Asymmetric organocatalytic monofluorovinylations

Article abstract of DOI:10.1021/ja110624k

The development of highly enantio-and diastereoselective organocatalytic monofluorovinylations is presented. Based on the application of β-fluoro-β-keto-benzothiazolesulfones, the formal addition of a monofluorovinylic anion synthon to a range of acyclic and cyclic enones, as well as imines, is shown. These procedures give selective access to both E-and Z-isomers of the monofluorovinylated products, which are isolated as the pure diastereoisomers in good to excellent yields with up to 99% ee. Furthermore, the application of this concept for the formation of highly enantioenriched bicylic compounds containing a monofluorovinyl moiety is also described. In addition, a mechanistic rationale for the observed E:Z-selectivities is presented.

Full text of DOI:10.1021/ja110624k

ARTICLE
pubs.acs.org/JACS
Asymmetric Organocatalytic Monofluorovinylations
Christian Borch Jacobsen, Martin Nielsen, Dennis Worgull, Theo Zweifel, Esben Fisker,
and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark
S Supporting Information
b
ABSTRACT: The development of highly enantio- and diaster-
eoselective organocatalytic monofluorovinylations is presented.
Based on the application of R-fluoro-β-keto-benzothiazolesul-
fones, the formal addition of a monofluorovinylic anion synthon
to a range of acyclic and cyclic enones, as well as imines, is
shown. These procedures give selective access to both E- and Z-
isomers of the monofluorovinylated products, which are iso-
lated as the pure diastereoisomers in good to excellent yields
with up to 99% ee. Furthermore, the application of this concept
for the formation of highly enantioenriched bicylic compounds containing a monofluorovinyl moiety is also described. In addition, a
mechanistic rationale for the observed E:Z-selectivities is presented.
’ INTRODUCTION
Introducing fluorine into organic molecules can have a pro-
found effect on their pharmacokinetic and pharmacodynamic
properties, and as such, the preparation of fluorine analogues of
biologically active compounds have been the subject of intense
research.1 Due to the electronegativity of the fluorine atom, its
presence on an alkene changes the electron distribution of the
alkene moiety, mimicking the dipolar nature of an amide bond.2
In this regard, monofluoroalkenes have long been known as
stable bioisosteres of amide bonds with respect to conforma-
tional interconversion and hydrolysis (Figure 1).2b,3 Recently,
this has led to several publications concerning the replacement of
amide bonds with monofluoroalkenes in biologically active
compounds.3a,4
Although methods for the formation of monofluoroalkenes
have seen a number of developments in recent years,5 procedures
Figure 1. Monofluoroalkenes as nonisomerable, nonhydrolyzable iso-
for forming optically active monofluoroalkenes with an R-stereo-
steres of amide bonds.
center are still scarce.6 As such, to the best of our knowledge,
the catalytic enantioselective addition of monofluoroalkenes
to a prochiral electrophile is unprecedented, although the
synthon might be the R-fluoro-β-keto-heteroarylsulfone 1,9
formed products are highly desirable, as the configuration of the
stereocenter adjacent to the monofluoroalkene has previously
been shown to be of importance for biological activity.7 In
addition, as E- and Z-monofluoroalkenes are possible bioiso-
steres for cisoid- and transoid-amide bonds, respectively (Figure 1),
the introduction of monofluoroalkenes with a high control of
E/Z-selectivity is potentially of great synthetic and pharmaceutical
interest but remains a challenging task, especially concerning the
formation of the E-isomers.5
We surmised that these problems could be overcome by
developing an enantioselective organocatalytic8 addition of a
monofluorovinylic anion synthon to a prochiral electrophile.
As outlined in the retrosynthetic analysis (Figure 2), such a
which upon reduction of the ketone moiety in 1 could undergo
a JuliaÀKocienski-like transformation.10
Here, we report the development of the first, highly enantio-
and diastereoselective monofluorovinylations of enones and
imines. The products are formed as either E- or Z-isomers from
a common intermediate and are generally isolated as the pure
isomer. Furthermore, a rationale for the stereochemical outcome
is presented. In addition, the developed procedure is also
demonstrated to be useful for the formation of optically active
bicylic monofluorovinyl compounds.
Received: November 26, 2010
Published: April 22, 2011
r
2011 American Chemical Society
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As proof of concept, we speculated whether it would be
possible to employ the easily accessible R-fluoro-β-keto-
benzothiazolesulfones 1 as nucleophiles for the asymmetric
organocatalytic monofluorovinylation of cyclic and acyclic en-
ones 2 (Figure 3), as well as imines (vide infra). Following the
addition, the adduct formed might selectively be converted into
the E- and Z-monofluoroalkenes E-3 and Z-3, by reduction of
the ketone moiety. In analogy with the commonly accepted
mechanism for the JuliaÀKocienski reaction,10 we assume
that the diastereochemistry in the formation of 3 is solely
based on the diastereoisomeric ratio between the R-sulfone
moiety and the reduced ketone (E-A or Z-A, Figure 3).
Therefore, the diastereoselectivity of the reduction deter-
mines the E:Z-ratio of the produced alkene 3. In order to
access both E-3 and Z-3 from the common intermediate,
we endeavored to develop two different one-pot reduction
protocols, leading to 3 with selective control of the E- or
Z-configuration of the monofluoroalkene moiety.
2a can be performed with 99% ee at 45 °C by reaction in
1,4-dioxane utilizing 10 mol % primary amine11 4as the organocatalyst,
we turned our attention to the subsequent reduction needed to
form selectively the E- or Z-isomer of the monofluorovinyl
product 3. Reducing intermediate 5aa with NaBH4 at room
temperature gives the desired product 3aa with an E:Z-ratio of
50:50 (Table 1, entry 1). It is observed that cooling alone does
not solve this selectivity problem (entry 2); however, the em-
ployment of LiBH4 as reducing agent at lowered temperature
improves the selectivity substantially. It was found that at 0 °C
E-3aa can be formed with an excellent E:Z-ratio of >98:<2 by
reducing 5aa with LiBH4 in a 1:1 mixture of 1,4-dioxane and
MeOH in a one-pot procedure (entry 3).
In order to obtain primarily the Z-isomer of 3aa, it is essential
to lower the amount of alcohol and change the reducing agent to
NaBH4. Furthermore, the addition of ZnCl2 improves the
selectivity toward the desired isomer (Table 1, entry 4 vs entry
5). Other salts such as CaCl2 and CeCl3 do not show the same
effect. Employing sterically more demanding alcohols is advanta-
geous (entries 5À8), and the product Z-3aa can be formed with
an E:Z-ratio of 10:90 by addition of neopentanol (2,2-dimethyl-
1-propanol) using NaBH4 as reducing agent and ZnCl2 as additive
at ambient conditions (entry 8), thereby practically reversing
the diastereoselectivity in this step. Moreover, we decided to
employ a simple oxidation of the alcohol moiety in 3 to
the corresponding ketone with DessÀMartin periodinane
(DMP), as this allows for the separation of the E- and
Z-diastereoisomers of the oxidized products 6 by flash column
chromatography, hereby enhancing the synthetic utility of
these reactions.
’ RESULTS AND DISCUSSION
Reactions of Cyclic and Acyclic Enones. Having established
that the addition of R-fluoro-β-keto-benzothiazolesulfone 1a
(Figure 3, R = Ph) to the iminium ion-activated cyclohexenone
Having established reaction conditions for the organocatalytic
step and subsequent reduction, we investigated the scope of the
reaction (Table 2). Commencing with the E-selective reduction,
it was found that both enantiomers of the product E-6aa can be
isolated in 71À72% yield with enantioselectivities of 99% and
96% ee, respectively, by employment of quasi-enantiomeric
catalysts 4 (epi-9-amino-quinidine) and quasient-4 (epi-9-ami-
no-quinine).
Figure 2. Schematic representation of (a) the enantioselective addition
of a monofluorovinylic anion synthon and (b) the presented enantio-
selective organocatalytic approach for the formation of optically active
monofluoroalkenes. Het = heteroarylsulfone.
Substituents on the electrophile are also well tolerated as
seen by the employment of 5,5-dimethylcyclohex-2-enone (2b)
yielding product E-6ab in 60% yield with an enantiomeric excess
Figure 3. Mechanistic proposal for the diastereoselective formation of the monofluoroalkene moiety.
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Table 1. Optimization of the E:Z-Ratio of the
Monofluorovinylationa
Table 2. E-Selective Formation of Optically Active Mono-
fluorovinyl Compounds E-6a
dioxane:
alcohol
temp
reductant
[10 equiv]
additive
entry
[°C]
[3 equiv]
E:Zb
1
2
3
4
5
6
7
8
1:1 (MeOH)
1:1 (MeOH)
1:1 (MeOH)
10:1 (iPrOH)
10:1 (iPrOH)
10:1 (MeOH)
10:1 (EtOH)
neopentanolc
in dioxane
rt
0
NaBH4
NaBH4
LiBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
À
50:50
50:50
>98:<2
26:74
13:87
20:80
16:84
10:90
À
0
À
À
ZnCl2
ZnCl2
ZnCl2
ZnCl2
rt
rt
rt
rt
rt
a All reactions performed one-pot with: step 1: 1a (0.10 mmol), 2a
(0.20 mmol), 4 (0.01 mmol) in 1 mL of 1,4-dioxane at 45 °C. Step 2:
conditions in Table 1 applied. Full conversion obtained in both steps in
c
all cases. b Determined by 19F NMR. 20 equiv to 1a (v/v dioxane/
alcohol ≈ 4.6:1). BT = benzothiazole.
of 99% ee. Both ring-expanded and -contracted electrophiles
can be employed, forming products E-6ac and E-6ad in 58%
and 43% yield, with 88% and 98% ee, respectively. In all cases,
the products are formed in good to excellent diastereomeric
ratios (from 83:17 up to >98:<2), and the products can be
isolated as the pure E-isomer. Acyclic enones are also feasible
substrates for this reaction, as shown by the employment
of trans-crotonophenone 2e. The products E-6aeÀE-6ee
are formed in 67À83% yield with enantiomeric excesses of
97 and 98% ee, respectively. As compared to the cyclic
substrates, the E:Z-ratio is maintained at an excellent level
of up to 94:6.
Investigating the scope with respect to the nucleophiles 1, it
was found that nucleophile 1b bearing a 2-naphthyl moiety
can be employed forming E-6ba with excellent stereoselecti-
vities and isolated in 86% yield. Substituents on the aromatic
moiety can be of either electron-withdrawing or -donating
character, and independent of their position, the products
E-6caÀE-6fa are isolated in 62À68% yield with enantio-
selectivities between 95% and 99% ee. Alkyl-substituted
nucleophiles can also be employed; however, due to degrada-
tion in the reduction step, the product was only isolated in
33% yield as a 3:1 mixture of E-Z-isomers for the n-propyl
variant tested.
a All reactions performed with: step 1: 1 (0.20 mmol), 2 (0.40
mmol), 4 (0.02 mmol) in 1,4-dioxane (2 mL) at 45 °C. See
Supporting Information for further details. E:Z-ratios deter-
mined by 19F NMR. Yields are isolated yields of the pure
E-isomer. Ee determined by CSP-HPLC. b quasient-4 used as
catalyst. c 20 mol % catalyst 4 employed at 60 °C. d Reaction stops
at 80% conversion (determined by 1H NMR). e Performed at
f
The scope with respect to the Z-selective formation of
products Z-6 is outlined in Table 3, and proved to be as broad
as the one presented above for the E-selective protocol. As such,
the products Z-6 can be formed with E:Z-ratios of up to 10:90
50 °C. Performed with: step 1: 1 (0.10 mmol), 2e (0.40 mmol),
quasient-4 (0.02 mmol) in 1,4-dioxane (0.5 mL) at 60 °C. See
Supporting Information for further details. g Isolated as a mixture
of the E:Z-isomers.
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Table 3. Z-Selective Formation of Optically Active Mono-
fluorovinyl Compounds Z-6a
Figure 4. Formation of monofluorinated bicyclo[2.2.2]oct-5-en-2-ones
(see Supporting Information for detailed reaction conditions).
a All reactions performed with: step 1: 1 (0.20 mmol), 2 (0.40 mmol), 4
(0.02 mmol) in 1,4-dioxane (2 mL) at 45 °C. See Supporting Informa-
tion for further details. E:Z-ratios determined by 19F NMR. Yields are
isolated yields of the pure Z-isomer. Ee determined by CSP-HPLC. b 20
mol % catalyst 4 employed at 60 °C. c Reaction stops at 80% conversion
(determined by 1H NMR). d Isolated as a mixture of the E:Z-isomers.
e Performed at 50 °C. f Performed with: step 1: 1 (0.10 mmol), 2e (0.40
mmol), quasient-4 (0.02 mmol) in 1,4-dioxane (0.5 mL) at 60 °C. See
Supporting Information for further details.
and isolated as the pure Z-isomer in up to 69% yield with up to
98% ee, proving that the developed procedure gives access to
both E- and Z-isomers of the obtained products.
The absolute configuration of the obtained products was
determined by X-ray crystallography of E-6ca (see Supporting
Information for further details).
Figure 5. Mechanistic rationale for the observed E:Z-selectivities.
Formation of Enantioenriched Bicylic Compounds Con-
taining a Monofluorovinyl Moiety. The bicyclo[2.2.2]oct-5-
en-2-ones motif is present in a number of natural products,12 and
analogous compounds have been successfully used as intermedi-
ates in the synthesis of decaline compounds.13 Envisioning that
novel optically active monofluorinated bicyclo[2.2.2]oct-5-en-2-
ones 7 might be formed by an intramolecular aldol reaction
followed by a Smiles rearrangement (Figure 4),9f we subjected
the adduct 5aa to a variety of bases. Aqueous solutions of
carbonate bases are successful in forming product 7aa; however,
a desulfonylated side-product is consistently formed, presumably
by the addition of water to the heteroaryl moiety, thus resulting
in a diminished yield of ∼50% for 7aa. To circumvent this
problem, organic bases can be employed, and to our delight,
the desired product 7aa was formed exclusively when adding
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DABCO to the solution containing 5aa in a one-pot manner.
As seen in Figure 4, the products 7, containing a tetra-
substituted monofluoroalkene, can be formed with a variety
of aryl substituents on the double bond. Hence, both ortho
substituents (7ea) as well as the larger 2-naphthyl substituent
(7ba) are well-tolerated.
the proposed mechanism for the reduction step does not involve
the fluorine atom in particular, as its sole role is to be the
least bulky substituent. If this mechanism is correct, reduction of
a nonfluorinated adduct under the developed conditions should
result in similar control of E:Z-selectivity. As such, to provide
further evidence to the proposed mechanism, a control experi-
ment was performed with a nonfluorinated precursor. The
analogous outcome strongly supports the proposed mechanism,
as application of the aforementioned reduction conditions
provide access to either E-8 or Z-8 (Figure 6). Futhermore, these
experiments reveal that our developed reduction protocols can be
extended and optimized to yield nonfluorinated products 8 with
both E- and Z-configuration, enhancing our previously reported
procedures.9d
Reactions of Imines. The successful development of mono-
fluorovinylations of cyclic and acyclic enones prompted us to
investigate the possibility of developing a protocol for the
stereoselective formation of monofluorovinylated peptide
analogues. As outlined in Figure 7, we anticipated that
formation of such compounds could be accomplished by
initial phase-transfer catalyzed (PTC)14 addition of nucleo-
philes 1 to imines formed from precursors 9,15 followed by
reduction of the obtained adduct by procedures similar to
those developed above.
By employing tetrabutylammonium bromide (TBAB) as cata-
lyst the monofluorovinylation procedure could be successfully
extended to include imine electrophiles. The products are for-
med in good yields with high E:Z-selectivities, independent of the
side chain present. As shown, the valine, leucine, alanine, and
methionine derivatives are easily accessible, and the products
are isolated as the pure diastereomer. Moreover, the presence
of an easily removable carbamate protection group, either
tert-butyl (Boc) or benzyl carbamate (Cbz), makes these
products ideal for employment in further reactions, e.g.
peptide-coupling reactions.
Mechanistic Proposal. As a mechanistic rationale for the
E:Z-ratio in 6 (Tables 2 and 3) we assume the diastereoselectivity
of the reduction of intermediate 5 to determine the E:Z-ratio of
the alkene formed. As this reduction is an addition to a carbonyl
adjacent to an R-chiral center, we suggest that the stereochemical
outcome can be explained by the Felkin-Ahn and Cram chelation
models. Under Felkin-Ahn conditions, one would expect the
most electron-withdrawing substituent to be aligned perpendi-
cular to the carbonyl moiety in the most reactive conformation of
5. This provides a stabilization of the carbonyl-LUMO by
σ*(C-EWG) and π*(CO) overlap, rendering the carbonyl more
reactive toward nucleophilic attack. Figure 5 shows in the upper
scheme a model with the sulfone moiety in this position, based
on the observed stereochemical outcome. This leads to mono-
fluoroalkene E-3 as attack of the hydride equivalent is pre-
sumed to occur only in the conformer where the fluorine
atom is present near the B€urgiÀDunitz trajectory, as this
minimizes the steric repulsion. Under chelation control, inter-
mediate 5 would be forced out of its most reactive conformation,
as chelation between the carbonyl, Zn(II), and the heteroaryl-
sulfone moiety is now favorable (Figure 5, bottom). Attack from
the least hindered side does provide the monofluoroalkene with
Z-configuration as observed experimentally. As seen in the figure,
We next endeavored to further develop these reactions into
asymmetric organocatalytic versions. Screening a range of reac-
tion conditions (see Supporting Information for further
details) led to the development of an asymmetric organoca-
talytic formation of monofluorovinylated dipeptide analo-
gues (Figure 8). Whereas Z-10aa, bearing an aromatic side-
chain, can be isolated only with a moderate enantiomeric
excess of 64% ee, the aliphatic side chain of imine precursor
9b proved more suitable for the developed catalytic system.
As such, the leucine derivate E-10ab can be isolated in 83%
yield with an enantiomeric excess of 84% ee, employing the
quinine-derived catalyst 11.
Figure 6. Employment of nonfluorinated nucleophiles in the addition
and reduction steps. E:Z-Ratios are based on H NMR of the crude
samples. Z-8 was isolated as a mixture of the E:Z-isomers, and the yields
are given for two steps and based on the nucleophile.
1
Figure 7. Development of a highly stereoselective formation of dipeptide analogues 10. PG = protection-group.
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Table 4. Stereoselective Formation of Monofluorovinylated Dipeptide Analogues 10a
a All reactions performed with: step 1: 1 (0.10 mmol), 9 (0.20 mmol), TBAB (0.02 mmol) in CH2Cl2 (0.5 mL) with 120 μL of conc. aq K3PO4 at room
temperature. See Supporting Information for further details. E:Z-ratios determined by 19F NMR. Yields are isolated yields of the pure isomer. b Step 1
performed in waterÀice bath. Boc = tert-butyl carbamate. Cbz = benzyl carbamate.
Figure 8. Employment of nucleophiles 1 in the asymmetric organocatalytic formation of dipeptide analogues 10. Reactions performed as in Table 4 at
À30 °C with catalyst 11 (10 mol %) instead of TBAB. See Supporting Information for further details.
’ CONCLUSION
by utilization of these novel nucleophiles. Furthermore, exten-
sion of the concept by employing imine electrophiles allowed us
to develop an asymmetric organocatalytic formation of mono-
fluorovinylated dipeptide analogues.
In summary, we have developed a range of R-fluoro-β-keto-
benzothiazolesulfones applicable for highly stereoselective
monofluorovinylations. As proof of concept, we have employed
these nucleophiles in the formal organocatalytic addition of
monofluorovinyl moieties with both E- and Z-configuration to
a range of cyclic and acyclic enones. The resultant products
are formed from a common intermediate with up to excellent
E:Z-ratios, and in general isolated as pure diastereomers in good
to excellent yields (up to 86%) as well as enantiopurities (up to
99% ee). Suggested mechanisms based on classical models
provide a rationale for the E:Z-selectivities observed experimen-
tally. Moreover, a series of interesting, optically active mono-
fluorinated bicyclo[2.2.2]oct-5-en-2-ones have been synthesized
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
kaj@chem.au.dk
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’ ACKNOWLEDGMENT
(9) For reviews on the employment on sulfones in organocatalysis,
see e.g.: Nielsen, M.; Jacobsen, C. B.; Holub, N.; Paix~ao, M. W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2010, 49, 2668. (b) Alba,
A. N. R.; Companyꢀo, X.; Rios, R. Chem. Soc. Rev. 2010, 39, 2018. For
recent examples on the employment of β-keto-heteroarylsulfones in
organocatalytic reactions see e.g.: (c) Nielsen, M.; Jacobsen, C. B.;
Paix~ao, M. W.; Holub, N.; Jørgensen, K. A. J. Am. Chem. Soc. 2009,
131, 10581. (d) Paix~ao, M. W.; Holub, N.; Vila, C.; Nielsen, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2009, 48, 7338. (e) Jacobsen,
C. B.; Lykke, L.; Monge, D.; Nielsen, M.; Ransborg, L. K.; Jørgensen,
K. A. Chem. Commun. 2009, 6554. (f) Holub, N.; Jiang, H.; Paix~ao,
M. W.; Tiberi, C.; Jørgensen, K. A. Chem.—Eur. J. 2010, 16, 4337.
(10) For a review on the JuliaÀKocienski reaction see: (a) Aïssa, C.
Eur. J. Org. Chem. 2009, 1831. In addition see: (b) Pospíꢁsil, J. Tetrahedron
Lett. 2011, 52, 2348.
(11) For reviews on the use of primary amines as organocatalysts,
see e.g.: (a) Chen, Y. Synlett 2008, 1919. (b) Xu, L.; Luo, J.; Lu, Y. Chem.
Commun. 2009, 1807. (c) Erkkil€a, A.; Majander, I.; Pihko, P. M. Chem.
Rev. 2007, 107, 5416.
(12) See e.g.: (a) Dong, S.; Hamel, E.; Bai, R.; Covell, D. G.; Beutler,
J. A.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2009, 48, 1494. (b) Kuo,
Y. H.; Chen, C. H.; Huang, S. L. Chem. Pharm. Bull. 1998, 46, 181.
(c) Chien, S. C.; Chang, J. Y.; Kuo, C. C.; Hsieh, C. C.; Yang, N. S.; Kuo,
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Thanks are expressed to the Carlsberg Foundation and
OChemSchool for financial support. D.W. thanks the Deutsche
Forschungsgemeinschaft. T.Z. thanks the Swiss National Science
Foundation. Thanks are expressed to Dr. Jacob Overgaard for
performing the X-ray analysis.
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dx.doi.org/10.1021/ja110624k |J. Am. Chem. Soc. 2011, 133, 7398–7404