Total synthesis of (±)-coerulescine and (±)-horsfiline

Article abstract of DOI:10.3762/bjoc.6.103

Wittig olefination-Claisen rearrangement protocol was applied to obtain 3-allyl oxindole. This oxindole was then converted to (±)-coerulescine and (±)-horsfiline.

Full text of DOI:10.3762/bjoc.6.103

Total synthesis of (±)-coerulescine and (±)-horsfiline
Mukund G. Kulkarni*, Attrimuni P. Dhondge, Sanjay W. Chavhan,
Ajit S. Borhade, Yunnus B. Shaikh, Deekshaputra R. Birhade,
Mayur P. Desai and Nagorao R. Dhatrak
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 876–879.
Department of Chemistry, University of Pune, Ganeshkhind,
Pune-411 007, Maharashtra, India
doi:10.3762/bjoc.6.103
Received: 09 July 2010
Email:
Accepted: 07 September 2010
Published: 27 September 2010
Mukund G. Kulkarni* - mgkulkarni@chem.unipune.ernet.in
* Corresponding author
Associate Editor: M. S. Sherburn
Keywords:
© 2010 Kulkarni et al; licensee Beilstein-Institut.
License and terms: see end of document.
alkaloids; Claisen rearrangement; Jones oxidation; spiro-oxindole;
Wittig olefination
Abstract
Wittig olefination–Claisen rearrangement protocol was applied to obtain 3-allyl oxindole. This oxindole was then converted to
(±)-coerulescine and (±)-horsfiline.
Introduction
The spiro[pyrrolidin-3,3′-oxindole] ring system is a widely dole] possessed significant activity against human breast cancer
distributed structural framework present in a number of cyto- cells. This work led to intense interest in the total synthesis of
static alkaloids. For example, coerulescine (1) and horsfiline (2) these alkaloids and their derivatives. Despite previous intensive
represent the simplest prototype members of this subfamily. studies, the total synthesis of coerulescine (1) and horsfiline (2)
Coerulescine (1) was isolated from the blue canary grass, remain attractive targets for demonstrating the efficacy of newer
Phalaris coerulescens [1,2]. Horsfiline (2) was first isolated in synthetic protocols.
1991 by Bodo from a Malaysian medical plant, Horsfieldia
superba Warb [3]. Several Myristicaceae are used as a source of Several synthetic approaches have been developed for the syn-
intoxicating snuffs [1-3]. Other members of this subfamily, such thesis of the spiro[pyrrolidin-3,3'-oxindole] framework for hors-
as spirotryprostatins A and B [4,5], elacomine [6] and rychno- filine and coerulescine [11-34], both in racemic and enan-
phylline [7,8], have more complex structures. The majority of tiomeric forms. These include the following oxidative
these alkaloids have interesting biological activities and phar- rearrangements: lead tetraacetate [3], sodium tungstate [11],
macological properties [9]. However, a crucial observation, tert-butyl hypochlorite [12] and N-bromosuccinimide [13].
reported by Danishefsky et al. [10], found that the unnatural Other approaches involve the Mannich reaction [14], ring
analogous 3 and 4 (Figure 1) of the spiro[pyrrolidin-3,3′-oxin- expansion reactions [15,16], 1,3-dipolar [3 + 2] cycloadditions
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Beilstein J. Org. Chem. 2010, 6, 876–879.
[35] furnished the corresponding allyl vinyl ether 5 as an insep-
arable mixture of E and Z isomers. However, the NMR signals
of the E and Z isomers in the olefinic region were well sepa-
rated, which allowed us to estimate the ratio of these isomers as
1:2. The mixture of allyl vinyl ethers was heated in refluxing
xylene to effect the Claisen rearrangement to obtain 4-pentenal
6 in 85% yield. Aldehyde 6 was transformed into acid 7 by
Jones oxidation, which was immediately converted to the ethyl
ester 8. Subsequently, reduction of the compound 8 with Zn and
NH4Cl resulted in clean cyclization leading to oxindole 9.
Figure 1: Spiro[pyrrolidin-3,3'-oxindoles].
After protecting the amide nitrogen with Boc, the oxindole 10
was treated with NaH, followed by ethyl chloroformate at 0 °C
[17-19], intramolecular radical cyclizations [20-24], electro- to give 11 in 80% yield. Oxidative cleavage of the allyl group
philic cyclization [25], asymmetric nitroolefination reaction was accomplished by catalytic osmium tetroxide and N-methyl-
[26], palladium asymmetric allylic alkylation [27], palladium- morpholine N-oxide (NMO), followed by cleavage of the diol
catalyzed domino Heck–cyanation [28], Pd-catalyzed intra- with sodium metaperiodate on silica in methylene chloride.
molecular cyanoamidation [29,30], NHC-mediated O- to Reductive amination of the aldehyde 12 was conducted using
C-carboxyl transfer [31], dimethyldioxirane (DMDO) mediated methylamine hydrochloride and NaBH3CN and gave spiro-
oxidation [32], and by tandem intramolecular photocycloaddi- oxindole 13. The Boc group of 13 was removed by treatment
tion–retro-Mannich reaction [33].
with 2.5 M HCl to give 14. Finally, chemoselective reduction of
amide 14 with n-BuLi and LAH (under the conditions reported
The Wittig olefination–Claisen rearrangement protocol [35] in [27]) gave coerulescine. Compound 1, on treatment with
provides a ready access to 4-pentenals, which have served as N-bromosuccinimide, gave the 5-bromo derivative, which upon
versatile intermediates for the synthesis of a number of natural heating with sodium methoxide in the presence of cuprous
products [36-44]. Therefore, we describe the successful applica- iodide gave horsfiline in 60% yield. The physical data of syn-
tion of the above protocol for the synthesis of the coerulescine thetic coerulescine and horsfiline were comparable in all
(1) and horsfiline (2) (Scheme 1).
respects with the literature data.
Results and Discussion
Conclusion
The Wittig olefination of o-nitrobenzaldehyde with allyl- In summary, we have described a new and efficient synthesis of
oxymethylenetriphenylphosphorane under standard conditions (±)-coerulescine and (±)-horsfiline.
Scheme 1: Reagents and conditions: a) CH2=CHCH2OCH2P+ Ph3Cl−, t-BuO− Na+, THF, 0 °C; b) xylene, reflux; c) Jones reagent, acetone, d)
H2SO4, EtOH, e) Zn, NH4Cl, EtOH, reflux, f) NaH, (Boc)2O, THF, 0 °C, g) NaH, ethyl chloroformate, THF, 0 °C, h) K2OsO4, NMO, NaIO4·SiO2, DCM,
i) MeNH2·HCl, NaCNBH3, THF j) 2.5 M HCl aq. THF, reflux; k) n-BuLi, LAH, THF, l) NBS, NaOMe, CuI, reflux.
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Supporting Information
doi:10.1016/S0040-4039(02)02267-0
Supporting Information File 1
Experimental and spectral data.
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