A short synthesis of (±)-laurene: Mechanistic reinvestigation in palladium-catalyzed cycloreductions of 1,6-enynes

Article abstract of DOI:10.1016/S0040-4039(00)01484-2

Two palladium-catalyzed cycloreduction strategies have been applied for the synthesis of laurene. Palladium-catalyzed cyclizations of 1,6-enynes initially form the corresponding alkylpalladium intermediates. While triethylsilane could directly reduce the intermediates to lead to the corresponding cycloreduced products, the intermediates in the presence of even excess formic acid underwent β-elimination to yield the dienes that were further reduced at the less hindered olefins to yield the cycloreduced products. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01484-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8365–8369
A short synthesis of ( )-laurene: mechanistic reinvestigation
in palladium-catalyzed cycloreductions of 1,6-enynes
Chang Ho Oh,* Je Wook Han, Joo Sung Kim, Sung Yong Um, Hyung Hoon Jung,
Won Hyung Jang and Ho Shik Won
Department of Chemistry, Hanyang University, Sungdong-Gu, Seoul 133-791, South Korea
Received 24 July 2000; revised 28 August 2000; accepted 1 September 2000
Abstract
Two palladium-catalyzed cycloreduction strategies have been applied for the synthesis of laurene.
Palladium-catalyzed cyclizations of 1,6-enynes initially form the corresponding alkylpalladium intermedi-
ates. While triethylsilane could directly reduce the intermediates to lead to the corresponding cycloreduced
products, the intermediates in the presence of even excess formic acid underwent b-elimination to yield the
dienes that were further reduced at the less hindered olefins to yield the cycloreduced products. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: palladium; laurene; enyne; cycloreduction; synthesis; formic acid; triethylsilane.
The sesquiterpene laurene, first isolated from Laurencia glandulifera and subsequently found
in several other Laurencia species, has significant steric crowding around a compact cyclopen-
tane ring.1 Despite a relatively simple substitution pattern on the cyclopentane skeleton, the
cis-1,2 relationship of the secondary methyl group with the p-tolyl group has made both the
stereoselective and enantioselective synthesis of this compound difficult.2 Two different basic
approaches are known to this end. One is conducted by group transformations from existing
five-membered carbocycles,3 and the other is the approach of controlling the newly formed
five-membered ring. The latter strategy mostly involves radical cyclization,4 anionic cyclization
via enolate or alkyllithium,5 and intramolecular carbenoid displacement by employing a
catalyst.6 Trost and co-workers found that the HꢀPdꢀX species, generated from a palladium
compound and a carboxylic acid, selectively added to an activated triple bond in the presence
of internal triple bonds or double bonds.7 This remarkable observation prompted us to pursue
more studies on palladium-catalyzed cyclization of unsaturated substrates such as enediynes,8
dienyne,9 triynes,10 and enynes.11 Employing triethylsilane or polymethylhydrosiloxane (PMHS)
as a hydrogen donor in their Pd-catalyzed enyne cyclizations successfully converted the enyne
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01484-2

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substrates to the corresponding cycloreduced products.12 Although this is a highly valuable
cycloreduction methodology applicable to diverse enyne substrates, one critical disadvantage is
the requirement of an excess of silanes, which should cause purification of the products to be
problematic. Recently, we reported an alternative method for enyne cycloreduction that could
provide easy access to the laurene skeletons via direct reduction of the alkylpalladium species by
the formate ligand.13 During extension of this methodology, we found that enynes conjugated
with a carbonyl group proceeded to the g,d-unsaturated carbonyl compounds via the diene
intermediates (Eq. (1)).14
(1)
The latter result has led us to reexamine our proposed mechanism of palladium-catalyzed
enyne cycloreductions, where we found structural uncertainty based upon NMR analyses of our
previously reported products. Here we wish to revise the mechanisms in palladium-catalyzed
enyne cycloreductions under different conditions and to apply the laurene synthesis. Thus, we
retested the enyne 1a, which is a good model substrate for the natural product laurene and is
very easy to prepare.
Cycloreductions of the enyne 1a were conducted under two conditions (A and B), and the
resultant products were separated by using preparative HPLC to give the products 2a, epi-2a,
1
3a, and epi-3a as shown in Scheme 1. H, 13C NMR, DEPT, COSY, TOCSY, HETCOR
1
experiments enabled us to accomplish complete H and 13C NMR signal assignments of
compounds 2a, epi-2a, and 3a and to confirm the relative configurations of each compound.
Coupling constants given by the DQF-COSY experiment were analyzed to identify the orienta-
tion of J-coupled proton networks and to see possible 5-membered ring puckering. In addition,
the temperature-dependency (−20ꢀ25°C) and variable mixing times (~m=50, 100, 250, 500 ms)
of NOESY experiments were carried out to observe the direct NOE connectivities exhibiting the
orientation of side chains.15
Scheme 1. Method A: 5 mol% Pd(OAc)2, 10 mol% PPh3, 1.2 equiv. HCOOH, toluene, 60°C, 1.0 h. Method B: 5 mol%
Pd2(dba)3, 10 mol% PPh3, 2 equiv. AcOH, 10 equiv. Et3SiH, toluene, 50°C, 2.0 h
Next, we prepared the enyne 1b as a laurene precursor as shown in Scheme 2. 4-Methylace-
tophenone was transformed to the diene 7 in two consecutive olefinations. Hydroboration of the
diene, followed by H2O2 oxidation, gave the alcohol 8. The alcohol 8 was oxidized to the
aldehyde 9 that was further transformed to the dibromoolefin 10. Elimination of dibromoolefin
10 with n-butyllithium at −78°C provided the enyne 1b in gram quantity (Scheme 2).

8367
Scheme 2. (a) MeOCHꢁPPh3, THF, −78°C to rt, 73%; (b) CH2ꢁCHCH2OH, p-TsOH (cat), xylene, heat, 78%; (c)
CH3PPh3Br, n-BuLi, THF, 70%; (d) (i) 9-BBN, THF, then (ii) H2O2, NaOH, 86%; (e) PCC, CH2Cl2, 68%; (f) CBr4,
PPh3, 84%; (g) n-BuLi, THF, 91%
As mentioned, a completion of the laurene synthesis required a stereoselective introduction of
the methyl substituent, which can be generated from cycloreduction of the enyne 1b (Scheme 3).
Scheme 3.
Under the best conditions we have tested, the enyne 1b did not furnish the desired laurene but
gave the cycloreduced product 2b in 69% yield (Method A). This result revealed that the present
alkyl-palladium intermediates were labile to form the diene 4b via b-elimination. A control
experiment was conducted by employing only a catalytic amount of formic acid or acetic acid
to give the diene 4b. The diene 4b was then further subjected to Method A in order to confirm
the real intermediate of this reaction as shown in Eq. (2). As expected, the palladium
acetate–HCOOH conditions reduced the diene to the product 2b exclusively. We could conclude
that formation of the laurene isomer resulted from reduction of the b-eliminated diene 4b of the
alkylpalladium intermediate.
(2)
To prevent such b-elimination, we have employed the Trost method in our system. When the
enyne 1b was treated with a catalytic amount of Pd2(dba)3, acetic acid and 10 equivalents of
triethylsilane, the enyne was cycloreduced to the natural product laurene along with its

8368
stereoisomer in combined 52% yield (Method B). To maximize the formation of our desired
laurene, we replaced triethylsilane in the Trost conditions by tributyltin hydride, catecholborane,
sodium hydride or sodium borohydride, but no successful results were obtained.
Following is a summary for the present studies. The enyne 1b was hydro- and subsequently
carbopalladated to the corresponding alkylpalladium intermediates I-b. In Method A, the
alkylpalladium intermediates readily underwent b-elimination to the diene 4b, which was
rebounded with HPdOOCH species to form presumably via the intermediate I-a and reduced to
give the product 2b as shown in Scheme 4. In Method B, the initially formed vinylpalladium
intermediate was carbopalladated to give the alkylpalladium intermediates I-b, which was
directly reduced by triethylsilane to yield the product 3b.
Scheme 4.
In conclusion, the synthesis of laurene was attempted by two palladium-catalyzed cycloreduc-
tion strategies. While triethylsilane directly reduced the intermediates I-b to lead to the
corresponding cycloreduced product 3b, formic acid did not. The intermediates in the presence
of 1.5 equivalents of formic acid underwent b-elimination to yield the diene 4b that was further
reduced at the less hindered olefin to yield the cycloreduced product 2b. Although the
b-elimination was facile in alkylpalladium intermediates, trapping such a CꢀPd sigma bond with
a hydrogen donor like triethylsilane has been accomplished. We believe that the present study
will provide more insight into regioselective syntheses of exomethylenecyclopentane derivatives.
Acknowledgements
We wish to acknowledge the financial support of Korea Research Foundation (D00312) made
in the program year of 1999.

8369
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