Stereoselective total synthesis of botryolide e and ophiocerin C

Article abstract of DOI:10.1002/hlca.201300203

A highly stereoselective approach to the total synthesis of the γ-lactone derivative botryolide E and tetrahydropyran derivative ophiocerin C via a common polyketide precursor by means of Prins cyclization and MacMillan α-aminoxylation sequence is described. The method can conveniently be utilized for the preparation of further related γ-lactone and tetrahydropyran derivatives. Copyright

Full text of DOI:10.1002/hlca.201300203

Helvetica Chimica Acta – Vol. 97 (2014)
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Stereoselective Total Synthesis of Botryolide E and Ophiocerin C
by Jhillu S. Yadav*, N. Mallikarjuna Reddy, Md. Ataur Rahman, A. Mallikarjuna Reddy, and
Attaluri R. Prasad
Centre for semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
(fax: 91-40-27160512; e-mail: yadavpub@iict.res.in)
A highly stereoselective approach to the total synthesis of the g-lactone derivative botryolide E and
tetrahydropyran derivative ophiocerin C via a common polyketide precursor by means of Prins
cyclization and MacMillan a-aminoxylation sequence is described. The method can conveniently be
utilized for the preparation of further related g-lactone and tetrahydropyran derivatives.
Introduction. – The natural products containing g-lactone moieties are known to
possess a variety of biological features [1], such as cytotoxic [2], antitumor [3], and
cyclooxygenase or phospholipase A2 inhibition activities [4]. These compounds are of
either bacterial or fungal origin. Botryolide E (1; Fig. 1), a g-lactone, has been isolated
from cultures of the fungicolous Botryotrichum sp. (NRRL 38180) by Gloer and co-
workers in 2008 [5], and it exhibited an antibacterial activity against Bacillus subtilis
(MTCC 441), Staphylococcus aureus (MTCC 96), and Escherichia coli (MTCC 443),
and an antifungal activity against Aspergillus niger (MTCC 1344) and Saccharomyces
cerevisiae (MTCC 171). The structure and relative configuration was established by a
NMR and ESI-MS analysis.
Another class of natural products, ophiocerins A – D (Fig. 2), which represent a
new type of tetrahydropyran derivatives, are isolated from cultures of the aquatic
fungus Ophioceras venezuelenser. The isolations, structures, absolute and relative
configurations of these compounds were reported by Reategui et al. in 2005 [6].
Fig. 1. Structures of botryolides A – E
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Fig. 2. Structures of ophiocerins A – D
Antagonistic effects among competing aquatic fungi have been reported from a
chemical standpoint [7]. The substituted tetrahydropyran moiety occurs in a wide
variety of natural products with diversified biological functions [8]. In continuation of
our efforts towards the synthesis of natural products, herein, we report a new total
synthesis of botryolide E (1) [9], and ophiocerin C (2) [10] via a common intermediate
3 using our recently developed methodology of Prins cyclization and MacMillan a-
aminoxylation sequence [11].
Results and Discussion. – The retrosynthetic analysis of botryolide E (1) and
ophiocerin C (2) is outlined in Scheme 1. It is envisaged that the target molecules 1 and
2 could be prepared from the common intermediate 3, which was proposed to be
formed by the MacMillan a-aminoxylation of 4. The tetrahydropyran core 5 could be
obtained via Prins cyclization between homoallylic alcohol 6 and acetaldehyde. We
envisioned that the polyhydroxy compound 3 would be a common chiral synthon for
accessing 1 and 2 via lactonization and SN2 cyclization, respectively.
The synthesis of botryolide E (1) was started with a Prins cyclization [12] between
the known homoallylic alcohol 6 and MeCHO. The (iodomethyl)-pyran 7 was obtained
from 6 in four steps [13]. Reductive opening of 7 gave alcohol 8 with the anti-1,3-diol
t
system. Protection of the secondary OH group in 8 as BuMe2Si (TBS) ether using
tBuMe2SiCl (TBSCl) and 1H-imidazole in CH2Cl2 furnished 9 in 94% yield. Ozonolytic
cleavage of olefinic bond of 9, followed by a-aminoxylation using nitrosobenzene and
l-proline in MeCN, followed by treatment with NaBH4 in MeOH, gave the crude a-
aminoxy alcohol, which on treatment with 30 mol-% CuSO4 · 5 H2O, furnished diol 3
[14] in 65% yield for two steps (Scheme 2).
Scheme 1. Retrosynthetic Analysis of Botryolide E and Ophiocerin C

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Scheme 2
a) Zn, EtOH, NaHCO3, reflux, 2 h; 92%. b) tBuMe2SiCl (TBSCl), 1H-imidazole, CH2Cl2, 08 – r.t., 4 h;
94%. c) O3, Ph3P, CH2Cl2, ꢀ 788. d) PhNO, l-Proline, MeCN, 3 h, ꢀ 208, then NaBH4, MeOH,
(AcO)2Cu, 12 h, r.t.; 65%.
Selective oxidation of diol 3 with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)
[15] and NaClO in CH2Cl2 provided a-hydroxy aldehyde 10, which was subjected to
(Z)-selective Wittig olefination [16], and subsequent lactonization using NaH and
(ArO)2P(O)CH2CO2Et in THF afforded g-butenolactone 11 in 82% yield. Depro-
tection of TBS ether with NH4F in MeOH furnished compound 12 in 79% yield, which,
on acetylation with Ac2O and pyridine in CH2Cl2, afforded compound 13 in 88% yield.
Finally, deprotection of the methoxymethyl (MOM) ether with Me3SiBr (TMSBr) in
CH2Cl2 gave botryolide E (1) in 73% yield [17] (Scheme 3). The spectroscopic and
analytical data for the synthetic compound are in accordance with those reported in the
literature [5][9].
After successful completion of the synthesis of botryolide E (1), we attempted the
synthesis of ophiocerin C (2) via the common intermediate 3 as depicted in Scheme 4.
Selective tosylation of diol 3 using TsCl, Et3N, and a catalytic amount of dibutyltin
oxide (Bu2SnO) in CH2Cl2 afforded compound 14 in 92% yield. Protection of the
secondary OH group in 14 as MOM ether using MOMCl and EtNiPr2 resulted in
Scheme 3
a) TEMPO (¼(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl), NaClO, KBr, CH2Cl2, 08, 3 h, 75%. b) NaH, (2-
iPr-C6H4O)2P(O)CH2CO2Et, THF, ꢀ 788 – r.t., 4 h; 82%. c) NH4F, MeOH, reflux, 12 h; 79%. d) Ac2O,
Py, CH2Cl2, 4 h; 88%. e) Me3SiBr (TMSBr), CH2Cl2, 3 h, ꢀ 408 – r.t.; 73%.

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Scheme 4
a) TsCl, Et3N, CH2Cl2, 0 8– r.t., 3 h; 92%. b) MeOCH2Cl (MOMCl), EtNiPr2, 4-(dimethylamino)pyridine
(DMAP), CH2Cl2, 08 – r.t., 3 h; 90%. c) Bu4NF, THF, 4 h. d) NaH, THF, 08 – r.t., 3 h; 72% for two steps.
e) TMSBr, CH2Cl2, 2 h, r.t.; 76%.
compound 15 in 90% yield. The Bu4NF-mediated desilylation, followed by SN2
cyclization [18] of 15 using NaH in THF, afforded the tetrahydropyran derivative 16 in
72% yield. Removal of the MOM groups with Me3SiBr in CH2Cl2 gave ophiocerin C (2)
in 76% yield. The spectroscopic and analytical data for the synthetic compound are in
accordance with those reported in the literature [6][10].
Conclusions. – In summary, we have described a new stereoselective approach to
botryolide E (1) and ophiocerin C (2) via a common intermediate 3. Prins cyclization,
MacMillan a-aminoxylation, (Z)-selective Wittig olefination, and lactonization were
the key steps in this synthesis.
N. M. R. and A. M. R. thank CSIR, New Delhi, for the award of a fellowship.
Experimental Part
General. All reagents were reagent-grade and used without further purification, unless specified
otherwise. Solvents for reactions were distilled prior to use: THF, toluene and Et2O were distilled from
Na and benzophenone ketyl; MeOH from Mg and I2; and CH2Cl2 from CaH2. All air- or moisture-
sensitive reactions were conducted under N2 or Ar in flame-dried or oven-dried glassware with magnetic
stirring. Column chromatography (CC): SiO2 (60 – 120 or 100 – 200 mesh) packed in glass columns.
Technical-grade AcOEt and petroleum ether used for CC were distilled prior to use. Optical rotation:
Jasco-DIP-360 digital polarimeter using a 1-ml cell with a 1-dm path length. FT-IR Spectra: PerkinElmer
FT-IR as KBr pellets in CHCl3, neat (as mentioned); ˜n in cmꢀ1. 1H- and 13C-NMR spectra: Varian Gemini
200, Bruker Avance 300 or Varian Innova 500 at 200, 300, or 500 MHz and r.t.; in CDCl3 or (D6)benzene;
d in ppm rel. to Me4Si as internal standard, J in Hz. ESI- and HR-ESI-MS: Finnigan MAT 1020B; in m/z.
(2R,4R)-4-(Methoxymethoxy)hept-6-en-2-ol (8). To a soln. of 7 [13] (2.5 g, 8.30 mmol) in EtOH
(60 ml), commercial Zn dust (10.83 g, 166.6 mmol) was added. The mixture was heated at 808 for 2 h and
then cooled to 258. Addition of solid NH4Cl (6.5 g) and Et2O (100 ml), followed by stirring for 5 min,
gave a gray suspension, which was filtered through a pad of Celite, and the filtrate was concentrated in
vacuo. Purification by CC gave 8 (1.33 g, 92%). Colorless liquid. Rf (AcOEt/hexane 3 :7) 0.6. [a]D27
ꢀ69.50 (c ¼ 1.30, CHCl3). IR (KBr): 3443, 3076, 2934, 1641, 1442, 1373, 1099, 1039. H-NMR (CDCl3,
300 MHz): 1.15 (d, J ¼ 6.6, 3 H); 1.49 – 1.55 (m, 2 H); 2.20 – 2.37 (m, 2 H); 2.55 (br., OH); 3.38 (s, 3 H);
3.73 – 3.88 (m, 1 H); 3.92 – 4.09 (m, 1 H); 4.57 – 4.67 (m, 2 H); 5.01 – 5.10 (m, 2 H); 5.64 – 5.85 (m, 1 H).
¼
1

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13C-NMR (CDCl3, 75 MHz): 23.3; 39.3; 42.8; 55.8; 64.0; 75.2; 96.2; 117.5; 134.2. ESI-MS: 175 ([M þ
H]þ), 192 ([M þ NH4]þ).
(4R,6R)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-4-(methoxymethoxy)hept-1-ene (9). To a soln. of 8
(1.28 g, 7.35 mmol) in dry CH2Cl2 (20 ml) were added 4-(dimethylamino)pyridine (DMAP; 20 mg), and
1H-imidazole (1.20 g, 17.64 mmol) in one portion, followed by tBuMe2SiCl (TBSCl; 1.32 g, 8.80 mmol) in
two portions at 08. The mixture was stirred for 4 h while slowly bringing it up to r.t. The reaction was
quenched with the sat. NH4Cl soln. (20 ml), and the mixture was extracted with CH2Cl2 (2 ꢁ 20 ml),
washed with brine (20 ml), dried (Na2SO4), and concentrated in vacuo. Purification of the crude by CC
(SiO2) afforded 9 (1.98 g, 94%). Colorless oil. Rf (AcOEt/hexane 1:9) 0.7. [a]2D7 ¼ ꢀ19.31 (c ¼ 4.32,
CHCl3). IR (KBr): 2932, 2892, 2858, 1466, 1374, 1253, 1148, 1097, 1043, 916, 833, 773. 1H-NMR (CDCl3,
300 MHz): 0.05 (s, 6 H); 0.88 (s, 9 H); 1.14 (d, J ¼ 6.0, 3 H); 1.48 – 1.54 (m, 2 H); 2.27 – 2.32 (m, 2 H); 3.34
(s, 3 H); 3.64 – 3.75 (m, 1 H); 3.88 – 4.01 (m, 1 H); 4.63 (s, 2 H); 5.02 – 5.07 (m, 2 H); 5.70 – 5.84 (m, 1 H).
13C-NMR (CDCl3, 75 MHz): ꢀ 4.7; ꢀ 3.9; 17.9; 24.4; 25.8; 39.7; 44.9; 55.4; 65.6; 75.1; 96.1; 117.0; 134.5.
ESI-MS: 289 ([M þ H]þ), 311 ([M þ Na]þ).
(2S,3S,5R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}-3-(methoxymethoxy)hexane-1,2-diol (3). O3 was
bubbled through a soln. of 9 (1.92 g, 6.6 mmol) in CH2Cl2 (20 ml) at ꢀ 788, until no starting material
was observed (TLC). The mixture was purged with N2 to remove the excess O3 and cooled to 08, and
Ph3P (3.49 g, 13.32 mmol) was added. The mixture was stirred for 2 h and then concentrated in vacuo.
After adding hexane, the mixture was filtered through Celite pad, and the residue washed with hexane.
The filtrate was dried (Na2SO4), concentrated under reduced pressure, and the crude aldehyde 4 was
used for the next reaction without further purification.
To a precooled (ꢀ208) MeCN (50 ml) soln. of crude 4 and nitrosobenzene (PhNO) (0.713 g,
6.6 mmol) was added l-proline (0.23 g, 2.0 mmol). The mixture was stirred at the same temp. for 12 h,
followed by the addition of MeOH (100 ml) and NaBH4 (0.453 g, 13.32 mmol) to the mixture, which was
stirred for 30 min, then CuSO4 · 5 H2O (1.28 g, 5.1 mmol) was added at 08. The mixture was allowed to stir
for 10 h at this temp. Then, MeOH was removed in vacuo, then H2O (50 ml) was added, the mixture was
extracted with CHCl3 (3 ꢁ 60 ml), and the combined org. phases were dried (Na2SO4) and concentrated
to give the crude diol, which was then purified by CC (SiO2) to give 3 (1.33 g, 65%). Colorless oil. Rf
(AcOEt/hexane 5 :5) 0.4. [a]2D7 ¼ ꢀ12.28 (c ¼ 1.75, CHCl3). IR (KBr): 3416, 2931, 2891, 2892, 2857, 1683,
1602, 1465, 1379, 1253, 1150, 1034, 834, 775. 1H-NMR (CDCl3, 300 MHz): 0.06 (s, 3 H); 0.08 (s, 3 H); 0.89
(s, 9 H); 1.18 (d, J ¼ 6.2, 3 H); 1.48 – 1.75 (m, 2 H); 2.32 (br., OH); 3.43 (s, 3 H); 3.53 – 3.75 (m, 4 H);
3.92 – 4.14 (m, 1 H); 4.63 – 4.76 (m, 2 H). 13C-NMR (CDCl3, 75 MHz): ꢀ 4.6; ꢀ 3.7; 17.9; 24.5; 25.8; 41.6;
55.8; 63.5; 65.3; 73.9; 79.6; 97.6. HR-ESI-MS: 309.2091 ([M þ H]þ), C14H33O5Siþ; calc. 309.2091).
(5S)-5-((2S,3R)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-(methoxymethoxy)butyl)furan-2(5H)-one
(11). To a soln. of 3 (0.43 g, 1.39 mmol) in CH2Cl2 (10 ml), cooled to 08 under N2, were added sat. aq.
NaHCO3 (10 ml), (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO; 21 mg, 0.134 mmol), and KBr
(182 mg, 2.45 mmol). The mixture was stirred at 08 for 10 min, and then 5% NaClO aq. (3.6 ml,
2.45 mmol) was added. After stirring for 20 min, the reaction was quenched with sat. aq. Na2S2O3, and the
mixture was extracted with AcOEt. The combined org. layer was washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo to give a crude product, which was purified by CC (SiO2) to afford
crude 10 (0.32 g 75%) as a colorless oil. The aldehyde 10, containing unidentified side-products, was used
in the next step without purification.
To a soln. of (2-iPr-C6H4O)2P(O)CH2COOEt (0.44 g, 1.08 mmol) in THF (10 ml) was added 60%
NaH (50 mg, 1.83 mmol) under N2. The reaction mixture was stirred at r.t. for 30 min, then cooled to
ꢀ 788. A soln. of 10 (0.32 g, 0.91 mmol) in THF (3 ml) was added to the mixture, which was stirred at r.t.
for 3 h, and then Et2O and H2O (10 ml) were added. The resulting mixture was extracted with Et2O, and
the combined org. layer was washed with brine, dried (NaSO4), filtered, and concentrated in vacuo to
give a crude product, which was purified by CC (SiO2) to afford (247 mg, 82%) of 11. Colorless oil. Rf
(AcOEt/hexane 3 :7) 0.65. [a]2D7 ¼ ꢀ64.6 (c ¼ 1.61, CHCl3). IR (KBr): 2955, 2930, 2856, 1758, 1156, 1038,
1
833, 775. H-NMR (CDCl3, 300 MHz): 0.05 (s, 3 H); 0.07 (s, 3 H); 0.88 (s, 9 H); 1.15 (d, J ¼ 6.0, 3 H);
1.36 – 1.57 (m, 2 H); 3.38 (m, 3 H); 3.91 – 4.08 (m, 1 H); 4.64 – 4.77 (m, 2 H); 5.20 – 5.26 (m, 1 H); 6.19
(dd, J ¼ 2.0, 5.6, 1 H); 7.51 (dd, J ¼ 1.5, 5.6, 1 H). 13C-NMR (CDCl3, 75 MHz): ꢀ 4.6; ꢀ 3.7; 24.5; 25.8;

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29.6; 40.5; 55.8; 64.9; 75.6; 84.5; 97.7; 122.7; 153.9; 174.7. HR-ESI-MS: 353.17547 ([M þ Na]þ,
C16H30NaO5Siþ; calc. 353.17547).
(5S)-5-[(1S,3R)-3-Hydroxy-1-(methoxymethoxy)butyl]furan-2(5H)-one (12). To a soln. of 11
(0.20 g, 0.6 mmol) in dry MeOH (10 ml) was added NH4F (224 mg, 6.0 mmol). The mixture was
refluxed for 12 h. After completion of the reaction, MeOH was removed in vacuo, H2O was added, and
the mixture was extracted with AcOEt (3 ꢁ 5 ml), dried (Na2SO4), and concentrated in vacuo.
Purification by CC afforded 12 (103 mg, 79%). Colorless oil. Rf (AcOEt/hexane 7:3) 0.4. [a]2D7 ¼ þ40.1
(c ¼ 0.66, CHCl3). IR (KBr): 3452, 2964, 1753, 1157, 1097, 1035. 1H-NMR (CDCl3, 300 MHz): 1.23 (d, J ¼
6.0, 3 H); 1.44 – 1.54 (m, 1 H); 1.59 – 1.70 (m, 1 H); 3.41 (s, 3 H); 3.95 – 4.09 (m, 2 H); 4.70 (m, 2 H);
5.09 – 5.15 (m, 1 H); 6.20 (dd, J ¼ 2.2, 6.0, 1 H); 7.47 (dd, J ¼ 1.5, 6.0, 1 H). 13C-NMR (CDCl3, 75 MHz):
23.5; 39.9; 56.1; 63.3; 75.5; 85.0; 97.9; 122.9; 153.2; 172.5. HR-ESI-MS: 239.08897 ([M þ Na]þ),
C10H16NaOþ5 ; calc. 239.08899).
(5S)-5-[(1S,3R)-3-(Acetyloxy)-1-(methoxymethoxy)butyl]furan-2(5H)-one (13). To a soln. of 12
(72 mg, 0.3 mmol) in dry CH2Cl2 (2 ml) at 08, Et3N (92 ml, 0.66 mmol) and DMAP (cat.) were added. The
mixture was stirred for 15 min, then Ac2O (40 ml, 0.4 mmol) was added slowly, and the mixture was
warmed to r.t. After stirring for 4 h, the mixture was diluted with CH2Cl2 (5 ml), and the reaction was
quenched by addition of H2O (3 ml). The org. layer was washed with brine (2 ꢁ 5 ml), dried (Na2SO4),
concentrated, and the residue was purified by CC to afford pure 13 (5.41g, 91%). Rf (AcOEt/hexane 6 :4)
0.6. [a]2D7 ¼ þ19.31 (c ¼ 4.32, CHCl3). IR (KBr): 2924, 2853, 1737, 1460, 1373, 1245, 1160, 1093, 1033.
1H-NMR (CDCl3, 300 MHz): 1.23 (d, J ¼ 6.79, 3 H); 1.44 – 1.55 (m, 1 H); 1.60 – 1.72 (m, 1 H); 3.36 (s,
3 H); 3.89 – 4.00 (m, 1 H); 4.97 – 5.06 (m, 1 H); 6.22 (dd, J ¼ 2.2, 1 H); 7.53 (dd, J ¼ 1.5, 6.0, 1 H).
13C-NMR (CDCl3, 75 MHz): 20.6; 29.6; 36.6; 56.2; 66.9; 74.4; 83.8; 97.9; 123.0; 153.5; 170.6; 172.5. HR-
ESI-MS: 281.0993 ([M þ Na]þ, C12H18NaO6þ ; calc. 281.0995).
(5S)-5-[(1S,3R)-3-(Acetyloxy)-1-Hydroxybutyl]furan-2-(5H)-one (1). Me3SiBr (TMSBr; 35 ml,
0.271 mmol) was added dropwise to a cold (ꢀ408) stirred soln. of 13 (35 mg, 0.135 mmol) in CH2Cl2
(3 ml). The mixture was stirred at ꢀ 408 for 1 h and at 08 for additional 2 h, poured into sat. aq. NaHCO3
soln., and extracted with CH2Cl2. The extract was dried (Na2SO4) and concentrated, and the residue was
subjected to CC to give 1 (21 mg, 73%). Colorless liquid. Rf (AcOEt/hexane 3 :7) 0.4. [a]2D7 ¼ ꢀ38.2 (c ¼
0.05, CHCl3). IR (KBr): 3446, 2926, 1738, 1374, 1248. 1H-NMR (CDCl3, 300 MHz): 1.27 (d, J ¼ 6.0, 3 H);
1.72 – 1.81 (m, 1 H); 1.85 – 1.94 (m, H); 2.03 (s, 3 H); 3.83 – 3.96 (m, 1 H); 5.0 – 5.17 (m, 1 H); 6.19 (dd,
J ¼ 2.2, 6.0, 1 H); 7.48 (dd, J ¼ 1.5, 6.0, 1 H). 13C-NMR (CDCl3, 75 MHz): 20.1; 21.3; 39.1; 68.6; 68.8;
85.42; 122.7; 153.76; 170.8; 172.7. HR-ESI-MS: 237.0734 ([M þ Na]þ, C10H14NaO5þ ; calc. 237.0733).
(2S,3S,5R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-hydroxy-3-(methoxymethoxy)hexyl 4-Methylben-
zenesulfonate (14). To a soln. of 3 (0.21 g, 0.68 mmol) in dry CH2Cl2 (5 ml), Et3N (284 ml, 2.03 mmol)
and Bu2SnO (cat.) were added. After 15 min. at 08 TsCl (0.194 g, 1.02 mmol) was added. The mixture was
allowed to warm to r.t. and stirred for 3 h. After completion of the reaction, H2O was added, and the
mixture was extracted with CH2Cl2 (3 ꢁ 10 ml). The org. layer was washed with sat. NaHCO3 (5 ml) and
H2O (5 ml). The combined org. phases were dried (Na2SO4) and concentrated under reduced pressure.
Flash CC of the crude afforded 14 (1.95 g, 95%). Gummy liquid. Rf (AcOEt/hexane 3 :7) 0.55. [a]D27
¼
ꢀ7.58 (c ¼ 1.45, CHCl3). IR (KBr): 3448, 2955, 2930, 2856, 1364, 1179, 1035, 833, 773. 1H-NMR (CDCl3,
300 MHz): 0.04 (s, 3 H); 0.06 (s, 3 H); 0.87 (s, 9 H); 1.15 (d, J ¼ 6.0, 3 H); 1.49 – 1.56 (m, 1 H); 1.58 – 1.68
(m, 1 H); 2.46 (m, 1 H); 3.33 (s, 3 H); 3.65 – 3.78 (m, 2 H); 3.88 – 4.04 (m, 2 H); 4.06 – 4.14 (m, 1 H);
4.58 – 4.65 (m, 2 H); 7.33 (d, J ¼ 8.3, 2 H); 7.79 (d, J ¼ 8.0, 2 H). 13C-NMR (CDCl3, 75 MHz): ꢀ 4.7;
ꢀ 3.9; 17.9; 21.6; 24.6; 25.8; 40.1; 55.6; 55.8; 65.2; 69.7; 75.5; 96.3; 96.7; 97.5; 120.9; 127.9; 129.7; 142.0;
114.7. HR-ESI-MS: 463.2186 ([M þ H]þ, C21H39O7SSiþ; calc. 463.2180).
(2S,3S,5R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}-2,3-bis(methoxymethoxy)hexyl 4-Methylbenzenesul-
fonate (15). To 14 (250 mg, 0.541 mmol) in anh. CH2Cl2 (6 ml) at 08 were added EtNiPr2 (564 ml,
3.24 mmol), DMAP (cat.), and MOMCl (121 ml, 1.61 mmol) successively, the resulting mixture was
stirred for 3 h at r.t., and then the reaction was quenched by adding H2O (10 ml), and the mixture was
extracted with CH2Cl2 (3 ꢁ 10 ml). The org. extracts were washed with brine (10 ml), dried (Na2SO4),
and concentrated under reduced pressure to remove the solvent, and the crude was purified by CC to
afford pure 15 (1.85 g, 90%). Colorless liquid. Rf (AcOEt/hexane 3 :7) 0.5. [a]2D7 ¼ ꢀ35.6 (c ¼ 0.65,
CHCl3). IR (KBr): 2970, 2926, 1357, 1178, 1092, 975. 1H-NMR (CDCl3, 300 MHz): 0.03 (s, 3 H); 0.05 (s,

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3 H); 0.86 (s, 9 H); 1.13 (d, J ¼ 6.0, 3 H); 1.28 – 1.34 (m, 1 H); 1.59 – 1.71 (m, 1 H); 2.46 (s, 3 H); 3.28 (s,
3 H); 3.32 (s, 3 H); 3.71 – 4.15 (m, 5 H); 4.50 – 4.64 (m, 4 H); 7.33 (d, J ¼ 8.3, 2 H), 7.78 (d, J ¼ 8.3, 2 H).
13C-NMR (CDCl3, 75 MHz): ꢀ 4.7; ꢀ 3.9; 17.9; 21.6; 24.6; 25.8; 40.1; 55.6; 55.8; 65.2; 69.7; 75.5; 96.3;
96.7; 97.5; 120.9; 127.9; 129.7; 142.0; 144.7.
(2R,4S,5S)-3,4,5,6-Tetrahydro-4,5-bis(methoxymethoxy)-2-methyltetrahydro-2H-pyran (16). To a
stirred soln. of 15 (190 mg, 0.375 mmol) in dry THF (5 ml) at 08, Bu4NF in THF (0.938 ml, 0.938 mmol)
was added, and then the mixture was stirred at r.t. for 4 h. After completion of the reaction, H2O was
added, and the mixture was extracted with AcOEt and concentrated to afford a crude alcohol. The crude
was further subjected to cyclization. To the alcohol in THF (2 ml) at 08 was added NaH (20 mg,
0.938 mmol), and the mixture was stirred for 2 h. H2O (2 ml) was added, and the mixture was extracted
with AcOEt, dried (Na2SO4), evaporated, and the residue was purified by CC to afford 16 (59 mg, 72%).
Colorless oil. Rf (AcOEt/hexane 3 :7) 0.4. [a]2D7 ¼ ꢀ33.8 (c ¼ 0.90, CHCl3). IR (KBr): 2926, 2854, 1710,
1605, 1164, 1035. 1H-NMR (CDCl3, 300 MHz): 1.20 (d, J ¼ 6.7, 3 H); 1.22 – 1.38 (m, 2 H); 2.02 – 2.12 (m,
1 H); 3.35 (s, 3 H); 3.39 (s, 3 H); 3.42 – 3.65 (s, 3 H); 4.01 – 4.13 (m, 2 H); 4.79 – 4.63 (m, 4 H). 13C-NMR
(CDCl3, 75 MHz): 21.2; 39.4; 55.2; 55.3; 68.8; 72.2; 76.6; 77.1; 95.8; 96.9. HR-ESI-MS: 243.1203 ([M þ
Na]þ, C10H20NaOþ5 ; calc. 243.1202).
(3S,4S,6R)-6-Methyltetrahydro-2H-pyran-3,4-diol (2). TMSBr (107 ml, 0.81 mmol) was added
dropwise to a cold (ꢀ408) stirred soln. of 16 (45 mg, 0.204 mmol) in CH2Cl2 (3 ml). The mixture was
stirred at ꢀ 408 for 0.5 h and at 08 for additional 4 h, poured into sat. aq. NaHCO3 soln., and extracted
with CH2Cl2. The extract was dried (Na2SO4), concentrated, and the residue was subjected to CC to
afford 2 (20 mg, 76%). White solid. Rf (60% AcOEt/hexane) 0.3. M.p. 81 – 838. [a]2D7 ¼ þ45.6 (c ¼ 0.1,
CH2Cl2). IR (KBr): 3413, 1460, 1380, 1262, 1136, 1080, 1006. 1H-NMR (CDCl3, 300 MHz): 1.20 (d, J ¼
6.0, 3 H); 1.90 – 1.98 (m, 2 H); 3.08 (m, 1 H); 3.38 – 3.56 (m, 3 H); 3.89 (dd, J ¼ 5.2, 11.3, 1 H). 13C-NMR
(CDCl3, 75 MHz): 21.1; 40.4; 69.5; 72.2; 72.6; 73.3. HR-ESI-MS: 155.0691 ([M þ Na]þ, C6H12NaO3þ ; calc.
155.0684).
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Received May 16, 2013