Highly Enantioselective O-H Bond Insertion Reaction of α-Alkyl- A nd α-Alkenyl-α-diazoacetates with Water

Article abstract of DOI:10.1021/jacs.0c04532

Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-catalyzed insertion of carbenes into the O-H bond of water can be used to incorporate water into the stereogenic center, but the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we report the first highly enantioselective O-H bond insertion reactions between water and α-alkyl- A nd α-alkenyl-α-diazoesters as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly suppressed competing side reactions, such as β-H migration, carbene dimerization, and olefin isomerization, and thus ensured good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the phosphoric acids and phosphoramides promoted highly enantioselective [1,2]- A nd [1,3]-proton transfer reactions of the enol intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the original driving force to involve the proton shuttle catalysts in this process.

Full text of DOI:10.1021/jacs.0c04532

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Article
Highly Enantioselective O–H Bond Insertion of #-Alkyl-#-
diazoacetates and #-Alkenyl-#-diazoacetates with Water
You Li, Yu-Tao Zhao, Ting Zhou, Meng-Qing Chen, Yi-Pan Li, Ming-
Yao Huang, Zhen-Chuang Xu, Shou-Fei Zhu, and Qi-Lin Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04532 • Publication Date (Web): 14 May 2020
Downloaded from pubs.acs.org on May 14, 2020
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Journal of the American Chemical Society
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Highly Enantioselective O–H Bond Insertion of α-Alkyl-α-diazoacetates
and α-Alkenyl-α-diazoacetates with Water
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You Li, Yu-Tao Zhao, Ting Zhou, Meng-Qing Chen, Yi-Pan Li, Ming-Yao Huang, Zhen-Chuang Xu,
Shou-Fei Zhu*, and Qi-Lin Zhou
The State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
ABSTRACT: Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-
catalyzed insertion of carbenes into the O–H bond of water can be used to incorporate water into the stereogenic center, but
the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we
report the first highly enantioselective O–H bond insertion reactions between water and α-alkyl- and α-alkenyl-α-diazoesters
as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral
phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly
suppressed competing side reactions, such as β-H migration, carbene dimerization, and olefin isomerization, and thus ensured
good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions
of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for
preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various
transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the
phosphoric acids and phosphoramides promoted highly enantioselective 1,2- and 1,3-proton transfer reactions of the enol
intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the
original driving force to involving the proton shuttle catalysts in this process.
a chiral dirhodium catalyst, but the enantiomeric excess (ee)
INTRODUCTION
was only 8%. In 2006, Fu and coworkers6c reported the first
highly enantioselective O–H insertion reactions of alcohols
with α-aryl-α-diazoacetates, which they accomplished by
using a chiral copper catalyst; however, when water was the
O–H bond donor, the enantioselectivity was poor (~15%
ee). We previously realized highly enantioselective O–H
bond insertion reactions of α-aryl-α-diazoacetates with
water by using copper or iron catalysts bearing chiral spiro
bisoxazoline ligands (Scheme 1a).6d,e However, these
reactions gave unsatisfactory results for α-alkyl-α-
diazoacetates and α-alkenyl-α-diazoacetates, which is
unfortunate because such transformations would afford
Water is a widely used chemical in industrial processes
because it is inexpensive, safe, and recyclable.1 However,
even though significant progress has been made in the field
of asymmetric catalysis during the past half century,2 there
have been only a few reports of the use of water as a
substrate in catalytic enantioselective reactions. Notable
examples of the use of water as a substrate in asymmetric
catalysis include Co(salen)-catalyzed kinetic resolution of
racemic epoxides by means of ring-opening reactions in
which water acts as a nucleophile3 and enantioselective
palladium-catalyzed allylic substitution reactions of
vinylethylene carbonates with water.4
useful α-alkyl-α-hydroxyacetates
and
α-alkenyl-α-
hydroxyacetates, respectively. Saito and coworkers6f
carried out an enantioselective O–H bond insertion reaction
of methyl α-phenyl-α-diazoacetate with water by using a
combined catalyst consisting of an achiral dirhodium
complex and quinine, but the enantioselectivity was only
moderate (<50% ee). Carbene transfer reactions involving
α-alkyl-α-diazoesters and α-alkenyl-α-diazoacetates are
challenging because the metal carbenes generated from
these compounds readily undergo a number of side
reactions, including β-H migration, rearrangement, and
carbene dimerization.5,8 Besides, the challenge of the
enantioselective version of O–H bond insertion reactions
between water and carbenes generated from α-alkyl-α-
diazoesters and α-alkenyl-α-diazoesters mainly attribute to
Transition-metal-catalyzed carbene insertion into the O–
H bond of water can be used to introduce all part of water
into the insertion products and thus represents an elegant
application of water.5 However, there are only a few
reported examples of asymmetric O–H insertion reactions
involving water,6 although highly enantioselective O–H
insertion reactions involving alcohols, phenols, and
carboxylic acids have been achieved.6c,7 As early as 1995,
Moody and coworkers6a reported diastereoselective O–H
insertion reactions of water and α-phenyl-α-diazoacetates
containing chiral ester moieties, obtaining diastereomeric
excesses of up to 50%. In 1997, Landais and coworkers6b
achieved the first enantioselective O–H bond insertion
reaction of α-cinnamyl-α-diazoacetate with water by using
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their elusive enantioselective determining steps. Many O–H bond insertion product 2a, and the enantioselectivities
1
2
3
4
5
6
7
8
pioneering works indicate that reactions of rhodium
carbenes with O-nucleophiles generate oxinium ylides or
enolate intermediates9 and the proton-transfer of these
intermediates is the chiral determining step but difficult to
control.
were low (entries 1–3). The β-H elimination product (3a)
and dimerization products 4a and 5a were the main
products generated under these conditions. Next, we tested
several commercially available chiral dirhodium catalysts,
but once again the yields of 2a and the enantioselectivities
were poor (entries 4–6). We then turned to combined
catalysts. Although combinations of Rh2(OAc)4 and basic
hydrogen-bond catalysts C1 and C2 (Figure 1) failed to
improve the outcome, combining Rh2(OAc)4 with chiral
spiro phosphoric acids C3 substantially improved the yields
of the desired insertion product and gave moderate ee
values (entries 9–15).10 Phosphoric acid (S)-C3g, which has
6,6-di(10-phenyl-9-anthracenyl) substituents, performed
the best (99% yield, 44% ee; entry 15). Further
investigation revealed that both the backbone and the
acidity of the phosphoric acid strongly affected its catalytic
performance. Phosphoric acid C4, which has a binaphthyl
scaffold, afforded only a moderate yield and ee (entry 16).
Highly acidic phosphoramide C5 gave an 18% ee (entry 17).
The achiral rhodium complexes greatly influenced the
yields as well as the enantioselectivities, with Rh2(esp)2
being the best choice (entries 18–21). Finally, we could
further improve the ee by changing the ester moiety of the
diazo compound (entries 23–26); the highest
enantioselectivity (95% ee) was obtained with a 2-phenyl-
2-propyl ester (entry 26).
Because the diversity of products that can be obtained via
O–H bond insertion reactions of water is restricted, the
practical utility of this method is limited. However, we
herein report
a protocol for unprecedented highly
9
enantioselective O–H bond insertion reactions between
water and carbenes generated from α-alkyl-α-diazoesters
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and α-alkenyl-α-diazoesters with catalysis by
a
combination of achiral dirhodium complexes and chiral
phosphoric acids or chiral phosphoramides (Scheme 1b).
The phosphoric acids or phosphoramides suppressed
competing β-H migration, carbene dimerization, and
isomerization and thus ensured good yields of the desired
products. Fine-tuning of the ester moiety facilitated
enantiocontrol of proton transfer reactions of the enolate
intermediates and resulted in excellent enantioselectivity.
Scheme 1. Catalytic Enantioselective O-H Bond
Insertion Reactions with Water
RESULTS AND DISCUSSION
We began by exploring the reaction between water and a
typical α-alkyl-α-diazoacetate, methyl 2-diazooctanoate (1a,
Table 1). First, we evaluated transition-metal catalysts
bearing chiral ligand L1 or L2 (Figure 1), which have been
shown to efficiently catalyze enantioselective O–H bond
Figure 1. Chiral Ligands and Catalysts Used in This Study
insertion
reactions
of
α-aryl-α-diazoesters.6d,,7c
Unfortunately, these catalysts gave poor yields of desired
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Table 1. Asymmetric O–H Bond Insertion Reactions of 1-Diazooctanoates (1a) with Water: Optimizing Reaction
Conditions a
1
2
3
4
5
6
7
8
9
10
11
12
13
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15
16
17
18
19
20
21
22
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26
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entry
catalyst
R
2a (yield%/ee%)b
3a/4a/5a
(yield%)b
1
CuSO4/L1/NaBArF
FeCl2.4H2O/L1/NaBArF
CuOTf/L2
Me
NDc
66/15/8
70/10/9
66/16/9
56/12/15
41/10/13
30/7/12
37/8/7
27/8/6
1/ND/1
5/ND/1
4/ND/2
2/ND/1
1/ND/1
1/ND/ND
1/ND/ND
19/10/6
10/10/3
10/7/8
6/5/4
2
Me
ND
3
Me
ND
4
Rh2(R-DOSP)4
Rh2(S-PTTL)4
Me
5/4
5
Me
27/20
41/28
45/2
6
Rh2(R-BDPCP)4
Rh2(OAc)4/C1
Rh2(OAc)4/C2
Rh2(OAc)4/C3a
Rh2(OAc)4/C3b
Rh2(OAc)4/C3c
Rh2(OAc)4/C3d
Rh2(OAc)4/C3e
Rh2(OAc)4/C3f
Rh2(OAc)4/C3g
Rh2(OAc)4/C4
Rh2(OAc)4/C5
Rh2(Oct)4/C3g
Rh2(TPA)4/C3g
Rh2(TFA)4/C3g
Rh2(esp)2/C3g
Rh2(esp)2/C3g
Rh2(esp)2/C3g
Rh2(esp)2/C3g
Rh2(esp)2/C3g
Rh2(esp)2/C3g
Me
7
Me
8
Me
49/5
9
Me
96/11
92/22
91/28
94/21
96/29
98/33
99/44
54/26
72/21
69/44
76/78
14/17
80/78
78/80
74/76
82/82
80/90
80/95
10
11
12
13
14
15
16
17
18
19
20
21
22d
23d
24d,e
25d,e
26d,e
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
50/14/12
11/2/1
10/7/1
5/8/6
Me
Me
tBu
Bn
5/4/5
CH(Ph)2
C(Me)2Ph
4/6/5
2/4/10
a Reaction conditions of entries 1-3: 0.2 mmol 1a, 1.0 mmol H2O, 5 mol % copper or iron salts, 6 mol % L1 or L2, 6 mol % NaBArF,
3 mL CHCl3, at room temperature (rt). Reaction conditions of entries 4-6: 0.2 mmol 1a, 1.0 mmol H2O, 1 mol % chiral dirhodium
catalyst, 3 mL CHCl3 at rt. Reaction conditions of entries 7-26: 0.2 mmol 1a, 1.0 mmol H2O, 1 mol % achiral dirhodium catalyst, 1
mol % C1-C5, 3 mL CHCl3 at rt. b Isolated yields, ee values were determined by GC using a Beta-325 chiral column. c Not detected. d
The reaction was performed at 0 °C. e Yields were determined by H NMR using 1,3,5-trimethoxy-benzene as an internal standard,
ee values were determined by HPLC equipped with AD-H chiral column.
1
Under the optimal conditions, O–H bond insertion
reactions of various α-alkyl-α-diazoacetates 1 with water
were evaluated (Scheme 2). Impressively, all the reactions
were complete within 1 min, and α-alkyl-α-diazoacetates
with linear or branched alkyl substituents gave high or
excellent enantioselectivities and good yields (2a–2i).
Generally, the ee values decreased as the steric bulk of the
alkyl group increased. When diazoesters bearing alkyl
groups with a terminal phenyl group were used, high ee
values were obtained, and the yields increased with alkyl
chain length (2j–2l). Because the diazo ester with a benzyl
group (1j) easily underwent β-H migration, we increased
the amount of phosphoric acid (S)-C3g to 2 mol % to get an
acceptable yield. This O–H bond insertion reaction showed
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good functional group tolerance; introduction of alkenyl, obtained on a gram scale at a catalyst loading as low as 0.5
1
2
3
4
5
6
7
8
alkynyl, ether, ester, and cyano groups on the alkyl chains
(1m–1t) only slightly affected the reaction outcome. In
addition, the reaction could be performed on a gram scale
with negligible effect on the yield and ee (2b, 1.7 g scale).
mol %. Under standard reaction conditions, the reaction of
methyl α-diazophenylacetate with water smoothly afforded
desired O-H bond insertion product with high yield (92%)
but very modest enantioselectivity (34%). These results
imply that the method developed in this study is
complementary to the previously reported methods.6d,e
Scheme 2. Enantioselective O–H Bond Insertion
Reactions of α-Alkyl-α-diazoacetates with Water:
Substrate Scope a
Scheme 3. Enantioselective O–H insertion Reactions of
α-Alkenyl-α-diazoacetates with Water: Substrate Scope
a
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a
Reaction conditions: 6/H2O/Rh2(TPA)4/(R)-C3d
=
a
Reaction conditions: 1/H2O/Rh2(esp)2/(S)-C3g
=
0.2:1.0:0.002:0.002 (mmol), in 3 mL CHCl3, at 0 °C. All reactions
completed within 1 min. Isolated yields were given. b Reaction
conditions: 6/H2O/Rh2(TPA)4/(S)-C5 = 0.2:1.0:0.002:0.002
(mmol), in 3 mL CHCl3, at 0 °C. All reactions completed in 1 min.
Isolated yields were given. c The data in parenthesis are of the
reaction performed at a gram-scale: 6a/H2O/Rh2(TPA)4/(R)-
0.2:1.0:0.002:0.002 (mmol), in 3 mL CHCl3, at 0 °C. All reactions
completed in 1 min. Isolated yields were given. The ee values
were determined with AS-H or OJ-3 chiral column. A gram-
scale experiment: 1b/H2O/Rh2(esp)2/(S)-C3g = 10:50:0.1:0.1
(mmol), in 150 mL CHCl3. c Used 2 mol % (S)-C3g.
b
d
C3d = 3.7:18.5:0.019:0.019 (mmol), in 30 mL CHCl3. DPM =
CH(Ph)2
The combination of achiral dirhodium complexes and
chiral Brønsted acids could also be extended to O–H bond
insertion reactions of α-alkenyl-α-diazoacetates with water
(Scheme 3). Systematic study of the reaction conditions
revealed that combining Rh2(esp)2 with chiral spiro
phosphoric acid (R)-C3d promoted O–H bond insertion
reactions of γ-aryl-γ-methyl-α-vinyldiazoesters with water,
affording products 7a–7l in high yields with high
enantioselectivities (see SI for details regarding
optimization of the reaction conditions). Like the reactions
of α-alkyl-α-diazoacetates, the reactions of α-alkenyl-α-
diazoacetates were very fast (going to completion in <1
min). The electronic and steric properties of substituents on
the phenyl groups of the diazo compounds had little effect
on the reaction outcome. For γ,γ-diaryl- and γ,γ-dialkyl-α-
vinyldiazoesters (7m), we used chiral spiro phosphoramide
(S)-C5, which has higher acidity and gave better results than
(S)-C3d. The same catalysis system was also successfully
used for highly enantioselective O–H bond insertion
reactions between water and (E)-γ-alkyl- and (E)-γ-aryl-α-
vinyl-α-diazoacetates (7n–7s). Finally, 7a could be
The O–H insertion reactions of α-alkyl-α-diazoacetates
with water provide a new route to multifunctionalized
chiral α-alkyl-α-hydroxyesters, which are useful building
blocks in organic synthesis and can undergo a wide variety
of transformations (Scheme 4A). For instance, insertion
product 2b could be transformed to corresponding acid 8 in
nearly quantitative yield by means of acidic hydrolysis (eq
a), and amidation of 8 with benzyl amine produced 9 in
good yield with retained ee (eq b).11 Chiral 1,2-diols 10 and
11 were prepared in high yields and retained ee values by
reduction of 2a (eqs c–e). Notably, 10 and 11 and
derivatives with different alkyl chains have been used in
syntheses of chiral natural products (Scheme 4B).12 α-
Fluoro carboxylic ester 12 was prepared by means of
stereochemistry-inverse fluorination of the hydroxy group
of 2a (Scheme 4A, eq f).13 Chiral α-fluoro carboxylic esters
have been used to synthesize bioactive compounds.14
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Scheme 4. Transformations and Potential Synthetic Scheme 5 Transformations and Potential Synthetic
1
Applications of the Insertion Products of α-Alkyl-α-
Applications of the Insertion Products of α-Alkenyl-α-
2
diazoesters with Water
diazoesters with Water
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Reaction conditions: (a) HCl, MeOH, 60 °C, 2 h. (b) BnNH2,
MeB(OH)2, PhCO2H, toluene, 10 h. (c) LiAlH4, THF, rt, 2 h. (d)
Chloro(1,1-dimethylethyl)dimethyl-silane, imidazole, DMF, rt,
1
h. (e) H2, Pd(OH)2/C, rt,
2
h. (f) N,N-
diethylamino)sulfurtrifluoride, DCM, -78 °C to rt, 10 h.
Insertion products 7, generated by O–H bond insertion
reactions of α-alkenyl-α-diazoacetates with water, are also
useful building blocks because of the presence of the ester,
hydroxy, and alkenyl groups on these molecules (Scheme 5).
For instance, reduction of 7a smoothly afforded corresponding
carboxylic acid 13, and hydrolysis generated 1,2-diol 14
(Scheme 5A, eqs a and b), with excellent yields and ee values in
both cases. Derivatives of 1,2-diols such as these have been
used for the synthesis of various natural products (Scheme
5B).15 In the presence of PPh3 and CCl4, the hydroxy group of 7a
could be smoothly replaced with a chlorine atom, affording 15
with retained ee (Scheme 5A, eq c). In addition, 7a underwent
an Eschenmoser–Claisen rearrangement to produce 16, which
has a chiral quaternary carbon center, in 98% yield with 91%
ee (eq d).16 Moreover, we used insertion products 7p and 7u to
synthesize bioactive compounds (Scheme 5C). Specifically,
cannabinoid receptor 1 inhibitor 18, which has a pyrrolidin-
2-one core structure, was prepared from 7p by means of an
allylic rearrangement–cyclization sequence (eqs e and f),17
demonstrating the potential utility of our protocol for the
synthesis of important chiral pyrrolidine-2-ones.18 In
addition, a formal synthesis of the chiral drug sertraline was
Reaction conditions: (a) HCl, MeOH, reflux. (b) LiAlH4, THF,
reflux. (c) PPh3, CCl4, reflux. (d) CH3C(OMe)2NMe2, xylene,
140 °C, reflux. (e) ArNCO, DCM, reflux, then Pd(OAc)2, Xantphos,
rt. (f) H2, Pd/C, then tBuOK. (g) ClCO2Et, then 3,4-
dichlorophenylboronic acid, Pd(OAc)2, 1,10-phenanthroline,
AgOTf. (h) ClCO2Et, then methyl 3-hydroxybenzoate, Pd(PPh3)4,
DCM, rt.
MECHANISTIC STUDIES
We carried out density functional theory calculations to
elucidate the mechanism of this rhodium(II)-catalyzed O–H
insertion reaction and to show how the spiro phosphoric
acids induced O–H insertion and regulated its
chemoselectivity and enantioselectivity. To reduce the
computational costs, we used the Rh2(OAc)4-catalyzed O–H
insertion reaction between methyl α-diazobutyrate and
water as a model. In the presence of (PhO)2P(O)OH (1
mol %), the model reaction gave insertion product methyl
2-hydroxybutanoate in 85% yield along with β-H migration
realized by subjecting 7p to
a palladium-catalyzed
stereospecific allylic arylation (eq f).19 Finally, endothelin
antagonist 20 was obtained through a stereospecific allylic
etherification reaction of insertion product 7u.20
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side-product methyl (Z)-but-2-enoate in 9% yield; in the migration and O–H insertion, we concluded that reduction
1
2
3
4
5
6
7
8
absence of the phosphoric acid, the corresponding yields
were 30% and 40% (see SI for details). We performed the
of the activation energy for transforming INT2 to Pdt is the
mechanism by which the chiral phosphoric acids suppress
side reactions. The fast reaction rate of the O–H bond
insertion might attribute to the high activity of dirhodium
catalyst as well as the efficient proton transfer promoted by
the phosphoric acid.
calculations
by
means
of
the
B3LYP-
D3(BJ)/def2TZVP//B3LYP/def2SVP method in chloroform
solution (using the SMD model) with the Gaussian 09
program package (see SI for details). Because the
dirhodium-complex-catalyzed decomposition of α-
diazoacetates has been reported previously in other O–H
bond insertion reactions, 5 we started our calculations with
a simplified rhodium carbene (CB). Once formed, CB can
insert into the O–H bond of water (Figure 2, right) or
undergo side reactions, such as β-H migration (Figure 2,
left). The calculated transition states for β-H migration,
which gives E-BP and Z-BP, are designated TS1 and TS2
and are 11.7 and 9.6 kcal/mol higher in energy than CB. The
calculations also showed that nucleophilic attack by water
on CB is very facile, having an activation free energy of only
6.9 kcal/mol via transition state TS3 and giving rhodium-
associated oxonium ylide INT1. Formation of INT1 is
followed by a quick intramolecular [1,3]-proton shift via
TS4 to generate rhodium-associated enol INT2.
Dissociation of the dirhodium complex from INT2 liberates
free enol INT3, a process that is not energetically difficult
because it is uphill by only 3.5 kcal/mol. The process of free
enol formation in O−H insertion reactions is consistent with
previous DFT calculations.7j,7m,7l,21 From free enol INT3,
several possible proton shift processes lead to the final
product (Pdt): a water-assisted [1,3]-proton shift via TS5
(∆Gsol = 23.8 kcal/mol) or via TS6 (∆Gsol = 17.6 kcal/mol) or
an enol intermediate self-catalyzed [1,3]-proton shift via
TS5 (∆Gsol = 14.3 kcal/mol). Other possible proton shift
processes that do not involve the phosphoric acid (PA) are
considered in the SI. The energy barriers to these proton-
shift processes are much higher than the energy barrier to
β-H migration. However, two PA-assisted keto–enol
tautomerization processes with much lower activation
energies are also possible. Specifically, our calculations
indicated that INT3 and PA can participate in a [1,2]- or
[1,3]-proton shift via seven-membered transition state TS9
or eight-membered transition state TS8, with activation
free energies of 3.2 and 3.5 kcal/mol, respectively. In
addition, the less bulky dirhodium catalyst Rh2(OAc)4 might
be involved in a PA-promoted [1,3]-proton shift that
proceeds via TS10 (∆Gsol = −2.1 kcal/mol), which is
consistent with the effect of varying the rhodium complex
on enantioselectivity (Table 1). The stepwise acid-base
process, which was proposed in a Morita-Ballis-Hillman
reaction,22 was also considered, but such process exhibited
much higher energy barrier (∆∆Gsol = 4.1 kcal/mol) than
that of proton-shuttle process according to the calculation
(Figure S8). By comparing the energy barriers of β-H
To explain how the chiral phosphoric acid controlled the
enantioselectivity, we propose a chiral control model based
on a [1,2]- or [1,3]-proton shift reaction of an enol species
(Figure 3). As a model reaction for density functional theory
calculations, we used the insertion reaction between water
and diazoester 1b with catalysis by Rh2(esp)2 and (S)-C3g
to afford (S)-2b. In this case, the proton shift most likely
involves a free enol species rather than a rhodium-
associated enol, because bulky phosphoric acid (S)-C3g can
be expected to prevent the bulky Rh2(esp)2 catalyst from
approaching the enol intermediate. Our calculations
showed that the most favorable pathway for the formation
of (R)-2b involves an (S)-C3g-promoted [1,3]-proton shift
reaction of an enol intermediate with cis-hydroxy via
transition state TSII-R, whereas the most favorable
pathway for the formation of (S)-2b involves an (S)-C3g-
promoted [1,2]-proton shift reaction of the enol
intermediate via transition state TSI-S. The energy of TSI-S
is 3.4 kcal/mol lower than that of TSII-R, which is in
agreement with results of the corresponding experiments.
Because the energy difference between cis- and trans-enol
is small (∆∆Gsol = 0.2 kcal/mol, Figure S5), we also calculated
the (S)-C3g-promoted [1,3]-proton shift reaction of an enol
intermediate with trans-hydroxy (Figures S6 and S7). The
calculation once again supports the pathway affording (S)-
2b. The [1,2]-proton shift is not allowed in this case.
Moreover, we tried a lot but failed to add Rh2(esp)2 into the
TS-I and TS-II shown in Figure 3 during the DFT calculation.
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We found that the energy difference between TSI-S and
TSII-R depends strongly on the O7-H8-O9 angle and the H4-
O5-C6-C7 dihedral angle (Figure 4). The former determines
the extent of overlap between the p orbital of C7 and the σ*
orbital of O9–H8, which in turn determines the strength of
the interaction between the enol and the phosphoric acid;
the latter correlates to the stability of the enol moiety. This
conclusion can be supported by comparing the geometries
of TSI-S and TSII-R: in the former, the O7-H8-O9 angle is
171° and the H4-O5-C6-C7 dihedral angle is −8.7°; whereas
the corresponding angles for the latter are 163° and −24.4°.
The angles for TSI-S are clearly much closer to the ideal
angles (180° for O7-H8-O9 and 0° for H4-O5-C6-C7). This
observation is consistent with previous calculations on
proton shift processes of other enol intermediates.23
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Figure 2. Computed Energy Surfaces for O−H Bond Insertion and β-H Migration
Figure 3. The Model of Chiral Control of Spiro Phosphoric Acid (S)-C3g
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Figure 4. Difference between TSI-S and TSII-R
Figure 6. Natural Bond Orbital Analysis of TSI-S and TSII-R.
Multiwfn and VMD were employed for visualization of the
results of natural bond orbital analysis.
∆Edis
34.3
30.9
∆∆Edis
-3.4
∆Edis(enol)
9.6
∆Edis(cat)
24.7
∆Eint
-51.4
-43.9
∆∆Eint
7.5
∆Eǂ
We also used distortion/interaction analysis to quantify
the difference between TSI-S and TSII-R (Figure 5).
TSI-S
-17.1
-13.0
∆∆Eǂ
4.1
Activation energy ∆Eǂ can be written as ∆Eǂ = ∆Edis + ∆Eint
,
TSII-R
12.7
18.2
where ∆Edis is the energy difference that arises from
structural changes leading to TS formation, and interaction
energy ∆Eint corresponds to the energy difference between
the distorted catalyst plus the enol and the complex in the
TS structures. Our calculations show that the interaction
energy is stronger in TSI-S than in TSII-R (∆∆Eint = 7.5
kcal/mol), which is consistent with the fact that the O7-H8-
O9 angle in TSI-S is closer to 180°. In addition, TSI-S has a
lower distortion energy in the enol than that of TSII-R
(∆∆Edis(enol) = 3.0 kcal/mol), because the planarity of the
enol is maintained during formation of TSI-S. Furthermore,
natural bond orbital analysis shows that the nO5 → π* C6–
C7 interaction in TSI-S is about 10.7 kcal/mol stronger than
that in TSII-R (Figure 6). This difference indicates that in
TSI-S, conjugation between the lone pairs at O5 (nO5) and
the π antibonding orbital of the C6–C7 double bond (π* C6–
∆∆Edis(enol)
3.0
∆∆Edis(cat)
-6.5
Figure 5. Distortion/Interaction Analysis of TSI-S and TSII-R.
A(cat) and B(enol) are the catalyst and the enol moieties in the
TSI-S, while A’(cat) and B’(enol) are the catalyst and the enol
moieties in the TSII-R. A is the optimized structure of the
catalyst, and B is the optimized structure of enol. All energetics
in this figure are in kcal/mol.
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277, 936. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
C7) is more efficient, owing to the more planar geometry of
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. Highly
Selective Hydrolytic Kinetic Resolution of Terminal Epoxides
Catalyzed by Chiral (Salen)CoIII Complexes. Practical Synthesis of
Enantioenriched Terminal Epoxides and 1,2-Diols. J. Am. Chem. Soc.
2002, 124, 1307. (c) Rossbach, B. M.; Leopold, K.; Weberskirh, R.
Self-assembled Nanoreactors as Highly Active Catalysts in the
Hydrolytic Kinetic Resolution (HKR) of Epoxides in Water. Angew.
Chem. Int. Ed. 2006, 45, 1309.
4 Khan, A.; Khan, S.; Khan, I.; Zhao, C.; Mao, Y.; Chen,Y.; Zhang, Y.
J. Enantioselective Construction of Tertiary C-O Bond via Allylic
Substitution of Vinylethylene Carbonates with Water and Alcohols.
J. Am. Chem. Soc. 2017, 139, 10733.
5 For selected reviews, see: (a) Doyle, M. P.; McKervey, M. A.; Ye,
T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds, Wiley, New York, 1998, chap. 8. (b) Miller, D. J.; Moody,
C. J. Synthetic Applications of the O-H Insertion Reactions of
Carbenes and Carbenoids derived from Diazocarbonyl and Related
Diazo Compounds. Tetrahedron 1995, 51, 10811. (c) Zhu, S.-F.;
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the enol moiety relative to that in TSII-R.
SUMMARY
In summary, we have realized the first highly
enantioselective O–H bond insertion reactions between
water and α-alkyl-α-diazoacetates and α-alkenyl-α-
diazoacetates, with combined catalysis by achiral
rhodium(II) carboxylates and chiral spiro phosphoric
catalysts. These mild reactions proceed rapidly and show
high yields, high to excellent enantioselectivities, and very
good functional group tolerance. The multifunctionalized
chiral α-alkyl- and α-alkenyl-α-hydroxyester products
readily undergo a variety of transformations and are
valuable synthons for bioactive compounds. Mechanistic
studies suggest that the addition of phosphoric acid is key
to the success of the reactions; the phosphoric acid not only
suppresses major side reactions involving the active
carbene species by accelerating proton transfer reactions of
the active intermediates but also exerts chiral control
during proton transfer reactions of the enol intermediates.
Our results can be expected to inspire other studies on
enantioselective reactions with water as a reagent.
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Zhou,
Q.-L.
Transition-Metal-Catalyzed
Enantioselective
Heteroatom-Hydrogen Bond Insertion Reactions. Acc. Chem. Res.
2012, 45, 1365. (d) Gillingham, D.; Fei N. Catalytic X–H Insertion
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M. A. Modern Organic Synthesis with α-Diazocarbonyl Compounds.
Chem. Rev. 2015, 115, 9981.
6 For a diastereoselective O-H bond insertion with water, see: (a)
Aller, E.; Brown, D. S.; Cox, G. G.; Miller, D. J.; Moody, C. J.
Diastereoselectivity in the O-H Insertion Reactions of Rhodium
Carbenoids Derived from Phenyldiazoacetates of Chiral Alcohols.
Preparation of α-Hydroxy and α-Alkoxy Esters. J. Org. Chem. 1995,
60, 4449. For enantioselective O-H bond insertion with water, see:
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Angew. Chem. Int. Ed. 2008, 47, 932. (e) Zhu, S.-F.; Cai, Y.; Mao, H.-
X.; Xie, J.-H.; Zhou, Q.-L. Enantioselective Iron-Catalysed O-H Bond
Insertions. Nat. Chem. 2010, 2, 546. (f) Saito, H.; Iwai, R.; Uchiyama,
T.; Miyake, S. Chiral Induction by Cinchona Alkaloids in the
Rhodium(II) Catalyzed O-H Insertion Reaction. Chem. Pharm. Bull.
2010, 58, 872.
7 For selected examples, see: (a) Chen, C.; Zhu, S.-F.; Liu, B.; Wang,
L.-X.; Zhou, Q.-L. Highly Enantioselective Insertion of Carbenoids
into O-H Bonds of Phenols: An Efficient Approach to Chiral α-
Aryloxycarboxylic Esters. J. Am. Chem. Soc. 2007, 129, 12616. (b)
Zhu, S.-F.; Song, X.-G.; Li, Y.; Cai, Y.; Zhou, Q.-L. Enantioselective
Copper-Catalyzed Intramolecular O-H Insertion: An Efficient
Approach to Chiral 2-Carboxy Cyclic Ethers. J. Am. Chem. Soc. 2010,
132, 16374. (c) Osako, T.; Panichakul, D.; Uozumi, Y.
Enantioselective Carbenoid Insertion into Phenolic O-H Bonds
with a Chiral Copper(I) Imidazoindolephosphine Complex. Org.
Lett. 2012, 14, 194. (d) Song, X.-G.; Zhu, S.-F.; Xie, X.-L.; Zhou, Q.-L.
Enantioselective Copper-Catalyzed Intramolecular Phenolic O-H
Bond Insertion: Synthesis of Chiral 2-Carboxy Dihydrobenzofurans,
Dihydrobenzopyrans, and Tetrahydrobenzooxepines. Angew.
Chem. Int. Ed. 2013, 52, 2555. (e) Xie, X.-L.; Zhu, S.-F.; Guo, J.-X.; Cai,
Y.; Zhou, Q.-L. Enantioselective Palladium-Catalyzed Insertion of α-
Aryl-α-diazoacetates into the O-H Bonds of Phenols. Angew. Chem.
Int. Ed. 2014, 53, 2978. (f) Gao, X.; Wu, B.; Huang, W.-X.; Chen, M.-
W.; Zhou, Y.-G. Enantioselective Palladium-Catalyzed C-H
Functionalization of Indoles Using an Axially Chiral 2,2’-Bipyridine
Ligand. Angew. Chem. Int. Ed. 2015, 54, 11956. (g) Kitagaki, S.;
Sugisaka, K.; Mukai, C. Synthesis of Planar Chiral
[2.2]Paracyclophane Based Bisoxazoline Ligands Bearing No
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures,
spectroscopic traces for mechanistic studies and
characterization data for products.
AUTHOR INFORMATION
Corresponding Author
*sfzhu@nankai.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(21625204, 21971119, 21790332, 21532003), the “111”
project (B06005) of the Ministry of Education of China, and the
National Program for Special Support of Eminent Professionals
for financial support. We also thank Professor Xiao-Song Xue
and Miss Biying Zhou of our institute for helpful discussion on
DFT calculation.
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