Geometry-Retentive C-Alkenylation of Lithiated α-Aminonitriles: Quaternary α-Alkenyl Amino Acids and Hydantoins

Article abstract of DOI:10.1002/anie.201704908

α-Amino nitriles tethered to alkenes through a urea linkage undergo intramolecular C-alkenylation on treatment with base by attack of the lithionitrile derivatives on the N′-alkenyl group. A geometry-retentive alkene shift affords stereospecifically the E

Full text of DOI:10.1002/anie.201704908

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition
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Accepted Article
Title: Geometry-retentive C-alkenylation of lithiated α-aminonitriles:
quaternary α-alkenyl amino acids and hydantoins
Authors: Josep Mas-Roselló, Shuji Hachisu, and Jonathan Clayden
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704908
Angew. Chem. 10.1002/ange.201704908
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10.1002/anie.201704908
Angewandte Chemie International Edition
COMMUNICATION
Geometry-retentive C-alkenylation of lithiated α-aminonitriles:
quaternary α-alkenyl amino acids and hydantoins
Josep Mas-Roselló,[a] Shuji Hachisu[b] and Jonathan Clayden[a]*
Abstract: α-Amino nitriles tethered to alkenes through a urea
linkage undergo intramolecular C-alkenylation on treatment with
base by attack of the lithionitrile derivatives on the N’-alkenyl group.
The geometry-retentive alkene shift affords stereospecifically the E
or Z isomer of the 5-alkenyl-4-iminohydantoin products from the
corresponding starting E- or Z-N’-alkenyl urea, each of which may be
formed from the same N-allyl precursor by stereodivergent alkene
isomerisation. The reaction, formally a nucleophilic substitution at an
sp2 carbon atom, allows the direct regioselective incorporation of
mono-, di-, tri- and tetrasubstituted olefins at the α-carbon of amino
acid derivatives. The initially formed 5-alkenyl iminohydantoins may
be hydrolysed and oxidatively deprotected to yield hydantoins and
unsaturated α-quaternary amino acids.
stereoselectivity. The migration step was not only highly tolerant
of steric hindrance, but also proceeds with retention of double
bond geometry, allowing the synthesis of both E and Z-alkenyl
amino acids.
Previous work:
alkenyl migration[11]
aryl migration[10]
R1
O
R1
O
R1
R1
Me
Me
base
base
Ph
N
N
Z
N
N
R2
H
Z
Ph
H
H2N
H2N
R2
via
organolithium
or enolate
via
organolithium
X
R3
R3
X
Z = Ar,[10a] CN,[10b] CO2R,[10b-d] CONHR[10d]
This work:
O
R1
Me
N
N
CN
O
R1
H
R1
R2
Me
CO2H
base
N
N
R2
CN
H2N
E- or Z-
stereo-
selectivity
E or Z
Amino acids bearing alkenyl α-substituents are inhibitors of
amino acid decarboxylase and transaminase enzymes, being
used as antibiotics, anticarcinogens and herbicides.[1] They are
also important structurally, allowing in situ peptide modification
by olefin metathesis.[2] Sterically constrained α,α-disubstituted-α-
amino acids (α-quaternary amino acids) are likewise important
components of bioactive compounds, and their incorporation into
peptides favours helical secondary structures[3] and offers
increased resistance to chemical and enzymatic degradation.[4]
E or Z
stereospecific
alkenyl
migration
Me
O
R1
N
Cl
N
CN
R2
Scheme 1. Alkenylation of an aminonitrile by N to C migration in a urea
derivative
The study began with N'-alkenyl urea E-3a, made by E-
selective Ru-catalysed rearrangement of N-allyl urea 2a,[12,13]
formed from Strecker-derived carbamoyl chloride 1a (Scheme 2).
Table 1 shows the results of treating E-3a with base, with the
aim of migrating the alkenyl group to the position α to the nitrile.
In general, α-quaternary amino acids and their derivatives,
such as biologically important 5,5-disubstituted hydantoins,[5]
may be made from their tertiary counterparts by alkylation or
rearrangement.[6] In addition, a small number of transition-metal-
catalyzed methods for the arylation of amino acid derived
enolates have recently been developed.[7] However, a general
method for the direct α-C-alkenylation of amino acids or their
derivatives, even in a racemic fashion, is lacking. Existing
approaches to α-alkenylated amino acids require activated
acetylenes as precursors,[8] or install the alkene by a multi-step
procedure.[9]
RuHCl(CO)(PPh3)3
(5 mol%)
O
O
O
Me
Me
N
N
CN
N
CN
N
N
CN
Cl
NHMe
THF,
70 °C, 16 h
PMP
PMP
1a
2a
3a 87%
(E:Z = 94:6)
MeO
Scheme 2. Synthesis of the E-N’-alkenylureidonitrile starting material.
Table 1. Reaction conditions for E-alkenylation.
In this paper we present a method for introducing a C-
alkenyl substituent into an α-amino acid derivative by using a
urea tether to link an α-amino nitrile with an N'-alkenyl
substituent. Treatment of this ureidonitrile with base promotes
migration of the N'-alkenyl substituent from nitrogen to carbon, in
a reaction that bears comparison with other reported migrations
of unsaturated substituents across the urea function (Scheme
1).[10,11] Four alternative methods were used to make the starting
O
O
base
(Table 1)
Me
PMP
N
Me
N
NH
PMP
N
N
N
3a
+
N
N
CN
PMP
THF
Me
M
O
4a
5
3aM
entry
base[a]
additive
time, T
3a E:Z[b] 4a/%[c] (E:Z)[b]
5/%[c,d]
N’-alkenylureas, each having characteristic
E
or
Z
[a]
[b]
J Mas-Roselló, Prof J Clayden, School of Chemistry, University of
Bristol, Cantock's Close, Bristol BS8 1TS, UK;
j.clayden@bristol.ac.uk
Dr S Hachisu, Syngenta Agrochemicals, Jealotts Hill Research
Station, Bracknell, Berks RG42 6EY, UK
1
2
3
4
KHMDS
KHMDS[e]
sec-BuLi
–
–
–
3 h, -78 °C 94:6
1 h, 0 °C 94:6
2 h, -78 °C >95:5
17 (66:34)
75 (>95:5)
46[f] (>95:5)
93 (>95:5)
50
5
0[g]
0[g]
Supporting information for this article is given via a link at the end of
the document.
sec-BuLi DMPU[h] 2 h, -60 °C >95:5
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10.1002/anie.201704908
Angewandte Chemie International Edition
COMMUNICATION
6[h]
7
sec-BuLi
2 h, -78 °C
2 h, -78 °C
0[e]
27
0[e]
53
65
5
6
KHMDS[e]
sec-BuLi DMPU[h] 2 h, -60 °C 74:26
–
1 h, 0 °C
74:26
73 (85:15)
89 (80:20)
5
0[g]
sec-BuLi[i]
0[e]
[a]KHMDS = potassium hexamethyldisilazide (2.5 equiv; 1.0 M in THF); sec-
BuLi (2.1 equiv; 1.4 M in cyclohexane) added to 3a in THF. [b]By 1H NMR. [c]
[a]2.1 equiv in THF unless otherwise stated. [b]Recovered starting material.
[c]>95:5 Z by NMR of crude reaction mixture. [d] DMPU added, 10% by volume
in THF. [e]Undetectable in 1H NMR spectrum of crude reaction mixture. [f]1.0
equiv. [g]Quenched by dropwise addition of 2,4,6-tri-tert-butylphenol (2.2
equiv). [h]2,4,6-tri-tert-butylphenol (1.0 equiv) added dropwise after 30 min;
methanol (excess) added after 1.5 h. [i]Reaction carried out in Et2O.
[c]
Isolated yield. [d]5 isolated as a single diastereoisomer. [e]Inverse addition;
[f]3a recovered (51%), E:Z >95:5; [g]Undetectable in 1H NMR spectrum of
crude reaction mixture; [h]DMPU
pyrimidinone, 10% by volume.
= 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
KHMDS at –78 °C was evidently basic enough to form a
metallated nitrile 3aM:[13,14] the principal product of the reaction
of 3a was 5 (entry 1), which results from anionic cyclisation[11,15]
of 3aM onto the alkene. Nonetheless, a small amount of a C-
alkenylated product 4a was formed, the yield of which increased
significantly on raising the temperature to 0 °C (entry 2).
Iminohydantoin 4a results from migration of the N-alkenyl
function to the α-carbon of the aminonitrile, followed by
cyclisation of the resulting ureide anion onto the nitrile function
(see Scheme 6 for a detailed mechanistic discussion). To
minimise formation of cyclisation product 5, the base was
changed to sec-BuLi[10b] with the aim of eliminating the proton
The optimised conditions of Table 1 (sec-BuLi in 10:1
THF:DMPU at –60 °C) led to decomposition of 2a (Table 2, entry
1). However, with sec-BuLi at a lower temperature and in the
absence of DMPU, Z-4a was formed as a single geometrical
isomer (entry 2).. No significant difference in reaction outcome
was observed with only 1 equiv of base (entry 3), so we assume
that the pKa of proposed lithiated intermediates 2aLi and 3aLi
(Scheme 3) must be similar enough to allow the alkene
migration to occur from an equilibrium of these two anions.
Using LDA to facilitate the necessary proton transfers gave little
change in the reaction outcome (entry 4), but γ-reprotonation of
2aLi2 using 2,4,6-tri-tert-butylphenol as a bulky proton source
showed a slight improvement in the yield of Z-4a (entry 5).
Optimally, deprotonation 2a at –78 °C with 2.1 equiv. sec-BuLi
followed by the slow addition of 1 equiv of the phenol allowed full
conversion to a single geometrical isomer of the product Z-4a in
65% yield (entry 6). Z-4a is formed by a remarkable one-pot
sequence of Z-stereoselective alkene isomerisation, geometry
retentive C-alkenylation, and iminohydantoin cyclisation of 2a.
Replacement of THF by Et2O interrupted the alkenyl shift (entry
source from the reaction mixture (entry 3).
Raising the
temperature to –60 °C and further activating the intermediate
lithionitrile by adding the solvating agent DMPU[11,16] returned an
excellent yield of the C-alkenylated product 4a (entry 4).
With both bases, at the higher temperatures (entries 2, 4),
4a was formed with complete E selectivity. Nonetheless, the
formation of some Z-4a in entry 1 suggested that Z products
might be formed under certain conditions from Z alkenyl urea
starting materials. Indeed, repeating the reactions with both
KHMDS and sec-BuLi using samples of 3a containing 26% of its
Z isomer gave a significant proportion of the Z isomer of 4a
(entries 5, 6) suggesting that the alkene migration may be
stereospecific.
7).
Scheme
3
summarises
the
proposed
deprotonation/reprotonation pathways leading from 2a to 4a.
base
(Table 2)
2a
NH
Me
PMP
N
O
O
Li
N
Li
N
O
N
N
N
CN
N
Z-4a
To explore this possibility further necessitated a Z-selective
synthesis of the alkenylurea starting materials. N-Allyllithium
Me
Me
PMP
PMP
Z-3aLi
2aLi
in THF (entries 1-6)
in Et2O (entry 7)
OH
base
(Table 2)
derivatives of amides, carbamates and ureas adopt
a Z
t-Bu
t-Bu
O
Li
N
Z-3a + 2a
configuration to facilitate interaction between the Li cation and
the carbonyl donor.[13,17] Accordingly, the geometry of products
obtained from lithiation and reprotonation of N-allyl ureidonitrile
2a was explored (Table 2).
N
O
t-Bu
N
Li
Me
PMP
Me
2aLi2
N
N
CN
PMP
Scheme 3. One-pot stereoselective Z-olefin isomerisation, geometry retentive
Table 2. Reaction conditions for Z-alkenylation.
alkenylation and cyclisation.
O
base
(Table 2)
Combining the results of Tables 1 and 2 allowed us to make
a range of amino-acid-derived E- or Z-alkenyl iminohydantoins
4a-g carrying a range of side chains R1 by the stereodivergent
strategy illustrated in Scheme 4. From allyl ureas 2, Ru
chemistry[12,13] gave E products and allyllithium chemistry[13,17]
gave Z products. Derivatives bearing linear alkyl substituents
such as 2a and 2d gave 5-alkenylated iminohydantoins E-4a, Z-
4a and Z-4e in good yield. Bulkier α- and β-branched
substituents were also tolerated in valine derivative E-4b and
phenylalanine derivatives E- and Z-4c. α-Alkenyl proline-derived
E-4f (which of course lacks the p-methoxyphenyl N-protecting
group) was obtained in 88% yield as a single isomer. The
reaction sequence leading to Z-4a was telescoped even further
Me
NH
PMP
N
+
N
N
CN
2a
THF
N
PMP
Me
O
Z-3a
Z-4a
entry
1[d]
2
base[a]
time, T
2a[b] /%
Z-3a[c] /%
Z-4a[c] /%
sec-BuLi
sec-BuLi
2 h, -60 °C
2 h, -78 °C
0[e]
7
0[e]
7
0[e]
56
56
56
62
3
sec-BuLi[f] 1 h, -78 °C
14
3
0[e]
9
4
LDA
5 h, -78 °C
2 h, -78 °C
5[g]
sec-BuLi
11
0[e]
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10.1002/anie.201704908
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COMMUNICATION
R4
to a one-pot process in which N-allyl urea 2a forms under the
same basic reaction conditions as the alkenyl isomerisation and
migration (method e).[18]
Me
O
R1
R3
6h-n
N
O
R1
Me
R3
R1
R2
N
N
CN
R2
R3
PMP
b
NH
R4
Cl
N
CN
PMP
N
R2
1
PMP
N
R4
a
Steric hindrance at the α-position means that N-allyllithiums
3h-n
35-78%
Me
O
4h-n
bearing substituents α to
N are protonated to yield Z-
alkenylureas with complete regioselectivity.[13,17] Thus the
trisubstituted Z-alkenes 4f (R2=Me) and 4g (R2=Ph) were formed
in good yields from 2f and 2g by treating firstly under basic
conditions that avoid alkenyl migration (sec-BuLi in Et2O or NaH
in DMF), and then with sec-BuLi in 10:1 THF:DMPU at –60 °C.
Ph
NH
PMP
NH
PMP
NH
PMP
PMP
NH
Me
N
N
N
N
O
N
N
N
N
Me
O
Me
O
Me
O
4h 89%
4i 79%
4j 84%a
4k 55%; 1.2:1b
R2
R1
O
R1
E-selective method:
RuHCl(CO)(PPh3)3
Me
(method a)
f
O
R1
N
N
CN
PMP
NH
N
Me
N
N
CN
PMP
N
R2
PMP
PMP
NH
O
Me
PMP
NH
E-3a-d
78-91%, >95:5 E:Z
PMP
NH
R2
N
N
N
E-4
Z-selective
methods:
RLi or NaH
(methods b-d)
N
N
N
2a-e (R2 = H)
2f (R2 = Me)
2g (R2 = Ph)
O
Me
O
Me
O
Me
Method b from 2a, c, e
4l 35%c
4m 63%
4n 81%; 1.8:1d
R2
R1
N
NH
Method c or d
from 2f, g
PMP
N
O
R1
f
O
N
R1
O
R1
Me
O
Me
N
N
CN
c
4o,p
1
Z-4
N
CN
PMP
N
N
R2
NLi
Z-3f,g
O
PMP
OLi
PMP
65-71%, <5:95 E:Z
3o,p
93-98%
NH
3oLi, 3pLi
NHMe
One-pot Z-selective method: RLi (method e)
O
N-methylallylamine
PMP
NH
OH
PMP
NH
OH
Ph
N
N
E or Z
E or Z
N
N
PMP
NH
Me
PMP
NH
Me
NH
Me
PMP
NH
O
O
N
N
N
O
N
N
N
N
N
4o 68%
O
4p 56%
O
O
Me
E-4a 93%; >95:5 E:Za
Z-4a 65%b or 54%e; <5:95 E:Z
E-4b 78%; >95:5 E:Za E-4c 62%; >95:5 E:Za E-4d 88%; >95:5 E:Za
Z-4c 54%; <5:95 E:Zb
Methods: a 2,6-lutidine, microwave, KI, CH3CN, 110-140 °C, 2-4 h; b sec-BuLi
(2.1 equiv); THF, DMPU (10:1), –60 °C, 1-16 h; c sec-BuLi (3 equiv); THF,
DMPU (10:1), –60 °C, 3 h .[a]After 6 h at –40 °C; [b]As a 1.2:1 E:Z isomeric
mixture from 3k (E:Z = 1.8:1); configuration determined by NOE; [c]4l obtained
after 16 h at –20 °C as a single diastereoisomer; relative configuration not
determined; [d]As a 1.8:1 E:Z isomeric mixture from 3n (E:Z = 2.5:1); alkene
configuration determined by NOE.
Ph
PMP
NH
PMP
NH
PMP
NH
N
N
N
N
N
N
O
Me
O
Me
O
Me
Z-4g 53%; <5:95 E:Zd
Z-4f 81%; <5:95 E:Zc
Z-4e 61%; <5:95 E:Zb
[a]Method a: RuHCl(CO)(PPh3)3 (5 mol%), THF, 70 °C, 16 h; [b]Method b: (i)
sec-BuLi (2.1 equiv), THF, -78 °C, 30 min.; (ii) t-Bu3C6H2OH (1 equiv), THF,
1.5 h; [c]Method c: (i) sec-BuLi (2.1 equiv), Et2O, -78 °C, 30 min.; (ii) t-
Bu3C6H2OH (2.1 equiv), Et2O, 5 min [d]Method d: NaH (1.2 equiv), DMF, rt, 3
h; [e]Method e from N-methylallylamine: (i) n-BuLi (1 equiv); (ii) 1a, THF, rt, 16
h; (iii) sec-BuLi (2.1 equiv), THF, -78 °C, 30 min.; (iv) t-Bu3C6H2OH (1.1 equiv),
THF, 2 h. Method f: sec-BuLi (2.1 equiv), THF, DMPU (10:1), –60 °C, 2-3 h.
Scheme 5. Hydantoins from N’-alkenyl-N-ureidonitriles
Formally, the alkenyl migration is
a
stereoretentive
nucleophilic substitution at a carbon sp2 centre.[20] To elucidate
further mechanistic details of this unusual transformation, the
rearrangement of E-3a was followed by in situ IR spectroscopy
(React-IR) (Scheme 6).[21] The experiments were carried out
without DMPU in order to avoid obscuring the carbonyl region of
the spectrum. In THF at –60 °C, E-3a shows two absorptions at
1673 and 1659 cm-1 which disappear over a period of 5 min on
treatment with 1 equivalent of sec-BuLi, being replaced by two
absorptions at 1665 and 1620 cm-1. The same spectrum is
generated by treating E-3a with sec-BuLi in Et2O at –78 °C,
conditions under which no migration of the alkenyl group takes
place, so we assign these new absorptions to lithionitrile
intermediate E-3aLi. A second equivalent of sec-BuLi in THF
leads immediately to the appearance of new IR absorptions.
One appears at 1563 cm-1, which we assign to 6Li by analogy
with previously similar reported intermediates,[11] and two more
absorptions appear at 1725 and 1645 cm-1 corresponding to E-
4aLi. 6Li and E-4aLi may coexist as an equilibrium, which is
driven to product E-4a upon quench with MeOH at –60 °C. The
identity of E-4aLi was confirmed by deprotonation of product E-
4a (see supporting information for details). The necessity for two
Scheme 4. Stereodivergent alkenylation
Alternative routes to the starting N-alkenyl ureas[13,19] allowed
a range of amino nitrile ureas bearing differently substituted
alkenes, 3h-n, to be prepared from imines 6h-n (Scheme 5). N-
Alkenylureas 3h-n were treated with sec-BuLi in THF and DMPU
to yield 4h-n. The in situ generation of N’-vinyl ureas from 3o,p
by base-mediated ring-opening of morpholine followed by alkene
migration[19a] gave C-vinyl products 4o and 4p. Cyclic and
acyclic tri- and even tetra-substituted olefin products 4h-k were
obtained in good yields, though yields dropped for the bulky
cyclic alkene product 4l. Transfer of complex cyclic and acyclic
natural-terpene-like alkenes gave products such as 4m (derived
from terpinolene) and 4n (derived from 2H-citral).
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10.1002/anie.201704908
Angewandte Chemie International Edition
COMMUNICATION
equivalents of alkyllithium to promote the migration suggests a
constitutes a divergent E or Z-stereoselective method for the C-
role for the alkyllithium in coordinating the urea carbonyl and
alkenylation of natural and unnatural amino acids.
[10e,f]
assisting the conformational change from 3aLi to 3aLi2
that
is necessary for the reacting substituents to approach one
another.
E or Z
E or Z
E or Z
R
R
R
H2N
CO2H
E-9a 81%a
PMP
O
b
PMP
NH
O
c
a
N
O
N
O
HN
O
Li
O
LiR
N
N
N
O
O
sec-BuLi
sec-BuLi
Me
Me
Me
Me
Me
N
N
Me
H
PMP
N
N
CN
in THF
or Et2O
in THF
N
N
N
PMP
H2N
CO2H
Z-9a 76%b
PMP
E- or Z-4a (R = Me) E-7a 99%; Z-7a 82% E-8a 74%; Z-8a 78%
E-7c 83%; Z-7c 65%
NC
E-8cc; Z-8cc
E- or Z-4c (R = Ph)
H
Me
ν 1665, 1620 cm–1
Li
Me
E-3a
ν 1673, 1659 cm–1
E-3aLi
Me
E-3aLi2 not detected
LiR
Ph
LiR
H2N
CO2H
E-9c 56%a,d
NH
O
O
O
H
a
d
N
N
N
syn carbo-
metallation
bond
rotation
anti
elimination
N
H
CO2H
Me
Me
N
PMP
CN
PMP
CN
N
N
N
N
Li
O
Me
O
Me
E-9d 84%a
Ph
H
Me
H
E-8d 74%
E-4d
H
Me
Li
H2N
CO2H
Z-9c 60%b,d
5LiA not detected
5LiB not detected
LiR
O
LiR
O
Me
PMP
O
N
N
Me
N
PMP
N
O
b
PMP
NH
O
MeOH
a
c
N
HN
Me
PMP
N
H
N
Li
N
PMP
N
N
N
N
sec-BuLi x 2
LiN
O
Me
H2N
CO2H
9h 62%
O
Me
O
Me
HN
E-4a ν 1740, 1661 cm–1
in THF
Me
H
4h
7h 99%
8h 92%
6Li ν 1563 cm–1
E-4aLi ν 1725, 1645 cm–1
[a]>95:5 E:Z by NMR; [b]<5:95 E:Z by NMR; [c]Not isolated; [d]Yield over two
steps from 7c. Methods (a) HCl (2 M, aq.)/MeOH 1:1, reflux, 48-72 h; (b) CAN
(4 equiv), CH3CN/H2O 2:1, 0 °C, 5 min; (c) NaOH (4 M, aq.), reflux, 48 h; (d)
NaOH (4 M, aq.)/1,4-dioxane 1:1, reflux, 72 h.
Scheme 7. Conversion of products into hydantoins 8 and quaternary α-alkenyl
amino acids 9.
In summary, this general, direct C-alkenylation of tertiary
amino nitriles allows the connective synthesis of alkenylated
hydantoins. The method is sterodivergent, providing either the E
of the Z isomer of the product from the same starting materials,
themselves available by simple Strecker and acylation chemistry.
Quaternary α-alkenyl amino acids are formed as single E or Z
isomers upon cleavage of the hydantoin products.
Scheme 6. Intermediates in the rearrangement of E-3a identified by ReactIR.
For clarity, solvation/aggregation of metallated species is not shown.
The formation of imidazolidinone 5 with KHMDS as base
(Scheme 2) suggested the possible intermediacy of a structure
such as 5Li, but (as with most cases of the related aryl
Acknowledgements
This work was funded by the EPSRC and Syngenta (CASE
studentship to J.M-R.).
migrations[10a,e]
)
we were unable to identify absorptions
corresponding to such a cyclic intermediate. Nonetheless, the
geometry-retentive stereospecificity of the reaction suggests that
the detailed pathway of the alkenyl migration may involve the
addition-elimination reaction shown in Scheme 6, in which syn-
carbometallation[22] to give 5LiA is followed anti elimination from
conformer 5LiB.
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E-4d likewise hydroysed in acid to give hydantoin E-8d.
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α-alkenyl amino acids 9. No alkene isomerisation was detected
during the cleavage of 4 to 9. Thus, the route from 2 to 9, via 4,
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
sec-BuLi
THF
DMPU
CN
Josep Mas-Roselló,
Shuji Hachisu and
Jonathan Clayden*
O
R
E- or Z-alkenylurea
derivatives of
aminonitriles
Me
hydrol.
NH
R
N
R
N
N
Z
Z
H2N
Z
PMP
PMP
N
CO2H
>95% Z
undergo
O
R
Page No. – Page
No.
O
Me
stereospecific N to C
alkenyl migration on
treatment with base,
forming alkenyl
hydantoins or (on
hydrolysis) alkenyl
amino acids of
biological and
Cl
N
CN
E- or Z-
selective
vinyl urea
formation
geometry-defined
α-alkenylated
α-amino acids
geometry-retentive
N to C alkene migration
PMP
+
[Ru]
NHMe
Geometry-retentive
C-alkenylation of
lithiated α-
aminonitriles:
quaternary α-
sec-BuLi
THF
DMPU
O
R
E
E
hydrol.
NH
Me
Me
R
N
R
N
N
CN
PMP
PMP
N
H2N
CO2H
alkenyl amino acids
and hydantoins
E
>95% E
O
pharmaceutical
utility.
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