Total Synthesis of Oridamycins A and B

Article abstract of DOI:10.1021/acs.orglett.5b01629

(Chemical Equation Presented) The total synthesis of both oridamycin A and oridamycin B was accomplished starting from a common synthetic intermediate readily prepared from geranyl acetate. The sequence utilizes an oxidative radical cyclization to construct the trans-decalin ring system, setting three of four contiguous stereocenters in one operation. The carbazole nucleus was forged through a one-pot process entailing acid-promoted dehydration followed by 6π-electrocyclization/aromatization.

Full text of DOI:10.1021/acs.orglett.5b01629

Letter
pubs.acs.org/OrgLett
Total Synthesis of Oridamycins A and B
Adam H. Trotta*
Tri-Institutional PhD Program in Chemical Biology, Laboratory for Bioorganic Chemistry, Memorial Sloan Kettering Cancer Center,
Sloan Kettering Institute, 1275 York Avenue, New York, New York 10065, United States
S
* Supporting Information
ABSTRACT: The total synthesis of both oridamycin A and oridamycin B was accomplished starting from a common synthetic
intermediate readily prepared from geranyl acetate. The sequence utilizes an oxidative radical cyclization to construct the trans-
decalin ring system, setting three of four contiguous stereocenters in one operation. The carbazole nucleus was forged through a
one-pot process entailing acid-promoted dehydration followed by 6π-electrocyclization/aromatization.
he xiamycin family of indolosesquiterpenes comprises
bioactive compounds recently isolated from several strains
Baran and co-workers, employing a cationic cyclization to
construct the monomer and a novel electrochemical dimeriza-
tion to generate the N−N linkage.3 Elegant syntheses of
xiamycin A (3), indosespene (4), sespenine, oridamycin A (1),
oridamycin B (2), and dixiamycin C have been reported by the
Li group, utilizing powerful radical cascades to construct the
trans-decalin ring systems.4
T
of Streptomyces.1 Among the family members are xiamycin A
(3), its biosynthetic precursor indosespene (4), and the
homodimers dixiamycin A/B (5), isolated as a mixture of
atropisomers about the N−N linkage (Figure 1). These
Structurally, these pentacyclic molecules possess a carbazole
nucleus fused to a trans-decalin ring system containing four
contiguous stereocenters, including two quaternary centers.
The major difference between the family members manifests at
the C16 quaternary center; oridamycin A (1) and oridamycin B
(2) each bear an axial carboxylic acid and an equatorial methyl/
hydroxymethyl, while xiamycin A (3), indosespene (4), and
dixiamycin A/B (5) contain an axially disposed methyl and an
equatorial acid (Figure 1). Biosynthetically, it is known that
xiamycin A (3) arises from precursor 6 through a selective
enzymatic oxidation mediated by XiaM (Figure 2A).5 It seems
plausible that intermediate 6 is also the biosynthetic precursor
of the oridamycins, likely proceeding through an analogous
methyl oxidation. Drawing inspiration from nature, we
anticipated utilizing a common synthetic intermediate to access
congeners from both the oridamycin and xiamycin families
(Figure 2B). Anticipating that biomimetic methyl oxidation of
intermediate 6 would be difficult to replicate in the flask, we
envisioned imparting the requisite oxidation pattern on a linear
precursor that would be cyclized under two distinct sets of
conditions to yield both of the desired C16 epimers. Employing
an oxidative radical cyclization cascade under standard
conditions would yield the stereochemistry associated with
the oridamycins, proceeding through transition state 10 to
produce intermediate 8 (Figure 2C).6 To access the C16
stereoisomer relevant to the xiamycin family, we envisioned
that introduction of a Lewis acid could invert the selectivity via
Figure 1. Selected members of the oridamycin and xiamycin families.
compounds display a range of interesting activities, including
antiviral and antibacterial properties.1 Notably, the N-linked
dimers dixiamycin A/B (5) are potent agents against both
methicillin resistant Staphylococcus aureus 134/94 and vanco-
mycin resistant Enterococcus faecalis 1528 R10.1e The closely
related monomers oridamycin A (1) and oridamycin B (2)
were isolated from Streptomyces sp. KS84 during screening for
activity against Saprolegnia spp., a water mold that infects
freshwater fish, including those raised in commercial aqua-
culture.2 These compounds have elicited significant interest
within the synthetic community; efficient total syntheses of
xiamycin A (3) and dixiamycin B (5) have been reported by
Received: June 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01629
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Letter
natural products. Finally, the trans-decalin ring system of 14
would be forged through an oxidative radical cyclization of a
linear precursor readily derived from geranyl acetate.10
Oridamycin A (1) would be synthesized in an analogous
fashion without requiring the C−H oxidation sequence.
In the forward direction, known compound 16 was readily
obtained from geranyl acetate in multigram quantities in three
operations (Scheme 2).10 Oxidative radical cyclization
proceeded smoothly under the standard conditions to give
alcohol 14 as a single diastereomer.11 Subsequent oxidation
with Dess-Martin periodinane afforded the corresponding
aldehyde, which was coupled with the Grignard reagent
generated from 17 to produce 13 as an inconsequential
mixture of diastereomers.9,12 Next, when considering the
dehydration of intermediate 13, we hypothesized that the
alcohol would be more prone to elimination if the Boc group
were removed, allowing for the electron-rich indole to more
readily participate in the process. To that end, substrate 13 was
treated with TFA, and to our surprise, the secondary alcohol
was cleanly eliminated to form a triene intermediate with the
Boc group still intact. Thus, this interesting result became the
foundation of a one-pot process to forge the free carbazole
directly from intermediate 13. In the event, treatment of a
solution of 13 in CH2Cl2 with TFA formed the desired triene,
which was not isolated but concentrated to remove solvent and
acid. Next, this material was dissolved in toluene and heated to
135 °C to induce a thermal 6π-electrocyclization/aromatization
sequence under aerobic conditions.9 Upon completion, TFA
was added at 45 °C to remove the Boc group, yielding free
carbazole 18. A stereoselective reduction using NaBH4
proceeded uneventfully, yielding oridamycin A methyl ester
(d.r. > 20:1). The final remaining operation entailed conversion
of the C16 axial methyl ester into the free acid. Initial attempts
at saponification using various hydroxide sources were
unproductive, likely due to the 1,3-diaxial relationship between
the C12 methyl and the C16 esterreminiscent of podocarpic
acid13which may impede formation of the requisite
tetrahedral intermediate.14 Accordingly, we utilized a nucleo-
philic cleavage protocol, allowing for successful dealkylation of
the ester. Thus, upon treatment with NaCN in DMSO at
elevated temperature, oridamycin A (1) was produced in 86%
yield, cleanly affording characterization quality material.15
To access oridamycin B (2), the route to oridamycin A (1)
was diverted from intermediate 13. The same sequence of
dehydration and electrocyclization was employed, but the Boc
group was preserved to produce the protected carbazole. The
ketone was smoothly converted into O-methyloxime derivative
12 as a prerequisite for the selective, late-stage C−H oxidation.
Upon treatment with PhI(OAc)2 and catalytic Pd(OAc)2 at
elevated temperature, compound 19 was cleanly produced in
69% yield. Next, global deprotection using a 3:1 mixture of aq 1
M HCl/acetone at 80 °C cleaved the acetate, removed the Boc
group, and hydrolyzed the O-methyloxime. A variety of
conditions were screened for this transformation, most of
which produced a significant amount of a presumed retro-Aldol
product, which was largely suppressed through the use of
acetone as a cosolvent. However, the elevated temperature
required to cleave the O-methyloxime appeared to cause a
significant amount of nonspecific decomposition, resulting in
diminished recovery. The product of the global deprotection
was unstable to silica, requiring reduction of the crude material
to produce oridamycin B methyl ester. Finally, treatment of this
compound with NaCN produced oridamycin B (2). Interest-
Figure 2. (A) Biosynthetic precursor for the xiamycin family, and
proposed precursor for the oridamycin family. (B) General strategy to
access both the xiamycin and oridamycin families from a common
linear precursor. (C) Proposed radical transition states for the
cyclization reactions.
chelation of the β-keto ester, producing transition state 11 en
route to intermediate 9.7
We reasoned that it would be expeditious to initiate our
synthetic efforts with the oridamycins, allowing for validation of
late-stage transformations before attempting to invert the
selectivity of the radical cyclization. Retrosynthetically, we
anticipated that the C16 hydroxymethyl of oridamycin B (2)
could arise from an oxime-directed, palladium-catalyzed C−H
oxidation of substrate 12 (Scheme 1).8 The C15 alcohol would
Scheme 1. Retrosynthesis of Oridamycin B
arise via axial hydride delivery onto a suitable ketone precursor.
The carbazole nucleus could be forged through 6π-electro-
cyclization/aromatization of an indole moiety appended to a
diene system, which would itself arise from dehydration of a
homoallylic alcohol such as 13.9 Grignard addition of a Boc-
protected indole onto a suitable aldehyde would provide
compound 13, containing all the requisite carbon atoms of the
B
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Scheme 2. Synthesis of Oridamycin A and B
1
ingly, it was found that the H NMR spectrum of 2 was pH
ACKNOWLEDGMENTS
■
dependent (see Supporting Information).
Prof. Samuel J. Danishefsky (MSKCC) is foremost acknowl-
edged for his intellectual mentorship. This material is based
upon work supported by the National Science Foundation
Graduate Research Fellowship under Grant No. 2014157713.
The MSKCC core facility is also acknowledged for mass
spectrometric assistance and for providing the necessary
instrumentation.
With the successful synthesis of the oridamycins, the next
phase of our program is aimed at accessing epimeric
intermediate 9 via Lewis acid chelation of the radical
intermediate during cyclization (see Figure 2).7 Realization of
this strategy could provide access to the xiamycin family from
the same linear precursor 7 used to generate the oridamycins.
Furthermore, we are optimistic that this transformation could
be rendered asymmetric through the use of a suitable chiral
ligand.16 Efforts are ongoing in our laboratory to validate these
assertions.
In conclusion, both oridamycin A and B were synthesized
from known compound 16 in six and nine steps, respectively.
The synthesis was diverted from common intermediate 13
harboring all of the carbon atoms contained within each natural
product. The successful construction of the oridamycins lays
the foundation for a unified synthetic strategy for this entire
class of indolosesquiterpenes.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data (including
spectra for new compounds). The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01629.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ahtrotta@gmail.com.
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