Synthetic studies of didemnaketal analogue - Construction of the (+)- and (-)-5,6-dihydroxy-3,7-dimethyl-octanal intermediates

Article abstract of DOI:10.1016/S0957-4166(98)00387-5

A synthetic procedure for construction of the (+)-(3R,5R,6R)-5,6- dihydroxy-3,7-dimethyl-octanal and (-)(3S,5S,6S)-5,6-dihydroxy-3,7-dimethyl- octanal derivatives, the intermediates for synthesis of the HIV-active di- demnaketal analogue, was developed via a series of reactions from the natural (-)-menthone.

Full text of DOI:10.1016/S0957-4166(98)00387-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3789–3795
Synthetic studies of didemnaketal analogue — construction of the
(+)- and (−)-5,6-dihydroxy-3,7-dimethyl-octanal intermediates
Ping Zhen Wang,a Yong Qiang Tu,a,∗ Li Yang,a Chang Zhi Dong a,† and William Kitching b
aDepartment of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000,
PR China
bDepartment of Chemistry, The University of Queensland, Brisbane, Qld 4072, Australia
Received 29 July 1998; accepted 17 September 1998
Abstract
A synthetic procedure for construction of the (+)-(3R,5R,6R)-5,6-dihydroxy-3,7-dimethyl-octanal and (−)-
(3S,5S,6S)-5,6-dihydroxy-3,7-dimethyl-octanal derivatives, the intermediates for synthesis of the HIV-active di-
demnaketal analogue, was developed via a series of reactions from the natural (−)-menthone. © 1998 Elsevier
Science Ltd. All rights reserved.
1. Introduction
The naturally occuring didemnaketals A (1) and B (2) are two important leading components isolated
from Ascidian didemnum sp. by D. J. Faulkner and co-workers,1 which exhibited significant inhibition of
HIV-1 protease. However, the further investigation regarding the synthesis and biological activity of these
kinds of spiroketals has not been reported. Our research interest in this field is focused on their synthetic
methodology and, as part of our recent research directed towards the total synthesis of the analogue 3,
we herein report an efficient procedure for the enantioselective synthesis of (+)- and (−)-5,6-dihydroxy-
3,7-dimethyl-octanal intermediates 5 and 23.
∗
†
Corresponding author. E-mail: tuyq@lzu.edu.cn
Present address: Laboratorie de Pharmacochimie Moleculaire, UFR de Chimie, Case 7066, University of Paris VII, France.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00387-5

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2. Results and discussion
Based on the retrosynthetic consideration (Scheme 1), synthesis of the target compound 3 is attributed
to that of the linear intermediate 4, which can be constructed from two intermediates 5 and 6. Further-
more, 5 can be synthesized from the (−)-menthone 7, a versatile natural source bearing an R-methyl
group.2
Scheme 1.
As shown in Scheme 2, (−)-menthone 7, when brominated with NBS and successively dehydro-
brominated with quinoline, formed the α,β-unsaturated menthone 8 in the yield of 68%,3 which was
epoxidized with H2O2:NaOH to provide the epoxy menthone 9 as the exclusive product.4 Treatment of 9
with 85% NH2NH2·H2O gave 10 as the only product and no other isomer was separated or even detected
by NMR spectroscopy.5 Thus the second stereogenic center was conveniently constructed. Protection of
10 with acetic anhydride followed by ozonization gave the linear ketoaldedyde 12.
Since the stereochemistry of the carbon in 3, corresponding to C-6 in 4 remained to be determined, our
initial effort was the construction of either the R- or S-configuration of C-6, which would be matched with
the natural products. Thus, we first protected 12 with 1,2-ethandithiol and then attempted to reduce 13
directly with NaBH4 or LiAlH4. Unfortunately, a very complicated mixture (not identified) was formed
in both cases. Thus, compound 12 was hydrolyzed with K2CO3/MeOH and spontaneously the self-
protected hemi-acetal 14 was formed which, though a mixture of two isomers, underwent an effectively
diastereoselective reduction when treated with NaBH4 at low temperature to give compound 15 as a
mixture of two isomers in high yield. In order to determine the absolute configuration of C-6, the aldehyde
group of the hemi-acetal 15 was protected with 1,2-ethandithiol and the two hydroxyls with acetone to

P. Z. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3789–3795
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Scheme 2.
give the compound 5. The NOESY technique demonstrated that the absolute configurations were 5R and
6R.
Alternatively, compound 5 could also be synthesized from a TBSCl (tert-butyldimethylsilyl chloride)
protected derivative 17 of 10. As shown in Scheme 3, 10 was protected with TBSCl and then ozonized
to give 18. Protection of 18 with 1,2-ethandithiol followed by reduction with Red-Al afforded the
intermediate 16 in good yield and diastereoselectivity (de>98%).
Scheme 3.
For the synthesis of the enantiomer of 3, a method for the synthesis of the enantiomer of 5 has also
been developed. This procedure simply included a three-step configurational conversion from 10 to 22
as shown in Scheme 4. Thus, oxidation of 10 with PCC followed by epoxidation and Wharton reaction
gave the enantiomer 22 of 10. Following the same procedures as (d)–(i) in Scheme 2, the synthesis of the

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P. Z. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3789–3795
enantiomer 23 was carried out. The total synthesis of 3 is still continuing and will be reported in the near
future.
Scheme 4.
3. Experimental
3.1. General
1
The H NMR, 13C NMR and DEPT data were recorded in CDCl3 solution with Brucker AM-80
or AM-400 MHz spectrometers. The chemical shifts are reported in ppm relative to TMS or CDCl3.
Optical rotations were determined on a JASCO J-20C polarimeter with a 0.2 dm tube. GC–MS, MS
and HRMS data were measured with EI (70 eV) or FAB techniques. Column chromatographies were
generally performed on silica gel (200–300 mesh) eluting with petroleum ether:EtOAc (30:1-→10:2.5)
and TLC inspections on silica gel F254 plates with petroleum ether:EtOAc (10:2.5) if not noted especially
below.
3.2. (2R,3R,5R)-2-Isopropyl-5-methyl-2,3-epoxy-cyclohexan-1-one 9
To a stirred solution of 8 (1.86 g, 12.2 mmol, prepared by a literature procedure3) and 4.6 ml of 30%
hydrogen peroxide in 30 ml methanol, was added 1 ml 6 N NaOH at room temperature. The mixture was
stirred for 7 h after which the solvent was removed in vacuo. The residue was extracted with ether (3×30
ml) and washed with brine, dried over Na2SO4 and purified by column chromatography to give 9 as a
25
1
colorless oil (1.46 g, 71%). [α] =+61 (c 1.0, MeOH); H NMR δ 3.46 (br, 1H), 2.75–1.65 (m, 6H),
D
1.10 (d, J=6.8 Hz, 6H), 0.90 (d, J=6.5 Hz, 3H). 13C NMR δ 205.5, 63.6, 57.2, 46.0, 31.7, 25.6, 23.7,
21.0, 18.4, 16.0.
3.3. (1R,5R)-2-Isopropyl-5-methyl-2,3-ene-cyclohexan-1-ol 10
To the compound 9 (150 mg, 0.89 mmol) was added 85% hydrazine hydrate (500 mg, 10 mmol) at
room temperature. After stirring for 10 min at room temperature, the mixture was heated slowly to reflux
(120°C) and kept at reflux temperature until the epoxy ketone 9 was completely dissolved. After cooling,
the reaction mixture was diluted with ether (50 ml) and then washed with water (3×10 ml) and brine
(2×10 ml), dried over Na2SO4 and purified by column chromatography to give 10 as a yellowish oil (89
mg, 65%). [α]25=+68 (c 0.57, EtOH); 1H NMR δ 5.53 (m, 1H), 4.11 (br s, 1H), 2.42 (heptet, J=7.0 Hz
D
1H), 2.15–1.24 (m, 7H), 1.05 (d, J=7.0 Hz, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H).

P. Z. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3789–3795
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3.4. (3R,5R)-2-Isopropyl-3-acetoxy-5-methyl-cyclohexene 11
To the compound 10 (950 mg, 6.2 mmol) were added acetic anhydride (3.46 g, 33.8 mmol) and 0.2
ml dry pyridine. The mixture was stirred for 20 h and then water (1 ml) was added. After stirring for 5
h, the system was neutralized with saturated NaCHO3 solution (ca. 30 ml) and then extracted with ether
(3×50 mL). The combined organic layer was washed with water (3×20 ml) and brine (3×20 ml), dried
over Na2SO4 and purified by column chromatography to give the pure product 11 (1.16 g, 96%) as a
yellowish oil. [α]25=+118 (c 0.02, CHCl3); 1H NMR δ 5.73 (br, 1H), 5.40 (br, 1H), 2.32–1.26 (m, 6H),
D
2.06 (s, 3H), 1.06 (d, J=6.7 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H), 0.85 (d, J=6.0 Hz, 3H).
3.5. (3R,5R)-3,7-Dimethyl-5-acetoxy-6-oxo-octanal 12
Into a cold (−78°C) solution of compound 11 (2.5 g, 12.76 mmol) in 30 ml MeOH and 150 ml CH2Cl2
was bubbled ozone until the solution became light blue. The ozone addition was stopped, and the solution
was stirred under argon at −78°C for 15 min and at 25°C for 30 min. Then zinc dust (15 g) and acetic
acid (33 ml) were added to the solution, and the resulting mixture was stirred at 25°C for 30 min and
filtered. The filtrate was neutralized with 5 N NaOH solution (100 ml), the organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3×60 ml). The combined organic layer was washed
with water (3×20 ml) and brine (3×20 ml), dried over Na2SO4 and purified by column chromatography
25
1
to give 12 (2.76 g, 95%) as a colorless oil. [α] =−6 (c 0.03, CHCl3); H NMR δ 9.76 (m, 1H), 5.20
D
(dd, J=10.7, 2.7 Hz, 1H), 2.80 (heptet, J=6.9 Hz, 1H), 2.40–1.70 (m, 5H), 2.15 (s, 3H), 1.16 (d, J=6.9
Hz, 3H), 1.07 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H); 13C NMR δ 210.9, 201.4, 170.4, 75.4, 51.0,
36.8, 36.7, 24.8, 20.6, 19.0, 18.9, 17.8.
3.6. (4R,6R)-2-Hydroxy-4-methyl-6-(20 -methylpropionyl)-tetrahydropyran 14
Compound 12 (1.7 g, 7.46 mmol) was dissolved in MeOH (15 ml) and then the solution was added
to a suspension of K2CO3 (3.4 g, 24.6 mmol) in MeOH (10 ml) and stirred for 2 h at room temperature.
The suspension was filtered, and the filtrate was washed with MeOH (3×10 ml) and then concentrated
in vacuo. The obtained residue was diluted with ether (100 ml), washed with saturated NH4Cl solution
(2×30 ml) and brine (2×30 ml), dried over Na2SO4 and purified by column chromatography to give the
mixture of two isomers of 14 in the ratio of 3:2 (determined by NMR spectra) as a colorless oil (1.29
g, 93%). 1H NMR (major) δ 5.47 (d, J=2.6 Hz, 1H), 4.60 (dd, J=12.0, 2.4 Hz, 1H), 3.12 (heptet, J=7.0
Hz, 1H), 1.95–1.23 (m, 5H), 1.08 (d, J=7.0 Hz, 6H), 0.95 (d, J=6.0 Hz, 3H); (minor) δ 4.79 (d, J=9.2
Hz, 1H), 4.04 (dd, J=12.0, 2.4 Hz, 1H), 2.99 (heptet, J=6.8 Hz, 1H), 1.95–1.23 (m, 5H), 1.08 (d, J=6.8
Hz, 6H), 1.01 (d, J=6.0 Hz, 3H); 13C NMR δ 213.8, 213.0, 96.4, 92.3, 79.6, 73.3, 41.0, 37.8, 37.4, 36.0,
35.8, 35.4, 30.0, 29.3, 23.8, 22.0, 21.6, 18.3, 18.2, 14.1; EI-MS (two isomers) m/z (%) 185 (M+−1, 4),
169 (30), 115 (64), 71 (100); FAB-HRMS: 169.1184, calcd for C10H16O2+H: 169.1224.
3.7. (4R,6R,7R)-2-Hydroxy-4-methyl-6-(10 -hydroxy-20-methylpropyl)-tetrahydropyran 15
To a cooled (−78°C), stirred solution of 14 (1.1 g, 5.90 mmol) in MeOH (30 ml) was added NaBH4
(210 mg, 5.90 mmol). The mixture was stirred at −78°C for 1 h, then the solvent was removed in vacuo.
The obtained residue was diluted with ether (50 ml) and washed with H2O (2×10 ml) and brine (2×10
ml), dried (Na2SO4) and purified by column chromatography to give the mixture of two isomers of 15
1
in the ratio of 1:1 as a colorless oil (1.08 g, 98%). H NMR (two isomers) δ 5.37 (d, J=2.5 Hz, 1H),

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P. Z. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3789–3795
4.77 (dd, J=9.7, 1.3 Hz, 1H), 4.07 (dt, J=9.7, 2.5 Hz, 1H), 3.54 (ddd, J=11.5, 3.5, 2.5 Hz, 1H), 3.38 (dd,
J=8.1, 3.5 Hz, 1H), 3.27 (dd, J=8.1, 3.5 Hz, 1H), 1.90–1.07 (m, 12H), 1.01 (d, J=6.4 Hz, 6H), 1.00 (d,
J=6.4 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.86, 0.88 (2d, J=6.6 Hz, 6H); 13C NMR δ 96.2, 92.2, 78.4, 78.1,
76.3, 69.7, 41.4, 38.4, 32.0, 31.4, 29.8, 29.3, 29.2, 28.7, 23.1, 22.3, 21.8, 19.0, 18.8, 18.7; EI-MS (two
isomers) m/z (%) 171 (M+−17, 8), 170 (M+−18, 13), 115 (92), 71 (100); FAB-HRMS: 171.1447, calcd
for C10H18O2+H: 171.1380.
3.8. (3R,5R,6R)-3,7-Dimethyl-5,6-dihydroxy-octanan-ethanedithiolketal 16
To a solution of 15 (200 mg, 1.06 mmol) in 5 ml CH2Cl2 were added 0.08 ml BF3·OEt2 and 1,2-
ethandithiol (0.11 ml, 1.31 mmol), and stirring was continued for 2 h at room temperature. After the
addition of water (2 ml), the mixture was extracted with CH2Cl2 (3×20 ml). The combined organic layer
was washed with brine (2×10 ml), dried over Na2SO4 and purified by column chromatography to give
25
1
16 (210 mg, 75%) as an amorphous solid. [α] =+23 (c 0.01, CHCl3); H NMR δ 4.60 (t, J=7.1 Hz,
D
1H), 3.78 (br, 1H), 3.31 (dd, J=8.1, 3.8 Hz, 1H), 3.23 (m, 4H), 2.11 (br, 2H), 1.82–1.20 (m, 6H), 1.01
(d, J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H); 13C NMR δ 80.2, 69.8, 51.6, 47.2,
38.3, 38.2, 36.6, 30.0, 29.5, 19.0, 18.7, 16.8; EI-MS m/z (%): 264 (M+, 6), 246 (56), 131 (59), 105 (100);
FAB-HRMS: 264.1200, calcd for C12H24S2O2: 264.1212.
3.9. (3R,5R,6R)-3,7-Dimethyl-5,6-acetonide-octanan-ethanedithiolketal 5
To a solution of 16 (55 mg, 0.208 mmol) in 2 ml dry acetone was added a catalytic amount of PTS. The
mixture was stood for 1 day at room temperature, and was then diluted with ether (20 ml) and washed with
saturated NaHCO3 solution (3×5 ml) and brine (2×5 ml), dried over Na2SO4 and purified by column
chromatography to give 5 as a yellowish oil (50 mg, 79%). [α]25=+69 (c 0.01, CHCl3); 1H NMR δ 4.51
D
(t, J=7.4 Hz, 1H), 4.05 (ddd, J=11.6, 5.0, 2.4 Hz, 1H), 3.59 (dd, J=9.8, 5.0 Hz, 1H), 3.08–3.21 (m, 4H),
1.61–1.87 (br, 1H), 1.55–1.75 (m, 5H), 1.39 (s, 3H), 1.27 (s, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6
Hz, 3H), 0.78 (d, J=6.6 Hz, 3H); 13C NMR δ 18.7, 19.0, 20.4, 26.2, 28.8, 27.3, 29.2, 35.8, 38.3, 38.3,
47.5, 51.5, 74.9, 83.9, 107.5; EI-MS m/z (%) 304 (M+, 15), 289 (43), 145 (64), 105 (100); FAB-HRMS:
305.1544, calcd for C15H28O2S2+H: 305.1602.
3.10. (3R,5R)-2-Isopropyl-3-t-butylchlorodimethoxy-5-methyl-cyclohexene 17
To a solution of 10 (730 mg, 4.74 mmol) in 2 ml dry DMF were added imidazole (717 mg, 11.8 mmol)
and tert-butyldimethylsilyl chloride (857 mg, 5.7 mmol). The mixture was stirred at room temperature
for 2 h, then diluted with ether (100 ml), washed successively with water (2×20 ml) and brine (2×20
ml), dried over Na2SO4 and concentrated to give 17 (1.14 g, 95%) as a colorless oil. 1H NMR δ 5.50 (br,
1H), 4.18 (br, 1H), 2.34–1.25 (m, 6H), 1.08 (d, J=6.0 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.0
Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H).
3.11. (3R,5R)-3,7-Dimethyl-5-t-butylchlorodimethoxy-6-oxo-octanal 18
Following the same procedure as 12, the compound 17 (1.34 g, 5.0 mmol) gave 18 (1.38 g, 92%) as a
1
colorless oil. H NMR δ 9.72 (t, J=1.8 Hz, 1H), 4.20 (dd, J=7.8, 5.2 Hz, 1H), 3.01 (m, 1H), 2.33–1.45
(m, 5H), 1.08 (d, J=6.9 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H), 0.92 (s, 9H), 0.05 (s,
6H).

P. Z. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3789–3795
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3.12. (3R,5R)-3,7-Dimethyl-5-t-butylchlorodimethoxy-6-oxo-octanan-ethanedithioketal 19
Following the same procedure as 16, the compound 18 (100 mg, 0.33 mmol) gave 19 (98 mg, 75%) as
a colorless oil. 1H NMR δ 4.63 (t, J=7.3 Hz, 1H), 4.20 (dd, J=9.0, 3.7 Hz, 1H), 3.70 (m, 1H), 3.23 (m,
4H), 2.70–1.62 (m, 5H), 1.16 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.5 Hz, 3H), 0.94 (s,
9H), 0.07 (s, 6H).
3.13. (3R,5R,6R)-3,7-Dimethyl-5,6-dihydroxy-octanan-ethanedithiolketal 16
To a solution of 19 (360 mg, 0.96 mmol) in toluene (10 ml) was added a solution of 10% vitride
(Red-Al) in toluene (7.5 ml) at −78°C under Ar. The mixture was stirred for 3 h at the same temperature
and then stirred overnight at room temperature. After the addition of water (2 ml) and 10% HCl solution
(5 ml), the mixture was extracted with ether (3×20 ml). The organic layer was washed with 10% HCl
solution (2×5 ml), saturated NaCHO3 solution (2×5 ml) and brine (2×5 ml), succesively, dried over
Na2SO4, and purified by column chromatography to afford 16 (200 mg, 80%) as an amorphous solid.
3.14. (S)-(+)-p-Menth-4-en-3-one 20
A solution of the alcohol 10 (2.10 g, 13.6 mmol) was added in one portion to the suspension of PCC
(5.03 g, 27.2 mmol) in dry CH2Cl2 (80 ml), and stirring was continued for 7 h at room temperature. After
addition of Florisil, the mixture was diluted with CH2Cl2 and filtered through Celite. Concentration of
the filtrate followed by column chromatography gave 20 as a colorless oil. [α]25=+48 (c 0.02, CHCl3).
D
The spectra data of 20 were consistent with those of its enantiomer.
3.15. (3S,5S,6S)-3,7-Dimethyl-5,6-acetonide-octanan-ethanedithiolketal 23
The procedures for syntheses of 21 to 23 were the same as those of their enantiomers above, and the
spectra data of all those compounds were consistent with those of their antipodals. The rotation of 23
was [α]25=−68 (c 0.01, CHCl3).
D
Acknowledgements
We are very grateful for the financial support provided by the Education Council of China.
References
1. Potts, B. C. M.; Faulkner, D. J. J. Am. Chem. Soc. 1991, 113, 6321.
2. Tu, Y. Q.; Moore, C. J.; Kitching, W. Tetrahedron: Asymmetry 1995, 6(2), 397.
3. Paquette, L. A.; Doehner, R. F. J. Org. Chem. 1980, 45, 5107.
4. Klein, E.; Ohloff, G. Tetrahedron 1963, 19, 1091.
5. Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615.