Enantioselective H-bond-directing approach for trienamine-mediated reactions in asymmetric synthesis

Article abstract of DOI:10.1002/anie.201204790

Right direction: The presented enantioselective strategy for the preparation of diversely functionalized tetrahydroxanthones is based on a trienamine-mediated cycloaddition between 2,4-dieneals and activated chromones. It is possibile to control the stere

Full text of DOI:10.1002/anie.201204790

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Chemie
DOI: 10.1002/anie.201204790
Asymmetric Catalysis
Enantioselective H-Bond-Directing Approach for Trienamine-
mediated Reactions in Asymmetric Synthesis**
Łukasz Albrecht, Fabio CruzAcosta, Alberto Fraile, Anna Albrecht, Jannie Christensen, and
Karl Anker Jørgensen*
Control of remote stereocenters constitutes an important
challenge in modern organic synthesis.[1,2] Despite limited
generality, asymmetric strategies enabling such functionaliza-
tions have found important applications in target-oriented
synthesis, thereby indicating their potential.[1e,2] In recent
years, dienamine- and trienamine-mediated reactions have
emerged as new tools that enable stereoselective functional-
izations of unsaturated aldehydes at the remote g- or e-
positions, respectively.[3,4] In this context, trienamine-based
strategies that allow stereocontrolled reactions at the carbon
atom seven bonds away from the stereocenter of the catalyst
are notable.[4] Classically, such aminocatalytic transformations
are realized using the steric shielding principle for stereo-
chemical induction.[5] However, important restrictions related
to the dienophile scope still exist. One solution to this
problem might rely on the application of H-bond-directing
aminocatalysts in trienamine chemistry (Scheme 1). Benefits
of such strategies relate not only to the dual activation of the
reaction partners, which positions them correctly in space,
thereby providing a well-defined stereochemical environ-
ment; more importantly, such strategies open the possibility
of accessing new reactivities and reaction profiles resulting in
further development of this field of chemistry.
Development of new synthetic strategies that lead to
pharmacologically active structural units is of high impor-
tance for the chemical community and constitutes an impor-
tant part of the drug discovery process. The tetrahydroxan-
thone structural unit (Scheme 2a) is often encountered in
nature and among pharmacologically active compounds.[6]
Scheme 2. a) Importance of the tetrahydroxanthone structural unit,
b) natural products containing this unit, and c) novel enantioselective
approach to this class of compounds.
Blennolide A, secalonic acid D, and a-diversonolic ester
(Scheme 2b) constitute representative examples of a rich
family of natural products containing the tetrahydroxanthone
unit. These compounds were isolated from fungi, bacteria,
and lichens and are well-recognized for their antibiotic
activity.[6,7]
Scheme 1. Remote functionalizations through H-bond-directed trien-
amine chemistry.
Given the biological properties of optically active tetra-
hydroxanthone derivatives and their wide occurrence in
nature, studies on a synthetic methodology that offers
a general and stereoselective access to this class of compounds
were initiated. It was anticipated that such an approach for
the preparation of tetrahydroxanthone derivatives could rely
on the trienamine-mediated reaction between chromones and
2,4-dienals (Scheme 2c).
[*] Dr. Ł. Albrecht, F. CruzAcosta, Dr. A. Fraile, Dr. A. Albrecht,
J. Christensen, Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry, Aarhus University
8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
[**] This work was made possible by grants from Aarhus University,
OChemSchool, Carlsberg Foundation, and FNU. F.C.A. thanks CSIC
for predoctoral JAE grant. We thank Dr. Jacob Overgaard for
performing X-ray analysis.
Herein, we present a new, enantioselective approach to
biologically relevant tetrahydroxanthone derivatives based
on a novel trienamine-mediated [4+2] cycloaddition with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204790.
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activated chromones as dienophiles. Furthermore, the possi-
bility to control the stereochemical outcome of organocata-
lytic trienamine-mediated reactions by an H-bond-directing
aminocatalyst is demonstrated.
Initial experiments identified the presence of the cyano
group in the 3-position of the starting chromone as a crucial
factor ensuring high reactivity, and more importantly, high
diastereoselectivity of the tested cycloaddition. Accordingly,
optimization studies were initiated using 5-methyl-2,4-hexa-
dienal 1a and 3-cyanochromone 2a[8] as model substrates
(Table 1; for full screening results, see the Supporting
(Table 1, entry 5). It should be noted, that for catalysts 7a,b
the use of N,N-diethylacetamide (DEA) was necessary to
achieve good catalytic activity. Further screening concerning
the effect of concentration (Table 1, entries 5, 7, 8) revealed
that higher dilutions were beneficial for the reaction outcome.
Finally, the amount of additive was screened (Table 1,
entries 8–11), and the results indicate the significant influence
of the amount of additive on both reactivity and enantiose-
lectivity of the reaction.
After having established the optimal reaction conditions
for the H-bond-directed [4+2] cycloaddition, we turned the
attention to the scope of the methodology (Table 2). Delight-
fully, the developed reaction proved general, as both electron-
rich (Table 2, entries 2–4) and electron-poor chromones
(Table 2, entries 5–7) could be applied to afford the target
products 3b–g in good yields (59–98%) and with high
enantioselectivities (88–91% ee). Furthermore, in all of the
cases, complete diastereoselectivity was observed. Longer
reaction times were required to achieve full conversion for
chromones 2b–d and 2g, thus indicating the influence of both
Table 1: Enantioselective synthesis of tetrahydroxanthone 3a: optimiza-
tion studies.[a]
Table 2: Enantioselective synthesis of tetrahydroxanthones 3: 3-cyano-
chromone scope.[a]
Entry Cat. Conc. [m] Additive t [h] Conv. [%][b] d.r.[c]
ee [%][d]
(equiv)
1
2
3
4
5
6
7
8
4a
4b 0.33
0.33
–
–
–
–
20
20
20
20
85
60
85
67
75
73
92
74
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
46[e]
60[e]
45[e]
76
87
82
5
6
0.33
0.33
7a[f] 0.33
7b[f] 0.33
7a[f] 0.1
DEA(4) 20
DEA(4) 20
DEA(4) 48
DEA(4) 48
DEA(8) 48
DEA(16) 48
DEA(32) 48
Entry
2
Reaction 3: Yield [%] d.r.[b]
time [h]
ee
[%][c]
89
7a[f] 0.05
7a[f] 0.05
7a[f] 0.05
7a[f] 0.05
>20:1 n.d.
9
10
11
92 (91) >20:1
87
>95
90
89
86
1
2
3
4
5
6
2a 48
3a: 91
3b: 98
3c: 80
>20:1 90
>20:1
>20:1
2b 96
2c 96
>20:1 90
[a] Reactions performed on a 0.1 mmol scale (see the Supporting
Information for details). Tf=trifluoromethanesulfonyl, TFA=trifluoro-
acetic acid. [b] Conversion of 2a as determined by 1H NMR spectros-
copy. The yield of isolated product 3a is given in parentheses.
>20:1 90
>20:1 88
>20:1 91
>20:1 90
1
[c] Determined by H NMR spectroscopy. [d] Determined after Ramirez
olefination by HPLC using a chiral stationary phase. [e] ent-3a was
obtained. [f] 16 mol% of catalyst applied.
2d 2 weeks 3d: 87
2e 48
2 f 48
3e: 96
3 f: 98
Information). Disappointingly, when classical sterically
demanding catalysts 4 or 5 were applied (Table 1, entries 1–
3), moderate enantioselectivities (45–60% ee) were obtained.
To overcome these difficulties we turned our attention to an
H-bond-directed catalytic approach.[4f,9] It was reasoned that
additional activation of 2a through hydrogen bonding should
lead to an increase in its reactivity and provide a well-defined
stereochemical environment resulting in enhanced enantio-
selectivity. To our delight, application of the H-bond-directing
catalysts 6 or 7 (Table 1, entries 4–6) led to a significant
improvement of the enantioselectivity (76–87% ee) with
squaramide-based organocatalyst 7a being the most effective
7
2g 96
3g: 59
>20:1 89
[a] Reactions were performed on a 0.2 mmol scale (see the Supporting
Information for details). [b] Determined by 1H NMR spectroscopy.
[c] Determined after Ramirez olefination by HPLC using a chiral sta-
tionary phase.
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electronic and steric factors on the reactivity of the 3-
cyanochromones.
In further studies, the possibility to utilize differently
substituted 2,4-dienals 1 in the developed H-bond-directed
[4+2] cycloaddition was evaluated (Scheme 3). To our
delight, different substituents could be present in the starting
Scheme 4. Enantioselective synthesis of tetrahydroxanthones 9 and 12
that contain d-lactone rings. DCE=dichloroethane.
fully controlled by decreasing the reaction temperature to
À208C, thereby affording 8 as a single diastereoisomer.
Interestingly, when NaBH(OAc)3 was employed as the
reducing agent, chemoselective reduction of the aldehyde
moiety could be achieved, thereby affording 10 in a mixture
with its corresponding hemiacetal 11 in a 3:1 ratio. Sub-
sequently, the crude reaction mixtures were subjected to
hydrolytic cyclization under acidic conditions. In such
a manner, the d-lactone ring was furnished affording 9 and
12 in good overall yields and as single diastereoisomers.
Further application studies were focused on the utilization
of the carbonyl groups of 3 for the introduction of an
additional tetrahydropyrane ring in the target products. Two
complementary routes enabling such functionalization were
elaborated. The first was initiated by a Wittig reaction of
tetrahydroxanthone 3a with stabilized ylide 13 followed by
chemo- and diastereoselective reduction of the ketone moiety
(Scheme 5). A subsequent, TFA-mediated, intramolecular
oxa-Michael reaction of 14 afforded the target product 15 in
a high 82% overall yield. Notably, the developed reaction
sequence allows the introduction of two new stereogenic
centers in a fully diastereoselective manner. In the second
approach, chemoselective reduction of the aldehyde moiety
of 3a was performed as the first step. Hereafter, Lewis acid
mediated reductive etherification of the originally formed
mixture of alcohol 10 and its hemiacetal 11 using triethylsi-
lane as a reducing agent was performed, and enabled
stereoselective construction of the tetrahydropyrane ring in
16 (Scheme 5). Importantly, both developed reaction sequen-
ces consisting of either two or three steps could be performed
without purification of the intermediates, thereby underlining
the high practicality of the developed synthetic strategies.
The absolute configuration of the products was unambig-
uously assigned by using single-crystal X-ray analysis of the
corresponding Ramirez olefination products derived from 3c
and 3j (Scheme 6a).[10] The absolute configuration of the
remaining products 3a, b, d–i, k, l was assigned by analogy.
The relative configuration of the newly introduced stereo-
genic centers in products 9, 15, and 16 was assigned by 1D
Scheme 3. Enantioselective synthesis of tetrahydroxanthones 3:
2,4-dienal scope (see the Supporting Information for details).
2,4-dienals 1, hereby further increasing the structural diversity
of the obtained products 3. Moreover, the introduction of an
additional stereogenic center in the 4-position of the target
tetrahydroxanthones proved possible. Notably, the reactions
proceeded with a very high and unprecedented[4] trans-
relationship between the C1 and C4 stereogenic centers in
3j,k that originate from the starting 2,4-dienals 1 (for
a discussion of the stereochemical outcome of the reaction,
see Scheme 6). Importantly, less reactive and more challeng-
ing, linear substrates could also be employed as demonstrated
for 2,4-hexadienal 1 f (1 with R1 = R2 = R3 = H in Scheme 3)
providing 3l.
After the successful development of an H-bond-directed
approach for trienamine-mediated reactions, the possibilities
of synthetic utilization of the obtained cycloadducts 3 were
investigated. We were particularly interested in the applica-
tion of the densely functionalized molecular scaffold of 3 for
the construction of various polycyclic structures. Initially we
investigated the possibility to introduce a d-lactone ring
system to the target products in a sequence of reactions that
involves reduction of the aldehyde moiety and a subsequent
hydrolytic cyclization onto the inherent cyano group. When
tetrahydroxanthone 3a was subjected to NaBH4 reduction,
both carbonyl groups in 3a were reduced (Scheme 4).
Importantly, the diastereoselectivity of this process could be
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Accordingly, it is assumed that the corresponding trienamine
=
À
=
intermediate reacts in the s-cis-(C3 C4 C5 C6) and s-cis-
=
À
=
(C1 C2 C3 C4) conformation and the reaction occurs
across the remote diene system. However, for steric reasons,
the presence of a substituent in the 4-position of 1 forces the
reaction to proceed through transition state B. In this case, the
sterically demanding R1 substituent positions itself away from
the first double bond of the trienamine system as well as from
the C2 substituent of the pyrrolidine catalyst. This reactive
conformation of the diene can account for the unprecedented
trans relationship between the C1 and C4 stereogenic centers
of 3. In both cases, proper alignment of the reactive diene
system with respect to the chromone dienophile is postulated
to be the crucial factor determining the stereochemistry of the
product. Nonetheless, the obtained results suggest that the
mechanism(s) of trienamine-mediated reactions can be
a rather complex issue and might be highly dependent on
the structure of the starting dienal. Computational studies in
an attempt to understand H-bond-directed trienamine-medi-
ated reactions are currently in progress.
Scheme 5. Introduction of a tetrahydropyrane ring into tetrahydroxan-
thone 3a.
In summary, the first H-bond-directed trienamine-medi-
ated [4+2] cycloaddition was developed, thereby demonstrat-
ing the viability of such an activation strategy. The reaction
between diversely substituted 2,4-dienals and 3-cyanochro-
mones proceeded smoothly and in a highly stereoselective
manner in the presence of a squaramide-containing amino-
catalyst. Furthermore, it was demonstrated that the obtained
cycloadducts can be chemo- and diastereoselectively trans-
formed into polycyclic products with high molecular and
stereochemical complexity that possess up to five stereogenic
centers. An unexpected stereochemical outcome of the
reaction was observed and a rationalization of the results
was provided.
Received: June 19, 2012
Published online: && &&, &&&&
Scheme 6. Configurational assignments and rationalization for the
stereochemical outcome of the H-bond-directed trienamine-mediated
cycloadditions. a) Crystal structures of the products of the Ramirez
olefination of 3c (right) and 3j (left). Blue N; red O, white H; gray C,
brown Br. b) Transition state models for the H-bond-directed trien-
amine-mediated cycloadditions and the corresponding products.
Keywords: asymmetric synthesis · organocatalysis ·
synthetic methods · tetrahydroxanthones · trienamines
.
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Communications
Asymmetric Catalysis
Ł. Albrecht, F. CruzAcosta, A. Fraile,
A. Albrecht, J. Christensen,
K. A. Jørgensen*
&&&& — &&&&
Enantioselective H-Bond-Directing
Approach for Trienamine-mediated
Reactions in Asymmetric Synthesis
Right direction: The presented enantio-
selective strategy for the preparation of
diversely functionalized tetrahydroxan-
thones is based on a trienamine-medi-
ated cycloaddition between 2,4-dieneals
and activated chromones. It is possibile
to control the stereochemical outcome of
such reactions by employing an H-bond-
directing aminocatalyst.
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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