A powerful hydrogen-bond-donating organocatalyst for the enantioselective intramolecular oxa-michael reaction of α,β-unsaturated amides and esters

Article abstract of DOI:10.1002/anie.201305492

Tuning the organocatalyst: An unprecedented enantioselective intramolecular oxa-Michael reaction of unactivated α,β-unsaturated amides and esters catalyzed by a powerful hydrogen-bond-donating organocatalyst has been developed. Furthermore, the products obtained from this reaction have been used for the straightforward asymmetric synthesis of several natural products and biologically important compounds. Copyright

Full text of DOI:10.1002/anie.201305492

Angewandte
Chemie
DOI: 10.1002/anie.201305492
Synthetic Methods
A Powerful Hydrogen-Bond-Donating Organocatalyst for the
Enantioselective Intramolecular Oxa-Michael Reaction of a,b-
Unsaturated Amides and Esters**
Yusuke Kobayashi, Yamato Taniguchi, Noboru Hayama, Tsubasa Inokuma, and
Yoshiji Takemoto*
The rapid and efficient synthesis of a target molecule still
represents a major challenge in the field of synthetic organic
chemistry. Chiral oxygen-containing heterocycles, such as
isoxazolines, isoxazolidines,[1] chromans,[2] and dihydrobenzo-
furans,[3] can be found in numerous natural products and
biologically active compounds, and significant efforts have
been directed towards the development of synthetic methods
that are capable of providing facile access to these materials.
In particular, O-heterocycles bearing an amide moiety,[4] such
as roxifiban[1c] and erythrococcamide,[2c,e] exhibit pharmaceut-
ically important activities (Figure 1). Related carboxylic
Scheme 1. A comparison of intramolecular oxa-Michael addition reac-
tions.
reported, using a,b-unsaturated thioesters[9] and imides[10] as
activated carboxylic acid equivalents [Scheme 1b]. However,
these approaches are limited, because they require an addi-
tional amidation step to obtain the corresponding amide
derivatives.[2e,3b,d,10] Furthermore, the products of these reac-
tions can also undergo retro-Michael/Michael racemization in
the presence of base;[1c,5] mild conditions and careful manip-
ulation are therefore required for their conversion into the
corresponding esters and amides. In contrast to the work
outlined above, the direct AIOM reaction of unactivated a,b-
unsaturated esters[11] [Scheme 1c] has received much less
attention, likely because of the poor reactivity of the Michael
acceptor[12] and the poorer reactivity of oxygen as a nucleo-
phile[5] compared with nitrogen or carbon nucleophiles.[13,14]
Therefore, this reaction may still be substantially improved,
especially in terms of enantioselectivity, the variation in the
O-heterocycles obtained, and their subsequent derivatiza-
tion.[11] Furthermore, to the best of our knowledge, there have
been no reports in the literature concerning the AIOM
reaction of much less activated a,b-unsaturated amides
[Scheme 1d], despite the number of different potential uses
of the amide functional group.[4] The development of a direct
and efficient AIOM reaction for unactivated esters and
amides would enable the straightforward synthesis of chiral
O-heterocycles bearing carboxylic acid equivalents, without
the need for multi-step processes [Scheme 1c and d]. In
Figure 1. Examples of biologically active carboxylic acids and amides
containing different O-heterocyclic scaffolds.
acids, such as acivicin[1d] and raxofelast,[3b,c] have been used
as biological tools for drug discovery and as key synthetic
intermediates for the construction of more complex deriva-
tives.
One of the most promising approaches to access these
chiral carboxylic acid derivatives involves the asymmetric
intramolecular oxa-Michael[5,6] reaction (AIOM) of a,b-
unsaturated aldehydes or ketones,[7] followed by an oxidation
reaction[7g] [Scheme 1a]. From the perspective of redox
economy,[8] a more efficient method has recently been
[*] Dr. Y. Kobayashi, Y. Taniguchi, N. Hayama, Dr. T. Inokuma,
Prof. Dr. Y. Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University
Institution, Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: takemoto@pharm.kyoto-u.ac.jp
[**] We thank Ryuta Kuramoto for experimental support. We gratefully
acknowledge a Grant-in-Aid for Scientific Research (Y.T.) on
Innovative Areas “Advanced Molecular Transformations by Orga-
nocatalysts” from MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305492.
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addition, this method has several advantages, in that a,b-
unsaturated esters and amides can be prepared using readily
available Wittig or Horner–Wadsworth–Emmons (HWE)
reagents, and the cyclized products are less likely to racemize
because the a-hydrogen atoms of esters and amides are less
acidic than those of ketones and thioesters.
Herein, we report the first AIOM reaction of a,b-
unsaturated amides using a newly developed powerful hydro-
gen-bond (HB)-donating organocatalyst. Bifunctional HB-
donor organocatalysts have become a particularly promising
approach to highly enantioselective reactions,[15] although
there is still a strong drive to improve their catalytic activities
and expand their scope of application. We envisaged that
improving their HB-donating ability could further activate
the poorly reactive Michael acceptor, and that this would be
more important[10] for an effective cyclization [Scheme 1d]
than increasing the basicity of the catalyst to activate the
O-nucleophile,[16] because it is well known that the products of
the oxa-Michael reaction often undergo retro-Michael reac-
tion.[5]
The a,b-unsaturated amide 1a, which bears a hydroxyl-
amine nucleophile (NOH), was selected as a substrate for the
screening of catalysts for the AIOM reaction (Table 1).
Although readily available organic bases such as triethyl-
amine and cinchonidine did not work at all in this reaction
(data not shown), bifunctional thiourea[15a,b] I moderately
promoted the cyclization of 1a to afford isoxazoline 2a in
88% yield and 81% ee after five days (Table 1, entry 1). The
use of squaramide III,[15f] which contains two HB-donating
form, led to slight improvements in the reaction time and
enantioselectivity, and gave 2a in an 88% yield (88% ee)
after four days (Table 1, entry 3). Encouraged by this result,
we investigated several other HB-donating catalysts bearing
a heterocyclic scaffold, such as benzimidazole[15g,h] IV, quina-
zoline[17a] (TQC) V, and the benzothiadiazines[17b] (TBCs) VI–
IX (entries 4–9). The results revealed that TBC VI gave the
best results, with the reaction reaching completion in 24 h to
give 2a in 92% yield and a high enantioselectivity (95% ee,
entry 6).[18] These results suggested that the HB-donating
ability plays a crucial role in the reaction by tightly binding
amide 1a, and providing excellent levels of catalytic activity.
To achieve a more powerful catalytic system, we proceeded to
design and evaluate a series of TBC-based organocatalysts
bearing an electron-withdrawing group on their aromatic ring,
and found that the fluorine-containing TBCs (FTBCs) VII–
IX improved the chemical yields (99%). These results
provide further indication of the importance of the HB-
donating ability of the catalyst (entries 7–9). Interestingly,
6-FTBC (VIII) gave the best enantioselectivity (97% ee),
presumably because of the catalytic activity derived from the
balance between the inductive and mesomeric effects of the
fluorine substituent (entry 8).[19]
With the optimized conditions in hand, we proceeded to
investigate the effect of the substituents (R1–R3) on the
amides 1 (Table 2). Catalyst VI could be successfully applied
to the cyclization of both tertiary (Table 2, entries 1–3) and
secondary amides (entries 4 and 5), with the corresponding
amides 2b–f obtained in 70–99% yields with ee values in the
range of 84–96%. In addition to the biological importance of
these compounds,[2] as discussed above, isoxazolidines 2 could
also be regarded as d-amino-b-hydroxy-amino acid equiva-
À
N H protons, which are conformationally fixed in the active
Table 1: Screening of the reaction conditions.
Table 2: Synthesis of the chiral isoxazolidines 2b–f.
Entry
Catalyst
Time [h]
Yield[a] [%]
ee[b] [%]
1
2
3
4
5
6
7
8
9
I
II
120
24
96
24
336
24
24
24
24
88
trace
88
trace
74
92
99
99
99
81
n.d.
88
n.d.
51
95
93
97
79
Entry Product
1
Conditions Yield[a] [%] ee[b] [%]
III
IV
V
VI
VII
VIII
IX
RT, 24 h
RT, 24 h
RT, 24 h
89
97
99
92
84
2
[a] Yields of isolated products. [b] The ee values were determined by
HPLC analysis on a chiral stationary phase. n.d.=not determined.
3
4
5
96
90
84
408C, 24 h 99
408C, 72 h 70
[a] Yields of isolated products. [b] The ee values were determined by
HPLC analysis on a chiral stationary phase.
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Scheme 2. Application of 2e to a concise formal total synthesis of
atrovastatin. Cbz=carbobenzyloxy.
À
lents, following the cleavage of the N O bond. With this in
mind, and to highlight the overall utility of 2, we performed
a concise formal total synthesis of atorvastatin (Scheme 2).[20]
Thus, amide 2e was readily converted into d-amino-b-
hydroxyester[21] 3 in three steps through N O bond cleav-
À
age[18] followed by a cross-Claisen condensation with tert-
butyl acetate to give intermediate 4, which is a known
intermediate for atorvastatin.[22,20]
We then focused on the AIOM reaction of a,b-unsatu-
rated amides 5 and esters 7 bearing phenolic OH groups
(Scheme 3). Pleasingly, a variety of different dihydrobenzo-
furans (6a–g; Scheme 3) were synthesized in good yields (70–
99%) and high enantioselectivities (83–96% ee), with methyl,
methoxy, nitro, and bromo groups being well tolerated under
the reaction conditions. In sharp contrast with literature
precedent for the oxa-Michael reaction of a,b-unsaturated
esters to give six-membered rings,[11] the current method
provided much higher enantioselectivities (89–96% ee) for
the synthesis of chromanes 6h and 6i. A gram-scale reaction
of 5b (1.15 g, 5.2 mmol) cleanly furnished the corresponding
amide 6b (1.12 g, 97%, 92% ee) with only 1.0 mol% of the
catalyst 6-FTBC (VIII), albeit with a longer reaction time.
The resulting Weinreb amides 6b, 6g, and 6i could, in
principle, be transformed into a variety of different ketones
following the coupling reaction with organolithium or orga-
nomagnesium reagents.[3d] The powerful catalytic activity of
the TBC catalyst was demonstrated by comparing its results
with those from the thiourea-type catalyst I (6a, 6d, 6h, and
6i). The chemical yields and enantioselectivities were
improved considerably by using the TBC. The absolute
configurations of the products were assigned as 2’R by
synthesizing the known ester 8a and comparing the optical
rotation data with the literature value.[11e] Pleasingly, the
construction of a chiral quaternary carbon center was also
successful, and the corresponding O-heterocycle 8d was
obtained in 75% yield with 86% ee. Much to our surprise,
an aliphatic OH group could be used as the nucleophile in this
AIOM reaction to furnish the chiral tetrahydrofuran 8e with
good enantioselectivity.
Scheme 3. Scope and limitations. Yields of isolated products. The ee
values were determined by HPLC analysis on a chiral stationary phase.
The stereochemistry of 6 was assigned in analogy to 8.
Scheme 4. Application of the TBC-catalyzed asymmetric oxa-Michael
reaction to the rapid asymmetric total synthesis of erythrococcamide B.
DCE=1,2-dichloroethane.
The greatest advantage of using the current AIOM
reaction of a,b-unsaturated amides is perhaps best demon-
strated by the rapid asymmetric total synthesis of the natural
product erythrococcamide B[2c,e] (6j) (Scheme 4). The readily
available lactone 9 was reduced with diisobutylaluminum
hydride (DIBAL) to the corresponding lactol 10, which was
then subjected to a HWE reaction to give the a,b-unsaturated
amide 5j. The first enantioselective synthesis of 6j was
subsequently achieved using the 6-FTBC-catalyzed oxa-
Michael reaction.
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singer, H. Fan, J. E. Gable, J. J. Irwin, A. Sali, K. M. Giacomini,
Proc. Natl. Acad. Sci. USA 2013, 110, 5480.
The high catalytic activity of 6-FTBC was further exem-
plified by the AIOM reaction of the a,b-unsaturated ester 7 f,
as the cyclization reaction proceeded at an unprecedentedly
low temperature,[11] affording the corresponding product 8 f in
97% yield with 94% ee (Scheme 5). The first enantioselective
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Scheme 5. Further application of the TBC-catalyzed asymmetric oxa-
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synthesis of raxofelast,[3b,c] which is used as an antioxidant to
modulate inflammatory response, was accomplished through
the double debenzylation of 8 f, followed by selective
acetylation of the phenolic OH group.
In conclusion, we have developed a powerful HB-
donating organocatalyst for the AIOM reaction, which
effectively activated relatively inert a,b-unsaturated amides
and esters as electrophiles, and facilitated the production of
a variety of chiral O-heterocycles with useful functional
groups for derivatization. The potential of organocatalysts of
this particular type could be further increased by refining the
design of the molecular structure of catalysts, and identifying
applicable reactions. Further studies to expand the scope of
this method are currently underway in our laboratory.
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aldehydes and ketones, see: a) E. Sekino, T. Kumamoto, T.
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Experimental Section
General procedure: The benzothiadiazine catalyst VI (3.2 mg,
0.01 mmol, 10 mol%) was added to a solution of 1, 5, or 7
(0.1 mmol) in CH2Cl2 (1.0 mL, 0.1m), and the resulting mixture was
stirred at ambient temperature for 24 h. The reaction mixture was
then evaporated, and the resulting crude residue was purified by
column chromatography on silica gel, eluting with n-hexane/ethyl
acetate to give the analytically pure compound 2, 6, or 8. The
enantiomeric ratios of all of the compounds were determined by
HPLC analysis on a chiral stationary phase.
Received: June 26, 2013
Published online: && &&, &&&&
Keywords: asymmetric synthesis · heterocycles ·
.
hydrogen bonding · Michael reaction · stereoselective catalysis
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[10] Diastereoselective intramolecular oxa-Michael reactions of a,b-
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[21] For a recent efficient synthesis, see: Y. K. Chen, M. Yoshida,
D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 9328.
[22] S. Mihashi, T. Sotoguchi, Y. Yuasa, H. Kumobayashi, Jpn. Kokai
Tokkyo Koho (1996), JP 08198832 A 19960806.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

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Angewandte
Communications
Communications
Synthetic Methods
Y. Kobayashi, Y. Taniguchi, N. Hayama,
T. Inokuma, Y. Takemoto*
&&&& — &&&&
A Powerful Hydrogen-Bond-Donating
Organocatalyst for the Enantioselective
Intramolecular Oxa-Michael Reaction of
a,b-Unsaturated Amides and Esters
Tuning the organocatalyst: An unprece-
dented enantioselective intramolecular
oxa-Michael reaction of unactivated a,b-
unsaturated amides and esters catalyzed
by a powerful hydrogen-bond-donating
organocatalyst has been developed.
Furthermore, the products obtained from
this reaction have been used for the
straightforward asymmetric synthesis of
several natural products and biologically
important compounds.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!