Synthesis of two dipeptide isosteres containing di- and trisubstituted E-configured double bonds

Article abstract of DOI:10.1055/s-2007-983783

The stereoselective syntheses of a Tyr-Tyr and a Pro-Pro E-alkene isostere are described. While the Tyr-Tyr isostere was synthesized following a convergent olefination strategy, the trisubstituted E-configured double bond of the Pro-Pro isostere was generated by an Ireland-Claisen rearrangement. The configuration of all key intermediates containing new stereocenters was determined by X-ray crystallography. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983783

2720
PAPER
Synthesis of Two Dipeptide Isosteres Containing Di- and Trisubstituted
E-Configured Double Bonds
Synthesis of
E
-Alk
i
ene
D
i
n
peptide Isost
aeres G. Bandur, Klaus Harms, Ulrich Koert*
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax +49(6421)2825677; E-mail: koert@chemie.uni-marburg.de
Received 26 April 2007; revised 4 June 2007
peptide by Fmoc-based solid-phase peptide synthesis
(SPPS).
Abstract: The stereoselective syntheses of a Tyr-Tyr and a Pro-Pro
E-alkene isostere are described. While the Tyr-Tyr isostere was
synthesized following a convergent olefination strategy, the trisub-
stituted E-configured double bond of the Pro-Pro isostere was gen-
erated by an Ireland–Claisen rearrangement. The configuration of
all key intermediates containing new stereocenters was determined
by X-ray crystallography.
Herein, we present the full details of the stereoselective
syntheses of a Tyr-Tyr and a Pro-Pro E-alkene isostere
which was published in preliminary form.3i,l The amino
acid tyrosine plays an important role, for example, in the
stability and ligand binding of WW-domains.4,5 These are
small three-stranded antiparallel b-sheet structures of 34–
40 amino acids that act as protein–protein interaction do-
mains by recognizing specific proline-rich motifs.4 Most
types of WW-domains known to date contain one to three
tyrosine residues as the most conserved residues in the
second strand.5
Key words: tyrosine, proline, E-alkenes, Ireland–Claisen rear-
rangement, Julia–Kocienski olefination
The replacement of dipeptide units in bioactive peptides
and proteins by synthetic isosteres is a useful tool for the
investigation of biomolecular recognition processes.
These backbone modifications generally consist in the
isosteric replacement of the amide unit in a peptide chain
possibly combined with the introduction of additional
functional groups. Since biodegradation is a great limita-
tion for the in vivo application of many biologically active
peptides, replacements of this type are often used to in-
crease the stability of the peptide towards proteolytic
cleavage. In some cases they may also alter pharmacoki-
netics in a favorable manner.1 In addition, the incorpora-
tion of amide bond isosteres is a convenient way to
elucidate the role of selected amide bonds in receptor
binding, as well as their influence on the secondary struc-
ture of peptides.
A synthetic approach to an (E)-Tyr-Tyr isostere of type 1
containing a disubstituted double bond can rely on Wittig-
type reactions,2,3 whereas the stereoselective construction
of the trisubstituted double bond in an (E)-Pro-Pro isos-
tere of type 2 requires a different synthetic strategy
(Figure 1). Our approach for 2 combines the stereoselec-
tive introduction of an allylic alcohol and a subsequent
Ireland–Claisen rearrangement.3f,i
HO
H
O
H
N
N
H
H
H
H
O
In this context, dipeptide isosteres, where the amide bond
is capable of serving both as a hydrogen bond donor and
the acceptor is replaced by an E-alkene which is incapable
of hydrogen bonding, are ideal replacements. This is be-
cause they show a high degree of structural rigidity and
hence closely resemble the amide bond with respect to
bond lengths and angles.2 However, hitherto this concept
has been rarely realized particularly due to the difficulties
associated with the stereoselective synthesis of E-alkene
isosteres. Though various syntheses of these isosters have
been published to date,3 most of them are limited to spe-
cific amino acids and lack general applicability. The syn-
thesis of such dipeptide isosteres consisting of amino
acids with functionalized side chains is an even greater
challenge since it requires a more complex protecting
group strategy especially if a specific protecting group
pattern is needed, for example, for the incorporation in a
1
2
OH
Figure 1 Two types of E-alkene isosteres
A protected L-tyrosine derivative was chosen as a versa-
tile chiral pool material for entrance to the synthesis of the
Tyr-Tyr E-alkene isostere. A stereoselective aldol reac-
tion using an Evans auxiliary6 to introduce the second ste-
reocenter and a Julia–Kocienski olefination7 to generate
the E-configured double bond were applied as key steps.
Sulfone 6 was prepared from the commercially available
protected tyrosine derivative 3 (Scheme 1). A 1-phenyl-
1H-tetrazolyl (PT) sulfonyl moiety was introduced for the
Julia–Kocienski olefination.7 Therefore, the acid 3 was
first converted into the corresponding alcohol by reduc-
tion of an in situ generated mixed carbonic acid anhydride
with sodium borohydride. The PT-thioether 4 was gener-
ated from the alcohol following the Mitsunobu protocol.
Since the Fmoc protecting group turned out to be unstable
towards the olefination conditions, it was replaced by the
SYNTHESIS 2007, No. 17, pp 2720–2730
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983783; Art ID: T07607SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of E-Alkene Dipeptide Isosteres
2721
trifluoroacetyl (TFA) group, which was introduced using After TBDPS deprotection of 11, the phenol formed need-
trifluoroacetic acid anhydride (TFAA). Fmoc deprotec- ed to be transferred into a tert-butyl ether, but various at-
tion under standard conditions followed by TFA protec- tempts using isobutylene and catalytic amounts of
tion of the free amine yielded the thioether 5 which was different acids failed as well as the use of a tert-butyl ha-
then oxidized to the sulfone 6 with 3-chloroperbenzoic lide combined with base. As previously reported, di-tert-
acid (MCPBA).
butyl dicarbonate can be used for the introduction of phe-
nolic tert-butyl ethers,10 but in our hands this method only
led to a 2:1 mixture of the tert-butyl ether and the corre-
sponding mixed carbonate. Finally the reaction succeeded
with tert-butyl 2,2,2-trichloroacetimidate (t-BuOTCA) in
the presence of catalytic amounts of pyridinium p-tolu-
enesulfonate (PPTS) after a prolonged reaction time of
three days. Reduction of the intermediate Weinreb amide
furnished aldehyde 12.
O
O
a,b
c,d
Fmoc
S
N
N
74%
89%
Fmoc
N
OH
N
N
H
H
N
O
Ph
3
4
O
O
Now the stage was set for the Julia–Kocienski olefination
to connect the N-terminal sulfone 6 and the C-terminal al-
dehyde 12 (Scheme 3). To this end, model couplings were
carried out with several aldehydes using different bases
and solvents. But even for sterically nonhindered alde-
hydes such as butyraldehyde, the E/Z selectivity could not
be improved beyond 2.1:1. The best results were obtained
using NaHMDS in 1,2-dimethoxyethane (DME) as sol-
vent, whereas the use of KHMDS which was reported to
give higher selectivities,7 only resulted in a decreased
yield. Therefore, sulfone 6 was deprotonated with
NaHMDS in DME and upon addition of aldehyde 12, the
desired alkene 13 was formed with modest E/Z selectivity
of 2.3:1 after deprotection of the THP acetal leading to al-
cohol 14, as determined by NMR spectroscopy. The chro-
matographic separation of E- and Z-isomer was carried
out at the alcohol stage. The configuration of the double
bond was assigned by 1H NMR coupling constants. In or-
der to introduce the N-Fmoc protection group for solid-
phase synthesis, the TFA amide was cleaved with diisobu-
tylaluminum hydride (DIBAL-H) followed by protection
of the free amine using Fmoc-N-hydroxysuccinimide
(FmocOSu). Oxidation with iodobenzene diacetate
(IBDA) and 2,2,6,6-tetramethyl-1-piperidinyloxy free
radical (TEMPO) in the last step furnished the b,g-unsat-
urated acid 15.11
e
O
S
O
TFA
S
TFA
87%
N
H
PT
N
H
PT
5
6
Scheme 1 Reagents and conditions: (a) i. ClCO2Et, NMM, THF,
–20 °C, ii. NaBH4, H2O, 0 °C; (b) PPh3, DIAD, PT–SH, 0 °C → r.t.;
(c) piperidine, DMF; (d) TFAA, pyridine, CH2Cl2, 0 °C → r.t.;
(e) MCPBA, CH2Cl2, 0 °C → r.t.
For the synthesis of the aldehyde 12 (Scheme 2), acylox-
azolidinone 9, which was available from 3-(4-hydrox-
yphenyl)propionic acid1 (7) via the benzyl-protected
intermediate 8, was converted into the corresponding tita-
nium enolate and allowed to react with s-trioxane as form-
aldehyde equivalent to give the aldol adduct 10 with a
diastereoselectivity of >98:2.8 The configuration was as-
signed by X-ray crystallography.9 Transformation of 10
into the Weinreb amide in the presence of the free primary
alcohol followed by THP protection furnished compound
11.
Xa
O
O
O
a,b
c,d
N
O
OH
O
O
78%
89%
7
8
BnO
HO
Bn
O
O
HO
Xa
f,g
e
a
Xa
b
O O
S
TFA
73%
85%
N
OTHP
TFA
53%
H
TBDPSO
N
PT
9
10
92%
H
TBDPSO
6
13
O
O
(E/Z 2.3:1)
THPO
O
THPO
N
O
h–j
O
O
68%
11
12
O
O
TBDPSO
c–e
TFA
Fmoc
N
OH
N
OH
Scheme 2 Reagents and conditions: (a) i. BnCl, KI, K2CO3, ace-
tone, reflux., ii. aq NaOH, reflux; (b) i. pivaloyl chloride, Et3N, THF,
–20 °C; ii. Xa–H, LiCl, r.t.; (c) Pd(OH)2, H2, MeOH–EtOAc (1:1); (d)
TBDPSCl, imidazole, DMF, 0 °C → r.t.; (e) i. TiCl4, CH2Cl2, 0 °C, ii.
DIEA, iii. s-trioxane, TiCl4; (f) Me3Al, Me(MeO)NH·HCl, CH2Cl2,
–10 °C; (g) DHP, PPTS, CH2Cl2, 0 °C → r.t.; (h) TBAF, AcOH, THF,
0 °C → r.t.; (i) t-BuOTCA, PPTS, CH2Cl2, 0 °C → r.t.; (j) DIBAL-H,
THF, –78 → –50 °C.
H
H
73%
14
15
O
O
Scheme 3 Reagents and conditions: (a) NaHMDS, DME, –78 °C,
then 12, –78 °C → r.t.; (b) p-TsOH, MeOH; (c) DIBAL-H, THF, –78
→ –50 °C; (d) FmocOSu, NaHCO3, acetone, H2O, 0 °C → r.t.; (e)
IBDA, TEMPO, CH2Cl2.
Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York

2722
N. G. Bandur et al.
PAPER
The Pro-Pro isostere was addressed next. Proline, as the TMSCl afforded the siloxy acid 21.3f,i,20 The Ireland–
only secondary amino acid, has special properties that set Claisen rearrangement proceeded via the proposed transi-
it apart from the other natural amino acids. Because of tion state 20 under 1,3-chirality transfer. The TBS ether in
both its cyclic structure and the secondary amino group it 21 was cleaved using tetrabutylammonium fluoride
has specific conformational effects on the peptide and (TBAF) in THF. The resulting a-hydroxy acid underwent
protein backbone and therefore often plays an important oxidative cleavage with Pb(OAc)4 in CHCl3–EtOAc. To
role in controlling the secondary structure of proteins.12
prevent isomerization of the b,g-unsaturated aldehyde
thus obtained, it was reduced immediately with NaBH4 in
MeOH to give alcohol 22 in 74% yield over four steps.
The structure of 22 in solid state was determined by X-ray
crystallography.3i In order to get an isostere suitable for
the incorporation in a peptide by Fmoc-based solid-phase
peptide synthesis, alcohol 22 was transformed into the N-
Fmoc protected acid 25. N-Deprotection of 22 with 50%
TFA in CH2Cl2 resulted in the secondary amine 23. As
shown for compound 22 by X-ray crystallography, the E-
configured C(6,7) double bond leads to an antiperiplanar
arrangement of H(C5) and H(C6) because of avoidance of
an 1,3-allylic strain.21 Selected NOE contacts observed
for compound 23 confirm the antiperiplanar conforma-
tional lock between C5 and C6 in solution (Scheme 5).
Peptide sequences adopting left-handed helical
a
polyproline II (PPII) conformation are often found at pro-
tein–protein interfaces where they play an important role
in the recognition process.13 Therefore, short PPII helical
peptides and peptidomimetics are interesting synthetic
targets because they can act as molecular probes for such
recognition events and have already been investigated in
recent years.14 Among the numerous ligands for protein–
protein interactions, the amino acid proline is crucial. The
cognate protein interaction modules, such as Src3 homo-
logy (SH3) domains, Eps15 homology (EH15) domains,
14-3-3 proteins, and WW domains typically recognize lin-
ear regions of 3–9 amino acids.4
As a starting point of the synthesis of the Pro-Pro isostere,
N-Boc-protected L-proline 16 was converted by borane
reduction and subsequent Swern oxidation into the
aldehyde 17.15 The alkenylation of 17 with cyclopent-1-
enyllithium prepared from 1-iodocyclopent-1-ene by io-
dine–lithium exchange with tert-butyllithium gave the de-
sired alcohol with a modest diastereoselectivity of 80:20
in 75% yield. If, however, the cyclopent-1-enyllithium
was prepared in situ from 1-chlorocyclopent-1-ene and
lithium metal,16 the addition proceeded with high stereo-
selectivity (96:4) to give after chromatographic purifica-
tion the S,R-alcohol 18 in 84% yield (Scheme 4). The
stereochemical assignment of 18 was possible from an X-
ray crystal structure.3i
BocN
a
O
N
TMSO
OTBS
O
TBSO
Boc
H
19
20
22
O
b–d
e
N
OTBS
N
74% (a–d)
OH
OH
O
21
88%
Boc
Boc
OH
H
4
H
H
H
8
5
6
7
N
H
H
N
H
11
OH
23
H
OH
c
a,b
H
N
N
selected NOE contacts in 23
84%
98%
O
O
Boc
Boc
17
16
Scheme 5 Reagents and conditions: (a) LDA, pyridine, TMSCl,
then addition of 19, THF, –100 °C → r.t.; (b) TBAF, THF,
0 °C → r.t.; (c) Pb(OAc)4, CHCl3, EtOAc, 0 °C; (d) NaBH4, MeOH,
0 °C; (e) TFA, CH2Cl2.
d
N
N
84%
OTBS
O
OH
18
Boc
Boc
O
19
To complete the synthesis of isostere 25, amine 23 was
treated with FmocOSu/NaHCO3 in acetone–H2O to give
the Fmoc-protected alcohol 24. The final oxidation of 24
using the Jones reagent yielded the desired carboxylic
acid 25 in nearly quantitative yield (Scheme 6).
Scheme 4 Reagents and conditions: (a) BH3·SMe2, THF, reflux; (b)
(COCl)2, DMSO, Et3N, CH2Cl2, –63 °C; (c) cyclopent-1-enyllithium,
Et2O, –78 °C; (d) tert-butyldimethylsilyloxyacetyl chloride, pyridine,
THF, 0 °C → r.t.
In summary, two novel E-alkene dipeptide isosteres were
synthesized. Whereas the synthesis of the Tyr-Tyr isostere
The Felkin–Anh selectivity observed in the addition of a
lithium alkenyl compound to N-Boc-prolinal (17 → 18) is
remarkably high.17 In contrast, organomagnesium re-
agents show weak chelation control.18 The alcohol 18 was
then converted into the siloxy acetate 19 using tert-bu-
tyldimethylsilyloxyacetyl chloride.19
a
b
23
N
N
82%
94%
OH
OH
O
Fmoc
Fmoc
24
25
With the allyl acetate 19 in hand, the stereoselective Ire-
land–Claisen rearrangement into the acid 21 was investi-
gated (Scheme 5).3f,i Treatment of ester 19 with LDA and
Scheme 6 Reagents and conditions: (a) FmocOSu, NaHCO3, ace-
tone–H2O (1:1), 0 °C → r.t.; (b) CrO3, H2SO4, acetone, 0 °C.
Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York

PAPER
Synthesis of E-Alkene Dipeptide Isosteres
2723
13C NMR (75 MHz, CDCl3): d = 156.4, 154.0, 143.84, 143.80,
141.3 (2 C), 132.3, 129.6 (2 C), 127.7 (2 C), 127.0 (2 C), 125.0 (2
C), 124.2 (2 C), 119.9 (2 C), 78.3, 66.6, 63.9, 54.1, 47.2, 36.6, 28.8
(3 C).
HRMS (ESI): m/z calcd for C28H31NO4 + Na [M + Na]+: 468.2145;
found: 468.2153.
15 relied on a convergent strategy highlighting a Julia–
Kocienski olefination to generate the E-configured double
bond, the synthesis of the Pro-Pro isostere 25 was accom-
plished by an efficient linear strategy containing an Ire-
land–Claisen rearrangement to establish the trisubstituted
E-configured double bond. Both isosteres were synthe-
sized with a protecting group pattern suitable for the use
in Fmoc-based SPPS towards the synthesis of correspond-
ing peptide analogues.
(S)-3-(4¢¢-tert-Butoxyphenyl)-2-[N-(9¢¢¢fluorenylmethoxycarbo-
nyl)amino]-1-(1¢-phenyl-1H-tetrazol-5¢-ylthio)propane (4)
Subsequently PPh3 (1.10 g, 4.21 mmol) and 1-phenyl-1H-tetra-
zolyl-5-thiol (1.00 g, 5.61 mmol) were added to a solution of the
above-prepared alcohol (1.25 g, 2.80 mmol) in THF (15 mL). At
0 °C, the mixture was treated dropwise with DIAD (1.06 mL,
5.05 mmol) and stirred for 2 h at r.t. The crude product was ad-
sorbed onto silica gel and purified by flash column chromatography
on silica gel (CH2Cl2–EtOAc, 10:1 or pentane–MTBE, 2:1) and the
pure thioether 4 (1.56 g, 92%) was obtained as a colorless solid; Rf =
0.35 (cyclohexane–MTBE, 1:1); [a]D19 –4.8 (c 1.22, CHCl3).
All nonaqueous reactions were carried out in an argon atmosphere
using standard Schlenk techniques. All solvents were distilled by
rotary evaporation. Solvents for nonaqueous reactions were dried
following standard procedures and stored under argon prior to use.
All commercially available reagents and reactants were used with-
out purification unless otherwise noted. Boc-L-prolinal and tert-bu-
tyldimethylsilyloxyacetyl chloride were prepared according to
literature procedures.13,17 Chromatographic purification of products
was performed on Merck Silica Gel 60 (230–400 mesh) unless oth-
erwise noted using a forced flow of eluents. Neutral silica gel was
purchased from Fuji Silysia (Chromatorex MB 100-40/75). Con-
centration under reduced pressure was performed by rotary evapo-
ration at 40 °C and appropriate pressure. Yields refer to purified and
spectroscopically pure products unless otherwise noted. Optical ro-
tations were measured on a PerkinElmer 241 polarimeter using
dried solvents and a 1 dm path length cell. IR spectra were recorded
on a Bruker IFS 200 or a Nicolet Magna-IR 750 spectrometer. The
absorption bands are given in wave numbers (cm–1), with intensities
reported as follows: s = strong, m = medium, w = weak, br = broad
band. NMR spectra were recorded on a Bruker ARX300 or
DRX500 spectrometer at room temperature. Chemical shifts are re-
ported in ppm with the solvent resonance as internal standard. Data
are reported as follows: s = singlet, d = doublet, t = triplet,
qi = quintet, m = multiplet, br = broad signal, p = pseudo. Mass
spectra were recorded on a Finnigan MAT TSQ 700 or MAT 95S
(both mass service of Philipps-Universität Marburg) or an Applied
Biosystems Model Q-Star (Prof. Marahiel, Philipps-Universität
Marburg). Elemental analyses were determined on a Heraeus CHN-
Rapid Analyzer (Philipps-Universität Marburg).
IR (KBr): 3349 (m), 2975 (m), 1689 (s), 1529 (s), 1501 (s), 1450
(w), 1386 (m), 1365 (m), 1258 (s), 1228 (m), 1162 (m), 1103 (w),
1044 (m), 761 (m), 741 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.74 (d, J = 7.6 Hz, 2 H), 7.54–
7.51 (m, 5 H), 7.49 (d, J = 7.6 Hz, 2 H), 7.38 (t, J = 7.4 Hz, 2 H),
7.27 (t, J = 7.4 Hz, 2 H), 7.09 (d, J = 8.1 Hz, 2 H), 6.92 (d,
J = 8.1 Hz, 2 H), 5.46 (br d, J = 8.1 Hz, 1 H), 4.31 (d, J = 7.1 Hz, 2
H), 4.28–4.19 (m, 1 H), 4.14 (t, J = 7.0 Hz, 1 H), 3.61 (dd, J = 13.8,
3.7 Hz, 1 H), 3.50 (dd, J = 13.8, 9.5 Hz, 1 H), 3.04 (dd, J = 13.7, 6.5
Hz, 1 H), 2.89 (dd, J = 13.7, 7.0 Hz, 1 H), 1.32 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 155.8, 154.5, 154.3, 143.8 (2 C),
141.2 (2 C), 133.5, 131.4, 130.2, 129.8 (2 C), 129.7 (2 C), 127.6 (2
C), 127.0 (2 C), 125.1, 125.0, 124.2 (2 C), 123.8 (2 C), 119.9 (2 C),
78.4, 66.7, 52.8, 47.1, 39.8, 37.0, 28.8 (3 C).
HRMS (ESI): m/z calcd for C35H35N5O3S + Na [M + Na]+:
628.2353; found: 628.2371.
(S)-2-Amino-3-(4¢¢-tert-butoxyphenyl)-1-(1¢-phenyl-1H-tetra-
zol-5¢-ylthio)propane
A solution of the thioether 4 (303 mg, 0.50 mmol) in DMF (5 mL)
was treated with piperidine (1 mL) and stirred for 2 h. Afterwards,
the solvent was evaporated, the residue was adsorbed onto silica
gel, and purified by flash column chromatography on silica gel
(pentane–MTBE, 1:1 → CHCl3–MeOH, 10:1). The title compound
free amine (192 mg, ~100%) was obtained as a colorless oil; Rf =
0.37 (CHCl3–MeOH, 9:1); [a]D20 +27.0 (c 1.35, CHCl3).
L-O-tert-Butyl-N-(9-fluorenylmethoxycarbonyl)tyrosinol
At –10 °C,
a solution of Fmoc-Tyr(t-Bu)-OH (3; 2.30 g,
5.00 mmol) in THF (7 mL) was treated with NMM (0.69 mL,
6.25 mmol). After dropwise addition of ethyl chloroformate
(0.48 mL, 5.00 mmol), the mixture was stirred at –10 °C for 30 min.
After removing the solid by filtration, the solution was added drop-
wise to a slurry of NaBH4 (473 mg, 12.50 mmol) in H2O (7 mL) at
0 °C. After 4 h stirring at 0 °C, MTBE (40 mL) and aq sat. NH4Cl
were added. The aqueous layer was extracted with MTBE
(2 × 40 mL) and the combined organic phases were washed with
brine (20 mL), and dried (Na2SO4). The crude product was purified
by flash column chromatography on silica gel (pentane–EtOAc, 2:1
→ 1:1). The product alcohol (1.777 g, 80%) was obtained as a col-
orless solid; Rf = 0.23 (cyclohexane–EtOAc, 1:1); [a]D19 –19.0
(c 1.11, CHCl3).
IR (film): 3469 (br, m), 2976 (m), 2933 (m), 2860 (w), 1673 (s),
1501 (s), 1440 (w), 1388 (m), 1366 (w), 1388 (m), 1162 (m), 1092
(w), 897 (m), 763 (m), 694 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 7.63–7.53 (m, 5 H), 7.10 (pd,
J = 8.3 Hz, 2 H), 6.94 (pd, J = 8.5 Hz, 2 H), 3.69 (dd, J = 13.3,
4.0 Hz, 1 H), 3.60–3.49 (m, 1 H), 3.33 (dd, J = 13.3, 7.4 Hz, 1 H),
2.95 (dd, J = 13.5, 5.2 Hz, 1 H), 2.69 (dd, J = 13.3, 4.0 Hz, 1 H),
2.52 (br s, 2 H), 1.33 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 154.3, 154.0, 133.5, 132.4, 130.0,
129.6 (2 C), 129.5 (2 C), 124.1 (2 C), 123.7 (2 C), 78.2, 51.8, 42.4,
40.5, 28.7 (3 C).
HRMS (ESI): m/z calcd for C20H26N5OS + Na [M + Na]+: 384.1853;
found: 384.1859.
IR (KBr): 3334 (br, m), 3062 (w), 2974 (m), 1689 (s), 1535 (s),
1505 (m), 1447 (w), 1365 (w), 1261 (m), 1233 (m), 1162 (m), 1085
(w), 1052 (w), 1023 (m), 739 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.75 (d, J = 7.3 Hz, 2 H), 7.55 (d,
J = 7.3 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 2 H), 7.30 (t, J = 7.3 Hz, 2 H),
7.08 (d, J = 7.6 Hz, 2 H), 6.91 (d, J = 7.8 Hz, 2 H), 5.12–4.91 (m, 1
H), 4.49–4.33 (m, 2 H), 4.19 (t, J = 6.6 Hz, 1 H), 3.99–3.82 (m, 1
H), 3.77–3.47 (m, 2 H), 2.87–2.74 (m, 2 H), 2.36–2.11 (m, 1 H),
1.32 (s, 9 H).
(S)-3-(4¢¢-tert-Butoxyphenyl)-2-(trifluoroacetylamino)-1-(1¢-
phenyl-1H-tetrazol-5¢-ylthio)propane (5)
To a solution of the above-prepared amine (1.06 g, 2.76 mmol) and
pyridine (0.67 mL, 8.29 mmol) in CH2Cl2 (60 mL), was added tri-
fluoroacetic anhydride (1.21 mL, 6.08 mmol) dropwise at 0 °C. The
mixture was stirred for 1 h at r.t. and quenched by the addition of aq
Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York

2724
N. G. Bandur et al.
PAPER
sat. NaHCO3 (30 mL). The layers were separated and the aqueous
phase was extracted with additional CH2Cl2 (2 × 30 mL). The com-
bined organic layers were washed with aq 1 M NaHSO4 (10 mL)
and brine (10 mL), and dried (Na2SO4). Purification of the crude
product by flash column chromatography on silica gel (pentane–
MTBE, 2:1) gave the amide 5 (1.18 g, 89%) as a colorless solid;
Rf = 0.29 (cyclohexane–MTBE, 1:1); [a]D19 –13.5 (c 1.02, CHCl3).
IR (film): 3030 (w), 1692 (s), 1610 (w), 1581 (w), 1514 (m), 1427
(m), 1384 (w), 1308 (m), 1239 (m), 1111 (w), 1014 (m), 827 (m),
735 (m), 694 cm–1 (m).
1H NMR (200 MHz, CDCl3): d = 11.66 (br s, 1 H), 7.05–7.28 (m, 5
H), 7.19–7.08 (m, 2 H), 6.98–6.86 (m, 2 H), 5.05 (s, 2 H), 2.91 (t,
J = 7.8 Hz, 2 H), 2.66 (t, J = 7.9 Hz, 2H).
13C NMR (50 MHz, CDCl3): d = 179.1, 157.3, 137.0, 132.4, 129.2
(2 C), 128.6 (2 C), 127.9, 127.5 (2 C), 114.8 (2 C), 70.0, 35.8, 29.7.
HRMS (EI): m/z calcd for C16H16O3 [M]+: 256.1099; found:
256.1102.
IR (KBr): 3320 (m), 2978 (w), 1697 (s), 1598 (w), 1550 (m), 1501
(m), 1388 (w), 1367 (w), 1235 (m), 1218 (m), 1179 (s), 1103 (m),
898 (w), 766 (m), 692 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.01 (br d, J = 7.6 Hz, 1 H), 7.62–
7.51 (m, 5 H), 7.16–7.09 (m, 2 H), 6.98–6.92 (m, 2 H), 4.58–4.43
(m, 1 H), 3.54 (dd, J = 14.8, 8.4 Hz, 1 H), 3.48 (dd, J = 14.9, 4.6 Hz,
1 H), 3.16 (dd, J = 13.8, 5.7 Hz, 1 H), 2.92 (dd, J = 13.8, 8.1 Hz, 1
H), 1.33 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 157.3 (q, J = 37 Hz), 154.6,
154.5, 133.2, 130.6, 130.5, 129.9 (2 C), 129.6 (2 C), 124.4 (2 C),
123.9 (2 C), 78.5, 52.6, 38.9, 35.8, 28.8 (3 C).
HRMS (ESI): m/z calcd for C22H25N5O2S + Na [M + Na]+:
480.1676; found: 480.1696.
Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.87;
H, 6.28
(4R)-4-Benzyl-3-[3¢-(4¢¢-benzyloxyphenyl)propionyl]-1,3-oxazo-
lidin-2-one (8)
A
solution of 3-(4¢-benzyloxyphenyl)propionic acid (3.59 g,
14 mmol) in THF (170 mL) and Et3N (5.82 mL, 42 mmol) was
cooled to –20 °C. After dropwise addition of pivaloyl chloride
(1.72 mL, 14 mmol), the resulting suspension was stirred for 2 h at
–20 °C. Afterwards, LiCl (593 mg, 14 mmol) and (R)-4-benzyl-1,3-
oxazolidin-2-one (2.48 g, 14.0 mmol) were added and the mixture
was stirred for 14 h at r.t. After evaporation of the solvent in vacuo,
the residue was redissolved in EtOAc (120 mL) and H2O (50 mL).
After phase separation, the organic phase was washed with aq 1 M
NaHCO3 (50 mL) and brine (30 mL), and dried (Na2SO4). The
crude product was purified by flash column chromatography on sil-
ica gel (pentane–EtOAc, 2:1) or recrystallization from refluxing
hexane–EtOAc (1:1) to give the acyloxazolidinone 8 (5.30 g, 91%)
as a colorless solid; mp 106 °C (hexane–EtOAc); Rf = 0.14 (hex-
ane–EtOAc, 3:1), 0.23 (hexane–EtOAc, 2:1); [a]D24 –48.4
(c 1.01, CHCl3).
(S)-3-(4¢¢-tert-Butoxyphenyl)-2-(trifluoroacetylamino)-1-(1¢-
phenyl-1H-tetrazol-5¢-ylsulfonyl)propane (6)
To a solution of thioether 5 (1.33 g, 2.70 mmol) in CH2Cl2 (30 mL),
was added MCPBA (2.39 g, 9.70 mmol) at 0 °C. After stirring for
16 h at r.t., aq sat. NaHCO3 (30 mL) and aq sat. NaHSO3 (30 mL)
were added. After phase separation, the aqueous layer was extracted
with CH2Cl2 (2 × 80 mL), and the combined organic phases were
washed with brine (20 mL) and dried (Na2SO4). The crude product
was purified by flash column chromatography on silica gel
(CH2Cl2–EtOAc, 20:1) and the sulfone 6 (1.19 g, 87%) was ob-
tained as a colorless solid; Rf = 0.11 (cyclohexane–MTBE, 2:1),
0.54 (cyclohexane–EtOAc, 1:1); [a]D27 –9.1 (c 1.23, CHCl3).
IR (film): 3058 (w), 3027 (w), 2940 (m), 2071 (w), 1769 (s), 1694
(s), 1511 (s), 1447 (m), 1385 (m), 1353 (m), 1317 (m), 1236 (s),
1219 (m), 1201 (m), 1167 (m), 1099 (m), 1006 (m), 744 (s), 703
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.47–7.27 (m, 8 H), 7.23–7.14 (m,
4 H), 6.96–6.78 (m, 2 H), 5.05 (s, 2 H), 4.66 (dddd, J = 9.7, 6.1, 3.7,
3.6 Hz, 1 H), 4.23–4.12 (m, 2 H), 3.37–3.14 (m, 3 H), 3.04–2.92 (m,
2 H), 2.75 (dd, J = 13.3, 9.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 172.5, 157.4, 153.4, 137.2, 135.2,
132.8, 129.6 (2 C), 129.4 (2 C), 128.9 (2 C), 128.5 (2 C), 127.9,
127.4 (2 C), 127.3, 114.9 (2 C), 70.1, 66.2, 55.1, 37.8, 37.3, 29.5.
HRMS (ESI): m/z calcd for C26H25NO4 [M + Na]+: 438.1676;
found: 438.1684.
IR (film): 3323 (m), 2982 (m), 2932 (w), 1703 (s), 1559 (m), 1508
(m), 1354 (s), 1220 (m), 1156 (s), 899 (w), 879 (w), 764 (m), 689
(w), 639 (m), 522 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.67–7.53 (m, 5 H), 7.11–7.03 (m,
2 H), 6.99–6.89 (m, 3 H), 4.84–4.67 (m, 1 H), 4.13 (dd, J = 15.3,
9.1 Hz, 1 H), 3.97 (dd, J = 15.3, 3.6 Hz, 1 H), 3.11 (dd, J = 13.8,
7.0 Hz, 1 H), 3.04 (dd, J = 13.8, 6.8 Hz, 1 H), 1.33 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 156.8 (q, J = 38 Hz), 155.1, 153.6,
132.7, 131.7, 129.75 (2 C), 129.72 (2 C), 129.3, 125.1 (2 C), 124.6
(2 C), 117.2, 78.8, 57.5, 47.5, 38.7, 28.8 (3 C).
HRMS (ESI): m/z calcd for C22H24F3N5O4S + Na [M + Na]+:
534.1393; found: 534.1401.
Anal. Calcd for C26H25NO4: C, 75.16; H, 6.06; N, 3.37. Found:
C, 75.19; H, 6.15; N, 3.24.
Anal. Calcd for C22H24F3N5O4S: C, 51.66; H, 4.73; N, 13.69.
Found: C, 50.99; H, 4.63; N, 13.54.
(4R)-4-Benzyl-3-[3¢-(4¢¢-hydroxyphenyl)propionyl]-1,3-oxazoli-
din-2-one
3-(4¢-Benzyloxyphenyl)propionic Acid
A mixture of 3-(4¢-hydroxyphenyl)propionic acid (7; 4.99 g,
30 mmol), benzyl chloride (13.9 mL, 120 mmol), KI (19.92 g,
120 mmol), and K2CO3 (16.59 g, 120 mmol) in acetone (70 mL)
was heated to reflux for 2 d. After cooling to r.t., aq 20% NaOH
(75 mL) was added and the mixture was again heated to reflux for
2 d. The resulting slurry was diluted with H2O (250 mL), cooled to
0 °C, and treated with concd HCl until the solid had dissolved. The
solution was extracted with CHCl3 (3 × 100 mL) and the combined
organic extracts were washed with brine (80 mL) and dried
(MgSO4). After recrystallization from refluxing EtOAc, 3-(4¢-ben-
zyloxyphenyl)propionic ccid (6.63 g, 86%) was obtained as a color-
less crystalline solid; mp 122 °C (EtOAc).
Pd(OH)2 on activated carbon (10 wt% Pd, 350 mg) was added to a
solution of the benzyl ether 8 (3.45 g, 8.30 mmol) in MeOH–EtOAc
(1:1, 200 mL) and the suspension was stirred vigorously under an
H2 atmosphere (1 bar) for 2 h. The catalyst was removed by filtra-
tion through a pad of Celite and the crude product was purified by
flash column chromatography on silica gel (pentane–EtOAc, 1:1) to
give the title compound (2.70 g, 100%) as a colorless solid; Rf =
0.33 (hexane–EtOAc, 1:1); [a]D24 –62.3 (c 1.18, CHCl3).
IR (film): 3411 (br, m), 3027 (w), 2954 (w), 1785 (s), 1762 (m),
1513 (m), 1443 (m), 1391 (s), 1374 (m), 1354 (m), 1305 (m), 1206
(s), 1115 (m), 1050 (m), 1015 (w), 979 (m), 826 (w), 743 (m), 704
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.37–7.25 (m, 3 H), 7.21–7.15 (m,
2 H), 7.14–7.07 (m, 2 H), 6.85–6.68 (m, 2 H), 5.47 (s, 2 H), 4.66
Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York

PAPER
Synthesis of E-Alkene Dipeptide Isosteres
2725
(dddd, J = 9.8, 6.0, 3.8, 3.8 Hz, 1 H), 4.23–4.09 (m, 2 H), 3.37–3.13
(m, 3 H), 3.04–2.85 (m, 2 H), 2.78 (dd, J = 13.4, 9.4 Hz, 1 H).
128.9 (2 C), 127.7 (4 C), 127.4, 119.6 (2 C), 66.0, 63.0, 55.5, 47.1,
37.9, 34.0, 26.5 (3 C), 19.4.
13C NMR (75 MHz, CDCl3): d = 172.6, 154.2, 153.6, 135.1, 132.3,
129.6 (2 C), 129.4 (2 C), 128.9 (2 C), 127.3, 115.3 (2 C), 66.2, 55.1,
37.8, 37.4, 29.5.
HRMS (ESI): m/z calcd for C36H39NSiO5 + Na [M + Na]+:
616.2490; found: 616.2492.
(2S)-3-(4¢-tert-Butyldiphenylsilyloxyphenyl)-2-hydroxymethyl-
N-methoxy-N-methylpropionamide
HRMS (ESI): m/z calcd for C19H19NO4 + Na [M + Na]+: 348.1206;
found: 348.1211.
Me(MeO)NH·HCl (4.83 g, 49.51 mmol) was suspended in CH2Cl2
(70 mL) and cooled to –10 °C. After the addition of Me3Al (2 M in
toluene, 24.8 mL, 49.51 mmol), the resulting solution was stirred at
r.t. for 1 h and again cooled to –10 °C. Afterwards, a solution of the
acyloxazolidinone 10 (3.45 g, 7.07 mmol) in CH2Cl2 (70 mL) was
added and the mixture was stirred for 72 h at –10 °C. The reaction
was quenched by the addition of aq 1 M Na/K-tartrate solution
(270 mL) and the resulting slurry was stirred vigorously for 1.5 h at
r.t. The layers were separated and the aqueous phase was extracted
with CH2Cl2 (2 × 180 mL) and MTBE (100 mL). The organic lay-
ers were pooled, washed with brine (150 mL), and dried (Na2SO4).
Purification by flash column chromatography on silica gel
(CH2Cl2–EtOAc, 4:1) yielded the title Weinreb amide (3.16 g,
94%) as a colorless oil; Rf = 0.24 (CH2Cl2–EtOAc, 2:1), 0.37
(CHCl3–MeOH, 10:1); [a]D20 –16.5 (c 1.04, CHCl3).
(4R)-4-Benzyl-3-[3¢-(4¢¢-tert-butyldiphenylsilyloxyphenyl)pro-
pionyl]-1,3-oxazolidin-2-one (9)
A solution of the above-prepared phenol (1.33 g, 4.1 mmol) and im-
idazole (737 mg, 12.3 mmol) in DMF (20 mL) was cooled to 0 °C
and treated with TBDPSCl (1.59 mL, 6.2 mmol). After 14 h at r.t.,
H2O (120 mL) was added and the mixture was extracted with
MTBE (3 × 60 mL). The organic layers were pooled, washed with
brine (60 mL) and dried (Na2SO4). After purification by flash col-
umn chromatography on silica gel (pentane–MTBE, 2:1), the TB-
DPS ether 9 (2.05 g, 89%) was obtained as a colorless viscous oil;
Rf = 0.31 (cyclohexane–MTBE, 2:1); [a]D25 –35.3 (c 1.08, CHCl3).
IR (film): 3029 (w), 2958 (m), 2931 (m), 2858 (m), 1783 (s), 1700
(s), 1608 (m), 1510 (s), 1473 (w), 1428 (w), 1387 (s), 1352 (m),
1255 (s), 1213 (m), 1113 (s), 920 (s), 824 (m), 745 (m), 702 (s), 503
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.75–7.66 (m, 4 H), 7.46–7.23 (m,
9 H), 7.21–7.12 (m, 2 H), 7.02–6.94 (m, 2 H), 6.93–6.65 (m, 2 H),
4.69–4.57 (m, 1 H), 4.20–4.10 (m, 2 H), 3.30–3.07 (m, 3 H), 2.77–
2.67 (m, 2 H), 2.72 (dd, J = 13.4, 9.6 Hz, 1 H), 1.09 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 172.5, 154.0, 153.4, 135.5 (4 C),
135.2, 133.1, 132.8 (2 C), 129.8 (2 C), 129.4 (2 C), 129.2 (2 C),
128.9 (2 C), 127.7, 127.3, 119.6 (2 C), 66.1, 55.1, 37.8, 37.3, 29.5,
26.6 (3 C), 19.4.
IR (film): 3424 (br, m), 2932 (m), 2858 (m), 1636 (m), 1609 (m),
1510 (s), 1423 (w), 1428 (m), 1390 (w), 1255 (s), 1113 (m), 919
(m), 822 (m), 702 (s), 502 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.74–7.66 (m, 4 H), 7.46–7.31 (m,
6 H), 6.96–6.88 (m, 2 H), 6.72–6.63 (m, 2 H), 3.74–3.62 (m, 2 H),
3.38 (s, 3 H), 3.20–3.05 (m, 1 H), 3.11 (s, 3 H), 2.86 (dd, J = 13.6,
7.3 Hz, 1 H), 2.69 (dd, J = 13.3, 7.6 Hz, 1 H), 1.64 (br s, 1 H), 1.08
(s, 9 H).
13C NMR (75 MHz, CDCl3): d = 175.8, 154.1, 135.5 (4 C), 133.00,
132.98, 131.6, 129.81 (2 C), 129.76 (2 C), 127.7 (4 C), 119.6 (2 C),
62.8, 61.2, 45.0, 33.9, 31.8, 26.5 (3 C), 19.4.
HRMS (ESI): m/z calcd for C35H37NSiO4 + Na [M + Na]+:
586.2384; found: 586.2363.
HRMS (ESI): m/z calcd for C28H35NSiO4 + Na [M + Na]+:
500.2228; found: 500.2229.
(4R,2¢S)-4-Benzyl-3-[3¢-(4¢¢-tert-butyldiphenylsilyloxyphenyl)-
2¢-hydroxymethylpropionyl]-1,3-oxazolidin-2-one (10)
(2S)-3-(4¢¢-tert-Butyldiphenylsilyloxyphenyl)-N-methoxy-N-
methyl-2-(tetrahydro-2H-pyran-2¢-yloxymethyl)propionamide
(11)
To a solution of the oxazolidinone 9 (7.02 mmol, 3.96 g) in CH2Cl2
(40 mL) at 0 °C, was added dropwise TiCl4 (7.72 mmol, 0.85 mL).
After 5 min, i-Pr2NEt (8.01 mmol, 1.4 mL) was added, whereupon
the solution turned dark purple. After the mixture was stirred at 0 °C
for 1 h, a solution of s-trioxane (8.01 mmol, 0.72 g) in CH2Cl2
(5 mL) was added, followed by TiCl4 (7.37 mmol, 0.81 mL). The
mixture was stirred for 3 h at 0 to 10 °C. Then aq sat. NH4Cl
(50 mL) was added and the layers were separated. After extraction
with additional CH2Cl2 (3 × 50 mL), the organic layers were pooled
and washed subsequently with H2O (2 × 25 mL) and brine (50 mL).
After drying (Na2SO4) and evaporation of solvents, the residue was
purified by flash column chromatography on silica gel (MTBE–
pentane, 1:2 → 1:1) to give compound 10 as a colorless foam; Rf =
0.14 (cyclohexane–MTBE, 2:1), 0.37 (cyclohexane–EtOAc, 1:1);
[a]D24 –75.0 (c 0.98, CHCl3).
To a solution of the above-prepared amide (1.93 g, 4.04 mmol) and
3,4-dihydro-2H-pyran (0.50 mL, 5.26 mmol) in CH2Cl2 (20 mL) at
0 °C was added PPTS (20 mg, 80 mmol) and the solution was stirred
for 16 h at r.t. The reaction was quenched by the addition of aq sat.
NaHCO3 (50 mL). The layers were separated and the aqueous layer
was extracted with CH2Cl2 (2 × 100 mL). The combined organic
extracts were washed with brine (50 mL) and dried (Na2SO4). After
purification by flash column chromatography on silica gel (pen-
tane–MTBE, 3:1 → 2:1), product 11 (1.84 g, 81%) was obtained as
a colorless oil; Rf = 0.26 (cyclohexane–MTBE, 1:1).
IR (film): 2936 (m), 2859 (m), 1714 (m), 1657 (m), 1510 (s), 1472
(w), 1428 (w), 1256 (s), 1201 (w), 1172 (w), 1115 (s), 1032 (m), 920
(m), 734 (m), 702 (m), 503 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.76–7.64 (m, 4 H), 7.48–7.30 (m,
6 H), 6.95–6.83 (m, 2 H), 6.70–6.60 (m, 2 H), 4.61–4.56 (m, 0.5 H),
4.55–4.49 (m, 0.5 H), 3.85 (t, J = 8.8 Hz, 0.5 H), 3.86–3.71 (m, 1.5
H), 3.54 (t, J = 9.2 Hz, 0.5 H), 3.52–3.33 (m, 2.5 H), 3.28 (s, 1.5 H),
3.22 (m, 1.5 H), 2.99 (m, 1.5 H), 2.97 (m, 1.5 H), 2.83–2.70 (m, 1
H), 2.67–2.57 (m, 1 H), 1.82–1.42 (m, 6 H), 1.01 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 174.6, 154.9, 135.5 (4 C), 133.08
+ 133.05 (1 C), 129.80 (2 C), 129.76, 129.71, 127.7 (4 C), 119.5 (2
C), 99.4 + 97.0 (1 C), 68.8 + 68.0 (1 C), 62.4 + 61.5 (1 C), 61.1,
43.6, 34.5, 31.9, 30.6 + 30.4 (1 C), 26.5 (3 C), 25.4, 19.6 + 19.0 (1
C), 19.4.
IR (KBr): 3506 (br, m), 3029 (w), 2930 (m), 2857 (m), 1780 (s),
1697 (s), 1510 (s), 1390 (m), 1350 (w), 1255 (s), 1210 (m), 1112
(m), 917 (m), 701 (s), 501 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.74–7.65 (m, 4 H), 7.43–7.26 (m,
9 H), 7.24–7.16 (m, 2 H), 6.96 (pd, J = 8.5 Hz, 2 H), 6.67 (pd,
J = 8.5 Hz, 2 H), 4.44 (dddd, J = 9.4, 7.6, 3.5, 2.1 Hz, 1 H), 4.26–
4.13 (m, 1 H), 4.03 (dd, J = 9.1, 2.1 Hz, 1 H), 3.90–3.70 (m, 2 H),
3.83 (dd, J = 8.2, 8.2 Hz, 1 H), 3.23 (dd, J = 13.5, 3.3 Hz, 1 H), 2.86
(dd, J = 13.4, 7.6 Hz, 1 H), 2.76 (dd, J = 13.4, 5.3 Hz, 1 H), 2.73
(dd, J = 13.3, 3.7 Hz, 1 H), 2.26 (br s, 1 H), 1.08 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 175.5, 154.3, 153.2, 135.5 (4 C),
135.2, 133.0, 132.9, 130.5, 129.9 (2 C), 129.8 (2 C), 129.5 (2 C),
Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York

2726
N. G. Bandur et al.
PAPER
HRMS (ESI): m/z calcd for C33H43NSiO5 + Na [M + Na]+:
584.2803; found: 584.2807.
(2S)-3-(4¢¢-tert-Butoxyphenyl)-2-(tetrahydro-2H-pyran-2¢-
yloxymethyl)propanal (12)
A solution of the above-prepared Weinreb amide (338 mg,
891 mmol) in THF (6 mL) was cooled to –78 °C and DIBAL-H
(1 M in petroleum ether, 0.98 mL, 0.98 mmol) was added dropwise.
After stirring the mixture for 1.5 h, it was warmed up to –55 °C. Af-
terwards, the mixture was added slowly to aq K/Na-tartrate solution
(1 M, 12 mL) at 0 °C. The resulting slurry was diluted with MTBE
(30 mL) and stirred for 30 min at r.t. The layers were separated and
the aqueous layer was extracted with MTBE (3 × 20 mL). The com-
bined organic extracts were washed with brine (15 mL) and dried
(Na2SO4). The crude product was purified by flash column chroma-
tography on neutral silica gel (pentane–MTBE, 4:1) to give the al-
(2S)-3-(4¢¢-Hydroxyphenyl)-N-methoxy-N-methyl- 2-(tetrahy-
dro-2H-pyran-2¢-yloxymethyl)propionamide
A solution of the TBDPS ether 11 (878 mg, 1.56 mmol) in THF
(25 mL) was cooled to 0 °C. Afterwards, a solution of TBAF
(740 mg, 2.34 mmol) and AcOH (0.13 mL, 2.34 mmol) in THF
(5 mL) was added and the mixture was stirred for further 30 min at
0 °C. After the addition of aq sat. NaHCO3 (25 mL) and EtOAc
(50 mL), the layers were separated and the aqueous phase was ex-
tracted with EtOAc (2 × 50 mL). The combined organic extracts
were washed with brine (30 mL) and dried (Na2SO4). The crude
product was purified by flash column chromatography on silica gel
(EtOAc–pentane, 1:1) to give the title compound (505 mg, ~100%)
as a colorless waxy solid; Rf = 0.12 (cyclohexane–EtOAc, 1:1).
dehyde 12 (243 mg, 85%) as
a colorless oil; Rf = 0.38
(cyclohexane–MTBE, 2:1).
IR (film): 2976 (m), 1726 (s), 1608 (s), 1507 (s), 1389 (m), 1366
(m), 1236 (m), 1162 (s), 1136 (w), 1034 (m), 898 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 9.83–9.76 (m, 1 H), 7.11–7.01 (m,
2 H), 6.94–6.86 (m, 2 H), 4.60–4.51 (m, 1 H), 4.05–3.90 (m, 1 H),
3.82–3.71 (m, 1 H), 3.60–3.43 (m, 2 H), 3.09–2.97 (m, 1 H), 2.89–
2.71 (m, 2 H), 1.86–1.44 (m, 6 H), 1.34 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 203.4 + 203.3 (1 C), 153.93 +
153.90 (1 C), 133.4 + 133.2 (1 C), 129.4, 129.3, 124.20, 124.19,
99.2 + 98.8 (1 C), 78.3, 65.3 + 65.1 (1 C), 62.1 + 62.0 (1 C), 53.7 +
53.6 (1 C), 31.4 + 31.1 (1 C), 30.43 + 30.37 (1 C), 28.8, 25.4 + 25.3
(1 C), 19.2 + 19.1 (3 C).
IR (film): 3364 (br, s), 2946 (m), 1632 (s), 1594 (m), 1515 (m),
1446 (w), 1352 (w), 1260 (w), 1227 (m), 1202 (w), 1137 (w), 1120
(m), 1030 (s), 986 (w), 966 (m), 905 (m), 872 (w), 841 (m), 552
cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 7.07–6.97 (m, 2 H), 6.78–6.68 (m,
2 H), 6.47–6.26 (m, 1 H), 4.67–4.59 (m, 0.5 H), 4.58–4.58 (m, 0.5
H), 3.98 (t, J = 9.0 Hz, 0.5 H), 3.89–3.75 (m, 1.5 H), 3.66 (t,
J = 9.2 Hz, 0.5 H), 3.59–3.36 (m, 2.5 H), 3.50 (s, 1.5 H), 3.46 (s, 1.5
H), 3.13 (s, 1.5 H), 3.11 (s, 1.5 H), 2.91–2.76 (m, 1 H), 2.74–2.61
(m, 1 H), 1.89–1.41 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 175.0, 154.8, 130.7 + 130.5 (1 C),
130.1 + 130.0 (2 C), 115.3 (2 C), 99.6 + 98.0 (1 C), 68.8 + 68.0 (1
C), 62.6 + 61.6 (1 C), 61.3, 43.5, 34.4, 32.1, 30.6 + 30.4 (1 C), 25.4,
19.7 + 18.9 (1 C).
HRMS (ESI): m/z calcd for C19H28O4 + Na [M + Na]+: 343.1880;
found: 343.1883.
(E,2R,5R)-2-(4¢¢-tert-Butoxybenzyl)-6-(4¢¢¢-tert-butoxyphenyl)-
5-trifluoroacetylamino-1-(tetrahydro-2H-pyran-2¢-yloxy)hex-
3-ene (13)
HRMS (ESI): m/z calcd for C17H25NO5 + Na [M + Na]+: 346.1625;
found: 346.1629.
A solution of the sulfone 6 (321 mg, 0.627 mmol) in DME (5 mL)
was cooled to –78 °C and NaHMDS (2 m in THF, 0.69 mL,
1.379 mmol) was added dropwise whereupon the solution turned
yellow. After 30 min at –78 °C, compound 12 (241 mg,
0.752 mmol) dissolved in DME (2.5 mL) was added dropwise. The
cooling bath was removed and the mixture was stirred for 12 h at
r.t. After the addition of phosphate buffer (pH 7, 2.5 mL), H2O
(2.5 mL) and MTBE (10 mL), the layers were separated and the
aqueous layer was extracted with MTBE (3 × 5 mL). The combined
organic extracts were washed with brine (10 mL) and dried
(Na2SO4). The crude product was purified by flash column chroma-
tography on silica gel (pentane–MTBE, 10:1 → 6:1 and pentane–
acetone 15:1 → 10:1) to give the olefin 13 (201 mg, 53%) as an in-
separable E/Z mixture; Rf = 0.20 (cyclohexane–acetone, 5:1). The
following spectral data were obtained from the diastereomeric mix-
ture of 13.
(2S)-3-(4¢¢-tert-Butoxyphenyl)-N-methoxy-N-methyl-2-(tetra-
hydro-2H-pyran-2¢-yloxymethyl)propionamide
A solution of the above-prepared phenol (288 mg, 0.89 mmol) in
CH2Cl2 (2.5 mL) was cooled to 0 °C and treated with t-BuOTCA
(0.32 mL, 1.78 mmol) and catalytic amounts of PPTS. After warm-
ing up to r.t., the mixture was stirred for 5 h, and three times at in-
tervals of several hours the same amounts of t-BuOTCA and PPTS
were added. The reaction was quenched by the addition of aq sat.
NaHCO3 (3 mL). After phase separation, the aqueous layer was ex-
tracted with CH2Cl2 (3 × 5 mL). The combined organic layers were
washed with brine (5 mL) and dried (Na2SO4) and the crude product
was purified by flash column chromatography on silica gel (pen-
tane–MTBE, 2:1) to give the title tert-butyl ether (257 mg, 76%) as
a colorless oil; Rf = 0.13 (cyclohexane–MTBE 2:1).
IR (film): 2975 (s), 2940 (s), 2871 (m), 1733 (s), 1655 (s), 1507 (s),
1389 (m), 1365 (m), 1236 (m), 1162 (s), 1137 (m), 1123 (m), 1077
(m), 1032 (s), 899 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.07–6.97 (m, 2 H), 6.87–6.76 (m,
2 H), 4.57–4.52 (m, 0.5 H), 4.51–4.45 (m, 0.5 H), 3.97 (t,
J = 8.8 Hz, 0.5 H), 3.81 (m, 1.5 H), 3.59 (m, J = 9.2 Hz, 0.5 H),
3.53–3.25 (m, 2.5 H), 3.42 (s, 1.5 H), 3.36 (s, 1.5 H), 3.09 (s, 1.5 H),
3.08 (s, 1.5 H), 2.86–2.73 (m, 1 H), 2.70–2.58 (m, 1 H), 1.80–1.36
(m, 6 H), 1.24 (s, 9 H).
IR (film): 3303 (m), 2977 (m), 1705 (s), 1608 (w), 1550 (w), 1507
(s), 1444 (w), 1390 (w), 1366 (m), 1236 (m), 1162 (s), 1032 (m),
898 cm–1 (m).
The isomers were separated and analyzed after the cleavage of their
THP acetals (see below).
(E,2R,5R)-2-(4¢-tert-Butoxybenzyl)-6-(4¢¢-tert-butoxyphenyl)-5-
trifluoracetylaminohex-3-enol (14)
The acetal 13 (162 mg, 267 mmol) was dissolved in a mixture of
Et2O–MeOH (1:1, 8 mL) and treated with p-TsOH (4 mg, 20 mmol)
at 0 °C. After warming up to r.t., the mixture was stirred for 4 h and
quenched by the addition of aq sat. NaHCO3 (10 mL). MTBE
(20 mL) was added and the layers were separated. The aqueous lay-
er was extracted with MTBE (2 × 10 mL) and the combined organic
extracts were washed with brine (15 mL) and dried (Na2SO4). After
evaporation of the solvent in vacuo, the E/Z mixture was separated
by flash column chromatography on silica gel (pentane–MTBE, 4:1
13C NMR (75 MHz, CDCl3): d = 153.7, 134.5 + 134.3 (1 C),
129.45, 129.39, 124.1 (2 C), 99.4 + 98.1 (1 C), 78.2, 68.8 + 68.1 (1
C), 62.5 + 61.6 (1 C), 61.2, 43.5, 34.7, 32.0, 30.6 + 30.4 (1 C), 28.8
(3 C), 25.4, 19.7 + 19.0 (1 C). C-1 was not observed.
HRMS (ESI): m/z calcd for C21H33NO5 + Na [M + Na]+: 402.2251;
found: 402.2256.
Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York

PAPER
Synthesis of E-Alkene Dipeptide Isosteres
2727
→ 2:1) to give the E-isomer 14 (90 mg, 65%) as a colorless oil and
the Z-isomer (39 mg, 28%) as a colorless waxy solid.
(E,2R,5R)-2-(4¢-tert-Butoxybenzyl)-6-(4¢¢-tert-butoxyphenyl)-5-
(9¢¢¢-fluorenylmethyloxycarbonyl)aminohex-3-enol
A solution of the above-prepared amine (30.5 mg, 72 mmol) in
H2O–acetone (1:1, 2 mL) was cooled to 0 °C and treated with
NaHCO3 (6.0 mg, 72 mmol) and FmocOSu (24.2 mg, 72 mmol). Af-
ter stirring for 16 h at r.t., phosphate buffer (pH 7, 3 mL) and CHCl3
(5 mL) were added. The layers were separated and the aqueous
phase was extracted with CHCl3 (2 × 5mL). The combined organic
extracts were washed with brine (10 mL) and dried (Na2SO4). The
crude product was purified using flash column chromatography on
silica gel (pentane–EtOAc, 2:1 or CHCl3–MeOH, 49:1) to afford
the title carbamate (45.2 mg, 97%) as a solid colorless foam; Rf =
0.35 (cyclohexane–EtOAc, 1:1), 0.26 (CHCl3–MeOH, 49:1);
[a]D21 –15.9 (c 1.03, CHCl3).
E-Isomer
Rf = 0.41 (cyclohexane–MTBE, 2:1); [a]D25 –31.2 (c 1.06, CHCl3).
IR (film): 3442 (br, m), 3298 (br, m), 2978 (m), 2931 (w), 1705 (s),
1603 (w), 1555 (w), 1507 (s), 1367 (m), 1236 (m), 1161 (s), 1017
(w), 897 (m), 757 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.05–6.84 (m, 8 H), 6.23 (br d,
J = 7.2 Hz, 1 H), 5.33 (dd, J = 15.5, 7.2 Hz, 1 H), 5.25 (dd, J = 15.4,
6.1 Hz, 1 H), 4.59 (ddd, J = 13.8, 7.0, 6.8 Hz, 1 H), 3.51 (dd,
J = 10.6, 4.6 Hz, 1 H), 3.34 (dd, J = 10.3, 7.3 Hz, 1 H), 2.80 (dd,
J = 13.6, 6.4 Hz, 1 H), 2.75 (dd, J = 13.0, 7.7 Hz, 1 H), 2.64 (dd,
J = 12.9, 5.8 Hz, 1 H), 2.54–2.34 (m, 1 H), 2.49 (dd, J = 12.7,
8.0 Hz, 1 H), 1.67 (br s, 1 H), 1.32 (s, 9 H), 1.31 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 156.3 (q, J = 37 Hz), 154.5, 153.7,
134.6, 134.1, 131.0, 129.9, 129.7 (2 C), 129.5 (2 C), 124.3 (2 C),
124.0 (2 C), 117.7, 78.5, 78.2, 64.9, 53.2, 47.1, 40.1, 36.7, 28.82 (3
C), 28.80 (3 C).
IR (film): 3429 (br, m), 3346 (br, m), 2977 (s), 2931 (m), 1704 (s),
1506 (s), 1476 (w), 1450 (m), 1390 (w), 1366 (m), 1236 (s), 1162
(s), 1032 (m), 897 (m), 758 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 7.77 (pd, J = 7.6 Hz, 2 H), 7.57
(pd, J = 7.4 Hz, 2 H), 7.41 (pt, J = 7.6 Hz, 2 H), 7.32 (pt, J = 7.4 Hz,
2 H), 5.46–5.22 (m, 2 H), 4.83–4.66 (m, 1 H), 4.48–4.26 (m, 3 H),
4.20 (t, J = 6.6 Hz, 1 H), 3.54–3.42 (m, 1 H), 3.34–3.23 (m, 1 H),
2.91–2.34 (m, 5 H), 1.78–1.57 (m, 1 H), 1.314 (s, 9 H), 1.306 (s, 9
H).
13C NMR (75 MHz, CDCl3): d = 155.5, 154.1, 153.5, 143.9 (2 C),
141.3 (2 C), 134.4, 132.5, 132.2, 132.0, 129.8 (2 C), 129.4 (2 C),
127.7 (2 C), 127.0 (2 C), 125.0 (2 C), 124.1 (2 C), 124.0 (2 C), 120.0
(2 C), 78.3, 78.1, 66.5, 64.8, 54.2, 47.3, 46.9, 40.9, 36.7, 28.8 (6 C).
HRMS (ESI): m/z calcd for C29H38F3NO4 + Na [M + Na]+:
544.2645; found: 544.2655.
Z-Isomer
Rf = 0.42 (cyclohexane–MTBE, 2:1); [a]D24 +25.2 (c 1.04, CHCl3).
IR (film): 3442 (br, m), 3298 (br, m), 2978 (m), 2932 (w), 1703 (s),
1608 (w), 1554 (w), 1507 (s), 1390 (w), 1367 (m), 1236 (m), 1161
(s), 1017 (w), 897 (m), 759 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.07–6.82 (m, 8 H), 6.39 (br d,
J = 6.0 Hz, 1 H), 5.41 (dd, J = 10.8, 10.4 Hz, 1 H), 5.31 (dd,
J = 10.8, 9.0 Hz, 1 H), 4.59 (ddd, J = 14.4, 7.9, 7.0 Hz, 1 H), 3.70
(dd, J = 10.5, 4.4 Hz, 1 H), 3.41 (dd, J = 10.1, 9.5 Hz, 1 H), 3.06–
2.92 (m, 1 H), 2.63 (dd, J = 13.4, 5.1 Hz, 1 H), 2.37 (dd, J = 13.9,
7.3 Hz, 1 H), 2.30 (dd, J = 13.9, 6.0 Hz, 1 H), 2.25 (dd, J = 13.5, 9.2
Hz, 1 H), 1.70 (br s, 1 H), 1.29 (s, 9 H), 1.23 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 156.8 (q, J = 37 Hz), 154.6, 153.7,
135.1, 134.3, 130.3, 129.7, 129.6 (2 C), 129.5 (2 C), 124.4 (2 C),
124.0 (2 C), 117.5, 78.5, 78.2, 65.9, 49.3, 43.8, 39.4, 37.2, 28.8 (3
C), 28.7 (3 C).
HRMS (ESI): m/z calcd for C42H49NO5 + Na [M + Na]+: 670.3503;
found: 670.3518.
(E,2R,5R)-2-(4¢-tert-Butoxybenzyl)-6-(4¢¢-tert-butoxyphenyl)-5-
(9¢¢¢-fluorenylmethyloxycarbonyl)aminohex-3-enoic Acid (15)
To a solution of the above-prepared alcohol (280 mg, 432 mmol) in
CH2Cl2 (6 mL) containing a small amount of H2O (2 drops), were
added iodobenzene diacetate (IBDA; 306 mg, 951 mmol) and
TEMPO (3.4 mg, 22 mmol) added subsequently. After stirring for
6 h, the mixture was diluted with CH2Cl2 (15 mL) and after the ad-
dition of aq sat. Na2S2O4 (5 mL), the resulting slurry was stirred vig-
orously for 30 min. The layers were separated and the aqueous layer
was extracted with CH2Cl2 (3 × 15 mL). The combined organic ex-
tracts were washed with brine (10 mL) and dried (Na2SO4). Purifi-
cation by flash column chromatography on silica gel (CHCl3–
MeOH, 49:1 and EtOAc–pentane, 1:1) afforded the b,g-unsaturated
HRMS (ESI): m/z calcd for C29H38F3NO4 + Na [M + Na]+:
544.2645; found: 544.2651.
(E,2R,5R)-5-Amino-2-(4¢-tert-butoxybenzyl)-6-(4¢¢-tert-butoxy-
phenyl)hex-3-enol
19
acid 15 (231 g, 79%); Rf = 0.24 (cyclohexane–EtOAc, 1:1); [a]D
–30.7 (c 0.32, CHCl3).
To a solution of the amide 14 (107 mg, 0.251 mmol) in MeOH
(5 mL) and H2O (1 mL), was added K2CO3 (174 mg, 1.257 mmol),
and the solution was heated to 50–60 °C for 3 h. Afterwards, the
crude product was adsorbed onto silica gel and purified by flash col-
umn chromatography on silica gel (CHCl3–MeOH, 10:1) to yield
the title amine (81 mg, 95%) as a colorless oil; Rf = 0.10 (CHCl3–
MeOH, 10:1); [a]D22 –1.3 (c 1.23, CHCl3).
IR (film): 3446 (m), 3324 (m), 2976 (s), 2913 (m), 1711 (s), 1506
(s), 1450 (w), 1365 (m), 1236 (s), 1161 (s), 1104 (w), 897 (m), 759
(m), 740 cm–1 (m).
1H NMR (500 MHz, 343 K, DMSO-d6): d = 11.98 (br s, 1 H), 7.85
(pd, J = 7.6 Hz, 2 H), 7.63 (pd, J = 7.6 Hz, 2 H), 7.40 (pt,
J = 7.4 Hz, 2 H), 7.31 (pt, J = 7.4 Hz, 2 H), 7.25–7.11 (m, 1 H), 7.05
(pd, J = 8.3 Hz, 2 H), 7.03–6.97 (m, 2 H), 6.83 (pd, J = 8.5 Hz, 2 H),
6.78 (pd, J = 8.5 Hz, 2 H), 5.57–5.42 (m, 2 H), 4.28–4.17 (m, 2 H),
4.15–4.07 (m, 1 H), 4.14 (t, J = 6.8 Hz, 1 H), 3.17–3.06 (m, 1 H),
2.90 (dd, J = 13.7, 7.6 Hz, 1 H), 2.69–2.57 (m, 3 H), 1.26 (s, 9 H),
1.22 (s, 9 H).
13C NMR (125 MHz, 343 K, DMSO-d6): d = 177.4, 153.2, 153.1 (2
C), 143.61, 143.59, 140.4 (2 C), 133.1, 132.64, 132.58, 129.3 (2 C),
129.1 (2 C), 127.3, 127.1 (2 C), 126.6 (2 C), 124.7 (2 C), 122.7 (2
C), 122.6 (2 C), 119.6 (2 C), 77.2, 77.1, 65.1, 53.6, 49.6, 46.5, 37.0,
28.28 (3 C), 28.26 (3 C). One benzylic C-atom was not observed be-
cause of a superposition with the DMSO-d6 signal.
IR (film): 3356 (br, m), 2976 (s), 2930 (m), 1607 (w), 1506 (s), 1389
(w), 1365 (m), 1235 (s), 1162 (s), 1017 (w), 924 (w), 898 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.04–6.96 (m, 4 H), 6.93–6.85 (m,
4 H), 5.44 (dd, J = 15.4, 6.7 Hz, 1 H), 5.26 (dd, J = 15.8, 7.8 Hz, 1
H), 3.54–3.45 (m, 2 H), 3.29 (dd, J = 10.7, 7.6 Hz, 1 H), 2.69–2.57
(m, 3 H), 2.56–2.37 (m, 2 H), 1.86 (br s, 3 H), 1.32 (s, 9 H), 1.31 (s,
9 H).
13C NMR (75 MHz, CDCl3): d = 153.9, 153.5, 136.9, 134.6, 133.5,
130.9, 129.6 (2 C), 129.4 (2 C), 124.1 (2 C), 124.0 (2 C), 78.3, 78.1,
65.1, 55.3, 47.0, 43.8, 37.0, 28.8 (6 C).
HRMS (ESI): m/z calcd for C27H40NO3 + Na [M + Na]+: 426.3003;
found: 426.3011.
HRMS (ESI): m/z calcd for C42H47NO6 [M + Na]+: 684.3296;
found: 684.3290.
Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York

2728
N. G. Bandur et al.
PAPER
[(1S)-1-tert-Butyloxycarbonylpyrrolidine-2-yl]-(1¢R)-cyclopent-
1¢-enylmethanol (18)
{(R)-[1-((S)-1-tert-Butyloxycarbonylpyrrolidin-2-yl)-(E)-meth-
ylidene]cyclopentyl}methanol (22)
A piece of Li rod (1 cm diameter, 4.63 g, 0.67 mol) was flattened to
a thickness of about 1 to 2 mm with a clean hammer. The flattened
Li was cut into pieces of approximately 1 × 0.2 mm and kept under
argon in a dry flask containing Et2O (150 mL) and broken glass
pieces. Freshly distilled (from CaCl2) 1-chlorocyclopent-1-ene
(23.74 g, 0.23 mol) was then added in one portion and the mixture
was stirred at r.t. for 3 h (exothermic!) and heated at 50 °C oil bath
temperature for 1 h. The resulting suspension was allowed to cool
down to r.t. and the supernatant solution was transferred to another
flask by a syringe and diluted with Et2O (650 mL). The solution was
cooled to –78 °C and the aldehyde 17 (19.8 g, 99.3 mmol) dis-
solved in Et2O (400 mL) was added dropwise. The solution was
maintained at –78 °C for 3 h, and then quenched by the addition of
i-PrOH (10 mL) and warmed up to r.t. After adding aq sat. NaHCO3
(400 mL), the mixture was vigorously stirred for 10 min. The aque-
ous layer was extracted with EtOAc (2 × 500 mL) and the com-
bined organic extracts were washed with brine (300 mL), dried
(Na2SO4) and concentrated. Flash column chromatography on silica
gel (CH2Cl2–EtOAc, 10:1 → 4:1) yielded the alcohol 18 (22.28 g,
84%) as a colorless solid. A sample for X-ray was obtained by sub-
sequent crystallization from CH2Cl2–cyclohexane; Rf = 0.22
(CH2Cl2–EtOAc 5:1); [a]D24 –83.2 (c 2.03, CHCl3).
At 0 °C, n-BuLi (2.5 M in hexane, 143 mmol, 57 mL) was added
dropwise to a solution of i-Pr2NEt (22 mL, 156 mmol) in THF
(250 mL). The solution was stirred at 0 °C for 15 min and cooled to
–100 °C. A mixture of chlorotrimethylsilane (48.5 mL, 384 mmol)
and pyridine (34 mL, 419 mmol) in THF (100 mL), which was pre-
viously prepared by the addition of chlorotrimethylsilane to a solu-
tion of pyridine in THF at 0 °C, was added dropwise to the LDA
solution at –100 °C whereupon a white precipitate was formed. Af-
ter 5 min, a solution of the ester 19 (15.34 g, 34.9 mmol) in THF
(120 mL) was added dropwise and the solution was stirred at
–100 °C for 30 min. The mixture was warmed up to r.t. over 1.5 h
and stirred at r.t. for 1.5 h. The reaction was quenched with aq 1 M
HCl (400 mL) at 0 °C and extracted with MTBE (3 × 600 mL). The
combined organic extracts were washed with brine (400 mL), dried
(Na2SO4) and concentrated to give the acid 21 (15.04 g, 98% crude
yield) as a pale yellow oil. Without further purification, the acid was
dissolved in THF (60 mL) and treated with Bu4NF (17.82 g,
68.2 mmol) dissolved in THF (60 mL) at 0 °C. The mixture was
warmed to r.t. and stirred for 1.5 h. After the addition of aq 0.5 M
HCl (300 mL), the mixture was stirred for 10 min and extracted
with EtOAc (2 × 300 mL). The organic layer was washed with brine
(200 mL), dried (Na2SO4) and concentrated to give the intermediate
a-hydroxy acid as a pale yellow oil. The crude a-hydroxy acid was
dissolved in EtOAc (500 mL) and cooled to 0 °C. A solution of
Pb(OAc)4 (16.63 g, 37.5 mmol) dissolved in CHCl3 (80 mL) was
added dropwise. The mixture was stirred at 0 °C for 15 min,
quenched with ethylene glycol (50 mL), diluted with EtOAc
(1000 mL), and the EtOAc layer was washed with H2O
(4 × 100 mL) and brine (100 mL). The organic layer was dried
(Na2SO4) and concentrated to yield the product aldehyde as a yel-
low oil. Due to its instability, the precursor b,g-unsaturated alde-
hyde was used without purification and dissolved in MeOH
(300 mL). The solution was cooled to 0 °C and NaBH4 (2.58 g,
68.2 mmol) was added in small portions under vigorous gas evolu-
tion. The mixture was stirred for 30 min at 0 °C and again NaBH4
(1.29 g, 34.1 mmol) was added. After stirring for further 30 min, aq
sat. NH4Cl (200 mL) was added and the mixture was extracted with
EtOAc (2 × 300 mL). The combined organic extracts were washed
with brine (200 mL), dried (Na2SO4), and concentrated. Flash col-
umn chromatography on silica gel (pentane–EtOAc, 1:1) gave the
alcohol 22 (7.07 g, 74% over 4 steps, 93% per step) as a colorless
solid. A sample for X-ray crystal structure analysis was obtained by
subsequent crystallization from CH2Cl2–cyclohexane; Rf = 0.23
(cyclohexane–EtOAc, 1:1); [a]D22 +4.2 (c 1.01, CHCl3).
1H NMR (500 MHz, DMSO-d6, 340 K): d = 5.58–5.49 (m, 1 H),
4.58 (br s, 1 H), 4.48–4.39 (m, 1 H), 3.84–3.71 (m, 1 H), 3.38–3.31
(m, 1 H), 3.24–3.17 (m, 1 H), 2.33–2.17 (m, 4 H), 1.92–1.85 (m, 2
H), 1.82 (qi, J = 7.4 Hz, 2 H), 1.70–1.60 (m, 2 H), 1.41 (s, 9 H).
13C NMR (125 MHz, DMSO-d6, 340 K): d = 145.9, 123.5, 77.7,
70.3, 59.7, 46.4, 31.9, 31.3, 27.9 (3 C), 24.3, 23.3, 22.7. The Boc-
C=O signal was not observed.
HRMS (ESI): m/z calcd for C15H25NO3 + Na [M + Na]+: 290.1732;
found: 290.1737.
[(2S)-1-tert-Butyloxycarbonylpyrrolidine-2-yl]-(R)-cyclopent-
1¢-enylmethyl tert-Butyldimethylsilyloxyacetate (19)
A solution of the alcohol 18 (22.14 g, 83.0 mmol) and pyridine
(20 mL, 249 mmol) in THF (40 mL) was cooled to 0 °C and freshly
prepared tert-butyldimethylsilyloxyacetyl chloride (17.39 g,
83.3 mmol) dissolved in THF (40 mL) was added dropwise. The
mixture was stirred at 0 °C for 1 h and at r.t. for further 30 min.
Then the mixture was diluted with MTBE (250 mL) and washed
with aq 0.5 N HCl (2 × 150 mL), aq sat. NaHCO3 (80 mL), and
brine (80 mL), dried (MgSO4), and concentrated. Flash column
chromatography on silica gel (pentane–MTBE, 9:1) gave the
ester 19 (30.65 g, 74%) as a colorless oil; Rf = 0.13 (cyclohexane–
MTBE, 9:1), 0.54 (cyclohexane–MTBE, 2:1); [a]D24 –62.7 (c 1.00,
CHCl3).
IR (film): 3478 (s), 2965 (s), 2872 (m), 1671 (s), 1407 (s), 1366 (m),
1249 (w), 1223 (w), 1157 (s), 1118 (m), 1064 (w), 1030 (s), 878 (w),
772 (m), 576 cm–1 (m).
1H NMR (500 MHz, DMSO-d6, 340 K): d = 5.20–5.13 (m, 1 H),
4.27 (dd, J = 5.3, 5.3 Hz, 1 H), 4.27–4.18 (m, 1 H), 3.39 (ddd,
J = 10.5, 5.3, 5.3 Hz, 1 H), 3.31–3.16 (m, 3 H), 2.48–2.37 (m, 2 H),
2.13 (ddd, J = 15.5, 8.2, 7.5 Hz, 1 H), 2.04–1.93 (m, 1 H), 1.84–1.75
(m, 1 H), 1.74–1.59 (m, 3 H), 1.53–1.41 (m, 3 H), 1.34 (s, 9 H).
13C NMR (125 MHz, DMSO-d6, 340 K): d = 153.3, 142.6, 123.0,
77.5, 64.4, 55.9, 46.5, 45.7, 32.3, 29.0, 28.3, 27.9 (3 C), 23.5, 22.9.
IR (film): 2955 (s), 2931 (s), 2856 (m), 1767 (m), 1740 (w), 1700
(s), 1473 (w), 1393 (s), 1366 (m), 1255 (m), 1146 (s), 839 (s), 780
cm–1 (m).
1H NMR (500 MHz, DMSO-d6, 340 K): d = 5.89–5.85 (m, 1 H),
5.58–5.55 (m, 1 H), 4.28 (d, J = 16.6 Hz, 1 H), 4.22 (d, J = 16.6 Hz,
1 H), 4.02–3.91 (m, 1 H), 3.36–3.28 (m, 1 H), 3.19–3.12 (m, 1 H),
2.33–2.21 (m, 4 H), 1.90–1.79 (m, 5 H), 1.75–1.66 (m, 1 H), 1.40
(s, 9 H), 0.88 (s, 9 H), 0.064 (s, 3 H), 0.062 (s, 3 H).
HRMS (ESI): m/z calcd for C16H27NO3 [M + Na]+: 304.1889;
found: 304.1902.
13C NMR (125 MHz, DMSO-d6, 340 K): d = 169.8, 153.0, 140.4,
125.6, 78.2, 72.8, 61.0, 57.7, 46.2, 32.1, 31.4, 27.8 (3 C), 25.3 (3 C),
25.0, 23.1, 22.4, 17.6, –5.81, –5.92.
Anal. Calcd for C16H27NO3: C, 68.29; H, 9.67; N, 4.98. Found:
C, 67.96; H, 9.60; N, 4.86.
HRMS (ESI): m/z calcd for C23H41NO5Si + Na [M + Na]+:
462.2652; found: 462.2665.
[(R)-2¢-((S)-1-Pyrrolidin-2-yl-(E)-methylidene)cyclopen-
tyl]methanol (23)
Trifluoroacetic acid (7 mL) was added to alcohol 22 (1.00 g,
3.55 mmol) in CH2Cl2 (20 mL), and the mixture was stirred for
Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York

PAPER
Synthesis of E-Alkene Dipeptide Isosteres
2729
30 min at r.t. Then the pH of the mixture was adjusted to 9–10 with
aq sat. Na2CO3 and aq 2 M NaOH and extracted with CHCl3–
i-PrOH (5:1, 10 × 50 mL). The combined organic extracts were
washed with brine (20 mL) and dried (Na2SO4). The solvent was
evaporated in vacuo. Flash column chromatography on silica gel
(CHCl3–i-PrOH–MeOH, 10:2:1 → CHCl3–i-PrOH, 1:1) yielded
the amino alcohol 23 (566 mg, 88%) as a colorless oil; Rf = 0.0
(CHCl3–MeOH, 10:1); [a]D20 –61.4 (c 2.20, CHCl3).
IR (film): 2955 (m), 2875 (m), 1699 (s), 1450 (m), 1417 (m), 1354
(m), 1243 (w), 1187 (m), 1116 (m), 758 (m), 741 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.76 (d, J = 7.4 Hz, 2 H), 7.61 (d,
J = 7.4 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 2 H), 7.30 (d, J = 7.4 Hz, 2 H),
5.65–5.53 (m, 0.5 H), 5.52–5.40 (m, 0.5 H), 4.54–4.31 (m, 3 H),
4.29–4.16 (m, 1 H), 3.58–3.28 (m, 3 H), 2.83–2.63 (m, 0.5 H), 2.44–
2.15 (m, 1.5 H), 2.14–1.42 (m, 8 H). Due to the restricted rotation
around the carbamate C–N bond at r.t., compound 25 occurs as a 1:1
mixture of rotational isomers.
13C NMR (75 MHz, CDCl3): d = 179.7, 154.9, 144.2, 144.1, 141.9,
141.31, 141.27, 127.6 (2 C), 126.97, 126.96, 125.1 (2 C), 125.0,
119.9 (2 C), 67.0, 57.0, 49.2, 47.4, 46.3, 32.0 29.9, 28.9, 25.1, 24.3.
IR (film): 3293 (br, m), 2954 (s), 2888 (s), 1431 (m), 1061 (m),
1032 (m), 753 cm–1 (w).
1H NMR (500 MHz, DMSO-d6): d = 5.18 (ddd, J = 8.0, 4.4, 2.3 Hz,
1 H), 3.45 (dd, J = 15.3, 8.0 Hz, 1 H), 3.38 (dd, J = 10.4, 5.5 Hz, 1
H), 3.16 (dd, J = 10.4, 8.9 Hz, 1 H), 2.86 (ddd, J = 9.9, 7.7, 5.3 Hz,
1 H), 2.68–2.60 (m, 1 H), 2.44–2.36 (m, 1 H), 2.31–2.23 (m, 1 H),
2.20–2.11 (m, 1 H), 1.83–1.74 (m, 1 H), 1.73–1.67 (m, 1 H), 1.66–
1.54 (m, 3 H), 1.53–1.39 (m, 2 H), 1.22–1.11 (m, 1 H).
HRMS (ESI): m/z calcd for C26H27NO4 + Na [M + Na]+: 440.1838;
found: 440.1837.
13C NMR (125 MHz, DMSO-d6): d = 143.6, 124.8, 64.6, 57.7, 46.6,
Acknowledgment
46.0, 32.4, 29.5, 29.1, 25.1, 23.8.
This work was supported by the Deutsche Forschungsgemeinschaft
(Forschergruppe 475).
HRMS (ESI): m/z calcd for C11H19NO [M + H]+: 182.1545; found:
182.1545.
References
{(R)-2¢-[1¢-((S)-1-(9¢¢-Fluorenylmethyloxycarbonyl)pyrrolidin-
2-yl)-(E)-methylidene]cyclopentyl}methanol (24)
(1) Reviews on peptidomimetics: (a) Giannis, A.; Kolter, T.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (b) Gante, J.
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To a stirred solution of the amino alcohol 23 (634 mg, 3.5 mmol)
and NaHCO3 (294 mg, 3.5 mmol) in H2O–acetone mixture (1:1,
10 mL) was added FmocOSu (1.18 g, 3.5 mmol) in one portion at
0 °C. The mixture was warmed up to r.t. and stirred overnight. The
pH was adjusted to 2–3 with aq 2 M HCl and the acetone was evap-
orated in vacuo. The residue was taken up in CHCl3 (100 mL),
washed with aq 0.1 M HCl (50 mL), H2O (50 mL), and brine
(50 mL), and dried (Na2SO4). Flash column chromatography
(CHCl3–MeOH, 49:1 or pentane–EtOAc, 2:1) gave the alcohol 24
as a colorless foam; Rf = 0.23 (cyclohexane–EtOAc, 1:1), 0.53
(CHCl3–MeOH, 10:1); [a]D22 +13.4 (c 1.10, CHCl3).
(c) Venkatesan, N.; Kim, B. H. Curr. Med. Chem. 2002, 9,
2243. (d) Tourwe, D. Synthesis of Peptides and
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IR (film): 3442 (br, s), 3065 (w), 2950 (s), 2871 (s), 1736 (m), 1693
(s), 1450 (s), 1416 (s), 1352 (s), 1243 (m), 1186 (m), 1099 (s), 1031
(m), 759 (m), 740 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.76 (d, J = 7.4 Hz, 2 H), 7.65–
7.54 (m, 2 H), 7.39 (t, J = 7.4 Hz, 2 H), 7.35–7.24 (m, 2 H), 5.42–
5.33 (m, 0.5 H), 5.32–5.23 (m, 0.5 H), 4.55–4.31 (m, 3 H), 4.29–
4.16 (m, 1 H), 3.59–3.42 (m, 4 H), 2.76–2.58 (m, 2 H), 2.45–1.42
(m, 10 H). Due to the restricted rotation around the carbamate C–N
bond at r.t., compound occurs as a 1:1 mixture of rotational isomers.
13C NMR (75 MHz, CDCl3): d = 154.8, 144.20, 144.17, 143.8,
141.3, 141.2 (2 C), 127.6 (2 C), 126.9 (2 C), 125.1, 125.0, 119.9 (2
C), 66.9, 65.2, 56.9, 47.4, 46.8, 46.3, 33.8, 32.7, 29.1, 24.3, 23.5.
HRMS (ESI): m/z calcd for C26H29NO3 [M + Na]+: 426.2045;
found: 426.2031.
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Kinoshita, T.; Odagaki, Y.; Oishi, S.; Tamamura, H.;
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(R)-2¢-{1¢-[(S)-1-(9¢¢-Fluorenylmethyloxycarbonyl)pyrrolidin-2-
yl]-(E)-methylidene}cyclopentanecarboxylic Acid (25)
The alcohol 24 (610 mg, 1.5 mmol) was dissolved in acetone
(60 mL) and cooled to 0 °C. Jones reagent (2.7 M, 1.6 mL,
3.78 mmol) was added dropwise and the mixture was stirred for
30 min at 0 °C until the color changed from purple to green. i-PrOH
(15 mL) was then added and the mixture was stirred for 5 min at r.t.,
diluted with H2O (100 mL) and extracted with CH2Cl2 (5 × 30 mL).
The combined organic extracts were dried (Na2SO4). Flash column
chromatography on silica gel (CHCl3–MeOH, 19:1 and EtOAc–
pentane, 1:1 → 2:1) gave acid 25 (550 mg, 94%) as a colorless
foam; Rf = 0.21 (cyclohexane–EtOAc, 1:2), 0.25 (CHCl3–MeOH,
10:1); tR 10.2 min (Rainin Dynamax C8; A: H2O, B: MeCN, 75 →
100% B in 25 min, 0.7 mL/min); [a]D22 –31.2 (c 0.70, CHCl3).
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Synthesis 2007, No. 17, 2720–2730 © Thieme Stuttgart · New York