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Enantioselective Iodine(I/III) Catalysis in Organic Synthesis
Andrea Flores,a Eric Cots,a Julien Bergès,a and Kilian Muñiza,b*
a

b

Institute for Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science, Av. Països Catalans 16, 43007
Tarragona, Spain
Fax: +34 977 920 224. E-mail: kmuniz@iciq.es
ICEA
Passeig Lluís Companys, 23, 08010 Barcelona, Spain

Abstract. Chiral aryliodine(III) reagents have provided an
advanced concept for enantioselective synthesis and catalysis.
With the advent of chiral iodine(I/III) catalysis, a large
number of different structures have been explored in the area.
The currently most prominent catalyst design is based on a
resorcinol core and the attachment of two lactic side chains
bearing ester or amide groups. It enables a privileged modular
catalyst synthesis, in which fine-tuning with respect to the
specific reaction requirement is straightforward. The present
overview summarizes the structural variation and
optimization of such chiral aryliodine catalysts and discusses
structural properties of the active iodine(III) catalyst states.
The status quo of enantioselective iodine(I/III) oxidation
catalysis with respect to intramolecular and intermolecular
reaction control is reviewed, and specific aspects of the
individual catalytic cycles are discussed.

1 Introduction
Organic chemistry relies on homogeneous asymmetric
catalysis as an important working horse for the
production of single enantiomers, which have a major
impact in biomedical and pharmaceutical sciences.
Due to this unparalleled importance of
enantiomerically pure compounds, conceptually new
endeavors to their synthetic availability are of utmost
importance and immediate interest. Within this
context, the traditional concept of man-made
homogeneous oxidation catalysis has been based on
the use of redox-active metals.[1] In this area, the
identification and development of suitable chiral
ligands[2-4] has played a major role in order to
accomplish defined, kinetically dominating reaction
pathways involving effective enantiodiscrimination.[4]
Such an approach is largely reminiscent of Nature’s
concept of metalloproteins,[5] which have generated a
versatile pool of oxygenation reactions. Their scope
has recently been significantly expanded through
directed evolution.[6] The advent of organocatalysis [7]
has provided an additional class of small organic
molecules that can be brought into play for
homogeneous oxidation.[8]
They can provide
complementary reactivity pathways with respect to
transition metals. Within the class of metal-free small
organic oxidants hypervalent iodine reagents have
been widely applied in organic synthesis as oxidants

Keywords: Chirality; Enantioselective Synthesis;
Homogeneous Catalysis; Iodine; Oxidation

by virtue of their low toxicity, commercial availability,
high stability towards atmospheric oxygen and
moisture, ease of recovery, easy handling and versatile
reactivity.[9] With the goal of providing greener
synthetic solutions to the field of oxidation reactions,
hypervalent iodine compounds have witnessed a
massive growth in the 21st century.[9]
The
accomplishment of rendering them catalytic has
broadened their scope further.[10] One of the
predominant current aims of these reagents is
complementing or replacing heavy-metal catalysts.
Iodine oxidants offer a high potential for the
improvement of known reactions and the development
of new synthetic transformations. Their nature as
polyvalent electrophiles and mild oxidants provides is
complemented by their environmental benignness that
circumvents the problem of toxicity mainly associated
to the use of some transition metals. Common
successful approaches are based on the use of
aryliodine(I) derivatives, which can be readily
oxidized to iodine(III) under the required reaction
conditions. For enantioselective transformations, the
catalyst design strategy is comparable to conventional
transition metal catalysis, in which ionic and/or
coordinative bonding of ligands is usually optimized
with regard to electronic and stereochemical properties
(Figure 1). For aryliodines, the chiral arene substituent
is covalently bound.

1

Figure 1. Main concepts for design of homogeneous
catalysts: transition metal and aryliodine(III) catalysts.

2 Chiral Aryliodine Catalysts
Suitable chiral iodine(III) structures have been
identified to a large extent. Following the general
advent of iodine(III) reagents as important synthetic
tools, enantioselective reaction control has been
devised following the principal aspect of introducing
chirality elements into the aryl substituent. Their
application in enantioselective synthesis has been
reviewed previously.[11] Although the resulting chiral
reagents have found significant application, the
synthesis of preformed iodine(III) centers can in some
cases be cumbersome. Clearly, a catalytic reaction
course, in which the active iodine(III) is repeatedly
generated in situ, represents the superior approach
from economic and practicability standpoint. Within
this context, non-racemic iodoarenes(I) have been
extensively developed since 2008 in order to arrive at
homogeneous catalytic performances. With respect to
such chiral aryliodine(I) catalysts, all major sources of
chirality have been investigated comprising central
chirality, axial chirality and helical chirality.
R2

OMe

R1
I

I

SO2tBu
I

Cl

N

I

1

3

2

4

R
I

I

R*

5

Èric Cots was born in 1994 in
Manresa, Barcelona (Spain).
After completing his bachelor
degree in chemistry at the Institut
Químic de Sarrià (URL), he
moved
to
University
of
Barcelona where he obtained his
MSc in Organic chemistry.
Currently he works at ICIQ in
Professor Muñiz’s group as a
PhD student, where he is
developing new reactions with
chiral iodine catalysis.
Julien Bergès was born in
Toulouse (France) in 1989 and
graduated in Chemistry at the
Ecole Supérieure de Chimie
Organique
et
Minérale
(Compiègne, France). In October
2013 he began his PhD in the
laboratory of Dr. Taillefer at
Ecole Nationale Supérieure de
Montpellier and received its PhD
degree in 2016 submitting a
thesis on the functionalisation of
aromatics rings by formation of C-C and C-N bonds
catalysed by copper, iron or under transition metal-free.
In July 2017, he joined the group of Professor Muñiz at
ICIQ as postdoctoral researcher. His current research
Author Portrait))
focused on the development of methodologies for
intermolecular C-H amination by electrophilic halide
reagents

I

R2

R*

Andrea Flores was born in 1994
in Cerdanyola del Vallès,
Barcelona (Spain). She studied
Chemistry at the Autonomous
University of Barcelona (Spain),
where she obtained her MSc in
2017. She joined the group of
Professor Muñiz at ICIQ in the
fall of 2018. Her PhD work
centers around the development
of chiral aryliodine catalysts.

I

O

R

N
R

6

R*

R*
I

7

OR*

n

8

Figure 2. Representative structures of chiral aryliodine(I)
catalysts.

Kilian Muñiz was born in 1970 in
Hildesheim (Germany). He
studied Chemistry at the
Universities
of
Hannover
(Germany) and Oviedo (Spain)
and at Imperial College (UK) and
earned his Doctorate in Organic
Chemistry for work with
Professor Bolm at RWTH
Aachen (Germany) in 1998. He
carried out postdoctoral research
with Professor Noyori at Nagoya
University (Japan), before starting his independent
research at Bonn University (Germany) with Professor
Dötz (2001-2005). From 2006 to 2009 he held a position
as Full Professor at the University of Strasbourg (France),
where he was also a member of the Institut Universitaire
de France. He moved to Spain in 2009 to join ICIQ in
Tarragona (Spain) as a group leader and became ICREA
Professor in 2010. His research interests include the

Author Portrait))

2

development of new catalysts for general use in oxidative
amination and diamination reactions of hydrocarbons.

One of the first examples of a chiral iodine catalyst 1
was developed by Kita and subsequently extended by
Zhang (Figure 2). It contains an electrophilic iodine
center and a carbon-based spiro-cyclic backbone with
defined chirality.[12] The privileged C2-symmetric
biaryl motif has also turned out useful as initially
shown for compounds 2 and 3 by Quideau, followed
by further developments from Einhorn and Kita.[13]
The stereochemical action of lesser popular C1symmetric structures has also been explored in the
architecture of iodoarenes and remains one of the most
used to the day for aryliodine catalysts. These catalysts
can contain one or more pre-installed chiral centers,
and their synthesis has been accomplished through
enantiopure starting materials. Different units attached
to the iodoarene core such as chiral alkyl substituents,
annelated rings or chiral pool-derived groups have thus
been effective for the design of catalysts such as 4-8
for a wide range of transformations.[14] As a common
feature, the sources of stereochemical information are
commonly attached in the proximity of the iodine, thus
placing them at the 2- or 2,6-positions of the iodoarene
core. This concept was later applied further in the
synthesis of modular aryliodine with 2,6dioxygenation motif by Ishihara, Muñiz, and other
researchers.[12b,15] Arguably, the most important
feature of a given chiral catalyst rests with a structural
composition that allows for its three-dimensional
adaption to a given substrate class within the
anticipated chemical transformation. Insight by
Ishihara and Fujita has identified lactic acid as a
suitable chiral pool-derived auxiliary in the design of
iodine catalysts.[16] Examples include the diester 9 and
the amides 10 and 11.
I

O

R2

O

O

O
O

R1

O

R2

R1
R3

toolbox approach

9
I

O

R4

O

N
H

O

O
O

R1

N
H

R1

X

R4

R4

N
R5

R3

O
O

R1

R1

R1 = Alkyl
N
R5

R4

X = OR', NHR', NR'2

R3
11
I

O
R6

N
H

O

O
O

R1

R1
12

X
R1

R3 = H, Alkyl

10
I
O

O
O

R1

R3
O

I
O

N
H

R6

Figure 3. Toolbox approach towards modular iodoarene
structures of the resorcinol/lactate nature.

This concept has been proven highly successful due to
the fact that structural fine-tuning of the catalysts can
be easily accomplished. The underlying modular
approach consists in condensation of the
corresponding 2-iodo resorcinol cores with lactic acid
derivatives and implementation of the ester and amide
function. A related conceptual toolbox is based on the
functionalization of the central resorcinol moiety with
vicinal N-acylated aminoalcohols. Although this
approach should provide a similarly attractive entry
into catalyst diversification, compounds of type 12
have so far been explored to a lesser extent.
The major important feature of the resorcinol-derived
catalysts rests with the effective formation of helical
chirality due to the intramolecular coordination of the
chiral side chains. The possibility for the creation of
effective chiral environments was first pointed out by
Ishihara referring to their potential ability to engage in
self n—s* interactions A between the carbonyl moiety
and the iodine (III) formed in situ, as well as Hbonding interaction B (Figure 4). [15b, 17]
O

X
I

O
O

X

O
O

R1

9-11

O

X

O

L1

I
X

R1

R4

L1

[O]

L2 O

O

or

in situ

HX

O

XH I

R4
A
n — σ* interactions

L2 O

O

R1
R4

B
hydrogen bonding
interactions

Figure 4. Hypothetical structural arrangements in modular
iodoarene-based structures.

Following pioneering insight by Ishihara,[18] this
context was indeed confirmed for the resorcinol
lactamides 13a,b, which could be oxidized to their
corresponding diacetoxy iodine(III) states (Figure
5).[19] X-ray analyses and solution structure
determination confirmed the presence of persistent
hydrogen bonds between the amide N-H and the
acetate oxygen atoms at the central iodine. This
hydrogen bonding induces a defined supramolecular
environment, which is induced by the stereogenic
center of the lactamide side chain. The same relative
helical chirality was determined for the related
secondary amide diacetoxy iodine(III) derivative 14a,
for which hydrogen bonding from a water molecule
was encountered by X-ray analysis. Formation of
supramolecular assemblies may not be limited to
intramolecular hydrogen bonding. Work by Hadad and
Sunoj using computational chemistry pointed towards
a more general helical folding in resorcinol-derived
chiral catalyst 14b, which is derived from a network of
non-covalent attractive interactions. For this prolinyl
lactamide-derived bis(trifluoroacetoxy) iodine(III)

3

14b, once again the same diastereomeric composition
of the helical chirality was determined by
computational chemistry suggesting that the lactic
stereochemistry is decisive. In this case, a network of
attractive noncovalent interactions were detected
including the indicated CH-FC interactions between

Figure 5. Structural elucidation of supramolecular
assemblies in chiral iodine(III) compounds.

Ishihara had also determined the induction of a related
supramolecular helical scaffold by hydrogen bonding
for the resorcinol aminoalcohol derivatives 15a and b.
For the iodine(III) bismethoxide complex 15a derived
from methanolysis of the corresponding bisacetoxy
reagent 15b, X-ray analysis provide unambiguous
demonstration of the chiral helical scaffold around the
central iodine(III) atom, in which the central chirality

methyl ester and methyl groups with the CF3-groups,
respectively.[20]

from the aminoether side chains is effectively
transferred through hydrogen bonding. Clearly,
additional investigation should uncover further aspects
regarding potential features for helical structure
formation such as the currently elusive n—s*
interactions. Such advanced understanding would also
provide further detailed design strategies on the
working mode of these privileged structures.
In the following, the status quo of iodine(I/III)catalyzed enantioselective oxidation is presented and
discussed.

4

3 Enantioselective Catalysis
3.1 Catalytic Dearomatization Reactions
The dearomatization reaction of phenols and
derivatives has been widely explored in the last decade.
Its potential application in molecular synthesis is the
major driving force in the development of new
methodologies.
Arguably,
the
oxidative
dearomatization of phenols is the most prominent
reaction in iodine(III)-mediated chemistry and it has
received significant consideration including the
development of enantioselective variants.[11b, 21]
The role of chiral iodine(III) reagent has evolved from
a stoichiometric variant to the catalytic version, as the
latter exhibits much better qualities as explained
above. This reaction has been developed in its intra or
intermolecular variants, depending on the inclusion or
absence of the nucleophile within the substrate
structure. Different functional groups regarding the
nucleophilic species have been applied including
alcohols, acids and amines.
Back in 2008, the first example of a catalytic
enantioselective oxidative dearomatization of phenols
was accomplished by Kita. In this study, the chiral C2symmetric spiro-diiodide 1a was employed as catalyst
and the dearomatized product was obtained from the
cyclization of the lateral carboxylic acid 16 upon the
a-position of the phenol, thus yielding the chiral orthospirolactone structure 17. While the stoichiometric
variant of the same transformation yielded up to 86%
ee, the catalytic version was slightly less productive
(up to 69% ee, Scheme 1).[22]
R5

OH

R4

O

R2

O

R3

R1
R3

O

R5

Catalyst,
OH Conditions

R2

R4

O

R1

16

17
Et

ethyl groups in the ortho positions of the catalyst 1b
permitted access to improved yields and significantly
higher enantioselectivities (up to 92% ee).[23] The
design of the optimized pre-catalyst was achieved by
the exploration of the chiral induction through the
extension of the equatorial positions next to the iodine
center to affect the chiral environment (Scheme 1).
The authors proposed a late stage transition-state
model based on the X-ray crystallography of the
product 17, in which a ligand exchange with the
naphthol oxygen at the formed iodine(III) catalyst 18
provides the intermediate C. At this stage, the
carboxylic acid attacks at the ipso position via the lesshindered Re-Face, yielding the observed R enantiomer
of the product 17 together with the reduced catalyst
containing one iodosoarene moiety (Scheme 2).[23]
CO2H

Et

16

I

11

Y

O

I

Et

I

- HY

O

Et

17

Y
I

C Et

18

Scheme 2. Transition state proposal for catalyst 18.

Throughout 2010, Ishihara applied a series of lactatebase chiral aryliodine catalysts 10 for application in
spirolactonization and accomplished notably high
yields and enantioselectivities (up to 92% ee, Scheme
3), even for the more reactive class of substituted 1hydroxy-2-naphthalenepropanoic acids. The authors
made use of their design motif for the resorcinol
bislactamide catalysts discussed above and thereby
confirmed the effectiveness of these structures for
enantioselective
catalysis.[15b,17] The
depicted
derivative 10a represents one of the most common
chiral iodine catalysts, and is often referred to as
Ishihara´s catalyst.

I
I

I
I

O

Y

[O]
HY

re-face attack

I

O
Mes

Et

N
H

O

O
O

N
H

Mes

10a

1a (15 mol%)
mCPBA, AcOH,
DCM, 0 ºC, 3 h
16 (R2 = H, Br,
R1 = R3 = R4 = R5 = H)
17: 68 - 70%, 65 - 69% ee

1b (5 - 15 mol%), mCPBA
CHCl3, 0 ºC, 6 - 12 h
16 (R1 = H, Ph; R2 = H, Bn, Br, Ph;
R3 = H, Br, N3, OBn, Ph;
R4 = H, N3, Ph; R5 = H, Me)
17: 20 - 96%, 40 - 92% ee

Scheme 1. Pioneeering catalytic
dearomatization of phenols by Kita.

enantioselective

In 2013, Kita performed a significant modification of
his oxidative dearomatization, as the introduction of

R5

OH

O
OH

R4

R1
R3

R2

16
R1 = H, OMe; R2 = H, Me, Cl
Br, Ph, COAr; R3 = H, OMe
R4 = H, OMe

CHCl3 or
CHCl3/CH3NO2
0 ºC

O

R5

10a (10 - 15 mol%),
mCPBA

O

R3

R2

O

R4

R1
17
3 - 94%,
0 - 92% ee

Scheme 3. Oxidative dearomatizative spirolactonization
with catalyst 10a.

5

Later on, the combination of such intramolecular
oxidative dearomatization reactions with a subsequent
Diels-Alder reaction were performed as a one-pot
domino methodology. A wide variety of lactone
products 22 were thus formed in high yields and
enantioselectivities from primary dearomatization
product 20 and alkenes 21. The successful catalyst 12a
was designed on the basis of the aminoalcohol
substitution pattern at resorcinol (Scheme 4).[18]
I

O
Mes

O

N
H

O
O

N
H

Scheme 5. Intramolecular dearomatization of 2-naphtol
derivatives.

In 2015, Ibrahim proceeded a further broadened
contribution to the structural diversification of the
spirolactonization, in which a new catalyst motif was
introduced. This chiral aryliodine(I) is derived from
the octahydrodimethanoanthracene structure, in which
the preferred para-methyl substituted derivative 7a
yielded a 67% ee of the desired product 17 (Scheme
6).[25]

Mes

R5

12a
OH

OH

O

R1

12a (1 - 10 mol%), mCPBA R1

R2

R4

CO2H

DCM or DCM/HFIP
-10 ºC or -20 ºC
18–24h

R3

OH
O

R2

O
21
(10 equiv.)

R4
R3

19

One-pot
25 ºC, 12h

20
78 - 88%,
91 - 98% ee

R1 = H, Me, Br, Cy, N-tosylpyrrolidine
R2 = H, Me, Br, OMe, Cy, N-tosylpyrrolidine
R3 = H, Me, Br, Cl
R4 = H, Me, Br, F
O

O
H O

21 =

Ph
N

O

O
O

OEt

Ph

Y
X

R2

22
66 - 98%,
89 - 99% ee

Scheme 4. Domino spirolactonization-Diels Alder reaction
with catalyst 12a.

Ishihara also observed for some cases that methanol as
additive could both accelerate the dearomatization
reaction and improve the enantioselectivity. Owing to
the capability of the resulting methoxyphenoxy iodine
derivative to prevent potential dissociation of the
catalyst, the formation of racemic product was greatly
suppressed. Recent results from the same group
provided
a
useful
methodology
for
the
spirolactonization of 2-naphtol derivatives 23 in
excellent yields and enantioselectivities. In both cases,
the chiral resorcinol-derived iodine catalyst 12a makes
use of the 2-aminoalcohol concept instead of the
common lactate-based scaffold (Scheme 5).[18, 24]
I

O
Mes

N
H

O

O
O

N
H

Mes

12a
O

OH

R1

CO2H
R5

R2

12a (5 mol%),
mCPBA, HFIP

R1

DCE, -20 ºC, 19h

R2

O
O

R4

R4
R3
23
R1 = H, Br; R2 = H, Me; R3 = H, Br, CN;
R4 = H, OMe, OMOM, OBn; R5 = H, F

R5

R3
24
50 - 99%,
87-99% ee

R1
R2

Catalyst,
Conditions

O

R2

R4

16

R3

R1

O

R4
R3

O

R5

R3

O

I

O

R1
17

I

I
7a (10 mol%), mCPBA,
CHCl3, CHCl3/ CH3NO2 or
CHCl3/TFE,
0 or -20 ºC, 19 h
16: R1 = R3 = R4 = R5 = H; R2 = H,
Br, Cl, CN, Ph
17: 36 - 65%, 18 - 67% ee

5a (10 - 100 mol%), wet mCPBA,
CHCl3, -40 ºC, <2 h
16: R1 = H, Ph; R2 = H, Br, Cl, Et,
N3, OBn;
R3 = R5 = H; R4 = H, N3
17: 42 - 84%, 59 - 78% ee

Scheme 6. Catalyst exploration for the spirolactonization
reaction.

The latest development towards enantioselective
dearomatization was provided by Kita in 2017, in
which he applied a series of novel catalysts making use
of a previously reported binaphthyl 3a. Both a catalytic
and stoichiometric amount of the iodoarenes 3a were
tested, obtaining up to 64% ee of the spirolactonized
product 17 for the catalytic variant, similar to the yields
and enantioselectivities obtained in the non-catalytic
reactions (Scheme 6).[13c, 26]
Ciufolini reported an important expansion of the
intramolecular dearomatization reaction, in which the
substrates 25 carried a primary alcohol as nucleophile
instead of the commonly employed carboxylic acid.
The reaction provided the desired products 26 with
high enantioselectivities. Concerning the catalyst, this
new dearomatization variant was successful using an
Ishihara-type iodoarene 12b. The efforts to accelerate
the reaction by a possible Thorpe-Ingold effect due to
geminal dimethyl substitution on the quaternary center
in a-position to the terminal alcohol were
unsatisfactory.
In
addition,
a
novel
aminospirocyclization reaction was reported, in which
the analogous heterocyclic products 28 were formed
from 27 in up to 67% ee (Scheme 7).[27]

6

I

O
Mes

N
H

and the corresponding products 36 were formed in up
to 89% ee (Scheme 10).[28]

O

O

O

tBu

tBu

N
H

Mes

12b

OH

12b (20 mol%),
mCPBA

Mes

O

O

N
H

O

DCM, -20 ºC

R
25
20 examples

I

O

O

OH

O

N
H

Mes

12a
HO

OH

R
26
<79%, <93% ee

O
12a (10 mol%),
mCPBA

O
n-Pr
R1 n-Pr

R3

O

R3

R1
R2

R2

OH

O
NHMs

12b (20 mol%),
mCPBA
DCM, -20 ºC

27

31

32

R1 = H; R2 = H, Cl, Ph, Me;
R3 = H, MeO

N
Ms
28
20%, 67% ee

Scheme 7. Catalytic spirolactonization with alcohol and
amide nucleophiles.

An additional example by Harned addressed the
intramolecular spiroetherification of the parasubstituted phenol derivative 29. The reaction was
performed by asymmetric catalysis with the rigid chiral
aryliodide 8a incorporating a tartaric bisamide unit.
Nevertheless, the yield and enantioselectivity of the
reaction remained comparably modest under the
explored conditions (Scheme 8).[14a]

53 - 81%, 82 - 93% ee

HO

OH

R4

O

O

R3

R2

34
54 - 80%,75 - 91% ee

33
R1 = H, Me; R2 = H, iPr,
Br, Cl; R3 = H, Me, (CH2)4;
R4 = H, Me, (CH2)4

Scheme 9. Catalytic synthesis of chiral masked orthoquinones.

N
H

8a (10 mol %),
mCPBA

O

O
O

N
H

TBS
O
O

MeCN, 16 h

29

I

O

O

8a
OH

CF3

CF3

F3C CF3

TBS
HO

R1
R2

NHMes

I O

O

R1

O O
MesHN

n-Pr
n-Pr

O

R4

12a (10 mol%),
mCPBA

n-Pr
n-Pr

R3

n-Pr
n-Pr

O

30
50%, 70:30 er

ent-10b
F3C

CF3

OH

O

R1

R1

Scheme 8. Harned’s catalyst 8a for spiroetherification.

ent-10b (10 mol%),
mCPBA, MeOH

O
O

A
complementary
intramolecular
oxidative
dearomatization was described by Ishihara. The
synthesis of masked ortho- and para-quinones
incorporating chiral acetal moieties was accomplished.
The reaction with standard catalyst 12a is straightforward for 1,2-dione derivatives 32 and 34, which
were formed with a maximum of 93% ee (Scheme 9).
The larger positional distance of the para-position
represented a more challenging transformation with
respect to enantioselective face recognition from chiral
iodine(III) attachment to the phenol-OH function. To
this end, a chiral amide 10b with a significantly
increased size of the anilide substituent was designed

F3C

CF3

OH

DCM, 0 ºC, 24h

O

O
O

35
R1 = Br, TBS, TBDPS

36
49 - 87%, 10 - 89% ee

Scheme 10. Catalytic synthesis of chiral masked paraquinones.

Gong and co-workers developed a new reaction
variant, in which an all-carbon stereogenic center was
formed throughout the course of dearomatization. In
particular, the authors reported the enantioselective
spirocyclization of 1-hydroxy-N-aryl-2-naphthamide
derivatives 37 enabled by chiral organoiodine catalysis
of the chiral resorcinol motif. They presented 12

7

different examples 38 displaying a maximum of up to
92% ee. The observed beneficial role of the TFE ligand
was rationalized by the reduced electron density at
iodine and by the resulting diminished dissociation
capability of the substrate. Coordinatively saturated
iodine(III) leads to the defined substrate-catalyst
adduct D (Scheme 11).[29] As to the model for
enantiotopic discrimination, cyclization onto the more
accessible Si face of the substrate was the consequence
of an effective shielding of the Re face by the proximity
of one of the N-phenylamide groups from the side arms
of catalyst 10c.

O
OH

Ar*I, mCPBA
DCM, rt

40

OH

39

O
OH

Ar*I, mCPBA
DCM, rt
41

O

CO2H MeO
I

O
Mes

O

N
H

O

N
H

Mes

*

Ar*I =

O
N

R2

O O

10c (15 mol%)
mCPBA, TFE, H2O

N

R3
R1

R3

37
R1 = H, Br; R2 = Me, Et, Ph
R3 = H, Ar, 4-Me, 4-tBu, 4-OMe

I
OMe

MeO

OMe

3a

5b

R2

MeNO2, -30 ºC
R1

I

CO2H

I

10c
OH

CO2H

O

5c

Scheme 12. First iodine-catalyzed enantioselective
intermolecular ortho-dearomatisation by Quideau.

38
42 - 80%, 82 - 92% ee
H
N

O

O

O

MesHN
O
O
N
H

O

I

OCH2CF3
O
O

NHMes
I

O

O

HN
D

Scheme 11. Formation of an all-carbon stereogenic centre
within the dearomatisation reaction.

8a

OH
R1

R1

CH3CN/H2O (9:1)

R2

R2
R3

Additional important recent accomplishments
extended the spirolactonization to an intermolecular
dearomatization reaction. In this area, Quideau
developed the first asymmetric phenol dearomatization
by the use of an external nucleophile and chiral iodine
catalysts 3a, 5b, 5c. They dwelled on the synthesis of
either the quinol derivative 40 or the epoxide-derived
molecule 41, by treating the starting material 39 with a
stoichiometric or catalytic amount of the iodoarene,
respectively. In this pioneering work, the enantiomeric
excess remained moderate with up to 50% ee for the
ortho-quinol 40 and 29% ee for the ortho-quinol
epoxide 41 (Scheme 12).[13a]
Later on, Harned
presented a methodology with catalyst 8a compatible
with the intermolecular oxidative dearomatisation of
phenols 42, which allowed the formation of parahydroxyquinols 43 with enantioselectivities as high as
60% ee (Scheme 13).[14a] The possibility of an
alternative catalyst design other than the previleged
structures 9-12 was discussed for this reaction,[30]
although its realization is still ongoing.

O

8a (10 mol%), mCPBA

42
R1 = H, Me, Cl, Br,
TMS, TBS, TIPS
R2 = H, Me, OMe;
R3 = Me, i-Pr

R3 OH
43
20 - 79%, <60% ee

Scheme 13. Aryliodine-catalyzed enantioselective
intermolecular para-dearomatisation by Harned.

Muñiz elaborated on the previous reaction,
specifically for the 2,4-substituted phenols 42. The use
of the modular lactic amide-based iodoarene 10d
allowed the obtainment of a substrate range that could
be oxidized to the corresponding quinols 43, some of
which
showed
increased
enantioselectivities.
Moreover, the reaction scope was broadened to the
tosylated aniline analogue 44, yielding the
dearomatized imine product 45 with up to 34% ee
(Scheme 14).[31] Clearly, these results demonstrate that
catalytic
intermolecular
dearomatizative
hydroxylation
with
synthetically
useful
enantioselectivities are within reach, and iodine(I/III)
catalysis should be the most promising tool for their
realization.

8

iPr

iPr

O

O

N
H

3.2 Formal Csp3-Functionalization

iPr

I

O

O

N
H

iPr

10d
O

OH

R1

10d (10 mol%),
mCPBA

R1

R2

ACN/H2O (9:1), -5 ºC

R2
OH

43
25 - 96%, 4 - 50% ee

42
R1 = H, Me, Br,
Cl, TBS, TIPS,tBu
R2 = H, Me

NTs

NHTs
10d (10 mol%),
mCPBA

Br

Br

ACN/H2O (9:1), -5 ºC

44

OH
45
42%, 30% ee

Scheme 14. Aryliodine-catalyzed enantioselective
intermolecular para-dearomatisation of phenols and aniline.
Recently, Maruoka designed some additional enantiopure
chiral organoiodine catalysts 8b,c, which are based on the
modification of a pivotal chiral hydroxyindanol scaffold
(Scheme 15).[32] In line with the general privileged motif, the
crucial chiral lactamide substituent at the phenyl ring was
maintained. Application of pre-catalysts 8b,c in the catalytic
intermolecular hydrative dearomatization of phenols 42 to
p-quinols 43 allowed for a significant selectivity increase,
resulting in up to 84% ee.

The application of iodine(III) catalysis to the
asymmetric α-functionalization of enolizable carbonyl
substrates has emerged as a powerful tool for the
stereoselective synthesis of α-substituted carbonyl
derivatives. Following traditional strategy,[33] this
methodology proceeds through an initial enolization of
the carbonyl group. After the enantioselective
oxidation of the activated alkene by the chiral
hypervalent iodine, the reductive substitution of the
iodine(III) catalyst allows the insertion of diverse
nucleophiles at the a-position of the carbonyl.[34]
Accordingly, different selective a-oxidative C-H
functionalization
reactions
(oxygenation,[35]
[36]
[37]
halogenation,
amination
or fluorination[38]
reactions) have been accomplished. The development
of suitable enantioselective iodine catalyses has
allowed for the introduction of stereogenic centers with
defined absolute configuration.
Wirth synthesized various enantiomerically pure
iodoarenes 5d-i that were employed for the
lactonization of 5-oxo-5-phenylpentanoic acid 46 with
mCPBA as a stoichiometric oxidant (Scheme 16).
Introduction of a weakly coordinating ligand at the
iodine(III) species was needed in order to generate the
active catalyst and was accomplished by pTsOH·H2O. While the yields and ee values of this
reaction were moderately high under these conditions,
they could be readily applied to an intermolecular αoxytosylation of propiophenones (vide infra, Scheme
18).[15a]

O

5d-i (10 mol%)
p-TsOH·H2O, mCPBA

O

Ph

OH

O
O

Ph

MeCN, r.t., 3-4 d

46

R

Ph
O

Ph

I

O

O

N
H

47
OH

OBn
I

O

O
O

CO2Et
CO2Et

O

5d, 46%, 3% ee

Ph

O
O

I

8b (R = H),
8c (R = Me)

O

I
I

CO2Et
CO2Et

5e, 28%, 3% ee

O

5f, 55%, 2% ee
Et

OH

R3
R1
R2
42

8b,c (10 mol%),
mCPBA

butanone/H2O (2:1) [8b,c] R
1
or MeCN/H2O (2:1) [8b]
or MeCN/CHCl3/H2O (7:1:2) [8b]
0 ºC, 17-97 h

with 8b
11 examples
[R1 = H, Me, F; R2 = Alkyl,
R3 = Br, OTs, C2H2TBDPS,
CON(Bn)2, CON(MeOMe)]
34 - 67%, 63 - 84% ee

O

O

O

R3

R2 OH
43

with 8c
4 examples
(R1 = H; R2 = Me; R3 = Cl,
F, TMS, CH2OTBDPS)
51 - 73%, 72 - 84% ee

Scheme 15. Aryliodine-catalyzed enantioselective
intermolecular para-dearomatisation by Maruoka.

O

O
I

O

Br

5g, 67%, 2% ee

I
5h, 55%, 2% ee

Scheme 16. Wirth’s
phenylpentanoic.

N

I
Br

lactonization

Me

O

N
5i, 36%, 1% ee

of

5-oxo-5-

In 2012, Moran and co-workers extended the
enantioselective oxidative cyclisation to an αlactonization of 5-oxo-5-phenylpentanoic acid 46
using chiral aryl iodide 6a as catalyst. Lactone 47 was
formed with 51% ee, which derives from a remarkably

9

high enantiotopic face recognition in this reaction
(Scheme 17).[14c]
I

O
N

Ph
OH

6a
O

6a (10 mol%)
mCPBA, TsOH·H2O

O

Ph

OH
46

CH2Cl2, r.t.

O
O

Ph

O

47

Scheme 17. Aryliodine-catalyzed enantioselective
intermolecular para-dearomatisation of phenols and aniline.

Following his pioneering work on the use of
preformed chiral iodine(III) reagents,[39] in 2007 Wirth
presented the first intermolecular α-oxytosylation of
ketones catalyzed by chiral Koser-type iodoarenes
using mCPBA as a stoichiometric co-oxidant, although
enantioselectivities remained low (Scheme 18).[15a] A
higher selectivity for the reaction of propiophenone
was achieved by introduction of the ester-based
precatalyst 5k. Owing to the presence of the additional
chiral menthyl moiety at the ortho position of the
aryliodine, an enantiomeric excess of 39% ee was
accomplished.[12b] In 2010, Wirth designed a series of
new chiral iodoarenes, which were also used as
catalysts for the enantiomerically enriched aoxytosylation of ketones. The best results were
obtained
using
the
bromophenyl-substituted
precatalyst 5g.[40] In 2011, the chiral spirobisindane
scaffold provided iodoarenes 1 explored as catalysts in
the same enantioselective α-oxygenation. The resulting
Koser-type iodine(III) catalysts were generated using
mCPBA. As to an important insight, the authors
suspected the acidity of TsOH to slightly promote
product racemization, which led to only moderate
enantiomeric excesses below 58%.[41] In addition,
Moran prepared a series of different chiral iodine
catalysts through the esterification or amidation of acid
chlorides. Use of the best precatalyst 6b in the αoxytosylation of propiophenone furnished the desired
product in 18% ee.[14c] Subsequently, Legault and
Guibault investigated an activation effect at the
iodine(III) catalyst by the introduction of sterically
demanding chiral substituents at the ortho position of
the aryliodine. In particular, the application of chiral
amides, oximes and hydrazones as sp2 Lewis bases was
envisioned. Structural analysis and DFT calculations
confirmed the observed acceleration to be the
consequence of an torsion-induced destabilization
within the iodine(III) catalyst.[42] The same group
carried out computational investigation to further
improve the enantioselectivies. They found out that the
most electrophilic dicationic intermediate derived from
the oxazoline derivative 5l, in which the oxygen atom
chelates the iodine center.[43] In 2013, Einhorn
introduced 3,3’-diiodo-BINOL-fused maleimides 5m

as chiral iodine(I) pre-catalysts. The initial focus of
their research was put into the optimization of the
standard a-oxytosylation of propiophenone, which
resulted in the choice of a catalyst structure and
reaction
conditions
providing
yields
and
enantioselectivities that are higher than in comparable
systems. The authors applied their methodology to
different examples giving moderate yields (up to 55%)
and enantioselectivities of up to 46% ee).[13b] The same
group further extended their methodology to additional
chiral biphenol-based structures, even though the
enantioselectivities of the reactions did not notably
surpass the ones from previous work.[11a] In the present
reaction, the low enantioselectivities obtained with
catalyst 10a provide a notably exception to its usual
superior performance.
Catalyst,
conditions

O

O

R2

R1

R2

R1

49

48
I

I

OMe

Et

OTs

I

Br

O
O
O
O

5j (10 mol%),
p-TsOH·H2O, mCPBA
MeCN, r.t., 48 h
R1 = Alkyl, Aryl; R2 = Alkyl, Ph
<10-86%, 1-28% ee

R

5k (10 mol%),
mCPBA, TsOH·H2O
MeCN, r.t.
R1 = Ph; R2 = Me
42%, 39% ee

I

I R

I

O
N
H

R

5g (10 mol%),
mCPBA, p-TsOH·H2O
MeCN, r.t.
R1 = Ph; R2 = Me
70%, 26% ee

N

R

Ph

Ph

O

OH
Cl

1 (10 mol%),
mCPBA, TsOH·H2O
AcOEt, r.t.
R1 = Alkyl, Aryl; R2 =Alkyl, Ph
8-65%, 8-58% ee

6b (10 mol%),
mCPBA, TsOH
MeCN, r.t.
R1 = Ph; R2 = Me
67%, 18% ee

5l (10 mol%),
TsOH, mCPBA
MeCN/DCM (1:1), r.t.
R1 = Alkyl, Aryl; R2 = Alkyl
60-80%, 32-48% ee

I
O
O

O

R

O

I

O
Mes

N

N
H

O

O
O

N
H

Mes

R

I
5m (10 mol%),
mCPBA, TsOH
DCM, 60 h, 20 ºC
R1 = Alkyl, Aryl; R2 = Alkyl, Ph
<87% yield, <51% ee

10a (10 mol %),
mCPBA, TSOH·H2O,
MeCN/ CH2Cl2, r.t., 24 h
73%, <5% ee

Scheme 18. Aryliodine-catalyzed α-oxytosylation of
ketones.

The observed difficulties to achieve high
enantioselectivities may derive from a mechanistic
bias. Within the catalytic cycle, two mechanistically
distinct modes of carbon-oxygen bond formation can
be considered. The reaction starts with the oxidative
conversion of the iodine(I) catalyst to the
corresponding chiral Koser derivative. Interaction with
the enol tautomer of propiophenone can result in two
different substrate-catalyst adducts. In intermediate F,
the substrate is C-bound to the chiral iodine(III)
moiety, while in intermediate E an enolate structure

10

provides an O-bound iodine(III). For F, direct SN2
reaction with tosylate affords the a-oxygenated
product 49. Alternatively, the reductive displacement
of iodine(III) can proceed through a nucleophilic attack
onto the C-C double bond in intermediate E yielding
the same product. Depending on the exact pathway, the
enantioinduction would either be set at the stage of the
enol coordination to iodine(III) (intermediate F), or
would require an effective shielding of one of the
diastereotopic faces of the double bond (intermediate
E). The elucidation of C- vs O-bound iodine(III)
enolates was recently explored by Norby and
Olofsson,[44] and Szpilman[45] and still constitutes an
ongoing investigation. Further mechanistic insight
should enable the development of effective iodine
catalysis for the present reaction.

O
R2

R1
49

OTs

L

I

O

O

O

N
H

OTs

O

Mes

N
H

27%, 78% ee

10a (20 mol %),
mCPBA, TSOH·H2O,
MeCN, r.t., 1.3 h
I

O
Ph

O

O

N

O

N

Ph

8 - 91%, 18 - 90% ee

Scheme 20. State-or-the-art aryliodine catalysts for the αoxytosylation of enolethers.

OTs
O

I Ar*
O

R2

R1
R2

48

O-bound E

OTs

and/or O
R1

49

50 R1 = Alk, Ar
R2 = Alk, Ar

Mes

R2

R1

11a (20 mol %),
mCPBA, TSOH·H2O
MeCN, r.t., 1.3 h

Ar*-I(OH)

R1

O

R2

R1

mCPBA
TsOH·H2O
Ar*-I

Catalyst,
conditions

OAc

R2
L I Ar*
C-bound F

Scheme 19. Proposed mechanisms for the asymmetric αoxytosylation of ketones.

As to a complementary strategy, preformed silyl
enolethers and related stabilized enolethers have
emerged as useful surrogates.[46] Regarding
enantioselective reactions, Legault discovered that the
application of the chiral iodine catalyst 10a allowed the
formation of the tosylated product 49. While free
propiophenone 48 provided almost racemic material,
the use of the preformed acetyl enolether 50a under
closely related conditions generated a synthetically
useful enantiomeric excess (Scheme 20). An even
more useful catalytic protocol was developed by the
use of the iodine catalyst 11a, which provided 49 with
enantiomeric excesses of up to 90%.[47]

In 2015, an enantioselective catalytic version of the
existing a-sulfonylation of ketones,[12a, 35c, 48] was
developed. The reaction used a combination of an axial
chiral Koser-type catalyst, mCPBA and free sulfonic
acid as combined activator and nucleophile source.
The reaction proceeded readily for several
sulfonamides providing the a-oxygenated products
with up to 68% ee.[49] In line with the mechanistic
discussion for the parent ketone substrates, the authors
suggested the involvement of two different
intermediates including an iodine-carbon bound
intermediate F and an O-bound enolate E. The former
one would furnish product 51 through an SN2 reaction.
The latter, which demands an attack at the alkene, was
favored and its involvement was corroborated by
theoretical investigation (Scheme 21).[50]

SO2tBu
I

Cl

2

O

O

2 (10 - 20 mol%),
mCPBA, R3SO2OH

R1
R2

R1
R2

AcOEt, r.t., 72 h

O3SR3

48
Ar*

I SO3R3
O
R1 or R
2

R2
E

51
18 - 75%,
8 - 68% ee

O
R1
I
R3O3S

Ar*
F

Scheme 21. Enantioselective α-sulfonylation of phenones.

11

In addition to the oxygenation reaction, Legault
obtained the related a-chlorinated 1-phenylbutanone
from the corresponding chloroalkene precursor using a
lactamide derived resorcinol iodine(I) reagent in
stoichiometric amounts in combination with mCPBA
and TsOH, and vinyl chloride. This interesting
approach provided an enantiomeric excess of 27%.[36]
In 2014, new insight on halogenation was reported
with the catalytic fluorination of b-dicarbonyl-type 52
by use of an efficient combination of chiral iodoarene
3, mCPBA and HF. Although the reaction was
completely selective, the enantioselectivities and
yields for the fluorinated products 53 remained
moderate (Scheme 22).[51]

the configuration. trans-Selective opening by
nucleophilic fluoride leads to the experimentally
observed (R)-enantiomer of the product.

I

O
R1

O

O

O

R1

R2
9a: R1 = O-D-menthyl, R2 = H
9b: R1 = O-D-menthyl, R2 = 3,5-(CF3)2-C6H3
O
CO2R'

R

9a,b (10 mol%),
mCPBA, NEt3·5HF

O
CO2R'

R

F

CHCl3, r.t.

53
33 - 74%, 66 - 92% ee

52

I
F

I

Ar*

I

52

3
O
CO2R
52
R = Me, L-Men, Ad

3 (15 mol%),
mCPBA, HF
Solvent, r.t., time

O

H
O

H

HF2

F

-2HF

O

Ar*
I F

F
O

I
O

Ar*

O

OEt
K

The mentioned transformation was significantly
improved by Rueping. HF·5NEt3 was identified as the
most suitable fluorine source, and the lactate/resorcinol
based iodine catalyst 9b was effectively modulated to
its best variant introducing a D-menthyl ester group.
The kinetic study of the reaction revealed that the ee of
the product is invariable over the course of the
fluorination indicating that no racemization is
involved. The yields remained moderate for this
fluorination, but the enantioselectivities were
significantly improved, giving up to 92% ee for the
fluorinated species 53 (Scheme 23).[38] An interesting
feature of the work consisted in the rationalization of
the observed enantioselection by computational
chemistry. Within reaction of the enolized form of the
substrate, the calculations show that an I-O bonded
intermediate J can be formed via G-I. After ruling out
a direct nucleophilic attack of the fluoride to the acarbon due to the observed opposite stereochemistry of
the products 53, the authors proposed a transition state
K, in which the iodine transfers from the carboxylic
oxygen to the a-carbon. Based on the calculations,
transition state J is enantioselectivity-determining as
the resulting intermediate K displays only a very low
energy barrier. Also, the pro-(R) TS is favored over its
analogous pro-(S) TS, according to the calculations.
From there, a double inversion of stereochemistry
takes place, in which Ar*-I is eliminated and a
hemiacetale formed, which implies a first inversion of

F

O

H

G

53
41 - 71%, 25 - 65% ee

Scheme 22. Enantioselective α-fluorination of ketoesters
(1).

F

I F
OEt Ar*

OEt

CO2R

H

O

O
Ar*IF

O

F
I AR*
O
OEt

J

I

enantiodetermining
transition state
53

Scheme 23. Enantioselective α-fluorination of ketoesters
(2).

Investigation on additional a-oxidation reactions of
carbonyls have resulted in interesting enantioselective
spiro-cyclization reactions. In 2014, Gong and coworkers
successfully
developed
the
first
intramolecular asymmetric oxidative C(sp2)-C(sp3)
cross-coupling
reaction
of
N1,N3diphenylmalonamides 54, which is catalyzed by chiral
iodide compounds. This stereoselective methodology
features the consecutive functionalization of four C-H
bonds to access optically active spirooxindoles
(Scheme 24).[52] The hypervalent iodine 15a was
generated in situ from the chiral aryliodine reagent 11b
and peracetic acid. The attached tertiary amide moiety
appeared to play a key role in the stereochemical
induction. Moreover, as discussed in the section on
supramolecular structure (vide supra), the chiral
stereogenic lactic center had a major impact on the
helical assembly formation and therefore on the
stereochemistry of the product than the proline
chirality. Based on previous studies,[53] the authors
suggested the formation of the stereogenic center by an

12

intramolecular Friedel-Crafts-type addition followed
by the oxidative cyclization via syn additionelimination favored through the Si face, giving product
55 with high enantioselectivity. Using density
functional computation, Hadad, Sunoj and co-workers
studied the detailed course of the stereoinduction with
the resorcinol-based chiral iodine catalyst 11b used by
Gong.[20] The generation of a chiral environment
around the iodine center, due to the presence of noncovalent interactions between the trifluoroacetate
ligands and the amide moieties was already outlined
above. From a mechanistic point of view, the substrate
underwent two sequential catalytic cyclization steps.
Hence, the chiral iodine participates twice in the cycle
demonstrating a highly efficient role as a catalyst,
particularly in the final enantioselectivity-determining
cyclization (Scheme 24).
I

O

MeO2C

O

O

N

O

CO2Me
N

11b
O
R1
N
R3

O

R2
N
R4

R4
N

11b (15 mol%),
MeCO3H,CF3CO2H,

O
R1

CH3NO2, r.t., 16 h

O
N
R3

54
R1 = H, 5ʼ-Me; R2 = H, %-Me, 5-Ph
R3 = Me, Bn; R4 = Me, Et, Bn

55
26-78%, 90% ee

R2

CF3CO2H

Ph
R3

N

Ph

R2

O
H
I
*Ar
O
F3CCO2
CF3CO2

O
R3

N
Ph

R2

N

R3
N

Ar*

R4

N R4
O
I

O

O2CCF3
Q

11b Ar*
[O]

P

CF3CO2

H
R3 N

O

N
I
R4
O
*Ar
R
R4
N

I
O

CF3CO2H

O R2

R1
O2CCF3
Ar* I
O2CCF3
15a

O
N R4

55
54
R3

[O]

Ph
N

O
Ar* I
O2CCF3

CF3CO2H

Ar*

R2

N
R3

I 11b

O

O
N
Ph

R4

CF3CO2

L
R3

Ph
N

O

O
I
*Ar

H

N

H

CF3CO2

R2

N

R3

R4
Ar*

Ph
N

O
I
O2CCF3
M

CF3CO2H

O
N
Ph

R4

Scheme 24. Enantioselective C(sp2)-C(sp3) cross-coupling
reaction to form optically active spirooxindoles.

After the generation of the I(III) catalyst 15a, the
catalytic cycle was suggested to start with the
formation of L and an abstraction of a methylene
proton. This promoted the formation of the Oiodonium intermediate M, which went through an

essential 1,3-migration to generate the low energy Ciodonium N. This atypical reaction was considered the
enantiocontrolling step. Next, an SN2 reaction between
the ortho carbon of the N8’-phenyl group and the
methylenic carbon took place forming the C-C bond of
the monooxindole structure O. A similar mechanistic
route via P-R ended the second ring formation
affording the desired chiral spiro-bisoxindole product
55. Due to the loss of chiral information arising from
the second enolization to Q the overall
stereoselectivity of the final product is solely
dependent on the second ring closure sequence.

3.3 Difunctionalization of Alkenes
Due to the coordination ability of their electron-rich
p-system, alkenes are suitable substrates for
enantioselective oxidation with electrophilic chiral
iodine catalysts.[11e,g] Alkenes represent a widespread
functional group and their functionalization within the
vicinal difunctionalization strategy is step-economic.
Iodine(I/III) catalysis adds the aspect of an
environmentally friendly synthesis. As a result of these
attractive aspects, iodine catalyzed asymmetric
difunctionalization reactions including oxygenations,
aminations and fluorinations have started to appear
more and more often throughout the last decade.
Taking into account that alkenes can also react with
the stoichiometric oxidant destined for the iodine
oxidation, the basic requirement for chemo- and/or
enantioselectivity in these I(I)/I(III) systems is either a
chemoselective oxidation of the aryliodine(I) catalyst
or a significant kinetic preference for the catalyzed
pathway over the non-catalyzed background reaction.
In 2012, Fujita developed the first example of an
asymmetric difunctionalization of internal alkenes 57
employing a chiral iodoarene 9c in a 10 mol% catalyst
loading and a peracid as the co-oxidant. In this case,
the starting material contained both oxygen atoms that
were oxidatively transferred to the alkene moiety. With
the generated lactate-based resorcinol catalyst 56, they
employed this strategy in the first stereoselective total
synthesis of hydroxymonocerins 60,61 from
preformed alkenylbenzoate substrates 57. The reaction
went through a cascade formation of the oxolane-fused
isochroman-1-one backbone by a double oxygenative
cyclization. The presence of the iodine(III) catalyst
was essential for the asymmetric intramolecular
oxylactonization, as the stereochemical outcome relied
on the prochiral face recognition through catalyst
control.[16d] Therefore, the preinstalled stereogenic
centers of the substrate do not dominate the
stereochemistry of the cyclisation event (Scheme
25).[16c] The exact courses of for enantioselective
induction in these reactions were discussed recently by
Fujita.[54]

13

Ar*
O

X I

O

rings were obtained, corresponding to oxazolines and
dihydrooxazines. Yields and enantioselectivities
ranged from moderate to good.[55] The mechanism
involved the in situ generation of iodine(III) catalyst,
which activated the alkene for an intramolecular attack
by the amide oxygen. The subsequent intermolecular
nucleophilic oxygenation at the carbon-iodine bond of
U regenerates the pre-catalyst 11c and releases the
cyclized product 68 (Scheme 27).

R
OTBS

si-face attack R

O

X

X

I

O

O

O

O

OMe R
R

(R,R)-56

O

O

S

O

58
OTBS
OMe R
O

R

57
Ar*

X I

O

X

O

O

O

I

re-face attack

O

O

X
OTBS

R

R

O

OMe R

O

O
O

I

O

59
T

(S,S)-56

O

O

N

O

N

Y
O

X

11c

MeO

11c (10 mol%),
Selectfluor, CF3CO2H

O

MeO
OH

O

HN

X = H, Y = OH; 60
X = OH, Y = H; 61

Scheme 25. Stereoselective
hydroxymonocerins.

total

synthesis

of

O

O
I

OH

OH

n-C5H11

n-C5H11
O

O
O

O
n-C5H11
O

1) 4 (10 mol%),
mCPBA,
CF3COOH, CH2Cl2, 0ºC

2) K2CO3, MeOH, H2O, 0ºC

O

62

65

63

+

+
HO

n-C5H11
O

O

O
O

O

O
I

4

HO

n-C5H11
O

O

O

64

66

O
catalysis products

background products

Scheme 26. Enantioselective synthesis of optically active 4hydroxyisochroman-1-ones.

OH

Ph
N

O

68
86%, 64% ee

67
H

Their ensuing study was based on the application of
the developed asymmetric methodology to synthesize
optically active 4-hydroxyisochroman-1-ones 63,64.
In this case, four possible stereoisomers could be
achieved in different ratios depending on the substrate
and the chiral hypervalent iodine, for which 4 was
chosen. Syn-selectivity was preferred by I(III)catalyzed reactions giving products 63 and 64 with
significant enantiomeric excess through a Woodwardtype mechanism. In contrast, the background antidioxygenation under the assistance of mCPBA
originated from a Prévost mechanism producing
racemic diastereomers 65 and 66 (Scheme 26).[16e]

N

MeCN, r.t.
then, NaOH

L
*Ar

U

Scheme 27. Enantioselective oxidative cyclization of Nalkenylamides.

Masson investigated the first enantioselective
sulfonyl- and phosphoryl-derived oxylactonization of
non-rigid 4-pentenoic acid derivatives. By using 20
mol% of a chiral iodine precursor 10a, mCPBA as cooxidant and sulfonic or phosphoric acid as
nucleophiles, the desired products 70 and 71 were
readily afforded. The common C2-symmetric
resorcinol iodine compound 10a with a secondary
lactamide moiety including a bulky 2,4,6-trimethyl
phenyl
group
provided
good
yield
and
enantioselectivity in both cases (Scheme 28).[56]
From a mechanistic point of view, the active aryl-l3iodane species of the Koser type underwent an
electrophilic addition to the double bond, forming a
chiral iodonium intermediate V. After the
lactonisation, nucleophile exchange at iodine of W and
subsequent nucleophilic addition within X by a
sulfonyl or phosphoryl group, the final g-lactones 70
and 71 were formed. In the determining transition state
of V, the blockage of the Si face of the substrate by the
catalyst is accomplished through n-s* interactions
between the iodine(III) center and the carbonyl oxygen
of the amide. This effective selection provides the
observed absolute enantioselective outcome (Scheme
28).

The same concept can be applied to the formation of
useful chiral heterocycles, such as oxazolines and
dihydrooxazines within intramolecular cyclization
onto prochiral faces of an alkene. In 2015, Moran
reported an oxidative cyclization of N-alkenylamides
67 using 10 mol % of a chiral iodine pre-catalyst 11c
and 2 equivalents of Selectfluor as the terminal
oxidant. Through this route, five and six-membered

14

I

O
Mes

O

N
H

OMe

O
O

N
H

Mes

I
4

10a
10a (10 mol%),
mCPBA, Et2O/TFE

O
OH
69

OH

O

R1 R1

Ar

69

R1
R1

R1

O

R
P R

O
O S Ar
O

O
n

Ar = 1-napht,
p
OH Ar = MeC6H4
n = 0; 1

71
23 - 76%,
58 - 86% ee

L = P(O)R2, S(O)2Ar
LOH

O
OL

Ar*

I

OL

mCPBA

Ar*

10a

70,71

I
OH

O
HO
R1

R1

69
R1

O

R1

L O

HO

O

O

Ar
O

*Ar

X

I

HO I
RO

O L
H 2O

R1
R1

N R

O

O
V

O

H
N

Cbz

R

4 (20 mol%)
NaBO3·4H2O

N X

Ph
Ph

3 equiv. AcOH
MeCN
25 ºC, 5h

N

Cbz

R

73

Scheme 29. Catalytic intramolecular diamination of
alkenes.

O
R1
R1

X

72

70
52 - 88%,
70 - 94% ee

O
S

O O
O

10a (20 mol%),
mCPBA, Et2O

O
n

R1

O
R = OPh
P
R
OH R = OBn
R

R1 R1

Ph Ph H
N

O

N

One of the first stoichiometric examples of alkene
fluorination by the action of hypervalent iodine was
reported in 2012 in the form of an intramolecular
aminofluorination, in which the fluorination proceeds
in the presence of HF·Py as fluorine source and
BF3·OEt2 as an activator.[60] Based on this work,
Nevado developed the enantioselective transformation
using a chiral hypervalent difluoroiodine(III) reagent,
obtaining the desired fluorinated piperidine derivatives
with up to 88% ee.[61] Subsequently, Kita and Shibata
developed a catalytic asymmetric version of the
mentioned reaction, in which axially chiral
bisiodine(III) is the in situ generated from 3 under the
combined action of mCPBA and HF. Nevertheless, the
yields were relatively lower than the ones from the
previous stoichiometric transformation (43–65%
yield) and the same concerned the enantioselectivities
of products 75 (0–70% ee) (Scheme 30).[51]

*Ar
W

I
HO

HO L

Scheme 28. Enantioselective oxidative cyclization of walkenylcarboxylic acids.

After successfully introduction of the stoichiometric
application of different chiral iodine(III) reagents,[57] in
2014 Wirth described the first catalytic intramolecular
diamination of alkenes 72. By using chiral hypervalent
iodine catalysis with 4, which included an oxidative
cyclization step followed by a reduction, they obtained
the corresponding diamines 73 with up to 86% ee
(Scheme 29).[58] Although a detailed structural
elucidation of the active iodine(III) catalyst remains a
future task, one can anticipate a rigid stereochemical
environment arriving from coordination of the pyridine
to the iodine(III) center.[9j] Related coordination was
recently confirmed in an achiral iodine(I/III) catalyzed
diacetoxylation and matches the concept of
intramolecular coordination at iodine(III).[59]

I
I

3
R

3 (15 mol%)

R
NHPG

HF source, mCPBA

R

R

F

74

N
PG
75

(3 examples)

46 - 68%, <70% ee

Scheme 30. Catalytic enantioselective version of the
aminofluorination reaction.

The most recent development in the intramolecular
aminofluorination of arylated allylic amines was
introduced by Jacobsen.[62] The use of chiral iodine(III)
catalysis with 9d provided elegant access to afluoroaziridines 77 with up to 97% ee. Subsequent
aziridine ring opening of these building blocks with a
range of nucleophiles yielded the analogous linear
structures with vicinal fluoroamino group in excellent
yields and enantioselectivities. Although 4- and 6membered rings could not be formed, the methodology

15

was successfully extended to one example of a 5membered ring 79. The syn/anti difference regarding
the relative stereochemistry of the products 77 and 79
was postulated to be the consequence of two different
pathways for the individual substrate classes, being
both successfully promoted by the same catalyst 9d,
which exercises high to complete face selection.
I

O

O

O

BnO

O

Bn

OBn
Bn

CO2Me
9d

NHTs

R

F

9d (10 mol%),
mCPBA, py 9HF
DCM, -30 ºC, 18 h

R

N
Ts

76

77
>20:1 d.r.
44 - 93%,61 - 97% ee
F
NHTs

O2N
2

9d (20 mol%),
mCPBA, py9HF
DCM, -30 ºC, 18 h

78

O2N
TsN
79
>20:1 d.r.
82%, 99% ee
(after recristallization)

Scheme 31. Catalytic enantioselective fluoroamination
reactions.

In the same context, Jacobsen elaborated an
enantioselective formation of 4-fluoroisochroman-1one 81 by the action of a 2-iodoorcinol-based catalyst
9e. The reaction accesses lactones incorporating
fluorinated stereogenic centers with high diastereoand enantioselectivity.
Alkyl, halide, or
trifluoromethoxy substitution pattern at the 6-, 5-, and
4-positions of 80 were generally well tolerated, with
the fluorolactone products 81 obtained in 80−96% ee.
However, substrates 80 carrying more electrondeficient trifluoromethyl or carbomethoxy groups led
to reduced yields and enantioselectivities (Scheme
32).[63]
I

O
BnO

O

iPr

iPr

O
O

OBn

R2
COOMe

DCM, -50 ºC, 24h

O

O
O

N
H

iPr

R2
R1

O

OAc

10d (10 mol%), TfOH (10 mol%),
AcOOH, AcOH, r.t.

R

F

9e (10 mol%),
mCPBA, pyr·9HF

N
H

iPr

I

O

10d

9e

R1

In 2016, Muñiz and Ishihara extended the use of
non-racemic hypervalent iodine catalysis to the
intermolecular diacetoxylation of alkenes and thereby
demonstrated the feasibility of iodine catalysis in
enantioselective alkene oxidation under full
intermolecular reaction control. The work has
precedence regarding a transformation that is
stoichiometric in chiral iodine(III) reagent. However,
the catalytic variant relied on structurally defined
catalysts. Fujita[16c] and Ishihara[23] firstly suggested
the spatial disposition of some hypervalent iodine(III)
reagents of the resorcinol lactate, while the present
work offered the first experimental rationalization and
exploitation of the resulting supramolecular assembly
and its application to intermolecular reaction control.
Based on the modular toolbox approach discussed
above in Figure 3, the required reactivity of the iodine
catalysts was fine-tuned for the mentioned
diacetoxylation reactions.
The first methodology is based on the use of catalyst
10d in combination with peracetic acid as the terminal
oxidant. This catalyst bearing a methyl group at the 4position of the aryl backbone and an N-arylamide
moiety at the arms performed kinetically superior than
related candidates. High yields and enantiomeric
excesses were provided when terminal styrene
derivatives 82 were employed as substrates (Scheme
33). As expected, the choice of peracetic acid as
oxidant excluded potential contribution via an
undesired background epoxidation.[19] The presence of
a catalytic amount of triflic acid was found beneficial.
In agreement with the mechanistic insight by Gade,[64]
the presence of this BrØnstedt acid is crucial for the
kinetic dominance of the chirally catalyzed pathway.
At the stage of the diacetoxy iodine(III) catalyst stage,
TfOH-promoted protonolysis removes one of the
acetate ligands and thereby provides the free site for
the selective coordination of one the prochiral faces of
the substrate. This step includes partial loss of the
helical arrangement from hydrogen bonding, but due
to the remaining chiral pocket of 13b,
enantiodiscrimination remains excellent.

then Ac2O, Py, DMAP, CH2Cl2, r.t.
82

OAc
R
83
52-94%,
63-94% ee

O
80

81
35 - 86%,
30 - 96% ee

Scheme 33. Enantioselective diacetoxylation of terminal
styrene derivatives.

Scheme 32. Catalytic enantioselective fluorolactonization.

16

I

O
O

O

intramolecular scenario usually outperforms the
intermolecular one.
Gilmour reported in 2016 the enantioselective
vicinal difluorination of alkenes 84,86 using a chiral,
non-racemic aryliodide derivative 11e for face
differentiation of prochiral allylic ethers.[66]
Subsequent work revealed the important insight that
lactate-derived catalysts in combination with
Selectfluor can be employed in order to exercise
effective intermolecular reaction control and obtain
fluorinated species such as 85 and 87 with
enantiomeric excess (Scheme 35).[67]

O
O

O

9f
9f (20 mol%),
Selectfluor®, TMSOTf,

R'

OAc
R'

AcOH, r.t., 12 h

R

then Ac2O, Py, DMAP, CH2Cl2, r.t.

R

OAc

83 R = H: 55-92%, 62-88% ee
R = CH2OAc: 42-65%, 78-95% ee

82

HOTf + TMSOHAc

TMS-F + H+

OAc

F
Ar*

BF4
N

I

O

BF4
Ar*

I

Z

I

Mes

AA

N

83 + HOTf

Cl

N
H

OTf

Cl
Ar*

O

I

O
R

83

2) Ac2O

O

O

+ HH2OTf

F

85, 54%, 61:39 er

84

11e (20 mol %),
Selectfluor, Amine:HF (1:5)

O

O
Br

DCE, r.t., 24h

Br

OAc

Ar

F

O

OTf

AB

1) H2O, AcOH

NO2

DCE, r.t., 24h

I Ar*

9f

Woodward
mechanism

Mes

11e (20 mol %),
Selectfluor, Amine:HF (1:5)

NO2
O

2 BF4

N
H

11e

Ar

N

O

R

AcOH

82

F N

O

O

86
AcOH

R

AC

Scheme 35. Enantioselective fluorination.

Scheme 34. Enantioselective diacetoxylation of terminal
and internal styrene derivatives.

I

O

O

O

MeO

As for the enantioselective intermolecular
diacetoxylation with peracetic acid, Selectfluor® can
also be employed as the terminal oxidant. In this case,
the active iodine(III) catalyst is generated from precatalyst 9f containing a 1-adamantyl ester moiety in
combination with TMSOTf, which exercises the same
role as the HOTf in the previous reaction. This
diacetoxylation variant was suitable for both terminal
styrenes and internal derivatives from cinammyl
alcohols and again afforded good enantioselectivities
and yields (Scheme 34).[65]
The catalytic cycle starts with the oxidation of the
chiral iodoarene 9f and by the action of trimethylsilyl
acetate and triflic acid generates the active cationic
state of the chiral I(III) catalyst AA. Upon addition of
the styrene substrate 82, AA exercises face recognition
and the generated enantioenriched iodooxygenated
intermediate AB from acetate incorporation is identical
to the one from catalytic diacetoxylation of styrenes
with peracetic acid. It provides the final product within
two pathways: a Woordward mechanism through the
formation of a dioxolonium derivative AC arising from
intramolecular displacement of the iodine(III), or by a
direct
reductive
deiodination
through
an
intermolecular SN2 reaction using a second acetate
nucleophile. As determined by control experiments,
both pathways are operative, although the

F

87, 30%, 70.5:29.5 er

O

Bn

OMe
Bn

CO2Me
9d

9d (20 mol%),
pyr·9HF, mCPBA

iPr

NH2

iPr

NH2

DCM, 72 h, 4 ºC
O

F

88

88

Ar*I
pyr·HF
m-CPBA

F

O

89
51%, 93% ee
>19:1 d.r.
F

F H FH

*Ar I
R1

R3

R2

O

F

R4
N

*Ar
R1
R5

I

R2

AD

H

R3 R4
N
O

R5

AE

F

Ar*I
F H F

89

R1 F

R3

R2 O

R4
N

R5

AF

17

Scheme 36. Enantioselective difluorination of acrylamides.

Jacobsen disclosed similar reactivity for substrate 88.
The method uses a nucleophilic fluorine source and the
conventional oxidant mCPBA in conjunction with the
related chiral iodine(I) catalyst 9d (Scheme 36). The
proposed catalytic cycle consists in the formation of
the chiral iodine(III) catalyst, which oxidizes the
alkene in a stereoselective way via AD. Highly
electron-deficient β-monosubstituted styrenes yielded
the corresponding syn-difluorination products, while
o-nitrostyrene derivatives and β,β-disubstituted
acrylamides 88 gave anti-difluorination, which is
believed to arise from anchimeric assistance by the
vicinal polar groups. Moreover, the difluorination of
trisubstituted cinnamate derivatives provided a wide
range of the desired products with 19:1 d.r. and 97%
ee, respectively. The use of arenes and amides with
alternative substitution gave different stereochemical
outcomes in the products.[68a] Another example of an
unprecedented alkene oxidation was developed by
Jacobsen, who reported a unique catalytic approach to
geminal difluorination products 91 (Scheme 37).[68b]
This transformation involves an initial iodofluorination
of 90 to difunctionalized AG. The required reductive
elimination of the aryliodine(III) does not arrive from
the common nucleophilic addition, but is trigged by an
aryl migration involving the phenonium ion AH.[9k]
This concept was previously introduced by Wirth in the
oxidation reaction of chalcones under stoichiometric
iodine(III) control.[69] Upon fluoride addition, the
subsequent rearrangement forms the final gemdifluoromethylated product 91 in high yields and
enantioselectivities. Again, catalyst fine-tuning is
accomplished
within
the
resorcinol/lactate
combination and the introduction of benzylic moieties
in the chiral position of the catalyst 9d was crucial for
high reactivity, and ultimately the enantioselectivity,
due to the decrease in reaction temperature. In addition
to
the
present
catalytic
transformation,
enantioselective transformations stoichiometric in
iodine(III) have been elaborated by Wirth.[69, 70] In
addition, an investigation on the electronic effect of a
4-CF3 substituent at the central aryl group of the
idoine(III) reagent was provided recently.[71]

I

O

O

O

BnO

O

Bn

9d

Ar

CO2Me

Ar

9d (10 mol%),
mCPBA, Py·9HF

R2

F
F

DCM, —20 or —
40 ºC, 60 - 72 h

R1

OBn
Bn

R2
R1

91
45 - 93%, 64 - 97% ee

90

O

Ar*IF

F H F

NH2

Ar

F

Ar
I

Ar

F H F
90

CONH2

AG
Ar*I

F
Ar

F
CONH2
91

F H F

F
CONH2

R3

H
AH

Scheme 37. Enantioselective geminal difluorination.

Building on a body of achiral reactions,[35a, 72] Muñiz
had already developed in 2011 an enantioselective
stoichiometric diamination of styrene and derivatives
82 using chiral iodine(III) reagents. Up to 95% ee
could be obtained under these conditions.[72b] This high
enantiomeric induction rose the question for catalytic
reaction conditions.
Recurring to the lactate/resorcinol toolbox for
catalyst optimization, the 4-methyl aryl iodide 11e
incorporating two chiral lactamide side chains resulted
as the optimum catalyst precursor. Suitable conditions
for the desired iodine(I/III) redox catalysis employed
3-chloroperbenzoic acid (mCPBA) as terminal
oxidant, which in the optimized MTBE/HFIP solvent
combination showed only negligible background
epoxidation. In this way, reaction proceeded in
excellent enantioselectivity with up to 98% ee for
terminal and internal styrenes (Scheme 38).[15c] This
protocol
pioneers
enantioselective
catalytic
diamination of alkenes under intermolecular reaction
control. As demonstrated for a vinyl steroid, the
reaction proceeds under complete catalyst control for
chiral substrates. The resulting vicinal diamines can be
readily transformed into the corresponding free 1-aryl
ethylene diamines, which represent useful building
block in synthesis. This context had been demonstrated
for the synthesis of alkaloid levamisole.[73]

18

O

I

O

O

N

O

N

11e
NMs2
NMs2

11e (10 - 20 mol%)
R

mCPBA, HNMs2,
MTBE/HFIP (3/1, v/v), -5 ˚C

82

R
92
22 examples,
54-87%, 91-98% ee

supramolecular helical environments and thus provide
the same face selection of the styrene substrate
providing identical absolute benzylic (S)-configuration
of the products. The major difference rests with the
chiral pockets within the helical assembly of the
catalysts. Inspection of the crystal structures from
Figure 2 reveals a significantly wider pocket for the
bisamide 14a, which adopts to the required spatial
trajectory for the bissulfonimide nucleophile, which
exercise a larger steric requirement than the acetate
nucleophile in the cases of catalysts 13a and 13b
(Scheme 39).

NMs2

R

R'

11e (20 mol%)

R'

R

mCPBA (2.1 equiv),
HNMs2 (2.5 equiv),

82

92
5 examples,
35-50%, 93-98% ee

MTBE/TFE (3/1, v/v), -20 oC
R

re-face
attack
O

AcO
O
Ar

82

Ar

re-face
attack

NMs2

N
H

O

Ar

I

H

O
O

N

Ar
O

Ms2N
Ar I

O
iPr2N

O

NMs2
O

(HY)n
O
NiPr2

R
Ms2N I NMs2

Ms2N

Ar*

Ar I
Ar*

AL

NMs2

AI

H2O + mCBA

mCPBA +
2 HNMs2

Ms2N
NMs2

Ar

I
Ar*

I
Ar*
AJ

11e
O

Ms2N

R

Ar
92

MsN

S

O

NMs2
Ar

R

NMs2

AK

Scheme 38. Enantioselective vicinal diamination.

Mechanistically, the diamination should proceed
through an iodine(III) catalyst state AL with two
incorporated bismesylimides at iodine. Here, the
enhanced dissociation capacity of the bismesylimide is
decisive, as it readily promotes a free coordination site
at the iodine center for efficient enantiotopic face
differentiation within substrate coordination AI. The
obtained high enantioselectivity originates from direct
amination at the benzylic position followed by
intramolecular de-iodination at stage AJ to
dioxooxathiazolidinium AK, which upon addition of
the remaining bismesylimide provides the final
products 92 as single diastereoisomers in excellent ee.
It is interesting to compare the stereochemical course
of the diacetoxylation and diamination reactions. For a
given absolute configuration of the lactic side chain of
the catalyst, both catalysts form identical

chiral supramolecular
scaffold

chiral supramolecular
scaffold

Scheme 39. Efficient face selection within individual chiral
supramolecular scaffols of catalysts related to 13a,b and
14a.

These results allow for a first prediction of absolute
chirality of products within a given catalytic oxidation
by chiral aryliodine(III) catalysts. They hold strong
promise for a possible future rationale design of
catalysts deriving from the lactate/resorcinol motif.
Clearly, more data on catalyst structure and reaction
transition states are required. Yet at the present stage,
this particular catalyst concept holds great promise as
evidenced from the large number of successful
applications discussed in the previous sections.

4 Conclusion
The status quo of iodine(I/III) oxidation catalysis
has reached a high level. It has proven to be applicable
to enantioselective reactions under intra- and
intermolecular reactions control tolerating a wide
range of different transferable groups including
oxygen atoms from alcohols and different kinds of
aids, nitrogen atoms from amides and fluorine atoms.
The quest for effective enantioselective oxidation has
resulted in a large number of chiral iodine catalysts,
which have been optimized both with respect to
structure and cooperation with the respective terminal
oxidant. Extensive efforts have been undertaken to
arrive at an advanced structure-reactivity relationship
for several of the chiral iodine catalysts, which in some
cases has already permitted the design of individual
iodine catalysts for specific transformations.
Continuous catalyst structure optimization within the
lactate/resorcinol family as well as the identification of

19

new catalyst structures will certainly continue within
the near future. The application of specifically
designed chiral aryliodine(I/III) catalysis has emerged
only recently, but already at the present stage holds
very high promise to become a rather general tool in
enantioselective oxidation catalysis.

Acknowledgements
The authors thank all current and past co-workers of the Muñiz
group for their experimental and intellectual contributions to this
research project. Their names are provided in the references. The
authors are grateful to the Spanish Ministerio de Economía y
Competitividad for continuous support of their research.

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22

REVIEW
Enantioselective Iodine(I/III) Catalysis in Organic
Synthesis
Adv. Synth. Catal. Year, Volume, Page – Page
Andrea Flores, Eric Cots, Julien Bergès, and Kilian
Muñiz*

From chiral catalyst design...
Ac Ac
Ar
O

H
N

O

O

H
N

I
O

O

Ar
O

...to highly enantioselective catalysis
chiral supramolecular
scaffold

O

AcO
O
Ar

N
H

O

Ar

I

H

O
O

N

Ar
O

23