Origin of stereocontrol in guanidine-bisurea bifunctional organocatalyst that promotes α-hydroxylation of tetralone-derived β-ketoesters: Asymmetric synthesis of β- And γ-substituted tetralone derivatives via organocatalytic oxidative kinetic resolution

Article abstract of DOI:10.1021/ja511149y

The mechanism of asymmetric α-hydroxylation of tetralone-derived β-ketoesters with guanidine-bisurea bifunctional organocatalyst in the presence of cumene hydroperoxide (CHP) was examined by means of DFT calculations to understand the origin of the stereo

Full text of DOI:10.1021/ja511149y

Article
pubs.acs.org/JACS
Origin of Stereocontrol in Guanidine-Bisurea Bifunctional
Organocatalyst That Promotes α‑Hydroxylation of Tetralone-Derived
β‑Ketoesters: Asymmetric Synthesis of β- and γ‑Substituted Tetralone
Derivatives via Organocatalytic Oxidative Kinetic Resolution
Minami Odagi,† Kota Furukori,† Yoshiharu Yamamoto,† Makoto Sato,‡ Keisuke Iida,†
Masahiro Yamanaka,‡ and Kazuo Nagasawa*,†
†Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei city,
184-8588, Tokyo Japan
‡Department of Chemistry, Faculty of Science, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, 171-8501, Tokyo Japan
S
* Supporting Information
ABSTRACT: The mechanism of asymmetric α-hydroxylation of
tetralone-derived β-ketoesters with guanidine-bisurea bifunctional
organocatalyst in the presence of cumene hydroperoxide (CHP)
was examined by means of DFT calculations to understand the
origin of the stereocontrol in the reaction. The identified
transition-state model was utilized to design an enantioselective
synthesis of β- or γ-substituted tetralones by catalytic oxidative
kinetic resolution reaction of tetralone-derived β-ketoesters. This
kinetic resolution reaction proceeded with high selectivity, and
selectivity factors (s value) of up to 99 were obtained. The
potential utility of this oxidative kinetic resolution method for
synthesis of natural products was confirmed by applying it to
achieve an enantioselective synthesis of (+)-linoxepin (13) from β-
substituted tetralone rac-7 in only six steps.
explained the roles of the three functional groups, i.e., one
guanidine and two urea groups, in the catalyst 2.3 Further
consideration of this TS model led us to design an oxidative
kinetic resolution reaction of β- or γ-substituted tetralone-
derived β-ketoesters rac-5 (Scheme 1c). In this reaction, we
found that corresponding β- and γ-substituted tetralones were
obtained with high enantioselectivity. Since there are few
methods for asymmetric synthesis of β- and γ-substituted
tetralones, mainly because of the instability of the precursors,
the present method should be practically useful for obtaining
chiral β- and γ-substituted tetralones. To confirm its utility, we
applied this method to a short synthesis of (+)-linoxepin (13),
which contains a β-substituted tetralone structure.
INTRODUCTION
■
We have developed a series of guanidine-bis(thio)urea bifunc-
tional compounds 1 and 2 as organocatalysts1 and have
employed them for Henry reaction,1a aza-Henry reaction,1d
Mannich-type reaction,1e,g and Friedel−Crafts reaction1f,h,i
(Scheme 1a). Even though these catalysts have flexible linear
structure, high enantioselectivities were obtained. In structure−
activity relationship studies, we found that the bifunctionality and
pseudo-C2 symmetrical structure of 1 and 2 were mandatory for
high selectivity. We proposed that these catalytic reactions
involve interactions of the guanidine moiety with nucleophiles
and the (thio)urea moiety with electrophiles (Scheme 1a).
We recently developed an α-hydroxylation reaction of
tetralone-derived β-ketoesters 3 with cumene hydroperoxide
(CHP) in the presence of guanidine-bisurea bifunctional
organocatalyst 2d (Scheme 1b).2 In this reaction, interactions
between guanidine and β-ketoester and between the urea group
and CHP appeared to be important for high enantioselectivity.
However, the roles of these functional groups and the influence
of the characteristic linear structures of the catalysts, including
the necessity of pseudo-C2 symmetric structure, remained
unclear. We herein carried out DFT calculations to obtain
mechanistic insight into this organocatalytic reaction. We
identified a transition-state (TS) model that reasonably
RESULTS AND DISCUSSION
■
DFT Calculation of α-Hydroxylation of Tetralone-
Derived β-Ketoesters Catalyzed by Guanidine-Bisurea
Bifunctional Organocatalyst. Transition structures for the α-
hydroxylation reaction of β-ketoester 3 catalyzed by 2d were
explored to elucidate the origin of the stereocontrol. Geometry
optimization and frequency analysis were performed by B3LYP4
Received: November 4, 2014
© XXXX American Chemical Society
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interactions play crucial roles in controlling the orientation of the
β-ketoester enolate.11 Moreover, the remaining two NHure of the
urea group activate cumene hydroperoxide (CHP) through
hydrogen-bonding interaction with oxygen attached to the
carbon in cumene. These comprehensive intra/intermolecular
interactions construct the compact chiral reaction field through
induced-fit-type structural changes.
Scheme 1
The distortion/interaction analysis12 of these diastereomeric
TS models indicated that two factors mainly contribute to the
stabilization of TS-S. The first factor is the intra- and
intermolecular attractive interaction modes (e.g., hydrogen-
bonding, π−π, and CH−π interactions). The hydrogen-bonding
networks around the β-ketoester enolate are much differentiated
between TSa-S and TSa-R. In the case of TSa-S, three NH
residues, i.e., two NHgua and one NHure, interact with the ketone
carbonyl (COket). In the case of TSa-R, on the other hand, two
NH residues (NHgua and NHure) interact with the ester carbonyl
(COest). Thus, TSa-S having the larger number of hydrogen-
bonding interactions is more effectively stabilized than TSa-R
due to electronically more negative COket than COest.13 In
addition, the intramolecular CH···F hydrogen bond in the
catalyst and the intermolecular π−π and CH−π interactions
between the catalyst and the substrates significantly stabilize
TSa-S (Figure 1). Whereas the intramolecular hydrogen bond in
the catalyst is similar, the intermolecular dispersion interactions
are slightly enhanced in TSb-S. The second factor is the steric
repulsion between the ester group of the β-ketoester enolate and
the 3,5-(CF3)2C6H3 group in the catalyst. The ester group in TS-
S is oriented to the outer side of the chiral space for the reaction,
and no significant steric hindrance is observed. On the other
hand, the ester group in TS-R is embedded in the narrow space
constructed by the Ar groups in the catalyst. The t-butyl ester
group in TSb-R causes serious steric constraint and significantly
decreases the interaction energy between the catalyst and the
substrates. In addition, the 3,5-(CF3)2C6H3 group is pushed out
to move CHP interacting with the urea moiety into an
unfavorable position in TSb-R (Figure 1).14 These structural
changes around the urea moiety in TSb-R decrease the CH−π
interaction between CHP and the β-ketoester enolate. There-
fore, the energy difference ΔG between TSb-S and TSb-R
becomes larger in the case of 3b bearing t-butyl ester owing to
destabilization of TSb-R.
a
Structure of guanidine-bis(thio)urea bifunctional organocatalysts 1
and 2, and a plausible model of the interaction with nucleophiles and
electrophiles. Previous α-hydroxylation of β-ketoesters 3 catalyzed by
2d. Oxidative kinetic resolution reaction of rac-5 explored in this
study.
b
c
and M05-2X5 functionals with the 6-31G* basis set6 using the
Gaussian 09 program.7 Thermodynamic properties were
estimated at 298.15 K at 1 atm. Various TS conformations and
activation modes in the α-hydroxylation of β-ketoester 3
catalyzed by 2d were explored using simplified chemical models
at the B3LYP/6-31G* level.8 Pseudo-C2 symmetric catalyst
structures, in which the guanidinium and the urea groups activate
β-ketoester enolate and oxidant, respectively, through hydrogen
bonds, were found to be relatively stable. Next, M05-2X/6-31G*
calculation was applied to take into account dispersion
interactions such as π−π and CH−π interactions of the Ar
groups in realistic chemical models (R1 = Me, R2 = H, R3 = Ph,
and Ar = 3,5-(CF3)2C6H3 in 2).9
The identified TS models are summarized in Figure 1. The
Gibbs free energy difference (ΔG) between TSa-S and TSa-R for
3a (R = Me) is calculated to be 0.81 kcal mol−1.10 When the ester
substituent of the β-ketoester enolate is changed from methyl to
t-butyl, i.e., 3b (R = t-Bu), ΔG between TSb-S and TSb-R
becomes larger, reaching 2.49 kcal mol−1. These results are
consistent with the experimental findings that the S-form is
obtained as the major product and higher selectivity is observed
in the case of 3b (Scheme 1b). The diasteromeric TS models for
3a (TSa: R = Me) and 3b (TSb: R = t-Bu) both have the
guanidinium-bisurea catalyst in a pseudo-C2 symmetric structure,
coordinating with the β-ketoester and oxidant through the
following interactions: (1) hydrogen-bonding interaction
between guanidinium NH and F of the 3,5-(CF3)2C6H3 group
and (2) attractive dispersion interactions of the aromatic rings
(Figure 1). In these TS models, four NH residues in the
guanidinium (NHgua) and urea groups (NHure) coordinate to
two carbonyl groups in the β-ketoester enolate 3, and these
Thus, as described above, our computational results
successfully account for the highly enantioselective α-hydrox-
ylation of tetralone-derived β-ketoesters by structurally flexible
guanidine-bisurea catalyst 2. Next, we explored whether this
information could be applied to asymmetric synthesis of β- and/
or γ-substituted tetralones.
Development of Oxidative Kinetic Resolution of β- and
γ-Substituted Tetralone-Derived β-Ketoesters. β- and γ-
Substituted carbonyl compounds are ubiquitous in natural
products, as well as biologically active molecules, and several
synthetic approaches, including enantioselective versions, have
been reported. The most widely used approaches include
asymmetric Michael reaction with α,β-unsaturated carbonyl
compounds and alkylation of dienolate derived from α,β-
unsaturated carbonyl compounds.15 These strategies have been
applied to a variety of α,β-unsaturated carbonyl compounds,
including linear as well as cyclic molecules, but they have several
limitations as regards substrates. One of the more serious
restrictions applies to tetralone derivatives. Although tetralone
structure is found in many biologically active molecules (Figure
2),16 derivatization at the β- or γ-position is difficult, because the
B
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Figure 1. Schematic representations (front view) and 3D structures (bottom and side views) of TS-S and TS-R (TSa: R = Me, TSb: R = t-Bu) for 3. β-
Ketoester enolate and CHP are indicated by ball and stick models; the catalyst is shown as a tube model; unimportant hydrogen atoms are omitted.
Distances are in Å.
Scheme 2. Functionalization of α,β-Unsaturated Tetralone Is
Difficult Because of Its Instability
Figure 2. Representative natural products bearing β- and/or γ-
substituted tetralone core structures.
corresponding α,β-unsaturated carbonyl compounds are un-
stable and quickly aromatized (Scheme 2).17 Therefore, new
methodologies are needed for enantioselective synthesis of β-
and/or γ-substituted tetralones.18−20 A representative approach
to construction of β- and/or γ-substituted tetralones involves
Diels−Alder reaction and intramolecular Friedel−Crafts acyla-
tion.21−23
the si-face due to the chirality of the catalyst 2 (Figure 3). Based
on this TS model, we anticipated that the stereochemistry of the
substituents at the β- or γ-positions in tetralone 5 would affect the
reactivity for α-hydroxylation (Scheme 1c). Indeed, in DFT
calculations of TS-S models for β- and γ-substituted tetralone
derivatives, the TS model with anti relations (e.g., R1, R3) of the
electrophilic OH group of CHP and the β- or γ-substituent is
energetically favored over the syn structure (e.g., R2, R4).24 These
effects are mainly due to weaker steric repulsion between CHP
and the β- or γ-substituent and a more stable flipped
conformation of the tetralone core moiety. These computations
strongly suggested that the anti-products 6A and 6B would be
In this context, we planned to demonstrate the usefulness of
our reaction by applying it to α-hydroxylation of tetralone-
derived β-ketoesters. DFT calculation suggested that the β-
ketoester group in tetralones 5 interacts with guanidinium and
urea groups in the catalyst 2, and the oxidant coordinates with the
remainder of the urea group in 2, then oxidation proceeds from
C
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groups on the phenyl group (rac-5b−j), oxidative kinetic
resolution reaction proceeded smoothly, and high enantiose-
lectivities were obtained for both oxidation products 6b−j (83−
90% ee) and recovered 5b−j (88−99% ee); high s values of 43−
99 were obtained (Table 2, entries 1−9). The substrate with a 1-
naphthyl substituent (rac-5k) also reacted efficiently, and 6k and
5k were obtained in 72% ee and 97% ee, respectively (s = 25,
Table 2). Moderate reactivities were observed for rac-5l−n
bearing an alkyl or aralkyl group at the β-position, and high
selectivities were obtained for oxidation products 6l−n (86−90%
ee) and for 5l−n (67−74% ee) (entries 11−13). On the other
hand, low reactivities were observed for rac-5o and rac-5p
bearing isopropyl and cyclohexyl groups, with moderate s values
of 18 and 20, respectively, although good selectivities were still
obtained for 6o (84% ee) and 6p (83% ee) (entries 14 and 15).
In the case of γ-substituted tetralones with phenyl and methyl
groups (rac-5q and rac-5r), resolution took place efficiently, and
high enantioselectivities were obtained for 6q (89% ee) and 6r
(91% ee) as well as recovered 5q (99% ee) and 5r (92% ee), with
s values of 89 and 69, respectively (entries 16,17).
Synthesis of (+)-linoxepin (13). The newly developed
oxidative kinetic resolution method for tetralones was applied to
the synthesis of (+)-linoxepin (13), which was isolated from
Linum perenne as a caffeic acid dimer possessing an oxidation-
prone dihydronaphthalene structure with a tetrasubstituted
double bond embedded in a highly strained dihydrooxepine ring
system (Scheme 3).26,27
Oxidative kinetic resolution of rac-7 was performed with
(R,R)-2d in the presence of CHP (0.75 equiv) in toluene, and
(−)-7 was obtained in 37% yield with 99% ee, together with
(+)-8 in 52% yield with 77% ee. Then, synthesis of (+)-linoxepin
(13) from (−)-7 was examined. The reaction of (−)-7 with triflic
anhydride in the presence of sodium hydride gave vinyl triflate 9,
which was subjected to Suzuki−Miyaura coupling reaction with
boron reagent 10 in the presence of Pd(PPh3)4. The TBS group
was removed, and lactonization was performed with 4 M HCl in
methanol. Then, benzyl group was removed under hydro-
genolysis conditions catalyzed by palladium on carbon to give
diol 12. Compound 12 was reacted with diethyl azodicarboxylate
(DEAD) in the presence of triphenyl phosphine to construct the
dihydrooxepine ring, affording (+)-linoxepin (13) in 88% yield.
Figure 3. Calculated TS model for oxidative kinetic resolution of β- and
γ-substituted tetralone-derived β-ketoesters 5 catalyzed by 2.
preferentially generated from β- or γ-methyl-substituted
tetralones, respectively, in the presence of catalyst 2 and CHP
(Figure 3). Based on these insights, we examined the oxidative
kinetic resolution of β-ketoesters rac-5 of tetralones bearing
substituents at the β- and/or γ-positions to obtain optically active
substituted tetralones.
Oxidative kinetic resolution was examined with rac-5a, bearing
a phenyl substituent at the β-position, and catalyst 2 under the
previously developed conditions in the presence of CHP (0.5
equiv). First, the catalyst structure was varied, focusing on the
chiral spacer part of the R group (Table 1).25 In the case of the
catalyst 2a, moderate selectivity was observed in kinetic
resolution, i.e., the oxidation product 6a was obtained in 33%
yield with 72% ee, and 5a was recovered in 74% yield, with 38%
ee (entry 1). By varying the R group (methyl, isopropyl, and
phenyl groups), the selectivity was increased (entries 2−4); in
the case of 2d, 6a was obtained in 40% yield with 91% ee and 5a
was recovered in 47% yield with 64% ee, and the s value was
found to be 41 (entry 4). We further optimized the reaction
conditions with the catalyst 2d, and 6a and 5a were obtained with
83% ee (49% yield) and 97% ee (42% yield), respectively, by
increasing the amount of CHP to 0.75 equiv and prolonging the
reaction time to 48 h (entry 5).
With the optimized conditions in hand (Table 1, entry 5), the
substrate scope for the oxidative kinetic resolution of β-
ketoesters bearing substituents at the β- or γ-position in tetralone
structure was investigated (Table 2). In the case of β-substituted
tetralones with electron-donating and electron-withdrawing
a
Table 1. Optimization of the Reaction Conditions
cat.
6a
5a
b
c
d
c
e
entry
R
yield [%]
ee [%]
yield [%]
ee [%]
s value
1
2
3
4
2a
2b
2c
2d
2d
Bn
Me
iPr
Ph
Ph
33
10
20
40
49
72
11
64
91
83
74
81
56
47
42
38
1
9
1
18
64
97
5
41
44
f
5
a
Reaction conditions: rac-5a (0.05 mmol), CHP (0.025 mmol) and K2CO3 (0.05 mmol) in the presence of 2 (5 mol %) in toluene (1.0 mL) at 0 °C
b
c
1
for 24 h. Determined by H NMR spectroscopy with isopropyl alcohol as an internal standard. Determined by HPLC analysis using a chiral
d
e
stationary phase. Yield of isolated product. The selectivity factor (s value) was calculated as follows: s value = kfast/kslow = In[1 − C(1 + ee6)]/In[1
f
− C(1 − ee6)] = In[(1 − C)(1 − ee5)]/In[(1 − C)(1 + ee5)]; C = ee5/(ee5 + ee6). The reaction was run with rac-5a (0.05 mmol), CHP (0.038
mmol, 0.75 equiv), and K2CO3 (0.05 mmol, 1.0 equiv) in the presence of 3d (5 mol %) in toluene (1.5 mL, 0.03 M) at 0 °C for 48 h. CHP =
cumene hydroperoxide.
D
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a
Table 2. Oxidative Kinetic Resolution of β- or γ-Substituted Tetralone Derivatives
rac-5
6
5
b
c
b
c
d
entry
R1
R2
yield [%]
ee [%]
yield [%]
ee [%]
s value
1
2
rac-5b
rac-5c
rac-5d
rac-5e
rac-5f
rac-5g
rac-5h
rac-5i
rac-5j
rac-5k
rac-5l
rac-5m
rac-5n
rac-5o
rac-5p
rac-5q
rac-5r
2-Cl-C6H5
3-Cl-C6H5
4-Cl-C6H5
2-CF3−C6H5
2-MeO-C6H5
3-MeO-C6H5
4-MeO-C6H5
4-Me-C6H5
3,5-MeO-C6H4
1-naphtyl
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Me
50 (6b)
47 (6c)
45 (6d)
50 (6e)
44 (6f)
48 (6g)
46 (6h)
48 (6i)
42 (6j)
55 (6k)
43 (6l)
90
89
87
90
88
89
83
84
89
72
90
86
88
84
83
89
91
44 (5b)
46 (5c)
44 (5d)
43 (5e)
42 (5f)
44 (5g)
43 (5h)
43 (5i)
44 (5j)
40 (5k)
43 (5l)
94
88
93
99
90
89
99
94
90
97
67
70
74
47
61
99
92
43
50
48
99
48
51
56
40
52
25
38
28
34
18
20
89
69
3
4
5
6
7
8
9
10
11
12
13
nPr
44 (6m)
45 (6n)
34 (6o)
37 (6p)
51 (6q)
48 (6r)
44 (5m)
42 (5n)
61 (5o)
53 (5p)
44 (5q)
45 (5r)
CH2CH2Ph
iPr
e
14
e
15
cyclohexyl
H
16
17
H
a
Reaction conditions: rac-5 (0.05 mmol), CHP (0.038 mmol) and K2CO3 (0.05 mmol) in the presence of 2d (5 mol %) in toluene (1.5 mL) at 0 °C
b
c
for 48 h. Yield of isolated product. Determined by HPLC analysis using a chiral stationary phase after decarboxylation under acidic conditions.
d
The selectivity factor (s value) was calculated as follows: s value = kfast/kslow = In[1 − C(1 + ee6)]/In[1 − C(1 − ee6)] = In[(1 − C)(1 − ee5)]/
e
In[(1 − C)(1 + ee5)]; C = ee5/(ee5 + ee6). The reaction was run with 1.5 equiv of CHP.
a
Scheme 3. Synthesis of (+)-Linoxepin (13)
CONCLUSIONS
■
DFT calculations were done to uncover the mechanism of the
highly enantioselective α-hydroxylation of tetralone-derived β-
ketoesters in the presence of structurally flexible guanidine-
bisurea bifunctional organocatalyst. The identified TS structure
indicated that the β-ketoester group of tetralone interacts with
guanidine and urea groups in the catalyst 2d, and oxidant
coordinates with the remainder of the urea group. The oxidation
then proceeds from the si-face owing to the chirality of the
catalyst. Based on the insights provided by this TS model, we
designed novel methodology for asymmetric synthesis of β- and/
or γ-substituted tetralones by oxidative kinetic resolution
reaction of tetralone-derived β-ketoesters, using guanidine-urea
bifunctional organocatalyst 2d and CHP. The kinetic resolution
reaction of various tetralone derivatives proceeded with high
selectivity; the selectivity factor (s value) reached 99. This
reaction was successfully applied to the synthesis of (+)-linox-
epin (13) in 6 steps from tetralone rac-7. We expect that it will
also be applicable to the synthesis of other natural products.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Experimental details and characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
Reagents and conditions: (a) (R,R)-2d (5 mol %), CHP (0.75 equiv),
K2CO3 (1.0 equiv), toluene, 0 °C, 72 h ((−)-7: 37%, 99% ee) ((+)-8:
52%, 77% ee); (b) Tf2O (1.2 equiv), NaH (2.0 equiv), Et2O, 0 °C to
RT, 0.5 h (74%); (c) 10 (1.2 equiv), Pd(PPh3)4 (5 mol %), KOH (5.0
equiv), 1,4-dioxane, 60 °C, 1 h (47%); (d) 4 M HCl/MeOH, RT, 3 h;
(e) H2 (balloon), Pd/C (10 wt %), MeOH, RT, 0.5 h (62%, 2 steps);
(f) DEAD (4.0 equiv), PPh3 (4.0 equiv), THF, 0 °C to RT, 0.5 h
(88%). CHP = cumen hydroperoxide, DEAD = diethyl azodicarbox-
ylate, THF = tetrahydrofuran.
AUTHOR INFORMATION
Corresponding Author
*knaga@cc.tuat.ac.jp
■
Notes
The authors declare no competing financial interest.
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Journal of the American Chemical Society
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(e) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358−
ACKNOWLEDGMENTS
■
15374. (f) Almas-i, D.; Alonso, D. A.; Gom
́
ez-Bengoa, E.; Naj
́
era, C. J.
We would like to dedicate this article to celebrate the 20th
anniversary of the Department of Biotechnology and Life
Science at Tokyo University of Agriculture and Technology. This
work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” (nos. 23105013 and 23105005) from The
Ministry of Education, Culture, Sports, Science and Technology,
Japan and MEXT-Supported Program for the Strategic Research
Foundation at Private Universities. M.O. was the recipient of a
Sasakawa Scientific Research Grant from The Japan Science
Society.
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(12) The energies of TS-S and TS-R were dissected into the distortion
(Edist) and interaction energies (Eint) for the two distorted fragments
(catalyst and substrates) constructing TS. The differences for each
energy (ΔEdist and ΔEint) between TS-S and TS-R were calculated by
the counterpoise method. The computational details are shown in
Supporting Information. The original distortion/interaction analysis,
see: (a) Morokuma, K.; Kitaura, K. I Chemical Applications of Atomic and
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