Reductive lithiation of methyl substituted diarylmethylsilanes: Application to silanediol peptide precursors

Article abstract of DOI:10.1021/ol102968g

Reductive lithiation of methyl-substituted diarylmethylsilanes using lithium naphthalenide represents a practical method for the preparation of the corresponding silyl lithium reagents. Their addition to chiral sulfinimines affords versatile precursors to

Full text of DOI:10.1021/ol102968g

ORGANIC
LETTERS
2011
Vol. 13, No. 4
732–735
Reductive Lithiation of Methyl Substituted
Diarylmethylsilanes: Application to
Silanediol Peptide Precursors
ꢀ
Dacil Hernandez, Rasmus Mose, and Troels Skrydstrup*
ꢀ
Center for Protein Structures, Department of Chemistry and Interdisciplinary
Nanoscience Center, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
Received December 8, 2010
ABSTRACT
Reductive lithiation of methyl-substituted diarylmethylsilanes using lithium naphthalenide represents a practical method for the preparation of the
corresponding silyl lithium reagents. Their addition to chiral sulfinimines affords versatile precursors to silanols and silanediols. The replacement
of the currently used diphenylsilane motif by a more labile diarylsilane moiety allows the selective hydrolysis of one or two aryl groups by
treatment with TFA.
Lithiosilanes play a valuable role as silicon transfer
reagents in organic and organometallic chemistry.1 In
organic synthesis, they have been used principally for the
nucleophilic introduction of protecting groups2 and also to
attach silyl groups to carbon as control elements for the
regio- and stereoselectivity in the synthesis of complex
molecules.3 The discovery of biologically active silicon-
containing structures in the quest for drug development
has increased the use of silylllithium reagents for the
incorporation of silicon in organic compounds.4
Sieburth and co-workers in 1998,5 as a new mimic of the
tetrahedral intermediate in peptide hydrolysis (Scheme 1).
The same group demonstrated that a range of these
silanediol isosteres displayed high inhibitory activities
against both aspartic and metalloproteases.5b,d,f
In previous work,6 we have reported an efficient ap-
proach to silanediol peptide mimics, which involves the
(5) (a) Sieburth, S. M.; Nittoli, T.; Mutahi, A. M.; Guo, L. Angew.
Chem., Int. Ed. 1998, 37, 812. (b) Chen, C.-A.; Sieburth, S. M.; Glekas,
A.; Hewitt, G. W.; Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.;
Cordova, B.; Jeffry, S.; Klabe, R. M. Chem. Biol. 2001, 8, 1161. (c)
Mutahi, M. W.; Nittoli, T.; Guo, L.; Sieburth, S. M. J. Am. Chem. Soc.
2002, 124, 7363. (d) Kim, J.; Glekas, A.; Sieburth, S. M. Bioorg. Med.
Chem. Lett. 2002, 12, 3625. (e) Kim, J.; Sieburth, S. M. J. Org. Chem.
2004, 69, 3008. (f) Kim, J.; Sieburth, S. M. Bioorg. Med. Chem. Lett.
2004, 14, 2853. (g) Kim, J.; Hewitt, G.; Carroll, P.; Sieburth, S. M.
J. Org. Chem. 2005, 70, 5781. (h) Juers, D. H.; Kim, J.; Matthews, B. W.;
Sieburth, S. M. Biochemistry 2005, 44, 16524. (i) Sieburth, S. M.; Chen,
C.-A. Eur. J. Org. Chem. 2006, 311.
One of the most recent and notable examples of silicon in
bioactive molecules is the silanediol group, introduced by
(1) (a) Tamao, K; Kawachi, A. Adv. Organomet. Chem. 1995, 38, 1.
(b) Lickiss, P. D.; Smith, C. M. Coord. Chem. Rev. 1995, 145, 75. (c)
Sekiguchi, A.; Lee, V. Y.; Nanjo, M. Coord. Chem. Rev. 2000, 210, 11. (d)
Uhlig, W. J. Organomet. Chem. 2003, 685, 70.
(2) (a) Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1. (b) Jones,
G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
(3) (a) George, M. V.; Peterson, D. J.; Gilman, H. J. Am. Chem. Soc.
1960, 82, 403. (b) Fleming, I.; Barbero, A.; Walker, D. Chem. Rev. 1997,
97, 2063. (c) Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 123, 1872.
(4) (a) Organ, M. G.; Buon, C.; Decicco, C. P.; Combs, A. P. Org.
Lett. 2002, 4, 2683. (b) Ballweg, D. M.; Miller, R. C.; Gray, D. L.;
Scheidt, K. A. Org. Lett. 2005, 7, 1403.
(6) (a) Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup,
T. J. Org. Chem. 2007, 72, 10035. (b) Nielsen, L.; Skrydstrup, T. J. Am.
ꢀ
Chem. Soc. 2008, 130, 13145. (c) Hernandez, D.; Lindsay, K. B.;
Nielsen, L.; Mittag, T.; Bjerglund, K.; Friis, S.; Mose, R.; Skrydstrup,
ꢀ
T. J. Org. Chem. 2010, 75, 3283. (d) Hernandez, D.; Nielsen, L.;
ꢀ
Lindsay, K. B.; Lopez-Garcıa, M. A.; Bjerglund, K.; Skrydstrup, T.
Org. Lett. 2010, 12, 3528.
r
10.1021/ol102968g
Published on Web 01/19/2011
2011 American Chemical Society

Table 1. Preparation of Diarylmethylsilanesa
Scheme 1. Silanediols Mimic the Tetrahedral Intermediate in
Peptide Hydrolysis
addition of alkyldiphenylsilyl lithium reagents to Ellman’s
sulfinimines as the key step(Scheme 2). This stereoselective
synthesis allows for both N- and C-terminus peptide
extension. Nevertheless, an important limitation of this
strategy is the final removal of the two phenyl groups to
unmask the silanediol. The diphenylsilyl motif has the
advantage of being stable toward a broad range of chemi-
cal transformations; however, its transformation to the
diol requires the initial use of a strong acid, usually TfOH,
not compatible with sensitive funcionalities present in
complex systems. We therefore set out to search for
modified precursors of silanediols to facilitate C-Si bond
cleavage with a milder acid thereby extending the scope of
the synthesis to other silanediol peptide mimics.
a ArMgX (2.1 equiv), THF, 0 °C, 18 h. b Isolated yields after column
chromatography on silica gel using pentane as solvent.
Scheme 2
these conditions diphenyl(methyl)silane afforded the dis-
ilane 17 in 80% yield (Table 2, entry 7). However, the
majority of the substituted diarylsilanes showed no reac-
tivity (5,7 6,7 8,7 and 9), and only in the case of the di(o-
tolyl)silane could the disilane be isolated in a 25% yield.
Diarylsilane 7 decomposed under the reaction conditions.
These results were not surprising. It has previously been
reported that substitution of the aromatic ring is not well
tolerated in lithiations of silyl chlorides, even though the
exact role of the phenyl substituents is not understood. It
has been proposed that they stabilize the negative charge
on silicon through π polarization,8 but this appears not to
be the only effect. Silanes containing a p-tolyl, p-biphenyl,
or p-methoxyphenyl group render the symmetric diarylte-
tramethyldisilane noncleavable by lithium,9 whereas p-
methoxyphenylchlorodimethylsilane does not react with
Li to form the disilane.8 Tri-o-tolylsilyl lithium10 and
mesityldimethylsilyl lithium11 are two exceptions to this
reactivity because the steric hindrance of these silanes
Herein, we report our results examining methyl substi-
tuted diarylmethylsilanes as alternative precursors to sila-
nediols. We have found that their lithiation using lithium
naphthalenide affords the corresponding diarylsilyl lithium
reagents that can successfully replace the currently used
diphenylsilyl lithium. The introduction of a more acid labile
diarylsilane moiety in peptide precursors facilitates the de-
protection of silanediols in acid conditions.
The desired methyl substituted diarylsilanes were easily
prepared in good to excellent yields by the addition of the
appropriate Grignard reagent to dichloro(methyl)silane
(Table 1). The diarylsilanes 47-9 were then subjected to lit-
hiation using the standard protocol with Li metal in THF.6b
All reactions were quenched with TMSCl, which allowed
us to isolate and purify the corresponding disilanes. Under
(8) (a) Lambert, J. B.; Schulz, W. J., Jr. Trivalent silyl ions. In The
Chemistry of Organic Silicon Compounds; Patai, S., Rappoport, Z., Eds.;
John Wiley & Sons: 1989; Vol. 1, Chapter 16, p 1007. (b) Tamao, K.;
Kawachi, A. Adv. Organomet. Chem. 1995, 38, 1.
(9) Rahman, N. A.; Fleming, I.; Zwicky, A. B. J. Chem. Res. (S)
1992, 292.
(10) George, M. V.; Peterson, D. J.; Gilman, H. J. Am. Chem. Soc.
1960, 82, 403.
€
(7) Weickgenannt, A.; Mewald, M.; Muesmann, T. W. T.; Oestreich,
M. Angew. Chem., Int. Ed. 2010, 49, 2223.
(11) Muller, H.; Weinzierl, U.; Seidel, W. Z. Anorg. Allg. Chem. 1991,
603, 15.
Org. Lett., Vol. 13, No. 4, 2011
733

MeSiLi, and (3,5-xylyl)2MeSiLi were successfully pre-
pared, obtaining the corresponding disilanes 12, 13, and
15 in good yields. The formation of (o-tolyl)2MeSiLi was
more problematic. During the lithiation step, the cleavage of
a tolyl-Si bond is produced to generate (o-tolyl)
MeHSiTMS after quenching with TMSCl. To avoid this
side reaction the temperature was lowered to -20 °C
affording 11 in 40% yield. The silanes 7 and 9 showed the
same reactivity observed using Li metal. The use of catalytic
amounts of LiNp was also attempted, but it required longer
reaction times giving the silyl lithium reagents in lower yields.
Table 2. Lithiation of Diarylmethylsilanes
Table 3. Addition of the Silyl Lithium Reagents to Sulfinimines
a Li (10 equiv), THF, rt, 4-24 h. b Li (10 equiv), naphthalene (1
equiv), THF, rt, 1 h; then the diarylsilane was added, and the mixture
stirred for 3-4 h. c Entry performed at -20 °C. d Starting material
recovered. e Decomposition of starting material.
a Isolated yields after column chromatography on silica gel.
prevents disilane formation. Cleavage of aryl-substituted
disilanes to form the corresponding silyl lithium has been
achieved, but only by using methyl lithium in conjunction
with the HMPA as an additive.12
These silyl lithium reagents were then examined for their
capacity to add to the chiral sulfinimines 18 and 19
following a standard procedure (Table 3).6a The corre-
sponding sulfinamides (entries 2-6) were obtained with
excellent diastereoselectivity in yields comparable with
the addition of diphenyl(methyl)silyl lithium (entry 1).6a
(o-Tolyl)2methylsilyl lithium gave the lowest yield due to
steric effects from the o-substituent on the aromatic ring
(entry 2). Treatment of sulfinimine 19 with (m-Tol)2MeSiLi
provided 23 in a similar yield (entry 4).
Sulfinimides 22,24,and25, the most promising as alternative
precursors of silanediols, were then converted to the acetamides
26-28 by removal of the chiral auxiliary via treatment with
anhydrous methanolic HCl followed by protection of the
amine with acetic anhydride and pyridine (Scheme 3).
The mechanism for the generation of the silyl lithium
reagents from silanes using Li metal involves an initial
electron transfer to the aryl group.14 The presence of
electron donating substituentswill, however, decreasetheir
propensity for reduction by Li. We therefore tested the
possibility of using a soluble reducing agent, such as lithium
naphthalenide (LiNp) or lithium 1-(dimethyl-amino)naph-
thalenide(LDMAN) previously exploitedby Kawachi and
Tamao,15 to lithiate a number of phenylsilylchlorides.
Silanes 4-9 were therefore subjected to the lithiation
procedure using LiNp (Table 2). (m-Tolyl)2MeSiLi, (p-tolyl)2
(12) Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337.
(13) Gilman, H.; Atwell, W. H.; Schwebke, G. L. J. Organomet.
Chem. 1964, 2, 369.
(14) Oestreich, M.; Auer, G.; Keller, M. Eur. J. Org. Chem. 2005, 184.
(15) Kawachi, A.; Tamao, K. Bull. Chem. Soc. Jpn. 1997, 70, 945.
Acetamides 26-28 were used to study the susceptibility
of the different methyl substituted diarylsilanes to acid
hydrolysis. Both triflic and trifluoroacetic acid were
734
Org. Lett., Vol. 13, No. 4, 2011

Trisiloxanes 29-32 displayed sufficient stability for col-
umn chromatography, and their hydrolysis with potas-
sium hydroxide in a mixture of deuterium oxide and d3-
acetonitrile afforded silanols 33-35 and silanediol 36 in
quantitative yields (Scheme 4).
Scheme 3. Removal of the Chiral Auxiliary
Scheme 4. Deprotection of Silanols and the Silanediol
examined, and the resulting silanols and silanediol were
protected with TMSCl and Et3N to obtain the trisiloxanes
as more stable precursors (Table 4). As was expected, the
aryl-silicon bonds in the three acetamides were cleaved in
the presence of TfOH leading to the protected silanediol 32
in good yields (entries 1a, 2a, and 3a). Different concentra-
tions of TFA in CH2Cl2 were then tested. The substrates 26
and 28, containing the m-tolyl or the 3,5-xylyl ring as
substituents, afforded the silanols 29 and 31 in all cases.
However, treatment of acetamide 27 with a 1:1 mixture of
TFA/CH2Cl2 followed by silylation with TMSCl provided
the protected silanediol 32. The reaction was stirred at rt
for 36 h to yield the desired compound in 80%.
In conclusion, we have reported a new approach for the
preparation of methyl substituted diarylsilyl lithium re-
agents and their utility in the synthesis of silanol and
silanediol peptide precursors. The new diarylmethylsilane
moieties fulfill all the requirements to replace the currently
used diphenylsilane: tolerance by the lithiation reaction,
diastereoselectivity during the sulfinimine addition, suffi-
cient acid stability to allow sulfinamide deprotection, and
lability by treatment with TFA. The di(p-tolyl)methylsil-
ane motif also emerges as a promising precursor for the
selective cleavage of one or both of the aryl-silane bonds.
It is intended that these results will be extended to the synth-
esis of more funtionalized silanol and silanediol containing
peptide mimics with potentially interesting biological ac-
tivity. These results will be reported in due course.
Table 4. Hydrolysis of Diarylsilanes
entry substrate
acida
product (%)b
Acknowledgment. We are deeply appreciative of gener-
ous financial support from the Danish National Research
Foundation, the Lundbeck Foundation, the Carlsberg
Foundation, and the Aarhus University. D.H. thanks the
~
Gobierno de Espana (MICINN) for a posdoctoral con-
tract (Programa Nacional de Movilidad de Recursos
1
2
3
26
27
28
(a) TfOH/CH2Cl2 (10 mL, 0.1 M) 32 (71)
(b) TFA/CH2Cl2 (2 mL, 0.5 M)
(c) TFA/CH2Cl2 (1 mL, 2.6 M)
(d) TFA/CH2Cl2 (1 mL, 6.5 M)
SM
29 (80)
29 (77)
(a) TfOH/CH2Cl2 (10 mL, 0.1 M) 32 (70)
(b) TFA/CH2Cl2 (2 mL, 0.5 M)
(c) TFA/CH2Cl2 (1 mL, 2.6 M)
(d) TFA/CH2Cl2 (1 mL, 6.5 M)
30 (79)
30 (66), 32 (10)
32 (80)
Humanos del Plan nacional de IþDþI 2008-2011).
(a) TfOH/CH2Cl2 (10 mL, 0.1 M) 32 (72)
Supporting Information Available. Experimental meth-
ods for the preparation of compounds 4-9, 11-16,
(b) TFA/CH2Cl2 (2 mL, 0.5 M)
(c) TFA/CH2Cl2 (1 mL, 2.6 M)
(d) TFA/CH2Cl2 (1 mL, 6.5 M)
31 (80)
31 (78)
1
21-36 and their characterization. Copies of H and 13
C
31 (70), 32 (5)
NMR spectra of the new compounds (7, 9, 11-16,
21-36). This material is available free of charge via the
Internet at http://pubs.acs.org.
a See Supporting Information for more details. b Isolated yields after
column chromatography on silica gel.
Org. Lett., Vol. 13, No. 4, 2011
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