Total Synthesis of Paecilomycin B

Article abstract of DOI:10.1021/acs.orglett.5b00983

Starting from the glucose-derived δ-lactone and the functionalized aryl bromide, the first total synthesis of naturally occurring paecilomycin B was achieved via functionalized aryl-β-C-glycoside synthesis using 2,4,6-triisopropylphenyllithium under Barbi

Full text of DOI:10.1021/acs.orglett.5b00983

Letter
pubs.acs.org/OrgLett
Total Synthesis of Paecilomycin B
Kiyomi Ohba*,†,‡ and Masaya Nakata‡
†Medicinal Chemistry Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama
227-0033, Japan
‡Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama
223-8522, Japan
S
* Supporting Information
ABSTRACT: Starting from the glucose-derived δ-lactone and the functionalized aryl bromide, the first total synthesis of
naturally occurring paecilomycin B was achieved via functionalized aryl-β-C-glycoside synthesis using 2,4,6-triisopropylphenyl-
lithium under Barbier-type reaction conditions and ring-closing metathesis as the key steps.
esorcylic acid lactones (RALs)including the potent
Our retrosynthetic strategy for the synthesis of paecilomycin
B (2) is presented in Scheme 1. We planned that the key
macrocyclization could be achieved via a ring-closing metathesis
(RCM)10 approach. An intermediate diene 14 would be
synthesized from carboxylic acid 15 by Mitsunobu esterifica-
tion11 using a commercially available chiral alcohol 16.
Carboxylic acid 15 could be accessed from spiroketal 17a
through the deoxygenation at the anomeric position and the
subsequent elongation of the vinyl group. Spiroketal 17a could
be obtained as a key step by a nucleophilic coupling reaction
between δ-lactone 18 and aryl bromide 19 using TIPPLi under
Barbier-type reaction conditions.9a Lactone 18 and bromide 19
could be synthesized from known compounds (vide infra).
δ-Lactone 18 was synthesized from the known glycoside
21,12 which was prepared from p-methoxyphenyl β-D-
glucopyranoside 20 in five steps (Scheme 2). The benzylidene
moiety of 3-deoxy glucoside 21 was removed by hydrogenation
to give the corresponding diol 22. The resulting hydroxy
groups of 22 were benzylated to afford 23 in an 83% two-step
yield. The removal of the p-methoxyphenyl group of 23 was
achieved using CAN13 to afford an anomeric mixture of 24.
The generated hydroxy group of 24 was oxidized with Dess−
Martin periodinane (DMP)14 to produce lactone 18 in 62%
yield from 23. Moreover, aryl bromide 19 was quantitatively
prepared from the known compound 2615 that was prepared
from 25 in four steps by the carbamoylation of its hydroxy
group (Scheme 3). The N,N-dimethylcarbamoyl group was
selected because of its inert character under acidic conditions
and moderate resistant ability for nucleophilic attack.
R
HSP90 inhibitor radicicol1 and hypothemycin,2 which
inhibits mitogen-activated protein kinases irreversiblyare
fungal polyketides characterized by a 14-membered macrocyclic
lactone and exhibit various biological activities. In these
respects, RALs have attracted much attention, and therefore,
many pharmacological and synthetic studies have been
reported.3
In 2010, Chen and Wei4 reported paecilomycins A−F (1−6)
as new RALs; they were first isolated from mycelial solid
cultures of Paecilomyces sp. SC0924 and showed high to
moderate antiplasmodial activities (Figure 1). Subsequently,
paecilomycins G−I (7−9)5 and paecilomycins J−M (10−13)6
were isolated. Among them, paecilomycin B (2) is structurally
of interest because it contains a tetrahydropyran moiety in its
14-membered lactone ring. Its oxygen bridge between C-1′ and
C-5′ is presumed to be formed by an intramolecular SN2
reaction between the epoxide and 5′-hydroxy group of
paecilomycin A (1).4a
As a result of the novelty of the structures and potent
biological activities, paecilomycins have attracted interest as a
fascinating target for total synthesis. Although the total
syntheses of paecilomycins E (5)4b,7 and F (6)4b,8 have been
successfully described, there is no synthetic report of other
paecilomycins. Recently, we reported a novel synthetic method
of aryl-β-C-glycosides having an ester, cyano, or carbonyl group
on the aromatic ring using 2,4,6-triisopropylphenyllithium
(TIPPLi) as a chemoselective halogen−lithium exchange
reagent.9a Thus, our finding motivated us to initiate the
synthesis of compound 2 that has an aryl-β-C-glycoside
scaffold. Herein, we describe the first asymmetric total synthesis
of paecilomycin B (2) based on the synthesis of functionalized
aryl-β-C-glycosides.
Received: April 6, 2015
© XXXX American Chemical Society
A
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Scheme 2. Synthesis of δ-Lactone 18
Scheme 3. Synthesis of Aryl Bromide 19
aqueous NH4Cl afforded 17a as the major coupling product
along with lactol 17c as the minor product in various molar
ratios of 3−20:1 (17a/17c) in good yields (see Supporting
Information). It is presumed that 17a was generated from 17c
by spontaneous lactonization. The C-β configurations of 17a
and 17c were confirmed by NOE measurement between H-2
and the aromatic proton (Figure 2).9b Thus, the coupling
reaction smoothly proceeded without any self-condensation
despite the presence of the ester and carbamoyl groups on the
aromatic group, which are sensitive to nucleophiles.
Figure 1. Structures of paecilomycins A−M, 1−13.
Scheme 1. Retrosynthesis of Paecilomycin B, 2
The direct deoxgenation at the anomeric position of the
spiroketal 17a using Et3SiH and BF3·Et2O failed to produce the
desired deoxygenated product but yielded only the desilylated
product 17b. Therefore, the spiroketal 17a was previously
converted into methyl glycoside 27.9a The treatment of 17a
with methanol/methanesulfonic acid afforded 27 in 67% yield,
accompanied by 20% recovery of 17b. The deoxygenation of 27
in the presence of Et3SiH, BF3·Et2O, and TFA proceeded
smoothly in a stereoselective manner9a,16 to afford the aryl-β-C-
glycoside 28. The C-β configuration of 28 was confirmed by
NOE measurement between H-1 and H-3/H-5 (Figure 3). The
selective acetolysis of its primary benzyl ether and subsequent
deacetylation gave alcohol 29 in 89% yield. Dess−Martin
oxidation of the primary hydroxy group of 29 afforded the
corresponding aldehyde 30. Because the Dess−Martin
oxidation followed by an aqueous workup yielded a mixture
of 30 and its hydrate, dehydration treatment with MS 4 Å was
required.17 Aldehyde 30 was subjected to a Nozaki−Hiyama−
Kishi coupling18 with vinyl iodide to give a coupling product
31a in 44% yield along with its C6′ epimer 31b in 45% yield.
The stereochemistry of C6′ of 31a was confirmed by the two-
step conversion into benzylidene acetal 36 which has a more
rigid conformation than 31a (Scheme 5). The coupling
constant (J5′,6′ = 9.3 Hz) and NOE measurement of 36
supported C6′R configuration. Unfortunately, the Grignard
reaction of 30 using vinyl magnesium bromide resulted in a low
yield, and a catalytic asymmetric approach18d,e did not succeed
to induce high stereoselectivity (data not shown). Therefore,
With lactone 18 and aryl bromide 19 in hand, we performed
the key nucleophilic addition reaction using TIPPLi under
Barbier-type reaction conditions (Scheme 4);9a i.e., to a
solution of TIPPLi in THF, which was readily prepared from
2,4,6-triisopropylphenyl bromide and n-BuLi at −78 °C, a
solution of a 1:1 mixture of 18 and 19 was added over a period
of 10 min at −78 °C. After stirring for 10 min, the reaction was
quenched with methanol to give the spiroketal 17a in an
excellent yield of 89% (basic quenching conditions). In
contrast, usual acidic quenching conditions by adding saturated
B
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Scheme 4. Synthesis of Paecilomycin B, 2
Scheme 5. Two-Step Conversion to 36 for the
Determination of the C6′ Configuration of 31a
Figure 2. Determination of the configurations of 17a and 17c.
MOM ether, and the resulting 32 was hydrolyzed with aqueous
NaOH, which was accompanied by the removal of a N,N-
dimethylcarbamoyl group to afford carboxylic acid 33 in 96%
yield from 31a. The subsequent treatment of diol 33 with
excess TBSCl/imidazole yielded a persilylated compound,
which was hydrolyzed with aqueous NaOH to produce
monosilylated product 15 in 73% yield. The precursor 14 for
RCM was obtained by Mitsunobu esterification between
benzoic acid 15 and chiral alcohol 16 in 70% yield. The
macrocyclization by RCM as the second key step using the
Grubbs-II catalyst successfully produced (E)-olefin 34 in 81%
yield as the sole cyclization product. The deprotection of 34
with methanesulfonic acid gave benzyl ether 35, and the
Figure 3. Determination of the configuration of 28.
the epimer 31b was converted into 31a by oxidation and
subsequent stereoselective reduction. The usage of Zn(BH4)2
as a reducing reagent in CH2Cl2 under high dilution conditions
afforded the desired alcohol 31a in 55% yield with the recovery
of 31b in 11% yield. Furthermore, Luche reduction gave only
the undesired 31b, and the Corey−Bakshi−Shibata reduction
did not afford 31a. The allyl alcohol of 31a was protected as its
19
C
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the coupling product to the stable C-β configuration and the following
lactonization might occur under reaction or quenching conditions.
(10) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (b) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450,
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subsequent exposure of 35 to TiCl4 furnished paecilomycin B
(2) in 96% yield from 34, whose analytical data, including MS,
1H, and 13C NMR, were identical to the reported data.4,20
In summary, we have achieved the first total synthesis of
paecilomycin B (2) based on a functionalized aryl-β-C-
glycoside synthetic method using TIPPLi, which started from
p-methoxyphenyl β-D-glucopyranoside 20 and 1-bromo-3,5-
dimethoxybenzene (25). The macrocyclization step was
achieved via RCM in good yield and stereoselectivity. Thus,
our aryl-β-C-glycoside synthetic method9a is applicable to
natural product synthesis because of its good functional group
tolerance.
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(15) (a) Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1982, 403.
(b) Selles, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4621.
̀
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2004, 6, 3751. (b) Deshpande, P. P.; Ellsworth, B. A.; Buono, F. G.;
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(20) The specific rotation value of our synthetic paecilomycin B (2)
is [α]D25 +85.5 (c 0.32, MeOH) (lit.4a [α]2D4 +40.4 (c 0.27, MeOH)).
Judging from literature data of 1H and 13C NMR, the difference might
be on the basis of the small amount of contaminated impurity in
natural paecilomycin B (2).
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00983.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ohba.kiyomi@mf.mt-pharma.co.jp.
Notes
The authors declare no competing financial interest.
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D
DOI: 10.1021/acs.orglett.5b00983
Org. Lett. XXXX, XXX, XXX−XXX