Asymmetric total syntheses of cochliomycin A and zeaenol

Article abstract of DOI:10.1002/ejoc.201200241

The first asymmetric total syntheses of two resorcylic acid lactones (RALs) - cochliomycin A and zeaenol - have been achieved in a divergent way. The main highlight of our strategy involves successful application of stereoselecive Keck allylation and Julia-Kocienski olefination to access an advanced intermediate, by starting from L-tartaric acid as a chiral pool compound. This intermediate is coupled with a trisubstituted benzoic acid to afford a common RCM precursor for both target molecules. Ring-closing metathesis at a late stage, followed by functional group manipulation, yielded the target molecules in an efficient way. Two resorcylic acid lactones (RALs) - cochliomycin A and zeaenol - have been synthesized for the first time by an enantiodivergent route from the common chiral pool compound L-tartaric acid. Copyright

Full text of DOI:10.1002/ejoc.201200241

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201200241
Asymmetric Total Syntheses of Cochliomycin A and Zeaenol
Nandan Jana[a] and Samik Nanda*[a]
Keywords: Lactones / Asymmetric synthesis / Metathesis / Synthetic methods / Macrocycles
The first asymmetric total syntheses of two resorcylic acid
lactones (RALs) – cochliomycin A and zeaenol – have been
achieved in a divergent way. The main highlight of our strat-
egy involves successful application of stereoselecive Keck
allylation and Julia–Kocienski olefination to access an ad-
ral pool compound. This intermediate is coupled with a tri-
substituted benzoic acid to afford a common RCM precursor
for both target molecules. Ring-closing metathesis at a late
stage, followed by functional group manipulation, yielded
the target molecules in an efficient way.
vanced intermediate, by starting from L-tartaric acid as a chi-
Introduction
Resorcylic acid lactones (RALs) have been known for
decades, with the first isolation of radicicol (monorden) in
1953,[1] followed by zearalenone in 1962,[2] LL-Z1640-2 in
1978,[3] and hypothemycin in 1980.[4] After that a series of
14-membered resorcylic acid lactones, such as radicicol A,[5]
aigialomycins A–E,[6] pochonins A–P,[7] and paecilomy-
cins A–F,[8] were reported as fungal polyketide metabolites.
All of these compounds have received considerable atten-
tion, due to their potent biological properties, which include
antifungal,[9] cytotoxic,[6,10] antimalarial,[10] antiviral, anti-
parasitic,[4,11] estrogenic,[12] nematicidal,[13] protein tyrosine
kinase, and ATPase inhibition activities.[14]
Scheme 1. Structures of some recently isolated RALs.
Recently two new 14-membered resorcylic acid lactones
each containing a rare natural acetonide group [cochliomy-
cins A and B (1 and 2, Scheme 1)] and one new 5-chloro-
substituted lactone [cochliomycin C (3)], together with four
known analogues – namely, zeaenol (4),[15] LL-Z1640-1
(5),[3] LL-Z1640-2 (6),[3] and paecilomycin F (7)[8] – were
obtained from the fungus Cochliobolus lunatus in the South
China Sea.[16] These lactones were evaluated against the lar-
val settlement of the barnacle Balanus amphitrite, and anti-
fouling activity was detected for the first time in this type
of metabolites.
The frameworks of cochliomycin A (1) and zeaenol (4)
are basically similar except for the acetonide linkage in 1
(Scheme 1). The diverse biological functions and curious
skeletal features of these lactones tempted us to synthesize
them. There are numerous reports containing total synthe-
ses of RALs,[17] but to the best of our knowledge no synthe-
ses of the two target molecules cochliomycin A and zeaenol
have been reported to date. One of the finest synthetic stra-
tegies reported for RALs involves a biomimetic synthesis
featuring a late-stage aromatization of suitably substituted
triketo esters, as demonstrated by Barett et al. in their total
synthesis.[17a,17b]
Present Work
Scheme 2 outlines our retrosynthetic analysis of cochlio-
mycin A (1) and zeaenol (4). We planned to adopt ring-
closing metathesis (RCM) at a late stage of the synthesis to
construct the 14-membered macrocyclic core. It was imag-
ined that the RCM precursor should be accessible through
a Mitsunobu esterification between secondary aliphatic
alcohol 9 and trisubstituted benzoic acid 8 and that the
aromatic acid 8 should be obtainable from 3,5-dihydroxy-
benzoic acid through formylation of a styrene-type com-
pound, whereas it was intended to synthesize the other chi-
ral alcohol intermediate 9 from l-tartaric acid through
asymmetric Keck allylation and Julia–Kocienski-type ole-
fination with sulfone 11. It was envisaged that the
[a] Department of Chemistry, Indian Institute of Technology,
Kharagpur, 721302, India
Fax: +91-3222-282252
E-mail: snanda@chem.iitkgp.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200241.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
N. Jana, S. Nanda
FULL PAPER
Scheme 2. Retrosynthetic analysis of cochliomycin A and zeaenol.
stereocenter in the sulfone 11 could be established by appli- Synthesis of Sulfone 11
cation of a metal/enzyme combined DKR (dynamic kinetic
resolution) strategy to racemic butane-1,3-diol.
The sulfone intermediate was synthesized by starting
from the known alcohol (R)-16 (Scheme 4), previously pre-
pared in our group[20d] by a metal/enzyme combined DKR
strategy.[20] The secondary hydroxy group in 16 was pro-
tected as a TBDPS (tert-butyldiphenylsilyl) ether by treat-
ment with imidazole/TBDPSCl, and removal of the PMB
group was successfully achieved with DDQ[21] to yield com-
pound 17 in 82% yield (two steps). Finally, the primary
hydroxy group was transformed into the corresponding 1-
phenyl-1H-tetrazol-5-yl sulfide 18 through a Mitsunobu re-
action, and subsequent MoIV-catalyzed oxidation[22] of 18
afforded the desired sulfone 11 in 88% yield over two steps.
Results and Discussion
Synthesis of Aromatic Acid 8
Trisubstituted benzoic acid 8, with a pendant vinyl
group, was synthesized from 3,5-dihydroxybenzoic acid in
seven steps (Scheme 3). The synthetic sequence started with
trimethylation of 3,5-dihydroxybenzoic acid with dimeth-
ylsulfate and K2CO3 as a base, followed by reduction of the
ester functionality with LAH in dry ether at 0 °C to give
3,5-dimethoxybenzyl alcohol (12, 94% yield in two steps).
PCC oxidation of the benzyl alcohol functionality and sub-
sequent one-carbon extension by Wittig olifination pro-
duced the substituted styrene 13 in 81.6% yield (two steps).
Vilsmeier–Haack formylation (POCl3 in DMF) of com-
pound 13 at –5 °C to room temperature for 8 h regiospecif-
ically introduced the aldehyde group in the position ortho
to the vinyl group to furnish compound 14 in 87% yield.
Selective demethylation with BBr3 afforded the aldehyde 15
in 92% isolated yield.[18] Finally, oxidation under Pinnick
conditions[19] provided the required benzoic acid derivative
8 in good yield (90% based on recovered aldehyde, overall
yield 54% from 3,5-dihydroxybenzoic acid).
Scheme 4. Reagents and conditions: (a) imidazole, TBDPSCl, 95%;
(b) DDQ, DCM/H2O (19:1), 86%; (c) PTSH, PPh3, DIAD, THF;
(d) (NH4)6Mo7O24·4H2O, H2O2, EtOH, (88% in two steps).
Synthesis of Alcohol 9
Synthesis of the alcohol fragment 9 began with the prep-
aration of aldehyde 10 (Scheme 5) in seven steps from the
known C2-symmetric diol 19. Monosilylation of 2,3-di-O-
isopropylidene-l-threitol (19) with TBSCl in THF in the
presence of NaH by McDougal’s protocol[23] afforded the
mono-TBS-protected acetonide 20 in 85% yield. Oxidation
of the free primary hydroxy group of 20 under Swern condi-
tions[24] afforded aldehyde 21 in excellent yield (90%). Alde-
hyde 21 was then subjected to Keck asymmetric allyl-
ation[25] to produce the allylic alcohol 22 in 78% yield with
a 19:1 diastereomeric ratio. Protection of the free hydroxy
group as a PMB ether (compound 23) was achieved by
treating compound 22 with NaH, PMBBr, and TBAI (tetra-
Scheme 3. Reagents and conditions: (a) Me2SO4 (3.5 equiv.),
K2CO3, acetone, reflux, 4 h 96%; (b) LAH, 0 °C, 1 h, 98%;
(c) PCC, DCM, 2 h, 85%; (d) Ph3PCH3+I–, KOtBu, THF,0 °C to
r.t. 96%; (e) POCl3, DMF, 0 °C to r.t., 8 h, 87%; (f) BBr3, DCM,
0 °C, 1 h, 92%; (g) NaClO2, Na2HPO4, 2-methylbut-2-ene, tBuOH/
H2O (1:1), 3 h, 60% (based on 30% recovered aldehyde).
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
Asymmetric Total Syntheses of Cochliomycin A and Zeaenol
Scheme 5. Reagents and conditions: (a) TBSCl (1 equiv.), NaH, THF, r.t., 1 h, 85%; (b) (COCl)2, Me2SO, Et3N, –78 °C, 90%; (c) allyltri-
butyltin, Ti(OPr)4, (S)-BINOL, toluene, –78 °C then –15 °C, 72 h, 78%; (d) PMBBr, NaH, THF, r.t., 88%; (e) TBAF, THF, r.t., 2 h, 92%;
(f) DMP, NaHCO3, DCM, r.t., 1.5 h, 94%; (g) 11, KHMDS, 18-c-6, THF, –78 °C, 0.5 h, 75%; (h) TBAF, THF, r.t., 24 h, 88%.
n-butylammonium iodide). Removal of the TBS group with Removal of the acetonide functionality in compound 1 was
TBAF afforded primary alcohol 24 in 81% yield (in two achieved by treatment with HCl (2 n) to afford the other
steps). Dess–Martin periodinane oxidation of alcohol 24 in target molecule – zeaenol (4) – in 92% yield. The analytical
the presence of NaHCO3 produced intermediate aldehyde data (1H, 13C NMR and optical rotation values) for both
10 in 94% yield.[26]
compounds are consistent with those of the natural prod-
Now that both aldehyde 10 and sulfone 11 were available ucts.
in enantiomerically pure forms, we tried Julia–Kocienski
olefination under several conditions. With LHMDS as a
base the reaction gave the desired olefin 25 in poor yield.
On the other hand, a good yield was achieved when
KHMDS was used as a base, but the obtained E/Z selectiv-
ity was not so desirable (E/Z = 2:1). The low selectivity
obtained seemed to be generated by some chelation effects
of oxygen functional groups (OTBDPS) in the sulfone 11
and the aldehyde 10 with potassium cation, so we tried
other conditions with employment of external additives to
stop this chelation. When 18-crown-6 was added, trans ole-
fin 25 was successfully obtained in good yield and with high
selectivity (75%, E/Z = 20:1). It had already been demon-
strated that the counterion of the applied base and the
polarities of the solvents exhibit a strong influence on the
stereochemical outcomes of reactions between aliphatic PT
Scheme 6. Reagents and conditions: (a) DIAD, PPh3, toluene,
sulfones and aliphatic aldehydes.[27] The effects of this addi-
tive on the stereochemistry of the olefin 25 were remarkable
and superior to those observed with HMPA as a cation che-
lator (E/Z 4:1). Careful removal of the secondary TBDPS
ether of olefin 25 with TBAF in room temperature afforded
the alcohol 9 in 88% yield (Scheme 5).
1.5 h, 85%; (b) DDQ, DCM/H2O (19:1), 86%; c) 2nd-generation
Grubbs catalyst, DCM, 40 °C, 6 h, 72%; (d) HCl (2 n), THF, 20 h,
92%.
Conclusions
Completion of the Synthesis
In conclusion, we have synthesized two RALs – cochlio-
With the vinyl-substituted benzoic acid 8 and suitably mycin A and zeaenol – for the first time, from the cheap
functionalized alcohol 9 to hand, the esterification reaction commercially available starting materials 3,5-dihydroxy-
between the two fragments under Mitsunobu conditions[28] benzoic acid and l-(+)-tartaric acid, in 6.5% and 6% overall
proceeded cleanly to generate ester 26 (Scheme 6) in 85% yields, respectively. Highlights of our synthetic venture in-
yield. To complete the total synthesis, macrocyclization and cluded effective Keck asymmetric allylation on a acetonide-
deprotection were required. Before ring closure the PMB protected aldehyde, an advantageous E-selective Julia–
group was removed by treatment with DDQ, because it was Kocienski olefination on a highly elaborate substrate, and a
potentially problematic in RCM as documented earlier.[20d] late-stage RCM reaction. Synthetic studies directed towards
Finally, compound 27, with two terminal olefins, furnished several structurally related RALs (cochliomycins B and C,
the target molecule cochliomycin A (1) in 72% yield upon paecilomycin F) are still under investigation in our labora-
treatment with the second-generation Grubbs catalyst.[29] tory.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
N. Jana, S. Nanda
FULL PAPER
and with saturated NaHCO3 solution, and finally with brine, fol-
lowed by drying with Na2SO4 and concentration in vacuo. The
crude product was dissolved in a minimum amount of hot MeOH
and recrystallized by slow addition of deionized water. The crystals
were filtered, rinsed with a cold MeOH/H2O mixture, and then
dried under vacuum to remove all water; yield 4.2 g (81%) as color-
Experimental Section
General Information: Unless otherwise stated, materials were ob-
tained from commercial suppliers and used without further purifi-
cation. THF and diethyl ether were distilled from sodium benzo-
phenone ketyl. Dimethylformamide (DMF) and dimethylsulfoxide
(DMSO) were distilled from calcium hydride. Reactions were moni-
tored by thin-layer chromatography (TLC) carried out on 0.25 mm
silica gel plates (Merck) with UV light, ethanolic anisaldehyde, and
phosphomolybdic acid/heat as developing agents. Yields refer to
chromatographically and spectroscopically homogeneous materials
unless otherwise stated. NMR spectra were recorded with Bruker
200 and 400 MHz spectrometers at 25 °C in CDCl3 with TMS as
the internal standard. 13C NMR spectra were recorded in a com-
plete proton decoupling environment. The chemical shift values are
1
less crystals, m.p. 46–47 °C. H NMR (200 MHz, CDCl3): δ = 9.8
(s, 1 H), 6.92 (s, 2 H), 6.61 (s, 1 H), 3.75 (s, 6 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 191.9, 161.3, 138.4, 115.4, 107.1, 55.6 ppm.
IR: ν = 2942, 2842, 1696, 1598 cm–1. HRMS (ESI): calcd. for
˜
C9H10O3Na [M + Na]+ 189.0528; found 189.0534.
1,3-Dimethoxy-5-vinylbenzene (13): KOtBu (5.6 g, 50 mmol,
2 equiv.) was added in one portion to a stirred suspension of meth-
yltriphenylphosphonium iodide (21 g, 55 mmol, 2.2 equiv.) in dry
diethyl ether (100 mL). The mixture was stirred for 2 h at room
temperature and then cooled to 0 °C, followed by the addition of
a solution of 3,5-dimethoxybenzaldehyde (4.15 g, 25 mmol) in dry
ether (20 mL) at the same temperature. The cooling bath was re-
moved and the mixture was allowed to come to room temperature.
Next, the reaction was quenched by addition of dry MeOH
(10 mL). The solvents were removed under reduced pressure and
the residue was passed through a short pad (4 cm) of silica gel with
petroleum ether/ethyl acetate 15:1 as eluent to give 3,5-dimeth-
oxystyrene (3.94 g, 96%) as a colorless oil. 1H NMR (200 MHz,
CDCl3): δ = 6.73–6.58 (m, 3 H), 6.42–6.40 (m, 1 H), 5.75 (dd, J =
17.4, 2.4 Hz, 1 H), 5.27 (dd, J = 17.4, 8.8 Hz, 1 H), 3.80 (s, 6
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 161.0, 139.7, 136.9,
1
listed as δH and δC for H and 13C, respectively. Optical rotations
were measured with a JASCO P1020 digital polarimeter. IR spectra
were recorded with a Perkin–Elmer Rx1 instrument. Mass spectral
analysis was performed at IICT, Hyderabad, India.
Methyl 3,5-Dimethoxybenzoate: Dimethyl sulfate (22 mL,
228 mmol, 3.5 equiv.) was added at room temperature to a mechan-
ically stirred suspension of 3,5-dihydroxybenzoic acid (10 g,
65 mmol) and K2CO3 (36 g, 260 mmol, 4 equiv.) in acetone
(100 mL). The reaction mixture was vigorously stirred at reflux for
4 h, then allowed to cool to room temperature and filtered. The
filter solid was rinsed with acetone (2ϫ 100 mL) and most of the
acetone was removed with a rotary evaporator. The residue was
diluted with NH4OH solution (5%, 50 mL), stirred for 5 min, and
extracted with Et2O (100 + 2ϫ 50 mL). The Et2O solution was
washed with HCl (5%) and then with saturated NaHCO3 solution,
dried with Na2SO4, and filtered, and the solvents were evaporated
to dryness (10 mbar) with a rotary evaporator. The crude product
was dissolved in hot MeOH (20 mL), and the solution was allowed
to cool to 23 °C, followed by slow dropwise addition of deionized
water (10 mL) to induce crystallization. The crystals were filtered
through a sintered frit, rinsed on the filter with a cooled (4 °C)
mixture of deionized water/methanol, and dried under vacuum to
remove all water to afford the methyl ester (yield = 96%) as a white
powder, m.p. 42 °C. 1H NMR (200 MHz, CDCl3): δ = 7.2 (s, 2 H),
6.65 (s, 1 H), 3.9 (s, 3 H), 3.82 (s, 6 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 166.9, 160.7, 132.1, 107.2, 105.8, 55.6, 52.4 ppm.
114.4, 104.4, 100.1, 55.4 ppm. IR: ν = 2938, 2836, 1592, 1458 cm–1.
˜
HRMS (ESI): calcd. for C10H12O2Na [M + Na]+ 187.0735; found
187.0729.
2,4-Dimethoxy-6-vinylbenzaldehyde (14): 1,3-Dimethoxy-5-vinyl-
benzene (13, 4.2 g, 25.6 mmol) was dissolved in anhydrous DMF
(350 mL) and the mixture was cooled to 0 °C. POCl3 (3.59 mL,
5.88 g, 38.4 mmol) was added dropwise over 5 min. The reaction
mixture was stirred for 30 min at 0 °C and the cooling bath was
removed. The reaction mixture was stirred for 8 h at room tempera-
ture, and water (300 mL) was added. The yellow mixture was ex-
tracted with CH2Cl2 (4ϫ 500 mL), dried (MgSO4), and filtered
through paper and the solvents were evaporated to dryness in
vacuo. Silica gel column chromatography (ethyl acetate/petroleum
ether 1:3) yielded the target aldehyde 14 in 87% yield as a white
solid (when stored in a refrigerator). 1H NMR (200 MHz, CDCl3):
δ = 10.46 (s, 1 H), 7.56 (dd, J = 17.2, 10.8 Hz, 1 H), 6.59 (d, J =
2.2 Hz, 1 H), 6.4 (d, J = 2.4 Hz, 1 H), 5.59 (dd, J = 17.2, 2.8 Hz,
1 H), 5.46 (dd, J = 10.8, 2.8 Hz, 1 H), 3.88 (s, 6 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 190.6, 164.8, 143.6, 136.6, 117.5, 116.4,
(3,5-Dimethoxyphenyl)methanol (12): Methyl 3,5-dimethoxybenz-
oate (4 g, 20.4 mmol) was added at 0 °C to a stirred suspension of
LAH (775 mg, 20.4 mmol) in dry ether (80 mL). The mixture was
stirred at 0 °C for 1 h and the reaction mixture was then carefully
quenched with saturated Na2SO4 solution. It was then filtered and
the solid was extracted with hot diethyl ether and concentrated
in vacuo to give almost pure (3,5-dimethoxyphenyl)methanol as a
colorless oil, which crystallized when stored, yield 3.36 g (99%),
105.7, 104.6, 97.5, 56.1, 55.7 ppm. IR: ν = 2940, 2841, 1673,
˜
1593 cm–1. HRMS (ESI): calcd. for C11H12O3Na [M + Na]+
215.0684; found 215.0688.
1
m.p. 47–47.5 °C. H NMR (200 MHz, CDCl3): δ = 6.50 (s, 2 H),
6.36 (s, 1 H), 4.6 (s, 2 H), 3.77 (s, 6 H) ppm. 13C NMR (50 MHz,
2-Hydroxy-4-methoxy-6-vinylbenzaldehyde (15): Aldehyde 14
(800 mg, 4.16 mmol) was dissolved in anhydrous CH2Cl2 (40 mL),
and BBr3 (8.3 mL, 1M, 8.3 mmol) was added over 5 min at 0 °C
under N2. The reaction mixture was stirred for 1 h at 0 °C, water
(20 mL) was added, and the phases were separated. The aqueous
CDCl ): δ = 161.0, 143.5, 104.6, 99.7, 65.2, 55.4 ppm. IR: ν = 3420,
˜
3
2940, 2064, 1609 cm–1. HRMS (ESI): calcd. for C9H12O3Na [M +
Na]+ 191.0684; found 191.0681.
3,5-Dimethoxybenzaldehyde: A solution of (3,5-dimethoxyphenyl)-
methanol (12, 5 g, 29.7 mmol) in CH2Cl2 (20 mL) was added drop- phase was extracted with additional CH2Cl2 (2ϫ 50 mL), the com-
wise at room temperature to a stirred suspension of pyridinium
chlorochromate (PCC, 9.35 g, 1.5 equiv.) in CH2Cl2 (80 mL). The
mixture was stirred at room temperature for 24 h and then filtered
through a pad of celite. The filter pad was washed with CH2Cl2
(2ϫ 30 mL). Most of the CH2Cl2 was removed under reduced pres-
sure, and the residue was diluted with Et2O (100 mL). The ether
solution was washed twice with NaOH (5%), then with HCl (5%)
bined organic extracts were dried (Na2SO4), and the solvents were
evaporated to dryness in vacuo. The crude material was purified
by silica gel column chromatography (ethyl acetate/petroleum ether
1:10) to give the target compound 15 (682 mg) as a white solid
1
material in 92% yield. H NMR (200 MHz, CDCl3): δ = 12.34 (s,
1 H), 10.04 (s, 1 H), 7.19–7.04 (m, 1 H), 6.42 (d, J = 2.4 Hz, 1 H),
6.29 (d, J = 2.4 Hz, 1 H), 5.65–5.44 (m, 2 H), 3.8 (s, 3 H) ppm. 13
C
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
Asymmetric Total Syntheses of Cochliomycin A and Zeaenol
NMR (50 MHz, CDCl3): δ = 193.2, 166.7, 166.1, 144.9, 132.1,
less oil. [α]2D5 = +12.4 (c = 1.0, MeOH). 1H NMR (200 MHz,
CDCl3): δ = 3.99–3.94 (m, 1 H), 3.87–3.81 (m, 2 H), 3.77–3.62 (m,
3 H), 2.57 (br., 1 H, –OH), 1.39 (s, 3 H), 1.37 (s, 3 H), 0.87 (s, 9
H), 0.05 (s, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 109.2,
121.3, 112.3, 107.3, 100.1, 55.8 ppm. IR: ν = 3447, 2980, 2365,
˜
1617 cm–1. HRMS (ESI): calcd. for C10H10O3Na [M + Na]+
201.0528; found 201.0533.
80.1, 76.5, 63.7, 62.8, 27.1, 27.0, 25.9, 18.3, –5.45 ppm. IR: ν =
˜
2-Hydroxy-4-methoxy-6-vinylbenzoic Acid (8): Aldehyde 15
(470 mg, 2.6 mmol) was dissolved in tBuOH (15 mL) and 2-meth-
ylbut-2-ene (8 mL, 2 m in THF). A solution of NaClO2 (80% pu-
rity, 1433 mg, 15.8 mmol) and NaH2PO4 (936 mg, 7.8 mmol) in
H2O (15 mL) was added to this mixture. After 2 h, the yellow, bi-
phasic reaction mixture was poured onto H2O (15 mL) and EtOAc
(30 mL). The mixture was acidified with HCl solution (1 m,
≈5 mL). The layers were separated. The organic solvent was dried,
filtered, and concentrated in vacuo. The crude material was puri-
fied by flash column chromatography (ethyl acetate/petroleum
ether 1:5) to give acid 8 (303 mg, 60%) as a solid. 1H NMR
3442, 2860, 1612, 1518 cm–1. HRMS (ESI): calcd. for C13H28O4S-
iNa [M + Na]+ 299.1655; found 299.1651.
(4R,5S)-5-[(tert-Butyldimethylsilyloxy)methyl]-2,2-di-
methyl-1,3-dioxolane-4-carbaldehyde (21): DMSO (2.82 mL,
39.8 mmol) was added at –78 °C to a solution of oxalyl chloride
(2.2 mL, 3.16 g, 24.9 mmol) in CH2Cl2 (100 mL), and the resulting
solution was stirred for 15 min. A solution of the monosilylated
alcohol 20 (5.5 g, 19.9 mmol) in CH2Cl2 (20 mL) was added drop-
wise at –78 °C over 30 min. After the solution had been stirred for
an additional 30 min, Et3N (8.38 mL, 59.7 mmol) was added and
(200 MHz, CDCl3): δ = 114.0 (br., 1 H), 7.45–7.32 (m, 1 H), 6.55 the reaction mixture was allowed to warm to room temperature
(d, J = 2.6 Hz, 1 H), 6.43 (d, J = 2.6 Hz, 1 H), 5.48 (dd, J = 17.2,
1.8 Hz, 1 H), 5.29 (d, J = 10.2, 1.8 Hz, 1 H), 3.85 (s, 3 H) ppm.
and stirred for 1 h. The reaction mixture was poured into aqueous
citric acid (10%) and extracted with CH2Cl2. The organic layer
13C NMR (50 MHz, CDCl3): δ = 175.1, 165.8, 165.0, 144.7, 138.1, was washed with saturated aqueous NaHCO3 and brine, dried with
116.3, 108.8, 102.4, 100.1, 55.4 ppm. IR: ν = 3450, 2931, 2857,
MgSO4, and concentrated under reduced pressure to give the crude
˜
1653 cm–1. HRMS (ESI): calcd. for C10H10O4Na [M + Na]+
217.0477; found 217.0472.
aldehyde 21 (4.9 g) as a pale yellow oil. [α]2D5 = +18.26 (c = 0.8,
1
MeOH). H NMR (200 MHz, CDCl3): δ = 9.75 (d, J = 1.8 Hz, 1
H), 4.34–4.29 (m, 1 H), 4.14–4.08 (m, 1 H), 3.79 (d, J = 4.4 Hz, 2
Compound 11: Diisopropyl azodicarboxylate (2 mL, 9.9 mmol) was
added at –20 °C to a solution of alcohol 17 (2.5 g, 7.26 mmol),
PPh3 (2.2 g, 8.32 mmol), and 1-phenyl-5-mercapto-1H-tetrazole
(PT–SH, 1.76 g, 9.9 mmol) in THF (40 mL). The reaction mixture
was stirred at 0 °C for 30 min, poured into water, and extracted
with ethyl acetate. The organic layer was washed with saturated
NaHCO3 solution and brine, dried with anhydrous MgSO4, and
concentrated in vacuo. The residue was chromatographed over sil-
ica gel. Elution with ethyl acetate/petroleum ether (1:3) gave sulfide
18 as a colorless oil. A mixture of (NH4)6Mo7O24·4H2O (1.236 g,
1.0 mmol) and H2O2 solution (30%, 5.0 mL) was added at 0 °C to
a solution of sulfide 18 (3.4 g, 6.9 mmol) in ethanol (60 mL). The
reaction mixture was stirred at room temperature for 6 h, poured
into Na2S2O3 solution (10%), and extracted with ethyl acetate. The
organic layer was washed with saturated NaHCO3 solution and
brine, dried with anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy; elution with ethyl acetate/petroleum ether (1:5) gave sulfone
H), 1.46 (s, 3 H), 1.40 (s, 3 H), 0.88 (s, 9 H), 0.07 (s, 6 H) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 200.7, 111.5, 82.0, 63.4, 62.9, 26.8,
26.3, 25.8, 18.3, –5.3, –5.4 ppm. IR: ν = 1710, 1696, 1598 cm–1.
˜
HRMS (ESI): calcd. for C13H26O4SiNa [M + Na]+ 297.1498; found
297.1492.
(S)-1-{(4S,5S)-5-[(tert-Butyldimethylsilyloxy)methyl]-2,2-dimethyl-
1,3-dioxolan-4-yl}but-3-en-1-ol (22): A dry round-bottomed flask
was charged with (S)-BINOL (141 mg, 0.49 mmol) and vacuum-
flame-dried powdered molecular sieves (4 Å). The flask was sealed
with a septum cap and flushed with N2. Toluene (30 mL) was
added by syringe. Titanium(IV) isopropoxide (73 μL, 0.246 mmol)
was added to the resulting stirred suspension dropwise by syringe,
resulting in an immediate color change to deep red. After the sys-
tem had been stirred for 2 h at ambient temperature, aldehyde 21
(4.5 g, 16.42 mmol) was added by syringe over 2 min. After stirring
for 5 min, the mixture was cooled to –78 °C in a cooling bath. After
this cooling, allyltributylstannane (7.64 mL, 8.16 g, 24.64 mmol)
was added by syringe down the sides of the reaction vessel over
11 as a colorless gummy oil in 88% yield (two steps). [α]2D5 = +1.67
1
(c = 1.1, MeOH). H NMR (200 MHz, CDCl3): δ = 7.73–7.54 (m, 5 min. The resulting mixture was stirred for 10 min and was then
4 H), 7.51 (s, 5 H), 7.48–7.33 (m, 6 H), 4.16–4.0 (m, 1 H), 3.92–3.6
(m, 2 H), 2.22–1.96 (m, 2 H), 1.15 (d, J = 6.2 Hz, 3 H), 1.10 (s, 9
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 153.5, 135.9, 135.8,
133.9, 133.4, 133.1, 131.5, 130.0, 129.8, 129.7, 127.9, 127.7, 125.1,
transferred to a freezer at –15 °C and allowed to stand for 72 h. At
this point, direct 1H NMR analysis of the reaction mixture showed
complete consumption of aldehyde. The reaction mixture was con-
centrated in vacuo to a total volume of ≈60 mL, and the orange/red
heterogeneous mixture was loaded directly onto a silica gel column
slurry-packed with petroleum ether. The column was eluted with
ethyl acetate/petroleum ether (1:10 then 1:5) to afford allylic
alcohol 22 (78%) as a pale yellow oil. [α]2D5 = –20.57 (c = 1.0,
MeOH). 1H NMR (200 MHz, CDCl3): δ = 5.97–5.86 (m, 1 H),
5.18–5.1 (m, 2 H), 4.31–4.3 (m, 1 H), 3.95–3.84 (m, 1 H), 3.80–3.67
(m, 3 H), 2.50–2.47 (m, 1 H), 2.46–2.22 (m, 1 H), 1.39 (s, 3 H),
1.37 (s, 3 H), 0.90 (s, 9 H), 0.08 (s, 6 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 134.8 (CH), 117.8 (CH2), 109.4, 81.1 (CH), 77.3 (CH),
70.2 (CH), 63.9 (CH2), 39.3 (CH2), 27.4 (Me), 27.0 (Me), 18.5,
67.3, 52.6, 31.1, 27.1, 23.0, 19.3 ppm. IR: ν = 3432, 2953, 2041,
˜
1654, 1426 cm–1.
(4S,5S)-{5-[(tert-Butyldimethylsilyloxy)methyl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}methanol (20): A solution of 2,3-di-O-isopropylidene-
d-threitol (19, 4 g, 24.7 mmol) in THF (20 mL) was added drop-
wise over 1 h at room temperature to a suspension of NaH (60%
dispersion in mineral oil, 1.98 g, 1.25 mol) in THF (80 mL). The
reaction mixture was stirred for an additional 1 h and cooled to
0 °C. A solution of TBSCl (3.73 g, 24.7 mmol) in THF (25 mL)
was added dropwise to the mixture over 1 h. Stirring was continued
for 30 min, and the reaction mixture was poured into crushed ice
(60 mL) and extracted with Et2O. The organic layer was washed
with brine, dried with MgSO4, and concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography (ethyl acetate/petroleum ether 1:9 then 1:1) on sil-
ica gel to afford the monosilylated alcohol (5.78 g, 85%) as a color-
–5.21 (Me), –5.26 (Me) ppm. IR: ν = 3419, 2846, 1616, 1598 cm–1.
˜
HRMS (ESI): calcd. for C16H32O4SiNa [M + Na]+ 339.1968; found
339.1973.
(4S,5S)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-[(S)-1-(4-methoxy-
benzyloxy)but-3-enyl]-2,2-dimethyl-1,3-dioxolane (23): Allyl alcohol
22 (2 g, 6.33 mmol) was taken up in dry THF (30 mL). NaH (60%
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
N. Jana, S. Nanda
FULL PAPER
dispersion in mineral oil, 253 mg, 6.33 mmol) was then added por-
tionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h.
Tetrabutylammonium iodide (TBAI, catalytic amount) was added,
followed by 4-methoxybenzyl bromide. The reaction mixture was
stirred for a further 2 h at room temperature. Water was added
carefully to quench any excess of NaH. The mixture was extracted
with EtOAc, and the organic solution was washed with water and
brine. Concentration and purification by silica gel chromatography
(ethyl acetate/petroleum ether 1:10) afforded the PMB-protected
compound 23 in 88% yield. [α]2D5 = +8.95 (c = 1.6, MeOH). 1H
NMR (200 MHz, CDCl3): δ = 7.24 (d, J = 8.4 Hz, 2 H), 6.86 (d,
solution of KHMDS (0.5 m in toluene, 4.32 mL, 2.16 mmol) was
added at –98 °C to a solution of sulfone 11 (936 mg, 1.8 mmol) and
18-crown-6 (714 mg, 2.7 mmol) in THF (40 mL). This solution was
stirred at –98 °C for 30 min and a solution of aldehyde 10 (600 mg,
1.8 mmol) in THF (10 mL) was added. The reaction mixture was
allowed to warm to room temperature over 2 h and poured into
saturated NH4Cl solution. This mixture was extracted with ethyl
acetate and the organic layer was washed with saturated NaHCO3
solution and brine. After drying with anhydrous magnesium sul-
fate, solvent was removed in vacuo and the residue was purified by
silica gel column chromatography with ethyl acetate/petroleum
J = 8.4 Hz, 2 H), 5.9–5.84 (m, 1 H), 5.18–5.06 (m, 2 H), 4.58 (d, J ether (1:20) to give 25 (842 mg, 75%) as a colorless oil. [α]2D5
=
1
= 11.2 Hz, 1 H), 4.5 (d, J = 11.2 Hz, 1 H), 4.14–4.0 (m, 2 H), 3.95–
3.56 (6 H), 2.41–2.37 (m, 2 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 0.89 (s,
9 H), 0.04 (s, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 159.3,
134.7, 130.6, 129.5, 117.4, 113.8, 109.1, 79.8, 79.1, 76.5, 72.0, 64.3,
–12.91 (c = 1.2, MeOH). H NMR (400 MHz, CDCl3): δ = 7.67–
7.43 (m, 4 H), 7.41–7.34 (m, 6 H), 7.22 (d, J = 7.6 Hz, 2 H), 6.84
(d, J = 7.6 Hz, 2 H), 5.82–5.71 (m, 2 H), 5.43–5.38 (m, 1 H), 5.08–
5.03 (m, 2 H), 4.62–4.51 (m, 2 H), 4.39 (t, J = 7.6 Hz, 1 H), 3.88–
55.4, 35.4, 27.4, 27.2, 26.1, 18.5, –5.1, –5.2 ppm. IR: ν = 2930, 3.84 (m, 1 H), 3.79–3.71 (4 H), 3.64–3.61 (m, 1 H), 2.36–2.05 (m,
˜
2857, 1612, 1514 cm–1. HRMS (ESI): calcd. for C24H40O5SiNa [M
+ Na]+ 459.2543; found 459.2537.
4 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.05 (12 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.0, 135.7, 134.6, 134.5, 131.6, 131.5,
130.46, 130.4, 129.5, 129.4, 129.2, 127.5, 127.4, 117.2, 113.6, 113.5,
108.5, 82.0, 78.5, 77.8, 72.5, 69.0, 55.2, 42.3, 35.7, 27.0, 26.9, 22.7,
{(4S,5S)-5-[(S)-1-(4-Methoxybenzyloxy)but-3-enyl]-2,2-dimethyl-
1,3-dioxolan-4-yl}methanol (24): The PMB-protected compound 23
(2.4 g, 5.5 mmol) was taken up in dry THF (20 mL). TBAF (1 m
in THF, 8.25 mL, 1.5 equiv.) was added, and the reaction mixture
was stirred for 2 h at room temperature. After this time, THF was
evaporated, water (20 mL) was added, the reaction mixture was
extracted with EtOAc (50 mL), and the organic layer was washed
with dilute NaHCO3 solution and brine and dried (MgSO4). It was
purified by flash chromatography (ethyl acetate/petroleum ether
1:5) to afford compound 24 in 90% yield. [α]2D5 = +20.38 (c = 1.5,
19.1 ppm. IR: ν = 2960, 2930, 1612, 1513 cm–1. HRMS (ESI):
˜
calcd. for C38H50O5SiNa [M + Na]+ 637.3325; found 637.3319.
(R,E)-5-{(4S,5S)-5-[(S)-1-(4-Methoxybenzyloxy)but-3-enyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}pent-4-en-2-ol (9): Compound 25 (770 mg,
1.25 mmol) was taken up in dry THF (10 mL). TBAF (1 m in THF,
2.5 mL, 2 equiv.) was added, and the reaction mixture was stirred
for 24 h at room temperature. After this time, THF was removed,
water (5 mL) was added, the reaction mixture was extracted with
EtOAc (50 mL), and the organic layer was washed with dilute
NaHCO3 solution and brine and dried (MgSO4). It was purified
by flash chromatography with ethyl acetate/petroleum ether (1:10)
to afford compound 9 in 88% yield. [α]2D5 = –20.68 (c = 1.5,
1
MeOH). H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.4 Hz, 2
H), 6.86 (d, J = 8.4 Hz, 2 H), 5.95–5.84 (m, 1 H), 5.27–5.11 (m, 2
H), 4.62 (d, J = 10.8 Hz, 1 H), 4.43 (d, J = 10.8 Hz, 1 H), 3.82–
3.78 (m, 1 H), 3.73–3.7 (4 H), 3.66–3.53 (m, 3 H), 2.58–2.53 (m, 1
H), 2.52–2.35 (m, 1 H), 1.41 (s, 3 H), 1.37 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.3, 133.6 (CH), 129.7, (CH), 129.6,
117.9 (CH2), 113.8, (CH), 108.9, 80.1 (CH), 78.8 (CH), 78.4 (CH),
71.4 (CH2), 63.4 (CH2), 55.1 (Me), 35.0 (CH2), 26.92 (Me), 26.91
1
MeOH). H NMR (400 MHz, CDCl3): δ = 7.24 (d, J = 7.6 Hz, 2
H), 6.85 (d, J = 7.6 Hz, 2 H), 5.86–5.54 (m, 3 H), 5.12–5.0 (m, 2
H), 4.58–4.41 (m, 3 H), 3.85–3.61 (6 H), 2.35–2.26 (m, 4 H), 1.42
(s, 3 H), 1.41 (s, 3 H), 1.14 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.2, 134.5, 131.6, 131.4, 130.5, 129.7,
117.5, 113.7, 108.7, 81.9, 79.2, 78.2, 72.4, 67.0, 55.3, 42.2, 35.8,
(Me) ppm. IR: ν = 3461, 2926, 1612, 1513 cm–1. HRMS (ESI):
˜
calcd. for C18H26O5Na [M + Na]+ 345.1678; found 345.1672.
27.0, 22.8, 22.7 ppm. IR: ν = 3447, 2982, 2932, 1610 cm–1. HRMS
˜
(ESI): calcd. for C22H32O5Na [M + Na]+ 399.2147; found 399.2142.
(4R,5S)-5-[(S)-1-(4-Methoxybenzyloxy)but-3-enyl]-2,2-dimethyl-1,3-
dioxolane-4-carbaldehyde (10): NaHCO3 (1.58 g, 18.8 mmol) was
added to a solution of 24 (1.25 g, 3.76 mmol) in CH2Cl2 (25 mL),
followed by Dess–Martin periodinane (1 g, 4.14 mmol). After 1 h,
a solution (1:1:1) of saturated NaHCO3, saturated Na2S2O3, and
H2O (30 mL total) was added. The resulting biphasic mixture was
stirred vigorously for 30 min. The layers were separated, and the
aqueous fraction was extracted with CH2Cl2 (25 mL). The organics
were dried, filtered, and concentrated in vacuo. The crude com-
pound was purified by silica gel column chromatography with ethyl
acetate/petroleum ether (1:10) to afford aldehyde 10 in 94% yield.
(R,E)-5-{(4S,5S)-5-[(S)-1-(4-Methoxybenzyloxy)but-3-enyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}pent-4-en-2-yl 2-Hydroxy-4-methoxy-6-
vinylbenzoate (26): Triphenylphosphane (546 mg, 2.08 mmol) and
DIAD (0.41 mL, 2.08 mmol) were added sequentially to a stirred
solution of acid 8 (202 mg, 1.04 mmol) and alcohol 9 (390 mg,
1.04 mmol) in dry toluene (10 mL). After 1.5 h, EtOAc (10 mL)
and H2O (5 mL) were added. The layers were separated and the
aqueous phase was extracted with EtOAc (2ϫ 15 mL). The com-
bined organic portions were washed with brine (20 mL), dried with
Na2SO4, and concentrated under reduced pressure, and the residue
was purified by silica gel column chromatography (ethyl acetate/
1
[α]2D5 = –5.05 (c = 1.4, MeOH). H NMR (200 MHz, CDCl3): δ =
9.75 (1 H), 7.31 (d, J = 8.4 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H),
5.96–5.82 (m, 1 H), 5.23–5.12 (m, 2 H), 4.69–4.57 (m, 2 H), 4.42–
4.15 (m, 2 H), 3.84 (s, 3 H), 3.83–3.67 (m, 1 H), 2.47–2.38 (m, 2
H), 1.53 (s, 3 H), 1.41 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 200.8 (CH), 159.5, 133.8 (CH), 130.3, 129.7 (CH), 118.2 (CH2),
113.9 (CH), 111.4, 82.4 (CH), 78.4 (CH), 78.2 (CH), 72.4 (CH2),
petroleum ether 1:20) to give 26 as a colorless syrup (85%). [α]2D5
=
1
–14.727 (c = 1.1, MeOH). H NMR (400 MHz, CDCl3): δ = 11.65
(1 H), 7.23–7.15 (m, 3 H), 6.85 (d, J = 7.8 Hz, 2 H), 6.38 (1 H),
6.30 (1 H), 5.78–5.5 (m, 3 H), 5.48–5.07 (m, 5 H), 4.5–4.22 (m, 3
H), 3.69–3.44 (8H), 2.39–2.17 (m, 4 H), 1.32 (s, 3 H), 1.29 (s, 3 H),
1.22 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.6, 165.0, 164.0, 159.2, 143.7, 138.7, 134.5, 132.2, 130.5, 129.5,
129.1, 128.3, 117.4, 115.4, 113.7, 108.8, 108.4, 100.2, 81.9, 78.7,
78.3, 72.4, 72.0, 55.4, 55.3, 38.8, 35.7, 27.0, 26.9, 19.6 ppm. IR:
55.4 (Me), 35.6 (CH ), 26.8 (Me), 25.9 (Me) ppm. IR: ν = 2980,
˜
2
2931, 1733, 1611 cm–1. HRMS (ESI): calcd. for C18H24O5Na [M +
Na]+ 343.1521; found 343.1516.
(4S,5S)-4-[(R,E)-4-tert-Butyldiphenylsilyloxypent-1-enyl]-5-[(S)-1-
(4-methoxybenzyloxy)but-3-enyl]-2,2-dimethyl-1,3-dioxolane (25): A
ν = 3447, 2982, 2933, 1718, 1651 cm–1. HRMS (ESI): calcd. for
˜
C32H40O8Na [M + Na]+ 575.2621; found 575.2615.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
Asymmetric Total Syntheses of Cochliomycin A and Zeaenol
(R,E)-5-{(4S,5S)-5-[(S)-1-Hydroxybut-3-enyl]-2,2-dimethyl-1,3-di-
Supporting Information (see footnote on the first page of this arti-
1
oxolan-4-yl}pent-4-en-2-yl 2-Hydroxy-4-methoxy-6-vinylbenzoate cle): H NMR and 13C NMR spectra for all new compounds and
(27): Compound 26 (430 mg, 0.778 mmol) was taken up in DCM/
H2O (20 mL, 19:1). DDQ (266 mg, 1.17 mmol) was added in one
portion. The reaction mixture was stirred at room temperature for
1 h and filtered, and the filtrate was washed with NaHCO3 (5%)
solution, water, and brine. The organic layer was dried (MgSO4)
and the solvents were evaporated. Purification by silica gel
chromatography (ethyl acetate/petroleum ether 1:10) afforded the
pure compound 27 in 86% yield. [α]2D5 = –15.57 (c = 0.6, MeOH).
1H NMR (400 MHz, CDCl3): δ = 11.7 (1 H), 7.30–7.22 (m, 1 H),
6.48 (s, 1 H), 6.39 (s, 1 H), 5.89–5.72 (m, 2 H), 5.71–5.55 (m, 1 H),
5.49–5.43 (m, 1 H), 5.25–5.19 (m, 2 H), 5.13–5.03 (m, 2 H), 4.44–
4.41 (m, 1 H), 3.90 (4 H), 3.66–3.61 (m, 1 H), 2.52–2.2.40 (m, 2
H), 2.26–2.03 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.31 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.7, 165.2,
164.2, 143.9, 138.7 (CH), 134.2 (CH), 132.2 (CH), 130.4, 129.9
(CH), 118.4 (CH2), 115.6 (CH2), 109.0, 108.6 (CH), 100.4 (CH),
82.8 (CH), 77.9 (CH), 72.2 (CH), 70.5 (CH), 55.6 (Me), 38.9 (CH2),
HPLC chromatograms of cochliomycin A and zeaenol.
Acknowledgments
Financial support from the Council of Scientific and Industrial Re-
search (CSIR) India is gratefully acknowledged [Grant: 02(0020)/
11/EMR-II]. We are also thankful to the Department of Science
and Technology (DST) India (IRPHA) for NMR instruments. N. J.
is thankful to CSIR-India for providing a research fellowship.
[1] P. Delmotte, J. Delmotte-Plaquee, Nature 1953, 171, 344–344.
[2] M. Stob, R. S. Baldwin, J. Tuite, F. N. Andrews, K. G. Gillette,
Nature 1962, 196, 1318–1318.
[3] G. A. Ellestad, F. M. Lovell, N. A. Perkinson, R. T. Harg-
reaves, W. J. McGahren, J. Org. Chem. 1978, 43, 2339–2343.
[4] M. S. R. Nair, S. T. Carey, Tetrahedron Lett. 1980, 21, 2011–
2012.
[5] N. Winssinger, S. Barluenga, Chem. Commun. 2007, 22–36.
[6] M. Isaka, C. Suyarnsestakorn, M. Tanticharoen, P. Kongsa-
eree, Y. Thebtaranonth, J. Org. Chem. 2002, 67, 1561–1566.
[7] a) V. Hellwig, A. Mayer-Bartschmid, H. Müller, G. Greif, G.
Kleymann, W. Zitzmann, H.-V. Tichy, M. Stadler, J. Nat. Prod.
2003, 66, 829–837; b) H. Shining, Y. Kawamura, A. Ikeda, M.
Aoki, N. Sakai, N. Fujimoto, A. Kawashima, Tetrahedron
2009, 65, 3446–3453.
37.4 (CH ), 27.17 (Me), 27.13 (Me), 19.9 (Me) ppm. IR: ν = 3438,
˜
2
2922, 2852, 2364, 1634 cm–1. HRMS (ESI): calcd. for C24H32O7Na
[M + Na]+ 455.2046; found 455.2040.
Cochliomycin A: The ester 28 (180 mg, 0.416 mmol) was taken up
in anhydrous degassed DCM (200 mL). The second-generation
Grubbs metathesis catalyst (25 mg, 0.029 mmol, 7 mol-%) was
added and the reaction mixture was allowed to stir at 40 °C for
6 h. The solution was concentrated and the contents of the flask
were directly loaded on a silica gel column. Flash chromatography
with ethyl acetate/petroleum ether (1:5) afforded pure cochliomy-
cin A in 72% yield as white solid (m.p. 68 °C). [α]3D0 = +10.6 (c =
[8] L. X. Xu, Z. X. He, J. H. Xue, X. P. Chen, X. Y. Wei, J. Nat.
Prod. 2010, 73, 885–889.
[9] W. T. Shier, A. C. Shier, W. Xie, C. J. Mirocha, Toxicon 2001,
39, 1435–1438.
[10] M. Isaka, A. Yangchum, S. Intamas, K. Kocharin, E. B. G.
Jones, P. Kongsaeree, S. Prabpai, Tetrahedron 2009, 65, 4396–
4403.
[11] a) W. A. Ayer, S. P. Lee, A. Tsuneda, Y. Hiratsuka, Can. J.
Microbiol. 1980, 26, 766–773.
[12] a) H. Boettger-Tong, L. Murthy, C. Chiappetta, J. L. Kirkland,
B. Goodwin, H. Adlercreutz, G. M. Stancel, S. Makela, Envi-
ron. Health Perspect. 1998, 106, 369–373; b) B. S. Katzenellen-
bogen, J. A. Katzenellenbogen, D. Mordecai, Endocrinology
1979, 105, 33–40.
[13] J. Dong, Y. Zhu, H. Song, R. Li, H. He, H. Liu, R. Huang, Y.
Zhou, L. Wang, Y. Cao, K. Zhang, J. Chem. Ecol. 2007, 33,
1115–1126.
[14] a) E. S. Abid, Z. Ouanes, W. Hassen, I. Baudrimont, E.
Creppy, H. Bacha, Toxicol. in vitro 2004, 18, 467–474; b) A.
Fürstner, K. Langemann, J. Am. Chem. Soc. 1997, 119, 9130–
9136; c) H. J. Kwon, M. Yoshida, K. Abe, S. Horinouchi, T.
Beppu, Biosci. Biotechnol. Biochem. 1992, 56, 538–539; d) P.
Chanmugam, L. Feng, S. Liou, B. C. Jang, M. Boudreau, G.
Yu, J. H. Lee, H. J. Kwon, T. Beppu, M. Yoshida, Y. Xia, C. B.
Wilson, D. Hwang, J. Biol. Chem. 1995, 270, 5418–5426; e) K.
Takehara, S. Sato, T. Kobayashi, T. Maeda, Biochem. Biophys.
Res. Commun. 1999, 257, 19–23; f) N. A. Giese, N. Lokker,
Int. Pat. WO9613259, 1996 [Chem. Abst. 1996, 457801]; g) J.
Nonomiya-Tsuji, T. Kajino, K. Ono, T. Ohtomo, M. Matsum-
oto, M. Shiina, M. Mihara, M. Tsuchiya, K. Matsumoto, J.
Biol. Chem. 2003, 278, 18485–18490.
[15] F. Sugawara, K. W. Kim, K. Kobayashi, J. S. Yoshida, N. Mur-
fushi, N. Takahashi, G. A. Strobel, Phytochemistry 1992, 31,
1987–1990.
[16] C. L. Shao, H. X. Wu, C. Y. Wang, Q. A. Liu, Y. Xu, M. Y.
Wei, P. Y. Qian, Y. C. Gu, C. J. Zheng, Z. G. She, Y. C. Lin, J.
Nat. Prod. 2011, 74, 629–633.
1
0.5, MeOH). H NMR (400 MHz, CDCl3): δ = 11.5 (s, 1 H), 7.16
(dd, J = 15.2, 2.4 Hz, 1 H), 6.47 (d, J = 2.4 Hz, 1 H), 6.39 (d, J =
2.4 Hz, 1 H), 5.98 (ddd, J = 15.0, 8.4, 4.8 Hz, 1 H), 5.72 (ddd, J =
15.2, 10.2, 2.8 Hz, 1 H), 5.55–5.48 (m, 1 H), 5.47–5.43 (m, 1 H),
4.56 (t, J = 8.0 Hz, 1 H), 4.23–4.19 (m, 1 H), 3.91–3.88 (m, 1 H),
3.81 (s, 3 H), 2.78–2.74 (br., 1 H), 2.55–2.24 (m, 4 H), 1.45 (s, 3
H), 1.44 (d, J = 6.4 Hz, 3 H), 1.37 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.9, 164.9, 164.0, 142.2, 134.1 (CH),
132.8 (CH), 129.7 (CH), 126.6 (CH), 108.5, 107.2 (CH), 104.5,
100.2 (CH), 81.6 (CH), 75.4 (CH), 70.6 (CH), 69.0 (CH), 55.5 (Me),
38.0 (CH2), 36.9 (CH2), 27.20 (Me), 27.18 (Me), 19.4 (Me) ppm.
IR: ν = 3401, 2929, 2365, 2341, 1680 cm–1. HRMS (ESI): calcd.
˜
for C22H28O7Na [M + Na]+ 427.1733; found 427.1727.
Zeaenol: HCl (2 n, 10 mL) was added to a solution of cochliomy-
cin A (80 mg, 0.198 mmol) in THF (10 mL) and the mixture was
stirred for 20 h, quenched with saturated aqueous NaHCO3 solu-
tion, and extracted with EtOAc. The organic layers were combined
and dried with anhydrous MgSO4, filtered, and concentrated under
reduced vacuum. The crude product was purified by flash column
chromatography with ethyl acetate/petroleum ether (3:2) to yield
zeaenol as a white powder (66 mg, 92%). [α]3D0 = –82.0 (c = 0.9,
1
MeOH). H NMR (400 MHz, CDCl3/CD3OD = 9:1): δ = 11.92 (s,
1 H), 7.06 (d, J = 15.2 Hz, 1 H), 6.4 (s, 1 H), 6.32 (s, 1 H), 5.96–
5.82 (m, 2 H), 5.63–5.58 (m, 1 H), 5.30–5.27 (m, 1 H), 4.14–4.05
(m, 1 H), 3.80–3.76 (4 H), 3.52–3.5 (m, 1 H), 2.66–2.56 (br., 3 H,
–OH), 2.52–2.14 (m, 4 H), 1.41 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.1, 164.9, 163.9, 142.9, 133.3 (CH),
131.1 (CH), 129.1 (CH), 128.6 (CH), 107.5 (CH), 103.7, 99.9 (CH),
77.3 (CH), 77.1 (CH), 73.2 (CH), 71.3 (CH), 55.3 (Me), 37.4 (CH2),
[17] a) I. Navarro, J. F. Basset, S. Hebbe, S. M. Major, T. Werner,
C. Howsham, J. Brackow, A. G. M. Barett, J. Am. Chem. Soc.
2008, 130, 10293–10298; b) F. Calo, J. Richardson, A. G. M.
Barett, Org. Lett. 2009, 11, 4910–4913; c) S. Sugiyama, S. Fuse,
35.7 (CH ), 19.3 (Me) ppm. IR: ν = 3442, 2932, 2852, 1696,
˜
2
1598 cm–1. HRMS (ESI): calcd. for C19H24O7Na [M + Na]+
387.1420; found 387.1422.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
N. Jana, S. Nanda
FULL PAPER
T. Takahasi, Tetrahedron 2011, 67, 6654–6658; d) V. Navickas,
M. E. Maier, Tetrahedron 2010, 66, 94–101; e) P. Srihari, B.
Mahankali, K. Rajendraprasad, Tetrahedron Lett. 2012, 53,
56–58; f) T. Hofmann, K. H. Altmann, C. R. Chim. 2008, 11,
1318–1335; g) N. Winssinger, J. C. Fontaine, S. Barluenga,
Curr. Top. Med. Chem. 2009, 9, 1419–1435; h) R. Jogireddy,
P. Y. Dakas, G. Valot, S. Barluenga, N. Winssinger, Chem. Eur.
J. 2009, 15, 11498–11506; i) R. M. Garbaccio, S. J. Stachel,
D. K. Baeschlin, S. J. Danishefsky, J. Am. Chem. Soc. 2001,
123, 10903–10908; j) T. Hofmann, K. H. Altmarm, Synlett
2008, 1500–1504; k) L. J. Baird, M. S. Timmer, P. H. Teesdale-
Spittle, J. E. Harvey, J. Org. Chem. 2009, 74, 2271–2277; l) S.
Barluenga, J. G. Fontaine, C. H. Wang, K. Aoudi, R. H. Chen,
K. Beebe, L. Neckers, N. Winssinger, ChemBioChem 2009, 10,
2753–2759; m) J. E. H. Day, A. J. Blake, C. J. Moody, Synlett
2009, 1567–1570; n) T. Takahashi, H. Ikeda, J. Tsuji, Tetrahe-
dron Lett. 1980, 21, 3885–3888; o) C. Napolitano, P. McArdle,
P. V. Murphy, J. Org. Chem. 2010, 75, 7404–7407; p) Z. Yang,
X. Geng, D. Solit, C. A. Pratilas, N. Rosen, S. J. Danishefsky,
J. Am. Chem. Soc. 2004, 126, 7881–7889; q) S. Barluenga, P. Y.
Dakas, Y. Ferandin, L. Meijer, N. Winssinger, Angew. Chem.
2006, 118, 4055; Angew. Chem. Int. Ed. 2006, 45, 3951–3954;
r) X. Geng, S. J. Danishefsky, Org. Lett. 2004, 6, 413–416; s)
C. C. Chrovian, B. Knapp-Reed, J. Montgomery, Org. Lett.
2008, 10, 811–814; t) C. A. LeClair, M. B. Boxer, C. J. Thomas,
D. J. Maloney, Tetrahedron Lett. 2010, 51, 6852–6855; u) H.
Miyatake-Ondozabal, A. G. M. Barett, Org. Lett. 2010, 12,
5573–5575; v) D. Martinez-Solorio, K. A. Belmore, M. P. Jen-
luenga, P.-Y. Dakas, M. Boulifa, E. Moulin, N. Winssinger, C.
R. Chim. 2008, 11, 1306–1317.
[18] a) J. M. Lansinger, R. Ronald, Synth. Commun. 1979, 9, 341–
349; b) G. N. Varseev, M. E. Maier, Angew. Chem. 2006, 118,
4885; Angew. Chem. Int. Ed. 2006, 45, 4767–4771; c) M. Pittel-
kow, U. Boas, J. B. Christensen, Org. Lett. 2006, 8, 5817–5820.
[19] B. S. Bal, W. E. Childers, H. W. Pinnick, Tetrahedron 1981, 37,
2091.
[20] a) J. H. Choi, Y. H. Kim, S. H. Nam, S. T. Shin, M.-J. Kim, J.
Park, Angew. Chem. 2002, 114, 2479; Angew. Chem. Int. Ed.
2002, 41, 2373; b) J. M. Kim, Y. I. Chung, Y. K. Choi, H. K.
Lee, D. Kim, J. Park, J. Am. Chem. Soc. 2003, 125, 11494; c)
A. B. L. Fransson, Y. Xu, K. Leijondahl, J. E. Bäckvall, J. Org.
Chem. 2006, 71, 6309–6316; d) N. Jana, T. Mahapatra, S.
Nanda, Tetrahedron: Asymmetry 2009, 20, 2622–2628.
[21] K. Horita, T. Yoshioka, Y. Tanaka, Y. Oikawa, O. Yonemitsu,
Tetrahedron 1986, 42, 3021–3028.
[22] K. Ishigami, H. Watanabe, T. Kitahara, Tetrahedron 2005, 61,
7546–7553.
[23] P. G. McDougal, J. G. Rico, Y.-I. Oh, B. D. Condon, J. Org.
Chem. 1986, 51, 3388–3390.
[24] A. J. Mancuso, D. S. Brownfain, D. Swern, J. Org. Chem. 1979,
44, 4148–4150.
[25] G. E. Keck, K. H. Tarbet, L. S. Geraci, J. Am. Chem. Soc.
1993, 115, 8467–8468.
[26] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[27] C. Aissa, Eur. J. Org. Chem. 2009, 1831–1844.
[28] M. C. Matos, P. V. Murphy, J. Org. Chem. 2007, 72, 1803–1806.
nings, J. Org. Chem. 2011, 76, 3898–3908; w) P.-Y. Dakas, R. [29] a) M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett.
Jogireddy, G. Valot, S. Barluenga, N. Winssinger, Chem. Eur.
J. 2009, 15, 11490–11497; x) P.-Y. Dakas, S. Barluenga, F.
Totzke, U. Zirrgiebel, N. Winssinger, Angew. Chem. 2007, 119,
7023; Angew. Chem. Int. Ed. 2007, 46, 6899–6902; y) S. Bar-
1999, 1, 953–956; b) D. M. Solorio, K. A. Belmore, M. P. Jen-
nings, J. Org. Chem. 2011, 76, 3898–3908.
Received: February 29, 2012
Published Online: ᭿
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20241
/KAP1
Date: 28-06-12 10:43:10
Pages: 9
Asymmetric Total Syntheses of Cochliomycin A and Zeaenol
Asymmetric Synthesis
Two resorcylic acid lactones (RALs) –
cochliomycin A and zeaenol – have been
synthesized for the first time by an enantio-
divergent route from the common chiral
pool compound l-tartaric acid.
N. Jana, S. Nanda* ........................... 1–9
Asymmetric Total Syntheses of Cochliomy-
cin A and Zeaenol
Keywords: Lactones
/ Asymmetric syn-
thesis / Metathesis / Synthetic methods /
Macrocycles
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9