Apparent catalytic generation of chiral metal enolates: Enantioselective dienolate additions to aldehydes mediated by Tol-BINAP Cu(II) fluoride complexes

Full text of DOI:10.1021/ja973331t

J. Am. Chem. Soc. 1998, 120, 837-838
837
Scheme 1
Apparent Catalytic Generation of Chiral Metal
Enolates: Enantioselective Dienolate Additions to
Aldehydes Mediated by Tol-BINAP‚Cu(II) Fluoride
Complexes
Jochen Kru¨ger and Erick M. Carreira*
Laboratory of Chemical Synthesis
California Institute of Technology
Pasadena, California 91125
Scheme 2
ReceiVed September 23, 1997
The development of catalytic, enantioselective methods for
carbonyl addition reactions is an important intense area of
investigation. The majority of approaches reported to date involve
the use of chiral Lewis acids that activate the aldehyde component
toward addition by enol silanes.1,2 In contrast, the development
and study of catalytic processes that recursively generate chiral
enolates which participate in enantioselective addition to alde-
hydes has little precedence.3-5 In this paper we report a process
which appears to proceed by catalytic generation of a chiral metal
dienolate initiated by a transition metal fluoride complex that is
readily assembled in situ upon mixing (S)-Tol-BINAP,6 Cu(OTf)2,
and (Bu4N)Ph3SiF2 (TBAT) in THF. The adducts are isolated
for a range of aldehydes in useful yields and up to 95%
enantiomeric excess (ee) utilizing as little as 2 mol % catalyst.
We have chosen to focus on the use of the silyl dienolate as
nucleophile since the acetoacetate products isolated are versatile
synthetic intermediates allowing access not only to δ-hydroxy
â-keto esters but also acetone and acetate derived aldol adducts
(Scheme 1).7 Moreover, the hydroxy keto esters that may be
prepared through this process have played an important role in
the ongoing development of HMG-CoA reductase inhibitors and
Vitamin D3 analogues.8
We reasoned that the labile fluoride counterion in a soft-
metal fluoride complex (Ag(I), Cu(II), or Ni(II)) would effect
desilylation of an enol silane with concomitant generation of
the corresponding enolate 4.10 The use of a chiral metal fluor-
ide complex would provide a chiral enolate that might lead
to an asymmetric aldol addition to afford 5.11 The completion
of a catalytic cycle would depend on the metal alcoholate 5
undergoing rapid silylation by the starting enol silane 2, a key
step that would regenerate metal enolate and effect catalyst turn-
over. This contrasts extant processes involving Lewis acid
mediated carbonyl additions wherein the corresponding metal
alcoholate intermediate undergoes silylation by the activated silyl
species 3.
Our interest in examining soft-metal fluoride complexes as
practical aldol addition catalysts led us to examine commercially
available optically active diphosphines as ligands.12 The synthesis
of the desired optically active complexes requires access to
anhydrous metal fluoride salt precursors. However, two well-
known aspects of metal fluoride chemistry hampered our efforts:
(1) preparative methods for the synthesis of simple metal fluoride
salts are unwieldy, and, more importantly, (2) metal fluoride salts
are difficult to solubilize in commonly employed organic sol-
vents.13 Thus, we examined a procedure employing the recently
reported crystalline, anhydrous fluoride source (Bu4N)-
Ph3SiF2 (TBAT) for the in situ generation of a soft-metal fluoride
complex.14
In the most commonly exploited mechanism for catalytic
enantioselective aldol addition reactions, an aldehyde is activated
upon coordination to a Lewis acid to afford 1 (Scheme 2). The
electrophilic complex is attacked by the enol silane 2 to produce
intermediate 3 that must undergo silylation at a rate faster than
the competing background rate of the silyl-catalyzed aldol addition
reaction.9
(1) For a leading discussion, see: Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; VCH: New York, 1993.
(2) For a recent discussion of a novel mechanistic model involving aldehyde
binding and activation in Lewis acid mediated additions, see: Corey, E. J.;
Barnes-Seeman, D.; Lee, T. W. Tetrahedron Lett. 1997, 38, 4351 and
references therein.
We have observed that treatment of a solution of (S)-Tol-
BINAP15 with Cu(OTf)2 and (Bu4N)Ph3SiF2 produces a complex
that effects the enantioselective addition of silyl dienolate 6 to a
(3) Recently, Denmark has reported a reaction process with dual activation
of nucleophilic and electrophilic reaction partners, see: Denmark, S. E.; Wong,
K. T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333.
(4) (a) For a report in which the involvement of a Pd enolate is suggested,
see: Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org. Chem. 1995, 60, 2648
and references therein. (b) For a report in which the involvement of a Ln
acetone enolate is suggested, see: Shibasaki, M.; Sasai, H.; Arai, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1236.
(5) Related processes wherein putative chiral metal enolates are generated
and undergo conjugate additions, isocyanoacetic ester aldol additions, nitroal-
dols, and enolate amination reactions, see: (a) Sasai, H.; Arai, T.; Satow, Y.;
Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194. (b) Ito, Y.;
Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (c) Sasi, H.;
Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114,
4418. (d) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452.
(6) (S)-Tol-BINAP is the accepted abbreviation for (S)-(-)-2,2′-bis(di-p-
tolylphosphino)-1,1′-binaphthyl, a commercially available diphosphine deriva-
tive.
(7) (a) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995,
41, 1435 and references therein. (b) Dritz, J. H.; Carreira, E. M. Tetrahedron
Lett. 1997, 38, 5579.
(8) (a) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J.; Deana,
A. A.; Gilfillan, J. L.; Huff, J. W.; Novello, F. C.; Prugh, J. D.; Smith, R. L.;
Willard, A. K. J. Med. Chem. 1985, 28, 347. (b) Zhu, G.-D.; Okamura, W.
H. Chem. ReV. 1995, 95, 1877.
(9) (a) Carreira, E. M.; Singer, R. A. Tetrahedron Lett. 1994, 35, 4323.
(b) Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117, 4570.
(10) For a study involving molybdenum, rhodium, and tungsten enolates,
see: (a) Slough, G. A.; Bergman R. G.; Heathcock, C. H. J. Am. Chem. Soc.
1989, 111, 938. (b) Burkhardt, E. R.; Doney, J. J.; Bergman, R. G.; Heathcock,
C. H. J. Am. Chem. Soc. 1987, 109, 2022.
(11) Nakamura, E.; Yamago, S.; Machii, D.; Kuwajima, I. Tetrahedron
Lett. 1988, 29, 2207.
(12) For a report of Ag(I)‚BINAP complexes that effect the addition of
allyltributyltin and tin enolates to aldehydes, see: Yanagisawa, A.; Nakashima,
H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723. (b)
Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.; Yamamoto,
H. J. Am. Chem. Soc. 1997, 119, 9319. It is important to note that
these systems prescribe high catalyst loading (10 mol %) and that the
Ag(I) complex functions as a Lewis acid without metalation of the nucleo-
phile.
(13) For a comprehensive review on the preparation and use of transition-
metal fluoride complexes, see: Doherty, N. M.; Hoffman, N. W. Chem. ReV.
1991, 91, 553.
(14) Oilscher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc. 1995,
117, 5166.
S0002-7863(97)03331-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/04/1998

838 J. Am. Chem. Soc., Vol. 120, No. 4, 1998
Table 1. Enantioselective Dienolate Additions
Communications to the Editor
Scheme 3
isolated in good yields and enantioselectivities. Thus, the fluoride
counterion is only responsible for initiating the catalytic cycle
and is not important in the generation of an active catalyst. The
results of an additional control experiment are consistent with a
model wherein the complex is involved in the generation of a
metal enolate and not exclusively as a chiral Lewis acid. When
the reaction is carried out by treatment of a solution of enol silane
6 and benzaldehyde (-78 °C) with 5 mol % (S)-BINAP‚Cu(OTf)2
in the absence of the fluoride additive, product formation is rapid
at -78 °C; however, analysis of the adduct isolated revealed that
it had been formed as a racemate.18
The reaction process we have described may be carried out on
preparative scale with as little as 0.5 mol % catalyst without
deleterious effects on reaction rate or product enantioselectivity.
We have conducted the addition reaction on multigram quantities
of furfural (entry 4) to afford the corresponding ad-
duct which is conveniently purified by a single crystallization
yielding 8 in >99% ee as determined by HPLC. Following a
short sequence of facile reactions, acid 9 and its corresponding
methyl ester 10 were prepared (Scheme 3); such intermediates
are important building blocks in the synthesis of HMG-CoA
reductase inhibitors.19
A new catalytic, enantioselective aldehyde addition process is
described which provides an efficient alternative to the well-
established methods for conducting enantioselective Mukaiyama
aldol reactions which have traditionally involved Lewis-acid
mediated additions of O-silyl enolates and aldehydes. The salient
features of this process include: (1) (S)-Tol-BINAP and Cu(OTf)2
are available from commercial sources at a nominal price; (2)
dienolate adducts are isolated in excellent yields and useful levels
of enantioselectivity. We have demonstrated the utility of this
efficient process in the synthesis of 9, a key intermediate in the
synthesis of HMG-CoA reductase inhibitors. Importantly, this
study provides a new mechanistic model for the development of
catalytic processes for aldehyde addition reactions wherein enol
silanes and chiral metal fluoride complexes are used to generate,
in a catalytic fashion, metal enolates that undergo enantioselective
aldol addition reactions. Continuing investigations in this labora-
tory will attempt to elucidate the identity of the various intermedi-
ate transition-metal complexes and further expand the scope of
the process.
a The enantiomeric excess was determined by HPLC analysis of the
2° alcohol product using a Chiralcel OD column or by conversion of
the adduct to the corresponding Mosher ester upon treatment with (R)-
(+)-MTPA-Cl and analysis by 1H NMR spectroscopy, see Supporting
Information for details. b The absolute configuration for the products
was established by comparison to the known compounds or by
conversion of each adduct to the corresponding â-hydroxy methyl
ketones which were independently synthesized (see ref 17).
range of aldehydes (eq 1 and Table 1).16 The process is quite
(1)
general for R,â-unsaturated, aromatic, and hetero-aromatic alde-
hydes; additionally, aliphatic aldehydes have been observed to
serve as substrates in the dienolate addition reaction to give
products with high levels of enantioselectivity, albeit poor yields
(<40%).
The results of some additional experiments highlight the unique
aspects of this process in comparison to other metal-catalyzed
enol silane aldehyde addition reactions. In support of the
hypothesis that a soft-metal enolate is an intermediate in the
reaction, we have observed that the reaction can be successfully
executed under conditions that directly promote transmetalation
of the enol silane in the absence of fluoride. When a solution of
enol silane 6 is successively treated with 10 mol % of either MeLi
or (Bu4N)Ph3SiF2 at 0 °C, followed by 5 mol % of (S)-BINAP‚
Cu(OTf)2 at -78 °C and benzaldehyde, the aldol adduct was
Acknowledgment. J.K. thanks the Deutsche Forschungsgemeinschaft
for a postdoctoral fellowship. This research has been supported by
generous grants from the NSF, NIH, the David and Lucille Packard
Foundation, Sloan Foundation, Merck, Pfizer, Eli Lilly, Zeneca, and
Upjohn.
Supporting Information Available: Experimental procedures and
spectral data for all compounds (6 pages). See any current masthead
page for ordering and Internet access instructions.
(15) In our intial studies we observed that the use of (S)-BINAP as ligand
affords the benzaldehyde aldol adduct in 88% ee and 90% yield. A brief
examination of other commercially available diphosphines led to identifying
(S)-Tol-BINAP as the ligand which provides optimal selectivities to date.
(16) The complexes prepared with AgOTf and Ni(OTf)2 were observed to
catalyze the addition of silyldienolates to aldehydes, albeit in diminished levels
of asymmetric induction.
(17) The absolute configuration of the adducts was established upon
hydrolysis of the dioxinones followed by decarboxylation and comparison of
the resulting methyl ketones to the same compounds independently prepared
using the method of Paterson: Paterson, I.; Goodman, J. M.; Lister, M. A.;
Schumann, R. C.; McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46,
4663.
JA973331T
(18) For pioneering developments of Cu(II) complexes as Lewis acids,
see: Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J.
Am. Chem. Soc. 1997, 119, 7893. (b) Evans, D. A.; Murry, J. A.; Kozlowski,
M. C. J. Am. Chem. Soc. 1996, 118, 5814.
(19) (a) Boberg, M.; Angerbauer, R.; Fey, P.; Kanhai, W.; Karl, W.; Kern,
A.; Ploschke, J.; Radtke, M. Drug Metab. Dispos. 1997, 25, 321. (b) Konioke,
T.; Araki, Y. J. Org. Chem. 1994, 59, 7849.