Enantioselective Total Synthesis of (+)-Iso-A82775C, a Proposed Biosynthetic Precursor of Chloropupukeananin

Article abstract of DOI:10.1021/acs.orglett.7b00085

(+)-Iso-A82775C is a proposed biosynthetic precursor of the chloropupukeananin family and an important intermediate for related natural products. The first enantioselective total synthesis of (+)-iso-A82775C (18 steps, 2.2% overall yield) toward the eventual biomimetic total synthesis of chloropupukeananin is described. The key steps are (1) the enantioselective Diels-Alder reaction of 4-bromo-3-hydroxy-2-pyrone with methyl 2-chloroacrylate using cinchonine as an organocatalyst and (2) the anti-selective Cu-mediated S_N2′ reaction to afford the axially chiral vinylallene moiety.

Full text of DOI:10.1021/acs.orglett.7b00085

Letter
pubs.acs.org/OrgLett
Enantioselective Total Synthesis of (+)-Iso-A82775C, a Proposed
Biosynthetic Precursor of Chloropupukeananin
Takahiro Suzuki,*,†,§ Soichiro Watanabe,‡ Susumu Kobayashi,§ and Keiji Tanino*,†
†Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
‡Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan
§Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda-shi, Chiba 278-8525, Japan
S
* Supporting Information
ABSTRACT: (+)-Iso-A82775C is a proposed biosynthetic pre-
cursor of the chloropupukeananin family and an important
intermediate for related natural products. The first enantioselective
total synthesis of (+)-iso-A82775C (18 steps, 2.2% overall yield)
toward the eventual biomimetic total synthesis of chloropupukea-
nanin is described. The key steps are (1) the enantioselective
Diels−Alder reaction of 4-bromo-3-hydroxy-2-pyrone with methyl
2-chloroacrylate using cinchonine as an organocatalyst and (2) the
anti-selective Cu-mediated SN2′ reaction to afford the axially chiral
vinylallene moiety.
(+)-Iso-A82775C (1) pestheic acid (2), and chloropupukeana-
nin (3) (Figure 1a) were isolated from the fermentation broth
of the plant endophytic fungus Pestalotiopsis fici by Che and
colleagues in 2008.1 Their recent studies2 revealed the
biosynthetic diversity of this fungus, resulting in numerous
products including chloropestolides A−G. These compounds
from the chloropupukeananin family consist of highly function-
alized bi- or tricyclic skeletons and show inhibitory activity
against HIV-1 replication and cytotoxicity against human tumor
cell lines. The proposed biosynthesis of the chloropupukeana-
nin family involves an intermolecular Diels−Alder reaction3
between 1 and 2 and a subsequent carbonyl−ene reaction. In
this context, studies involving the biomimetic synthesis of 3
using model compounds have been reported by Snider’s group4
and by us.5
Structurally, (+)-iso-A82775C is a diastereomer of the
known fungal natural product A82775C (4)6 and its
enantiomer spartinoxide (5)7 (Figure 1b). The former was
isolated from an unknown terrestrial fungus collected in Egypt,
and the latter was isolated from a marine-derived fungus and
identified as an inhibitor of human leukemia elastase in 2010.
These compounds are members of a family of naturally
occurring cyclohexene epoxides8 possessing an unsaturated C5
side chain, such as eutypoxides,9 asperpentyn,10 harveynone,11
and panepoxydone.12 However, only a few examples possess
two unsaturated C5 side chains.13 To the best of our
knowledge, there is no compound that possesses both a prenyl
group and an axially chiral vinylallene group other than
compounds 1, 4, and 5. In addition, 1 is considered to be an
important biosynthetic intermediate of the related natural
products pestaloficinol A−L14 and pestalofone A−E15 (see the
Supporting Information). Because of its important role in the
biosynthesis of chloropupukeananin as well as its interesting
structural features, we attempted the total synthesis of (+)-iso-
A82775C.
Received: January 10, 2017
Figure 1. Iso-A82775C and related compounds.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00085
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Letter
Our retrosynthetic analysis of (+)-iso-A82775C is outlined in
Scheme 1. We considered that the stereoselective construction
We first investigated the intermolecular Diels−Alder reaction
of pyrone 919 and methyl 2-chloroacrylate under basic
conditions (Table 1). With 0.5 equiv of i-Pr2NEt as a base,
the Diels−Alder reaction (in CH2Cl2 at 0 °C) gave the
cycloadducts in 91% yield as a mixture of endo adduct 8 and exo
adduct 8′ (8/8′ = 2.1:1; Table 1, entry 1). Use of natural
cinchona alkaloids as the base (Table 1, entries 2−5) increased
the diastereoselectivity to give the desired adduct 8 (dr = 3.0−
5.8:1), albeit with moderate enantiomeric excess. According to
Deng’s work,18b quinine-based catalysts (Table 1, entries 6−8)
resulted in a slight decrease in the endo/exo and enantiose-
lectivity. The endo/exo selectivity was increased to 8.4:1 when
0.5 equiv of quinidine in toluene was used (Table 1, entry 11).
A lower catalyst loading (0.1 equiv of quinidine) slightly
increased the endo/exo selectivity; however, the enantiomeric
excess was not satisfactory (Table 1, entry 12). On the other
hand, the reaction using 0.1 equiv of cinchonine in toluene gave
the desired adduct 8 with 67% ee (dr = 3.6:1) (Table 1, entry
13). To our delight, recrystallization of the endo cycloadduct 8
(67% ee; Table 1, entry 13) from EtOAc/n-hexane gave
enantiomerically pure crystalline (−)-8 (>99% ee) in 42% yield
from pyrone 9. The absolute stereochemistry of cycloadduct
(−)-8 was determined by X-ray crystallographic analysis
(Figure 2).20
With enantiomerically pure 8 in hand, we focused on its
transformation to the cross-coupling precursor 7 (Scheme 2).
Selective reduction of the ester group of endo adduct 8 with
LiBH4 followed by TES protection of the resulting alcohol gave
silyl ether 12.21 DIBAL reduction of the lactone afforded α-
hydroxylactol 13 as a diastereomeric mixture.22 Criegee
oxidation of lactol 13 with Pb(OAc)4 in the presence of
NaHCO3 furnished cyclohexenone 14 in 43% overall yield
from 8. TBS protection of the secondary alcohol, deprotection
of the primary alcohol, and in situ diastereoselective reduction
using NaBH(OAc)323 gave 1,3-diol 15 as a single diastereomer.
Protection of the 1,3-diol with TES groups (TESCl, imidazole)
gave the desired silyl ether 7 in quantitative yield.
Scheme 1. Retrosynthetic Analysis of 1
of the labile vinylallene and epoxide groups of 1 in the final
stage of the total synthesis could be a serious challenge. The
former could be accomplished by an SN2′ reaction to propargyl
chloride using a vinylcopper reagent5b,16 and the latter by
neighboring-group-directed catalytic epoxidation. Thus, we set
alkyne 6 as a precursor for the final stage, which could also be a
common intermediate for both ent-4 and 5. Installation of the
prenyl group of alkyne 6 could be achieved by Pd-catalyzed
cross-coupling with bromide 7. According to Okamura’s
pioneering work on the total synthesis of eutypoxide B,17 the
base-catalyzed Diels−Alder reaction of 3-hydroxy-2-pyrone and
2-chloroacrylate could construct the requisite stereocenters of
bromide 7. Especially, the tertiary alkyl chloride stereocenter is
essential for the stereoselective construction of the vinylallene
group. Thus, the Diels−Alder reaction of 4-bromo-3-hydroxy-
2-pyrone (9) and methyl 2-chloroacrylate using a tertiary amine
could give the endo cycloadduct 8 stereoselectively. We
expected that the optically active cycloadduct 8 could be
obtained by the enantioselective Diels−Alder reaction using
chiral amines,18 such as cinchona alkaloids. Herein we report
the first enantioselective total synthesis of (+)-iso-A82775C.
Table 1. Diels−Alder Reaction between Pyrone 9 and Methyl 2-Chloroacrylate under Basic Conditions
a
b
entry
base (equiv)
i-Pr2NEt (0.5)
solvent
temp (°C)
time (h)
yield (%)
8/8′
ee of 8 (%)
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
Et2O
0
0
48
39
40
36
40
60
72
40
40
64
40
40
40
91
94
97
93
94
90
86
90
99
95
97
99
99
2.1:1
5.7:1
3.0:1
5.7:1
3.1:1
3.7:1
3.1:1
1.3:1
5.6:1
6.2:1
8.4:1
9.2:1
3.6:1
−
−42
−48
39
quinine (0.5)
3
cinchonidine (0.5)
quinidine (0.5)
cinchonine (0.5)
(DHQD)2PHAL (0.5)
10 (0.5)
0
4
0
5
0
49
6
0
31
7
25
0
35
8
11 (0.5)
45
9
quinidine (0.5)
quinidine (0.5)
quinidine (0.5)
quinidine (0.1)
cinchonine (0.1)
0
40
10
11
12
13
25
0
37
toluene
toluene
toluene
31
0
34
0
67
a
b
1
Determined by H NMR analysis. Determined by HPLC analysis.
B
DOI: 10.1021/acs.orglett.7b00085
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Suzuki−Miyaura coupling (Pd2(dba)3, P(t-Bu)3)24 with allyl-
boronic acid pinacol ester afforded allylcyclohexene 16 in 40%
yield. Standard Stille coupling conditions (allyl-Sn(n-Bu)3 and
Pd(PPh3)4) using N-methyl-2-pyrrolidone (NMP) as a solvent
gave 16 in quantitative yield. Unfortunately, the Stille coupling
of 7 with prenyl-Sn(n-Bu)3 was unsuccessful, resulting in only a
trace amount of 17. Cross-metathesis of 16 with 2-methylbut-2-
ene using Grubbs’ second-generation catalyst afforded
prenylcyclohexene 17 in 91% yield. The three-step trans-
formation from 17 to terminal alkyne 6 (selective deprotection,
Dess−Martin oxidation of the resulting primary alcohol, and
Seyferth−Gilbert homologation) was successful in 66% yield,
whereas the Ohira−Bestmann reaction resulted in decom-
position of the aldehyde.
Figure 2. ORTEP drawing of endo adduct (−)-8.
After the deprotection of alkyne 6 with TBAF, hydroxyl-
group-oriented epoxidation of the resulting diol using a
catalytic amount of VO(OEt)3 and TBHP25 afforded epoxide
18 as a single diastereomer. After protection of the diol with
TES groups, a Cu-mediated anti-SN2′ reaction was best carried
out using CuCN and isopropenyl-MgBr to give vinylallene 20
as a single diastereomer along with the starting material 19.26
Other methods, including our conditions previously reported in
model studies,4 resulted in decomposition of the epoxide
moiety and formation of a terminal allene.16 Desilylation of the
resulting mixture of vinylallene 20 and alkyne 19 provided
(+)-1 (30%, two steps) and diol 18 (59%). Thus, the total
synthesis of (+)-1 was completed in 2.2% overall yield from
pyrone 9 (18 steps). All of the spectral data (1H NMR, 13C
NMR, IR, HRMS, and [α]D) of synthetic (+)-1 were in good
accordance with those of natural (+)-iso-A82775C reported by
Che et al.1
Scheme 2. Preparation of Cross-Coupling Precursor 7
In conclusion, we have achieved the first total synthesis of
(+)-iso-A82775C. Characteristic features of the present syn-
thesis are (1) the enantioselective Diels−Alder reaction of
pyrone 9 with methyl 2-chloroacrylate using cinchona alkaloids
and (2) the anti-selective Cu-mediated SN2′ reaction to afford
the labile vinylallene moiety. Our synthetic strategy represents
an efficient means for preparing natural products related not
only to (+)-iso-A82775C but also to chloropupukeananin.
Further investigation toward the biomimetic total synthesis of
chloropupukeananin is currently underway.
Next, we attempted the installation of the prenyl side chain
by the use of cross-coupling reactions (Scheme 3). Treatment
of bromide 7 with various allylmetal reagents, such as Mg and
Zn, in the presence of a Pd catalyst gave almost no reaction.
Scheme 3. Completion of the Total Synthesis of (+)-1
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00085.
Crystallographic data for (−)-8 (CIF)
1
Experimental procedures and H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: takahiro-suzuki@sci.hokudai.ac.jp.
*E-mail: ktanino@sci.hokudai.ac.jp.
ORCID
Takahiro Suzuki: 0000-0002-3842-1025
Keiji Tanino: 0000-0002-0580-0125
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.7b00085
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Organic Letters
Letter
(21) Direct reduction of the ester and lactone groups of 8 with
DIBAL or LiAlH4 gave a complex mixture as a result of aromatization
of the cyclohexene ring.
(22) The stereochemistry was not identified because of the instability
of lactol 13.
ACKNOWLEDGMENTS
■
This research was supported in part by a Grant-in-Aid for
Young Scientists (B) (KAKENHI 22790022 and 24790025)
from the Japan Society for the Promotion of Science. We thank
the Naito Foundation, the Uehara Memorial Foundation, the
Kurata Memorial Hitachi Science and Technology Foundation,
and the Research Foundation for Pharmaceutical Sciences for
financial support.
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(25) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12,
63−74.
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D
DOI: 10.1021/acs.orglett.7b00085
Org. Lett. XXXX, XXX, XXX−XXX