Catalytic Asymmetric Synthesis of α,α-Difluoromethylated and α-Fluoromethylated Tertiary Alcohols

Article abstract of DOI:10.1021/acs.orglett.9b02792

The catalytic asymmetric synthesis of α,α-difluoromethylated tertiary alcohols is described, using an asymmetric dihydroxylation reaction. This protocol using either the AD-mix-α or AD-mix-β allowed an easy access to these valuable fluorinated chiral buil

Full text of DOI:10.1021/acs.orglett.9b02792

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalytic Asymmetric Synthesis of α,α-Difluoromethylated and
α‑Fluoromethylated Tertiary Alcohols
Wei-Sheng Huang, Marie-Leonie Delcourt, Xavier Pannecoucke, Andre
́ ́
B. Charette,‡
†
†
†
,
†,§
,†
Thomas Poisson,*
and Philippe Jubault*
†
Normandie Universite,
́
INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France
Centre in Green Chemistry and Catalysis, Faculty of Arts and Sciences, Department of Chemistry, Universite
Box 6128, Station Downtown, Montreal, Quebec H3C 3J7, Canada
Institut Universitaire de France, 1 rue Descartes, 75231 Paris, France
S Supporting Information
‡
́
de Montreal, P.O.
́
́
́
§
*
ABSTRACT: The catalytic asymmetric synthesis of α,α-
difluoromethylated tertiary alcohols is described, using an
asymmetric dihydroxylation reaction. This protocol using
either the AD-mix-α or AD-mix-β allowed an easy access to
these valuable fluorinated chiral building blocks, which have
been obtained with excellent yields and er. In addition, the
reaction was extended to the α-fluoromethylated analogues.
he synthesis of molecules containing one fluorine atom or
a fluorinated group has received a significant attention
over the past ten years. This interest mainly results from the
omethylated sulfoximine based reagent to introduce the CF H
2
16
T
motif on ketones after desulfoximination (eq 7). Finally, in
2019 Lassaletta described the catalytic asymmetric addition of
hydrazones onto α,α-difluoromethylated ketones providing the
tertiary alcohols with moderate enantioselectivities using chiral
growing importance of the fluorinated molecules in the drug
1
discovery process, crop science, or material sciences. Indeed,
17
once introduced into a molecule the fluorine atom or the
fluorinated group can drastically change the biological and/or
the physicochemical properties of the molecules. Hence,
impressive efforts were dedicated to the introduction of the
squaramide or thiourea catalysts (eq 8). As part of our recent
efforts to afford new methods to build up molecules containing
1
8
the difluoromethyl motif,
we aimed at providing a
complementary strategy to access enantioenriched α,α-
difluoromethyl tertiary alcohols using a chiral catalyst.
The venerable Sharpless asymmetric dihydroxylation reac-
tion (ADR) is a powerful tool to build-up enantioenriched
2
fluorine atom or fluorinated groups. Among these groups, the
CF H one received less attention despite its high potential as
2
3
an alcohol or thiol bioisoster. Recently, Lippard demonstrated
4
that this motif can carry out H-bonding interactions.
19
tertiary alcohols, using a chiral catalyst, from olefins.
Moreover, the stereospecific construction of a chiral center
Impressive efforts and contributions led to the development
of practical and robust catalytic systems. However, the
application of these systems to the synthesis of α-fluorinated
alcohols is restricted to a few examples using trifluoromethy-
bearing a CF H group has been underexplored, in contrast to
2
5
the formation of F- or CF -containing stereogenic centers.
3
Regarding the catalytic asymmetric formation of α,α-
difluoromethyl alcohols, only a handful of straightforward
procedures was reported to date (Figure 1). Secondary
enantioenriched alcohols can be obtained from the asymmetric
20
lated olefins. Hence, we report herein the use of this
powerful reaction manifold to access the α,α-difluoromethyl
tertiary alcohols with high enantiomeric ratios from the
6
reduction of the corresponding ketones (eq 1), an aldol
7
corresponding HCF -containing olefins. This practical and
2
reaction with α,α-difluoroacetaldehyde (eq 2), or the
8
9
efficient method affords a straightforward access to these
difficult to build up enantioenriched building blocks.
At the outset of the study, we investigated the ADR of α,α-
asymmetric allylation of the latter (eq 3). Alternatively, Hu
1
0
and Leroux reported the diastereoselective addition of
difluoromethyl nucleophiles, as surrogates of the HCF2
anion, prior to their conversion into the enantioenriched
α,α-difluoromethyl secondary alcohols (eq 4). Besides,
although often restricted to few examples, α,α-difluoromethyl
tertiary alcohols were obtained from catalytic asymmetric
difluoromethylated styrene 1a in the presence of AD-mix-α
(
Table 1). Using AD-mix-α (Os: 0.2 mol %) in a mixture of
organic solvent and water (1:1) at 0 °C for 24 h, the
asymmetric dihydroxylation of 1a was optimized. First,
alcohols were tested as a cosolvent, and EtOH and iPrOH
afforded the desired dihydroxylated product 2a in moderate
1
1
12
13
14
alkylation, allylation, propargylation, or aldol reactions
on α,α-difluoromethylated ketones with moderate to excellent
enantioselectivities (eq 5). On the other hand, Mikami
described the Pd-catalyzed ene-reaction on α,α-difluoromethy-
Received: August 7, 2019
15
lated pyruvates (eq 6), while Hu used a chiral difluor-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02792
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield (51%) and an excellent 96:4 er. Note that ethylene glycol
was inefficient in our reaction (entry 5). In order to get 2a in a
synthetically useful yield, the reaction time was increased to 72
h, and the product 2a was isolated in 90% yield with a 95:5 er
(
entry 6). An additional survey of solvent (1,4-dioxane and
acetone) did not afford an increase of the yield or the er
entries 7 and 8). Finally, the use of the AD-mix-β, under
(
identical reaction conditions, allowed the access to the other
enantiomer of 2a with a similar yield (88%) and a slightly
better er (2.5:97.5, entry 9).
With the optimized conditions set up, we turned our
attention to the extension of the scope of the reaction (Scheme
1
). First, the scale of the reaction with 1a was increased to 4
mmol using AD-mix-β and 2a was isolated in an excellent 98%
and a similar 3:97 er, demonstrating the synthetic utility of the
method. Then, methyl-substituent on the aromatic ring of the
α,α-difluoromethylstyrenes at the para, meta, and ortho
position were tested with the two catalysts (AD-mix-α and
AD-mix-β). Both para- and meta-substituted derivatives 2b and
2
c were obtained in good yield with excellent er (up to 99:1),
while the ortho-substituted derivative 2d was obtained in low
yields (13% and 14%) and modest er with both catalysts.
Surprisingly, the xylyl derivative 1e gave 2e with a higher yield
and er. Α methoxy substituent was also tolerated and the para-
and ortho- substituted derivatives 2f and 2g were isolated in
moderate yields with good to excellent er. The 1- and 2-
naphthyl derivatives 2h and 2i were submitted to the
dihydroxylation conditions, and the expected products were
obtained with very good to excellent er and an excellent yield
in the case of 2h.
Similarly to the ortho-substituted derivatives 2d and 2e, the
peri-substitution hampers the efficiency of the process as 2i was
isolated in modest yields (40% and 56%). Halogen substituents
were well tolerated since the fluoro, chloro, and bromo
substituted α,α-difluoromethyl tertiary alcohols 2j, 2k, and 2l
were isolated in excellent yields with excellent er. The thienyl
tertiary alcohol 2m was obtained in good yields and excellent
er, showing the compatibility of a sulfur-containing hetero-
cycle. Pleasingly, the methodology was extended to the
aliphatic derivative 1n and the corresponding α,α-difluor-
omethyl tertiary alcohol 2n was isolated in decent yields and
obtained with moderate to good er. Then, as the
Figure 1. State of the art and present strategy.
Table 1. Optimization of the Asymmetric Dihydroxylation
a
of 1a Using AD-mix-α
b
c
entry
solvent
EtOH
iPrOH
amyl alcohol
tBuOH
ethylene glycol
tBuOH
1,4-dioxane
Acetone
tBuOH
yield (%)
er
monofluoromethyl motif (CH F) is important in the drug
2
1
2
3
4
5
6
7
8
24
30
31
51
NR
90
77
75
88
73.5:26.5
76:24
93.5:6.5
96:4
discovery process, as demonstrated by its presence on the
structure of the blockbuster Advair, for instance, we tested α-
monofluoromethylated styrene derivatives under our standard
conditions. To our delight, the methodology was readily
−
extended to the CH F derivatives, which were isolated in
d
2
95:5
94:6
91:9
d
excellent yields (70% to 93%). In all cases, the er is excellent
(97:3 to 99:1), although a bit lower in the case of 4a (92:8
with AD-mix-α and 9.5:90.5 with AD-mix-β). The reaction was
also tested on other styrene derivatives substituted with a
fluorinated group at the α-position. Unfortunately, the
CF CO Et and CF PO(OEt) derivatives were unreactive
d
,
de
9
2.5:97.5
a
Reaction conditions: 1a (0.1 mmol), AD-mix-α (Os: 0.2 mol %),
b
c
Solvent:H O (1:1, 1 mL), 0 °C, 24 h. Isolated yield is reported. The
enantiomeric ratio (er) was determined by HPLC analysis on a chiral
stationary phase. 72 h instead of 24 h. AD-mix-β was used instead of
AD-mix-α. NR: no reaction.
2
2
2
2
2
d
e
under our reaction conditions, whereas the α-CF CH OTBS
2 2
21
substituent was tolerated. The product 6 was isolated in
moderate yields with both AD-mix-α and AD-mix-β. In the
latter case the er is moderate, while a lower er of 87:13 is
obtained with AD-mix-α. Finally, the reaction was extended to
β-difluoromethyl and β-trifluoromethyl styrenes 7a and 7b. In
both cases a very high level of enantioselectivity was observed
with the AD-mix-α and -β catalytic systems and 8a and 8b
were isolated in moderate yields (49−53%).
yields (24% and 30%) and modest enantiomeric ratios (er),
73.5:26.5 and 76:24, respectively (entries 1 and 2). Then, amyl
alcohol and tBuOH were evaluated (entries 3 and 4). Amyl
alcohol gave a similar yield as EtOH and iPrOH, while the er
was increased to 93.5:6.5. Pleasingly, tBuOH gave a higher
B
DOI: 10.1021/acs.orglett.9b02792
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
d
Scheme 1. Scope of the Reaction
a
b
c
d
The reaction was carried out on a 4 mmol scale. Reaction time, 6 days. Reaction was carried out at 20 °C. 1 or 2 (0.25 mmol), AD-mix-α or -β
(Os: 0.2 mol %), tBuOH:H O (1:1, 2.5 mL), 0 °C, 72 h. Enantiomeric ratio (er) was determined by HPLC analysis on a chiral stationary phase.
2
Then, we demonstrated the versatility and the synthetic
utility of these chiral α,α-difluoromethyl tertiary alcohols
the AD reaction of these fluorinated olefins follows the
empirical rules for the prediction of the selectivity of the AD
19b
(
Scheme 2).
reaction using AD-mix-α and -β. In the same vein, sulfate 9
was transformed into the corresponding iodo alkane 11 in 75%
yield without alteration of the er. Finally, the azide 12 was
First, chiral alcohol 2a was readily converted into the
corresponding cyclic sulfate 9 in 75% yield and a similar er.
Then, this versatile platform was reduced into the correspond-
ing alcohol 10 in 66% yield and a 4.5:95.5 er. Note that the
absolute configuration was determined as S, by comparison
readily obtained after the reaction of 9 with NaN in 79% yield.
3
A subsequent reduction of the latter followed by a N-
protection to avoid a tedious purification gave 13 in 68% yield
over 2 steps with a 2.5:97.5 er.
17
with the literature data. This finding provides us the clue that
C
DOI: 10.1021/acs.orglett.9b02792
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthetic Utility of the α,α-Difluoromethyl
Tertiary Alcohol 2a
ACKNOWLEDGMENTS
■
a
This work was partially supported by Normandie Universite
NU), the Region Normandie, the Centre National de la
Recherche Scientifique (CNRS), Universite de Rouen
Normandie (URN), INSA Rouen Normandie, Labex SynOrg
ANR-11-LABX-0029) and Innovation Chimie Carnot (I2C).
́
(
́
́
(
W.-S.H thanks the Labex SynOrg (ANR-11-LABX-0029) for a
doctoral fellowship. T.P. thanks the Institut Universitaire de
France for support and the CNRS Emergence program for
funding. A.B.C. thanks the Labex SynOrg (ANR-11-LABX-
0029) for a chair of excellence.
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AUTHOR INFORMATION
Corresponding Authors
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10) (a) Batisse, C.; Cespedes Davila, M. F.; Castello, M.; Messara,
*
E-mail: thomas.poisson@insa-rouen.fr.
E-mail: philippe.jubault@insa-rouen.fr.
ORCID
*
A.; Vivet, B.; Marciniak, G.; Panossian, A.; Hanquet, G.; Leroux, F. R.
Tetrahedron 2019, 75, 3063. (b) Batisse, C.; Panossian, A.; Hanquet,
G.; Leroux, F. R. Chem. Commun. 2018, 54, 10423.
Thomas Poisson: 0000-0002-0503-9620
Philippe Jubault: 0000-0002-3295-9326
Notes
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11) Neves-Garcia, T.; Vel
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ez, A.; Martínez-Ilarduya, J. M.; Espinet,
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The authors declare no competing financial interest.
D
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poorly selective (er < 60:40).
E
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