Organic Reactions with
Self-Assembly Supramolecules

Literature Seminar #2
2024/7/18
M2 Arii

Outline
Outline1. Introduction
1-1. Supramolecular Chemistry1-2. Metal-Ligand Self-Assembling Supramolecule
2. Unimolecular Reaction with Supramolecule2-1. Aza-Cope Rearrangement
2-2. Nazarov Cyclization
2-3. Aza-Prins Cyclization
3. Reaction with Metal Encapsulated within Supramolecules
3-1. Development of C(sp3)-C(sp3) Coupling Reaction with Supramolecules
3-2. Development of Coupling Reaction with Cu / Pd in Water
3-3. Selective Catalytic Hydrogenation Independent of Chain Length
4. Stereoselective Reaction by Host Size and Flexibility
4-1. Stereoisomer of Self-Assembly Complex
4-2. Stereoselectivity by Host Size (Prins Reaction)
4-3. Stereoselectivity by Host Flexibility (Aza-Darzens Reaction)
5. Summary1Outline
Outline1. Introduction
1-1. Supramolecular Chemistry1-2. Metal-Ligand Self-Assembling Supramolecule
2. Unimolecular Reaction with Supramolecule2-1. Aza-Cope Rearrangement
2-2. Nazarov Cyclization
2-3. Aza-Prins Cyclization
3. Reaction with Metal Encapsulated within Supramolecules
3-1. Development of C(sp3)-C(sp3) Coupling Reaction with Supramolecules
3-2. Development of Coupling Reaction with Cu / Pd in Water
3-3. Selective Catalytic Hydrogenation Independent of Chain Length
4. Stereoselective Reaction by Host Size and Flexibility
4-1. Stereoisomer of Self-Assembly Complex
4-2. Stereoselectivity by Host Size (Prins Reaction)
4-3. Stereoselectivity by Host Flexibility (Aza-Darzens Reaction)
5. Summary2

Host-Guest Chemistry

1-1
Supramolecular Chemistry

Introduction4+cHost-Guest ChemistryN

Host-Guest interaction : Many noncovalent bonds Guest・ electrostatic interactions
・ dipole-dipole interactions fragile and reversible
・ hydrogen bond・ hydrophobic interactions
Stronger with multiple bonds

NH
H

H
NH

Host

N

O
8

HN

O

O
Pd

+

H

H

2

HH
N

O
Host-11

+
N

N

N

O
OC
Rh
O
O
P
NMe2
O

Pd

N
O
O

=

N

Guest

Paul J. Lusby, et al., J. Am. Chem. Soc. 2018, 140, 2862.

Fig. 2 | Organic
transformations promo=
substitution reaction to generate helicat
by the urea functionalities. c, SupramoleN
N
O
reaction with para-quinone.
d, TandemrZnof aryl amidesa twisted-cis
conON
N enforcesacid source, this cage enabled a m
acid-sensitive reagents such as imi
NunderwentO ligand
substitution wi
Oin situ deprotected by host-7, to g
Another example of a host containi
3
is J.
the
supramolecular
Joost N. H. Reek,sis
et al.,
Am.
Chem. Soc. 2015, trigonal
137, 2680.p

Pd

N

Host

Pd

N

N

1-1

Classical Supramolecular Chemistry▶ Examples of classical host molecules

Introduction
OH

O
O
HO
O
Review
OH OHOOHOO also withOits shape, and rate
substrate’shydrophobicity
but
O
O
O
OH
+
Na+ (kcat/kuncat) as high asK250-foldaccelerations
were observed. O
HO
OH
OH
Encapsulation of substrates
have powerful OconO can also O
OOO
sequences for the regioselectivity of host-mediation transOH
35
HO
formations. Breslow and Campbell,Ostudying the chlorinationOHOof anisole by hypochlorous acid, found that cyclodextrins couldOOH
15-crown-5-ether
be used to manipulate 18-crown-6-ether
the distribution of products. In the OH
OHO HOabsence of any host, chlorination of anisole gives a mixture of o- O
OH
Cavities are hydrophobic.
O
Encapsulate
alkalimetal
ionsand p-chloroanisole. Encapsulation of anisole within
α-cycloFigure
1. (Left) Schematic and (right) space-ﬁlling structures of αdextrin, however, shields the ortho sites from substitution
due to HO a α-cyclodextrin
cyclodextrin,
cyclic hexamer of glucose and early host applied in(α-CD)
the speciﬁc orientation within the host cavity (Figure 2). The

supramolecular▶① Reactions using cyclodextrin asa host catalysis.

Guest : organic molecules

β-, and γ-cylodextrins (6, 7, or 8 glucose units, respectively), thehost cavity is ∼5.6−8.8 Å in diameter. The upper and lower rims
Host for organic moleculesof these cylindrical structures contain a network of hydroxylorganic
molecules
encapsulated.
groups, whileVarious
the wallsof thetoroidalaremoleculebound ahydrophobic Structure
cavity. Lyophilicof organic substrates ofknown bindingby X-rays.
appropriate size
was observed in aqueous solution as well as
Easy to synthesize derivatives
organic solvents, with the orientation of guest molecules
controlled by both steric constraint and the polar seam of
Figure 2. Chlorinationof anisole
encapsulated reactionby α-cyclodextrin.
p-selective
chlorinationhydrogen bonds at the cavity boundary.
Cyclodextrins had much to recommend them as 4supraproduct ratio is dictated by the relative amounts of bound andRonaldBreslow mimics:
and Peter Campbell,
J. Am. Chem.
91, 3085.
molecular
enzymetheir structure
had Soc.
been1969,
unambigu-

Classical Supramolecular Chemistry

1-1

Introduction▶② Reactions using cyclodextrin derivativies
OAc

0.10 M acetate buffer (pH 5.17)

O2N

O

HO

O
HO

OH OHO

Host
OH
O
OH
O
HO

O

OHO HO

O

O

HO

O
HO

OH

O2N

4 times faster than with PCA-Ni2+
103 times faster than under no catalyst

OH

O
OH

OH

α-cyclodextrin-PCA-Ni2+

N

O

Ni

O
OH
O
OH
O

O

N

N O

reaction center

O N

N
Ni

N

N O

PCA-Ni2+(pyridine-carboxaldoxime)OH

α-cyclodextrin-PCA-Ni2+

Encapsulate phenyl groups
Extremely close to the reaction center5
Breslow, R. and Overman, L. E., J. Am. Chem. Soc. 1970, 92, 1075.

alkyl groups such as adamantanes position the reactive maleimide
for its carbonyl groups to make good contacts with the organized
1-1
H-bonding network at the cavitand rim. The maleimides’ double▶③
Application to Catalytic Reactions
bonds remain exposed above the receptor for reaction. The in–
Both
guest
affinityto HostProblem,out exchange rate
for speciesof thistype andis onproductthe order haveof 2 s−1
far faster than the cycloaddition rate.6b The rapid exchange of
product and reactant positions
the receptor
to act as a from
catalyst,
Dissociationof products
Host
not just a promoter of the reaction. In addition, cycloaddition
to this olefin would increase the steric bulk of the product withO
HO
O
respect to reactant, lowering its binding affinity and reducing
NOH
1 (20 mol%)product inhibition.
N The proposed reaction mechanism is shown
mesitylene-d12
O
in Fig. 2.
23℃

Classical Supramolecular Chemistry

Introduction

O

O

O
H
N

O

NH

HN
O

O
N
H

HN

Fig. 1HNOOHydrogen bond

O

O

O

exposurekcat/kuncat = 34

R

R

R

R

O

O

maleimide-1 complex
O
O
N
H

NH
R=C11H23O
The deep1 cavitandO used as catalyst; minimized representation of

Product : Dissociation due to steric hindrance

6
Richard J. Hooley and Julius Rebek Jr., Org. Biomol. Chem. 2007, 5, 3631.

1-2

Development of Supramolecular Chemistry
Introduction

Noncovalent microenvironment catalysts
・ Inspired by enzymes
・ High chemoselectivity
・ High stereoselectivity

organotransition metal catalysts
・ Accelerate difficult reactions
・ Developed regardless of biology

Integrating them will lead to the development of supramolecular chemistry.
Different environments from bulk solutions
Conformational control over the Guest
Advantage

Shifts in equilibria to generate reactive species
Dramatic increase in effective concentration

Host structure is rigid.
Existing Problems

Difficult to synthesize Host with complex structure
7

Metal-Ligand Self-Assembling Supramolecule

1-2

Introduction

Metallosupramolecular Host : the use of metal−ligand bonding
Self-assembles into the most stable structure because of reversible bonding
Chemical
Organizing
force Reviews
for the construction of symmetric coordination cages

Easy to synthesize derivatives
More flexible structure than a host consisting only of covalent bonds▶ First reported metal-ligand self-assembling supramolecule
Mg2+

O
EtO

1) MeMgI2) (COCl)2
3) NH4Cl/H2O

O[NH4+]4OEt

too small for organic molecule
Larger Ligands 2+
Figure 6. (a) Synthesis of magnesium salt containing a ditopic malonate ligand and Mg andLarger Metals
Possibility
to functionas Host“adamantoid”
magnesium
coordination
complex 13, showing only one of six ligands for clarity.
cavity8Hans Georg von Schnering, et al., Angew. Chem., Int. Ed. Engl. 1988, 27, 851.

1-2esearchMetal-Ligand Self-Assembling Supramolecule▶ Metal-ligand self-assembling Host supramolecule

Introduction

nternal microenvironments that12­areO
n. Upon encapsulation,
guests areOOat the molecularlevel via theseNH
13 Å
ameters deﬁned at the macroscopic 3+
Ga
tions of this control include (i)m solventO HNand nonencapsulatedOtional control
over the guest, (iii)Oe reactive species, and (iv) dramatic
12Symmetrical structure
entrations upon
multiple[Ga4Lbinding
6]
among
others, control the relative
Solubility
CavityFigure 1. (a) Crystal structure ofd transition
statesandDodecaanionicanionof substratesHydrophobic
microenvironment
sufficient
representation
ofofhost
2 [Ksize
12(Ga41
Solublewater and a wealth ofCan be used as Host
ortunities
toin achievepolar organic solvents
Excludes the bulk solution
includingcatalysis,1 reactive intersubstitution pattern in 1 (Figur
3
Flexibility
Guestsmical
sensing, and the mimicryofoxidation state metal hosts have4
Cationic/neutral molecules
Movable arene walls via rotation of amide bonds
signalwith
transduction,
multicatalytic
commonly used to generatehydrophobic
6 groups
Encapsulated guests of various shapes.
adaptive binding, and information
9
Ga(III)−triscatecholate hasaKenneth N. Raymond, et al., Inorg. Chem. 2009, 48, 111.

The Properties of Metallosupramolecular Hosts

1-2

Introduction▶ Iminium formation in water under basic conditions
H
N

H
N

or

R
R1

O
R1

N

R

R

[Ga4L6]12-

OH
R2

R1

R1=Me, Et
R2

N

R
OH
R2

pH 11〜11.5

R2=Me〜C7H15
Iminium formation in basic water
Kenneth N. Raymond, et al., J. Am. Chem. Soc. 2006, 128, 14464.

▶ β-hydroxyphosphonium ion formation in water

OH

O
HPEt3

[Ga4L6]12-

PEt3

OH
PEt3

undetectedin bulk solution
β-hydroxyphosphonium ion formation in water
Kenneth N. Raymond, et al., Eur. J. Org. Chem. 2004, 4552.

Shift the equilibrium in the direction of generating cations

10

Outline
Outline1. Introduction
1-1. Supramolecular Chemistry1-2. Metal-Ligand Self-Assembling Supramolecule
2. Unimolecular Reaction with Supramolecule2-1. Aza-Cope Rearrangement
2-2. Nazarov Cyclization
2-3. Aza-Prins Cyclization
3. Reaction with Metal Encapsulated within Supramolecules
3-1. Development of C(sp3)-C(sp3) Coupling Reaction with Supramolecules
3-2. Development of Coupling Reaction with Cu / Pd in Water
3-3. Selective Catalytic Hydrogenation Independent of Chain Length
4. Stereoselective Reaction by Host Size and Flexibility
4-1. Stereoisomer of Self-Assembly Complex
4-2. Stereoselectivity by Host Size (Prins Reaction)
4-3. Stereoselectivity by Host Flexibility (Aza-Darzens Reaction)
5. Summary11

Aza-Cope Rearrangement

2-1

Unimolecular Reaction with Supramolecule

37 mol%N

D2O/DMSO-d6=1/99

H 2O

N

O

Aza-Cope rearrangement
OTs
kcat/kuncat=84

OTs

Similar to transition state conformation
N

OTs
N

Encapsulated
N

N

H 2O

O

12
Kenneth N. Raymond and F. Dean Toste, et al., J. Am. Chem. Soc. 2018, 140, 6591.

OTs

Nazarov Cyclization

2-2

Unimolecular Reaction with Supramolecule

7 mol%HOO

D2O/DMSO-d6=1/1, 72℃

O

O
HN

Nazarov cyclization
kcat/kuncat
Journal of the American Chemical SocietyHN=2.1×106O

Kenneth N. Raymond, et al., Article
J. Am. Chem. Soc. 2010, 132, 6938.

Not linear conformation

Increased basicity
due to encapsulation

13
Kenneth N. Raymond and F. Dean Toste, et al., J. Am. Chem. Soc. 2018, 140, 6591.

Aza-Prins Cyclization

2-3

Unimolecular Reaction with Supramolecule

20 mol%N

N
H

Formic Acid

[Ga4L6]12-

O

100℃

H

OH

H

CD3OD/D2O=1/3
rt, 40 h

H+

+H2O
-CH2O

H 2O

N

eq

NH

N

ax

N

N
H
Encapsulated

Encapsulate iminium
Conformational control in transition states
14David M. Kaphan, F. Dean Toste, Robert G. Bergman, and Kenneth N. Raymond, J. Am. Chem. Soc. 2015, 137, 9202.

consistent with the experimental observations, we va
at nitrogen in order to gain further insigh
Aza-Prinssubstitution
Cyclization1). Parent N-methylUnimolecular
substrateReaction
2a underwent
full cowith Supramolecule

2-3▶SchemeDeuterium
Labeling
Study
2. Deuterium
Labeling
Study

ium Labeling Study▶ Effect of N Substitution on Reactivity
Table 1. Eﬀect of N Substitution on Reactivity

15 mol%20 mol%15 mol%size
exclusionapD 8.0, [PO43−] = 100 mM. bCalcluated by ratio of ext
to starting material by 1H NMR spectroscopy. cConveramine product (3) was observed in conjunction with theIntramolecularhydrogentransferthe
wasconfirmed.of anwith 3 equiv of formaldehyde and 20 mol % clus
appearance
of benzaldehyde,
suggesting
intermediacy
MeOD in D2O solvent mixture at room tempera
iminium
species groupresultingfrom hydridetoThe methyl
at position
2 wasabstraction
identifiedalphaas axial.
nitrogen, which undergoes hydrolysis.
Increasing the chain length of N-alkyl substitut
The observation of quantitative deuterium incorporation
sharp decrease in conversion: N-ethyl, -propyl
from the cyclization of amine 2-d3, in addition to thesubstrates proceeded to 53, 43, and 9%
b data are consistent with s
These
appearance of benzaldehyde in the cyclization of apD
2i, NHis [POrespectively.
3−8.0,
4 ] = 100 mM. Calcluated by ratio of extracte
imposed bycongested interior c of the cluste
consistent with
N an aza-Prins cyclization
N a mechanism involving
NMR
spectroscopy. Conversion
to starting materialby 1Hthe
alpha
to
the
amine
inhibits
reactivity
completwith subsequent transannular 1,5-hydride transfer from the
NaxialSubstrate specificity
by sizeexclusionMeelevated temperatures (Table 1, entries 6 andmethyl group
H to the nascent tertiary carbocation (Scheme 1).
removal of the methyl group on the carbon backb
We hypothesize
divergent reactivity
is the result of the3) wasobserved thatin thisconjunction
with the15
restoredreactivity for the
N-isopropyl
substrate(T
constrictive
binding of
thecluster cavityofwhichfavorswith
more
3
equiv
of
formaldehyde
and
20
mol
%
clusterizaldehyde,
suggesting
theintermediacy
an
David
M.
Kaphan,F.
Dean
Toste,
RobertG.
Bergman,andKennethN.
Raymond,
J.
Am.
Chem.
Soc.
2015,
137,
9202.
8). One possible explanation for this phenomcompact transition states. This constrictive binding results in a

Outline
Outline1. Introduction
1-1. Supramolecular Chemistry1-2. Metal-Ligand Self-Assembling Supramolecule
2. Unimolecular Reaction with Supramolecule2-1. Aza-Cope Rearrangement
2-2. Nazarov Cyclization
2-3. Aza-Prins Cyclization
3. Reaction with Metal Encapsulated within Supramolecules
3-1. Development of C(sp3)-C(sp3) Coupling Reaction with Supramolecules
3-2. Development of Coupling Reaction with Cu / Pd in Water
3-3. Selective Catalytic Hydrogenation Independent of Chain Length
4. Stereoselective Reaction by Host Size and Flexibility
4-1. Stereoisomer of Self-Assembly Complex
4-2. Stereoselectivity by Host Size (Prins Reaction)
4-3. Stereoselectivity by Host Flexibility (Aza-Darzens Reaction)
5. Summary
16

3-1

Approach to Coupling Reactions with Supramolecule
Reaction with Metal Encapsulated within Supramolecules

Traditional Approach

L
[M]
L

Supramolecular approaches

R
R

R R

L

R Nu
L
[M]
L

R

[M]
L

X

L [M]

R
R
L [M]

R Nu
L [M]

R
R

R
X

R X
R X

Ligands always bind to metal

L [M]

R R

Supramolecules bind in only one step.

Selectively accelerate only the slowest step and not affect the others17

C(sp3)-C(sp3) Reductive Elimination

3-1

Reaction with Metal Encapsulated within Supramolecules▶ Initial trial
10 mol%
Me3P
Me

Au

I
Me

MeOH-d4, 25℃

L [M]

Me3P Au I

R

Me Me
L [M]

R Nu

k=4.7×10-6 Ms-1+
Inhibition of catalyst by Et4P : k=9.5×10-10 Ms-1

L [M]

R
R

R
X

R X

I
Me3P
Me
Pt
Me3P Me Me

R

L [M]

R R

10 mol%Me3P
MeOH-d4, 25℃

I

Au

Me

Me Me

PMe3

k=1.8×10-5 Ms-1+
Inhibition of catalyst by Et4P : k=7.9×10-9 Ms-1

Possible Mechanism
Ln
Me

M

X
Me

Me
Ln

Me
Ln

M
Me

M

k

Ln

M X

Me Me

Me

18
Kenneth N. Raymond, and F. Dean Toste, et al., J. Am. Chem. Soc. 2016, 138, 9682.

C(sp3)-C(sp3) Reductive Elimination

3-1

Reaction with Metal Encapsulated within Supramolecules▶ Phosphine ligand effects▶ Other reductive elimination

10 mol%
R 3P
Me

Au

I

R 3P

Au I

Me

MeOH-d4, 25℃

entry

PR3

k [Ms-1]

k’ [Ms-1] +Et4P+

1

PMe3

4.7×10-6

9.5×10-102

PEt3

1.5×10-2

1.8×10-73

PPh3

no acceleration

−

Me Me

Reaction coordinate Diagrams→Appendix
Reasons for the acceleration of PEt3
・ Increased hydrophobicity
・ Optimal size for cavity
・ Au(Ⅲ) cation stabilized→ Pre-equilibrium shifts toward favorable

10 mol% Me3P
Me3P
Et

Au

Au I

I
Et

Cl
Me3P
Me
Pt
Me3P
Me
Me
O

MeOH-d4, 25℃

10 mol%MeMe
k=7.6×10-3 Ms-1
Me3P
Me3P

MeOH-d4, 25℃

Pt

Me
Cl

O
Me

Me

k=2.2×10-3 Ms-1

Changing the size of the Host molecule
may lead to the respective chemical
selectivity.

19
Kenneth N. Raymond, and F. Dean Toste, et al., J. Am. Chem. Soc. 2016, 138, 9682.

encapsulated 3 and the host (Figure 2c). A 2D NOESY
experiment of the product indicated correlation between thearomatic peaks and one set of DMPE methyl peaks. Thisobservation provided initial support for copper phosphonium
with Metal Encapsulated within Supramolecules
4, where an aryl-dimethylphosphonium ion hadReaction
formed at one
phosphine, while the other remained coordinated to the
Halide abstractor (NaBArF) (2.0 eq.)
starting
copper center (by analogy to the {1H}31P shift of the P
P Cu I
23
Iodobenzene (2.0 eq.)
P Cu
Further evidenceof Ian aryl phosphonium
material).
P
D
O,
rt
(2.0
eq.)
Br
Cu
Ar I
2
copper(I)species was obtained by independently preparing
rt, 12 hCu X
PP
ethyldimethyl(phenyl)phosphonium
5(see
SupportingP
is an atypicalP catalyst for traditional Ullmann-type
Ar
Information, p S6) and subjecting it to the M4L6 assembly.
reactions, it proved to be an ideal species for this
Ar
1
31
The
{
H}
P
NMR
shift
of
the
encapsulated
phosphonium
5
on due to its high stability under aqueous conditions, 1.0 eq.
product
was identical to that of one of the phosphine signalsentryof the Halide abstractor solvent
ses from its low solubility in water. In contrast, thereductive
asymmetric
DMPE
backboneofarylphosphonium
copperX
ated analogues rapidly disproportionated in aqueous
elimination
species 4. Lastly, electrospray ionization
mass spectrometryendering direct comparison between the hostD 2O
trace
+
1
(ESI-MS) conﬁrmed encapsulated 4, predominantly detected
system and the potential background organometallic
in the −3 and −4 charge states (see Supporting Information, p
spectroscopically challenging.
oxdation
Ar I Due to the Plow
D 2O
no conversion−
2
PS22), verifying that the species
isI monocationic, with thePof 2, no reactivity
was observed upon combination
addition
ligated to copper.
benzene in water,
Cu even after long reaction times andCu iodide (from iodobenzene) stillCu
DCM
not detected
+
3
While
the
resultingCu(I)−Iphosphonium
product (4) was
More interesting
still is the lack of reactivity
P in Ar I
P
ArP
unexpected, it implies room-temperature carbon−iodine
nal organic solvents (such as methylene chloride andDCM
no conversion−
4oxidative addition with encapsulated 3 followed by rapide), where both 2 and iodobenzene are fully soluble.
aryl−phosphine reductive elimination via a putative Cu(III)hese negative controls in both aqueous and organic
MeCN
no conversion+
5
intermediate (II, Scheme 1). Lack of reactivity in control
soughtto determine if reactivity was possible
under
Co-encapsulated
Encapsulated
studies indicated that reaction progress is speciﬁc to cage 1 andence of supramolecular host 1. It has been
MeCN
no conversion−
6
raises the question as to the exact role of the host in thisated previously that 1 functions as a halide abstractor
eutral organometallics, promoting encapsulation oftransformation and whether the same reactivity could be

3-2

Development of Coupling Reaction in Water

Confirmation of product generation

Candidate for coupling reactions in water.

20
F. Dean Toste, et al., J. Am. Chem. Soc. 2019, 141, 1701.

3-2

Development of Coupling Reaction in Water
Reaction with Metal Encapsulated within Supramolecules
C(sp2)-C(sp3) coupling reaction product

Et3P
1/2
Pd
Me

Cl
Cl

Ar

PEt3

Pd

I (2.0 eq.)

D2O, rt

PEt3

Me

Me
1.0 eq.

Me PEt3
reductive
elimination

Cl
Ar
Et3P
Pd
Me

Encapsulated

I

Et3P
Pd
Me
Ar

oxdation
addition
I

I
Et3P
Pd
Ar
Me

Co-encapsulated

Candidate for coupling reactions in water.
Possibility of Pd(IV) complex that can also undergo C(sp2)−C(sp3) reductive elimination

21
F. Dean Toste, et al., J. Am. Chem. Soc. 2019, 141, 1701.

Selective Catalytic Hydrogenation
oleﬁns (3 and 5, respectively). Good conversion of methyl-

if 1 could discriminate between methyl- and ethyl-substituted

3-3

oleﬁn
(3) waswhile ethyl-oleﬁnstarting
material (5)Reaction
withobserved
Metal Encapsulated
withinSupramolecules
was recovered in high yield (Figure 2a).
In the analogous
Communicationof the American
Chemical▶ Journal
Difference
in reactivity
by Society
olefin position[Rh][BF4]

10 mol%Table 1. Screening of General Hydrogenation PReactivity for
Rh(COD) BF4
Simple Oleﬁnic Substrates by Catalyst 1P
10 mol%[Rh][BF4]▶ Competitive reduction reaction] 10 mol%
supported and free catalyst [Rh][BF
oﬀeredpromise for realizing
selective oleﬁn hydrogenation.
10 mol%A competition experiment was then performed to determine
if 1 could discriminate between methyl- and ethyl-substituted
oleﬁns (3 and 5, respectively). Good conversion of methyloleﬁn (3) was observed while ethyl-oleﬁn starting material (5)was recovered in high yield (Figure 2a). In the analogous
4a12h reaction time. bReactions performed at 50 °C.
[Rh][BF4]

10 mol%10 mol%oleﬁn, but signiﬁcantly faster (1 h versus 12 h) thansupramolecular catalyst 1. To verify that this reactivity
diﬀerence was due to host encapsulation ofc 2, a standard
control reaction was performed: to in situ formed 1 was added
strongly binding
guest Et4N+ (as salt [Et4N][Cl]), resulting inab
28 C Buffer (pH 8.0)
12h reaction
time.of Reactions
50 °C.
ejection
2 and Et4performed
N-blockedathost.
With the cavity of thehost blocked, complex 2 maintained the same levels ofOnlyreactivity
olefins at(>99%
specific
positionsbe selectively
conversion,
1 canh) since
it was no reduced.
longerencapsulated
demonstratingthat encapsulation does modify
Anionic
substrates
are also acceptable.
reactivity.
oleﬁn, but
signiﬁcantly faster (1 h versus 12 h) thanoccurseven between
molecules.
Figure 2.Selectivity
Competition
experiments
to demonstrate
divergent
selectivity of free catalyst 2 compared to the supramolecular22
supported catalyst 1. (a) Supramolecular supported size-selective
F.
Dean Toste,ofetmethylal., J. vsAm.
Chem. Soc.
11806.
hydrogenation
ethyl-oleﬁn.
(b) 2019,
Catalyst141,
2 showsnoJournal of the American Chemical Society

Communicati

Selective Catalytic Hydrogenation

3-3 and high conversion was realized upon warming theobserved,
eaction mixture (Figure 3a, 9). In agreement with the results Journal Reaction
with Metal Encapsulated within Supramoleculesof the American
Chemical Society▶ Application to Alkyne[Rh][BF4]

10 mol%▶ Use of larger host[Rh][BF4]

10 mol%10 mol%10 mol%b.

[Rh][BF4]

10 mol%10 mol%[Rh][BF4]

10 mol%10 mol%Figure 4. (a) Supramolecular host supported hydrogenatiotrans,trans-2,4-hexadiene-1-ol (12) to cis-3-hexen-1-ol (13).
Underdideuteriumcan
conditions,selective
1,4-addition was obse
Selectivity
be variedby changing
to yield
singleofmajor
isomer 14.
the asize
the host.

Reaction proceeds without complete
the encapsulation
walls, leading toof host-selected
product 13. To fur
the substrate.

Figure 3. Supramolecular supported catalyst selectively hydrogenates
the 1,4-addition mechanism, the analogous reac
Selectivity
similar(a)toHydrogenation
alkenesalkynes basedon size-exclusion.
of methyl-alkyne Figuresupport
5. (a) Minor conversion of 15 was observed using catalyst 1.
was16performed
7 providedPosition
cis-alkene 8takes
at roomprecedence
temperature andheating
aﬀorded fully Catalyst
provides withgooddeuterium
conversiongas.
of From
15 tothis
thereaction,
singlyoverreactivity
doubly productdeuterated
cis-product(14)between
was exclusively
obserhydrogenated9.
(b)Competition
betweenmethyland
ethyl-alkynehydrogenated17.
(b)Competition
two
acids
with
in determining selectivity.
Interestingly,
theshow
productof conversion,
this transformationa si(7 and 10, respectively) provided size-selective hydrogenation of 7 diﬀerent
alkane lengths
similarindicating23was
remoteand full recovery of 10. (c) Methyl-alkene 11 was selectively group isomer
goodregioselective
and diastereoselec
does
notindicating
aﬀect
reactivity.
F. DeanToste,
et al.,
J. Am.
Chem. Soc. 2019,
141, 11806.
33

Outline
Outline1. Introduction
1-1. Supramolecular Chemistry1-2. Metal-Ligand Self-Assembling Supramolecule
2. Unimolecular Reaction with Supramolecule2-1. Aza-Cope Rearrangement
2-2. Nazarov Cyclization
2-3. Aza-Prins Cyclization
3. Reaction with Metal Encapsulated within Supramolecules
3-1. Development of C(sp3)-C(sp3) Coupling Reaction with Supramolecules
3-2. Development of Coupling Reaction with Cu / Pd in Water
3-3. Selective Catalytic Hydrogenation Independent of Chain Length
4. Stereoselective Reaction by Host Size and Flexibility
4-1. Stereoisomer of Self-Assembly Complex
4-2. Stereoselectivity by Host Size (Prins Reaction)
4-3. Stereoselectivity by Host Flexibility (Aza-Darzens Reaction)
5. Summary
24

Stereoisomer of Self-Assembly Complex

4-1

Stereoselective Reaction by Host Size and Flexibility

Self-AssemblyComplexes consisting of three bidentate ligands

The chiralities of the four metals match.
Racemic supramolecules are obtained.
Δ

Λ

Δ

M

M

Δ-[M(A-A)3]

Λ-[M(A-A)3]

Λ
Λ

Δ

Λ

Δ
enantiomer

ΔΔΔΔ

ΛΛΛΛ

Chiral ligand/chiral guest makes a chiral diastereomeric mixture.
Δ

diastereomer
Δ

Δ

R
Δ
(R)-ΔΔΔΔ

Λ

Δ

Λ

R
Λ
(R)-ΛΛΛΛΛR

racemic
supramoleculesS

diastereomer

Λ

Δ
Δ

S
Δ
(S)-ΔΔΔΔΛΛSΛ(S)-ΛΛΛΛ25

n 28 November 2014. Downloaded on 10/02/2015 23:23:53.
sed under a Creative Commons Attribution 3.0 Unported Licence.

4-2

Racemic

Enantiopure

100
100 mMport
phStereoselectivity by Host Size
Stereoselective Reaction by Host Size and Flexibility
portionsdistof
Smaller cavity
Larger cavity
distribution
trial
trials produchachanges inI
CAM Initially,cho=catecholamide
choice mixof hmixturesfo
100 mM phosphatebuﬀerandco
CAM-Nap, 1
CAM-Pyr, 3
and 2. The
ena
portions of the reaction
mixenantiomer
ime1
distributions measuredbyimentisresinoFig. 1 K12Ga4L6 assemblies
discussedin thiswork.
Spher
trialsproduct
ratioswere
fou
N(CGa3+ centers and lines represent
ligands
asresidual
depictedvarichanges incosolventcomposTAMecholamide, TAM ¼ terephthalamide, Nap¼ variednaphthalene=terephthallamide
obs
Initially, diﬀerences
inbetw
proene). Only one ligand enantiomer is shown forobserved
2 and 4. Pobthanchoiceofhostchelator
were
are omitted for clarity.
than
with
D
aged
mixtures following
treatmen
aged
produ
men
and 2. The extent towhich
enments race(58/
enantiomers
TAM-Nap, 2
TAM-Pyr, 4 (S)-5a and26(R)-5
Kenneth N. Raymond, et al., Chem.racemic
Sci. 2015, 6, 1383.
Results and discussion
5age Article

Stereoselectivity by Host Size

▶ Diastereoselectivity

Open Access Article. Published on 28 November 2014. Downloaded on 10/0
This article is licensed under a Creative Commons Attribution

4-2

View A

ChemicaStereoselective Reaction by Host Size and Flexibility▶ Enantioselectivity
factor (s; eqn (1)),44 which is determined by DDG‡ betw

stereomeric transition states. It was hypothesized that iof substrates was increased, an increase in s may be obse
to increased steric interactions between encapsulated
and the aromatic walls of L4-2, which are presumably thethat induce enantioselectivity in these reactions.31,38
Toward this end, selectivity factors were measured f
starting materials 5a and 5b (1 : 1 MeOD-d4/100 mM phbuﬀer cosolvent, pD 5.00, 25 " C). While L4-2 exhib
chiral discrimination for 5a (s ¼ 1.8; DDG‡ ¼ 0.35 kca
selectivity increased for larger substrate 5b (s ¼ 4.45;
Scheme 10.88
Generalin thecyclizationsof (a) chirakcalconditions
mol$1). eﬀective
Following
thisobservation,
prod
Smallercavityasubstratesresulting
5a–c andfrom(b) achiral
5c withcatalysts
1–4. 50mM
the substrate
cyclizationof 5cwith hosts
D4-2
phosphate buﬀer, pH 7.50; b100 mM phosphate buﬀer, pD 8.00; c1 : 1
stericwere Larger
compared.
In thehindrance
latter case, an analogous tr
MeOD-d4/100 mM phosphate buﬀer, pD 8.00; d1 : 1 MeOD-d4/100
eobserved;
product
enantioselectivity
was greaterwhenmM phosphatebuﬀer,
pD 5.00;
product not observed
by 1H
NMR
‡
One
enantiomerismoref(entry 2b, 61% ee; DDG ¼ 1.14 kca
cavitywasused
spectroscopy or GC-MS. A single trans product was exclusively
favorable
theother.
formed; therelativeat theScheme1)31stereochemistry
relativethan
to a larger
one1-position(entry 4b,(–Me/–nPr$33% ee$1
could not0.56
be unambiguously
determined.
Selectivity
measurements
kcal mol ; Scheme1). In further
supportof thishave an estimated error of #3%.
smaller
degree of recognition(indicatedby small diﬀe
Enantioselectivity: Small
Host
Smaller cavity
product selectivity and conversion) was observedof 5a and host D4-4 (entries 6a and 7a) com
Trans conformation destabilizedresultingenantiomers
Smaller
Larger (!)-1 and 2
fromtreatmentof smaller
5a–c
with
analogous trials withhosthosts
D4-2 (entries 2a
Racemic
3
1 it was observed
compared
to
(!)-3
and
4.
Generally,
thatnotion
transWhile these observations are consistent with the
Diasteroselectivity : Large Host
selectivity
increaseswithcavity size,2 whichmay
Enantiopure
4 also accompany
magnitudeof host-mediatedenantioinduction
increa27 thesean improvementincatalytic
eﬃciency.
Consistent
withguest size (or decreases with host cavity size), it should
N. Raymond,
et al., Chem. Suggest
Sci. 2015, that6, 1383.
observations, Kenneth
gas-phase
DFT calculations.
theOutline
Outline1. Introduction
1-1. Supramolecular Chemistry1-2. Metal-Ligand Self-Assembling Supramolecule
2. Unimolecular Reaction with Supramolecule2-1. Aza-Cope Rearrangement
2-2. Nazarov Cyclization
2-3. Aza-Prins Cyclization
3. Reaction with Metal Encapsulated within Supramolecules
3-1. Development of C(sp3)-C(sp3) Coupling Reaction with Supramolecules
3-2. Development of Coupling Reaction with Cu / Pd in Water
3-3. Selective Catalytic Hydrogenation Independent of Chain Length
4. Stereoselective Reaction by Host Size and Flexibility
4-1. Stereoisomer of Self-Assembly Complex
4-2. Stereoselectivity by Host Size (Prins Reaction)
4-3. Stereoselectivity by Host Flexibility (Aza-Darzens Reaction)
5. Summary
28

guest, which lowered the yield of the reaction to 10% after 24
are exceedingly rare within a self-assembled container
h. This result demonstrates the necessity of the host cavity for
4-3 molecule.
the reaction to proceed eﬃciently (Scheme 2c).
Given our previous results employing iminium intermediates
ReactionusbytoHost
Size
Flexibility
These Stereoselective
initial results encouraged
exploretheandgenerationin reactions catalyzed by 1, we ﬁrst sought to identify aof more complex products where diastereomeric selectivity
nucleophile that would be compatible with the host and the
could be investigated. Acetaldehyde was ﬁrst selected as areaction conditions, and which could be employed in a
mol%which could undergo the reaction withcoupling 5partner,
multicomponent
reaction. These eﬀorts identiﬁed
ethylNH2O(racemic)aniline and
EDA to provide disubstituted N-phenylaziridines
diazoacetate
as Oa nucleophile
thatSociety
R2
Journalof the(EDA)
AmericanChemicalpubs.acs.org/JACSComm
2 met these requireR
where the formation of both cis- and trans-aziridines
would bements and showed a propensity to bind to host OEt
1. Next, weNCO
2Et aniline,1
possible(Scheme3a).
The
presence
of
5
mol
%
1
with
examinedtheamine
component
requiredforformationoftheDE-AC02-05CH1123).
We thank the LBNL Cataly
Scheme 7. ProposedRMechanism
for Aza-Darzen
Reaction
pH 8 H2O, 100mM K3PO4,H
N2electrophilic
iminiumcomponent
withformaldehyde,
intheR1 Energy Sciences (BES) p
supported
within the Raymond Tetrahedron
50% MeOH,
16 h by DOE Basicpresence of 1 and EDA. While basic amines (BnNH2 andSchemeaccess
3. (a) toEﬀect
n-Aldehyde
Substituent
on of Chemis
ESIofMS.
We thank
College
IPrNH)
andamides
(AcNH
)
did
not
aﬀord
any
desiredReactivity
and(b)
BlockedHost
Control(Reportedas▶ Scope22▶ Mechanism
facilityforresources
provided
and
the
staﬀ
for their
azirdine, we found that aniline and aqueous formaldehyde (37NMR Yields)
Instruments in CoC-NMR are supported in par
wt %) coupled with EDA to form N-phenylaziridine 2a in an
aza-Darzens reaction, promoted by catalytic amounts of host 1
S10OD024998.
(Scheme 2a). Building on this initial result, we sought to ﬁnd

Aza-Darzens Reaction with Supramolecule

Journalof theAmericanChemicalSociety
Scheme2. (a)
InitialScreeningfor Multicomponent
AzaDarzens Reaction, (b) Scope of Monosubstituted Aziridines
Scheme As
4. Eﬀectof Yields)
Aryl Substitution
on Disubstituted(Reported
Isolatedand (c) Blocked
Host
Aziridine
Synthesis(Reportedas
NMR
Yields)Control (Reported as NMR Yield)■

REFERENCES
pubs.acs.org/JACS

Communication(1) Rizzuto, F. J.; von Krbek, L. K. S.; Nitschke, J. R. S

catalyzed by 1, gave the trisubstituted N-phenylaziridine in
Binding Multiple Guests in Metal−Organic Cages. Nat.
70% yield, with excellent selectivity for the trans-(Me, CO2Et)2019, 3, 204−222.
diastereomer as determined by 1D NOE correlation (Scheme(2)Further
Zhang,substitutionD.; Ronson,
T. K.;
Nitschke,
J. R.tolerated
Function
6, 8b).
of theα-diazo
ester wasvia Subcomponent Self-Assembly. Acc. Chem. Res. 2018
optimalreactionconditions Aziridine
and explore
the scopeof thisas
2436.
Scheme6. Trisubstituted
Synthesis(Reported
reaction.
While
poorT. solubilityof thecomponents
Cook,R.; Stang,P. reaction
J. RecentDevelopme
NMR(3)
Yields)precluded
reactivity
inwater,
andpure
methanolgave
poorMeta
Preparation and Chemistry of Metallacycles andreactivity
due to the lackof aRev.
hydrophobic
driving
force for the
Coordination.
Chem.
2015, 115,
7001−7045.
encapsulationof reagentsthe host,
a 50%C.(v/v)(4) Wiester,M. J.;within
Ulmann,P. A.;using
Mirkin,A. Enzymethanol/pH
8
water
mixture,N-phenylaziridine(2a)
was AnBased Upon Supramolecular Coordination Chemistry.
isolated in good yield and at low catalyst loading (82%,Int. Ed. 2011, 50, 114−137.
Scheme 2b). Substitution on the aniline ring was tolerated for(5) Mastalerz, M. andPorousShape-Persistent
Organic
both electron-withdrawing-donatinggroups at boththeThree-component reactions with supramolecular para pounds
Size, Geometry,
Function.
(2b,c) ofandDifferent
meta positions(2d,e), andprovidingthe Acc
2018, 51, N-phenylaziridines
2411−2422.
in moderate yield. As aevidencethat selectivity
the cavity of this supramolecular assembly is corresponding
Trans
(6)
Taylor,L.
L.
K.;
Riddell,I. A.;trans-aziridine
Smulders, 29
M.(3)M. J. Se
acetaldehyde,
and
EDA
gave
the
N-phenyl
essential for the multicomponent reaction observed. We to some degree; however, yields1 diminishedwhen
thelongerα-73
as the major
diastereomer(20:1,
H
NMR)
in
68%
yield.
Thisof Functional Discrete Three-Dimensional Architecture
N. RaymondF. DeanToste, etal., J. Am.
Soc. 2020,
142,again733.
envision that this reaction could inspire theKenneth
developmentof andpropylsubstituted
α-diazo
esterChem.
was employed
(8e),

4-3

New Ga(III)-Containing Enantiopure Hosts
Stereoselective Reaction by Host Size and Flexibility
12Enantiopure [Ga4L6] complex

Figure 2. Nine new Ga(III)-containing enantiopure hosts prepared from structurally related biscatecholate ligands.

The only difference : Substituents of the ligand near the apex

the SI). Optimized
conditions for host synthesis required slow
Scheme 2. Asymmetric Aza-Darzens Condensation・
addition of the base by a syringe pump while heating theCatalyzed by Host 4
reaction mixture to 72 °C in ethanol. After cooling,
Relates to the flexibility of the opening
precipitation with diethyl ether enabled the isolation of thehosts by ﬁltration as yellow powders (Figure 2). 1H NMR of30
these hosts with the addition of a strongly boundguest,
Kenneth N. Raymond and F. Dean Toste, et al., J. Am. Chem. Soc. 2020, 142, 733.

Divergent Selectivity in Enantiopure
Hosts
pubs.acs.org/JACS

4-3 of the American Chemical Society
Journal

ArticleStereoselective Reaction by Host Size and Flexibility

Figurep-substituent
3. Divergent selectivity in enantiopure host-catalyzed aza-Darzens reaction.

The differences in reactions between
4-methylaniline
and 4-chloroaniline
subjected to the
Difficultto enter thewere
cavityreaction, disparate selectivity for aziridines 3e and 3f was
supramolecules are striking.
observed acrossthecatalyst
series.
A
similartrend
inselectivity
Decrease in both yield and ee
31
for aziridine 3c of weaker magnitude was observed when the
N. Raymond and F. Dean Toste, et al., J. Am. Chem. Soc. 2020, 142, 733.
smaller 4-ﬂuoroaniline was used in the reaction. Kenneth
In contrast,conﬁrmed the structure be
exchanged guest 13 the fastest were those that provided thewith each corner adopting
4-3 degreehighestof selectivity inthe aza-Darzens
reaction. and Enantioselectivity
RelationshipbetweenFlexibility(R)-naphthyl(Fig
Stereoselective Reaction
by Host Sizeamides
and Flexibility

ΔG‡ kex : flexibility

Optimal model substrate
Chiral center
Large 4-substitution on its aromatic ring

Figure 6. Single crystal XRD

similar to the cavity size
average Ga−Ga distance
Figure 5. Correlation of reaction
enantioselectivity
ﬂexibility
Flexible
structure to host Highenantioselectivity
average Ga−Ga distanceo32
as measured by SIR NMR exchange kinetics of model salt 13.
host
and
ho
Kenneth N. Raymond and F. Dean Toste, et al.,structures
J. Am. Chem.ofSoc.
2020,1142,
733.

aldehyde
as a coupling
partner,reaction to proceedeﬀectively.
Investigating
thewhichscopepdiminishedenantioselectivity.
4-3
Relationship between
Metalbut
Ions
and Host
Flexibility
host 14-mediatedasymmetrictransformation
revealed
Stereoselective Reaction by Host Size and Flexibility
pubs.acs.org/JACS
Al(III)-Derived
Hosts metal ionssubstrate
sizeArticle
again playeda key role in the host-cat▶ Relationshipbetweenand host
flexibility
CONCLUSIONS
reaction.
High
selectivity
was maintained for 3-subst
generates a more rigid architecture (Figure 5). When host 15
1 is a competent
cataanilines asreaction,
well asitEnantiopure
aldehydes ofhost
diﬀerent
lengths. Simila
was employed as a catalyst for the aza-Darzens
proved to be less selective than the galliumand indium-based
Darzens
providing
substituted
anilines
are alsocondensation,
tolerated in thereaction,enanwihosts, providing aziridine in 77% ee and 47% yield. bonding distance : Al-O < Ga-O < In-O
98% ee andexcellentyields.the
This
high
smalleranilineprovidinghighestThe best-in-class catalyst, indium-derived
host4-ﬂuoro-substituted
14, was used
remarkable,
thatusehostand selectivity.
One
notable considering
outlier was theof
to investigate the scope of the asymmetrictransformation(Scheme 4). The racemic host-2-catalyzed
performing
chiralligand,catalyst
aldehydeaza-Darzens
as a coupling
partner,whichgood reao
flexibility: 15< 2 <provided
14
group, with enantioinduction being
but diminished enantioselectivity.
Scheme 4. Scope of aza-Darzens Reaction Catalyzed bymolecular chirality. The aza-Darzens
In(III)-derived Host 14
CONCLUSIONS
as a tool to probe the eﬀect of host aand ninegallium
Enantiopure host enantioselectivity,
1 is a competent catalyst
fornew
asymmetr
hosts weresynthesized.
Studying thesecellent yield, and ESI HRMS conﬁrms
Darzens thecondensation,
providingenantioselectivityofreactionsinvolvinglargersubstrates
lea
e new hosts. Despite hosts 1, 98%
14, and
15 excellent
ee andyields.
This highdegreeof selectisuggestingthatthat these hosts have ddentical ligands, diﬀerences inremarkable,
the cavity considering・ High yieldshost 1 contains no
the ortransition
nt can be observed by comparing
the chiralaccommodate
performing
ligand,directingstate.
func
・ High catalyst
enantioselectivity
selectivity
in thebeing
aza-Darzens
condens
apsulated guests (see the SI). In
addition,group,
with enantioinduction
the resultof・ p-substitutes
are allowed.
theTheexchange
rate ofa model non
host 14 exchanged model molecular
guest 13chirality.
aza-Darzens
condensation
was
thatofthe
most
ﬂexible hostsarthan its gallium-based counterpart,as a tool to proberevealing
the eﬀect
hostarchitecture
on re
the
reaction. The
obse
thesis that indium would lowerenantioselectivity,
the barrier
and condensationnine new gallium-based
supramolcorrelates
to selectivity
andhosts
that33reveale
the cr(Figure5). conﬁrms
When subjected
tothewereaza-synthesized.
hosts
Studying
these new
ESI HRMS
theshows
diﬀerence
intocavity
on
4-methoxyaniline
as theKennethN.involving
Raymond and
F. Deanlittle
Toste,
et al., J. Am.
Chem.
Soc.
2020,volume
142, 733.
reactionslargersubstrates
lead
disparatereacpitereaction
hosts 1,with
14, and15

on with ether provides■■

Outline
Outline1. Introduction
1-1. Supramolecular Chemistry1-2. Metal-Ligand Self-Assembling Supramolecule
2. Unimolecular Reaction with Supramolecule2-1. Aza-Cope Rearrangement
2-2. Nazarov Cyclization
2-3. Aza-Prins Cyclization
3. Reaction with Metal Encapsulated within Supramolecules
3-1. Development of C(sp3)-C(sp3) Coupling Reaction with Supramolecules
3-2. Development of Coupling Reaction with Cu / Pd in Water
3-3. Selective Catalytic Hydrogenation Independent of Chain Length
4. Stereoselective Reaction by Host Size and Flexibility
4-1. Stereoisomer of Self-Assembly Complex
4-2. Stereoselectivity by Host Size (Prins Reaction)
4-3. Stereoselectivity by Host Flexibility (Aza-Darzens Reaction)
5. Summary
34

and free catalyst oﬀered promise for realizing
Summarysupported
selective oleﬁn hydrogenation.

5

Table 1. Screening of General Hydrogenation Reactivity for
Simple Oleﬁnic Substrates by Catalyst 1

ax

N

N

A competition experiment was then performed toSummary
determine
if 1 could discriminate between methyl- and ethyl-substituted
oleﬁns (3 and 5, respectively). Good conversion of methylP Cu
P observed while ethyl-oleﬁn starting
oleﬁn (3) wasmaterial(5)
I
Cu
was recovered in high yield (Figure 2a). In the analogousPHof the American
Chemical Society
EncapsulatedArI

pubs.acs.org/JACS
Co-encapsulated

7. Proposed
Mechanism forofAza-Darzen
Acceleration
reaction Reaction
he Raymond Tetrahedron
Selectivity change

P

Ar

Communication

DE-AC02-05CH1123).Reductive
We thank theElimination
LBNL Catalysis FacilityOsupported by DOE Basic
Energy Sciences(BES) program for
Coupling
ReactionsO
accessto ESI MS. We thank College of Chemistry’s NMR
O
NHfacility for resources provided and the staﬀ for their assistance.
Instruments in CoC-NMR are supported in part by NIH
S10OD024998.

■

REFERENCES
cavity(1) Rizzuto, F. J.; von Krbek, L. K. S.; Nitschke, J. R. Strategies forOO
Binding Multiple Guests in Metal−Organic Cages. Nat. Rev. Chem.
O
2019, 3, 204−222.
(2) Zhang, D.; Ronson, T.
K.; Nitschke,Catalytic
J. R. Functional Capsules
Stereoselectivity
Selectivea12h reaction time. bReactions performed at 50 °C.
via Subcomponent Self-Assembly.
Acc. Chem. Res. 2018, 51, 2423−
by Host Size and Flexibility
Hydrogenation
2436.
(3) Cook, T. R.; Stang, P. J. Recent Developments in theand Chemistry of Metallacycles and Metallacages via
oleﬁn, but signiﬁcantly faster (1 h versus 12 h) Preparation
than
Coordination.
Chem. Rev. 2015, 115, 7001−7045.
supramolecular catalyst 1. To verify that this reactivity(4) Wiester, M. J.; Ulmann, P. A.; Mirkin, C. A. Enzyme Mimics
diﬀerence was due to host encapsulation of 2, a standard
Based Upon Supramolecular Coordination Chemistry. Angew. Chem.,
control reaction was performed: to in situ formed 1 was added+
Int.inEd. 2011, 50, 114−137.
strongly binding guest Et4N (as salt [Et4N][Cl]), resulting
35
28
ejection of 2 and Et4N-blocked host. With the cavity of (5)the Mastalerz, M. Porous Shape-Persistent Organic Cage
ComHN

host blocked, complex 2 maintained the same levels ofAppendixC(sp3)-C(sp3) Reductive Elimination

3-1

Appendix▶ Phosphine
Energeticligand
Analysiseffects
of Me3P vs. Et3P reductive elimination
L = PEt 3

L = PMe 3
Transition State For
Background
Reductive Eliminationgstabilizationof TS forreductive
elimination

stabilizationof TS forreductive
eliminationfTransition State For
Cluster Catalyzed
Reductive Elimination

e

c
d

I1

b

I1
I2

bindingenergyI2
bindingenergy

a

SM

SM

PDT

L
Me

Au

I
Me

L Au

Me
Me

PDT

I2

I1

SM

+ I
L Au

Me
Me

e = ∆∆G‡ for catalyzed observed rate = 2.5 kcal/mol (68 fold at 298 K)
g = ∆∆G‡ for background observed rate = 0.79 kcal/mol (3.8 fold at 298 K)(c + e) - (b + c) = e - b = ∆∆G‡ for kcat = 2.2 kcal/mol (38 fold at 298 K)

+ I

L
Me

Au

+

I

Me

PDT

Difference in binding energy between (PMe3)Me2Au(III)+ and (PEt3)Me2Au(III)+b = ∆∆G for binding = e - (e-b) = 2.5-2.2 kcal/mol = 0.3 kcal/mol
Difference in total activation energy relative to backgrounds
f + g = ∆∆G‡ for PMe 3 catalyzed vs. uncatalyzed
e + f = ∆∆G‡ for PEt 3 catalyzed vs. uncatalyzed∆∆∆G‡ = (e + f) - (f + g) = e - g = 2.5 - 0.79 = 1.7 kcal/mol

37
Kenneth N. Raymond, and F. Dean Toste, J. Am. Chem. Soc. 2016, 138, 9682.

ate of 2.0 × 10−2 s−1 was measured for the combined
3-1
ion/reductive
elimination process. For comparison,
do-ﬁrst-order rate of oxidative addition of methyl▶ Dual catalysts
6 at 45 °C was measured to be 4.38 × 10−4 s−1. This
clearly suggests thatMethefailure Me
to detect 26 under
3PPt
10 mol%in theconditions is due to its rapid consumption
Me
P
Me
3
of theMesupramolecularcatalyst.
Me Me
I
together, these observations suggest an overall
5 mol%+ process in which the trans-isomers
m for theof the +d Pt(IV)
complexes
lie on cycle, with 5 serving as Me
a 3Sn F
SnMe
4
gaged oﬀ-cycle restingstate andreservoir (Figure 15).
MeOH-d
4/D2O=8/2, 45℃+
addition precedes transmetalation, and 26 is rapidly +by the supramolecularcatalyst.38 This mechanism is KI
KF

Application of Dual Catalysis Cycle
O

tBu

Appendix

12­

N
H
O
O
NH

O
Ga3+

O

HN
O

O
O
tBu

NH

38
Kenneth N. Raymond, and F. Dean Toste, J. Am. Chem. Soc. 2016, 138, 9682.

formed. The identity of the products, 8 and 9, was veriﬁed bydirect analogy to authentically prepared phosphonium salts.
3-2
The generation of these products is indicative of iodoarene

supramolecular cages can provide access to host-selective
Development of Coupling
Reactionin Waterreactiontrajectories.
Appendix

Confirmation of product generation (Pd complex)

Figure 3. (a) 1H NMR analysis (500 MHz, 25 °C) of palladium(II) monomer 7 encapsulated in host 1. (b) Coencapsulation of aryl iodide and 7.
(c) 1H NMR analysis after addition of iodobenzene, indicating encapsulation of phosphonium products 8 and 9.
1704

DOI: 10.1021/jacs.8b11842
39
J. Am. Chem. Soc. 2019, 141, 1701−1706

F. Dean Toste, et al., J. Am. Chem. Soc. 2019, 141, 1701.

3-3

Selective Catalytic Hydrogenation
AppendixCommunication

Figure 5. (a) Minor conversion of 15 was observed using catalyst 1.
Catalyst 16 provides good conversion of 15 to the singlyhydrogenated product 17. (b) Competition between two acids with
diﬀerent alkane lengths show similar conversion, indicating remotegroup does not aﬀect reactivity.

agreement with similar conversions observed with two
Figure 4. (a) Supramolecular host supported hydrogenation ofcarboxylic acid substrates of diﬀerent alkyl lengths (Figure
rans,trans-2,4-hexadiene-1-ol (12) to cis-3-hexen-1-ol (13). (b)5b), which are proposed to undergo conversion in this way due
Under dideuterium conditions, selective 1,4-addition was observedto unfavorable coulombic interactions.
o yield a single major isomer 14.
In conclusion, we have demonstrated the abilityof a40
supramolecular-supportedhydrogenation catalyst to perform
F. Dean Toste, et al., J. Am. Chem. Soc. 2019, 141, 11806.

Stereoselectivity by Host Size

4-2

ccess Article. Published on 28 November 2014. Downloaded on 10/02/2015 23:23:53.
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Chemical Science

Scheme 2

1

View Article Online

Appendix

Edge Article

Proposed mechanisms for host-catalyzed Prins cyclizations, where stepwise (k1, k2) or concerted (k3) pathways are plausible.

41
Kenneth N. Raymond, et al., Chem. Sci. 2015, 6, 1383.

oacetate(EDA)
as athenucleophile
met tothese
guest, which
loweredyield of thethat
reaction
10% requireafter 24
nts
andshowedapropensity
to
bind
to
host
1.
Next,
h.4-3
This result demonstrates the necessity of the host cavity we
for
mined
the amine
component
required
for formationof thethe reaction
to proceed
eﬃciently(Scheme2c).
trophilic
iminiumcomponentin theThese initial
results
encouragedwith
us toformaldehyde,
explore the generation
senceof 1complex
and EDA.
While
basicdiastereomericamines (BnNH
of moreproducts
whereselectivity
2 and
could
be investigated.
Acetaldehyde
wasaﬀordﬁrst selected
as aNH
amides (AcNH
any desired2) and2) did notcoupling
partner,undergo formaldehyde
the reactionNHdine,
we foundthat2whichanilinecould
and aqueous(37
O withanilineandEDA
toprovidedisubstituted
N-phenylaziridines%) coupled with EDA to form
2a in anO N-phenylaziridine
R2 wouldwhere
theformationof
bothcisandtrans-aziridinesbe1
Darzens reaction, promoted by catalytic amounts of hostOEt
1
possible(Scheme3a).
The
presence
of
5
mol
%
1
with
aniline,heme 2a). Building on thisRinitialHresult, we sought
N2 to ﬁndaniline and EDA to provide disubstituted N-phenylaziridines
6, 8b). Furthwhere the formation of both cis- and trans-aziridines would be
Scheme 6. T
possible (Scheme 3a). The presence of 5 mol % 1 with aniline,

Aza-Darzens Reaction with Supramolecule

NMR Yields

Appendix

Scheme 3. (a) Eﬀect of n-Aldehyde Substituent on
Reactivity and (b) Blocked Host Control (Reported as
5 mol%NMR Yields)(racemic)
R2
N
CO2Et
pH
8
H
O,
100
mM
K
PO
,
2
3
4
acetaldehyde, and EDA gave the N-phenyl
R1 trans-aziridine (3) to some degr
1
50% MeOH, 16 has the major diastereomer (20:1, H NMR) in 68% yield. This propyl subst
selectivity for the trans diastereomer was maintained for demonstratin▶ Inhibition
propanal(4) and Experiments
butanal (5); however, yields and selectivity transformatio
In order tnomajor
eﬀect onselectivity. Aswhen
previously
observed(6)whenwasfor the trans productdiminishedpentanal
componentc
was used as a coupling partner, size exclusion also
employed. pentanal
The
lack
of
reactivity
withpentanal
was
attributed
conducted.
F
appears to play a role in the aniline component. For example,
components
to the increased
size
of
this
substrate
preventing
coencapsuthe formation of 3-methylaniline-derived trans-aziridineof aniline, aoccurred
53% yield in reactivity.
24:1 trans selectivity
(4b),
while
lation within
1 andinsubsequent
The high
selectivity
between theminimalreactivity was observedin theAza-Darzens
host-catalyzed reaction(20:1)
forthetrans-aziridine
inthisreactionaminal, witho
pubs.acs.org/JACS
Communicationof 3,5-dimethylaniline (4f).
or within the
catalyzed by The
1 was
surprising,asliterature
examplesfor
thisexperiments with 3,5-dimethylaniline (Scheme 4, 4f)
encapsuandpentanal(Scheme3b,
6)
areconsistentwiththereaction typically provide the cis-aziridine as the major isomer thatcatalyzed by 1, gave the trisubstituted N-phenylaziridine inmight
31 scope
hypothesisthat
iminium
be small theenoughto ﬁt of thisbe favo
reactionconditions
andmustwhen α-diazo
estersare theemployed
as explore
nucleophiles.
70% yield, with excellent selectivity for the trans-(Me, CO2Et)- optimal
within the host for the reaction to proceed eﬃciently. + the aniline
While
poor
solubility
thereactioncomponents
In contrast,
whenreaction
withtheEtα-4N - formation indiastereomer as determined by 1D NOE correlation (Scheme reaction.
Therefore,
thethesize
limitation wasofoftheperformed
third component,
blocked
1,
only
minor
backgroundconversion(ca.
7%)
the association.
diazo ester, wasester as totheinexaminedwater,using
anda larger
puretert-butyl
methanolgave
poor
6, 8b). Further substitution of the α-diazo ester was tolerated precluded reactivity
resulted in no
nucleophilic wascomponentof the Aza-Darzens
reaction(Schemeaziridine
product
observed(Scheme3b).
Furtherreactivity due
thelarger
lackα-diazoof a hydrophobic
drivingofforce
thetheα-diazo e5a).togave only an 11%
the forinvestigationofThistheproduct ester
revealed
that the yieldcis-aziridine
optimalconditions Aziridine
and explore
the scopeof thisas
NMR time sc
Schemereaction
6. Trisubstituted
Synthesis(Reported
encapsulationof reagents within
theas host,using
a 50% (v/v)
was formedScheme
in the5.uncatalyzed
process
opposedto the trans- was perform
reaction.
While poor solubility of the reaction components(a) Eﬀect of Bulky
Ester
on
Aza-Darzens
NMR Yields)
8 water
mixture,N-phenylaziridine(2a) components
wasaziridine generated
when
the hostHost
cavitywas(Reported
not blocked.
This
precluded reactivity in water, and pure methanol gave poor methanol/pH
Reaction and(b) Blocked
Controlas NMR
showed ﬁrstgood
yield
and atcatalyst andloading
reversal inin Yields)
selectivity
betweenthe low
host-catalyzed
back- (82%,reactivity due to the lack of a hydrophobic driving force for the isolated
in α-diazo
Substitution
on thatthe theanilineringinterior
was tolerated
for w
ground2b).
reactionsdemonstrates
conﬁnedof the consistentencapsulation of reagents within the host, using a 50% (v/v) Schemetheﬁrst-orde
hostelectron-withdrawing
not only accelerates theandreactionbut alsogroups
overrides
the themethanol/pH 8 water mixture, N-phenylaziridine (2a) was both-donatingat bothacetaldehyde,
and
EDA
gave
the
N-phenyltrans-aziridine(3)
for iminium
inherent
diastereoselectivityof the uncatalyzed
process.
isolated in good yield and at low catalyst loading (82%, para1functioning
and meta (20:1,
positions(2d,e),
providingtheas Several
the(2b,c)major
diastereomer
NMR)
in 68%
yield.
substitutions
on the anilineHring
were tolerated
at theThis
Scheme 2b). Substitution on the aniline ring was tolerated forexperiments,
corresponding
in moderate
yield. As
selectivity
for N-phenylaziridines
the transalldiastereomer
maintained
for a bymeta and para
positions,of which werewas
selective
for the catalyzed
both electron-withdrawing and -donating groups at both theester wpropanal(4) andbutanaltrans-aziridine(5); however,yields anddisubstituted
N-phenyl(Scheme4). selectivity
Both diazopara (2b,c) and meta positions (2d,e), providing thebinding equi734
forthe transandproductwhen pentanalelectron-rich-deﬁcientdiminishedrings were reactive,
and there(6)was wascorresponding N-phenylaziridines in moderate yield. As alation of an
acetaldehyde, and EDA gave the N-phenyl trans-aziridine (3)employed. The lack of reactivity with pentanal was attributed
42driven by theto somehowever,yields1Hdiminishedthe longer
https://dx.doi.org/10.1021/jacs.9b13177 Inside the as
as themajordegree;
diastereomer(20:1,NMR) in when
68% yield.
This α-734 to the increased size of this substratepreventing
Am. Chem.
Soc. 2020,
142,coencapsu733−737 142,
Kenneth
Chem.
Soc.
2020,
733.
additiontopropyl substituted α-diazo ester was employed (8e),againN. Raymond and F. Dean Toste, et al., J.J.Am.

Scheme 3. (a) Eﬀect of n-Aldehyde Substituent oneme
2. (a) Initial Screening for Multicomponent AzaReactivityand (b) Blocked Host Control (Reported as▶ Scopezens
Reaction,
NMR Yields) (b) Scope of Monosubstituted Aziridines
ported As Isolated Yields) and (c) Blocked Host
ntrol (Reported as NMR Yield)

4-3(m, 6H), 6.19 – 6.09 (m, 2H). 13C NMR (151 MHz, DMSO) δ 167.70, 167.23,
12-149.28, 148.13, 133.09,
132.71, 129.34, 129.23, 128.81, 128.42, 126.09, 123.65, 124.724(q, 6
J = 281.8 Hz), 121.27, 119.28,
118.93, 117.91, 117.60, 53.62 (q, J = 30.6 Hz). 19F NMR (565 MHz, DMSO-d6) δ -72.05 (d, J = 9.0Appendix
Hz).

Synthesis of [Ga L ]

R*
NH

O
O

6

R*

OH

O

OH

HN

NHO

O

NH

4 Ga(acac)3

HN *
R

O

EtOH, KOH
72 oC
OHN

NH

HO

12

O

O

OH O

O

HN
*R O

= Ga(III)

CF3

Et

R* =
(4,R) 90%

iPr(5,R) 74%

Ph(6,R) 87%

Cy(7,R) 96%

Ph(8,R) 90%(9,R) 90%F
(10,R) 82%

Me(11,R) 52%

Ph(12,R) 71%

Ligand S4a (0.075 mmol, 6 equiv.) and Ga(acac)3 (18.4 mg, 0.05 mmol, 4 equiv.) weredissolved/suspended in degassed wet ethanol (4 mL, 200 uL added H2O) and heated to 72°C. After 15 minutes, KOH (12.6 mg, 0.225 mmol, 18 equiv.) as a solution in wet ethanol (2 mL,
100 uL added H2O) was added slowly at 0.015 mL/min via syringe pump to the heterogeneous
reaction. Upon complete addition of KOH, the yellow reaction mixture became a homogeneous
solution, and the reaction was allowed to cool to rt. The host was then precipitated via additionof diethyl ether (15 mL) to the stirring solution. The yellow solid was then collected by filtration
and washed with diethyl ether (15 mL) to give the desired supramolecular complex.
11

43
Kenneth N. Raymond and F. Dean Toste, et al., J. Am. Chem. Soc. 2020, 142, 733.

y-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.201801026 by University Of Tokyo, Wiley Online Library on [17/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Cr

4-3

niversity Of Tokyo, Wiley Online Library on [17/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Aza-Darzens Reaction with α-diazoesters

Reviews

cis-aziridine

67

with

simultaneous

elimination 44of

N2

18673899, 2018, 22, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.201801026 by University Of

1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

treatment ofof 68 and69 with and1 equivalentof imine
7
Gong group’s.[36] Studies on the relationship between
titanium
complexmediated
the formation of a series ofthea mixture
33(Schemean ion 1pair consistingof ainboroxinateanion
8
amides 33
moderate
to excellent yields (40–99 %),BINOL-derived ligands used in this reaction shownthat 23).
3,3’-This is a,b-epoxy
34
and a protonated iminium.2 Subsequently, the crystal structure
9
excellent diastereoselectivities (only the cis-isomer was obsubstituents have considerable impact on the stereochemistry.
35of the active catalyst waselucidated by X-ray diffraction
10
3 andserved),enantioselectivities
of up to 99 % ee. This approach
Thus, 3,3’-diiodobinaphthol ligand 34 in combination
with
36
analysis, providing
criticalunderstandings
into molecular recog114[63] of structurally varied aldehydes 1, suchtolerated
a
broad
range
tetrabutoxyzirconium,
catalyzed
thereactionofN-phenyldiazo37
nition between the catalyst and its substrates.
12
The mechanism of the5chiral VANOL-BOROX Brønsted acid
13
38
Scheme 19. Catalytic asymmetric one-pot ADR catalyzed
by ProPhenol ligands.
6
mediated aziridination reactionof EDA (60) and imines 71 was
14
39
7
examined through an experimental
kinetic isotope effects and15
40
theoreticalthat
calculations
combinedstudy.[52] As a result, Wulff’s
16synthesis.[53a] However, Wipf et al.[57] suggested
increasing
8
41suggested
implicationof a stepwise mechanism,
17
the steric bulk at the 3,3’-positions ofgroup
BINOL
ligands thewould
9
42 21. Catalytic asymmetric aziridination catalyzed by chiral binaphthol
Schemewhere
reversible
formationofadiazonium
ion intermediate18
improve the facial control in this aziridination reaction. Indeed,10
borate.
43(gauche-72/anti-72) antecedes to SN2-like ring closure to form
19
this group examined the introduction of different bulky arene
cis-aziridine 67 with 11
simultaneous elimination of N2
20
44
substituents at the 3,3’-positions of BINOL ligands and found
12report examines the role of borate(Scheme 24). A very recent
21
45
that, in particular, 64 as chiral ligand with
2-phenylnaphthaleneesters of BINOL as chiral catalyst
in the aziridination reaction.[64]parts N-protected imines. Although acid-mediated cleavage of22
13
46
moietyaffordedN-Bhaziridines
65
with
a
significant
MEDPM group was difficult to achieve, p-methoxy substituted
Analyzing the structures 14
of borate esters of BINOL, that were23
47
of theenantiocontrol
process(Scheme21).
benzhydryl protecting enhancement
groups such as
DAM,
BUDAM and of the
producedwithdifferent
stoichiometric combinations of BINOL
24
15
48
This
chemistry
been widelyin 3 termsof the or absence of a base, pyroborates,
MEDAM
were readily cleaved
fromaziridines has
67 without
ring- exploredand B(OPh)in the presence
25
1649
openingside reactions. nature and structural design of catalysts,
spiroborates
and boroxinate
26
the influenceof N- species can be generated. Wulff’s
and structure
the catalyst,
group foundthat borate 17
species derived from BINOL were not
27
50Regarding the naturesubstitution
in of
imine
partner mechaand the relevanceof diazocarbon1
11
18 of VAPOL and VANOL. Under thenisticanalysescatalystsgroupthan thoseand toB NMR)
28yl compound.
In an( Heffort
discover inferiora protectingfor
51 studies through spectroscopic
reactionconditions,
BINOLand high-resolution mass
have been
performed
29
19forms a boroxinate and spiroborate
the spectrum
nitrogen atomof aziridines,
allowing
its easy
removalfor52
species that give opposite
disclosing the presence of two species which have been
30
20 asymmetric inductions in thethe access to N-H-aziridines without any ring-opening side
53
aziridination reaction.
identified
as mesoborate 68 and pyroborate 69 in ratios
31
21
reactions and affording high asymmetric inductions,
Wulff et al.
54
Another relevant aspect in Scheme
this asymmetricrangingfrom 1 : 3–5 (Scheme 23).[61] Studies with catalysts
32
23. BorateBrønsted
catalystsacid
species B1, B2 and B3 generated from V
22theirled
attention
to the effect55
catalyzed substituents
aziridination on
reactionis the structure of the diazoenrichedin B1 orturned
B2 species
to the conclusionthat of different
33
Scheme 20. Catalytic asymmetric aziridination mediatedby chiral eitherboron acid23
the N-diaryl unit of imine derivative. This revision led to thewith biaryl VAPOL and VANOL ligands.
34
56
classificationofN-protecting
groupsbetterthanthebenzhydryl
24
35
Scheme 13. Catalytic enantioselective DR between diazoacetamides and aldehydes.
57
36
group,
interms
ofasymmetricinductionandoverallyieldsof25
the active catalyst in the VAPOL or VANOL mediated asymmet37 well exemplified byaziridines
67,
affordingcleanerandfasterreactionsthis catalytic asymmetric process has been
ric aziridination reaction is B2 species, since this gave26consid38 (!)-chloroampheChemCatChem 2018,10, 509222).
– 5114www.chemcatchem.org! 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim(SchemeThe N-protecting
groups examined were5099
dianisylWulff’s group in the preparation of antibiotic
erably higher
enantioselectivities and rates than the
B127
catalyst.
39
[58]
[59]
methyl (DAM), tetra-tert-butyldianisylmethyl (BUDAM), [62]tetnicol, which was prepared in four steps in an optically pure28
In 2009, further investigations by Wulff’s group proposed
40
form starting from p-nitrobenzaldehyde,[54] and later, in theramethyldiphenylmethyl (MEDPM)[60] and tetramethyldianisyl29before,
41
that the active catalyst is not a Lewis acid, as suggested
synthesis of BIRT-377, a leukointegrin LFA-1
antagonist develmethyl (MEDAM).[60] The results showed that the N-MEDAM
42
but a boroxinate based Brønsted acid 70 (B3) derived 30
from theoped as an agent for the treatment of immune
and inflammaimines 66 were found to be superior to, not only the N-DAM
43
31
treatmentofamixture
of
68
and
69
with
1
equivalent[55]
tory disorders. Afterwards, this efficient44asymmetric aziridinaimines, but also to the formerly reported N-benzhydryl and N-of imine
32[56](Scheme23).inThis
is an ionfor
pairtheconsistinga boroxinate
BUDAM
imines,particularimines ofderivedfrom anion
tion was also exploited by Chen et al. 45
for the total synthesis
and aaldehydes.
protonatedcrystal22,33
structure46
aliphatic
Foriminium.
instance,Subsequently,
as shown inthe
Schemeof the antibacterial florfenicol.
Wiley VCH
Mittwoch, 14.11.2018
34
t
of
the
activecatalyst
waselucidatedby
X-ray
diffraction
aromatic
(R
=
Ph)
and
aliphatic(R=
In contrast to VANOL and VAPOL471822
which
are
similarly
Bu)
N-MEDAM
imines66/ 120922[S. 5099/5114]
35
48 linear biaryls such asprovidingunderstandings
intoasymmetricmolecular recogeffective for this transformation, the use ofgaveanalysis,
better yields
and criticalenantioselectivities
in the36
nition between
catalyst
its substrates.
BINOL ligands gave poor induction in49 the chiral aziridine
aziridination
reactionthe
thanthoseandobserved
for their[63]counter50
37 acid
The mechanism of the chiral VANOL-BOROX Brønsted
51
reactionof GmbH
EDA &(60)and Weinheim
imines3871 was
ChemCatChem 2018, 10, 5092 – 5114
www.chemcatchem.org
5103 mediated aziridination! 2018 Wiley-VCH
VerlagCo. KGaA,
52
39 andexamined through an experimental kinetic isotope effects
53[52]
40Wulff’s
54
theoretical calculations combined study. As a result,
41
55
group suggested the implication of a stepwise mechanism,
42
Scheme 21. Catalytic asymmetric aziridination56
catalyzed by chiral binaphthol
where reversible formation of a diazonium ion intermediate
Scheme 24. Suggested SN2-like mechanism for boron-mediated azirid
Scheme 22. Boron-catalyzed “aza-Darzens like” reaction of aliphatic and aromatic N-protected imines.
57
borate.
reaction.
(gauche-72/anti-72) antecedes to SN2-like ring closure43
to form

Appendix44

4-3

Divergent Selectivity in Enantiopure Hosts

host-catalyzed aza-Darzens reaction.

subjected to thees 3e and 3f wastrend in selectivity
observed when theaction. In contrast,
a coupling partner,
ed for aziridine 3bs consistent with 3pact conﬁguration
it more readily
ts. As a result, thegreatest diﬀerenceseries.
lowest yields, they
ree of backgroundvity and disparate
determine if the
f the backgroundre selective hostd with an increasedve catalyst (Figure
in NMR yield was
d modest. Conductmetric addition of a

Appendix

Figure 4. (a) Increased catalyst loading for the host-9-catalyzed azaDarzens reaction provides similar enantioselectivity as 2 mol %45
catalyst loading ofKenneth
host 9.N.Host
9 blocked
by a Toste,
strongly
bound
Raymondand F. Deanet al.,
J. Am.guest
Chem. Soc. 2020, 142, 733.

同社磐田工場でメントール（図７右）が年産 1,000 ト

4-3た。反応 度向上が反応
ン規模で製 されている。
Relationship between
Flexibility and Enantioselectivity

れば、エナンチオ選択性
Appendix

５ 不斉合成と反応温度
前節までの解説では，鏡像異性体のそれぞれを L-型
もしくは D-型と表現した。この立体化学の表記法は，適用する反応系の検討に持しながら数百倍の 度
した 4)（図８）。

基準となる糖質化合物から仮想的な化学変換に基づいて命名されるもので，一般性に乏しいため，現在では３次元的な分子構 から一定の規則に基づいて機械的に命名する R/S 表記法が IUPAC（国際純正および応用化学連合）によって定められている。不斉合成の選択性は，(S)体と(R)体の分子数から鏡像体過剰率（Enantiomeric
Excess, %ee）で評価される（式１）。

全く選択性がない場合（図３）では，0%ee であり，完全な選択性が実現された場合には，100%ee である。

６ 光学活性体：偏光と一方，1884 年に提唱された Arrhenius の式によれば，鏡有機化学に詳しい読

像体過剰率(%ee）は反応 度定数 k を介して関係付け

用語がここまで出ないのられる。すなわち，鏡像体過剰率は反応温度(T)の関数

不斉炭素原子を持つ化合として表現される（式２）。

せると，偏光面の角度がていた。これを旋光度と線のオレンジ色の光か水
46

実際，触媒的不斉合成反応は反応温度に極めて敏感
が，この特性が「光学活
Tohru Yamada, JEMEA
Bulletin 2021,
6, 10