An efficient synthesis of (±)-grandisol featuring 1,5-enyne metathesis

Article abstract of DOI:10.1021/jo9020375

(Chemical Equation Presented) An eight-step synthesis of (±)-grandisol features a key sequence involving a high-yielding, microwave-assisted enyne metathesis to yield a 1-alkenylcyclobutene that is semihydrogenated to yield a silyl-protected grandisol. Metathesis catalyst screens revealed an intriguing trend whereby substrate conversion correlated strongly with the identity of the ligands on the catalyst. In addition, new reactivity of 1-alkenylcyclobutenes toward hydrogenation is described.

Full text of DOI:10.1021/jo9020375

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SCHEME 1. Retrosynthesis of (()-Grandisol
An Efficient Synthesis of (()-Grandisol Featuring
1,5-Enyne Metathesis
Thomas J. A. Graham, Erin E. Gray, James M. Burgess, and
Brian C. Goess*
Department of Chemistry, Furman University,
3300 Poinsett Highway, Greenville, South Carolina 29613
framework of grandisol. Our retrosynthetic analysis is
described in Scheme 1. We envisioned the vinylcyclo-
butane core of grandisol arising from a semihydrogenation
(monohydrogenation) of vinylcyclobutene 1. Substituted
vinylcyclobutene 1 can be prepared from enyne 2 in a
metathesis cyclization. 2 may be prepared from commer-
cially available R-methyl-γ-butyrolactone using standard
synthetic manipulations.
brian.goess@furman.edu
Received September 21, 2009
SCHEME 2. Challenges Associated with Selective Semihydro-
genation of 1
An eight-step synthesis of (()-grandisol features a key
sequence involving a high-yielding, microwave-assisted
enyne metathesis to yield a 1-alkenylcyclobutene that is
semihydrogenated to yield a silyl-protected grandisol.
Metathesis catalyst screens revealed an intriguing trend
whereby substrate conversion correlated strongly with
the identity of the ligands on the catalyst. In addition, new
reactivity of 1-alkenylcyclobutenes toward hydrogena-
tion is described.
The hydrogenation of 1 to 3 is a formidable synthesis
challenge (Scheme 2); it must proceed with regioselectivity
(preferential hydrogenation of the cyclic alkene over the
acyclic alkene to instead form 4), diastereoselectivity
(preferential hydrogenation from the face of the cyclobutene
bearing the methyl group over the ethyloxy group to instead
form 5), and chemoselectivity (preferential semihydrogena-
tion of the diene over further hydrogenation of the inter-
mediate monoene to instead form 6). The reactivity of
1-alkenylcyclobutenes have not been extensively studied,3
and no comprehensive strategy exists for the regioselective
semihydrogenation of dienes in general and of conjugated
dienes in particular.4 However, for the conversion of 1 to 3,
we anticipated being able to obtain the desired regioselec-
tivity by taking advantage of the enhanced reactivity of the
cyclobutene due to its inherent ring strain.5 Furthermore, we
Grandisol is the primary constituent of the grandlure, a
mixture of four pheromones that comprise the sex attractant
of the cotton boll weevil. Cotton boll weevils cause signifi-
cant damage to cotton crops, and grandlure-filled traps are
one means used to protect against boll weevil infestation and
its associated economic consequences. The extraction of
grandlure components from large collections of dead weevils
is tedious and unpleasant, making efficient synthetic routes
an attractive alternative to harvesting. Furthermore, racemic
grandisol has proven equally effective at attracting boll
weevils as the natural enantiomer,1 rendering moot the need
for enantioselective syntheses for agricultural purposes.
Historically, the alkenylcyclobutane core of grandisol has
presented a challenge to synthetic chemists and has served
as a proving ground for new methodologies.2 Herein we
report the use of a 1,5-enyne metathesis reaction as the key
step in a straightforward and efficient assembly of the carbon
(3) For cycloadditions, see: (a) Park, J. D.; Frank, W. C. J. Org. Chem.
1964, 29, 1445. (b) Thummel, R. P. J. Am. Chem. Soc. 1976, 98, 628. (c)
Thummel, R. P.; Nutakul, W. J. Org. Chem. 1977, 42, 300. (d) Thummel, R.
P.; Cravey, W. E.; Nutakul, W. J. Org. Chem. 1978, 43, 2473. (e) Markgraf, J.
H.; Greeno, E. W.; Miller, M. D.; Zaks, W. J. Tetrahedron Lett. 1983, 24, 241.
(f) Doecke, C. W.; Garratt, P. J.; Shahriari-Zavareh, H.; Zahler, R. J. Org.
Chem. 1984, 49, 1412. For an oxidation, see: (g) Takeda, A.; Tsuboi, S;
(1) Hibbard, B. E.; Webster, F. X. J. Chem. Ecol. 1993, 19, 2129.
(2) Citations for 34 previously reported syntheses of grandisol may be
found in ref 4 in the Supporting Information. Some of these syntheses are
competitive with the present synthesis in terms of efficiency, and most
describe a methodological advance. In particular, we direct interested readers
to five manuscripts that are representative of the variety of excellent
chemistries inspired by grandisol: refs. f, q, y, ff, and dd.
Sakai, F.; Tanabe, M. J. Org. Chem. 1974, 39, 3098.
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(4) Tungler, A.; Hegedus, L.; Fodor, K.; Farkas, G.; Furcht, A.; Karancsi,
Z. P. In The Chemistry of Dienes and Polyenes; Rapaport, Z., Ed.; John Wiley
and Sons: New York, 2000; Vol. 2, p 992.
(5) Wiberg, K. B. Angew. Chem., Int. Ed. Engl. 1986, 25, 312.
226 J. Org. Chem. 2010, 75, 226–228
Published on Web 12/03/2009
DOI: 10.1021/jo9020375
r
2009 American Chemical Society

Graham et al.
JOCNote
SCHEME 3. Synthesis of (()-Grandisola
aReagents and conditions: (a) (i) LDA, (ii) allyl bromide, THF, -78 °C,
91%; (b) DIBAL-H, PhCH3, -78 °C, 95%; (c) TBDPSCl, imidazole,
DMF, 60 °C, 92%; (d) CH3COC(N2)PO(OCH3)2, K2CO3, CH3OH,
87%; (e) (i) LDA, (ii) CH3OTf, THF, -78 °C, 91%; (f) 10 (20 mol%),
CH2Cl2, microwave, 75 °C, 83%; (g) Raney Ni, iPrOH, hexanes, 63%;
(h) see ref 12.
FIGURE 1. Result of catalyst screen. Percentages shown are con-
version yields of the microwave reaction estimated from analysis of
the crude NMR. Values in parentheses are isolated yields obtained
using our sealed tube conditions (vide infra).
expected that increasing the steric bulk of the alcohol
through its conversion to a bulky silyl ether (for instance,
P = TBDPS, 1a) might promote diastereoselective hydro-
genation from the opposite, less hindered face. Finally,
though we hoped the inherent difference in reactivity of the
strained cyclobutene would allow us to easily achieve the
desired chemoselectivity, given the known sensitivity of
hydrogenation reactions to substrate structure, catalyst,
and solvent6 and how little is known about the inherent
reactivity of vinylcyclobutenes, we anticipated an empirical
screen of reaction conditions might be necessary.
Our synthesis (Scheme 3) began with allylation of
R-methyl-γ-butyrolactone followed by reduction of the lac-
tone to yield lactol 7. Silylation of the open-chain form of 7
gave aldehyde 8. Alkynylation of the aldehyde with the
Bestmann-Ohira reagent followed by methylation of the
terminal alkyne generated enyne 9, the substrate for our key
methathesis cyclization.
TABLE 1. Results of Representative Regioselective Semihydrogena-
tions of 1a after 10 Minutes of Reaction Time
catalystc
solvent
temp
1aa
3a
4ab
6a
Pd/C
Pd/C
Pd/C
Pd/C
THF
THF
25 °C
0 °C
25 °C
25 °C
25 °C
25 °C
25 °C
15%
14%
42%
0%
0%
0%
31%
35%
19%
35%
43%
43%
70%
10%
11%
10%
12%
12%
5%
44%
40%
29%
53%
45%
52%
22%
PhCH3
EtOH
hexane
EtOH
iPrOH
Pd/C
Pd/CaCO3
Raney Nid
0%
8%
aPercentages based on relative NMR integrations of distinctive peaks
and scaled to 100%. bProduct 5a was formed in <5% yield in each run.
c5 mol %. dPerformed in the absence of a hydrogen atmosphere.
of catalysts 10f13 is likely due to their enhanced stability at
the elevated temperatures that are rapidly achieved with
microwave irradiation. Such trends have been observed
previously in microwave-assisted olefin metatheses.9
In an effort to expand the utility of this reaction to those
without access to a microwave reactor, we developed a
thermal, sealed tube protocol (sealed tube, CH2Cl2, 75 °C,
30 min) that gives lower yields than the microwave condi-
tions described above yet significantly higher yields than the
open flask yields reported in the literature.7 Three of the four
catalysts that led to complete consumption of 9 were eval-
uated under our sealed tube conditions (Figure 1). Though
the sealed tube yields are lower than what can be achieved
under microwave conditions, they are synthetically useful
and complement the seminal results previously reported.7
The hydrogenation of 1a proved challenging, with stan-
dard hydrogenation procedures generally leading within
minutes to complete consumption of 1a and formation of
significant amounts of fully hydrogenated 6a along with
lesser amounts of desired 3a (see Scheme 2) and other
isomers (Table 1). Simple variations on solvent, temperature,
and catalyst did not lead to increased production of 3a. On
the basis of previous observations that the adsorbed hydro-
gen on the surface of Raney Ni alone is sufficient to prevent
full hydrogenation of alkynes,10 we hoped that complete
reduction to 6a might be prevented through use of Raney Ni
When 1,5-enyne 9 was exposed to conditions previously
reported by Campagne et al. to induce a metathesis cycliza-
tion for a variety of substrates7 (catalyst 10, microwave
irradiation, CH2Cl2, 75 °C, 30 min), vinylcyclobutene 1a
was isolated in 83% yield. Notably, this yield is higher than
any reported in the literature,7 possibly due to the Thorpe-
Ingold effect.8 Encouraged by this result, we performed a
comprehensive catalyst screen to determine which catalyst
structural feature(s) facilitated the transformation. All but
one catalyst bearing a mesityl-disubstituted N-heterocyclic
carbene ligand (10f13) led to complete consumption of 9
1
within 30 min at 75 °C as determined by crude H NMR
(Figure 1). Of the remaining catalysts, those bearing a
tricyclohexylphosphine ligand (15f17) showed moderate
conversions, and those bearing an o-tolyl ligand showed
poor conversions (18, 19). NMR analyses of crude reaction
mixtures revealed evidence of catalyst decomposition espe-
cially in reactions catalyzed by 15f17, indicating the success
(6) For a comprehensive treatment, see: (a) Kluwer, A. M.; Elsevier, C. J. In
The Handbook of Homogeneous Hydrogenation; de Vreis, J. G., Elsevier, C. J.,
Eds.; Wiley-VCH: Weinheim, Germany, 2007. (b) Nishimura, S. Handbook of
Heterogeneous Catalytic Hydrogenation for Organic Synthesis; John Wiley
and Sons: New York, 2001. (c) Freifelder, M. Catalytic Hydrogenation in
Organic Synthesis: Procedures and Commentary; John Wiley and Sons: New
York, 1978.
(7) Debleds, O.; Campagne, J. J. Am. Chem. Soc. 2008, 130, 1562.
(8) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
1915, 107, 1080. (b) For an example in the context of a metathesis reaction,
(9) For a review of microwave-assisted olefin metatheis, see: (a) Coquerel,
Y.; Rodriguez, J. Eur. J. Org. Chem. 2008, 1125. Also see the following
references therein: (b) Efskind, J.; Undheim, K. Tetrahedron Lett. 2003, 44,
2837. (c) Michaut, M; Boddaert, T.; Coquerel, Y.; Rodriguez, J. Synthesis
2007, 2867.
(10) (a) Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc. 2006, 128, 14028.
(b) Soukup, M.; Widmer, E. Tetrahedron Lett. 1991, 32, 4117.
€
see: Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746.
J. Org. Chem. Vol. 75, No. 1, 2010 227

Graham et al.
JOCNote
without a hydrogen atmosphere. We were pleased to dis-
cover that this was indeed the case; the desired isomer 3a was
isolated in 63% yield.11 Conditions for cleaving the silyl
protective group have been previously reported, and it
occurs in quantitative yield.12
metathesis that proceeds in high yield and discovery of new
insights into the reactivity of 1-alkenylcyclobutenes, a com-
pound class whose reactivity has not yet been extensively
studied.
Notably, the undesired diastereomer 5a was not observed
in any significant quantity during the Raney Ni hydrogena-
tion of 1a, indicating the stereoselectivity of the transforma-
tion is indeed controlled by the substrate. To provide further
support for this hypothesis, we deprotected 1a (TBAF, THF,
81%) to form alcohol 1b and attempted the Raney Ni
hydrogenation on this substrate. 1H NMR analyses of crude
reaction samples throughout the reaction indicated no dia-
stereoselectivity (essentially 1:1 production of 3b/5b), which
stands in stark contrast to the diastereoselective reaction
observed with 1a, which bears a large protective group.13
We have, therefore, described a synthetic sequence where-
in (()-grandisol may be prepared in eight steps and 33%
overall yield from commercially available R-methyl-γ-butyr-
olactone. Key advances in this synthesis include develop-
ment of a non-microwave-assisted method for a 1,5-enyne
Experimental Section
Procedure for Thermal, Sealed Tube Preparation of 1a. Note:
sealed tube experiments should always be conducted behind a
safety shield.
To a solution of 9 (467 mg, 1.19 mmol) in anhydrous CH2Cl2
(31 mL) was added 10 (150 mg, 20 mol %). The flask was then
briefly purged with argon and sealed. The flask was then
submerged in a preheated 75 °C oil bath and allowed to stir
for 35 min. The flask was removed, cooled in an ice bath, and
concentrated to give a green residue. Biotage column chroma-
tography (2% Et2O/pentane) afforded 1a as a colorless oil
(309 mg, 66%).
Acknowledgment. Financial support from ACS-PRF
(47106-GB1), Research Corporation (CC7044/7165),
and NIH-NCRR (P20 RR-016461) to B.G. is gratefully
acknowledged. We thank the Milliken Foundation for
providing critical instrumentation, and Biotage, LLC for
use of a microwave reactor. T.G. acknowledges Furman
University for a research fellowship.
(11) This compound has been previously reported (see ref 12). 1H and 13
C
NMR spectra, included in the Supporting Information, match the data
reported in the literature. HRMS data were not previously reported for this
compound and have been included in the Supporting Information.
(12) (a) Narasaka, K.; Kusama, H.; Hayashi, Y. Bull. Chem. Soc. Jpn.
1991, 64, 1471. (b) Kim, D.; Kwak, Y. S.; Shin, K. J. Tetrahedron Lett. 1994,
35, 9211.
Supporting Information Available: Detailed experimental
procedures for the preparation of all new compounds re-
ported in Schemes 2 and 3 along with corresponding char-
acterization data and the complete citation for ref 2. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(13) The 1H NMR analyses of these crude reaction mixtures were
simplified by the fact that 5b is fragranol,14 a known natural product, whose
chemical shifts are distinct from those of 3b (grandisol).
(14) Bernard, A. M.; Frongia, A.; Secci, F.; Delogu, G.; Ollivier, J.;
€
Pieras, P. P.; Salaun, J. Tetrahedron 2003, 59, 9433.
228 J. Org. Chem. Vol. 75, No. 1, 2010