Stereoselective total synthesis of (3S,5S)-1,7-bis(4-hydroxyphenyl)heptane-3,5-diol, (3S,5S)-alpinikatin, and its diastereoisomers

Article abstract of DOI:10.1002/hlca.201500073

Stereoselective synthesis of the diarylheptanoids, (3S,5S)-1,7-bis(4-hydroxyphenyl)heptane-3,5-diol (1), (3S,5S)-alpinikatin (3), and their diastereoisomers (2 and 4, resp.), was achieved from readily available 4-hydroxybenzaldehyde. The synthetic sequenc

Full text of DOI:10.1002/hlca.201500073

Helvetica Chimica Acta – Vol. 98 (2015)
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Stereoselective Total Synthesis of (3S,5S)-1,7-Bis(4-hydroxyphenyl)heptane-
3,5-diol, (3S,5S)-Alpinikatin, and Its Diastereoisomers
by Kunuru Venkatesham, Sudina Purushotham Reddy, Baggu Chinnababu, and
Katragadda Suresh Babu*
Division of Natural Products Chemistry, Natural Products Laboratory, CSIR-Indian Institute of
Chemical Technology, Hyderabad-500 007, India
(phone: þ 91-40-27191881; fax: þ 91-40-27160512; e-mail: suresh@iict.res.in)
Stereoselective synthesis of the diarylheptanoids, (3S,5S)-1,7-bis(4-hydroxyphenyl)heptane-3,5-diol
(1), (3S,5S)-alpinikatin (3), and their diastereoisomers (2 and 4, resp.), was achieved from readily
available 4-hydroxybenzaldehyde. The synthetic sequences involve Brownsꢀs allylation and Et2Zn
mediated diastereoselective alkynylation reaction as key steps.
Introduction. – In recent decades, diarylheptanoids play an important role in
medicinal and synthetic organic chemistry. Diarylheptanoids are structurally distinctive
plant metabolites and have been mainly isolated from Zingiber, Curcuma, Alpinia,
Viscum, Alnus, and Myrica species [1]. These diarylheptanoids are exhibiting a broad
range of biological and pharmacological properties. Especially, linear diarylheptanoids
show antiplatelet, anti-inflammatory, antiproliferative, cytotoxic, and prostaglandin-
E2-inhibitory activities [2]. Diarylheptanoids, particularly linear diarylhepatanoids with
a 1,3-diol system, have attracted the attention of both biologists and chemists in recent
years. (3S,5S)-1,7-Bis(4-hydroxyphenyl)heptane-3,5-diol (1; Fig.) was first isolated in
1996 by Wu et al [3a]. It was also isolated from the seeds of Alpinia blepharocalyx in
2001 by Kadota and co-workers [3b]. The structure of 1 was confirmed on the basis of
its spectroscopic data, and it exhibits significant antiproliferative activity against murin
colon 26-L5 carcinoma and human HT-1086 fibrosarcoma with ED50 values of 12.8 and
94.4 mm, respectively. (3S,5S)-Alpinikatin (3; Fig.), a structurally related linear
Figure. Structures of diarylheptanoids 1 – 4
ꢁ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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diarylheptanoid, was isolated from the AcOEt extract of the seeds of Alpinia
katsumadai by Seo and co-workers in 2011 [4]. In continuation of our program towards
the synthesis of biologically active compounds [5], we developed a simple and flexible
route to the total synthesis of (3S,5S)-1,7-bis(4-hydroxyphenyl)heptane-3,5-diol (1),
(3S,5S)-Alpinikatin (3), and its C(5)-diastereoisomers 2 and 4, respectively, from
commercially available 4-hydroxybenzaldehyde (5).
The target molecules 1 – 4 can be easily envisaged from the chiral homoallyl alcohol
derivative 10, which was prepared via Brownꢀs alkylation reaction of an aldehyde
derived from 4-hydroxybenzaldehyde (5; Scheme 1).
Scheme 1. Retro Synthetic Analysis
Results and Discussion. – As outlined in Schemes 1 – 3, the syntheses of compounds
1 – 4 started with the commercially available starting material 4-hydroxybenzaldehyde
(5). This aldehyde was converted to the unsaturated ester 6 according to a known
procedure [6]. Reduction of the C¼C bond in compound 6 with NiCl2 · 6 H2O/NaBH4 in
MeOH afforded the saturated ester 7 in 92% yield [7]. The latter was again reduced
with DIBAL-H in dry CH2Cl2 to furnish the corresponding aldehyde 8 [6], which was
subjected to Brownꢀs asymmetric allylation [8] with 1m solution of (þ)-allyl[di(isopi-
nocamphenyl)borane] [9] in pentane to furnish the chiral allylic alcohol 9 [9] in 88%
yield (97% ee, determined by chiral HPLC). The homo allylic secondary OH group in
9 was protected as tert-butyl(dimethyl)silyl (TBS) ether 10 by treatment with TBSÀCl
and imidazole in 93% yield. Further, this terminal alkene 10 was subjected to OsO4-
catalyzed dihydroxylation and NaIO4-mediated cleavage to give the corresponding
aldehyde 11 [10] in 86% yield. Aldehyde 11 was reacted with 1-(benzyloxy)-4-
ethynylbenzene [11] by using Et2Zn in toluene (10 mmol) and a catalytic solution of
(S)-BINOL (1 mmol), PhOH (1 mmol), and (iPrO)4Ti (2.5 mmol) in dry ether to
afford compound 12 in 96% yield (98% de), and its diastereoisomer 13 was achieved by
using (R)-BINOL in 94% yield (97% de). Further, each of the two isomers 12 and 13
was subjected to debenzylation using 10% Pd/C in the presence of H2 gas to give
the corresponding phenols 14 and 15 in 75 and 73% yield, respectively. Finally,

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Scheme 2
a) NiCl2 · 6 H2O, NaBH4, MeOH, 08 to r.t., 1 h; 92%. b) DIBAL-H, CH2Cl2, À 788, 0.5 h; 93%. c)
AllylBIpc2 (from (þ)-Ipc2BCl and allylmagnesium bromide), Et2O, À 1008, 1 h; 88%. d) TBSÀCl,
Imidazole, CH2Cl2, 08 to r.t., 6 h; 93%. e) 1) OsO4, NMO, acetone/H2O (9 :1), r.t., 2 h; 2) NaIO4, THF/
H2O (6 :4), 08 to r.t., 1 h; 86%. f) For 12: 1-(benzyloxy)-4-ethynylbenzene, Et2Zn, (S)-BINOL,
(iPrO)4Ti, PhOH, 96%; for 13: 1-(benzyloxy)-4-ethynylbenzene, Et2Zn, (R)-BINOL, (iPrO)4Ti, PhOH,
94%. g) H2, Pd/C, AcOEt, 24 h; 75 and 73%, resp. h) TBAF, THF, 08 to r.t., 12 h; 98 and 96%, resp.
deprotection of the TBS group in 14 and 15 by using Bu4NF (TBAF) in THF gave the
desired target compounds (3S,5S)-1,7-bis(4-hydroxyphenyl)heptane-3,5-diol (1) in
98% yield, and its diastereoisomer 2 in 96% yield.
The other target molecules 3 and 4 were achieved from the intermediate 11, which
was reacted with phenylacetylene by using Et2Zn in toluene (10 mmol) and a catalytic
amount of (R)-BINOL (1 mmol), PhOH (1 mmol) and (iPrO)4Ti (2.5 mmol) in dry
Et2O to obtain compound 16 in 93% yield (97% de). The other diastereoisomer 17 was

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Scheme 3
a) For 16: phenylacetylene, Et2Zn, (R)-BINOL, (iPrO)4Ti, PhOH, 5 h; 93%; for 17: phenylacetylene,
Et2Zn, (S)-BINOL, (iPrO)4Ti, PhOH, 5 h; 92%. b) Red-Alꢂ, THF, 08 to r.t., 0.5 h; 96 and 95%, resp. c)
TiCl4, CH2Cl2, 08 to r.t., 1 h; 90 and 89% resp.
prepared from the same intermediate 11 by reacting Et2Zn in toluene and (S)-BINOL
in 92% yield (98% de). The alkyne intermediates 16 and 17 were reduced with Red-Alꢂ
in THF to obtain the corresponding trans-alkenes 18 and 19 in 96 and 95% yields,
respectively. Finally, deprotection of the TBS and Bn groups was achieved by treatment
of 18 and 19 with TiCl4 [12] in CH2Cl2 to afford the target compounds 3 and 4 in 90 and
89% yields, respectively. The physical and spectroscopic properties of 1 and 3 were in
complete agreement with those reported for the natural products [3][4].
In conclusion, the stereoselective syntheses of the natural diarylheptanoids 1 and 3,
and its diastereoisomers 2 and 4 were successfully achieved with high yields from the
commercially available starting material 4-hydroxybenzaldehyde (5) by applying
Brownꢀs asymmetric allylation, and Et2Zn-mediated diastereoselective alkynylation as
the key steps.
The authors K. V, S. P. R, and B. C. are grateful to UGC-CSIR, New Delhi, India, for financial
support in the form of fellowship.
Experimental Part
General. All the reagents and solvents were of anal. grade and used without further purification,
unless otherwise stated. Technical-grade AcOEt and hexanes used for column chromatography (CC)
were distilled before use. THF, when used as solvent for reactions, was freshly distilled from Na/
benzophenone ketyl. All the reactions were performed under N2 in flame or oven-dried glassware with
magnetic stirring. Column chromatography (CC): silica gel (SiO2, 60 – 120 mesh) packed in glass

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columns. Optical rotations: Anton Paar MLP 200 modular circular digital polarimeter by using a 2-ml cell
with path length of 1 dm. FT-IR Spectra: PerkinElmer 683 IR spectrophotometer; neat or as thin films in
KBr optics; n˜ in cmÀ1. 1H- and 13C-NMR spectra: Bruker-Avance 300 instrument (at 300 MHz, resp.) at
r.t., in CDCl3; d in ppm rel. to Me4Si as internal standed, J in Hz. MS: Agilent Technologies LCMSD trap
SL spectrometer; in m/z.
Ethyl 3-[4-(Benzyloxy)phenyl]propanoate (7) [8]. To a cooled (08) stirred soln. of 6 [7] (7 g,
24.8 mmol) in MeOH (50 ml) was added NiCl2 · 6 H2O (4.9 g, 0.2 mmol). To this soln., NaBH4 (1.8 g,
49.6 mmol) was added portionwise at 08, and the mixture was stirred at r.t. for 0.5 h. The reaction was
quenched with ice-cubes, and the mixture was extracted with AcOEt (3 Â 75 ml). The combined org.
layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was
purified by CC (AcOEt/hexane) to give 7 (6.47 g, 92%) as colorless liquid. IR (neat): 2981, 1732, 1512,
1174, 736. 1H-NMR (300 MHz, CDCl3): 7.40 – 7.14 (m, 5 H); 7.11 (d, J ¼ 8.6, 2 H); 6.90 (d, J ¼ 8.6, 2 H);
5.03 (s, 2 H); 4.12 (q, J ¼ 7.1, 14.0, 2 H); 2.89 (t, J ¼ 7.6, 2 H); 2.53 (t, J ¼ 8.0, 2 H); 1.23 (t, J ¼ 7.17, 3 H).
13C-NMR (75 MHz, CDCl3): 172.9; 157.1; 137.0; 132.8; 129.2; 128.4; 127.8; 127.3; 114.7; 69.9; 60.3; 36.1;
30.0; 14.7. ESI-MS: 307 ([M þ Na]þ).
(3S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol (9) [6]. To a soln. of 7 (5.0 g, 17.5 mmol) in CH2Cl2
(25 ml) was added DIBAL-H (20% in toluene, 8.8 ml, 17.5 mmol) dropwise down the walls of the flask at
À 708. After completion of the reaction (monitored by TLC), it was quenched by addition of MeOH
(5 ml) at 08 followed by addition of sat. sodium potassium tartrate soln. (10 ml), and was stirred at r.t. for
6 h. The org. layer was separated, and the aq. layer extracted with CH2Cl2 (3 Â 60 ml). The combined org.
layer was washed with brine (2 Â 75 ml), dried (Na2SO4), and the org. solvent evaporated under reduced
pressure. The crude product was purified by CC (SiO2, 30% AcOEt/hexane) to give aldehyde 8 (3.88 g,
92%) [6] as colorless viscous liquid.
To a soln. of 8 (3 g, 12.4 mmol) in 32 ml of Et2O at À 788, 1m soln. of (þ)-allylBIpc2 [8] in pentane
(14.09 ml, 14.1mmol) was added. The mixture was stirred for 20 h, at À 788 and then warmed to 08. The
reaction was quenched by the slow addition of 1 ml of 3n NaOH and 12 ml of 30% H2O2, and then the
mixture was heated to reflux for 1 h. The aq. layer was extracted (2 Â 30 ml) with Et2O. The combined
org. layers were washed with sat. NaHCO3, H2O, brine, dried (MgSO4), and concentrated in vacuo. The
crude product was purified by CC (30% AcOEt/hexane) to afford 9 (3.10 g, 88%) as colorless oil. [a]D24
¼
À10 (c ¼ 1.6, CHCl3) ([a]2D4 ¼ À16 (c ¼ 1.8, CHCl3) [9]). IR (neat): 3440, 2924, 2850, 1610, 1508, 1457,
1377, 1236, 1175, 1018. 1H-NMR (300 MHz, CDCl3): 7.40 – 7.13 (m, 5 H); 7.07 (d, J ¼ 8.7, 2 H); 6.88 (d, J ¼
8.7, 2 H); 5.5 – 5.2 (m, 1 H); 5.19 – 5.07 (m, 1 H); 5.02 (s, 2 H); 3.69 – 3.57 (m, 1 H); 2.80 – 2.56 (m, 2 H);
2.35 – 2.12 (m, 2 H); 1.79 – 1.68 (m, 2 H); 1.58 (br. s, 1 H). 13C-NMR (75 MHz, CDCl3): 157.0; 137.2;
129.3; 128.5; 127.8; 127.4; 118.3; 114.5; 69.0; 42.0; 38.5; 31.1. ESI-MS: 305 ([M þ Na]þ).
({(3S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-yl}oxy)(tert-butyl)dimethylsilane (10). To a stirred soln.
of 9 (2.4 g, 8.49 mmol) in CH2Cl2 (15 ml) was added imidazole (1.73 g, 25.49 mmol), followed by (tert-
butyl)(dimethyl)silyl chloride (2.55 g, 16.98 mmol) at 08. The mixture was stirred at r.t. for 24 h. After
completion of the reaction, the mixture was diluted with H2O (20 ml) and extracted with CH2Cl2 (2 Â
20 ml). The combined org. layers were washed with brine (20 ml), dried (Na2SO4), and concentrated,
the crude product was purified by CC (5% AcOEt/hexane) to give 10 (3.13 g, 93%) as colorless oil.
[a]2D4 ¼ À10 (c ¼ 1.2, CHCl3). IR (neat): 2932, 1748, 1512, 1250, 833. 1H-NMR (300 MHz, CDCl3): 7.46 –
7.29 (m, 5 H); 7.08 (d, J ¼ 8.49, 2 H); 6.89 (d, J ¼ 8.49, 2 H); 5.89 – 5.74 (m, 1 H); 5.04 (t, J ¼ 8.8, 4 H);
3.80 – 3.70 (m, 1 H); 2.71 – 2.46 (m, 2 H); 2.26 (t, J ¼ 6.6, 2 H); 1.78 – 1.64 (m, 2 H); 0.91 (s, 9 H); 0.03 (s,
6 H). 13C-NMR (75 MHz, CDCl3): 156.8; 137.1; 135.0; 134.9; 129.1; 128.4; 127.8; 127.4; 116.8; 114.6; 71.5;
69.9; 41.8; 38.8; 30.8; 29.6; 25.0; 4.4. ESI-MS: 419 ([M þ Na]þ).
(3S)-5-[4-(Benzyloxy)phenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}pentanal (11) [10]. To a soln. of 10
(2.5 g, 7.5 mmol) in a mixture of acetone/H2O 3 :1 (20 ml) was added OsO4 (0.48 ml, 4% aq. soln.,
0.075 mmol) and N-methylmorpholine N-oxide (NMO; 1.7 g, 2.6 mmol) at 258, and stirred for 5 h, the
solvent was evaporated, and the residue was extracted with AcOEt (30 ml). The org. layers were washed
with brine (10 ml), dried (Na2SO4), and concentrated in vacuo. To a soln. of above crude diol in a mixture
of THF/H2O 4 :1 (50 ml), NaIO4 (2.4 g, 11.6 mol) was added, and the mixture was stirred for 1 h at 258.
The solid was removed by filtration, and the filtrate was extracted with AcOEt (40 ml). The org. layers
were washed with brine (10 ml), dried (Na2SO4), and concentrated in vacuo. The crude aldehyde was

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purified by CC (5% AcOEt/hexane) to give aldehyde 11 (2.16 g, 86%) as colorless liquid. [a]2D4 ¼ À0.1
1
(c ¼ 0.1, CHCl3). IR (neat): 3425, 2926, 1725, 1511, 1243. H-NMR (300 MHz, CDCl3): 9.81 (t, J ¼ 2.2,
1 H); 7.4 – 7.30 (m, 5 H); 7.08 (d, J ¼ 8.5, 2 H); 6.90 (d, J ¼ 8.5, 2 H); 5.04 (s, 2 H); 4.26 – 4.21 (m, 1 H);
2.63 – 2.56 (m, 4 H); 1.86 – 1.80 (m, 2 H); 0.9 (s, 9 H); 0.07 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 202.0;
157.0; 139.2; 137.0; 133.9; 129.1; 128.5; 127.8; 127.4; 114.8; 114.0; 70.0; 67.6; 50.7; 39.7; 31.8; 30.5; 25.7; À
4.41; À 4.66. ESI-MS: 437 ([M þ K]þ).
(3R,5S)- and (3S,5S)-1,7-Bis[4-(benzyloxy)phenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}hept-1-yn-3-ol
(12 and 13, resp.). To a soln. of Et2Zn (0.134, 1.1 m) in toluene (12 ml, 10.0 mmol) was added a soln. of 1-
(benzyloxy)-4-ethynylbenzene (2.08 g, 10.0 mmol) in dry toluene (3 ml) at r.t., and the mixture was
heated for 1 h at reflux. A soln. of BINOL ((S)-BINOL and (R)-BINOL for 12 and 13, resp.; 0.286 g,
1.0 mmol), PhOH (1 ml, 1.0 mmol), and (iPrO)4Ti (0.710 ml, 2.5 mmol) in anh. Et2O (3 ml) was stirred
for 30 min. This soln. was added to the mixture, which was stirred for 1 h at r.t. before adding aldehyde 11
(1 g, 2.5 mmol). The entire mixture was stirred for 4 h at r.t., after completion of the reaction, the
reaction was quenched with a NH4Cl soln. (12 ml), and the mixture was extracted with AcOEt (2 Â
10 ml). The combined org. layer was washed with 2n NH4Cl (2 Â 5 ml), NaHCO3 (2 Â 5 ml), and brine
(10 ml), dried (MgSO4), and evaporated under reduced pressure. The crude residue was separated by CC
(7% AcOEt/hexane) to give 12 (1.46 g, 96%) with 98% de (determined by RP-HPLC (Atlantis dC18
column, 4.6 Â 150, 5 mm; mobile phase, 80% MeCN in H2O, flow rate, 1.0 ml/min, detection at 210 nm, tR
32.152 min) as colorless oil. [a]2D4 ¼ À7.5 (c ¼ 0.4, CHCl3). IR (neat): 3448, 2925, 1508, 1244, 832.
1H-NMR (300 MHz, CDCl3): 7.46 – 7.29 (m, 12 H); 7.10 (d, J ¼ 8.3, 2 H); 6.9 (d, J ¼ 8.3, 6 H); 5.04 (d, J ¼
5.2, 4 H); 4.88 – 4.81 (m, 1 H); 4.23 – 4.09 (m, 1 H); 2.64 – 2.49 (m, 2 H); 2.06 – 1.86 (m, 4 H); 0.92 (s,
9 H); 0.11 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 158.8; 157.0; 137.1; 136.1; 134.2; 133.1; 129.2; 128.6;
128.6; 128.1; 127.9; 127.5; 125.8; 114.8; 88.8; 84.5; 70.0; 60.4; 42.7; 38.9; 30.5; 25.9; À 4.22; À 4.54. ESI-
MS: 629 ([M þ Na]þ).
Data of 13. Colorless oil. Yield: 1.43 g (94%). 97% de (determined by RP-HPLC (Atlantis dC18
column, 4.6 Â 150, 5 mm; mobile phase, 80% MeCN in H2O, flow rate, 1.0 ml/min, detection at 210 nm, tR
26.069 min). [a]D24 ¼ À17.5 (c ¼ 0.1, CHCl3). IR (neat): 3448, 2925, 1508, 1244, 832. 1H-NMR (300 MHz,
CDCl3): 7.12 – 7.06 (m, 12 H); 7.10 (d, J ¼ 8.3, 2 H); 6.90 (d, J ¼ 8.3, 6 H); 5.04 (d, J ¼ 5.2, 4 H); 4.79 – 4.72
(m, 1 H); 4.07 – 3.98 (m, 1 H); 2.65 – 2.53 (m, 2 H); 1.97 – 1.74 (m, 4 H); 0.92 (s, 9 H); 0.11 (s, 6 H).
13C-NMR (75 MHz, CDCl3): 158.8; 157.0; 137.1; 136.1; 134.2; 133.1; 129.2; 128.6; 128.6; 128.1; 127.9;
127.5; 125.8; 114.8; 88.8; 84.5; 70.0; 60.4; 42.7; 38.9; 30.5; 25.9; À 4.22; À 4.54. ESI-MS: 629 ([M þ Na]þ).
4,4’-[(3S,5S)- and (3S,5R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-5-hydroxyheptane-1,7-diyl]diphenol
(14 and 15, resp.). 10% Pd/C (0.008 g, 0.00008 mmol) was added to a soln. of 12 and 13 (0.5 g,
0.0008 mmol) in AcOEt (5 ml). The mixture was stirred overnight under H2 atmosphere. After the
completion of reaction, the mixture was filtered through Celite, and the resulting filtrate was
concentrated in vacuo. The residue was purified by CC (40% AcOEt/hexane) to give 14 (0.265 g,
1
75%) as colorless liquid. [a]2D4 ¼ À5 (c ¼ 0.3, CHCl3). IR (neat): 3404, 2930, 1513, 1244, 831. H-NMR
(300 MHz, CDCl3): 7.02 (dd, J ¼ 8.3, 16.6, 4 H); 6.74 (dd, J ¼ 6.7, 8.3, 4 H); 5.13 (br. s, 1 H); 4.99 (br. s,
1 H); 4.03 (m, 2 H); 3.74 – 3.65 (m, 1 H); 2.76 – 2.41 (m, 4 H); 1.91 – 1.69 (m, 4 H); 1.68 – 1.58 (m, 2 H);
0.89 (s, 9 H); 0.08 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 153.8; 133.6; 129.3; 115.2; 71.7; 68.1; 40.6; 39.5;
38.0; 31.3; 30.7; 25.8; À 4.62; À 4.71. ESI-MS: 453 ([M þ Na]).
Data of 15. Colorless liquid. Yield: 0.258 g (73%). [a]3D4 ¼ À7.0 (c ¼ 0.4, CHCl3). IR (neat): 3404,
2930, 1513, 1250, 831.1H-NMR (300 MHz, CDCl3): 7.02 (dd, J ¼ 8.3, 16.6, 4 H); 6.75 (dd, J ¼ 4.4, 8.3, 4 H);
5.13 (br. s, 1 H); 4.99 (m, 1 H); 4.07 – 3.97 (m, 1 H); 3.75 – 3.64 (m, 1 H); 2.76 – 2.45 (m, 4 H); 1.92 – 1.72
(m, 2 H); 1.72 – 1.58 (m, 4 H); 0.91 (s, 9 H); 0.09 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 153.9; 133.6;
129.3; 115.2; 72.9; 70.7; 60.5; 42.5; 39.9; 39.3; 30.7; 30.0; 25.8; À 4.0; À 4.7. ESI-MS: 453 ([M þ Na]þ).
(3S,5S)- and (3R,5S)-1,7-Bis(4-hydroxyphenyl)heptane-3,5-diol (1 and 2, resp.). To a soln. of 14 and
15 (50 g, 0.116 mmol) in THF (3 ml), TBAF (1.0m soln. in THF, 0.116 ml, 0.116 mmol) was added
dropwise at 08. The mixture was stirred at r.t. for 12 h. After completion of the reaction, the solvent was
removed in vacuo, and the crude residue was separated by CC (50% AcOEt/hexane) to afford 1 (34 mg,
1
96%) as colorless oil. [a]2D4 ¼ À15 (c ¼ 0.4, MeOH). IR (neat): 3448, 2924, 1633, 1220, 771. H-NMR
(300 MHz, CDCl3): 7.02 (d, J ¼ 8.3, 4 H); 6.74 (d, J ¼ 9.0, 4 H); 4.04 (br. s, 2 H); 3.50 – 3.46 (m, 2 H);

Helvetica Chimica Acta – Vol. 98 (2015)
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2.80 – 2.65 (m, 4 H); 1.87 – 1.60 (m, 6 H). 13C-NMR (300 MHz, CDCl3): 154.2; 132.8; 128.7; 114.6; 67.4;
42.8; 39.1; 30.6. ESI-MS: 339.2 ([M þ Na]þ).
Data of 2. Yield: 34 mg (95%). Colorless oil. [a]2D4 ¼ À5 (c ¼ 0.8, MeOH). IR (neat): 3449, 2922,
1636, 1223, 762. 1H-NMR (300 MHz, CDCl3): 7.02 (d, J ¼ 7.5, 4 H); 6.74 (d, J ¼ 7.5, 4 H); 3.38 – 3.32 (m,
2 H); 2.76 – 2.49 (m, 4 H); 1.82 – 1.66 (m, 4 H); 1.62 – 1.55 (m, 2 H). 13C-NMR (300 MHz, CDCl3): 154.3;
132.8; 129.0; 114.9; 71.5; 42.4; 39.5; 30.0. ESI-MS: 339.2 ([M þ Na]þ).
(3S,5S)- and (3R,5S)-7-[4-(Benzyloxy)phenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylhept-1-
yn-3-ol (16 and 17, resp.). To a soln. of Et2Zn in toluene (10 ml, 10.0 mmol) was added a soln. of
phenylacetylene (1.02 g, 10.0 mmol) in dry toluene (1 ml) at r.t., and the mixture was heated at reflux for
1 h. A catalyst soln. of BINOL ((R)- and (S)-BINOL for 16 and 17, resp.) (0.286 g, 1.0 mmol), PhOH
(94 mg, 1.0 mmol), and (iPrO)4Ti (0.78 ml, 2.5 mmol) in anh. Et2O (3 ml) was stirred for 35 min. This
soln. was added to the mixture, and the mixture was stirred for 1 h at r.t. before adding aldehyde 11 (1 g,
2.5 mmol). The entire mixture was stirred for 4 h at r.t., after completion of the reaction, the reaction was
quenched with NH4Cl (10 ml) and extracted with AcOEt (2 Â 10 ml). The combined org. layer was
washed with 2n HCl (2 Â 5 ml), NaHCO3 (2 Â 5 ml), and brine (10 ml), dried (MgSO4), and evaporated
under reduced pressure. The crude product was purified by CC (5% AcOEt/hexane) to give 16 (1.16 g,
93%) with 97% de (determined by RP-HPLC (Atlantis dC18 column, 4.6 Â 150, 5 mm, mobile phase, 80%
MeCN in H2O, flow rate, 1.0 ml/min, detection at 210 nm, tR 20.274 min) as colorless oil. [a]2D4 ¼ À7.5 (c ¼
0.1, CHCl3). IR (neat): 3449, 2929, 1640, 1245, 765. 1H-NMR (300 MHz, CDCl3): 7.45 – 7.27 (m, 10 H);
7.09 (d, J ¼ 8.3, 2 H); 6.87 (d, J ¼ 8.3, 2 H); 5.01 (s, 2 H); 4.81 – 4.74 (m, 1 H); 4.07 – 3.99 (m, 1 H); 2.68 –
2.52 (m, 2 H); 2.13 – 1.80 (m, 4 H); 0.91 (s, 9 H); 0.09 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 157.0; 137.2;
134.4; 131.7; 129.2; 128.5; 128.3; 127.9; 127.4; 122.6; 114.8; 89.9; 85.2; 70.2; 61.6; 44.0; 39.8; 30.2; 25.9; À
4.1; À 4.65. ESI-MS: 523 ([M þ Na]þ).
Data of 17. Colorless oil. Yield: 1.15 g (92%). 97% de (determined by RP-HPLC (Atlantis dC18
column, 4.6 Â 150, 5 mm, mobile phase, 80% MeCN in H2O, flow rate, 1.0 ml/min, detection at 210 nm, tR
15.956 min). [a]2D4 ¼ À22.5 (c ¼ 0.2, CHCl3). IR (neat): 3446, 2928, 1074, 769. 1H-NMR (300 MHz,
CDCl3): 7.46 – 7.27 (m, 10 H); 7.1 (d, J ¼ 8.3, 2 H); 6.89 (d, J ¼ 8.3, 2 H); 5.03 (s, 2 H); 4.90 – 4.83 (m, 1 H);
4.24 – 4.16 (m, 1 H); 2.65 – 2.54 (m, 2 H); 2.07 – 2.00 (m, 2 H); 1.92 – 1.82 (m, 2 H); 0.92 (s, 9 H); 0.11 (s,
6 H). 13C-NMR (75 MHz, CDCl3): 157; 137.1; 134.1; 131.6; 129.1; 128.5; 128.2; 127.8; 127.4; 122.7; 114;
90.0; 84.5; 70.0; 60.4; 42.4; 38.9; 30.4; 25.8; À 4.28; À 4.6. ESI-MS: 523 ([M þ Na]þ).
(1E,3S,5S)- and (1E,3R,5S)-7-[4-(Benzyloxy)phenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-
hept-1-en-3-ol (18 and 19, resp.). To a cooled soln. (08) of propargylic alcohols 16 and 17 (0.2 g,
0.4 mmol) in THF (10 ml), Red-Alꢂ (70 wt.-% in toluene, 1.82 ml, 1 mmol) was added dropwise. The
mixture was stirred for 0.5 h at 08, and the reaction was carefully quenched with a sat. aq. Na2SO4 soln.,
AcOEt was added, and the mixture was warmed to r.t. The org. layer was washed with brine, and the
combined org. extracts were dried (Na2SO4), and concentrated under reduced pressure. The crude
product was purified by CC (30% AcOEt/hexane) to provide allylic alcohol 18 (0.192 g, 96%) as
1
colorless oil. [a]D24 ¼ À25 (c ¼ 0.4, CHCl3). IR (neat): 3414, 2923, 1509, 1239, 750. H-NMR (300 MHz,
CDCl3): 7.45 – 7.28 (m, 10 H); 7.11 (d, J ¼ 8.5, 2 H); 6.89 (d, J ¼ 8.6, 2 H); 6.62 (d, J ¼ 15.8, 1 H); 6.27 (dd,
J ¼ 6.2, 16.0, 1 H); 5.03 (s, 2 H); 4.68 – 4.63 (m, 1 H); 4.04 – 3.98 (m, 1 H); 2.77 – 2.59 (m, 2 H); 1.89 – 1.74
(m, 4 H); 0.9 (s, 9 H); 0.11 (s, 6 H). 13C-NMR (75 MHz, CDCl3): 157.0; 137.1; 136.5; 134.1; 131.8; 130.0;
129.2; 128.5; 127.8; 127.6; 127.4; 126.4; 114.8; 70.6; 70.0; 68.8; 42.5; 39.3; 31.7; 30.9; 25.8; À 3.99; À 4.63.
ESI-MS: 525 ([M þ Na]þ).
Data of 19. Yield: 0.190 g (95%). Colorless oil. [a]2D4 ¼ À6.6 (c ¼ 0.1, CHCl3). IR (neat): 3449, 2929,
1510, 1244, 1075, 773. 1H-NMR (300 MHz, CDCl3): 7.44 – 7.28 (m, 10 H); 7.08 (d, J ¼ 8.5, 2 H); 6.89 (d,
J ¼ 8.5, 2 H); 6.62 (d, J ¼ 15.8, 2 H); 6.27 (dd, J ¼ 6.1, 15.8, 1 H); 5.03 (s, 2 H); 4.50 – 4.44 (m, 1 H); 4.06 –
3.99 (m, 1 H); 2.67 – 2.52 (m, 2 H); 1.86 – 1.80 (m, 4 H); 0.93 (s, 9 H); 0.11 (s, 6 H). 13C-NMR (75 MHz,
CDCl3): 156.9; 137.1; 136.1; 134.3; 132.1; 129.6; 129.1; 128.4; 127.8; 127.4; 127.3; 126.4; 114.8; 113.8; 71.9;
71.5; 69.9; 43.2; 39.8; 30.0; 25.8; À 3.99; À 4.63. ESI-MS: 525 ([M þ Na]þ).
(1E,3S,5S)- and (1E,3R,5S)-7-(4-Hydroxyphenyl)-1-phenylhept-1-ene-3,5-diol (3 and 4, resp.). To a
stirred soln. of 18 and 19 (50 mg, 0.09 mol) in CH2Cl2 (5 ml), TiCl4 (1m in CH2Cl2, 0.07 ml, 0.03 mmol)
was added at 08, and the mixture was stirred at the same temp. for 1 h. The reaction was quenched with
solid NaHCO3 (30 mg), and filtered, the solvent was removed under reduced pressure. The crude residue

1314
Helvetica Chimica Acta – Vol. 98 (2015)
was separated by CC (50% AcOEt; hexane) to afford 3 (26 mg, 89%) as colorless sticky liquid. [a]D24
¼
À9 (c ¼ 0.3, MeOH). IR (neat): 3449, 2925, 1513, 1254; 749. 1H-NMR (300 MHz, CDCl3): 7.41 – 7.20 (m,
5 H); 7.04 (d, J ¼ 8.4, 2 H); 6.73 (d, J ¼ 8.4, 2 H); 6.59 (d, J ¼ 15.8, 1 H); 6.26 (dd, J ¼ 6.2, 16.0, 1 H); 3.96 –
3.87 (m, 1 H); 3.37 – 3.33 (m, 1 H); 2.77 – 2.53 (m, 2 H); 1.82 – 1.70 (m, 4 H). 13C-NMR (75 MHz, CDCl3):
154.1; 136.3; 132.6; 131.9; 130.5; 128.7; 128.5; 127.7; 126.6; 125.6; 114.0; 68.7; 67.0; 43.2; 39.0; 30.3. ESI-
MS: 321.0 ([M þ Na]þ).
Data of 4. Yield: 26 mg (88%). Colorless sticky liquid. [a]2D4 ¼ 19.0 (c ¼ 0.9, CHCl3). IR (neat): 3449,
2925, 1254, 749. 1H-NMR (300 MHz, CDCl3): 7.41 – 7.20 (m, 5 H); 7.03 (d, J ¼ 8.3, 2 H); 6.75 (d, J ¼ 8.1,
2 H); 6.58 (d, J ¼ 15.8, 1 H); 6.21 (dd, J ¼ 6.4, 15.8, 1 H); 4.54 – 4.44 (m, 1 H); 3.95 – 3.78 (m, 1 H); 2.73 –
2.53 (m, 2 H); 1.81 – 1.67 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 154.0; 136.1; 132.3; 131.1; 130.5; 129.3;
128.3; 127.5; 127.3; 126.5; 125.4; 114.1; 70.5; 68.5; 43.0; 39.0; 29.9. ESI-MS: 321 ([M þ Na]þ).
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Received March 23, 2015