Biocatalytic Approach for the Total Synthesis of (-)-Malyngolide and Its C(5)-Epimer

Article abstract of DOI:10.1002/hlca.201500237

An enzymatic approach has been successfully utilized in the total synthesis of (-)-malyngolide and its C(5)-epimer. The required configuration was established by an enzymatic kinetic resolution and Sharpless asymmetric dihydroxylation.

Full text of DOI:10.1002/hlca.201500237

Helv. Chim. Acta 2016, 99, 267 – 272
267
FULL PAPER
Biocatalytic Approach for the Total Synthesis of (–)-Malyngolide and Its C(5)-Epimer
by Nikhil Srivastava and Basi V. Subba Reddy*
Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India (phone: +91-40-27193535;
fax: +91-40-27160512; e-mail: basireddy@iict.res.in)
An enzymatic approach has been successfully utilized in the total synthesis of (–)-malyngolide and its C(5)-epimer. The
required configuration was established by an enzymatic kinetic resolution and Sharpless asymmetric dihydroxylation.
Keywords: Malyngolide, Antibiotic activity, Enzymatic resolution, Asymmetric dihydroxylation, d-Lactone.
and co-workers [3] recently isolated a dimer of 1a, which
also shows antimalarial activity against Plasmodium falci-
Introduction
The six-membered d-lactone-containing natural products, parum. (–)-Malyngolide (1a) has drawn our interest toward
e.g., (–)-malyngolide (1a) and its diastereoisomers 1b – 1d its synthesis, because of its superior biological activity as
and (R)-tanikolide (Fig.), were isolated as marine metabo- compared to its other diastereoisomers (Fig.).
lites from the lipid extract of marine cyanobacterium, Lyn- Consequently, Mukaiyama and co-workers [4] reported
gbya majuscula, which was collected from the coast of
Hawai [1]. Marine cyanobacteria are considered as a rich
source of secondary metabolites, which are evaluated as
potent anticancer agents. The cytotoxicity of these marine
metabolites against tumor cell lines is under clinical trials.
In addition, some of them have been used as templates for
the first total synthesis of (–)-malyngolide. Later on, a
large number of syntheses of 1a have been reported by
various groups employing chiron approach, asymmetric
induction, and RCM strategy [5], Subsequently,
Trost et al. [6] also reported its asymmetric version by
enantioselective ring opening of an epoxide using a chiral
the development of new anticancer drugs [2]. Furthermore, Pd(0) complex.
many chemically diverse d-lactone-containing compounds
are known to exhibit diverse biological activities such as
Results and Discussion
Following our interest in the total synthesis of natural
cytotoxicity, anti-inflammatory, and antibacterial behavior.
Among them, (–)-malyngolide (1a) shows potential antibi-
otic activity against Staphylococcus, Pseudomonas, and products [7], we herein report an efficient synthetic route
Mycobacterium smegmatis, but no activity against for the total synthesis of (–)-malyngolide (1a) and its epi-
Escherichia coli and Pseudomonas aeruginosa. Gerwick
mer 1b. In our retrosynthetic analysis, we proposed
Figure. Examples of d-lactone-containing natural products.
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© 2016 Verlag Helvetica Chimica Acta AG, Zurich
DOI: 10.1002/hlca.201500237

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Helv. Chim. Acta 2016, 99, 267 – 272
that the target molecule can be synthesized from the (methyl)triphenylphosphonium bromide using LiHMDS
intermediate 9, which in turn could be prepared by the
dihydroxylation of olefin 8. The intermediate 8 might be
synthesized from a chiral alcohol 2, which in turn could (prepared in situ from chiral ligand (DHQ)2PHAL, OsO4,
furnished the olefin 8 in 70% yield (Scheme 2).
Asymmetric dihydroxylation of 8 using AD-mix-a
be prepared by enzymatic kinetic resolution (Scheme 1).
Our synthetic sequence began with a known precur-
sor, i.e., mono-benzyl alcohol 2, which was synthesized by
K3[Fe(CN)6], and methanesulfonamide) gave a mixture of
two diasteoisomeric diols 9a/9b in a ratio of 6:4, which
1
was confirmed by the H-NMR spectrum [14]. Protection
the kinetic resolution of racemic 2-methylpropane-1,3-diol of diols 9a/9b with TBDPSCl gave a mixture of mono-
using Pseudomonas fluorescens as reported by Santaniello silyl ethers 10a/10b. Debenzylation of the latter using
and co-workers [8]. The required alcohol 2 was obtained Pd/C (10% w/w) under H2 atmosphere afforded the diols
with 90% ee. Oxidation of 2 under Swern conditions [9]
followed by Horner–Wadsworth–Emmons reaction with
11a/11b. Subsequent oxidative lactonization of diols
11a/11b using TEMPO/BAIB led to a mixture of d-lactones
triethyl phosphonoacetate afforded the a,b-unsaturated 12a/12b in 60% yield. Eventual deprotection of TBDPS
ester 3 with a ratio of (E)/(Z) 98:2 in 80% yield [10]. group from the d-lactone gave the target molecules,
Hydrogenation of the C=C bond in compound 3 using (–)-malyngolide (1a) in 55% and its C(5)-epimer (1b) in
NiBH4 (generated in situ from NiCl2 ꢀ 6 H2O and NaBH4 33% yield, which were successfully separated by flash
in MeOH) afforded the saturated ester 4 in 96% yield chromatography (Scheme 3). The spectroscopic data for
[11]. Treatment of the saturated ester 4 with LiAlH4 gave both diastereoisomers were identical with the data
the mono-benzyl alcohol 5 in 90% yield [12]. Oxidation
of the later under Swern conditions afforded the alde-
hyde, which was further treated with nonylmagnesium
bromide (2.0 equiv., 1M in Et2O) to give the alcohol 6 as
a mixture of two diastereoisomers in 66% yield [13].
reported in [5e][15].
In summary, we have successfully achieved the
required configuration of the methyl center with good
enantiomeric excess by an enzymatic kinetic resolution
approach, which is one of the imperative criteria for the
Subsequent oxidation of 6 under Swern conditions gave biological activity of (–)-malyngolide (1a), which differen-
the ketone 7 in 77% yield and Wittig olefination of 7 with tiates it from other diastereoisomers. In earlier reports,
Scheme 1. Retrosynthetic pathway.
Scheme 2. Synthesis of olefin 8.
a) 1) (COCl)2 (2.0 equiv.), DMSO (4.0 equiv.), ꢁ78 °C, 2 h, (2R)-3-(benzyloxy)-2-methylpropanal; 2) (EtO)2P(O)CH2COOEt (1.2 equiv.), EtN
(iPr)2 (1.5 equiv.), LiBr (1.6 equiv.), MeCN, 20 °C to r.t., 12 h; 80%. b) NaBH4 (2.0 equiv.), NiCl2 ꢀ 6 H2O, (0.2 equiv.) MeOH, 0 °C to r.t., 1 h;
96%. c) LiAlH4, 0 °C, 15 min; 90%. d) 1) (COCl)2 (2.0 equiv.), DMSO (4.0 equiv.), ꢁ78 °C, 2 h; 2) nonylmagnesium bromide (1.0M in Et2O,
45 ml, 2.0 equiv.) at 0 °C to r.t., 0.3 h; 66%. e) DMSO (4.0 equiv.), (COCl)2 (2.0 equiv.), ꢁ78 °C, 2 h; 77%. f) MePh3PBr (3.0 equiv.), LiHMDS
(1.0M in THF, 3.0 equiv.), 0 °C to r.t., 5 h; 70%.
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Helv. Chim. Acta 2016, 99, 267 – 272
269
Scheme 3. Synthesis of (–)-malyngolide and its (–)-C(5)-epimer.
a) (DHQ)2PHAL (5 mol%), OsO4 (0.5 mol%), K3[Fe(CN)6] (3.0 equiv.), K2CO3 (3.0 equiv.), MeSO2NH2 (1.0 equiv.), tBuOH/H2O (1:1), 0 °C,
12 h; 80% (9a/9b 60:40 dr, inseparable). b) TBDPSCl, imidazole, CH2Cl2; 82%. c) Pd/C (10% w/w), AcOEt, H2, r.t., 5 h; 84%. d) TEMPO (0.2
equiv.), BAIB (2.5 equiv.), CH2Cl2/H2O (2:1), 1 h; 80%. e) TBAF, dry THF, r.t., 0.3 h.
the required configuration of the Me center was achieved DMSO (15.7 ml, 222.2 mmol) at ꢁ78 °C. After stirring at
by chiral induction approach [5]. For the construction of ꢁ78 °C for 20 min, a soln. of 2 (10 g, 56.1 mmol) in anh.
the chiral quaternary center, Sharpless dihydroxylation CH2Cl2 (70 ml) was added dropwise. After stirring for
approach has been utilized to accomplish the total synthe-
sis of (–)-malyngolide and its C(5)-epimer.
another 20 min at the same temperature, Et3N (56 ml,
392.0 mmol) was added, and the mixture was stirred at
ꢁ30 °C for an additional 30 min. The mixture was poured
into H2O (200 ml) and extracted thrice with Et2O
(400 ml). The combined org. layers were washed with
brine (250 ml), dried (MgSO4), and concentrated in vacuo
to afford (2R)-3-(benzyloxy)-2-methylpropanal [9] as
pale-yellow oil. A mixture of triethyl phosphonoacetate
(13.8 g, 62.0 mmol), MeCN (150 ml), and LiBr (7.1 g,
82.6 mmol) was stirred at 20 °C for 15 min, and then EtN
N. S. thanks CSIR, New Delhi, for the award of a
fellowship.
Experimental Part
General
Column chromatography (CC): silica gel (SiO2; E. Merck, (iPr)2 (14.2 ml, 77.5 mmol) was added portionwise. After
100 – 200 mesh). Optical rotations: Anton Paar MCP 200 stirring for 15 min,
soln. of (2R)-3-(benzyloxy)-2-
digital polarimeter using a 1 ml cell with a 1 dm path
methylpropanal (9.2 g, 51.6 mmol) in MeCN (60 ml) was
a
length. IR Spectra: Thermo Nicolet Nexus 670 spectrome- added, and the resulting mixture was stirred at 20 °C for
1
ter; v in cmꢁ1. H-NMR Spectra: Bruker-300 and Varian 12 h. After completion, as indicated by TLC, the mixture
~
Unity 500 spectrometer in CDCl3; d in ppm rel. to Me4Si was then poured into 1M aq. HCl soln. (300 ml) under
as internal standard, J in Hz. 13C-NMR Spectra: Bruker- vigorous stirring, and the aq. layer was extracted with
300 and Varian Unity 500 spectrometer at 75 or 125 MHz
in CDCl3; d in ppm rel. to CDCl3 as internal standard (d
AcOEt. The combined org. layers were washed with
brine, dried (MgSO4), and concentrated in vacuo. Purifi-
(C) 77 ppm). ESI-MS: Finnigan MAT1020B or micromass cation by flash chromatography over SiO2 (100 – 200
VG 70-70H spectrometer operating at 70 eV using a
direct inlet system; in m/z.
mesh) afforded the product 3 [10] as colorless liquid
(11.5 g, 80% yield). Rf (10% AcOEt/petroleum ether
25
(2R)-3-(Benzyloxy)-2-methylpropan-1-ol (2) [8]. Vis- (PE)) 0.35. ½aꢂD = +7.0 (c = 0.2, CHCl3). IR (neat): 2978;
25
cous liquid. ½aꢂD = ꢁ2.6 (c = 2.2, EtOH). IR (neat): 3398,
2867; 1718; 1653; 1454; 1270; 1185; 1097; 1035; 739; 698.
1H-NMR (500 MHz, CDCl3): 1.90 (d, J = 6.8, 3 H); 1.29
2959, 2871, 1454, 1364, 1096, 1038, 739, 698. 1H-NMR
(500 MHz, CDCl3): 0.88 (d, J = 6.8, 3 H): 2.03 – 2.15 (m, (t, J = 7.1, 3 H); 2.61 – 2.71 (m, 1 H); 3.35 – 3.45 (m, 2
1 H); 3.43 (t, J = 8.2, 1 H); 3.52 – 3.58 (m, 1 H); H); 4.19 (q, J = 7.1, 2 H); 4.52 (s, 2 H); 5.83 – 5.89 (dd,
3.59 – 3.66 (m, 2 H); 4.52 (s, 2 H); 7.26 – 7.40 (m, 5 H). J = 15.7, 1.3, 1 H); 6.92 – 6.93 (dd, J = 15.7, 8.8, 1 H);
13C-NMR (125 MHz, CDCl3): 13.4; 35.5; 67.6; 73.2; 75.2;
7.26 – 7.38 (m, 5 H). 13C-NMR (125 MHz, CDCl3): 14.1;
127.5; 127.6; 128.3; 137.9. ESI-MS: 203 ([M + Na]+). HR- 15.9; 36.6; 60.1; 72.9; 73.7; 120.8; 127.4; 127.4; 128.2; 138.0;
ESI-MS: 203.10468 ([M + Na]+, C11H16NaO+2; calc.
203.10425).
151.0; 166.5. ESI-MS: 271 ([M + Na]+). HR-ESI-MS:
271.13016 ([M + Na]+, C15H20NaO+3; calc. 271.13047).
Ethyl (4R)-5-(Benzyloxy)-4-methylpentanoate (4). To
an ice-cooled soln. of 3 (11.5 g, 46.3 mmol) and NiCl2 ꢀ 6
Ethyl
(3). To
(4R,2E)-5-(Benzyloxy)-4-methylpent-2-enoate
stirred soln. of oxalyl chloride (7.8 ml,
a
111.1 mmol) in anh. CH2Cl2 (150 ml) was added dry H2O (2.1 g, 9.2 mmol) in MeOH (200 ml) was added
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Helv. Chim. Acta 2016, 99, 267 – 272
NaBH4 (3.4 g, 92.7 mmol) in small portions [11]. The
reaction temperature was kept at 0 °C. After complete
addition, the mixture was stirred for 1 h at room tempera-
ture. The resulting black precipitate was filtered and
washed with MeOH (2 9 75 ml). The solvent was
removed under reduced pressure, and the residual mix-
ture was diluted with H2O (100 ml) and extracted with
AcOEt (2 9 100 ml). The combined org. layers were
within 10 min. After addition, the ice bath was removed,
and the mixture was allowed to warm to room tempera-
ture over 30 min, and then quenched with a sat. aq.
NH4Cl soln., and extracted thrice with AcOEt. The com-
bined org. extracts were dried (Na2SO4), concentrated in
vacuo and purified by CC to give two diastereoisomeric
secondary alcohols (2R,5S)- and (2R,5R)-1-(benzyloxy)-2-
methyltetradecan-5-ol (6) [13] (4.0 g, 66% yield from 5).
25
washed with H2O and brine, and dried (Na2SO4). Rf (10% AcOEt/PE) 0.20. Liquid. ½aꢂD = ꢁ1.9 (c = 0.54,
Removal of the solvent under reduced pressure followed CHCl3). IR (neat): 3404, 2926, 2854, 1457, 1368, 1097,
by flash chromatography over SiO2 (100 – 200 mesh) 735, 697. 1H-NMR (300 MHz, CDCl3): 0.84 – 0.90 (m, 3
afforded 4 as colorless liquid (10.5 g, 96% yield). Rf (10% H); 0.91 – 0.98 (m,
3 H); 1.20 – 1.61 (m, 20 H);
25
AcOEt/PE) 0.37. ½aꢂD = +2.7 (c = 0.39, CHCl3). IR
1.67 – 1.87 (m, 1 H); 3.16 – 3.41 (m, 2 H); 3.46 – 3.70 (m,
2 H); 4.50 (s, 2 H); 7.23 – 7.40 (m, 5 H). 13C-NMR
(neat): 2959, 2931, 2866, 1788, 1733, 1454, 1372, 1179,
1098, 737, 698. 1H-NMR (500 MHz, CDCl3): 0.94 (d, (125 MHz, CDCl3): 14.0; 17.0; 17.2; 22.6; 25.6; 25.6; 25.7;
J = 6.7, 3 H); 1.25 (t, J = 7.0, 3 H); 1.43 – 1.56 (m, 1 H); 29.2; 29.3; 29.4; 29.5; 29.6; 29.6; 31.8; 32.7; 33.3; 33.5; 34.6;
1.73 – 1.87 (m, 2 H); 2.25 – 2.42 (m, 2 H); 3.25 – 3.36 (m, 34.6; 37.3,37.4; 62.9; 72.0; 72.2; 72.9; 72.9; 75.6; 75.8;
2 H); 4.11 (q, J = 7.1, 2 H); 4.49 (s, 2 H); 7.26 – 7.38 (m, 127.4; 127.4; 127.5; 127.5; 128.2; 138.6; 138.6. ESI-MS:
5 H). 13C-NMR (75 MHz, CDCl3): 14.1; 16.7; 28.7; 31.9;
32.9; 60.1; 72.8; 75.2; 127.3; 127.3; 128.2; 138.4; 173.7.
ESI-MS: 273 ([M + Na]+). HR-ESI-MS: 273.14553
([M + Na]+, C15H22NaO+3; calc. 273.14612).
357 ([M + Na]+). HR-ESI-MS: 335.29507 ([M + H]+,
+
C22H39O3 ; calc. 335.29446).
(2R)-1-(Benzyloxy)-2-methyltetradecan-5-one (7). To
a stirred soln. of oxalyl chloride (1.5 ml, 20.9 mmol) in
dry CH2Cl2 (30 ml) at ꢁ78 °C was added DMSO (2.7 ml,
41.9 mmol). After 30 min, a soln. of the secondary alco-
(4R)-5-(Benzyloxy)-4-methylpentan-1-ol (5). To a stir-
red suspension of LiAlH4 (2.2 g, 60.4 mmol) in dry THF
(120 ml) at 0 °C was added dropwise a soln. of 4 (10.0 g, hol 6 (3.5 g, 10 mmol) in 15 ml of CH2Cl2 was added
40.3 mmol) in dry THF (80 ml). The resulting mixture
was allowed to stir for 15 min at the same temperature,
and then reaction was quenched with a sat. soln. of
over 12 min. After 0.3 h, Et3N (10.5 ml) was added, and
the mixture was allowed to stir at room temperature for
1 h. The mixture was poured into H2O (150 ml) and
Na2SO4. The resulting precipitate was filtered and washed extracted thrice with Et2O (200 ml). The combined org.
with AcOEt (2 9 100 ml). The combined org. extracts extracts were washed with brine (100 ml), dried (MgSO4),
were dried (Na2SO4), concentrated in vacuo, and purified concentrated in vacuo and purified by CC to give 7 as a
by flash chromatography over SiO2 (100 – 200 mesh) to liquid (2.7 g, 77% yield from 6). Rf (10% AcOEt/PE)
25
afford 5 [12] as colorless liquid (8.0 g, 90% yield). Rf 0.50. ½aꢂD = +2.8 (c = 0.33, CHCl3). IR (neat): 2954, 2926,
25
(30% AcOEt/PE) 0.35. ½aꢂD = +4.0 (c = 1, CH2Cl2). IR 2855, 1714, 1456, 1369, 1098, 772. 1H-NMR (500 MHz,
(neat): 3382, 2932, 2864, 1731, 1454, 1364, 1098, 1071, 738,
1
CDCl3): 0.84 – 0.90 (m, 3 H); 0.92 (d, J = 6.5, 3 H);
698. H-NMR (300 MHz, CDCl3): 0.94 (d, J = 6.7, 3 H); 1.22 – 1.33 (m, 12 H); 1.37 – 1.48 (m, 2 H); 1.50 – 1.63
1.09 – 1.33 (m, 1 H); 1.42 – 1.71 (m, 4 H); 1.72 – 1.92 (m, (m, 2 H); 1.67 – 1.87 (m, 2 H); 2.33 – 2.49 (m, 3 H);
1 H); 3.18 – 3.41 (m, 2 H); 3.62 (t, J = 6.0, 2 H); 4.50 (s, 2
H); 7.27 – 7.44 (m, 5 H). 13C-NMR (125 MHz, CDCl3): 13C-NMR (125 MHz, CDCl3): 14.0; 16.9; 22.6; 23.8; 27.6;
16.9; 29.5; 29.9; 33.1; 62.8; 72.9; 75.7; 127.3; 127.4; 128.2; 29.2; 29.3; 31.5; 31.8; 33.0; 40.3; 42.7; 72.9; 75.5; 127.4;
3.22 – 3.34 (m, 2 H); 4.49 (s, 2 H); 7.27 – 7.39 (m, 5 H).
138.4. ESI-MS: 231 ([M + Na]+). HR-ESI-MS: 209.15293 127.4; 128.2; 138.5; 211.4. ESI-MS: 355 ([M + Na]+). HR-
([M + H]+, C13H21O+2; calc. 209.15361).
ESI-MS: 355.26068 ([M + Na]+, C22H36NaO+2; calc.
355.26075).
(2R)-1-(Benzyloxy)-2-methyltetradecan-5-ol (6). To a
stirred soln. of oxalyl chloride (4.0 ml, 57.6 mmol) in anh.
CH2Cl2 (150 ml) was added DMSO (8.1 ml, 115.3 mmol)
at ꢁ78 °C. After 20 min, a soln. of 5 (6.0 g, 28.8 mmol)
in CH2Cl2 (50 ml) was added dropwise at ꢁ78 °C. After
stirring for another 20 min, Et3N (28 ml) was added and
({[(2R)-2-Methyl-5-methylidenetetradecyl]oxy}methyl)-
benzene (8). To a soln. of (methyl)triphenylphosphonium
bromide, (7.0 g, 19.8 mmol) in dry THF was added
LiHMDS (1M in THF, 19.8 ml) at 0 °C, and the mixture was
stirred for 45 min, and then compound 7 (2.2 g, 6.6 mmol)
the resulting mixture was allowed to stir at ꢁ30 °C for was added. The resulting mixture was allowed to stir at
30 min. Upon completion, the mixture was poured into 25 °C for 4 h. After completion, the mixture was quenched
H2O (150 ml) and extracted thrice with Et2O (200 ml). with a sat. aq. NH4Cl soln. (50 ml) and extracted with
The combined org. extracts were washed with brine
(150 ml), dried (MgSO4), and concentrated in vacuo. This
AcOEt (2 9 100 ml). The org. extracts were washed with
brine (2 9 50 ml) and dried (Na2SO4). Removal of the sol-
(4R)-5-(benzyloxy)-4-methylpentanal vent followed by flash chromatography over SiO2 afforded
crude
aldehyde
(5.2 g, 25.2 mmol) was then dissolved in dry THF (80 ml)
and cooled to 0 °C. To this mixture, nonylmagnesium
bromide (1.0M in Et2O, 45 ml, 2.0 equiv.) was added
the product 8 as a colorless liquid (1.4 g, 70% yield). Rf
25
(10% AcOEt/PE) 0.80. ½aꢂD = +5.7 (c = 0.1, CHCl3). IR
(neat): 3423, 3070, 2961, 2933, 2894, 2859, 1721, 1468, 1427,
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Helv. Chim. Acta 2016, 99, 267 – 272
271
1294, 1269, 1108, 703. 1H-NMR (300 MHz, CDCl3): 129.5; 129.7; 133.0; 134.1; 134.7; 135.5. ESI-MS: 625
0.83 – 0.92 (m, 3 H); 0.95 (d, J = 6.6, 3 H); 1.18 – 1.47 (m, 14 ([M + Na]+). ([M + Na]+,
HR-ESI-MS: 625.40649
H); 1.47 – 1.63 (m, 2 H); 1.68 – 1.88 (m, 1 H); 1.90 – 2.15 C39H58NaO3Si+; calc. 625.40474).
(m, 4 H); 3.20 – 3.40 (m, 2 H); 4.50 (s, 2 H); 4.69 (s, 2 H);
(2R,5RS)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-
7.26 – 7.42 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 14.1; 17.0; methyltetradecane-1,5-diol (11). To a stirred soln. of 10
22.6; 27.8; 29.3; 29.4; 29.5; 29.5; 31.7; 31.8; 33.2; 33.3; 36.0; (0.75 g, 1.24 mmol) in AcOEt (15 ml) was added 10%
72.9; 75.8; 108.4; 127.3; 127.4; 128.2; 138.7; 150.2. ESI-MS: Pd/C (75 mg) and kept for 5 h at room temperature
353 ([M + Na]+).
under H2 pressure. The mixture was filtered over Celite,
concentrated under reduced pressure, and then purified
(2RS)-2-[(3R)-4-(Benzyloxy)-3-methylbutyl]undecane-
1,2-diol (9). To
3.03 mmol) in a 1:1 mixture of BuOH (15.1 ml) and H2O colorless liquid 11 (0.50 g, 84% yield). Rf (20% AcOEt/
a stirred soln. of olefin 8 (1.0 g, by flash chromatography over SiO2 afforded the diol as a
t
25
(15.1 ml) were added sequentially K3[Fe(CN)6] (2.9 g, PE) 0.20. Liquid. ½aꢂD = ꢁ1.4 (c = 0.33, CHCl3). IR
9.09 mmol), K2CO3 (1.25 gm, 9.09 mmol), (DHQ)2PHAL (neat): 3419, 2930, 2856, 1721, 1454, 1369, 1272, 1108,
(118 mg, 0.15 mmol, 5 mol %), MeSO2NH2 (0.287 g, 1076, 1016, 753, 703. 1H-NMR (600 MHz, CDCl3):
3.03 mmol, 1.0 equiv.), and OsO4 (0.15 ml of a 0.1M soln.
in H2O, 0.5 mol %) at 0 °C. The resulting soln. was stir-
red at the same temperature for 12 h, and then the reac-
0.86 – 0.92 (m, 6 H); 1.07 (s, 9 H); 1.21 – 1.33 (m, 18 H);
1.37 – 1.61 (m, 3 H); 3.39 – 3.51 (m, 4 H); 7.36 – 7.46 (m,
6 H); 7.65 (d, J = 7.5, 4 H). 13C-NMR (75 MHz, CDCl3):
tion was quenched with an aq. Na2SO3 soln. (50 ml). The 14.1; 16.5; 16.5; 19.2; 22.6; 23.4; 23.4; 26.3; 26.8; 29.2; 29.5;
aq. layer was extracted with AcOEt (50 ml 9 2). The 29.6; 30.2; 31.8; 32.8; 32.8; 35.9; 36.0; 36.1; 36.1; 67.8;
combined org. layers were washed with a sat. aq. NaCl
68.6; 68.7; 74.4; 127.7; 129.7; 133.0; 135.5. ESI-MS:
soln. (40 ml), dried (MgSO4), concentrated in vacuo, and 535 ([M + Na]+). HR-ESI-MS: 535.35661 ([M + Na]+,
purified by flash chromatography over SiO2 to afford the C32H52NaO3Si+; calc. 535.35779).
unseparable diastereoisomers, (2RS)-2-[(3R)-4-(benzyl-
oxy)-3-methylbutyl]undecane-1,2-diol (9; 0.84 g, 80%
(3R,6RS)-6-({[tert-Butyl(diphenyl)silyl]oxy}methyl)tet-
rahydro-3-methyl-6-nonyl-2H-pyran-2-one (12). To a stir-
25
yield) [14]. Rf (30% AcOEt/PE) 0.25. Liquid. ½aꢂD = +4.8 red soln. of diol 11 (400 mg, 0.78 mmol) in a mixture of
(c = 0.17, CHCl3). IR (neat): 3421, 2925, 2854, 1720, 1458,
CH2Cl2 (6 ml) and H2O (3 ml), TEMPO (24 mg,
1
1379, 1273, 1097, 735, 697. H-NMR (300 MHz, CDCl3): 0.15 mmol) and BAIB (628 mg, 1.95 mmol) were added
0.84 – 0.91 (m, 6 H); 0.93 (d, J = 1.5, 3 H); 0.95 (d, at 0 °C and then stirred at room temperature for 1.0 h.
J = 1.5, 3 H); 1.23 – 1.31 (m, 16 H); 1.37 – 1.54 (m, 4 H); After completion, the mixture was extracted with CH2Cl2
1.67 – 1.88 (m, 1 H); 3.31 (d, J = 6.0, 2 H); 3.45 (s, 2 H); (2 9 20 ml), dried (Na2SO4), and concentrated in vacuo.
4.50 (s, 2 H); 7.21 – 7.42 (m, 5 H). 13C-NMR (75 MHz,
CDCl3): 14.0; 17.0; 17.1; 22.6; 23.2; 23.3; 26.9; 27.1; 29.2;
Purification by flash chromatography over SiO2 afforded
the lactone 12 as unseperable diastereoisomers (250 mg,
25
29.5; 29.6; 30.1; 31.8; 32.6; 32.6; 33.7; 35.5; 35.6; 67.9; 72.9; 65% yield). Rf (10% AcOEt/PE) 0.55. Liquid. ½aꢂD = ꢁ8.2
74.6; 75.5; 76.5; 76.9; 77.4; 127.4; 127.5; 128.2; 138.4. (c = 0.33, CHCl3). IR (neat): 3448, 2952, 2855, 1734, 1636,
ESI-MS: 387 ([M + Na]+). HR-ESI-MS: 387.28827 1461, 1382, 1109, 765, 702, 613. 1H-NMR (300 MHz,
([M + Na]+, C23H40NaO+3; calc. 387.28697).
(2R,5RS)-1-(Benzyloxy)-5-({[tert-butyl(diphenyl)silyl]-
oxy}methyl)-2-methyltetradecan-5-ol (10). To a stirred
CDCl3): 0.80 – 0.94 (m, 6 H); 1.06 (d, J = 3.9, 9 H);
1.21 – 1.32 (m, 14 H); 1.54 – 1.67 (m, 3 H); 1.68 – 1.94 (m,
1
H); 1.98 – 2.19 (m, 1 H); 2.27 – 2.49 (m, 2 H);
soln. of 9 (0.50 g, 1.37 mmol) in dry CH2Cl2 (20 ml) were 3.51 – 3.63 (m, 2 H); 7.36 – 7.48 (m, 6 H); 7.61 – 7.77 (m,
added TBDPSCl (0.30 ml, 1.37 mmol) and imidazole
(0.14 g, 2.0 mmol) at 0 °C, and the mixture was stirred at
4 H). 13C-NMR (125 MHz, CDCl3): 13.7; 16.7; 16.9;
18.8; 22.3; 22.3; 22.7; 24.8; 25.0; 26.4; 26.5; 26.8; 27.3; 28.9;
room temperature for 45 min. The reaction was quenched 28.9; 29.1; 29.1; 29.3; 29.5; 29.6; 29.8; 31.0; 31.4; 31.5; 35.1;
with H2O (2 9 10 ml), the mixture was extracted with 35.1 37.1; 37.9; 66.8; 68.1; 85.4; 85.4; 127.4; 129.4; 129.5;
CH2Cl2 (2 9 50 ml), dried (Na2SO4), and concentrated in 129.8; 132.3; 132.4; 132.5; 132.6; 135.2; 135.2; 135.2; 135.3;
vacuo. Flash chromatography over SiO2 gave the unsepa- 137.1; 174.2; 174.6. ESI-MS: 531 ([M + Na]+). HR-ESI-
rable TBDPS ethers 10 as a colorless liquid (0.85 g, 82%
25
MS: 531.32470 ([M + Na]+, C32H48NaO3Si+; calc.
yield). Rf (10% AcOEt/PE) 0.35. Liquid. ½aꢂD = +3.4 531.32649).
(c = 0.16, CHCl3). IR (neat): 3389, 3069, 2929, 2856, 1718,
1588, 1466, 1426, 1388, 1360, 1111, 820, 701. 1H-NMR
(300 MHz, CDCl3): 0.84 – 0.95 (m, 6 H); 1.05 – 1.10 (m,
(–)-Malyngolide (1a) and (–)-5-epi-Malyngolide (1b).
To a stirred soln. of lactone 12 (150 mg, 0.29 mmol) in
dry THF was added 1.0M TBAF in THF (0.5 ml, 1.5
24 H); 1.21 – 1.30 (m, 4 H); 1.38 – 1.50 (m, 1 H); equiv.) at 0 °C. The resulting mixture was allowed to stir
1.54 – 1.65 (m, 1 H); 2.16 – 2.28 (m, 1 H); 3.15 – 3.37 (m, for 20 min at room temperature. After completion, the
2 H); 3.46 (s, 2 H); 4.48 (s, 2 H); 7.29 – 7.48 (m, 10 H); reaction was quenched with a sat. NaHCO3 soln. (20 ml)
7.61 – 7.77 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 14.0; and extracted with AcOEt (2 9 10 ml). The org. extracts
17.1; 19.2; 22.6; 23.3; 24.7; 26.5; 26.6; 26.8; 27.0; 27.6; 27.8; were washed with brine (2 9 50 ml) and dried (Na2SO4).
27.9; 27.9; 29.2; 29.5; 29.6; 30.2; 31.8; 33.0; 33.9; 35.8; 68.8; Removal of the solvent followed by purification on CC
72.9; 74.4; 75.6; 127.3; 127.4; 127.4; 127.6; 128.2; 129.0;
over SiO2 afforded the pure 1a and 1b [5e][15].
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www.helv.wiley.com

272
Helv. Chim. Acta 2016, 99, 267 – 272
C. Iwata, Chem. Commun. 1997, 1755; e) N. Maezaki,
Y. Matsumori, T. Shogaki, M. Soejima, H. Ohishi, T. Tanaka,
(–)-Malyngolide (= (3R,6S)-Tetrahydro-6-(Hydroxy-
methyl)-3-methyl-6-nonyl-2H-pyran-2-one; 1a). Colorless
liquid. Yield: 55% (55 mg). Rf (20% AcOEt/PE) 0.20.
C. Iwata, Tetrahedron 1998, 54, 13087; f) Z. Wan, S. G. Nelson,
ꢀ
J. Am. Chem. Soc. 2000, 122, 10470; g) M. Carda, S. Rodrıguez,
E. Castillo, A. Bellido, S. Dıaz-Oltraa, J. A. Marco, Tetrahedron
25
½aꢂD = ꢁ12.5 (c = 1, CHCl3), ꢁ12.8 (c = 1.8, CHCl3). IR
ꢀ
(neat): 3415, 2925, 2854, 1725, 1461, 1377, 1212, 1109, 741.
1H-NMR (300 MHz, CDCl3): 0.88 (t, J = 6.9, 3 H);
1.20 – 1.39 (m, 19 H); 1.48 – 1.84 (m, 3 H); 1.85 – 2.19
(m, 2 H); 2.34 – 2.58 (m, 1 H); 3.48 (d, J = 12.0, 1 H);
3.66 (d, J = 12.0, 1 H). 13C-NMR (75 MHz, CDCl3): 14.0;
17.1; 22.6; 23.6; 25.1; 26.2; 29.2; 29.4; 29.6; 29.9; 31.8; 35.5;
36.4; 67.7; 86.8; 175.0. ESI-MS: 293 ([M + Na]+). HR-ESI-
MS: 293.20756 ([M + Na]+, C16H30NaO+3; calc. 293.20872).
2003, 59, 857; h) S. Ohira, T. Ida, M. Moritani, T. Hasegawa,
J. Chem. Soc., Perkin Trans. 1 1998, 293.
[6] B. M. Trost, W. Tang, J. L. Schulte, Org. Lett. 2000, 2, 4013.
[7] B. V. S. Reddy, B. P. Reddy, T. Pandurangam, J. S. Yadav,
Tetrahedron Lett. 2011, 52, 2306; B. P. Reddy, T. Pandurangam,
J. S. Yadav, B. V. S. Reddy, Tetrahedron Lett. 2012, 53, 5749;
B. V. S. Reddy, P. S. Reddy, B. P. Reddy, J. S. Yadav, A. A.
K. Ghamdi, Tetrahedron Lett. 2013, 54, 5758; B. V. S. Reddy,
B. P. Reddy, P. S. Reddy, Y. J. Reddy, J. S. Yadav, Tetrahedron
Lett. 2013, 54, 4960; B. V. S. Reddy, P. S. Reddy, B. P. Reddy,
J. S. Yadav, Synlett 2014, 25, 501.
(–)-5-epi-Malyngolide
(=
(3R,6R)-Tetrahydro-6-
(Hydroxymethyl)-3-methyl-6-nonyl-2H-pyran-2-one; 1b).
Colorless liquid. Yield: 33% (35 mg). Rf (20% AcOEt/PE)
[8] P. Grisenti, P. Ferraboschi, A. Manzocchi, E. Santaniello, Tetra-
hedron 1992, 48, 3827; E. Santaniello, S. Casati, P. Ciuffreda,
L. Gamberoni, Tetrahedron: Asymmetry 2004, 15, 3177; T. Ake-
boshi, Y. Ohtsuka, T. Ishihara, T. Sugai, Adv. Synth. Catal.
2001, 343, 624.
25
0.25. ½aꢂD = ꢁ19.0 (c = 1, CHCl3), ꢁ18.4 (c = 0.7, CHCl3).
IR (neat): 3445, 2925, 2854, 1727, 1462, 1377, 1331, 1256,
1211, 1083, 800, 723. 1H-NMR (300 MHz, CDCl3): 0.87
(t, J = 6.9, 3 H); 1.23 – 1.33 (m, 19 H); 1.55 – 1.71 (m, 2 H);
1.72 – 1.84 (m, 1 H); 1.86 – 2.02 (m, 2 H); 2.35 – 2.54
(m, 1 H); 3.60 (s, 2 H). 13C-NMR (100 MHz, CDCl3): 14.0;
17.2; 22.6; 23.1; 25.4; 27.0; 29.2; 29.4; 29.6; 29.9; 31.8; 35.1;
37.4; 67.6; 86.2; 175.2. HR-ESI-MS: 293.20915 ([M + Na]+,
C16H30NaO+3; calc. 293.20872).
[9] A. J. Mancuso, S.-L. Huang, D. Swern, J. Org. Chem. 1978, 43,
2480.
[10] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masamune, W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25,
2183; S. Lemaire-Audoire, P. Vogel, J. Org. Chem. 2000, 65,
3346.
[11] R. C. Wade, J. Mol. Catal. 1983, 18, 273; T. Satoh, K. Nanba,
S. Suzuki, Chem. Pharm. Bull. 1971, 19, 817.
[12] C. Rink, F. Sasse, A. Zubriene, D. Matulis, M. E. Maier, Chem.
– Eur. J. 2010, 16, 14469; J. S.Yadav, N. N. Yadav, T. S. Rao,
B. V. S. Reddy, A. A. K. A. Ghamdi, Eur. J. Org. Chem. 2011,
4603.
REFERENCES
[1] J. H. Cardellina II, R. E. Moore, E. V. Arnold, J. Clardy,
J. Org. Chem. 1979, 44, 4039; I. P. Singh, K. E. Milligan, W. H.
Gerwick, J. Nat. Prod. 1999, 62, 1333.
[13] D. F. Taber, R. P. Meagley, D. J. Doren, J. Org. Chem. 1996,
61, 5723.
[2] M. Costa, J. Costa-Rodrigues, M. H. Fernandes, P. Barros,
V. Vasconcelos, R. Martins, Mar. Drugs 2012, 10, 2181.
[14] K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J.
Hartung, K. S. Jeong, H. L. Kwong, K. Morikawa, Z. M.
Wang, D. Xu, X.-L. Zhang, J. Org. Chem. 1992, 57, 2768; H.
C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483; P. G. Reddy, S. Baskaran, J. Org. Chem. 2004,
69, 3093.
ꢀ
[3] M. Gutierrez, K. Tidgewell, T. L. Capson, N. Engene,
A. Almanza, J. Schemies, M. Jung, W. H. Gerwick, J. Nat.
Prod. 2010, 73, 709.
[4] Y. Sakito, S. Tanaka, M. Asami, T. Mukaiyama, Chem. Lett.
1980, 9, 1223.
[15] B. Giese, R. Rupaner, Liebigs Ann. Chem. 1987, 231.
€
[5] a) J.-R. Pougny, P. Rollin, P. Sinay, Tetrahedron Lett. 1987, 23,
4929; b) M.-C. Trinch, J.-C. Florent, C. Monneret, Tetrahedron
1988, 44, 6633; c) M. Asaoka, S. Hayashibe, S. Sonoda,
H. Takei, Tetrahedron 1991, 41, 6967; d) N. Maezaki,
Y. Matsumori, T. Shogaki, M. Soejima, T. Tanaka, H. Ohishi,
Received September 12, 2015
Accepted January 20, 2016
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
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