Stereoselective total synthesis of iso-cladospolide B and the 12 membered-macrolactone (6S,12R)-6-hydroxy-12-methyloxacyclododecane-2,5-dione

Article abstract of DOI:10.1002/hlca.201500030

Total syntheses of iso-cladospolide B (1) and the 12-membered macrolactone (6S,12R)-6-hydroxy-12-methyloxacyclododecane-2,5-dione (2), a non-natural product, were achieved from a common intermediate starting from commercially available 1,9-nonane diol.

Full text of DOI:10.1002/hlca.201500030

Helvetica Chimica Acta – Vol. 98 (2015)
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Stereoselective Total Synthesis of Iso-Cladospolide B and the 12 Membered-
Macrolactone (6S,12R)-6-Hydroxy-12-methyloxacyclododecane-2,5-dione
by Pendyala Venkata Arun Kumar, Venkata Satyanarayana Mallula, and Palakodety Radha Krishna*
D-211, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500007, India
(phone: þ 91-40-27193158; fax: þ 91-40-27160387; e-mail: prkgenius@iict.res.in)
Total syntheses of iso-cladospolide B (1) and the 12-membered macrolactone (6S,12R)-6-hydroxy-
12-methyloxacyclododecane-2,5-dione (2), a non-natural product, were achieved from a common
intermediate starting from commercially available 1,9-nonane diol.
Introduction. – Natural products from marine-derived fungi or soil-derived fungi
are the source of many drugs showing diverse biological and pharmacological
properties [1]. Cladospolides A – D [2 – 4] structurally resemble marine-derived
hexaketide macrolactones, but differ in the position of OH functional groups. They
are isolated from Cladosporium sp. and exhibit plant growth retardant activity towards
rice seedlings. Amongst all, Cladospolide D [5] isolated from Cladosporium sp. FT-
0012 shows antimicrobial activity against Mucor racemosus and Pyricularia oryzae with
IC50 values of 0.15 and 29 mg mlÀ1. A g-butenolide skeleton containing iso-cladospolide
B (Fig.) was isolated along with cladospolide B by Ireland and co-workers from marine
fungi isolate I96S215 [6]. Another polyketide metabolite (6R,12S)-6-hydroxy-12-
methyloxacyclododecane-2,5-dione, a 12-membered macrolactone, which structurally
resembles cladospolides was isolated from the endophytic fungal strain Cladosporium
tenuissimum LR463 of Maytenus hookeri [7]. Based on the significant activity of this
class of molecules, several syntheses were reported for iso-cladospolide B ((4S,5S,11S)
as well as (4S,5S,11R)) [8]. All these diastereomers are commonly referred to as iso-
cladospolides due to the smaller ring-size compared to the ring-size of the parent
compound cladospolide. Some inconsistencies in the optical rotational values are noted
in the literature, e.g., Prasad et al. [8g][8j] have synthesized both the (4S,5S,11S)-
isomer and its enantiomer and hence they share opposite sign of optical rotation with
Figure. Structures of natural products and a non-natural product
ꢀ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 98 (2015)
almost same numerical values. However, others [8a][8f] report low negative values for
the (4S,5S,11R)-isomer maybe due to the low optical purity. More recently, Gonzµlez
et al. [8l] described the synthesis of both the diastereoisomers ((4S,5S,11S) and its 11-
epimer), assigned their configurations and recorded their individual optical rotation
values.
As part of our interest in the synthesis of lactone-containing molecules [9], we
have recently accomplished the first stereoselective total synthesis of (6R,12S)-6-
hydroxy-12-methyl-1-oxacyclododecane-2,5-dione (2a) [10]. Herein, we report the
total synthesis of iso-cladospolide B (1) with (4S,5S,11R) configuration and of a non-
natural product and enantiomer of (6R,12S)-6-hydroxy-12-methyl-1-oxacyclodo-
decane-2,5-dione (2a), i.e., (6S,12R)-6-hydroxy-12-methyloxacyclododecane-2,5-dione
(2) [11]. The strategy for the synthesis of 1 described herein is general, using
commercially available inexpensive starting materials. Compound 2 was synthesized
from a common intermediate thus emphasizing the multiple usefulness of the inter-
mediates.
Results and Discussion. – Retrosynthetic analysis of both iso-cladospolide B (1) and
the 12-membered macrolide 2 were encompassed in Scheme 1. Accordingly, com-
pounds 1 and 2 could be prepared from g-butyrolactone 3, identified as the common
intermediate, through their respective chemical conversions. g-Butyrolactone 3 in turn
could be synthesized from diol 5 by the saturation of the C¼C bond, spontaneous
cyclization to form a hydroxylactone followed by the protection of the ensuing OH
group as its MOM-ether. Diol 5 could be derived from 6 by the conversion of the
alkynol into a conjugated diene and subsequent regioselective Sharpless asymmetric
dihydroxylation of the distal C¼C bond. Compound 6 could be derived from optically
pure 7a by its ring-opening reaction, followed by the protection of the ensuing OH
group as TBDPS ether, deprotection of the PMB ether oxidation of the primary alcohol
into the aldehyde, followed by ethyl propynoate anion addition. Epoxide 7a could be
derived from commercially available inexpensive starting material nonane-1,9-diol (8)
by adopting standard functional group conversions such as: selective mono protection
of one of its OH groups as PMB ether, conversion of the other into an olefinic
functionality by an oxidation/Wittig reaction-set, followed by m-CPBA oxidation and
resolution of the thus obtained racemic epoxide under Jacobsenꢁs (Hydrolytic kinetic
resolution) conditions.
Firstly, synthesis of 1 was initiated from nonane-1,9-diol (8; Scheme 2). Thus,
selective monoprotection of diol 8 (PMBBr, NaH, THF, 08) gave the known compound
9 [12] (76%). The latter was converted into its iodide (TPP, I2, imidazole, THF, 08) and
subsequently into a terminal C¼C bond (t-BuOK, THF, 08 – r.t.) through an elimination
reaction to afford 10 (89%). Epoxide 7 (84%) was formed from 10 (m-CPBA, CHCl3,
08 – r.t.) followed by Jacobsenꢁs hydrolic kinetic resolution [13] ((S,S)-Salen-Co(OAc)
catalyst, AcOH, toluene) to furnish optically pure 7a (44%). Ring-opening reaction of
oxirane 7a with LiAlH4 (THF, 08 – r.t.) afforded 11 (80%). Silyl protection of 11 under
conventional conditions ((tert-butyl)diphenylsilyl chloride (TBDPSCl), imidazole,
CH2Cl2) gave 12 (88%). Deprotection of the PMB-ether group in 12 with DDQ (DDQ,
CH2Cl2/H2O 19 :1, 08) furnished 13 (82%). Oxidation of alcohol 13 to the
corresponding aldehyde under Swern conditions followed by its quenching with Li-

Helvetica Chimica Acta – Vol. 98 (2015)
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Scheme 1. Retrosynthetic Analysis of Compounds 1 and 2
ethyl propynoate (LiHMDS, THF, À 788) gave alkynol 6 (57% over two steps). Next,
alkynol 6 was transformed into the conjugated diene ester 14 (78%) under phosphine
conditions (Ph3P, benzene, 858). Regioselective Sharpless asymmetric dihydroxylation
[14] of the distal olefin in 14 (AD-mix-a, MeSO2NH2, t-BuOH/H2O 1:1, 08) furnished 5
(82%).
Further, saturation of the second olefinic functionality in 5 (Pd/C, H2, r.t.) and
concomitant cyclization in one-pot led to g-butyrolactone 15 (84%). MOM-ether
protection of 15 (MOMCl, DIPEA, DMAP, CH2Cl2, 08 – r.t.) gave 3 (83%), which was
converted to butenolide 16 by using an addition-elimination protocol (PhSeBr, LDA,
THF; H2O2, CH2Cl2; 54%) [15]. Deprotection of both silyl and MOM ether groups of
16 (TiCl4, CH2Cl2, 08 – r.t.) afforded 1 (68%). The physical and spectroscopic data of 1
matched with the reported iso-cladospolide B [6].
Next, g-butyrolactone 3 was converted to the 12-membered macrolide 2, a non-
natural product target. As outlined in Scheme 3, 3 was transformed into 1,4-diol 17
(LiBH4, MeOH, THF, 08 – r.t.; 85%). Selective mono-silyl protection of the primary
alcohol (TBDMSCl, imidazole, CH2Cl2, 08 – r.t.) gave compound 18 (90%), followed

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Scheme 2. Synthesis of Iso-Cladospolide B (1)
a) NaH, PMBBr, THF, 08 – r.t., 4 h; 76%. b) 1. TPP, I2, imidazole, THF, 08, 10 min; 2. t-BuOK, THF,
08 – r.t.; 89%. c) m-CPBA, CHCl3, 08 – r.t., 3 h; 84%. d) (S,S)-Jacobsenꢁs catalyst, AcOH, toluene,
08 – r.t., 16 h; 44%; e) LiAlH4, THF, 08 – r.t., 30 min; 80%. f) TBDPSCl, imidazole, CH2Cl2, 08 – r.t., 4 h;
88%. g) DDQ, CH2Cl2/H2O 19 :1, 08, 20 min; 82%. h) 1. (COCl)2, DMSO, Et3N, CH2Cl2, 1 h, À 788;
81%; 2. LiHMDS, ethyl propynoate, THF, À 788, 30 min, 72%. i) Ph3P, benzene, reflux, 2 h; 78%. j) AD-
mix-a, MeSO2NH2, t-BuOH/H2O 1:1; 82%. k) Pd/C, H2, AcOEt, 12 h; 84%. l) MOMCl, DIPEA,
CH2Cl2, DMAP, 08 – r.t., 4 h; 83%. m) 1. PhSeBr, LDA, THF, 08 – r.t., 30 min; 2. H2O2, CH2Cl2, 2 h; 54%.
n) TiCl4, 08 – r.t., 2 h; 68%.
by PMB ether protection (PMBBr, NaH, THF, 08 – r.t.) of the secondary alcohol to give
19 (82%). Selective deprotection of the TBDMS ether (PPTS, MeOH, r.t.) in 19
afforded 20 (79%), which on subsequent oxidation (TEMPO, BAIB, H2O/CH2Cl2 1 :1,
08 – r.t.) gave acid 4 (85%). Deprotection of the TBDPS ether group (HFÀPy, THF,
08 – r.t.) yielded seco-acid 21 (88%). Macrolactonization of 21 under Yamaguchi
conditions [16] (Et3N, trichlorobenzoyl chloride, THF, 08 – r.t., DMAP, toluene, 908)
gave 22 (79%), followed by PMB ether deprotection under conventional conditions
(DDQ, CH2Cl2/H2O 19 :1, 08) to yield alcohol 23 (82%).
The latter was then oxidized (DessÀMartin periodinane, CH2Cl2, 08) [17] to furnish
24 (89%) and further deprotection of the MOM-group in 24 (TFA, CH2Cl2, 08 – r.t.)
afforded compound 2 (72%) as colorless needles with m.p. 119 – 1218 and [a]2D5 ¼ À40.0
(c ¼ 0.2, MeOH).

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Scheme 3. Synthesis of the 12-Membered Macrolactone 2
a) LiBH4, MeOH, THF, 08 – r.t., 30 min; 85%. b) TBDMSCl, imidazole, CH2Cl2, 08 – r.t., 2 h; 90%. c)
PMBBr, NaH, THF, 08 – r.t., 4 h; 82%. d) PPTS, MeOH, r.t., 3 h; 79%. e) TEMPO, BAIB, H2O/CH2Cl2
1:1, 08 – r.t., 4 h; 85%. f) HFÀPy, THF, 08 – r.t., 2 h; 88%. g) 2,4,6-trichlorobenzoyl chloride, Et3N, THF,
8 h, 08 – r.t., DMAP, toluene, 908, 20 h; 79%. h) DDQ, CH2Cl2/H2O 19 :1, 20 min; 82%. i) DessÀMartin
periodinane (DMP), CH2Cl2, 08 – r.t., 1 h; 89%. j) TFA, CH2Cl2, 08 – r.t., 2 h; 72%.
Conclusions. – In summary, we have accomplished the stereoselective total
synthesis of the iso-cladospolide B (1; overall yield 1.50%) and a hitherto unreported
12-membered non-natural macrolide 2 (overall yield 0.63%), wherein Jacobsenꢁs
hydrolytic kinetic resolution, Sharpless asymmetric dihydroxylation, and Yamaguchi
macrolactonization reactions were successfully employed for the synthesis of both the
target molecules from a common intermediate.
Experimental Part
General. Org. solns. were dried (anh. Na2SO4) and concentrated below 408 in vacuo. Air sensitive
reagents were transferred by double-ended needle. TLC: Merck 60 F254 silica-gel plates. Column

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Helvetica Chimica Acta – Vol. 98 (2015)
chromatography (CC): silica gel (SiO2, 60 – 120, 100 – 200 mesh; Acmeꢀs). Yields refer to chromato-
graphically and spectroscopically (1H- and 13C-NMR) homogenous material. Optical rotations: JASCO
P-1020 instrument and [a]D values were in units of 10À1 deg cm2 gÀ1 at 258. IR Spectra: PerkinElmer IR-
683 spectrophotometer with NaCl optics. 1H-NMR Spectra: Varian Gemini 200, Bruker Avance-300,
Unity 400, and Inova 500 instruments; in CDCl3 (7 – 10 mm soln.); d in ppm rel. to Me4Si as internal
standard, J in Hz. 13C-NMR Spectra (50 MHz and 75 MHz): Varian Gemini FT-200 and Bruker Avance
300 spectrometer in CDCl3 (7 – 10 mm soln.); d in ppm rel. to Me4Si as internal standard. MS: Finnigan
Mat 1210 double focusing mass spectrometer operating at a direct inlet system and ESI-MS was
measured using ion-trap mass spectrometer; in m/z. The software ACD/Name Version 1.0, developed by
M/s Advanced Chemistry Development Inc., Toronto, Canada, assisted nomenclature used in the
experimental section.
1-Methoxy-4-[(non-8-en-1-yloxy)methyl]benzene (10). To the stirred soln. of primary alcohol 9 [12]
(11.0 g, 39.29 mmol), in THF (110 ml), TPP (30.8 g, 117.82 mmol), imidazole (3.94 g, 58.93 mmol), and
I2 (29.8 g, 117.82 mmol) were added, and the mixture was allowed to stir for 10 min. After completion of
the reaction, the mixture was diluted with AcOEt (80 ml), the org. layer was washed with H2O (80 ml)
followed by brine (80 ml). The combined org. layers were dried (Na2SO4), evaporated in vacuo to give
the corresponding iodo compound, a brown colored sticky oil, which was used for the next reaction.
To a stirred soln. of t-BuOK (5.28 g, 47.15 mmol) in dry THF (50 ml), the iodo compound (50 ml)
was added, and the mixture stirred for 2 h. The reaction was quenched with aq. sat. NH4Cl (60 ml) before
warming to r.t. Then, the mixture was diluted with H2O (50 ml) and extracted with AcOEt (2 Â 50 ml).
The combined org. layers were washed with H2O (50 ml) and brine (50 ml), dried (Na2SO4), and
evaporated in vacuo. The residue was purified by CC (6% AcOEt in hexane) leading to 10 (9.18 g, 89%
yield) as a colorless oil. IR (neat): 3052, 3016, 1632, 1543, 1080. 1H-NMR (300 MHz, CDCl3): 7.19 (d, J ¼
9.1, 2 H); 6.81 (d, J ¼ 8.3, 2 H); 5.83 – 5.67 (m, 1 H); 5.00 – 4.86 (m, 2 H); 4.38 (s, 2 H); 3.78 (s, 3 H); 3.38
(t, J ¼ 6.7, 2 H); 2.02 (q, J ¼ 6.7, 2 H); 1.63 – 1.50 (m, 2 H); 1.43 – 1.23 (m, 8 H). 13C-NMR (75 MHz,
CDCl3): 159.0; 139.1; 130.7; 129.2; 114.1; 113.6; 72.4; 70.1; 55.2; 33.7; 29.7; 29.3; 29.0; 28.8; 26.1. ESI-MS:
285 ([M þ Na]þ). HR-MS: 285.1838 ([M þ Na]þ, C17H26NaOþ2 ; calc. 285.1830).
(2S)-2-{7-[(4-Methoxybenzyl)oxy]heptyl}oxirane (7a). To a stirred soln. of 10 (9.13 g, 34.8 mmol) in
CHCl3 (60 ml) at 08, m-CPBA (11.9 g, 69.6 mmol, 50% dispersion in H2O) was added, the aq. layer was
separated, dried (Na2SO4), anhydr. m-CPBAwas added, and the mixture stirred for 3 h. The mixture was
filtered, the filtrate washed with sat. NaHCO3 (3 Â 40 ml), dried (Na2SO4) and concentrated under
reduced pressure. The crude product was purified by CC (12% AcOEt in hexane) to obtain 7 (8.14 g,
84%) as a colorless liquid, which was used as such in next step.
A mixture of (þ)-(S,S)-N,N’-bis(3,5-di-(tert-butyl)salicylidene)-1,2-cyclohexanediaminocobalt(II)
(0.095 g, 0.15 mmol) in toluene (0.5 ml) and AcOH (0.017 g, 0.29 mmol) was stirred while open to the air
for 1 h at r.t. The mixture was concentrated under reduced pressure, and the brown residue ((S,S)-N,Nꢀ-
bis(3,5-di-(tert-butyl)salicylidene)-1,2-cyclohexanediamino-CoIII-acetate, [CoIII(salen)(AcO)] complex)
was dried under vacuum. The racemic epoxide 7 (8.14 g, 29.3 mmol) was added in one portion at 08, and
H2O (0.289 ml, 0.016 mmol) was added dropwise over 5 min. The mixture was allowed to warm to r.t. and
stirred for 16 h. The residue purified by CC (10% AcOEt in hexane) gave the terminal epoxide 7a
(3.90 g, 44% yield) as a colorless oil. [a]2D5 ¼ À68.7 (c ¼ 0.2, CHCl3). IR (neat): 3029, 2996, 1563, 1234,
1096. 1H-NMR (500 MHz, CDCl3): 7.19 (d, J ¼ 8.4, 2 H); 6.81 (d, J ¼ 8.4, 2 H); 4.38 (s, 2 H); 3.78 (s, 3 H);
3.38 (t, J ¼ 6.4, 2 H); 2.85 – 2.79 (m, 1 H); 2.67 (t, J ¼ 3.9, 1 H); 2.41 – 2.36 (m, 1 H); 1.60 – 1.21 (m, 12 H).
13C-NMR (75 MHz, CDCl3): 158.9; 130.5; 129.0; 113.5; 72.3; 69.9; 55.0; 52.2; 46.9; 32.3; 29.5; 29.2; 28.1;
25.9; 25.7. ESI-MS: 301 ([M þ Na]þ). HR-MS: 301.1783 ([M þ Na]þ, C17H26NaOþ3 ; calc. 301.1779).
(2R)-9-[(4-Methoxybenzyl)oxy]nonan-2-ol (11). LiAlH4 (0.707 g, 20.8 mmol) was taken in a round
bottomed flask and THF (10 ml) was added very slowly at 08. To it, compound 7a (3.86 g, 13.9 mmol)
dissolved in THF (30 ml) was added at the same temp. and allowed to stir for 30 min. The reaction was
quenched with sat. Na2SO4 and filtered through Celite, washed with AcOEt (40 ml). The solvent was
removed under reduced pressure and purified by CC (12% AcOEt in hexane) to afford 11 (3.11 g, 80%)
as a colorless liquid. [a]2D5 ¼ À101.6 (c ¼ 0.1, CHCl3). IR (neat): 3519, 3024, 1537, 1123. 1H-NMR
(500 MHz, CDCl3): 7.22 (d, J ¼ 8.6, 2 H); 6.84 (d, J ¼ 8.6, 2 H); 4.40 (s, 2 H); 3.79 (s, 3 H); 3.78 – 3.72 (m,
1 H); 3.40 (t, J ¼ 6.2, 2 H); 1.63 – 1.52 (m, 2 H); 1.50 – 1.23 (m, 10 H); 1.17 (d, J ¼ 6.2, 3 H). 13C-NMR

Helvetica Chimica Acta – Vol. 98 (2015)
1121
(75 MHz, CDCl3): 159.0; 130.7; 129.2; 113.7; 72.4; 70.1; 68.1; 55.2; 39.2; 29.6; 29.5; 29.3; 26.1; 25.6; 23.4.
ESI-MS: 303 ([M þ Na]þ). HR-MS: 303.1936 ([M þ Na]þ, C17H28NaOþ3 ; calc. 303.1936).
tert-Butyl({(2R)-9-[(4-methoxybenzyl)oxy]nonan-2-yl}oxy)diphenylsilane (12). To a stirred soln. of
alcohol 11 (3.07 g, 10.9 mmol) in CH2Cl2 (20 ml), imidazole (2.20 g, 32.9 mmol) was added at 08 and
stirred for 0.5 h. Then TBDPSCl (3.39 ml, 13.08 mmol) was added, and the mixture was stirred for
additional 12 h at r.t.. The mixture was diluted with CH2Cl2 (20 ml), the org. layer was washed with H2O
(20 ml) followed by brine (20 ml). The combined org. layers were dried (Na2SO4), evaporated in vacuo
and purified by CC (5% AcOEt in hexane) to afford 12 (5.00 g, 88%) as a colorless liquid. [a]2D5 ¼ À199.4
1
(c ¼ 0.2, CHCl3). IR (neat): 3058, 3024, 1537, 1584, 1118, 1088. H-NMR (300 MHz, CDCl3): 7.69 – 7.58
(m, 4 H); 7.41 – 7.27 (m, 6 H); 7.20 (d, J ¼ 8.3, 2 H); 6.81 (d, J ¼ 8.3, 2 H); 4.39 (s, 2 H); 3.78 (s, 3 H);
3.67 – 3.55 (m, 1 H); 3.37 (t, J ¼ 6.4, 2 H); 1.60 – 1.45 (m, 2 H); 1.40 – 1.12 (m, 13 H); 1.03 (s, 9 H).
13C-NMR (75 MHz, CDCl3): 159.0; 135.8; 135.5; 129.6; 129.3; 127.4; 113.7; 72.5; 70.2; 69.6; 55.3; 39.4;
29.7; 29.6; 29.4; 27.1; 26.1; 25.1; 23.2; 19.2. ESI-MS: 541 ([M þ Na]þ). HR-MS: 541.1876 ([M þ Na]þ,
C33H46NaO3Siþ; calc. 541.1885).
(8R)-8-{[tert-Butyl(diphenyl)silyl]oxy}nonan-1-ol (13). To a soln. of PMB ether 12 (4.96 g,
9.58 mmol) in a mixture of CH2Cl2 and H2O (45 ml, 19 :1), DDQ (6.52 g, 28.7 mmol) was added at 08,
and the mixture was stirred for 20 min at r.t. The reaction was quenched with sat. NaHCO3 soln. (25 ml),
extracted with CH2Cl2 (3 Â 25 ml), washed with H2O (25 ml) and brine (25 ml). The combined org.
layers were dried (Na2SO4), evaporated in vacuo, and purified by CC (15% AcOEt in hexane) to afford
13 (3.13 g, 82%) as a colorless liquid. [a]2D5 ¼ À43.6 (c ¼ 0.1, CHCl3). IR (neat): 3574, 3054, 1543, 1146.
1H-NMR (500 MHz, CDCl3): 7.67 – 7.60 (m, 4 H); 7.41 – 7.29 (m, 6 H); 3.83 – 3.76 (m, 1 H); 3.58 (t, J ¼ 6.9,
2 H);1.54 – 1.41 (m, 2 H); 1.38 – 1.09 (m, 13 H); 1.03 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 135.9; 129.4;
127.4; 69.6; 63.0; 39.4; 32.7; 29.7; 29.3; 27.0; 25.6; 25.1; 23.2; 19.3. ESI-MS: 421 ([M þ Na]þ). HR-MS:
421.2531 ([M þ Na]þ, C25H38NaO2Siþ; calc. 421.2538).
Ethyl (11R)-11-{[tert-Butyl(diphenyl)silyl]oxy}-4-hydroxydodec-2-ynoate (6). To a stirred soln. of
oxalyl chloride (1.36 ml, 15.6 mmol) in dry CH2Cl2 (20 ml), DMSO (2.20 ml, 31.16 mmol) was added at
À 788 and stirred for 30 min at same temp., followed by the addition of alcohol 13 (3.10 g, 7.79 mmol) in
CH2Cl2 (25 ml), and the mixture was stirred for 1 h at À 788. The reaction was quenched with Et3N
(6.5 ml, 46.74 mmol) added at À 788, and stirred for further 15 min. The mixture was extracted with
CH2Cl2 (2 Â 20 ml), washed with H2O (20 ml) and brine (20 ml). The combined org. layers were dried
(Na2SO4) and concentrated in vacuo to give an aldehyde (2.50 g, 81%) as a pale yellow syrup, which was
used for the next reaction.
To a stirred soln. of ethylpropiolate (0.680 g, 6.94 mmol) in THF (10 ml) at À 788, LiHMDS (1.0m in
hexanes, 9.5 ml, 9.46 mmol) was slowly added, and the whole mixture was stirred at À 788 for 1 h. Then,
the aldehyde (2.50 g, 6.31 mmol) in THF (15 ml) was added dropwise to the mixture at À 788, and stirring
was continued for 30 min. The reaction was quenched with aq. sat. NH4Cl (20 ml) before warming to r.t.
The mixture was diluted with H2O (15 ml) and extracted with Et2O (2 Â 20 ml). The combined org. layers
were washed with brine (15 ml), dried (Na2SO4), and evaporated in vacuo. The residue purified by CC
(10% AcOEt in hexane) resulted in the alkynol 6 (2.25 g, 72%) as colorless oil. [a]2D5 ¼ À102.1 (c ¼ 0.2,
CHCl3). IR (neat): 3247, 3027, 2140, 1674, 1543, 1138. 1H-NMR (500 MHz, CDCl3): 7.67 – 7.61 (m, 4 H);
7.41 – 7.30 (m, 6 H); 4.44 – 4.38 (m, 1 H); 4.22 (q, J ¼ 6.9, 2 H); 3.81 (sext., J ¼ 5.9, 1 H); 1.75 – 1.64 (m,
2 H); 1.49 – 1.35 (m, 5 H); 1.32 (t, J ¼ 6.9, 3 H); 1.28 – 1.10 (m, 8 H); 1.04 (s, 9 H). ESI-MS: 517 ([M þ
Na]þ). HR-MS: 517.2757 ([M þ Na]þ, C30H42NaO4Siþ; calc. 517.2750).
Ethyl (2E,4E,11R)-11-{[tert-Butyl(diphenyl)silyl]oxy}dodeca-2,4-dienoate (14). A mixture of alky-
nol 6 (2.21 g, 4.47 mmol) and PPh3 (1.40 g, 5.36 mmol) in benzene (20 ml) was stirred under reflux for 2 h.
The solvent was removed under reduced pressure and the crude product was purified by CC (5% AcOEt
in hexane) to give the conjugated diene ester 14 (1.67 g, 78% yield). [a]2D5 ¼ À127.0 (c ¼ 0.3, CHCl3). IR
(neat): 3047, 1734, 1672, 1638, 1531, 1121. 1H-NMR (300 MHz, CDCl3): 7.68 – 7.59 (m, 4 H); 7.42 – 7.28 (m,
6 H); 7.22 – 7.13 (m, 1 H); 6.17 – 6.00 (m, 2 H); 5.73 (d, J ¼ 15.3, 1 H); 4.18 (q, J ¼ 6.9, 2 H); 3.86 – 3.73 (m,
1 H); 2.09 (q, J ¼ 6.7, 2 H); 1.42 – 1.12 (m, 14 H); 1.04 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 167.3; 145.1;
144.7; 135.8; 129.4; 128.3; 127.4; 119.1; 69.4; 60.2; 39.2; 32.9; 29.7; 27.0; 26.2; 24.9; 23.2; 19.2; 14.3. ESI-
MS: 501 ([M þ Na]þ). HR-MS: 501.2796 ([M þ Na]þ, C30H42NaO3Siþ; calc. 501.2801).

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Ethyl (2E,4S,5S,11R)-11-{[tert-Butyl(diphenyl)silyl]oxy}-4,5-dihydroxydodec-2-enoate (5). Into a
100 ml round bottom flask, 16 ml of t-BuOH, 16 ml of H2O, AD-mix-a (4.77 g, 1.4 g/mmol) and
MeSO2NH2 (0.327 g, 3.41 mmol) were added. The mixture was stirred at r.t. for 5 min, and cooled to 08.
To this cooled soln., compound 14 (1.63 g, 3.41 mmol) was added, and the mixture was stirred for 24 h at
08. The reaction was quenched with sat. Na2SO4 at r.t. The mixture was diluted with AcOEt (30 ml), and
after separation of the layers, the aq. layer was further extracted with AcOEt (2 Â 30 ml). The combined
org. layers were washed with brine (20 ml) and dried (Na2SO4). The crude mixture was purified by flash
CC (25% AcOEt in hexane) to give 5 (1.44 g, 82% yield) as clear colorless oil. [a]2D5 ¼ À248.7 (c ¼ 0.5,
CHCl3). IR (neat): 3587, 3521, 3022, 1547, 1092. 1H-NMR (500 MHz, CDCl3): 7.67 – 7.58 (m, 4 H); 7.43 –
7.29 (m, 6 H); 6.87 (dd, J ¼ 15.4, 4.9, 1 H); 6.09 (d, J ¼ 15.4, 1 H); 4.19 (q, J ¼ 7.2, 2 H); 4.09 – 4.00 (m,
1 H); 3.85 – 3.74 (m, 1 H); 3.52 – 3.41 (m, 1 H); 2.22 (br. s, OH), 1.85 (br. s, OH), 1.53 – 1.11 (m, 16 H);
1.04 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 167.3; 150.3; 132.6; 128.3; 127.4; 119.1; 76.2; 75.2; 69.4; 60.2;
39.2; 33.2; 30.5; 27.3; 26.2; 24.7; 23.2; 19.2; 14.3. ESI-MS: 535([M þ Na]þ). HR-MS: 535.2863 ([M þ
Na]þ, C30H44NaO5Siþ; calc. 535.2856).
(5S)-5-[(1S,7R)-7-{[tert-Butyl(diphenyl)silyl]oxy}-1-hydroxyoctyl]dihydrofuran-2(3H)-one (15).
Pd/C (10 mg, 10% wet weight) was added to a soln. of compound 5 (1.40 g, 2.73 mmol) in AcOEt
(10 ml). The mixture was stirred for 12 h under H2. After the completion of the reaction, the mixture was
filtered through Celite and washed with AcOEt (15 ml), the filtrate was concentrated in vacuo and,
purified by CC (22% AcOEt in hexane) to provide the hydroxylactone 15 (1.08 g, 84%) as colorless oil.
1
[a]2D5 ¼ À133.3 (c ¼ 0.3, CHCl3). IR (neat): 3510, 3014, 1754, 1514, 1132. H-NMR (300 MHz, CDCl3):
7.67 – 7.58 (m, 4 H); 7.40 – 7.27 (m, 6 H); 4.34 – 4.27 (m, 1 H); 3.84 – 3.76 (m, 1 H); 3.56 – 3.41 (m, 1 H);
2.60 – 2.41 (m, 2 H); 2.22 – 1.98 (m, 2 H); 1.53 – 1.10 (m, 13 H); 1.03 (s, 9 H). 13C-NMR (75 MHz, CDCl3):
177.1; 135.8; 129.4; 127.4; 82.8; 73.5; 69.4; 39.2; 32.8; 29.4; 28.6; 26.9; 25.3; 24.9; 24.0; 23.2; 19.2. ESI-MS:
491([M þ Na]þ). HR-MS: 491.2599 ([M þ Na]þ, C28H40NaO4Siþ; calc. 491.2593).
(5S)-5-[(5S,11R)-11,14,14-Trimethyl-13,13-diphenyl-2,4,12-trioxa-13-silapentadecan-5-yl]dihydro-
furan-2(3H)-one (3). To a stirred soln. of 15 (1.04 g, 2.22 mmol) in CH2Cl2 (8 ml), DIPEA (1.16 ml,
6.66 mmol), MOMCl (0.54 ml, 3.33 mmol), and DMAP (cat.), were added at 08 and stirred at r.t. for 6 h.
The mixture was extracted with CH2Cl2 (2 Â 15 ml), and the combined org. layers were washed with H2O
(12 ml), brine (12 ml) and dried (Na2SO4). The solvent was evaporated in vacuo and the residue purified
by CC (16% AcOEt in hexane) to furnish 3 (0.95 g, 83%) as a colorless oil. [a]2D5 ¼ À55.3 (c ¼ 0.2,
1
CHCl3). IR (neat): 3010, 1514, 1164. H-NMR (300 MHz, CDCl3): 7.68 – 7.59 (m, 4 H); 7.42 – 7.28 (m,
6 H); 4.86 – 4.79 (m, 2 H); 4.53 – 4.43 (m, 1 H); 3.85 – 3.74 (m, 1 H); 3.56 – 3.47 (m, 1 H); 3.36 (s, 3 H);
2.60 – 2.37 (m, 2 H); 2.34 – 2.12 (m, 1 H); 2.09 – 1.94 (m, 1 H); 1.60 – 1.12 (m, 13 H); 1.04 (s, 9 H).
13C-NMR (75 MHz, CDCl3): 177.1; 135.8; 129.4; 127.4; 96.4; 81.3; 78.8; 69.4; 55.9; 39.3; 30.0; 29.7; 28.5;
27.0; 25.1; 24.1; 23.2; 22.7; 19.3. ESI-MS: 535 ([M þ Na]þ). HR-MS: 535.2864 ([M þ Na]þ,
C30H44NaO5Siþ; calc. 535.2856).
(5S)-5-[(5S,11R)-11,14,14-Trimethyl-13,13-diphenyl-2,4,12-trioxa-13-silapentadecan-5-yl]furan-
2(5H)-one (16). To a soln. of LDA (prepared from diisopropyl amine (1.12 ml, 6.4 mmol) and BuLi
(2.48 ml, 2.5m soln. in hexane, 6.2 mmol, at À 788) compound 3 (0.41 g, 0.80 mmol) in THF was added
dropwise, under Ar at À 788. The mixture was slowly warmed up À 308 and stirred for 1.5 h. It was then
cooled to À 788, and a THF soln. of PhSeBr (1.23 g, 5.2 mmol) was introduced into the flask and allowed
to stir for 2 h at À 308. It was quenched with aq. NH4Cl (10 ml) and extracted with Et2O (3 Â 25 ml). The
combined org. layers were washed with H2O (12 ml), brine (12 ml), and dried (Na2SO4). Solvent was
evaporated in vacuo to furnish the crude selenolactone, which was used as such in the next step.
To a soln. of crude selenolactone in CH2Cl2 (10 ml), H2O2 (2.1 ml of 30% w/v in H2O) was added and
allowed to stir for 1 h at r.t. H2O (20 ml) was added to the mixture and extracted with CH2Cl2 (3 Â 15 ml).
The combined org. layers were washed with sat. Na2S2O3 (15 ml), brine (15 ml), and dried (Na2SO4). The
solvent was evaporated in vacuo and the residue was purified by CC (16% AcOEt in hexane) to furnish
16 (0.22 g, 54%) as colorless oil. [a]2D5 ¼ À58.4 (c ¼ 0.3, CHCl3). IR (neat): 3024, 3016, 1638, 1523, 1132.
1H-NMR (500 MHz, CDCl3): 7.68 – 7.59 (m, 5 H); 7.42 – 7.28 (m, 6 H); 6.19 (dd, J ¼ 6.0, 2.0, 1 H); 5.27 –
5.21 (m, 1 H); 4.86 – 4.79 (m, 2 H); 3.82 – 3.77 (m, 1 H); 3.74 – 3.68 (m, 1 H); 3.36 (s, 3 H); 1.62 – 1.20 (m,
10 H); 1.15 (d, J ¼ 6.0, 3 H); 1.03 (s, 9 H). 13C-NMR (150 MHz, CDCl3): 174.8; 157.5; 135.7; 129.4; 127.4;

Helvetica Chimica Acta – Vol. 98 (2015)
1123
122.9; 96.6; 81.1; 79.5; 69.4; 55.9; 39.3; 32.7; 30.1; 27.0; 25.3; 24.1; 23.2; 19.3. ESI-MS: 533 ([M þ Na]þ).
HR-MS: 533.2705 ([M þ Na]þ, C30H42NaO5Siþ; calc. 533.2699).
(5S)-5-[(1S,7R)-1,7-Dihydroxyoctyl]furan-2(5H)-one (1). To a stirred soln. of 16 (0.18 g,
0.35 mmol) in CH2Cl2 (2 ml), TiCl4 (0.065 g, 0.35 mmol) in CH2Cl2 (2 ml) was added at 08, and the
mixture was stirred for 2 h. The mixture was treated with sat. NaHCO3 soln. (5 ml) and extracted with
Et2O (2 Â 20 ml). The combined org. layers were washed with H2O (20 ml), dried (Na2SO4), and
concentrated. The crude product was purified by CC (45% AcOEt in hexane) to afford 1 (0.054 g, 68%)
1
as colorless liquid. [a]2D5 ¼ À82.3 (c ¼ 0.2, MeOH). IR (neat): 3391, 3014, 1746, 1514, 1132. H-NMR
(500 MHz, CD3OD): 7.65 (dd, J ¼ 6.0, 1.5, 1 H); 6.18 (dd, J ¼ 6.0, 2.0, 1 H); 5.08 (quint., J ¼ 2.0, 1 H);
3.82 – 3.76 (m, 1 H); 3.74 – 3.69 (m, 1 H); 1.62 – 1.53 (m, 3 H); 1.48 – 1.32 (m, 7 H); 1.15 (d, J ¼ 6.0, 3 H).
13C-NMR (150 MHz, CD3OD): 175.8; 157.1; 122.7; 88.2; 71.6; 68.5; 40.1; 34.2; 30.6; 26.82; 26.79; 23.51.
ESI-MS: 251([M þ Na]þ). HR-MS: 251.1263 ([M þ Na]þ, C12H20NaOþ4 ; calc. 251.1259).
(4S,5S,11R)-11-{[tert-Butyl(diphenyl)silyl]oxy}-5-(methoxymethoxy)dodecane-1,4-diol (17). To a
stirred soln. of 3 (0.5 g, 0.98 mmol) in THF (5 ml) at 08 was sequentially added MeOH (0.04 ml,
0.98 mmol) and LiBH4 (0.03 g, 1.18 mmol). After 30 min, the reaction was quenched with sat. aq. NH4Cl
(20 ml) and extracted with Et2O (2 Â 40 ml). The org. layers were dried (Na2SO4) and concentrated in
vacuo and the crude product was purified by CC (23% AcOEt in hexane) to afford 17 (0.43 g, 85%) as
colorless oil. [a]D25 ¼ À124.8 (c ¼ 0.3, CHCl3). IR (neat): 3584, 3391, 3028, 1514, 1246, 1154. IR (neat):
3584, 3391, 3028, 1514, 1246, 1154. 1H-NMR (500 MHz, CDCl3): 7.70 – 7.61 (m, 4 H); 7.41 – 7.30 (m, 6 H);
4.66 (d, J ¼ 6.4, 1 H); 4.62 (d, J ¼ 6.4, 1 H); 3.81 (q, J ¼ 5.9, 1 H); 3.70 – 3.59 (m, 2 H); 3.51 – 3.45 (m, 1 H);
3.40 (s, 3 H); 3.32 – 3.25 (m, 1 H); 1.93 – 1.84 (m, 1 H); 1.78 – 1.56 (m, 3 H); 1.55 – 1.10 (m, 13 H); 1.04 (s,
9 H). 13C-NMR (75 MHz, CDCl3): 135.8; 129.4; 127.4; 97.3; 83.9; 72.8; 69.5; 62.9; 55.8; 39.3; 31.0; 30.2;
29.2; 27.0; 26.2; 25.1; 23.2; 22.6; 19.2. ESI-MS: 539 ([M þ Na]þ). HR-MS: 539.3173 ([M þ Na]þ,
C30H48NaO5Siþ; calc. 539.3169).
(8S,9S,15R)-9-(Methoxymethoxy)-2,2,3,3,15,18,18-heptamethyl-17,17-diphenyl-4,16-dioxa-3,17-disi-
lanonadecan-8-ol (18). To a stirred soln. of 1,4-diol 17 (0.4 g, 0.78 mmol) in CH2Cl2 (4 ml), imidazole
(0.16 g, 2.34 mmol) was added at 08, and the mixure was stirred for 0.5 h. Then, TBDMSCl (0.18 g,
1.17 mmol) was added, and the mixture was stirred for 12 h at r.t. The mixture was diluted with CH2Cl2
(4 ml), the org. layer was washed with H2O (6 ml) followed by brine (6 ml). The combined org. layers
were dried (Na2SO4), evaporated in vacuo, and purified by CC (12% AcOEt in hexane) to afford 18
(0.44 g, 90%) as colorless liquid. [a]2D5 ¼ À98.2 (c ¼ 0.2, CHCl3). IR (neat): 3497, 3036, 1525, 1258, 1137.
1H-NMR (300 MHz, CDCl3): 7.65 – 7.56 (m, 4 H); 7.37 – 7.25 (m, 6 H); 4.60 (s, 2 H); 3.80 – 3.70 (m, 1 H);
3.60 (t, J ¼ 5.6, 2 H); 3.48 – 3.38 (m, 1 H); 3.34 (s, 3 H); 3.28 – 3.20 (m, 1 H); 1.70 – 1.10 (m, 17 H); 1.03 (s,
9 H); 0.86 (s, 9 H); 0.03 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 135.8; 129.4; 127.4; 97.0; 82.8; 72.6; 69.5;
63.2; 55.7; 39.4; 30.8; 29.7; 27.0; 26.8; 25.9; 25.3; 25.2; 23.2; 19.3; 17.1; À 5.3. ESI-MS: 653 ([M þ Na]þ).
HR-MS: 653.4027 ([M þ Na]þ, C36H62NaO5Si2; calc. 653.4033).
(5R,11S,12S)-12-[(4-Methoxybenzyl)oxy]-11-(methoxymethoxy)-2,2,5,17,17,18,18-heptamethyl-3,3-
diphenyl-4,16-dioxa-3,17-disilanonadecane (19). A soln. of alcohol 18 (0.4 g, 0.63 mmol) in dry THF
(4 ml) was added to a suspension of NaH (0.75 g, 1.89 mmol) in THF (6 ml) under N2 atmosphere at 08
and was stirred for 30 min. To this, a soln. of PMBBr (0.12 g, 0.6 mmol) in dry THF (5 ml) was added, and
the mixture was allowed to stir for 6 h at r.t. The reaction was quenched with sat. aq. NH4Cl soln. (8 ml)
and extracted with AcOEt (2 Â 10 ml). The org. layer was washed with H2O (2 Â 10 ml) and brine
(15 ml). The combined org. layers were dried (Na2SO4), evaporated in vacuo, and purified by CC (6%
AcOEt in hexane) to afford 19 (0.39 g, 82%) as a yellow oil. [a]2D5 ¼ À41.1 (c ¼ 0.4, CHCl3). IR (neat):
3068, 3046, 1562, 1525, 1267, 1137. 1H-NMR (500 MHz, CDCl3): 7.64 (d, J ¼ 6.2, 4 H); 7.42 – 7.28 (m, 6 H);
7.20 (d, J ¼ 8.5, 2 H); 6.80 (d, J ¼ 8.4, 2 H); 4.63 (d, J ¼ 6.8, 1 H); 4.56 (d, J ¼ 6.7, 1 H); 4.46 (2d, AB
pattern, J ¼ 11.3, 7.7, 2 H); 3.83 – 3.78 (m, 1 H); 3.77 (s, 3 H); 3.60 – 3.47 (m, 3 H); 3.41 – 3.34 (m, 1 H);
3.32 (s, 3 H); 1.68 – 1.09 (m, 17 H); 1.03 (s, 9 H); 0.87 (s, 9 H); 0.02 (s, 6 H). 13C-NMR (75 MHz, CDCl3):
158.7; 135.9; 129.5; 129.4; 127.4; 127.3; 113.7; 96.8; 79.8; 78.7; 72.0; 69.5; 63.2; 55.6; 55.2; 39.4; 29.9; 29.8;
29.4; 27.0; 26.8; 26.2; 25.9; 25.2; 23.2; 19.2; 16.8; À 5.2. ESI-MS: 773 ([M þ Na]þ). HR-MS: 773.4614
([M þ Na]þ, C44H70NaO6Siþ2 ; calc. 773.4609).
(4S,5S,11R)-11-{[tert-Butyl(diphenyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-5-(methoxymethoxy)do-
decan-1-ol (20). To a stirred soln. of compound 19 (0.36 g, 0.48 mmol) in MeOH (4 ml), the pyridinium

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Helvetica Chimica Acta – Vol. 98 (2015)
salt of p-toluenesulfonic acid (0.15 g, 0.6 mmol) was added at r.t., and the mixture was allowed to stir for
2 h. The solvent was removed under reduced pressure, purified by CC (15% AcOEt in hexane) to afford
20 (0.24 g, 79%) as a yellow oil. [a]2D5 ¼ À74.4 (c ¼ 0.5, CHCl3). IR (neat): 3557, 3029, 1527, 1142.
1H-NMR (300 MHz, CDCl3): 7.64 (d, J ¼ 6.2, 4 H); 7.41 – 7.29 (m, 6 H); 7.20 (d, J ¼ 7.9, 2 H); 6.81 (d, J ¼
8.4, 2 H); 4.62 (d, J ¼ 6.4, 1 H); 4.57 (d, J ¼ 6.7, 1 H); 4.52 (d, J ¼ 10.9, 1 H); 4.42 (d, J ¼ 11.4, 1 H); 3.84 –
3.78 (m, 1 H); 3.77 (s, 3 H); 3.69 – 3.60 (m, 1 H); 3.60 – 3.52 (m, 2 H); 3.46 – 3.40 (m, 1 H); 3.33 (s, 3 H);
1.75 – 1.10 (m, 17 H); 1.04 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 159.3; 135.9; 129.7; 129.4; 127.5; 127.4;
113.7; 96.9; 79.9; 78.5; 72.0; 69.6; 62.9; 55.7; 55.3; 39.4; 31.9; 29.7; 29.4; 27.0; 25.9; 25.2; 23.2; 22.7; 19.3.
ESI-MS: 659 ([M þ Na]þ). HR-MS: 659.3738 ([M þ Na]þ, C38H56NaO6Siþ; calc. 659.3744).
(4S,5S,11R)-11-{[tert-Butyl(diphenyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-5-(methoxymethoxy)do-
decanoic Acid (4). To a stirred soln. of compound 20 (0.21 g, 0.33 mmol) in CH2Cl2/H2O (1:1, 2 ml) at 08,
BAIB (0.329 g, 0.99 mmol), and TEMPO (0.0155 g, 0.099 mmol) were added and stirred at r.t. for 4 h.
The mixture was diluted with CHCl3 (10 ml) and washed with sat. Na2S2O3 (10 ml) and brine (20 ml), and
dried (Na2SO4), concentrated in vacuo, and purified by CC (18% AcOEt in hexane) to afford 4 (0.166 g,
85%) as a yellow oil. [a]2D5 ¼ À112.8 (c ¼ 0.3, CHCl3). IR (neat): 3248, 3029, 1709, 1527, 1290, 1142.
1H-NMR (500 MHz, CDCl3): 7.67 – 7.59 (m, 4 H); 7.40 – 7.27 (m, 6 H); 7.19 (d, J ¼ 8.3, 2 H); 6.80 (d, J ¼
8.3, 2 H); 4.61 (d, J ¼ 6.7, 1 H); 4.55 (d, J ¼ 6.7, 1 H); 4.51 (d, J ¼ 11.3, 1 H); 4.40 (d, J ¼ 10.9, 1 H); 3.87 –
3.78 (m, 1 H); 3.77 (s, 3 H); 3.60 – 3.50 (m, 1 H); 3.49 – 3.40 (m, 1 H); 3.32 (s, 3 H); 2.46 – 2.20 (m, 2 H);
1.97 – 1.80 (m, 1 H); 1.75 – 1.59 (m, 1 H); 1.57 – 1.09 (m, 13 H); 1.04 (s, 9 H). 13C-NMR (75 MHz, CDCl3):
178.5; 159.2; 135.8; 129.6; 129.4; 127.4; 113.7; 96.8; 78.6; 78.2; 72.1; 69.5; 55.7; 55.2; 42.6; 39.4; 30.5; 29.7;
27.0; 26.1; 25.9; 25.1; 24.6; 23.2; 19.2. ESI-MS: 673 ([M þ Na]þ). HR-MS: 673.3528 ([M þ Na]þ,
C38H54O7NaSiþ; calc. 673.3536).
(4S,5S,11R)-11-Hydroxy-4-[(4-methoxybenzyl)oxy]-5-(methoxymethoxy)dodecanoic Acid (21). To
a stirred soln. of compound 4 (0.14 g, 0.22 mmol) in dry THF, HFÀPy (0.28 ml, 0.28 mmol) was added and
stirred for 12 h at r.t. The reaction was quenched with CuSO4 soln. (10 ml), extracted with AcOEt (2 Â
5 ml), washed with H2O (5 ml), and brine (5 ml). The combined org. layers were dried (Na2SO4),
concentrated in vacuo, and purified by CC (30% AcOEt in hexane) to afford 21 (0.080 g, 88%) as
colorless liquid. [a]2D5 ¼ À52.3 (c ¼ 0.2, CHCl3). IR (neat): 3279, 3068, 1714, 1278, 1108. 1H-NMR
(300 MHz, CDCl3): 7.19 (d, J ¼ 8.3, 2 H); 6.80 (d, J ¼ 8.3, 2 H); 4.61 (d, J ¼ 6.7, 1 H); 4.55 (d, J ¼ 6.7, 1 H);
4.51 (d, J ¼ 11.3, 1 H); 4.40 (d, J ¼ 10.9, 1 H); 4.04 – 3.98 (m, 1 H); 3.77 (s, 3 H); 3.60 – 3.50 (m, 1 H);
3.49 – 3.40 (m, 1 H); 3.32 (s, 3 H); 2.46 – 2.20 (m, 2 H); 1.98 – 1.83 (m, 1 H); 1.77 – 1.58 (m, 1 H); 1.55 –
1.09 (m, 13 H). 13C-NMR (75 MHz, CDCl3): 178.5; 159.2; 129.4; 127.4; 113.7; 96.8; 78.6; 78.2; 72.1;
66.3; 55.7; 55.2; 41.4; 39.4; 30.5; 29.7; 27.0; 25.1; 24.6; 23.1. ESI-MS: 417 ([M þ Na]þ). HR-MS: 435.2366
([M þ Na]þ, C22H36NaOþ7 ; calc. 435.2359).
(5S,6S,12R)-5-[(4-Methoxybenzyl)oxy]-6-(methoxymethoxy)-12-methyloxacyclododecan-2-one
(22). To a stirred soln. of acid 21 (0.065 g, 0.16 mmol) in dry THF (5 ml), Et3N (0.066 ml, 0.48 mmol) was
added at r.t., and the mixture was stirred for 0.5 h. 2,4,6-Trichlorobenzoyl chloride (0.059 ml, 0.192 mmol)
was added, and the mixture was stirred for 8 h at r.t. The solvent was evaporated, the residue diluted with
toluene (10 ml), then DMAP (0.195 g, 1.60 mmol) was added, and the mixture was stirred for 20 h at 908.
Toluene was evaporated, and the crude residue purified by CC (5% AcOEt in hexane) to afford cyclic
ester 22 (0.049 g, 79%) as a colorless liquid. [a]2D5 ¼ À13.2 (c ¼ 0.4, CHCl3). IR (neat): 3023, 2872, 1728,
1131, 1062. 1H-NMR (500 MHz, CDCl3): 7.19 (d, J ¼ 8.3, 2 H); 6.80 (d, J ¼ 8.3, 2 H); 5.05 – 5.00 (m, 1 H);
4.61 (d, J ¼ 6.7, 1 H); 4.55 (d, J ¼ 6.7, 1 H); 4.51 (d, J ¼ 11.3, 1 H); 4.40 (d, J ¼ 10.9, 1 H); 3.77 (s, 3 H);
3.60 – 3.50 (m, 1 H); 3.49 – 3.40 (m, 1 H); 3.32 (s, 3 H); 2.45 – 2.29 (m, 2 H); 2.15 – 2.05 (m, 1 H); 1.84 –
1.74 (m, 1 H); 1.73 – 1.63 (m, 1 H); 1.51 – 1.17 (m, 9 H); 1.12 (d, J ¼ 6.3, 3 H). 13C-NMR (75 MHz,
CDCl3): 172.5; 159.2; 129.4; 127.4; 113.7; 96.8; 72.7; 72.2; 72.1; 71.7; 55.7; 55.2; 31.7; 30.8; 29.7; 29.2; 27.1;
25.2; 20.6; 19.5. ESI-MS: 417 ([M þ Na]þ). HR-MS: 417.2258 ([M þ Na]þ, C22H34NaOþ6 ; calc. 417.2253).
(5S,6S,12R)-5-Hydroxy-6-(methoxymethoxy)-12-methyloxacyclododecan-2-one (23). To a soln. of
compound 22 (0.035 g, 0.09 mmol) in a mixture of CH2Cl2 and H2O (5 ml, 19 :1), DDQ (0.22 g,
0.98 mmol) was added at 08 and the mixture was stirred for 20 min. at r.t. The reaction was quenched with
sat. NaHCO3 soln. (5 ml), extracted with CH2Cl2 (3 Â 15 ml) and washed with H2O (5 ml) and brine
(5 ml). The combined org. layers were dried (Na2SO4), evaporated in vacuo, and purified by CC (8%
AcOEt in hexane) to afford 23 (0.02 g, 82%) as a colorless liquid. [a]2D5 ¼ À11.9 (c ¼ 0.1, CHCl3). IR

Helvetica Chimica Acta – Vol. 98 (2015)
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(neat): 3489, 1721, 1476, 1234. H-NMR (300 MHz, CDCl3): 5.05 – 5.01 (m, 1 H); 4.61 (d, J ¼ 6.7, 1 H);
4.55 (d, J ¼ 6.7, 1 H); 3.87 – 3.79 (m, 1 H); 3.42 – 3.36 (m, 1 H); 3.32 (s, 3 H); 2.47 – 2.29 (m, 2 H); 2.16 –
2.07 (m, 1 H); 1.82 – 1.71 (m, 1 H); 1.70 – 1.63 (m, 1 H); 1.50 – 1.18 (m, 9 H); 1.12 (d, J ¼ 6.3, 3 H).
13C-NMR (75 MHz, CDCl3): 172.5; 96.8; 74.4; 72.1; 69.6; 55.2; 31.7; 30.8; 29.7; 28.8; 27.1; 25.2; 22.9; 19.5.
ESI-MS: 297 ([M þ Na]þ). HR-MS: 297.1871 ([M þ Na]þ, C14H26NaOþ5 ; calc. 297.1885).
(6S,12R)-6-(Methoxymethoxy)-12-methyloxacyclododecane-2,5-dione (24). To a stirred soln. of
alcohol 23 (0.020 g, 0.07 mmol) in dry CH2Cl2 (2 ml), DessÀMartin periodinane (0.045 g, 0.11 mmol) was
added at 08, and the mixture was allowed to stir for 2 h at r.t.. The reaction was quenched with aq. soln. of
NaHCO3/hypo (1:1, 1 ml) and mixture was extracted with CH2Cl2 (2 Â 5 ml), washed with H2O (5 ml)
and brine (5 ml). The combined org. layers were dried (Na2SO4), concentrated in vacuo, and purified by
CC (5% AcOEt in hexane) to afford ketone 24 (0.018 g, 89%) as a colorless syrup. [a]2D5 ¼ À56.3 (c ¼ 0.1,
CHCl3). IR (neat): 1721, 1715, 1467, 1259. 1H-NMR (300 MHz, CDCl3): 4.93 – 4.81 (m, 1 H); 4.61 (d, J ¼
6.7, 1 H); 4.55 (d, J ¼ 6.7, 1 H); 4.18 (t, J ¼ 5.9, 1 H); 3.48 – 3.34 (m, 1 H); 3.32 (s, 3 H); 2.65 (t, J ¼ 15.7,
1 H); 2.58 – 2.39 (m, 2 H); 1.66 (q, J ¼ 6.5, 1 H); 1.65 – 1.56 (m, 2 H); 1.48 – 1.35 (m, 1 H); 1.34 – 1.24 (m,
6 H); 1.17 (d, J ¼ 6.2, 3 H). 13C-NMR (50 MHz, CDCl3): 212.3; 171.2; 95.9; 83.7; 69.6; 55.2; 38.1; 31.7;
30.2; 29.7; 29.4; 28.3; 22.9; 19.5. ESI-MS: 295 ([M þ Na]þ). HR-MS: 295.1871 ([M þ Na]þ, C14H24NaO5þ ;
calc. 295.1885).
(6S,12R)-6-Hydroxy-12-methyloxacyclododecane-2,5-dione (2). A stirred soln. of 24 (0.018 g,
0.07 mmol) in CH2Cl2 (2 ml) was treated with TFA (0.2 ml) at 08 and stirred at r.t. for 2 h. The reaction
was neutralized with solid NaHCO3, and the crude mixture was extracted with AcOEt (3 Â 5 ml) and
dried (Na2SO4). The solvent was evaporated and the residue was purified by CC (6.5% AcOEt in
hexane) to furnish 2 (0.010 g, 0.07 mmol) in 72% as colorless needles. M.p. 119 – 1218. [a]2D5 ¼ À40.0 (c ¼
0.2, MeOH). IR (neat): 3452, 2919, 1718, 1702, 1470, 1256. 1H-NMR (500 MHz, (D6)acetone): 4.76 (sext.,
J ¼ 6.3, 1 H); 4.24 – 4.22 (m, 1 H); 3.13 – 3.06 (m, 1 H); 2.60 – 2.47 (m, 2 H); 2.44 – 2.40 (m, 1 H); 1.84 –
1.79 (m, 1 H); 1.71 (quint., J ¼ 6.8, 1 H); 1.46 – 1.37 (m, 2 H); 1.23 – 1.13 (m, 6 H); 1.03 (d, J ¼ 6.3, 3 H).
13C-NMR (75 MHz, (D6)acetone): 212.6; 172.0; 77.2; 71.7; 35.0; 33.5; 32.2; 30.1; 27.9; 21.4; 20.7; 20.0. ESI-
MS: 251 ([M þ Na]þ). HR-MS: 251.1267 ([M þ Na]þ, C12H20NaO4þ ; calc. 251.1263).
Two of the authors (P. V. A. and V. S. M.) thank the CSIR, New Delhi, India for financial support in
the form of a fellowships.
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Received February 3, 2015