A cross-metathesis route to functionalized α-methyl α-substituted amino acids

Article abstract of DOI:10.1002/adsc.200600446

A chemoenzymatic approach to the synthesis of functionalized α-methyl α-substituted amino acids is detailed. This involves amidasemediated enzymatic resolution of α-methyl α-substituted side-chain ω-unsaturated amino acids followed by functionalization via cross-metathesis.

Full text of DOI:10.1002/adsc.200600446

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DOI: 10.1002/adsc.200600446
A Cross-Metathesis Route to Functionalized a-Methyl
a-Substituted Amino Acids
Roy P. M. Storcken,a Lavinia Panella,b Floris L. van Delft,a Bernard Kaptein,b
Quirinus B. Broxterman,b Hans E. Schoemaker,b and Floris P. J. T. Rutjesa,*
a
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen,
The Netherlands
Fax : (+31)-24-365-3393; e-mail: F.Rutjes@science.ru.nl
DSM Pharmaceutical Products – Advanced Synthesis Catalysis & Development, PO Box 18, 6160 MD Geleen,
b
The Netherlands
Received: August 31, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A chemoenzymatic approach to the syn-
thesis of functionalized a-methyl a-substituted
amino acids is detailed. This involves amidase-
mediated enzymatic resolution of a-methyl a-sub-
stituted side-chain w-unsaturated amino acids fol-
lowed by functionalization via cross-metathesis.
Scheme 1. Retrosynthesis of enantiopure side-chain w-unsa-
Keywords: amino amidase; cross-metathesis;
turated a-methyl a-amino acids.
enzyme catalysis; a-methyl a-substituted amino
acids; side-chain w-unsaturated a-amino acids
ample opportunity for further synthetic derivatiza-
tion.[8]
Enantiopure a-methyl a-allylglycine amide (R)-7
and the corresponding acid (S)-10 were synthesized
Enantiomerically pure a,a-disubstituted a-amino previously in our lab via a chemoenzymatic strat-
acids, especially a-methyl a-substituted amino acids, egy.[4,7] The synthesis of the homologous a-amino
are of increasing interest for the agrochemical and acids 11 and 12 proceeded in a different manner as
pharmaceutical industry.[1] Compared to their a-H shown in Scheme 2, but also involved an enzymatic
counterparts, peptides containing one or more such resolution to obtain the (S)-a-amino acids in enantio-
amino acids are less prone to epimerization, display pure form. The strategy commenced with methyl ace-
enhanced metabolic stability and possess different toacetate (4), which via standard alkylation with the
folding behavior.[2] In line with our research on meta- required olefin, hydroxide-mediated saponification
thesis applications of side-chain w-unsaturated a-H- and subsequent acidic decarboxylation was converted
amino acids,[3] and inspired by successful ring-closing into ketones 5 and 6 in good overall yields. Subjection
metathesis examples of a-methyl a-substituted amino to Strecker conditions, followed by partial nitrile hy-
[4]
acids fromour own
and other groups,[5] we set out drolysis (NaOH, PhCHO, MeOH) and subsequent
to explore the viability of a cross-metathesis[6] route Schiff base hydrolysis (4 N HCl) provided the a-
to prepare functionalized a-methyl a-substituted amino acid amides 8 and 9 in good overall yields.
amino acids. As a result, we herewith report that by They were made salt-free via extraction froma basic
combining enzymatic resolution of the racemic a,a- water layer (pH 10) with CH2Cl2 and after concentra-
disubstituted side-chain w-unsaturated amino acid tion subjected to whole cells from Mycobacterium ne-
amides 3[4,7] with subsequent cross-metathesis on the oaurum ATCC 25795 in an aqueous solution starting
terminal olefin functions, the functionalized a-amino at pH 8.3. After 18 h, the reaction mixtures were
acids 1 are readily accessible (Scheme 1). Although worked up, the products were separated and purified
we will not discuss any follow-up chemistry of the via ion exchange chromatography. Chiral HPLC anal-
functionality introduced in the final products, it will ysis showed excellent ees for a-amino acids (S)-11
be clear that the resulting functional group provides and (S)-12 of 99 and 98.5%, respectively. These num-
Adv. Synth. Catal. 2007, 349, 161 – 164
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161

Roy P. M. Storcken et al.
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Next, we screened a series of differently protected
racemic a-methyl a-amino acid derivatives (14–17) in
combination with olefinic precursors in cross-metathe-
sis reactions (Table 1). Based on various examples of
cross-metathesis on a-H-amino acids,[9] the reactions
were conducted in the presence of 5 mol% of the
second generation Grubbs catalyst (13) and four
equivalents of the cross-metathesis partner in toluene
at roomtemperature. In the case of Boc-derivative 14
reasonable yields were obtained with all five olefins
to provide the a-amino acids 20–24 (entries 1–5). Be-
sides the desired product, which in all entries was iso-
lated as an inseparable mixture of E/Z-isomers (gen-
erally ranging from3:1 to 6:1, based on 1H NMR), in
all cases trace amounts of dimeric a-amino acid meta-
thesis products were obtained (<5%). Slightly lower
cross-metathesis yields were obtained with tosyl and
acetyl protecting groups in combination with styrene
(entries 6 and 7). In addition, a series of olefins was
reacted with the industrially interesting formyl-pro-
tected a-amino acid 17, which provided a-amino acids
27–30 in satisfactory yields (entries 8–11). Unlike the
other metathesis products, the acrylate adduct 30 was
obtained as a single E-isomer.[10] Finally, the racemic
Boc-protected a-amino acid amides 18 and 19 were
Scheme 2. Chemoenzymatic synthesis of a-amino acids 11
and 12.[a] Conversion 40%, E-ratio>250.[b] Conversion
51%, E-ratio>200.
bers, combined with those of the corresponding subjected to cross-metathesis in combination with 2-
amides result in enantiomeric ratios (E) of >250 and vinyl-1,3-dioxolane as the metathesis partner, leading
>200, respectively, which are in line with previous ob- to the desired products 31 and 32 in 74 and 71%
servations.[4,7]
yield, respectively (entries 12 and 13).
Table 1. Cross-metathesis reactions.
Entry
Amino acid
PG
X
n
R1
Product
Yield [%][a]
1
2
3
4
5
6
7
8
14
14
14
14
14
15
16
17
17
17
17
18
19
Boc
Boc
Boc
Boc
Boc
Ts
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
NH2
1
1
1
1
1
1
1
1
1
1
1
1
2
CH
CH2SiMe3
CH
Ph
CH2CH
Ph
Ph
CH
Ph
n-hexyl
CO2Et
G
20
21
22
23
24
25
26
27
28
29
30
31
32
45 (69)[b]
70
66
64
55 (64)[c]
42[c]
46
Ac
CHO
CHO
CHO
CHO
Boc
Boc
49
9
49[c]
55
10
11
12
13
70
74
71
CH
CH
NH2
[a]
Isolated yields. In all cases, trace amounts (<5%) of homo-dimerized amino acids were also obtained.
[b]
[c]
Yield determined by GC.
Yield determined by 1H NMR.
162
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Adv. Synth. Catal. 2007, 349, 161 – 164

Cross-Metathesis Route to Functionalized a-Methyl a-Substituted Amino Acids
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neoaurum ATCC 25795 (1.05 g). The reaction mixture was
shaken at 200 rpmand 37 8C for 18 h. After removal of the
cells by centrifugation, the acid and amide were separated
by strongly basic ion-exchange resin column chromatogra-
phy (Dowex 1”8) to provide (S)-12 (4.20 g, 42%) and (R)-9
(4.00 g, 40%). The enantiopurity of acid and amide was de-
termined by chiral HPLC (Sumichiral OA 5000).
To further underline the viability of this strategy, a
series of experiments was carried out on a somewhat
larger scale with the enantiopure a-amino acid deriva-
tives 33–35, which were obtained via esterification
(SOCl2, MeOH) and subsequent N-protection (Cbz-
OSu, MeCN) of a-amino acids (S)-10–12 (Scheme 3).
Physical and Spectroscopic Data of the a-Methyl a-
Amino Acids
(S)-12: ee 98.5%; [a]D: +10.8 (c 0.83, MeOH); mp >2008C
(dec); IR: n=2954, 1584, 1398, 910 cmÀ1
;
1H NMR
(400 MHz, CD3OD): d=5.81 (ddt, J=16.9, 10.2, 6.7 Hz,
1H), 5.03 (d, J=17.1 Hz, 1H), 4.96 (d, J=10.2 Hz, 1H),
2.08 (dt, J=7.0, 7.0 Hz, 2H), 1.91–1.84 (m, 1H), 1.70–1.62
(m, 1H), 1.58–1.36 (m, 2H), 1.44 (s, 3H); 13C NMR
(75 MHz, CD3OD): d=176.8, 138.5, 115.0, 61.4, 36.5, 32.6,
23.4, 22.3; HR-MS (ESI+): m/z=158.1197, calcd. for
C8H16NO2 (M+H+): 158.1181.
Scheme 3. Synthesis of dioxolane-substituted side-chain w-
unsaturated a-methyl a-amino acids.
(S)-11: ee 99%; [a]D: +13.6 (c 1.02, MeOH); mp >2008C
(dec); IR: n=2984, 1575, 1403, 1368, 914 cmÀ1 1H NMR
;
(400 MHz, CD3OD): d=5.82 (ddt, J=16.8, 10.2, 6.5 Hz,
1H), 5.07 (d, J=17.1 Hz, 1H), 4.98 (d, J=10.2 Hz, 1H),
2.19 (m, 1H), 2.07 (m, 1H), 1.96 (m, 1H), 1.74 (m, 1H),
1,46 (s, 3H); 13C NMR (75 MHz, CD3OD): d=175.8, 136.7,
115.0, 61.1, 36.1, 27.5, 22.4; HR-MS (ESIÀ): m/z=142.0894,
calcd. for C7H12NO2 (MÀH+): 142.0868.
The vinyldioxolane was chosen as the cross-metathe-
sis reactant in view of its versatile reactivity. In con-
trast to the previous small scale experiments, cross-
metathesis on gram scale proceeded sluggishly at
roomtemperature which led us to conduct the reac-
tions at 958C. To reach a maximum conversion, the
catalyst was added in portions of 1 mol% over 5 h
time, leading to products 36–38 in reasonable yields.
At this temperature, a considerable amount of dimer-
ized vinyldioxolane was also formed and removed via
chromatography. Finally, hydrogenation of derivative
36 led to the amino ester 39 in 89%. The latter is a
potentially relevant a-Me-derivative of the a-amino
acid l-allysine ethylene acetal, which is a useful build-
ing block for various synthetic applications.[11]
In conclusion, new examples of enzymatic resolu-
tion of a-methyl a-substituted a-amino acids using an
amino amidase of Mycobacterium neoaurum ATCC
25795 are detailed. The resulting amides and a-amino
acids have been evaluated as partners in cross-meta-
thesis reactions in combination with a variety of ole-
fins. Generally, these reactions proceeded reasonably
well giving rise to the corresponding functionalized
side-chain w-unsaturated a-amino acids. Finally, the
reaction was successfully applied to prepare a series
of enantiomerically pure dioxolane-substituted a-
amino acids.
Representative Example of a Cross-Metathesis
Reaction
To a solution of (S)-33 (1.60 g, 5.80 mmol) and 2-vinyl-1,3-
dioxolane (2.88 mL, 28 mmol) in dry and oxygen-free tolu-
ene (60 mL) at 958C was catalyst 13 (245 mg, 5 mol%)
added in five portions. After heating for 17 h, the reaction
mixture was concentrated and filtered over a path of silica
gel (EtOAc/heptane 1:2) to give (S)-36 in crude form. The
crude E/Z-isomeric mixture of 36 was dissolved in MeOH
(50 mL), treated with Pd/C (79 mg of 5 wt%) and stirred
under an H2 atmosphere for 22 h. The mixture was filtrated
over Celite, concentrated and purified by column chroma-
tography (CH2Cl2/MeOH 9:1) to afford (S)-39 as an amor-
phous solid; yield: 537 mg (89%); [a]D: +11.3 (c 1.0,
CH2Cl2); IR: n=3620, 2958, 2863, 1735, 1121, 607 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=4.76–4.72 (m, 1H), 3.89–
3.71 (m, 4H), 3.62 (s, 1H), 1.64–1.18 (m, 6H), 1.23 (s, 3H);
13C NMR (75 MHz, CDCl3): d=177.2, 103.7, 64.4, 57.4, 51.8,
40.7, 33.7, 26.0, 18.5; HR-MS (CI): m/z=218.1394, calcd. for
C10H20NO4 (M+H+): 218.1392.
Acknowledgements
DSM Research is kindly acknowledged for financial support.
T. Sonke and M. Boesten (DSM Research) are kindly ac-
knowledged for assistance with the enzymatic resolutions and
chiral HPLC analyses, respectively.
Experimental Section
Representative Example of the Enzymatic
Resolution:
To a 10 wt% aqueous solution of 9 (10.0 g, 64.1 mmol) at
pH 8.3 was added a whole cell suspension of Mycobacterium
Adv. Synth. Catal. 2007, 349, 161 – 164
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163

Roy P. M. Storcken et al.
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164
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