Effect of ligand structure on the zinc-catalyzed Henry reaction. Asymmetric syntheses of (-)-denopamine and (-)-arbutamine

Article abstract of DOI:10.1021/ol020077n

(Matrix presented) Syntheses of variously modified ligands for the dinuclear zinc catalysts for the asymmetric aldol and nitroaldol (Henry) reactions are reported. Catalytic enantioselective nitroaldol reactions promoted by these modified ligands led to efficient syntheses of the β-preceptor agonists (-)-denopamine and (-)-arbutamine.

Full text of DOI:10.1021/ol020077n

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2621-2623
Effect of Ligand Structure on the
Zinc-Catalyzed Henry Reaction.
Asymmetric Syntheses of
(−)-Denopamine and (−)-Arbutamine
Barry M. Trost,* Vince S. C. Yeh, Hisanako Ito, and Nadine Bremeyer
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received April 15, 2002
ABSTRACT
Syntheses of variously modified ligands for the dinuclear zinc catalysts for the asymmetric aldol and nitroaldol (Henry) reactions are reported.
Catalytic enantioselective nitroaldol reactions promoted by these modified ligands led to efficient syntheses of the â-receptor agonists (−)-
denopamine and (−)-arbutamine.
The nitroaldol (Henry) reaction is an atom-economic ap-
proach to â-hydroxynitroalkanes, valuable synthetic inter-
mediates.1 The asymmetric version of this reaction through
the use of heterobimetallic catalysis with lanthanide binol
systems by the group of Shibasaki was not known until quite
recently.2 As part of our study of a new dinuclear zinc
catalyst for the aldol reaction,3 we demonstrated the utility
To test the effect of the pKa of the phenol on the reaction,
ligands 1b-d (Figure 1) were synthesized as shown in
of this new system for the nitroaldol reaction using our
standard ligand 1a as shown in eq 1.4 To ascertain the
structural features important for the chiral recognition, we
systematically varied the ligand and report our results herein.
Scheme 1. The preparation of dibromides 4 was based upon
literature precedents.5 The reactivity of the dibromides 4 led
to their immediate use in the substitution reaction. For the
synthesis of 1a the substitution was performed with triethyl-
amine in methylene chloride using proline methyl ester
followed by addition of ArMgBr, or potassium carbonate in
DMF using diphenylprolinol 3a.6 For the remaining ex-
amples, potassium carbonate in DMF was employed. Methyl
(1) For recent reviews on nitroaldol reactions, see: (a) Rosini, G. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford,
1996; Vol. 2, p 321. (b) Luzzio, F. A. Tetrahedron 2001, 57, 915. (c) Ono,
N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001;
Chapter 3, p 30.
(2) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418. (b) Sasai, H.; Tokunaga, T.; Watanabe, S.;
Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388. (c) For
a review, see: Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1236.
(3) (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (b)
Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. (c)
Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497.
(4) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861.
(5) (a) Van Der Boom, M. E.; Liou, S.-Y.; Ben-David, Y.; Shimon, L.
J. W.; Milstein, D. J. Am. Chem. Soc. 1998, 120, 6531. (b) Arnaud, N.;
Picard, C.; Cazaux, L.; Tisnes, P. Tetrahedron 1997, 53, 13757. (c) Finn,
L, J. Appl. Chem. 1951, 1, 524. (d) Mendoza, J. Nieto, M. P. Prados, P.
Sanchez, C. Tetrahedron 1990, 46, 671-682.
(6) (a) Kanth, J. V. B.; Periasamy, M. Tetrahedron 1993, 49, 5127. (b)
Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.; Carroll, J. D.;
Corley, E. G.; Desmond, R. Org. Synth. 1997, 74, 50 and references therein.
10.1021/ol020077n CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/19/2002

Initial efforts focused upon the reactions using ligands that
retained the diphenylcarbinol moiety and varied the phenol
unit, i.e., ligands 1a-f. The nitroaldol reaction of an aliphatic
and an aromatic aldehyde was pursued as shown in eq 3
and Table 1. The results indicate that varying the substitution
on the phenol ring had little effect on ee except for p-methoxy
(1d) where a dramatic decrease occurred in both cases
Table 1. Nitroaldol Reaction with Ligands 1a-fa
Figure 1.
% isolated
entry
ligand
product
T (°C)
yield
% eeb
groups were placed at the meta positions of the aryl ring to
influence the conformations of the proline with the anticipa-
tion that such buttressing effects would rigidify the chiral
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1b
1c
1d
1e
1f
1a
1a
1b
1c
1d
1e
1f
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
-25
-60
-25
-25
-25
-35
-25
-25
-35
-25
-25
-25
-35
-25
52
58
52
44
45
36
44
75
85
61
43
27
30
52
86
88
84
88
37
77
78
87
91
88
93
22
89
82
Scheme 1. Synthesis of Ligandsa
a All reactions were performed on 1 mmol scale using 5 mol % catalyst,
5 equiv of CH3NO2, at 0.33 M in THF at the indicated temperature for 16
h unless noted otherwise. b Determined by chiral HPLC; see Supporting
Information for details.
a (a) NaOH, HCHO, H2O, rt; (b) HBr, HOAc, rt; (c) K2CO3,
DMF, rt; (d) (C2H5)3N, CH2Cl2, rt; (e) ArMgBr, THF, rt.
(entries 5 and 12). Placing fluorine in the para position, on
the other hand, gave a slight increase in ee (entries 4 and
11). A greater temperature dependence was observed with
the aromatic aldehyde (entry 8 vs 9) compared with the
aliphatic aldehyde (entry 1 vs 2).
space. The parent phenol was prepared from the known
diester7 as shown in eq 2. Since our model envisions that
Since the reactions were run for a fixed time, the isolated
yields are more reflective of the rate of the reaction.
Interestingly, reactions employing the “parent” ligand 1a
appear to be the fastest.
The impact of the diaryl carbinol moiety of the ligands
was examined in the context of the aromatic aldehyde 6a-c
(eq 4). Surprisingly, the effects of variation of the aryl groups
are modest. The biphenyl ligand 2b gave small but real
increases in ee compared to the “parent” (Table 2, entries 1
the aryl groups of the diarylcarbinol help define the chiral
space, varying the size of the aryl rings as in 2a,b should
vary the steric demands of the chiral space. This series of
ligands was synthesized by the route depicted in Scheme 1.
Finally, the effect of the pKa of the tertiary hydroxyl group
was also probed by synthesizing ligand 2c as outlined in
Scheme 1.
(7) (a) Bertz, S. H. Synthesis 1980, 708. (b) Fahrni, C. J.; Pfaltz, A.
HelV. Chim. Acta 1998, 81, 491.
2622
Org. Lett., Vol. 4, No. 16, 2002

(-)-Denopamine9 (13), a selective â1-adrenoceptor agonist
that is clinically effective in congestive cardiomyopathy, is
available from (R)-7a as shown in Scheme 2. As above,
Table 2. Nitroaldol Reactions with Ligands 1a-c and 2a-ca
% isolated
entry
ligand
product
yield
ee (%)a
Scheme 2. Asymmetric Synthesis of (-)-Denopaminea
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1c
2a
2b
2c
1a
2a
2b
1a
1c
2a
2b
2c
7a
7a
7a
7a
7a
7b
7b
7b
7c
7c
7c
7c
7c
59
40
72
88
64
65
89
88
69
40
68
47
50
87
87
84
90
84
83
89
85
78
87
85
86
85
a (a) H2, 10% Pd/C, ethanol, rt; (b) t-C4H9COCl, (C2H5)3N, THF,
-78 to 0 °C to 10 then add 9, (C2H5)3N, -78 to 0 °C; (c) LAH,
Et2O, 40 °C; (d) HCl, KF, MeOH, rt.
a All reactions were performed on a 1 mmol scale using 10 mol %
catalyst, 10 equiv CH3NO2 at 0.33 M in THF at -35 °C for 24 h.
b Determined by chiral hplc; see Supporting Information for details.
catalytic hydrogenation formed the amine 9, which was
coupled to the arylacetic acid 10 via the mixed anhydride
method to form amide 11. Reduction to amino alcohol 12
followed by the deprotection completed the synthesis of (-)-
denopamine, [R]D -28.1 (c 1.2, CH3OH), mp 162-163 °C
[lit.9f [R]D -27.5 (c 0.95, CH3OH), mp 163-164 °C].
Starting from commercially available 4-hydroxybenzalde-
hyde, this five-step synthesis proceeded in 43% overall yield.
This approach for the asymmetric aldol and nitroaldol
reaction benefits from the ease of modifying the chiral space
as shown herein. The biphenyl-type ligand 2b provides some
enhancement and has been adopted as our standard for the
nitroaldol with aryl aldehydes. This finding is in accord with
the notion that the conformation of the diarylcarbinol moiety
creates the chiral space responsible for enantiodiscrimination
in these dinuclear zinc complexes.
vs 4, 6 vs 8, and 9 vs 12). Thus, this ligand was adopted as
the standard. Similarly, the naphthyl ligand 2a gave a more
enhanced selectivity for 7b (Table 2, entry 6 vs 7).
The important physiological roles that arylethanol amines
play has led to many analogues being developed for coronary
diseases. The asymmetric nitroaldol addition provides ready
access to such compounds. For example, (-)-arbutamine8
(8b), a mixed â1-â2 adrenoreceptor agonist useful as an
exercise stimulating agent (ESA), is readily available asym-
metrically via an asymmetric nitroaldol reaction. The absolute
configuration of these types of targets requires use of R,R-
ligands. Thus (R)-7b was reduced and acylated to form amide
8a as shown in eq 5 in analogy to the work of Shibasaki8e
Acknowledgment. We are indebted to the National
Institutes of Health (GM1598) and the National Science
Foundation for their generous support of our programs. Mass
spectra were provided by the Mass Spectrometry Regional
Center of the University of California-San Francisco, sup-
ported by the NIH Division of Research Resources.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization (IR, 1H, 13C NMR,
HRMS) of all key compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
except that diphenyl chlorophosphate was employed for the
coupling step. Reduction (92% yield) and global desilylation
(90% yield) as described completed the synthesis of (-)-
arbutamine (8b), [R]D -17.3 (c 1.03, C2H5OH), mp 54-58
°C [lit.8e [R]D -18.5 (c 1.6, C2H5OH), mp 55-58 °C].
OL020077N
(9) Biological activities: (a) Yokoyama, H.; Yanagisawa, T.; Taira, N.
J. CardioVasc. Pharmacol. 1988, 12, 323. (b) Bristow, M. R.; Hershberger,
R. E.; Port, J. D.; Minobe, W.; Rasmussen, R. Mol. Pharmacol. 1989, 35,
295. Syntheses: (c) Nogushi, K.; Irie, K. Japanese Patent 79 70,233, 1979;
Chem. Abstr. 1979, 91, 630. (d) Nogushi, K.; Irie, K. Japanese Patent 79
70,231, 1979; Chem. Abstr. 1979, 91, 630. (e) Ikezaki, M.; Umino, N.;
Gaino, M.; Aoe, K.; Iwakuma, T.; Ohishi, T. Yakugaku Zasshi 1986, 106,
80. (f) Corey, E. J.; Link, J. O. J. Org. Chem. 1991, 56, 442. (g) Brown, R.
F. C.; Donohue, A. C.; Jackson, W. R.; McCarthy, T. D. Tetrahedron 1994,
50, 13739.
(8) (a) Tuttle R. R.; Brown, C. E. Eur. Pat. Appl. 329,464; Chem Abstr.
1991, 114, 602. (b) Tuttle R. R.; Brown, C. E. U.S. Patent 5,395,970, 1989,
1995 (both to Gensia); Chem. Abstr. 1996, 124, 331421. (c) Young, M.;
Pan, W.; Wiesner, D.; Bullough, G.; Balow, G.; Potter, S.; Metzner, K.;
Mullane, K. Drug DeV. Res. 1994, 32, 19. (d) Hammond, H. K.; Mckirnan,
M. D. J. Am. Coll. Cardiol. 1994, 23, 475. (e) For previous asymmetric
synthesis, see: Takaoka, E.; Yoshikawa, N.; Yamada, Y. M. A.; Sasai, H.;
Shibasaki, M. Heterocycles 1997, 46, 157.
Org. Lett., Vol. 4, No. 16, 2002
2623