Decarbonylative radical coupling of α-aminoacyl tellurides: Single-step preparation of γ-amino and α,β-diamino acids and rapid synthesis of gabapentin and manzacidin A

Article abstract of DOI:10.1002/anie.201410186

A new radical-based coupling method has been developed for the single-step generation of various γ-amino acids and α,β-diamino acids from α-aminoacyl tellurides. Upon activation by Et₃B and O₂ at ambient temperature, α-aminoacyl tellurides were readily converted into α-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (-)-manzacidin A.

Full text of DOI:10.1002/anie.201410186

Angewandte
Chemie
DOI: 10.1002/anie.201410186
Radical Reactions
Hot Paper
Decarbonylative Radical Coupling of a-Aminoacyl Tellurides:
Single-Step Preparation of g-Amino and a,b-Diamino Acids and
Rapid Synthesis of Gabapentin and Manzacidin A**
Masanori Nagatomo, Hayato Nishiyama, Haruka Fujino, and Masayuki Inoue*
Abstract: A new radical-based coupling method has been
developed for the single-step generation of various g-amino
acids and a,b-diamino acids from a-aminoacyl tellurides.
Upon activation by Et3B and O2 at ambient temperature,
a-aminoacyl tellurides were readily converted into a-amino
carbon radicals through facile decarbonylation, which then
reacted intermolecularly with acrylates or glyoxylic oxime
ethers. This mild and powerful method was effectively
incorporated into expeditious synthetic routes to the pharma-
ceutical agent gabapentin and the natural product
(À)-manzacidin A.
A
lkyl amines and their derivatives are key substructures in
biologically important molecules, including alkaloids, pep-
tides, and pharmaceuticals. Accordingly, the development of
novel and efficient methods for their synthesis is an inten-
sively investigated field of utmost importance. Coupling
processes are particularly desirable, as a variety of complex
nitrogen-containing compounds can be readily produced by
assembly of simple fragments. Radical reactions are generally
powerful, yet highly chemoselective, and thus are potentially
suitable for such processes.[1]
Scheme 1. Previous and present methods for the generation of
a-amino carbon radicals, and possible reaction mechanism of the
decarbonylative radical coupling.
a-Amino carbon radicals have served as useful species for
[2]
À
the intermolecular construction of C C bonds (Scheme 1).
In the context of coupling methods, N,X-acetals and a-amino
acids have been typically used for the generation of a-amino
carbon radicals.[3] Namely, radical formation and subsequent
and tertiary a-amino carbon radicals from a-aminoacyl
tellurides. The high utility of this coupling process was
demonstrated by the single-step preparation of g-amino
acids and a,b-diamino acids and the syntheses of the
anticonvulsant gabapentin and the alkaloid (À)-manzaci-
din A.
À
coupling were realized by homolytic cleavage of the C X
[6]
bond of N,X-acetals (X = Br,[4] SePh,[5] SC( S)OEt ) or the
=
[8]
decarboxylation of a-amino acids (Z = H[7] or N(C S)R ).
=
Despite these important advances, most of these methods
suffer from a narrow substrate scope, which is due to the
chemical instability of the precursors or the employment of
relatively harsh conditions (e.g., high temperature, irradia-
tion). Therefore, the versatility of a-amino carbon radicals
has not been fully explored thus far. Herein, we report a mild
and generic method for the formation of primary, secondary,
To achieve facile radical generation at ambient temper-
À
ature, we planned to incorporate a weak C Te bond into the
substrate (Scheme 1).[9–11] As we presumed that the C Te
À
bond of a N,Te-acetal would easily undergo heterolytic
cleavage by electron donation from the nitrogen lone pair,
the carbonyl group was inserted between the a-amino carbon
À
atom and the PhTe group. C Te homolysis of acyl telluride
1 would first lead to acyl radical A;[12] decarbonylation would
then give rise to requisite a-amino carbon radical B.
Intermediate B would react intermolecularly with acrylate
2a or glyoxylic oxime ether 4 to provide protected g-amino
acid 3 and a,b-diamino acid 5, respectively. A prerequisite to
realize this scenario is that decarbonylation from A occurs
prior to the intermolecular reaction of A with 2a or 4.
Although the rate of decarbonylation is generally slower than
that of decarboxylation, stabilization of the resulting radical B
[*] Dr. M. Nagatomo, H. Nishiyama, H. Fujino, Prof. Dr. M. Inoue
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: inoue@mol.f.u-tokyo.ac.jp
[**] This research was financially supported by the Funding Program for
Next Generation World-Leading Researchers (JSPS), a Grant-in-Aid
for Scientific Research (A) to M.I., and a Grant-in-Aid for Young
Scientists (B) (JSPS) to M.N.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410186.
[13]
À
is known to accelerate C C homolysis.
Therefore, we
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Table 1: Synthesis of g-amino acid derivatives from 1a and 2a–f.[a]
expected that the orbital interaction between the alkyl radical
and the adjacent nitrogen lone pair in B would favorably
affect the rapid formation of B from A.[14]
Eleven structurally distinct a-aminoacyl tellurides 1a–k
were prepared from readily available N-Boc-protected
a-amino acids 6a–k in a single step (Scheme 2). For instance,
Entry
2
R4
R5
R6
3
Yield [%]
1
2
3
4
5
6
2a
2b
2c
2d
2e
2 f
H
H
H
H
H
CO2Me
H
Me
Me
Me
Bn
Bn
Me
3aa
3ab
3ac
3ad
3ae
3af
78
61
71
50
75
79
OAc
NPhth
F
CF3
H
[a] Conditions: 1a (1 equiv), 2 (2 equiv), Et3B (3 equiv), (Me3Si)3SiH
(3 equiv), CH2Cl2 (0.02m), air, RT. Phth=phthaloyl.
tively. Moreover, the reaction of 1a with dimethyl fumarate
(2 f) furnished b-methoxycarbonyl-g-amino acid 3af
(entry 6). Remarkably, these reactions enabled the one-step
construction of the neurotransmitter g-aminobutyric acid
(GABA) in a protected form (3aa) as well as of its a- or b-
functionalized artificial analogues 3ab–af.[18]
À
The synthetic generality of the decarbonylative C C bond
formation was further corroborated by applying 1b–k as the
radical donors and methyl acrylate 2a as a radical acceptor
(Scheme 3). The corresponding primary a-amino carbon
radicals from glutamic acid derived 1b and dihydroxyphenyl-
alanine-derived 1c were efficiently formed in the presence of
Scheme 2. Preparation of a-aminoacyl tellurides. Reagents and condi-
tions: 6 (1 equiv), isobutyl chloroformate (1.2 equiv), N-methylmor-
pholine (1.2 equiv), THF (0.2m), 08C, 30 min; (PhTe)2 (1 equiv),
NaBH4 (3 equiv), THF (0.2m), MeOH (2m), 08C, 30 min; RT, 30 min.
Boc=tert-butyloxycarbonyl, TBS=tert-butyldimethylsilyl.
N-Boc-protected glycine 6a was transformed into its acti-
vated ester by condensation with isobutyl chloroformate, and
was then treated in situ with PhTeNa, which had been
prepared from (PhTe)2 and NaBH4, providing a-aminoacyl
telluride 1a. Tellurides 1b–k were obtained in the same
fashion, and all of the products were found to be stable to air,
light, and silica gel. It is also noteworthy that Boc (1a–k), TBS
(1c,e), and acetonide (1k) groups were all tolerated under
these conditions.
Next, we explored the intermolecular radical 1,4-addition
of glycine derivative 1a to various acrylates (Table 1). Acyl
tellurides had previously been converted into the acyl radicals
either by thermolysis (> 1008C) or UV photolysis.[15] We
[16]
À
found that a combination of Et3B and O2 promoted C Te
bond homolysis under significantly milder conditions.
Namely, when 1a and methyl acrylate (2a; 2 equiv) were
treated with Et3B (3 equiv) and (Me3Si)3SiH (3 equiv) in
CH2Cl2 under air, g-amino acid 3aa was smoothly produced at
ambient temperature within 15 minutes (entry 1). The poten-
tial side product between the acyl radical and 2a was not
detected, confirming that decarbonylation from the acyl
radical proceeded even at room temperature. The primary
radical prepared from 1a underwent intermolecular reactions
with acrylates 2b, 2c,[17] 2d, and 2e (entries 2–5) to produce
the protected a-hydroxy (3ab), a-amino (3ac), a-fluoro
(3ad), and a-trifluoromethyl (3ae) g-amino acids, respec-
Scheme 3. Synthesis of g-amino acid derivatives from 1b–k and 2a.
Conditions: 1 (1 equiv), 2a (2 equiv), Et3B (3 equiv), (Me3Si)3SiH
(3 equiv), CH2Cl2 (0.02m), air, RT. [a] racemate. [b] 15:1 d.r.
2
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Et3B, (Me3Si)3SiH, and air, leading to 3b and 3c, respectively,
after their addition to 2a. Under the same conditions, proline
derivatives 1d and 1e and pipecolinic acid derivative 1 f were
converted into the adducts 3d, 3e, and 3 f, respectively,
through the intermediacy of the secondary carbon radicals. In
the case of 1e, the preexisting a-oriented tert-butyldimethyl-
silyloxy group induced diastereoselectivity to provide 3e as
the major isomer (15:1 d.r.). Furthermore, the reactions of
a,a-disubstituted aminoacyl tellurides 1g–k resulted in 3g–k
by addition of the tertiary carbon radicals, and thus enabled
the formation of tetrasubstituted carbon atoms in an inter-
molecular fashion. It is well-established that the decarbon-
ylation rates of acyl radicals to form primary, secondary, and
tertiary radicals differ by several orders of magnitude.[13] The
decarbonylation of substrates 1a–k was shown to be consis-
tently faster than the intermolecular reaction of the acyl
radicals, supporting the potent accelerating effect of the
a-amino groups towards CO ejection. Taken together, the
results in Table 1 and Scheme 3 confirmed that the present
mild procedure is highly general for synthesizing primary,
secondary, and tertiary amine analogues of GABA in the
presence of a variety of polar functional groups.
both the radical initiating and terminating reagent. As
proposed in Scheme 1, whereas hydrogen transfer from
(Me3Si)3SiH is necessary for the formation of 3 from
a-carbonyl radical C, the aminyl radical is likely to be directly
trapped by Et3B with ejection of an ethyl radical,[16] and
protonation of the resulting boron amide D by H2O leads to 5.
This operationally simpler procedure was shown to be
effective for the synthesis of 5b–d from 1b–d. Intermolecular
formation of the sterically congested bonds between the
nitrogen-substituted carbon atom and a tri- (5b) or tetrasub-
stituted carbon atom (5c and 5d) showed the power of the
present reaction in fragment assembly. Furthermore, the
application of Oppolzerꢀs camphorsultam derivative 7[21]
enabled the stereoselective addition of the glycyl radical,
resulting in the formation of 8 in 3.3:1 d.r.
The applicability of the new radical coupling method was
further demonstrated by the syntheses of the pharmaceutical
agent gabapentin and the natural product manzacidin A, both
of which possess g-amino acid substructures (Scheme 5). First,
gabapentin, which has been widely used as a therapeutic
Not only g-amino acid derivatives, but also a,b-diamino
acid derivatives, which are key structural fragments of many
biologically active compounds,[19] were prepared by using 4 as
an alternative radical acceptor (Scheme 4). The a-amino
carbon radical that was generated from 1a, Et3B (3 equiv),
=
and air underwent 1,2-addition to the C N bond of O-benzyl-
protected ethyl glyoxylate oxime 4 (2 equiv), affording 5a at
ambient temperature.[20] Addition of a hydrogen source was
not required in this reaction, suggesting that Et3B functions as
Scheme 5. Synthesis of gabapentin and total synthesis of (À)-manzaci-
din A. Reagents and conditions: a) 1a (1 equiv), 9 (1.1 equiv), Et3B
(3 equiv), CH2Cl2 (0.02m), air, RT; b) aqueous HCl (6m), reflux, 52%
(2 steps); c) isobutyl chloroformate, N-methylmorpholine, THF, 08C;
(PhTe)2, NaBH4, THF, MeOH, 08C, 79%; d) 13 (1.1 equiv), 2c
(1 equiv), Et3B (3 equiv), (Me3Si)3SiH (3 equiv), (CH2Cl)2 (0.1m), air,
508C, 83% (1:1 d.r. at C4); e) NH2NH2·H2O, MeOH, reflux;
f) CF3CO2H, CH(OMe)3, RT; aqueous HCl (6m), reflux; g) NaH, 17,
DMF, RT, 33% (over 3 steps, 1:1 d.r. at C4).
agent for epilepsy and neuropathic pain,[22] was synthesized in
two steps. When glycine derivative 1a was treated with Et3B
under air in the presence of 9 (1.1 equiv), adduct 10 was
obtained through an efficient intermolecular coupling that
installed the quaternary center.[23] Treatment of 10 with
aqueous HCl (6m) at reflux in turn induced simultaneous
removal of the Boc and acetonide groups and, after decar-
boxylation, gave rise to gabapentin as its HCl salt (11).
Finally, an expeditious total synthesis of the natural
bromopyrrole alkaloid (À)-manzacidin A (18) was accom-
Scheme 4. Synthesis of a,b-diamino acid derivatives. Conditions:
1 (1 equiv), 4 (2 equiv), Et3B (3 equiv), CH2Cl2 (0.02m), air, RT. [a] The
formation of PhTeEt was observed. [b] 1:1 d.r. [c] 7 was used as
a radical acceptor; 3.3:1 d.r.
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plished (Scheme 5).[24,25] We specifically designed the enan-
tiopure oxazolidine-acyl telluride 13 as the coupling partner
of acrylate 2c in this synthesis. By employing the conditions
described in Scheme 2, the known carboxylic acid 12[26] was
first transformed into 13. Then, 13 (1.1 equiv) was subjected
to the radical coupling conditions with 2c at 508C. Although
the stereochemical information at the C6 position of 13 was
lost upon radical generation, the remaining aminal stereo-
center, with the b-oriented tBu group, only permitted
approach of 2c at the a-face, resulting in the construction of
14 with the desired C6 stereochemistry in 83% yield (1:1 d.r.
at C4).[27] Having realized the key coupling reaction, the
N-phthaloyl group of 14 was removed using hydrazine to
provide amine 15. When the amine was subjected to
CF3CO2H and CH(OMe)3, removal of the Boc group and
formation of the cyclic formadine took place. The crude
mixture was next treated with aqueous HCl (6m) to induce
hydrolysis of the methyl ester and removal of the pivalalde-
hyde N,O-acetal, leading to tetrahydropyrimidine 16. Lastly,
the 4-bromopyrrole ester was constructed from 16 and 17
using NaH, delivering pure (À)-manzacidin A (18) and its
C4 epimer after HPLC purification. The physical data of
synthetic 18 (1H and 13C NMR, IR, and [a]D) are identical to
those of 18 from the natural source.[24,25]
In summary, we have developed a new general radical-
based method for the single-step construction of various
g-amino and a,b-diamino acids from a-aminoacyl tellurides.
Primary, secondary, and tertiary a-amino carbon radicals
were smoothly generated through facile decarbonylation by
treatment with Et3B/O2 or Et3B/(Me3Si)3SiH/O2 at ambient
temperature. The advantageous features of this procedure are
operational simplicity, mild reaction conditions, high compat-
ibility with diverse polar functional groups, and efficient
intermolecular formation of hindered bonds. The synthetic
robustness was further exemplified by the efficient assembly
of gabapentin and (À)-manzacidin A from simple fragments.
Consequently, this decarbonylative radical coupling will serve
as a novel and valuable strategy for streamlining convergent
syntheses of architecturally complex alkaloids, natural and
artificial amino acids/peptides, and pharmaceuticals.
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Received: October 17, 2014
Published online: && &&, &&&&
Keywords: amino acids · natural products · radical reactions ·
.
tellurium · total synthesis
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À
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Communications
Radical Reactions
M. Nagatomo, H. Nishiyama, H. Fujino,
M. Inoue*
&&&& — &&&&
Decarbonylative Radical Coupling of
a-Aminoacyl Tellurides: Single-Step
Preparation of g-Amino and a,b-Diamino
Acids and Rapid Synthesis of Gabapentin
and Manzacidin A
Upon activation by Et3B and O2 at
ambient temperature, a-aminoacyl tel-
lurides were readily converted into a-
amino carbon radicals through facile
decarbonylation, which then reacted
intermolecularly with acrylates or glyox-
ylic oxime ethers to generate variousg-
amino and a,b-diamino acids. This mild
and powerful coupling method was also
applied to the synthesis of gabapentin
and the natural product(À)-manzaci-
din A.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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