Enantioselective Synthesis of the C23–C33 Fragment of Aetheramide A and Its C32 Epimer

Article abstract of DOI:10.1002/ejoc.201701416

The key aetheramide A intermediate with the natural (R,R,R) configuration along with the one having the unnatural (R,S,R) configuration was synthesized. The synthesis of both stereoisomers was accomplished by Suzuki coupling of two advanced chiral building blocks: (R,R)- and (R,S)-vinylboronates and an (R)-iodoalkene. The former was prepared from (R)-mandelic acid, and the latter was prepared by enantioselective allylation of 3-iodoacrylaldehyde.

Full text of DOI:10.1002/ejoc.201701416

A Journal of
Accepted Article
Title: Enantioselective Synthesis of the C23-C33 Aetheramide A
Fragment and Its C32-Epimer
Authors: Tibor Peňaška, Petr Koukal, and Martin Kotora
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701416
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10.1002/ejoc.201701416
European Journal of Organic Chemistry
COMMUNICATION
Enantioselective Synthesis of the C23-C33 Aetheramide A
Fragment and Its C32-Epimer
Tibor Peňaška[a,b] Petr Koukal,[a] and Martin Kotora*[a]
Dedication
Abstract: The key aetheramide A intermediate with natural (R,R,R)
configuration along with the one having unnatural (R,S,R)
configuration were synthesized. The syntheses of both stereoisomers
were accomplished by using Suzuki coupling of two advanced chiral
steps starting from ethyl cinnamate.[9] It should be noted that in all
syntheses the construction of stereocenters was based on the use
of stoichiometric amounts of chiral auxiliaries. A related class of
compounds possessing similar structural features like
aetheramides are nannocystines.[10]
building blocks: (R,R)- and (R,S)-vinyl boronates and
a (R)-
iodoalkene. The former was prepared from (R)-mandelic acid and the
We envisioned that the key ester 1 could be synthesized from
a readily available natural chiral starting material and by
enantioselective allylation of an aldehyde (Scheme 1). Moreover,
the convergent synthetic approach would also allow synthesis of
various diastereoisomers. We presumed that the fragment 1
could be prepared by the Suzuki coupling of chiral building blocks
latter by enantioselective allylation of 3-iodoacryl aldehyde.
The research in the area of natural products provides a large
palette of novel compounds possessing versatile biological
activity which drives development of new drugs. Aetheramides A
2
and 3. The building block 2 was to be formed by
(Scheme 1) and
B are secondary metabolites of novel
diastereoselective ethynylation of (R)-mandelic aldehyde
prepared from (R)-mandelic acid 4. The second chiral building
block 3 was expected to be prepared by cross-metathesis
reaction of methyl acrylate and the product of enantioselective
catalytic allylation of (E)-3-iodomethacryldehyde 5, which can be
prepared from methyl diethylmalonate 6.[11]
myxobacteria genus Aetherobacter rufus (Aether was a god of
light in Greek mythology) isolated and characterized by Müller´s
group in 2012.[1] Aetheramides are macrocyclic compounds
possessing six stereogenic centers, comprising a polyketide
moiety and two amino acids. These structurally interesting cyclic
depsipeptides show potential anti-HIV activity (IC50 = ~15 nM),
cytostatic activity against human colon tumor (IC50 = 110 nM), and
also antifungal activity against Candida albicans,[2] which
represents over 80% of all forms of human candidosis.[3]
OMe
HO
Aetheramides have become an interesting synthetic target,
due to their structure and bioactivity. An enantioselective
synthesis of a MEM-protected aetheramide A derivative starting
from ethyl cinnamate was published by Akasapu et al. in 2014.[4]
The same year, a preparation of a polyketide precursor of
aetheramides from a chiral furyl carbinol was reported by Prasad
et al.[5] Enantioselective total syntheses of aetheramides A and B
and other stereoisomers thereof were accomplished by He et al.
from an achiral starting material in 15 steps and 5.3% overall yield
for aetheramide A and 3.6% for aetheramide B.[6] Still in 2016 He
et al. reported a preparation of aetheramides A and B by using a
different strategy (15-steps, 4.7% overall yield).[7] Three different
approaches were also tested in synthesis of the protected
aetheramide by Prasad et al. in 2017.[8] The total synthesis of
aetheramide A was also accomplished by Kalesse et al. in 2016
(18 steps, 0.24% overall yield). One of the key fragments along
its synthesis was ester 1 (the C23-C33 fragment) possessing
three stereogenic centers, Its preparation was accomplished in 9
CO2Me
O
O
O
Me
Me
N
OTBS
NH Me Me 23
Me
OMe
OTBS
Me
O
O
27
32
1
OMe
33
OH
Me
Aetheramide A
OTBS
OH
CO2H
BPin
OTBS
4
2
+
CO2Me
Me
CO2Et
I
I
EtO2C
Me
OMe
3
Me
OMe
6
5
[a]
T. Peňaška, P. Koukal, Prof. Dr. M. Kotora
Department of Organic Chemistry
Scheme 1. Retrosynthetic analysis of the C23-C33 Aetheramide A fragment 1.
Faculty of Science, Charles University
Hlavova 8, 128 43 Praha 2, Czech Republic
E-mail: kotora@natur.cuni.cz
http://orgchem.natur.cuni.cz/kotora/
A visiting student from Department of Organic Chemistry
Faculty of Natural Sciences, Comenius University in Bratislava,
Mlynská dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia
The synthesis of vinyl pinacol boronates (R,R)- and (R,S)-2
(Scheme 2) started from commercially available (R)-mandelic
acid 4. Esterification of 4 with MeOH provided 7 in 88 % yield[12]
,
[b]
which was followed by protection of hydroxyl with the TBS group
giving rise to 8 in almost quantitative yield (99 %).[13] The next step,
reduction of the ester to an aldehyde by using DIBAL[13] furnished
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701416
European Journal of Organic Chemistry
COMMUNICATION
9 in 84% yield. The second stereocenter was generated through
nucleophilic addition of ethynylmagnesium chloride to aldehyde 9
giving rise to a 1:4 mixture of (R,R)-syn- and (R,S)-anti-10 in 90%
isolated yield. The syn and anti diastereoisomers were readily
separable by column chromatography on silica gel.[14] The
preferential formation of (R,S)-10 suggests that the addition was
controlled by steric factors and not by chelatation of the
magnesium atom to the oxygen atom.
in 96% yield. The subsequent cross-metathesis of (R)-5 with
methyl acrylate catalyzed by Grubbs 2nd generation catalyst (2
mol-%) furnished (R)-3 exclusively as E-isomer in 82 % yield and
97% ee.[19]
Me
CO2H
12, 69%
Me
CO2Et
Me
a
b
c
I
I
OH
EtO2C
6
13, 88%
Next, protection of both isomers, (R,S)- and (R,R)-10), with
the TBS group furnished the respective alkynes (R,S)- and (R,R)-
11 in identical 93% isolated yields. Then hydroboration of both
alkynes to yield 2 followed. Although this transformation was
assumed to be a rather easy step, it proved otherwise. Initially, a
simple hydroboration with HBPin was attempted, but, surprisingly,
no reaction was observed and the alkyne was recovered intact.
After some experimental work (see SI for details), it was found
that hydroboration with HBPin catalyzed by RhCl(CO)(PPh3)2 (2
mol%)[15,16] under microwave irradiation at 100 °C for 1 h provided
selectively the desired vinyl boronate 2 (E/Z = 99/1) in 70%
isolated yield. Thus, vinyl boronates (R,R)- and (R,S)-2 were
prepared in 6 steps from 4 with the overall yields of 6 and 34%,
respectively.
Me
Me
Me
d
e
f
I
I
I
CHO
OH
(R)-15, 87%, 97%ee
OMe
(R)-5, 96%
14, 95%
iPr
iPr
iPr
O
P
O
Me
O
I
(R)-3, 82%, 97%ee
CO2Me
OH
iPr
OMe
iPr
(R)-TRIP PA
iPr
Scheme 3. Preparation of iodoester 3. a) 1. NaH, Et2O, reflux, 2 h; 2. CHI3, Et2O,
20 °C→reflux, overnight; 3. KOH, EtOH, H2O, reflux, overnight; b) LiAlH4, Et2O,
20 °C, 3 h; c) MnO2, toluene, 35 °C, 24 h; d) allylboronic pinacol ester, (R)-TRIP-
PA (2.5 mol-%), toluene, -40 °C, 4 days; e) MeI, NaH, THF, 0°C→20 °C, 2 h; f)
methylacrylate, Grubbs 2nd generation catalyst (2 mol-%), CuI, Et2O, reflux, 3 h.
OH
CO2H
OH
CO2Me
7, 88%
OTBS
CO2Me
a
b
4
8, 99%
With both synthetic building blocks 2 and 3 in hand, we
proceeded with the last step of the synthesis – the coupling
affording 1. Thus the coupling of (R,R)-2 with (R)-3 at 20 °C
provided the desired key aetheramide precursor (R,R,R)-1 within
1 hour in excellent 91% isolated yield and 97% ee (Scheme 4).
The successful course of the reaction under these mild reaction
conditions was enabled by the use of thallium(I) ethoxide as a
base (TlOEt is converted to thallium(I) hydroxide by the reaction
with water).[20,21] In an analogical manner proceeded coupling of
(R,S)-2 and (R)-3 giving rise to the hitherto unknown
diastereoisomer (R,S,R)-1 in 79 % isolated yield and 97% ee.[22]
OTBS
OTBS
OTBS
c
d
e
CHO
, 84%
OH
OTBS
9
10
11
(R,R)- + (R,S)- (1/4)
(R,R)- , 93%
90% combined yield
(R,S)-11, 93%
Me
Me
Me
OTBS
O
f
2
(R,R)- , 70%
B
Me
(R,S)-2, 70%
O
OTBS
Scheme 2. Preparation of boronic acid esters (R,R)- and (R,S)-2. a) p-
toulenesulfonic acid, MeOH, reflux, 12 h; b) TBSCl, imidazole, DMF, 20 °C, 12
h; c) DIBAL, Et2O, -78 °C, 30 min; d) ethynylmagnesium chloride, THF, 0 °C, 1
h ((R,R)-10 and (R,S)-10 separated in 18 and 72% yields, respectively); e)
TBSCl, imidazole, DMF, 20 °C, 12 h; f) HBPin, Rh(PPh3)2(CO)Cl (2 mol-%),
CH2Cl2, 100 °C, MWI, 1 h
OTBS
OMe
CO2Me
OTBS
Me
(R,R)-2
1
a
aetheramide A fragment (R,R,R)- , 91%, 97% ee
+
3
or
OTBS
OMe
2
CO2Me
(R,S)-
The chiral iodoester 3 was also synthesized in six steps
(Scheme 3). Methylmalonate 6 was converted in two consecutive
steps to carboxylic acid 12 in 69% yield.[17] Reduction of acid 12
with LiAlH4 yielded alcohol 13 in 88% yield.[18] Oxidation with
MnO2 followed and a solution of aldehyde 14 in toluene was
obtained after simple filtration of MnO2. The exact concentration
OTBS
Me
1
(R,S,R)- , 79%, 97% ee
Scheme 4. Preparation of aetheramide A fragment 1: a) Pd(PPh3)4 (20 mol-%)
EtOTl (1.5 eq), THF/H2O (3/1), 60 min, 20 °C.
1
of this stock solution was determined by using H NMR. Then
enantioselective allylation of aldehyde 14 with allyl
pinacolboronate catalyzed by (R)-TRIP-PA was carried out
providing iodoalcohol (R)-15 in 87% isolated yield and excellent
enantioselectivity of 97% ee.[11] The reaction sequence continued
with methylation of the hydroxyl group to yield methyl ether (R)-5
In summary, we accomplished preparation of the key
advanced precursor of aetheramide A - (R,R,R)-polyketide
fragment. It was synthesized from two chiral building blocks that
were prepared from simple starting materials in 6 steps,
respectively. Its (R,S,R)-stereoisomer has also been prepared by
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10.1002/ejoc.201701416
European Journal of Organic Chemistry
COMMUNICATION
[7]
N. Qi, Z. Wang, S. R. Allu, Q. Liu, J. Guo, Y. He, J. Org. Chem. 2016, 81,
12466−12471.
the same method. Since mandelic acid 4 is commercially
available in both enantiomeric forms and enantioselective
allylation of 2-iodomethacryldehyde catalyzed by chiral TRIP-PAs
or N,N’-dioxides10 can provide both enantiomers, the outlined
method can, in principle, allow to access all possible enantiomers
of 1.
[8]
[9]
O. Revu, K. R. Prasad, J. Org. Chem. 2017, 82, 438−460.
L. Gerstmann, M. Kalesse, Chem. Eur. J. 2016, 22, 11210−11212.
[10] For nannocystin characterisation, see: H. Hoffmann, H. Kogler, W. Heyse,
H. Matter, M. Caspers, D. Schummer, C. Klemke-Jahn, A. Bauer, G.
Penarier, L. Debussche, M. Brçnstrup, Angew. Chem. Int. Ed. 2015, 54,
10145–0148. Synthesis nannocystin Ax: Poock, C.; Kalesse, M. Org. Lett.
2017, 19, 4536-4539.
[11] P. Koukal, J. Ulč, D. Nečas, M. Kotora, Eur. J. Org. Chem. 2016, 12,
2110−2114. For another paper dealing with allylation of haloacryl
aldehydes, see: E. Matoušová, P. Koukal, B. Formánek, M. Kotora, Org.
Lett. 2016, 18, 5656−5659.
Experimental Section
For details see SI.
[12] V. Valerio, C. Madelaine, N. Maulide, Chem. Eur. J. 2011, 17, 4742−4745.
[13] Y. Kobayashi, Y. Takemoto, T. Kamijo, H. Harada, Y. Ito, S. Terashima,
Tetrahedron. 1992, 48, 1853−1868.
Acknowledgements
[14] M. Kotora, E. Negishi, Tetrahedron Lett. 1996, 37, 9041−9042.
[15] S. Pereira, M. Srebnik, Tetrahedron Lett. 1996, 19, 3283−3286.
[16] For the recent example of catalytic hydroboration of alkynes, see: K.
Wang, R. W. Bates, Synthesis 2017, 49, 2749-2752.
Authors gratefully acknowledge financial support from the Czech
Science Foundation (P207/11/0587), Tibor Peňaška thanks the
National Scholarship Programme of the Slovak Republic.
[17] D. Menche, J. Hassfeld, J. Li, K. Mayer, S. Rudolph, J. Org. Chem. 2009,
74, 7220−7229.
[18] D. R. Brandt, K. M. Pannone, J. J. Romano, E. G. Casillas, Tetrahedron
2013, 69, 9994−10002.
Keywords: aetheramide • catalysis • enantioselective allylation •
hydroboration • Suzuki coupling
[19] K. Voigtritter, S. Ghorai, B. H. Lipshutz, J. Org. Chem. 2011, 76,
4697−4702.
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[22] No racemization was observed during the course of the synthesis. Since
(R,R)- and (R,S)-2 were prepared from enantiomeric ally pure (R)-
mantellic acid and no racemization was observed during the course of
the reaction, the final enantiopurity of (R,R,R)- and (R,S,R)-1 is reflected
by enantiopurity of (R)-2.
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European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Tibor Peňaška, Petr Koukal, and Martin
Kotora*
Page No. – Page No.
Enantioselective Synthesis of the
C23-C33 Aetheramide A Fragment
and Its C32-Epimer
C23-33 fragments of aetheramide A fragments with natural (R,R,R) and unnatural
(R,S,R) configuration were synthesized from (R)-madelic acid and
3-iodomethacrylaldehyde with the use of catalytic enantioselective allylation.
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