Full Paper
last three examples, in which the authors took a new approach
in the form of establishing a phase separation between the or-
ganic solution phase (containing the substrate together with
the chiral lipophilic anion) and the solid phase (containing the
insoluble stoichiometric cationic reagent). The poor solubility
of the latter precluded background reaction but did allow the
reaction with its salt with the chiral lipophilic anion.
Figure 3. Concept behind halonium-ion-promoted Wagner–Meerwein trans-
position of allylic alcohols, and the idea of inducing chirality by means of
a chiral counterion. Hal=F, Cl, Br or I.
The regio- and stereocontrolled functionalization of carbon–
carbon double bonds 1 is of primordial importance in organic
synthesis. Transition-metal-free electrophilic activation of ole-
fins has been largely dominated by halofunctionalization reac-
tions.[10] These reactions involve the capture of transient halira-
nium ions 2, formed from olefin/dihalogen association, by
inter- or intramolecular nucleophiles (Figure 2).[11]
rangements, operating through anionic phase-transfer technol-
ogy. The key practical aspects of the title transformation, such
as reaction optimization studies and the establishment of
a substrate scope will be combined with mechanistic aspects,
such as kinetic and isotopic kinetic data. Combined with linear
free energy relationships, this study will culminate at a reasona-
ble picture of the reaction mechanism.
Results and Discussion
Figure 2. Electrophilic halofunctionalization of alkenes, and the special case
With a small library of enantiopure (Ra)-BINOL-derived, 3,3’-bis-
aryl disubstituted phosphoric acids Ly (y=1–12) in hand, reac-
tion optimization studies were carried out next.[23] Optimization
experiments were carried out with the strained allylic alcohol
A1, Selectfluor as the fluorinating reagent, and the set of acids
Ly (see Table 1).
of an halocyclization reaction.
The halocyclization process (intramolecular nucleophile trap-
ping) represents the most studied halofunctionalization reac-
tion.[12] In sharp contrast to the exhaustively studied bromocyc-
lization process,[13,14a,b] engineering enantioselectivity in fluo-
ro-,[8,9,15] chloro-,[16] and iodocyclization[14] reactions remains
challenging and lacks generality in terms of substrate scope.
This constitutes an important handicap to the synthetic com-
munity due to the primordial role of fluorinated[17] and iodinat-
ed[18] organic molecules in natural products, pharmaceuticals
and agrochemicals. Iodinated compounds are also valuable
precursors that provide access to more complex molecular
frameworks.[19]
In the course of the preliminary catalyst screening per-
formed in toluene at ambient temperature, the employment of
highly sterically congested phosphoric acids L4–6, related to the
notorious (Ra)-TRIP (TRIP=3,3’-bis(2,4,6-triisopropylphenyl)-1,1’-
binaphthyl-2,2’-diyl hydrogenphosphate) scaffold,[24] turned out
to be crucial for accessing practical enantioselectivities (ca.
70% ee) of the product b-fluoro spiroketone B1 (Table 1, en-
tries 4–6). Interestingly, phosphoric acids bearing isopropyl (L4)
and cyclopentyl (L6) substituents at positions X and Y outper-
formed acid L5 that bears cyclohexyl groups at these same po-
sitions. The addition of Na2CO3 base turned out to be detri-
mental for the success of the title fluorination-induced semi-pi-
nacol rearrangement, in terms of both the yield and the enan-
tioselectivity. Thus, when employing phosphoric acid L4 in the
absence of the sodium carbonate additive (entry 8), a signifi-
cant drop in conversion and enantiomeric excess was noted.
This observation proves that it is the conjugate base of the
acidic precatalyst, a chiral lipophilic phosphate anion, which is
the catalytically active species in the title reaction.
Even less studied is the related halogenation-initiated semi-
pinacol rearrangement. In this last reaction, the transiently
formed a-hydroxy haliranium ion 4 undergoes a Wagner–Meer-
wein alkyl migration, leading to the formation of synthetically
prized b-halogenated ketones.[20]
Whereas the chlorination- and bromination-initiated
Wagner–Meerwein rearrangements of electron-rich cyclic enol
ethers were recently shown to be amenable to asymmetric cat-
alysis,[21] the development of truly enantioselective catalytic flu-
orination-[22] and iodination-initiated variants remains a great
challenge.
The fact that our reaction obeys the chiral anion phase-
transfer paradigm (PTC) was supported by the complete loss
of reactivity in the non-polar toluene solvent observed in the
absence of the phosphoric acid promoter (Table 1, entry 9).
Nevertheless, the reactivity could be recovered when passing
to the more polar acetonitrile solvent, a solvent that is known
to solubilize Selectfluor to some extent (entry 10). In this case,
the recovered b-fluoro spiroketone B1 was of course racemic.
It is important to point out here that both the enantioselec-
tivity as well as the diastereoselectivity of the present transfor-
mation are controlled by the catalyst structure. Thus, racemic
Reasoning that the postulated haliranium ion intermediate 4
bears a net positive charge (Figure 3), we were interested to
see whether a chiral anion (derived from a BINOL-phosphoric
acid, for example) could induce asymmetry into the subse-
quent Wagner–Meerwein rearrangement step.
The transposition of simple allylic alcohols 3 was of particu-
lar interest to us, as it would lead to the formation of valuable
all-carbon quaternary stereogenic centres. The present Full
Paper will deal with the description of the scope and limita-
tions of the halogenation-initiated Wagner–Meerwein rear-
&
&
Chem. Eur. J. 2015, 21, 1 – 24
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!
Romanov-Michailidis, Fedor
