Stereocontrolled synthesis of methyl silanediol peptide mimics

Article abstract of DOI:10.1021/jo701907d

(Chemical Equation Presented) The treatment of chiral sulfinimines with (methyldiphenylsilyl)lithium gives α-(methyldiphenylsilyl)-sulfinamides with excellent diastereoselectivity, and in good yield. The presence of α-protons on the imines is also well tolerated. The sulfanamide auxiliary is easily removed via treatment with methanolic HC1 and the resulting amine extended into peptide chains accordingly. The diphenylsilyl moiety is a resilient protecting group for the corresponding silanediol, which can be unmasked via treatment with TfOH, followed by aqueous hydrolysis. The crude silanediol may be isolated and purified as its corresponding bis-TMS siloxane via protection with TMSC1, and converted back to the desired silanediol via hydrolysis with aqueous KOH. Efforts to apply this approach to biologically relevant silanediol peptide mimics, with a view to protease inhibition, are described.

Full text of DOI:10.1021/jo701907d

Stereocontrolled Synthesis of Methyl Silanediol Peptide Mimics
Lone Nielsen, Karl B. Lindsay,* Jesper Faber, Niels Christian Nielsen, and
Troels Skrydstrup*
Center for Insoluble Protein Structures, Department of Chemistry and Interdisciplinary Nanoscience
Center, UniVersity of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
kbl02@chem.au.dk; ts@chem.au.dk
ReceiVed August 30, 2007
The treatment of chiral sulfinimines with (methyldiphenylsilyl)lithium gives R-(methyldiphenylsilyl)-
sulfinamides with excellent diastereoselectivity, and in good yield. The presence of R-protons on the
imines is also well tolerated. The sulfinamide auxiliary is easily removed via treatment with methanolic
HCl and the resulting amine extended into peptide chains accordingly. The diphenylsilyl moiety is a
resilient protecting group for the corresponding silanediol, which can be unmasked via treatment with
TfOH, followed by aqueous hydrolysis. The crude silanediol may be isolated and purified as its
corresponding bis-TMS siloxane via protection with TMSCl, and converted back to the desired silanediol
via hydrolysis with aqueous KOH. Efforts to apply this approach to biologically relevant silanediol peptide
mimics, with a view to protease inhibition, are described.
Introduction
Sieburth et al. reported the silanediol analogue 1 of a known
hydroxyethylene-containing HIV-protease inhibitor to have a
Proteases constitute a large and important class of enzymes,
realized by the vast number of physiological processes in which
they are involved including digestion, growth, differentiation,
cell signaling, immunological defense, and apoptosis among
others.1 Furthermore, they play a crucial role in the disease
progression of cancers and infections as well as inflammatory,
cardiovascular, and respiratory disorders.1 Four major types of
proteases exist, namely the aspartic, serine, cysteine, and
metalloproteases, dubbed according to their active site func-
tionality. Because of their essential physiological roles, proteases
have become significant therapeutic targets, and motifs mimick-
ing the tetrahedral intermediate of peptide hydrolysis (e.g.,
hydroxyethylene, phosphinate, boronic acid, and ketomethylene
isosteres) have been successfully applied in the design of potent
protease inhibitors.1,2
(2) For some examples of peptide isosteres, see: (a) Garbe, D.; Sieber,
S. A.; Bandur, N. G.; Koert, U.; Marahiel, M. A. ChemBioChem 2004, 5,
1000. (b) 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. (c) Wipf, P.; Henninger, T. C.; Geib, S. J. J. Org. Chem.
1998, 63, 6088. (d) Wipf, P.; Henninger, T. C. J. Org. Chem. 1997, 62,
1586. (e) Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875. (f) Theberge,
C. R.; Zercher, C. K. Tetrahedron 2003, 59, 1521. (g) Steinmetzer, T.;
Zhu, B. Y.; Konishi, Y. J. Med. Chem. 1999, 42, 3109. (h) Hoffman, R.
V.; Tao, J. Tetrahedron 1997, 53, 7119. (i) Deziel, R.; Plante, R.; Caron,
V.; Grenier, L.; Llinas-Brunet, M.; Duceppe, J.-S.; Malenfant, E.; Moss,
N. J. Org. Chem. 1996, 61, 2901. (j) 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. (k)
Benedetti, F.; Berti, F.; Norbedo, S. J. Org. Chem. 2002, 67, 8635. (l) Tao,
J.; Hoffman, R. V. J. Org. Chem. 1997, 62, 6240. (m) Righi, G.; Ronconi,
S.; Bonini, C. Eur. J. Org. Chem. 2002, 1573. (n) Benedetti, F.; Magnan,
M.; Miertus, S.; Norbedo, S.; Parat, D.; Tossi, A. Bioorg. Med. Chem. Lett.
1999, 9, 3027. (o) Tamamura, H.; Kato, T.; Otaka, A.; Fujii, N. Org. Biomol.
Chem. 2003, 1, 2468. (p) Akaji, K.; Teruya, K.; Aimoto, S. J. Org. Chem.
2003, 68, 4755. (q) Datta, A.; Veeresa, G. J. Org. Chem. 2000, 65, 7609.
(r) 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. (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.
Over the past decade, the Sieburth group has introduced the
silanediol moiety as a new tetrahedral intermediate isostere with
applications as aspartic and metalloprotease inhibitors.3 Si-
lanediols represent good mimics of the tetrahedral intermediate
formed during peptide bond hydrolysis, because of their
reluctance to dehydrate as opposed to their carbon counterparts.4
(1) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43,
305-341.
10.1021/jo701907d CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/15/2007
J. Org. Chem. 2007, 72, 10035-10044
10035

Nielsen et al.
SCHEME 1
SCHEME 2
FIGURE 1. Silanediol-based protease inhibitors.
Ki value of 2.7 nM against this protease,3b and a silanediol
analogue 2 of a known ketone-containing inhibitor of angio-
tensin-converting enzyme with an IC50 of 3.8 nM.3f,g These
inhibitory values are comparable to those of the parent
compounds from which they were derived. The mode of binding
was recently confirmed by a crystal structure of a silanediol
inhibitor 3 in the active site of the metalloprotease thermolysin.3g
The impressive results obtained by Sieburth and co-workers
demonstrate the applicability of silanediols as tetrahedral
intermediate analogues. This pioneer work raises the questions
whether the silanediol moiety can be exploited as a general motif
for the rational design of protease inhibitors and if silanediol
protease inhibitors are qualified drug candidates. To answer
these questions, a versatile and stereoselective synthesis of
silanediol peptide mimics is highly desirable.
Sieburth’s group has successfully synthesized enantiopure
silanediol tripeptide analogues,3e,g but their synthetic strategy
relies on a linear introduction of the required functional groups
and therefore may not be ideal in a screening process where
many compounds are to be synthesized in a short time.
Furthermore, construction of the R-silylamine moiety occurs
without stereocontrol.3g
Organ et al. have proposed an alternative synthesis applying
a platinum-catalyzed hydrosilylation of an olefin followed by
conversion to a silyllithium reagent and addition to an imine to
yield racemic R-silylamine.5 This short and convergent strategy
affords easy access to the desired diorganodiphenylsilane
species, but similarly offers no control of the stereocenter R to
the silicon atom.
Inspired by these interesting results regarding synthesis and
applications of silanediol peptide analogues, we focused our
initial studies on the stereoselective synthesis of an R-silylamine
structure.
and in high diastereoisomeric ratios. Ph2MeSiLi is easily
prepared from Ph2MeSiCl and lithium metal,7 and optically
pure sulfinimines are easily obtained by the condensation of
optically pure (R)-tert-butanesulfinamide and aldehydes.8-10
Sulfinimines of this type developed by Davis9 and Ellman10
have found prolific use as electrophiles, reacting cleanly and
with excellent stereoselectivity with a diverse range of nucleo-
philes providing rapid access to chiral amines.8-10 An advantage
of the tert-butanesulfoxide auxiliary is its ease of subse-
quent removal by using hydrogen chloride in methanol10g and
the conversion of the resulting ammonium salt to a carbamate6
or an amide by using standard procedures.8 According to
Scheidt, sulfinimine substrates with R-protons are not well
tolerated in the silyllithium addition reactions,6 reporting
only a single result with the imine derived from acetophenone.
As that particular imine is very highly enolizable, we felt
encouraged to investigate whether imines derived from less
enolizable aldehydes would undergo smooth addition with
silyllithiums.
In this paper, we describe the stereoselective synthesis
of R-silylamines from tert-butanesulfinimines and Ph2MeSiLi.
We have found that imines with R-protons are reasonably well
tolerated in the addition reactions and also imines bearing
fully protected alcohols and amines undergo smooth addition.
The resulting sulfinamides were easily deprotected and coupled
to N-protected amino acids applying standard solution-
phase peptide coupling conditions. With use of this approach
methyldiphenylsilane di- and tripeptide mimics were pre-
pared; furthermore, one of these was elaborated into a meth-
R-Silylamines can be prepared by the addition of silyl anions
to chiral tert-butanesulfinimines 4 (Scheme 1) as reported by
Scheidt et al.6 The additions usually work in good to high yields
(6) Ballweg, D. M.; Miller, R. C.; Gray, D. L.; Scheidt, K. A. Org. Lett.
2005, 7, 1403.
(7) Fleming, I.; Roberts, R. S.; Smith, S. C. J. Chem. Soc., Perkin Trans.
1 1998, 1209.
(8) For a comprehensive review see: Morton, D.; Stockman, R. A.
Tetrahedron 2006, 62, 8869 and references cited therein.
(9) For a recent perspective on the Davis sulfinimide chemistry, see:
Davis, F. A. J. Org. Chem. 2006, 71, 8993.
(10) For selected examples see: (a) Brinner, K. M.; Ellman, J. A.
Org. Biomol. Chem. 2005, 3, 2109. (b) Weix, D. J.; Shi, Y.; Ellman,
J. A. J. Am. Chem. Soc. 2005, 127, 1092. (c) Kochi, T.; Ellman,
J. A. J. Am. Chem. Soc. 2004, 126, 15652. (d) Schenkel, L. B.; Ellman,
J. A. Org. Lett. 2004, 6, 3621. (e) Kochi, T.; Tang, T. P.; Ellman,
J. A. J. Am. Chem. Soc. 2003, 125, 11276. (f) Kochi, T.; Tang, T. P.; Ellman,
J. A. J. Am. Chem. Soc. 2002, 124, 6518. (g) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (h) Liu, G.; Cogan,
D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64,
1278.
(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.; 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) Sieburth, S. M.; Chen, C.-A. Eur. J. Org. Chem. 2006, 311.
(4) Apeloig, Y. In The chemistry of organic silicon compounds; Patai,
S., Rappoport, Z., Eds.; John Wiley & Sons: New York, 1989; Vol. 1, pp
57-225.
(5) Organ, M. G.; Buon, C.; Decicco, C. P.; Combs, A. P. Org. Lett.
2002, 4, 2683.
10036 J. Org. Chem., Vol. 72, No. 26, 2007

Synthesis of Methyl Silanediol Peptide Mimics
TABLE 1. Preparation of Sulfinimines
Access to the desired sulfinimines was achieved from the
corresponding aldehydes/ketone by condensation with tert-
butanesulfinamide employing reaction conditions reported by
others (Table 1). Sulfinimines 20-22 were prepared with use
of MgSO4 in the presence of catalytic p-toluenesulfonic acid in
CH2Cl2 heated at reflux.10h Sulfinimines 24-31 were prepared
by employing Cs2CO3 as the dehydrating agent in CH2Cl2 at
reflux.12 Both approaches are simple and convienient, though
the former may be preferable when employing substrates with
more acidic R-protons. Nevertheless, the two methods proved
unsuccessful for the preparation of sulfinimine 23, and thus a
third method was employed. Treatment of tert-butane sulfina-
mide with Ti(OEt)4, in the presence of excess acetone in THF
at reflux, afforded the desired sulfinimine as reported previously
by Ellman et al.10h
The key step in the synthesis was the addition of a silyllithium
nucleophile to an imine in a stereoselective manner as described
by Scheidt et al.6 With the requisite sulfinimines in hand initial
studies were undertaken. Treatment of chloro(methyl)diphenyl-
silane with excess lithium metal in THF affords a solution of
(methyldiphenylsilyl)lithium after 4 h at rt. Attempts to react
this reagent with sulfinimines at rt or 0 °C only afforded
complex mixtures of products. However, dropwise addition of
this solution to a precooled (-78 °C) solution of the sulfinimine
in THF gave good results affording the desired addition products
in good yields. It was pleasantly surprising that even substrates
derived from aldehydes/ketones with enolizable protons per-
formed well under the reaction conditions, though in extreme
cases (Table 2; entries 3 and 4) the yield was somewhat
diminished. The diastereoselectivity for the reaction was gener-
ally excellent, and in several cases no minor isomer was
detectable by NMR (entries 2, 3, 6, 7, and 10). Where the minor
isomer was detected, it could frequently be easily separated by
simple flash column chromatography (entries 1, 5, and 9), and
in these cases the diastereoselectivity has been assigned based
upon the 1H NMR spectra of the crude mixture. The only
exception was compound 39 (entry 8), which was isolated as a
92:8 diastereoisomeric mixture. The diastereoisomeric ratio for
compound 42 (entry 11) has not been determined due to
extensive line broadening attributed to carbamate rotamers.
Stereochemical assignment of the major isomer was based upon
results previously reported by Scheidt et al.,6 where an open
transition state is assumed with corresponding Felkin-Ahn
stereocontrol.
Curiously, when the imine 31 was subjected to the same
reaction conditions the desired R-silylsulfinamide was not
obtained. Rather, the product 47, isolated in 56% yield, was
that derived from a double aza-Brook rearrangement13 as
depicted in Scheme 3. Formation of this product can be
rationalized by the enhanced stabilization in the carbanion 44
afforded by the electron-withdrawing cyano group, and that this
anion eliminates a tert-butyl sulfoxide anion to afford a second
imine 45. Further reaction with excess Ph2MeSiLi followed by
a second aza-Brook rearrangement would then afford disilazane
47 after workup.
a Method A: MgSO4, PPTS. Method B: Ti(OEt)4. Method C: Cs2CO3.
ylsilanediol dipeptide mimic via conversion to its TMS-
trisiloxane followed by base hydrolysis.
Results and Discussion
Elaboration of the addition products into silanediol peptide
isosteres was achievable in several steps. Initial removal of the
sulfinamide auxiliary via treatment with anhydrous methanolic
Synthesis of Precursors. Aldehyde 8 was prepared from
amine 6 in three steps via N-Boc protection, p-methoxybenzy-
lation, and finally treatment with aqueous acetic acid (Scheme
2). Aldehydes 16, 17, and 18 were prepared via monoprotection
of the corresponding diols, followed by Swern11 oxidation as
described in the Supporting Information. All other aldehydes
are commercially available.
(11) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(12) Higashibayashi, S.; Tohmiya, H.; Mori, T.; Hashimoto, K.; Nakata,
M. Synlett 2004, 457.
(13) Duff, J. M.; Brook, A. G. Can. J. Chem. 1977, 55, 2589.
J. Org. Chem, Vol. 72, No. 26, 2007 10037

Nielsen et al.
TABLE 2. Additions of Ph2CH3SiLi to Sulfinimines
TABLE 3. N-Terminal Extension of r-Silylamines
a Entry performed with racemic substrate. b Second step performed with
Ac2O, NEt3.
approach is limitless, thus we have limited our own investiga-
tions to the peptides depicted in Table 3 and Scheme 4, applying
only those sulfinamides that mimic naturally occurring amino
acid residues.
Conversion of the above peptides into silanediols was
envisioned to be achieved via reaction of the diphenylsilane
moiety with TfOH, followed by aqueous hydrolysis of the
resulting adduct as reported by Sieburth et al.3 Isolation of the
silanediol directly from this approach is, however, not possible
due to the propensity for silanediols to form oligomers in
concentrated and/or nonpolar conditions.3h In previous ap-
proaches the crude silanediol is converted to the corresponding
silane difloride for example by treatment with concentrated HF.3
It has also been suggested that the crude silanediol obtained
after hydrolysis can be treated with chlorotrimethylsilane and
triethylamine to facilitate isolation as its corresponding
trisiloxane.3c This trisiloxane is also an excellent precursor, and
under aqueous basic conditions will hydrolyze to reform the
silanediol.
a Not determined due to carbamate rotamers.
HCl readily gave the amine salts which were then converted to
the desired amides by using standard peptide coupling methods
(Table 3).
Further extension of these peptides with additional amino
acids is of course also possible by applying standard stepwise
extension of the N-terminal via peptide coupling (Scheme 4).
The number of amino acid combinations available with this
10038 J. Org. Chem., Vol. 72, No. 26, 2007

Synthesis of Methyl Silanediol Peptide Mimics
SCHEME 3
SCHEME 4
mixture of 58 and 59, respectively. Increasing the reaction time
to 4.5 h changed this ratio to 3:2 in favor of trisiloxane 58. The
consumption of starting material is extremely rapid (less than
5 min), as visualized by thin-layer chromatography, indicating
that the first phenyl group is cleaved much faster than the
second. These findings also support the participation of the
amide carbonyl in benzene departure from silicon as proposed
by Sieburth et al.3h Hydrolysis of the protected adduct 58 via
treatment with aqueous KOH in D2O and CD3OD then afforded
the clean solution of silanediol 60 (and TMS2O) as indicated
1
by H NMR analysis of the crude reaction mixture.
In keeping with a continued interest in the synthesis of
peptidomimetic protease inhibitors within the group, we elected
to convert compound 54 into a silanediol as depicted in Scheme
6. It was expected that the carbamate protecting group would
not survive the harsh conditions required hence it was removed
via hydrogenolysis with PdCl2 and then the resulting free amine
was converted to a simple amide 61 via an EDC-promoted
coupling with phenylacetic acid. Diphenylsilane 61 was treated
with triflic acid for 20 h to ensure complete conversion.
Subsequent addition of aqueous ammonia followed by TMS
protection of the resulting silanediol 62 afforded the trisiloxane
63 in an acceptable 47% yield. Finally, treatment of compound
63 with KOH in a mixture of D2O and CD3OD regenerated the
silanediol 62, a mimic of the dipeptide PhCH2CO-Pro-Val-OH.
SCHEME 5
Finally the tripeptides 56 and 57 were also converted into
silanediols in the same manner, as depicted in Scheme 7. As
before, conversion of the carbamate moiety into an amide was
necessary, achieved in 52% and 73% yield for compounds 64
and 65, respectively, over the two steps. The diphenylsilane 64
was reacted with TfOH, over 1 d, followed by aqueous
hydrolysis with NH4OH affording the TMS-protected silanediol
66 in 41% yield after treatment with TMSCl and NEt3.
Treatment of diphenylsilane 65 with TfOH for 1 d, then aqueous
The simple peptide 52 was selected for the initial deprotection
study and was treated with TfOH in dichloromethane followed
by aqueous ammonia (Scheme 5). Treatment of the crude
silanediol with TMSCl and NEt3 afforded the chromatographi-
cally stable bis-TMS protected adduct 58 together with the
partially deprotected adduct 59 as a mixture of diastereoisomers.
Allowing the deprotection to proceed for 25 min afforded a 2:5
SCHEME 6
J. Org. Chem, Vol. 72, No. 26, 2007 10039

Nielsen et al.
SCHEME 7
The pure product was obtained by column chromatography
(increasing polarity from 5% to 20% EtOAc in pentane as eluant),
which gave the title compound (227 mg, 1.408 mmol, 85%) as an
NH4OH and finally TMSCl, afforded the protected adduct 67
in 34% yield for the three steps. It is expected that the protected
adducts 66 and 67 will be converted into their corresponding
silanediols once an appropriate protease has been selected for
testing.
1
oil. H NMR (400 MHz, CDCl3) δ (ppm) 2.29 (s, 3H), 2.13 (s,
3H), 1.18 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm) 182.8,
55.9, 30.3, 23.6, 21.9 (3C). HRMS C7H15NOS [M + Na+] calcd
184.0772, found 184.0807.
Conclusions
Method C: (R)-tert-Butylsulfinamide (200 mg, 1.65 mmol) and
the aldehyde (2.00 mmol, 1.2 equiv) were dissolved in CH2Cl2 (8
mL), then Cs2CO3 (652 mg, 2.00 mmol, 1.2 equiv) was added. The
mixture was heated to reflux for 18 h, cooled, and filtered through
a pad of celite. The solids were washed with CH2Cl2, and the
combined filtrates were evaporated in vacuo. The pure product was
obtained by column chromatography with the stated solvent system.
(N(E),S(R))-2-Methyl-N-(2-methylpropylidene)-2-propane-
sulfinamide (24).12 The title compound was prepared from (R)-
tert-butylsulfinamide (180 mg, 1.50 mmol) according to Method
C. Increasing polarity from 5% to 20% EtOAc in pentane was used
as eluant for column chromatography giving 231 mg (1.32 mmol,
88%) as an oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.86 (d, J )
4.8 Hz, 1H), 2.59 (hep d, J ) 7.2, 4.0 Hz, 1H), 1.06 (s, 9H), 1.04
(d, J ) 7.2 Hz, 3H), 1.04 (d, J ) 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ (ppm) 173.2, 56.1, 34.6, 22.0 (3C), 18.6, 18.6.
HRMS C8H17NOS [M + Na+] calcd 198.0929, found 198.0932.
General Method for the Addition of (Diphenylmethylsilyl)-
lithium to Sulfinimines. Lithium (42 mg, 6.00 mmol, 12 equiv)
was suspended in THF (5 mL) under an atmosphere of argon, and
then diphenylmethylchlorosilane (0.31 mL, 349 mg, 1.50 mmol, 3
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 cooled to -78 °C under an
atmosphere of argon. To this cooled solution was added the solution
of (methyldiphenylsilyl)lithium 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 was allowed to warm to rt. The mixture
was poured into water (50 mL) and extracted with EtOAc (3 × 20
mL), and the combined organic portions were dried (MgSO4),
filtered, and evaporated in vacuo. The pure product was obtained
by column chromatography with the stated solvent system.
Herein, we have reported the first studies toward a modular
approach to C-terminal silanediol peptide mimics. A series of
compounds of this type will be synthesized and tested against
a range of proteases for any relevant activity. It is intended that
these results will be extended to afford peptide mimics where
the silanediol is imbedded within the peptide, by replacement
of the terminal methyl group by a C-terminal peptide chain.
Such an extension would give rapid and flexible access to true
silanediol peptide isosteres.
Experimental Procedures
Methods for Prepartion of Sulfinimines. Method A: (R)-tert-
Butylsulfinamide (200 mg, 1.65 mmol) and the aldehyde (2.00
mmol, 1.2 equiv) were dissolved in CH2Cl2 (8 mL) then MgSO4
(993 mg, 8.25 mmol, 5 equiv) and pyridinium tosylate (20 mg,
0.083 mmol, 0.05 equiv) were added. The mixture was heated to
reflux for 18 h, cooled, and filtered. The solids were washed with
CH2Cl2, and then the combined filtrates were evaporated in vacuo.
The pure product was obtained by column chromatography, using
the stated solvent system.
(N(E),S(R))-2-Methyl-N-(3-methylbutylidene)-2-propanesulfi-
namide (21).14 The title compound was prepared from (R)-tert-
butylsulfinamide (253 mg, 2.09 mmol) according to Method A.
Increasing polarity from 5% to 10% EtOAc in pentane was used
as eluant for column chromatography giving 374 mg (1.98 mmol,
95%) as an oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.05 (t, J )
5.2 Hz, 1H), 2.40 (ddd, J ) 6.8, 5.6, 1.6 Hz, 2H), 2.05 (m, 1H),
1.19 (s, 9H), 0.98 (d, J ) 6.8 Hz, 3H), 0.98 (d, J ) 6.8 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ (ppm) 169.4, 56.5, 45.0, 26.2, 22.6,
22.5, 22.4 (3C). HRMS C9H19NOS [M + Na+] calcd 212.1085,
found 212.1087.
Method B: (S(R))-2-Methyl-N-(methylethylidene)-2-propane-
sulfinamide (23).15 (R)-tert-Butylsulfinamide (200 mg, 1.65 mmol)
was dissolved in THF (13 mL) then acetone (0.64 mL, 8.25 mmol)
and Ti(OEt)4 (1.90 mL, 8.25 mmol) were added. The mixture was
heated to reflux for 44 h, then cooled to rt before it was poured
into a rapidly stirred solution of NaHCO3. After the solution was
stirred for 5 min, celite was stirred into the slurry and the suspension
was filtered through a pad of celite. The solids were washed with
EtOAc (3 × 10 mL), and the combined filtrates were transferred
to a separatory funnel. The aqueous portion was separated and
extracted with EtOAc (2 × 10 mL), and the combined organic
portions were dried (MgSO4), filtered, and evaporated in vacuo.
(S(R))-N-[(R)-1-(Methyldiphenylsilyl)ethyl]-2-methyl-2-pro-
panesulfinamide (32). The title compound was prepared from imine
20 (80 mg, 0.543 mmol) according to the general method. Increasing
polarity from 15% to 60% EtOAc in pentane was used as eluant
for column chromatography giving 173 mg (0.500 mmol, 92%) as
1
an oil. H NMR (400 MHz, CDCl3) δ (ppm) 7.60-7.52 (m, 4H),
7.44-7.30 (m, 6H), 3.46 (dq, J ) 10.8, 7.6 Hz, 1H), 2.71 (d, J )
10.8 Hz, 1H), 1.45 (d, J ) 7.6 Hz, 3H), 1.05 (s, 9H), 0.60 (s, 3H).
13C NMR (100 MHz, CDCl3) δ (ppm) 135.0 (2C), 134.9 (2C), 133.9
(2C), 129.7 (2C), 127.9 (2C), 127.9 (2C), 56.1, 42.0, 22.5 (3C),
19.5, -5.8. HRMS C19H27NOSSi [M + Na+] calcd 368.1480, found
368.1480.
1,1-Dimethylethyl ((S)-2-{[(R)-1-(Methyldiphenylsilyl)ethyl]-
amino}-2-oxo-1-(phenylmethyl)ethyl)carbamate (48). Sulfina-
mide 32 (173 mg, 0.501 mmol) was dissolved in MeOH (10 mL)
containing 0.4 M anhydrous HCl. The mixture was stirred at rt for
4 h, and all volatiles were removed in vacuo, which gave the crude
amine (139 mg, 0.50 mmol, 99%) as its corresponding HCl salt.
(14) Staas, D. D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R.
G. J. Org. Chem. 2002, 67, 8276.
(15) Lanter, J. C.; Chen, H.; Zhang, X.; Sui, Z. Org. Lett. 2005, 7, 5905.
10040 J. Org. Chem., Vol. 72, No. 26, 2007

Synthesis of Methyl Silanediol Peptide Mimics
This was dissolved in CH2Cl2 (20 mL), and NMM (0.50 mL, 4.54
mmol), Boc-L-Phe-OH (265 mg, 1.00 mmol), HOBt (169 mg, 1.10
mmol), and EDC‚HCl (213 mg, 1.10 mmol) were added. The
mixture was stirred at rt for 2 d, 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 5% to 25% EtOAc in pentane as eluant),
which gave the title compound (211 mg, 0.432 mmol, 86%) as a
(()-2-(Acetylamino)-N-[(R)-1-(methyldiphenylsilyl)-3-meth-
ylbutyl]acetamide (51). Sulfinamide 33 (275 mg, 0.71 mmol) was
dissolved in MeOH (25 mL) containing 0.4 M anhydrous HCl. The
mixture was stirred at rt for 5 h, and all volatiles were removed in
vacuo, which gave the crude amine as its HCl salt. This was
dissolved in CH2Cl2 (25 mL), and NMM (0.35 mL, 3.18 mmol),
N-acetylglycine (162 mg, 1.38 mmol), and EDC‚HCl (223 mg, 1.16
mmol) were added. The mixture was stirred at rt for 18 h, 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 80% to 100% EtOAc in
pentane as eluant), which gave the title compound (135 mg, 0.35
mmol, 50%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ (ppm)
7.58-7.50 (m, 4H), 7.45-7.33 (m, 6H), 6.14 (s, 1H), 5.60 (d, J )
7.8 Hz, 1H), 3.74 (qABd, J ) 16.0, 5.2 Hz, 2H), 1.93 (s, 3H), 1.62-
1.50 (m, 1H), 1.42-1.24 (m, 2H), 0.92 (d, J ) 6.4 Hz, 3H), 0.84
(d, J ) 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 170.7,
168.3, 134.8 (2C), 134.7 (2C), 134.5, 134.1, 129.7, 129.5, 128.0
(2C), 127.9 (2C), 43.5, 40.4, 36.3, 25.2, 23.5, 22.7, 21.1, -6.1.
HRMS C22H30N2O2Si [M + Na+] calcd 405.1974, found 405.1990.
(()-N-[(R)-1-(Methyldiphenylsilyl)-2-phenylethyl]aceta-
mide (52). Sulfinamide 34 (80 mg, 0.19 mmol) was dissolved in
MeOH (10 mL) containing 0.4 M anhydrous HCl. The mixture
was stirred at rt for 5 h, and all volatiles were removed in vacuo,
which gave the crude amine as its HCl salt. This was dissolved in
dry CH2Cl2 (10 mL) under a nitrogen atmosphere. Acetic anhydride
(0.14 mL, 1.48 mmol) and triethylamine (0.052 mL, 0.38 mmol)
were added and the reaction mixture was stirred at rt for 1 h. The
reaction was quenched with water (10 mL) and acidified with 2 M
HCl to pH 5. After separation of the phases, the organic extract
was washed with brine, dried (Na2SO4), and filtered and the solvent
was removed in vacuo. Toluene (2 mL) was added and removed
in vacuo twice. The pure product was obtained by column
chromatography (increasing polarity from 5% to 33% EtOAc in
pentane as eluant), which gave the title compound (47 mg, 0.13
mmol, 69%). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.62-7.56 (m,
4H), 7.45-7.37 (m, 6H), 7.23-7.08 (m, 5H), 5.06 (br d, J ) 10.8
Hz, 1H), 4.46 (td, J ) 10.8, 4.4 Hz, 1H), 3.00 (dd, J ) 14.0, 4.0
Hz, 1H), 2.67 (dd, J ) 14.0, 10.8 Hz, 1H), 1.74 (s, 3H), 0.59 (s,
3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 169.4, 139.4, 135.1
(2C), 135.0 (2C), 134.7, 134.5, 129.9, 129.9, 129.0 (2C), 128.4
(2C), 128.3 (2C), 128.2 (2C), 126.4, 39.7, 37.5, 23.3, -5.0. HRMS
C23H25NOSi [M + Na+] calcd 382.1603, found 382.1603.
1,1-Dimethylethyl (S)-2-({[(R)-2-Methyl-1-(methyldiphenylsilyl)-
propyl]amino}carbonyl)pyrrolidine-1-carboxylate (53). Sulfi-
namide 36 (300 mg, 0.86 mmol) was dissolved in MeOH (25 mL)
containing 0.4 M anhydrous HCl. The mixture was stirred at rt for
18 h, and all volatiles were removed in vacuo, which gave the crude
amine as its corresponding HCl salt. This was dissolved in CH2Cl2
(40 mL), and NMM (0.47 mL, 4.30 mmol), Boc-L-Pro-OH (190
mg, 0.86 mmol), HOBt (264 mg, 1.72 mmol), and EDC‚HCl (333
mg, 1.72 mmol) were added. The mixture was stirred at rt for 2 d,
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 (25% EtOAc in pentane as eluant),
which gave the title compound (330 mg, 0.707 mmol, 82%) as a
colorless solid. 1H NMR (400 MHz, CDCl3 55 °C) δ (ppm) 7.59-
7.56 (m, 4H), 7.37-7.31 (m, 6H), 4.23-4.20 (m, 1H), 4.12-4.09
(m, 1H), 3.36-3.28 (m, 2H), 2.22-2.12 (m, 1H), 2.01-1.92 (m,
1H), 1.85-1.77 (m, 3H), 1.40 (s, 9H), 0.86 (d, J ) 6.8 Hz, 3H),
0.77 (d, J ) 6.8 Hz, 3H), 0.66 (s, 3H). 13C NMR (100 MHz, CDCl3
50 °C) δ (ppm) 171.9, 156.7, 135.7 (2C), 134.9 (4C), 129.4 (2C),
128.0 (4C), 80.3, 60.6 (br), 47.0, 43.9 (br), 30.6, 28.4 (4C), 24.3
(br), 22.2, 19.4, -4.3. HRMS C27H38N2O3Si [M + Na+] calcd
489.2539, found 489.2519.
1
colorless solid. H NMR (400 MHz, CDCl3) δ (ppm) 7.53-7.30
(m, 10H), 7.22-7.15 (m, 3H), 7.12-7.05 (m, 2H), 5.79 (d, J )
9.6 Hz, 1H), 5.10 (br s, 1H), 4.22 (app br q, J ) 7.2 Hz, 2H), 2.94
(d, J ) 6.8 Hz, 2H), 1.37 (br s, 9H), 1.15 (d, J ) 7.6 Hz, 3H), 0.50
(s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 170.5, 155.5, 136.7,
134.8 (2C), 134.8 (2C), 134.7, 133.7, 129.7 (2C), 129.2 (3C), 128.4
(2C), 128.0 (2C), 127.9 (2C), 126.6, 79.8, 56.0, 38.4, 32.8, 28.1
(3C), 16.9, -5.9. HRMS C29H36N2O3Si [M + Na+] calcd 511.2393,
found 511.2392.
1,1-Dimethylethyl (S)-2-({[(R)-1-(Methyldiphenylsilyl)ethyl]-
amino}carbonyl)pyrrolidine-1-carboxylate (49). Sulfinamide 32
(129 mg, 0.385 mmol) was dissolved in MeOH (10 mL) containing
0.4 M anhydrous HCl. The mixture was stirred at rt for 4 h, and
all volatiles were removed in vacuo, which gave the crude amine
as its corresponding HCl salt. This was dissolved in CH2Cl2 (10
mL), and NMM (0.385 mL, 3.49 mmol), Boc-L-Pro-OH (166 mg,
0.770 mmol), HOBt (130 mg, 0.846 mmol), and EDC‚HCl (164
mg, 0.846 mmol) were added. The mixture was stirred at rt for 2
d, 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 5% to 35%
EtOAc in pentane as eluant), which gave the title compound (128
1
mg, 0.292 mmol, 76%) as a colorless solid. H NMR (400 MHz,
CDCl3) δ (ppm) 7.60-7.45 (m, 4H), 7.44-7.30 (m, 6H), 6.73 (br
s, 0.5H), 5.88 (br s, 0.5H), 4.22-4.06 (m, 2H), 3.40-3.10 (m, 2H),
2.22-1.50 (m, 4H), 1.46-1.20 (m, 9H), 1.16 (d, J ) 8.0 Hz, 3H),
0.60 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 171.9 (br),
155.5/154.6 (br), 134.8 (4C), 134.1 (2C), 129.6 (2C), 128.0 (4C),
80.1, 61.2/60.0 (br), 46.7, 32.8/32.0 (br), 30.9 (br), 28.2 (3C), 24.4/
23.4 (br), 17.0, -6.1 (br). HRMS C25H34N2O3Si [M + Na+] calcd
461.2236, found 461.2219.
Phenylmethyl ((S)-2-{[(R)-3-Methyl-1-(methyldiphenylsilyl)-
butyl]amino}-2-oxo-1-(phenylmethyl)ethyl)carbamate (50). Sul-
finamide 33 (89 mg, 0.230 mmol) was dissolved in MeOH (10
mL) containing 0.4 M anhydrous HCl. The mixture was stirred at
rt for 5 h, and all volatiles were removed in vacuo, which gave the
crude amine as its HCl salt. This was dissolved in CH2Cl2 (12 mL),
and NMM (0.10 mL, 0.91 mmol), Cbz-L-Phe-OH (134 mg, 0.45
mmol), HOBt (73 mg, 0.48 mmol), and EDC‚HCl (94 mg, 0.49
mmol) were added. The mixture was stirred at rt for 18 h, poured
into water (35 mL), and extracted with CH2Cl2 (3 × 25 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 25% EtOAc in
pentane as eluant), which gave the title compound (129 mg, 0.228
1
mmol, 99%) as a colorless solid. H NMR (400 MHz, CDCl3) δ
(ppm) 7.52-7.16 (m, 18H), 7.12-7.02 (m, 2H), 5.39 (d, J ) 10.4
Hz, 1H), 5.22 (m, 1H), 5.05 (s, 2H), 4.36-4.24 (m, 2H), 3.03 (dd,
J ) 13.6, 5.6 Hz, 1H), 2.88 (dd, J ) 13.6, 7.2 Hz, 1H), 1.47-1.36
(m, 1H), 1.32-1.20 (m, 2H), 0.90 (d, J ) 6.4 Hz, 3H), 0.77 (d, J
) 6.8 Hz, 3H), 0.46 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm)
170.0, 156.0, 136.7, 136.3, 135.3 (2C), 135.1 (2C), 134.5, 134.1,
130.0, 129.9, 129.6 (2C), 128.9 (2C), 128.8 (2C), 128.5 (2C), 128.3,
128.3 (4C), 127.1, 67.2, 56.6, 40.5, 38.3, 36.3, 24.9, 23.7, 21.2,
-5.3. HRMS C35H40N2O3Si [M + Na+] calcd 587.2706, found
587.2722.
Phenylmethyl (S)-2-({[(R)-2-Methyl-1-(methyldiphenylsilyl)-
propyl]amino}carbonyl)pyrrolidine-1-carboxylate (54). Sulfi-
J. Org. Chem, Vol. 72, No. 26, 2007 10041

Nielsen et al.
namide 36 (150 mg, 0.40 mmol) was dissolved in MeOH (20 mL)
containing 0.4 M anhydrous HCl. The mixture was stirred at rt for
5 h, and all volatiles were removed in vacuo, which gave the crude
amine as its HCl salt. This was dissolved in CH2Cl2 (20 mL), and
NMM (0.24 mL, 2.16 mmol), Cbz-L-Pro-OH (112 mg, 0.45 mmol),
HOBt (135 mg, 0.86 mmol), and EDC‚HCl (166 mg, 0.86 mmol)
were added. The mixture was stirred at rt for 42 h, poured into
water (20 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 (40% EtOAc in pentane as eluant), which gave
the title compound (180 mg, 0.359 mmol, 89%) as a colorless solid.
1H NMR (400 MHz, CDCl3 60 °C) δ (ppm) 7.58-7.52 (m, 4H),
7.39-7.28 (m, 11H), 5.20 (d, J ) 12.4 Hz, 2H), 4.27-4.23 (m,
1H), 4.09 (dd, J ) 10.4, 5.2 Hz, 1H), 3.46-3.38 (m, 2H), 2.18-
2.08 (m, 1H), 1.95 (oct, J ) 6.8 Hz, 1H), 1.90-1.81 (m, 3H), 0.84
(d, J ) 6.8 Hz, 3H), 0.72 (d, J ) 6.8 Hz, 3H), 0.63 (s, 3H). 13C
NMR (100 MHz, CDCl3, 50 °C) δ (ppm) 171.5 (br), 156.5 (br),
136.6, 135.6 (2C), 134.9 (4C), 129.5 (2C), 128.6 (2C), 128.0 (7C),
67.3, 61.1 (br), 47.1 (br), 44.1 (br), 30.5, 28.2 (br), 24.4 (br), 22.2,
19.5, -4.4. HRMS C30H36N2O3Si [M + Na+] calcd 523.2393, found
523.2405.
Phenylmethyl ((S)-1-Methyl-2-[((S)-{[(R)-2-methyl-1-(meth-
yldiphenylsilyl)propyl]amino}carbonyl)pyrrolidin-1-yl]-2-oxo-
ethyl)carbamate (56). Boc-protected amine 53 (165 mg, 0.35
mmol) was dissolved in dry CH2Cl2 (2 mL), and TFA (2 mL) was
added. The reaction was stirred for 1 h at rt and concentrated in
vacuo. This was dissolved in CH2Cl2 (25 mL), and NMM (0.2 mL,
1.8 mmol), Cbz-L-alanine (82 mg, 0.35 mmol), HOBt (108 mg,
0.71 mmol), and EDC‚HCl (136 mg, 0.71 mmol) were added. The
mixture was stirred at rt for 50 h, poured into water (20 mL), and
extracted with CH2Cl2 (2 × 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 10% to 40% EtOAc in pentane as eluant), which gave
the title compound (140 mg, 0.24 mmol, 70%) as a colorless solid.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.58-7.55 (m, 4H), 7.38-
7.33 (m, 11H), 6.70 (d, J ) 10.4 Hz, 1H), 5.69 (d, J ) 7.2 Hz,
1H), 5.11 (d, J ) 12.4 Hz, 1H), 5.07 (d, J ) 12.4 Hz, 1H), 4.52
(quin, J ) 7.2 Hz, 1H), 4.43 (d, J ) 6.8 Hz, 1H), 4.12-4.10 (m,
1H), 3.63-3.57 (m, 1H), 3.51-3.47 (m, 1H), 2.22-2.15 (m, 1H),
2.14-2.06 (m, 1H), 1.97-1.87 (m, 2H), 1.74-1.64 (m, 1H), 1.30
(d, J ) 7.2 Hz, 3H), 0.81 (d, J ) 6.8 Hz, 3H), 0.77 (d, J ) 6.8 Hz,
3H), 0.68 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 172.6,
170.3, 155.7, 136.5, 135.5, 135.5, 134.9 (2C), 134.9 (2C), 129.6,
129.5, 128.6 (2C), 128.2, 128.1 (2C), 128.0 (2C), 128.0 (2C), 66.9,
60.0, 48.3, 47.3, 44.1, 30.4, 26.9, 25.2, 22.0, 19.6, 18.8, -4.7.
HRMS C33H41N3O4Si [M + Na+] calcd 594.2764, found 594.2756.
Phenylmethyl (S)-2-Methyl-1-[(S)-2-({[(R)-2-methyl-1-(meth-
yldiphenylsilyl)propyl]amino}carbonyl)pyrrolidin-1-ylcarbonyl]-
propylcarbamate (57). Boc-protected amine 53 (165 mg, 0.35
mmol) was dissolved in dry CH2Cl2 (2 mL), and TFA (2 mL) was
added. The reaction was stirred for 1 h at rt and concentrated in
vacuo, redissolved in CH2Cl2, and evaporated to dryness giving
the crude amine as its corresponding TFA salt. This was dissolved
in CH2Cl2 (25 mL), and NMM (0.2 mL, 1.8 mmol), Cbz-L-valine
(91 mg, 0.35 mmol), HOBt (108 mg, 0.71 mmol), and EDC‚HCl
(136 mg, 0.71 mmol) were added. The mixture was stirred at rt for
50 h, then poured into water (20 mL) and extracted with CH2Cl2
(2 × 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 10% to 33%
EtOAc in pentane as eluant), which gave the title compound (161
mg, 0.27 mmol, 77%) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.58-7.53 (m, 4H), 7.38-7.31 (m, 11H), 6.38
(d, J ) 10.4 Hz, 1H), 5.47 (d, J ) 9.2 Hz, 1H), 5.10 (d, J ) 12.4
Hz, 1H), 5.05 (d, J ) 12.4 Hz, 1H), 4.32 (dd, J ) 9.2, 6.0 Hz,
1H), 4.27 (dd, J ) 8.4, 3.2 Hz, 1H), 4.10 (dd, J ) 10.4, 6.0 Hz,
1H), 3.72-3.65 (m, 1H), 3.61-3.53 (m, 1H), 2.03-1.86 (m, 4H),
1.72-1.64 (m, 1H), 0.98 (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.8 Hz,
3H), 0.84 (d, J ) 6.8 Hz, 3H), 0.81 (d, J ) 6.8 Hz, 3H), 0.67 (s,
3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 171.9, 170.7, 156.5,
136.5, 135.5, 135.5, 134.9 (2C), 134.8 (2C), 129.6, 129.5, 128.6
(2C), 128.2, 128.1 (2C), 128.0 (2C), 128.0 (2C), 67.0, 60.3, 57.5,
47.7, 44.3, 31.4, 30.7, 27.6, 25.2, 22.0, 19.9, 19.7, 17.5, -4.7.
HRMS C35H45N3O4Si [M + Na+] calcd 622.3077, found 622.3068.
N-((()-1-{Methylbis[(trimethylsilyl)oxy]silyl}-2-phenylethyl)-
acetamide (58) and N-[(()-1-{Methyl(phenyl)[(trimethylsilyl)-
oxy]silyl}-2-phenylethyl]acetamide (59). Diphenylsilane 52 (47
mg, 0.13 mmol) was dissolved in dry CH2Cl2 (10 mL) under a
nitrogen atmosphere and cooled to 0 °C in an ice bath. Triflic acid
(0.12 mL, 1.3 mmol) was added dropwise and the reaction was
stirred for 4.5 h while being allowed to warm to rt. The reaction
was cooled to 0 °C, concd NH4OH (0.30 mL, 1.9 mmol) was added,
and the reaction was stirred for another 50 min at 0 °C. The reaction
was quenched with water (10 mL) and the pH adjusted to 8-9 by
adding 2 M HCl. The phases were separated and the aqueous phase
was extracted with CH2Cl2 (10 mL). The combined organic extracts
were washed with brine (15 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was dissolved in dry CH2Cl2
(10 mL) and cooled to 0 °C in an ice bath. Chlorotrimethylsilane
(0.33 mL, 2.6 mmol) and triethylamine (0.22 mL, 1.6 mmol) were
added and the reaction was stirred at 0 °C for 2.5 h. The reaction
was quenched with water (10 mL), the phases were separated, and
the organic extract was washed with water (10 mL) and brine (10
mL), dried (Na2SO4), filtered, and concentrated. The pure products
were obtained by column chromatography (25% EtOAc in pentane
as eluant), which gave compound 58 (28 mg, 0.073 mmol, 56%)
and compound 59 as a mixture of diastereoisomers (18 mg, 0.048
mmol, 37%). 58: 1H NMR (400 MHz, CDCl3) δ (ppm) 7.28-
7.18 (m, 5H), 5.12 (br d, J ) 9.2 Hz, 1H), 3.63 (td, J ) 9.2, 5.6
Hz, 1H), 2.91 (dd, J ) 14.0, 5.6 Hz, 1H), 2.70 (dd, J ) 14.0, 9.2
Hz, 1H), 1.87 (s, 3H), 0.12 (s, 9H), 0.09 (s, 9H), 0.03 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ (ppm) 169.4, 139.6, 129.2 (2C), 128.4
(2C), 126.3, 41.6, 36.3, 23.5, 2.0 (6C), -1.2. HRMS C17H33NO3-
Si3 [M + Na+] calcd 406.1666, found 406.1663. 59a (first
diastereoisomer): 1H NMR (400 MHz, CDCl3) δ (ppm) 7.57-
7.55 (m, 2H), 7.43-7.35 (m, 3H), 7.25-7.10 (m, 5H), 5.13 (br d,
J ) 9.2 Hz, 1H), 3.83 (ddd, J ) 10.8, 9.2, 4.8 Hz, 1H), 2.88 (dd,
J ) 14.4, 4.8 Hz, 1H), 2.69 (dd, J ) 14.4, 10.8 Hz, 1H), 1.81 (s,
3H), 0.39 (s, 3H), 0.14 (s, 9H). 59b (second diastereoisomer): 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.57-7.55 (m, 2H), 7.43-7.35
(m, 3H), 7.25-7.10 (m, 5H), 5.01 (br d, J ) 9.6 Hz, 1H), 3.96
(ddd, J ) 10.8, 9.6, 4.4 Hz, 1H), 3.01 (dd, J ) 14.4, 4.4 Hz, 1H),
2.57 (dd, J ) 14.4, 10.8 Hz, 1H), 1.77 (s, 3H), 0.40 (s, 3H), 0.14
(s, 9H). MS C20H29NO2Si2 calcd 394.2, found 394.2.
(()-N-{1-[Dihydroxy(methyl)silyl]-2-phenylethyl}acet-
amide (60). Trisiloxane 58 (17 mg, 0.044 mmol) was dissolved in
CD3OD (0.3 mL) and transferred via syringe to a solution of KOH
(3 mg, 0.055 mmol) in D2O (0.5 mL). The reaction was stirred
under nitrogen at rt for 18 h and directly subjected to NMR analysis.
Yield not determined. 1H NMR (400 MHz, D2O/CD3OD) δ (ppm)
7.27-7.14 (m, 5H), 3.44 (dd, J ) 12.8, 3.6 Hz, 1H), 3.00 (dd, J )
14.4, 3.6 Hz, 1H), 2.60 (dd, J ) 14.4, 12.8 Hz, 1H), 1.76 (s, 3H),
-0.05 (s, 3H). 13C NMR (100 MHz, D2O/CD3OD) δ (ppm) 173.0,
142.2, 129.8 (2C), 129.1 (2C), 126.8, 45.5, 36.6, 22.8, -1.9. MS
C11H17NO3Si [M + K+] calcd 278.1, found 278.1.
(S)-N-[(R)-2-Methyl-1-(methyldiphenylsilyl)propyl]-1-(phen-
ylacetyl)pyrrolidine-2-carboxamide (61). Cbz-protected amine 54
(65 mg, 0.13 mmol) was dissolved in absolute EtOH (7 mL) before
concd HCl (2 drops) and Pd/C 10% (15 mg) were added. The
system was flushed with nitrogen before being subjected to a
positive atmosphere of hydrogen and heated to 50 °C. After 1, 3,
and 6.5 h another portion of Pd/C 10% was added, and after 19 h,
PdCl2 (11 mg, 0.065 mmol) was added to furnish the complete
conversion of starting material after a further 3 h. The reaction
mixture was cooled to rt, filtered through celite, and washed with
CH2Cl2. The combined filtrates were evaporated in vacuo, and then
10042 J. Org. Chem., Vol. 72, No. 26, 2007

Synthesis of Methyl Silanediol Peptide Mimics
toluene (2 mL) was added and removed in vacuo to give the crude
amine as its HCl salt. This was dissolved in CH2Cl2 (10 mL), and
DIPEA (0.11 mL, 0.65 mmol), phenylacetic acid (22 mg, 0.16
mmol), HOBt (39 mg, 0.26 mmol), and EDC‚HCl (49 mg, 0.26
mmol) were added. The mixture was stirred at rt for 47 h, then
poured into water (40 mL) and extracted with CH2Cl2 (2 × 40
mL). The combined organic portions were dried (MgSO4), filtered,
and evaporated in vacuo. The pure product was obtained by column
chromatography (increasing polarity from 10% to 50% EtOAc in
pentane as eluant), which gave the title compound (48 mg, 0.099
mmol, 76%) as a colorless solid. Major rotamer: 1H NMR (400
MHz, CDCl3) δ (ppm) 7.61-7.56 (m, 4H), 7.43-7.23 (m, 11H),
6.95 (d, J ) 10.0 Hz, 1H), 4.46 (d, J ) 6.8 Hz, 1H), 4.05 (dd, J )
10.0, 5.6 Hz, 1H), 3.53-3.40 (m, 2H), 2.27-2.21 (m, 1H), 2.07-
1.98 (m, 1H), 1.95-1.85 (m, 2H), 1.71-1.61 (m, 1H), 0.79 (d, J
) 6.8 Hz, 3H), 0.71 (d, J ) 6.8 Hz, 3H), 0.70 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ (ppm) 171.3, 170.7, 135.8 (2C), 134.9 (2C),
134.9 (2C), 134.4, 129.5, 129.4, 129.1 (2C), 128.8 (2C), 128.0 (2C),
127.9 (2C), 127.0, 60.0, 47.8, 44.4, 42.1, 30.4, 27.2, 25.1, 22.1,
19.7, -4.7. Minor rotamer (inter alia): 1H NMR (400 MHz, CDCl3)
δ (ppm) 5.92 (br d, J ) 10.6 Hz, 1H), 4.33 (dd, J ) 10.6, 5.2 Hz,
1H), 4.20 (dd, J ) 8.4, 2.4 Hz 1H). 13C NMR (100 MHz, CDCl3)
δ (ppm) 134.9, 134.4, 128.7, 128.6, 128.3, 61.8, 46.9, 43.2, 41.4,
31.9, 30.5, 22.7, 22.5, 19.5. HRMS C30H36N2O2Si [M + Na+] calcd
507.2444, found 507.2441.
Cbz-protected amine 56 (69 mg, 0.12 mmol) was dissolved in
absolute EtOH (5 mL) before concd HCl (2 drops) and Pd/C 10%
(15 mg) were added. The system was flushed with nitrogen before
being subjected to a positive atmosphere of hydrogen and heated
to 50 °C. After 1.5 h another portion of Pd/C 10% was added, and
after 6 h, PdCl2 (11 mg, 0.065 mmol) was added to furnish the
complete conversion of starting material after a further 1 h. The
reaction mixture was cooled to rt, filtered through celite, and washed
with CH2Cl2. The combined filtrates were evaporated in vacuo, and
then toluene (2 mL) was added and removed in vacuo to give the
crude amine as its HCl salt. This was dissolved in CH2Cl2 (10 mL),
and NMM (0.07 mL, 0.61 mmol), phenylacetic acid (19 mg, 0.13
mmol), HOBt (38 mg, 0.24 mmol), and EDC‚HCl (47 mg, 0.24
mmol) were added. The mixture was stirred at rt for 42 h, then
poured into water (10 mL) and extracted with CH2Cl2 (2 × 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 50% to 100% EtOAc in
pentane as eluant), which gave the title compound (35 mg, 0.063
1
mmol, 52%) as a colorless solid. H NMR (400 MHz, CDCl3) δ
(ppm) 7.56-7.53, (m, 4H), 7.38-7.27 (m, 11H), 6.52 (br d, J )
10.8 Hz, 1H), 6.38 (br d, J ) 6.8 Hz, 1H), 4.70 (quint, J ) 6.8 Hz,
1H), 4.40 (dd, J ) 8.0, 2.4 Hz, 1H), 4.10 (dd, J ) 10.8, 5.6 Hz,
1H), 3.67-3.57 (m, 1H), 3.55 (s, 2 H), 3.49-3.44 (m, 1H), 2.18-
2.11 (m, 1H), 1.96-1.86 (m, 2H), 1.73-1.64 (m, 2H), 1.22 (d, J
) 6.8 Hz, 3H), 0.80 (d, J ) 6.8 Hz, 3H), 0.74 (d, J ) 6.8 Hz, 3H),
0.65 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 172.4, 170.3,
170.3, 135.5, 135.4, 134.9 (4C), 134.8, 129.6, 129.5, 129.4 (2C),
129.0 (2C), 128.1 (2C), 128.0 (2C), 127.4, 60.0, 47.3, 46.8, 44.1,
43.7, 30.5, 27.1, 25.1, 22.1, 19.6, 18.4, -4.6. HRMS C33H41N3O3-
Si [M + Na+] calcd 578.2815, found 578.2836.
(S)-N-{(R)-2-Methyl-1-[dihydroxy(methyl)silyl]propyl}-1-(phen-
ylacetyl)pyrrolidine-2-carboxamide (62). Trisiloxane 63 (30 mg,
0.058 mmol) was dissolved in CD3OD (0.3 mL) under nitrogen.
D2O (0.3 mL) and KOH dissolved in D2O (0.077 M, 0.1 mL, 0.0077
mmol) were added and the reaction was placed in a sonicator for
1
5 h. The reaction mixture was used directly for NMR. H NMR
(400 MHz, D2O/CD3OD) major rotamer δ (ppm) 7.37-7.20 (m,
5H), 4.40 (dd, J ) 8.8, 4.0 Hz, 1H), 3.77-3.48 (m, 4H), 3.03 (d,
J ) 6.4 Hz, 1H), 2.36-2.27 (m, 1H), 2.20-2.07 (m, 1H), 2.04-
1.87 (m, 3H), 0.91 (d, J ) 6.8 Hz, 3H), 0.87 (d, J ) 6.4 Hz, 3H),
-0.07 (s, 3H); minor rotamer (inter alia) δ (ppm) 4.57 (dd, J )
8.4, 2.4 Hz, 1H), 3.14 (d, J ) 6.0 Hz, 1H), -0.05 (s, 3H).
(S)-N-((R)-2-Methyl-1-{methylbis[(trimethylsilyl)oxy]silyl}-
propyl)-1-(phenylacetyl)pyrrolidine-2-carboxamide (63). Diphe-
nylsilane 54 (24 mg, 0.049 mmol) was dissolved in dry CH2Cl2 (5
mL) under a nitrogen atmosphere and cooled to 0 °C in an ice
bath. Triflic acid (0.04 mL, 0.49 mmol) was added dropwise and
the reaction was stirred at 0 °C for 20 h while being allowed to
warm to rt. The reaction was cooled to 0 °C, concd NH4OH (0.11
mL, 0.74 mmol) was added, and the reaction was stirred for another
2 h at 0 °C. The reaction was quenched with water (2 mL) and the
pH adjusted to 9 by dropwise addition of 2 M HCl. The two phases
were concentrated and trace water removed by consecutive addition
of toluene (2 mL) and removal in vacuo. The residue was dissolved
in dry CH2Cl2 (5 mL) under a nitrogen atmosphere and cooled to
0 °C in an ice bath. Chlorotrimethylsilane (0.090 mL, 0.74 mmol)
and triethylamine (0.070 mL, 0.49 mmol) were added and the
reaction mixture was stirred at 0 °C for 2 h. The reaction was
quenched with water (5 mL), the phases were separated, and the
organic extract was washed with water (5 mL) and brine (5 mL),
dried (Na2SO4), filtered, and concentrated. The product was purified
by column chromatography (25% EtOAc in pentane as eluant) to
(S)-N-[(R)-2-Methyl-1-(methyldiphenylsilyl)propyl]-1-[(S)-3-
methyl-2-(phenylacetamido)butanoyl]pyrrolidine-2-carboxam-
ide (65). Cbz-protected amine 57 (68 mg, 0.11 mmol) was dissolved
in absolute EtOH (5 mL), before concd HCl (2 drops) and Pd/C
10% (15 mg) were added. The system was flushed with nitrogen
before being subjected to a positive atmosphere of hydrogen and
heated to 50 °C for 5.5 h. The reaction mixture was cooled to rt,
filtered through celite, and washed with CH2Cl2. The combined
filtrates were evaporated in vacuo, and then toluene (2 mL) was
added and removed in vacuo to give the crude amine as its HCl
salt. This was dissolved in CH2Cl2 (10 mL), and then NMM (0.062
mL, 0.57 mmol), phenylacetic acid (18 mg, 0.12 mmol), HOBt
(35 mg, 0.23 mmol), and EDC‚HCl (43 mg, 0.23 mmol) were
added. The mixture was stirred at rt for 43 h, then poured into
water (10 mL) and extracted with CH2Cl2 (2 × 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 40% to 50% EtOAc in
pentane as eluant), which gave the title compound (48 mg, 0.082
mmol, 73%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ (ppm)
7.57-7.52 (m, 4H), 7.37-7.25 (m, 11H), 6.27 (br d, J ) 10.8 Hz,
1H), 6.09 (br s, 1H), 4.57 (dd, J ) 8.8, 6.8 Hz, 1H), 4.24 (dd, J )
8.0, 2.8 Hz, 1H), 4.09 (dd, J ) 10.8, 6.0 Hz, 1H), 3.78-3.70 (m,
1H), 3.64-3.51 (m, 3H), 2.06-2.00 (m, 1H), 1.95-1.82 (m, 4H),
1.72-1.64 (m, 1H), 0.90 (d, J ) 6.8 Hz, 3H), 0.83 (d, J ) 6.4 Hz,
3H), 0.78 (d, J ) 6.8 Hz, 3H), 0.76 (d, J ) 6.4 Hz, 3H), 0.66 (s,
3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 171.6, 170.9, 170.8,
135.5, 135.4, 134.9 (2C), 134.8 (3C), 129.6, 129.6, 129.4 (2C),
129.0 (2C), 128.0 (2C), 128.0 (2C), 127.4, 60.3, 55.5, 47.8, 44.3,
43.8, 31.4, 30.7, 27.7, 25.1, 22.0, 19.9, 19.6, 17.6, -4.6. HRMS
C35H45N3O3Si [M + Na+] calcd 606.3128, found 606.3098.
(S)-N-((R)-2-Methyl-1-{methylbis[(trimethylsilyl)oxy]silyl}-
propyl)-1-[(S)-2-(phenylacetamido)propanoyl]pyrrolidine-2-car-
boxamide (66). Diphenylsilane 64 (17.6 mg, 0.032 mmol) was
dissolved in dry CH2Cl2 (5 mL) under a nitrogen atmosphere and
cooled to 0 °C in an ice bath. Triflic acid (0.028 mL, 0.32 mmol)
was added dropwise and the reaction was stirred at 0 °C for 25 h
while being allowed to warm to rt. The reaction was cooled to
1
give the title compound (12 mg, 0.0265 mmol, 47%). H NMR
(400 MHz, CDCl3) δ (ppm) 7.32-7.21 (m, 5H), 6.84 (d, J ) 10.4,
1H), 4.61 (dd, J ) 8.0, 1.6 Hz, 1H), 3.70 (s, 2H), 3.66-3.40 (m,
2H), 3.26 (dd, J ) 10.4, 5.2 Hz, 1H), 2.46-2.39 (m, 1H), 2.21-
2.08 (m, 1H), 1.99-1.90 (m, 1H), 1.87-1.71 (m, 2H), 0.82 (d, J
) 6.8 Hz, 3H), 0.78 (d, J ) 6.8 Hz, 3H), 0.11 (s, 9H), 0.10 (s,
9H), 0.05 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 171.2,
170.8, 134.5, 129.2 (2C), 128.8 (2C), 127.0, 60.1, 47.8, 46.5, 42.2,
29.8, 27.2, 25.3, 21.3, 19.6, 1.9 (6C), -0.7. HRMS C24H44N2O4-
Si3 [M + Na+] calcd 531.2507, found 531.2501.
(S)-N-[(R)-2-Methyl-1-(methyldiphenylsilyl)propyl]-1-[(S)-2-
(phenylacetamido)propanoyl]pyrrolidine-2-carboxamide (64).
J. Org. Chem, Vol. 72, No. 26, 2007 10043

Nielsen et al.
0 °C, concd NH4OH (0.075 mL, 0.48 mmol) was added, and the
reaction was stirred for another 2.5 h at 0 °C. The reaction was
quenched with water (2 mL) and the pH adjusted to 9 by dropwise
addition of 2 M HCl. The two phases were concentrated and trace
water removed by consecutive addition of toluene (2 mL) and
removal in vacuo. The residue was dissolved in dry CH2Cl2 (5 mL)
under a nitrogen atmosphere and cooled to 0 °C in an ice bath.
Chlorotrimethylsilane (0.061 mL, 0.48 mmol) and triethylamine
(0.044 mL, 0.32 mmol) were added and the reaction was stirred at
0 °C for 20 h. The reaction was quenched with water (5 mL), the
phases were separated, and the organic extract was washed with
water (5 mL) and brine (5 mL), dried (Na2SO4), filtered, and
concentrated. The product was purified by column chromatography
(increasing polarity from 40% to 50% EtOAc in pentane as eluant)
addition of 2 M HCl. The two phases were concentrated and trace
water removed by consecutive addition of toluene (2 mL) and
removal in vacuo. The residue was dissolved in dry CH2Cl2 (5 mL)
under a nitrogen atmosphere and cooled to 0 °C in an ice bath.
Chlorotrimethylsilane (0.078 mL, 0.61 mmol) and triethylamine
(0.057 mL, 0.41 mmol) were added and the reaction was stirred at
0 °C for 2 h. The reaction was quenched with water (5 mL), the
phases were separated, and the organic extract was washed with
water (5 mL) and brine (5 mL), dried (Na2SO4), filtered, and
concentrated. The product was purified by column chromatography
(increasing polarity from 20% to 50% EtOAc in pentane as eluant)
1
to give the title compound (8.4 mg, 0.014 mmol, 34%). H NMR
(400 MHz, CDCl3) δ (ppm) 7.36-7.28 (m, 5H), 6.42 (br d, J )
10.4 Hz, 1H), 6.07 (br d, J ) 9.2 Hz, 1H), 4.61 (dd, J ) 9.2, 6.4
Hz, 1H), 4.47 (dd, J ) 8.0, 2.8 Hz, 1H), 3.79-3.73 (m, 1H), 3.63-
3.53 (m, 3H), 3.26 (dd, J ) 10.4, 5.2 Hz, 1H), 2.36-2.29 (m, 1H),
2.21-2.10 (m, 1H), 2.00-1.90 (m, 2H), 1.88-1.78 (m, 2H), 0.93
(d, J ) 6.4 Hz, 3H), 0.87 (d, J ) 6.8 Hz, 3H), 0.85 (d, J ) 6.8 Hz,
3H), 0.79 (d, J ) 6.8 Hz, 3H), 0.10 (s, 18H), 0.05 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 171.8, 170.9, 170.7, 134.9, 129.5
(2C), 129.1 (2C), 127.4, 60.3, 55.5, 47.8, 46.5, 43.9, 31.6, 30.0,
27.6, 25.3, 21.2, 19.8, 19.7, 17.7, 1.97 (3C), 1.95 (3C), -0.6. HRMS
C29H53N3O5Si3 [M + Na+] calcd 630.3191, found 630.3195.
1
to give the title compound (7.6 mg, 0.013 mmol, 41%). H NMR
(400 MHz, CDCl3) δ (ppm) 7.36-7.28 (m, 5H), 6.61 (br d, J )
10.4, 1H), 6.41 (br d, J ) 6.8 Hz, 1H), 4.73 (quin, J ) 6.8 Hz,
1H), 4.57 (dd, J ) 8.0, 2.0 Hz, 1H), 3.65-3.58 (m, 1H), 3.57 (s,
2H), 3.53-3.48 (m, 1H), 3.27 (dd, J ) 10.4, 5.2 Hz, 1H), 2.46-
2.39 (m, 1H), 2.22-2.10 (m, 1H), 2.03-1.94 (m, 1H), 1.88-1.75
(m, 2H), 1.29 (d, J ) 6.8 Hz, 3H), 0.83 (d, J ) 6.4 Hz, 3H), 0.82
(d, J ) 6.8 Hz, 3H), 0.11 (s, 18H), 0.04 (s, 3H). 13C NMR (100
MHz, CDCl3) δ (ppm) 172.4, 170.3 (2C), 134.8, 129.5 (2C), 129.1
(2C), 127.4, 60.0, 47.2, 46.9, 46.3, 43.8, 29.8, 26.8, 25.3, 21.3,
19.5, 18.7, 1.9 (6C), -0.7. HRMS C27H49N3O5Si3 [M + Na+] calcd
602.2878, found 602.2874.
(S)-N-((R)-2-Methyl-1-{methylbis[(trimethylsilyl)oxy]silyl}-
propyl)-1-[(S)-3-methyl-2-(phenylacetamido)butanoyl]pyrrolidine-
2-carboxamide (67). Diphenylsilane 65 (24 mg, 0.041 mmol) was
dissolved in dry CH2Cl2 (5 mL) under a nitrogen atmosphere and
cooled to 0 °C in an ice bath. Triflic acid (0.040 mL, 0.41 mmol)
was added dropwise and the reaction was stirred at 0 °C for 22 h
while being allowed to warm to rt. The reaction was cooled to 0
°C, concd NH4OH (0.10 mL, 0.61 mmol) was added, and the
reaction was stirred for another 2 h at 0 °C. The reaction was
quenched with water (2 mL) and the pH adjusted to 9 by dropwise
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foundation,
the Lundbeck Foundation, the Carlsberg Foundation, and the
University of Aarhus.
Supporting Information Available: Experimental methods for
the preparation of compounds 7, 8, 16-18, 20, 22, 25-31, 33-
42, and 47 and copies of 1H NMR and 13C NMR spectra for
compounds 7, 8, 16-18, 20-42, 47-54, and 56-71. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO701907D
10044 J. Org. Chem., Vol. 72, No. 26, 2007