Total Synthesis and Structural Confirmation of the Antimalarial Naphthopyrone Lasionectrin

Article abstract of DOI:10.1021/acs.orglett.5b03202

The total synthesis of lasionectrin, a naphthopyrone metabolite of an Acremonium-like fungus collected in Equatorial Guinea, is reported. Divergent access to four stereoisomers confirmed the natural product to be the enantiomer of the originally proposed structure. Highlights of the synthesis include ring opening of a chiral oxetane using a thiol, a highly E-selective Julia-Kocienski olefination, and a modified Sharpless/Upjohn dihydroxylation. Palladium-catalyzed carbonylative lactonization was used to assemble the fused naphthopyrone ring system.

Full text of DOI:10.1021/acs.orglett.5b03202

Letter
pubs.acs.org/OrgLett
Total Synthesis and Structural Confirmation of the Antimalarial
Naphthopyrone Lasionectrin
Vincent L. Poral, Daniel P. Furkert,* and Margaret A. Brimble*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
S
* Supporting Information
ABSTRACT: The total synthesis of lasionectrin, a naph-
thopyrone metabolite of an Acremonium-like fungus collected
in Equatorial Guinea, is reported. Divergent access to four
stereoisomers confirmed the natural product to be the
enantiomer of the originally proposed structure. Highlights
of the synthesis include ring opening of a chiral oxetane using a thiol, a highly E-selective Julia−Kocienski olefination, and a
modified Sharpless/Upjohn dihydroxylation. Palladium-catalyzed carbonylative lactonization was used to assemble the fused
naphthopyrone ring system.
monocerin ring system.3 Ester 3 would be available from
asionectrin (1) is a tetracyclic naphthopyrone natural
regioselective halogenation and palladium-catalyzed carbon-
ylation of the naphthalene core, which could be accessed by
Julia−Kocienski olefination of suitably substituted aldehyde 4
and sulfone 5.
The synthesis of the naphthaldehyde fragment (Scheme 2)
began from Horner−Wadsworth−Emmons coupling of com-
Lproduct that was isolated in 2012 from fermentation of the
fungus Lasionectria (F-176,994).1 The Acremonium-like fungus
was colleced from leaf litter in Equatorial Guinea as part of a
screening program for fungal metabolites inspired by genomic
sequencing of species from the order Hypocreales. Lasionectrin
was isolated by fractionation of extracts exhibiting in vitro
activity against Plasmodium falciparum Pf3D7. The develop-
ment of novel malaria therapeutics is a pressing global issue,
with resistance established against the most readily available
drug, chloroquine, and emerging against frontline treatments
such as artemesinin. Lasionectrin can be considered a
benzannulated congener of the monocerin (2) family of
benzopyrones, which are active against multidrug-resistant P.
falciparum K1.2 The all-R 3,4-cis-4,12-trans stereochemistry was
proposed for 1 on the basis of the 3R,4R configuration of 2 and
1H NMR NOESY correlations.1 No synthetic work toward
lasionectrin has been reported to date.
Scheme 2. Synthesis of Naphthaldehydes 11a and 11b
Our initial strategy for the synthesis of 1 (Scheme 1) hinged
on the formation of the bicyclic core from ester 3 using
hypervalent iodine reagents, inspired by recent work toward the
mercially available 3,5-dimethoxybenzaldehyde (6) with diester
phosphonate 74 to afford cinnamic ester 8 in 73% yield.5
Exposure of 8 to trifluoroacetic acid in dichloromethane
delivered the expected carboxylic acid 9 by deprotection of the
tert-butyl ester, along with a minor byproduct identified as the
fully cyclized naphthalene 10.6 The reaction was readily
optimized to favor this cyclization product, directly providing
the desired naphthol 10 in 83% yield, a small improvement
over previously reported two-step sequences for the synthesis
of similar compounds.7 Ester 10 was then converted to two
potential Julia−Kocienski coupling partners, TBS-protected
naphthaldehyde 11a and the corresponding acetate 11b, using
standard transformations.
Scheme 1. Initial Retrosynthetic Analysis of Lasionectrin (1)
Received: November 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03202
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The preparation of the requisite sulfone 5 (Scheme 3)
commenced with ring expansion of enantiopure (S)-2-
to nearly quantitative with excellent E selectivity (Table 1, entry
8).
In order to elaborate olefin 16a into a suitable substrate for
the proposed hypervalent iodine cyclization, the phenolic TBS
ether was selectively deprotected using DBU in aqueous
acetonitrile (Scheme 4).11 Attempts to halogenate the resultant
Scheme 3. Synthesis of Sulfone 5 via Enantiopure Oxetane
13
Scheme 4. Unsuccessful Hypervalent Iodine Cyclization
propyloxirane (12)8 to obtain oxetane 13 using trimethylsul-
foxonium iodide in the presence of tert-butoxide.9 Ring opening
was then effected with phenyltetrazole thiol 14 in the presence
of lithium bromide to give chiral alcohol 15 (>98% ee, HPLC).
Silyl protection and subsequent oxidation of the sulfide then
afforded the desired sulfone 5 in excellent yield over the two
steps. Attempts to effect Julia−Kocienski coupling of
naphthaldehyde 11a and sulfone rac-510 using standard
conditions (KHMDS or LHMDS as the base, DME or THF
as the solvent) proved largely unsuccessful (Table 1, entries 1
naphthol 17 using pyridinium tribromide resulted in only
undesired para- or dihalogenation. Pleasingly, the use of
morpholine−iodine complex12 selectively afforded the desired
ortho product 17 in high yield. Because of the instability of
iodide 17, it was immediately protected as the acetate 18.
Attempts to effect carbonylation of the iodide to give ester 19
were unsuccessful using a variety of methods,13 with
protodehalogenation predominantly occurring. Eventually,
carbonylation was successfully achieved in a sealed tube at
120 °C under a carbon monoxide atmosphere in the presence
of palladium acetate and triethylamine.14
Table 1. Julia−Kocienski Coupling of Fragments 11 and 5
With the desired ester rac-19 in hand, the key hypervalent
iodine cyclization was investigated. Unfortunately, despite the
precedent for the monocerin system, all attempts to form fused
naphthopyran lactone 20 using iodobenzene diacetate (PIDA)
or iodobenzene bistrifluoroacetate (PIFA) under a wide variety
of conditions resulted only in decomposition. Although
disappointing, this result served to highlight the electronic
differences between the benzopyran ring system of monocerin
and the naphthopyran system of lasionectrin, which are likely
responsible for the contrasting reactivities observed.
Because of this setback, an alternative synthetic approach was
required in order to install the fused naphthopyrone ring
system. Returning to ester 19, a dihydroxylation−lactoniza-
tion−SN2 substitution sequence was briefly investigated
(Scheme 5). The secondary silyl ether was first removed
using TBAF buffered with acetic acid, and the resulting free
alcohol was converted to the corresponding tosylate 21.
entry
11
conditions
additive
yield (%)
E:Z
a
1
11a
11a
11a
11a
11a
11a
11b
11b
KHMDS, DME
LHMDS, THF
LHMDS, THF
LHMDS, DME
KMHDS, THF
KHMDS, THF
KHMDS, THF
KHMDS, THF
−
−
0
13
71
69
60
94
75
98
−
2
3
4
5
6
7
94:6
94:6
90:10
98:2
98:2
98:2
98:2
LiBr
LiBr
LiBr
LiCl
LiCl
LiCl
b
8
a
Aldehyde 11a or 11b was added to the base + sulfone 5 mixture at
−78 °C, and the resulting mixture was then warmed to rt overnight.
Precooled base + sulfone 5 mixture was added to aldehyde 11a or
11b and LiCl at −20 °C, and the resulting mixture was then warmed
to 0 °C after 2 h.
b
Scheme 5. Kinetic Preference for Five-Membered Lactone
a
Formation
and 2). Lithium bromide or chloride was found to be essential
to obtain useful yields of the olefin. These conditions
additionally conferred high selectivity for the desired E isomer
(Table 1, entries 3 and 4).
Optimization of the base and solvent finally delivered the
desired TBS-protected product in 94% yield with excellent E
selectivity (Table 1, entry 6). Later in our investigation it was
found that an acetate group on the naphthol delivered greater
synthetic efficiency, so the olefination was also performed on
naphthaldehyde 11b, affording a 75% yield of the correspond-
ing acetate-protected product 16b (Table 1, entry 7).
Pleasingly, reversing the order of addition and altering the
reaction temperature from −78 to −20 °C improved the yield
a
Bold bonds indicate cis relative stereochemistry only.
B
DOI: 10.1021/acs.orglett.5b03202
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Organic Letters
Letter
However, Sharpless asymmetric dihydroxylation of the olefin
delivered only lactone 22, indicating that the expected kinetic
preference for five-membered lactonization clearly ruled out the
possibility of initial tetrahydropyranone formation followed by
intramolecular SN2 substitution of the tosylate by the benzylic
alcohol.
Scheme 6. Successful Lasionectrin Endgame via
Carbonylative Lactonization
This result indicated that the tetrahydrofuran ring would
need to be installed before introduction of the six-membered
lactone. Accordingly, our strategy was readjusted to form the
tetrahydrofuran ring via a dihydroxylation−intramolecular SN2
sequence, which would then be followed by palladium-catalyzed
carbonylation/lactonization. Our revised route (see Scheme 6)
began from acetate 16b, which was directly accessed in the
Julia−Kocienski coupling (see Table 1). Removal of the TBS
group revealed the secondary alcohol, which was converted to
the tosylate using a mixture of pyridine and dichloromethane.
This solvent mixture was important, as the use of neat pyridine
resulted in substantial formation of the corresponding chloride,
presumably via nucleophilic substitution of the initially formed
tosylate.
With alkene 23 in hand, the dihydroxylation−SN2 cyclization
sequence was investigated. Sharpless conditions proved
unsuccessful, giving either no conversion or decomposition of
the starting material (Table 2, entries 1 and 2). The use of
tation, the carbonylation was successfully achieved in the
presence of palladium diacetate using molybdenum hexacar-
bonyl as the in situ source of carbon monoxide.15 Concomitant
lactonization led to the formation of a mixture of the fully
cyclized naphthopyran 4,12-trans and 4,12-cis diastereoisomers
in 63% yield, which were chromatographically separable at this
point. Several reagents for selective demethylation peri to the
free phenol were unsuccessful (BBr3,16 BCl3,17 EtSH18), but
heating the individual methyl ethers at 160 °C in NMP in the
presence of lithium chloride19 successfully afforded both the
natural product target lasionectrin (1) as a coloress solid and
the 4,12-cis diastereoisomer (12-epi-1).
Table 2. Dihydroxylation of Tosylate 23
1
Comparison of the H and 13C NMR spectra of synthetic
and natural 1 showed excellent agreement in all respects. In
particular, the three methine protons at the ring junctions,
namely, H3 (5.24 ppm), H4 (4.93 ppm), and H12 (4.33 ppm),
resonated at identical chemical shifts in the two spectra. In
contrast, differing shifts were observed for the corresponding
protons in the synthetic 4,12-cis diastereoisomer 12-epi-1: H3
(5.10 ppm), H4 (4.66 ppm), and H12 (4.17 ppm). A NOESY
correlation between methines H3 and H12 in 12-epi-1 that is
absent in 1 served to confirm the original assignment of the
relative stereochemistry at C3, C4, and C12. The measured
specific rotation of +148 (c 0.17, MeOH), however, was in
disagreement with the value reported at the time of isolation
[−43.8 (c 0.17, MeOH)]. To unambiguously confirm the
structure of the natural product, (−)-1, rac-1, (+)-12-epi-1, and
rac-12-epi-1 (box in Scheme 6) were additionally prepared
beginning from (2R)-12 and rac-12, respectively. Chiral HPLC
entry
conditions
temp
yield (%) 24a:24b
a
a
c
1
2
3
4
5
Sharpless
Sharpless
0 to rt
55 °C
rt
0
0
−
−
d
b
Upjohn
97
68
68
1:1
4:1
1:4
b
Upjohn with (DHQ)2PHAL
rt
b
Upjohn with (DHQD)2PHAL
0 °C
a
Sharpless: AD-mix-α, MeSO2NH2 (1 equiv), t-BuOH/H2O (1:1).
Upjohn: OsO4 (5 mol %), NMO (2.1 equiv), acetone/H2O (1:1),
b
c
d
ligand (10 mol %). No reaction. Decomposed.
Upjohn conditions effected a complete turnaround, affording
an inseparable mixture of the cyclized tetrahydrofurans 24a and
24b, where intramolecular displacement of the tosyl group
occurred spontaneously following dihydroxylation, in nearly
quantitative yield (Table 2, entry 3). Useful selectivity (24a:24b
= 4:1) was achieved by the inclusion of the chiral Sharpless
ligand (DHQ)2PHAL in the Upjohn dihydroxylation con-
ditions (Table 2, entry 4), and the selectivity could be readily
reversed (24a:24b = 1:4) using the pseudoenantiomeric ligand
(DHQD)2PHAL.
Removal of the acetate and ortho iodination of the free
phenol using the morpholine−iodine complex conditions
(Scheme 6) gave a mixture of the iodides 25a and 25b in
excellent yield. Initial attempts to form the fused pyranofuran
by carbonylation of the iodide followed by intramolecular
cyclization using the previously successful conditions resulted
predominantly in protodehalogenation. After some experimen-
i
(Chiralpak AD-H, PrOH/hexane) established that synthetic
(+)-1 (ee = 97%) and (−)-1 (ee = 98%) were essentially
enantiopure and exhibited specific rotations of +148 (c 0.17,
MeOH) and −138 (c 0.16, MeOH), respectively. Similar
purities and specific rotations were also established for the 4,12-
cis diastereomers (−)-12-epi-1 [ee = 97%; −192 (c 0.13,
CHCl3)] and (+)-12-epi-1 [ee = 99%; +197 (c 0.13, CHCl3)].
Taken together, these data indicate that the relative stereo-
chemistry of C12 with respect to C3 and C4 is the key
determinant of the specific rotation in these systems and that
lasionectrin (−)-1 is the antipode of the structure initially
reported by Reyes et al.
C
DOI: 10.1021/acs.orglett.5b03202
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Organic Letters
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(11) For the use of DBU as a selective desilylating reagent, see:
Yeom, C.-E.; Kim, H. W.; Lee, S. Y.; Kim, B. M. Synlett 2007, 2007,
146−150.
In summary, the first total synthesis of the natural product
lasionectrin (1) has been achieved. The stereochemistry at C12
was installed by ring opening of an enantiopure oxetane, and
the two key structural components were united using a highly
E-selective Julia−Kocienski olefination. After hypervalent
iodine cyclization proved unsuccessful, assembly of the target
structure was achieved through a modified Sharpless/Upjohn
dihydroxylation followed by an SN2 cyclization/carbonylative
lactonization sequence. The synthesis provided convenient
access to the lasionectrin diastereomers (+)-12-epi-1 and
(−)-12-epi-1 for stereochemical elucidation and will enable
subsequent comparative investigation of their biological activity.
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03202.
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Experimental procedures (PDF)
Spectra and chiral HPLC traces for 1, 12-epi-1, and 26
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*d.furkert@auckland.ac.nz
*m.brimble@auckland.ac.nz
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.5b03202
Org. Lett. XXXX, XXX, XXX−XXX