Highly enantioselective acylation of acyclic meso 1,3-diols through synergistic isothiourea-catalyzed desymmetrization/chiroablative kinetic resolution

Article abstract of DOI:10.1021/acs.orglett.5b00707

A general and highly efficient organocatalyzed desymmetrization of acyclic meso 1,3-diols through acyl transfer using chiral isothioureas is described. The introduction of π-systems in the acyclic substrates provided new opportunities in terms of reactivi

Full text of DOI:10.1021/acs.orglett.5b00707

Letter
pubs.acs.org/OrgLett
Highly Enantioselective Acylation of Acyclic Meso 1,3-Diols through
Synergistic Isothiourea-Catalyzed Desymmetrization/Chiroablative
Kinetic Resolution
Jeremy Merad, Prashant Borkar, Tracy Bouyon Yenda, Christele Roux, Jean-Marc Pons, Jean-Luc Parrain,
́
́
̀
Olivier Chuzel,* and Cyril Bressy*
́
Aix Marseille Universite, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
S
* Supporting Information
ABSTRACT: A general and highly efficient organocatalyzed
desymmetrization of acyclic meso 1,3-diols through acyl
transfer using chiral isothioureas is described. The introduction
of π-systems in the acyclic substrates provided new
opportunities in terms of reactivity, enantioselectivity and
synthetic potential. To reach this high level of enantioselec-
tivity (up to er >99:1), the reaction proceeds through a
synergistic mechanism involving a desymmetrization reaction
and a chiroablative kinetic resolution process. This methodology was used with success as the sole enantioselective catalytic step
(developed on a gram scale) to achieve the total synthesis of the antiosteoporotic diarylheptanoid (−)-diospongin A (7 steps).
Syn 1,3-diol units are ubiquitous in polyketide natural products
and analogues thereof. It is the case for many important
commercialized drugs such as the antibiotic amphotericin B1 and
the cholesterol-lowering atorvastatin2 (Lipitor) (Figure 1). Since
Ishihara et al.8c led to an excellent enantioselectivity (97:3 er)
albeit only with a specific substrate. This limited number of
efficient enantioselective catalyzed acyl transfer processes on
acyclic meso 1,3-diols highlights the difficulty of this trans-
formation, which could be explained by numerous degrees of
freedom that do not facilitate the enantiocontrol.9 More rigidity
could be brought by the introduction of π-systems thus providing
allylic strains10 and hence reducing the number of conformations
in the transition state.
Moreover π-systems could supply supramolecular stabilizing
interactions, such as cation−π11 and π−π12 interactions, between
the substrate and the catalyst. Finally π-systems, especially
double bonds, are particularly convenient for further trans-
formations.
Figure 1. Drugs bearing syn 1,3-diol units.
Herein, we report an efficient, general, and highly
enantioselective organocatalytic acylative13 desymmetrization
process of acyclic meso 1,3-diols. Mechanistically the reaction
proceeds through a synergistic process involving a desymmet-
rization and a chiroablative kinetic resolution based on the
Horeau principle.14 Inspired by the concept of stereoablative
reactions15 developed by Stoltz where the enantioselectivity
results from the destruction of a stereogenic center (Scheme 1b),
chiroablative reactions amplify the enantiopurity of a product by
transforming the minor enantiomer into a symmetric achiral
molecule (without lost of stereogenic centers) (Scheme 1c).
Finally, the presence of the double bonds in the desymmetrized
products was exploited in various postfunctionalizations and
illustrated by the total synthesis of (−)-diospongin A.
the hydroxylated part of these molecules is fundamental for their
biological activity, the stereocontrol of the syn 1,3-diol moieties3
is crucial in their synthesis. In the past, several stereoselective
strategies were developed to elaborate this important structural
motif mainly by securing the enantiocontrol of a β-
hydroxyketones precursor and then ensuring a syn-diastereose-
lective reduction4 (Scheme 1a). Interestingly, among the
numerous possible approaches to prepare the syn 1,3-diol
motif, the catalytic enantioselective desymmetrization of an
acyclic meso precursor strategy5,6 has been undoubtedly
underexplored. In contrast to all the classical approaches,
attention is first given to the diastereoselective preparation of
the achiral meso substrates while the enantioselectivity is
controlled in a late stage.7 To the best of our knowledge, only
three studies8 involving an organocatalytic approach have been
reported in the literature but two of these afforded only moderate
levels of enantioselectivity.8a,b The third example reported by
Received: March 10, 2015
Published: April 13, 2015
© 2015 American Chemical Society
2118
DOI: 10.1021/acs.orglett.5b00707
Org. Lett. 2015, 17, 2118−2121

Organic Letters
Letter
a
Scheme 1. Approaches to Acyclic Syn 1,3-Diols
Table 1. Selected Optimization Experiments
b
catalyst
(x mol %)
temp
(°C)
yield 3a
d
entry
anhydride
(4a) (%)
er
1
2
3
4
5
1a (8)
1a (8)
1a (8)
1a (8)
1b (8)
1b (8)
1b (2)
(MeCO)2O
(EtCO)2O
(i-PrCO)2O
(EtCO)2O
(EtCO)2O
(EtCO)2O
(EtCO)2O
0
53 (4)
42 (5)
42 (18)
56 (8)
50 (50)
62 (29)
83.1:16.9
88.2:11.8
61.4:38.6
91.1:8.9
98.1:1.9
96.6:3.4
99.1:0.9
0
0
−10
−10
−10
−20
efg
, ,
6
7
efg
, ,
c
78 (18)
a
Typical experiment: 2a (50 mg, 0.18 mmol), i-Pr2NEt (45 μL, 0.27
mmol), Na2SO4 (100 mg), and catalyst (8 mol %) in CH2Cl2 (760
μL) was cooled before addition of anhydride (34 μL, 0.27 mmol).
b
c
d
1
Determined by H NMR. Isolated yield. Determined by HPLC
e
column Lux-Cellulose-2, hexane/ethanol 80/20, 1 mL/min. Per-
formed in 2.5 h. Without Na2SO4. 1.2 equiv of anhydride and 1.2
f
g
equiv of i-Pr2NEt.
Scheme 2. Scope of the Desymmetrization
Birman’s isothiourea catalyst (1a) was chosen for the first
desymmetrization attempts, as it afforded particularly good
results in the kinetic resolution of alcohols bearing π-
systems.16,17 The optimization study was conducted on syn-
1,7-diphenylhepta-1,6-dien-3,5-diol (2a), easily prepared follow-
ing a two-step sequence18 (Table 1). The screening of the
acylating reagent nature revealed the importance of this
parameter (Table 1, entries 1−3). Indeed, propionic anhydride
(Table 1, entry 2) provided, after 18 h, the best enantioselectivity
(88.2:11.8 er) but with low conversion (47%) in the preparation
of 3a. Cooling the reaction to −10 °C (Table 1, entry 4)
improved both the yield and selectivity (91:9 er), while switching
to Smith’s HyperBTM catalyst (1b)19 afforded significantly
increased conversion and selectivity (Table 1, entry 5) with a
reduced reaction time (98.1:1.9 er in 2.5 h). Full consumption of
anhydride led to the formation of a large amount of meso diester
4a. Reduced amounts of base and anhydride improved the yield
in 3a (Table 1, entry 6). Finally cooling to −20 °C and using only
2 mol % of catalyst gave a better yield of the virtually
enantiomerically pure monoester 3a (Table 1, entry 7). The
presence of Na2SO4 recommended in the Birman’s seminal
study16 did not benefit the reaction using catalyst 1b (Table 1,
entries 6 and 7). With these optimized conditions in hand, we
then explored the scope of the desymmetrization on various
precursors (Scheme 2). In the syn-1,7-diarylhepta-1,6-dien-3,5-
diol series, the nature of the aryl groups was first examined.
Hence different aromatic substituents were tested such as 2-
methoxy (3b), 4-methoxy (3c), and 4-chloro (3e), and all
afforded comparable levels of enantioselectivity. Heteroaromatic
substituents such as 2-furyl groups (3d) could be used without
alteration of either the yield or selectivity (98.4:1.6 er). The
replacement of aromatic groups by a methyl group had a limited
a
er determined after acylation with 4-bromobenzoic anhydride.
impact on the selectivity (3f), while additional substituents on
the double bonds (3g and 3h) could be added leading also to
excellent results. Then we examined the influence of the aromatic
groups on a series of syn-1,3-diarylpropane-1,3-diols (3i−m).
Hence, the desymmetrization of diol 2i using isothiourea 1b led
to monoester 3i in high yield and with an er up to 99.1:0.9 thus
demonstrating the generality of the method. Various substitution
patterns with electron-donating substituents (3k and 3l) or
electron-withdrawing atoms (3m) were examined, and all gave
2119
DOI: 10.1021/acs.orglett.5b00707
Org. Lett. 2015, 17, 2118−2121

Organic Letters
Letter
excellent results. The enantioselective acyl transfer was also
successfully performed on substrates bearing heteroaromatic
groups such as thiophenes (3j). In order to evaluate the influence
of the double bonds on the enantioselectivity, the reaction was
performed on yashabushidiol A (2n). The reaction rate
drastically slowed down (incomplete conversion after 2.5 h)
and the enantiomeric ratio of 3n dropped to 60.4:39.6,
highlighting the importance of the unsaturations.
Scheme 4. Scalability of the Desymmetrization and
Application to the Enantioselective Total Synthesis of
(−)-Diospongin A
The presence of a significant amount of diester 4a suggested
that the observed enantioselectivity could result from a
synergistic combination of two highly enantioselective steps,20
a desymmetrization followed by a chiroablative kinetic resolution
both catalyzed by isothiourea 1b as also observed by Birman in a
single case.20b To corroborate this hypothesis, the enantiomeric
excess of 3a was monitored during the course of transformation.
Interestingly, an amplification of the enantioselectivity was
observed at higher conversion, validating our initial assumption.
This increase correlates also with the concomitant formation of
diester 4a.18 Several postfunctionalizations based on the rich
chemistry pertaining to allylic alcohols21 were examined as
depicted in Scheme 3. First, a highly diastereoselective (dr
Scheme 3. Postfunctionalizations
a catalyst loading lowered to 0.5 mol %.28 The iodocyclization of
ent-3a afforded iodopyran 9 in a complete regioselective fashion,
with excellent diastereoselectivity (up to >20:1 dr) and complete
conservation of the initial enantiomeric ratio. The relative and
absolute configuration of tetrahydropyran 9 was confirmed by X-
ray diffraction.29 The reduction of the C−I bond under radical
conditions followed by a mild hydrolysis led to Uenishi’s
intermediate 10.25f Wacker oxidation on the styrenyl moiety of
pyran 10 under the modified conditions described by Grubbs30
led to the natural product in only 7 steps, without the
requirement of a single protecting group31 and, most
importantly, involving only one catalytic enantioselective step
as the synthesis relies on a hidden symmetry approach.32
In conclusion we developed a general, scalable method to
desymmetrize easily available acyclic meso 1,3-diol substrates
through nucleophilic organocatalysis. The high substrate
tolerance and excellent level of enantioselectivity of this
methodology (up to >99:1 er) contrast with previous
approaches. The π-systems are fundamental for the efficiency
of the desymmetrization and also synthetically useful for
subsequent post-transformations. This was demonstrated
through an efficient total synthesis of (−)-diospongin A33
involving a unique enantioselective step with a low catalytic load
below 1 mol %. Also we have shown that a synergistic
combination of a desymmetrization and chiroablative kinetic
resolution steps catalyzed by a chiral isothiourea resulted in an
amplification of the level of enantioselectivity. We think that this
synergistic process between two consecutive enantioselective
steps catalyzed by the same entity could be generalized for the
preparation of valuable chiral building blocks useful in total
synthesis.
>95:5) and completely chemoselective epoxidation of ent-3g
directed by the free hydroxyl group was performed using
VO(acac)2 as the catalyst,22 leading to monoepoxide 5. This
intermediate was submitted to a benzoylation followed by an
ozonolysis to give the complex ketone 5 bearing four stereogenic
centers in only five steps (Scheme 3, sequence 1). Then, the
carbon skeleton of monoester ent-3a was reorganized in
dihydroxyallylsilane 8. After silylation of monoester 3a with
allylchlorodimethylsilane, the resulting silylether 7 was trans-
formed through ring-closing metathesis furnishing an unstable
siloxane,23 which was opened by addition of MeLi (Scheme 3,
sequence 2). All these transformations led to interesting chiral
building blocks bearing syn 1,3-diols diversely functionalized
without significant alteration of the enantiomeric ratio compared
to the ones of their precursors ent-3a and ent-3g, respectively.
With this methodology, the total synthesis of a diarylheptanoid
natural product was next investigated (Scheme 4), focusing our
efforts on the antiosteoporotic (−)-diospongin A24,25 which
bears a tetrahydropyran ring. The desymmetrization of meso diol
2a26 was performed on a preparative scale (1.00 g)27 with a
highly reproducible yield and selectivity (77%, 99.1:0.9 er) using
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds are provided including the CIF file of molecule 9.
2120
DOI: 10.1021/acs.orglett.5b00707
Org. Lett. 2015, 17, 2118−2121

Organic Letters
Letter
1055. For the expression concerning multiple enantioselective
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Houk, K. N.; Birman, V. B. J. Am. Chem. Soc. 2008, 130, 13836. (c) Li, X.;
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This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cyril.bressy@univ-amu.fr.
*E-mail: olivier.chuzel@univ-amu.fr.
Notes
The authors declare no competing financial interest.
(17) For reviews on nucleophilic organocatalysts, see: (a) Taylor, J. E.;
Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012, 41, 2109. (b) De
Rycke, N.; Couty, F.; David, O. R. P. Chem.Eur. J. 2011, 17, 12852.
(18) See the Supporting Information for experimental details.
(19) (a) Joannesse, C.; Johnston, C. P.; Concellon, C.; Simal, C.; Philp,
D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48, 8914. (b) West, T. H.;
Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2014,
136, 4476 and references therein.
(20) Selected examples of such transformations: (a) Schreiber, S. L.;
Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525.
(b) Birman, V. B.; Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237.
(c) Armstrong, R. J.; Smith, M. D. Angew. Chem., Int. Ed. 2014, 53,
12822. (d) Mori, K.; Ichikawa, Y.; Kobayashi, M.; Shibata, Y.; Yamanaka,
M.; Akiyama, T. J. Am. Chem. Soc. 2013, 135, 3964. (e) Roux, C.; Candy,
M.; Pons, J.-M.; Chuzel, O.; Bressy, C. Angew. Chem., Int. Ed. 2014, 53,
766. For a review, see: Glueck, D. S. Catal. Sci. Technol. 2011, 1, 1099.
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Chem., Int. Ed. 2013, 52, 1890.
ACKNOWLEDGMENTS
■
The authors warmly thank Dr. X. Bugaut (iSm2) for fruitful
discussions. We deeply acknowledge Dr. N. Vanthuyne, M. Jean
(HPLC, iSm2), and Dr. M. Giorgi (RX, Spectropole). Aix
́
Marseille Universite, 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. and C.R.) are also gratefully
acknowledged for funding.
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