A temporary-bridge strategy for enantioselective organocatalyzed synthesis of aza-seven-membered rings

Article abstract of DOI:10.1039/c4cc07731h

We report the first enantioselective organocatalyzed domino synthesis of azepane moieties. This temporary-bridge strategy is based on a conceptually original annulation of ambident electrophilic and 1,4-bis-nucleophilic α-ketoamides with 1,3-bis-electrophilic enals. The obtained oxygen-bridged azepanes can be selectively transformed into optically active azepanone, azepanol or azepanedione derivatives of high synthetic value. This journal is

Full text of DOI:10.1039/c4cc07731h

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A temporary-bridge strategy for enantioselective
organocatalyzed synthesis of aza-seven-membered
rings†
Cite this: Chem. Commun., 2014,
50, 15605
Received 30th September 2014,
Accepted 14th October 2014
Sebastien Goudedranche, David Pierrot, Thierry Constantieux, Damien Bonne* and
´
Jean Rodriguez*
DOI: 10.1039/c4cc07731h
www.rsc.org/chemcomm
We report the first enantioselective organocatalyzed domino synth-
esis of azepane moieties. This temporary-bridge strategy is based on
a conceptually original annulation of ambident electrophilic and
1,4-bis-nucleophilic a-ketoamides with 1,3-bis-electrophilic enals. The
obtained oxygen-bridged azepanes can be selectively transformed into
optically active azepanone, azepanol or azepanedione derivatives of
high synthetic value.
The design of new efficient enantioselective organocatalyzed domino
transformations is a very active field of research especially for
synthesizing complex cyclic enantiopure molecules from easily
accessible acyclic starting materials in an environmentally
friendly way.1 In this context, enantioselective organocascades
of five-2 and six-membered cycles3 are well documented, while
accessing the parent seven-membered cycles still constitutes a
Scheme 1 Organocatalytic approaches and the temporary-bridge strategy
to synthesize seven-membered cycles.
real synthetic challenge4,5 due to the need to overcome a negative bridging step, when properly functionalized 1,4-bis-nucleophile
entropic factor during the ring closing step.6 As rare examples of 1 bearing an additional electrophilic center reacts with 1,3-bis-
success in this field, in the benzoxepinone series, two closely related electrophile 2 possessing a latent nucleophile that results in the
enantioselective carbene-catalyzed formal [4+3] heterocycloadditions concomitant formation of three covalent bonds. In a subsequent
have been proposed (Scheme 1a).7 Additionally, a very recent chiral step, the bridge could be selectively cleaved (revealing step),
phosphoric acid (CPA)-catalyzed enantioselective intramolecular allowing the formation of a highly functionalized optically active
Mannich reaction has been known to give access to dibenzo[1,4]- seven-membered ring system 4.
diazepine scaffolds (Scheme 1b).8 Hence, an efficient complementary
To pursue this new strategy, the selection of the two bridging
organocatalyzed domino reaction to synthesize challenging medium- units is crucial in terms of ready availability and compatibility with
sized ring systems in optically active forms is highly desirable and of the mild reaction conditions required to reach a high level of
relevance for synthetic purposes. Herein, we report our new organo- stereocontrol. We propose the use of a-ketoamides 1,10 possessing
catalytic approach to synthesize seven-membered rings based on a multiple reactive sites,11 as potential 1,4-bis-nucleophiles that could
temporary-bridge strategy,9 which circumvents difficulties associated be combined with 1,3-bis-electrophilic enals 2 following a Michael–
with the construction of medium-sized rings by direct cyclization hemiaminalization sequence affording intermediate 5 (Scheme 2).12
routes (Scheme 1c). The designed domino approach is based on This step would be potentially highly reversible and contra-
organocatalyzed domino formation of bicyclo[3.2.1]octane derivative thermodynamic but the possible temporary formation of an internal
3. The overall cascade is thermodynamically driven by the final oxygen tether by a final intramolecular hemiacetalization step of the
highly electrophilic ketone could drive the reaction toward the
´
Aix Marseille Universite, CNRS, Centrale Marseille, ISM2 UMR 7313, 13397,
formation of 3 possibly stabilized by an intramolecular hydrogen
bond. The overall thermodynamically driven process allows direct
access to a 7-aza-8-oxa-bicyclo[3.2.1]octane with concomitant for-
mation of three covalent bonds and the creation of up to four
stereogenic centers. This molecular scaffold is found in several
Marseille, France. E-mail: damien.bonne@univ-amu.fr, jean.rodriguez@univ-amu.fr
† Electronic supplementary information (ESI) available: Procedures and spectral
data for new compounds as well as optimization of the reaction conditions. CCDC
1015393. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4cc07731h
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a prolonged reaction time was required to drive the reaction to
completion (entry 6).
With this final set of optimized conditions in hand,18 the
scope of the three bond-forming process was next explored with
a variety of 3-aryl a,b-unsaturated aldehydes (Scheme 3). The
reaction worked well with aromatic rings bearing either
electron-donating or electron-withdrawing groups including
sterically demanding ortho functionalization or an anthracenyl
substituent, as well as a heteroaromatic ring. The corresponding
products 3b–e were obtained in good to high yields with acceptable
to very high diastereoselectivities from 4 : 1 to 420 : 1 dr, but with
uniformly high enantioselectivities in the range 95–97% ee. Simi-
larly, it was found that a broad range of ketoamides 1 could readily
participate in this reaction. Increasing the size of the R1 group
resulted in generally higher diastereoselectivities (420 : 1 dr for
R1 = i-Pr in 3c, 3i, 3n, and 3q). Interestingly, the use of 2-oxo-N-
phenylpropanamide (1c, R1 = H) resulted in the formation of the
desired bicyclic products 3f and 3g as single diastereomers with
excellent enantioselectivities (ee = 97%). These results indicate a
highly diastereoselective intramolecular hemiacetalization with the
stereoselective creation of two stereogenic centers, which is
Scheme 2 Use of a-ketoamides 1 for the synthesis of nitrogen-containing
seven-membered cycles.
natural products such as the neurotoxin samandarine,13 the anti-
malarial ribasine14 or deglycocadambine, a new alkaloid recently
isolated from the twigs and the leaves of Emmenopterys henryi.15
Moreover, taking advantage of the ring strain release by selective
cleavage of the oxa-bridged system will provide a straightforward
access to highly functionalized optically active azepane derivatives.
We began to test our designed system for the synthesis of bicyclic
products 3. We first investigated this reaction with ketoamide 1a and
cinnamaldehyde (2a) as starting materials using Hayashi–Jørgensen
catalyst 6 (Table 1).16 The reaction conducted in toluene did not
proceed at all after 15 h (entry 1). Dichloromethane as well as
acetonitrile proved to be unsuitable solvents for this reaction, as only
small quantities of Michael adducts were recovered after similar
reaction times (entries 2 and 3). Gratifyingly, the use of ethanol
afforded the desired product 3a in very good yield, as only two
diastereomers (dr = 3 : 1) and with excellent enantioselectivity for
both diastereomers (entry 4). Slightly more acidic trichloroethanol
allowed the formation of 3a with a better diastereoselectivity while
high yield and high enantioselectivity were maintained (entry 5).
Finally the reaction temperature was lowered to ꢀ7 1C,17 which
resulted in an increase of the diastereoselectivity to 8 : 1 even if
Table 1 Reaction optimisationa
Entry
Solvent
Time
Yieldb (%)
drc
eed,e (%)
1
2
3
4
5
6
Toluene
15 h
15 h
15 h
15 h
24 h
3 d
0
0
0
92
91
94
—
—
—
3 : 1
5 : 1
7 : 1
—
—
—
97 [86]
99 [88]
99
f
CH2Cl2
CH3CN f
EtOH
CCl3CH2OH
CCl3CH2OHg
a
Reaction conditions: ketoamide 1a (0.2 mmol, 1.0 equiv.) and catalyst
6 (10 mol%) were dissolved in the solvent (2 mL) and stirred for 15 min
(0 1C or ꢀ7 1C). Then, cinnamaldehyde (2a) (2 equiv.) was added and the
b
mixture was stirred for the time and temperature indicated. Isolated
yields after flash chromatography. Determined by 1H NMR of the crude
c
d
e
reaction products. Determined by chiral HPLC analysis. Values in
brackets are for the minor diastereomer. 10–15% of the Michael adduct
was isolated. The reaction was conducted at ꢀ7 1C.
a
f
Scheme 3 Scope of the domino temporary-bridge approach. Values in
g
brackets are for the minor diastereomer. b The reaction was conducted at 0 1C.
15606 | Chem. Commun., 2014, 50, 15605--15608
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consistent with the fact that only two diastereomers were produced interesting molecules such as (ꢀ)-balanol,22 (ꢀ)-cobactin T,23
when a-ketoamides with R1 not equal to H were involved.
and SQ-33351 (Fig. 1).24 Therefore, a general and efficient
In addition, a-ketoamides having various electron-donating strategy to afford such azacyclic rings would be very useful to
or electron-withdrawing substituents on the phenyl ring or design new synthetic routes toward these bioactive compounds
bearing a pyridine nucleus also proceeded very well in this and their analogs.
cascade reaction, thus affording the azepane derivatives (3k–p)
First, bicyclic ring 3c was easily reduced using the borane–THF
in good to excellent yields and high diastereo- and enantio- complex (1.05 equiv.) to afford azepan-3-one moiety 4a in good
selectivities.19 Finally, the robustness of the transformation was yield with no erosion of chiral information (Scheme 5). Also, using
shown by performing gram scale preparations of 3a, 3c and 3g, three equivalents of the BH3–THF complex, the ketone moiety
which proceeded without any difficulty in excellent yields with could be diastereoselectively reduced yielding azepan-3-ol derivative
good stereoselectivities. Concerning the stereochemical assign- 4b bearing three contiguous stereogenic centers in good yield and
ment, 3p was crystallized and both the relative and absolute excellent stereoselectivity on a synthetically useful mmol scale. This
configurations of these bicyclic structures were unambiguously transformation was accomplished on other bicyclic substrates 3
identified by X-ray diffraction as (3R,4S,5R,7S).20
with similar success (see ESI†). Next, we found that Martin’s
Scheme 4 shows our current understanding of the reaction sulfurane reagent25 efficiently triggered a remote dehydration of
pathway and its thermodynamically driven stereochemical out- 3c giving the corresponding unsaturated azepan-2,3-dione 4c in
come. The initial kinetically controlled Michael addition step good yield with full retention of the stereochemical information.
involves (Z)-enolate 7 and iminium ion 8.21 In the resulting Interestingly, adding two equivalents of 1,1,1,3,3,3-hexafluoro-2-
conformationally restrained environment, the Re face of the phenylpropan-2-ol in the reaction mixture furnished the function-
thermodynamic (Z)-enolate 7 preferentially interacts with the Si alized azepan-2,3-dione 4d bearing three stereogenic centers with
face of iminium ion 8 accounting for the formation of the an interesting 15 : 1 dr and a preserved 94% ee. This opens the way
(3S,4R)-Michael adduct 9. Then, nucleophilic addition of the for the introduction of an additional point of diversity in the final
amide nitrogen atom to give azepane 5 could in theory occur on azepane structure.26
both diastereotopic faces of aldehyde 7 giving rise reversibly to the
We have demonstrated the feasibility and the efficiency of a
two resulting diastereomers 3 and 30 after an hemiacetalization new organocatalytic temporary-bridge approach to synthesize
step. However, the formation of bicyclic product 30 is hampered by optically active nitrogen-containing seven-membered cycles.
the presence of strong 1,3-diaxial steric interactions between the R2
substituent and the amide moiety.
Following our initial temporary-bridge strategy to synthesize
azepane rings, we next moved to the development of synthetically
useful transformations of bicyclic products 3 in order to release
highly functionalized optically active azepanes. These hetero-
cycles are present in numerous natural products and biologically
Fig. 1 Examples of natural and non-natural products featuring the chiral
azepane scaffold.
Scheme 5 Transformations of bicyclic compound 3c into various func-
Scheme 4 Plausible thermodynamically driven mechanism.
tionalized azepanes.
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