The first total synthesis of natural acetogenin, chatenaytrienin-1, was performed in 10 steps and in 41% overall yield using cross-cyclomagnesiation of (6Z)-heptadeca-1,2,6-triene and trideca-11,12-dien-1-ol tetrahydropyran acetal with EtMgBr in the presence of Mg metal and the Cp2TiCl2 catalyst (10 mol %) as the key step of the synthesis.
The first total synthesis of natural acetogenin, chatenaytrienin-1, was performed in 10 steps and in 41% overall yield using cross-cyclomagnesiation of (6Z)-heptadeca-1,2,6-triene and trideca-11,12-dien-1-ol tetrahydropyran acetal with EtMgBr in the presence of Mg metal and the Cp2TiCl2 catalyst (10 mol %) as the key step of the synthesis.
Acetogenins, an abundant,
structurally diverse group of natural
compounds, are isolated from the Annonaceae plants, representing nonbranched
fatty acids (C32–C34) with a γ-lactone
moiety.[1] In most cases, acetogenin molecules
contain additional hydroxy, keto, epoxy, tetrahydrofuran, or tetrahydropyran
groups as well as double and triple bonds. The enhanced interest in
this class of compounds is due to a wide range of biological activities
they exhibit such as antibacterial, immunosuppressive, antimalarial,
anticancer, and antiprotozoal activities.[2] Moreover, it has been shown that acetogenins, as well as compounds
containing a 2,5-bis(hydroxymethyl)tetrahydrofuran moiety, are capable
of exerting a cytotoxic effect on multidrug-resistant tumors due to
inhibition of the ATP synthesis and are among the most active of currently
known mitochondrial complex I inhibitors.[3] In addition, acetogenins can interact with DNA polymerases and topoisomerases,
thus affecting the synthesis of deoxyribonucleic acids in the cell.[4] The possibility of affecting the regulation of
cell cycle by relatively low concentrations of these substances, together
with pronounced antitumor action and a relatively beneficial effect
on healthy cells, makes this class of compounds promising for the
development of new highly effective antitumor agents. Since plants
produce exceptionally low (nanogram) quantities of acetogenins, a
chemical synthesis is the only option for obtaining these compounds
for practical use. It is important to ensure high stereoselectivity
of the resulting compounds since the activity of these bioregulators
is crucially affected by the geometry of the double bonds and asymmetric
centers present in molecules.[5]Currently,
quite a number of examples of synthesizing of structurally
diverse acetogenins and their analogues have been reported in the
literature; in the vast majority of cases, these are representatives
of the acetogenin family containing one to three furan moieties in
the molecule, with the major synthetic strategy being successive assembly
of the molecule from small blocks by known C–C bond formation
protocols.[6] Despite that an effective approach
to cascade cyclization of the above-described unsaturated compounds
has now been developed; at the same time, it has been shown that the
crucial factor dictating the stereoselective formation of tetrahydrofurans
and hydroxyl groups is a strict stereoconfiguration of substituents
at the double bonds.The Ru-catalyzed oxidative cyclization
of 1Z,5Z-dienes yields only anti,anti-stereoisomers of 2,5-bis(hydroxymethyl)tetrahydrofurans,
which exhibit
the highest antitumor and antibacterial activities.[7]Development of the strategy for the total synthesis
of acetogenins
containing tetrahydrofuran moieties via the oxidative cyclization
of the appropriate bis-methylene-separated di- and polyenes is mainly
hampered, in our opinion, by the lack of an efficient synthetic approach
to the latter. A survey of literature indicates that methods used,
most often, to generate the 1Z,5Z-diene moiety are based on the Wittig reaction, olefin metathesis,
and stereoselective catalytic hydrogenation of acetylenes.[8] The task becomes more challenging if the synthesis
implies the formation of compounds containing three or more Z-double bonds.The previously developed Ti-catalyzed
homo- and cross-cyclomagnesiation
of 1,2-dienes, which leads to strictly stereoselective formation of
metal–carbon and carbon–carbon bonds, could be successfully
utilized as a convenient and versatile tool in the stereoselective
synthesis of various 1Z,5Z-diene
derivatives (Scheme ).[9]
Scheme 1
Ti-Catalyzed Homo- and Cross-Cyclomagnesiation
of 1,2-Dienes
The results reported
in the papers mentioned above[9] can be used
for the synthesis of a broad range of natural
biologically active compounds, higher 5Z,9Z-dienoic acids, insect pheromones, lembehynes, unique macrocarbocycles,
and also acetogenins.[4,10]In particular, previously,
we developed an original five-step synthesis
of a natural acetogenin, muricadienin 1, a bioprecursor
of cis-solamin 2 (Figure ),
giving the product in ∼60% yield. The synthesis involved cross-cyclomagnesiation
of functionally substituted allenes with EtMgBr in the presence of
Mg metal (halogen ion acceptor) and catalyzed by Ti complexes as the
key step. In addition, we previously found that muricadienin exhibits
inhibitory activity in vitro against key cell cycle enzymes human
topoisomerases I and IIα and has high cytotoxicity against humanembryonic kidney cells HEK293 (IC50 = 0.39 μM).[4]
Figure 1
Structures of muricadienin, chatenaytrienin-l and 4,cis-solamin and membranacin.
Structures of muricadienin, chatenaytrienin-l and 4,cis-solamin and membranacin.Considering the practical value of research aimed at the search
for new preparative approaches for the syntheses of natural biologically
active compounds with a Z-polyunsaturated hydrocarbon
chain and also to study the applicability of reactions we developed
for the preparation of more structurally sophisticated acetogenins,
here, we intended to synthesize chatenaytrienin-1 3 using
the Ti-catalyzed cross-cyclomagnesiation of 1,2-dienes as the key
step.Chatenaytrienin-l 3, which was isolated in
1998 by
Gleye and co-workers from Annona muricata, is a natural triene bioprecursor of Annonaceous acetogenin, membranacin 5, containing a bis-THF moiety (Figure ).[11]When
our study was started, only a single example of synthesizing
a structurally similar homologue of compound 3, chatenaytrienin-4 4, was available from the literature. Compound 4 was prepared in 15 steps in an overall yield of 6%.[12]
Results and Discussion
Initially, we carried out the
retrosynthetic analysis of the chatenaytrienin-l 3, which
implied the successive synthesis of (11Z,15Z,19Z)-triaconta-11,15,19-trienoic
acid 6 by means of catalytic cross-cyclomagnesiation
followed by the construction of α-substituted butenolide, with
the Fries rearrangement being the final step of the synthesis of the
target triene (Scheme ).
Scheme 2
Retrosynthetic Analysis of Chatenaytrienin-1
The initial monomer needed for the preparation of Z,Z,Z-trienoic acid 6, (6Z)-heptadec-1,2,6-triene 10, was
synthesized in several steps using the alkylation of commercially
available dodec-1-yne 8 with ethylene oxide (Scheme ).[13] The subsequent selective hydrogenation of alcohol 12 was carried out in the presence of Brown’s catalyst
P2–Ni and afforded unsaturated alcohol 9 with Z-configuration of the double bond in ∼98% yield.[14] Ethynylation of compound 13, obtained
by bromination of alcohol 9 with LiBr,[15] on treatment with lithium acetylenide yielded (5Z)-hexadec-5-en-1-yne 14 in a quantitative
yield.[16] Allene 10 was obtained
from alkyne 14 by the Crabbé reaction that involves
refluxing with paraformaldehyde, dicyclohexylamine, and copper iodide.[17]
Scheme 3
Synthesis of (6Z)-Heptadeca-1,2,6-triene
According to the developed synthetic strategy,
(11Z,15Z,19Z)-triaconta-11,15,19-trienoic
acid 6 was prepared by the cross-cyclomagnesiation of
(6Z)-heptadeca-1,2,6-triene 10 and trideca-11,12-dien-1-ol
tetrahydropyran acetal 11 with EtMgBr in the presence
of Mg metal and the Cp2TiCl2 catalyst (10 mol
%) at room temperature (Scheme ). The reaction proceeded via the intermediate magnesacyclopentane 15, which was hydrolyzed to give (11Z,15Z,19Z)-triaconta-11,15,19-trien-1-ol tetrahydropyran
acetal 16 in 85% yield. The subsequent oxidation of tetrahydropyran
acetal 16 with the Jones reagent gave the desired Z,Z,Z-trienoic acid 6.
Scheme 4
Titanium-Catalyzed Cross-Cyclomagnesiation of Allenes
All that remains for the synthesis of chatenaytrienin-l 3 was the formation of the terminal butenolide moiety, which
was effected
by a method that proved useful,[18] based
on the Fries rearrangement catalyzed by DMAP (Scheme ). Indeed, O-acylation of cyclic β-keto
ether 7, which was obtained from (S)-ethyl
lactate by a reported two-step procedure,[19] with acid 6 followed by the DMAP-initiated rearrangement
afforded triene 17, which was then undergo reduction
by NaBH3CN in acetic acid to produce α-alkylated
butenolide 18 in a yield of more than 97%.
Scheme 5
Fries Rearrangement:
Introduction of the Terminal α-Substituted
Butenolide
The hydroxyl group in the C3-position
of butenolide was eliminated
by successive synthesis of triflate 19 and its reduction
with Bu3SnH catalyzed by Pd2(dba)3; this gave the target chatenaytrienin-l 3 in ∼91%
yield.[8k]
Conclusions
Thus,
we have achieved the first stereoselective 10 step synthesis
of chatenaytrienin-l using Ti-catalyzed cross-cyclomagnesiation of
aliphatic and oxygenated 1,2-dienes with the Grignard reagent. This
study demonstrates the enormous synthetic potential of the proposed
method as a convenient tool for stereoselective preparation of 1Z,5Z-diene systems. Currently, our efforts
are focused on the synthesis of a number of natural homologues of
chatenaytrienin-l to obtain larger amounts of these products and conduct
extensive studies of their antitumor, antibacterial, and antiparasitic
activities.
Experimental Section
General Information
1-Dodecyne,
lithium acetylide,
ethylene diamine complex, nickel (II) acetate tetrahydrate (Ni(OAc)2·4H2O), dicyclohexylamine, copper (I) iodide
(CuI), bis(cyclopentadienyl)titanium (IV) dichloride (Cp2TiCl2), 4-dimethylaminopyridine (DMAP), N,N′-dicyclohexylcarbodiimide (DCC), sodium
cyanoborohydride (NaBH3CN), trifluoromethanesulfonic anhydride
(Tf2O), and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) were obtained from Sigma-Aldrich and Acros
organics. All reactions were carried out under an argon atmosphere. 1H and 13C NMR spectra were obtained using a Bruker
Ascend 500 spectrometer in CDCl3 operating at 500 MHz for 1H and 125 MHz for 13C and a Bruker AVANCE 400 spectrometer
in CDCl3 operating at 400 MHz for 1H and 100
MHz for 13C. IR spectra were recorded on a Bruker VERTEX
70V using KBr discs over the range of 400–4000 cm–1. Mass spectra of MALDI TOF/TOF positive ions (matrix of sinapic
acid) are recorded on a mass spectrometer Bruker Autoflex III Smartbeam.
Elemental analyses were measured on a 1106 Carlo Erba apparatus. Individuality
and purity of the synthesized compounds were controlled using TLC
on Sorbfil plates; anisic aldehyde in acetic acid was used as a developer.
Column chromatography was carried out on Acrus silica gel (0.060–0.200
mM).
Cross-Cyclomagnesiation of (6Z)-Heptadeca-1,2,6-triene
(10) and 2-(Trideca-11,12-dien-1-yloxy)tetrahydro-2H-pyran (11) by EtMgBr in the Presence of Mg
Metal and Cp2TiCl2 Catalyst (General Procedure)
Diethyl ether (50 mL), (6Z)-heptadeca-1,2,6-triene 10 (2.3 g, 10.0 mmol), 2-(trideca-11,12-dien-1-yloxy)tetrahydro-2H-pyran 11 (2.3 g, 8.4 mmol), EtMgBr (66.8
mL, 100.2 mmol) (as 1.5 M solution in Et2O), Mg powder
(3.0 g, 125.8 mmol), and Cp2TiCl2 (0.4 g, 1.8
mmol) were charged into a glass reactor with stirring under argon
(∼0 °C). The reaction mixture was heated to 20–22
°C and stirred for 24 h. The reaction mixture was treated with
a 5% solution of NH4Cl in H2O (30 mL) and extracted
with diethyl ether (2 × 100 mL). The combined organic phases
were dried over MgSO4 and filtrated. Then, the solvent
was removed under reduced pressure. Silica gel column chromatography
(hexane/EtOAc = 35:1) of the residue gave compound 16.
Oxidation of 2-[(11Z,15Z,19Z)-Triaconta-11,15,19-trien-1-yloxy]tetrahydro-2H-pyran 16 with Jones Reagent
To a
solution of 2-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yloxy]tetrahydro-2H-pyran 16 (8.0 g, 15.3 mmol) in acetone (100
mL) and CH2Cl2 (25 mL) at room temperature,
Jones reagent (18.7 mL) was added dropwise. The reaction mixture was
stirred at room temperature for 1 h, quenched with water (50 mL),
and concentrated to remove the excess of acetone and CH2Cl2. Then, the aqueous layer was extracted with diethyl
ether (3 × 100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column
chromatography using hexane/EtOAc = 30:1 as the elution solvent to
afford (11Z,15Z,19Z)-triaconta-11,15,19-trienoic acid 6.
Synthesis
of (5S)-4-Hydroxy-5-methyl-3-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]furan-2(5H)-one (18)
DIPEA (2.3 mL, 13.3 mmol)
was added to a suspension of butenolide 7 (1.5 g, 13.3
mmol), fatty acid 6 (5.2 g, 11.7 mmol), 4-DMAP (0.4 g,
3.3 mmol), and DCC (2.7 g, 13.3 mmol) in DCM (50 mL) at 0 °C.
The reaction mixture was stirred overnight with warming to room temperature.
The yellow solution was filtered, and the solid was washed with diethyl
ether. The filtrate was concentrated, and the residue was dissolved
in ethyl acetate. The organic phase was washed with a solution of
1 N HCl and brine, dried over MgSO4, filtrated, and concentrated
under reduced pressure. To remove residual urea derivative, the mixture
was dissolved in diethyl ether, filtrated, and concentrated in vacuo
to yield a brownish solid that was directly used in the subsequent
reduction step. To this end, the crude product was dissolved in acetic
acid (30 mL), and NaBH3CN (5.3 g, 23.4 mmol) was slowly
added at 10 °C. The reaction mixture was stirred overnight with
warming to room temperature and then poured into a solution of 1 N
HCl (10 mL). The aqueous layer was extracted with ethyl acetate (3
× 50 mL). The combined organic phases were washed with H2O and brine, dried over MgSO4, filtrated, and concentrated
in vacuo (3 × codestillation with toluene to remove acetic acid).
The title compound 18 was obtained in analytically pure
product.
Synthesis of (2S)-2-Methyl-5-oxo-4-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]-2,5-dihydrofuran-3-yl
Trifluoromethanesulfonate (19)
DIPEA (2.5 mL,
14.1 mmol) was added to a stirred solution of compound 18 (5.0 g, 9.4 mmol) in DCM (100 mL) at room temperature. The solution
was cooled to −78 °C and Tf2O (3.1 g, 1.9 mL,
10.9 mmol) was slowly added. The mixture was stirred at −78
°C for 2 h. After complete conversion, DCM (20 mL) was added,
and the reaction mixture was extracted with a solution of 1 N HCl
(100 mL). The combined organic phases were washed with H2O, brine, dried over MgSO4, and filtrated. The solvents
were removed under reduced pressure. Silica gel column chromatography
(hexane/EtOAc = 30:1) of the residue gave triflate 19.
Synthesis
of (5S)-5-Methyl-3-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]furan-2(5H)-one (Chatenaytrienin-l 3)
Pd2(dba)3 (13.7 mg, 0.015 mmol, 1.5 mol %) and PPh3 (39.3 mg, 0.15 mmol, 15.0 mol %) were dissolved in dry THF
(10 mL). After stirring for 5 min at room temperature, triflate 19 (0.7 g, 1.0 mmol) and Bu3SnH (0.8 mL, 3.0 mmol)
were added to the orange solution. The mixture was heated to 50 °C
and stirred at this temperature for 5 h. After complete conversion
of the starting material, the reaction was cooled to room temperature,
diluted with H2O (10 mL), and extracted with diethyl ether
(3 × 30 mL). The combined organic phases were dried over MgSO4 and filtrated. Then, the solvents were removed under reduced
pressure. Silica gel column chromatography (hexane/EtOAc = 20:1) of
the residue gave chatenaytrienin-l 3.
Scheme 1
Figure 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5