Enantioselective total synthesis of natural 11,12-epoxycembrene-C

Article abstract of DOI:10.1016/S0040-4039(00)00982-5

The first enantioselective total synthesis of (+)-11,12-epoxycembrene-C (1), a novel naturally occurring cembranoxide isolated from tropical marine soft coral, was achieved via a general approach by employing an intramolecular McMurry coupling and Sharpless asymmetric epoxidation as key steps from readily available starting materials. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00982-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7465–7469
Enantioselective total synthesis of natural
11,12-epoxycembrene-C
Yulin Li,a,* Zuosheng Liu,a Jiong Lan,a Jing Li,a Lizeng Peng,a Weidong Z. Li,a Ying Lia
and Albert S. C. Chanb
aNational Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University,
Lanzhou 730000, PR China
bDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University,
Hong Kong, PR China
Received 15 May 2000; revised 8 June 2000; accepted 9 June 2000
Abstract
The first enantioselective total synthesis of (+)-11,12-epoxycembrene-C (1), a novel naturally occurring
cembranoxide isolated from tropical marine soft coral, was achieved via a general approach by employing
an intramolecular McMurry coupling and Sharpless asymmetric epoxidation as key steps from readily
available starting materials. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cembrane diterpenoid; McMurry coupling; Sharpless epoxidation; 11,12-epoxycembrene-C; total synthesis.
Cembranoids, a family of 14-membered cyclic diterpenoid natural products existing in
terrestrial and especially in marine organisms,1 are of great interest to synthetic organic chemists
and biologists because of their unique structure and wide range of biological activities.2
Naturally occurring cembranoid epoxides (cembranoxides) have been found as chemical compo-
nents of various tropical marine soft corals and represent a class of oxidative metabolites of
cembrane diterpenes. (+)-11,12-Epoxycembrene-C (1), a novel cembrane epoxide, was first
isolated in 1978 by Bowden and co-workers3 from the Australian soft coral Sinularia grayi,
which has subsequently been found in various marine soft corals, i.e. Nephthea sp.,4 Lobophytum
sp.,5,6 Eunicea sp.,7 and Sinularia sp.8 Its chemical structure was determined by means of
extensive spectroscopic techniques and chemical degradation.3 The absolute stereochemistry of
the epoxide function of 1 was deduced as (11S,12S) indirectly by Horeau’s method.5
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00982-5

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Stereoselective and enantioselective construction of the epoxide functionality in the macro-
cyclic cembrane skeleton comprises a challenging task for total synthesis. A general, facile and
highly stereoselective synthetic method for the synthesis of cembranoxides such as 1 is highly
desirable as well as the assignments of the absolute stereochemistry of the epoxide function
unambiguously. In continuation of our on-going program on the asymmetric synthetic studies of
cembranoids, we report the first total synthesis of 1 in this paper.
The low-valent titanium-induced intramolecular dicarbonyl olefination coupling (McMurry
reaction)9 is proven to be a valuable and versatile protocol for the construction of carbocyclic
skeleton and has been illustrated in a great number of natural product syntheses as well as
highly strained non-natural compounds. The strong reducing conditions and extended reaction
times normally used make the process incompatible with the easily reducible functional groups
elsewhere in the substrate. Less reactive ester or lactone carbonyl in the substrate might survive
under the usual conditions for the reductive olefination of the keto aldehyde precursors
mediated by low-valent titanium and be left intact although very few examples under these
circumstances have been reported in the literature.10,11
The general strategic plan is depicted in Scheme 1. The epoxide group of 1 would be
introduced enantioselectively by Sharpless asymmetric epoxidation (SAE)12 of the corresponding
trisubstituted carbocyclic allylic alcohol 2. Accordingly, the cembrane ring would be closed by
means of the well-developed intramolecular McMurry coupling of the keto aldehyde 3, which
bears an a,b-unsaturated ester carbonyl moiety inert under the reaction conditions. In turn,
substrate 3 could be obtained by assembly of two pieces via Wadsworth–Horner–Emmons
olefination.
Scheme 1.
The total synthesis of 11,12-epoxycembrene-C (1) is detailed in Scheme 2. Allylic alcohol 5,
readily available13 from geranyl acetate (4) in four steps, was converted into the corresponding
vinyl ether by a known procedure14 catalyzed by Hg(OAc)2, which was then subjected to the
thermal Claisen rearrangement15 in a sealed tube at 110°C providing predominantly the desired
trans aldehyde 616 in a ratio of 93:7 as determined by GC. Homoprenyl iodide 717 was

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transformed to phosphono-ester 8 in 88% yield by a standard method,17 which was then exposed
to m-CPBA in CH2Cl2 to give the epoxide 9 in 93% yield. The Wadsworth–Horner–Emmons
coupling18 of phosphono-ester 9 with aldehyde 6 mediated by LDA led to ester 10 in 73% yield
1
as a mixture of an equal amount of geometric isomers as determined by H NMR. Ketone 11
was obtained by the rearrangement19 of the epoxide 10 (E+Z) catalyzed by LiClO4. Saponifica-
tion of 11 and subsequent MnO2 oxidation (72%, two steps) gave the keto aldehyde 3, which
was added slowly via a syringe pump to a slurry of low-valent titanium reagent (prepared by the
in situ reduction of TiCl4 with zinc power9) in THF under reflux for 6 h to afford the desired
carbocyclic ester 12 as the readily separable E and Z isomers (1:1) by silica gel column
chromatography in a combined yield of 48%. Basic hydrolysis of the esters 12E and 12Z gave
acids 13 (R=H) and 14 (R=H), respectively, corresponding to crotocembraneic acid and
neocrotocembraneic acid, respectively,20 two novel cembranoids isolated from the stem bark of
the Thai traditional medicinal plant Croton oblongifolius, based on the spectroscopic comparison
with the natural products.
Scheme 2. Reagents and conditions: (a) Ref. 13; (b) 1. Hg(OAc)2, ethyl vinyl ether, reflux, 83%; 2. sealed tube, 110°C,
90%; (c) NaH, (EtO)2P(O)CH2CO2Et, DMF, 60°C, 88%; (d) m-CPBA, CH2Cl2, 0°C, 93%; (e) LDA, THF, −78°C, 30
min then aldehyde 6, −78°C to 23°C, 73%; (f) LiClO4, C6H6, reflux, 81%; (g) 1. K2CO3, MeOH, 23°C; 2. MnO2,
n-hexane, 23°C, 72%; (h) TiCl4, Zn, THF, reflux, 48%
Reduction of ester 13 with LiAlH4 in ether gave allylic alcohol 2 in 92% yield, which was
epoxidized under Sharpless asymmetric epoxidation12 conditions with
epoxy alcohol 15 in 85% yield and 95% ee as determined by high resolution (400 MHz) H
D
-(−)-DET to afford
1

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NMR analysis of the corresponding Mosher’s ester21 (Scheme 3). Standard iodination22 of 15
(Ph3P, imidazole, Py, I2) and subsequent reductive dehalogenation23 of the corresponding
intermediary iodide with NaBH3CN in HMPA furnished the title compound 1, which showed
identical spectroscopic properties (1H, 13C NMR) with those of natural product as well as the
specific rotation of the synthetic 1 {[h]D18 +109.1 (c 0.75, CHCl3)} and that of natural product
reported {[h]D +117 (c 0.09, CHCl3)}.3
Scheme 3. Reagents and conditions: (a) LiAlH4, Et2O, rt, 92%; (b) Ti(OiPr)4,
D-(−)-DET, t-BuOOH, CH2Cl2, −20°C,
85%; (c) 1. Ph3P, I2, imidazole, Py, Et2O–CH3CN (3:1), 0°C, 90%; 2. NaBH3CN, HMPA, THF, 60°C, 90%
In summary, the first enantioselective total synthesis of (+)-11,12-epoxycembrene-C (1) has
been accomplished via a macro-olefination strategy by using titanium-mediated McMurry
coupling as the key step and the Sharpless asymmetric epoxidation for the introduction of chiral
epoxide function. Based on the enantioselective Sharpless epoxidation, we assume that the
configuration of natural (+)-11,12-epoxycembrene-C (1) might be (11S,12S).
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China
(Grant No. 29672015).
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