Chemoenzymatic routes to polyoxygenated cyclooctenones related to the eastern hemisphere of the macrolactam tripartilactam

Article abstract of DOI:10.1002/asia.201301233

Polyoxygenated cyclooctenones closely related to the enantiomeric form of the Eastern hemisphere of the structurally and biogenetically unusual macrolactam tripartilactam have been assembled from an enzymatically-derived and homochiral cis-1,2-dihydrocatechol. Key steps include the oxidative cleavage of the chlorinated double bond within a derivative of the starting cis-1,2-dihydrocatechol and a ring-closing metathesis reaction to establish the required eight-membered ring. Copyright

Full text of DOI:10.1002/asia.201301233

COMMUNICATION
DOI: 10.1002/asia.201301233
Chemoenzymatic Routes to Polyoxygenated Cyclooctenones Related to the
Eastern Hemisphere of the Macrolactam Tripartilactam
Yen Vo, Martin G. Banwell,* and Anthony C. Willis[a]
Abstract: Polyoxygenated cyclooctenones closely related to
the enantiomeric form of the Eastern hemisphere of the
structurally and biogenetically unusual macrolactam triparti-
lactam have been assembled from an enzymatically-derived
and homochiral cis-1,2-dihydrocatechol. Key steps include
the oxidative cleavage of the chlorinated double bond
within a derivative of the starting cis-1,2-dihydrocatechol
and a ring-closing metathesis reaction to establish the re-
quired eight-membered ring.
In 2012 Oh and co-workers reported the isolation of the
tricyclic macrolactam tripartilactam (1) from a Streptomyces
sp. found in the brood ball of the dung beetle Copris tripar-
titus.[1] The structure of this architecturally novel compound,
which incorporates a cyclobutane fused, on its opposing
faces, to both an 8- and an 18-membered ring, was estab-
lished using a combination of spectroscopic techniques, most
notably various 2D NMR spectroscopic methods. Mosher
ester analyses were used to determine the absolute configu-
ration of the stereogenic centers associated with the Eastern
hemisphere while that of the remote methyl-bearing carbon
C24 (located in the Western hemisphere) was identified
through degradation and chemical correlation studies. Al-
though the compound showed no significant antimicrobial
or anticancer properties, it proved to be a moderate inhibi-
tor of Na+/K+ ATPase (IC50 of 16.6 mgmLꢀ1). Intriguingly, it
has been suggested[1] that the macrocyclic and polyunsatura-
ted lactam 2, a thus far undetected species in nature, engag-
es in a transannular [2+2]-photocycloaddition reaction as
the final step in the biogenesis of tripartilactam (1). Some
support for such a proposal follows from earlier observa-
tions[2] that the structurally related macrolactam sceliphro-
lactam (3), of undefined stereochemistry at the associated
sp3-hybridized carbons, has been isolated from another
insect-associated Streptomyces sp.
The unique structural features and seemingly unusual bio-
synthetic origins of natural product 1 have prompted us to
pursue its total synthesis. Two distinct approaches to the
challenging[3] polyoxygenated cyclooctane substructure that
represents the characteristic Eastern hemisphere of triparti-
lactam have now been explored and the outcomes of the rel-
evant studies are reported herein. Each of these approaches
exploited the enzymatically-derived and enantiomerically
pure cis-1,2-dihydrocatechol 4[4] as starting material and
while the reaction sequences used ultimately lead to the op-
tical antipodes of the relevant
substructures, the availability of
compound ent-4[5] means that
the natural enantiomeric forms
of these systems are accessible
by exactly the same means.
In the first approach it was envisaged that an intramolecu-
lar [2+2]-cycloaddition reaction between a terminal allene
and a suitably tethered and carbonyl-conjugated alkene
could deliver an adduct incorporating the target substruc-
ture[6] and wherein the associated cyclobutane ring had been
assembled in near a biomimetic fashion, namely through for-
ꢀ
ꢀ
mation of the C8 C17 and C9 C16 bonds (tripartilactam
numbering). Syntheses of substrates suitable for testing this
strategy are shown in Scheme 1 and began with the treat-
ment of metabolite 4 with N-bromosuccinimide in aqueous
THF. Conversion of the resulting bromotriol into the corre-
sponding acetonide 5 (78% from 4)[7] was achieved using
2,2-dimethoxypropane (2,2-DMP) in the presence of p-tol-
uenesulfonic acid (p-TsOH). Reaction of compound 5 with
[a] Y. Vo, Prof. M. G. Banwell, Dr. A. C. Willis
Research School of Chemistry
Institute of Advanced Studies
The Australian National University
Canberra ACT 0200 (Australia)
E-mail: Martin.Banwell@anu.edu.au
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201301233.
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Martin G. Banwell et al.
Scheme 1. Synthesis of the allenes 18 and 20. a) NBS, 4:1 v/v THF/water, 0–188C, 4 h; b) 2,2-DMP, p-TsOH, 188C, 2 h, 78%, 2 steps; c) NaH, THF, 08C,
1 h, 86%; d) DIBAl-H, Et2O, ꢀ78 to 08C, 2 h, 90%; e) TBS-Cl, imidazole, DMF, 188C, 2 h, 98%; f) O3, pyridine, 4:1 v/v CH2Cl2/MeOH, ꢀ788C, 0.5 h
then Ph3P, 18 8C, 1 h, 86%; g) ethynylmagnesium bromide, Et2O, ꢀ78 to ꢀ158C, 1 h, 95% of a ca. 1.4:1 mixture of 10 and 11; h) 2-(4-methoxy-
benzyloxy)-4-methylquinoline, (+)-camphor-10-sulfonic acid (cat.), CH2Cl2, 408C, 16 h, 90% (for 12) and 83% (for 13); i) paraformaldehyde, CuI,
iPr2NH, dioxane, 1008C, 24 h, 78% (for 14) and 86% (for 15); j) HCl·HN
k) H2C=CHMgBr, Et2O, ꢀ788C, 1 h, 21% (for 18), 57% (for 19), 71% (for 20) and 14% (for 21).
G
sodium hydride in THF then afforded the previously report-
ed epoxide 6 (86%).[7] Regioselective reductive cleavage of
compound 6 through hydride addition to the allylic carbon
of the epoxide ring could be achieved using DIBAl-H, thus
providing the crystalline homoallylic alcohol 7 (90%).[8]
Ozonolysis of the readily derived TBS-ether 8 (98%) of
compound 7 in the presence of methanol followed by reduc-
tive work-up using triphenylphosphine afforded the w-oxo-
ester 9[8] (86%) that reacted with ethynylmagnesium bro-
mide at ꢀ788C to give a 1.4:1 mixture of the epimeric and
chromatographically separable propargylic alcohols 10 and
11 (95% combined yield). Independent treatment of each of
these compounds with 2-(4-methoxybenzyloxy)-4-methyl-
quinoline[9] in the presence of catalytic quantities of
(+)-camphor-10-sulfonic acid then afforded the correspond-
ing p-methoxybenzyl (PMB) ethers 12 (90%) and 13
(83%), respectively. Subjection of each of these products to
the Searles–Crabbꢁ allene-forming protocol[6b,10] using para-
formaldehyde in the presence of cuprous iodide and diiso-
propylamine then gave the anticipated compounds 14
(78%) and 15 (86%), respectively. When treated with N,O-
dimethylhydroxylamine hydrochloride in the presence of
isopropylmagnesium bromide, the allenic esters 14 and 15
gave the corresponding and crystalline Weinreb amides 16
(86%) and 17 (77%), respectively.[8] Reaction of the former
amide with vinylmagnesium bromide at ꢀ788C afforded the
targeted enone 18 (21%), but the major product of the reac-
tion was the adduct of this with N,O-dimethylhydroxyla-
mine, namely the b-aminoketone 19, which was obtained in
57% yield. When the epimeric amide 17 was reacted under
the same conditions, but using a modified work-up, the de-
sired vinyl ketone 20 (71%) was obtained as the major
product, although it was accompanied by the related amino-
ketone 21 (14%).[11]
While compounds 18 and 20 bear some resemblance to
the Eastern hemisphere of the putative biogenetic precursor
2 of tripartilactam (1), neither could be engaged in the
hoped-for intramolecular [2+2]-cycloaddition reaction[6] so
as to assemble bicycloACTHNUTRGNEUGN[6.2.0]decane substructures associated
with the title natural product. Various reaction conditions
were explored including those involving thermolysis, photo-
lysis, and metal ions but all to no avail. Despite such out-
comes, the reaction sequence defined above provides ready
ꢀ
access to scaffolds strongly resembling the C8 C18 segment
of compound 2 and in principle, therefore, is capable of
being elaborated to this putative biogenetic precursor to tri-
partilactam (1). Of necessity, any such elaboration will re-
quire, among other things, the stereoselective elimination of
ꢀ
the elements of PMBOH across the C14 C15 positions of
these fragments.
In light of the lack of participation of compounds 18 and
20 in the desired [2+2]-cycloaddition process, alternate
routes to polyoxygenated cyclooctanones resembling the
Eastern hemisphere of the target natural product 1 were
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Martin G. Banwell et al.
Scheme 2. Synthesis of the cyclooctanes 25–33. a) Ph3P=CH2, THF, 0 to 188C, 2 h, 76%; b) HCl·HN
G
magnesium bromide, THF, ꢀ788C, 1 h; d) Grubbsꢂ II (cat.), CH2Cl2, 408C, 2 h, 78%, 2 steps; e) DMDO, CH2Cl2, 0–188C, 16 h, 75%; f) DBU, CH2Cl2,
188C, 6 h, 91%; g) cinnamoyl chloride, DMAP, pyridine, CH2Cl2, 408C, 48 h, 19% (for 28) and 68% (for 29); h) Ac2O, DMAP, pyridine, 408C, 24 h,
85%, two steps; i) phenyl thionochloroformate, DMAP, pyridine, CH2Cl2, 408C, 48 h, 35%, two steps; j) CH2Cl2, Et3N, microwave irradiation, 1008C,
4 h, 87%; k) LiOH, 2:1 v/v MeOH/water, 188C, 2 h, 90%.
pursued. An ultimately successful route to such motifs is
shown in Scheme 2. This employs, as the pivotal step, a ring-
closing metathesis (RCM) reaction[12] to assemble the re-
quired eight-membered ring, thus allowing for the possibility
of introducing the four-membered ring associated with
target 1 through a [2+2]-cycloaddition process that is com-
plementary to the one pursued above (and proposed in the
biogenetic conversion 2!1). Specifically, then, the w-oxo-
ester 9 (readily obtained from compound 4 in six steps as
shown Scheme 1) was subjected to a Wittig olefination reac-
tion, and the resulting unsaturated ester 22 (76%) was then
converted into the corresponding Weinreb amide 23 (92%)
under standard conditions. Reaction of the latter compound
with allylmagnesium bromide afforded the rather sensitive
b,g-unsaturated ketone 24,[13] but under carefully controlled
conditions 24 could be engaged in a RCM reaction when
treated with Grubbsꢂ second-generation catalyst,[14] thereby
affording the expected cyclooctenone 25[8] in 78% yield
(from 23).[15] For the purposes of introducing additional
functionality into the newly formed eight-membered ring,
the alkene was treated with dimethyldioxirane (DMDO),[16]
thus providing, in a completely stereoselective manner, the
epoxide 26[8] (75%). Treatment of compound 26 with 1,8-
(N,N-dimethylamino)pyridine (DMAP) gave a chromato-
graphically separable mixture of acetal 28 (19%) and enone
29[8] (68%) while analogous acetylation of compound 27
(using acetic anhydride and DMAP) only gave the corre-
sponding enone 30[8] (85%). Similarly, treatment of com-
pound 27 with phenyl thionochloroformate[17] afforded the
anticipated thiocarbonate 31, albeit in just 35% yield (over
the two steps from epoxide 26). Two further and potentially
significant reactions of the b,g-unsaturated enone 25 were
its ready methylenation, upon microwave irradiation in the
presence of dichloromethane and triethylamine,[18] to give
the dienone 32 (87%) and its epimerization to the corre-
sponding trans-ring-fused isomer 33[8] (90%) on exposure to
LiOH in THF/water.
Efforts are now underway to elaborate compounds such
as 25–32, each of which embodies the polyoxygenated cyclo-
octane-containing Eastern hemisphere of ent-tripartilactam
(ent-1), into more advanced precursors to this target. Results
will be reported in due course.
Acknowledgements
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU) resulted in a fully re-
We thank the Australian Research Council and the Institute of Advanced
Studies for generous financial support.
giocontrolled cleavage of the epoxide ring and the forma-
tion of the g-hydroxy-a,b-unsaturated-enone 27a that exists
almost exclusively (as judged by analysis of the derived
spectral data) in the lactol form 27b (91%). Reaction of
this material with cinnamoyl chloride in the presence of 4-
Keywords: cis-1,2-dihydrocatechol · cyclooctenone · enzyme
catalysis · metathesis · tripartilactam
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Martin G. Banwell et al.
CCDC 956514 (9), CCDC 956515 (16), CCDC 956516 (17),
CCDC 956517 (25), CCDC 956518 (26), CCDC 956519 (29),
CCDC 956520 (30), and CCDC 956521 (33) contain the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif. Selected data and
ORTEPS are provided in the Supporting Information.
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Received: September 10, 2013
Published online: November 4, 2013
[8] The structures of compounds 7, 9, 16, 17, 25, 26, 29, 30, and 33 were
confirmed by single-crystal X-ray analysis. CCDC 956513 (7),
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