Late-stage β-epimerization. A stereodivergent to stereoconvergent relay to the first total synthesis of (+)-murolic acid

Article abstract of DOI:10.1002/ejoc.201301287

The first total synthesis of (+)-murolic acid is accomplished in 17 steps from ester 9 in 14.8 % overall yield. The key steps involve asymmetric dihydroxylation, orthoester Johnson-Claisen rearrangement and α-methylenation using Stiles reagent. A beneficial late stage β-epimerization reverted a stereodivergent relay to a stereoconvergent completion of an efficient synthesis of (+)-murolic acid. The first total synthesis of (+)-murolic acid is accomplished in 17 steps from ester 9 in 14.8 % overall yield. The key steps involve asymmetric dihydroxylation, orthoester Johnson-Claisen rearrangement and α-methylenation using Stiles reagent. A beneficial late-stage β-epimerization increased the efficiency of the synthesis. Copyright

Full text of DOI:10.1002/ejoc.201301287

FULL PAPER
DOI: 10.1002/ejoc.201301287
Late-Stage β-Epimerization. A Stereodivergent to Stereoconvergent Relay to
the First Total Synthesis of (+)-Murolic Acid
Rodney A. Fernandes,*[a] Pradnya H. Patil,[a] and Asim K. Chowdhury[a]
Keywords: Total synthesis / Natural products / Asymmetric synthesis / Rearrangement / Epimerization
The first total synthesis of (+)-murolic acid is accomplished
in 17 steps from ester 9 in 14.8% overall yield. The key steps
involve asymmetric dihydroxylation, orthoester Johnson–
Claisen rearrangement and α-methylenation using Stiles rea-
gent. A beneficial late stage β-epimerization reverted a
stereodivergent relay to a stereoconvergent completion of an
efficient synthesis of (+)-murolic acid.
these natural products either in racemic or enantiopure
form using starting materials from the chiral pool, chiral
auxiliaries, or by applying catalytic asymmetric methodolo-
gies.[5,10,11] In the course of our studies directed toward the
enantioselective synthesis of paraconic acids[10,11] we be-
came interested in the synthetically untouched molecule,
murolic acid.
Introduction
Naturally occurring plant glycosides have been known
for a long time,[1] and the plant family of lichens has con-
tributed to a few of them.[1] A few macrocyclic lipid glycos-
ides have also been isolated.[1–3] The associated interesting
bioactivities and the intriguing structural complexity in
these molecules have provided the impetus towards de-
veloping new synthetic strategies for their chemical synthe-
sis.[3] Rezanka et al.[4] isolated several new glycosides having
murolic (1), protoconstipatic (2), and allo-murolic (3) acids
as the aglycones and the oligosaccharide moiety made of
one or two sugars (glucose and apiose or rhamnose or xyl-
ose or arabinose) linked through the C-18 hydroxy group
of the aglycon (Figure 1). Five of these isolated glycosides
4a–e have murolic acid (1) as the aglycon. Murolic acid be-
longs to the family of paraconic acids,[5] which constitute a
small class of variously functionalized chiral γ-lactones. In
addition to the presence of a –CO2H group at the β-posi-
tion of the γ-butyrolactone ring, these compounds also bear
an alkyl chain at the γ-carbon atom and either a methyl or
a methylene group at the α-position. They display varied
stereochemical relationships of substituents on the adjacent
carbon atoms, and have been isolated from different species
of moss, lichens, fungi and cultures of Penicillium sp.[6] In
the past few years paraconic acids have been prominent
synthetic targets due to their various pharmacological
properties including antibacterial,[7] antifungal,[7b] antitu-
mor,[8] and growth-regulating effects.[9] The activity arises
mainly due to the α,β-unsaturated carbonyl system, which
acts as a Michael acceptor to varied biological nucleophiles.
A number of syntheses have been developed leading to
Figure 1. Structures of paraconic acids and murolic acid glycosides.
Herein, we report the first synthesis of (+)-murolic acid
by utilizing asymmetric dihydroxylation,[12] orthoester
Johnson–Claisen rearrangement,[13] and α-methylenation
using Stiles reagent[14] as key steps. A beneficial late stage
β-epimerization reverted the stereodivergent relay to a
stereoconvergent first total synthesis of (+)-murolic acid.
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, Maharashtra, India
E-mail: rfernand@chem.iitb.ac.in
http://www.chem.iitb.ac.in/~rfernand/default.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301287.
Eur. J. Org. Chem. 2014, 237–243
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perature Wittig olefination provided the mixture of α,β-un-
saturated esters 16/17 (Z/E = 2.3:1). The mixture was ef-
ficiently separated by flash column chromatography to give
16 (68%) and 17 (29%). However, the same reaction using
the Still–Gennari protocol delivered 16 in 81% and 17 in
7% isolated yields.[20]
Results and Discussion
The retrosynthetic analysis of (+)-murolic acid is high-
lighted in Scheme 1. The lactone 5 is an advanced interme-
diate featuring a β-vinyl bond as a masked group for gener-
ation of -CO2H at the β-position with the active α-position
available for methylenation. The synthesis of lactone 5 was
visualized through orthoester Johnson–Claisen rearrange-
ment of allyl alcohol 6. The latter could be assembled
through Wittig olefination of aldehyde from 7. The terminal
diol 7 was planned through asymmetric dihydroxylation of
8, with the latter being accessed through sequential Wittig
olefination of the aldehyde from 9.
Scheme 2. Synthesis of separable diastereomers 16 and 17. Reagents
and conditions: (a) i. DIBAL-H (1.2 equiv.), CH2Cl2, –78 °C, 1.5 h;
ii. Wittig salt 10 (1.2 equiv.), nBuLi (1.2 equiv.), THF, –78 °C, 4 h,
room temp., 6 h, 85%; (b) H2, Pd(OH)2/C, EtOH, balloon pressure,
room temp., 2 h, 85%; (c) i. (COCl)2 (1.5 equiv.), DMSO
(3.0 equiv.), CH2Cl2, –78 °C, 10 min, alcohol 12, 45 min, Et3N
(5.0 equiv.), CH2Cl2, –78 °C, 30 min, room temp., 1 h;
ii. Ph3P+MeI–(1.2 equiv.), nBuLi (1.2 equiv.), THF, 0 °C to room
temp., 3 h, 86% (two steps); (d) K3Fe(CN)6 (3.0 equiv.), K2CO3
(3.0 equiv.), (DHQD)2AQN (1.12 mol-%), K2OsO4·2H2O (0.4 mol-
%), MeSO2NH2 (1.0 equiv.), tBuOH/H2O (1:1), 0 °C, 24 h, 94%;
Scheme 1. Retrosynthesis of (+)-murolic acid (1).
(e) i. p-methoxy
benzaldehyde
dimethylacetal
(2.0 equiv.),
Accordingly, the forward synthesis was initiated from
known compound 9[15] (Scheme 2). DIBAL-H mediated re-
duction of the ester to the corresponding aldehyde and sub-
sequent Wittig olefination with the requisite ylide from
10[16] gave olefin 11 in 85% yield. Hydrogenation of 11
using Pearlman’s catalyst in iPrOH solvent resulted in si-
multaneous reduction of the alkene bond and debenz-
ylation, producing alcohol 12 in 65%yield. Performing the
same reaction in EtOH gave 12 in 85% yield. Oxidation of
pTsOH·H2O (cat.), benzene, room temp., 12 h; ii. DIBAL-H
(3.0 equiv.), –78 °C, CH2Cl2, 3 h, 84% (two steps); (f) i. DMP
(1.5 equiv.), CH2Cl2, room temp., 3 h; ii. Ph3P=CHCO2Et
(2.5 equiv.), MeOH, –40 °C to room temp., 24 h, 16 (68%), 17
(29%); (g) i. DMP (1.5 equiv.), CH2Cl2, room temp., 3 h;
ii. (CF3CH2O)2POCH2CO2Et (1.1 equiv.), KHMDS (1.1 equiv.),
18-crown-6 (2.0 equiv.), THF, 0 °C, 15 min, then –78 °C, aldehyde
from 15, 2 h, 16 (81%), 17 (7%).
DIBAL-H mediated reduction of 16 and 17 provided pri-
the primary alcohol to aldehyde (Swern oxidation), fol- mary allyl alcohols 6 (95%) and 18 (92%), respectively
lowed by one-carbon Wittig olefination resulted in forma- (Scheme 3). The lactone moiety was efficiently assembled
tion of terminal olefin 13 (86%).[17] The Sharpless asym- by orthoester Johnson–Claisen rearrangement[13,11b] of allyl
metric dihydroxylation of 13 using hydroquinidine (anthra- alcohol 6 with trimethylorthoacetate and catalytic prop-
quinone-1,4-diyl) diether [(DHQD)2AQN] ligand[12b] pro- ionic acid in toluene at reflux to deliver the γ,δ-unsaturated
vided the desired diol 14 in excellent yields (94%) and ester, which, upon one-pot lactonization using trifluoro-
95.5:4.5 dr.[18] The diol differentiation was manifested by acetic acid (TFA)-mediated debenzylation, gave anti/syn
following a standard procedure[19] by conversion into p- lactones 5/19 as a mixture in a ratio of 3.5:1.[21] The lactone
methoxybenzylidene (PMB) acetal, and DIBAL-H medi- diastereomers were efficiently separated by column
ated reduction to deliver monoprotected PMB ether 15 chromatography to afford 5 (68%) and 19 (21%). Surpris-
(84%). Oxidation of the primary alcohol with Dess–Martin ingly, the unmasking of TBDSMS ether also occurred with
periodinane gave the corresponding aldehyde, and low-tem- concomitant trifluoromethyl acetate protection. This was
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Total Synthesis of (+)-Murolic Acid
confirmed by the absence of signals arising from the late[4a,24] as well the optical rotation, synthetic material
TBDMS group in the H NMR spectrum and also by the [α]2D5 = +10.5 (c = 0.12, CHCl3) and natural isolate[4a]
1
19F NMR spectra of 5 and 19.[22] Similarly, trans-allyl [α]D24 = +11.2 (c = 0.14, CHCl3).
alcohol 18 provided a mixture of 5/19, albeit with a lower
diastereoselectivity (1.3:1). These results are in agreement
with our recent study.[11b]
Scheme 4. Synthesis of (+)-murolic acid (1). Reagents and condi-
tions: (a) i. O3, CH2Cl2, –78 °C, 20 min, then Me2S, –78 °C, 2 h,
room temp., 2 h; ii. NaClO2 (2.3 equiv.), NaH2PO4·2H2O
Scheme 3. Synthesis of separable lactones 5 and 19. Reagents and
(2.3 equiv.), cyclohexene (3.0 equiv.), tBuOH/H2O (2:1), room
conditions: (a) i. DIBAL-H (2.5 equiv.), CH2Cl2, –20 °C, 2 h, room
temp., 12 h, 20 (80%), 21 (78%), (20/21, 79% from 5/19 mixture);
temp., 2 h, 6 (95%), 18 (92%); (b) i. (MeO)3CMe (10.0 equiv.), tolu-
(b) i. MeOMgOCO2Me (38.0 equiv.), DMF, 135 °C, 60 h; ii. CH2O,
N-methylaniline, AcOH, NaOAc, room temp., 2.5 h, (58% from 20,
46% from 21), (54% from 20/21 mixture).
ene, EtCO2H (cat.), reflux, 48 h; ii. TFA/CH2Cl2 (1:9), 0 °C to
room temp., 12 h 5 (68%), 19 (21%) from 6, 5 (48%), 19 (39%)
from 18 (two steps).
Two-stage ozonolytic cleavage of the vinyl bond in 5 and
Conclusions
subsequent Pinnick oxidation[23] efficiently generated the β-
The first total synthesis of (+)-murolic acid has been ac-
complished. Notable features include asymmetric dihydrox-
ylation of the terminal olefin, orthoester Johnson–Claisen
rearrangement to install the lactone moiety, the use of the
β-vinyl group for conversion into the CO2H group, and α-
methylenation using Stiles reagent. A beneficial late-stage
carboxylic acid group to provide 20 in 80% yield
(Scheme 4). Finally, α-methylenation using Stiles reagent[14]
followed by treatment with N-methylaniline and formalde-
hyde (with trifluoroacetate removal in situ), efficiently deliv-
ered (+)-murolic acid in 58% yield. Similar oxidation of the
vinyl bond in 19 led to acid 21 (78%). The α-methylenation
β-epimerization reverted the stereodivergent strategy into a
of compound 21 and trifluroacetate removal, astonishingly,
stereoconvergent relay leading to the completion of the first
synthesis of (+)-murolic acid in 17 steps from 9 and overall
yields of 14.8%.
gave (+)-murolic acid through epimerization of the β-CO2H
group in 46% yield. We believe the epimerization might be
occurring at the diacid 22 stage through activation of the β-
carbon center. This beneficial epimerization led to the same
molecule, (+)-murolic acid. This is a remarkable feature that
Experimental Section
was previously unknown in paraconic acid synthesis.[10,11]
General Remarks: Anhydrous reactions were carried out under an
atmosphere of Ar or N2. Solvents and reagents were purified by
standard methods. Thin-layer chromatography was performed on
EM 250 Kieselgel 60 F254 silica gel plates; the spots were visual-
Alternatively, after orthoester Johnson–Claisen rearrange-
ment, the unseparated mixture of 5/19 (92%) was subjected
to ozonolytic cleavage and oxidation to give the acid 20/
21 in 79% yield. This mixture when subjected to final α-
1
ized either under a UV lamp or by staining with KMnO4. H and
13C NMR spectra were recorded at 400 and 100 MHz respectively,
methylenation to give (+)-murolic acid, which was isolated
in 54% yield. There was an excellent correlation of spectro-
and the chemical shifts are based on the TMS peak (δ = 0.00 ppm)
1
scopic data between the synthetic material and natural iso- for H NMR and the central CDCl3 peak (δ = 77.00 ppm) in 13C
Eur. J. Org. Chem. 2014, 237–243
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R. A. Fernandes, P. H. Patil, A. K. Chowdhury
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NMR spectra. IR samples were prepared by evaporation from
CHCl3 on CsBr plates. High-resolution mass spectra were obtained
by using positive electrospray ionization by TOF method.
aqueous layer was extracted with CH2Cl2 (3ϫ 50 mL). The com-
bined organic extracts were washed with water, brine, dried
(Na2SO4), and concentrated to give the crude aldehyde (0.497 g),
which was used directly in the next reaction. To a slurry of methyl-
triphenylphosphonium iodide (0.651 g, 1.61 mmol, 1.2 equiv.) in
THF (10 mL) at 0 °C was added n-BuLi (1.6 m in THF, 1.0 mL,
1.60 mmol, 1.2 equiv.). The mixture was stirred for 30 min, then a
solution of the above aldehyde (0.497 g) in THF (10 mL) was
added. After stirring for 3 h, the reaction mixture was quenched by
adding satd. aq. NH4Cl (3 mL) and extracted with EtOAc (3ϫ
20 mL). The combined organic layers were washed with water,
brine, dried (Na2SO4), and concentrated. The residue was purified
by column chromatography (petroleum ether/EtOAc, 9:1) to pro-
vide 13 (0.425 g, 86%) as a colorless oil. [α]2D5 = –6.8 (c = 1.04,
(R,Z)-16-Benzyloxyhexadec-4-en-2-yloxy(tert-butyldimethyl)silane
(11): To a stirred solution of ester 9 (2.2 g, 8.93 mmol) in anhydrous
CH2Cl2 (50 mL) at –78 °C under an Ar atmosphere was added
DIBAL-H (25 wt.-% in toluene, 6.1 mL, 10.71 mmol, 1.2 equiv.)
over a period of 1 h. The reaction mixture was stirred at –78 °C for
1 h and then quenched with satd. aq. sodium potassium tartrate
solution (20 mL). Stirring was continued for 1 h at room temp. and
the aqueous layer was extracted with CH2Cl2 (3ϫ 50 mL). The
combined organic layers were washed with water, brine, dried
(Na2SO4), and concentrated to give the crude aldehyde (1.8 g),
which was used for the next reaction without further purification.
To a solution of Wittig salt 10[16] (7.12 g, 10.71 mmol, 1.2 equiv.)
in THF (20 mL) at 0 °C was added nBuLi (1.6 m in THF, 6.7 mL,
10.71 mmol, 1.2 equiv.). The reaction mixture was stirred for
30 min, then cooled to –78 °C and a solution of the above aldehyde
(1.8 g) in THF (10 mL) was added slowly. The reaction mixture
was warmed to room temp. over 12 h, then the reaction was
quenched with satd. aq. NH4Cl (15 mL) and THF was removed
under reduced pressure. The aqueous layer was extracted with
EtOAc (4ϫ 20 mL) and the combined organic layers were washed
with water, brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography (petroleum ether/
CHCl3) {ref.[17] [α]2D2 = –8.0 (c = 20, CHCl )}. IR (CHCl ): ν =
˜
3
3
2927, 2855, 2738, 1642, 1464, 1373, 1255, 1178, 1136, 1047, 910,
836, 806, 773, 666 cm–1. 1H NMR (400 MHz, CDCl3/TMS): δ =
5.86–5.74 (m, 1 H), 5.02–4.89 (m, 2 H), 3.81–3.72 (m, 1 H), 2.11–
2.01 (m, 2 H), 1.43–1.22 (m, 24 H), 1.11 (d, J = 6.1 Hz, 3 H), 0.89
(s, 9 H), 0.05 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
139.2, 114.1, 68.7, 39.8, 33.8, 29.7, 29.68, 29.6, 29.5, 29.2, 29.0,
25.9, 25.8, 23.8, 18.2, –4.4, –4.7 ppm. HRMS (ESI+): calcd. for
[C23H48OSi + H]+ 369.3554; found 369.3561.
(2R,16R)-(tert-Butyldimethylsilyloxy)hepadecane-1,2-diol (14): To a
mixture of K3Fe(CN)6 (2.68 g, 8.14 mmol, 3.0 equiv.), K2CO3
EtOAc, 19:1) to afford olefin 11 (3.50 g, 85%) as a colorless oil. (1.125 g, 8.14 mmol, 3.0 equiv.), MeSO2NH2 (0.258 g, 2.71 mmol,
[α]2D5 = +1.7 (c = 0.66, CHCl ). IR (CHCl ): ν = 2927, 2855, 1463,
1.0 equiv.), (DHQD)2AQN (0.026 g, 0.03 mmol, 1.12 mol-%), and
˜
3
3
1361, 1255, 1100, 1005, 836, 774, 733, 697 cm–1
.
1H NMR K2OsO4·2H2O (4.0 mg, 0.01084 mmol, 0.4 mol-%) were added
(400 MHz, CDCl3/TMS): δ = 7.35–7.26 (m, 5 H), 5.47–5.33 (m, 2 tBuOH (7 mL) and water (14 mL). The mixture was stirred for
H), 4.50 (s, 2 H), 3.83–3.76 (m, 1 H), 3.46 (t, J = 6.7 Hz, 2 H),
2.23–2.15 (m, 2 H), 2.06–1.97 (m, 2 H), 1.65–1.58 (m, 4 H), 1.35–
1.26 (m, 14 H), 1.12 (d, J = 6.0 Hz, 3 H), 0.89 (s, 9 H), 0.05 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.7, 133.8, 131.6,
128.3, 127.6, 127.4, 72.8, 70.5, 68.8, 37.5, 29.8, 29.7, 29.6, 29.5,
5 min and cooled to 0 °C in an ice bath. To the cooled mixture, a
solution of olefin 13 (1 g, 2.71 mmol) in tBuOH (7 mL) was added.
The mixture was stirred at 0 °C for 24 h and then the reaction was
quenched with solid Na2SO3 and the mixture was stirred for
30 min. The solution was extracted with EtOAc (3ϫ 20 mL) and
29.48, 29.3, 27.4, 26.2, 25.9, 23.4, 18.2, –4.6, – 4.7 ppm. HRMS the combined organic layers were washed with 2 n KOH (10 mL),
(ESI+): calcd. for [C29H52O2Si + K]+ 499.3368; found 499.3378.
brine, dried (Na2SO4), and concentrated. The residue was purified
by silica gel column chromatography (petroleum ether/EtOAc, 1:1)
to give 14 (1.027 g, 94%) as a colorless oil. [α]2D5 = –9.9 (c = 0.1,
(R)-15-tert-Butyldimethylsilyloxyhexadecan-1-ol (12): To a solution
of olefin 11 (0.5 g, 1.085 mmol) in EtOH (10 mL) was added 10wt.-
% Pd(OH)2/C (50 mg) under an Ar atmosphere. The resulting reac-
tion mixture was stirred at room temp. under a H2 atmosphere
(balloon pressure) for 2 h and then filtered through a pad of Celite
and washed with EtOAc (2ϫ 50 mL). The filtrate was concentrated
and the residue was purified by silica gel column chromatography
(petroleum ether/EtOAc, 6:1) to afford alcohol 12 (0.344 g, 85%)
CHCl ). IR (CHCl ): ν = 3392, 2929, 2855, 1465, 1374, 1254, 1187,
˜
3
3
1134, 1067, 1006, 939, 836, 807, 720, 663 cm–1 1H NMR
.
(400 MHz, CDCl3/TMS): δ = 3.80–3.62 (m, 3 H), 3.47–3.40 (m, 1
H), 2.02–1.98 (br. s, 1 H, OH), 1.86 (br. s, 1 H, OH), 1.59–1.21 (m,
26 H), 1.11 (d, J = 6.0 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 72.3, 68.7, 66.6, 39.7, 33.0, 29.7,
29.6, 25.9, 25.8, 25.6, 23.8, 18.1, –4.5, –4.8 ppm. HRMS (ESI+):
calcd. for [C23H50O3Si + Na]+ 425.3421; found 425.3422. The dia-
stereomeric ratio was determined to be 95.5:4.5 by conversion into
tribenzoate and HPLC analysis.
as a colorless oil. [α]2D5 = –6.8 (c = 0.1, CHCl ). IR (CHCl ): ν =
˜
3
3
3346, 2927, 2855, 1464, 1374, 1255, 1134, 1057, 836, 808, 774, 721,
1
663 cm–1. H NMR (400 MHz, CDCl3/TMS): δ = 3.78–3.72 (m, 1
H), 3.64 (t, J = 6.6 Hz, 2 H), 1.59–1.53 (m, 6 H), 1.38–1.25 (m, 20
H), 1.11 (d, J = 6.1 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 68.7, 63.1, 39.7, 32.8, 29.7, 29.64,
(2R,16R)-16-(tert-Butyldimethylsilyloxy)-2-(4-methoxybenzyl-
oxy)heptadecan-1-ol (15): To a solution of diol 14 (1 g, 2.48 mmol)
29.6, 29.59, 29.4, 25.9, 25.8, 25.7, 23.8, 18.2, –4.4, –4.7 ppm. in anhydrous benzene (30 mL) were added p-methoxybenzaldehyde
HRMS (ESI+): calcd. for [C22H48O2Si + Na]+ 395.3316; found
395.3310.
dimethylacetal (0.85 mL, 4.97 mmol, 2.0 equiv.) and pTsOH·H2O
(catalytic amount). The reaction mixture was stirred at room temp.
for 12 h and then concentrated. The residue was purified by silica
gel column chromatography (petroleum ether/EtOAc, 19:1) to give
the intermediate acetal (1.1 g) as a colorless oil, which was used in
the next reaction.
(R)-tert-Butyl(heptadec-16-en-2-yloxy)dimethylsilane (13): A solu-
tion of DMSO (0.29 mL, 4.03 mmol, 3.0 equiv.) in anhydrous
CH2Cl2 (15 mL) was gradually added to a solution of oxalyl chlor-
ide (0.18 mL, 2.01 mmol, 1.5 equiv.) in CH2Cl2 (15 mL) at –78 °C
over a period of 10 min. After stirring for 15 min, a solution of
alcohol 12 (0.5 g, 1.34 mmol) in CH2Cl2 was added and the reac-
tion mixture was stirred for 45 min. Et3N (0.94 mL, 6.70 mmol,
5 equiv.) was added and the mixture was stirred for 30 min. After
warming to room temp. over 1 h, water (5 mL) was added and the
To a solution of the above acetal (1.1 g, 2.11 mmol) in anhydrous
CH2Cl2 (20 mL), at –78 °C under an Ar atmosphere, was added
DIBAL-H (25wt.-% in toluene, 3.6 mL, 6.32 mmol, 3.0 equiv.) over
a period of 20 min. The mixture was stirred for 5 h, then the reac-
tion was quenched with a satd. aq. sodium potassium tartrate solu-
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Total Synthesis of (+)-Murolic Acid
tion (5 mL). Stirring was continued for 1 h at room temp., then the
aqueous layer was extracted with CH2Cl2 (3ϫ 20 mL). The com-
bined organic extracts were washed with water, brine, dried
(Na2SO4), and concentrated. The residue was purified by silica gel
column chromatography (petroleum ether/EtOAc, 6:1) to give 15
(1.09 g, 84% from 14) as a colorless oil. [α]2D5 = –9.2 (c = 0.24,
29.6, 29.57, 29.5, 29.45, 25.9, 25.8, 25.1, 23.8, 18.1, 14.3, –4.5,
–4.8 ppm. HRMS (ESI+): calcd. for [C35H62O5Si + Na]+ 613.4259;
found 613.4256.
Preparation of 16 and 17 by using the Still–Gennari Procedure:[20]
To a solution of alcohol 15 (0.14 g, 0.267 mmol) in CH2Cl2 (20 mL)
was added Dess–Martin periodinane (0.17 g, 0.4 mmol, 1.5 equiv.)
in one portion and the reaction was stirred at room temp. for 3 h.
The mixture was filtered through a Celite pad and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (petroleum ether/EtOAc, 19:1)
to afford the aldehyde (0.138 g) as a colorless oil, which was imme-
diately used in the next reaction.
CHCl ). IR (CHCl ): ν = 3442, 2928, 2855, 1614, 1587, 1514, 1464,
˜
3
3
1373, 1361, 1302, 1250, 1173, 1130, 1070, 1040, 880, 835, 808, 720,
666 cm–1 1H NMR (400 MHz, CDCl3/TMS): δ = 7.23 (d, J =
.
8.7 Hz, 2 H), 6.84 (d, J = 8.7 Hz, 2 H), 4.51 (d, J = 11.1 Hz, 1 H),
4.42 (d, J = 11.1 Hz, 1 H), 3.76 (s, 3 H), 3.75–3.74 (m, 1 H), 3.73–
3.70 (m, 1 H), 3.48–3.41 (m, 2 H), 1.95 (br. s, 1 H, OH), 1.61–1.18
(m, 26 H), 1.07 (d, J = 6.0 Hz, 3 H), 0.84 (s, 9 H), 0.004 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.3, 130.6, 129.4,
113.9, 79.5, 71.2, 68.7, 64.3, 55.3, 39.8, 30.8, 29.8, 29.7, 29.67, 29.6,
29.57, 25.9, 25.8, 25.4, 23.8, 18.2, –4.4, –4.7 ppm. HRMS (ESI+):
calcd. for [C31H58O4Si + Na]+ 545.3997; found 545.3996.
To a solution of freshly prepared ethyl bis(2,2,2-trifluoroethyl)-
phosphonoacetate[20b] (0.0976 g, 0.294 mmol, 1.1 equiv.) and 18-
crown-6 (0.141 g, 0.534 mmol, 2.0 equiv.) in anhydrous THF
(7 mL) at 0 °C was added KHMDS (1M in THF, 0.3 mL,
0.3 mmol, 1.1 equiv.) and the reaction mixture was stirred for
15 min. It was then cooled to –78 °C and a solution of the above
aldehyde (0.138 g) in THF (1 mL) was added. The mixture was
stirred for 2 h, then the reaction was quenched with satd. aq.
NH4Cl. The solution was extracted with Et2O (3ϫ 15 mL) and the
combined organic layers were dried (Na2SO4) and concentrated.
The residue was purified by column chromatography (petroleum
ether/EtOAc, 19:1) to afford 16 (0.128 g, 81% from 15) as a color-
less oil. Further elution gave 17 (0.011 g, 7% from 15) as a colorless
oil. Data for 16 and 17 were the same as detailed above.
(4R,18R,Z)-Ethyl 18-(tert-Butyldimethylsilyloxy)-4-(4-methoxy-
benzyloxy)nonadec-2-enoate (16) and (4R,18R,E)-Ethyl 18-(tert-
Butyldimethylsilyoxy)-4-(4-methoxybenzyloxy)nonadec-2-enoate
(17): To a solution of alcohol 15 (0.310 g, 0.592 mmol) in CH2Cl2
(35 mL) was added Dess–Martin periodinane (0.377 g,
0.889 mmol, 1.5 equiv.) in one portion, and the reaction was stirred
at room temp. for 3 h. The mixture was filtered through a Celite
pad and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (petro-
leum ether/EtOAc, 19:1) to afford the aldehyde (0.3 g) as a colorless
oil, which was immediately used in the next reaction.
(4R,18R,Z)-18-(tert-Butyldimethylsilyloxy)-4-(4-methoxybenzyl-
oxy)nonadec-2-en-1-ol (6): To a solution of ester 16 (0.35 g,
0.592 mmol) in CH2Cl2 (20 mL) at –20 °C was added DIBAL-H
(25wt.-% in toluene, 0.85 mL, 1.48 mmol, 2.5 equiv.). The mixture
was stirred for 2 h, then warmed to room temp. and the reaction
was quenched with satd. aq. sodium potassium tartrate solution
and the mixture was stirred for 2 h. The solution was extracted
with CH2Cl2 (3ϫ 20 mL) and the combined organic extracts were
washed with water, brine, dried (Na2SO4), and concentrated. The
residue was purified by column chromatography (petroleum ether/
To a solution of the above aldehyde (0.3 g) in MeOH (10 mL) at
–40 °C was added (carbethoxymethylene)triphenylphosphorane
(0.502 g, 1.44 mmol, 2.5 equiv.). The reaction mixture was stirred
at –40 °C for 5 h, then warmed to room temp. and stirred for 12 h
and then concentrated. To the residue was added petroleum ether
to precipitate Ph3P=O. The white solid was filtered and washed
with petroleum ether. The filtrate was concentrated and the residue
was purified by flash silica gel column chromatography (petroleum
ether/EtOAc, 19:1) to afford 16 (0.238 g, 68% from 15) as a color-
less oil. Further elution gave 17 (0.102 g, 29% from 15) as a color-
less oil.
EtOAc, 7:3) to afford 6 (0.309 g, 95%) as a colorless oil. [α]2D5
+10.3 (c = 0.46, CHCl ). IR (CHCl ): ν = 3431, 3000, 2928, 2855,
=
˜
3
3
1613, 1587, 1514, 1464, 1373, 1361, 1302, 1173, 1134, 1039, 940,
835, 809, 721, 666 cm–1. 1H NMR (400 MHz, CDCl3/TMS): δ =
7.25 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.83–5.76 (m,
Compound 16: [α]2D5 = –2.9 (c = 0.2, CHCl ). IR (CHCl ): ν = 2927,
˜
3
3
2855, 1722, 1646, 1614, 1587, 1514, 1464, 1410, 1387, 1302, 1249,
1186, 1132, 1083, 1039, 834, 774 cm–1
.
1H NMR (400 MHz, 1 H), 5.50–5.44 (m, 1 H), 4.51 (d, J = 11.5 Hz, 1 H), 4.29 (d, J =
CDCl3/TMS): δ = 7.24 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2
11.5 Hz, 1 H), 4.25–4.17 (m, 1 H), 4.16–4.03 (m, 2 H), 3.80 (s, 3
H), 6.19–6.13 (m, 1 H), 5.90–5.85 (m, 1 H), 5.02–4.97 (m, 1 H),
H), 3.80–3.74 (m, 1 H), 1.35–1.25 (m, 26 H), 1.11 (d, J = 6.1 Hz,
4.46 (d, J = 11.3 Hz, 1 H), 4.33 (d, J = 11.3 Hz, 1 H), 4.17 (q, J = 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H) ppm. 13C NMR (100 MHz,
7.1 Hz, 2 H), 3.80 (s, 3 H), 3.79–3.72 (m, 1 H), 1.52–1.22 (m, 29 CDCl3): δ = 159.1, 133.3, 131.4, 130.5, 129.3, 113.7, 73.8, 69.7,
H), 1.11 (d, J = 6.1 Hz, 3 H), 0.85 (s, 9 H), 0.04 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 165.9, 159.1, 151.4, 130.6, 129.4,
120.9, 113.6, 74.7, 70.9, 68.6, 60.1, 55.2, 39.7, 35.0, 29.7, 29.64,
29.6, 29.59, 29.57, 29.5, 25.9, 25.8, 25.2, 23.8, 18.1, 14.2, –4.5,
–4.8 ppm. HRMS (ESI+): calcd. for [C35H62O5Si + Na]+ 613.4259;
found 613.4264.
68.7, 58.7, 55.2, 39.7, 35.5, 29.7, 29.63, 29.6, 29.55, 29.5, 25.9, 25.8,
25.3, 23.8, 18.1, –4.5, –4.8 ppm. HRMS (ESI+): calcd. for
[C33H60O4Si + Na]+ 571.4153; found 571.4151.
(4R,18R,E)-18-(tert-Butyldimethylsilyloxy)-4-(4-methoxybenzyl-
oxy)nonadec-2-en-1-ol (18): Prepared from 17 (0.035 g, 0.059 mmol)
by a procedure similar to that described for 6, to afford 18 (0.030 g,
92%) as a colorless oil. [α]2D5 = +12.7 (c = 0.4, CHCl3). IR (CHCl3):
Compound 17: [α]2D5 = +2.6 (c = 0.1, CHCl ). IR (CHCl ): ν = 2928,
˜
3
3
2855, 1723, 1614, 1514, 1465, 1370, 1298, 1251, 1173, 1092, 1040,
985, 836, 771 cm–1. 1H NMR (400 MHz, CDCl3/TMS): δ = 7.25
(d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 6.87–6.82 (m, 1 H),
ν = 3430, 2995, 2927, 2855, 1613, 1586, 1514, 1464, 1376, 1298,
˜
1250, 1173, 1070, 1039, 974, 836, 668 cm–1. 1H NMR (400 MHz,
CDCl3/TMS): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2
6.02–5.97 (m, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.29 (d, J = 11.4 Hz, H), 5.84–5.77 (m, 1 H), 5.64–5.57 (m, 1 H), 4.51 (d, J = 11.5 Hz,
1 H), 4.22 (q, J = 7.1 Hz, 2 H), 3.93–3.88 (m, 1 H), 3.81 (s, 3 H), 1 H), 4.29 (d, J = 11.5 Hz, 1 H), 4.21–4.17 (m, 2 H), 3.79 (s, 3 H),
3.79–3.73 (m, 1 H), 1.31 (t, J = 7.14 Hz, 3 H), 1.42–1.22 (m, 26 3.80–3.73 (m, 2 H), 1.69–1.24 (m, 26 H), 1.11 (d, J = 6.0 Hz, 3 H),
H), 1.12 (d, J = 6.1 Hz, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 166.3, 159.2, 148.7, 130.2, 129.3,
121.8, 113.7, 77.7, 70.6, 68.6, 60.4, 55.2, 39.7, 34.9, 29.67, 29.63,
0.89 (s, 9 H), 0.05 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 159.0, 132.5, 131.6, 130.8, 129.3, 113.7, 79.1, 69.8, 68.7, 63.0,
55.2, 39.7, 35.6, 29.7, 29.65, 29.6, 29.58, 29.5, 25.9, 25.8, 25.4, 23.8,
Eur. J. Org. Chem. 2014, 237–243
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
241

R. A. Fernandes, P. H. Patil, A. K. Chowdhury
FULL PAPER
18.2, –4.5, –4.7 ppm. HRMS (ESI+): calcd. for [C33H60O4Si +
Na]+ 571.4153; found 571.4148.
1168, 1043, 1026, 967, 869, 669 cm–1. 1H NMR (400 MHz, CDCl3/
TMS): δ = 5.13–5.06 (m, 1 H), 4.64–4.58 (m, 1 H), 3.13–3.06 (m,
1 H), 2.94 (dd, J = 17.9, 8.4 Hz, 1 H), 2.81 (dd, J = 17.9, 9.6 Hz,
1 H), 1.83–1.41 (m, 4 H), 1.34 (d, J = 6.3 Hz, 3 H), 1.35–1.25 (m,
22 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.4, 174.9, 157.4
(q), 114.8 (q), 82.1, 76.8, 45.6, 35.5, 32.0, 29.84, 29.8, 29.7, 29.6,
29.5, 29.3, 29.2, 25.3, 25.2, 19.6 ppm. 19F NMR: δ = –75.4 ppm.
HRMS (ESI+): calcd. for [C22H35O6F3 + Na]+ 475.2278; found
475.2277.
(R)-15-[(2R,3R)-5-Oxo-3-vinyltetrahydrofuran-2-yl]pentadecan-2-yl
2,2,2-Trifluoroacetate (5) and (R)-15-[(2R,3S)-5-Oxo-3-vinyltetra-
hydrofuran-2-yl]pentadecan-2-yl 2,2,2-Trifluroacetate (19): To a
solution of allyl alcohol 6 (0.82 g, 1.49 mmol) in toluene (20 mL)
was added trimethylorthoacetate (1.9 mL, 14.94 mmol, 10.0 equiv.)
and propionic acid (cat.). The reaction mixture was heated to reflux
for 48 h, cooled, and concentrated. The residue was dissolved in
CH2Cl2 (7 mL), trifluoroacetic acid (1.15 mL, 14.94 mmol, (2R,3S)-5-Oxo-2-[(R)-14-(2,2,2-trifluroacetoxy)pentadecyl]tetra-
10.0 equiv.) was added at 0 °C and the mixture was stirred for 12 h,
then concentrated under reduced pressure and the residue was puri-
fied by column chromatography (petroleum ether/EtOAc, 9:1) to
provide the mixture of lactones 5/19 (0.597 g, 92%) as a colorless
oil. Analysis of the mixture by 1H NMR spectroscopy indicated an
anti/syn ratio of 3.5:1. The mixture was separated by flash column
chromatography (petroleum ether/EtOAc, 9:1) to give 5 (0.441 g,
68%) as a colorless oil. Further elution gave 19 (0.136 g, 21%) as
a colorless oil.
hydrofuran-3-carboxylic Acid (21): The title compound was pre-
pared from 19 (0.090 g, 0.207 mmol) by a procedure similar to that
described for the conversion of 5 into 20 to afford 21 (0.073 g,
78%) as a white solid (m.p. 103–105 °C); [α]2D5 = +32.9 (c = 0.08,
CHCl ). IR (CHCl ): ν = 3499, 3016, 2928, 2855, 1780, 1737, 1550,
˜
3
3
1468, 1384, 1301, 1170, 1034, 668 cm–1
.
1H NMR (400 MHz,
CDCl3/TMS): δ = 5.14–5.06 (m, 1 H), 4.70–4.61 (m, 1 H), 3.50–
3.44 (m, 1 H), 2.91 (dd, J = 17.6, 5.3 Hz, 1 H), 2.70 (dd, J = 17.6,
8.6 Hz, 1 H), 1.74–1.51 (m, 4 H), 1.35 (d, J = 6.3 Hz, 3 H), 1.45–
1.19 (m, 22 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.3,
174.7, 157.1 (q), 114.5 (q), 80.4, 76.6, 42.5, 35.3, 31.9, 31.8, 31.2,
29.6, 29.5, 29.46, 29.4, 29.3, 29.27, 29.1, 25.8, 24.9, 19.4 ppm. 19F
Compound 5: [α]2D5 = +38.3 (c = 0.18, CHCl ). IR (CHCl ): ν =
˜
3
3
3020, 2929, 2856, 1778, 1546, 1512, 1466, 1439, 1381, 1323, 1171,
929, 669 cm–1. 1H NMR (400 MHz, CDCl3/TMS): δ = 5.76–5.67
(m, 1 H), 5.20–5.17 (m, 2 H), 5.16–5.07 (m, 1 H), 4.16–4.11 (m, 1
H), 2.80–2.65 (m, 2 H), 2.46 (dd, J = 17.2, 10.5 Hz, 1 H), 1.73–
1.50 (m, 4 H), 1.34 (d, J = 6.3 Hz, 3 H), 1.41–1.20 (m, 22 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 175.7, 156.8 (q), 135.7, 117.8,
114.5 (q), 84.7, 76.5, 46.3, 35.3, 35.2, 33.5, 29.55, 29.52, 29.45,
29.35, 29.28, 29.26, 29.2, 29.1, 25.61, 25.56, 24.9, 19.3 ppm. 19F
NMR: δ = –75.4 ppm. HRMS (ESI+): calcd. for [C22H35O6F3
+
Na]+ 475.2278; found 475.2280.
(2R,3S)-2-[(R)-14-Hydroxypentadecyl]-4-methylene-5-oxotetra-
hydrofuran-3-carboxylic Acid [(+)-Murolic Acid; 1]: Stiles reagent[14]
(2 m in DMF, 3.0 mL, 6.0 mmol, 39.0 equiv.) was added under an
Ar atmosphere to 20 (70 mg, 0.155 mmol) and the solution was
stirred at 135 °C for 60 h. After cooling, the mixture was acidified
with dropwise addition of cold 10% HCl (30 mL) at 0 °C, then
CH2Cl2 (50 mL) was added and the mixture was stirred for 0.5 h.
The aqueous layer was extracted with EtOAc (4ϫ 50 mL), then the
combined organic layers were washed with brine, dried (Na2SO4),
and concentrated. The residue was treated with 4 mL of a freshly
prepared stock solution [HOAc (20 mL), 37 % formaldehyde in
water (15 mL), N-methylaniline (5.2 mL) and NaOAc (0.6 g)] and
the mixture was stirred for 3 h at room temp. Acidic brine solution
(40 mL, containing 4 mL concd. aqueous HCl) was added and the
aqueous layer was extracted with Et2O (5ϫ 30 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and con-
centrated. The residue was purified by silica gel flash column
chromatography (petroleum ether/EtOAc/acetic acid, 1:9:0.2) to
provide 1 (33 mg, 58 %) as white solid (m.p. 106–108 °C; ref.[4a]
112.5 °C); [α]2D5 = +10.5 (c = 0.12, CHCl3) {ref.[4a] [α]2D4 = +11.2 (c
NMR: δ = –75.4 ppm. HRMS (ESI+): calcd. for [C23H37O4F3
+
H]+ 435.2722; found 435.2716.
Compound 19: [α]2D5 = +35.8 (c = 0.22, CHCl ). IR (CHCl ): ν =
˜
3
3
2928, 2856, 1783, 1501, 1466, 1384, 1338, 1170, 1119, 924, 777,
1
724 cm–1. H NMR (400 MHz, CDCl3/TMS): δ = 5.80–5.71 (m, 1
H), 5.20–5.18 (m, 2 H), 5.16–5.07 (m, 1 H), 4.52–4.45 (m, 1 H),
3.19–3.11 (m, 1 H), 2.70 (dd, J = 17.4, 8.1 Hz, 1 H), 2.44 (dd, J =
17.4, 5.6 Hz, 1 H), 1.72–1.47 (m, 6 H), 1.34 (d, J = 6.3 Hz, 3 H),
1.39–1.21 (m, 20 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.2,
157.0 (q), 133.9, 117.9, 114.5 (q), 83.2, 76.5, 43.0, 35.3, 34.6, 30.7,
29.5, 29.46, 29.4, 29.36, 29.3, 29.27, 29.2, 29.1, 25.6, 25.58, 24.9,
19.3 ppm. 19F NMR: δ = –75.4 ppm. HRMS (ESI+): calcd. for
[C23H37O4F3 + H]+ 435.2722; found 435.2711.
(2R,3R)-5-Oxo-2-[(R)-14-(2,2,2-trifluroacetoxy)pentadecyl]tetra-
hydrofuran-3-carboxylic Acid (20): A solution of vinyl lactone 5
(0.120 g, 0.276 mmol) in CH2Cl2 (25 mL) was cooled to –78 °C and
a stream of O3/O2 was bubbled through the reaction mixture until
the blue color of unreacted O3 appeared. The reaction mixture was
quenched with Me2S (0.6 mL) and stirred for 1 h at –78 °C and for
2 h at room temp. The mixture was concentrated to give the crude
aldehyde (0.120 g), which was used directly for the next reaction.
The crude aldehyde was dissolved in tBuOH (3 mL) and cyclohex-
ene (68 mg, 0.828 mmol, 3.0 equiv.) and a solution of sodium chlo-
rite (57.4 mg, 0.635 mmol, 2.3 equiv.) and sodium dihydrogenphos-
phate (99 mg, 0.635 mmol, 2.3 equiv.) in water (1.5 mL) were added
dropwise over 10 min. The resulting mixture was stirred at room
temp. for 12 h, then the reaction was quenched with satd. aq.
NH4Cl. tBuOH was removed under vacuo, the aqueous layer was
extracted with EtOAc (3ϫ 10 mL), and the combined organic lay-
ers were washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by column chromatography (petroleum ether/
= 0.14, CHCl )}. IR (CHCl ): ν = 3446, 2919, 2851, 1745, 1717,
˜
3
3
1663, 1515, 1470, 1404, 1255, 1131, 1022, 965, 928, 815, 718 cm–1.
1H NMR (400 MHz, CDCl3/TMS): δ = 6.40 (d, J = 3.0 Hz, 1 H),
6.01 (d, J = 2.7 Hz, 1 H), 4.81 (dt, J = 7.1, 5.9 Hz, 1 H), 3.86–3.75
(m, 1 H), 3.64–3.58 (m, 1 H), 1.78–1.68 (m, 2 H), 1.65–1.26 (m, 24
H), 1.19 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 173.1, 168.5, 132.8, 125.5, 79.0, 68.6, 49.7, 39.0, 35.6, 29.7,
29.5, 29.44, 29.4, 29.38, 29.3, 29.2, 29.18, 29.0, 25.6, 24.7,
23.2 ppm. HRMS (ESI+): calcd. for [C21H36O5 + H]+ 369.2642;
found 369.2634.
(+)-Murolic Acid (1) from a Mixture of 20/21: Prepared from 20/21
(50 mg, 0.111 mmol) by a procedure similar to that described for
the conversion of 20 into 1 to afford 1 (0.073 g, 54%) as a white
solid. [α]2D5 = +10.3 (c = 0.05, CHCl3).
Supporting Information (see footnote on the first page of this arti-
EtOAc, 1:9) to afford 20 (100 mg, 80%) as a white solid (m.p. 114– cle): Preparation and characterization of precursors; 1H, 13C, 19F
116 °C); [α]2D5 = +13.5 (c = 0.1, CHCl ). IR (CHCl ): ν = 3402,
NMR spectra; comparison of spectral data of synthetic material
with natural isolate.
˜
3
3
2920, 2852, 1783, 1750, 1723, 1646, 1472, 1380, 1336, 1238, 1191,
242
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 237–243

Total Synthesis of (+)-Murolic Acid
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Acknowledgments
This work was supported by the Industrial Research and Consul-
tancy Centre (IRCC), IIT-Bombay. P. H. P. thanks the University
Grants Commission (UGC), New Delhi and A. K. C. thanks the
Council of Scientific and Industrial Research (CSIR), New Delhi
for research fellowships.
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[21] Diastereomeric ratio was determined by 1H NMR spectro-
scopic analysis.
[22] For 19F NMR spectra see the Supporting Information.
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1
[24] For H and 13C NMR spectroscopic comparison, see the Sup-
porting Information.
Received: August 27, 2013
Published Online: November 28, 2013
Eur. J. Org. Chem. 2014, 237–243
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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