2: An efficient catalyst for highly regioselective allylic alkylations of chelated amino acid ester enolates

Article abstract of DOI:10.1002/chem.201402825

Chelated amino acid ester enolates are excellent nucleophiles for ruthenium-catalyzed allylic alkylations. Although [Cp*Ru(MeCN) ₃]PF₆ was found to be the most reactive catalyst investigated, with the resulting allyl complexes reacting at temperatures as low as -78°C, unfortunately the process took place with only moderate regio- and diastereoselectivity. In contrast, [(p-cymene)RuCl₂]₂ allowed allylations to be performed with a high degree of regioretention. Secondary allyl carboxylates with a terminal double bond were found to be the most reactive substrates, giving rise to the branched amino acids with perfect regioretention and chirality transfer. In this case, no isomerization of the Ru-allyl complex formed in situ was observed, in contrast to the analogues palladium complexes. This isomerization-free protocol can also be used for the synthesis of (Z)-configured γ,δ-unsaturated amino acid derivatives, starting from (Z)-allylic substrates. Here, the more reactive phosphates were found to be superior to the carboxylates, providing the required amino acids in almost quantitative yield with perfect regio- and stereoretention. Therefore, the Ru-catalyzed allylation reactions are well positioned to overcome the drawbacks of Pd-catalyzed processes.

Full text of DOI:10.1002/chem.201402825

DOI: 10.1002/chem.201402825
Full Paper
&
Allylic Alkylation
[
(p-Cymene)RuCl ] : An Efficient Catalyst for Highly Regioselective
2
2
Allylic Alkylations of Chelated Amino Acid Ester Enolates
[a]
Anton Bayer and Uli Kazmaier*
Abstract: Chelated amino acid ester enolates are excellent
nucleophiles for ruthenium-catalyzed allylic alkylations. Al-
though [Cp*Ru(MeCN) ]PF was found to be the most reac-
ity transfer. In this case, no isomerization of the Ru–allyl
complex formed in situ was observed, in contrast to the ana-
logues palladium complexes. This isomerization-free proto-
col can also be used for the synthesis of (Z)-configured g,d-
unsaturated amino acid derivatives, starting from (Z)-allylic
substrates. Here, the more reactive phosphates were found
to be superior to the carboxylates, providing the required
amino acids in almost quantitative yield with perfect regio-
and stereoretention. Therefore, the Ru-catalyzed allylation
reactions are well positioned to overcome the drawbacks of
Pd-catalyzed processes.
3
6
tive catalyst investigated, with the resulting allyl complexes
reacting at temperatures as low as À788C, unfortunately the
process took place with only moderate regio- and diastereo-
selectivity. In contrast, [(p-cymene)RuCl ] allowed allylations
2
2
to be performed with a high degree of regioretention. Sec-
ondary allyl carboxylates with a terminal double bond were
found to be the most reactive substrates, giving rise to the
branched amino acids with perfect regioretention and chiral-
Introduction
Transition-metal-catalyzed allylic alkylations have become pow-
erful and efficient tools in organic synthesis, allowing a wide
[
1]
range of CÀC and CÀheteroatom couplings. Although, in ear-
lier days the scenery was clearly dominated by the Pd-catalysts,
during the last one or two decades a range of other late-transi-
[
1,2]
tion-metals have made their way into the limelight. This sig-
nificantly increased the synthetic potential of this protocol, be-
cause each transition metal has its own characteristics and can
show different reaction behavior compared with palladium.
For examples, if terminal allyl complexes (C) are formed, either
from linear (A) or from branched substrates (B), the regioselec-
tivity of the nucleophilic attack on the allyl complex strongly
depends on the transition metal used (Scheme 1). Whereas p-
allyl palladium complexes are generally attacked at the sterical-
ly least hindered position (generating the linear products D
and E), other metals such as Mo, W, or Ir give rise to the
Scheme 1. Transition-metal-catalyzed allylic substitution.
In their pioneering work, Tsuji et al. investigated allylations
of b-ketoesters using branched allyl carbonate B (Scheme 1,
[6]
R=Me, X=OCOOEt). They found [RuH (PPh ) ] to be a highly
2
3 3
active catalyst, giving rise to a mixture of substitution products
(D/E/F=10:58:32) that was similar to the ratio obtained with
Pd- and Ni-complexes, but contrary to Rh-catalysts, which de-
livered the branched product F preferentially. Watanabe ob-
served a “Rh-type” regioselectivity when using [Ru(cod)(cot)]
[
2]
[3]
[4]
branched product F preferentially. In contrast, Rh or Ru
[7]
show a high tendency for regioretention, although especially
in case of Ru, the regioselectivity strongly depends on the Ru-
(cod: cyclooctadiene, cot: cyclooctatriene). They also ob-
3
served, that complexes such as [(h -allyl)Ru(CO) Br] show ambi-
3
[
4]
catalyst used. Considering that the Ru-catalyzed process does
not necessarily require the conversion of an allylic alcohol into
philic behavior, reacting both as electrophiles (in allylic alkyla-
[8]
tions) and as nucleophiles (in carbonyl additions).
[
5]
a better leaving group, but can be used directly, the Ru-cata-
lyzed allylation is still rather underdeveloped.
In general, a high tendency towards the branched product is
observed for Ru-complexes containing Cp* as an electron-do-
[8b]
nating, sterically demanding ligand. Excellent reactivities and
selectivities were described for [Cp*Ru(MeCN) ]PF by Trost
[a] Dr. A. Bayer, Prof. Dr. U. Kazmaier
3
6
[9]
Institut fꢀr Organische Chemie, Universitꢁt des Saarlandes
Im Stadtwald, Geb. C4.2, 66041 Saarbrꢀcken (Germany)
Fax: (+49)681-3022409
et al. in 2002. Independent of the substrates (A or B) used,
almost identical yields and regioselectivities were obtained,
clearly indicating that the same p-allyl-Ru-complex C (M=Ru)
is formed. This situation is comparable to the Pd-catalyzed re-
actions, although the nucleophilic attack occurs preferentially
E-mail: u.kazmaier@mx.uni-saarland.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402825.
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[
23]
at the sterically more hindered position (comparable to Ir, Mo
and W-catalysts). When optically pure substrates of type B
were used, complete chirality transfer into the product was ob-
served, indicating that the Ru-p-allyl-complexes do not under-
go p-s-p-isomerization as the Pd-complexes do. Based on
these observations, a range of different Cp*-Ru-complexes
have been developed and evaluated, especially by the groups
esting effects.
Compared with the standard nucleophiles
(malonates, etc.) the chelated enolates show the high reactivity
of “nonstabilized” enolates combined with a (thermal) stabiliza-
tion through the chelating metal salt. Thus, these enolates do
not need to be reacted at 08C or room temperature (as is the
case for malonates) but can be allylated at temperatures as
low as À788C or even lower. This allows isomerization process-
[
10]
[11]
[22d,24]
of Bruneau
and Pregosin.
The high regioselectivity ob-
es in Pd-catalyzed reactions to be suppressed,
and results
tained with these types of complexes can be explained by the
in excellent selectivities in Rh-catalyzed processes
[25]
formation of an unsymmetric p-allyl-Ru-complex and a strong
(Scheme 3). Herein, we describe in detail the evaluation of
Ru-catalyzed allylations of chelated glycine enolates.
[
12]
shielding effect of the Cp* ligand. Enantiomerically enriched
branched alkylation products F can not only be obtained from
enantiomerically pure B, but also from the linear substrates A
[
13]
by using chiral ligands on Ru. Interestingly, the opposite re-
gioselectivities were observed with [Ru (CO) ] and the biden-
3
12
tate diphenylphosphinylbenzoic acid (DPPBA) ligand, which
[
14]
gives rise to the linear products almost exclusively.
A different reaction behavior is found in allylations catalyzed
[15]
by [(p-cymene)RuCl ] /PPh as reported by Kawatsura. With
2
2
3
this catalyst, a high degree of regioretention is observed with
linear as well as with branched allylic substrates. This effect is
not only observed with terminal allylic substrates such as A
and B, but also with 1,3-disubstituted systems, and a perfect
chirality transfer (retention) is found with this catalyst. Howev-
er, the catalytic activity of the cymene–Ru complex is lower
compared with the Cp* system. Although these substrates un-
dergo allylic substitution with most nucleophiles at room tem-
perature, the cymene complex requires higher temperatures
Scheme 3. Allylic alkylations of chelated enolates (Tfa=trifluoroacetyl).
Results and Discussion
[16]
for allylations of the “standard nucleophile” malonate.
Al-
We started our investigations under the optimized conditions
found in Pd- and Rh-catalyzed reactions. Trifluoroacetic acid
(TFA)-protected tert-butylglycinate (TfaGlyOtBu) was used as
a Zn-chelated enolate, because this enolate gave by far the
best yields and selectivities (Scheme 3). The allyl substrate was
used in excess to favor complete conversion of the enolate. As
catalyst, we used Kawatsura’s [(p-cymene)RuCl ] /PPh
3
though the mechanistic details of this divergent reaction be-
havior is not yet understood, it could be assumed that the
cymene–Ru complexes do not react via a (unsymmetrical) p-
allyl-intermediate, but more via a (s-p)-enyl-type complex, as
[
3]
proposed for Rh-catalyzed reactions. In this case, the regio-
and stereoretention can be explained by an anti-S 2’ formation
N
2 2
of the (s-p)-enyl-Ru complex, which is also attacked in an anti-
SN2’ mode by the nucleophile, resulting in overall retention
(5 mol%) because of its high regioretention and chirality trans-
fer. We used several leaving groups that gave good results in
previous investigations. Whereas allyl carbonates and carboxy-
lates were excellent substrates in Pd-catalyzed allylations,
phosphates have been found to be superior in Rh-catalyzed
processes. The results are summarized in Table 1.
(Scheme 2).
In the previously reported allylations using Ru-complexes,
mainly stabilized carbanions such as malonates and b-ketoest-
ers have been used, as well as several hetero-nucleophiles
[
14b,17]
[18]
[5c,19]
such as amines,
alcohols, or thiols.
Recently, we re-
Surprisingly, the yields obtained were only moderate, and
were, in all cases, in the range of 16 to 20%, independent of
ported the Ru-catalyzed allylic alkylations of chelated amino
acid ester enolates leading to g,d-unsaturated amino acid de-
the leaving group. The regioselectivity towards the branched
[
20]
[23d]
rivatives. Our group has been investigating reactions of che-
product 2a
was excellent for allyl carbonate 1a and carbox-
[
21]
[22]
lated enolates of amino acids and peptides with p-allyl
ylates 1b and 1c (Table 1, entries 1–3), but was significantly
lower with phosphate 1d (entry 4). Even more surprising was
the completely unselective formation of 2a observed with this
leaving group, whereas good selectivities were obtained with
the carboxylates (entries 2 and 3).
complexes for several years and observed a number of inter-
To increase the yield, we decided to take advantage of the
thermal stability of the chelated enolates. In contrast to
normal, nonchelated ester enolates, which decompose during
warming to temperatures higher than À208C, the chelated
enolates can be heated in tetrahydrofuran (THF) to reflux for
several hours without decomposition. Therefore, after warming
the reaction mixtures to room temperature overnight (Meth-
Scheme 2. Proposed reaction mode of (cymeneRuCl
2 2
) -catalyzed allylations
with regio- and stereoretention ([Ru]=cymeneRuL ).
2
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Table 1. Ru-catalyzed allylic alkylations using secondary allyl carboxylates
and phosphates.
Table 2. Influence of ligands on Ru-catalyzed allylic alkylations of secon-
dary allyl benzoate 1c.
[
d]
[d]
Entry Ru catalyst
x
ligand
y
Yield Ratio Ratio 2a
%] 2a/3a anti/syn
[
1
2
3
4
5
6
7
8
9
1
[(p-cymene)RuCl
2
2
2
2
2
2
2
2
2
2
]
]
]
]
]
]
]
]
]
]
2
2
2
2
2
2
2
2
2
2
5
5
5
5
5
5
5
5
2
2
2
2
PPh
P(2-furyl)
P(o-tolyl)
3
10 83
10 83
10 55
10 71
10 62
10 82
10 46
10 54
98:2 88:12
98:2 88:12
98:2 86:14
95:5 72:28
98:2 87:13
98:2 84:16
90:10 75:25
91:9 79:21
96:4 81:19
95:5 78:22
90:10 54:46
73:27 82:18
[(p-cymene)RuCl
[(p-cymene)RuCl
[(p-cymene)RuCl
[(p-cymene)RuCl
[(p-cymene)RuCl
[(p-cymene)RuCl
[(p-cymene)RuCl
[(p-cymene)RuCl
[(p-cymene)RuCl
3
[
a]
[c]
[c]
Entry
1
X
y
z
Method
Yield Ratio
Ratio 2a
3
[
b]
[%]
2a/3a anti/syn
[a]
PCy
P(OMe)
P(OEt)
3
1
2
3
4
5
6
7
8
9
1a OCOOEt
1b OAc
1c OBz
1d OPO(OEt)
1b OAc
1c OBz
1d OPO(OEt)
1c OBz
1c OBz
1e OCOOtBu 1.5
1e OCOOtBu 1.5
1e OCOOtBu 1.5
0.5 2.5
0.5 2.5
0.5 2.5
0.5 2.5
0.5 2.5
0.5 2.5
0.5 2.5
A
A
A
A
B
16
20
20
18
33
50
70
76
83
81
82
73
98:2 78:22
99:1 90:10
99:1 89:11
88:12 52:48
99:1 89:11
98:2 87:13
88:12 49:51
98:2 88:12
98:2 88:12
99:1 89:11
99:1 90:10
99:1 89:11
3
3
P(OPh)
MeCN
3
2
2
[
b]
SIMes·HCl
4
4
75
82
36
92
[
c]
0
SIPr·HCl
B
B
1
1
[RuCl
2
(PPh
3
)
3
]
–
–
12
[Cp*Ru(MeCN) ]PF
3 6
1.2
1.5
5
5
5
2
1
A
A
A
A
A
[
a] Cy=cylohexyl. [b] SIMes=N,N’-bis(2,4,6-trimethylphenyl)imidazolin-2-
10
ylidene. [c] SIPr=N,N’-bis(2,6-diisopropyl)imidazolin-2-ylidene. [d] Ratios
determined by GC analysis (ChiraSil-Val).
1
1
12
[
a] Reaction conditions: Method A: THF, À788C to RT, 16 h; Method B:
THF, À788C to RT, 16 h, 608C, 3 h. [b] Yield calculated based on the minor
component. [c] Ratios determined by GC analysis (ChiraSil-Val). LHMDS=
lithium hexamethyl disilazide; Bz=benzoyl.
Replacing PPh by P(furyl) had no influence on the reaction
3
3
at all. Probably for steric reasons, the catalyst obtained with
P(o-tolyl) was slightly less active, although the selectivity was
3
od A) they were then heated to 608C for 3 h (Method B).
Indeed, under these conditions, the yields could be increased
significantly without affecting the regio- and stereoselectivity
unchanged, indicating that the attack of the nucleophile on
the Ru-allyl intermediate is subject to electronic rather than
[27]
steric control. Interestingly, a significant drop in the diaste-
(Table 1, entries 5–7). With phosphate 1d, a yield of 70% could
reoselectivity was observed in the presence of PCy . With
3
be obtained, which is acceptable (entry 7), but the yields of
the carboxylates were still moderate. Therefore, we next varied
the substrate/enolate ratio to investigate this influence. Allyl-
benzoate 1c was used as substrate, and a strong increase of
the yield was observed when the enolate was used in (slight)
excess (entries 8 and 9) even under the milder reaction condi-
tions A. In this case, 5 mol% Ru-catalyst/1c was used. The best
results were obtained with 1.5 equiv enolate, and the use of
a higher excess resulted in no further improvement. A compa-
rable result was obtained with carbonate 1e (entry 10), and
this substrate was also used to also investigate the amount of
catalyst required (entries 10–12). With 2 mol% catalyst almost
the same yields and selectivities were obtained, whereas re-
ducing the amount to only 1 mol% resulted in a slight drop to
phosphite ligands, a comparable degree of regioretention was
found (Table 2, entries 5 to 7). The diastereoselectivity de-
creased with increasing steric demand of the ligand. Addition
of the bidentate ligand dppe completely suppressed the reac-
tion, probably by blocking the free coordination side on the
catalyst.
The dissociating ligand does not necessarily have to be a P-
ligand. Acetonitrile does the same job, and the results ob-
tained herewith were comparable to those obtained with
P(OPh) (Table 2, entry 8). This forced us to investigate also the
3
influence of some carbene ligands, as well as other Ru-cata-
lysts. The carbene complexes were found to be nearly as
active as the PPh complex but slightly less regioselective; the
3
diastereoselectivity was worse (entries 9 and 10). A significant
drop in both yield and diastereoselectivity was observed when
[RuCl (PPh ) ] was used (entry 11). By far the most active cata-
73%, but was still in a preparatively useful range. Based on
these results, we used 1.2–1.5 equiv enolate/substrate and
2
3 3
2
mol% catalyst for our further investigations.
lysts were the RuCp* complexes, which all gave excellent yield,
but unfortunately by far the lowest regioselectivity (entry 12).
Therefore, we used the original [(cymene)RuCl ] /PPh catalyst
In a second set of experiments, we investigated the influ-
ence of the catalyst/ligand system on the regio- and stereose-
lective outcome of the reaction.
2
2
3
for subsequent investigations. It should be mentioned that, in
all cases, the linear product (E)-3 was formed exclusively.
Besides the catalyst, the structure of the attacking nucleo-
phile should also have a strong influence. With this assump-
tion, we also varied the protecting groups on the glycine
(Table 3). In analogy to Pd- and Rh-catalyzed allylations, by far
the most selective reactions were observed with the N-Tfa-pro-
[
15]
According to Kawatsura and Itoh, added PPh initiates the
3
dissociation of the dimeric Ru-complex through formation of
[
26]
[(cymene)RuCl (PPh ) ],
which actually enters the catalytic
2
3 3
cycle. Therefore, because one might expect an influence of this
dissociating ligand on the reaction, we screened a set of phos-
phanes, phosphites as well as carbene ligands (Table 2).
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1
c started at À558C to give the branched product 2c in good
Table 3. Influence of the protecting groups (PG) on the chelated enolate.
yield and excellent regioselectivity (entry 1), the linear sub-
strates were found to be significantly less active. Here, the
temperature needed to be increased to À358C to initiate the
reaction. The yields obtained were also much lower, even
when the reaction mixture was warmed to room temperature
(
entries 2 and 3). Whereas 1c and (E)-4c gave the branched
product 2c with almost the same anti/syn-selectivity, the (Z)-
substrate reacted almost completely unselectively. In contrast,
the regioselectivity was better in the case of (Z)-4c (compared
with (E)-4c). Interestingly, absolutely no isomerization was ob-
served. Application of 1c and (E)-4c resulted in the formation
of (E)-3a exclusively, whereas only (Z)-3a was obtained from
[
a]
[a]
Entry
PG
R
Yield
%]
Major product
Ratio
2/3
Ratio 2
[
anti/syn
[
23d]
1
2
3
4
5
6
Tfa
Tfa
Boc
Cbz
Cbz
Ts
tBu
Me
tBu
tBu
Me
Me
83
74
86
79
74
57
2a
98:2
99:1
99:1
99:1
99:1
99:1
88:12
74:26
60:40
71:29
40:60
33:67
[
28]
2b
2c
2d
(
Z)-4c. The allyl-Ru complex formed in situ from the (Z)-sub-
[
28]
strate clearly differs significantly from complexes formed from
(E)-4c and 1c, which might be similar (same diastereoselectiv-
ity for 2c). The different degree of regioretention (88 vs. 72%)
might be a result of the higher reaction temperature required
for the reaction of (E)-4c. To test this conclusion, we also inves-
tigated the corresponding phosphates, which we found to be
more reactive, although less selective, at least in the case of
branched substrate 2d. Indeed, all the substrates reacted
smoothly at À788C, albeit without any diastereoselectivity.
As observed previously, the branched substrate 2d also re-
acted without significant regioretention, whereas the regiose-
lectivity of the linear substrates increased, probably because of
the lower reaction temperature. Especially the (Z)-configured
phosphate provided (Z)-3a almost exclusively (Table 4, entry 6).
2e
[
28]
2 f
[
a] Ratios determined by GC analysis (ChiraSil-Val). Boc=tert-butoxycar-
bonyl; Cbz=carbobenzyloxy.
tected t-butyl glycinate (entry 1) used in the optimization stud-
ies. The corresponding methyl ester (entry 2) was significantly
less diastereoselective. Even worse was the situation with the
carbamate protecting groups (entries 3–5). The Boc-protected
t-butyl ester gave the branched product as an almost 1:1 mix-
ture. With the Cbz-protected derivative, the anti-selectivity was
slightly better, but the corresponding methyl ester provided
even the syn diastereomer pref-
erentially (entries 4 and 5). So
far, the highest syn-selectivity
Table 4. Allylic alkylations using primary and secondary allylic substrates.
was obtained with the N-tosylat-
ed methyl ester. From these re-
sults, a clear tendency can be
observed: The anti-isomer is fa-
vored by small N- and large O-
protecting groups, and vice
versa for the syn-isomer. The
yields obtained were generally
good, and the regioselectivity
was almost perfect, irrespective
of the glycine derivative used.
Although no influence of the
nucleophile on the degree of re-
gioretention was found, there
should be an influence by the al-
lylic substrate used. The position
of the leaving group on the allyl
moiety might have an influence,
as well as the nature of the sub-
stituents (aliphatic or aromatic).
Therefore, we compared the re-
sults obtained with branched 1c
with those obtained with the
linear crotyl derivatives (E)- and
[a]
[b]
[b]
Entry
Substrate
X
Cat.
Ligand
Yield
[%]
Ratio
Ratio 2
2/(E)-3/(Z)-3
anti/syn
1
2
3
4
5
6
7
8
9
1c
OBz
OBz
OBz
OPO(OEt)
OPO(OEt)
OPO(OEt)
OBz
OBz
OBz
OBz
OBz
OBz
OBz
OBz
OBz
A
A
A
A
A
A
A
A
A
A
A
A
B
PPh
PPh3
3
83
43
34
90
93
85
75
44
30
82
20
21
92
41
13
98:2:0
28:72:0
12:0:88
64:36:0
20:80:0
1:0:99
88:12
88:12
41:59
39:61
55:45
n.d.
81:19
90:10
44:56
78:22
75:25
51:49
82:18
86:14
36:64
(E)-4c
(Z)-4c
1d
(E)-4d
(Z)-4d
1c
(E)-4c
(Z)-4c
1c
(E)-4c
(Z)-4c
1c
PPh
PPh
PPh
PPh
SIPr
SIPr
SIPr
3
3
3
3
2
2
2
96:4:0
40:60:0
13:0:87
95:5:0
19:81:0
16:0:84
73:27:0
45:55:0
49:0:51
1
0
SIMes
SIMes
SIMes
–
–
–
1
1
12
13
1
1
4
5
(E)-4c
(Z)-4c
B
B
[
2 2 3 6
a] Catalyst A: [(p-cymene)RuCl ] ; Catalyst B: [Cp*Ru(MeCN) ]PF . [b] Ratios determined by GC analysis (ChiraSil-
(
Z)-4c (Table 4). Whereas the re-
Val). n.d.=not determined.
action of the branched substrate
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These results clearly indicate that 1d and (E)-4d do not form
the same allyl-Ru-intermediate, otherwise the regioselectivity
should be similar. For comparison, we also investigated the in-
fluence of the ligand, using the carbene ligands SIPr and SIMes
(entries 7–12). The same tendency was observed as with PPh3.
The branched substrate 1c was the most reactive and most re-
gioselective, although the diastereoselectivity was slightly
lower compared with the phosphane catalyst. The linear sub-
strates gave only very moderate yields, especially in the case
of the SIMes-ligand, for which the yield dropped to 20%,
whereas 80% yield was obtained with 1c (entries10–12). The
same effect was also observed in reactions catalyzed by the
Trost catalyst (entries 13–15), which was also the least selec-
tive. In this case, a large difference in the reactivity was ob-
served between (E)-4c and (Z)-4c. Whereas the (E)-isomer al-
ready started to react at À788C, the (Z)-isomer required warm-
ing to À158C, and even then the yield was only 13%
(entry 15).
These studies clearly indicate that branched allylic alcohols
should be activated as carboxylates such as benzoate (1), and
that phosphates are the leaving group of choice for linear sub-
strates 4, especially the (Z)-isomers. In these cases, an excellent
degree of regioretention can be obtained, in combination with
good yield and diastereoselectivity. With respect to selectivity,
the cymene-catalyst is superior to the Cp* complex, while this
is the more reactive one. The diastereoselectivities of the reac-
tion leading to 2a from 1c and (E)-4c are comparable, where-
as the degree of regioretention differed significantly.
Scheme 4. Mechanistic proposal for Ru-catalyzed allylic alkylations.
axial methyl group interacting directly with the cymene ligand,
comparable to intermediate H. The fact that no (Z)-3a is
formed from 1c indicates that such a scenario probably does
not occur. This might explain the lower reactivity of the (Z)-
substrates compared with the (E)-isomers. Probably the allyl
ligand coordinates the other way round with the methyl-sub-
stituent distal to the cymene ligand (M, N). The resulting differ-
ent complex geometry might explain the completely different
reaction behavior of the (Z)-substrate. Probably, the (s+p)-
enyl complex is formed first, as indicated by the excellent re-
gioselectivity observed with (Z)-4a at À788C. During warm-up,
isomerization towards a p-allyl complex becomes reasonable,
resulting in a drop of regioselectivity.
The high levels of regioretention obtained with 1c can be
nicely explained by a double S ’-type mechanism (Scheme 4).
N
Nucleophilic attack of the sterically demanding Ru-complex on
the sterically unhindered terminal position of 1c should pro-
vide an s-allyl-Ru complex. Coordination of the (E)-double
bond towards the Ru generates an (s+p)-enyl complex G,
which is attacked by the nucleophile in a S ’-mode. In princi-
N
ple, a (Z)-double bond can also be formed in the S ’ step, but,
N
in this case, the methyl substituent should interact with the
cymene ring on the Ru (H). This would explain why no (Z)-3c
is formed from 1c. In principle, the scenario should be compa-
rable for the linear substrates 4, although a nucleophilic attack
of the Ru complex on the substituted double bond should be
sterically hindered, which can explain the higher reaction tem-
peratures required and the lower yields. Reaction of (E)-4c
should give rise to a secondary s-Ru bond with significant in-
teractions of the methyl substituent and the ligands on Ru.
This steric repulsion should extend the s-bond, and shorten
the p-bond (I), generating a situation very close to a p-allyl
complex (K). Nucleophilic attack on such an intermediate
should be less regioselective compared with the “unhindered”
To evaluate the scope and limitations of this protocol, we
subjected a range of branched allylic acetates and benzoates 5
[20]
to our optimized reaction conditions (Table 5). Replacing the
methyl group of 1a (entry 1) by a linear alkyl chain or by an
isopropyl substituent resulted in a decrease of regio- and ste-
reoselectivity (entries 2 and 3). In contrast, good regioselectivi-
ties were obtained with tertiary benzoates (entry 4) and aryl-
substituted substrates (5 and 6). An excellent yield was ob-
tained with the p-brominated substrate 5e, and the halogenat-
ed amino acid 6e should be a suitable substrate for further
modifications through cross-coupling reactions. Considering
that no isomerizations were observed during our previous
studies, we also subjected some enantiomerically enriched al-
lylic substrates to our reaction conditions to investigate the
chirality transfer (entries 7–9). In all examples, perfect chirality
transfer was observed, indicating that the Ru-catalyzed process
is an important alternative to the Pd-catalyzed reactions, which
result in complete loss of the stereogenic information if termi-
nal p-allyl complexes are formed.
(
s+p)-enyl complex G. Nevertheless, such a p-allyl complex K
should be structurally rather similar to G, and nucleophilic
attack at the sterically more hindered positions should proceed
in a similar way. This would explain the comparable diastereo-
selectivities obtained for 2a.
The situation is different in the case of (Z)-4c. If this sub-
strate reacts in an analogous fashion to those of the two other
substrates, a (s+p)-enyl complex L should be formed with an
Chem. Eur. J. 2014, 20, 10484 – 10491
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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whereas linear (Z)-configured
amino acids are obtained from
the corresponding phosphates.
Applications of these reactions
for the modification of peptides
and natural products are under
investigation.
Table 5. Allylic alkylations using secondary allyl carboxylates 5.
1
2
[a]
[a]
Entry Substrate Config. ee
%]
R
R
R
Yield Major product Ratio
Ratio 6
anti/syn
Config. 6 ee
[%]
[
[%]
6/7
1
2
3
4
5
6
7
8
9
1c
5a
5b
5c
5d
5e
1c
5d
5 f
(R/S)
(R/S)
(R/S)
(R/S)
(R/S)
(R/S)
(S)
–
–
–
–
–
–
Ph Me
Me Pent
Ph iPr
Ph Me
Me Ph
H
H
H
83
90
87
2a
6a
6b
6c
6d
6e
2a
6d
6 f
98:2 88:12
89:11 83:17
84:16 40:60
(R/S)
(R/S)
(R/S)
(R/S)
(R/S)
(R/S)
(2S,3S)
(2S,3R)
(2S,3S)
–
–
–
–
–
–
96
97
95
Experimental Section
Me 86
98:2
–
General remarks
H
H
H
H
H
75
98
87
97
83
96:4 81:19
96:4 71:29
97:3 83:17
97:3 82:18
97:3 76:24
Ph p-BrPh
All air- or moisture-sensitive reac-
tions were carried out in dried
glassware (>1008C) under an at-
mosphere of nitrogen. Dried sol-
vents were distilled before use:
THF was distilled from LiAlH4,
CH Cl was dried with CaH before
96 Ph Me
97 Me Ph
95 Ph Et
(R)
(S)
[a] Ratios determined by GC analysis (ChiraSil-Val).
2
2
2
distillation. The products were purified by flash chromatography
on silica gel columns (Macherey–Nagel 60, 0.063–0.2 mm). Mixtures
of ethyl acetate and hexane were generally used as eluents. Analyt-
ical TLC was performed on pre-coated silica gel plates (Macherey–
Nagel, Polygram SIL G/UV254). Visualization was accomplished
Table 6. Allylic alkylations using (Z)-allyl substrates 4.
with UV-light and KMnO solution. Melting points were determined
4
1
with a MEL-TEMP II apparatus and are uncorrected. H and
C NMR spectra were recorded with a Bruker AC-400 [400 MHz
H) and 100 MHz ( C)] spectrometer in CDCl . Chemical shifts are
1
3
1
13
(
3
[
a]
reported in ppm relative to TMS, and CHCl was used as the inter-
3
Entry Substrate
X
R
Yield Ratio
Product
nal standard. Selected signals for the minor regio- and diastereo-
mers are extracted from the spectra of the isomeric mixture. Re-
gioisomeric and diastereomeric ratios were determined by GC anal-
ysis using an l-ChiraSilVal capillary column (25 m ꢁ 0.25 mm). Ni-
trogen was used as carrier gas. Mass spectra were recorded with
a Finnigan MAT 95 spectrometer using the CI technique. Elemental
analyses were performed at Saarland University. All compounds
[
%]
6/(Z)-7
[
25]
1
2
3
4
(Z)-4 f
(Z)-4g
(Z)-4h
(Z)-4i
OBz
OBz
OPO(OEt)
OPO(OEt)
Et
56
7:93
3:97
1:99
1:99
7 f
[
[
24d]
24d]
CH
CH
CH
2
2
2
OTBDMS 40
7g
7h
2
2
OPMP
OBn
95
98
[
24d]
7i
[
a] Ratios determined by GC analysis (ChiraSil-Val). TBDMS=tert-butyldi-
methylsilyl; PMP = p-methoxphenyl.
[20,23d,24d,27]
not described here have been reported previously.
Synthesis of starting materials
The second big advantage of the Ru-catalyzed process com-
pared with the Pd-protocol is the isomerization-free allylation
with the (Z)-configured allylic substrates. To establish whether
the excellent results observed especially with (Z)-4d are gener-
al, we subjected a range of functionalized substrates to our re-
action conditions (Table 6). The general trend that allylic phos-
phates are superior to benzoates was confirmed. The ethyl
substituted benzoate (Z)-4 f gave better results than the previ-
ously investigated (Z)-4c. The functionalized substrates (Z)-4g–
i reacted with perfect regioretention, providing the (Z)-config-
ured linear products (Z)-7 exclusively. With the phosphates,
almost quantitative yield was obtained.
Allylic alcohols as precursors for 1a–e and 5c were purchased
from commercial suppliers. The racemic precursors for the other
esters 5, were prepared by addition of vinylmagnesiumbromide to
the corresponding aldehyde. The (Z)-configured alcohol required
for the (Z)-substrates (Z)-4c and (Z)-4d was obtained by ether
[29]
cleavage of 2,5-dihydrofuran and the (E)-isomer was obtained by
[30]
reduction of (E)-crotyl ethyl ester. The racemic allylic alcohols
were converted into the benzoates, acetates, carbonates, and
phosphates by standard methods. Compounds (Z)-4h and (Z)-4i
[
24d]
were prepared as described previously.
(
Compounds (S)-1c and
[31]
S)-5 f were obtained by the method described by Feringa et al.
The enzymatic racemic resolution of 5d using the immobilized
[32]
lipase Novozyme 450 gave allylic acetate (R)-5d.
Ruthenium-catalyzed allylic alkylations; General procedure
Conclusion
A solution of hexamethyldisilazane (335 mg, 2.07 mmol) in THF
We have shown that [(cymene)RuCl ] -catalyzed allylic alkyla-
2
2
(2.0 mL) was prepared in a Schlenk flask under nitrogen. After the
tions are a powerful alternative to Pd-catalyzed reactions. Espe-
cially with highly reactive chelated enolates, the reactions take
place free of isomerization with excellent regioretention and
chirality transfer. This allows the stereoselective synthesis of b-
branched amino acids from secondary allyl carboxylates,
solution was cooled to À208C, a solution of n-butyllithium (1.6m
in hexanes, 1.17 mL, 1.88 mmol) was added slowly, the cooling
bath was removed, and stirring was continued for 10 min. The so-
lution was cooled to À788C and the TFA-protected tert-butyl glyci-
nate (171 mg, 0.75 mmol), dissolved in THF (1 mL), was added to
Chem. Eur. J. 2014, 20, 10484 – 10491
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10489
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
the freshly prepared LHMDS solution. After 10 min, a solution of
2S,3R) min; (E)-3d: t =113.87 (<1%; 2R), 115.09 (<1%; 2S) min; el-
R
dried ZnCl (123 mg, 0.90 mmol) in THF (1.0 mL) was added and
emental analysis calcd (%) for C H NO (319.40): C 67.69, H 7.89,
2
18 25
4
stirring was continued for 30 min at À788C.
N 4.38; found: C 67.51, H 7.92, N 4.48.
tert-Butyl 3-isopropyl-2-(trifluoroacetamido)pent-4-enoate (6b):
According to the general procedure for ruthenium-catalyzed allylic
alkylations N-TFA-protected tert-butyl glycinate (171 mg,
A
0
(
solution was prepared from [(p-cymene)RuCl2]2 (6.4 mg,
.01 mmol) and triphenylphosphane (5.2 mg, 0.02 mmol) in THF
1 mL), and stirred for 5 min at RT, during which time it became
[
33]
0
.75 mmol) was reacted with allyl benzoate 5b
(79 mg,
red. The allyl substrate (0.50 mmol) was added and the resulting
solution was added slowly to the chelated enolate at À788C. The
mixture was allowed to warm to RT overnight. The solution was di-
luted with diethyl ether (20 mL) before 1m KHSO4 (10 mL) was
added. After separation of the layers, the aqueous layer was ex-
tracted twice with diethyl ether and the combined organic layers
were dried over Na SO . The solvent was evaporated in vacuo, and
0
.39 mmol). Flash chromatography (silica gel; hexanes/ethyl ace-
tate, 98:2) gave rise to a mixture of 6b (anti/syn, 40:60) and 7b
6b/7b, 84:16) in 87% yield (105 mg, 0.34 mmol) as a colorless oil.
(
1
H NMR (400 MHz, CDCl ): d (syn-6b; 60%)=0.89 (d, J=6.9 Hz, 3H;
3
CHCH ), 1.10 (d, J=6.6 Hz, 3H; CHCH ), 1.49 (s, 9H; CCH ), 1.78 (m,
3
3
3
1
H; CCH ), 2.04 (ddd, J=10.4, 9.1, 5.3 Hz, 1H; NCHCH), 4.68 (dd,
3
2
4
J=8.2, 5.2 Hz, 1H; NCH), 5.07 (dd, J=16.9, 1.8 Hz, 1H; CHCH ), 5.22
the crude product was purified by flash chromatography (SiO2).
The isomeric ratios were determined by CG analysis of the crude
product (before chromatography). The configuration was assigned
according to reported data of the predominant, known com-
pounds.
2
(
1
dd, J=10.1, 1.8 Hz, 1H; CHCH ), 5.47 (ddd, J=16.9, 10.4 Hz,
0.4 Hz, 1H; CHCH ), 6.81 ppm (br s, 1H; NH); C NMR (100 MHz,
2
2
13
CDCl ): d=20.6 (q, CHCH ), 28.0 (q, CHCH ), 28.4 (d, CHCH ), 53.4
3
3
3
3
(
d, CHNH), 55.0 (d, NCHCH), 83.4 (s, CCH ), 115.7 (q, J=287.9 Hz,
3
CF ), 120.0 (t, CHCH ), 135.0 (d, CHCH ), 156.7 (s, J =37.7 Hz;
3
2
2
8,F
tert-Butyl 2-(N-tert-butyloxycarbonylamino)-amino-3-methyl-4-
pentenoate (2c): According to the general procedure for rutheni-
um-catalyzed allylic alkylations N-Boc-protected tert-butyl glycinate
1
CF CO), 169.4 ppm (s, COO); H NMR (400 MHz, CDCl ): d (anti-6b;
3
3
4
6
0%, selected signals)=0.90 (d, J=7.0 Hz, 3H; CHCH ), 1.02 (d, J=
3
.6 Hz, 3H; CHCH ), 1.47 (s, 9H; CCH ), 1.66 (m, 1H; CCH ), 2.28
3
3
3
(
171 mg, 0.75 mmol) was reacted with allyl benzoate 1c (88 mg,
.50 mmol). Flash chromatography (silica gel; hexanes/ethyl ace-
tate, 95:5) gave rise to a diastereomeric mixture (anti/syn, 6:4) of
c in 86% yield (123 mg, 0.43 mmol) as a colorless oil and as
(ddd, J=9.7, 8.0, 4.7 Hz, 1H; NCHCH), 4.70 (dd, J=8.7, 5.1 Hz, 1H;
0
NCH), 5.11 (dd, J=16.6, 1.7 Hz, 1H; CHCH ), 5.23 (dd, J=10.3,
2
1
.8 Hz, 1H; CHCH ), 5.55 (dd, J=16.7, 10.3, 9.6 Hz, 1H; CHCH ), 6.55
2 2
2
13
(
(
br s, 1H; NH); C NMR (100 MHz, CDCl ): d=19.2 (q, CHCH ), 19.7
3 3
q, CHCH ), 28.1 (d, CHCH ), 53.9 (d, CHNH), 54.4 (d, NCHCH), 83.1
1
a single regioisomer (rs: 99:1). H NMR (400 MHz, CDCl ): d (anti-2c,
3
3
3
6
9
8
0%)=1.08 (d, J=6.9 Hz, 3H; CHCH ), 1.44 (s, 9H; CCH ), 1.46 (s,
3
3
(
s, CCH ), 120.0 (t, CHCH ), 134.0 (d, CHCH ), 168.6 ppm (s, COO).
3
2
2
H; CCH ), 2.72 (m, 1H; CHCH ), 4.17 (m, 1H; CHNH), 4.92 (d, J=
3
3
1
H NMR (400 MHz, CDCl ): d [(E)-7b; selected signals]=2.54 (m,
3
.5 Hz, 1H; NH), 5.04–5.12 (m, 2H; CHCH ), 5.72 ppm (m, 1H;
2
2
H; NCHCH ), 4.50 (dt, J=7.5, 5.3 Hz, 1H; NCH), 5.19 (m, 1H;
2
1
3
CHCH2); C NMR (100 MHz, CDCl ): d=16.0 (q, CHCH ), 28.0 (q,
3
3
CH CHCHCH), 5.51 (m, 1H; CH CHCHCH), 6.81 ppm (br s, 1H; NH);
2
2
CCH ), 28.3 (q, CCH ), 40.4 (d, CHCH ), 58.0 (d, CHNH), 79.6 (s,
3
3
3
13
C NMR (100 MHz, CDCl ): d=34.8 (t, NCHCH ), 52.7 (d, NCH), 119.1
3
2
OCCH ), 81.8 (s, OCCH ), 116.3 (t, CHCH ), 138.0 (d, CHCH ), 155.7 (s,
3
3
2
2
(
8
d, CH CHCH), 132.8 (d, CH CHCH); GC (l-Chirasil-Val; 808C, 10 min,
08C to 1808C, 18Cmin , 20 min): t =28.39 (6b, 2R,3R), 29.21
R
1
2
2
NCO), 170.9 ppm (s, COO); H NMR (400 MHz, CDCl ): d (syn-2c;
3
À1
4
1
0%, selected signals)=1.04 (d, J=7.0 Hz, 3H; CHCH ), 2.62 (m,
3
(6b, 2R,3S), 34.10 (6b, 2S,3R), 34.64 (6b, 2S,3S), 37.71 [(E)-7b, 2R],
13
H; CHCH ), 5.02 ppm (d, J=8.5 Hz, 1H; NH); C NMR (100 MHz,
3
4
3
2.45 [(E)-7b, 2S] min; HRMS (CI): m/z calcd for C H F NO :
14 22 3 3
09.1552 [M] ; found: 309.1468.
CDCl ): d=15.3 (q, CHCH ), 40.9 (d, CHCH ), 57.7 (d, CHNH), 81.9 (s,
3
3
3
+
OCCH ), 115.7 (t, CHCH ), 139.0 (d, CHCH ), 155.4 (s, NCO), 170.7 (s,
3
2
2
À1
COO); GC (l-Chirasil-Val; 808C, 10 min, 808C to 1808C, 18Cmin ,
0 min): t =47.93 (2R,3R), 49.15 (2R,3S + 2S,3S), 50.15 (2S,3R) min;
HRMS (CI): m/z calcd for C H NO : 286.2013 [M+H] ; found:
2
R
Acknowledgements
+
15
28
4
2
86.2021.
Financial support by the Deutsche Forschungsgemeinschaft
Ka 880/6) and the Fonds der Chemischen Industrie is grateful-
tert-Butyl 2-(N-benzyloxycarbonylamino)-amino-3-methyl-4-pen-
tenoate (2d): According to the general procedure for ruthenium-
catalyzed allylic alkylations, N-Cbz-protected tert-butyl glycinate
(
ly acknowledged.
(
199 mg, 0.75 mmol) was reacted with allyl benzoate 1c (88 mg,
.50 mmol). Flash chromatography (silica gel; hexanes/ethyl ace-
tate, 95:5) gave rise to a diastereomeric mixture (anti/syn, 71:29) of
d in 79% yield (126 mg, 0.39 mmol) as a colorless oil and as
0
Keywords: allylation · amino acids · enols · regioselectivity ·
ruthenium
2
1
a single regioisomer (rs: 99:1). H NMR (400 MHz, CDCl ): d (anti-
3
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2
d; 71%)=1.09 (d, J=6.9 Hz, 3H; CHCH ), 1.46 (s, 9H; CCH ), 2.76
3 3
(
m, 1H; CHCH ), 4.27 (dd, J=8.8, 4.5 Hz, 1H; CHNH), 5.04–5.10 (m,
3
4
7, 258–297; c) Transition Metal Catalyzed Enantioselective Allylic Substi-
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H; CHCH ), 5.11 (m, 2H; CH Ph), 5.18 (d, J=8.7 Hz, 1H; NH), 5.67
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berg, 2012.
13
(
m, 1H; CHCH ), 7.27–7.37 ppm (m, 5H; ArH); C NMR (100 MHz,
2
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3
3
3
CHNH), 66.9 (t, CH Ph), 82.1 (s, OCCH ), 116.6 (t, CHCH ), 128.1 (d,
2
3
2
ArC), 128.1 (d, ArC), 128.5 (d, ArC), 136.3 (d, CHCH ), 137.7 (s, ArC),
2
1
1
56.2 (s, NCO), 170.5 ppm (s, COO); H NMR (400 MHz, CDCl ): d
3
(
2
syn-2d; 29%, selected signals)=1.06 (d, J=7.0 Hz, 3H; CHCH ),
3
.65 (m, 1H; CHCH ), 5.28 ppm (d, J=9.0 Hz, 1H; NH); C NMR
3
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13
(
100 MHz, CDCl ): d=15.2 (q, CHCH ), 40.9 (d, CHCH ), 58.1 (d,
3 3 3
CHNH), 116.0 (t, CHCH ), 138.7 ppm (d, CHCH ); GC (Chirasil-Val;
2
2
À1
8
08C, 10 min, 808C to 1808C, 18Cmin , 20 min): t =106.54 (34%;
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shi), Wiley-VCH, Weinheim, 2004, pp. 129–152.
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2
R,3R), 107.33 (14%; 2R,3S), 107.61 (36%; 2S,3S), 108.19 (15%;
Chem. Eur. J. 2014, 20, 10484 – 10491
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Received: March 28, 2014
Revised: May 5, 2014
Published online on July 7, 2014
Chem. Eur. J. 2014, 20, 10484 – 10491
www.chemeurj.org
10491
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