Synthesis of highly functionalized phenylalanine derivatives via cross-enyne metathesis reactions

Article abstract of DOI:10.1016/S0040-4020(02)01178-X

A new method for the synthesis of constrained phenylalanine derivatives is described. In this regard, the simple synthesis of acyclic diene building blocks embodying an α-amino acid moiety has been achieved. The diene building blocks have been prepared by cross enyne-metathesis reaction as a key step. The Diels-Alder reaction of the dienes with a dienophile such as dimethyl acetylenedicarboxilate (DMAD) followed by oxidation of the resulting cycloadduct gave highly substituted phenylalanine derivatives.

Full text of DOI:10.1016/S0040-4020(02)01178-X

Tetrahedron 58 (2002) 9203–9208
Synthesis of highly functionalized phenylalanine derivatives via
cross-enyne metathesis reactions
*
Sambasivarao Kotha, Somnath Halder and Enugurthi Brahmachary
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai, 400 076, India
Received 7 June 2002; revised 26 August 2002; accepted 19 September 2002
Abstract—A new method for the synthesis of constrained phenylalanine derivatives is described. In this regard, the simple synthesis of
acyclic diene building blocks embodying an a-amino acid moiety has been achieved. The diene building blocks have been prepared by cross
enyne-metathesis reaction as a key step. The Diels–Alder reaction of the dienes with a dienophile such as dimethyl acetylenedicarboxilate
(DMAD) followed by oxidation of the resulting cycloadduct gave highly substituted phenylalanine derivatives. q 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
To explore our building block approach to unusual AAA
syntheses we were interested in preparing dienes such as 4,
that can deliver highly substituted Phe derivatives via the
Diels–Alder strategy. Compounds of type 4 have been
prepared via the palladium-catalyzed coupling reaction
between g-iodo allylglycine derivatives and alkenes.
However, the Diels–Alder chemistry of these dienes was
not explored.5 In this connection, we were interested in
developing an alternative strategy. Towards this goal,
initially we attempted alkylation of ethyl isocyanoacetate
with 2-bromomethyl-1,3-butadiene 56 and sulfolene bro-
mide 67 to prepare the diene 7 under several reaction
conditions and were unsuccessful (Scheme 1).8
Unusual a-amino acids (AAA) are useful in modulating the
stability and activity of therapeutically useful peptides.1 In
this respect the development of synthetic methods that can
generate a series of unusual AAA derivatives is useful for
structure–activity relationship. Towards this goal, we
conceived ‘building block approach’ that can deliver a
series of AAA derivatives with varing steric and electronic
properties.2–4 In this regard, we have synthesized dienes 1–
3 (Fig. 1) in our laboratory which are useful precursors for
the synthesis of highly functionalized 2-indanyl glycine and
Tic derivatives, which are the constrained analogs of
phenylalanine (Phe).3 Dienes 2 and 3 were prepared using
the enyne metathesis reaction as a key step. Also, in
connection with our interest to prepare cyclic amino acid
derivatives and peptides we have utilized ring-closing
metathesis as a key reaction.4 Here we describe the full
details for the preparation of various Phe derivatives using
the cross-enyne metathesis reaction as a key step.
To overcome these problems we considered a cross-enyne
metathesis reaction where 1,3-dienes can be generated from
alkyne and alkene moieties (Scheme 2). Grubbs catalyst
[bis(tricyclohexylphosphine)benzylidine ruthenium(lV)
dichloride] was used for the metathesis reactions in the
present study.
To prepare highly functionalized Phe derivative 9 by the
building block approach, it was considered that the diene
containing amino acid moiety can deliver the highly
Figure 1.
Keywords: amino acids and derivatives; metathesis; dienes; Diels–Alder
reaction.
*
Corresponding author. Fax: þ91-22-572-3480;
e-mail: srk@chem.iitb.ac.in
Scheme 1. (i) Base (ii) CNCH2CO2Et, HCl (iii) D.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01178-X

9204
S. Kotha et al. / Tetrahedron 58 (2002) 9203–9208
Scheme 2.
functionalized Phe derivative after Diels–Alder reaction
with a suitable dienophile (Scheme 3).9
Scheme 4. (i) Propargyl bromide, K2CO3, CH3CN (ii) 1N HCl, RT (iii)
tBuCOCl, Et3N, or Ac2O, CH2Cl2, RT.
different functionalized dienes, no metathesis product was
obtained. The metathesis reaction was successful only with
allyl acetate and allyl phenyl ether. Towards the synthesis of
diene 8, the allyl building block embodying an amino acid
moiety was prepared and found to be inert towards cross
metathesis reaction with various alkynes.12
2. Results and discussion
Towards the synthesis of dienes such as 4, various acetylene
building blocks containing an amino acid moiety were
prepared from Schiff-base N-(diphenyl-methyelene)glycine
ester 10 or 11.10
Having several dienes in hand, we next studied the Diels–
Alder (DA) chemistry with dienophiles such as DMAD and
subsequent oxidation of the Diels–Alder adduct with DDQ
to give highly functionalized Phe derivatives. Thus, the
Diels–Alder reaction13 of diene 18 with DMAD in dry
toluene in the presence of a pinch of hydroquinone (to avoid
polymerization) in a sealed tube at 1208C gave the Diels–
Alder adduct which was directly aromatized by DDQ
oxidation to give highly functionalized derivatives of Phe 22
(Scheme 6).
Alkylation of 10 (R¼Me) with propargyl bromide in the
presence of K2CO3/acetonitrile reflux gave the propargyl-
ated derivative. Since propargylated Schiff-base was
unstable it was hydrolyzed with 1N HCl and the resulting
amino ester 12 was protected with acetic anhydride and
trimethylacetyl chloride in dry DCM at RT to obtain acetyl
derivative 14 (mp 78–798C) and trimethylacetyl derivative
15 (as a semi solid), respectively. Reaction of 11 (R¼Et)
with propargyl bromide and subsequent hydrolysis to the
amino ester 13 followed by protection with acetic anhydride
and trimethylacetyl chloride gave the acetyl derivative 16
(mp 69–708C) and trimethylacetyl derivative 17 (as a
liquid), respectively (Scheme 4).
The structure of 22 was in full agreement with its spectral
data. The 1H NMR spectrum showed singlets at d 2.02 and
2.08 due to O-acetyl and N-acetyl functional group,
1
respectively. In H NMR spectrum a doublet of part of
Having prepared several acetylene building blocks, the
cross-enyne metathesis reaction of 14 with allyl acetate
using Grubbs catalyst11 in refluxing benzene gave the diene
18 as a 1:1 cis/trans mixture (Scheme 5). Attempts to
separate the cis/trans isomers were not successful. More-
over, the stereochemistry of the diene is of no consequence
in the final target molecule.
AB system at d 3.17 (J1¼5.3 Hz, J2¼13.8 Hz) and another
doublet of part of AB system at d 3.26 (J1¼5.8 Hz,
J2¼13.8 Hz) showed the presence of diastereotopic CH2
protons.
Various other Phe derivatives (23–25) prepared by this
route are shown in Table 2. All the products were fully
characterized by their spectral data and the details are
presented in Section 4. The yield of the Diels–Alder
step is moderate (40–62%) and in entry 3 (Table 2)
unreacted starting diene was isolated from the reaction
mixture.
To generalize the metathesis reaction, various other dienes
19–21 were prepared under cross-metathesis reaction
conditions as outlined in Table 1. All the products were
characterized with appropriate spectral data and the details
are described in Section 4.
To improve the yield of the Diels–Alder step we have tried
several reaction conditions such as microwave assisted
When the cross metathesis reaction was tried with different
alkenes such as allyl alcohol and allyl silane to obtain
Scheme 3.
Scheme 5. CH2vCHCH2OAc, Grubbs catalyst.

S. Kotha et al. / Tetrahedron 58 (2002) 9203–9208
Table 1. List of dienes prepared by cross-enyne metathesis
Entry AAA building block Olefin Diene (yield)
9205
Table 2. List of Phe derivatives
Entry
Diene
Product (yield)a
1
1
18
2
3
4
2
19
20
21
3
4
Diels–Alder reaction and Lewis acid (ZnCl2, AlCl3 and
BF3OEt2) catalyzed DA reaction. However, we found, there
was no improvement in the yield of the products.
a
Yields refer to combined yields for both Diels–Alder and oxidation
reactions.
3. Conclusions
spectra were obtained on JEOL JMS-DX 303 GC-MS
instrument. The FAB mass spectra were obtained on JEOL
SX 102/DA-6000 Mass spectrometer. UV spectra were
obtained on Shimadzu UV-2100 or UV-260 instrument.
Room temperature IR spectra were obtained on Nicolet
Impact-400 FT IR spectrometer.
The cross-enyne metathesis reaction and Diels–Alder
strategy has been found to be a useful method for the
synthesis of various highly functionalized Phe derivatives.
The diene building blocks prepared here are useful for the
creation of combinatorial libraries.
4.1. General procedure for the preparation of acetylene
building blocks
4. Experimental
A solution of Schiff-base (1 equiv.) in dry acetonitrile was
addedpropargylbromide (1.5 equiv.) and potassiumcarbonate
(5 equiv.). The resulting heterogeneous mixture was refluxed
for 20–30 h (TLC monitoring). The reaction mixture was
cooled, filtered, and the filtrate was concentrated at reduced
pressure. The residue was taken in diethyl ether and washed
with water, brine and dried over MgSO4. The evaporation of
solvent gave the crude product, which was dissolved in diethyl
ether and 1N HCl was added at RT and stirred for 10–15 h.
Then, the aqueous layer was separated and washed with excess
diethyl ether to remove unwanted organic residues. The
aqueous layer was basified with ammonia solution to pH ,10
and then extracted with ethyl acetate. The combined ethyl
acetate layer was washed with water, brine and dried over
MgSO4. Evaporation of the solvent gave amino ester.
Diethyl ether, tetrahydrofuran, benzene and toluene were
dried by distilling benzophenone ketyl. Chloroform,
dichloromethane and acetonitrile were distilled over
phosphorus pentoxide. Allylacetate was purchased from
E. Merck (India) limited. Grubbs catalyst was purchased
from Strem Chemicals, Newburyport, MA, USA. Mps were
obtained on a Labhosp or Veego melting point apparatus
and are uncorrected. NMR spectra were recorded on a
Bruker 300 or 500 MHz instrument. High resolution mass
A solution of amino ester (1 equiv.) in dry dichloromethane
was added acetic anhydride or trimethylacetyl chloride
Scheme 6. (i) DMAD, toluene, D (ii) DDQ, C6H6, D.

9206
S. Kotha et al. / Tetrahedron 58 (2002) 9203–9208
(3 equiv.) and a pinch of DMAP or triethylamine. The
reaction mixture was stirred at RT for 24 h. Then, the
solvent was removed and the residue was taken in ethyl
acetate and washed with water, brine and dried over MgSO4.
The evaporation of solvent gave the crude product, which
was purified by silica gel flash column chromatography.
Elution of the column with ethyl acetate petroleum ether
mixture gave the product.
4.1.3. Ethyl-2-acetylamino-4-pentynoate (16). A solution
of ethyl N-(diphenylmethylene)glycinate 11 (3 g,
11.2 mmol), propargyl bromide (2 g, 16.8 mmol) and
potassium carbonate (7.7 g, 56 mmol) in dry acetonitrile
(55 mL) was reflux for 20 h. The reaction mixture was
filtered and the filtrate was concentrated under reduced
pressure and was extracted with diethyl ether (150 mL).
Evaporation of solvent gave the crude product (3.42 g,
100%), The crude alkylated product (2.1 g, 6.88 mmol) was
hydrolyzed in diethyl ether (15 mL) and 1N HCl (9 mL), at
RT for 12 h, work up according to the general procedure
gave amino ester 13 (660 mg, 68%) as a yellow oil.
4.1.1. Methyl-2-acetylamino-4-pentynoate (14). Methyl
N-(diphenylmethylene)glycinate (10) (1.7 g, 6.71 mmol),
propargyl bromide (1.2 g, 10.08 mmol) and potassium
carbonate (4.6 g, 33.6 mmol) in dry acetonitrile (25 mL)
was refluxed for 24 h. The reaction mixture was filtered and
the filtrate was concentrated under reduced pressure and was
extracted with diethyl ether (100 mL), washed with water
(20 mL), brine (15 mL) and dried over MgSO4. Evaporation
of solvent gave the crude alkylated Schiff-base product
(1.76 g, 90%). The crude alkylated product (3.1 g,
10.65 mmol) was hydrolyzed in diethyl ether (25 mL) and
1N HCl (10 mL) stirred at RT for 24 h. Work up according
to the general procedure gave amino ester 12 (975 mg, 72%)
as a light yellow oil.
The amino ester 13 (660 mg, 4.68 mmol), acetic anhydride
(1.43 g, 14.0 mmol) and a pinch of DMAP in dry
dichloromethane (18 mL) was stirred for 24 h at RT, then
the solvent was removed and work up according to the
general procedure. The crude product was purified by silica
gel flash column chromatography. Elution of the column
with 20% ethyl acetate petroleum ether mixture gave 16 as a
white solid (634 mg, 74%). Mp: 69–708C. IR (KBr): n
3319, 1731, 2123, 1640 cm21. 1H NMR (300 MHz, CDCl3):
d 1.30 (t, J¼7.3 Hz, 3H, CO2CH2Me), 2.03 (t, J¼2.6 Hz,
1H, CuCH), 2.06 (s, 3H, NHCOMe), 2.77–2.79 (m, 2H,
CHCH2), 4.20–4.31 (m, 2H, CO2CH2Me), 4.73 (td,
J1¼4.4 Hz, J2¼8.0 Hz, 1H, CHCH2), 6.35 (br s, 1H, NH).
13C NMR (75.4 MHz, CDCl3): d 14.3, 22.7, 23.4, 50.8, 62.2,
71.7, 78.7, 169.9, 170.6. Mass: m/z 183 (Mþ). HRMS: m/z
(positive ion FAB) for (MþH) C9H14NO3; calcd 184.0973;
found: 184.0976.
A solution of amino ester 12 (735 mg, 5.78 mmol) in dry
dichloromethane (15 mL) was added acetic anhydride
(1.77 g, 17.35 mmol) and a pinch of DMAP. The reaction
mixture was stirred at RT for 24 h. Then, the solvent was
removed and the residue was taken in ethyl acetate
(100 mL) and washed with water (20 mL), brine (20 mL)
and dried over MgSO4. Evaporation of solvent under
reduced pressure gave the crude product, which was purified
by silica gel flash column chromatography. Elution of the
column with 17% ethyl acetate/petroleum ether mixture
gave 14 (783 mg, 80%) as a white solid. Mp: 78–798C. IR
4.1.4. Ethyl-2-trimethylacetylamino-4-pentynoate (17).
Amino ester 13 (587 mg, 4.16 mmol), trimethylacetyl
chloride (2 g, 16.6 mmol) and triethylamine (1.68 g,
16.64 mmol), in dichloromethane (dry) (35 mL) was stirred
at RT for 3 h, then the solvent was removed and work up
according to the general procedure. The crude product was
purified by silica gel flash column chromatography. Elution
of the column with 7.5% ethyl acetate/petroleum ether
mixture gave 17 as a thick liquid (703 mg, 75%). IR (neat):
(KBr): n 3308, 2120, 1736, 1642 cm21
.
1H NMR
(300 MHz, CDCl3): d 2.04 (t, J¼2.6 Hz, 1H, CuCH),
2.07 (s, 3H, NHCOCH3), 2.78 (dd, J1¼2.6 Hz, J2¼4.7 Hz,
2H, CHCH2), 3.80 (s, 3H, CO2Me), 4.76 (td, J1¼4.7 Hz,
J2¼7.7 Hz, 1H, CHCH2), 6.34 (br s, 1H, NH). Mass: m/z
169 (Mþ). Anal: for C8H11NO3; calcd 56.80 (C), 6.55 (H),
8.28 (N); found: 56.47 (C), 6.49 (H), 8.19 (N).
n 3375, 2121, 1741, 1657 cm21 1H NMR (300 MHz,
.
CDCl3): d 1.20 (s, 9H, CMe3), 1.30 (t, J¼7.5 Hz, 3H,
CO2CH2Me), 2.00 (t, J¼2.7 Hz, 1H, CuCH), 2.71–2.86
(m, 2H, CH2CH), 4.17–4.33 (m, 2H, CO2CH2Me), 4.67 (td,
J1¼4.5 Hz, J2¼7.5 Hz, 1H, CH2CH), 6.49 (br s, 1H, NH).
13C NMR (75.4 MHz, CDCl3): d 14.1, 22.2, 27.3, 38.7, 50.3,
61.8, 71.3, 78.4, 170.6, 178.2. HRMS: m/z (EI) for
C12H19NO3; calcd 225.1365; found: 225.1366.
4.1.2. Methyl-2-trimethylacetylamino-4-pentynoate (15).
A solution of amino ester 12 (320 mg, 2.51 mmol) in dry
dichloromethane (20 mL) was added trimethylacetyl
chloride (1.2 g, 9.95 mmol) and triethylamine (1.01 g,
10.0 mmol). The reaction mixture was stirred at RT for
3 h. Then, the solvent was removed and the residue was
taken in ethyl acetate (100 mL) and washed with water
(20 mL), brine (20 mL) and dried over MgSO4. Solvent was
evaporated under reduced pressure and the crude product
was purified by silica gel flash column chromatography.
Elution of the column with 15% ethyl acetate/petroleum
ether mixture gave 15 (463 mg, 87%) as a pure semi solid
4.2. General procedure for cross-enyne metathesis
reaction
A solution of alkyne building block (1 equiv.), alkene
(allylacetate) (5 equiv.) in dry benzene (10 mL) was
degased by passing nitrogen for 30 min. Then, Grubbs
catalyst RuCl2(CHC6H5)PCy3 (10–12 mol%) was added
and refluxed for 40–50 h under nitrogen. The solvent was
removed under reduced pressure and the crude product was
purified by silica gel flash column chromatography. Elution
with ethyl acetate/petroleum ether mixture gave the dienes.
1
product. IR (neat): n 3361, 1754, 2121, 1655 cm21. H
NMR (300 MHz, CDCl3): d 1.24 (s, 9H, CMe3), 2.03 (t,
J¼2.6 Hz, 1H, CuCH), 2.73–2.80 (m, 2H, CHCH2), 3.80
(s, 3H, CO2Me), 4.73 (td, J1¼4.7 Hz, J2¼7.7 Hz, 1H,
CHCH2), 6.5 (br s, 1H, NH). 13C NMR (75.4 MHz, CDCl3):
d 22.4, 27.5, 38.9, 50.5, 52.9, 71.6, 78.5, 171.3, 178.4. Mass:
m/z 211 (Mþ). HRMS: m/z (positive ion FAB) for (MþH)
C11H18NO3; calcd 212.1287; found: 212.1282.
4.2.1. (E/Z) 7-Acetoxy-2-acetylamino-4-methylene-hept-
5-enoic acid methyl ester (18). Alkyne building block 14

S. Kotha et al. / Tetrahedron 58 (2002) 9203–9208
9207
(150 mg, 0.88 mmol), benzene (dry) (10 mL), allyl acetate
(477 mg, 4.76 mmol) and Grubbs catalyst (10 mol%),
refluxed for 48 h. The column was eluted with 25% ethyl
acetate/petroleum ether mixture to give 18 (107 mg, 45%)
building block 17 (100 mg, 0.44 mmol), benzene (dry)
(10 mL), allyl acetate (223 mg, 2.23 mmol) and Grubbs
catalyst (12 mol%), refluxed for 50 h. The column was
eluted with 8% ethyl acetate/petroleum ether mixture to
give 21 (81 mg, 56%) as a brown liquid. IR (neat): n 3369,
1
as a brown liquid. IR (neat): n 3273, 1742, 1658 cm21. H
1
NMR (300 MHz, CDCl3): d 2.00 (s, 3H, OCOMe), 2.01 (s,
3H, OCOMe), 2.08 (s, 3H, NHCOMe), 2.09 (s, 3H,
NHCOMe), 2.60–2.80 (m, 4H, H-3), 3.72 (s, 3H,
CO2Me), 3.73 (s, 3H, CO2Me), 4.61–4.71 (m, 2H, H-2),
4.73–4.77 (m, 4H, H-7), 4.85–6.32 (m, 8H, alkene-H), 6.47
(d, J¼6.6 Hz, 2H, NH). Mass: m/z 269 (Mþ). HRMS: m/z
(EI) for C9H15NO3 (M2C4H4O2); calcd 185.1052; found:
185.1055.
1742, 1663 cm21. H NMR (300 MHz, CDCl3): d 1.19 (s,
9H, CMe3), 1.21 (s, 9H, CMe3), 1.28 (t, 6H, J¼6.9 Hz,
CO2CH2Me), 2.06 (s, 3H, OCOMe), 2.09 (s, 3H, OCOMe),
2.55–2.78 (m, 4H, H-3), 4.13–4.23 (m, 4H, CO2CH2Me),
4.50–4.63 (m, 4H, H-7), 4.68–4.79 (m, 2H, H-2), 4.86–
5.99 (m, 8H, alkene-H), 6.3 (d, J¼6.6 Hz, 2H, NH). HRMS:
m/z (EI) for C17H27NO5; calcd 325.1889; found: 325.1877.
4.3. General procedure for the Diels–Alder reaction and
DDQ oxidation
4.2.2. (E/Z) 7-Acetoxy-2-(2,2-dimethyl-propionyl amino)-
4-methylene-hept-5-enoic acid methyl ester (19). Alkyne
building block 15 (100 mg, 0.47 mmol), benzene (dry)
(8 mL), allyl acetate (210 mg, 2.1 mmol) and Grubbs
catalyst (8 mol%), refluxed for 60 h. The column was
eluted with 17% ethyl acetate/petroleum ether mixture to
give 19 (49 mg, 47%, based on starting material recovered
30 mg) as a brown liquid. IR (neat): n 3381, 1749,
In a sealed tube, a solution of diene (1 equiv.), DMAD
(3 equiv.) and catalytic amount of hydroquinone in dry
toluene was heated at 110–1408C under nitrogen for 40–
50 h. Then, the solvent was removed under reduced pressure
and the crude product was purified by silica gel flash
column chromatography. Elution of the column with ethyl
acetate/petroleum ether mixture to give Diels–Alder
adduct. Subsequently the Diels–Alder adduct (1 equiv.)
was oxidized with DDQ (2–3 equiv.) in refluxing benzene
(dry) for 48 h, which was purified by passing through silica
gel column chromatography. Elution of the column with
ethyl acetate/petroleum ether mixture to give the aromatized
product.
1
1650 cm21. H NMR (300 MHz, CDCl3): d 1.19, (s, 9H,
CMe3), 1.20 (s, 9H, CMe3), 2.07 (s, 3H, OCOMe), 2.08 (s,
3H, OCOMe), 2.60–2.79 (m, 4H, H-3), 3.72 (s, 3H,
CO2Me), 3.73 (s, 3H, CO2Me), 4.58–4.68 (m, 2H, H-2),
4.70–4.75 (m, 4H, H-7), 4.88–6.01 (m, 8H, alkene-H), 6.12
(d, J¼7.6 Hz, 2H, NH). HRMS: m/z (EI) for C16H25NO5;
calcd 311.1732; found: 311.1730.
4.3.1. 3-Acetoxymethyl-5-(2-acetylamino-2-methoxy car-
bonyl-ethyl)-phthalic acid dimethyl ester (22). Diene 18
(60 mg, 0.22 mmol), DMAD (100 mg, 0.70 mmol) and dry
toluene (3 mL), heated at 1208C for 36 h. The column was
eluted with 70% ethyl acetate/petroleum ether mixture to
give the Diels–Alder adduct (37 mg, 40%). Subsequently
the Diels–Alder adduct (22 mg, 0.05 mmol) was oxidized
with DDQ (23 mg, 0.10 mmol) in refluxing benzene (dry)
(4 mL) for 48 h. The column was eluted with 60% ethyl
acetate/petroleum ether mixture to give the aromatized
product 22 (17.5 mg, 80%) as a semi-solid. UV (CHCl3):
lmax nm (1, M21 cm21), 282.5 (1.41£103), 246.0
4.2.3. (E/Z) 7-Acetoxy-2-acetylamino-4-methylene-hept-
5-enoic acid ethyl ester (20). Alkyne building block 16
(150 mg, 0.82 mmol), benzene (dry) (12 mL), allyl acetate
(410 mg, 4.1 mmol), Grubbs catalyst (6 mol%), refluxed for
48 h. The column was eluted with 30% ethyl acetate/
petroleum ether mixture to give 20 (86 mg, 37%) as a brown
liquid. IR (neat): n 3301, 1741, 1660 cm21 1H NMR
.
(300 MHz, CDCl3): d 1.28 (t, J¼7.3 Hz, 6H, CO2CH2Me),
1.99 (s, 6H, OCOMe), 2.08 (s, 6H, NHCOMe), 2.57–2.73
(m, 4H, H-3), 4.20 (m, 4H, CO2CH2Me), 4.62–4.69 (m, 2H,
H-2), 4.73–4.77 (m, 4H, H-7), 4.85–5.99 (m, 8H, alkene-
H), 6.44 (d, J¼7.3 Hz, 2H, NH). HRMS: m/z (EI) for
C12H17NO3 (M2CH3CO2H); calcd 223.1208; found:
223.1217.
1
(3.47£103). IR (KBr): n 3366, 1738, 1660 cm21. H NMR
(300 MHz, CDCl3): d 2.02 (s, 3H, OCOMe), 2.08 (s, 3H,
NHCOMe), 3.17 (doublet of part of AB system, J1¼5.3 Hz,
J2¼13.8 Hz, 1H, diastereotopic proton CHaCHb), 3.26
(doublet of part of AB system, J1¼5.8 Hz, J2¼13.8 Hz,
1H, diastereotopic proton CHaCHb), 3.76 (s, 3H, CO2Me),
3.89 (s, 3H, CO2Me), 3.93 (s, 3H, CO2Me), 4.87–4.93 (m,
1H, CHNHCOMe), 5.12 (s, 2H, CH2OCOMe), 5.95 (d,
J¼7.5 Hz, 1H, NH), 7.35 (d, J¼1.6 Hz, 1H, Ar–H), 7.67 (d,
J¼1.6 Hz, 1H, Ar–H). 13C NMR (125 MHz, CDCl3): d
20.6, 22.9, 37.0, 52.4, 52.5, 52.6, 52.7, 63.0, 128.9, 130.4,
133.0, 133.8, 134.2, 137.8, 165.7, 168.3, 169.5, 170.2,
171.3. Mass: m/z 410 (Mþ1). HRMS: m/z (EI) for
C18H19NO8 (M2CH3OH); calcd 377.1110; found:
377.1101.
4.2.4. (E/Z) 7-Acetoxy 2-(2,2-dimethyl-propionyl amino)-
4-methylene-hept-5-enoic acid ethyl ester (21). Alkyne

9208
S. Kotha et al. / Tetrahedron 58 (2002) 9203–9208
4.3.2. 3-Acetoxymethyl-5-[2-(2,2-dimethyl-propionyl-
amino)-2-methoxycarbonyl-ethyl]-phthalic acid dimethyl
ester (23). Diene 19 (10 mg, 0.03 mmol), DMAD (15 mg,
0.10 mmol) and dry toluene (3 mL) was heated at 1108C for
42 h. The column was eluted with 80% ethyl acetate/
petroleum ether mixture to give the Diels–Alder adduct
(9 mg, 62%). Subsequently the Diels–Alder adduct (7 mg,
0.015 mmol) was oxidized with DDQ (7 mg, 0.03 mmol) in
refluxing benzene (dry) (3 mL) for 16 h. The column was
eluted with 80% ethyl acetate/petroleum ether mixture to give
aromatized product 23 (6.3 mg, 90%). UV (CHCl3): lmax nm
(1, M21cm21), 247.0 (3.85£103). IR (KBr): nmax 3414, 1742,
ether mixture to give aromatized product 25 (23 mg, 77%)
as a semi-solid. UV (CHCl3): lmax nm (1, M21cm21), 245.5
(2.58£103), 282.0 (8.40£102). IR (KBr): nmax 3414, 1742,
1
1670 cm21. H NMR (300 MHz, CDCl3): d 1.19 (s, 9H,
CMe3), 1.30 (t, J¼7.1 Hz, 3H, CO2CH2Me), 2.08 (s, 3H,
OCOMe), 3.19 (doublet of part of AB system, J1¼4.9 Hz,
J2¼13.8 Hz, 1H, diastereotopic proton CHaCHb), 3.29
(doublet of part of AB system, J1¼5.8 Hz, J2¼13.8 Hz,
1H, diastereotopic proton CHaCHb), 3.87 (s, 3H, CO2Me),
3.93 (s, 3H, CO2Me), 4.17–4.25 (m, 2H, CO2CH2Me),
4.80–4.86 (m, 1H, CHNHCOCMe3), 5.11 (s, 2H, CH2-
OCOMe), 6.17 (d, J¼6.8 Hz, 1H, NH), 7.35 (d, J¼1.6 Hz,
1H, Ar–H), 7.68 (d, J¼1.6 Hz, 1H, Ar–H). 13C NMR
(125 MHz, CDCl3): d 13.9, 20.5, 27.2, 29.3, 36.8, 38.6, 52.4
(2C?), 52.6, 61.7, 63.0, 128.7, 130.7, 133.1, 133.8, 134.0,
138.0, 165.4, 165.6, 168.3, 171.0, 177.8. HRMS: m/z (EI)
for C23H31NO9; calcd 465.1998; found: 465.1977.
1
1670 cm21. H NMR (300 MHz, CDCl3): d 1.18 (s, 9H,
CMe3), 2.07 (s, 3H, OCOMe), 3.18 (doublet of part of AB
system, J1¼8.1 Hz, J2¼13.8 Hz, 1H, diastereotopic proton
CHaCHb), 3.29 (doublet of part of AB system, J1¼8.7 Hz,
J2¼13.8 Hz, 1H, diastereotopic proton CHaCHb), 3.70 (s, 3H,
CO2Me), 3.87 (s, 3H, CO2Me), 3.92 (s, 3H, CO2Me), 4.85–
4.87 (m, 1H, CHNHCOCMe3), 5.10 (s, 2H, CH2OCOMe),
6.13 (d, J¼7.1 Hz, 1H, NH), 7.30 (s, 1H, Ar–H), 7.60 (s, 1H,
Ar–H). 13C NMR (75.4 MHz, CDCl3): d 20.7, 27.3, 37.0,
38.7, 52.5, 52.6, 52.7, 63.1, 128.9, 130.8, 133.2, 133.9, 134.2,
138.1, 165.7, 168.5, 170.3, 171.5, 178.0. HRMS: m/z (EI) for
C22H29NO9; calcd 451.1842; found: 451.1838.
Acknowledgements
We would like to acknowledge the DST for the financial
support, RSIC Bombay for providing the spectral data. S. H.
Thanks IIT-Bombay for the award of the research
fellowship.
4.3.3. 3-Acetoxymethyl-5-(2-acetylamino-2-ethoxycar-
bonyl-ethyl)-phthalic acid dimethyl ester (24). Diene 20
(105 mg, 0.37 mmol), DMAD (151 mg, 1.06 mmol) and
toluene (dry) (3 mL), heated at 1408C for 5 days. The column
was eluted with 50% ethyl acetate/petroleum ether mixture to
give the Diels–Alder adduct (55 mg, 53% based on starting
material recovered 36 mg). Subsequently the Diels–Alder
adduct (34 mg, 0.08 mmol) was oxidized with DDQ (32 mg,
0.14 mmol) in refluxing benzene (dry) (5 mL) for 48 h. The
column was eluted with 50% ethyl acetate/petroleum ether
mixture to give the aromatized product 24 (28 mg, 83%) as a
semi solid. UV (CHCl3): lmax nm (1, M21cm21), 246.0
(3.90£103), 282.0 (1.65£103). IR (KBr): nmax 3369, 1740,
1663 cm21. 1H NMR (300 MHz, CDCl3):d 1.21(t, J¼7.2 Hz,
3H, CO2CH2Me), 1.95 (s, 3H, OCOMe), 2.01 (s, 3H,
NHCOMe), 3.17 (doublet of part of AB system, J1¼4.2 Hz,
J2¼13.8 Hz, 1H, diastereotopic proton CHaCHb), 3.17
(doublet of part of AB system, J1¼4.8 Hz, J2¼13.8 Hz, 1H,
diastereotopic proton CHaCHb), 3.80 (s, 3H, CO2Me), 3.86
(s, 3H, CO2Me), 4.09–4.16 (m, 2H, CO2CH2Me), 4.77–
4.83 (m, 1H, CHNHCOMe), 5.05 (s, 2H, CH2OCOMe),
5.92 (d, J¼7.8 Hz, 1H, NH), 7.29 (d, J¼1.5 Hz, 1H, Ar–H),
7.62 (d, J¼1.5 Hz, 1H, Ar–H). 13C NMR (75.4 MHz,
CDCl3): d 14.0, 20.6, 22.9, 37.1, 52.5, 52.6, 52.8, 61.7, 63.1,
129.0, 130.6, 133.1, 133.9, 134.2, 138.0, 165.6, 168.2,
169.5, 170.0, 170.9. HRMS: m/z (EI) for C19H21NO8
(M2CH3OH); calcd 391.1267; found: 391.1248.
References
1. (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993,
32, 1244. (b) Liskamp, R. M. J. Recl. Trav. Chim. Pays-Bas
1994, 113, 1.
2. (a) Kotha, S.; Brahmachary, E. Tetrahedron Lett. 1997, 38,
3561. (b) Kotha, S.; Sreenivasachary, N.; Brahmachary, E.
Tetrahedron Lett. 1998, 39, 2805.
3. (a) Kotha, S.; Brahmachary, E.; Sreenivasachary, N. Tetra-
hedron Lett. 1998, 39, 4095. (b) Kotha, S.; Sreenivasachary,
N. Eur. J. Org. Chem. 2001, 3375.
4. (a) Kotha, S.; Sreenivasachary, N. Bioorg. Med. Chem. Lett.
1998, 8, 257. (b) Kotha, S.; Sreenivasachary, N.; Mohanraja,
K.; Durani, S. Bioorg. Med. Chem. Lett. 2001, 11, 1421.
5. Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50, 2623.
6. Martinez, A. G.; Contelles, J. L. M. Synthesis 1982, 742.
7. Simpkins, N. S. Sulphones in Organic Synthesis. Pergamon:
Oxford, 1993.
8. (a) Kotha, S.; Brahmachary, E. Bioorg. Med. Chem. Lett.
1997, 7, 2719. (b) Kotha, S.; Brahmachary, E. J. Org. Chem.
2000, 65, 1359.
9. (a) Kotha, S.; Halder, S.; Brahmachary, E.; Ganesh, T. Synlett
2000, 853. For recent examples of cross-enyne metathesis
reaction see (b) Mori, M.; Tonogaki, K.; Nishiguchi, N. J. Org.
Chem. 2002, 67, 224. (c) Banti, D.; North, M. Tetrahedron
Lett. 2002, 43, 1561. (d) Conesa, S. R.; Candal, P.; Jimenez,
C.; Rodriguez, J. Tetrahedron Lett. 2001, 42, 6699. (e) Manas,
M. M.; Pleixats, R.; Santamaria, A. Synlett 2001, 1784.
10. O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663.
11. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
12. Halder, S. Ph.D. thesis, IIT-Bombay, 2002.
4.3.4. 3-Acetoxymethyl-5-[2-(2,2-dimethyl-propionyl-
amino)-2-ethoxycarbonyl-ethyl]-phthalic acid dimethyl
ester (25). Diene 21 (39 mg, 0.11 mmol), DMAD (50 mg,
0.35 mmol) and dry toluene (2 mL), heated at 1408C for
24 h. The column was eluted with 20% ethyl acetate/
petroleum ether mixture to give the Diels–Alder adduct
(33.5 mg, 60%). Subsequently the Diels–Alder adduct
(30 mg, 0.06 mmol) was oxidized with DDQ (24 mg,
0.10 mmol) in refluxing benzene (dry) (3 mL) for 48 h.
The column was eluted with 85% ethyl acetate/petroleum
13. (a) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis. Pergamon: Oxford, 1990. (b) Fringuelli, F.;
Taticchi, A. Dienes in the Diels–Alder Reaction. Wiley:
New York, 1990.