Stereoselective synthesis of α,α-chlorofluoro carbonyl compounds leading to the construction of fluorinated chiral quaternary carbon centers

Article abstract of DOI:10.1002/anie.200801682

(Chemical Equation Presented) "F-antastic" chiral molecules: Asymmetric syntheses of α,α-chlorofluoro carbonyl compounds have been developed. Nucleophilic substitutions of an α,α- chlorofluoroketone thus obtained with azide or thiol nucleophiles provide v

Full text of DOI:10.1002/anie.200801682

Communications
DOI: 10.1002/anie.200801682
Fluorinated Molecules
Stereoselective Synthesis of a,a-Chlorofluoro Carbonyl Compounds
Leading to the Construction of Fluorinated Chiral Quaternary Carbon
Centers**
Kazutaka Shibatomi* and Hisashi Yamamoto*
The preparation of fluorine-containing organic molecules has
attracted considerable attention in the field of pharmaceutical
and agricultural chemistry.[1] One of the most challenging
synthetic operations used to access these molecules is the
stereoselective construction of a fluorinated chiral carbon
center.[2] Various stereoselective electrophilic fluorination
reagents have been developed for this purpose.[3] Following a
study by Hintermann and Togni,[4a] efficient catalytic asym-
metric fluorination reactions of b-ketoesters have been
reported.[4b,e] Organocatalytic enantioselective a-fluorination
reactions of aldehydes have also been successfully realized.[5]
Although the field of asymmetric a-fluorination is progress-
Scheme 1. Methodology for the selective construction of fluorinated
chiral quaternary carbon centers. Nu=nucleophile.
ing steadily, a flexible route for the stereoselective construc-
tion of fluorinated quaternary carbon centers is still required.
We propose the synthesis of optically active a,a-chlorofluoro
carbonyl compounds, which can be stereoselectively con-
verted into various chiral molecules with a fluorinated
quaternary carbon by nucleophilic substitution (Scheme 1).
Surprisingly little attention has been given to the synthesis of
optically active a,a-chlorofluoro carbonyl compounds[6] or
their selective transformation.[7] Herein, we disclose the first
enantioselective synthesis of a,a-chlorofluoro carbonyl com-
pounds from simple aldehydes or ketones, and their subse-
quent transformation into a variety of optically active
molecules in which the fluorinated quaternary carbon
center is adjacent to the carbonyl group.
asymmetric a halogenation, which introduces another halo-
gen substituent (Cl or F), and would provide optically active
a,a-chlorofluoro carbonyl compounds. We chose a-chloroal-
dehydes 1 as precursors because they can be easily synthe-
sized from simple aldehydes.[8] As summarized in Table 1,
various a,a-chlorofluoro aldehydes 3 were successfully syn-
thesized with high enantioselectivity (e.r. values ranging from
91:9 to > 99:1) from racemic a-chloroaldehydes (rac-1) and
N-fluorosuccinimide (NFSI) in the presence of organocatalyst
2, which was developed by Jørgensen et al.[5b] A lower
reaction temperature slightly increased the enantioselectivity
of the reaction (Table 1, compare entries 1 and 3 to entries 2
and 4). Although the fluorination of sterically hindered
aldehyde required higher temperature (258C), the product 4d
was obtained in high yield and with an excellent enantiose-
lectivity (e.r. > 99:1; Table 1, entry 6).
Next, the enantioenriched a,a-chlorofluoro aldehydes 3
were successfully transformed into unsymmetrical a,a-
chlorofluoro ketones. Thus, in situ treatment of 3a or 3b
with a Grignard reagent followed by oxidation using the
Dess–Martin reagent afforded the corresponding a,a-chloro-
fluoro ketones 5 and 6, respectively, without loss of optical
purity (Scheme 2); this result clearly expands the range of
accessible a,a-chlorofluoro carbonyl compounds.
Our initial studies focused on the organocatalytic asym-
metric synthesis of a,a-chlorofluoro aldehydes. According to
our synthetic plan (Scheme 1), simple a fluorination or
chlorination of carbonyl compounds would be followed by
[*] Prof. Dr. K. Shibatomi
Department of MaterialsScience
Toyohashi University of Technology
1-1 Hibarigaoka, Tempaku-cho, Toyohashi, Aichi 441-8580 (Japan)
Fax: (+81)532-48-5833
Prof. Dr. H. Yamamoto
After using organocatalysis for the successful synthesis of
enantioenriched a,a-chlorofluoro carbonyl compounds, we
turned our attention to the direct synthesis of a,a-chloro-
fluoro ketones from a-unsubstituted ketones. There are few
reports on the enantioselective a halogenation of simple
ketones.[9,10] We have previously reported the asymmetric
chlorination of silyl enolates, which is mediated by zirconi-
um(IV) chloride and chiral a,a-dichloromalonate,[9] and
presently this may be the best system for the asymmetric
a halogenation of highly substituted ketones. We initially
synthesized racemic a,a-chlorofluoro-1-tetralone (8) by the
Department of Chemistry
The University of Chicago
5735 South EllisAvenue, Chicago, IL 60637 (USA)
Fax: (+1)773-702-0805
E-mail: yamamoto@uchicago.edu
Homepage: http://yamamotogroup.uchicago.edu/
[**] We thank the NIH (grant no. 2 R01 GM068433-05) and Merck for
financial support. K.S. acknowledges a fellowship from the Toyo-
hashi University of Technology Fostering Program for Young
Researchers.
Supporting information for thisarticle isavailable on the WWW
under http://dx.doi.org/10.1002/anie.200801682.
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Chemie
Table 1: Organocatalytic asymmetric synthesis of a,a-chlorofluoro alde-
hydes 3 en route to alcohols 4.[a]
Scheme 3. Racemic synthesis of a,a-chlorofluoro-1-tetralone (8).
NCS=N-chlorosuccinimide, Selectfluor=1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bistetrafluoroborate, TMS=trimethylsilyl.
Entry
Product
T [8C]
Yield [%][b]
e.r.[c]
94:6
96:4
94:6
96:4
1[d]
2
25
0
25
0
88
85
75
62
3[d]
4
5
0
81
91:9
6[e]
7
25
0
86[f]
>99:1[f]
<5[g]
n.d.[h]
[a] All reactionswere carried out uinsg 3 equivalentsof racemic
a-chloroaldehyde (rac-1) and 10 mol% of catalyst 2 with respect to
NFSI in MTBE (methyl tert-butyl ether; 0.25m) unless otherwise noted.
[b] Yieldsof isolated product 4. [c] Enantiomeric ratiosof alcohols 4 were
determined by HPLC on a chiral stationary phase or by GC analysis.
[d] Reaction time was12 h. [e] Reaction time was30 h with 30 mol% of
2. [f] Yield of the isolated product and enantiomeric ratio were
determined after conversion of the product into the 3,5-dinitrobenzoate
owing to the volatility of 4d. [g] Determined by 1H NMR spectroscopy of
the crude product. [h] n.d.=not determined.
Scheme 4. Asymmetric synthesis of (À)-8. TBDMS=tert-butyldimethyl-
silyl, Tf=trifluoromethanesulfonyl.
With a successful asymmetric synthesis of a,a-chloro-
fluoro carbonyl compounds in hand, we tried the nucleophilic
substitution reaction of (À)-8. Sodium azide or thiols worked
very well as nucleophiles to afford the corresponding
substituted products 11–14 in high yields (Scheme 5). Notably,
the reactions proceeded without loss of optical purity. This
means that the reactions proceed in a rigorous SN2 fashion.
Scheme 2. Asymmetric synthesis of a,a-chlorofluoro ketonesby using
organocatalysis. Bn=benzyl, nHex=n-hexyl.
electrophilic chlorination of a fluorinated silyl enolate.[11]
Fortunately, 8 could also be obtained from a-fluoro-1-
tetralone (7)[12] by treatment with N-chlorosuccinimide
(NCS) following the formation of silyl enolate in situ
(Scheme 3). Notably, 8 was stable when left at room temper-
ature for one month.
Following the racemic synthesis of 8, we then proceeded
with its enantioselective preparation using chiral a,a-
dichloromalonate by using a method developed earlier.[9]
The best result was obtained by the reaction of tert-
butyldimethylsilyl enolate (9) with chiral a,a-dichloromalo-
nate (10) to give
Scheme 5. SN2 reactionsof ( À)-8.
In summary, we have described the enantioselective
synthesis of a,a-chlorofluoro aldehydes and ketones from
simple carbonyl compounds. These compounds can be con-
verted into various optically active molecules having fluori-
nated chiral quaternary carbon centers by using nucleophilic
substitution. We believe that the present methodology allows
access to a newclass of fluorinated chiral organic molecules.
Received: April 10, 2008
Published online: June 24, 2008
(À)-8 in 82% yield with an e.r. of 94:6 (Scheme 4). A single
recrystallization from n-hexane/2-propanol (9:1) gave crystals
of (À)-8 in 65% yield with a lower enantiopurity, while the
mother liquor had an e.r. of 97:3.
Keywords: asymmetric catalysis · chlorination · fluorination ·
.
organocatalysis · SN2 reactions
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