Crystallization-induced asymmetric transformation (CIAT) with simultaneous epimerization at two stereocenters. A short synthesis of conformationally constrained homophenylalanines

Article abstract of DOI:10.1016/j.tetlet.2004.12.048

CIAT of aza-Michael adducts allows simultaneous build up of two stereocenters. A consequent short and efficient synthesis affords simple access to the both antipodes of various conformationally restricted homophenylalanines.

Full text of DOI:10.1016/j.tetlet.2004.12.048

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 975–978
Crystallization-induced asymmetric transformation (CIAT)
with simultaneous epimerization at two stereocenters. A short
synthesis of conformationally constrained homophenylalanines
a,
Andrej Kolarovic, Dusan Berkes, Peter Baran and Frantisek Povazanec
b
a
ˇ a
ˇ
ˇ
*
ˇ
ˇ
a
´
Department of Organic Chemistry, Slovak Technical University, Radlinskeho 9, 81237 Bratislava, Slovak Republic
bDepartment of Chemistry, University of Puerto Rico, Rio Piedras, PO Box 23346, San Juan, PR 00931-3346, USA
Received 20 October 2004;revised 1 December 2004;accepted 8 December 2004
Abstract—CIAT of aza-Michael adducts allows simultaneous build up of two stereocenters. A consequent short and efficient syn-
thesis affords simple access to the both antipodes of various conformationally restricted homophenylalanines.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Crystallization-induced asymmetric transformation
(CIAT)1,2 is an attractive mode of stereoselective synthe-
sis since it relies on the action of thermodynamic con-
trol, and not kinetics, as is usually observed in various
methods of asymmetric synthesis. In other words, it is
not necessary to work at low temperatures and simple
and readily available chiral auxiliaries can be used to
build anew stereogenic center. Over the last decade, sev-
eral papers have appeared indicating itsꢀ industrial
potential.3
in high yields and purity (Scheme 1).7,8 The first and the
last example of this kind was described forty years ago
by Openshaw and Whittaker, in an elegant synthesis
of (ꢀ)-emetine.9
CIAT is essentially in its fundament a process of equili-
bration, with crystallization causing continuous dis-
equilibration in the solution. Thus the equilibrium of
the whole system is shifted toward one isomer.10 The
reaction itself runs in solution and therefore the medium
used can play a crucial role in its success or failure.11
Our research program is focused on applications of
CIAT to the synthesis of a-amino acids.4 At the end
of 1998, being inspired by the results of Urbach and He-
nig,5 we developed a method for the asymmetric synthe-
sis of homophenylalanine derivatives based on a
reversible aza-Michael reaction. However, Kaneka
researchers were a step ahead.6 We have decided to con-
tinue research in this field and have turned our attention
to stereoselective reductions of c-oxo-a-amino acids4a
and the application of aminoalcohols as auxiliaries in
CIAT.4b Here we would like to present a remarkable
phenomenon, whereby simultaneous epimerization at
two stereocenters leads to only one of four stereoisomers
For successful CIAT there are four basic conditions
which should be kept in mind:
1. The reaction must be reversible.
2. At least one of the final stereoisomers must crystallize
under the reaction conditions.
O
Ph
O
HN
i
COOH
(CH2)n
COOH
(CH2)n
Keywords: Amino acids and derivatives;Asymmetric synthesis;Crys-
tallization;Michael reactions;Reduction.
1 n = 1
2 n = 2
3 n = 1
4 n = 2
*
Corresponding author at present address: Dipartimento di Scienze
Chimiche, Universita degli Studi di Padova, via Marzolo 1, 35131
Padova, Italy. Tel.: +39 340 8776983;fax: +39 049 8275239;e-mail
addresses: andrej.kolarovic@unipd.it;akola@pobox.sk
Scheme 1. Reagents and conditions: (i) 1.1 equiv (R)-phenylethyl-
amine, MeOH/H2O, 5 days, 81% (3), resp. 80% (4);>95% of the major
diastereomer in both cases.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.048

ˇ
A. Kolarovic et al. / Tetrahedron Letters 46 (2005) 975–978
976
3. The driving force of the process is based on the equa-
tion v1 5 v2, where v1 and v2 are overall rates of inter-
conversion between stereoisomers A and B. However,
rate constants of interconversion k1, k2 can be equal.
4. The stereoisomers A and B may not preferentially
co-crystallize in a form of mixed crystals xAÆyB.12
Ph
O
OH HN
O
iii
Ph
H.HCl
11
COOH
N
10
i, ii
NH2
COOH
Ph
In our case, CIAT is based on a reversible aza-Michael
reaction, the retro-Michael being catalyzed by excess of
the base. A strong point of this system is that in the
course of the reaction the amino acid formed has a dra-
matically different solubility in comparison with the
mixture of starting compounds. Therefore, it is not a
serious problem to find reaction conditions to meet the
first three points mentioned above. These circumstances
lead us to the conclusion that, unlike most cases, CIAT
of covalent diastereomers could be more than just a
coincidentally observed phenomenon. Aza-Michael
addition to substrates of general formula 5 (Fig. 1), un-
der the conditions of CIAT, has the potential to become
apart of the efficient asymmetric synthesis of various
amino acids. However, the concept has to be proven.
A first step toward this aim was achieved through suc-
cessful application of the method to substrates 6.4c
O
HN
iv
COOH
12
3
v
Ph
OH HN
COOH
13
Scheme 3. Reagents and conditions: (i) NaBH4/MnCl2, MeOH, 0–
5 ꢁC, dr = 3:2;(ii) crystallization, 45%, dr = 11:1;(iii) 4 M HCl, 70%,
dr >95:5;(iv) H 2/Pd/C, 1 M HCl/MeOH, 63% (unoptimized);(v)
NaBH4, MeOH, 64% (unoptimized), dr >97:3.
C18
C19
The configuration of derivatives 3 and 4 was assigned by
means of their structural modification (Schemes 2, 3,
vide supra) as well as by X-ray crystallography (deriva-
tive 4; Fig. 2).13
C17
C20
C16
C15
C14
The c-oxo-a-amino acids 3 and 4 were further used for
synthesis of conformationally restricted homophenylala-
nines (Hfe) 9 and 12 (Schemes 2, 3). Generally, con-
strained amino acids are widely employed as a subunit
of unnatural peptides and peptidomimetics with the
aim of studying ligand–receptor interactions and finding
a selective/potent receptor agonist/antagonist.
C13
O1
C3
C1
C4
N1
O2
C2
C12
O3
C11
C10
C9
C5
O
XH
COOH
EWG
Y
C7
5
6
C6
EWG = COR, NO2, ...
X = COO, SO3, ...
Y = H, 4-MeO
C8
Figure 1.
Figure 2.
2-Indanylglycine (Igl) 12 has been used as a component
of peptides interacting with tachykinin,14a bradyki-
nin,14b–d and somatostatin14e receptors. What is note-
worthy is that its presence is crucial for a selective
antagonistic interaction with the B1-receptor, with affin-
ity in the picomolar range.14d To the best of our knowl-
edge, the synthesis and application of the amino acid 9
have not yet been described.15
Ph
Ph
COOH
O
HN
OH HN
i
COOH
7
4
iii
ii
iv
O
NH2
COOH
O
Ph
The reduction of amino acid 4 in the system NaBH4/
4a
N
H.HCl
MnCl2 is highly stereoselective (dr >97:3), as a result
9
8
of concurring 1,2-induction and chelation.16 The lactoni-
zation of hydroxy acid 7 leads to cyclic derivative 8.
This allows application of NOE-experiments to assign
the relative configuration of the newly built stereocen-
ters.17 The hydrolysis of lactone 8 results again in
Scheme 2. Reagents and conditions: (i) NaBH4/MnCl2, MeOH, 88%,
dr >97:3;(ii) H 2/Pd/C, 1 M HCl/MeOH, 71% (unoptimized);(iii) H
Pd/C, 4 M HCl/THF, 63% (unoptimized);(iv) 4 M HCl, 82%,
dr >95:5.
/
2

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A. Kolarovic et al. / Tetrahedron Letters 46 (2005) 975–978
977
5421;(e) Bendahl, L.;Hammershøi, A.;Jensen, D. K.;
formation of hydroxy acid 7, as determined by HPLC,
and thus the potential inversion of configuration at C-
10 in the course of lactonization could be excluded. Re-
moval of the activating carbonyl group of acid 4 as well
as the auxiliary can be smoothly accomplished in one
step, even though employing acidic conditions.18 Analy-
sis on column CROWNPACK CR(+) confirms that epi-
merization at C-20 operates only in small scale (ꢁ4%).
As an alternative a two step reductive sequence (i–iii)
can be used.
Larsen, S.;Riisager, A.;Sargeson, A. M.;Sørensen, H. O.
J. Chem. Soc., Dalton Trans. 2002, 3054–3064;(f) Tsubaki,
K.;Miura, M.;Morikawa, H.;Tanaka, H.;Kawabata, T.;
Furuta, T.;Tanaka, K.;Fuji, K. J. Am. Chem. Soc. 2003,
125, 16200–16201;(g) Trankler, K. A.;Corey, J. Y.;Rath,
N. P. J. Organomet. Chem. 2003, 686, 66–74;(h) Yama-
nari, K.;Ito, R.;Yamamoto, S.;Konno, T.;Fuyuhiro, A.;
Kobayashi, M.;Arakawa, R. J. Chem. Soc., Dalton Trans.
´
´
ˇ
2003, 380–386;(i) Marchalı n, S.;Cvopova , K.;Kriz , M.;
Baran, P.;Oulyadi, H.;Daich, A. J. Org. Chem. 2004, 69,
4227–4237.
2. Terms like ꢁcrystallization-induced dynamic resolutionꢀ
(CIDR) or ꢁsecond-order asymmetric transformationꢀ are
also used frequently as well as some others. However, it
should be pointed out that the term ꢁresolutionꢀ is
appropriate only in connection with enantiomers and
their respective salts.
3. Selected examples: (a) Silverberg, L. J.;Dillon, J. L.;
Vemishetti, P.;Sleezer, P. D.;Discordia, R. P.;Hartung,
K. B. Org. Proc. Res. Dev. 2000, 4, 34–42;(b) Kemper-
man, G. J.;Zhu, J.;Klunder, A. J. H.;Zwanenburg, B.
Org. Lett. 2000, 2, 2829–2831;(c) Boesten, W. H. J.;
Seerden, J. P. G.;DeLange, B.;Dielemans, H. J. A.;
Elsenberg, H. L. M.;Kaptein, B.;Moody, H. M.;Kellogg,
R. M.;Broxterman, Q. B. Org. Lett. 2001, 3, 1121–1124;
(d) Aelterman, W.;Lang, Y.;Willemsens, B.;Vervest, I.;
Leurs, S.;DeKnaep, F. Org. Proc. Res. Dev. 2001, 5, 467–
Unlike acid 4, oxo acid 3 (Scheme 3) is reduced by
NaBH4/MnCl2 with low stereoselectivity (dr = 3:2). This
result can be rationalized by the fact that the five-mem-
bered ring fused with benzene is rather planar and af-
fords low stereodiscrimination in a chelation model.
Due to its higher planarity, acid 10 possessing the syn-
10,20-configuration has a rather high torsional strain.
Another factor worth mentioning is that, when com-
pared with oxo acid 4, the space distance between the
nitrogen and carbonyl oxygen in 3 is higher. This poten-
tially prevents efficient chelation. However, this aspect
was not studied further using other Lewis acids with
higher ionic radii. Anyway, it is possible to isolate hy-
droxy acid 10 in much better purity (dr = 11:1) and rea-
sonable yield (45%) after crystallization.19
ˇ
471;(e) Kos mrlj, J.;Weigel, L. O.;Evans, D. A.;Downey,
C. W.;Wu, J. J. Am. Chem. Soc. 2003, 125, 3208–3209;(f)
Brands, K. M. J.;Payack, J. F.;Rosen, J. D.;Nelson, T.
D.;Candelario, A.;Huffman, M. A.;Zhao, M. M.;Li, J.;
Craig, B.;Song, Z. J.;Tschaen, D. M.;Hansen, K.;
Devine, P. N.;Pye, P. J.;Rossen, K.;Dormer, P. G.;
Reamer, R. A.;Welch, Ch. J.;Mathre, D. J.;Tsou, N. N.;
McNamara, J. M.;Reider, P. J. J. Am. Chem. Soc. 2003,
125, 2129–2135;(g) Singh, J.;Kronenthal, D. R.;Schw-
inden, M.;Godfrey, J. D.;Fox, R.;Vawter, E. J.;Zhang,
B.;Kissick, T. P.;Patel, B.;Mneimne, O.;Humora, M.;
Papaioannou, C. G.;Szymanski, W.;Wong, M. K. Y.;
Chen, C. K.;Heikes, J. E.;DiMarco, J. D.;Qiu, J.;
Deshpande, R. P.;Gougoutas, J. Z.;Mueller, R. H. Org.
Lett. 2003, 5, 3155–3158;(h) Barrett, R.;Caine, D. M.;
Cardwell, K. S.;Cooke, J. W. B.;Lawrence, R. M.;Scott,
Again, as in the case of acid 7, the relative configuration
of stereocenters in 10 can be assigned via cyclization and
NOE experiments. Remarkably, reduction of oxo acid 3
with NaBH4 alone is highly stereoselective and leads to
hydroxy acid 13. The configuration of derivative 13 de-
duced by comparison with a sample of acid 10 (NMR,
HPLC) as well as studies of itsꢀ ability to lactonize. Lact-
onization of 13 is, as expected, much slower (ca. 2 days
vs 4 h for the hydroxy acid 10) and leads to derivative
11. In other words, formation of a lactone with the
trans-configuration is not observed and a slow epimeri-
zation allows preparation of 11.20 The absolute configu-
ration of the amino acid 12 was assigned by comparison
with the published optical rotation15a as well as by com-
parative analysis of racemic and chiral samples on col-
umn CROWNPACK CR(+).
˚
P.;Sjolin, A . Tetrahedron: Asymmetry 2003, 14, 3627–
3631;(i) Kiau, S.;Discordia, R. P.;Madding, G.;
Okuniewicz, F. J.;Rosso, V.;Venit, J. J. J. Org. Chem.
2004, 65, 4256–4261.
ˇ
4. (a) Berkes, D.;Kolarovic , A.;Povaz anec, F. Tetrahedron
Lett. 2000, 41, 5257–5260;(b) Kolarovic , A.;Berkes , D.;
ˇ
ˇ
In summary, we have described CIAT in conjunction
with the syntheses of various conformationally con-
strained homophenylalanines. Applications of CIAT to
other conjugate systems are being studied.
ˇ
ˇ
Baran, P.;Povazˇanec, F. Tetrahedron Lett. 2001, 42, 2579–
ˇ
2582;(c) Jakubec, P.;Berkes , D.;Povaz anec, F. Tetrahe-
dron Lett. 2004, 45, 4755–4758.
ˇ
5. Urbach, H.;Henning, R. Tetrahedron Lett. 1984, 25,
1143–1146.
6. Yamada, M.;Nagashima, N.;Hasegawa, J.;Takahashi, S.
Tetrahedron Lett. 1998, 39, 9019–9022.
Acknowledgements
7. Typical experimental procedure: (R)-Phenylethylamine
(1.1 equiv) was added to a stirred suspension of requisite
acid in 50% aqueous MeOH (c = 0.2 mol dmꢀ3). The
resulting mixture was stirred for 5–6 days at room
temperature, dr being monitored by HPLC. Precipitated
crystalline solid was filtered off, washed with a small
amount of MeOH and Et2O, and dried under reduced
pressure.(2R,20R,100R)-(10-Oxo-10,20,30,40-tetrahydronaph-
Financial support by the Slovak Grant Agency No. 1/
9250/02 is gratefully acknowledged.
References and notes
1. Recent examples: (a) Kanomata, N.;Ochiai, Y. Tetrahe-
dron Lett. 2001, 42, 1045–1048;(b) Lee, S. K.;Lee, S. Y.;
Park, Y. S. Synlett 2001, 1941–1943;(c) Matsumoto, T.;
Kasai, T.;Tatsumi, K. Chem. Lett. 2002, 346–347;(d)
Komatsu, H.;Awano, H. J. Org. Chem. 2002, 67, 5419–
thalen-20-yl)-(100-phenylethylamino)ethanoic
acid
(4).
White crystalline solid, mp = 163–164 ꢁC;yield = 80%;
20
½aꢂD ꢀ88 (c 0.8, THF/1 M HCl = 4/1); 1H NMR (DCl,
acetone-d6): d 7.90 (d, 1H, J = 7.8, H–Ar), 7.75 (m, 2H,

ˇ
A. Kolarovic et al. / Tetrahedron Letters 46 (2005) 975–978
978
H–Ar), 7.60–7.45 (m, 4H, H–Ar), 7.35–7.31 (m, 2H, H–
ꢀ137 (c 0.6, THF/1 M HCl = 4/1); 1H NMR (DCl,
DMSO-d6): d 7.12–6.96 (m, 4H, H–Ar), 3.88 (br s, 1H,
H-2), 2.90–2.48 (m, 4H, H-20, H-40A, H-40B, H-10A),
2.32–2.16 (m, 1H, H-10B), 1.96–1.86 (m, 1H, H-30A),
1.64–1.46 (m, 1H, H-30B); 13C NMR (DCl, DMSO-d6): d
170.4 (C-1);136.1, 135.1, 129.5, 129.3, 126.6, 126.4 0
Ar), 4.86 (d, 1H, J = 6.6, H-100), 4.12 (d, 1H, J = 1.8, H-2),
3.67 (m, 1H, H-20), 3.12–2.98 (m, 2H, H-40), 2.46 (m, 1H,
H-30A), 2.15 (m, 1H, H-30B), 1.90 (d, 3H, J = 6.6, H-200);
13C NMR (DCl, acetone-d6): d 196.1 (C-10);169.2 (C-1);
144.9, 136.2, 134.8, 132.2, 130.3, 129.9, 129.7, 129.4, 127.8,
0
127.3 (C–Ar);60.4, 58.1 (C-1 00, C-2);49.7 (C-2 );29.6, 26.7
(C–Ar);56.7 (C-2);36.0 (C-2 0);31.3, 29.1, 25.8 (C-1
C-30, C-40).
,
00
(C-30, C-40);20.4 (C-2 ).
8. Synthesis of derivatives of 4 via a-imino esters: Ferraris,
D.;Young, B.;Cox, C.;Drury, W. J.;Dudding, T.;
Lectka, T. J. Org. Chem. 1998, 63, 6090–6091.
19. Experimental data: The starting amino acid 3 (2.00 mmol,
0.619 g) was suspended in MeOH (30 mL). MnCl2Æ4H2O
(0.20 equiv, 0.40 mmol, 0.079 g) was added and the
mixture was placed on an ultrasonic reactor for 0.5 min
to attain a finer suspension of the reagents. The mixture
was cooled down to 0 ꢁC and whilst being stirred, NaBH4
(2.00 equiv, 4.00 mmol, 0.151 g) was added over 10 min.
The mixture was stirred for a subsequent 10 min (t = 0–
5 ꢁC). In the same manner, an additional two portions of
NaBH4 (2 · 2.00 equiv) were added, one after another.
Later on, cooling was removed and the last 2 equiv of
NaBH4 were added at 20 ꢁC. After a short period of
stirring (30 min), the mixture was quenched with water
(30 mL) and 10% K2CO3 (5 mL), the precipitated salts
were filtered off and the pH of the filtrate adjusted to 6
(4 M HCl). Crystallization was initiated by ultrasound and
the pH value was concurrently adjusted to 6. The product
was filtered off, washed with a small amount of EtOH and
dried under reduced pressure, yielding 0.28 g (45%) of a
white powdery solid 10 (dr = 11:1). Mp = 187–188 ꢁC;
9. (a) Openshaw, H. T.;Whittaker, N. J. Chem. Soc. 1963,
1461–1471;the same approach was later applied to slightly
modified structures: (b) Clark, R. D.;Kern, J. R.;Kurz, L.
J.;Nelson, J. T. Heterocycles 1990, 31, 353–366.
10. We could imagine analogous asymmetric processes run-
ning in biphasic systems gas/liquid, liquid/liquid, or gas/
solid. However, to the best of our knowledge, such
processes have not yet been described. For a regioselective
process running under the same principle, see: Noyori, R.;
Uchiyama, M.;Nobori, T.;Hirose, M.;Hayakawa, Y.
Aust. J. Chem. 1992, 45, 205–225.
11. For discussion see Ref. 4b.
12. For discussion of points 3 and 4, see: Hassan, N. A.;
Bayer, E.;Jochims, J. C. J. Chem. Soc., Perkin Trans. 1
1998, 3747–3757.
13. Crystal data for 4: C20H22ClNO3, M = 359.84,
0.26 · 0.24 · 0.12 mm, monoclinic, space group P21 (No.
20
1
˚
4), a = 6.069(1), b = 12.217(2), c = 12.833(2) A, b =
½aꢂD +35 (c 0.4, 1 M NaOH); H NMR (NaOD, D2O): d
7.55–7.25 (m, 9H, H–Ar), 3.76 (q, 1H, J = 6.6, H-100), 3.27
(d, 1H, J = 6.6, H-2), 2.91 (d, 2H, J = 9.0, H-300), 2.52–2.40
(m, 1H, H-20), 1.41 (d, 3H, J = 6.6, H-200);H-1 in signal of
H2O; 13C NMR (NaOD, D2O): d 183.7 (C-1);146.5, 146.3,
146.3, 131.8, 131.6, 130.4, 130.3, 129.8, 128.0, 127.5 (C–
98.688(2)ꢁ, V = 940.5(2) A , Z = 2, Dc = 1.271 g cmꢀ3, l
3
˚
(Mo Ka) = 2.21 cmꢀ1, T = 298 K, 2hmax = 46.54ꢁ, 4103
reflections measured, 2364 unique (Rint = 0.0140). The
refinement (228 variables, one restriction) based on F
converged with R = 0.0242, Rw = 0.0248, and GOF =
1.101 using 2316 unique reflections (I > 2r(I)).
0
0
Ar);79.7 (C-1 );060 4.5, 59.5 (C-2, C-1 00);48.3 (C-2 );35.0
14. (a) Josien, H.;Lavielle, S.;Brunissen, A.;Saffroy, M.;
Torrens, Y.;Beaujouan, J. C.;Glowinski, J.;Chassaing,
G. J. Med. Chem. 1994, 37, 1586–1601;(b) Sejbal, J.;
Cann, J. R.;Stewart, J. M.;Gera, L.;Kotovych, G.
J. Med. Chem. 1996, 39, 1281–1292;(c) Galoppini, C.;
Meini, S.;Tancredi, M.;Di Fenza, A.;Triolo, A.;
Quartara, L.;Maggi, C. A.;Formaggio, F.;Toniolo, C.;
Mazzucco, S.;Papini, A.;Rovero, P. J. Med. Chem. 1999,
42, 409–414;(d) Amblard, M.;Bedos, P.;Olivier, Ch.;
Daffix, I.;Luccarini, J. M.;Dodey, P.;Pruneau, D.;
Paquet, J. L.;Martinez, J. J. Med. Chem. 2000, 43, 2382–
2386;(e) Hocart, S. J.;Jain, R.;Murphy, W. A.;Taylor, J.
E.;Coy, D. H. J. Med. Chem. 1999, 42, 1863–1871.
15. Synthesis of (S)-12: (a) Long, A.;Baldwin, S. W. Tetra-
hedron Lett. 2001, 42, 5343–5345;(b) derivatives of ( S)-
and (R)-12:Burk, M. J.;Gross, M. F.;Martinez, J. P. J.
Am. Chem. Soc. 1995, 117, 9375–9376.
(C-30);26.0 (C-2 ).
20. Selected data: (10R,3R,3aR,8bS)-3-(10-Phenylethylamino)-
3,3a,4,8b-tetrahydroindeno[1,2-b]furan-2-one hydrochlo-
20
ride (11). White solid, mp = 189–192 ꢁC; ½aꢂD +150
(c 0.5, DMSO); 1H NMR (acetone-d6): d 7.86–7.79 (m,
2H, H–Ar), 7.51–7.38 (m, 4H, H–Ar), 7.34–7.19 (m, 3H,
H–Ar), 6.22 (d, 1H, J = 8.1, H-8b), 5.18 (q, 1H, J = 6.9, H-
10), 4.08 (dddd, 1H, J3,3a = 7.5, J4A,3a = 8.4, J4B,3a = 1.5,
J8b,3a = 8.1, H-3a), 3.55 (d, 1H, J = 7.5, H-3), 3.35 (dd,
1H, J4A,3a = 8.4, J4A,4B = 17.4, H-4A), 3.01 (dd, 1H,
J4B,3a = 1.5, J4A,4B = 17.4, H-4B), 1.93 (d, 3H, J = 6.9,
H-20); 13C NMR (DMSO-d6): d 171.5 (C-2);141.9, 141.9,
137.8, 130.0, 129.1, 129.0, 128.1, 127.4, 125.7, 125.5
(C–Ar);85.9 (C-8b);57.6, 56.0 (C-3, C-1 0);41.0 (C-3a);
0
36.0 (C-4);19.9 (C-2 ).
(R)-Aminoindan-2-yl ethanoic acid (12). White solid,
20
mp = 254–256 ꢁC (lit.14a mp = 225 ꢁC); ½aꢂD ꢀ54 (c 0.4,
16. Reductions of related racemic derivatives: Merla, B.;
Grumbach, H. J.;Risch, N. Synthesis 1998, 1609–1614.
17. As mentioned above, the structure of 4 is fully character-
ized by X-ray crystallography.
THF/1 M HCl = 4/1) [lit.14a +28 for (S)-configuration
(1 N HCl, c 0.11)]; 1H NMR (DCl, DMSO-d6): d 7.22–
7.06 (m, 4H, H–Ar), 3.99 (d, 1H, J = 4.5, H-2), 3.06–2.78
(m, 5H, H-10, H-20, H-30); 13C NMR (DCl, DMSO-d6): d
170.4 (C-1);141.8, 141.7, 126.9, 124.7 (C–Ar);55.2 (C-2);
18. (2R,20S)-Amino-(10,20,30,40-tetrahydronaphthalen-20-yl)-
20
0
ethanoic acid (9). White solid, mp = 246–248 ꢁC; ½aꢂD
40.6 (C-20);35.5, 35.2 (C-1 , C-30).