2
V. D. Möschwitzer et al. / Tetrahedron Letters xxx (2013) xxx–xxx
substrate 4a in 24 h at room temperature with 2 mol % of Rh(I)
and 35 bar H2. The additional steric bulk of the Boc group of 3a
is likely responsible for the slower reaction rate, achieving only
67% conversion in the same time, based on the crude 1H NMR spec-
trum, despite a higher catalyst loading of 5 mol %.
The enantiomeric excess was determined by chiral HPLC on an
ODH column and was found to be P98% for compounds 6. X-ray
crystal structures (Supplementary data) were obtained for 6a and
6b although the data obtained did not permit unambiguous deter-
mination of the absolute stereochemistry. Instead, the absolute
stereochemistry was investigated by conversion of each enantiomer
of 6a produced by hydrogenation using (R,R) and (S,S) Me-DuPHOS
as ligand, via amino acids 7, into diastereomeric derivatives 8
by reaction with N -(2,4-dinitro-5-fluorophenyl)-L-alaninamide
Figure 1. X-ray crystal structure of 4a showing the Z geometry of the olefin. The
methyl ester is disordered across two sites.
a
(FDAA), otherwise known as Marfey’s reagent (Scheme 4).13 The
two diastereomeric Marfey derivatives were analyzed by reverse
phase HPLC and their retention times compared. Marfey observed
that for the
a
-amino acids tested, the (
D,
L) diastereomer eluted
with a longer retention time than the corresponding (L, L
) diaste-
reomer.13 On this basis, catalytic hydrogenation with ligand (S,S)
Me-DuPHOS affords the product 6a(S) with the same configuration
as proteinogenic amino acids, in accordance with the stereoselec-
tivity reported for hydrogenation of methyl (Z)-a-acetamidocinna-
mate using the same catalyst.12
Removal of the benzyl groups from 7 was attempted using
hydrogenolysis with Pd(OH)2 on carbon (Pearlmans’s catalyst).14
At H2 pressures of 15–30 bar, the pyrimidine ring was reduced
but the benzyl groups remained in place, affording compound 9
(Scheme 5). Catalytic transfer hydrogenation of 7 using ammonium
formate and Pd/C also proved ineffective at removing the benzyl
groups. Oxidative debenzylation using ceric ammonium nitrate
(CAN) in aqueous acetonitrile15 was successful, but led to inconve-
nient isolation of the polar and water soluble product from residual
inorganic salts. In contrast to Bn, the PMB group displays greatly
enhanced acid lability allowing complete deprotection of 6 to 10
to be achieved by a two-step acid treatment that permitted
straightforward and quantitative recovery of the product as a
hydrochloride salt (Scheme 6). The pyrimidine ring of 10 was then
hydrogenated cleanly to afford guanidine 11.
Scheme 3. Asymmetric hydrogenation. Isolated yields are given in parentheses.
Reagents and conditions: (i) Rh(COD)2BF4, Me-DuPHOS, 35 bar H2, rt, 24 h.
but the coupling was still unsuccessful, also in agreement with
observations of poorer reactivity at the 5 position of pyridines.7c
We therefore turned to an alternative strategy using a Heck
reaction8 to append the aminopyrimidine heterocycle to a pro-
tected aminoacrylic acid derivative to yield compounds 3a,b and
4a,b as single isomers (Scheme 2). Optimal conditions for the Heck
coupling were found to be PdCl2, (o-tol)3P, with NaHCO3 as base,
and Bu4NCl as the phase transfer catalyst in DMF at elevated tem-
perature.8c,d The presence of Boc protecting groups on either com-
ponent was detrimental to the yield, affording a complex mixture,
and necessitated use of a lower temperature. Under these condi-
tions a homocoupled bipyrimidine was also isolated in up to 20%
yield, which had been previously described as a side product of
the reaction of 5-bromopyrimidines under Pd catalysis.9 The prec-
edent is for Heck coupling of acetamidoacrylic acid and its esters to
afford a Z-configured olefin with a high selectivity.10 The geometry
of 4a was investigated by 1H NMR spectroscopy and revealed a
NOESY cross peak between the NH and the pyrimidine aryl CH pro-
tons, which is most consistent with a Z configuration. Single crys-
tals of 4a were subjected to X-ray structural analysis which also
supported the NMR assignment of a Z geometry (Fig. 1).
In conclusion, we have presented the synthesis from achiral
starting materials of a pair of amino acids with heterocyclic side
chains. The molecular recognition abilities of the aminopyrimidine
and guanidine functionality within their side chains will make
these amino acids valuable building blocks from which to
The
a-carbon stereocenter was introduced using Rh(I)-cata-
lyzed asymmetric hydrogenation with a bidentate phosphine li-
gand (Scheme 3). The reaction was sluggish with DIPAMP11 as
ligand, whereas Me-DuPHOS12 afforded conversion of >90% of
Scheme 5. Hydrogenation of the pyrimidine ring. Reagents and conditions:
(i) Pd(OH)2, 15 bar H2, MeOH.
Scheme 4. Preparation of Marfey derivatives. Reagents and conditions: (i) 6 M HCl, 110 °C, 6 h; (ii) FDAA, Cs2CO3, 40 °C, 2 h.
M?schwitzer, Vicki D.
