Synthesis of non-proteinogenic phenylalanine analogues by Suzuki cross-coupling of a serine-derived alkyl boronic acid

Article abstract of DOI:10.1016/j.tetlet.2003.12.154

Protected serine-derived boronic acids have been prepared as β-anionic alanine equivalents, and undergo efficient Suzuki cross-coupling with a variety of aryl halides to give, after elaboration, non-proteinogenic phenylalanine analogues.

Full text of DOI:10.1016/j.tetlet.2003.12.154

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2467–2471
Synthesis of non-proteinogenic phenylalanine analogues by
Suzuki cross-coupling of a serine-derived alkyl boronic acid
Joanne E. Harvey, Martin N. Kenworthy and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 3 December 2003;accepted 23 December 2003
Abstract—Protected serine-derived boronic acids have been prepared as b-anionic alanine equivalents, and undergo efficient Suzuki
cross-coupling with a variety of aryl halides to give, after elaboration, non-proteinogenic phenylalanine analogues.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The synthesis of enantiopure non-proteinogenic a-amino
acids is of great importance due to their roles as phar-
maceuticals, chiral ligands and building blocks in natural
product synthesis. Among recent developments in the
preparation of such compounds1 has been the modifi-
cation of readily available derivatives of proteinogenic
a-amino acids.2–7 In particular, anionic equivalents of
alanine have been exploited by Jackson and co-workers,6
whose zinc-alanine species can be transmetallated and
coupled with electrophiles.
nucleophilicity, leading to a lack of reactivity, and their
propensity to undergo b-hydride elimination after
transmetallation. A judicious choice of catalyst and
conditions can, however, overcome these problems.9–12
For instance, we have previously utilised the
homoalanine and bishomoalanine boranes 1, 2 and 3,
prepared by hydroboration of the corresponding alk-
enes, in Suzuki cross-couplings to access a variety
of non-proteinogenic amino acids.3 We also attempted
to hydroborate dehydroamino acid derivatives to obtain
alaninyl-organoborane reagents, but without success.13
BR2
BR2
BR2
BocN
CbzHN
CO2Me
BocHN
CO2Me
O
BR2 = 9-BBN
2
3
1
Organoboron reagents, particularly boronic acids, are
rapidly increasing in popularity as the nucleophilic
components in palladium-catalysed cross-coupling
reactions due to their stability, ready preparation and
lack of toxicity.8 Traditionally, in contrast to aryl- and
alkenylboron species, alkyl reagents were not considered
suitable for cross-coupling reactions due to their low
We were therefore pleased to find, during the course of
our recent work in this area,7 that the organolithium
reagents 5 (Scheme 1), prepared from L-serine via
chlorides 4, could be quenched with triisopropylborate
and the intermediate boronic esters hydrolysed to afford
the boronic acids 6.
The purpose of the present work was to determine
whether the alkyl boronic acids 6 would be amenable
to the Suzuki cross-coupling reaction and, in the first
instance, whether phenylalanine analogues could be
Keywords: Amino acid;Suzuki;Cross-coupling;Boronic acid.
* Corresponding author. Tel.: +44-01904-432606;fax: +44-01904-43-
4523;e-mail: rjkt1@york.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.154

2468
J.E.Harvey et al./ Tetrahedron Letters 45 (2004) 2467–2471
Cl
OH
Li
B(OH)2
OR
i-v
vi
OR
OR
H2N
CO2H
BocHN
BocLiN
BocHN
4a R = MOM
4b R = SEM
5a R = MOM
5b R = SEM
6a R = MOM
6b R = SEM
L-serine
Scheme 1. Reagents and conditions:7 (i) CH3COCl, MeOH, 0–65 ꢁC;(ii) (Boc) 2O, NEt3, THF, 0–20 ꢁC (74% over two steps);(iii) C 2Cl6, PPh3,
CH2Cl2;(iv) LiBH 4, EtOH, THF, 0–20 ꢁC (69% over two steps);(v) MOMCl or SEMCl, N( i-Pr)2Et, CH2Cl2, 0–20 ꢁC (78% of 4a;83% of 4b);(vi)
n-BuLi, THF, )78 ꢁC then lithium naphthalenide then B(Oi-Pr)3 then 0.5 M HCl (80% of 6a;77% of 6b). MOM ¼ methoxymethyl;SEM ¼ 2-(tri-
methylsilyl)ethoxymethyl.
Table 1. Optimisation of the Suzuki cross-coupling reaction of alkylboronic acids 6a and 6b with halobenzenesa
B(OH)2
OR
Ph
OR
PhX
Pd cat.
BocHN
BocHN
additive(s)
solvent
6a R = MOM
6b R = SEM
7a R = MOM
7b R = SEM
temperature
Entry
R
Catalyst (mol %)
Solvent
Temperature PhX (equiv)
(ꢁC)
Additive(s)
(equiv)
Time
Yieldb (%)
i
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
SEM
PdCl2(dppf) (9)
THF/H2O
(10:1)
70
PhBr
(2.0)
PhBr
(2.2)
PhBr
(1.2)
PhBr
(1.2)
PhBr
(2.2)
PhBr
(2.1)
PhBr
(2.2)
PhBr
(1.7)
PhBr
(1.1)
PhBr
(1.0)
PhBr
(1.8)
PhBr
(1.9)
PhBr
(2.0)
PhI
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
16 h
3 d
54
79
54
63
71
47
17
41
0
ii
PdCl2(dppf) (9)
THF/H2O
(10:1)
70
iii
iv
PdCl2(dppf) (9)
THF/H2O
(10:1)
70
3 d
PdCl2(dppf) (3 · 4)
PdCl2(dppf) (9)
THF/H2O
(10:1)
70
5 d
v
THF/H2O
(10:1)
Dioxane
70
Tl2CO3 (2.6) 23 h
vi
Pd(PPh3)4 (11)
100
75
K2CO3 (3)
Cs2CO3
20 h
2.5 d
2 d
vii
viii
ix
Pd2(dba)3, dppf (10)
Pd(PPh3)2(succ)Br (9)
Pd(OAc)2, PCy3 (10)
Dioxane
THF/H2O
(10:1)
Dioxane
70
K2CO3 (3)
KOt-Bu (3)
KOt-Bu (3)
K2CO3 (3)
100
25
3 d
x
Pd(OAc)2,
P(t-Bu)2Me (5)
PdCl2(dppf) (9)
Dioxane
24 h
3 d
0
xi
THF/H2O
(10:1)
THF
70
78
59
72
73
0
xii
xiii
xiv
xv
xvi
SEM
PdCl2(dppf) (10)
PdCl2(dppf) (9)
PdCl2(dppf) (9)
PdCl2(dppf) (9)
PdCl2(dppf) (9)
80 (sealed
tube)
70
K2CO3 (3),
Ag2O (2.5)
K2CO3 (3),
Ag2O (2.5)
K2CO3 (3),
Ag2O (2.5)
K2CO3 (3),
Ag2O (2.5)
K2CO3 (3),
Ag2O (2.5)
15 h
21 h
21 h
21 h
21 h
SEM
THF
THF
THF
THF
SEM
70
70
70
(2.1)
PhCl
(2.2)
PhOTf
(2.2)
SEM
SEM
0c
a All reactions performed on ca. 0.11–0.23 mmol scale at ca. 0.1 mol LÀ1 concentration.
b Yields are based on boronic acids 6a or 6b.
c Addition of LiI (2.2 equiv) gave no improvement.
synthesised in this way. To this end, the MOM-pro-
tected compound 6a was treated with bromobenzene
using a variety of catalysts and conditions as shown in
Table 1. Thus, the conditions reported by Molander
and Yun,11 involving palladium(II) dichloro-1,10-
bis(diphenylphosphino)ferrocene [PdCl2(dppf)] as cata-
lyst in THF/H2O at reflux gave 54% of the protected
phenylalaninol 7a after 16 h (entry i). By increasing the
All new compounds were fully characterised spectroscopically and
by HRMS.

J.E.Harvey et al./ Tetrahedron Letters 45 (2004) 2467–2471
2469
Table 2. Suzuki cross-coupling of alkyl boronic acid 6b with aromatic
halidesa
reaction time, we were able to improve the yield to 79%
after 3 days (entry ii). Reduction in the amount of
added electrophile was detrimental to the yield (entry
iii). Adding the catalyst in batches did not rectify this
problem, 63% yield being obtained when 12 mol % was
added in three batches over 2 days followed by refluxing
the reaction for a further 3 days (entry iv). In an effort
to increase the rate of transmetallation, usually con-
sidered to be the rate-limiting step,14 thallium carbon-
ate15 was substituted for potassium carbonate. This did
provide 71% yield after only 1 day (entry v), but the
high toxicity of this reagent encouraged us to investi-
gate alternative means for activation. A number of
other catalyst systems were tested16 (entries vi–x) but
none gave satisfactory results. Of particular note, the
electron-rich phosphine ligands PCy3 and P(t-Bu)2Me12
(entries ix and x) did not allow formation of any
product. A control reaction in the absence of bromo-
benzene confirmed that the substrate boronic acid 6a
degraded under these conditions.
B(OH)2
OSEM
Ar
ArX (2.2 eq.)
OSEM
PdCl2(dppf).CH2Cl2
(9 mol%), K2CO3
(3.0 eq.), Ag2O
(2.5 eq.), THF,
70 ºC, 21 h
BocHN
BocHN
8-16
6b
Entry
Ar–X
Yieldb (%)
Product
i
65
8
MeO
Br
Br
ii
65
70
9
O2N
iii
10
Br
NO2
iv
67
11
We also explored the use of the SEM-protected com-
pound 6b as our concurrent work7 showed that more
flexibility was available in its deprotection than in that of
the MOM group. Thus, reaction of 6b with bromobenz-
ene under the best prior conditions gave 78% of the SEM-
protected phenylalaninol 7b after 3 days (entry xi).
Activation of alkyl boronic acid couplings with silver(I)
oxide has been pioneered by Falck and co-workers10 and
Mu and Gibbs.17 Following the conditions optimised by
Falck and co-workers,10 we obtained a 59% yield of
product 7b after 15 h at 80 ꢁC in a sealed tube (entry xii).
Simply performing the reaction at reflux under atmo-
spheric pressure for 21 h increased the yield to 72% (entry
xiii). As expected, iodobenzene also provided good
results (73%, entry xiv), whereas chlorobenzene did not
react at all (entry xv). Surprisingly, our efforts to perform
the reaction with phenyl trifluoromethylsulfonate
(PhOTf) were not successful (entry xvi), despite such
conditions being used previously with triflates.10
Br
O2N
O
Br
v
58
52
12
13
O
Br
vi
MeO
Br
Br
vii
73
14
15
viii
19 (27c)
S
I
ix
35
16d
I
The results obtained from bromo- and iodobenzene
were encouraging,18 and so these conditions were
applied to a range of electrophiles using boronic acid 6b
(Table 2). We were pleased to observe that the electron-
rich p-bromoanisole gave a respectable yield of product
a All reactions performed on 0.10–0.13 mmol scale at ca. 0.1 mol LÀ1
concentration.
b Yields are based on boronic acid 6b.
c Reagents and conditions: 3.2 M aqueous NaOH (3.0 equiv),
Pd(PPh3)4 (6 mol %), 1,4-dioxane, 100 ꢁC, 2 days.
d 0.5 equiv of dihalide used;doubly coupled product 16 formed:
8
(entry i), as did the electron-deficient system
p-bromonitrobenzene (entry ii), affording coupled 9. It
was established that 1,2- and 1,3-substitution patterns
were tolerated by using o- and m-bromonitrobenzenes
(providing 10 and 11) (entries iii and iv). These results
were particularly encouraging in light of the poorer
yields with ortho-substituted electrophiles obtained by
Jackson et al. in their related methodology.6a;c Fur-
thermore, the steric hindrance at the reacting alanine
centre of boronic acid 6b is indicated by its slower
reaction when compared to the substrates of Falck and
co-workers10 and Molander and Yun,11 and so the good
yield obtained in the ortho case is especially gratifying.
The presence of carbonyl functionalities in the electro-
phile was tolerated as indicated by use of 4-bromoace-
tophenone (entry v) and methyl 4-bromobenzoate (entry
vi). Reaction of 1-bromonaphthalene with the boronic
NHBoc
OSEM
SEMO
BocHN
16
acid 6b under the standard conditions also proceeded
smoothly and efficiently to provide product 14 (entry
vii).
Unfortunately, these conditions did not provide satis-
factory results when heterocyclic electrophiles were

2470
J.E.Harvey et al./ Tetrahedron Letters 45 (2004) 2467–2471
Ar
Ph
Ar
Ar
ii, iii, iv
Cl-
i
v
+
OSEM
OH
BocHN
CO2Me
H3N
CO2H
BocHN
7b Ar = Ph
Ar = p-C6H4NO2
BocHN
17 Ar = Ph
18 Ar = p-C6H4NO2
19 Ar = Ph
20 Ar = p-C6H4NO2
21
9
Scheme 2. Reagents and conditions: (i) CH3COCl, MeOH then (Boc)2O, NEt3, THF (72% of 17, 86% of 18);(ii) Dess–Martin periodinane, CH 2Cl2;
(iii) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O;(iv) Me 3SiCHN2, PhMe, MeOH (three steps: 75% of 19, 51% of 20);(v) 6 M aqueous
HCl, anisole (quantitative).
used. Thus, 3-bromofuran, 3-bromopyridine, 2-bromo-
pyridine-N-oxide and ethyl 2-chlorooxazole-4-carboxy-
late provided none of the expected products. 3-
Bromothiophene gave the coupled product 15 in only
19% yield (entry viii) and prolonged reaction times did
not significantly improve the results. Reversion to the
non-silver promoted reaction conditions of Molander
and Yun11 was not beneficial either. Occasionally, the
use of a stronger base has allowed successful Suzuki
cross-coupling of heterocycles,19 but here only a mar-
ginal improvement was observed with aqueous sodium
hydroxide.
alkene hydroboration. We have also demonstrated the
utility of the Falck and co-workers10 methodology on
complex structures with a variety of functionalities.
Current work is focusing on the extension of this Suzuki
methodology to the synthesis of unsaturated a-amino
acid derivatives.
Representative procedure
The boronic acid 6b (41 mg, 0.12 mmol), K2CO3 (49 mg,
0.35 mmol), PdCl2(dppf)ÁCH2Cl2 (8.6 mg, 0.011 mmol)
and Ag2O (68 mg, 0.29 mmol) were placed under Ar.
Tetrahydrofuran (1.0 mL) and 4-bromoanisole (30 lL,
0.24 mmol) were added and the resulting mixture was
refluxed for 21 h. The reaction mixture was filtered
through a 0.5 cm pad of Celitee and eluted with diethyl
ether (40 mL). The filtrate was concentrated to afford a
yellow oil. Subjection of this material to flash chroma-
tography [1:3 diethyl ether/petroleum ether (40–60 ꢁC)]
and concentration of the appropriate fractions (Rf 0.18)
provided tert-butyl 2-(4-methoxyphenyl)-1-(2-trimethyl-
A doubly coupled product, 16, could be isolated in a
modest 35% yield by reacting the boronic acid 6b with
0.5 equiv of 1,4-diiodobenzene (entry ix). Such aryl-
scaffolded systems are potentially useful as synthetic
building blocks20 and as peptidomimetics, particularly
as analogues of cysteines.21
The bromobenzene and p-bromonitrobenzene systems
were demonstrated to be amenable to a modest scale-up
(ca. 0.46 mmol), giving a reasonable 63% yield of 7b and
a better 71% yield of 9, respectively. No problems are
foreseen in further scale-ups.
silanylethoxymethoxymethyl)ethylcarbamate 8 as a pale
20
yellow oil (31 mg, 65%). ½aŠ )13.1 (c 0.93, CHCl3).
D
Found (CIþ): 412.2520. C21H38NO5Si requires (MHþ):
412.2519 (0.1 ppm error). mmax/cmÀ1 (thin film) 3359,
2953, 1714, 1613, 1513, 1248, 1173. 1H NMR (400 MHz,
CDCl3) d 7.13 (d, J 8.2 Hz, 2H), 6.82 (d, J 8.2 Hz, 2H),
4.92 (broad d, J 8.0 Hz, 1H), 4.68 (m, 2H), 3.89 (broad
m, 1H), 3.78 (s, 3H), 3.63 (m, 2H), 3.46 (m, 2H), 2.86
(dd, J 13.1, 4.9 Hz, 1H), 2.75 (dd, J 13.1, 8.2 Hz, 1H),
1.42 (s, 9H), 0.95 (m, 2H), 0.03 (s, 9H). 13C NMR
(100 MHz, CDCl3) 158.3 (C), 155.5 (C), 130.5 (CH),
130.3 (C), 114.0 (CH), 95.4 (CH2), 79.3 (C), 68.6 (CH2),
65.5 (CH2), 55.4 (CH3), 51.9 (CH), 37.1 (CH2), 28.5
(CH3), 18.2 (CH2), )1.3 (CH3).
Compounds 7b and 9 were SEM-deprotected to afford
alcohols 17 and 18 (Scheme 2) in 72% and 86% yields,
respectively. A two-step oxidation to the carboxylic
acids and immediate methyl ester formation7 provided
the known protected amino acids 19 and 20 in 75% and
51%, respectively, over three steps. The optical rotations
of these esters matched their literature values,22 thus
indicating that the stereochemical integrity at the a-
position has been maintained throughout the chemical
transformations from
compound 19 afforded
L
-serine. Global deprotection of
-phenylalanine hydrochloride
L
(21) in good yield, thus demonstrating that the amino
acids are accessible from the Suzuki products. The
optical rotation of this final product matched the liter-
Acknowledgements
23
23
23
ature value {½aŠ )8.1 (c 0.91, H2O);[lit.
½aŠ )8.2
D
D
The authors thank the Ramsay Memorial Fellowships
Trust (J.E.H.) and Elsevier (M.N.K.) for funding.
(c 1, H2O)]} and other data were in accordance with the
structure. It is expected that conversion of the other
SEM-protected coupling products 8 and 10–16 to the
respective amino acids will proceed equally efficiently.
References and notes
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aryl halides. This procedure complements our earlier
reports3 dealing with the preparation of higher homo-
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