Collective synthesis of natural products sharing the dihydro-γ-ionone core

Article abstract of DOI:10.1002/ejoc.201500208

We decided to follow the so-called "collective total synthesis" approach to synthesize several structurally different molecules from a common intermediate possessing appropriate stereochemistry and functionalities. As the common precursor for the efficient preparation of these bioactive molecules, we chose (+)-3,4-dihydro-γ-ionone (1), a natural compound present in minor quantities in ambergris and in the plant Bellardia trixago. Thus, we report herein the enantioselective synthesis of siccanochromene F (2), metachromins U (3) and V (4), and bicyclic squalene derivative 5 as well as the formal syntheses of ambrein (6), phenazinomycin (7), and (-)-siccanin (8).

Full text of DOI:10.1002/ejoc.201500208

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FULL PAPER
DOI: 10.1002/ejoc.201500208
Collective Synthesis of Natural Products Sharing the Dihydro-γ-Ionone Core
Alexis Castillo,[a] Lucia Silva,[b] David Briones,[c] José F. Quílez del Moral,*[a] and
Alejandro F. Barrero*[a]
Keywords: Natural products / Organocatalysis / Molecular diversity / Chiral pool
We decided to follow the so-called “collective total synthe-
sis” approach to synthesize several structurally different mol-
ecules from a common intermediate possessing appropriate
stereochemistry and functionalities. As the common precur-
sor for the efficient preparation of these bioactive molecules,
we chose (+)-3,4-dihydro-γ-ionone (1), a natural compound
present in minor quantities in ambergris and in the plant
Bellardia trixago. Thus, we report herein the enantioselective
synthesis of siccanochromene F (2), metachromins U (3) and
V (4), and bicyclic squalene derivative 5 as well as the formal
syntheses of ambrein (6), phenazinomycin (7), and (–)-sic-
canin (8).
Introduction
tions, mainly owing to innate and acquired resistance to
antimicrobial drugs) and P. putida but not SDH from Esch-
erichia coli or Corynebacterium glutamicum. Species-selec-
tive inhibition is unique among SDH inhibitors, and this
makes siccanin a potential lead compound for new chemo-
therapeutics. To date, only one enantioselective and two ra-
cemic total syntheses of siccanin have been reported.[8f–8i]
Together with siccanin, siccanochromenes were also iso-
lated from H. siccans. One of these molecules is siccano-
chromene F (2).[3] Metachromins U and V (3 and 4) were
isolated from the marine sponge Thorecta reticulata. The
cytotoxicities of these compounds were assessed against a
panel of human tumor cell lines (SF-268, H460, MCF-7,
and HT-29) and a mammalian cell line (CHOK1). Both
compounds are cytotoxic against all of these cell lines, and
metachromin V is the most active [50% growth inhibition
(GI50) 2.1–10 μm].[4] Compound 5 is a bicyclic squalene de-
rivative, isolated from an anoxic sulfur-rich sediment in
Lake Cadagno, Switzerland.[5] This triterpene possesses a
hydrocarbon skeleton not reported in living organisms.
Phenazinomycin (7), isolated from Streptomyces sp. WK-
2057, belongs to the group of phenazine antibiotics.[7a] This
compound is also active against P 388 leukemia cells and
also shows in vivo activity against murine tumors.[7b] Phen-
azinomycin also possesses antitrypanosomal activities both
in vitro and in vivo.[7c]
Nature provides an almost endless source of impressive
structural diversity. However, it is also recognized that the
myriad of complex and diverse natural products is ulti-
mately derived from a limited number of common precur-
sors. Inspired by this concept[1] and to mimic the action of
nature, we used natural (+)-3,4-dihydro-γ-ionone (1) as a
common precursor[2] for the syntheses of 2–8 (Figure 1).[3–8]
The significant decrease in the total number of steps is one
of the main advantages of this methodology.
Siccanin (8) is a mold metabolite isolated from the cul-
tured broth of the pathogenic plant fungus Helminthospos-
ium siccans, a parasitic organism of rye grass.[8a] Siccanin
possesses remarkable antifungal activity against some
pathogenic fungi of the genera Trichophyton (the cause of
the skin infection trichophytosis), Epidermophyton, and
Microsporum.[8b] Thus, clinical tests showed that siccanin
was effective against superficial fungal infections,[8c] includ-
ing those of the opportunistic fungus Candida albicans.[8d]
It has been reported recently by Mogi that siccanin is a
species-selective succinate dehydrogenase (SDH) inhibi-
tor.[8e] These studies have renewed interest in this molecule.
Siccanin inhibits bacterial SDH from Pseudomonas aerugi-
nosa (one of the leading causes of hospital-acquired infec-
[a] Department of Organic Chemistry, University of Granada,
Avda. Fuentenueva, 18071 Granada, Spain
Ambrein (6) is a major constituent of ambergris, which
is a concretion formed by sperm whales that has been
highly valued since ancient times and is currently used in
the fabrication of expensive perfumes.[6a] Recently, the anti-
oxidant and antiinflammatory activities of ambrein were
also reported.[6b,6c] The total synthesis of this triterpene was
previously achieved,[6d–6f] and this compound was very re-
cently obtained enzymatically.[6g]
E-mail: jfquilez@ugr.es, afbarre@ugr.es
http://www.ugr.es/~sinmobio/
[b] Department of Chemistry, University of Beira Interior,
Rua Marquês d’Ávila e Bolama, 6200 Covilhã, Portugal
[c] Department of Chemical and Energy Technology, Rey Juan
Carlos University,
C/ Tulipán s/n, 28933 Móstoles, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500208.
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FULL PAPER
Figure 1. Natural products sharing the dihydro-γ-ionone core.
We started our study into the feasibility of using 1 as a
common intermediate for transformation into a collection
Results and Discussion
Our first aim was to find a protocol that gave access to of natural products with the synthesis of siccanochromene
(+)-3,4-dihydro-γ-ionone (1) on a multigram scale as F (2) and siccanin (8). In designing a synthetic route toward
quickly and straightforwardly as possible. 3,4-Dihydro-γ- siccanochromene F (2), we envisioned a convergent ap-
ionone is present only in minor amounts in the aerial parts proach based on the coupling of the chiral natural synthon
of Bellardia trixago.[9b,2a] However, in this plant, the TRIX 1 with commercially available 2,6-dihydroxy-4-methylaceto-
chemotype contains significant proportions of trixagol (9a), phenone (10) by an organocatalytic cascade reaction
an adequate precursor of 1 through degradative oxid- (Scheme 2).
ation.[2] Thus, when dried aerial parts (1 kg) were extracted
This coupling process is based on the protocol described
with a Soxhlet system with hexane as the solvent, 9a (5.4 g by Kabbe for the syntheses of these kinds of products.[10]
per kg of plant) was obtained after acid–base fractionation, Despite the amazing advances in organocatalysis in the last
defatting, and chromatographic purification.[2a] Further ex- decade,[11] it should be noted that this field did not exist as
perimentation was then required to avoid the time-consum- we know it now when Kabbe reported this process, which
ing isolation of 9a. If dry leaves, stems, and flowers are ex- could be considered as one of the first examples of an or-
tracted separately with hexane by using a Soxhlet appara- ganocatalyzed reaction.
tus, the monomalonyl ester of trixagol (9b) is only found in
To evaluate the feasibility of our approach, including the
development of an asymmetric version, we chose the com-
the flowers in up to 24.8 g per kg.[2b,2c]
The observation that the inflorescence is covered by hairs mercially available 2-decanone (11) as a model starting
and resin glands led us to try a selective extraction of 9 methyl ketone. Different parameters that could determine
by macerating the fresh flowers in different solvents. Good the outcome of the reaction were considered, namely, the
results were found for methyl tert-butyl ether (MTBE) at presence of an acid, the influence of molecular sieves, and
1
room temperature, and the H NMR spectrum of the ex- the quantity of pyrrolidine required. Thus, after some ex-
tract showed a high proportion of the monomalonyl ester perimentation, we found the best experimental conditions.
of trixagol, together with minor quantities of benzoic acid Although the presence of acid is not required, molecular
and fats (Scheme 1). By this method, the monomalonyl es- sieves are essential for the completion of the reaction. Ex-
ter of trixagol (9b) was obtained (up to 30 g per kg of plant cellent yields (96%) were obtained when 1.5 equiv. of pyrr-
material, which corresponds to 23 g of trixagol). Standard olidine were used, although acceptable yields (80%) were
oxidative degradation of the crude extract with catalytic also produced when the amount of amine was reduced to
OsO4 and excess NaIO4 in tBuOH afforded pure 1 (9.2 g 0.3 equiv. The use of only 0.15 equiv. of pyrrolidine in-
per kg of flowers, after one column chromatography purifi- creased the reaction time excessively (up to a week) and
cation, weighed after drying).
also reduced the efficiency of the process (60%).
2
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Collective Synthesis of Natural Products Sharing the Dihydro-γ-Ionone Core
Scheme 1. Selective multigram production of 1 from its natural source B. trixago.
would involve the initial formation of the enamine–imine
derived from the acyclic methyl ketone. The second would
assume the generation of the enamine produced by the reac-
tion of the acetophenone with pyrrolidine (Scheme 3). At
this point, it should be noted that the mechanism would
Scheme 2. Retrosynthetic analysis for siccanochromene F and (–)-
siccanin.
Mechanistically, this pyrrolidine-based protocol consists
of a cascade aldol–dehydration–oxa-Michael organocata-
lytic reaction that proceeds via enamine intermediates and
is favorable towards enamine–iminium catalysis.[11a] How-
ever, as the relative tendency of both linear ketones and
acetophenone to form enamines has been recently reported
to be similar,[12a] the mechanism for this transformation
could be initiated by two different amine activations as pro-
posed by Kabbe in his original report.[10] The first one Scheme 3. Mechanism proposed for the Kabbe reaction.
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involve the use of only 1 equiv. of ketone donor in either steric demand hampering the nucleophilic attack of the en-
case (in reported aldolization reactions, the ketone donor is amine of the methyl ketone and bearing in mind the proven
generally used in large excess) and also 1 equiv. of a second reactivity of primary amines in aldol reactions,[15] we de-
unactivated ketone acceptor (only activated ketone ac- cided to use this kind of amine to generate the desired dia-
ceptors as α-keto acids, α-keto esters, or α-keto phosphona- stereoselectivity. However, neither the use of chiral amino
tes were reported to act as ketone acceptors in proline-cata- acids such as tryptophan[15c] nor the use of primary amines
lyzed intermolecular aldolization reactions).[13]
such as 1-phenylethylamine produced any diastereoselectiv-
To obtain some data to help us to discern between both ity.
mechanistic proposals, we reacted 10 with pyrrolidine in
Once the conditions for the chromanone generation had
toluene under reflux by using a Dean–Stark apparatus. As been optimized, we addressed the synthesis of siccano-
the reaction of the thus-generated enamine I with 11 pro- chromene F and consequently that of siccanin (Scheme 4).
duced chromanone 12, we postulate that the second initia- Thus, the reaction of 1 with 10 in the presence of 0.3 equiv.
tion step is the one most likely to occur (Scheme 3).[12b] of pyrrolidine led to desired chromanone 13 in 85% yield
Through the proposed mechanism, the employment of a [92% based on recovered starting material (brsm)] as an
chiral amine could result in the asymmetric generation of epimeric mixture at C-9. The Sharpless asymmetric di-
the chiral center created by a stereoselective oxa-Michael hydroxylation[16] of ketoolefin 13 with AD-mix β generated
addition to the α,β-unsaturated iminium III. In this regard, the readily separable mixture of diols 14 with complete dia-
there is ample evidence of the involvement of pyrrolidine- stereoselectivity. At this point, the efficiency of the ap-
based secondary amines in the reversible formation of en- proach was significantly improved as the chromanone moi-
amine–imine intermediates.[14] Thus, chiral pyrolidine deriv- ety of the undesired epimer 14a could be epimerized to
atives, namely, proline, proline methyl ester, and di- form 14b in 50% yield by treatment with NaSEt in N,N-
phenylprolinol methyl ether,[11] were tested for the enantio- dimethylformamide (DMF) under reflux.[8i] The same
selective synthesis of chromanone 12. Unfortunately, in all quantity (50%) of unaltered 14a was also recovered. This
cases, the yields were negligible (Յ5%) even after several process meant that, practically, the mixture of epimers at
days of reaction, and no enantiomeric excesses were de- C-9 generated in the formation of chromanone 13 could be
tected. As this lack of reactivity could be due to the high derived into the desired 9S diastereomer. (+)-Siccanochro-
Scheme 4. Synthesis of (+)-siccanochromene F: Formal synthesis of (–)-siccanin.
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Collective Synthesis of Natural Products Sharing the Dihydro-γ-Ionone Core
mene F was finally generated by acid treatment of the benz- chromanones 18a and 18b in excellent yields, and the epi-
ylic alcohol obtained after the lithium aluminium hydride mers could be separated by standard silica gel chromatog-
(LAH) reduction of 14b (Scheme 4).
raphy. At this point, we were unable to determine the con-
Once the synthesis of siccanochromene F was achieved, figuration of ketones 18a and 18b at C-9 either by NMR
the formal synthesis of (–)-siccanin only required the spectroscopy or by circular dichroism studies. Fortunately,
chemoselective protection of the aromatic hydroxyl to pro- we obtained appropriate crystals of the less-polar dia-
duce diol 15, which was reported to be an intermediate in stereomer 18a. The molecular structure of 18a was obtained
the enantioselective synthesis of siccanin by Trost et al.[8h,8i] from single-crystal X-ray diffraction data.[18] The structure
This transformation was achieved in acceptable yield by the of 18a was solved and refined in the monoclinic space
treatment of 2 with MeI in the presence of Cs2CO3 group P21. Details of the data collection and structure re-
(Scheme 4). A noteworthy fact is that intermediate 15 was finement are summarized in Table S1 in the Supporting In-
generated after 17 steps in the seminal work of Trost et formation. The unit cell contains two identical molecules of
al.,[8g] a number that is considerably reduced in our ap- 18a in the asymmetric unit, as can be observed in Figure 2.
proach (only five steps).
To continue with our synthetic approach, we chose ran-
By continuing with our collective approach with (+)-3,4- domly the less-polar isomer 18a, as Motti et al. did not
dihydro-γ-ionone (1) as a common precursor and taking assign any configuration in their report of the isolation of
advantage again of the Kabbe reaction, the synthesis of metachromin U.[4] To conclude the synthesis of meta-
cytotoxic metachromin U (3) was performed as depicted in chromin U from 18a, the generation of the chromene was
Scheme 5. It should be noted at this point that none of the required. However, when we subjected the benzylic alcohol
configurations of the stereogenic centers in this molecule derived from 18a to the same acidic conditions that gener-
were assigned when this natural product was described.[4]
ated the chromene scaffold in the synthesis of siccano-
The appropriate acetophenone, 16, for the synthesis of chromene F, only the decomposition of the starting materi-
metachromin U can be obtained by persulfate oxidation of als was observed, and this suggested that milder conditions
commercially available 2-hydroxy-3-methoxyacetophenone, would be required for this transformation. Thus, the diiso-
as described by Simpson.[17] However, an attempted con- butylaluminium hydride (DIBALH) reduction of ketone
densation of γ-ionone (1) with 2,5-dihydroxy-3-methoxy- 18a and the subsequent treatment of the corresponding
acetophenone (16) in the presence of pyrrolidine resulted in crude reaction mixture with mesyl chloride in pyridine led
the total degradation of the aromatic scaffold. We attrib- to the direct elimination of the mesylate group to produce
uted this change of reactivity to the new electronic distribu- chromene 3 after tetra-n-butylammonium fluoride (TBAF)
1
tion caused by the presence of the hydroquinone moiety induced silyl ether deprotection. The MS as well as the H
and decided to try to overcome this situation by protecting and 13C NMR spectroscopy data of our synthetic meta-
the new aromatic hydroxyl as its silyl ether, 17. Gratifyingly, chromin U match completely those of the natural product.
the exposure of a mixture of acetophenone 17 to the pres- In addition, the sign of the optical rotation for the natural
ence of pyrrolidine led to the targeted epimeric mixture of ([α]D = +20.1, CH2Cl2) and synthetic metachromin U ([α]D
Scheme 5. Synthesis of (+)-metachromin U.
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Figure 2. ORTEP perspective of 18a. Thermal ellipsoids are drawn at the 50% probability level. Hydrogen atoms have been removed for
more clarity. Selected atoms have been labeled.
= +28, MeOH) coincide; therefore, the assignment of both
the relative and the absolute configuration of the natural
product is that shown in Scheme 5.
Metachromin V was the third of the molecules that we
planned to expediently access from our common precursor
1 (Scheme 6). The application of the Horner–Wadsworth–
Emmons protocol to 1 furnished the required two-carbon
homologation. The corresponding unsaturated ester 19 was
reduced with DIBALH to give 20 (74% in two steps).
Alcohol 20 was treated with PBr3 to give the allylic bromide
21. The synthesis of the merosesquiterpene scaffold of
metachromin V was attempted through the copper-cata-
lyzed coupling of bromide 21 and the Grignard reagent
derived from bromide 22 (Scheme 6). The bromide 22
was reacted with magnesium metal in THF under reflux
for 30 min, and a solution of allylic bromide 21 and
[19]
Li2CuCl4 was transferred into this mixture to afford the
target coupling product 23 in an acceptable yield. The direct
demethylation of 23 with sodium thiolate afforded partial
Scheme 6. Synthesis of metachromin V.
deprotection and partial degradation of the starting mate-
rial. Finally, demethylation to natural metachromin 4 was laboratories (Scheme 7).[22] The homocoupling reaction of
performed by ceric ammonium nitrate (CAN) oxidation of allylic bromide 21 in the presence of catalytic quantities of
23 to quinone 24 and subsequent reduction.[20] The spectro- TiIII and an excess of Mn afforded 5 (54%), accompanied
scopic data of synthetic 4 agree with those reported for the by the corresponding α,γЈ isomer (27%). Thus, compound
natural compound. As we were in the final phase of the 5 was synthesized from 1 in only three steps. The prepara-
drafting of this article, Serra et al. reported the enantio- tion of allylic bromide 21 in only three steps could also be
selective synthesis of metachromin V by a closely related applied to the formal synthesis of the antitumor antibiotic
protocol.[21]
phenazinomycin (7), as Kitahara reported that the coupling
Continuing with our idea of proving the versatility of of bromide 21 with the silyl ether derivative of the natural
(+)-3,4-dihydro-γ-ionone as a precursor for the expedient compound 1-hydroxyphenazine afforded phenazinomycin
synthesis of natural products, we addressed the synthesis of (7), although in low yields.[7d] It must be highlighted that
cyclosqualene dimer 5. The key step in our approach to 5 the synthesis of allylic bromide 21 from (+)-3,4-dihydro-γ-
was the TiIII-catalyzed regioselective α,αЈ-homocoupling of ionone was achieved in only three steps, whereas Kitahara
allylic halide 21 through a protocol developed in our reported the generation of 21 in 23 steps.
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Collective Synthesis of Natural Products Sharing the Dihydro-γ-Ionone Core
convergent synthesis of ambrein (Scheme 9). It should be
noted that this plant was successfully cultivated by some
of us; thus, the sustainable availability of this compound is
guaranteed.
Scheme 7. Formal synthesis of phenazinomycin.
Finally, ambrein (6) was the last molecule to be prepared
from (+)-3,4-dihydro-γ-ionone. Remarkably, the formal
synthesis of ambrein was planned to involve the use of two
renewable chiral starting materials (Scheme 8).
Scheme 9. Formal synthesis of ambrein.
The synthesis of 26 from sclareol could be straightfor-
wardly achieved by following a OsO4-mediated catalytic
protocol previously described by some of us[24] to degrade
the sclareol lateral chain and afford acetoxyaldehyde 25.
The LAH reduction of 25 produced optically pure 26 in
two steps from sclareol (Scheme 9). The monocyclic moiety
needed for the synthesis of ambrein, that is, is terminal alk-
yne 28, could be prepared from (+)-3,4-dihydro-γ-ionone
by the protocol described by Negishi for the conversion of
methyl ketones into terminal acetylenes.[25] However, the
application of this one-step protocol failed to deliver the
terminal alkyne and invariably led to the isomerization of
the exocyclic double bond. The generation of the desired 28
was accomplished after the isolation of the corresponding
enol phosphate intermediate 27 and the reaction of this de-
rivative with only 1.1 equiv. of lithium diisopropylamide
(LDA). Under these conditions, acetylene 28 was obtained
in 67% yield, together with a 25% yield of allene 29.
It should be remarked at this point that Mori employed
14 steps in the construction of intermediate 26 from geran-
ylacetone (one separation of enantiomers included) and 17
steps to produce 28 from (S)-3-hydroxy-2,2-dimethylcy-
clohexanone.
Scheme 8. Retrosynthetic analysis of ambrein.
Thus, although 1 would be the origin of the monocyclic
part of ambrein, the bicyclic moiety of this triterpene was
anticipated to originate from sclareol, a diterpenic natural
product isolated from cultivated Salvia sclarea or recently
produced by genetic engineering.[23] In our retrosynthetic
analysis, the formal synthesis of ambrein required the inter-
Conclusions
We have described an expedient process for the
ception of intermediates 24 and 26, from which Mori[6d] multigram production of (+)-3,4-dihydro-γ-ionone (1) from
generated the mono- and bicyclic synthons I and II in his its natural source B. trixago. The capability of 1 to achieve
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A. Castillo, L. Silva, D. Briones, J. F. Quílez del Moral, A. F. Barrero
FULL PAPER
Komiyama, Y. Takahashi, H. B. Woodruff, J. Antibiot. 2010,
63, 579; d) Y. Kinoshita, T. Kitahara, Tetrahedron Lett. 1997,
38, 4993–4996.
different natural products has been shown with the synthe-
sis of siccanochromene F (2, four steps, 18.9% yield; 23.7%
brsm), metachromins U (3, five steps, 22.0%) and V (4, six
steps, 17.3% yield), and bicyclic squalene derivative (5, four
steps, 28.2% yield) as well as the formal synthesis of
ambrein (6; intermediate 24: two steps, 67% yield; interme-
diate 26: two steps, 61.6% yield), siccanin (7; intermediate
15: four steps, 12.3% yield, 15.4% brsm), and phenazino-
mycin (8; intermediate 20: two steps, 52.5% yield). Other
elements of interest of this work include the optimization
and mechanistic proposal for the organocatalyzed Kabbe
reaction, the TiIII-catalyzed homocoupling of allylic alcohol
19, and the use of a second natural renewable source and
enantiopure starting material in addition to 1 for the formal
synthesis of ambrein.
[8] a) K. J. Ishibashi, J. Antibiot., Ser. A 1962, 15, 161; b) M. G.
Belloti, L. Riviera, Chimioterapia 1985, 4, 431; c) N. Kitano,
F. Kondo, K. Kusano, K. Ishibashi, US 3974291, 1976; d) M.
Matsuki, H. Hanatsu, T. Watanabe, A. Ogasawara, T. Mikami,
T. Matsumoto, Biol. Pharm. Bull. 2006, 29, 919; e) T. Mogi, T.
Kawakami, H. Arai, Y. Igarashi, K. Matsushita, M. Mori, K.
Shiomi, S. Omura, S. Harada, K. Kita, J. Biochem. 2009; 146,
383; f) M. Kato, K. Heima, Y. Matsuma, A. Yoshikoshi, J. Am.
Chem. Soc. 1981, 103, 2434; g) B. M. Trost, F. J. Fleitz, W. J.
Watkins, J. Am. Chem. Soc. 1996, 118, 5146; h) B. M. Trost,
H. C. Shen, J. P. Surivet, Angew. Chem. Int. Ed. 2003, 42, 3943;
Angew. Chem. 2003, 115, 4073; i) B. M. Trost, H. C. Shen, J. P.
Surivet, J. Am. Chem. Soc. 2004, 126, 12565.
[9] a) L. Ruzicˇka, C. F. Seidel, M. Pfeiffer, Helv. Chim. Acta 1948,
ˇ
31, 827; b) A. F. Barrero, J. F. Sanchez, F. G. Cuenca, Phyto-
chemistry 1988, 27, 3676.
[10] a) H. J. Kabbe, Synthesis 1978, 886; b) H. J. Kabbe, A. Widdig,
Angew. Chem. Int. Ed. Engl. 1982, 21, 247; Angew. Chem. 1982,
94, 254.
[11] a) For reviews, see: C. Grondal, M. Jeanty, D. Enders, Nature
Chemistry 2010, 2, 167; b) D. W. C. MacMillan, Nature 2008,
455, 304.
Experimental Section
Full experimental data as well as characterization and NMR spec-
tra of new compounds are given in the Supporting Information.
[12] a) D. Sánchez, D. Bastida, J. Burés, C. Isart, O. Pineda, J. Vilar-
rasa, Org. Lett. 2012, 14, 536; b) although the rates of enamine
formation of acetophenone and alkyl ketones are similar ac-
cording to ref.[12a], the fact that 10 is electronically different to
acetophenone could account for the observed selective enamine
formation.
Acknowledgments
Financial support for this work was provided by the Junta de And-
alucia (grant number P08-FQM-3596) and Ministerio de Economía
y Competitividad (MEC) (grant number CTQ-2010-16818).
[13] S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev.
2007, 107, 541.
[14] a) C. Palomo, A. Mielgo, Angew. Chem. Int. Ed. 2006, 45, 7876;
Angew. Chem. 2006, 118, 8042; b) K. L. Jensen, G. Dickmeiss,
H. Jiang, L. Albrecht, K. A. Jørgensen, Acc. Chem. Res. 2012,
45, 248; c) W. Wang, H. Li, J. Wang, L. Zu, J. Am. Chem. Soc.
2006, 128, 10354 and references cited therein.
[15] a) L.-W. Xu, Y. Lu, Org. Biomol. Chem. 2008, 6, 2047; b) L.-
W. Xu, J. Luo, Y. Lu, Chem. Commun. 2009, 1807; c) Z. Jiang,
Z. Liang, X. Wua, Y. Lu, Chem. Commun. 2006, 2801.
[16] a) G. A. Crispino, K. B. Sharpless, Tetrahedron Lett. 1992, 33,
4273; b) E. J. Corey, M. C. Noe, S. Lin, Tetrahedron Lett. 1995,
36, 8741; c) E. J. Corey, J. Zhang, Org. Lett. 2001, 3, 3211.
[17] T. H. Simpson, J. Org. Chem. 1963, 28, 2107.
[18] CCDC-980367 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. For additional X-ray
data, see Supporting Information.
[19] M. Lang, W. Stieglich, Synthesis 2005, 5, 1019.
[20] T. Yoshimura, H. Kisyuku, T. Kamei, K. Takabatake, M.
Shindo, K. Shishido, ARKIVOC (Gainesville, FL, U.S.) 2003,
247.
[21] a) S. Serra, A. A. Cominettia, V. Lissoni, Nat. Prod. Commun.
2014, 9, 303.
[22] A. F. Barrero, M. M. Herrador, J. F. Quílez del Moral, P. Arte-
aga, J. Arteaga, M. Piedra, E. M. Sánchez, Org. Lett. 2005, 7,
2301.
[23] M. Schalk, L. Pastore, M. A. Mirata, S. Khim, M. Schouwey,
F. Deguerry, V. Pineda, L. Rocci, L. Daviet, J. Am. Chem. Soc.
2012, 134, 18900.
[1] a) S. B. Jones, B. Simmons, A. Mastracchio, D. W. C. MacMil-
lan, Nature 2011, 475, 183; b) J. Wang, S.-G. Chen, B.-F. Sun,
G.-Q. Lin, Y.-J. Shang, Chem. Eur. J. 2013, 19, 2539; c) H. Li,
X. Wang, B. Hong, X. Lei, J. Org. Chem. 2013, 78; d) E. E.
Anagnostaki, A. L. Zografos, Chem. Soc. Rev. 2012, 41, 5613;
e) W. R. J. D. Galloway, A. Isidro-Llobet, D. R. Spring, Nature
Commun. 2010, 1, 80; f) G. Valot, J. García, V. Duplan, C.
Serba, S. Barluenga, N. Wissinger, Angew. Chem. Int. Ed. 2012,
51, 5391–5394; Angew. Chem. 2012, 124, 5487–5490; g) K. Foo,
I. Ussi, D. C. G. Götz, E. W. Werner, D. Holte, P. Baran, An-
gew. Chem. Int. Ed. 2012, 51, 1–6; Angew. Chem. 2012, 124, 1.
[2] a) J.-T. de Pascual, E. Caballero, C. Caballero, M. Medarde,
A. F. Barrero, M. Grande, Tetrahedron 1982, 38, 1837; b) A. F.
Barrero, M. M. Herrador de Pino, P. Arteaga, H. J. Rodrig-
uez Dieguez, WO 2010103145 A1, 2009; c) A. F. Barrero,
M. M. Herrador, P. Arteaga, A. Castillo, A. F. Arteaga, Nat.
Prod. Commun. 2011, 6, 1.
[3] K. Hirai, K. T. Suzuki, S. Nozoe, Tetrahedron 1971, 27, 6057.
[4] S. P. B. Ovenden, J. L. Nielson, C. H. Liptrot, R. H. Willis,
D. M. Tapiolas, A. D. Wright, C. A. Motti, J. Nat. Prod. 2011,
74, 1335.
[5] A. Behrens, P. Schaeffer, S. Bernasconi, P. Albrecht, Geochim.
Cosmochim. Acta 2000, 64, 3327.
[6] a) G. Ohloff, in: Fragrance Chemistry (Ed.: E. T. Theimer), Ac-
ademic Press, New York, 1982, p. 535; b) M. Raza, M. S. Alo-
rainy, A. A. Alghashm, Food Chem. Toxicol. 2007, 45, 1614; c)
S. A. Taha, Med. Sci. Res. 1994, 22, 97; d) K. Mori, H. Ta-
mura, Liebigs Ann. Chem. 1990, 361; e) H. Tanimoto, T. Orit-
ani, Tetrahedron 1997, 53, 3527; f) N. Fujiwara, M. Kinoshita,
H. Akita, Tetrahedron: Asymmetry 2006, 17, 3037; g) D. Ueda,
T. Hoshino, T. Sato, J. Am. Chem. Soc. 2013, 135, 18335.
[7] a) S. Funaama, S. Eda, K. Komiyama, S. Omura, T. Tokunaga,
Tetrahedron Lett. 1989, 30, 3151; b) S. Omura, S. Eda, S. Fu-
nayama, K. Komiyama, Y. Takahashi, H. B. Woodruff, J. Anti-
biot. 1989, 42, 1037; c) S. Omura, S. Eda, S. Funayama, K.
[24] A. F. Barrero, E. A. Manzaneda, J. Altarejos, S. Salido, J. M.
Ramos, M. S. Simmonds, W. M. Blaney, Tetrahedron 1995, 51,
7435.
[25] E. Negishi, A. O. King, J. M. Tour, Org. Synth. 1986, 64, 44–
49.
Received: February 12, 2015
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50208
/KAP1
Date: 14-04-15 12:59:34
Pages: 9
Collective Synthesis of Natural Products Sharing the Dihydro-γ-Ionone Core
Natural Products
The expedient enantioselective synthesis of
several natural products from a common
precursor, (+)-3,4-dihydro-γ-ionone, is de-
scribed. The production of this natural
compound in multigram scale from the ex-
tract Bellardia trixago is the basis of this
approach.
A. Castillo, L. Silva, D. Briones,
J. F. Quílez del Moral,*
A. F. Barrero* ................................. 1–10
Collective Synthesis of Natural Products
Sharing the Dihydro-γ-Ionone Core
Keywords: Natural products / Organocata-
lysis / Molecular diversity / Chiral pool
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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