Efficient and practical Ag-catalyzed cycloadditions between arylimines and the Danishefsky diene

Article abstract of DOI:10.1021/ja030033p

An efficient Ag-catalyzed method for asymmetric addition of the Danishefsky diene to various aryl imines to afford cycloadducts in ≥89% ee and ≥85% isolated yield is reported. Reactions are effected with 0.1-1 mol % catalyst (4 °C), and the chiral ligand is readily prepared from commercially available materials, including the inexpensive i-Leu. These catalytic asymmetric cycloadditions can be carried out without the use of solvent or with undistilled THF in air. A first generation supported chiral catalyst that effectively promotes the cycloaddition reaction and can be recycled (five cycles) is described. Copyright

Full text of DOI:10.1021/ja030033p

Published on Web 03/14/2003
Efficient and Practical Ag-Catalyzed Cycloadditions between Arylimines and
the Danishefsky Diene
Nathan S. Josephsohn, Marc L. Snapper,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received January 17, 2003; E-mail: amir.hoveyda@bc.edu
Table 1. Ag-Catalyzed Enantioselective Cycloaddition between
Arylimines and 2a
Danishefsky’s diene (1) is a versatile reagent in chemical
synthesis.1 A set of transformations that involve the use of 1 is the
Diels-Alder cycloaddition with imines (eq 1);2 these reactions
deliver chiral N-containing heterocycles that can be converted to
functionalized piperidines. Several catalytic enantioselective variants
of the above process have been reported.3 These protocols often
require up to 20-40 mol % catalyst and only afford appreciable
selectivities (usually <90% ee) when specific structural require-
ments are met.3a,b Cycloadditions promoted by low catalyst loadings
(1 mol %) are available when strongly electrophilic imines and
fully functionalized derivatives of 1 are utilized (Me groups at C2
and C4).3c
3a, AgOAc
(mol %)
entry
Ar
yield (%)b
ee (%)e
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
1-naphth
2-naphth
p-OMe
p-Cl
2a
2a
2a
2b
2c
2d
2e
2f
1.0
0.5
0.1
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
94
92
78
94
>98
86
98
91
92
>98
89
93
92
88
90
95
91
90
89
91
92
92
o-Br
Herein we disclose an efficient Ag-catalyzed asymmetric addition
of 1 to aryl imines to afford cycloadducts in >77% yield and >89%
ee. Reactions are effected in the presence of e1 mol % catalyst (4
°C). The chiral ligand is a phosphine prepared from an inexpensive
amino acid and other commercially available materials.4 Catalytic
transformations can be carried out neat or with undistilled THF in
air. A recyclable supported chiral catalyst is also described.
To identify optimal conditions, we probed the transformations
of different imines derived from 2-naphthaldehyde (e.g., 2c, Table
1). After it was established that the derived o-anisidyl imine
undergoes Diels-Alder reactions most efficiently, parallel libraries5
of amino acid-based ligands, metal salts, and additives were
examined. These investigations led us to establish that treatment
of 2a with 1.5 equiv of diene 1, 1 mol % 3a, 1 mol % AgOAc, and
1 equiv of i-PrOH (THF, 4 °C) followed by HCl workup affords
cycloadduct 4a in 93% ee and 94% isolated yield. As the data in
entry 2 of Table 1 indicate, the catalytic cycloaddition can be
effected in 92% ee and yield with only 0.5 mol % loading. The
reaction proceeds to >98% conv with 0.1 mol % of the chiral Ag
complex (entry 3), albeit with diminished enantioselectivity (88%
ee). Moreover, a range of arylimines, including sterically hindered
(e.g., 2b, entry 4) substrates or those that bear electron-donating
(e.g., 2d and 2f) or electron-withdrawing substituents (e.g., 2g and
2h), can be employed to access the desired piperidines in g89%
ee and g86% isolated yield.
m-NO2
p-NO2
2-furyl
2g
2h
2i
10
11
a Conditions: All reactions run under N2 atm (12 h). b Isolated yields.
c Determined by chiral HPLC (Chiralcel OJ for entries 1-3, 6-8; chiralcel
OD for entries 4, 5, and 11 and chiralcel AD for entries 9 and 10).
Scheme 1. Catalytic Cycloadditions Performed without Solvent
and in Air
of i-PrOH, significantly lower conversions and enantioselectivities
are obtained. As an example, even with 10 mol % catalyst loading,
addition of 1 to 2c proceeds to only 30% conv after 24 h (4 °C) to
provide 4c in 43% ee (compare to entry 1, Table 1). Other proton
sources such as t-BuOH, MeOH, or water (see Scheme 1) can be
used as additives or cosolvents; in 1:1 THF:H2O, formation of 4c
(91% ee) proceeds to >98% conv (5 mol % 3a). (4) As shown in
Scheme 1, cycloadditions can be carried out effectively in the
absence of solvent with minor diminution in selectivity and yield.
Although reactions in Table 1 are effected under N2, as the examples
in Scheme 1 indicate, asymmetric cycloadditions proceed in air
and with undistilled commercial THF with high selectivity and
yield. (5) During screening studies, we established that the steric
and electronic properties of the amide terminus can have a notable
effect on enantioselectivity or conversion. Representative data are
shown in Table 2.
Several additional points are noteworthy: (1) The presence of
the o-OMe group in imine substrates is required for high enanti-
oselectivity but not reactivity. For example, reaction of phenyl and
o-tolyl derivatives of 4c proceed to >90% conv under conditions
shown in Table 1 but afford the cycloaddition product in only 35-
40% ee. (2) In contrast to the previously reported catalytic
asymmetric additions to imines,6 dipeptide phosphines give sig-
nificantly lower selectivity and efficiency levels. (3) In the absence
9
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J. AM. CHEM. SOC. 2003, 125, 4018-4019
10.1021/ja030033p CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Effect of Amide Moiety on Ag-Catalyzed Enantioselective
Cycloadditionsa
entry
R
conv (%)
ee (%)
1
2
3
4
5
6
p-OMeC6H4
p-CF3C6H4
2,6-Me2C6H3
NHBu
Bn
NH(OMe)
a
b
c
d
e
f
>98
75
53
>98
>98
52
92
88
28
80
80
20
studies will include investigating the role of i-PrOH additive and
whether it is involved in shuttling Me3Si from O to N (or vice
versa) and/or the release of Ag from product. These studies will
explore the coordination geometry of the Ag center(s) by establish-
ing the kinetic details of the catalytic cycle and the exact structure
(stoichiometry) of the reactive substrate-catalyst complex.
a See Table 1 for reaction conditions.
Because of the robustness of these asymmetric catalytic trans-
formations and the significance of piperidines to biological
chemistry, the availability of an effective supported ligand consti-
tutes an important aspect of this research, particularly in relation
to high throughput enantioselective synthesis. The data in eq 2
summarize results of our initial studies; ligand 5 can be reused
through at least five cycles.7 It should be noted that cycloadditions
with 5 are performed in air and with undistilled THF (fresh AgOAc
added for each cycle), and lower enantioselectivities are consistent
with the data shown in entry 5 of Table 2 (3e, NHBn vs NAr
terminus).
Acknowledgment. This work was supported by the NIH (GM-
57212).
Supporting Information Available: Experimental procedures and
spectral and analytical data for reaction products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Danishefsky, S. J.; DeNinno, M. P. Angew. Chem., Int. Ed. Engl. 1987,
26, 15-23.
(2) Kerwin, J. F.; Danishefsky, S. J. Tetrahedron Lett. 1982, 23, 3739-3742.
(3) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed.
1998, 37, 979-981. (b) Kobayashi, S.; Kusakabe, K.; Kimoyama, S.;
Ishitani, H. J. Org. Chem. 1999, 64, 5220-5221. (c) Yao, S.; Johannsen,
M.; Hazell, R. G.; Jorgensen, K. A. Angew. Chem., Int. Ed. 1998, 37,
3121-3124. For a noncatalytic enantioselective cycloaddition, see: (d)
Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264-3265.
(4) For previous reports regarding amino acid-based phosphine ligands, see:
(a) Gilbertson, S. R.; Collibee, S. E.; Agarkov, A. J. Am. Chem. Soc.
2000, 122, 6522-6523. (b) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H.
J. Am. Chem. Soc. 2001, 123, 755-756. (c) Mizutani, H.; Degrado, S. J.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779-781. (d) Luchaco-
Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-8193.
(e) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 13362-13363. (f) Hird, A. W.; Hoveyda, A. H. Agnew. Chem., Int.
Ed. In press. (g) Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. In
press.
(5) (a) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-
1671. (b) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36,
1704-1707. (c) Hoveyda, A. H. In Handbook of Combinatorial Chemistry;
Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim,
2002; pp 991-1016.
(6) (a) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.;
Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 4284-4285. (b) Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657-
2658. (c) Jospehsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2001, 123, 11594-11599. (d) Porter, J. R.; Traverse,
J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984-
985. (e) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409-10410.
(7) See the Supporting Information for results of recycling studies.
(8) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677-680.
(9) For conjugate additions to the corresponding carbamates (cyclic products
obtained), see: Comins, D. L.; LaMunyon, D. H.; Chen, X. J. Org. Chem.
1997, 62, 8182-8187.
(10) Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin Trans. 1
1990, 1213-1214.
(11) Bhattarai, K.; Cainelli, G.; Panunzio, M. Synlett. 1990, 229-230.
As the examples in eqs 3 and 4 illustrate, enantioenriched cyclic
amines8 can be functionalized diastereoselectively. Noteworthy is
the rupture of the piperidine ring that occurs upon treatment of 4a
with the alkylcuprate9 to afford the derived acyclic â-amino ketone
(Mannich addition product). Subsequent stereoselective reduction10
(10:1, syn:anti) and removal of the o-anisidyl group11 delivers amino
alcohol 7 (93% ee).
Future research will involve the development of catalytic
asymmetric cycloadditions with aliphatic imines, processes which
will likely involve in situ imine formation/cycloaddition6e and might
require a different chiral ligand.5c Upcoming detailed mechanistic
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