Asymmetric synthesis of simplactones A and B

Article abstract of DOI:10.1002/hlca.201100018

A new, simple, and short route for the synthesis of simplactones A (1) and B (2) was achieved from a synthetically prepared chiral auxiliary, i.e., the Oppolzer camphor-derived sultam 4, and (4-methoxybenzyl)-protected 3-hydroxypropanal, in 52 and 48% ove

Full text of DOI:10.1002/hlca.201100018

Helvetica Chimica Acta – Vol. 94 (2011)
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Asymmetric Synthesis of Simplactones A and B
by Peddikotla Prabhakar, Dasari Ramesh, Singanaboina Rajaram, Dorigondla Kumar Reddy,
and Yenamandra Venkateswarlu*
Natural Products Laboratory, Organic Chemistry Division – I, Indian Institute of Chemical Technology,
Hyderabad – 500007, India
(phone: þ 91-40-27193167; fax: þ 91-40-27160512; e-mail: luchem@iict.res.in)
A new, simple, and short route for the synthesis of simplactones A (1) and B (2) was achieved from a
synthetically prepared chiral auxiliary, i.e., the Oppolzer camphor-derived sultam 4, and (4-methoxy-
benzyl)-protected 3-hydroxypropanal, in 52 and 48% overall yield, respectively, and with high
diastereoselectivity (Schemes 2 and 3).
Introduction. – Simplactones are pharmacologically active marine secondary
metabolites isolated from the Caribbean sponge Plakortis simplex [1]. Simplactones
show in vitro cytotoxic activity against WEHI 164, murine fibrosarcoma cells.
Simplactone A (1) and simplactone B (2) were first isolated by Fattorusso and co-
workers in 1999 [1]. The configuration of the structures was revised by Ogasawara and
co-workers by the synthesis from enantiomerically pure 4-(cumyloxy)cyclopent-2-en-1-
one [2], and the structures were asymmetrically synthesized by OsorioꢀLozada and
Olivo through a double-diastereoselective acetate aldol reaction [3]. Recently, Kamal
and co-workers [4] and Rama Rao and co-workers [5] reported a synthesis of
simplactone A [4] and simplactone B [5], respectively. Structurally, this type of lactones
show very good cytotoxic activity against WEHI 164, and many biologically active
compounds like mevinolin, massiolactone [6], compactin, pironetin, phomalactone,
and asperlin [7] contained this type of lactone moiety.
The biological potential of these compounds has stimulated us to synthesize 1 and 2
with Oppolzerꢀs camphor-derived sultam, which can be simply prepared compared with
other chiral auxiliaries. The retrosynthetic analysis for the synthesis of 1 and 2 is shown
in Scheme 1 starting from (4-methoxybenzyl)-protected 3-hydroxypropanal and N-
butanoylbornane-10,2-sultam (3). In this Oppolzer aldol addition, the ꢁsynꢀ aldol
reaction is giving a higher diastereomer excess (94% de) when compared to the ꢁantiꢀ
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 1. Retrosynthetic Analysis
aldol reaction with a de of 86%. Hence, we followed this approach for the synthesis of
simplactones A and B.
Results and Discussion. – The stereoselective synthesis of simplactones A (1) and B
(2) was carried out as shown in Schemes 2 and 3. Thus, the (2S)-N-butanoylbornane-
10,2-sultam (3) [8] was subjected to asymmetric aldol reactions under two different
conditions. When the reaction was carried out with 3.0 equiv. of (4-methoxybenzyl)-
protected 3-hydroxypropanal, 3.0 equiv. of TiCl4, and 2.2 equiv of iPr2NEt, the resulting
major product was the ꢁantiꢀ product 4 [9] (de 86% by chiral HPLC; 84% yield)
(Scheme 2). However, when the reaction was carried out with 1.0 equiv. of (4-
methoxybenzyl)-protected 3-hydroxypropanal, 1.0 equiv. of TiCl4, and 1.2 equiv. of
iPr2NEt, the resulting major product was the ꢁsynꢀ product 10 [8 – 10] (de 94% by chiral
HPLC; 92% yield) (Scheme 3). Hence we are reporting the same route for the
synthesis of both simplactone isomers.
The ꢁantiꢀ aldol compound 4 was further treated with LiAlH4 [10] in dry Et2O at 08
for 4 h, to give ꢁantiꢀ diol 5 in 95% yield (Scheme 2), and in the same way, the ꢁsynꢀ diol
11 was obtained in 95% yield (Scheme 3). The two OH groups in both isomers 5 and 11
were protected with tBuMe2SiOTf in the presence of 2,6-lutidine [11] in dry CH2Cl2 to
give 6 and 12, respectively, in 95% yield. The (4-methoxybenzyl)-protecting group in 6
and 12 was removed with DDQ [12] to give 7 in 89% yield and 13 in 90% yield,
respectively, which were oxidized with iodobenzene diacetate [13] and TEMPO (cat.)
in dry CH2Cl2 to give 8 in 90% yield and 14 in 88% yield. The removal of the tBuMe2Si
groups in 8 and 14 was achieved by treatment with Bu4NF [14] in dry THF furnishing
lactols 9 and 15 in 90% yield. Finally, compounds 9 and 15 were oxidized with
iodobenzene diacetate and TEMPO (cat.) in dry CH2Cl2 at 08 to give the required
compounds 1 and 2 in good yield. The structures of 1 and 2 were established by their IR,
1H- and 13C-NMR, and mass spectra, and their optical rotations were identical with
those of the natural products reported by OsorioꢀLozada and Olivo [3].

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Scheme 2
i
a) (4-Methoxybenzyl)-protected 3-hydroxypropanal, TiCl4, Pr2NEt, dry CH2Cl2, 3 h; 84%. b) LiAlH4,
dry Et2O, 4 h; 95%. c) (tert-Butyl)dimethylsilyl trifluoromethanesulfonate (tBuMe2SiOTf ¼ TBSOTf),
2,6-lutidine (¼2,6-dimethylpyridine), dry CH2Cl2, 1 h; 95%. d) DDQ (4,5-dichloro-3,6-dioxocyclohexa-
1,4-diene-1,2-dicarbonitrile), CH2Cl2, H2O, 2 h; 89%. e) Iodobenzene diacetate, (¼ bis(acetato-
kO)phenyliodine), cat. 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO), dry CH2Cl2, 3 h; 90%. f)
Bu4NF, THF, 2 h; 90%. g) Iodobenzene diacetate, cat. TEMPO, dry CH2Cl2, 3 h; 89%.
In conclusion, we have achieved a simple, short, and efficient total synthesis of
simplactones A (1) and B (2) from (4-methoxybenzyl)-protected 3-hydroxypropanal
and (2S)-N-butanoylbornane-10,2-sultam (3) in an overall yield of 52 and 48%,
respectively. The advantage of this synthesis compared with the previous report [3] is
the use of only one chiral auxiliary for the ꢁantiꢀ and ꢁsynꢀ isomers, the difference in the
reaction conditions being the amount of TiCl4 and aldehyde with respect to the chiral
auxiliary 3. In the synthesis of simplactones A and B reported by OsorioꢀLozada and
Olivo [3], two different chiral auxiliaries were used in a first step, and a further chiral
auxiliary was present in a subsequent step.
The authors are thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi,
India, for the financial support, and to Dr. J. S. Yadav, Director, Indian Institute of Chemical Technology
(IICT), for his encouragement.
Experimental Part
General. Solvents were dried over standard drying agents and freshly distilled prior to use. The
reagents were purchased from Aldrich and Acros and were used without further purification unless
otherwise stated. All moisture-sensitive reactions were carried out under N2. Org. solns. were
concentrated in vacuo below 408. Column chromatography (CC): silica gel (Acmeꢀs 60 – 120 mesh).
Optical rotations: Horiba high sensitive polarimeter SEPA-300 at 258. IR Spectra: PerkinꢀElmer-IR-683

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 3
i
a) (4-Methoxybenzyl)-protected 3-hydroxypropanal, TiCl4, Pr2NEt, dry CH2Cl2, 3 h; 92%. b) LiAlH4,
t
dry Et2O, 4 h; 95%. c) BuMe2SiOTf, 2,6-lutidine, dry CH2Cl2, 1 h; 95%. d) DDQ, CH2Cl2, H2O, 2 h ;
90%. e) Iodobenzene diacetate, cat. TEMPO, dry CH2Cl2, 3 h; 88%. f) Bu4NF, THF, 2 h; 90%. g)
Iodobenzene diacetate, cat. TEMPO, dry CH2Cl2, 3 h; 88%.
spectrophotometer with NaCl optics; ˜n in cmꢀ1 1H- (300 MHz) and 13C-NMR (75 MHz) Spectra:
.
Bruker-Avance-300 instrument; in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. MS:
Agilent-Technologies-1100 instrument (Agilent Chemistation software); in m/z.
(2S)-N-Butanoylbornane-10,2-sultam (¼1-[(3aR,6R,7aS)-Tetrahydro-8,8-dimethyl-2,2-dioxido-3H-
3a,b-methano-2,1-benzisothiazol-1(4H)-yl]butan-1-one; 3). To a stirred soln. of (þ)-camphor-derived
sultam (5 g, 23.25 mmol) and butanoyl chloride (4.88 ml, 46.51 mmol) in dry benzene (50 ml) under N2
was added anh. CuCl2 (0.62 g, 4.65 mmol), and the mixture was refluxed for 12 h. The hot mixture was
filtered, the filter, washed with CH2Cl2 (20 ml), the combined filtrate concentrated and, the residue
purified by CC: 3 (6.0 g, 92%). Colorless crystals. [a]2D5 ¼ þ91.9 (c ¼ 1.0, CHCl3). 1H-NMR: 3.82 (t, J ¼
6.2, 1 H); 3.39 (q, J ¼ 13.5, 2 H); 2.63 (q, J ¼ 8.3, 2 H); 2.01 – 2.11 (m, 2 H); 1.81 – 1.91 (m, 3 H); 1.68 (q,
J ¼ 7.2, 2 H); 1.32 – 1.45 (m, 2 H); 1.14 (s, 3 H); 0.96 (s, 3 H); 0.96 (t, J ¼ 7.2, 3 H). ESI-MS: 286 ([M þ
1]þ).
(2R,3R)-2-Ethyl-3-hydroxy-5-[(4-methoxyphenyl)methoxy]-1-[(3aR,6R,7aS)-tetrahydro-8,8-di-
methyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]-pentan-1-one (4). To a cooled (ꢀ 788)
soln. of 3 (1.0 g, 3.5 mmol) in dry CH2Cl2 (20 ml) and TiCl4 (1.15 ml, 3.0 equiv.) was added slowly iPr2NEt
(1.85 ml, 2.2 equiv.), and the mixture was stirred for 90 min, followed by addition of (4-methoxybenzyl)-
protected 3-hydroxypropanal (2.0 g, 10.3 mmol) at ꢀ 788, and further stirring for 90 min. After
completion of the reaction (TLC), the reaction was quenched with sat. NH4Cl soln. (10 ml), the mixture
extracted with CH2Cl2 (3 ꢁ 20 ml), the extract dried (Na2SO4) and concentrated, and the residue purified
by CC (hexane/AcOEt 4 :1): 4 (1.42 g, 84%). Colorless liquid. [a]2D5 ¼ þ40 (c ¼ 0.8, CHCl3). IR (neat):
1
3479, 2959, 2929, 1688, 1513, 1244. H-NMR: 7.20 (d, J ¼ 8.3, 2 H); 6.80 (d, J ¼ 8.3, 2 H); 4.41 (s, 2 H);
3.98 – 4.09 (m, 1 H); 3.87 (t, J ¼ 6.0, 1 H); 3.78 (s, 3 H); 3.52 – 3.67 (m, 2 H); 3.42 (q, J ¼ 13.5, 2 H); 3.18
(br. s, 1 H); 3.07 (q, J ¼ 5.2, 1 H); 2.07 (d, J ¼ 6.0, 2 H); 1.77 – 1.94 (m, 6 H); 1.33 – 1.46 (m, 2 H); 1.26 (s,
1 H); 1.16 (s, 3 H); 0.98 (s, 3 H); 0.92 (t, J ¼ 7.5, 3 H). 13C-NMR: 171.1; 159.58; 129.35; 128.65 (2 C);

Helvetica Chimica Acta – Vol. 94 (2011)
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113.54 (2 C); 72.86; 72.10; 67.47; 65.40; 55.26; 53.28; 52.51; 44.58 (2 C); 40.93; 34.86; 32.90; 26.40; 21.68;
20.69; 19.94 (2 C); 11.62. ESI-MS: 480 ([M þ 1]þ).
(2S,3R)-2-Ethyl-5-[(4-methoxyphenyl)methoxy)pentane-1,3-diol (5). To a cooled (08) stirred
suspension of LiAlH4 (168 mg, 4.42 mmol) in dry Et2O (20 ml) was added 4 (1.0 g, 2.96 mmol), and
the mixture was stirred for 3 h at 08. After completion of the reaction (TLC), the reaction was quenched
with sat. NH4Cl soln., the mixture extracted with AcOEt (5 ꢁ 10 ml), the extract dried (Na2SO4) and
concentrated, and the residue purified by CC (hexane/AcOEt 7:3): pure 5 (760 mg, 95%). Colorless
liquid. [a]2D5 ¼ ꢀ4.54 (c ¼ 0.6, CHCl3). IR (neat): 3419, 2926, 2863, 1612, 1512, 1247, 1086, 1033. 1H-NMR:
7.19 (d, J ¼ 8.3, 2 H); 6.83 (d, J ¼ 9.0, 2 H); 4.44 (s, 2 H); 3.81 (dt, J ¼ 2.2, 5.2, 2 H); 3.79 (s, 3 H); 3.67 –
3.75 (m, 1 H); 3.54 – 3.67 (m, 2 H); 1.67 – 1.77(m, 1 H); 1.51 – 1.55 (m, 1 H); 1.23 – 1.46 (m, 3 H); 0.94 (t,
J ¼ 7.55, 3 H). 13C-NMR: 159.5; 129.45; 129.36 (2 C); 113.87 (2 C); 76.46; 73.15; 69.64; 63.89; 55.26;
46.63; 34.64; 21.37; 11.77. ESI-MS: 291 ([M þ Na]þ).
(5R,6S)-6-Ethyl-5-{2-[(4-methoxyphenyl)methoxy]ethyl}-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-
disilaundecane (6). To a cooled (08) soln. of 5 (400 mg, 1.49 mmol) and 2,6-lutidine (0.672 ml, 6.28 mmol,
t
2 equiv.) in dry CH2Cl2 (10 ml) was added BuMe2SiOTf (0.696 ml, 2.86 mmol), and the mixture was
stirred at r.t. for 45 min. After completion of the reaction (TLC), the reaction was quenched with sat.
NH4Cl soln. (5 ml), the mixture extracted with CH2Cl2 (3 ꢁ 10 ml), the extract dried (Na2SO4) and
concentrated, and the residue purified by CC (hexane/AcOEt 9 :1): pure 6 (700 mg, 95%). Pale yellow
liquid. [a]2D5 ¼ ꢀ4.11 (c ¼ 0.8, CHCl3). IR (neat): 2929, 2856, 1639, 1250, 1092. 1H-NMR: 7.25 (d, J ¼ 9.06,
2 H); 6.87 (d, J ¼ 9.06, 2 H); 4.41 (d, J ¼ 2.26, 2 H); 3.92 – 4.04 (s, 1 H); 3.80 (s, 3 H); 3.42 – 3.60 (m, 4 H);
1.60 – 1.85 (m, 1 H); 1.23 – 1.60 (m, 3 H); 1.04 – 1.21 (m, 1 H); 0.90 (t, J ¼ 7.55, 3 H); 0.88 (s, 9 H); 0.87 (s,
9 H); 0.04 (s, 6 H); 0.02 (s, 6 H). 13C-NMR: 159.5; 129.34; 129.25 (2 C); 113.86 (2 C); 73.13; 72.81; 69.67;
63.90; 55.20; 48.43; 43.3; 34.58; 25.85 (3 C); 25.59 (3 C); 19.1 (2 C); 10.38; ꢀ 3.6 (2 C); ꢀ 5.7 (2 C). ESI-
MS: 519 ([M þ Na]þ).
(3R,4S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4-{{[(tert-butyl)dimethylsilyl]oxy}methyl}hexan-1-ol
(7). To a soln. of 6 (600 mg, 1.2 mmol) in CH2Cl2/H2O 9 :1 (20 ml) was added DDQ (329 mg,
1.44 mmol), and the mixture was stirred at r.t. for 2 h. After completion of the reaction (TLC), the
mixture was neutralized with sat. NaHCO3 soln. (5 ml) and extracted with CH2Cl2 (3 ꢁ 10 ml), the
combined org. phase washed with brine (10 ml), dried (Na2SO4), and concentrated, and the residue
purified by CC (hexane/AcOEt 7:3): pure 7 (400 mg, 89%). Pale yellow liquid. [a]2D5 ¼ þ2.72 (c ¼ 0.6,
CHCl3). IR (neat): 3462, 2955, 1635,1219. 1H-NMR: 4.03 – 4.11 (m, 1 H); 3.67 (q, J ¼ 6.0, 2 H); 3.43 – 3.64
(m, 2 H); 1.56 – 1.75 (m, 2 H); 1.23 – 1.37 (m, 2 H); 1.02 – 1.17 (m, 1 H); 0.92 (t, J ¼ 7.55, 3 H); 0.89 (s,
18 H); 0.08 (s, 3 H); 0.07 (s, 3 H); 0.04 (s, 3 H); 0.03 (s, 3 H). 13C-NMR: 71.52; 61.68; 60.88; 47.90; 35.37;
29.70; 25.87 (6 C); 25.63; 20.34; 12.35; ꢀ 4.46 (2 C); ꢀ 5.49 (2 C). ESI-MS: 377 ([M þ 1]þ).
(3R,4S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4-{{[(tert-butyl)dimethylsilyl]oxy}methyl}hexanal (8).
To a cooled (08) soln. of 7 (300 mg, 0.79 mmol) in dry CH2Cl2 (15 ml) were added iodobenzene
diacetate (384 mg, 1.19 mmol) and TEMPO (24.9 mg, 0.15 mmol), and the mixture was stirred at r.t. for
4 h. After completion of the reaction (TLC), the reaction was quenched with sat. NH4Cl soln. (5 ml), the
mixture extracted with CH2Cl2 (3 ꢁ 10 ml), the combined org. layer washed with brine (10 ml), dried
(Na2SO4), and concentrated, and the residue purified by CC (hexane/AcOEt 9 :1): pure 8 (270 mg,
90%). Pale yellow liquid. [a]2D5 ¼ þ6.0 (c ¼ 1.0, CHCl3). IR (neat): 2956, 2857, 1728, 1253, 1089.
1H-NMR: 9.80 – 9.76 (m, 1 H); 4.43 – 4.50 (m, 1 H); 3.57 – 3.68 (m, 1 H); 3.48 (dd, J ¼ 7.5, 10.5, 1 H);
2.44 – 2.64 (m, 1 H); 1.51 – 1.69 (m, 1 H); 1.05 – 1.20 (m, 2 H); 0.92 (t, J ¼ 7.5, 3 H); 0.89 (s, 9 H); 0.87 (s,
9 H); 0.07 (s, 3 H); 0.04 (s, 9 H). 13C-NMR: 202.85; 68.36; 62.34; 48.64; 47.30; 25.86 (6 C); 18.5 (2 C);
18.1; 12.4; ꢀ 4.48 (2 C); ꢀ 5.46 (2 C). ESI-MS: 397 ([M þ Na]þ).
(4R,5S)-5-Ethyltetrahydro-2H-pyran-2,4-diol (9). To a cooled (08) soln. of 8 (200 mg, 0.53 mmol) in
dry THF (10 ml) was added 1.0m Bu4NF in THF (0.53 ml, 0.53 mmol), and the mixture was stirred for 2 h
at 08. After completion of the reaction (TLC), the reaction was quenched with sat. NH4Cl soln. (5 ml),
the mixture extracted with AcOEt (3 ꢁ 10 ml), the combined org. phase washed with brine (10 ml), dried
(Na2SO4), and concentrated, and the residual liquid purified by CC (hexane/AcOEt 7:3): pure 9 (70 mg,
90%). Pale yellow liquid. [a]2D5 ¼ þ16.5 (c ¼ 3.0, CHCl3). IR (neat): 3453, 2924, 1639, 1381, 1048.
1H-NMR: 5.31 (t, J ¼ 3.0, 1 H); 4.72 (br. s, 1 H); 4.63 (dd, J ¼ 3.0, 6.0, 1 H); 4.17 – 4.10 (m, 1 H); 3.69 (dd,
J ¼ 3.7, 10.3, 1 H); 3.53 (dd, J ¼ 6.7, 11.3, 1 H); 1.98 (br. s, 1 H); 1.77 – 1.86 (m, 1 H); 1.50 – 1.69 (m, 2 H);

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1.30 – 1.47 (m, 1 H); 0.96 (t, J ¼ 6.7, 3 H). 13C-NMR: 92.83; 67.73; 61.52; 43.76; 37.03; 21.08; 11.28. ESI-
MS: 147 ([M þ 1]þ).
(4R,5S)-5-Ethyltetrahydro-4-hydroxy-2H-pyran-2-one (1). To a cooled (08) soln. of 9 (40 mg,
0.27 mmol) in dry CH2Cl2 (10 ml) were added iodobenzene diacetate (88 mg, 0.27 mmol) and TEMPO
(cat.), and the mixture was stirred at r.t. for 4 h. After completion of the reaction (TLC), the reaction was
quenched with sat. NH4Cl soln. (5 ml), the mixture extracted with CH2Cl2 (3 ꢁ 10 ml), the combined org.
layer washed with brine (10 ml), dried (Na2SO4), and concentrated, and the residual liquid purified by
CC (hexane/AcOEt 4 :1): pure 1 (35 mg, 89%). Colourless liquid. [a]2D5 ¼ þ23.0 (c ¼ 1.0, CHCl3) [3]. IR
(neat): 3420, 2945, 1721, 1415, 1205. 1H-NMR: 4.38 (dd, J ¼ 10.4, 11.2, 1 H); 4.21 (dd, J ¼ 5.1, 11.2, 1 H);
4.10 (br. s, 1 H); 2.90 (br. s, 1 H); 2.72 (dd, J ¼ 3.6, 17.8, 1 H); 2.61 (dd, J ¼ 3.6, 17.8, 1 H); 1.80 – 1.98 (m,
1 H); 1.40 – 1.50 (m, 1 H); 1.25 – 1.38 (m, 1 H); 0.98 (t, J ¼ 7.5, 3 H). 13C-NMR: 170.6; 69.2; 64.4; 39.2;
39.1; 19.2; 11.1. ESI-MS: 145 ([M þ 1]þ).
(2S,3R)-2-Ethyl-3-hydroxy-5-[(4-methoxyphenyl)methoxy]-1-[(3aR,6R,7aS)-tetrahydro-8,8-di-
methyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]pentan-1-one (10). As described for 4,
with 3 (1.0 g, 3.5 mmol), TiCl4 (0.38 ml, 1.0 equiv.), CH2Cl2 (20 ml), iPr2NEt (0.73 ml, 1.2 equiv.), and (4-
methoxybenzyl)-protected 3-hydroxyproanal (0.68 g, 3.5 mmol): pure 10 (1.55 g, 92%). White solid.
[a]2D5 ¼ þ33.07 (c ¼ 0.7, CHCl3). IR (KBr): 3509, 2956, 2878, 1691, 1613, 1515, 1022. 1H-NMR: 7.20 (d, J ¼
8.3, 2 H); 6.81 (d, J ¼ 8.3, 2 H); 4.41 (s, 2 H); 3.99 – 4.11 (m, 1 H); 3.87 (t, J ¼ 6.0, 1 H); 3.78 (s, 3 H);
3.53 – 3.67 (m, 2 H); 3.43 (q, J ¼ 13.5, 2 H); 3.19 (d, J ¼ 1.51, 1 H); 3.08 (q, J ¼ 5.2, 1 H); 2.07 (d, J ¼ 6.79,
2 H); 1.65 – 1.96 (m, 7 H); 1.33 – 1.51 (m, 2 H); 1.16 (s, 3 H); 0.97 (s, 3 H); 0.92 (t, J ¼ 7.5, 3 H). 13C-NMR:
175.1; 159.0; 130.1; 129.22 (2C); 113.68 (2 C); 72.66; 70.05; 68.33; 65.25; 55.18; 53.20; 52.49; 48.3; 47.6;
44.56; 38.57; 33.89; 32.89; 26.32; 21.67; 20.71; 19.83; 11.02. ESI-MS: 502 ([M þ Na]þ).
(2R,3R)-2-Ethyl-5-[4-methoxyphenyl)methoxy]pentane-1,3-diol (11). As described for 5, with
LiAlH4 (166 mg, 4.36 mmol), Et2O (20 ml), and 10 (1.4 g, 2.92 mmol) (quenching with sat. Na2SO4
soln.): pure 11 (740 mg, 95%). Colorless liquid. [a]2D5 ¼ ꢀ16.0 (c ¼ 0.7, CHCl3). IR (neat): 3419, 2926,
2863, 1612, 1086, 1033. 1H-NMR: 7.19 (d, J ¼ 8.3, 2 H); 6.83 (d, J ¼ 9.0, 2 H); 4.44 (s, 2 H); 4.03 (td, J ¼ 3.0,
9.8, 1 H); 3.79 (s, 3 H); 3.55 – 3.75 (m, 4 H); 1.84 – 1.99 (m, 1 H); 1.51 – 1.65 (m, 2 H); 1.22 – 1.39 (m, 2 H);
0.95(t, J ¼ 7.5, 3 H). 13C-NMR: 159.67; 129.43; 129.35 (2 C); 113.86 (2 C); 75.97; 73.12; 69.89; 64.20;
55.25; 46.09; 31.79; 19.03; 12.28. ESI-MS: 291 ([M þ Na]þ).
(5R,6R)-6-Ethyl-5-{2-[(4-methoxyphenyl)methoxy]ethyl}-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-
3,9-disilaundecane (12). As described for 6, with 11 (400 mg, 1.49 mmol), CH2Cl2 (20 ml), 2,6-lutidine
(0.672 ml, 6.28 mmol), and tBuMe2SiOTf (0.696 ml, 2.86 mmol) (quenching with sat. NH4Cl soln.
(10 ml)): 12 (700 mg, 95%). Pale yellow liquid. [a]2D5 ¼ þ3.75 (c ¼ 0.8, CHCl3). IR (neat): 2931, 2858,
1513, 1464, 1250, 1094. 1H-NMR: 7.25 (d, J ¼ 8.3, 2 H); 6.87 (d, J ¼ 8.3, 2 H); 4.41 (s, 2 H); 3.91 – 4.00 (m,
1 H); 3.80 (s, 3 H); 3.6 – 3.68 (dd, J ¼ 5.2, 9.8, 1 H); 3.41 – 3.58 (m, 3 H); 1.54 – 1.86 (m, 2 H); 1.23 – 1.48
(m, 3 H); 0.91 (t, J ¼ 7.5, 3 H); 0.88 (s, 9 H); 0.87 (s, 9 H); 0.04 (s, 6 H); 0.02 (s, 6 H). 13C-NMR: 159.72;
129.34; 129.22 (2 C); 113.83 (2 C); 75.90; 73.10; 69.85; 67.40; 64.14; 55.21; 48.17; 46.40; 25.86 (4 C); 25.60
(2 C); 18.99 (2 C); 12.23; ꢀ 3.63 (2 C); ꢀ 4.62 (2 C). ESI-MS: 519 ([M þ Na]þ).
(3R,4R)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4-{{[(tert-butyl)dimethylsilyl]oxy}methyl}hexan-1-ol
(13). As described for 7, with 12, CH2Cl2/H2O 9 :1, and DDQ. After completion of the reaction, the
mixture was diluted with H2O (10 ml) and extracted as described for 7: pure 13 (410 mg, 90%). Pale
1
yellow liquid. [a]D25 ¼ ꢀ2.7 (c ¼ 0.5, CHCl3). IR (neat): 3453, 2929, 2858, 1638, 1253, 1090. H-NMR:
3.94 – 4.04 (m, 1 H); 3.61 – 3.73 (m, 3 H); 3.51 – 3.59 (m, 1 H); 1.59 – 1.79 (m, 2 H); 1.32 – 1.46 (m, 1 H);
1.23 – 1.32 (m, 2 H); 0.93 (t, J ¼ 7.5, 3 H); 0.89 (s, 9 H); 0.88 (s, 9 H); 0.09 (s, 3 H); 0.06 (s, 3 H); 0.03 (s,
6 H). 13C-NMR: 71.52; 61.68; 60.89; 47.90; 35.37; 25.87 (6 C); 20.34; 18.72 (2 C); 12.35; ꢀ 4.54 (2 C); ꢀ
5.45 (2 C). ESI-MS: 377 ([M þ 1]þ).
(3R,4R)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4-{{[(tert-butyl)dimethylsilyl]oxy}methyl}hexanal (14).
As described for 8, with 13, CH2Cl2, iodobenzene diacetate, and TEMPO: pure 14 (260 mg, 88%). Pale
yellow liquid. [a]2D5 ¼ ꢀ4.0 (c ¼ 1.5, CHCl3). IR (neat): 2927, 2856, 1635, 1219. 1H-NMR: 9.78 – 9.74 (m,
1 H); 4.31 – 4.37 (m, 1 H); 3.57 – 3.68 (m, 2 H); 2.43 – 2.63 (m, 2 H); 1.69 – 1.92 (m, 1 H); 1.18 – 1.66 (m,
1 H); 1.02 – 1.17 (m, 1 H); 0.92 (t, J ¼ 7.5, 3 H), 0.89 (s, 9 H); 0.86 (s, 9 H); 0.06 (s, 3 H); 0.04 (s, 3 H); 0.04
(s, 6 H). 13C-NMR: 202.56; 68.25; 60.88; 48.52; 48.38; 25.86 (4 C); 25.77 (2 C); 20.36; 18.18; 18.03; 12.21;
ꢀ 4.56 (2 C); ꢀ 4.97 (2 C). ESI-MS: 397 ([M þ Na]þ).

Helvetica Chimica Acta – Vol. 94 (2011)
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(4R,5R)-5-Ethyltetrahydro-2H-pyran-2,4-diol (15). As described for 9, with 14, THF, and 1.0m
Bu4NF in THF: pure 15 (70 mg, 90%). Pale yellow liquid. [a]2D5 ¼ ꢀ32.3 (c ¼ 1.0, CHCl3). IR (neat):
3450, 2923, 2854, 1639, 1460, 1220. 1H-NMR: 5.35 (t, J ¼ 3.0, 1 H); 4.95 (br. s, 1 H); 3.63 – 3.90 (m, 2 H);
3.27 (dd, J ¼ 6.0, 12.0, 1 H); 2.15 (br. s, 1 H); 1.70 – 1.86 (m, 1 H); 1.55 – 1.69 (m, 2 H); 1.15 – 1.52 (m,
2 H); 0.94 (t, J ¼ 6.7, 3 H). 13C-NMR: 93.67; 69.66; 62.41; 45.19; 38.97; 21.37; 11.70. ESI-MS: 147 ([M þ
1]þ).
(4R,5R)-5-Ethyltetrahydro-4-hydroxy-2H-pyran-2-one (2). As described for 1, with 15, CH2Cl2,
iodobenzene diacetate, and TEMPO: pure 2 (34 mg, 88%). Colorless liquid. [a]2D5 ¼ ꢀ24.0 (c ¼ 1.0,
CHCl3) [3]. IR (neat): 3475, 2989, 2930, 1721, 1265, 1014. 1H-NMR: 4.44 (dd, J ¼ 5.2, 10.4, 1 H); 3.90 –
4.05 (m, 1 H); 2.78 (dd, J ¼ 5.8, 11.6, 1 H); 2.52 (dd, J ¼ 5.8, 11.6, 1 H); 1.50 – 1.88 (m, 2 H); 1.20 – 1.45 (m,
1 H); 1.01 (t, J ¼ 7.55, 3 H). 13C-NMR: 171.0; 69.1; 67.8; 42.5; 38.4; 20.8; 11.1. ESI-MS: m/z 145 ([M þ
1]þ).
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Received January 13, 2011