Enantioselective organocatalytic iodination-initiated Wagner-Meerwein rearrangement

Article abstract of DOI:10.1021/ol402981z

The present manuscript describes a high-yielding enantioselective semipinacol transposition, initiated by an electrophilic iodination event. The title transformation makes use of the anionic phase-transfer catalysis (PTC) paradigm for chirality induction. Thus, when combined appropriately, the insoluble cationic iodinating reagent S₉ and the lipophilic phosphoric acid L₉ act as an efficient source of chiral iodine that performs the semipinacol transposition of strained allylic alcohols A _x to β-iodo spiroketones B_x in good yields and with high levels of diastereo- and enantio-induction. The product β-iodo spiroketones could be derivatized stereospecifically and without stereoerosion, giving rise to products inaccessible directly from a semipinacol rearrangement.

Full text of DOI:10.1021/ol402981z

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5890–5893
Enantioselective Organocatalytic
Iodination-Initiated WagnerꢀMeerwein
Rearrangement
ꢀ ꢀ
Fedor Romanov-Michailidis, Laure Guenee, and Alexandre Alexakis*
Department of Organic Chemistry, University of Geneva, quai Ernest Ansermet 30,
CH-1211 Geneva 4, Switzerland
Alexandre.Alexakis@unige.ch
Received October 16, 2013
ABSTRACT
The present manuscript describes a high-yielding enantioselective semipinacol transposition, initiated by an electrophilic iodination event. The
title transformation makes use of the anionic phase-transfer catalysis (PTC) paradigm for chirality induction. Thus, when combined appropriately,
the insoluble cationic iodinating reagent S9 and the lipophilic phosphoric acid L9 act as an efficient source of chiral iodine that performs the
semipinacol transposition of strained allylic alcohols Ax to β-iodo spiroketones Bx in good yields and with high levels of diastereo- and enantio-
induction. The product β-iodo spiroketones could be derivatized stereospecifically and without stereoerosion, giving rise to products
inaccessible directly from a semipinacol rearrangement.
The regio- and stereocontrolled functionalization of
carbonꢀcarbon double bonds is of primordial importance
in organic synthesis. Transition-metal-free electrophilic acti-
vation of olefins has been largely dominated by halofunction-
alization reactions.1 These reactions involve the capture of
transient haliranium ions, formed from olefin/dihalogen as-
sociation, by inter- or intramolecular nucleophiles.2 By far,
the halocyclization process (intramolecular nucleophile) re-
presents the most studied halofunctionalization reaction.3 In
sharp contrast to the exhaustively studied bromocyclization
process,4,7a,7b engineering enantioselectivity in fluoro-,5
chloro-,6 and iodocyclization7 reactions remains challenging
and lacks generality in terms of substrate scope. This con-
stitutes an important handicap to the synthetic community
due to the primordial role of iodinated organic molecules in
natural products, pharmaceuticals, and agrochemicals.8aꢀd
Iodinated compounds are also valuable precursors that pro-
vide access to more complex molecular frameworks.8e
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r
10.1021/ol402981z
Published on Web 11/06/2013
2013 American Chemical Society

Far less studied is the related halogenation/semipinacol
rearrangement cascade.9 In this last reaction, the transi-
ently formed haliranium ion undergoes a Wagnerꢀ
Meerwein alkyl migration, leading to the formation of
synthetically valuable β-halogenated ketones (Figure 1).
Whereas the chlorination- and bromination-initiated
WagnerꢀMeerwein rearrangements of electron-rich cyclic
enol ethers were shown to be amenable to asymmetric
catalysis,10 the development of enantioselective catalytic
fluorination- and iodination-initiated variants remains
underexplored.11 Very recently, we have proposed a solu-
tion to the above problem by adapting the anionic phase-
transfer catalysis (PTC) protocol to the fluorination/
semipinacol case.12 In the present manuscript, we wish to
report a new achiral-reagent/chiral-counterion catalytic sys-
tem that enables a highly stereoselective iodination/semipina-
col transposition sequence to take place. To the best of our
knowledge, a catalytic asymmetric protocol for the iodina-
tion-initiated WagnerꢀMeerwein rearrangement is unprece-
dented in the literature.
chloride at room temperature. To our great delight, the
iodination/semipinacol reaction sequence took place smoothly
and afforded the expected β-iodo spiroketone B1 as a single
diastereomer and in 91% isolated yield (Scheme 1). Seeking
a suitable asymmetric PTC system, we repeated the above
reaction in a less polar solvent (toluene) in the presence of a
base and catalytic amounts of the lipophilic chiral phospho-
ric acid L4 (TRIP).15 Disappointingly, even though the
reaction did proceed to completion, the recovered β-iodo
spiroketone was racemic.
Scheme 1. Optimization of the Iodinating Reagent S1ꢀ9
Figure 1. Concept behind enantioselective halonium ion-initiated
WagnerꢀMeerwein transposition of allylic alcohols. Hal = F, Cl,
Br, or I.
Next, given the remarkable success of Selectfluor in
anionic phase-transfer catalysis, we turned our attention
to DABCO-derived triply charged cations (S1ꢀ9) as po-
tential iodinating reagents (Scheme 1). These salts were
readily synthesizedusing experimental procedures adapted
from the literature.7b Dissapointingly, when employing S1,
the “exact” iodo analog of Selectfluor, no reaction was
observed under our previously established PTC conditions.
This observation could be tentatively explained by the
unfavored predissociation equilibrium of S1, generating
insufficient amounts of the monoligated iodine(I) intermedi-
ate required for reactivity with alkenes.13 Switching to the
bulkier and more lipophilic salts S2 and S3 turned out to be
beneficial for reactivity. When combined with catalytic L4 in
toluene, both of these iodinating reagents afforded full
conversion of A1 to B2, albeit with only insignificant levels
of asymmetric induction (ca. 60:40 e.r.).
We began our studies with the reaction of allylic cyclo-
butanol A1 with (collidine)2IþPF6 (S0) in methylene
ꢀ
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Org. Lett., Vol. 15, No. 22, 2013
5891

We speculated that one possible rationalization for the
low enantiomeric ratios observed with our PTC system
gravitated around the olefin-to-olefin halogen exchange
problem, known to occur between the transient iodonium
cations and leading to product racemization.14
Table 1. Optimization of the Reaction Conditionsa,f
In an attempt to solve for this problem, we were
intrigued by the possibility of further exploring the steric
and electronic parameters of the nitrogen substituent (R)
of the iodinating reagent (Scheme 1). Following this logic,
further fluorination of the benzene ring of the R substituent
afforded a more active reagent (S4), but the enantiomer ratio
remained unacceptably low (64:36 e.r.). Replacing the
benzene ring with the bulkier 9-anthracenyl substituent
(S5) led to a concomitant drop in yield and in stereoselectiv-
ity. Gratifyingly, switching to the more sterically demanding
2,4,6-tris(isopropyl)phenyl substituent (S6) improved the
enantiomeric ratio markedly (85:15 e.r.). A similar effect
was obtained when employing the branched benzhydryl-
based substituents (S8 and S9, both 86:14 e.r.). Of note,
increasing the size of the R substituent further by using the
2,4,6-tris(cyclopentyl)phenyl group (S7) instead of the 2,4,6-
tris(isopropyl)phenyl one completely inhibited the reactivity.
Encouraged by these preliminary results, we selected the
iodinating reagent S9 for further optimization studies.
A quick overview of synthetically accessible enantiopure
phosphoric acids L1ꢀ11, using toluene as the solvent and
Na2CO3 as the base, revealed L9 as being optimal (Table 1,
entry 9). Changing the base from Na2CO3 to Na3PO4
improved the enantiomeric ratio from 87:13 to 89:11,
accordingly (entry 12). Fluorinated aromatic solvents such
as PhF or PhCF3 led to quasi racemic product mixtures
(entries 13, 14). Including n-hexane into a binary solvent
mixture with toluene, which proved to be beneficial for the
related fluorination/semipinacol transposition,12 did not
increase the enantiomeric excess in the present iodination/
semipinacol reaction sequence (entry 18). The switch to the
less polar para-xylene solvent also did not increase the
enantiomeric excess (entry 15). Gratifyingly, when carrying
out the reaction in ethylbenzene as the solvent, an important
increase of the selectivity was observed (91:9 e.r.). Further
adjustments, including dilution of the reaction medium
coupled with extension of the reaction time, afforded the
optimal conditions for the title transformation (entry 20).
With the optimal reaction conditions being established, the
substrate scope of our newly developed iodination-initiated
WagnerꢀMeerwein rearrangement was investigated. To this
end, strained allylic alcohols A1ꢀ25 were reacted with iodinat-
ing reagent S9 and catalytic amounts of enantiopure phos-
phoric acid L9 under biphasic Na3PO4/ethylbenzene
conditions. The results are summarized in Scheme 2.
yieldb
entry
Lx
base
solvent
PhMe
[%]
erc
1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L9
L9
L9
L9
L9
L9
L9
L9
L9
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
64
8
59:41
n.d.
2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhF
3
78
68
0
54:46
86:14
n.d.
4
5
6
22
66
67
73
52
60
76
86
88
74
79
82
70
85
87
87:13
82:18
79:21
87:13
66:34
37:63d
89:11
53:47
52:48
88:12
84:16
85:15
87:13
91:9
7
8
9
10
11
12
13
14
15
16
17
18
19
20e
PhCF3
p-Xyl
PhH
(i-Pr)2O
PhMe/n-Hex 1:1
PhEt
PhEt
93:7
a Reaction conditions: see Supporting Information. b Isolated yield
after flash chromatography. c Determined by chiral HPLC. d The oppo-
site enantiomer was obtained. e Molar concentration decreased to
0.05 M; reaction time increased to 72 h; S9 reduced to 1.3 equiv. f A
single diastereoisomer was obtained in each case. p-Xyl = para-xylene.
n-Hex = n-hexane. n.d. = not determined.
the enantioselective iodination/ring-expansion reaction se-
quence, which occurred equally well with scaffolds based on
tetralone (X = CH2, e.g. B1), chromanone (X = O, e.g. B8),
and benzosuberone (X = CH2CH2, B25) ring systems. A
distinct feature of the iodination reaction is its high tolerance
toward substitution at positions C5 (e.g., B4), C6 (e.g., B22),
and C7 (e.g., B24) of the phenyl ring. A much narrower
substitution tolerance was observed for the fluorination
reaction. The title enantioselective transformation was also
less sensitive to substituent electronic effects when compared
to the previously reported fluorination analog.
Both, three- (n = 0, products B13ꢀ21) and four-membered
(n = 1, products B1ꢀ12) allylic alcohols were amenable to
(14) (a) Brown, R. S.; Nagorski, R. W.; Bennet, A. J.; McClung,
R. E. D.; Aarts, G. H. M.; Klobukowski, M.; McDonald, R.; Santarsiero,
B. D. J. Am. Chem. Soc. 1994, 116, 2448–2456. (b) Neverov, A. A.; Brown,
R. S. J. Org. Chem. 1996, 61, 962–968. (c) Brown, R. S. Acc. Chem. Res.
1997, 30, 131–137.
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Goddard, R.; List, B. Synlett 2010, 14, 2189–2192.
(16) The stereochemistry of compound B8 was confirmed by X-ray
diffraction analysis. CCDC 965243 contains all of the crystallographic
data for this paper. These data are available free of charge from The
Cambridge Crystallographic Data Centre under www.ccdc.cam.ac.uk/
data_request/cif.
5892
Org. Lett., Vol. 15, No. 22, 2013

Scheme 2. Substrate Scope of the Iodination/Semipinacol Re-
action Sequence
Scheme 3. Stereospecific Derivatization of the Products
sense of absolute induction is opposite to that observed
for the related fluorination-initiated WagnerꢀMeerwein re-
arrangement.12 The relative configuration was consistent
with selective migration of the CꢀC bond that is anti to the
iodonium bridge.
Very importantly, the hereby disclosed transformation
was readily amenable to scale-up. Thus, allylic alcohol A8
was converted into the corresponding spiro β-iodoketone
B8 in excellent yield and without a drop in the enantios-
electivity (Scheme 3). Furthermore, two product β-iodo-
ketones (B8 and B9) were subjected to an SN2 reaction with
sodium azide. Under optimized experimental conditions,
the reaction took place stereospecifically and products
C
8ꢀ9 were recovered in respectable yields.
In conclusion, we have shown that an enantioselective
iodination-initiated WagnerꢀMeerwein transposition of
strained allylic alcohols is feasible under phase-transfer
conditions, when employing an appropriate achiral-reagent/
chiral-counterion catalytic system. The observed stereo-
selectivities reported to date are the best for this type of
reaction. Kinetic and computational studies, aimed at
shining light on the stereodivergency between the iodina-
tion and the fluorination reactions, are currently underway
in our laboratory.
Supporting Information Available. Detailed experimen-
tal procedures, spectroscopic characterization of newly
synthesized compounds, and chiral HPLC and SFC
chromatograms. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 2. X-ray crystal structure of B8 (ellipsoids set at 50%).16
Single crystals of B8 were grown for X-ray diffraction
analysis (Figure 2).16 It is fascinating to note that, for an
identically configured enantiopure phosphoric acid, the
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5893