Further studies toward the stereocontrolled synthesis of silicon-containing peptide mimics

Article abstract of DOI:10.1021/jo100301n

Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant silanediol dipeptide mimics are also described. This includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide.

Full text of DOI:10.1021/jo100301n

pubs.acs.org/joc
Further Studies toward the Stereocontrolled Synthesis of
Silicon-Containing Peptide Mimics
ꢀ
Dacil Hernandez, Karl B. Lindsay, Lone Nielsen, Tina Mittag, Klaus Bjerglund, Stig Friis,
ꢀ
Rasmus Mose, and Troels Skrydstrup*
Center for Insoluble Protein Structures, Department of Chemistry and Interdisciplinary Nanoscience Center,
Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
Received February 17, 2010
Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines
and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based
protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically
encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate
and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic
methodology for accessing biologically relevant silanediol dipeptide mimics are also described. This
includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a
diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide.
Introduction
metalloprotease ACE (Figure 2).3 This compound is an analo-
gue of an N-acylated Phe-Ala-Pro tripeptide, in which the
Phe-Ala peptide bond is replaced by a silanediolmethylene
moiety. Silanediol inhibitors of the HIV protease 4,4 an aspartyl
protease, and thermolysin 6,5 a metalloprotease, have also been
prepared (Figure 2). All three silanediol inhibitors were desig-
ned as analogues of known protease inhibitors containing
different TI-mimicking motifs, namely, ketomethylene (1),
phosphinate (3), and hydroxyethylene (5). The silanediol ana-
logues demonstrated Ki values comparable to those of their
parent compounds. The mode of binding was recently con-
firmed by a crystal structure of a silanediol inhibitor 3 in the
active site of the metalloprotease thermolysin.6
The silanediol peptide inhibitor 7, which targets the human
neutrophil elastase (HNE), a serine protease, has also been
reported.7 It is not obvious how the silanediol mimics the TI of
serine protease hydrolysis, but some interaction with the active
site serine is likely to occur. The oxy-anion hole comprises
hydrogen bond donors, for example, amides in the peptide
Silicon represents an important option for the isosteric
replacement of carbon in the quest for discovery and impro-
vement of bioactive compounds.1 In particular its size and
tetrahedral nature give it all the important features of a
carbon atom, but with some differences. For example a Si-C
bond is slightly longer than a C-C bond,1g and the forma-
tion of double bonds at a silicon atom is strongly disfavored
as a result of poor p-orbital overlap.1f,k,m In stark contrast to
the hydrated carbonyl (geminal diol), silicon diols do not
form the corresponding silicones via the elimination of
water. In fact, this aversion to sp2 hybridization has been
cleverly exploited by the Sieburth group for the preparation
of several protease inhibitors containing silicon diols, which
exert their effect by behaving as admirable mimics for the
tetrahedral intermediate in peptide hydrolysis (Figure 1).2
The proof of concept was achieved with a series of silanediol
peptide mimics such as 2 prepared as an inhibitor of the
DOI: 10.1021/jo100301n
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Published on Web 04/27/2010
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2010 American Chemical Society

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FIGURE 1. Silanediol-based isosteres mimic the tetrahedral inter-
mediate (TI) in peptide hydrolysis.
backbone, which contribute to stabilizing the oxygen anion,8
and these may similarly engage in hydrogen bonding to the
silanediol unit.
All silanediol-based inhibitors are functionalized mole-
cules, which mimic a dipeptide unit. The key step in all
syntheses of a silanediol peptide mimic is the introduction
of the two functionalized alkyl substituents at silicon, which
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Martinez, J.; Sagan, S. J. Pept. Res. 2004, 63, 290. (k) Wiberg, N.; Vasisht,
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J.; Bienz, S. Helv. Chim. Acta 2004, 87, 1681. (m) Sekiguchi, A.; Kinjo, R.;
Ichinohe, M. Science 2004, 305, 1755. (n) Liu, G.; Sieburth, S. M. Org. Lett.
2005, 7, 665. (o) Englebienne, P.; Van Hoonacker, A.; Herst, C. V. Drug Design
Rev.-Online 2005, 2, 467. (p) Ilg, R.; Burschka, C.; Schepmann, D.; W€unsch, B.;
Tacke, R. Organometallics 2006, 25, 5396. (q) Grossman, S. A.; Carson, K. A.;
Phuphanich, S.; Batchelor, T.; Peereboom, D.; Nabors, L. B.; Lesser, G.;
Hausheer, F.; Supko, J. G. Neuro-Oncol. 2008, 10, 608. (r) Tacke, R.; Popp, F.;
M€uller, B.; Theis, B.; Burschka, C.; Hamacher, A.; Kassack, M. U.; Schepmann,
D.; W€unsch, B.; Jurva, U.; Wellner, E. ChemMedChem 2008, 3, 152. (s) Cavelier,
F.; Marchand, D.; Martinez, J. Chem. Biodiversity 2008, 5, 1279. (t) Mortensen,
M.; Husmann, R.; Veri, E.; Bolm, C. Chem. Soc. Rev. 2009, 38, 1002. (u) Daud,
A. I.; Dawson, J.; DeConti, R. C.; Bicaku, E.; Marchion, D.; Bastien, S.; Hausheer,
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15, 2479.
FIGURE 2. Silanediol-based protease inhibitors.
typically requires two separate steps. Furthermore and de-
pending on the amino acid composition of the dipeptide, in
most cases the syntheses would also need to be sufficiently
flexible for the installment of two stereogenic carbon centers
in the R- and β-position to the silicon center, which increases
the complexity of the synthetic route to these compounds.
The first syntheses of the silanediol-based protease inhibitors
reported by Sieburth and co-workers involved nucleophilic
substitution of halosilanes as the means to construct the
carbon-silicon bonds.3f,g This strategy was successfully ap-
plied to the synthesis of nine inhibitors against three different
proteases, but the synthetic routes followed were mainly de-
signed for the specific peptide needed. Later, another procedure
for the synthesis of silanediol peptide mimics was proposed
(Scheme 1).9 This synthesis utilizes a platinum-catalyzed hy-
drosilylation of an olefin directly followed by lithiation and
(2) For some examples of peptide isosteres, see: (a) Wipf, P.; Fritch, P. C.
J. Org. Chem. 1994, 59, 4875. (b) Leftheris, K.; Kline, T.; Vite, G. D.; Cho,
Y. H.; Bhide, R. S.; Patel, D. V.; Patel, M. M.; Schmidt, R. J.; Weller, H. N.;
Andahazy, M. L.; Carboni, J. M.; Gullo-Brown, J. L.; Lee, F. Y. F.; Ricca,
C.; Rose, W. C.; Yan, N.; Barbacid, M.; Hunt, J. T.; Meyers, C. A.; Seizinger,
B. R.; Zahler, R.; Manne, V. J. Med. Chem. 1996, 39, 224. (c) Deziel, R.;
Plante, R.; Caron, V.; Grenier, L.; Llinas-Brunet, M.; Duceppe, J.-S.;
Malenfant, E.; Moss, N. J. Org. Chem. 1996, 61, 2901. (d) Tao, J.; Hoffman,
R. V. J. Org. Chem. 1997, 62, 6240. (e) Wipf, P.; Henninger, T. C. J. Org.
Chem. 1997, 62, 1586. (f) Hoffman, R. V.; Tao, J. Tetrahedron 1997, 53, 7119.
(g) Wipf, P.; Henninger, T. C.; Geib, S. J. J. Org. Chem. 1998, 63, 6088. (h)
Benedetti, F.; Magnan, M.; Miertus, S.; Norbedo, S.; Parat, D.; Tossi, A.
Bioorg. Med. Chem. Lett. 1999, 9, 3027. (i) Steinmetzer, T.; Zhu, B. Y.;
Konishi, Y. J. Med. Chem. 1999, 42, 3109. (j) Righi, G.; Ronconi, S.; Bonini,
C. Eur. J. Org. Chem. 2002, 1573. (k) Datta, A.; Veeresa, G. J. Org. Chem.
2000, 65, 7609. (l) Benedetti, F.; Berti, F.; Norbedo, S. J. Org. Chem. 2002, 67,
8635. (m) Oishi, S.; Kamano, T.; Niida, A.; Odagaki, Y.; Hamanaka, N.;
Yamamoto, M.; Ajito, K.; Tamamura, H.; Otaka, A.; Fujii, N. J. Org. Chem.
2002, 67, 6162. (n) Theberge, C. R.; Zercher, C. K. Tetrahedron 2003, 59,
1521. (o) Akaji, K.; Teruya, K.; Aimoto, S. J. Org. Chem. 2003, 68, 4755. (p)
Tamamura, H.; Kato, T.; Otaka, A.; Fujii, N. Org. Biomol. Chem. 2003, 1,
2468. (q) Hom, R. K.; Gailunas, A. F.; Mamo, S.; Fang, L. Y.; Tung, J. S.;
Walker, D. E.; Davis, D.; Thorsett, E. D.; Jewett, N. E.; Moon, J. B.; John, V.
J. Med. Chem. 2004, 47, 158. (r) Garbe, D.; Sieber, S. A.; Bandur, N. G.;
Koert, U.; Marahiel, M. A. ChemBioChem 2004, 5, 1000. (s) Niida, A.;
Tomita, K.; Mizumoto, M.; Tanigaki, H.; Terada, T.; Oishi, S.; Otaka, A.;
Inui, K.-i.; Fujii, N. Org. Lett. 2006, 8, 613.
(3) (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.;
Sieburth, S. M. Bioorg. Med. Chem. Lett. 2004, 14, 2853. (e) Kim, J.; Hewitt,
G.; Carroll, P.; Sieburth, S. M. J. Org. Chem. 2005, 70, 5781. (f) Sieburth,
S. M.; Chen, C.-A. Eur. J. Org. Chem. 2006, 311.
(4) 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.
(5) (a) Kim, J.; Glekas, A.; Sieburth, S. M. Bioorg. Med. Chem. Lett. 2002,
12, 3625. (b) Kim, J.; Sieburth, S. M. J. Org. Chem. 2004, 69, 3008.
(6) Juers, D. H.; Kim, J.; Matthews, B. W.; Sieburth, S. M. Biochemistry
2005, 44, 16524.
(7) (a) Mills, J. S.; Showell, G. A. Expert Opin. Invest. Drugs 2004, 13,
1149. (b) Showell, G. A.; Montana, J. G.; Chadwick, J. A.; Higgs, C.; Hunt, H. J.;
MacKenzie, R. E.; Price, S.; Wilkinson, T. J. Silicon diols, effective inhibitors of
human leukocyte elastase. Organosilicon Chemistry VI: From Molecules to
Materials; Wiley-VCH: Weinheim, 2005; pp 569-574.
(8) Berg, J.; Tymoczko, J.; Stryer, L. Biochemistry, 5th ed.; W. H. Free-
man and Company: New York, 2002.
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4, 2683.
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SCHEME 1. An Alternative Synthetic Strategy toward Silanediol Peptide Mimics
SCHEME 2. Preparation of β-Silyl Acid Precursor Useful in
Silanediol Peptide Mimics Synthesis
SCHEME 3. Previous Additions of Ph2CH3SiLi to Chiral
Sulfinimines
addition to an N-silylimine. In two steps, this provides the
silane; however, no substituent is present in the position β to the
silicon, and no asymmetric control at the R-center is under-
taken. Nevertheless, construction of the central silicon carbon
framework and simultaneous introduction of the primary
amine is achieved in two steps, which make this synthetic
approach attractive.
Recently, Sieburth reported a second and elegant synthetic
approach toward silanediol peptide mimics focused on the
preparation of β-silyl carboxylic acid precursors. This ap-
proach applied a magnesium-mediated cyclization of a di-
chlorodiphenylsilane and a diene to yield a 2,5-dihydrosilole
(Scheme 2). Hydroboration followed by hydrofluoric acid
promoted ring opening gave the fluorosilane, and further
functionalization was accomplished through nucleophilic
displacement of the fluoride or by converting the fluorosi-
lane into its corresponding silyl lithium reagent and addi-
tion to an electrophile. The alkene was envisaged cleaved
under oxidative conditions to give a β-silyl carboxylic acid,
and application of the homochiral borane Ipc-BH2 yielded
enantiopure material.10
bond. Although this approach proved to be a potentially
viable route to this new class of protease inhibitors, extension
of the C-terminus to provide the true silanediol peptide
mimics was not undertaken.
Herein, we report our results directed at extending the
scope of the synthesis of silanediol peptide mimics. Our
recent focus has been placed on facilitating synthetic access
to more complex amino acid mimics possessing functiona-
lized/reactive side chains while also allowing for both N- and
C-terminus end peptide extensions.
We have previously disclosed the synthesis of simple
C-terminal silanediol peptide mimics, via the coupling of a
diphenylsilyl lithium reagent with an appropriate Ellman
sulfinimine (Scheme 3).11a This allowed us to mimic the
simple amino acids with aliphatic and aromatic side chains
and extend the peptide chain at the N-terminus. However
more complex amino acid side chains were not included in
that study. In a subsequent report, we developed a method
for the two-step assembly of the carbon-silicon backbone of
the dipeptide mimic including a hydrosilylation of terminal
alkenes with diphenylsilane for the formation of the first
C-Si bond, followed by lithiation of the resulting hydrido-
silane and a highly diastereoselective addition to an optically
active tert-butanesulfinimine, to generate the second C-Si
Results and Discussion
Synthesis of New Amino Acid Mimics. To expand upon the
library of available diphenyl silane building blocks for incor-
poration into peptide synthesis, initial focus was placed upon
preparation of methyldiphenylsilanes substituted with the 20
side chains of genetically encoded amino acids. From our
previous study we had demonstrated that rapid access to
simple mimics could be achieved directly for those com-
pounds containing unreactive side chains such as aliphatic
and aromatic groups. Thus the mimics of alanine (8), valine
(9), phenylalanine (10), and leucine (11) were readily avail-
able (Scheme 3).11a Furthermore, we had also demonstrated
that protected alcohols, and doubly protected amines were
well tolerated in the coupling reaction.
(10) Sen, S.; Purushotham, M.; Qi, Y.; Sieburth, S. M. Org. Lett. 2007, 9,
4963.
(11) (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.
Using the same protocol as earlier published,11a involving
lithiation of the silyl chloride with lithium metal in THF at
room temperature followed by its addition to a cold ethereal
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solution of the sulfinimine, we have found that the protected
versions of serine (13), tyrosine (15), and threonine (17) can
also be directly prepared from the diphenylmethylsilyl
lithium addition to sulfinimines 12, 14, and 16, respectively,
in satisfactory to good yields (Scheme 4).
carbamate 19, which is more practical in terms of peptide
synthesis. Further manipulation of 19 by transformation of the
alcohol into the corresponding mesylate 20 and then treatment
with NaN3 supplied the azide 21, which for the purposes of
peptide synthesis can also be thought of as a protected amine.
Finally, liberation of the free amine from the azide 21 was
readily achieved with Pearlman’s catalyst under a hydrogen
atmosphere.
Because of the strongly basic conditions encountered
during the silyl lithium coupling reaction, it was deemed
prudent to introduce more reactive amino acid side chains
after the addition. While we have previously demonstrated
that doubly protected amines can be employed in the cou-
pling reaction with the diphenylmethylsilyl lithium reagent,
we have found it more practical to introduce the nitrogen
functionality after the coupling reaction, via the correspond-
ing protected alcohol (Scheme 5). This is due in part to the
presence of rotamers of doubly protected nitrogen groups
complicating the spectra, which makes it problematic to
determine the diastereoselectivity of the addition reaction.
Furthermore, the additional handling of the protection
groups made this approach longer and lower-yielding.
Hence, we endeavored to introduce nitrogen functionality
after the addition reaction.
To access additional amino acid analogues representing pro-
line and arginine as depicted in Scheme 7, we started with the
previously reported addition product 23.11a Oxidative removal
of the PMB group, hydrolysis of the sulfinamide 23, and repro-
tection as the carbamate then afforded the free alcohol 25, which
was converted to the corresponding mesylate 26 using standard
methods. When mesylate 26 was treated with NaH, it cyclized
rapidly providing the proline mimic 27 in excellent yield. Sub-
jection of the same mesylate 26 to NaN3 in DMF gave the
corresponding azide 28, which could easily be reduced to afford
the free amine 29. Conversion of amine 29 into the arginine
mimic 30 was then obtained by treatment with N,N0-di-Boc-N00-
triflylguanidine, which produced the desired side chain in exce-
llent overall yield. This example demonstrates that the p-meth-
oxybenzyl group (PMB) may also be used and can be selectively
removed without affecting the acid labile sulfinamide, though
global deprotection can also be accomplished if necessary.
In a similar approach, oxidation of the side chain alcohol
in 33 could be accomplished by applying Jones’ reagent
(Scheme 8). This gave direct access to the mimic of aspartic
acid 34, which could also be converted to the asparagine
mimic 35 by treatment with pivaloyl chloride followed by
gaseous ammonia. Unfortunately, attempts to promote the
same sequence starting from the alcohol 25 to access the
corresponding glutamic acid and glutamine analogues was
not successful. This was ascribed to the possibility for
cyclization of the intermediate aminoaldehyde to the corre-
sponding five-membered ring hemiaminal.
To generate the silicon analogue of the amino acid lysine, we
started from the addition product 18 (Scheme 6) obtained in a
79% yield (see Experimental Section). Deprotection of the
alcohol and the sulfinamide auxiliary was readily achieved,
followed by reprotection of the amine as its corresponding Boc
SCHEME 4. Synthesis of Serine, Tyrosine, and Threonine
Mimics
C-Terminal End Extension. With an extended armory of
amino acid side chains available, we next turned our atten-
tion toward extension of the C-terminus. We have previously
reported the use of functionalized diphenylhydridosilanes in
coupling reactions applying a protocol involving direct
lithiation of the silane and addition to the sulfinimine,11b
and it was felt that this approach would serve well here. One
substrate (38) in particular drew our attention, as this
represented the three-carbon fragment required for the pre-
paration of the glycine mimic at the C-terminus, requiring a
mere deprotection and oxidation of the alcohol moiety up to
the corresponding acid. Thus silanediol mimics of the
Xaa-Gly peptide bond were expected to be prepared
(Scheme 9).
SCHEME 5. Modification of the Amino Acid Side Chains after
the Coupling Reaction
SCHEME 6. Introduction of Nitrogen into the Amino Acid Chain; Synthesis of a Lysine Building Block
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SCHEME 7. Preparation of Proline and Arginine Mimics
SCHEME 8. Preparation of Aspartate and Asparagine Mimics
and a byproduct. To circumvent possible issues regarding
isolation of the polar carboxylic acid, the crude product was
subjected to EDC-promoted peptide coupling with tert-butyl
glycinate (Scheme 10).
Purification gave the expected dipeptide analogue 42 in
58% yield, and the byproduct was identified as azasilinanone
43, isolated in a 17% yield. This byproduct may be formed by
initial oxidation of the alcohol to an aldehyde and cyclization
to give a hemiaminal. Oxidation will then lead to the lactam.
It was not clear to us whether the hemiaminal formation
occurred because of the strongly acidic conditions or because
the hydration and oxidation of the aldehyde was too slow.
One way to perform oxidations under mild conditions is by
the use of nitroxyl radicals such as TEMPO. The oxidative
species in this reaction is the corresponding oxoammonium
salt, which can either be prepared in advance or generated in
situ by use of a primary oxidant. The latter allows the use of
catalytic amounts of TEMPO. The oxidation is sufficiently
mild to afford aldehydes from primary alcohols, but specific
reaction conditions, particularly use of water as a cosolvent,
allows oxidation to carboxylic acids.
SCHEME 9. Lithiation of Hydridosilanes and Subsequent
Addition to Sulfinimine
SCHEME 10. Preliminary Oxidation Studies
Various possibilities for the primary oxidant and reaction
conditions are available.13 Our first choice was to apply
sodium chlorite as the primary oxidant and sodium hypo-
chlorite as cocatalyst in a mixture of acetonitrile and a
phosphate buffer.14 These conditions, nevertheless, proved
to be too mild, and only the alcohol starting material was
observed in the crude reaction mixture (Table 1, entry 1).
The next attempted conditions applied sodium hypochlorite
as the primary oxidant and potassium bromide as a cocatalyst.
In addition, tetrabutylammonium bromide (TBAB) was used
as a phase-transfer catalyst in a biphasic solvent system con-
sisting of dichloromethane and saturated sodium bicarbonate
as buffer.13,15 These reaction conditions did not lead to the
Silylsulfinamide 39 was used as a model compound for the
alcohol oxidation (Scheme 10). Sulfinamide and THP re-
moval had already been accomplished using dry HCl in
methanol, and the obtained ammonium salt was reprotected
with a Boc protecting group under standard conditions to
obtain 40. Oxidation was first performed using Jones oxida-
tion conditions,12 which gave the expected carboxylic acid 41
(13) Nooy, A. E. J. d.; Besemer, A. C.; van Bekkum, H. Synthesis 1996,
1153.
(14) Zhao, M. M.; Li, J.; Mano, E.; Song, Z. J.; Tschaen, D. M. Org.
Synth. 2005, 81, 195.
(15) Orgueira, H. A.; Bartolozzi, A.; Schell, P.; Litjens, R. E. J. N.;
Palmacci, E. R.; Seeberger, P. H. Chem.-Eur. J. 2003, 9, 140.
(12) Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
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TABLE 1. Different Attempts for the Oxidation of the Primary Alcohol
entry
reactant
conditions
product
1
2
3
4
40
40
44
40
TEMPO (cat.), NaOCl (cat.), NaOCl2(aq), CH3CN, phosphate buffer pH = 6.7, 35 °C
TEMPO (cat.), KBr (cat.), TBAB (aq), NaClO2 (aq), NaHCO3 (satd), CH2Cl2, 0 °C
NaClO2 (aq), Na2HPO4 (aq), t-BuOH, CH3CN, 2-methyl-2-butene
RuCl3 (cat.), NaIO4, CH3CN, EtOAc, H2O, rt
SM
44
41
41
carboxylic acid 41 but instead the corresponding aldehyde 44
(Table 1, entry 2). We attempted to oxidize the aldehyde to 44
applying the mild oxidant sodium chlorite in aqueous sodium
dihydrogenphosphate and a solvent mixture of tert-butanol,
acetonitrile, and 2-methyl-2-butene.16 The oxidation furnished
an impure sample of the carboxylic acid containing both
azasilinanone 43, unconverted alcohol from the first oxidation,
and other unidentified side products (entry 3).
Finally, we went on to explore a transition-metal-catalyzed
oxidation (Table 1, entry 4). Ruthenium(III) chloride was app-
lied together with sodium m-periodate as the primary oxidant
in a solvent mixture of acetonitrile, ethyl acetate, and water.
Ethyl acetate was employed as one of the solvents instead of the
more commonly used tetrachloromethane.17 These conditions
with an in situ generated perruthenate18 gave a cleaner con-
version of the alcohol to the desired carboxylic acid 41, which
was subsequently coupled to glycine using standard conditions
with EDC to give the dipeptide mimic 42 in 63% yield over two
steps. This result demonstrated how the prepared silyl sulfina-
mide 39 could be converted to a Boc-protected dipeptide mimic
and further applied in peptide coupling chemistry.
For practical application of this work, an interesting target
was suggested. The human elastase inhibitor 7 (Figure 2) has
demonstrated excellent inhibitory activity; however, the syn-
thetic approach to this compound provided a 1:1 mixture of
stereoisomers at the R-position to the silicon atom. We felt
application of the above approach would allow for the
synthesis of either diastereoisomer of the target compound
and facilitate identification of the more active of the two
compounds. Beginning with the commercially available
aldehyde 45, conversion to the imine and addition of the
silyl lithium reagent 47 proceeded without incident produ-
cing compound 48 (Scheme 11). Global deprotection and
reprotection of the amine were followed by oxidation of the
free alcohol up to the corresponding acid 50. The acid was
not isolated, rather it was coupled directly to n-butylamine
using standard conditions affording the butylamide 51 in
47% yield for the 2 steps. Two successive cycles of N-term-
inal deprotection with TFA followed by peptide coupling
afforded the fully protected peptide 53 in excellent overall
yield. Treatment with TfOH followed by aqueous basic
hydrolysis afforded the silane diol 55 directly.3g To facilitate
isolation and purification this compound was immediately
reacted with HF, which converted the silanediol into difluoro-
silane 54. Finally, conversion back to the silanediol 55 can
be readily achieved by treatment with aqueous NaOH.
Importantly, the approach depicted in Scheme 11 not only
is shorter and higher yielding than the previously reported
synthesis of 7 but yielded only a single diastereoisomer of
the final target.
The same approach was applied to another potential
target, the fibrillating hexapeptide Asn-Phe-Gly-Ala-Ile-
Leu (NFGAIL), a short fragment of the 37-residue human
islet amyloid polypeptide (hIAPP) found in pancreatic
deposits in type II diabetes patients, which is closely linked
to β cell deterioration.19
We have recently been interested in developing analogues
of this sequence in order to investigate how the structural
alterations in this sequence will influence fibrillation.20 This
sequence displays an internal glycine residue, and a deriva-
tive with the phenylalanine-glycine peptide bond replaced by
a silanediol methylene moiety may be prepared by the
developed method.
As illustrated in Scheme 12, synthesis of the diphenylsilane
NFGAIL derivative 64 was initiated by addition of the pre-
viously prepared silyllithium 57 to sulfinimine 56, which gave
silylsulfinamide 58 in 47% yield and a dr of 95:5 (Scheme 12).
Silyl lithium addition to this sulfinimine has also previously
resulted in a relatively low yield, which was attributed to
increased R proton acidity.11a Deprotection and protection of
the amine with a Boc group occurred in 74% yield to furnish
alcohol 59. Ruthenium-catalyzed oxidation and EDC-pro-
moted peptide coupling to the previously prepared tripeptide
6120 gave the pentapeptide mimic 62 in a 59% yield. Final
peptide coupling with asparagine (63) produced the protected
hexapeptide 64.21
Conclusions
In summary, we have investigated the possibility of ex-
tending the approach for generating silicon-containing di-
peptides to more elaborate amino acids with functionalized
side chains. The addition of alkyldiphenylsilyl lithium to
(19) Tatarek-Nossol, M.; Yan, L.-M.; Schmauder, A.; Tenidis, K.;
Westermark, G.; Kapurniotu, A. Chem. Biol. 2005, 12, 797. Tenidis, K.;
Waldner, M.; Bernhagen, J.; Fischle, W.; Bergmann, M.; Weber, M.; Merkle,
M.-L.; Voelter, W.; Brunner, H.; Kapurniotu, A. J. Mol. Bio. 2000, 295,
1055. Kapurniotu, A.; Schmauder, A.; Tenidis, K. J. Mol. Bio. 2002, 315,
339.
(20) Mittag, T.; Otzen, D. E.; Nielsen, N. C.; Skrydstrup, T. J. Org. Chem.
2009, 74, 7955.
(21) Attempts to cleave the Si-Ph bonds upon treatment with triflic acid
as for the diphenylsilane 53, followed by transformation to the difluoride,
were not successful, possibly because of sensitivity of the terminal Boc group
to these highly acidic conditions. Nevertheless, we are currently investigating
the fibrillating properties of the diphenylsilane analogue of this hexapeptide,
as well as its ability to perhaps inhibit the fibrillation process of the parent
peptide.
(16) Boger, D. L.; Curran, T. T. J. Org. Chem. 1992, 57, 2235.
(17) Hilty, F.; Brun, K.; Heimgartner, H. Helv. Chim. Acta 2004, 87, 2539.
(18) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625.
3288 J. Org. Chem. Vol. 75, No. 10, 2010

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SCHEME 11. Synthesis of Serine Protease HNE Inhibitor
SCHEME 12. Synthesis of Diphenylsilane Derivative 64 of the Fibrillating Hexapeptide NFGAIL
Ellman’s sulfinamine as the key step has been elaborated on
to include amino acid mimics of Ala, Val, Leu, Phe, Ser, Thr,
Tyr, Pro, Arg, Asp, Asn, and Lys. The synthesis is stereo-
selective and incorporates the opportunity for both N- and
C-terminus peptide extension. We have successfully demon-
strated the application of this method for the synthesis of
two dipeptide mimics of the type Xaa-Gly as fragments of
a potential human neutrophil elastase inhibitor and as a
J. Org. Chem. Vol. 75, No. 10, 2010 3289

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Hernandez et al.
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silicon-containing analogue of the fibrillating peptide NFG-
AIL. Ongoing work in this area is directed at the preparation
of the remaining genetically encoded side chains, together
with other natural and non-natural amino acid building
blocks of medicinal interest. Further to this, we are interested
in the development of a more general approach to functio-
nalized hydrido- or chloro- diphenylsilanes, which should
allow for the preparation of many more silanediol dipeptide
mimics of the type Xaa-Xaa. These results will be reported
in due course.
(2C), 128.0 (2C), 127.9 (2C), 127.8 (2C), 127.5, 73.4, 73.1, 56.3,
48.3, 22.6 (3C), -4.8. HRMS C26H33NO2SSi [M þ Naþ] calcd
474.1893, found 474.1887.
(R)-N-((R)-5-(tert-Butyldimethylsilyloxy)-1-(methyldiphenyl-
silyl)pentyl)-2-methylpropane-2-sulfinamide (18). It was pre-
pared from sulfinimine 77 following the previous general proce-
dure. The pure product was obtained by column chromatogra-
phy using 5% to 25% EtOAc in pentane as eluant giving 18 (792
mg, 1.53 mmol, 79%) as an oil. 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.59-7.49 (m, 4H), 7.43-7.32 (m, 6H), 3.54 (t, J = 6.4
Hz, 2H), 3.36 (ddd, J = 10.0, 7.6, 4.4 Hz, 1H), 2.78 (d, J = 10.0
Hz, 1H), 1.90-1.76 (m, 1H), 1.71-1.32 (m, 5H), 1.01 (s, 9H),
0.88 (s, 9H), 0.63 (s, 3H), 0.02 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 135.1 (2C), 135.0 (2C), 134.7, 134.6, 129.84,
129.82, 128.2 (3C), 127.9, 63.1, 56.4, 47.0, 33.6, 32.9, 26.1 (3C),
23.8, 22.7 (3C), 18.5, -4.9, -5.1 (2C). HRMS C28H47NO2SSi2
[M þ Naþ] calcd 540.2758, found 540.2764.
Experimental Procedures
General Procedures for Preparation of Sulfinimines. Method
A. (R)-tert-Butylsulfinamide (200 mg, 1.65 mmol) was dissolved
in dry CH2Cl2 (10 mL), and the aldehyde (2.0 mmol, 1.2 equiv),
PPTS (20 mg, 0.08 mmol, 0.05 equiv) and MgSO4 (993 mg,
8.25 mmol, 5 equiv) were added. The reaction was heated at
reflux for 18 h. Then the reaction mixture was filtered, and the
solids were washed with CH2Cl2 (2 ꢀ 10 mL). The combined
filtrates were evaporated in vacuo, and the pure product was
obtained by column chromatography, using the stated solvent
system.
Method B. (R)-tert-Butylsulfinamide (200 mg, 1.65 mmol)
and the aldehyde (2.0 mmol, 1.2 equiv) were dissolved in CH2Cl2
(10 mL), and Cs2CO3 (652 mg, 2.0 mmol, 1.2 equiv) was added.
The mixture was heated to reflux for 18 h, then cooled and
filtered through a pad of Celite. The solids were washed with
CH2Cl2, and then the combined filtrates were evaporated in
vacuo. The pure product was obtained by column chromato-
graphy, using the stated solvent system.
(R)-tert-Butyl 5-Hydroxy-1-(methyldiphenylsilyl)pentylcarba-
mate (19). Sulfinamide 18 (792 mg, 1.53 mmol) was dissolved in
anhydrous HCl in MeOH (40 mL, 0.5 M), and the mixture was
stirred at rt for 3 h. All volatiles were removed in vacuo giving
the crude amino alcohol. The residue was dissolved in dry
CH2Cl2 (20 mL), and then Boc2O (323 mg, 1.54 mmol) and
NEt3 (323 mg, 3.23 mmol) were added. The mixture was stirred
at rt for 18 h, then 2 M NaOH (aq) (20 mL) was added, and
stirring was continued vigorously for a further 2 h. The mixture
was poured into water (30 mL) and extracted with CH2Cl2 (3 ꢀ
20 mL). The combined organic portions were dried (MgSO4),
filtered, and evaporated in vacuo. The pure product was ob-
tained by column chromatography (increasing polarity from
10% to 50% EtOAc in pentane as eluant), which gave 19 (464
1
mg, 1.19 mmol, 78%) as a colorless oil. H NMR (400 MHz,
General Procedure for the Addition of (Diphenylmethylsilyl)lithium
to Sulfinimines. Lithium (42 mg, 5.0 mmol, 12.0 equiv) was
suspended in THF (5 mL) under an argon atmosphere, and then
diphenylmethylchlorosilane (0.31 mL, 1.50 mmol, 3.0 equiv) was
added, before the mixture was stirred at rt for 4 h. In a separate flask
the sulfinimine (0.50 mmol, 1 equiv) was dissolved in THF (5 mL),
and the solution was cooled to -78 °C under an argon atmosphere.
To this cooled solution was added the solution of lithium diphenyl-
methylsilane dropwise over 5 min via syringe. The solution was
stirred at -78 °C for 18 h, then water (2 mL) was added, and the
mixture allowed to warm to rt. The mixture was poured into water
(50 mL) and extracted with EtOAc (3 ꢀ 20 mL). The combined
organic portions were dried (MgSO4), filtered, and evaporated in
vacuo. The pure product was obtained by column chromatography.
General Procedure for the Addition of (Diphenylalkylsilyl)lithium
to Sulfinimines. Hydridosilane (0.20 mmol, 2 equiv) was dissolved
in dry THF (2 mL), and then freshly cut lithium pieces (15 mg,
2.0 mmol, 10 equiv) were added. The mixture was stirred under an
argon atmosphere for 4 h, by which time the mixture had turned a
rich dark brown color. In a separate flask, the imine (0.10 mmol)
was dissolved in dry THF (2 mL), and the solution was cooled to
-78 °C. To this cooled solution was added the silyl lithium reagent
(2 mL) dropwise via syringe over 3-5 min. The solution was stirred
at -78 °C for 18 h, then water (2 mL) was added, and the mixture
allowed to warm to rt and treated as in the previous procedure.
(R)-N-((R)-2-(Benzyloxy)-1-(methyldiphenylsilyl)ethyl)-2-
methylpropane-2-sulfinamide (13). It was prepared from sulfini-
mine 12 following the previous general procedure. The pure
product was obtained by column chromatography using 1:2:7
Et2O/EtOAc/pentane as eluant, giving 13 (162 mg, 0.36 mmol,
CDCl3) δ (ppm) 7.60-7.52 (m, 4H), 7.43-7.33 (m, 6H), 4.31 (d,
J = 10.0 Hz, 1H), 3.82 (td, J = 10.4, 3.2 Hz, 1H), 3.62-3.48 (m,
2H), 2.10 (br s, 1H), 1.66-1.34 (m, 6H), 1.39 (s, 9H), 0.60 (s,
3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 156.6, 135.0 (2C),
134.9 (2C), 134.7, 134.4, 129.74, 129.68, 128.1 (4C), 79.2, 62.6,
38.6, 32.2, 31.8, 28.4 (3C), 23.0, -5.6. HRMS C23H33NO3Si
[M þ Naþ] calcd 422.2122, found 422.2134.
(R)-5-(tert-Butoxycarbonylamino)-5-(methyldiphenylsilyl)pentyl
Methanesulfonate (20). The alcohol 19 (464 mg, 1.19 mmol) was
dissolved in CH2Cl2 (30 mL), and then NEt3 (237 mg, 2.37 mmol)
and MsCl (204 mg, 1.78 mmol) were added. The mixture was
stirred at rt for 30 min, then poured into water (50 mL), and
extracted with CH2Cl2 (3 ꢀ 20 mL). The combined organic
portions were dried (MgSO4), filtered, and evaporated in vacuo.
The pure product was obtained by column chromatography
(increasing polarity from 15% to 40% EtOAc in pentane as
eluant), which gave 20 (544 mg, 1.14 mmol, 96%) as a colorless
1
oil. H NMR (400 MHz, CDCl3) δ (ppm) 7.58-7.50 (m, 4H),
7.44-7.33 (m, 6H), 4.23 (d, J = 10.4 Hz, 1H), 4.15 (t, J = 6.4 Hz,
2H), 3.79 (td, J = 10.0, 2.8 Hz, 1H), 2.94 (s, 3H), 1.87-1.74 (1H),
1.70-1.30 (m, 5H), 1.39 (s, 9H), 0.59 (s, 3H). 13C NMR (100MHz,
CDCl3) δ (ppm) 156.4, 135.02 (2C), 134.95 (2C), 134.5, 134.3,
129.9, 129.8, 128.2 (4C), 79.3, 70.2, 38.5, 37.4, 31.5, 28.7, 28.5 (3C),
23.0, -5.6. HRMS C24H35NO5SSi [M þ Naþ] calcd 500.1897,
found 500.1897.
(R)-tert-Butyl 5-Azido-1-(methyldiphenylsilyl)pentylcarbamate
(21). Mesylate 20 (544 mg, 1.14 mmol) was dissolved in DMF
(20 mL), and then NaN3 (740 mg, 11.39 mmol) was added. The
mixture was stirred at rt for 18 h, then poured into water (50 mL)
and extracted with EtOAc (3 ꢀ 50 mL). The organic portion was
dried (MgSO4), filtered, and evaporated in vacuo. The pure
product was obtained by column chromatography (increasing
polarity from 5% to 10% EtOAc in pentane as eluant), which
gave 21 (432 mg, 1.02 mmol, 89%) as a colorless oil. 1H NMR (400
MHz, CDCl3) δ (ppm) 7.58-7.52 (m, 4H), 7.46-7.33 (m, 6H),
4.22 (d, J = 10.8 Hz, 1H), 3.80 (td, J = 10.8, 3.2 Hz, 1H),
1
72%) as a colorless oil. H NMR (400 MHz, CDCl3) δ (ppm)
7.24-7.60 (m, 15H), 4.56 (d, J = 11.6 Hz, 1H), 4.40 (d, J = 11.6
Hz, 1H), 4.01 (dd, J = 9.6, 3.2 Hz, 1H), 3.71 (dd, J = 9.6, 3.2 Hz,
1H), 3.56 (dt, J = 10.4, 3.2 Hz, 1H), 3.51 (d, J = 10.4 Hz, 1H),
1.08 (s, 9H), 0.67 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm)
138.2. 135.2 (2C), 135.0 (2C), 134.8, 134.7, 129.7, 129.6, 128.3
3290 J. Org. Chem. Vol. 75, No. 10, 2010

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3.24-3.14 (m, 2H), 1.70-1.30 (m, 6H), 1.40 (s, 9H), 0.59 (s, 3H).
13C NMR (100 MHz, CDCl3) δ (ppm) 156.4, 135.1 (2C), 135.0
(2C), 134.6, 134.4, 129.84, 129.79, 128.2 (4C), 79.2, 51.5, 38.7, 31.7,
28.6, 28.5 (3C), 24.3, -5.5. HRMS C23H32N4O2Si [M þ Naþ]
calcd 447.2187, found 447.2198.
(R)-3-(tert-Butoxycarbonylamino)-3-(methyldiphenylsilyl)-
propanoic Acid (34). A round-bottomed flask containing a solu-
tion of compound 33 (125 mg, 0.34 mmol) in CH2Cl2 (4 mL) and
acetone (4 mL) was cooled to 0 °C. Jones reagent (1 mL) was
added to the stirred mixture, after which it was allowed to warm
to rt. After 1 h 15 min more Jones reagent (0.2 mL) was added,
followed by additional 30 min of stirring. After phase separation
3 M HCl (2 mL) was added to the aqueous portion, which was
subsequently extracted with CH2Cl2 (5 ꢀ 30 mL). The combined
organic phases were dried (MgSO4), filtered, and evaporated in
vacuo. The pure product was obtained by column chromatogra-
phy (increasing polarity from 0:1:2 to 5:995:0 HCO2H/EtOAc/
pentane as eluant) afforded 34 (70 mg, 0.18 mmol, 54%) as a
colorless wax. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.56-7.54
(m, 4H), 7.42-7.36 (m, 6H), 4.76 (d, J = 8.4 Hz, 1H), 4.14 (br s,
1H), 2.65 (dd, J = 16.0, 2.8 Hz, 1H), 2.45 (dd, J = 16.0, 8.0 Hz,
1H), 1.37 (s, 9H), 0.67 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ (ppm) 177.7, 156.2, 135.0 (2C), 135.00 (2C), 134.97 (2C),
130.0, 129.9, 128.3 (2C), 128.2 (2C), 79.8, 36.7, 36.1, 28.4 (3C),
-5.3. HRMS C21H27NO4Si [M þ Naþ] calcd 408.1607, found
408.1622.
(R)-tert-Butyl 3-Amino-1-(methyldiphenylsilyl)-3-oxopropyl-
carbamate (35). In a three necked round-bottomed flask, dry
NEt3 (0.15 mL, 1.1 mmol) was added to a solution of compound
34 (66 mg, 0.17 mmol) in CH2Cl2 (6 mL), and the mixture was
cooled to 0 °C. PivCl (80 mg, 0.65 mmol) was then added, and
the reaction mixture was stirred for 40 min. Ammonia was
bubbled through the solution, which resulted in the immediate
precipitation of white salts. After having stirred for 30 min
under an atmosphere of ammonia, the reaction was quenched
with water (30 mL) and extracted with CH2Cl2 (5 ꢀ 20 mL). The
combined organic portions were dried (MgSO4), filtered, and
evaporated in vacuo. The pure product was obtained by column
chromatography (increasing polarity from 30% to 100%
EtOAc in pentane as eluant), which gave 35 (31 mg, 0.08 mmol,
47%) as a colorless oil. [R]D þ6 (c 1.10, CHCl3). 1H NMR (400
MHz, CDCl3) δ (ppm) 7.57-7.53 (m, 4H), 7.42-7.36 (m, 6H),
6.82 (br s, 1H), 5.47 (br s, 1H), 4.73 (d, J = 10.4 Hz, 1H), 4.07
(td, J = 10.4, 3.2 Hz, 1H), 2.57 (dd, J = 16.8, 2.8, Hz, 1H), 2.37
(dd, J = 16.8, 10.8 Hz, 1H), 1.37 (s, 9H), 0.66 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ (ppm) 174.2, 157.1, 135.0 (2C), 134.9 (2C),
133.6 (2C), 130.13, 130.08, 128.4 (2C), 128.3 (2C), 80.2, 38.6,
36.3, 28.4 (3C), -5.6. HRMS C21H28N2O3Si [M þ Naþ] calcd
407.1767, found 407.1776.
(R)-tert-Butyl 1-((3-Hydroxypropyl)diphenylsilyl)-3-methyl-
butylcarbamate (49). Sulfinamide 48 (768 mg, 1.50 mmol) was
dissolved in anhydrous 0.5 M HCl in MeOH (15 mL), and the
mixture was stirred at rt for 18 h. All volatiles were removed in
vacuo to give the crude amine as its hydrochloride salt. This was
dissolved in CH2Cl2 (15 mL), and then NEt3 (0.83 mL, 6.00
mmol) and Boc2O (645 mg, 3.0 mmol) were added. The mixture
was stirred at rt for 18 h, and then 2 M NaOH (15 mL) was
added. The mixture was stirred vigorously for a further 2 h. The
two phases were separated, and the aqueous portion was
extracted with CH2Cl2 (3 ꢀ 20 mL). The combined organic
portions were dried (MgSO4), filtered, and evaporated in vacuo.
The pure product was obtained by column chromatography
(increasing polarity from 1% to 3% MeOH in CH2Cl2), which
gave 49 (470 mg, 1.10 mmol, 73%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.57 (dd, J = 7.6, 1.2 Hz, 2H), 7.51
(dd, J = 7.6, 1.2 Hz, 2H), 7.46-7.34 (m, 6H), 4.12 (d, J = 10.4
Hz, 1H), 4.03 (td, J = 11.6, 2.4 Hz, 1H), 3.63-3.49 (m, 2H), 2.04
(s, 1H), 1.73-1.50 (m, 2H), 1.50-1.43 (m, 1H), 1.40 (s, 9H),
1.36-1.04 (m, 4H), 0.97 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 6.8 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 156.3, 135.7
(2C), 135.4 (2C), 133.5, 133.0, 129.8, 129.7, 128.12 (2C), 128.07
(2C), 79.1, 65.2, 41.3, 35.9, 28.5 (3C), 26.8, 25.0, 23.8, 21.3,
(R)-tert-Butyl 5-Amino-1-(methyldiphenylsilyl)pentylcarba-
mate (22). Azide 21 (432 mg, 1.02 mmol) was dissolved in MeOH
(30 mL), and Pd(OH)2/C was added (52 mg, 0.37 mmol). The
mixture was stirred under an atmosphere of hydrogen for 18 h.
The mixture was filtered through a plug of Celite and silica gel,
and the solids were washed with MeOH. The combined filtrates
were evaporated in vacuo giving 22 (389 mg, 0.98 mmol, 96%) as
a colorless foam. 1H NMR (400 MHz, CDCl3) δ (ppm)
7.57-7.50 (m, 4H), 7.42-7.32 (m, 6H), 4.31 (d, J = 10.8 Hz,
1H), 3.80 (td, J = 10.0, 2,0 Hz, 1H), 2.64-2.54 (m, 2H), 1.63-
1.26 (m, 8H), 1.38 (s, 9H), 0.58 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 156.3, 135.0 (2C), 134.9 (2C), 134.8, 134.5,
129.7, 129.6, 128.0 (4C), 79.0, 42.1, 38.8, 33.5, 31.9, 28.4 (3C),
24.3, -5.6. HRMS C23H34N2O2Si [M þ Naþ] calcd 421.2282,
found 421.2287.
(R)-tert-Butyl 2-(Methyldiphenylsilyl)pyrrolidine-1-carboxy-
late (27). The mesylate 26 (68 mg, 0.15 mmol) was dissolved in
DMF (3 mL), and then NaH (20 mg, 60% dispersion in oil, 0.40
mmol) was added. The mixture was stirred at rt for 1 h, by which
time TLC indicated all starting material had been consumed.
The mixture was poured into water (50 mL) and extracted with
EtOAc (3 ꢀ 50 mL). The organic portion was washed with water
(2 ꢀ 25 mL), dried (MgSO4), filtered, and evaporated in vacuo.
The pure product was obtained by column chromatography
(5% EtOAc in pentane as eluant) which gave 27 (38 mg, 0.103
1
mmol, 70%) as a colorless oil. [R]D -46 (c 1.27, CHCl3). H
NMR (400 MHz, CDCl3) δ (ppm) 7.60-7.52 (m, 4H),
7.42-7.30 (m, 6H), 4.00-3.83 (m, 1H), 3.60-3.32 (m, 1H),
3.16-2.97 (m, 1H), 2.12-1.90 (m, 1H), 1.90-1.76 (m, 1H),
1.74-1.60 (m, 1H), 1.56-1.15 (m, 10H), 0.66 (br s, 3H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 155.0 (br), 135.8 (br), 135.1
(2C), 135.0 (2C), 134.2 (br), 129.4 (2C), 127.9 (4C), 79.5/
78.7 (br), 46.8, 34.5 (br), 28.8/28.5 (3C), 25.9 (br), 24.6 (br),
-3.4 (br). HRMS C22H29NO2Si [M þ Naþ] calcd 390.1860,
found 390.1862.
N00-(R)-4-(tert-Butoxycarbonylamino)-4-(methyldiphenylsilyl)-
butyl)-N,N0-di-tert-butyloxycarbonyl-guanidine (30). Azide 28
(240 mg, 0.58 mmol) was dissolved in MeOH (18 mL), and
Pd(OH)2 was added (30 mg, 0.23 mmol). The mixture was stirred
under an atmosphere of hydrogen for 18 h, and then the flask was
flushed with nitrogen. The mixture was filtered through a plug of
Celite and silica gel, and the solids were washed with MeOH. The
combined filtrates were evaporated in vacuo giving the crude free
amine that was used without further purification. The amine (225
mg, 0.58 mmol) was dissolved in CH2Cl2 (24 mL), and then NEt3
(364 μL, 265 mg, 2.63 mmol) and N,N0-di-Boc-N00-triflylguani-
dine (259 mg, 0.65 mmol) were added. The mixture was stirred at
rt for 30 min, then diluted with CH2Cl2 (50 mL), and washed with
2 M NaHSO4 (75 mL) and satd NaHCO3 (75 mL). The organic
portion was dried (MgSO4), filtered, and evaporated in vacuo.
The pure product was obtained by column chromatography
(increasing polarity from 5% to 20% EtOAc in pentane as
eluant), which gave 30 (265 mg, 0.42 mmol, 72%) as a color-
less oil. [R]D -4 (c 1.56, CHCl3). 1H NMR (400 MHz, CDCl3)
δ (ppm) 11.42 (br s, 1H), 8.26 (t, J = 4.8 Hz, 1H), 7.57 (m,
4H), 7.42-7.30 (m, 6H), 4.33 (d, J = 10.4 Hz, 1H), 3.78 (td, J =
10.8, 2.0 Hz, 1H), 3.44-3.30 (m, 2H), 1.75-1.34 (m, 4H), 1.48
(s, 9H), 1.47 (s, 9H), 1.37 (s, 9H), 0.58 (s, 3H). 13C NMR (100
MHz, CDCl3) δ (ppm) 156.4, 156.2, 153.3, 151.5, 135.1 (2C),
135.0 (2C), 134.5, 134.3, 129.8, 129.7, 128.2 (4C), 83.1, 79.2, 40.6,
38.8, 29.3, 28.4 (3C), 28.3 (3C), 28.1 (3C), 27.9, 27.0, -5.5.
HRMS C33H50N4O6Si [M þ Naþ] calcd 649.3392, found
649.3397.
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7.4. HRMS C25H37NO3Si [M þ Naþ] calcd 450.2435, found
HOBt (214 mg, 1.40 mmol), NMM (136 μL, 1.40 mmol), and
finally EDC (133 mg, 0.70 mmol) were added. The mixture was
stirred at rt for 18 h, then poured into water (30 mL) and
extracted with CH2Cl2 (3 ꢀ 15 mL). The combined organic
portions were dried (MgSO4), filtered, and evaporated in vacuo.
The pure product was obtained by column chromatography
(increasing polarity from 1% to 5% MeOH in CH2Cl2 as
eluant), which gave the title compound 53 (170 mg, 0.25 mmol,
450.2528.
(R)-tert-Butyl 1-((3-(Butylamino)-3-oxopropyl)diphenylsilyl)-
3-methylbutylcarbamate (51). Alcohol 49 (83 mg, 0.20 mmol, 1.0
equiv) was dissolved in a mixture of MeCN (1 mL), ethyl acetate
(1 mL), and H2O (1.5 mL), and NaIO4 (171 mg, 0.80 mmol, 4.1
equiv) and RuCl3 (1 mg) were added. The reaction was stirred at
rt for 2 h, and then H2O (5 mL) was added. The mixture was
extracted with ethyl acetate (2 ꢀ 10 mL), and the combined
organic extracts were dried (MgSO4), filtered, and concentrated
in vacuo to give the crude carboxylic acid. The residue was
dissolved in CH2Cl2 (3 mL), and then NMM (100 mg, 0.95
mmol), n-butylamine (150 mg, 2.03 mmol), HOBt (98 mg, 0.63
mmol) and finally EDC (181 mg, 0.95 mmol) were added. The
mixture was stirred at rt for 1 d, then poured into water (40 mL)
and extracted with CH2Cl2 (3 ꢀ 20 mL). The combined organic
portions were dried (MgSO4), filtered, and evaporated in vacuo.
The pure product was obtained by column chromatography
(increasing polarity from 5% to 50% EtOAc in pentane as
eluant), which gave 51 (148 mg, 0.30 mmol, 62%) as a colorless
solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.55 (dd, J = 7.6,
1.6 Hz, 2H), 7.48 (dd, J = 7.6, 1.6 Hz, 2H), 7.45-7.33 (m, 6H),
5.64 (br s, 1H), 4.20 (d, J = 10.4 Hz, 1H), 4.02 (td, J = 11.2, 2.8
Hz, 1H), 3.25-3.06 (m, 2H), 2.28 (ddd, J = 14.4, 12.0, 5.2 Hz,
1H), 2.04 (ddd, J = 14.4, 11.2, 6.0 Hz, 1H), 1.72-1.60 (m, 1H),
1.50-1.20 (m, 8H), 1.40 (s, 9H), 0.95 (d, J = 6.8 Hz, 3H), 0.89 (t,
J = 7.2 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 174.1, 156.3, 135.7 (2C), 135.4 (2C), 132.9,
132.4, 130.0, 129.9, 128.22 (2C), 128.17 (2C), 79.2, 40.9, 39.4,
35.7, 31.8, 30.7, 28.5 (3C), 25.1, 23.8, 21.3, 20.2, 13.8, 7.8.
HRMS C29H44N2O3Si [M þ Naþ] calcd 519.3013, found
519.3043.
tert-Butyl (2S,3R)-1-((R)-1-((3-(Butylamino)-3-oxopropyl)-
diphenylsilyl)-3-methylbutylamino)-3-methyl-1-oxopentan-2-yl-
carbamate (52). Carbamate 51 (148 mg, 0.30 mmol) was dis-
solved in CH2Cl2 (3 mL), and then TFA (1.5 mL) was added.
The mixture was stirred at rt for 1 h, before all volatiles were
removed in vacuo, giving the crude amine as its trifluoroacetate
ammonium salt. The residue was dissolved in CH2Cl2 (3 mL),
and then HOBt (201 mg, 1.30 mmol), NMM (127 μL, 1.30
mmol), N-Boc-isoleucine (136 mg, 0.59 mmol), and EDC
(124 mg, 0.65 mmol) were added. The mixture was stirred at rt
for 18 h, then poured into water (40 mL) and extracted with
CH2Cl2 (3 ꢀ 20 mL). The combined organic portions were dried
(MgSO4), filtered, and evaporated in vacuo. The pure product
was obtained by column chromatography (increasing polarity
from 20% to 60% EtOAc in pentane as eluant), which gave the
title compound 52 (168 mg, 0.28 mmol, 92%) as a colorless solid.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.55-7.30 (m, 10H), 5.99
(br s, 1H), 5.68 (d, J = 9.6 Hz, 1H), 4.91 (d, J = 8.4 Hz, 1H),
4.50-4.40 (m, 1H), 3.78 (t, J = 7.6 Hz, 1H), 3.23-3.08 (m, 2H),
2.32 (ddd, J = 14.4, 12.0, 4.8 Hz, 1H), 1.99 (ddd, J = 14.4, 11.2,
6.0 Hz, 1H), 1.87-1.77 (m, 1H), 1.61-1.49 (m, 1H), 1.49-1.24
(m, 9H), 1.40 (s, 9H), 1.04-0.94 (m, 1H), 0.93-0.76 (m, 15H).
13C NMR (100 MHz, CDCl3) δ (ppm) 174.3, 171.2, 155.9,
135.6 (2C), 135.4 (2C), 132.3, 132.1, 130.14, 130.09, 128.31
(2C), 128.25 (2C), 80.1, 60.2, 40.3, 39.4, 36.7, 34.7, 31.8, 30.7,
28.4 (3C), 25.0, 24.8, 23.7, 21.1, 20.2, 15.7, 13.9, 11.4, 8.1.
HRMS C35H55N3O4Si [M þ Naþ] calcd 632.3854, found
632.3865.
1
91%) as a colorless solid. [R]D -16 (c 1.34, CHCl3). H NMR
(400 MHz, CDCl3) δ (ppm) 7.82-7.72 (m, 3H), 7.59 (s, 1H),
7.56-7.52 (m, 2H), 7.50-7.33 (m, 10H), 7.20 (dd, J = 8.0, 1.6
Hz, 1H), 5.92 (d, J = 8.8 Hz, 1H), 5.79 (t, J = 5.6 Hz, 1H), 5.65
(d, J = 10.4 Hz, 1H), 4.37 (ddd, J = 12.0, 10.4, 2.8 Hz, 1H), 4.14
(dd, J = 8.8, 6.8 Hz, 1H), 3.67 (AB system, J = 15.6 Hz, 2H),
3.14 (td, J = 7.2, 6.0 Hz, 2H), 2.30 (ddd, J = 14.4, 11.6, 4.4 Hz,
1H), 2.01 (ddd, J = 14.4, 11.2, 6.4 Hz, 1H), 1.81-1.70 (m, 1H),
1.48-1.16 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H), 0.82 (d, J = 6.4
Hz, 3H), 0.82-0.75 (m, 1H), 0.75-0.68 (m, 9H). 13C NMR (100
MHz, CDCl3) δ (ppm) 174.1, 170.9, 170.4, 135.7 (2C), 135.4
(2C), 133.7, 132.6, 132.3, 132.2, 132.1, 130.2, 130.1, 129.0,
128.34 (2C), 128.30 (2C), 128.2, 127.8, 127.7, 127.0, 126.6,
126.2, 58.4, 44.0, 40.2, 39.4, 36.5, 34.8, 31.7, 30.7, 25.1, 24.6,
23.6, 21.1, 20.2, 15.6, 13.9, 11.3, 7.8. HRMS C42H55N3O3Si
[M þ Naþ] calcd 700.3905, found 700.3910.
(2S,3R)-N-((R)-1-((3-(Butylamino)-3-oxopropyl)difluorosilyl)-
3-methylbutyl)-3-methyl-2-(2-(naphthalen-2-yl)acetamido)penta-
namide (54). Diphenylsilane 53 (50.8 mg, 0.076 mmol) was
dissolved in dry CH2Cl2 (5 mL) under an argon atmosphere
and cooled to 0 °C in an ice bath. Triflic acid (0.1 mL, 15 equiv,
1.14 mmol) was added dropwise, and the reaction was stirred at
0 °C for 24 h while being allowed to warm to rt. The reaction was
cooled to 0 °C, diluted with CH2Cl2 (5 mL), concd NH4OH (0.3
mL) was added, and the reaction was stirred for another 1 h at
0 °C. Then 48% HF solution (0.2 mL) was added, to give a pH of
2-3. Stirring was continued for 30 min and after addition of
CH2Cl2 (10 mL), the solution was washed with water (10 mL)
and saturated NaCl (10 mL), dried (Na2SO4), filtered, and
concentrated to give 54 (37.5 mg, 0.068 mmol, 89%) as a syrup.
1H NMR (400 MHz, CDCl3) δ (ppm) 8.19 (br s, 1H), 7.82-7.77
(m, 3H), 7.73 (s, 1H), 7.49-7.48 (m, 2H), 7.37 (dd, J = 8.4, 1.6
Hz, 1H), 6.74 (br s, 1H), 5.77 (br s, 1H), 4.50 (t, J = 8.4 Hz, 1H),
3.71-3.80 (m, 2H), 3.20 (dt, J = 7.2, 6.0 Hz, 1H), 2.77-2.74 (m,
1H), 2.26 (ddd, J = 15.6, 12.8, 8.0 Hz, 1H), 1.80-1.73 (m, 1H),
1.63-1.56 (m, 1H), 1.49-1.25 (m, 8H), 1.04-0.96 (m, 2H),
0.91-0.76 (m, 15H). 13C NMR (100 MHz, CDCl3) δ (ppm)
175.0, 173.9, 171.9, 133.7, 132.7, 132.0, 128.9, 128.2, 127.83,
127.79, 127.1, 126.6, 126.2, 55.8, 43.7, 39.7, 38.8, 38.4 (dd, J =
26.5, 21.2 Hz), 37.0, 31.7, 30.7, 25.9, 25.0, 23.7, 21.0, 20.2, 15.3,
13.9, 11.9 (t, J = 20.4 Hz), 11.1.
(2S,3R)-N-((R)-1-((3-(Butylamino)-3-oxopropyl)dihydroxy-
silyl)-3-methylbutyl)-3-methyl-2-(2-(naphthalen-2-yl)acetamido)-
pentanamide (55). Difluorsilane 54 (5 mg, 0.009 mmol) was
dissolved in a mixture of CD3CN (0.1 mL) and D2O (0.4 mL),
and 0.2 M NaOH solution in D2O (0.1 mL) was added. The
reaction was stirred for 30 min, and the mixture was used directly
for NMR. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.96-7.92 (m,
3H), 7.84 (br s, 1H), 7.61-7.55 (m, 2H), 7.48 (br d, J = 7.6 Hz,
1H), 4.14 (d, J = 8.4 Hz, 1H), 3.67 (AB system, J = 14.4 Hz,
2H), 3.20 (dd, J = 12.0, 2.4 Hz, 1H), 3.10 (t, J = 6.8 Hz, 2H),
2.25-2.14 (m, 2H), 1.91-1.81 (m, 1H), 1.48-1.39 (m, 4H),
1.34-1.24 (m, 4H), 1.15-1.08 (m, 1H), 0.88 (d, J = 6.8 Hz,
3H), 0.87 (t, J = 7.6 Hz, 3H), 0.83 (t, J = 7.6 Hz, 3H), 0.73 (d,
J = 6.0 Hz, 3H), 0.72 (d, J = 6.0 Hz, 3H), 0.70-0.63 (m, 2H).
13C NMR (100 MHz, CDCl3) δ (ppm) 175.8, 174.3, 172.5, 133.3,
133.0, 132.2, 128.0, 127.6, 127.5 (2C), 127.3, 126.2, 125.8, 55.6,
42.2, 39.0, 38.9, 38.6, 36.3, 30.9, 29.6, 25.2, 24.6, 22.9, 19.9, 19.6,
14.6, 13.1 (2C), 10.2.
(2S,3R)-N-((R)-1-((3-(Butylamino)-3-oxopropyl)diphenyl-
silyl)-3-methylbutyl)-3-methyl-2-(2-(naphthalen-2-yl)acetamido)-
pentanamide (53). Carbamate 52 (168 mg, 0.28 mmol) was
dissolved in CH2Cl2 (3 mL), and then TFA (1.5 mL) was added.
The mixture was stirred at rt for 90 min, before all volatiles were
removed in vacuo, giving the crude amine as its trifluoroacetate
ammonium salt. The glassy residue was dissolved in CH2Cl2
(3 mL), and then 2-napthylacetic acid (120 mg, 0.63 mmol),
3292 J. Org. Chem. Vol. 75, No. 10, 2010

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tert-Butyl (5S,8R,14S,17S,20S)-8-Benzyl-17-sec-butyl-20-iso-
butyl-14-methyl-3,6,12,15,18,21-hexa-oxo-1,1,1,9,9-pentaphe-
nyl-2,7,13,16,19,22-hexaaza-9-silatetracosan-5-ylcarbamate (64).
Trifluoroacetic acid (3 mL) was added to a solution of pentapep-
tide analogue 62 (59 mg, 0.07 mmol) in CH2Cl2 (3 mL). The
mixture was stirred at rt for 1 h, and then the solvents were
evaporated in vacuo giving the crude trifluoroacetate ammonium
salt as a colorless gum. The crude material was redissolved in
CH2Cl2 (3 mL) and N-methyl morpholine (41 μL, 0.37 mmol),
Boc-L-Asn(Trt)-OH (63) (39 mg, 0.08 mmol), EDC (28 mg, 0.15
mmol), and HOBt (23 mg, 0.15 mmol) were added. The mixture
was stirred at rt for 2 days and then poured into water (10 mL).
The aqueous phase was extracted with CH2Cl2 (3 ꢀ 10 mL), and
the combined organic portions were dried (MgSO4), filtered, and
evaporated in vacuo. The pure product was obtained by column
chromatography (increasing polarity from 50% to 90% EtOAc
in CH2Cl2 as eluant), which gave 64 (76 mg, 0.07 mmol, 88%) as a
colorless solid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.57-7.60
(m, 4H), 7.38-7.48 (m, 6H), 7.09-7.27 (m, 20H), 4.17-4.43 (m,
3H), 4.25 (q, J = 7.2 Hz, 1H), 4.18 (d, J = 6.8 Hz, 1H), 3.17 (q,
J = 7.2 Hz, 1H), 3.17 (q, J = 7.2 Hz, 1H), 2.93 (d, J = 12.4 Hz,
1H), 2.64 (dd, J = 14.0, 11.6 Hz, 1H), 2.16-2.38 (m, 4H),
1.80-1.87 (m, 1H), 1.43-1.64 (m, 6H), 1.40 (s, 9H), 1.16-1.29
(m, 1H), 1.26 (d, J = 7.2 Hz, 3H), 1.09 (t, J = 7.6 Hz, 3H),
0.86-0.91 (m, 12H). 13C NMR (400 MHz, CD3OD) δ (ppm)
176.9, 175.6, 174.1, 173.3 (2C), 171.4, 157.2, 145.8 (3C), 140.9,
136.6 (2C), 136.5 (2C), 133.8, 133.5, 131.12, 131.09, 130.0 (6C),
129.9 (2C), 129.32 (4C), 129.27 (2C), 128.7 (6C), 127.8 (3C),
127.2, 80.8, 71.7, 59.4, 53.4, 53.1, 51.0, 41.7, 41.0, 40.3, 38.1, 38.0,
35.3, 30.8, 28.8 (3C), 26.0, 25.8, 23.5, 22.0, 17.5, 16.0, 14.8, 11.6,
8.3. HRMS C68H85N7O8Si [M þ Naþ] calcd 1178.6121, found
1178.6127.
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Found-
ation, the Lundbeck Foundation, the Carlsberg Foundation,
and the University of Aarhus. D.H. thanks the Gobierno de
~
ꢀ
Espana (Ministerio de Ciencia e Innovacion) for a posdoctoral
contract (Programa Nacional de Movilidad de Recursos
Humanos del Plan nacional de IþDþI 2008-2011).
Supporting Information Available: Experimental methods
for the preparation of compounds 12, 14-17, 23-26, 28, 29,
31-33, 39-44, 46, 48, 56, 58, 59, and 62 and their characteriza-
tion. Copies of 1H NMR and 13C NMR spectra of the new
compounds (12-22, 24-28, 30-35, 40, 42, 43, 48-55, 58-60,
62, and 64). This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 10, 2010 3293