First enantioselective total synthesis of (-)-13-hydroxyneocembrene

Article abstract of DOI:10.1016/S0040-4039(00)01873-6

The first enantioselective total synthesis of (-)-13-hydroxyneocembrene (1), a naturally occurring cembranoids isolated from soft coral Sarcophyton trocheliophorum, was achieved via a general approach by employing intramolecular McMurry coupling as a key step from (S)-(+)-carvone.

Full text of DOI:10.1016/S0040-4039(00)01873-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 275–277
First enantioselective total synthesis of
(−)-13-hydroxyneocembrene
Zuosheng Liu, Tao Zhang and Yulin Li*
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University,
Lanzhou 730000, PR China
Received 11 September 2000; revised 13 October 2000; accepted 20 October 2000
Abstract—The first enantioselective total synthesis of (−)-13-hydroxyneocembrene (1), a naturally occurring cembranoids isolated
from soft coral Sarcophyton trocheliophorum, was achieved via a general approach by employing intramolecular McMurry
coupling as a key step from (S)-(+)-carvone. © 2000 Elsevier Science Ltd. All rights reserved.
Cembranoids, a family of 14-membered cyclic diter-
penoid natural products existing in terrestrial and espe-
cially in marine organism,1 are of great interest to
synthetic organic chemists and biologists because of
their unique structure and wide range of biological
activities.2 (−)-13-Hydroxyneocembrene (1), a cembra-
noid which was isolated in 1988 by Suleimenova et al.
from the soft coral Sarcophyton trocheliophorum,3 has
been shown to be an effective inductor of the release of
labeled glucose from the lecithincholesterol liposomes
and has cytostatic activities.4 Its chemical structure was
characterized spectroscopically and the absolute
configuration of 1 has been defined to be (1S,13S) by
X-ray structural analysis of its p-nitrobenzoate.3 The
total synthesis of ( )-1 has been accomplished by our
group.5 In continuation of our on-going program on
Scheme 1.
Keywords: cembrene diterpenoid; McMurry coupling; 13-hydroxyneocembrene; total synthesis.
* Corresponding author. Tel.: +86-9318912595; fax: +86-931-8912283; e-mail: liyl@lzu.edu.cn
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01873-6

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Z. Liu et al. / Tetrahedron Letters 42 (2001) 275–277
the asymmetric synthetic studies of cembranoids, we
report the first total synthesis of (−)-1 in this letter.
the presence of a catalytic amount of benzoic acid in
refluxing toluene9 for 72 h generated only (E)-alkene
adduct 10 in 82.0% yield. Saponification of 10 gave the
alcohol 11. The e.e. value of the alcohol 11, determined
The strategic plan was depicted in Scheme 1. The
cembrane ring would be constructed by means of the
well-developed intramolecular McMurry coupling6 of
the keto aldehyde precursor 2. Preparation of the
macrocylization precursor 2 involves a convergent cou-
pling of allylic phenyl sulphone 3 derived from 6-
1
by high resolution (400 MHz) H NMR analysis of the
corresponding Mosher’s ester 11a,10 was 95%. The alco-
hol 11 was protected with TBDPSCl11 and followed by
reduction with Dibal-H in CH2Cl2 at −78°C afforded
the allylic alcohol 12. Chlorination of 12 with NCS-
Ph3P in THF12 gave the chloride 5.
methyl-5-hepten-2-one (4) with allylic chloride
derived from (S)-(+)-carvone (6).
5
Oxidation of 6-methyl-5-hepten-2-one (4) by SeO2 (0.2
equiv.) in the presence of 70% tert-butylhydroperoxide
in CH2Cl2 and protection of the ketone group with a
large excess of ethylene glycol using oxalic acid as a
catalyst in refluxing benzene gave the ethylene acetal
13. Chlorination of 13 with NCS-Ph3P and treatment of
the corresponding chloride with anhydrous PhSO2Na in
DMF14 gave the benzene sulfonyl derivative 3. The
addition of catalytic amount of NaHCO3 prevented
hydrolysis of the acetal protection group.
The total synthesis of (−)-13-hydroxyneocembrene (1)
is detailed in Scheme 2. Stereoselective reduction of
(S)-(+)-carvone with LiAlH4 in ether7 gave the cis-(–)-
carveol, which was protected with Ac2O in pyridine to
afford carvyl acetate 7 in 98.9% yield. Ozonolysis fol-
lowed by reduction with dimethyl sulfide8 gave the keto
aldehyde 8 in 62.4% yield. Treatment of keto aldehyde
8 with a catalytic mount of NH4Cl in MeOH gave the
acetal 9 in 88.0% yield. Reaction of a-acetoxy ketone 9
with carboethoxymethylene-triphenylphosphorane in
13
Scheme 2. Reagents and conditions: (a) 1. LiAlH4, Et2O, −78°C, 2 h; 2. Ac2O, Py, DMAP, 23°C, 98.9%. (b) 1. O3,
CH2Cl2ꢀMeOH (3:2), −78°C; 2. Me2S, −78°Cꢀ23°C, 24 h, 62.4%. (c) NH4Cl, MeOH, 50°C, 6 h, 88.0%. (d) Ph3PꢁCHCO2Me,
PhCO2H, toluene, reflux, 72 h, 82.0%. (e) K2CO3, MeOH, 23°C, 1 h, 93.1%. (f) C6H5C(OMe)(CF3)CO2H, DCC, DMAP, CH2Cl2,
23°C, 6 h, 94.0%. (g) 1. TBDPSCl, imidazole, DMF, 23°C, 2 h, 90.9%; 2. Dibal-H, CH2Cl2, −78°C, 2 h, 86.9%. (h) NCS, Ph3P,
THF, 23°C, 12 h, 92.0%. (i) 1. SeO2, t-BuOOH, CH2Cl2, 23°C, 3 h, 50.3%; 2. Oxalic acid, HOCH2CH2OH, C6H6, reflux, 6 h,
92.0%. (j) 1. NCS, Ph3P, THF, 23°C, 12 h, 80%; 2. PhSO2Na, DMF, NaHCO3, 23°C, 24 h, 74%. (k) 1. n-BuLi, −78°C, 30 min
then added 5, −78°Cꢀ23°C, 2 h, 92.4%; 2. Na(Hg), Na2HPO4, MeOH,, 23°C, 6 h, 90.6%. (l) p-TsOH, acetone, 40°C; 4 h, 89.0%.
(m) 1. TiCl4, Zn, Py, DME, reflux, 10 h, 81.2%; 2. n-Bu4NF, THF, 60°C, 24 h, 85.0%.

Z. Liu et al. / Tetrahedron Letters 42 (2001) 275–277
277
Coupling reaction of chloride 5 with the lithium salt of
3 (formed by treatment with n-BuLi in THF at −78°C)
in THF at −78°C proceeded smoothly to afford cou-
pling adduct, which gave the reduced product 14 by
treatment with Na(Hg) in MeOH.15 Treatment of 14
with a catalytic amount of p-TsOH in acetone gave the
keto aldehyde 2. The cyclization precursor 2 was added
slowly via a syringe pump to a suspension of low-valent
titanium reagent (preformed by in situ reduction of
TiCl4 with zinc in the presence of a trace amount of
pyridine16) in DME under reflux over 10 h to afford the
desired cyclized ethers consisting of (−)-3E, 7E, 11E-
13-(tert-butyldiphenylsiloxy)-neocembrene and its 3Z
isomer in a ratio of approximately 2.5:1 (by 400 MHz
1HNMR).8 Desilylation of cyclized ether with tetra-n-
butylammonium fluoride (TBAF) in THF17 at 60°C for
24 h gave (−)-13-hydroxyneocembrene (1), which has
showed identical spectral data with those of natural
product 1 reported.3 The optical property of synthetic 1
{[h]2D5 −122 (c 0.5, MeOH)} is comparable with that of
natural product {[h]2D0 −150 (c 0.2, MeOH)}. Accord-
ingly, the absolute stereochemistry of the C-1 and C-13
of natural product 1 is concluded as (1S,13S).
2. (a) Tius, M. A. Chem. Rev. 1988, 88, 719–732. (b) Cox,
N. J. G.; Mills, S. D.; Pattenden, G. J. Chem. Soc.,
Perkin Trans 1 1992, 1313–1321 and references cited
therein.
3. Suleimenova, A. M.; Kalinovskii, A. I.; Raldugin, V. A.;
Shevtsov, S. A.; Bagryanskaya, Y. I.; Gatilov, Y. V.;
Kuznetsova, T. A.; Elyalcov, G. B. Khim, Prir. Soedin.
1988, (4), 535–540 (Russ.); Chem. Nat. Compd. 1988,
453–458 (Engl.).
4. Kuznetsova, T. A.; Popov, A. M.; Agafonova, I. G.;
Suleimenova, A. M.; Elyakov, G. B. Khim. Prir. Soedin.
1989, (1), 137–139; Chem. Abstr. 1989, 111, 4655a.
5. Xing, Y.-C.; Cen, W.; Lan, J.; Li, Y.; Li, Y.-L. J. Chin.
Chem. Soc. (Taipei) 1999, 46, 595–600.
6. For reviews, see: (a) Furstner, A.; Bogdanovic, B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2442–2469. (b) McMurry,
J. E. Chem. Rev. 1989, 89, 1513–1524. (c) Lenoir, D.
Synthesis 1989, 883–897. (d) McMurry, J. E. Acc. Chem.
Res. 1983, 16, 405–411.
7. Garver, L.; Eikeren, P. J. Org. Chem. 1976, 41, 2273–
2274.
8. McMurry, J. E.; Bosch, G. K. J. Org. Chem. 1987, 52,
4885–4893.
9. Larson, G. L.; Prieto, J. A.; Herha´ndez, A. Tetrahedron
Lett. 1981, 22, 1575–1578.
10. (a) Hassner, A.; Alexanian, V.Tetrahedron Lett. 1978, 19,
4475–4478. (b) For example, see: Smith, P. M.; Thomas,
E. J. J. Chem. Soc., Perkin Trans. 1 1998, (21), 3541–
3556.
In summary, first enantioselective total synthesis of
(−)-13-hydroxyneocembrene (1) has been accomplished
via a macro-olefination strategy by using titanium-
mediated McMurry coupling as the key step.
11. Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53,
2975–2977.
Acknowledgements
12. Bose, A. K.; lal, B. Tetrahedron Lett. 1973, 14, 3937–
3940.
13. Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc.
1977, 99, 5526–5528.
14. Mao, J.-M.; Li, Y.; Hou, Z.-J.; Li, Y.-L.; Liang, X.-T.
Sci. China (Ser. B) 1992, 35, 257–261.
This work was financially supported by the National
Natural Science Foundation of China (Grant No.
20072012).
15. For review, see: Na´jera, C.; Yus, M. Tetrahedron 1999,
55, 10547–10658.
References
16. Li, W.-D. Z.; Li, Y.; Li, Y.-L. Tetrahedron Lett. 1999, 40,
965–968.
17. Li, Y.-L.; Li, W.-D. Z.; Li, Y. J. Chem. Soc., Perkin
Trans. 1 1993, (15), 2953–2956.
1. Tursch, B.; Braeckman, J. C.; Dolaze, D.; Kaisin, M. In
Marine Natural Products: Chemical and Biological Per-
spectives; Scheuer, P. J., Ed.; Academic: New York, 1978;
Vol. 2, pp. 247–296.
.
.