Catalytic asymmetric synthesis of homoallylic alcohols: Chiral amplification and chiral poisoning in a titanium/BINOL catalyst system

Full text of DOI:10.1021/ja952115m

J. Am. Chem. Soc. 1996, 118, 1217-1218
Table 1. Chiral Amplification in Catalysis with Nonracemic
1217
Catalytic Asymmetric Synthesis of Homoallylic
BINOL/Ti Catalysts
Alcohols: Chiral Amplification and Chiral
Poisoning in a Titanium/BINOL Catalyst System
J. W. Faller,* D. W. I. Sams, and X. Liu
Department of Chemistry, Yale UniVersity
New HaVen, Connecticut 06511-8118
ReceiVed June 27, 1995
(R)-BINOL
ee (%)a
yield of 3 (%)b
ee of 3 (%)c
configuration of 3d
Efficient methods for the enantioselective Lewis acid-
catalyzed syntheses of homoallylic alcohols have been discussed
in four recent reports. In each case, the catalyst employed was
0
1
0
33
50
>90
>95
>95
>95
>95
>95
0
26
46
76
81
1
2
(R)
(R)
(R)
(R)
(R)
1
derived from the reaction of Ti(O-i-Pr)4 or TiCl 2(O-i-Pr)2 with
(R)- or (S)-BINOL. These reactions are synthetically very
useful, as all the reagents are readily available from commercial
sources; however, the high cost of the resolved (R)- or (S)-
BINOL employed in these reactions is a practical considera-
70, 90, 100
>95
a
In the nonracemic BINOL, (R)-BINOL was in excess. b Determined
1
by H NMR measurements on reaction mixtures (after 70 h). The
2
c
tion despite one’s ability to recycle some of the ligand. We
reactions using lower ee catalysts proceeded more slowly. Measured
by GC using a cyclodex-B chiral column. d Determined Via optical
rotation measurements/GC retention times compared to pure samples
of 3 prepared by the method of Keck.1
have focused on the reaction of benzaldehyde with allyl
tributyltin Via a modification of a method of Keck employing
such a titanium/BINOL catalyst and have found that this
system displays chiral amplification and chiral poisoning
1
b
occurs at only one titanium center during each cycle. It would
follow that the reactivity of a given center is modified by the
presence of the other metal. In effect, one can consider the
other end of the dimer as a titanium-containing ligand which
modifies the reactiVity of the center directly inVolVed in the
reaction. When enantiomerically enriched BINOL is employed
in the glyoxylate ene reaction, the monomeric unit formed from
the enantiomer of BINOL in lower concentration is effectively
sequestered through the formation of the unreactive meso dimer.
This leaves the remaining BINOL, now in effectively much
greater enantiomeric excess (ee), to be contained in homochiral
dimers of much greater activity. Thus, relatively small ee’s in
the BINOL can produce much greater ee’s in the product. While
we have not carried out molecular weight determinations, it is
probable that a similar mechanism is involved in the chiral
amplification found in the asymmetric allylation reaction. This
suggests that the meso dimer Ti2(O-i-Pr)4[(R)-BINOL][(S)-
BINOL] is less competent as a catalyst than the homochiral
dimers Ti2(O-i-Pr)4[(R)-BINOL]2 or Ti2(O-i-Pr)4[(S)-BINOL]2,
and thus chiral amplification is observed.
phenomena. The chiral poisoning strategy allows the use of
2
the much less expensive racemic form of BINOL in this
reaction while still producing a homoallylic alcohol with high
enantiomeric purity.
We began by investigating the reaction in which partially
resolved BINOL (0.6 mmol) and Ti(O-i-Pr)4 (0.6 mmol) were
heated under reflux in CH2Cl2 (4 mL) in the presence of 800
mg of 4 Å molecular sieves (ms) for 1 h before addition of
benzaldehyde 1 (2 mmol) at room temperature and subsequent
addition of allyltributyltin 2 (2.2 mmol) at -78 °C. Under these
conditions, the catalysts are employed at 30 mol % (titanium
to aldehyde).3 The reaction was allowed to proceed for 70 h at
-
23 °C before the product was isolated by a modification of
4
the method of Keck. The results, as summarized in Table 1,
show a positive nonlinear effect (NLE) in correlating product
enantiomeric purity with the ee of the BINOL, i.e., chiral
amplification. Keck also observed a NLE in an analogous
1c
system. Mikami and Nakai et al. have observed a similar NLE
in the glyoxylate ene reaction catalyzed by a catalyst derived
from TiX2(O-i-Pr)2 (X ) Cl or Br) and enantiomerically
enriched BINOL.5 Based on molecular weight studies, they
attribute the NLE in this reaction to the formation of dimeric
structures of general formula Ti2X4[BINOL]2. This suggests
that the meso dimer, Ti2X4[(R)-BINOL][(S)-BINOL], has a
lower activity than either of the homochiral dimers, Ti2X4[(R)-
BINOL]2 or Ti2X4[(S)-BINOL]2. Although the mechanism is
One might consider that the (R)-BINOL-titanium moiety is
deactivating the (S)-BINOL complex by forming the meso
dimer, or Vice Versa. This suggested to us that we might be
able to develop an even less active dimer by substituting an
(R)- or (S)-BINOL-titanium moiety with a different resolved
diol-titanium moiety in the dimeric species.
6
-12
uncertain,
one can rationalize the result by assuming that
the dimers are the principal active species and that each reaction
(6) NLEs can be explained by reactive dimers7,8 or monomers.8,9
Assuming that unreactive dimers dissociate into active monomers is also
9
(1) (a) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-
an attractive mechanism; however, dimers as the principal active species
5
,10,11
Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001. (b) Keck, G. E.; Tarbet, K.
H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467. (c) Keck, G. E.;
Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543. (d) Keck,
G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827.
have been implicated in some diolate-titanium reactions
owing to a
first-order dependence on dimer.1
0,11
It is also possible that even higher
aggregates, such as trimers, could be important.1
1,12
(7) (a) Puchot, C.; Samuel, O.; Du n˜ ach, E.; Zhao, S.; Agami, C.; Kagan,
H. B. J. Am. Chem. Soc. 1986, 108, 2353-2357. (b) Guillaneux, D.; Zhao,
S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994,
116, 9430-9439.
(
2) For example, prices quoted in the Aldrich catalog (1995) are as
follows: (R)-BINOL, $219.00 for 5 g; (S)-BINOL, $278.00 for 5 g; and
racemic BINOL, $18.90 for 5 g.
1
(3) Keck employs titanium/BINOL systems at 10 mol % (aldehyde to
(8) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49-69. (b) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chem.
Soc. 1995, 117, 4832-4842.
titanium). Since some of the titanium is in the form of reduced activity
complexes in our experiments, we employ a higher titanium concentration
in these reactions to ensure that the reaction proceeds to completion (see
Table 2, entry 1).
(9) Corey, E. J. J. Org. Chem. 1990, 55, 1693.
(10) Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 113.
(11) Boyle, T. J.; Eilerts, N. W.; Heppert, J. A.; Takasugawa, F.
Organometallics 1994, 13, 2218-2229.
(
4) The workup procedure was identical to that described in ref 1b
(
method A), except that chromatographic separation was achieved using
5
b
preparative TLC plates (silica gel 60 F254) and 5% acetone in hexanes as
eluant.
(12) Martin, C. Ph.D. Thesis, MIT, Cambridge, MA, 1990. Dimeric
7
and trimeric structures in crystal structures have been quoted as information
from Prof. B. Sharpless. A solid state structure could be that of a more
insoluble form and may not represent the nature of important oligomers in
solution.
(5) (a) Terada, M.; Mikami, K.; Nakai, T. J. Chem. Soc., Chem. Commun.
1
1
990, 1623. (b) Kitamoto, D. H.; Imma, H.; Nakai, T. Tetrahedron. Lett.
995, 36, 1861-1864.
0
002-7863/96/1518-1217$12.00/0 © 1996 American Chemical Society

1
218 J. Am. Chem. Soc., Vol. 118, No. 5, 1996
Communications to the Editor
Table 2. Chiral Poisoning of Racemic BINOL Titanium Isopropoxide
a
poison (mmol)
entry no.
D-DIPT
Ti(O-i-Pr)
4
R in RCHO
yield of 3 (%)b
ee of 3 (%)c
configuration of 3d
1
2
3
4
5
6
7
8
0.00
0.24
0.30
0.40
0.60
0.60
0.60
0.60
0.00
0.20
0.20
0.20
0.20
0.20
0.20
0.20
Ph
Ph
Ph
Ph
Ph
65
44
40
47
63
33
25
37
0
19
39
81
91
82
86
92
(S)
(S)
(S)
(S)
(S)
(S)
6 11
c-C H
trans-PhCHdCH
2-furfuryl
e
nd
a
Each catalyst contained 0.4 mmol of racemic BINOL, 0.4 mmol of Ti(O-i-Pr)
4
, 4 mL of CH
2 2
Cl , and 800 mg of 4 Å molecular sieves in
c
b
1
addition to the poison indicated in this column. Determined by H NMR measurements on crude reaction mixtures. Entries 1-5 measured by
d
GC using a cyclodex-B chiral column. Entries 6-8 determined by chiral shift reagent, Eu(hfc)
3
.
Determined Via optical rotation measurements/
GC retention times compared to pure samples of 3 prepared by the method of Keck.1 Not determined.
e
This is effectively a chiral poisoning strategy13,14 for this reac-
contrast, when (S)-BINOL, DIPT, and Ti(O-i-Pr)4 were heated
under reflux for 1 h before addition of 1 and 2, the chiral alcohol
was observed in 20% yield (>95% ee) after 70 h at -20 °C.
tion, i.e., utilizing a catalyst synthesized from racemic BINOL
and then selectively deactivating one enantiomeric moiety of
the catalyst with a poison. The utility of such a strategy has
previously been demonstrated by us with asymmetric hydro-
3
The addition of the DIPT/Ti(O-i-Pr)4 poison therefore appears
to deactivate the (R)-BINOL catalyst more effectively than the
(S)-BINOL catalyst. Hence, addition of this poison to a catalyst
derived from racemic BINOL leads to preferential deactivation
of the (R)-BINOL catalyst and the observed ee’s of 3.15 We
attribute the chiral poisoning behavior to the probable formation
of the mixed dimeric species Ti2(O-i-Pr)4[(R)-BINOL][DIOL]
and Ti2(O-i-Pr)4[(S)-BINOL][DIOL]. When the diol is diiso-
propyl D-tartrate, the mixed dimer containing (R)-BINOL is less
active than that containing (S)-BINOL, and this leads to the
1
3
genation catalysts prepared from racemic phosphines. The
important feature of the model described aboVe to explain the
NLE is that one titanium monomer unit can act as a poison to
deactiVate another. This suggests that the best poison would
be a titanium complex, not a purely organic inhibitor.
The poisons chosen were derived from Ti(O-i-Pr)4 and an
enantiopure chiral diol in a 1:1 to 1:3 stoichiometry and were
generated in situ during the preparation of the catalyst. In a
typical reaction, racemic BINOL (0.4 mmol), diisopropyl
D-tartrate (DIPT) (0.2-0.6 mmol), and Ti(O-i-Pr)4 (0.6 mmol)
were heated under reflux in CH2Cl2 (4 mL) in the presence of
1
6
observed ee’s observed in 3.
The Ti(O-i-Pr)4/[DIPT] complex did not catalyze the reaction,
whereas the Ti(O-i-Pr)4/[(rac)-BINOL] was a rather poor
catalyst and gave racemic product. A fascinating feature of this
system is that mixing two mediocre catalysts produces a new
one of reasonable activity that gives a high ee.
4
Å molecular sieves (800 mg) for 1 h. Benzaldehyde 1 (2
mmol) was then added at room temperature before addition of
allyltributyltin 2 (2.2 mmol) at -78 °C. The resulting mixture
was kept at -23 °C for 70 h before workup as previously
1
described. Our results are summarized in Table 2. Moderate
Acknowledgment. We are grateful to the National Science Founda-
tion for supporting this work.
to good ee’s were observed in 3 depending upon the specific
diol employed. Diethyl L-tartrate gave the (R)-product with
PhCHO; whereas (2R,3R)-(-)-2,3-butanediol gave the (S)-
product in 68% ee. The best results were obtained with a poison
produced from DIPT and Ti(O-i-Pr)4. It should be noted that
the Ti(O-i-Pr)4/tartrate poison mixtures displayed no catalytic
actiVity on their own in the reaction of 1 with 2.
In an effort to understand the mechanism of this poisoning
phenomenon, we carried out a series of reactions employing
resolved BINOL under a protocol similar to that for the
poisoning reactions discussed above. When (R)-BINOL, DIPT,
and Ti(O-i-Pr)4) were heated under reflux for 1 h before addition
of 1 and 2, no product 3 was observed after 70 h at -20 °C. In
JA952115M
(15) In an alternative procedure, the titanium tartrate poison was prepared
separately and then added to the titanium catalyst prepared from racemic
BINOL. This catalyst also showed chiral poisoning phenomena, but the
best results were obtained by preparing the mixture in situ.
(16) The role of the excess tartrate is unclear. We presume that n is
probably 2, but could possibly be 1 in the Ti2(O-i-Pr)2n[BINOL][DIOL]3-n.
Depending on relative equilibrium constants, (DIPT)xTiy(O-i-Pr)z complexes
would make a portion of the total number of (DIPT)Ti monomeric units
unavailable to form dimers containing (R)-BINOL (analogous to the
7b
“
reservoir effect” ). We presume that the improvements in ee with higher
concentrations of DIPT are a consequence of shifting equilibria to produce
more deactivated Ti2(O-i-Pr)4[(R)-BINOL][DIPT]. Although displacing two
O-i-Pr from Ti(O-i-Pr)4 is straightforward, removing all of the i-OPr groups
from the titanium should be more difficult.5b Excess tartrate could also
potentially slow other acid-catalyzed routes that might competitively yield
low ee product. We are continuing our efforts to determine the nature of
the various complexes in these mixtures.
10
(
13) (a) Faller, J. W.; Parr, J. J. Am. Chem. Soc. 1993, 115, 804. (b)
Faller, J. W.; Tokunaga, M. Tetrahedron Lett. 1993, 34, 7359-7362. (c)
Faller, J. W. Pure Appl. Chem. 1994, 66, 1463-1469.
(
14) (a) Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 789.
(
b) Brown, J. M.; Maddox, P. J. Chirality 1991, 3, 345.