Catalytic enantioselective difluoroalkylation of aldehydes

Article abstract of DOI:10.1002/anie.201303551

Copper-catalyzed bond scission of pentafluorobutane-1,3-diones generates difluoroenolates that react with aldehydes to give a wide range of chiral α,α-difluoro-β-hydroxy ketones within a few hours in up to 99 % yield and 92 % ee. The synthetic utility of this reaction is demonstrated with the stereoselective synthesis of a chiral anti-1,3-diol exhibiting a central difluoromethylene unit and efficient conversion to a 2,2-difluoro-3-hydroxy carboxylic acid. Copyright

Full text of DOI:10.1002/anie.201303551

Angewandte
Chemie
Communications
Asymmetric Catalysis
P. Zhang, C. Wolf*
&&&& — &&&&
Catalytic Enantioselective
Difluoroalkylation of Aldehydes
Copper-catalyzed bond scission of pen-
tafluorobutane-1,3-diones generates
difluoroenolates that react with aldehydes
to give a wide range of chiral a,a-difluoro-
b-hydroxy ketones within a few hours in
up to 99% yield and 92% ee. The syn-
thetic utility of this reaction is demon-
strated with the stereoselective synthesis
of a chiral anti-1,3-diol exhibiting a central
difluoromethylene unit and efficient con-
version to a 2,2-difluoro-3-hydroxy car-
boxylic acid.
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DOI: 10.1002/anie.201303551
Asymmetric Catalysis
Catalytic Enantioselective Difluoroalkylation of Aldehydes**
Peng Zhang and Christian Wolf*
In recent years, chiral organofluorine compounds have
become increasingly attractive synthetic targets because
they often afford superior lipophilicity, bioavailability, and
resistance to metabolic degradation compared to the non-
fluorinated parent compounds.[1] The incorporation of
a difluoromethylene group is particularly interesting because
the high electronegativity of fluorine leads to increased dipole
moments, conformational changes, hydration of adjacent
carbonyl groups, and reduced pKa values of acidic function-
alities.[2] The stable hydrates of gem-difluoromethylene
ketones have been shown to mimic tetrahedral intermediates
of HIV1 protease and other important proteolytic enzymes,
and therefore have significant therapeutic potential.[3]
in situ generation of the nucleophile. Few processes that
À
couple the C C bond scission of a prenucleophile with
asymmetric catalysis have been reported.[11] Prager, Ogden,
and Colby have shown that hexafluoroacetone and its
pentafluorobutane-1,3-dione derivatives can afford carban-
À
ions suitable for achiral C C bond formation when 3–
4 equivalents of lithium salts or potassium tert-butoxide are
used.[12] Our group recently prepared pentafluorinated b-
hydroxy ketones in high yields by LHMDS-promoted gen-
eration of difluoroenolates from readily available 1-aryl and
1-alkyl 2,2,4,4,4-pentafluorobutane-1,3-dione hydrates.[13]
However, all these methods are noncatalytic and yield
racemic products.
In strong contrast to the general success of trifluorome-
thylations using TMSCF3 (Ruppert–Prakash reagent),[4] the
corresponding difluoromethylation with the significantly less
reactive TMSCHF2 has been unsuccessful.[5] While the syn-
thesis of b-hydroxy esters with isolable difluoroketene silyl
acetals has been accomplished by Iseki et al. with high
asymmetric induction,[6] the formation of a,a-difluoro-b-
hydroxy ketones from difluoroenolates and aldehydes has
proven to be complicated. To date, several
We have now developed a catalytic enantioselective
method that produces a series of a,a-difluoro-b-hydroxy
ketones from aldehydes through direct difluoromethylation
with a,a-difluoroenolates generated in situ from trifluoro-
methyl a,a-difluorinated b-keto gem-diol 1 and its derivatives
(Scheme 1). An asymmetric aldol reaction between the
monofluorinated analogue of 1 and nonenolizable N-benzyl
isatins was recently reported by Fang, Wu, and co-workers.[14]
racemic
methods
typically
involving
TMSCF2SO2Ph or PhSO2CF2H as enolate pre-
cursors have been developed.[7] But the use of
a,a-difluoroenolates in asymmetric reactions
with aldehydes and ketones has remained
a major challenge. The asymmetric nucleophilic
addition of a zinc difluoroenolate complex to
selected aldehydes and an Et2Zn-mediated
Reformatsky-type reaction with ethyl iodofluor-
oacetate and ketones have only been accom-
plished with stoichiometric amounts of chiral
amino alcohols.[8] A catalytic procedure for the
asymmetric synthesis of a,a-difluoro-b-hydroxy
ketones from aromatic and aliphatic aldehydes
has been elusive to date and few allylic alkyla-
tions restricted to cyclic monofluoroenolates[9] or
aldol condensations using monofluoroacetone
have been reported.[10]
Scheme 1. Initial analysis of the catalytic difluoromethylation of aldehydes.
À
Importantly, this work is based on C C bond formation
We envisioned that the difficulties and limitations encoun-
tered with fluorinated carbanions could be addressed by mild
followed by trifluoroacetate cleavage and therefore does not
allow incorporation of a CF2 unit. By contrast, our approach
results in the incorporation of a difluoromethylene rather
than a monofluoromethylene moiety next to the chiral center
[*] P. Zhang, Dr. C. Wolf
À
and the trifluoroacetate is cleaved prior to the C C bond-
forming step.
Department of Chemistry, Georgetown University
37th and O Streets, Washington, DC 20057 (USA)
E-mail: cw27@georgetown.edu
During initial NMR and ReactIR analysis of the effect of
additives, base, solvent, and other parameters on this reaction
we found that catalytic bond cleavage of 1 and subsequent
Homepage: http://www.thewolfgrouponline.com/
[**] This research was supported by The American Chemical Society
Petroleum Research Fund (52737-ND1).
À
C C bond formation is indeed possible in the presence of 10–
20 mol% of magnesium, copper, and zinc salts (see the
Supporting Information). We then continued with the screen-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303551.
2
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ing of chiral metal complexes to determine whether this
reaction sequence can also be accomplished with practical
asymmetric induction. The reaction of prenucleophilic 1 and
benzaldehyde in the presence of 10 mol% of copper(II)
triflate or copper(II) acetate and bisoxazolidine L1 gave the
desired product 2 in up to 55% ee within 1 hour.[15] Although
1 was quantitatively consumed, the yields were generally
below 30% due to a predominant side reaction leading to 2,2-
difluoro-1-phenylethanone (3). We then employed enantioen-
riched 2 in our reaction procedure to determine whether the
À
C C bond-formation step is reversible. However, neither
a sign of racemization nor formation of 3 was observed. The
same analysis with 3 confirmed that the protonation of
intermediate enolate 4 is irreversible under the conditions
used. Apparently, the formation of 3 occurs by means of
protonation of 4 by the Et3NH+ by-product (Scheme 1). We
therefore attempted to avoid formation of triethylammonium
by using silyl enolether 5 and the TMS analogue 6 in
combination with TBAF and CsF, and explored typical
Mukaiyama aldol conditions with Ti(OiPr)4. But 2 was still
obtained in low yields and ee values. These results underscore
the general difficulty in producing chiral a,a-difluoro-b-
hydroxy ketones such as 2 using 5 and other isolated
difluoroenolates as discussed above.[5,7,8] However, the
replacement of 1 with 7, which reduces the amount of
triethylammonium formed without changing the pathway of
in situ enolate formation, did also not improve results.
Screening of a wide range of organic and inorganic bases in
various solvents then showed that 2 can be formed in 67%
yield and 26% ee when Me2Zn is used in toluene. At this
point, we decided to apply several bisoxazoline ligands to our
general reaction protocol. While the results obtained in the
presence of catalytic amounts of copper(II) triflate and L2–L9
varied considerably, L10–l12 showed remarkable promise
(Figure 1). We were very pleased to find that 2 is formed in
almost quantitative yields and 61–68% ee within 1 h when
these ligands are employed in THF.
Figure 1. Result of screening chiral ligands and a MOPAC computation
of the loaded catalyst (hydrogens are omitted for clarity). Reaction
conditions: diol (0.2 mmol), Cu(OTf)2 (25 mol%), ligand (30 mol%),
PhCHO (2 equiv), Et3N (2 equiv) in toluene, 258C. a) THF, b) Cu(OTf)2
(10 mol%), ligand (12 mol%).
We therefore further modified the ligand structure and
prepared L13 and L14 (Scheme 2).[18] A change of the relative
configuration of the adjacent phenyl rings in L10, as in anti
derivative L13, improved the enantioselectivity and introduc-
tion of a cyano group to the methylene bridge further
increased catalytic activity and yield. With L14 in hand, we
were able to decrease the catalyst loading to 5 mol% and
obtained 2 as well as analogues 8–10 in up to 98% yield and
Based on the wealth of crystal structures of CuII–
bisoxazoline complexes available in the literature, one can
assume that the transition state involves a distorted square-
planar geometry although coordination of a counterion lead-
ing to a square pyramid is also possible.[16] Computational
analysis of the CuII–L11 complex loaded with benzaldehyde
and enolate 4 correctly predicts the observed stereochemical
outcome (verified by NMR analysis of Mosher ester deriv-
atives) and is in agreement with a distorted square-planar CuII
complex (Figure 1 and the Supporting Information). Our
screening results also revealed that anionic ligands exhibiting
a delocalized negative charge in the backbone, in particular
semicorrin L12, allow completion of the reaction within 1 h.
We assumed that Pfaltzꢀs semicorrins should generally favor
displacement of the aldol product from the copper center
without compromising its Lewis acidity.[17] We then rational-
ized that this type of more active catalyst would enable us to
perform the reaction at lower temperature to improve ee
values while the competing protonation of the enolate to by-
product 3 would remain relatively slow and thus not affect
yields.
Scheme 2. Synthesis and single-crystal X-ray structure of L14.
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92% ee using 1.2 equivalents of benzaldehyde at 108C
Table 1: (Continued)
(Table 1, entries 1–4).[19]
Entry
Aldehyde
Product
t [h]
Yield[b]
[%]
ee[c]
[%]
21
22
3
3
87[d]
90[d]
79
77
Table 1: Scope of the enantioselective aldol reaction.[a]
Entry
Aldehyde
Product
t [h]
Yield[b]
[%]
ee[c]
[%]
[a] Reaction conditions: diol (0.4 mmol), Cu(OTf)2 (5 mol%), L14
(6 mol%), aldehyde (1.2 equiv), Et3N (2 equiv) in 2 mL of THF. [b] Yields
of isolated products. [c] Determined by HPLC on a chiral stationary
phase. [d] Diol (0.2 mmol), Cu(OTf)2 (20 mol%), L14 (24 mol%), Et3N
(2 equiv), aldehyde (2 equiv), 258C.
1
2
3
4
5
6
7
8
9
2.5
5
97
96
98
88
99
90
88
92
90
83
91
92
77
82
79
78
81
82
We then applied a wide range of aldehydes to evaluate the
reaction scope. In general, high yields and ee values were
obtained with electron-rich and electron-deficient substrates
(Table 1, entries 5–9). Importantly, this method tolerates the
presence of amines, ketones, esters and other functional
groups (Table 1, entries 10–12 and 15), and the reaction with
sterically hindered aldehydes gave 19 and 20 with 79–85%
yield and 84–87% ee (Table 1, entries 13 and 14). Finally, the
copper-catalyzed aldol reaction between the 2-naphthyl-
substituted geminal diol and various aldehydes, including
enolizable substrates such as cyclohexanecarboxaldehyde and
3-phenylpropionaldehyde, gave 24–28 in up to 94% yield and
88% ee (Table 1, entries 18–22).
5
1
3
2
6
6
Our procedure provides unprecedented access to impor-
tant chiral building blocks, including 2,2-difluoro-1,3-propa-
nols.[20] For example, the reduction of 8 with DIBAL produces
anti-29 in high yields and with excellent diastereoselectivity
(Scheme 3).[13] This establishes a convenient entry to C1- and
7
10
11
12
2
93
86
90
80
76
76
6
23
13
14
15
6
85
79
92
84
87
85
11
4
16
17
18
19
20
5
7
8
8
7
91
88
94
89
88
80
73
88
82
82
Scheme 3. Formation of a representative anti-2,2-difluoro-1,3-diol and
a 2,2-difluoro-3-hydroxy acid.
C2-symmetric anti-1,3-diol motifs, which appear in many
natural products and are of great pharmaceutical interest.
Alternatively, we realized that the Baeyer–Villiger oxidation
followed by mild hydrolysis affords the first asymmetric route
to 2,2-difluoro-3-hydroxy carboxylic acids, which are crucial
precursors of several enzyme inhibitors and other biologically
active compounds.[21] Oxidation of 25 with m-CPBA to the
4
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[2] D. OꢀHagan, Chem. Soc. Rev. 2008, 37, 308 – 319.
corresponding 2-naphthoate 30 and basic hydrolysis gave 2,2-
difluoro-3-hydroxy acid 31 in 85% yield and 86% ee.
In conclusion, we have introduced a practical method for
the catalytic enantioselective addition of a,a-difluoroenolates
to aldehydes using 5 mol% of copper(II) triflate and a new
bisoxazoline ligand which can be easily prepared in two steps.
High yields and ee values were obtained with a wide range of
prenucleophiles and aldehydes, including aliphatic substrates,
under mild conditions and in short reaction times. The value
of this reaction is highlighted by the stereoselective reduction
and Baeyer–Villiger oxidation of a,a-difluoro-b-hydroxy
ketones to give an anti-2,2-difluoro-1,3-propanol and a 2,2-
difluoro-3-hydroxy carboxylic acid, respectively. Further
investigation of catalytic reactions between a,a-difluoroeno-
lates and other electrophiles is currently underway in our
laboratory.
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Experimental Section
Ligand L14 (11.6 mg, 0.024 mmol) and Cu(OTf)2 (7.2 mg,
0.020 mmol) were dissolved in 1 mL of anhydrous THF under
nitrogen at room temperature and stirred for 1 min. Then, 1-(2-
naphthyl)-2,2,4,4,4-pentafluorobutane-1,3-dione hydrate (128.0 mg,
0.4 mmol) was added, and the solution was stirred for an additional
minute followed by addition of 0.48 mmol of aldehyde (1.2 equiv-
alents) dissolved in 0.5 mL of THF. The mixture was then transferred
to a jacketed flask using another 0.5 mL of THF, cooled to 108C, and
stirred for another 10 min. Finally, triethylamine (2 equivalents) was
added. After completion of the reaction, solvents were removed and
the crude residue was loaded directly onto a silica gel column.
Chromatographic purification (EtOAc/hexanes 1:10) gave 120 mg
(0.38 mmol, 96%, 92% ee) of 8 as a white solid. 1H NMR (400 MHz,
CDCl3) d = 3.11 (d, J = 4.5 Hz, 1H), 5.37 (ddd, J = 4.5 Hz, 4.5 Hz,
18.5 Hz, 1H), 7.36–7.45 (m, 3H), 7.51–7.57 (m, 3H), 7.63 (ddd, J =
1.2 Hz, 1.2 Hz, 7.5 Hz, 1H), 7.87 (dd, J = 8.8 Hz, 8.8 Hz, 2H), 7.92 (d,
J = 8.2 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 8.61 ppm (s 1H). 13C NMR
(100 MHz, CDCl3) d = 73.5 (dd, JC-F = 22.7 Hz, 28.1 Hz), 115.9 (dd, JC-
F = 257.0 Hz, 264.7 Hz), 124.7, 127.1, 127.8, 128.1, 128.3, 128.6, 129.0,
129.5, 130.2, 132.2, 133.3, 134.8, 136.1, 190.7 ppm (dd, JC-F = 29.4 Hz,
31.6 Hz). The ee value was determined by HPLC on Chiralpak AS
using IPA/hexanes (10:90) as the mobile phase. Anal. calcd. for
C19H14F2O2: C 73.07, H 4.52; found: C 73.04, H 4.68.
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Received: April 25, 2013
Published online: && &&, &&&&
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Keywords: aldol reaction · asymmetric catalysis ·
cleavage reactions · fluoroenolates · reactive intermediates
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