Asymmetric and Geometry-Selective α-Alkenylation of α-Amino Acids

Article abstract of DOI:10.1002/anie.201813984

Both E- and Z-N′-alkenyl urea derivatives of imidazolidinones may be formed selectively from enantiopure α-amino acids. Generation of their enolate derivatives in the presence of K⁺ and [18]crown-6 induces intramolecular migration of the alkeny

Full text of DOI:10.1002/anie.201813984

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Asymmetric and Geometry-selective α-Alkenylation of α-Amino
Acids
Authors: Hossay Abas, Josep Mas-Roselló, Mostafa Mahmoud
Amer, Derek J. Durand, Robin R. Groleau, Natalie Fey, and
Jonathan Clayden
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813984
Angew. Chem. 10.1002/ange.201813984
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10.1002/anie.201813984
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric and Geometry-selective α-Alkenylation of α-Amino
Acids
Hossay Abas, Josep Mas-Roselló, Mostafa Mahmoud Amer, Derek J. Durand, Robin R. Groleau,
Natalie Fey, Jonathan Clayden*
Abstract: Both E- and Z-N’-alkenyl urea derivatives of
imidazolidinones may be formed selectively from enantiopure α-
amino acids. Generation of their enolate derivatives in the presence
of K+ and 18-crown-6 induces intramolecular migration of the alkenyl
group from N’ to Cα with retention of double bond geometry. DFT
calculations indicate a partially concerted substitution mechanism.
Hydrolysis of the enantiopure products under acid conditions reveals
quaternary α-alkenyl amino acids with stereodivergent control of
both absolute configuration and double bond geometry.
enriched α-arylated quaternary amino acids by combining the
electronically versatile intramolecular SNAr chemistry
characteristic of N-aryl ureas[20,21] with Seebach’s ‘self-
regeneration of stereocenters’ methodology (Scheme 1a).[22] We
have found that N’-alkenyl groups likewise migrate from N’to
C within anionic derivatives of ureas,[23,24] and we now report a
practical method for the α-functionalisation of amino acids with
alkenyl substituents (Scheme 1b) in which both the absolute
configuration of the stereogenic centre and geometric
configuration of the double bond are controlled.
N’-Alkenylureas 3 may be made by isomerization of their
N’-allyl congeners,[25] so we began by preparing N’-allylureido
Introducing a fourth substituent to the α-carbon of amino acids
confers valuable structural and functional properties on their
derivatives.[1] These quaternary amino acid residues promote
helical structures and increase the proteolytic stability of
peptides and proteins.[2] While there are many methods for the
α-alkylation of amino acids, the introduction of unsaturated (sp2)
substituents at this position has proved more challenging
synthetically.[3] α-Alkenyl α-amino acids are nonetheless
themselves an important class of structures, displaying a wide
range of biological activities such as inhibition of decarboxylase
enzymes,[4,5] or antibiotic[6] and anticarcinogen[7] activity.
imidazolidinones
2
(Scheme
2)
from
L-alanine. Either the syn or the anti diastereoisomer of 2a could
be made selectively from a common imine intermediate 1a by
choice of conditions, with acylation of the imine with a carbamoyl
chloride at elevated temperatures giving syn-2a,[3] and anti-2a
being obtained by acylating N-methylallylamine with the anti
carbamoyl chloride generated using phosgene and pyridine.[26]
Me
N
Me
Me
O
Me
O
N
S
N
Me
N
Me
S
O
N
O
Method c
Method d
S
N
S
N
S
N
O
O
t-Bu
Me
anti-2a 81%,
>95:5 anti:syn
N
t-Bu
(a) Published work: Asymmetric α-arylation of amino acids by intramolecular SNAr reactions
t-Bu
Me
Me
intra-
molecular
SNAr
Ar
(E,2S)-3a 89%
>95:5 E:Z; >95:5 anti:syn
(Z,2S)-3a 71%
<5:95 E:Z; 25:75 anti:syn
Ar
Ar
Me
R
R
R
R
N
hydrolysis
Method a
N
O
Me
O
O
H2N
COOH
N
N
H2N
COOH
O
HN
Me
Me
S
CO2Me
O
N
α-aryl quaternary
amino acid
N
1a 84%
t-Bu
t-Bu
Me
Me
H2N
HN
t-Bu
Method b
Me
(b) This Work: Asymmetric and geometry-retentive α-alkenylation of amino acids
intramolecular
vinylic
substitution
Me
O
Me
Me
N
N
Me
S
Me
R
N
O
Me
Me
hydrolysis
R
N
R
N
R
N
R
S
O
N
R
O
O
O
N
Method d
O
Method c
O
N
R
N
HN
Me
O
H2N
COOH
O
N
H2N
COOH
N
N
N
t-Bu
t-Bu
α-alkenyl quaternary
t-Bu
Me
t-Bu
Me
Me
t-Bu
Me
Me
syn-2a 55%,
<5:95 anti:syn
amino acid
(E,2R)-3a 95%
>95:5 E:Z; <5:95 anti:syn
(Z,2R)-3a 98%
<5:95 E:Z; 10:90 anti:syn
Scheme 1. Arylation and alkenylation of amino acid derivatives by N’ → C
migration across a urea tether.
Scheme 2. Stereodivergent formation of N’-alkenylureido imidazolidinones.
Method a: 1. COCl2 (1.5 equiv) THF, 2 h, rt; 2. pyridine (2 equiv), 16 h, rt. 2.
N’-Me-N’-allyl amine (1.1 equiv), Et3N (1.2 equiv), MeCN, rt. 2-16 h. Method b:
1. N’-Me-N’-allylcarbamoyl chloride (1.2 equiv), DMAP (5 mol%), 1,2-DCE
(1,2-dichloroethane), reflux, 4 d. Method c: RuHClCO(PPh3)3 (5 mol%), THF,
70 °C, 16 h. Method d: 1. LDA (3 equiv), THF, –78 °C, 1 h; 2. (t-Bu)3C6H2OH
(3 equiv).
Existing synthetic approaches to enantiopure α-alkenylated
amino acid derivatives rely on multi-step reaction sequences,[8–
12]
typically requiring the introduction of a functionalised chain
(such as an alcohol or an alkyl selenoxide) at the α position,[13–15]
the use of activated acetylene electrophiles,[16–18] or [2,3]-
sigmatropic rearrangements of allylic amines.[19] We recently
reported[3] a direct and general synthesis of enantiomerically
The N-allyl ureas 2 were isomerized to the E-alkenyl ureas E-3
with a Ru catalyst and to Z-alkenyl ureas Z-3 by γ reprotonation
of the Z-configured allyllithium derivative of 2 with a bulky proton
source (Scheme 2).[24,27] These methods allowed the
stereodivergent formation of four stereoisomers of 3a as starting
materials for alkenyl migration having either 2R or 2S
configuration at the tert-butyl-bearing centre and either E or Z
double bond geometry.
[*]
Dr. H. Abas, Dr. J. M-Roselló, M. M. Amer, D. Durand, R. R.
Groleau, Dr. N. Fey, Prof. J. Clayden
School of Chemistry
Cantock’s Close, Bristol BS8 1TS (UK)
E-mail: j.clayden@bristol.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201813984
Angewandte Chemie International Edition
COMMUNICATION
Table 1. N → C migration of an E-alkenyl substituent.
propose that this selectivity arises because an allyl anion 7 is
formed that may be reprotonated either by an intramolecular Z-
O
selective 1,7-proton transfer shift, or by
unselective intermolecular proton
a
geometrically
N
RMeN
alkenyl
migration
O
transfer from
N
Me
t-Bu
hexamethyldisilazane. Following this rationale, we added 1
equiv. KHMDS slowly over 30 mins to limit the amount of
disilazane in the reaction mixture and hence favour selective
intermolecular proton transfer (entry 4). These conditions gave
63% of the Z-migrated product, with only trace amounts of the E
isomer (94:6 Z:E).
base, THF
t h, T °C
Me
N
Me
N
E-5a
O
N
O
N
O
O
N
N
acyl shift,
ring opening
O
N
N
t-Bu
Me
t-Bu
Me
Me
(E,2S)-3a
(E,2S)-4a
O
HN
Me
t-Bu
6
Table 2. N → C migration of a Z-alkenyl substituent.
Entry
Basea
Additive
t, T
Recovered
Yield
Yield
6
E-3a [%][b]
E-5a
[%][b,c]
–
[%][b]
50d
anti-2a
1. KHMDS, 18-crown-6
THF, t h, 0 °C
(Z,2S)-3a
1. KHMDS, 18-crown-6
THF, t h, 0 °C
1
2
3
LDA
–
–
–
2 h, 0 °C
2 h, 0 °C
4 h, 20 °C
–
>95e
–
KHMDS
KHMDS
–
–
Me
intra-
molecular
proton shift
O
N
H
Me
K
N
alkenyl
38
30
O
migration
N
N
Me2N
O
O
O
N
O
N
N
Me
4
5
KHMDS 18-c-6f,g 0.5 h, 0 °C
KHMDS 18-c-6f,i
4 h, 0 °C
–
–
60, 54h
–
–
N
t-Bu
t-Bu
Me
2. MeI
t-Bu
Me
75h, 84h,i,j
7
Z-5a
(Z,2S)-4a
[a] LDA = lithium diisopropylamide (2 equiv; 0.6 M in THF) added to 3a in
THF, or 3a in THF added to KHMDS = potassium hexamethyldisilazide (2
Entry
SM
equiv
t
yield 5a
Z:E[c]
equiv; 1.0
M
in THF). [b] Yield determined by 1H NMR using
KHMDS[a]
2
[%][b]
70
hexamethylbenzene as internal standard except entry 5. [c] >95:5 E:Z; >95:5
dr. R = H except entry 5. [d] Also formed in 83% yield in presence of DMPU.
[e] Anti diastereoisomer. [f] 18-c-6 added as a 1 M solution in THF. [g] 10
equiv. [h] Isolated yield. [i] 2.2 equiv. [j] MeI added after 4 h at 0 °C; R = Me.
1
2
3
3a
2a
2a
4 h
4 h
1 h
>95:5
85:15
>95:5
2
66
0.5
34[d]
The N → C migration of the alkenyl groups of 3 was explored
using (E,2S)-3a (Table 1). Treatment with LDA gave an enolate
4a, but at 0 °C this enolate underwent 1,2-acyl transfer of the
carbamoyl group followed by ring opening give the imine 6 (entry
1). KHMDS promotes aryl migration to enolates,[3] but was
insufficiently basic to deprotonate the starting material at 0 °C
(entry 2). At 20 °C KHMDS delivered a single diastereoisomer of
5a, still accompanied by 30% of the unwanted acyl migration
product 6 (entry 3). The key to selective migration turned out to
be 18-crown-6 (18-c-6), which disfavoured the unwanted
formation of 6: KHMDS with 10 equiv 18-c-6 gave 5a in 60%
yield after 30 min (entry 4), rising to 75% yield after 4 h with 2.2
equiv 18-c-6 (entry 5). Purification of the product (and eventual
conversion to the free amino acid) was simplified by quenching
the product with methyl iodide, which gave the rearranged N,N-
dimethylurea E-5a (R = Me) in 84% yield. The product E-5a (R =
Me) was formed as a single (E,S,S) diastereoisomer, with
migration of the alkenyl group to the less hindered face of the
imidazolidinone and retention of E double bond geometry.
These optimal conditions were applied to the Z-isomer (Table
2, entry 1) using a mixture of (Z,2S)-3a (Scheme 1) epimeric at
the α-stereocentre, but configurationally uniform at the tert-butyl-
bearing centre. Migration of the Z alkene was successful, giving
a single diastereoisomer of Z-5a in 70% yield (the migration is
diastereoselective) and, remarkably, as a single Z-geometrical
isomer (the migration is geometrically stereospecific).
Strong base promotes both the isomerisation of the N-allylurea
starting material to the Z alkene and the subsequent migration
step, so a three-step, one-pot transformation of anti-2a to 5a
was explored. Under the optimized migrating conditions (Table
2, entry 2), N-allyl imidazolidinone 2a gave 66% of the desired
product 5a, but with a Z:E ratio of 85:15 ratio. 0.5 Equiv KHMDS
gave only 34% of 5a, but with >95:5 Z:E selectivity (entry 3). We
4
2a
1[e]
1 h
63
94:6
[a] KHMDS added to substrate + 3 equiv. 18-crown-6 in THF over 5 mins
unless otherwise stated. [b] Isolated yield. [c] From 1H NMR of crude reaction
mixture. [d] 55% unreacted starting material recovered. [e] KHMDS added
over 30 mins.
The alkenylation was explored with a range of natural and
non-natural amino acids (Scheme 3). All four possible isomers of
L-alanine derived ureido imidazolidinone 5a were made with
retention of the double bond geometry. A further range of
imidazolidinones derived from amino acids bearing alkyl (5b),
arylalkyl (5c), unsaturated (5d), benzylic (5e) and branched (5f)
side chains likewise rearranged successfully, giving consistently
high yields of the Z substituted products in which the alkene has
migrated anti to the tert-butyl group. Notably, the bulky leucine-
derived imidazolidone (Z,2S)-3f was Z-alkenylated to give Z-5f
in 77% with complete diastereocontrol, and an X-ray crystal
structure[28] of the product confirmed its stereochemistry.
Functionalised side chains were tolerated, with Z-alkenylated
derivatives of L-methionine Z-5g, Z- L-Tyr 5h, Z- L-dopa 5i, and
Z- L-Trp derivatives 5k all forming with high yield, excellent dr
and full Z selectivity.
The E-isomers E-5b-5i were obtained in moderate to good
yields, with the exception of the hindered L-Leu-derived
imidazolidinone E-5f. Non-aromatic substrates displayed
excellent retention of the E double bond geometry during the
migration, but Phe and its congeners displayed lower selectivity.
In contrast to the Z isomers, the diastereoselectivity of the
rearrangement depended on the steric bulk of the amino acid
side chain, dropping from >95:5 dr with alanine-derived E-5a to
74:26 dr for E-5e and 60:40 dr for E-5b. With leucine-derived E-
5f, the major product became the diastereoisomer with the
alkenyl group cis to the bulky tert-butyl group. We assume that
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10.1002/anie.201813984
Angewandte Chemie International Edition
COMMUNICATION
the less sterically demanding
E
alkenyl groups favour
a
This observation led us to expect that more bulky alkenes
would migrate more diastereoselectively, so we looked to
expand the scope of the N-alkenylureas that undergo the
rearrangement. Three methods for the synthesis of N-
alkenylureas,[24,25] are shown in Scheme 4: starting materials 3
lacking a 1-substituent were most readily prepared by the
sulfinate-promoted condensation of the urea 8 with an aldehyde
(Method a).[29,30] This method failed with ketones, so 1,1-
disubstituted alkenes (eg 3m) were instead made by acylation of
an N-methyl ketimine with the carbamoyl chloride 9.
Alternatively, the one-pot method from Scheme 2 allowed
access to complex variants directly from their N-allyl isomers.[31]
geometry where the amino acid side chain, especially if hindered
(i.e. R > Me) competes for the anti relationship with the tert-butyl
group.
Me
O
Me
O
O
O
N
N
R
R
a
R
a
R
S
Me2N
t-Bu
N
Me2N
t-Bu
N
N
S
N
S
O
O
O
O
N
N
N
N
t-Bu
t-Bu
Me
Me
Me
Me
(E,2S)-3
E-5
(Z,2S)-3
or (Z,2R)-3
Z-5
or (E,2R)-3
or ent-E-5
or ent-Z-5
Conditions a: 1. KHMDS (2 equiv), 18-crown-6 (2.2 equiv), THF, 0 °C; 2. MeI, 1 h, 0 °C
O
O
O
1. R'CHO, p-TolSO2Na
H2O, HCO2H, rt, 24 h
2. DBU, THF, 1 h, rt
3. NaH, MeI, THF
NH2
R
Me2N
N
Me2N
t-Bu
N
Me2N
N
O
O
O
O
N
S
t-Bu
Method a
O
N
N
N
t-Bu
t-Bu
N
Me
Me
Me
Me
E-5a, 84%
>95:5 dr; >95:5 E:Z,
97:3 er
ent-E-5a, 80%
>95:5 dr; >95:5 E:Z,
>99:1 er
Z-5a, 70%
8
>95:5 dr; <5:95 E:Z,
[63%; >95:5 dr; 6:94 E:Z]b
>99:1 er
Method d
Me
Method b
R'R''C=NMe
KI, lut
1. KHMDS,
18-c-6,
THF, 0 °C
Cl
N
R
R
O
R
Z or E
Z or E
O
N
S
t-Bu
O
N
S
Me2N
t-Bu
N
O
O
O
Ph
O
O
O
µw, 120 °C
4 h
2. MeI
1 h, 0 °C
N
N
N
t-Bu
Me
Me
Me2N
N
Me2N
N
Me2N
N
Me
3
9
O
O
O
5
O
R
N
N
N
t-Bu
t-Bu
t-Bu
Me
Me
Z-5b, 82%c
94:6 dr; <5:95 E:Z
E-5b, 30%+29%d
60:40 dr; >95:5 E:Z
Me
Z-5c, 76%
>95:5 dr; <5:95 E:Z
E-5c, 51%+26%d
63:37 dr; >95:5 E:Z
Method c
R'
N
N
O
ent-Z-5a, 72%
>95:5 dr; <5:95 E:Z,
>99:1 er
S
Me
t-Bu
N
1. KHMDS, 18-c-6, THF, 0 °C
2. MeI, 1 h, 0 °C
10
Me
Z or E
Z or E
Z or E
O
O
S
O
O
O
Me2N
N
Me2N
N
O
O
Me2N
N
Me2N
N
Me2N
N
O
O
O
N
Me
N
t-Bu
t-Bu
5m, 66%b,d; >95:5 dr
N
N
N
Me
t-Bu
t-Bu
t-Bu
5l, 82%a,d; 67:33 dr
Me
Me
Me
X-ray crystal
structure of 5m
Z-5d, 72%
Z-5f, 77%
>95:5 dr; <5:95 E:Z
E-5f, 30%
Z-5g, 96%
Ph
>95:5 dr; <5:95 E:Z
E-5d, 67%c
>95:5 dr; <5:95 E:Z
E-5g, 41%+16%d
69:31 dr; >95:5 E:Z
78:22 dr; 77:23 E:Ze
24:76 dr; >95:5 E:Z
O
O
Me2N
N
Me2N
N
O
O
N
N
t-Bu
t-Bu
Me
5n, 72%a,d; 95:5 dr
Me
5o, 52%c
>95:5 dr; >95:5 E:Z
X-ray crystal
structure of 5o
MeO
X-ray crystal
structure of Z-5f
OMe
X-ray crystal
structure of Z-5g
OBn
O
Z or E
Z or E
Me2N
N
O
O
from (S)-citronellal
O
O
N
Ph
O
t-Bu
Me2N
t-Bu
N
Me
5p, 43%a,d, 42%c
>95:5 dr
Me2N
N
N
O
Me2N
t-Bu
N
O
N
5q, 56%c
>95:5 dr
N
t-Bu
Me
Me
Me
H
O
H
Z-5e, 91%
>95:5 dr; <5:95 E:Z
E-5e, 50%
Z-5h, 78%
>95:5 dr; <5:95 E:Z
E-5h, 59%
H
OMe
O
74:26 dr; major dia. 77:23 E:Z
67:33 dr; major dia. 80:20 E:Z
Me2N
N
H H
O
Me2N
t-Bu
N
MeO
OMe
O
Me
N
F
N
N
t-Bu
5s, 32%+46%a,f; >95:5 dr
from estrone
5r, 47%+20%a,e; >95:5 dr
Me
Me
O
O
O
Scheme 4. N → C alkenylation with a range of alkenes
Me2N
N
Me2N
N
Me2N
N
O
O
O
[a] Starting material 3 by Method a; [b] Starting material 3 by method b; [c]
By method c; [d] By method d. [e] Isolated E and Z isomers from a 75:25 E:Z
mixture of starting materials. [f] Isolated E and Z isomers from a 40:60 E:Z E:Z
mixture of starting materials.
N
N
N
t-Bu
t-Bu
t-Bu
Me
Z-5i, 90%
>95:5 dr; <5:95 E:Z
Me
Me
Z-5j, 45%
>95:5 dr; <5:95 E:Z
Z-5k, 74%
>95:5 dr; <5:95 E:Z
Scheme 3. Asymmetric stereodivergent alkenylation[a]
Scheme 4 shows the results of migrating these substituted
alkenes. Mono-, di- and tri-substituted alkene products 5l-q were
obtained in moderate to high yields, with complete geometrical
fidelity and (with the exception of the simple vinylated product 5l)
[a] Yields and selectivities by conditions a unless otherwise indicated. [b] By
one-pot isomerisation-migration method: 1. 18-c-6 (2.2 equiv), KHMDS (1-3
equiv), THF, 0 °C; 2. MeI, 1 h, 0 °C. [c] Isolated yield of pure major (S,S)-
diastereoisomer. [d] Isolated yields of major and minor diastereoisomers
respectively. [e] Starting from (2S)-3d as an 85:15 E:Z mixture.
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10.1002/anie.201813984
Angewandte Chemie International Edition
COMMUNICATION
Hydrolysis of the products 5 in acid[32] afforded the HCl salts
of the amino acids without compromising the alkene geometry or
enantiomeric purity (Scheme 6). Treatment with Boc2O returned
readily isolable N-protected α-alkenylated amino acids in good
yields.
with complete diastereoselectivity. The steroid-derived 3r and
the terpene-derived 3s rearranged stereospecifically (the
product ratio matched the starting material ratio) to give the
unusual ‘hybrid’ steroid amino acid derivative 5r and the
terpenoid amino acid derivative 5s.
The detailed mechanism of the reaction is intriguing. The
migrating alkenes are electron-rich N-acylenamines typically
unsusceptible to attack by nucleophiles. A similar lack of
requirement for electron-deficient activating groups was noted in
the corresponding arylation reactions,[3] where a conformational
preference for the nucleophilic enolate to lie very close to the
aromatic ring seems to underlie the reactivity.
In summary, the enantioselective introduction of an alkenyl
substituent to the α position of an amino acid is made possible
by the diastereoselective rearrangement of an N’-alkenyl urea in
which double bond geometry is reliably retained. Various
stereoselective routes may be used to install the desired
configurations in the starting material, and, provided certain
conditions are met, the products are formed with excellent
stereocontrol. Hydrolysis to valuable Cα quaternary alkenyl
amino acids is possible by simple aqueous hydrolysis.
antarafacial
migration of
counterion
(E,2S)-3a
KHMDS
(E,S)-5a
MeI
Me
Me
18-c-6
H
K
H
H
Me
1.34
Me
K
(–)
K
(–)
1.43
H
1.40
1.34H
1.48
(–)
N1.55
1.67
Acknowledgements
Me
Me
N
Me
O
Me
H
MeN
H
K
(–)N
H
Me
Me
1.58
1.53
1.58
Me
O
N
O
N
O
(–)
(–)
N
O
N
O
O
O
syn
elimi-
nation
syn
addition
to C=C
This work was supported by the ERC and EPSRC, the EPSRC
Centre for Doctoral Training in Catalysis (EP/L016443/1),
Syngenta (CASE award to JM-R) and the Presidential
Leadership Program of Egypt (scholarship to MMA).
N
N
N
N
t-Bu
t-Bu
t-Bu
Me
E-1
t-Bu
Me
Me
Me
E-2
E-TS
37.18
41.36
E-3
energyb relative to E-1c
energyb relative to Z-1d
7.50
–90.96
–83.65
15.61
Scheme 5. Mechanism considered computationally.[a]
Keywords: α-Alkenylation
• Stereodivergent • Quaternary
[a] Calculated bond lengths given in Å. [b] Calculated relative Gibbs free
energies in kJ mol–1 [B3LYP-D3, 6-31+G(d), LACV3P on K, PCM (solvent=thf),
298 K]; [c] For reaction of E-3a; [d] For reaction of Z-3a.
Amino Acids • Rearrangement • DFT
We used standard DFT calculations (see SI for full
computational details) to probe the mechanism of reaction of E
and Z-3a, as set out [for (E,2S)-3a] in Scheme 5. After
deprotonation, the charge on the enolate oxygen is stabilized by
coordination to [K+18-c-6] to give E-1. Development of the
energetically accessible syn-carbometallation intermediate E-2
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A
transition state E-TS could be located that involved concerted
shortening of the C-C bond between the alkenyl group and Cα
(to 1.58 Å) and lengthening of the C-N bond (to 1.67 Å). E-TS
can be reached by an effective inversion of planar configuration
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[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
O
1. NaOH (1M)
H2O, dioxane
6M HCl
EtOH
R
R
R
O
O
Me2N
t-Bu
N
O
H2N
.HCl
11
BocHN
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sealed tube
110-115 °C
18 h
2. Boc2O
N
OH
OH
Me
5
12
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Ph
CO2H
[15]
[16]
Ph
N
Me
BocHN
CO2H
BocHN
BocHN
CO2H
BocHN
CO2H
BocHN
CO2H
(E,S)-12a, 70%
(E,S)-12e, 72%a (Z,S)-12e, 67%
(Z,S)-12a, 67%
[17]
[18]
[19]
(Z,S)-12k, 57%
Scheme 6. Hydrolysis to protected quaternary amino acids.
[a] Starting material and product are 77:23 E:Z
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10.1002/anie.201813984
Angewandte Chemie International Edition
COMMUNICATION
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[28]
Some epimerisation of the α centre also occurred, but this
turned out to be inconsequential for later steps in the
sequence.
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Raised temperatures (>150 °C) led to competing
intramolecular hydroamination of the alkene, to give
azetidine by-products.
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COMMUNICATION
R
α-alkenyl quaternary amino acids
Hossay Abas, Josep Mas-Roselló,
RE
H2N
COOH
RZ
Mostafa Mahmoud Amer, Derek J.
Durand, Robin R. Groleau, Natalie Fey,
Jonathan Clayden*
E or Z
R
stereodivergent formation
of enamido
imidazolidinone
R or S
COOH
H2N
hydrolysis
RE
E or Z
RZ
RE
R
RZ
N
Page No. – Page No.
RE
intramolecular
vinylic
substitution
RZ
R
Me
O
K
KHMDS
18-crown-6
R
N
Asymmetric and Geometry-selective
α-Alkenylation of α-Amino Acids
Me
O
O
N
O
O
N
N
0 °C, THF
Me2N
O
R or S
t-Bu
N
N
N
Me
t-Bu
t-Bu
Me
Me
Both E- and Z-N’-alkenyl urea derivatives of imidazolidinones may be formed
selectively from enantiopure α-amino acids. Generation of their enolate
derivatives in the presence of K+ and 18-crown-6 induces intramolecular
migration of the alkenyl group from N’ to Cα with retention of double bond
geometry. DFT calculations indicate a partially concerted substitution mechanism.
Hydrolysis of the enantiopure products under acid conditions reveals quaternary
α-alkenyl amino acids with stereodivergent control of both absolute configuration
and double bond geometry.
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