Enantioselective organocatalytic epoxidation using hypervalent iodine reagents

Article abstract of DOI:10.1016/j.tet.2006.07.055

A rare example of a hypervalent iodine reagent participating in a 1,4-heteroconjugate addition reaction is reported for the organocatalytic, asymmetric epoxidation of α,β-unsaturated aldehydes using imidazolidinone catalyst 1. Development of an 'internal syringe pump' effect via the slow release of iodosobenzene from an iminoiodinane source provides high levels of reaction efficiency and enantiomeric control in the asymmetric epoxidation of electron-deficient olefins. ¹⁵N NMR studies were conducted to elucidate the reaction pathways that lead to catalyst depletion in the presence of prototypical oxidants. These NMR studies also provided the mechanistic foundation for the application of iminoiodinanes as an internal slow release oxidant to circumvent these catalyst depletion pathways.

Full text of DOI:10.1016/j.tet.2006.07.055

Tetrahedron 62 (2006) 11413–11424
Enantioselective organocatalytic epoxidation using hypervalent
iodine reagents
*
Sandra Lee and David W. C. MacMillan
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Received 29 June 2006; accepted 12 July 2006
Available online 23 August 2006
Abstract—A rare example of a hypervalent iodine reagent participating in a 1,4-heteroconjugate addition reaction is reported for the organo-
catalytic, asymmetric epoxidation of a,b-unsaturated aldehydes using imidazolidinone catalyst 1. Development of an ‘internal syringe pump’
effect via the slow release of iodosobenzene from an iminoiodinane source provides high levels of reaction efficiency and enantiomeric control
in the asymmetric epoxidation of electron-deficient olefins. 15N NMR studies were conducted to elucidate the reaction pathways that lead to
catalyst depletion in the presence of prototypical oxidants. These NMR studies also provided the mechanistic foundation for the application of
iminoiodinanes as an internal slow release oxidant to circumvent these catalyst depletion pathways.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
upon the Weitz–Scheffer reaction,10 wherein a nucleophilic
chiral peroxide adds to an enone or enal (Fig. 1). This strat-
egy of hydroperoxide delivery via a homogeneous chiral
metal complex has been adopted and developed by Enders11
in a stoichiometric manner and in a catalytic approach by
Jackson12 and Shibasaki.13 Alternatively, asymmetric phase
transfer agents have been utilized to transport a reactive
oxo-species to olefin substrates as epitomized in the work
of Roberts14 using polyamino acids and in the cinchona
alkaloid-derived salts of Lygo15 and Corey.16
The enantioselective catalytic oxidation of olefins is argu-
ably one of the most powerful transformations known to
practitioners of chemical synthesis.1 Indeed, since the inven-
tion of the Sharpless asymmetric epoxidation,2 there has
been an ever-increasing demand for catalyst-controlled
processes that allow efficient and predictable access to
enantioenriched oxiranes. Significant efforts to expand the
scope of such catalytic epoxidations have been made via
the seminal contributions of Jacobsen3 and Katsuki4 using
metal-ligated systems for the electrophilic delivery of oxy-
gen. Complementary to these established organometallic
strategies, Shi,5 Denmark,6 Yang,7 and Armstrong8 have de-
veloped an elegant organocatalytic approach that relies upon
a ketone-derived dioxirane catalyst for the asymmetric epoxi-
dation of trisubstituted and 1,2-trans-disubstituted alkenes.
These epoxidation methods are applicable to several olefin
classes; however, they do not encompass the enantioselec-
tive epoxidation of electron-deficient olefins.
Mg-Catalyzed Jackson Epoxidation
O
R'
R'
OH
O
catalyst
EtO
EtO
MgBu2
R
O
R
O
TBHP, 4Å MS
OH
O
R = aryl, alkyl; R' = Me, Et, aryl
81–94% ee
Ln-BINOL Catalyzed Shibasaki Epoxidation
R
Ln(O-iPr)3
Ln = La,Yb
Enantioselective Catalytic Epoxidation of Olefins
OR'
OR'
O
oxidant,
catalyst
OH
OH
R
O
asymmetric
O
R
O
CMHP or TBHP
4Å MS
organometallic or
organocatalyst
R = H, CH2OH
R = Ph, Me, i-Pr; R' = alkyl, Ph
83–94% ee
epoxide products = stereodefined sp3 electrophile
versatile electrophile for chemical synthesis applications
Corey Phase-Transfer Epoxidation
Me
OBn
OR'
OR'
O
Existing technologies for the enantioselective epoxidation of
olefins9 via LUMO-lowering activation have been founded
N
catalyst
Br
R
O
R
O
KOCl
N
91–99% ee
Keywords: Epoxidation; Organocatalysis; Enantioselective; Iodosobenzene.
* Corresponding author. Tel.: +1 626 395 6044; fax: +1 626 795 3658;
e-mail: dmacmill@caltech.edu
R = aryl, Cy, n-C5H11; R' = aryl
Figure 1. General methods for catalytic nucleophilic epoxidations.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.055

11414
S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
Most recently, Jørgensen and co-workers17 have demon-
strated the asymmetric organocatalytic epoxidation of a,b-
unsaturated aldehydes using iminium catalysis. In these
elegant studies, a variety of enals rapidly underwent asym-
metric epoxidation using hydrogen peroxide as the stoichio-
metric oxidant in the presence of a proline-derived catalyst.
In this publication, we further demonstrate the use of our chi-
ral imidazolidinone salts as iminium activation catalysts for
the asymmetric epoxidation of a,b-unsaturated aldehydes.
This transformation provides rapid access to enantio-
enriched 1,2-trans-formyl epoxides, an ambiphilic class of
electrophile of known value in chemical synthesis.18
cyclopropanation studies that were ongoing in our labora-
tory.19a In that methodology, a pendent thionium moiety
functions as a suitable leaving group for intramolecular en-
amine cyclization to yield three-membered carbocycles.
With this in mind, we recognized that an analogous epoxi-
dation mechanism would rely on the judicious selection of
an ambiphilic oxygen source that could function as a viable
nucleophile for the conjugate addition step, yet would be
suitably electrophilic (via incorporation of an electronega-
tive leaving group (LG)) to enable intramolecular enamine
oxidation and oxirane formation.
2. Results and discussion
In 2002, we initiated studies to develop a novel organocata-
lytic strategy for the asymmetric epoxidation of electron-
deficient olefins based upon the activation principle of
iminium catalysis. Having demonstrated the capacity of chi-
ral amines to function as asymmetric catalysts and building
on previous successes in cycloadditions and 1,4-conjugate
additions,19 it was anticipated that a nucleophilic oxygen
that incorporated a suitable leaving group could add with
enantiofacial selectivity to an iminium-activated a,b-unsatu-
rated aldehyde (Fig. 2). Subsequent enamine formation
followed by intramolecular trapping of the pendent electro-
philic oxygen with concomitant expulsion of the oxygen-
tethered leaving group should then produce an oxirane
(Fig. 3). At the outset of these studies, we felt that the pro-
posed cyclization step had good precedent given related
2.1. Preliminary investigations
Our studies began with an investigation to define potential
oxygen sources that would participate in the requisite 1,4-
heteroconjugate addition/enamine cyclization. Initial exper-
iments were performed with crotonaldehyde and a variety of
commercially available oxidants in the presence of catalyst
1$trifluoroacetic acid (TFA) salt. To our delight, the desired
2,3-epoxyaldehyde product (2) was readily accessed using
a variety of oxygen sources (Table 1). Implementation of
m-CPBA provided the epoxide product 2 with encouraging
selectivity levels (Table 1, entry 3, 73% ee); however, studies
to define the utility of this reagent (solvent, temperature) re-
sulted in little improvement in overall enantiocontrol. The
use of peroxides, such as tert-butyl hydrogen peroxide and
hydrogen peroxide20 also provided the desired oxirane
with notable enantioselectivities (Table 1, entries 4 and 5).
However, attempts to employ such oxidants with less reac-
tive substrates (such as cinnamaldehyde) resulted mainly
in the production of the catalyst N-oxide derivative, a catalyst
depletion pathway that significantly reduces reaction effi-
ciency. Unfortunately, bleach and pyridine N-oxide were
not found to be viable reagents for this process (Table 1,
entry 6).
O
Me
N
X
Me
Me
N
Ph
Me
X
Si-face
blocked
Re-face
exposed
R
catalyst-aldehyde
iminium complex
O
LG
We next examined the use of hypervalent l3-iodanes as
potential oxidants for this organocatalytic Weitz–Scheffer
reaction. While iodosobenzene is routinely employed as an
oxygen transfer agent in metal-oxo mediated epoxidations,21
Figure 2. Rationale of catalyst-controlled enantioselectivity utilizing an
MM3-2 model of the catalyst.
Me
Me
O
•HX
O
N
Table 1. Initial survey of oxygen sources for epoxidation
20 mol% 1•TFA
Me
Me
O
O
Me
Me
N
H
O
oxidant (1 eq)
Ph
H2O
H2O
Me
Me
O
O
catatyst 1
CH2Cl2 (0.2 M)
18 h, –30 °C
(3 equiv)
2
Me
Me
O
Me
Me
O
N
N
X
X
Entry
Oxidant
% Conversiona
% eeb
Me
Me
Me
Me
N
N
1
2
3
4
5
6
7
Pyridine N-oxide
OXONEÒ
m-CPBA
NR
NR
34
35
9
—
—
73
69
59
0
Ph
Ph
R
O
R
iminium
t-BuOOHc
Me
N
O
d
H2O2
NaOCle
PhI]O
9
43
Me
Me
N
72
LG
Ph
Me
O
LG
LG
a
O
enamine
Conversion determined by GC relative to methyl benzyl ether.
b
c
d
e
Enantiomeric excess determined by chiral GC analysis (Chiraldex G-TA).
Used as 5 M solution in decane.
Used as a 50% solution in water.
R
Figure 3. Proposed organocatalytic cycle for oxirane formation and the
generation of an a,b-epoxy aldehyde.
Used as a 5.25% solution in water.

S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
11415
Table 2. Effect of solvent on the epoxidation reaction
Table 3. Effect of acid co-catalyst on the epoxidation reaction
20 mol% 1•TFA
20 mol% 1•TFA
O
O
PhI=O (1 eq)
PhI=O (1 eq)
Me
Me
Me
Me
O
O
O
O
solvent (0.2 M)
20 h, –30 °C
CH2Cl2 (0.2 M)
18 h, –30 °C
(3 equiv)
2
(3 equiv)
2
% Conversiona
% eeb
Entry
Solvent
3a
% Conversionb
% eec
Entry
HX
pKa
1
2
3
4
5
6
7
8
9
DMF (10% H2O)
MeCN
Acetone
CH2Cl2
THF
THF (10% H2O)
CHCl3
Ether
—
36.6
21.0
8.9
7.5
—
4.8
4.3
2.4
87
55
41
50
14
12
45
29
63
25
33
42
80
76
75
82
63
64
1
2
3
4
5
6
TfOH
HClO4
p-TSAc
TFA
ꢀ14
ꢀ10
ꢀ2.6
ꢀ0.3
1.3
74
68
50
42
27
27
87
88
76
72
72
69
DCAd
CNAe
2.5
a
Conversion determined by GC relative to benzyl ether.
Enantiomeric excess determined by chiral GC analysis (Chiraldex G-TA).
p-Toluenesulfonic acid.
Dichloroacetic acid.
Cyanoacetic acid.
b
c
d
e
Toluene
a
See Ref. 38.
Conversion determined by GC relative to tridecane.
Enantiomeric excess determined by chiral GC analysis (Chiraldex G-TA).
b
c
pathway to kinetically out-compete the non-catalyzed (race-
mic) process.
its oxidative properties generally derive from the electro-
philic character of the hypervalent iodine. However, there
are a few reported cases in which iodosobenzene has been
found to possess sufficient ylide character to participate in
nucleophilic addition via the oxygen center.22 Given the
remarkable lability of the phenyliodonio moiety (w106 times
better leaving group than triflate),21 we postulated that
the use of hypervalent l3-iodanes might enable a rapid
ring closure from the electrophilic character of the hyperva-
lent iodine and thereby minimize the intervention of a
reversible oxo-conjugate addition (an equilibrium process
that would diminish kinetic enantiocontrol). Moreover, we
presumed that the oxidation byproduct, iodobenzene, would
have no deleterious impact on the organocatalytic cycle
(Fig. 3).
The influence of temperature on this epoxidation protocol
was next investigated (Table 4). As expected on the basis
of Boltzman distributions, a significant improvement in
enantioselectivity was realized by lowering the reaction tem-
perature. More surprising, however, was the accompanying
increase in reaction efficiency with the same temperature
trend. Subsequent studies (vide infra) have revealed that
lower temperatures are essential to avoid detrimental reac-
tion pathways such as catalyst oxidation and substrate
decomposition.
Having established what we believed to be the optimal oxida-
tion conditions, we next examined the scope of the olefin
component in this organocatalytic oxirane formation. As re-
vealed in Table 5, a,b-unsaturated aldehydes that incorporate
alkyl group substituents are susceptible to iodosobenzene
epoxidation with good efficiency and enantioselectivities
(entries 1–3, 80–93% ee). To our disappointment, however,
substrates that form more stabilized iminium species with
catalyst 1 (such as cinnamaldehyde, entry 4) demonstrated
diminished conversion and lower levels of asymmetric
induction. At this juncture we hypothesized that a catalytic
cycle wherein the 1,4-oxygen addition step is rate determin-
ing would be consistent with these findings. Moreover, we
rationalized that implementation of a more nucleophilic
iodosobenzene source should therefore provide an increase
Indeed, exposure of crotonaldehyde to iodosobenzene in the
presence of catalyst 1$TFA provided epoxide 2 with encour-
aging levels of enantiocontrol (Table 1, entry 7, 72% ee). A
survey of reaction media (Table 2) revealed that high dielec-
tric solvents typically enabled superior efficiencies while
lower dielectric systems provided higher asymmetric induc-
tion. Balancing this apparent dichotomy, CH2Cl2 and CHCl3
demonstrated useful efficiencies while maintaining optimal
enantioselectivity (Table 2, entries 4 and 7, 80–82% ee).
On this basis, we selected halogenated media for further
exploratory studies.
The impact of the Brønsted acid co-catalyst component on
this organocatalytic epoxidation was next examined. As
revealed in Table 3, an apparent correlation was observed
between reaction conversion/enantiocontrol and the pKa of
the acid co-catalyst. More specifically, stronger acids, such
as TfOH and HClO4, provided the epoxide adduct with use-
ful selectivities and yields (entries 1 and 2, pKa ꢀ10 to ꢀ14,
87–88% ee), while acids with higher pKa rendered poor con-
versions (entries 5 and 6, pKa 1.3–2.5, 27% conversion). This
trend can be rationalized on the basis that the stronger acid
co-catalyst enables a higher equilibrium content of the cata-
lyst–substrate iminium adduct thereby increasing the rate of
addition–cyclization sequence.23 Moreover, the observed
enantioselectivity is likely to track reaction efficiency given
the traditional requirements for the catalyst-controlled
Table 4. Effect of temperature on reaction efficiency and selectivities
20 mol% 1•TfOH
O
PhI=O (1 eq)
Me
Me
O
O
CH2Cl2 (0.2 M)
T (°C)
2
Entry
T (ꢁC)
Time (h)
% Conversiona
% eeb
1
2
3
4
ꢀ20
ꢀ30
ꢀ40
ꢀ50
18
20
15
15
49
74
98
100
83
87
89
93
a
Conversion determined by GC relative to benzyl ether.
Enantiomeric excess determined by chiral GC analysis (Chiraldex G-TA).
b

11416
S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
Table 5. Organocatalytic epoxidations with iodosobenzene: initial studies
2.2. Secondary investigation: alternative iodosobenzene
sources and the internal syringe pump effect
20 mol% 1•TfOH
O
ArI=O (1 eq)
R
R
O
O
We next examined a range of hypervalent l3-iodane sources
that we expected would slowly release iodosobenzene
monomer when subjected to water or mild acid (Table 6).
These studies were specifically performed with cinnamalde-
hyde with the anticipation that we might see an improvement
in enantioselectivity with this substrate in comparison to
analogous experiment with PhI]O (Table 5, entry 4, 73%
ee). As revealed in Table 6, the use of commercially available
diacetoxy iodosobenzene in the presence of water did indeed
provide the desired epoxide with enhanced levels of enantio-
control (entry 1, 84% ee); however, bis(trifluoroacetoxy)
iodosobenzene and Koser’s salt provided the oxirane 3 with
poor efficiency (entries 2 and 3, 7–10% yield). Given that
hypervalent I–N systems have been established to be less
stable than the corresponding I–O class, we next examined
the use of iminoiodanes as potential iodosobenzene surro-
gates in the presence of water or acid. To our great delight,
exposure of cinnamaldehyde to [(nosylimino)iodo]benzene
(NsNIPh) in the presence of catalyst 1 and 1 M acetic acid
did indeed furnish epoxide 3 with excellent levels of conver-
sion and enantiocontrol (entry 4, 100% conversion, 92% ee).
It is noteworthy that arylsulfonylimino(aryl)iodanes are
stable, easily storable compounds21 that we have determined
will function as controlled release iodosobenzene oxidants in
the presence of acid or water (vide infra).
T (°C)
Entry
R
ArI]O
T (ꢁC) Time (h) % Yield % eea
1
2
3
4
5
6
Meb
n-Prb
i-Prc
PhI]O
PhI]O
PhI]O
PhI]O
PhI]O
ꢀ50
ꢀ50
ꢀ40
ꢀ40
ꢀ50
10
15
15
15
15
15
100d
93e
86e
78f
45
93
88
80
73
85
85
Phc
CO2Me
n-Prb
p-MePhI]O ꢀ40
21
a
Enantiomeric excesses were determined by chiral GC analysis (Chiraldex
G-TA).
Three equivalents of starting aldehyde in CH2Cl2 (0.075 M).
One equivalent of aldehyde in CHCl3 (0.25 M).
Yield based on NMR analysis using benzyl ether as a standard.
Yield based on isolation of corresponding epoxy alcohol.
Stereochemical determination via correlation to literature, see Section 3.
b
c
d
e
f
in both reaction rate and enantioselectivity. To this end, p-Me
iodosobenzene24 was prepared and employed in an analo-
gous epoxidation protocol (Table 5). Surprisingly, this
more nucleophilic oxidant provided lower levels of reaction
efficiency (Table 5, entry 5, 21% yield) in comparison to the
less nucleophilic iodosobenzene (Table 5, entry 2, 93%
1
yield). A subsequent H NMR investigation has revealed
that p-Me iodosobenzene rapidly participates in imidazolidi-
none oxidation, a catalyst depletion pathway that has a dra-
matic impact on overall catalyst efficiency and conversion
(Fig. 4, Ar¼p-MePh).25 Intriguingly, 1H NMR studies have
also revealed that a slower variant of the same catalyst de-
composition pathway is observed using iodosobenzene as
the reaction oxidant (Fig. 4, Ar¼Ph). At this stage, we pre-
sumed that the diminished enantioselectivities observed in
the cinnamaldehyde epoxidation case (Table 5, entry 4) could
be attributed to the intervention of a catalyst oxidation path-
way that is competitivewith the iminium-catalyzed addition–
cyclization step. With respect to the relative capacities of
iodosobenzene and p-Me iodosobenzene to function as
catalyst oxidants, we have determined that the tolyl-derived
system is more soluble in halogenated solvents than its
polymeric phenyl iodide counterpart. As a result, the relative
concentration of p-Me iodosobenzene in solution was found
to be much higher, a scenario that dramatically increases the
rate of catalyst oxidation and leads to greatly diminished
conversions with this iodane. On this basis, we began to focus
upon identifying alternative sources of hypervalent iodane,
which could be employed to slowly generate reactive iodoso-
benzene monomerinsitu, and indoing sofunctionasatypeof
‘internal syringe pump’. In this manner, we hoped the imid-
azolidinone would partition exclusively towards iminium
formation with the aldehyde substrate, thereby avoiding
catalyst oxidation and depletion.
2.3. Epoxidation substrate scope
Having established the optimal oxidation conditions for
epoxide formation, we next examined the scope of the
a,b-unsaturated aldehyde component in this organocatalytic
transformation. As revealed in Table 7, a variety of enal ole-
fins can be successfully utilized with both high stereoselec-
tivity and efficiency in the presence of NsNIPh. For example,
Table 6. Alternative iodosobenzene sources
20 mol% 1•HClO4
O
oxidant (1.5 eq)
O
O
CHCl3 (0.25 M)
–30 °C
(1 equiv)
3
Entry
1
Oxidant
Additive
Water
% Conversiona % eeb
OAc
I
OAc
68
10
7
84
71
76
OCOCF3
2
I
I
Water
Water
OCOCF3
OH
3c
OTs
Me
Me
O
O
oxidized
catalyst
species
N
N
•TfOH
Bn
ArI=O
CD2Cl2 (0.075M)
10 h, –30 °C
N
Ns
t-
t-
Bu
Bu
4
I
Bn
N
H
N
H
Water
71
80
92
1 M AcOH
100
Ar = Ph, 99%
Ar = p-MePh, 47%
Ar = Ph, 1%
Ar = p-MePh, 53%
1
Conversion determined by 1H NMR analysis using MeOBn as a standard.
Enantiomeric excess determined by chiral GC analysis (Chiraldex G-TA).
Koser’s salt ¼ [(hydroxy)(tosyloxy)iodo]benzene.
a
b
c
Figure 4. Mode of catalyst degradation when utilizing PhI]O and
p-MePhI]O as the reagent in the epoxidation reaction.

S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
11417
Table 7. Enantioselective organocatalytic epoxidation: scopea
2.4.1. 1H NMR studies on the controlled release of mono-
meric iodosobenzene from NsNIPh. A low temperature 1H
NMR study (ꢀ30 ꢁC) was performed to investigate the con-
version of NsNIPh to monomeric iodosobenzene in the pres-
ence of deuterated chloroform and 1 M acetic acid (AcOD).
As revealed in Figure 5, the sulfonamide (NsNIPh) does in-
deed undergo slow hydrolysis to provide a steady increase in
the concentration of monomeric iodosobenzene over the
course of 6 h. It is important to note that diacetoxy iodoso-
benzene (5%) and hemi-hydrolyzed nosyliodosobenzene
(1%) were also present in the reaction solution.26 In contrast,
20 mol% 1•HClO4
O
NsNIPh (1.5 eq)
R
O
R
O
CH2Cl2-AcOH (0.15 M)
–30 °C
(1 equiv)
Entry
R
Time (h)
% Yield
88c
% eeb
93
1
2
Me
10
15
72
88
Me
3
4
13
16
77
92
92
1
when the analogous H NMR experiment was performed
with oligomeric iodosobenzene, we observed the immediate
formation of a relatively high concentration of iodosobenz-
ene monomer (38%) that remained constant over the course
of this 6-h study. Again, diacetoxy iodosobenzene (2%) was
detected in this experiment. These NMR studies clearly
demonstrate that the proposed slow release of monomeric
iodosobenzene from NsNIPh (‘internal syringe pump’
effect) is not only feasible, but likely operational.
95d
3
5
6
BzO
15
11
89e
86
85
87
BOC
N
7
8
9
12
12
6
86
90
92
97
MeO2C
2.4.2. 15N NMR studies on catalyst depletion as a function
of oxidant concentration. To investigate the role of mono-
meric iodosobenzene concentration on catalyst depletion
(via a variety of presumed amine oxidation pathways), we
next turned to 15N NMR studies. In this context, we first in-
vestigated the use of 15N isotopically labeled imidazolidi-
none 4 as a catalyst for the epoxidation of cinnamaldehyde
using (a) oligomeric iodosobenzene and (b) NsNIPh as the
respective reaction oxidants. It should be noted that in
both cases, reaction efficiencies and enantioselectivities
were observed that were within experimental error of the
corresponding results observed with catalyst having natural
abundance nitrogen. With respect to catalyst depletion, we
observed striking differences in both the rate and nature
of imidazolidinone decomposition as a function of these
two oxidants and presumably, therefore, the corresponding
iodosobenzene monomer concentration. As illustrated in
92d
89d
O2N
Br
10
8
93d
93
a
Products are single diastereomers, except in entry 1 (dr¼1:7).
Enantiomeric excess determined by chiral GC and SFC analysis.
Yield determined by NMR analysis.
CHCl3 was used as solvent.
Iodosobenzene was used as the oxidant at ꢀ40 ꢁC.
b
c
d
e
the use of the previously problematic cinnamaldehyde sys-
tem now provides the corresponding epoxide in 92% yield
and 92% ee (entry 8). Moreover, electronic variation of the
aryl ring substituents of this cinnamate system is well toler-
ated (entries 9 and 10, 89–92% yield, 92–97% ee). A variety
of olefin components that incorporate alkyl substituents of
varying steric demand can also be implemented (entries 1–3,
72–88% yield, 88–93% ee). It is important to note that
functionalities that are often susceptible to oxidation (e.g.,
electron-deficient amines, electron-rich olefins) are compat-
ible with NsNIPh, demonstrating its utility as a mild
ambiphilic oxygen source (entries 4 and 6, 86–95% yield,
87–92% ee). It should also be noted that enals that incorpo-
rate electron-withdrawing groups (e.g., R¼CO2Me) do not
provide the desired epoxide under these conditions. This
issue was resolved by utilizing iodosobenzene as the oxidant
as demonstrated in Table 5, entry 5.
2.4. Mechanistic studies
In an attempt to gain further insight into the inherent advan-
tages of using NsNIPh in comparison to iodosobenzene
in this organocatalytic epoxidation, various NMR studies
were undertaken to examine (a) the controlled release of mo-
nomeric iodosobenzene from NsNIPh and (b) the subsequent
effect of the monomeric iodosobenzene concentration on the
rate of imidazolidinone catalyst oxidation.
Figure 5. The solution content of monomeric iodosobenzene (PhIO) versus
time as a function of iodane source.

11418
S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
Me
Me
O
O
Me
O
and only imine adduct 5 is formed in observable quantities
after 6 h (Fig. 7d). Notably, significant quantities of the
active catalyst 4 remain after 6 h when NsNIPh is employed,
highlighting that the ‘internal syringe pump’ concept is
critical to achieving useful levels of catalyst efficiency
within this epoxidation protocol.
N
N
N
HO
t-Bu
t-Bu
t-Bu
15N
15N
H
15N
H
Bn
Bn
Bn
PhI=O
5
6
7
CDCl3-1M AcOD
–30 °C, 6 h
26%
18%
31%
Me
O
Me
O
In summary, we have further established iminium catalysis
as a valuable strategy for asymmetric synthesis in the context
of an enantioselective enal epoxidation protocol. This new
organocatalytic reaction allows for the enantioselective for-
mation of oxiranes from a wide array of electronically and
sterically diverse a,b-unsaturated aldehydes. Fundamental
to these studies has been the recognition that hypervalent
iodine reagents are suitable oxidants for organocatalytic
Weitz–Scheffer epoxidations using imidazolidinone catalyst
1. Optimal levels of reaction efficiency and enantiocontrol
have been accomplished using an ‘internal syringe pump’
protocol wherein the controlled release of monomeric
iodosobenzene from an in situ iminoiodinane source is
accomplished using a mild acid. NMR studies (15N) have
revealed that this slow, in situ production of monomeric
iodosobenzene from NsNIPh is central to alleviating losses
in catalytic efficiency arising from a variety of imidazolidi-
none oxidation pathways.
N
N
NsN=IPh
•HClO4
Bn
6 + 7
0%
CDCl3-1M AcOD
–30 °C, 6 h
t-Bu
t-Bu
Bn
15N
15N
H
4
5
58%
Figure 6. Mode of catalyst degradation when utilizing iodosobenzene or
NsNIPh in the epoxidation of cinnamaldehyde as observed by 15N NMR.
Figure 6, the use of oligomeric iodosobenzene leads to the
formation of three catalyst-derived amines over the course
of the reaction, namely imine 5, aminol 6, and the corre-
sponding trans catalyst isomer 7. In contrast, the analogous
reaction that employs NsNIPh leads only to the formation of
the corresponding imine 5 (Fig. 7). It should be noted that
isolation and separate resubjection of catalyst derivatives
5, 6, and 7 to the outlined epoxidation conditions have con-
firmed that each of these amine species is catalytically inac-
tive. More important, however, is that the rate of catalyst
consumption appears to be a function of the source of mono-
meric iodosobenzene. As revealed in Figure 7, real time 15N
NMR studies performed on a low temperature epoxidation
reaction with oligomeric iodosobenzene clearly demon-
strates that the formation of imine 5 occurs within the first
20 min of the reaction protocol (Fig. 7a). Moreover, after
6 h there is almost complete conversion of the catalyst to
amine derivatives 5, 6, and 7 (Fig. 7b). In contrast, the use
of the slow release oxidant NsNIPh results in almost no for-
mation of catalyst oxidation products after 20 min (Fig. 7c),
3. Experimental
3.1. General
Commercial reagents were purified prior to use following
the guidelines of Perrin and Armarego.27 Iodosobenzene
reagents were synthesized and iodometrically titrated for
purity prior to use.28 All non-aqueous solvents were purified
according to the method of Grubbs29 and were transferred
Me
O
Me
O
(a)
(c)
N
N
t-
t-
15N
15N
Bu
Bu
Bn
Bn
H
H
4
Me
O
Me
O
4
N
N
t-
t-
Bu
Bu
15N
15N
Bn
Bn
5
5
Me
O
(b)
(d)
Me
O
cis
trans
catalyst
N
N
catalyst
t-
t-
Me
O
Bu
15N
Bn
Me
Bu
15N
Bn
N
O
Me
O
5
5
N
t-
N
15N
HO
Bu
Bn
H
15N
t-
t-
Bn
Bu
15N
H
Bu
Bn
H
7
6
4
Figure 7. Catalyst degradation products during epoxidations mediated by iodosobenzene (a, c) and NsNIPh (b, d), as observed by 15N NMR.

S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
11419
under nitrogen via syringe or cannula. Organic solutions
were concentrated under reduced pressure on a B€uchi rotary
evaporator using an ice-water bath for volatile compounds.
Chromatographic purification of products was accomplished
using force-flow chromatography on ICN 60 32–64 mesh sil-
ica gel 63 according to the method of Still30 and where noted,
Iatrobeads 6RS-8060 was used in place of silica gel. Thin-
layer chromatography (TLC) was performed on EM Re-
agents 0.25 mm silica gel 60-F plates. Visualization of the
developed chromatogram was performed by fluorescence
extracted with Et2O (2ꢂ4 mL). The organic layer was then
dried over Na2SO4 and concentrated in vacuo and the result-
ing residue was purified by column chromatography (sol-
vents noted) to provide the title compounds.
3.3. Synthesis and characterization
3.3.1. 15N-labeled (2R,5R)-2-tert-butyl-5-benzyl-3-
methylimidazolidin-4-one (4). To a three-necked 100 mL
round-bottom flask equipped with a reflux condenser and
magnetic stirrer were added L-phenylalanine (98% 15N-
labeled, 3.0 g, 18.05 mmol) and methanol (36 mL) under an
Ar atmosphere. Thionyl chloride (3.3 mL, 45.1 mmol) was
then added dropwise at which time the reaction mixture be-
came homogenous with exotherm and evolution of gas. The
resulting solution was then refluxed for 12 h and then cooled
to room temperature and partitioned with aqueous NaHCO3
(30 mL) and EtOAc (2ꢂ30 mL). The separated organic
layers were combined, dried over Na2SO4, and concentrated
in vacuo. The resulting residue was purified on a short plug
of silica gel and washed with EtOAc (20 mL) to yield 15N-
labeled (R)-methyl 2-amino-3-phenylpropanoate as a clear
oil (3.22 g, quantitative yield).
1
quenching, anisaldehyde, KMnO4 or ninhydrin stain. H
and 13C NMR spectra were recorded on a Mercury 300
(300 MHz or 75 MHz) or an Inova 500 (500 MHz and
125 MHz) as noted, and are internally referenced to residual
1
protio solvent signals. Data for H NMR are reported as
follows: chemical shift (d ppm), multiplicity (s ¼ singlet, d ¼
doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), integration,
coupling constant (hertz), and assignment. Data for 13C NMR
are reported in terms of chemical shift. 15N NMR spectra
were externally referenced to 7 M nitromethane in deuterated
chloroform and are reported in terms of chemical shift. IR
spectra were recorded on a Perkin–Elmer Paragon 1000 spec-
trometer and are reported in terms of frequency of absorption
(cmꢀ1). Mass spectra were obtained from the California
Institute of Technology Mass Spectral facility. Gas liquid
chromatography (GLC) was performed on Hewlett–Packard
6850 and 6890 Series gas chromatographs equipped with
split-mode capillary injection system and flame ionization
detectors using Bodman Chiraldex G-TA and Varian Chirasil-
Dex-CB (30 mꢂ0.25 mm) columns. Supercritical fluid chro-
matography (SFC) was performed on a Berger Minigram
equipped with a variable-wavelength UV detector using
a Chiralpak AD-H column (25 cm) and AD guard (5 cm).
To the resulting methyl ester (3.22 g, 18.05 mmol) was
added methylamine (8 M in EtOH, 10 mL) and the resulting
solution was stirred at room temperature for 12 h under an
Ar atmosphere. The reaction was then diluted with 0.5 M
aqueous HCl (20 mL) and partitioned by EtOAc (2ꢂ
20 mL). The separated organic layers were combined, dried
over Na2SO4, and concentrated in vacuo to give 15N-
labeled (R)-2-amino-N-methyl-3-phenylpropanamide as a
clear oil (3.22 g, quantitative yield).
3.2. General epoxidation procedures
To a dry, three-necked 100 mL round-bottom flask equip-
ped with a reflux condenser, Dean–Stark trap, and magnetic
stir bar was added FeCl3 (586 mg, 3.61 mmol) under an N2
atmosphere. A solution of the amide (3.22 g, 18.05 mmol)
and pivaldehyde (2.10 mL, 18.05 mmol) in toluene
(36 mL) was added by cannula addition to the flask contain-
ing FeCl3. The reaction was refluxed for 12 h under an Ar
atmosphere and cooled to room temperature before diluting
with brine (50 mL) and partitioning with EtOAc
(2ꢂ30 mL). The separated organic layers were combined,
dried over Na2SO4, and concentrated in vacuo to give
3.2.1. General epoxidation procedure A (using PhIO).
A solution of the trifluoromethanesulfonic acid salt of
(2R,5R)-2-tert-butyl-5-benzyl-3-methylimidazolidin-4-one
(0.2 equiv) in dichloromethane (0.075 M) was prepared in
a scintillation vial equipped with a magnetic stir bar at
ꢀ50 or ꢀ40 ꢁC (as noted) and stirred for 10 min. The alde-
hyde (3.0 equiv) and iodosobenzene (1.0 equiv) were then
added to form a light yellow suspension and the reaction
mixture was stirred at constant temperature for 10–15 h until
no further conversion was observed as determined by TLC
analysis. The cold solution was then filtered through Celite,
washed with ether, and concentrated in vacuo. The resulting
residue was purified by column chromatography (solvents
noted) to provide the title compounds.
1
a brown oil. H NMR shows a cis:trans ratio of 1.2:1.0.
The desired cis-isomer was purified from the trans-isomer
by flash chromatography (silica gel, 50% EtOAc in hex-
anes) to yield the title compound as a yellow crystalline
solid (2.13 g, 48% yield). IR (film) 3338, 2958, 1700,
1395, 1101, 700 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
3.2.2. General epoxidation procedure B (using NsNIPh).
A scintillation vial equipped with a magnetic stir bar was
charged with perchloric acid (70 wt %, 0.2 equiv), dichloro-
methane, and 20 vol % of 1 M AcOH (0.15 M), and
(2R,5R)-2-tert-butyl-5-benzyl-3-methylimidazolidin-4-one
(0.2 equiv) and allowed to stir for 10 min at ꢀ30 ꢁC.
The aldehyde (1.0 equiv) and [(nosylimino)iodo]benzene
(1.5 equiv) were then added to form a light yellow suspen-
sion in an icy solution, which was stirred at constant temper-
ature for 6–16 h until complete consumption of the starting
material was observed. The resulting solution was then
treated with pH 7 buffer, filtered through Celite, and
d 7.32–7.22 (m, 5H, aryl H), 4.07 (s, 1H, N,N-acetal H),
3.72–3.71 (br m, 1H, a-amino H), 3.17 (dt, 1H, J¼3.8,
13.5 Hz, benzyl H), 2.95 (ddd, 1H, J¼2.5, 8.0, 13.5 Hz,
benzyl H), 2.30 (s, 3H, N-CH3), 1.76 (br s, 1H, NH),
0.85 (s, 3H, C(CH3)3); 13C NMR (125 MHz, CDCl3)
d 175.46, 142.90, 138.06, 129.78, 128.76, 126.82, 82.65
15NꢀC
15NꢀC
(d, J
¼3:02 Hz), 59.58 (d, J
¼3:64 Hz), 38.43 (d,
15NꢀC
15NꢀC
15NꢀC
J
J
¼2:39 Hz), 35.19 (d, J
¼1:76 Hz), 25.51 (d,
¼1:13 Hz); 15N NMR (50 MHz, CDCl3) d ꢀ337.08;
15N NMR (50 MHz, CDCl3–1 M AcOH) for the HClO4
salt of the title compound, d ꢀ336.35; HRMS (FAB+) exact
mass calculated for [M]+ (C15H22N15NO) requires m/z

11420
S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
247.1703, found m/z 247.1726; [a]D ꢀ46.4 (c 1.10,
filtered and washed with cold ether and dried under reduced
pressure to yield the title compound as a white solid (18 mg,
24% yield). IR (KBr) 2961, 1780, 1657, 1495, 1253,
CHCl3).
3.3.2. 15N-labeled (2S,5R)-2-tert-butyl-5-benzyl-3-methyl-
imidazolidin-4-one (8). The title compound was prepared
and isolated from the procedure for 15N-labeled (2R,5R)-2-
tert-butyl-5-benzyl-3-methylimidazolidin-4-one as a yellow
crystalline solid (1.57 g, 35% yield). IR (film) 3306, 2953,
706 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.35–7.23 (m,
1
5H, aryl H), 4.79 (dd, 1H, J¼3.0, 5.4 Hz, a-amino H),
4.00 (dd, 1H, J¼5.4, 13.8 Hz, benzyl H), 3.35 (dd, 1H,
J¼3.0, 13.5 Hz, benzyl H), 3.09 (s, 3H, N-CH3), 1.29 (s,
9H, C(CH3)3); 13C NMR (125 MHz, CDCl3) d 178.98,
175.16, 132.28, 130.27, 129.19, 128.59, 128.17, 61.05,
35.91, 35.86, 29.10, 28.54, 26.62; HRMS (FAB+) exact
mass calculated for [M+H]+ (C15H21N2O2) requires m/z
261.1603, found m/z 261.1605; [a]D +4.2 (c 1.24, CHCl3).
1
1684, 1394, 1096, 700 cmꢀ1; H NMR (300 MHz, CDCl3)
d 7.33–7.22 (m, 5H, aryl H), 3.85–3.83 (br m, 1H, a-amino
H), 3.81 (t, 1H, J¼1.5 Hz, N,N-acetal H), 3.11 (dt, 1H,
J¼3.6, 14.1 Hz, benzyl H), 2.89 (ddd, 1H, J¼2.7, 6.9,
14.1 Hz, benzyl H), 2.89 (s, 3H, N-CH3), 1.86 (br s, 1H,
NH), 0.90 (s, 3H, C(CH3)3); 13C NMR (75 MHz, CDCl3)
d 175.53, 137.68, 129.70, 128.74, 126.89, 83.62 (d,
The title compound was also synthesized using 15N-labeled
(2R,5R)-2-tert-butyl-5-benzyl-3-methylimidazolidin-4-one
using the above procedure. 15N NMR (50 MHz, CDCl3–1 M
AcOD) d ꢀ134.06.
15NꢀC
15NꢀC
J
¼3:02 Hz), 59.71 (d,
J
¼4:08 Hz), 38.77,
37.93, 31.54, 25.57; 15N NMR (50 MHz, CDCl3)
d ꢀ337.68; HRMS (FAB+) exact mass calculated for
[M+H]+ (C15H23N15NO) requires m/z 248.1781, found m/z
247.1790; [a]D ꢀ60.0 (c 1.13, CHCl3).
3.3.5. (2R,3S)-3-Methyloxirane-2-carbaldehyde (2). Pre-
pared according to general epoxidation procedure A using
crotonaldehyde (296 mL, 3.57 mmol) in CD2Cl2 at ꢀ50 ꢁC
with benzyl ether as an internal standard to establish NMR
yield. After filtration through silica gel, the title compound
was obtained in a 100% NMR yield and 93% ee.
3.3.3. (R)-2-tert-Butyl-4-benzyl-1-methyl-1H-imidazol-
5(4H)-one (6). A scintillation vial equipped with a stir
bar was charged with dichloromethane (5 mL), iodobenzene
˚
diacetate (403 mg, 1.25 mmol), and activated 3 A molecular
sieves (500 mg). After stirring for 10 min, (2R,5R)-2-
tert-butyl-5-benzyl-3-methylimidazolidin-4-one (61.6 mg,
0.25 mmol) was added to the vial and the reaction was stirred
for 3 h at room temperature. The reaction was filtered
through Celite, concentrated in vacuo, and purified by flash
chromatography (Iatrobeads, 50% Et2O in pentanes) to yield
the title compound as a clear oil (51.9 mg, 85% yield). It
should be noted that the crude reaction (as observed by
NMR) initially produces the acetate addition product of the
imine, which upon work-up and purification causes elimina-
tion of the acetate to yield the imine product. IR (film) 2961,
Also prepared according to general epoxidation procedure B
with crotonaldehyde (296 mL, 3.57 mmol) in CD2Cl2 and
mesitylene as an internal standard to establish NMR yield.
After filtration through silica gel, the title compound was
obtained in an 88% NMR yield and 93% ee. Material for
characterization was obtained by flash chromatography
(Iatrobeads, 20% Et2O in pentanes). IR (film) 3416, 2965,
1
2929, 1443, 1380, 1124, 871 cmꢀ1; H NMR (300 MHz,
CDCl3) d 9.00 (d, 1H, J¼6.0 Hz, CHO), 3.30 (qd, 1H,
J¼2.1, 5.1 Hz, CH oxirane), 3.08 (dd, 1H, J¼2.1, 6.3 Hz,
CH oxirane), 1.42 (d, 3H, J¼5.1 Hz, CH3); 13C NMR
(75 MHz, CDCl3) d 198.59, 60.23, 53.06, 17.06; HRMS
(EI+) exact mass calculated for [M]+ (C4H6O2) requires
m/z 86.03678, found m/z 86.03649; [a]D +47.9 (c 2.7,
CHCl3). The enantiomeric purity was determined on the al-
cohol product, which was prepared by an NaBH4 reduction,
and analyzed by GLC analysis using a Bodman G-TA col-
umn (40 ꢁC isotherm, 12 psi); (2R,3S) isomer tR¼57.1 min,
(2R,3S) isomer tR¼58.7 min.
1706, 1636, 1495, 1425, 1395, 1366, 1232, 701, 665 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 7.38–7.21 (m, 5H, aryl H),
4.73 (br s, 1H, a-imino H), 3.96 (dd, 1H, J¼1.5, 14.4 Hz,
benzyl H), 3.90 (d, 1H, J¼14.7 Hz, benzyl H), 3.07 (s, 1H,
N-CH3), 0.97 (s, 9H, C(CH3)3); 13C NMR (125 MHz,
CDCl3) d 169.12, 165.44, 135.72, 130.99, 129.58, 128.72,
126.98, 91.85, 36.76, 31.26, 26.34; HRMS (EI+) exact
mass calculated for [M]+ (C15H20N2O) requires m/z
244.1576, found m/z 244.1586; [a]D ꢀ76.3 (c 1.22, CHCl3).
3.3.6. (2R,3S)-3-Propyloxirane-2-carbaldehyde (Table 5,
entry 2 and Table 7, entry 2). Prepared according to general
epoxidation procedure A using (E)-hex-2-enal (591 mL,
5.09 mmol) at ꢀ50 ꢁC. After stirring for 15 h, this reaction
was filtered through silica, washed with dichloromethane
(30 mL), and cooled to 0 ꢁC. Reduction to the alcohol was
performed on the crude reaction solution by adding ethanol
(1 mL) and NaBH4 (770 mg, 20.4 mmol). The reaction was
quenched with a saturated solution of Rochelle’s salt
(30 mL) on completion as judged by TLC. The alcohol prod-
uct was extracted with dichloromethane (3ꢂ30 mL) and
concentrated in vacuo at 0 ꢁC, before purifying by flash
chromatography (silica gel, 50% Et2O in pentanes) to afford
the title compound as a clear, colorless oil in 93% yield
(182 mg, 1.57 mmol), 88% ee.
The title compound was also synthesized using 15N-labeled
(2R,5R)-2-tert-butyl-5-benzyl-3-methyl-imidazolidin-4-one
using the above procedure. 15N NMR (50 MHz, CDCl3–1 M
AcOD) d ꢀ42.2.
3.3.4. (5R)-2-tert-Butyl-5-benzyl-2-hydroxy-3-methyl-
imidazolidin-4-one HCl salt (7). A scintillation vial equip-
ped with a stir bar was charged with dichloromethane
(5 mL) and 1 M AcOH (1 mL), iodosobenzene (161 mg,
0.5 mmol), and (2R,5R)-2-tert-butyl-5-benzyl-3-methyl-
imidazolidin-4-one (61.6 mg, 0.25 mmol). The reaction
was stirred for 2 h at room temperature before filtration
and concentration in vacuo. Purification was by flash chro-
matography (silica gel, 40% EtOAc in hexanes) and the iso-
lated residue was dissolved in HCl (2 M in diethyl ether,
125 mL) and dichloromethane (12.5 mL) and cooled to
ꢀ70 ꢁC to facilitate precipitation. The precipitate was
Also prepared according to general epoxidation procedure B
using (E)-hex-2-enal (234 mL, 2.0 mmol) to afford the title

S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
11421
compound as a clear, colorless oil (162 mg, 72% yield, 88%
ee) after silica gel chromatography (silica gel, 30–70% Et2O
in pentanes, linear gradient). IR (film) 2962, 2935, 2875,
1731, 1671, 1534, 1458, 1378, 1350, 1125, 1092, 1044,
915.1, 737.5 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 9.01 (d,
1H, J¼6.3 Hz, CHO), 3.23 (td, 1H, J¼2.1, 5.1, 7.8 Hz, CH
oxirane), 3.13 (dd, 1H, J¼1.8, 6.3 Hz, CH oxirane), 1.69–
1.50 (m, 4H, CH2CH2), 0.98 (t, 3H, J¼7.2 Hz, CH3); 13C
NMR (75 MHz, CDCl3) d 198.8, 59.34, 56.83, 33.39,
19.39, 13.98; HRMS (EI+) exact mass calculated for
[MꢀH]+ (C6H9O2) requires m/z 113.0603, found m/z
113.0602; [a]D +11.4 (c 2.38, CHCl3). The enantiomeric pu-
rity was determined by GLC using a Bodman G-TA column
(70 ꢁC isotherm, 15 psi, flow¼1.3 mL/min); (2R,3S) isomer
tR¼8.87 min, (2S,3R) isomer tR¼9.79 min.
101.0240; [a]D +4.1 (c 0.75, CHCl3). The enantiomeric pu-
rity was determined by SFC using a Chiralpak AD-H column
(5–50% EtOH, linear gradient, 100 bar, 80 ꢁC oven,
flow¼4.0 mL/min); (2S,3S) isomer tR¼23.9 min, (2R,3R)
isomer tR¼27.0 min.
3.3.9. (2R,3S)-3-Cyclohexyloxirane-2-carbaldehyde
(Table 7, entry 3). Prepared according to general epoxida-
tion procedure
B
using 3-cyclohexylacrylaldehyde32
(147 mg, 1.06 mmol) to afford the title compound as a clear,
colorless oil (124 mg, 77% yield, 92% ee) after flash chro-
matography (silica gel, 20% Et2O in pentanes with 1%
1
Et3N). IR (film) 2928, 2853, 1730, 1450 cmꢀ1; H NMR
(300 MHz, CDCl3) d 8.98 (d, 1H, J¼6.0 Hz, CHO), 3.17
(dd, 1H, J¼1.8, 6.3 Hz, CH oxirane), 3.02 (dd, 1H, J¼2.1,
6.6 Hz, CH oxirane), 1.85–1.66 (m, 5H), 1.41–1.30 (m,
1H), 1.26–1.05 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 198.9, 61.05, 58.28, 39.51, 29.72, 28.91, 26.24, 25.68,
25.60; HRMS (EI+) exact mass calculated for [MꢀH]+
(C9H13O2) requires m/z 153.0916, found m/z 153.0910;
[a]D +75.6 (c 1.02, CHCl3). The enantiomeric purity was de-
termined by GLC using a Varian Chirasil-Dex-CB column
(80 ꢁC isotherm, 15 psi, flow¼1.0 mL/min); (2S,3R) isomer
tR¼42.07 min, (2R,3S) isomer tR¼46.87 min.
These data correlated with literature 1H and 13C NMR spec-
troscopic values for (2S, 3R)-3-propyloxirane-2-carbalde-
hyde.31
3.3.7. ((2R,3S)-3-Isopropyloxiran-2-yl)methanol (Table
5, entry 3). Prepared according to general epoxidation
procedure
A using (E)-4-methylpent-2-enal (592 mL,
5.09 mmol) and iodosobenzene (1.52 g, 6.92 mmol) in
dichloromethane (18.3 mL) at ꢀ40 ꢁC. After stirring for
15 h, this reaction was filtered through silica gel, washed
with dichloromethane (50 mL), and cooled to 0 ꢁC. Reduc-
tion to the alcohol was performed on the crude reaction
solution by adding ethanol (1 mL) and NaBH4 (770 mg,
20.4 mmol). The reaction was quenched with a saturated
solution of Rochelle’s salt (30 mL) on completion as judged
by TLC. The alcohol product was extracted with dichloro-
methane (3ꢂ30 mL) and concentrated invacuo at 0 ꢁC, before
purifying by flash chromatography (silica gel, 30–50% Et2O
in pentanes, linear gradient) to afford the title compound as
a clear, colorless oil in 86% yield (505 mg, 4.35 mmol), 80%
ee. IR (film) 2963, 2930, 1459, 1067, 895.1, 669.3 cmꢀ1; 1H
NMR (300 MHz, CDCl3) d 3.99 (ddd, 1H, J¼2.4, 5.7,
12.3 Hz, CHOH), 3.70 (ddd, 1H, J¼4.20, 7.20, 12.3 Hz,
CHOH), 3.02 (dt, 1H, J¼3.00, 3.90 Hz, CH oxirane), 2.81
(dd, 1H, J¼2.40, 6.90 Hz, CH oxirane), 1.70–1.59 (m, 1H,
CHMe2), 1.08 (d, 3H, J¼6.60 Hz, CH3), 1.02 (d, 3H,
J¼6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3) d 61.86,
61.14, 57.36, 30.07, 19.02, 18.37; HRMS (EI+) exact mass
calculated for [MꢀH]+ (C6H11O2) requires m/z 115.0759,
found m/z 115.0702; [a]D ꢀ14.0 (c 0.74, CHCl3). The enan-
tiomeric purity was determined by GLC analysis of the
crude aldehyde product (60 ꢁC isotherm, 12 psi); (2R,3S)
isomer tR¼12.8, (2S, 3R) isomer tR¼16.2 min.
1
This data correlated with literature H and 13C NMR spec-
troscopic values.31
3.3.10. (2R,3S)-3-(Pent-4-enyl)oxirane-2-carbaldehyde
(Table 7, entry 4). Prepared according to general epoxida-
tion procedure B using 3-(E)-octa-2,7-dienal33 (270 mg,
2.18 mol) to afford the title compound as a clear, colorless
oil (292 mg, 95% yield, 92% ee) after flash chromatography
(silica gel, 20% Et2O in pentanes). IR (film) 1729, 1440,
1148, 993.1, 914.4, 849.0 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 8.99 (d, 1H, J¼6.3 Hz, CHO), 5.82–5.69 (m,
1H, CH¼CH2), 5.04–4.94 (m, 2H, CH¼CH2), 3.11 (dd,
1H, J¼1.8, 6.3 Hz, CH oxirane), 3.23–3.19 (m, 1H, CH
oxirane), 2.10 (q, 2H, J¼6.9 Hz, CH2), 1.71–1.52 (m, 4H,
CH2CH2); 13C NMR (75 MHz, CDCl3) d 198.9, 61.05,
58.28, 39.51, 29.72, 28.91, 26.24, 25.68, 25.60; HRMS
(EI+) exact mass calculated for [MꢀH]+ (C8H11O2) requires
m/z 139.0760, found m/z 139.0759; [a]D +48.8 (c 1.10,
CHCl3). The enantiomeric purity was determined by GLC
using a Chirasil-DEX CB column (80 ꢁC isotherm, 15 psi,
flow¼1.0 mL/min); (2S,3R) isomer tR¼21.75 min, (2R,3S)
isomer tR¼22.27 min.
3.3.11. ((2R,3S)-3-Formyloxiran-2-yl)methyl benzoate
(Table 7, entry 5). Prepared according to general epoxida-
tion procedure A using (E)-3-formylallyl benzoate34
(104 mg, 0.55 mol) to afford the title compound as a clear,
colorless oil (101 mg, 89% yield, 85% ee) after flash chro-
matography (silica gel, 20% EtOAc in hexanes). IR (film)
3.3.8. (2R,3R)-Methyl 3-formyloxirane-2-carboxylate
(Table 5, entry 5). Prepared according to general epoxida-
tion procedure A using 1 equiv of (E)-methyl 3-formylacry-
late (250 mg, 2.19 mol) in dichloromethane (0.25 M) at
ꢀ50 ꢁC. The title compound was isolated as a clear, color-
less oil (128 mg, 45% yield, 85% ee) after flash chromato-
graphy (silica gel, 30% ether in pentanes). IR (film) 3447,
1
3447, 1723, 1273, 1111, 710 cmꢀ1; H NMR (300 MHz,
CDCl3) d 9.10 (d, 1H, J¼6.3 Hz, CHO), 8.08–8.04 (m,
2H, aryl H), 7.63–7.57 (m, 1H, aryl H), 7.49–7.44 (m, 2H,
aryl H), 4.75 (dd, 1H, J¼3.0, 12.6 Hz, CH2), 4.34 (dd, 1H,
J¼5.4, 12.6 Hz, CH2), 3.68 (m, 1H, CH oxirane), 3.44 (dd,
1H, J¼2.1, 6.3 Hz, CH oxirane); 13C NMR (75 MHz,
CDCl3) d 197.01, 166.15, 133.72, 129.97, 129.35, 128.73,
63.13, 56.73, 54.0; HRMS (EI+) exact mass calculated for
[M]+ (C11H10O4) requires m/z 206.0579, found m/z
1744, 1441, 1212 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d 9.05 (d, 1H, J¼6.3 Hz, CHO), 3.62 (dd, 1H, J¼1.5,
6.3 Hz, oxirane CH), 3.76 (d, 1H, J¼1.8 Hz, oxirane CH),
3.83 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) d 195.03,
57.68, 53.37, 50.92; HRMS (EI+) exact mass calculated
for [M]+ (C4H5O3) requires m/z 101.0239, found m/z

11422
S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
206.0581; [a]D +16.0 (c 1.12, CHCl3). The enantiomeric
purity was determined by SFC using a Chiralpak AD-H
column (5–50% EtOH, linear gradient, 100 bar, 35 ꢁC
oven, flow¼4.0 mL/min); (2S,3R) isomer tR¼4.19 min,
(2R,3S) isomer tR¼4.96 min.
the title compound as a clear, yellow oil (134 mg, 86% yield,
87% ee) after flash chromatography (silica gel, 25% EtOAc
in hexanes). IR (film) 3436, 2915, 2361, 1678, 1413, 1164,
852 cmꢀ1 1H NMR (300 MHz, CDCl3) d 8.99 (d, 1H,
;
J¼18.0 Hz, CHO), 4.08 (br d, 2H, J¼10.5 Hz, piperidine
CH2), 3.26–3.21 (m, 1H, CH oxirane), 3.09 (dd, 1H,
J¼1.8, 6.3 Hz, CH oxirane), 3.72–3.63 (m, 2H, piperidine
CH2), 1.72–1.61 (m, 3H, piperidine CH2), 1.42 (s, 9H,
C(CH3)3), 1.21–1.15 (m, 2H, piperidine CH2); 13C NMR
(75 MHz, CDCl3) d 198.36, 151.03, 79.63, 59.29, 55.27,
43.92, 38.31, 34.44, 32.38, 32.03, 28.64; HRMS (EI+) exact
mass calculated for [M]+ (C14H23NO4) requires m/z
269.1627, found m/z 269.1628; [a]D +30.9 (c 0.95,
CHCl3). The enantiomeric purity was determined by
SFC analysis using a Chiralpak AD-H column (5–50%
EtOH, linear gradient, 100 bar, 35 ꢁC oven, flow¼4.0 mL/
min); (2S, 3R) isomer tR¼6.97 min, (2R, 3S) isomer
tR¼7.74 min.
3.3.12. tert-Butyl 4-(((2R,3S)-3-formyloxiran-2-yl)-
methyl)piperidine-1-carboxylate (Table 7, entry 6). A
solution of tert-butyl 4-((E)-3-(methoxycarbonyl)allyl)piperi-
dine-1-carboxylate35 (1.8 g, 6.68 mmol) in ether (60 mL) in a
100 mL round-bottom flask was equipped with a magnetic
stir bar and was cooled to ꢀ78 ꢁC. DIBAL (1 M in hexanes,
13.4 mL) was added dropwise to the flask and the reaction
was stirred at constant temperature for 15 min before warm-
ing to 0 ꢁC. After 3 h, the reaction was quenched by the addi-
tion of a saturated solution of Rochelle’s salt (30 mL) and
was stirred at room temperature until the biphasic solution
no longer effervesces and both layers became clear. The or-
ganic layer was extracted, dried, and concentrated in vacuo.
The resulting oil was purified by flash chromatography (silica
gel, 20% EtOAc in hexanes) to yield tert-butyl 4-((E)-3-
hydroxybut-2-enyl)piperidine-1-carboxylate as a clear oil
(1.1 g, 61% yield). IR (film) 3436, 2915, 1669, 1429,
3.3.13. Methyl 3-((2R,3S)-3-formyloxiran-2-yl)propa-
noate (Table 7, entry 7). Prepared according to general
epoxidation procedure B using (E)-methyl 5-formylpent-4-
enoate36 (142 mg, 1.0 mol) to afford the title compound as
a clear, colorless oil (137 mg, 86% yield, 90% ee) after flash
chromatography (silica gel, 40% Et2O in pentanes). IR (film)
1731, 1438, 1175 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 9.03
(d, 1H, J¼6.3 Hz, CHO), 3.72 (s, 3H, CO2CH3), 3.38–3.34
(m, 1H, CH oxirane), 3.20 (dd, 1H, J¼2.0, 6.0 Hz, CH oxir-
ane), 2.52 (t, 2H, J¼6.9 Hz, CH2CO2Me), 2.15–1.88 (m, 2H,
CH2CH2CO2Me); 13C NMR (75 MHz, CDCl3) d 198.06,
151.08, 59.29, 55.81, 52.16, 30.11, 26.66; HRMS (EI+)
exact mass calculated for [MꢀH]+ (C7H9O4) requires m/z
157.0501, found m/z 157.0501; [a]D +27.3 (c 1.25,
CHCl3). The enantiomeric purity was determined by GLC
using a Chirasil-DEX CB column (90 ꢁC isotherm, 15 psi,
flow¼1.0 mL/min); (2R,3S) isomer tR¼60.62 min, (2S,3R)
isomer tR¼62.23 min.
1
1160 cmꢀ1; H NMR (300 MHz, CDCl3) d 5.65–5.62 (m,
2H, CH]CH), 4.08 (t, 2H, a-hydroxy CH2), 4.03 (br s, 1H,
OH), 3.20 (br t, 2H, J¼12.0 Hz, piperidine CH2), 1.98 (t,
2H, J¼6.0 Hz, CH]CH–CH2), 1.65 (br s, 1H, piperidine
CH2), 1.60 (br s, 1H, piperidine CH2), 1.40 (s, 9H,
C(CH3)3), 1.27 (m, 1H, piperidine CH2), 1.07 (ddd, 2H,
J¼4.2, 12.0, 24.6 Hz, piperidine CH2); 13C NMR (75 MHz,
CDCl3) d 155.10, 130.99, 130.69, 79.45, 63.80, 39.42,
36.31, 32.09, 43.92, 39.42, 36.31, 32.09, 31.14, 28.67;
HRMS (EI+) exact mass calculated for [M]+ (C14H25NO3) re-
quires m/z 255.1834, found m/z 255.1837.
In a scintillation vial equipped with a magnetic stir bar was
a solution of tert-butyl 4-((E)-3-hydroxybut-2-enyl)piperi-
dine-1-carboxylate (198 mg, 0.78 mmol), N-methylmorpho-
˚
line N-oxide (96 mg, 0.82 mmol), and activated 3 A
3.3.14. (2R, 3S)-3-Phenyloxirane-2-carbaldehyde (3)
(Table 7, entry 8). Prepared using general epoxidation
procedure A using cinnamaldehyde (159 mL, 1.26 mmol)
and iodosobenzene (378 mg, 1.72 mmol) in dichloro-
methane (5.04 mL) at ꢀ40 ꢁC. Flash chromatography (silica
gel, 30% Et2O in pentanes) afforded the title compound as a
clear, light yellow oil in a 71% yield (133 mg, 0.90 mmol),
78% ee.
molecular sieves (150 mg) in dichloromethane (4 mL) at
room temperature. After 5 min, tetrapropylammonium per-
ruthenate (14 mg, 0.04 mmol) was added in one portion.
The reaction was complete after 30 min and was filtered
through a pad of Celite and concentrated in vacuo and
purified by flash chromatography (silica gel, 20% acetone
in pentanes) to yield tert-butyl 4-((E)-3-formylallyl)piperi-
dine-1-carboxylate as a light yellow oil (160 mg, 80% yield).
IR (film) 2929, 1691, 1417, 1365, 1240, 1163, 976, 866,
Prepared according to general epoxidation procedure B
using cinnamaldehyde (94.4 mL, 0.75 mmol), 1 M AcOH
(0.75 mL), and chloroform (3.0 mL). Flash chromatography
(silica gel, 30% Et2O in pentanes) afforded the title com-
pound as a clear, light yellow oil (101 mg, 92% yield, 92%
769 cmꢀ1 1H NMR (300 MHz, CDCl3) d 9.48 (d, 1H,
;
J¼8.1 Hz, CHO), 6.78 (dt, 1H, J¼7.2, 15.9 Hz, CH]CH),
6.01 (ddd, 1H, J¼1.2, 2.7, 9.0 Hz, CHO–CH]CH), 3.20
(br d, 2H, J¼11.1 Hz, piperidine CH2), 2.66 (br t, 2H,
J¼12.0 Hz, piperidine CH2), 2.24 (t, 2H, J¼7.5 Hz, piperi-
dine CH2), 1.67 (br s, 1H, piperidine CH2), 1.64 (br s, 1H, pi-
peridine CH2), 1.39 (s, 9H, C(CH3)3), 1.07 (ddd, 2H, J¼3.0,
13.8, 25.8 Hz, piperidine CH2); 13C NMR (75 MHz, CDCl3)
d 193.90, 156.20, 154.95, 134.64, 79.62, 43.92, 39.76, 35.73,
32.08, 28.62; HRMS (EI+) exact mass calculated for [M]+
(C14H23NO3) requires m/z 253.1678, found m/z 253.1671.
ee). IR (film) 1726, 1460, 1137, 990.8, 754.3, 697.9 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 9.20 (d, 1H, J¼6.0 Hz,
CHO), 7.39–7.28 (m, 5H, aryl H), 4.17 (d, 1H, J¼2.1 Hz,
CH oxirane), 3.45 (dd, 1H, J¼2.1, 6.0 Hz, CH oxirane);
13C NMR (75 MHz, CDCl3) d 197.1, 129.4, 129.0, 125.9,
63.2, 56.9; HRMS (EI+) exact mass calculated for [M]+
(C9H8O2) requires m/z 148.0524, found m/z 148.0522;
[a]D +35.8 (c 0.76, CHCl3). The enantiomeric purity was de-
termined by GLC analysis using a Bodman G-TA column
(90 ꢁC isotherm, 15 psi, flow¼1.0 mL/min); (2S,3R) isomer
tR¼29.9 min, (2R,3S) isomer tR¼33.1 min.
The title compound was prepared according to general epox-
idation procedure B using tert-butyl 4-((E)-3-formylallyl)-
piperidine-1-carboxylate (156 mg, 0.62 mmol) to afford

S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
11423
2. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974.
Absolute sense of rotation and spectroscopic data was in
agreement with reported literature values.37
3. Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801.
4. Irie, R.; Noda, K.; Ito, Y.; Masumoto, N.; Katsuki, T.
Tetrahedron Lett. 1990, 31, 7345.
5. Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
6. Denmark, S. E.; Forbes, D. C.; Hays, D. S.; DePue, J. S.; Wilde,
R. G. J. Org. Chem. 1995, 60, 1391.
7. Yang, D.; Wong, M. K.; Yip, Y. C. J. Org. Chem. 1995, 60,
3887.
3.3.15. (2R,3S)-3-(4-Nitrophenyl)oxirane-2-carbalde-
hyde (Table 7, entry 9). Prepared according to general
epoxidation procedure B using 4-nitrocinnamaldehyde
(138 mg, 0.75 mmol) using 1 M AcOH (0.75 mL) and chlo-
roform (3.0 mL). Flash chromatography (silica gel, 40%
Et2O in hexanes with 2% NEt3) afforded the title compound
as a light yellow solid (154 mg, 89% yield, 97% ee). IR
1
(film) 1727, 1605, 1520, 1349 cmꢀ1; H NMR (300 MHz,
8. Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621.
9. For a review of the epoxidation of electron-deficient olefins,
see: Porter, M. J.; Skidmore, J. Chem. Commun. 2000, 1215
and references therein.
10. Weitz, E.; Scheffer, A. Ber. Dtsch. Chem. Ges. 1921, 54,
2327.
11. (a) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. 1996,
35, 1725; (b) Enders, D.; Zhu, J.; Kramps, L. Liebigs Ann. Recl.
1997, 1101.
12. (a) Elson, C. L.; Jackson, R. F. W.; MacDonald, S. F. J.; Murray,
P. J. Angew. Chem., Int. Ed. 1997, 36, 410; (b) Jacques, O.;
Richards, S. J.; Jackson, R. F. W. Chem. Commun. 2001, 2712.
13. (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed.
1997, 36, 1237; (b) Bougauchi, M.; Wantabe, S.; Arai, T.;
Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329.
14. Dhanda, A.; Drauz, K.-H.; Geller, T. P.; Roberts, S. M.
Chirality 2000, 12, 313.
CDCl3) d 9.19 (d, 1H, J¼6.0 Hz, CHO), 8.21 (dd, 2H,
J¼2.4, 9.1 Hz, aryl H), 7.46 (dd, 2H, J¼2.4, 9.1 Hz, aryl
H), 4.26 (d, 1H, J¼1.8 Hz, CH oxirane), 3.41 (dd, 1H,
J¼1.8, 5.7 Hz, CH oxirane); 13C NMR (75 MHz, CDCl3)
d 195.4, 141.2, 126.3, 123.8, 62.5, 55.3; HRMS (EI+) exact
mass calculated for [M]+ (C9H7NO4) requires m/z 193.0375,
found m/z 193.0374; [a]D ꢀ13.0 (c 1.18, CHCl3). The enan-
tiomeric purity was determined by GLC analysis using
a Chirasil-DEX CB column (120 ꢁC ramp 5 ꢁC/min to
145 ꢁC, 15 psi, flow¼1.0 mL/min); (2S,3R) isomer tR¼
74.8 min, (2R,3S) isomer tR¼75.9 min.
3.3.16. (2R,3S)-3-(4-Bromophenyl)oxirane-2-carbalde-
hyde (Table 7, entry 10). Prepared according to general
epoxidation procedure B using 4-bromocinnamaldehyde
(158 mg, 0.75 mmol) using 1 M AcOH (0.75 mL) and chlo-
roform (3.0 mL). Flash chromatography (silica gel, 30%
Et2O in pentanes with 2% NEt3) afforded the title compound
as a clear oil (158 mg, 93% yield, 93% ee). IR (film) 1727,
15. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998, 39,
1599; (b) Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55,
6289.
1490, 1070, 1011, 824.6 cmꢀ1
;
1H NMR (300 MHz,
16. Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
17. Marigo, M.; Poulsen, T. B.; Zhang, W.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 6964.
18. Antoniotti, S.; Dunach, E. Synthesis-Stuttgart 2003, 18,
2753.
CDCl3) d 9.16 (d, 1H, J¼6.0 Hz, CHO), 7.48 (d, 2H,
J¼9.0 Hz, aryl H), 7.14 (d, 2H, J¼9.0 Hz, aryl H), 4.11 (d,
1H, J¼1.8 Hz, CH oxirane), 3.37 (dd, 1H, J¼1.7, 6.2 Hz,
CH oxirane); 13C NMR (75 MHz, CDCl3) d 196.6, 132.2,
127.5, 62.92, 56.28; HRMS (EI+) exact mass calculated
for [M]+ (C9H7O2Br) requires m/z 225.9629, found m/z
225.9626; [a]D ꢀ10.5 (c 0.945, CHCl3). The enantiomeric
purity was determined by HPLC analysis of the alcohol
using a Chiralpak AD column (5% EtOH/hexanes, flow¼
1.0 mL/min); (2R,3S) isomer tR¼33.7 min, (2S,3R) isomer
tR¼36.9 min.
19. (a) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 3240; (b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 1172; (c) Ouellet, S. G.; Tuttle, J. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32; (d)
Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan,
D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482; (e)
Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 1192; (f) Paras, N. A.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 7894; (g) Paras,
N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370.
20. For a recent article that elegantly employs these oxidants in an
enantioselective epoxidation using a different amine catalyst,
see Ref. 17.
21. For excellent reviews on hypervalent iodine, see: (a) Stang, P.
Chem. Rev. 1996, 96, 1123; (b) Wirth, T.; Ochiai, M.;
Varvgolis, A.; Zhdankin, V. V.; Koser, G. F.; Tohma, H.;
Kita, Y. Topics in Current Chemistry: Hypervalent Iodine
Chemistry -/- Modern Developments in Organic Synthesis;
Springer: Berlin, 2002; Vol. 224.
Acknowledgements
D.W.C.M. would like to acknowledge and thank all of the
authors (and friends) in this special issue for making the
time and taking the effort to compose and submit a manu-
script on this occasion. This work is dedicated to them and
their continued efforts to push back the frontiers of the
evergreen field of chemical synthesis. Financial support
was provided by the NIHGMS (R01 GM66142-01) and
kind gifts were from Amgen and Merck. S.L. is grateful
for an NPSC fellowship from Amgen.
22. For an example of a 1,4-addition with iodosobenzene, see: (a)
Pettus, L. P.; Van De Water, R. W.; Pettus, T. R. R. Org. Lett.
2001, 3, 905; For examples of nucleophilic attack by the oxy-
gen of iodosobenzene, see: (b) Moriarty, R. M.; Gupta, S. C.;
Hu, H.; Berenschot, D. R.; White, K. B. J. Am. Chem. Soc.
1981, 103, 686; (c) Zefirov, N. S.; Kozhushkov, S. I.;
Zhdankin, V. V.; Safronov, S. O. Zh. Org. Khim. 1989, 25, 1109.
23. Iminium content is observable by 1H NMR.
References and notes
1. (a) Jacobsen, E. N. Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH: New York, NY, 1993; pp 159–202; (b) Johnson,
R. A.; Sharpless, K. B. Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, NY, 1993; pp 103–158.

11424
S. Lee, D. W. C. MacMillan / Tetrahedron 62 (2006) 11413–11424
28. (a) Saltzman, H.; Sharefkin, J. G. Org. Synth. 1973, 5, 658; (b)
24. (a) Sawaguchi, M.; Aruba, S.; Hara, S. Synthesis 2002, 13,
1802; (b) For a discussion of substituent effects on the phenyl
ring of hypervalent iodides, see: Harden, G. J. J. Chem. Soc.,
Perkin Trans. 2 1995, 1883 and Gao, Y.; Jiao, X.; Fan, W.;
Shen, J.-K.; Shiu, Q.; Basolo, F. J. Coord. Chem. 1993, 29,
349; (c) Note: other substituted iodosobenzenes (p-NO2,
o-Me, and o-Cl) were found to be much less efficient than
unfunctionalized iodosobenzene.
25. For examples of non-metal mediated oxidations by iodoso-
benzene, see: (a) Huang, W.-J.; Singh, O. V.; Chen, C.-H.;
Choiu, S.-Y.; Lee, S.-S. Helv. Chim. Acta 2002, 85, 1069; (b)
Tohma, H.; Maegawa, T.; Takizawa; Kita, Y. Adv. Synth.
Catal. 2002, 344, 328; (c) Ueno, M.; Nabana, T.; Togo, H.
J. Org. Chem. 2003, 68, 6424; (d) Sohmiya, H.; Kimura, T.;
Fujita, M.; Ando, T. Tetrahedron 1998, 54, 13737.
ꢀ
Simandi, L. I.; Nemeth, S.; Besenyei, G. Tetrahedron Lett.
1993, 34, 6105.
ꢀ
29. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
30. Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43,
2923.
31. Righi, G.; Chionne, A.; Bonini, C. Eur. J. Org. Chem. 2000,
3127.
32. Martin, S. F.; Garrison, P. J. Tetrahedron Lett. 1977, 44, 3875.
33. Singh, O. V.; Han, H. Org. Lett. 2004, 6, 3067.
34. Guziec, F. S.; Luzzio, F. A. J. Org. Chem. 1982, 47, 1787.
35. Orlek, B. S. Synlett 1993, 758.
36. Kukovinets, O. S.; Kasradze, V. G.; Chernukha, E. V.;
Odinokov, V. N.; Dolidze, A. V.; Galin, F. Z.; Spirikhin,
L. B.; Abdullin, M. I.; Tolstikov, G. A. Russ. J. Org. Chem.
1999, 35, 1156.
26. Concentrations of iodosobenzene species were calculated rela-
tive to benzyl methyl ether (internal standard) and were deter-
mined after removal of oligomeric iodosobenzene by filtration
through Celite.
37. Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2001, 123, 9474.
27. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
38. CRC Handbook of Chemistry and Physics, 81st ed.; Lide,
D. R., Ed.; CRC: Boca Raton, FL, 2000.