Synthesis of the conformationally constrained tyrosine analogues, (R)- and (S)-5-hydroxy-2-aminoindan-2-carboxylic acids

Article abstract of DOI:10.1021/jo902438s

(Chemical Equation Presented) The conformationally constrained tyrosine analogues, (R)- and (S)-5-hydroxy-2-aminoindan-2-carboxylic acids, were prepared by chromatographic separation of diastereomeric dipeptide derivatives formed from N-Boc-L-phenylalanin

Full text of DOI:10.1021/jo902438s

pubs.acs.org/joc
CCTAs may stabilize the R-helical and β-turn motifs in
Synthesis of the Conformationally Constrained
Tyrosine Analogues, (R)- and (S)-5-Hydroxy-2-
aminoindan-2-carboxylic Acids
peptides due to achievement of low-energy conformations.1
Restriction of side chain flexibility can affect signal transduc-
tion, resulting in antagonistic behavior of constrained peptides.
CCTAs have been used to develop structure-activity relation-
ships (SARs).8,9 Incorporation of CCTAs produced useful
information about the conformational requirements for pep-
tide hormone/opioid receptor interactions.8-10
Francis N. Murigi, Gary S. Nichol, and Eugene A. Mash*
Department of Chemistry and Biochemistry, University of
Arizona, Tucson, Arizona 85721-0041
While the use of enantiomerically pure amino acids is
important in establishing a SAR, some CCTAs, including
Hai, are not available in enantiomerically pure form.3,8,9
This Note describes a method for the preparation of (R)-1
and (S)-1, the enantiomers of Hai.
emash@u.arizona.edu
Received November 13, 2009
Amino acids (R)-1 and (S)-1 were prepared as outlined
in Schemes 1 and 2. 4-Methoxy-1,2-dimethylbenzene (2) was
brominated at -70 °C to afford bromide 311 in 91% yield
(Scheme1). Bromide3was subjected to free radical bromination
to give tribromide 4 in 60% yield.12 Reaction of tribromide 4
with ethyl isocyanoacetate following the method of Kotha13
produced 5 in 57% yield. Acid hydrolysis of 5 gave racemic
amino ester 6 in 87% yield. Coupling of 6 with N-Boc-L-phenyl-
alanine using (benzotriazol-1-yloxy)tris(dimethylamino)phos-
phonium hexafluorophosphate14 (BOP reagent) afforded a mix-
ture of diastereomers 7 in 93% yield. Although diastereomers 7
were separable by gravity-driven silica gel column chromato-
graphy (see the Supporting Information), diastereomer separa-
tion was effected at a later point in the synthesis.
The conformationally constrained tyrosine analogues,
(R)- and (S)-5-hydroxy-2-aminoindan-2-carboxylic acids,
were prepared by chromatographic separation of diastereo-
meric dipeptide derivatives formed from N-Boc-L-phenyl-
alanine. Absolute configurations were assigned by X-ray
crystallographic analysis.
Treatment of the mixture of diastereomers 7 with trifluor-
oacetic acid removed the Boc group, and reaction of the free
amine with phenylisothiocyanate gave a 1:1 mixture of the
diastereomeric thioureas (S,S)-8 and (R,S)-8 in 90% yield
over two steps (Scheme 1). These diastereomers were sepa-
rated by repeated cycles of gravity-driven column chromato-
graphy on 70-230 mesh silica gel 60 eluted with 10% ethyl
acetate/dichloromethane. Results of this separation are sum-
marized in Table 1. The absolute stereochemistries of the
separated diastereomers were assigned by means of an X-ray
crystallographic analysis of the less polar thiourea, (R,S)-8
(Figure 1).15
L-Tyrosine is a nonessential amino acid involved in protein
phosphorylation, a process important in regulation of cel-
lular processes including cell growth and differentiation.1-3
Enzymes involved in the transfer of the phosphoryl group
from adenosine-50-triphosphate to the tyrosine residues of
proteins are known as protein tyrosine kinases (PTKs).
Researchers are interested in understanding how PTKs
recognize substrates.3,4 Some reported studies involve PTK
substrate modification where the tyrosine residue is re-
placed with conformationally constrained tyrosine analogues
(CCTAs), such as R-methyltyrosine1 (R-MeTyr), β-methyl-
tyrosine5 (β-MeTyr), 6-hydroxy-2-aminotetralin-2-carboxy-
lic acid1 (Hat), 5-hydroxy-2-aminoindan-2-carboxylic acid6
(Hai), and 6-hydroxytetrahydroisoquinoline-3-carboxylic
acid7 (6-OH-Tic).
Thiourea (R,S)-8 was heated in TFA to afford the amino
ester (R)-9 in 80% yield (Scheme 2). Hydrogenolysis of
(R)-9 with 10% Pd/C in ethanol gave amino ester (S)-10 in
(8) Deeks, T.; Crooks, P. A.; Waigh, R. D. J. Med. Chem. 1983, 26, 762–
765.
(9) Mosberg, H. I.; Lomize, A. L.; Wang, C.; Kroona, H.; Heyl, D. L.;
Sobczyk-Kojiro, K.; Ma, W.; Mousigian, C.; Porreca, F. J. Med. Chem.
1994, 37, 4371–4383.
€
(1) Obrecht, D.; Lehmann, C.; Ruffieux, R.; Schonholzer, P.; Muller, K.
€
Helv. Chim. Acta 1995, 78, 1567–1587.
(2) Ruzza, P.; Calderan, A.; Osler, A.; Elardo, S.; Borin, G. Tetrahedron
Lett. 2002, 43, 3769–3771.
(10) Rizo, J.; Gierasch, L. M. Annu. Rev. Biochem. 1992, 61, 387–418.
(11) Tomita, M. Yakugaku Zasshi 1936, 56, 814–828.
(12) Reaction of 2 with NBS under conditions that favor free radical
intermediates is sluggish and produces a complex mixture of products; see
Gruter, G.-J. M.; Akkerman, O. S.; Bickelhaupt, F. J. Org. Chem. 1994, 59,
4473–4481.
ꢀ
(3) Ruzza, P.; Cesaro, L.; Tourwe, D.; Calderan, A.; Biondi, B.; Maes, V.;
Menegazzo, I.; Osler, A.; Rubini, C.; Guiotto, A.; Pinna, L. A.; Borin, G.;
Donella-Deana, A. J. Med. Chem. 2006, 49, 1916–1924.
(4) Wang, D.; Cole, P. A. J. Am. Chem. Soc. 2001, 123, 8883–8886.
(13) Kotha, S.; Brahmachary, E. J. Org. Chem. 2000, 65, 1359–1365.
(14) Castro, B.; Dormoy, J. R.; Dourtoglou, B.; Evin, G.; Selve, C.;
Ziegler, J. C. Synthesis 1976, 751–752.
ꢀ
(5) Tourwe, D.; Mannekens, E.; Diem, T. N. T.; Verheyden, P.; Jaspers,
H.; Toth, G.; Peter, A.; Kertesz, I.; Torok, G.; Chung, N. N.; Schiller, P. W.
ꢀ
ꢀ
ꢀ
€ €
J. Med. Chem. 1998, 41, 5167–5176.
(6) Pinder, R. M.; Butcher, B. H.; Buxton, D. A.; Howells, D. J. J. Med.
Chem. 1971, 14, 892–893.
(7) VanAtten, M. K.; Ensinger, C. L.; Chiu, A. T.; McCall, D. E.;
Nguyen, T. T.; Wexler, R. R.; Timmermans, P. B. M. W. M. J. Med. Chem.
1993, 36, 3985–3992.
(15) Crystal data for (R,S)-8: C29H30BrN3O4S; M = 596.53 g mol-1, T =
100(2) K, Cu KR, thin colorless plates, orthorhombic, P212121, a =
˚
10.2029(2), b = 10.3818(2), c = 25.7025(4) A, R = 90°, β = 90°, γ = 90°,
3
V = 2722.52(9) A , Z = 4, 5021 reflections, Rint 0.0567, GOF on F2 = 1.196,
˚
R1 = 0.0433 and wR2 = 0.1011 ([F2 > 2σ]), R1 = 0.0463 and wR2 = 0.1024
(all data).
DOI: 10.1021/jo902438s
r
Published on Web 01/22/2010
J. Org. Chem. 2010, 75, 1293–1296 1293
2010 American Chemical Society

Murigi et al.
JOCNote
SCHEME 1. Synthesis of Diastereomers (S,S)-8 and (R,S)-8a
TABLE 1. Separation of Diastereomeric Thioureas (S,S)-8 and (R,S)-8
by Gravity-Driven Silica Gel Column Chromatography
fraction
composition
amount
1
2
3
4
5
100% (R,S)
95þ% (R,S)
mixture
1.18 g (36%)
270 mg (8%)
100 mg (3%)
20 mg (0.6%)
1.32 g (40%)
95þ% (S,S)
100% (S,S)
FIGURE 1. ORTEP of the less polar thiourea, (R,S)-8.
aReagents and yields: (a) Br2, CH2Cl2, -70 °C, 91%. (b) NBS, CCl4, hν,
60%. (c) CNCH2CO2Et, K2CO3, TBAI, CH3CN, C6H5Cl, 57%. (d) HCl,
EtOH, EtOAc, 87%. (e) Boc-L -Phe, BOP, Et3N, DMF, 93%.
(f) TFA, CH2Cl2. (g) C6H5NCS, Et3N, EtOH, 90% (two steps).
afford a crude product. Purification by flash chromatography
(230-400 mesh silica) with 10% CH2Cl2/hexanes gave 7.00 g
(32.5 mmol, 91%) of 3 as crystalline solid, mp 29-30 °C (lit.11
mp 30-32 °C), Rf 0.49 (5% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 2.16 (s, 3H), 2.21 (s, 3H), 3.84 (s, 3H), 6.68 (s, 1H), 7.26
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 18.5, 19.8, 56.3, 108.0,
113.8, 130.0, 133.8, 136.8, 153.7.
SCHEME 2. Synthesis of (S)-1a
1-Bromo-4,5-bis(bromomethyl)-2-methoxybenzene (4). N-Bromo-
succinimide (1.66 g, 9.30 mmol) was added to a solution of 3
(2.00 g, 9.30 mmol) in CCl4 (24 mL) under argon. A 250 W heat
lamp was positioned near the reaction flask to ensure a gentle
reflux. After2 h, additionalNBS(1.66g, 9.30 mmol)was addedto
the reaction mixture and refluxing continued for 2 h. The solution
was allowed to cool to rt and filtered, then the solid was washed
with CCl4 (30 mL). The combined filtrates were washed with sat.
NaHCO3 (30 mL), sat. Na2SO3 (30 mL), and brine (30 mL), dried
with Na2SO4, filtered, and concentrated in vacuo to yield a pale
yellow oil. Ethyl acetate (10 drops) was added and the oil kept at
-22 °C overnight to form crystals. The white crystalline solid was
collected by filtration to afford 2.07 g (5.55 mmol, 60%) of 4,
aReagents and yields: (a) TFA, 72 °C, 80%. (b) H2, Pd/C, EtOH, 83%.
(c) 48% HBr, CH3CO2H, heat, 75%.
mp 85-86 °C; Rf 0.43 (10% EtOAc/hexanes); IR (KBr, cm-1
)
1
83% yield.16 Treatment of (S)-10 with 48% aqueous HBr
cleaved the ester and ether bonds, producing amino acid (S)-
1 in 75% yield. In a similar manner, thiourea (S,S)-8 was
transformed to amino acid (R)-1 (not depicted). Compound
(S)-1 was characterized by X-ray crystallographic analysis
(see the Supporting Information). The CD spectra of (S)-1
and (R)-1 confirm they are enantiomeric (see the Supporting
Information).
2972, 1596, 1496, 1274, 1044; H NMR (500 MHz, CDCl3) δ
3.90 (s, 3H), 4.56 (s, 2H), 4.58 (s, 2H), 6.85 (s, 1H), 7.53 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 29.2, 29.4, 56.4, 112.1, 113.9,
129.7, 135.6, 137.1, 156.3; HRGCMS (EIþ) calcd for C9H9Br3O
(Mþ) 369.8203, found 369.8223.
Ethyl 5-Bromo-2-isocyano-6-methoxyindan-2-carboxylate (5).
Dry acetonitrile (45 mL) was added to a flask containing ethyl
isocyanoacetate (0.44 mL, 0.45 g, 3.97 mmol) under argon.
Finely ground potassium carbonate (6.67 g, 48.03 mmol),
tetrabutylammonium iodide (0.30 g, 0.80 mmol), and a solution
of 4 (1.48 g, 3.97 mmol) in chlorobenzene (45 mL) were added to
the flask. The reaction mixture was heated in an oil bath at
85-90 °C for 10 h, cooled to rt and filtered, then the residue was
thoroughly washed with acetonitrile. Volatiles were removed
under reduced pressure to give a brown oily residue that was
dissolved in a 1:1 mixture of EtOAc and diethyl ether (250 mL).
The solution was washed with water (90 mL ꢀ 2) and brine
(90 mL), dried with anhydrous MgSO4, filtered, and concen-
trated under reduced pressure to give a brown oil. Flash
chromatography (230-400 mesh silica) with 15% EtOAc/hex-
anes afforded 0.73 g (2.25 mmol, 57%) of 5 as a white solid, mp
Experimental Section
1-Bromo-2-methoxy-4,5-dimethylbenzene (3). A solution of bro-
mine (1.84 mL, 5.72 g, 35.8 mmol) in CH2Cl2 (200 mL) was added
dropwise to a solution of 3,4-dimethylanisole (2, 5.00 mL, 4.87 g,
35.8 mmol) in CH2Cl2 (300 mL) at -70 °C under argon until a pale
orange color was observed. The pale orange solution was washed
with sat. NaHCO3 (150 mL), sat. Na2SO3 (100 mL), and brine
(100mL), driedwithMgSO4, filtered, and concentrated in vacuo to
(16) Hydrogenolysis of bromide 9 affords a convenient method for
introduction of an isotopic label into the resolved amino acid.
100-101 °C; Rf 0.48 (30% EtOAc/hexanes); IR (KBr, cm-1
)
1294 J. Org. Chem. Vol. 75, No. 4, 2010

Murigi et al.
JOCNote
2977, 2145, 1743, 1485, 1226, 1064; 1H NMR (600 MHz,
CDCl3) δ 1.32 (t, 3H, J = 7.3 Hz), 3.37 (d, 2H, J = 15.6 Hz),
3.60 (d, 1H, J = 17.4 Hz), 3.63 (d, 1H, J = 17.4 Hz), 3.85 (s,
3H), 4.29 (q, 2H, J = 7.3 Hz), 6.77 (s, 1H), 7.38 (s, 1H); 13C
NMR (150 MHz, CDCl3) δ 13.9, 45.3, 46.1, 56.3, 63.2, 68.3,
108.2, 110.9, 129.0, 130.9, 138.6, 155.7, 158.9, 168.1; HRMS
(ESI) calcd for C14H14BrNO3Na (M þ Na)þ 346.00493, found
346.00492.
1040; 1H NMR (500 MHz, CDCl3) δ 1.17 (t, 3H, J = 7.0 Hz),
2.98 (dd, 1H, J = 8.0, 13.5 Hz), 3.00 (d, 1H, J = 16.0 Hz), 3.08
(d, 1H, J = 17.0 Hz), 3.26 (dd, 1H, J = 6.0, 14.0 Hz), 3.39 (d,
1H, J = 16.0 Hz), 3.53 (d, 1H, J = 16.5 Hz), 3.84 (s, 3H), 4.13
(m, 2H), 5.20 (q, 1H, J = 7.0 Hz), 6.65(s, 1H), 6.68 (s, 1H), 6.84
(d, 1H, J = 7.0 Hz), 7.02 (d, 2H, J = 7.5 Hz), 7.20 (m, 7H), 7.26
(s, 2H), 7.32 (t, 2H, J = 7.5 Hz), 8.19 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 14.1, 37.8, 42.8, 43.2, 56.3, 59.0, 61.8, 66.0,
108.2, 110.0, 124.7, 126.9, 127.0, 128.6, 128.8, 129.2, 129.9,
132.5, 135.8, 136.2, 140.5, 155.1, 170.3, 172.1, 179.6; HRMS
(ESI) calcd for C29H30BrN3O4SNa (M þ Na)þ 618.10326,
found 618.10213. Data for (S,S)-8: [R]25D þ7.36 (c 2.00, CHCl3);
3303, 3221, 3038, 1722, 1657, 1522, 1495, 1234, 1040; 1H NMR
(500 MHz, CDCl3) δ 1.19 (t, 3H, J = 7.0 Hz), 2.97 (dd, 1H,
J = 8.0, 13.5 Hz), 2.98 (d, 1H, J = 16.5 Hz), 3.07 (d, 1H, J =
16.5 Hz), 3.27 (dd, 1H, J = 6.0, 13.5 Hz), 3.44 (d, 1H, J = 16.5
Hz), 3.46 (d, 1H, J = 16.5 Hz), 3.83 (s, 3H), 4.14 (m, 2H), 5.17
(q, 1H, J = 7.5 Hz), 6.52 (s, 1H), 6.66 (s, 1H), 6.86 (d, 1H, J =
7.0 Hz), 7.03 (d, 2H, J = 7.5 Hz), 7.22 (m, 6H), 7.26 (s, 1H),
7.33 (t, 2H, J = 7.5 Hz), 8.11 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 14.1, 38.0, 42.5, 43.5, 56.3, 59.2, 61.8, 66.1, 108.4,
110.1, 124.7, 127.0, 127.1, 128.6, 128.8, 129.3, 129.9, 132.7,
135.8, 136.2, 140.3, 155.1, 170.3, 172.0, 179.7; HRMS (ESI)
calcd for C29H30BrN3O4SNa (M þ Na)þ 618.10326, found
618.10213.
Ethyl (R)-2-Amino-5-bromo-6-methoxyindan-2-carboxylate
[(R)-9]. A solution of (R,S)-8 (500 mg, 0.84 mmol) in TFA
(10 mL) was heated at reflux for 2 h. The reaction mixture
was allowed to cool to rt and added to water (20 mL). The
aqueous solution was extracted with hexanes (3 ꢀ 30 mL) and
these extracts were discarded. The aqueous phase was basified to
pH 9.0 by addition of aqueous NH4OH and extracted with
EtOAc (3 ꢀ 50 mL). The EtOAc extracts were combined,
washed with brine (40 mL), dried over MgSO4, filtered, and
concentrated in vacuo to give an orange oil. Flash chromatog-
raphy (230-400 mesh silica) with EtOAc as elutant afforded
(R)-9 as a colorless oil (210 mg, 0.67 mmol, 80%), which later
Ethyl 2-Amino-5-bromo-6-methoxyindan-2-carboxylate (6). A
solution of 5 (1.61 g, 4.97 mmol) in a mixture of EtOAc (16 mL),
absolute EtOH (32 mL), and concd HCl (5.75 mL) was stirred
for 20 h at rt. Volatiles were then removed in vacuo to leave a
pale yellow solution (about 2 mL). Water (50 mL) was added
and the resulting aqueous solution was basified with concd
NH4OH to pH 9.0. The aqueous solution was extracted with
EtOAc (3 ꢀ 50 mL), then the organic extracts were washed with
brine (50 mL), dried with MgSO4, filtered, and concentrated in
vacuo to give a brown oil. Flash chromatography (230-400
mesh silica) with EtOAc as elutant afforded 1.36 g (4.33 mmol,
87%) of 6 as a white solid, mp 38-39 °C; Rf 0.39 (100% EtOAc);
mp 196-197 °C; Rf 0.50 (25% EtOAc/benzene); IR (KBr, cm-1
)
1
IR (KBr, cm-1) 3370, 2968, 1724, 1486, 1215, 1049; H NMR
(500 MHz, CDCl3) δ 1.27 (t, 3H, J = 7.0 Hz), 1.75 (s, 2H), 2.78
(d, 1H, J = 15.5 Hz), 2.79 (d, 1H, J = 16.0 Hz), 3.45 (d, 1H, J =
15.5 Hz), 3.48 (d, 1H, J = 16.0 Hz), 3.84 (s, 3H), 4.20 (q, 2H, J =
7.0 Hz), 6.76 (s, 1H), 7.34 (s, 1H); 13C NMR (125 MHz, CDCl3)
δ 14.2, 45.3, 46.1, 56.4, 61.4, 65.5, 108.8, 109.9, 129.2, 133.8,
141.2, 155.0, 176.0; HRMS (ESI) calcd for C13H17BrNO3 (M þ
H)þ 314.03863, found 314.03871.
Ethyl (R,S)-5-Bromo-2-(3-phenyl-2-(3-phenylthioureido)pro-
panamido)-6-methoxyindan-2-carboxylate [(R,S)-8] and Ethyl
(S,S)-5-Bromo-2-(3-phenyl-2-(3-phenylthioureido)propanamido)-
6-methoxyindan-2-carboxylate [(S,S)-8]. BOP reagent (3.93 g,
8.88 mmol) was added to a solution of 6 (1.86 g, 5.92 mmol),
N-(Boc)-L-phenylalanine (2.36 g, 8.88 mmol), and triethylamine
(2 mL) in DMF (27 mL). The reaction mixture was stirred at
rt for 18 h, then diluted with EtOAc (200 mL) and water
(100 mL). The phases were separated and the aqueous phase
extracted with EtOAc (2 ꢀ 75 mL). The organic extracts were
combined, washed with 1 M HCl (2 ꢀ 80 mL), water (100 mL),
sat. NaHCO3 (2 ꢀ 80 mL), water (2 ꢀ 100 mL), and brine
(100 mL), then dried over anhydrous MgSO4 and filtered.
Volatiles were removed in vacuo to give a solid. Flash chromato-
graphy (230-400 mesh silica) with 50% EtOAc/hexanes affor-
ded a mixture of diastereoisomers 7 as a white solid (3.10 g, 5.52
mmol, 93%). These diastereomers could be separated chroma-
tographically and characterized (see the Supporting Informa-
tion). Alternatively, TFA (35 mL) was added to a solution of the
above mixture of diastereomers in CH2Cl2 (35 mL). After the
reaction was stirred for 2 h at rt, the solution volume was
reduced to ∼6 mL with use of a rotavap and basified to pH 9
by addition of 2 M NaOH. The resulting aqueous solution was
extracted with CH2Cl2 (3 ꢀ 100 mL), then the extracts were
combined, dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo to give a pale yellow solid (2.76 g). This solid was
dissolved in ethanol (35 mL) and triethylamine (1.6 mL) and
phenylisothiocyanate (3.39 g, 3.00 mL, 25.1 mmol) were added
with stirring. A white solid precipitated after 30 min, and stirring
was continued for 90 min. Volatiles were removed in vacuo to
leave a pale orange solid. Flash chromatography (230-400
mesh silica) with 30% EtOAc/hexanes as elutant afforded a
mixture of diastereomers 8 (2.98 g, 4.99 mmol, 90%) as a white
solid. Repeated gravity chromatography on silica gel (70-230
mesh) eluted with 10% EtOAc/CH2Cl2 achieved separation of
diastereomers (see Table 1). The stereochemistry of the less
polar diastereomer was established as (R,S) by single crystal
solidified to a white solid, mp 55-56 °C; Rf 0.38 (EtOAc); [R]24
D
-0.98 (c 2.00, CHCl3); IR (KBr, cm-1) 3369, 2967, 1724, 1486,
1049; 1H NMR (500 MHz, CDCl3) δ 1.26 (t, 3H, J = 7.0 Hz),
1.74 (s, 2H), 2.77 (d, 1H, J = 16.0 Hz), 2.79 (d, 1H, J = 16.0 Hz),
3.45 (d, 1H, J = 15.5 Hz), 3.47 (d, 1H, J = 15.5 Hz), 3.83 (s, 3H),
4.18 (q, 2H, J = 7.0 Hz), 6.75 (s, 1H), 7.33 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ 14.2, 45.2, 46.0, 56.3, 61.3, 65.4, 108.7,
109.8, 129.1, 133.7, 141.1, 154.9, 176.0; HRMS (ESI) calcd for
C13H17BrNO3 (M þ H)þ 314.03863, found 314.03871.
Ethyl (S)-2-Amino-5-methoxyindan-2-carboxylate [(S)-10]. To
a solution of (R)-9 (320 mg, 1.02 mmol) in ethanol (10 mL)
in a hydrogenation vessel was added 10% Pd/C (90 mg). The
mixture was shaken under hydrogen at 60 psi for 2 d and filtered,
then the solid residue was washed with ethanol and CH2Cl2. The
filtrates were concentrated in vacuo to leave an orange oil. The
oil was dissolved in EtOAc (60 mL), washed with sat. NaHCO3
(2 ꢀ 20 mL), water (20 mL), and brine (20 mL), dried with
anhydrous MgSO4, filtered, and concentrated in vacuo to a pale
orange oil. Flash chromatography (230-400 mesh silica) with
80% EtOAc/hexanes as elutant gave (S)-10 as a colorless oil
(200 mg, 0.85 mmol, 83%), Rf 0.45 (5% MeOH/CH2Cl2); [R]24
D
-11.9 (c 3.00, CHCl3); IR (NaCl plate, cm-1) 3369, 2935, 1727,
1493, 1049; 1H NMR (500 MHz, CDCl3) δ 1.27 (t, 3H, J = 7.0
Hz), 1.77 (s, 2H), 2.78 (d, 1H, J = 15.0 Hz), 2.81 (d, 1H, J = 16.0
Hz), 3.46 (d, 1H, J = 15.5 Hz), 3.52 (d, 1H, J = 16.0 Hz), 3.75 (s,
3H), 4.19 (q, 2H, J = 7.0 Hz), 6.71 (dd, 1H, J = 2.0, 8.0 Hz), 6.74
(s, 1H), 7.07 (d, 1H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ
14.2, 45.5, 46.3, 55.4, 61.2, 65.4, 110.3, 112.7, 125.2, 132.3, 141.8,
159.0, 176.3; HRMS (ESI) calcd for C13H18NO3 (M þ H)þ
236.1281, found 236.1279.
X-ray diffraction analysis. Data for (R,S)-8: [R]25 -18.4 (c
D
2.00, CHCl3); mp 184-185 °C; Rf 0.58 (25% EtOAc/benzene);
IR (KBr, cm-1) 3303, 3221, 3038, 1722, 1657, 1522, 1495, 1234,
J. Org. Chem. Vol. 75, No. 4, 2010 1295

Murigi et al.
JOCNote
(S)-5-Hydroxy-2-aminoindan-2-carboxylic Acid [(S)-1]. A solu-
tion of 48% aqueous HBr (2.5 mL) in acetic acid (4.0 mL)
was prepared in a flask under argon. The solution was stirred
for 30 min and transferred via syringe to a second flask contain-
ing (S)-10 (300 mg, 1.27 mmol) under argon. The result-
ing solution was stirred for 30 min, then placed in an oil bath
heated to 100 °C. After 24 h, the reaction mixture was allowed
to cool to rt and transferred with stirring into a 250 mL beaker
containing ice (4 g), 1 M HCl (3 mL), and diethyl ether (10 mL).
The phases were separated, the aqueous layer was extracted with
diethyl ether (2ꢀ15 mL), and the extracts were discarded. The
aqueous phase was placed in an ice-water bath and the pH
adjusted to 6.33 by addition of 6 M NaOH solution. The
product began to precipitate, and the mixture was kept at
4 °C overnight. The solid was then collected by filtration,
affording 184 mg (0.95 mmol, 75%) of (S)-1 as a solid,
Ethyl (R)-2-Amino-5-methoxyindan-2-carboxylate [(R)-10]. Using
a procedure analogous to that described for the synthesis of
(S)-10, (S)-9 (320 mg, 1.02 mmol) afforded (R)-10 as a colorless
oil (222 mg, 0.94 mmol, 92%), Rf 0.43 (5% MeOH/CH2Cl2);
[R]24D 11.0 (c 2.20, CHCl3); IR (NaCl plate, cm-1) 3369, 2935,
1727, 1493, 1049; 1H NMR (500 MHz, CDCl3) δ 1.27 (t, 3H, J =
7.0 Hz), 1.80 (s, 2H), 2.79 (d, 1H, J = 15.5 Hz), 2.82 (d, 1H, J =
15.5 Hz), 3.47 (d, 1H, J = 15.5 Hz), 3.53 (d, 1H, J = 16.0 Hz),
3.76 (s, 3H), 4.20 (q, 2H, J = 7.0 Hz), 6.71 (dd, 1H, J = 2.0, 8.0
Hz), 6.75 (s, 1H), 7.08 (d, 1H, J = 8.0 Hz); 13C NMR (125 MHz,
CDCl3) δ 14.2, 45.5, 46.3, 55.4, 61.2, 65.4, 110.3, 112.8, 125.3,
132.3, 141.9, 159.1, 176.3; HRMS (ESI) calcd for C13H18NO3
(M þ H)þ 236.1281, found 236.1279.
(R)-5-Hydroxy-2-aminoindan-2-carboxylic Acid [(R)-1]. Using
a procedure analogous to that described for the synthesis of (S)-1,
(R)-10 (491 mg, 2.09 mmol) afforded (R)-1 (314 mg, 1.62 mmol,
78%) as a solid, mp >270 °C dec; [R]24D 2.12 (c 1.00, 1 M HCl);
mp >280 °C dec; [R]24 -3.83 (c 1.00, 1 M HCl); IR (KBr,
D
cm-1) 3191, 1643, 1552, 1405; 1H NMR (500 MHz, D2O/
NaOD) δ 2.46 (d, 1H, J=15.5 Hz), 2.48 (d, 1H, J=16.5 Hz),
3.06 (d, 1H, J = 15.5 Hz), 3.12 (d, 1H, J=16.5 Hz), 6.23 (dd,
IR (KBr, cm-1) 3191, 1643, 1552, 1405; H NMR (500 MHz,
1
D2O/NaOD) δ 2.52 (d, 1H, J = 15.5 Hz), 2.55 (d, 1H, J = 16.0
Hz), 3.12 (d, 1H, J = 15.5 Hz), 3.18 (d, 1H, J = 16.5 Hz), 6.29
(dd, 1H, J = 2.0, 8.0 Hz), 6.34 (s, 1H), 6.80 (d, 1H, J = 8.0 Hz);
13C NMR [125 MHz, D2O/NaOD (CD3OD used as reference)] δ
46.2, 47.0, 67.4, 115.5, 117.7, 126.1, 127.8, 144.0, 166.0, 185.4;
HRMS (ESI) calcd for C10H12NO3 (M þ H)þ 194.0812, found
194.0810.
1H, J = 2.0, 8.0 Hz), 6.28 (s, 1H), 6.74 (d, 1H, J = 8.0 Hz); 13
C
NMR [125 MHz, D2O/NaOD (CD3OD used as reference)] δ
46.2, 47.1, 67.4, 115.5, 117.7, 126.1, 127.7, 144.1, 166.1, 185.5;
HRMS (ESI) calcd for C10H12NO3 (M þ H)þ 194.0812, found
194.0810.
Ethyl (S)-2-Amino-5-bromo-6-methoxyindan-2-carboxylate
[(S)-9]. Using a procedure analogous to that described for the
synthesis of (R)-9, (S,S)-8 (500 mg, 0.84 mmol) afforded (S)-9 as
a colorless oil (225 mg, 0.72 mmol, 86%) that later solidified to a
white solid, mp 53-54 °C, Rf 0.34 (EtOAc); [R]23D 1.74 (c 1.00,
CHCl3); IR (KBr, cm-1) 3369, 2967, 1724, 1486, 1049; 1H NMR
(500 MHz, CDCl3) δ 1.27 (t, 3H, J = 7.0 Hz), 1.78 (s, 2H), 2.78
(d, 1H, J = 15.5 Hz), 2.80 (d, 1H, J = 16.0 Hz), 3.46 (d, 1H, J=
15.5 Hz), 3.48 (d, 1H, J = 16.0 Hz), 3.84 (s, 3H), 4.20 (q, 2H, J=
7.0 Hz), 6.76 (s, 1H), 7.34 (s, 1H); 13C NMR (125 MHz, CDCl3)
δ 14.2, 45.3, 46.1, 56.4, 61.4, 65.5, 108.8, 109.9, 129.2, 133.7,
141.2, 155.0, 176.0; HRMS (ESI) calcd for C13H17BrNO3
(M þ H)þ 314.03863, found 314.03871.
Acknowledgment. The authors thank the donors of the
Petroleum Research Fund, administered by the American
Chemical Society, for support of this research.
Supporting Information Available: General experimental
methods, compound characterization data for the separated dia-
1
stereomer (R,S)-7, copies of H and 13C NMR spectra for com-
pounds 1 and 3-10, CD spectra for compounds (S)-1, (R)-1, (S)-9,
and (R)-9, and structure reports and crystallographic information
files (CIFs) for compounds (S)-1 and (R,S)-8. This material is
available free of charge via the Internet at http://pubs.acs.org.
1296 J. Org. Chem. Vol. 75, No. 4, 2010