Asymmetric catalysis: Resin-bound hydroxyprolylthreonine derivatives in enamine-mediated reactions

Article abstract of DOI:10.1002/anie.200801811

Control of stereochemistry is achieved using two TentaGel-bound di-tert-butoxyprotected hydroxyprolyl-threonine catalysts (see picture, sphere represents TentaGel). These catalysts mediate asymmetric tandem enamine/Michael reactions with high enantioselectivity and complete diastereoselectivity; the choice of catalyst depends on the desired absolute configuration. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200801811

Angewandte
Chemie
DOI: 10.1002/anie.200801811
Organocatalysis
Asymmetric Catalysis: Resin-Bound Hydroxyprolylthreonine
Derivatives in Enamine-Mediated Reactions**
Richard D. Carpenter, James C. Fettinger, Kit S. Lam, and Mark J. Kurth*
Control of relative and absolute stereochemistry with step-
economy[1,2] presents a continuing challenge in organic syn-
thesis.[3] Asymmetric crossed aldols have historically involved
chiral auxiliaries or O-trapped organometallic intermediates;
the latter operate by either a Zimmerman–Traxler or an open
transition-state model.[4] However, auxiliaries lengthen syn-
theses, and organometallics typically require careful control
of reaction conditions and have limited functional-group
tolerance. Enamines, however, predominantly react at the C-
terminus, and generally deliver products under ambient
reaction conditions.[3] The C2-symmetric trans-2,5-dimethyl-
pyrrolidine reagent is used in asymmetric enamine reactions.
However, it suffers from poor efficacy and is scarce. Although
several asymmetric syntheses exist for the preparation of this
reagent,[5] its limited commercial availability suggests that
these lengthy protocols have not impacted supply.[6]
The group of Chandrasekhar was the first to use l-proline
to prepare chromanones (1; Scheme 1)[17] in a method
requiring the use of DMF, owing to the zwitterionic nature
Scheme 1. a) Retrosynthetic analysis of chromanones (1) and the
structures of resin-bound catalyst A,its diastereomer B,and,the off-
resin analogue of A,catalyst C (spheres represent Tentagel resin).
This problem has been somewhat alleviated by proline-
derived organocatalysts, which have been under intense
investigation in recent years and discussed in reports from
the groups of Yamamoto[7] and Miller.[8] Reactions of
supported (both hetero- and homogeneous)[9] and non-
supported[10] organocatalysts have been reviewed. When
applied to aldol condensations, heterogeneous supported
organocatalysts often require high catalyst loading[11] and long
reaction times,[12] while delivering varied enantioselectivi-
ties.[11–13] Non-supported organocatalysts often require
extended reaction times,[14] have strict solvent require-
ments,[15] and produce variable yields.[16]
of proline.[18] Chromanones are medicinally pertinent hetero-
cycles[19] and the chroman parent system has been found in
natural products such as sappone B[20] and robustadial,[21] in
addition to being a bioisostere for the hydantoin moiety.[22]
Indeed, chromanones have many biomedical applications
and, consequently, have received considerable synthetic
attention.[23] The laboratories of Enders, McKervey, and
Scheidt have reported asymmetric preparations of chroma-
nones, however these routes have modest enantioselectiv-
ity,[24] and require advanced precursors.[25,26]
Clearly, there is a need to develop a practical asymmetric
route to optically active chromanones and to advance
asymmetric solid-phase catalysts for enamine-mediated reac-
tions. Herein, we focus on TentaGel-bound (TG-bound)
catalysts to facilitate recoverability and reusability as well as
to expedite syntheses through microwave-assisted reac-
tions.[27,28] We report the synthesis of resin-bound asymmetric
pyrrolidine catalysts A and B (see Scheme 1), with applica-
tions toward the syntheses of optically active chromanones as
well as other enamine-derived molecular targets.
The development of catalyst A is outlined in Table 1. Each
catalyst (A, D–G) is bound to TentaGel resin, which was
chosen for its relative inertness and hydrophilicity. The
catalysts are prepared rapidly by solid-phase peptide synthe-
sis.[29,30a] For catalyst evaluation, the starting materials,
solvent, and relative quantity of catalyst (1 mol%) were
held constant as the catalyst, temperature, and reaction time
were varied. After the time indicated, all the samples were
subjected to microwave irradiation for 11 min at 1108C.[31]
Table 1, Entry 7 shows the reaction conditions and catalyst
(catalyst A) yielding the highest enantiomeric excess (ee).[30b]
An increase in ee is detected as substituents are altered from
[*] R. D. Carpenter,Dr. J. C. Fettinger,Prof. M. J. Kurth
Department of Chemistry
University of California-Davis
Davis,CA 95616 (USA)
Fax: (+1)530-752-8895
E-mail: mjkurth@ucdavis.edu
Homepage: http://chemgroups.ucdavis.edu/~kurth/index.htm
Prof. K. S. Lam
Division of Hematology/Oncology,Department of Internal Medicine
University of California-Davis Cancer Center
Sacramento,CA 95817 (USA)
[**] This work was supported by the National Science Foundation (NSF;
CHE-0614756) and the National Institute for General Medical
Sciences (GM076151). NMR spectrometers used in this work were
funded in part by the NSF (CHE-0443516 and CHE-9808183). RDC
thanks the American Chemical Society’s Division of Medicinal
Chemistry for Predoctoral Fellowship support (sponsored by Sanofi-
Aventis),the Howard Hughes Medical Institute for their Med into
Grad Fellowship,and UC Davis for their R. Bryan Miller Graduate
Fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801811.
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Table 1: Reaction conditions for the development of catalyst A
Entry Catalyst[a]
T [8C] t [h][b] Yield entA:entB[c]
[%]
1
2
3
4
5
6
7
8
Pro-Phe-TG (D)
Pro-Phe-TG (D)
Pro-Ile-TG (E)
0
25
25
25
8
1
3
1
1
4
1
0.5
–
–
80
68
83
86
78
86
89
60:40
65:35
83:17
70:30
94:6
Pro-Ser(tBu)-TG (F)
Hyp(tBu)-Ser(tBu)-TG (G) 25
Hyp(tBu)-Thr(tBu)-TG (A) 10
Hyp(tBu)-Thr(tBu)-TG (A) 25
Hyp(tBu)-Thr(tBu)-TG (A) 50
98:2
74:26
[a] All TG-bound catalysts give entA/entB with complete diastereoslec-
tivity. [b] Each reaction was heated under microwave irradiation for 11
min at 1108C. [c]Ratio determined by chiral HPLC analysis[30b]
Scheme 2. a) Following enantioselective enamine attack to give a
single b-hydroxy ketone (e.g., R,R with B),subsequent heating yields
an enone which undergoes diastereoselective equatorial Michael
additon. b) Various experiments performed to investigate the mecha-
nism to enantiopure chromanones where Ar=5-F-2-HOC6H3: Expt. A:
B,4- tBu-c-C6H9O RT,2 h; Expt. B: B,3-Me- c-C6H9O, D; Expt. C: 1) D;
DD; Expt. D: 1) B,3-Me- c-C6H9O,RT,1 h; then D; 2) B, (R)-3-Me-c-
C6H9O,RT,1 h; then D; 3) B,3-Me- c-C6H9O,RT,1 h; filter B,add A;
then D; Expt. E: 3-Me-c-C6H9O,RT,1 h,filter B,then D; Expt. F: B,4-
tBu-c-C6H9O,RT,1 h,then D; Expt. G: Hyp(tBu)Ser(tBu)C(O)NHBu
(C),3-Me- c-C6H9O,RT,1 h; D; Expt. H: 2-Me-c-C6H9O,RT,1 h,then D.
benzyl (amino acid Phe) to sec-butyl (Ile) to a linear tert-
butyl-ether [Ser(tBu)] to a branched tert-butyl-ether [Thr-
(tBu)]. Another increase in ee is detected when 2-carbox-
amidopyrrolidine (Pro) is substituted with the bulkier trans-4-
tert-butoxy-2-carboxamidopyrrolidine [Hyp(tBu)]. The posi-
tioning of both sterically encumbering branched tert-butyl
ethers on the a face allows the b face to react faster with the
(S)-enantiomer of rac-3-methylcyclohexanone (2 equiv) at
room temperature. The optimal range for kinetic resolution is
within Æ 108C of room temperature. If cooled further
(Table 1, Entry 1), the enamine does not react with the
ketone, and starting materials are recovered. If warmed to
508C (Table 1, Entry 8), kinetic resolution is reduced.
A series of experiments, given in Scheme 2, were designed
to determine the likely sequence of events in this tandem
aldol/Michael reaction. The catalyst and acetophenone pro-
duce a resin-bound enamine, which undergoes diastereose-
lective equatorial attack[32a] onto the substituted cycloalka-
none to yield a b-hydroxyketone (Expt. A; a known
compound[33]). Room-temperature kinetic resolution was
confirmed by the drastic reduction in ee when the reaction
mixture is heated immediately with the catalyst (Expt. B).
Heating without the catalyst (Expt. C) only resulted in
recovery of starting materials. Use of the matched (R)-3-
methylcyclohexanone yielded an identical result as did
changing the catalyst (from B to A) prior to heating (Expt.
D). Heating the reaction mixture without the catalyst resulted
in reduced diastereoselectivity (equatorial:axial) for the
phenoxy Michael addition (Expt. E).[21] Complete diastereo-
selectivity is obtained with catalyst B (as well as with catalyst
A) suggesting that it functions as either a base or an a,b-
unsaturated iminium species. Equatorial preference was
confirmed by X-ray crystallography (Expt. F). Interestingly,
an off-resin derivative of catalyst A (C; see Scheme 1)
requires 10 mol% for comparable efficacy (Expt. G). Positive
nOes confirm a trans relative configuration between the ether
oxygen and 2-methyl moieties (Expt. H).[30c] The catalyst is
recovered by filtration, and has been redeployed over forty
times without loss of efficiency or turnover. This durability
Scheme 3. Aldol,Michael,Robinson annulation,and Mannich reac-
tions demonstrating the utility of catalysts A and B. Reaction con-
ditions a) RT,3-4 h; b) 0 8C to RT, 6 h; c) 08C to RT,6 h,then
microwave irradiation,11 min,110 8C; d) RT,5 h. e) Catalysts A and B
can control a–d stereocenters.
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Chemie
Table 2: Chromanones delivered by catalysts A and B.[a]
times. The catalysts are simple to
prepare, easily recovered, and can
be reused several times. These cat-
alysts were utilized in a variety of
enamine-mediated reactions with
high facial selectivity and tolerate
a
variety of functional groups.
Alternatively, the unreacted 3-sub-
stituted cycloalkanones are
obtained with high optical purity,
providing facile access to versatile
synthetic precursors from readily
available racemic starting materials.
R1, R2
R3
Catalyst
Product
Yield [%]
ee [%][b]
[a]2D5
Received: April 17, 2008
Published online: July 15, 2008
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
entA-2
entB-2
entA-3
entB-3
entA-4
entB-4
entA-5
entB-5
entA-6
entB-6
entA-7
entB-7
entA-8
entB-8
9
78
83
71
77
83
81
86
89
90
83
76
80
82
87
74
70
89
94
97
99
95
96
94
98
93
98
95
97
92
95
90
93
–
+57.6
À56.8
À17.1
+16.8
+61.9
À62.5
À80.1
+80.4
+33.9
À33.2
+49.9
À49.4
À57.3
+56.6
–
4-OEt
4-OMe
4-F
-CH2CH(R3)(CH2)2-
-CH2CH(R3)(CH2)3-
-CH2CH(R3)(CH2)3-
-CH2CH(R3)(CH2)2-
-CH2CH(R3)(CH2)2-
-CH(R3)(CH2)4-
Keywords: asymmetric catalysis ·
.
heterocycles ·
heterogeneous catalysis ·
solid-phase synthesis ·
stereoselectivity
6-OCH3
5-Et
4-OEt
5-F
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-CH(R3)(CH2)4-
5,6-(CH)4
5-Cl
-CH(R3)CH2O(CH2)2-
-CH(R3)CH2NAc(CH2)2-
9
10
10
–
–
–
–
–
–
H
[a] Catalyst (A or B),MeOH,RT,then microwave irradiation,110 8C,11 min. The reaction gives complete
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