The direct synthesis of novel enantiomerically pure α-amino acids in protected form via Suzuki cross-coupling

Article abstract of DOI:10.1016/S0040-4039(00)01174-6

Protected allylglycine has been hydroborated and the intermediate organoborane employed in Suzuki coupling reactions with a number of olefinic, aromatic and heteroaromatic bromides and iodides to produce a range of novel α-amino acids in good, unoptimised yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01174-6

Tetrahedron Letters 41 (2000) 7115±7119
The direct synthesis of novel enantiomerically pure a-amino
acids in protected form via Suzuki cross-coupling
Philip N. Collier,a Andrew D. Campbell,a Ian Patelb and Richard J. K. Taylora,*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bAstraZeneca, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK
Received 24 June 2000; accepted 12 July 2000
Abstract
Protected allylglycine has been hydroborated and the intermediate organoborane employed in Suzuki
coupling reactions with a number of ole®nic, aromatic and heteroaromatic bromides and iodides to
produce a range of novel a-amino acids in good, unoptimised yields. # 2000 Elsevier Science Ltd. All
rights reserved.
The synthesis of non-proteinogenic a-amino acids continues to be an area of great interest
amongst the synthetic community. Such compounds are of interest in their own right and have
also been widely employed as building blocks for the preparation of products with interesting
biological activities.1,2 In a recent publication, we described the novel organoborane homoalanine
anion equivalent 1 which was simply and e€ectively transformed into a range of known and novel
non-proteinogenic a-amino acids under mild conditions (Scheme 1).3 Similar transformations
were subsequently reported by Sabat and Johnson.4
Scheme 1.
The success of the above methodology encouraged us to investigate the viability of the direct
utilisation of unsaturated amino acids, in protected form, in a similar hydroboration±Suzuki
* Corresponding author. E-mail: rjkt1@york.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01174-6

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coupling sequence proceeding via organoboron intermediate 2 (Scheme 2). Such an approach
would avoid the need for a subsequent oxidative step, minimising the risk of racemisation and
extending the range of compatible substituents. This chemistry would be ideally suited to
analogue synthesis given the scope of the Suzuki coupling process.5
Scheme 2.
A number of amino acid-derived anionic reagents have been developed1,3,4 but most have the
carboxylic acid at a reduced level. The Jackson method using organozinc derivatives 3 is note-
worthy, however, in that the acids are simply protected as esters.1e Jackson reagents 3 have been
employed to prepare a wide range of phenylalanines, homophenylalanines and bishomophenyl-
alanines. We hoped that the organoboron reagents 2 would prove equally valuable from a
synthetic viewpoint and would be advantageous in terms of reagent preparation. Herein, we
report the successful realisation of this concept for the preparation of novel a-amino acids by the
direct hydroboration and Suzuki coupling of protected allyl glycine (Scheme 2, n=1). We chose
to utilise protected allyl glycine in these preliminary studies as its successful hydroboration±oxidation
has been recently described.6
(l)-Allyl glycine 4 is commercially available or can be readily prepared using literature
methods.6b,7 Boc-protection of 4 followed by esteri®cation with trimethylsilyldiazomethane gave
the protected amino ester 5 {[ꢀ]D +18.8 (c 1.0, CHCl3); lit.6b [ꢀ]D +19.3 (c 1.5, CHCl3)} required
as substrate for hydroboration±Suzuki coupling studies (Scheme 3).
Scheme 3.
The hydroboration of alkene 5 with 9-BBN proceeded smoothly using 2 equivalents of the
borane in THF. We next investigated the Suzuki coupling reactions of the organoborane derived
from 5 with vinyl and aryl halides. [1,10-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
[PdCl2(dppf)]5b was used as catalyst in view of its success in our earlier studies. The results of the
coupling reactions are summarised in Table 1.8
The reaction proceeded in good yield with an iodoacrylate (entry i) and the product 6a retained
the Z-alkenyl stereochemistry present in the coupling partner (J=11.6 Hz). Electron rich vinyl
bromides were also viable Suzuki coupling partners as illustrated by the reaction with 2-bromo-
propene producing adduct 6b (entry ii). Subsequent studies focused on aryl halides and it was

7117
Table 1
Hydroboration±Suzuki cross-coupling of 5 with unsaturated halidesa,b,c
found that the palladium-catalysed coupling reaction with iodobenzene gave the expected
product 6c in 62% yield (entry iii). Both electron-withdrawing and electron-donating substituted
aromatic iodides were successful candidates in the couplings [entries iv and v(a)] producing
adducts 6d and 6e, respectively; an activated aryl bromide also coupled successfully giving 6f in
64% yield [entry v(b)]. 2-Bromopyridine also underwent ecient coupling (entry vi) and product
6g displayed spectroscopic data consistent with those previously reported for the racemic material.10
The stereochemical integrity of the hydroboration±Suzuki coupling sequence was con®rmed by
conversion of anisole derivative 6e into the known amino acid 7 by hydrolysis with 6 M HCl at
70ꢀC (Scheme 4): the optical rotation of 7 was in good agreement with the published value {[ꢀ]D
+31.2 (c 0.33, 5 M HCl:DMF, 1:1); lit.11 [ꢀ]D (enantiomer) ^31.8 (c 2.0, 5 M HCl:DMF, 1:1)}.
In summary, we have demonstrated that the hydroboration±Suzuki coupling of protected allyl
glycine provides a convenient procedure for the preparation of a range of novel, unnatural
a-amino acids. We believe that the simplicity of this procedure, coupled to its compatibility with
easily oxidised and reduced functional groups,12 will be of value to the synthetic community. We
are currently optimising the results described above and looking at the use of newly discovered13
catalyst systems to extend the method to encompass coupling to aryl chlorides. We are also
extending the hydroboration±Suzuki coupling methodology to vinyl glycine (Scheme 2, n=0),

7118
higher vinylogues (Scheme 2, nꢁ2) and to alkynyl analogues. In addition, we are developing a
polymer-supported version of this methodology to establish a combinatorial approach to the
synthesis of unnatural amino acids.
Scheme 4.
Acknowledgements
We thank AstraZeneca and the University of York for ®nancial assistance (P.N.C.).
References
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Oxford, 1989; (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539±1650; (d) Hanessian, S.; McNaughton-Smith, G.;
Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789±12854, and references cited therein; (e) Jackson,
R. F. W.; Moore, R. J.; Dexter, C. S.; Elliott, J.; Mowbray, C. E. J. Org. Chem. 1998, 63, 7875±7884; (f) Dondoni,
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E. J. Org. Chem. 1999, 64, 9211±9216; (h) Sibi, M. P.; Rutherford, D.; Renhowe, P. A.; Li, B. J. Am. Chem. Soc.
1999, 121, 7509±7516.
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8. All new compounds were fully characterised by high ®eld NMR spectroscopy and by HRMS.
9. Representative procedure (Table 1, entry iii): To alkene 5 (133 mg, 0.58 mmol) in THF (2 ml) at 0ꢀC under N2 was
added 9-BBN (0.5 M in THF, 2.32 ml, 1.16 mmol) and the reaction was warmed to rt and stirred for 2 h until TLC
showed consumption of starting material (ca. 90 min). Degassed DMF (1 ml) was added followed by careful
addition (H2 evolution) of aq. K3PO4 (3 M, 0.39 ml, 1.2 mmol) followed by quick addition of iodobenzene (124
mg, 0.61 mmol) and ®nally PdCl2(dppf) (23 mg, 5 mol%) under N2. The reaction was stirred overnight and the
solvent removed in vacuo using an oil pump rotary evaporator. The residue was taken up in ether (15 ml) and
saturated NaHCO3 (15 ml). The aqueous layer was re-extracted with ether (20 ml) and the combined organic
layers were dried (MgSO4), ®ltered and concentrated in vacuo to give the crude product as a brown oil which was
puri®ed by column chromatography on silica gel (light petroleum:ethyl acetate, 4:1) to give 6c (110 mg, 62%) as a

7119
colourless oil, Rf 0.35 (light petroleum:ethyl acetate, 3:1); [ꢀ]D +21.3 (c 0.23, CHCl3); ꢁmax. (CHCl3)/cm^1 3369,
t
3025, 1745, 1715; ꢂH (270 MHz, CDCl3) 1.44 (9H, s, Bu), 1.54±1.91 (4H, m, 2ÂCH2), 2.55±2.70 (2H, m, CH2),
3.72 (3H, s, CH3), 4.28±4.42 (1H, m, CH), 4.99 (1H, d, J=8.0, NH), 7.13±7.34 (5H, m, ArH); ꢂC (67.9 MHz,
CDCl3) 27.7 (CH2CH2CH2), 28.9 (CH3), 32.9 (CHCH2), 35.9 (CH2C), 52.9 (CH3), 53.9 (CH), 80.5 (C(CH3)3),
126.5, 129.0 (Â2), 142.3 (Ar), 156.0 ((N)CˆO), 174.0 (CˆO); m/z (CI) 325 (MNH4 +, 1%), 308 (MH+, 7%);
HRMS (CI): found MH+: 308.1857. C17H26NO4 requires: 308.1862 (1.7 ppm error).
10. El Marini, A.; Roumestant, M.-L.; Pappalardo, L.; Viallefont, P. Bull. Soc. Chim. Fr. 1989, 554±558.
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in coupling with 31e but 53% unoptimised yield from the reaction with 2 (n=1).
13. (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550±9561; (b) Littke, A. F.;
Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020±4028.