A concise, asymmetric synthesis of methyl (1S,2R)-1-amino-2,3-dihydro- 1H-indene-2-carboxylate: A novel, constrained β-amino ester

Article abstract of DOI:10.1055/s-1999-2982

The concise, asymmetric synthesis of methyl (1S,2R)-1-amino-2,3-dihydro- 1H-indene-2-carboxylate is reported using a novel tandem conjugate addition, intramolecular electrophilic trap to construct the indane skeleton.

Full text of DOI:10.1055/s-1999-2982

LETTER
1919
A Concise, Asymmetric Synthesis of Methyl (1S,2R)-1-Amino-2,3-dihydro-1H-
indene-2-carboxylate: A Novel, Constrained b-Amino Ester
David A. Price
Department of Discovery Chemistry, Pfizer Central Research, Sandwich, Kent, CT13 9NJ, UK
Fax +44 (01304) 658422; E-mail: david_a_price@sandwich.pfizer.com
Received 8 September 1999
enolate with an intramolecular electrophile to form the in-
Abstract: The concise, asymmetric synthesis of methyl (1S,2R)-1-
dane skeleton. There had been a previous report of the in-
amino-2,3-dihydro-1H-indene-2-carboxylate is reported using a
termediate
ester
enolate
undergoing
further
novel tandem conjugate addition, intramolecular electrophilic trap
to construct the indane skeleton.
7
intramolecular Michael additions, however, the intramo-
lecular reaction with alkyl halides was unprecedented.
Key words: b-amino acid, conjugate addition, lithium amide, cin-
namate, ester enolate
The synthesis of the necessary precursor 4 was accom-
plished in two steps from the readily available 2-methyl-
benzaldehyde (Scheme 2).
There has been considerable recent interest in the synthe-
1
sis of b-amino acids and their incorporation into peptides
and proteins. Peptides composed of b-amino acids display
2
intriguing secondary structure and have shown potential
as medicinal agents. In particular, they are poor substrates
for proteases and display improved metabolic stability
3
compared to peptides composed of a-amino acids.
During our research it became necessary to prepare the
constrained b-amino ester 6. A search of the literature pro-
vided a racemic synthesis of the cis isomer by the reaction4
of indene with chlorosulfonyl isocyanate and hydrolysis.
Scheme 2
However, the trans isomer, to the best of our knowledge, With multigram quantities of 4 in hand the conjugate ad-
has not been prepared. Our initial route involved the con- dition of the chiral lithium amide 1 could be attempted.
jugate addition of lithium (R)-(a-methylbenzyl)benzyl- Dropwise addition of 4 as a THF solution to the preformed
5
amide 1 to the constrained cinnamate 2. Due to the unre- lithium amide proved to be not only the most convenient
active nature of the conjugate acceptor this approach conditions but also the highest yielding. The lithium
proved unsuccessful with no addition occurring. There is amide underwent a highly diastereoselective conjugate
literature precedent that addition of chlorotrimethylsilane addition to generate the ester enolate. The enolate then re-
to lithium amides improves their reactivity profile due to acted intramolecularly with the pendant benzyl bromide
6
the in situ generation of lithium chloride. However, even to provide the indane skeleton 3 in 80% yield following
8
after the addition of chlorotrimethylsilane and warming of purification. Analysis of the proton nmr, prior to flash
the reaction no product was observed.
column chromatography, showed a 14:1 ratio of diastere-
oisomers that were inseparable by chromatography. Two
equivalents of the lithium amide 1 were required for com-
plete consumption of the conjugate acceptor as excess
lithium amide acted as a base deprotonating the ester 3 as
it was formed. Using a single equivalent of lithium amide
gave a 40% yield of 3 with the same degree of diastereo-
selectivity. The reaction was also extremely rapid and was
complete in under five minutes at -78ºC, compared to the
normal one hour required for conjugate addition to a cin-
namate. This may be due to the in situ generation of lithi-
um bromide which increases the reactivity of the lithium
amide and so shortens the reaction time.9
Scheme 1
The lack of reaction using 2 as a conjugate acceptor could At this stage we were uncertain of the relative stereo-
be due to the phenyl ring being locked in conjugation with chemistry about the indane ring although literature prece-
7
the double bond. We postulated a novel approach to 3 via dent suggested that it was the trans isomer. The proton
t
the conjugate addition of lithium (R)-(a-methylben- nmr of 3 remained unchanged after stirring with KO Bu at
zyl)benzylamide and trapping of the intermediate ester room temperature. This suggests that both diastereoiso-
Synlett 1999, No. 12, 1919–1920 ISSN 0936-5214 © Thieme Stuttgart · New York

1
920
D. A. Price
LETTER
References and Notes
(
1) Matthews, J. L.; Braun, C.; Guibourdenche, C.; Overhand, M.;
Seebach, D. In Enantioselective Synthesis of b-Amino Acids;
Juaristi, E., Ed.; Wiley: New York, 1996.
(2) Seebach, D.; Abele, S.; Gademann, K.; Jaun, B. Angew.
Chem., Int. Ed. Engl. 1999, 38, 1595.
(
3) Gademann, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew.
Chem., Int. Ed. Engl. 1999, 38, 1223. Poenaru, S.; Lamas, J.
R.; Folkers, G.; Lopez de Castro, J.; Seebach, D.; Rognan, D.
J. Med. Chem. 1999, 42, 2318.
(4) Ohki, H.; Inamoto, Y.; Kawabata, K.; Kamimura, T.; Sakane,
K. J. Antibiot. 1991, 44, 546.
5) Davies, S. G.; Ichihara, O. Tetrahedron Asymmetry 1991, 2,
(
183. Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A.
S. J. Chem. Soc., Chem. Commun. 1993, 1153. Davies, S. G.;
Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1129.
6) Price, D. A.; Simpkins, N. S.; MacLeod, A. M.; Watt, A. P.
Tetrahedron Lett. 1994, 35, 6159. Lipshutz, B. H.; Wood, M.
R.; Lindsley, C. W. Tetrahedron Lett. 1995, 36, 4385.
7) Voigt, K.; Lansky, A.; Noltemeyer, M.; de Meijere, A. Liebigs
Ann. Chem. 1996, 899. Urones, J. G.; Garrido, N. M.; Diez,
D.; Dominguez, S. H.; Davies, S. G. Tetrahedron Asymmetry
(
(
Scheme 3
1
997, 8, 2683.
mers in the 14:1 mixture possessed the thermodynamical-
ly stable trans stereochemistry across the indane ring.10
Conclusive proof of the relative stereochemistry of the
major diastereoisomer generated in this reaction came lat-
er when the stereochemistry of 6 was assigned using nOe
(
8) The experimental procedure is as follows: n-butyl lithium
(2.96ml of a 2.50M solution in hexane, 7.41mmol) was added
dropwise to a THF (40ml) solution of (R)-(a-
methylbenzyl)benzylamine (1.56g, 7.41mmol) at -78ºC. The
resultant pink solution was stirred for 30 minutes and a THF
(
5ml) solution of 4 (1.00g, 3.36mmol) was added dropwise.
1
1
experiments and comparison to literature data. The ab-
solute stereochemistry of 3 is by analogy to numerous ex-
amples reported in the literature where the lithium amide
After stirring for ten minutes water (10ml) was added and the
reaction warmed to room temperature. The solvent was
removed in vacuo and the residue dissolved in EtOAc (100ml)
and washed, citric acid (30ml, 1M aqueous), water (30ml),
is used as a chiral nucleophile.5, 7, 10
1
brine (30ml) and dried (MgSO ). The solvent was removed
4
The inseparable mixture of diastereoisomers were stirred
in methanolic HCl and after flash column chromatgraphy
only a single diastereoisomer 5 was observed in the proton
nmr. The synthesis of methyl (1S,2R)-1-amino-2,3-dihy-
dro-1H-indene-2-carboxylate was completed by transfer
hydrogenation and recrystallisation of the hydrochloride
and the residue purified by chromatography on silica gel using
2% EtOAc:pentane as eluant to furnish 3 as a clear oil (1.15g,
8
0%) as a 14:1 ratio of diastereoisomers; d (400MHz;
H
CDCl ) major diastereoisomer 7.43-7.11 (14H, m), 4.90 (1H,
3
d, J 4.8), 4.03 (1H, q, J 6.8), 3.68 and 3.59 (2H, AB system,
JAB 14.8), 3.14 (1H, dd, J 15.2, 8.8), 3.05 (1H, ddd, J 8.8, 4.8,
4
.8), 2.97 (1H, dd, J 15.2, 4.8), 1.42 (9H, s), 1.27 (3H, d, J
1
2
+
salt from hot EtOH.
6.8); LRMS m/z 428, MH .
(
9) Bunn, B. J.; Simpkins, N. S. J. Org. Chem. 1993, 58, 533.
Bunn, B. J.; Simpkins, N. S.; Spavold, Z.; Crimmin, M. J. J.
Chem. Soc., Perkin Trans. 1 1993, 3113.
In summary the novel, constrained b-amino ester 6 has
been rapidly prepared. The key step is a novel, diastereo-
selective tandem conjugate addition, electrophilic trap of
the ester enolate. Further studies to extend the scope of
this reaction are planned.
(
10) Davies, S. G.; Ichihara, O.; Lenoir, I.; Walters, I. A. S. J.
Chem. Soc., Perkin Trans. 1 1994, 1411.
(11) Rosen, W. E.; Dorfman, L.; Linfield, M. P. J. Org. Chem.
964, 29, 1723.
12) Data for methyl (1S,2R)-1-amino-2,3-dihydro-1H-indene-2-
1
(
2
5
Acknowledgement
carboxylate 6: [a]
D
-57.4 (c 1.08 in MeOH); m.p. 218-219ºC;
(
Found: C, 57.23; H, 6.11; N, 5.98. C H NO .HCl.0.1H O
1
1
13
2
2
I would like to thank T. Peakman for his expertise and help with the
nOe experiments.
requires C, 57.12; H, 6.28; N, 6.06%); d (400MHz; CD OD)
H
3
7.56 (1H, d, J 7.3), 7.41 (3H, m), 5.16 (1H, d, J 6.4), 3.79 (3H,
s), 3.53 (1H, dd, J 15.9, 9.3), 3.45 (1H, ddd, J 9.3, 6.9, 6.4),
+
3
.27 (1H, dd, 15.9, 6.9), LRMS m/z 192, MH .
Article Identifier:
437-2096,E;1999,0,12,1919,1920,ftx,en;L15999ST.pdf
1
Synlett 1999, No. 12, 1919–1920 ISSN 0936-5214 © Thieme Stuttgart · New York