Asymmetric amplification in catalysis by trans-1,2-diaminocyclohexane bistriflamide

Article abstract of DOI:10.1021/ol062653b

(Figure Presented) A strong asymmetric amplification is observed in the addition of diethylzinc on aromatic aldehydes in the presence of the bistriflamide of trans-1,2-diaminocyclohexane 3a. The asymmetric amplification originates from the insolubility of

Full text of DOI:10.1021/ol062653b

ORGANIC
LETTERS
2007
Vol. 9, No. 2
251-253
Asymmetric Amplification in Catalysis
by trans-1,2-Diaminocyclohexane
Bistriflamide
Tummanapalli Satyanarayana, Benoit Ferber, and Henri B. Kagan*
Laboratoire de Catalyse Mole´culaire (UMR 8182), Institut de Chimie Mole´culaire et
des Mate´riaux d’Orsay, UniVersite´ Paris-Sud, 91405 Orsay, France
kagan@icmo.u-psud.fr
Received October 30, 2006
ABSTRACT
A strong asymmetric amplification is observed in the addition of diethylzinc on aromatic aldehydes in the presence of the bistriflamide of
trans-1,2-diaminocyclohexane 3a. The asymmetric amplification originates from the insolubility of the catalyst precursor 3a of low enantiomeric
excess (ee), with a concomitant large increase of ee for the minor soluble part of 3a. Controlled mono-N-acetylation of 3a (20% ee) at
allowed isolation of 4 possessing 90% ee.
−78 °C
Enantioselective addition of organozincs on aldehydes is of
great synthetic importance.1 One popular procedure is the
system developed in 1989 by Ohno and Kobayashi, exempli-
fied by the addition of diethylzinc on benzaldehyde 1a at
-78 °C in the presence of stoichiometric amounts of
Ti(OiPr)4 and 1 mol % equiv of a bissulfonamide derived
from trans-1,2-diaminocyclohexane such as 3a (Figure 1).2
In the specific case of alcohol 2a, ee’s up to 97% have been
observed. The authors kept 3a and Ti(OiPr)4 in toluene at
40 °C before cooling to -78 °C and adding Et2Zn and
aldehyde 1. An alternate and convenient procedure, also
giving 97% ee, was subsequently developed by Walsh et
al., by mixing first 3a and Et2Zn at 23 °C before adding
Ti(OiPr)4 and aldehyde 1.3 The authors proposed a revised
mechanism which is in agreement with the absence of a
nonlinear effect. In 2002, we reported that the Ohno-
Kobayashi protocol led to a strong asymmetric amplification,4
and recently, we used this protocol in a sequential combina-
tion of two asymmetric amplifications;5 the mechanistic
(1) (a) Knochel, P.; Perea, J. J. A.; Jones, P. Tetrahedron 1998, 54, 8275-
8319 and references therein. (b) Ostwald, R.; Chavant, P.-Y.; Stadtmuller,
H.; Knochel, P. J. Org. Chem. 1994, 59, 4143-4153.
(2) (a) Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno,
M. Tetrahedron Lett. 1989, 30, 7095-7098. (b) Yoshioka, M.; Kawakita,
T.; Ohno, M. Tetrahedron Lett. 1989, 30, 1657-1660. (c) Takahashi, H.;
Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S. Tetrahedron 1992,
48, 5691-5700.
(3) (a) Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J.
Am. Chem. Soc. 1998, 120, 6423-6424. (b) Pritchett, S.; Woodmansee, D.
H.; Gantzel, P.; Walsh, P. J. Tetrahedron Lett. 1998, 39, 5941-5942.
(4) Luukas, T. O.; Fenwick, D. R.; Kagan, H. B. C. R. Chimie 2002, 5,
487-491.
(5) Satyanarayana, T.; Kagan, H. B. Chem.-Eur. J. 2006, 12, 5785-
5789.
10.1021/ol062653b CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/19/2006

higher than 96-98%. This interesting ee enrichment of 3a
in solution was also successfully transferred to products when
3a was employed as the catalyst in Et2Zn addition on
aldehydes. By taking advantage of the information in Table
1, some catalytic reactions were undertaken (Table 2) using
Table 2. Use of 3a of Low ee as the Catalyst in the Reaction
of Et2Zn on Aldehyde 1ba
entry
initial ee % of 3a
conversion %
ee % of (R)-2bb
1
2
15.0
10.0
>95
>95
97
93
a (1R,2R)-3a (20 mol % equiv) dissolved in EtOAc was taken into a
Schlenk tube, and EtOAc was removed under reduced pressure. 1 mL of
toluene was added and warmed at 55 °C for 30 min. Then, it was rapidly
cooled to -78 °C followed by the addition of all reactants. After 3 h,
reactions were quenched with 1 N HCl. bMeasured by HPLC on Chiralcel
OD-H.
Figure 1. Addition of diethylzinc on aldehydes.
implications were shortly discussed.4 We wish to report here
that the asymmetric amplification associated to the Ohno-
Kobayashi procedure is correlated with the insolubility of
catalyst precursor 3a in toluene. We previously observed that,
when catalyst precursor 3a and Ti(OiPr)4 are first mixed in
toluene and then heated at various temperatures, the system
does not seem fully homogeneous.6 To study this problem,
we performed several experiments. First, it was found that
the asymmetric amplification was unchanged if the catalyst
precursor 3a was heated alone at 55 °C in toluene, before
cooling to -78 °C and then introducing all the reactants.
The composition of the solutions was analyzed at -78 °C
before addition of the reactants, by filtering the solid and
evaporating the solvent. Results in toluene and in some other
solvents are reported in Table 1.
3-methoxybenzaldehyde 2b. ee enrichment of 3a in these
conditions (as high as 96-98% ee starting from 10% ee)
very reasonably correlates with the enantiomeric excess of
the product 2. A reaction of Et2Zn addition on 2b using 15%
ee 3a performed in toluene at -78 °C gave the corresponding
alcohol with 97% ee.
We have also noticed reactions becoming quite slow for
low ee’s of the precatalyst, as already reported.4 This is in
agreement with the great differences of solubility of enan-
tiopure and racemic 3a. It is the reason the catalyst loading
has been increased here from 1 mol % equiv to 20 mol %
equiv to speed up the reaction. The melting points of
enantiopure and racemic 3a are 189 and 240 °C, respectively
(measured using DSC). This is a good indication of the
racemate formation in the crystallization of rac-3a. It is
interesting to point out that N-acetylation of 3a (20% ee) by
20 mol % equiv of acetyl chloride in toluene at -78 °C in
the presence of NEt3 (20 mol % equiv) allowed recovery of
the monoacetyl derivative 4 (90% ee) in agreement with the
expected high ee of the soluble part of 3a.
Table 1. ee Enrichment of 3a [10% ee with (1R,2R)-excess] in
Various Solvents after a Resting Time of 10 min at -78 °Ca
filtrate 3a
ee %c
(amount)
precipitate 3a
ee %c
(amount)
amount of 3aa
(mg)
solvent (1 mL)b
toluene
94.5
94.5
>96 (5.0 mg)
toluene (1 mL) + >99d (3.0 mg) 11 (82.0 mg)
10 (82.0 mg)
Nonlinear effects in asymmetric catalysis have attracted
a lot of interest since the initial report in 19867 and led to
many developments (some reviews: refs 8-11). Asymmetric
amplification [(+)-nonlinear effect] is interesting from both
synthetic and mechanistic points of view (some reviews :
refs 11 and 12) and is very helpful in asymmetric
autocatalysis.12-14 Recently, Blackmond and co-workers
hexane (1.5 mL)
18.9
18.9
18.9
CH2Cl2
diethyl ether
toluene
89 (3.0 mg)
50 (4.0 mg)
>98 (1.5 mg)
7 (14.0 mg)
2 (13 mg)
2 (15 mg)
a A standard 0.25 M solution of 10% ee (1R,2R)-3a in EtOAc was
prepared and used throughout all the above experiments. bEtOAc was
removed under reduced pressure. 1 mL of toluene was added and warmed
at 55 °C for 30 min and rapidly cooled to -78 °C followed by quick
filtration by suction filtration. cee of 3a was determined by 19F NMR using
(7) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H.
B. J. Am. Chem. Soc. 1986, 108, 2353-2357.
(8) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922-
2959.
d
quinidine as the shift reagent. The minor enantiomer was not detected in
this case.
(9) Avalos, M.; Babiano, R.; Cintas, P.; Jimene`z, J. L.; Palacios, J. C.
Tetrahedron: Asymmetry 2000, 11, 2845-2874.
(10) Kagan, H. B.; Luukas, T. O. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 1999; Vol. 1, pp 101-118.
The data in Table 1 show that 3a with an ee as small as
10% leaves a precatalyst in toluene at -78 °C with an ee
(11) Kagan, H. B.; Fenwick, D. R. Top. Stereochem. 1999, 22, 257-
296.
(6) In our paper from 2002 (ref 4), we hypothesized that (+)-NLE in
this reaction could be due to the reservoir effect where a diastereomeric
organometallic species of racemic composition would be formed external
to the catalytic system and did not consider the insolubility issue.
(12) Soai, K.; Shibata, T.; Sato, I. Acc. Chem. Res. 2000, 33, 382-390.
(13) Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995, 378,
767-768.
(14) Blackmond, D. G. AdV. Synth. Catal. 2002, 344, 156-158.
252
Org. Lett., Vol. 9, No. 2, 2007

investigated several examples of asymmetric amplifications
involving organocatalysts.15,16 They discovered that the partial
solubility of an enantioimpure catalyst such as proline may
lead to a substantial increase of ee for the soluble part. This
is common to the numerous amino acids that give rise to a
racemate crystallization. In that case, the soluble part has a
high ee which is determined by the eutectic composition of
the system. We noticed a similar situation with bistriflate
3a. We calculated the eutectic composition from the values
of the melting points of racemic and enantiopure 3a
according to the procedure given in refs 17 and 18 and found
a value of 96% ee. This is virtually the same as the eutectic
composition in the solubility diagram, i.e., in the tertiary
phase system.19 Therefore, we took this 96% ee as the
eutectic composition of saturated solutions of 3a in a solvent.
However, it is lower than the measured ee of saturated
solutions of 3a in toluene or a toluene/hexane mixture (entries
1, 2, and 5; Table 1). Possibly, this arises from the fast
cooling of the solution from 55 °C to -78 °C, giving the
deposit of a large amount of racemic crystals without
allowing the system to reach to an equilibrium of eutectic
composition.20 This explains reactions that become sluggish
with a low ee of 3a. Also, solvent presence can have an
effect on the eutectic composition.16b The controlled mono-
N-acetylation of 3a (20% ee) into 4a (90% ee) clearly shows
that it is possible to trap the soluble and enantioenriched 3a
chemically at -78 °C. To verify the fact that (+)-NLE in
this reaction is solely due to the ee enrichment of 3a in
solution (arising from the insolubility of the racemic part of
3a) and not due to the involvement of any kind of homochiral
and heterochiral organometallic complexes, we have per-
formed a reaction following a procedure similar to the one
reported by Walsh.3 First, Et2Zn was added to a partially
soluble solution of 3a with 26% ee in toluene at room
temperature which resulted in the quick formation of a clear
homogeneous solution. When this mixture was then cooled
to -78 °C followed by the addition of Ti(OiPr)4 and
benzaldehyde, it provided the corresponding product 2a with
21% ee, indicating the absence of NLE which is consistent
with results obtained by Walsh.3 This result clearly excludes
the possible involvement of homochiral and heterochiral
aggregates of organometallic species. Thus, the (+)-NLE in
this reaction arises exclusively from the ee enrichment of
3a in solution. One can now envisage taking advantage of
the high ee of partially soluble 3a at -78 °C in running
catalytic reactions other than organozinc additions on alde-
hydes. We are looking for such possibilities.
(15) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem., Int.
Ed. 2004, 43, 3317-3321.
The plot eeauxiliary ) f(eeproduct) is a sensitive tool for
investigating catalytic systems. The various procedures of
catalyst preparation may or may not generate a nonlinear
effect. In the present case, the asymmetric amplification
observed with the Ohno-Kobayashi protocol is clearly
associated to the strong increase in ee of the precatalyst 3a
for the fraction present in solution. It may also be noted here
that the presence of NLE does not indicate the involvement
of two or more chiral ligands in the catalytic cycle. This
conclusion emphasizes the importance of complementary
studies to draw mechanistic conclusions based on the
observed NLE.
(16) (a) Klussmann, M.; Iwamura, H.; Mathews, S. P.; Wells, D. H.,
Jr.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 521-
525. (b) Klussmann, M.; White, A. J. P.; Armstrong, A.; Blackmond, D.
G. Angew. Chem., Int. Ed. 2006, 45, 7985-7989.
(17) Calculations of the eutectic composition:
Acknowledgment. We thank Universite´ Paris-Sud and
CNRS for their financial support. T.S. acknowledges the
Universite´ Paris-Sud and Pierre Fabre Co. for postdoctoral
fellowships. B.F. acknowledges Institut de Chimie des
Substances Naturelles (CNRS, Gif-sur-Yvette) for financial
support. We thank Dr. F. Pitchen (Pierre Fabre Co.) and Prof.
P. Berthet (Universite´ Paris-Sud) for useful discussions.
(a) the Schro¨der-Van Laar equation [ln x ) ∆Hfenant/R(1/Tenant - 1/T)]18a
defines the part of the curve (BC part of the below plot) where the mixture
behaves like a conglomerate, and (b) the Prigogine-Defay equation [ln
4x(1 - x) ) 2∆Hfrac/R(1/Trac - 1/T′)]18b allows us to draw the part of the
curve (AB part of the below plot) where the mixture behaves like a racemic
compound. In (a) and (b), ∆Hfenant (5556 cal/mol), ∆Hfrac (10 697 cal/mol),
Supporting Information Available: Experimental pro-
cedures, DSC plots, and the eutectic composition determi-
nation. This material is available free of charge via the
Internet at http://pubs.acs.org.
Tenant (462 K), and Trac (513 K) are enthalpies of fusion and melting points,
respectively, of enantiopure and racemic compounds 3a (measured on DSC)
at 25 °Cf300 °Cf25 °C (at 2 °C/min) and x ) mole fraction of the more
abundant enantiomer (0.5 < x < 1).
OL062653B
(18) (a) Enantiomers, Racemates and Resolutions; Jacques, J., Collet,
A., Wilen, S. H., Eds.; John Wiley: New York, 1981; Chapter 2.2, Section
2.2.3, pp 46-47. (b) Enantiomers, Racemates and Resolutions; Jacques,
J., Collet, A., Wilen, S. H., Eds.; John Wiley: New York, 1981; Chapter
2.3, Section 2.3.2, pp 90-91.
(20) In the case of racemate crystallization (if the solubility of racemate
crystals is lower than enantiopure crystals), it is in fact possible to obtain
a pure enantiomer from solution when the crystallization is carried out
rapidly in a small quantity of solvent without allowing the system to reach
the solubility equilibrium, i.e., the eutectic composition.21
(21) Enantiomers, Racemates and Resolutions; Jacques, J., Collet, A.,
Wilen, S. H., Eds.; John Wiley: New York, 1981; Chapter 3.3, Section
3.3.3, pp 195-196.
(19) Enantiomers, Racemates and Resolutions; Jacques, J., Collet, A.,
Wilen, S. H., Eds.; John Wiley: New York, 1981; Section 5.1.11, pp 289-
290.
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