Total Synthesis of Ileabethoxazole, Pseudopteroxazole, and seco-Pseudopteroxazole

Article abstract of DOI:10.1002/anie.201510568

The total syntheses of ileabethoxazole, pseudopteroxazole, and seco-pseudopteroxazole, three antituberculosis diterpenoids that had been isolated from Pseudopterogorgia elisabethae, were accomplished in a collective fashion. A cascade alkyne carbopalladation/Stille reaction was exploited to construct a triene precursor with suitable geometry. A fully substituted arene was then assembled through a key 6π electrocyclization/aromatization sequence, and served as an advanced common intermediate. Two radical cyclizations led to the formation of the five- and six-membered rings of ileabethoxazole and pseudopteroxazole, respectively, with the desired stereochemistry, and a straightforward side-chain elongation delivered seco-pseudopteroxazole.

Full text of DOI:10.1002/anie.201510568

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International Edition: DOI: 10.1002/anie.201510568
German Edition: DOI: 10.1002/ange.201510568
Natural Products Very Important Paper
Total Synthesis of Ileabethoxazole, Pseudopteroxazole, and
seco-Pseudopteroxazole
Ming Yang, Xiaowen Yang, Hongbin Sun, and Ang Li*
Dedicated to Professor K. C. Nicolaou on the occasion of his 70th birthday
Abstract: The total syntheses of ileabethoxazole, pseudopter-
oxazole, and seco-pseudopteroxazole, three antituberculosis
diterpenoids that had been isolated from Pseudopterogorgia
elisabethae, were accomplished in a collective fashion. A
cascade alkyne carbopalladation/Stille reaction was exploited
to construct a triene precursor with suitable geometry. A fully
substituted arene was then assembled through a key 6p elec-
trocyclization/aromatization sequence, and served as an
advanced common intermediate. Two radical cyclizations led
to the formation of the five- and six-membered rings of
ileabethoxazole and pseudopteroxazole, respectively, with the
desired stereochemistry, and a straightforward side-chain
elongation delivered seco-pseudopteroxazole.
T
uberculosis (TB) has long been a severe threat to human
Figure 1. Benzoxazole-containing diterpenoids 1–3 and biogenetically
related natural products 4–6.
health.[1] In recent years, the rapid increase in multidrug-
resistant and extensively drug-resistant TB infections and TB/
HIV co-infection raises the demand for more effective
chemotherapeutics.[2] Natural products provide an unparal-
leled source of lead compounds for anti-TB drug develop-
ment.[3] Ileabethoxazole, pseudopteroxazole, and seco-pseu-
dopteroxazole (1–3, Figure 1) are benzoxazole alkaloids that
were isolated by Rodríguez and co-workers from the Car-
ibbean sea whip Pseudopterogorgia elisabethae and display
promising inhibitory activity against Mycobacterium tuber-
culosis.[4] From structural and biosynthetic perspectives, these
molecules belong to a large and diverse diterpenoid family
isolated from the same species,[5] and some of their congeners
(4–6) are shown in Figure 1. Notably, a significant number of
the family members possess multisubstituted aromatic cores,
which enhances the difficulty of their chemical synthesis.[6]
Corey and co-workers reported the first total syntheses of the
originally proposed and revised structures of 2[7] by employing
an intramolecular Diels–Alder and a Robinson annulation
strategy, respectively. The Harmata group then disclosed
a synthesis of 2 based on benzothiazine chemistry.[8] Recently,
Williams and Shah accomplished the first total synthesis of
1 with a congested five-membered ring, which featured an
elegant Pauson–Khand strategy.[9] Herein, we report collec-
tive total syntheses of 1–3 that are based on an electro-
cyclization/aromatization strategy.
We first undertook a retrosynthetic analysis of ileabe-
thoxazole (1) and pseudopteroxazole (2; Scheme 1). The
À
À
initial disconnections at the C5 C12 and C5 C13 bonds of the
five- and six-membered rings, respectively, generate arene 7
[*] Dr. M. Yang, X. Yang, Prof. Dr. A. Li
State Key Laboratory of Bioorganic and Natural Products Chemistry
Collaborative Innovation Center of Chemistry for Life Sciences
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: ali@sioc.ac.cn
Homepage: http://angligroup.sioc.ac.cn
X. Yang, Prof. Dr. H. Sun
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and
State Key Laboratory of Natural Medicines
China Pharmaceutical University
24 Tongjia Xiang, Nanjing 210009 (China)
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201510568.
Scheme 1. Retrosynthetic analysis of 1 and 2.
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as a common intermediate. Metal-mediated or free-radical
cyclization could be used to effect the ring closures. Inspired
by Nicolaouꢀs seminal synthesis of the endiandric acids[10] as
well as other elegant work in the electrocyclization area,[11–13]
we envisioned a one-pot 6p electrocyclization/aromatization
process to forge the aromatic core of 7. Similar strategies were
exploited to build tetra- and pentasubstituted arenes in our
synthesis of daphenylline, rubriflordilactone A, tubingen-
sin A, xiamycin A, and oridamycins A and B.[14] However,
examples of assembling fully substituted arenes by such
strategies are rare, presumably owing to the difficulty
associated with preparing geometrically suitable hexasubsti-
tuted triene substrates. To construct a triene such as 8, we
envisioned to take advantage of a tandem alkyne carbopalla-
dation/Stille reaction between alkynyl triflate 9 and oxazolyl
stannane 10, based on the pioneering work of Suffert and
DMP oxidation and subsequent triflate formation (KHMDS,
PhNTf2) furnished compound 9 with good overall efficiency.
The following alkyne carbopalladation/Stille cascade reaction
À
was crucial not only for the formation of the two C C bonds
=
but also for the geometric control of the central C C bond of
8. Although THF, benzene, and toluene have been reported to
be suitable solvents for similar transformations,[15] in this case,
we only observed trace amounts of the cascade product when
these solvents were used; gradual decomposition of the
starting materials was predominant. DMF turned out to be
a favorable solvent for the formation of the desired product 8,
whereas the direct Stille–Migita coupling between triflate 9
and stannane 10 and homodimerization of 10 were compet-
itive side reactions. Under the optimized conditions [Pd-
(PPh3)4 (10 mol%), 10 (1.1 equiv), 808C], 8 was obtained in
an acceptable yield (55%) as a single geometric isomer.
Notably, LiCl was found to promote the direct coupling over
the cascade reaction. Exposure of 8 to air at 1408C smoothly
provided the fully substituted arene 15 in 68% yield.
others.[15] The geometry of the central C C bond of 8 would
=
be secured by a mechanism of oxidative addition/cis alkyne
insertion/transmetalation/reductive elimination. Compound 9
was traced back to commercially available (+)-isopulegol
(11). Notably, a series of analogues could be flexibly obtained
from the common intermediate 7.
With 15 in hand, we investigated the formation of the five-
membered ring for the synthesis of ileabethoxazole by
a Heck-type cyclization strategy (Scheme 3). Treatment of
The synthesis commenced with the assembly of fully
substituted arene intermediate 15 (Scheme 2). (+)-Isopulegol
(11) was subjected to a Mitsunobu reaction (DIAD, PPh3,
para-nitrobenzoic acid) followed by basic hydrolysis to obtain
alcohol 12 (93% yield over two steps) with an inverted
secondary hydroxy group. This hydroxy group was essential to
direct the hydroboration/peroxide cleavage process in a dia-
stereoselective manner (ca. 2.3:1).[16] Monosilylation (chlo-
ride 13,[17] imidazole) of the resultant mixture of diols
afforded compound 14 (a single diastereomer was obtained
after column chromatography, 65% yield over two steps).
Scheme 3. Synthesis of 12-epi-ileabethoxazole. TBAF=tetrabutylammo-
nium fluoride.
15 with AgF selectively removed the oxazole TIPS group to
give 16 in 95% yield.[18] Cleavage of the C Si bond of 16 with
À
ICl,[19] followed by release of the primary hydroxy group with
HF·py, afforded the corresponding iodine-substituted alcohol,
which then underwent DMP oxidation, yielding aldehyde 17
with good overall efficiency. An olefinic side chain was
elaborated by Julia–Kocienski olefination[20] with tetrazolyl
sulfone 18 and KHMDS at À558C, leading to trans alkene 19
(73% yield) as a single geometric isomer. We examined
a variety of Heck reaction conditions for the 5-exo-trig
cyclization of 19; Pd(OAc)2, PPh3, and Ag2CO3 as a crucial
additive at 708C turned out to be an optimal combination.[21]
Desilylation (TBAF, AcOH) of the cyclization product
provided compound 20 (52% over two steps) as a single
diastereomer, which was confirmed to be 12-epi-ileabethox-
azole by NMR spectroscopy. The orientation of the C18
methyl group may influence the transition state of the Heck-
Scheme 2. Construction of common intermediate 15. DIAD=diiso-
propyl azodicarboxylate, DMF=N,N-dimethyl formamide,
KHMDS=potassium bis(trimethylsilyl)amide, Tf =trifluoromethanesul-
fonyl, TIPS=triisopropylsilyl.
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type cyclization, resulting in a non-epimerizable tertiary C12
center. We postulated that the desired stereochemistry at C12
could be established by thermodynamic control, according to
the trans orientation of the methyl and alkenyl substituents in
the natural product.
We then turned our attention to an alternative cyclization
strategy for ileabethoxazole synthesis (Scheme 4). Treatment
Scheme 5. Syntheses of pseudopteroxazole and seco-pseudopteroxa-
zole. DIBAL-H=diisobutylaluminum hydride, phen=1,10-phenanthro-
line.
key closure of the six-membered ring relied on a radical
cyclization by organocatalytic SOMO catalysis.[27] The two-
carbon side chain was installed through a three-step sequence
(Wittig reaction, hydrogenation, and DIBAL-H reduction),
giving aldehyde 27 in 69% overall yield. This compound was
subjected to the MacMillan conditions[27a] [secondary amine
28 (30 mol%), [Fe(phen)3](PF6)3 (2.6 equiv), À208C] to
provide tetracycle 29 in 60% yield as a single diastereomer.
Scheme 4. Synthesis of ileabethoxazole. AIBN=2,2’-azobis(2-methyl-
propionitrile), DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
=
Wittig olefination with Ph3P CMe2 afforded 2. seco-Pseu-
of aldehyde 17 with Seyferth–Gilbert reagent 21 and tBuOK
gave terminal alkyne 22 in 91% yield.[22] Notably, under
Bestmann conditions (Ohira–Bestmann reagent, K2CO3,
MeOH),[23] epimerization at the carbonyl a-position occurred
rapidly. Elongation of 22 with a two-carbon unit was effected
according to Fuꢀs method (23, CuI) with good efficiency.[24]
The resultant compound 24 was first subjected to reductive
Heck conditions;[25] however, 6-endo-dig cyclization products
were obtained predominately. Fortunately, under conven-
tional radical conditions (AIBN, Bu3SnH, 808C), 5-exo-dig
cyclization proceeded smoothly to afford 25 (87% yield) as an
inconsequential geometric mixture. Exposure of this com-
dopteroxazole (3) was obtained from 27 by a similar olefina-
tion method. The spectroscopic and physical properties of
synthetic 2 and 3 are identical to those reported for the
natural products.
In summary, we have accomplished the total syntheses of
ileabethoxazole, pseudopteroxazole, and seco-pseudopterox-
azole (1–3) in a collective manner. The key step was a one-pot
6p electrocyclization/aromatization sequence, which effi-
ciently constructed the multisubstituted arene scaffold from
a geometry-defined hexasubstituted triene. This work pro-
vides a versatile synthetic approach to analogues of benzox-
azole diterpenoids and may facilitate their biological studies.
=
pound to DBU at 408C migrated the exocyclic C C bond to
a thermodynamically more favorable position, which mean-
while established the C12 stereochemistry (12:1 d.r.). Treat-
ment of the resultant a,b-unsaturated ester with an excess of
MeLi provided ileabethoxazole (1) in 66% yield over two
steps; its structure was confirmed by X-ray crystallography
(see Scheme 4).[26] The spectroscopic and physical properties
of this synthetic sample were consistent with those reported
for the natural product and Williamsꢀ synthetic sample.
We completed the syntheses of pseudopteroxazole (2) and
seco-pseudopteroxazole (3) from the common intermediate
Acknowledgements
We thank Prof. Yong-Qiang Tu for helpful discussions.
Financial support was provided by the Ministry of Science
& Technology (2013CB836900), the National Natural Science
Foundation of China (21525209, 21290180, 21172235, and
21222202), the Shanghai Science and Technology Commission
(15JC1400400), and the China Postdoctoral Science Founda-
tion (2014M551480 and 2015T80470, to M.Y.).
À
15 (Scheme 5). Exposure of 15 to HF·py broke the two C Si
bonds and generated the primary alcohol in 91% yield, which
Keywords: arenes · diterpenoids · electrocyclization ·
underwent DMP oxidation to aldehyde 26 (86% yield). The
radical reactions · total synthesis
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Received: November 14, 2015
Published online: January 22, 2016
Angew. Chem. Int. Ed. 2016, 55, 2851 –2855
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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