A new class of modular chiral ligands with fluxional groups

Article abstract of DOI:10.1021/ja035979d

In ligand design for asymmetric catalysis, the usual norm is to derive the face shielding elements from a chiral source. New ligands in which the face shielding is determined by fluxional groups are introduced. Their design, modular synthesis, and experim

Full text of DOI:10.1021/ja035979d

Published on Web 07/15/2003
A New Class of Modular Chiral Ligands with Fluxional Groups
Mukund P. Sibi,* Ruzhou Zhang, and Shankar Manyem
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
Received May 6, 2003; E-mail: Mukund.Sibi@ndsu.nodak.edu
Scheme 1
Ligand design and synthesis is a central challenge in asymmetric
catalysis.1 In developing chiral ligands, their design should allow
for tuning through easy modification of substituents. Often,
synthesis of a modified ligand requires a new chiral source. An
alternative approach is one in which a fluxional blocking group is
incorporated into a parent chiral ligand.2,3 This would obviate the
need for multiple chiral sources and would allow the synthesis of
a family of ligands with steric groups of varying size from a single
chiral source.
Scheme 2
We have been interested in the design of chiral ligands for use
in a variety of asymmetric transformations. Thus, we needed a
flexible ligand design so that ligands with structural diversity would
be readily available. This work reports the synthesis and proof of
principle for a new class of modular ligands that incorporate
fluxional groups to control face selectivity.
We have designed a new ligand system 1 containing a core
dihydropyrazole moiety with chirality (R3) residing remotely to the
fluxional group R as shown in Scheme 1. The ligand design
incorporates the following features: (1) It has two nitrogen atoms
which can form a five-membered chelate with Lewis acids. (2) The
permanent chirality (R3) indirectly controls the orientation of the
fluxional N1 substituent in a metal complex (structure 2 or 3). (3)
The fluxional N1 substituent R plays a major role in face shielding.
The permanent chiral center need not necessarily serve a face
shielding role, so long as it dictates the conformation of R. (4) The
stereocontrol element (R) can be varied simply by alkylation. (5)
The chiral portion (R3) of the molecule is derived from various
chiral amines which can be obtained commercially or synthesized
independently. (6) When an amino alcohol is used as the chiral
source, then R3 contains a hydroxyl group. In this case, the ligands
are potentially tridentate. (7) A modular synthesis provides diverse
ligands (four diversity points: variation in R, R1, R2, and R3).
The synthesis of the new ligands was achieved in a straightfor-
ward manner from the known4 bromomethyl mesityloxide 4 in three
steps (Scheme 2). Treatment of the bromide with a chiral amine
followed by reaction with hydrazine gave the parent dihydropyra-
zole compound. We chose three commercially available chiral
amines to prepare the ligands, and the fourth was prepared in two
steps from proline methyl ester. The parent compound was then
alkylated with the appropriate fluxional group to furnish ligands
6-13. The unoptimized overall yields for the ligand synthesis
ranged from 30% to 45%.5
Table 1. Ligands with Fluxional Groups in Diels-Alder Reactions
Cu(OTf)2
Zn(OTf)2
yield
(%)a,b
ee endo
(exo)d
yield
(%)a,b
ee endo
(exo)d
c
c
entry
ligand
endo/exo
endo/exo
1
2
3
4
5
6
7
8
6
7
8
9
10
11
12
13
93
87
96
77
83
90
90
77
4.6
5.8
4.5
3.7
4.6
3.2
2.4
5.2
51 (46)
78 (61)
76 (71)
62 (75)
59 (60)
82 (92)
92 (97)
08 (04)
87
92
90
94
95
85
83
77
2.8
4.9
4.0
3.0
3.9
3.4
3.8
18.5
23 (19)
32 (12)
41 (02)
18 (14)
54 (41)
89 (87)
96 (95)
0 (0)
a For reaction conditions, see the Supporting Information. b Isolated yield.
c Diastereomer ratio determined by 1H NMR (500 MHz). d Determined by
chiral HPLC.
group (Me < Ph < 1-Naph; 7-9) had an inverse relationship with
selectivity: as the size of the group increased, the ee for endo adduct
decreased (entries 2-4). These results suggest that there may be
dissonance between the permanent and fluxional chiral groups. A
simple change in the chiral amine portion to pseudoephedrine
(ligands 10-12), a ring-unconstrained analogue of the proline
ligands, gave more gratifying results (entries 5-7). In this series,
both Cu and Zn(OTf)2 gave high selectivity for the endo adduct.
More interestingly, the level of selectivity was dependent on the
size of the fluxional group (ethyl < benzyl < naphthylmethyl: 10
< 11 < 12): the larger the size, the higher the selectivity for both
With the ligands at hand, we evaluated their effectiveness in the
Diels-Alder reaction between acrylate 14 and cyclopentadiene
using copper and zinc triflate as the Lewis acids (eq 1 and Table
1).5 Reactions with the chiral Lewis acid derived from copper and
zinc triflates and prolinol ligands 6-9 were initially evaluated
(entries 1-4). Of the two Lewis acids, Cu(OTf)2 gave higher
selectivity. The size of the substituent R1 on the remote proline
ring (methyl vs phenyl 6 vs 7) had an impact on selectivity with
the larger phenyl group leading to a higher ee for endo 16 (compare
entry 2 to entry 1). In the proline series, the size of the fluxional
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J. AM. CHEM. SOC. 2003, 125, 9306-9307
10.1021/ja035979d CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Evaluation of Different Dienophiles in Diels-Alder
Reactions Using Fluxional Ligands 11 and 12 and Zinc Triflate
reaction with cyclopentadiene is very efficient (reactions take <5
h for completion at 0 °C, entry 1). Similarly, reaction with
cyclohexadiene was also highly efficient and selective (entry 2).
The less reactive dienes took longer reaction time for completion.
The power of the modular ligand design is apparent in reactions
with the less reactive substrates. For example, in reactions with 26
at room temperature, the bulkier ligand 12 gave higher selectivity
in contrast to reaction with 11 (compare entry 4 to entry 3). The ee
for the reaction could be improved to >90% by cooling the reaction
to 0 °C (compare entry 5 to entry 4). A similar trend of an increase
in ee using ligand 12 was observed for reactions with dienes 27
(entries 6-8) and 28 (entries 9 and 10).
We have a tentative model for the observed selectivity with
ligand 12 and Cu or Zn as the Lewis acid. The requirement of a
hydroxyl group for obtaining high selectivity suggests an octahedral
environment around the metal (see structure: the yellow atom
represents a triflate for clarity). The observed product stereochem-
istry is consistent with the naphthyl group shielding the re face of
the substrate. In conclusion, we have developed a novel class of
modular ligands, containing fluxional groups, which provide highly
organized structures to control face selectivity. Evaluation of these
new ligands and congeners in other asymmetric transformations is
underway.
yield
(%)a
ee endo
(exo)c
entry
ligand
subs.
prod.
endo/exob
1d
2
3
11
11
11
12
12
14
17
18
19
20
16
21
22
23
24
85
82
86
94
90
3.4
17
6.0
1.5
1.3
89 (87)
90 (80)
96 (94)
94 (94)
96 (-)
4
5d
a Isolated yield. b Diastereomer ratio determined by 1H NMR (500 MHz).
c Determined by chiral HPLC. d Reaction at 0 °C.
Table 3. Evaluation of Different Dienes in Diels-Alder Reactions
temp.,
°C
yield
(%)a
ee endo
(exo)b
entry
diene
prod.
ligand
1c
2d
3
4
5
15
25
26
26
26
27
27
27
28
28
16
29
30
30
30
31
31
31
32
32
12
11
11
12
12
11
12
12
12
12
0
83
86
54
81
69
60
67
67
67
27
96 (95)
98 (70)
69
89
95
64
79
90
76
rt
rt
rt
0
rt
rt
0
Acknowledgment. This work was supported by the National
Science Foundation (NSF-CHE-9983680 and NSF-EPS-0132289).
6
7
8
Supporting Information Available: Characterization data for
compounds 6-32 and experimental procedures (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
9e
10
rt
0
82
References
a Isolated yield. b Determined by chiral HPLC. c endo:exo ) 3.8:1.
d endo:exo ) 40:1. e 6.9:2.6:1 mixtures of isomers; ee is for the major
isomer.
(1) For reviews, see: (a) Comprehensive Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vols. I-III.
(b) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New
York, 2000. (c) Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and
Applications of Asymmetric Synthesis; Wiley: New York, 2001. (d) Seyden
Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis;
Wiley: New York, 1995. (e) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 35, 325.
(2) For the use of meso and achiral ligands in asymmetric synthesis, see: (a)
Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802. (b) Costa,
A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2002, 124, 6929. (c) Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh,
P. J. Org. Lett. 2001, 3, 2161. (d) Mikami, K.; Terada, M.; Korenaga, T.;
Matsumoto, Y.; Matsukawa, S. Acc. Chem. Res. 2000, 33, 391. (e) Becker,
J. J.; White, P. S.; Gagne´, M. R. J. Am. Chem. Soc. 2001, 123, 9478. (f)
Chavarot, M.; Byrne, J. J.; Chavant, P. Y.; Guindet, P.; Valle´e, Y.
Tetrahedron: Asymmetry 1998, 9, 3889. (g) Mikami, K.; Aikawa, K.;
Ysa, Y.; Jordy, J. J.; Yamanaka, M. Synlett 2002, 1561.
the endo as well as the exo isomer. These results clearly suggest
that the size of the fluxional group is a primary determinant of
face selectivity. The outstanding level of selectivity with Zn(OTf)2
is worthy of note, because it has only shown marginal effectiveness
when used in combination with a variety of ligands in Diels-Alder
reactions.6 The absolute stereochemistry of 16 was determined to
be S using ligands 10-12 and either Cu or Zn(OTf)2 as the Lewis
acid.5 The near racemic reaction with 13 indicates that a hydroxyl
group on the ligand is required for obtaining high selectivity
(compare entries 6 and 8).
(3) Achiral templates with fluxional groups in synthesis, see: (a) Sibi, M.
P.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2001,
123, 8444. (b) Corminboeuf, O.; Quaranta, L.; Renaud, P.; Liu, M.;
Jasperse, C. P.; Sibi, M. P. Chem.-Eur. J. 2003, 9, 28. (c) Sibi, M. P.;
Liu, M. Org. Lett. 2001, 3, 4181.
Having established that stereocontrol using ligands with fluxional
groups is efficient, we investigated their utility in DA reactions of
more complex substrates (eq 2, Table 2). As can be discerned from
the table, a variety of dienophiles provide DA adducts with high
enantioselectivity (entries 1-5). It is important to note that in these
reactions, ligand 11, a ligand containing a moderately bulky benzyl
substituent, provides excellent levels of selectivity at room tem-
perature.
(4) (a) Bloch, R. Synthesis 1978, 140. (b) Babadjamian, A.; Kessat, A. Synth.
Commun. 1995, 25, 2203.
(5) For the synthesis of ligands, reaction conditions for DA reactions, ee
determination, and product stereochemical analysis, see the Supporting
Information.
(6) For DA reactions using Zn(OTf)2 as a Lewis acid, see: (a) Takacs, J. M.;
Quincy, D. A.; Shay, W.; Jones, B. E.; Ross, C. R., II. Tetrahedron:
Asymmetry 1997, 8, 3079. (b) Evans, D. A.; Kozlowski, M. C.; Tedrow,
J. S. Tetrahedron Lett. 1996, 37, 7481.
The next series of experiments involved the evaluation of
different dienes in cycloadditions with 14 using Zn(OTf)2 as a Lewis
acid and 11 or 12 as a ligand (eq 3, Table 3). As discussed earlier,
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