Novel synthesis of α-amino acid derivatives through triethylborane- induced solid-phase radical reactions

Full text of DOI:10.1021/jo982466u

2174
J . Org. Chem. 1999, 64, 2174-2175
Sch em e 1a
Novel Syn th esis of r-Am in o Acid Der iva tives
th r ou gh Tr ieth ylbor a n e-In d u ced Solid -P h a se
Ra d ica l Rea ction s
Hideto Miyabe, Yumi Fujishima, and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada,
Kobe 658-8558, J apan
Received December 22, 1998
Combinatorial chemistry has became a core technology
for the rapid development of novel lead compounds in the
pharmaceutical industry and for the optimization of thera-
peutic efficacy.1 The extension of radical reactions to solid-
phase reactions would allow further progress in combina-
torial organic synthesis. Thus, the development of solid-
phase radical reactions is a new subject of considerable
interest. A few reports have recently demonstrated that
radical cyclization could be performed on solid supports by
using AIBN or SmI2 as a radical initiator.2-4 Sibi’s group
more recently reported the first studies on the solid-phase
intermolecular radical reaction using allyl stannanes and
AIBN.5 Triethylborane has the potential to induce solution-
phase radical reactions at low reaction temperature, and a
wide range of synthetically useful reactions using trieth-
ylborane as a radical initiator are available.6 In conjunction
with our studies on the triethylborane-induced radical
chemistry in solution,7 we now report the results of experi-
ments to probe the utility of triethylborane in the solid-phase
intermolecular radical reactions. As shown below, the in-
termolecular carbon radical addition to the carbon-nitrogen
double bond of the glyoxylic oxime ethers anchored to a
polymer support provides a new efficient carbon-carbon
bond-forming method for the synthesis of R-amino acid
derivatives.8
a
Key: (a) HO2CCdNOBn, DCC, DMAP, CH2Cl2, 20 °C, 12 h (for
1); HO2CCdNOBn, 2,6-dichlorobenzoyl chloride, Py, DMF, 20 °C, 12
h (for 2); (b) Et3B, 1 h; or RI, Bu3SnH, Et3B, 1 h; (c) TFA/CHCl3 (1:3,
v/v), 20 °C, 30 min.
Ta ble 1. Eth yl Ra d ica l Ad d ition to 1 a n d 2a
entry
oxime
solvent
T (°C)
product
yieldb (%)
1
2
3
4
1
2
1
1
CH2Cl2
CH2Cl2
toluene
CH2Cl2
20
20
20
4a
4a
4a
4a
71
57
83
61
-78
a
All reactions were carried out with Et3B in hexane (3.6 equiv).
b
Yields of isolated product 4a from 1 or 2.
Wang resin and TentaGel OH resin (Scheme 1).9 The
glyoxylic oxime ether (HO2CCdNOBn) could be attached to
Wang resin by the treatment with DCC in the presence of
DMAP in CH2Cl2 at 20 °C for 12 h to give the resin-bound
glyoxylic oxime ether 1 in ca. 70% loading level.10 The
loading level of the Wang resin-bound glyoxylic oxime ether
1 was determined to be 0.83 mmol/g by quantification of
nitrogen by elemental analysis. TentaGel OH resin-bound
glyoxylic oxime ether 2 was prepared from HO2CCdNOBn
in ca. 90% loading level by the treatment with 2,6-dichlo-
robenzoyl chloride in the presence of pyridine in DMF at 20
°C for 12 h.
As a preliminary experiment, we chose two simple gly-
oxylic oxime ethers 1 and 2 anchored to a polymer support
as a model substrate and investigated several reaction
conditions for attachment of the glyoxylic oxime ether to
To test the viability of triethylborane as a radical initiator
on solid support, we first investigated the simple addition
of an ethyl radical, generated from triethylborane and O2,
to the Wang resin-bound glyoxylic oxime ether 1 (Table 1,
entry 1). To a flask containing glyoxylic oxime ether 1 and
undegassed CH2Cl2 was added a commercially available 1.0
M solution of triethylborane in hexane, and then the reaction
mixture was stirred at 20 °C for 1 h. The resin 3a was then
filtered and washed successively with CH2Cl2, AcOEt, and
then MeOH, and the subsequent cleavage of the resin with
* To whom correspondence should be addressed. E-mail: taknaito@
kobepharma-u.ac.jp.
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1998, 3293; (b) Chem. Rev. 1997, 97(2), 347-510. (c) Hermkens, P. H. H.;
Ottenheijm, H. C. J .; Rees, D. C. Tetrahedron 1997, 53, 5643. (d) Balkenhohl,
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(8) Oxime ethers are well-known to be excellent radical acceptors because
of the extra stabilization of the intermediate aminyl radical provided by
the adjacent oxygen atom. See: (a) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri,
K.; Kiguchi, T.; Naito, T. J . Org. Chem. 1998, 63, 4397. (b) Iserloh, U.;
Curran, D. P. J . Org. Chem. 1998, 63, 4711. (c) Boiron, A.; Zillig, P.; Faber,
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J . M. J . Org. Chem. 1997, 62, 1202. (e) Clive, D. L. J .; Zhang, J . Chem.
Commun. 1997, 549. (f) Keck, G. E.; Wager, T. T. J . Org. Chem. 1996, 61,
8366. (g) Bhat, B.; Swayze, E. E.; Wheeler, P.; Dimock, S.; Perbost, M.;
Sanghvi, Y. S. J . Org. Chem. 1996, 61, 8186. (h) Kim, S.; Lee, I. Y.; Yoon,
J .-Y.; Oh, D. H. J . Am. Chem. Soc. 1996, 118, 5138. (i) Hollingworth, G. J .;
Pattenden, G.; Schulz, D. J . Aust. J . Chem. 1995, 48, 381. (g) Chiara, J . L.;
Marco-Contelles, J .; Khiar, N.; Gallego, P.; Destabel, C.; Bernabe´, M. J .
Org. Chem. 1995, 60, 6010. (k) Santagostino, M.; Kilburn, J . D. Tetrahedron
Lett. 1995, 36, 1365. (l) Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T.;
Hiramatsu, H. Tetrahedron Lett. 1995, 36, 253.
(4) (a) Berteina, S.; De Mesmaeker, A. Tetrahedron Lett. 1998, 39, 5759.
(b) Berteina, S.; Wendeborn, S.; De Mesmaeker, A. Synlett 1998, 1231.
(5) Sibi, M. P.; Chandramouli, S. V. Tetrahedron Lett. 1997, 38, 8929.
(6) For reviews, see: (a) Renaud, P.; Gerster, M. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2562. (b) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J .;
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Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177. (d) Snider, B.
B. Chem. Rev. 1996, 96, 339. For selected examples, see: (e) Sibi, M. P.; J i,
J . Angew. Chem., Int. Ed. Engl. 1997, 36, 274. (f) Porter, N. A.; Wu, J . H.;
Zhang, G.; Reed, A. D. J . Org. Chem. 1997, 62, 6702. (g) Mase, N.; Watanabe,
Y.; Ueno, Y.; Toru, T. J . Org. Chem. 1997, 62, 7794. (h) Guindon, Y.; Gue´rin,
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Tetrahedron: Asymmetry 1996, 7, 2417. (l) Urabe, H.; Yamashita, K.; Suzuki,
K.; Kobayashi, K.; Sato, F. J . Org. Chem. 1995, 60, 3576.
(9) Wang and TentaGel OH resins purchased from Novabiochem were
used in all experiments.
(10) Glyoxylic oxime ether (HO2CCdNOBn) was readily prepared from
O-benzyloxyamine hydrochloride and glyoxylic acid monohydrate. See the
Supporting Information and also see: Kolasa, T.; Sharma, S. K.; Miller, M.
J . Tetrahedron 1988, 44, 5431.
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10.1021/jo982466u CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/05/1999

Communications
J . Org. Chem., Vol. 64, No. 7, 1999 2175
Ta ble 2. Solid -P h a se Syn th esis of r-Am in o Acid s 4b-ga
TFA/CHCl3 (1:3, v/v) gave the crude ethylated R-amino acid
4a as a TFA salt. Purification of the resulting R-amino acid
4a was accomplished by a combination of Amberlite IR-120B
(eluting with MeOH) and the preparative TLC (MeOH/
CHCl3 1:10, v/v) to afford the free amino acid 4a .11 In this
reaction, triethylborane acts as not only a radical initiator
but also a terminator to trap the intermediate benzyl-
oxyaminyl radical without interference of the polystyrene
skeleton of the resin. Thus, the radical reaction cycle
involving the regeneration of the ethyl radical proceeds by
this quite simple procedure, which does not require the use
of moisture-sensitive irritant tin hydride. The important role
of triethylborane has been already explained by two groups.7,12
The ethyl radical addition to TentaGel resin-bound glyoxylic
oxime ether 2 proceeded also in slightly low chemical
efficiency under the same reaction conditions (Table 1, entry
2). In regard to the solvent effect, the replacement of CH2-
Cl2 with a nonpolar aromatic solvent such as toluene was
found to be also effective for triethylborane-induced solid-
phase radical reactions to give the ethylated products 4a in
83% yield from 1 (Table 1, entry 3). It is important to note
that good chemical yield was observed at -78 °C (Table 1,
entry 4). These results suggest that triethylborane works
well as an effective radical initiator for the solid-phase
radical reaction even at low reaction temperature.
To test the generality of the solid-phase radical reaction
using triethylborane, we investigated the reaction using
different radical precursors that afforded moderate to good
yields of alkylated products 4b-g (Table 2). As in the case
of 4a , to a flask containing glyoxylic oxime ether 1 and
undegassed CH2Cl2 were successively added isopropyl iodide,
tributyltin hydride, and triethylborane as a radical initiator,
and then the reaction mixture was stirred at 20 °C for 1 h.
The isopropylated R-amino acid derivative 4b was obtained
in 66% yield from 1 after cleavage of the resin followed by
purification, accompanied with a small amount of the
ethylated product 4a , which was formed by the competitive
reaction with the ethyl radical generated from triethylborane
(Table 2, entry 1). The often tedious workup to remove excess
entry
RI
solvent
productb
yieldc (%)
1
2
3
4
5
6
7
i-PrI
i-PrI
c-hexyl I
t-BuI
s-BuI
i-BuI
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4b
4b
4c
4d
4e
4d
4g
66
42
61
78
71
24
28
adamantyl I
a
All reactions were carried out with RI (7.1 equiv), Bu3SnH
b
(2.1 equiv), and Et3B in hexane (1.1 equiv) at 20 °C. The
ethylated product 4a was obtained in ca. 5-30% yields. c Yields
of isolated products 4b-g from 1.
tin residues from the reaction mixture is eliminated in the
solid-phase methodology by washing of the resin with
solvents. Not only secondary alkyl radicals such as isopropyl,
cyclohexyl, and sec-butyl radicals but also a bulky tert-butyl
radical worked well under similar reaction conditions,
allowing facile incorporation of structural variability (Table
2, entries 1-5). This reaction will be particularly useful
because there currently exists no general synthetic method
for the construction of a wide range of aliphatic R-amino
acids using glyoxylic imines as the starting material.13 The
unstable primary alkyl radicals such as isobutyl radical and
a more bulky adamantyl radical were less effective for the
present solid-phase intermolecular radical reaction (Table
2, entries 6 and 7).
In conclusion, we have demonstrated that triethylborane
can be applied to the solid-phase radical reaction. Further-
more, the radical addition to glyoxylic oxime ethers anchored
to a polymer support provides direct access to unnatural
R-amino acids as useful building blocks exemplified by the
recent progress in the fields of combinatorial chemistry and
drug discovery. The newly found solid-phase radical reac-
tions are run without any special precautions such as drying,
degassing, and purification of solvents and reagents and are
thus readily adaptable to parallel synthesis.14
Ack n ow led gm en t. We wish to thank the Ministry of
Education, Science, Sports and Culture of J apan and the
Science Research Promotion Fund of the J apan Private
School Promotion Foundation for research grants.
(11) All compounds 4a -g were characterized by 1H NMR, 13C NMR, and
HRMS.
(12) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998,
780.
(13) Glyoxylic imines are convenient starting materials for the synthesis
of R-amino acids through ene reactions, cycloadditions, or the nucleophilic
additions of organometallic reagents or enolate anion equivalents.
(14) All reactions were run in commercially available solvents and with
reagents without requiring any special precautions.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and NMR spectra for obtained compounds.
J O982466U