Asymmetric Total Syntheses of Aetheramides and Their Stereoisomers: Stereochemical Assignment of Aetheramides

Article abstract of DOI:10.1021/acs.orglett.6b02371

The concise total syntheses of the potent HIV inhibitors aetheramides A and B (IC₅₀ values of 15 and 18 nM), as well as three pairs of their stereoisomers, were achieved, which allowed the complete stereochemical assignment of aetheramides for the first time. With a longest linear sequence of 15 steps, the convergent, fully stereocontrolled route provided aetheramides A and B in 5.3% and 3.6% yields, respectively. The synthetic strategy features efficient Stille coupling for macrocyclization, asymmetric aldol reactions to establish the ambiguous stereochemistries at C-17 and C-26, and implementation of mild conditions to avoid the epimerization of the sensitive polyketide moiety and the migration of the labile lactone.

Full text of DOI:10.1021/acs.orglett.6b02371

Letter
pubs.acs.org/OrgLett
Asymmetric Total Syntheses of Aetheramides and Their
Stereoisomers: Stereochemical Assignment of Aetheramides
Na Qi,† Srinivasa Rao Allu,† Zhanlong Wang, Qiang Liu, Jian Guo,* and Yun He*
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road,
Shapingba, Chongqing 401331, P. R. China
S
* Supporting Information
ABSTRACT: The concise total syntheses of the potent HIV
inhibitors aetheramides A and B (IC50 values of 15 and 18
nM), as well as three pairs of their stereoisomers, were
achieved, which allowed the complete stereochemical assign-
ment of aetheramides for the first time. With a longest linear
sequence of 15 steps, the convergent, fully stereocontrolled
route provided aetheramides A and B in 5.3% and 3.6% yields,
respectively. The synthetic strategy features efficient Stille
coupling for macrocyclization, asymmetric aldol reactions to
establish the ambiguous stereochemistries at C-17 and C-26, and implementation of mild conditions to avoid the epimerization
of the sensitive polyketide moiety and the migration of the labile lactone.
Scheme 1. Retrosynthetic Analysis of Aetheramide B and Its
C-17 and C-26 Stereoisomers 2a−d
yxobacteria is known as a famous natural product
Mproducer, and many of its second metabolites feature
unique structures and novel mechanisms of action.1 Aether-
group in 2010.2 Aetheramides A and B (Figure 1) were isolated
from A. rufus (SBSr003), the first stain of Aetherobacter, in 2012.
Aetheramides A and B potently inhibited HIV-1 infection with
IC50 values of 15 and 18 nM, respectively, and showed cytostatic
activity against human colon carcinoma (HCT-116) cells with
IC50 values of 110 nM. They also exhibited moderate antifungal
activity against Candida albicans.3
obacter is a new myxobacterial genus discovered by Muller’s
̈
Aetheramides A and B possess structurally distinctive cyclic
depsipeptide with six chiral centers, a unique polyketide moiety
and two amino acid residues, in which D-3-(4-hydroxy-3-
methoxyphenyl)-2(methylamino)propanoic acid (D-mNMe-
Tyr) had not been previously reported in natural products.
Aetheramides are structurally distinct from all reported HIV
inhibitors4 and may be associated with novel mechanisms of
action. Despite vigorous efforts, the absolute stereochemistries at
Received: August 9, 2016
Figure 1. Structures and activities of aetheramides A and B.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02371
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of D-Fmoc-mNMeTyr 5
Scheme 4. Syntheses of Vinyl Iodo Acids 9a−d
C-17 and C-26 remained undetermined.3 Moreover, aether-
amides were isolated in small amounts, and their further studies
were hampered.
The syntheses of aetheramides were expected to be
challenging. The ester migration between the two adjacent
hydroxyl groups at C-33 and C-34 was reported, and
aetheramides A and B reached a 1:1 equilibrium in MeOH
within 24 h.3 In addition, the epimerization at C-17 could be
easily triggered under either basic or acidic conditions.
Therefore, their syntheses require carefully planned transform-
ations under mild conditions. Due to the unique structures and
promising biological activities, several groups have focused on
the syntheses of aetheramides.5 Herein, we disclose concise and
efficient asymmetric syntheses of aetheramides, as well as three
pairs of their stereoisomers. The undetermined absolute
stereochemistries of aetheramides were completely established
for the first time.
Aetheramide B was chosen as the first target. Since the
stereochemistries of C-17 and C-26 were undetermined, the
syntheses of all possible structures (2a−d) of aetheramide B
were planned. As shown in the retrosynthetic analysis (Scheme
1), the 21-membered macrocycle core could be constructed via
the intramolecular Stille coupling6 of vinylstannane−vinyl iodide
precursors 3a−d, which could be assembled through the
condensations of vinyl iodo acids 9a−d and vinylstannane
amine 4, respectively. Vinyl iodo acids 9a−d could in turn be
derived from esters 12a,b, which were planned to arise from
aldehyde 137 through asymmetric vinylogous Mukaiyama aldol
reaction (VMAR). Vinylstannane amine 4 could be prepared
from the sequential condensations of (E)-vinylstannane alcohol
6, Fmoc-L-valine and the novel D-mNMeTyr fragment 5. The
vinylstannane group in 6 could be generated from the terminal
alkyne in 7, which could be readily accessed from trans-ethyl
cinnamate 8.
The novel D-Fmoc-mNMeTyr fragment 5 is an important
component of vinylstannane amine 4, whose synthesis is shown
in Scheme 2. Iodo-D-serine 148 was allowed to react with aryl
iodide 159 under Negishi conditions. The best result was
achieved by applying the combination of Pd2(dba)3 and Sphos,10
furnishing compound 16 in 89% yield. The removal of the TBS
group with TBAF, followed by the hydrolysis of the ester with
lithium hydroxide, provided acid 17, which was again protected
with a TBS group to afford acid 18 in excellent yield. The N-
methylation of 18 with NaH/MeI/THF provided optically pure
19 in 75% yield.11 The Boc group in 19 was removed with TFA,
followed by the treatment with FmocCl to yield Fmoc-protected
fragment 5 in 92% yield.
Scheme 3. Synthesis of Vinylstannane Amine 4
B
DOI: 10.1021/acs.orglett.6b02371
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Syntheses of Aetheramide A (1a), Aetheramide B (2a), and Their C-17 and C-26 Stereoisomers 1b−d and 2b−d
The syntheses of vinyl iodo acids 9a−d were a challenge due to
the difficulty in constructing the stereocenter of the isolated
methoxyl group at C-26 and the adjacent (E)-1-iodo-2-methyl
olefin. A number of synthetic strategies were examined, and an
efficient route was developed as shown in Scheme 4. With
tryptophane-based B-phenyloxazaborolidinone OXB-A16 as
chiral Lewis acid and THF as solvent, alcohol 29a was obtained
in 84% yield and 94% ee from aldehyde 13 under an optimized
condition. Alcohol 29b could also be prepared with chiral Lewis
acid OXB-B in good yield and ee value following a similar
procedure. Alcohols 29a,b were then methylated. The trans-
formation from the unsaturated esters 12a,b to alcohols 30a,b
were found to be quite challenging due to the sensitivity of the
iodo olefin moiety to most reducing conditions. Eventually, the
combination of LiAlH4 and proper solvents (CH2Cl2/THF, 1:1)
provided 30a,b in excellent yields. Oxidation of alcohols 30a,b
into aldehydes 11a,b followed by Wittig reaction with 31 led to
esters 32a,b. After DIBAL-H reduction and DMP oxidation, the
resulting aldehydes 10a,b were subjected to Evans aldol reactions
with chiral auxiliaries 33a,b followed by the hydrolysis of the
amides to provide key vinyl iodo acids 9a−d.
With acids 9a−d and amine 4 in hand, the synthesis of
aetheramide B was embarked (Scheme 5). Under an optimized
coupling condition, the coupling between 9a−d and 4 afforded
vinylstannane−vinyl iodide precursors 3a−d in 55%−64% yields
using HATU/DIPEA/DMF. The moderate yields were the
consequence of the instability of acids 9a−d under amide-
coupling conditions. The intramolecular Stille coupling of 3a−d
was critical in the total synthesis. With precursor 3a, many
catalytic systems were screened. Pd2(dba)3/AsPh3/DIPEA17 was
found to be the most efficient, and the cyclization of 3a was
completed in 1 h at room temperature in 82% yield. The other
three macrocycles 35b−d were also obtained in good yields
under the same reaction conditions. Subsequently, the oxidation
of the hydroxyl group at C-19 with DMP produced compounds
36a−d in excellent yields. Fortunately, the configuration of C-17
was not influenced under these oxidation conditions, and 36a−d
were obtained as optically pure products.
Scheme 6. Direct Synthesis of Aetheramide A
The synthesis of vinylstannane amine 4 started from trans-
ethyl cinnamate 8 (Scheme 3), which was subjected to the
standard Sharpless asymmetrical dihydroxylation to provide
optically pure diol 20 in 90% yield and 99% ee.12 The diol was
then protected with acetonide, and the ethyl ester was reduced to
aldehyde and subsequently converted into terminal alkyne by
Ohira−Bestmann reagent.13 The acetonide group was then
removed using Amberlyst 15, and the resulting diol 23 was
monoprotected with TES group to afford 24 and 7 in 50% and
46% yields, respectively, when the reaction was carried out at
room temperature for an extended period of time. Silyl ether 24
could be obtained in 70% yield when the reaction was conducted
at 0 °C for 3 h. Silyl ethers 7 and 24 could be used for the
syntheses of the 21-membered macrocycles 2a−d and the 22-
membered macrocycles 1a−d, respectively, or easily recycled via
diol 23.
Hydrostannation of alkyne 7 with Bu3SnH and Pd(PPh3)2Cl2
led to (E)-vinylstannane alcohol 6.14 The ester-coupling reaction
of 6 with Fmoc-L-valine in the presence of DCC/DMAP
provided the desired ester 25 in 80% yield. The removal of the
Fmoc group in 25 was found to be a bit complicated. The
classical condition using piperidine led to unidentified products.
Amine 26 could finally be obtained in excellent yield using DBU/
HOBt/DMF,15 and its coupling with the D-Fmoc-mNMeTyr
fragment 5 and subsequent deprotection of the Fmoc group in
27 with piperidine led to key vinylstannane amine 4 smoothly.
The final deprotection of the silyl groups in 36a−d was also
crucial. To remove the TES and TBS in 36a−d, a large number of
C
DOI: 10.1021/acs.orglett.6b02371
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Author Contributions
deprotection conditions were examined. Conditions with acid
reagents (such as CSA) always provided a significant amount of
unidentified polar byproducts. To our pleasure, the deprotection
of 36a was efficient with TBAF/AcOH (molar ratio 1:1, 0.02 M
in THF), providing 2a in 61% yield and its 22-membered isomer
1a from ester migration in 30% yield. Following the same
reaction conditions, compounds 2b−d and 1b−d were obtained
in combined yields of 66%−70%: 28%−42% for 2b−d and 28%−
38% for 1b−d. The concentration of TBAF/AcOH was
important for this deprotection, as more concentrated TBAF/
AcOH resulted in messy products. Fortunately, the stereocenter
at C-17 in 1a−d and 2a−d was not impacted under the
optimized conditions. Compound 1c could migrate to 2c
spontaneously even in solvents other than MeOH and reach a
ratio of 3.5/1 (1c/2c) rapidly; however, pure 1a,b, 1d, and 2a−d
remained unchanged for at least 2 months at 4 °C.
†N.Q. and S.R.A. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21572027 and 21372267),
the Postdoctoral Science Foundation of China (No.
2014M562285), and the Chongqing Postdoctoral Research
Grant (No. Xm2014030). We thank Professor Rolf Muller
(Helmholtz Institute for Pharmaceutical Research Saarland) for
helpful discussions.
̈
REFERENCES
(1) Weissman, K. J.; Muller, R. Nat. Prod. Rep. 2010, 27, 1276.
(2) Garcia, R.; Gerth, K.; Stadler, M.; Dogma, I. J., Jr.; Muller, R. Mol.
■
1
The H NMR and 13C NMR of 1a−d and 2a−d were
̈
compared with those of natural aetheramides A and B.3 The 1H
NMR and 13C NMR of 1a (17R,26R) and 2a (17R,26R), as well
as their 2D spectra (COSY, HSQC, and HMBC), matched the
reported spectra and/or data nicely.18 On the other hand, the
spectra of 1b−d and 2b−d exhibited significant differences from
the reported data. Thus, the two undetermined stereochemistries
at C-17 and C-26 in aetheramides A and B were assigned as 17R
and 26R.
Aetheramide A (1a) could be synthesized more directly from
silyl ether 24, following a similar reaction sequence (Scheme 6;
see the Supporting Information for details). The final
deprotection of the silyl groups again proved to be sensitive.
The use of TBAF/AcOH led to a complex mixture. After careful
screening of reaction conditions, 0.05 M CSA in MeOH was
found to be effective for the deprotection, affording 1a in 89%
yield. Aetheramide B (2a) from ester migration was not observed
under this deprotection condition. The overall yield for
aetheramide A was 5.3% with 15 linear steps. Aetheramide B
(2a) could be obtained from aetheramide A (1a) via ester
migration.
In summary, a concise and efficient asymmetric route was
developed to synthesize aetheramides A and B, as well as three
pairs of their stereoisomers. Aetheramides A and B were
synthesized in a longest linear sequence of 15 steps with overall
yields of 5.3% and 3.6%, respectively, starting from commercially
available trans-ethyl cinnamate 8. The ambiguous stereo-
chemistries at C-17 and C-26 were assigned as 17R and 26R,
respectively, by comparing the NMR data of the synthetic
samples with the reported. This is the first time the absolute
stereochemistries of aetheramides have been fully established.
The syntheses of more aetheramide analogues and their
biological evaluations are underway, and the results will be
reported in due course.
̈
Phylogenet. Evol. 2010, 57, 878.
(3) Plaza, A.; Garcia, R.; Bifulco, G.; Martinez, J. P.; Huttel, S.; Sasse, F.;
Meyerhans, A.; Stadler, M.; Muller, R. Org. Lett. 2012, 14, 2854.
̈
(4) Celebeside A, a 26-membered depsipeptide with a negative
phosphate moiety, has some related structural features and weakly
inhibits HIV-1 infection (IC50, 2 μM). Plaza, A.; Bifulco, G.; Keffer, J. L.;
Lloyd, J. R.; Baker, H. L.; Bewley, C. A. J. Org. Chem. 2009, 74, 504.
(5) (a) Ghosh, A. K.; Rao, K. V.; Akasapu, S. Tetrahedron Lett. 2014, 55,
5191. (b) Revu, O.; Prasad, K. R. Synlett 2014, 25, 2887. (c) Gerstmann,
L.; Kalesse, M. During the submission of the manuscript, a total
synthesis of aetheramide A in 18 linear steps with an overall yield of 0.2%
appeared online. However, the stereochemistry of C-17 remained
undetermined, and the 13C NMR spectrum of aetheramide A was not
reported due to some difficulties. They attempted the total synthesis of
aetheramide B but were not successful. Chem. - Eur. J. 2016, 22, 11210.
(6) For reviews of intramolecular Stille coupling, see: (a) Duncton, M.
A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1, 1235.
(b) Pattenden, G.; Sinclair, D. J. J. Organomet. Chem. 2002, 653, 261.
For representative examples of intramolecular Stille coupling, see:
(c) Brodmann, T.; Janssen, D.; Kalesse, M. J. Am. Chem. Soc. 2010, 132,
13610. (d) Sato, E.; Tanabe, Y.; Nakajima, N.; Ohkubo, A.; Suenaga, K.
Org. Lett. 2016, 18, 2047.
(7) Gieseler, M. T.; Kalesse, M. Org. Lett. 2011, 13, 2430.
(8) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599.
(9) Manda, S.; Nakanishi, I.; Ohkubo, K.; Uto, Y.; Kawashima, T.;
Hori, H.; Fukuhara, K.; Okuda, H.; Ozawa, T.; Ikota, N.; Fukuzumi, S.;
Anzai, K. Chem. Commun. 2008, 626.
(10) Ross, A. J.; Lang, H. L.; Jackson, R. F. W. J. Org. Chem. 2010, 75,
245.
(11) Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55, 906.
(12) Kim, E. J.; An, K. M.; Ko, S. Y. Bull. Korean Chem. Soc. 2006, 27,
2019.
(13) (a) Gallant, P.; D’Haenens, L.; Vandewalle, M. Synth. Commun.
1984, 14, 155. (b) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J.
̈
Synlett 1996, 1996, 521.
(14) Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. J. Org. Chem. 2007,
72, 3868.
(15) Bu, X.; Xie, G.; Law, C. W.; Guo, Z. Tetrahedron Lett. 2002, 43,
2419.
ASSOCIATED CONTENT
* Supporting Information
■
S
(16) Simsek, S.; Horzella, M.; Kalesse, M. Org. Lett. 2007, 9, 5637.
(17) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(b) Nicolaou, K. C.; Murphy, F.; Barluenga, S.; Ohshima, T.; Wei, H.;
Xu, J.; Gray, D. L. F.; Baudoin, O. J. Am. Chem. Soc. 2000, 122, 3830.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02371.
Experimental procedures and characterization data for
products (PDF)
(18) In the original paper, Muller’s group reported 13C NMR data for
̈
aetheramides A and B; however, no 13C NMR spectra were provided. In
Kalesse’s paper on the total synthesis of aetheramide A, no 13C NMR
data or spectrum was provided. Through our syntheses, large enough
amounts of aetheramides A and B were obtained, and 13C NMR data and
clean spectra are provided in the Supporting Information.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: guojian5218@163.com.
*E-mail: yun.he@cqu.edu.cn.
D
DOI: 10.1021/acs.orglett.6b02371
Org. Lett. XXXX, XXX, XXX−XXX