Catalysis by amino acid-derived tetracoordinate complexes: Enantioselective addition of dialkylzincs to aliphatic and aromatic aldehydes

Article abstract of DOI:10.1021/ol0063151

Me₂Zn and Et₂Zn added to aromatic and aliphatic aldehydes in the presence of 3 mol % of 2. (S)-1-Phenylethanol (91% ee) and (S)-1-phenylpropanol (86% ee) were synthesized from benzaldehyde and (S)-1-furan-2-yl-1-propanol (86% ee) from 2-furaldehyde. Nonanal and 3-phenylpropanal provided (S)-3-undecanol (96% ee) and (S)-1-phenyl-3-pentanol (94% ee). A solid-phase variant was effective with reduced ee's (e.g., 86% ee → 79% ee) for (S)-1-phenylpropanol.

Full text of DOI:10.1021/ol0063151

ORGANIC
LETTERS
2
000
Vol. 2, No. 19
003-3006
Catalysis by Amino Acid-Derived
Tetracoordinate Complexes:
3
Enantioselective Addition of Dialkylzincs
to Aliphatic and Aromatic Aldehydes
Brian D. Dangel and Robin Polt*
Department of Chemistry, The UniVersity of Arizona, Tucson, Arizona 85721
polt@u.arizona.edu
Received July 10, 2000
ABSTRACT
2 2
Me Zn and Et Zn added to aromatic and aliphatic aldehydes in the presence of 3 mol % of 2. (S)-1-Phenylethanol (91% ee) and (S)-1-phenylpropanol
(86% ee) were synthesized from benzaldehyde and (S)-1-furan-2-yl-1-propanol (86% ee) from 2-furaldehyde. Nonanal and 3-phenylpropanal
provided (S)-3-undecanol (96% ee) and (S)-1-phenyl-3-pentanol (94% ee). A solid-phase variant was effective with reduced ee’s (e.g., 86% ee
f 79% ee) for (S)-1-phenylpropanol.
1
7
Long since the early pioneering work of McKenzie, asym-
occasionally a tridentate manner. After a search of the
metric synthesis has become one of the cornerstones of
organic synthesis. While McKenzie used a chiral auxiliary
literature, we could find no examples of tetradentate ligands
used in the addition of organozinc reagents to aldehydes.
As part of our efforts to develop a “universal ligand”, we
were pleasantly surprised to find that a tetracoordinate zinc
complex, formed from the amino acid-derived ligand system
described previously, worked quite well as a catalyst for
the addition of alkylzincs to both aromatic and aliphatic
aldehydes.
(
menthol) for his work, the ideal or aspirational enantio-
selective reaction would use a cheap, renewable source of
2
chirality and would require only catalytic amounts (e.g.,
3
8
multiplication of chirality). The addition of organozinc
4
reagents to aldehydes in the presence of catalytic amounts
of chiral ligands is among the most successful catalytic
5
reactions of this type. Almost all the work with organozinc
(
5) (a) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833. (b) Noyori, R.;
Kitamura, M. Angew. Chem. 1991, 103; Angew. Chem., Int. Ed. Engl. 1991,
0, 49. (c) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
reagents has utilized chiral ligands possessing a â-amino
6
alcohol moiety, which can bind zinc in a bidentate or
3
New York, 1994; pp 255 ff. (d) Evans, D. A. Science 1988, 240, 420.
(6) (a) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc.
1989, 111, 4028. (b) Itsuno, S.; Frechet, J. M. J. Org. Chem. 1987, 52,
4142. (c) Smaardijk, A. A.; Wynberg, H. J. Org. Chem. 1987, 52, 135. (d)
Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986,
108, 6071. (e) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2923. (f)
Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura, A. Chem. Lett. 1983, 841.
(g) Chittenden, R. A.; Cooper, C. H. J. Chem. Soc. C 1970, 49.
(7) (a) Adams, H.; Bailey, N. A.; Fenton, D. E.; He, Q.-Y. J. Chem.
Soc., Dalton Trans. 1996, 2857. (b) Corey, E. J.; Yuen, P. W.; Hannon, F.
J.; Wierda, D. A. J. Org. Chem. 1990, 55, 784.
(
1) McKenzie, A. J. Chem. Soc. 1904, 1249.
(
2) Brunner, H.; Zettlmeier, W. Handbook of EnantioselectiVe Catalysis
with Transition Metal Compounds, Vol II; VCH: Weinheim, 1993.
(
3) (a) Seebach, D.; Langer, W HelV. Chim. Acta 1979, 62, 1701. (b)
Seebach, D.; Beck, A. K.; Roggo, S.; Wonnacott, A. Chem. Ber. 1985,
18, 3673. (c) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M.
Tetrahedron 1994, 50, 4363.
4) (a) Erdik, E. Organozinc Reagents in Organic Synthesis; CRC
1
(
Press: New York, 1996. (b) Knochel, P.; Jones, P. Organozinc Reagents:
A Practical Approach; Oxford Press: New York, 1999.
1
0.1021/ol0063151 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/19/2000

The reaction of Et
presence of chiral ligand 1 was evaluated. For these studies
Table 1) the reactive Zn complex 2 was formed in situ
2
Zn with ArCHO and RCHO in the
as an alkyl donor. Only one ethyl group was transferred from
Et Zn at an appreciable rate. The second ethyl group was
transferred, but much more slowly. In every case the major
isomer was the S-enantiomer, [(S)-(-)-1-phenyl-1-propanol]
in 82-86% ee.
9
2
II
(
It is noteworthy that, contrary to reports of studies
performed with bidentate “Soai-type” catalysts, the polar
Table 1. Solvent Studies
2
solvent THF enhanced the enantioselectivity of Et Zn addi-
tions (Table 1). When toluene was used (rxn 3), the reactions
went to completion, but the ee’s dropped to 6%. Using a
2
:1 mixture of toluene and THF decreased the ee’s to 63%
(rxn 4).
Given these results, several aldehydes were screened using
II
3
mol % of the Zn -L-Phe-L-Phe complex 2 (Table 2). A
Table 2. Aromatic versus Aliphatic Substrates
a
Isolated yields (tields in parentheses based on GC peak areas).
b
Determined by chiral GC: (S)-1-phenyl-propanol, Chiraldex â-PH (100
C isotherm).
°
from Et
complex formed readily in d
2
Zn and ligand 1. NMR studies showed that the zinc
-THF or d -toluene. In THF
8
8
one molecule of solvent appeared to coordinate axially to
allow the zinc metal to adopt a square pyramidal geometry.
The complex was stable in a dry, oxygen-free atmosphere.
Complex formation was found to be complete after an hour
at reflux. Once formed, the reaction mixture was cooled to
-
78 °C and the aldehyde was added in a single portion.
Using a syringe pump, an equimolar amount of Et Zn in THF
2
a
Purified yields (yields in parentheses based on GC peak areas).
was added and the reaction continued for 16 h at rt. Analysis
b Determined by chiral GC: 1-phenylpropan-1-ol, Chiraldex â-PH (100 °C
isotherm); 1-furylpropan-1-ol, Chiraldex γ-TA (60 °C isotherm); (R)-
of the product mixture was performed by capillary GC.
(
(
-)-Mosher’s ester of 1-phenylpentan-3-ol and 3-undecanol, Chiraldex â-TA
II
The C
2
-symmetric Zn -L-Phe-L-Phe complex 2 catalyzed
140 °C isotherm). c Purified by flash, followed by sublimation. Observed
d
2
the quantitative addition of Et Zn to PhCHO when 3-5 mol
[R]D ) + 23.6°; literature [R]D ) +23.8° (refs 10a and 10b). Product
purified by flash, followed by distillation. Observed [R]D ) + 7.48°;
literature [R]D ) + 7.79° (ref 10c).
%
of catalyst was used. THF was found to be the best solvent
for the additions, but was not necessary for complex
formation. With 1 mol % of catalyst the reaction proceeded
but was incomplete after 16 h (rxn 1). EtZnI was not effective
slight increase in enantioselectivity was observed when
dimethylzinc was substituted for diethylzinc in the addition
to benzaldehyde (rxn 5 vs rxn 2). 2-Furaldehyde gave ee’s
similar to those seen with benzaldehyde (rxn 6). Aliphatic
aldehydes provided excellent ee’s with this catalyst. Addition
to 3-phenylpropanal (rxn 7) yielded pure (S)-(+)-1-phenyl-
pentan-3-ol (94% ee), following chromatography and sub-
limation. The optical rotation of the sublimed alcohol was
(8) (a) Dangel, B.; Clarke, M.; Haley, J.; Sames, D.; Polt, R. J. Am.
Chem. Soc. 1997, 119, 10865. (b) For related ligands, see: Havranek, M.;
Singh, A.; Sames, D. J. Am. Chem. Soc. 1999, 121, 8965. (c) Trost, B. M.;
Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759.
(9) Ligand 2 (219 mg, 0.3 mmol, 3 mol %) was azeotropically dried
with PhCH3 and then dissolved in 3 mL of THF. A 0.5 M solution of Et2-
Zn in THF (0.64 mL, 0.32 mmol, 3.2 mol %) was added to 2 and heated
to reflux for 1 h. After Zn insertion was complete, the reaction mixture
was cooled to -78 °C and PhCH2CH2CHO (1.34 g, 10.0 mmol) was added
in a single portion. More 0.5 M Et2Zn solution in THF (26 mL, 13.0 mmol,
+
(
23.6° (c ) 1.56; CHCl
rxn 8) provided (S)-(+)-3-undecanol (96% ee) after chro-
matography and vacuum distillation. The optical rotation of
3
). Similarly, addition to nonanal
1
.3 equiv) was then added dropwise, and the mixture was allowed to warm
slowly to rt. After 16 h the reaction was quenched with 1 M HCl and worked
up in the usual manner to provide (S)-1-phenyl-3-pentanol. A detailed
protocol may be found in the Supporting Information.
10
the distilled alcohol was +7.48° (c ) 0.91; ethanol). Both
3004
Org. Lett., Vol. 2, No. 19, 2000

of these reactions were run on a 1-g scale, and the
enantiomeric purity of the each alcohol was confirmed by
formation of the corresponding Mosher esters ( H NMR and
permit simultaneous reactions to be run in parallel.11
Preliminary results with the “Wang-supported L-Phe-L-Phe
1
12
catalyst” 5 are shown in Table 4. The Et
2
Zn-activated resin
chiral GC). Despite the higher enantioselectivities observed
with the aliphatic aldehydes, the reactions were complicated
by significant formation (∼50% of the reaction mixture) of
the corresponding aldol products.
Table 4. Solid-Phase Ligand Functions As Catalyst with Only
Slightly Reduced Enantioselectivities
Further studies with the L-Ala-L-Ala 3 and L-Val-L-Val 4
complexes have been performed (Table 3). As expected, the
Table 3. Enantioselectivity Depends on Steric Bulk of Amino
Acid Residue
was then used multiple times without degradation of either
the yields or the enantioselectivities (rxn 14 and 15).13
Overall, the yields were only slightly diminished relative to
the solution-phase catalyst, and the ee’s were lower. Since
the ee seemed to increase upon reuse of the catalyst (rxn
1
5), it was assumed that Et
affected the enantioselection. Thus, for the next reaction (rxn
6) the L-Phe-L-Phe-bearing resin was “washed” with excess
Et Zn prior to use. The conversion was monitored by GC as
2
Zn removed impurities that
1
2
a function of time and temperature (rxn 16a-c). As expected,
a
Isolated yields (yields in parentheses based on GC peak areas).
b
Determined by chiral GC: 1-phenylpropan-1-ol, Chiraldex â-PH (100 °C
(11) (a) Mathur, N. K.; Narang, C. K.; Williams, R. E. Polymers as Aids
in Organic Chemistry; Academic Press: New York, 1980. (b) Review:
Pittman, C. U. In ComprehensiVe Organometallic Chemistry; Wilkinson,
G., Ed.; Pergamon Press: Oxford, 1982; Chapter 55. (c) Kobayashi, N.;
Iwai, K. J. Polym. Sci. Polym. Chem. Ed. 1980, 18, 923. (d) Tsuboyama,
S. Bull. Chem. Soc. Jpn. 1966, 39, 698. (e) Soai, K.; Niwa, S.; Wantanabe,
M. J. Org. Chem. 1988, 53, 927. (f) Soai, K.; Niwa, S.; Wantanabe, M. J.
Chem. Soc., Perkin Trans. 1 1989, 109. (g) Itsuno, S.; Frechet, J. M. J. J.
Org. Chem. 1987, 52, 4140. (h) Itsuno, S.; Sakurai, Y.; Ito, K.; Maruyama,
T.; Nakamura, S.; Frechet, J. M. J. J. Org. Chem. 1990, 55, 304. (i)
Lorsbach, B. A.; Kurth, M. J. Chem. ReV. 1999, 99, 1549. (j) Holte, P.;
Wijgergangs, J.; Thijs, L.; Zwanenburg, B. Org. Lett. 1999, 2, 1095. (k)
Yang, X.; Sheng, J.; Da, C.; Wang, H.; Su, W.; Wang, R.; Chan, A. S. C.
J. Org. Chem. 2000, 65, 295.
isotherm); (R)-(-)-Mosher’s ester of 1-phenylpentan-3-ol and 3-undecanol,
c
Chiraldex â-TA (140 °C isotherm). Products were purified by flash
chromatography, follwed by sublimation (1-phenylpentan-3-ol) or distillation
(3-undecanol).
decreased bulk of the amino acid residues (L-Ala) on the
catalyst caused a decrease in selectivity for both aromatic
and aliphatic aldehydes (rxn 9 and 10). With increased steric
demand (L-Val), enhanced stereoselection was observed with
benzaldehyde (rxn 11). In contrast, the aliphatic aldehydes
showed diminished enantioselectivity and reduced yields (rxn
(12) The L-Phe-L-Phe Schiff Base ligand has been synthesized using both
the Merrifield and Wang resins: (a) Merrifield, R. B. J. Am. Chem. Soc.
1963, 85, 2149. (b) Lu, G.; Mojsov, S.; Tam, J. P.; Merrifield, R. B. J.
1
2 and 13).
Org. Chem. 1981, 46, 3433. (c) Wang, S. J. Am. Chem. Soc. 1973, 95,
Optimization of a catalyst for particular applications will
be facilitated by the use of solid-phase variants, which will
1328.
(13) (a) Vidal-Ferran, A.; Bampos, N.; Moyano, A.; Peric a` s, M. A.; Riera,
A.; Sanders, J. K. M. J. Org. Chem. 1998, 63, 6309. (b) Liu, G.; Ellman,
J. A. J. Org. Chem. 1995, 60, 7712. (c) Wantanabe, M.; Soai, K. J. Chem.
Soc., Perkin Trans. 1 1994, 837. (d) Soai, K.; Wantanabe, M.; Yamamoto,
A. J. Org. Chem. 1990, 55, 4140. (e) Itsuno, S.; Frech e` t, J. M. J. Org.
Chem. 1987, 52, 4140.
(10) (a) Lutz, C.; Jones, P.; Knochel, P. Synthesis 1999, 2, 312. (b) Lutz,
C.; Knochel, P. J. Org. Chem. 1997, 62, 7895. (c) Soai, K.; Yokoyama, S.;
Ebihara, K.; Hayasaka, T. J. Chem. Soc., Chem. Commun. 1987, 1609.
Org. Lett., Vol. 2, No. 19, 2000
3005

the rate of product formation increased with increasing time
and temperature. Surprisingly, the ee’s were enhanced as
well. The explanation for this behavior may involve increased
swelling of the polymer at higher temperatures, “uncoiling”
of the polystyrene backbone, or other effects.14
atoms, with the “inner zinc” functioning as a chiral Lewis
acid and the “outer zinc” functioning as the alkyl donor
(Figure 1). The role of the THF is not clear. It may be
1
7
2
required in order to effect alkyl transfer from Et Zn to the
“inner zinc” (Soai mechanism) or may simply prevent
aggregation. Obviously, further study will be required for a
complete understanding of this new catalyst system.
Assuming that two zinc atoms are involved in alkyl
transfer, the inner zinc is surrounded by electron-donating
nitrogens, while the outer zinc is only solvated by exchange-
able oxygens.15 Given the observed results, the mechanism
Acknowledgment. We thank the U.S. Army (DAMD 17-
9-1-9539) and the Arizona Disease Control Research
Commission for the support of this work and Prof. Michael
Doyle for use of his capillary GC.
9
may be related to the “ate” or “ate-like” mechanism proposed
16
by Kitamura or may involve reversed roles for the two zinc
Supporting Information Available: Complete experi-
mental procedures, spectral characterization of the ligands
1
13
and intermediates ( H NMR, C NMR, and IR), GC traces,
and column conditions used. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0063151
(
14) Odian, G. Principles of Polymerization; John Wiley: New York,
1
981; Chapter 9, p 654.
(
15) (a) Wittig, G. Quart. ReV. 1966, 191. (b) Tochtermann, W. Angew.
Chem., Int. Ed. Engl. 1966, 5, 351. (c) Uchiyama, M.; Furumoto, S.; Saito,
M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1997, 119, 11425.
(
16) (a) Kitamura, M.; Oka, H.; Noyori, R. Tetrahedron 1999, 55, 3605.
b) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998,
20, 9800. (c) Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63, 8998.
d) Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5233. (e) Corey,
E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237.
17) (a) Gladysz, J. A.; Boone, B. J. Angew. Chem., Int. Ed. Engl. 1997,
(
1
(
(
3
6, 551. (b) Evans, D. A.; Rovis, T.; Johnson, J. S. Pure Appl. Chem. 1999,
1, 1407. (c) Shibasaki, M.; Groger, H. Top. Organomet. Chem. 1999, 2,
199. (d) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi,
Figure 1. Possible mechanisms for the observed facial enantiose-
lectivity.
7
S. Tetrahedron 1992, 48, 5691.
3006
Org. Lett., Vol. 2, No. 19, 2000