Tris(2,6-diphenylbenzyl)silyl group as a new and highly effective protector for carboxylic acids: Unusual behavior of such carboxylic esters toward common nucleophiles and bases [17]

Full text of DOI:10.1021/ja001940m

10238
J. Am. Chem. Soc. 2000, 122, 10238-10239
Tris(2,6-diphenylbenzyl)silyl Group as a New and
Highly Effective Protector for Carboxylic Acids:
Unusual Behavior of Such Carboxylic Esters toward
Common Nucleophiles and Bases
Atsuko Iwasaki, Yuichiro Kondo, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science
Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Department of Chemistry, Graduate School of Science
Hokkaido UniVersity, Sapporo 060-0810, Japan
ReceiVed June 2, 2000
Carboxylic acids are found in almost all living organisms and
are certainly indispensable compounds. They also play an
important role in organic chemistry and hence are often utilized
in their protective forms for two reasons: (1) The acidic proton
of the carboxyl functional group (-COOH) can be masked by
conversion to the corresponding esters and amides. (2) The car-
bonyl group of -COOH can be protected as oxazolines and ortho
esters to prevent against nucleophilic attack and/or R-deprotona-
tion.1 However, the latter carbonyl protection has not been widely
utilized due to the troublesome functional group transformation
of multifunctional molecules.2-5 Here we report that the bowl-
shaped tris(2,6-diphenylbenzyl)silyl (TDS) group can be success-
fully utilized as a new and highly effective protector of carboxylic
acids against various nucleophilic attacks and R-deprotonation.
Figure 1. ORTEP diagram of the TDS acetate 2a.
temperature for several hours to furnish TDS esters 2 in moderate
to high yields. The primary structure of TDS acetate 2a was
determined by single-crystal X-ray diffraction analysis as shown
in Figure 1.7
The TDS esters 2 thus prepared are found to be unusually stable
toward a variety of reactive nucleophiles and bases. Indeed,
reaction of TDS propionate 2b with excess BuLi (2.5 equiv) at
-78 °C for 1 h resulted, after quenching with benzaldehyde
acceptor at -78 °C, in recovery of most (∼97%) of the starting
TDS ester 2b.8 Attempted deuteration with D2O in place of
benzaldehyde also gave the TDS ester 2b in almost quantitative
yield without any deuterium incorporation. The stability of TDS
propionate 2b toward excess BuLi (2.5 equiv) under various
reaction conditions is reported as follows: ∼93% recovery of
2b at -78 °C for 5 h; 74% recovery of 2b at -40 °C for 1.5 h;9
24% recovery of 2b at -20 °C for 1 h.10 Other alkyllithiums
(MeLi and t-BuLi), Grignard reagents (MeMgBr),11 and base
(LDA) gave similar results at -78 °C for 5 h (95-98% recovery
of the TDS ester 2b). In marked contrast, however, treatment of
the previously known bulky tert-butyldiphenylsilyl propionate (3b)
and 2,6-di-tert-butyl-4-methylphenyl propionate (4b) with BuLi
(1.2-2.5 equiv) in THF at -78 °C for 1 h and subsequent addition
of benzaldehyde at this temperature gave rise to ester cleavage
product 5 and aldol 6 (R ) CH3), respectively, as major
products.12-14 Other TDS esters, 2c and 2d, exhibited similar
unreactivity toward RLi nucleophiles at -78 °C for several hours.
However, only TDS acetate 2a is somewhat susceptible toward
The requisite TDS-Br can be conveniently synthesized from
commercially available 2-chloro-6-phenyltoluene in a four-step
sequence as shown in Scheme 1.6
Protection of a series of carboxylic acids 1 with TDS-Br can
be effected by treatment with AgOTf in CH2Cl2 at room
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley & Sons: New York, 1999; pp 372-453.
(2) Oxazoline protection: (a) Wehrmeister, H. L. J. Org. Chem. 1961, 26,
3821. (b) Haidukewych, D.; Meyers, A. I. Tetrahedron Lett. 1972, 3031. (c)
Vorbru¨ggen, H.; Krolikiewicz, K. Tetrahedron Lett. 1981, 22, 4471. (d) Schow,
S. R.; Bloom, J. D.; Thompson, A. S.; Winzenberg, K. N.; Smith, A. B., III.
J. Am. Chem. Soc. 1986, 108, 2662. (e) Kashima, C.; Arao, H. Synthesis 1989,
873.
(3) Oxazole protection: Wasserman, H. H.; McCarthy, K. E.; Prowse, K.
S. Chem. ReV. 1986, 86, 845.
(4) Oxazolidine protection: (a) Seebach, D.; Fadel, A. HelV. Chim. Acta
1985, 68, 1243. (b) Burger, K.; Rudolph, M.; Fehn, S. Angew. Chem., Int.
Ed. Engl. 1993, 32, 285. (c) Walter, M. W.; Adlington, R. M.; Baldwin, J.
E.; Chuhan, J.; Schofield, C. J. Tetrahedron Lett. 1995, 36, 7761. (d) Burger,
K.; Windeisen, E.; Pires, R. J. Org. Chem. 1995, 60, 7641. (e) Paleo, M. R.;
Sardina, F. J. Tetrahedron Lett. 1996, 37, 3403.
(5) Ortho ester protection: (a) DeWolfe, R. H. Synthesis 1974, 153. (b)
Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571. (c) Voss, G.; Gerlach,
H. HelV. Chim. Acta 1983, 66, 2294. (d) Wakamatsu, T.; Hara, H.; Ban, Y.
J. Org. Chem. 1985, 50, 108. (e) White, J. D.; Kuo, S.-c.; Vedananda, T. R.
Tetrahedron Lett. 1987, 28, 3061. (f) Waldmu¨ller, D.; Braun, M.; Steigel, A.
Synlett 1991, 160. (g) Smith, A. B., III; Leahy, J. W.; Noda, I.; Remiszewski,
S. W.; Liverton, N. J.; Zibuck, R. J. Am. Chem. Soc. 1992, 114, 2995. (h)
Zager, C.; Scharf, H. D. Liebigs Ann. Chem. 1993, 447. (i) Vasudevan, S.;
Watt, D. S. J. Org. Chem. 1994, 59, 361. (j) Nicolaou, K. C.; Theodorakis,
E. A.; Rutjes, F. P. J. T.; Sato, M.; Tiebes, J.; Xiao, X.-Y.; Hwang, C.-K.;
Duggan, M. E.; Yang, Z.; Couladouros, E. A.; Sato, F.; Shin, J.; He, H.-M.;
Bleckman, T. J. Am. Chem. Soc. 1995, 117, 10239. (k) Charette, A. B.; Chua,
P. Tetrahedron Lett. 1997, 38, 8499. (l) Wipf, P.; Xu, W.; Kim, H.; Takahashi,
H. Tetrahedron 1997, 53, 16575.
(7) The single crystal of 2a was obtained by recrystallization from
dichloromethane/hexane solvents. Crystal structure data for 2a: C59H48O2Si,
Mw ) 817.10, triclinic, space group P1h, a ) 13.6993 Å, b ) 30.9205 Å, c )
12.2388 Å, V ) 4691.1 Å3, Z ) 2, Dcalcd ) 1.217 g cm-1, R1 ) 0.222.
(8) The butylation product of benzaldehyde, 1-phenyl-1-pentanol, was
obtained in 91% yield.
(9) Quenching of this solution with benzaldehyde (2.5 equiv) gave erythro-
aldol product (16%) and TDS-OH (5%). This result indicates 16% of
R-deprotonation and 5% of ester cleavage.
(10) Ester cleavage product, TDS-OH (73%) without R-deprotonation.
(11) Attempted reaction of 2b in THF with MeMgBr (2.5 equiv) in ether
at room temperature for 5 h resulted in recovery of most of the 2b (∼98%).
(6) Weber, W. P. Silicon Reagents for Organic Synthesis; Springer-
Verlag: Berlin, 1983.
10.1021/ja001940m CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/28/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 10239
Scheme 1a
a Conditions: (a) catalytic NiCl2(dppe) (5 mol %), PhMgBr; (b) catalytic (PhCO2)2 (5 mol %), NBS; (c) Mg, HSiCl3; (d) Br2.
R-deprotonation with RLi to furnish an aldol product upon
reaction with benzaldehyde.15
Figure 2. Space-filling model of the TDS acetate 2a.
Scheme 2a
a Conditions: (a) AcOH/THF/H2O (4:2:1), 40 °C, 4 h; (b) LiAlH4 (3
The high shielding effect of the bowl-shaped TDS moiety
equiv)/THF, 0 °C, 0.5 h and 25 °C, 5 h; (c) KOBut (10 equiv)/DMSO,
toward carboxyl and even R-protons was also verified by carrying
25 °C, 1 h; (d) Py‚HF/THF (1:2), 50 °C, 5 h; (e) DIBAH (5 equiv),
out a 1H NMR spectral study of TDS caproate 2c in CDCl3, where
toluene, 0 °C, 0.5 h; (f) 1 N HCl/THF (1:10), 40 °C, 4 h; (g) aqueous
the upfield shift of pentyl protons in 2c compared to other caproyl
NaOH/EtOH/THF (1:1:2), 50 °C, 5 h.
analogues, 3c and 4c, is clearly observed.
carboxyl moiety for shielding against nucleophilic attack and
1
R-deprotonation. This inference is in accord with the H NMR
data on the upfield shift of ester protons in TDS caproate 2c.
The functional group susceptibility of the TDS esters 2 for
various acidic and basic conditions is summarized in Scheme 2.
Under certain deprotection conditions, the TDS esters 2 can be
conveniently cleaved to the corresponding carboxylic acids 1 and
alcohols, as exemplified by conversion of TDS ester 2d to acid
1 (R ) (CH2)3Ph) with KOBut in DMSO (or Py‚HF in THF)16
and Ph(CH2)4OH with DIBAH in CH2Cl2.1
Based on the X-ray data, a space-filling model of the TDS
acetate 2a is depicted in Figure 2, suggesting the existence of an
appropriate molecular pocket around acetyl protons as well as
Acknowledgment: We thank Mr. Hazumi Nomura for performing
the X-ray analysis of TDS acetate 2a.
(12) Lipshutz, B. H. Tetrahedron Lett. 1983, 24, 127.
(13) Haner, R.; Laube, T.; Seebach, D. J. Am. Chem. Soc. 1985, 107, 5396.
(14) Reaction of 2,6-di-tert-butyl-4-methylphenyl propionate (4b) with BuLi
(1.2-2.5 equiv) in THF at -78 °C for 1 h and quenching with D2O at this
temperature gave 2,6-di-tert-butyl-4-methylphenyl R-deuteriopropionate in
98% yield.
(15) For example, reaction of TDS acetate 2a in THF with BuLi (1.5 equiv)
in hexane at -78 °C for 2 h and subsequent treatment with PhCHO (1.5 equiv)
at -78 °C for 30 min gave aldol product in 48% yield with 46% recovery of
2a.
Supporting Information Available: Representative experimental
procedure as well as spectroscopic characterization of all new compounds
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
JA001940M
(16) Tris(2,6-diphenylbenzyl)silyl fluoride (TDS-F) was also isolated in
99% yield.