molecules
Review
Recent Advances in Substrate-Controlled Asymmetric
Induction Derived from Chiral Pool α-Amino Acids
for Natural Product Synthesis
Seung-Mann Paek 1 , Myeonggyo Jeong 2 , Jeyun Jo 2 , Yu Mi Heo 1 , Young Taek Han 3 and
Hwayoung Yun 2, *
1
2
3
*
College of Pharmacy, Research Institute of Pharmaceutical Science, Gyeongsang National University,
Jinju daero, Jinju 52828, Korea; [email protected] (S.-M.P.); [email protected] (Y.M.H.)
College of Pharmacy, Pusan National University, Busan 46241, Korea; [email protected] (M.J.);
[email protected] (J.J.)
College of Pharmacy, Dankook University, Cheonan 31116, Korea; [email protected]
Correspondence: [email protected]; Tel.: +82-51-510-2810; Fax: +82-51-513-6754
Academic Editors: Carlo Siciliano and Constantinos M. Athanassopoulos
Received: 15 June 2016; Accepted: 18 July 2016; Published: 21 July 2016
Abstract: Chiral pool α-amino acids have been used as powerful tools for the total synthesis of
structurally diverse natural products. Some common naturally occurring α-amino acids are readily
available in both enantiomerically pure forms. The applications of the chiral pool in asymmetric
synthesis can be categorized prudently as chiral sources, devices, and inducers. This review
specifically examines recent advances in substrate-controlled asymmetric reactions induced by the
chirality of α-amino acid templates in natural product synthesis research and related areas.
Keywords: chiral pool; α-amino acid; natural product; total synthesis; asymmetric induction
1. Introduction
The chiral pool approach is highly attractive in the asymmetric total synthesis of bioactive
natural products with diverse and complex architectures [1,2]. This strategy is one of the best
methods available to synthetic organic chemists for establishing pivotal stereocenters in optically active
compounds [3–7]. The chiral pool is a versatile tool, comprising naturally occurring chiral molecules
such as carbohydrates, amino acids, terpenes, alkaloids, and hydroxyacids [2,6]. They include
enantiomerically enriched species that can be synthetically transformed into the desired target
molecules. Chiral pool materials are also inexpensive and commercially available, making them
adequate for use in accessing natural products and bioactive compounds [2]. The usage of the chiral
pool in asymmetric synthesis can be classified in three general categories, as shown in Figure 1:
(a) chiral sources, used as building blocks containing built-in stereocenters for target molecules;
(b) chiral devices, employed as useful tools for enantioselective catalysts and auxiliaries; and (c) chiral
inducers, applied to the generation of new stereocenters in a substrate-controlled manner [1–7].
The chiral inducer strategy is a highly efficient method to exploit advantages of both the chiral source
and device approach at the same time.
The specific aim of this review is to present useful applications of enantiomerically enriched
α-amino acids as substrate-controlled asymmetric inducers in natural product synthesis from 2011
to May 2016. Chirally pure α-amino acids are very useful materials due to diversity of functional
group and ease of commercial use [7]. The α-amino acids described in this review are illustrated in
Figure 2. The use of amino acids as chiral sources and devices for asymmetric synthesis is not covered.
Also, synthesis of acyclic or cyclic peptide natural products is not included.
Molecules 2016, 21, 951; doi:10.3390/molecules21070951
www.mdpi.com/journal/molecules
Molecules 2016, 21, 951
Molecules 2016, 21, 951
Molecules 2016, 21, 951
Molecules 2016, 21, 951
2 of 13
2 of 13
2 of 13
2 of 13
Figure 1.
1. Three
Three categories
categories of
of chiral
chiral pool
pool use
use in
in asymmetric
asymmetricsynthesis.
synthesis.
Figure
Figure 1. Three categories of chiral pool use in asymmetric synthesis.
Figure 1. Three categories of chiral pool use in asymmetric synthesis.
Figure 2. Representative α‐amino acids.
Figure 2.
2. Representative
Representative α-amino
α‐amino acids.
acids.
Figure
Figure 2. Representative α‐amino acids.
2. Chiral Pool: Proline
2. Chiral Pool: Proline
2. Chiral
ChiralPool:
Pool: Proline
2.
Recently, aProline
wide range of natural and non‐natural product syntheses using proline as the chiral pool
Recently, a wide range of natural and non‐natural product syntheses using proline as the chiral pool
Recently,
a
wide
and non‐natural
non-natural
product syntheses
prolinepolyhydroxylated
as
the chiral
chiral pool
pool
material
in a substrate‐controlled
manner
have been reported.
Suh et al. using
synthesized
Recently,
a wide range
range of
of natural
natural
and
product
syntheses
proline
as the
material
in a substrate‐controlled
manner
have been reported.
Suh et al. using
synthesized
polyhydroxylated
material
in a
substrate-controlled
manner
al.
indolizidine
alkaloids,
1‐deoxy‐6,8a‐di‐epi‐castanospermine
(4)Suh
andet1‐deoxy‐6‐epi‐castanospermine
(7),
material
in
a alkaloids,
substrate‐controlled
manner have
have been
been reported.
reported.
al. synthesized
synthesized polyhydroxylated
polyhydroxylated
indolizidine
1‐deoxy‐6,8a‐di‐epi‐castanospermine
(4)Suh
andet1‐deoxy‐6‐epi‐castanospermine
(7),
indolizidine
alkaloids,
1-deoxy-6,8a-di-epi-castanospermine
(4)
and
1-deoxy-6-epi-castanospermine
(7),
that
that
can
act
as
selective
α‐glycosidase
inhibitors
[8,9].
L
‐Proline
was
utilized
as
a
platform
to
construct
indolizidine
alkaloids,
(4) and
(7),
that can act as
selective1‐deoxy‐6,8a‐di‐epi‐castanospermine
α‐glycosidase inhibitors [8,9]. L‐Proline
was1‐deoxy‐6‐epi‐castanospermine
utilized as a platform to construct
can
as
selective
α-glycosidase
inhibitors
[8,9].1.
L(E)‐Silyl
-Proline
waswas
utilized
as aas
platform
construct
thea
the act
indolizidine
skeleton,
as shown
ininhibitors
Scheme
enol
ether
2, obtained
fromtoL‐proline
via
that
can
act
as
selective
α‐glycosidase
[8,9].
L‐Proline
utilized
a
platform
to
construct
the indolizidine skeleton, as shown in Scheme 1. (E)‐Silyl enol ether 2, obtained from L‐proline via a
indolizidine
skeleton,
as
shown
in
Scheme
1.
(E)-Silyl
enol
ether
2,
obtained
from
L
-proline
via
a
known
known
protocol
[10,11],
underwent
an
aza‐Claisen
rearrangement
to
produce
the
corresponding
the
indolizidine
as shown inan
Scheme
1. (E)‐Silyl
enol ether 2,toobtained
‐proline via a
known
protocolskeleton,
[10,11], underwent
aza‐Claisen
rearrangement
producefrom
the Lcorresponding
protocol
[10,11],
underwent
anyield.
aza-Claisen
rearrangement
to produce
theproduce
corresponding
9-membered
9‐membered
lactam
3 in 66%
This
transformation
was
impressive
not
only because
it created a
known
protocol
[10,11],
underwent
an
aza‐Claisen
rearrangement
to
the
corresponding
9‐membered lactam 3 in 66% yield. This transformation was impressive not only because it created a
lactam
3 in 66%
yield.
transformation
wastransition
impressive
notbut
only
because
it created
a new
stereogenic
new stereogenic
center
through
a 6‐membered
state,
also
because
it afforded
a cis‐azoninone
9‐membered
lactam
3 This
in
66%
yield.
This transformation
was
impressive
not
because
it
created a
new stereogenic
center
through
a 6‐membered
transition state,
but
also because
itonly
afforded
a cis‐azoninone
center
through
a
6-membered
transition
state,
but
also
because
it
afforded
a
cis-azoninone
framework
framework
simultaneously.
The
final
product
4
was
afforded
after
subsequent
transformations.
Similarly,
new
stereogenic
center
through
a
6‐membered
transition
state,
but
also
because
it
afforded
a
cis‐azoninone
framework simultaneously. The final product 4 was afforded after subsequent transformations. Similarly,
simultaneously.
final
product
4 was
after
subsequent
transformations.
Similarly,
(Z)‐silyl enol
etherThe
5 was
converted
into
trans‐azoninone
6 under
microwave‐assisted
conditions.
It is
framework
simultaneously.
The
final product
4afforded
was afforded
subsequent
transformations.
Similarly,
(Z)‐silyl enol
ether 5 was converted
into trans‐azoninone
6after
under
microwave‐assisted
conditions.
It is
(Z)-silyl
enol
ether
5
was
converted
into
trans-azoninone
6
under
microwave-assisted
conditions.
It
is
noteworthy
that
the
syn‐diol
moiety
of
the
azoninone
skeleton
was
created
via
chiral
communication
of
(Z)‐silyl
enolthat
ether
was converted
into
6 under
conditions. It of
is
noteworthy
the5syn‐diol
moiety of
thetrans‐azoninone
azoninone skeleton
was microwave‐assisted
created via chiral communication
noteworthy
that
the
syn-diol
moiety
of
the
azoninone
skeleton
was
created
via
chiral
communication
the
L
‐proline
stereocenter
during
aza‐Claisen
rearrangement‐induced
ring
expansion.
The
transition
noteworthy
the syn‐diol
moiety
of the azoninone
skeleton was created
viaexpansion.
chiral communication
of
the L‐prolinethat
stereocenter
during
aza‐Claisen
rearrangement‐induced
ring
The transition
of
the
Lin
-proline
stereocenter
during
aza-Claisen
rearrangement-induced
ringexpansion.
expansion.
The1transition
transition
states
bothstereocenter
these
conversions
made
it possible
for the sole chiral center
of
amino acid
to induce
the
L‐proline
during
aza‐Claisen
rearrangement‐induced
ring
The
states in both these conversions made it possible for the sole chiral center of amino acid 1 to induce
states
in both
both
these conversions
conversions
it possible
possible
for6.the
the sole
sole chiral
chiral center
center of
of amino
amino acid
acid 11 to
to induce
induce
additional
chirality
in cis or transmade
azoninones
3 and
states
in
these
it
for
additional
chirality
in cis or transmade
azoninones
3 and
6.
additional
chirality
in
cis
or
trans
azoninones
3
and
6.
additional chirality in cis or trans azoninones 3 and 6.
Scheme 1. Total syntheses of castanospermines 4 and 7.
Scheme 1. Total syntheses of castanospermines 4 and 7.
Scheme
7.
Scheme 1.
1. Total
Total syntheses
syntheses of
of castanospermines
castanospermines 44 and
and 7.
Molecules 2016, 21, 951
3 of 13
Molecules 2016, 21, 951
3 of 13
Molecules 2016, 21, 951
3 of 13
Another
applicationof
ofLL‐proline
-prolineisissummarized
summarized
Scheme
Anothersubstrate-controlled
substrate‐controlledchiral
chiralinduction
induction application
inin
Scheme
2. 2.
Srihari
et
al.
accomplished
the
stereoselective
total
synthesis
of
alkaloid
(´)-allonorsecurinine
(10)
[12].
Srihari
et al. accomplished
the stereoselective
totalapplication
synthesis ofofalkaloid
(−)‐allonorsecurinine
(10) [12].
Another
substrate‐controlled
chiral induction
L‐proline
is summarized in Scheme
2.
ToSrihari
create
the
stereocenter
in
the
lactone
moiety
of
10,
precursor
8
was
readily
prepared
from
L-proline
To
create
the
stereocenter
in
the
lactone
moiety
of
10,
precursor
8
was
readily
prepared
from
L
‐proline
et al. accomplished the stereoselective total synthesis of alkaloid (−)‐allonorsecurinine (10)
[12].
inTo
three
steps.
The
reaction
magnesium
bromide
withα‐amidoketone
α-amidoketone
in
three
steps.
TheGrignard
Grignard
reaction
of isopropenyl
isopropenyl
magnesium
with
create
the stereocenter
in the
lactoneof
moiety
of 10, precursor
8 wasbromide
readily prepared
from L‐proline8 8
afforded
tertiary
alcohol
9
in
high
yield
and
with
excellent
facial
selectivity,
with
the
pivotaltertiary
tertiary
afforded
tertiary
alcohol
9 in high
yieldof
and
with excellent
facial selectivity,
pivotal
in
three steps.
The
Grignard
reaction
isopropenyl
magnesium
bromidewith
withthe
α‐amidoketone
8
alcohol
moiety
inin9alcohol
via
Si-face
to the
the facial
carbonyl
group.With
Withkey
key
intermediate
alcohol
moiety
9constructed
constructed
viayield
Si‐face
addition
carbonyl
group.
intermediate
afforded
tertiary
9 in high
andaddition
with excellent
selectivity,
with
the
pivotal
tertiary9 9
inalcohol
hand,
subsequent
classical
such
as Aldol
andcarbonyl
Horner–Wittig
reactions,
providedfinal
final
in
hand,
subsequent
classicalreactions,
reactions,
such
and
Horner–Wittig
provided
moiety
in 9 constructed
via Si‐face
addition
to the
group. reactions,
With
key intermediate
9
product
10,10,
a Euphorbiaceae
alkaloid.
product
a Euphorbiaceae
alkaloid.
in
hand,
subsequent
classical
reactions, such as Aldol and Horner–Wittig reactions, provided final
product 10, a Euphorbiaceae alkaloid.
Scheme 2. Total synthesis of (−)‐allonorsecurinine (10).
Scheme 2. Total synthesis of (´)-allonorsecurinine (10).
Scheme 2. Total synthesis of (−)‐allonorsecurinine (10).
Cycloaddition reactions have also been adapted for the proline‐derived total synthesis of natural
Cycloaddition
have also
adapted
for the proline-derived
totaland
synthesis
of natural
products.
Sarpongreactions
etreactions
al. completed
the been
impressive
syntheses
ent‐citrinalin Btotal
(15)
cyclopiamine
B
Cycloaddition
have also
been adapted
for the of
proline‐derived
synthesis
of natural
products.
Sarpong
et
al.
completed
the
impressive
syntheses
of
ent-citrinalin
B
(15)
and
cyclopiamine
B
(16)
(16) as shown
in Scheme
3 [13–15]. The
authors utilized
the chirality
of D‐proline
forand
thecyclopiamine
stereoselective
products.
Sarpong
et al. completed
the impressive
syntheses
of ent‐citrinalin
B (15)
B
as(16)
shown
in Scheme
3 [13–15].
authors
utilized
the
of
D -proline
forthe
thecyanoamide
stereoselective
construction
of
cis‐fused
ringThe
system
within
final products
15 and
Unsaturated
12
as shown
inaScheme
3 [13–15].
The
authors
utilized
thechirality
chirality
of16.
D‐proline
for
stereoselective
construction
ofofafrom
ring
system
withinover
finalseven
products
cyanoamide
was prepared
D‐proline
55% within
yield
steps
forand
use
as Unsaturated
a dienophile
in the key
construction
acis-fused
cis‐fused
ring in
system
final
products
1515
and
16.16.
Unsaturated
cyanoamide
12
12was
wasprepared
prepared
from
D
-proline
in
55%
yield
over
seven
steps
for
use
as
a
dienophile
inthe
thekey
key
face‐selective
Diels‐Alder
reaction.
When
diene
13
underwent
cycloaddition
with
12
in
the
from D‐proline in 55% yield over seven steps for use as a dienophile inpresence
face-selective
Diels-Alder
reaction.
When
diene
13
underwent
cycloaddition
with
12
in
the
presence
of Lewis acid [16],
desired reaction.
product 14
was diene
obtained
in 73% yieldcycloaddition
after a basic work‐up.
dienophile
face‐selective
Diels‐Alder
When
13 underwent
with 12 inAs
the
presenceof
Lewis
acid acid
[16],
desired
product
14 was
obtained
in 73%
yield
after
a basic
dienophile
12 Lewis
provided
a[16],
convex
face
environment
in obtained
the bicyclic
ring
system,
diene
13work-up.
approached
β‐face of12
of
desired
product
14 was
in 73%
yield
after
a basic
work‐up.As
Asthe
dienophile
provided
a convex
face face
environment
in the
bicyclic
ring
system,
diene
13 13
approached
thethe
β-face
ofofthe
theprovided
unsaturated
lactam
ring
selectively,
establishing
the
twosystem,
adjacent
stereocenters
in tricyclic
ketone
12
a convex
environment
in the
bicyclic
ring
diene
approached
β‐face
unsaturated
lactam
ring
selectively,
establishing
the
two
adjacent
stereocenters
in
tricyclic
ketone
14
simultaneously.
Subsequent
steps
transformed
14
into
ent‐citrinalin
B
(15)
and
cyclopiamine
B
(16).
the unsaturated lactam ring selectively, establishing the two adjacent stereocenters in tricyclic ketone14
simultaneously.
Subsequent
steps
transformed
14 14
into
ent-citrinalin
(16).
14 simultaneously.
Subsequent
steps
transformed
into
ent‐citrinalinB B(15)
(15)and
andcyclopiamine
cyclopiamine B (16).
Scheme 3. Total syntheses of ent‐citrinalin B (15) and cyclopiamine B (16).
Scheme3.3.Total
Totalsyntheses
syntheses of
of ent-citrinalin
ent‐citrinalin B
Scheme
B (15)
(15) and
andcyclopiamine
cyclopiamineBB(16).
(16).
Memory of chirality is a very special case. Recently, Kim et al. reported the first total synthesis of
(−)‐penibruguieramine
Ais(22),
employing
a biomimetic
approach
(Schemethe
4) first
[17,18].
17 was
Memory of chirality
a very
special case.
Recently, Kim
et al. reported
totalAcid
synthesis
of
Memory of chirality is a very special case. Recently, Kim et al. reported the first total synthesis
coupled with L‐proline t‐butyl
(18) in the
presence of DCC,
providing
amide
19, an intramolecular
(−)‐penibruguieramine
A (22),ester
employing
a biomimetic
approach
(Scheme
4) [17,18].
Acid 17 was
of (´)-penibruguieramine A (22), employing a biomimetic approach (Scheme 4) [17,18]. Acid 17 was
aldol reaction
in 79%
yield.
of 19 of
to DCC,
sodium
ethoxide
enabled
theintramolecular
pyrrolizidine
coupled
with Lprecursor,
‐proline t‐butyl
ester
(18) Exposure
in the presence
providing
amide
19, an
coupled
with
L-proline t-butyl ester (18) in the presence of DCC, providing amide 19, an intramolecular
backbone
and precursor,
two additional
stereogenic
centers of 19
21 to be
established
through
memory
of chirality
aldol
reaction
in 79%
yield. Exposure
sodium
ethoxide
enabled
the pyrrolizidine
aldol
precursor, in 79%
yield.
Exposure
of 19amide
to sodium
ethoxide
enabled
the pyrrolizidine
andreaction
concomitant
kinetic
resolution.
When
19 was
treated
withmemory
a base,
central
backbone
and twodynamic
additional
stereogenic
centers
of 21 to be established
through
ofitschirality
backbone
and
twohave
additional
stereogenic
centers
of 21 to
be established
through
memory
of chirality
chirality
should
been kinetic
deleted
by deprotonation.
However,
enolate
20 with
contained
a chiral
axis,
and
concomitant
dynamic
resolution.
When amide
19 was
treated
a base,
its central
and
concomitant
dynamic
kinetic
resolution.
When
amide
19
was
treated
with
a
base,
its
central
resulting
in
memory
of
chirality
and
hampering
racemization.
Impressively,
the
dynamic
kinetic
chirality should have been deleted by deprotonation. However, enolate 20 contained a chiral axis,
chirality
should
have been
deleted
by deprotonation.
However,
enolate
contained
a From
chiral
axis,
resolution
racemic
methine
occurred,
creating an
α‐chiral
center
in the 20
amide
this
resulting
inofmemory
of chirality
and
hampering
racemization.
Impressively,
themoiety.
dynamic
kinetic
resulting
in
memory
of
chirality
and
hampering
racemization.
Impressively,
the
dynamic
kinetic
transformation,
bicyclicmethine
amide 21
was obtained
in 77%
with
10% of
resolution
of racemic
occurred,
creating
an yield,
α‐chiral
center
in the
thecorresponding
amide moiety.elimination
From this
resolution
of racemic
methine
occurred,
creating
an yield,
α-chiral
the
amide
moiety.
From
this
product. Following
an
uneventful
reduction
procedure,
(−)‐penibruguieramine
A was
produced
from
transformation,
bicyclic
amide 21
was
obtained
in 77%
withcenter
10% ofinthe
corresponding
elimination
transformation,
bicyclic
amide
21
was
obtained
in
77%
yield,
with
10%
of
the
corresponding
elimination
amide
21
in
86%
yield
(two
steps).
product. Following an uneventful reduction procedure, (−)‐penibruguieramine A was produced from
product.
Following
an uneventful
amide 21
in 86% yield
(two steps).reduction procedure, (´)-penibruguieramine A was produced from
amide 21 in 86% yield (two steps).
Molecules 2016, 21, 951
4 of 13
Molecules 2016, 21, 951
4 of 13
Molecules 2016, 21, 951
4 of 13
Scheme 4. Total synthesis of penibruguieramine A (22).
Scheme
4. Total synthesis of penibruguieramine A (22).
Scheme 4. Total synthesis of penibruguieramine A (22).
3. Chiral Pool: Tryptophan
3. Chiral Pool: Tryptophan
Tryptophan,
an aromatic amino acid, has been used as a precursor in the total synthesis of
3. Chiral
Pool: Tryptophan
Tryptophan,
an with
aromatic
amino acid,
has beenframework.
used as a precursor
the total
synthesisserves
of natural
natural products
indole‐derived
heterocyclic
The indole in
moiety
of tryptophan
an
amino acid,
has beenarylation,
used
asindole
a precursor
thetryptophan
total
synthesis
of as
products
withtemplate
indole-derived
heterocyclic
framework.
The
moiety
of
serves
as a Tryptophan,
good
foraromatic
a copper‐catalyzed
asymmetric
as
depicted
ininScheme
5 [19].
Reisman
natural
products
with
indole‐derived
heterocyclic
framework.
The
indole
moiety
of
tryptophan
serves
et template
al. investigated
and optimized these
reaction conditions.
After
an extensive
survey of
bidentate
a good
for a copper-catalyzed
asymmetric
arylation,
as depicted
in Scheme
5 [19].
Reisman
asligands
a goodand
template
for a copper‐catalyzed
asymmetric
arylation,
as depicted
in
Scheme
5 [19].
Reisman
electrophiles
under
(CuOTf)
2
PhMe
catalyst,
cyclic
dipeptide
23
in
the
presence
of
L1
and
et al. investigated and optimized these reaction conditions. After an extensive survey of bidentate
et[Ph
al.2I]OTf
investigated
and
optimized these
reaction
conditions.
After an
extensive survey minimizing
of bidentate
afforded
pyrroloindololine
24
in
high
yield
and
excellent
diastereoselectivity,
ligands and electrophiles under (CuOTf)2 PhMe catalyst, cyclic dipeptide 23 in the presence of L1 and
ligands
and electrophiles
under
(CuOTf)
2 PhMe catalyst, cyclic dipeptide 23 in the presence of L1 and
the undesired
C‐2 arylated
product.
Two
newly created stereogenic centers were induced by the
[Ph2[Ph
I]OTf
afforded
pyrroloindololine
24
in
high yield and excellent diastereoselectivity, minimizing the
2I]OTf afforded pyrroloindololine 24 in high yield and excellent diastereoselectivity, minimizing
chirality
of tryptophan in a substrate‐controlled manner.
undesired
C-2 arylated
product.
Two newly
createdcreated
stereogenic
centers
were were
induced
by the
the undesired
C‐2 arylated
product.
Two newly
stereogenic
centers
induced
bychirality
the
of tryptophan
in
a
substrate-controlled
manner.
chirality of tryptophan in a substrate‐controlled manner.
Scheme 5. Cu‐catalyzed arylation of cyclo‐(Trp‐Phe) 23.
This conversion strategy
was
directly
to theoftotal
synthesis of23.
(+)‐naseseazine A (28) and
Scheme
5. applied
Cu‐catalyzed
arylation
cyclo‐(Trp‐Phe)
Scheme 5. Cu-catalyzed arylation of cyclo-(Trp-Phe) 23.
(+)‐naseseazine B (30) (Scheme 6) [20]. To construct the tetracyclic framework of 28, cyclic alanine‐
tryptophan
dimer 25 was
selected
a chiraldirectly
precursor.
Thetotal
pivotal
arylation
diketopiperazine
25 with
This conversion
strategy
wasasapplied
to the
synthesis
ofof
(+)‐naseseazine
A (28)
and
This
conversion
strategy
was
directly
to
synthesis
of of
(+)-naseseazine
A (28)
advanced
electrophile
26
in the
presence
of (CuOTf)
2 PhMe
andtotal
L2 provided
desired
pyrroloindoline
27
(+)‐naseseazine
B (30)
(Scheme
6) applied
[20]. To
construct
thethe
tetracyclic
framework
28, cyclic alanine‐
and tryptophan
(+)-naseseazine
Bwas
(30)
(Scheme
6) [20].
ToThe
construct
the
tetracyclic
framework
in
moderate
yield.
compound
was
conveniently
constructed
from
tetracyclic
intermediate
27of 28,
dimer
25Final
selected
as a28chiral
precursor.
pivotal arylation
of diketopiperazine
25 with
using
a Larock
indolization
[21,22].
Additionally,
another
naturaldesired
product,
(+)‐naseseazine
advanced
electrophile
26 in
thestrategy
presence
of selected
(CuOTf)
2 PhMe
and
L2precursor.
provided
27 of
cyclic
alanine-tryptophan
dimer
25 was
as a chiral
The pyrroloindoline
pivotal
arylation
was obtained
stereoselectively
from
cyclic
proline‐tryptophan
29,2 employing
similar
inB,moderate
yield.
Finaladvanced
compound
28 was
conveniently
tetracyclic
intermediate
27
diketopiperazine
25 with
electrophile
26 in the constructed
presenceprecursor
offrom
(CuOTf)
PhMe
andaL2
provided
synthetic
sequence.
using
a
Larock
indolization
strategy
[21,22].
Additionally,
another
natural
product,
(+)‐naseseazine
desired pyrroloindoline 27 in moderate yield. Final compound 28 was conveniently constructed from
applying this methodology
to simple carboxamide
31 afforded
pyrroloindololine
B, wasInterestingly,
obtained stereoselectively
from cyclic
proline‐tryptophan
precursor
29, employing
a similar
tetracyclic
intermediate
27 using a Larock
indolization
strategy [21,22].
Additionally,
another
natural
compound
32, possessing the opposite stereochemistry in the C‐2 and C‐3 positions. This discrepancy
synthetic
sequence.
product, (+)-naseseazine B, was obtained stereoselectively from cyclic proline-tryptophan precursor 29,
shows
that amino applying
acids provide
a tremendous to
opportunity
for the diastereoselective
synthesis of the
Interestingly,
this methodology
simple carboxamide
31 afforded pyrroloindololine
employing
a similar synthetic
sequence.
pyrroloindololine
framework
as
shown
in
Scheme
7.
compound 32, possessing the opposite stereochemistry in the C‐2 and C‐3 positions. This discrepancy
Interestingly, applying
this
methodology
to simple
31 afforded
pyrroloindololine
utilized
as a chiral pool
reagentcarboxamide
infor
the
total
synthesis
of prenylated
showsTryptophan
that amino was
acidsalso
provide
a tremendous
opportunity
the
diastereoselective
synthesisindole
of the
compound
32,(−)‐brevicompanine
possessing
the opposite
stereochemistry
in(40)
the(Scheme
C-2 and8)C-3
discrepancy
alkaloids
B (38)
and
(+)‐aszonalenin
[23].positions.
Carreira etThis
al. reported
pyrroloindololine
framework as
shown
in
Scheme 7.
shows
amino
acids
a tremendous
opportunity
diastereoselective
synthesis
a that
highly
diastereoselective
and
regioselective
iridium‐catalyzed
reverse
prenylation
reaction.
Theof the
Tryptophan
was provide
also utilized
as a chiral pool
reagent infor
thethe
total
synthesis
of prenylated
indole
reaction
of
readily
available
L‐tryptophan
methyl
ester
33
with
tertiary
carbonate
34
in
the
presence
pyrroloindololine
framework
as
shown
in
Scheme
7.
alkaloids (−)‐brevicompanine B (38) and (+)‐aszonalenin (40) (Scheme 8) [23]. Carreira et al. reported
ofhighly
[{Ir(cod)Cl}
2] and
phosphoramidite
ligandiridium‐catalyzed
35 [24]
furnished
hexahydropyrrolo[2,3‐b]indole
was
also
utilized
as a chiral
pool
reagent
inreverse
the
total
synthesisreaction.
of prenylated
aTryptophan
diastereoselective
and regioselective
prenylation
The
(−)‐exo‐36
in
58%
yield.
Initially,
the
exo/endo
ratio
of
the
prenylation
was
low (1.3:1).
However,
it et al.
indole
alkaloids
(´)-brevicompanine
B (38)methyl
and (+)-aszonalenin
(40) quite
(Scheme
8)
Carreira
reaction
of readily
available L‐tryptophan
ester 33 with tertiary
carbonate
34 [23].
in the
presence
was
improved
to
>20:1
by
extensive
optimization
of
base,
ligand,
and
reaction
temperature.
Importantly,
of [{Ir(cod)Cl}
] and phosphoramidite
ligand 35 [24]
furnished hexahydropyrrolo[2,3‐b]indole
reported
a highly 2diastereoselective
and regioselective
iridium-catalyzed
reverse prenylation reaction.
the installation of two vicinal stereogenic centers was controlled by the chirality of tryptophan. After
(−)‐exo‐36
in
58%
yield.
Initially,
the
exo/endo
ratio
of
the
prenylation
was quite
low (1.3:1).
However,
The reaction of readily available L-tryptophan methyl ester 33 with
tertiary
carbonate
34 init the
this successful result, (−)‐brevicompanine B (38) [25], a plant growth regulator, was finally obtained
was improved
to >20:1] by
extensive optimization of base, ligand, and reaction temperature. Importantly,
presence
of [{Ir(cod)Cl}
2 and phosphoramidite ligand 35 [24] furnished hexahydropyrrolo[2,3-b]indole
the
installation
of
two
vicinal
centers
by the was
chirality
tryptophan.
After
(´)-exo-36 in 58% yield. Initially,stereogenic
the exo/endo
ratiowas
of controlled
the prenylation
quiteoflow
(1.3:1). However,
this successful result, (−)‐brevicompanine B (38) [25], a plant growth regulator, was finally obtained
it was improved to >20:1 by extensive optimization of base, ligand, and reaction temperature.
Importantly, the installation of two vicinal stereogenic centers was controlled by the chirality of
tryptophan. After this successful result, (´)-brevicompanine B (38) [25], a plant growth regulator,
Molecules 2016, 21, 951
5 of 13
Molecules 2016, 21, 951
Molecules 2016, 21, 951
5 of 13
5 of 13
was finally obtained from iterative amidations in good yield. The total synthesis of another alkaloid,
from
iterative
in good yield. The total synthesis of another alkaloid, (+)‐aszonalenin
Molecules
2016, 21,amidations
951
of(40)
13
(+)-aszonalenin
(40)
[26],
a substance
Phuman
inhibitor
forsynthesis
the human
neurokinin-1
receptor,
was 5efficiently
from
amidations
in good
yield.
The neurokinin‐1
total
of another
alkaloid,
(+)‐aszonalenin
(40)
[26], aiterative
substance
P inhibitor
for the
receptor,
was
efficiently
completed
from
[26],
a substance
P inhibitor
for
human
receptor,
was efficiently completed from
completed
from Dmethyl
-tryptophan
ester
39neurokinin‐1
via asynthesis
similar
synthetic
Dfrom
‐tryptophan
esterin
39methyl
viathe
ayield.
similar
synthetic
procedure.
iterative
amidations
good
The
total
of
another procedure.
alkaloid, (+)‐aszonalenin (40)
D‐tryptophan
methyl
ester 39 for
via the
a similar
synthetic
procedure.
[26], a substance
P inhibitor
human
neurokinin‐1
receptor, was efficiently completed from
D‐tryptophan methyl ester 39 via a similar synthetic procedure.
Scheme 6. Total synthesis of (+)‐naseseazines A and B.
Scheme
6.6.Total
and
Scheme
Totalsynthesis
synthesis of
of (+)-naseseazines
(+)‐naseseazines AAand
B. B.
Scheme 6. Total synthesis of (+)‐naseseazines A and B.
Scheme 7. Diastereoselective cyclization for pyrroloindoline skeleton.
Scheme
Diastereoselective cyclization
cyclization for
skeleton.
Scheme
7. 7.
Diastereoselective
forpyrroloindoline
pyrroloindoline
skeleton.
Scheme 7. Diastereoselective cyclization for pyrroloindoline skeleton.
Scheme 8. Total syntheses of (−)‐brevicompanine B (38) and (+)‐aszonalenin (40).
Scheme
(38)and
and(+)‐aszonalenin
(+)‐aszonalenin(40).
(40).
Scheme8.
8. Total
Total syntheses
syntheses of
of (−)‐brevicompanine
(−)‐brevicompanine BB (38)
Scheme 8. Total syntheses of (´)-brevicompanine B (38) and (+)-aszonalenin (40).
Molecules 2016, 21, 951
6 of 13
Molecules 2016, 21, 951
6 of 13
A more recent example of tryptophan-templated chiral pool synthesis is illustrated in Scheme 9.
A more
recent example
of tryptophan‐templated
chiral pool(45)
synthesis
is illustrated in Scheme
Baran et al.
accomplished
the total
syntheses of verruculogen
and fumitremorgin
A (46), 9.
which
Molecules
2016,
21, 951
6 of 13
Baran
et
al.
accomplished
the
total
syntheses
of
verruculogen
(45)
and
fumitremorgin
A
(46),
which
both contain a unique eight-membered endoperoxide [27–29]. Diastereoselective Pictet-Spengler
both contain a unique eight‐membered endoperoxide [27–29]. Diastereoselective Pictet‐Spengler
cyclization
of 42,
prepared
N-Boc-L-tryptophan
methyl
ester (41), with TBDPS-protected
A more
recent
examplefrom
offrom
tryptophan‐templated
chiral
pool synthesis
in Scheme 9.
cyclization
of
42, prepared
N‐Boc‐L‐tryptophan
methyl
ester (41),is illustrated
with TBDPS‐protected
peroxy-aldehyde
43
gave
tricycle
44.
Although
the
facial
selectivity
was relativelyAlow
major
Baran
et
al.
accomplished
the
total
syntheses
of
verruculogen
(45)
and
fumitremorgin
(46),(2:1),
which
peroxy‐aldehyde 43 gave tricycle 44. Although the facial selectivity was relatively low (2:1),
major
diastereomer
44 was
effectively
exploited
to endoperoxide
finish
thethe
total
syntheses.
The
chirality
both
contain
a44unique
eight‐membered
[27–29].
Diastereoselective
Pictet‐Spengler
diastereomer
was
effectively
exploited
to finish
total
syntheses.
The
chiralityof
oftryptophan
tryptophan from
the chiral
pool
was
critical
for
creating
the
new
stereocenter
in
the
indole
system.
The
pivotal
methoxy
cyclization
of
42,
prepared
from
N‐Boc‐
L
‐tryptophan
methyl
ester
(41),
with
TBDPS‐protected
from the chiral pool was critical for creating the new stereocenter in the indole system. The pivotal
peroxy‐aldehyde
43
gave
tricycle
44.
Although
the
facial
selectivity
was
relatively
low
(2:1),
major
groupmethoxy
in precursor
42precursor
was introduced
by Ir-catalyzed
borylation
and Chan-Lam
coupling
[30].
group in
42 was introduced
by Ir‐catalyzed
borylation
and Chan‐Lam
coupling
[30].
diastereomer 44 was effectively exploited to finish the total syntheses. The chirality of tryptophan
from the chiral pool was critical for creating the new stereocenter in the indole system. The pivotal
methoxy group in precursor 42 was introduced by Ir‐catalyzed borylation and Chan‐Lam coupling [30].
Scheme 9. Total syntheses of verruculogen (45) and fumitremorgin A (46).
Scheme
9. Total syntheses of verruculogen (45) and fumitremorgin A (46).
4. Chiral Pool: Tyrosine
4. Chiral Pool: Tyrosine
Scheme 9. Total syntheses of verruculogen (45) and fumitremorgin A (46).
Various natural product syntheses have started from chiral pool reagent tyrosine, which can be
Various
natural
product syntheses
have started Tokuyama
from chiral
pool
reagent
which
transformed
into
enantiomerically
pure intermediates.
et al.
reported
the tyrosine,
total synthesis
of can
4.
Chiral Pool:
Tyrosine
be transformed
into
enantiomerically
pure
intermediates.
Tokuyama
et
al.
reported
the
dimeric alkaloid (−)‐acetylaranotin 49 in 2012 (Scheme 10) [31,32]. Alkaloid 49 features a dihydrooxepine total
Various
natural
product
syntheses haveketone
started
chiral
pool reagent
tyrosine,
which 49
canfeatures
be
synthesis
of dimeric
alkaloid
(´)-acetylaranotin
4948infrom
2012
(Scheme
10) [31,32].
Alkaloid
backbone
synthesized
from α,β‐unsaturated
by
olefin
isomerization,
Wharton
rearrangement,
transformed
into
enantiomerically
pure
intermediates.
Tokuyama
et
al.
reported
the
total
synthesis
of
Baeyer‐Villiger backbone
oxidation, and
further steps.
Theα,β-unsaturated
total synthesis commenced
preparation
of
a dihydrooxepine
synthesized
from
ketone 48with
by the
olefin
isomerization,
dimeric
alkaloid
(−)‐acetylaranotin
49
in
2012
(Scheme
10)
[31,32].
Alkaloid
49
features
a
dihydrooxepine
enone
48 via oxidative Baeyer-Villiger
dearomatization oxidation,
of N‐Cbz‐L‐tyrosine
(47) and
subsequent
conjugate
addition
of
Wharton
rearrangement,
and further
steps.
The total
synthesis
commenced
backbone
synthesized
frommoiety.
α,β‐unsaturated
ketone 48
by olefin
isomerization,
Wharton rearrangement,
the
transition
state
amino
This
remarkable
reaction
was
previously
developed
and
described
with the preparation of enone 48 via oxidative dearomatization of N-Cbz-L-tyrosine (47) and
Baeyer‐Villiger
oxidation,
and further
steps. The total
synthesis
the preparation
by Wipf et al. [33].
oxidative
dearomatization
of the
phenol commenced
moiety in 47,with
transition
states, of
T1
subsequent
conjugateAfter
addition
of the
transition state
amino
moiety.
This two
remarkable
reaction
was
enone
48
via
oxidative
dearomatization
of
N‐Cbz‐
L
‐tyrosine
(47)
and
subsequent
conjugate
addition
of
and T2, for concomitant conjugate addition are possible. T1 was more stable, due to having less A1,3‐strain
previously
developed
and
described
by Wipf
et al. [33].
After
oxidative
dearomatization
of the phenol
the
transition
stateoxygen),
amino
moiety.
This
remarkable
reaction
was
previously
and described
(H and
carbonyl
resulting
in 48
being obtained
exclusively
as the developed
major diastereomer.
This
moiety
in
47,
two
transition
states,
T
and
T
,
for
concomitant
conjugate
addition
are
possible.
1
2
by
Wipf
et selectivity
al. [33]. After
oxidative
dearomatization
of the phenol
moiety
twoinducers.
transition states, T
T11 was
high
facial
further
demonstrates
the superiority
of amino
acidsinas47,
chiral
1,3 -strain (H and carbonyl oxygen), resulting in 48 being
1,3
moreand
stable,
due
to
having
less
A
obtained
T2, for concomitant conjugate addition are possible. T1 was more stable, due to having less A ‐strain
(H and as
carbonyl
oxygen),
resulting inThis
48 being
obtained
exclusively
as thedemonstrates
major diastereomer.
This
exclusively
the major
diastereomer.
high facial
selectivity
further
the superiority
high acids
facial selectivity
further demonstrates the superiority of amino acids as chiral inducers.
of amino
as chiral inducers.
Scheme 10. Total synthesis of (−)‐acetylaranotin (49).
Alkene asymmetric dihydroxylation is another example of tyrosine utilized as a chiral template.
Scheme
10. Total synthesis
of (−)‐acetylaranotin
(49).
The stereoselective synthesis
of pyrrolidinone
alkaloid
rigidiusculamide
A was completed by Krishna
Scheme 10. Total synthesis of (´)-acetylaranotin (49).
Alkene asymmetric dihydroxylation is another example of tyrosine utilized as a chiral template.
Alkene
asymmetric
dihydroxylation
is another
example
of tyrosine
utilized
as a chiral
template.
The stereoselective
synthesis
of pyrrolidinone
alkaloid
rigidiusculamide
A was
completed
by Krishna
The stereoselective synthesis of pyrrolidinone alkaloid rigidiusculamide A was completed by
Molecules 2016, 21, 951
7 of 13
Molecules 2016, 21, 951
7 of 13
Krishna et al. (Scheme 11) [34,35]. To incorporate the syn-diol moiety in 53, they dihydroxylated 51
Molecules
2016, 21,11)
951 [34,35]. To incorporate the syn‐diol moiety in 53, they dihydroxylated 51 using
7 ofthe
13
et
al. (Scheme
using the Upjohn method (OsO4 /NMO) [36]. This transformation afforded desired diol 52 as a
Upjohn method (OsO4/NMO) [36]. This transformation afforded desired diol 52 as a single diastereomer
single
diastereomer
in 69% To
yield.
The chirality
of γ-lactam 52
thought
to be responsible
for
et 69%
al.
(Scheme
11)chirality
[34,35].
incorporate
the syn‐diol
in was
53, they
dihydroxylated
51 usingpure
the the
in
yield. The
of γ‐lactam
52 was
thought moiety
to be responsible
for
the enantiomerically
enantiomerically
pure
tyrosine-induced
α-facial
selectivity.
Finally,
the
O-benzyl
group
in
52
Upjohn method (OsO
4/NMO)
[36]. This
transformation
afforded
desired
as a single diastereomer
tyrosine‐induced
α‐facial
selectivity.
Finally,
the O‐benzyl
group
in 52 diol
was52
deprotected
to afford thewas
deprotected
to
afford
the
originally
proposed
structure
of
rigidiusculamide
A.
Unfortunately,
in 69% yield.
The chirality
of γ‐lactam
52 was thought
be responsible
forexperimental
the enantiomerically
originally
proposed
structure
of rigidiusculamide
A. to
Unfortunately,
the
data waspure
not the
experimental
identical
toFinally,
that
of the
the [35].
authenticgroup
natural
product
[35].
tyrosine‐induced
selectivity.
O‐benzyl
in 52
was deprotected
to afford the
identical
todata
that was
ofα‐facial
thenot
authentic
natural
product
originally proposed structure of rigidiusculamide A. Unfortunately, the experimental data was not
identical to that of the authentic natural product [35].
Scheme11.
11.Total
Totalsynthesis
synthesis of
of rigidiusculamide
Scheme
rigidiusculamideAA(53).
(53).
5. Chiral Pool: Serine
5. Chiral Pool: Serine
Scheme 11. Total synthesis of rigidiusculamide A (53).
Serine,
containing
a hydroxymethyl group, has also been used as the powerful chiral pool reagent
5. Chiral
Pool:
Serine
containing
a hydroxymethyl
group,Ahas
also been impressive
used as theexample,
powerfulthe
chiral
pool reagent in
inSerine,
the synthesis
of complex
target molecules.
particularly
enantioselective
the synthesis
of
complex
target
molecules.
A
particularly
impressive
example,
the
enantioselective
synthesis
Serine,
hydroxymethyl
group,
also
as the
powerful
pool reagent
synthesis
of containing
(−)‐α‐kainica acid
(60), in which
Zhouhas
and
Li been
et al.used
present
a unique
SmIchiral
2‐catalyzed
[3
+ 2]
in the synthesis
of
complex
target
molecules.
impressive
the
of (´)-α-kainic
acidcycloaddition
(60),
in which
Zhou
and
etAal.particularly
present
a unique
SmI2example,
-catalyzed
[3 enantioselective
+ 2]
intramolecular
reaction
withLiexcellent
diastereoselectivity,
is summarized
inintramolecular
Scheme 12
synthesis
ofreaction
(−)‐α‐kainic
(60), indiastereoselectivity,
which
Zhousynthesized
and Li et
present
a unique
SmI
2‐catalyzed
+ 2]key
cycloaddition
withacid
excellent
is al.
summarized
in
Scheme
12HCl
[37,38].
The
[37,38].
The
key
precursor,
cyclopropane
56, was
from
D‐serine
methyl
ester
(55)[3
using
intramolecular
cycloaddition
reaction
with
excellent
diastereoselectivity,
is
summarized
in
Scheme
12
conventional
protocols.56,
When
cyclopropanefrom
56 was
treatedmethyl
with samarium
ketyl
radical
precursor,
cyclopropane
was synthesized
D -serine
ester HCldiiodide,
(55) using
conventional
[37,38].
The
key
precursor,
cyclopropane
56,
was
synthesized
from
D
‐serine
methyl
ester
HCl
(55)
using
57 was When
initiallycyclopropane
formed. Rapid56cleavage
of thewith
cyclopropyl
ring
and subsequent
cycloaddition
was
protocols.
was treated
samarium
diiodide,
ketyl radical
57 was initially
conventional
protocols.
When
56 was
treated
with
samarium
diiodide, ketyl
observed,
which
afforded
bicyclic ketone
in good
yield.
It was
hypothesized
thatradical
ketyl
formed.
Rapid
cleavage
ofdesired
thecyclopropane
cyclopropyl
ring59and
subsequent
cycloaddition
was
observed,
57 was 57
initially
formed. Rapid
cleavage ofenolate
the cyclopropyl
ring and
subsequent
cycloaddition
was
radical
spontaneously
transformed
created chiral
which
afforded
desired bicyclic
ketoneinto
59 in goodradical
yield.58.ItThis
wasnewly
hypothesized
thatcenter
ketylfavored
radical 57
observed,
which
afforded
desired
bicyclic
ketone
59
in
good
yield.
It
was
hypothesized
that
ketyl
2,3‐trans stereoselectivity
via radical
facial control
from
the sole
chiral chiral
center center
from the
chiral amino
spontaneously
transformedover
into2,3‐cis
enolate
58. This
newly
created
favored
2,3-trans
radical
57 spontaneously
transformed
radical
58. Thisof
newly
created
chiral
center favored
acid.
With
key intermediate
59 in hand,into
theenolate
asymmetric
synthesis
kainoid
60 was
accomplished
via
stereoselectivity over 2,3-cis via facial control from the sole chiral center from the chiral amino acid.
stereoselectivity
a2,3‐trans
high‐yielding
sequence.over 2,3‐cis via facial control from the sole chiral center from the chiral amino
With
keyWith
intermediate
59 in hand,
the asymmetric
synthesis
of of
kainoid
via a
acid.
key intermediate
59 in hand,
the asymmetric
synthesis
kainoid60
60was
was accomplished
accomplished via
high-yielding
sequence.
a high‐yielding sequence.
Scheme 12. Total synthesis of (−)‐α‐kainic acid (60).
Scheme 12. Total
synthesis
of
(−)‐α‐kainic
acid (60).
The synthesis of iso‐haouamine
B issynthesis
another of
example
(Scheme
13) [39,40]. Structurally, this
Scheme 12. Total
(´)-α-kainic
acid (60).
alkaloid, 64, consists of an indeno‐tetrahydropyridine core fused to a highly distinctive 11‐membered
The synthesis
of iso‐haouamine
B is another
example (Scheme oxidative
13) [39,40].
Structurally,
p‐cyclophane
ring. Trauner
et al. investigated
a substrate‐controlled
phenol
couplingthis
to
The
synthesis
of
iso-haouamine
B
is
another
example
(Scheme
13)
[39,40].
Structurally,
alkaloid, 64,
of an indeno‐tetrahydropyridine
coreprecursor
fused to a enone
highly62
distinctive
11‐membered
establish
theconsists
indeno‐tetrahydropyridine
ring. Coupling
was readily
preparedthis
alkaloid,
64, consists
anL‐serine
indeno-tetrahydropyridine
core fused62toprepared,
a highly
distinctive
11-membered
p‐cyclophane
ring.ofTrauner
et al.
investigated
a substrate‐controlled
oxidative
phenolactivation
coupling
to
from
N‐Boc
protected
(61).
With desired
intermediate
carbonyl
by
establish
the
indeno‐tetrahydropyridine
ring. of
Coupling
precursor
enone
62
was
readily enol
prepared
p-cyclophane
ring.
Trauner
et al. investigated
a the
substrate-controlled
oxidative
phenol
coupling
triflic
anhydride
and
concomitant
1,4‐addition
electron‐rich
aromatic
ring
produced
ether to
from N‐Boc
protected L‐serine (61). With
desired
intermediate
62enone
prepared,
carbonyl
establish
the indeno-tetrahydropyridine
ring.
Coupling
precursor
62 was
readilyactivation
preparedby
from
triflic anhydride and concomitant 1,4‐addition of the electron‐rich aromatic ring produced enol ether
Molecules 2016, 21, 951
8 of 13
N-Boc protected L-serine (61). With desired intermediate 62 prepared, carbonyl activation by triflic
Molecules 2016, 21, 951
8 of 13
anhydride and concomitant 1,4-addition of the electron-rich aromatic ring produced enol ether 63 in
Molecules 2016,
21, During
951
8 of 13
moderate
yield.
the crucial
addition
process,
the syn-substituted
cyclopentane
skeleton
was
63 in moderate
yield. During
the crucial
addition
process,
the syn‐substituted
cyclopentane
skeleton
constructed
without
racemization.
The
new
quaternary
stereogenic
center
in
63
was
ultimately
derived
was constructed without racemization. The new quaternary stereogenic center in 63 was ultimately
63 in moderate yield. During the crucial addition process, the syn‐substituted cyclopentane skeleton
from
the chiral
stereocenter
in 62.
derived
from pool
the chiral
pool stereocenter
in 62.
was constructed without racemization. The new quaternary stereogenic center in 63 was ultimately
derived from the chiral pool stereocenter in 62.
Scheme13.
13.Total
Total synthesis
synthesis of
of iso‐haouamine
Scheme
iso-haouamineBB(64).
(64).
Scheme 13. Total synthesis of iso‐haouamine B (64).
More recently, Ciufolini et al. described the total synthesis of (+)‐erysotramidine (70) using an
More
recently, Ciufolini et al. described the total synthesis of (+)-erysotramidine (70) using an L-serine
L‐serine derivative (Scheme 14) [41,42]. Advanced oxazoline 67, prepared from L‐serine methyl ester
More
recently,
et al. described
the 67,
total
synthesis
of (+)‐erysotramidine
(70)
using
an
derivative
(Scheme
14) Ciufolini
[41,42].
Advanced
oxazoline
prepared
from
-serine
methyl into
ester
(66)
via
(66) via DCC coupling
and Burgess
reagent‐induced
cyclization
[43],Lwas
converted
enone
68 DCC
as
L‐serine derivative (Scheme 14) [41,42]. Advanced oxazoline 67, prepared from L‐serine methyl ester
coupling
and Burgess
reagent-induced
cyclization
[43],
was converted
into enone
68 as aenone
precursor
a precursor
for stereoselective
Michael
cyclization.
Exposure
of electronically
deficient
68 infor
(66) via DCC coupling and Burgess reagent‐induced cyclization [43], was converted into enone 68 as
stereoselective
Michael
cyclization.
Exposure
of electronically
enone
68 in CHin
CH2Cl2 to TsOH
resulted
in the desired
tetracyclic
core of 69 deficient
as a single
diastereomer
excellent
2 Cl
2 to TsOH
a precursor for stereoselective Michael cyclization. Exposure of electronically deficient enone 68 in
resulted
in the desired
tetracyclic
coregroup
of 69 as
a single
diastereomer
in excellent
yield.
Although
yield. Although
the serine
hydroxyl
could
approach
the two reactive
Michael
acceptors,
thethe
CH2Cl2 to TsOH resulted in the desired tetracyclic core of 69 as a single diastereomer in excellent
serine
hydroxyl
group
could
approach
the
two
reactive
Michael
acceptors,
the
formation
of
desired
formation of desired product 69 was favored. The high diastereoselectivity was assumed to result
yield. Although the serine hydroxyl group could approach the two reactive Michael acceptors, the
from the
minimization
of unwanted
nonbonding interactions
between
the methyl
group and
product
69 was
favored. The
high diastereoselectivity
was assumed
to result
fromester
the minimization
formation of desired product 69 was favored. The high diastereoselectivity was assumed to result
[44,45]. interactions
The pseudoaxial
conformation
of the
methyl
resulted
from[44,45].
the
of acylamido
unwanted group
nonbonding
between
the methyl
ester
groupester
andgroup
acylamido
group
from the minimization of unwanted nonbonding interactions between the methyl ester group and
chirality
of
serine.
After
this
chiral
communication,
(+)‐erysotramidine
(70)
was
synthesized
from
key
Theacylamido
pseudoaxial
conformation
the methylconformation
ester group resulted
from the
chirality
serine.from
Afterthe
this
group
[44,45]. The of
pseudoaxial
of the methyl
ester
group of
resulted
synthetic
intermediate(+)-erysotramidine
69 using further manipulations.
chiral
communication,
(70)
was
synthesized
from
key
synthetic
intermediate
chirality of serine. After this chiral communication, (+)‐erysotramidine (70) was synthesized from key 69
using
further
manipulations.
synthetic
intermediate
69 using further manipulations.
Scheme 14. Total synthesis of (+)‐erysotramidine (70).
Scheme 14. Total synthesis of (+)‐erysotramidine (70).
6. Chiral Pool: Alanine Scheme 14. Total synthesis of (+)-erysotramidine (70).
The stereocenter
in alanine, a simple chiral pool reagent, has also provided good opportunities for
6. Chiral
Pool: Alanine
6. Chiral Pool: Alanine
chiral induction. Gouault et al. accomplished the asymmetric total synthesis of dendrobate alkaloid
The stereocenter in alanine, a simple chiral pool reagent, has also provided good opportunities for
(+)‐241D
(74) and isosolenopsin
(Scheme
Structurally,
these alkaloids
consist of
The stereocenter
in alanine, a (76)
simple
chiral 15)
pool[46–48].
reagent,
has also provided
good opportunities
chiral induction. Gouault et al. accomplished the asymmetric total synthesis of dendrobate alkaloid
Vinylogous
lactams 72 and the
73, which
were used
assynthesis
chiral precursors,
were
forcis‐2,6‐dialkylpiperidine.
chiral
induction.
Gouault
et
al.
accomplished
asymmetric
total
of
dendrobate
(+)‐241D (74) and isosolenopsin (76) (Scheme 15) [46–48]. Structurally, these alkaloids consist
of
cis‐2,6‐dialkylpiperidine. Vinylogous lactams 72 and 73, which were used as chiral precursors, were
Molecules 2016, 21, 951
9 of 13
alkaloid (+)-241D (74) and isosolenopsin (76) (Scheme 15) [46–48]. Structurally, these alkaloids consist
2016, 21, 951
9 of 13
of Molecules
cis-2,6-dialkylpiperidine.
Vinylogous lactams 72 and 73, which were used as chiral precursors,
Molecules
2016, prepared
21, 951
9 of 13 of
were
readily
from N-Boc protected D-alanine 71 [49]. The catalytic hydrogenation
readily prepared from N‐Boc protected D‐alanine 71 [49]. The catalytic hydrogenation of Boc‐deprotected
Boc-deprotected amine 73 finally gave the target molecule, (+)-241D (74), via stereoselective reduction
amine
finally gave
target
molecule,
(+)‐241D
reductionof
ofBoc‐deprotected
both the alkene
readily73
prepared
fromthe
N‐Boc
protected
D‐alanine
71 (74),
[49]. via
Thestereoselective
catalytic hydrogenation
of and
bothketone.
the alkene
and
ketone.
In
addition,
key
intermediate
75,
which
was
transformed
into
In gave
addition,
key intermediate
75, which
was
transformedreduction
into enantiopure
alkaloid
amine 73 finally
the target
molecule, (+)‐241D
(74), via
stereoselective
of both the
alkene
enantiopure
alkaloid isosolenopsin
(76),
was obtainedunder
by hydrogenation
under The
similar
conditions.
The
isosolenopsin
was obtained
by
hydrogenation
conditions.
newly
generated
and ketone. In(76),
addition,
key intermediate
75, which wassimilar
transformed
into enantiopure
alkaloid
newly
generated
stereogenic
centers
in
74
and
75
were
affected
by
the
chirality
of
D
-alanine.
The
total
stereogenic
centers
in 74obtained
and 75 were
affected by the
chirality
of conditions.
D‐alanine. The
synthesis
of
isosolenopsin
(76), was
by hydrogenation
under
similar
The total
newly
generated
synthesis
of isosolenopsin
(76) was using
completed
using deoxygenation
and Boc-deprotection
steps.
isosolenopsin
(76)
was
completed
deoxygenation
and
Boc‐deprotection
steps.
stereogenic centers in 74 and 75 were affected by the chirality of D‐alanine. The total synthesis of
isosolenopsin (76) was completed using deoxygenation and Boc‐deprotection steps.
Scheme15.
15.Total
Totalsyntheses
syntheses of
of (+)-241D
(+)‐241D (74)
Scheme
(74)and
andisosolenopsin
isosolenopsin(76).
(76).
Scheme 15. Total syntheses of (+)‐241D (74) and isosolenopsin (76).
7. Chiral Pool: Threonine
7. Chiral Pool: Threonine
7. Chiral
Pool:acid
Threonine
α‐Amino
threonine is a special chiral pool reagent, containing an extra stereocenter. Recently,
acid
threoninethe
is a special
chiralofpool
reagent,
containingacid
an extra
stereocenter. Recently,
α-Amino
Seeberger
et
al.
published
synthesis
protected
legionaminic
80 stereocenter.
from D‐threonine
as a
α‐Amino acid threonine istotal
a special
chiral pool
reagent,
containing an
extra
Recently,
Seeberger
et
al.
published
the
total
synthesis
of
protected
legionaminic
acid
80
from
D -threonine as
starting
material
(Scheme
16)
[50,51].
Conventional
protection
of
chiral
pool
reagent
77,
followed
Seeberger et al. published the total synthesis of protected legionaminic acid 80 from D‐threonine asbya
a starting
material
(Scheme
16) [50,51].
Conventional
protection
of chiral
pool
reagent7877,infollowed
DIBAL‐H
reduction,
provided
chiral Conventional
aldehyde
78 in
high
yield
[52].
With
threoninal
hand,
starting material
(Scheme
16) [50,51].
protection
of chiral
pool reagent
77, followed
by
bytreatment
DIBAL-Hwith
reduction,
provided
chiral
aldehyde
78
in
high
yield
[52].
With
threoninal
78
in hand,
2‐lithiofuran
resulted
in
desired
alcohol
79.
Although
the
organometallic
addition
DIBAL‐H reduction, provided chiral aldehyde 78 in high yield [52]. With threoninal 78 in hand,
treatment
with 2-lithiofuran
resulted inmixture,
desired alcohol
79.syn‐configured
Although the organometallic
addition
reaction
could
a diastereomeric
desired
79, was obtained
treatment
withproduce
2‐lithiofuran
resulted in desired the
alcohol
79. Although the alcohol,
organometallic
addition
reaction
could
produce
a
diastereomeric
mixture,
the
desired
syn-configured
alcohol,
79,
was
obtained
with
a
5:1
ratio
and
in
80%
isolated
yield.
This
stereoselectivity
was
caused
by
the
chirality
of
threonine
reaction could produce a diastereomeric mixture, the desired syn‐configured alcohol, 79, was obtained
with
a
5:1
ratio
and
in
80%
isolated
yield.
This
stereoselectivity
was
caused
by
the
chirality
amino
acid
viaand
Cram‐chelation
of the
nucleophilicwas
addition
The
newlyofgenerated
with a 5:1
ratio
in 80% isolatedcontrol
yield. This
stereoselectivity
caused[53].
by the
chirality
threonine of
threonine
amino
acid
via Cram-chelation
control
ofnucleophilic
the within
nucleophilic
addition
newly
generated
stereogenic
center
served
as a keycontrol
stereocenter
in
C‐6
legionamic
acid
(81).
amino acid
via
Cram‐chelation
of the
addition
[53].[53].
TheThe
newly
generated
stereogenic
center
served
as
a
key
stereocenter
in
C-6
within
legionamic
acid
(81).
stereogenic center served as a key stereocenter in C‐6 within legionamic acid (81).
Scheme 16. De novo synthesis of orthogonally protected legionaminic acid 80.
Scheme16.
16.De
Denovo
novosynthesis
synthesis of
of orthogonally
orthogonally protected
80.80.
Scheme
protectedlegionaminic
legionaminicacid
acid
8. Conclusions
8. Conclusions
Naturally occurring chiral pool α‐amino acids provide synthetic chemists with a powerful tool
8. Conclusions
for the
incorporation
of pivotal
optically
active
natural chemists
products.with
Untila now,
α‐amino
Naturally
occurring
chiralstereocenters
pool α‐aminoinacids
provide
synthetic
powerful
tool
Naturally
occurring
chiral
pool
α-amino
acids
provide
synthetic
chemists
with
a powerful
tool
acids
have
been
exploited
for
use
not
only
as
chiral
sources
and
devices,
but
also
as
chiral
inducers
for the incorporation of pivotal stereocenters in optically active natural products. Until now, α‐amino
forinthe
incorporation
pivotal stereocenters
in optically
activeInnatural
products.
Until
now, α-amino
strategies
for exploited
theofsynthesis
of not
complex
target
molecules.
this review,
many
of
acids
have been
for use
only as
chiral
sources and
devices,
but also
as applications
chiral inducers
acids
have
been
exploited
for
use
not
only
as
chiral
sources
and
devices,
but
also
as
chiral
inducers
α‐amino
acids
chiral
inducers
in a substrate‐controlled
manner
were specifically
discussed.
in strategies
forasthe
synthesis
of complex
target molecules. In
this review,
many applications
of in
To
establish
challenging
product architectures,
chirality
of α‐amino
acids
α‐amino
acids
as chiralstereocenters
inducers in in
a natural
substrate‐controlled
manner the
were
specifically
discussed.
was
applied
to
a
remarkable
variety
of
reactions,
such
as
rearrangement,
cyclization,
cycloaddition,
To establish challenging stereocenters in natural product architectures, the chirality of α‐amino acids
was applied to a remarkable variety of reactions, such as rearrangement, cyclization, cycloaddition,
Molecules 2016, 21, 951
10 of 13
strategies for the synthesis of complex target molecules. In this review, many applications of α-amino
acids as chiral inducers in a substrate-controlled manner were specifically discussed. To establish
challenging stereocenters in natural product architectures, the chirality of α-amino acids was applied
to a remarkable variety of reactions, such as rearrangement, cyclization, cycloaddition, nucleophilic
addition to carbonyls, and hydrogenation. To conclude, attempts at utilizing α-amino acids as chiral
inducers for the creation of new stereogenic centers will continue.
Acknowledgments: This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2015R1C1A1A02036681).
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript:
Ac
Ala
BBN
Bn
Boc
Bu
Cbz
cod
DCE
DCC
DIBAL-H
DMAP
DME
DTBP
Et
Fmoc
HATU
KHMDS
LDA
Leu
LHMDS
Me
Mes
MS
MW
NMO
Phe
TBAI
TBDPS
TBS
Tf
TFA
THF
TIPS
Trp
Ts
Acetyl
Alanine
Borabicyclo[3.3.1]nonane
Benzyl
t-Butoxycarbonyl
Butyl
Benzyloxycarbonyl
1,5-Cyclooctadiene
1,1-Dichloroethane
N,N'-Dicyclohexylcarbodiimide
Diisobutylaluminum hydride
N,N-4-Dimethylaminopyridine
1,2-Dimethoxyethane
2,6-Di-tert-butylpyridine
Ethyl
9-Fluorenylmethoxycarbonyl
O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate
Potassium bis(trimethylsilyl)amide
Lithium diisopropylamide
Leucine
Lithium bis(trimethylsilyl)amide
Methyl
Mesityl
Molecular sieves
Microwave
N-Methylmorpholine N-oxide
Phenylalanine
Tetra-n-butylammonium iodide
t-Butyldiphenylsilyl
t-Butyldimethylsilyl
Trifluoromethanesulfonyl
Trifluoroacetic acid
Tetrahydrofuran
Triisopropylsilyl
Tryptophan
p-toluenesulfonyl
References
1.
2.
3.
4.
Casiraghi, G.; Zanardi, F. Stereoselective Approaches to Bioactive Carbohydrates and Alkaloids-With a Focus
on Recent Syntheses Drawing from the Chiral Pool. Chem. Rev. 1995, 95, 1677–1716. [CrossRef]
Rouf, A.; Taneja, S.C. Synthesis of Single-enantiomer Bioactive Molecules: A Brief Overview. Chirality 2014,
26, 63–78. [CrossRef] [PubMed]
Blaser, H.-U. The Chiral Pool as a Source of Enantioselective Catalysts and Auxiliaries. Chem. Rev. 1992, 92,
835–852. [CrossRef]
Nugent, W.A.; RajanBabu, T.V.; Burk, M.J. Beyond Nature’s Chiral Pool: Enantioselective Catalysis in
Industry. Science 1993, 259, 479–483. [CrossRef] [PubMed]
Molecules 2016, 21, 951
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
11 of 13
Goti, A.; Cicchi, S.; Cordero, F.M.; Fedi, V.; Brandi, A. A Straightforward Route to Enantiopure Pyrrolizidines
and Indolizidines by Cycloaddition to Pyrroline N-Oxides Derived from the Chiral Pool. Molecules 1999, 4,
1–12. [CrossRef]
Haleema, S.; Vavan Sasi, P.; Ibnusaud, I.; Polavarapu, P.L.; Kagan, H.B. Enantiomerically pure compounds
related to chiral hydroxy acids derived from renewable resources. RSC Adv. 2012, 2, 9257–9285. [CrossRef]
Singh, P.; Samanta, K.; Das, S.K.; Panda, G. Amino acid chirons: a tool for asymmetric synthesis of
heterocycles. Org. Biomol. Chem. 2014, 12, 6297–6339. [CrossRef] [PubMed]
Yun, H.; Kim, J.; Sim, J.; Lee, S.; Han, Y.T.; Chang, D.-J.; Kim, D.-D.; Suh, Y.-G. Asymmetric Syntheses of
1-Deoxy-6,8a-di-epi-castanospermine and 1-Deoxy-6-epi-castanospermine. J. Org. Chem. 2012, 77, 5389–5393.
[CrossRef] [PubMed]
Winchester, B.G.; Cenci di Bello, I.; Richardson, A.C.; Nash, R.J.; Fellows, L.E.; Ramsden, N.G.; Fleet, G.
The structural basis of the inhibition of human glycosidases by castanospermine analogues. Biochem. J. 1990,
269, 227–231. [CrossRef] [PubMed]
Paek, S.-M.; Kim, N.-J.; Shin, D.; Jung, J.-K.; Jung, J.-W.; Chang, D.-J.; Moon, H.; Suh, Y.-G. A Concise Total
Synthesis of (+)-Tetrabenazine and (+)-α-Dihydrotetrabenazine. Chem. Eur. J. 2010, 16, 4623–4628. [CrossRef]
[PubMed]
Taniguchi, Y.; Inanaga, J.; Yamaguchi, M. Use of 1,8-Diazabicyclo[5.4.0]undec-7-ene in Preparation of
Trimethylsilyl Enol Ethers and Trimethylsilylacetylenes. Bull. Chem. Soc. Jpn. 1981, 54, 3229–3230. [CrossRef]
Reddy, A.S.; Srihari, P. A facile approach to the synthesis of securinega alkaloids: stereoselective total
synthesis of (´)-allonorsecurinine. Tetrahedron Lett. 2012, 53, 5926–5928. [CrossRef]
Mercado-Marin, E.V.; Garcia-Reynaga, P.; Romminger, S.; Pimenta, E.F.; Romney, D.K.; Lodewyk, M.W.;
Williams, D.E.; Andersen, R.J.; Miller, S.J.; Tantillo, D.J.; et al. Total synthesis and isolation of citrinalin and
cyclopiamine congeners. Nature 2014, 509, 318–324. [CrossRef] [PubMed]
Bond, R.F.; Boeyens, J.C.A.; Holzapfel, C.W.; Steyn, P.S. Cyclopiamines A and B, novel oxindole metabolites
of Penicillium cyclopium westling. J. Chem. Soc. Perkin Trans. 1 1979, 1751–1761. [CrossRef]
Pimenta, E.F.; Vita-Marques, A.M.; Tininis, A.; Seleghim, M.H.R.; Sette, L.D.; Veloso, K.; Ferreira, A.G.;
Williams, D.E.; Patrick, B.O.; Dalisay, D.S.; Andersen, R.J.; Berlinck, R.G.S. Use of Experimental Design for
the Optimization of the Production of New Secondary Metabolites by Two Penicillium Species. J. Nat. Prod.
2010, 73, 1821–1832. [CrossRef] [PubMed]
Kishi, Y.; Nakatsubo, F.; Aratani, M.; Goto, T.; Inoue, S.; Kakoi, H. Synthetic approach towards tetrodotoxin.
I. Diels-Alder reaction of α-oximinoethylbenzoquinones with butadiene. Tetrahedron Lett. 1970, 11, 5127–5128.
[CrossRef]
Kim, J.H.; Lee, S.; Kim, S. Biomimetic Total Synthesis of (´)-Penibruguieramine A Using Memory of Chirality
and Dynamic Kinetic Resolution. Angew. Chem. Int. Ed. 2015, 54, 10875–10878. [CrossRef] [PubMed]
Zhou, Z.-F.; Kurtán, T.; Yang, X.-H.; Mándi, A.; Geng, M.-Y.; Ye, B.-P.; Taglialatela-Scafati, O.; Guo, Y.-W.
Penibruguieramine A, a Novel Pyrrolizidine Alkaloid from the Endophytic Fungus Penicillium sp. GD6
Associated with Chinese Mangrove Bruguiera gymnorrhiza. Org. Lett. 2014, 16, 1390–1393. [CrossRef]
[PubMed]
Kieffer, M.E.; Chuang, K.V.; Reisman, S.E. Copper-Catalyzed Diastereoselective Arylation of Tryptophan
Derivatives: Total Synthesis of (+)-Naseseazines A and B. J. Am. Chem. Soc. 2013, 135, 5557–5560. [CrossRef]
[PubMed]
Raju, R.; Piggott, A.M.; Conte, M.; Aalbersberg, W.G.L.; Feussner, K.; Capon, R.J. Naseseazines A and
B: A New Dimeric Diketopiperazine Framework from a Marine-Derived Actinomycete, Streptomyces sp.
Org. Lett. 2009, 11, 1390–1393. [CrossRef] [PubMed]
Larock, R.C.; Yum, E.K. Synthesis of Indoles via Palladium-Catalyzed Heteroannulation of Internal Alkynes.
J. Am. Chem. Soc. 1991, 113, 6690–6692. [CrossRef]
Garfunkle, J.; Kimball, F.S.; Trzupek, J.D.; Takizawa, S.; Shimamura, H.; Tomishima, M.; Boger, D.L.
Total Synthesis of Chloropeptin II (Complestatin) and Chloropeptin I. J. Am. Chem. Soc. 2009, 131,
16036–16038. [CrossRef] [PubMed]
Ruchti, J.; Carreira, E.M. Ir-Catalyzed Reverse Prenylation of 3-Substituted Indoles: Total Synthesis of
(+)-Aszonalenin and (´)-Brevicompanine B. J. Am. Chem. Soc. 2014, 136, 16756–16759. [CrossRef] [PubMed]
Diebolt, O.; Tricas, H.; Freixa, Z.; van Leeuwen, P.W.N.M. Strong π-Acceptor Ligands in Rhodium-Catalyzed
Hydroformylation of Ethene and 1-Octene: Operando Catalysis. ACS Catal. 2013, 3, 128–137. [CrossRef]
Molecules 2016, 21, 951
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
12 of 13
Kusano, M.; Sotoma, G.; Koshino, H.; Uzawa, J.; Chijimatsu, M.; Fujioka, S.; Kawano, T.; Kimura, Y.
Brevicompanines A and B: New plant growth regulators produced by the fungus, Penicillium brevicompactum.
J. Chem. Soc. Perkin Trans. 1 1998, 1, 2823–2826. [CrossRef]
Kimura, Y.; Hamasaki, T.; Nakajima, H.; Isogai, A. Structure of aszonalenin, a new metabolite of aspergillus
zonatus. Tetrahedron Lett. 1982, 23, 225–228. [CrossRef]
Feng, Y.; Holte, D.; Zoller, J.; Umemiya, S.; Simke, L.R.; Phil, S.B. Total Synthesis of Verruculogen and
Fumitremorgin A Enabled by Ligand-Controlled C-H Borylation. J. Am. Chem. Soc. 2015, 137, 10160–10163.
[CrossRef] [PubMed]
Cole, R.J.; Kirksey, J.W.; Moore, J.H.; Blankenship, B.R.; Diener, U.L.; Davis, N.D. Tremorgenic Toxin from
Penicillium verruculosum. Appl. Microbiol. 1972, 24, 248–250. [PubMed]
Yamazaki, M.; Suzuki, S.; Miyaki, K. Tremorgenic Toxins from Aspergillus fumigatus FRES. Chem. Pharm. Bull.
1971, 19, 1739–1740. [CrossRef] [PubMed]
Shade, R.E.; Hyde, A.M.; Olsen, J.-C.; Merlic, C.A. Copper-Promoted Coupling of Vinyl Boronates and
Alcohols: A Mild Synthesis of Allyl Vinyl Ethers. J. Am. Chem. Soc. 2010, 132, 1202–1203. [CrossRef]
[PubMed]
Fujiwara, H.; Kurogi, T.; Okaya, S.; Okano, K.; Tokuyama, H. Total Synthesis of (´)-Acetylaranotin.
Angew. Chem. Int. Ed. 2012, 51, 13062–13065. [CrossRef] [PubMed]
Nagarajan, R.; Huckstep, L.L.; Lively, D.H.; DeLong, D.C.; Marsh, M.M.; Neuss, N. Aranotin and Related
Metabolites from Avachniofus Aureus I. Determination of Structure. J. Am. Chem. Soc. 1968, 90, 2980–2982.
[CrossRef]
Wipf, P.; Kim, Y.; Goldstein, D.M. Asymmetric Total Synthesis of the Stemona Alkaloid (´)-Stenine. J. Am.
Chem. Soc. 1995, 117, 11106–11112. [CrossRef]
Krishna, P.R.; Reddy, B.K. Total Synthesis of a Pyrrolidin-2-one with the Structure Proposed for the Alkaloid
Rigidiusculamide A. Helv. Chim. Acta 2013, 96, 1564–1570. [CrossRef]
Li, J.; Liu, S.; Niu, S.; Zhuang, W.; Che, Y. Pyrrolidinones from the Ascomycete Fungus Albonectria
rigidiuscula. J. Nat. Prod. 2009, 72, 2184–2187. [CrossRef] [PubMed]
Vanrheenen, V.; Kelly, R.C.; Cha, D.Y. An improved catalytic OsO4 oxidation of olefin to cis-1,2-glycols using
tertiary amine oxides as the oxidant. Tetrahedron Lett. 1976, 17, 1973–1976. [CrossRef]
Luo, Z.; Zhou, B.; Li, Y. Total Synthesis of (´)-(α)-Kainic Acid via a Diastereoselective Intramolecular [3 + 2]
Cycloaddition Reaction of an Aryl Cyclopropyl Ketone with an Alkyne. Org. Lett. 2012, 14, 2540–2543.
[CrossRef] [PubMed]
Murakami, S.; Takemoto, T.; Shimizu, Z. The effective principle of Digenea simplex Aq. I. Separation of the
effective fraction by liquid chromatography. J. Pharm. Soc. Jpn. 1953, 73, 1026–1028.
Matveenko, M.; Liang, G.; Lauterwasser, E.M.W.; Zubía, E.; Trauner, D. A Total Synthesis Prompts the
Structure Revision of Haouamine B. J. Am. Chem. Soc. 2012, 134, 9291–9295. [CrossRef] [PubMed]
Garrido, L.; Zubía, E.; Ortega, M.J.; Salvá, J. Haouamines A and B: A New Class of Alkaloids from the
Ascidian Aplidium haouarianum. J. Org. Chem. 2003, 68, 293–299. [CrossRef] [PubMed]
Paladino, M.; Zaifman, J.; Ciufolini, M.A. Total Synthesis of (+)-3-Demethoxyerythratidinone and
(+)-Erysotramidine via the Oxidative Amidation of a Phenol. Org. Lett. 2015, 17, 3422–3425. [CrossRef]
[PubMed]
Ito, K.; Furukawa, H.; Haruna, M. Studies on the Erythrina Alkaloids. VII. Alkaloids of Erythrina arborescens
ROXB. (2). Structures of New Alkaloids, Erysotramidine, Erytharbine and 11-Hydroxyerysotrine. Yakugaku Zasshi
1973, 93, 1617–1621. [PubMed]
Wipf, P.; Miller, C.P. A New Synthesis of Highly Functionalized Oxazoles. J. Org. Chem. 1993, 58, 3604–3606.
[CrossRef]
Chow, Y.L.; Colòn, C.J.; Tan, J.N.S. A(1,3) interaction and conformational energy of axial-axial 1,3-dimethyl
interaction. Can. J. Chem. 1968, 46, 2821–2825. [CrossRef]
Lunazzi, L.; Macciantelli, D.; Tassi, D.; Dondoni, A. Conformational studies by dynamic nuclear magnetic
resonance. Part 17. Stereodynamic processes in hindered piperidyl-amides and -amidines. J. Chem. Soc.
Perkin Trans. 2 1980, 717–723. [CrossRef]
Gouault, N.; Le Roch, M.; de Campos Pinto, G.; David, M. Total synthesis of dendrobate alkaloid (+)-241D,
isosolenopsin and isosolenopsin A: application of a gold-catalyzed cyclization. Org. Biomol. Chem. 2012, 10,
5541–5546. [CrossRef] [PubMed]
Molecules 2016, 21, 951
47.
48.
49.
50.
51.
52.
53.
13 of 13
Edwards, M.W.; Daly, J.W.; Myers, C.W. Alkaloids from a Panamanian Poison Frog, Dendrobates speciosus:
Identification of Pumiliotoxin-A and Allo-pumiliotoxin Class Alkaloids, 3,5-Disubstituted Indolizidines,
5-Substituted 8-Methylindolizidines, and a 2-Methyl-6-nonyl-4-hydroxypiperidine. J. Nat. Prod. 1988, 51,
1188–1197. [CrossRef] [PubMed]
Leclercq, S.; Daloze, D.; Braekman, J.C. Synthesis of the Fire Ant Alkaloids, Solenopsins. A Review. Org. Prep.
Proced. Int. 1996, 28, 499–543. [CrossRef]
Gouault, N.; le Roch, M.; Cheignon, A.; Uriac, P.; David, M. Enantiospecific Synthesis of Pyridinones as
Versatile Intermediates toward Asymmetric Piperidines. Org. Lett. 2011, 13, 4371–4373. [CrossRef] [PubMed]
Matthies, S.; Stallforth, P.; Seeberger, P.H. Total Synthesis of Legionaminic Acid as Basis for Serological
Studies. J. Am. Chem. Soc. 2015, 137, 2848–2851. [CrossRef] [PubMed]
Zunk, M.; Kiefel, M.J. The occurrence and biological significance of the α-keto-sugars pseudaminic acid and
legionaminic acid within pathogenic bacteria. RSC Adv. 2014, 4, 3413–3421. [CrossRef]
Liang, X.; Lee, C.-J.; Chen, X.; Chung, H.S.; Zeng, D.; Raetz, C.R.H.; Li, Y.; Zhou, P.; Toone, E.J. Syntheses,
structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold. Bioorg. Med. Chem.
2011, 19, 852–860. [CrossRef] [PubMed]
Szechner, B.; Achmatowicz, O.; Galdecki, Z.; Fruziński, A. Synthesis and absolute configuration of
four diastereoisomeric 1-(2-furyl)-2-aminobutane-1,3-diols. Tetrahedron 1994, 50, 7611–7624. [CrossRef]
© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).