Chiral phosphoric acid-governed anti-diastereoselective and enantioselective Hetero-Diels - Alder reaction of glyoxylate

Article abstract of DOI:10.1021/ja904749x

(Chemical Equation Presented) A highly enantioselective anti-diastereoselective hetero-Diels-Alder reaction between a glyoxylate and siloxy- or methoxydienes using a chiral phosphoric acid catalyst that possesses less bulky phenyl groups at the 3 and 3′ p

Full text of DOI:10.1021/ja904749x

Published on Web 08/20/2009
Chiral Phosphoric Acid-Governed Anti-Diastereoselective and
Enantioselective Hetero-Diels-Alder Reaction of Glyoxylate
Norie Momiyama, Hideaki Tabuse, and Masahiro Terada*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received June 10, 2009; E-mail: mterada@mail.tains.tohoku.ac.jp
Table 1. Preliminary Studya
Hetero-Diels-Alder reactions between dienes and carbonyl
compounds have served as an extremely valuable method for the
preparation of dihydropyrans.1 The development of catalytic
enantio- and diastereoselective variants is an area of considerable
importance.2 Previous studies mainly have demonstrated the use
of chiral Lewis acid catalysts to control high levels of stereose-
lectivity (eq 1).3 It is noteworthy that vicinal substituents of the
dihydropyran were established exclusively with syn selectivity.
Presumably, the syn selectivity observed in previous reports is due
to the following intrinsic nature of the chiral Lewis acid catalyst:
(i) dominant secondary π-orbital interactions and (ii) the steric
demand of the chiral Lewis acid catalyst, as the diene could
approach the aldehyde with an endo alignment to avoid the steric
repulsion between the incoming diene and the catalyst.4 In contrast,
instances of alternative exo-oriented enantioselective processes,
which would correspond to anti selectivity, have yet to be fully
developed.5 We now report the first example of a highly enantio-
and anti-selective hetero-Diels-Alder reaction between a glyoxylate
and siloxy- or methoxydienes induced by chiral binaphthol-derived
phosphoric acid 1a as a catalyst (eq 2).
yield,
b
4aa/5aa ee,
d
c
entry
cat. (mol %)
conditions
%
anti:syn
%
1
2
3
4
5
6
1a (5)
1a (2)
toluene, r.t., 24 h
toluene, r.t., 24 h
95
92
>99:1
>99:1
1:1
1:2
1:5
99/-
97/-
-/-
3/3
-/65
-/29
BF3 ·OEt2 (100) toluene, -78 °C, 1 h 70
6 (100)
1b (5)
1c (5)
CH2Cl2, -78 °C, 1 h 43
toluene, r.t., 24 h
toluene, r.t., 24 h
62
50
1:25
a The reactions were conducted with 2 and 3aa in the presence of
catalyst. b Isolated yield. c Determined by 1H NMR (see the Supporting
Information). d Determined by chiral GC.
acid catalyst on the diastereoselectivity, using either BF3 ·OEt2 as
a monodentate Lewis acid or binaphthol-derived 68 as a slightly
bulkier catalyst (Table 1, entries 3 and 4). In both cases, diaster-
eomeric mixtures of the products were obtained in moderate to good
yields. More importantly, the reaction using 6 exhibited a slightly
higher syn selectivity than that using BF3 ·OEt2. The resulting
diastereoselectivities indicate that (i) the secondary π-orbital
interactions are weak in the present hetero-Diels-Alder reaction
and (ii) the steric demand of the catalyst seems to be the dominant
factor in increasing the syn selectivity. To support these consid-
erations, the diastereoselectivity was evaluated using the representa-
tive chiral phosphoric acids 1b and 1c, which possess bulkier aryl
groups at the 3 and 3′ positions, thus constraining the area around
the activation site (Table 1, entries 5 and 6). In each of these two
cases, the syn-dihydropyran 5aa was obtained as the major product,
in accordance with the diastereoselectivity that was previously
reported. The significant enhancement of the syn diastereoselec-
tivities using 1b and 1c suggests that the substituents at the 3 and
3′ positions of the chiral phosphoric acid provide an important
element of stereochemical control in the transition state (TS).
Among previously proposed mechanisms, although Mukaiyama
aldol mechanism cannot be excluded completely, the differences
in diastereoselectivities can be rationalized by TS structures via
the concerted [4 + 2] cycloaddition mechanism (Scheme 1).9 For
1b- and 1c-catalyzed reactions, the endo orientation of the diene
to the aldehyde (TS1) is preferred over the exo orientation (TS2)
because of the steric hindrance between the diene substituents and
the bulky aryl groups of the catalyst around the activation site. For
In view of our previous success in promoting catalytic asym-
metric reactions using chiral phosphoric acids,6 we began to
investigate the corresponding process using (2Z,4E)-tert-butyldim-
ethylsilyloxy-2,4-hexadiene (3aa) in the presence of chiral phos-
phoric acid 1a and 4 Å molecular sieves. Initial results with 1a
revealed that although chiral Lewis acids have typically provided
the optically active syn adduct, chiral phosphoric acid 1a was
uniquely efficient in affording anti adduct 4aa in 95% yield with
99% ee as a single diastereomer (Table 1, entry 1).7 Even with 2
mol % catalyst loading, adduct 4aa was obtained in excellent yield
without detrimental effects on the enantioselectivity and anti
diastereoselectivity (Table 1, entry 2).
Having achieved this unprecedented anti selectivity, we directed
our subsequent efforts toward considering the diastereoselectivity
in this reaction. At first, reactions between ethyl glyoxylate 2 and
siloxydiene 3aa were conducted to evaluate the effect of the Lewis
9
12882 J. AM. CHEM. SOC. 2009, 131, 12882–12883
10.1021/ja904749x CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Stereoselective Elaboration of Dihydropyrans
Scheme 1. Plausible Transition-State Structures
7. Reduction of 7 with NaBH4 afforded the 3,4-syn-alcohol 8 with
excellent diastereoselectivity. No loss of stereochemical integrity
was observed during any of these processes.
In summary, we have developed a chiral phosphoric acid-
catalyzed completely enantioselective and anti-diastereoselective
hetero-Diels-Alder reaction of ethyl glyoxylates that displays a
wide substrate scope for a series of siloxy- and methoxydienes.
The diastereoselectivities presented are disparate to those previously
reported for hetero-Diels-Alder reactions catalyzed by a chiral
Lewis acid. The method described herein provides a practical
approach for the stereoselective construction of dihydropyran
derivatives. Further mechanistic studies regarding these stereochem-
istries are ongoing and will be reported in due course.10
Table 2. Scope of Siloxy and Methoxy Dienesa
Acknowledgment. Support was provided by JSPS via a Grant-
in-Aid for Scientific Research (Grant 20245021) and by the Naito
Foundation.
Supporting Information Available: Experimental details, charac-
1
terization data, GC and HPLC enantiomer analysis, and H and 13C
NMR spectra for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) (a) Ooi, T.; Maruoka, K. In ComprehensiVe Asymmetric Catalysis I-III;
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Weinheim, Germany, 2002; pp 151-186.
(2) For representative recent reviews of asymmetric hetero-Diels-Alder
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a The reactions were conducted with 2 and 3 in the presence of 5 mol
c
% 1a. b Isolated yield. Determined by H NMR. d Determined by chiral
1
GC or HPLC (see the Supporting Information).
the 1a-catalyzed reaction, the much smaller phenyl groups at the 3
and 3′ positions of 1a allow the dienes to occupy an exo orientation
(TS3). The endo selectivity (TS4) is not favorable because of the
steric repulsion between the diene substituents and glyoxylate 2.
The scope of the anti-diastereoselective and enantioselective
reaction was investigated under optimized reaction conditions (Table
2). In general, the siloxydienes provided the desired adducts in high
yields with excellent enantioselectivities and anti-diastereoselec-
tivities (entries 1-3 and 5). The alkenyl-substituted siloxydiene
resulted in a decrease in reactivity, although high stereoselectivity
was maintained (entry 4). Furthermore, methoxydienes (3b) were
also well-tolerated, providing the corresponding anti-dihydropyrans
4 predominantly with excellent enantioselectivities (entries 7-10).
Dihydropyran 4af can also function as an excellent substrate for
enolate-based stereoselective transformations (Scheme 2). 4af was
selectively protonated using acetic acid to afford the 5,6-anti-ketone
(5) Only one example of the catalytic asymmetric trans-selective hetero-Diels-
Alder reaction has been reported using Danishefsky’s dienes. See: Ya-
mashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc. 2003,
125, 3793.
(6) For general reviews, see: (a) Akiyama, T. Chem. ReV. 2007, 107, 5744.
(b) Terada, M. Chem. Commun. 2008, 4097. For an example of an
enantioselective reaction of an aldehyde, see: (c) Terada, M.; Soga, K.;
Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122.
(7) In the present chiral phosphoric acid system, the 1H NMR spectrum of the
crude product from the reaction of 3aa with 2 catalyzed by 1a revealed
the exclusive presence of cycloadduct 4aa without the production of a
Mukaiyama aldol adduct intermediate during the course of the reaction.
(8) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264.
(9) The two-hydrogen-bond model of the TS structure has been proposed on
the basis of our previous report (see ref 6c).
(10) The manuscript is in preparation.
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