Toward an integrated route to the vernonia allenes and related sesquiterpenoids

Article abstract of DOI:10.3762/bjoc.7.104

The synthesis of a model endocyclic allene related to the vernonia allenes is described. Fragmentation of a suitable decalin derivative gave the simplified germacrane scaffold. Computational analysis of this and related substrates provides insight into th

Full text of DOI:10.3762/bjoc.7.104

Toward an integrated route to the vernonia allenes
and related sesquiterpenoids
Da Xu, Michael A. Drahl and Lawrence J. Williams*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 937–943.
Department of Chemistry and Chemical Biology, Rutgers, The State
University of New Jersey, 610 Taylor Road, Piscataway, NJ 08854,
USA
doi:10.3762/bjoc.7.104
Received: 03 May 2011
Accepted: 09 June 2011
Published: 05 July 2011
Email:
Lawrence J. Williams* - lawjw@rci.rutgers.edu
This article is part of the Thematic Series "Allene chemistry".
Guest Editor: K. M. Brummond
* Corresponding author
Keywords:
C–C fragmentation; endocyclic allene; natural product; total synthesis
© 2011 Xu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The synthesis of a model endocyclic allene related to the vernonia allenes is described. Fragmentation of a suitable decalin deriva-
tive gave the simplified germacrane scaffold. Computational analysis of this and related substrates provides insight into the stereo-
electronic requirements of C–C fragmentation. The overall strategy to access these and other sesquiterpenes and the key steps in the
present sequence are also discussed.
Introduction
Well over 150 allene-containing natural products are known compounds with these sequiterpenoid structures, examples of
[1-5]. Among these, intriguing complex structures were which are given in Figure 1 (4–12) [17-23]. Although many of
assigned by Bohlmann and co-workers to isolates from the these isolates have not been characterized with regard to their
aerial parts of Vernonia species collected mainly from northern biological function, there is a rich variety of germacranes from
Brazil about 30 years ago (1–3, Figure 1) [6-8]. These bicyclic terrestrial plants, algae, and insect pheromones that purportedly
germacranolides are the only known endocyclic allene- have anticancer, antifungal, and antibiotic activity, among
containing natural products. Interestingly, no synthetic studies others. For example, parthenolide (6) has anti-inflammatory and
of these complex natural products have been reported, perhaps anti-hyperalgesic effects and induces apoptosis of human acute
in part due to the limited number of routes for cyclic allene myelogenous leukemia stem and progenitor cells [24]; eupahe-
construction that are sufficiently mild to effect allene formation liangolide A (7) is cytotoxic to human oral epidermoid (KB),
in complex settings [9-16].
cervical epitheloid (Hela), and liver (hepa59T/VGH) carcinoma
cells [21]; sinugibberodiol (10) exhibits beneficial multidrug
Our interest in the vernonia allenes was motivated in part by a resistance properties in mammalian tumor cells [25];
desire to identify, and to simplify access to, useful bioactive eleganolactone B (11) inhibits the proliferation of the HL-60
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Beilstein J. Org. Chem. 2011, 7, 937–943.
Figure 1: Known natural endocyclic allenes and related germacranes.
human promyelocytic leukemia cell line in a dose-dependent thesis of a model 10-membered endocyclic allene of type 14
manner [26], and ester derivatives of salonitenolide 12 show (Scheme 1).
promising antibacterial activity [27].
Results and Discussion
We have initiated a study that aims to integrate the chemical Advanced intermediates with a high degree of unsaturation have
syntheses of compounds in this structure space into a single, greater potential use in an integrated routing strategy than more
late-stage-divergent, route [28]. A pluripotent route that would highly oxidized products, since not all targets in the group of
enable direct access to a broad range of these targets would be compounds of interest share identical oxidation states or
useful and would offer advantages over single-target routes, patterns. Recently, we reported the synthesis of 9- and
especially in terms of overall step economy. Given the difficul- 10-membered cyclopolyenes [28,38], including a new stereo-
ties associated with the stereoselective preparation of endo- specific allene synthesis via C–C fragmentation. This transfor-
cyclic allenes, and the fact that such structures are largely unex- mation appears well-suited for access to the vernonia targets
plored, we focused on the vernonia allenes. Moreover, we and related compounds [15]. The method relies on suitably
expected that such allenes contain the coded reactivity to access functionalized vinyl triflates [39-41]. In general, C–C fragmen-
many sesquiterpenoid variants, especially in light of new tation reactions appear to be sensitive to the precise structure of
methods of transforming allenes to diverse motifs [29-37]. the cyclic system involved, and small, apparently minor, struc-
Herein we report our efforts toward this goal with a short syn- tural changes may severely retard the reaction [38]. For
Scheme 1: C–C fragmentation strategy to yield endocyclic allenes.
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Beilstein J. Org. Chem. 2011, 7, 937–943.
Scheme 2: Endocyclic allene 17.
example, in our original disclosure, endocyclic allene 17 was studied [38]. Analogous to entry 2, this system contains an
formed from trans-decalin derivative 16 by way of the known unsaturated site adjacent to the hydroxy/alkoxide. The torsion
compound 15 (Scheme 2) [42]. However, the vinyl triflate (16, angles of the scissile bonds for this entry are approximately
R = OH) resisted fragmentation under standard basic condi- 163°. Importantly, this compound is known to undergo base-
tions, whereas, the silyl ether (16, R = OTMS) underwent
smooth fragmentation upon exposure to TBAF.
Table 1: Computed torsion angles for potential C–C fragmentation
substrates.a
The ideal orientation for the two bonds that cleave in a C–C
fragmentation reaction is antiperiplanar [43-46]. However, to
our knowledge, the minimum torsion angle required for frag-
mentation is not known, and no computational mechanistic
study on these reactions has appeared as a guide in this regard.
Admittedly, there are distinct differences between fragmenta-
entry
Substrate
R (R’)
torsion angle
tion and substitution; nevertheless, by analogy to SN2 reactions,
C–C fragmentation substrates with angles significantly less than
180° may fail due to inadequate relative orientation [47,48]. For
our purposes, we aimed to identify a scaffold that would readily
adopt the ideal, or near-ideal, stereoelectronic arrangement
necessary for C–C fragmentation, and yet, would have the
potential to accept further structural modification without
intrinsic change, should that become necessary or desirable.
I: OH (OH)
II: OH (O−)
III: O− (OH)
IV: O− (O−)
153°
155°
156°
see text
1
V: OH
VI: O−
175°
176°
2
3
4
5
Table 1 summarizes the ground state computational modeling of
several C–C fragmentation substrates. The Gaussian suite of
programs, with the B3LYP functional and the 6-31G(d,p) basis
set, was used to generate these data [49-60]. The hydroxy
derivatives (R/R’ = OH) and the corresponding alkoxides in
vacuum were taken together to approximate the torsion angle of
the anion fragmentation precursors. The trans-decalin system of
entry 1 (c.f. Scheme 2) is highly constrained. The relevant
torsion angles are around 155°, thus deviate significantly from
180°. This is true for the mono anions II and III as well as the
diol I. Interestingly however, the dianion does not represent a
stable structure, and instead gives the endocyclic allene via
fragmentation, as observed experimentally. Entry 2 shows a cis-
decalin system. Low energy conformers were identified for
these species [59]. The lowest energy conformer gave the
greatest torsion angles (~175°) for both the alcohol V and the
alkoxide VI, and these approach 180°. For comparison
purposes, the cis-hydrindane derivative in entry 3 was also
VII: OH
VIII: O−
164°
162°
IX: OH
X: O−
174°
177°
XI: OH
XII: O−
171°
170°
aDFT: B3LYP functional, 6-31G(d,p) basis set.
939

Beilstein J. Org. Chem. 2011, 7, 937–943.
induced fragmentation to give the (E)-alkene in excellent yield substrate should be able to adopt conformers with the proper
[61]. Among the substituted variants we considered, we were orientation for fragmentation and may well tolerate substitution.
intrigued by the cis-decalin derivative of entry 4. The ester Given the uncertainties associated with the computational
functionality was taken as a prototype for substitution at this analysis and the precise requirements for fragmentation, it was
position and represents the potential for both steric and elec- not clear that even this model compound would undergo C–C
tronic effects. In this case, although both compounds exhibit fragmentation to give the corresponding endocyclic allene.
similar torsion angles (~175°), there appears to be a significant Consequently, we aimed to prepare 24 by a direct and modular
difference between the orientation of the ester relative to the route.
adjacent C–C double bond. For the neutral (R = OH) com-
pound, the ester is coplanar with the double bond, whereas the Scheme 3 depicts a concise route to 24 and 25. Beginning with
ester is twisted out of planarity for the alkoxide (R = O−). This the commercially available diketone 18, acid promoted Michael
appears to be an electrostatic influence. The behavior noted in addition with acrolein gave aldehyde 19. A two step procedure,
entry 4 was not unique to the cis-decalin system and the analo- via 20, was employed to obtain the (Z)-bromoolefin 21.
gous cis-hydrindane exhibits similar behavior (entry 5): The Initially, we examined the direct formation of 21 via
ester group of the hydroxy entry 5 is coplanar with the alkene, bromomethyltriphenylphosphonium bromide (Scheme 4). This
whereas the ester is twisted out of planarity for the alkoxide (R reaction was inefficient and gave both the (E)- and (Z)-
= O−) [62].
bromoolefins as well as dibromoolefin 20. Bromo group scram-
bling under basic Wittig reaction conditions is known [63], and
In light of the above data, we targeted compound 24 (c.f. 14, the usual procedure for Wittig reagent formation with slow ad-
Scheme 1) to extend the C–C fragmentation to cis-decalins and dition of 19 (1 h) gave 21 with the desired olefin geometry but
to provide an important model for our synthetic studies. This with low selectivity and yield (see below). Rapid addition of 19
Scheme 3: Preparation of endocyclic allene 25.
Scheme 4: Bromo-olefination products from diketone aldehyde 19.
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Beilstein J. Org. Chem. 2011, 7, 937–943.
(1 min), gave the desired product in 26% yield. The use of 2.42–2.15 (m, 5H), 1.76 (ddt, J = 14.7, 12.1, 2.2 Hz, 1H), 1.63
HMPA and/or iodomethyltriphenylphosphorane [64,65] was (d, J = 2.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 205.90,
examined and failed to improve the reaction profile, as did 202.06, 140.21, 132.05, 97.82, 89.33, 41.94, 32.71, 26.71,
varying the ratio of Wittig reagent relative to aldehyde (1–3 26.05, 19.93; ESIMS m/z: [M + Na]+calcd for C11H14NaO,
equiv), solvent (THF and toluene), and aldehyde concentration 185.1; found, 185.0.
(0.035–0.09 M). The yield of the reaction was low under all the
conditions examined (13–26%) [66]. The known behavior of
Supporting Information
bromomethyltriphenylphosphonium bromide under these
strongly basic conditions, and the poor solubility of reactive
Supporting Information File 1
species in THF, account for these results [63].
General experimental methods and analytical data, 1H and
13C NMR spectra of compounds 18–25 and computed
structural coordinates for entries 1–5 in Table 1.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-104-S1.pdf]
Alternatively, the Z-vinyl bromide 21 was readily obtained via
dibromo-olefination of the aldehyde followed by selective
removal of the (E)-bromide with n-Bu3SnH and catalytic Pd(0)
(19→21, Scheme 3). A simple sequence was utilized to furnish
allene precursor 24: Thus 21 was converted to bicycle 22 under
Nozaki–Hiyama–Kishi conditions [67,68], followed by silyl
ether formation (→23) [69] and triflation to produce the desired
decalin 24. There is little precedent for Nozaki–Hiyama–Kishi
addition to ketones [67,68], but the reaction proceeded without
problems in serviceable yield. Brief exposure of 24 to anhy-
drous fluoride conditions effected clean C–C fragmentation to
give the functionalized 10-membered endocyclic allene 25 in
good yield.
Acknowledgements
Financial support from the NIH (GM-078145) is gratefully
acknowledged.
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69.This reaction was accompanied by silylenol ether byproduct formation.
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