Copper-Catalyzed Asymmetric Conjugate Additions of Bis(pinacolato)diboron and Dimethylzinc to Acyl- N-methylimidazole Michael Acceptors: A Highly Stereoselective Unified Strategy for 1,3,5,... n (OH, Me) Motif Synthesis

Article abstract of DOI:10.1021/acs.orglett.9b00479

A unified strategy for the construction of prevalent 1,3,5,...n (OH, Me) motifs based on consecutive copper-catalyzed asymmetric conjugate borylation (ACB) and methylation (ACA) reactions involving α,β-unsaturated 2-acyl-N-methylimidazoles is described. Good yields and high diastereoselectivities have been obtained in ACA and ACB reactions for both matched and mismatched pairs as illustrated in the synthesis of syn/anti and anti/anti (Me, OTBS, Me) and (OH, OTBS, Me) motifs.

Full text of DOI:10.1021/acs.orglett.9b00479

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Asymmetric Conjugate Additions of
Bis(pinacolato)diboron and Dimethylzinc to Acyl‑N‑methylimidazole
Michael Acceptors: A Highly Stereoselective Unified Strategy for
1,3,5,...n (OH, Me) Motif Synthesis
†
‡
‡,§
Renata Marcia de Figueiredo,†
́
́
Jimmy Lauberteaux, Christophe Crevisy, Olivier Basle,
Marc Mauduit,*,‡ and Jean-Marc Campagne*,†
†
́
Institut Charles Gerhardt Montpellier, UMR 5253 CNRS-UM-ENSCM, Ecole Nationale Superieure de Chimie, Avenue Emile
Jeanbrau, Montpellier 34296 Cedex 6, France
‡
́
Univ Rennes, Ecole Nationale Superieure de Chimie de Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France
S
* Supporting Information
ABSTRACT: A unified strategy for the construction of prevalent
1,3,5,...n (OH, Me) motifs based on consecutive copper-catalyzed
asymmetric conjugate borylation (ACB) and methylation (ACA)
reactions involving α,β-unsaturated 2-acyl-N-methylimidazoles is
described. Good yields and high diastereoselectivities have been
obtained in ACA and ACB reactions for both matched and mismatched
pairs as illustrated in the synthesis of syn/anti and anti/anti (Me, OTBS,
Me) and (OH, OTBS, Me) motifs.
The transition-metal-catalyzed asymmetric conjugate addi-
tion (ACA) of hard and soft nucleophiles to electron deficient
alkenes has emerged as an efficient methodology for the selective
formation of C−C and C−heteroatom bonds4 and thus offers
opportunities to tackle synthetic problems associated with the
synthesis of such 1,3,5,...n (OH, Me) motifs. In the past decade,
electron-deficient alkenes bearing the postfunctionalizable
acylimidazole fragment have emerged as privileged substrates
in ACA.5 Recently, we efficiently engaged this family of
substrates in the copper-catalyzed enantioselective conjugate
addition of dimethylzinc to form all-carbon methyl-substituted
chiral scaffolds (ACA, Scheme 1, eq a),6 and highlighted the
synthetic potential of this methodology in the iterative
construction of chiral (poly)deoxypropionate motifs.6b In
regard to the stereoselective introduction of the hydroxyl
group, the asymmetric conjugate borylation (ACB) of boron
reagents to α,β-unsaturated carbonyl compounds has attracted
considerable interest in the recent years.7−9 Nevertheless, and to
the best of our knowledge, the construction of 1,3 diols through
consecutive ACB reactions has only been scarcely described.
Only two papers, both starting from unsaturated esters, have
described such consecutive ACB reactions, albeit with moderate
to good diastereoselectivities.8 Whiting and co-workers have
obtained low to moderate diastereoselectivities (from 58:42 to
92:8 for the match pairs and 58:42 to 87.5:12.5 for the mismatch
pairs) starting from borylated starting material.8a In the second
paper,8b Oestreich and co-workers described the enantioselec-
olyketides are a broad and structurally diverse class of
Psecondary metabolites with various medicinal applications,
as illustrated, for example, by the development of erythromycin,
amphotericin, or eribulin.1 Efficient strategies have been
developed for the iterative construction of polyacetates,
polypropionates, and poly-deoxypropionate motifs.2,3 On the
other hand, and despite the prevalence of 1,3,5,...n (OH, Me)
motifs in biologically relevant molecules (Figure 1), no practical
and broadly applicable unified strategy has been developed to
date for the synthesis of these units with high stereocontrol.
Received: February 5, 2019
Figure 1. Natural products embedding the 1,3,5,...n (OH, Me) motifs.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00479
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Organic Letters
Letter
Scheme 1. Copper-Catalyzed ACA and ACB Involving α,β-
Unsaturated 2-Acyl-N-methylimidazoles and Related
Iterative Processes
Table 1. Screening of Chiral Ligands L1−L6 for the Copper-
a
Catalyzed ACB with Model Substrate 1a
b
c
entry
Cu salt
Cu(OTf)2
ligand
NMR yield (%)
ee (%)
1
2
3
4
5
6
7
8
92
86
84
73
61
82
67
84
0
0
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(MeCN)4PF6
L1
L2
L3
L4
L5
L6
L6
49
76
85
16
98
98
d
Scheme 2. Diastereoselectivity Issues in the ACB from
Unsaturated Ester 3
a
Reaction conditions: all reactions were carried out in a glovebox at
0.2 mmol scale: (1) Cu salt (4 mol %), L (6 mol %), NaOtBu (20 mol
%), THF 30 min, then B2pin2 (1.1 equiv), THF, 10 min, then 1a (1
equiv), MeOH (2 equiv), THF, rt, 16 h; (2) NaBO3·4H2O (6 equiv),
b
1
THF/H2O (1/1), rt, 2 h. Determined by H NMR spectroscopy
c
with mesitylene as internal standard. Enantiomeric excesses were
determined by HPLC on a chiral stationary phase. Reaction carried
d
out in the presence of 4 Å MS using the classical Schlenk technique.
develop a practical unified strategy for the stereoselective
synthesis of 1,3,5,...n (OH, Me) motifs.
We report herein that Cu/Taniaphos efficiently catalyzes the
addition of bis(pinacolato)diboron (B2pin2) to α,β-unsaturated
2-acyl-N-methylimidazoles with high enantioselectivies. Fur-
thermore, thanks to the postfunctionalization of the acylimida-
zole fragment, we demonstrate that various 1,3,5-(OH, Me)
motifs could be synthesized in good yields and excellent
stereoselectivities through the consecutive Cu-catalyzed ACB/
ACA.
a
1
Diastereomeric ratios were determined by H NMR on the crude
products.
The copper-catalyzed conjugate addition of B2pin2 was
initially investigated on the model compound 1a (R = C7H15)
bearing a nonsubstituted acyclic chain, and for the sake of
simplicity, the enantiomeric excess was measured after oxidation
on the corresponding hydroxyl compound 2a. In the presence of
a catalytic amount of Cu(OTf)2 (4 mol %), NaOtBu (20 mol %),
and using B2pin2 (1.1 equiv), we could first demonstrate that the
borylation reaction proceeded efficiently in the absence of ligand
to afford the racemic product in 92% yield. This initial result
highlighted the necessity of developing a stable and robust chiral
catalytic system in order to prevent undesired racemic
background catalysis (Table 1, entry 1).
tive borylation from TBSO derivatives, and in this case, a
moderate 89:11 diastereoselectivity for both match and
mismatch pairs was observed.
On the other hand, the construction of 1,3 OH/Me moieties
through ACB reactions is to the best of our knowledge not yet
described. We used the optimized ACB conditions developed
for esters derivatives7a,8b on model compound (S)-3 derived
from citronellal with, however, disappointing diastereoselectiv-
ities (Scheme 2, see also the SI). There is thus room for
improvement to develop a general system for consecutive ACA
and ACB reactions. Thanks to the success obtained in ACA
reactions with acylimidazole reactions (Scheme 1, eq b), we thus
embarked on ACB reactions with such substrates to ideally
On the basis of our recent success with the copper-catalyzed
enantioselective transfer of methyl to α,β-unsaturated 2-acyl-N-
B
DOI: 10.1021/acs.orglett.9b00479
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Organic Letters
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Scheme 3. Substrate Scope for the Copper-Catalyzed ACB
Scheme 5. Diastereoselectivity Issues in the Construction of
1,3 (Me,OH) Motifs
with β-Substituted α,β-Unsaturated 2-Acyl-N-
a−c
methylimidazoles 1a−j Catalyzed by L6/Cu(MeCN)4PF6
a
1
Diastereomeric ratios were determined by H NMR on the crude
products.
Scheme 6. Synthesis of Homologated 2-Acyl-N-
methylimidazole 13
a
Reaction conditions: all reactions have been carried out at a 0.2
mmol scale: (1) Cu salt (4 mol %), L6 (6 mol %), NaOtBu (20 mol
%), 4 Å MS, THF 30 min, then B2pin2 (1.1 equiv), THF, 10 min, then
1a (1 equiv), MeOH (2 equiv), THF, rt, 16 h; (2) NaBO3·4H2O (6
b
equiv), THF/H2O (1/1), rt, 2 h. Yield of isolated product.
c
Enantiomeric excesses were determined by HPLC on a chiral
d
stationary phase. Moderate yield due to the instability of the starting
material. The reaction was performed in Et2O instead of THF.
e
Scheme 4. Determination of the Absolute Configuration of
Compound 5c
Scheme 7. Stereocontrolled Synthesis of 1,3,5 (Me, OH, Me)
Units
methylimidazoles, the ACB was first evaluated in the presence of
the unsymmetrical chiral NHC ligands L1 or L2.10 Unfortu-
nately, despite excellent conversions and isolated yields, the
expected compound 2a was obtained, respectively, in a racemic
form and with moderate 49% ee (Table 1, entries 2 and 3). More
promising results were observed when moving to C2-symmetric
bisphosphines as illustrated with the 76% ee obtained using (R)-
C
DOI: 10.1021/acs.orglett.9b00479
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Organic Letters
Letter
homologation/ACB/ACA for the construction of 1,3,5 (Me,
OH, Me) and 1,3,5 (OH, OH, Me) subunits.
Scheme 8. Stereocontrolled Synthesis of 1,3,5 (OH, OH, Me)
Units
The scale-up reaction was first attempted on acylimidazole 1b
(Scheme 3) bearing a long alkyl chain. Fruitfully, moving from a
0.2 to 2.0 mmol scale proved experimentally more practical and
beneficial in terms of isolated yield (84% vs 68%) with no change
in the enantiomeric excess (98%).
In order to determine the absolute configuration of the newly
formed stereogenic carbon centers, the borylated acylimidazole
5c was converted into the corresponding ester 6c and
subsequently oxidized in the presence of NaBO3 to the hydroxyl
derivative 7c in 49% yield (over three steps, Scheme 4). The
observed rotation (−40, c = 1, CHCl3) compares favorably with
the rotation described by Zhou for the (R) compound (−35.6, c
= 1, CHCl3).13 Accordingly, the (R) absolute configuration was
attributed to compounds 2a−g obtained with (R),(RP)-
Taniaphos.14
Then, to evaluate the diastereoselectivity outcome in the
presence of a remote methyl group, our asymmetric catalytic
borylation system was attempted using compound 8 derived
from (R)-citronellal (Scheme 5).6 In the presence of (R),(RP)-
Taniaphos, the expected compound (3R,5R)-9 was obtained in
good 75% yield and an excellent >95:5 diastereomeric ratio. The
diastereoselectivity for the mismatched pair could then be
evaluated using the (S) enantiomer of 8 in the presence (R),
(RP)-Taniaphos. In this case, the (3R,5S)-9 compound was
obtained with an excellent >95:5 dr and in 68% yield, which
could be improved to 84% at larger scale (2 mmol).
Interestingly, the above results evidenced no significant
match/mismatch effect and demonstrated that the control of
the selectivity is mainly governed by the copper chiral catalyst
and is the real benefit of acylimidazoles over esters in these
diastereoselective ACB reactions (see Scheme 2).
With the aim of fulfilling the requirements for adequate
methodology, the introduction of a third, either Me or OH,
stereogenic center was next considered starting from compound
(3R,5S)-9. However, the transformation of 9 to the correspond-
ing homologated unsaturated acylimidazole 13 proved more
challenging than initially expected. Indeed, after protection of
the secondary alcohol of 9 with a TBS or a benzyl group, all
attempts to transform the acylimidazole to an ester, aldehyde, or
Weinreb amide failed in our hands. Fortunately, the borylated
compound 10 (84% yield after ACB) could efficiently be
converted to the TBS-protected ester 11, which was further
homologated to the desired functionalized α,β-unsaturated 2-
acyl-N-methylimidazole (5R,7S)-13 (Scheme 6).
Binap (Table 1, entry 4). Screening more elaborated bi-
sphosphines such as (R),(SP)-Josiphos L4, (R),(SP),(SP′)-
Mandyphos L5, and (R),(RP)-Taniaphos L6 led to enhanced
enantioinduction with the identification of L6 as the most
efficient ligand affording 2a in satisfactory 67% yield and
excellent 98% ee (Table 1, entry 7).11 Nevertheless, when the
scale of the reaction was increased and the reaction was
performed outside the glovebox, it was later evidenced that its
efficiency could be impacted by water traces. Fortunately,
replacement of Cu(OTf)2 by the less hygroscopic Cu-
(MeCN)4PF6 (in the presence of 4 Å molecular sieves)
provided a robust catalytic system allowing the formation of
the desired product 2a with both high 84% yield and excellent
98% enantiomeric excess (Table 1, entry 8).
With the optimized conditions in hand, the scope of the ACB
reaction was next investigated with a variety of α,β-unsaturated
2-acyl-N-methylimidazole substrates (Scheme 3). As illustrated
in Scheme 3, the reaction is very efficient with unsaturated
acylimidazoles 1 bearing acyclic aliphatic chain substituents
leading to the hydroxylated products 2a−d in high yield and
with very high enantioselectivity (98% ee). Interestingly,
functionalized side chains are also well tolerated (see 2e,f).
On the other hand, the reaction appeared to be more sensitive to
steric hindrance. In fact, while only a slight decrease of the
enantioselectivity was observed for the isobutyl-substituted
product 2g, substrates 1h and 1i with bulkier γ-branched alkyl
substituents resulted under the standard conditions, in reduced
enantiocontrol (40 and 53% ee, respectively), which could be
moderately improved using diethyl ether as the reaction solvent
(66 and 73% ee’s, respectively). Finally, the trifluoromethylated
derivative 1j was nicely hydrated, leading to compound 2j in
45% yield and 96% ee.12
From compound (5R,7S)-13, the ACA reaction was first
attempted. As illustrated in Scheme 7, the matched reaction in
the presence of L1 proved efficient. Complete conversion, 81%
isolated yield, and an excellent >95:5 diastereoselectivity could
be observed. When the same reaction was carried out with ent-
L1 a small mismatch effect could be detected (90% conversion
and 70% isolated yield) with, however, a very good 94:6
diastereoselectivity.
In related ACB reactions from (5R,7S)-13, the syn,anti
(3R,5R,7S)-15 and anti,anti (3S,5R,7S)-15 have been obtained
in good yields and excellent diastereoselectivities (>95:5 dr)
with no marked differences between the match and mismatch
pairs (Scheme 8). Interestingly, the diastereotopic signals of the
CH2 groups (C2 carbon) of the two diastereomers appear very
Having developed an efficient asymmetric borylation reaction
with acylimidazole substrates, several key criteria needed to be
addressed to ensure successful implementation in total synthesis
strategies: (i) applicability of the catalytic system on larger scale;
(ii) determination of the absolute configuration of the secondary
alcohols; (iii) diastereoselectivity outcomes in the presence of
1,3 remote Me or (protected) OH; and (iv) practical
1
differently in the H NMR spectrum acquired in CDCl3
(Scheme 8).
D
DOI: 10.1021/acs.orglett.9b00479
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Letter
́
́
(4) (a) Mauduit, M.; Basle, O.; Clavier, H.; Crevisy, C.; Denicourt-
Nowicki, A. In Comprehensive Organic Synthesis II; Knochel, P.,
Molander, G. A., Eds.; Elsevier, 2014; Vol. 4, p 186. (b) For a seminal
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In conclusion, Cu/Taniaphos catalyzed efficiently the β-
borylation of α,β-unsaturated 2-acyl-N-methylimidazoles. After
NaBO3-mediated oxidation, the corresponding secondary
alcohols were obtained in high yields and enantioselectivities
(10 examples, 66−98%). Excellent enantioselectivities (93 to
98% ee) were obtained with aliphatic chains, including
functionalized ones, with the exception of γ-branched substrates
which gave moderate selectivity (up to 73% ee). Following the
readily postfunctionalization of acylimidazole fragment, consec-
utive Cu-catalyzed ACB/ACA recations were successfully
achieved, leading to 1,3,5-(Me, OH, Me) and 1,3,5-(OH, OH,
Me) motifs in good yields and excellent stereoinductions (>95:5
dr). We have thus been able to propose a unified strategy for the
construction of highly desirable 1,3,5,...n (OH, Me) motifs
prevalent in biologically relevant molecules. Implementation of
this methodology in the total synthesis of natural products is
currently underway in our laboratories.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00479.
Spectral data (PDF)
Experimental procedures (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
́
́
*E-mail: jean-marc.campagne@enscm.fr.
*E-mail: marc.mauduit@ensc-rennes.fr.
ORCID
́
́
́
Olivier Basle: 0000-0002-4551-473X
Renata Marcia de Figueiredo: 0000-0001-5336-6071
Marc Mauduit: 0000-0002-7080-9708
Jean-Marc Campagne: 0000-0002-4943-047X
Present Address
§
́
(O.B.) LCC-CNRS, Universite de Toulouse, CNRS, Toulouse,
(8) (a) Pujol, A.; Whiting, A. J. Org. Chem. 2017, 82, 7265−7279.
(b) Hartmann, E.; Oestreich, M. Org. Lett. 2012, 14, 2406−2409.
(9) For selected reviews, see: (a) Westcott, S. A.; Fernandez, E. Adv.
Organomet. Chem. 2015, 63, 39−130. (b) Hemming, D.; Westcott, S.
A.; Santos, W. L.; Steel, P. G.; Fritzemeier, R. Chem. Soc. Rev. 2018, 47,
7477−7494. (c) Neeve, E.; Geier, S.; Mkhalid, I.; Westcott, S.; Marder,
T. Chem. Rev. 2016, 116, 9091−9161.
France.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The project was supported by funds from the ENSCM, the
ENSCR, the CNRS, and the Fondation pour le developpement
■
(10) Tarrieu, R.; Dumas, A.; Thongpaen, J.; Vives, T.; Roisnel, T.;
́
́
́
Dorcet, V.; Crevisy, C.; Basle, O.; Mauduit, M. J. Org. Chem. 2017, 82,
1880−1887.
(11) For the seminal use of Taniaphos ligand in the ACB reactions of
cyclic enones and lactones, see ref 7b.
de la chimie des substances naturelles et ses applications (JL
PhD grant). Special thanks to Takasago Company for a generous
gift of citronellal.
(12) The relatively low (45%) yield obtained in this reaction is mainly
due to the unoptimized oxidation reaction: 10% of the protodeborated
compound could also be isolated. Moreover, compound 2j and pinacol
are unseparable by flash chromatography, thus requiring elimination of
the pinacol byproduct by evaporation in vacuo. Under these
purification conditions, undesired slow sublimation of 2j could also
be observed.
(13) Bao, D.; Wu, H.; Liu, C.; Xie, J.; Zhou, Q. Angew. Chem., Int. Ed.
2015, 54, 8791−8794.
(14) (S) configurations for compounds 2h, 2i, and 2j due to inversed
priorities in the CIP system.
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