Constrained phenylalanine derivatives by enyne metathesis and Diels-Alder reaction

Article abstract of DOI:10.1002/1099-0690(200102)2001:4<787::AID-EJOC787>3.0.CO;2-N

A conceptually new approach for the synthesis of indane-based α-amino acid derivatives is reported. In this regard, the synthesis of five-membered exocyclic and five-membered inner-outer ring diene building blocks (7 and 15) containing α-amino acid moieties is described. Diene 15 is prepared by an enyne metathesis reaction as a key step. In this paper, a full account of our work regarding the Diels-Alder reaction of these dienes with various dienophiles, and the subsequent oxidation of the cycloadducts to give various indane-based α-amino acid derivatives is reported.

Full text of DOI:10.1002/1099-0690(200102)2001:4<787::AID-EJOC787>3.0.CO;2-N

FULL PAPER
Constrained Phenylalanine Derivatives by Enyne Metathesis and Diels؊Alder
Reaction
Sambasivarao Kotha,*[a] Nampally Sreenivasachary,[a] and Enugurthi Brahmachary[a]
Keywords: Amino acids / Cycloadditions / Drug research / Metathesis / Peptidomimetics
A conceptually new approach for the synthesis of indane-
based α-amino acid derivatives is reported. In this regard, the
synthesis of five-membered exocyclic and five-membered in-
ner-outer ring diene building blocks (7 and 15) containing α-
amino acid moieties is described. Diene 15 is prepared by an
enyne metathesis reaction as a key step. In this paper, a full
account of our work regarding the Diels−Alder reaction of
these dienes with various dienophiles, and the subsequent
oxidation of the cycloadducts to give various indane-based
α-amino acid derivatives is reported.
Introduction
With this in mind, it was of interest to prepare dienes
containing an AAA moiety which might be useful for the
preparation of indane-based AAAs. A few examples of un-
saturated AAAs have been reported in the literature.[11] Un-
fortunately, some of these derivatives are very delicate com-
pounds, and, consequently, very limited work about the
utility of these unsaturated systems in the synthesis of com-
plex AAAs has been reported. In the present paper, as a
continuation of our interest in the preparation of various
constrained Phe analogs, such as indane systems with ex-
tended appendages,[8] we would like to report the full details
of our efforts using the enyne metathesis and a DielsϪAlder
reaction as key steps.
The possibility of utilizing cycloaddition reactions for the
synthesis of cyclic AAAs appears to be an attractive option.
In this regard, the dienes 2 and 3 containing α,α-dialkylated
amino acid moieties were identified as possible building
blocks for the synthesis of various Ind derivatives using a
DielsϪAlder reaction as the key step. Thus, the [4ϩ2] cyclo-
addition reaction of exocyclic diene 2 with a suitable dien-
ophile, followed by oxidation, is expected to provide the
linearly substituted Ind derivatives. Similarly, the inner-
outer ring diene 3 delivers the angularly substituted Ind de-
rivatives (Scheme 1).
Incorporation of constrained α-amino acids (AAAs) in a
given peptide chain limits the number of possible confirma-
tions.[1] For example, indanylglycine (Ind, R ϭ H) 1 is a
constrained analogue of phenylalanine (Phe) in which the
rotational freedom of the aromatic ring is restrained due to
an additional methylene bridge. Indane-based amino acids
have been used in the design of chemotactic peptides[2] and
also for analyzing the binding pockets of substance P.[3]
Among the unusual AAAs, α,α-dialkylated and cyclic
AAAs have attracted increased attention because they
stiffen the backbone of peptides through the formation of
helices and β-turns.[4] Only the simplest members of cyclic
AAAs are ordinarily used because general methods for the
synthesis of complex AAAs are not available. In this con-
text, the development of novel AAAs with a strong prefer-
ence for well-defined regions of backbone conformational
space would increase the tools available to the protein
chemist.[5] Traditionally, the BuchererϪBerg method has
been used to prepare indane-based AAAs.[6] However, this
method doesn’t tolerate sensitive functional groups in the
aromatic ring.[7] In this regard, a comprehensive approach
to indane-based AAAs based on our ‘‘building block ap-
proach’’ is useful for the synthesis of complex derivatives
with varying steric and electronic properties.[8,9] The cyclo-
addition approach to AAAs is conceptually different from
the other known routes. This approach involves generation
of the benzene ring with a [4ϩ2] cycloaddition reaction as
the key step, while the other methods rely on manipulation
of preformed benzene derivatives.[10] Since the DielsϪAlder
strategy can create considerable functionality in the final
target by appropriate selection of the reacting partners, this
Scheme 1
strategy is useful for the introduction of diverse func- Results and Discussion
tionality in indane-based AAAs.
For the synthesis of 2, our attention focused on the pre-
[a]
Department of Chemistry, Indian Institute of Technology-
Bombay,
paration of 2,3-bis(iodomethyl)-1,3-butadiene (5a) as a key
precursor, and in this regard tetrabromide 4 was prepared
according to the literature procedure (Scheme 2).[12] Thus,
addition of bromine to 2,3-dimethyl-1,3-butadiene at 0 °C
followed by reaction with N-bromosuccinimide gave tetra-
bromide 4, which was converted into 2,3-bis(bromomethyl)-
Mumbai-400 076, India
Fax: (internat.) ϩ91-22/572-3480
Email: srk@chem.iitb.ernet.in
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/eurjoc or from
the author.
Eur. J. Org. Chem. 2001, 787Ϫ792
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
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787

S. Kotha, N. Sreenivasachary, E. Brahmachary
FULL PAPER
1,3-butadiene (5b) by a Zn/Cu-mediated reductive debrom- Table 1. Synthesis of indane-based α-amino acid derivatives by a
ination reaction.[13] Since the dibromide 5b is known to be
[4ϩ2] cycloaddition strategy from diene 7
highly unstable and difficult to handle, the corresponding
diiodide 5a, which is more stable than the dibromide, was
chosen. Although diene 5a polymerizes readily in the solid
state, it can be stored at 0 °C as an ethereal solution (0.1
) for several months.
Scheme 2. Reagents: (i) Br2, CCl4, 0 °C; (ii) NBS, AIBN, CCl4, ∆;
(iii) KI, Na2S2O3·5H2O, acetone, 45 °C; (iv) CNCH2CO2Et, 8,
NaH, DMSO/ether, 10 °C; (v) HCl, EtOH; (vi) Ac2O, DMAP
The dialkylation of ethyl isocyanoacetate 8 with 5a under
mild reaction conditions using NaH/DMSO-ether gave the
coupling product 6.[14] Attempts to purify the isonitrile 6
[a]
Yields refers to combined isolated yields for both the
[b]
by silica gel or alumina column chromatography resulted in
extensive decomposition. So, in the subsequent attempts 6
was hydrolyzed to the amino ester by simply stirring with 1
 HCl in ethanol. This amino ester was converted into the
N-acetyl derivative 7 as shown in Scheme 2. The structure
DielsϪAlder and DDQ products. Ϫ Ts ϭ p-toluenesulfonyl.
In order to prepare the angularly substituted Ind derivat-
ives by a DielsϪAlder approach, the key inner-outer ring
diene building block 15 was identified (Scheme 4). In this
regard, a ring-closing enyne-metathesis reaction is known
to provide access to 1-vinylcycloalkene derivatives from
acyclic enyne derivatives. Towards this objective the syn-
thesis of the required enyne derivative 16 was conceived by
two independent routes. Initially the enyne 16 was synthe-
sized using ethyl isocyanoacetate as a glycine equivalent.[14]
Sequential allylation and propargylation of ethyl isocy-
anoacetate 8 under phase transfer catalysis (PTC) condi-
tions gave 17, which on hydrolysis with 1  HCl, followed
by acetylation, gave the enyne building block 16 in 6% over-
all yield.
1
of 7 was deduced based on spectral data. In the H NMR
spectrum, compound 7 shows a triplet at δ ϭ 1.25 (J ϭ
7.1 Hz) and a quadruplet at δ ϭ 4.19 (J ϭ 7.1 Hz) due to
the presence of the ethyl ester. It also displays two singlets
at δ ϭ 1.97 and 5.82 due to the acetyl and amide protons,
respectively. The 13C NMR spectrum of 7 shows nine sig-
nals at δ ϭ 14.0 (q), 23.1(q), 43.3 (t), 61.5 (t), 62.7 (s), 106.3
(t), 144.2 (s), 170.1 (s) and 172. 2 (s) supporting the pres-
ence of C2 symmetry in the molecule.
The DielsϪAlder reaction of diene 7 with dimethyl ace-
tylenedicarboxylate (DMAD) at room temperature gave the
adduct 9 in good yield (Scheme 3). The dehydrogenation of
the cycloadduct 9 in the presence of DDQ gave the 5,6-
bis(methoxycarbonyl) Ind derivative 10 (93% overall yield
for two steps).
Scheme 4
The major problem here was that the required mono allyl
compound was formed as the minor product and the un-
desired dialkylated product was formed as the major prod-
uct. In addition, the mono allyl derivative was found to be
highly volatile. In order to improve the yield of the building
Scheme 3
The other dienophiles such as methyl propiolate, ethynyl block 16, a propargylation and allylation sequence was also
p-tolylsulfone (14),[15] and naphthoquinone underwent a attempted, although to little effect.
similar [4ϩ2] cycloaddition reaction, and subsequent oxida-
Since the benzophenone Schiff base 18 is known to un-
tion of the adducts with DDQ[16] gave the corresponding dergo stepwise alkylation under PTC conditions[17] the two-
Ind derivatives 11؊13, respectively; these results are sum- step alkylation of 18 with propargyl bromide in the presence
marized in Table 1.
of K2CO3 gave 19 (Scheme 5). Subsequent allylation under
788
Eur. J. Org. Chem. 2001, 787Ϫ792

Constrained Phenylalanine Derivatives by Enyne Metathesis and DielsϪAlder Reaction
FULL PAPER
solid-liquid PTC conditions gave the enyne derivative 20. adducts and dehydrogenation with DDQ gave the angularly
Hydrolysis of 20, followed by acetylation, gave the enyne substituted Ind derivatives (21؊25, Table 2). In entry no.
building block 16.
2, a regioisomeric mixture of products was obtained and
attempts to isolate these compounds were not successful.
However, in entry no. 3, after considerable efforts, only
compound 12 was isolated, and its spectral data confirmed
that it was identical to that of the material obtained from
diene 7. Compound 23 was obtained in an impure form.
Since most of the DielsϪAlder adducts were found to be
contaminated with a small amount of aromatized products,
as indicated by NMR spectroscopic data, no special at-
tempts were made to isolate and characterize these adducts.
Scheme 5. (i) Allyl bromide, nBu4NHSO4, K2CO3; (ii) propargyl
bromide, nBu4NHSO4, K2CO3; (iii) HCl, EtOH; (iv) Ac2O, DMAP,
CH2Cl2; (v) propargyl bromide, K2CO3; (vi) allyl bromide, KOH,
nBu4NBr; (vii) 1  HCl, ether
Conclusions
To conclude, a new and general methodology has been
developed for the synthesis of linear and angularly substi-
tuted indane-based α,α-AA derivatives by a [4ϩ2] cycload-
dition strategy. The angularly substituted diene 15 is pre-
pared using enyne metathesis reaction as a key step. Since
the DielsϪAlder reaction[19] is useful for the preparation of
various polycyclic frames, the methodology described here
is of immense potential in the preparation of various con-
strained Phe analogues. The α,α-AA derivatives prepared
here are not accessible by other conventional methods, such
as the BuchrerϪBurg method.
The enyne derivative 16 was subjected to the RCM reac-
tion in the presence of GrubbsЈ ruthenium catalyst
[Cl2(PCy3)2RuϭCHPh][18] to give the inner-outer ring diene
15 in 75% isolated yield (Scheme 4). The 13C NMR spectral
data [75.4 MHz, CDCl3: δ ϭ 14.0, 23.0, 42.6, 44.3, 61.5,
64.1, 115.1, 126.6, 132.5, 140.2, 170.0, 173.5] of 15 con-
firmed its structure. The treatment of diene 15 with various
dienophiles in refluxing benzene (or toluene) gave the cyclo
Table 2. Synthesis of angularly substituted indane-based AAA de-
rivatives by a [4ϩ2] cycloaddition strategy from the inner-outer ring
diene 15
Experimental Section
Diethyl ether, tetrahydrofuran, benzene and toluene were dried by
distilling over benzophenone ketyl. Chloroform, dichloromethane,
carbon tetrachloride and acetonitrile were distilled over phos-
phorus pentoxide. p-Toluenesulfonyl chloride (TsCl) was purified
by dissolving in ether and washing with 20% aq. NaOH solution
and water and then crystallized from ether. Aluminum chloride was
sublimed before use. Ethyl isocyanoacetate and DDQ were pur-
chased from Aldrich Chemical Co. LiAlH4, KHCO3 were obtained
from Fluka. Methyl propiolate and bis(trimethylsilyl)acetylene
were purchased from Lancaster Synthesis. The dienes 7 and 15 are
unstable: they can only be stored at 0 °C for a few days and it was
difficult to get the elemental analyses.
Precaution: Ethyl isocyanoacetate and the electrophiles used in this
study are lachrymators and irritants and must be handled with proper
care. Some of them are also potent mutagens.
Ethyl 3,4-Dimethylene-1-isocyanocyclopentane-1-carboxylate (6): To
a stirred solution of ethyl isocyanoacetate 8 (100 mg, 0.86 mmol)
and 5a (319 mg, 0.95 mmol) in dry DMSO/ether (4 mL, 1:1) was
added a suspension of NaH (63 mg, 2.65 mmol; 60% in mineral
oil, used after washing with dry hexane) in dry ether at 0 °C. The
brown reaction mixture was stirred for 15 min at 10 °C. Then, the
reaction mixture was quenched with ice-cold water and extracted
with ether (3 ϫ 20 mL). The combined organic phase was filtered
to remove the yellow polymeric material and the filtrate was
washed with water, brine and dried over MgSO4. Evaporation of
the solvent gave the crude product 6 (120 mg, 71%) as a brown
liquid, which was used in the subsequent reaction without further
purification. Attempts to purify compound 6 by a silica gel column
[a]
[b]
Isolated combined yields for two steps. Ϫ
Overall yield for
both isomers
Eur. J. Org. Chem. 2001, 787Ϫ792
789

S. Kotha, N. Sreenivasachary, E. Brahmachary
FULL PAPER
resulted in extensive decomposition of the product. IR (neat): ν˜ ϭ
52.6, 62.0, 65.7, 125.0, 131.2, 143.8, 168.1, 170.1, 172.5. Ϫ MS:
m/z ϭ 363 [Mϩ]. Ϫ C18H21NO7 (363.36): calcd. C 58.99, H 5.78,
N 3.82; found C 59.33, H 5.64, N 3.73.
2140, 1740 cmϪ1
.
Ethyl 1-Acetamido-3,4-dimethylenecyclopentane-1-carboxylate (7):
To the crude isonitrile derivative 6 (120 mg, 0.63 mmol) in absolute
ethanol (4 mL) was added conc. HCl (4 drops) at 0 °C and the
reaction mixture was stirred at 20Ϫ25 °C for 30 min. Then, the
solvent was evaporated under reduced pressure. The residue ob-
tained was dissolved in water, basified with ammonia solution
(pH ϭ 10) and then extracted with ethyl acetate (3 ϫ 10 mL). The
combined organic extract was washed with water and brine, and
then dried. Evaporation of the solvent gave the amino ester (61 mg,
54%) as a brown liquid which was used in the next step without
Ethyl 2-Acetamido-6-bis(methoxycarbonyl-2-carboxylate (11):
A
mixture of diene 7 (8 mg, 0.03 mmol), methyl propiolate (5.65 mg,
0.06 mmol) and a pinch of hydroquinone in dry toluene (4 mL) was
heated at 100Ϫ110 °C for 24 h. Evaporation of the solvent and
purification of the crude product by silica gel column chromato-
graphy with ethyl acetate/hexane (1:1) as eluent gave the
DielsϪAlder adduct as a colorless liquid (9 mg, 93%). IR (neat):
ν˜ ϭ 3245 (NH), 1745, 1635 cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 1.25 (t, J ϭ 7.1 Hz, 3 H), 1.98 (s, 3 H), 2.58 (d, J ϭ 16.3 Hz,
2 H), 2.86 (s, 4 H), 3.05 (dd, J ϭ 10.9, 8.2 Hz, 2 H), 3.76 (s, 3 H),
4.20 (q, J ϭ 7.1 Hz, 2 H), 6.06 (s, 1 H), 7.01Ϫ7.25 (m, 1 H). Ϫ
MS: m/z ϭ 307 [Mϩ].
The cycloadduct (9 mg, 0.03 mmol) obtained in the above reaction
and DDQ (7.98 mg, 0.35 mmol) in dry benzene were refluxed under
a N2 atmosphere for 3 h. Evaporation of the solvent and purifica-
tion of the product by silica gel column chromatography with ethyl
acetate/hexane (1:1) as eluent gave 11 (8 mg, 87%) as a colorless
liquid. UV (CHCl3): λmax (ε, Ϫ1 cmϪ1) ϭ 245 (2654) nm. Ϫ IR
(KBr): ν˜ ϭ 3328, 1745, 1636 cmϪ1. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.24 (t, J ϭ 7.1 Hz, 3 H), 1.96 (s, 3 H), 3.31 (d 1/2
Abq, J ϭ 16.8, 13.7 Hz, 2 H), 3.64 (d 1/2 ABq, J ϭ 18.2, 18.5 Hz,
2 H), 3.90 (s, 3 H), 4.21 (q, J ϭ 7.1 Hz, 2 H), 6.07 (s, 1 H), 7.25
(1/2 ABq, J ϭ 7.7 Hz, 1 H), 7.86 (1/2 ABq, J ϭ 3.6 Hz, 1 H), 7.90
(s, 1 H). Ϫ MS: m/z ϭ 305 [Mϩ]. Ϫ EI-HRMS (C16H19NO5): calcd.
305.1263; found 305.1251.
any further purification. IR (neat): ν˜ ϭ 3445, 1740 cmϪ1
.
To a solution of the above amino ester (60 mg, 0.38 mmol) and 4-
(dimethylamino)pyridine (DMAP) (5 mg) in dry CH2Cl2 (2 mL)
was added a solution of acetic anhydride (84.5 mg, 0.82 mmol) in
CH2Cl2 (2 mL) at room temp. The mixture was stirred for 1 h and
then diluted with CH2Cl2 (10 mL), washed with water and brine,
and dried. Evaporation of the solvent and purification of the crude
product by a silica gel column with ethyl acetate/hexane (1:2) as
eluent gave 7 (43 mg, 60%) as a white crystalline solid. M.p. 93Ϫ95
°C. Ϫ IR (KBr): ν˜ ϭ 3270, 1740, 1645 cmϪ1. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 1.25 (t, J ϭ 7.1 Hz, 3 H), 1.97 (s, 3 H),
2.80 (1/2 ABq, J ϭ 16.3 Hz, 2 H), 3.07 (t 1/2 ABq, J ϭ 16.6, 2.7 Hz,
2 H), 4.19 (q, J ϭ 7.1 Hz, 2 H), 4.97 (d, J ϭ 1.3 Hz, 2 H), 5.46 (d,
J ϭ 1.6 Hz, 2 H), 5.82 (br s, 1 H). Ϫ 13C NMR (75.4 MHz, CDCl3):
δ ϭ 14.0 (q), 23.1 (q), 43.3 (t), 61.5 (t), 62.7 (s), 106.3 (t), 144.2 (s),
170.1 (s), 172.2 (s). Ϫ MS: m/z ϭ 223 [Mϩ].
General Procedure for the Diels؊Alder Reaction of Dienes: A solu-
tion of the diene (1 mmol), dienophile (1 mmol) and a catalytic
amount of hydroquinone in toluene (or benzene) was refluxed until
completion of the reaction (TLC monitoring). Subsequently, the
DielsϪAlder adduct was treated with DDQ in refluxing benzene
(or toluene) to give the aromatized product. Evaporation of the
solvent and purification of the crude product on a silica gel column
with ethyl acetate/hexane (1:1) as eluent gave the aromatized prod-
uct.
Ethyl 2-Acetamido-6-(p-toluenesulfonyl)indane-2-carboxylate (12):
A solution of diene 7 (14 mg, 0.06 mmol), tosyl acetylene 14 (7.2
mg, 0.07 mmol) and a pinch of hydroquinone in dry benzene was
refluxed under N2 for 24 h. Evaporation of the solvent and puri-
fication of the crude product on a silica gel column with ethyl acet-
ate/hexane (1:3) as eluent gave the cycloadduct as a white crystal-
line solid (19 mg, 99%, Mp, 84Ϫ86 °C).
The adduct (16 mg, 0.05 mmol) obtained in the above reaction was
refluxed in the presence of DDQ (15 mg, 0.06 mmol) in dry ben-
zene under N2 for 24 h. Evaporation of the solvent and purification
of the residue on a neutral alumina column eluting with ethyl acet-
ate/hexane (1:1) gave the aromatized product 12 (15.4 mg, 97%) as
Ethyl 2-Acetamido-5,6-bis(methoxycarbonyl)-4,7-dihydroindanecar-
boxylate (9): A solution of diene 7 (10 mg, 0.04 mmol) and DMAD
(9.5 mg, 0.06 mmol) in dry benzene (3 mL) containing a pinch of
hydroquinone was reacted according to the general procedure for
24 h at room temp. Evaporation of the solvent and purification of
the crude product on a silica gel column with ethyl acetate/hexane
(1:1) as eluent gave 9 (15 mg, 98%) as a colorless sticky solid. IR
(KBr): ν˜ ϭ 3245, 1745, 1635 cmϪ1. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.25 (t, J ϭ 6.9 Hz, 3 H), 1.99 (s, 3 H), 2.61
(1/2 ABq, J ϭ 15.9 Hz, 2 H), 2.99 (s, 4 H), 3.02 (1/2 ABq, J ϭ
17.4 Hz, 2 H), 3.78 (s, 6 H), 4.20 (q, J ϭ 7.14 Hz, 2 H), 6.07 (s,
1 H). Ϫ MS: m/z ϭ 365 [Mϩ].
1
a sticky solid. IR (neat): ν˜ ϭ 3340, 1743, 1638 cmϪ1. Ϫ H NMR
(300 MHz, CDCl3): δ ϭ 1.21 (t, J ϭ 7.1 Hz, 3 H), 1.94 (s, 3 H),
2.41 (s, 3 H), 3.34 (d 1/2 Abq, J ϭ 17.0, 11.7 Hz, 2 H), 3.58 (d 1/
2 ABq, J ϭ 17.2, 17.1 Hz, 2 H), 4.19 (q, J ϭ 7.1 Hz, 2 H), 6.16 (s,
1 H), 7.30 (1/2 ABq, J ϭ 8.4 Hz, 2 H), 7.72 (s, 1 H), 7.75Ϫ7.82
(m, 2 H), 7.81 (1/2 ABq, J ϭ 7.8 Hz, 2 H). Ϫ EI-HRMS
(C20H21NO3S [M Ϫ CH2O2]): calcd. 355.0878; found 355.0905.
Ethyl 2-N-(Diphenylmethylene)propargylglycinate (19): To a solu-
tion of ethyl N-(Diphenylmethylene)glycinate (18;3.0 g, 11.2 mmol)
in dry acetonitrile (55 mL) were added propargyl bromide (2 g,
16.8 mmol) and potassium carbonate (7.7 g, 56 mmol). The re-
sulting heterogeneous mixture was refluxed for 30 h. The reaction
mixture was cooled, filtered and concentrated under reduced pres-
sure. The residue was taken up in ether (200 mL) and washed with
water, brine and dried over MgSO4. The evaporation of solvent
Ethyl 2-Acetamido-5,6-dicarbomethoxyindane-2-carboxylate (10): A
mixture of compound 9 (16.4 mg, 0.04 mmol) and DDQ (10.2 mg,
0.04 mmol) in dry benzene was refluxed under N2 for 10 h. Evap-
oration of the solvent and purification of the crude product on a
neutral alumina column with ethyl acetate/hexane (1:1) as eluent
gave the aromatized product 10 (15.5 mg, 95%) as a white crystal-
line solid. M.p. 145Ϫ146 °C. Ϫ UV (CHCl3): λmax (ε, Ϫ1 cmϪ1) ϭ gave the product, which was purified by flash column chromato-
248 (2096) nm. Ϫ IR (KBr): ν˜ ϭ 3326, 1750, 1629cmϪ1. Ϫ 1H graphy (neutral alumina, 1:20 ethyl acetate/hexane) to give 19 (2.8
NMR (300 MHz, CDCl3): δ ϭ 1.23 (t, J ϭ 7.1 Hz, 3 H), 1.96 (s, 3 g 86%) as a brown colored liquid. IR (neat): ν˜ ϭ 3295, 2124, 1738
1
H), 3.36 (1/2 ABq, J ϭ 17.2 Hz, 2 H), 3.62 (1/2 ABq, J ϭ 17.0 Hz,
cmϪ1. Ϫ H NMR (300 MHz, CDCl3): 1.26 (t, J ϭ 7.2 Hz, 3 H,),
2 H), 3.89 (s, 6 H), 4.21 (q, J ϭ 7.1 Hz, 2 H), 6.14 (s, 1 H), 7.54 1.95 (t, J ϭ 3.0 Hz, 1 H), 2.7Ϫ2.9 (m, 2 H), 4.18 (q, J ϭ 6 Hz, 2
(s, 2 H). Ϫ 13C NMR (75.43 MHz, CDCl3): δ ϭ 14.0, 23.2, 43.1, H), 4.28 (t, J ϭ 5.1 Hz, 1 H), 7.2Ϫ7.8 (m, 10 H).
790
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Constrained Phenylalanine Derivatives by Enyne Metathesis and DielsϪAlder Reaction
FULL PAPER
Ethyl 2-Allyl-N-(diphenylmethylene)-2-propargylglycinate (20): A
stirred solution of n-tetrabutylammonium bromide (143 mg,
Ethyl
8-Acetamido-3,4-dihydro-5H-cyclopenta[e]-1,4-naphthoqui-
none-8-carboxylate (24): A solution of the diene 15 (25 mg,
0.44 mmol) and KOH (750 mg, 13.4 mmol) in dry acetonitrile 0.11 mmol), benzoquinone (12.1 mg, 0.11 mmol) and a catalytic
(15 mL) was added to a solution of 19 (1.365 g, 4.47 mmol) and
allyl bromide (812 mg, 6.71 mmol) in acetonitrile (10 mL) at 0 °C
over a period of 5 min. The reaction mixture was then stirred for
6 h at 0Ϫ10 °C. At the conclusion of the reaction (TLC mon-
itoring), the reaction mixture was filtered and concentrated, the
residue was taken up in ether (150 mL), and washed with water
and brine, dried over MgSO4 and concentrated. The residue was
purified on a flash alumina column (1:20, ethyl acetate/hexane) to
give 20 (1.2 g, 77%) as a colorless liquid. IR (neat): ν˜ ϭ 3300,
amount of hydroquinone (1 mg) in dry toluene (3 mL) was refluxed
for 2 days. The solvent was concentrated under reduced pressure
and the crude product was purified on a silica gel column with
ethyl acetate/hexane (2:3) as eluent to give the cycloadduct (34.4
mg, 93%) as a thick liquid. Subsequently, this adduct (20 mg,
0.06 mmol) and DDQ (13.4 mg, 0.05 mmol) were refluxed in tolu-
ene (3 mL) for 24 h. The solvent was then evaporated and the res-
idue was purified by flash column chromatography (silica gel, 1:5
ethyl acetate/hexane) to give 24 as a dark brown liquid (13.1 mg,
1731cmϪ1. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.12 (t, J ϭ 67%). IR (neat): ν˜ ϭ 3296, 1732 cmϪ1. Ϫ 1H NMR (300 MHz,
7.2 Hz, 3 H), 1.9 (t, J ϭ 2.4 Hz, 1 H) 2.8Ϫ2.9 (m, 4 H), 3.75 (q, CDCl3) δ ϭ 1.23 (t, J ϭ 7.2 Hz, 3 H), 1.98 (s, 3 H), 3.53 (1/2 ABq,
J ϭ 7.2 Hz, 2 H), 5.1Ϫ5.2 (m, 2 H), 5.7Ϫ5.9 (m, 1 H), 7.1Ϫ7.8 (m, J ϭ 17.7 Hz, 1 H) 3.74 (1/2 ABq, J ϭ 17.7 Hz, 1 H), 3.82 (d, J ϭ
10 H).
2.7 Hz, 2 H), 4.22 (q, J ϭ 7.2 Hz, 2 H), 6.30 (s, 1 H), 6.92 (ABq,
J ϭ 10.5 Hz, 2 H), 7.56 (d, J ϭ 7.8 Hz,1 H) 8.01 (d, J ϭ 7.8 Hz, 1
H). Ϫ UV (CHCl3): λmax (ε, Ϫ1 cmϪ1) ϭ 250 (8.6 ϫ 103), 358
(2.06 ϫ 103). Ϫ EI-HRMS (C18H17NO5): calcd. 327.1106; found
327.1104.
Hydrolysis of the Enyne Building Block (20): To a solution of glycin-
ate 20 (700 mg, 2.02 mmol) in diethyl ether (15 mL) was added 1
 HCl (3 mL). The reaction mixture was stirred at room temp. for
24 h. The ether layer was then discarded and the aqueous layer
basified with ammonia solution to pH ഠ 10. The reaction mixture
was then extracted with ethyl acetate. The combined organic ex-
tracts were washed with water and brine, dried over MgSO4 and
concentrated to give the amino ester as a light yellow oil (347 mg,
95%). IR (neat): ν˜ ϭ 3371, 2119, 1733 cmϪ1. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 1.20 (t, J ϭ 6.0 Hz, 3 H), 1.88 (br s, 2 H),
2.06 (t, J ϭ 2.7 Hz, 1 H), 2.31Ϫ2.70 (m, 4 H), 4.21 (q, J ϭ 7.2 Hz,
2 H), 5.01Ϫ5.23 (m, 2 H), 5.61Ϫ5.82 (m, 1 H).
Acknowledgments
We are thankful to DST, New Delhi for the financial support. N.
S and E. B thank CSIR, New Delhi for the award of Fellowships.
We also thank RSIC-Mumbai, TIFR & Dr. M. S. Nair for record-
ing the spectral data.
[1]
C. Cativiela, M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry
Ethyl N-acetamido-(؎)2-allyl-4-pentynoate (16): To a solution of
the above amino ester (346 mg, 1.9 mmol) in dichloromethane
(20 mL) was added a catalytic amount of DMAP and acetic anhyd-
ride (520 mg, 5.0 mmol). The resulting reaction mixture was stirred
at room temp. for 8 h. Then, the reaction mixture was concentrated
and the residue was chromatographed on a silica gel column (1:5
ethyl acetate/hexane) to give crystalline product 16 (300 mg, 70%).
M.p. 90Ϫ91 °C. Ϫ IR (neat): ν˜ ϭ 3419 1735, 2121, 1647cmϪ1. Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 1.30 (t, J ϭ 7.2 Hz, 3 H), 1.96
(t, J ϭ 2.4 Hz, 1 H), 2.09 (s, 3 H), 2.49 (dd, J ϭ 7.5, 13.5 Hz, 1
H), 2.79 (d 1/2 ABq, J ϭ 2.7, 16.8 Hz, 1 H), 3.12 (dd, J ϭ 7.5,
13.5 Hz, 1 H), 3.34 (d 1/2 ABq, J ϭ 3.0, 17.1 Hz, 1 H), 4.26 (dq,
J ϭ 1.8, 5.4 Hz, 2 H), 5.07Ϫ5.15 (m, 2 H), 5.53 (m, 1 H), 6.35 (s,
1 H). Ϫ 13C NMR (75.43 MHz, CDCl3): δ ϭ 14.2, 23.8, 25.0, 39.0,
62.2, 62.7, 70.8, 79.3, 119.6, 131.5, 169.5, 171.8. Ϫ MS: m/z ϭ 223
[Mϩ]. Ϫ C12H17NO3 (223.27): calcd. C 64.53, H 7.67, N 6.27; found
C 64.31, H 7.41, N 6.01.
2000, 11, 645; S. E. Gibson, N. Guillo, M. J. Tozer, Tetrahedron
1999, 55, 585; A. Giannis, T. Kolter, Angew. Chem. Int. Ed.
Engl. 1993, 32, 1244; R. O. Duthaler, Tetrahedron 1997, 50,
1539; R. M. Williams, Synthesis of Optically Active α-Amino
Acids, Pergamon Press, Oxford, 1989; M. Goodman, H. Shao,
Pure Appl. Chem. 1996, 68, 1303; J. Gante, Angew. Chem. Int.
Ed. Engl. 1994, 33, 1699; R. M. J. Liskamp, Angew. Chem. Int.
Ed. Engl. 1994, 33, 305; C. E. Toniolo, Benedetti, ISI Atlas of
Science; Biochemistry 1988, 225.
[2]
E. Gavuzzo, G. Lucente, F. Mazza, G. P. Zecchini, M. P. Parad-
isi, G. Pochetti, I. Torrini, Int. J. Peptide. Protein. Res. 1991,
38, 268; I. Torrini, G. P. Zecchini, M. P. Paradisi, G. Lucente,
E. Gavuzzo, F. Mazza, G. Pochetti, S. Spisani, A. L. Giuliani,
Int. J. Peptide. Protein. Res. 1991, 38, 495.
[3]
H. Josien, S. Lavielle, A. Brunissen, M. Saffroy, Y. Torrens, J-
C. Beaujouan, J. Glowinski, G. Chassaing, J. Med. Chem. 1994,
37, 1586.
[4]
P. Balaram, Curr. Opin. Struct. Biol. 1992, 2, 845; C. L.
Wysong, T. S. Yokum, M. L. McLaughlin, R. P. Hammer.
ChemTech 1997, 26.
[5]
V. W. Cornish, P. G. Schultz, Curr. Opin. Struct. Biol. 1994,
Ethyl (؎)-1-Acetamido-3-cyclopentene-3-vinyl-1-carboxylate (15):
To a solution of the enyne building block 16 (200 mg, 0.86 mmol)
in CH2Cl2 (10 mL) was added GrubbsЈ catalyst [Cl2(PCy3)2Ruϭ
CHPh] (73 mg 0.086 mmol) (10 mol%) and the reaction mixture
was stirred at room temp. for 24 h under an argon atmosphere. The
reaction mixture was then concentrated under vacuum and purified
on a silica gel column by eluting with petroleum ether/ethyl acetate
(5:1) to give 15 (150 mg, 75%) as a crystalline product. M.p. 85Ϫ86
°C. Ϫ IR (neat): ν˜ ϭ 3296, 1732, 1663 cmϪ1. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 1.26 (t, J ϭ 7.2 Hz, 3 H), 1.98 (s, 3 H),
2.74 (dd, J ϭ 16.2, 16.7 Hz, 2 H), 3.17 (dd, J ϭ 16.5, 15.9 Hz, 2
H), 4.21 (q, J ϭ 7.2 Hz, 2 H), 5.04Ϫ5.12 (m, 2 H), 5.62 (s, 1 H)
6.10 (s, 1 H), 6.51 (dd, J ϭ 10.8, 17.4 Hz, 1 H). Ϫ 13C NMR
(75.43 MHz, CDCl3): δ ϭ 14.0, 22.9, 42.5, 44.3, 61.5, 64.1, 115.1,
126.5, 132.5, 140.1, 170.0, 173.4. Ϫ MS: m/z ϭ 223 [Mϩ]. Ϫ EI-
4, 601.
[6]
F. Trigalo, D. Buisson, R. Azerad, Tetrahedron Lett. 1988, 29,
6109.; A. Bhandari, D. G. Jones, J. R. Schulleck, K.Vo, C. A.
Schunk, L. L. Tamanaha, D.Chen, Z. Yuan, M. C. Needels,
M. A. Gallop, Bioorg. Med. Chem. Lett. 1998, 8, 2303 and
references cited therein.
[7]
G. L. Grunwald, S. H. Kuttab, M. A. Pleiss, J. B. Mangold, P.
Sione, J. Med. Chem. 1980, 23, 754.
[8] [8a]
S. Kotha, E. Brahmachary, J. Org. Chem. 2000, 65, 1359.
Ϫ
Ϫ
[8b] S. Kotha, N. Sreenivasachary, Chem. Commun. 2000, 503.
[8c]
S. Kotha, E. Brahmachary, Tetrahedron Lett. 1997, 38,
[8d]
3561. Ϫ
S. Kotha, E. Brahmachary, N. Sreenivasachary,
Tetrahedron Lett. 1998, 39, 4095.
[9]
C. R. Ganellin, Adv. Drug. Res, Vol 4, 163; B. Hong, S. Sarshar,
Org. Pre. Proc. Int. 1999, 31, 1.
S. Kotha, E. Brahmachary, Bioorg. & Med. Chem. Lett. 1997,
7, 2719 and references cited therein
A. Mazon, C. Najera, J. Ezequerra, C. Pedregal, Tetrahedron
Lett. 1995, 36, 7697; B. Møller, K. Undheim, Tetrahedron 1998,
54, 5789 and references cited therein.
[10]
[11]
HRMS (C10H12NO3 [M
194.0815.
Ϫ C2H5]): calcd. 194.0817; found
Eur. J. Org. Chem. 2001, 787Ϫ792
791

S. Kotha, N. Sreenivasachary, E. Brahmachary
FULL PAPER
[12]
D. P. G. Hamon, P. R. Spurr, Synthesis 1981, 873 and refer-
21, 3491; M. J. O’Donnell, R. L. Plot, J. Org. Chem. 1982, 47,
2663; A. Lopez, M. Moreno-Manas, R. Pleixats, A. Roglans,
Tetrahedron 1996, 52, 8365; E. A. Mash, L. J. Williams, S. S.
Pfeiffer, Tetrahedron Lett. 1997, 38, 6977.
G. M. Schuster, S. Blechert, Angew. Chem. Int. Ed. Engl. 1997,
36, 2036; Alkene Metathesis in Organic Synthesis (Ed.: A.
Furstner), Spinger, Berlin, 1998; A. Kinoshita, M. Mori, Syn-
lett 1994, 1020; R. H. Grubbs, S. J. Miller, G. C. Fu, Acc. Chem.
Res. 1995, 28, 446.
ences cited therein.
[13]
A. C. Cope, F. Kagan, J. Am. Chem. Soc. 1958, 80, 5499; Y.
Gaoni, S. Sadeh, J. Org. Chem. 1980, 45, 871 and references
[18]
[19]
cited therein.
[14]
For reviews on the synthetic utility of α-metalated isocyanides
see: D. Hoppe, Angew. Chem. Int. Ed. Engl. 1974, 13, 789; U.
Schollkopf, D. Hoppe, R. Jentsch, Chem. Ber. 1975, 108, 1592;
K. Ramalingam, D. Kalvin, R. W. Woodard, J. Lebel. Comp.
1984, 21, 833.
C. P. Dell, J. Chem. Soc., Perkin Trans. 1 1998, 3873; W. Carru-
thers, Cycloaddition Reactions in Organic Synthesis, Pergamon
Press, Oxford, 1990; F. Fringuelli, A. Taticchi, Dienes in the
DielsϪAlder Reaction, John Wiley, New York, 1990.
Received July 27, 2000
[15]
L. Waykole, L. Paquette, Org. Synth. 1988, 67, 149; E. Corey,
R. A. Ruden, Tetrahedron Lett. 1973, 1495; J. A. Miller, G.
Zweifel, Synthesis 1983, 128.
[16]
P. P. Fu, R. G. Harvey, Chem. Rev. 1978, 78, 317.
[17]
G. Stork, A. Y. W. Leong, A. M. Touzin, J. Org. Chem. 1976,
[O00393]
792
Eur. J. Org. Chem. 2001, 787Ϫ792