Convenient Synthesis of 3,4-methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid and Its Derivatives as Doubly Constrained Nonproteinogenic Amino Acid Derivatives

Article abstract of DOI:10.1021/jo9917994

Three strategies for the synthesis of the novel, doubly constrained, 3,4-methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and its derivatives were evaluated. Only cyclocondensation of the mono(triphenyl)phosphonium salt derived from 1,2-bis(bromomethyl)benzene with N-alkoxycarbonyloxamates in 1,2-dimethoxyethane in the presence of potassium carbonate and subsequent cyclopropanation with dimethylsulfoxonium methylide in dimethyl sulfoxide furnished suitable O-and N-protected derivatives of 3,4-methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in a convenient way. A detailed 2D DQF-COSY and 2D NOESY NMR analysis of the rotational isomerism of the latter bicyclic amino acid derivatives was performed. Various O- and N-protection protocols were worked out to afford access to a whole range of new derivatives of the title amino acid, suitable for peptide synthesis.

Full text of DOI:10.1021/jo9917994

J . Org. Chem. 2000, 65, 5469-5475
5469
Con ven ien t Syn th esis of
3,4-m eth a n o-1,2,3,4-tetr a h yd r oisoqu in olin e-3-ca r boxylic Acid a n d
Its Der iva tives a s Dou bly Con str a in ed Non p r otein ogen ic Am in o
Acid Der iva tives
J o´zsef Czombos,†,¶ Wim Aelterman,† Alexey Tkachev,‡ J ose´ C. Martins,§ Dirk Tourwe´,|
Antal Pe´ter, Ge´za To´th,# Ferenc Fu¨lo¨p,$ and Norbert De Kimpe*,†
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences,
University of Gent, Coupure Links 653, B-9000 Gent, Belgium, Novosibirsk Institute of Organic
Chemistry, Novosibirsk, 630090 Russia, HNMR Center (HNMR) and Laboratory of Organic Chemistry
(ORGC), Free University of Brussels, Pleinlaan 2, B-1050 Brussels, Belgium, Department of Inorganic
and Analytical Chemistry, University of Szeged, P.O. Box 440, H-6701 Szeged, Hungary, Biological
Research Center, Hungarian Academy of Sciences, Isotope Laboratory, B-Level, P.O. Box 521,
H-6701 Szeged, Hungary, and Institute of Pharmaceutical Chemistry, University of Szeged,
P.O. Box 121, H-6701 Szeged, Hungary
norbert.dekimpe@rug.ac.be
Received November 19, 1999
Three strategies for the synthesis of the novel, doubly constrained, 3,4-methano-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylic acid and its derivatives were evaluated. Only cyclocondensation of the
mono(triphenyl)phosphonium salt derived from 1,2-bis(bromomethyl)benzene with N-alkoxycar-
bonyloxamates in 1,2-dimethoxyethane in the presence of potassium carbonate and subsequent
cyclopropanation with dimethylsulfoxonium methylide in dimethyl sulfoxide furnished suitable O-
and N-protected derivatives of 3,4-methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in a
convenient way. A detailed 2D DQF-COSY and 2D NOESY NMR analysis of the rotational
isomerism of the latter bicyclic amino acid derivatives was performed. Various O- and N-protection
protocols were worked out to afford access to a whole range of new derivatives of the title amino
acid, suitable for peptide synthesis.
In tr od u ction
There is currently considerable interest in the synthe-
sis of peptides incorporating conformational constraints.
These peptidomimetics often provide both enhanced
biological activities and greater proteolytic stabilities.1
The concept of the topographical design of peptide ligands
with improved selectivity and metabolic stability was
introduced by Hruby et al.2 A particular three-dimen-
sional arrangement of the peptide side chains is obtained
by appropriately constraining, biasing or fixing the side-
chain conformers. This approach requires the availability
of a set of amino acids with complementary conforma-
tional properties.
The phenylalanine side chain has been constrained by
the use of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
1 (Tic), 2-aminotetraline-2-carboxylic acid 2 (Atc), 2-
aminoindane-2-carboxylic acid 3 (Aic),3 and 4-amino-
F igu r e 1. Depiction of various nonproteinogenic amino acids
obtained by constraining the side chain in phenylalanine:
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1 (Tic), 2-
aminotetraline-2-carboxylic acid 2 (Atc), 2-aminoindane-2-
carboxylic acid 3 (Aic), and 4-amino-1,2,4,5-tetrahydrobenzo-
[c]azepin-3-one 4 (Aba), and the newly synthesized 3,4-
methano-Tic 5.
† University of Gent.
‡ Novosibirsk Institute of Organic Chemistry.
§ HNMR Center (HNMR), Free University of Brussels.
| Laboratory of Organic Chemistry (ORGC), Free University of
Brussels.
Department of Inorganic and Analytical Chemistry, University of
Szeged.
1,2,4,5-tetrahydrobenzo[c]azepin-3-one 4 (Aba)4 (Figure
1). Tic has been successfully used in the synthesis of
#
Hungarian Academy of Sciences.
Institute of Pharmaceutical Chemistry, University of Szeged.
On leave from the Department of Organic Chemistry, University
$
¶
of Szeged, Szeged, Hungary.
(3) Schiller, P. W.; Weltrowska, G.; Nguyen, T. M.-D.; Lemieux, C.;
Chung, N. N.; Marsden, J . B.; Wilkes, B. C. J . Med. Chem. 1991, 34,
3125-3132.
(4) Tourwe´, D.; Verschueren, K.; Frycia, A.; Davis, P.; Porreca, F.;
Hruby, V. J .; Toth, G.; J aspers, H.; Verheyden, P.; Van Binst, G.
Biopolymers 1996, 38, 1-12.
(1) Biagini, S. C. G.; North, M. In Amino Acids, Peptides and
Proteins Specialist Periodicals Reports; Davies, J . S., Ed.; The Royal
Society of Chemistry: London, 1996; Vol. 27, Chapter 3..
(2) Hruby, V. J .; Al-Obeidi, F.; Kazmierski, W. Biochem. J . 1990,
268, 249-262.
10.1021/jo9917994 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

5470 J . Org. Chem., Vol. 65, No. 18, 2000
Czombos et al.
Sch em e 1a
a
Key: (i) 1 equiv of NCS, diethyl ether, 0 °C to rt, 1 h; (ii) 1.2 equiv of Et3N, diethyl ether, 0 °C to rt, 2 h; (iii) 2 equiv of NCS, diethyl
ether, 0 °C to rt, 1 h; (iv) 2 equiv of Et3N, diethyl ether, 0 °C to reflux, 20 h, 90%.
Sch em e 2a
a
Key: (i) 5 equiv of PhCH2I, acetone, rt, 4 d; (ii) 8 equiv of NaBH4, ethanol, rt, 1 h; (iii) Me3SO+I-, NaH, DMSO, rt, 1 d or CH2N2,
diethyl ether, Pd(OAc)2, rt, 2 h.
bradykinin antagonists,5 ACE inhibitors,6 renin inhibi-
tors7 and opioid antagonists.8-10 The incorporation of a
Tic residue at an internal position in a peptide has been
shown to result in a gauche (+) conformation for its side
chain, whereas a Tic residue at the N-terminal position
takes up a gauche (-) conformation.2 As a result of its
secondary amine structure, however, the Tic residue
causes a cis/trans conformational equilibrium around the
peptide bond, which complicates the interpretation of the
conformational data. For instance, for the δ-opioid an-
tagonist Tyr-Tic-Phe-Phe-OH (TIPP-OH), models for the
receptor-bound conformation having either a trans or a
cis Tyr-Tic peptide bond have been proposed.11
Cyclopropane amino acids or methano amino acids are
of broad interest as biological probes, enzyme inhibitors,
and conformationally constrained analogues of native
amino acids.12 Since the cyclopropane ring introduces a
steric constraint into the amino acid, changes in chemical
reactivity of the functional groups result. The cyclopro-
pane ring exhibits a certain “unsaturated character”,
which results in a restriction of the torsion angles about
the CR-CdO bond to small values, due to conjugation of
the carbonyl group with the ring. More specifically, the
1-aminocyclopropane carboxylic acid residue has been
shown to exhibit a marked preference for the conforma-
tional space φ, ψ ) (90°, 0°, i.e., for the position i + 2 of
type I and type II â-turns.13 For methano methionine, a
preference for the γ-turn conformation has been ob-
served.14 In peptides, significant changes are caused in
the conformation, which in turn may affect the ability of
the peptide to fit a receptor.12 It is interesting, therefore,
to synthesize the hitherto unknown 3,4-methano-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid 5 (Figure 1) and
its derivatives as a combination of a sterically constrained
1-aminocyclopropane-1-carboxylic acid and a 1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid, which might
reduce the structural promiscuity present in each of them
separately.
To synthesize the title compound 5, two important
problems had to be solved. First, it was necessary to
prepare a 1,2-dihydroisoquinoline-3-carboxylic acid de-
rivative, e.g., 7 (Scheme 1), which has often been con-
sidered to be a very unstable species. Second, the
cyclopropanation of a 1,2-dihydroisoquinoline moiety,
bearing an electron-attracting carboxyl function adjacent
to the double bond, should be accomplished, with subse-
quent focus on a suitable deprotection protocol, leaving
the cyclopropane unit untouched. Many of the substituted
1,2-dihydroisoquinolines are rather difficult to prepare
and to purify.15-17 Common methods for the synthesis can
be classified in two approaches: (1) reduction of isoquino-
lines or isoquinolinium salts,15 and (2) construction of the
1,2-dihydroisoquinoline skeleton either by cyclization of
N-benzylaminoacetaldehyde dialkyl acetals15,16 or by
Wittig reaction of N-alkoxycarbonylcarbamates with
ω-halogenated phosphorus ylides.17 Ethyl 1,2-dihydro
isoquinoline-3-carboxylate was previously prepared in six
steps in an overall yield of 20% by intramolecular 1,3-
dipolar cycloaddition, but the compound proved unstable
in air.18
The present paper describes a facile synthesis of 3,4-
methano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
5 via cyclopropanation of the corresponding N- and
O-protected 1,2-dihydroisoquinoline derivatives 17a ,b
with dimethylsulfoxonium methylide (Schemes 3 and 4).
The N-protected dihydro compounds 17a -c were pre-
pared via Wittig reaction of the phosphorus ylide of 16
with N-alkoxycarbonyloxamates 14a -c and subsequent
ring closure (Scheme 3).17
(5) Kyle, D. J .; Martin, J . A.; Farmer, S. G.; Birch, R. M. J . Med.
Chem. 1991, 34, 1230-1233.
(6) Klutchko, S.; Blankley, C. J .; Fleming, R. W.; Hinkley, J . M.;
Werner, A. E.; Nordin J .; Holmes, A.; Hoefle, M. L.; Cohen, D. M. J .
Med. Chem. 1986, 29, 1953-1961.
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T.; Batley, B. L.; Lunney, E. A.; Ryan, M. J .; Hicks, G. W. Bioorg. Med.
Chem. Lett. 1994, 4, 2029-2034.
(8) Kazmierski, W.; Hruby, V. J . Tetrahedron 1988, 44, 697-710.
(9) Schiller, P. W.; Nguyen, T. M.-D.; Weltrowska, G.; Wilkes, B.
C.; Marsden, B. J .; Lemieux, C.; Chung, N. N. Proc. Natl. Acad. Sci.
U.S.A. 1992, 89, 11871-11875.
(10) Tancredi, T.; Salvadori, S.; Amodeo, P.; Picone, D.; Lazarus, L.
H.; Bryant, S. D.; Guerrini, R.; Marzola, G.; Temussi, P. A. Eur. J .
Biochem. 1994, 224, 241-247.
(15) Dyke, S. F. Adv. Heterocycl. Chem. 1972, 14, 279-329.
(16) Perschonok, C. D.; Lantos, I.; Finkelstein, J . A.; Holden, K. G.
J . Org. Chem. 1980, 45, 1950-1953.
(11) Wilkes, B. C.; Schiller, P. W. Biopolymers 1995, 37, 391-400.
(12) Stammer, C. H. Tetrahedron 1990, 46, 2231-2254.
(13) Toniolo, C.; Crisma, M.; Formaggio, F.; Benedetti, E.; Santini,
A.; Iacovino, R.; Saviano, M.; Di Blasio, B.; Pedone, C.; Kamphuis J .
Biopolymers 1997, 40, 519-522.
(17) Bazureau, J . P.; Le Roux, J .; Le Corre, M. Tetrahedron Lett.
1988, 29, 1921-1922.
(18) Liu, J .-M.; Young, J .-J .; Li, Y.-J .; Sha, C.-K. J . Org. Chem. 1986,
51, 1120-1123.
(14) Burgess, K.; Ke, C.-Y. J . Org. Chem. 1996, 61, 8627-8631.

Doubly Constrained Nonproteinogenic Amino Acid Derivatives
J . Org. Chem., Vol. 65, No. 18, 2000 5471
Sch em e 3a
tion with N-chlorosuccinimide (NCS) and subsequent
dehydrochlorination with triethylamine (Scheme 1). The
N-chlorination of Tic methyl ester 6 in dry diethyl ether
with 1 equiv of NCS at 0 °C to room temperature for 1 h
proceeded well, as monitored by TLC. The corresponding
N-chloro compound was fairly stable in solution under
an inert atmosphere, but all attempts to isolate it
resulted in significant decomposition. The addition of 1.2
equiv of triethylamine to the reaction mixture of the
N-chloro compound at 0 °C and further stirring at room
temperature for 2 h resulted in a complex mixture of
which the 1H NMR spectrum showed the presence of
starting material 6 (23%), 1,2-dihydroisoquinoline de-
rivative 7 (66%), and the aromatized isoquinoline deriva-
tive 8 (11%). When 2 equiv of NCS and 2 equiv of
triethylamine were used and the reaction was run for
20 h under reflux, a complete conversion to methyl
isoquinoline-3-carboxylate 8 was attained. Any attempt
to produce an N-protected derivative of 7 by reaction of
the crude reaction mixture (containing 66% of dihydro
compound 7) with methyl chloroformate, di-tert-butyl
dicarbonate, or acetic anhydride failed.
An alternative route was evaluated by reduction of a
functionalized quaternary isoquinolinium salt 9 (Scheme
2). Reduction of the N-methyl quaternary salt derived
from ethyl isoquinoline-3-carboxylate proceeded in a
facile way with NaBH4 in ethanol.18 In an analogous
manner, the N-benzyl quaternary salt 9 was prepared
in 81% yield by reaction with 5 equiv of benzyl iodide in
acetone at room temperature for 4 days in the dark.
Benzyl iodide was prepared from benzyl bromide with
NaI in acetone at room temperature for 1 day. Reduction
of compound 9 with an excess of NaBH4 in ethanol at
room temperature for 1 h took place quantitatively, as
monitored by TLC. The isolated dihydro compound 10
proved to be quite unstable in air. However, it was
a
Key: (i) 1.1 equiv of (COCl)2, 1,2-dichloroethane, ∆, 16 h; (ii)
2 equiv of ROH, diethyl ether, 0 °C to rt, 2-4 h; (iii) 2.2 equiv of
PPh3, benzene, ∆, 8 h; (iv) 1.5 equiv of 14a -c, DME, 2 equiv of
K2CO3, ∆, 8 h; (v) 1.34 equiv of Me3SO+I-, 1.28 equiv of NaH,
DMSO, rt, 1 d.
Sch em e 4a
1
possible to analyze it by H and 13C NMR, IR, and mass
spectroscopy. Attempts to produce compound 11 via the
cyclopropanation of methyl 2-benzyl-1,2-dihydroisoquino-
line-3-carboxylate 10 with diazomethane and dimethyl-
sulfoxonium methylide failed (Scheme 2).
The third attempted approach consisted in building up
the skeleton of the 1,2-dihydroisoquinoline-3-carboxylic
acid derivatives, following the synthesis of 2-methoxy-
carbonyl-1,2-dihydroisoquinoline-3-carboxylic acid ester
17a in a Wittig reaction and ring closure17 (Scheme 3).
Ethoxycarbonylcarbonyl isocyanate 13 was prepared by
a known method21 from ethyl oxamate 12 with a slight
excess of oxalyl chloride in 1,2-dichloroethane under
reflux for 16 h. The functionalized isocyanate 13 reacted
with the corresponding dry alcohols in diethyl ether at 0
°C to room temperature to afford the 2-alkoxycarbonyl-
oxamates 14a -c in 90-95% yield. The monophospho-
nium salt 16 was prepared from 1,2-bis(bromomethyl)-
benzene 15 and an excess of triphenylphosphine in
benzene under reflux for 8 h according to a literature
method.22 Ethyl 2-alkoxycarbonyl-1,2-dihydroisoquino-
line-3-carboxylates 17a -c were prepared in one step
from an excess of oxamate 14a -c and the phosphorus
ylide derived of 16 in 1,2-dimethoxyethane at 85 °C for
a
Key: (i) 10 equiv of 6 N HCl, ∆, 1 d, 57%; (ii) 1.5 equiv of 1 N
NaOH, rt, 1 d, 91%; (iii) 5 equiv of 4 N NaOH, ∆, 1 d, 95%; (iv) 10
equiv of 6 N HCl, ∆, 1 d, then propylene oxide, EtOH, rt, 30 min,
69%; (v) HCl, diethyl ether, rt, 30 min, then propylene oxide,
EtOH, rt, 30 min, 86%; (vi) 12 N HCl, EtOAc, rt, 30 min, NaHCO3
92% or HCl, diethyl ether, rt, 30 min, 90% (hydrochloride); (vii)
2.5 equiv of 1 N NaOH, rt, 1 d, ion exchange, 42%.
Resu lts a n d Discu ssion
The first approach to the preparation of methyl 1,2-
dihydroisoquinoline-3-carboxylate 7 was the selective
oxidation of Tic methyl ester19 6 by means of N-chlorina-
(20) Dyke, S. F.; Sainsbury, M.; Evans, J . R. Tetrahedron 1973, 29,
213-220.
(21) Speziale, A. J .; Smith, L. R. J . Org. Chem. 1962, 27, 3742-
3743.
(19) Hayaski, K.; Ozaki, Y.; Nuniami, K.-I.; Yoneda, N. Chem.
Pharm. Bull. 1983, 31, 312-314.
(22) Griffin, C. E.; Martin, K. R.; Douglas, B. E. J . Org. Chem. 1962,
27, 1627-1631.

5472 J . Org. Chem., Vol. 65, No. 18, 2000
Czombos et al.
8 h17 (Scheme 3). The reaction products 17a -c were
purified by Kugelrohr distillation and/or silica gel chro-
matography. In contrast with the N-unprotected or
N-benzyl-protected methyl 1,2-dihydroisoquinoline-3-car-
boxylates18 7 or 10, these urethanes proved stable for
months at room temperature. During the synthesis,
minor amounts of numerous unstable compounds were
formed, as detected by TLC. These impurities decom-
posed during standing for a few days at room tempera-
ture, which facilitated purification of the main com-
pounds 17a -c. Thus, 17a was purified by Kugelrohr
distillation and silica gel chromatography, while 17b
could not be distilled, but column chromatography re-
sulted in a pure crystalline compound in high yield. In
contrast, the 2-benzyloxycarbonyl derivative 17c was
formed in much lower yield, with many side-products.
Most of the contaminants were separated by silica gel
chromatography (30% diethyl ether/hexane) but the
purified product (yield 40%) was still a mixture of two
revealed a gradual broadening and finally a coalescence
of the major with the minor signals. Moreover, in the 2D
NOESY spectra at 40 °C, intense exchange cross-peaks
were observed between the major and minor resonances
of the CH2 protons at C-1. Since the largest chemical shift
differences between the major and the minor conformers
are observed for the CH2 protons at C-1 and for the
methyl protons of the carbamate function, the isomerism
can be attributed to a slow rotation about the urethane
amide bond, as expected.
Because of the steric constraint caused by the cyclo-
propane ring, a decreased chemical reactivity of the
functional groups is anticipated.15 Hydrolysis of the ethyl
ester 18a to carboxylic acid 19a with 1 N NaOH pro-
ceeded at room temperature during 1 day, but the
sterically more hindered 18b reacted only under more
drastic conditions toward 19b: 5 equiv of 4 N NaOH at
100 °C for 1 day (Scheme 4). Under these conditions, 18a
decomposed completely to give numerous ninhydrine-
positive spots on TLC. With 6 N HCl under reflux for 1
day, 18a was converted into N-protected amino acid 19a ,
together with some decomposition products. The Boc
protecting group of 18b and 19b was removed conven-
tionally with trifluoroacetic acid,28 with EtOAc/aqueous
12 N HCl29 or preferably with HCl/diethyl ether (17 g of
dry HCl in 100 mL of diethyl ether) because the hydro-
chlorides of 20 and 5 were easily handled, in contrast to
the corresponding TFA salts. The hydrochloride salt of
amino acid 5 was readily prepared in 71% yield from the
fully protected compound in one step by hydrolysis with
an excess of 6 N HCl at 100 °C for 1 day. The new free
amino acid 5 was prepared in 97% yield from its
hydrochloride with an excess of propylene oxide in
ethanol30 at room temperature for 30 min, this completing
the first synthesis of this doubly sterically constrained
bicyclic amino acid.
1
compounds (according to H NMR), displaying a single
Rf value in any solvent combination, and it was therefore
not characterized further, nor transformed into the
corresponding 3,4-methano-Tic.
In the 1H NMR spectra of compounds 17a -c, the δ
value of the olefinic hydrogen at position 4 is very
characteristic, close to the aromatic region (δ ∼7 ppm).
However, a literature report published a much lower δ
value.18 The chemical shift of the hydrogen at position 4
of ethyl 1,2-dihydroisoquinoline-3-carboxylate was as-
signed to 5.15 ppm in CDCl3.18 We have located this
hydrogen signal at 6.41 ppm for compound 7, 7.07 ppm
for 17a and 6.96 ppm for 17b, all in CDCl3.
Cyclopropanation of ethyl 2-alkoxycarbonyl-1,2-dihy-
droisoquinoline-3-carboxylate 17a ,b with diazomethane
failed when CuCl23 or Pd(II) acetate24 catalysis was
applied. Dimethylsulfoxonium methylide25 can cyclopro-
panate compounds which are susceptible to Michael
addition. Enhancement of the withdrawal of electron
density from the C-C double bond facilitates the reac-
tion.26 Dimethylsulfoxonium methylide proved a very
efficient cyclopropanating agent for compounds 17a ,b
(Scheme 3). Using a literature procedure27 to generate
the ylide from trimethylsulfoxonium iodide with NaH in
DMSO, the cyclopropanation reaction with compounds
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR and 13C NMR
spectra, including DEPT31 spectra, were recorded at 270 and
67.8 MHz, respectively, except for the NMR temperature study
and the 2D DQF-COSY32 and 2D NOESY33 spectra, which were
recorded at 500 MHz on a spectrometer equipped with a digital
lock system and an SGI O2 system for spectrometer control.
All 2D spectra were recorded in the phase-sensitive mode,
using TPPI.34 The total recycling delay was 2 s. Processing
consisted in multiplication with a π/2-shifted squared sinebell
in F2 and F1, followed by zero-filling along F1, yielding a final
2K by 2K complex data matrix after Fourier transformation
and polynomial baseline correction. For the DQF-COSY32 and
NOESY33 spectra, 512 FIDs of 4096 data points, 32 scans each
were recorded. For the NOESY33 spectrums, a mixing time of
500 ms was used. IR spectra were obtained on a Perkin-Elmer
spectrometer. Mass spectra were recorded at 70 eV. HRMS
spectra were recorded on a Finnigan 8200 instrument with
1
17a ,b was monitored by H NMR spectroscopy (disap-
pearance of the olefinic H-4 signal). Quantitative reaction
took place during 24 h at room-temperature yielding
17a ,b (Scheme 3). A higher temperature, e.g., 60 °C, did
not reduce the reaction time significantly.
The N-protected methano amino acid derivatives 18a ,b
exist as mixtures of two conformational isomers, as
1
indicated by their H NMR spectra. The ratio of the two
conformers was 7:3 for 18a and 8:2 for 18b. A complete
assignment of all the signals of the major and the minor
isomers of 18a was performed at 500 MHz, using 2D
DQF-COSY and 2D NOESY spectra recorded at 40 °C.
Clear proof of the conformational isomerism was obtained
from a temperature study between 30 and 80 °C, which
(28) Lundt, R. S.; J ohansen, N. L.; Volund, A.; Markussen, J . Int.
J . Pept. Protein Res. 1978, 12, 258-268.
(29) Donati, D.; Garzon-Abusbeth, A.; Natalini, B.; Marchioro, C.;
Pelliciari, R. Tetrahedron 1996, 52, 9901-9908.
(30) J imenez, J . M.; Ortuno, R. M. Tetrahedron: Asymmetry 1996,
7, 3203-3208.
(23) Doering, W. v. E.; Roth, W. R. Tetrahedron 1963, 19, 715-737.
(24) Paulissen, R.; Hubert, A. J .; Teyssie, P. Tetrahedron Lett. 1972,
1465-1466.
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1983, 48, 323-327.
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1982, 104, 6800-6801.
1364.
(26) Reddy, M. V. R.; Reddy, D. B.; Reddy, P. V. R.; Vijayalakshami,
S. Org. Prep. Proced. Int. 1991, 23, 633-638.
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Chem. 1972, 37, 2436-2443.
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967-974.

Doubly Constrained Nonproteinogenic Amino Acid Derivatives
J . Org. Chem., Vol. 65, No. 18, 2000 5473
an electron impact ionization technique (70 eV). Column
chromatography was performed on silica gel (0.035-0.07 mm)
with different solvent combinations, via initial TLC analysis.
TLC solvent systems: A: CHCl3/acetone ) 9/1, B: CHCl3/
MeOH ) 9/1, C: diethyl ether/hexane ) 4/6, D: diethyl ether/
hexane ) 1/1, E: n-BuOH/AcOH/H2O ) 4/1/1.
t, J ) 7.1 Hz, CH3-CH2), 3.86 (3H, s, O-CH3), 4.41 (2H, q, J
) 7.1 Hz, O-CH2), 8.86 (1H, br s, NH); 13C NMR (CDCl3) δ
13.9 (CH3-CH2), 53.6 (O-CH3), 64.0 (O-CH2), 150.9, 155.4,
159.4 (3 × CdO); IR (KBr, cm-1) 1710, 1738, 1788 (CdO); MS
m/z (rel int) 175(0.3, M+), 59 (100); HRMS analysis C6H9NO5
requires M+ 175.04807, found M+ 175.04803.
Ethyl oxamate and 1,2-bis(bromomethyl)benzene were com-
mercially available products and were used as received.
2-Ben zyl-3-m eth oxyca r bon ylisoqu in olin iu m Iod id e 9.
A solution of 2.24 g (12 mmol) of methyl isoquinoline-3-
carboxylate19 8 and 13.08 g (60 mmol) of benzyl iodide in 5
mL of dry acetone was kept in the dark at room temperature
for 4 days. The reaction could be monitored by TLC. Dry
diethyl ether (50 mL) was added to the deep-brown solution
in order to precipitate the oily quaternary salt. Trituration
several times with diethyl ether resulted in a solid material,
which was recrystallized from methanol/diethyl ether to afford
3.92 g (81%) of light-brown crystals: Rf 0.1 (A); mp 112-114
°C; 1H NMR (CDCl3) δ 4.01 (3H, s, OCH3), 6.62 (2H, s, Ph-
CH2), 7.35-7.46 (5H, m, Ph-CH2), 8.1-8.26 (3H, m, aromatic
H), 8.81 (1H, s, aromatic H), 9.07 (1H, s, H-4), 11.74 (1H, s,
H-1);13C NMR (CDCl3) δ 54.7 (O-CH3), 62.1 (Ph-CH2), 128.0,
132.7, 133.0 (aromatic quaternary C), 128.7, 129.3, 129.7,
131.8, 133.6 (aromatic CH), 136.8 (C-3), 138.8 (C-4), 153.7 (C-
1), 160.7 (COO); IR (KBr, cm-1) 1755 (CdO).
Eth yl N-ter t-bu toxyca r bon yloxa m a te 14b: oil; yield
1
93%; Rf 0.66 (A); H NMR (CDCl3) δ 1.40 (3H, t, J ) 7.1 Hz,
CH3-CH2), 1.52 (9H, s, ((CH3)3), 4.39 (2H, q, J ) 7.1 Hz, OCH2),
9.13 (1H, br s, NH); 13C NMR (CDCl3) δ 13.9 (CH3-CH2), 27.9
((CH3)3), 63.5 (OCH2), 83.6 ((CH3)3 C-O), 149.3, 155.6, 159.8
(3 × CdO); IR (NaCl, cm-1) 1710, 1739, 1786 (CdO); MS m/z
(rel int), no M+, 57(100). Anal. Calcd for C9H15NO5: C, 49.76;
H, 6.96; N, 6.45. Found: C, 49.98; H, 6.79; N, 6.49.
Eth yl N-Ben zyloxyca r bon yloxa m a te 14c. A total of 1.1
equiv of benzyl alcohol was used, with stirring for 4 h at room
temperature, giving an oil, yield 95% (containing about 5% of
benzyl alcohol), Rf 0.62 (A). Compound 14c is quite unstable,
and no satisfactory elemental analysis or HRMS data could
be obtained: 1H NMR (CDCl3) δ 1.38 (3H, t, J ) 7.2 Hz, CH3-
CH2), 4.37 (2H, q, J ) 7.2 Hz, OCH2), 5.24 (2H, s, Ph-CH2),
7.33-7.42 (5H, m, Ph-CH2), 8.92 (1H, br s, NH); 13C NMR
(CDCl3) δ 13.8 (CH3-CH2), 63.9 (OCH2), 68.4 (Ph-CH2), 128.4,
128.6, 128.7, 128.8, 128.9 (aromatic CH), 134.6 (aromatic
quaternary C) 150.2, 155.5, 159.3 (3 × CdO); IR (NaCl, cm-1
)
Meth yl 2-Ben zyl-1,2-d ih yd r oisoqu in olin e-3-ca r boxy-
la te 10. To a stirred suspension of 1.22 g (3 mmol) of
quaternary salt 9 in 30 mL of ethanol was added 0.23 g (6
mmol) of NaBH4 in small portions under nitrogen at 0 °C. The
as yet undissolved portion of the salt dissolved immediately,
and the brown color changed to yellow. Stirring was continued
1710, 1732, 1790 (CdO); MS m/z (rel int) 251 (3, M+), 145 (81),
91 (100).
2-(Br om om eth yl)ben zyltr ip h en ylp h osp h on iu m Br o-
m id e 16. This phosphonium salt was prepared according to a
literature procedure22 from 1,2-bis(bromomethyl)benzene 15
and triphenylphosphine in benzene under reflux during 8 h:
yield 98%; mp 238-240 °C (lit.22 mp 253-256 °C, yield 92%).
The crude product was used for the next step. A purified
sample, still containing 3-4% of the bis-phosphonium salt (1H
NMR) was obtained by recrystallization from ethanol/diethyl
ether: 1H NMR (CDCl3) δ 3.92 (2H, s, CH2Br), 5.39 (2H, d,
2J HP )14.2 Hz, CH2-P), 7.09-7.28 and 7.64-7.86 (19H, m,
aromatic H); 31P NMR (CDCl3 109 MHz, ref 85% H3PO4) δ
22.31. Anal. Calcd for C26H23Br2P: C, 59.34; H, 4.41. Found:
C, 59.99; H, 4.46.
E t h yl 2-Alk oxyca r b on yl-1,2-d ih yd r oisoq u in olin e-3-
ca r boxyla te 17a -c. These N-protected enaminoesters were
prepared according to a general literature method.17 A mixture
of 20 mmol (1.5 equiv) of carbamate 14a -c, 7.02 g (13.3 mmol)
of phosphonium salt 16 and 2.7 g (26.6 mmol) of dry K2CO3 in
50 mL of dry 1,2-dimethoxyethane was stirred at 85 °C for 8
h under a nitrogen atmosphere. After the reaction mixture was
cooled, 50 mL of water was added, and the solution was
extracted with dichloromethane (3 × 40 mL) and dried over
MgSO4. The solvent was evaporated off at reduced pressure,
and the residue was extracted with diethyl ether. The ethereal
solution was cooled in order to remove triphenylphosphine
oxide by crystallization. After filtration and evaporation of the
solvent, the crude products were purified by Kugelrohr distil-
lation and/or silica gel chromatography.
for 1 h at room temperature. TLC analysis revealed
a
quantitative reaction and a single product. The reaction
mixture was evaporated to dryness at 30 °C in vacuo, 10 mL
of water was added to the residue, and the solution was
extracted with diethyl ether. The combined extracts were
washed with 10 mL of water and dried over MgSO4. Evapora-
tion in vacuo afforded 0.75 g (90%) of a pale-yellow oil, which
1
was immediately subjected to analysis: Rf 0.9 (A); H NMR
(CDCl3) δ 3.83 (3H, s, O-CH3), 4.13 (2H, s, Ph-CH2 or H-1),
4.15 (2H, s, Ph-CH2 or H-1), 6.99 (1H, s, H-4), 7.17-7.39 (9H,
m, aromatic H); 13C NMR (CDCl3) δ 51.1 and 55.1 (Ph-CH2
and C-1), 52.1 (O-CH3) 118.5 (C-4), 125.1, 125.5, 127.2, 127.4,
128.3, 128.4, 128.6 (aromatic CH), 129.6, 131.8, 137.8, 138.5
(aromatic quaternary C and C-3), 165.4 (COO); IR (NaCl, cm-1
)
1711 (CdO), 1600 (CdC); MS m/z (rel int) 279 (14, M+), 91
(100).
Eth oxyca r bon ylca r bon yl Isocya n a te 13. This compound
was prepared analogously to a literature method.21 A total of
58.5 g (0.5 mol) of ethyl oxamate 12 was suspended in 500
mL of dry 1,2-dichloroethane, and 69.8 g (0.55 mol) of oxalyl
chloride was added. The resulting mixture was refluxed for
16 h, moisture being rigorously excluded. The solvent was
distilled off at normal pressure, using a 30 cm Vigreux column,
and the residue was further distilled under reduced pressure
without a column, to afford 48.8 g (68%) of compound 13: bp
Eth yl 2-Meth oxyca r bon yl-1,2-d ih yd r oisoqu in olin e-3-
ca r boxyla te 17a . The crude product was purified by Kugel-
rohr distillation: bp 120-130 °C (0.05 Torr) (lit.17 bp 135 °C
(1.3 Torr, yield 61%), followed by silica gel chromatography
(40% diethyl ether/hexane); colorless oil; yield 73%; Rf 0.44 (D);
1H NMR (CDCl3) δ 1.35 (3H, t, J ) 7.1 Hz, CH3-CH2), 3.71
(3H, s, OCH3), 4.31 (2H, q, J ) 7.1 Hz, O-CH2), 4.81 (2H, s,
H-1), 7.07 (1H, s, H-4), 7.14-7.31 (4H, m, aromatic H); 13C
NMR (CDCl3) δ 14.3 (CH3-CH2), 47.0 (C-1), 53.2 (OCH3), 61.3
(OCH2), 123.4, 125.3, 127.0, 127.9, 129.6 (aromatic CH and
C-4), 130.0, 130.6, 132.8 (aromatic quaternary C and C-3),
154.1 (NCOO), 163.7 (C-COO); IR (NaCl, cm-1) 1622 (CdC),
1710, 1760 (CdO); MS m/z (rel int) 261 (13, M+), 132 (100).
Eth yl 2-ter t-Bu toxyca r bon yl-1,2-d ih yd r oisoqu in olin e-
3-ca r boxyla te 17b. The oily crude product was purified by
silica gel chromatography (20% diethyl ether/hexane), afford-
ing a crystalline product: mp 85-86 °C (MeOH/H2O); yield
1
78 °C (10 Torr); H NMR (CDCl3) δ 1.44 (3H, t, J ) 7.1 Hz,
CH3-CH2), 4.46 (2H, q, J ) 7.1 Hz, O-CH2); 13C NMR (CDCl3)
δ 13.9 (CH3-CH2), 65.6 (O-CH2), 134.3 (NCO), 157.6, 158.1,
(2 × CdO); IR (NaCl, cm-1) 1715, 1737, 1780 (CdO), 2239 (Nd
CdO); MS m/z (rel int) 142 (4, M+ - 1), 91 (100).
Gen er a l P r oced u r e for Eth yl N-Alk oxyca r bon yloxa m -
a tes 14a -c. A solution of 7.15 g (0.05 mol) of ethoxycarbon-
ylcarbonyl isocyanate 13 in 50 mL of dry diethyl ether was
cooled in an ice bath. To this stirred solution, 0.1 mol of the
corresponding dry alcohol in 10 mL of dry ether was added
dropwise over a period of 15 min. The reaction mixture was
stirred further for 2-4 h at room temperature. Evaporation
of the solvent in vacuo afforded oily or crystalline products
which were generally sufficiently pure (>95%) for the next
step.
Eth yl N-Meth oxyca r bon yloxa m a te 14a . During the ad-
dition of methanol, this compound partially crystallized: yield
1
80%; Rf 0.58 (C); H NMR (CDCl3) δ 1.38 (3H, t, J ) 7.2 Hz,
1
90%; purity 100% (by H NMR); mp 90-92 °C (diethyl ether),
CH3-CH2), 1.43 (9H, s, (CH3)3), 4.31 (2H, q, J ) 7.2 Hz, OCH2),
4.80 (2H, s, H-1), 6.96 (1H, s, H-4), 7.18-7.29 (4H, m, aromatic
slightly hygroscopic; Rf 0.46 (A); 1H NMR (CDCl3) δ 1.41 (3H,

5474 J . Org. Chem., Vol. 65, No. 18, 2000
Czombos et al.
H); 13C NMR (CDCl3) δ 14.3 (CH3-CH2), 28.0 ((CH3)3), 46.5
(C-1), 61.3 (O-CH2), 81.8 ((CH3)3 C), 122.1 (C-4), 125.4, 126.8,
127.7, 129.3 (aromatic CH), 130.2, 131.1, 132.9 (aromatic
quaternary C and C-3), 152.3 (NCOO), 164.2 (C-COO); IR
(KBr, cm-1) 1630 (CdC), 1709, 1720 (CdO); MS m/z (rel int)
303 (9, M+), 202 (100); HRMS analysis C17H21NO4 requires M+
303.14705. found M+ 303.14747. Anal. Calcd for C17H21NO4:
C, 67.31, H, 6.98, N, 4.62; found. C, 67.77, H, 7.35, N,5.02.
Gen er a l P r oced u r e for Eth yl 2-Alk oxyca r bon yl-3,4-
m et h a n o-1,2,3,4-t et r a h yd r oisoq u in olin e-3-ca r b oxyla t e
18a ,b. Sodium hydride (0.31 g, 12.8 mmol, 0.51 g of 60% oily
dispersion) was washed three times with hexane. After
decantation, the remaining hexane was removed under vacuum.
The vacuum was released to a dry nitrogen source, and 2.95 g
(13.4 mmol) of dry trimethylsulfoxonium iodide was added. The
mixture was stirred, and 10 mL of dry dimethyl sulfoxide
(distilled over CaH2) was added dropwise. A vigorous evolution
of hydrogen ensued, which ceased after 15-20 min. After
additional stirring for 15 min, 10 mmol of the dihydroisoquino-
line compound 17a ,b in 10 mL of dry dimethyl sulfoxide was
added at room temperature and stirring was continued for 1
day. The reaction could be monitored by 1H NMR. The reaction
mixture was poured into 50 mL of cold water and extracted
with diethyl ether (3 × 60 mL). The combined extracts were
washed with water, dried over MgSO4 and evaporated in
vacuo, giving an oily or crystalline crude product. The com-
pounds were obtained as mixtures of rotational isomers, as
shown by their 1H and 13C NMR spectra. The NMR data on
the minor isomer (if resolved) are given between square
brackets. In most cases, the J values for the minor isomers in
the 1H NMR spectra were exactly the same as those for the
major isomers, unless otherwise indicated.
was cautiously acidified with 2 N HCl. The resulting white
precipitate was filtered off, washed with water, and dried to
afford 0.45 g (91%) of compound 19a : mp 199-200 °C (ethyl
acetate/hexane); Rf 0.47 (B); 1H NMR (CDCl3) δ 1.24 [1.29] (1H,
dd, J ) 4.6, 6.9 Hz, cyclopropane CH2), 2.26 [2.32] (1H, dd, J
) 4.6, 9.9 Hz, cyclopropane CH2), 2.81 (1H, dd, J ) 7.3, 9.9
Hz, H-4), 3.75 [3.77] (3H, s, OCH3), 4.18 [4.28] (1H, d, J )
15.8 Hz, H-1), 4.87 [4.73] (1H, d, J ) 15.8 Hz, H-1) 7.11-7.41
(4H, m, aromatic H), 10.50 (1H, br s, COOH); 13C NMR δ 27.7
[27.4] (C-4), 28.7 [28.2] (cyclopropane CH2), 39.6 [39.9] (C-3),
44.3 [44.9] (C-1), 53.2 [53.1] (OCH3), 126.2, 126.8, 127.5, 128.9
[125.9, 127.7, 129.1] (aromatic CH), 132.6, 134.7 [133.0, 134.6]
(aromatic quaternary C), 156.7 [156.1] (NCOO), 178.1 [177.8]
(C-COO); IR (KBr, cm-1) 1690, 1720 (CdO); MS m/z (rel int)
247 (32, M+); HRMS analysis C13H13NO4 requires M+ 247.08446,
found M+ 247.08454.
B. Hyd r olysis w ith 6 N HCl. 0.55 g (2 mmol) of compound
18a was refluxed with 3.3 mL (20 mmol) of 6 N HCl for 1 day.
The oily compound gradually solidified. The cooled suspension
was filtered and the precipitate was washed with water and
dried in vacuo to give 0.28 g (57%) of compound 19a , mp 199
°C (ethyl acetate/hexane). TLC and all spectral data were
identical to the data given above.
2-ter t-Bu toxyca r bon yl-3,4-m eth a n o-1,2,3,4-tetr a h yd r o-
isoqu in olin e-3-ca r boxylic Acid 19b. To a solution of 0.64
g (2 mmol) of compound 18b in 4 mL of 1,4-dioxane was added
2.5 mL (10 mmol) of 4 N NaOH, and the mixture stirred for 1
day at 100 °C. The hydrolysis could be checked by TLC. The
reaction mixture was evaporated in vacuo to half its volume,
and 5 mL of water was added to dissolve the solid mass. This
aqueous solution was acidified with 10% aqueous citric acid,
and the resulting white precipitate was filtered off, washed
with water and dried in vacuo (alternatively, the precipitate
could be extracted with 3 × 15 mL of ethyl acetate) to afford
0.55 g (95%) of compound 19b: mp 196-198 °C dec (diethyl
ether/hexane); Rf 0.61 (B); 1H NMR (CDCl3) δ 1.20 [1.25] (1H,
dd, J ) 4.5 Hz, J ) 7.1 Hz, cyclopropane CH2), 1.45 [1.49]
(9H, s, (CH3)3), 2.23 [2.31], (1H, dd, J ) 4.6, 9.9 Hz, cyclopro-
pane CH2), 2.79 (1H, dd, J ) 7.3, 9.6 Hz, H-4), 4.13 [4.19] (1H,
d, J ) 15.8 Hz, H-1) 4.83 [4.66] (1H, d, J ) 15.8 Hz, H-1),
7.14-7.39 (4H, m, aromatic H); 13C NMR (CDCl3) δ 27.8 [27.3]
(C-4), 28.3 [28.2] ((CH3)3), 28.6 (cyclopropane CH2), 39.8 [39.7]
(C-3), 43.5 [45.1] (C-1), 80.6 [81.0] ((CH3)3-C), 126.3, 126.7,
127.3, 128.8 [126.0, 126.3, 127.5, 129.1] (aromatic CH), 133.1,
135.0 [132.8] (aromatic quaternary C), 155.1 [154.7] (NCOO),
178.7 [178.3] (C-COO); IR (KBr, cm-1) 1700, 1715 (CdO); MS
m/z (rel int) 289 (2, M+); HRMS analysis C16H19NO4 requires
M+ 289.13141, found 289.13148.
Eth yl 2-Meth oxyca r bon yl-3,4-m eth a n o-1,2,3,4-tetr a h y-
d r oisoqu in olin e-3-ca r boxyla te 18a : an oil, which solidified
on standing; yield 80%; mp 72-73 °C (diethyl ether/hexane);
1
Rf 0.46 (D); H NMR (CDCl3) δ 1.13 [1.19] (1H, dd, J ) 4.5,
7.1 Hz, cyclopropane CH2) 1.27 (3H, t, J ) 7.1 Hz, CH3-CH2),
2.21 [2.28] (1H, dd, J ) 4.6, 9.9 Hz, cyclopropane CH2), 2.69
[2.70] (1H, dd, J ) 6.9, 9.9 Hz, H-4), 3.72 [3.74] (3H, s, OCH3),
4.1-4.34 (3H, m, OCH2 and one H-1), 4.86 [4.72] (1H, d, J )
15.8 Hz, one H-1), 7.8-7.39 (4H, m, aromatic H); 13C NMR
(CDCl3) δ 14.3 [14.2] (CH3-CH2), 27.0 [26.5] (C-4), 28.1 [27.6]
(cyclopropane CH2), 39.9 [40.3] (C-3) 44.4 [44.9] (C-1), 59.5
[59.8] (OCH3), 61.4 (O-CH2), 126.1 [125.9], 126.6, [126.4] 127.4
[127.6], 129.0 [129.2] (aromatic CH), 133.0 [133.4], 134.9
(aromatic quaternary C), 156.7 [155.7] (NCOO), 171.8 [171.4]
(C-COO); IR (NaCl, cm-1) 1710, 1740 (CdO); MS m/z (rel int)
275 (9, M+), 202 (80), 115 (100); HRMS analysis C15H17NO4
requires M+ 275.11575, found M+ 275.11531. Anal. Calcd for
E t h yl 3,4-Met h a n o-1,2,3,4-t et r a h yd r oisoq u in olin e-3-
ca r boxyla te 20. To a solution of 0.37 g (1 mmol) of compound
18b in 10 mL of ethyl acetate was added 4 mL of 12 N HCl,
and the mixture was stirred for 30 min at room temperature.
The reaction mixture was next treated cautiously with 20 mL
of saturated NaHCO3 and additional solid NaHCO3 until it
became slightly basic. The organic layer was separated and
the aqueous phase was extracted twice with ethyl acetate. The
combined organic extracts were dried over MgSO4 and evapo-
rated in vacuo to afford 0.2 g (92%) of compound 20 as a
C
15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.23; H,
6.63; N, 5.44.
E t h yl 2-ter t-b u t oxyca r b on yl-3,4-m et h a n o-1,2,3,4-t et -
r a h yd r oisoqu in olin e-3-ca r boxyla te 18b: yield 81%; mp
1
97-98 °C (MeOH/H2O); Rf 0.59 (C); H NMR (CDCl3) δ 1.11
[1.17] (1H, dd, J ) 4.6, 7.1 Hz, cyclopropane CH2), 1.30 [1.27]
(3H, t, J ) 7.1 Hz, CH3-CH2), 1.44 [1.49] (3H, s, (CH3)3), 2.19
[2.27] (1H, dd, J ) 4.6, 9.9 Hz, cyclopropane CH2), 2.68 [2.67]
(1H, dd, J ) 7.1, 9.8 Hz, H-4), 4.13 (1H, d, J ) 15.8 Hz, H-1),
4.23 (3H, Hz, q, J ) 7.1, OCH2) 4.82 [4.65] (1H, d, J ) 15.8
Hz, H-1), 7.12-7.42 (4H, m, aromatic H); 13C NMR (CDCl3) δ
14.4 [14.23] (CH3CH2), 27.7 [26.5] (C-4), 28.1 [27.5] (cyclopro-
pane CH2), 28.4 ((CH3)3), 40.0 (C-3), 43.5 [45.2] (C-1), 61.3
[61.2] (O-CH2), 80.1 [80.5] ((CH3)3C), 126.1, 127.3, 128.9, 133.2
[125.9, 126.5, 127.4, 129.1] (aromatic CH), 133.2, 135.2 [133.5,
135.3] (aromatic quaternary C), 155.0 [154.5] (NCOO), 172.3
[171.8] (CCOO); IR (KBr, cm-1) 1705, 1730 (CdO); MS m/z
1
colorless oil: Rf 0.63 (E); H NMR (CDCl3) δ 1.30 (3H, t, J )
7.3 Hz, CH3-CH2), 1.55 (1H, t, J ) 5.9 Hz, cyclopropane CH2),
1.80 (1H, dd, J ) 5.8, 9.8 Hz, cyclopropane CH2), 2.47 (1H,
dd, J ) 5.9, 9.9 Hz, H-4), 3.76, (1H, d, J ) 16.0 Hz, H-1), 3.93
(1H, d, J ) 16.0 Hz, H-1), 4.23 (2H, q, J ) 7.3 Hz, OCH2),
7.02-7.31 (4H, m, aromatic H); 13C NMR (CDCl3) δ 14.2 (CH3-
CH2), 18.0 (cyclopropane CH2), 23.7 (C-4), 43.9 (C-3), 44.9 (C-
1), 61.3 (O-CH2), 125.9, 126.0, 126.9, 128.4 (aromatic CH),
133.2, 134.7 (aromatic quaternary C), 173.3 (COO); IR (NaCl,
cm-1) 1717 (CdO), 3318 (NH); MS m/z (rel int) 217 (22, M+),
144 (100); HRMS analysis C13H15NO2 requires M+ 217.11028,
found M+ 217.11032. The hydrochloride of compound 20 was
prepared in ether with HCl/diethyl ether from the base 20,
(98% yield) or from compound 18b with HCl/diethyl ether (17
g of dry HCl in 100 mL of diethyl ether) at room temperature
for 30 min (90% yield). Recrystallized from MeOH/diethyl
(rel int) 317 (11, M+), 217 (87), 144 (96); HRMS analysis C18H23
NO4 requires M+ 317.16271, found M+ 317.16278.
-
2-Meth oxyca r bon yl-3,4-m eth a n o-1,2,3,4-tetr a h yd r oiso-
qu in olin e-3-ca r boxylic Acid 19a . A. Hyd r olysis w ith 1 N
Na OH. To a solution of 0.55 g (2 mmol) of compound 18a in 3
mL of methanol was added 3 mL (3 mmol) of 1 N NaOH, and
the mixture was stirred at room temperature for 1 day. The
hydrolysis could be monitored by TLC. The methanol was
evaporated off at 40 °C in vacuo, and the cold aqueous solution
1
ether: mp 166-167 °C; H NMR (CDCl3) δ 1.22 (3H, t, J )

Doubly Constrained Nonproteinogenic Amino Acid Derivatives
J . Org. Chem., Vol. 65, No. 18, 2000 5475
7.1 Hz, CH3CH2), 1.97 (2H, d, J ) 8,6 Hz, cyclopropane CH2),
2.93 (1H, t, J ) 8.6 Hz, H-4), 4.14 (1H, d, J ) 15.5 Hz, H-1),
4.27 (2H, q, J ) 7.1 Hz, O-CH2), 4.31 (1H, d, J ) 15.5 Hz,
H-1), 7.17-7.41 (4H, m, aromatic H); 13C NMR (CDCl3) δ 14.1
(CH3-CH2), 17.9 (cyclopropane CH2), 23.2 (C-4), 41.6 (C-3), 43.1
(C-1), 62.9 (O-CH2), 125.7, 131.2 (aromatic quaternary C),
127.5, 127.7, 128.6, 128.7 (aromatic CH), 168.1 (COO). Anal.
Calcd for C13H16NO2Cl: C, 61.54; H, 6.36; N, 5.52. Found: C,
61.60; H, 6.84; N, 5.16.
9.9 Hz, H-4), 4,03 (1H, d, J ) 15.5 Hz, H-1), 4.18 (1H, d, J )
15.5 Hz, H-1) 7.11-7.38 (4H, m, aromatic H); 13C NMR (D2O,
ref. acetonitrile) δ 14.4 (cyclopropane CH2), 20.6 (C-4), 42.4
(C-3), 43.4 (C-1), 126.2, 131.1 (aromatic quaternary C), 126.4,
126.7, 127.8, 128.1 (aromatic CH), 172.8 (COO); HRMS
analysis
C
11H11NO2 requires M+ 189.07898, found M+
189.07878; MS m/z (rel int) 189 (2, M+), 144 (100).
Meth od B. A mixture of 0.159 g (0.5 mmol) of compound
18b and 0.83 mL (1.25 mmol) of 6 N HCl was heated at 100
°C for 1 day. The reaction mixture was then evaporated to
dryness in vacuo. The white solid residue was recrystallized
from MeOH/diethyl ether resulting in 0.08 g (71%) of 5.HCl.
The free amino acid 5 was prepared with propylene oxide as
described above. HRMS of the R-amino acid hydrochloride
5.HCl: at high temperature (225 °C), the salt dissociated into
HCl and the free R-amino acid, which requires M+ 189.07898
for C11H11NO2, found M+ 189.07848.
Meth od C. A mixture of 0.127 g (0.5 mmol) of compound
20.HCl and 1.25 mL (1.25 mmol) of 1 N NaOH was stirred at
room temperature for 1 day. The free amino acid was isolated
by chromatography on a column containing Dowex-50X 8-100
ion-exchange resin (elution with 5% NH4OH), resulting in 0.04
g (42%) of compound 5. This material was identical to the
compound obtained according to the procedures described
above.
3,4-Meth a n o-1,2,3,4-tetr a h yd r oisoqu in olin e-3-ca r box-
ylic Acid 5. Meth od A. A suspension of 0.289 g (1 mmol) of
compound 19b in 3 mL of dry CH2Cl2 was treated with 4 mL
of HCl/diethyl ether (17 g of dry HCl in 100 mL of diethyl
ether), and the mixture was stirred for 30 min at room
temperature. The reaction mixture was next evaporated to
dryness in vacuo. The solid hydrochloride was treated with
dry diethyl ether and the mixture was filtered to afford 0.20 g
(89%) of the amino acid hydrochloride (5‚HCl), which was
recrystallized from MeOH/diethyl ether: mp 191-192 °C dec;
1H NMR (D2O, ref 1,4-dioxane) δ 1.88 (2H, d, J ) 7.9 Hz,
cyclopropane CH2), 2.88 (1H, t, J ) 8.2 Hz, H-4), 4.12 (1H, d,
J ) 15.5 Hz, H-1), 4.28 (1H, d, J ) 15.5 Hz, H-1), 7.15-7.42
(4H, m, aromatic H); 13C NMR (D2O, ref. acetonitrile) δ 16.4
(cyclopropane CH2), 23.6 (C-4), 42.6 (C-3), 43.2 (C-1), 125.3,
132.4 (aromatic quaternary C), 128.1, 129.4, 129.8 (aromatic
CH), 172.3 (COO); IR (KBr, cm-1) 1740 (CdO). To 0.160 g (0.7
mmol) of the above hydrochloride, dissolved in 5 mL of ethanol,
2.5 mL of propylene oxide was added. The mixture was stirred
at room temperature for 30 min, during which the amino acid
5 precipitated. The reaction mixture was evaporated to dryness
in vacuo at 30 °C. The white solid residue was treated with
dry diethyl ether, the mixture was filtered and the solid was
dried in a desiccator to afford 0.13 g (97%) of amino acid 5:
Ack n ow led gm en t. J .C.M. is a postdoctoral fellow
of the Fund for Scientific Research-Flanders (Belgium)
(F.W.O.). The Fund for Scientific Research-Flanders
(FWO-Vlaanderen) (Belgium), INTAS, and the Flemish
Ministry of Science and Technology (Bilateral Scientific
and Technological Cooperation Flanders-Hungary) are
thanked for financial support.
1
mp 188 °C dec; Rf 0.63 (E); H NMR (D2O, ref 1,4-dioxane) δ
1.62 (1H, dd, J ) 6.6, 6.9 Hz, cyclopropane CH2), 1.68 (1H,
dd, J ) 6.9, 9.9 Hz, cyclopropane CH2), 2.63 (1H, dd, J ) 6.6,
J O9917994