An efficient ring-closing metathesis reaction of geminally disubstituted olefins using first generation Grubbs' catalyst: Enantiospecific synthesis of pacifigorgianes

Article abstract of DOI:10.1016/j.tetlet.2003.08.076

An efficient ring closing metathesis reaction with first generation Grubbs' catalyst [PhCH=RuCl₂(PCy₃)₂] involving geminally disubstituted olefins has been discovered. It has been extended to the enantiospecific synthesis of pacifigorgiane sesquiterpenes.

Full text of DOI:10.1016/j.tetlet.2003.08.076

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7817–7820
An efficient ring-closing metathesis reaction of geminally
disubstituted olefins using first generation Grubbs’ catalyst:
enantiospecific synthesis of pacifigorgianes
A. Srikrishna* and Dattatraya H. Dethe
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 18 June 2003; revised 4 August 2003; accepted 14 August 2003
Abstract—An efficient ring closing metathesis reaction with first generation Grubbs’ catalyst [PhCHꢀRuCl2(PCy3)2] involving
geminally disubstituted olefins has been discovered. It has been extended to the enantiospecific synthesis of pacifigorgiane
sesquiterpenes.
© 2003 Elsevier Ltd. All rights reserved.
The last decade has witnessed an exponential growth in
the application of the olefin metathesis reaction in
organic synthesis.1 The catalytic nature of the reaction
in combination with its operational simplicity, the
remarkable tolerance of the catalyst 1 to various func-
tional groups and its stability to various conditions are
key factors responsible for the increased use of this
reaction, particularly the intramolecular version, i.e. the
ring-closing metathesis (RCM) reaction. Of the three
commonly employed catalysts 1–3, developed by
Schrock and Grubbs, the first generation Grubbs’ cata-
lyst 1 is more selective, less reactive, generally provides
a cleaner reaction and is less expensive. In general, the
catalyst 1 is found to be highly selective towards termi-
nal monosubstituted olefins to form disubstituted cyclic
olefins, and is reluctant to react with sterically demand-
ing geminally disubstituted olefins to yield trisubstituted
olefins. It is well documented that a more reactive
catalyst, such as the highly sensitive Schrock molybde-
num catalyst 2 or the Grubbs’ second generation ruthe-
nium catalyst 3, is required for generating tri- and
tetrasubstituted cyclic olefins by RCM reactions of
dienes.2,3 Now we have discovered a highly efficient
RCM reaction using the Grubbs’ first generation cata-
lyst 1 and involving a geminally disubstituted olefin.
Herein, we report our finding, and its extension to the
enantiospecific synthesis of the pacifigorgiane
sesquiterpenes.
We realised that C-6 allylation of (R)-carvone 4 fol-
lowed by an RCM reaction would be a convenient
method for the enantiospecific generation of
hydrindanes, and that it would be possible to generate
both cis- and trans-hydrindanes by controlling the
stereochemistry at C-6. In order to generate the
hydrindanes containing a bridgehead methyl group (as
in the CD rings of steroids), (R)-carvone 4 would have
to be converted into both epimers of 6-allyl-6-methyl-
carvone. Kinetic alkylation of 4 using LDA and allyl
bromide generated a 6:1 epimeric mixture of 6-allylcar-
vones 5, which on a second alkylation with LDA and
methyl iodide generated, exclusively, the cis-6-allyl-6-
methylcarvone 6.4 Reversing the sequence of alkyla-
tions transformed 4 into the trans-6-allyl-6-methyl-
carvone 7 (Scheme 1).
As expected, the RCM reactions of the compounds 6
and 7 with Grubbs’ catalyst 1 under a variety of
conditions were found to be inefficient. For example,
refluxing a 0.005 M methylene chloride solution of the
compounds 6 or 7 with 20 mol% of the catalyst 1 for 12 h
generated the hydrindanones 8 or 9 in only 10–15%
yields (Scheme 2). In contrast, the RCM reaction of the
* Corresponding author. Fax: +91-80-3600683; e-mail: ask@
orgchem.iisc.ernet.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.076

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A. Srikrishna, D. H. Dethe / Tetrahedron Letters 44 (2003) 7817–7820
diate ruthenium carbenoid, population of the reactive
rotamer B dominates because of the steric repulsion
between ruthenium carbenoid and butyl group on the
next carbon atom in the rotamer A, thus accelerating
the reaction. This was further substantiated by carrying
out the RCM reactions of the alcohols 12 and 13.
Treatment of the alcohol 13, containing the allyl and
butyl side chains cis to each other, with 10 mol% of the
catalyst 1 in refluxing methylene chloride for 4 h fur-
nished the RCM product 16, [h]2D2=−122 (c 2.4,
CHCl3), in near quantitative yield (Scheme 3). In con-
trast, reaction of the alcohol 12, containing the allyl
and butyl groups in trans-pseudo diaxial orientation,
was found to be inefficient and produced only 10% of
the RCM product 17, [h]2D2=−114 (c 0.35, CHCl3), after
8 h reflux with 10 mol% of the catalyst 1.
Scheme 1.
compounds 10 and 11, which were prepared from 6 and
7 by a 1,3-alkylative enone transposition strategy via
the alcohols 12 and 13, were found to be extremely easy
even under mild conditions. Treatment of the cis-iso-
mer 10 with 10 mol% of the catalyst 1 in methylene
chloride at room temperature for 30 min furnished the
hydrindanone 14, [h]D23=−99 (c 0.9, CHCl3), in quanti-
tative yield. In a similar manner, RCM of the trans-iso-
mer 11 under the same conditions furnished the
hydrindanone 15, [h]D23=+69 (c 2.7, CHCl3), again in
quantitative yield.†
Figure 1.
Scheme 3.
After the discovery of an efficient RCM reaction for the
enantiospecific generation of hydrindanes 14–16, it has
been extended to the enantiospecific synthesis of the
pacifigorgiane sesquiterpenes. In 2001, Konig and
coworkers reported6 the isolation of five pacifigorgiadi-
enes 18–22 from the liverwort Frullania fragilifolia,
belonging to a small group of hydrindane based
sesquiterpenes pacifigorgianes, found to be present in
both marine and terrestrial sources. The first member of
this group, ichthyotoxic pacifigorgiol 23 was isolated7
from the Pacific gorgonian coral Pacifigorgia cf. adam-
sii and also from the essential oil of Valeriana offici-
nalis, and the second member tamariscol 24 was
isolated8 from the liverwort Frullania tamarisci.
Scheme 2.
One possible reason for the dramatic acceleration of the
RCM reaction of the compounds 10 and 11 under mild
conditions in comparison with that of 6 and 7 could be
the entropy effect.5 As shown in Fig. 1, in the interme-
† Yields refer to isolated and chromatographically pure products. All
the compounds reported here exhibited spectral data (IR, 1H and
13C NMR and mass spectra) consistent with their structures.

A. Srikrishna, D. H. Dethe / Tetrahedron Letters 44 (2003) 7817–7820
7819
It was readily identified that addition of the isobutyl
group followed by a RCM reaction transforms 6-allyl-
carvones 5 into pacifigorgianes.9 Thus, careful column
chromatography of the epimeric mixture of allylcar-
vone 5 on silica gel furnished the trans-isomer 5t.
Generation of the kinetic enolate of 5t with LDA at
−70°C followed by quenching with acetic acid gener-
ated the cis-isomer 5c (Scheme 4). Sonochemically
accelerated Barbier reaction of 5t with lithium and
isobutyl bromide furnished the allyl alcohols 25 and 26
in a 2:1 ratio. Oxidation of the alcohols 25 and 26 with
PCC and silica gel in methylene chloride furnished the
enone 27, [h]2D4=+77 (c 2.8, CHCl3). Similarly, Barbier
reaction of 5c gave the alcohol 28, which on oxidation
furnished the enone 29, [h]2D5=+214 (c 1.7, CHCl3).
Scheme 6.
In order to find the effect of the ring olefin on the
RCM, the reaction was carried out on the saturated
compound. Thus, reaction of 6-allylcarvone 5 with zinc
and potassium hydroxide in refluxing ethanol furnished
the dihydro compound 35 (Scheme 7). Barbier reaction
of the compound 35 with isobutyl bromide and lithium
furnished the tert-alcohol 36, [h]2D2=−11.3 (c 7, CHCl3).
RCM of 36, containing the isobutyl and allyl side
chains in a trans-diequatorial orientation, with 10
mol% of the catalyst 1 in refluxing methylene chloride
for 4 h was also found to be efficient, like that of 26,
and furnished the pacifigorgia-7-en-2-ol 37, [h]2D3=+29
(c 0.7, CHCl3), in near quantitative yield.
Scheme 4.
In line with the earlier observations, reaction of the
enones 27 and 29 with 10 mol% of the catalyst 1 in
refluxing methylene chloride for 3 h furnished pacifigor-
gia-2,7-dien-4-ones 30, [h]2D4=+20 (c 3.5, CHCl3), and
31, [h]2D2=−137 (c 1.1, CHCl3), in quantitative yield
(Scheme 5). The RCM reaction of the alcohol 28,
containing the isobutyl and allyl groups trans-diaxial to
each other, was found to be inefficient, like that of 12,
and produced the RCM product 32, [h]2D2=−202 (c 0.4,
CHCl3), in less than 10% yield after refluxing in methyl-
ene chloride with 15 mol% of the catalyst 1 for 12 h
(Scheme 6). Whereas the alcohol 26 containing the
isobutyl and allyl groups in a trans-pseudo diequatorial
orientation furnished a 1:1 mixture of the pacifigorgia-
3,7-dien-2-ol 33, [h]D24=−94 (c 1.2, CHCl3), and starting
material in quantitative yield under the same condi-
tions. In contrast, treatment of the alcohol 25 with 10
mol% of the catalyst 1 in refluxing methylene chloride
for 3 h furnished the pacifigorgia-3,7-dien-2-ol 34,
[h]2D4=−103 (c 2, CHCl3), in quantitative yield.
Scheme 7.
In conclusion, we have discovered an efficient RCM
reaction with first generation Grubbs’ catalyst 1 involv-
ing geminally disubstituted olefins. The presence of an
alkyl group on the carbon next to the allyl bearing
carbon, either in a cis orientation or in a trans-diequa-
torial orientation or on an sp2 carbon was found to
accelerate the RCM reaction of the allyl group with the
isopropenyl group. It has been further extended to the
enantiospecific synthesis of a number of pacifigorgianes.
Scheme 5.

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A. Srikrishna, D. H. Dethe / Tetrahedron Letters 44 (2003) 7817–7820
4. Gesson, J.-P.; Jacquesy, J.-C.; Renoux, B. Tetrahedron
Acknowledgements
1989, 45, 5853–5866.
We thank Professor H. Suryaprakash Rao for helpful
discussions.
5. (a) Jung, M. E. Synlett 1999, 843–846. For a similar
entropic effect in rhodium carbenoid CꢁH insertion reac-
tion, see: (b) Srikrishna, A.; Gharpure, S. J. Chem.
Commun. 1998, 1589–1590. For a tributylstannyl medi-
ated entropic effect for the generation of eight-membered
cyclic ethers by the RCM reaction, see: (c) Linderman,
R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H. J. Am. Chem.
Soc. 1997, 119, 6919–6920.
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