An efficient synthesis of the fully elaborated isoindolinone unit of muironolide A

Article abstract of DOI:10.1021/ol401354a

An efficient stereocontrolled construction of the fully substituted isoindolone subunit of muironolide A is described. The approach is centered on the intramolecular Diels-Alder reaction between the enol form of the β-keto amide and an α,β,γ,δ-unsaturated ester, followed by the installation of the cyclohexene double bond.

Full text of DOI:10.1021/ol401354a

ORGANIC
LETTERS
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Vol. XX, No. XX
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An Efficient Synthesis of the Fully
Elaborated Isoindolinone Unit
of Muironolide A
Qing Xiao, Kyle Young, and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93106-9510, United States
zakarian@chem.ucsb.edu
Received May 14, 2013
ABSTRACT
An efficient stereocontrolled construction of the fully substituted isoindolone subunit of muironolide A is described. The approach is centered on
the intramolecular DielsÀAlder reaction between the enol form of the β-keto amide and an r,β,γ,δ-unsaturated ester, followed by the installation
of the cyclohexene double bond.
Muironolide A is a tetrachlorinated marine metabolite
isolated in minute quantities from a specimen of Phorbas1
that is also known to produce phorboxazoles A and B.2
The halogenation in muironolide A is present in the form
of a trichloromethyl group attached to a carbinol stereo-
center, with an additional chloro substituent at the cyclo-
propyl group (Figure 1). Another structural element
characteristic of muironolide A is the 16-membered bis-
lactone that incorporates a conformationally intriguing
hexahydro-1H-isoindolone subunit, which is the focus of
this study. Remarkably, using microcryoprobe NMR
spectroscopy,3 Molinski et al. fully elucidated the structure
of muironolide A with only 90 μg (152 nmol) of the
material available. This exceedingly small amount was
insufficient to investigate biological activity of the natural
product, although an initial screen indicated notable activ-
ity against the HCT116 cancer cell line.1 In a sense,
muironolide A can be categorized as a “nearly extinct”
natural product; considering that its reisolation from the
natural source is not feasible, the chemical synthesis is the
only alternative to provide material for elucidation of its
biological function. Accordingly, our goal is to develop a
robust and scalable synthesis of muironolide A.
Figure 1. Structure of muironolide A.
In the preliminary synthetic study we concentrated on the
development of an efficient, concise entry to the iso-
indolinone subunit of muironolide A by a suitable intra-
molecular DielsÀAlder (IMDA) cycloaddition, identifying
compound 1 as a key target of the study (Scheme 1).4,5
Isoindolinone 1 is closely related to the heterocyclic subunit
of the natural product and contains most of its structural
information. At the onset, our synthetic planning has been
informed by conformational analysis of the bicyclic ring
system. The pattern of substitution in isoindolinone 1 forces
(1) Dalisay, D. S.; Morinaka, B. I.; Skepper, C. K.; Molinski, T. F.
J. Am. Chem. Soc. 2009, 131, 7552–7553.
(2) (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117,
8126–8131. (b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy,
J. W. J. Am. Chem. Soc. 1996, 118, 9422–9423.
(3) Molinski, T. F. Nat. Prod. Rep. 2010, 27, 321–329.
r
10.1021/ol401354a
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disconnection to simple acyclic amide 4a, along with its
enol form 4b that is properly functionalized for the
cycloaddition process. Another benefit of this design is
the potential for Lewis acid complexation to the β-keto
amide 4a/4b that could eventually enable a catalytic asym-
metric variant of the IMDA approach to the isoindolinone
core of muironolide A.6
Scheme 1
To gauge the feasibility of this design in greater detail, we
investigated the DielsÀAlder reaction with both the 4E- and
4Z-isomers of 4a. The common carboxylic acid counterpart
was used in the form of dioxinone 8, and its three-step
synthesis from ethyl (2E)-2,4-dimethyl-2-pentenoate
is shown in Scheme 2a. Reduction of the substrate with
i-Bu2AlH and Swern oxidation afforded 2,4-dimethyl-
2-pentenal (6), and its olefination with reagent 7 delivered
requisite dioxinone 8.7 For the (4E)-amide precursor
(Scheme 2b), oxidation of (E)-4-bromo-3-methyl-2-butene-
1-ol8 followed by a Wittig 2-carbon elaboration provided
ester 11, and its direct reaction with 4-methoxybenzylamine
completed the short synthesis of the E-amine counterpart.
The synthesis of the amine counterpart of (4Z)-4a required a
late-stage ester installation; therefore, Z-amine 15 was pre-
pared in three steps from propargyl alcohol as shown in
Scheme 2c. Copper-catalyzed methylmagnesation of propar-
gyl alcohol followed by the iodine quench afforded (Z)-3-
iodo-2-methyl-propen-1-ol.9 The synthesis was completed by
the Kumada coupling with vinylmagnesium bromide10 and a
one-pot elaboration of the hydroxy group to PMB-protected
amine 15.
Investigation of the IMDA reaction began with amide
(4E)-4a, which was readily accessed by an efficient thermal
coupling between dioxinone 8 and amine 12 with pyridinium
p-toluenesulfonate in toluene at reflux (Scheme 3).11 Early
experimentation revealed that heating the substrate in
toluene at reflux results in a clean, highly endo-selective
cyclization to 16, reaching 90% conversion after 18 h (see
Figure S1 in the Supporting Information for the kinetic
profile). No additive was required. Performing the reaction
under basic conditions (Cs2CO3, EtOAc, 25 °C; LiN(SiMe3)2,
THF, 0 °C; n-Bu4NF, THF, 0 °C)6,12 generally offered no
it to adopt a rather strained conformation in the ground
state. A similar conformational preference was found for
muironolide A by NMR spectroscopic studies.1 In contrast,
a potential precursor to 1, intermediate 2, adopts a less
strained half-chair conformation, suggesting that an IMDA
approach based on isomerization of 2 into conjugation is
likely to be thermodynamically unfavorable. The prediction
based on this analysis is also supported by experimental
observations reported recently by Molinski et al. in their
elegant synthetic approach to muironolide A. The attempted
rearrangement of the double bond in an intermediate similar
to 2 into conjugation with the lactam carbonyl group was
found to be problematic.5
(6) For an example of a strategic application of an IMDA reaction
involving an enol derived from a β-keto carbonyl precursor as a diene
counterpart, see: Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans,
D. A. J. Am. Chem. Soc. 2007, 129, 8968–8969. See also refs 12cand 15.
(7) Boeckman, R. K., Jr.; Thomas, A. J. J. Org. Chem. 1982, 47,
2823–2824.
(8) (a) Yamashita, M. Y.; Yasumoto, T.; Rawal, V. H. Heterocycles
1998, 48, 79–93. (b) Babler, J. M.; Buttner, W. J. Tetrahedron Lett. 1976,
17, 239–241. (c) Van, T. N.; De Kimpe, N. Tetrahedron 2000, 56, 7969–
7973.
As a tactical solution to this problem, we considered
β-keto amide 3a as a precursor to 1, which by way of its
enol form 3b enables an IMDA or double Michael
(9) (a) Duboudin, J. G.; Jousseaume, B.; Saux, A. J. Organomet.
Chem. 1979, 168, 1–11. (b) Liu, F.; Negishi, E. J. Org. Chem. 1997, 62,
8591–8594.
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2009, 38, 3022–3034. (b) Clemens, R. J.; Witzeman, J. S. J. Am. Chem.
Soc. 1989, 111, 2186–2193.
(4) For selected reviews on the intramolecular DielsÀAlder reaction,
see: (a) Funk, R. L.; Vollhardt, K. P. C. Chem. Soc. Rev. 1980, 9, 41–61.
(b) Brieger, G.; Bennet, J. N. Chem. Rev. 1980, 80, 63–97. (c) Ciganek, E.
Org. React. 1984, 32, 1–374. (d) Roush, W. R. Intramolecular
DielsÀAlder Reactions. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp
513À550. (e) Winkler, J. D. Chem. Rev. 1996, 96, 167–176. (f) Bear,
B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820–
849. (g) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698. (h) Takao, K.-i.;
Munakata, R.; Tadano, K.-i. Chem. Rev. 2005, 105, 4779–4807. (j)
Tadano, K.-i. Eur. J. Org. Chem. 2009, 4381–4394. (k) Juhl, M.; Tanner,
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(12) Examples of related intermolecular cyclizations: (a) Yang, Z.;
Shannon, D.; Truong, V.-L.; Deslongchamps, P. Org. Lett. 2002, 4,
€
4693–4696. (b) Petrovic, D.; Bruckner, R. Org. Lett. 2011, 13, 6524–
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advantages and resulted in either low reactivity or decom-
position. Carrying out the original thermal IMDA reaction
inthepresenceoftriethylaminealsohadnoeffectontherate
of the reaction (Figure 2). Collectively, these observations
are indicative of a pericyclic process rather than a stepwise
anionic double Michael addition pathway.6,12
steps. Heating of this compound in toluene at reflux again
resulted in smooth intramolecular cycloaddition, albeit at
a somewhat slower rate than that of the corresponding
isomer (4E)-4a (see Figure S1 in the Supporting Informa-
tion for the kinetic profile). In contrast to the cyclization of
the E-isomer, the product of exo-cyclization was favored,
and similarly a high level of diastereocontrol exceeding
30:1 was observed. The stereochemistry of 3a was ascer-
tained through chemical correlation by its three-step con-
version to aldehyde 19.
Scheme 2
Scheme 3
The significance of the IMDA cyclization of (4Z)-4a is
that it directly provides the ring system of muironolide A
with the correct stereochemistry. The fully assembled
isoindolinone ring system was reached by the installation
of the C8,C9-double bond in three straightforward trans-
formations: (1) reduction of the ketone (NaBH4, CeCl3,
MeOH); (2) methanesulfonation (CH3SO2Cl, Et3N); and
(3) elimination (DBU, PhMe, 85 °C), which afforded 21 in
64% yield after the three steps.
Finally, the stereochemical aspects of the IMDA reac-
tions of isomers (4E)-4b and (4Z)-4b, the reactive enol
forms of (4E)-4a and (4Z)-4a, deserve a comment. The
alternative transition structures (TSs) for the exo and endo
DielsÀAlder cycloaddition of (4E)-4b and (4Z)-4b are
depicted in Scheme 5. Upon consideration of these struc-
tures, we hypothesize that the effect of secondary orbital
interactions is countered by the hydrogen bond stabilizing
the reactive enol form of the substrate. This hydrogen
bonding is not possible for the exo TS of (4E)-4b and the
endo TS of (4Z)-4b. This is expected to substantially
destabilize these conformations, resulting in the observed
mode of high diastereoselectivty for the two isomers. We
observed a notably lower diastereoselectivity of ∼5:1 for
the IMDA reaction of the corresponding trimethylsilyl enol
Reduction of 16 with NaBH4 in the presence of CeCl3 in
methanol selectively afforded 17, whose relative stereo-
chemistry was corroborated by comprehensive NOE
experiments. Further treatment of 17 with i-Bu2AlH and
MnO2 produced unsaturated aldehyde, which could be
effectively epimerized at the C4 position upon exposure to
piperidinium trifluoroacetate at 75 °C.13 The relative con-
figuration of aldehyde 19, which has the same stereochem-
istry at C4 as muironolide A, was also established by NOE
experiments.
The IMDA reaction of (4Z)-4a was investigated next
(Scheme 4). The substrate was prepared in two steps from
dioxinone 8 and amine 15, which included the direct amide
formation followed by site-selective cross-metathesis with
methyl acrylate,14 providing (4Z)-4a in 77% yield over two
(13) (a) Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc. 2008, 130,
3774–3776. (b) Stivala, C. E.; Zakarian, A. Org. Lett. 2009, 11, 839–842.
(c) Araoz, R.; Servent, D.; Molgo, J.; Iorga, B. I.; Fruchart-Gaillard, C.;
Benoit, E.; Gu, Z.; Stivala, C.; Zakarian, A. J. Am. Chem. Soc. 2011, 133,
10499–10511. (d) Stivala, C. E.; Zakarian, A. Tetrahedron Lett. 2007, 48,
6845–6848.
(14) (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 3783–3784. (b) Garber, S. B.; Kingsbury,
J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168–
8179. (c) Dewi, P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005, 46,
577–580.
(15) For an example of an IMDA reaction with silyl enol ethers
derived from β-keto carbonyl compounds, see: Grimaud, L.; Ferezou,
J.-P.; Prunet, J.; Lallemand, J.-Y. Tetrahedron 1997, 53, 9253–9268.
Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 4
Scheme 5. Proposed Transition Structures for the IMDA
Reactions of Enol Tautomers (4E)-4b and (4Z)-4b
ethers15 favoring the same diastereomer (PhMe, reflux, 60 h),
suggesting that the secondary orbital interactions do not
influence the stereochemical course of the reaction, and the
conformational preferences appear to be reinforced by
hydrogen bonding in the enol form.
In closing, we validated an IMDA approach to the core
isoindolinone subunit of muironolide A, an exceedingly
scarce marine natural product characterized by Molinski
in 2009 using state-of-the-art nanoscale NMR technology.
This approach potentially capitalizes on the hydrogen-
bond stabilization of the reactive enol form of the β-keto
amide substrate to achieve the desired high diastereoselec-
tivity. The product can be rapidly advanced to the fully
functionalized indolinone ring system of the natural pro-
duct with the correct stereochemical relationship of the
substituents. The reported process paves the way for the
develoment of an enantioselective variant based on Lewis
acid catalysis, which is currently under active investigation
in our laboratory.
Supporting Information Available. General experimen-
1
tal procedures, characterization data, and copies of H
and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Dr. Hongjun Zhou (UC Santa
Barbara) is thanked for continued assistance with NMR
spectroscopy. This work is supported by the NIH/NIGMS
(R01 GM077379) and kind additional funding from
Amgen and Eli Lilly.
The authors declare no competing financial interest.
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