Highly active chiral phosphoramide-Zn(II) complexes as conjugate acid-base catalysts for enantioselective organozinc addition to ketones

Article abstract of DOI:10.1021/ol702074a

(Chemical Equation Presented) A highly efficient enantioselective organozinc (R²Zn) addition to ketones catalyzed by chiral phosphoramide-Zn(II) complexes (1-10 mol %) has been developed. These complexes serve as conjugate Lewis acid-Lewis base

Full text of DOI:10.1021/ol702074a

ORGANIC
LETTERS
2
007
Vol. 9, No. 22
535-4538
Highly Active Chiral
4
Phosphoramide−Zn(II) Complexes as
Conjugate Acid
−Base Catalysts for
Enantioselective Organozinc Addition to
Ketones
Manabu Hatano, Takashi Miyamoto, and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa,
Nagoya, 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
Received August 22, 2007
ABSTRACT
A highly efficient enantioselective organozinc (R
has been developed. These complexes serve as conjugate Lewis acid
inexpensive natural amino acid (i.e., -valine). From a variety of nonactivated aromatic and aliphatic ketones, the corresponding optically
active tertiary alcohols were obtained in high yields with high enantioselectivities (up to 98% ee) under the mild reaction conditions.
2
Zn) addition to ketones catalyzed by chiral phosphoramide−Zn(II) complexes (1−10 mol %)
−Lewis base catalysts. Chiral phosphoramides are derived from an
L
Optically active secondary and tertiary alcohols are versatile
building blocks for the synthesis of natural products and
pharmaceuticals. In particular, the enantioselective addition
enantioselective organozinc addition to ketones, in sharp
contrast to aldehydes, due to steric and electronic constraints
regarding the substrates and/or reagents, and hence it is still
a challenge to establish a high level of asymmetric induction
1
of organometal reagents to carbonyl compounds is an
important synthetic method that gives the enantioenriched
alcohols via carbon-carbon bond formation under the mild
4
-6
as well as a high yield. We report here highly active and
simple chiral phosphoramide-Zn(II) complexes as conjugate
2
,3
7
conditions. However, there are few examples of catalytic
Lewis acid-Lewis base catalysts for the enantioselective
organozinc addition to ketones to obtain the desired tertiary
(
1) (a) Fuji, K. Chem. ReV. 1993, 93, 2037-2066. (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388-401. (c) Ram o´ n,
(4) (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445-446.
(b) Ram o´ n, D. J.; Yus, M. Tetrahedron Lett. 1998, 39, 1239-1242. (c)
Garc ´ı a, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
10970-10971. (d) Garc ´ı a, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641-3644.
(e) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544-9545. (f)
Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538-6539. (g) Li, H.;
Garica, C.; Walsh, P. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5425-
5427.
D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149-183.
(2) (a) Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura, A. Chem. Lett.
1
2
983, 841-842. (b) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823-
824. (c) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071-6072. (d) Weber, B.; Seebach, D. Tetrahedron 1994,
0, 6117-6128.
3) For reviews: (a) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856.
5
(
(
b) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824. (c) Pu, L.
(5) For reviews: (a) Ram o´ n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004,
43, 284-287. (b) Betancort, J. M.; Garc ´ı a, C.; Walsh, P. J. Synlett 2004,
749-760.
Tetrahedron 2003, 59, 9873-9886. (d) Hatano, M.; Miyamoto, T.; Ishihara,
K. Curr. Org. Chem. 2007, 11, 127-157.
1
0.1021/ol702074a CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/29/2007

Scheme 1. Chiral Phosphoramide 1-Zn(II) Complex as a
Conjugate Lewis Acid-Lewis Base Catalyst
alcohols in high to excellent yields (Scheme 1). These chiral
Zn(II) catalysts, which are simply prepared in situ, are
derived from an inexpensive natural amino acid (i.e.,
L-valine).
Figure 1. Catalytic enantioselective phenylation to 2a. Condi-
tions: (a) Reactions were examined in 0.25 M heptane unless
otherwise noted. (b) Reactions were examined in 0.5 M heptane.
(c) 1 mol % of 1d was used.
In our preliminary study of catalytic enantioselective
organozinc addition to aldehydes, chiral Zn(II)-BINOLates
bearing phosphoramides at the 3,3′-positions were designed
as highly effective conjugate Lewis acid-Lewis base
equiv) in heptane at room temperature (Figure 1).11 Fortu-
nately, simply designed 1a gave 3a with high enantioselec-
tivity (80% ee), although the yield was low (30%). Chiral
ligand 1b or 1c bearing a pyrrolidinyl or piperidinyl group
8
-10
catalysts.
However, these Zn(II)-BINOLates did not
catalyze the reaction of ketones and organozinc reagents, and
a significant amount of the aldol products was obtained
instead of the desired products. To develop conjugate Lewis
acid-Lewis base catalysts with ketones, we first investigated
the L-valine-derived chiral phosphoramide ligand (1, 10 mol
2
instead of a NMe group in 1a showed improved catalytic
activity, but the enantioselectivitiy was the same or de-
creased. However, 1d bearing a P-(1-naphthyl) moiety
showed a considerable improvement in both yield and
enantioselectivity (up to 95% ee). After optimization, 3a was
obtained in 98% yield with 92% ee by using 1 mol % of 1d.
%) in the catalytic enantioselective phenylation of 4′-
chloroacetophenone (2a) with Ph Zn (1 equiv) and Et Zn (2
2
2
We next examined the generality of this catalysis for other
ketones (Figure 2). For aryl ketones with either an electron-
withdrawing or electron-donating group (2a-c and 2g),
cyclic ketones (2d-f), heteroaryl ketones (2h and 2i), and
R,â-unsaturated ketone (2j) with 10 mol % of (S)-1d, high
enantioselectivities (91-98% ee) and high yields (up to 98%)
were observed in products 3a-j. Moreover, aliphatic ketones
(2k and 2l) also provided the corresponding tertiary alcohols
(
6) (a) Hui, A.; Zhang, J.; Fan, J.; Wang, Z. Tetrahedron: Asymmetry
2
006, 17, 2101-2107. (b) Jeon, S.-J.; Li, H.; Garc ´ı a, C.; LaRochelle, L.
K.; Walsh, P. J. J. Org. Chem. 2005, 70, 448-455. (c) Jeon, S.-J.; Li, H.;
Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416-16425. (d) Forrat, V. J.;
Pieto, O.; Ram o´ n, D. J.; Yus, M. Chem. Eur. J. 2006, 12, 4431-4445.
(
7) Shibasaki’s pioneering work of bifunctional nonconjugate acid-base
chemistry. See reviews: (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002,
02, 2187-2209. (b) Shibasaki, M.; Kanai, M.; Funabashi, K. Chem.
1
Commun. 2002, 1989-1999. (c) Kanai, M.; Kato, N.; Ichikawa, E.;
Shibasaki, M. Synlett 2005, 1491-1508. (d) Kanai, M.; Kato, N.; Ichikawa,
E.; Shibasaki, M. Pure Appl. Chem. 2005, 77, 2047-2052. (e) Shibasaki,
M.; Matsunaga, S. Chem. Soc. ReV. 2006, 35, 269-279. In particular, with
PdO moieties: (f) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 1999, 121, 2641-2642. (g) Takamura, M.; Hamashima,
Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39,
(3k and 3l) with 80-82% ee in high yields. In particular, a
1
-g-scale (5 mmol) preparation of (R)-3a was established in
91% yield with 93% ee by using 3 mol % of (R)-1d in
heptane at room temperature for 24 h, which is the key
intermediate in the synthesis of the antihistamine drug
1
650-1652. (h) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2000, 122, 6327-6328. (i) Hamashima, Y.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 7412-7413. (j) Funabashi,
K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
12
clemastine (4) (Scheme 2).
1
0784-10785.
Encouraged by the efficient phenylation to ketones, we
(
8) (a) Hatano, M.; Miyamoto, T.; Ishihara, K. AdV. Synth. Catal. 2005,
next examined ethylation with Et
the reaction of aryl and heteroaryl ketones with 3 equiv of
Et Zn proceeded smoothly at room temperature for 16-24
2
Zn (Figure 3). As expected,
3
1
7
47, 1561-1568. (b) Hatano, M.; Miyamoto, T.; Ishihara, K. Synlett 2006,
762-1764. (c) Hatano, M.; Miyamoto, T.; Ishihara, K. J. Org. Chem. 2006,
1, 6474-6484. For our account, see: (d) Ishihara, K.; Sakakura, A.;
Hatano, M. Synlett 2007, 686-703.
(
2
9) Precedent chiral phosphoramide ligands in Et2Zn addition to alde-
hydes: (a) Soai, K.; Hirose, Y.; Ohno, Y. Tetrahedron: Asymmetry 1993,
(11) Pionnering work of phenylation to aldehydes with Ph2Zn/Et2Zn
4
, 1473-1474. (b) Hulst, R.; Heres, H.; Fitzpatrick, K.; Peter, N. C. M.
systems: Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mu n˜ iz, K. Angew.
Chem., Int. Ed. 2000, 39, 3465-3467. Also see: (a) Bolm, C.; Hildebrand,
J. P.; Mu n˜ iz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284-
3308. (b) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm. C. Chem. Soc.
ReV. 2006, 35, 454-470.
(12) (a) Ebn o¨ ther, A.; Weber, H.-P. HelV. Chim. Acta 1976, 59, 2462-
2468. (b) Nikiforov, T.; Stanchev, S.; Milenkov, B.; Dimitrov, V. Synth.
Commun. 1990, 20, 1977-1981.
W.; Kellogg, R. M. Tetrahedron: Asymmetry 1996, 7, 2755-2760. (c)
Brunel, J.-M.; Constantieux, T.; Legrand, O.; Buono, G. Tetrahedron Lett.
1
1
998, 39, 2961-2964. (d) Shi, M.; Sui, W.-S. Tetrahedron: Asymmetry
999, 10, 3319-3325.
(
10) Chiral phosphine oxides in asymmetric catalysis, for reviews see:
(
a) Brunel, J. M.; Buono, G. Top. Curr. Chem. 2002, 79-105. (b) Molt,
O.; Schrader, T. Synthesis 2002, 2633-2670.
4536
Org. Lett., Vol. 9, No. 22, 2007

Figure 3. Catalytic enantoselective ethylation to ketones. Condi-
tions: (a) Reactions were examined in 0.33 M heptane.
membered chelation in a chair conformation with a ketone
(TS-1 and TS-2; also see Scheme 1). Cyclic amino groups
of 1b and 1c, having more basic and less hindered characters
due to electronic and steric factors, would smoothly coor-
dinate to the Zn(II) center rather than the NMe
2
group of
Figure 2. Catalytic enantioselective phenylation to ketones.
Conditions: (a) Reactions were examined in 0.5 M heptane.
1
a. Thus, yields with 1b and 1c were improved from that
with 1a, although a piperidinyl group of 1c might cause too
much hindrance to ketones leading to lower enantioselctivity
(
see Figure 1). Unlike the P-phenyl moieties of 1a-c,
h in the presence of 10 mol % of (S)-1d, and the desired
tertiary alcohols (5) were obtained in high yields with high
enantioselectivities (91-96% ee). To the best of our knowl-
edge, this is the first example of the highly efficient ethylation
of ketones under mild reaction conditions by simply mixing
sterically demanding P-(1-naphthyl) moieties of 1d would
coordinate to the Zn(II) centers with a more appropriate
conformation. Probably the i-Pr moiety (“up” in Figure 4)
2
substrate, Et Zn, and the chiral ligand in a solvent.
Scheme 2. A 1-g-Scale Synthesis of (R)-3a toward
Clemastine
Figure 4. Proposed transition state assemblies.
of the L-valine backbone might relay the direction of two
1
-naphthyl moieties, “down” and “up”, respectively. Ulti-
mately, the bulkiness of the “up”-1-naphthyl moiety would
preferentially induce the coordination of the Et Zn reagent,
Finally, plausible transition-state assemblies in catalytic
enantioselective ethylations are shown in Figure 4, which
should be regarded as a working model. Chiral ligand (S)-1
2
which is activated by the PdO moiety, to the CdO moiety
of 2. Therefore, six-membered cyclic transition states would
be stabilized by using 1d. In particular, Si-face attack via
TS-1, which leads to (S)-product, should be favored exclu-
sively without conspicuous steric repulsion between the i-Pr
and Et
2
Zn would make up the N,N-chelated EtZn(II) center
1
2
1
2 13
as a Lewis acid to activate a ketone (2, R COR , R > R ).
The PdO moiety as a Lewis base, which is electrodonatively
activated through conjugation among Zn-N-PdO bonds,
2
would coordinate to the Et Zn reagent, leading to six-
1
and pyrrolidinyl moieties of (S)-1d and the R group of 2.
In summary, we have developed a highly efficient enan-
tioselective organozinc addition to not only aldehydes14 but
(
13) We confirmed that 1 equiv of ethane gas was released when 1 equiv
each of Et2Zn and 1d were mixed at room temperature.
Org. Lett., Vol. 9, No. 22, 2007
4537

also ketones using conjugate Lewis acid-Lewis base phos-
phoramide-Zn(II) catalysts. These chiral Zn(II) catalysts,
which are simply prepared in situ, are derived from an
inexpensive natural amino acid (i.e., L-valine). From a variety
of aromatic and aliphatic ketones, optically active tertiary
alcohols were obtained in high yields with high enantiose-
lectivities (up to 98% ee) under the mild reaction conditions.
Further investigations on the scope and mechanistic aspects
are under way.
Foundation, Toyoaki Schlorship Foundation, and General
Sekiyu Research & Development Encouragement & As-
sistance Foundation.
Note Added after ASAP Publication. References 7 and
8
2
2
were incomplete in the version published ASAP September
9, 2007; the revised version was published ASAP October
, 2007, with apologies to Prof. Masakatsu Shibasaki and
co-workers for the omission of their work.
Acknowledgment. Financial support for this project was
provided by Grant-in-Aid for Young Scientists B (19750072)
of MEXT, Toray Science Foundation, Hattori-Hokokai
Supporting Information Available: Experimental pro-
cedures and spectral data, as well as copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) 10 mol % of (S)-1b catalyzed the reaction of benzaldehyde and
Et2Zn (3 equiv) in toluene at 0 °C for 12 h, and the corresponding (S)-Et-
adduct was obtained in 97% yield with 95% ee.
OL702074A
4538
Org. Lett., Vol. 9, No. 22, 2007