Catalytic enantioselective hetero-Diels-Alder reactions of an azo compound

Article abstract of DOI:10.1021/ja066726y

This communication describes studies in which an azo hetero-Diels-Alder adduct was furnished in high regio- and enantioselectivity using azopyridine as a reagent and silver as a catalyst. The obtained hetero-Diels-Alder adduct was easily converted to the corresponding chiral 1,4-diamino alcohol. Copyright

Full text of DOI:10.1021/ja066726y

Published on Web 12/20/2006
Catalytic Enantioselective Hetero-Diels-Alder Reactions of an Azo
Compound
Masanori Kawasaki and Hisashi Yamamoto*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received September 22, 2006; E-mail: yamamoto@uchicago.edu
Scheme 1. Azo Hetero-Diels-Alder Reaction
The hetero-Diels-Alder reaction is one of the most useful
reactions in organic chemistry because multifunctionalized com-
pounds can be constructed in a single step.1 The catalytic enanti-
oselective version of this process has attracted much attention in
modern organic chemistry. We recently reported the catalytic highly
enantioselective nitroso hetero-Diels-Alder reaction using nitroso
pyridine as a dienophile in the presence of a chiral copper catalyst.2
Encouraged by this success, we focused on hetero-Diels-Alder
reaction using a 2-azopyridine derivative since this reaction with
azo compounds (azo hetero-Diels-Alder reaction) produces 1,4-
diamines.3 These structural motifs are important building blocks
as well as 1,4-amino alcohols. For example, these structures are
found in pharmaceutically important compounds such as HIV
protease inhibitors.4 Diastereoselective azo hetero-Diels-Alder
reactions using a chiral auxiliary have been developed;5 however,
despite several efforts toward an enantioselective version of this
process,6 there are no reports of a catalytic highly enantioselective
azo hetero-Diels-Alder reaction. We herein report the catalytic
highly regio- and enantioselective azo hetero-Diels-Alder reaction
(Scheme 1).
2-Azopyridine (1) was prepared in two steps from commercially
available 2-hydrazinopyridine.7 On the basis of our previous results,
we chose for initial investigations the hetero-Diels-Alder reaction
of acyclic silyloxydiene 2a with (R)-BINAP and CuPF6(CH3CN)4
catalyst.2,8 Unfortunately, we were unable to observe any chiral
induction. Thus, several metal catalysts were surveyed,9 and we
found that the combination of AgOTf and (R)-BINAP in THF
produced adduct 3a with 55% ee. Encouraged by this result, various
ligands and solvents were tested (Table 1). The use of (R)-BINAP
as a ligand and CH3CN or EtCN as a solvent gave 3a with 94% ee
(Table 1, entries 5 and 6). EtCN was selected as a solvent to obtain
high reproducibility. Next, the ratio of (R)-BINAP to AgOTf was
checked since we previously had observed that three types of the
Ag-BINAP complex were formed in THF.10 The 2:1 ratio of
AgOTf to (R)-BINAP was found to be optimal, producing an adduct
3a with >99% ee. It should be noted that decreased enantioselec-
tivity was observed by chiral biphosphine ligands with narrow
dihedral angles (entries 7 and 8) which are expected to generate a
1:1 complex of Ag ligand preferentially.
Table 1. Optimization of Reaction Conditions
yield
(%)
ee
entry
ligand
solvent
(%)b
1
2
3
(R)-BINAP (10 mol %)
(R)-BINAP (10 mol %)
(R)-BINAP (10 mol %)
(R)-BINAP (10 mol %)
(R)-BINAP (10 mol %)
(R)-BINAP (10 mol %)
(R)-Difluorophos (10 mol %)
(R)-Segphos (10 mol %)
(R)-BINAP (5 mol %)
(R)-BINAP (20 mol %)
THF
Et2O
73
74
63
72
61
62
76
71
87
26
55
56
67
80
94
94
30
20
toluene
CH2Cl2
CH3CN
EtCN
EtCN
EtCN
EtCN
EtCN
4
5a
6
7
8
9
10
>99
0
a Reaction was conducted at -40 °C. b Enantiomeric excess value was
determined by HPLC (Supporting Information).
gave an adduct 3j with high regio- and enantioselectivity (Table 2,
entry 10). Meanwhile, the enantioselectivity of the reaction using
silyloxydiene 2k with a phenyl group was decreased dramatically
(Table 2, entry 11).
The products can be cleanly converted into the corresponding
diamino alcohols. For example, deprotection of the TIPS group of
3a with TBAF/AcOH12 followed by reduction and protection of
the resulting alcohol gave 4a as a single diastereomer. Removal of
the pyridine ring was cleanly achieved by the known procedure,2c
accompanied by the conversion of a 2,2,2-trichloroethoxycarbonyl
group to a methoxycarbonyl group. The resulting amine was
protected with a trifluoroacetyl group to afford 5a. To cleave the
N-N bond of 5a, 5a was treated with SmI2 to give 6a in 71%
yield (Scheme 2).13 Thus, two amino groups are differentiated for
further transformation.
The absolute and relative configurations of azo hetero-Diels-
Alder adducts were assigned by X-ray crystallographic analysis.
Deprotection of Troc and TIPS groups followed by reduction
afforded 7a as a single diastereomer. Subsequently, 7a was
converted into 4-bromobenzoate derivative 8a which was crystal-
lized from Et2O (Scheme 3 and Supporting Information).
In summary, we have developed a highly regio-, diastereo-, and
enantioselective azo hetero-Diels-Alder reaction using 2-azopy-
Having an optimized condition in hand, the applicability of this
reaction was studied for the functionalized silyloxydienes 2b-2j.11
All of the reactions proceeded in high yields and enantioselectivities,
with complete regio- and diastereoselectivities.
The dialkyl-substituted dienes generally gave high enantiose-
lectivities (Table 2, entries 1, 2, and 5). Silyloxydiene 2c with a
sterically hindered substituent afforded 3c with slightly decreased
enantioselectivity. Lewis basic substituents such as ester, ether,
protected alcohols, and protected amine (Table 2, entries 4 and 6-8)
were also used in the reaction and produced highly functionalized
products enantioselectively. Silyloxydiene 2j having a 2-furyl group
9
16482
J. AM. CHEM. SOC. 2006, 128, 16482-16483
10.1021/ja066726y CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction with Various Dienesa
complete ref 4h. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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yield
(%)
ee
entry
diene
R1
R2
(%)b
1
2
3
4
5
6
7
8
9
2a
Me
Me
n-C5H11
i-Pr
87 >99
84
65
2b Me
2c Me
2d Me
2e
2f
95
84
98
92
90
95
98
98
92
55
CH2CH2CH2CO2Me 74
Bn
Me
Me
i-Bu
CH2OBn
74
85
82
84
77
78
70
4-MOMO-Bn
CH2CH2CH2OTBS
2g
2h CH2CH2CH2OTBS
2i
2j
CH2CH2CH2NNsBoc i-Bu
10
Me
2-Furyl
Ph
11c
2k Me
a Reaction was conducted with AgOTf (10 mol %), (R)-BINAP (5 mol
%), azopyridine (1 equiv), and silyloxydiene (2 equiv) under Ar at -78 °C
and gradually warmed to -40 °C over 3 h. b Enantiomeric excess value
was determined by HPLC (Supporting Information). c 20 mol % of AgOTf
and 10 mol % of (R)-BINAP were used.
Scheme 2. Conversion to Protected Diamino Alcohola
a Conditions: (a) (i) TBAF, AcOH, (ii) NaBH4, (iii) TlPSOTf, NEt3,
65% (3 steps); (b) (i) MeOTf, (ii) NaOH, (iii) TFAA, NEt3, 71% (3 steps);
(c) SmI2, MeOH, 71%.
Scheme 3. Determination of Absolute Stereochemistrya
a Conditions: (a) (i) Zn, AcOH, (ii) TBAF, AcOH, (iii) NaBH4, 53%
(3 steps).
(7) For synthesis of similar compounds, see: Srinivasan, V.; Jebaratnam, D.
J.; Budil, D. E. J. Org. Chem. 1999, 64, 5644.
(8) The reaction of 2-triisopropylsilyloxy-1,3-cyclohexadiene with CuPF6(CH3-
CN)4 and (R)-BINAP gave the corresponding adduct with >99% ee. The
origin of this result is being investigated in our laboratory.
(9) Reactions using the following metal catalysts were checked on TLC: Al,
B, Mg, Zn, Ti, Sc, Hf, Yb, Zr, In, La. None of them accelerated the
reaction.
(10) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5360.
(11) For synthesis of silyloxydienes, see: (a) Nakashima, D.; Yamamoto, H.
J. Am. Chem. Soc. 2006, 128, 9626. (b) Yamamoto, Y.; Yamamoto, H.
Angew. Chem., Int. Ed. 2005, 44, 7082.
(12) Excess amount of AcOH was necessary to avoid epimerization of the
methyl group via retro-Michael reaction.
(13) For SmI2-mediated cleavage of the N-N bond with trifluoroacetyl group,
see: (a) Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867. (b)
Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637.
ridine (1) and silver(I)-BINAP 2:1 catalyst. This catalytic process
could be one of the effective synthetic routes to a number of chiral
1,4-diamines which are pharmaceutically important compounds.
Further studies of the detailed mechanism of the reaction and
synthetic applications are currently underway in our laboratory.
Acknowledgment. Support of this research was provided by
National Institutes of Health (NIH) Grant No. GM068433-01, and
Merck Research Laboratories. We thank Dr. Ian M. Steel for X-ray
crystallographic analysis.
Supporting Information Available: Experimental details, spec-
troscopic data, including determination of absolute configuration, and
JA066726Y
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