Total synthesis of TK-57-164A, isariotin F, and their putative progenitor isariotin e

Article abstract of DOI:10.1002/anie.200904716

[Chemical equation presented]

Full text of DOI:10.1002/anie.200904716

Angewandte
Chemie
DOI: 10.1002/anie.200904716
Biomimetic Synthesis
Total Synthesis of TK-57-164A, Isariotin F, and Their Putative
Progenitor Isariotin E**
Jacob Y. Cha, Yaodong Huang, and Thomas R. R. Pettus*
Cyclohexenone monoepoxides enjoy widespread attention
because of their useful properties and structural complexity.[1]
In a search for bioactive secondary metabolites of entomo-
pathic fungi-afflicting insects, Bunyapaiboonsri et al. reported
isolating two novel compounds, isariotin E (3) and F (2) along
with the known bicycle TK-57-164A (1), a compound
previously described as an agricultural bactericide.[2, 3] Isar-
iotin F (2) exhibited activity against the malaria parasite
Plasmodium falciparum K1, three cancer cell lines (KB, BC,
NCI-H187), and nonmalignant (Vero) cells (IC50 = 5.1, 15.8,
2.4, 1.6, and 2.9 mm, respectively). Furthermore Bunyapai-
boonsri et al. speculated that isariotin E (3) might serve as the
biosynthetic progenitor of 1 and 2 (Scheme 1). However, the
paucity of compound 3 thwarted investigation of its specu-
lated biosynthetic pathway as well as biological evaluation.
Natural products 1–3 contain a diverse array of congested
and reactive functionality. Seven contiguous stereocenters are
embedded within the [3.3.1]-bicyclic framework of 1;
expressed functionality includes both secondary and tertiary
alcohols, an epoxide, a methyl ether, a hydrophobic amide,
and a bridging carbonyl group. A trans-decalin-like system
possessing an ethereal ring union describes the skeleton of 2.
The periphery features five stereogenic centers; a stereo-
defined hemiketal derived from a secondary alcohol, an
allylic chloride/enone moiety, and the same tertiary alcohol
and amide functionalities found in 1. Similarly, five stereo-
centers comprise the backbone of the spirocycle 3. It includes
Scheme 1. Metabolites from Isaria tenuipes BCC 12625 and our syn-
thetic plan.
the same tertiary alcohol, epoxide, and amide functionalities
found in 1, but also a highly electrophilic enone and a
hemiketal consisting of a tertiary alcohol. Given these
structural attributes coupled to the putative biosynthesis
and biological activity of these compounds, we felt that all
three natural products warranted our attention. Herein, we
detail our strategy for the total synthesis of isariotin E (3),
isariotin F (2), and TK-57-164A (1).
Benefiting from Bunyapaiboonsriꢀs insight,[2] we sus-
pected that the [3.3.1]-bicyclic nonane core found in com-
pound 1 might arise via the intermediacy of an enol formed by
the diastereoselective conjugate addition of methoxide to
compound 3 (Scheme 1). An observation of a similar epoxide
directed conjugate addition reported by Ogita and co-workers
for scyphostatin supported this notion.[4] However, the out-
come of this reaction was far from assured given the report
from Nishiyama and co-workers on an indiscriminate
Michael/aldol cascade affording gymnastatin F.[5] The ethe-
real trans-decalin skeleton of 2 was imagined to be derived
from a chloride triggered epoxide-opening event with 3,
which would generate a free secondary alcohol which could
serve as the new center for hemiketalization to afford the
bicycle 2. We speculated that the core of the spirocycle 3 could
arise from a related dissymmetric 2,5-cyclohexadienone, 4,
provided that the necessary series of chemoselective and
diastereoselective reactions could be developed to success-
fully transform its conjoined enone and vinylogous ester
[*] J. Y. Cha, Y. Huang, Prof. T. R. R. Pettus
Department of Chemistry and Biochemistry, University of California
Santa Barbara, Santa Barbara, CA 93106-9510 (USA)
Fax: (+1)805-893-5690
E-mail: pettus@chem.ucsb.edu
[**] T.R.R.P. is grateful for financial support from National Institute of
General Medical Sciences (64831-06) for this work and related
studies on scyphostatin. We thank Taridorn Buajarern for providing
1H and 13C NMR spectral data for 1, 2, and 3 in [D6]acetone for
comparative purposes. We appreciate Dr. Arkady Krasovskiy for his
insightful ideas regarding epoxide opening with lanthanide halides.
This project has also benefited from earlier studies of R. W.
Van De Water and C. Hoarau within our group.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904716.
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9519

Communications
functional groups. The dissymmetric spirolactone 4 was
manner, reminiscent of a reaction developed by Wardrop
et al. for the production of spiroamides from nitrenes.[10] To
our delight, sequential exposure of the acid 5 to hypervalent
iodine and DBN provided the spirocyclic lactone 4 as the
major diastereomer (61% overall yield, > 12:1 d.r.); this
outcome was confirmed by nOe examination of the chroma-
tographically separable isomers.[11]
To capitalize upon the directing effect of the tertiary
alcohol,[12] we next exposed the dienone 4 to pyrrolidine.
Without purification, the corresponding enone-amide partici-
pated in sequential nucleophilic epoxidation (tert-butyl
hydroperoxide, DBN) and afforded a syn-epoxide (62%
yield, single diastereomer, see the Supporting Information).
Relactonization proceeded upon the addition of acetic acid
and furnished the spirolactone 13 (92% yield).
Having successfully established four of the stereocenters,
we imagined that stereoselective reduction of the carbonyl
residues and rearrangement should complete the synthesis of
isariotin E (3) from the vinylogous ester 13. The necessary
diastereocontrol required to prevent an undesired Payne
rearrangement required a two-step reduction protocol. The
vinylogous ester 13 undergoes reduction with sodium boro-
hydride to afford the corresponding syn-epoxy alcohol, which
underwent additional reduction as a crude reaction mixture
using Dibal-H to arrive at a hemiketal; a compound that we
have tentatively assigned as the lactol 14 (56% overall yield,
one diastereomer). Treatment of this allylic alcohol function-
ality with trichloroacetic acid (1:10 H2O/CH2Cl2) resulted in
isariotin E (3) in 74% yield. The NMR data for the synthetic
compound 3 matched those of isariotin E in every respect,
concluding the first total synthesis for 3.
envisioned to serve as a key platform, whose fixed geometry
might enable smooth exchange of amine functionality. It
could arise from an ipso dearomatization of the unnatural
amino acid 5, a resorcinol surrogate of tyrosine, which we
suspected could be procured through a Horner–Wadsworth–
Emmons olefination with the commercially available benzal-
dehyde 6, and subsequent reduction. With regards to the
selection of the starting amine protecting group (R’), our
decision to capitalize upon the amino acid construction
method of Schmidt et al.,[6] and the customary questions of
functional group compatibility constrained our choices to
carbamates.
Our route therefore began with O-Boc protection of the
commercially available phenol 6 (Scheme 2). We found that
in the presence of 1,1,3,3-tetramethyl guanidine (TMG), the
differentially protected benzaldehyde 7 can be elaborated
with N-Boc-protected phosphonate 8,[7] prepared using the
protocol of Schmidt et al., to afford the vinyl carbamate 9
(78% yield, E/Z 1:9, > 10 g scale). For our purposes, both of
these olefinic isomers proceeded to compound 10 upon
hydrogenation (Pd/C, H2), and therefore improvement of this
ratio necessitated no further attention. Global removal of
-NBoc and -OBoc residues in compound 10 (5:1 CH2Cl2/
TFA) afforded the corresponding ammonium salt, which
subsequently underwent selective amide bond formation with
the acid 11 to produce the amide 12 (82% yield). Additional
hydrolysis of the methyl ester 12 with lithium hydroxide
afforded compound 5 (88% yield). With the desired monop-
rotected resorcinol tyrosine analogue in hand, we were poised
to test the oxidative dearomatization of the dissymmetric
resorcinol.[8,9] We hoped that the methoxy and amine residues
would emerge being positioned on opposite sides of the
With ample quantities of the hemiketal 3 in hand, we were
positioned to test the putative skeletal rearrangements
(Scheme 3). Initially, we suspected that both isariotin F (2)
conjoined spirocyclic molecule in
a diastereoselective
Scheme 2. Synthesis of isariotin E (3). Reagents and conditions: a) Boc2O (1.5 equiv), NEt3 (3.0 equiv), DMAP (0.1 equiv), CH2Cl2, RT, 12 h,
>95%; b) 7 (1.3 equiv), TMG (1.5 equiv), THF, RT, 18 h, 78%; c) Pd/C (0.04 equiv), H2, EtOAc/MeOH (1:1), RT, 12 h, >95%; d) TFA/CH2Cl2
(1:5), RT, 24 h, concentrate; then 13 (1.3 equiv), EDCI (1.3 equiv), NEt3 (5.0 equiv), DMF, RT, 16 h, 82%; e) LiOH·H2O (3.0 equiv), THF/MeOH/
H2O (1:1:1), RT, 20 h, 88%; f) PhI(OAc)2 (1.5 equiv), TFA (2.3 equiv), CH2Cl2, 08C!RT, 3 h; g) DBN (0.5 equiv), CH2Cl2, RT, 2 h, 61% over two
steps, >12:1 d.r.; h) pyrrolidine (1.5 equiv), CH2Cl2, RT, 14 h, concentrate; then tBuOOH (10 equiv), DBN (10 equiv), CH2Cl2, RT, 6 h, 62%;
i) AcOH (5 equiv), CH2Cl2, reflux, 8 h, 92%; j) NaBH4 (3.0 equiv), THF/H2O (10:1), 08C, 30 min; k) Dibal-H (4.5 equiv), CH2Cl2, ꢀ788C, 10 min,
56% over 2 steps; l) Cl3CCO2H (11 equiv), CH2Cl2/H2O (10:1), RT, 6 h, 74%. Boc=tert-butoxycarbonyl, DMAP=4-dimethylaminopyridine,
TMG=1,1,3,3,-tetramethylguanidine, THF=tetrahydrofuran, TFA=trifluoroacetic acid, EDCI=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride, DMF=N,N-dimethylformamide, DBN=1,5-diazabicyclo[4.3.0]non-5-ene, Dibal-H=diisobutylaluminum hydride.
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Angewandte
Chemie
Keywords: biomimetic synthesis · cyclization · dearomatization ·
.
resorcinol · total synthesis
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and TK-57-164A (1) were artifacts from the isolation of 3.
However, we were unable to cause isariotin E (3) to convert
into either 1 or 2 using prior isolation conditions (CaCl2,
MeOH, 2 days). We were therefore extremely gratified to find
that exposure of isariotin E (3) to a freshly prepared solution
of NaOMe in MeOH provided the formidable [3.3.1]-bicyclic
framework of TK-57-164A (1) in nearly quantitative yield and
perfect diastereoselective control (> 95% yield, single dia-
stereomer). Alternatively, we found that treatment of isar-
iotin E (3) with cerium(III) chloride heptahydrate in aceto-
nitirile for 16 hours led to what we believe, from preliminary
1H NMR analysis, to be the chloride 2 along with an aldehyde,
and epimeric or isomeric lactols. However, upon standing and
solidfying over four days, this complex mixture smoothly
converged into isariotin F (2) in good yield (86% from 3).
NMR data for synthetic 1 and 2 matched those of natural 1
and 2 in every respect.
In summary, we successfully traversed the gauntlet of
reactive functional groups presented by these molecules to
complete the first total synthesis of isariotin E (3, 12 steps,
7.8% overall yield), isariotin F (2, 13 steps, 6.7% overall
yield), and TK-57-164A (1, 13 steps, 7.7% overall yield). The
chemistry developed for manipulating dissymmetric cyclo-
hexadienones offers new potential for synthesizing other
family members and analogues in a fairly rapid manner,
possibly resulting in new compounds with greater selectivity
and enhanced potency. The reported syntheses prove efficient
because of their protecting group and redox economy, a
natural consequence of following biological pathways.[13]
Furthermore, the unusual conditions required for the last
two transformations suggest that compounds 1 and 2 may
indeed be natural products supporting Bunyapaiboonsriꢀs
original biosynthetic postulate. These three total syntheses
also substantiate our confidence in the unique synthetic
opportunities available to disymmetric cyclohexadienones
displaying conjoined enone and vinylogous ester components
and their potential for complex molecule synthesis.[14] We
speculate that similar synthetic potential is not achievable for
cyclohexadienone derivatives derived from o-tyrosine
because of a propensity for dimerization.
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[7] Commercially available, but for large scale preparation, see:
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[9] While superficially related to prior tyrosine dearomatizations
that yield symmetric spirocyclic cyclohexadienone lactones
demonstrated by P. Wipf, we are aware of only one other prior
diastereoselective dearomatization yielding
a dissymmetric
spirocyclic cyclohexadienone lactone, see: G. Plourde, R.
Spaetzel, J. S. Kwasnitza, T. W. Scully, Molecules 2007, 12,
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[10] a) D. J. Wardrop, M. S. Burge, W. Zhang, J. A. Ortiz, Tetrahedron
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Chem. 2005, 70, 10271 – 10284.
[11] The initial dearomatization affords a separable 1.35:1.00 ratio of
diastereomers which epimerizes to 12:1 upon addition of DBN.
A full account of dearomatization and epimerization studies will
be reported in due course.
[12] For a nice review of symmetric dienone reactivity see: a) P. Wipf,
J.-K. Jung, Chem. Rev. 1999, 99, 1469 – 1480, and references cited
therein. For examples of hydroxy-directed syn-epoxidation
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Saha-Mꢂller, Synlett 2002, 510 – 512; c) K. Zilbeyaz, E. Sahin, H.
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Received: August 24, 2009
Revised: October 1, 2009
Published online: November 17, 2009
Angew. Chem. Int. Ed. 2009, 48, 9519 –9521
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www.angewandte.org
9521