Application of divergent multi-component reactions in the synthesis of a library of peptidomimetics based on γ-amino-α,β-cyclopropyl acids

Article abstract of DOI:10.1016/j.tet.2005.09.016

The multi-component condensation of organozirconocene, aldimine and zinc carbenoid was applied to the stereoselective synthesis of cyclopropane amino acid derivatives. These compounds served as scaffolds for the preparation of a 46-member library. The C-

Full text of DOI:10.1016/j.tet.2005.09.016

Tetrahedron 61 (2005) 11488–11500
Application of divergent multi-component reactions
in the synthesis of a library of peptidomimetics based on
g-amino-a,b-cyclopropyl acids
*
Peter Wipf, Stefan Werner, Grace H. C. Woo, Corey R. J. Stephenson, Maciej A. A. Walczak,
Claire M. Coleman and Leslie A. Twining
Center for Chemical Methodologies and Library Development (UPCMLD), University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 15 July 2005; revised 24 August 2005; accepted 2 September 2005
Available online 28 September 2005
Abstract—The multi-component condensation of organozirconocene, aldimine and zinc carbenoid was applied to the stereoselective
synthesis of cyclopropane amino acid derivatives. These compounds served as scaffolds for the preparation of a 46-member library. The C-
and N-termini of the cyclopropane amino acid derivatives were diversified by condensations with ten amines and ten acylating agents,
respectively. To improve yields and accelerate library synthesis, most products were prepared under microwave irradiation and purified by
polymer-bound scavengers and SPE methodology. All compounds were analyzed by LC–MS and a representative selection was fully
characterized.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Multi-component reactions such as the Ugi and Passerini
reactions have had a significant influence on industrial
structure–activity relationship (SAR) analyses and pharma-
ceutical library syntheses.1 The Ugi four-component
condensation provides amino acid analogs from readily
available aldehydes, carboxylic acids, and amines, and less
easily accessible isocyanides,2 but only a single product
structure is obtained from a given set of starting materials.
We have recently introduced the concept of divergent multi-
component reactions (DMCRs),3 whereby reaction con-
Scheme 1. Choice of solvent influences product formation.
ditions such as the choice of solvent4 or the order of addition
of reagents5 influence the reaction pathway and thus provide
a rapid access to different scaffolds (Schemes 1 and 2).6
In addition to the discovery of new C,C-bond forming
cascade reactions,7 we have directed our DMCR
methodology toward the synthesis of peptidomimetics8
such as (E)-alkene peptide isosteres (j[RC]CH], d-amino-
b,g-unsaturated amino acids, with RZalkyl, aryl, H, F, and
CF3),9 cyclopropane dipeptide isosteres (j[RCp], d-amino-
b,g-cyclopropyl amino acids),9a,c and, in an extension of the
Keywords: Indexed library; Microwave irradiation; Polymer-bound
scavengers.
*
Corresponding author. Tel.: C1 412 624 8606; fax: C1 412 624 0787;
e-mail: pwipf@pitt.edu
Scheme 2. Order of reagent addition influences product formation.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.016

P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
11489
biological properties of these peptidomimetics,4e we now
report a new, more expedient synthesis of DPhg as well as
the synthesis of a 46-member library of DPhg derivatives.
2. Results and discussion
Synthetic methodology. In our recent approach to g-amino-
a,b-cyclopropyl acids,11 we described a 9-step (including
resolution) sequence relying upon sequential Grieco
elimination–alkene oxidation to introduce the C-terminal
carboxylate function. This strategy introduced several steps
that complicated the scale up for preparative purposes. We
have now been able to optimize this sequence to allow the
multi-gram synthesis of the enantiomerically pure cyclo-
propyl amino acid derivatives 6 and 7 in a more efficient
fashion (Scheme 3). Addition of Cp2ZrHCl24 to TBDPS-
protected propargyl alcohol 1, followed by sequential
transmetallation to dimethylzinc, addition to N-diphenyl-
phosphinylimine and treatment with bis(iodomethyl)-
zinc$DME complex25 afforded the desired amide 2 in an
overall yield of 67% and in high diastereomeric ratio
(O19:1). Removal of the TBDPS group with TBAF and
oxidation of the resulting alcohol afforded the carboxylic
acid which could be converted into the methyl ester
hydrochloride salt 3 under acidic conditions (HCl in
MeOH). The racemate 3 was resolved by formation of the
diastereomeric salts with L- and D-tartaric acid. The
hydrochloride salts 3 were first converted to the free amines
that were co-crystallized with tartaric acid in an ethanol–
water mixture affording 5. The corresponding diastereo-
meric salt (recovered from the filtrate) was an amorphous
solid, which was not easily crystallized. Formation of the
D-tartaric acid salt facilitated its crystallization. Indeed, after
only three crystallizations, over 80% of the initial amine
could be recovered in the form of enantiomerically pure
salts. Pure g-amino-a,b-cyclopropyl acids (ee O95%)
could be obtained by washing the crystalline salts 4 and 5
with an aqueous solution of K2CO3 at 0 8C in chloroform.
X-ray structure analysis of a diastereomeric derivative was
used to assign the absolute configuration of 4 and 5.11 The
free amines were transformed into the Cbz-protected amino
acid methyl esters 6{1,1} and 7{1,1} or the N-diphenyl-
phosphinyl amides 6{1,3} and 7{1,3}.
Figure 1. Peptidomimetics based on isosteric amide bond replacements or
amino acid backbone chain extensions.
principle of vinylogy for a-amino acids,10 backbone-
modified g-amino-a,b-cyclopropyl acids (Fig. 1).11
The scissile peptide bond is in part responsible for poor
pharmacokinetic properties, low oral bioavailability and
rapid proteolytic degradation of oligopeptides composed of
natural amino acid residues. Peptidomimetics have the
potential to provide increased metabolic stability and better
oral bioavailability.12 The replacement of peptide bonds
with transition-state analogs such as hydroxyethylene,13
hydroxyethylamine,14 dihydroxyethylene15 or ketomethyl-
ene16 groups has produced chimeric molecules that combine
improved pharmacokinetic properties and higher potency.
Isosteric replacements such as (E)- or (Z)-alkenes,17 (E)- or
(Z)-methylalkenes,9,18 (Z)-fluoroalkenes,19 cyclopropyl
rings9,11,20 or larger ring systems21 do not only prevent
hydrolytic cleavage but also incorporate conformational
constraints into the peptide backbone. This may allow for a
tighter binding to a target enzyme or receptor leading to
increased potency. We recently introduced the cyclo-
propane amino acid derivative DPhg (Fig. 2).11 In contrast
to alkenes which have the potential to undergo isomeriza-
tion or oxidation, cyclopropanes display an increased
chemical and metabolic stability.22 X-ray and solution
structural analyses have shown that cyclopropane-contain-
ing peptides occupy biologically relevant conformational
space.9,11
Library design. For the generation of a focused library, both
C- and N-termini of the cyclopropane peptidomimetics were
modified. Instead of synthesizing a complete 12!12 matrix
for 6 and 7, i.e., 288 compounds, an indexed library design
was chosen.26 In an indexed library, only one substituent is
varied at a time while all other substituents remain
unchanged. Accordingly, a two-dimensional matrix is
divided into two one-dimensional matrices (Fig. 3). In the
present example, two 12!12 matrices were transformed
into four 12!1 matrices, i.e., 48 compounds. Since two
compounds appear in two matrices, only 46 compounds
were synthesized to encompass a similar chemical space as
two 12!12 matrices. If compounds A{1,4} and A{3,1} in
Figure 3 show activity in an initial screen, compound
A{3,4} can be synthesized and evaluated in a subsequent
screen.
Figure 2. Phenylglycine derived cyclopropane amino acid residue; the
D-prefix is used for amino acids that have a cyclopropane ring inserted into
the backbone chain between carbonyl-C and a-C.
The DPhg residue can be accessed stereoselectively by the
three component condensation of an alkenylzirconocene,23
an aldimine and a dihalomethane-derived zinc carbenoid
species. As a starting point for further investigation of the
For an efficient library synthesis, polymer- or silica-bound

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P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
Scheme 3. Preparation of cyclopropane amino acid derivatives DPhg 6{1,1}, 6{1,3}, 7{1,1} and 7{1,3}.
Figure 3. Traditional versus indexed library.
reagents and SPE scavenging and separation techniques
were applied.27 To further accelerate the library workflow,
most reactions were carried out in an automated Emrys
Optimizer single-mode microwave reactor.
C-Terminal functionalizations. The two esters 6{1,3} and
7{1,3} were hydrolyzed in parallel and the free acids were
extracted using an ALLEXis system.28 Each batch was
divided into eleven parts; the free acid was added directly to
the library, and the remaining 10 parts were transformed
into amides. In order to obtain a broad distribution of
Figure 4. Building blocks 8{3–12} for C-terminal functionalizations.

P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
11491
pharmacokinetic properties for the library,29 a diverse set of
10 amines was chosen (Fig. 4). While methylamine (8{3})
was selected due to its small size, cyclopropanemethyl-
amine (8{4}) was chosen due to its chain branching as well
as its lipophilic character. Several aromatic and hetero-
aromatic amines (8{5–10}) that can act as hydrogen bond
donors were also selected. Polar functions were represented
by alaninol (8{11}) and tryptamine (8{12}).
30 min. The reagents and polymer beads were removed by
filtration of the reaction mixture through a silica-bound
carbonate cartridge. This protocol was fast and allowed the
synthesis of 10 library members in 2–3 h. Methylamine
(8{3}), cyclopropanemethylamine (8{4}), benzylamine
(8{5}), 4-methylsulfonylbenzylamine (8{6}), 2-amino-
methylpyridine (8{7}), 5-methyl-2-furanmethanamine
(8{8}) and (1,5-dimethyl-1H-pyrazol-3-yl)methylamine
(8{9}) afforded the corresponding amides in moderate to
good yields and high purities (Table 1). Subsequent
purification was not necessary.
The drawback of this diverse set of building blocks 8{3–12}
was that three different protocols for amide coupling were
required (Scheme 4). The most efficient protocol (protocol
A)30 involved polymer-bound carbodiimide and 1-hydroxy-
benzotriazole as coupling reagents. These reagents were
added in excess to a solution of the acid in chlorobenzene
and stirred for 5 min before an equimolar amount of amine
was added. Microwave irradiation at 100 8C for 5 min
afforded the corresponding amides. In order to drive
reactions to completion, volatile amines were added in
excess and the reaction mixture was irradiated at 60 8C for
While protocol A worked well for most amines, for the
syntheses of 6{10,3} and 7{10,3} the use of EDCI as the
coupling reagent in the presence of HOBt was found to be
advantageous, and the reaction mixture was stirred for 12 h
at room temperature (protocol B). All water-soluble
components were removed by ChemElut extraction. Since
this extract contained a significant amount of impurities,
automated parallel chromatography on SiO2 with the ISCO
Optix 10 system was necessary to afford the library
members in high purity.
When the coupling protocols A or B were applied to the
amidation with tryptamine (8{12}), the product was
obtained in low yield, and with (R)-(K)-2-amino-1-
propanol (8{11}) no product was formed. A more efficient
coupling reagent such as 3-(diethoxyphosphoryloxy)-1,2,3-
benzotriazin-4(3H)-one (DEPBT)31 had to be used (protocol
C). This method provided the desired amides in moderate
yields and high purities, but it involved time-consuming
additional aqueous extractions by the ALLEXis system and
parallel chromatography on SiO2 with the ISCO Optix 10
instrumentation.
Applying the three protocols A–C, a sublibrary of 20
C-terminal derivatized cyclopropyl carboxamides was
successfully prepared. The use of polymer-bound reagents
and scavenging techniques for most substrates significantly
decreased the time needed for the library synthesis.
N-Terminal functionalizations. In addition to the C-terminal
functionalizations of DPhg derivatives, N-phosphinylation,
N-sulfonylation, N-carbamoylation and N-acylation further
expanded the compound collection. The building blocks
6{1,2} and 7{1,2} were prepared by hydrogenolysis of
6{1,1} and 7{1,1}, followed by immediate conversion to the
corresponding ammonium salts (Scheme 5). Compounds
6{1,2} and 7{1,2} were treated with 10 structurally diverse
acylating reagents 9{3–12} (Fig. 5), including one
phosphinyl chloride, one chloroformate, two sulfonyl
chlorides and six acyl chlorides to afford the 20 N-acyl
derivatives 6{1,3–12} and 7{1,3–12}.
In a typical N-acylation procedure, microwave irradiation of
a suspension of the ammonium salts 6{1,2} or 7{1,2}
(1.0 equiv), PS-DMAP (1.2 equiv), triethylamine
(2.0 equiv) and the corresponding acylating agent 9{3–12}
at 100 8C for 10 min in CH2Cl2 afforded the crude
N-acylated products. Resin-bound scavengers were found
to be ideal for purification because of ease, speed (avoiding
chromatography) and the ability to proceed in parallel
fashion. Upon cooling to room temperature, the reaction vial
Scheme 4. C-Terminal functionalizations.

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P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
Table 1. C-Terminal functionalizations, isolated yields (purity by LC–MS with ELS detection)
R1
Protocol
6{1,3}, (95)
6{2,3}, (94)
7{1,3}, (95)
7{2,3}, (94)
A
A
6{3,3}, 23 (97)
6{4,3}, 35 (91)
7{3,3}, 30 (98)
7{4,3}, 44 (O99)
A
A
A
6{5,3}, 81 (92)
6{6,3}, 82 (94)
6{7,3}, 66 (O99)
7{5,3}, 92 (98)
7{6,3}, 98 (95)
7{7,3}, 77 (96)
A
A
6{8,3},a 72 (94)
7{8,3},a 84 (91)
7{9,3},a 72 (98)
6{9,3},a 73 (O99)
B
C
C
6{10,3}, 69 (91)
6{11,3}, 46 (98)
6{12,3}, 53 (98)
7{10,3}, 72 (95)
7{11,3}, 44 (97)
7{12,3},b 68 (97)
a Traces of amine were removed by product precipitation in diethylether.
b With protocol B, 7{12,3} was obtained in 23% yield.
containing the crude product was charged with MP-
trisamine32,33 (1.0 equiv) and MP-isocyanate33 (1.0 equiv),
and microwave irradiation in the automated Emrys
Optimizer microwave reactor was resumed at 100 8C for
5 min. Finally, the reaction mixture was subjected to an
aqueous work-up by passage through a ChemElut SPE
cartridge preconditioned with saturated aqueous NaHCO3
solution to remove the resin-bound reagents and the
triethylammonium chloride salt. The eluant was collected
and concentrated to dryness using a centrifugal vacuum
evaporator (Genevac HT-4) to provide the desired amides
(Table 2).
purity of 96% (Table 1). The N-functionalized amides
6{1,3–12} and 7{1,3–12} were obtained in an average yield
of 91% and in an average purity of 95% (Table 2).
3. Conclusions
We have optimized our DMCR approach to DPhg and
applied it toward the preparation of a diverse indexed
library of backbone-extended cyclopropane amino acid
derivatives. Modern parallel synthesis techniques were
used for the synthesis of 46 library members in an average
purity of 95% after resin-based scavenging and SPE
purification. Product yields varied depending on the
reactant structure, but in most cases, the desired products
were generated in good to excellent yields. The library
members were obtained in an average yield of 78% and in
an average amount of 24 mg. This study represents a
further demonstration of the utility of multi-component
reactions for diversity-oriented small molecule library
synthesis.34 Biological evaluation of this library will be
reported in due course.
Library analysis. The purity of all 46 library members was
determined by reversed-phase HPLC with ELS and MS
detection. Twelve library members (26%) were analyzed by
1H NMR and five library members (11%) were fully
1
characterized by H NMR, 13C NMR, 31P NMR, IR, MS,
HRMS and mp. All library members were obtained in
O85% purity by ELS detection and none had to be
repurified by chromatography on SiO2. The C-terminal
functionalized amides 6{3–12,3} and 7{3–12,3} were
isolated in an average yield of 64% and in an average

P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
11493
Scheme 5. N-Terminal functionalizations.
4. Experimental
4.1. General
All moisture-sensitive reactions were performed under an
atmosphere of N2 and glassware was flame dried under
vacuum prior to use. DME and THF were dried by
distillation over Na/benzophenone, Et3N was dried by
distillation over CaH2. Toluene and CH2Cl2 were purified
by filtration through activated alumina. Me2Zn (2.0 M in
toluene) and Et2Zn (neat) were purchased from the Aldrich
Chemical Company. Cp2ZrHCl,35 PhCH]NP(O)Ph236 and
alkyne 137 were prepared according to literature protocols.
PS-Carbodiimide, PS-DMAP, MP-isocyanate and MP-
trisamine were purchased from Argonaut, silica-bound
carbonate SPE cartridges from Silicycle and ChemElut
1003 cartridges from Varian. Unless stated otherwise,
solvents or reagents were used without further purification.
Analytical thin layer chromatography (TLC) was performed
on pre-coated silica gel 60 F-254 plates (particle size 0.040–
0.055 mm, 230–400 mesh) and visualization was accom-
plished with a 254 nm UV light and/or by staining with
Vaughn’s reagent (4.8 g of (NH4)6Mo7O24$4H2O and
0.20 g of Ce(SO4)2 in 100 mL of 3.5 N H2SO4 solution).
NMR spectra were recorded in CDCl3 (298 K) at either
300.1 MHz (1H), 75.5 MHz (13C) or 121.5 MHz (31P) using
a Bruker Avance 300 with XWIN-NMR software. Chemical
shifts (d) are reported in parts per million (ppm) with the
Figure 5. Building blocks 9{3–12} for N-terminal functionalizations.

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P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
Table 2. N-Terminal functionalizations, isolated yields (purity by LC–MS with ELS detection)
R2
Protocol
6{1,1}, (99)
6{1,2},a (93)
7{1,1}, (O99)
7{1,2},a (90)
D
6{1,3}, 97 (96)
7{1,3}, O99 (90)
D
D
6{1,4}, O99 (92)
6{1,5}, O99 (96)
7{1,4}, 98 (96)
7{1,5}, O99 (O99)
D
6{1,6}, O99 (99)
7{1,6}, 87 (93)
D
D
6{1,7}, O99 (88)
6{1,8}, 95 (O99)
7{1,7}, 97 (92)
7{1,8}, 92 (99)
D
6{1,9}, O99 (92)
7{1,9}, O99 (99)
D
D
D
6{1,10}, 89 (97)
6{1,11}, 85 (97)
6{1,12}, 52 (92)
7{1,10}, 83 (97)
7{1,11}, 76 (95)
7{1,12}, 97 (92)
a Purity by UV with detection at 240 nm.
residual solvent peak used as an internal standard. For 31P
NMR, Ph3P (d K5.5) was used as an external standard.
Data are reported as follows: chemical shift, multiplicity
(sZsinglet, dZdoublet, tZtriplet, qZquartet, mZmulti-
plet, bsZbroad singlet, bdZbroad dublet, btZbroad triplet,
app.Zapparent), coupling constants and integration. IR
spectra were obtained on a Nicolet AVATAR 360 FTIR
E.S.P. Spectrometer. Mass spectra were obtained on a
Waters QTof API US. Melting points were obtained on a
MelTemp melting point apparatus with digital temperature
reading and are reported uncorrected. Optical rotations were
obtained on a Perkin–Elmer 241 polarimeter. All micro-
wave assisted reactions were performed in an Emrys
Optimizer single mode microwave reactor (Biotage) using
2–5 mL Emrys process vials.
4.1.1. N-(R*)-(((1R*,2R*)-2-(tert-Butyldiphenylsilyloxy-
methyl)cyclopropyl)(phenyl)-methyl)-P,P-diphenylphos-
phinamide (2). In a cooled flask (0 8C), Cp2ZrHCl (12.7 g,
49.1 mmol) was suspended in dry CH2Cl2 (125 mL) and
alkyne 1 (14.5 g, 49.1 mmol) was added immediately. The
reaction mixture was warmed to room temperature, stirred
for 30 min and the resultant light yellow solution was cooled
to K78 8C and treated with Me2Zn (24.6 mL, 49.1 mmol,
2.0 M in toluene). The reaction mixture was warmed to 0 8C
and N-diphenylphosphinylimine (5.00 g, 16.4 mmol) was
added. The mixture was heated under reflux for 30 h, cooled
to 0 8C and treated with a solution of (CH2I)2Zn$DME
(81.9 mmol) in CH2Cl2 (20.0 mL). This zinc carbenoid
complex was prepared by dropwise addition of CH2I2
(13.2 mL, 164 mmol) to a solution of Et2Zn (neat, 10.1 g,

P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
11495
81.9 mmol) in CH2Cl2 (20.0 mL) and DME (8.51 mL,
81.9 mmol) at K30 8C. After stirring for 10 min at K30 8C,
the resultant solution was transferred via cannula. After
warming to room temperature, the reaction mixture was
stirred for 12 h, cooled to 0 8C, carefully quenched with satd
NH4Cl and extracted with EtOAc (3!). The combined
organic layers were washed with water, brine, dried
(Na2SO4) and evaporated. The residue was purified by
chromatography on SiO2 (hexanes/EtOAc 3/2) to give 2
(6.80 g, 67%) as a colorless foam: IR (neat) 3189, 3070,
3028, 2930, 2857, 1590, 1471, 1455, 1438, 1428, 1190,
6 h, the solution was poured into dry diethyl ether (350 mL),
cooled to K20 8C and filtered to afford the methyl ester 311
(1.72 g, 83%).
4.1.3. (1S,2S)-2-((S)-1-Amino-1-phenylmethyl)cyclopro-
pane carboxylic acid methyl ester D-tartrate salt (4) and
(1R,2R)-2-((R)-1-amino-1-phenylmethyl)cyclopropane
carboxylic acid methyl ester L-tartrate salt (5). A solution
of the methyl ester 3 (1.04 g, 4.30 mmol) in ice (10 g) and
chloroform (75 mL) was treated with 1 M K2CO3
(25.0 mL). The layers were separated and the aqueous
layer was extracted with CHCl3 (3!) and EtOAc (2!). The
combined organic layers were dried (Na2SO4) and
evaporated and the resulting free amine (850 mg, 96%)
was dissolved in ethanol (15.0 mL) and treated with
L-tartaric acid (622 mg, 4.14 mmol). The reaction mixture
was heated at reflux for 10 min (white suspension formed),
and water was added until the solid material dissolved.
Ethanol (10.0 mL) was added and the mixture was allowed
to stand for 24 h at room temperature. The mixture was
filtered to give a colorless solid (725 mg) which was
recrystallized from ethanol/water (20:1) to afford 511
(604 mg, 41%) as a crystalline solid. The filtrates from
two crystallizations were combined, concentrated and
dissolved in water. Ice was added, followed by chloroform
and 1 M K2CO3 (25.0 mL). The aqueous layer was extracted
with CHCl3 (3!) and EtOAc (2!) and the combined
organic layers were dried and evaporated. The free amine
was dissolved in a mixture of ethanol (10.0 mL) and water
(1.5 mL) and D-tartaric acid (368 mg, 2.45 mmol) was
added. The mixture was heated until all solid materials
dissolved, treated with ethanol (10.0 mL), and slowly
cooled to room temperature. Filtration afforded 411
(614 mg, 42%) as a colorless crystalline solid.
1
1111 cmK1; H NMR d 7.93–7.86 (m, 2H), 7.75–7.62 (m,
7H), 7.47–7.33 (m, 12H), 7.31–7.24 (m, 4H), 3.80 (dt, JZ
10.0, 7.9 Hz, 1H), 3.63 (dd, JZ10.6, 5.4 Hz, 1H), 3.42 (dd,
JZ10.6, 6.2 Hz, 1H), 3.32–3.28 (m, 1H), 1.23–1.08 (m,
2H), 1.01 (s, 9H), 0.51 (dt, JZ8.5, 5.1 Hz, 1H), 0.42 (dt, JZ
8.5, 5.2 Hz, 1H); 13C NMR d 143.32 (d, JCPZ4.5 Hz),
135.52 (d, JCPZ8.0 Hz), 133.82, 132.24 (d, JCPZ9.6 Hz),
131.91 (d, JCPZ9.3 Hz), 131.61 (d, JCPZ8.6 Hz), 131.41,
129.48, 128.37, 128.20, 128.13, 127.96, 127.53, 126.96,
126.79, 66.15, 58.16, 26.83, 24.72 (d, JCPZ5.7 Hz), 20.33,
19.09, 8.45; MS (ESI) m/z (intensity) 1253 ([2MCNa]C,
23), 1231 ([2MCH]C, 20), 638 ([MCNa]C, 35), 616
([MCH]C, 100), 538 (29); HRMS (ESI) m/z calculated for
C39H43NO2PSi (MCH) 616.2801, found 616.2799.
4.1.2. (1R*,2R*)-2-((R*)-1-Amino-1-phenylmethyl)cyclo-
propane carboxylic acid methyl ester hydrochloride salt
(3). Amide 2 (6.80 g, 11.0 mmol) was dissolved in THF
(100 mL), cooled to 0 8C and treated with TBAF (13.8 mL,
13.8 mmol, 1.0 M in THF). The solution was warmed to
room temperature, stirred for 10 h, quenched with sat.
NH4Cl and extracted with EtOAc (3!). The combined
organic layers were washed with water, brine, dried
(Na2SO4) and evaporated. The residue was purified by
chromatography on SiO2 (CH2Cl2/acetone 2/3) to afford the
corresponding alcohol (3.45 g, 83%) as a colorless solid.
Mp 170.3–172.0 8C; IR (KBr) 3422, 3231, 2850, 1654,
4.1.4. (1S,2S)-2-((S)-(Benzyloxycarbonylamino)phenyl-
methyl)cyclopropane carboxylic acid methyl ester
(6{1,1}) and (1R,2R)-2-((R)-(benzyloxycarbonylamino)-
phenyl-methyl)cyclopropane carboxylic acid methyl
ester (7{1,1}). The tartrate salt 4 (0.48 g, 1.34 mmol) was
dissolved in EtOAc (5.0 mL) and water (5.0 mL), cooled to
0 8C followed by NaHCO3 (0.56 g, 6.68 mmol) and benzyl
chloroformate (0.22 mL, 1.60 mmol). The mixture was
stirred at 0 8C for 2 h, diluted with water, extracted with
CH2Cl2 (3!) and the combined organic layers were washed
with brine, dried (Na2SO4) and evaporated. Purification by
chromatography on SiO2 (hexanes/EtOAc 17/3) afforded
6{1,1}11 (0.43 g, 95%): [a]DC51.5 (c 1.1, CHCl3).
According to the same protocol, tartrate salt 5 (0.57 g,
1.60 mmol), NaHCO3 (0.67 g, 8.00 mmol), benzyl chloro-
formate (0.28 mL, 1.92 mmol) in EtOAc (5.0 mL) and
water (5.0 mL) afforded 7{1,1}11 (0.53 g, 97%): [a]D
K48.6 (c 1.0, CHCl3).
1
1637, 1458, 1439 cmK1; H NMR d 8.11–8.06 (m, 2H),
7.91–7.87 (m, 2H), 7.56–7.32 (m, 11H), 5.01 (bs, 1H), 4.08
(dd, JZ11.1, 3.8 Hz, 1H), 3.53 (bs, 1H), 3.29 (bs, 1H), 2.86
(t, JZ10.7 Hz, 1H), 1.44–1.32 (m, 1H), 1.10–0.99 (m, 1H),
0.41 (dt, JZ8.5, 5.3 Hz, 1H), 0.26 (dt, JZ8.7, 5.3 Hz, 1H);
13C NMR d 143.00 (d, JCPZ10.4 Hz), 133.67, 133.13 (d,
JCPZ9.4 Hz), 131.69 (d, JCPZ9.4 Hz), 131.17, 129.43,
128.95, 128.84, 128.65, 128.48, 127.68, 126.67, 66.37,
61.43, 26.71, 23.04, 9.16; MS (EI) m/z (intensity) 377 (MC,
3), 359 (4), 347 (6), 306 (67), 356 (10), 201 (100), 176 (9);
HRMS (EI) m/z calculated for C19H12NOP [MKC4H7-
O]C306.1034, found 306.1048.
This alcohol (3.25 g, 8.61 mmol) was suspended in
acetonitrile (100 mL) and pH 6.7 phosphate buffer
(100 mL). The biphasic mixture was warmed to 45 8C and
treated with TEMPO (135 mg, 0.861 mmol), NaClO2
(1.95 g, 21.5 mmol) and NaClO (2.46 mL, 1.72 mmol,
0.7 M aqueous solution). After 12 h, the reaction mixture
was cooled to room temperature, treated with methanol
(5.0 mL), 10% HCl (300 mL) and extracted with EtOAc
(3!). The combined organic layers were washed with
brine, dried (Na2SO4) and evaporated. The resultant foam
was dissolved in methanol (50.0 mL), cooled to 0 8C and
HCl gas was bubbled through the solution for 5 min. After
4.1.5. (1S,2S)-2-((S)-(Diphenylphosphinylamino)phenyl-
methyl)cyclopropane carboxylic acid methyl ester
(6{1,3}) and (1R,2R)-2-((R)-(diphenylphosphinylamino)-
phenylmethyl)cyclopropane carboxylic acid methyl ester
(7{1,3}). The tartrate salt 4 (608 mg, 1.71 mmol) was
dissolved in water (15.0 mL) and placed in a separatory
funnel. Ice was added and the cold mixture was treated with
1 M K2CO3 solution (15.0 mL) and extracted with CHCl3
(3!) and EtOAc (2!). The combined organic layers were

11496
P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
dried (Na2SO4) and evaporated to afford the free amine as a
colorless oil. The residue was dissolved in dry CH2Cl2
(15.0 mL), cooled to 0 8C and treated with Ph2P(O)Cl
(809 mg, 3.42 mmol) followed by DIPEA (1.18 mL,
6.75 mmol). The reaction mixture was warmed to room
temperature, stirred for 10 h, diluted with EtOAc, washed
with 10% HCl, water, brine, dried (Na2SO4) and concen-
trated. The residue was purified by chromatography on SiO2
(CH2Cl2/acetone 4/1, containing 1% v/v Et3N) to afford
6{1,3}11 (664 mg, 96%) as a colorless solid: [a]DC34.2 (c
0.8, CHCl3). According to the same protocol, 5 (600 mg,
1.69 mmol), Ph2P(O)Cl (800 mg, 3.38 mmol) and DIPEA
(1.18 mL, 6.75 mmol) in dry CH2Cl2 (15.0 mL) afforded
7{1,3}11 (644 mg, 94%) as a colorless solid: [a]D K34.8 (c
0.8, CHCl3).
amines (8{3} and 8{4}) were irradiated for 30 min at
60 8C. After cooling to room temperature, the microwave
tubes were uncapped and the reaction mixtures (including
the resin) were loaded onto SPE-cartridges (prepacked with
500 mg silica-bound carbonate and preconditioned with
CH2Cl2 (1.0 mL)). The SPE-cartridges were washed three
times with CH2Cl2 (2.0 mL each). The eluants were
collected via gravity filtration. Evaporation of all volatile
components in a centrifugal vacuum evaporator (Genevac
HT-4) provided the desired amides in yields of 23–98%
(Table 1).
General protocol B. 1-(3-Dimethylaminopropyl)-3-ethyl-
carbodiimide hydrochloride (28.8 mg, 0.150 mmol,
2.0 equiv) and 1-hydroxybenzotriazole (15.3 mg,
0.113 mmol, 1.5 equiv) were added to a solution of the
acid in chlorobenzene. The reaction mixture was stirred for
5 min at room temperature before 2-aminonaphthalene
(8{10}) (188 mL of a 0.4 M solution in chlorobenzene,
0.075 mmol, 1.0 equiv) was added. The vials were sealed,
purged with argon and stirred at room temperature for 12 h.
The reaction mixtures were loaded onto ChemElut
cartridges (3.0 mL cartridges, preconditioned for 5 min
with 2.0 mL water) and washed with CH2Cl2 (2!2.0 mL).
The eluants were collected via gravity filtration and all
volatile components were removed in vacuo. Automated
parallel chromatography on SiO2 (ISCO Optix 10 System,
4 g cartridges, hexanes to hexanes/EtOAc, 1:1), followed by
evaporation of all volatile components in a centrifugal
vacuum evaporator (Genevac HT-4) provided the desired
amides in yields of 69–72% (Table 1).
4.2. C-Terminal functionalizations
A solution of the cyclopropyl amino acid methyl esters
6{1,3} and 7{1,3} (0.935 mmol), respectively, in a mixture
of methanol (10.0 mL) and THF (2.0 mL) was treated at
room temperature with 1.0 M NaOH (10.0 mL). The
resulting suspension was stirred until a clear solution was
obtained (6 h). The resulting free acids 6{2,3} and 7{2,3}
were extracted using an automated liquid–liquid extraction
system (ALLEXis:28 add 1.0 M HCl (20.0 mL), add EtOAc
(20.0 mL), mix three times, extract lighter phase, add
EtOAc (20.0 mL), mix three times, extract lighter phase,
add EtOAc (20.0 mL), mix three times, extract lighter
phase, add saturated aqueous NaCl solution (15.0 mL), mix
three times, extract lighter phase). The organic phases were
dried (MgSO4) and all volatile components were removed in
vacuo. The free acids were obtained in an average yield of
88% as colorless crystals (0.83 mmol). Each acid was
dissolved in chlorobenzene (22.0 mL) and divided into
eleven 2–5 mL Emrys process vials (0.0750 mmol each).
Compounds 6{2,3} and 7{2,3} dissolved only upon heating
to 60 8C in a water bath. Twenty vials (ten vials of each
acid) were used to synthesize the corresponding amides
according to the general protocols A–C, the remaining two
vials contained the two free acids 6{2,3} and 7{2,3} as part
of the desired library and all volatile components were
removed in vacuo from these vials.
General protocol C.31 3-(Diethoxyphosphoryloxy)-1,2,3-
benzotriazin-4(3H)-one (44.9 mg, 0.150 mmol, 2.0 equiv)
and the corresponding amine were added to a solution of the
acid in chlorobenzene. (R)-(K)-2-Amino-1-propanol
(8{11}) was added as 0.4 M solution in chlorobenzene
(281 mL, 0.113 mmol, 1.5 equiv), whereas tryptamine
(8{12}) (18.1 mg, 0.113 mmol, 1.5 equiv) was added neat.
After treating the reaction mixture with triethylamine
(30.4 mg, 0.300 mmol, 4.0 equiv) the tube was sealed,
purged with argon and stirred at room temperature for 12 h.
The crude products were extracted using an automated
liquid–liquid extraction system (ALLEXis:28 add aqueous
saturated NaCl solution (15.0 mL), add EtOAc (20.0 mL),
mix three times, extract lighter phase, add EtOAc
(20.0 mL), mix three times, extract lighter phase, add
EtOAc (20.0 mL), mix three times, extract lighter phase,
add aqueous 1 M HCl (15.0 mL), mix three times, extract
lighter phase, add saturated NaHCO3 solution (15.0 mL),
mix three times, extract lighter phase, add saturated NaCl
solution (15.0 mL), mix three times, extract lighter phase).
The combined organic layers were dried (MgSO4) and all
volatile components were removed in vacuo. Automated
parallel chromatography on SiO2 (ISCO Optix 10 System,
4 g cartridges, hexanes to EtOAc), followed by evaporation
of all volatile components in a centrifugal vacuum
evaporator (Genevac HT-4) provided the desired amides
in yields of 44–68% (Table 1).
General protocol A.30 PS-carbodiimide (loading
1.20 mmol/g, 125 mg, 0.150 mmol, 2 equiv) and
1-hydroxybenzotriazole (15.3 mg, 0.113 mmol, 1.5 equiv)
were added to the acid in chlorobenzene. The reaction
mixture was stirred for 5 min at room temperature before
addition of the amine. Volatile amines such as methylamine
(8{3}) (33 wt% in ethanol, 143 mL, 1.88 mmol, 25.0 equiv)
and cyclopropanemethylamine (8{4}) (30.2 mg,
0.375 mmol, 5.0 equiv) were added in excess. Benzylamine
(8{5}), 2-aminomethylpyridine (8{7}), 5-methyl-2-furan-
methanamine (8{8}) and (1,5-dimethyl-1H-pyrazol-3-
yl)methylamine (8{9}) were added as 0.4 M solution in
chlorobenzene (188 mL, 0.0750 mmol, 1.0 equiv).
4-Methylsulfonylbenzylamine hydrochloride (8{6})
(8.9 mg, 0.075 mmol, 1.0 equiv) was added neat, followed
by triethylamine (15.2 mg, 0.150 mmol, 2.0 equiv). After
addition of the amines, the microwave tubes were sealed and
irradiated for 5 min (hold time) at 100 8C (applying an
initial power of 200 W). Reactions involving volatile
4.2.1. (1S,2S)-2-((S)-(Diphenylphosphinylamino)phenyl-
methyl)cyclopropane carboxylic acid cyclopropylmethyl
amide (6{4,3}). According to the general protocol A,

P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
11497
(6{4,3}) (11.8 mg, 35%) was obtained as colorless crystals.
Mp 198 8C; IR (KBr) 3400, 3151, 2859, 1645, 1529,
9.9 Hz, 1H), 3.20–3.02 (m, 2H), 2.04–1.96 (m, 1H), 1.65–
1.55 (m, 1H), 1.38–1.32 (m, 1H), 1.05–0.97 (m, 1H), 0.72–
0.66 (m, 1H), 0.53–0.47 (m, 2H), 0.27–0.22 (m, 2H).
1
1436 cmK1; H NMR d 7.92–7.78 (m, 4H), 7.55–7.26 (m,
12H), 3.54 (dd, JZ10.2, 6.0 Hz, 1H), 3.39 (app. q, JZ
9.9 Hz, 1H), 3.20–3.02 (m, 2H), 2.04–1.96 (m, 1H), 1.65–
1.55 (m, 1H), 1.38–1.32 (m, 1H), 1.05–0.97 (m, 1H), 0.72–
0.66 (m, 1H), 0.53–0.47 (m, 2H), 0.27–0.22 (m, 2H); 13C
4.2.7.
(1R,2R)-2-((R)-(Diphenylphosphinylamino)-
phenylmethyl)cyclopropane carboxylic acid (5-methyl-
furan-2-ylmethyl)amide (7{8,3}). According to the general
protocol A, (7{8,3}) (30.4 mg, 84%) was obtained as
colorless crystals. Mp 170 8C; IR (KBr) 3165, 3058, 2920,
NMR d 172.1, 142.6 (d, JCPZ8.7 Hz), 133.1 (d, JCP
Z
129.0 Hz), 132.7 (d, JCPZ9.5 Hz), 132.1 (2 signals
overlapping), 131.7 (d, JCPZ9.5 Hz), 130.3, 128.8, 128.7,
128.5, 127.6, 126.3, 60.3, 44.3, 29.0, 23.5, 12.5, 10.8, 3.4,
3.3; 31P NMR d 22.9; MS (ESI) m/z (rel. intensity) 467
([MCNa]C, 100), 445 ([MCH]C, 27); HRMS (ESI) m/z
calculated for C27H30N2O2P (MCH) 445.2045, found
445.2024.
1653, 1541, 1437, 1186 cmK1; H NMR d 7.86–7.78 (m,
1
4H), 7.71 (app. t, JZ4.1 Hz, 1H), 7.51–7.28 (m, 11H), 6.14
(d, JZ2.6 Hz, 1H), 5.88 (bs, 1H), 4.43–4.30 (m, 2H), 3.50
(dd, JZ10.1, 4.1 Hz, 1H), 3.38 (app. q, JZ9.6 Hz, 1H),
2.26 (s, 3H), 2.02–1.96 (m, 1H), 1.64–1.58 (m, 1H), 1.41–
1.35 (m, 1H), 0.72–0.66 (m, 1H); 13C NMR d 172.0, 150.8
(d, JCPZ87.7 Hz), 142.5 (d, JCPZ8.9 Hz), 133.9, 132.7 (d,
4.2.2. (1S,2S)-2-((S)-(Diphenylphosphinylamino)phenyl-
methyl)cyclopropane carboxylic acid 4-methane-
sulfonylbenzylamide (6{6,3}). According to the general
protocol A, (6{6,3}) (34.4 mg, 82%) was obtained as
JCPZ9.5 Hz), 132.2 (d, JCPZ7.0 Hz), 132.0 (d, JCP
2.8 Hz), 131.9 (d, JCPZ2.8 Hz), 131.6 (d, JCPZ9.5 Hz),
130.4, 128.7, 128.6 (d, JCPZ4.7 Hz), 128.5 (d, JCP
4.5 Hz), 127.6, 126.3, 107.7, 106.1, 60.3, 36.8, 29.0, 23.5,
13.6, 12.5; 31P NMR d 22.9; MS (ESI) m/z (rel. intensity)
507 ([MCNa]C, 100), 485 ([MCH]C, 22); HRMS (ESI)
m/z calculated for C29H29N2O3PNa (MCNa) 507.1814,
found 507.1798.
Z
Z
1
colorless crystals: H NMR d 8.66 (app. t, JZ5.6 Hz, 1H),
7.88–7.77 (m, 6H), 7.56 (d, JZ8.2 Hz, 2H), 7.51–7.26 (m,
11H), 4.58 (dd, JZ15.9, 6.7 Hz, 1H), 4.50–4.43 (m, 1H),
3.73 (dd, JZ10.8, 6.1 Hz, 1H), 3.31 (app. q, JZ9.7 Hz,
1H), 3.00 (s, 3H), 2.16–2.07 (m, 1H), 1.62–1.54 (m, 1H),
1.45–1.39 (m, 1H), 0.74–0.68 (m, 1H).
4.2.8.
(1R,2R)-2-((R)-(Diphenylphosphinylamino)-
phenylmethyl)cyclopropane carboxylic acid (1,5-
dimethyl-1H-pyrazol-3-ylmethyl)amide (7{9,3}). Accord-
ing to the general protocol A, (7{9,3}) (26.0 mg, 72%) was
4.2.3. (1S,2S)-2-((S)-(Diphenylphosphinylamino)phenyl-
methyl)cyclopropane carboxylic acid (pyridin-2-
ylmethyl)amide (6{7,3}). According to the general protocol
A (6{7,3}) (23.8 mg, 66%) was obtained as colorless
1
obtained as colorless crystals: H NMR d 7.90–7.75 (m,
4H), 7.52–7.23 (m, 12H), 6.01 (s, 1H), 4.45 (dd, JZ15.1,
5.6 Hz, 1H), 4.30 (dd, JZ15.1, 5.3 Hz, 1H), 3.72 (s, 3H),
3.52 (dd, JZ5.8, 3.8 Hz, 1H), 3.45 (app. q, JZ8.9 Hz, 1H),
2.21 (s, 3H), 1.98–1.92 (m, 1H), 1.70–1.65 (m, 1H), 1.38–
1.31 (m, 1H), 0.73–0.66 (m, 1H).
1
crystals: H NMR d 8.53 (d, JZ4.2 Hz, 1H), 8.13 (app. t,
JZ5.3 Hz, 1H), 7.89–7.77 (m, 4H), 7.60 (app. td, JZ7.7,
1.6 Hz, 1H), 7.50–7.29 (m, 12H), 7.15 (dd, JZ6.6, 5.3 Hz,
1H), 4.60, 4.56 (d of AB, JZ16.2, 5.6 Hz, 2H), 3.63 (dd,
JZ9.9, 6.1 Hz, 1H), 3.46 (app. q, JZ9.7 Hz, 1H), 2.10–
2.04 (m, 1H), 1.74–1.65 (m, 1H), 1.41–1.34 (m, 1H), 0.77–
0.71 (m, 1H).
4.3. N-Terminal functionalizations
General protocol D. A 5 mL microwave tube was charged
with PS-DMAP (loading 1.6 mmol/g, 0.046–0.13 mmol,
1.2 equiv), ammonium salt 6{1,2} or 7{1,2} (0.038–
0.11 mmol, 1.0 equiv), respectively, and the solids were
suspended in dry CH2Cl2 (0.75–2.0 mL). The suspension
was treated with triethylamine (0.076–0.22 mmol,
2.0 equiv) and the acylating reagent 9{3–12} (0.046–
0.13 mmol, 1.2 equiv). The tube was capped and irradiated
in the microwave for 10 min (hold time) at 100 8C (applying
an initial power of 200 W). After cooling to room
temperature, MP-trisamine33 (loading 3.0 mmol/g, 0.038–
0.11 mmol, 1.0 equiv) and MP-isocyanate32,33 (loading
1.54 mmol/g, 0.038–0.11 mmol, 1.0 equiv) were added to
the crude reaction mixture and the microwave irradiation
was resumed for 5 min (hold time) at 100 8C (applying an
initial power of 200 W). Upon cooling, the reaction
mixture was transferred to a ChemElut SPE-cartridge
(preconditioned with saturated aqueous NaHCO3, 2.0 mL)
and washed five times with CH2Cl2 (1.0 mL each). The
CH2Cl2 eluant was collected and concentrated (Genevac
HT-4) to afford the pure products.
4.2.4. (1S,2S)-2-((S)-(Diphenylphosphinylamino)phenyl-
methyl)cyclopropane carboxylic acid naphthalen-2-
ylamide (6{10,3}). According to the general protocol B
(6{10,3}) (26.9 mg, 69%) was obtained as colorless
1
crystals: H NMR d 10.74 (s, 1H), 8.41 (s, 1H), 7.99–7.95
(m, 4H), 7.81–7.76 (m, 4H), 7.60–7.33 (m, 13H), 3.54 (dd,
JZ10.5, 5.4 Hz, 1H), 3.37 (app. q, JZ9.4 Hz, 1H), 2.30–
2.20 (m, 1H), 1.70–1.50 (m, 2H), 1.80–1.74 (m, 1H).
4.2.5.
(1R,2R)-2-((R)-(Diphenylphosphinylamino)
phenylmethyl)cyclopropane carboxylic acid methyl-
amide (7{3,3}). According to the general protocol A,
(7{3,3}) (9.1 mg, 30%) was obtained as colorless crystals:
1H NMR d 7.91–7.77 (m, 4H), 7.54–7.30 (m, 12H), 3.62
(dd, JZ9.9, 5.8 Hz, 1H), 3.34 (app. q, JZ9.6 Hz, 1H), 2.78
(d, JZ4.7 Hz, 3H), 1.98–1.88 (m, 1H), 1.65–1.57 (m, 1H),
1.39–1.33 (m, 1H), 0.68–0.62 (m, 1H).
4.2.6.
(1R,2R)-2-((R)-(Diphenylphosphinylamino)
(phenyl)methyl)cyclopropane carboxylic acid cyclo-
propylmethylamide (7{4,3}). According to the general
protocol A, (7{4,3}) (14.7 mg, 44%) was obtained as
colorless crystals: 1H NMR d 7.92–7.78 (m, 4H), 7.55–7.26
(m, 12H), 3.54 (dd, JZ10.2, 6.1 Hz, 1H), 3.38 (app. q, JZ
4.3.1. (1S,2S)-2-((S)-(Diphenylphosphinylamino)phenyl-
methyl)cyclopropane carboxylic acid methyl ester
(6{1,3}). According to the general protocol D, 6{1,2}

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P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
(25 mg, 0.10 mmol), PS-DMAP (80 mg, 0.12 mmol),
triethylamine (30 mL, 0.20 mmol), diphenyl phosphinic
chloride (24 mL, 0.12 mmol), MP-isocyanate (70 mg,
0.10 mmol) and MP-trisamine (35 mg, 0.10 mmol) in
CH2Cl2 (2.0 mL) afforded 6{1,3} (37 mg, 87%) as a
ing to the general protocol D, 7{1,2} (15 mg, 0.062 mmol),
PS-DMAP (50 mg, 0.074 mmol), triethylamine (20 mL,
0.12 mmol),
benzenesulfonyl
chloride
(11 mg,
0.074 mmol), MP-isocyanate (40 mg, 0.062 mmol) and
MP-trisamine (21 mg, 0.062 mmol) in CH2Cl2 (1.5 mL)
afforded 7{1,5} (23 mg, O99%) as a pale yellow solid: 1H
NMR d 7.67 (d, JZ7.7 Hz, 2H), 7.48 (t, JZ7.5 Hz, 1H),
7.36 (dd, JZ7.5, 7.7 Hz, 2H), 7.21–7.16 (m, 3H), 7.09–7.05
(m, 2H), 5.16 (bd, JZ6.2 Hz, 1H), 3.92 (app. t, JZ7.1 Hz,
1H), 3.66 (s, 3H), 1.87–1.78 (m, 1H), 1.72–1.66 (m, 1H),
1.19–1.13 (m, 1H), 0.93–0.87 (m, 1H).
1
colorless solid: H NMR d 7.94–7.87 (m, 2H), 7.75–7.68
(m, 2H), 7.56–7.42 (m, 5H), 7.36–7.30 (m, 6H), 3.88 (app.
q, JZ8.8 Hz, 1H), 3.62 (s, 3H), 3.34 (bt, JZ7.7 Hz, 1H),
1.99–1.88 (m, 1H), 1.81–1.75 (m, 1H), 1.17–1.11 (m, 1H),
0.90–0.85 (m, 1H).
4.3.2.
(1S,2S)-Methyl-2-((S)-phenyl(naphthalene-
sulfonylamido)methyl)cyclopropanecarboxylate (6{1,6}).
According to the general protocol D, 6{1,2} (10 mg,
0.041 mmol), PS-DMAP (31 mg, 0.049 mmol), triethyl-
amine (11 mL, 0.082 mmol), 1-naphthalene sulfonylchloride
(12 mg, 0.049 mmol), MP-isocyanate (25 mg, 0.041 mmol)
and MP-trisamine (13 mg, 0.041 mmol) in CH2Cl2 (1 mL)
4.3.6. (1R,2R)-Methyl 2-((R)-(benzamido)(phenyl)
methyl)cyclopropanecarboxylate (7{1,8}). According to
the general protocol D, 7{1,2} (20 mg, 0.082 mmol), PS-
DMAP (63 mg, 0.098 mmol), triethylamine (23 mL,
0.16 mmol), benzoylchloride (11 mL, 0.098 mmol), MP-
isocyanate (55 mg, 0.082 mmol) and MP-trisamine (28 mg,
0.082 mmol) in CH2Cl2 (1.5 mL) afforded 7{1,8} (24 mg,
92%) as a colorless solid. Mp 160–161 8C; IR (KBr) 3362,
1
afforded 6{1,6} (16 mg, 97%) as a pale yellow solid: H
NMR d 8.55 (d, JZ8.4 Hz, 1H), 8.02 (d, JZ7.6 Hz, 1H),
7.95 (d, JZ8.2 Hz, 1H), 7.88 (d, JZ8.2 Hz, 1H), 7.66–7.55
(m, 2H), 7.35 (dd, JZ7.8, 7.6 Hz, 1H), 7.03 (t, JZ7.2 Hz,
1H), 6.95 (app. t, JZ7.2 Hz, 2H), 6.86 (d, JZ7.2 Hz, 2H),
5.25 (bd, JZ6.2 Hz, 1H), 3.82 (app. t, JZ6.4 Hz, 1H), 3.59
(s, 3H), 1.81–1.72 (m, 1H), 1.58–1.52 (m, 1H), 1.12–1.06
(m, 1H), 0.89–0.80 (m, 1H).
1
3030, 2949, 1725, 1635 cmK1; H NMR d 7.80–7.77 (m,
2H), 7.55–7.31 (m, 8H), 6.49 (bd, JZ8.4 Hz, 1H), 4.85
(app. t, JZ8.4 Hz, 1H), 3.69 (s, 3H), 2.04–1.93 (m, 2H),
1.37–1.31 (m, 1H), 1.08–1.01 (m, 1H); 13C NMR d 174.04,
166.71, 140.73, 134.27, 131.50, 128.71, 128.47, 127.71,
126.98, 126.70, 55.56, 51.75. 26.82, 18.99, 14.13; MS (EI)
m/z (rel. intensity) 309 (MC, 14), 278 (15), 222 (46), 204
(48), 129 (60), 105 (73), 77 (100); HRMS (EI) m/z
calculated for C19H19NO3 309.1365, found 309.1368.
4.3.3. (1S,2S)-Methyl 2-((S)-(nicotinamido)(phenyl)
methyl)cyclopropanecarboxylate (6{1,9}). According to
the general protocol D, 6{1,2} (25 mg, 0.10 mmol), PS-
DMAP (80 mg, 0.12 mmol), triethylamine (30 mL,
0.20 mmol), 2-pyridinecarbonyl chloride (22 mg,
0.12 mmol), MP-isocyanate (70 mg, 0.10 mmol) and MP-
trisamine (35 mg, 0.10 mmol) in CH2Cl2 (2.0 mL) afforded
6{1,9} (35 mg, O99%) as an off white solid. Mp 143–
144 8C; IR (KBr) 3367, 3090, 3028, 3003, 2952, 1722,
4.3.7. (1R,2R)-Methyl 2-((R)-(nicotinamido)(phenyl)
methyl)cyclopropanecarboxylate (7{1,9}). According to
the general protocol D, 7{1,2} (15 mg, 0.062 mmol), PS-
DMAP (50 mg, 0.074 mmol), triethylamine (20 mL,
0.12 mmol), nicotinoyl chloride (11 mg, 0.074 mmol),
MP-isocyanate (40 mg, 0.062 mmol) and MP-trisamine
(21 mg, 0.062 mmol) in CH2Cl2 (1.5 mL) afforded 7{1,9}
1
1639 cmK1; H NMR d 8.98 (d, JZ1.8 Hz, 1H), 8.69 (dd,
1
JZ1.9, 4.8 Hz, 1H), 8.13 (ddd, JZ1.8, 1.9, 8.1 Hz, 1H),
7.43–7.28 (m, 6H), 7.08 (bd, JZ7.8 Hz, 1H), 4.78 (app. t,
JZ8.5 Hz, 1H), 3.64 (s, 3H), 2.05–1.84 (m, 2H), 1.36–1.30
(m, 1H), 1.08–1.02 (m, 1H); 13C NMR d 174.21, 164.93,
152.00, 147.91, 140.62, 135.48, 130.01, 128.67, 127.73,
126.64, 123.41, 56.02, 51.85, 26.80, 19.20, 14.46; MS (EI)
m/z (rel. intensity) 310 (MC, 3), 279 (9), 250 (11), 224 (70),
204 (74), 195 (23), 129 (31), 106 (87), 78 (100); HRMS (EI)
m/z calculated for C18H18N2O3 (M) 310.1317, found
310.1306.
(20 mg, O99%) as an off white solid: H NMR d 8.99 (d,
JZ1.9 Hz, 1H), 8.71 (dd, JZ4.8, 1.8 Hz, 1H), 8.13 (ddd,
JZ8.0, 1.9, 1.8 Hz, 1H), 7.44–7.29 (m, 6H), 6.87 (bd, JZ
7.5 Hz, 1H), 4.80 (app. t, JZ8.4 Hz, 1H), 3.66 (s, 3H),
2.05–1.94 (m, 2H), 1.37–1.31 (m, 1H), 1.09–1.02 (m, 1H).
4.3.8. (1R,2R)-Methyl 2-((R)-phenyl(pyrazine-2-carbox-
amido)methyl)cyclopropanecarboxylate
(7{1,10}).
According to the general protocol D, 7{1,2} (15 mg,
0.062 mmol), PS-DMAP (50 mg, 0.074 mmol), triethyl-
amine (20 mL, 0.12 mmol), 2-pyrazinecarbonyl chloride
(11 mg, 0.074 mmol), MP-isocyanate (40 mg, 0.062 mmol)
and MP-trisamine (21 mg, 0.062 mmol) in CH2Cl2 (1.5 mL)
afforded 7{1,10} (15 mg, 76%) as an orange solid: 1H NMR
d 9.42 (d, JZ1.4 Hz, 1H), 8.77 (d, JZ2.4 Hz, 1H), 8.54 (dd,
JZ2.4, 1.5 Hz, 1H), 8.23 (bd, JZ4.9 Hz, 1H), 7.45–7.32
(m, 5H), 4.82 (app. t, JZ8.8 Hz, 1H), 3.68 (s, 3H), 2.08–
1.92 (m, 2H), 1.38–1.31 (m, 1H), 1.08–1.01 (m, 1H).
4.3.4. (1S,2S)-Methyl 2-((S)-(5-methylisoxazole-3-car-
boxamido)(phenyl)methyl)cyclopropanecarboxylate
(6{1,11}). According to the general protocol D, 6{1,2}
(25 mg, 0.10 mmol), PS-DMAP (80 mg, 0.12 mmol),
triethylamine (30 mL, 0.20 mmol), 5-methyl-isoxazole-3-
carbonyl chloride (18 mg, 0.12 mmol), MP-isocyanate
(70 mg, 0.10 mmol) and MP-trisamine (35 mg,
0.10 mmol) in CH2Cl2 (2.0 mL) afforded 6{1,11} (30 mg,
1
95%) as an off white solid: H NMR d 7.44–7.31 (m, 5H),
4.4. LC–MS analysis
7.21 (bd, JZ7.7 Hz, 1H), 6.45 (s, 1H), 4.74 (app. t, JZ
8.6 Hz, 1H), 3.69 (s, 3H), 2.49 (s, 3H), 2.02–1.90 (m, 2H),
1.38–1.27 (m, 1H), 1.04–0.98 (m, 1H).
LC–MS analysis was performed on a Thermo Finnigan
octopole ion trap with APCI probe (positive ion detection
mode), using a reversed-phase C18 column (acetonitrile/1%
acetic acid in water 3/2, 1 mL/min). ELS detection was
performed using split flow from the HPLC and a PL-ELS
4.3.5. (1R,2R)-Methyl 2-((R)-phenyl(benzenesulfonyl-
amido)methyl)cyclopropanecarboxylate (7{1,5}). Accord-

P. Wipf et al. / Tetrahedron 61 (2005) 11488–11500
11499
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Acknowledgements
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