Spontaneous resolution of julia-kocienski intermediates facilitates phase separation to produce Z - And e -monofluoroalkenes

Article abstract of DOI:10.1021/jacs.5b02112

The monofluoroalkene motif is important in drug development as it serves as a peptide bond isostere and is found in a number of biologically active compounds with various pharmacological activities. Direct olefination of carbonyl compound is a straightfor

Full text of DOI:10.1021/jacs.5b02112

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Spontaneous Resolution of Julia-Kocienski Intermediates Facilitates
Phase Separation to Produce Z- and E‑Monofluoroalkenes
Yanchuan Zhao, Fanzhou Jiang, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The monofluoroalkene motif is important in
drug development as it serves as a peptide bond isostere and is
found in a number of biologically active compounds with
various pharmacological activities. Direct olefination of carbon-
yl compound is a straightforward way to prepare mono-
fluoroalkenes; however, these methods often result in a
mixture of Z- and E-isomers that cannot be easily separated.
We discovered a unique spontaneous resolving reaction that simultaneously addresses the problems in the synthesis and
separation of Z- and E-monofluoroalkenes. The reaction is accompanied by a highly efficient spontaneous kinetic resolution and
phase labeling of monofluoroalkene precursors which allows the separation of Z- and E-monofluoroalkenes by liquid−liquid
extraction. The application of the method is demonstrated by the synthesis and separation of potential anticancer agents, which
are inseparable by HPLC.
Moreover, as fluorine is an isostere of hydrogen, monofluor-
oalkenes are promising alternatives to their nonfluorinated
analogues when pursuing novel bioactive compounds.7
Olefination of carbonyl compounds is one of the most
straightforward methods to prepare various alkenes.8 Although
both Z and E nonfluorinated alkenes are easily accessible
through the Wittig, Horner−Wadsworth−Emmons or modified
Julia reaction, tuning the Z/E selectivity of a monofluoroolefi-
nation reaction remains challenging.9 Furthermore, as a result
of the difficulty in separation, monofluoroalkene products are
often obtained and characterized as an inseparable mixture of Z
and E isomers.9f−h This is obvious from the fact that Z/E ratio
of the monofluoroalkene products is often the same prior to
and after purification. Extractive separation of Z- and E-
monofluoroalkenes generated from carbonyl olefination re-
action via the above-mentioned strategy is very appealing
(Scheme 1); however, the realization of this idea is hampered
by the lack of selective phase labeling reaction of the E- or Z-
monofluoroalkene.10 Herein, we report a spontaneous resolving
reaction that simultaneously addresses the challenges in the
synthesis and separation of Z- and E-monofluoroalkenes. The
reaction is accompanied by a highly efficient spontaneous
kinetic resolution and phase labeling of a pair of diastereomeric
monofluoroalkene precursors which allows the separation of Z-
and E-monofluoroalkenes by liquid−liquid extraction.
INTRODUCTION
■
Stereoisomers usually possess different biological activity
accompanied by relatively similar physical and chemical
properties,1 thus making their separation important but
challenging. Chromatographic methods are typically required
to allow the separation of the stereoisomers, but these
technologies are expensive and laborious.2 Liquid−liquid
extraction is one of the most commonly used workup
procedures in organic synthesis, which partitions a mixture
into different liquid phases.3 It represents as an ideal separation
technology in terms of simplicity and low cost. Therefore,
extractive separation of stereoisomers is highly desirable and
attracts great interest.4 The key elements that lead to a
successful extractive separation of stereoisomers comprise a
kinetic resolution of the isomers and a phase labeling of one
isomer to allow its transfer from organic phase to aqueous or
fluorous phase (Scheme 1).5 As the kinetic resolution step must
Scheme 1. Strategy for Extractive Separation of
Stereoisomers
be efficient enough to enable a satisfactory separation of both
isomers, most of the reported examples of extractive separation
rely on enzymatic kinetic resolution.5
Monofluoroalkene is recognized as mimetic of the peptide
bond and widely used as a structural or mechanistic probe in
biological studies.6 As a result of its enhanced stability toward
proteases, the monofluoroalkene-bearing protein-based drug is
expected to have a longer circulation time in the body.
Despite being of a similar size to hydrogen atom, fluorine
atom often carries a significant negative charge which makes it
behave as a bigger substituent than hydrogen during a reaction.
As a result, the control of the Z/E selectivity of a fluorinated
Received: February 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b02112
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Article
alkene is different from their nonfluorinated analogues. We
have recently revealed that difluoromethyl 2-pyridyl sulfone (2-
PySO2CF2H) displayed a superior performance than other
heteroaryl sulfones in Julia-Kocienski difluoroolefination
reactions.11 Improved reactivities were also observed in the
reactions with alkyl halides, imines and lactones.12 The striking
effect of 2-pyridyl(sulfonyl) group in synthesizing diversified
organofluorine compounds prompted us to examine its
potential in preparing stereoisomerically pure monofluoroal-
kenes.
RESULTS AND DISCUSSION
■
We began our investigation by preparing the monofluorinated
2-pyridyl benzyl sulfone (1a) by fluorination using N-
fluorobenzenesulfonimide (NFSI) (Scheme 2).13 Initial studies
Scheme 2. Preparation of the Monofluoroolefinating
Reagent in This Study
using 2-naphthaldehyde (2a) as a model substrate revealed that
1a displayed a good reactivity and gave the monofluoroalkene
product 3a in good yield, while the Z/E selectivity was not
satisfactory even after screening a series of solvents and bases.
Although this result seemed to support the fact that the control
of the Z/E selectivity in monofluoroolefination of carbonyl
compounds is a formidable task, we were intrigued by the
observation that Z/E selectivity of our reaction varied if
different workup procedures were employed (Scheme 3). The
Scheme 3. Distinct Z/E Selectivity Observed with Different
Workup Procedure
Figure 1. Proposed explanation of the kinetic resolution of sulfinate
intermediate 5a.
crystallography (as shown in Figure 1b). This result revealed
that the aqueous soluble species with a 19F NMR of −181 ppm
is the corresponding sulfinate salt 5a-E (Figure 1a). With the
above information, the key elements of the mechanism of this
reaction are described as following: (1) the sufinate salts 5a-Z
and 5a-E produced from Smiles rearrangement14 exhibit
distinct stability. (2) Intermediate 5a-Z spontaneously and
rapidly decomposed to monofluoroalkene 3a-Z at room
temperature (Figure 1d, (1)), whereas its diastereomeric
isomer 5a-E only broke down upon addition of an acid (Figure
1d, (2)). In other words, a kinetic resolution of the sulfinate
intermediates 5a occurred as a result of distinct energy barriers
for decomposition of intermediates 5a-Z and 5a-E.
We realized that this reaction simultaneously possesses
characters of spontaneous resolution and phase labeling/
switching that are desirable for an extractive separation of
stereoisomers (as shown in Scheme 1). With this mechanistic
information, we speculated on the possibility of an extractive
separation of Z- and E-monofluoroalkenes, the protocol of
which is depicted in Figure 2. The key element that led to the
success of this protocol is the aqueous soluble nature of
sulfinate intermediate 5-E that allows its separation from the
Z to E ratio in the reaction quenched with aqueous
hydrochloric acid (HCl, 3 M) was 1.14:1, while it changed to
>99:1 when water was used instead of HCl. Because in both
cases, a similar yield of isomer 3a-Z was obtained, we assumed
that monofluoroalkene 3a-E was generated only when the
reaction system became acidic. Unfortunately, the attempt to
isolate the compound correlated to the production of 3a-E was
not successful by column chromatography. To gain more
insight into this interesting observation, we monitored the
current monofluoroolefination reaction via 19F NMR (Figure
1c). Two new species was observed when the reaction was
warmed to ambient temperature. The doublet at −115 ppm
was identified as the monofluoroalkene 3a-Z (Figure 1a).
Interestingly, instead of the anticipated product 3a-E which
should appear at −95 ppm (Figure 1b), an unknown species
with a doublet signal at −181 ppm was observed. Direct
isolation of this species is difficult as a result of its aqueous
soluble nature. By treatment with CH3I, a new species with a
19F NMR of −173 ppm was produced, the structure of which
was determined to be a methylated sulfone (6a-E) by X-ray
B
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Table 1. Synthesis and Separation of Z- and E-
b
Monofluoroalkene with Reagent 1a
Figure 2. Schematic illustration of the protocol for the synthesis and
separation of Z- and E-monofluoroalkenes.
monofluoroalkene product 3-Z by liquid−liquid extraction.
After the separation of 3-Z, the other alkene 3-E was generated
by treatment of 5-E with an acid. In addition to a highly
efficient kinetic resolution of the sulfinate intermediates, we
were also aware that the sulfinate 5-E has to be sufficiently
stable during the extraction that is generally performed at
ambient temperature. As the Li−O bond is the strongest
among M-O bonds (M = Li+, Na+, K+), we surmised the use of
a lithium as the counterion should impart the desired stability
of sulfinate 5-E. Furthermore, to achieve a highly stereo-
selective transformation of sulfinate 5-E to the alkene 3-E, a
suitable acid was required. After a survey of reaction conditions,
we found the use of lithium bis(trimethylsilyl)amide
(LiHMDS) as the base and p-toluenesulfonic acid monohydrate
(TsOH·H2O) as the acid allows the realization of the above-
mentioned protocol (Figure 2). Under the optimized
conditions, monofluoroolefination of 2a produced monofluor-
oalkene 3a-Z in 46% yield (Z/E > 99:1) and its isomer 3a-E in
37% yield (Z/E < 1:99). We next applied this protocol in
accessing structurally diverse Z- and E-monofluoroalkenes. As
shown in Table 1, both Z- and E-isomers of monofluoroalkenes
could be obtained in highly geometrically enriched form using
this spontaneous resolving reaction. The olefination reactions
proceeded smoothly in the presence of either electron-donating
or electron-withdrawing groups. The subsequent liquid−liquid
extraction allowed the facile separation of the Z and E isomers.
Pharmaceutically important heteroaromatics such as pyridine
and thiophene are also compatible with the current protocol
(Table 1, 3g and 3n). Satisfactory separation was also achieved
with monofluoroalkenes derived from enolizable aliphatic
(Table 1, 3m) and α,β-unsaturated aldehydes (Table 1, 3o),
thus demonstrating the broad applicability of the current
method. Notably, the Z to E ratio of most monofluoroalkene
product 3-E (3a-E, 3c-E, 3d-E, etc.) is equal or lower than 1:99,
while lower selectivity of product 3-E was observed in the
reactions with electron richer aldehydes (2b, 2l−2o). In these
cases, zwitterionic intermediates were likely to be involved in
decomposition of sulfinate intermediate of 5-E in addition to
the regular antielimination pathway.9b,15
To evaluate the influence of the substituent on our approach,
we prepared a variety of α-fluoro-2-pyridylsulfone reagents 1
(Table 2) and used 2-naphthaldehyde as a model substrate.
Similar to the results obtained with reagent 1a, both Z and E
monofluoroalkenes 4-Z and 4-E were obtained in highly
geometrically enriched form (Table 2).
Notably, the present methodology simultaneously meets the
demanding expectations of simplicity and efficiency in the
synthesis and the separation. No catalyst is required for kinetic
resolution and no additional reagent or special solvent is
necessary for the phase labeling/switching. All of the desired
elements for extractive separation of ismoers are contained in
the starting materials of the reaction. In this system, the starting
materials are first phase labeled to produce two aqueous soluble
a
b
An amount of 2.2 equiv of LiHMDS was used. Experiments were
performed with 1a (1.0 mmol), aldehyde 2 (1.2 mmol) and LiHMDS
(1.8 mL, 1.0 M in THF) in DMF/HMPA (3.3 mL, v/v = 10:1).
Isolated yields were reported. Z/E ratio was determined by 19F NMR
analysis of the crude material and was given in parentheses.
precursors of the alkene products (sulfinate intermediates) and
one of the precursors is spontaneously phase delabeled and
goes into the organic phase.
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Table 2. Synthesis and Separation of Z- and E-
Monofluoroalkene with Structurally Diverse Reagents 1
Scheme 4. Synthetic Applications of the Current
Spontaneous Resolving Reaction
a
a
Experiments were performed with 1 (1.0 mmol), aldehyde 2a (1.2
mmol) and LiHMDS (1.8 mL, 1.0 M in THF) in DMF/HMPA (3.3
mL, v/v = 10:1). Isolated yields were reported. Z/E ratio was
determined by 19F NMR analysis of the crude material and was given
in parentheses
the increasing expectations for economy and efficiency during
synthesis and separation. We expect this strategy will find wide
applications in life sciences and related fields, facilitate the drug
screening process, and stimulate further exploration of novel
spontaneous resolving systems.
To demonstrate the utilities of the current spontaneous
resolving reaction in accessing both Z- and E-monofluor-
oalkenes via extractive separation, we applied it to the
preparation of the fluorinated combretastatin analogues.
Combretastatin A-4 is one of the most potent antimitotic
agents which possess a strong cytotoxicity against various
cancer cells.16 Fluorinated combretastatin is thus interesting
and had been synthesized through a multistep sequence.17 It
was found that the Z and E isomers could not be separated by
preparative HPLC. In contrast, our protocol employing reagent
1g smoothly afforded fluorinated analogues of combretastatin
A-4 (3p-E) and its isomer (3p-Z), in highly geometrically
enriched form (Scheme 4, reaction (1)). Notably, the reactive
phenol group was tolerated in the current reaction, which
mitigated the need of functional group protection. In a similar
way, the fluorinated analogues of anticancer agents DMU-211
(3q-Z)18 and its isomer (3q-E), could also be prepared
(Scheme 4, reaction (2)). Given that both isomers are often
required in the screening of pharmaceutical activity, fast access
to both Z and E monofluoroalkenes is an additional benefit of
the current protocol.
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic data in CIF format. Synthetic procedures and
characterization of compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*jinbohu@sioc.ac.cn.
■
Notes
The authors declare the following competing financial
interest(s): The authors have filed a patent on this technology.
ACKNOWLEDGMENTS
■
We thank J. A. Kalow and C. Ni for critical reading of the
manuscript and Y. Yang for helpful discussion. This work was
supported by the National Basic Research Program of China
(2015CB931900, 2012CB215500), the National Natural
Science Foundation of China (21372246, 21421002), Shanghai
QMX program (13QH1402400) and the Chinese Academy of
Sciences.
CONCLUSIONS
■
In conclusion, we have discovered a spontaneous resolving
reaction that allows the synthesis and the separation of the Z-
and E-monofluoroalkenes. No catalyst is required for kinetic
resolution and no additional reagent or special solvent is
necessary for the phase labeling/switching. The current
methodology demonstrates the feasibility of spontaneous
resolving reactions and represents a new strategy that meets
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