Catalytic, Highly Enantio, and Diastereoselective Nitroso Diels-Alder Reaction

Article abstract of DOI:10.1021/ja049849w

This communication presents studies that nitroso Diels?Alder adduct has been furnished in uniformly high yield and high enantioselectivity using nitrosopyridine as a substrate and copper as a catalyst. The obtained Diels?Alder adduct was easily transforme

Full text of DOI:10.1021/ja049849w

Published on Web 03/12/2004
Catalytic, Highly Enantio, and Diastereoselective Nitroso Diels-Alder
Reaction
Yuhei Yamamoto and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received January 9, 2004; E-mail: yamamoto@uchicago.edu
Table 1. Reaction with Various 2-Nitrosopyridinesa,b
The nitroso Diels-Alder reaction is remarkable especially
because of its unique diastereoselectivity when 1,4-amino-oxo
stereocenters are produced in a single operation. Reported here is
the catalytic enantioselective version of this process with achiral
dienes and aryl nitroso derivatives, which depends on a readily
available copper catalyst. A number of other approaches to
enantioselective nitroso Diels-Alder reactions, mainly using chiral
substrates, have been described recently.1 The development of the
entry
nitroso
yield, %
ee, %
new method was guided by the following considerations. Nitroso
compounds exist in organic solvents as a monomer-azetoxy dimer
equilibrium.2 Whiting has reported the ability of Lewis acids to
form stable complexes with the azetoxy dimer of aryl nitroso
compounds.3 This causes difficulty for the successful asymmetric
nitroso Diels-Alder reaction for organic synthesis. We are
interested in generating chelated monomeric nitroso derivatives with
suitable Lewis acid catalysis. This idea is illustrated for the specific
case of a 2-nitrosopyridine derivative in eq 1, the system of which
is quite flexible: for example, substituents at the 6-position would
increase steric demand to form a fixed chiral environment around
the nitroso functional group.
1
2
3
4
1a
1b
1c
1d
>99
>99
>99
>99
59
87
86
77
a Reaction was conducted with 10 mol % of catalysis, 1 equiv of
nitrosopyridine, and 1.5 equiv of cyclohexadinene under N2 atomsphere at
-85 °C and gradually warmed to -20 °C in 5 h. b ee value was determined
by HPLC (Supporting Information).
Chart 1. Effects of Ligand on Enantioselectivitya,b
2-Nitrosopyridine was prepared in two steps from 2-amino-
pyridine simply following the reported procedure.2c,4 We chose for
initial investigations the hetero Diels-Alder reaction of cyclohexa-
diene with (S)-BINAP-Cu(I)PF6(MeCN)4 catalyst5 since copper
coordination to nitroso derivative is well-known.6 The reaction was
conducted at -85 °C and gradually warmed to -20 °C to produce
the adduct 3a in quantitative yield with 59% ee. Encouraged by
this result, we next introduced alkyl groups at the 6-position of
2-nitrosopyridine, which gave much higher enantioselecvities, as
shown in Table 1. Among them, the 6-methyl derivatives gave us
the most satisfactory results. Fortunately, this reagent is easy to
obtain from the commercially available 6-methyl-2-aminopyridine.
Next, various chiral phosphine ligands were surveyed (Chart 1).
Although p-Tol-BINAP showed almost no change in enantiose-
lectivity, significant and uniformly increased selectivity was
observed by using a chiral biphosphine ligand with a narrow
dihedral angle.7 The best enantioselectivity was observed with
SEGPHOS, giving >90% ee. These observations clearly indicated
that the copper catalyst is very effective and that these reactions
proceed via a highly organized transition state.
a Reaction was conducted with 10 mol % of catalysis, 1 equiv of
nitrosopyridine, and 1.2 equiv of cyclohexadinene under N2 atomsphere at
-85 °C and gradually warmed to -20 °C in 5 h. b ee value was determined
by HPLC (Supporting Information).
product. Even more noteworthy is the fact that reactions with
2-substituted 1,3-cyclohexadienes proceeded in a completely regio-
selective manner.8 Thus, the reaction with 2-methyl, 2-phenyl, or
2-tert-butyldimethylsiloxy-1,3-cyclohexadienes provided the single
nitroso Diels-Alder adduct, where the R2 substituents are close to
nitrogen, with excellent enantioselectivities.
The Diels-Alder adduct can easily be transformed to protected
amino alcohols. Cleavage of the N-O bond was performed by Mo-
(CO)6 and NaBH4.9 The resulting alcohol and amine were protected
by TBS and Tosyl group, respectively. Quaternization of pyridine
followed by treatment of NaOH afforded protected amino alcohol
6 in good yield without loss of enantioselectivity (Scheme 1).10
The absolute stereochemical course of the reaction was found
to be in accord with the mechanistic model.11 It is well-known that
the first and third quadrants are more crowded than the second and
fourth quadrants for (S)-BINAP transition-metal complexes (Figure
1).12
Table 2 summarizes the excellent results obtained for six different
dienes of widely varying structure using 10 mol % of copper catalyst
at -85 °C under standard conditions. All reactions proceeded to
completion, and the desired cyclic adduct was the only detectable
9
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J. AM. CHEM. SOC. 2004, 126, 4128-4129
10.1021/ja049849w CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction with Various Dienesa,b
grant from the University of Chicago. We acknowledge Dr. Ian
Steele for X-ray measurements. We thank Takasago International
Corporation for its generous gift of (S)-SEGPHOS and (R)-H8-
BINAP. Y.Y. thanks Dr. K. Suzuki, BANYU Pharmaceutical Co.
Ltd. for generous support.
Supporting Information Available: Experimental details and
spectroscopic data, including determination of absolute configuration
(PDF, CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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a Reaction was conducted with 10 mol % of catalysis, 1 equiv of
nitrosopyridine, and 1.2 equiv of diene under N2 atomsphere at -85 °C
and gradually warmed to -20 °C in 5 h. b ee value was determined by
HPLC (Supporting Information). c Structure was determined by X-ray
analysis (Supporting Information). d (S)-BINAP was used instead of (S)-
SEGPHOS. e After single recrystallization (hexanes/Et2O).
Scheme 1. Conversion to Protected Amino Alcohola
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a Reaction conditions: (a) Mo(CO)6, NaBH4, MeCN/H2O. (b) TBSCl,
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Figure 1. Plausible chelate intermediate.
We believe that the reactions expressed herein provide a useful
new paradigm for enantioselective synthesis. Further, the present
concepts should present clear guidance for the design of still more
effective catalysts for nitroso Diels-Alder reaction.
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Acknowledgment. Support of this research was provided by
SORST project of Japan Science and Technology Agency (JST),
National Institutes of Health (NIH) GM068433-01, and a starter
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