Total synthesis of (±)-naphthacemycin A 9, possessing both antibacterial activity against methicillin-resistant Staphylococcus aureus and circumventing effect of β-lactam resistance

Article abstract of DOI:10.1038/ja.2016.141

The total synthesis of KB-3346-5A₉, named naphthacemycin A₉, has been accomplished by combining the D?tz reaction and Suzuki-Miyaura cross coupling as well as employing Friedel-Crafts reaction with dienone-phenol rearrangement as key steps. We also describe the preparation of the simplified tetarimycin A and naphthacemycin A analogs as a model study, which coincidentally reveal unique properties of naturally occurring naphthacene-5,6,11(12H)-trione framework. The synthesized compounds were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE) to elucidate their structure-activity relationships (SARs), the results of which agreed with a previously reported preliminary SAR study of tetarimycin A.

Full text of DOI:10.1038/ja.2016.141

The Journal of Antibiotics (2016), 1–8
2016 Japan Antibiotics Research Association All rights reserved 0021-8820/16
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&
ORIGINAL ARTICLE
Total synthesis of (± )-naphthacemycin A , possessing
9
both antibacterial activity against methicillin-resistant
Staphylococcus aureus and circumventing effect of
β-lactam resistance
Tomoyasu Hirose, Yasuhiro Kojima, Hidehito Matsui, Hideaki Hanaki, Masato Iwatsuki, Kazuro Shiomi,
Satoshi Ōmura and Toshiaki Sunazuka
The total synthesis of KB-3346-5A , named naphthacemycin A , has been accomplished by combining the Dötz reaction and
9
9
Suzuki–Miyaura cross coupling as well as employing Friedel–Crafts reaction with dienone-phenol rearrangement as key steps.
We also describe the preparation of the simplified tetarimycin A and naphthacemycin A analogs as a model study, which
coincidentally reveal unique properties of naturally occurring naphthacene-5,6,11(12H)-trione framework. The synthesized
compounds were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant
Enterococcus (VRE) to elucidate their structure-activity relationships (SARs), the results of which agreed with a previously
reported preliminary SAR study of tetarimycin A.
The Journal of Antibiotics advance online publication, 7 December 2016; doi:10.1038/ja.2016.141
1
6
INTRODUCTION
metabolites is related to tetarimycin A, whereas the naphthacene
Methicillin-resistant Staphylococcus aureus (MRSA) is a typical framework is related to fasamycins.1
7,18
Brady and co-workers also
1
6–18
drug-resistance organism and is a major cause of nosocomial identified both tetarimycin A and fasamycins as antibiotics.
The
1
,2
infection.
Currently, five anti-MRSA drugs are available: anti-MRSA activity of fasamycins was found to involve inhibition of
vancomycin; teicoplanin; arbekacin; linezolid; and daptomycin.7 FabF, an enzyme involved in type II fatty acid (FASII) biosynthesis,
However, owing to problems such as side effects and the emergence of based on the results of FASII elongation assays and in silico docking
highly drug-resistance strains, the development of new anti-MRSA studies using the crystal structure of Escherichia coli FabF.1
3
4
5
6
7,18
drugs is a high priority.
The antibacterial activity mechanisms of naphthacemycins A and
Research in the field of infection control sciences at the Kitasato tetarimycin A are thought to be the same as that of the fasamycins due
Institute is yielding success in the search for novel microbial secondary to their related structures, but to date no studies have confirmed this
metabolites that exhibit selective anti-pathogenic activities and com- hypothesis. Indeed, ( − )-naphthacemycin A8 (8) and A9 (9) in
pounds that our group has designated ‘anti-infective agents’. On the particular exhibit both circumventing effect of β-lactam resistance
basis of our anti-infective agents concept, originally proposed by (that is, imipenem) and anti-MRSA activity.15 The minimal inhibitory
8
−1
S. Ōmura, a screening system was established to identify microbial concentration (MIC) of imipenem against MRSA is 32 μg ml when
−
1
circumventors of imipenem resistance in MRSA, resulting in the used alone, but when used in combination with 0.5 μg ml of 2,
isolation and structure determination of various natural products, as a representative example, the MIC of imipenem changes to
including stemphones, cyslabdan
9
10,11
12,13
0.125 μg ml− 1, a 256-fold enhancement of activity. Interestingly,
and xanthoradones.
More recently, through continuous screening for new microbial the circumventing effect of the naphthacemycins A extends only to
circumventors of β-lactam resistance in MRSA in our laboratory, imipenem against MRSA and not to aminoglycosides, glycopeptides,
a culture broth of Streptomyces sp. KB-3346-5 exhibited very potent tetracyclines and quinolones.14,15
activity. Activity-guided purification led to the discovery of 11 new
The naphthacemycins A are composed of naphthacene structure
compounds, KB-3346-5A1 to KB-3346-5A , namely designated (A, B, C and D-rings) and the asymmetric E-ring moiety, and exhibit
11
1
4,15
naphthacemycin A1 to A11 (1–11).
These compounds have a atropisomeric properties. However, the absolute configurations of the
characteristic skeleton composed of 7-phenylnaphthacene-5,6,11 naphthacemycins A have yet to be determined. X-ray structure analysis
(
12H)-trione (Figure 1). The naphthacene framework of these novel revealed that (− )-naphthacemycin A (8) and A (9) have a distorted
8 9
Graduate School of Infection Control Sciences and Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan
Correspondence: Dr S Ōmura or Professor T Sunazuka, Graduate School of Infection Control Sciences and Kitasato Institute for Life Sciences, Kitasato University, 5-9-1,
Shirokane, Minato-ku, Tokyo 108-8641, Japan.
E-mail: omuras@insti.kitasato-u.ac.jp or sunazuka@lisci.kitasato-u.ac.jp
Received 13 September 2016; revised 28 October 2016; accepted 1 November 2016

Total synthesis of ( ± )-naphthacemycin A
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T Hirose et al
2
5
,6-dicarbonyl moiety.15 Undoubtedly, their β-lactam-potentiating RESULTS AND DISCUSSION
effect and scarcity in natural environment attract organic synthetic Retrosynthetic analysis of ( ± )-naphthacemycin A9
and medicinal chemists to embark on their synthesis. To date, the total According to the retrosynthetic analysis of (± )-naphthacemycin
synthesis of tetarimycin A has been reported only by Shia and A9 (9) described in Scheme 1, 9 can be constructed by Brønsted
acid-mediated intramolecular Friedel–Crafts cyclization to form B-ring
from the precursor 12, followed by C–H oxidation to introduce the
carbonyl function into the B-ring. Precursor 12 would be prepared by
Suzuki–Miyaura coupling between the benzyl halide (as the equivalent
co-workers, who employed a very efficient approach involving
Hauser-Kraus annulation as key step in constructing the
naphthacene-5,6,11(12H)-trione framework. Our group is engaged
in the total synthesis of bioactive natural products from
microorganisms20,21 and was attracted to the fascinating biological
profile of the naphthacemycins A. Here we report the total synthesis of
a
1
9
of A-ring) and aryl-borane (13) in conjunction with the Dötz
reaction.2
2–28
This reaction facilitates construction of the quinone
moiety of the C-ring from an alkynyl-borane (14) and aryl
chromium–carbene complex (15). The Dötz reaction between
terminal alkynes and a chromium–carbene complex typically gives a
single regioisomer; however, unsymmetrically substituted internal
alkynes give mixtures of the two possible regioisomers.29–32 On the
other hand, incorporation of a boron unit into an unsymmetrically
substituted internal alkyne is a rapid and efficient approach for the
reliable and predictable synthesis of hydroquinone and quinone
boronate esters, with excellent regioselectivity due to the Lewis
(
± )-naphthacemycin A9 (9) and preparation of some artificial
analogs. We also elucidated the structure-activity relationships
SARs) of these compounds based on analyses of their antibacterial
(
activity.
acid/base interaction [CO → B(OR) ] in the metallohexatriene
2
intermediate, as shown in Scheme 1.3
3–35
The substrate of the Dötz
reaction can be prepared by Suzuki–Miyaura coupling between the
corresponding D and E-ring units (16 and 17).
Synthesis of the model naphthacene-5,6,11(12H)-trione
framework (25)
Our synthesis commenced with the preparation of naphthacene
compound 25 as a simpler model framework lacking the E-ring
of the naphthacemycins A and two phenolic alcohols on A-ring
(
Scheme 2). Alkynylboronate ester 1436 underwent Dötz reaction with
the p-methoxyphenylchromium–carbene complex (19), which was
prepared by chromination of 4-bromoanisole (18; corresponding to
‘D-ring’ moiety). The crucial Dötz reaction in our synthetic strategy
was then examined under various conditions by changing the solvents
and/or temperature. The optimized conditions for Dötz reaction were
Figure 1 Naphthacemycins, tetarimycin A and fasamycins.
Scheme 1 Retrosynthetic analysis of ( ± )-naphthacemycin A9 (9).
The Journal of Antibiotics

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3
Scheme 2 Synthesis of model naphthacene-5,6,11(12H)-trione compound (25). A full color version of this figure is available at The Journal of Antibiotics
journal online.
as follows: microwave irradiation at 130 °C for 5 min in 0.05 M Et O and C-rings to assume a planer structure of keto-enol structure
2
solution in sealed tube, followed by methylation of the generated (Scheme 3), we attempted to synthesize the more complex model
hydroxyl group with MeI in the presence of Cs CO to produce the compound 36 by incorporating two hydroxy groups on A-ring of 25.
2
3
desired naphthalylboronic ester (20) in 55% from 19 as the sole
regioisomer. Regioselectivity of Dötz reaction and the structure of 2, Suzuki–Miyaura coupling of the boronic ester (20) with the benzyl
0 was confirmed by the NOE observation of the precursor of 20 bromide derivative (26), which was prepared from commercially
Supplementary Information). Suzuki–Miyaura coupling reaction was available 2,4-dihydroxybenzaldehyde in 82% yield for 3 steps
According to the established model synthesis illustrated in Scheme
2
(
realized between 20 and benzyl bromide (21; corresponding to ‘A ring’ (Supplementary Information), afforded the adduct (27) in 91% yield
moiety) by palladium catalyst to give the adduct in quantitative yield, (Scheme 3). Subsequently, the two protective p-toluenesulfonyl (Ts)
with subsequent Friedel–Crafts cyclization under H SO /AcOH groups of 27 were replaced with methyl groups to yield the precursor
2
4
(
1/4 v/v) acidic condition to yield the tetracyclic product (22) in for Friedel–Crafts cyclization (28) (68% for 2 steps), which has a
9
3% yield. Oxidation of the hydroquinone dimethyl ether moiety of higher electron density in the A-ring than that of bis-tosylate (27) and
2
2 with cerium ammonium nitrate (CAN) afforded the quinone is thus a more suitable electron donor for the next cationic cyclization
derivative (23) in 74% yield, along with the peroxidated product (24) step. Indeed, tosyl substitution of the A-ring of 27 was completely
in 18% yield. Although the efficiency of the reaction producing the suppressed during Friedel–Crafts cyclization. In addition, attempted
desired benzylic alcohol (24) was low, the C–H oxidation of the Suzuki–Miyaura coupling of 20 with dimethoxybenzyl bromide under
benzylic position proceeded with CAN in the presence of H O while several conditions was also unsuccessful. Friedel–Crafts cyclization of
2
the hydroquinone moiety was oxidized. When compound (23) was 28 under acidic conditions identical to those used for the preparation
subjected to the same optimized oxidation conditions in which 23 was of 22 as shown in Scheme 2 gave the cyclized compound (29) in 83%
synthesized from 22 over a three-cycle repetition, 24 was obtained yield. Cyclized compound (29) contained an undesired spiro[4.5]
from 23 in 73% yield. Finally, oxidation of the benzylic alcohol of 24 frame and exhibited demethylation of the p-methoxy position of the
with MnO2 yielded the preliminary model compound (25), the A-ring. As compound 29 was selectively generated in our system, the
structure of which was confirmed by single-crystal X-ray diffraction formation of such a spirocyclic frame would be more preferable under
analysis (CCDC1511863). From the ORTEP plot of 25, the benzo- Brønsted acid-mediated Friedel–Crafts cyclization, although Kende
quinone moiety normally induces the planer conformation is slightly and co-worker reported an example of ring expansion in a spirocyclic
twisted, which could cause dipolar repulsion between 5,6-dicarbonyl frame via dienone-phenol rearrangements in several spirocyclic
moieties on B and C-rings. This observation resembles the three- dienone derivatives in the presence of CF3CO2H in CH2Cl2.37
dimensional form of the crystalline tetarimycin A, as previously Successful ring expansion was observed by using Lewis acid for
1
6
presented by Brady and co-workers.
dienone-phenol rearrangements with our substrate. We found that the
spirocyclic frame is formed in the presence of a Brønsted acid, such as
Synthesis of more functionalized model naphthacene compound (36) H SO and AcOH, but not in the presence of Lewis acids. The
2
4
Turning our interest to the stability of the twisted form of dienone-phenol rearrangements of 29 proceed with TiCl as the most
4
naphthacene framework (25), the relief of which could lead the B appropriate Lewis acid in our experiments in CH Cl2 solution,
2
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Total synthesis of ( ± )-naphthacemycin A
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T Hirose et al
4
Scheme 3 Incomplete synthesis of more complex model compound (36 and 39).
producing the desired naphthacene derivative (30), which was very afford the epoxy-quinone (32) in 83% yield for 2 steps. For conversion
rapidly oxidized under air atmosphere to the corresponding quinone of the B-ring epoxide of 32 to a ketone, direct one-pot imination of
methide (31) in 76% yield. For further oxidation of 31 to the target the quinone methide oxide moiety was carried out. After the addition
model compound (36), epoxidation of 31 with hydrogen peroxide of methylamine to the epoxide, the generated 1,2-hydroxylamine was
under basic condition, followed by oxidation with AgO/HNO3 to immediately aromatized in the A-ring position via successive
The Journal of Antibiotics

Total synthesis of ( ± )-naphthacemycin A
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5
β-elimination of the tertiary alcohol and tautomerization of the our scheme for the synthesis of model compounds having a C7
resulting quinone methide to afford the benzylic imine (33) in 88% substitution is applicable to the production of such natural
yield. Subsequently, benzyl protection of the phenolic alcohol of 33 products, as evidenced by our total synthesis of ( ± )-naphthacemycin
was then carried out, giving rise to 34, which without purification was A9 (9).
subjected to further hydrolysis to give 35 as a single keto-enol
tautomeric isomer in 59% yield for 2
steps. Unfortunately, Total synthesis of ( ± )-naphthacemycin A9 (9)
deprotection of the benzyl group of 35 under a variety of conventional We next approached the total synthesis of racemic naphthacemycin
conditions (hydrogenations with Pd/C or Pd(OH) ; Burch reduction;
A9 (9), which differs only in having an aryl function at the C7 position
2
in the planar structure of model compound of 36. Therefore, to access
BF •OEt with EtSH; oxidative conditions such as RuO with NaIO )
3
2
2
4
9
, 2,4-dimethoxy-6-methylphenyl boronic acid, prepared from a
did not provide the target molecule (36), even though the
deprotection reaction proceeded, and only prompt decomposition or
polymerization of the product was observed.
Alternatively, we examined the preparation of 39 as a similar model
compound in order to confirm the stability of the 1,3-dicarbonyl
moiety on the B- and C-rings in relation to the oxygen substituted
A-ring (Scheme 3). To introduce a carbonyl function on the B-ring,
the quinone methide moiety of 31 was temporarily reduced to phenol
corresponding bromobenzene (40), was subjected to Suzuki–Miyaura
coupling with 2-bromo-5-methoxyphenyl iodide (41)39 to furnish the
biphenyl product (42) in 76% for 2 steps (Scheme 4). Chromination
of 42 gave the corresponding chromium–carbene complex (43) in
7
7% yield. Dötz reaction of 43 with an alkynylboronic ester (14)36 was
then performed under microwave irradiation. We initially expected
that the Dötz reaction of 43 would afford the desired phenylboronic
ester (45) as the sole product in a predictable manner. However, the
yield of 45 was unsatisfactory (14%) and was accompanied by the
production of an undesired cyclobutenone derivatives (44) in 40%
yield. This was probably due to steric interaction between the methoxy
group and the aryl function (E-ring) connecting to D-ring, resulting in
a twisted bond forming between the phenyl ring (D-ring) and the
vinyl moiety. As a result, formation of the cyclobutenone proceeded
via ‘path a’ preferentially to the desired quinone formation via ‘path b’,
as illustrated in Scheme 4. Nevertheless, the vinyl ketene intermediate
of Dötz reaction tended to become the cyclopentenone via [2+2]
cyclization.
Moser and co-workers provided evidence that the chromium-free
vinyl ketene is slowly converted to an equilibrium mixture of vinyl
ketene and cyclobutenone at room temperature (Scheme 4).40 In
addition, in the approach for synthesizing annulated hydroquinones,
the 4-aryl groups of respective cyclobutenones can be converted to
quinone products via selective electrocyclic ring opening of the
cyclobutenone to the corresponding conjugated ketene, followed by
ring closure to provide the hydroquinone, as reported by Moore and
using NaBH in MeOH, then the generated phenolic hydroxyl group
4
of the air sensitive product was immediately protected with an acetyl
group to afford 37 in 95% yield for 2 steps. Subsequently, C–H
oxidation of benzyl position of 37 was carried out under modified
CAN oxidation condition in the presence of H O while the oxidation
2
of hydroquinone moiety proceeded. Further oxidation of the benzyl
alcohol was examined without purification of 38; however, the desired
product (39) was not obtained under any of the oxidation conditions
examined (for example, MnO , Dess-Martin[O], Parikh-Doering[O],
2
3
8
DEAD-ZnBr2, TPAP-NMO, PCC and PDC), even though the
oxidation reaction proceeded.
With respect to synthesis of originally designed model com-
pound (36 or 39), it was confirmed that the 5,6-dione portion in
the naphthacene-5,6,11(12H)-trione framework is very unstable.
Interestingly, the 5,6-dione is stable and conserved in naturally
occurring naphthacemycins A and tetarimycin A. We therefore
hypothesized that the relatively bulky functions at the C7 position
of the naphthacene-5,6,11(12H)-trione framework (methyl for
tetarimycin A and aryl for the naphthacemycins A) contribute to
the stability of the whole structure (Figure 2). In case of the model
compounds, the dipole interaction between the C5 and C6 carbonyls
is relieved by keto-enol isomerization of the C5 carbonyl in
conjunction with the C4 phenol alcohol. In contrast to the model
compounds, C7 substitution of the natural products creates a steric
interaction with the C6 carbonyl, which guides the twisted conforma-
tion of the benzoquinone moiety, eliminating the repulsion associated
with the C5, C6-dicarbonyl in the natural products. On the basis of
41
Perri (Scheme 4).
Encouraged by these reports, we carried out thermal rearrangement
of the cyclobutenone product (44), and after optimization of the
reaction condition, this approach was turned out to be successful, in
that 44 could be converted under microwave irradiation at 160–180 °C
in toluene to yield the half methyl-ether quinone, which was
immediately methylated to furnish 45 in 42% (69% based on
recovered 44) (Scheme 4). Again Suzuki–Miyaura coupling of 45 with
2
6 performed to furnish the corresponding product (47) in 75% yield
these observations and the characteristics of the naturally occurring over a 4-cycle repetition, which was necessary due to the low reactivity
naphthacene-5,6,11(12H)-trione framework, we conclude that of 45. After performing the same replacement process (63% for
2
steps) that was done for model compound 28, acid-mediated
Friedel–Crafts cyclization was carried out to afford the corresponding
spirocyclic-dienone (48) as an inseparable diastereomixture (d.r. = 1:1)
in 83% yield. Oxidation with CAN under optimized conditions let to
conversion of 48 into the spirocyclic-quinone in 76% yield, which was
followed by dienone-phenol rearrangement using TiCl to give the
4
naphthacene product in 44% yield (83% based on recovered SM).
CAN oxidation to the quinone after the dienone-phenol
rearrangement reaction was not successful. However, acetylation
of the generated phenol followed by oxidation of the benzyl
position using CAN gave the desired the benzyl alcohol (49) as an
inseparable diastereomixture (d.r. = 1:1). The crucial oxidation
Figure 2 Plausible reason for the stability of the naturally occurring of the benzyl alcohol of 49 to a ketone, which is characterized
naphthacene-5,6,11(12H)-trione compounds.
by a troublesome dipole interaction on the B and C-rings,
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Total synthesis of ( ± )-naphthacemycin A
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6
Scheme 4 Completion for synthesis of ( ± )-naphthacemycin A9 (9).
was not successful under conditions (for example, PCC at room we attempted the chemoselective demethylation reaction using
temoperature, Swern[O], MnO , Dess-Martin[O] and Jones[O]) other it by boron trihalides to take advantage of the coordination of the
2
than PCC at 80 °C (59% yield). After deacetylation under basic B-ring carbonyl function, but the reaction did not work. Fortunately,
condition to afford methyl-naphthacemycin A9 (50) (63% yield), the reaction proceeded well with CeCl ·7H O-NaI in MeCN under
3
2
the final chemoselective demethylation was examined. At first, reflux,42 furnishing the target ( ± )-9 in 64% yield.
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Total synthesis of ( ± )-naphthacemycin A
T Hirose et al
9
7
Using HPLC analysis of ( ± )-9 and natural ( − )-9 with a chiral Evaluation of antibacterial activity
column, we next confirmed the atropisomer of compound (Figure 3). The antibacterial activity (vide ante) of synthetic naphthacemycin A9
The chirality of 9 was clearly observed, and both the ( − ) and and the related model compounds along with some derivatives
(
+)-antipodes of synthetic ( ± )-9 were separated without racemization (51, 52, 53 and 54; see the Supplementary Information for preparation
method) from (− )-9 was examined in vitro against 13 Gram-positive
and individually characterized. Synthetic ( − )-9 was identical to
bacteria using standard serial-dilution techniques.43 As summarized in
1
4,15
1
13
naturally occurring ( − )-9
in all respects ( H NMR, C NMR,
Table 1, naphthacemycin A not only showed potent anti-MRSA and
HRMS) with the chiroptical property, and also synthetic (+)-9 was
9
2
3
anti-VRE, the compound also exhibited activity against macrolide-
identical as antipode of natural ( − )-9 {syn-( − )-9, [α]
−46.0
D
2
7
and linezolid-resistant S. aureus activities, with MIC values for each
(
[
c 0.05, MeOH); syn-(+)-9, [α]
+43.6 (c 0.05, MeOH); nat-(− )-9,
D
tested bacteria in the μg ml− range. Previously, Shia et al. reported
the preliminary SARs for tetarimycin A, which is identical to the
naphthacene moiety of 9 (that is, the A,B,C,D-ring of 9), and its
related analogs.19 They reveled that alkylation of a hydroxyl group in
the A-ring so that it cannot form a hydrogen bond with a carbonyl of
the B-ring abolishes the antibiotic activity. Our preliminary SAR
studies agreed with the results of Shia et al.19 with respect to the
complete elimination of the activity for 25, 35, 53 and 54. In contrast,
the acylation of the hydroxyl group(s) on the A-ring of the
naphthacene moiety had no effect on antibacterial activity. In addition,
a comparison of (± )-9, ( − )-9 (natural type) and (+)-9 (antipode of
the natural type) indicated that atropisomeric chirality dose not
contribute to the antibacterial activity. Importantly, this new class of
antibiotics exhibited anti-MRSA activity almost equal to its anti-VMC
1
19
2
3
15
α]D −44.1 (c 0.2, MeOH) }.
activity; thus, we hypothesize that these antibiotic compounds act in
which has been
identified as an alternative target in drug-resistance bacteria.
Figure 3 HPLC analysis of natural and synthetic 9. HPLC condition:
DAICEL CHIRALPAK IE 10ø ×250 mm, UV detection at 277 nm, 50% disrupting a unique target enzyme, such as FASII,1
7,18
−
1
i-PrOH/hexane mobile phase, flow rate 3.0 ml min
.
Table 1 MICs of naphthacemycin A (9) and related compounds against different bacterial strains43
9
MICs (μg ml−1)
Strains/compounds
VCM
Synthetic ( ± )-9
Synthetic ( − )-9
Synthetic (+)-9
25
35
50
51
52
53
54
S. aureus FDA209Pa
S. aureus Smitha
1
4
2
2
2
2
2
2
1
2
4
4
8
4
4
2
2
1
2
2
2
2
4
4
4
4
4
4
2
2
1
1
2
2
2
1
4
4
4
8
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
32
32
2
2
2
1
1
1
1
1
4
2
2
2
4
2
1
1
1
1
1
1
1
2
4
2
2
2
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
464
2
MRSA KUB853b
1
4
MRSA KUB854b
MRSA 70b
1
4
0.5
8
MRSA 92–1191b
S. aureus KUB857c
S. aureus KUB858d
VISA Mu50
S. aureus KUB860e
E. faecalis ATCC29212f
E. faecalis NCTC12201g
E. faecium NCTC12204h
1
32
1
32
1
8
8
432
432
432
432
432
2
4
4128
4128
Abbreviations: MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible Staphylococcus aureus; VCM, Vancomycin; VISA, VCM-intermediate S. aureus.
a
MSSA: FDA209P and Smith.
MRSA: MRSA KUB853, KUB854, MRSA 70, and MRSA 92–1191: MRSA strains isolated from clinical patients.
b
c
Macrolide-resistant S. aureus KUB857: inducible resistant strain; encoded by erm gene.
d
Macrolide-resistant S. aureus KUB858: constitutively resistant strain; encoded by erm gene.
e
Linezolid-resistant S. aureus KUB860.
f
Enterococcus faecalis ATCC29212: susceptible strain.
g
VCM-resistant E. faecalis NCTC12201: encoded by vanA gene.
h
VCM-resistant E. faecium NCTC12204: encoded by vanA gene.
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Total synthesis of ( ± )-naphthacemycin A
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8
CONCLUSION
14 Ōmura, S. et al. KB-3346-5 substances, their fermentative manufacture, and anti-
bacterial agents containing them. Jpn. Kokai Tokkyo Koho JP2009046404A (2009).
We have achieved the total synthesis of ( ± )-naphthacemycin A (9).
9
15 Ōmura, S. et al. in Splendid Gifts from Microorganisms 5th edn (ed. Ōmura, S.)
The synthesis scheme featured the Dötz reaction expanding to
Suzuki–Miyaura coupling to produce a highly substituted hydroqui-
none, Friedel–Crafts cyclization, and dienone-phenol rearrangement.
The longest linear sequence involved 16 steps to 9 from commercially
available 40. This synthetic process provides viable routes for the
synthesis of naphthacemycins and new potential analogs thereof. Our
results also revealed how twisting of the benzoquinone moiety relaxes
the dipole interaction between two neighboring parallel carbonyls set
on the originally planer naphthacene framework, thus stabilizing the
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CONFLICT OF INTEREST
The authors declare no conflict of interest.
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The Journal of Antibiotics