Total synthesis and structural revision of the marine macrolide neopeltolide

Article abstract of DOI:10.1021/ja710080q

The total synthesis and structural revision of the marine natural product neopeltolide is reported. The key bond-forming step involves a Lewis acid-catalyzed intramolecular cyclization to install the tetrahydropyran ring and the macrocycle simultaneously. This type of cyclization is the first of its kind and assembles the carbon backbone of the natural product efficiently. The synthesis of the reported structure revealed differences in the data between the natural and synthetic material. After significant investigation, the diastereomeric molecule with the C11 and C13 configurations inverted was synthesized using the initial route. This compound matches the data reported for neopeltolide (¹H, ¹³C, HRMS, IR, NOESY, [α]), thereby establishing the correct overall structure for this potent macrolide natural product, including the relative and absolute stereochemistry. Copyright

Full text of DOI:10.1021/ja710080q

Published on Web 12/28/2007
Total Synthesis and Structural Revision of the Marine Macrolide Neopeltolide
Daniel W. Custar, Thomas P. Zabawa, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received November 6, 2007; E-mail: scheidt@northwestern.edu
Scheme 1. Synthetic Plan
Bioactive marine natural products continue to be a source of
potential therapeutic compounds as well as inspiration to develop
new synthetic strategies for their construction.1 Rich sources of
promising compounds are the marine sponges from the order
Lithistida that are found in warm water environments.2 Recently,
Wright and co-workers reported the isolation and structure elucida-
tion of the marine macrolide neopeltolide (1) from sponges most
closely related to the genus Daedalopelta Sollas.3 Neopeltolide is
an extremely potent inhibitor of tumor cell proliferation with IC50
values against lung adenocarcinoma (A549), ovarian sarcoma (NCI/
ADR-RES), and murine leukemia (P388) of 1.2, 5.1, and 0.56 nM,
respectively. The molecular formula and tricyclic nature of neopel-
tolide was determined by 13C NMR spectroscopy and mass
spectrometry. The planar structure was proposed on the basis of
one- (1D) and two-dimensional (2D) 1H NMR techniques, including
advanced TOCSY and COSY experiments. A foreshadowing of
the problems regarding the structure included HMBC experiments
which surprisingly did not connect the C2-C8 and C9-C16 spin
systems. The relative stereochemistry of 1 was assigned on the basis
of coupling constants, advanced 1D NOE and 2D NOESY
experiments, but the absolute stereochemistry of neopeltolide was
not reported.
Scheme 2. Dioxinone Fragment Synthesisa
The key structural attributes of neopeltolide include a 2,6-cis-
tetrahydropyran unit encircled by a 14-membered macrolactone and
an oxazole side chain at C5 that is found in the natural product
leucascandrolide A. We were immediately drawn to neopeltolide
because we envisioned the embedded tetrahydropyran could be
constructed using our recently developed Lewis acid-catalyzed
cyclization.4 The plan was to utilize this stereoselective process as
the key bond-forming event, thereby constructing the tetrahydro-
pyran ring and the macrolactone simultaneously (Scheme 1). Since
our previous intermolecular reactions were highly diastereoselective,
we anticipated that the configuration of C3 would control the
cyclization to deliver diequatorial substituents at C3 and C7. The
linear precursor to this macrocyclization (4) would be constructed
from dioxinone acid 5 and alcohol 6. We did not fully appreciate
the convergency of our plan until questions regarding stereochem-
istry of 1 arose.
The synthesis of acid 5 began with the Ti(IV)-(R)-BINOL-
catalyzed aldol reaction between dienoxy silane 85 and the protected
saturated aldehyde (7) to afford secondary alcohol 9 in 63% yield
and 88% ee (Scheme 2).6 The protection of the alcohol and
subsequent two-step conversion of the primary silyl ether to the
carboxylic acid furnished the dioxinone acid 5 poised for the
fragment assembly acylation (Scheme 4). The synthesis of the target
alcohol commenced with the two-step conversion of â-hydroxy ester
107 to Weinreb amide 11.8 The addition of the alkyl lithium derived
from 12 to this amide afforded the extended ketone 13.9,10 The
removal of the PMB group and a selective Evans-Tischenko
reduction11 generated alcohol 14 with the requisite anti stereo-
chemistry. A careful methylation of 14 and hydrolysis of the
benzoate furnished the necessary alcohol 6.
a Conditions: (a) Ti(i-PrO)4, (R)-BINOL, 4 Å sieves, CH2Cl2. (b) TBS-
OTf, 2,6-lutidine, CH2Cl2. (c) pPTs, EtOH. (d) PDC, DMF.
Scheme 3. Alcohol Fragment Synthesisa
a Conditions: (a) H2N(Me)OMe‚Cl, i-PrMgBr, THF. (b) PMB-OC(N-
H)CCl3, pPTs, cyclohexane/CH2Cl2. (c) t-BuLi, pentane/Et2O, -78 °C. (d)
DDQ, pH 7 buffer, CH2Cl2. (e) SmI2, PhCHO, THF, 0 °C. (f) MeOTf,
DTBMP, CH2Cl2. (g) K2CO3, MeOH.
proceeded smoothly with HF‚pyridine, and the resulting diol
underwent a selective oxidation of the primary alcohol with
TEMPO13 to generate acyclic aldehyde 4. In the key step, scandium-
(III) triflate promoted the macrocyclization of 4 to produce the fully
elaborated 14-membered ring. Although the yield for this Prins-
type transformation is modest, a high degree of complexity is
generated in this single unprecedented step. The tricyclic dioxinone
(15) was converted to alcohol 2 by heating in wet DMSO followed
by a selective reduction of the ketone with NaBH4. Much to our
surprise, a Mitsunobu reaction with alcohol 2 and carboxylic acid
314 produced a compound whose spectra were similar, but not
identical, to the natural product. At this point, extensive NOE
The fragment coupling of 5 and 6 was accomplished using
Yamaguchi’s protocol12 (Scheme 4).The removal of both silyl ethers
9
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C O M M U N I C A T I O N S
Scheme 4. Fragment Coupling and Initial Synthesisa
alcohol followed by a Mitsunobu reaction with acid 3. Gratifyingly,
1
the H and 13C spectra of macrocycle 21 match the reported data
for neopeltolide. The NOESY and HRMS data and optical rotation
confirmed that compound 21 is indeed neopeltolide.15 It seems that
the challenges assigning the relative stereochemistry of this natural
product arise from the flexibility of the macrocycle which can orient
the C9-C11-C13 methine protons for the original NOE correla-
tions.18
In conclusion, the total synthesis of the marine macrolide
neopeltolide has been accomplished. The key bond-forming event
involves the Lewis acid-catalyzed cyclization between a dioxinone
and in situ generated oxocarbenium ion to generate the THP ring
and macrocycle concurrently. This macrocyclization strategy is the
first of its kind and will be applied to future natural product targets.
The route detailed herein is convergent and flexible, thereby
allowing for the synthesis of multiple diastereomers that facilitated
the structural revision and absolute stereochemistry determination
of neopeltolide. These studies reinforce the vital role that total
synthesis continues to play in determining the actual structures of
promising natural products.
a Conditions: (a) 2,4,6-trichlorobenzoyl chloride, DMAP, THF. (b)
HF‚pyridine, THF. (c) TEMPO, H5C6I(OAc)2, CH2Cl2. (d) Sc(OTf)3, CaSO4,
MeCN. (e) DMSO, H2O, 130 °C. (f) NaBH4, MeOH, 0 °C. (g) DIAD, Ph3P,
3, benzene.
Scheme 5. Completion of the Synthesisa
Acknowledgment. This work has been generously supported
by the Sloan Foundation, Abbott, Amgen, AstraZeneca, 3M,
GlaxoSmithKline and Boehringer-Ingelheim. We thank Dr. Thad
Franczyk and Professor Regan Thomson for helpful discussions
and Dr. Amy Wright for providing copies of NMR spectra.
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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a Conditions: see conditions for Scheme 4.
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The discrepancies between our synthetic 1 and the isolation data
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Cope reaction16 had intervened in our intramolecular scandium-
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rations at C3, C5, and C7, thereby producing diastereomer 17
instead of neopeltolide (Scheme 5).17 We decided to test this oxonia-
Cope hypothesis by starting with the opposite configuration at C3.
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1. Accordingly, 16 was prepared using Ti(IV)-(S)-BINOL and then
taken through the synthesis. For a second time, the installation of
the oxazole side chain did not produce 1, but diastereomer 17. An
NOE analysis of 17 indicated that the C3, C5, and C7 configurations
were indeed inverted relative to 1, thereby ruling out the oxonia-
Cope process and reinforcing our earlier premise that the first route
had accessed the original neopeltolide structure.
After careful consideration of the original data in conjunction
with our synthetic efforts, we postulated that the correct structure
for neopeltolide was the diastereomer with C11 and C13 inverted
compared to 1. Given our convergent approach, testing this
hypothesis was straightforward. The desired alcohol 18 with
inverted stereochemistry at C11 and C13 was prepared in a similar
manner to that for 6.15 The esterification, deprotection, and selective
oxidation steps proceeded smoothly. After the scandium(III)-
promoted macrocyclization, the dioxinone was heated in DMSO
to afford the ketone (20). The fully elaborated structure (21) was
assembled by reduction of the carbonyl of 20 to the equatorial
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(18) During review of this work, a synthesis of neopeltolide with the correct
revised structure was reported, see: Youngsaye, W.; Lowe, J. T.; Pohlki,
F.; Ralifo, P.; Panek, J. S. Angew. Chem., Int. Ed. 2007, 46, 9211-9214.
We arrived at the stereochemical reassignment of neopeltolide completely
independently of the Panek studies.
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