Organocatalytic Enantioselective Acyloin Rearrangement of α-Hydroxy Acetals to α-Alkoxy Ketones

Article abstract of DOI:10.1002/anie.201701098

We report an unprecedented organocatalytic enantioselective acyloin rearrangement of α,α-disubstituted α-hydroxy acetals. In the presence of a catalytic amount of chiral binol-derived N-triflyl phosphoramide, α-hydroxy acetals rearranged to α-alkoxy ketones in good to high yields with high enantioselectivities. Formation of an ion pair between the in situ generated oxocarbenium ion and the chiral phosphoramide anion was proposed to be responsible for the highly efficient transfer of chirality. Conditions for removal of cyclohexyl and cyclopentyl groups from the corresponding α-alkoxy ketones were uncovered underpinning their potential general utility as hydroxy protecting groups. Conversion of the rearranged products to the enantioenriched α-hydroxy ketone, 1,2-diol, β-amino alcohol and 1,4-dioxane was also documented.

Full text of DOI:10.1002/anie.201701098

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International Edition: DOI: 10.1002/anie.201701098
German Edition: DOI: 10.1002/ange.201701098
Asymmetric Synthesis
Organocatalytic Enantioselective Acyloin Rearrangement of
a-Hydroxy Acetals to a-Alkoxy Ketones
Hua Wu, Qian Wang, and Jieping Zhu*
Abstract: We report an unprecedented organocatalytic enan-
tioselective acyloin rearrangement of a,a-disubstituted a-
hydroxy acetals. In the presence of a catalytic amount of
chiral binol-derived N-triflyl phosphoramide, a-hydroxy ace-
tals rearranged to a-alkoxy ketones in good to high yields with
high enantioselectivities. Formation of an ion pair between the
in situ generated oxocarbenium ion and the chiral phosphor-
amide anion was proposed to be responsible for the highly
efficient transfer of chirality. Conditions for removal of
cyclohexyl and cyclopentyl groups from the corresponding a-
alkoxy ketones were uncovered underpinning their potential
general utility as hydroxy protecting groups. Conversion of the
rearranged products to the enantioenriched a-hydroxy ketone,
1,2-diol, b-amino alcohol and 1,4-dioxane was also docu-
mented.
Scheme 1. Enantioselective catalytic acyloin rearrangement.
benium ions have been developed.[9] On the other hand,
asymmetric transformations involving acylic oxocarbenium
ion remained rare.[10,11] In connection with our ongoing
research program dealing with organocatalytic enantioselec-
tive transformations,[12] we became interested in enantiose-
lective carbenium ion-based rearrangement processes and
documented an asymmetric vinylogous pinacol rearrange-
ment.[13,14] We report herein a Brønsted acid-catalyzed
enantioselective acyloin rearrangement of a,a-disubstituted
a-hydroxy acetals to a-alkoxy ketones[15] (Scheme 1b) and
their subsequent transformations. Conditions for removal of
cyclohexyl and cyclopentyl groups from the a-alkoxy ketones
were uncovered underpinning their potential general utility as
hydroxy protecting groups.
2,2-Bis(cyclohexyloxy)-1,1-diphenylethan-1-ol (1a) was
chosen as a test substrate. With BINOL-derived chiral
phosphoric acids (CPAs),[16–17] the best result was obtained
with 3b affording rearranged product 2a in 8% yield with an
e.r. of 80:20 (toluene, 708C, entry 2, Table 1). A dramatic
increase in yield was observed when N-triflyl phosphoramides
(3e–3h, Figure 1),[18] stronger Brønsted acids, were used as
catalysts (entries 5–8) with 3h being the best (52% yield, e.r.
90.5:9.5). Imidodiphosphate 3i[8i] was ineffective affording
only a trace amount of the rearranged product (entry 9).
Using 3h as a catalyst, conditions were further surveyed
varying the solvents, the additives and the reaction temper-
ature. The optimum conditions consisted of performing the
rearrangement of 1a in cyclohexane (c = 0.1m) at 508C in the
presence of 3h (0.1 equiv) and 5 ꢀ molecular sieves. Under
these conditions, a-alkoxy ketone 2a was isolated in 91%
yield with 96:4 e.r. (entry 19). The (S)-absolute configuration
of 2a was determined by comparison with the authentic
sample (see below).
A
cyloin (a-ketol) rearrangement involves a 1,2-alkyl(aryl)
shift that converts a-hydroxy ketone (aldehyde) to its
isomer.[1] The reaction has been exploited in the synthesis
and structural modification of terpenoids[1] and is involved in
the biosynthesis of several families of natural products.[2]
While the reaction generates a new stereocenter, the rever-
sibility of this process renders the development of enantio-
selective version challenging. In this regard, the seminal
papers of Maruoka[3] and of Wulff[4] dealing with the chiral
Lewis acid-catalyzed asymmetric acyloin rearrangements of
a-hydroxy aldehyde and imine, respectively, are noteworthy
(Scheme 1a).[5] To the best of our knowledge, these are the
only examples known to date and the enantioselective
organocatalytic acyloin rearrangement remains unknown.[6]
Catalytic asymmetric transformations involving nucleo-
philic addition to oxocarbenium ion has attracted much
attention recently. The lack of basic site of oxocarbenium ion
species for coordination to Lewis acid or for H-bond
formation made the creation of a chiral environment
around this highly reactive cationic species very difficult.[7]
To date, the most innovative and successful concept is without
doubt the chiral ion-pair approach[8] and a number of
enantioselective transformations featuring cyclic and rela-
tively stable (benzo)pyrylium- or (iso)chroman-type oxocar-
[*] Dr. H. Wu, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products, Institute of Chemical
Sciences and Engineering, Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
The scope of this rearrangement was illustrated in
Scheme 2. A wide range of substrates bearing substituents
with different electronic properties (alkyl, Cl, F, MeO) at
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201701098.
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Table 1: Optimization of the reaction conditions.[a]
Entry
B*-H
Solvent
M.S.
T [8C]
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3h
3h
3h
3h
3h
3h
3h
3h
3h
3h
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
THF
CyH
MTBE
CyH
CyH
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
50
RT
50
trace
8
trace
trace
38
43
21
52
trace
69
13
79
27
39
21
97
83
–
80:20
–
–
48.5:51.5
48:52
36:64
90.5:9.5
–
88:12
92:8
94:6
70.5:29.5
95:5
92:8
94:6
96:4
97:3
96:4
9
10
11
12
13
14
15
16
17
18
19[e]
3 ꢁ[d]
4 ꢁ[d]
5 ꢁ[d]
5 ꢁ[d]
5 ꢁ[d]
5 ꢀ[d]
CyH
CyH
CyH
CyH
29
Scheme 2. Scope of acyloin rearrangement of a-hydroxy acetals. [a]
The e.r. was determined by reducing the ketones to the corresponding
alcohols. [b] At 608C, 5 d. [c] At 108C. [d] Benzene as the solvent,
1008C, 2 h. [e] 3h (0.15 equiv). [f] Cyclopentane as the solvent, 08C. [g]
At room temperature. [h] At 708C. [i] At 408C. chex=cyclohexyl.
95 (91)[f]
[a] 1a (0.05 mmol), chiral Brønsted acid 3 (0.005 mmol), solvent
(0.5 mL), T [8C], 12 h. [b] Determined by 1H NMR analysis of the crude
reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.
[c] Determined by SFC analysis on a chiral stationary phase.
[d] M.S.=molecular sieves, 40 mg. [e] Reaction time 3 days. [f] Isolated
yield. CyH=cyclohexane.
ment. Therefore, non-stereoselective acyloin rearrangement of
1a to (Æ)-2a followed by 3h-catalyzed enolization/enantiose-
lective protonation of enediol was not responsible for the
formation of enantioenriched 2a.[19] A possible reaction path-
way accounting for the conversion of 1 to 2 is depicted in
Scheme 3. Hydrogen bonding between a-hydroxy acetal 1 and
N-triflyl phosphoramide 3h could generate two possible
intermediates A and B, which might be in equilibrium. We
assumed that B with a 9-membered double H-bonded system
would be the predominant form.[20] Elimination of R’OH from
intermediate B would produce the key oxonium cation which,
with the assistance of the remaining H-bond, would form
a tight ion pair C with chiral phosphoramide anion creating
therefore a chiral environment. Subsequent enantioselective
1,2-carbon shift would afford product 2 with concurrent
regeneration of catalyst 3h. However, concerted mechanism
or a pathway involving the formation of the phosphate acetal
intermediate cannot be excluded at the present stage of
Figure 1. Structures of representative CPAs and chiral phosphor-
amides.
different positions (para, meta and ortho) underwent the
rearrangement to afford the corresponding a-alkoxy ketones
in good to high yields with high enantioselectivities (2a–2m).
The benzyl group can also migrate albeit with diminished
enantioselectivity (2n). The acyloin rearrangement of a-
hydroxy acetals with different alkoxy residues, such as diethyl,
diisopropyl, dibutyl, dicyclopentyl, dicycloheptyl and di(3-
phenyl)propyl acetals, proceeded smoothly to provide the
rearranged products 2o–2t in good to high yields and high
enantioselectivities. Furthermore, acetals derived from the
functionalized alcohols are tolerated furnishing 2u–2w with-
out event. The presence of alkyl chloride in the rearranged
products provided a handle for post-functionalization (see
below). Finally, rearrangement of 1a performed on
a 1.0 mmol scale proceeded smoothly to afford 2a with
similar synthetic efficiency (93% yield, 95:5 e.r.).
Submitting the racemic a-alkoxy ketone 2a to our standard
conditions led to the recovery of (Æ)-2a without enantioenrich-
Scheme 3. Possible reaction pathway.
2
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development.[10e,13] In addition to the desired rearrangement
product 2, a small amount of aldehydes 4 and 5 were also
isolated in some cases (Scheme 3). Attack of adventurous
water to the oxonium intermediate C followed by elimination
of R’OH would produce aldehyde 4, while 1,2-alkoxy migra-
tion via the benzylic cation D generated from intermediate A
would produce 5.
A racemization-free deprotection of cyclohexyl ether is
subsequently developed.[21] After having screened different
Lewis acids and Brønsted acids (see the Supporting Informa-
tion (SI)), we were pleased to find that benzoin 6 can be
isolated in 92% yield with 3% loss of enantiopurity by simply
stirring a CH2Cl2 solution of 2a at room temperature in the
presence of an excess of BF3·Et2O for 15 min (Scheme 4a).
Performing the deprotection of 2a in CDCl3 and monitoring
1
the progress by H NMR allowed us to identify the presence
Scheme 5. Synthetic transformations of a-alkoxy and a-hydroxy
ketones.
(MeNH2·HCl, NaBH3CN, MeOH, RT) afforded a mixture of
(À)-ephenamine and (À)-pseudoephenamine 13 in 71% yield
(d.r. 2:1).[28]
Scheme 4. Deprotection of cyclohexyl and cyclopentyl ethers.
of cyclohexene in the reaction mixture (see SI). This result
indicated that the reaction went through most probably the
cyclohexyl cation intermediate. In line with this assumption,
cyclopentyl ether 2r was deprotected under identical con-
ditions to 6 with only 1% loss of enantiopurity (Scheme 4b),
whereas ethyl ether 2o was inert under these reaction
conditions.
In summary, we developed the first example of chiral N-
triflyl phosphoramide-catalyzed enantioselective acyloin
rearrangement of a,a-disubstituted a-hydroxy acetals. Gen-
eration of the chiral ion pair between the oxocarbenium ion
and the chiral phosphoramide anion might be responsible for
this unprecedented enantioselective 1,2-carbon shift process.
We also documented the mild conditions for removal of
cyclohexyl and cyclopentyl groups from the corresponding a-
alkoxy ketones with little erosion of enantiopurity.
Both (R)- and (S)-6 are known compounds whose physical
data are well described. Comparison of the optical rotation of
our synthetic benzoin 6 with those of the literature data and the
SFC trace of the commercially available (R)-benzoin 6 allowed
us to conclude that our synthetic compound has the (S)
configuration (see SI). The absolute configuration of 2a and all
other a-alkoxy ketones was assigned as (S) accordingly.
Further transformations of a-alkoxy ketone 2 were
performed to illustrate its synthetic potential (Scheme 5).
Reduction of a-alkoxy ketone 2o with Red-Al afforded the
anti-7 in 92% yield,[22] while the Meerwein–Ponndorf–Verley
reduction of 2o [Al(OiPr)3/iPrOH] gave the syn-7 in 93%
yield with excellent diastereoselectivities in both cases.[23] On
the other hand, nucleophilic addition of ethylmagnesium
bromide and (4-methoxyphenyl)magnesium bromide to 2o at
08C afforded mono-protected diols 8 and 9, respectively, in
high yields with excellent diastereoselectivities.[24] Addition of
benzylmagnesium chloride to 2u gave tertiary alcohol 10
which, under basic conditions, was converted to 1,4-dioxane
11, an important structural motif found in natural products
and pharmaceuticals.[25] The enantioenriched benzoin 6
obtained from the deprotection of 2a was similarly trans-
formed to the enantioenriched polyfunctionalized 1,2-diol
12,[26] an analogue of marsupol,[27] in 76% yield with excellent
diastereoselectivity (d.r. > 20:1). Reductive amination of 6
Acknowledgements
Financial supports from EPFL (Switzerland) and Swiss
National Science Foundation (SNSF) are gratefully acknowl-
edged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: acyloin rearrangement · chiral Brønsted acid ·
ion pair · organocatalyst · a-alkoxy ketone
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À
´
[10] C O bond formation: a) I. Coric, S. Vellalath, B. List, J. Am.
Manuscript received: January 31, 2017
Revised: March 22, 2017
Final Article published: && &&, &&&&
ˇ
´
Chem. Soc. 2010, 132, 8536; b) I. Coric, S. Mꢂller, B. List, J. Am.
Chem. Soc. 2010, 132, 17370; c) J. H. Kim, I. Coric, S. Vellalath,
ˇ
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4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Synthesis
H. Wu, Q. Wang, J. Zhu*
&&&& — &&&&
Organocatalytic Enantioselective Acyloin
Rearrangement of a-Hydroxy Acetals to
a-Alkoxy Ketones
Selective shift: In the presence of a chiral
binol-derived catalyst a-hydroxy acetals
rearrange, via an ion pair intermediate, to
a-alkoxy ketones with high enantioselec-
tivities. Conditions for removal of cyclo-
hexyl and cyclopentyl groups from the
corresponding a-alkoxy ketones were
uncovered underpinning their potential
utility as general hydroxy protecting
groups.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!