are her main research
field. She is also interested in
the study of intermolecular in-
teractions and in conformation-
al analysis of biomolecules.
Tiziana Benincori became as-
sociate professor of organic
chemistry in 2002 at the Univer-
sity of Insubria where she is cur-
rently performing research
combining chirality and hetero-
cyclic chemistry. Her special in-
terests include the design of
chiral functional compounds
based on atropisomeric bihet-
eroaromatic scaffolds that pro-
vide electronically tunable chiral
diphosphane ligands at an in-
dustrial scale level, while the
corresponding oxides perform
efficiently as organocatalysts.
More recent investigations have
been focused on developing
highly enantioselective ‘inher-
ently chiral’ electroactive poly-
heteroaromatic materials in
which the stereogenic element
and the electroactive backbone
coincide.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–L

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S. Rossi et al.
Account
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Pathway A
substrate (SB)
LB
(Lewis base)
–
+
Cl
Cl
Cl
Si
Cl
–
Cl
Si
Cl
+
C
Cl
Cl
Si
LB
LB
Cl
LB
R
LB
Cl
LB
R
LB
R
LB
SB
R = Allyl
R Si
Cl
Si LB
Cl
Cl
R
SB
R
Cl
iv
i
ii
iii
silicon-based
Lewis acid
pentacoordinate
neutral silicon
species
hexacoordinate
neutral silicon
species
pentacoordinate
hexacoordinate cationic
cationic
silicon species
silicon species
R = Allyl, Cl
Nucleophile (Nu),
Pathway B
R = Cl
Base
Pathway C
Nucleophile (Nu)
R = Cl
substrate
(SB)
Cl
Si
SB
Si
LB
R
LB
Nu
LB
R
LB
Nu
Nu SB
Cl
Cl
v
+ Base.HCl
neutral hexacoordinate
vi
silicon species
Scheme 1 Reaction pathways involving hypercoordinate silicon species generated by bisphosphine oxide coordination to silicon tetrachloride and to
allyltrichlorosilane
served in the Lewis base catalyzed direct (double) aldol re-
action of ketones or activated esters with aldehydes mediat-
ed by SiCl4.
S
O
PAr2
O
O
N
P
Ph2P
Ph2
PAr2
O
PPh2
PPh2
O
N
S
O
2 The BITIOPO Family
Ar = Ph,
Ar = 4-Tol, Tol-BINAPO (2)
BINAPO (1)
TetraMe-BITIOPO
N-Me-2-BINPO
(4)
(3)
S
O
The Lewis basicity of the P=O polarized bond means
that phosphine oxides have found widespread applications
in organocatalysis.11 The use of C2-symmetric bisphosphine
oxides has received particular attention because they are
able to generate chiral hypervalent hexacoordinate specie ii
in a well-defined geometry, which is a key factor that deter-
mines the stereochemical outcome. Nowadays many differ-
ent bisphosphine oxides are known to act as good organo-
catalysts in Lewis base (LB)-catalyzed Lewis acid (LA)-me-
diated reactions. A selection of the most important
representatives of this class of chiral ligands is reported in
Scheme 2. It must be noted that, before our contribution,
only BINAPO (1) and Tol-BINAPO (2) were employed in this
type of transformations. In 2000, with the idea of investi-
gating the behavior of a series of phosphine oxides display-
ing different electronic and steric properties, some of us re-
ported the synthesis of a promising bisphosphine oxide
based on a biheteroaryl scaffold, TetraMe-BITIOPO (3).12
A few years later we investigated the use of 3, 3-indolyl-
based N-Me-2-BINPO (4), and catalyst BITIANPO (5), de-
rived from 3,3′-bibenzothiophene, in the enantioselective
catalytic addition of allyltrichlorosilane to aldehydes and
the stereoselective opening of meso-epoxides.13 A structur-
ally novel class of chiral bisphosphine oxides was reported
in 2009, when Ready synthesized the bisphosphine oxide 6
containing an allene backbone, which was efficiently em-
ployed in the asymmetric ring-opening of meso-epoxides.14
One year later, it was reported that SEGPHOSO (7) and DIO-
PO (8) promoted the stereoselective reductive aldol reac-
O
O
O
PPh2
PPh2
PPh2
O
O
Ph
PPh2
PPh2
O
Ph
O
S
Ph2P
O
O
SEGPHOSO
(7)
BITIANPO
(6)
(5)
O
O
P
O
O
O
O
PPh2
O
O
N
X
PPh2
PPh2
O
O
P
Ph2P
O
O
DIOPO
(8)
DMPP-DIOPO
(10) X = O
(11) X = NH
(9)
O
O
O
O
PPh2
PAr2
PPh2
PPh2
O
(CH2)6
PAr2
O
PPh2
O
O
Ar = 3,5-tBu2-4-MeOC6H2
(12)
(13)
(14)
N
N
N
N
N
O
O
O
PPh2
O
Bn
Bn
N
N
P
PAr2
PMP
PMP
O
O
Ph2
PPh2
O
PAr2
O
PPh2
O
N
N
O
N
N N
PMP = 4-MeOC6H4
(16)
(17)
(15)
Scheme 2 Most common bisphosphine oxides employed as organo-
catalysts in LB-catalyzed LA-mediated reactions
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–L

D
S. Rossi et al.
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tion in the presence of trichlorosilane;15 aryl group-modi-
fied DIOP dioxides, such as 2,8-dimethylphenoxaphos-
phine-DIOPO 9 were also found to be effective in promoting
the phosphonylation of conjugated aldehydes.16 In 2012,
our group reported that proline-based catalysts 10 and 11
could also be used in the stereoselective aldol reactions of
activated thioesters17 and, one year later, BridgePHOS ox-
ide18 12, spiro-type19 catalyst 13 and conformationally rigid
atropisomeric chiral diene phosphine oxide 14, based on
(Z,Z)-2,3-bis[1-(diphenylphosphinyl)ethylidene]tetralin,20
were reported to be efficient catalysts in SiCl4 mediated re-
actions.21 Very recently, tropos BIPHEPO-ligand 15 and cat-
alysts 16 and 17, based on a bis(triazolyl) scaffold, have
found applications in the enantioselective Abramov type
phosphonylation of aldehydes22 and in the organocatalyzed
reductive aldol reaction.23
The ability of these phosphine oxides to act as organo-
catalysts is essentially related to their geometric and elec-
tronic properties; stereogenic axes as well as the presence
of bulky substituents close to the catalytic center are essen-
tial to achieve good level of stereoselectivity. Their electron-
ic properties are strictly connected to the chemical efficien-
cy of the process; indeed, electron-deficient phosphine ox-
ides do not activate silicon-based Lewis acids as opposed to
electron-rich phosphine oxides.11
In the last few years, in a continuation of our investiga-
tions into the use of chiral phosphine oxides as organocata-
lysts, we have synthesized a small library of heteroaromatic
phosphine oxides based on the easily accessible 3,3′-bithio-
phene scaffold (Scheme 3). Modifications were introduced
on the aryl groups connected to the phosphorus atoms,24
and on the substituents of the chiral backbone,25 in an at-
tempt to modulate the electronic characteristics of the two
P=O double bonds and to modify the chiral pocket induced
in the coordination of the silicon-based Lewis acid. Racemic
MPP-tetraMe-BITIOPO (18), PMP-tetraMe-BITIOPO (19) and
the most electron-rich MMP-tetraMe-BITIOPO (20) were
synthesized starting from commercially available 2,5-di-
methylthiophene, which was converted into dibrominated
compound 22 according to a reported procedure.12 After the
reaction with n-BuLi followed by the addition of the desired
diarylphosphoryl chloride, it was possible to obtain Te-
traMe-BITIOPO 3 derivatives 18–20 in racemic form.
The corresponding optically pure phosphine oxides
were then isolated by HPLC on chiral stationary phase.24
The synthesis of phosphine oxide 21 instead starts from
commercially available 3,3′-bithiophene 23, which was eas-
ily brominated to afford compound 24. Tetraphenyl-substi-
tuted compound 25 was then obtained by a regioselective
Suzuki coupling with phenyl boronic acid. Reaction of
25 with n-BuLi and ditolylphosphinic chloride followed by
R
S
O
PAr2
R
R
PAr2
O
S
R
(3) R = Me, Ar = Ph
TetraMe-BITIOPO
(18) R = Me, Ar = 3,5-Me2C6H3
(19) R = Me, Ar = 4-MeOC6H4
(20) R = Me, Ar = 3,5-(CH3)2-4-MeOC6H2
(21) R = Ph, Ar = 4-Tol
MPP-TetraMe-BITIOPO
PMP-TetraMe-BITIOPO
MMP-TetraMe-BITIOPO
TetraPh-Tol-BITIOPO
a) Synthesis of TetraMe-BITIOPOs derivates
S
S
S
O
O
1) n-BuLi
PAr2
PAr2
resolution
3 steps
Br
Br
S
2) Ar2P(O)Cl
PAr2
O
PAr2
O
S
S
S
(22)
Racemic form
(3) Ar = Ph
(18) Ar = 3,5-Me2C6H3
(19) Ar = 4-MeOC6H4
(20) Ar = 3,5-Me2-4-MeOC6H2
b) Synthesis of TetraPh-Tol-BITIOPO (21)
Ph
Ph
Ph
Ph
S
Br
S
S
S
S
O
S
S
O
1) n-BuLi
2) (4-Tol)2PCl
P(4-Tol)2
PhB(OH)2
Br
P(4-Tol)2
Br
Br
Ph
Br
Br
Br
Ph
Ph
Br2
Ph
Ph
resolution
Ph
3) H2O2
P(4-Tol)2
O
P(4-Tol)2
O
S
S
S
Ph
Br
Ph
(21)
(23)
(24)
(25)
Racemic form
Scheme 3 Synthetic strategies for the preparation of chiral bithiophene-based phosphine oxides
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–L

E
S. Rossi et al.
Account
Synlett
in situ oxidation with hydrogen peroxide allowed TetraPh-
Tol-BITIOPO 21 to be obtained in racemic form.25 Once
again, by resolution with enantioselective HPLC on a chiral
stationary phase, both the antipodes were obtained in en-
antiopure form. The absolute configuration of these phos-
phine oxides was determined by electronic circular dichro-
ism and optical rotation dispersion spectra analysis.
The performance of these phosphine oxides were subse-
quently investigated over the last five years in a few organo-
catalytic stereoselective transformations mediated by the
presence of a silicon-based Lewis acids. The present article
focuses on the more recent results obtained with bihet-
eroaromatic phosphino oxides in stereoselective reac-
tions.26
mol%.14 NMR data and kinetic studies suggested that the
mechanism of this transformation follows pathway A re-
ported in Scheme 1, in which only one chloride per SiCl4 is
active under the reaction conditions and the hypervalent
silicon species generated by the coordination of the Lewis
base to SiCl4 does not change over the course of the reac-
tion.29 However, further mechanistic investigations are re-
quired to clarify all the species involved.
4 Enantioselective Allylation of Aldehydes
In 2005, Nakajima et al. reported the first example of an
organocatalytic and enantioselective addition of allyltri-
chlorosilane to aromatic aldehydes using chiral phosphine
oxide BINAPO (1).27,30 Reaction with benzaldehyde gave the
corresponding homoallylic alcohol 30 in low yields and
with poor enantioselectivities even after 24 h (Scheme 4). A
more detailed investigation of the reaction conditions re-
vealed that the presence of 5 equiv of iPr2NEt and 1.2 equiv
of Bu4N+I– as additives were mandatory to decrease the re-
action time and to increase the chemical and stereochemi-
cal efficiency of the process. However, in neither case were
aliphatic aldehydes suitable substrates for this transforma-
tion. The reaction is highly stereospecific; (E)-crotyltrichlo-
rosilane affords the syn-31 product whereas (Z)-crotyltri-
chlorosilane leads to the formation of the anti-31 product,30
in accordance with the formation of a cationic and hexaco-
ordinated hypervalent silicon species iv.
3 Enantioselective Opening of Epoxides
The first example of enantioselective synthesis of chlo-
rohydrins through a phosphine oxide-catalyzed SiCl4-medi-
ated meso-epoxide ring-opening reaction was reported in
2005 by Nakajima and co-workers.27 A catalytic amount of
BINAPO 1, in the presence of a stoichiometric amount of
iPr2NEt, afforded chlorohydrin 27 derived from stilbene ox-
ide 26 with 94% yield and 90% ee when operating at –78 °C
for 4 h (Table 1). The presence of a stoichiometric amount of
base such as iPr2NEt is crucial for this type of reaction, since
it acts as HCl-scavenger, which is responsible of rapid, non-
stereoselective background reaction.
O
OH
Table 1 Enantioselective Opening of Epoxides
(S)-BINAPO (10 mol%)
SiCl3
H
CH2Cl2, RT
SiCl4
iPr2NEt
catalyst (10 mol%)
30a
29a
Ph
Ph
OH
Cl
O
without additives, 24 h:
with iPr2NEt and Bu4NI, 4 h:
32% yield, 36% ee
92% yield, 43% ee
Ph
Ph
CH2Cl2, –78 °C
26
27
(E)
(Z)
O
OH
OH
Entry Catalyst
Time (h)
Yield (%)
ee (%)
SiCl3
SiCl3
E:Z 77:23
E:Z 1:99
H
1
(S)-BINAPO (1)
(S)-Tol-BINAPO (2)
(S)-TetraMe-BITIOPO (3)
6
4
4
94
92
99
97
92
90
59
81
95
17
(S)-BINAPO,
2
iPr2NEt, Bu4NI
anti-31
syn-31
(syn:anti 77:23)
(syn:anti 99:1)
3
12
12
2
87% yield, 46% ee
92% yield, 4% ee
4a
5
Scheme 4 Enantioselective allylation of benzaldehyde promoted by
(R,R)-DIOPO (8)
BINAPO
a 0.1 mol% of catalyst was used.
Better results were obtained when biheteroaryldiphos-
phine oxides were employed (Table 2).13,24,25 At 0 °C in the
presence of iPr2NEt and using CH3CN as the solvent of
choice, high yields and enantioselectivities were generally
observed, even in the absence of Bu4N+I–. Electron-rich
phosphine oxides such as (S)-N-Me-2-BINPO and (S)-Te-
traMe-BITIOPO showed high catalytic activity, providing
the homoallylic alcohol 30a in 83% and 81% yield, and 85%
and 93% ee, respectively (entries 2 and 4), clearly improving
Derivatives of BINAPO, such as Tol-BINAPO 2, showed
lower selectivities compared with BINAPO itself (Table 1,
entries 1 and 2);27 however, biheteroaromatic bisphosphine
oxide 3 catalyzed the opening of stilbene oxide in quantita-
tive yield with comparable enantioselectivity.13 DIOPO (8)
is almost completely unselective in this type of transforma-
tion,28 whereas catalyst 6 leads to the formation of the de-
sired product in 95% ee even when it is employed at 0.1
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F
S. Rossi et al.
Account
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the modest 51% ee obtained with (S)-Tol-BINAPO. The most
electron-deficient diphosphine oxide (S)-BITIANPO did not
promote the reaction in appreciable yields. (S)-PMP-Te-
traMe-BITIOPO (19) exhibited comparable chemical
efficiency to (S)-TetraMe-BITIOPO also at –20 °C (entry 6),
whereas (S)-MMP-TetraMe-BITIOPO 20 and (S)-MPP-Te-
traMe-BITIOPO 18 afforded the compound 30a in modest to
good yields and lower enantioselectivity (entries 5 and 7).
With (S)-TetraPh-Tol-BITIOPO 21, the homoallylic alcohol
30a was isolated in 87% yield and 70% ee, which was in-
creased to 94% by changing the reaction media.
aldehydes react slower than electron-rich aldehydes, but in
both cases, high levels of enantioselectivities were reached,
often higher than 80%. Catalysts 3 and 21 were also em-
ployed in the more challenging allylation of cinnamalde-
hyde to give product 30h; (S)-TetraPh-Tol-BITIOPO behaved
better than (S)-TetraMe-BITIOPO (complete conversion and
70% ee, entry 22 vs. 55% yield and 55% ee, entry 16).
5 Enantioselective Direct (Double) Aldol-
Type Reaction with Ketones
As illustrated in Scheme 1, if a nucleophile coordinated
to the silicon atom is present during the generation of spe-
cies iii, Pathway C is preferred. As a consequence, after the
dissociation of a chlorine atom from the neutral hexacoor-
dinate species v, species vi will be formed, containing both
the substrate and the nucleophile, and favoring the forma-
tion of a new carbon–carbon bond by an intramolecular ap-
proach. According to this mechanism, it was found that cy-
clic ketones can react with an aromatic aldehyde in the
presence of phosphine oxide as organocatalyst and a stoi-
chiometric amount of iPr2NEt and SiCl4 to afford -hydroxy
ketones in high yield and with high diastereo- and enantio-
selectivities.
The reaction is called a direct aldol reaction because the
coordination of the ketone to the hypervalent silicon spe-
cies v in the presence of iPr2NEt leads to the formation of
the trichlorosilyl enol ether in situ, which will perform a in-
tramolecular nucleophilic attack to the aromatic aldehydes,
that is also coordinated to the silicon atom. In 2009, Nakajima
and co-workers reported the synthesis of enantiomerically
enriched -hydroxy ketones according to this approach.31
The reaction between cyclohexanone 31a and benzalde-
hyde 29a was investigated in the presence of stoichiometric
amounts of SiCl4 and a catalytic amount of enantiomerical-
ly pure (S)-BINAPO at 0 °C for 2 hours. -Hydroxy-ketone
32a was obtained in 81% yield with 86:14 anti:syn ratio and
in 54% ee for the major isomer (Scheme 5).
Table 2 Enantioselective Allylation of Aromatic Aldehydes Promoted
by Biheteroaromatic Phosphine Oxides
catalyst (10 mol%)
iPr2NEt ( 2 equiv)
O
OH
SiCl3
+
R
H
R
CH3CN, 0 °C, 40 h
30a–l
29a–l
Entry Ar
Catalyst
Product Yield ee (%)
(%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(S)-Tol-BINAPO (2)
(S)-N-Me-2-BINPO (4)
(S)-BITIANPO (5)
30a
30a
30a
30a
55
83
<5
85
55
76
52
87
50
51
55
95
83
95
98
55
98
49
46
50
60
98
51
81
nd
93
38
86
27
70
94
93
95
83
87
91
81
55
23
94
96
90
76
70
2
3
4
(S)-TetraMe-BITIOPO (3)
5a
6a
7a
8
(S)-MPP-TetraMe-BITIOPO (18) 30a
(S)-PMP-TetraMe-BITIOPO (19) 30a
(S)-MMP-TetraMe-BITIOPO(20) 30a
(S)-TetraPh-Tol-BITIOPO (21)
30a
9b
(R)-TetraPh-Tol-BITIOPO (21) 30a
10
4-O2NC6H4
4-ClC6H4
(S)-TetraMe-BITIOPO (3)
(S)-TetraMe-BITIOPO (3)
30b
30c
30d
30e
30f
11
12
13
14
15
16
17
18c
19
20
21
22
2-MeOC6H4 (S)-TetraMe-BITIOPO (3)
3-MeOC6H4 (S)-TetraMe-BITIOPO (3)
4-MeOC6H4 (S)-TetraMe-BITIOPO (3)
1-naphthyl
(E)-styryl
(S)-TetraMe-BITIOPO (3)
(S)-TetraMe-BITIOPO (3)
(S)-TetraMe-BITIOPO (3)
30g
30h
30i
SiCl4 (1.5 equiv)
PhCH2CH2
iPr2NEt (10 equiv)
(S)-BINAPO (10 mol%)
OH
OH
O
O
O
O
4-MeOC6H4 (R)-TetraPh-Tol-BITIOPO (21) 30f
+
+
Ph
Ph
EtCN, 0 °C, 2 h
Ph
H
4-ClC6H4
4-O2NC6H4
2-thienyl
(E)-styryl
(R)-TetraPh-Tol-BITIOPO (21) 30b
(S)-TetraPh-Tol-BITIOPO (21)
(S)-TetraPh-Tol-BITIOPO (21)
(S)-TetraPh-Tol-BITIOPO (21)
30c
30l
31a
29a
anti-32a
syn-32a
81% yield,
86:14 anti:syn, 54% ee (anti)
30h
Scheme 5 Enantioselective direct aldol-type reactions between cyclo-
hexanone and benzaldehyde catalyzed by (S)-BINAPO
a Reaction was performed at –20 °C for 72 h.
b Reaction was performed using CH2Cl2 as solvent.
c Reaction was performed using a 1:1 mixture of CH3CN/CH2Cl2 as solvent.
A more efficient version of the direct aldol reaction be-
tween ketones and aldehydes has been developed by our
group using the more electron-rich Tetra-Me-BITIOPO and
its modifications; the direct aldol-type reaction mediated
by SiCl4 was performed using 2 equiv of ketone 31a, 1 equiv
Catalysts (S)-TetraMe-BITIOPO and (S)-TetraPh-Tol-BI-
TIOPO 21 efficiently promoted the addition of allyltrichlo-
rosilane to aromatic aldehydes having either electron-with-
drawing or electron-donating substituents. Electron-poor
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–L

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S. Rossi et al.
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Table 4 Tetra-Me-BITIOPO-Catalyzed Aldol Condensation of Ketones with Different Aromatic Aldehydes
SiCl4 (3 equiv)
iPr2NEt (10 equiv)
(S)-TetraMe-BITIOPO (3) (10 mol%)
OH
O
O
OH
O
X
O
+
+
Ar
Ar
Ar
H
CH2Cl2, –25 °C, 30 h
X
X
29a-l
31a–c
anti-32b–n
syn-32b–n
Entry
Ar
4-O2NC6H4
X
Product
Yield (%)
anti:syn ratio
% ee anti
1
2
CH2
32b
32c
32d
32e
32f
71
56
55
57
65
55
42
40
36
40
41
87:13
98:2
90:10
92:8
94:6
98:2
92:8
93:7
98:2
58:42
91:9
93
71
87
77
83
77
87
77
51
60
77
4-ClC6H4
2-ClC6H4
4-F3CC6H4
CH2
CH2
CH2
CH2
3
4
5
3,5-(F3C)2C6H3
4-Tol
6
CH2
CH2
CH2
CH2
CH2CH2
O
32g
32h
32i
7a
8
4-MeOC6H4
1-naphthyl
2-furyl
9
32l
10
11
4-O2NC6H4
Ph
32m
32n
a Reaction performed at –45 °C.
of benzaldehyde, and 10 mol% of the desired BITIOPO cata-
lyst in the presence of 10 equiv of iPr2NEt at –25 °C for 30 h
using CH2Cl2 as solvent. According to this procedure, -hy-
droxy ketones were synthesized in higher yields and with
higher levels of diastereo- and enantioselectivities (Table
3).24,32
and 2). MPP-tetraMe-BITIOPO 18 and catalyst 20 promoted
the allylation of benzaldehyde with chemical and stereo-
chemical efficiency comparable to that of TetraMe-BITIOPO
(entry 5), whereas catalyst 19 and 21 afford the desired al-
dol product in high yield and high anti:syn ratios, albeit
with lower levels of enantioselectivity.
The methodology was then extended to different alde-
hydes and ketones; selected results are reported in Table 4.
Both electron-withdrawing and electron-donating substi-
tuted aldehydes led to the formation of the corresponding
aldol products in good yield. 4-Nitrobenzaldehyde 29b
forms -hydroxy-ketone 32b with better enantioselectivi-
ties compared to other electron-poor substituted alde-
hydes; however, high diastereoselectivity was observed us-
ing electron-rich 4-methoxybenzaldehyde. Heterocyclic ke-
tones can also be employed as aldol donors in this Lewis
base-catalyzed SiCl4-mediated direct aldol condensation:
ketone 31n afforded the aldol product with 91:9 anti:syn
ratio and 77% ee (Table 4, entry 11) for the major isomer.
Unfortunately, in this transformation, aliphatic aldehydes
are completely unreactive.32 A stereoselective model of di-
rect aldol reaction of cyclohexanone catalyzed by BITIOPO
phosphine oxides was also proposed on the basis of NMR
investigations; according to this data, a chair-like six-mem-
bered cyclic transition-state vi′ can be hypothesized to be
responsible for the experimentally observed anti-selectivi-
ty (Scheme 6). It was also demonstrated that aliphatic alde-
hydes are completely unreactive due to the formation of the
chlorohydrin derived from species vii.33
Table 3 Direct Aldol Reaction of Cyclohexanone Catalyzed by BITIOPO
Phosphine Oxides
SiCl4 (3 equiv)
iPr2NEt (10 equiv)
catalyst (10 mol%)
OH
OH
O
O
O
O
+
+
Ph
Ph
Ph
H
CH2Cl2, –25 °C, 30 h
31a
29a
anti-32a
syn-32a
(2 equiv)
Entry Catalyst
Yield (%) anti:syn
% ee
(anti)
ratio
1
2
3
4
5
6
(S)-BINAPO (1)
64
70
77
70
67
70
89:11
93:7
40
81
75
34
72
51
(S)-TetraMe-BITIOPO (3)
(R)-MPP-TetraMe-BITIOPO (18)
(R)-PMP-TetraMe-BITIOPO (19)
(R)-MMP-TetraMe-BITIOPO (20)
(S)-TetraPh-Tol-BITIOPO (21)
88:12
77:23
88:12
95:5
Under these conditions, (S)-TetraMe-BITIOPO showed
better performance compared to (S)-BINAPO, leading to the
formation of aldol product 32a in 70% yield, 93:7 anti:syn
ratio and 81% ee for the anti enantiomer (Table 3, entries 1
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–L

H
S. Rossi et al.
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higher diastereoselectivities and comparable enantioselec-
tivities than those observed with (S)-BINAPO (Table 5, entry
1–3).35 Under the optimized reaction conditions (CH2Cl2 as
solvent, –40 °C, 20 h of reaction time) different aldehydes
were reacted with acetophenone 34a in the presence of
stoichiometric amounts of SiCl4 and iPr2NEt. It was found
that aldehydes bearing electron-withdrawing groups react-
ed with acetophenone in higher yields, while electron-rich
aldehydes were less reactive; however, the opposite trend
was observed for the enantioselectivity (entries 4–9). The
reaction of differently substituted acetophenones with al-
dehydes functionalized with either electron-withdrawing
or electron-donating groups was investigated. Modest
yields and diastereoselectivities ranging from 61:39 up to
85:15 were observed. Reaction with heteroaromatic alde-
hydes such as furfural and thiophen-2-carbaldehyde in
combination with 4-nitroacetophenone afforded the prod-
ucts in 90% ee for the chiro-35 isomer (entries 14 and 15).
From a mechanistic point of view, it has been postulated
that the stereoselectivity of the reaction is controlled both
by the phosphine oxide and the silyl enol ether intermedi-
ate that reacts with a new molecule of aldehyde.34 However,
other studies should be performed to clarify the species in-
volved in this transformation.
+
+
–Cl
cyclohexanone
RCHO, iPr2NEt
Cl
Cl
OH
O
Cl–
LB
O
R
LB
Si
Si Cl
LB
Cl
LB
O
R
Cl
vi'
32
iii
H
Cl
Cl
R
LB
O
Si
LB
O
Cl
vii
Scheme 6 Species involved in the direct aldol reaction of ketones cata-
lyzed by BITIOPO phosphine oxides
However, it was found that aliphatic aldehydes can act
as aldol donors by enolization with SiCl4 with an amine
base in a direct, crossed aldol addition.31 Thus, we investi-
gated the reaction between aromatic and aliphatic alde-
hydes in the presence of (S)-TetraMe-BITIOPO (3) as or-
ganocatalyst (Scheme 7). The cross condensation between
aldehydes was studied and the aldol products were con-
verted into the corresponding diols by NaBH4 reduction to
facilitate isolation. Reaction between benzaldehyde 29a and
isobutyraldehyde performed at 0 °C afforded the 1,3-diol
33a with modest yield and enantiomeric excess, while 4-ni-
trobenzaldehyde afforded the product 33b in 93% ee.
6 Enantioselective Direct Aldol-Type Reac-
tion with Esters
1) SiCl4 (3 equiv)
iPr2NEt (10 equiv)
(S)-TetraMe-BITIOPO (3) (10 mol%)
OH
O
A natural extension of direct, stereoselective, catalytic
aldol reactions was realized by our group by using activated
esters as the nucleophile reaction partner. In 2011, we re-
ported the first example of an organocatalytic and stereose-
lective direct aldol reaction of trifluoromethyl thioesters
catalyzed by phosphine oxides and mediated by SiCl4.36
It is known that ester compounds are not good nucleop-
hilic partners in aldol reactions because of the relatively in-
ert nature of the proton at the -position of the ester func-
tion. However, thanks to the activation of weak SiCl4 Lewis
acid by the coordination of the phosphine oxide, it was pos-
sible to synthesize -hydroxy-activated thioesters with
high levels of enantio- and diastereo selection. Different en-
antiomerically pure phosphine oxides such as (S)-BINAPO
1, (S)-BITIANPO 5, (S)-TetraMe-BITIOPO 322 and (S)-TetraPh-
Tol-BITIOPO 2132 were investigated as possible catalysts in
the direct aldol reaction of trifluoroethyl phenylthioacetate
36a to benzaldehyde in the presence of 3 equiv of SiCl4, 10
equiv of iPr2NEt for 18 h at 0 °C (Table 6). Reaction of acti-
vated trifluoroethyl thioester 35a with benzaldehyde and
catalyzed by (S)-BINAPO or (S)-BITIANPO afforded -hy-
droxy trifluoroethyl thioester 36a in low yield (entries 1
and 2).
+
CH2Cl2, –45 °C, 18 h
O
Ar
OH
Ar
H
2) NaBH4, EtOH, RT, 30 min
29a Ar = Ph
29b Ar = 4-O2NC6H4
29c Ar = 4-ClC6H4
33a 55% yield, 48% ee
33b 55% yield, 93% ee
33c 55% yield, 48% ee
Scheme 7 Direct cross-aldol reaction between aldehydes
By a simple variation of the reaction stoichiometry of
the direct aldol reaction, it is also possible to promote the
double direct aldol reaction between methyl aryl ketones
and aromatic aldehydes.34 As for the cross-aldol reaction,
the enantiopure 1,3-diol led rapidly to a decomposition
process, so the crude products were reacted with acetic an-
hydride to afford the corresponding more stable diacetate
derivatives. Moreover, compound 35 is isolable in two dias-
tereoisomeric forms, only one of which is chiral (chiro-35).
On the other hand, the meso-35 form can exist as two dia-
stereoisomers due to the presence of an achirotopic, stereo-
genic center.
The reaction between 1 equiv of acetophenone 34a and
2.2 equiv of benzaldehyde 29a was first investigated in the
presence of stoichiometric amounts of SiCl4 and 10 mol% of
enantiomerically pure (S)-TetraMe-BITIOPO or (S)-TetraPh-
Tol-BITIOPO 21. In both cases, product 35a was isolated in
good yield, high chiro:meso ratio and up to 75% ee, showing
The use of more electron-rich (S)-TetraMe-BITIOPO al-
lowed the aldol product to be synthesized in 80% yield, 98:2
syn:anti ratio with 89% of ee for the syn enantiomer (Table
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S. Rossi et al.
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Table 5 Tetra-Me-BITIOPO-Catalyzed Aldol Condensation of Ketones with Aromatic Aldehydes
OAc
R
O
1) SiCl4, iPr2NEt, catalyst (10 mol%)
CH2Cl2, –40 °C, 20 h
OAc
R
O
O
O
Ar
AcO
+
+
Ar
AcO
R
H
Ar
Me
2) Ac2O, Py
R
R
29a-i
34a–c
chiro-35a–o
meso-35a–o
Entry
R
Ar
Catalyst
Product
Yield (%)
chiro:meso ratio % ee (chiro)
1a
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(S)-BINAPO (1)
35a
35a
35a
35b
35c
35d
35e
35f
86
61
64
65
63
51
40
43
55
45
71
51
35
40
35
78:22
88:12
86:14
80:20
90:10
70:30
73:27
89:11
89:11
92:8
70
75
60
70
41
26
91
80
41
71
25
27
55
90
90
Ph
(S)-TetraMeBITIOPO (3)
(S)-TetraPh-Tol-BITIOPO (21)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
(S)-TetraMeBITIOPO (3)
3
Ph
4
4-ClC6H4
4-F3CC6H4
4-O2NC6H4
4-MeOC6H4
4-Tol
5
6
7
8
9
1-naphthyl
2-furyl
35g
35h
35i
10
11
12
13
14
15
4-F3CC6H4
4-MeOC6H4
4-F3CC6H4
2-furyl
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
85:15
86:14
88:12
83:17
61:39
35l
35m
35n
35o
2-thienyl
a Reaction performed at –60 °C using 5 equiv of Hex2NMe and a mixture of EtCN/CH2Cl2 as solvent.
6, entry 3). As before, catalyst 21 exhibits intermediate
properties between phosphine oxides (entry 4). Also in this
case, the reaction involves the in situ formation of the tri-
chlorosilyl ketene thioacetal viii by addition of a tertiary
amine to the trifluoroethyl thioester in the presence of sili-
con tetrachloride. This species is activated by a catalytic
amount of (S)-TetraMe-BITIOPO to react with an aldehyde,
which is also coordinated to the chiral cationic hypervalent
silicon species. The observed inversion of the diastereose-
lectivity compared to the aldol reaction depends on the
‘pinwheel’ conformation37 adopted by the O-silyl enolate to
minimize the steric repulsion between bulky peripheral
groups (Scheme 8).
(S)-TetraMe-BITIOPO 3 was used as the catalyst of
choice to evaluate the scope of the enantioselective direct
aldol-type reaction of activated thioesters (Table 7). The re-
action works well with several aromatic and heteroaromat-
ic aldehydes, leading to high syn:anti stereoselectivity and
enantioselectivities generally higher than 80% and often
higher than 90%. Interestingly, cinnamic aldehyde also re-
acted under the present experimental conditions, affording
Table 6 Direct Aldol Reaction of Trifluoroethyl Phenylthioacetate Catalyzed by Phosphine Oxides
SiCl4 (3 equiv)
iPr2NEt (10 equiv)
catalyst (10 mol%)
benzaldehyde (1 equiv)
O
O
OH
OH
O
+
Ph
Ph
S
CF3
Ph
S
CF3
S
CF3
CH2Cl2, 0 °C, 18 h
Ph
Ph
35a
syn-36a
anti-36a
Entry
Catalyst
Yield (%)
syn:anti ratio
% ee (syn)
1
2
3
4
(S)-BINAPO (1)
35
9
97:3
96:4
98:2
76:24
81
79
89
60
(S)-BITIANPO (5)
(S)-TetraMe-BITIOPO (3)
(S)-TetraPh-Tol-BITIOPO (21)
80
74
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J
S. Rossi et al.
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Synlett
tained when the S-pyridyl moiety was replaced with S-aryl
substituents. In this case, aldehydes bearing electron-do-
nating groups afforded the corresponding aldol products
with higher levels of diastereo- and enantioselectivity than
electron-poor aldehydes: product 38l was obtained in 76%
yield, 84:16 syn:anti ratio and 92% ee (entry 10). Computa-
tional analysis on transition states were also performed to
elucidate the origin of the stereoselection, confirming the
experimentally observed outcome.
Base
SiCl4(LB)2
O
O
H
SiCl4(LB)2
+ iPr2NEt
SiCl4(LB)2
Ar
Ar
O
RS
SR
S
H
Ph
– iPr2NEt·HCl
R
I
pinwheel conformation
SiCl3(LB)2
O
Ph
S
R
viii
Scheme 8 In situ formation of silyl ketene thioacetal viii promoted by
the presence of SiCl4 and iPr2NEt
7 Conclusions
compound 36i in good yield, with complete syn diastereo-
control, and 83% ee. The O-silylenolate viii features the E-
configuration according to the Cahn, Ingold, Prelog rules
and the Z-configuration in the conventional enolate no-
menclature (priority order S > O). For this reason, even if the
mechanism of this transformation is similar to the direct al-
dol reaction of ketones, the final major isomer presents the
syn arrangement.
In 2015, we further extended the scope of this reaction
using less reactive, but more available and less expensive S-
arylthioesters and S-pyridyl thioesters (Table 8).38 syn--
Hydroxy thioesters 38a and 38b were obtained as major
isomers in modest to good yields, but with generally lower
stereo- and enantioselectivities, probably due to a competi-
tive interference in the formation of the catalytic hyperva-
lent species by the pyridyl residue. Better results were ob-
This overview has highlighted the use of chiral phos-
phine oxides in Lewis acid-mediated Lewis base-catalyzed
reactions. The combination of catalytic amounts of such
readily available chiral Lewis bases with trichlorosilyl de-
rivatives and silicon tetrachloride led to the development of
many successful enantioselective organic transformations.
In this picture, electron-rich biheteroaromatic phosphine
oxides often proved to be very efficient catalysts, able to
guarantee better performances than BINAP-derived cata-
lysts, not only as chemical yields but especially as stereo
and enantioselectivity.
Considering the wide availability of several chiral bihet-
eroaromatic phosphines and the possibility to further tune
the catalytic behavior of this wide class of molecules,
bithiophene-based and analogous biheteroaromatic-based
Table 7 Tetra-Me-BITIOPO-Catalyzed Condensation of Trifluoroethyl Thioesters with Aldehydes
SiCl4 (3 equiv)
iPr2NEt (10 equiv)
(S)-TetraMe-BITIOPO (10 mol%)
O
O
OH
OH
O
O
Ar2
+
+
Ar1
S
CF3
Ar1
S
CF3
Ar1
H
S
CF3
CH2Cl2, 0 °C, 15 h
Ar2
Ar2
29a–i
35a–e
syn-36b–o
anti-36b–o
Entry
Ar1
Ar2
Ph
Product
Yield (%)
syn:anti ratio
% ee (syn)
1a
2a,b
3
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
4-Tol
36b
36c
36d
36e
36f
36g
36h
36i
51
40
33
51
41
25
37
63
37
57
65
51
>98:2
88:12
80:20
>98:2
66:34
>98:2
>98:2
>98:2
88:12
80:20
>98:2
96:4
83
81
55
85
63
93
91
83
71
95
85
80
Ph
Ph
4
Ph
5
1-naphthyl
2-thienyl
2-furyl
(E)-styryl
Ph
Ph
6
Ph
7
Ph
8
Ph
9
4-FC6H4
36l
10
11
12
Ph
3,4-(MeO)2C6H3
4-HOC6H4
36m
36n
36o
Ph
Ph
4-iBuC6H4
a Reaction time was extended to 40 h.
b Reaction performed at –40 °C.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–L

K
S. Rossi et al.
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Synlett
Table 8 Tetra-Me-BITIOPO-Catalyzed Condensation of S-Aryl Thioesters with Different Aldehydes
SiCl4 (3 equiv)
iPr2NEt (10 equiv)
(S)-TetraMe-BITIOPO (10 mol%)
O
O
OH
OH
O
O
Ar2
+
+
Ar1
SAr3
Ar1
SAr3
Ar1
H
SAr3
CH2Cl2, 0 °C, 24 h
Ar2
Ar2
37a–d
syn-38a–p
anti-38a–p
Entry
Ar1
Ph
Ar2
Ar3
2-Py
Product
Yield (%)
syn:anti ratio
% ee (syn)
1
2
Ph
38a
38b
38c
38d
38e
38f
14
15
62
58
76
69
35
80
44
76
59
61
44
47
>98:2
80:20
71:29
>99:1
75:25
82:18
92:8
rac
rac
74
48
41
53
69
73
51
92
68
91
70
87
4-ClC6H4
Ph
Ph
2-Py
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
Ph
4
2,4,6-Me3C6H2
4-F3CC6H4
4-MeOC6H4
2-Tol
Ph
5
Ph
6
Ph
7
Ph
38g
38h
38i
8
3-Tol
Ph
67:33
69:31
84:16
69:31
92:8
9
1-naphthyl
2-furyl
Ph
10
11
12
13
14
Ph
38l
4-FC6H4
2,6-Me2C6H3
Ph
Ph
38m
38n
38o
38p
Ph
4-FC6H4
4-iBuC6H4
66:34
61:39
Ph
phosphine oxides represent an interesting class of chiral li-
gands, which offer a lot of space for further exploration and
application in many other organic transformations.
Such a chiral backbone may be modified either sterical-
ly or electronically by introducing different substituents on
the biheteroaromatic scaffold and on the aromatic rings
bound to the phosphorous atom.
Furthermore, it should be noted that the use of alkyl
phosphine oxides, which are easily generated by oxidation
of the corresponding phosphines, is still unexplored. We
believe that it is important to investigate these derivatives
in view of further extending the diversity and complexity of
suitable organocatalysts in LB-catalyzed LA-mediated
stereoselective transformations.
G. L. Angew. Chem. Int. Ed. 2005, 44, 4682. (e) Denmark, S. E.;
Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560. (f) Denmark,
S. E.; Eklov, B. M. Chemistry 2008, 14, 234. (g) Denmark, S. E.;
Lee, W. Chem. Asian J. 2008, 3, 327. (h) Orito, Y.; Nakajima, M.
Synthesis 2006, 1391. (i) Sugiura, M.; Nakajima, M. Allylations of
C–O and C–N Double Bonds and Related Reactions, In Comprehen-
sive Chirality; Elsevier 2012, 214. (j) Kotani, S.; Sugiura, M.;
Nakajima, M. Chem. Rec. 2013, 13, 362. (k) Nakajima, M.; Kotani,
S.; Sugiura, M. Synlett 2014, 25, 631. (l) Benaglia, M.; Guizzetti,
S.; Pignataro, L. Coord. Chem. Rev. 2008, 252, 492. (m) Beutner,
G. L.; Denmark, S. E. In Inventing Reactions, Topics in Organome-
tallic Chemistry; Springer: Berlin, Heidelberg, 2013, 55.
(n) Rendler, S.; Oestreich, M. Synthesis 2005, 1727.
(3) Denmark, S. E.; Eklov, B. M.; Yao, P. J.; Eastgate, M. D. J. Am.
Chem. Soc. 2009, 131, 11770.
(4) (a) Benaglia, M.; Guizzetti, S.; Rossi, S. Silicate-Mediated Stereo-
selective Reactions Catalyzed by Chiral Lewis Bases, In Catalytic
Methods in Asymmetric Synthesis; John Wiley & Sons, Inc: Wein-
heim, 2011, 579–624. (b) Rossi, S.; Denmark, S. E. Lewis Base-
Catalyzed, Lewis Acid-Mediated Reactions (n → *), In Lewis Base
Catalysis in Organic Synthesis; Wiley-VCH: Weinheim, 2016,
1039–1076. (c) Denmark, S. E.; Beutner, G. L. Principles, Defini-
tions, Terminology, and Orbital Analysis of Lewis Base-Lewis Acid
Interactions Leading to Catalysis, In Lewis Base Catalysis in
Organic Synthesis; Wiley-VCH: Weinheim, 2016, 31–54.
(d) Kočovský, P.; Malkov, A. V. Lewis Bases as Catalysts in the
Reduction of Imines and Ketones with Silanes (n → *), In Lewis
Base Catalysis in Organic Synthesis; Wiley-VCH: Weinheim,
2016, 1077–1112. (e) Malkov, A. V.; Kočovský, P. Lewis Base-
Catalyzed Reactions of SiX3-Based Reagents with C=O, C=N (n →
*), In Lewis Base Catalysis in Organic Synthesis; Wiley-VCH:
Funding Information
This work was conducted with financial support from Università degli
Studi di Milano, Italy (Piano Sostegno alla Ricerca - PSR2018 grant to
SG).
U
n
i
v
ersità
d
e
g
l
i Stu
d
idiM
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(P
S
R
2
0
1
8)
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–L