Chiral triarylcarbenium ions in asymmetric Mukaiyama aldol additiosn

Full text of DOI:10.1021/ja970900o

J. Am. Chem. Soc. 1997, 119, 11341-11342
11341
Scheme 1a
Chiral Triarylcarbenium Ions in Asymmetric
Mukaiyama Aldol Additions
Chien-Tien Chen,* Shi-Deh Chao, Kuao-Chung Yen,
Chung-Horng Chen, Iy-Chen Chou, and Sang-Weng Hon
Department of Chemistry, National Taiwan
Normal UniVersity, Taipei, Taiwan 117
ReceiVed March 18, 1997
The Mukaiyama aldol reaction is one of the most versatile
synthetic methods for stereoselective carbon-carbon bond
formation. Asymmetric catalysis of this category utilizing chiral
complexes derived from B, Al, Sn(II), Ti(IV), Cu(II), Pd(II),
and Ln(III) has been explored in the past 10 years with
significant breakthroughs.1 Mukaiyama and co-workers have
documented novel uses of various trityl salts serving as efficient
catalysts in various aldol type transformations,2 highlighting their
potential in asymmetric variations. Nevertheless, several in-
trinsic and pending problems still hinder their practical design
in that context. First, the reacting carbenium ion center is sp2-
hybridized. Placement of the three flanking aryl groups in a
chiral environment is so far impossible due to the extremely
low barrier to racemization of chiral carbenium ions.3 Second,
in sharp contrast to most existing chiral Lewis acids generated
from chiral natural sources (e.g., diols, diamines, amino acids,
and tartrates),1,4 no natural skeleton has been found that is
relevant to the triarylmethyl scaffold. Third, the precise nature
of the catalytic species in these transformations remains elusive
in view of the recent elegant mechanistic study by Bosnich.5
Apparently, development of new types of chiral Lewis acids
with reactive carbenium-based centers are essential in view of
their potential impact on both mechanistic and synthetic utility
aspects. We describe herein our preliminary findings toward
this end.
Platzek and Snatzke have reported the synthesis of C2-
symmetric diol 1, a common skeleton in various anti-inflam-
matory drugs, in scalemic form.6 This resolved (10R,11R)-1,
was utilized as a conceivable trityl ion precursor, whose
enantiomeric purity was determined to be >99% enantiomeric
excess (ee) by HPLC analysis on a chiral support (Chiralcel
OJ). We have so far accessed two different 10,11-dialkyl
(dimethyl and diethyl) substituted C2-symmetric trityl salts. To
convert the alcohol moieties into methyl appendages, the diol-1
was mesylated with methanesulfonyl chloride (MsCl) in CH2-
Cl2 in the presence of Et3N (6 equiv). Reduction of the resultant
dimesylate with LiEt3BH (3 equiv) in anhydrous THF provided
10,11-dimethyldibenzosuberane (2) in essentially quantitative
yield (Scheme 1). In a similar manner, the scalemic diol 1 was
transformed in 96% yield to the corresponding ditosylate by
treatment with TsCl in the presence of Et3N and catalytic
4-(dimethylamino)pyridine (DMAP). Double SN2 displacement
(a) Key: (a) (i) MsCl/Et3N/CH2Cl2, (ii) LiBEt3H/THF, 0 °C f rt;
(b) (i) TsCl/Et3/N/CH2Cl2, cat. DMAP, (ii) Me2CuLi/ether, -10 °C.
Scheme 2
of the ditosylate with (CH3)2CuLi at -10 °C provided the diethyl
analog 3 quantitatively.7 These two dialkyldibenzosuberanes
were readily oxidized at ambient temperature to the respective
ketones, 4 and 5, by KMnO4 (2.5 equiv) in benzene using
dicyclohexano-18-crown-6 as a phase transfer catalyst.8 Both
ketones were obtained in 91% yields.
To probe the stereoelectronic influence of the 5-aryl group
on the structure, reactivity, and selectivity of triarylcarbenium
ions in the aldol process, two representative aryl appendages
(tert-BuC6H4 and 2,6-(MeO)2C6H3) were selected in addition
to the parent phenyl group.9 The requisite trityl alcohols, 6 and
7a-c, were prepared in 84-98% yields by aryllithium addition
to the respective dibenzosuberones.10
Independent treatment of 1-aryldibenzosuberols, 6 and 7a,b
(Ar ) Ph and 4-tert-butylphenyl), with an appropriate acid (HX)
in the presence of a water scavenger (acetic anhydride) allowed
the preparation of the corresponding chiral trityl salts, 9a,b and
10a-c, with three different counter ions (TfO-, ClO4-, and
PF6-).11 In all cases, the reddish orange salts could be obtained
in good yields (80-98%) by gradual addition of cold diethyl
ether into the reaction media at 0 °C to induce crystallization
(Scheme 2). In some instances, these highly moisture- and heat-
sensitive materials can even be obtained in analytically pure
form (i.e., 9b and 10a), allowing for unambiguous determination
of composition. The 2,6-dimethoxy substituted trityl alcohol
7c was not amenable to the Dauben procedure11 (HX/Ac2O)
due to the extreme solubility of the resulting trityl salts in acetic
anhydride. The final targeted hexachloroantimonates, 10d (Ar
) 4-tert-BuC6H4) and 10e (Ar ) 2,6-(MeO)2C6H3), could only
be generated in situ by a Meerwein salt-promoted ionization of
the appropriate trityl methyl ethers (8b and 8c), recently
developed in our laboratories.9 The requisite methyl ether
precursors were formed in 93% (8b) and 82% (8c) yields,
respectively, by the standard Williamson etherification (NaH/
CH3I) of the corresponding alcohols (Scheme 1).12
(1) For leading references for each case, see: (B and Al) (a) Kiyooka,
S.-I.; Kaneko, Y.; Kume, K.-I. Tetrahedron Lett. 1992, 33, 4927. (b) Parmee,
E. R.; Tempkin, O.; Masamune, S. J. Am. Chem. Soc. 1991, 113, 9365. (c)
Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907.
(d) Hattori, K.; Yamamoto, H. Tetrahedron 1994, 50, 2785. (Sn(II)) (e)
Kobayashi, S.; Hayashi, T. J. Org. Chem. 1995, 60, 1098. (Ti(IV)) (f) Singer,
R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360. (g) Mikami,
K.; Takasaki, T.; Matsukawa, S.; Maruta, M. Synlett 1995, 1057. (h)
Mukaiyama, T.; Inubushi, A.; Suda, S.; Hara, R.; Kobayashi, S. Chem. Lett.
1990, 1015. (Cu(II)) (i) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J.
Am. Chem. Soc. 1996, 118, 5814. (Pd(II)) (j) Sodeoka, M.; Ohrai, K.;
Shibasaki, M. J. Org. Chem. 1995, 60, 2648. (Ln(III)) (k) Uotsu, K.; Sasai,
H.; Shibasaki, M. Tetrahedron: Asymmetry 1995, 6, 71.
(7) Posner G. H. Org. React. 1975, 22, 253.
(2) (a) Kobayashi, S. Kagaku Kogyo 1989, 42, 245 and references cited
therein. (b) Denmark, S. E.; Chen, C.-T. Tetrahedron Lett. 1994, 35, 4327.
(3) (a) Wallis, E. J. J. Am. Chem. Soc. 1931, 53, 2253. (b) Gomberg,
M.; Gorden, W. E. J. Am. Chem. Soc. 1935, 73, 119. (c) Wallis, E. S.;
Adams, F. H. J. Am. Chem. Soc. 1933, 55, 3338.
(8) Sam, D. J.; Simmons, H. E. J. Am. Chem. Soc. 1972, 94, 4024.
(9) A total of six different aryl groups were surveyed in model studies.
Chen, C.-T.; Chao, S.-D; Yen, K.-C. Manuscript in preparation.
(10) (a) McEwen, W. E.; Janes, A. B.; Knapczyk, J. W.; Kyllingstad,
V. L.; Shiau, W.-I.; Shore, S.; Smith, J. H. J. Am. Chem. Soc. 1978, 100,
7304. (b) Borhan, B.; Wilson, J. A.; Gasch, M. J.; Ko, Y.; Kurth, D. M.;
Kurth, M. J. J. Org. Chem. 1995, 60, 7375.
(4) Blaser, A. P. Chem. ReV. 1992, 92, 935.
(5) Hollis, T. K.; Bosnish, B. J. Am. Chem. Soc. 1995, 117, 4570.
(6) Platzek, J.; Snatzke, G. Tetrahedron 1987, 43, 4947 and references
cited therein.
(11) Dauben, H. J., Jr.; Honnen, L. R.; Harmon, K. M. J. Org. Chem.
1960, 25, 1442.
S0002-7863(97)00900-1 CCC: $14.00 © 1997 American Chemical Society

11342 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Communications to the Editor
Table 1. Chiral Triarylcarbenium-Ion-Mediated Mukaiyama Aldol
Addition between Benzaldehyde and Acetate-Derived Silyl Ketene
Actal
Scheme 3
time yield
entry
Ar
X (catalyst) (h) (%)a ee (%)b config.c
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-tert-BuC6H4
4-tert-BuC6H4
4-tert-BuC6H4
OTf (9a)
ClO4 (9b)
ClO4 (10a)
3
6
3
75
3
S
S
methathesis between tritylated aldolates and R3SiX.16 Under
such circumstances, silyl catalysis completely took over once
the trityl ions were tied up. To evaluate the extreme asymmetric
discrimination with our devised chiral template, one full
equivalent of trityl perchlorate 10a was used in this model aldol
addition. The â-hydroxy ester 11 was obtained in 50% ee, albeit
with significant diminution of chemical yields from 52% to 22%
(entries 3 and 6).
92 12
52 24 (4d)
67 16
R
R
R
R
R
R
R
R
ClO4 (10a) 4.5
ClO4 (10a)
ClO4 (10a)e
ClO4 (10b)
PF6 (10c)
6
3
3
3
4
4
99 11
22 50
40 38 (27d)
20 32 (19d)
SbCl6 (10d)
48
53 22
6 (8d)
10 2,6-(MeO)2C6H3 SbCl6 (10e)
The production of scalemic â-hydroxy ester 11 in the chiral
carbenium-ion-mediated aldol process strongly suggest that a
trityl-ion-catalyzed pathway originally proposed by Mukaiyama2
is operable to some extent (path a, Scheme 3). For an efficient
regeneration of the chiral catalyst, the exchange process between
the tritylated aldolate and the released R3SiX (path b) must have
a faster rate than that of the R3SiX-catalyzed reaction (path c).
An alternative reaction pathway would involve an initial
exchange between the silyl group on O-ethyl SKA and the trityl
ion to give a chiral O-trityl ketene acetal followed by a R3SiX-
catalyzed aldol reaction (path d). Similarly, this exchange
process has to be faster than path c to secure asymmetric
generation of the aldol product.
Two independent lines of evidence led to the exclusion of
the last mechanistic scenario. First, instead of observing any
O-trityl ketene acetal formation, only trace amount of C-trityl
acetate 13 was produced when O-ethyl SKA was mixed with
an equal amount of chiral trityl perchlorate 10a at -78 °C.17
The C-trityl acetate formation became more significant when
the reaction was warmed to the ambient temperature. Second,
treatment of the independently prepared C-trityl acetate, 12 (R
) H) or 13 (R ) Et), with benzaldehyde (1 equiv) in the
presence of TBSOTf or TBSClO4 under similar aldol conditions
provided no trityl alcohols or aldol products. This result rules
out any possible electrophile-promoted C f O trityl transfer to
reform the trityl ketene acetal.
In conclusion, we have documented the first example of
asymmetric Mukaiyama aldol additions mediated by chiral
triarylcarbenium ions, albeit with significant intervention of the
unproductive silyl catalysis. Searches for a better chiral trityl
ion candidate that can adopt a more rigid conformation and
exhibit a more reactive carbenium ion center are currently
underway.
Acknowledgment. We are grateful to Prof. Scott E. Denmark
(University of Illinois) for his support and advice during the early stages
of this work. We thank Prof. Edwin Vedejs for enlightening suggestions
regarding mechanistic aspects of this system. The National Science
Council (NSC 86-2113-M-003-001 and NSC 86-2732-M-003-001) of
the Republic of China for a generous support of this research is greatly
acknowledged.
a Isolated yields. b Determined by HPLC analysis on Chiralcel OD
column. c Correlated by the optical rotation of the corresponding acid
with the literature value. d From the aldol reaction with TMS ketene
acetal. e One equivalent of catalyst was added.
Our targeted aldol addition involves the slow addition of
O-ethyl silyl ketene acetal (SKA) to benzaldehyde with catalytic
chiral trityl salts (10-20 mol %) at -78 °C. This most
challenging scenario was found to proceed smoothly, leading
to enantiomerically enriched ethyl 3-hydroxy-3-phenylpropi-
onate (11) in good yields after protodesilylation of the inital
silylated aldolate (Table 1).
The extent and sense of asymmetric induction were highly
dependent on silyl substituents, counterions,2b steric bulk of R
groups, substitution pattern on the pending aromatic rings, and
reaction time. The use of trimethylsilyl (TMS) ketene acetal
consistently led to a lower level of asymmetric induction in the
aldol process as compared with the tert-butyldimethylsilyl (TBS)
analog. Best results were achieved by the employment of trityl
perchlorates (10a,b) and hexafluorophosphate (10c). The free
â-hydroxy ester 11 was obtained with enantioselectivities of
up to 38%. A significant drop in enantioselectivity (entries 1
and 9) was observed in the triflate (9a) and hexachloroanti-
monate (10d) presumably due to the facile intervention of silyl
and SbCl5 catalysis, respectively.9,13 Both 10,11-dimethyl- and
-diethyl-substituted trityl perchlorates, 9b and 10a, effectively
catalyze the aldol reaction leading to 11 in >92% yields with
a similar magnitude of enantiocontrol. However, a complete
reversal in the sense of asymmetric induction was observed
(entries 2 and 5).14,15 Trityl salts containing the 4-tert-
butylphenyl group uniformly led to higher enantioselectivities
as compared with the parent (Ar ) Ph) analogs (entries 3, 7,
and 8). It should be pointed out that gradual decoloration of
triarylcarbenium ions was observed in most instances. However,
upon addition of extra SKA, the aldol reaction still proceeded
with prolonged reaction time (6 h) (entries 3-5). The chemical
yield was increased by 47% (from 52% to 99%) with a
concomitant drop in the enantiomeric excess of 11 to half of
its original value (from 24% to 11%). These results indicate
that trityl ions were gradually consumed presumably due to slow
Supporting Information Available: Preparation and full spectro-
scopic characterization of 2-6, 7a-c, 8b-c, 9b, 10a, and 11-13 (23
pages). See any current masthead page for ordering and Internet access
instructions.
(12) Stoochnoff, B. A.; Benoiton, N. L. Tetrahedron Lett. 1973, 21.
(13) For selected R3SiOTf-mediated aldols: (a) Mukai, C.; Hashizume,
S.; Nagami, K.; Hanaoka, M. Chem. Pharm. Bull. 1990, 38, 1509. (b)
Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44, 4259.
(14) The absolute configuration of the â-hydroxy ester 11 was determined
by comparison of the optical rotation of the corresponding acid with the
literature value. Boaz, N. W. J. Org. Chem. 1992, 57, 4289.
(15) X-ray crystallographic analysis of 7c shows highly inhomogeneous
packing of both conformers (unpublished results). This unexpected opposite
sense of asymmetric induction may be attributed to a facile equilibration
between two trityl ion conformations with the 10,11-dimethyl substituents
diaxially and diequatorially disposed. See also: Vedejs, E.; Erdman, D.
E.; Powell, D. R. J. Org. Chem. 1993, 58, 2840.
JA970900O
(16) (a) We surmise that the attack of silyl ketene acetal at the para
position of the phenyl group in trityl ions 9b and 10a may be responsible
for their gradual consumption.16b This presumption can explain the uniformly
better performance observed with the 4-tert-butylphenyl analogs. (b) Zaugg,
H. E.; Michaels, R. J.; Baker, E. J. J. Am. Chem. Soc. 1968, 90, 1800.
(17) C-Tritylation of silyl enol ethers with trityl chloride in the presence
of Lewis acids has been documented, see: Reetz, M. T.; Stephan, W. Liebigs
Ann. Chem. 1980, 4, 533.