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6 Benanomicin–Pradimicin Antibiotics (Sugar–Polyketide Hybrids)

6 Benanomicin–Pradimicin Antibiotics (Sugar–Polyketide Hybrids)

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456



13 Hybrid Natural Products



R1

O

HO

O HO

E



D



HO



O



C



NH

3



A



14



MeO



B



4

5



HO



R1



CO2H



O

HO



R2



O

R3O 2

R

R3



pradimicin A



Me



NHMe



β-D-xylose



pradimicin B



Me



NHMe



H



pradimicin D



H



NHMe



β-D-xylose



benanomicin A Me



OH



β-D-xylose



benanomicin B

(pradimicin C)



Me



NH2



β-D-xylose



pradimicin S



Me



NHMe



BMY-28864a



CH2OH NMe2



a



HO

HO

HO3SO



O

HO



β-D-xylose



synthetic derivative



Figure 13.13 Benanomicin—pradimicin antibiotics.



involvement of the carboxyl group of D-alanine for Ca2ỵ binding [49]. Recently, a

solid-state NMR study suggested a 2 : 1 : 2 solid aggregate of pradimicin A/Ca2ỵ/

Man-OMe (Figure 13.14) [50]. The 3-Me, C(4), C(5), C(14), and carbons on

D-alanine are located close to methyl a-D-mannopyranoside suggesting recognition

via Ca2ỵ-coordination, two hydrogen bonds, and CH/p interaction with the A-ring.

Biological studies elucidated that BpAs bind to the mannose-rich glycans on

gp120, a glycoprotein present on the HIV envelope that mediates entry into the

host cell [51]. In terms of the emergence of drug-resistant strains, pradimicin A has

a high genetic barrier since more than five N-glycosylation site deletions in gp120

are required to acquire moderate drug resistance.

13.6.3

Medicinal Chemistry



While highly active antiretroviral therapy (HAART) significantly decreased the

mortality rate in HIV-infected individuals, prevention of the HIV transmission is

an important aim in the combat against HIV/AIDS, as HAART only allows

suppression, but not elimination of the virus. A recent in vitro study showed a

promising means of preventing HIV infections by combined use of tenofovir

(antiviral agent) and pradimicin (carbohydrate-binder) [52]. The concept is to

inhibit two different processes of the HIV infection; namely blocking the reverse

transcription step inside the virus-infected cell, and preventing the viral entry.



13.7 Angucyclines (Sugar---Polyketide Hybrids)



HO

HO

HO



HO

O



MeO



Ca2+



OMe



O

HO

HO



O



Me

HN



MeHN

O O



HO

O

HO



O



O



HO



D-xyl



O



cross peaks observed between carbon signals for

pradimicin A and those for Man-OMe

Figure 13.14 Model of mannose recognition by pradimicin A.



13.6.4

Synthesis



A divergent synthetic route of the BpAs has been reported [53], featuring a

tetracycle platform that allows assembly of different sugars, amino acids, and the

E-ring (Scheme 13.11A) .

Scheme 13.11B and C outlines the access to this key synthetic intermediate: (i)

the trans-relationship of the C(5), C(6)-diol is set by the pinacol cyclization of a

biraryl dialdehyde [54]; (ii) the absolute stereochemistry is achieved by the

stereospecificity of this cyclization, transferring the axial stereochemistry into

chiral centers of the diol; (iii) the axially chiral starting material in turn is available

by the asymmetric lactone ring opening; and (iv) the mono protection of the C(5),

C(6) diol, necessary for the regioselective O-glycosylation, was realized by the

semipinacol cyclization: the reductive coupling of acetal–aldehyde by using SmI2 and

BF3ÁOEt2 in the presence of MeOH.



13.7

Angucyclines (Sugar---Polyketide Hybrids)

13.7.1

Occurrence and Biosynthesis



The angucyclines [55] belong to an emerging class of polycyclic natural products. In

contrast to the linearly fused tetracyclic framework of the anthracyclines, such as

adriamycin which is of clinical importance, the structures of the angucyclines are

characterized by an L-shaped (angular) tetracycle, as found in aquayamycin, from

which the class name came. Both of these classes of natural products share the

decaketide biosynthetic precursor, but the different modes of folding lead to their

angular/linear tetracyclic molecular framework (Scheme 13.12).



457



458



13 Hybrid Natural Products



A Tetracyclic platform to BpAs.



O



CO2R



OMe



NH2



BnO

MeO BnO



#2 amidation



MeO

OR

OSiR3



#1 glycosylation

F



OH



Cl

MeO



BnO



#3 E-ring

annulation



O 1

R



O



AcO

AcO



B chirality transfer: pinacol cyclization

CO2Me

MeO

MeO MeO

SmI2



O



BzO

AcO



CO2Me



MeO

MeO MeO



BF3 OEt2



CHO

CHO



Cl

MeO



MeOH



Cl



OH

MeO



>99% ee



>99% ee



HO



C asymmetric lactone ring opening and semi-pinacol cyclization

O



O



MeO

Cl



CO2Me

H 2N



MeO HO HO



OH



O



Cl



OH OSi(i-Pr3)



MeO



CO2Me



OSi(i-Pr3)



HN



OH



OMe

CO2Me



BnO

MeO BnO



CHO

OBn



Cl

MeO



>99% ee



OBn



BnO

MeO BnO



SmI2

BF3 OEt2

MeOH



Cl



CO2Me



OH

MeO



BnO

>99% ee



Scheme 13.11 Regio- and stereocontrolled access to BpAs synthetic intermediate.



The angucyclines are divided into two subgroups depending on the presence/

absence of the angular hydroxyls. In addition, angucyclines often display C- as well

as O-glycosidic modifications (Figure 13.15).

In addition to the congeners with a typical L-shaped framework (classical

angucyclines), so-called nonclassical members are known, in which the frameworks

undergo rearrangement, opening, and ring enlargement or contraction, as

represented by the benzonaphthopyranone skeleton of the gilvocarcin–ravidomycin

antibiotics (Scheme 13.13).



13.7 Angucyclines (Sugar---Polyketide Hybrids)



angucycline



anthracycline



O

O

HO



O



OH



OH

OH



OH



O



HO

HO



O



OH



HO



O



MeO



aquayamycin

O

O

O



O



O



O



O

O



S-Enz

O



O

O



OH O



NH2

HO



S-Enz



O

O



O



adriamycin



O

O



O



O



O



O

O



O



Scheme 13.12 Curved/linear frameworks of angucyclines and anthracyclines.



13.7.2

Bioactivity



In spite of diverse biological activities reported for the angucyclines, including

enzyme inhibitory, antibacterial, antiviral, anticancer effects, and platelet aggregation, none of the members have so far been developed into clinical use due to



O

O

HO

O

O

O

O



HO



OH

O



O

HO



O



O



OMe



O

AcO

Me2N



HO



HOO

O



O



O

HO



O



O



landomycin E



HO

Figure 13.15 Angucyclines.



OMe



O



vineomycin A1



O



HO



O



O



HO

O



O



OH



OH



O

O



ravidomycin



459



460



13 Hybrid Natural Products



OH

HO

O



HO

O



O



[O]

HO



O



O



HO

MeO



CHO

CO2H



O



HO



OMe



OH



MeO



MeO

O



OMe



OH



O



MeO

O



OH



O

gilvocarcin V



OH



OH



OH



Scheme 13.13 Postmodification to nonclassical angucyclines.



toxicity or solubility issues. Studies on the mechanism of antitumor action of the

angucyclines suggested a difference from that of anthracyclines [56]. Changes in

the oligosaccharide moiety is sometimes nontrivial [57].

A recent biological study on landomycin E (LE) [58] revealed, in contrast to the

anthracyclines, that it does not inhibit topoisomerase II in line with its weak DNA

intercalation properties, due presumably to the noncoplanar structure. Instead of

the altered cell cycle distribution, LE treatment induces mitochondrial dysfunctions

with distinctly higher potency than adriamycin. Notably, LE is only a weak substrate

for the overexpressing ABC-transporters such as P-gp and MRP1, and is not

transported by breast cancer resistance protein (BCRP). Thus, the LE-related

angucyclines are promising candidates as antitumor drugs, featuring a contrast to

the clinical use of anthracyclines, which suffer from rapid development of resistant

tumor cells.

With the modified chromophore, some of the nonclassical angucyclines show

unique bioactivities. For example, gilvocarcin V (¼ designating the presence of a

vinyl group) intercalates into DNA and gives a covalent adduct under light

irradiation, inducing single-strand breaks in supercoiled DNA [59]. The [2 ỵ 2]

photocycloadduct was identied, arising from the reaction between the vinyl group

in gilvocarcin V and a thymidyl residue in DNA (Scheme 13.14) [60]. Not

surprisingly, gilvocarcin M (methyl) does not show such activity.

13.7.3

Synthesis



Synthetic challenges presented by the angucyclines include (i) constructing the

polycyclic skeletal with dense oxygen functions and stereochemical complexity and

(ii) C-glycoside and/or O-glycoside formations. To solve these issues, effective

synthetic strategies and tactics are necessary.



13.7 Angucyclines (Sugar---Polyketide Hybrids)



MeO



MeO



OH



MeO



MeO

OH



O



O



DNA

hν (>300 nm)



O

gilvocarcin V



O



DNA



OH



OH



N



O

N

H



O



O



Scheme 13.14 [2 ỵ 2]-Photocycloadduct of gilvocarcin V and DNA.



Suzuki and Matsumoto have extensively studied the synthesis of this class of

natural products, particularly the congeners with C-glycosides [61]. The key tactic to

hybridize the polyketide-derived aromatic and the carbohydrate is the “O ! Cglycoside rearrangement” inspired by the putative biosynthetic process. Benzanthrin B has a bis-glycoside structure, one as an O-glycoside and the other as a

C-glycoside. The biosynthetic hypothesis was the cascade of the initial O-glycoside

formation followed by the rearrangement to the corresponding C-glycoside, which

paved a way to install C-glycoside in chemical synthesis (Scheme 13.15) [62].

The total synthesis of aquayamycin illustrates the effective use of this aryl

C-glycosylation (Scheme 13.16) [63]. D-Olivosyl acetate reacts with mono-protected

iodo-resorcinol in the presence of a Lewis acid, giving the product with C-glycoside

linkage at the ortho-position to a phenol. Incremental development of the tetracyclic

HO

Me2N



Me2N OH

O



O



HO



(RO)n



O



O



O



O



(RO)n

O



H



O



?



HO



OH



benzanthrin B

OH

(RO)n



O



+



(RO)n



(RO)n



O



O



step 1



X



step 2



Lewis acid

low temp



O-glycoside

O

OH

C-glycoside



Scheme 13.15 O ! C-Glycoside rearrangement.



461



462



13 Hybrid Natural Products



OSiR3



O



BnO

BnO



+

OAc



I

HO



Cp2HfCl2

AgOTf



via O-glycoside



BnO



HO

HO



Sugar

BnO



O



SO2Ph



MeO



OH



HO

O



+



O



Sugar

HO

O

aquayamycin



BnO



OMe



OSiR3

OBn



pinacol coupling

O



OH



O



I

O



O



O



O

O

HO



BnO

BnO

O



OMe

OMe

Sugar



OSiR3

O



O



CHO

OBn



Scheme 13.16 Total synthesis of aquayamycin.



framework was then achieved via benzyneolen [2 ỵ 2]-cycloaddition, Hauser

annulation, and pinacol coupling. Other examples for the application of O !

C-glycoside rearrangement for total synthesis of aryl C-glycoside antibiotics include

vineomycinone B2 methyl ester [64], galtamycinone [65], C10, [66] and gilvocarcins

(see above) [67].

A biomimetic approach to construct the angucyclines was reported by Yamaguchi

et al. by way of multiple-Claisen condensation to give a polyketide construct,

leading to the total synthesis of urdamycinone B (Scheme 13.17) [68].

Recently, the first synthesis of landomycin A was achieved (Scheme 13.18) [69].

Glycosylation was troublesome, because the glycosyl acceptor is a phenol within an

electron-deficient naphthoquinone and hydrogen bonded to the nearby carbonyl.

Also, conditions leading to aromatization of the chromophore need to be omitted.

Finally, anionic condition using glycosyl iodide as donor yielded the monoglycosylated aglycons [70]. Assembly with the pentasaccharide followed by

dehalogenation and deprotection enabled the total synthesis. A hexasaccharide

library may contribute to biological and medicinal chemistry studies [71].

13.8

Furaquinocins (Polyketide---Terpene Hybrids)

13.8.1

Occurrence



Furaquinocins were isolated around 1990 from Streptomyces sp. KO-3988 as a

cytocidal compound against HeLa S3 and BI6 melanoma cells (Figure 13.16)

[72,73]. These compounds share a polyketide-derived naphthofurandione chromophore, differing in the isoprenoid-derived side chain.



13.8 Furaquinocins (Polyketide---Terpene Hybrids)



HO



OEt

O

OEt



O



RO

RO



O

1) –



CO2Me







2) Ca(OAc)2



HO



OMe

O



Sugar

O



O



O

OMe



O

O



O

S



O

O



CO2Me

Sugar



Sugar



CO2Me



OH



HO



O



S



RO

O



OR



OH



OH



O



HO

HO



HO

O

urdamycinone B

Scheme 13.17 Biomimetic approach toward the angucycline skeleton.



BnO

O



BnO



KHMDS, 18-Crown-6



HO



BnO



O

OCH2Ar

Ar = (C6H4)p-NO2



Br

TBSO

AcO



Br

RO

AcO

R = TBS

R=H



O

I

AcO

O



AcO

O

O



O

I



O

O

AcO



O



O



O



O



OCH2Ar



TBAF

1) TBSOTf

2) Raney Ni, H2

3) DDQ

4) NaOMe



NPh



O

I



O



BnO

O



CF3



O



HO



I



HO

O



AcO

HO

O

HO

O

O



O



O

O

HO



O



O



HO

Scheme 13.18 Total synthesis of landomycin A.



O



O

HO



O



landomycin A



O



O



OH



463



464



13 Hybrid Natural Products



O



O



A



B



R1



R1

C



MeO



furaquinocin A

B

C

D

F

H



R2

OH



R3



O



R2



R3



OH H OH

OH OH H

H

H

H

OH H

H

H OH H

OH OH OH



Figure 13.16 Furaquinocins.



13.8.2

Biosynthesis



Biosynthesis of furaquinocins is still under study. Early incorporation experiments

suggested that furaquinocins are derived from a pentaketide, two mevalonates, and

two C1 units from L-methionine [74]. The gene cluster analyses showed that the

naphthalene moiety is fully functionalized prior to the prenylation [75]. A recent

report showed that a heterologous expression of the partial biosynthetic gene

cluster leads to the accumulation of an intermediate with an amino group that is

not involved in the final product (Scheme 13.19) [76].

13.8.3

Synthesis



The synthetic challenge posed by the furaquinocin class of antibiotics is related to the

CÀÀC bond between the naphthoquinone and the isoprenoid moieties encompassing

a quaternary carbon atom. Such a steric demand makes the seemingly easy

transformation inaccessible. Another challenge is the stereochemical control at two

vicinal stereogenic centers. Three groups complete the total synthesis.

Smith et al. built the quaternary center by cuprate addition to a butenolide, where

the unfavored stereoisomer was mainly produced (Scheme 13.20) [77]. After

separation, the Diels–Alder reaction with a siloxydiene constructed the naphthoquinone, giving furaquinocin C.

HO

5x



O

HO



S CoA



O



OH



O



OH



O



NH2



O

HO



OH



OH

O



HO



OH



OH

furaquinocins



MeO



OH

O



MeO



OH

O



Scheme 13.19 Biosynthesis of furaquinocins.



13.8 Furaquinocins (Polyketide---Terpene Hybrids)



O



O



Me2CuLi

TMSCl



O



O



O



O



O

O



(1:1.8)



O



1) LDA; TMSCl

2) LDA; TMSCl



O



O



Br

+ TMSO



MeO



O



O



furaquinocin C



MeO



OTMS



O



O



OH



Scheme 13.20 Smith synthesis of furaquinocin C.



Suzuki and coworkers planned to use a Lewis acid-mediated 1,2-shift of epoxy

alcohol derivatives (Scheme 13.21) [78]. However, the o,o-disubstituted aryl groups

did not undergo 1,2-shift, in contrast to “normal aromatics.”

A viable approach was developed based on the 1,2-shift of an alkynyl group to

construct a key intermediate with the quaternary stereogenic center (Scheme 13.22)

[79]. Alkynyl groups with a poor migratory aptitude can be rendered reactive by

conversion to the corresponding cobalt complex [80]. After assembly of two

building units by a Sonogashira reaction, the naphthofuran structure was subjected

to an intramolecular Claisen condensation of a dihydrofuran intermediate. The

epoxide prepared with high stereoselectivity served as a branching point to

furaquinocins A, B, D, and H by combining suitable vinyllithiums to construct the

side chain moiety.

Trost initially examined the formation of a formylnaphthofuran as a common

intermediate to the furaquinocins via the Pd-catalyzed asymmetric allylic alkylation

to control the absolute stereochemistry (Scheme 13.23) [81]. However, the highly

substituted naphthalene failed to undergo this conversion, due to steric hindrance.

A revised plan by Trost allowed the syntheses of several furaquinocins

(Scheme 13.24). 2-Iodoresorcinol was treated with chiral palladium catalyst in the

presence of excess cyanoallyl carbonate to give bis-allyl ether, which was converted

to trisubstituted dihydrobenzofuran in an optically pure form by a reductive Heck

H



O

MeO



MeO

OTMS

OMe



TiCl4, Et3SiH



OH



HO

MeO

OH



O

OMe

(hydrogen

1,2-shifted product)



OMe

not observed

(aryl group

1,2-shifted product)



Scheme 13.21 Attempt to form quaternary center via 1,2-shift of an aryl group.



465



466



13 Hybrid Natural Products



O

OTMS

Me3Si



HO



1) Co2(CO)8

2) TiCl4, Et3SiH



OH



3) CAN



Me3Si



BnO



single isomer



I

CO2Me



MeO

MeO



HO

BnO



OR



O



BnO



OH



O

MeO



OMe



CO2Me



MeO



MeO



MeO



BnO



O



BnO



CHO



MeO



OMEM



MeO



MeO



O



O



furaquinocins

(A, B, D, H)



OMEM

MeO



Scheme 13.22 Total syntheses of furaquinocins A, B, D, and H.



OH



MOMO



MOMO



O



OCO2Me



MeO

MOMO



OSiR3



cat. PdLn



X



MeO

MOMO



OSiR3



Scheme 13.23 Asymmetric allylic alkylation failed with a hexasubstituted naphthalene.



HO

I



+



OH

O



CN

OAc



99% ee



OCO2Me

CN



O

cat. Pd2(dba)3 CHCl3

cat. ligand



O



2.85 equiv



O

Br



CN

I NC



MeO



side chain

OTIPS



Scheme 13.24 Trost syntheses of furaquinocins A, B, and E.



1) cat. PdCl2(CH3CN)2

HCO2H, PMP

2) Ac2O

3) recrystallization



NPh

O



furaquinocins

(A, B, E)



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