Hydroxylamine-Mediated Anthrapyranone Formation, Solving 5-exo/6-endo Issue toward Synthesis of Pluramycin-Class Antibiotics

Article abstract of DOI:10.1021/acs.orglett.9b04127

In our synthetic study on pluramycin-class antibiotics, an unexpected issue arose, i.e., unfavorable regioselectivity of 5-exo rather than 6-endo cyclization to form the pyranone ring. The issue was solved by an addition-elimination process of a phenol-ynone substrate. AZADOL was specifically effective, enabling the first synthesis of saptomycinone H.

Full text of DOI:10.1021/acs.orglett.9b04127

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Hydroxylamine-Mediated Anthrapyranone Formation, Solving
5‑exo/6-endo Issue toward Synthesis of Pluramycin-Class Antibiotics
Jun Shimura, Yoshio Ando, and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan
S
* Supporting Information
ABSTRACT: In our synthetic study on pluramycin-class antibiotics, an unexpected issue arose, i.e., unfavorable regioselectivity
of 5-exo rather than 6-endo cyclization to form the pyranone ring. The issue was solved by an addition−elimination process of a
phenol−ynone substrate. AZADOL was specifically effective, enabling the first synthesis of saptomycinone H.
he pluramycins constitute a class of antitumor antibiotics,
Scheme 1. Synthetic Plan of 2 and 5-exo/6-endo Issue
T
as represented by pluramycin A (1; Figure 1).1 By
Figure 1. Pluramycins.
Nature’s ingenuity, they share a composite structure of several
well-aligned motifs for targeting/cleaving DNA: amino
sugar(s) for the sequence specificity, a tetracyclic core for
the major-groove binding, and a side chain epoxide for the
strand scission via N-alkylation.2,3
Along these lines, we began the synthetic study of 2, which
encountered an unexpected difficulty in the A-ring cyclization
of 1,3-diketone 5 (Scheme 1): the 5-exo cyclization prevailed
over the electronically favored 6-endo cyclization to give
furanone 6.
In this letter, we wish to describe a unique solution to this
issue via the discovery of a hydroxylamine-mediated addition−
elimination process, achieving the synthesis of 2 (see abstract
graphic).
Scheme 2 shows the preparation of ynal 4. Dihydroxylation
of methyl angellate (8) and acetalization of the resulting diol
gave acetonide 9. Reduction of 9 with DIBAL-H gave alcohol
10, which was converted to aldehyde 11 by Swern oxidation,11
Potent bioactivities of these compounds have attracted
sizable interest in their synthesis,4 which is not easy due to the
structure complexity and chemical sensitivity. Only two total
syntheses of C-glycosylated structures have been achieved to
date,5,6 which, however, dealt with the targets without an
epoxide function at the side chain. Note the synthesis of the
epoxide-bearing congeners would suffer from complication by
potential issues for installing this sensitive functionality.7
We set out to address this issue by setting saptomycinone H
(2) as a model target.8,9 Scheme 1 shows our original synthetic
plan. Anthrone 3 was set as the starting material, to be
envisioned for future application to the C-glycosylated
structures.10 Ynal 4 has a protected 1,2-diol as a latent
epoxide, assuming the late-stage formation of the stereodefined
oxirane ring.
Received: November 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04127
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Scheme 2. Synthesis of Side Chain 4
Table 1. Cyclization of 5
entry
base
solvent
temp.
time/h 7/%
6/%
a
c
b
1
2
3
4
5
6
K2CO3
DMAP
NaOH
MeOH
MeOH
MeOH
EtOH
0 °C → rt
rt
rt
0 °C → rt
0 °C
rt
52
55
20
9
48
15
−
−
−
−
−
−
quant.
71
quant.
76
quant.
74
d
d
e
f
Et2NH
a
b
Et3N
CH2Cl2
DMSO
c
d
PMe3
a
b
c
d
e
f
3.0 equiv. 0.01 M. 1.0 equiv. 0.02 M. 2.0 equiv. Et2NH, EtOH =
1/1vol (0.01 M).
and further to dibromoolefin 12. Treatment of 12 with
NaN(SiMe3)2 at −78 °C gave bromoacetylene 13, which was
converted into ynal 4 by treatment with n-BuLi followed by the
reaction with 4-formylmorpholine (14).12 We noted that the
direct conversion of 12 into the corresponding lithium
acetylide (n-BuLi, THF, −78 °C) followed by addition of 14
was low-yielding.
Scheme 4. 6-endo vs 5-exo Cyclizations
For the assembly of the entire carbon skeleton, anthrone
156b,13 was enolized with LDA (2.8 equiv, 0 °C, THF) and
treated with ynal 4 at −78 °C, giving aldol 16 as a mixture of
four diastereomers in 93% yield (Scheme 3). Oxidation of 16
with IBX14 gave 1,3-diketone 5 in 83% yield.15
Scheme 3. Conversion to Diketone 5
processes are durable for the 6-endo and 5-exo cyclizations,19
we ascribed the prevalence of the 5-exo cyclization to the steric
factor that overrides the electronic factor.
Hoping to enable the desired 6-endo cyclization, we decided
to make two substrate structure modifications (Scheme 5).
(1) Conversion of 1,3-diketone A into the corresponding
phenol B: The basis was that all successful precedents of
the 6-endo cyclizations of ynones exploited phenols,
rather than a 1,3-diketone, as the internal nucleophile. A
With ynone 5 in hand, the projected A-ring cyclization was
examined. As the first attempt, ynone 5 was treated with
K2CO3 (entry 1, Table 1). The starting material 5 was slowly
consumed (MeOH, 0 °C → room temperature, 52 h).
Surprisingly, the single product, thus obtained, was not the
expected pyranone 7, but furanone 6 in quantitative yield.16
Further efforts using various other bases or nucleophilic
catalysts failed to give the desired pyranone 7, resulting
invariably in the exclusive 5-exo cyclizations (entries 2−6).17
The result was totally unexpected, since the electronic
consideration naturally pointed to the conjugate addition to
the ynone, producing pyranone 7 as the expected product. In
contrast, our previous total synthesis of saptomycin B exploited
diketone 17 as a viable substrate for the key A-ring cyclization
(Scheme 4),18 giving only the six-membered product 18. The
structural difference of 17 and 5 is the steric bulk around the
C2 reaction site: the C14 center in 5 is quaternary, while it is
tertiary in 17. Since Baldwin’s rule predicts that the dig
Scheme 5. Two Substrate Modifications
B
DOI: 10.1021/acs.orglett.9b04127
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
promising aspect was that some examples included
Table 2. A-Ring Formation from 22
substrates with a C14-quaternary center.20
(2) Conversion of ynone B to β-substituted enone C:
Inspired by our previous experience,20a,21 we envisioned
that the intermediacy of C may enable the 6-endo
cyclization via an addition−elimination process.
With these scenarios in mind, we examined the conversion
of 1,3-diketone 5 into phenol−quinone 21 (Scheme 6).
Scheme 6. Oxidation of 5
a
b
c
d
Solvent (0.02 M). Et2NH, EtOH = 1/2 vol. 3.0 equiv. 2.0 equiv.
e
No reaction.
cyclization (entry 2). The expectation was a minute amount of
methoxide in equilibrium acting as a nucleophile. With the idea
of using nucleophilic catalysis, DABCO27 and Me3P28 were
used, which, contrary to our expectation, resulted in the
exclusive 5-exo cyclization (entries 3 and 4). Use of a thiolate
anion was not effective, resulting in no reaction (entry 5).
Implications from these experiments include the following:
(1) the planned 1,4-addition of X− (or X:) to alkynone 22 is
not easy, and (2) it seems that a direct cyclization of phenol 22
to the internal triple bond is competing even under slightly
basic conditions, where the 5-exo cyclization is favored.
At this juncture, we noticed that the side product 23
obtained in the previous experiment has the required β-X-
substituted enone structure (X = aminoxy) and may serve as a
viable cyclization precursor. Despite uncertainty, a perfect
solution to the problem was provided (Scheme 7).
Treatment of 1,3-diketone 5 with oxoammonium salt 1922
(CH3CN, −35 °C) gave α-oxy-adduct 20 in 78% yield.23,24
For further conversion into quinone 21, α-oxy-adduct 20 was
treated with PhI(OCOCF3)225 in H2O and CH3CN. However,
none of the desired product 21 was obtained, only giving an
intractable mixture of unidentified products. By contrast, the
same reaction in MeOH and CH2Cl2 (v/v = 1/2) gave the
corresponding acetal 22 in 60% yield, and thus, we decided to
use 22 as a substrate to address the viability of the cyclization,
B → C → D.
β-Aminoxyenone 23 underwent clean A-ring formation,
upon treatment with K2CO3 in MeOH, giving pyranone 25 in
Scheme 7. A-Ring Formation from AZADOL-Adduct 23
It would be appropriate to note here that the reaction of 20
→ 22 gave small, varying amounts of enone 23 as a side
product, which was not seen during the reaction, but formed if
the crude products were kept standing. Indeed, the formation
of 23 was suppressed by quick workup, where the yield of 22
was improved to 71%. We ascribed it to the 1,4-addition of 2-
hydroxy-2-azaadamantane, AZADOL (24) to ynone 22, which
later guided us to a breakthrough.
Having ynone 22 in hand, we tested its conversion to the
planned intermediate, β-X-substituted enone C, which would
hopefully cyclize in a 6-endo fashion. To this end, ynone 22
was treated with various nucleophiles, and the results are
summarized in Table 2.
When Et2NH was used as a nucleophile, the major product
was furanone 2626 via the 5-exo cyclization, and pyranone 25
was obtained only in low yield (entry 1).20a,21 Treatment of 22
with K2CO3 in MeOH18 also led to a preferential 5-exo
C
DOI: 10.1021/acs.orglett.9b04127
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Letter
virtually quantitative yield. Importantly, an exclusive 6-endo
cyclization occurred.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ksuzuki@chem.titech.ac.jp.
ORCID
Pleasingly, we further learned that enone 23 is available in
excellent yield from ynone 22 by the reaction with AZADOL
(24). The efficacy of this hydroxylamine in this context is
ascribable to high nucleophilicity by the α-effect,29 enabling
the 1,4-addition under neutral conditions. An additional
feature in 24 is a conformationally locked adamantane-like
structure. In contrast, two other hydroxylamines 27 and 28
proved less effective.30 Furthermore, the −ONR2 moiety is
significantly less donating than an OR or an NR2 moiety (the
inverse α-effect),29b thereby not deactivating the β-carbon in
enone 23 toward the nucleophilic attack.
After a long quest, the 6-endo cyclization became realized via
an addition−elimination process by using AZADOL (24) as a
nucleophile and a nucleofuge.
Scheme 8 shows the synthesis of 2. To remove the methyl
ether, tetracycle 25 was treated with MgI2·OEt2 (CH3CN, 50
Yoshio Ando: 0000-0002-0063-7672
Keisuke Suzuki: 0000-0001-7935-3762
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Yoshiharu Iwabuchi and Dr. Yusuke Sasano
(Tohoku University) for kindly providing a synthetic
procedure of oxoammonium salt 19. We are grateful to Prof.
Igor V. Alabugin (Florida State University) for helpful
discussion. This research was supported by JSPS KAKENHI
Grants JP16H06351 and JP26810018.
DEDICATION
Scheme 8. Synthesis of Saptomycinone H (2)
■
Dedicated to Prof. Takenori Kusumi on the occasion of his
77th birthday (Kiju).
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ASSOCIATED CONTENT
* Supporting Information
■
S
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04127.
Full experimental procedure, characterization data, and
NMR spectra for all new compounds (PDF)
D
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E
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