Studies towards the total synthesis of hygrocins A and B

Article abstract of DOI:10.1016/j.tetlet.2013.12.017

The western segment of hygrocins A-B has been synthesized through the coupling of a chiral C5-C13 synthon with the sterically demanding hexasubstituted naphthalenic core. The C5-C13 chiral fragment has been assembled via a stereoselective Johnson orthoest

Full text of DOI:10.1016/j.tetlet.2013.12.017

Tetrahedron Letters 55 (2014) 821–825
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies towards the total synthesis of hygrocins A and B
a
a
a
Sivappa Rasapalli a, , Gopalakrishna Jarugumilli , Gangadhara Rao Yarrapothu , Hamza Ijaz ,
⇑
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
⇑
Corresponding author. Tel.: +1 508 999 8276; fax: +1 508 999 9167.
E-mail address: srasapalli@umassd.edu (S. Rasapalli).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.12.017

822
S. Rasapalli et al. / Tetrahedron Letters 55 (2014) 821–825
O
H
H
OH
O
N
O
HO
HO
O
CDCl3
O
O
O
HO
O
NH
1,2
HN
O
addition
O
O
O
O
HO
(ref. 4)
O
OH
8
O
R
1, 4
addition
HO
Hygrocin A(1)
(3)
O
HO
Me
O
O
H
N
O
H
N
1
'
5
R =
R =
'
6
2
DivergolideB(10)
not isolated
''
1
A
C
B
O
''
2
(12)
3
''
4
6
'
1
4
O
R
O
H
5
OH
O
''
5
O
O
6
O
O
R
O
O
O
HO
7
9
8
2
1
O
O
O
1
1
0
1
NH
OH
(6)
(7)
Me
R =
R =
R = Me
Hygrocin B (2)
DivergolideC( )
Putative Precursors
4
R =
O
1, 4
addition
O
H
N
O
R
OH
H
O
HO
(9)
HO
R =
R =
DivergolideA
(11)
O
1, 2
O
Me not isolated
addition
NH
HO
O
O
acyl
O
migration
O
O
O
HO
OH
O
8
8
Divergolide D (5)
not isolated
Figure 1. Novel ansamacrolides: Hygrocins and divergolides and their biosynthetic relations.
their biomedicinal potential further.15 As can be seen from our ret-
rosynthetic analysis of hygrocins A (1) and B (2) shown in
Scheme 1, we proposed to assemble the hygrocin A in a non-biomi-
metic fashion and planned to rely on its intrinsic biomimetic trans-
formation to hygrocin B via 1,4-addition. Disconnection of the
macrolide 1 either at the lactam (C100–N) or lactone (C11/12–OH
and C500) sites offers either the macrolactamization or macrolacton-
ization as strategies to assemble the macrocyclic skeleton from
the western fragment 13 and 2-methyl-2-propenedioic acid. Our
fragment based disconnection of western segment 13 at C4–C5
identified two synthons, namely chiral fragment 14 and the
aromatic core 15. We initially focused our efforts on the synthesis
of the chiral (C5–C13) fragment 14 and we intended to develop a
scalable and cost effective stereoselective route that allows orthog-
onal protection of the C11 and C12 hydroxyl groups while
accommodating different substituents at C12 and amenable for
installation of different functionalities on C5 suitable for
coupling.16 Keeping the above criteria and our resources in focus,
the stereochemistry of the target molecules was planned to be
obtained via the chiral pool synthesis through stereoselective
Johnson orthoester variant of the Claisen rearrangement, whose
synthetic utility is well appreciated by the synthetic community
due to its predictable high diastereoselectivity.17
O
O
B
O
H
N
H
N
1
'
O
5
'
6
2
''
2
1
C
A
''
3
''
4
6
HO
'
HO
1
4
O
5
'
'
O
5
O
O
O
6
O
HO
O
7
9
13
O
8
2
1
1
1
0
1
OH
2
1
1N NaOH
[ref: 4]
O
NH2
HO
4
5
O
O
6
HO
8
OH
13
O
5
8
O
O
R"'
N
6
R"'
7
OH
12
13
Accordingly, our synthetic efforts commenced with the com-
10
11
HO
mercially available
(C5–C13) fragment with the requisite stereochemistry and func-
tional groups, as shown in Scheme 2. Thus, -glucose diacetonide
D-glucose diacetonide 16 to obtain the chiral
9
Br
15
OH
1
4
D
16 was converted to aldehyde 17 following the literature proce-
dure.18 Wittig olefination of aldehyde 17 with n-propylidenetri-
phenyl phosphorane (generated in situ from n-C3H7PPh3+Brꢀ and
n-BuLi) at ꢀ78 °C gave the Z-olefin 1819 with good (>95:5 Z:E) ste-
reoselectivity. Deprotection of the secondary acetonide in 18 by
treatment with 80% acetic acid under reflux conditions provided
a 1:1 mixture of anomeric hemiacetals whose subsequent NaBH4
Scheme 1. Retrosynthesis of Hygrocin A and B (1 and 2).
reduction resulted in triol 19. Triol 19 was converted to the 1,2-
acetonide to give the enantiomerically pure allylic alcohol 20. Grat-
ifyingly, allylic alcohol 20 underwent smooth [3,3]-sigmatropic
rearrangement at 130 °C with triethyl orthoacetate (10 equiv) in

S. Rasapalli et al. / Tetrahedron Letters 55 (2014) 821–825
823
O
1. NaH, BnBr, THF
O
O
cat.TBAI, 70 oC, 10 h
PPh3+ Br-
-BuLi, THF
1. 80% AcOH, H2O
8 h, 94%
O
O
2. AcOH:H2O (1:1), 55 oC, 5 h
O
O
n
BnO
O
O
BnO
O
HO
16
-78 oC to rt, 20 h
85%, (Z:E > 95:5)
2. NaBH4, THF:H2O (8:2)
3. NaIO4, MeOH: H2O(1:1)
45 min, 89% over 3 steps
O
O
17
18
8 h, 0 oC to rt, 95%
CH3C(OEt) 3, 10.0 equiv.
cat. propionic acid
reflux, 2.5 h
O
O
Acetone, cat.pTSA
rt, 12 h,
2 N HCl, EtOH
rt, 3 h
OH
OH
OH
O
O
O
OH
O
94%
quantitative yield
90%
OBn
OBn
19
OBn
20
21
OH
Et3N, nBu2SnO,
TsCl, 8 h
ImH, PPh3, I2
DCM, 2 h
O
OH
LAH, THF
O
OH
0 oC to rt, 6 h
OH
HO
O
O
OBn
80%
92%
24
75%
OBn
OH
OBn OTs
23
22
NaH, BnBr
O
H
OBn
CN
OBn
DIBAL-H
I
I
THF, cat. TBAI
10 min
NaCN, DMF
12 h, rt
OBn
OBn
CH2Cl2
-78 oC, 1 h
70%
OBn
OBn
OBn
65%
90%
27
25
26
28
Scheme 2. Synthesis of chiral C5–C13 fragment 28.
the presence of catalytic propionic acid to provide ester 21 exclu-
sively as a single diastereomer in quantitative yield.20 Deprotection
of the acetonide group of ester 21 in ethanolic 2 M HCl provided
the diol 22. The substrate 22 is ideal for divergent synthesis of
the chiral fragments with various side chains at C12 (e.g. C12-isob-
utenyl substitution for divergolides) by oxidation of the primary-
OH to aldehyde, and Wittig olefination.21 We planned the deoxy-
genation of the primary alcohol for installation of the C12-methyl
substituent required for hygrocins A and B (1 and 2). Towards this
direction, the primary hydroxyl group of 22 was selectively tosy-
lated in the presence of nBu2SnO/NEt3/TsCl to obtain the compound
23 in 92% yield. The stereochemical and structural conformation of
23 was secured through X-ray crystallography of the single crystals
grown in dichloromethane (Fig. 2).
The concomitant reduction of the ester and tosylate functional-
ities of 23 with LiAlH4 provided the diol 24. The diol 24 was selec-
tively converted to primary iodide 25 which in turn enabled the
protection of the secondary hydroxyl group. It is pertinent to men-
tion that this synthetic design allows for the orthogonal protection
of the C11 and C12 hydroxyl groups that would allow selective
deprotection at the later stages in the synthesis for esterification.
For establishing the conditions for elaboration of the ansabridge,
we decided to place another benzyl protection and proceed with
elaboration of ansa bridge of hygrocins A–B. Thus, we converted
the secondary hydroxyl group of 25 to benzyl ether 26 under
NaH/BnBr conditions which was subsequently converted to nitrile
27 using NaCN/DMF. Reduction of 27 with DIBAL-H proceeded
uneventfully resulting in the clean formation of aldehyde 28.
Having constructed the chiral fragment 28 in an enantiopure
form, we extended the chemistry established en route our efforts
to divergolides for aromatic core.8 Briefly, we had obtained the aro-
matic core 31 via well-established cycloaddition chemistry of
modified Danishefsky’s diene 29 with quinone 30. Bromination of
the cycloadduct under NBS conditions in dilute CHCl3 solution
provided the bromoquinone which was subsequently converted
to naphthalenic bromide 32 by Luche reduction followed by meth-
ylation of the resulting bisphenol.22
Figure 2. Solid state structure of compound 23.
problematic in such sterically hindered systems.23 Pleasingly, the
coupling reaction of the lithiated naphthalenic core 32 with ali-
phatic chiral aldehyde 28 proceeded with moderate yield (60%,
not optimized) to provide the alcohol 33 as a diastereomeric mix-
ture, as shown in Scheme 3. Careful oxidation of 33 under DMP/
pyridine conditions provided ketone 34 in good yield as a mixture
of atropisomers in a 1:1 ratio, based on 1H NMR analysis.24 At this
point, we decided to converge the synthesis with the fragment 13
that Cai et al., had obtained by hydrolysis of the natural hygrocin A
(1) in order to confirm the stereochemical assignment of C8 before
we proceeded too far with the total synthesis. However, the at-
tempts to effect the global deprotection of 34 to obtain 13 under
After gaining access to both the synthons 28 and 32, we began
to investigate the critical C4–C5 bond which is known to be

824
S. Rasapalli et al. / Tetrahedron Letters 55 (2014) 821–825
publication Nos. CCDC 922930 and CCDC 922929, respectively.
O
Copies of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44
0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk). Supplemen-
tary data (general experimental procedures, NMR spectra and
X-ray crystal structural info) of this manuscript can be obtained
free of charge.
O
O
NHBoc
30
1. toluene, 75 oC
TMSO
2. SiO2, EtOAc
(open flask)
3. NBS, CHCl3, rt, 0.5 h
63 % over 3 steps
29
31
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2013.12.017.
OMe
OMe
NHBoc
n-BuLi, THF
-78 oC, 0.5 h,
CeCl3.7H2O, NaBH4
THF/H2O
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MeO
28, -78 oC, 0 .5 h
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Conclusions
In summary, we have successfully synthesized the western seg-
ment of hygrocins A and B (1 and 2). The required variously func-
tionalized and protected chiral fragments with the requisite
stereochemistry of the targets i.e. C8 (R), C9 = C10 (E), C11 (S),
C12 (S) have been accessed via a chiron approach. The aromatic
core obtained through cycloaddition chemistry has been utilized
in establishing the coupling of chiral fragments through C4–C5
bond formation as a viable approach for further studies towards
completion of the total synthesis of hygrocins A–B. Our efforts thus
far, would lay the platform for us to assign the stereochemical
assignments of the hygrocins A–B especially to that of C8 which
had remained unassigned for nearly a decade since their isolation.
Our efforts to develop a divergent synthesis of the chiral fragments
for both the families i.e., divergolides and hygrocins and their
structural analogues via ester 21, and completion of the total
synthesis of the targets is under progress and the results will be
reported in due course.
Acknowledgment
This work was supported through the Startup and Healey Foun-
dation funds of UMass Dartmouth, and partly from Microbiotix,
Inc, Worcester. S.R. acknowledges the NSF-MRI program (Grant
no. CHE 1229339) for funds to purchase the 400 MHz NMR
spectrometer.
Supplementary data
9. For recent reviews on ansamycin natural products, see: (a) Wrona, I. E.;
Agouridas, V.; Panek, J. S. C. R. Acad. Sci 2008, 11, 1483–1522; (b) Floss, H. G.;
Yu, T. W. Chem. Rev. 2005, 105, 621–632; (c) Funayama, S.; Cordell, G. A. Studies
in Natural Products Chemistry Atta-ur-Rahman; Springer: Amsterdam, 2000. 23,
51–106; d A. Bryskier, Antimicrobial Agents. Bryskier A., Ed.; ASM Press:
Washington, DC, 2005; pp. 906–924.
Crystallographic data (excluding structure factors) for the
structures 23 and 31 in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary

S. Rasapalli et al. / Tetrahedron Letters 55 (2014) 821–825
825
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