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
[1]
[2]
[3]
[4]
C. Cativiela, M. D. Díaz-de-Villegas, Tetrahedron
Asymmetry 2007, 18, 569–623.
C. Toniolo, M. Crisma, F. Formaggio, C. Peggion,
Biopolymers 2001, 60, 396–419.
D. J. Leonard, J. W. Ward, J. Clayden, Nature 2018, 562,
105–109.
C. Danzin, P. Casara, N. Claverie, B. W. Metcalf, J. Med.
Chem. 1981, 24, 16–20; C. D. McCune, M. L. Beio, J. M.
Sturdivant, R. de la Salud-Bea, B. M. Darnell, D. B.
Berkowitz, J. Am. Chem. Soc. 2017, 139, 14077-14089.
D. B. Berkowitz, W.-J. Jahng, M. L. Pedersen, Biorgan.
Med. Chem. Lett. 1996, 6, 2151–2156.
J. P. Scannell, D. L. Pruess, T. C. Demny, L. H. Sello, T.
Williams, A. Stempel, J. Antibiot. 1972, 25, 122–127.
M. J. Tisdale, Biochem. Pharmacol. 1980, 29, 501–508.
D. Seebach, H. M. Bürger, C. P. Schickli, Liebigs Ann.
Chem. 1991, 669–684.
J. Clayden, E. W. Collington, S. Warren, Tetrahedron Lett.
1993, 34, 1327–1330.
J. Clayden, A. B. McElroy, S. Warren, J. Chem. Soc. Perkin
Trans 1 1995, 1913–1934.
D. B. Berkowitz, J. M. McFadden, M. K. Sloss, J. Org.
Chem. 2000, 65, 2907–2918.
M. C. Jones, S. P. Marsden, D. M. M. Subtil, Org. Lett.
2006, 8, 5509–5512.
is supported by chelation of the [K+18-c-6] counterion.
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
of the carbanion, either by antarafacial counterion migration
involving a “windscreen wiper” motion of [K+18-c-6], or by the
approach of a second counterion (see SI). Rotation around the
former double bond in the carbanionic intermediate, which would
erode the selectivity, is prevented by steric interactions.
Progression towards the migration product E-3 by syn-
elimination is then thermodynamically favorable, and results in
retention of double bond geometry.
[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
T. Weber, R. Aeschimann, T. Maetzke, D. Seebach, Helv.
Chim. Acta 1986, 69, 1365–1377.
sealed tube
110-115 °C
18 h
2. Boc2O
N
OH
OH
Me
5
12
M. Di Giacomo, V. Vinci, M. Serra, L. Colombo,
Tetrahedron Asymmetry 2008, 19, 247–257.
D. Ma, W. Zhu, J. Org. Chem. 2001, 66, 348–350.
A. Rubio, J. Ezquerra, Tetrahedron Lett. 1995, 36, 5823–
5826.
E. Tayama, T. Igarashi, H. Iwamoto, E. Hasegawa, Org.
Biomol. Chem. 2012, 10, 339–345.
D. Uraguchi, Y. Ueki, A. Sugiyama, T. Ooi, Chem. Sci.
2013, 4, 1308–1311.
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
A. Armstrong, D. P. G. Emmerson, Org. Lett. 2011, 13,
This article is protected by copyright. All rights reserved.