An expeditious asymmetric synthesis of the polyketide unit present in HIV-inhibitory depsipeptides aetheramide A and B

Article abstract of DOI:10.1055/s-0034-1379476

The enantioselective synthesis of the polyketide unit present in depsipeptides aetheramide A and B, which possess potent HIV-inhibitory activity, is accomplished from a chiral furyl carbinol.

Full text of DOI:10.1055/s-0034-1379476

LETTER
▌2887
lAettner Expeditious Asymmetric Synthesis of the Polyketide Unit Present in
HIV-Inhibitory Depsipeptides Aetheramide A and B
Polyketide Unit of Aetheramide A and B
Omkar Revu, Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560 012, India
Fax +91(80)23600529; E-mail: prasad@orgchem.iisc.ernet.in
Received: 05.08.2014; Accepted after revision: 21.09.2014
OMe
Abstract: The enantioselective synthesis of the polyketide unit
present in depsipeptides aetheramide A and B, which possess potent
HO
HIV-inhibitory activity, is accomplished from a chiral furyl carbi-
nol.
O
O
8
O
5
Key words: macrolactones, natural products, depsipeptides, HIV-
inhibitors
N
NH Me
1
O
O
15
Natural products with varied structural diversity and ac-
tivity serve as excellent leads in drug discovery progres-
sion.1 Given that a large number of lead molecules of
therapeutic significance have their origin in natural prod-
ucts, there has been continuing interest in the isolation,
synthesis, and evaluation of natural products and ana-
logues as potential therapeutics.2 Recently, Müller’s
group reported the isolation of two new depsipeptides,
aetheramide A (1) and B (2) from a novel myxobacterial
genus Aetherobacter (Figure 1).3 Aetheramides A and B
are 22- and 21-membered macrolactones that contain a
unique polyketide moiety and a dipeptide residue.4
Aetheramides contain six stereogenic centers in which the
absolute configuration of the two stereogenic centers at
C8 and C15 was not established.4 The aetheramides were
shown to exhibit potent inhibitory activity of HIV-1, with
IC50 values of 0.015 μM, and good cytotoxic activity
against HCT-116 cells (IC50 0.11 μM). Hitherto, no total
synthesis of aetheramides has been reported and, herein,
we disclose our efforts in the expeditious assembly of the
polyketide unit present in aetheramides.5
20
OMe
OH
aetheramide A (1)
OMe
HO
O
H
N
N
O
O
Me
O
O
OH
OMe
aetheramide B (2)
Figure 1 Aetheramides A and B
OMe
HO
Pioneering work by Kobayashi’s group established the
use of furan as a but-2-ene-1,4-dione equivalent in the to-
tal synthesis of natural products by hydrolytic ring open-
ing of furan.6 This reaction has been somewhat neglected;
although recently we have utilized this sequence in the to-
tal synthesis of macrolactone natural products.7 In a con-
tinuation of our efforts, we planned the synthesis of the
polyketide unit 3 by elaboration of the keto aldehyde 4,
which can be synthesized readily from the oxidation of the
furan unit present in the protected furyl carbinol 5
(Scheme 1). Amide coupling of the protected polyketide
acid unit 3 with the amino acid fragment and macrolacton-
ization would thus lead to the synthesis of aetheramides
and their derivatives.
O
O
O
O
HO
O
N
NH
O
OPG
O
Ph
OMe
OMe
OPG
OH
3
aetheramide A (1)
OPG
Ph
OPG
O
H
O
Ph
O
5
4
Scheme 1 Retrosynthesis for aetheramide A
SYNLETT 2014, 25, 2887–2890
Advanced online publication: 27.10.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379476; Art ID: st-2014-d0653-l
© Georg Thieme Verlag Stuttgart · New York

2888
O. Revu, K. R. Prasad
LETTER
TBHP, Ti(Oi-Pr)4
TBSCl
imidazole, DMAP
CH2Cl2, 0 °C
2 h, 95%
NBS, NaHCO3
furan, pyridine
acetone–H2O
2 h, 80%
Ph
L-(+)-DIPT, 4 Å MS
CH2Cl2, –21 °C, 48 h
43%, 99% ee
Ph
Ph
O
O
O
OH
(+)- 6
OH
( )- 6
OTBS
5
OTBS
O
OTBS
(EtO)2POC(Me)CO2Et, LiHMDS
THF, –78 °C, 2 h, 91%
NaBH4, CeCl3⋅7H2O, MeOH
Ph
OEt
Ph
Ph
O
r.t. to –78 °C, 1.5 h, 87%
O
O
4
7
OTBS
O
OTBS
O
O
NHMe(OMe)⋅HCl, i-PrMgCl
MOMCl, DIPEA, DMAP, CH2Cl2
0 °C to r.t., 8 h, 93%
Ph
OEt
OEt
THF, 0 °C, 1 h, 85%
OMOM
OH
8
9
THPO
OTBS
OTBS
OTHP
BrMg
(S)-CBS, BH3⋅SMe2, THF
Me
-25 °C, 10 h, 82%
Ph
N
Ph
THF, 0 °C, 1 h, 83%
O
OMOM
10
OMe
OMOM
11
THPO
THPO
OTBS
OTBS
NaH, MeI, DMF, 0 °C to r.t.
80%
Ph
OH
Ph
OMe
OMOM
OMOM
12
13
Scheme 2 Synthesis of the diene unit 13
Accordingly, the synthesis began with the gram-scale product 18 in 90% yield for two steps. Protection of the al-
preparation of the known chiral furyl carbinol 6 by Shar- cohol in 18 as its silyl ether 19 and cleavage of the thi-
pless asymmetric kinetic resolution of the racemate in azolodinone afforded carboxylic acid 3, representing the
43% yield (Scheme 2).8 Protection of the secondary alco- polyketide unit of the aetheramides, in 60% yield
hol furnished TBS ether 5, which, on reaction with N-bro- (Scheme 3).13 Further elaboration of the acid to
mosuccinimide (NBS) in aqueous acetone, afforded keto aetheramide A involving peptide coupling and subse-
aldehyde 4 in 80% yield. Elaboration of the aldehyde in 4 quent macrolactonization is underway.
through Wittig–Horner olefination gave the (E)-α,β-un-
In conclusion, a facile synthesis of the polyketide frag-
ment present in depsipeptides aetheramide A and B has
been accomplished from the chiral furyl carbinol 6. The
procedure is operationally simple and is applicable to the
saturated ester 7 in 91% yield. Reduction of the keto
group in 7 produced the corresponding alcohol 89 in 87%
yield, which was protected as its MOM ether 9 in 93%
yield. The ester in 9 was transformed into the correspond-
synthesis of analogues of the aetheramides.
ing Weinreb amide 10, which, on reaction with {4-[(tetra-
hydro-2H-pyran-2-yl)oxy]butyl}magnesium bromide,10
Acknowledgment
afforded ketone 11 in 83% yield. Oxazaborolidine-medi-
ated CBS reduction11 of the ketone furnished alcohol 12 in
82% yield, and this was converted into methyl ether 13 in
excellent yield.
O.R. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a Research Fellowship.
Removal of the THP group in 13 afforded primary alcohol
14 in 84% yield. Alcohol 14 was oxidized by using 2-io-
Supporting Information for this article is available online
at
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doxybenzoic acid (IBX) to the aldehyde, which, on Wittig 10.1055/s-00000083.SunogIpimfirantoSuIpg
n
fonirtat
ori
olefination, furnished the (E)-α,β-unsaturated ester 15,
which was reduced with diisobutylaluminum hydride
(DIBAL-H) to provide allylic alcohol 16 in 87% yield.
Oxidation of the alcohol in 16 with MnO2 to the aldehyde
followed by Nagao aldol reaction12 furnished the aldol
References and Notes
(1) Koehn, F. E.; Carter, G. E. Nat. Rev. Drug Discovery 2005,
4, 206.
(2) Butler, M. S. J. Nat. Prod. 2004, 67, 2141.
Synlett 2014, 25, 2887–2890
© Georg Thieme Verlag Stuttgart · New York

LETTER
Polyketide Unit of Aetheramide A and B
2889
O
EtO
HO
OTBS
OTBS
i) IBX, EtOAc, reflux, 3 h
PPTS, MeOH, r.t., 6 h
84%
13
Ph
OMe
Ph
OMe ii) Ph3PC(Me)CO2Et, toluene
reflux, 1 h, 95% for 2 steps
OMOM
15
OMOM
14
O
OH
S
HO
N
S
i) MnO2, CH2Cl2, reflux, 2 h
ii) 17, TiCl4, i-Pr2NEt, CH2Cl2
DIBAL-H, CH2Cl2, –78 °C
30 min, 87%
OTBS
–25 °C, 30 min
then aldehyde, –20 °C, 10 min
OTBS
Ph
OMe
90% for 2 steps
Ph
OMe
OMOM
OMOM
16
18
O
O
OTES
OTES
S
N
HO
S
S
O
TESOTf, pyridine
CH2Cl2, –50 °C to r.t.
2 h, 92%
LiOH, H2O2
THF, H2O
S
N
OTBS
OTBS
r.t., 2 h, 60%
17
Ph
OMe
Ph
OMe
OMOM
OMOM
3
19
Scheme 3 Synthesis of the polyketide unit 3 present in aetheramide A
(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) Numbering of the macrolactone as reported by Muller et al.
in the isolation paper, see ref. 3.
(5) While this manuscript was in preparation, a report
concerning the synthesis of the macrocyclic aetheramide A
was published, see: Ghosh, A. K.; Rao, K. V.; Akasapu, S.
Tetrahedron Lett. 2014, 55, 5191.
(6) (a) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K.
J. Org. Chem. 1998, 63, 7505. (b) Kobayashi, Y.; Kumar, G.
B.; Kurachi, T.; Acharya, H. P.; Yamazaki, T.; Kitazume, T.
J. Org. Chem. 2001, 66, 2011.
(11) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551. The stereochemistry of the alcohol in 12
resulting from the reduction of ketone 11 was assigned based
on the reduction of analogous ketones. See ref. 7d.
(12) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue,
T.; Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391.
(13) All compounds exhibited satisfactory analytical data. Data
for selected compounds:
Compound 8: [α]D24 +71.5 (c 1.05, CHCl3); IR (neat): 3442,
2954, 2929, 1700, 1587 cm–1; 1H NMR (400 MHz, CDCl3):
δ = 7.40–7.22 (m, 5 H), 7.08 (d, J = 11.2 Hz, 1 H), 6.58–6.45
(m, 1 H), 5.81 (dd, J = 15.2, 4.8 Hz, 1 H), 4.44 (d,
J = 7.2 Hz, 1 H), 4.27 (br. s, 1 H), 4.20 (q, J = 7.2 Hz, 2 H),
2.97 (d, J = 2.4 Hz, 1 H), 1.89 (s, 3 H), 1.28 (t, J = 7.2 Hz,
3 H), 0.90 (s, 9 H), 0.05 (s, 3 H), –0.18 (s, 3 H); 13C NMR
(100 MHz, CDCl3): δ = 168.5, 140.5, 138.8, 137.3, 128.1
(2 × C), 127.8, 127.5, 127.1, 127.0 (2 × C), 78.1, 76.6, 60.6,
25.7 (3 × C), 18.1, 14.3, 12.6, –4.6, –5.0; HRMS: m/z calcd
for C22H34O4Si + Na: 413.2124; found: 413.2124.
(7) (a) Prasad, K. R.; Revu, O. J. Org. Chem. 2014, 79, 1461.
(b) Sunnam, S. K.; Prasad, K. R. Tetrahedron 2014, 70,
4552. (c) Sunnam, S. K.; Prasad, K. R. Synthesis 2013, 45,
1991. (d) Prasad, K. R.; Pawar, A. B. Org. Lett. 2011, 13,
4252.
(8) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, Y. J. Org.
Chem. 1989, 54, 2085.
Compound 14: [α]D24 –48.8 (c 0.65, CHCl3); IR (neat):
3450, 2932, 2888, 1725, 1458, 1099 cm–1; 1H NMR (400
MHz, CDCl3): δ = 7.35–7.20 (m, 5 H), 6.36 (dd, J = 15.0,
11.2 Hz, 1 H), 5.89 (d, J = 11.2 Hz, 1 H), 5.43 (dd, J = 15.2,
7.2 Hz, 1 H), 4.68 (d, J = 5.2 Hz, 1 H), 4.63 (dd, J = 6.8,
2.0 Hz, 1 H), 4.55 (dd, J = 6.8, 2.0 Hz, 1 H), 4.19 (t,
J = 6.8 Hz, 1 H), 3.62–3.52 (m, 2 H), 3.40 (t, J = 7.2 Hz,
1 H), 3.10 (br s, 6 H), 2.31 (br s, 1 H), 1.56 (s, 3 H), 1.55–
1.45 (m, 2 H), 1.44–1.20 (m, 4 H), 0.84 (s, 9 H), 0.02 (s,
3 H), –0.12 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ =
141.4, 137.2, 129.9, 128.7, 127.5 (2 × C), 127.1, 127.0
(2 × C), 126.9, 94.3, 87.0, 80.7, 77.7, 62.3, 55.7, 55.1, 33.2,
(9) The diastereomeric ratio of the product was found to be ca.
95:5, as estimated by 1H NMR spectroscopic analysis. The
stereochemistry of the major diastereomer was assigned
based on previously reported reduction of structurally
similar ketones. See refs. 7a–d.
(10) The Grignard reagent was prepared from the corresponding
tetrahydro-2H-pyran-2-yloxybutyl bromide, which was
synthesized according to a previously described procedure,
see: Grieco, P. A.; Larsen, S. D. J. Org. Chem. 1986, 51,
3553.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2887–2890

2890
O. Revu, K. R. Prasad
LETTER
32.4, 25.7 (3 × C), 21.9, 18.1, 10.9, –4.9, –5.1; HRMS: m/z
calcd for C27H46O5Si + Na: 501.3012; found: 501.3013.
Compound 3: [α]D24 –19.4 (c 0.5, CHCl3); IR (neat): 3400,
2919, 1710, 1655, 1087 cm–1; 1H NMR (400 MHz, CDCl3):
δ = 7.40–7.15 (m, 5 H), 6.34 (dd, J = 15.2, 11.0 Hz, 1 H),
5.87 (d, J = 10.8 Hz, 1 H), 5.45–5.30 (m, 2 H), 4.70 (d,
J = 5.2 Hz, 1 H), 4.66 (d, J = 6.8 Hz, 1 H), 4.58 (d,
J = 6.8 Hz, 1 H), 4.21 (t, J = 6.2 Hz, 1 H), 4.10 (d,
J = 7.8 Hz, 1 H), 3.42 (dd, J = 7.2, 4.0 Hz, 1 H), 3.15 (s,
3 H), 3.14 (s, 3 H), 2.70–2.58 (m, 1 H), 2.28–1.95 (m, 2 H),
1.90–1.80 (m, 1 H), 1.61 (s, 3 H), 1.60 (s, 3 H), 1.45–1.20
(m, 3 H), 1.14 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 8.0 Hz, 9 H),
0.87 (s, 9 H), 0.58 (q, J = 8.0, 6 H), 0.04 (s, 3 H), –0.10 (s,
3 H); 13C NMR (100 MHz, CDCl3): δ = 177.8, 141.6, 137.4,
137.3, 135.6, 130.1, 128.8, 127.6 (2 × C), 127.2 (3 × C),
127.1, 94.5, 87.6, 80.9, 80.4, 77.8, 55.7, 55.2, 33.8, 29.7,
26.8, 25.8 (3 × C), 25.7, 18.3, 12.9, 11.0, 10.9, 6.8 (3 × C),
4.7 (3 × C), –4.8, –4.9; HRMS: m/z calcd for C39H68O7Si2 +
Na: 727.4401; found: 727.4401.
Synlett 2014, 25, 2887–2890
© Georg Thieme Verlag Stuttgart · New York

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