Synthesis of benzene-1-alanine-3-glycine as carba analogues of cystine

Article abstract of DOI:10.1081/SCC-200048407

Methodology has been developed for the synthesis of C₄-carba- bridged cystine analogues with a 1,3-disubstituted phenyl group inserted into the chain. Stereoselective bromobenzylation of the Schoellkopf chiron and a subsequent bromine-lithium e

Full text of DOI:10.1081/SCC-200048407

Synthetic Communicationsw, 35: 193–200, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048407
Synthesis of Benzene-1-Alanine-3-Glycine as
Carba Analogues of Cystine
Eline Bredal Furenes, Jaco Luijendijk,
Jon Efskind, and Kjell Undheim
Department of Chemistry, University of Oslo, Oslo, Norway
Abstract: Methodology has been developed for the synthesis of C4-carba-bridged
cystine analogues with a 1,3-disubstituted phenyl group inserted into the chain. Stereo-
¨
selective bromobenzylation of the Schollkopf chiron and a subsequent bromine-lithium
exchange provided a lithiated species for conversion to a higher order cyanocuprate.
The latter was cross-coupled with an a-bromoacylaminoacetate. Subsequent mild
acid hydrolysis provided orthogonally protected amino acids.
Keywords: Cystine substitutes, carba-bridged cystines, benzene-1-alanine-3-glycine,
mixed arylhomocuprate alkylation
INTRODUCTION
Cystine is a disulfide that constitutes a main structural element in peptide and
protein architectures. When cystine exerts mainly a skeletal, structural
function, isosteric structures may be envisaged to take its place. We have
for some time been involved in the preparation of conformationally con-
strained a-amino acids as carba-analogues of cystine.[1] Conformational con-
straints that affect secondary and tertiary peptide structures by incorporation
of noncoded amino acids may provide useful information and understanding
of structural requirements for bioactivity.[7,8]
Cystine can be regarded as a four-atom bridged bis(a-amino acid). The
–CH2SSCH2- bridge between the two glycine moieties in cystine has been
Received in Poland October 25, 2004
Address correspondence to Kjell Undheim, Department of Chemistry, University of
Oslo, N-0315, Oslo, Norway. Fax: þ47 22855507; E-mail: kjellu@kjemi.uio.no

194
E. B. Furenes et al.
replaced with all-carbon C4-bridges between the a-carbon of the glycines.
Conformational constraints have been conferred on these molecules by
insertion of aromatic or heteroaromatic rings.[1] In Scheme 1, cystine has
been drawn in a cisoid form A. A vicinal bis(alanine) substituted benzene
can be regarded as dicarba analogues of cystine as indicated by structure
B.[2–4] A phenyl ring carrying two glycine functionalities in the 1,4-
positions constitutes another C4-bridge as in structure C.[5]
A third possibility for a C4-bridge would be a benzene substituted with an
alanine and a glycine unit in a 1,3-relationship as in structure D. This report
describes an initial effort to develop methodology for the preparation of
structure D carba analogues of cystine. The para-analogue, the 1,4-isomer,
is also included in this attempt to develop new methodology and can be
regarded as a carba-C5 homologue of cystine.
RESULTS AND DISCUSSION
The synthesis involved initial introduction in a stereoselective manner of the
alanine unit and thereafter the glycine unit. The former operation was by alky-
¨
lation of the lithiated Schollkopf chiron (2R)-2-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazine at 2788C with 3- and 4-bromobenzyl bromide, respectively.
Scheme 2 shows high yields of the benzylated products 2 and high diastereo-
selectivity. Any unwanted diastereomer was removed during flash chro-
matography. Pure enantiomers were used in the subsequent work. The
electrophile carries a bromine substituent in the benzene ring for a subsequent
metal-mediated carbon-carbon bond formation in the construction of the
glycine unit. The bromobenzene substrates 2 were lithiated by nBuLi. Selec-
tivity for halogen-metal exchange was seen, and no significant proton abstrac-
tion from the heterocyclic 2-position was observed. Nor did we observe any
¨
significant metal-halogen exchange between the lithiated Schollkopf inter-
mediate and the bromine in the benzene ring. The findings agree with
results reported recently over lithiation of the 4-bromo derivative 2b.[6]
Scheme 1.

Synthesis of C4-Carba-Bridged Cystine Analogues
195
Scheme 2.
For the introduction of the glycine unit, we have successfully adapted the
methodology developed by Steglich with an electrophilic glycine equivalent
in the form of an N-acylamino-2-bromoacetate and cross-coupling with
higher order mixed cuprates.[9] As electrophile, we used a-bromohippuric
acid ethyl ester, which was prepared from the hippuric ester and NBS in the
presence of AIBN.[10]
In the cuprate-mediated coupling, a mixed higher order cuprate was used
¨
to facilitate a high conversion of the valuable Schollkopf intermediate 2. As
recommended by Lipshutz, the dummy ligand was the 2-thienyl substituent,
which has a low transfer rate from the complex.[11,12] The mixed higher
order cuprate was prepared from the 2-thienyl lower order cuprate (2-
Th)Cu(CN)Li, which was mixed with the lithiated benzyl intermediate 3 at
2788C to form the mixed cuprate 4, before a solution of the a-bromohippuric
ester 6 was added. The coupling reaction proceeded for 2.5 hr at 08C. The
protected glycine products 5a and 5b were obtained in 56 and 60% yield,
respectively.
The bromoglycine reactant 6 is a racemate. The products 5 are diastereo-
meric mixtures at the glycyl carbon, and chromatography and NMR spectra
were consistent with a 1 : 1 stereoisomeric relationship. Both stereoisomers
possessed very similar chromatographic properties. No serious attempt was
made in this preliminary work to carry out a separation of the stereoisomers.
The stereoisomeric mixtures of products were hydrolyzed by 0.1 M TFA
in acetonitrile to provide the phenyl-bridged glycine-alanine derivatives 7 and
8 in high yields (Scheme 3).
All the functional groups in the products 7 and 8 are differently protected.
This approach in principle provides orthogonally protected bridged amino

196
E. B. Furenes et al.
Scheme 3.
acids. A change of the protecting group in glycine from benzoyl to benzylox-
ycarbonyl would provide useful building units for peptide chemistry once
enantiomeric molecules become available from a separation of diasteromers
at some intermediate step in this synthesis, or by stereoselective introduction
of the glycine moiety.
In conclusion, a method for the preparation of (benzene-1-a-alanine-3-a-
glycine)benzene is described. Main reactions are a stereoselective bromoben-
¨
zylation of the Schollkopf chiron and a subsequent bromine-lithium exchange
before conversion to a higher order cuprate and cross-coupling with an
a-bromoacylaminoacetate. Subsequent mild hydrolysis provides orthogonally
protected amino acids.
EXPERIMENTAL
1H NMR spectra were recorded in CDCl3 at 500 or 300 MHz with Bruker DPX
500, DPX. The 13C spectra were recorded in CDCl3 at 125 MHz on a Bruker
DPX 500, or at 75 MHz with DPX 300 instrument. Chemical shifts are
reported in ppm with residual CHCl3 (7.24 ppm) and CDCl3 (77 ppm) as refer-
ences. J values are given in Hz.
Dry THF was distilled from sodium and benzophenone under argon.
(2S,5R)-2-(3-Bromobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazine (2a)
A solution of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.00 g,
5.43 mmol) in THF (40 mL) under argon was lithiated by the addition of
nBuLi (4.33 mL, 1.3 M in hexane) at 2788C, the mixture stirred at this temp-
erature for 30 min, and a solution of 3-bromobenzyl bromide (1.49 g,

Synthesis of C4-Carba-Bridged Cystine Analogues
197
5.96 mmol) in THF (10 mL) was added dropwise. The resultant mixture was
stirred at 2788C for 1 hr and allowed to reach ambient temperature
overnight. The reaction was terminated by addition of saturated aqueous
ammonium chloride and the mixture extracted with diethyl ether
(2 ꢀ 15 mL), the extracts dried (MgSO4) and the solvent distilled off. The
residue was subjected to flash chromatography on silica gel using 30% Et2O
in hexane. The product was a colorless oily material; yield 1.18 g (95%).
(Found: C, 54.59; H, 5.96; N, 7.94. Calc. for C16H21BrN202: C, 54.40; H,
5.99; N, 7.93%). HRMS: M 354.0778. Calc. for C16H21Br81N2O3:
354.0766; nmax(film/cm21) 2960 (m), 2943 (m), 1697 (s), 1567 (w), 1435
(m), 1239 (s), 1195 (m), 1111 (w), 1015 (m); dH(CDCl3) 0.60 and 0.94
(d, 2 ꢀ 3H, J 6.8 Hz, CH(CH3)2), 2.12–2.19 (dsep, 1H, J 2.8 and 6.8 Hz,
CH(CH3)), 3.01–3.07 (m, 2H, CH2Ph), 3.41–3.43 (m, 1H, H-2), 3.66, 3.69
(2 ꢀ s, 6H, 2 ꢀ OCH3), 4.26 (dd, 1H, J 2.8 Hz, H-5), 7.00–7.08, 7.00–7.31
(m, 4H, Ar); dC(CDCl3) 16.4 and 18.9 (CH(CH3)2), 31.3 (CH(CH3)2), 39.5
(CH2Ph), 52.1, 52.3 (2 ꢀ OCH3), 56.2 (C-5), 60.3 (C-2), 121.7 (Ar-Br),
128.3, 129.3 (4 ꢀ C, Ar), 136.4 (C-Ar), 162.0, 163.9 (C-3, C-6); m/z (EI)
354 (11%, Mþ), 352 (11, Mþ), 184 (9), 183 (78), 182 (12), 171 (10), 169
(11), 142 (8), 141 (100), 140 (6).
(2S,5R)-2-(4-Bromobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazine (2b)
Compound 2b was prepared as above using 4-bromobenzyl bromide; yield
92% of a white solid material. A similar synthesis has recently been
described, and the compound characterised by spectroscopy.[6]
(2R/S,2S0,5R0)-2-Benzoylamino-2-[3-(5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-ylmethyl)phenyl]acetic acid ethyl ester (5a)
A solution of 2-lithiated thiophene (1.25 mmol) in THF (5 mL) was added
dropwise to anhydrous CuCN (112 mg, 1.25 mmol) in THF (1 mL) at
2788C under argon. The mixture was warmed to 08C to provide a clear
solution, which was cooled down again to 2788C. Subsequently, a solution
of lithiated (2S,5R)-2-(3-bromobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazine 2a (1.12 mmol) in THF (10 mL) was added. The lithiated
species was prepared by treating the bromo derivative 2a (394 mg,
1.25 mmol) in THF (10 mL) with nBuLi (1.25 mmol). The resultant solution
was allowed to reach 08C, subsequently recooled to 2788C and a solution
of 2-benzoylamino-2-bromoacetic acid ethyl ester 6 (286 mg, 1.0 mmol) in
THF (1 mL) added. The reaction mixture was allowed to reach 08C and
stirred at this temperature for 2.5 hr. The reaction was quenched by addition
of saturated aqueous ammonium chloride. The two phases were separated,
the aqueous phase extracted with diethyl ether, the combined ether solutions

198
E. B. Furenes et al.
dried (MgSO4), filtered, and evaporated. The residual material was subjected
to flash chromatography on silica gel using EtOAC:hexane 3 : 7. The product
was a pale yellow oily material; yield 283 mg (56%). (Found: C, 67.75; H,
7.66; N, 8.44. Calc. for C27H33N3O5: C, 67.62; H, 7.64; N 8.64%). HRMS:
M 480.2479. Calc. for C27H33N3O5: 480.2454; nmax(film/cm21) 3029(w),
2959 (s), 2943 (s), 2871 (m), 1737 (w), 1697 (s), 1461 (m), 1436 (m), 1366
(m), 1308 (m), 1239 (s), 1014 (s); dH(CDCl3) 0.61 and 0.94 (2 ꢀ d, 2 ꢀ 3
H, J 6.8 Hz, CH(CH3)2), 1.23 (2 ꢀ t, 3H, OCH2CH3), 2.07–2.19 (m, 1H,
CH(CH3)2), 3.05–3.07(m, 2H, J 4.9 Hz, CH2Ar), 3.30–3.33 (m, 1H, H-2),
3.67, 3.71 (2 ꢀ d, 6H, 2 ꢀ OCH3), 4.17–4.24 (m, 2H, OCH2CH3), 4.26–
4.31 (m, 1H, H-5), 5.69–5.73 (m, 1H, CHNH), 7.03 (d, 1H, J 8.1 Hz, NH),
7.09–7.11, 7.24–7.39, 741–7.46, and 7.78–7.80 (9H, Ar); dC(CDCl3) 13.8,
13.9 (2 ꢀ OCH2CH3), 14.1 (CH(CH3)2), 18.8 and 18,9 (CH(CH3)2), 31.0
(CH(CH3)2), 39.6 (CH2Ar), 52.2, 52.3 (2 ꢀ OCH3), 56.3 (C-5), 56.5
(CHNH), 60.2 (C-2), 126.7 (CH, Ar), 126.7, 128.5 (CH, Ar), 130.5 (CH,
Ar), 131.7 (CH, Ar), 133.7 134.5, 138.0 (3 ꢀ C, Ar), 162.3, 163.9
(2 ꢀ CO), 166.5, 171.0 (C-3, C-6); m/z (EI) 479 (8%, Mþ), 406 (16), 298
(10), 297 (64), 250 (11), 223 (6), 184 (12), 177 (12), 176 (82), 141 (100),
105 (76), 91 (12).
(2R/S,2S0,50R)-2-Benzoylamino-2-[4-(5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-ylmethyl)phenyl]acetic acid ethyl ester (5b)
Compound 5b was prepared as above from lithiated (2S,5R)-2-(4-bromobenzyl)-
5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine 2b (1.12 mmol), lithiated
thiophene (1.25 mmol), anhydrous CuCN (1.25 mmol) which as a higher
mixed cuprate was reacted with 2-benzoylamino-2-bromoacetic acid ethyl
ester 6 (1.0mmol) as described for 5a (see above). The product was isolated
in 60% yield (303mg) as a pale yellow oil after flash chromatography on
silica gel using EtOAc:hexane 3 : 7. (Found: C, 67.69; H, 7.01; N, 8.74. Calc.
for C26H33N3O5: C, 67.62; H, 6.94; N 8.78%). HRMS: M 480.2456. Calc. for
C26H33N3O5: 480.2454; nmax(film/cm21) 2960(m), 2871 (w), 1741 (m), 1697
(s), 1670 (m), 1515 (m), 1436 (m), 1239 (s), 1194 (m), 1015 (m); dH(CDCl3)
0.61 and 0.94 (2 ꢀ d, 6H, J 6.8 Hz, CH(CH3)2), 1.23 (t, 3H, J 7.0 Hz,
OCH2CH3), 2.11 (ds, 1H, J 2.8, 6.8 Hz, CH(CH3)2), 3.04–3.09 (m, 2H, J
4,9 Hz, CH2Ar), 3.29–3.33 (m, 1H, H-5), 3.67, 3.71 (2 ꢀ s, 6H, 2 ꢀ OCH3),
4.05–4.12 (m, 2H, CH2CH3), 4.21–4.24 (m, 1H, H-5), 5.63–5.67 (m, 1H,
CHNH), 7.22 (AB, 4H, Ar), 7.42–7.53, 7.80–7.83 (5H, Ph); dC(CDCl3) 13.5
(OCH2CH3), 16.4 and 18.9 (2 ꢀ CH(CH3)2), 31.2 (CH(CH3)2), 39.6 (CH2Ph),
52.1, 52.3 (2 ꢀ OCH3), 56.4 (C-5), 56.5 (CHNH), 60.2 (C-2), 65.8
(OCH2CH3), 126.7 (CH, Ar), 128.5 (CH, Ph), 130.5 (CH, Ar), 131.7 (CH,
Ph), 133.7 134.5, 138.0 (3 ꢀ C, Ar), 162.3, 163.9 (C-3, C-6), 171.0 (2 ꢀ CO);
m/z (EI) 479 (7%, Mþ), 406 (25), 298 (7), 297 (46), 250 (20), 223 (9), 184
(28), 183 (99), 176 (63), 141 (92), 105 (100), 91 (12).

Synthesis of C4-Carba-Bridged Cystine Analogues
199
Ethyl 2-benzoylamino-2-bromoacetate (6)[10]
A solution of ethyl 2-benzoylaminoacetate (9.98 g, 48.2 mmol), NBS (10.50 g,
48.2 mmol) and AIBN (200 mg) in dry tetrachloromethane (150 mL) was
heated under reflux for 5 hr, and the solvent distilled off at reduced
pressure. The residue was purified by crystallisation from EtOAc-hexane;
yield 11.30 g (82%) of a white crystalline material. dH(CDCl3) 1.35 (t, 3H,
J 7.1 Hz, CH2CH3), 4.34 (dq, 2H, J 0.7 and 7.1 Hz, CH2CH3), 6.63 (d, 1H,
J 10.1 Hz, CHBr), 7.41–7.56 (m, 3H, Ar), 7.81 (dd, 2H, Ar); dC(CDCl3)
13.8 (CH2CH3), 50.0 (CH2CH3), 63.2 (CHBr), 127.4 (2 ꢀ CH, Ar), 128.8
(2 ꢀ CH, Ar), 132.3 CH, Ar), 132.8 (1C, Cq, Ar), 165.6, 166.9 (2 ꢀ CO).
(2S,100R/S)-2-Amino-3-[3-(1-benzoylamino-1-
ethoxycarbonylmethyl]propionic acid methyl ester (7)
Trifluoroacetic acid (15 mL, 0.2 M) was added to a solution of (2R/S,2S0,5R0)-
2-benzoylamino-2-[3-(5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-
ylmethyl)phenyl]acetic acid ethyl ester 5a (124 mg, 0.28 mmol) in acetonitrile
(15 mL) and the solution stirred at ambient temperature for 3 days. The
reaction was quenched by dropwise addition of conc. aqueous ammonia to
pH 10, and the mixture extracted with dichloromethane (3 ꢀ 10 mL). The
organic solution was dried (MgSO4), filtered, evaporated and the residual
material subjected to flash chromatography on silica gel using 5% EtOH in
CH2Cl2. The product was a solid material; yield 79 mg (75%). HRMS: M
384.1685. Calc. for C21H24N2O2: 384.1672; nmax(film/cm21) 3370 (m),
2956 (m), 1739 (s), 1656 (m), 1580 (m), 1515 (s), 1487 (m), 1139 (m),
1178 (s), 1022 (m); dH(CDCl3) 1.22 (t, 3H, J 7.0 Hz, OCH2CH3), 1.99
(s, 2H, NH2), 2.81–2.90, 3.08–3.12 (m, 2H, CH2Ph), 3.67, (s, 3H, OCH3),
3.65–375 (m, 1 H, CHNH2), 4.10–4.31 (m, 2H, OCH2CH3), 5.72 (d, 1H,
CHNH), 7.11–7.21 (2 ꢀ CH, Ar and NH), 7.36–7.58 (5 ꢀ CH2Ar), 7.78–
7.81 (2 ꢀ 6H, Ar); dC(CDCl3) 14.0 (OCH2CH3), 52.0 (CH2Ph), 56.8 (OCH2
and OCH3), 62.1 (CHNH, CHNH2), 125.8, 127.1, 128.2, 128.6, 129.2,
129.5, 131.8 (CH, Ar), 133.6, 137.0, 137.9 (Cq, Ar), 166.5 (CO2Me),
CO2Et), 170.9 (COPh); m/z (EI) 384 (0.5%, Mþ), 326 (7), 325 (25), 311
(12), 298 (12), 297 (55), 251 (7), 250 (9), 223 (8), 204 (26), 190 (8), 177
(9), 176 (70), 147 (10), 105 (100), 104 (23).
(2S,100R/S)-2-Amino-3-[4-(1-benzoylamino-1-
ethoxycarbonylmethyl]propionic acid methyl ester (8)
Compound 8 was prepared as above from (2R/S,2S0,5R0)-2-benzoylamino-2-
[4-(5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-ylmethyl)phenyl]acetic
acid ethyl ester 5b (182 mg, 0.40 mmol) in acetonitrile (20 mL) and TFA
(20 mL, 0.2 M). The product was a pale yellow oily material; yield 129 mg

200
E. B. Furenes et al.
(84%). HRMS: M 384.1672. Calc. for C21H24N2O2: 384.1685; nmax(film/
cm21) 3366 (m), 2955 (m), 1739 (s), 1659 (m), 1609 (m), 1580 (m), 1524
(m), 1487 (m), 1446 (m), 1337 (m), 1197 (m), 1022 (m); dH(CDCl3) 1.19
(t, 3H, J 7.0 Hz, OCH2CH3), 1.52 (s, 2H, NH2), 2.75–3.11 (m, 2H, CH2Ph),
3.69, (s, 3H, OCH3), 3.67–3.73 (m, 1H, CHNH2), 4.06–4.34 (m, 2H,
OCH2CH3), 5.72 (d, 1H, CHNH), 7.11–7.23, (2 ꢀ CH2Ar, Ar and NH);
7.32–7.52 (5 ꢀ CH, Ar), 7.78–7.83 (2 ꢀ CH2Ar); dC (CDCl3) 14.0
(OCH2CH3), 52.0(CH2Ph), 55.6, 56.5(OCH2CH3 and OCH3), 62.4 (CHNH,
CHNH2), 127.1, 127.4, 127.5, 129.9, 131.8 (CH, Ar), 133.6, 135.2, 137.7
(C, Ar), 166.7, (CO2Me, CO2Et), 170.9 (COPh); m/z (EI) 384 (0.5%, Mþ)
326 (5), 325 (20), 311 (12), 298 (17), 297 (79), 251 (8), 224 (23), 147 (8),
106 (8), 105 (100), 77 (29).
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