A convergent synthesis of a twelve-membered macrolide natural product, (6R,12S)-6-hydroxy-12-methyl-1-oxacyclododecane-2,5-dione

Article abstract of DOI:10.1002/hlca.201200064

A new polyketide metabolite, the twelve-membered macrolide 1, isolated from the endophytic fungal strain Cladosporium tenuissimum LR 463 of Maytenus hookeri, whose structure had been determined as (6R,12S)-6-hydroxy-12-methyl-1- oxacyclododecane-2,5-dione, was synthesized for the first time by a convergent strategy via Yamaguchi esterification of 2 with 3 and ring-closing metathesis (RCM) to afford the cyclic ester 1 that was eventually transformed to the target molecule. However, the total synthesis revealed that the assigned structure of the natural product is not correct.

Full text of DOI:10.1002/hlca.201200064

Helvetica Chimica Acta – Vol. 95 (2012)
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A Convergent Synthesis of a Twelve-Membered Macrolide Natural Product,
(6R,12S)-6-Hydroxy-12-methyl-1-oxacyclododecane-2,5-dione
by Palakodety Radha Krishna* and Pendyala Venkata Arun Kumar
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500607, India
(phone: þ 91-40-27193158; fax: þ 91-40-27160387; e-mail: prkgenius@iict.res.in)
A new polyketide metabolite, the twelve-membered macrolide 1, isolated from the endophytic
fungal strain Cladosporium tenuissimum LR 463 of Maytenus hookeri, whose structure had been
determined as (6R,12S)-6-hydroxy-12-methyl-1-oxacyclododecane-2,5-dione, was synthesized for the
first time by a convergent strategy via Yamaguchi esterification of 2 with 3 and ring-closing metathesis
(RCM) to afford the cyclic ester 1 that was eventually transformed to the target molecule. However, the
total synthesis revealed that the assigned structure of the natural product is not correct.
Introduction. – Endophytic fungi constitute an important source of biologically
active chemical compounds with significant pharmacological activity, which can be
further employed as lead compounds. Colletotrichum magna, a non-pathogenic
endophytic fungus, on inoculation of watermelon and cucumber seedlings, rapidly
induces systematic defense responses which include the production of peroxidase,
phenylalanine ammonia-lyase, lignin, and salicylic acid. A hexaketide lactone 1 was
isolated [1] along with the known cladospolides (cladospolides A and B, and
isocladospolide B) from the fermented strain Cladosporium tenuissimum LR 463 of
Maytenus hookeri. As part of our interest in the synthesis of bioactive natural products
[2], here we report the synthesis of 1 (Fig.) by a convergent strategy. Structurally, this
natural product bears close resemblance to cladospolides [3]. Our strategy involves the
esterification of the respective acid component and alcohol moiety under Yamaguchi
conditions, followed by the Grubbsꢀ catalyst-mediated ring-closing metathesis (RCM)
to afford the cyclic ester. The cyclic ester was transformed to the target macrolide.
Figure. Proposed structure of the natural product (6R,12S)-6-hydroxy-12-methyl-1-
oxacyclododecane-2,5-dione
Interesting structural features coupled with the biological activity of the isolated
natural product has attracted us to embark on its first total synthesis. Here, we report
our synthetic efforts en route to 1 achieved through the respective key intermediates 2
and 3 (Scheme 1).
ꢁ 2012 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Scheme 1. Retrosynthetic Scheme
As depicted in Scheme 2, the synthesis of fragment 2 was initiated with the
preparation of 9 [4] from d-mannitol. Then, the corresponding primary alcohol was
generated by hydroboration of 9 with cyclohexene, BH3 · Me2S, THFat 08 in 87% yield,
followed by its conversion into para-methoxybenzyl (PMB)-ether with PMB-Br and
NaH in THF at 08 to afford 10 in 85% yield. Diol 11 was formed from 10 by the
deprotection of the acetal group with 60% aqueous AcOH at room temperature in 70%
yield. The primary OH group of the diol 11 was protected with Ts group (TsCl/Et3N/
CH2Cl2/08/room temperature, 72%), leading to oxirane 12 (69%) upon treatment with
K2CO3 in MeOH.
Scheme 2. Synthesis of Fragment 2
a) See [4]. b) 1. BH3 · Me2S, cyclohexene/THF, 08 to r.t., 3 h; 2. NaOH, 30% H2O2, 2 h; 87%; 3. PMB-Br
(¼ para-methoxybenzyl bromide), NaH, THF, 08, 6 h; 85%. c) 60% AcOH, r.t., 12 h; 70%. d) 1. Et3N,
TsCl, CH2Cl2, 08 to r.t., 4 h; 72%; 2. K2CO3/MeOH, r.t., 1 h; 69%. e) CuI, VinylMgBr, THF, ꢀ 208, 1 h;
87%. f) 1. (tBu)Ph2SiCl (TBDPS-Cl), 1H-imidazole, CH2Cl2, 08 to r.t., 12 h, 92%; 2. 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ), CH2Cl2/H2O, 19 :1; 87%. g) 1. (COCl)2/DMSO, Et3N, CH2Cl2,
t
ꢀ 788, 1 h; 89%; 2. NaClO2, NaH2PO4 · 2 H2O, BuOH, 2-methylbut-2-ene, 08 to r.t., 2 h; 79%.

Helvetica Chimica Acta – Vol. 95 (2012)
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Ring-opening reaction of oxirane 12 with vinylmagnesium bromide [5] in the
presence of CuI in THF at ꢀ 208 gave homoallylic alcohol 13 (87%). Silyl protection of
13 ((tBu)Ph2SiCl (TBDPS-Cl)/1H-imidazole/CH2Cl2; 92%), followed by the removal
of the PMB group under conventional conditions (DDQ in CH2Cl2/H2O, 19 :1)
furnished 14 in 87% yield. Oxidation of the latter to the corresponding aldehyde (89%)
under Swern conditions, followed by a second oxidation [6] with NaClO2, NaH2PO4 ·
2 H2O in t-BuOH and 2-methylbut-2-ene gave the acid 2 (79%). As outlined in
Scheme 3, the coupling of the two fragments 2 and (2S)-hex-5-en-2-ol (3; commercially
available) via Yamaguchi esterification [7] (Et3N/2,4,6-trichlorobenzoyl chloride/
DMAP/THF/08) gave 4 (69%). Subsequently, the Grubbsꢀ catalyst [8] mediated
RCM (G-II/CH2Cl2/reflux) of compound 4 afforded the cyclic ester 5 (80%) as (E)/
(Z)-mixture in a ratio of 34 :66. However, no efforts were made to separate the
geometrical isomers, since the presence of the mixture bears little relevance in the later
part of the synthesis.
Scheme 3. Synthesis of the Target Compound 1
a) 1. 2,4,6-Trichlorobenzoyl chloride, Et3N, THF, 08 to r.t., 4 h; 2. 4-(dimethylamino)pyridine (DMAP),
toluene, 08 to r.t., 2 h; 69%. b) Grubbs-II, CH2Cl2, reflux, 5 h; 80%. c) H2, Pd/C, MeOH, r.t., 12 h; 84%.
d) DessꢀMartin periodinane, CH2Cl2, 08 to r.t., 2 h; 89%. e) HF-pyridine/THF, r.t., 12 h; 86%.
Hence, removal of the Bn group as well as the hydrogenation of the C¼C bond
(10% Pd-C/H2/r.t.) was carried out in one-pot to produce 6 (84%). Hydroxy compound
6 was then oxidized using DessꢀMartin periodinane [9] at 08 to give 7 (89%), and
subsequent removal of the TBDPS group by HF-pyridine in THFafforded compound 1
(86%; white solid, m.p. 119 – 1218; [a]1D9 ¼ þ37.2 (c ¼ 0.3, MeOH; [1]: [a]D19 ¼ ꢀ39.5
(c ¼ 0.57, MeOH)). However, the spectroscopic data of 1 (1H- and 13C-NMR) differed
from the reported data of the natural product, and, in addition, the optical rotation
value ([a]1D9 ) of the synthetic sample 1 shows the opposite sign of rotation than the
reported value. Therefore, the structure of macrolide 1 was erroneously assigned and
hence a structural revision is needed for the natural product.
In summary, the stereoselective total synthesis of the twelve-membered macrolide
natural product was attempted by a convergent strategy wherein oxirane ring-opening
reaction, Yamaguchi esterification, and ring-closing metathesis were the key steps. The

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mismatched spectroscopic data revealed that the structure was erroneously assigned,
and hence structural revision was necessary.
Experimental Part
General. Reactions were carried out under N2 in anh. solvents such as CH2Cl2 and THF. All reactions
were monitored by TLC (silica-coated plates; visualizing with a-napthol charring). Org. solns. were dried
(Na2SO4) and concentrated below 408 under reduced pressure in a Bꢀchi rotary evaporator. All column
chromatographic (CC) separations were performed using silica gel (SiO2; Acmeꢀs, 60 – 120 mesh) with
AcOEt and hexane as eluents. TLC was performed on Merck 60 F254 silica gel plates. Yields refer to
chromatographically and spectroscopically (1H- and 13C-NMR) homogeneous material. Air-sensitive
reagents were transferred by syringe and double-ended needle. Optical rotations: JASCO P-1020
instrument; [a]D values in units of 10ꢀ1 deg cm2 gꢀ1 at 258. IR Spectra: Perkin-Elmer IR-683
spectrophotometer with NaCl optics. 1H- and 13C-NMR: Varian Gemini 200 MHz, Bruker Avance-
300 MHz, Unity 400 MHz, and Inova 500 MHz for 1H, and Varian Gemini FT-200 MHz and Bruker
Avance 300 MHz spectrometers for 13C at 50 MHz and 75 MHz, resp., with 7 – 10 mm solns. in CDCl3,
TMS as internal standard; J values are given in Hz. MS: Finnigan Mat 1210 double focusing mass
spectrometer operating at a direct inlet system; ESI-MS was recorded with ion-trap mass spectrometer.
4-O-Benzyl-5,6-O-(cyclohexane-1,1-diyl)-2,3-dideoxy-1-O-(4-methoxybenzyl)-d-erythro-hexitol
(10). To a stirred soln. of cyclohexene (2.65 g, 32.5 mmol) in dry THF (20 ml), BH3 · Me2S (1.45 ml,
16.2 mmol) was added at 08, and the mixture was stirred for 2 h to form a white solid. Then, compound 9
(1.64 g, 5.4 mmol) in dry THF (10 ml) was added at 08, and then the mixture was stirred for 3 h.
Afterwards, MeOH (1.2 ml, 27.08 mmol) was added to the mixture, followed by the addition of 2n NaOH
(16.7 ml), 30% H2O2 (4.9 ml), and then stirred for 2 h. The mixture was diluted with AcOEt (50 ml). The
org. layer was washed with H2O (2 ꢁ 20 ml) and brine (20 ml). The combined org. layers were dried
(Na2SO4), evaporated in vacuo, and purified by CC (SiO2, 60 – 120 mesh; 22% AcOEt/hexane) to afford
a yellow oil (1.51 g, 87%).
This yellow oil (1.48 g, 4.6 mmol) in dry THF (10 ml) was added to a suspension of NaH (0.28 g,
6.9 mmol) in THF (3 ml) under N2 at 08, and the mixture was stirred for 30 min. To this, a soln. of PMB-
Br (1.10 g, 5.54 mmol) in dry THF (5 ml) was added, and the mixture was stirred for 6 h at r.t. The
reaction was quenched with sat. aq. NH4Cl soln. (5 ml), and the mixture was extracted with AcOEt (2 ꢁ
30 ml). The org. layer was washed with H2O (2 ꢁ 30 ml) and brine (30 ml). The combined org. layers
were dried (Na2SO4), evaporated in vacuo, and purified by CC (SiO2, 60 – 120 mesh; 10% AcOEt/
hexane) to afford 10 (1.73 g, 85%). Yellow oil. [a]2D5 ¼ þ15.8 (c ¼ 1.5, CHCl3). IR (neat): 3049, 2988,
1634, 1282, 1114, 1062, 739, 702. 1H-NMR (300 MHz, CDCl3): 7.29 – 7.26 (m, 7 arom. H); 6.78 (d, J ¼ 8.3, 2
arom. H); 4.56 (AB, J ¼ 11.7, 2 H); 4.37 (br. s, 2 H); 4.00 (quint., J ¼ 6.0, CH2O); 3.82 (t, J ¼ 6.7, CHꢀO);
3.76 (s, MeO); 3.52 – 3.47 (m, CHꢀO); 3.42 – 3.30 (m, 2 CHꢀO); 1.73 – 1.55 (m, 6 CH2); 1.38 (s, CH2).
13C-NMR (75 MHz, CDCl3): 159.1; 138.5; 130.5; 129.1; 128.2; 127.7; 127.4; 113.6; 109.4; 78.7; 77.4; 72.7;
72.3; 69.8; 65.8; 55.1; 36.1; 34.8; 27.8; 25.2; 25.1; 23.9; 23.7. ESI-MS: 463 ([M þ Na]þ). HR-MS: 463.2475
([M þ Na]þ, C27H36NaOþ5 ; calc. 463.2460).
(2R,3S)-3-(Benzyloxy)-6-[(4-methoxybenzyl)oxy]hexane-1,2-diol (¼4-O-Benzyl-2,3-dideoxy-1-O-
(4-methoxybenzyl)-d-erythro-hexitol; 11). To 10 (1.70 g, 3.8 mmol), 60% aq. AcOH (15 ml) was added
at r.t., and the mixture was stirred for 12 h. After completion of reaction, the reaction was quenched with
solid NaHCO3, and the mixture was extracted with AcOEt (3 ꢁ 50 ml). The solvent was evaporated in
vacuo and purified by CC (SiO2, 60 – 120 mesh; 40% AcOEt/hexane) to afford 11 (0.96 g, 70%).
Colorless liquid. [a]2D5 ¼ þ27.8 (c ¼ 0.9, CHCl3). IR (neat): 3446, 2924, 1611, 1245, 1174, 1064, 741, 699.
1H-NMR (200 MHz, CDCl3): 7.32 – 7.14 (m, 7 arom. H); 6.77 (d, J ¼ 8.8, 2 arom. H); 4.48 (br. s, 2 H); 4.34
(br. s, 2 H); 3.74 (s, MeO); 3.66 – 3.51 (m, 3 CHꢀO); 3.51 – 3.34 (m, 3 CHꢀO); 3.15 (br. s, OH); 1.74 – 1.55
(m, 2 CH2). 13C-NMR (75 MHz, CDCl3): 159.1; 138.1; 130.2; 129.2; 128.3; 127.7; 113.6; 80.3; 72.5; 72.3;
69.8; 63.4; 55.1; 26.6; 25.1. ESI-MS: 383 ([M þ Na]þ). HR-MS: 383.1816 ([M þ Na]þ, C21H28NaO5þ ; calc.
383.1834).
5,6-Anhydro-4-O-benzyl-2,3-dideoxy-1-O-(4-methoxyphenyl)-d-erythro-hexitol (12). To a stirred
soln. of 11 (0.93 g, 2.58 mmol) in CH2Cl2 (20 ml), Et3N (0.72 ml, 5.18 mmol) was added at 08, and the

Helvetica Chimica Acta – Vol. 95 (2012)
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mixture was stirred for 0.5 h. Then, TsCl (0.49 g, 2.16 mmol) was added, and the soln. was stirred for 4 h
at r.t. Then, the mixture was diluted with CH2Cl2 (20 ml), and washed with H2O (20 ml) and brine
(20 ml). The combined org. layers were dried (Na2SO4), evaporated in vacuo, and purified by CC (SiO2,
60 – 120 mesh; 20% AcOEt/hexane) to afford a pale yellow oil (0.96 g, 72%). Then, the yellow oil (0.93 g,
1.81 mmol) was dissolved in MeOH (10 ml), and K2CO3 (0.48 g, 0.32 mmol) was added at r.t., and the
mixture was stirred for 1 h. After consumption of all the starting material, the reaction was quenched
with NH4Cl soln. (3 ml), MeOH was evaporated under reduced pressure, the residue was extracted with
AcOEt (4 ꢁ 3 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 (SiO2, 60 – 120 mesh; 18% AcOEt/hexane) to afford
12 (0.43 g, 69%). Colorless liquid. [a]2D5 ¼ ꢀ17.3 (c ¼ 0.8, CHCl3). IR (neat): 3049, 2955, 1618, 1250, 1104,
1062, 741, 701. 1H-NMR (200 MHz, CDCl3): 7.26 – 7.16 (m, 7 arom. H); 6.82 (d, J ¼ 8.4, 2 arom. H); 4.62
(AB, J ¼ 11.7, 1 H of OꢀCH2ꢀPh); 4.42 (AB, J ¼ 11.7, 1 H of OꢀCH2ꢀPh); 4.37 (br. s, 2 H); 3.78 (s, MeO);
3.39 (t, J ¼ 5.1, 2 CHꢀO); 3.28 – 3.23 (m, CHꢀO); 2.88 – 2.83 (m, 1 H, epoxy); 2.73 – 2.63 (m, 2 H, epoxy);
1.84 – 1.56 (m, 2 CH2). 13C-NMR (75 MHz, CDCl3): 159.0; 138.4; 130.5; 129.1; 128.2; 127.6; 113.6; 77.6;
72.4; 72.2; 69.7; 55.2; 53.4; 45.4; 29.4; 25.4. ESI-MS: 365 ([M þ Na]þ). HR-MS: 365.1742 ([M þ Na]þ,
C21H26NaOþ4 ; calc. 365.1729).
(4R,5S)-5-(Benzyloxy)-8-[(4-methoxybenzyl)oxy]oct-1-en-4-ol (13). To a stirred soln. of 12 (0.4 g,
1.18 mmol) in dry THF (5 ml), CuI (0.2 g, 1.18 mmol) was added, and the mixture was stirred for 10 min.
A 1m soln. of vinylmagnesium bromide (1.77 ml, 1.77 mmol) was added at ꢀ 208, and the mixture was
stirred for 1 h. The reaction was quenched with sat. aq. NH4Cl, the mixture was extracted with AcOEt,
and the org. layer was washed with H2O (5 ml), followed by brine (5 ml). The combined org. layers were
dried (Na2SO4), concentrated in vacuo, and purified by CC (SiO2, 60 – 120 mesh; 20% AcOEt/hexane)
to afford 13 (0.38 g, 87%). Colorless liquid. [a]2D5 ¼ þ1.4 (c ¼ 0.2, CHCl3). IR (neat): 3450, 3051, 2934,
1
1627, 1584, 1263, 1106, 1053, 740, 698. H-NMR (200 MHz, CDCl3): 7.35 – 7.17 (m, 7 arom. H); 6.79 (d,
J ¼ 8.4, 2 arom. H); 5.92 – 5.71 (m, CH2¼CH); 5.16 – 5.05 (m, CH2¼CH); 4.53 (br. s, 2 H); 4.38 (br. s,
2 H); 3.78 (s, MeO); 3.73 (t, J ¼ 4.4, CHꢀO); 3.42 – 3.38 (m, 3 CHꢀO); 2.23 (t, J ¼ 7.7, CH2¼CHꢀCH2);
1.97 (br. s, OH); 1.81 – 1.57 (m, 2 CH2). 13C-NMR (75 MHz, CDCl3): 159.0; 138.3; 134.9; 130.5; 129.2;
128.3; 127.8; 127.6; 117.6; 113.7; 81.3; 72.5; 72.0; 71.1; 69.9; 55.2; 36.9; 25.6; 25.5. ESI-MS: 393 ([M þ
Na]þ). HR-MS: 393.2036 ([M þ Na]þ, C23H30NaOþ4 ; calc. 393.2042).
(4S,5R)-4-(Benzyloxy)-5-{[(tert-butyl)(diphenyl)silyl]oxy}oct-7-en-1-ol (14). To a stirred soln. of 13
(0.35 g, 0.94 mmol) in CH2Cl2 (3.5 ml), 1H-imidazole (0.19 g, 2.82 mmol) was added at 08, and the
mixture was stirred for 0.5 h, then TBDPS-Cl (0.29 ml, 1.12 mmol) was added, and the mixture was
stirred for 12 h at r.t. The mixture was diluted with CH2Cl2 (4 ml), and the org. layer was washed with
H2O (10 ml), followed by brine (10 ml). The combined org. layers were dried (Na2SO4), evaporated in
vacuo, and purified by CC (SiO2, 60 – 120 mesh; 5% AcOEt/hexane) to afford a colorless liquid (0.53 g,
92%). This liquid was dissolved (0.5 g, 0.82 mmol) in a CH2Cl2/H2O 19 :1 (5 ml), DDQ (0.22 g,
0.98 mmol) was added at 08, and the soln. was stirred for 20 min at r.t. The reaction was quenched with
sat. NaHCO3 soln. (5 ml), and the mixture was extracted with CH2Cl2 (3 ꢁ 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 (SiO2, 60 – 120 mesh; 12% AcOEt/hexane) to afford 14 (0.35 g, 87%). Colorless liquid.
1
[a]2D5 ¼ ꢀ11.8 (c ¼ 0.3, CHCl3). IR (neat): 3448, 2951, 2857, 1618, 1595, 1216, 1104, 1064, 699. H-NMR
(200 MHz, CDCl3): 7.72 – 7.62 (m, 4 arom. H); 7.39 – 7.16 (m, 11 arom. H); 5.68 – 5.47 (m, CH2¼CH);
4.96 – 4.80 (m, CH2¼CH); 4.47 (AB, J ¼ 11.7, 1 H of OꢀCH2ꢀPh); 4.27 (AB, J ¼ 11.3, 1 H of OꢀCH2ꢀPh);
3.93 – 3.86 (m, CHꢀO); 3.47 (t, J ¼ 5.8, CH2O); 3.29 (d, J ¼ 5.5, CHꢀO); 2.22 (t, J ¼ 6.6, CH2¼CHꢀCH2);
1.70 – 1.42 (m, 2 CH2); 1.06 (br. s, 3 Me). 13C-NMR (75 MHz, CDCl3): 138.9; 136.1; 136.0; 135.9; 134.7;
134.3; 133.7; 129.5; 129.1; 128.1; 127.7; 127.4; 127.1; 117.0; 81.5; 74.0; 71.8; 62.8; 38.1; 29.6; 29.2; 27.1; 26.8;
26.1; 19.3. ESI-MS: 511 ([M þ Na]þ). HR-MS: 511.2623 ([M þ Na]þ, C31H40NaO3Siþ; calc. 511.2644).
(4S,5R)-4-(Benzyloxy)-5-{[(tert-butyl)(diphenyl)silyl]oxy}oct-7-enoic Acid (2). To a stirred soln. of
oxalyl chloride (0.09 ml, 0.97 mmol) in dry CH2Cl2 (2 ml), DMSO (0.14 ml, 1.95 mmol) was added at
ꢀ 788, and the mixture was stirred for 30 min at same temp., followed by the addition of 14 (0.32 g,
0.65 mmol) in CH2Cl2 (1.5 ml), and the mixture was stirred for 1 h at ꢀ 788. The reaction was quenched
with Et3N (0.42 ml, 3.9 mmol) at ꢀ 788, and the soln. was stirred for further 15 min. The mixture was
extracted with CH2Cl2 (2 ꢁ 20 ml), and washed with H2O (5 ml) and brine (5 ml). The combined org.

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layers were dried (Na2SO4) and concentrated in vacuo to give the intermediate aldehyde (0.25 g, 89%) as
a pale-yellow syrup, which was used for the next reaction.
The aldehyde (0.25 g, 0.51 mmol) was dissolved in t-BuOH/2-methylbut-2-ene 2 :1 (2.5 ml). To this
soln., NaClO2 (0.09 g, 1.03 mmol) and NaH2PO4 · 2 H2O (0.16 g, 1.03 mmol), dissolved in minimum
amount of H2O, were added at 08, and the mixture stirred for 2 h at r.t. The solvent was removed under
reduced pressure, and extracted with AcOEt (2 ꢁ 3 ml), washed with H2O (5 ml) and brine (5 ml). The
combined org. layers were dried (Na2SO4), concentrated in vacuo, and purified by CC (SiO2, 60 – 120
mesh; 18% AcOEt/hexane) to afford 2 (0.2 g, 79%). Yellow oil. [a]2D5 ¼ ꢀ18.1 (c ¼ 0.3, CHCl3). IR
(neat): 3445, 2926, 2855, 1709, 1109, 702. 1H-NMR (400 MHz, CDCl3): 7.68 – 7.63 (m, 4 arom. H); 7.40 –
7.16 (m, 11 arom. H); 5.57 – 5.47 (m, CH2¼CH); 4.93 – 4.80 (m, CH2¼CH); 4.46 (AB, J ¼ 11.7, 1 H of
OꢀCH2ꢀPh); 4.23 (AB, J ¼ 11.7, 1 H of OꢀCH2ꢀPh); 3.89 (t, J ¼ 6.2, CHꢀO); 3.34 (d, J ¼ 9.2, CHꢀO);
2.41 – 2.26 (m, 2 CHꢀO); 2.20 (t, J ¼ 6.9, CH2¼CHꢀCH2); 2.02 – 1.93 (m, 1 H of CH2); 1.88 – 1.80 (m, 1 H
of CH2); 1.05 (br. s, 3 Me). 13C-NMR (75 MHz, CDCl3): 178.9; 146.9; 138.4; 136.1; 134.4; 133.5; 129.6;
128.2; 127.5; 117.3; 80.4; 73.5; 71.6; 38.2; 29.7; 27.0; 24.3; 19.3. ESI-MS: 525 ([M þ Na]þ). HR-MS:
525.2434 ([M þ Na]þ, C31H38NaO4Siþ; calc. 525.2437).
(2S)-Hex-5-en-2-yl (4S,5R)-4-(Benzyloxy)-5-{[(tert-butyl)(diphenyl)silyl]oxy}oct-7-enoate (4). To a
soln. of 2 (0.18 g, 0.36 mmol) and Et3N (0.15 ml, 1.07 mmol) in dry THF (2 ml), 2,4,6-trichlorobenzoyl
chloride (0.11 ml, 0.72 mmol) was added dropwise at 08, and then the mixture was stirred at r.t. for 4 h.
The solvent was evaporated, and the residue was diluted in toluene (2 ml), treated with DMAP (0.11 g,
0.89 mmol) and 3 (0.042 g, 0.42 mmol). After 2 h, toluene was evaporated in vacuo, and the residue was
purified by CC (SiO2, 60 – 120 mesh; 0.5% AcOEt/hexane) to afford 4 (0.17 g, 69%). Colorless liquid.
1
[a]2D5 ¼ ꢀ13.2 (c ¼ 0.4, CHCl3). IR (neat): 2945, 2875, 1723, 1108, 1062. H-NMR (400 MHz, CDCl3):
7.68 – 7.63 (m, 4 arom. H); 7.40 – 7.18 (m, 11 arom. H); 5.81 – 5.68 (m, CH2¼CH); 5.58 – 5.46 (m,
CH2¼CH); 5.05 – 4.89 (m, CH2¼CH); 4.88 – 4.79 (m, CH2¼CH, CHꢀOCO); 4.44 (AB, J ¼ 11.6, 1 H of
OꢀCH2ꢀPh); 4.24 (AB, J ¼ 11.6, 1 H of OꢀCH2ꢀPh); 3.88 (t, J ¼ 5.2, CHꢀO); 3.33 (d, J ¼ 5.6, CHꢀO);
2.39 – 2.13 (m, CH2ꢀCOOH, CH2¼CHꢀCH2); 2.10 – 1.91 (m, CH2¼CHꢀCH2); 1.90 – 1.78 (m, 1 H of
CH2); 1.70 – 1.60 (m, 1 H of CH2); 1.56 – 1.47 (m, 1 H of CH2); 1.39 – 1.32 (m, 1 H of CH2); 1.14 (d, J ¼ 6.0,
Me); 1.06 (br. s, 3 Me). 13C-NMR (75 MHz, CDCl3): 173.4; 138.7; 137.8; 136.0; 135.8; 135.4; 134.5; 129.6;
128.2; 127.5; 117.2; 114.9; 80.6; 73.8; 71.7; 70.1; 38.2; 35.0; 30.9; 29.6; 27.0; 24.9; 19.9; 19.3. ESI-MS: 607
([M þ Na]þ). HR-MS: 607.3247 ([M þ Na]þ, C37H48NaO4Siþ; calc. 607.3220).
(5S,6R,12S)-5-(Benzyloxy)-6-{[(tert-butyl)(diphenyl)silyl]oxy}-12-methyl-1-oxacyclododec-8-en-2-
one (5). To a soln. of 4 (0.15 g, 0.25 mmol) in CH2Cl2 (150 ml), Grubbsꢀ second-generation catalyst
(0.03 g, 0.04 mmol, 10 mol-%) was added, and the mixture was stirred at reflux for 5 h under N2. The
solvent was evaporated in vacuo, and the residue was purified by CC (SiO2, 60 – 120 mesh; 0.6% AcOEt/
hexane) to afford 5 (0.12 g, 80%). Thick syrup. IR (neat): 2940, 2884, 1718, 1116, 1040. 1H-NMR
(400 MHz, CDCl3): 7.68 – 7.60 (m, 4 arom. H); 7.38 – 7.19 (m, 11 arom. H); 5.39 (t, J ¼ 14.6, 0.34 olef. H);
5.17 (t, J ¼ 10.5, 0.66 olef. H); 4.91 – 4.82 (m, 0.66 olef. H); 4.81 – 4.70 (m, 0.34 olef. H); 4.63 – 4.54 (m,
CHꢀOCO); 4.32 – 4.18 (m, 2 H); 4.01 – 3.94 (m, CHꢀO); 3.06 – 3.01 (m, CHꢀO); 2.61 – 2.48 (m, CH2);
2.47 – 2.38 (m, 1 allylic H); 2.30 – 2.13 (m, 1 allylic H); 2.12 – 1.99 (m, 2 allylic H); 1.98 – 1.80 (m, 1 H of
CH2); 1.79 – 1.69 (m, CH2); 1.67 – 1.55 (m, 1 H of CH2); 1.24 (d, J ¼ 5.6, 1.98 H of Me); 1.20 (d, J ¼ 6.0,
1.02 H of Me); 1.06 (br. s, 3 Me). ESI-MS: 579 ([M þ Na]þ). HR-MS: 579.2896 ([M þ Na]þ,
C35H44NaO4Siþ; calc. 579.2901).
(5S,6R,12S)-6-{[(tert-Butyl)(diphenyl)silyl]oxy}-5-hydroxy-12-methyl-1-oxacyclo-dodecan-2-one
(6). To a stirred soln. of 5 (0.11 g, 0.19 mmol) in MeOH (1 ml) 10% Pd/C (cat.) was added under H2 for
12 h. The mixture was filtered through a pad of Celite, washed with MeOH (3 ml), concentrated in vacuo,
and purified by CC (SiO2, 60 – 120 mesh, 3% AcOEt/hexane) to afford 6 (0.075 g, 84%). Colorless liquid.
1
[a]2D5 ¼ ꢀ11.9 (c ¼ 0.1, CHCl3). IR (neat): 3493, 2914, 1718, 1486, 1240. H-NMR (300 MHz, CDCl3):
7.68 – 7.65 (m, 4 arom. H); 7.40 – 7.30 (m, 6 arom. H); 4.97 – 4.94 (m, CHꢀOCO); 3.77 – 3.73 (m, CHꢀO);
3.52 (br. s, CHꢀO); 2.54 – 2.43 (m, CH2); 2.15 (t, J ¼ 14.7, 1 H of CH2); 1.63 – 1.43 (m, 2 CH2); 1.42 – 1.33
(m, CH2); 1.31 – 1.25 (m, 5 H of CH2); 1.19 (d, J ¼ 6.0, Me); 1.06 (br. s, 3 Me). 13C-NMR (75 MHz,
CDCl3): 172.4; 135.8; 129.6; 127.7; 79.7; 75.8; 69.5; 32.4; 31.9; 29.7; 27.0; 22.7; 21.1, 19.5; 18.9. ESI-MS: 491
([M þ Na]þ). HR-MS: 491.2603 ([M þ Na]þ, C28H40NaO4Siþ; calc. 491.2594).

Helvetica Chimica Acta – Vol. 95 (2012)
1629
(6R,12S)-6-{[(tert-Butyl)(diphenyl)silyl]oxy}-12-methyl-1-oxacyclododecane-2,5-dione (7). To a
stirred soln. of 6 (0.05 g, 0.11 mmol) in dry CH2Cl2 (2 ml), DessꢀMartin periodinane (0.05 g, 0.13 mmol)
was added at 08, and was the mixture was stirred for 2 h at r.t. The reaction was quenched with aq. soln. of
NaHCO3/Hypo 1:1 (1 ml), and the mixture was extracted with CH2Cl2 (2 ꢁ 5 ml), and washed with H2O
(5 ml) and brine (5 ml). The combined org. layers were dried (Na2SO4), concentrated in vacuo, and
purified by CC (SiO2, 60 – 120 mesh; 1% AcOEt/hexane) to afford 7 (0.043 g, 89%). White syrup. [a]D25
¼
þ46.3 (c ¼ 0.1, CHCl3). IR (neat): 2948, 1747, 1706, 1248. 1H-NMR (300 MHz, CDCl3): 7.60 (dd, J ¼ 17.9,
6.5, 4 arom. H); 7.44 – 7.41 (m, 2 arom. H); 7.38 (t, J ¼ 6.5, 4 arom. H); 4.93 – 4.81 (m, CHꢀOCO); 4.18 (t,
J ¼ 5.9, CHꢀO); 3.49 – 3.35 (m, CHꢀO); 2.65 (t, J ¼ 15.7, 1 H of CH2); 2.56 – 2.38 (m, CH2); 1.66 (q, J ¼
6.5, 1 H of CH2); 1.63 – 1.54 (m, CH2); 1.45 – 1.37 (m, 1 H of CH2); 1.32 – 1.23 (m, 3 CH2); 1.17 (d, J ¼ 6.5,
3 H CH2); 1.13 (br. s, 3 Me). 13C-NMR (50 MHz, CDCl3): 212.3; 171.1; 135.6; 129.9; 127.8; 78.9; 71.9;
33.6; 32.5; 32.0; 29.6; 28.7; 26.9; 20.0; 19.6. ESI-MS: 489 ([M þ Na]þ). HR-MS: 489.2430 ([M þ Na]þ,
C28H38NaO4Siþ; calc. 489.2437).
(6R,12S)-6-Hydroxy-12-methyl-1-oxacyclododecane-2,5-dione (1). To a stirred soln. of 7 (0.028 g,
0.06 mmol) in dry THF, HF-pyridine (0.28 ml, 0.28 mmol) was added, and the mixture was stirred for 12 h
at r.t. The reaction was quenched with CuSO4 soln. (10 ml), and the mixture was extracted with AcOEt
(2 ꢁ 5 ml), and washed with H2O (5 ml) and brine (5 ml). The combined org. layers were dried
(Na2SO4), concentrated in vacuo, and purified by CC (SiO2, 60 – 120 mesh; 6.5% AcOEt/hexane) to
afford 1 (0.012 g, 86%). White solid. M.p.: 119 – 1218. [a]2D5 ¼ þ37.2 (c ¼ 0.3, MeOH). IR (neat): 3452,
1
2919, 1718, 1702, 1470, 1256. H-NMR (500 MHz, (D6)acetone): 4.76 (sext., J ¼ 6.3, CHꢀOCO); 4.24 –
4.22 (m, CHꢀO); 3.13 – 3.06 (m, 1 H of CH2); 2.60 – 2.47 (m, CH2); 2.44 – 2.40 (m, 1 H of CH2); 1.84 –
1.79 (m, 1 H of CH2); 1.71 (quint., J ¼ 6.8, 1 H of CH2); 1.46 – 1.37 (m, CH2); 1.23 – 1.13 (m, 3 CH2);
1.03 (d, J ¼ 6.3, Me). 13C-NMR (75 MHz, (D6)acetone): 212.6; 171.5; 77.3; 71.9; 35.0; 33.7; 32.3; 30.1;
28.2; 21.7; 20.9; 20.1. ESI-MS: 251 ([M þ Na]þ). HR-MS: 251.1266 ([M þ Na]þ, C12H20NaOþ4 ; calc.
251.1259).
One of the authors (P. V. A. ) thanks the CSIR, New Delhi, for financial support in the form of a
fellowship.
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Received February 10, 2012