The first stereoselective total synthesis of naturally occurring, bioactive (3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol and the synthesis of its enantiomer

Article abstract of DOI:10.1002/hlca.201200165

The first stereoselective total synthesis of the naturally occurring anti-emetic diarylheptanoid (3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1) was accomplished starting from 4-hydroxybenzaldehyde and involving a Sharpless kinetic resolution and

Full text of DOI:10.1002/hlca.201200165

Helvetica Chimica Acta – Vol. 96 (2013)
289
The First Stereoselective Total Synthesis of Naturally Occurring, Bioactive
(3R,5R)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol and the Synthesis of
Its Enantiomer1)
by Parigi Raghavendar Reddy, Chithaluri Sudhakar, Jayprakash Narayan Kumar, and Biswanath Das*
Organic Chemistry Division-I, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
(phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
The first stereoselective total synthesis of the naturally occurring anti-emetic diarylheptanoid
(3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1) was accomplished starting from 4-hydroxy-
benzaldehyde and involving a Sharpless kinetic resolution and an asymmetric epoxidation as the key
steps (Scheme 2). The enantiomer 1a of this compound was also simultaneously prepared.
Introduction. – Diarylheptanoids constitute an important class of natural products
as they possess various interesting biological properties, such as anti-inflammatory,
antioxidant, and anticancer activites [1]. A large number of these compounds have
been isolated from nature [2]. Some of them contain a 1,3-diol system. The linear
diarylheptanoid (3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1) was iso-
lated from Alpinia officinarum (Zingiberaceae) [3]. The compound exhibits anti-emetic
activity. Thus, 1 is an important target for total synthesis. However, it is interesting that,
though the synthesis of several stereoisomers and analogues of 1 have already been
reported [4], the synthesis of 1 itself has not yet been disclosed. Here, we report the first
stereoselective total synthesis of 1. Its enantiomer 1a was also simultaneously prepared.
Results and Discussion. – The retrosynthetic analysis (Scheme 1) revealed that
compound 1 or 1a can be synthesized from the acetonide derivative 2 or 2a,
respectively, and benzyltriphenylphosphonium ylide 3. The compound 2 or 2a can in
turn be prepared from the achiral allyl alcohol 4 generated from 4-hydroxybenzalde-
hyde (5).
The present synthesis of 1 and 1a was initiated (Scheme 2) by converting 5 [5] into
its benzyl ether [5] followed by Wittig olefination with Ph3PCHCOOEt and subsequent
reduction with LiBH4 to yield the known alcohol 6 [5]. The latter was oxidized under
Swern conditions, and the corresponding aldehyde was treated with 4-methoxybenzyl
(PMB)-protected propargyl alcohol (4-MeOC6H4CH2OCH2CꢀCH) and BuLi to
1
)
Part 59 in the series ꢂSynthetic Studies on Natural Productsꢃ.
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 1. Retrosynthetic Pathway of 1 and 1a
furnish the acetylenic compound 7. The reduction of 7 with LiAlH4 in THF under reflux
[6] afforded the (E)-configured allyl-alcohol 4 (major isomer) along with a small
amount of its (Z)-isomer, which was separated by column chromatography. The
Sharpless kinetic resolution [7] of 4 with ((þ)-diisopropyl tartrate (þ)-DIPT,
titanium(IV) isopropoxide ((iPrO)4Ti), and tert-butyl hydroperoxide (tBuOOH)
resulted in the formation of the chiral epoxy alcohol 8a and the allyl alcohol 9. Next,
compound 9 underwent Sharpless asymmetric epoxidation [5] with (ꢁ)-DIPT,
t
(iPrO)4Ti, and BuOOH to generate the enantiomeric epoxy alcohol 8. Compounds 8
and 8a were separately treated with Red-Alꢄ (sodium bis(2-methoxyethoxy)aluminium
hydride solution in toluene) in THF to give the diols 10 and 10a, respectively. The two
OH groups of these diols were protected by preparing the acetonide derivatives 2 and
2a, and subsequently the protecting PMB group was removed with DDQ (¼ 4,5-
dichloro-3,6-dioxocyclohexol-1,4-diene-1,2-dicarbonitrile) to generate the alcohols 11
(from 10) and 11a (from 10a). Each of the alcohols 11 and 11a was again oxidized under
Swern conditions, and the corresponding aldehydes were subjected to Wittig olefination
with Ph3P¼CHPh to afford the olefins 12 and 12a, respectively, along with minor
amounts (10%) of their (Z)-isomers, which were separated by column chromatog-
raphy. The protecting acetonide group of 12 and 12a was removed by treatment with p-
toluenesulfonic acid (TsOH) in MeOH followed by hydrogenation in the presence of
Pd/C to yield the diols 1 and 1a, respectively. The optical and spectroscopic (1H-, and
13C-NMR and MS) properties of 1 were identical to those of the naturally occurring
(3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol [3]. The spectroscopic proper-
ties of 1a were identical to those of 1, but its optical-rotation value was reverse.
In conclusion, we developed the first stereoselective total synthesis of the anti-
emetic compound (3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1) starting
from 4-hydroxybenzaldehyde. The synthesis of its enantiomer was also accomplished.
The method can be utilized for the synthesis of related diarylheptanoids which can be
employed for bioevaluation.
The authors thank UGC and CSIR, New Delhi, for financial assistance.

Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 2. Synthesis of 1 and 1a
291
i) NaH, BnBr, THF, 08 to r.t., 4 h; 80%. ii) Ph3P¼CHCOOEt, CH2Cl2, r.t., 8 h; 82%. iii) LiBH4, H2O,
Et2O, 08 to r.t., 24 h; 91%. iv) 1. (COCl)2, DMSO, Et3N, ꢁ 788; 82%; 2. BuLi, dry THF, 4-
MeOC6H4CH2OCH2CꢀCH, ꢁ 788 , 3.5 h; 90%. v) LiAlH4, dry THF, 08 to reflux, 3 h; 78%. vi)
t
(iPrO)4Ti, (þ)-DIPT, BuOOH, dry CH2Cl2, ꢁ 208, 6 h; 46% (8a), 53% (9). vii) (iPrO)4Ti, (ꢁ)-DIPT,
tBuOOH, dry CH2Cl2, ꢁ 208 , 7 h; 66%. viii) Red-Alꢄ, dry THF, 08 to r.t., 2 h; 72% (10), 74% (10a). ix)
TsOH (cat.), 2,2-dimethoxypropane, CH2Cl2, r.t., 0.5 h; 95% (2), 94% (2a). x) DDQ, CH2Cl2/H2O 19 :1,
r.t., 2 h; 63% (11), 64% (11a). xi) 1. (COCl)2, DMSO, Et3N, ꢁ 788, 3.5 h; 80%; 2. (Ph3PCH2Ph)Br, BuLi,
dry THF, 4 h; 78% (12), 75% (12a). xii) 1. TsOH, MeOH, 3 h; 2. H2, Pd/C, 2 h; 60% (1), 63% (1a).
Experimental Part
General. All commercially available reagents were used directly without further purification unless
otherwise stated. The solvents used were all of AR grade and were distilled under dry N2 where
necessary. All reactions were performed in predried apparatus unless otherwise stated. Yields were those

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of purified compounds unless otherwise stated. TLC: silica gel 60 F254 plates (SiO2; Merck). Column
chromatography (CC): silica gel (SiO2; 60 – 120 mesh; Qingdao Marine Chemical, P. R. China). Optical
rotations: Jasco-DIP-300 digital polarimeter. NMR Spectra: Gemini-200 spectrometer; in CDCl3; d in
ppm rel. to Me4Si as internal standard, J in Hz. ESI-MS: VG-Autospec-micromass instrument; in m/z.
HR-MS: QSTAR-XL-Hybrid MS system (Applied Biosystems); in m/z.
6-[4-Methoxyphenyl)methoxy)-1-[4-(phenylmethoxy)phenyl]hex-4-yn-3-ol (7). To a stirred soln. of
oxalyl chloride (8.07 ml, 132.20 mmol) in dry CH2Cl2 (160 ml), DMSO (0.55 ml, 18.2 mmol) was added at
ꢁ 788, and the mixture was stirred at ꢁ 788 for 0.5 h. A soln. of 6 (16 g, 66.11 mmol) in dry CH2Cl2
(60 ml) was added at ꢁ 788, and the mixture was stirred for 1.5 h at ꢁ 788 Et3N (27.59 ml, 198.01 mmol)
was added at 08, and the mixture was stirred for an additional 30 min. After completion of the reaction,
the mixture was diluted with H2O (30 ml) and extracted with CH2Cl2 (2 ꢂ 100 ml). The combined org.
layers were washed with brine (60 ml), dried (Na2SO4), and concentrated to give 3-[4-(phenyl-
methoxy)phenylpropanal (13.01 g, 82%). Because of extensive oxidation of the aldehyde to the
corresponding acid, we used it immediately for the next step.
Under N2, 1.6m BuLi in hexane (46.87 ml, 75 mmol) was added to a soln. of the PMB ether of
propargyl alcohol (¼1-methoxy-4-[(prop-2-yn-1-yloxy)methyl]benzene; 13.2 g, 75 mmol) in dry THF
(150 ml) at ꢁ 788, and the mixture was stirred for 30 min. Finally, a soln. of 3-[4-(phenylmethoxy)phe-
nyl]propanal (12.0 g, 50.0 mmol) in dry THF (80 ml) was added and the mixture stirred for 3 h at ꢁ 788.
After completion of the reaction, the mixture was quenched with sat. aq. NH4Cl soln. (20 ml) and then
extracted with AcOEt (2 ꢂ 100 ml), the extract dried (Na2SO4) and concentrated, and the residue
1
purified by CC: pure 7 (1.74 g, 90%). H-NMR (200 MHz): 7.37 – 7.12 (m, 7 H); 7.01 (d, J ¼ 8.0, 2 H);
6.80 – 6.72 (m, 4 H); 4.90 (s, 2 H); 4.42 (s, 2 H); 4.29 (t, J ¼ 7.0, 1 H); 4.06 (s, 2 H); 3.66 (s, 3 H); 3.29 (br. s,
1 H); 2.64 (t, J ¼ 7.0, 2 H); 1.98 – 1.83 (m, 2 H). 13C-NMR (50 MHz): 159.2; 156.9; 137.1; 133.4; 129.4;
129.2; 129.1; 128.3; 127.6; 127.2; 114.5; 113.3; 87.9; 80.6; 71.1; 69.6; 61.2; 56.9; 55.0; 39.6; 30.4. ESI-MS: 439
([M þ Na]þ). Anal. calc. for C27H28O4 (416.51): C 77.89, H 6.73; found: C 77.94, H, 6.68.
6-[(4-Methoxyphenyl)methoxy]-1-[4-(phenylmethoxy)phenyl]hex-4-en-3-ol (4). To the suspension
of LiAlH4 (6.57 g, 173.07 mmol) in dry THF (60 ml) under N2 at 08 was added 7 (18.0 g, 43.26 mmol) in
dry THF (75 ml), and the mixture was refluxed for 3 h. After the completion of the reaction, the mixture
was cooled to 08 and diluted with Et2O, and the reaction was quenched with sat. aq. Na2SO4 soln. (20 ml).
When the effervescence subsided, the mixture was filtered through a pad of Celite and the pad washed
with hot AcOEt (90 ml). The filtrate was washed with brine (2 ꢂ 30 ml), dried (Na2SO4), and
concentrated, and the residue purified by CC: 4 (14.10 g, 78%). [a]2D2 ¼ ꢁ0.42 (c ¼ 1.0, CHCl3). 1H-NMR
(200 MHz): 7.42 – 7.23 (m, 5 H); 7.20 (d, J ¼ 8.0, 2 H); 7.05 (d, J ¼ 8.0, 2 H); 6.82 (d, J ¼ 8.0, 2 H); 6.80 (d,
J ¼ 8.0, 2 H); 5.74 – 5.68 (m, 2 H); 4.99 (s, 2 H); 4.40 (s, 2 H); 4.17 – 4.11 (m, 1 H); 4.10 – 4.03 (m, 1 H);
3.98 – 3.85 (m, 1 H); 3.78 (s, 3 H); 2.68 – 2.55 (m, 2 H); 1.82 – 1.72 (m, 2 H). 13C-NMR (50 MHz): 159.1;
157.2; 137.2; 135.7; 134.1; 130.2; 129.4; 129.3; 128.5; 127.8; 127.4; 114.5; 113.8; 72.0; 71.8; 69.9; 69.7; 55.2;
38.9; 31.0. ESI-MS: 441 ([M þ Na]þ). Anal. calc. for C27H30O4 (418.53): C 77.51, H 7.18; found: C 77.58, H
7.15.
(1S)-1-{(2S,3S)-3-{[(4-Methoxyphenyl)methoxy]methyl}oxiran-2-yl}-3-[4-(phenylmethoxy)phenyl]-
propan-1-ol (8a). To a suspension of powdered molecular sieves (4 ꢅ; 3 g) in dry CH2Cl2 (140 ml),
(iPrO)4Ti (5.66 ml,19.13 mmol), and (þ)-DIPT (3.92 ml, 22.96 mmol) were added sequentially at ꢁ 208.
After stirring for 30 min, 4 (16.0 g, 38.27 mmol) in dry CH2Cl2 (60 ml) was added, and stirring was
continued for another 30 min at ꢁ 208. Then tBuOOH (3.50 ml, 21.05 mmol) was added and the stirring
continued for another 5 h at ꢁ 208. After completion of the reaction, the mixture was quenched by the
addition of H2O (15 ml) and allowed to reach r.t. by stirring for 30 min. After recooling to 08, 30% (w/v)
aq. NaOH soln. (10 ml, sat. with brine) was added, and the mixture was stirred at 08 for 1 h. The mixture
was extracted with Et2O (2 ꢂ 40 ml), the combined org. extract washed with brine (2 ꢂ 20 ml), dried
(Na2SO4), and concentrated, and the residue purified by CC: pure 9 (8.48 g, 53%) and 8a (7.67 g, 46%).
8a: [a]2D2 ¼ ꢁ0.42 (c ¼ 1.4, CHCl3).
Data of (3R)-6-[(4-Methoxyphenyl)methoxy]-1-[4-(phenylmethoxy)phenyl]hex-4-en-3-ol (9):
1H-NMR (200 MHz): 7.42 – 7.28 (m, 5 H); 7.21 (d, J ¼ 8.0, 2 H); 7.05 (d, J ¼ 8.0, 2 H); 6.86 (d, J ¼ 8.0,
2 H); 6.85 (d, J ¼ 8.0, 2 H); 5.00 (s, 2 H); 4.50 (d, J ¼ 14.0, 1 H); 4.41 (d, J ¼ 14.0, 1 H); 3.79 (s, 3 H);
3.66 – 3.58 (m, 1 H); 3.48 – 3.39 (m, 1 H); 3.17 – 3.11 (m, 1 H); 3.10 – 3.02 (m, 1 H); 2.88 – 2.80 (m, 1 H);

Helvetica Chimica Acta – Vol. 96 (2013)
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2.77 – 2.58 (m, 2 H); 1.94 (br. s, 1 H); 1.90 – 1.69 (m, 2 H). 13C-NMR (50 MHz): 159.7; 157.8; 137.9; 134.2;
130.0; 129.5; 129.3; 128.5; 127.9; 127.7; 115.0; 114.1; 73.1; 72.2; 70.0; 69.2; 58.3; 55.2; 35.5; 30.8. ESI-MS:
457 ([M þ Na]þ). Anal. calc. for C27H30O5 (434.52): C 74.65, H 6.91; found: C 74.78, H 6.88.
(1R)-1-{(2R,3R)-3-{[(4-Methoxyphenyl)methoxy]methyl}oxiran-2-yl}-3-[4-(phenylmethoxy)phe-
nyl]propan-1-ol (8). As described for 8a, with molecular sieves (4 ꢅ, 2 g), CH2Cl2 (60 ml), (iPrO)4Ti
(5.66 ml, 19.11 mmol), (ꢁ)-DIPT (3.60 ml, 21.01 mmol), 9 (8 g, 19.13 mmol) instead of 4, CH2Cl2
(50 ml), and tBuOOH (7.97 ml, 47.84 mmol, stirring for 6 h). Extraction with Et2O (2 ꢂ 80 ml).
CC afforded pure 8 (5.50 g, 66%). [a]2D2 ¼ þ0.40 (c ¼ 1.0, CHCl3). Spectoscopic data: identical to those
of 8a.
(2S,4R)-1-[(4-Methoxyphenyl)methoxy]-6-[4-(phenylmethoxy)phenyl]hexane-2,4-diol (10). To a
stirred soln. of 8 (5.0 g, 11.52 mmol) in dry THF (50 ml) under N2 at 08 was added Red-Alꢄ soln. in
toluene (6.84 ml, 34.55 mmol of 70% w/w) and the mixture was stirred at r.t. for 2 h. After completion of
the reaction, the mixture was quenched with sat. aq. NH4Cl soln. (20 ml) and then extracted with AcOEt
(100 ml). The combined org. extract was washed with brine, dried (Na2SO4), and concentrated and the
residue purified by CC: pure 10 (3.61 g, 72%). [a]2D2 ¼ þ3.2 (c ¼ 2.3, CHCl3). 1H-NMR (200 MHz): 7.40 –
7.23 (m, 5 H); 7.19 (d, J ¼ 8.0, 2 H); 7.05 (d, J ¼ 8.0, 2 H); 6.82 (d, J ¼ 8.0, 4 H); 5.01 (s, 2 H); 4.48 (d, J ¼
14, 1 H); 4.42 (d, J ¼ 14.0, 1 H); 4.08 – 4.02 (m, 1 H); 3.88 – 3.81 (m, 1 H); 3.78 (s, 3 H); 3.41 (dd, J ¼ 12.0,
4.0, 1 H); 3.31 (dd, J ¼ 12.0, 7.0, 1 H); 2.75 – 2.69 (m, 1 H); 2.66 – 2.59 (m, 1 H); 1.80 – 1.49 (m, 4 H).
13C-NMR (50 MHz): 159.9; 157.2; 138.2; 134.1; 130.0; 129.9; 129.8; 129.0; 128.1; 127.8; 113.9; 113.1; 77.8;
73.4; 71.9; 70.5; 55.8; 39.9; 39.3; 30.5. ESI-MS: 459 ([M þ Na]þ). Anal. calc. for C27H32O5 (436.54): C
74.31, H 7.34; found: C 74.22, H 7.39.
(2R,4S)-1-[(4-Methoxyphenyl)methoxy]-6-[4-(phenylmethoxy)phenyl]hexane-2,4-diol (10a). As de-
scribed for 10: 10a (74%). [a]2D2 ¼ ꢁ2.9 (c ¼ 2.0, CHCl3). Spectroscopic data: identical to those of 10.
(4S,6R)-4-{[(4-Methoxyphenyl)methoxy]methyl}-2,2-dimethyl-6-{2-[4-(phenylmethoxy)phenyl]ethyl}-
1,3-dioxane (2). To 10 (3.5 g, 8.02 mmol) in dry CH2Cl2 (30 ml), 2,2-dimethoxypropane (20 ml) was
added followed by the addition of a cat. amount of TsOH. The mixture was stirred for 30 min at r.t. After
completion of the reaction, sat. aq. NaHCO3 soln. (10 ml) was added, the mixture extracted with CH2Cl2
(3 ꢂ 30 ml), the combined org. layer dried (Na2SO4) and concentrated, and the residue purified by CC:
pure 2 (3.63 g, 95%). [a]2D2 ¼ þ10.67 (c ¼ 2.9, CHCl3). 1H-NMR (200 MHz): 7.41 – 7.22 (m, 5 H); 7.15 (d,
J ¼ 8.0, 2 H); 7.02 (d, J ¼ 8.0, 2 H); 6.79 (d, J ¼ 8.0, 2 H); 6.77 (d, J ¼ 8.0, 2 H); 5.00 (s, 2 H); 4.50 (d, J ¼
14.0, 1 H); 4.41 (d, J ¼ 14.0, 1 H); 4.05 – 3.97 (m, 1 H); 3.78 (s, 3 H); 3.66 – 3.60 (m, 1 H); 3.42 – 3.30 (m,
2 H); 2.66 – 2.59 (m, 1 H); 2.57 – 2.51 (m, 1 H); 1.75 – 1.49 (m, 4 H); 1.42 – 1.34 (m, 3 H); 1.33 (s, 3 H).
13C-NMR (50 MHz):159.2; 157.2; 137.3; 134.1; 129.4; 129.3; 129.2; 128.5; 127.7; 127.3; 114.9; 113.2; 100.3;
73.1; 72.8; 70.0; 66.9; 65.8; 55.0; 38.2; 35.2; 31.0; 25.1; 24.9. ESI-MS: 499 ([M þ Na]þ). Anal. calc. for
C30H36O5 (476.60): C 75.63, H 7.56; found: C 75.74, H 7.53.
(4R,6S)-4-{[(4-Methoxyphenyl)methoxy]methyl}-2,2-dimethyl-6-{2-[4-(phenylmethoxy)phenyl]ethyl}-
1,3-dioxane (2a). As described for 2: 2a (94%). [a]2D2 ¼ ꢁ10.4 (c ¼ 2.2, CHCl3). Spectroscopic data:
identical to those of 2.
(4S,6R)-2,2-Dimethyl-6-{2-[4-(phenylmethoxy)phenyl]ethyl}-1,3-dioxan-4-methanol (11). To a soln.
of 2 (3.5 g, 7.35 mmol) in CH2Cl2/H2O 19 :1 was added DDQ (5.0 g, 22.02 mmol) at r.t. in portions. The
mixture was stirred for 2 h at r.t. and filtered. The filtrate was concentrated and the residue purified by
CC: 11 (1.64 g, 63.0%). [a]2D2 ¼ þ2.7 (c ¼ 0.9, CHCl3). 1H-NMR (200 MHz): 7.96 (d, J ¼ 8.0, 2 H); 7.42 –
7.31 (m, 5 H); 6.99 (d, J ¼ 8.0, 2 H); 5.12 (s, 2 H); 4.38 – 4.32 (m, 1 H); 4.16 – 4.10 (m, 1 H); 3.71 – 3.65 (m,
1 H); 3.58 – 3.51 (m, 1 H); 2.76 – 2.69 (m, 1 H); 2.37 – 2.29 (m, 1 H); 1.90 – 1.52 (m, 4 H); 1.26 (s, 6 H).
13C-NMR (50 MHz): 156.4; 141.0; 129.7; 129.6; 128.8; 128.1; 127.8; 114.9; 96.5; 74.0; 70.2; 69.9; 40.2; 40.0;
31.7; 27.1; 26.8. ESI-MS: 379 ([M þ Na]þ). Anal. calc. for C22H28O4 (356.46): C 74.16, H 7.87; found: C
74.24, H 7.81.
(4R,6S)-6-2,2-Dimethyl-6-{2-[4-(phenylmethoxy)phenyl]ethyl}-1,3-dioxan-4-methanol (11a). As de-
scribed for 11: 11a (64%). [a]2D2 ¼ ꢁ2.9 (c ¼ 0.9, CHCl3). Spectroscopic data: identical to those of 11.
(4S,6R)-2,2-Dimethyl-4-[(1E)-2-phenylethenyl]-6-{2-[4-(phenylmethoxy)phenyl]ethyl}-1,3-dioxane
(12). To a stirred soln. of oxalyl chloride (0.5 ml, 8.42 mmol) in dry CH2Cl2 (20 ml), DMSO (0.38 ml,
12.62 mmol) was added at ꢁ 788, and the mixture was stirred at ꢁ 788 for 0.5 h. A soln. of 11 (1.5 g,
4.21 mmol) in CH2Cl2 (10 ml) was added at ꢁ 788, and the mixture was stirred for 1.5 h at ꢁ 788 Et3N

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(0.74 ml, 20.99 mmol) was added at 08, and the mixture was stirred for an additional 30 min. After
completion of the reaction, the mixture was diluted with H2O (5 ml) and extracted with CH2Cl2
(2 ꢂ 20 ml) and the extract washed with brine (20 ml), dried (Na2SO4), and concentrated to give
(4S,6R)-2,2-dimethyl-6-{2-[4-(phenylmethoxy)phenyl]ethyl}-1,3-dioxan-4-carboxaldehyde (1.3 g, 80%).
Because of extensive oxidation of the aldehyde to the corresponding acid, we used it immediately for the
next step.
To a soln. containing benzyltriphenylphosphonium bromide (1.5 g, 5.48 mmol) in dry THF (5 ml)
was added dropwise 1.6m BuLi in hexane (2.52 ml, 4.03 mmol) via a syringe under N2 at r.t. After stirring
for 10 min, the preceding aldehyde (1.3 g, 3.67 mmol), diluted in dry THF, was dropwise added to the red-
orange Wittig reagent. The mixture was stirred for 4 h at r.t. to afford a yellow soln. with a white
precipitate. Then CH2Cl2 and sat. NH4Cl soln. were added until pH 6. The aq. layer was extracted with
CH2Cl2, the combined org. layer dried (MgSO4) and concentrated, and the residue purified by CC: 12
1
(1.2 g, 78%). [a]D22 ¼ þ5.6 (c ¼ 0.9, CHCl3). H-NMR (200 MHz): 7.99 (d, J ¼ 8.0, 2 H); 7.53 – 7.48 (m,
4 H); 7.41 – 7.29 (m, 6 H); 7.10 (d, J ¼ 8.0, 2 H); 6.88 (dd, J ¼ 14.0, 7.0, 1 H); 6.28 (d, J ¼ 14.0, 1 H); 5.29 (s,
2 H); 4.65 – 4.58 (m, 1 H); 3.72 – 3.65 (m, 1 H); 2.63 – 2.56 (m, 2 H); 1.73 – 1.49 (m, 4 H); 1.42 (s, 6 H).
13C-NMR (50 MHz): 157.0; 141.8; 137.4; 134.7; 130.2; 129.8; 129.7; 128.9; 128.2; 128.0; 114.9; 96.5; 70.2;
68.8; 68.5; 39.8; 39.4; 31.6; 31.0. ESI-MS: 451 ([M þ Na]þ). Anal. calc. for C29H32O3 (428.56): C 81.31, H
7.48; found: C 81.25, H 7.54.
(4R,6S)-2,2-Dimethyl-4-[(1E)-2-phenylethenyl]-6-{2-[4-(phenylmethoxy)phenyl]ethyl}-1,3-dioxane
(12a). As described for 12: 12a (75%). [a]2D2 ¼ ꢁ5.2 (c ¼ 1.5, CHCl3). Spectroscopic data: identical to
those of 12.
(3R,5R)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol (1). A soln. of 12 (200 mg, 2.80 mmol) in
MeOH (5 ml) in the presence of TsOH (10 mg) was stirred for 3 h. After the completion of the reaction,
concentration afforded the crude diol. This residue of unsaturated diol in MeOH (15 ml) in the presence
of a cat. amount of Pd/C was stirred for 2 h under H2 (1 atm). After filtration and concentration, the
crude residue was purified by CC: 1 (82 mg, 60%). [a]2D2 ¼ þ9.2 (c ¼ 1.1, CHCl3); 1H-NMR (200 MHz):
7.26 – 7.12 (m, 5 H); 6.93 (d, J ¼ 8.0, 2 H); 6.71 (d, J ¼ 8.0, 2 H); 4.02 – 3.89 (m, 2 H); 2.81 – 2.50 (m, 4 H);
1.89 – 1.69 (m, 4 H); 1.60 (t, J ¼ 6.0, 2 H). 13C-NMR (50 MHz): 154.2; 142.0; 133.4; 129.4; 128.4; 128.3;
126.0; 115.5; 69.0; 68.9; 42.4; 39.1; 39.0; 32.1; 31.2. ESI-MS: 301 ([M þ H]þ). Anal. calc. for C19H24O3
(300.39): C 76.00, H 8.00; found: C 76.18, H 8.06.
(3S,5S)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol (1a). As described for 1: 1a (63%). [a]D22
ꢁ10.2 (c ¼ 1.3, CHCl3). Spectroscopic data: identical to those of 1.
¼
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Received March 29, 2012