Oxidative allylic rearrangement of cycloalkenols: Formal total synthesis of enantiomerically pure trisporic acid B

Article abstract of DOI:10.3762/bjoc.7.54

Enantiomerically highly enriched unsaturated β-ketoesters bearing a quaternary stereocenter can be utilized as building blocks for the synthesis of natural occurring terpenes, i. a., trisporic acid and its derivatives. An advanced building block has been

Full text of DOI:10.3762/bjoc.7.54

Oxidative allylic rearrangement of cycloalkenols:
Formal total synthesis of enantiomerically pure
trisporic acid B
Silke Dubberke1, Muhammad Abbas2 and Bernhard Westermann*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 421–425.
1Leibniz Institute of Plant Biochemistry, Department of Bioorganic
Chemistry, Weinberg 3, D-06120 Halle (Saale), Germany, 2Chair of
Advanced Proteomics and Cytomics Research, Faculty of Science,
Department of Zoology, King Saud University, P.O. Box 2455, 11415
Riyadh, Saudi Arabia and 3Martin-Luther-University, Department of
Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale),
Germany
doi:10.3762/bjoc.7.54
Received: 20 December 2010
Accepted: 22 March 2011
Published: 11 April 2011
Associate Editor: B. Stoltz
Email:
© 2011 Dubberke et al; licensee Beilstein-Institut.
License and terms: see end of document.
Bernhard Westermann* - bernhard.westermann@ipb-halle.de
* Corresponding author
Keywords:
enzymatic resolution; natural products; oxidative rearrangement; pig
liver esterase (PLE); trisporic acid B
Abstract
Enantiomerically highly enriched unsaturated β-ketoesters bearing a quaternary stereocenter can be utilized as building blocks for
the synthesis of natural occurring terpenes, i. a., trisporic acid and its derivatives. An advanced building block has been synthesized
in a short reaction sequence, which involves an oxidative allylic rearrangement initiated by pyridinium dichromate (PDC) as the
key step.
Introduction
The generation of chiral, non-racemic compounds bearing a β-ketoesters (±)-1a,b (Scheme 1) to provide a convenient access
stereogenic quaternary carbon centre is of great interest [1-8]. to highly functionalized cyclohexenones in optically pure form.
Therefore, much effort has been directed towards the synthesis In addition, we show that non-racemic chiral α-substituted,
of this stereogenic unit and solutions have been found, e.g., by β-ketoesters such as (−)-1c can be easily obtained by the
Christoffers and d’Angelo [9-11]. We have already disclosed enzyme-catalyzed hydrolysis of the ester moiety.
our results to obtain these products highly enantiomerically
enriched by pig liver esterase (PLE) catalyzed saponification of The β-ketoesters 1 are of particular interest because they can be
α-substituted β-ketoesters [12,13]. We have now extended this envisioned as suitable starting materials for natural product
methodology towards the saponification of unsaturated syntheses and have important technical applications. For
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Beilstein J. Org. Chem. 2011, 7, 421–425.
Scheme 1: PLE (pig liver esterase)-catalyzed saponification of β-ketoesters 1.
example, enantiomerically pure 1a can be used as building biosynthesis of the trisporic acid, mating species of the oppo-
block for the synthesis of dienes leading to nagilactones, 1b has site sex have to cooperate. It has been suggested, that these
been utilized for the preparation of ferroelectric liquid crystals carotenoid-derived substances both regulate and stimulate the
[14,15]. Starting from (−)-1c a vast number of cyclohexene first stages of sexual development [17,19]. In this publication,
carboxylic acid-based natural products bearing additional alkyl the formal total synthesis of optically pure (9Z)-trisporic acid
substituents can be synthesized. These structural features can be methyl ester (1R,9Z)-4 (Figure 1) will be described, starting
found in the cyclic framework of (9E)- and (9Z)-trisporic acid B from the methyl (1R)-1,3-dimethyl-2-oxocyclohex-3-ene-1-
((9E)-3, (9Z)-3) and its methyl esters (9E)-4 and (9Z)-4, which carboxylate ((−)-1c, Scheme 1) [21,22].
are very potent fungal pheromones [16-20]. Both the 9E and the
9Z isomer occur naturally (Figure 1).
Results and Discussion
Precursor for the synthesis of racemic cyclohexenone (±)-1c is
methyl 2-methyl-3-oxopentanoate (5), which upon addition of
acrolein undergoes a tandem Michael/aldol-reaction sequence
(Scheme 2) [11]. To obtain optically pure β-ketoester 1c, the
racemate 1c is resolved by a pig liver esterase (PLE)-catalyzed
saponification reaction. As in other cases reported earlier, the
racemic β-ketoesters are hydrolyzed with high stereoselectivity
allowing the isolation of optically pure esters (–)-1. The corres-
ponding hydrolysis products, the (+)-β-ketoacids decarboxylate
and racemize to cyclohexenones 2 during the enzymatic reac-
tion and workup (Scheme 1) [12,14]. Treatment of (±)-1c in
phosphate buffer at pH 7.0 led to selective saponification of the
(S)-isomer (+)-1c to give rac-2c.
The enantiomeric excess of (−)-1c was monitored during the
reaction, and after completion of the reaction the enantiomeric
excess was determined to be >99% by GLC using a cyclodex-
trin modified stationary phase (LIPODEX E). The R-configura-
tion at the stereocenter was established by chemical correlation
Figure 1: (9E)- and (9Z)-trisporic acid B.
Trisporic acids have been isolated from cultures of mucora- [10,14].
ceous fungi: Blakeslea trispora, Mucor mucedo and
Phycomyces blakesleeanus [16]. They stimulate caratenogen- The first step towards the synthesis of cyclohexenone (+)-7,
esis and zygophore (sex cell) formation. Interestingly, for the which is the key building block in our synthesis, was the
Scheme 2: Synthesis and PLE-catalyzed saponification of β-ketoester 1c.
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Beilstein J. Org. Chem. 2011, 7, 421–425.
incorporation of a C2 unit into β-ketoester (−)-1c (Scheme 3). All solvents were dried over standard drying agents; THF was
This was achieved by adding ethynyl magnesium bromide in freshly distilled over sodium prior to use. Enzymatic reactions
THF at room temperature. The cyclohexenol (+)-6 can be were monitored by Methrom 702 SM Titrino titrator, chiral
isolated in 79% yield with a diastereomeric ratio of 96:4. GLC was performed with a LIPODEX E column (12 m),
However, the configuration at the newly created stereogenic provided by Macherey&Nagel, Germany. Pig liver esterase
centre need not be determined since it is destroyed in the next (PLE) was purchased from Sigma. Reactions were monitored
step, the PDC-catalyzed rearrangement to (+)-7. After 7 h, no by TLC on silica gel 60 F254. Column chromatography was
starting material was detected by TLC, allowing the isolation of performed on silica gel 60 (70–230 mesh, ASTM). Melting
the desired cyclohexenone 7 in 91% yield. Although steric points were determined with a Gallenkamp melting point appa-
interference was believed to be a major obstacle of this process, ratus in open capillaries and are uncorrected. Optical rotations
this factor turned out to be unimportant. It is assumed, that the were measured in solution at 589 nm with a PerkinElmer 241
transition state during [3,3]-sigmatropic rearrangement is as polarimeter on a 1.00 dm cell. 1H (200 MHz) and 13C (50 MHz)
shown in Scheme 3 [23,24], where the hydroxyl group is fixed NMR spectra were recorded with a Bruker AMX-200 with
in a pseudo-axial orientation, any other orientation would cause TMS as internal reference. Coupling constants J are given in
severe steric interaction with the 3-methyl group.
Hz, the carbon multiplicities were assigned by DEPT 135 pulse
sequence techniques (s = singlet, d = doublet, t = triplet, q =
In conclusion, the key intermediate R-(+)-7, which can be quadruplet). IR spectra were recorded with a Nicolet 510 FT-IR
utilized as an enantiomerically pure starting material in spectrometer, and GC–MS analysis was performed with a
Suzuki’s elegant protocol [25] towards the synthesis of racemic Finnigan MAT Magnum System 240, Varian GC 3400 DB 5.
(9E)-trisporic acid B methyl ester (9E)-4, has been synthesized Elemental analysis was carried out with a PerkinElmer
enantiomerically pure in a two step procedure starting from elemental analysator 240 at the University of Paderborn,
optically pure β-ketoester (−)-1c in an overall yield of 65%. Germany.
Furthermore, we have shown that the oxidative allylic
rearrangement of cycloalkenols can be carried out easily despite Methyl (−)-(1R)-1,3-dimethyl-2-oxocyclohex-3-ene-1-
a high degree of functionalization and steric interactions. There- carboxylate (1c). Methyl 2-methyl-3-oxopentanoate (5)
fore, this method should be applicable additionally to the syn- (3.42 g, 24.0 mmol) was added dropwise to a solution of
thesis of a great number of natural products such as cassiol sodium methoxide prepared from sodium (0.02 g, 0.9 mmol)
[26,27].
and methanol (30 mL). The reaction mixture was cooled to 0 °C
(ice bath), after which freshly distilled acrolein (1.34 g,
24.0 mmol) in methanol (8 mL) was added dropwise. Stirring
Experimental
General. All air- and moisture-sensitive reactions were was continued at 20 °C for approx. 12 h. The mixture was
performed under an argon atmosphere in oven-dried glassware. cooled in ice, and HCl (gas) introduced until the color changed
Scheme 3: Synthesis of key building block (+)-7.
423

Beilstein J. Org. Chem. 2011, 7, 421–425.
to red (approximately after 2–3 h); stirring was then continued Methyl (+)-(1R)-2-ethynyl-1,3-dimethyl-4-oxocyclohex-2-
at 20 °C for about 12 h. The reaction mixture was filtered and ene-1-carboxylate (7). PDC (0.72 g, 1.90 mmol) was added to
evaporated to dryness. After the addition of a catalytic amount a solution of 6 (0.20 g, 0.90 mmol) in abs CH2Cl2 (5 mL) in the
of hydroquinone the dark brown residue was heated at 180 °C presence of a catalytic amount of hydroquinone. The resulting
for 1 h and then purified by distillation under reduced pressure suspension was heated under reflux in an argon atmosphere for
to give (±)-1c (1.70 g, 40%). The kinetic resolution was carried 7 h. At the end of the reaction, ethyl acetate (1 mL) was added
out as follows: To phosphate buffer (pH 7.0, 0.1 M, KH2PO4/ and the product separated from the chromium salts by passage
K2HPO4, 200 mL) was added (±)-1c (1.50 g, 8.2 mmol) and through a short column of silica gel (petroleum/ethyl acetate
PLE (100 µL) and the resulting mixture stirred at 20 °C. The pH 9:1) to give 7 (0.18 g, 91%) as a colorless oil. The product
was maintained constant by periodic addition of NaOH (2 N). required storage in a freezer to prevent polymerization. Rf = 0.1
During the reaction, the ee value was monitored by GLC (petroleum/ethyl acetate 9:1);
+48.4 (c 0.98, CHCl3);
(LIPODEX E). After the reaction was complete, the mixture IR (film): 3262, 2984, 2955, 2100, 1736, 1674, 1593 cm−1;
was acidified with aqueous HCl to pH 2 and extracted overnight 1H NMR (CDCl3): δ 1.57 (s, 3H, CH3), 1.89–2.00 (m, 2H,
using a continuous liquid/liquid extractor with Et2O. After CH2), 2.03 (s, 3H, CH3), 2.39–2.57 (m, 2H, CH2), 2.50 (s, 1H,
drying of the organic layer (MgSO4), the solvent was evapo- ≡CH), 3.76 (s, 3H, OCH3); 13C NMR (CDCl3): δ 14.8 (q), 24.4
rated and the remaining oily residue distilled in a Kugelrohr (q), 33.9, 34.7 (2 t), 47.5 (s), 53.0 (q), 80.6 (s, C≡), 92.5 (d,
apparatus to afford (−)-1c (590 mg, 39%); bp 88 °C/1.1 Torr; ≡CH), 138.2, 141.5 (2 s, C=C), 174.7 (s, CO), 197.4 (s, CO);
−81.2 (c 1.55, CHCl3); IR (film): 2978, 2872, 1736, GC–MS (70 eV) m/z (%): 207 (100) [M + H]+, 191 (50), 178
1676 cm−1; 1H NMR (CDCl3): δ 1.27 (s, 3H, CH3), 1.70 (s, 3H, (23), 150 (21), 119 (65), 91 (50); Anal. Calcd for C12H14O3
CH3), 1.68–1.85 (m, 1H), 2.21–2.44 (m, 3H), 3.59 (s, 3H, (206.2): C, 69.89; H, 6.84. Found: C, 69.72; H, 7.03.
OCH3), 6.58 (dd, J = 3.2 Hz, 1H, =CH); 13C NMR (CDCl3): δ
16.7 (q), 20.6 (q), 23.6, 33.9 (2 t), 52.6 (q), 53.5 (s), 134.9 (s, Acknowledgements
=C-), 144.5 (d, =CH), 173.6 (s, CO), 197.6 (s, CO); GC–MS We gratefully acknowledge support by the Graduierten-
(80 eV) m/z (%): 182 (25), 167 (28), 150 (50), 135 (15), 123 förderung (grant to S. D.) and the Fonds der Chemischen Indus-
(41), 95 (22), 82 (100), 79 (14); Anal. Calcd for C10H14O3 trie. Some of the experiments were carried out at the University
(182.2): C, 65.92; H, 7.74. Found: C, 65.78; H, 7.75.
of Paderborn, Germany. For the support in Paderborn, we are
indebted to Prof. Krohn.
Methyl (+)-(1R,2R*)-2-ethynyl-2-hydroxy-1,3-dimethyl-
cyclohex-3-ene-1-carboxylate (6). To a solution of (−)-1c
(0.50 g, 2.75 mmol) in THF (5 mL), was added dropwise over a
period of 30 min ethynyl magnesium bromide (0.5 M in THF;
9.05 mL, 4.53 mmol) at 20 °C. Stirring at this temperature was
continued for 1 h, and then the reaction mixture was quenched
by adding sat. aq NH4Cl-solution (3 mL). The organic layer was
separated, and the aqueous phase extracted with Et2O (3 ×
50 mL). The organic layers were combined and washed in turn
with 10% HCl, brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by column chroma-
tography (silica gel, petroleum/ethyl acetate 9:1) to give color-
less crystals of 6 (0.45 g, 79%); mp 79.2 °C; Rf = 0.21 (petro-
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