Stereodefined rhodium-catalysed 1,4-H/D delivery for modular syntheses and deuterium integration

Article abstract of DOI:10.1038/s41929-021-00643-9

Deuterium-incorporated compounds are of high interest owing to their importance in the pharmaceutical industry, organic synthesis and materials science. So far, the integration of deuterium into the inert, saturated magic methyl or methylene groups of covalent molecules remains challenging. Here, we present a 1,4-H delivery of allylic metallic species to provide a highly stereoselective and straightforward approach to 3-methyl-2(E)-enals or -enones from readily available 2,3-allenols and organoboronic acids. The reaction accommodates many synthetically versatile functional groups as well as multi-pharmacophores, and is not limited to the formation of 3-methyl derivatives. By applying 1,4-H or D delivery, deuterium atom(s) from differently deuterated allenols can be edited into the methyl or methylene groups of versatile organic skeletons, resulting in the efficient formation of 4-monodeuterated, 1,4- and 4,4-doubly deuterated, and 4,4,4-triply deuterated 2(E)-enals or -enones. These powerful platform molecules can provide straightforward paths to other deuterated compounds for different purposes. [Figure not available: see fulltext.].

Full text of DOI:10.1038/s41929-021-00643-9

Articles
https://doi.org/10.1038/s41929-021-00643-9
Stereodefined rhodium-catalysed 1,4-H/D
delivery for modular syntheses and deuterium
integration
1,4
1,4
1
2
3
ꢀ✉
1
ꢀ✉
Weiyi Wangꢀ ꢀ , Yibo Yuꢀ ꢀ , Bao Cheng , Huayi Fang , Xue Zhangꢀ ꢀ , Hui Qian and
Shengming Maꢀ ꢀ1,3
ꢀ✉
Deuterium-incorporated compounds are of high interest owing to their importance in the pharmaceutical industry, organic syn-
thesis and materials science. So far, the integration of deuterium into the inert, saturated magic methyl or methylene groups
of covalent molecules remains challenging. Here, we present a 1,4-H delivery of allylic metallic species to provide a highly ste-
reoselective and straightforward approach to 3-methyl-2(E)-enals or -enones from readily available 2,3-allenols and organo-
boronic acids. The reaction accommodates many synthetically versatile functional groups as well as multi-pharmacophores,
and is not limited to the formation of 3-methyl derivatives. By applying 1,4-H or D delivery, deuterium atom(s) from differently
deuterated allenols can be edited into the methyl or methylene groups of versatile organic skeletons, resulting in the efficient
formation of 4-monodeuterated, 1,4- and 4,4-doubly deuterated, and 4,4,4-triply deuterated 2(E)-enals or -enones. These
powerful platform molecules can provide straightforward paths to other deuterated compounds for different purposes.
euteration is essential and is widely used in the pharmaceuti- the catalytic cycle, which affords synthetically and/or medicinally
cal industry1–3, organic synthesis4,5 and materials science6–8
.
versatile 2-alkenals or 2-alkenones with an excellent stereoselectiv-
D
In drug discovery, deuteration has great potential to improve ity under very mild conditions (Fig. 1d, left). By applying this pro-
the pharmacological profiles of lead compounds or to enable the tocol, a deuterium atom is edited into the methyl or the methylene
tracing of metabolic pathways to elucidate a drug’s mechanism of groups of versatile organic skeletons via its robust delivery from the
action1–3 (Fig. 1a). On the other hand, the magic methyl effect has C(D)OH moiety of differently deuterated, readily available allenols
been extensively observed in natural products9,10 and in medicinal (Fig. 1d, right).
chemistry11–18 (Fig. 1a,b). For example, the incorporation of a methyl
group into certain lead compounds can dramatically boost their Results
potency15 (Fig. 1b, bottom). Thus, due to the corresponding effects Reaction discovery and optimization. Carbometallation of
of deuterium atoms on the absorption, distribution, metabolism and allenes has become one of the most common approaches for the
excretion3,19 of compounds, the robust generation of CHnD3−n (n=0, facile formation of A-type allylic metallic species48,49. We there-
1, 2) groups in covalent molecules is of high current interest. So far, fore attempted the Rh-catalysed reaction of 2,3-butadienol 1a
the modular creation of differently deuterated methyl and methy- with 3-methoxyphenyl boronic acid 2a to test the concept shown
lene groups in covalent molecules remains a fundamental chal- in Fig. 1c, under the same conditions as for the syn-hydroarylation
lenge20–28 (Fig. 1a). Organic transition metal species are involved in of propargylic alcohols50. Different from the expected hydroaryla-
catalytic reactions29–31 and are prevalent in medicinal chemistry14,32 tion reaction50, a new product, 3-(m-methoxyphenyl)but-2(E)-enal
and materials science33,34. In a β-H elimination reaction, the metal E-3aa, was formed in a highly stereoselective manner, albeit in
picks up a hydrogen atom in an alkyl metallic species. The frequently 12% NMR yield (Table 1, entry 1). Through careful analysis of its
used A-type allylic metallic species may also undergo this type of structure, we noticed that the carbon atom in the 4-position may
β-H elimination to afford 1,3-dienes, in which intermediate B35–37 is indeed have received a hydrogen atom from the carbon atom in the
generated during the process of obtaining the hydrogen atom (Fig. 1-position of 1a during this transformation. After further optimiza-
1c, path a and path b). We envisioned that the hydrometallation of tion, we observed that 2-enal E-3aa could be formed in 77% NMR
the C3=C4 bond instead of the C1=C2 bond in intermediate B would yield in the presence of [Cp*RhCl2]2 (where Cp* is pentamethylcy-
yield an isomeric allylic intermediate C (Fig. 1c, path c), formulating clopentadienyl) (2.5mol%), Cu(OAc)2·H2O (1.2 equiv.) and NaOAc
a concept for allylic C–H activation38–47 that eventually results in a (20mol%) in MeOH at room temperature in air (entry 2). Solvent
metal-carried 1,4-H delivery. Challenges involve control of the regi- screening showed that tetrahydrofuran (THF) was optimal (entries
oselectivity in terms of the two C=C bonds in intermediate B, and 2–7). A 90% NMR yield of E-3aa was observed when the reaction
the realization of clear-cut, one-way transformation.
was conducted with 1.0 equiv. of Cu(OAc)2·H2O (entry 8); how-
Here we report a reaction of organoboronic acids with ever, it could also be used in catalytic amounts (entries 9 and 10).
2,3-allenols, co-catalysed by Rh and Cu and using air to complete The efficiency decreased when the reaction was carried out in the
1Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, Shanghai, P. R. China. 2Department of
Chemistry, Fudan University, Shanghai, P. R. China. 3State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
4
✉
Academy of Sciences, Shanghai, P. R. China. These authors contributed equally: Weiyi Wang, Yibo Yu. e-mail: xzhang@sioc.ac.cn; qian_hui@fudan.edu.cn;
masm@sioc.ac.cn
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Articles
a
c
Deuterated bioactive compounds
Design of 1,4-H delivery involving allylic metallic species
O
H1
+
M
H
Hydrogen picked up by metal
Me
M
B
H
Path b
4
1
MH1
4
D3CO
D3CO
Me
1
+
N
Austedo
3
2
3
2
(FDA approved for treatment of chorea
associated with Huntington disease)
H1
M
H
4
1
Hydrogen delivered by metal
1,4-H delivery products
Me
CD3
Path c
M
Me Me
3
2
Alkyl metallic
species
Allylic metallic
species
OAc
H1
C20-D3-retinyl acetate
M
C
Me
A
(Phase II trials for treatment of Stargardt disease)
4
1
2
3
D
D
Challenge: controllable
nC5H11
H1
O
d
H1 H2
H2
H3
Rh/Cu-co-catalysed reaction of 2,3-allenols with organoboronic acids (this work)
EtO
H
OH
RT001
R′
H
4
R′
•
Mono-, double-,
triple deuteration
(Phase II/III trials for treatment of
infantile neuroaxonal dystrophy)
Rh Cu
Air
O
1
3
4
R″
2
+
R
1
R″
3
2
b
RB(OH)2
Methyl groups in natural products and medicinal chemistry
1,4-H delivery
In natural products
Me
O
Me
1,4-H/D delivery
Me
Dendrolasin (ref. 9
)
Divergent deuteration
Modular creation of differently deuterated methyl groups
Modular syntheses
O
Me
Me
Me
Me Me
Me
O
O
H
D
D
H
D
D
H
D
D
O
O
O
Mokupalide (ref. 10
)
Me
and
In medicinal chemistry
Cl
d1-methyl
d2-methyl
d3-methyl
O
O
Me
S
O
H
Creation of differently deuterated methylene groups
N
N
N
S
H
D
H
D
H
D
D
O
O
O
R
O
O
O
183-fold potency boost
D
R = H
R = Me
Bioactive and pharmacophore
structures
in thrombin-inhibitory
d1′-methyl
d1-methylene
d2-methylene
activities (ref. 15
)
Fig. 1 | the importance of deuterated compounds, the magic methyl effect and strategies for deuteration. a, Selected examples of deuterated bioactive
compounds. FDA, United States Food and Drug Administration. b, Methyl groups in natural products (top) and medicinal chemistry (bottom). c, The
concept of 1,4-H delivery. d, Rh/Cu-co-catalysed reaction of 2,3-allenols with organoboronic acids involving 1,4-H/D delivery.
absence of NaOAc (entry 11), and an NMR yield of only 4% E-3aa nitro (E-3am)—were tolerated. 2-Naphthyl and heteroaryl groups
was obtained in the absence of Cu(OAc)2·H2O (entry 12), indicating such as thienyl and furyl can also be incorporated in the products
the critical roles of the acetate anion and the Cu salt. Further evalu- with decent yields (E-3ao to E-3ar). The loading of [Cp*RhCl2]2
ation of other Rh catalysts indicated that neither Rh(i) nor Rh(ii) could be reduced to 1.0mol% (E-3aa, E-3ac, E-3ad, E-3ae, and
catalysts could catalyse this transformation (entries 13–16).
E-3al). X-ray crystallography analysis of E-3ak further confirmed
the structure of the product and its stereochemistry. In addition
Substrate scope and applications. With the optimized condi- to primary allenols, secondary allenols also worked well under the
tions (Table 1, entry 10) in hand, we next examined the substrate standard conditions, affording corresponding 2(E)-enones in high
scope for the generation of 3-methyl-substituted products (Fig. 2a). yields (Fig. 2a, bottom). Notably, we found that the scope of boronic
It is noteworthy that, in all cases, an excellent E-stereoselectivity acids was not limited to arylboronic acids: an alkenylboronic acid
was achieved without affording the Z-isomers. At first, a variety also gave the desired 2,4-dienone product (E,E)-3du, and even
of commercially available arylboronic acids bearing different sub- alkylboronic acids could be employed to afford the correspond-
stituents were reacted with 2,3-butadienol 1a (Fig. 2a, top). Both ing ketones with good yields (E-3cv, E-3iv and 3dw). The struc-
electron-rich and electron-deficient arylboronic acids reacted to ture and stereochemistry of the 2(E)-enone products were further
afford the corresponding products (E-3aa to E-3ar) in high yields, confirmed by the single-crystal X-ray diffraction analysis of E-3ed.
with the more electron-rich arylboronic acids giving the higher Gram-scale reaction of allenol 1f with boronic acid 2d afforded
yields. Importantly, a variety of synthetically useful functional a 76% yield of the desired product E-3fd as single isomer under
groups—including methoxy (E-3aa and E-3ad), bromo (E-3ae the standard conditions. The reaction is not limited to the synthe-
and E-3af), chloro (E-3ag), fluoro (E-3ah), trifluoromethyl (E- ses of 3-methyl-substituted products; 4-aryl or alkyl-substituted
3ai), acetyl (E-3aj), methoxycarbonyl (E-3ak), cyano (E-3al) and 2,3-allenols were also successful in this transformation, affording
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Table 1 | Optimization of the reaction conditions
?
H4 = H1?
H4
B(OH)2
H
Rh catalyst (x mol%)
H1
H
NaOAc (20 mol%)
MeO
•
O
+
OH
Cu(OAc)2·H2O (y)
Solvent, r.t., air balloon
12 h
OMe
1a
2a (1.5 equiv.)
E-3aa
entry
Rh catalyst
x
y
Solvent
NMR yielda
(%)
1b
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Rh(PPh3)3Cl
[Rh(cod)Cl]2
[Rh(C2H4)2Cl]2
[Rh(OAc)2]2
RhCl3
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5
0
MeOH
MeOH
Dioxane
Toluene
THF
12
77
79
75
86
81
51
90
85
86
62
4
2
1.2ꢀequiv.
1.2ꢀequiv.
1.2ꢀequiv.
1.2ꢀequiv.
1.2ꢀequiv.
1.2ꢀequiv.
1.0ꢀequiv.
20ꢀmol%
5ꢀmol%
5ꢀmol%
0
3
4
5
6
MeCN
7
Dichloromethane
8
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
9
10
11c
12
13
14
15
16
17
5ꢀmol%
5ꢀmol%
5ꢀmol%
5ꢀmol%
5ꢀmol%
0
2.5
2.5
2.5
5
2
1
0
0
The reaction was conducted with 0.5ꢀmmol 1a, 0.75ꢀmmol 2a, x mol% Rh catalyst, 20ꢀmol% NaOAc and y equivalents or mol% Cu(OAc)2·H2O in 2.5ꢀml solvent at room temperature for 12ꢀh with an air
balloon. aThe yield was determined by 1H NMR analysis using dibromomethane as the internal standard. bThe reaction was conducted with 15ꢀmol% AgBF4 under argon for 4ꢀh. cThe reaction was conducted
without NaOAc.
the desired 3-non-methyl-substituted products E-3ka, E-3lo, E- 2,3-butadienol 1a (Fig. 3b). Third, this strategy was used to assem-
3mb, E-3nx and E-3od in 53–70% yields (Fig. 2b).
ble multiple structurally complex, biologically active molecular
Because α,β-unsaturated enals and enones are versatile build- units into one single, more complex molecule (Fig. 3c). For exam-
ing blocks in organic synthesis, such products have a wide range of ple, diacetone-d-glucose and lithocholic acid could be efficiently
synthetic applications (for details, see Supplementary Fig. 3). The incorporated into E-3saa with 80% yield. Finally, E-3uy—which
2-enal E-3ad could undergo 1,2-addition with EtMgBr, a condensa- contains bioactive units from adapalene, estrone and lithocholic
tion reaction with ethyl acetate in the presence of lithium diisopro- acid—was successfully constructed.
pylamide, and a Wittig reaction to afford the corresponding allyl
alcohols E-4 (86% yield) and E-5 (91% yield) and the 1,3-diene Mechanistic investigation and divergent deuteration. To elu-
(E,E)-6 (85% yield). The α,β-unsaturated enone E-3fd could cidate the mechanism, the reaction was carried out using allenol
undergo Suzuki coupling and reduction with NaBH4 to afford E-7 1v-d1, which contains a deuterium atom at the α-position of the
(86% yield) and E-8fd (91% yield) in high yields.
hydroxyl group. This reaction afforded E-3vd-d1 in 86% yield with
The α,β-unsaturated carbonyl motif in these products is one of 99% deuterium incorporation at the allylic position (Fig. 4a), con-
the common warheads of targeted covalent inhibitors51–53. Here we firming the 1,4-D delivery concept shown in Fig. 1c. This 1,4-D
further demonstrate the scope of this reaction via the incorpora- delivery was further optimized to develop a controllable method
tion of molecular units with potential bioactivity into the enals or for precise deuterium incorporation into methyl and methylene
enones (Fig. 3). By applying sequential alkynylation, an allena- groups (Fig. 4b): the ATA reaction of deuterated propargylic alco-
tion of terminal alkyne (ATA) reaction54 and the current reaction, hols (PA-d1 and PA-d2) and non-deuterated paraformaldehyde
a variety of structurally complex molecules were modified using afforded α-deuterated allenols (1-d1 and 1-d2′), which reacted with
three different strategies. First, the alkynylation of structurally organoboronic acids under the standard conditions to afford the
complex aldehydes followed by an ATA reaction afforded ter- corresponding β-monodeuterated methyl 2(E)-enones (d1-methyl
minal allenols (1j and 1p) or 3-substituted allenols (1q and 1r), products) or 1,4-doubly deuterated 2(E)-enals (d1′-methyl prod-
which reacted with various organoboronic acids to afford corre- ucts). Similarly, starting from non-deuterated propargylic alcohols
sponding unsaturated aldehyde compounds (E-3qd and E-3rd) (PA) and fully deuterated paraformaldehyde, d2-methyl products
and ketones ((S)-E-3jt and E-3pe) (Fig. 3a). Second, structurally (E-3-d2) were afforded. β-Trideuterated methyl enones (d3-methyl
complex molecules with biological activity—such as estrone and products) were also afforded from deuterated propargylic alcohols
glycyrrhetinic acid—were easily incorporated into the organobo- (PA-d1) and deuterated paraformaldehyde. The d3-methyl group
ronic acids (2y and 2z), enabling the syntheses of corresponding could also be successfully incorporated into the structurally com-
unsaturated aldehydes (E-3ay and E-3az) by their reactions with plex and potentially bioactive molecules E-3iy-d3 and E-3daa-d3.
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a
Synthesis of β-methyl-substituted E-enals and enones
[Cp*RhCl2]2 (2.5 mol%)
NaOAc (20 mol%)
OH
Me
O
RB(OH)2
•
+
R1
R1
Cu(OAc)2 ·H 2O (5 mol%)
THF, r.t., air balloon
R
1
2 (1.5 equiv.)
E-3
2,3-Butadienol with various boronic acids
Me
Me
Me
Me
Me
Me
MeO
Br
O
O
O
O
O
O
O
O
O
Me
MeO
Br
E-3aaa, 76%, 12 h
E-3ab, 64%, 10 h
E-3aca, 81%, ~5 h
E-3ada, 86%, 10 h
E-3aea, 81%, ~24 h
E-3af, 81%, 8 h
Me
Me
Me
Me
Me
Cl
O
O
F
F3C
Ac
MeO2C
E-3ag, 68%, 12 h
E-3ah, 61%, 8.5 h
E-3ai, 68%, 17 h
E-3aj, 67%, 13 h
E-3ak, 73%, 6 h
CCDC 1939682
Me
Me
Me
Me
Me
Me
Me
NC
O2N
O
O
O
O
O
O
O
S
O
S
Ph
E-3ala, 71%, 12.5 h
E-3am, 63%, 7 h
E-3an, 70%, 7 h
E-3ao, 76%, 7 h
E-3ap, 71%, 12 h
E-3aq, 63%, 12 h
E-3ar, 74%, 12 h
Secondary 2,3-allenols with various boronic acids
Me Me
O
O
Me
Me
O
Me
O
Me
Ph
MeO
MeO
MeO
MeO
MeO
Me
E-3bd, 70%, 13 h
Me
E-3cd, 86%, 12 h
E-3dd, 86%, 12 h
E-3ed, 86%, 12 h
Me
CCDC 1939713
Me
O
Me
O
O
O
Cy
nC5H11
Br
MeO
OHC
MeO
O
E-3fd, 83%, 12 h
76% (1.2669 g), 22 h
Me Me
E-3gd, 82%, 8 h
E-3hs, 81%, 21 h
Me Me
E-3id, 71%, 12 h
Me
O
O
Me
Me
O
O
Me
Me
Me
Me
nPr
Me
n
-C5H11
NC
E-3cvb, 80%, 15 h
E-3ivb, 77%, 15 h
3dwb, 58%, 12 h
E-3jt, 81%, 38 h
Synthesis of β-non-methyl-substituted E-enals
(E,E)-3du, 60%, 12 h
b
R2
R
[Cp*RhCl2]2 (2.5 mol%)
NaOAc (20 mol%)
R2
•
RB(OH)2
+
OH
Cu(OAc)2·H2O (5 mol%)
THF, r.t., air balloon
O
1
2 (1.5 equiv.)
E-3
Me
F3C
S
nPr
Ph
MeO
Me
O
O
O
O
O
MeO
E-3ka, 66%, 27 h
E-3lo, 53%, 22 h
E-3mb, 58%, 24 h
E-3nxc, 60%, 22 h
E-3odb, 70%, 16 h
Fig. 2 | Scope of the reaction of allenols 1 with organoboronic acids 2. The reaction was conducted with 1.0ꢀmmol 1, 1.5ꢀmmol 2, 2.5ꢀmol% [Cp*RhCl2]2,
20ꢀmol% NaOAc and 5ꢀmol% Cu(OAc)2·H2O in 5ꢀml THF at room temperature (r.t.) with a balloon of air. a, Synthesis of β-methyl-substituted E-enals
(top) and enones (bottom). b, Synthesis of β-non-methyl-substituted E-enals. a1.0ꢀmol% [Cp*RhCl2]2 was used. bThe reaction was carried out at 50 °C.
cThe yield was determined by 1H NMR analysis using dibromomethane as the internal standard. The aldehyde was not stable during the isolation. We
characterized the corresponding alcohol after reduction with NaBH4.
Furthermore, this powerful approach could also realize controllable
To further disclose the mechanism, we performed reactions
deuteration of the methylene group, as shown in the syntheses of with allenol 1f (Fig. 5a, reaction 1) and allyl alcohol E-8fd (Fig. 5a,
E-3wa-d1 and E-3wa-d2.
reaction 2) under the standard conditions. Both reactions failed to
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Me
O
OH
(CH2O)n
B(OH)2
Cu
OH
CHO
MgBr
ATA
Rh
Air
Alkynylation
OH
O
CHO
Covalent inhibitors with
multi-pharmacophores
a
O
O
Modified allenols with general boronic acids
Cl
Cl
Me
OH
Me
N
N
Me
O
Me
OH
Me
Me
Me
O
Me
Me
Me
2t
2e
•
•
(6S)-1j
From (–)-citronellal
(S)-E-3jt, 77%
96% e.e.
1p
Br
NC
OMe
OMe
From indomethacin
E-3pe, 91%
MeO
H
MeO
H
O
Me
Me
O
Me
Me
H
H
O
O
S
2d
S
2d
O
OH
O
OH
O
O
H
H
•
•
O
O
O
1r
1q
From D(+)-10-camphorsulfonyl chloride
From adapalene
E-3rd, 80%
E-3qd, 62%
MeO
MeO
b
2,3-Butadienol with modified boronic acids
Me
B(OH)2
Me Me
Me
Me Me
O
O
O
B(OH)2
O
Me
H
H
Me
H
H
H
H
H
H
O
1a
1a
Me
Me
Me Me
O
Me Me
O
H
H
H
H
Me
Me
O
2y
From estrone
O
E-3ay, 81%
2z
E-3az, 61%
From 18β-glycyrrhetinic acid
MeO2C Me
MeO2C Me
B(OH)2
cModified allenols with modified boronic acids
OH
O
Me
Me
O
B(OH)2
CO2tBu
H
H
O
O
O
OH
+
O
H
O
H
O
+
H
Me
Et
O
Me Me
Me
Me
OH
Me
O
2ab
1t
O
From (S)-2-methylbutan-1-ol
From rosuvastatin precursor
Me
Me
2aa
1s
From diacetone-D-glucose
Me
Me
From lithocholic acid
Me
O
H
Me
O
O
H
CO2tBu
H
H
H
O
O
O
O
O
Me
Me
O
OH
Me
O
Me
Me
Me
Et
O
E-3tab, 80%
O
O
E-3saa, 80%
H
OH
Me
Me
H
•
H
H
O
Me
Me
B(OH)2
Me
Me
OH
Me
H
H
O
MeO
H
S
H
O
OH
O
•
Me
O
1u
From adapalene and lithocholic acid
2y
1q
From D(+)-10-camphorsulfonyl chloride
H
From estrone
H
MeO
O
Me
Me
H
H
O
S
O
O
H
H
O
H
H
O
H
H
H
H
H
Me
Me
OH
Me
H
H
Me
O
E-3qy, 67%
Me
E-3uy, 32% (13% recovery of 1u)
O
Fig. 3 | Modular incorporation of pharmacophores. a, Reaction of modified allenols with general boronic acids. b, Reaction of 2,3-butadienol with modified
boronic acids. c, Reaction of modified allenols with modified boronic acids.
afford the related ketones 9 and E-3fd, which excludes the possibil- Rh-catalysed isomerization of allylic alcohol55–57—can be excluded.
ity of 9 and E-8fd as intermediates. Thus, the mechanism involving We determined the kinetic isotope effect to be approximately 1.0
rhodium alkoxide intermediates B′1 and B′2—which occurs in the (Fig. 5b), which demonstrated that the C–H bond cleavage was
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a
Deuterium-labelling experiment
H
(99%)
O
H
D
OH
B(OH)2
nC6H13
Standard conditions
12 h
•
nC6H13
+
D
(>99%)
MeO
MeO
2d (1.5 equiv.)
1v-d1
E-3vd-d1, 86%
b
Divergent stereoselective synthesis of differently deuterated enals and enones
Precise D-incorporation in methyl groups
H
H
H
D
H
D
OH
OH
D
OH
D
O
O
(CH2O)n
•
•
R1
D
D
D
D
1-d1
1-d2′
d1-methyl
d1′-methyl
PA-d2
For monosubstituted allenols
D
D
O
D
D
(CD2O)n
D
H
7.5 mol% CuI, 1.4 equiv.iPr2NH
dioxane, 110 °C
D
D
O
OH
OH
OH
RB(OH)2
D
•
D
•
+
R1
R1
R1
Standard
conditions
D
For 1,3-disubstituted allenols
H
D
d3-methyl
d2-methyl
1-d2
1-d3
PA-d1
R-CHO
R-CDO
40 mol% CuBr2,
dioxane, 110 °C
Ph
Ph
Precise D-incorporation in methylene groups
D
N
H
D
OH
PA
OH
D
OH
D
H
OH
D
D
O
O
R
•
R
•
1.0 equiv.
R1
R1
R1
1-d1′
1-d2″
d1-methylene
d2-methylene
Precise D-incorporation in methyl groups
H
d1-methyl
d1′-methyl
(>99%)
O
(98%)
O
H
(98%)
O
H
H
(96%)
O
D
D
D
D
From:
H
H
H
From:
H
OH
OH
Me
MeO
MeO
nC5H11
•
•
R1
D
(97%)
D
(97%)
D
D
(>99%)
NC
MeO
1-d1
1a-d2′
E-3aa-d2′, 82%
E-3ga-d1, 89%
E-3dt-d1, 70%
E-3id-d1, 80%
H
H
(96%)
H
(96%)
D
d2-methyl
D
H
O
O
(>99%)
(>99%)
(>99%)
D
D
D
H
H
D
Cl
From:
D
H
D
D
D
(97%)
D
(97%)
O
O
O
OH
Me
MeO
O
nC5H11
D
•
R1
E-3ag-d2′, 78%
E-3ap-d2′, 69%
H
1-d2
(>99%)
NC
MeO
(96%)
H
H
(96%)
O
E-3ga-d2, 82%
E-3dt-d2, 66%
E-3id-d2, 78%
D
D
H
H
O
d3-methyl
D
D
(98%)
D
O
(>99%)
D
O
(>99%)
D
(97%)
D
D
(97%)
D
S
D
D
D
O
E-3ar-d2′, 72%
E-3ao-d2′, 80%
MeO
Me
nC5H11
Precise D-incorporation in methylene groups
Br
NC
MeO
From:
E-3ga-d3, 82%
E-3dt-d3, 70%
E-3id-d3, 81%
(97%)
O
OH
From:
D
H
D
•
nC5H11
OH
D
(>99%)
(>99%)
D
D
D
D
O
MeO
Br
D
•
Br
D
D
D
nC5H11
R1
O
(>99%)
(>99%)
Me
Me
O
1w-d1
1-d3 (>99%)
nC5H11
H
E-3wa-d1, 66%
(97%)
O
H
H
H
O
From:
(>99%)
D
D
O
OH
D
O
Me
O
•
nC5H11
O
Me
O
O
MeO
D
E-3iy-d3, 52%
E-3daa-d3, 83%
nC5H11
Br
Me
(99%)
1w-d2
Me
E-3wa-d2, 72%
Fig. 4 | Divergent syntheses of deuterated compounds. Standard conditions: 1 equiv. 1, 1.5 equiv. 2, 2.5ꢀmol% [Cp*RhCl2]2, 20ꢀmol% NaOAc and 5ꢀmol%
Cu(OAc)2·H2O in THF at r.t. with a balloon of air. a, Deuterium labelling experiment. b, Divergent syntheses of differently deuterated enals and enones.
not the rate-determining step. To pursue a further understanding 31G(d)-LANL2DZ level of theory to investigate the reaction energy
of the mechanism, we performed density functional theory calcu- profiles, using 2,3-butadienol 1a and phenyl boronic acid 2b as the
lations at the M06/6-311+G(d,p)-SDD/IEFPCM(THF)//M06/6- model substrates (for more detailed information, see Supplementary
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NaTure CaTalySiS
Articles
a
b
Kinetic isotope effect experiments
OH
Control experiments
OH
O
Standard conditions, 12 h
Reaction 1
•
•
•
nC5H11
H
Ar1
H
H
1i
Standard conditions,
[Rh]
O
•
1f
Br
9, 0%
90% recovery of 1f
H
H
H
D
nC5H11
O
nC5H11
O
5 min
or
+
2d
or
Ar1
Reaction 3
1.5 equiv.
Ar
Ar
B′1
OH
Ar1 = 4-Br-C6H4
Ar2 = 4-MeO-C6H4
E-3id
24%
E-3id-d1
kH/kD = 0.96
•
nC5H11
25%
D
Ar = 4-MeO-C6H4
Me OH
Me
O
1i-d1
Standard conditions, 24 h
Reaction 2
Ar2
Ar1
Standard conditions,
5 min
[Rh]
MeO
Br
1i
1i-d1
0.1 mmol
2d
0.3 mmol
E-3id
16%
E-3id-d1
17%
+
+
+
E-8fd
E-3fd, 0%
97% recovery of E-8fd
Me
O
Reaction 4
0.1 mmol
Ar2
Ar1
kH/kD = 0.94
B′2
c
Density functional theory calculations and the proposed catalytic cycle
O2
Cp*
Rh
H
RB(OH)2
O
H
AcOB(OH)2
Cp*Rh
CuI
Cp*
Rh
CuII
•
Cp*Rh
OAc
Cp*Rh
R1
Ph
H
H
OAc
H
D
O
R
O
H
R
A
OH
R1
Cp*
Rh
TS2_a
O
B
OH
6.9
The catalytic cycle
involving 1,4-D delivery
•
OH
TS1
5.2
O
H
TS2_a
H
D
•
1
E-3
TS2_b
D
H
H
2b
Cp*Rh
B
Cp*Rh
D
4.7
H
O
INT4_b
Cp*Rh
O
5.3
Rh
H
OH
R1
D
0.0
INT1
H
H
–0.1
Cp*
O
R1
•
1a
– HOAc
R1
R
OAc
R
INT2
14.9
H
–5.6
INT4_b
R
D
–5.2
INT3
C
TS2_b
–10.2
Cp*
Rh
INT4_a
AcOB(OH)2
Cp*
Rh
H
H
H
Cp*
Rh
Cp*
Rh
O
O
Cp*
Rh
Ph
Ph
H
Ph
O
H
O
–27.4
O
O
O
H
H
B
OH
Cp*
•
B
OH
INT6
O
OH
Rh
–36.8
H
OH
INT3
H
INT4_a
INT1
INT2
INT5
Ph
OH
Cp*
–45.8
Rh
Cp*
O
INT8
–48.7
OAc
Rh
OH
INT7
H
H
O
H
RhCp*
O
Ph
Cp*
Ph
O
HOAc
Rh
Ph
OH
TS3
–58.3
–58.9
TS4
–61.5
Ph
H
INT9
Cp*
4.8
–66.3
Rh
O
H
INT10
Cp*
O
–71.3
Ph
O H
Rh
H
O
INT11
HOAc
Ph
Ph
RhCp*
O
HOAc
Carborhodation
Rh-mediated hydride migration and reductive elimination
Transmetalation
TS4
TS2_a
TS3
TS2_b
Fig. 5 | Mechanistic studies. Standard conditions: 1 equiv. 1, 1.5 equiv. 2, 2.5ꢀmol% [Cp*RhCl2]2, 20ꢀmol% NaOAc and 5ꢀmol% Cu(OAc)2·H2O in THF at
r.t. with a balloon of air. a, Control experiments. b, Kinetic isotope effect experiments. kH is the rate of the reaction associated with 1i; kD is the rate of the
reaction associated with 1i-d1. c, Density functional theory calculations at the M06/6-311ꢀ+ꢀG(d,p)-SDD/IEFPCM(THF)//M06/6-31ꢀG(d)-LANL2DZ level
of theory, and the proposed catalytic cycle. Free energies are given in kcal mol−1 with respect to iNt1.
Methods). The Gibbs energies incorporate the solvent effect of THF. 5.3kcal mol−1, resulting in the formation of INT3. The subsequent
As shown in Fig. 5c, the transmetallation of [Cp*RhOAc]+ INT1 dissociation of B(OAc)(OH)2 and the coordination of the allene
2
with 2b proceeds via TS1, which requires an activation energy of moiety of 1a provides the metal-η -allene intermediates: both C=C
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NaTure CaTalySiS
Articles
bonds of 2,3-butadienol 1a could coordinate with the Rh(iii) cen- many functional groups as well as pharmacophores, and—via the
tre to generate the intermediates INT4_a or INT4_b, in which the corresponding 1,4-H or D delivery—provides a controllable strat-
hydroxyl group also coordinates to the Rh(iii) centre. INT4_a is egy for the precise incorporation of deuterium into the methyl and
found to be lower in free energy than INT4_b by 4.6kcal mol−1. methylene groups of covalent molecules from differently deuter-
The subsequent insertion of the coordinated allenic C=C double ated 2,3-allenols. The reaction is co-catalysed by [Cp*RhCl2]2 and
bond into the Rh–C bond via TS2_a or TS2_b would provide the Cu(OAc)2, with the assistance of oxygen from air to complete the
same π-allyl Rh(iii) complex INT5, which could easily isomerize catalytic cycle. Further studies, including investigation of the poten-
to a more stable π-allyl Rh(iii) complex INT7, with the coordina- tial bioactivity of the products and further synthetic applications,
tion of the hydroxyl group occurring via the intermediate σ-allyl are currently ongoing in our laboratory.
Rh(III) complex INT6. Moreover, the transition structure TS2_a,
which is associated with the more stable precursor INT4_a, is cal- Methods
culated to be less favourable than TS2_b by 2.2kcal mol−1 (6.9 ver-
General procedure for the synthesis of enals or enones 3. To a Schlenk fask
we added [Cp*RhCl2]2 (15.5mg, 0.025mmol), NaOAc (16.4mg, 0.20mmol),
sus 4.7kcal mol−1) due to the existence of steric hindrance between
Cu(OAc)2·H2O (10.0mg, 0.05mmol), 2 (1.5mmol, 1.5 equiv.), 1 (1.0mmol, 1
equiv.) and THF (5ml) sequentially. Te reaction was then carried out at room
the hydroxyl and the phenyl group in TS2_a. Notably, the coordi-
nation of the hydroxyl group with the Rh(iii) centre stabilizes the
π-allyl Rh(iii) complex INT7 by 11.9kcal mol−1 compared with the
kinetically favourable intermediate INT5. Subsequent isomeriza-
tion of INT7 afforded the precursor for the hydride transfer, INT8,
in which the coordination of the hydroxyl group to the Rh(iii) cen-
tre is replaced by an agostic interaction between the metal and the
hydrogen atom. A hydrogen bond formed between the hydroxyl
group of INT8 and an acetate anion leads to the generation of com-
plex INT9, which is exergonic by 13.1kcal mol−1 (relative to INT8).
Subsequent hydride migration is realized with the assistance of the
acetate and proceeds through a concerted transition state TS3, in
which the acetate anion acts as a base to deprotonate the hydroxylic
hydrogen while the coordinated hydrogen migrates to the Rh(iii)
centre. This hydride-transfer step is exergonic (with an exergo-
nicity of 7.4kcal mol−1) and requires an activation barrier of only
0.6kcal mol−1 (TS3), affording the Rh(iii) hydride complex INT10.
Subsequently, the reductive-elimination step—which involves the
migration of the hydride ligand to the terminal allylic carbon and
the simultaneous coordination of the reductive Rh(i) centre to the
C=C bond of the final 2-alkenal product E-3ab—needs to overcome
a free-energy barrier of 4.8kcal mol−1 (TS4). Finally, the oxidation
of Rh(i) with Cu in air regenerates the Rh(iii) catalyst to complete
the catalytic cycle. Overall, the carborhodation step features the
highest free-energy barrier of the whole process (14.9kcal mol−1,
TS2_b), and is therefore most likely to be the rate-limiting step. It
is noteworthy that the Rh(iii) centre readily acts as a shuttle in the
hydrogen relay to facilitate the 1,4-hydride transfer process (from
INT9 to INT11), making it both thermodynamically and kineti-
cally favourable and therefore not the rate-determining step; this is
confirmed by the data shown in Fig. 5b.
On the basis of these data, we propose a catalytic cycle
(Fig. 5c, top right) that is different from the original concept shown in
Fig. 1c. At first, [Cp*RhOAc]+ undergoes transmetallation with the
organoboronic acid to generate [Cp*RhR]+ species A. Subsequent
syn-insertion and allylic Rh coordination with OH result in the
exclusive formation of the stereodefined allylic rhodium interme-
diate C, in which the hydride participates in an agostic interaction
with the Rh through further rotation about the C–C single bond.
Subsequent deprotonation of the hydroxyl group and β-D elimina-
tion mediated by OAc− leads to the formation of allylic Rh species
D, which results in the formation of the product E-3 and Cp*Rh
species via reductive elimination. The catalytically active species
[Cp*RhOAc]+ can be regenerated via the oxidation of Cp*Rh spe-
cies using oxygen from air and acetate anion under Cu catalysis, to
complete the catalytic cycle.
temperature under an atmosphere of air from a balloon until completion of the
reaction as monitored by thin-layer chromatography. Te crude reaction mixture
was fltered through a short column of silica gel, eluted with ethyl acetate (4 × 5ml)
and concentrated. Te residue was purifed by chromatography on silica gel to
aford the pure product.
Data availability
Experimental procedures, characterization of the compounds and density
functional theory calculations are available in the Supplementary Information.
Crystallographic data for the structures reported in this Article have been
deposited at the Cambridge Crystallographic Data Centre, under deposition
numbers CCDC 1939682 (E-3ak) and 1939713 (E-3ed). Copies of the data can be
obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data
are available from the corresponding authors upon reasonable request.
Received: 16 September 2020; Accepted: 26 May 2021;
Published online: 8 July 2021
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acknowledgements
Financial support from the National Natural Science Foundation of China (grant
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experiments. X.Z. and H.F. performed the density functional theory calculations. W.W.,
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3
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additional information
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41929-021-00643-9.
Correspondence and requests for materials should be addressed to X.Z., H.Q. or S.M.
Peer review information Nature Catalysis thanks Jie An, Yu Lan and the other,
anonymous, reviewer(s) for their contribution to the peer review of this work.
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