Synthesis of a chiral quaternary carbon center bearing a fluorine atom: Enantio- and diastereoselective guanidine-catalyzed addition of fluorocarbon nucleophiles

Full text of DOI:10.1002/anie.200900964

Angewandte
Chemie
DOI: 10.1002/anie.200900964
Asymmetric Synthesis
Synthesis of a Chiral Quaternary Carbon Center Bearing a Fluorine
Atom: Enantio- and Diastereoselective Guanidine-Catalyzed Addition
of Fluorocarbon Nucleophiles**
Zhiyong Jiang, Yuanhang Pan, Yujun Zhao, Ting Ma, Richmond Lee, Yuanyong Yang,
Kuo-Wei Huang, Ming Wah Wong,* and Choon-Hong Tan*
À
The C F bond is highly polarized and its unique properties
are often understood by considering its stereoelectronic
interactions with neighboring bonds or lone pairs of elec-
trons.[1] Whereas natural organofluoro compounds are rare,
synthetic fluorinated compounds are useful in areas such as
materials, agrochemicals, pharmaceuticals, and fine chemi-
cals.[2] Strategic fluorination is commonly used in contempo-
rary medicinal chemistry to improve metabolic stability,
bioavailability, and protein–drug interactions.[3] The replace-
ment of metabolically active hydrogen atoms with fluorine
atoms increases the in vivo lifetime of drugs. As such,
fluorine-containing compounds are ubiquitous in blockbuster
drugs, for example, fluoxetine (antidepressant), atorvastatin
(cholesterol-lowering), and ciprofloxacin (antibacterial). The
specific incorporation of fluorine in a regio- and stereoselec-
tive manner has thus become the most pivotal consideration
in the synthesis of fluorinated compounds. To date, both
nucleophilic fluorination[4] and electrophilic fluorination[5]
methods have been developed.
opening of epoxides with fluoride sources using salen/
chromium complexes (salen = bis(salicylidene)ethylenedia-
mine) as catalysts.[10] The use of a fluorocarbon nucleophile
such as 1-fluorobis(phenylsulfonyl)methane (FBSM) as a
synthetic equivalent of monofluoromethane was effectively
exploited in a Mitsunobu reaction,[11] Michael reaction,[12a]
Mannich reaction,[12b] and palladium-catalyzed allylation.[12c]
The amination of 2-fluoro-tert-butyl benzoylacetate under
phase-transfer conditions was found to proceed with moder-
ate enantioselectivity.[13] Other novel approaches towards
chiral quaternary carbon centers bearing a fluorine atom
include the enantioselective decarboxylation of a-fluoro-b-
ketoesters.[14] To the best of our knowledge, a highly
enantioselective and diastereoselective reaction using a
fluorocarbon nucleophile has not yet been reported.
We are keen to develop bicyclic guanidines as general
Brønsted base catalysts, and we found that these bases work
particularly well with conjugate addition type reactions
providing adducts with high ee values.[15] We have previously
shown that adduct 1 can be obtained by the guanidine-
catalyzed addition of ethyl benzoylacetate and N-ethyl
maleimide with an ee value of 90% and a d.r. of 1:1
[Eq. (1)].[15c] When 1 was used for the electrophilic fluorina-
tion reaction using 1.2 equivalents of Selectfluor, 2a was
With the huge number of potential applications, asym-
metric C F bond formation has been become a subject of
À
intense research and has emerged as an important goal in
organic chemistry.[6] Hintermann and Togni reported the first
example of an enantioselective catalytic electrophilic a-
fluorination using a titanium/taddol complex (taddol = tetra-
aryl-1,3-dioxolane-4,5-dimethanol) and Selectfluor.[7] The
emergence of other stable sources of electrophilic fluorinating
agents such as N-fluorobenzenesulfonimide (NFSI) and the
use of other metal complexes allowed the scope of asym-
[8]
À
metric C F bond formation to be dramatically expanded.
À
Organocatalytic approaches for asymmetric C F bond trans-
formation using proline and cinchona alkaloids and their
derivatives as catalysts have recently been shown to be a
viable alternative.[9] Catalytic enantioselective nucleophilic
fluorination is not common; however, one example is the ring
obtained with a d.r. of 7:3. The reaction proceeded slowly and
required two days to achieve 30% conversion [Eq. (1);
structure of major diastereoisomer is shown]. Conducting
the experiment at low temperature should give a higher d.r.
value, but this was not feasible because of the slow rate of the
reaction.
[*] Dr. Z. Jiang, Y. Pan, Y. Zhao, T. Ma, R. Lee, Y. Yang, Prof. K.-W. Huang,
Prof. M. W. Wong, Prof. C.-H. Tan
Department of Chemistry, National University of Singapore (NUS)
3 Science Drive 3, Singapore 117543 (Singapore)
Fax: (+65)6779-1691
The use of 2-substituted benzoylacetates,[16a] such as a-
E-mail: chmwmw@nus.edu.sg
fluoro-b-ketoester 4a,[16b] as the fluorocarbon nucleophile is
chmtanch@nus.edu.sg
À
an alternative approach for making the C F bond in 2a. The
[**] This work was supported by ARF grants (R-143-000-337-112 and R-
143-000-342-112) from the National University of Singapore.
À
strong inductive effect of the C F bond in a-fluoro-b-
ketoester 4a should increase the acidity of the a-carbon
atom. We have shown previously that a more acidic donor will
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900964.
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3627

Communications
result in an increase in the rate of reaction of the guanidine-
and electron-donating substrates, as well as the heteroaro-
matic substrate 4l (Table 2, entry 11) gave excellent results.
Linear Michael acceptors such as trans-4-oxo-4-arylbuten-
amides 6a and 6b [Eq. (2)] were also found to be suitable for
catalyzed reactions.[15c] The increase in the acidity was verified
by comparing the pKa values of ethyl benzoylacetate (9.85)
and a-fluoro-b-ketoester 4a (8.20).[17]
In the presence of 5 mol% of catalyst 3, a-fluoro-b-
ketoester 4a and various N-alkyl maleimides (Table 1, 5a–f)
underwent conjugate additions to afford adducts with excel-
Table 1: Highly enantioselective and diastereoselective reactions
between a-fluoro-b-ketoester 4a and N-alkyl maleimides 5a–f.
Entry
5
R
t [h]
2
Yield [%][a]
d.r.[b]
ee [%][c]
1
2
3
4
5
6
5a Et
5b Me
5c cyclohexyl
5d Bn
5e n-hexyl
5 f t-butyl
2
6
6
3
3
12
2a
2b
2c
2d
2e
2 f
99
99
99
91
87
99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
96
95
96
93
95
97
this reaction. 4-Oxo-4-arylbutenamides were previously
shown to participate in Michael reactions of arylboronic
acids catalyzed by rhodium complexes.[19a] Aza-Michael
reactions with 4-oxo-4-arylbutenamides were also reported
to show high regioselectivities.[19b] Initial investigations using
aryl a-fluoro-b-ketoesters 4i and 4k, showed low reactivity
towards the arylbutenamides. Optimization studies revealed
that with 10 equivalents of triethylamine as an additive[15e]
and an increase in the catalyst loading to 20 mol%, adducts
were obtained in excellent enantioselectivities (up to 96%),
diastereoselectivities (99:1), and regioselectivities.[20]
To shed light on the mechanism of the guanidine-
catalyzed addition, density functional theory (DFT) calcula-
tions at the B3LYP/6-31G* level were performed.[21] The
catalytic reaction is initiated by a proton transfer from the a-
fluoro-b-ketoester to the guanidine catalyst 3 to form a
hydrogen-bonded complex between the guanidinium cation
and the ketoester anion. This ion-pair complex is character-
ized by two hydrogen bonds between the guanidinium NH
protons and the oxygen atoms of the carbonyl groups in the a-
fluoro-b-ketoester.[22a] The complex has a large binding
energy of À49 kJmolÀ1 with respect to the two neutral
substrates. It is important to note that the corresponding
neutral guanidine/enol complex is significantly less stable (by
14 kJmolÀ1) than the ion-pair complex.
[a] Yield of isolated product. [b] Determined by 1H NMR analysis.
[c] Determined by HPLC methods.
lent ee values (93–97%). Excellent diastereoselectivities
(d.r. > 99:1) were also observed.[18] Under the same reaction
conditions, the reaction was additionally explored using
several substituted aryl a-fluoro-b-ketoesters 4b–l (Table 2).
High enantioselectivities (up to > 99% ee) and diastereose-
lectivities (> 99:1 d.r.) were observed for different substitu-
tion patterns on the aromatic ring. Both electron-withdrawing
Table 2: Highly enantioselective and diastereoselective reactions
between aryl a-fluoro-b-ketoesters 4b–l and 5a.
Entry
4
Ar
R
2
Yield [%][a] d.r.[b]
ee [%][c]
1
2
3
4
5
4b 4-NO2C6H4
4c 4-CF3C6H4
4d 4-ClC6H4
4e 4-BrC6H4
4 f 4-(4-BrC6H4)-
C6H4
4g 4-MeOC6H4
4h 4-BnOC6H4
4i 3,5-Me2C6H3
4j 2-naphthyl
4k 3-MeOC6H4
4l 2-thiophenyl
Et 2g
Et 2h
Et 2i
Me 2j
Me 2k
80
83
98
85
99
98:2
>99:1
>99:1
83
96
95
>99:1 95[97][d]
>99:1 93[>99][e]
The maleimide would then approach the guanidinium/
ketoester ion-pair complex to form a pretransition-state
complex; two possible structures, face-on and side-on, of
this complex are conceivable.[22a] In the side-on complex, the
guanidinium catalyst forms hydrogen bonds with both reac-
tants, whereas the guanidinium catalyst forms hydrogen
bonds only with the b-ketoester substrate in the face-on
complex.[22a] Likewise, face-on and side-on approaches are
6
7
8
9
10
11
Et 2l
Et 2m
Me 2n
Me 2o
Et 2p
Et 2q
87
99
99
99
99
99
>99:1
>99:1
>99:1
96
97
96
>99:1 96[>99][e]
>99:1
>99:1
96
93
À
possible for the C C bond-forming transition state (TS). The
[a] Yield of isolated product. [b] Determined by 1H NMR analysis.
[c] Determined by HPLC methods. [d] À608C, 24 h, 99% yield, d.r.
>99:1, 1.0 mmol scale. [e] ee values improved after a single recrystal-
lization.
side-on TS is strongly preferred over the face-on TS mainly
because of the stronger hydrogen bond associated with the
maleimide carbonyl group. Hence, the guanidine catalyst in
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this catalytic reaction is best described as a bifunctional
catalyst.[22b]
attempt at reducing the ketone moiety in the fluorinated
adduct 2 f with NaBH4 (THF, À788C), resulted in a diaste-
reomeric ratio of 1:1. Subsequently, we tried several other
reducing agents and found that TiCl4/BH3·Me2S[24] resulted in
perfect diastereoselectivity; only one diastereoisomer 8a,
with three contiguous chiral centers, was obtained [Eq. (3)].
The relative and absolute configuration of 8b was confirmed
by single-crystal X-ray analysis.[25] The antiperiplanar orien-
tation of sC-H with s*C-F was clearly demonstrated in the
crystal structure of 8b. Both the chelation-controlled addi-
tion[24] (Figure 2, A) and Felkin–Anh[26] (Figure 2, B) models
predicted the correct diastereoisomer.
On the basis of the fact that there are two potential
À
centers for forming C C bonds in maleimide and various
modes of approach between the two reactants, there are four
plausible side-on transition states. The relative energies of the
most stable transition states leading to the formation of (S,R)-,
(S,S)-, (R,S)-, and (R,R)-products are 0, 10, 18, and
20 kJmolÀ1, respectively. The calculated preference for the
(S,R)-stereoisomer is in excellent agreement with the
observed high enantioselectivty and diastereoselectivity. The
optimized geometries of the four transition states are shown
in Figure 1. Interestingly, only one of the two carbonyl
Figure 2. Models for highly diastereoselective reduction of 2j,k.
The interest in b-amino acids and b-peptides arises from
the desire to understand protein folding as well as its potential
as mimics of naturally occurring peptides.[27] Current method-
ologies did not describe a simple, direct approach to prepare
a-fluoro-b-amino acids, particularly the concomitant con-
Figure 1. Optimized (B3LYP/6-31G*) geometries of the four transition
states leading to the (S,R)-, (S,S)-, (R,S)-, and (R,R)-products. Calcu-
lated relative energies are given in square brackets in kJmolÀ1 and the
bond lengths are given in ꢀ.
À
struction of a quaternary C F bond. Mannich reactions
between b-ketoesters and imines can be catalyzed with
organocatalysts, most commonly, the bifunctional cinchona
alkaloids and chiral Brønsted acids.[28] a-Fluoro-b-ketoesters
were shown to form well-defined transition states with
bicyclic guanidine that led to highly diastereoselective and
enantioselective reactions. We extended this concept to
Mannich reactions and our preliminary results show that a-
fluoro-b-ketoester 4n added to imines 10a and 10b each with
a high level of diastereoselectivity and enantioselectivity.
Optimization of the reaction and investigations to determine
the absolute configuration of b-amino esters 10a and 10b is
ongoing.
oxygens of the b-ketoester forms a hydrogen bond with a
guanidinium NH proton in all cases. The calculated relative
energies of various transition states can be rationalized in
terms of the relative strength of the hydrogen-bond inter-
actions. The calculated intrinsic barriers are relatively small,
for example, 30 kJmolÀ1 for the (S,R)-induced TS. The pre-TS
complex,[22a] having an interaction energy of À24 kJmolÀ1,
brings the reactants and catalyst in close proximity. As a
result, the energy required for structural and electronic
reorganization to form the transition state is significantly
smaller. The calculated activation barrier for the (S,R)-
induced TS is fairly small (30 kJmolÀ1), which is consistent
with the low-temperature requirement of this catalytic con-
jugate addition reaction.
In conclusion, we have developed a highly enantioselec-
tive and diastereoselective guanidine-catalyzed conjugate
addition of fluorocarbon nucleophiles. Several compounds
having chiral quaternary carbon centers bearing a fluorine
atom and contiguous chiral centers were obtained. The
mechanism for the catalysis and the origin of stereoselectivity
were investigated by DFT methods. Our calculations strongly
Fluorohydrins are important precursors in the synthesis of
monofluorinated analogues of natural products.[23] Our first
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Communications
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support the observed remarkable stereoselectivity. The
bifunctional mode of the guanidine catalyst was clearly
demonstrated in the transition states.
Experimental Section
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Representative procedure for the synthesis of 2a: 2-Fluoroethyl
benzoyl acetate 4a (25.2 mg, 0.12 mmol, 1.2 equiv) and N-ethyl
maleimide 5a (12.5 mg, 0.1 mmol, 1.0 equiv) were dissolved in
toluene (795 mL). The reaction was stirred at À508C for 30 minutes,
and then a precooled solution of catalyst 3 (0.005 mmol, 0.05 equiv,
1.12 mg in 5 mL toluene) was added. The reaction mixture was stirred
at À508C and monitored by TLC. After 2 h, the reaction was
completed. Flash chromatography afforded product 2a (33.1 mg,
99% yield) as a colorless oil.
Received: February 19, 2009
Published online: April 17, 2009
Keywords: asymmetric catalysis · fluorine · guanidine ·
.
Michael addition · transition states
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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