Water, an Essential Element for a ZnII -Catalyzed Asymmetric Quinone Diels-Alder Reaction: Multi-Selective Construction of Highly Functionalized cis-Decalins

Abstract

A Zn(II) complex of a C2‐chiral bisamidine‐type sp2N bidentate ligand (LR) possessing two dioxolane rings at both ends catalyzes a highly efficient quinone asymmetric Diels‐Alder reaction (qADA) between o‐alkoxy‐p‐benzoquinones and 1‐alkoxy‐1,3‐butadienes to constructs highly functionalized chiral cis‐decalins, proceeding in up to a >99:1 enantiomer ratio with a high generality in the presence of H2O (H2O:Zn(II) = 4‐6:1). In the absence of water, little reaction occurs. The loading amount of the chiral ligand can be minimized to 0.02 mol% with a higher Zn/LR ratio. This first success is ascribed to a supramolecular 3‐D arrangement of substrates, in which two protons of an “H2O–Zn(II)” reactive species make a linear hydrogen bond network with a dioxolane oxygen atom and one‐point‐binding diene; the Zn(II) atom captures the electron‐accepting two‐points‐binding quinone fixed on the other dioxolane oxygen atom via an n‐π* attractive interaction. The mechanisms has been supported by 1H‐NMR study, kinetics, X‐ray crystallographic analyses of the related Zn LR complexes, and ligand and substrate structure‐reactivity‐selectivity relationship.

Full text

Accepted Article
CHEMISTRY
AN ASIAN JOURNAL
A sister journal of Angewandte Chemie
and Chemistry – A European Journal
A Journal of
www.chemasianj.org
Title: Water, an Essential Element for a Zn(II)-Catalyzed Asymmetric
Quinone Diels-Alder Reaction: Multi-selective Construction of
Highly Functionalized cis-Decalins
Authors: Kyosuke Morimoto, Thien Phuc Le, Sudipta Kumar Manna,
Chaithanya I. N. Kiran, Shinji Tanaka, and Masato Kitamura
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Asian J. 10.1002/asia.201900995
Link to VoR: http://dx.doi.org/10.1002/asia.201900995

COMMUNICATION
Water, an Essential Element for a Zn(II)-Catalyzed Asymmetric
Quinone Diels-Alder Reaction: Multi-selective Construction of
Highly Functionalized cis-Decalins
Kyosuke Morimoto†, Thien Phuc Le†, Sudipta Kumar Manna, I. N. Chaithanya Kiran, Shinji Tanaka,
and Masato Kitamura*
Abstract: A Zn(II) complex of a C2-chiral bisamidine-type sp2N
bidentate ligand (LR) possessing two dioxolane rings at both ends
catalyzes a highly efficient quinone asymmetric Diels-Alder reaction
(qADA) between o-alkoxy-p-benzoquinones and 1-alkoxy-1,3-
butadienes to constructs highly functionalized chiral cis-decalins,
proceeding in up to a >99:1 enantiomer ratio with a high generality in
the presence of H2O (H2O:Zn(II) = 4–6:1). In the absence of water,
little reaction occurs. The loading amount of the chiral ligand can be
minimized to 0.02 mol% with a higher Zn/LR ratio. This first success
is ascribed to a supramolecular 3-D arrangement of substrates, in
which two protons of an “H2O–Zn(II)” reactive species make a linear
hydrogen bond network with a dioxolane oxygen atom and one-
point-binding diene; the Zn(II) atom captures the electron-accepting
two-points-binding quinone fixed on the other dioxolane oxygen
atom via an n-π* attractive interaction. The mechanisms has been
supported by 1H-NMR study, kinetics, X-ray crystallographic
analyses of the related ZnLR complexes, and ligand and substrate
structure-reactivity-selectivity relationship.
Intermolecular Diels-Alder (DA) reactions of unsymmetrical p-
benzoquinones and 1,3-dienes have been recognized as one of the
most powerful methods for synthesizing many complex natural
products[1] ever since Woodward reported the first historic syntheses
of cortisone and cholesterol using 2-methoxy-5-methyl-1,4-
benzoquinone (1a (p = r = H; q = CH3 in 1, Figure 1)) in 1952.[2]
As shown in Figure 1, combination of achiral dienophile 1 with
CH3O, p, q, and r substituents at C1(2), C1(3), C1(5), and C1(6)
and achiral diene 2 with w, x, y, and z substituents at C2(4), C2(3),
C2(2), and C2(1) lead to 16 possible stereoisomers of DA adducts, 3,
4, 5, and 6 by varying site-, diastereo- (endo/exo-), regio-, and
enantio-selectivities. Although the multiple requirements for these
selectivities have been mitigated through an understanding of the
endo rule,[3] calculated transition-state structures,[4] and by using an
appropriate Lewis acid catalyst, the catalytic asymmetric Diels-Alder
reaction of p-benzoquinone (qADA) has still remained at an early
stage in comparison to the well-studied DA of simple acrylate
derivatives. The catalysts for qADA are limited to binolate–
Ti(IV),[5] tridentate pyridyl-bisoxazoline–Sm(III) and –Gd(III),[6]
cationic oxazaborolidines,[7,8] and tridentate Schiff base–Cr(III).[9]
These chiral Lewis acids yield a high stereoselectivity in the
dienophile/diene combination specific to each qADA but require a
high catalyst loading (4–20 mol%) at low temperature under strictly
anhydrous conditions using molecular sieves (MS) or a glove box.
In particular, qADA of 1a-type 2-alkoxybenzoquinone and 1-alkoxy-
1,3-butadiene 2 (z = OR) is the most attractive to construct highly
functionalized chiral cis-decalins toward the natural product
synthesis.[10] The best result was reported by Smith in 2017[11] using
chiral dialkoxide–Ti(IV) complex[12,13] (20 mol%; MS 4A; –78 °C to
–40 °C) to construct a key chiral intermediate with a 93:7
enantiomer ratio (er) for the total synthesis of (–)-nahuoic acid. A
highly reactive, multi-selective, and productive catalyst functioning
under ambient conditions has not yet been realized in qADA. In this
paper, we report a breakthrough in this challenging qADA field
through the development of a Zn(II) complex of our original chiral
bisamidine-type sp2N bidentate ligand, (R,R)-Naph-diPIM-dioxo-
iPr (LR) (Figure 2a), that operates in the presence of “H2O” at
ambient temperature.
Figure 1. Asymmetric Diels−Alder reaction of quinone (qADA) requiring
multiple selectivities. C1(6)Si indicates the Si face of C(6) of dienophile 1.
Absolute configurations of the three carbon stereogenic centers at C(4a),
C(8a), and z-substituted C(8) or C(5) of qADA adducts are shown.
The bisamidine ligand LR looks similar to a privileged sp2N ligand,
R-BOX (R = t-Bu or Ph)[14] (Figure 2b), but totally different. LR
possesses the following unique electronic and steric properties: i)
high planarity and rigidity with two sp2N atoms fixed to the same
side; ii) ca. 90° bite angle; iii) an extended π-conjugated system
showing pyridine-level π-accepting ability; iv) high σ-donating
ability derived from the two amidine units; v) a wider C2 chiral
reaction site constructed by a 5,5,6,6,5,5 ring system that fuses two
dioxolane rings up and down at the both ends; vi) sterically
congested di-i-Pr-substituted dioxolane rings; and vii) existence of
O
O
p
CH3O
q
r
w
z
+
O
O
p
CH3O
w
z
q
r
y
x
x
y
O
O
p
CH3O
z
w
q
r
y
x
O
O
p
H3CO
w
z
q
r
x
y
O
O
p
CH3O
z
w
q
r
y
x
O
O
q
r
w
z
p
OCH3
x
y
O
O
q
r
z
w
p
OCH3
y
x
O
O
q
r
w
z
p
OCH3
x
y
O
O
q
r
z
w
p
OCH3
y
x
C1(5)-C1(6) site
endo/regio
C1(6)Re-C2(1)Si
C1(6)Re-C2(4)Si
exo/regio
C1(6)Re-C2(1)Re
C1(6)Re-C2(4)Re
priority rule:
p, q, r, w, x, y ≤ C < z ≤ O
8a
4a
87
6
5
4
3
21
RS
R
4a
8a
56
7
8
1
2
34
RR
S
6
5
4
3
21
43
2
1
C1(5)=C1(6) site
C1(2)-C1(3) site
endo/regio
C1(2)Si-C2(1)Re
C1(2)Si-C2(4)Re
exo/regio
C1(2)Si-C2(1)Si
C1(2)Si-C2(4)Si
(4aR,8aR,8S)-3(4aS,8aS,5R)-4(4aR,8aR,8R)-3(4aS,8aS,5S)-4
(4aR,8aS,5R)-5(4aS,8aS,5S)-6(4aR,8aS,5S)-5(4aS,8aS,5R)-6
12
endo
C1(6)Si-C2(1)Re C1(6)Si-C2(4)Re
exo
C1(6)Si-C2(1)Si C1(6)Si-C2(4)Si
C1(2)=C1(3) site
endo exo
C1(2)Re-C2(1)Si C1(2)Re-C2(4)Si C1(2)Re-C2(1)Re C1(2)Re-C2(4)Re
regio regio
regio regio
8a
4a
87
6
5
4
3
21
S
R
S
8a
4a
87
6
5
4
3
21
S
S
S
8a
4a
87
6
5
4
3
21
RR
R
8a
4a
87
6
5
4
3
21
S
S
S
4a
8a
56
7
8
1
2
34
RS
S
8a
4a
87
6
5
4
3
21
S
R
S
(4aS,8aS,8R)-3
(4aR,8aR,5S)-4
(4aS,8aS,8S)-3
(4aR,8aR,5R)-4
(4aS,8aR,5S)-5
(4aR,8aR,8R)-6
(4aS,8aR,5R)-5
(4aR,8aR,8S)-6
enantio
K. Morim oto, T. P . Le, Dr. S. K. Mannna, Dr. I. N . C. Kiran, Dr. S.
Tanaka, and Dr. M. Kitamura*
Graduate School of Pharmaceutical Sciences
Nagoya University
Nagoya, Japan
E-mail: kitamura@ps.nagoya-u.ac.jp
[†] These authors contributed equally to this work.
Supporti ng infor mation for t his article is given via a link at the end of
the document.
10.1002/asia.201900995
Accepted Manuscript
Chemistry - An Asian Journal
This article is protected by copyright. All rights reserved.

COMMUNICATION
the dioxolane oxygen lone pair n orbital at the reaction site. A series
of properties i)–vi) of LR enhance its metal-capturing ability and
stabilize the corresponding metal complexes with various
geometrical structures; LR has been successfully used to catalyze
efficient asymmetric reactions.[15–18] We assume that the electron
accepting and two-points bindindg benzoquinone dienophile in the
qADA would be chirally fixed by the characteristics v)–vii) in the 2nd
or 4th quadrant through coordination to an appropriate MXn–LR
(Figure 2a), facilitating stereocontrol.[19] Various MXn–R-BOX
complexes have been well studied in highly enantioselective DA
reactions of acrylate,[20–23] but not effective for qADA.[24]
Figure 2. sp2N-Based bidentate ligands. Characteristics of Naph-diPIM-dioxo-
iPr (LR; a) and the related representative chiral bidentate ligand R-BOX (b)
and the corresponding M–LR and M–t-Bu-BOX complexes. Circle
distinguished by white and black quadrants with 1–4 numbers represents the
coordination regions made by horizontal and vertical lines crossing the central
M atom. Black regions are sterically crowded.
The standard quinone dienophile and diene were set to
C1(2)OCH3/C1(5)CH3-1,4-benzoquinone (1a) and one-point-
binding C2(1)OCH3-1,3-butadiene (2a), respectively (Table 1,
reaction scheme), and MXn was screened under the standard
conditions of [MXn] = [LR] = 5 mM (1 mol%), [1a] = 0.50 M, [2a]
= 1.0 M, 1,4-dioxane (589 ppm H2O, Grubbs solvent purification
system), 27 °C, and 4 h. Mg(OTf)2, Fe(OTf)3, Al(OTf)3, Cu(OTf)2,
AgOTf, and Sn(OTf)2 showed little reactivity, [25] whereas Zn(OTf)2
afforded (4aR,8aR,8S)-3a in 91% yield with a >99:1 er without
generation of any other stereoisomers, 4a, 5a, and 6a (Table 1, entry
1). Little reaction occurred under the standard conditions using
Zn(II) complexes of achiral Naph-diPIM, which lacks the dioxolane
rings of Naph-diPIM-dioxo-iPr (LR) as well as those of (S,S)-R-BOX
(R = t-Bu or Ph) or Phen (entries 2–5). The water content exerted a
significant effect on the reactivity. Contrary to previous reports,[5–
7,9,11] little reaction occurred in 1,4-dioxane dried over MS 4A or 5A
(entries 6 and 7). By increasing the concentration of H2O in 1,4-
dioxane, the reactivity was gradually enhanced and maximized at
360–500 ppm of H2O (4–6 mol amounts for Zn(II)) (entries 8–
11).[25] A further increase in the water content lowered the reactivity
without deteriorating the selectivity. A wide range of solvents was
usable, although the enantioselectivity was slightly reduced and the
Table 1. Catalytic qADA of dienophile 1a and diene 2a using a 1:1 mixture of
Zn(OTf)2 and sp2N-based bidentate ligands.
entry
ligand
H2O
(ppm)
% yield of 3a
3a/4a[a]
er of 3a[b]
1
LR
589
91
>99:1
>99:1
2
Naph-
diPIM[c]
589
<5
—
—
3
(S,S)-t-
Bu-BOX
589
<5 (<5)[d]
—
(—)[d]
—
(—)[d]
4
(S,S)-
Ph-BOX
589
<5 (85)[d]
— (90:10)[d]
— (77:23)[d]
5
Phen[e]
589
0
—
—
6
LR
9[f]
<5
—
—
7
LR
17[g]
<5
—
—
8
LR
60
<5
—
—
9
LR
360
>99
>99:1
>99:1
10
LR
475
>99
>99:1
>99:1
11
LR
880
65
>99:1
>99:1
Conditions: [1a] = 0.50 M; [2a] = 1.0 M, [Zn(OTf)2] = [LR] = 5.0 mM (1 mol%),
1,4-dioxane (Grubbs purification system; 589 ppm H2O), 27 °C, 4 h. Content
of H2O was measured by Karl Fischer titration. [a] Determined by 1H-NMR
analysis. [b] Determined by HPLC analysis. [c] 1,2,11,12-
Tetrahydronaphtho[1,2-b:7,8-b’]dipyrroloimidazole.[18] See below. [d] Value in
parenthesis is the result obtained by using 5 mol% of Zn(OTf)2 and chiral
ligand at 27 °C for 24 h. [e] 1,10-Phenanthroline. See bellow. [f] 1,4-Dioxane
(589 ppm H2O) containing MS 4A (100 mg) for 1.0 mmol 1a was used after
24-h stirring at 27 °C. [g] 1,4-Dioxane (589 ppm H2O) containing MS 5A (100
mg) for 1.0 mmol 1a was used after 24-h stirring at 27 °C.
reaction time was increased with other solvents than 1,4-dioxane.
The optimal H2O amount, reaction time, and enantioselectivity for
other solvents was as follows: THF (347 ppm, 48 h, 98:2 er);
CPME (351 ppm, 24 h, 97:3 er); toluene (106 ppm, 24 h, 97:3 er);
acetone (119 ppm, 4 h, 95:5 er), CH3CN (800 ppm, 24 h, 98:2 er),
CHCl3 (351 ppm, 24 h, 96:4 er); and t-BuOH (370 ppm, 24 h, 97:3
er).[25] In all cases, a decrease in the H2O content to 4–11 ppm
significantly lowered the reactivity. Little reaction occurred in DMA
irrespective of H2O content. The presence of the two oxygen atoms at
the reaction site with a spatially accessible environment and “H2O” in the
reaction system are essential for achieving high reactivity and selectivity.
N
N N
N
O
O O
O
RR
N N
O O
R R
(S,S)-R-BOX
R = t-Bu or Ph
SS
(R,R)-Naph-diPIM-dioxo-iPr
LR
highly rigid and planar
55
66
existence of
O lone pairs
in reaction site
55
highly σ-donative
bisamidines fixed to
the same side
pyridine-level
π-acceptivity
~90°
bite angle
clear C2 chiral
pocket with a
relatively large
capacity
M
OO
OO
N
NN
N
12
43
M
NN
O O
M–(S,S)-t-Bu-BOX
M–LR
sterically
congested
sterically
congested
a b
O
O
CH3O
OCH3
+
Zn(OTf)2
ligand
O
CH3O
OCH3
H
1a 2a
O
6
5
4
3
21
4
3
2
1
8a
4a
87
6
5
4
3
21
(4aR,8aR,8S)-3a
+ l l l
O
CH3OH
O
8a
4a
87
6
5
4
3
21
(4aS,8aS,5R)-4a
+
OCH3
1,4-dioxoane
4 h, 27 °C
N
N N
N
Naph-diPIM
NN
Phen
10.1002/asia.201900995
Accepted Manuscript
Chemistry - An Asian Journal
This article is protected by copyright. All rights reserved.

COMMUNICATION
The effect of the Zn/LR ratio on the reactivity was also significant
(Table 2). In the absence of Zn(OTf)2 and LR, no reaction occurred
(entry 1). Zn(OTf)2 itself was at least two orders less reactive than
the catalyst prepared in a 1:1 ratio of Zn(OTf)2 and LR (entries 2
and 3). With a 1:2 ratio of Zn(OTf)2 and LR, the reactivity was
nearly lost (entry 4). On the other hand, an increase in the Zn/LR
ratio from 1:1 enhanced the reactivity (entries 4–6 and 8–11): With
Zn(OTf)2:LR = 10:1, the reaction completed in 1 h with little
deterioration of the er (entry 8). Even in the presence of 0.02 mol%
of LR, the reaction was completed to give quantitatively
(4aR,8aR,8S)-3a with a 98:2 er (entry 10). Further decrease in the
catalyst loading to 0.01 mol% deteriorated the enantioselectivity to
94:6 (entry 11).
Figure 3 shows the molecular structures of
[Zn(H2O)(LR)2](OTf)2 (7) and [ZnLR(Phen)2](OTf)2 (8) in the
crystals.[25] In the complex 7, one H2O coordinates to the central
Zn(II) atom to make a trigonal bipyramidal geometry with sp2N(1),
sp2N(2), sp2N(1’) and sp2N(2’) (N(1)–Zn–N(2) bite angle, 93°;
N(2’)–Zn–N(1’), 93°). The trigonal plane is made by the H2O
oxygen atom, sp2N(2) of LR, and sp2N(1’) of another LR. The
sp2N(1) and sp2N(2’) occupy the apical positions. Two hydrogen
atoms of H2O–Zn(II), Ha and Hb, make a liner hydrogen bond
Table 2. Effect of Zn/LR ratio and catalyst loading on the reactivity and
enantioselectivity.
entry
[Zn(OTf)2]
(mM)
[LR]
(mM)
LR
(mol%)
Zn/ LR
yield
(%)[a]
er[b]
1
0
0
0
—
0
—
2
5
0
0
—
<5
—
3[c]
5
5
1
1:1
>99
>99:1
4
5
10
2
1:2
6
94:6
5
10
5
1
2:1
>99[d]
>99:1
6
25
5
1
5:1
>99[e]
99:1
7[f]
25
5
1
5:1
<5
—
8
50
5
1
10:1
>99[g]
99:1
9
2.5
0.5
0.1
5:1
99[h,i]
99:1
10[j]
2.5
0.5
0.02
5:1
94[i,k]
98:2
11[j]
2.5
0.25
0.01
10:1
99[i,k]
94:6
Conditions: [1a] = 0.50 M; [2a] = 1.0 M, 1,4-dioxane (360 ppm H2O), 27 °C, 4
h unless otherwise specified. Dienophile 1a was not fully dissolved. In all
cases only 3a was obtained. [a] Determined by 1H-NMR analysis. [b]
Determined by HPLC analysis. [c] Enough conditions for the Zn(LR)2
generation: 27 °C for 1 h and then 100 °C for 1 h. [d] 3 h. [e] 1 h. [f] 1,4-
Dioxane (589 ppm H2O) was dried over MS 4A (10 %w/w, 12 h, 27 °C) prior to
use. [g] 1 h. [h] 48 h. [i] Isolated yield. [j] [1a] = 2500 mM, [2a] = 5000 mM.
[k] 168 h.
network with the dioxolane O(1) (1.24 Å) in the 2nd quadrant and
the other dioxolane O(1’) (1.81 Å) in the 1st quadrant. Ligand LR at
the front side is located in the sterically disfavored 4th quadrant,
indicating that there is an attractive donor-acceptor-type interaction
between the dioxolane O(3) n orbital and naphthalene π* orbital
(O–sp2C = 3.09 Å).[26] Complex 8 takes a Λ stereochemistry, in
which the two Phen ligands occupy the spatially crowded 2nd and 4th
quadrants to make an octahedral geometry with the LR bite angle of
91° (N(1)–Zn–N(2)). Short distances of O(1)–sp2C = 3.12 Å,
O(1)–sp2N(1’) = 3.04 Å, O(3)–sp2C = 3.18 Å, and O(3)–sp2N(2’)
= 3.08 Å show that the π-extended two Phen ligands are induced by
nO(1) and nO(3) orbitals into the sterically disfavored quadrants in the
same way as the case of 7. These two molecular structures implicate
the involvement of such a hydrogen bond and n/π* attractive
interaction in the transition state of the present qADA.[27]
Figure 3. Molecular structures of [Zn(H2O)(LR)2](OTf)2 (7) and Λ-
[Zn(LR)(Phen)2](OTf)2 (8) in the crystals. –OTf: omitted for clarity. In complex
7, a linear hydrogen bond network, O(1)---Ha–O–Hb---O(1’), is constructed. In
both complexes 7 and 8, another LR or two Phen ligands are stabilized by n-π*
interactions in the sterically crowded quadrants.
Figure 4 illustrates the supposed mechanism for attaining high
reactivity and multi-selectivity in the ZnLR-catalyzed 1a/2a qADA
using 1,4-dioxane containing H2O. Taking into consideration the
structural characteristics of 7 and 8, we propose the dicationic aqua
complex [Zn(H2O)LRSn](OTf)2 (S: solvent, H2O, 1a, 2a, etc.; n = 0,
1, or 2) (ZnLR, A) as the catalytically reactive species. A
disproportionates to the less reactive [Zn(LR)2Sn](OTf)2 (Zn(LR)2)
and Zn(OTf)2, but excess Zn(OTf)2 retards this process to enhance
the rate:[25] A 1:1 mixture of Zn(OTf)2 and LR afforded a 91:9
mixture of ZnLR and Zn(LR)2 after 3 h at 27 °C, whereas the ratio
was increased to 99:1 with a 2:1 ratio and use of 5 mol amounts of
O
Zn
OO
OO
N
N
N
N
N
N
O
2+
N
N
12
43
HHOO
O
Zn
OO
OO
N
NN
N
2+
N
N
N
N
O
O2’
O1’
O1
O2
O3’
O4’
O3O4
Zn
N1 N2
N2’
N1’
HaHb
3.09
1.81
1.24
O1
O2
O3 O4
N1 N2
Zn
3.04
3.12
3.08
3.18
78
ab
linear
hydrogen bond
network
n-π*
attractive
interaction
n-π*
attractive
interaction
sterically
disfavored
region
sterically
disfavored
region
N(1)ZnN(2) = 93.14
N(1)ZnO = 83.89
N(1)ZnN(1’) = 99.37
N(2’)ZnN(1’) = 92.87
N(2’)ZnO = 79.19
N(2’)ZnN(2) = 95.00
N1’
N2’
N1“
N2“
N(2)ZnO = 133.84
N(1’)ZnO = 117.64
N(2)ZnN(1’) = 108.31
N(1)ZnN(2’) = 162.37
N(1)ZnN(2) = 91.12
N(1)ZnN(2’) = 97.07
N(1)ZnN(1’) = 93.03
N(1)ZnN(1’’) = 93.98
N(2’’)ZnN(2) = 94.51
N(2’’)ZnN(2’) = 91.05
N(2’’)ZnN(1’) = 81.76
N(2’’)ZnN(1’’) = 76.82
N(2)ZnN(2’) = 95.20
N(2)ZnN(1’’) = 96.23
N(2’)ZnN(1’) = 76.36
N(1’)ZnN(1’’) = 91.30
N(1)ZnN(2’’) = 169.67
N(2)ZnN(1’) = 170.63
N(2’)ZnN(1’’) = 163.92
trigonal bipyramidal with N2–N1’–O plane octahedral with Λ stereochemistry
12
43
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Zn(OTf)2 toward LR completely suppressed the disproportionation.
Little reaction occurred in a 5:1 Zn(OTf)2/LR system using 1,4-
dioxane dried over MS 4A (Table 2, entry 7), supporting the
importance of H2O for generating the reactive species and excluding
the mechanism that ZnLR and Zn(OTf)2 independently activate the
dienophile and diene.
Figure 4. Supposed mechanism for catalysis and enantioface selection in the
ZnLR-catalyzed qADA of dienophile 1a and diene 2a. –OTf: omitted. S:
solvent, H2O, 1a, 2a, etc.; n = 0, 1, or 2. Coordination timing of 1a and 2a to A
may be reversed.
First, A captures 1a and 2a as two-points- and one-point-binding
substrates, respectively, to generate C via B. Then, a rate-
determining bond recombination occurs in C to give the qADA
adduct by regenerating A, completing the catalytic cycle. Consistent
with this view, the reaction followed 1st order kinetics for [ZnLR]0,
[1a]0, and [2a]0.[25] The enantioface of 1a is determined at the stage
of generation of B6Si, in which the C1(5)Re=C1(6)Si of 1a faces the
front side in the 4th quadrant. The region is sterically disfavored by
the di-i-Pr-substituted dioxolane ring, but the lone pair n orbital
induces the quinone dienophile 1a into the 4th quadrant in a similar
manner observed with 7 and 8. The n-π* interaction for the highly
electron-acceptive p-benzoquinone 1a should be much stronger
than that for LR and Phen. The C1(5)=C1(6) double bond possesses
a lower LUMO coefficient and is more reactive than the electron-
donative CH3O-substituted C1(2)=C1(3), which determines the
site-selectivity. Furthermore, the two-points-binding of 1a to the
Lewis acidic Zn(II) decreases the LUMO level and enhances the
reactivity.[19]
One-point-binding 2a interacts with B6Si via a hydrogen bond
between the C2(1)OCH3 oxygen atom and HR of HSHRO–Zn(II),
HS of which is fixed by another hydrogen bond with the dioxolane
oxygen atom in the 2nd quadrant as observed in 7. In the resulting
C6Si,1Re with a linear hydrogen bond network, the C1(6)Si of 1a faces
the C2(1)Re of 2a. The C6Si,1Re intermediate is electronically matched
for a δ–C1(6)= δ+C1(5)/ δ+C2(1)–δ–C2(4) combination and
geometrically well arranged for making secondary orbital
interactions, determining the diastereoselectivity and leading to a
smooth qADA to furnish the endo-adduct (4aR,8aR,8S)-3a as the
sole product.[28] The C2(1)OCH3/HR hydrogen bond changes the
reaction mode from intermolecular to intramolecular to accelerate
the rate-determining step but also controls the regioselectivity for
the unsymmetrical diene.
Proton HR of B6Re, in which the C1(5)Si=C1(6)Re of 1a is faced to
the front side in the 4th quadrant, also captures the C2(1)OCH3 of 2a
to give C6Re,1Si and C2Si,1Re, from which enantiomers (4aS,8aS,8R)-3a
and (4aS,8aR,5S)-5a are generated, respectively. However, the
contribution of both C6Re,1Si and C2Si,1Re is thought to be negligible for
the B6Si-derived C6Si,1Re and C2Re,1Si because B6Re-derived C
intermediates are geometrically disfavored for the endo-transition
state with a maximized orbital interaction in either a
C1(6)=C1(5)/C2(1)–C2(4) or C1(2)=C1(3)/C2(1)–C2(4)
combination. Predominant contribution of C6Si,1Re in the 1a/2a
qADA realizes high reactivity and multi-selectivity.
Table 4 summarizes the relationship between 1 and 2, reactivity,
and selectivity, which was investigated using 2:1 Zn(OTf)2/LR with
a ligand loading of 0.5 mol%. Generality was high with the following
three requirements satisfied: i) no substituent at C1(3) of quinone
dienophile 1; ii) existence of an alkoxy oxygen atom at C1(2) of 1;
and iii) existence of an alkoxy oxygen atom at C2(1) of diene 2.
These requirements can be well explained by the H2O–Zn(II)LR-
involved mechanism in Figure 4 as described below.
The methyl group at C1(5) of 1a could be replaced with H, allyl,
and i-Pr (entries 1–5). Use of the enantiomeric ZnLS catalyst
furnished the enantiomeric 3a (entry 3). Introduction of a t-Bu
group decreased the reactivity, although the high selectivity was
maintained (entry 6). All of C1(5)H/C1(6)H-, C1(5)CH3/C1(6)H-,
C1(5)H/C1(6)CH3-, and C1(5)CH3/C1(6)CH3-substituted
C1(2)OCH3-quinones were usable (entries 1, 2, 7 and 8). With the
C1(5)CH3/C1(6)CH3-quinone, two consecutive quaternary
stereogenic centers were installed into C3(4a) and C3(8a) of the cis-
decalin product 3 (entry 8). The enantioselectivity was lost by
introduction of a CH3 group at C1(3) (entry 9); this is explained by
the inability to make the two-points-binding of C1(1)=O and
C1(2)OCH3 to Zn(II) because the lone pair of C1(2)OCH3 is forced
to be anti to the C1(1)=O lone pair to avoid a steric repulsion from
the C1(3)CH3 group. The lowered reactivity and selectivity of p-
xyloquinone (entry 10) also supports the importance of a two-
points-binding of dienophile to forming the C intermediate. The
methyl of C2(1)OCH3 of 2a could be replaced with an easily
removable p-methoxybenzyl (PMB) group (entry 11), increasing
the synthetic utility. In this reaction, the reliability of the present
qADA was confirmed on a 15-g scale.[25] When the C2(1)OCH3 of
2a was replaced with t-butyl dimethyl silyloxy (TBSO), AcO, tert-
butoxycarbonyl amino (BocNH), CH3S, or a CH3 group, the
reactivity and selectivity were both significantly decreased (entries
12–16). The C2(1)OTBS-substituted diene (entry 12) would not
be able to efficiently interact with H2O–Zn(II)LR because of the
geometrically
disfavored
to move endo-TS
Zn2+/LR = 1:1, ZnLR:Zn(LR)2 = 91:9
Zn2+/LR = 2:1, ZnLR:Zn(LR)2 = 99:1
Zn2+/LR = 5:1, ZnLR:Zn(LR)2 = >99:1
electronically
disfavored
[Zn(H2O)LRSn]2+
Zn(OTf)2 + LR
ZnLR (A)
B6Si B6Re
2+
Zn
OO
OO
N
NN
N
O
HS
HR
O
O
OSi
5
6
2+
Zn
OO
OO
N
NN
N
O
HS
HR
O
O
O
Si
C6Si,1Re C6Re,1Si
2+
Zn
OO
OO
N
NN
N
O
HS
HR
O
O
O
O
Si
5
1
2+
Zn
OO
OO
N
NN
N
O
HS
HR
Re
O
O
O
O
5
6
1
4
C2Re,1Si C2Si,1Re
2+
Zn
OO
OO
N
NN
N
O
HS
HR
O
O
O
O
2+
Zn
OO
OO
N
NN
N
O
HS
HR
O
O
O
O
Si
Re
1
4
Re
Si
1
4
8a
4a
87
6
5
4
3
21
RS
R
OCH3
CH3OH
O
O
(4aR,8aR,8S)-3a
SR
S
OCH3
CH3OH
O
O
(4aS,8aS,8R)-3a
1a 1a
2a 2a
4a
8a
5
6
7
8
1
2
3
4
RR
S
OCH3
OCH3
H
O
O
(4aR,8aS,5R)-5a
SS
R
OCH3
OCH3
H
O
O
(4aS,8aR,5S)-5a
3
3
8a
4a
87
6
5
4
3
21
4a
8a
5
6
7
8
1
2
3
4
2
Re
4
6
3
2
3
2
1/2 [Zn(LR)2Sn]2+ + 1/2 Zn(OTf)2
H2O
after 3 h at 27 °C
Si
Re 5
6
2
Re
12
43
–A–A
–A–A
Zn(LR)2
Re
Si
Si
Re
linear
hydrogen bond
network
n-π*
attractive
interaction
δ–
δ+
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COMMUNICATION
Table 4. Scope and Limitation of the ZnLR-Catalyzed qADA
Entry
Product 3
Time, h
% yield[a]
Er of 3[b]
Entry
Product 3
Time, h
% yield[a]
Er of 3[b]
1
2
3[c]
4
5
6
q =
H
CH3
CH3
allyl
i-Pr
t-Bu
1
12
12
20
20
20
97 (>99)
99 (>99)
99 (>99)
96 (>99)
95 (>99)
26 (26)
98:2
>99:1
1:>99
99:1
>99:1
>99:1
17
20
0 (—)
—
18
4
95 (>99)
96:4
7
20
98 (>99)
>99:1
19
20
z =
OCH3
OMOM
2
2
98 (>99)
97 (>99)
98:2
97:3
8
20
90 (>99)
>99:1
9
12
93 (>99)
53:47
21[j]
22[j]
z =
OCH3
OMOM
48
48
85 (96)
88 (>99)
>99:1
>99:1
10[d,e]
72
55 (—)
(3:4 =
55:45)[f]
82:18
23
24
z =
OCH3
OMOM
20
10
96 (99)
93 (98)
>99:1
>99:1
11[g]
12[d,e]
13[d]
14
15[i]
16[c,d]
z =
OPMB
OTBS
OAc
NHBoc
SCH3
CH3
20
72
72
72
168
168
97 (>99)
41 (50)
10 (15)
74 (77)
93 (95)
0 (—)
99:1
89:11
70:30[h]
66:34[h]
92:9
—
25
20
95 (>99)
99:1
26[d,e]
168
91 (95)
(3:5 =
45:55)
>99:1
Reactions were carried out at 27 °C in 1,4-dioxane (360 ppm H2O) under the conditions of [dienophile] = 0.5 M; [diene] = 1.0 M; [Zn(OTf)2] = 5 mM (1.0 mol%);
[LR] = 2.5 mM (0.5 mol%) on a ca. 100-mg scale unless otherwise specified. [a] Isolated yield. Value in parenthesis is 1H-NMR yield. [b] Determined by HPLC
analysis. [c] LS was used instead of LR. [d] 40 °C. [e] [Zn(OTf)2] = [LR] = 5 mM (1 mol%). [f] The relative and absolute configurations of the C(8a)H/C(8)OCH3
regioisomer were not determined. [g] 15-g scale. [h] The absolute configuration was not determined. [i] 60 °C. [j] After treatment by silica gel (100 mg for 1
mmol of 1a; 1.5 h).
large size and lowered donating ability of the TBSO oxygen atom.
In the case of the C2(1)OAc- or NHBoc-substituted diene (entries
13 and 14), the most electron donative and coordinative C=O
oxygen atom is located at the two-atoms elongated position from the
case of C2(1)OCH3 that can directly interact with H2O–Zn(II),
intervening to take the desired C structure. Replacement of the
C2(1)OCH3 of 1a with C2(1)SCH3 (entry 15) would also destruct
the C-type structure by a direct coordination of the high affinity
sulfur atom to Zn(II). The reactivity was significantly decreased
with either the C2(1)CH3-substituted diene or 3-TBSO-1,3-
O
O
p
CH3O
q
r
w
z
+
y
x
6
5
4
3
21
43
2
1
12
Zn(OTf)2 (1 mol%)
LR (0.5 mol%)
1,4-dioxane
H2O (360 ppm)
27 °C
w
z
r
q
O
O
OCH3
p
w
z
CH3O
O
O
q
r
4a
8a 84a
8a
1
45
8
p
35
x
y
x
y
+
z
w
CH3O
O
O
q
r
4a
8a 8
p
4
y
x
+
CH3O
O
O
q
HOCH3
4a
8a
CH3O
O
OH
OTBS
CH3O
O
OOCH3
H
CH3O
O
OOCH3
H
CH3O
O
Oz
H
H
CH3O
O
OOCH3
CH3O
O
OOCH3
H
H
CH3O
O
O
O
OOCH3
H
CH3O
O
Oz
H
CH3O
O
OHz
4a
8a
CH3O
O
OOCH3
H
CH3O
O
OOCH3
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COMMUNICATION
butadiene (entries 16 and 17), which has no alkoxy group at C2(1),
because the C intermediate cannot be formed via an interaction with
B. The Danishefsky-Kitahara diene possessing C2(1)OCH3
smoothly reacted with 1a to give the qADA adduct with a 96:4 er
(entry 18). Introduction of a CH3 substituent at C2(4) of 2a
simultaneously constructed four stereogenic centers with high
selectivity in combination with various 1a-type dienophiles (entries
19–24). The C2(1)OCH3 group could be replaced with
C2(1)OCH2OCH3 (OMOM) (entries 20, 22, and 24).[11] qADA
adducts obtained in the reaction of 1a with a
C2(1)OCH3/C2(4)CH3- or C2(1)OMOM/C2(4)CH3-substituted
diene easily underwent elimination; therefore, the reaction mixture
was treated with silica gel to convert the adducts to the
corresponding hexadiene product with a >99:1 er in 85–88% yields
(entries 21 and 22). A diene bridged between C2(1) and C2(4) was
used to quantitatively furnish the tricyclic qADA adduct with a 99:1
er (entry 25). When a C1(5)CH3/C1(6)CH3-substituted dienophile
was used in combination with a C2(1)OCH3/C2(4)CH3-substituted
diene, the site selectivity for the C1(5)=C1(6)/C1(2)=C1(3) double
bond was lost to provide two enantiomerically pure qADA adducts 3
and 5 (entry 26). In the corresponding C1(6)CH3/C2(4)CH3-
substituted C6Si,1Re-type intermediate, two tri-substituted
sp2C1(5)CH3 and sp2C1(6)CH3 must react with two di-substituted
sp2C2(1)OCH3 and sp2C2(4)CH3, requiring a higher energy than
the simple C6Si,1Re case. As a result, the contribution of an
electronically disfavored but geometrically favored C2Re,1Si-type
intermediate would be relatively increased to give the
C1(2)Re=C1(3)Si-site-selected product 5. Reasonable justification for
the substrate-reactivity-selectivity relationship in Table 4 strongly
supports the mechanism in Figure 4.
In summary, we have discovered that a Zn(II) complex of a
bisamidine-type sp2N-based bidentate ligand, (R,R)-Naph-diPIM-
dioxo-iPr (LR), efficiently catalyzes the challenging qADA in the
presence of H2O under ambient conditions. A catalyst loading of 0.5
mol% is generally acceptable and can be reduced to 0.02 mol% by
increasing the Zn/LR ratio. One “H2O” molecule is captured by the
Lewis acidic Zn(II) and one dioxolane oxygen lone pair of LR to
furnish a chiral reaction site possessing another dioxolane oxygen
lone pair. In the spatially accessible environment that facilitates n-π*
interactions and hydrogen bonding, o-alkoxy-p-benzoquinones 1
and 1-alkoxy-1,3-butadienes 2 (z = OR) are supramolecularly
arranged to realize a highly efficient qADA. The H2O–Zn(II)LR-
catalyzed qADA furnishes highly functionalized cis-decalins with
high site-, diastereo- (endo/exo-), regio-, and enantio-selectivities.
Four consecutive carbon stereogenic centers and two consecutive
quaternary carbon centers can be installed. This first high
performance qADA should provide chemists in the fields of total
synthesis, medicinal chemistry, and process chemistry with a
powerful tool for asymmetric syntheses of pharmaceutically
important complex natural and unnatural products.[1]
Understanding the mechanism underlying the present qADA should
provide important guidelines for the design of various chiral key
intermediates and future chiral catalysts.
Acknowledgements
This work was aided by JSPS KAKENHI Grant Number
JP16H02274, JP18H04250, and JP17H17415, the Platform Project
for Supporting Drug Discovery and Life Science Research funded by
Japan Agency for Medical Research and Development (AMED;
Grant Number JP18am0101099), an Advanced Catalytic
Transformation program for Carbon utilization (ACT-C; Grant
Number JPMJCR12YC) from Japan Science and Technology
Agency (JST), and The Sumitomo Foundation.
Keywords: Asymmetric catalysis • Diels-Alder reaction •
Homogeneous catalyst • sp2N bidentate ligand • Zinc
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Entry for the Table of Contents
COMMUNICATION
A new [Zn(H2O)LR]2+ complex has
been developed to realize a highly
efficient asymmetric quinone-Diels-
Alder reaction. The presence of the
two oxygen atoms of LR at the
reaction site with a spatially
accessible environment and “H2O” in
the reaction system are essential. o-
Alkoxy-p-benzoquinone and 1-alkoxy-
1,3-butadiene are fixed by a linear
hydrogen bond network and n-π*
attractive interaction to realize the
high reactivity and multi-selectivity.
Kyosuke Morimoto, Thien Phuc Le,
Sudipta Kumar Manna, I. N. Chaithanya
Kiran, Shinji Tanaka, Masato Kitamura*
Page No. – Page No.
Water, an Essential Element for a
Zn(II)-Catalyzed Asymmetric Quinone
Diels-Alder Reaction: Multi-selective
Construction of Highly Functionalized
cis-Decalins
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