Article
Stereo- and Regiocontrolled Syntheses of
Exomethylenic Cyclohexane β-Amino
Acid Derivatives
Loránd Kiss 1 , Enikő Forró 1 , György Orsy 1 , Renáta Ábrahámi 1 and Ferenc Fülöp 1,2, *
Received: 15 October 2015 ; Accepted: 19 November 2015 ; Published: 27 November 2015
Academic Editor: Derek J. McPhee
1
2
*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary;
[email protected] (L.K.); [email protected] (E.F.);
[email protected] (G.O.); [email protected] (R.Á.)
Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged,
H-6720 Szeged, Eötvös 6, Hungary
Correspondence: [email protected]; Tel.: +36-62-545-564
Abstract: Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4-methylenecy
clopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic β-lactams
by transformation of the ring olefinic bond through three different regio- and stereocontrolled
hydroxylation techniques, followed by hydroxy group oxidation and oxo-methylene
interconversion with a phosphorane. Starting from an enantiomerically pure bicyclic β-lactam
obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure led to
the preparation of both dextro- and levorotatory cyclohexane analogues of icofungipen.
Keywords: amino acids; selectivity; hydroxylation; Wittig reaction; icofungipen
1. Introduction
As a consequence of their high biological potential, cyclic β-amino acids are of importance
in medicinal chemistry. These compounds are both elements of bioactive products and building
blocks in peptide research. Several small molecular entities, such as the cyclopentane derivative
cispentacin (1) and oxetane derivative oxetin (2), possess strong antifungal and antibacterial
activities [1–13]. An exomethylene function plays an essential role in the structures of some
cyclic β-amino acids. The β-amino acid (1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid
(icofungipen, PLD-118, 3) and several analogues (4–6) exhibit strong antifungal properties
(Figure 1). The (´)-(1R,2S)-2-Amino-4-methylenecyclopentane carboxylic acid was analyzed by
Bayer. This compound, previously known as BAY 10-8888, was licensed to Glaxo-SmithKline
Research Centre Zagreb Ltd. (formerly PLIVA) and renamed PLD-118; its generic name is
icofungipen. Icofungipen is a cyclic β-amino acid, which differs in chemistry, biology, and mechanism
of action from other antifungal compound classes. Its mechanism of action is based on the inhibition
of isoleucyl-tRNA synthetase, intracellular inhibitory concentrations at the target site being achieved
by active accumulation in susceptible fungi [14–18].
The most efficient multigram-scale asymmetric synthetic route to icofungipen involves the
asymmetric desymmetrization of the meso-anhydride of a cyclopentane exo-methylenedicarboxylic
acid. In the key step, highly enantioselective, quinine-mediated alcoholysis of the meso-anhydride,
followed by Curtius rearrangement and Pd-catalyzed removal of the protecting groups affords
icofungipen (absolute configurations 1R,2S) with ee = 99.5% [14–18].
Molecules 2015, 20, 21094–21102; doi:10.3390/molecules201219749
www.mdpi.com/journal/molecules
Molecules 2015, 20, 21094–21102
Molecules 2015, 20, page–page
Molecules 2015, 20, page–page
CO2H
CO2H
NH2
NH2
cispentacin (1)
cispentacin (1)
Molecules 2015, 20, page–page
NH2
NH2
oxetin (2)
oxetin (2)
CO2H
NH2
NH2
icofungipen (3)
icofungipen (3)
CO2H
CO2H
CO2H
CO2H
NH2
4 NH2
4
NH2
CO2H
CO2H
CO2H
CO2H
O
O
O
CO2H
NH2
5 NH2
5
CO2H
CO2H
CO2H
6
NH2
NH2
NH2
NH2
6
cispentacin
(1)
icofungipen
(3)
Figure 1.
1. Some
Some biologically
biologically
interesting
cyclic
β-amino acids.
acids.
oxetin
(2)
Figure
interesting
cyclic
β-amino
Figure 1. Some biologically interesting cyclic β-amino acids.
CO2H
CO2H
CO2H
2. Results and Discussion
2. Results
Resultsand
andDiscussion
Discussion
2.
A convenient and simple novel
regio- and stereocontrolled
synthetic procedure for the access to
NH2
NHregioNH2 procedure
A convenient
convenient and
and simplenovel
novel
andstereocontrolled
stereocontrolled
synthetic
procedure
access
2regio-and
A
synthetic
forfor
thethe
access
to
5with an exomethylene
4
cyclohexane
analogues simple
of icofungipen
is described,
group in different
positions.
6
to
cyclohexane
analogues
of
icofungipen
is
described,
with
an
exomethylene
group
in
different
cyclohexane
of icofungipen
is described,
exomethylenehydroxylation,
group in different
positions.
Cyclohexeneanalogues
β-amino acids
were subjected
to regio-with
andan
stereoselective
oxidation
and
Figuresubjected
1.
Some biologically
interesting
cyclic
β-amino
acids.
positions. Cyclohexene
β-amino
acids
were
subjected
to
regioand
stereoselective
hydroxylation,
Cyclohexene
β-amino
acids
were
to
regioand
stereoselective
hydroxylation,
oxidation
and
oxo-methylene interconversion as illustrated in the retrosynthetic scheme (Scheme 1).
oxidation and oxo-methylene
interconversion
illustrated
in the retrosynthetic
scheme
oxo-methylene
interconversion
as illustrated inasthe
retrosynthetic
scheme (Scheme
1). (Scheme 1).
2. Results and Discussion
CO2Et
CO2Et stereo- and
CO2A
Etconvenient and simple novel regioand
stereocontrolled synthetic
forand
the access to
CO2Et
oxidation
regioselective
CO2procedure
Et stereoCO2Et Wittig reaction O
HO
cyclohexane
analogues
with an exomethylene groupregioselective
in different positions.
Wittig
reactionof icofungipen is described,
oxidation
O
HO
NHBoc
NHBoc
Cyclohexene
β-amino acids were subjected
to regio- and stereoselectiveNHBoc
hydroxylation,
oxidation and
hydroxylation
NHBoc
NHBoc
NHBoc
hydroxylation
oxo-methylene
interconversion as illustrated in the retrosynthetic scheme
(Scheme
1).
Scheme 1. Retrosynthetic route to exomethylene cyclohexane β-amino esters.
and
Scheme
Retrosynthetic route
β-amino
esters.
COto
CO2Et stereoCO2Et 1.
2Etexomethylene cyclohexane
Scheme
1.
Retrosynthetic
route
to
exomethylene
cyclohexane
β-amino esters.CO2H
Wittig
reaction
oxidation
regioselective
O
CO2H
CO2H
NH2
NH2
HO
The first synthetic approach was based
on selective hydroxylation
via iodolactonization.
NHBoc
NHBoc hydroxylation
NHBoc
NH2
The cyclohexene
first synthetic
approach
was
based
on selective
hydroxylation
via
iodolactonization.
Racemic
cis-β-amino
acid
(±)-7
underwent
regioand
stereoselective
iodolactonization
and
The
first
synthetic
approach
was
based
on
selective
hydroxylation
via
iodolactonization.
Scheme 1. Retrosynthetic
route
to exomethylene
cyclohexane
β-amino esters. iodolactonization and
Racemic
cyclohexene
cis-β-amino
acid
(±)-7
underwent
regioand
stereoselective
deiodination
by elimination
to afford
lactone
(±)-8. Subsequent
lactone
opening in iodolactonization
(±)-8 with NaOEt
Racemic
cyclohexene
cis-β-amino
acidlactone
(˘)-7 underwent
regio- and
stereoselective
deiodination
byfollowed
elimination
to afford
(±)-8. Subsequent
lactone
opening in
(±)-8 with
NaOEt
at
0
°C
for
1
h,
by
C-C
double
bond
saturation,
yielded
5-hydroxylated
β-amino
ester
(±)-9.
The
first
synthetic
approach
was
based
on
selective
hydroxylation
via
iodolactonization.
and
deiodination
by elimination
to afford
lactone
(˘)-8.yielded
Subsequent
lactone opening
in (˘)-8
with
at
0
°C
for
1
h,
followed
by
C-C
double
bond
saturation,
5-hydroxylated
β-amino
ester
(±)-9.
Racemic
cyclohexene
cis-β-amino
acid
(±)-7
underwent
regioand
stereoselective
iodolactonization
and
When
the
lactone
opening
with
NaOEt
was
performed
at
20
°C
for
12
h,
isomerization
occurred
with
˝ C for 1 h, followed by C-C double bond saturation, yielded 5-hydroxylated β-amino
NaOEt
at
0
When
the
lactone
opening
with
NaOEt
performed
at
20
°C
for
12
h,
isomerization
occurred
with
deiodination
by elimination
to affordwas
lactone
(±)-8. Subsequent
lactone
opening
in (±)-8 with NaOEt
the participation
of the
the lactone
active hydrogen
at
C-1,NaOEt
leading,
after
C=C reduction,
to
the
thermodynamically
ester
(˘)-9.
with
was
performed
at 20 ˝β-amino
C the
for thermodynamically
12
h, (±)-9.
isomerization
at 0When
°C for
1the
h, followed
byopening
C-C double
bond leading,
saturation,
yielded
5-hydroxylated
ester
the
participation
ofdiastereoisomer
active hydrogen
at
C-1,
after
C=C
reduction,
to
more
stable
trans
(±)-10
(Scheme
2)
[19].
When the
the lactone
opening with
NaOEt
was performed
at 20
°C
for 12
h, isomerization
occurred
with
occurred
with
participation
of
the
active
hydrogen
at
C-1,
leading,
after
C=C
reduction,
to the
more stable trans diastereoisomer (±)-10 (Scheme 2) [19].
the
participation
of
the
active
hydrogen
at
C-1,
leading,
after
C=C
reduction,
to
the
thermodynamically
thermodynamically more stable trans diastereoisomer (˘)-10 (Scheme 2) [19].
more stable trans diastereoisomer (±)-10 (Scheme 2) [19].
Scheme 2. Synthesis of 5-hydroxylated β-amino ester diastereoisomers (±)-9 and (±)-10 [19].
Scheme 2. Synthesis of 5-hydroxylated β-amino ester diastereoisomers (˘)-9 and (˘)-10 [19].
By a2.modification
earlier-describedβ-amino
method, [3]
oxidation
of (±)-9 and (±)-10
Scheme
Synthesis of
of an
5-hydroxylated
ester
diastereoisomers
(±)-9with
andpyridinium
(±)-10 [19].
2. Synthesis
β-amino
ester
and
(±)-10 [19].
afforded
the diastereoisomers
corresponding
oxo(±)-9
ester
stereoisomers
chlorochromate
(PCC)
in5-hydroxylated
CH2Cl2 at 20 °C
By aScheme
modification
of of
an
earlier-described
method,
[3] oxidation
of
(˘)-9
and (˘)-10 with
(±)-11 and (±)-12 [19]. Icofungipen analogues (±)-13 and (±)-14
were
next
synthesized
from
(±)-11 and
˝
By
a
modification
of
an
earlier-described
method,
[3]
oxidation
of
(±)-9
and
(±)-10
with pyridinium
at 20 C
afforded the corresponding
oxo ester
pyridinium
chlorochromate
(PCC)
in CH2 Cl2 exchange
(±)-12 via Wittig
reactions
by oxo-methylene
with the phosphorane
generated
from
By
a
modification
of
an
earlier-described
method,
[3]
oxidation
of
(±)-9
and
(±)-10
with
pyridinium
2Cl
2 atIcofungipen
20
°C
afforded
the
corresponding
oxo
ester
stereoisomers
chlorochromate
(PCC)
in
CH
stereoisomers
(˘)-11
and
(˘)-12
[19].
analogues
(˘)-13
and
(˘)-14
were
next
synthesized
methyltriphenylphosponium bromide/t-BuOK at 0 °C (Scheme 3).
at 20 °C (±)-13
afforded
corresponding
oxo esterfrom
stereoisomers
chlorochromate
(PCC)Icofungipen
in CH2Cl2 analogues
(±)-11 (˘)-11
and (±)-12
and the
(±)-14
wereexchange
next synthesized
(±)-11 and
from
and[19].
(˘)-12 via Wittig
reactions by oxo-methylene
with the phosphorane
(±)-11
and
(±)-12
[19].
Icofungipen
analogues
(±)-13
and
(±)-14
were
next
synthesized
from
(±)-11from
and
˝
(±)-12
via
Wittig
reactions
by
oxo-methylene
exchange
with
the
phosphorane
generated
generated from methyltriphenylphosponium bromide/t-BuOK at 0 C (Scheme 3).
(±)-12
via Wittig reactions by
oxo-methyleneatexchange
with3).the phosphorane generated from
methyltriphenylphosponium
bromide/t-BuOK
0 °C (Scheme
methyltriphenylphosponium bromide/t-BuOK at 02 °C (Scheme 3).
21095
2
2
Molecules 2015, 20, 21094–21102
Molecules 2015, 20, page–page
Molecules 2015, 20, page–page
Molecules
HO2015, 20, page–page
CO2Et
HO
HO
PCC, CH2Cl2
CO2Et
O
CO2Et
O
PCC,
CH2Cl73%
2
°C, 14
CO
O
2Et 20
PCC,
CHh,
NHBoc
2Cl2
(±)-9
20 °C, 14 h, 73%
NHBoc 20
°C, 14 h, 73%
NHBoc
(±)-9
(±)-9
O
CO2Et
PCC, CH2Cl2
CO2Et
Ph3P-Me Br
CO2Et THF, t-BuOK
CO2Et
Ph P-Me Br
CO
CO
2Et
2Et
NHBoc
NHBoc
Ph33P-Me Br
0 °C, t-BuOK
7 h, 66%
(±)-13
THF,
(±)-11
NHBoc THF, t-BuOK
NHBoc
NHBoc 0 °C, 7 h, 66%
(±)-13 NHBoc
(±)-11
0
°C,
7
h,
66%
(±)-13
(±)-11 CO Et
HO
CO2Et
2
Ph3P-Me Br
O
CO2Et THF, t-BuOK
HO
CO2Et
CO2Et
PCC,
CH2Cl77%
2
Ph P-Me Br
20
°C, 14
O
CO
HO
CO
CO
PCC,
CHh,
2Et
2Et
2Et
NHBoc
NHBoc
2Cl2
NHBoc
Ph33P-Me Br
0
°C,
7
h,
70%
(±)-12
(±)-10
THF, t-BuOK
(±)-14
NHBoc THF, t-BuOK
NHBoc 20 °C, 14 h, 77%
NHBoc
NHBoc 0 °C, 7 h, 70%
NHBoc 20 °C, 14 h, 77%
NHBoc
(±)-12
(±)-10 3. Synthesis of racemic exomethylene
(±)-14
0
°C,
7
h,
70%
Scheme
cyclohexane
β-amino
esters
(±)-13
and
(±)-14.
(±)-12
Scheme
cyclohexane β-amino esters (˘)-13 (±)-14
and (˘)-14.
(±)-103. Synthesis of racemic exomethylene
Scheme 3. Synthesis of racemic exomethylene cyclohexane β-amino esters (±)-13 and (±)-14.
3. Synthesisapproach
of racemic exomethylene
cyclohexane icofungipen
β-amino esters analogues
(±)-13 and (±)-14.
The Scheme
next synthetic
to novel cyclohexane
consisted in
The next synthetic approach to novel cyclohexane icofungipen analogues consisted
hydroxylation
of
the
olefinic
bond
of
the
cyclohexene
cis-β-amino
ester
(±)-15
via
cis-diastereoselective
The next synthetic
approach
to
novel
cyclohexane
icofungipen
analogues
consisted
in
in hydroxylation
of theapproach
olefinic to
bond
of cyclohexane
the cyclohexene
cis-β-amino
ester consisted
(˘)-15 via
The next
synthetic
novel
icofungipen
analogues
in
epoxidation
with
MCPBA
and
regioselective
reductive
oxirane
opening
with
NaBH
4, [20–21] with the
hydroxylation
of the olefinic
bond of
the cyclohexene
cis-β-amino
ester
(±)-15 via cis-diastereoselective
cis-diastereoselective
epoxidation
with
MCPBA andcis-β-amino
regioselective
reductive
opening with
hydroxylation
ofatthe
olefinic
bondinof
the4-hydroxylated
cyclohexene
ester
(±)-15 viaoxirane
cis-diastereoselective
hydride attack
C-5,
resulting
the
β-aminoopening
ester
diastereoisomers
(±)-17with
and,the
at
epoxidation
with
MCPBA
and
regioselective
reductive
oxirane
with
NaBH
4
,
[20–21]
NaBH4 , [20,21]
with
the and
hydride
attack atreductive
C-5, resulting
in
the 4-hydroxylated
β-amino
ester
epoxidation
with
MCPBA
regioselective
oxirane
opening
with
NaBH
4, [20–21] with the
higher temperature,
isomerization
at the active
methyne
(±)-18
(Scheme 4) [22].
It may
hydride
attack at (˘)-17
C-5,through
resulting
inhigher
the 4-hydroxylated
β-amino
ester
diastereoisomers
(±)-17
and, be
at
diastereoisomers
and, atin
temperature, through
isomerization
at the active
hydride
attack
atwas
C-5,synthesized
resulting
the 4-hydroxylated
β-amino
ester(±)-15
diastereoisomers
(±)-17methyne
and, at
noted
that
(±)-18
earlier
in
an
alternative
way
from
[22].
higher
temperature,
through
isomerization
at the was
active
methyne earlier
(±)-18 (Scheme
4) [22]. It
may
be
(˘)-18
(Scheme
4)
[22].
It
may
be
noted
that
(˘)-18
synthesized
in
an
alternative
way
from
higher temperature, through isomerization at the active methyne (±)-18 (Scheme 4) [22]. It may be
noted
that
(±)-18 was synthesized earlier in an alternative way from (±)-15 [22].
(˘)-15that
[22].(±)-18
noted
was synthesized earlier in an alternative way
from (±)-15 [22].
CO2Et
NaBH , EtOH
4
CO2Et MCPBA, CH Cl
2 2
CO2Et MCPBA,
Cl
0 °C, 5 h,CH
63%
CO
2Et MCPBA, CH22Cl22
NHBoc
(±)-15
0 °C, 5 h, 63%
NHBoc 0 °C, 5 h, 63%
NHBoc
(±)-15
(±)-15
CO2Et
O
O
O
CO2Et
CO
2Et
NHBoc
(±)-16
NHBoc
NHBoc
20
°C, 3
h, 62%
NaBH
, EtOH
NaBH44, EtOH HO
20 °C, 3 h, 62%
20 °C, 3 h, 62% HO
HO
NaBH4, EtOH
CO2Et
CO
2Et
NHBoc
(±)-17
(±)-17
(±)-17
NHBoc
NHBoc
CO2Et
CO2Et
70
°C, 3, h,
53%
NaBH
EtOH
CO
2Et
NHBoc
NaBH44, EtOH HO
(±)-18
70 °C, 3 h, 53%
NHBoc
70 °C, 3 h, 53% HO
HO
NHBoc
(±)-18
Scheme 4. Synthesis of 4-hydroxylated β-amino ester diastereoisomers (±)-17 and
(±)-18
(±)-18 [22].
(±)-16
(±)-16
Scheme4.4.Synthesis
Synthesisof
of4-hydroxylated
4-hydroxylatedβ-amino
β-aminoester
esterdiastereoisomers
diastereoisomers(˘)-17
(±)-17 and
(±)-18 [22].
Scheme
and (˘)-18
[22].
Scheme 4. Synthesis
of 4-hydroxylated
β-amino
ester oxidized
diastereoisomers
(±)-17toand
[22].
Hydroxylated
esters (±)-17
and (±)-18 were
readily
with PCC
oxo(±)-18
esters
(±)-19 and
(±)-20Hydroxylated
[22]. Compounds
(±)-21
and
(±)-22,
with
the
methylene
function
at
position
4,
isomers
of (±)-13
esters
(±)-17
and
(±)-18
were
readily
oxidized
with
PCC
to oxo
esters
(±)-19
and
Hydroxylated esters
esters (±)-17
(˘)-17and
and(±)-18
(˘)-18
were
readily
oxidized
with
PCC
to oxo
esters
(˘)-19
were
readily
oxidized
with
PCC
to
oxo
esters
(±)-19
and
and
(±)-14,
were
readily
prepared
from
(±)-19
and
(±)-20
in
Wittig
reactions
with
the
phosphorane
(±)-20
[22]. Compounds
(±)-21 and (±)-22,
with
the methylene
function at position
4, isomers
of
(±)-13
and (˘)-20
[22]. Compounds
and with
(˘)-22,
the methylene
at position
4, of
isomers
(±)-20
[22]. in
Compounds
(±)-21 (˘)-21
and (±)-22,
thewith
methylene
functionfunction
at position
isomers
(±)-13
generated
situ from
methyltriphenylphosponium
bromide/t-BuOK
(Scheme
5).4, the
and
(±)-14,
were
readily
prepared
from
(±)-19
and
(±)-20
in
Wittig
reactions
with
phosphorane
of (˘)-13
(˘)-14,
were
readilyfrom
prepared
(˘)-19inand
(˘)-20
in Wittig
with the
and
(±)-14,and
were
readily
prepared
(±)-19 from
and (±)-20
Wittig
reactions
withreactions
the phosphorane
generated
in situ
from methyltriphenylphosponium
bromide/t-BuOK
(Scheme 5). (Scheme 5).
phosphorane
generated
in
situ
from
methyltriphenylphosponium
bromide/t-BuOK
generated in situ from methyltriphenylphosponium bromide/t-BuOK (Scheme 5).
CO Et
CO2Et
CO2Et
PCC, CH2Cl2
Ph3P-Me Br
2
CO2Et
CO2Et Ph
THF,
t-BuOK
Br
P-Me
CO
CO
2Et
2Et Ph 3P-Me Br
NHBoc
NHBoc
3
0 °C, 7 h, 63%
THF, t-BuOK
(±)-19
(±)-21 NHBoc
t-BuOK
HO
O
NHBoc THF,
°C, 7 h, 63%
NHBoc
HO
O
NHBoc 00 °C,
7
h,
63%
(±)-19
(±)-21
(±)-19
(±)-21
CO2Et
CO2Et
Ph3P-Me Br
CO2Et
CO2Et
CO2Et
PCC,
CH2Cl79%
2
THF,
t-BuOK
20
°C, 14
CO
Br
CO
2Et Ph
CO
PCC,
CHh,
2Et
3P-Me Br
O
NHBoc
HO
NHBoc
2Et
2Cl2
NHBoc
Ph
3P-Me
0
°C,
7
h,
66%
(±)-18
(±)-20
t-BuOK
(±)-22
NHBoc THF, t-BuOK
HO
NHBoc 20 °C, 14 h, 79% O
NHBoc
NHBoc 0THF,
HO (±)-18 NHBoc 20 °C, 14 h, 79% O
°C,
7
h,
66%
NHBoc
(±)-20
0
°C,
7
h,
66%
(±)-22
Scheme
cyclohexane β-amino esters (±)-21 and (±)-22.
(±)-185. Synthesis of racemic exomethylene
(±)-20
(±)-22
Scheme 5. Synthesis of racemic exomethylene cyclohexane β-amino esters (±)-21 and (±)-22.
Scheme
Synthesis
of racemic exomethylene
cyclohexane
β-amino
esters (±)-21 and
(±)-22.
Other
regio-5.5.and
stereoisomers
synthesized
by regioand stereoselective
iodolactonization
Scheme
Synthesis
of racemicwere
exomethylene
cyclohexane
β-amino
esters (˘)-21 and
(˘)-22.
HO
CO2Et
PCC,
CH2Cl82%
2
°C, 14
CO
PCC,
CHh,
2Et 20
NHBoc
2Cl2
(±)-17
NHBoc 20 °C, 14 h, 82%
NHBoc 20 °C, 14 h, 82%
(±)-17
(±)-17
CO2Et
PCC, CH2Cl2
O
and deiodination
β-aminocyclohex-3-enecarboxylic
(±)-23,and
followed
by selective
lactone opening
Other regio- of
and
stereoisomers were synthesizedacid
by regiostereoselective
iodolactonization
Other
regioand
stereoisomers
were
synthesized
by
regioand
stereoselective
iodolactonization
withdeiodination
NaOEtregioand of
hydrogenation
of the
amino
lactone
intermediate
(±)-24bytoselective
furnish
analogously
to
Other
and
stereoisomers
were
synthesized
by
regiostereoselective
iodolactonization
and
β-aminocyclohex-3-enecarboxylic
acid
(±)-23,and
followed
lactone
opening
and
deiodination
of β-aminocyclohex-3-enecarboxylic
acid (±)-23, followed
by (±)-26
selective
lactone6)opening
(±)-8
(Scheme
2)
the
3-hydroxylated
β-amino
ester
stereoisomers
(±)-25
and
(Scheme
[23].
and deiodination
of β-aminocyclohex-3-enecarboxylic
acid (˘)-23,(±)-24
followed
by selective
lactone
with
NaOEt and hydrogenation
of the amino lactone intermediate
to furnish
analogously
to
with NaOEt and hydrogenation of the amino lactone intermediate (±)-24 to furnish analogously to
(±)-8 (Scheme 2) the 3-hydroxylated β-amino ester stereoisomers (±)-25 and (±)-26 (Scheme 6) [23].
(±)-8 (Scheme 2) the 3-hydroxylated β-amino ester stereoisomers (±)-25 and (±)-26 (Scheme 6) [23].
21096
3
3
3
Molecules 2015, 20, 21094–21102
opening
with
NaOEt and hydrogenation of the amino lactone intermediate (˘)-24 to furnish
Molecules 2015,
20, page–page
analogously to (˘)-8 (Scheme 2) the 3-hydroxylated β-amino ester stereoisomers (˘)-25 and (˘)-26
Molecules 2015, 20, page–page
(Scheme 6)Molecules
[23]. 2015, 20, page–page
Scheme 6. Synthesis of 3-hydroxylated β-amino ester stereoisomers (±)-25 and (±)-26 [6].
Scheme
[6].
Scheme6.6.Synthesis
Synthesisof
of3-hydroxylated
3-hydroxylatedβ-amino
β-aminoester
esterstereoisomers
stereoisomers(˘)-25
(±)-25 and
and (˘)-26
(±)-26 [6].
A modification of an earlier-described method [23] was next used: oxidation of hydroxylated
Scheme
6. Synthesis
of
3-hydroxylated
β-amino
ester stereoisomers (±)-25 and (±)-26 [6].
amino
esters
(±)-25
(±)-26
with PCC in method
CH
2Cl2 at room temperature led to the corresponding cis
A modification
of
earlier-described
[23]
of an
anand
earlier-described
method
[23] was
was next
next used:
used: oxidation of hydroxylated
and trans keto esters (±)-27 and (±)-28 [23]. Although cis-keto aminocarboxylate (±)-27 afforded the
amino esters (±)-25
(˘)-25and
and(±)-26
(˘)-26with
withPCC
PCCininCH
CH
Cl
at
room
temperature
to the
corresponding
2Cl
2
at
room
temperature
ledinled
to
the
corresponding
cis
2 2
Wittig productofonan
treatment
with methyltriphenylphosphonium
tetrahydrofurane
A modification
earlier-described
method [23] wasbromide/t-BuOK
next used: oxidation
of hydroxylated
cis
keto
esters
(˘)-27
and
(˘)-28
[23]. cis-keto
Although
(˘)-27
andand
transtrans
ketoto esters
(±)-27of and
(±)-28
[23].
Although
afforded
the
due
the presence
thewith
active
hydrogen
isomerization
occurredaminocarboxylate
atcis-keto
C-2 under aminocarboxylate
alkaline (±)-27
conditions
amino esters
(±)-25
and (±)-26
PCC
in CH
2Cl2 at room temperature led to the corresponding cis
afforded
the
Wittig
productwith
on methyltriphenylphosphonium
treatment
with
bromide/t-BuOK
and gave
thermodynamically
more stable
(±)-29methyltriphenylphosphonium
(only the relative
stereochemistry isin
shown),
in
Wittig product
on the
treatment
bromide/t-BuOK
tetrahydrofurane
and trans which
keto esters
(±)-27
and (±)-28
[23]. Although
cis-keto
aminocarboxylate
(±)-27
afforded the
the amino
andto
carboxylate
functionsof
arethe
in a trans
relationship;
trans
amino
ester (±)-28
reactedconditions
in
the hydrogen
presence
active
hydrogen
occurred
at C-2
duetetrahydrofurane
to the presence
ofdue
the
active
isomerization
occurred
atisomerization
C-2 under
alkaline
Wittig product
onphosphonium
treatment with
in ester
tetrahydrofurane
with the
salt inmethyltriphenylphosphonium
the presence of t-BuOK to yield (±)-29bromide/t-BuOK
stereoisomer with the
and
under
alkaline
conditions and gave
thestable
thermodynamically
stable
(˘)-29 (onlyisthe
relative
and gave
the thermodynamically
more
(±)-29 (only the more
relative
stereochemistry
shown),
in
thethe
transactive
arrangement
(Scheme
7).
due to thecarbamate
presenceinof
hydrogen
isomerization
occurred at C-2 under alkaline conditions
stereochemistry
shown),
in which
the amino
and
carboxylate
functions
in aester
trans(±)-28
relationship;
which the aminoisand
carboxylate
functions
are in
a trans
relationship;
transare
amino
reacted
and gave the thermodynamically
more stable (±)-29 (only the relative stereochemistry
is shown), in
CO2Et
CO
Et
2
trans
amino
ester
(˘)-28
reacted
with
the
phosphonium
salt
in
the
presence
of
t-BuOK
to
yield
(˘)-29
with the phosphonium salt in the presence of t-BuOK to yield (±)-29 stereoisomer with the ester
and
which the amino and carboxylate functions are in a trans relationship; trans amino ester (±)-28 reacted
stereoisomer
the ester
and
carbamate
in
the
trans
arrangement
(Scheme
7).
carbamate in with
the trans
arrangement
(Scheme
7).
NHBoc
with the phosphonium saltNHBoc
in the presence of t-BuOK to yield (±)-29 stereoisomer
with the ester and
OH
OH
carbamate in the trans
arrangement
(Scheme 7).
CO Et
CO
Et
(±)-26
(±)-25
2
2
PCC, CH2Cl2
CO220
Et °C, 14 h, 72%
PCC, CH2Cl2
20 °C, 14 h, 72%
NHBoc
CO2Et
NHBoc
CO2Et
CO2Et
OH CO2Et
OH
Ph3P-Me Br
Ph3P-Me Br
NHBoc
NHBoc
(±)-26
(±)-25
THF, t-BuOK
THF,
t-BuOK
NHBoc
NHBoc
OH
OH
NHBoc
0 °C,PCC,
7 h, 61%
PCC, CH2Cl2 0 °C, 7 h, 63%
CH2Cl
2
(±)-26
O
(±)-25 O
(±)-27
20 °C,
14 h, 72%
(±)-29
20 °C, 14 h,(±)-28
72%
PCC, CH2Cl2
PCC, CH2Cl2
Scheme
7.
Synthesis
of
racemic
(±)-29.
CO2Et 20 °C, 14 h, 72%
20CO
°C,2Et
14 h,Ph
72%
CO2Et
Ph3P-Me Br
3P-Me Br
The isomerization
of cis-(±)-27 at C-2 during theCO
Wittig
reaction with methyltriphenylphosponium
CO2Et THF,
CO2Et
2Et
t-BuOK
THF,
t-BuOK
Br through trans
Phto3P-Me
Ph3(±)-28
P-Me
NHBoc
NHBoc
NHBoc
bromide/t-BuOK
in THF
give (±)-29
amino ester
isBr
depicted in Scheme
8.
0 °C, 7 h, 63%
0 °C, 7 h, 61%
O
O
THF,
t-BuOK
NHBoc
NHBoc THF, t-BuOK
NHBoc
(±)-27
(±)-29
0 °C, 7 h, 63%
0 °C, 7 h, 61% (±)-28
O
O
(±)-27
Scheme7.7. Synthesis
Synthesis
of racemic
racemic(˘)-29.
(±)-29.
(±)-29 of
(±)-28
Scheme
Scheme 7. Synthesis of racemic (±)-29.
The isomerization of cis-(±)-27 at C-2 during the Wittig reaction with methyltriphenylphosponium
The isomerization of cis-(˘)-27 at C-2 during the Wittig reaction with
bromide/t-BuOK in THF
to give
(±)-29 of
through
trans
ester (±)-28
is(±)-28.
depicted in Scheme 8.
Scheme
8. Formation
(±)-29 from
(±)-27amino
through trans-amino
ester
The isomerization of
cis-(±)-27
at C-2 during
the
Wittig
with
methyltriphenylphosponium
methyltriphenylphosponium
bromide/t-BuOK
in
THF
toreaction
give (˘)-29
through trans amino ester
bromide/t-BuOK
to give
through
trans
amino
ester (±)-28
is to
depicted
8.
(˘)-28 is depicted
inTHF
Scheme
8. (±)-29
The in
above
experiments
(27→29
and 28→29)
with
the racemates
led us
suppose in
thatScheme
both
enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam.
For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by
CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24].
4
Scheme 8. Formation of (±)-29 from (±)-27 through trans-amino ester (±)-28.
Scheme 8. Formation of (±)-29 from (±)-27 through trans-amino ester (±)-28.
8. Formation
of (˘)-29
from (˘)-27
through
trans-amino
ester
The aboveScheme
experiments
(27→29
and 28→29)
with
the racemates
led
us (˘)-28.
to suppose that both
enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam.
The above experiments (27→29 and 28→29) with the racemates led us to suppose that both
For this purpose, therefore, enantiomerically21097
pure β-lactam (+)-30 (ee = 99%) was prepared by
enantiomers of 29 could be obtained by starting
from an enantiomerically pure bicyclic lactam.
CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24].
For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by
CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24].
4
Molecules 2015, 20, 21094–21102
The above experiments (27Ñ29 and 28Ñ29) with the racemates led us to suppose that both
enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam.
For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by
CAL-B-catalyzed
ring-opening of racemic lactam (˘)-30 (Scheme 9) [24].
Molecules 2015, 20, page–page
Molecules 2015, 20, page–page
Molecules 2015, 20, page–page
Scheme 9. Synthesis
Synthesis of
of enantiomerically
enantiomerically pure lactam
lactam (+)-30.
Scheme
Scheme 9.
9. Synthesis of
enantiomerically pure
pure lactam (+)-30.
(+)-30.
Enantiomerically pure β-lactam (+)-30 was next transformed by an earlier-published procedure [23]
Enantiomerically
β-lactam
(+)-30(+)-30
was next
transformed
by an earlier-published
procedure [23]
Enantiomericallypure
pure
β-lactam
was
next transformed
by an earlier-published
to the corresponding N-Boc amino acid, which was then converted to enantiopure bicyclic lactone
to
the corresponding
amino
acid,
which
was
then
converted
to
enantiopure
bicyclic
lactone
procedure
[23] to the N-Boc
corresponding
N-Boc
amino
acid,
which
was
then
converted
to
enantiopure
Scheme 9. Synthesis of enantiomerically pure lactam (+)-30.
(−)-24 (Scheme 10).
(−)-24
(Scheme
10).
bicyclic lactone (´)-24 (Scheme 10).
Enantiomerically pure β-lactam (+)-30 was next transformed by an earlier-published procedure [23]
Boc2O, NaOH
1S CO H
1S was
1S O
CO then
H converted
2
to the corresponding
N-Boc amino acid, which
to enantiopure
Boc
O, NaOH
1S bicyclic
CO2H lactone
1S CO22H
1S O 18% HCl, 0 °C
H22O/THF
(−)-24 (Scheme 10). 18% HCl, 0 °C
H2O/THF
NH
6R NH
6R 1S
(+)-30
(+)-30
6R
O
0 °C to RT
1 h, 76%
1 h, 76%
18% HCl, 0 °C
NH
1 h, 76%
(+)-30
0
°C
to
RT
2R NH2HCl
14
h,NaOH
88%
2HCl Boc14
2O,h,
2R NH
1S
88%
(-)-32CO2H
H2O/THF
(-)-32
2R NH2HCl
0 °C to RT
14 h, 88%
(-)-32
1S
1S
O
8S
O
8S NHBoc
1S
5R O NHBoc
O
5R O
8S
(-)-24
(-)-24
DBU, THF
DBU, THF
65 °C, 5 h, 69%
65 °C, 5 h, 69%
DBU, THF
4S
4S
I
I
4S
1S
1S
2R NHBoc
NHBoc
1S 2R
CO2H
(-)-23
(-)-23
KI, NHBoc
I2, NaHCO3
2R
KI,
2, NaHCO
H2IO,
CH2Cl23
(-)-23
H
O,
CH
2
2Cl2
20 °C, 18 h, 74%
20KI,
°C,
18
h,
74%
I , NaHCO
2
3
O
H2O, CH2Cl2
8S
O
8S
20
°C,
NHBoc 18 h, 74%
5S 1S
O NHBoc
5S O O
8S
(-)-33
(-)-33NHBoc
NHBoc 65 °C, 5 h, 69% I
5S O
5R O
Scheme 10. Synthesis of enantiomer lactone
(−)-24.
(-)-24
Scheme 10. Synthesis of enantiomer lactone (−)-24.
Scheme 10. Synthesis of enantiomer(-)-33
lactone (´)-24.
On treatment with NaOEt
at 0 °C,
optically
pure lactone
(−)-24
gave the all-cis 3-hydroxylated
Scheme
10. Synthesis
of enantiomer
lactone
(−)-24.
On treatment with NaOEt at 0 °C, optically pure lactone (−)-24 gave the all-cis 3-hydroxylated
˝
β-amino
ester
(−)-34,
[23]
whereas
at
room
temperature
for
14
h
isomerization
atall-cis
C-1 led
to (−)-35 [23].
On treatment
with
NaOEt
at at
0 room
C, optically
pure lactone
(´)-24
gave theat
3-hydroxylated
β-amino
ester
(−)-34,
[23]
whereas
temperature
for 14 h(−)-24
isomerization
C-1
led
to (−)-35 [23].
On
treatment
with
NaOEt
at
0
°C,
optically
pure
lactone
gave
the
all-cis
3-hydroxylated
On catalytic
hydrogenation,
these compounds
afforded
hydroxylated
cyclohexane
β-amino
esterhydrogenation,
(´)-34,
[23] whereas
room temperature
for14
14hhisomerization
isomerization
at C-1 ledβ-amino
to (´)-35esters
[23].
On
catalytic
theseatcompounds
afforded
cyclohexane
β-amino ester
(−)-34, [23] whereas
at room temperature
for hydroxylated
at C-1 led toβ-amino
(−)-35 [23].esters
(+)-25
and
(−)-26,
[6]
respectively,
in
enantiomerically
pure
form
(Scheme
11)
[23].
On catalytic
hydrogenation,
these
hydroxylated
cyclohexane
β-amino
On
catalytic
hydrogenation,
these
compounds afforded
afforded
hydroxylated
cyclohexane
estersesters
(+)-25
and
(−)-26,
[6] respectively,
incompounds
enantiomerically
pure
form (Scheme
11) [23]. β-amino
(+)-25(+)-25
and and
(´)-26,
[6]
respectively,
in
enantiomerically
pure
form
(Scheme
11)
[23].
(−)-26, [6] respectively, in enantiomerically pure form (Scheme 11) [23].
Scheme
11.11.
Synthesis
stereoisomers
(+)-25
and
(−)-26.
Scheme
Synthesisofofamino
amino ester
ester stereoisomers
(+)-25
and
(−)-26.
Scheme
Scheme 11.
11. Synthesis
Synthesis of
of amino
amino ester
ester stereoisomers
stereoisomers (+)-25
(+)-25 and
and (´)-26.
(−)-26.
Analogously
to the
racemates,(+)-25
(+)-25and
and (−)-26
(−)-26 [23]
oxidation
to the
corresponding
Analogously
to the
racemates,
[23]underwent
underwent
oxidation
to the
corresponding
Analogously
(+)-25
(−)-26
[23]
underwent
oxidation
to the corresponding
to
the
racemates,
(+)-25
and
(´)-26
[23]
underwent
oxidation
enantiopure
cis
and
trans
(+)-27
and
(−)-28
(ee
=
99%).
enantiopure cis and trans (+)-27 and (−)-28 (ee = 99%).
enantiopure
and trans
(+)-27
and (−)-28
(ee
On cis
reaction
with
phosphorane
generated
in
situ
bromide/
(´)-28
(ee==99%).
99%).
On reaction
with
phosphorane
generated
in
situ from
frommethyltriphenyphosphonium
methyltriphenyphosphonium
bromide/
t-BuOK,
(+)-27with
participated
in isomerization
at C-2
to give
themethyltriphenyphosphonium
thermodynamically more stable (+)-29
On
reaction
phosphorane
generated
in situ
from
bromide/
t-BuOK, (+)-27 participated in isomerization at C-2 to give the thermodynamically more stable (+)-29
(ee =(+)-27
90.6%),participated
while under in
similar
conditions (−)-28
yielded
opposite
enantiomer (−)-29
(ee =stable
86.6%).(+)-29
t-BuOK,
isomerization
at C-2
to giveitsthe
thermodynamically
more
21098
(ee = 90.6%),
while
under
similar
conditions
(−)-28
yielded its
opposite
enantiomer
(−)-29
(ee = 86.6%).
The
chiral
centers
at
C-1
or
C-2
in
(+)-27
may
theoretically
both
be
affected
(both
active
hydrogens)
(ee = 90.6%), while under similar conditions (−)-28 yielded its opposite enantiomer (−)-29 (ee = 86.6%).
The chiral
centers
at C-1 or C-2
in (+)-27
may theoretically
both be affected
(both
active hydrogens)
but this
was not
C-2 underwent
isomerization,
to the(both
thermodynamically
The chiral
centers
at observed.
C-1 or C-2Only
in (+)-27
may theoretically
bothleading
be affected
active hydrogens)
but this
was
not
observed.
Only
C-2
underwent
isomerization,
leading
to
the
thermodynamically
more stable derivative (+)-29 with the carbamate and ester groups in a trans relative relationship.
but this was not observed. Only C-2 underwent isomerization, leading to the thermodynamically
more stable derivative (+)-29 with the carbamate and ester groups in a trans relative relationship.
Molecules 2015, 20, 21094–21102
On reaction with phosphorane generated in situ from methyltriphenyphosphonium
bromide/t-BuOK, (+)-27 participated in isomerization at C-2 to give the thermodynamically
more stable (+)-29 (ee = 90.6%), while under similar conditions (´)-28 yielded its opposite enantiomer
(´)-29 (ee = 86.6%). The chiral centers at C-1 or C-2 in (+)-27 may theoretically both be affected
(both active hydrogens) but this was not observed. Only C-2 underwent isomerization, leading to
the thermodynamically more stable derivative (+)-29 with the carbamate and ester groups in a trans
relative
relationship.
(Scheme 12).
Molecules
2015, 20, page–page
1S CO2Et
2S
3R
NHBoc
20 °C, 14 h, 70%
OH
(+)-25
1S CO2Et
2S
NHBoc
O
(+)-27
1R CO2Et
2S
3R
PCC, CH2Cl2
PCC, CH2Cl2
NHBoc 20 °C, 14 h, 76%
OH
(-)-26
1R CO2Et
2S
NHBoc
O
(-)-28
Ph3P-Me Br
1S CO2Et
2R
t-BuOK, THF
0 °C, 7 h, 39%
NHBoc
(+)-29
Ph3P-Me Br
1R CO2Et
2S
t-BuOK, THF
0 °C, 7 h, 42%
NHBoc
(-)-29
Scheme 12. Synthesis of amino ester enantiomers (+)-29 and (−)-29.
Scheme 12. Synthesis of amino ester enantiomers (+)-29 and (´)-29.
3. Experimental Section
3. Experimental Section
3.1. General Procedure for the Methylenation of Oxo Esters
3.1. General Procedure for the Methylenation of Oxo Esters
To a solution of methyltriphenylphosphonium bromide (2 mmol) in THF (15 mL), t-BuOK
To
a solution
of methyltriphenylphosphonium
in THF (15 mL), t-BuOK
(1 equiv.)
was added
and the solution was stirred for bromide
15 min at (2
20 mmol)
°C. The β-aminooxocarboxylate
(1 equiv.)
thenand
added
the mixture
was further
After 6 h, water
(1 equiv.)
was was
added
theand
solution
was stirred
for 15stirred
min at this
20 ˝temperature.
C. The β-aminooxocarboxylate
(15
mL)
was
added,
and
the
mixture
was
extracted
with
CH
2
Cl
2
(2
×
15
mL).
The
organic
layer6 was
(1 equiv.) was then added and the mixture was further stirred at this temperature. After
h, water
dried
(Na
2SO4) and concentrated, and the crude product was purified by column chromatography on
(15 mL) was added, and the mixture was extracted with CH2 Cl2 (2 ˆ 15 mL). The organic layer was
9:1).
driedsilica
(Na2gel
SO(n-hexane/EtOAc
4 ) and concentrated, and the crude product was purified by column chromatography
on silica
gel (n-hexane/EtOAc 9:1).
Ethyl (1R*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(±)-13]. A colorless oil,
yield: 66%. Rf = 0.65 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.22 (t, 3H, CH3, J = 7.00 Hz),
Ethyl1.41
(1R*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate
[(˘)-13].
A colorless
(s, 9H, t-Bu), 1.71–1.80 (m, 1H, CH2), 1.83–1.90 (m, 1H, CH2), 2.09–21 (m, 1H,
CH2), 2.23–2.30
(m, oil,
1
yield:1H,
66%.
(n-hexane/EtOAc
(CDCl(m,
MHz):
δ = 1.22
(t, 3H,
3 , 400
f = 0.65(m,
CH2),R2.32–2.38
1H, CH2), 2.57–2.634:1);
(m, 1H,H-NMR
CH2), 2.82–2.88
1H, H-1),
3.96–4.02
(m, 1H,
H-2),CH3 ,
13C-NMR
J = 7.00
Hz), 1.41
(s, OCH
9H, t-Bu),
1.71–1.80
(m,
CH(brs,
1H, CH
(m, 1H,
4.07–4.20
(m, 2H,
2), 4.63–4.70
(m, 2H,
CH1H,
2), 5.38
1H, N-H). (m,
(DMSO,
100 MHz):
2 ), 1.83–1.90
2 ), 2.09–21
14.9, 29.1,(m,
30.1,1H,
32.3,CH
32.8,
46.8,
47.9,
60.6,
78.6,
109.4,
147.1,
158.0,
173.0.
Anal.
Calcd
for
C
15
H
25
NO
4: 1H,
CH2 ),δ =2.23–2.30
),
2.32–2.38
(m,
1H,
CH
),
2.57–2.63
(m,
1H,
CH
),
2.82–2.88
(m,
2
2
2
C
63.58,
H
8.89,
N
4.94;
found:
C
63.20,
H
8.61,
N
4.68.
H-1), 3.96–4.02 (m, 1H, H-2), 4.07–4.20 (m, 2H, OCH2 ), 4.63–4.70 (m, 2H, CH2 ), 5.38 (brs, 1H, N-H).
13 C-NMR (DMSO, 100 MHz): δ = 14.9, 29.1, 30.1, 32.3, 32.8, 46.8, 47.9, 60.6, 78.6, 109.4, 147.1, 158.0,
Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(±)-14]. A white solid,
173.0. Anal. Calcd for C15 H25 NO4 : C 63.58, H 8.89, N 4.94;
found: C 63.20, H 8.61, N 4.68.
1
mp 102–103 °C; yield: 70%. Rf = 0.6 (n-hexane/EtOAc 4:1); H-NMR (CDCl3, 400 MHz): δ = 1.21 (t, 3H,
CH3, J = 7.00 Hz), 1.41 (s, 9H, t-Bu), 2.06–2.19 (m, 1H, CH2), 2.24–2.43 (m, 5H, CH2, H-1), 3.79–3.86
Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(˘)-14].
A white solid,
(m, 1H, H-2), 4.11–4.20 (m, 2H, OCH2), 4.42 (brs, 1H, N-H), 4.70–4.73 (m, 2H, CH2). 13C-NMR (DMSO,
˝ C; yield: 70%. R = 0.6 (n-hexane/EtOAc 4:1); 1 H-NMR (CDCl , 400 MHz): δ = 1.21
mp 102–103
3 Anal. Calcd for
100 MHz): δ = 14.9, 29.1, 33.3,f33.6, 36.7, 50.3, 50.9, 60.7, 78.3, 110.2, 146.0, 156.0, 173.7.
(t, 3H,
, J 4:=C7.00
Hz),
1.41N(s,
9H,
t-Bu),
2.06–2.19
(m,
C15CH
H253NO
63.58,
H 8.89,
4.94;
found:
C 63.22,
H 9.11,
N 1H,
4.69. CH2 ), 2.24–2.43 (m, 5H, CH2 , H-1),
3.79–3.86 (m, 1H, H-2), 4.11–4.20 (m, 2H, OCH2 ), 4.42 (brs, 1H, N-H), 4.70–4.73 (m, 2H, CH2 ).
13 C-NMR
Ethyl (1R*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate
[(±)-21].
A white
solid,156.0,
(DMSO, 100 MHz): δ = 14.9, 29.1, 33.3, 33.6, 36.7, 50.3, 50.9, 60.7,
78.3, 110.2,
146.0,
mp
56–58
°C;
yield:
63%.
R
f = 0.6 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.16 (t, 3H,
173.7. Anal. Calcd for C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.22, H 9.11, N 4.69.
CH3, J = 7.10 Hz), 1.43 (s, 9H, t-Bu), 1.79–1.86 (m, 1H, CH2), 1.88–2.03 (m, 1H, CH2), 2.11–2.19 (m, 1H,
CH
2), 1.23–1.33 (m, 1H, CH2), 2.38–2.45 (m, 2H, CH2), 2.77–2.82 (m, 1H, H-1), 4.09–4.23 (m, 3H, OCH2,
Ethyl (1R*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate
[(˘)-21]. A white solid,
H-2), 4.78–4.80
(m, 1H, =CH), 4. 83–4.86 (m, 1H, =CH), 5.06 1(brs, 1H, N-H). 13C-NMR (CDCl3, 100 MHz):
˝
mp 56–58 C; yield: 63%. Rf = 0.6 (n-hexane/EtOAc 4:1); H-NMR (CDCl3 , 400 MHz): δ = 1.16 (t, 3H,
δ = 14.6, 26.4, 28.8, 32.5, 39.8, 45.4, 49.7, 60.9, 79.6, 111.4, 144.5, 155.4, 173.7. Anal. Calcd for C15H25NO4:
CH3 , J = 7.10 Hz), 1.43 (s, 9H, t-Bu), 1.79–1.86 (m, 1H, CH2 ), 1.88–2.03 (m, 1H, CH2 ), 2.11–2.19 (m, 1H,
C 63.58, H 8.89, N 4.94; found: C 63.23, H 8.60, N 4.68.
CH2 ), 1.23–1.33 (m, 1H, CH2 ), 2.38–2.45 (m, 2H, CH2 ), 2.77–2.82 (m, 1H, H-1), 4.09–4.23 (m, 3H,
Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate [(±)-22]. A white solid,
mp 99–101 °C; yield: 66%. Rf = 0.55 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.21 (t, 3H,
CH3, J = 7.10 Hz), 1.41 (s, 9H, t-Bu), 1.78–1.88 (m,
1H, CH2), 1.89–1.98 (m, 1H, CH2), 2.00–2.10 (m, 2H,
21099
CH2), 2.29–2.38 (m, 1H, CH2), 2.56–2.61 (m, 1H, CH2), 2.62–2.69 (m, 1H, H-1), 3.83–3.96 (m, 1H, H-2),
4.17–4.24 (m, 2H, OCH2), 4.60 (brs, 1H, N-H), 5.79–5.82 (m, 2H, =CH), 13C-NMR (DMSO, 100 MHz):
Molecules 2015, 20, 21094–21102
OCH2 , H-2), 4.78–4.80 (m, 1H, =CH), 4. 83–4.86 (m, 1H, =CH), 5.06 (brs, 1H, N-H). 13 C-NMR (CDCl3 ,
100 MHz): δ = 14.6, 26.4, 28.8, 32.5, 39.8, 45.4, 49.7, 60.9, 79.6, 111.4, 144.5, 155.4, 173.7. Anal. Calcd for
C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.23, H 8.60, N 4.68.
Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate [(˘)-22]. A white solid,
mp 99–101 ˝ C; yield: 66%. Rf = 0.55 (n-hexane/EtOAc 4:1); 1 H-NMR (CDCl3 , 400 MHz): δ = 1.21
(t, 3H, CH3 , J = 7.10 Hz), 1.41 (s, 9H, t-Bu), 1.78–1.88 (m, 1H, CH2 ), 1.89–1.98 (m, 1H, CH2 ), 2.00–2.10
(m, 2H, CH2 ), 2.29–2.38 (m, 1H, CH2 ), 2.56–2.61 (m, 1H, CH2 ), 2.62–2.69 (m, 1H, H-1), 3.83–3.96
(m, 1H, H-2), 4.17–4.24 (m, 2H, OCH2 ), 4.60 (brs, 1H, N-H), 5.79–5.82 (m, 2H, =CH), 13 C-NMR
(DMSO, 100 MHz): δ = 14.6, 27.8, 28.8, 32.8, 40.5, 48.2, 61.0, 78.0, 110.9, 144.9, 152.0, 173.8. Anal. Calcd
for C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.78, H 8.66, N 5.23.
Ethyl (1S*,2R*)-2-(tert-butoxycarbonylamino)-3-methylenecyclohexanecarboxylate [(˘)-29]. A white solid,
mp 75–77 ˝ C; yield: 63%. Rf = 0.65 (n-hexane/EtOAc 4:1); 1 H-NMR (CDCl3 , 400 MHz): δ = 1.22
(t, 3H, CH3 , J = 7.10 Hz), 1.22–1.30 (m, 1H, CH2 ) 1.40 (s, 9H, t-Bu), 1.75–1.84 (m, 2H, CH2 ), 1.95–2.02
(m, 1H, CH2 ), 2.07–2.19 (m, 1H, CH2 ), 2.21–2.28 (m, 1H, CH2 ), 2.39–2.43 (m, 1H, H-1), 4.11–4.20
(m, 2H, OCH2 ), 4.24–4.35 (m, 1H, H-2), 4.39 (brs, 1H, N-H), 4.79–4.83 (m, 2H, CH2 ). 13 C-NMR (DMSO,
100 MHz): δ = 14.9, 26.6, 29.1, 29.7, 34.8, 50.7, 55.0, 60.6, 78.3, 107.7, 147.9, 155.7, 173.9. Anal. Calcd for
C15 H25 NO4 : C 63.58, H 8.89, N 4.94; found: C 63.80, H 8.60, N 5.22.
3.2. Characterization of the Enantiomerically Pure Substances
The ee values for (+)-27 and (´)-28 were determined on a HPLC (ChiralPak IA, Chiral
Technologies Europe, Illkirch-Graffenstaden, France) 5 µ column (0.4 cm ˆ 1 cm): for (+)-27 (ee 99%),
mobile phase: n-hexane/2-propanol (80/20); flow rate 0.5 mL/min; detection at 205 nm; retention
time (min): 11.14 (for antipode: 10.68); for (´)-28 (ee 99%), mobile phase: n-hexane/2-propanol
(70/30); flow rate 0.5 mL/min; detection at 205 nm; retention time (min): 11.8 (for antipode: 25.1).
The ee values for (´)-29 and (+)-29 were determined on a HPLC (ChiralPak IA) 5 µ column
(0.4 cm ˆ 1 cm), for (´)-29 (ee 90%): mobile phase: n-hexane/2-propanol (70/30); flow rate
0.5 mL/min; detection at 205 nm; retention time (min): 9.25; for (+)-29 (ee 86%): mobile phase:
n-hexane/2-propanol (70/30); flow rate 0.5 mL/min; detection at 205 nm; retention time (min): 10.36.
All 1 H-NMR spectra recorded for the enantiomeric substances were the same as for the
corresponding racemic counterparts.
(1S,2R)-2-Aminocyclohex-3-enecarboxylic acid hydrochloride
mp 203–206 ˝ C; yield: 76%. rαs25
D = ´89.5 (c 0.335, EtOH).
[(´)-32]
[20,21].
A
white
solid;
(1S,2R)-2-(tert-Butoxycarbonyl)cyclohex-3-enecarboxylic acid [(´)-23]. A white solid; mp 115–118 ˝ C;
yield: 88%. rαs25
D = ´26.6 (c 0.315, EtOH), (for the opposite enantiomer see reference [23]).
tert-Butyl (1S,4S,5S,8S)-4-iodo-7-oxo-6-oxabicyclo[3.2.1]octan-8-ylcarbamate [(´)-33]. A white solid;
mp 50–53 ˝ C; yield: 74%. rαs25
D = ´54.4 (c 1.9, EtOH) (for the opposite enantiomer, see reference [23]).
tert-Butyl (1S,5R,8S)-7-oxo-6-oxabicyclo[3.2.1]oct-3-en-8-ylcarbamate [(´)-24]. A white solid;
mp 157–159 ˝ C; yield: 69%. rαs25
D = ´107.6 (c 0.35, EtOH) (for the opposite enantiomer, see
reference [23]).
Ethyl (1S,5R,6S)-6-(tert-butoxycarbonyl)-5-hydroxycyclohex-3-enecarboxylate [(´)-34]. A colorless oil;
yield: 92%. rαs25
D = ´21.6 (c 0.375, EtOH) (for the opposite enantiomer, see reference [23]).
Ethyl (1R,5R,6S)-6-(tert-butoxycarbonyl)-5-hydroxycyclohex-3-enecarboxylate [(´)-35]. A colorless oil;
yield: 56%. rαs25
D = ´79.6 (c 0.48, EtOH) (for the opposite enantiomer, see reference [23]).
21100
Molecules 2015, 20, 21094–21102
Ethyl (1S,2S,3R)-2-(tert-butoxycarbonyl)-3-hydroxycyclohexanecarboxylate [(+)-25]. A white solid;
mp 76–79 ˝ C; yield: 87%. rαs25
D = +24.6 (c 0.62, EtOH).
Ethyl (1R,2S,3R)-2-(tert-butoxycarbonyl)-3-hydroxycyclohexanecarboxylate [(´)-26]. A white solid;
mp 92–94 ˝ C; Yield: 47%. rαs25
D = ´38.4 (c 0.61, EtOH), (for the opposite enantiomer see reference [23]).
Ethyl (1S,2S)-2-(tert-butoxycarbonyl)-3-oxocyclohexanecarboxylate [(+)-27]. A colorless oil; yield: 70%.
rαs25
D = +54.3 (c 0.415, EtOH), (for the racemic compound, see reference [23]).
Ethyl (1R,2S)-2-(tert-butoxycarbonyl)-3-oxocyclohexanecarboxylate [(´)-28]. A white solid; mp 85–88 ˝ C;
yield: 76%. rαs25
D = ´12.7 (c 0.53, EtOH) (for the racemic compound see reference [23]).
Ethyl (1S,2R)-2-(tert-butoxycarbonyl)-3-methylenecyclohexanecarboxylate [(+)-29]. A colorless oil; yield:
39%. rαs25
D = +25.8 (c 0.38, EtOH); ee = 90.6%.
Ethyl (1R,2S)-2-(tert-butoxycarbonyl)-3-methylenecyclohexanecarboxylate [(´)-29]. A colorless oil; yield:
42%. rαs25
D = ´14.1 (c 0.33, EtOH); ee = 86.7%.
4. Conclusions
Cyclohexane β-amino esters with an extracyclic methylene at position 3, 4 or 5 have been
regio- and stereoselectively synthetized from 2-aminocyclohexenecarboxylic acid regioisomers by
transformation of the ring olefinic bond via three different regio- and stereocontrolled hydroxylation
procedures, followed by deoxygenation through oxo-methylene interconversion via Wittig reactions.
An enantiodivergent route starting from a bicyclic β-lactam enantiomer permitted the synthesis of
both enantiomers of a cyclohexane icofungipen analogue.
Acknowledgments: We are grateful to the Hungarian Research Foundation (OTKA No K100530 and K115731)
for financial support. This paper was supported by the János Bolyai Research Scholarship (L.K.) of the Hungarian
Academy of Sciences.
Author Contributions: L.K. and F.F. designed, planed research and interpreted the results. E.F., G.O. and R.A.
carried out of the synthetic work. All authors discussed the results, prepared and commented on the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors in mg quantities.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open
access article distributed under the terms and conditions of the Creative Commons by
Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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