A Versatile Method for the Preparation of Enantiomeric Benzene-1,2-bis(alanine) Derivatives

Article abstract of DOI:10.1081/SCC-120026849

A versatile method for the preparation of dicarba analogues of cystine as substituted benzene-, dihydrobenzene-, and tetrahydrobenzene-1,2-bis(alanine) derivatives is described. The partially saturated products resulted from Diels-Alder adduct formation w

Full text of DOI:10.1081/SCC-120026849

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A Versatile Method for the Preparation of Enantiomeric
Benzene-1,2-bis(alanine) Derivatives
Bjørg S. Møller a & Kjell Undheim a
a Department of Chemistry , University of Oslo , Oslo, Norway
Published online: 21 Aug 2006.
To cite this article: Bjørg S. Møller & Kjell Undheim (2003) A Versatile Method for the Preparation of Enantiomeric
Benzene-1,2-bis(alanine) Derivatives, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:24, 4209-4220, DOI: 10.1081/SCC-120026849
To link to this article: http://dx.doi.org/10.1081/SCC-120026849
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 24, pp. 4209–4220, 2003
A Versatile Method for the
Preparation of Enantiomeric
Benzene-1,2-bis(alanine) Derivatives
*
Bjørg S. Møller and Kjell Undheim
Department of Chemistry,
University of Oslo, Oslo, Norway
ABSTRACT
A versatile method for the preparation of dicarba analogues of
cystine as substituted benzene-, dihydrobenzene-, and tetrahydro-
benzene-1,2-bis(alanine) derivatives is described. The partially
saturated products resulted from Diels-Alder adduct formation
with stereoselectively prepared (2R,7R)-2,7-diacetamido-4,5-bis
(methylene)octane-1,8-dioic acid dimethyl ester. Aromatization of
the dihydro adducts by manganese dioxide provided the parent
benzene-1,2-bis(alanine) derivatives.
*Correspondence: Kjell Undheim, Department of Chemistry, University of
Oslo, N-0315 Oslo, Norway; Fax: 47 855 507; E-mail: kjell.undheim@kjemi.
uio.no.
4209
DOI: 10.1081/SCC-120026849
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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4210
Møller and Undheim
Key Words: Dicarba cystines; Rigid bis(a-amino acids); Benzene-
1,2-bis(alanines).
INTRODUCTION
Incorporation of conformationally constrained noncoded amino
acids into peptides will affect secondary and tertiary peptide
structures and thereby provide useful information about structural
requirements for bioactivity.[1] We have reported on synthetic routes
for the preparation of conformationally restricted or stiffened amino
acid analogues (vide infra) and in particular for the preparation of
dicarba analogues of cystine which is a main structural element in peptide
and protein architecture. When cystine exerts mainly a skeletal, structural
function, isosteric structures may be envisaged to take its place. In some
cases it may also be desirable to replace cystine with a nonreducible
isosteric analogue. In the structurally simplest case, when the -CH2-
S-S-CH2- bridge between the two glycine a-carbons in (R)-cystine is
replaced by an all-carbon -(CH2)4-bridge, the new C4-bridge amino
acid (S,S )-2,7-diaminosuberic acid [(S,S)-2,7-diaminooctanedioic acid]
is a nonreducible isosteric dicarba analogue of cystine. Early studies of
the replacement of cystine by (S,S)-2,7-diaminosuberic acid in essential
peptides include work with peptides such as oxytocin, calcitonin, and
somatostatin.[2]
In Sch. 1 cystine has been drawn in a cisoid form A. The dicarba
analogues B–E can be regarded as derived from the cisoid form, the
alkene B from (R)-cystine, the ring structures C–E from (S )-cystine.
Replacement of the disulfide linkage with an ethylene unit will increase
the conformational freedom of the bridged amino acid as compared
to cystine. Substitution in the C4-bridge, however, will increase conform-
ational constraints and may be explored for subtle-tuning of
conformational constraints in the amino acid and its derived peptides.
For the purpose of generating molecules with strongly favored
conformers, two vicinal hydroxy substituents have been introduced and
fixed as a five-membered acetal in the bridge.[3] Additional substitution at
the glycine a-carbon provides conformationally constrained quaternary
bridged cystine analogues.[4]
We and others have introduced conformational constraints by
insertion of a C–C double bond in the chain with trans-stereo-
chemistry[3,5–7] and with cis-stereochemistry as in structure B in
Sch. 1.[3,5] Additional carbosubstitution in the unsaturated bridge has

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Enantiomeric Benzene-1,2-bis(alanine) Derivatives
4211
Scheme 1.
been effected.[5] C4-Bridged structures with triple bond insertion
have been described.[8,9] Additional a-substitution in the glycine with
propargyl units, and with allyl and propenyl units, provide novel and
highly unsaturated and conformationally constrained bridge amino
acids.[9] Such structures have been employed as intermediates in the
preparation of strongly rigidified cystine substitutes in which the
a-carbons of the amino acid were embedded in annulated cyclic bridge
structures.[10,11] Benzene-1,4-bis(glycine) constitutes another C4-bridge
structure with high conformational restrictions related to cis-confor-
mational species of cystine.[12] a,a0-Substitution in o-xylene will provide
a C4-bridge with an inserted benzene ring between two glycine units as
drawn in structure C in Sch. 1. Groups of corresponding dihydrobenzene
D and tetrahydrobenzene E derivatives become accessible by the work
herein described.
The aromatic structure C can also be regarded as benzene-1,2-bis
(alanine).[13] The latter was first prepared by a,a0-dibromo-1,2-xylene
alkylation of lithiated Seebach chiron (S)-2-t-butyl-1-t-butyloxy-
carbonyl-3-methyl-4-imidazolidinone. High yield and diastereoselectivity
were obtained.[14] The methodology suffers from the vigorous acidic
conditions required for hydrolytic cleavage of the imidazolidinone
intermediate, and is thus limited to the preparation of acid stable
products as in the present case.[14] Hydrolysis of the alkylation product
from the Schollkopf chiron (S )-2,5-dihydro-3,6-dimethoxy-2-isopropyl-
pyrazine is normally effected under mild acid conditions to furnish
the new amino acid. Good stereoselectivity in the alkylation reactions

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4212
Møller and Undheim
is often observed. However, the stereoselectivity was moderate with
the lithiated Schollkopf chiron and a,a0-dichloro-1,2-xylene.[13]
Moderate stereoselectivity has also been observed with related vicinal
dialkylating agents. It is our experience, however, that the diastereomeric
products are readily separated by flash chromatography.[13] In an
alternative approach for the preparation of benzene-1,2-bis(alanine), a
benzophenone-derived glycine imine was used as substrate for enantio-
selective alkylation under phase transfer conditions with chiral quater-
nary ammonium salts derived from cinchona alkaloids. The bridged
bis-imine product was formed in a moderate yield, but with high enantio-
meric excess using a,a0-dibromo-1,2-xylene. Subsequent hydrolysis under
mild acidic conditions furnished the amino acid.[7] In a second procedure,
the chiron (S,S )-1,4-bis(2-phenethyl)diketopiperazine was alkylated
with a,a0-dibromo-1,2-xylene resulting in high diastereoselectivity.
Strongly acidic conditions, 57% HI, were used for the hydrolysis to
furnish the amino acid product.[15]
RESULTS AND DISCUSSION
In a search for a versatile method which would allow access to both
aromatic, dihydro, and tetrahydro benzene rings inserted into the
C4-bridge, the 1,3-diene (2R,7R)-2,7-diacetamido-4,5-bis(methylene)
octane-1,8-dioic acid dimethyl ester (3) in Sch. 2 was the substrate.
The substrate 1 was prepared in a two-step process, initially by
alkylation of lithiated (S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-
pyrazine with 2,3-dibromopropene which proceeded with high diastereo-
selectivity (92%, de. 94%).[16] A subsequent homocoupling gave the
substrate 1 under Pd(0)-catalysis. Mild conditions for acid hydrolysis
provided the stereochemically pure diamine 2 (Sch. 2). For the
Diels-Alder reaction the amino groups were protected by acylation.
For simplicity acetylation was used to provide the substrate 3. In the
literature the diethyl ester analogue of the acetylated compound 3 has
been described as a stereoisomeric mixture after a preparation from ethyl
a-acetamido-4-tributylstannyl-4-pentenoate by
a copper(II) nitrate
mediated homocoupling process.[17] In a different approach, the lithium
enolate from the benzophenone imine of glycine ethyl ester and
1,4-dibromo-2,3-dimethylenebutane were reacted under the influence
of Pd(0)-catalysis to form the corresponding bis(imino) ester. Acid
hydrolysis of the product yielded a stereoisomeric mixture.[6]
An initial attempt to effect a Diels-Alder reaction with the bulky
diene 1 as substrate was unsatisfactory. The homocoupled diene 1 was

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Enantiomeric Benzene-1,2-bis(alanine) Derivatives
4213
Scheme 2.
therefore hydrolyzed to the corresponding amino acid and the amino
groups protected by acetylation. Anisole was found to be a good solvent
for the Diels-Alder reaction at 180ꢀC. The principle is illustrated with
ethyl propiolate and diethyl acetylenedicarboxylate as dienophiles. High
yields of the dihydrobenzene adducts 4 and 5 resulted. The products
belong to the group D classification in Sch. 1.
Aromatization reactions with activated manganese dioxide gave the
benzene bis(amino acid) derivatives 6 and 7 in almost quantitative yields.
For the preparation of tetrahydrobenzene-bridged dicarba analogues
E of cystine (Sch. 1), olefinic dienophiles were used. From the reaction
with methyl vinyl ketone the tetrahydro derivative 8 was isolated as a
stereoisomeric 1:1 mixture. The apparent lack of stereoselectivity may
result from epimerization of the acetyl group under the conditions of
the reaction, or simply for lack of stereocontrol in the adduct formation.
With N-phenylmaleinimide as dienophile, the tetrahydrobenzene
adduct 9 was isolated in high yield.
In conclusion, we describe a versatile method for the preparation of
substituted benzene-, dihydrobenzene-, and tetrahydrobenzene-1,2-bis
(alanine) derivatives as sterically constrained dicarba analogues of

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4214
Møller and Undheim
Scheme 3.
cystine. The partially saturated products resulted from Diels-Alder
adduct formation with stereoselectively prepared (2R,7R)-2,7-diacet-
amido-4,5-bis(methylene)octane-1,8-dioic acid dimethyl ester. Aroma-
tization of the dihydro Diels-Alder adducts by manganese dioxide
provided the parent benzene-1,2-bis(alanine) derivatives.
EXPERIMENTAL
1
The H NMR spectra were recorded at 200 MHz or 300 MHz and
the 13C NMR spectra at 50 MHz or 75 MHz. The mass spectra under
electron impact conditions were recorded at 70 eV (EI). Methane was
used for chemical ionization (CI). The spectra are presented as m/z
(% rel. int). Infrared spectra were recorded on a Nicolet Magna FT-IR
550 spectrometer using ATR (attenuated total reflectance).
(2R,7R)-2,7-Diacetamido-4,5-bis(methylene)octane-1,8-dioic acid dimethyl
ester (3). Acetic anhydride (0.44 g, 4.32 mmol) in dry dichlorometane
(5 mL) was added dropwise to a solution of (2R,7R)-2,7-diamino-4,5-bis
(methylene)octane-1,8-dioic acid dimethyl ester (2) (0.46 g, 1.79 mmol) and
4-(N,N-dimethylamino)pyridine (0.53 g, 4.32 mmol) in dry dichloromethane
(20 mL) under argon at 0ꢀC. The mixture was stirred at 0ꢀC for 2h, at
ambient temperature for 3 h, diluted with dichloromethane, and washed
with 10% aqueous ammonium chloride. The dried (MgSO4) solution was
evaporated, and the product was purified by flash chromatography on silica
gel using CH2Cl2:MeOH 20:1. Yield: 0.58 g (94%) of a yellow solid.

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Enantiomeric Benzene-1,2-bis(alanine) Derivatives
4215
M.p.: 207–210ꢀC. Found: C, 56.04; H, 7.13. Calcd. for C16H24N2O6: C, 56.46;
H, 7.11%. [a]D ꢁ48.6 (c¼ 0.0078 in CHCl3). IR (ATR plate): ꢀmax cmꢁ1 3292
(m), 3078 (w), 2999 (w), 2955 (m), 1740 (s), 1743 (s), 1652 (s), 1655 (s), 1541
(m), 1436 (m), 1374 (m), 1270 (w), 1208 (m), 1013 (w), 909 (w), 752 (w).
1HNMR (CDCl3): ꢁ 1.99 (s, 6H, 2 ꢂ C-CH3), 2.71 (dd, J 6.2 and 14.3 Hz,
2H, 2 ꢂ CH2C¼), 2.86 (dd, J 5.1 and 14.3 Hz, 2H, 2 ꢂ CH2C¼), 3.71 (s, 6H,
2ꢂ OCH3), 4.69 (ddd, J 5.1, 6.2 and 8.3 Hz, 2H, 2 ꢂ CHCH2), 4.97 (s, 2H,
2ꢂ ¼CH2), 5.19 (s, 2H, 2 ꢂ ¼CH2), 6.69 (d, J 8.3 Hz, 2H, 2 ꢂ NH).
13CNMR (CDCl3):
ꢁ
23.5 (2 ꢂ C-CH3), 36.7 (2 ꢂ CH2C¼), 51.3
(2 ꢂ NCHCH2), 52.6 (2 ꢂ OCH3), 116.5 (2 ꢂ ¼CH2), 140.3 (2 ꢂ C¼CH2),
168.9 (2 ꢂ NC¼O), 171.7 (2 ꢂ OC¼O). MS(EI): 340 (2, Mþ), 309 (2), 297
(5), 281 (7), 222 (19), 210 (100), 190 (18), 180 (40), 168 (67), 150 (39), 108 (70),
88 (82), 43 (74).
Dimethyl (20R,200R)-3,6-dihydro-4-ethoxycarbonylbenzene-1,2-bis(20-
acetamido-30-propionate) (4). (2R,7R)-2,7-Diacetamido-4,5-bis(methy-
lene) octane-1,8-dioic acid dimethyl ester (3) (63 mg, 0.186 mmol) and
ethyl propiolate (24 mg, 0.242 mmol) were heated together in dry anisole
(2.5 mL) in a sealed tube at 180ꢀC for 14 h. The anisole was removed by
distillation at reduced pressure and the residual product was purified by
flash chromatography on silica gel using CH2Cl2:MeOH 20:1. Yield:
78 mg (96%) of a yellow-white solid. M.p.: 146–149ꢀC. [a]D ꢁ34.6
(c ¼ 0.073 in CHCl3). IR (ATR plate): ꢀmax cmꢁ1 3287 (m), 3069 (w),
2984 (w), 2955 (m), 2852 (w), 1744 (s), 1718 (s), 1655 (s), 1541 (m),
1437 (m), 1373 (m), 1274 (s), 1216 (s), 1179 (m), 1134 (m), 1022 (m),
1
758 (m). H NMR (CDCl3): ꢁ 1.24 (t, J 7.1 Hz, 3H, CH2CH3), 1.96 (s,
3H, COCH3), 1.97 (s, 3H, COCH3), 2.38 (dd, J 9.5 and 14 Hz, 1H,
CH2CCH2C), 2.46 (dd, J 9.4 and 14 Hz, 1H, CH2CCH2CH), 2.55 (dd,
J 6.5 and 14 Hz, 1H, CH2CCH2CH), 2.60 (dd, J 6.0 and 14.0 Hz, 1H,
CH2CCH2C), 2.82 (s, 4H, ¼CHCH2 and ¼CCH2C¼), 3.69 (s, 3H,
OCH3), 3.70 (s, 3H, OCH3), 4.14 (q, J 7.1 Hz, 2H, CH2CH3), 4.5–4.8
(m, 2H, 2 ꢂ CH-NH), 6.58 (d, J 7.7 Hz, 1H, NH), 6.72 (d, J 7.4 Hz, 1H,
NH), 6.84 (s, 1H, ¼CH-CH2). 13C NMR (CDCl3): ꢁ 14.2 (CH2CH3),
22.7, 22.8 (2 ꢂ NCOCH3), 30.2, 31.5 (¼CHCH2 and ¼CCH2C¼), 34.4
(NCHCH2), 35.0 (NCHCH2), 50.6, 51.0 (2 ꢂ NCHCH2), 52.5
(2 ꢂ OCH3), 60.5 (CH2CH3), 125.4 (NCHCH2), 127.2, 127.3
(3 ꢂ ¼C-CH2), 135.2 (¼CHCH2), 166.3 (C¼CCO2), 170.4, 170.5
(2 ꢂ NHC¼O), 172.7, 172.8 (2 ꢂ CH-CO2). MS(EI): 438 (2, Mþ), 437
(5), 409 (14), 395 (1), 393 (4), 364 (6), 349 (2), 332 (13), 294 (11), 262
(27), 248 (32), 204 (23), 88 (48), 43 (100).
Dimethyl (20R,200R)-3,6-dihydro-4,5-bis(ethoxycarbonyl)benzene-1,2-
bis(20-acetamido-30-propionate) (5). (2R,7R)-2,7-Diacetamido-4,5-bis
(methylene)octane-1,8-dioic acid dimethyl ester (3) (64 mg, 0.188 mmol)

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4216
Møller and Undheim
and diethyl acetylenedicarboxylate (42 mg, 0.245 mmol) were heated
together in dry anisole (2.5 mL) in a sealed tube at 180ꢀC for 14 h. The
anisole was distilled off at reduced pressure and the product was purified
by flash chromatography on silica gel using CH2Cl2:MeOH 20:1. Yield:
70 mg (73%) of a white solid. M.p.: 150–153ꢀC. HRMS: Calcd. for
C24H34N2O10: 510.2213. Found: 510.2203. [a]D ꢁ36.8 (c ¼ 0.0176 in
CHCl3). IR (ATR plate): ꢀmax cmꢁ1 3280 (m), 3065 (w), 2985 (m), 2956
(w), 1732 (s), 1728 (s), 1659 (s), 1542 (m), 1438 (m), 1371 (m), 1297 (s),
1
1219 (s), 1176 (m), 1140 (m), 1037 (m), 1022 (m), 755 (m). H NMR
(CDCl3): ꢁ 1.25 (t, J 7.1 Hz, 6H, 2 ꢂ CH2CH3), 1.98 (s, 6H, 2 ꢂ CCH3),
2.42 (dd, J 9.3 and 14.2 Hz, 2H, 2 ꢂ CHCH2), 2.59 dd, J 6.3 and 14.2 Hz,
2H, 2 ꢂ CHCH2), 2.93 (s, 4H, 2 ꢂ ¼CCH2C¼), 3.70 (s, 6H, 2 ꢂ OCH3),
4.18 (q, J 7.1 Hz, 4H, 2 ꢂ CH2CH3), 4.64 (ddd, J 6.3, 7.4 and 9.3 Hz, 2H,
2 ꢂ CHCH2), 6.64 (d, J 7.4 Hz, 2H, 2 ꢂ NH). 13C NMR (CDCl3): ꢁ 14.0
(2 ꢂ CH2CH3), 22.7 (2 ꢂ CCH3), 32.3 (2 ꢂ ¼CCH2C¼), 34.5 (2 ꢂ
CHCH2), 50.7 (2 ꢂ NCHCH2), 52.5 (2 ꢂ OCH3), 61.3 (2 ꢂ CH2CH3),
125.7 (2 ꢂ CHCH2-C¼), 131.7 (2 ꢂ ¼CC¼O), 167.2 (2 ꢂ C¼C-CO2),
170.4 (2 ꢂ NC¼O), 172.5 (2 ꢂ CHCO2). MS(EI): 510 (2, Mþ), 481 (6),
479 (4), 451 (2), 435 (20), 393 (20), 380 (3), 366 (17), 334 (17), 320 (100),
276 (21), 264 (12), 250 (13), 245 (12), 204 (19), 88 (22), 43 (31).
Dimethyl
(20R,200R)-4-ethoxycarbonylbenzene-1,2-bis(20-acetamido-
3-propionate) (6). Dimethyl (20R,200R)-3,6-dihydro-4-ethoxycarbonyl-
benzene-1,2-bis(20-acetamido-30-propionate) (4) (68 mg, 0.155 mmol)
was stirred together with activated manganese dioxide (310 mg) in
dioxane (5 mL) at ambient temperature for 3 h. The reaction mixture
was filtered, the filtrate evaporated and the product further purified by
flash chromatography on silica gel using CH2Cl2:MeOH 20:1. Yield:
66 mg (98%) of a yellow-white solid. M.p.: 152–156ꢀC. HRMS: Calcd.
for C21H28N2O8: 436.1845. Found: 436.1835. [a]D ꢁ38.1 (c ¼ 0.032 in
CHCl3). IR (ATR plate): ꢀmax cmꢁ1 3287 (m), 3061 (w), 2985 (w), 2955
(m), 1745 (s), 1720 (s), 1657 (s), 1547 (m), 1537 (m), 1437 (m), 1372 (m),
1275 (s), 1215 (s), 1179 (m), 1135 (m), 1023 (m), 756 (m). 1H NMR
(CDCl3): ꢁ 1.33 (t, J 7.1 Hz, 3H, CH2CH3), 1.85 (s, 3H, NCOCH3),
1.87 (s, 3H, NCOCH3), 2.96 (dd, J 9.0 and 14.3 Hz, 1H, CHCH2), 3.04
(dd, J 9.2 and 14.6 Hz, 1H, CHCH2), 3.22 (dd, J 6.0 and 14.6 Hz, 1H,
CHCH2), 3.24 (dd, J 5.8 and 14.3 Hz, 1H, CHCH), 3.68 (s, 3H, OCH3),
3.71 (s, 3H, OCH3), 4.30 (q, J 7.1 Hz, 2H, CH2CH3), 4.7–5.0 (m, 2H,
2 ꢂ CHNH), 6.59 (d, J 7.8 Hz, 1H, NH), 6.72 (d, J 7.4 Hz, 1H, NH), 7.16
(d, J 8.0 Hz, 1H, H-5), 7.73 (d, J 1.8 Hz, 1H, H-2), 7.79 (dd, J 1.8 and
8.0 Hz, 1H, H-6). 13C NMR (CDC3): ꢁ 14.2 (CH2CH3), 22.5, 22.6
(2 ꢂ NCOCH3), 34.4, 34.9 (2 ꢂ NCHCH2), 52.1, 52.2 (2 ꢂ NCHCH2),
52.4, 52.5 (2 ꢂ OCH3), 60.9 (CH2CH3), 128.2 (C-6), 129.1 (C-1), 129.7

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Enantiomeric Benzene-1,2-bis(alanine) Derivatives
4217
(C-5), 131.3 (C-2), 135.1 (C-3), 140.2 (C-4), 166.1 (Ar-CO2), 170.0, 170.3
(2 ꢂ NHC¼O), 172.1, 172.2 (2 ꢂ CH-CO2). MS(EI): 436 (37, Mþ),
405 (10), 404 (34), 393 (16), 391 (14), 377 (15), 362 (11), 347 (7), 331
(18), 318 (25), 307 (15), 286 (20), 276 (44), 258 (72), 216 (85), 204 (62),
88 (64), 43 (100).
Dimethyl (2R0,200R)-4,5-bis(ethoxycarbonyl)benzene-1,2-bis(20-acet-
amido-30-propionate (7). Dimethyl (20R,200R)-3,6-dihydro-4,5-bis(ethoxy-
carbonyl)benzene-1,2-bis(20-acetamido-30-propionate) (5) (54 mg, 0.106
mmol) was stirred together with activated manganese dioxide (250 mg)
in dioxane (5 mL) at ambient temperature for 3 h, the reaction mixture
filtered, the filtrate evaporated and the residual material subjected to flash
chromatography on silica gel using CH2Cl2:MeOH 20:1. Yield: 52 mg
(98%) of a white solid. M.p.: 139–142ꢀC. HRMS: Calcd. for
C24H32N2O10: 508.2057. Found: 508.2059. [a]D ꢁ35.5 (c ¼ 0.049 in
CHCl3). IR (ATR plate): ꢀmax cmꢁ1 3281 (m), 3062 (w), 2984 (m), 2956
(m), 1728 (s), 1656 (s), 1546 (m), 1537 (m), 1438 (m), 1371 (m), 1297 (s),
1219 (s), 1139 (m), 1037 (m), 1022 (m), 755 (m). 1H NMR (CDCl3): ꢁ 1.32
(t, J 7.1 Hz, 6H, 2 ꢂ CH2CH3), 1.90 (s, 6H, 2 ꢂ NCOCH3), 3.05 (dd, J 8.3
and 14.4 Hz, 2H, 2 ꢂ CHCH2), 3.21 (dd, J 6.3 and 14.4 Hz, 2H,
2 ꢂ CHCH2), 3.70 (s, 6H, 2 ꢂ OCH3), 4.30 (q,
J 7.1 Hz, 4H,
2 ꢂ CH2CH3), 4.83 (ddd, J 6.3, 7.4 and J 8.3 Hz, 2H, 2 ꢂ NCHCH2),
6.55 (d, J 7.4 Hz, 2H, 2 ꢂ NH), 7.41 (s, H-3, H-6). 13C NMR (CDCl3):
ꢁ 14.1 (2 ꢂ CH2CH3), 22.8 (2 ꢂ NCOCH3), 34.6 (2 ꢂ NCHCH2), 52.2
(2 ꢂ NCHCH2), 52.6 (2 ꢂ OCH3), 61.7 (2 ꢂ CH2CH3), 130.6 (C-1, C-2),
130.8 (C-3, C-6), 138.4 (C-4, C-5), 167.0 (2 ꢂ Ar-CO2), 170.2
(2 ꢂ NHC¼O), 171.9 (2 ꢂ CH-CO2). MS(EI): 508 (15, Mþ), 477 (3),
463 (35), 449 (6), 433 (49), 419 (6), 403 (37), 391 (18), 379 (16), 362
(41), 344 (17), 333 (56), 304 (32), 288 (21), 274 (89), 44 (100).
Dimethyl
(20R,200R)-4-acetyl-3,4,5,6-tetrahydrobenzene-1,2-bis(20-
acetamido-30-propionate) (8). (2R,7R)-2,7-Diacetamido-4,5-bis(methy-
lene) octane-1,8-dioic acid dimethyl ester (3) (72 mg, 0.212 mmol) and
methyl vinyl ketone (19 mg, 0.275 mmol) were heated together in dry
anisole (2.5 mL) in a sealed tube at 180ꢀC for 14 h. The anisole was
distilled off at reduced pressure and the residual material subjected to
flash chromatography on silica gel using CH2Cl2:MeOH 20:1. Yield:
61 mg (70%) of a yellow oil. HRMS: Calcd. for C20H30N2O7: 410.2053.
1
Found: 410.2049. H NMR (CDCl3): ꢁ 1.4–2.0 (m, 2H, CH2CH2CH),
1.98 (s, 3H, NCOCH3), 2.00 (s, 3H, NCOCH3), 1.9–2.2 (m, 4H,
CH2CHCH2C¼ and ¼CCH2CH2), 2.14 (s, 3H, CHCOCH3), 2.3–2.7
(m, 5H, 2 ꢂ NCHCH2 and CHCOCH3), 3.70 (s, 3H, OCH3), 3.71 (s,
3H, OCH3), 4.5–4.8 (m, 2H, 2 ꢂ NCHCH2), 6.39 (d, J 7.6 Hz, 1H,
NH), 6.5–6.7 (m, 1H, NH). 13C NMR (CDCl3):
ꢁ 22.8, 22.9

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4218
Møller and Undheim
(2 ꢂ NCOCH3), 24.7 (CH2CH2CH), 27.8, 27.9 (CHCOCH3), 28.3, 28.8,
30.6, 31.1 (CH2CHCH2C¼ and CH2CH2CH), 35.0, 35.3, 35.4
(2 ꢂ NCHCH2), 46.9, 47.3 (CH2CHCH2), 50.7, 50.8, 50.9, 51.2
(2 ꢂ NCHCH2), 52.5 (2 ꢂ OCH3), 128.1, 128.9, 129.0 (2 ꢂ CH2C¼), 170.2,
170.3, 170.4 (2 ꢂ NC¼O), 172.7, 172.8, 172.9 (2 ꢂ CHCO2), 210.7, 210.8
(CHCOCH3). MS(EI): 410 (3, Mþ), 379 (2), 267 (2), 351 (2), 319 (19), 280
(75), 260 (6), 250 (10), 238 (31), 179 (52), 88 (62), 43 (100).
Dimethyl (R,R)-a,a0-acetamido-1,2,3,6-tetrahydro-N-phenylphthali-
mide-4,5-dipropionate (9). (R,R)-2,7-Diacetamido-4,5-bis(methylene)
octane-1,8-dioic acid dimethyl ester (71 mg, 0.206 mmol) and N-phenyl-
maleimide (47 mg, 0.269 mmol) were heated together in anisole (2.5 mL)
at 180ꢀC for 14 h. The solution was evaporated to dryness at reduced
pressure and the product was isolated from the residue by flash chroma-
tography on silica gel using CH2Cl2:MeOH 20:1. Yield: 82 mg (77%) of a
yellow–white solid. M.p.: 88–90ꢀC. HRMS: Calcd. for C26H31N3O8:
513.2111. Found: 513.2109. [a]D ꢁ35.5 (c ¼ 0.0049 in CHCl3). IR
(ATR plate): ꢀmax cmꢁ1 3357 (m), 3288 (m), 3064 (w), 3008 (w), 2955
(m), 2851 (w), 1741 (s), 1707 (s), 1654 (s) 1540 (m), 1500 (m), 1437 (m),
1
1379 (m), 1206 (m), 753 (m). H NMR (CDCl3): ꢁ 1.92 (s, 3H, C-CH3),
1.94 (s, 3H, C-CH3), 2.2–2.8 (m, 8H, 4 ꢂ CHCH2), 3.1–3.4 (m, 2H,
2 ꢂ NCO-CH), 3.67, 3.68 (s, 3H, 2 ꢂ OCH3), 4.5–4.8 (m, 2H,
2 ꢂ CHNH), 6.53 (d, J 8.0 Hz, 1H, NH), 6.67 (d, J 7.7 Hz, 1H, NH).
13C NMR (CDCl3):
ꢁ
22.6 (NCOCH3), 22.7 (NCOCH3),
28.6 (NCOCHCH2), 29.3 (NCOCHCH2), 34.9 (NCHCH2), 35.2
(NCHCH2), 39.3 (NCOCH), 39.6, (NCOCH), 50.8 (NCHCH2), 51.6
(NCHCH2), 52.4 and 52.5 (2 ꢂ OCH3), 126.1 (C-2, C-6), 128.5 (C-4),
128.9 (C-3, C-5), 131.3 (CH2C¼), 131.4 (CH2C¼), 131.7 (C-1), 170.2
(NHC¼O), 170.3 (NHC¼O), 172.1 (CH-CO2), 172.5 (CH-CO2),
178.7, 179.0 (2 ꢂ NCOCH). MS(EI): 513 (10, Mþ), 482 (7), 454 (8),
422 (29), 395 (5), 383 (100), 363 (32), 353 (21), 341 (80), 335 (20), 324
(20), 293 (60), 281 (50).
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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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Received in the UK July 4, 2003