Epoxidation of peptidyl olefin isosteres. Stereochemical induction effect of chiral centers at four adjacent C(α) positions

Article abstract of DOI:10.1016/S0040-4020(00)00036-3

Four tripeptidyl olefin isosteres were prepared, each of which contains a single chiral center derived from the bulky amino acid phenylalanine at positions corresponding to the P₂-P'₂ positions of a protease substrate. The effect of these chiral centers on the stereochemical outcome of mCPBA epoxidation of the olefin functionality was studied. A chiral center at P₂ or P'₂ position has no significant effect, and the P'₁ position exerts a small stereoselectivity. A chiral center at the P₁ position, on the other hand, has a profound chiral induction effect on the epoxidation reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00036-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1505–1516
Epoxidation of Peptidyl Olefin Isosteres. Stereochemical
Induction Effect of Chiral Centers at Four Adjacent Ca Positions
*
Nurit Perlman, Mordechai Livneh and Amnon Albeck
The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel
Received 11 October 1999; revised 15 December 1999; accepted 6 January 2000
Abstract—Four tripeptidyl olefin isosteres were prepared, each of which contains a single chiral center derived from the bulky amino acid
phenylalanine at positions corresponding to the P2–P02 positions of a protease substrate. The effect of these chiral centers on the stereo-
chemical outcome of mCPBA epoxidation of the olefin functionality was studied. A chiral center at P2 or P02 position has no significant effect,
and the P01 position exerts a small stereoselectivity. A chiral center at the P1 position, on the other hand, has a profound chiral induction effect
on the epoxidation reaction. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
epoxides.8 In the present study we explored the effect of the
P2–P029 four individual chiral centers adjacent to the olefinic
peptide isostere of tripeptides on the stereochemical
outcome of the mCPBA epoxidation reaction. Such infor-
mation may be useful in the design of epoxy- and other
peptide isosteres. The origin of the observed stereoselec-
tivity, whether being due to simple steric interference or
due to specific hydrogen bonding between substrate and
oxidant, was also addressed.
Peptidyl epoxides bearing the epoxide moiety at their
C-terminal (exo peptidyl epoxides) have been used as
protease inhibitors1 or as starting building blocks for peptide
isosteres2,3 and other compounds.4 Stereoselective pro-
cedures for the preparation of both the erythro and the
threo isomers of such peptidyl epoxides and N-protected
a-amino epoxides were introduced.2c,5 Endo peptidyl epox-
ides, where the epoxide is an isosteric replacement of a
peptide bond of a di- or a polypeptide, were also studied
as potential protease inhibitors,6 but much less work was
carried out on their stereoselective synthesis. The stereo-
selectivity of the epoxidation of the dipeptide olefinic
analogs Phe-Gly, Phe-Phe and Phe-d-Phe was studied.6a,7
Oxidative epoxidation of b-hydroxyselenides was also
introduced as a route to sterically well defined endo peptidyl
Results
Synthesis of peptidyl olefins
A set of four tripeptidyl olefins, 8a–d (Scheme 1), was
synthesized, each of which contains a single chiral center
Scheme 1. The peptidyl olefins bearing a single stereogenic center at four positions adjacent to the olefin.
Keywords: peptide analogs/mimetics; stereocontrol; epoxidation; enzyme inhibitors.
* Corresponding author. Tel.: ϩ972-3-531-8862; fax: ϩ972-3-535-1250; e-mail: albecka@mail.biu.ac.il
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00036-3

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N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
derived from the bulky substituted phenylalanine. The other
two amino acids in each peptide olefin are either the unsub-
stituted glycine or an unsubstituted alkane (Scheme 1).
Therefore, the effect of each individual chiral center in the
four possible positions, P2–P02, on the stereoselectivity of
the epoxidation reaction could be studied.
was reacted with the phosphonium ylide of 3-hydroxypropyl
triphenylphosphonium bromide (1a), to give a 1.6:1 trans/
cis mixture of olefin 3a in 47% yield. Standard deprotection
(giving 4a), N-terminal coupling to N-Cbz-phenylalanine
(giving 6a), Jones’ oxidation to the C-terminal carboxylic
acid 7a (57% yield) and esterification (52% yield) provided
the P2 peptide olefin analog Cbz-Phe-GlyC[CHyCH]-
GlyOMe (8a, Scheme 2A). For the P1 peptide olefin 8b
(Cbz-Gly-PheC[CHyCH]GlyOMe), N-trityl-phenylalaninal
(2b) was prepared from phenylalanine methyl ester via
protection–reduction–oxidation sequence, as previously
described.5d It was reacted with the same ylide, derived
from 3-hydroxypropyl triphenylphosphonium bromide,
yielding a 1.6:1 cis/trans mixture of the olefin 3b in 60%
yield. Deprotection of the amino group (giving 4b, 78%
yield), coupling with N-Cbz-glycine (giving 6b, 60%
yiled), Jones’ oxidation to 7b (27% yield) and esterification
(76% yield) completed the synthesis of the tripeptide P1
olefin analog 8b (Scheme 2A). The P01 peptide olefin 8c
(PhCH2CH2-C[CHyCH]Phe-GlyOMe) was prepared in a
few steps, starting with 3-phenylpropanal and the ylide of
the phenylalanine phosphonium salt analog 1c. The Wittig
reaction afforded hydroxy olefin 4c in low (24%) yield. The
reason for the difficulty of this reaction is unclear and no
optimization experiments were carried out. It was followed
by Jones’ oxidation (yielding 5c, 50% yield) and coupling
(in 43% yield)—with glycine methyl ester (Scheme 2B).
The P02 peptide olefin 8d (PhCH2CH2-C[CHyCH]Gly-
PheOMe) was prepared by the Wittig reaction between
the same aldehyde (3-phenylpropanal) and the phospho-
nium ylide of 3-hydroxypropyl triphenylphosphonium
bromide 1a (78% yield of 4d, 1.2:1 trans/cis ratio), followed
by Jones’ oxidation (yielding 5d, 87% yield) and coupling
with phenylalanine methyl ester (58% yield, Scheme 2B).
The olefin dipeptide unit was prepared by the Wittig reac-
tion between N-protected a-amino aldehydes (for the P2 and
P1 chiral center analogs) or a simple non-chiral aldehyde
(for the P01 and P02 analogs) and phosphonium salts corre-
sponding to the C-terminal amino acid of the olefin dipep-
tide isostere (Scheme 2). These were either glycine or
phenylalanine derivatives. The former (1a) was prepared,
in quantitative yield (after crystallization), from bromo-
propanol and triphenyl phosphine. The latter (1c) was
prepared in four steps from diethyl benzylmalonate (via
the corresponding diol, mono tosylate and bromo alcohol),
in moderate yield. For peptide olefins bearing P01 and P02
substituents, the appropriate phosphonium ylide was
condensed with 3-phenylpropanal, thus mimicking the
amino acid phenylalanine but excluding its amino group
and chirality.
The key aldehyde for the synthesis of the P2 peptide olefin
isostere 8a, N-protected glycinal (2a), was prepared in two
ways: glycine methyl ester was protected, in 90% yield, by
either trityl chloride or p-anisylchlorodiphenylmethane.
These protecting groups enabled the following Wittig
reaction to proceed in good yield.5d The ester functionality
was then reduced by DIBALH directly to the desired
aldehyde (60% yield). Alternatively, aminoethanol was
similarly N-protected (81% yield), followed by Swern
oxidation ((COCl)2, DMSO, 60% yield). The aldehyde
Scheme 2. Synthesis of peptidyl epoxides. Reagents: (i) BuLi, THF; (ii) HCl, acetone; (iii) CrO3, H2SO4; (iv) Cbz-(R2)amino acid, DCC, THF; (v) (R0 ) amino
2
acid methyl ester, DCC or CDI, THF; (vi) CH2N2, ether; (vii) mCPBA, CH2Cl2.

N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
1507
Table 1. The induced chirality exerted by the P2–P02 chiral centers on the epoxidation reaction
Position
Peptidyl epoxide
Isomeric ratioa
trans Epoxide (major/minor)
cis Epoxide (major/minor)
P2
Cbz-Phe-Gly-epoxy-GlyOMe
Cbz-Gly-Phe-epoxy-GlyOMe
PhCH2CH2-epoxy-Phe-GlyOMe
PhCH2CH2-epoxy-Gly-PheOMe
1.09
Ͼ30b
1.9
1.22
Ͼ30b
4.5
P1
P01
P02
1.10
1.08
a Calculated from 600 MHz 1H NMR or 150 MHz 13C NMR spectra of the crude reaction products.
b Only one isomer was detected by NMR.
The epoxidation reaction
Stereoselectivity
The four olefins, 8a–d, were treated with mCPBA, yielding
the corresponding epoxides 9a–d in moderate to good yield
(typically 50–90%). In most cases, the mixture of trans and
cis olefins was not separated prior to the epoxidation
reaction, and the mixture of the crude epoxides (containing
up to four isomers) was analyzed by 600 MHz 1H NMR or
(150 MHz) 13C NMR spectroscopy (Table 1).
The data clearly demonstrates that a chiral center four bonds
away from the olefin (the P2 and P02 analogs 8a and 8d) has a
negligible chiral induction on the epoxidation reaction. The
P01 olefin analog, PhCH2CH2-C[CHyCH]Phe-GlyOMe
(8c) exhibited only a poor (31% de in the trans isomer) to
moderate (64% de in the cis isomer) stereoselectivity of the
epoxidation reaction (see below). It is only the P1 analog,
Cbz-Gly-PheC[CHyCH]GlyOMe (8b), that undergoes a
highly stereoselective epoxidation (only one diastereomer
was detected), as was previously observed for similar ter-
minal olefin2,5d and endo olefin7 systems. This selectivity is
exhibited both for the trans and the cis olefins. We tenta-
tively assigned a threo relative configuration for their
product epoxides 9b ([3R,4R]-3,4-trans epoxy and
[3S,4R]-3,4-cis epoxy). This assignment is based on the
known stereoselectivity of this epoxidation reaction on
terminal olefins5d,k and a similar endo olefin,7 and on
comparison with published data for a similar epoxide.7
Discussion
Synthesis
A variety of synthetic approaches were applied for the
synthesis of olefin dipeptide isosteres.6a,10 In the present
study we utilized the Wittig reaction with N-protected
a-amino aldehydes. Racemization at Ca of a-amino
aldehydes during Wittig reactions is of concern. Neverthe-
less, our previous experience shows that this can be avoided
under careful experimental conditions.5d Furthermore, the
present study concentrates on the epoxidation reaction of
peptidyl olefins that bear a single chiral center. Therefore,
racemization at this center will not affect the analysis of the
stereochemical outcome of the epoxidation reaction in terms
of relative stereochemistry. The Wittig reaction yields both
trans and cis olefins. Therefore, we were able to determine
the stereochemistry of the epoxidation reaction of both
isomers. The dipeptide olefin can then be coupled on both
amino and carboxy termini to the appropriately protected
amino acids or peptides to form the desired peptide olefin.
Furthermore, we assigned the major isomer of all other
epoxides as also bearing a relative threo configuration.
(Note that the absolute configuration of the epoxidic carbons
of the P1 and P2 epoxides, 9b and 9a, is the opposite of the
corresponding carbons of the corresponding isomers of the
P01 and P02 epoxides, 9c and 9d.) This assignment is
1
supported by the H NMR spectra of the different isomers.
In all cases, the same epoxidic proton (H3 in the P1 and P2
peptidyl epoxides and H6 in the P01 and P02 epoxides) of the
major isomer resonates at lower field than the corresponding
proton of the minor isomer. The same trend was observed
previously both by us1a,5e and by others.7
The Wittig reaction yields a mixture of trans and cis
isomers. This ratio could be controlled, to a limited degree,
by the reaction conditions (molar amount of the base, its
cation nature, side-chain substitution on the phosphonium
salt).11 In all the Wittig reactions disscussed in this work, the
phosphonium ylide (1) contained an unprotected g-hydroxy
substituent and two molar equivalents of BuLi were used as
a base. Therefore, a ‘trans selective’ reaction was expected.
Indeed, three of the four reactions yielded an excess of the
trans isomer (1.2–2.4:1 trans/cis ratio) and only one
reaction yielded a moderate (1.6:1) excess of the cis isomer.
To demonstrate the ‘cis selective’ Wittig protocol, an
O-silyl phosphonium salt 1e was prepared from the corre-
sponding bromopropyl silyl ether. It was reacted with
3-phenyl propanal, using only one molar equivalent of
BuLi. As expected, this reaction afforded the corresponding
olefin 4e in a 8.5:1 cis/trans ratio. Efficient deprotection
afforded the dipeptide olefin 4d in high cis/trans ratio.
The results presented here emphasize that only the chiral
center of the P1 amino acid exerts a significant chiral induc-
tion on the epoxidation of peptidyl olefin isosteres. The P01
analog has a minor effect, and the effect diminishes com-
pletely as the chiral center is removed further away from the
double bond to be epoxidized. These results are in good
agreement with the trend observed by Jenmalm et al.7
However, it should be emphasized that in the present
work we analyzed the isolated effect of a chiral center at
the P01 position, while Jenmalm and co-workers measured a
cooperative effect of two adjacent chiral centers.
The present set of epoxidation experiments also clearly
demonstrate that the stereoselectivity observed in the epoxi-
dation reaction is not due to a simple steric effect, but rather
stems from selective complexation (H-bonding) of the
amide functionality with the incoming peracid.5d,12 This is

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N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
Scheme 3. Proposed transition states for the epoxidation of P1 (A) and P01 (B) peptidyl olefins. The different degree of stereoselectivity for the trans and cis
isomers of the P01 peptidyl olefin can also be explained in terms of T.S. stability (C).
evident from the fact that although in both the P1 and the P01
analogs the chiral center is one C–C bond away from the
olefin, the selectivity it induces is markedly different. This
difference may be explained in terms of the stability of the
transition state of the ‘complexed’ epoxidation reaction;
whereas the epoxidation of the P1 peptidyl olefin (8b)
features a five-membered ring transition state (Scheme
3A),5d,12 the P01 peptidyl olefin (8c) should undergo
complexed epoxidation via a six-membered ring transition
state (Scheme 3B). While the former has two partially sp2
hybridized atoms (the amide nitrogen and the olefin carbon),
the latter has as many as three partially sp2 hybridized atoms
(the amide nitrogen and carbon and the olefin carbon).
Therefore, it is expected that the five-membered ring
transition state of the former reaction is more stable than
the six-membered ring transition state of the latter, and
therefore contributes more to the stereoselectivity of the
overall epoxidation reaction.
COSY experiments, while 13C NMR assignments were
supported by off-resonance heteronuclear decoupling,
DEPT or 2-D hetero COSY experiments. Mass spectra
were recorded in DCI mode with methane as the reagent
gas, unless otherwise indicated. TLC was performed on E.
Merck 0.2 mm precoated silica gel F-254 plates, and viewed
by phosphomolybdic acid or Cl2/KI-tolidine.13 Chroma-
tography refers to flash column chromatography,14 carried
out on silica gel 60 (230–400 mesh ASTM, E. Merck).
Anhydrous solvents were dried and freshly distilled (THF
and toluene from sodium/benzophenone, and CH2Cl2 from
CaCl2).
Phosphonium salts
(Ph)3Pϩ(CH2)3OH BrϪ (1a). (Ph)3P (9.8 g, 37.4 mmol)
was heated to 120ЊC under argon atmosphere. Then
3-bromo-1-propanol (5.2 g, 37.4 mmol) was added. After
5 min, a white precipitate was formed. After heating for
additional 10 min, the solid was dissolved in EtOH
(30 ml) and ether was added for crystallization. The crystals
were filtered and washed with ether, affording 15.1 g of the
The different stereoselectivity exhibited by the trans and cis
P01 olefins is also interesting. While epoxidation of the
former proceeds with only 31% de, the latter yields the
two epoxides in 64% de. This difference may be explained
in terms of the relative stability of the two epoxidation
transition states of each of the isomers. The energetic
difference between the threo (major) and erythro (minor)
transition states of the cis isomer is larger than that of the
trans isomer due to steric repulsion between the R01 side
chain and the olefinic substituent (Scheme 3C).
1
phosphonium salt (96% yield). Mp 229–230ЊC. H NMR:
1.84 (m, 2H, CH2CH2CH2); 3.82 (m, 4H, PCH2, CH2O);
7.75 (m, 15H, Ph3). 13C NMR: 20.36 (d, Jˆ52.0 Hz,
PCH2); 25, 96 (d, Jˆ4.2 Hz, CH2CH2CH2); 60.31 (d,
Jˆ16.9 Hz, CH2O); 118.54 (d, Jˆ85 Hz), 131.54 (d,
Jˆ12 Hz), 133.56 (d, Jˆ9.5 Hz), 135.05 (d, Jˆ2.5 Hz)
(Ph). MS 262: (Ph3Pϩ, 100), 243 (MϪHBr–Ph, 57), 223
(44), 183 (58), 178 (45), 168 (63), 141 (64), 115 (48).
HRMS for C15H16OP (MϪHBr–Ph): calcd 243.0939,
found 243.0950.
Experimental
General
PhCH2CH(CH2OH)2. Diethyl benzyl malonate (50 ml,
215 mmol) was added dropwise (within 1–2 h) to a refluxing
suspension of LiAlH4 (5.63 g, 150 mmol) in dry THF
(250 ml). After further 20 h in reflux, the reaction mixture
was cooled to rt and carefully treated with 0.5 M HCl
(70 ml). Extraction with ether (5×200 ml) and evaporation
of the organic phase afforded the diol as white, thick oil,
which solidified on standing (19.4 g, 117 mmol). Further
1H and 13C NMR spectra were recorded at 600 or
300 MHz and 150 or 75 MHz, respectively, in CDCl3,
unless otherwise specified. Chemical shifts are reported in
ppm relative to TMS in CDCl3 or relative to solvent
1
resonance in other solvents. H NMR assignments were
supported by homonuclear decoupling or homonuclear

N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
1509
continuous extraction (in a commercial liquid/liquid con-
tinuous extractor) overnight afforded additional 3.2 g
(19 mmol) of the product (total 22.6 g, 63% yield). A
sample was crystallized from ether/hexane, mp 58–60ЊC.
1H NMR: 2.00 (m, 1H, CH); 2.61 (d, Jˆ7.5 Hz, 2H,
PhCH2); 3.64 (dd, Jˆ10.5, 6.9 Hz, 2H, CH2OH); 3.77 (dd,
Jˆ10.6, 3.7 Hz, 2H, CH2OH); 3.91 (bs, 2H, OH); 7.15–7.30
(m, 5H, Ph). 13C NMR: 34.05 (PhCH2); 43.81 (CH); 63.97
(CH2OH); 125.90, 128.23, 128.83, 139.75 (Ph). MS: 167
(MHϩ), 166 (Mϩ), 148 (54), 130 (24), 118 (26), 117 (88),
104 (25), 92 (44), 91 (100). HRMS for C10H15O2: calcd
167.1072, found 167.1062.
1.9 Hz, 2H, o-PhCH2); 7.20 (m, 3H, m, p-PhCH2); 7.66–
7.80 (m, 15H, Ph3P). 13C NMR: 23.67 (d, Jˆ54.8 Hz,
PCH2); 38.23 (d, Jˆ4.0 Hz, CH); 38.73 (d, Jˆ6.0 Hz,
PhCH2); 62.68 (d, Jˆ7.1 Hz, CH2O); 118.70 (d, Jˆ
85.2 Hz, i-Ph3P); 126.48 (p-PhCH2); 128.56 (m-PhCH2);
129.12 (o-PhCH2); 130.38 (d, Jˆ6.5 Hz, m-Ph3P); 133.67
(d, Jˆ9.9 Hz, o-Ph3P); 134.90 (d, Jˆ2 Hz, p-Ph3P); 138.49
(i-PhCH2). MS: 333 (MϪHBr–Ph, 100), 262 (Ph3Pϩ, 100),
201 (18), 183 (23), 91 (16). HRMS for C22H22OP (MϪHBr–
Ph): calcd 333.1408, found 333.1394.
t
(Ph)3Pϩ(CH2)3OSi(Me)2tBu BrϪ (1e). Br(CH2)3OSi(Me)2 Bu
(9.5 g, 37.5 mmol) and (Ph)3P (9.8 g, 37.4 mmol) were
refluxed in cyclohexane overnight. The white precipitate
was filtered and washed with hexane, affording the phos-
TsOCH2CH(CH2Ph)CH2OH. Pyridine (4.78 ml, 59
mmol) was added to a solution of 2-benzyl-1,3-propanediol
(9.83 g, 59 mmol) and TsCl (11.66 g, 61 mmol) in chloro-
form (75 ml). After 5 days of stirring at rt, HCl (conc.,
20 ml) was added and the phases separated. The organic
phase was washed with NaHCO3 (sat. aq. solution) and
brine, dried over MgSO4, filtered and evaporated to dryness.
The mono tosyl ester product was purified by chroma-
tography (EtOAc/hexane 1:1), affording 12.28 g (65%
1
phonium salt (7.3 g, 38% yield). H NMR: 0.04 (s, 6H,
SiCH3); 0.867 (s, 9H, CCH3); 1.91 (m, 2H, CH2CH2CH2);
3.74 (m, 2H, PCH2); 3.82 (bt, Jˆ14.8 Hz, 2H, CH2O); 7.32,
7.69–7.87 (m, 15H, Ph3). 13C NMR: Ϫ4.44 (SiCH3); 19.03
(C); 21.04 (d, Jˆ57 Hz, PCH2); 26.53 (CCH3); 26.81
(CH2CH2CH2); 61.39 (d, Jˆ15 Hz, CH2O); 119.39 (d,
Jˆ84 Hz), 130.91, 134.14 (d, Jˆ9 Hz), 135.66 (Ph).
1
yield). H NMR: 2.07 (m, 1H, CH); 2.40 (s, 3H, CH3);
2.55 (dd, Jˆ13.8, 7.5 Hz, 1H, PhCH2); 2.62 (dd, Jˆ14.1,
7.5 Hz, 1H, PhCH2); 3.51 (dd, Jˆ11.1, 6.6 Hz, 1H,
CH2OH); 3.58 (dd, Jˆ11.1, 5.1 Hz, 1H, CH2OH); 3.97
(dd, Jˆ9.9, 5.4 Hz, 1H, CH2OTs); 4.06 (dd, Jˆ9.8,
4.7 Hz, 1H, CH2OTs); 7.02–7.24 (m, 5H, Ph); 7.29 (d,
Jˆ8.1 Hz, 2H, Ts); 7.74 (d, Jˆ8.4 Hz, 2H, Ts). 13C NMR:
21.34 (CH3); 33.23 (PhCH2); 42.23 (CH); 60.94 (CH2O);
69.49 (CH2OTs); 126.00, 127.60, 128.20, 128.74, 129.69,
132.31, 138.53, 144.72 (Ph). MS: 321 (MHϩ, 91), 191 (25),
148 (58), 131 (100), 117 (38). HRMS for C17H21O4S: calcd
321.1161, found 321.1164.
N-protection
Protection of glycine methyl ester or amino ethanol with
p-anisylchlorodiphenylmethane was carried out by the
method applied for simple tritylation, according to
published procedure.15
(MeOPh)(Ph)2CNHCH2COOMe. 89% yield. 1H NMR:
3.13 (s, 2H, CH2); 3.55 (s, 3H, CO2Me); 3.72 (s, 3H,
PhOMe); 6.77–7.48 (m, 14H, Ph). 13C NMR: 45.69
(CH2); 51.57 (COOMe); 55.01 (PhOMe); 70.17 (C);
113.12, 126.32, 127.81, 128.40, 129.72, 137.34, 145.53,
157.93 (Ph); 172.62 (CO2). MS: 362 (MHϩ, 4), 284 (57),
273 (100). HRMS for C23H24NO3: calcd 362.1756, found
362.1755.
BrCH2CH(CH2Ph)CH2OH. To a solution of the tosylate
(10.7 g, 33.4 mmol) in toluene (50 ml) were added NaBr
(14.8 g, 144 mmol in 50 ml of water) and tetrabutyl ammo-
nium bromide (1.8 g, 5.6 mmol). After 6 days of reflux, the
phases were separated, the aqueous phase extracted with
toluene (50 ml) and the combined organic phase was
washed successively with saturated NaHCO3 aq. solution
(100 ml) and brine (2×100 ml) and dried over MgSO4.
Filtration and evaporation afforded 5.0 g (21.8 mmol) of
(MeOPh)(Ph)2CNHCH2CH2OH. 81% yield. 1H NMR:
2.36 (t, Jˆ6.1 Hz, 2H, NCH2); 3.68 (t, Jˆ6.1 Hz, 2H,
CH2O); 3.79 (s, 3H, Me); 6.8–7.5 (m, 14H, Ph). 13C
NMR: 45.88 (NCH2); 54.96 (Me); 62.24 (CH2O); 69.96
(C); 112.99, 126.07, 127.64, 128.40, 129.66, 137.97,
146.08, 157.74 (Ph). MS: 333 (Mϩ), 273 (100), 256 (36),
165 (71), 152 (39). HRMS for C22H23NO2: calcd 333.1729,
found 333.1724.
1
the bromo alcohol (65% yield). H NMR: 2.24 (m, 1H,
CH); 2.79 (d, Jˆ6.4 Hz, 2H, CH2Ph); 3.49 (dd, Jˆ10.2,
5.0 Hz, 1H, CH2Br); 3.65 (dd, Jˆ10.3, 4.2 Hz, 1H,
CH2Br); 3.75 (dd, Jˆ10.9, 7.2 Hz, 1H, CH2OH); 3.81 (dd,
Jˆ10.9, 5.2 Hz, 1H, CH2OH); 7.20–7.45 (m, 5H, Ph). 13C
NMR: 35.25 (CH2); 35.41 (CH2Br); 43.84 (CH); 63.01
(CH2O); 126.20, 128.37, 128.94, 138.86 (Ph). MS: 228,
230 (Mϩ), 210, 212 (6), 131 (100), 117 (32), 105 (51), 91
(85). HRMS for C10H1379BrO: calcd 228.0150, found
228.0169.
N-protected a-amino aldehyde could be obtained either by
standard DIBAH reduction5d of the methyl ester (60% yield)
or by Swern oxidation16 of the corresponding alcohol in
60% yield. It was transferred to the next reaction without
further purification.
Ph3PϩCH2CH(CH2Ph)CH2OH BrϪ (1c). Prepared as
described above for 1a in 50% yield. It was obtained as
white crystalline material. H NMR: 2.12–2.21 (m, 1H,
CH); 2.33 (dd, Jˆ13.7, 6.3 Hz, 1H, CH2Ph); 2.63 (ddd,
Jˆ13.7, 8.4, 1.5 Hz, 1H, CH2Ph); 2.84 (ddd, Jˆ16.2,
12.9, 6.0 Hz, 1H, PCH2); 3.50 (ddd, Jˆ11.6, 3.4, 2.3 Hz,
1H, CH2O); 3.55 (dd, Jˆ11.7, 6.2 Hz, 1H, CH2O); 4.70
(ddd, Jˆ16.1, 14.0, 4.8 Hz, 1H, PCH2); 6.87 (dd, Jˆ7.8,
(MeOPh)(Ph)2CNHCH2CHO (2a). 1H NMR: 2.33 (s, 2H,
CH2); 3.74 (s, 3H, Me); 6.75–7.43 (m, 14H, Ph); 9.5 (s, 1H,
CHO). 13C NMR: 21.39 (CH2); 55.11 (Me); 70.14 (C);
113.24, 126.49, 127.86, 128.43, 129.76, 137.41, 145.61,
158.07 (Ph); 199.27 (CHO).
1
Ph3CNHCH(CH2Ph)CHO (2b). Prepared as previously
described.5d

1510
N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
Wittig reaction
128.02, 129.01, 129.61, 129.89 (Ph); 136.18 (CHy (cis));
136.87 (CHy (trans)); 138.75, 138.92, 146.77, 146.89 (Ph).
MS (EI): 433 (Mϩ), 342 (6), 243 (100), 165 (20), 91 (7).
HRMS for C31H31NO: calcd 433.2406, found 433.2494.
To a suspension of the phosphonium salt (7.2 mmol) in THF
(50 ml) at 0ЊC under argon atmosphere, was added BuLi
(1.6 M in hexane, 14 mmol). The solution was stirred for
30 min, followed by addition of the aldehyde (3.5 mmol,
except for phenyl propionaldehyde where 8 mmol were
taken) in THF (5 ml). Stirring was continued at rt overnight.
Excess phosphonium salt was precipitated with hexane
(ϳ30 ml) and filtered off. CH2Cl2 (80 ml) was added and
extracted with water (3×80 ml). The organic layer was dried
(MgSO4) and evaporated to dryness.
PhCH2CH2CHyCHCH(CH2Ph)CH2OH (4c). 2.4:1 trans/
cis mixture (after chromatography, 3:7 ether/hexane), 24%
yield. 1H NMR: 2.12 (ddd, Jˆ7.1, 4.1, 1.7 Hz, 1H,
PhCH2CH2 (trans)); 2.17 (ddd, Jˆ7.1, 2.5, 1.6 Hz, 1H,
PhCH2CH2 (trans)); 2.26 (m, 2H, PhCH2CH2 (trans));
2.41 (m, 1H, CH (trans)); 2.60 (m, 2H, CHCH2Ph); 2.75
(m, 1H, CH (cis)); 3.30 (dd, Jˆ10.7, 7.4 Hz, 1H, CH2O
(trans)); 3.31 (dd, Jˆ10.5, 7.2 Hz, 1H, CH2O (cis)); 3.45
(dd, Jˆ10.5, 5.1 Hz, 1H, CH2O (trans)); 3.45 (dd, Jˆ10.5,
5.5 Hz, 1H, CH2O (cis)); 5.14 (ddt, Jˆ11.0, 9.8, 1.2 Hz, 1H,
yCH (cis)); 5.18 (ddt, Jˆ15.5, 8.3, 1.3 Hz, 1H, yCH
(trans)); 5.41 (dtd, Jˆ15.3, 6.7, 0.7 Hz, 1H, CHy (trans));
5.49 (dtd, Jˆ11.1, 7.2, 0.6 Hz, 1H, CHy (cis)); 7.23–7.40
(m, 10H, Ph). 13C NMR: 29.35 (PhCH2CH2 (cis)); 34.20
(PhCH2CH2 (trans)); 35.48 (PhCH2 (cis)); 35.57 (PhCH2
(trans)); 37.57 (PhCH2 (trans)); 37.84 (PhCH2 (cis));
42.26 (CH (cis)); 46.85 (CH (trans)); 64.91 (CH2O
(trans)); 65.56 (CH2O (cis)); 125.66, 125.73, 128.00,
128.07, 128.12, 128.31, 128.77, 129.00 (Ph); 130.44
(CHy (cis)); 131.20 (CHy (trans)); 131.98 (CHy (cis));
132.33 (CHy (trans)); 139.72 (Ph (trans)); 139.80 (Ph
(cis)); 141.50 (Ph (trans)); 141.58 (Ph (cis)). MS: 267
(MHϩ, 3.5), 249 (100), 171 (58), 145 (58), 131 (36).
HRMS for C31H31NO: calcd 267.1749, found 267.1764.
(MeOPh)(Ph)2CNHCH2CHyCHCH2CH2OH (3a). 1.6:1
trans/cis mixture, which was separated by chromatography
(1:4 ether/hexane), 47% yield.
cis Isomer: 1H NMR: 2.07 (dt, Jˆ7.5, 6.3 Hz, 2H,
CH2CH2O); 2.81 (d, Jˆ6.4 Hz, 2H, NCH2); 3.49 (t,
Jˆ6.3 Hz, 2H, CH2O); 3.74 (s, 3H, MeO); 5.45 (dt,
Jˆ10.8, 7.5 Hz, 1H, yCH); 5.71 (dt, Jˆ10.7, 6.9 Hz, 1H,
CHy); 7.12–7.47 (m, 14H, Ph). 13C NMR: 30.74
(CH2CH2O); 40.36 (NCH2); 55.08 (MeO); 61.65 (CH2O);
70.53 ((Ph)3C); 113.05, 126.18, 127.74, 127.87, 128.49,
128.74, 129.75, 137.94, 146.04, 157.79 (CyC, Ph). MS:
374 (MHϩ, 8), 296 (7), 273 (100), 197 (11), 167
(10.2). HRMS for C25H28NO2: calcd 374.2120, found
374.2100.
trans Isomer: 1H NMR: 2.25 (q, Jˆ6.2 Hz, 2H, CH2CH2O);
2.73 (d, Jˆ5.4 Hz, 2H, NCH2); 3.58 (t, Jˆ6.3 Hz, 2H,
CH2O); 3.72 (s, 3H, MeO); 5.53 (dt, Jˆ15.3, 6.6 Hz, 1H,
yCH); 5.68 (dt, Jˆ15.3, 5.5 Hz, 1H, CHy); 7.3–7.45 (m,
14H, Ph). 13C NMR: 35.69 (CH2CH2O); 45.80 (NCH2);
55.03 (MeO); 61.75 (CH2O); 70.25 ((Ph)3C); 113.00,
126.10, 126.16, 127.09, 127.69, 128.40, 128.45, 129.72,
129.65, 131.86, 138.09, 146.19, 157.71 (CyC, Ph). MS:
374 (MHϩ, 10), 296 (9), 273 (100), 197 (20), 167 (13).
HRMS for C25H28NO2: calcd 374.2120, found 374.2160.
PhCH2CH2CHyCHCH2CH2OH (4d). 1.2:1 trans/cis
mixture (after chromatography, 1:1 CH2Cl2/hexane), 78%
yield. 1H NMR: 2.23 (q, Jˆ6.9 Hz, 2H, CH2CH2O
(trans)); 2.24 (q, Jˆ6.8 Hz, 2H, CH2CH2O (cis)); 2.35 (q,
Jˆ7.5 Hz, 2H PhCH2CH2 (trans)); 2.39 (q, Jˆ7.5 Hz, 2H,
PhCH2CH2 (cis)); 2.67 (t, Jˆ7.8 Hz, 2H, PhCH2 (trans));
2.69 (t, Jˆ7.5 Hz, 2H, PhCH2 (cis)); 3.53 (t, Jˆ6.6 Hz, 2H,
CH2O (trans)); 3.56 (t, Jˆ6.3 Hz, 2H, CH2O (cis)); 5.35
(dtt, Jˆ15.3, 6.9, 1.2 Hz, 1H, yCH (trans)): 5.38 (dtt,
Jˆ10.8, 7.5, 1.3 Hz, 1H, yCH (cis)); 5.56 (dtt, Jˆ15.0,
6.6, 1.3 Hz, 1H, CHy (trans)); 5.58 (dtt, Jˆ10.8, 7.2,
1.5 Hz, 1H, CHy (cis)); 7.14–7.31 (m, 5H, Ph). 13C
NMR: 29.20 (PhCH2CH2 (cis)); 30.68 (CH2CH2O (cis));
34.37 ((PhCH2CH2 (trans)); 35.72 (PhCH2 (trans)); 35.76
(PhCH2 (cis)); 35.86 (CH2CH2O (trans)); 61.82 (CH2O
(trans)); 62.08 (CH2O (cis)); 125.78 (yCH (cis)); 126.73
(yCH (trans)); 125.97, 128.23, 128.41, 128.45 (Ph);
131.93 (CHy (cis)); 133.03 (CHy (trans)); 141.73 (Ph).
MS (DCI-i-butane): 177 (MHϩ), 159 (MHϩϪH2O), 131
(MϩϪC2H4OH), 91 (C7Hϩ7 ).
(Ph)3CNHCH(CH2Ph)CHyCHCH2CH2OH (3b). 1.6:1
cis/trans mixture (after chromatography, 1:4 ether/hexane),
1
60% yield. H NMR: 1.39 (ddtd, Jˆ14.7, 7.3, 6.6, 1.5 Hz,
1H, CH2CH2O (cis)); 1.67 (ddtd, Jˆ14.7, 7.3, 6.6, 1.7 Hz,
1H, CH2CH2O (cis)); 1.94 (dt, Jˆ7.4, 5.9 Hz, 2H,
CH2CH2O (trans)); 2.19 (dd, Jˆ12.5, 8.6 Hz, 1H, CH2Ph
(cis)); 2.23 (dd, Jˆ12.7, 4.7 Hz, 1H, CH2Ph (cis)); 2.30 (dd,
Jˆ13.0, 8.4 Hz, 1H, CH2Ph (trans)); 2.48 (dd, Jˆ13.0,
5.4 Hz, 1H, CH2Ph (trans)); 3.00 (dt, Jˆ10.4, 6.6 Hz, 1H,
CH2O (cis)); 3.11 (dt, Jˆ10.4, 6.5 Hz, 1H, CH2O (cis)); 3.17
(ddd, Jˆ8.5, 8.0, 5.4 Hz, 1H, NCH (trans)); 3.27 (dt,
Jˆ10.8, 5.9 Hz, 1H, CH2O (trans)); 3.34 (dt, Jˆ10.7,
5.8 Hz, 1H, CH2O (trans)); 3.47 (td, Jˆ9.0, 4.7 Hz, 1H,
NCH (cis)); 4.78 (dt, Jˆ15.2, 7.4 Hz, 1H, yCH (trans));
5.01 (dt, Jˆ10.9, 7.3 Hz, 1H, yCH (cis)); 5.20 (ddt,
Jˆ15.4, 8.0, 1.0 Hz, 1H, CHy (trans)); 5.34 (ddt, Jˆ11.0,
9.4, 1.6 Hz, 1H, CHy (cis)); 6.8–7.6 (m, 10H, Ph
(cisϩtrans)). 13C NMR: 31.19 (CH2CH2O (cis)); 35.70
(CH2CH2O (trans)); 43.85 (CH2Ph (cis)); 44.14 (CH2Ph
(trans)); 52.95 (NCH (cis)); 57.37 (NCH (trans)); 61.67
(CH2O (trans)); 61.97 (CH2O (cis)); 71.57 (Ph3C) (trans));
71.75 (Ph3C) (cis)); 124.00 (CHy (cis)); 125.59 (CHy
(trans)); 125.94, 126.04, 126.31, 126.55, 127.64, 127.72,
Alternatively, the same hydroxy olefin could be obtained by
Wittig reaction (as described above) with O-protected
phosphonium salt 1e, followed by deprotection.
t
PhCH2CH2CHyCHCH2CH2OSi(Me)2 Bu (4e). 8.5:1 cis/
trans mixture (after chromatography, 1:20 CH2Cl2/hexane),
1
41% yield. H NMR: 0.033 (s, 6H, SiCH3 (cis)); 0.034 (s,
6H, SiCH3 (trans)); 1.00 (s, 9H, CCH3 (cis)); 1.01 (s, 9H,
CCH3 (trans)); 2.18 (q, Jˆ6.9 Hz, 2H, CH2CH2O (cis));
2.32 (q, Jˆ7.7 Hz, 2H, PhCH2CH2 (cis)); 2.62 (t, Jˆ
7.7 Hz, 2H, PhCH2 (cis)); 3.49 (t, Jˆ7.0 Hz, 2H, CH2O
(cis)); 3.55 (t, Jˆ6.9 Hz, 2H, CH2O (trans)); 5.35 (dt,

N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
1511
Jˆ10.8, 7.0 Hz, 1H, yCH (cis)); 5.45 (dt, Jˆ10.8, 7.0 Hz,
1H, CHy (cis)); 7.11–7.25 (m, 5H, Ph). 13C NMR: Ϫ5.24
(SiCH3 (cis)); Ϫ4.68 (SiCH3 (trans)); 18.37 (C); 25.97
(CCH3); 29.26 (CH2CH (cis)); 31.13 (CH2CH (cis)); 34.52
(CH2CH (trans)); 35.98 (PhCH2); 36.28 (CH2CH (trans);
62.90 (CH2O (cis)); 63.29 (CH2O (trans)); 125.77 (Ph);
126.49 (CH (cis)); 127.21 (CH (trans)); 128.25, 128.45
(Ph); 130.56 (CH (cis)); 131.54 (CH (trans)); 142.00 (Ph).
MS: 291 (MHϩ, 8), 275 (25), 233 (100), 159 (30), 117 (40),
91 (60), 75 (62).
Jˆ5.7, 4.8 Hz, 1H, NCH (trans)); 3.56 (t, Jˆ6.3 Hz, 2H,
CH2O (trans)); 3.84 (dt, Jˆ13.7, 7.4 Hz, 1H, NCH (cis));
5.46 (ddd, Jˆ10.8, 6.0, 4.9 Hz, 1H, ˆCH (cis)); 5.50 (dd,
Jˆ10.8, 5.1 Hz, 1H, CHy (cis)); 5.51 (dt, Jˆ15.3, 4.8 Hz,
1H, yCH (trans)); 5.55 (dd, Jˆ15.3, 5.4 Hz, 1H,
CHˆ(trans)); 7.16–7.29 (m, 5H, Ph). 13C NMR: 30.95
(CH2CH2O (trans)); 35.62 (CH2CH2O (cis)); 44.38
(CH2Ph (cis)); 44.59 (CH2Ph (trans)); 49.52 (NCH
(trans)); 54.79 (NCH (cis)); 60.92 (CH2O (trans)); 61.35
(CH2O (cis)); 126.28, 128.3, 129.26 (Ph); 126.89, 128.13
(CHy); 135.22 (CHy (cis)); 136.15 (CHy (trans)); 138.33
(Ph (cis)); 138.55 (Ph (trans)).
PhCH2CH2CHyCHCH2CH2OH (4d). PhCH2CH2CHy
t
CHCH2CH2OSi(Me)2 Bu (240 mg, 0.83 mmol) was stirred
with Bu4NF (2.5 mmol) in THF (10 ml) for 1 h. Water
(20 ml) was added and the solution extracted with CH2Cl2
(3×20 ml). The organic layer was extracted successively
with water pH 2.5 and neutral water (20 ml each), dried
over MgSO4 and evaporated to dryness. Chromatography
(1:1 CH2Cl2/hexane) afforded 124 mg of the free alcohol
as a 8.3:1 cis/trans mixture (85% yield).
Coupling with Cbz-amino acid
N-Cbz-amino acid (0.87 mmol), DCC (0.89 mmol) and the
amino alcohol or amino ester (0.77 mmol) (when the amino
alcohol was presented as the hydrochloride salt in water,
Na2CO3 was added to pH 9.5) were stirred in THF (5 ml)
at rt overnight. The reaction mixture was filtered to remove
the precipitation, CH2Cl2 (20 ml) was added and
extracted successively with 1 M HCl, saturated
Na2CO2 and water (20 ml each), dried on MgSO4 and
evaporated to dryness.
Removal of the N-protecting group
H2NCH2CHyCHCH2CH2OH·HCl (4a). The N-protected
alcohol 3a (370 mg, 1 mmol) was stirred with conc. HCl
(3.1 mmol) in acetone (20 ml) at rt overnight. Then the
acetone was evaporated and water (4 ml) and ether (4 ml)
were added. After separation, the aqueous phase was
extracted with ethyl acetate (2×10 ml). The product, in the
aqueous phase, was transferred to the next reaction without
further purification.
PhCH2OCONHCH(CH2Ph)CONHCH2CHyCHCH2CH2OH
(6a). 20% Overall yield for the deprotection–coupling
steps. Purification (and isomer separation) was carried out
by chromatography (ethyl acetate/hexane 1:1).
1
cis Isomer: H NMR: 2.26 (m, 2H, CH2CH2O); 3.01 (dd,
Jˆ13.4, 7.5 Hz, 1H, CHCH2Ph); 3.08 (dd, Jˆ13.5, 5.9 Hz,
1H, CHCH2Ph); 3.57 (dd, Jˆ10.5, 5.1 Hz, 1H, CH2OH);
3.60 (dd, Jˆ9.9, 3.7 Hz, 1H, CH2OH); 3.74 (dd, Jˆ14.4,
6.5 Hz, 1H, NCH2); 3.79 (dd, Jˆ14.2, 6.2 Hz, 1H, NCH2);
4.32 (q, Jˆ7.4 Hz, 1H, NCH); 5.07 (s, 2H, PhCH2O); 5.41
(s, 1H, NHCH); 5.45 (dtt, Jˆ10.7, 7.2, 1.3 Hz, 1H, CHy);
5.54 (dt, Jˆ10.7, 7.9 Hz, 1H, yCH); 6.22 (s, 1H, NHCH2);
7.19–7.36 (m, 10H, Ph). 13C NMR: 30.54 (CH2CH2O);
36.18 (NCH2); 38.76 (CHCH2Ph); 56.40 (NCH); 61.26
(CH2OH); 67.02 (PhCH2O); 126.96, 127.26, 128.03,
128.22, 128.54, 128.65, 129.35, 130.71, 132.05, 132.11
(CyC, Ph); 156 (OCON); 170.65 (CON). MS: 383 (MHϩ,
32), 339 (100), 275 (41), 257 (14), 191 (16). HRMS for
C22H27N2O4: calcd 383.1971, found 383.1950.
cis Isomer: 1H NMR (D2O): 2.47 (q, Jˆ6.3 Hz, 2H,
CH2CH2O); 3.73 (t, Jˆ6.3 Hz, 2H, CH2O); 3.81 (d,
Jˆ7 Hz, 2H, NCH2); 5.76 (dt, Jˆ11, 7.3 Hz, 1H, CH);
5.97 (dt, Jˆ11, 7.5 Hz, 1H, CH). 13C NMR: 34.86
(CH2CH2O); 41.53 (NCH2); 61.05 (CH2O); 123.40, 135.69
(CyC).
trans Isomer: 1H NMR (D2O): 2.60 (q, Jˆ6.5 Hz, 2H,
CH2CH2O); 3.85 (d, Jˆ7 Hz, 2H, NCH2); 3.92 (t,
Jˆ6.5 Hz, 2H, CH2O); 5.93 (dt, Jˆ15.5, 7.0 Hz, 1H, CH);
6.18 (dt, Jˆ15.6, 7.4 Hz, 1H, CH). 13C NMR: 29.81
(CH2CH2O); 36.19 (NCH2); 60.54 (CH2O); 122.23, 134.22
(CyC). MS: 102 (MHϩ, 100), 85 (8), 84 (9), 70 (5). HRMS
for C5H12NO: calcd 102.0919, found 102.0910.
trans Isomer: 1H NMR: 2.20 (qd, Jˆ6.4, 1 Hz, 2H,
CH2CH2O); 3.03 (d, Jˆ6.9 Hz, 2H, CHCH2Ph); 3.58 (t,
Jˆ6.2 Hz, 2H, CH2OH); 3.71 (t, Jˆ5.4 Hz, 2H, NCH2);
4.41 (q, Jˆ8 Hz, 1H, NCH); 5.00 (d, Jˆ12.3 Hz, 1H,
PhCH2O); 5.05 (d, Jˆ12.3 Hz, 1H, PhCH2O); 5.72 (d,
Jˆ7.6 Hz, 1H, NHCH); 5.35 (dtt, Jˆ15.4, 5.8, 2 Hz, 1H,
CHy); 5.44 (dt, Jˆ15.4, 7 Hz, 1H, yCH); 6.42 (s, 1H,
NHCH2); 7.16–7.33 (m, 10H, Ph). 13C NMR: 35.40
(CH2CH2O); 38.72 (CHCH2Ph); 41.18 (NCH2); 56.33
(NCH); 61.46 (CH2OH); 66.92 (PhCH2O); 126.87, 127.82,
127.87, 128.11, 128.44, 129.152, 129.27, 129.48, 129.85,
136.45 (CyC, Ph); 156.03 (OCON); 170.86 (CON). MS:
383 (MHϩ, 31), 365 (9), 339 (100), 275 (40), 191 (8).
HRMS for C22H27N2O4: calcd 383.1971, found 383.1960.
H2NCH(CH2Ph)CHyCHCH2CH2OH (4b). The N-pro-
tected alcohol 3b (340 mg, 0.78 mmol) was refluxed with
conc. HCl (1.7 mmol) in acetone (25 ml) for 4.5 h. Then
CH2Cl2 (30 ml) was added and extracted with HCl 1 M
(3×30 ml) and the layers were separated. The aqueous
phase was adjusted to pH 9.5 (with solid Na2CO3) and
extracted with ethyl acetate (3×50 ml). Drying (MgSO4)
and evaporation afforded the free amine as a 1.1:1 trans/
cis mixture in 78% yield. 1H NMR: 2.09 (dq, Jˆ13.8,
5.1 Hz, 1H, CH2CH2O (cis)); 2.24 (q, Jˆ6.2 Hz, 2H,
CH2CH2O (trans)); 2.35 (obscured, 1H, CH2CH2O (cis));
2.61 (dd, Jˆ13.4, 8.0 Hz, 1H, CH2Ph (trans)); 2.66 (dd,
Jˆ13.1, 7.7 Hz, 1H, CH2Ph (cis)); 2.76 (dd, Jˆ13.8,
8.4 Hz, 1H, CH2Ph (cis)); 2.78 (dd, Jˆ13.4, 8.0 Hz, 1H,
CH2Ph (trans)); 3.45 (ddd, Jˆ10.5, 8.4, 5.0 Hz, 1H, CH2O
(cis)); 3.53 (dt, Jˆ10.5, 5.5 Hz, 1H, CH2O (cis)); 3.54 (td,
PhCH2OCONHCH2CONHCH(CH2Ph)CHyCHCH2CH2OH
(6b). 1:1 cis/trans mixture (after chromatography, ethyl

1512
N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
acetate/hexane 1:1), 60% yield. 1H NMR: 1.95 (dqd,
Jˆ14.5, 4.9, 1.5 Hz, 1H, CH2CH2O (cis)); 2.15 (q,
Jˆ6.0 Hz, 2H, CH2CH2O (trans)); 2.31 (dtdd, Jˆ14.5,
9.0, 5.0, 1.0 Hz, 1H, CH2CH2O (cis)); 2.68 (dd, Jˆ13.5,
7.8 Hz, 1H, CHCH2Ph (cis)); 2.75 (dd, Jˆ13.5, 7.0 Hz,
1H, CHCH2Ph (trans)); 2.81 (dd, Jˆ13.5, 6.75 Hz, 1H,
CHCH2Ph (trans)); 2.86 (dd, Jˆ13.5, 6.0 Hz, 1H,
CHCH2Ph (cis)); 2.93 (bs, 1H, OH (trans)); 3.34 (bs, 1H,
OH (cis)); 3.40 (m, 1H, CH2OH (cis)); 3.49 (bs, 2H, CH2OH
(trans)); 3.50 (m, 1H, CH2OH (cis)); 3.68 (dd, Jˆ16.0,
5.5 Hz, 1H, NCH2 (cis)); 3.69 (dd, Jˆ16.0, 5.0 Hz, 1H,
NCH2 (trans)); 3.74 (dd, Jˆ15.5, 5.5 Hz, 1H, NCH2
(cis)); 3.77 (dd, Jˆ15.5, 5.5 Hz, 1H, NCH2 (trans)); 4.63
(dt, Jˆ13.0, 7.0 Hz, 1H, NCH (trans)); 4.82 (quintet,
Jˆ8.0 Hz, 1H, NCH (cis)); 5.06 (s, 2H, PhCH2O); 5.31 (t,
Jˆ10 Hz, 1H, CHy (cis)); 5.42 (td, Jˆ10.0, 5.0 Hz, 1H,
yCH (cis)); 5.43 (m, 2H, CyC (trans)); 5.99 (t, Jˆ5.5 Hz,
1H, NHCH2 (trans)); 6.02 (t, Jˆ5.8 Hz, 1H, NHCH2 (cis));
6.82 (d, Jˆ8.3 Hz, 1H, NHCH (trans)); 6.93 (d, Jˆ6.8 Hz,
1H, NHCH (cis)); 7.09–7.31 (m, 10H, Ph). 13C NMR: 30.84
(CH2CH2O (cis)); 35.35 (CH2CH2O (trans)); 40.88
(CHCH2Ph) (cis)); 41.00 (CHCH2Ph) (trans)); 44.33
(NCH2); 48.31 (NCH) (cis)); 52.01 (NCH) (trans)); 61.17
(CH2OH (cis)); 61.29 (CH2OH (trans)); 66.89 (PhCH2O);
126.41, 127.81, 128.04, 128.18, 128.37, 129.25, 129.33,
129.45, 130.82, 131.43, 136.03, 137.00, 137.26 (CyC,
Ph); 156.66 (OCON); 168.52 (CON (trans)); 168.71
(CON (cis)). MS: 383 (MHϩ, 100), 365 (14), 339 (88),
209 (75), 165 (88). HRMS for C22H27N2O4: calcd
383.1971, found 383.1960.
Jˆ7.8 Hz, 2H, PhCH2CH2 (cis)); 2.59 (dt, Jˆ13.8, 7.8 Hz,
1H, PhCH2CH2 (trans)); 2.66 (dt, Jˆ13.6, 8.4 Hz, 1H,
PhCH2CH2 (trans)); 2.66 (dd, Jˆ13.7, 8.2 Hz, 1H,
CHCH2Ph (cis)); 2.76 (dd, Jˆ13.6, 7.9 Hz, 1H, CHCH2Ph
(trans)); 3.07 (td, Jˆ8.1, 6.4 Hz, 1H, CHCH2 (trans)); 3.17
(dd, Jˆ13.7, 6.3 Hz, 1H, CHCH2Ph (trans)); 3.19 (dd,
Jˆ13.6, 5.6 Hz, 1H, CHCH2Ph (cis)); 3.32 (tdd, Jˆ9.3,
5.6, 1.0 Hz, 1H, CHCH2 (cis)); 3.73 (s, 3H, Me (cis));
3.73 (s, 3H, Me (trans)); 3.87 (dd, Jˆ18.4, 5.4 Hz, 1H,
NCH2 (cis)); 3.90 (dd, Jˆ18.3, 5.3 Hz, 1H, NCH2 (cis));
3.91 (dd, Jˆ18.4, 5.4 Hz, 1H, NCH2 (trans)); 3.93 (dd,
Jˆ18.3, 5.2 Hz, 1H, NCH2 (trans)); 5.43 (ddt, Jˆ10.9,
9.9, 1.4 Hz, 1H, yCH (cis)); 5.44 (ddt, Jˆ15.4, 8.4,
1.1 Hz, 1H, yCH (trans)); 5.50 (dt, Jˆ15.4, 6.3 Hz, 1H,
CHy (trans)); 5.59 (dtd, Jˆ10.8, 7.5, 0.9 Hz, 1H, CHy
(cis)); 5.64 (t, Jˆ5.0 Hz, 1H, NH (cis)); 5.83 (t, Jˆ5.1 Hz,
1H, NH (trans)); 7.05–7.26 (m, 10H, Ph). 13C NMR: 29.34
(PhCH2CH2 (cis)); 34.01 (PhCH2CH2 (trans)); 35.24
(PhCH2CH2 (cis)); 35.41 (PhCH2CH2 (trans)); 38.10
(CHCH2Ph); 41.26 (NCH2); 46.98 (CHCH2 (cis)); 52.23
(CHCH2 (trans), OMe); 125.82 (yCH (trans)); 127.72
(yCH (cis)); 126.16, 128.22, 128.49, 129.22 (Ph); 133.01
(CHy (cis)); 134.19 (CHy (trans)); 139.34, 141.52 (Ph);
170.24, 172.93, 173.19 (COO, CON). MS: 352 (MHϩ,
100), 260 (14). HRMS for C22H26NO3: calcd 352.1913,
found 352.1925.
Oxidation of the alcohol to the corresponding acid
Jones oxidation17 of the alcohol afforded the corresponding
acid. It was purified by a triple extraction procedure:
extraction into organic phase (ether or ethyl acetate) directly
from the acidic Jones’ reaction, extraction back into sat.
NaHCO3 aqueous solution, acidification of the latter to
pH 1 by conc. HCl and re-extraction into organic phase.
Drying over MgSO4, filtration and evaporation afforded
the acid, which was transferred to the next reaction, either
coupling with an amine or esterification, without further
purification.
PhCH2CH2CHyCHCH2CONHCH(CH2Ph)CO2Me (8d).
9.1:1 cis/trans mixture (after chromatography, CH2Cl2/
1
ethanol 20:1), 58% yield. H NMR: (cis isomer) 2.32 (m,
2H, PhCH2CH2); 2.64 (t, Jˆ7.7 Hz, 2H, Ph CH2CH2); 2.91
(dd, Jˆ7.5, 1.1 Hz, 2H, CH2CO); 3.06 (dd, Jˆ13.8, 5.8 Hz,
1H, CHCH2Ph); 3.13 (dd, Jˆ13.8, 5.8 Hz, 1H, CHCH2Ph);
3.71 (s, 3H, OMe); 4.83 (dt, Jˆ7.8, 5.7 Hz, 1H, NCH);
5.49 (dt, Jˆ10.8, 7.4 Hz, 1H, yCH); 5.67 (dt, Jˆ10.6,
7.2 Hz, 1H, CHy); 6.00 (d, Jˆ7.3 Hz, 1H, NH); 7.04–
7.30 (m, 10H, Ph). 13C NMR: 29.31 (PhCH2CH2 (cis));
34.16 (PhCH2CH2 (trans)); 35.10 (CH2CO (cis)); 35.47
(PhCH2CH2 (cis)); 35.59 (PhCH2CH2 (trans)); 37.93
(PhCH2CH (cis)); 40.32 (CH2CO (trans)); 52.22 (OMe
(cis)); 53.13 (NCH (cis)); 122.09 (yCH (cis)); 122.96
(yCH (trans)); 126.04, 127.17, 128.42, 128.48, 128.59,
129.30 (Ph); 134.04 (CHy (cis)); 135.53 (CHy (trans));
170.23 (CON (cis)); 170.6 (CON (trans)); 171.99 (CO2
(cis)). MS: 352 (MHϩ, 100), 320 (7), 292 (5), 272 (11),
180 (29), 91 (5).
PhCH2OCONHCH(CH2Ph)CONHCH2CHyCHCH2-
CO2H (7a)
1
cis Isomer: 57% yield. H NMR: 3.03 (m, 2H, CHCH2Ph);
3.11 (d, Jˆ7.2 Hz, 2H, CH2CO2); 3.76 (m, 2H, NCH2); 4.40
(q, Jˆ5.6 Hz, 1H, NCH); 5.04 (d, Jˆ13.1 Hz, 1H,
PhCH2O); 5.07 (d, Jˆ13.1 Hz, 1H, PhCH2O); 5.41 (dt,
Jˆ10.6, 6.7 Hz, 1H, CHˆ); 5.64–5.70 (m, 2H,
yCHϩNHCH); 6.25 (t, Jˆ4.5 Hz, 1H, NHCH2); 7.14–
7.34 (m, 10H, Ph). 13C NMR: 32.79 (CH2CO2); 36.48
(NCH2); 38.67 (CHCH2Ph); 56.35 (NCH); 67.13
(PhCH2O); 124.71, 127.06, 127.99, 128.23, 128.37,
128.53, 128.67, 129.27, 129.36, 136.23 (CyC, Ph); 156.14
(OCON); 171.25, 174.81 (CON, CO2).
PhCH2CH2CHyCHCH(CH2Ph)CONHCH2CO2Me (8c).
The acid (0.29 mmol) (see below) was stirred with 1,1-
carbonyldiimidazole (0.34 mmol) in THF (5 ml) under
argon atmosphere for 1.5 h. Then Gly-OMe (0.35 mmol)
was added and the solution was stirred overnight. The
solvent was evaporated to dryness and purification was
carried out by chromatography (ether/hexane 1:4), affording
1
trans Isomer: 53% yield. H NMR: 3.01 (d, Jˆ6.9 Hz, 2H,
CH2CO2); 3.03 (m, 2H, CHCH2Ph); 3.75 (m, 2H, NCH2);
4.45 (q, Jˆ6.7 Hz, 1H, NCH); 5.01 (d, Jˆ12.3 Hz, 1H,
PhCH2O); 5.06 (d, Jˆ12.3 Hz, 1H, PhCH2O); 5.39 (dt,
Jˆ15.6, 5.8 Hz, 1H, CHy); 5.51 (dt, Jˆ15.0, 7.5 Hz, 1H,
yCH); 5.85 (d, Jˆ8.2 Hz, 1H, NHCH); 6.43 (s, 1H,
NHCH2); 7.17–7.33 (m, 10H, Ph). 13C NMR: 37.13
(CH2CO2); 38.74 (CHCH2Ph); 40.87 (NCH2); 56.38
1
the product as a 2.1:1 trans/cis mixture in 43% yield. H
NMR: 2.12 (dqd, Jˆ14.2, 7.4, 1.6 Hz, 1H, PhCH2CH2
(cis)); 2.19 (dqd, Jˆ14.9, 7.8, 1.5 Hz, 1H, PhCH2CH2
(cis)); 2.32 (dq, Jˆ14.2, 6.5 Hz, 1H, PhCH2CH2 (trans));
2.34 (dq, Jˆ14.0, 6.3 Hz, 1H, PhCH2CH2 (trans)); 2.46 (t,

N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
1513
(NCH); 67.09 (PhCH2CH2); 124.28, 126.97, 127.92, 128.17,
Esterification
128.49, 128.61, 129.29, 129.43, 136.34 (CyC, Ph); 156.190
(OCON); 171.179, 175.156 (CON, CO2). MS: 397
(MHϩ, 44), 353 (65), 289 (40), 243 (44), 191 (100).
HRMS for C22H25N2O5: calcd 397.1763, found
397.1735.
The acid (0.1 mmol) was suspended in ether (5 ml) and
diazomethane (0.3 M solution in ether, 1 ml) was added
until the acid was dissolved completely and the solution
turned yellow. After stirring overnight, the solvent was
evaporated to dryness. The product ester was purified by
chromatography.
PhCH2OCONHCH2CONHCH(CH2Ph)CHyCHCH2CO2H
1
(7b). 2:1 trans/cis mixture, 27% yield. H NMR (acetone-
d6): 2.6–3.1 (m, 4H, CH2CO2ϩCHCH2Ph); 3.64 (s, 2H,
NCH2); 4.58 (m, 1H, NCH (trans)); 4.75 (m, 1H, NCH
(cis)); 4.95 (s, 2H, PhCH2O); 5.45 (m, 2H, CHyCH); 6.42
(s, 1H, NH); 7.00–7.27 (m, 10H, Ph). 13C NMR (acetone-
d6): 31.87 (CH2CO2 (cis)); 36.43 (CH2CO2 (trans)); 40.26
(CHCH2Ph) (cis)); 40.45 (CHCH2Ph) (trans)); 43.5 (NCH2
(cis)); 43.58 (NCH2 (trans)); 47.89 (NCH (cis)); 51.38
(NCH) (trans)); 65.56 (PhCH2O); 122.81, 123.48, 125.66,
125.72, 127.29, 127.61, 127.66, 127.84, 128.97, 131.40,
132.65, 136.73, 137.50, 137.66 (CyC, Ph); 156.08
(OCON); 167.89 (CON); 171.44 (CO2 (cis)); 171.50 (CO2
(trans)). MS: 397 (MHϩ, 54), 379 (20), 353 (94), 305 (16),
289 (54), 271 (75), 209 (16), 171 (100). HRMS for
C22H25N2O5: calcd 397.1763, found 397.1730.
PhCH2OCONHCH(CH2Ph)CONHCH2CHyCHCH2-
CO2Me (8a)
cis Isomer: Chromatography (2:1 hexane/ethyl acetate).
52% yield. 1H NMR: 3.02 (dd, Jˆ13.5, 7.5 Hz, 1H,
CHCH2Ph); 3.08 (d, Jˆ7.2 Hz, 2H, CH2CO2); 3.12 (dd,
Jˆ13.5, 5.8 Hz, 1H, CHCH2Ph); 3.67 (s, 3H, Me); 3.79
(m, 2H, NHCH2); 4.36 (q, Jˆ6.1 Hz, 1H, CHCH2Ph);
5.08 (bs, 2H, PhCH2O); 5.35 (d, Jˆ6 Hz, 1H, NHCH);
5.43 (dt, Jˆ10.2, 7 Hz, 1H, CHy); 5.68 (dtt, Jˆ10.6, 7.5,
1.5 Hz, 1H, yCH); 5.86 (t, Jˆ5 Hz, 1H, NHCH2); 7.22–
7.37 (m, 10H, Ph). 13C NMR: 32.65 (CH2CO2) 36.41
(NHCH2); 38.77 (CHCH2Ph); 52.07 (Me); 56.37
(CHCH2Ph); 67.09 (PhCH2O); 124.86 (CHy); 128.06,
128.25, 128.41, 128.56, 128.73, 129.27 (Ph); 129.33
(CHy); 136.24, 136.40 (Ph); 170.55, 171.79 (CON, CO2).
MS: 411 (MHϩ, 55), 367 (84), 303 (50), 271 (100). HRMS
for C23H27N2O5: calcd 411.1920, found 411.1930.
PhCH2CH2CHyCHCH(CH2Ph)CO2H (5c). 2.4:1 trans/
1
cis mixture, 49% yield. H NMR: 2.16 (ddtd, Jˆ14.5, 9.0,
7.2, 1.4 Hz, 1H, PhCH2CH2 (cis)); 2.25 (ddtd, Jˆ15.3, 8.5,
6.6, 1.6 Hz, 1H, PhCH2CH2 (cis)); 2.30 (qd, Jˆ7.3, 0.7 Hz,
2H, PhCH2CH2 (trans)); 2.36 (ddd, Jˆ13.7, 8.7, 6.7 Hz, 1H,
PhCH2CH2 (cis)); 2.49 (ddd, Jˆ13.7, 8.7, 6.4 Hz, 1H,
PhCH2CH2 (cis)); 2.59 (dt, Jˆ13.5, 7.4 Hz, 1H, PhCH2CH2
(trans)); 2.63 (dt, Jˆ13.3, 7.4 Hz, 1H, PhCH2CH2 (trans));
2.67 (dd, Jˆ13.5, 8.5 Hz, 1H, CHCH2Ph (cis)); 2.79 (dd,
Jˆ13.5, 7.5 Hz, 1H, CHCH2Ph (trans)); 3.07 (dd, Jˆ13.5,
7.5 Hz, 1H, CHCH2Ph (trans)); 3.07 (dd, Jˆ13.5, 6.8 Hz,
1H, CHCH2Ph (cis)); 3.27 (dt, Jˆ8.0, 7.6 Hz, 1H,
CHCH2Ph (trans)); 3.56 (dddd, Jˆ10.0, 6.9, 1.7, 1.0 Hz,
1H, CHCH2Ph (cis)); 5.41 (ddt, Jˆ11.0, 10.0, 1.6 Hz, 1H,
yCH (cis)); 5.46 (ddt, Jˆ15.5, 8.5, 1.2 Hz, 1H, yCH
(trans)); 5.53 (dt, Jˆ15.5, 6.4 Hz, 1H, CHy (trans)); 5.56
(dtd, Jˆ11.0, 7.4, 1.0 Hz, 1H, CHy (cis)); 7.03–7.27 (m,
10H, Ph). 13C NMR: 29.33 (PhCH2CH2 (cis)); 34.14
(PhCH2CH2 (trans)); 35.24 (PhCH2CH2 (cis)); 35.43
(PhCH2CH2 (trans)); 38.38 (CHCH2Ph); 45.94 (CHCH2Ph
(cis)); 50.82 (CHCH2Ph (trans)); 125.78 (yCH (trans));
125.83 (yCH (cis)); 126.31, 126.37, 126.43, 126.87,
128.22, 128.27, 128.35, 128.40, 129.06 (Ph); 132.82
(CHy (cis)); 133.66 (CHy (trans)); 138.43, 141.47 (Ph);
180.02 (CO2 (cis)); 180.17 (CO2 (trans)). MS: 281 (MHϩ,
100), 263 (70), 235 (72), 131 (88), 91 (35). HRMS for
C19H21O2: calcd 281.1542, found 281.1543.
trans Isomer: Chromatography (2:1 hexane/ethyl acetate).
71% yield. 1H NMR: 2.96 (d, Jˆ7.1 Hz, 2H, CH2CO2); 2.98
(dd, Jˆ13.0, 7.8 Hz, 1H, CHCH2Ph); 3.07 (dd, Jˆ13.0,
5.6 Hz, 1H, CHCH2Ph); 3.63 (s, 3H, Me); 3.72 (m, 2H,
NHCH2); 4.32 (q, Jˆ7.2 Hz, 1H, CHCH2Ph); 5.02 (d,
Jˆ12.2 Hz, 1H, PhCH2O); 5.04 (d, Jˆ12.2 Hz, 1H,
PhCH2O); 5.35 (obscured, 1H, NHCH); 5.36 (dt, Jˆ16.0,
5.3 Hz, 1H, CHy); 5.51 (dtt, Jˆ15.4, 7.0, 1.5 Hz, 1H,
yCH); 5.76 (t, Jˆ5.2 Hz, 1H, NHCH2); 7.15–7.32 (m,
10H, Ph). 13C NMR: 37.32 (CH2CO2); 38.77 (CHCH2Ph);
40.94 (NHCH2); 51.89 (Me); 56.44 (CHCH2Ph); 67.10
(PhCH2O); 124.68 (CHy); 127.08, 128.07, 128.26,
128.56, 128.74, 129.34 (Ph); 129.45 (CHy); 136.10,
136.43 (Ph); 155.94 (OCON); 170.51, 171.81 (CON,
CO2). MS: 411 (MHϩ, 50), 367 (97), 303 (100), 271 (88).
HRMS for C23H27N2O5: calcd 411.1920, found 411.1920.
PhCH2OCONHCH2CONHCH(CH2Ph)CHyCHCH2CO2Me
(8b). 4.5:1 trans/cis mixture (after chromatography, ether),
1
76% yield. H NMR: 2.76 (dd, Jˆ16, 7 Hz, 1H, CHCH2Ph
(cis)); 2.83 (dd, Jˆ13.5, 7.5 Hz, 1H, CHCH2Ph (trans));
2.86 (dd, Jˆ13.5, 7.5 Hz, 1H, CHCH2Ph (trans)); 2.90
(dd, Jˆ16.5, 7.9 Hz, CHCH2Ph (cis)); 2.91 (m, 1H,
CH2CO2 (cis)); 3.03 (d, Jˆ6.7 Hz, 2H, CH2CO2 (trans));
3.08 (dd, Jˆ18.0, 7.5 Hz, 1H, CH2CO2 (cis)); 3.63 (s, 3H,
Me (cis)); 3.66 (s, 3H, Me (trans)); 3.79 (m, 2H, NCH2
(cisϩtrans)); 4.75 (quint, Jˆ6.9 Hz, 1H, NCH (trans));
4.86 (quint, Jˆ7 Hz, 1H, NCH (cis)); 5.12 (s, 2H,
PhCH2O (cisϩtrans)); 5.42 (m, 1H, NHCH2); 5.43
(obscured, 1H, CHy (cis)); 5.54 (dd, Jˆ14.6, 5.6 Hz, 1H,
CHy (trans)); 5.63 (dt, Jˆ14.5, 7.0 Hz, 1H, yCH (trans));
5.66 (m, 1H, yCH (cis)); 6.11 (d, Jˆ6.5 Hz, 1H, NHCH
(trans)); 6.16 (d, Jˆ7 Hz, 1H, NHCH (cis)); 6.98–7.36
(m, 10H, Ph). 13C NMR: 32.76 (CH2CO2 (cis)); 37.28
(CH2CO2 (trans)); 40.98 (CHCH2Ph); 44.66 (NCH2);
PhCH2CH2CHyCHCH2CO2H (5d). 9.1:1 cis/trans
mixture, 87% yield. 1H NMR: (cis isomer) 2.37 (q,
Jˆ7.7 Hz, 2H, PhCH2CH2); 2.68 (t, Jˆ7.5 Hz, 2H,
PhCH2); 3.02 (d, Jˆ6.4 Hz, 2H, CH2CO2); 5.51–5.70 (m,
2H, CHyCH); 7.05–7.30 (m, 5H, Ph). 13C NMR: 29.31
(PhCH2CH2 (cis)); 32.48 (CH2CO2 (cis)); 34.19
((PhCH2CH2 (trans)); 35.42 (PhCH2 (cis)); 35.54 (PhCH2
(trans)); 37.64 (CH2CO2 (trans)); 120.86 (yCH (cis));
121.49 (yCH (trans)); 125.92, 128.32, 128.41 (Ph);
132.75 (CHy (cis)); 134.40 (CHy (trans)); 141.45 (Ph).
MS: 191 (MHϩ, 12), 173 (88), 145 (18), 131 (37), 91 (100).

1514
N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
48.06 (NCH (cis)); 51.43 (NCH (trans)); 51.76 (Me); 65.75
(PhCH2O (cis)); 67.11 (PhCH2O (trans)); 123.35, 125.52,
126.71, 128.13, 128.30, 128.44, 128.59, 129.47, 133.01,
136.90 (CyC, Ph); 156.53 (OCON); 168.09 (CON\CO2
(cis)); 168.23, 171.65 (CONϩCO2 (trans)); 171.79
(CON\CO2 (cis)). MS: 411 (MHϩ, 86), 367 (100), 318
(12), 303 (63), 209 (51). HRMS for C23H27N2O5: calcd
411.1920, found 411.1940.
Jˆ6.0 Hz, 1H, NHCH2 (minor)); 6.18 (t, Jˆ6.0 Hz, 1H,
NHCH2 (major)); 7.15–7.35 (m, 10H, Ph). 13C NMR:
36.84 (CH2CO2); 38.65 (CHCH2Ph); 39.91, 40.07 (NCH2);
52.02, 52.15 (OCHϩMe); 55.93, 55.98 (CHO); 56.43
(NCH); 67.17 (PhCH2O); 127.12, 128.06, 128.24, 128.55,
128.75, 129.28, 129.74, 130.18, 133.34, 136.08, 136.29
(Ph); 155.91 (OCON); 170.0, 171.32 (CON, CO2). HRMS
for C23H27N2O6: calcd 427.1869, found 427.1860.
PhCH2OCONHCH2CONHCH(CH2Ph)CHOCHCH2CO2Me
Epoxidation
(9b). 4.4:1 trans/cis mixture (after chromatography, ethyl
1
acetate/CHCl3/hexane 5:3:2), 34% yield. H NMR: 2.36
Peptide (0.05 mmol), mCPBA 50% (0.06 mmol), K2HPO4
(0.07 mmol) were stirred in CH2Cl2 (1 ml) and H2O (10 ml)
overnight. The solution was washed successively with
saturated NaHCO3, 5% Na2SO3, saturated NaHCO3, water
and brine (1 ml each), and dried over MgSO4. Evaporation
to dryness afforded the product, which was purified by
chromatography.
(dd, Jˆ17, 8 Hz, 1H, CH2CO2 (cis)); 2.41 (dd, Jˆ17.0,
6.5 Hz, 1H, CH2CO2 (trans)); 2.54 (dd, Jˆ17, 6 Hz, 1H,
CH2CO2 (cis)); 2.59 (dd, Jˆ16.0, 4.0 Hz, 1H, CH2CO2
(trans)); 2.84 (m, 2H, CHCH2Ph (cis)); 2.88 (dd, Jˆ13.0,
7.8 Hz, 1H, CHCH2Ph (trans)); 2.89 (bs, 1H, CHO (trans));
2.94 (dd, Jˆ13.0, 7.0 Hz, 1H, CHCH2Ph (trans)); 3.03 (dd,
Jˆ7, 4 Hz, 1H, CHO (cis)); 3.09 (bt, Jˆ4 Hz, 1H, OCH
(trans)); 3.31 (dt, Jˆ8.0, 4.5 Hz, 1H, OCH (cis)); 3.67 (s,
3H, Me (cis)); 3.69 (s, 3H, Me (trans)); 3.79 (dd, Jˆ16.5,
5.5 Hz, 1H, NCH2 (trans)); 3.81 (dd, Jˆ16.5, 5.1 Hz, 1H,
NCH2 (trans)); 3.82 (dd, Jˆ16.5, 5.5 Hz, 1H, NCH2 (cis));
3.90 (dd, Jˆ16.5, 6.0 Hz, 1H, NCH2 (cis)); 3.99 (qd, Jˆ8,
6 Hz, 1H, NCH (cis)); 4.47 (tdd, Jˆ9.0, 7.5, 3.0 Hz, 1H,
NCH (trans)); 5.14 (s, 2H, PhCH2O); 5.33 (bt, Jˆ5 Hz, 1H,
NHCH2 (trans)); 5.40 (bt, 1H, NHCH2 (cis)); 6.01 (d,
Jˆ8.0 Hz, 1H, NHCH (trans)); 6.30 (d, Jˆ7.2 Hz, 1H,
NHCH (cis)); 7.12–7.37 (m, 10H, Ph). 13C NMR: 36.79
(CH2CO2 (trans)); 39.06 (CHCH2Ph (trans)); 44.62
(NCH2 (trans)); 44.8 (NCH2 (cis)); 49.00 (NCH (trans));
49.73 (NCH (cis)); 51.70 (OCH (trans)); 52.03 (Me
(trans)); 53.52 (OCH (cis)); 57.15 (CHO (cis)); 58.05
(CHO (trans)); 65.32 (PhCH2O (trans)); 126.93, 128.18,
128.32, 128.62, 128.68, 129.35, 136.64 (Ph (trans));
127.05, 127.94, 129.51 (Ph (cis)); 168.68, 170.43 (CON,
CO2 (trans)). MS: 427 (MHϩ, 100), 383 (11), 273 (33).
HRMS for C23H27N2O6: calcd 427.1869, found 427.1820.
PhCH2OCONHCH(CH2Ph)CONHCH2CHOCHCH2-
CO2Me (9a)
cis Isomer: (1:0.82 diasteriomeric ratio). Purified by chro-
matography (ethyl acetate/CHCl3/hexane 5:3:2), 55% yield.
1H NMR: 2.44 (dd, Jˆ16.4, 6.8 Hz, 1H, CH2CO2 (major));
2.46 (dd, Jˆ16.5, 6.8 Hz, 1H, CH2CO2 (minor)); 2.69 (dd,
Jˆ16.4, 6 Hz, 1H, CH2CO2 (minor)); 2.70 (dd, Jˆ16.4,
6 Hz, 1H, CH2CO2 (major)); 2.92 (td, Jˆ6, 4 Hz, 1H,
CHO); 3.04 (dd, Jˆ13.5, 7.5 Hz, 1H, CHCH2Ph); 3.12 (m,
1H, CHCH2Ph); 3.22 (td, Jˆ6.5, 4.1 Hz, 1H, OCH (major));
3.26 (td, Jˆ6, 4 Hz, 1H, OCH (minor)); 3.31 (dt, Jˆ14.4,
6.0 Hz, 1H, NCH2 (major)); 3.37 (dt, Jˆ14.1, 6.1 Hz, 1H,
NCH2 (major)); 3.38 (obscured, 2H, NCH2 (minor)); 3.70 (s,
3H, Me (minor)); 3.71 (s, 3H, Me (major)); 4.42 (m, 1H,
NCH); 5.08 (d, Jˆ13.3 Hz, 1H, PhCH2O); 5.10 (d,
Jˆ13.5 Hz, 1H, PhCH2O); 5.39 (d, Jˆ4.1, 1H, NHCH);
6.24 (bt, 1H, NHCH2 (minor)); 6.28 (t, Jˆ5.25 Hz, 1H,
NHCH2 (major)); 7.17–7.36 (m, 10H, Ph). 13C NMR:
33.53 (CH2CO2); 37.86, 37.92 (NCH2); 38.74 (CHCH2Ph);
52.23, 52.32, 52.37(CHO\Me); 53.93 (OCH major); 54.00
(OCH minor); 56.46 (NCH); 67.18 (PhCH2O); 127.15,
128.07, 128.26, 128.56 128.77, 129.13, 129.31, 129.81,
132.09, 133.60, 134.67, 136.26 (Ph); 155.5 (OCON);
168.74, 170.81, 171.19 (CON, CO2). MS: 427 (MHϩ, 54),
369 (11), 319 (19), 257 (17), 192 (20), 164 (22), 114 (21), 91
(100). HRMS for C23H27N2O6: calcd 427.1869, found
427.1870.
PhCH2CH2CHOCHCH(CH2Ph)CONHCH2CO2Me (9c).
8.7:4.9:4.6:1 trans(major)/cis(major)/trans(minor)/cis(minor)
(after chromatography, hexane/ethyl acetate 2:1, which
separated the major from the minor isomers), 58% yield.
1
Major isomers: H NMR: 1.18 (dddd, Jˆ14.2, 9.5, 7.2,
3.8 Hz, 1H, PhCH2CH2 (cis)); 1.37 (dddd, Jˆ14.2, 9.2,
8.3, 5.5 Hz, 1H, PhCH2CH2 (cis)); 1.62 (dddd, Jˆ14.2,
9.5, 6.6, 5.9 Hz, 1H, PhCH2CH2 (trans)); 1.67 (dddd,
Jˆ14.1, 9.6, 6.9, 4.5 Hz, 1H, PhCH2CH2 (trans)); 2.24
(td, Jˆ8.8, 6.6 Hz, 1H, CHCH2Ph (trans)); 2.32 (ddd,
Jˆ9.5, 8.7, 6.2 Hz, 1H, CHCH2Ph (cis)); 2.46–2.54 (m,
PhCH2CH2 (cisϩtrans), CHO (trans)); 2.58 (ddd, Jˆ14.1,
9.5, 5.7 Hz, 1H, PhCH2CH2 (trans)); 2.65 (ddd, Jˆ14.4, 9.0,
5.4 Hz, 1H, PhCH2CH2 (cis)); 2.76 (dd, Jˆ13.9, 8.6 Hz, 1H,
CHCH2Ph (cis)); 2.78 (dd, Jˆ13.9, 9.4 Hz, 1H, CHCH2Ph
(trans)); 2.86 (dd, Jˆ8.3, 2.2 Hz, 1H, OCH (trans)); 2.92 (q,
Jˆ4.1 Hz, 1H, CHO (cis)); 3.15 (dd, Jˆ9.7, 4.2 Hz, 1H,
OCH (cis)); 3.22 (dd, Jˆ14.0, 6.3 Hz, 1H, CHCH2Ph
(trans)); 3.26 (dd, Jˆ13.9, 6.2 Hz, 1H, CHCH2Ph) (cis));
3.75 (s, 3H, Me (cis)); 3.76 (s, 3H, Me (trans)); 4.02 (dd,
Jˆ18.3, 5.1 Hz, 1H, NCH2 (trans)); 4.04 (dd, Jˆ18.3,
5.1 Hz, 1H, NCH2 (cis));4.08 (dd, Jˆ18.3, 5.5 Hz, 1H,
NCH2 (cisϩtrans)); 6.46 (t, Jˆ5.0, 1H, NH (cis)); 6.47 (t,
trans Isomer: (1:0.92 diasteriomeric ratio). Purified by chro-
matography (ethyl acetate/CHCl3/hexane 2:2:1), 92% yield.
1H NMR: 2.47 (dd, Jˆ16.6, 6.5 Hz, 1H, CH2CO2 (major));
2.49 (dd, Jˆ16.5, 6.6 Hz, 1H, CH2CO2 (minor)); 2.53 (dd,
Jˆ16.5, 4.9 Hz, 1H, CH2CO2 (major)); 2.55 (dd, Jˆ16.5,
4.7 Hz, 1H, CH2CO2 (minor)); 2.78 (m, 1H, CHO (minor));
2.83 (m, 1H, CHO (major)); 2.90 (ddd, Jˆ6.5, 5.0, 2.2 Hz,
1H, OCH (major)); 3.01–3.12 (m, CHCH2PhϩOCH
(minor)); 3.27 (dt, Jˆ14.5, 5.8 Hz, 1H, NCH2 (minor));
3.30 (m, 1H, NCH2 (major)); 3.54 (ddd, Jˆ13.7, 5.5,
4.3 Hz, 1H, NCH2 (minor)); 3.56 (dt, Jˆ14.7, 5.8 Hz, 1H,
NCH2 (major)); 3.70 (s, 3H, Me); 4.42 (q, Jˆ6.7 Hz, 1H,
NCH); 5.07 (d, Jˆ12.3 Hz, 1H, PhCH2O); 5.08 (d,
Jˆ12.3 Hz, 1H, PhCH2O); 5.47 (d, Jˆ8.7, 1H, NHCH
(major)); 5.49 (d, Jˆ9.6, 1H, NHCH (minor)); 6.17 (t,

N. Perlman et al. / Tetrahedron 56 (2000) 1505–1516
1515
Jˆ5.0, 1H, NH (trans)); 7.05–7.28 (m, 10H, Ph). 13C NMR:
29.10 (PhCH2CH2 (cis)); 31.61 (PhCH2CH2 (trans)); 32.40
(PhCH2CH2 (cis)); 33.15 (PhCH2CH2 (trans)); 34.56
(CHCH2Ph (trans)); 34.47 (CHCH2Ph (cis)); 41.30 (NCH2
(trans)); 41.39 (NCH2 (cis)); 46.61 (CHCH2Ph (cis)); 50.62
(CHCH2Ph (trans)); 52.36 (OMe (cisϩtrans)); 57.67 (CHO
(cis)); 58.18 (OCH (cis)); 59.04 (OCH (trans)); 59.36 (CHO
(trans)); 126.07, 126.11, 126.60, 128.25, 128.31, 128.45,
128.56, 128.94, 129.23, 138.64, 140.90 (Ph); 170.18
(cisϩtrans), 171.98 (trans), 172.18 (cis) (CON, CO2).
MS: 368 (MHϩ, 100), 350 (73). HRMS for C22H24NO4:
calcd 368.1862, found 368.1899.
minor)); 6.37 (d, Jˆ7.9, 1H, NH (trans major)); 6.38 (d,
Jˆ7.9, 1H, NH (trans minor)); 7.04–7.28 (m, 10H, Ph).
13C NMR: 29.780 (PhCH2CH2 (cis)); 32.031 (PhCH2CH2
(trans)); 32.570 (PhCH2CH2 (cis)); 33.424 (PhCH2CH2
(trans)); 35.286, 35.433 (CH2CO (cis)); 37.888, 37.972
(CHCH2Ph (cis)); 39.055 (CH2CO (trans)); 52.321
(OMe); 53.255 (OCH (cis)); 53.401 (NCH); 54.723,
54.810 (OCH (trans)); 56.450 (CHO (cis)); 58.157, 58.216
(CHO (trans)); 126.140, 126.236, 127.160, 128.442,
128.548, 128.588, 129.234, 129.315, 135.820, 135.860,
140.931 (Ph); 169.411, 171.879 (CON, CO2). MS: 368
(MHϩ, 100), 350 (37), 180 (41). HRMS for C22H24NO4:
calcd 368.1862, found 368.1830.
1
Minor isomers: H NMR: 1.82–1.89 (m, 2H, PhCH2CH2
(trans)); 2.29 (td, Jˆ9.5, 4.7 Hz, 1H, (CHCH2Ph (cis));
2.46 (ddd, Jˆ9.2, 6.2, 5.4 Hz, 1H, (CHCH2Ph (trans));
2.71 (ddd, Jˆ13.9, 9.1, 7.3 Hz, 1H, PhCH2CH2 (trans));
2.78 (ddd, Jˆ13.7, 9.0, 6.3 Hz, 1H, PhCH2CH2 (trans));
2.96 (dd, Jˆ13.8, 5.0 Hz, 1H, CHCH2Ph (trans)); 2.95–
2.99 (m, 2H, CHOCH (trans)); 3.09 (obscured, CHO
(cis)); 3.10 (dd, Jˆ13.8, 9.3 Hz, 1H, CHCH2Ph (trans));
3.10 (obscured, CHCH2Ph (cis)); 3.15 (dd, Jˆ12.0,
4.8 Hz, 1H, CHCH2Ph (cis)); 3.27 (dd, Jˆ9.1, 4.2 Hz, 1H,
OCH (cis)); 3.72 (s, 3H, Me (trans)); 3.84 (dd, Jˆ18.4,
4.8 Hz, 1H, NCH2 (trans)); 4.01 (dd, Jˆ18.3, 5.6 Hz, 1H,
NCH2 (trans)); 5.89 (t, Jˆ5.6, 1H, NH (trans)); 7.16–7.29
(m, 10H, Ph). 13C NMR: 30.19 (PhCH2CH2 (cis)); 32.05
(PhCH2CH2 (trans)); 32.86 (PhCH2CH2 (cis)); 33.46
(PhCH2CH2 (trans)); 35.53 (CHCH2Ph (trans)); 37.19
(CHCH2Ph (cis)); 40.99 (NCH2 (cis)); 41.13 (NCH2
(trans)); 48.68 (CHCH2Ph (cis)); 50.76 (CHCH2Ph
(trans)); 52.36 (OMe (transϩcis)); 57.23 (trans), 57.69
(trans), 58.08 (cis), 58.94 (cis) (CHOϩOCH); 126.08,
126.57, 128.39, 128.48, 128.55, 128.92, 141.04 (Ph);
169.98, 171.24 (CON, CO2). MS: 368 (MHϩ, 84), 351
(39), 350 (100); 297 (35). HRMS for C22H24NO4: calcd
368.1862, found 368.1853.
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10:9.3:1.1:1 cis(major)/cis(minor)/trans(major)/trans(minor)
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5.7, 3.5 Hz, 1H, CHO (cis major)); 3.03 (ddd, Jˆ5.8, 3.4,
2.6 Hz, 1H, CHO (cis minor)); 3.07 (dd, Jˆ13.9, 6.2 Hz,
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CHCH2Ph (cis minor)); 3.15 (dd, Jˆ13.9, 5.8 Hz, 1H,
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