Studies toward total synthesis of divergolides C and D

Article abstract of DOI:10.1021/ol400528g

A facile synthesis of the western segment of divergolides C and D has been developed. Exploratory studies with two disconnections, i.e., C4-C5 vs C5-C6, for elaboration of the ansa bridge to the sterically demanding hexasubstituted naphthalenic aromatic c

Full text of DOI:10.1021/ol400528g

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1736–1739
Studies toward Total Synthesis of
Divergolides C and D
Sivappa Rasapalli,*,† Gopalakrishna Jarugumilli,† Gangadhara Rao Yarrapothu,†
James A. Golen,† and Arnold L. Rheingold‡
Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth,
North Dartmouth, Massachusetts 02747, United States, and Department of Chemistry
and Biochemistry, University of California San Diego, La Jolla, California 92093-0358,
United States
srasapalli@umassd.edu
Received February 26, 2013
ABSTRACT
A facile synthesis of the western segment of divergolides C and D has been developed. Exploratory studies with two disconnections, i.e., C4ꢀC5
vs C5ꢀC6, for elaboration of the ansa bridge to the sterically demanding hexasubstituted naphthalenic aromatic core using a chiral synthon
assembled from D-glucose via a stereoselective Johnson orthoester rearrangement is described. The studies set the stage for the completion of
the total synthesis of the biologically important novel ansamycins, divergolides C and D, and their structural congeners.
Ever since the discovery of the antibacterial rifamycin B,
ansamycins continue to evoke interest of synthetic and
medicinal chemists as antibiotic and antineoplastic
agents.1 Recently, structurally unique ansa macrolides
have been isolated from Streptomyces sp. HKI0576, an
endophyte of the mangrove tree Bruguiera gymnorrhiza,
and have been named divergolides AꢀD (1ꢀ4) (Figure 1)
due to the possibility of divergent biosynthetic origin.2
Divergolides C and D (3 and 4) are structurally very
close to hygrocins A and B (5 and 6), another family of
metabolites isolated from Streptomyces hygroscopicus.3
However, divergolides C and D (3 and 4) differ from
† University of Massachusetts Dartmouth.
‡ University of California San Diego.
(1) For recent reviews on ansamycin natural products, see: (a)
Wrona, I. E.; Agouridas, V.; Panek, J. S. C. R. Acad. Sci., Paris 2008,
11, 1483. (b) Floss, H. G.; Yu, T. W. Chem. Rev. 2005, 105, 621. (c)
Funayama, S.; Cordell,G. A. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam, 2000; Vol. 23, p 51.
(d) Bryskier, A. In Antimicrobial Agents; Bryskier, A., Ed; ASM Press:
Figure 1. Ansa macrolides isolated from Streptomyces sp.
Washington, DC, 2005, 906.
€
(2) Ding, L.; Maier, A.; Fiebig, H. H.; Gorls, H.; Lin, W. H.; Peschel,
G.; Hertweck, C. Angew. Chem., Int. Ed. 2011, 50, 1630.
(3) Cai, P.; Kong, F. M.; Ruppen, M. E.; Glasier, G.; Carter, G. T.
J. Nat. Prod. 2005, 68, 1736.
hygrocins A and B (5 and 6) in their unprecedented
isobutenyl side chain at C12 and oxidation states of the
r
10.1021/ol400528g
Published on Web 03/25/2013
2013 American Chemical Society

Scheme 1. Retrosynthesis of Divergolides C and D (3 and 4)
aminonaphthoquinone, while the overall topology is con-
served, except for the shorter bridge seen in divergolide D
(4). Although the aromatic cores of divergolides C and D
differ profoundly from one another, a common biosyn-
thetic proposal involving an amino hydroxybenzoic acid
(AHBA)-primed common naphthoquinone polyketide
precursor has been proposed.2,4 The differences in the
aromatic cores and in the sizes of the ansa bridge are
reflected in the diverse bioactivities of divergolides AꢀD
(1ꢀ4). For example, divergolide D (4) showed promising
anticancer activities while divergolides AꢀC (1ꢀ3) exhib-
ited decent antibacterial activities. As aptly pointed by
Hertweck et al., this unique macrolide family offers the
opportunity for undertaking a natural product based
medicinal chemistry approach for developing novel leads
for antibacterial and anticancer activities. Because of their
structural complexity and diversity in biological acitivities,
divergolides AꢀD (1ꢀ4) have attracted the attention of
synthetic chemists, and the first reports describing syn-
thetic approaches have been published recently.5 We set
out to develop a total synthesis of divergolides C (3) and D
(4), amenable to large-scale production of structural ana-
logues, to explore their biomedicinal potential.
Scheme 2. Synthesis of Formyl Naphthalene Core
consideration and planned to rely on the putative biomi-
metic annulations of N-acylated naphthoquinone for the
formation of the C-ring of the tricyclic aromatic cores.
Our initial foray that involved utilization of 3-methylsa-
licylic acid (15) met with a roadblock in the final conversion of
the desoxy-AB core 16 to 17.6 Hence, we resorted to a well-
established route in the synthesis of aromatic cores of ansam-
ycins, i.e., DielsꢀAlder reaction of modified Danishefsky’s
dienes with quinones, to obtain the naphthalenic core 17
and planned to introduce the required C3 carbonyl at a later
stage as shown in Scheme 2. Thus, the requisite diene 18 and
the quinone 19 were prepared following the literature
protocols7 whose cycloaddition provided the quinone
As can be seen from our retrosynthetic analysis of the
divergolides C (3) and D (4), shown in Scheme 1, discon-
nection of the biomimetic macrolide precursors 7/8 at the
lactam (C100-N) and lactone (C11/12-OH and C500) sites
provides options to assemble the macrolide skeleton. Our
fragment-based approach identified three synthons, namely
aromatic core 10, chiral fragment 11, and 2-methyl-2-pen-
tenedioic acid 12. We initially focused our efforts on synth-
esis of the AB-rings of the tricyclic core of the targets under
(4) For a recent comprehensive review on the biosynthesis of ansa-
mycins, see: Kang, Q.; Shen, Y.; Bai, L. Nat. Prod. Rep. 2012, 29, 243.
(5) (a) Kuttruff, C. A.; Geiger, S.; Cakmak, M.; Mayer, P.; Trauner,
D. Org. Lett. 2012, 14, 1070. (b) Zhao, G.; Wu, J.; Dai, W.-M. Synlett
2012, 23, 2845. (c) Pennington, L. L.; Moody, C. J. Abstracts of Papers,
238th ACS National Meeting, Washington, DC; American Chemical Society:
Washington, DC, 2009.
(6) Rasapalli, S.; Jarugumilli, G.; Yarrapothu, G. R.; Golen, J. A.;
Rheingold, A. L. Tetrahedron Lett. 2013, http://dx.doi.org/10.1016/j.
tetlet.2013.03.022.
(7) (a) Nawrat, C. C.; Lewis, W.; Moody, C. J. J. Org. Chem. 2011,
76, 7872. (b) Kuttruff, C. A.; Geiger, S.; Cakmak, M.; Mayer, P.;
Trauner, D. Org. Lett. 2012, 14, 1070.
Org. Lett., Vol. 15, No. 7, 2013
1737

Scheme 3. Synthesis of Ansa C6ꢀC12 Fragment
20 in decent yield. Quinone 20 was subjected to a series
of transformations involving bromination, reduction,
O-methylation, lithiation, and formylation to obtain the
aldehyde 17 in good overall yield.8
Treatment of the Z-olefin 24 with a catalytic amount of
concentrated HCl in MeOH provided a 1:1 mixture of
anomers 25 whose free secondary hydroxyl group is ideally
placed for orthogonal protection. However, with the inten-
tion of establishing the chemistry required for the elabora-
tion of the ansa bridge onto aromatic core 17, we converted
the secondary hydroxyl group of 25 to benzyl ether 26 under
NaH and BnBr conditions. Compound 26 was in turn
converted to hemiacetal as 1:1 mixture of R and β anomers
whose Wittig olefination with isopropylidenetriphenyl
phosphorane13 (generated in situ from i-C3H7PPh3þBrꢀ
and n-BuLi) gave allylic alcohol 27 in good yield.
With the optically pure allylic alcohol 27 in hand, the
stage was set toascertain the efficacyof Johnson orthoester
rearrangement.14 Pleasingly, refluxing compound 27 at
130 °C for 3 h in triethyl orthoacetate (10 equiv) in the
presence of a catalytic amount of propionic acid provided
ester 28 exclusively as a single diastereomer in quantitative
yield.15 In light of our successful model studies6 for C5ꢀC6
bond formation, it made sense to convert the ester to the
appropriate halide for the eventual conversion into
the organomagnesium derivative of the chiral C6ꢀC12
fragment. Accordingly, ester 28 was reduced with LiAlH4
to give primary alcohol 29, which in turn was converted to
primary iodide 30 under Appel reaction conditions.16
Having accessed both synthons, i.e., 17 and 30, on a
multigram scale, we attempted the formation of organomag-
nesium with the iodide 30, albeit unsuccessfully. After a few
Having obtained the required AB-aromatic core 17 with
pendent aldehyde for further elaboration, we turned our
focus to the synthesis of the chiral fragment 11. At the outset,
we wanted to develop a scalable and cost-effective stereo-
selective route for the (C6ꢀC12) fragment 11 that allows
orthogonal protection of the C11 and C12 hydroxyl groups
while accommodating different substituents at C12.9
Keeping the above criteria and our resources in focus,
the stereochemistry of the target molecules was mapped
via the chiral pool synthesis through the stereoselective
Johnson orthoester variant of the Claisen rearrange-
ment, whose synthetic utility is underlined by its pre-
dictable high diastereoselectivity.10
Our synthetic efforts commenced with the commercially
available D-glucose diacetonide 22 to obtain the fragment
11 with the requisite stereochemistry and functional
groups, as shown in Scheme 3. Thus, D-glucose diacetonide
22 was converted to aldehyde 23 following the literature
procedure.11 Wittig olefination of aldehyde 23 with
n-propylidenetriphenyl phosphorane (generated in situ
from n-C3H7PPh3þBrꢀ and n-BuLi) at ꢀ78 °C gave the
Z-olefin 2412 with good (>95:5 Z/E) stereoselectivity.
(8) For an alternative approach to 17, see: Kuttruff, C. A. Disser-
€
€
tation, Ludwig-Maximilians-Universitat Munchen, 2012, ISBN
9783843906005.
(9) We plan on extending this route to the total synthesis of hygrocins
A and B.
(10) Fernandes, R. A.; Ingle, A. B.; Chaudhari, D. A. Eur. J. Org.
Chem. 2012, 1047.
(13) Tzirakis, M. D.; Alberti, M. N.; Orfanopoulos, M. Org. Lett.
2011, 13, 3364.
(14) (a) Hiersemann, M.; Nubbemeyer, U. The Claisen Rearrange-
ment; Wiley-VCH: Weinheim, 2007. (b) Castro, A. M. Chem. Rev. 2004,
104, 2939. (c) Nubbemeyer, U. Synthesis 2003, 961. (d) Hiersemann, M.;
Abraham, L. Eur. J. Org. Chem. 2002, 1461.
€
€
(11) Schworer, C. J.; Oberthur, M. Eur. J. Org. Chem. 2009, 6129.
(12) (a) Byrne, P. A.; Gilheany, D. G. J. Am. Chem. Soc. 2012, 134,
9225. (b) Tortosa, M. Angew. Chem., Int. Ed. 2011, 50, 3950. (c) Sharma,
G. V. M; Vepachedu, S. R. Tetrahedron 1991, 47, 519. (d) Anderson,
R. C.; Fraser-Reid, B. J. Org. Chem. 1985, 50, 4786.
(15) Fernandes, R. A.; Ingle, A. B.; Chaudhari, D. A. Eur. J. Org.
Chem. 2012, 1047 and references cited therein.
€
(16) Prusov, E.; Rohm, H.; Maier, M. E. Org. Lett. 2006, 8, 1025.
1738
Org. Lett., Vol. 15, No. 7, 2013

Scheme 4. Succesful Elaboration of Ansa Bridge via Coupling of the Advanced Synthons
unsuccessful attempts, we found that t-BuLi was more
effective for lithiation of the iodide 30. Although this lithiated
30 proved successful in coupling with simple electrophiles,17
to our dismay it did not react with aldehyde 17.
with moderate yield (65%, unoptimized) to provide the
alcohol 31b as a mixture of diastereomers. Careful
oxidation of 31b under DMP/pyridine conditions
provided ketone 34 in good yield as a mixture of
atropisomers.20
The C5ꢀC6 disconnection turned outtobe notassimple
asitappeared from our model studies;similarly, Trauneret
al. have also faced problems with this disconnection.4,7 We
reasoned that electronic factors might be operative in
comparison to aldehyde 16 that had been shown earlier
tocouple with 2-ethylhexylmagnesiumbromide.6 Even our
efforts to couple lithiated 30 with aldehyde 16 were of no
avail to form the C5ꢀC6 bond to access 31a, ruling out
electrophilicity or steric issues of the aromatic partner as
reasons for failure.18 We finally resorted to the reversal of
the polarity of the intermediates and planned the coupling
of the two synthons via C4ꢀC5 bond formation.19 This
approach required the homologation of the iodo com-
pound 30 to aldehyde 33. This task was accomplished via
nitrile chemistry under standard conditions with good
yields as shown in Scheme 4.
In summary, we have synthesized the westernsegment of
divergolides C and D (3 and 4). The requisite aromatic
fragments are prepared on large scale via a reliable cy-
cloaddition approach. We have also successfully con-
structed the variously functionalized chiral fragments
with the requisite stereochemistry of the targets, i.e., C8
(R), C9dC10 (E), C11(S), C12(S), via a chiron approach.
Two complementary strategies for the coupling of the
advanced synthons via C4ꢀC5 and C5ꢀC6disconnections
were evaluated, and we established the robustness of the
C4ꢀC5 over C5ꢀC6 as a suitable approach for our further
studies toward completion of the total synthesis of diver-
golides C and D (3 and 4). The chemistry described herein
is also applicable for the synthesis of divergolides A and B
(1 and 2) aswellashygrocins A and B (5 and 6). Our studies
in this direction will be reported in due course.
Gratifyingly, the coupling reaction of the lithiated
naphthalenic core 21 with aliphatic aldehyde 33 proceeded
Acknowledgment. This work was supported through
the startup and Healey Foundation funds of UMass Dart-
mouth and partly from Microbiotix, Inc, Worcester.
(17) Lithiated 30 reacted succesfully with an amide derived from
3- methylsalicylic acid: Rasapalli, S.; Jarugumilli, G.; Yarrapothu, G. R.
Unpublished results.
(18) We are currently exploring the different options for utilizing 16/
17 in total synthesis of divergolides AꢀD.
Supporting Information Available. Complete experi-
mental procedures, including 1H and 13C spectra of all new
compounds. X-ray data (CIF) for 17. This material is
availablefreeofchargevia the Internet at http://pubs.acs.org.
(19) (a) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc.
1990, 112, 6348.
(20) (a) Eliel, E. Basic Organic Stereochemistry; Wiley: New York,
2001. (b) Dinh, P. M.; Howarty, J. A.; Hudnott, A. R.; Williams, J. M. J.;
Harris, W. Tetrahedron Lett. 1996, 37, 7623. (b) Roush, W. R.; Coffey,
D. S.; Madar, D. J. J. Am. Chem. Soc. 1997, 119, 11331. (c) Roush,
W. R.; Coffey, D. S. J. Org. Chem. 1996, 60, 4412.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
1739