Br?nsted Base-Catalyzed Transformation of α,β-Epoxyketones Utilizing [1,2]-Phospha-Brook Rearrangement for the Synthesis of Allylic Alcohols Having a Tetrasubstituted Alkene Moiety

Article abstract of DOI:10.1021/acs.orglett.0c01765

A stereoselective transformation of α,β-epoxyketones into alkenylphosphates having a hydroxymethyl group on the β-carbon was established by utilizing the [1,2]-phospha-Brook rearrangement under Br?nsted base catalysis. The reaction involves the catalytic generation of an α-oxygenated carbanion located at the α-position of an epoxide moiety through the [1,2]-phospha-Brook rearrangement and the following epoxide opening. Further transformation of the alkenylphosphates by the palladium-catalyzed cross-coupling reaction with Grignard reagents provided allylic alcohols having a stereodefined all-carbon tetrasubstituted alkene moiety.

Full text of DOI:10.1021/acs.orglett.0c01765

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Letter
Brønsted Base-Catalyzed Transformation of α,β-Epoxyketones
Utilizing [1,2]-Phospha-Brook Rearrangement for the Synthesis of
Allylic Alcohols Having a Tetrasubstituted Alkene Moiety
Azusa Kondoh, Naoko Tasato, Takuma Aoki, and Masahiro Terada*
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ABSTRACT: A stereoselective transformation of α,β-epoxyke-
tones into alkenylphosphates having a hydroxymethyl group on the
β-carbon was established by utilizing the [1,2]-phospha-Brook
rearrangement under Brønsted base catalysis. The reaction involves
the catalytic generation of an α-oxygenated carbanion located at
the α-position of an epoxide moiety through the [1,2]-phospha-Brook rearrangement and the following epoxide opening. Further
transformation of the alkenylphosphates by the palladium-catalyzed cross-coupling reaction with Grignard reagents provided allylic
alcohols having a stereodefined all-carbon tetrasubstituted alkene moiety.
that uses readily available starting compounds is highly
anticipated to expand the scope of accessible allylic alcohols.7
We have been focusing on the [1,2]-phospha-Brook
rearrangement as a useful tool for the development of novel
synthetic reactions under Brønsted base catalysis.8 Specifically,
we utilize the rearrangement for the catalytic generation of
carbanions of less acidic compounds from the corresponding
carbonyl compounds with dialkyl phosphites through the
formal umpolung process.9 During the course of our study on
the extension of the utility of the methodology, we envisioned
the direct catalytic transformation of α,β-epoxyketones into
hydroxymethyl-substituted alkenylphosphates for use in the
synthesis of allylic alcohols having a stereodefined tetrasub-
stituted alkene moiety. The designed reaction is shown in
Scheme 1. Treatment of α,β-epoxyketone 1 having a
substituent on the α-carbon with dialkyl phosphite 2 in the
presence of a catalytic amount of Brønsted base would result in
the 1,2-addition of the anion of 2 generated by the
deprotonation, providing alkoxide A. Subsequently, the
migration of the dialkoxyphosphoryl moiety from carbon to
oxygen, i.e., the [1,2]-phospha-Brook rearrangement, would
proceed to form carbanion B located at the α-position of the
epoxide moiety. Finally, the epoxide opening, where the release
of ring strain serves as the driving force, would occur in a
stereoselective manner10 and the following protonation would
proceed to afford trisubstituted alkenylphosphate 3 along with
regeneration of the Brønsted base catalyst or the anion of 2 to
llylic alcohols are a fundamental structural motif found in
Auseful organic materials and an important class of
versatile building blocks for organic synthesis.1 Therefore,
the synthesis of allylic alcohols having various types of
substituent patterns has gained considerable attention and
been intensively studied. However, the methods for the
synthesis of allylic alcohols possessing a stereodefined
multisubstituted alkene moiety, particularly a tetrasubstituted
one, are still underdeveloped.2 One of the most direct
approaches for the synthesis of allylic alcohols is the 1,2-
addition of alkenyl nucleophiles to aldehydes and ketones.
However, this approach requires the preparation of alkenyl
nucleophiles and is generally troublesome, which limits its
application to the synthesis of allylic alcohols possessing a
tetrasubstituted alkene moiety.3 The 1,2-reduction of α,β-
unsaturated carbonyl compounds or the 1,2-addition of
nucleophiles to those compounds is also a reliable approach
for the synthesis of allylic alcohols. However, the preparation
of an α,β-unsaturated carbonyl compound having a tetrasub-
stituted alkene moiety is a formidable task.2,4 On the other
hand, the carbometalation of propargyl alcohols followed by
the trapping of the resulting alkenyl metal species with
electrophiles or the transformation by the transition-metal-
catalyzed cross-coupling reaction was established as an
alternative approach for the synthesis of allylic alcohols
possessing a tetrasubstituted alkene moiety.5,6 This approach
involves the construction of a tetrasubstituted alkene moiety
through the sequential introduction of two substituents onto
an alkyne moiety of readily available propargyl alcohols and,
thus, is more practical than conventional approaches. However,
the accessible allylic alcohols are still limited even with this
approach. Therefore, the development of conceptually new
approaches characterized by an operationally simple protocol
Received: May 26, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01765
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. Our Reaction Design for the Synthesis of Allylic
Alcohols Having a Tetrasubstituted Alkene Moiety
Table 1. Screening of Reaction Conditions
b
yield (%)
c
entry
base
solvent
2
R
3 (Z/E)
5
6a
1
2
3
4
5
6
7
8
P2-tBu
P4-tBu
P1-tBu
TBD
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
THF
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2b
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
iPr
Me
iPr
91 (91/9)
89 (91/9)
52 (93/7)
12 (75/25)
77 (86/14)
71 (88/12)
81 (84/16)
83 (88/12)
66 (89/11)
66 (87/13)
86 (86/14)
89 (95/5)
88 (90/10)
97 (96/4)
<1
<1
45
78
7
18
<1
6
16
5
<1
<1
<1
<1
5
7
<1
4
9
4
7
7
7
9
tBuOK
KHMDS
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
P2-tBu
complete the catalytic cycle. Alkenylphosphates are widely
used in transition metal-catalyzed cross-coupling reactions.11
Thus, we expected that the phosphate moiety of 3 would be
converted into carbon-based substituents, providing a variety
of allylic alcohols 4 having a stereodefined all-carbon
tetrasubstituted alkene moiety. Based on this reaction design,
we report herein the stereoselective synthesis of trisubstituted
alkenylphosphate under Brønsted base catalysis. The trans-
formation of the phosphate moiety into carbon-based
substituents via the palladium-catalyzed cross-coupling reac-
tion is also described.
9
Et2O
10
11
12
13
toluene
CH2Cl2
DMF
DMF
DMF
8
5
5
<1
d
14
a
Conditions: 1a (0.25 mmol), 2 (0.25 mmol), base (0.025 mmol),
b
c
solvent (1.0 mL), −40 °C, 5 h. NMR yields. Z/E ratio was
d
determined by 1H NMR analysis of the crude mixtures. The reaction
was conducted with 2b (1.5 equiv, 0.38 mmol).
To ascertain the viability of the designed reaction, our
investigation commenced with the treatment of 1a, which has a
phenyl group on the keto moiety and a methyl group on the α
carbon, with diethyl phosphite (2a) in the presence of a
catalytic amount of P2-tBu (pKBH+ = 21.5 in DMSO)12 in
DMF at −40 °C for 5 h. The intended reaction proceeded
smoothly to provide 3aa as a 91:9 Z/E mixture in 91% NMR
yield along with α,β-unsaturated ketone 6a as the byproduct
(Table 1. entry 1).13,14 Thereafter, the screening of Brønsted
bases was carried out. Among the organic bases tested, P4-tBu
(pKBH+ = 30.3) provided 3aa with a comparable result to P2-
tBu (entry 2), whereas the use of less basic P1-tBu (pKBH+
=
15.7) and TBD (1,5,7-triazabicyclo[4.4.0.]dec-5-ene) resulted
in the reduction of yields of 3aa and the formation of
substantial amounts of epoxy alcohol 5aa (entries 3 and 4).
Furthermore, inorganic bases having strong basicity, such as
tBuOK and KHMDS, were less effective than P2-tBu (entries 5
and 6). The screening of solvents was then carried out (entries
7−11), and DMF was the solvent of choice from the point of
view of both yield and Z/E selectivity (entry 1 vs entries 7−
11). Examination of other dialkyl phosphites revealed that the
employment of sterically bulkier diisopropyl phosphite (2b)
improved Z/E selectivity (entry 12).15 Finally, the use of 1.5
equiv of diisopropyl phosphite suppressed the formation of
byproduct 6a, and desired 3ab was obtained in 97% NMR
yield with 96:4 Z/E ratio (entry 14). Allylic alcohol 3ab was
converted into corresponding tert-butyl(dimethyl)silyl ether
7ab in one-pot for easy isolation in pure form, and 7ab was
obtained in 89% isolated yield (eq 1). The reaction in a larger
scale using 2.0 mmol of 1a and 5.0 mol % P2-tBu proceeded
without any problem (94% isolated yield with 96:4 Z/E ratio).
At this stage, some control experiments were carried out
(Scheme 2). First, epoxyphosphate 8aa, which would be
potentially formed by the protonation of highly basic
carbanion (B in Scheme 1), was treated with P2-tBu in
DMF. As a result, 3aa was not formed at all, and most of 8aa
Scheme 2. Control Experiments
was recovered. This result indicates that 8aa does not
participate in the reaction and the epoxide opening occurs
directly from the carbanion generated via the [1,2]-phospha-
Brook rearrangement without undergoing the competing
undesirable protonation. This result also shows the benefit of
our methodology, that is, the catalytic generation of the
B
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carbanion of a less acidic compound utilizing the [1,2]-
phospha-Brook rearrangement. This transformation was
accomplished owing to the generation of the carbanion of
8aa, which was difficult to accomplish by direct deprotonation
even with organosuperbases, such as P2-tBu.16 Next, the
synthesis of 7aa was attempted by using a conventional
method for the synthesis of alkenylphosphates. Ketone 9 was
treated with a stoichiometric amount of LDA and the resulting
lithium enolate was trapped with diethyl chlorophosphate. As a
result, 7aa was obtained in modest yield with moderate Z/E
selectivity along with the formation of byproduct 6a. This
experiment emphasizes the efficiency of the newly developed
transformation for the stereoselective synthesis of alkenylphos-
phates having a hydroxymethyl group on the β-carbon.
Scheme 4. Reaction with Substrates Having a Substituent on
the β-Carbon
With the optimized reaction conditions in hand, the scope of
α,β-epoxyketones was investigated. First, the scope of
substituents on the keto moiety was examined (Scheme 3).
Scheme 3. Substrate Scope
a
b
TBSCl (5.0 equiv) and imidazole (6.0 equiv) were used. TBSCl
(4.0 equiv) and imidazole (4.8 equiv) were used.
Next, derivatization based on the hydroxy group of
alkenylphosphates 3 was attempted (Scheme 5). Treatment
Scheme 5. Derivatization of 3ab
a
b
Isolated yields. Determined by 1H NMR analysis of the crude
c
d
e
mixtures. At −20 °C. At rt. With diethyl phosphite (2a) at −60 °C.
A variety of (hetero)aryl groups could be employed as
substituents, and the corresponding alkenylphosphates were
obtained in good yields. Among them, 1e having a sterically
hindered o-tolyl group reduced the Z/E selectivity. An alkyl
group was also applicable as the substituent although the yield
was moderate. The substituent on the α-carbon was then
screened. Substrates having other alkyl groups, such as ethyl
and benzyl groups, underwent the reaction without any
problem, and the corresponding 7hb and 7ib were obtained
in high yields with good Z/E selectivities. In the case of 1j
having a phenyl group, the reaction with diisopropyl phosphite
(2b) was rather sluggish. On the other hand, the reaction with
diethyl phosphite (2a) proceeded smoothly to provide 7ja as a
single Z isomer in good yield.
Further investigation was carried out with substrates having
a substituent on the β-carbon (Scheme 4). As a result, both
aryl and alkyl groups were applicable as a substituent at that
position. In the case of substrates without a substituent on the
α-carbon, 1k−1n, the reaction provided the corresponding
trisubstituted alkenylphosphates in good yields with slightly
lower Z/E selectivities. Substrates 1o and 1p having
substituents on both the α- and β-carbons were also tested,
and 7ob and 7pb were successfully obtained in high yields,
respectively.
of Z isomer of 3ab with PBr3 provided corresponding allylic
bromide 10. Subsequently, the alkylation with dimethyl
malonate as the pronucleophile was performed to provide 11
in good overall yield. Importantly, in the course of the
derivatization, the phosphate moiety was intact and the
stereochemistry of the alkene moiety was maintained. Thus,
the present reaction would be potentially applicable to the
synthesis of a variety of stereodefined multisubstituted
alkenylphosphates.
Finally, we examined the palladium-catalyzed cross-coupling
reaction of 7 to accomplish the synthesis of allylic alcohols
having an all-carbon tetrasubstituted alkene moiety (Scheme
6). Brief screening of the reaction conditions with 7ab as the
substrate revealed that PdCl2(PCy3)2 (Cy = cyclohexyl)
efficiently catalyzed the cross-coupling reaction with aryl
Grignard reagents to provide 12aa and 12ab in good yields
with retention of the stereochemistry of the alkene moiety.17
Similar reaction conditions were applied to the reaction with
methylmagnesium bromide and corresponding 12ac was
obtained in good yield. The reaction with butylmagnesium
bromide resulted in a moderate yield of 12ad along with a
substantial amount of reduced product 14, whereas the use of
cyclopentylmagnesium bromide exclusively provided 14. The
reactions of 7gb and 7ib proceeded without any problem. In
C
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reagents with retention of the stereochemistry of the alkene
moiety. This newly developed operationally simple protocol
opens up an avenue for the synthesis of allylic alcohols having a
stereodefined tetrasubstituted alkene moiety.
Scheme 6. Transformation of 7 via Palladium-Catalyzed
Cross-Coupling Reaction with Grignard Reagents
a
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01765.
Additional experimental results, experimental proce-
dures, and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Masahiro Terada − Department of Chemistry, Graduate School
of Science, Tohoku University, Sendai 980-8578, Japan;
orcid.org/0000-0002-0554-8652; Email: mterada@
tohoku.ac.jp
Authors
Azusa Kondoh − Research and Analytical Center for Giant
Molecules, Graduate School of Science, Tohoku University,
Sendai 980-8578, Japan; orcid.org/0000-0001-7227-8579
Naoko Tasato − Department of Chemistry, Graduate School of
Science, Tohoku University, Sendai 980-8578, Japan
Takuma Aoki − Department of Chemistry, Graduate School of
Science, Tohoku University, Sendai 980-8578, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01765
a
Conditions: 7 (0.10 mmol), Grignard reagent (0.30 mmol),
b
PdCl2(PCy3)2 (5.0 μmol), THF (1.0 mL), 70 °C, 24 h. NMR
yields. Isolated yield is shown in parentheses. Determined by H
NMR analysis of the crude mixtures. 14 was obtained in 20%
isolated yield (Z/E = 6/94). 14 was obtained in 72% NMR yield (Z/
E = 14/86). In Et2O at 40 °C. With Pd2(dba)3 (2.5 μmol) and (4-
MeC6H4)3P (10 μmol).
c
1
Notes
d
e
The authors declare no competing financial interest.
f
g
ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Scientific
Research (S) (JP16H06354) from the Japan Society for the
Promotion of Science (JSPS).
the case of 7ja with methylmagnesium bromide, the reaction
provided the corresponding product in good yield albeit with
the slight degradation of the Z/E ratio. 7kb also participated in
the cross-coupling reaction with both aryl- and methylmagne-
sium bromide and corresponding products 12ka and 12kc
having a trisubstituted alkene moiety were generated in good
to high yields. 7ob was much less reactive than the other
substrates. After additional screening of catalysts, the catalyst
generated from Pd2(dba)3 and tri(p-tolyl)phosphine was found
to facilitate the reaction to provide 12oa in 83% NMR yield.
Many silylethers 12 were difficult to isolate in pure form by
silica gel column chromatography because of the inseparable
phosphine residue derived from the palladium complexes, and
thus, the products were isolated as the corresponding allylic
alcohols 13 after the desilylation by treatment with aqueous
HCl in methanol or TBAF in THF.17
In conclusion, we have developed a stereoselective trans-
formation of α,β-epoxyketones into alkenylphosphates having a
hydroxymethyl group on the β-carbon by utilizing the [1,2]-
phospha-Brook rearrangement under Brønsted base catalysis.
The reaction involves the catalytic generation of an α-
oxygenated carbanion located at the α-position of an epoxide
moiety through the [1,2]-phospha-Brook rearrangement and
the following epoxide opening. The resulting alkenylphos-
phates are amenable to further transformation by the
palladium-catalyzed cross-coupling reaction with Grignard
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E
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Organic Letters
pubs.acs.org/OrgLett
Letter
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G.-Z.; Peters, E. M.; Peters, K.; von Schnering, H. G.; Walz, L.
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1996, 1996, 1055−1081.
(13) The Z/E configuration of 3aa was determined by NOE analysis.
See the Supporting Information for details
(14) 6a would form through the 1,5-migration of the diethox-
yphosphoryl group followed by β-elimination.
(15) The use of diphenyl phosphite resulted in no reaction.
(16) Treatment of 8aa with P4-tBu provided results similar to those
of P2-tBu.
(17) See the Supporting Information for details.
F
https://dx.doi.org/10.1021/acs.orglett.0c01765
Org. Lett. XXXX, XXX, XXX−XXX