Enantioselective Lewis base catalyzed phosphonyldifluoromethylation of allylic fluorides using a: C -silyl latent pronucleophile

Article abstract of DOI:10.1039/d0cc01815e

The first enantioselective phosphonyldifluoromethylation is enabled by the use of diethyl (difluoro(trimethylsilyl)-methyl)phosphonate reagent as a latent pronucleophile in the Lewis base catalyzed substitution of allylic fluorides. The reaction proceeds

Full text of DOI:10.1039/d0cc01815e

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Enantioselective Lewis Base Catalyzed
Phosphonyldifluoromethylation of Allylic Fluorides Using C-Silyl
Latent Pronucleophile
Received 00th January 20xx,
Accepted 00th January 20xx
You Zi, Markus Lange and Ivan Vilotijevic*
DOI: 10.1039/x0xx00000x
The first enantioselective phosphonyldifluoromethylation is
enabled by the use of diethyl (difluoro(trimethylsilyl)-
methyl)phosphonate reagent as a latent pronucleophile in Lewis
base catalyzed substitution of allylic fluorides. The reaction
proceeds as
a kinetic resolution to produce both the
difluoromethylphosphonate products and the remaining fluorides
in good yields and with high stereoselectivity. The use of cinchona
based alkaloid catalysts enables the facile synthesis of both
enantiomers of the difluoromethylphosphonate products.
Difluoromethyl group, an oxygen bioisoster and a lipophilic
hydrogen-bond donor, is commonly used in medicinal
chemistry as a replacement for hydroxyl groups that improves
the properties of biologically active molecules.1 In a similar vein,
difluoromethylphosphonate motifs (–CF2P(O)(OR)2) have
emerged as metabolically stable bioisosters of phosphates.2
They are surprisingly resistant to hydrolysis and therefore
bioavailable unlike the typical phosphate analogues. The
phosphonic acids mimic the tetrahedral transition state in
hydrolysis of peptides which may also be the basis for biological
activity of numerous difluoromethylphosphonate containing
enzyme inhibitors.3 Pioneering examples include protein
tyrosine phosphatase (PTP) inhibitors (
phosphorylation inhibitors (
and analogues of phosphoenolpyruvate (
A
, Scheme 1),4 STAT3
6
B
),5 mimics of sugar phosphates (
C)
D
).7 The resulting
demand for difluoromethylphosphonates has inspired the
development of strategies to introduce this structural motif into
drug like molecules (Scheme 1b).8 These include nucleophilic
additions and substitutions with difluoromethylphosphonato
anion with suitable electrophiles,9 additions of the
difluoromethylphosphonato radical to π-systems,10 and the
transition metal catalyzed coupling reactions for synthesis of
aryldifluoromethylphosphonates.11 Despite the abundance of
Scheme
1 (a) Examples of biologically active difluoromethylphosphonates (b)
Comparison of this work with the previous methods for phosphonyldifluoromethylation
and the use of latent (pro)nucleophiles in Lewis base catalysis.
currently limited to substrate controlled diastereoselective
reactions.9c,9g A catalyst controlled enantioselective method to
introduce difluoromethylphosphonates while creating and
controlling the configuration of an adjacent stereogenic center
would be an enabling factor for further studies of this important
bioisostere.12 With this in mind, we set off to develop a method
to produce such chiral bioisosteres of alkyl or allyl phosphates
in enantioselective fashion.
naturally
occurring
chiral
organophosphates,
the
stereoselective methods to prepare difluoromethylpho-
sphonates featuring an adjacent stereogenic center are
Allylic substitutions have long served as a powerful tool for
stereoselective synthesis both as transition metal and Lewis
base catalyzed reactions, the latter considered an important
part of the green chemistry toolbox.13 The most common
a. Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller
University Jena, Humboldtstr. 10, 07743 Jena, Germany. Email:
ivan.vilotijevic@uni-jena.de.
† Electronic Supplementary Information (ESI) available: Detailed experimental
procedures and characterization data for new compounds. See
DOI: 10.1039/x0xx00000x
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requirement for higher concentration of the fluoriVdieewtAhratictlecOonulilnde
drive kinetic resolution to completion DwOiI:th10.1r0e3s9p/eDc0tCCto018t1h5eE
reagent, further optimization studies were focused on reactions
using equimolar quantities of allylic fluoride and the reagent
(Scheme 2b). The variables in reaction conditions screen
included: the identity of chiral catalyst, catalyst loading,
reaction solvent, temperature and concentration (for details of
optimization studies please see supporting information). In 5:1
mixture of dioxane and THF at 0 °C with 10 mol% (DHQD)2PHAL
catalyst, the reactions of 1a and
2 proceeded to close to 50%
conversion after 51 hours and afforded the allylation product
3a in 47% yield and 98:2 ratio of enantiomers (Scheme 2b).
Scheme 2 Early optimization studies and the kinetic resolution of 1a.
Lewis base catalyzed allylic substitutions utilize Morita-Baylis-
Hillman adducts as electrophiles,13c,13d but the scope of these
reactions for N- and C-centered nucleophiles is limited.14 To
address these challenges, we introduced the concept of latent
nucleophiles, molecules that are not nucleophilic themselves
but can be activated to act as nucleophiles in Lewis base
catalyzed reactions.15 C- and N-trialkylsilyl latent
(pro)nucleophiles16 undergo enantioselective Lewis base
catalyzed allylation with allylic fluorides (Scheme 1b).15,17 In
these reactions, the formation of the activated nucleophile
depends on the decomposition of the silicate intermediate
formed by nucleophilic addition of the fluoride to the silyl group
of the latent pronucleophiles.15a,17a,18 We hypothesized that this
strategy could be generally applicable to a variety of stabilized
C-nucleophiles and useful in addressing specific synthetic
problems.
Here,
we
report
that
(difluoro(trime-
thylsilyl)methyl)phosphonates serve as versatile latent
pronucleophiles in Lewis base catalyzed substitutions of allylic
fluorides and enable the development of the first
enantioselective method to introduce (diethoxyphospho-
ryl)difluoromethyl group, while controlling the configuration of
the adjacent stereogenic center.
The feasibility of our approach was evaluated using
commercially available diethyl (difluoro(trimethylsilyl)methyl)-
phosphonate
2 in DABCO catalyzed allylic substitution of allylic
fluoride 1a, derived from the Morita-Baylis-Hillman alcohol
adduct of acrylic ester and benzaldehyde (Scheme 2a). Good
yields in this reaction were achieved only if excess of the latent
pronucleophile
2 was used to increase the conversion of the
fluoride to the corresponding (difluoromethyl)phosphonate 3a
.
Accordingly, the initial optimization efforts using chiral Lewis
base catalysts were made with superstoichiometric quantities
of 2. In the presence of (DHQD)2PHAL catalyst, most reactions
proceeded with good enantioselectivity but, despite the use of
excess of the reagent, yields for the desired allylation product
remained close to, but below 50%. This was indicative of a
kinetic resolution scenario,17a where one of the enantiomers of
allylic fluoride readily reacts with the chiral catalyst while the
other enantiomer remains unchanged.
To reconcile the need for superstoichiometric quantities of
the reagent that would increase conversion rates and the
Scheme 3 Enantioselective (DHQD)2PHAL catalyzed allylic substitution of allylic fluorides
1 using 2 as the latent pronuclephile. Selectivity factor19 (s) was based on recovered 1.
2 | J. Name., 2012, 00, 1-3
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Closely monitoring the reaction progress showed that the ratio a starting material to produce R-3i with same stereoselectivity
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DOI: 10.1039/D0CC01815E
of enantiomers in product remained nearly constant and in 80% yield in the presence of (DHQ)2PHAL.
throughout the reaction, but that of the allylic fluoride steadily
increased with time/conversion (Scheme 2b).
In addition to serving as a bioisostere of phosphates,
difluoromethylphosphonate strongly influences conformational
Upon optimization of the reaction conditions, the reaction preferences of the product which can be exploited to control
scope for allylic fluorides was evaluated (Scheme 3). The low stereoselectivity in subsequent transformation. For example,
reaction rates allowed for close monitoring of the kinetic simple hydrogenation of analogues containing N-heterocycles
resolution reactions by NMR and/or HPLC on chiral stationary instead of the difluoromethylphosphonate proceeds with low
phase. The reactions were allowed to run until there were no diastereoselectivity (1.4:1)15b while the same reactions of
further changes in the er of the remaining allylic fluoride or difluoromethylphosphonate analogues afford only the syn
when it reached the level equal or higher than 99:1. A range of diastereomer of
6 in nearly quantitative yield of 96% (Scheme
esters, including methyl, ethyl, n-butyl, benzyl and t-butyl esters 5a).
(
1a
products S-3a
enantioselectivity (95:5 to 98:2 er). The presence of electron by examining the DABCO-catalyzed reactions of allylic fluoride
withdrawing groups in allylic fluorides 1g 1l noticeably 1a with the related latent pronucleophiles: TMS-
increased the reaction rates and the difluoromethane and the diethyl (1-(trimethylsilyl)ethyl)pho-
(difluoromethyl)phosphonate products S-3g 3l were isolated in sphonate (Scheme 5b). failed to react with the allylic fluoride
both good yields (38-55%) and enantioselectivities (90:10 to while the phosphonate containing alkylsilane afforded the
96:4 er). Allylic fluorides featuring halogen substituents 1m 1p desired product although in low yields (unoptimized results).
were also well tolerated under the optimal conditions, and all This indicates that the formation and decomposition of the
gave the products S-3m 3p in good yields (42-49%,) with silicate intermediate may be the determining factor for the
-
1e), were investigated and converted to the corresponding
The effects of the fluorine atoms and the phosphonate on
-
3e in good yields (34-47%) with good the stability of the activated nucleophile were briefly explored
-
7
-
8
7
8
-
,
9
-
excellent degrees of stereocontrol (95:5 to 97:3 er). The outcome of the reaction.
reactions with allylic fluorides bearing electron rich aromatic
substituents 1q-1u were subsequently carried out. These
uniformly required longer time to reach half-conversion but
ultimately led to satisfactory outcomes with yields between
30% and 45% and enantiomeric ratios between 94:6 and 97:3.
Installing alkyl instead of aryl substituents lowered the reaction
rates to synthetically impractical level (3f). In most reactions,
the enantiomeric ratio for the remaining ally fluorides R-1 was
99:1 er or higher. Absolute configuration of the products was
assigned by analogy to similar reactions using (DHQD)2PHAL.
Switching the catalyst to (DHQD)2PHAL pseudoenantiomer,
(DHQ)2PHAL, unsurprisingly resulted in the preferential
formation of the other enantiomer although with slightly lower
stereoselectivity (4:96 er for R-3a and 8:92 for R-3i
,
unoptimized results, Scheme 4). Furthermore, the
enantioenriched allylic fluoride R-1i (>99:1 er) recovered from
the (DHQD)2PHAL catalyzed reactions could be used as
Scheme
5 Diastereoselective hydrogenation of S-3q and influences of the
difluoromethylphosphonate on stereochemical outcome. Attempted reactions of 1a
with related latent pronucleophiles.
In conclusion, the first enantioselective method to introduce
a phosphate bioisostere, -CF2P(O)(OR)2, has been developed by
using diethyl (difluoro(trimethylsilyl)me-thyl)phosphonate
reagent
2 as a latent pronucleophile in Lewis base catalyzed
substitution of allylic fluorides. The reactions proceed as kinetic
resolution of the racemic fluorides which affords both the
difluoromethylphosphonate product and the recovered allylic
fluoride in good yields and with high enantiomeric ratios. The
reactions are operationally simple, use commercially available
reagent and catalysts and transform readily available Morita-
Baylis-Hillman
fluorides
to
the
stable
difluoromethylphosphonates. Both enantiomers of the product
can be readily accessed and they are amenable to further
stereoselective transformations owing to the conformational
effects of the difluoromethylphosphonate.
Scheme 4 Comparative test with (DHQ)2PHAL instead of (DHQD)2PHAL and reaction with
enantioenriched allylic fluoride.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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191, 63; (e) W. Huang, J. Chen, D. Hong, W. Chen, X. Cheng, Y.
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This work was supported by the Carl-Zeiss Foundation
(endowed professorship to I.V.), Friedrich Schiller University
Jena and the State of Thuringia (graduate fellowship to M.L.) is
gratefully acknowledged. We thank Dr. Peter Bellstedt, and Dr.
Nico Ueberschaar for their support with NMR and MS analysis.
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16 We use the term latent nucleophile for N-silyl compounds
because the silyl group attenuates the nucleophilicity of the
otherwise nucleophilic N-H analogue. For C-centered
nucleophile, the preferred term is latent pronucleophile
because both the C-silyl compound and the C-H analogue are
normally not nucleophilic (latent) and are therefore only
pronucleophiles.
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the most stable anion/weakest base. For N-trialkylsilyl latent
nucleophiles, this is always the N-centered anion by virtue of
all N-H compounds being more acidic than the corresponding
alkanes. The same strategy applied to C-trialkylsilyl latent
ponucleophiles, requires the stabilized carbon nucleophile to
be produced to avoid selectivity issues (stabilized C-
nucleophile vs. alkyl nucleophile). Shibata has shown that CF3
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There are no conflicts to declare.
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