Tetrahedron Letters
Studies towards the total synthesis of hygrocins A and B
a
a
a
Sivappa Rasapalli a, , Gopalakrishna Jarugumilli , Gangadhara Rao Yarrapothu , Hamza Ijaz ,
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James A. Golen a, Paul G. Williard b
a Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, MA 02747, United States
b Department of Chemistry, Brown University, Providence, RI 02912, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The western segment of hygrocins A–B has been synthesized through the coupling of a chiral C5–C13 syn-
thon with the sterically demanding hexasubstituted naphthalenic core. The C5–C13 chiral fragment has
been assembled via a stereoselective Johnson orthoester rearrangement of an optically pure allylic alco-
Received 8 October 2013
Revised 3 December 2013
Accepted 6 December 2013
Available online 12 December 2013
hol derived from D-glucose. Our studies lay the platform for the determination of the absolute configura-
tion of the unassigned C8-stereocenter of the title compounds in addition to the completion of the total
synthesis of the unique ansamacrolides hygrocins A and B.
Published by Elsevier Ltd.
Keywords:
Ansamycins
Divergolides
Claisen rearrangement
Naphthoquinone
Non-biomimetic
Ansamycins, the predominant class of 3-amino-5-hydroxy ben-
zoic acid (AHBA) derived natural products, display extensive biolog-
ical and pharmaceutical activities, and are used as antibiotics,
anticancer agents and enzyme inhibitors.1 They are characterized
by a macrocyclic lactam structure (Fig. 1), in which an aliphatic ansa
chain forms a bridge between two non-adjacent positions of the
chromophore.2 Ansamycins are classified into two types on the basis
ofthestructuralfeaturesofthearomaticcore3: (1) naphthalenic ans-
amycins (e.g. rifamycins,4 naphthomycins,5 streptovaricin,6 etc.)
that exhibit antimicrobial activities (2) benzenic ansamycins (gel-
danamycin,7 herbimycin,8 etc.) that possess anti-cancer activities.
The AHBA-derived secondary metabolites are mostly produced
by Actinomycetes and continue to fascinate both basic and applied
research scientists alike, by virtue of their complex biosynthetic
and biochemical pathways as well as by their pharmacological
potential.9 Recently isolated hygrocins A (1) and B (2), unique
naphthalenic ansamycins, isolated by Cai et al., from the fermenta-
tion broth of Streptomyces hygroscopicus, have been shown to
possess anti-bacterial activity, although weaker compared to
rifamycins.10 Hygrocins A and B (1 and 2) feature an unusual
ansabridge which is a hybrid of macrolide and macrolactam.
Hygrocins resemble divergolides A–D (9, 10, 4 and 5) isolated from
Streptomyces sp. HKI0576, an endophyte of the mangrove tree
Bruguiera gymnorrhiza.11 During their original isolation studies
Cai et al., have noticed the conversion of hygrocin A (1) to
compound 3 which has close resemblance with divergolide D (5)
in its aromatic core and differs only in its side chain at C12 and
in its bridge size. Due to this close similarity, we expected divergo-
lide C (4) to have similarity with hygrocin B (2), hence, revisited
the isolation details of Hertweck et al., and concluded that indeed
divergolide C has also been isolated at the oxidation states of the
aminonaphthoquinone of hygrocin B as shown in structure 4.12
This revision allows invoking of the polyketide biosynthetic pre-
cursor 6 for hygrocins similar to 7 that was proposed by Hertweck
et al., for the divergolides, which is thought to be derived from the
ABHA-PKS pathway via a Baeyer–Villigerase disruption that al-
lowed the formation of macrolide with optional acylmigration.5,13
This putative biosynthesis proposal finds support from the instabil-
ity of hygrocin A and its conversion into 3, a new 1, 2-addition
product which could potentially be called as ‘‘hygrocin D’’. By
extending the mapping exercise,14 it is also conceivable that poly-
ketide shunt could have produced other hygrocins containing oxa-
aromatic cores such as 11 and 12 akin to divergolides A and B (9
and 10) that would possibly be isolated in future. In the light of
the above discussion and the similarities in structures and biosyn-
thesis, the unassigned stereochemistry of C8 (C14 as per Cai’s num-
bering) is presumed to be (R) by extrapolation to the C8
configuration of the related centre in the divergolide family, whose
stereochemistry in turn has been secured through the crystal
structure of 9.
Attracted by the unique structural features and impressive bio-
activities of these novel ansamacrolides, we initiated a research
program to obtain the structural analogues of these novel ansa-
macrolides in biomimetic and non-biomimetic fashions to explore
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Corresponding author. Tel.: +1 508 999 8276; fax: +1 508 999 9167.
0040-4039/$ - see front matter Published by Elsevier Ltd.