J. Org. Chem. 1993, 58, 5130-5134
5130
Improved Protocols for the Selective Deprotection of Trialkylsilyl Ethers Using Fluorosilicic Acid Anthony
S.
Pilcher and Philip DeShong*
Department of Chemistry and Biochemistry, The University of Maryland, College Park, Maryland 20742 Received March 11, 1993*
Improvements for the application of aqueous fluorosilicic acid to the selective cleavage of tertbutyldimethylsilyl ethers in the presence of triisopropylsilyl ethers are described. Deprotection conditions have been optimized for cleavage selectivity, tolerance by acid-labile compounds, and cleavage rate. Mechanistic features of the desilylation reaction are discussed.
J. Org. Chem. 1993.58:5130-5134. Downloaded from pubs.acs.org by UNIV OF NEW ENGLAND on 10/03/18. For personal use only.
Introduction
ethers.6 Specifically, a TBDMS ether was deprotected in the presence of a TIPS ether (81 % selectivity7) or a tertbutyldiphenylsilyl (TBDPS) ether (100% selectivity). Presumably, fluorosilicic acid is the active cleaving reagent formed in situ by the reaction of HF with glass. To our knowledge, this is the first reagent with the general ability to effectively differentiate between a TBDMS and TIPS group in a cleavage reaction. In addition to selectivity, this reagent has additional advantages over other siliconoxygen cleaving agents. For example, unlike tetraalkylammonium or alkali fluorides or NaH,3c HgSiFe is not a threat to base-sensitive compounds. Also, fluorosilicic acid does not have the oxidizing properties of NBS2k nor the strong nucleophilic character ofNaNa.31· The deprotection reaction conditions employing HgSiFg are catalytic and, therefore, are not as acidic as those using HF2i or HCl.2i As a result, certain acid-labile moieties are retained during the deprotection. These features of the HgSiFe-based cleavage protocol indicated that it was a superior reagent for the removal of silyl ether functions. Accordingly, we believed that a thorough investigation of the scope and limitations of this hypervalent silicon reagent was warranted. In this paper, we provide three new sets of deprotection protocols which are superior to those initially reported.5 Each protocol is tailored for different experimental situations. For example, a stoichiometric amount of H2S1F6 in -BuOH is employed to obtain optimum selectivity between two different trialkylsilyl ether protecting groups. When the acid sensitivity Of other functionalities is a concern, a catalytic amount of HgSiFe in 9/1 CHgCN/t-BuOH is the reagent of choice. Finally, when selectivity is not a concern, HgSiFg in CH3CN gives the fastest cleavage while maintaining tolerance by acidsensitive groups. In addition to the discussion of reaction protocols, several mechanistic features of the cleavage reaction with fluorosilicic acid are discussed.
Silyl ethers have attained a position of prominence in the area of hydroxyl group protection due to their ease of formation and removal and their stability to a wide range of reagents and reaction conditions.* The ferf-butyldimethylsilyl (TBDMS) and triisopropylsilyl (TIPS) ethers are among the most popular protecting groups for hydroxyl functions in synthetic chemistry as they are generally readily introduced and are robust to a variety of reaction conditions. The fact that either of these two silyl ethers can be attached regioselectively1 further increases their 1
utility. One limitation of silicon-based protecting groups is that, although a variety of methods have been developed for the cleavage of the silicon-oxygen bond,2 few of these methods allow for effective differentiation between two trialkylsilyl moieties3 and none are capable of reliably differentiating between a TBDMS and a TIPS ether. Selective deprotecting agents could be applied to advantage in complex synthetic sequences in which two protected hydroxyl groups must be unmasked at different stages of a synthesis. During the course of the total synthesis of tirandamycin B, it was noted that aqueous HF solutions that had come in contact with glass were able to selectively remove a TBDMS group while in the presence of a TIPS moiety.4 Solutions of HF which had not been exposed to glass were
unreactive under identical conditions. This remarkable observation indicated that the reaction of HF and glass provided the active cleaving reagent. In subsequent experiments,5 we demonstrated that fluorosilicic acid (HgSiFe) served as a selective cleaving agent for trialkylsilyl Abstract published in Advance ACS Abstracts, August 15, 1993. (1) Lalonde, M.; Chan, T. H. Synthesis 1985, 817. (2) (a) Green, T. W.; Wuts, P. G. M. In Protective Groups in Organic Synthesis; John Wiley & Sons, Inc.: New York, 1991; pp 80-83. (b) Otera, J.; Nozaki, H. Tetrahedron Lett. 1986,27,5743. (c) Olsson, L. I. Acta Pharm. Suec. 1986, 23, 370. (d) Otera, J.; Niibo, Y.; Nozaki, H.; Chikada, S. Synthesis 1988,328. (e) Solladé-Cavallo, A.; Khiar, N. Synth. Commun. 1989, 19, 1335. (f) Bou, V.; Vilarrasa, J. Tetrahedron Lett. 1990,37,567. (g) Cort, A. D. Synth. Commun. 1990,20,757. (h) Cormier, J. F. Tetrahedron Lett. 1991,32,187. (i) Cunico, R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797. (j) Newton, R. F.; Reynolds, D. P. Tetrahedron Lett. 1979, 41, 3981. (k) Batten, R. J.; Dixon, A. J.; Taylor, R. J. K.; Newton, R. F. Synthesis 1980, 234. (3) (a) Prakash, C.; Samir, S.; Blair, I. A. Tetrahedron Lett. 1989,30, 19. (b) Monger, S. J.; Parry, D. M.; Roberts, S. M. J. Chem. Soc., Chem. Commun. 1989, 381. (c) Shekhani, M. S.; Khan, K. M.; Mahmood, K.; Shah, P. M.; Malik, S. Tetrahedron Lett. 1990, 37,1669. (d) Corey, E. J.; Yi, K. Y. Ibid. 1992, 33, 2289. (4) Shimshock, S. J.; Waltermire, R. E.; DeShong, P. J. Am. Chem. Soc. 1991, 113, 791. (5) Pilcher, A. S.; Hill, D. K.; Shimshock, S. J.; Waltermire, R. E.; DeShong, P. J. Org. Chem. 1992, 57, 2492. •
0022-3263/93/1958-5130$04.00/0
Results and Discussion The mechanism that
previously6 proposed for the
was
cleavage of silylethers using HgSiFe is outlined in Scheme I. In this mechanism, reversible loss of fluoride ion from
hexafluorosilicate dianion
1
provides
a
pentacoordinate
(6) It is probable that previous investigators have inadvertently employed solutions of aqueous fluorosilicic acid by using aqueous HF in glass vessels or transferring aqueous HF solutions in glass pipettes. In these investigations, all manipulations employed appropriate polymer containers (see Experimental Section for details). (7) Selectivity in these competitive deprotection reactions is defined as percent of the desired protected alcohol minus percent of the undesired protected alcohol. ©
1993 American Chemical Society
Deprotection of Trialkylsilyl Ethers
J. Org. Chem., Vol. 58, No. 19,1993 Table I. Deprotection Solvent Comparison % % temp time
Scheme I 1-
2H+ .fii
F
71
F
H+
l/F
-
W
•f F
HF
R-OH R-O-SiR'a
2H
*
pH"
H*
F—Si— O
_/|
F
R'jSiOH
P
\ R
'F
F'l
hF
/—OH,
,'- "* '%
HF
Scheme II
fTT
l e;
2H+
y
C4H.-0H ---
F—Si—O-C4H9 F
2
u+ H
F
6
2"
F
fTT l/F
H+
|
F—Si—O-C4H9
F)°
R-O-SiR'a
F
.Ti"
entry
solvent
(°C)
1
acetonitrile ethanol 2-propanol 2-methyl-2-propanol
0 0 0
2 3 4
23
(h) 0.17 8.0
~71 ~82
5131
%
9®
10®
selectivity7
1
70 89 89 100
69 87 89 100
1.5 0
0
“Yields determined by GC analysis (±2%); see Experimental Section for details.
ment of fluorine by another ligand in the SiLe2- complex should reduce the Lewis acidity of the silicon atom, and second, other ligands also act as competitive binders (vide supra). These two effects are expected to be equal for silyl ether substrates independent of steric bulk of the alkyl groups residing on silicon. However, any ligand that is larger than fluorine will also slow the deprotection reaction by increasing steric crowding in the octahedral ligand sphere around silicon as shown in Scheme II. This steric hindrance of an alcohólate ligand attached to the hypervalent silicon species (i.e., 6 and 7) should affect the binding of the silyl ether with bulkier substituents, leading to enhanced selectivity between TBDMS and TIPS cleavage. According to this hypothesis, using an alcohol as the solvent instead of acetonitrile would result in increased selectivity with regard to cleavage. In a competitive deprotection study between BnOTBDMS (9) andBnOTIPS (10), the use of HzSiFe in alcohols
HF
F—SÍ-O-C4H9 FZ
OTIPS
OTBDMS
7
0.42 equiv. H^iFg
R/+XSiR'3
+
5.0 mL solvent
8
silicate monoanion intermediate 2 which serves as a Lewis acid and binds the silyl ether to give hypervalent silicate derivative 3. This activates the silicon-oxygen bond of the silyl ether for cleavage. Under the aqueous acidic conditions, water attacks the silicon group of 3, resulting in formation of hexavalent silicate 4 and trialkylsilanol 5. Hydrolysis of 4 releases the alcohol and regenerates hexafluorosilicate 1. Evidence to support the mechanism outlined in Scheme 1 is that the initial product of desilylation is trialkylsilanol 5 and not the trialkylsilyl fluoride, the product anticipated from fluoride attack on anion 3.8·9 Also, addition of either additional water or alcohols such as 2-propanol and t-BuOH, which serve as Lewis bases and compete with the silyl ether for binding to silicate 2, dramatically retard the rate of desilylation under standard conditions. This mechanistic hypothesis for desilylation suggests that other potential Lewis bases present in the reaction mixture, besides the silyl ether substrate, will compete with the silyl ether for binding to fluorosilicate derivative 2 and slow the deprotection reaction rate. First, replacets) Control experiments have shown that trialkylsilanol 5 is slowly transformed to silyl fluoride as the deprotection proceeds. Under the reaction conditions, trialkylsilyl fluoride does not hydrolyze to provide silanol 5. (9) An alternative mechanism involving attack by silicate dianion 1 at the silicon of the silyl ether to produce a fluoride-bridged intermediate (see: Damrauer, R.; Simon, R. A.; Kanner, B. Organometallics 1988, 7, 1161. Corriu, R. J. P.; Perg.R.; Reye, C. Tetrahedron 1983,3,999) is not viable in this process since silyl fluoride, not silanol, would be the product
of cleavage. (10) The pH of 0.01 M solutions of HzSiFg and HF are comparable (pH 2-3).
9
10
1.0 equiv.
1.0 equiv.
led to improved selectivity for removal of TBDMS, although longer reaction times were required. In addition, selectivity and reaction time increased as the steric bulk of the alcohol increased, as anticipated by the hypothesis (vide supra). The results are summarized in Table I. As indicated in Table I, utilization of -BuOH as solvent gave complete selectivity for the removal of the TBDMS ether, but the protracted reaction time was a drawback. By increasing the quantity of H2S1F6 to 1.0 molar equiv, the reaction time was reduced to 6.3 h, while selectivity was only slightly decreased (95%). This protocol was employed to selectively deprotect bis-silyl ether 12 on a preparative scale affording a 91 % yield of alcohol 13 and demonstrating the usefulness of the method. TIPSOv
/=\ x—y
1
xotbdms
equiv. HjSIFs
R1
