Double Catalytic Kinetic Resolution (DoCKR) of Acyclic anti-1,3-Diols: The Additive Horeau Amplification

Article abstract of DOI:10.1002/anie.201709844

The concept of a synergistic double catalytic kinetic resolution (DoCKR) as described in this article was successfully applied to racemic acyclic anti-1,3-diols, a common motif in natural products. This process takes advantage of an additive Horeau amplif

Full text of DOI:10.1002/anie.201709844

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Accepted Article
Title: Double Catalytic Kinetic Resolution (DoCKR) of Acyclic anti-1,3-
Diols using Additive Horeau Amplification
Authors: Cyril Bressy, Jérémy Merad, Prashant Borkar, Frédéric Caijo,
Jean-Marc Pons, Jean-Luc Parrain, and Olivier Chuzel
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10.1002/anie.201709844
Angewandte Chemie International Edition
COMMUNICATION
Double Catalytic Kinetic Resolution (DoCKR) of Acyclic
anti-1,3-Diols using Additive Horeau Amplification
Jérémy Merad,[a] Prashant Borkar,[a] Frédéric Caijo,[b] Jean-Marc Pons,[a] Jean-Luc Parrain,[a]
Olivier Chuzel*[a] and Cyril Bressy*[a]
Abstract: The concept of synergistic double catalytic kinetic
resolution (DoCKR) described in this article, was successfully
applied to racemic acyclic anti-1,3-diols, a common motif in natural
products. This process takes advantage of an additive Horeau
(1) In the subtractive Horeau amplification, the minor enantiomer
obtained after the first transformation is the substrate of the
second transformation. The polyfunctionalized substrates
involved in this first category are either prochiral[3,4] or meso
compounds.[3,5]
amplification
involving
two
successive
enantioselective
organocatalytic acylations reactions, and leading to diesters and
recovered diols with high enantiopurities. It was first developed with
C2-symmetrical diols and then further extended to non-C2-
symmetrical anti diols to prepare useful chiral building blocks. The
(2) In the additive Horeau amplification, the major enantiomer
formed after the first reaction is rapidly consumed in the second
enantioselective
(or
diastereoselective)
transformation.[6]
However, and oppositely to subtractive processes, examples of
additive amplifications involving starting materials with pre-
existing stereocenters are extremely scarce (Scheme 1).[7]
protocol is highly practical as it only requires
1 mol% of a
commercially available organocatalyst and leads to easily separable
products. This procedure was applied to the shortest reported total
synthesis of (+)-cryptocaryalactone, a natural product with anti-
germinative activity.
2nd catalytic
enantioselective
filter
1st catalytic
enantioselective
filter
Racemic
ultra major
enantiomer
major
enantiomer
fast
fast
How can one improve the enantioselectivity outcome of a
reaction on a wide scope? This is a recurring question during the
development of any given catalytic enantioselective
transformation. The indispensable optimization stage improves
the enantiomeric ratio (er) of a reaction through the variations of
the chemical and/or physical parameters of the transformation.
Usually, er enhancement is rapidly accompanied by a narrowing
of the reaction scope. Most of the time, the rational design of the
catalyst structure is the only option to improve reactivity and
selectivity. This fine tuning is nonetheless time consuming while
it can result in negligible improvements due to the difficulty of
+
minor
enantiomer
ultra minor
enantiomer
slow
slow
moderate to high
enantioselectivity
excellent
enantioselectivity
inseparable
enantiomers
with pre-existing
stereocenters
Final products with high er easily separable
by chromatography on silica gel
Scheme 1. Additive Horeau amplification applied to substrates bearing pre-
considering
all
the
parameters
involved
in
the
existing stereocenters.
enantiodetermining transition state.
On the other hand, the Horeau principle[1] is responsible for the
improvement of enantioselectivity in some reactions relying on
polyfunctionalized substrates. By applying at least two identical
successive enantioselective transformations, the second
reaction can act as an additional sterecontrolling filter improving
the enantiopurity of the final product. Since the pioneering works
of Horeau in the 70's, such amplification of enantioselectivity
was observed in several catalytic transformations.[2,3,5e] In
enantioselective catalysis, the Horeau amplification can be
divided into two main categories:
Although observed many times, the Horeau amplification is still
considered as an anecdotal phenomenon. By considering the
synthetic potential supported by the Horeau principle in
enantioselective catalysis, we supposed that this concept could
be used as a synthetic strategy by itself. Indeed, it could
constitute an alternative approach to laborious catalyst fine-
tuning while keeping high enantioselectivities and broad reaction
scopes. In practice, the syntheses designed on this principle
would require minimal optimization stage and remain effective
with moderately selective catalysts. In order to validate this
hypothesis we identified the double catalytic kinetic resolution
(DoCKR) of acyclic anti 1,3-diols as a relevant transformation,
complementary to our previous study.[5d] Indeed, this widespread
stereodefined scaffold is, to a large extent, responsible for the
biological activity of numerous polyketides such as dictyostatin,
ripostatin B, fostriecin and peluroside A.[8] Consequently, the
control of relative and absolute configurations is particularly
pivotal.[9] Generally, these motifs are reached thanks to the
preparation of an enantioenriched β-hydroxyketone followed by
its anti-diastereoselective reduction[10] (Scheme 2a). However,
few methods are catalytic and enantioselective.[6f,6g,11] In view, a
[a]
[a]
Dr. J. Merad, Dr. P. Borkar, Prof. Dr. J.-M. Pons, Dr. J.-L. Parrain,
Dr. O. Chuzel, Prof. Dr. C. Bressy
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille,
France
E-mail: olivier.chuzel@univ-amu.fr and cyril.bressy@univ-amu.fr
Dr. F. Caijo
Demeta SAS, 6 rue Pierre Joseph Colin, Biopole, 35500, Rennes,
France
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201709844
Angewandte Chemie International Edition
COMMUNICATION
conceptually
opposite
approach
setting
first
the
identify a combination of propionic anhydride with 1 mol% of
HyperBTM as extremely efficient in terms of yield and selectivity.
Indeed, under these standard conditions, diol 1a was recovered
in 41% yield (out of a maximum of 50%) and 99.6:0.4 er while
diester 2a was produced in 41% yield (out of a maximum of
50%) and 98.0:2.0 er. As expected, the small monoester fraction
3a (6%) was obtained with a poor selectivity serving in the
process as the sacrificial part (Scheme 3). Interestingly, the
small initial amount of syn diol contaminating the racemic anti
diol was also captured as its monoester. It is noteworthy that
each fraction is easily separable by simple chromatography
making this process easy to handle.
diastereoselectivity and then securing the enantiocontrol could
offer new opportunities. We envisioned that this second step
could be provided by an enantioselective acylation of the
corresponding anti diols (Scheme 2b). However, such
organocatalytic KR of acyclic anti 1,3-diols[12] remains
unprecedented because it faces massive challenges: 1) the high
flexibility of the substrates and the lack of catalysts able to
induce an efficient stereocontrol; 2) the potential formation of
multiple side products and undesired isomers.
We assumed that such a challenging transformation could be
achieved thanks to an additive Horeau amplification. It could
result from a DoCKR process in which a first enantioselective
esterification would be followed by a second acyl transfer on the
major enantiomer (Scheme 2c). The produced diester and the
recovered diol of opposite absolute configurations should both
OH OH
(R,R)-1a
41%, dr > 20/1, er = 99.6:0.4
be obtained with
monoester fraction would constitute the sacrificial part of the
amplifying process.
a high level of enantioselectivity. The
O
HyperBTM
(1 mol%)
(EtCO)2O
(1.05 equiv)
+
Me
O
OH
OH OH
DIPEA
(1.05 equiv)
CH2Cl2
3a
rac-1a
dr > 20/1
6%, dr (anti/syn) = 4/1
er (anti) = 65.6:34.4
(a) Classical approach: enantiocontrol then diastereocontrol
!20 °C, 2.5 h
+
O
O
diastereoselective
reduction
enantioselective
transformation
OH
O
OH OH
R'
S
N
s = 28
Me
Me
O
O
N
Substrates
R
R'
R
!-hydroxyketone
HyperBTM
Me
Me
(S,S)-2a
41%, dr > 20/1, er = 98.2:1.8
(b) This work: diastereocontrol then enantiocontrol
OH OH
R'
R
O
R
Scheme 3. Validation of the hypothesis and optimized conditions of the
DoCKR.
diastereoselective
preparation
enantioselective
acylation
high er
+
OH OH
R'
Substrates
R
O
racemic
R
O
O
R
To confirm the beneficial effect of the double enantioselective
acylation, the KR of racemic monoester 3a was conducted under
similar conditions but with reduced amounts of anhydride and
base (Scheme 4). As expected, the single enantioselective acyl
transfer resulted in lower levels of selectivity and a s value[14] of
17. This value was brought up to 28 when the DoCKR process
was performed onto related diol 1a (Entry 1, Table 1). The
additive Horeau amplification can then convert a reaction
Access to both enantiomers
Practical, scalable
Mild conditions
R'
Synergistic mechanism
Low catalyst loading
Highly enantioselective
high er
Broad scope
(c) Mechanistic scenario of DoCKR of anti-1,3-diols: Additive Horeau Amplification
1st Kinetic Resolution
O
O
O
OH OH
R'
O
OH
R'
O
O
R'
slow
slow
R
R
R
O
R
R
O
R
O
recovered diol
displaying
a
moderate intrinsic selectivity into
a
highly
+
+
+
enantioselective synthetic methodology.
OH OH
R'
O
OH
R'
O
O
R'
fast
fast
R
R
R
R
R
R
O
produced diester
monoester as
sacrificial part
Me
O
OH
2nd Kinetic Resolution
O
HyperBTM
(1 mol%)
(EtCO)2O
(0.55 equiv)
Me
O
OH
(R,R)-3a
er = 87.0:13.0
Scheme 2. (a) Classical approach to prepare enantioenriched acyclic anti 1,3-
diols (b) DoCKR for acyclic racemic anti 1,3-diols. (c) Mechanistic scenario of
the DoCKR.
DIPEA
(0.55 equiv)
CH2Cl2
+
rac-3a
dr > 20/1
O
O
Me
Me
O
O
!20 °C, 2.5 h
C = 49%
s = 17
(S,S)-2a
er = 88.3:11.7
We started our study with the C2-symmetrical substrate 1a,
synthesized in only two steps (dr > 20:1). This compound
displays two easy post-transformable C-C double bonds
providing rigidity and possible interactions with the catalyst.
Based on our previous works and deliberately avoiding any
catalyst screening we selected the commercial available Smith’s
HyperBTM[13] as a promising chiral catalyst. A brief optimization
of the reaction conditions (see supporting informations) led us to
Scheme 4. KR of racemic monoester 3a.
The scope of the DoCKR was then examined with racemic
C2-symmetrical 1,3-diols bearing π-systems in allylic or benzylic
positions (Table 1). Excellent results were obtained for both
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10.1002/anie.201709844
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allylic diols (1a-d) and benzylic diols (1e-h) series. Indeed, diols
were recovered in 40-46% yield in enantiopure form in many
cases, which correspond to excellent s values between 15 and
73. Similar results were obtained for the diesters with yields
> 40% and er > 97:3. Due to the symmetry of the substrates, it
does not matter on which hydroxyl group, the first acylation
happens. It seems reasonable to propose that the two
successive acylation reactions on one enantiomer of the anti
1,3-diol occur approximately at the same kinetic rate. The
efficiency and the scalability of this new method were
demonstrated by running the reaction with racemic diol 1a on a
3.5 g scale. Optically active diol 1a (1.40 g) and diester 2a (2.03
g) were obtained with comparable excellent yields and
selectivities using a reduced amount of catalyst (0.5 mol%)
(entry 1). In order to push further the limits, we examined the
DoCKR of a diol without π-system nearby the reactive centers
(entry 9). Racemic yashabushidiol was tested under the
standard conditions giving a monoester and the corresponding
diester with poor enantioselectivity but the recovered diol in 21%
yield with very high er (> 99:1).
Table 1. DoCKR of C -symmetrical 1,3-diols.[a]
2
We expected that
a significant step forward would be
accomplished in term of synthetic potential if this methodology
was applicable to unsymmetrical anti 1,3-diols. In such cases,
the rates of the two successive acylation reactions might be
significantly different leading to a more complex kinetic sorting.
Different series of substrates were prepared and evaluated in
acylative DoCKR: diversely substituted anti hepta-1,6-dien-3,5-
diols (1i-k), anti 1,3-diarylpropan-1,3-diols (1l-n) and anti 1,5-
diaryl-pent-1-en-3,5-diols (1o-s). With these three series, s
values between 18 and 79 were obtained. High levels of
enantioselectivity were reached with comparable yields for both
the recovered diols and the diesters. The transformation
tolerates heterocycles such as furan or thiophene derivatives
(Table 2, entries 5, 6 and 11), as well as trisubstituted double
bonds (Table 2, entries 2, 3, 9 and 10). Finally the DoCKR of
anti 1,3-diol 1t, presenting one benzylic alcohol and one
secondary hydroxyl group without π-system at its proximity (e.g
in allylic or benzylic position), was examined. The
enantioselectivity of the recovered diol was not affected by this
structural change remaining at a high level (99.5:0.5 er) while
the er of its diester was slightly lower. Its s value (27 for 1t) was
quite similar to the unsaturated precursor 1o (s = 29). This last
example pinpoints the strong potential of the DoCKR process,
able to overcome a challenging selective transformation.
Rec. diol[e]
Yield (%)[b]
(er)[c]
Diester[e]
Yield (%)[b]
(er)[c]
Entry
rac-diol
s[d]
OH OH
40[f]
(98.4:1.6)
41[f]
(99.3:0.7)
1
28
1a
OH OH
40
(97.6:2.4)
40
(98.9:1.1)
2
16
1b
Cl
Cl
OH OH
43
44
(99.6:0.4)
3
4
51
15
(>99.9:0.1)
Me
Me
1c
OH OH
40
(97.1:2.9)
44
(98.3:1.7)
Br
Br
1d
OH OH
46
(98.7:1.3)
46
(98.1:1.9)
5
6
46
60
51
73
7
1e
MeO
OH OH OMe
Table 2. DoCKR of non-C -symmetrical 1,3-diols.[a]
44
40
(99.9:0.1)
2
(>99.9:0.1)
1f
Rec. diol[e]
Yield (%)[b]
(er)[c]
Diester[e]
Yield (%)[b]
(er)[c]
Entry
rac-diol
s[d]
OH OH
43
42
(97.4:2.6)
7
OMe
OH OH
(>99.9:0.1)
1g
Me
Me
38
43
1
22
(99.7:0.3)
(95.8:4.2)
1i
OMe
OH OH
45
45
(98.6:1.4)
8
OH OH
(>99.9:0.1)
1h
F
F
38
(99.7:0.3)
43
(98.0:2.0)
2
3
4
22
21
18
Br
1j
OH OH
9[g]
21%
(99.5:0.5)
19%
(61.2:38.8)
OH OH
34
33
rac-Yashabushidiol
Me
(>99.9:0.1)
(88.5:11.5)
Br
1k
OH OH
[a] Typical experiment performed on 0.5 mmol of racemic diol under
the standard conditions. [b] isolated yield. [c] determined by HPLC with
chiral phase, for details see the supporting information section. [d]
based on recovered diol. [e] dr > 20:1 in all cases. [f] Run on 3.5 g of
racemic diol with 0.5 mol% of catalyst. [g] Monoester was also
produced in 50% yield and 70.6:29.4 er.
41
47
(97.7:2.3)
(96.5:3.5)
1l
Cl
F
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10.1002/anie.201709844
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COMMUNICATION
OH OH
OMe
43
(99.1:0.9)
47
(98.5:1.5)
5
30
79
S
1m
OMe
OH OH
49
38
6
(97.4:2.6)
(98.2:1.8)
O
1n
F
OH OH
39
(99.9:0.1)
40
(98.2:1.8)
7
8
29
24
1o
OH OH
39
43
(99.7:0.3)
(96.2:3.8)
1p
OMe
OH OH
40
(99.6:0.4)
40
(97.9:2.1)
9
25
39
24
27
Me
1q
Scheme 5. Total synthesis of (+)-cryptocaryalactone.
OH OH
41
43
(98.4:1.6)
10
11
12
(>99.9:0.1)
Br
1r
organocatalyzed acylation (0.5 – 1 mol% catalyst loading) gives
an easy access to both enantiomers of a given acyclic anti 1,3-
diol with high yields and enantioselectivities. The methodology
was successfully applied to C2-symmetrical substrates and then
further extended to the challenging and unprecedented cases of
non-C2-symmetrical anti 1,3-diols. To the best of our knowledge,
the use of such non-symmetrical substrates bearing pre-existing
stereocenters in amplified systems was not reported so far.
Finally, the effectiveness of the DoCKR was applied to an
efficient total synthesis of (+)-cryptocaryalactone using a single
catalytic enantioselective step. This flexible approach leads to
both enantiomers, which are useful in total synthesis of natural
product containing stereocenters with unassigned absolute
configuration. All in all, we strongly believe that the concept of
DoCKR could be of broader utility for the synthetic community
and potentially transposed to other bifunctional substrates.
OH OH
36
38
(90.3:9.7)
(>99.9:0.1)
S
1s
OH OH
41
37
(99.5:0.5)
(86.9:13.1)
1t
[a] Typical experiment performed on 0.5 mmol of racemic diol under
the standard conditions. [b] isolated yield. [c] determined by HPLC with
chiral phase, for details see the supporting information section. [d]
based on recovered diol. [e] dr > 20:1 in all cases.
We decided to apply this methodology to the total synthesis of
(+)-cryptocaryalactone,[15]
a
natural germination inhibitor
Acknowledgements
(Scheme 5). The acylation reaction of the virtually enantiopure
diol 1a with vinylacetic acid under classical conditions [DCC,
DMAP cat., CH2Cl2, rt] gave monoester 4 (80%) accompanied
by a small amount of diester (15%). The formed triene 4 then
underwent a ring-closing metathesis reaction using the highly
active catalyst 5[16] to afford lactone 6. Migration of the internal
double bond under DBU catalysis[17] followed by an acylation
reaction afforded (+)-cryptocaryalactone.[18] This hidden
symmetry strategy[19] represents the shortest synthesis of this
target reported to date.[20] Additionally, no protecting group was
The authors warmly acknowledge Dr. X. Bugaut (AMU, iSm2) for
proof reading, Dr. N. Vanthuyne, M. Jean (HPLC, iSm2) and Dr.
M. Giorgi (RX, Spectropole, FR 1739). Aix Marseille Université
(AMU), CNRS, COST ORCA Action 0905 (Organocatalysis), the
French Research Ministry (Grant to J.M.) and Agence Nationale
de la Recherche (Orcademe project ANR-10-JCJC-0710, Grant
to P.B.) are also gratefully acknowledged for funding.
Keywords: Organocatalysis • Kinetic resolution • Amplification
required for this synthesis,[21] which employed
organocatalytic enantioselective step.[22]
a unique
of enantioselectivity • Isothioureas • Cryptocaryalactone
In conclusion, we described a highly enantioselective synthetic
separation of acyclic anti 1,3-diols, which are ubiquitous
structural motifs in nature. This development was made possible
by the design of a synergistic double catalytic kinetic resolution
(DoCKR) and by a full exploitation of the additive Horeau
principle. This efficient, general and scalable method using an
[1]
[2]
[3]
[4]
J.-P. Vigneron, M. Dhaenes, A. Horeau, Tetrahedron 1973, 29, 1055.
V. Rautenstrauch, Bull. Soc. Chim. Fr. 1994, 131, 515.
For review, see: D. S. Glueck, Catal. Sci. Technol. 2011, 1, 1099.
Selected examples: a) S. L. Schreiber, T. S. Schreiber, D. B. Smith, J.
Am. Chem. Soc. 1987, 109, 1525; (b) A. C. Spivey, S. J. Woodhead, M.
Weston, B. I. Andrews, Angew. Chem. Int. Ed. 2001, 40, 769; Angew.
This article is protected by copyright. All rights reserved.

10.1002/anie.201709844
Angewandte Chemie International Edition
COMMUNICATION
Chem. 2001, 113, 791 b) K. Mori, Y. Ichikawa, M. Kobayashi, Y.
Shibata, M. Yamanaka, T. Akiyama, J. Am. Chem. Soc. 2013, 135,
3964; c) R. J. Armstrong, M. D. Smith Angew. Chem. Int. Ed. 2014, 53,
12822; Angew. Chem. 2014, 126, 13036; d) T. Osako, Y. Uozimi, Org.
Lett. 2014, 16, 5866; e) S. Tuong, A. Limouni, Q. Wang, M.-X. Wang, J.
Zhu, Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201709133.
New Methods and Applications, Chap 3, pp75-122, Ed. Todd, M.,
Wiley-VCH, Weinheim, 2014; c) Arseniyadis, S.; Spivey A. Regio- and
Position Selective Reactions and Desymmetrizations in Comprehensive
Enantioselective Organocatalysis, Chap 41, Vol 3, pp1225-1284, Ed.
Dalko, P. I., Wiley-VCH, Weinheim 2013; d) C. Müller, P. R. Schreiner,
Angew. Chem. Int. Ed. 2011, 50, 6012; Angew. Chem. 2011, 123,
6136; e) H. Pellissier, Adv. Synth. Catal. 2011, 353, 1613.
[5]
Selected examples: a) B. S. Lucas, S. D. Burke, Org. Lett. 2003, 5,
3915; b) V. B. Birman, H. Jiang, X. Li, Org. Lett. 2007, 9, 3237; c) C.
Roux, M. Candy, J.-M. Pons, O. Chuzel, C. Bressy, Angew. Chem. Int.
Ed. 2014, 53, 766; Angew. Chem. 2014, 126, 785; d) J. Merad, P.
Borkar, T. Bouyon Yenda, C. Roux, J.-M. Pons, J.-L. Parrain, O. Chuzel,
C. Bressy, Org. Lett. 2015, 17, 2118; for review in a context of total
synthesis: e) J. Merad, M. Candy, J.-M. Pons, C. Bressy, Synthesis
2017, 49, 1938.
[13] a) C. Joannesse, C. P. Johnston, C. Concellon, C. Simal, D. Philp, A. D.
Smith, Angew. Chem. Int. Ed. 2009, 48, 8914; for reviews on chiral
isothioureas as organocatalysts, see: b) J. Merad, J.-M. Pons, O.
Chuzel, C. Bressy Eur. J. Org. Chem. 2016, 5589 and also c) V.B.
Birman, Aldrichimica Acta 2016, 49, 23.
[14] H. B. Kagan, J.-C. Fiaud, Top. Stereochem. 1988, 18, 249.
[15] Isolation: (a) Govindachari, T. R.; Parthasarathy, P. C.; Modi, J. D. Ind.
J. Chem. 1972, 10, 149; (b) Spencer, G. F.; England, R. E.; Wolf, R. B.
Phytochemistry 1984, 23, 2499-2500.
[6]
Selected examples: Alkenes: a) G. A. Crispino, P. T. Ho, K. B.
Sharpless, Science 1993, 259, 64; b) S. El Baba, K. Sartor, J.-C. Poulin,
H. B. Kagan, Bull. Chim. Soc. Fr. 1994, 131, 525; c) Y. Huang, A. M.
Walji, C. H. Larsen, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127,
15051; d) J. Zhou, J. W. Ogle, Y. Fan, V. Banphavichit, Y. Zu, K.
Burgess, Chem. Eur. J. 2007, 13, 7162; e) N. J. Green, A. L. Lawrence,
G. Bojase, A. L. Willis, M. N. Paddon-Row, M. S. Sherburn, Angew.
Chem. Int. Ed. 2013, 52, 8333; Angew. Chem. 2013, 125, 8491.
Ketones: f) M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo, H.
Kumobayashi, S. Akutagawa, T. Ohta, H. Takaya, R. Noyori, J. Am.
Chem. Soc. 1988, 110, 629; g) A. K. Dilger, V. Gopalasamuthiram, S. D.
Burke, J. Am. Chem. Soc. 2007, 129, 16273; h) Y. Lu, I. S. Kim, A.
Hassan, D. J. Del Vall, M. J. Krische, Angew. Chem. Int. Ed. 2009, 48,
5018; Angew. Chem. 2009, 121, 5118. Enolates: i) J. A. Enquist, B. M.
Stoltz, Nature 2008, 453, 1228.
[16] Clavier, H.; Caijo, F.; Borré, E.; Rix, D.; Boeda, F.; Nolan, S. P.;
Mauduit, M. Eur. J. Org. Chem. 2009, 4254-4265. Unlike catalyst 5,
classical metathesis catalysts are leading to a mixture of products.
[17] Virroleaud, M.-A.; Bressy, C.; Piva, O. Tetrahedron Lett. 2003, 44,
8081-8084.
[18] CCDC 1440921 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from Cambridge
Crystallographic Data center via www.ccdc.cam.ac.uk/data_request/cif.
[19] About the total synthesis of natural products with an economy of chiral
reagents by our group, see: (a) Candy, M.; Audran, G.; Bienaymé, H.;
Bressy, C.; Pons, J.-M. J. Org. Chem. 2010, 75, 1354-1359; (b) Candy,
M.; Tomas, L.; Parat, S.; Heran, V.; Bienaymé, H.; Pons, J.-M.; Bressy,
C. Chem. Eur. J. 2012, 18, 14267-14271 and ref 5d.
[7]
[8]
[9]
a) J. C. Ruble, J. Tweddell, G. Fu, J. Org. Chem. 1998, 63, 2794; b) P.
Kumar, P. S. Chowdhury, M. Pandey, Adv. Synth. Catal. 2013, 355,
1719.
[20] Previous syntheses: (a) Meyer, H. H. Liebigs Ann. Chem. 1984, 977-
981 (> 9 steps); (b) Mori, Y.; Furukawa, H. Chem. Pharm. Bull. 1994,
42, 2161-2163 (> 16 steps); (c) Sabitha, G.; Bhaskar, V.; Reddy, S. S.
S.; Yadav, J. S. Tetrahedron 2008, 64, 10207-10213 (> 13 steps); (d)
Krishna, P. R.; Lopinti, K.; Reddy, K. L. N. Beilstein J. Org. Chem. 2009,
5, doi:10.3762/bjoc.5.14 (> 11 steps); (e) Sabitha, G.; Vangala, B.;
Reddy, S. S. S.; Yadav, J. S. Helv. Chim. Acta 2010, 93, 329-338 (16
steps); (f) Balasubramanyam, P.; Reddy, G. C.; Salvanna, N.; Das, B.
Synthesis 2011, 3706-3710 (12 steps); (g) Yadav, J. S.; Bhunia, D. C.;
Ganganna, B. Tetrahedron Lett. 2012, 53, 2496-2499 (9 steps).
[21] For reviews, see: (a) Saicic, R. N. Tetrahedron 2014, 70, 8183-8218;
(b) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193-205; (c)
Hoffmann, R. W. Synthesis 2006, 3531-3541.
For review, see: a) D. Herkommer, B. Schmalzbauer, D. Menche, Nat.
Prod. Rep. 2014, 31, 456; b) M. Kretschmer, D. Menche, Synlett 2010,
2989; c) K.-S. Yeung, I. Paterson, Chem. Rev. 2005, 105, 4237.
For review, see: S. E. Bode, M. Wolberg, M. Müller, Synthesis 2006,
557.
[10] For the two major reductive methods, see: a) D. A. Evans, K. T.
Chapman, E. M. Carreira, J. Am. Chem. Soc. 1988, 110, 3560; b) D. A.
Evans, A. H. Hoveyda, J. Am. Chem. Soc. 1990, 112, 6447.
[11] Aldol-Tischenko process : a) C. M. Mascarenhas, S. P. Miller, P. S.
White, J. P. Morken, Angew. Chem. Int. Ed. 2001, 40, 601; Angew.
Chem. 2001, 113, 621; b) V. Gnanadesikan, Y. Horiuchi, T. Ohshima,
M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 7782; Dynamic process: c)
B. Martin-Matute, M. Edin, J.-E. Bäckvall, Chem. Eur. J. 2006, 12, 6053.
[12] For reviews on non-enzymatic catalytic KR, see: a) R. Gurabrahamam,
Y.-S. Cheng, W.-Y. Huang, K. Chen, ChemCatChem 2016, 8, 86-96; b)
H. Pellissier, Catalytic Kinetic Resolution, in Separation of Enantiomers:
[22] For reviews about total syntheses involving an enantioselective
organocatalysis, see: (a) Abbasov, M. E.; Romo, D. Nat. Prod. Rep.
2014, 31, 1318-1327; (b) Marques-Lopez, E.; Herrera, R. P.;
Christmann, M. Nat. Prod. Rep. 2010, 27, 1138-1167; (c) de Figueiredo,
R. M.; Christmann M. Eur. J. Org. Chem. 2007, 2575-2600.
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10.1002/anie.201709844
Angewandte Chemie International Edition
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COMMUNICATION
Jérémy Merad, Prashant Borkar,
Frédéric Caijo, Jean-Marc Pons,
Jean-Luc Parrain, Olivier Chuzel*,
Cyril Bressy*
Page No. – Page No.
Double Catalytic Kinetic Resolution
(DoCKR) of Acyclic anti-1,3-Diols
using Additive Horeau Amplification
Give a second chance to your catalyst! The concept of synergistic double
catalytic kinetic resolution (DoCKR) was successfully applied to racemic acyclic
anti-1,3-diols, a common motif in natural products. The double organocatalyzed
acylation led to diesters and recovered diols with high enantiopurities. It was first
developed with C2-symmetrical diols and then further extended to non-C2-
symmetrical anti diols to prepare useful chiral building blocks.
This article is protected by copyright. All rights reserved.