A New Ligand Scaffold for Catalytic Asymmetric Alkylzinc Additions to Aldehydes

Article abstract of DOI:10.1021/ol025600c

matrix presented 1,3-Azole derivatives of 2-aminocyclohexanecarboxylic acid represent a new class of bidentate ligands for metal-mediated catalytic asymmetric synthesis. N-[2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)cyclohexyl]methanesulfonamide (6) is particu

Full text of DOI:10.1021/ol025600c

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1197-1200
A New Ligand Scaffold for Catalytic
Asymmetric Alkylzinc Additions to
Aldehydes
Peter Wipf* and Xiaodong Wang
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf+@pitt.edu
Received January 22, 2002
ABSTRACT
1,3-Azole derivatives of 2-aminocyclohexanecarboxylic acid represent a new class of bidentate ligands for metal-mediated catalytic asymmetric
synthesis. N-[2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)cyclohexyl]methanesulfonamide (6) is particularly well suited for the addition of alkylzinc
reagents to aliphatic aldehydes in high enantiomeric excess.
The development of new classes of chiral ligands for metal-
catalyzed asymmetric transformations is an important goal
of contemporary organic chemistry. While ligands based on
the binaphthyl,1 salen,2 bisoxazoline,3 and tartrate4 scaffolds
have been extraordinarily successful in many synthetic
transformations,5 there is still considerable incentive to
diversify the family of chiral ligand architectures. Among
the most important design criteria for metal ligand develop-
ment are the spatial orientation of chelating heteroatoms, a
ready structural modification, and, of course, convenient
access to both enantiomers in high enantioselectivity.
We have recently reported the preparation of amino-
cyclohexanecarboxylic acids 1 by catalytic asymmetric
Diels-Alder methodology (Figure 1).6,7 While a major
application of these compounds lies in the preparation of
water-soluble â-peptide foldamers,8 we envisioned that the
disposition of two neighboring functional groups on the
synthetically readily modified cyclohexane scaffold would
lend itself to effective metal ligand design. We now report
the preparation of several aminooxazoline and -thiazoline
congeners based on this motif and the experimental validation
of the effectiveness of this new ligand architecture in highly
enantioselective diethylzinc additions to aliphatic aldehydes.9
Selective saponification of imide 2,6 followed by modified
Curtius rearrangement with DPPA,10 provided carbamate 3
in 80% yield (Scheme 1). Catalytic hydrogenation of the
(1) Noyori, R. Pure Appl. Chem. 1981, 53, 2315.
(2) Ito, Y. N.; Katsuki, T. Bull. Chem. Soc. Jpn. 1999, 72, 603.
(3) Pfaltz, A. Acta Chem. Scand. 1996, 50, 189.
(4) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001,
40, 92.
(5) Tye, H.; Comina, P. J. J. Chem. Soc., Perkin Trans. 1 2001, 1729.
(6) Wipf, P.; Wang, X. Tetrahedron Lett. 2000, 41, 8747.
(7) For a related approach, see: Bolm, C.; Schiffers, I.; Dinter, C. L.;
Defrere, L.; Gerlach, A.; Raabe, G. Synthesis 2001, 1719.
(8) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Seebach, D.;
Matthews, J. L. Chem. Commun. 1997, 2015.
(9) For a recent comprehensive review of organozinc additions, see: Pu,
L.; Yu, H.-B. Chem. ReV. 2001, 101, 757.
(10) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203.
Figure 1. Dihydroxylated cis- and trans-aminocyclohexane â-ami-
no acid building blocks.
10.1021/ol025600c CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/14/2002

Scheme 1
Figure 2. N-Sulfonated cis- and trans-aminocyclohexane oxazo-
lines as test ligands for asymmetric catalysis.
Somewhat to our surprise, adding to the bulk of the R2
substituent by replacing the isopropyl group with a tert-butyl
or a phenyl group (entries 7 and 8, respectively) did not have
Scheme 2
alkene moiety with concomitant removal of the Cbz-group,
N-mesylation, and hydrolysis of the methyl ester led to
carboxylic acid 4 as the precursor for the introduction of
heterocyclic substituents. Upon activation of the acid with
oxalyl chloride and condensation with (L)-valinol, the
intermediate amide 5 was cyclodehydrated11 to give oxazo-
line 6 in excellent overall yield. Protection of the hydroxy
group of 5 with TBS-Cl, formation of the thioamide with
Lawesson reagent, cleavage of the silyl ether, and cyclo-
dehydration12 with Deoxo-Fluor led to thiazoline 7 in 54%
yield from acid 4.
a noticeable effect on the enantioselectivity either. Accord-
ingly, we decided to investigate the effect of the sulfonyl
group. While the 2,4,6-trimethylbenzenesulfonyl (Mts) and
the nosyl (Ns) groups in the R1 position lowered the
enantiomeric excess, the triflate 13 provided a small increase
In a series of analogous transformations, oxazolines 8-16
were prepared (Figure 2).13 A preliminary evaluation of the
structure-activity relationships in this new class of chiral
ligands for asymmetric catalysis was established by the
Table 1. Ligand-Accelerated Asymmetric Et2Zn Addition to
Benzaldehyde
14
addition of Et2Zn to benzaldehyde (Scheme 2).
Our initial studies were conducted with the tosyl derivative
8 (Table 1, entries 3-6). Even in the presence of only 2
mol % of 8, (R)-17 was obtained in 89% yield and 80% ee
after a 22 h reaction time at 0 °C. Lowering the reaction
temperature had a dramatic effect in decreasing the reaction
rate, but the enantioselectivity was essentially temperature
independent. In addition, increasing the amount of 8 to 5
mol % loading did not provide a further increase in % ee.
entry
ligand (mol %)
temperature
yield (ee)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
6 (2)
7 (2)
8 (2)
8 (2)
8 (2)
0 °C
0 °C
0 °C
91% (86%)b
89% (85%)b
89% (80%)b
31% (76%)b
93% (78%)b
94% (80%)b
78% (78%)b
90% (80%)b
33% (58%)b
12% (4%)b
-15 °C
22 °C
0 °C
8 (5)
9 (2)
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
10 (2)
11 (2)
12 (2)
13 (2)
14 (2)
14 (2)
14 (5)
15 (2)
16 (2)
(11) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos,
K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541.
(12) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org.
Lett. 2000, 2, 1165.
(13) In all cases, ligand enantiomeric excess exceeded 99%.
(14) In a typical reaction, a solution of benzaldehyde (0.50 mmol) and
ligand (0.010 mmol) in hexanes (1.2 mL) was treated with a 1.0 M solution
of diethyl zinc in hexanes (1.10 mL, 1.10 mmol) at 0 °C. The reaction
mixture was stirred for 20-40 h at 0 °C, quenched by addition of 1 M
HCl, and extracted with CH2Cl2. The combined organic layers were dried
(MgSO4), concentrated, and chromatographed on SiO2 (ethyl acetate/
hexanes) to give the secondary alcohol as a colorless oil. Toluene could
also be used as a reaction solvent, leading to slightly slower reaction rates
but similar yields of products and % ee.
54% (88%)b
58% (48%)c
57% (51%)c
88% (49%)c
67% (3%)c
-30 °C
0 °C
0 °C
0 °C
62% (45%)c
a Determined by chiral HPLC (Chiracell OD) unless noted otherwise.
b (R)-17 was formed. c (S)-17 was formed.
1198
Org. Lett., Vol. 4, No. 7, 2002

in enantiomeric excess to 88%, but in the presence of this
ligand the reaction did not proceed as quickly as with tosylate
8 (entries 9-11).
The high enantioselectivity obtained with ligand 6 and
R-branched as well as linear aliphatic aldehydes compares
well to the frequently low to modest asymmetric inductions
reported for this class of substrates in the literature.9 Most
comparable to 6-16 are Bolm’s ferrocenyl oxazolines that
combine planar and central chirality elements and catalyze
the addition of diethylzinc to heptanal in 87% ee at 5 mol
% ligand loading.16 In contrast, Hou’s bidentate ferrocenyl
oxazolines only provided a 71% ee for diethylzinc addition
to cyclohexanecarboxaldehyde.17 From a structural point of
view, sulfonylaminooxazoline and -thiazoline ligands 6-16
are most closely related to the chiral (2-sulfonylamino)-
phenyloxazolines reported by Fujisawa18 and Mikami19 that
have been employed for enantioselective Diels-Alder,
cyclopropanation, and C-H bond activation reactions.
However, the latter ligands have not yet been explored for
asymmetric zinc additions and do not offer the same level
of control in scaffold configurations, metal complex bite
angles, and substitution patterns as ligands 6-16.
For comparison, we also tested the cis-aminooxazolines
14-16, even though molecular modeling predicted that the
geometry for bidentate metal chelation between the sulfon-
amide and oxazoline nitrogens was not as favorable as in
the trans-configured congeners. Indeed, the % ee values
under a variety of reaction conditions did not exceed 51%,
and now (S)-17 was the predominantly formed enantiomer
(Table 1, entries 12-16). This change in enantiofacial
selectivity in the diethyl zinc addition clearly illustrates the
importance of the cyclohexane C(2)-stereocenter but might
also be the consequence of a monodentate interaction of
chiral ligands 14-16 with zinc. In terms of overall yield
and enantioselectivity, the trans-oxazoline mesylate 6 pro-
vided the best results (entry 1), and since the corresponding
thiazoline 7 was not superior but required three additional
synthetic steps, we decided to further investigate the scope
of this process by focusing on ligand 6.
The facial selectivity of the ligand 6/diethyl zinc reagent
can be explained by coordination of the aldehyde substrate
syn to the oxazoline isopropyl group of a distorted tetrahedral
zinc complex (Figure 3). This leaves the re-face of the
Substitution at the phenyl ring of the aromatic aldehydes
decreased the reaction rate and also led to small decreases
in the enantioselectivity of the ethylzinc addition process
(Table 2, entries 1 and 2). Cinnamaldehyde only provided a
Table 2. Asymmetric Et2Zn Addition to Aldehydes at 0 ˚C in
the Presence of 2 mol % of Chiral Ligand 6. In All Cases, the
(R)-Configuration at the Secondary Alcohol Carbon Was
Obtained as the Major Enantiomer
entry
substrate
time
yield (ee)a
1
2
3
4
5
6
7
8
9
(p-Cl)PhCHO
52 h
43 h
45 h
21 h
23 h
25 h
26 h
28 h
23 h
79% (72%)
81% (80%)
47% (41%)
91% (11%)
97% (83%)
68% (>98%)b
80% (91%)c
80% (94%)c
95% (92%)d
(p-MeO)PhCHO
(E)-PhHCdCHCHO
BnO(CH2)2CtCCHO
PhCH2CH2CHO
c-C6H11CHO
(L)-citronellal
(R)-citronellal
n-C7H15CHO
a Determined by chiral HPLC (Chiracell OD) unless noted otherwise.
b Determined by chiral GC. c de determined by GC analysis. d Determined
by comparison of rotation values with literature data.15
47% yield of addition product in 41% ee after 45 h at 0 °C
(entry 3). While, in general, low reaction rates were
associated with a low enantiomeric excess of the secondary
alcohol products, this did not apply to all substrates.
5-Benzyloxypent-2-ynal reacted rapidly, but with no signifi-
cant enantiofacial differentiation (entry 4). In contrast,
aliphatic aldehydes provided the highest enantioselectivities.
Hydrocinnamaldehyde led to 83% ee, and the secondary
alcohol products from cyclohexanecarboxaldehyde and oc-
tanal were formed in >98% and 92% ee, respectively (entries
6 and 9). From the enantiomeric (L)- and (R)-citronellal, two
diastereomeric addition products were formed in 91% and
94% de (entries 7 and 8), thus establishing predominant
reagent control over substrate diastereoselectivity in the
addition process.
Figure 3. Stereoview and CPK model of an acetaldehyde complex
with the methylzinc adduct to ligand 6. Complex geometry was
optimized semiempirically with PM3 parametrization using Spartan.
carbonyl group relatively open to nucleophilic attack, and
addition would accordingly occur opposite to the sulfonamide
(15) Ishizaki, M.; Fujita, K.; Shimamoto, M.; Hoshino, O. Tetrahedron:
Asymmetry 1994, 5, 411.
(16) Bolm, C.; Muniz-Fernandez, K.; Seger, A.; Raabe, G.; Gu¨nther, K.
J. Org. Chem. 1998, 63, 7860.
(17) Deng, W.-P.; Hou, X.-L.; Dai, L.-X. Tetrahedron: Asymmetry 1999,
10, 4689.
(18) (a) Ichiyanagi, T.; Shimizu, M.; Fujisawa, T. J. Org. Chem. 1997,
62, 7937. (b) Ichiyanagi, T.; Shimizu, M.; Fujisawa, T. Tetrahedron 1997,
53, 9599.
(19) Mikami, K.; Hatano, M.; Terada, M. Chem. Lett. 1999, 55.
Org. Lett., Vol. 4, No. 7, 2002
1199

substituent. If the oxazoline substituents or the sulfonamide
functions become too sterically demanding, the reaction rate
is expected to decrease and the selectivity drops, as was
experimentally observed. The presence of the cyclohexane
backbone and the sterically demanding environment around
the zinc atom leads to a conformational rigidity that is
essential for high asymmetric induction and blocks inter-
molecular aggregation. The latter effect is most likely what
allows catalyst loadings to remain relatively small at 2 mol
% in comparison with standard asymmetric zinc additions
to aldehydes and explains the lack of dependence of product
% ee on catalyst loadings.
In conclusion, the new pseudo-C2-symmetric bidentate
ligand 6 is well suited for accelerating the catalytic asym-
metric addition of diethylzinc to aldehydes. The high
enantiomeric excess that was obtained with aliphatic alde-
hydes and the low level of ligand loading clearly validate
the efficacy of the newly designed and structurally readily
modified family of aminocyclohexane azoles 6-16 for
asymmetric catalysis. Further applications of these chiral
ligands in metal-mediated synthetic methodology are cur-
rently under investigation and will be reported in due course.
Acknowledgment. This work has been supported by a
grant from the National Science Foundation (CHE-0078944)
and awards from Novartis and Lilly & Co. The authors thank
Prof. Scott Nelson (University of Pittsburgh) for helpful
discussions.
Supporting Information Available: Experimental pro-
cedures and spectral data for ligands 6 and 7, including copies
of 1H and 13C NMR. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL025600C
1200
Org. Lett., Vol. 4, No. 7, 2002