Catalytic asymmetric syntheses of tyrosine surrogates

Article abstract of DOI:10.1021/jo801577t

(Chemical Equation Presented) Amino acid esters 5-11 as tyrosine mimics have been synthesized in excellent enantioselectivity (up to 99.6% ee) and in good overall chemical yields. The key step in the sequence was the Burk's [Rh(COD)(2R,5R)-Et-DuPhos]BF₄-catalyzed asymmetric hydrogenation of enamides with a variety of reactive functional groups.

Full text of DOI:10.1021/jo801577t

Catalytic Asymmetric Syntheses of Tyrosine Surrogates
Xiaojun Han,* Rita L. Civiello, Haiquang Fang, Dedong Wu, Qi Gao,
Prasad V. Chaturvedula, John E. Macor, and Gene M. Dubowchik
Neuroscience DiscoVery Chemistry, Research & DeVelopment, Bristol-Myers Squibb Company,
5 Research Parkway, Wallingford, Connecticut 06492
xiaojun.han@bms.com
ReceiVed July 21, 2008
Amino acid esters 5-11 as tyrosine mimics have been synthesized in excellent enantioselectivity (up to
99.6% ee) and in good overall chemical yields. The key step in the sequence was the Burk’s
[Rh(COD)(2R,5R)-Et-DuPhos]BF4-catalyzed asymmetric hydrogenation of enamides with a variety of
reactive functional groups.
Introduction
Tyrosine is one of four natural amino acids (histidine,
phenylananine, tryptophan, and tyrosine) that contain aromatic
moieties. In biological systems, the uniqueness of tyrosine rests
on its phenolic -OH acting as both hydrogen bond donor and
acceptor and its electron-rich aromatic ring capable of engaging
in π-π stacking interactions. Tyrosine surrogates have been
used in pharmaceutical research to improve the potency,
pharmacokinetic properties and binding selectivity of target
molecules.1
As a part of a medicinal chemistry project, we required
tyrosine surrogates 1 shown in Figure 1, where various NH-
containing heterocycles could be used to probe SAR as well as
provide good pharmacokinetic properties. For example, the
presence of the heterocyclic ring could fine-tune the electron
density of the phenyl ring and potentially modulate π-π
stacking interactions in the active site.2 We envisioned that these
amino acid esters could be synthesized by the asymmetric
hydrogenation of enamides 2, which could be obtained by
olefination of aldehydes 3 and ylide 4.
FIGURE 1. Tyrosine mimetics and their retro synthetic analysis.
amino acid 6b and its cation-π interaction properties were
reported.3 A seven step racemic synthesis of free oxoindole
amino acid 7 (without CBz protection) was reported in 1979.4
Racemic amino acids 8-10 have been synthesized by the
reaction of substituted benzyl bromides with sodioethylaceta-
midomalonate or its equivalent, and were used as DOPA and
dopamine analogues to study their effects on dopamine ꢀ-hy-
droxylase and tyrosinase.5 They have also been prepared in
racemic form by nitration of 4-aminophenylalanine to study their
potential as inhibitors of norepinephrine biosynthesis.6 The
The structures of the amino acid esters synthesized in this
paper are shown in Figure 2. The asymmetric synthesis of indole
(3) Carlier, P. R.; Lam, P. C.-H.; Wong, D. M. J. Org. Chem. 2002, 67,
6256–6259.
(4) Atkinson, J. G.; Wasson, B. K.; Fuentes, J. J.; Girard, Y.; Rooney, C. S.
Tetrahedron Lett. 1979, 2857–2860.
(1) (a) Song, Y.-L.; Peach, M.; Roller, P. P.; Qiu, S.; Wang, S.; Long, Y.-Q.
J. Med. Chem. 2006, 49, 1585–1596. (b) Dolle, R. E.; Machaut, M.; Martinez-
Teipel, B.; Belanger, S.; Cassel, J. A.; Stabley, G. J.; Graczky, T. M.; DeHaven,
R. N. Bioorg. Med. Med. Chem. 2004, 14, 3545–3548.
(2) (a) South, C. R.; Burd, C.; Weck, M. Acc. Chem. Res. 2007, 40, 63–74.
(b) Lewis, D. F. V.; Jacobs, M. N.; Dickins, M. Drug DiscoVery Today 2004, 9,
530–7. (c) Nose, T. Peptide Science 2003, 39, 9–12.
(5) (a) Loriga, M.; Paglietti, G.; Sparatore, F.; Pinna, G.; Sisini, A. IL
Farmaco 1992, 47, 439–448. (b) Schmidhammer, H.; Hohenlohe-Oehringen,
K. Sci. Pharm. 1983, 51, 8–16. (c) Zenker, N.; Talaty, C. N.; Callery, P. S.;
Wright, J.; Hubbard, L. S.; Johnson, E. M., Jr. J. Heterocyclic Chem. 1983, 20,
435–437.
(6) Milkowski, J. D.; Miller, F. M., Jr.; Zenker, N. J. Med. Chem. 1970, 13,
741–742.
8502 J. Org. Chem. 2008, 73, 8502–8510
10.1021/jo801577t CCC: $40.75 2008 American Chemical Society
Published on Web 10/15/2008

Catalytic Asymmetric Syntheses of Tyrosine Surrogates
FIGURE 2. Protected amino acids described in this paper.
SCHEME 1. Synthesis of Indazole Amino Acid Ester 5
SCHEME 2. Synthesis of Amino Acid Esters 6a and 21
enantiopure amino ester 27 (Scheme 3), a common precursor
to amino acid esters 8-10, was prepared by enzymatic resolu-
tion.7 Racemic amino acid esters 31 and 32 (Scheme 5),
intermediates toward benzoxalone amino ester 11 (X ) H) were
synthesized to study their potential as R-amino-3-hydroxy-5-
methyl-4-isoxazolepropanic acid (AMPA) agonist.8 Racemic
amino ester 32 was also used as a specific biomarker of
pheomelanin, a melanin pigment occurring in the hair and skin
of mammals to detect disease and drug usage.9 Herein we report
the asymmetric synthesis of these unnatural amino acids.
the carboxylic acids were protected as methyl esters, the amino
group was protected as the NHCBz derivative, and the indazole
and indole NH moieties were protected as the N-SES (SES )
trimethylsilylethanesulfuryl) functionalities. N-SES protection
was chosen because of its stability toward normal peptide-bond
forming and acidic-deprotection conditions. Its strong electron
withdrawing ability was also envisioned to increase the stability
of electron-rich enamides and perhaps accelerate asymmetric
hydrogenation of less electron-rich enamides (Vide infra).
The synthesis of indazole amino ester 5 is shown in Scheme
1. The reaction of aldehyde 1210 and SESCl11 afforded SES-
protected aldehyde 13a. The olefination12 of aldehyde 13a with
Results and Discussions
I. The Synthesis of Indazole, Indole and Indolinone Amino
Acid Esters (5-7). For the synthesis of amino acid esters 5-7,
(11) (a) Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J. P.
Tetrahedron Lett. 1986, 27, 2099–2102. (b) Weinreb, S. M.; Chase, C. E.; Wipf,
P.; Venkatraman, S. Org. Synth. 1998, 75, 161–169. (c) Huang, J.; Widlanski,
T. S. Tetrahedron Lett. 1992, 33, 2657–2660. (d) SESCl has become available
from Aldrich since 2007 at $330.50/5g (CAS# 106018-85-3). The starting
material to make SESCl, Me3SiCH2CH2SO3Na, is also available from Aldrich
at $82.7/5g (CAS# 18143-40-3). In our hands, the conditions described by
Widlanski11c were advantageous because purification was accomplished by quick
silica gel filtration rather than distillation. This is especially convenient for small
scale syntheses.
(7) Porter, J.; Dykert, J.; Rivier, J. Int. J. Peptide Protein Res. 1987, 30,
13–21.
(8) Hill, R. A.; Wallace, L. J.; Miller, D. D.; Weinstein, D M.; Shams, G.;
Tai, H.; Layer, R. T.; Illins, D.; Uretsky, N. J.; Danti, S. N. J. Med. Chem.
1997, 40, 3182–3191.
(9) (a) Patil, D. G.; Chedekel, M. R. J. Org. Chem. 1984, 49, 997–1000. (b)
Wakamatsu, K.; Ito, S. Pigment Cell Res. 2002, 15, 174–183.
(10) DeLucca, G. V. US 6313110 B1.
(12) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold,
R.; Meyer, R.; Riedl, B. Synthesis 1992, 487–490.
J. Org. Chem. Vol. 73, No. 21, 2008 8503

Han et al.
SCHEME 3. Synthesis of Amino Acid Ester 28
SCHEME 4. Synthesis of Amino Acid Esters 8-10
ylide 4 provided enamide 14a. The asymmetric hydrogenation
of 14a under Burk’s conditions13 afforded amino ester 5 in 95%
yield and 99.0% ee (Scheme 1).
The treatment of indole amino ester 21 with PyHBr•Br2,
followed by the removal of t-BuOH in Vacuo and exposure of
the residue to Zn in AcOH, afforded amino acid ester 7 in 41%
yield without loss of chirality (eq 1).17 Dibromo amino acid
ester 22 (35%) along with tribromo compound 23 (4%) were
also formed and their structures were determined by X-ray
diffraction (see Supporting Information),18 confirming generation
of the R configuration. The formation of side-product 23 in
which the third bromine atom was substituted at C6, instead of
the more electron-rich C7 position, suggested a possible
directing influence of the NHCBz group.19
We were also interested in the catalytic enantioselective
synthesis of BOC-protected indazole amino ester 5b, since the
corresponding indole amino ester 6b has been reported.3 Boc-
protected enamide 14b was prepared by the reaction of aldehyde
12 with Boc2O,14 followed by olefination.12 It is interesting to
note that 14b did not undergo hydrogenation under the asym-
metric hydrogenation conditions described above, and only a
progressive loss of the Boc protecting group occurred with
increasing catalyst loading. When enamide 15, prepared by the
reaction of 14b with TMSCl,15 was submitted to the above
asymmetric hydrogenation conditions (3 mol % and 25 mol %
catalyst loading), again no reaction occurred, suggesting that
the free indazole NH was perhaps complexing with rhodium.16
The synthesis of indole amino ester 6a is illustrated in Scheme
2. We were unable to obtain indole aldehyde 19 by the reaction
of 1H-indole-5-carbaldehyde with SESCl under various condi-
tions. Therefore, we carried out SES-protection of ester 16 with
SESCl to afford 17 in 76% yield. Aldehyde 19 was obtained
by sequential reaction of 17 with DIBAL-H and activated MnO2.
Enamide 20 was generated as described above. The same
asymmetric hydrogenation conditions with 0.56 mol% of the
catalyst converted 20 to 6a in 98% yield and 98.4% ee.
Treatment of 6a with CsF11a afforded 21 in 96% yield and 86%
ee. Racemization occurred to some extent in the deprotection
of methyl ester 6a [6a (98.4% ee) f 21 (86.0% ee)], but we
did not observe any loss of chirality under identical conditions
at a later stage deprotection following elaboration of both amino
and acid portions of 6a to amides.
(1)
II. The Synthesis of Benzotriazole, Benzoimidazolone,
Benzoimidazole Amino Acid Esters (8-10). The amino acid
esters (8-10) could be synthesized from the common diami-
(13) (a) Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372. (b) Burk, M. J.;
Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125–
10138. For the mechanistic study of the asymmetric hydrogenation of enamides
employing Burk’s catalyst, see: (c) Armstrong, S. K.; Brown, J. M.; Burk, M. J.
Tetrahedron Lett. 1993, 34, 879–882. For a similar general approach for the
enantioselective synthesis of aminobenzazepinone, see our prior publication: (d)
Prasad, C. V. C.; Mercer, S. E.; Dubowchik, G. M.; Macor, J. E. Tetrahedron
Lett. 2007, 48, 2661–2665.
(14) Grehn, L.; Ragnarsson, U. Angew Chem, Int. Ed. 1984, 23, 296–301.
(15) Kaiser Sr, E.; Picart, F.; Kubiak, T.; Tam, J.; Merrifield, R. B. J. Org.
Chem. 1993, 58, 5167–5175.
(16) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 3, 3157–
3159.
(17) Marfat, A.; Carta, M. P. Tetrahedron Lett. 1987, 28, 4027–4030.
(18) Full crystallographic data have been deposited to the Cambridge
Crystallographic Data Center (CCDC reference number 694858). Copies of the
data can be obtained free of charge via the internet at http://www.ccdc.cam.
ac.uk.
8504 J. Org. Chem. Vol. 73, No. 21, 2008

Catalytic Asymmetric Syntheses of Tyrosine Surrogates
SCHEME 5. Synthesis of Amino Acid Ester 11
nophenyl intermediate 28 (Scheme 3). 3,4-Dinitrobenzoic acid
24 was converted to its aldehyde 2520 by sequential reactions
with BH3•THF21 and PCC.22 The reaction of aldehyde 25 with
ylide 4 afforded the pure (Z)-isomer enamide 26 in 77% yield
after crystallization from EtOAc and flash chromatography on
silica gel using CH2Cl2 as eluent. We found these two
purification steps were necessary in preparation for the rapid
and highly enantioselective hydrogenation reaction (26 f 27).
The asymmetric hydrogenation of enamide 26 with 0.5 mol%
of the catalyst provided amino ester 27 in 98% yield and 99.6%
ee. The two nitro groups were cleanly reduced to give 28 using
Zn and HCO2NH4.23 Diamine 28 was stored either as an acetate
salt or as a hydrochloride salt.
Diamine 28 was converted into amino acid esters 8-10 as
shown in Scheme 4. Benzotriazole amino ester 8 was obtained
in 80% yield and 99.6% ee (two steps, from 27) by the reaction
of 28 (X ) OAc) with NaNO2.5 The reaction of diamine 28 (X
) Cl) and carbonyl diimidazole afforded benzoimidazolone
amino ester 9 in 50% yield (2 steps, from 27).5 The ee of amino
ester 9 was not determined. Finally, 2-methylbenzimidazole
amino ester 10 was obtained in 81% yield and 97.6% ee (2
steps, from 27) by heating diamine 28 (X ) OAc) in AcOH at
reflux for 4 h.5
III. The Synthesis of Benzoxalone Amino Acid Esters
(11, 11a-e and 33). The olefination of aldehyde 29 with ylide
4 afforded enamide 30 in 80% yield (Scheme 5). Asymmetric
hydrogenation of enamide 30 with Burk’s catalyst produced
amino ester 31 in 99% yield and 99.6% ee. Reduction of the
nitro group in 31 was accomplished by treatment with Fe and
NH4Cl.24 Aminophenol 32 was first converted to a CF3CO2H
salt, then an HCl salt.25 Aminophenol 32•HCl was reacted with
CDI in the presence of Et3N to produce amino acid ester 11
(60% yield from 31).
We were also interested in obtaining amino acid esters with
aromatic halogen substitutents for SAR studies, since it has been
shown that halogens may impart favorable biological and
pharmacokinetic properties. Equally important, the halogen
substituent could be used for transition metal (such as Pd)
catalyzed coupling reactions to provide more complex unnatural
amino acid ester analogues. Among the various classes of amino
acid esters we have synthesized (indazole 5, indole 6, indolinone
7; benzotriazole 8, benzoimidazolone 9, benzoimidazole 10; and
benzoxalone 11) we believed benzoxalone 11 would be the
easiest substrate to study in direct halogenation reactions to form
6-X and 7-X substituted amino acids for our medicinal chemistry
project needs.26 Indeed, after some experimentation, we were
able to prepare 6 and 7- Cl and Br, and 7-I substituted
benoxalones (11a-e) (Scheme 6). Using typical conditions for
electrophilic halogenation of electron rich aromatics, the reaction
of 11 with NCS or NBS in AcOH for 16 h at 100 °C produced
6-Cl- and 6-Br-substituted benzoxalones 11a and 11b in 32%
and 34% yield, respectively. After trying different halogenation
conditions, it was discovered that bromobenzoxalone 11c could
be obtained in an 80% yield by the reaction of 11 with NBS in
the presence of silica gel at rt for 6 h in CH2Cl2. Bromination
of electron-rich aromatics using NBS/SiO2/CH2Cl2 was first
reported by Kende.27 No reaction occurred with NCS under the
same conditions. However, when this reaction was run in
dichloroethane at 90 °C for 16 h in the presence of silica gel,
7-chlorobenzoxalone 11d and 6-chlorobenzoxalone 11a were
formed in 10% and 19% yield, respectively. In the presence of
silica gel, the reaction of 11 with I2 or NIS in either CH2Cl2 or
(CH2Cl)2 at rt or at reflux gave no desired product. Benzoxalone
11e was obtained in 40% yield by the reaction of 11 with
IPy2BF428 in dichloroethane at 90 °C for 6 h in the presence of
silica gel. The structures of halogenated benzoxalones 11a-e
were determined primarily by NMR analysis. Chemical shifts
were assigned by 1H, 13C, DEPT, COSY, HMQC, and HMBC.
The connectivity of key protons and carbons were determined
by HMQC and HMBC. These halogenated compounds could
indeed be used as the substrates for palladium-catalyzed
coupling reactions.29 For example, the reaction of 11c with
Zn(CN)2 [10% Pd(PPh3)4, DMF, 80 °C, 3 h] afforded nitrile
33 in 90% yield.30
Conclusion
In conclusion, we have achieved the asymmetric synthesis
of tyrosine mimetics, in which the phenol in the amino acid
has been replaced by indazole, indole, indolinone, benzotriazole,
benzoimidazolone, benzoimidazole, and benzoxalone, to afford
(19) Barluenga, J.; Alvarez-Gutierrez, J. M.; Ballesteros, A.; Gonzalez, J. M.
Angew. Chem., Int. Ed. 2007, 46, 1281–1283.
(20) Goldstein, H.; Voegeli, R. HelV. Chim. Acta 1941, 26, 1125–1128.
(21) Kende, A. S.; Fludzinski, P. Org. Synth., Coll. 1990, 7, 221–223.
(22) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647–2650.
(23) Gowda, D. C.; Mahesh, B.; Gowda, S. Ind. J. Chem., Sec. B: Org. Chem.
2001, 40B, 75–77, A variety of reduction conditions were screened for this
transformation. Only the employed conditions gave a clean reaction.
(24) (a) Ramadas, K.; Srinivasan, N. Synth. Commun. 1992, 22, 3189–3195.
Fe/NH4Cl was first reported by Shih to reduce aromatic nitro compounds: (b)
Shih, Y.-T. Huaxue Xuebao 1956, 22, 352–355.
(25) Aminophenol 32•HCl was better than 32•TFA for both storage and the
reaction of 32 with CDI in the presence of DIEA to form 11. HCl was not added
directly to the reaction mixture of 31 due to the concern that hydrogen formed
by the reaction of Fe and aq. HCl could remove CBz group.
(26) The reaction of indazole 5 with NBS under various conditions produced
mainly 3-Br-substituted indazole, while the reactions of 6-10 with NBS gave
multi-component mixtures.
(27) Kende, A. S.; Deng, W.-P.; Zhong, M.; Guo, X.-C. Org. Lett. 2003, 5,
1785–1788.
(28) IPy2BF4: A review: (a) Barluenga, J. Pure Appl. Chem. 1999, 71, 431–
436. Iodination of aromatic compounds: (b) Barluenga, J.; Gonzalez, J. M.;
Garcia-Martin, M. A.; Campos, P. J.; Asensio, G. J. Org. Chem. 1993, 58, 2058–
2060.
(29) Hartz, R. A.; Nanda, K. K.; Ingalls, C. L. Tetrahedron Lett. 2005, 46,
1683–1686.
(30) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B.;
King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887–890.
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Han et al.
SCHEME 6. Synthesis of Amino Acid Esters 11a-e and 33
NMR (CDCl3, 75 MHz) δ 190.9, 143.7, 141.3, 133.1, 129.0, 125.6,
125.2, 113.8, 51.4, 9.8, -2.1; HRMS (M - H)-; calcd for
C13H17N2O3SiS: 309.0729, found 309.0721.
unnatural amino acid esters 5-11 in good overall chemical
yields and extremely high enantioselectivities (up to 99.6% ee).
The key steps involved an olefination to form enamides and
subsequent asymmetric hydrogenation using Burk’s Rhodium
complex of EtDuphos. The success of these reactions highlight
the robustness of Burk’s catalyst and provide easy access to
these amino acid esters for pharmaceutical use in the synthesis
of novel analogs. The reaction sequence employed here should
be useful for making other unnatural amino acids esters of either
enantiomeric configuration.
2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfo-
nyl)-1H-indazol-5-yl]-acrylic Acid Methyl Ester (14a). 1,1,3,3-
Tetramethylguanidine (0.68 mL, 5.43 mmol) was added to a
solution of N-(benzyloxycarbonyl)-R-phosphonoglycine trimethyl
ester (1.88 g, 5.69 mmol) in THF (40 mL). After stirring at rt for
15 min, the mixture was cooled to -78 °C and a solution of 13a
(1.6 g, 5.17 mmol) in THF (15 mL) was added slowly. The resulting
reaction mixture was stirred at -78 °C for 2 h and then allowed to
warm to rt over 3 h. The solvents were removed in Vacuo and the
residue was subjected to flash chromatography using CH2Cl2/
hexanes (2:3) containing 1% Et3N as eluent to afford the title
compound as a 95:5 Z/E mixture (determined by the integration of
-CHdC(CO2Me)(NHCBz), 2.45 g, 92% yield). For the Z isomer:
1H NMR (CDCl3, 300 MHz) δ 8.16 (s. 1H), 7.98 (d, J ) 8.8 Hz,
1H), 7.86 (s, 1H), 7.67 (d, J ) 8.8 Hz, 1H), 7.46 (s, 1H), 7.34-7.27
(m, 5H), 6.55 (bs, 1H), 5.09 (s, 2H), 3.83 (s, 3H), 3.41-3.35 (m,
2H), 0.91-0.85 (m, 2H), -0.02 (s, 9H); 13C NMR (CDCl3, 75
MHz) δ 165.7, 153.7, 140.9, 135.9, 130.8, 130.7, 130.1, 128.6,
128.5, 128.3, 125.4, 124.2, 123.0, 113.1, 67.7, 52.9, 51.2, 9.8, -2.0;
HRMS (M + NH4)+ calcd for C24H33N4O6SiS: 533.1890, found
533.1893.
(R)-2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethane-
sulfonyl)-1H-indazol-5-yl]-propionic Acid Methyl Ester (5). In a
flame-dried 500 mL Parr hydrogenation bottle, a solution of 14a
(860 mg, 1.67 mmol) in MeOH (20 mL) and CH2Cl2 (20 mL) was
degassed by a flow of N2 for 30 min. (-)-1,2-bis((2R,5R)-2,5-
diethylphospholano)benzene(cyclooctadiene) rhodium (I) tetrafluo-
roborate (13 mg, 0.020 mmol, 1.2 mol%, weighed into a small vial
under N2 atmosphere in a glovebag) was quickly added to the
reaction mixture. The reaction mixture was purged with 5 vacuum/
H2 cycles, and then agitated for 2 h at 60 psi H2. Prior to its removal
from the Parr hydrogenation apparatus, the reaction mixture was
purged with 3 vacuum/N2 cycles. The solvent was evaporated and
the residue was subjected to flash chromatography using EtOAc/
hexanes (gradient, 1:4 to1:2) as eluent to afford the title compound
as a white solid (817 mg, 95% yield and 99.0% ee). The ee was
determined by HPLC analysis (Chiracel-OD column, 4.6 × 250
mm, 10 µm; 80% hexane/20% ethanol @1.0 mL/min for 20 min;
λ ) 213 nm; tR ) 13.9 min for the R-enantiomer and tR ) 11.2
Experimental Section
2-Trimethylsilanyl-ethanesulfonyl chloride, SESCl [the Modi-
fied Procedure].11c Sulfuryl chloride (SO2Cl2, 43 mL, 539 mmol)
was added over 3 min to a clear solution of PPh3 (129 g, 490 mmol)
in CH2Cl2(200 mL) stirred at 0 °C in a flame-dried three-neck
round-bottom flask. After 5 min, the ice-water bath was removed
and TMSCH2CH2SO3Na (50 g, 245 mmol) was added in portions
over 10 min. The resulting white suspension was stirred at rt for
16 h and then filtered through a pad of Celite. The filtrate was
concentrated to ca. 50 mL. EtOAc/hexanes (1:3, 1000 mL) and
Celite (40 g) were added. The mixture was stirred at room
temperature for 15 min and filtered through a pad of Celite. The
filtrate was concentrated and the residue was subjected to flash
column chromatography using EtOAc/hexanes (1:3) as the eluent
to give the title compound as a light tan liquid (41.9 g, 85% yield).
1H NMR (CDCl3, 500 MHz) δ 3.61-3.57 (m, 2H), 1.32-1.27 (m,
2H), 0.10 (s, 9H). The prepared SESCl was stored under N2 in a
freezer for two months without significant decomposition (<5%).
1-(2-Trimethylsilanyl-ethanesulfonyl)-1H-indazole-5-carbalde-
hyde (13a). To a solution of 1H-indazole-5-carbaldehyde (10.0 g,
68.4 mmol) and Et3N (28.6 mL, 205 mmol) in CH2Cl2 (300 mL)
was added freshly prepared SESCl (20.6 g, 103 mmol). The reaction
mixture was stirred at rt for 18 h and then washed with water (400
mL). The organic layer was separated, dried over MgSO4 and
filtered. The filtrate was concentrated and subjected to flash column
chromatography (gradient; 1:7 EtOAc/hexanes to 1:4 EtOAc/
hexanes) to afford the title compound as a white solid (15.1 g, 71%
yield). 1H NMR (CDCl3, 300 MHz) δ 10.10 (s, 1H), 8.40 (s, 1H),
8.30 (s, 1H), 8.21 (d, J ) 8.8 Hz, 1H), 8.07 (dd, J ) 8.8, 1.5 Hz,
1H), 3.46-3.40 (m, 2H), 0.88-0.82 (m, 2H), -0.02 (s, 9H); 13C
8506 J. Org. Chem. Vol. 73, No. 21, 2008

Catalytic Asymmetric Syntheses of Tyrosine Surrogates
min for S-enantiomer). 1H NMR (CDCl3, 300 MHz) δ 8.17 (s, 1H),
7.98 (d, J ) 8.8 Hz, 1H), 7.47 (s, 1H), 7.35-7.25 (m, 6H),
5.29-5.24 (m, 1H), 5.08 (dd, J ) 19.0, 12.1 Hz, 2H), 4.73-4.67
(m, 1H), 3.73 (s, 3H), 3.38-3.32 (m, 2H), 3.29 (dd, J ) 14.2, 5.6
Hz, 1H), 3.19 (dd, J ) 13.9, 5.6 Hz, 1H), 0.91-0.85 (m, 2H),
-0.02 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 171.8, 155.6, 140.4,
140.3, 136.2, 131.9, 130.8, 128.6, 128.4, 128.2, 125.5, 121.6, 113.2,
67.2, 55.0, 52.6, 51.1, 38.0, 9.7, -2.0; HRMS (M + NH4)+ calcd
for C24H35N4O6SiS: 535.2047, found 535.2051.
tert-Butyl 5-formyl-1H-indazole-1-carboxylate (13b). A solution
of (BOC)2O (388 mg, 1.78 mmol) in CH2Cl2 (2 mL) was added
dropwise at rt to a solution of 1H-indazole-5-carbaldehyde (273
mg, 1.87 mmol), DMAP (114 mg, 0.94 mmol), and Et3N (260 ul,
1.87 mmol) in CH2Cl2 (10 mL). The resulting bright-yellow solution
was stirred at rt for 16 h. The solvents were removed in Vacuo and
the residue was subjected to flash column chromatography using
EtOAc/hexanes (1:1) containing 1% Et3N as eluent to afford the
title compound as a brownish yellow liquid (414 mg, 90% yield).
1H NMR (CDCl3, 500 MHz) δ 10.08 (s, 1H), 8.38 (s, 1H), 8.34 (s,
1H), 8.25 (d, J ) 8.5 Hz, 1H), 8.04 (d, J ) 8.8 Hz, 1H), 1.71 (s,
9H); 13C NMR (CDCl3, 125 MHz) δ 191.8, 149.0, 142.5, 140.6,
133.0, 128.3, 126.4, 125.8, 115.3, 85.7, 27.8; HRMS (M + H)+
calcd for C13H15N2O3: 247.1083, found 247.1089.
3.18 (m, 2H), 0.84 - 0.80 (m, 2H), -0.06 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 167.3, 137.7, 130.3, 128.3, 125.9, 125.5, 124.0, 112.8,
108.3, 52.2, 51.2, 10.1, -2.1; HRMS (M - H)-, calcd for
C16H22NO4SSi 352.1039, found 352.1043.
[1-(2-Trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl]-metha-
nol (18). DIBAL-H (82.9 mL, 1 M in toluene, 82.9 mmol) was
added slowly to a solution of 17 (8.81 g, 25.9 mmol) in toluene
(200 mL) at 0 °C. After stirring at 0 °C for 45 min, the reaction
was quenched by the addition of MeOH (26 mL), finely ground
Na2SO4•10H2O (194 g) and Celite (26 mL). The mixture was
warmed to rt over 1 h and filtered through a pad of Celite. The
solvents were removed in Vacuo to afford the title compound as a
viscous liquid, which solidified upon standing to give a white solid
(8.08 g, 100% yield). 1H NMR (CDCl3, 500 MHz) δ 7.87 (d, J )
8.5 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J ) 3.7 Hz, 1H), 7.35 (dd, J )
8.6, 1.5 Hz, 1H), 6.66 (d, J ) 3.7 Hz, 1H), 4.79 (s, 2H), 3.18-3.14
(m, 2H), 1.73 (s, 1H), 0.85-0.82 (m, 2H), -0.06 (s, 9H); HRMS
(M + Na)+ calcd for C14H21NNaO3SSi 324.0909, found 324.0915.
1-(2-Trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carbalde-
hyde (19). A solution of 18 (2.1 g, 6.74 mmol) in CH2Cl2 (30 mL)
was added at 0 °C to a mixture of activated MnO2 (22 g,
azeotropically dried with toluene twice) and CH2Cl2 (70 mL) in a
500 mL round-bottom flask. The reaction mixture was stirred at 0
°C for 30 min and filtered through a pad of Celite. The solvents
were removed in Vacuo to afford the title compound as a white
(Z)-tert-Butyl 5-(2-(Benzyloxycarbonylamino)-3-methoxy-3-oxo-
prop-1-enyl)-1H-indazole-1-carboxylate (14b). Compound 14b was
prepared from 13b (416 mg, 1.69 mmol) according to the procedure
described for the preparation of 14a. Purification by flash chroma-
tography using EtOAc/hexanes (1:2) as eluent gave the title
1
solid (1.8 g, 86% yield). H NMR (CDCl3, 500 MHz) δ 10.06 (s,
1H), 8.15 (s, 1H), 8.01 (d, J ) 8.6 Hz, 1H), 7.87 (dd, J ) 8.6, 1.5
Hz, 1H), 7.54 (d, J ) 3.4 Hz, 1H), 6.80 (d, J ) 3.6 Hz, 1H), 3.24
- 3.20 (m, 2H), 0.86 - 0.82 (m, 2H), -0.06 (s, 9H); 13C NMR
(CDCl3, 125 MHz) δ 191.9, 138.5, 132.3, 130.7, 128.8, 125.3,
125.1, 113.6, 108.4, 51.4, 10.2, -2.1; HRMS (M - H)- calcd for
C14H18NO3SSi 308.0777, found 308.0782.
1
compound (550 mg, 72% yield). H NMR (CDCl3, 500 MHz) δ
8.10 (s, 1H), 7.98 (m, 2H), 7.72 (dd, J ) 8.8, 1.2 Hz, 1H), 7.34 (s,
1H), 7.22 (br s, 5H), 5.00 (s, 2H), 3.65 (s, 3H), 1.57 (s, 9H); 13C
NMR (CDCl3, 125 MHz) δ 207.0, 166.1, 155.0, 149.2, 140.1, 139.7,
132.6, 130.7, 129.7, 128.9, 128.5, 128.3, 126.5, 125.8, 123.5, 114.7,
85.3, 67.2, 52.6, 27.9; HRMS (M + H)+ calcd for C24H26N3O6:
452.1822, found 452.1826.
2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfo-
nyl)-1H-indol-5-yl]-acrylic Acid Methyl Ester (20). Compound 20
was prepared from 19 (1.6 g, 5.17 mmol) according to the procedure
described for the preparation of 14a. Purification by flash chroma-
tography using CH2Cl2/hexanes (2:3) containing 1% Et3N as eluent
afforded the title compound (1.9 g, 75% yield) as a 92:8 Z/E mixture
(determined by the integration of CO2CH3, for Z isomer it was at
(Z)-Methyl 2-(benzyloxycarbonylamino)-3-(1H-indazol-5-yl)acry-
late (15). A 4 M solution of phenol in CH2Cl2 (6 mL) and a 4 M
solution of chlorotrimethylsilane in CH2Cl2 (2 mL) were mixed
together and then passed through a plug of sodium carbonate. The
TMS-phenol solution in CH2Cl2 was added to a solution of 14b
(1.0 g, 2.2 mmol) in CH2Cl2 (2 mL) and the reaction mixture was
stirred at rt until disappearance of the starting material was complete.
The solvent was removed in Vacuo and the residue was subjected
to flash column chromatography using EtOAc/hexanes containing
1% Et3N (1:1, then 3:1) as eluent to give the title compound (600
mg, 77% yield). 1H NMR (CDCl3, 500 MHz) δ 8.02 (s, 1H), 7.90
(s, 1H), 7.60 (d, J ) 8.8 Hz, 1H), 7.51 (s, 1H), 7.37 (d, J ) 8.6
Hz, 1H), 7.35-7.27 (m, 5H), 5.11 (s, 2H), 3.83 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 166.0, 154.0, 134.0, 135.8, 133.0, 129.7,
128.6, 128.3, 127.0, 123.6, 122.9, 120.7, 115.4, 110.0, 67.6, 52.8,
28.6; HRMS (M + H)+, calcd C19H18N3O4: 352.1297, found
352.1304.
1
3.79 ppm and E isomer 3.65 ppm). For the Z isomer: H NMR
(CD3CN, 500 MHz) δ 7.96 (s, 1H), 7.91 (d, J ) 8.5 Hz, 1H), 7.66
(d, J ) 8.5 Hz, 1H), 7.56 (d, J ) 3.7 Hz, 1H), 7.51 (s, 1H), 7.43
- 7.35 (m, 5H), 7.67 (d, J ) 3.7 Hz, 1H), 5.16 (s, 2H), 3.79 (s,
3H), 3.42 - 3.38 (m, 2H), 0.87 - 0.83 (m, 2H), -0.04 (s, 9H); 13C
NMR (126 MHz, ACETONITRILE-d3) δ ppm 166.27, 155.00,
135.80, 133.79, 131.11, 129.06, 128.91, 128.66, 128.47, 128.22,
126.67, 124.86, 124.01, 118.01, 113.61, 108.09, 67.12, 52.48, 51.25,
10.11, -2.74; HRMS (M + NH4)+ calcd for C25H34N3O6SSi
532.1938, found 532.1940.
(R)-2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethane-
sulfonyl)-1H-indol-5-yl]-propionic Acid Methyl Ester (6a). Com-
pound 6a was prepared according to the procedure described for
the preparation of 5: [3.21 g of 20, 23 mg (0.56 mol %) of
[Rh(COD)L]BF4, L ) (R,R)-Et-DuPhos, MeOH (60 mL), CH2Cl2
(60 mL), H2 (60 psi), rt, 2 h]. Purification by flash chromatography
using EtOAc/hexanes (1:3) as eluent gave the title compound as
an off-white foamy solid (3.15 g, 98% yield, 98.4% ee). The ee
was determined by HPLC analysis (Chiralcel-OD column, 4.6 ×
250 mm, 10 µm; 80% hexane/20% EtOH @ 1.0 mL/min. for 14
min; λ ) 214 nm; tR ) 9.7 min for R- and 7.6 min for
1-(2-Trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carboxylic Acid
Ethyl Ester (17). A solution of 1H-Indole-5-carboxylic acid ethyl
ester 16 (10.31 g, 58.8 mmol) in DMF (50 mL) was added dropwise
at 0 °C to a mixture of NaH (1.83 g, 76.4 mmol) in DMF (150
mL). After stirring at 0 °C for 30 min, a solution of SESCl (17.7
g, 88.2 mmol) in DMF (100 mL) was added slowly at 0 °C. The
mixture was stirred for 2 h, quenched with saturated aqueous NH4Cl
(200 mL) and extracted with EtOAc (300 mL). The organic layer
was separated and the aqueous layer was extracted with additional
EtOAc (2 × 150 mL). The combined organic extracts were washed
with brine (3 × 150 mL), dried over anhydrous Na2SO4, and filtered.
The filtrate was concentrated and the resulting residue was subjected
to flash column chromatography using CH2Cl2/hexanes (2:3) as
eluent to afford the title compound as a white solid (15.8 g, 76%
1
S-enantiomer). H NMR (CD3OD, 500 MHz) δ 7.82 (d, J ) 8.5
Hz, 1H), 7.52 (d, J ) 3.5 Hz, 1H), 7.50 (s, 1H), 7.32-7.26 (m,
6H), 7.23 (d, J ) 8.0 Hz, 1H), 6.71 (d, J ) 4.0 Hz, 1H), 5.05 (d,
J ) 12.5 Hz, 1H), 5.01 (d, J ) 12.5 Hz, 1H), 4.51 (dd, J ) 9.2,
5.5 Hz, 1H), 3.72 (s, 3H), 3.35 - 3.32 (m, 2H), 3.28 (dd, J ) 14.0,
5.2 Hz, 1H), 3.06 (dd, J ) 14.0, 9.4 Hz, 1H), 0.75 - 0.72 (m, 2H);
13C NMR (CD3OD, 125 MHz) δ 172.9, 157.3, 137.2, 134.6, 132.4,
131.2, 128.5, 128.0, 127.7, 127.6, 125.9, 122.1, 113.0, 107.6, 66.5,
1
yield). H NMR (CDCl3, 500 MHz) δ 8.36 (d, J ) 1.5 Hz, 1H),
8.03 (dd, J ) 9.0, 2.0 Hz, 1H), 7.92 (d, J ) 8.5 Hz, 1H), 7.50 (d,
J ) 3.5 Hz, 1H), 6.75 (d, J ) 3.5 Hz, 1H), 3.94 (s, 3H), 3.21 -
J. Org. Chem. Vol. 73, No. 21, 2008 8507

Han et al.
56.3, 51.8, 50.4, 37.5, 10.1, -3.2; HRMS (M + NH4)+ Calc for
C25H36N3O6SSi 534.2094, found 534.2100.
was removed to afford (3,4-dinitrophenyl)-methanol as a light
yellow solid (100% yield). 1H NMR (CDCl3, 500 MHz) δ 7.91(d,
J ) 8.0 Hz, 1H), 7.89 (s, 1H), 7.71 (dd, J ) 8.5, 1.0 Hz, 1H), 4.87
(s, 2H), 2.30 (s, 1H).
2-Benzyloxycarbonylamino-3-(1H-indol-5-yl)-propionic Acid
Methyl Ester (21). CsF (2.11 g, 13.9 mmol) was added to a solution
of 6a (715 mg, 1.39 mmol) in CH3CN (50 mL). The resulting
suspension was heated at 80 °C for 3 h. After cooling to rt, the
solvent was removed in Vacuo and the residue was subjected to
flash chromatography using CH2Cl2/MeOH/Et3N (93:5:2) as eluent
to afford the title compound as a tan viscous oil (470 mg, 96%
yield, 86.0% ee). The ee was determined by HPLC analysis
(Chiralpak-AD column, 4.6 × 250 mm, 10 µm; A ) EtOH, B )
0.05% diethylamine/hexane, 85%B @ 1.0 mL/min for 30 min; λ
) 223 nm; tR ) 23.7 min for R- and 21.9 min for S-enantiomer).
1H NMR (CD3OD, 500 MHz) δ 7.39 (s, 1H), 7.36 - 7.26 (m, 7H),
7.22 (d, J ) 3.0 Hz, 1H), 6.97 (dd, J ) 7.8, 1.5 Hz, 1H), 6.40 -
6.39 (m, 1H), 5.06 (d, J ) 12.5 Hz, 1H), 5.02 (d, J ) 12.5 Hz,
1H), 4.48 (dd, J ) 8.5, 6.0 Hz, 1H), 3.70 (s, 3H), 3.21 (dd, J )
14.0, 6.0 Hz, 1H), 3.02 (dd, J ) 14.0, 8.75 Hz, 1H); 13C NMR
(CD3OD, 125 MHz) δ 173.4, 157.4, 137.1, 135.8, 128.7, 128.5,
128.0, 127.7, 127.3, 125.1, 122.7, 120.8, 111.4, 101.4, 66.6, 56.7,
51.8, 38.0; HRMS (M + H)+ Calc. for C20H21N2O4 353.1501, found
353.1508.
A solution of (3,4-dinitro-phenyl)-methanol (95.3 g, 481 mmol)
in CH2Cl2 (500 mL) was added all at once to a suspension of PCC
(156 g, 722 mmol) in CH2Cl2 (900 mL). After stirring at rt for
1.5 h, 1.5 L of diethyl ether was added. The supernatant was
decanted from the black gum and the insoluble residue was washed
thoroughly with CH2Cl2 (3 × 250 mL). The combined organic
mixtures were filtered through a pad of Florisil to afford a light
bright-yellow clear solution. The solvents were removed in Vacuo
and the residue was subjected to flash column chromatography using
CH2Cl2 as eluent to afford the title compound as a yellow solid
1
(52.7 g, 71% yield). H NMR (CDCl3, 300 MHz) δ 8.45 (d, J )
1.5 Hz, 1H), 8.28 (dd, J ) 8.1, 1.5 Hz, 1H), 8.07 (d, J ) 8.1 Hz,
1H); 13C NMR (CD3OD, 125 MHz) δ 187.7, 139.2, 134.2, 126.2,
125.7.
2-Benzyloxycarbonylamino-3-(3,4-dinitro-phenyl)-acrylic Acid
Methyl Ester (26). Compound 26 was prepared from 3,4-dinitro-
benzaldehyde 25 (61.4 g, 313 mmol) according to the procedure
described for the preparation of 14a. Once the reaction reached
completion, the solvents were removed in Vacuo. The yellow residue
was dissolved in 4.5 L of EtOAc, washed with 1.5 L of 1N H2SO4,
H2O twice, brine, dried over Na2SO4 and filtered. The filtrate was
concentrated under vacuum and the residue was recrystallized from
EtOAc (20 g crude product/100 mL of EtOAc). The yellow crystals
were collected and further purified by flash column chromatography
using CH2Cl2 as eluent. The title compound was obtained as yellow
2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)-
propionic Acid Methyl Ester (7) and 2-Benzyloxycarbonylamino-
3-(2,3-dibromo-1H-indol-5-yl)-propionic Acid Methyl Ester (22).
PyHBr3 (1.28 g, 4.02 mmol) was added in portions over 30 min to
a stirred solution of 21 (0.47 g, 1.34 mmol) in t-BuOH (10 mL) at
rt. After stirring at rt for 3.5 h, t-BuOH was removed in Vacuo and
the residue was extracted with EtOAc, washing with brine twice.
The combined organic extracts were dried over Na2SO4 and filtered.
The filtrate was concentrated and the resulting residue was
azeotropically dried with anhydrous EtOH. AcOH (10 mL) and
Zn powder (0.88 g, 13.4 mmol) were added and the mixture was
stirred overnight at rt. After AcOH was removed in Vacuo, the
residue was subjected to flash column chromatography using
EtOAc/hexanes (1:3, then 3:2) as eluent to afford the title compound
7 as a white solid (202 mg, 41% yield) and compound 22 (238
mg, 35% yield) along with 23 (31 mg, 4% yield) as a tan solid.
For compound 7: The ee was determined by HPLC analysis
(Chiralpak-AD column, 4.6 × 250 mm, 10 µm; A ) IPA, B )
0.05% diethylamine/heptane, 70% B @ 1.0 mL/min for 22 min; λ
) 251 nm; tR ) 17.6 min for R- and 14.7 min for S-enantiomer).
1H NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.36-7.31 (m, 5H),
6.94 (s, 1H), 6.91 (d, J ) 8.0 Hz, 1H), 6.73 (d, J ) 7.5 Hz, 1H),
5.26 (d, J ) 8.0 Hz, 1H), 5.11 (d, J ) 12.0 Hz, 1H), 5.05 (d, J )
12.5 Hz, 1H), 4.61 (dd, J ) 13.5, 6.0 hz, 1H), 3.72 (s, 3H), 3.45
(s, 2H), 3.10 (dd, J ) 14.0, 5.5 Hz, 1H), 3.00 (dd, J ) 14.0, 6.0
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 177.7, 172.2, 155.7, 141.7,
136.3, 129.8, 128.9, 128.6, 128.3, 128.2, 125.8, 125.6, 109.8, 67.1,
55.1, 52.5, 38.0, 36.; HRMS (M + H)+ Calc. for C20H21N2O5
369.1450, found 369.1454. For compound 22: 1H NMR
(CD3COCD3, 500 MHz) δ 11.15 (s, 1H), 7.35 (br s, 2H), 7.30 (br
s, 4H), 7.16-7.15 (m, 1H), 6.68-6.67 (m, 1H), 5.03 (s, 2H), 4.56
1
crystals (96.7 g, 77% yield). H NMR (CDCl3, 500 MHz) δ 7.85
(d, J ) 1.5 Hz, 1H), 7.74 (d, J ) 8.0 Hz, 1H), 7.62 (dd, J ) 8.5,
1.5 Hz, 1H), 7.35-7.34 (m, 3H), 7.34 (br s, 2H), 7.23 (s, 1H),
6.95 (br s, 1H), 5.07 (s, 2H), 3.90 (s, 3H);); 13C NMR (DMSO-d6,
125 MHz) δ 164.8, 154.0, 142.1, 140.6, 139.8, 136.1, 134.5, 130.4,
128.3, 128.0, 127.7, 125.8, 125.6, 125.0, 66.3, 52.6.
(R)-2-Benzyloxycarbonylamino-3-(3,4-dinitro-phenyl)-propion-
ic Acid Methyl Ester (27). Compound 27 was prepared according
to the procedure described for the preparation of 5: [3.61 g of 26,
29.7 mg (0.50 mol %) of [Rh(COD)L]BF4, L ) (R,R)-Et-DuPhos,
MeOH (50 mL), CH2Cl2 (50 mL), H2 (60 psi), rt, 2 h]. The residue
was purified by flash column chromatography using EtOAc/hexanes
(1:1) as eluent to afford the title compound as a light tan gummy
solid (3.56 g, 98% yield and 99.6% ee). The ee was determined by
HPLC analysis (Chiralpak AD column, 4.6 × 250 mm, 10 µm; A
) EtOH, B ) hexane; 40% B @ 1.0 mL/min for 14 min; λ ) 208
nm; tR ) 10.9 min for R enatiomer and 6.9 min for S enatiomer).
1H NMR (CDCl3, 500 MHz) δ 7.80 (d, J ) 8.0 Hz, 1H), 7.63 (s,
1H), 7.45 (d, J ) 8.0 Hz, 1H), 7.38 - 7.31 (m, 5H), 5.37 (d, J )
6.0 Hz, 1H), 5.13-5.05 (m, 2H), 4.68 (d, J ) 6.0 Hz, 1H), 3.71 (s,
3H), 3.36 (dd, J ) 13.5, 5.0 Hz, 1H), 3.17 (dd, J ) 13.5, 6.0 Hz,
1H);); 13C NMR (DMSO-d6, 125 MHz) δ 171.4, 155.8, 145.7,
141.9, 140.3, 136.7, 134.9, 128.2, 127.7, 127.4, 126.0, 125.4, 65.4,
54.2, 52.1, 35.5.
(R)-2-Benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propi-
onic Acid Methyl Ester (28). To a suspension of 27 (1.45 g, 3.6
mmol) and Zn power (1.41 g, 21.6 mmol) in MeOH (50 mL,
degassed with a flow of N2 for 2 h), HCO2NH4 (2.27 g, 36 mmol)
was added in portions at 0 °C. After stirring at rt overnight, the
solvents were removed. Toluene (30 mL, degassed) and EtOAc
(30 mL, degassed) were added, followed by HOAc (3 mL), diluting
further with these solvents until all organic solids had dissolved.
Then, the mixture was washed with H2O, brine, dried over Na2SO4
and filtered. The filtrate was concentrated in Vacuo to afford
28•HOAc as a reddish gummy solid (1.23 g, 85% yield). HRMS
(M + H)+ calcd for C18H22N3O4 344.1610, found 344.1616.
3-(1H-Benzotriazol-5-yl)-2-benzyloxycarbonylamino-propion-
ic Acid Methyl Ester (8). To a solution of 28•HOAc (2.68 g, 6.65
mmol) in AcOH (30 mL) and H2O (40 mL), was added a solution
of NaNO2 (0.46 g, 6.65 mmol) in H2O (8 mL) dropwise at rt. After
(s, 1H), 3.71 (s, 3H), 3.32-3.29 (m, 1H), 3.16-3.12 (m, 1H); 13
C
NMR (CD3COCD3, 125 MHz) δ 172.6, 156.4, 137.6, 135.7, 130.2,
128.7, 128.13, 128.04, 127.76, 124.9, 119.0, 111.8, 110.7, 92.7,
66.3, 56.5, 51.9, 38.0; HRMS (M
C20H18Br2N2NaO4 530.9531, found 530.9535.
+
Na)+ Calc for
3,4-Dinitro-benzaldehyde (25). BH3•THF (1 M in THF, 800 mL,
800 mmol) was added at -20 °C over 45 min to a solution of
3,4-dinitrobenzoic acid 24 (93.5 g, 441 mmol) in THF (300 mL).
After stirring at -20 °C for 1 h, the mixture was warmed to rt and
stirring was continued overnight. The mixture was quenched by
the addition of 32 mL of 1:1 HOAc/H2O. The solvents were
removed in Vacuo and the residue was poured into 1000 mL of
ice-cold saturated aqueous NaHCO3 with vigorous stirring over 15
min. The mixture was extracted with EtOAc (3 × 500 mL) and
the combined organic extracts were washed with saturated aqueous
NaHCO3, brine and dried over Na2SO4. After filtration, the solvent
8508 J. Org. Chem. Vol. 73, No. 21, 2008

Catalytic Asymmetric Syntheses of Tyrosine Surrogates
stirring at rt for 20 min, the mixture was cooled to 0 °C and conc.
NH3•H2O was added to adjust the pH to 11. The mixture was
extracted with EtOAc twice in the presence of solid NaCl. The
organic extracts were dried over Na2SO4 and filtered. The solvents
were removed in Vacuo and the residue was subjected to flash
column chromatography using EtOAc/hexanes (6:4) as eluent to
L ) (R,R)-Et-DuPhos, MeOH (60 mL), CH2Cl2 (60 mL), H2 (60
psi), rt, 4 h]. The residue was purified by flash chromatography
using straight CH2Cl2 as eluent to afford the title compound as an
off yellow solid (5.94 g, 99% yield and 99.6% ee). The ee was
determined by HPLC analysis (Chiralpak AD column, 4.6 × 250
mm, 10 µm; A ) EtOH, B ) heptane; 40% B @ 1.0 mL/min for
20 min; λ ) 282nm; tR ) 14.8 min for R-enantiomer and 9.7 min
for S-enantiomer). 1H NMR (CDCl3, 500 MHz) δ 7.97 (d, J ) 9.0
Hz, 1H), 7.36-7.30 (m, 5H), 6.90 (s, 1H), 6.71 (d, J ) 8.5 Hz,
1H), 5.29 (d, J ) 7.0 Hz, 1H), 5.11 (d, J ) 12.5 Hz, 1H), 5.07 (d,
J ) 12.0 Hz, 1H), 4.68 (dd, J ) 13.0, 6.0 Hz, 1H), 3.74 (s, 3H),
3.20 (dd, J ) 13.5, 5.0 Hz, 1H), 3.05 (dd, J ) 13.5, 6.0 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ 171.3, 155.6, 155.0, 147.3, 136.1,
132.7, 128.6, 128.4, 128.2, 125.3, 121.5, 120.5, 67.3, 54.3, 52.8,
38.4. HRMS (M + H)+ Calc for C18H19N2O7 375.1192, found
375.1194.
1
afford the title compound as a tan solid (2.12 g, 94% yield). H
NMR (CD3OD, 500 MHz) δ 7.75 (d, J ) 8.5 Hz, 1H), 7.58 (s,
1H), 7.31-7.25 (m, 5H), 7.18 (d, J ) 8.5 Hz, 1H), 5.39 (d, J )
8.0 Hz, 1H), 5.10 (d, J ) 12.0 Hz, 1H), 5.05 (d, J ) 12.0 Hz, 1H),
4.74 (dd, J ) 13.5, 6.0 Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J ) 14.0,
5.5 Hz,1H), 3.22 (dd, J ) 13.5, 6.0 Hz, 1H); 13C NMR (CD3OD,
125 MHz) δ 172.1, 156.0, 136.1, 128.6, 128.3, 128.1, 67.2, 55.2,
52.7, 38.5; HRMS (M + H)+ calcd for C18H19N4O4 355.1406, found
355.1410.
(R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-1H-ben-
zoimidazol-5-yl)-propionic Acid Methyl Ester (9). To a solution
of 28•2HCl (600 mg, 1.44 mmol) in THF (125 mL) was added
Et3N (320 mg, 3.17 mmol). A fine precipitate was observed. N,N′-
Carbonyldiimidazole (280 mg, 1.73 mmol) was added all at once
and the reaction mixture was stirred overnight at rt. After filtration
to remove the fine precipitate, the filtrate was concentrated and
subjected to flash column chromatography using MeOH/CH2Cl2
(1:12) as eluent to give the title compound (313 mg, 59% yield).
1H NMR (CD3OD, 300 MHz) δ 7.28 (m, 5H), 6.94-6.85 (m, 3H),
5.01 (dd, J ) 20.3, 12.6 Hz, 2H), 4.44 (dd, J ) 9.1, 5.5 Hz, 1H),
3.68 (s, 3H), 3.15 (dd, J ) 13.5, 5.5 Hz, 1H), 2.92 (dd, J ) 13.5,
9.1 Hz, 1H); 13C NMR (CD3OD, 75 MHz) δ 174.0, 158.4, 158.2,
138.2, 131.7, 131.0, 129.8, 129.4, 129.0. 128.7, 123.6, 111.1, 110.2,
67.6, 57.4, 52.7, 38.8; HRMS (M + H)+ Calc for C19H20N3O5
370.1403, found 370.1408.
(R)-methyl 3-(4-amino-3-hydroxyphenyl)-2-(benzyloxycarbony-
lamino)propanoate Hydrochloride (32). Fe (3.7 g, 66.4 mmol) and
NH4Cl (5.9 g, 111 mmol) were added at 0 °C to a solution of 31
(2.07 g, 5.53 mmol) in a mixture of MeOH (degassed, 200 mL)
and H2O (degassed, 200 mL). After stirring at rt for 48 h, CF3CO2H
(7 mL) was added, swirling until the mixture was a clear dark-red
solution containing unreacted Fe powder. The mixture was filtered
and the filtrate was concentrated in Vacuo. The residue was extracted
with EtOAc (2 × 150 mL) and the combined organic layers were
washed with brine, dried over Na2SO4, and filtered. HCl (4.2 mL,
4 M in dioxane) was added to the filtrate. The solvents were
removed in Vacuo to afford 32•HCl as a tan foamy solid (80%
1
yield). H NMR (CD3OD, 500 MHz) δ 7.34-7.28 (m, 5H), 7.20
(d, J ) 8.0 hz, 1H), 6.88 (s, 1H), 6.78 (d, J ) 7.5 Hz, 1H),
5.05-5.00 (m, 2H), 4.42 (dd, J ) 8.5, 5.0 Hz, 1H), 3.70 (s, 3H),
3.65 (s, 1H), 3.33 (br s, 2H), 3.11 (dd, J ) 14.0, 5.0 hz, 1H), 2.90
(dd, J ) 13.5, 9.0 Hz, 1H); 13C NMR (CD3OD, 125 MHz) δ 172.5,
157.4, 151.2, 140.2, 137.0, 128.5, 128.0, 127.7, 123.8, 120.9, 117.0,
116.9, 67.2, 55.7, 52.0, 37.2; HRMS (M + H)+ Calc for C18H21N2O5
345.1450, found 345.1454.
(R)-2-Benzyloxycarbonylamino-3-(2-methyl-1H-benzoimidazol-
5-yl)-propionic acid methyl ester (10). A solution of 28•HOAc (640
mg) in AcOH (8 mL) was heated at 130 °C for 4 h. The mixture
was poured into H2O and cooled to 0 °C. After the pH was adjusted
to 8 by adding solid NaHCO3 in portions, the aqueous mixture was
extracted with EtOAc (3 × 100 mL). The combined organic layers
were washed with H2O, brine, dried over Na2SO4 and filtered. The
filtrate was concentrated to afford the title compound as a brown
(R)-2-Benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzoox-
azol-6-yl)-propionic Acid Methyl Ester (11). To a solution of
32•HCl (1.17 g, 3.07 mmol) and iPrNEt2 (1.60 mL, 9.21 mmol) in
CH2Cl2 (85 mL) at 0 °C, was added a solution of N,N′-carbonyl-
diimidazole (498 mg, 3.07 mmol) in CH2Cl2 (15 mL). After stirring
at 0 °C for 4 h, the solvents were removed in Vacuo and the residue
was subjected to flash column chromatography using EtOAc/
hexanes (1:1) as eluent to afford the title compound as a white
solid (579 mg, 51% yield). 1H NMR (CDCl3, 500 MHz) δ 9.07 (s,
1H), 7.37-7.29 (m, 5H), 6.96 (s, 1H), 6.90 (d, J ) 8.0 Hz, 1H),
6.87 (d, J ) 8.0 Hz, 1H), 5.36 (d, J ) 8.0 Hz, 1H), 5.11 (d, J )
12.0 Hz, 1H), 5.07 (d, J ) 12.5 Hz, 1H), 4.65 (dd, J ) 13.5, 5.5
Hz, 1H), 3.74 (s, 3H), 3.17 (dd, J ) 14.0, 5.5 Hz, 1H), 3.07 (dd,
J ) 14.0, 6.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 171.9, 155.7,
155.5, 144.1, 136.2, 130.8, 128.6, 128.42, 128.38, 128.2, 125.1,
111.1, 109.8, 67.2, 55.1, 52.6, 38.3; HRMS (M + H)+ calcd for
C19H19N2O6 371.1243, found 371.1246.
1
foamy solid (554 mg, 95% yield). H NMR (CDCl3, 500 MHz) δ
7.39 (d, J ) 8.5 Hz, 1H), 7.35 (s, 1H), 7.26 - 7.22 (m, 5H), 7.06
(d, J ) 8.0 Hz, 1H), 5.03 (d, J ) 12.5 Hz, 1H), 4.99 (d, J ) 13.0
hz, 1H), 4.51 (dd, J ) 8.5, 5.5 Hz, 1H), 3.70 (s, 3H), 3.27 (dd, J
) 13.5, 5.0 Hz, 1H), 3.03 (dd, J ) 14.0, 9.0 Hz, 1H), 2.55 (s, 3H);
13C NMR (125 MHz, CD3OD) δ 173.0, 157.4, 152.2, 137.2, 131.2,
128.4, 127.9, 127.6, 123.5, 66.5, 56.5, 51.7, 37.9, 13.3; HRMS (M
+ H)+ Calc for C20H22N3O4 368.1610, found 368.1616.
2-Benzyloxycarbonylamino-3-(3-hydroxy-4-nitro-phenyl)-
acrylic Acid Methyl Ester (30). Compound 30 was prepared using
3-hydroxy-4-nitrobenzaldehyde 29 (14.1 g, 84.2 mmol) according
to the method described for the preparation of 14a. Once the
reaction had reached completion, the solvents were removed in
Vacuo. The yellow residue was dissolved in 1.5 L of EtOAc, washed
with 1N H2SO4 (500 and 250 mL), H2O twice, brine, dried over
Na2SO4 and filtered. The filtrate was concentrated in Vacuo and
the resulting residue was recrystallized from EtOAc. The yellow
crystals were collected and further purified by flash column
chromatography using CH2Cl2 as eluent to afford the title compound
as pale-yellow crystals (25.1 g, 80% yield). 1H NMR (CDCl3, 500
MHz) δ 7.93 (d, J ) 9.0 Hz, 1H), 7.32 (br s, sH), 7.28 (br s, 2H),
7.17 (s, 1H), 7.16 (d, J ) 2.0 Hz, 1H), 7.01 (dd, J ) 9.0, 2.0 Hz,
1H), 6.74 (br s, 1H), 5.06 (s, 2H), 3.86 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 165.0, 154.9, 152.8, 144.0, 135.5, 132.9, 128.6, 128.5,
128.2, 127.2, 125.8, 125.1, 120.6, 120.2, 68.0, 53.3; HRMS (M +
H)+ Calc for C18H17N2O7 373.1036, found 373.1044.
(R)-Methyl 2-(benzyloxycarbonylamino)-3-(5-chloro-2-oxo-2,3-
dihydrobenzo[d]oxazol-6-yl)propanoate (11a). A mixture of ben-
zoxalone 11 (700 mg, 1.89 mmol), NCS (315 mg, 2.36 mmol) and
AcOH (20 mL) was heated at 100 °C for 16 h. The solvents were
removed in Vacuo and the residue was subjected to flash chroma-
tography using EtOAc/hexanes (4:6, then 1:1) as eluent to afford
1
the title compound as an off-white solid (242 mg, 32% yield). H
NMR (CD3COCD3, 500 MHz) δ 10.47 (s, 1H), 7.36-7.28 (m, 6H),
7.20 (s, 1H), 6.80 (d, J ) 8.5 Hz, 1H), 5.05 (d, J ) 12.5 Hz, 1H),
5.00 (d, J ) 12.5 Hz, 1H), 4.65-4.60 (m, 1H), 3.73 (s, 3H), 3.43
(dd, J ) 14.0, 5.0 Hz, 1H), 3.08 (dd, J ) 14.0, 10.5 Hz, 1H); 13C
NMR (CD3COCD3, 125 MHz) δ 172.2, 156.5, 154.5, 143.1, 137.5,
130.8, 129.0, 128.9, 128.7, 128.2, 128.0, 112.8, 110.9, 66.3, 54.3,
52.1, 35.8; HRMS (M + H)+ calcd for C19H18ClN2O6 405.0853,
found 405.0858.
(R)-2-Benzyloxycarbonylamino-3-(3-hydroxy-4-nitro-phenyl)-
propionic Acid Methyl Ester (31). Compound 31 was prepared
according to the procedure described for the preparation of
compound 5: [6.0 g of 30, 106 mg (1.0 mol %) of [Rh(COD)L]BF4,
J. Org. Chem. Vol. 73, No. 21, 2008 8509

Han et al.
(R)-Methyl 2-(benzyloxycarbonylamino)-3-(5-bromo-2-oxo-2,3-
dihydrobenzo[d]oxazol-6-yl)propanoate (11b). A mixture of ben-
zoxalone 11 (1070 mg, 2.89 mmol), NBS (643 mg, 3.61 mmol)
and AcOH (30 mL) was heated at 100 °C for 16 h. The solvents
were removed in Vacuo and the residue was subjected to flash
chromatography using EtOAc/hexanes (4:6, then 1:1) as eluent to
afford the title compound as a light-yellow solid (446 mg, 34%
yield). 1H NMR (CD3COCD3, 500 MHz) δ 10.46 (s, 1H),
7.36-7.28 (m, 7H), 6.82 (d, J ) 8.5 Hz, 1H), 5.05 (d, J ) 12.5
Hz, 1H), 5.00 (d, J ) 12.5 Hz, 1H), 4.67-4.62 (m, 1H), 3.73 (s,
3H), 3.43 (dd, J ) 14.0, 5.0 Hz, 1H), 3.10 (dd, J ) 14.0, 10.5 Hz,
1H); 13C NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 154.2,
143.7, 137.6, 131.1, 130.6, 128.7, 128.2, 128.0, 118.2, 113.9, 112.9,
66.2, 54.3, 52.1, 38.3; HRMS (M + H)+ calcd for C19H18BrN2O6
449.0348, found 449.0356.
(R)-Methyl 2-(benzyloxycarbonylamino)-3-(4-iodo-2-oxo-2,3-di-
hydrobenzo[d]oxazol-6-yl)propanoate (11e). In a flame-dried 50 mL
sealed tube, benzoxalone 11 (324 mg, 0.876 mmol) and IPy2BF4
(409 mg, 1.1 mmol) were stirred in ClCH2CH2Cl (20 mL). Once
the mixture became a clear solution, SiO2 (3.24 g) was added and
the tube was sealed. After heating at 90 °C for 5 h, the solvents
were removed and the residue was subjected to flash chromatog-
raphy using EtOAc/hexanes (1:2) as eluent to afford the title
1
compound as a light-yellow solid (175 mg, 40% yield). H NMR
(CD3COCD3, 500 MHz) δ 10.47 (s, 1H), 7.46 (s, 1H), 7.37-7.29
(m, 5H), 7.22 (s, 1H), 6.74 (d, J ) 8.5 Hz, 1H), 5.07 (d, J ) 12.5
Hz, 1H), 5.02 (d, J ) 12.5 Hz, 1H), 4.54-4.49 (m, 1H), 3.72 (s,
3H), 3.23 (dd, J ) 14.0, 5.0 Hz, 1H), 3.01 (dd, J ) 14.0, 9.5 Hz,
1H); 13C NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 153.4,
143.3, 137.6, 134.1, 133.64, 133.60, 128.7, 128.2, 128.0, 110.7,
71.1, 66.3, 56.0, 52.0, 37.1; HRMS (M + H)+ calcd for
C19H18IN2O6 497.0210, found 497.0214.
(S)-Methyl 2-(Benzyloxycarbonylamino)-3-(4-cyano-2-oxo-2,3-
dihydrobenzo[d]oxazol-6-yl)propanoate (33). Bromide 11c (200 mg,
0.45 mmol), Zn(CN)2 (58 mg, 0.50 mmol), and Pd(PPh3)4 (104
mg, 0.09 mmol) were weighed into a 100 mL Schlenck flask and
the flask was evacuated and filled with N2 (3 times). DMF (10 mL,
degassed by passing a stream of N2 through it for 30 min) was
transferred Via cannula into the flask and the reaction mixture was
again purged with 5 vacuum/N2 cycles. After heating at 80 °C for
3 h, the solvents were removed in Vacuo and the residue was
subjected to flash chromatography using EtOAc/hexanes (2:3) as
eluent to afford the title compound as a white solid (160 mg, 90%
yield). 1H NMR (CD3COCD3, 500 MHz) δ 10.27 (s, 1H), 7.31 (br
s, 4H), 7.29-7.26 (m, 1H), 7.19 (s, 1H), 7.13 (s, 1H), 5.73 (d, J )
7.9 Hz, 1H), 5.14-5.10 (m, 2H), 4.75-4.70 (m, 1H), 3.79 (s, 3H),
3.24 - 3.20 (m, 1H), 3.05-3.00 (m, 1H); 13C NMR (CD3COCD3,
125 MHz) δ 171.9, 156.1, 153.7, 144.1, 136.0, 132.2, 131.8, 128.7,
128.4, 128.1, 127.3, 115.5, 114.7, 93.5, 67.5, 55.0, 53.1, 38.2, 31.6;
HRMS (M + H)+ calcd for C20H18N3O6 396.1196, found 396.1200.
(S)-Methyl 2-(Benzyloxycarbonylamino)-3-(4-bromo-2-oxo-2,3-
dihydrobenzo[d]oxazol-6-yl)propanoate (11c). In a flame-dried 250
mL round-bottom flask, benzoxalone 11 (418 mg, 1.13 mmol) and
NBS (221 mg, 1.24 mmol) were stirred in anhydrous CH2Cl2 (70
mL). Once the mixture became a clear solution, SiO2 (2.5 g, silica
gel 60, 230-240 mesh ASTM, EMD) was added and the resulting
mixture was stirred at rt for 4 h. The solvents were removed in
Vacuo and the residue was subjected to flash chromatography using
EtOAc/hexanes (2:3) as eluent to afford the title compound as a
1
light-yellow solid (408 mg, 80% yield). H NMR (CD3COCD3,
500 MHz) δ 10.71 (s, 1H), 7.35-7.28 (m, 6H), 7.21 (s, 1H), 6.75
(d, J ) 7.5 Hz, 1H), 5.06 (d, 12.5 Hz, 1H), 5.02 (d, J ) 12.5 Hz,
1H), 4.56-4.51 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J ) 14.0, 5.0 Hz,
1H), 3.03 (dd, J ) 14.0, 10.0 Hz, 1H); 13C NMR (CD3COCD3,
125 MHz) δ 172.2, 156.4, 153.8, 144.4, 137.6, 133.7, 129.8, 128.7,
128.2, 128.0, 127.8, 110.1, 100.9, 66.3, 55.9, 52.0, 37.3; HRMS
(M + H)+ calcd for C19H18BrN2O6 449.0348, found 449.0354.
(R)-Methyl 2-(benzyloxycarbonylamino)-3-(4-chloro-2-oxo-2,3-
dihydrobenzo[d]oxazol-6-yl)propanoate (11d) and (11a). In a flame-
dried 50 mL sealed tube, benzoxalone 11 (373 mg, 1.01 mmol)
and NCS (168 mg, 1.26 mmol) were stirred in ClCH2CH2Cl (20
mL). Once the mixture became a clear solution, SiO2 (3.73 g) was
added and the tube was sealed. After heating at 90 °C for 16 h, the
solvents were removed in Vacuo and the residue was subjected to
flash chromatography using EtOAc/hexanes (1:2) as eluent to afford
both compound 11d (40 mg, 10% yield) and compound 11a (78
Acknowledgment. Dedicated to Professor E. J. Corey on the
occasion of his 80th birthday. We thank Dr. Jeffrey Campbell
for his helpful discussion regarding the preparation of SESCl,
Daniel R. Schroeder for 2D NMR studies, Edward S. Kozlowski
for ee determinations, Pan Li and Marie D’Andrea for providing
HRMS data.
1
mg, 19% yield) as off-white solids. For compound 11d: H NMR
(CD3COCD3, 500 MHz) δ 7.37-7.27 (m, 5H), 7.18 (d, J ) 1.0
Hz, 1H), 7.16 (s, 1H), 6.76 (d, J ) 8.5 hz, 1H), 5.06 (d, J ) 12.5
Hz, 1H), 5.02 (d, J ) 12.5 Hz, 1H), 4.55-4.51 (m, 1H), 3.72 (s,
3H), 3.26 (dd, J ) 14.0, 5.0 Hz, 1H), 3.04 (dd, J ) 14.0, 9.5 Hz,
1H); 13C NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 154.0,
144.8, 137.6, 133.3, 128.7, 128.2, 128.0, 127.9, 125.0, 66.3, 55.9,
52.0, 37.3; HRMS (M + H)+ calcd for C19H18ClN2O6 405.0853,
found 405.0858.
Supporting Information Available: 1H and 13C NMR
spectra for all new compounds, HPLC traces for all ee
determinations and ORTEP drawings of compounds 22 and 23.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801577T
8510 J. Org. Chem. Vol. 73, No. 21, 2008