Synthesis of (+)-(R)-methyl 2-aminotetraline-2-carboxylate: The hydroxypinanone method versus the bislactim method

Article abstract of DOI:10.1016/S0957-4166(01)00158-6

The methyl ester of 2-aminotetraline-2-carboxylic acid (Atc-OMe), an important residue for modified peptides, could only be synthesized from the Schoellkopf bislactim method, the hydroxypinanone method leading, during the second step, to elimination inste

Full text of DOI:10.1016/S0957-4166(01)00158-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 967–969
Synthesis of (+)-(R)-methyl 2-aminotetraline-2-carboxylate:
the hydroxypinanone method versus the bislactim method
Arlette Solladie´-Cavallo,a,* Luisa M. Martin-Cabrejas,a Giorgio Caravattib and Marc Langb
aECPM/Universite L. Pasteur, 25 rue Becquerel, 67087 Strasbourg cedex 2, France
bNovartis Pharma AG, Oncology Research, K-136.4.23, 4002 Basel, Switzerland
Received 27 February 2001; accepted 2 April 2001
Abstract—The methyl ester of 2-aminotetraline-2-carboxylic acid (Atc-OMe), an important residue for modified peptides, could
only be synthesized from the Scho¨llkopf bislactim method, the hydroxypinanone method leading, during the second step, to
elimination instead of alkylation toward the expected spiro product. The (+)-(R)-Atc-OMe was thus obtained in three steps and
55% overall yield from the (−)-(R)-bislactim derived from
D
-valine. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
3. Alkylation of (S,S,S)-(−)-iminoglycinate 2
As part of our work to investigate the effect of confor-
mationally constrained amino acids at the X+1 position
of the Grb2-SH2 consensus sequence pTyr-X+1-Asn-
X+3,1 we required optically active 2-aminotetraline-2-
carboxylic acid (Atc). However, until now, only racemic
Atc has been prepared and used. We report here a short
(three steps) enantioselective synthesis of (+)-(R)-Atc-
OMe 8 through diastereoselective dialkylation of glyci-
nate derivatives.
Alkylation of (S,S,S)-(−)-iminoglycinate 2, derived
from (S,S,S)-(−)-hydroxypinanone, which usually pro-
vides highly diastereoselective alkylations,2,3 was envis-
aged first. (S,S,S)-Iminoglycinate 2 was prepared in
95% yield from (S,S,S)-hydroxypinanone and ethyl gly-
cinate following the usual procedure.2–4 The lithium
enolate was generated at −78°C with LHMDS and
alkylation with the dibromide 1 at −78°C afforded the
desired adduct 3 as a single diastereoisomer 3I5 in 98%
yield (Scheme 1).
2. Alkylating agent 1
This first alkylation occurred, as expected, at the ben-
zylic position, as can be seen from the ABX system
observed in the H NMR spectrum (200 MHz).
1
Alkylating agent 1 was obtained in two steps (LiAIH4
reduction followed by CBr4/PPh3 bromination) and
65% isolated yield from commercially available
homophthalic acid.
However, whatever the base used for the second alkyla-
tion step (LHMDS/THF, LDA/THF, t-BuOK/MeCN
Me
Me
HO
Me
HO
HO
N
CO2Et
N
CO2Et
N
CO2Et
Base
1) LHMDS (2 equiv.)
2) 1
Br
(SSS)-2
4
(SSS,R)-3I : 98% [α]D = +77 (c=1, CHCl3)
Scheme 1.
* Corresponding author.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00158-6

968
A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 967–969
or LiBr/NEt3/THF), the elimination compound 45 was
the only new product observed, while 3I was recovered
in ꢀ60% yield; no trace of the desired spiro adduct was
detected.
After hydrolysis and neutralization, the methyl ester of
2-aminotetraline-2-carboxylic acid (Atc-OMe) 8,9 hav-
ing a (+)-rotation in EtOH and MeOH, was isolated in
98% yield (55% overall yield from the starting substrate
5) with an identical enantiomeric purity to that of 7I.
4. Alkylation of (R)-(−)-bislactim ether 5
5. Determination of the R-configuration of 8
We thus switched to Scho¨llkopf’s substrates, which had
already been successfully used to prepare quaternary
amino acids.6,7
On the basis of the trans-addition usually observed,6
the starting (R)-bislactim ether used should provide
Atc-OMe having the (R)-configuration and, as a matter
of fact, a NOESY experiment (Bruker AC 400) on
adduct 7I exhibits a correlation spot between an isopro-
pyl methyl group and a hydrogen atom of the AB
system (Hequatorial) corresponding to the isolated ben-
zylic CH2. This indicates that the configuration of 7I is
(R,R) (Fig. 1). Moreover, NOESY also exhibits a corre-
lation spot between the second H of the AB system and
the axial H of the non-benzylic CH2 (Fig. 1), which is
easily identified as non-benzylic by its position (l=2.23
ppm) and as axial from the pattern, i.e. a double triplet
Commercially available (R)-(−)-bislactim ether 5 was
treated with BuLi at −78°C to provide the lithium
derivative 5a (Scheme 2). Alkylation with the dibro-
mide 1 then afforded the desired adduct 68 as a 93/7
mixture of the two possible diastereomers. Here again,
the first alkylation occurred at the benzylic position, as
can be seen from the ABX systems observed for both
1
diastereomers in the H NMR spectrum of the crude
product.
3
Using the same base (BuLi) and more diluted solutions
(0.1 M in THF instead of 0.3 M in THF used for the
first step), the desired spiro compound 7I8 was obtained
(2J=3Jtrans=12.5 Hz, Jgauche=5 Hz). A conformational
study of (R,R)-7I using PM3 from MOPAC shows a
conformation having the following: a flat heterocycle,
ring A in a twisted form, the methyls of the methoxy in
a cis relationship with the N atoms and a methyl of the
1
as a single diastereomer (only one AB system in the H
NMR spectrum of the crude product).
Ha
Ha
OMe
N
N
Li
Br
2
OMe
BuLi
N
1
+ 6II : 7%
5
OMe
Br
N
MeO
N
MeO
95%
Br
N
MeO
(2R,5S)-6I : 93%
[α]D = +19 (c=3, CHCl3)
2
(-)-(R)-5
5a
BuLi
Ha
Li
OMe
N
MeO2C
H2N
OMe
N
2
5
98%
N
MeO
65%
N
MeO
Br
(R)-8 : Atc-OMe
(2R,5R)-7I : 99%
2
6a
[α]D = +20 (c=1.2, EtOH)
[α]D = +2 (c=1.7, CHCl3)
Scheme 2.
Me
N
H
H
Me
NOE
O
O
N
O
Heq
Me
Hax
NOE
Me
NOE
N
O
N
(A) Heq
H
Hax
N
O
A
Ha
O
N
H
H
ax (B)
(R,R)-8I
Hax
NOE
Figure 1.

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 967–969
969
isopropyl group above the heterocycle is the most sta-
ble,10 consistent with the NOESY observed (Fig. 1).
The small value of 3.5 Hz found for JHH between Ha
and the methine proton of the isopropyl is consistent
with a dihedral angle (Ha–C–C–H) of 60–90° and with
a methyl positioned ‘above’ the ring (as elucidated by
NOESY and simulation).
part of an ABX system, 3J=3 and 8 Hz, 1H), 4.20 (q,
2H), 3.60 (m, 2H), 3.35 (AB of the ABX, 2J=12 Hz,
3J=3 and 8 Hz, 2H overlapped with m, 2H), 2.45 (bm,
3
2
1H), 2.20 (m, 1H), 1.90 (m, 3H), 1.45 (d, J=11 Hz, 1H),
1.32 (s, 3H), 1.28 (t, 3H), 1.20 (s, 3H), 0.35 (s, 3H); 13C
NMR (CDCl3): 178.4, 170.7, 137.0, 135.3 (C), 130.3,
129.2, 126.6 (CH arom.), 76.0 (C), 63.3 (CH), 60.7 (CH2),
49.6, 37.8 (CH), 37.6, 36.1, 34.9, 32.7 (CH2), 31.8 (C),
27.8 (CH3), 27.5 (CH2), 26.8, 22.4, 21.8, 13.8 (CH3).
It is worth noting that the variation of the chemical
shift of proton Ha (Scheme 2) from compound 5 to
compounds 6I and then 7I indicates that the first
intermolecular alkylation step occurred in a trans fash-
ion, as expected. In the starting bislactim ether 5 proton
Ha appears at 4.0 ppm (overlapped with the CH2
signal), while in adduct 6I proton Ha (assigned through
decoupling of the isopropyl proton, a double septuplet
at 2.2 ppm) is located at 3.4 ppm (0.6 ppm shielding),
consistent with the presence of an aromatic ring in a cis
relationship and also consistent with literature
results11,12 for similar aromatic-substituted compounds.
Thus, in compound 7I, where the aromatic ring is
constrained away from Ha, its signal (doublet) moved
again to 4.0 ppm. Therefore, it is reasonable to con-
clude that compound 6I has a trans structure. Com-
pound 7I, having an (R,R)-configuration, demonstrates
that the second alkylation step also occurred in a trans
fashion.
1
Compound 4: H NMR (200 MHz, CDCl3): similar to 31
but olefinic signals at 5.70 (dd, 2J=1.5 Hz, 3J=18 Hz,
IH) and 5.30 (dd, 2J=1.5 Hz, 3J=11 Hz, 1H) and
disparition of the CH2ꢀCH2 signals at 3.5 and 3.3 ppm.
6. For reviews, see: (a) Scho¨llkopf, U. Top. Curr. Chem.
1983, 109, 65; (b) Williams, R. M. Synthesis of Optically
Active h-Aminoacids; Pergamon Press: Oxford, 1989.
7. Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int.
Ed. Engl. 1981, 20, 798.
8. Compound 6I: [h]2D0=+19 (c 3.0, CHCl3). Anal. calcd for
C18H25BrN2O2: C, 56.70; H, 6.61. Found: C, 56.50; H,
6.56. 1H NMR (200 MHz, CDCl3): 7.15 (bs, 4H), 4.28
(m, 1H, X part of an ABX system), 3.74 (s, 3H), 3.63 (s,
3H), 3.51 (pseudo t, 2H, XX% part of an AA%XX% system),
3.45 (d, 1H, 3J=3.5 Hz), 3.25 (m, 3H, AA% part of the
AA%XX% system superimposed with A part of the ABX
2
system), 2.96 (dd, 1H, B part of the ABX system, J=14
Hz, 3Jꢀ6.5 Hz), 2.18 (sept.d, 1H, 3J=6.5 and 3.5 Hz),
0.97 (d, 3H, 3J=6.5 Hz), 0.62 (d, 3H, 3J=6.5 Hz); 13C
NMR (CDCl3): 163.8 (C), 162.6 (C), 137.8 (C), 136.2 (C),
130.9 (CH), 129.4 (CH), 126.6 (2 CH), 60.2 (CH3), 57.0
(CH3), 52.3 (CH), 36.6 (CH2), 36.2 (CH2), 32.3 (CH2),
31.2 (CH), 19.0 (CH3), 16.4 (CH3). Compound 7I: [h]2D0=
In conclusion, (+)-(R)-Atc-OMe has been obtained
from (−)-(R)-bislactim through two consecutive trans-
alkylation steps.
1
+2 (c 1.7, CHCl3). H NMR (400 MHz, CDCl3): 7.11 (m,
Acknowledgements
3
3H), 7.03 (m, 1H), 4.00 (d, 1H, J=3.5 Hz, Ha), 3.70 (s,
2
3H), 3.52 (s, 3H), 3.44 (d, 1H, J=16.5 Hz), 3.22 (ddd,
1H, 2J=16.5 Hz, 3Jꢀ12 and 5 Hz), 2.69 (ddd, 1H,
The authors thank Mme A. Klein for important techni-
cal participation and M. M. Schmitt for the 2D NMR
experiments.
3
2
2J=16.5 Hz, Jꢀ2.5 and 5.5 Hz), 2.54 (d, 1H, J=16.5
Hz), 2.29 (d.sept., 1H), 2.23 (td, 1H, 2J=12.5 Hz, 3Jꢀ
2
3
12.5 and 5 Hz), 1.67 (ddd, 1H, J=12.5 Hz, Jꢀ2.5 and
5.5 Hz), 1.11 (d, 3H, 3J=6.5 Hz), 0.76 (d, 3H, 3J=6.5
Hz); 13C NMR (CDCl3): 165.9 (C), 161.2 (C), 136.3 (C),
134.8 (C), 129.0 (CH), 128.4 (CH), 125.3 (CH), 125.2
(CH), 60.6 (CH3), 56.4 (C), 52.5 (CH), 52.2 (CH), 40.4
(CH2), 33.6 (CH2), 31.1 (CH3), 25.2 (CH2), 19.4 (CH3)
and 17.0 (CH3).
References
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9. Compound (R)-8: [h]D20=+20 (c 1.26, EtOH) and +17 (c
1.01, MeOH); 1H NMR (200 MHz, CDCl3): 7.11 (m,
4H), 3.74 (s, 3H), 3.30 (d, 1H, A part of an AB system,
2J=16.5 Hz), 2.95 (m, 2H, AB part of an ABXY system),
2
2.74 (d, 1H, B part of the AB system, J=16.5 Hz), 2.20
(ddd, 1H, X part of the ABXY system, 2J=13.5 Hz,
3Jꢀ6 and 10 Hz), 1.89 (m, 1H, Y part of the ABXY
system), 1.65 (s, 2H, NH2). Anal. calcd for C13H18ClNO2:
C, 61.05; H, 7.09; N, 5.47. Found: C, 60.77; H, 6.96; N,
5.32.
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10. It is 1.7 and 2.7 kcal/mol lower than for the other two
conformations of the isopropyl, and 4 kcal/mol lower
than the one having ring A in a boat conformation and
the isopropyl group in the best orientation.
11. Kopple, K. D.; Marr, D. H. J. Am. Chem. Soc. 1967, 89,
6193.
5. Compound 31: [h]2D0=+77 (c l, CHCl3). Anal. calcd for
C24H32BrNO3: C, 62.35; H, 6.92. Found: C, 62.11; H,
1
6.85. H NMR (200 MHz, CDCl3): 7.1 (bm, 4H)
.
, 4.47 (X
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