Organocatalytic atroposelective aldol condensation: Synthesis of axially chiral biaryls by arene formation

Article abstract of DOI:10.1002/anie.201402441

Axially chiral compounds are of significant importance in modern synthetic chemistry and particularly valuable in drug discovery and development. Nonetheless, current approaches for the preparation of pure atropisomers often prove tedious. We demonstrate here a synthetic method that efficiently transfers the stereochemical information of a secondary amine organocatalyst into the axial chirality of tri-ortho-substituted biaryls. An aromatic ring is formed during the dehydration step of the described aldol condensation cascade, leading to highly enantioenriched binaphthyl derivatives. The fundamental course of the reaction is related to the biosynthesis of aromatic polyketides. Head-turning! An organocatalytic atroposelective aldol condensation to tri-ortho-substituted biaryls is described. Key to the process is an efficient transfer of the stereochemical information of a secondary amine catalyst into the axis of chirality of binaphthyl products. The reaction proceeds analogous to the aromatic polyketide biosynthesis and is distinct in its initiation by virtue of dienamine formation. This method allows for the synthesis of axially chiral biaryls with remarkable atroposelectivity of up to e.r. 99:1.

Full text of DOI:10.1002/anie.201402441

Angewandte
Chemie
DOI: 10.1002/anie.201402441
Synthetic Methods
Hot Paper
Organocatalytic Atroposelective Aldol Condensation: Synthesis of
Axially Chiral Biaryls by Arene Formation**
Achim Link and Christof Sparr*
Dedicated to Professor Andreas Pfaltz
Abstract: Axially chiral compounds are of significant impor-
tance in modern synthetic chemistry and particularly valuable
in drug discovery and development. Nonetheless, current
approaches for the preparation of pure atropisomers often
prove tedious. We demonstrate here a synthetic method that
efficiently transfers the stereochemical information of a secon-
dary amine organocatalyst into the axial chirality of tri-ortho-
substituted biaryls. An aromatic ring is formed during the
dehydration step of the described aldol condensation cascade,
leading to highly enantioenriched binaphthyl derivatives. The
fundamental course of the reaction is related to the biosynthesis
of aromatic polyketides.
C
yclase and aromatase proteins catalyze specific intramo-
lecular aldol addition and dehydration reactions in aromatic
polyketide biosynthesis (PKS). The acetate-derived, highly
reactive poly-b-ketones are temporarily stabilized by PKS
proteins and subsequently folded selectively into the corre-
sponding cyclic structure to form discrete resorcinol deriva-
tives after a dehydration step (Scheme 1a; e.g. orsellinic
acid). This biocatalytic reaction cascade allows for the
regulation of a striking number of polyketide natural products
that participate in various biological processes.[1] Considering
this fascinating functionality, it is not surprising that analo-
gous condensation reactions were implemented for prepara-
tive, synthetic chemistry to access aromatic compounds. In
seminal work by Harris, Barrett, Yamaguchi, and others,
innovative strategies for polyketide synthesis have been
realized in which the intramolecular aldol addition is trig-
gered by the formation of an enolate anion.[2]
Scheme 1. a) Aromatic polyketide biosynthesis of orsellinic acid. CYC:
cyclase, ARO: aromatase. b) Atroposelective aldol condensation to tri-
ortho-substituted biaryls catalyzed by secondary amines.
reactions by enamine activation, b) the prospect of trans-
ferring central to axial chirality during a dehydration step, and
c) the large driving force and irreversibility of arene forma-
tion.[5,6] These compelling features motivated us to undertake
synthetic studies towards an organocatalytic atroposelective
variant of aromatic polyketide biosynthesis.
Owing to the ideal reactivity of a-acidic aldehydes with
chiral secondary amine organocatalysts, ketoaldehyde sub-
strates that lead to axially chiral binaphthyl derivatives by an
aldol condensation reaction were considered as a suitable
starting point for our exploration (Scheme 1b). Archetypical
poly-b-ketones exist in solution as a mixture of keto and enol
tautomers. The b- and d-keto groups were therefore replaced
by an aryl and an olefin functional group to obtain a more
defined synthetic model. Through the course of the reaction,
the a-carbon atom is activated by dienamine formation and,
as a consequence of the ortho disubstitution and the
Z geometry of the olefin, positioned precisely over the keto
group by the rotation depicted in Scheme 1b. An effective
transfer of stereochemical information from the catalyst to
the axial chirality of the product would culminate the process
by giving access to enantioenriched C1-symmetric biaryls.
We began our studies with a modular synthesis of a model
substrate precursor from readily available starting materials.
The LiCl-promoted Br/Mg exchange of 1,2-dibromobenzene
(1) described by Knochel was followed by the addition of
In this context we envisaged that the scope of application
of the aldol condensation to aromatic compounds could be
further extended, if the cyclization event is initiated by an
alternative process, namely by formation of dienamines.[3,4]
This proposal is based on following considerations: a) the
array of methods for enantioselective catalytic aldol addition
[*] A. Link, Dr. C. Sparr
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: christof.sparr@unibas.ch
Homepage: http://www.chemie.unibas.ch/~sparr
[**] We thank Prof. Dr. K. Gademann for generous financial support,
Novartis AG for an Excellence Scholarship for Life Sciences, Priv.-
Doz. Dr. D. Hꢀussinger for assistance with NMR spectroscopy, and
Dr. M. Neuburger for X-ray crystallography.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402441.
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Table 1: In situ generation of substrate 5a[a] and optimization of reaction
parameters of the atroposelective aldol condensation.[b]
Scheme 2. Synthesis of the substrate precursor (Æ)-4a. a) iPrMgBr·
LiCl, THF, 1, À158C, then 2; b) 3-Butyn-1-ol, CuI, [Pd(PPh3)4], iPr2NH;
c) Ni(OAc)2·4H2O, NaBH4, EtOH, H2, then (Æ)-3a and ethylene-
diamine; 73% over three steps.
1-naphthaldehyde (2; Scheme 2).[7] A subsequent Sonoga-
shira cross-coupling reaction with 3-butyn-1-ol and a fully
Z-selective hydrogenation of (Æ)-3a on colloidal nickel
resulted in a 73% yield over three steps.[8] This short reaction
sequence allowed for the efficient preparation of substrate
precursor(Æ)-4a, poised for later conversion to the z-ketoal-
dehyde 5a by a double oxidation process.
Oxidation using Dess–Martin periodinane (DMP) pro-
vided substrate 5a in 91% yield (Table 1).[9] When inves-
tigating the stability of compound 5a, we found that the
z-ketoaldehyde is stable as a solution in CDCl3 over an
extended period of time, but slowly decomposes in isolated
form. Gratifyingly, the reaction mixture after the oxidation
step was amenable to purification over poly-4-vinylpyridine
to furnish 5a as a CDCl3 solution of high purity.
Having established the in situ generation of the substrate,
we embarked on the key experiments by using privileged
secondary amine catalysts (Table 1). Intriguingly, when
l-proline 7 was used, the desired binaphthalene carbaldehyde
(aS)-6a could be isolated and a promising enantiomeric ratio
was measured (entry 1; e.r. 88:12). Product formation was
also observed when MacMillan imidazolidinones 8–10 were
employed. In this case, the absence of atroposelectivity
suggests that competing general-base catalysis is operational
(entries 2–4). Additionally, the performance of TMS-diaryl-
prolinol catalysts 11 and 12 was assessed (entries 5 and 6).
These experiments also indicated lack of stereoinduction and
we therefore turned our attention to proline derivatives 13
and 14 (entries 7 and 8).[10,11] After catalyst 13 proved
inefficient, excellent atroposelectivity was achieved by
employing pyrrolidinyl-tetrazole catalyst 14 (entry 8; e.r.
99:1). In quest of optimal reaction parameters, we evaluated
the effect of substrate concentration and solvent mixtures. A
high substrate concentration was found to be advantageous
(entries 8–10), while solvent mixtures resulted in slightly
lower selectivity (entries 11 and 12). However, dilution with
CD3OD had only a marginal effect on the efficiency of the
process (entry 12 versus entry 8).
Entry
Cat.
Solvent
T
e.r.[c]
1
2
3
4
5
6
7
8
7
8
9
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
308C
408C
508C
608C
88:12
49:51
51:49
45:55
59:41
49:51
57:43
99:1
96:4
94:6
96:4
98:2
10
11
12
13
14
14
14
14
14
14
14
14
14
9
CDCl3 (4ꢁ)[d]
CDCl3 (8ꢁ)[e]
CDCl3/C6D6 (1:3)[d]
CDCl3/CD3OD (1:3)[d]
CDCl3
CDCl3
CDCl3
CDCl3
10
11
12
13
14
15
16
98:2
97:3
96:4
94:6
[a] 3.0 equiv DMP, 3.0 equiv D2O for 14 h at RT; filtration over poly-4-
vinylpyridine; 91%. [b] The reactions were performed with 10 mol%
7–14 at a concentration of 40 mmolLÀ1. [c] Determined by HPLC.
[d] 10 mmolLÀ1. [e] 5.0 mmolLÀ1
.
examined the response to increased reaction temperatures by
measuring the corresponding enantioselectivity (entries 13–
16). A remarkably linear temperature dependence of stereo-
control was observed in this series of experiments. It is
noteworthy that an unusually high atroposelectivity could be
sustained at temperatures of up to 608C (entry 16; e.r. 94:6).
Nonetheless, to combine enantiocontrol and practicality, we
continued our investigations with reactions at room temper-
ature.
An indication for the configurational stability of the
product was obtained by heating a solution of (aS)-6a (958C,
3 h). HPLC analysis showed an unaffected enantiomeric
ratio; considerable thermal atropisomerization is therefore
not expected even at elongated reaction times. Moreover, we
In order to determine the optimal catalyst loading, we
compared the data obtained after a reaction time of 46 h
(Table 2). The highest atroposelectivity was observed at 5 and
10 mol% catalyst loading, while conversion to 6a was similar
for both cases (entries 3 and 4). The required catalyst loading
2
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Table 2: Influence of the catalyst loading on conversion and selectivity.[a]
Table 3: Scope of the atroposelective aldol condensation under the
optimized reaction conditions.[a]
Entry
14
Conversion to 6a[b]
e.r.[c]
1
2
3
4
5
1.0 mol%
2.5 mol%
5.0 mol%
10 mol%
20 mol%
27%
48%
69%
71%
87%
97:3
98:2
99:1
99:1
98:2
[a] The reactions were performed at RT and 50 mmolLÀ1 in CDCl3 for
46 h. [b] Determined by NMR spectroscopy. [c] Determined by HPLC.
Yield[b]
74%
[a]D
e.r.[d]
99:1
[c]
Entry
1
Product
t
could therefore be reduced by half for the remainder of the
studies.
With the optimized reaction conditions in hand, we
focused on the scope and limitations of the reaction
(Table 3). Binaphthalene carbaldehyde (aS)-6a was obtained
in 74% yield and 99:1 atroposelectivity after 68 h reaction
time (entry 1). It bears mentioning that the Z–E isomer-
ization of the dienamine can be sufficiently prevented under
these reaction conditions.[13] The corresponding phenanthryl-
naphthaldehyde (aS)-6b could also be prepared by the
described method in comparable yield and excellent selec-
tivity (entry 2; e.r. 99:1). However, substrates with substitu-
ents at the 2- or 8-position of the naphthalene moiety were not
converted to the corresponding binaphthalene carbaldehydes
and represent the limitations of the reaction.[14] The electron-
withdrawing propensity of the difluorophenyl group was
reflected by a shorter reaction time and an improved yield,
while a satisfyingly high level of stereocontrol was retained
(entry 3; 89%, e.r. 98:2). This is in contrast to the reduced
reaction rate and the perceivable reduction of atroposelec-
tivity for the tetrafluoro derivative (aS)-6d (entry 4; e.r. 96:4).
Moreover, electron-rich aryls were also efficiently annulated,
albeit extended reaction times were required (entries 5 and
6). Again, a remarkable degree of stereoinduction was
attained, demonstrating the generality of the method. The
absolute configuration of the products was established by
derivatization to known compounds and X-ray crystallo-
graphic studies. Using (S)-pyrrolidinyl-tetrazole catalyst 14,
these determinations are in accordance with an (aS) config-
uration.[15]
In summary, we report a novel synthetic strategy for the
atroposelective preparation of unsymmetrically substituted
1,1’-binaphthalene-2-carbaldehydes. The excellent enantio-
control of the process stems from the efficient transfer of
stereochemical information of the catalyst into the axis of
chirality of biaryl products. To the best of our knowledge, this
is the first example of atroposelective secondary amine
catalysis. Furthermore, we describe an unprecedented initia-
tion of the aldol condensation to aromatic compounds, which
are not readily accessible otherwise. The application of this
strategy to other substrate classes and mechanistic investiga-
tions addressing the intricacies of the chirality transfer are
currently in progress in our group and will be reported in due
course.
68 h
À104.0
+116.7
À56.8
2
3
67 h
28 h
76%
89%
99:1
98:2
4
88 h
66%
À110.9
96:4
5
6
87 h
86 h
74%
67%
À204.7
À171.2
98:2
99:1
[a] The reactions were performed with 150 mmol 5a–f and 5.0 mol% 14
at RT and 25 mmolLÀ1 dilution. [b] Yield of isolated product. [c] Mea-
sured at RT in CHCl3 (c 1.00). [d] Determined by HPLC.
Keywords: aldol reaction · atropisomerism · enantioselectivity ·
.
organocatalysis · polyketides
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Published online: && &&, &&&&
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[15] CCDC 988866 [(À)-(aS)-6a] and CCDC 988867 [(À)-(aS)-6d]
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4
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Chemie
Communications
Synthetic Methods
A. Link, C. Sparr*
&&&& — &&&&
Organocatalytic Atroposelective Aldol
Condensation: Synthesis of Axially Chiral
Biaryls by Arene Formation
Head-turning! An organocatalytic
reaction proceeds analogous to the aro-
atroposelective aldol condensation to tri-
ortho-substituted biaryls is described. Key
to the process is an efficient transfer of
the stereochemical information of a sec-
ondary amine catalyst into the axis of
chirality of binaphthyl products. The
matic polyketide biosynthesis and is dis-
tinct in its initiation by virtue of dien-
amine formation. This method allows for
the synthesis of axially chiral biaryls with
remarkable atroposelectivity of up to e.r.
99:1.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!