Ring-closing metathesis of allylsilanes as a flexible strategy toward cyclic terpenes. Short syntheses of teucladiol, isoteucladiol, poitediol, and dactylol and an attempted synthesis of caryophyllene

Article abstract of DOI:10.1021/jo101439h

The development of a strategy consisting of allylsilane ring-closing metathesis and subsequent S_E′ electrophilic desilylation (allylsilane RCM/S_E′) to construct exo-methylidenecycloalkanes is described. Its utility is documented in short syntheses of teucladiol and poitediol. A key transformation in the synthesis of teucladiol is an aldol addition that establishes three stereochemical relationships in one step with ≥10:1 diastereoselectivity and provides a fascinating example of double stereodifferentiation/kinetic resolution with racemic reaction partners in the context of natural product synthesis. The synthesis of (±)-teucladiol required five steps from cyclopentenone and proceeded in 28% overall yield; adaptation of this route to an enantioselective synthesis of (-)-teucladiol enabled the determination of the absolute configuration of this terpene natural product. The use of fluoride-mediated conditions in the final desilylation step preserves the location of the alkene, delivering the natural product (±)-isoteucladiol (five steps and 21% yield from cyclopentenone). The synthesis of poitediol showcases the power of RCM for constructing eight-membered rings and features a highly diastereoselective epoxidation/fluoride-mediated fragmentation sequence for installing the exo-methylidene group with an adjacent hydroxyl-bearing stereocenter. The synthesis of (±)-poitediol required seven steps and proceeded in 18% overall yield. Again, fluoride-mediated desilylation of a late-stage intermediate (with retention of double-bond location) delivered the natural product (±)-dactylol (seven steps and 24% yield). Efforts directed toward incorporating the RCM/S_E′ sequence into a synthesis of caryophyllene are also disclosed. While ultimately unsuccessful, these efforts resulted in the identification of a novel metal alkylidene-promoted deallylation reaction of terminal 1,4-dienes. A possible mechanism for this unexpected deallylation reaction of 1,4-dienes is provided.

Full text of DOI:10.1021/jo101439h

pubs.acs.org/joc
Ring-Closing Metathesis of Allylsilanes As a Flexible Strategy toward
Cyclic Terpenes. Short Syntheses of Teucladiol, Isoteucladiol, Poitediol,
and Dactylol and an Attempted Synthesis of Caryophyllene
Matthew S. Dowling and Christopher D. Vanderwal*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025
cdv@uci.edu
Received July 26, 2010
0
The development of a strategy consisting of allylsilane ring-closing metathesis and subsequent SE
0
electrophilic desilylation (allylsilane RCM/SE ) to construct exo-methylidenecycloalkanes is de-
scribed. Its utility is documented in short syntheses of teucladiol and poitediol. A key transformation
in the synthesis of teucladiol is an aldol addition that establishes three stereochemical relationships in
one step with g10:1 diastereoselectivity and provides a fascinating example of double stereodiffer-
entiation/kinetic resolution with racemic reaction partners in the context of natural product
synthesis. The synthesis of (()-teucladiol required five steps from cyclopentenone and proceeded
in 28% overall yield; adaptation of this route to an enantioselective synthesis of (-)-teucladiol
enabled the determination of the absolute configuration of this terpene natural product. The use of
fluoride-mediated conditions in the final desilylation step preserves the location of the alkene,
delivering the natural product (()-isoteucladiol (five steps and 21% yield from cyclopentenone). The
synthesis of poitediol showcases the power of RCM for constructing eight-membered rings and
features a highly diastereoselective epoxidation/fluoride-mediated fragmentation sequence for
installing the exo-methylidene group with an adjacent hydroxyl-bearing stereocenter. The synthesis
of (()-poitediol required seven steps and proceeded in 18% overall yield. Again, fluoride-mediated
desilylation of a late-stage intermediate (with retention of double-bond location) delivered the
natural product (()-dactylol (seven steps and 24% yield). Efforts directed toward incorporating the
RCM/SE0 sequence into a synthesis of caryophyllene are also disclosed. While ultimately unsuccess-
ful, these efforts resulted in the identification of a novel metal alkylidene-promoted deallylation
reaction of terminal 1,4-dienes. A possible mechanism for this unexpected deallylation reaction of
1,4-dienes is provided.
6908 J. Org. Chem. 2010, 75, 6908–6922
Published on Web 09/13/2010
DOI: 10.1021/jo101439h
2010 American Chemical Society
r

Dowling and Vanderwal
JOCArticle
Introduction
Because of their impressive structural diversity,1,2 terpenes
have long served as a source of inspiration for the develop-
ment of strategies and tactics in organic synthesis; however,
this same diversity of architectures also renders the develop-
ment of a completely general strategy for the synthesis of
terpenes difficult. Inspired by the unusual tetracyclic archi-
tecture of echinopine A3 (1, Figure 1), we sought to develop
an efficient method for synthesizing the exo-methylidenecyclo-
heptane function (highlighted in red) present in this natural
product. While contemplating potential solutions to this
problem, we recognized that exo-methylidenecycloalkanes
occur frequently in terpene natural products. To the best of
our knowledge, no truly general strategy has been reported
for the synthesis of this functional group arrangement that is
characterized by the presence of a thermodynamically less
stable exocyclic alkene. The majority of the reported routes
to natural products containing exo-methylidenecycloalkanes
utilize either ketone olefination processes,4 the elimination of
a suitable leaving group,5 or an annulation sequence involv-
ing a vinyl organometallic reagent or intermediate6 to install
the exocyclic alkene.
Exemplary exo-methylidenecycloalkane-bearing terpenes
include echinopine A (1),3 caryophyllene (2),7 teucladiol (3),8
poitediol (4),9 eupahualin D (7),10 and cladiellisin (8)11
(Figure 1); these natural products demonstrate the variety
of ring sizes and substitution patterns found in this large
subset of terpenes. Many terpenes that contain exo-meth-
ylidenecycloalkanes are coproduced withtheir thermodynam-
ically more stable endocyclic isomers as a consequence of
their biogenetic derivation from cationic cyclization reac-
tions12 (see isoteucladiol [5]13 and dactylol [6],14 Figure 1,
and Scheme 1). An ideal strategy for accessing exo-methyl-
idenecycloalkanes would also provide the flexibility to gen-
erate these endocyclic isomers from late-stage intermediates;
moreover, the ability to introduce diverse functional groups
adjacent to the exocyclic alkene would be substantially
useful.
FIGURE 1. Representative terpenes bearing the exo-methylidene-
cycloalkane motif (in red) and two closely related natural products
bearing the corresponding endocyclic alkene.
SCHEME 1. Generic Polycyclic Terpene Biosynthesis Showing
the Origin of Both the Endocyclic and Exocyclic Alkene Isomers
(1) Tholl, D. Curr. Opin. Plant Biol. 2006, 9, 297–304.
(2) For a discussion relating to monoterpenes and sesquiterpenes, see:
€
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Gu, Y.-C.; Zamir, L. O.; Kiyota, H. Org. Lett. 2008, 10, 701–704.
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(5) For a recent example, see: Williams, M. J.; Deak, H. L.; Snapper,
M. L. J. Am. Chem. Soc. 2007, 129, 486–487.
(6) For pertinent examples, see: (a) Piers, E.; Karunaratne, V. Tetrahedron
1989, 45, 1089–1104. (b) Wender, P. A.; Fuji, M.; Husfeld, C. O.; Love, J. A.
Org. Lett. 1999, 1, 137–140.
We recently conceived of a straightforward strategy for
constructing exo-methylidenecycloalkanes.15 Our two-step
approach involves ring-closing olefin metathesis16 of allyl-
silanes of type 9, with subsequent SE0 electrophilic desilylation
of the resultant trisubstituted allylsilane 10 to generate
the exo-methylidenecycloalkane motif (11, Scheme 2a).
ꢀ
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SCHEME 2. (a) Strategy to Access exo-Methylidenecycloalkanes (E = electrophile (H, Cl, OH, carbon electrophiles, etc.)); (b) Known
RCM-Based Allylsilane Syntheses; (c) Sakurai’s Precedent for Accessing Both Exocyclic and Endocyclic Alkenes from a Common Cyclic
Allylsilane
Ring-closing metathesis of allylic silanes has been reported;17
for example, silacycles have been forged according to the
metathesis process 12 f 1318,19 (Scheme 2b), and cyclic
allylsilanes with the silicon atom attached directly to the ring
have also been made by RCM (see 14 f 15).20 Examples of
allylsilane cross-metathesis are also known (not shown).21 In
spite of all of these precedents, prior to our work, cyclic allyl-
silanes of specific type 10 had never been made by RCM. With
respect to the second key step in our strategy, myriad examples
of electrophilic desilylation of allylsilanes are known.22 Given
these literature precedents, it was surprising that the combina-
tion of these simple reaction types into a cohesive strategy to
access the exo-methylidenecycloalkane motif common to many
terpene natural products had never been reported. The closest
precedent that shares the spirit of our design is the strategy
reported by Sakurai in 1982,23 which involved the Diels-Alder
reaction of 2-trimethylsilylmethylbutadiene with typical dieno-
philes to afford compounds of type 16, followed by SE0 electro-
philic desilylation to afford the exocyclic alkene (Scheme 2c).
Conditions for desilylation that retained the location (endo-
cyclic) of the alkene were also reported. This report clearly docu-
mented the versatility of cyclic allylsilanes of type 10 that we
hoped to use in our work. However, because of the requisite
cycloaddition step, this earlier work was limited to the genera-
tion of six-membered rings.
Virtues of the strategy outlined in Scheme 2a for the
synthesis of exo-methylidenecycloalkanes include the fol-
lowing: (1) Ring-closing olefin metathesis is an efficient
and functional-group-tolerant method for constructing nor-
mal, medium, and large rings.16 (2) Allylsilanes are readily
introduced by a variety of reliable procedures (see below)24
and are relatively stable species that can be carried through
multistep reaction sequences. (3) In addition to simple pro-
todesilylation of allylsilane 10 to give 19 (Scheme 3), this
versatile intermediate is amenable to multiple productive
transformations to other motifs frequently found in terpene
natural products, including (1) epoxidation/fluoride-mediated
olefination to produce allylic alcohols of type 20;22a,b (2)
(17) For a general review on the synthesis of silicon derivatives with
ruthenium catalysts, see: Marciniec, B.; Pietraszuk, C. Top. Organomet.
Chem. 2004, 11, 197–248.
(18) For X = O, see: (a) Chang, S.; Grubbs, R. H. Tetrahedron Lett.
1997, 38, 4757–4760. (b) Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38,
7861–7864. (c) Cassidy, J. H.; Marsden, S. P.; Stemp, G. Synlett 1997, 1411–
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Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1999, 121, 8251–8259.
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W. A. L. Tetrahedron Lett. 2008, 49, 7403–7405. (f) Taylor, R. E.; Engelhardt,
F. C.; Schmitt, M. J.; Yuan, H. J. Am. Chem. Soc. 2001, 123, 2964–2969.
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T. Chem. Commun. 2001, 1802–1803. (h) Funk, T. Org. Lett. 2009, 11
4998–5001.
(19) For X = CH2, see: (a) Leconte, M.; Pagano, S.; Mutch, A.; Lefebvre,
F.; Basset, J. M. Bull. Soc. Chim. Fr. 1995, 132, 1069–1071. (b) Anhaus, J. T.;
Gibson, V. C.; Clegg, W.; Collingwood, S. P. Organometallics 1993, 12,
1780–1789. (c) Landais, Y.; Mahieux, C.; Schenk, K.; Surange, S. S. J. Org.
Chem. 2003, 68, 2779–2789. (d) Ahmad, I.; Falck-Pedersen, M. L.; Undheim,
K. J. Organomet. Chem. 2001, 625, 160–172. (e) Hammaecher, C.; Bouillon,
J.-P.; Portella, C. Tetrahedron 2009, 65, 5527–5534. (f) Hoshi, T.; Yasuda,
H.; Sanji, T.; Sakurai, H. Bull. Chem. Soc. Jpn. 1999, 72, 821–827. (g)
Mahieux, C.; Laguerre, M.; Landais, Y.; Pianet, I. Magn. Reson. Chem.
2004, 42, 467–473.
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Lett. 2003, 5, 1859–1861. (b) Miller, J. F.; Termin, A.; Koch, K.; Piscopio,
A. D. J. Org. Chem. 1998, 63, 3158–3159. (c) Heo, J.-N.; Micalizio, G. C.;
Roush, W. R. Org. Lett. 2003, 5, 1693–1696. (d) Heo, J.-N.; Holson, E. B.;
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J.-M.; de Fays, L.; Laguerre, M.; Ghosez, L. Tetrahedron 2004, 60, 7325–
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355–358. (b) Hosomi, A.; Iguchi, H.; Sasaki, J.; Sakurai, H. Tetrahedron Lett.
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application of this strategy to a synthesis of caryophyllene
(2),7 which yielded some unanticipated findings.
SCHEME 3. Versatility of RCM-Derived Cyclic Allylsilanes
Results and Discussion
Although published examples of cross and ring-closing
metathesis reactions involving allylsilanes are numerous, as
0
are cases of allylsilane SE electrophilic desilylation, to the
best of our knowledge the synthesis of an exo-methylidene-
cycloalkane using the two-step sequence shown in Scheme 2a
had not been reported. In order to establish the feasibility of
this two-step reaction sequence, a model substrate, 43, was
constructed as shown in Scheme 5. Conjugate addition of
butenylmagnesium bromide to methyl cinnamate afforded
known ester 42,31 which was converted into allylsilane 43
according to Bunnelle’s protocol.30a Exposure of 43 to the
Grubbs first-generation catalyst (see Grubbs I, Scheme 5)32
in dichloromethane at reflux afforded the homodimer 44 in
65% yield. The desired cyclic trisubstituted allylsilane 45 was
not detected in the crude reaction mixture. This result was
not surprising, because it is known that this relatively
unreactive catalyst often fails to effect the formation of cyclic
trisubstituted olefins.33 Exposure of 43 to the Grubbs second-
generation catalyst (Grubbs II)34 furnishe0d allylsilane
45 in 89% yield, which underwent smooth SE protodesily-
lation23a in the presence of p-TsOH. The exo-methylidene-
cyclohexane product (46) proved to be very stable to p-TsOH
in Et2O; exposure of this compound to excess acid for 24 h
did not lead to isomerization to the more stable endocyclic
alkene. With success in this simple model system, we aimed
to demonstrate its utility in complex contexts by incorporat-
ing this two-step strategy into discrete syntheses of teucladiol
(3), poitediol (4), and caryophyllene (2), rather than demon-
strating the scope of the strategy with a series of simple and
uninteresting substrates.
Teucladiol: Background. Teucladiol (3, Figure 1) is a
guaiane sesquiterpene that was first isolated in 1993 by de
la Torre and co-workers8 from the aerial parts of Teucrium
leucocladum, a flowering plant found in Egypt. The structure
and relative stereochemistry of teucladiol were determined
using a combination of one- and two-dimensional NMR
techniques. Since this initial disclosure, teucladiol has been
isolated from a variety of terrestrial sources35 including the
Egyptian weed Pluchea dioscoridis,13 the green rabbitbrush
(Chrysothamnus viscidiflorus) in the western United States,35a
the aerial parts of the plant Croton arboreous in Mexico,35b
the stem of the peacock flower (Caesalpinia pulcherrima) in
Thailand,35c the rhizome of the plant Notopterygium incisum
0
halogenation via an SE mechanism to deliver allylic halides
with exocyclic alkenes (10 f 21);25 (3) fluoride-mediated
desilylation to provide the endocyclic alkene (22) from the
same allylsilane precursor (enabling the synthesis of either the
more stable or the less stable alkene regioisomer at will);23b and
(4) the generation of new carbon-carbon bonds via Sakurai
reactions (10 f 23)26 or potential oxidative coupling with
enamines according to MacMillan’s procedure for organo-
catalytic SOMO catalysis (10 f 24),27 which would both
ultimately deliver much more complex structures.28
There are a wide variety of methods for incorporting
allylsilanes into organic substrates, which adds to the overall
flexibility of this approach. They can generally be divided
into methods that bring in the allylsilane unit via a nucleo-
philic reagent (Scheme 4a)29 and methods that construct the
allylsilane from other functional groups (Scheme 4b).30 Of
particular importance to the work described in this report are
the conjugate addition reactions of cuprates derived from
2-(3-trimethysilyl-1-propenyl)magnesium bromide (26) as
developed by Trost,29a the indium-mediated allylation of
carbonyl electrophiles starting from allylic iodide 30 as de-
scribed by Remuson,29c and the method of Bunnelle that treats
esters with excess trimethylsilylmethylmagnesium chloride and
cerium trichloride followed by a Peterson elimination (see 35
to 37).30a
Full details describing the incorporation of the strategy
shown in Scheme 2a into syntheses of teucladiol (3, Figure 1)8
and poitediol (4)9 are included below, along with a previously
undisclosed account of the synthesis of the natural products
isoteucladiol (5)13 and dactylol (6)14 from intermediates orig-
inally used to make 3 and 4, respectively, and attempted
(25) For fluorination, see ref 18e. For chlorination, see: Kusama, H.;
Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura, N.;
Morihira, K.; Kuwajima, I. J. Am. Chem. Soc. 2000, 122, 3811–3820.
(26) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295–1298.
(27) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan,
D. W. C. Science 2007, 316, 582–585.
(28) These C-C bond forming reactions have the potential for great
utility when combined with our allylsilane RCM strategy; however, this
sequence is not the focus of this particular study.
(31) Aggarwal, V. K.; Daly, A. M. Chem. Commun. 2002, 2490–2491.
(32) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1995, 34, 2039–2041.
(33) For example, see: Sabui, S. K.; Venkateswaran, R. V. Tetrahedron
Lett. 2004, 45, 2047–2048.
(34) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.;
Scholl, M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 2546–2558.
(29) (a) Trost, B. M.; Coppola, B. P. J. Am. Chem. Soc. 1982, 104, 6879–
6881. (b) Hoffman, H. M. R.; Eggert, U.; Gibbels, U.; Giesel, K.; Koch, O.;
Lies, R.; Rabe, J. Tetrahedron 1988, 44, 3899–3918. (c) Bardot, V.; Remuson,
R.; Gelas-Mialhe, Y.; Gramain, J.-C. Synlett 1996, 37–38. (d) Molander,
G. A.; Shubert, D. C. Tetrahedron Lett. 1986, 27, 787–790.
(30) (a) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28,
6261–6264. (b) Andrianome, M.; Delmond, B. Tetrahedron Lett. 1985, 26,
6341–6342. (c) Nicolaou, K. C.; Li, A.; Edmonds, D. J.; Tria, G. S.; Ellery,
S. P. J. Am. Chem. Soc. 2009, 131, 16905–16918.
(35) (a) Ahmed, A. A.; Hegazy, M.-E. F.; Hassan, N. M.; Wojcinska, M.;
Karchesy, J.; Pare, P. W.; Mabry, T. J. Phytochemistry 2006, 67, 1547–1553.
(b) Aguilar-Guadarrama, A. B.; Rios, M. Y. J. Nat. Prod. 2004, 67, 914–917.
(c) Pranithanchai, W.; Karalai, C.; Ponglimanont, C.; Subhadhirasakul, S.;
Chantrapromma, K. Phytochemistry 2009, 70, 300–304. (d) Wu, S.-B.; Zhao,
Y.; Fan, H.; Hu, Y.-H.; Hamann, M. T.; Peng, J.-N.; Starks, C. M.; O’Neil-
Johnson, M.; Hu, J.-F. Planta Med. 2008, 74, 1812–1817. (e) Abdel-Kader,
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SCHEME 4. Representative Methods for the Synthesis of 2-Substituted-3-trimethylsilyl-1-propenes
SCHEME 5. Synthesis of Model exo-Methylidenecyclohexane 46
in China,35d and the aerial parts of the flowering plant
Cleome droserifolia in Saudi Arabia.35e Mabry and co-workers
have shown teucladiol to be moderately cytotoxic against
the MCF-7 and MDA-MB-435 breast cancer cell lines with
EC50 = 50 μg/mL.35a No synthesis of teucladiol has been re-
ported prior to (or since) our initial communication in 2009.15
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SCHEME 6. Retrosynthetic Analysis of Teucladiol
SCHEME 7. Anticipated Stereochemical Course of Aldol Coupling between (()-54 and (()-51
The major synthetic challenge posed by teucladiol involves
the controlled installation of five contiguous stereogenic
centers, four of which are present on the seven-mem-
bered ring embedded in teucladiol’s bicyclo[5.3.0]decane
framework.36
metalation of 2-bromopropene to cyclopentenone and trap-
ping of the resulting enolate with pivaldehyde gives 53 as a
single diastereomer in 80% yield (eq 1).40 The stereochemical
result of this reaction is consistent with trans-addition of the
nucleophile and electrophile and anti-selective aldol addition
of the ring-constrained E-enolate proceeding via a closed
transition state. The three contiguous stereocenters found in
53 map directly onto teucladiol (3) with the correct relative
configuration, which indicated that a related three-component
coupling process might be suitable for a synthesis of teucladiol.
It was further anticipated that aldol coupling of the racemic
enolate (()-54 (Scheme 7), derived from conjugate addition of
cyclopentenone (49) and organometallic 50, with aldehyde (()-51,
might proceed with a high level of double diastereodifferen-
tiation41 to provide the desired stereoisomer (()-48 with the
correct relative configuration at the isopropyl-bearing C7. The
pertinent aldol addition is anticipated to proceed through a
closed transition state; this prediction is supported by the
stereochemical outcome of Snider’s three-component coupling
reaction. The transition-state assembly between enolate (R)-54
and aldehyde (S)-51 depicted as 55 at the top of Scheme 7 (or
the enantiomeric pair of (S)-54 and (R)-51, not shown) corre-
sponds to a Felkin-Anh addition, a preference that is known
to be enhanced when E-enolates are employed,42 and would
Teucladiol: Retrosynthetic Analysis and Synthetic Planning.
Our general retrosynthetic plan for teucladiol is shown in
Scheme 6. It was anticipated that teucladiol could be generated
from ketone 47 in two steps via substrate-controlled methyl-
cerium addition followed by allylsilane protodesilylation. Ke-
tone 47, in turn, would be derived from diene 48 through a ring-
closing olefin metathesis reaction.37 This compound (48) was
envisioned to arise from a diastereoselective tandem vicinal
difunctionalization reaction38 between cyclopentenone (49), an
organometallic reagent (50) derived from 2-bromoallyltri-
methylsilane (25, Scheme 4a), and aldehyde 51.39 If successful,
this three-component coupling process38a would set four of the
five stereogenic centers found in teucladiol and assemble all but
one of the necessary carbon atoms.
ꢀ
(38) For pertinent reviews, see: (a) Toure, B. B.; Hall, D. G. Chem. Rev.
2009, 109, 4439–4486. (b) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed.
Engl. 1984, 23, 847–876. (c) Chapdelaine, M. J.; Hulce, M. Org. React. 1990,
38, 225–653.
With respect to the proposed three-component coupling
reaction (49 þ 50 þ 51 f 48), Snider has shown that
conjugate addition of the organocuprate derived from
ꢀ
(39) Ibrahem, I.; Cordova, A. Angew. Chem., Int. Ed. 2006, 45, 1952–
1956.
(40) Snider, B. B.; Yank, K. J. Org. Chem. 1992, 57, 3615–3626.
(41) (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1–30. (b) Kolodiazhnyi, O. I. Tetrahedron 2003, 59,
5953–6018.
(42) For a discussion, see: Cowden, C. J.; Paterson, I. Org. React. 1997,
51, 1–200.
(36) For a recent review on synthetic approaches to this ring system, see:
Foley, D. A.; Maguire, A. R. Tetrahedron 2010, 66, 1131–1175.
(37) Nakashima, K.; Fujisaki, N.; Inoue, K.; Minami, A.; Nagaya, C.;
Sono, M.; Tori, M. Bull. Chem. Soc. Jpn. 2006, 79, 1955–1962.
J. Org. Chem. Vol. 75, No. 20, 2010 6913

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TABLE 1. Optimization of the Three-Component Coupling Sequence to Generate 48
entry
copper source
Cul
Li(2-thienyl)CuCN
CuBr SMe2
solvent
temperature (°C)
equivalents (()-51
yielda
1
Et2O
Et2O
Et2O
THF
Et2O
Et2O
Et2O
Et2O
-78
1.0
1.2
1.2
1.5
1.3
2.0
1.0
2.1
2.0
2.1
15-28%
trace
30%
0%
trace
15%
35%
39%
34%
60%d
2b
3
-78 to -50
-78
3
4
CuBr SMe2
Cul PBu3
Cul PBu3
-78
3
5b
6b
7c
8c
9c
10c
-78
3
3
-78
CuCN
CuCN
CuCN
CuCN
-78
-78
Et2O/hexanes (3:1)
Et2O/THF (19:1)
-78
-78
aIsolated yield after column chromatography. b1 equiv of 25 and 2 equiv of t-BuLi were used in this reaction. c2.2 equiv of 25, 4.2 equiv of t-BuLi, and
1.05 equiv of CuCN were used in this reaction. ddr of reaction as determined from crude 1H NMR: g10:1.
produce the diastereomer required for a synthesis of teucladiol.
In contrast, aldol coupling between (R)-54 and (R)-51 corres-
ponding to 56 (or the enantiomeric pair (S)-54 and (S)-51, not
shown) should be disfavored due to the presence of a destabiliz-
ing interaction between the bulky isopropyl group and the vinyl
hydrogen of the cyclopentene in the pretransition-state assem-
bly. This predicted preference of reactivity of one enantiomer
of enolate with one enantiomer of aldehyde would represent
an interesting and unusual example of double stereodifferentia-
tion/kinetic resolution of two chiral but racemic reaction
partners.
it was isolated in low and variable yields (15-28%). The major
identifiable side products resulted from oxidative dimerization
of the cuprate and 1,2-addition to cyclopentenone. Subsequent
experiments examined the use of other copper sources, and
copper cyanide emerged as the reagent of choice for this
reaction, routinely affording the desired product in 35% yield
(entry 7). Utilizing two equivalents of the readily available
aldehyde (()-51 provided a modest improvement in yield
(entry 8). Optimization of solvent demonstrated that a 19:1
mixture of diethyl ether/THF proved ideal among those
examined, furnishing the desired product in g10:1 diastereo-
1
Trost first demonstrated the utility of 2-metalated allyl-
silane reagents in organic synthesis in the early 1980s. For
example, the Grignard reagent 26 (Scheme 4) derived from
2-bromoallyltrimethylsilane (25) was shown to add in a
conjugate manner to cyclohexenone in high yields in the
presence of catalytic copper(I) iodide.29a Attempts to form
and utilize stoichiometric cuprates derived from reductively
metalated derivatives of 2-bromoallyltrimethylsilane were
reported to be unsuccessful,29a because the desired reactivity
was complicated by competitive oxidative dimerization of
the cuprate. This result caused us some concern regarding the
feasibility of the proposed three-component coupling reac-
tion (49 þ 50 þ 51 f 48) because the majority of high-
yielding tandem vicinal difunctionalization reactions that
are triggered by the addition of an organocuprate to a cyclic
conjugate acceptor utilize stoichiometric cuprates.38,40
Teucladiol: Synthesis. Table 1 outlines our attempts to
develop a one-pot tandem vicinal difunctionalization sequence
to access 48. Initial experiments adhered closely to the proce-
dure used by Snider in his synthesis of 53 (eq 1),40 which
involved reductive lithiation43 of 2-bromoallyltrimethylsilane
in diethyl ether, forming the stoichiometric Gilman reagent,
treating the resultant cuprate with cyclopentenone, and trap-
ping the resulting enolate with aldehyde (()-51 at -78 °C
selectivity as determined by H NMR analysis of the crude
reaction product and in 60% isolated yield after column
chromatography (entry 10). These results suggest that small
quantities of THF help to suppress oxidative dimerization of
the cyanocuprate; on the other hand, when used as the sole
solvent, THF appears detrimental to aldol addition (entry 4).
The high level of diasteroselection observed in this three-
component coupling reaction indicates that there is a strong
kinetic preference for aldol coupling between (R)-54 and (S)-51
(and its enantiomeric pair) relative to that between (R)-54 and
(R)-51 (and its enantiomeric pair), as predicted by the analysis
shown in Scheme 7.
With a reliable route to aldol adduct 48 in hand, subse-
quent efforts focused on converting this material into teu-
cladiol (Scheme 8). Attempted ring-closing olefin metathesis
of 48 failed, likely due to coordination of the intermediate
ruthenium alkylidene with the pendant alcohol.44 While in situ
protection of the hydroxy group with Lewis acids was
considered,45 we opted to mask the secondary alcohol with
a triethylsilyl ether to aid in both the ring-closing metathesis
reaction and a later step. Silyl ether 58 underwent smooth
ring-closing olefin metathesis in the presence of the Grubbs
(44) For other examples of unsuccessful RCM in the presence of a free
alcohol, see: (a) Rhee, H. J.; Beom, H. Y.; Kim, H.-D. Tetrahedron Lett.
2004, 45, 8019–8022. (b) Fujiwara, K.; Koyama, Y.; Doi, E.; Shimawaki, K.;
Ohtaniuchi, Y.; Takemura, A.; Souma, S.-I.; Murai, A. Synlett 2002, 1496–
1499.
1
(entry 1, Table 1). H NMR analysis of the crude reaction
mixture suggested that the reaction had proceeded with a useful
level of diastereoselectivity to provide 48 (see below); however,
(45) For the in situ protection of a carbonyl function that interfered with
€
ring-closing metathesis, see: Furstner, A.; Langemann, K. J. Am. Chem. Soc.
1997, 119, 9130–9136.
(43) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1–46.
6914 J. Org. Chem. Vol. 75, No. 20, 2010

Dowling and Vanderwal
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SCHEME 8. Synthesis of (()-Teucladiol and (()-iso-Teucladiol
second-generation catalyst (see Grubbs II in Scheme 5) to
furnish bicyclic 59 in 89% yield. NOESY and COSY NMR
analysis of 61 (the TMS congener of 59) confirmed the
expected and desired stereochemical outcome of the three-
component coupling reaction.
of the methylcerium addition reaction, and was efficiently
0
removed under conditions required for SE protodesilylation
of the allylsilane.
Enantioselective Synthesis of (-)-Teucladiol. A synthesis
of enantiomerically enriched teucladiol was realized by
incorporating enantiomerically enriched aldehyde (-)-51
into a modified version of the three-component coupling
sequence shown above (Scheme 9). Aldehyde (-)-51 could be
prepared in enantiomerically enriched form through utilization
of the Myers pseudoephedrine amide alkylation technology49
or in fewer steps through organocatalytic SOMO R-allylation
of isovaleraldehyde using a modified version of MacMillan’s
procedure.26,50 Enolsilane (()-68 was produced in racemic
form through conjugate addition of the cyanocuprate derived
from 2-bromoallyltrimethylsilane 25 to cyclopentenone fol-
lowed by trapping of the resulting enolate with TMSCl.
Regeneration of the corresponding lithium enolate from enol-
silane (()-68 was achieved through treatment with n-BuLi;
addition of anhydrous zinc chloride51 presumably led to the
zinc enolate, which was trapped with enantiomerically enriched
aldehyde (-)-51 (precursor alcohol (-)-67 had 95% ee) to give
(-)-48 in 36% yield (theoretical maximum ca. 50%) and
88% ee.52 Conversion of (-)-48 into (-)-teucladiol (3) was
achieved using the same four-step sequence from our synthesis
of (()-teucladiol (Scheme 8) and proved that the absolute
configuration of natural teucladiol is that depicted in Figure 1
and Scheme 8. Incorporating aldehyde (-)-51 into the identical
one-pot, three-component coupling sequence utilized for the
synthesis of (()-48 delivered (-)-48 in 35% yield (theoretical
maximum ca. 50%) and 83% ee. Although the yields for these
two procedures are essentially the same, it appears that the
use of the zinc enolate generated from enolsilane (()-68 in
the stepwise procedure leads to slightly better retention of
enantioselectivity. While an ideal enantioselective synthesis
It was anticipated that addition of a methyl nucleophile to
ketone 59 would proceed with a high level of diastereoselec-
tion to give 60 as a result of steric shielding of the re-face of
the ketone by the adjacent triethylsilyl ether. Slow addition
of 59 as a solution in THF to the organocerium reagent46
derived from methyllithium at -95 °C with gradual warming
to -78 °C afforded an 87:13 mixture of diastereomers at C4,
which were isolated in a combined 92% yield. These two
isomers were separable, and the desired diastereomer was
isolated in 71% yield. Exposure of 60 to p-toluenesulfonic
acid in diethyl ether led to protodesilylation of both the
allylsilane and the silyl ether to afford racemic teucladiol (3)
in 85% yield. Alternatively, exposure of 60 to CsF, KOt-Bu,
and 1,3-diaminopropane in DMSO at 150 °C under micro-
wave irradiation afforded the natural product 4β,6β-
dihydroxy-1R,5β(H)-guai-9-ene (iso-teucladiol, 5)13 in 76%
yield and in moderate purity (contaminated with small
quantities of teucladiol), thus demonstrating the versatility
of cyclic allylsilane 60 in particular and this strategy for
terpene synthesis in general.
The optimized route to racemic teucladiol required a total
of five operations from cyclopentenone and known aldehyde
51 and proceeded in 28% overall yield. Besides featuring a
high level of step47 and redox48 economy, this synthesis
constitutes one of the most concise synthetic routes to a
guaiane sesquiterpene. Notable features include a highly
diastereoselective three-component coupling reaction that
establishes four contiguous stereogenic centers, the use of an
allylsilane RCM/SE0 sequence to construct the exo-methyliden-
ecycloalkane motif, and the efficient use of a TES protecting
group, which served to enable the key ring-closing olefin
metathesis reaction, likely influenced the diastereoselectivity
(49) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
(50) Because of isolation difficulties related to the volatility of the
product, we used THF as solvent instead of the recommended DME;
presumably this protocol change led to the slightly depressed enantioselec-
tivity (88% ee) of this transformation relative to those reported in ref 26.
(51) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D.
J. Am. Chem. Soc. 1973, 95, 3310–3324.
(46) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392–4398.
(47) Wender, P. A.; Croatt, M. P.; Witulski, B. Tetrahedron 2006, 62,
7505–7511.
(48) Burns, N. Z.; Baran, P. S.; Hoffman, R. W. Angew. Chem., Int. Ed.
2009, 48, 2854–2867.
(52) Under these conditions, other diastereomers, presumably from the
mismatched combination, are observed in the crude reaction mixture.
J. Org. Chem. Vol. 75, No. 20, 2010 6915

Dowling and Vanderwal
JOCArticle
SCHEME 9. Synthesis of (-)-Teucladiola
aDMP = Dess-Martin periodinane.
of (-)-48 would incorporate enantioenriched enolate (R)-54,
the asymmetric conjugate addition of sp2-hybridized organo-
metallics to cyclopentenone with productive use of the resulting
enolate is not a well-developed process.53 Our goal was simply
to use inexpensive materials to rapidly determine the absolute
configuration of teucladiol.
Poitediol: Background. Poitediol (4) was isolated by Feni-
cal and Clardy from the red seaweed Laurencia poitei in 1978
in the waters off the coast of the Florida Keys.9 This unusual
cyclooctane-containing natural product is thought to arise
from a halogen solvolysis/rearrangement sequence of a more
typical sesquiterpene skeleton, although no specific bioge-
netic postulate has been put forth.54 As a result, and unlike
most sesquiterpenes that display exo-methylidenecycloal-
kanes, poitediol’s exocyclic alkene is not directly adjacent
to a ring junction. The structure of poitediol was secured by
X-ray crystallographic analysis. Gadwood reported the only
prior synthesis of poitediol in 1984.55 While his synthesis
elegantly exploits an oxy-Cope rearrangement to forge poi-
tediol’s eight-membered ring, the entire route required 26
steps and proceeded in approximately 1% overall yield. Five
syntheses of the related cyclooctene natural product dactylol
(6, Scheme 10) have been reported;55b,56 Furstner’s efficient
€
1996 synthesis of this sesquiterpene56e was one of the first to
showcase the effectiveness of RCM for medium-ring forma-
tion (see below) and served as an inspiration for our study
toward poitediol. It is also noteworthy that Gadwood was
able to transform synthetic poitediol into dactylol under
dissolving metal reducing conditions.55b,56a
Poitediol: Retrosynthetic Analysis and Synthetic Planning.
Eight-membered rings are widely considered to be the most
difficult ring size to construct due to the presence of desta-
bilizing transannular interactions and ring strain.57 Over the
past decade and a half, however, ring-closing metathesis has
emerged as a useful method for directly forming eight-
membered rings.58 In this context, poitediol was viewed as
an attractive target, as it would allow us to test the applica-
bility of our allylsilane RCM/SE0 strategy for the synthesis of
exo-methylidenecyclooctenes, in this case with the simulta-
neous stereoselective introduction of an adjacent hydroxyl
group. Thus, poitediol (4) would be derived from allylsilane
€
ꢁ
ꢀ
(53) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M.
Chem. Rev. 2008, 108, 2796–2823.
(56) (a) Gadwood., R. C. J. Chem. Soc., Chem. Commun. 1985, 123–124.
(b) Paquette, L. A.; Ham, W. H. J. Am. Chem. Soc. 1987, 109, 3025–3036. (c)
Feldman, K. S.; Wu, M.-J.; Rotella, D. P. J. Am. Chem. Soc. 1990, 112, 8490–
8496. (d) Molander, G. A.; Eastwood, P. R. J. Org. Chem. 1995, 60, 4559–
(54) The fascinating conversion of africanol into a molecule with the
precapnellane skeleton by Matsumoto presents a possible biosynthetic link
between “normal” sesquiterpene architectures and that of poitediol. See:
Hayasaka, K.; Ohtusuka, T.; Shirahama, H.; Matsumoto, T. Tetrahedron
Lett. 1985, 26, 873–876.
(55) (a) Gadwood, R. C.; Lett, R. M.; Wissinger, J. E. J. Am. Chem. Soc.
1984, 106, 3869–3870. (b) Gadwood, R. C.; Lett, R. M.; Wissinger, J. E. J.
Am. Chem. Soc. 1986, 108, 6343–6350.
€
4565. (e) Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746–8749.
(57) (a) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881–930. (b) Petasis,
N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757–5821.
(58) Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740–
5750.
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SCHEME 10. Structure of Dactylol and Synthetic Approach to Poitediol
SCHEME 11. Synthesis of Poitediol (4), Dactylol (6), “iso-Dactylol” (75), and Chlorinated Analogue 76
69 (Scheme 10), which molecular models suggest should
undergo diastereoselective allylsilane oxidation in the desired
sense, as the re-face appears to be blocked by the adjacent
OTMS moiety as a result of the conformational bias of the
cyclooctene ring. Allylsilane 69 would be produced through
RCM of diene 70, which would be derived from ketone 71
result of this reaction is consistent with the known tendency of
2,3-disubstituted cyclopentenone-derived enols to give the thermo-
dynamically preferred trans-product following kinetic protona-
tion.59 Indium-mediated reductive allylation of ketone 71 with
allyl iodide 30 followed by in situ silylation gave 70 in 55%
yield as a 4:1 mixture of diastereomers in favor of the isomer
shown. This method of allylsilane introduction is distinct from
that employed in our teucladiol synthesis and represents the
third different method for introducing this key functionality
showcased in this report. Exposure of the diastereomeric
mixture of 70 to the Grubbs second-generation catalyst
(see Grubbs II in Scheme 5) in refluxing dichloromethane gave
crude cyclooctene 69, which was epoxidized with buffered
m-CPBA. Fluoride-promoted fragmentation of this crude silyl
epoxide with TBAF furnished pure poitediol (4) in 46% yield
over three steps from 70. 0While this sequence does not techni-
cally make use of the SE reactivity of the allylsilane, the net
transformation accomplished just such an oxidation. The
structure of synthetic poitediol was confirmed by X-ray crystallo-
graphic analysis, since a complete set of NMR data was not
available.9 The versatility of cyclic allylsilane 69 was demon-
strated by its transformation into the natural product dactylol
through an allylation reaction.29c Ketone 71 is known; it was a
56e
€
key intermediate in Furstner’s synthesis of dactylol (6).
Poitediol: Synthesis. Our synthesis of poitediol makes use
€
of a slight modification of Furstner’s procedure for produc-
ing ketone 71, an important intermediate in his dactylol
synthesis. Tandem vicinal difunctionalization of cyclopente-
none with dimethylcuprate and the commercially available
aldehyde 72 gave adduct 73 in 93% yield (Scheme 11). In our
hands, the use of copper bromide dimethylsulfide complex
3
in this three-component coupling reaction afforded a much
€
better yield of 73 than we obtained using Furstner’s procedure,
which utilized copper iodide tributylphosphine complex. The
3
aldol adduct 73 was dehydrated with methanesulfonyl chloride
in the presence of DMAP and triethylamine to furnish enone 74.
Chemo- and stereoselective reduction of the enone was
achieved with tributyltin hydride in the presence of catalytic
Pd(PPh3)4 and zinc chloride to afford ketone 71 as a single
diastereomer in 79% yield over two steps. The stereochemical
(59) Zimmerman, H. E.; Wang, P. J. Org. Chem. 2003, 68, 9226–9232.
J. Org. Chem. Vol. 75, No. 20, 2010 6917

Dowling and Vanderwal
JOCArticle
SCHEME 12. Retrosynthetic Analysis of Caryophyllene
(6) through fluoride-mediated protodesilylation, the formation
0
there was some concern regarding the viability of this key
ring-closing metathesis reaction because it is known that the
formation of trisubstituted olefins in nine- to 12-membered
rings using ring-closing olefin metathesis can be difficult,
especially when one of the alkenes in the substrate is R-
branched.63-66 Despite these concerns, we reasoned that the
substrate for the key ring-closing metathesis reaction, triene
78, should be relatively easy to construct; the allylsilane
function in this triene would be derived from the correspond-
ing ester 79 using Bunnelle’s methodology.30a The ester
precursor to the allylsilane would, in turn, enable its forma-
tion via conjugate addition reaction of the organocuprate
derived from Grignard reagent 81 to known cyclobutene 80.
Diene 82 is a known, easily prepared compound that should
serve as a reasonable precursor to an organometallic reagent
such as 81.
Caryophyllene: Attempted Synthesis. The known cyclobu-
tene ester 80 was prepared using a modification of Fleming’s
procedure (Scheme 13).67 Thermal [2þ2] cycloaddition be-
tween methyl acrylate and enamine 83 derived from pyrrol-
idine and isobutyraldehyde gave cyclobutane 84, which was
quaternized with methyl iodide. The resulting ammonium
salt was treated with methanolic sodium methoxide in pen-
tane to furnish cyclobutene ester 80 in 84% yield over four
steps. Although this sequence of reactions is identical to
Fleming’s original route to this useful cyclobutene,67 the
overall yield is much improved, and the total time for the
sequence is dramatically decreased.
of the “iso-dactylol” (75, not a known natural product) by SE
protodesilylation, and the synthesis of a chlorinated congener
of poitediol (76).
Caryophyllene: Background, Retrosynthetic Analysis, and
Synthetic Planning. Caryophyllene (2) is a widely distributed
natural product that is most abundantly produced by the
clove tree Eugenia caryophyllata.7 This sesquiterpene has
attracted a significant amount of interest from synthetic
chemists as a result of its intriguing trans-fused bicyclo-
[7.2.0]decane carbon framework, which incorporates both
an exo-methylidene function and an endocyclic trisubsti-
tuted E-alkene.60 Our interest in this natural product is
derived from the presence of the exo-methylidenecyclono-
nene, which suggested that a concise approach to caryophyl-
lene might be possible through utilization of our allylsilane
0
RCM/SE desilylation strategy. Thus, the key step in our
proposed sequence toward caryophyllene would be ring-
closing olefin metathesis of 78 to generate cyclononene 77
(Scheme 12). Examination of molecular models suggested
that this transformation is feasible, and several examples of
successful cross-metathesis61 and ring-closing62 olefin me-
tathesis reactions of 1,4-dienes have been reported; however,
(60) (a) Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem. Soc. 1964, 86,
485–492. (b) Ohtsuka, Y.; Niitsuma, S.; Tadokoro, H.; Hayashi, T.; Oishi, T.
J. Org. Chem. 1984, 49, 2326–2332. (c) McMurry, J. E.; Miller, D. D.
Tetrahedron Lett. 1983, 24, 1885–1888. (d) Larionov, O. V.; Corey, E. J.
J. Am. Chem. Soc. 2008, 130, 2954–2955.
(61) Yoshimura, T.; Yakushiji, F.; Kondo, S.; Wu, X.; Shindo, M.;
Shishido, K. Org. Lett. 2006, 8, 475–478.
(62) (a) Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.; Chou,
T.-C.; Dong, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 10913–10922.
(b) Rivkin, A.; Cho, Y. S.; Gabarda, A. E.; Yoshimura, F.; Danishefsky, S. J.
J. Nat. Prod. 2004, 67, 139–143.
(63) For an example involving a failed nine-membered ring closure, see:
Paquette, L. A.; Dong, S.; Parker, G. D. J. Org. Chem. 2007, 72, 7135–7147.
(64) (a) Helmboldt, H.; Hiersemann, M. J. Org. Chem. 2009, 74, 1698–
€
1708. (b) Helmboldt, H.; Kohler, D.; Hiersemann, M. Org. Lett. 2006, 8,
1573–1576.
The known TBS-protected alcohol 82 was prepared using
a nickel-catalyzed three-component coupling process devel-
oped by Ikeda and co-workers.68 Treatment of 82 with
bromine/triphenylphosphine afforded alkyl bromide 86
directly69 in nearly quantitative yield, which was trans-
formed into the corresponding Grignard reagent (81) under
standard conditions. In the presence of trimethylsilyl
chloride, DMPU, and a catalytic amount of copper bro-
(65) One potential problem is formal excision of a methylene unit via
alkene isomerization and subsequent ring-closure (see: Joe, D.; Overman,
L. E. Tetrahedron Lett. 1997, 38, 8635–8638. ), although the eight-membered
ring corresponding to caryophyllene would likely be prohibitively strained to
close.
(66) For the successful generation of trisubstituted olefin-containing
nine-membered rings, see: (a) Crimmins, M. T.; Ellis, J. M. J. Am. Chem.
Soc. 2005, 127, 17200–17201. (b) Crimmins, M. T.; Ellis, J. M. J. Org. Chem.
2008, 73, 1649–1660. (c) Gurjar, M. K.; Nayak, S.; Ramana, C. V. Tetra-
mide dimethylsulfide complex, Grignard reagent 81 under-
3
went smooth conjugate addition to cyclobutene ester 80 to
give 79 in 67% yield as a 5:1 mixture of diastereomers in
which the major isomer was tentatively assigned the trans-
configuration.70 Conversion of the ester function in 79 into
ꢀ
rez-Fernandez, J.; Collado, I. G.;
Hernandez-Galan, R. Synlett 2008, 339–342. (e) Becker, J.; Bergander, K.;
€
Frohlich, R.; Hoppe, D. Angew. Chem., Int. Ed. 2008, 47, 1654–1657. (f)
Hamel, C.; Prusov, E. V.; Gertsch, J.; Schweizer, W. B.; Altmann, K.-H.
hedron Lett. 2005, 46, 1881–1884. (d) Ramı
´
(67) Fleming, I.; Rowley, M. Tetrahedron 1986, 42, 3181–3198.
(68) Ikeda, S.-I.; Miyashita, H.; Sato, Y. Organometallics 1998, 17, 4316–
4318.
ꢀ
ꢀ
´
(69) Aizpurua, J. M.; Cossıo, F. P.; Palomo, C. J. Org. Chem. 1986, 51,
Angew. Chem., Int. Ed. 2008, 47, 10081–10085.
4941–4943.
6918 J. Org. Chem. Vol. 75, No. 20, 2010

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JOCArticle
SCHEME 13. Attempted Synthesis of the Caryophyllene Bicyclo[9.2.0]undecane Ring System Leads to Deallylation under Alkene
Metathesis Conditions
an allylsilane was accomplished via Peterson olefination to
give allylsilane 78 in 53% unoptimized yield as an apparent
9:1 mixture of diastereomers. With the key intermediate in
hand, efforts were focused on effecting the challenging ring-
closing olefin metathesis reaction to generate the cyclono-
nene ring (78 f 77). Unfortunately, and despite extensive
evaluation of various metathesis initiators (Grubbs second-
generation catalyst, Hoveyda-Grubbs second-generation
catalyst,71 Schrock catalyst,72 and several others) under
various sets of conditions (dichloromethane, toluene, or
hexanes at reflux, all at ca. 1 mM), the desired cyclononene
77 was never detected. Instead, the major identifiable prod-
uct of the reactions was 87, the result of a deallylation
reaction. The highest yield of this compound was achieved
when 78 was exposed to the Grubbs second-generation
catalyst (see Grubbs II in Scheme 5) in hexanes at reflux
(75%). Attempts to circumvent this destructive process
included masking the trisubstituted alkene as its correspond-
ing epoxide (which would have ultimately provided cary-
ophyllene oxide, not shown). While the deallylation process
was certainly prevented, this substrate decomposed appar-
ently without ring closure upon exposure to Grubbs II at
100 °C in toluene.
ring-closing olefin metathesis with the remaining trisubsti-
tuted alkene within 91 would generate a molecule of 1,4-
cyclohexadiene (92)73 and eventually a second molecule of 87
(via metal alkylidene 93). In order to provide further circum-
stantial evidence for this mechanistic proposal with another,
simpler substrate, the trisubstitued skipped diene 86 was
exposed to the Grubbs second-generation catalyst in CDCl3
in a closed reaction vessel and heated to 40 °C. After 2 h, 1H
NMR analysis of the reaction mixture showed a 0.4:1
mixture of 92 and 95. Another mechanistic scenario that
cannot be ruled out at this time involves direct catalyst attack
on the trisubstituted alkene of the starting material: in
effect, a cross-metathesis deallylation procedure that could
certainly eventuate molecules of 1,4-cyclohexadiene. The
simplest and most direct mechanistic possibility, involving
ring-closing metathesis of 88 to generate cyclopropene, is
unlikely from an energetic standpoint. All mechanistic sce-
narios that we have entertained to this point are troubling in
one way or another. For example, the dimerization-based
mechanism shown in Scheme 14 requires selective intermo-
lecular metathesis of a trisubstituted alkene in the presence of
a disubstituted one. Clearly, more experiments are required
to gain a better mechanistic understanding of this interesting
deallylation reaction that apparently becomes operative with
1,4-dienes when more kinetically favored metathetical pro-
cesses are not available.
To the best of our knowledge, the metal alkylidene-
promoted deallylation of 1,4-dienes is a novel process. A
potential mechanism for the transformation of 78 into 87 is
shown in Scheme 14. According to this proposal, dimeriza-
tion of starting material is followed by metathetical cleavage
of one of the trisubstituted olefins of dimer 89 to afford one
equivalent of 87 and metal carbene 91. In the case where
the dimer was produced with the new alkene Z-configured,
Conclusions
0
Allylsilane ring-closing metathesis/SE electrophilic desi-
lylation is a powerful strategy for synthesizing exo-methyl-
idenecycloalkanes that are embedded in numerous terpene
natural products. The power of this strategy has enabled
concise syntheses of teucladiol (racemic: five steps, 28%
overall yield; enantioenriched: five steps, 16% overall yield)
and poitediol (seven steps, 18% overall yield). Syntheses of
the natural products iso-teucladiol and dactylol, as well as
unnatural analogues, were realized using advanced inter-
mediates en route to teucladiol and poitediol, respectively.
Attempted incorporation of this strategic combination of
(70) This stereochemical assignment is based on two observations from
subsequent experiments (see Scheme 13): (1) Conversion of the ester function
in 79 (with dr = ca. 5:1) into the corresponding allylsilane (78), in a reaction
that is known to be sensitive to steric hindrance, affords a 9:1 mixture of
diastereomers, suggesting that the major diastereomer is less hindered than
the minor diastereomer. (2) Diene 87 does not appear to undergo ring-closing
metathesis to form the corresponding bicyclo[4.2.0]octane, which should be
possible if the stereochemistry is cis. Unfortunately, all attempts to confirm
this stereochemical assignment with NOE experiments provided ambiguous
results.
(71) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179.
(72) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875–3886.
(73) For generation of 1,4-cyclohexadiene in a related manner, see:
Guiard, S.; Santelli, M.; Parrain, J.-L. Synlett 2001, 553–556.
J. Org. Chem. Vol. 75, No. 20, 2010 6919

Dowling and Vanderwal
JOCArticle
SCHEME 14. Possible Mechanism for the Metal Alkylidene-Promoted Deallylation of Skipped Dienes and Circumstantial Evidence for
the Proposed Mechanism
reactions into a synthesis of caryophyllene failed to deliver
the natural product because a novel deallylation reaction of
the starting 1,4-diene preempted the challenging ring closure.
Because of the ubiquity of the exo-methylidenecycloalkane
motif in terpene natural pro0ducts, many more applications
of the allylsilane RCM/SE strategy in natural product
synthesis are likely.
pressure. Compounds not included in this Experimental Section
have been previously documented in ref 15.
Isoteucladiol (5). Argon was bubbled through a mixture of 60
(7.00 mg, 0.017 mmol), CsF (25.0 mg, 0.165 mmol), KOt-Bu
(18.0 mg, 0.165 mmol), and 1,3-diaminopropane (0.013 mL,
0.165 mmol) in DMSO (0.6 mL) for 20 min. The reaction
mixture was sealed and heated to 150 °C in a microwave for
45 min. The cooled black reaction mixture was poured into
saturated aqueous NH4Cl (10 mL) and extracted with Et2O (2 ꢀ
15 mL). The combined organic layers were washed with brine
(10 mL), dried over MgSO4, filtered, and evaporated in vacuo to
afford an apparent 4:1 mixture of isoteucladiol/teucladiol by 1H
NMR as a clear oil. The crude material was purified by column
chromatography (HP SiO2, 98:2 to 92:8 hexanes/EtOAc) to
afford 5 (3 mg, ca. 85% pure, 76% yield) as a clear oil. Rf =
0.28 (65:35 hexanes/EtOAc); spectral data were obtained on a
cut fraction and were consistent with those reported previously
for the natural product.13 1H NMR (500 MHz, CDCl3) δ 5.50
(d, J = 9.3 Hz, 1H), 4.14 (m, 1H), 2.44 (s, 1H), 2.25-2.35 (m,
2H), 2.26 (d, J = 3.0 Hz, 1H), 2.09 (dd, J = 12.0, 9.5 Hz, 1H),
1.88-1.60 (m, 6H), 1.66 (s, 3H), 1.32 (s, 3H), 1.25-1.30 (m, 1H),
1.03 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 139.5, 126.4, 81.4, 72.6, 57.7, 50.7, 42.5,
40.1, 28.7, 26.8, 24.5, 24.4, 23.4, 21.7, 21.6; IR (thin film) ν 2958,
1455 cm-1; HRMS (ESI) m/z calc for C15H26O2Na (M þ Na)þ
261.1830, found 261.1837.
Experimental Section
General Experimental Details. All reactions were performed
under a nitrogen or argon atmosphere using oven-dried glass-
ware. All solvents were dried by passing through activated
alumina columns. 1H and 13C NMR spectra were obtained on
500 or 600 MHz spectrometers at 298 K, unless otherwise
indicated. Chemical shifts are reported in parts per million
(ppm) using the internal solvent residual of CDCl3 at 7.26 for
1H NMR and 77.23 for 13C NMR as the internal reference.
Coupling constants are reported in hertz (Hz), and the peak
multiplicity is listed as follows: s, singlet; d, doublet; t, triplet; q,
quartet; p, pentet; m, multiplet. Column chromatography was
performed using 230-400 mesh silica gel (SiO2) or 230-400
mesh high-preformance silica gel with the indicated solvent
system. Reactions were monitored by thin-layer chromatogra-
phy (TLC) carried out on 0.25 mm coated commercial silica gel
plates (F254 precoated glass plates) using iodine as visualizing
agent and vanillin or KMnO4 and heat as a developing
agent. Melting points are uncorrected. p-Toluenesulfonic acid
monohydrate was dried by azeotropic removal of water with
toluene and recrystallized from hexanes/ethyl acetate prior to
use. DMPU was distilled from CaH under reduced pressure.
Chlorotrimethylsilane was distilled from CaH at atmospheric
Dactylol (6). A solution of crude allylsilane 69 (27.0 mg, 0.074
mmol) [from the ring-closing metathesis reaction of 70] and CsF
(11.3 mg, 0.074 mmol) in a mixture of H2O (0.05 mL) and DMF
(0.75 mL) was heated to 120 °C for 4 h. The cooled reaction
mixture was treated with more CsF (40.0 mg, 0.263 mmol) and
again heated to 120 °C. After an additional 3.5 h, the cooled
6920 J. Org. Chem. Vol. 75, No. 20, 2010

Dowling and Vanderwal
JOCArticle
reaction mixture was poured into NH4Cl (15 mL) and extracted
with Et2O (2 ꢀ 15 mL). The combined organic layers were dried
over MgSO4, filtered, and evaporated in vacuo. The crude
material was purified by column chromatography (SiO2, 100:0
to 98:2 hexanes/EtOAc) to afford 6 (8 mg, 62% from 70) as a
white solid with mp = 45-47 °C [lit.14 50.3-51.5 °C]. Spectral
data were consistent with those reported previously.56e Rf =
0.38 (9:1 hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ
5.51-5.55 (m, 1H), 2.40 (d, J = 13.5 Hz, 1H), 2.19 (d, J =
13.5 Hz, 1H), 1.98 (dd, J = 12.9, 10.5 Hz, 1H), 1.88-1.95 (m,
1H), 1.84 (s, 3H), 1.71-1.76 (m, 3H), 1.59 (dd, J = 6.7, 13.2 Hz,
1H), 1.39 (dd, J = 7.84, 14.6 Hz, 1H), 1.13-1.20 (m, 1H), 1.10
(dd, J = 7.8, 11.3 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H), 0.92 (s, 3H),
0.91 (s, 3H), 0.83 (d, J = 14.6 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 135.5, 125.1, 83.4, 53.0, 42.9, 40.1, 39.32, 39.26, 36.6,
35.3, 29.4, 28.9, 27.9, 19.3; IR (thin film) ν 2951, 2866, 1469,
1015, 859 cm-1; HRMS (NH3-CI GCMS) m/z calc for
C15H30NO (M þ NH4)þ 240.2327, found 240.2335.
5.10 (s, 1H), 4.74 (dd, J = 4.0, 12.6 Hz, 1H), 2.47 (d, J = 13.7
Hz, 1H), 2.38 (d, J = 13.7 Hz, 1H), 2.06 (t, J = 13.6 Hz, 1H),
1.95-2.02 (m, 1H), 1.94 (s, 1H), 1.70-1.85 (m, 5H), 1.35 (dd,
J = 6.9, 15.1 Hz, 1H), 1.17-1.25 (m, 1H), 1.04 (dd, J = 7.3, 11.5
Hz, 1H), 0.97 (s, 3H), 0.95 (d, J = 6.6 Hz, 3H), 0.88 (s, 3H); 13
C
NMR (125 MHz, CDCl3) δ 145.1, 118.8, 79.3, 65.6, 51.9, 45.9,
39.2, 39.0, 38.7, 35.6, 33.5, 31.4, 29.6, 28.3, 18.9; IR (thin film) ν
2952, 2866, 1471, 1016, 916; HRMS (NH3-CI GCMS) m/z calc
for C15H29ClNO (M þ NH4)þ 274.1938, found 274.1948.
Cyclobutene Ester 80. The preparation of 80 is based on a
modified version of a procedure described by Fleming.67
A
mixture of isobutyraldehyde (6.30 mL, 69.3 mmol) and pyrrol-
idine (5.20 mL, 62.4 mmol) in benzene (150 mL) was heated to
reflux in a flask outfitted with a Dean-Stark trap and a reflux
condenser. After 6 h, the reaction mixture was cooled to rt and
evaporated under reduced pressure. The residue was diluted
with acetonitrile (100 mL), and methyl acrylate (6.20 mL,
68.6 mmol) was added; the resulting mixture was heated at
reflux for 3 h. The cooled reaction mixture was concentrated
under reduced pressure to afford an amber oil (10.16 g), which
was diluted with CH3CN (24 mL). The resulting solution was
treated with iodomethane (7.48 mL, 120 mmol) and allowed to
stir at rt. After 14 h at rt, the reaction mixture was concentrated
to afford a brown solid. This solid was dissolved in MeOH
(100 mL) and added to a two-phase mixture of sodium methoxide
(11.40 g, 211.7 mmol) dissolved in methanol (300 mL) and
pentane (400 mL). The reaction mixture was stirred vigorously
for 1 h, at which point the two phases were separated. The
methanol phase was extracted with pentane (2 ꢀ 150 mL), then
dilutedwithwater(150mL) andextractedwithpentane/Et2O (2:1,
3 ꢀ 150 mL). The combined organiclayers werewashed with 0.5N
HCl (50 mL), water (200 mL), and brine (2 ꢀ 200 mL) and dried
over MgSO4. Filtration through SiO2, followed by evaporation
in vacuo, afforded 80 as an amber oil (7.33 g, 84% from pyrrolidine).
The spectral properties of 80 were consistent with those reported
previously.1 Rf = 0.48 (92:8 hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3) δ 6.83 (s, 1H), 3.72 (s, 3H), 2.42 (s, 2H), 1.22 (s, 6H).
Diene 82. We adopted the procedure reported by Ikeda and
co-workers, who previously described the preparation of diene
82.68 1H NMR data reported for this compound in Ikeda’s
publication appear to correspond to a lower homologue of 82
(their compound 5c); therefore, we fully characterized this diene.
To a cooled (0 °C) solution of Ni(acac)2 (493 mg, 1.91 mmol) in
THF (191 mL) was added trimethylaluminum (27.6 mL, 49.6
mmol, 15% in hexane) over the course of 10 min. The resulting
black reaction mixture was stirred at 0 °C for 5 min, then treated
with alkyne 85 (7.40 g, 40.2 mmol) followed by allyl chloride
(3.12 mL, 38.3 mmol). The reaction mixture was stirred at 0 °C
for an additional 30 min, then allowed to warm to rt and stirred
for an additional 1.5 h. The reaction mixture was poured into
0.5 N HCl (350 mL) and extracted with pentane (3 ꢀ 250 mL). The
combined organic layers were washed with saturated aqueous
NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, and
filtered through a plug of SiO2, eluting with pentane. Concentra-
tion in vacuo afforded 82 as a 92:8 mixture of regioisomers (9.81 g,
>99%). Rf = 0.45 (9:1 hexanes/CH2Cl2). Spectral data for the
major isomer, 82: 1H NMR (600 MHz, CDCl3) δ 5.80 (m, 1H),
5.20 (t, J = 7.2 Hz, 1H), 5.02 (dt, J = 17.2, 1.6 Hz, 1H), 4.95 (d,
J= 20.1 Hz, 1H), 3.68 (t, J= 7.0 Hz, 2H), 2.75 (t, J= 7.0 Hz, 2H),
Isodactylol (75). [Note: As described below, this reaction was
worked up several times in order to monitor the progress of the
reaction by 1H NMR, because TLC analysis was not possible.] A
solution of 69 (30.0 mg, 0.082 mmol) in Et2O (1.6 mL) was
treated with p-TsOH (28.0 mg, 0.162 mmol), and the solution
was stirred at rt. After 1.66 h, the reaction mixture was poured
into saturated aqueous NaHCO3 (10 mL) and extracted with
Et2O (2 ꢀ 15 mL). The combined organic layers were dried over
MgSO4, filtered, and evaporated in vacuo to afford a clear oil,
which was diluted with Et2O (1.6 mL) and treated with p-TsOH
(28.0 mg, 0.162 mmol). After 2.25 h, the reaction mixture was
poured into saturated aqueous NaHCO3 (10 mL) and extracted
with Et2O (2 ꢀ 15 mL). The combined organic layers were dried
over MgSO4, filtered, and evaporated in vacuo to afford a clear
oil, which was diluted with Et2O (1.2 mL) and treated with
p-TsOH (28.0 mg, 0.162 mmol). After 4 h, the reaction mixture
was poured into saturated aqueous NaHCO3 (10 mL) and
extracted with Et2O (2 ꢀ 15 mL). The combined organic layers
were dried over MgSO4, filtered, and evaporated in vacuo to
afford a clear oil. The crude material was purified by column
chromatography (SiO2, 100:0 to 98:2 hexanes/EtOAc) to afford
75 (13 mg, 71%) as a white solid with mp = 37-39 °C. Rf = 0.45
1
(9:1 hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 4.99 (s,
1H), 4.79 (s, 1H), 2.40-2.47 (m, 3H), 2.20-2.56 (m, 1H), 2.17 (d,
J=12.9 Hz, 1H), 1.97 (ddt, J=7.4, 9.1, 13.0 Hz, 1H), 1.80-
1.85 (m, 1H), 1.65-1.78 (m, 3H), 1.34 (dd, J=14.9, 6.9 Hz, 1H),
1.10-1.20 (m, 2H), 1.02 (dd, J = 6.9, 11.3 Hz, 1H), 0.95 (d, J=
6.7 Hz, 3H), 0.92 (s, 3H), 0.87 (d, J = 14.9 Hz, 1H), 0.83 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 147.2, 113.4, 79.0, 51.9, 43.4,
39.01, 38.99, 36.4, 35.4, 34.2, 33.3, 31.1, 29.8, 28.2, 19.0; IR
(thin film) ν 2951, 2865, 1458, 1251, 1042, 894; HRMS (NH3-CI
GCMS) m/z calc for C15H30NO (MþNH4)þ 240.2327, found
240.2324.
Allyl Chloride (76). A solution of crude allylsilane 69 (23.0 mg,
0.063 mmol) [from the ring-closing metathesis reaction of 70] in
MeOH (2.5 mL) was treated with NCS (67.0 mg, 0.508 mmol)
and stirred at rt. After 1 h, the reaction mixture was poured into
a solution of saturated aqueous sodium sulfite (10 mL) and
extracted with Et2O (2 ꢀ 15 mL). The combined organic layers
were washed with brine (10 mL), dried over MgSO4, filtered, and
evaporated in vacuo to afford a clear oil. The crude product was
immediately treated with water (0.05 mL) and a solution of
TBAF (1 mL, 1 M in THF) and stirred at rt. After 20 h, the
reaction mixture was poured in saturated aqueous NH4Cl
(10 mL) and extracted with Et2O (2 ꢀ 25 mL). The combined
organic layers were dried over MgSO4, filtered, and evaporated
in vacuo. The crude material was purified by column chromato-
graphy (SiO2, 100:0 to 97:3 hexanes/EtOAc) to afford 76
(4.0 mg, 25% from 70) as an oily residue. Rf = 0.43 (4:1
2.22 (t, J = 7.0 Hz, 2H), 1.62 (s, 3H), 0.90 (s, 9H), 0.03 (s, 6H); 13
C
NMR (125 MHz, CDCl3) δ 137.5, 133.8, 123.5, 114.4, 62.6, 43.2,
32.5, 26.1, 16.5, -5.1; IR (thin film) ν 2929, 2857, 1472, 1255, 1099,
836 cm-1; HRMS (NH3-CI GCMS) m/z calc for C14H29OSi
(M þ H)þ 241.1988, found 241.1984.
Bromide 86. To a cooled (0 °C) solution of PPh3 (6.68 g,
25.5 mmol) in CH2Cl2 (100 mL) was added bromine (1.29 mL,
25.0 mmol). The ice water bath was removed, and the reaction
was allowed to slowly warm to rt over 20 min, which resulted in
1
hexanes/EtOAc); H NMR (500 MHz, CDCl3) δ 5.31 (s, 1H),
J. Org. Chem. Vol. 75, No. 20, 2010 6921

Dowling and Vanderwal
JOCArticle
the formation of a white precipitate. The reaction mixture was
then treated with neat 82 (1.2 g, 5.0 mmol, 92:8 mixture of
regioisomers) and allowed to stir at rt for 1 h. The reaction
mixture was filtered through SiO2 eluting with hexanes (300 mL),
and the filtrate was evaporated in vacuo. The resulting residue
was subjected to column chromatography eluting with pentane
to afford 86 as a clear oil (923 mg, 97%). Rf = 0.41 (hexanes);
1H NMR (500 MHz, CDCl3) δ 5.80 (ddt, J = 17.1, 10.8, 6.1 Hz,
1H), 5.28 (t, J = 7.3 Hz, 1H), 5.04 (dd, J = 17.1, 1.7 Hz, 1H),
4.98 (dd, J = 10.8, 1.7 Hz, 1H), 3.44 (t, J = 7.5 Hz, 2H), 2.77 (t,
J = 7.0 Hz, 2H), 2.56 (t, J = 7.5 Hz, 2H), 1.63 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 136.8, 133.4, 124.9, 114.7, 43.0, 32.3,
The reaction mixture was stirred at -78 °C for 2 h and rt for 48 h.
The reaction mixture was then poured into saturated aqueous
NH4Cl (100 mL) and extracted with CH2Cl2 (3 ꢀ 100 mL). The
combined organic layers were washed with water (50 mL), dried
over MgSO4, filtered, and concentrated in vacuo to afford an oil,
which was dissolved in CH2Cl2 (20 mL) and treated with SiO2 (2g).
The slurry was stirred at rt for 4 h, the solvents were removed
in vacuo, and the crude material was purified by column
chromatography (SiO2, 100:0 to 95:5 hexanes/EtOAc) to afford
allylsilane 78 (237 mg, 53%, ca. 9:1 mixture of diastereomers) as
a clear oil. Rf = 0.41 (hexanes); 1H NMR (500 MHz, CDCl3) δ
5.80 (ddt, J = 17.1, 10.5, 6.2 Hz, 1H), 5.15 (t, J = 7.0 Hz, 1H),
5.02 (dd, J = 17.1, 1.4 Hz, 1H), 4.95 (dd, J = 10.5, 1.4 Hz, 1H),
4.60 (s, 1H), 4.52 (s, 1H), 2.75 (t, J = 6.6 Hz, 2H), 2.25 (q, J =
9.1 Hz, 1H), 1.1.80-2.00 (m, 4H), 1.77 (t, J = 8.5 Hz, 1H), 1.61
(s, 3H), 1.43-1.50 (m, 3H), 1.40 (t, J = 10.0 Hz, 1H), 1.06 (s,
3H), 1.04 (s, 3H), 0.00 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
151.2, 137.7, 137.1, 121.2, 114.3, 104.9, 48.9, 43.0, 40.2, 38.4,
33.5, 32.5, 31.6, 29.7, 25.4, 22.6, 16.2, -0.9; IR (thin film) ν 2952,
1634, 1248, 852 cm-1; HRMS (NH3-CI GCMS) m/z calc for
C20H37Si (M þ H)þ 305.2664, found 305.2666.
31.7, 15.7; IR (thin film) ν 2975, 1638, 1434, 1266, 912 cm-1
;
HRMS (EI GCMS) m/z calc for C8H13Br (M)þ 188.0201, found
188.0196.
Grignard Reagent 81. To solid Mg0 ribbons (83.0 mg, 3.43
mmol) in THF (5.2 mL) was added 86 (500 mg, 2.64 mmol). The
reaction mixture was stirred at rt, and the magnesium was
clearly being consumed after ca. 20 min. After stirring at rt for
2 h, the solution of putative Grignard reagent 81 was used
directly in the next step.
Cyclobutane 79. A suspension of CuBr SMe2 (44.0 mg, 0.216
Diene 87. A solution of 78 (20.0 mg, 0.066 mmol) in deoxy-
genated hexanes (44 mL) was treated with the Grubbs second-
generation catalyst (11.1 mg, 0.013 mmol). The reaction mixture
was stirred at rt for 15 min, then heated to 60 °C for 1 h. The
cooled reaction mixture was filtered through a plug of silica gel,
eluting with hexanes. Concentration of the filtrate afforded 87
(13 mg, 75%) as a clear oil. The 1H NMR spectrum of 87
provided in the Supporting Information was taken after chro-
matography on silica gel (pentane). Rf = 0.46 (hexanes); 1H NMR
(500 MHz, CDCl3) δ 4.69 (s, 1H), 4.66 (s, 1H), 4.60 (s, 1H), 4.51
(s, 1H), 2.25 (q, J = 8.9 Hz, 1H), 1.94 (q, J = 8.4 Hz, 1H), 1.87
(m, 1H), 1.78 (t, J = 10.0 Hz, 1H), 1.71 (s, 3H), 1.55 (m, 3H),
1.46 (d, J = 9.4 Hz, 2H), 1.40 (t, J = 10.1 Hz, 1H), 1.07 (s,
3H), 1.04 (s, 3H), 0.10 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 150.9, 146.4, 109.4, 104.8, 48.6, 42.8, 39.9, 36.3, 33.3, 31.3,
29.3, 25.2, 22.5, 22.4, -1.1; IR (thin film) ν 2952, 1247, 851
cm-1; HRMS (NH3-CI GCMS) m/z calc for C17H33Si (M þ H)þ
265.2352, found 265.2349.
3
mmol) in THF (2 mL) was cooled to -78 °C and treated
sequentially with DMPU (0.52 mL, 4.32 mmol), TMSCl
(0.658 mL, 5.18 mmol), and 80 (302 mg, 2.16 mmol). The
reaction mixture was stirred at -78 °C for 10 min, then treated
with the Grignard reagent 81 prepared above dropwise over 5
min, which caused the reaction mixture to become viscous. The
reaction mixture was allowed to stir at -78 °C for 1 h and then
slowly warm to -20 °C over the course of 1 h. The reaction
mixture was then poured into 1 N HCl (40 mL). The product was
extracted with pentane (3 ꢀ 45 mL), and the combined organic
layers were washed with brine (30 mL), dried over Na2SO4,
filtered, and concentrated in vacuo to afford crude product,
which was subjected to column chromatography on SiO2
(hexanes/Et2O, 100:0 to 97:3) to provide 79 (364 mg, 67%, ca.
5:1 mixture of diastereomers) as a clear oil. Rf = 0.55 (9:1,
hexanes/EtOAc); 1H NMR (500 MHz, CDCl3) δ 5.80 (ddt, J =
17.1, 11.1, 6.1 Hz, 1H), 5.13 (t, J = 7.1 Hz, 1H), 5.02 (d, J = 17.1
Hz, 1H), 4.95 (d, J = 10.1 Hz, 1H), 3.67 (s, 3H), 2.74 (t, J = 6.7
Hz, 2H), 2.61 (q, J = 9.2 Hz, 1H), 2.16 (q, J = 8.2 Hz, 1H),
1.85-1.95 (m, 3H), 1.78 (t, J = 9.7 Hz, 1H), 1.59 (s, 3H),
1.44-1.52 (m, 2H), 1.09 (s, 3H), 1.03 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 176.2, 137.6, 136.6, 121.5, 114.3, 51.7, 48.2,
39.5, 37.4, 36.5, 34.8, 32.4, 30.6, 29.1, 22.4, 16.1; IR (thin film) ν
2951, 2863, 1736, 1434, 1168 cm-1; HRMS (ESI) m/z calc for
C16H26O2Na (M þ Na)þ 273.1830, found 273.1834.
Acknowledgment. The UC Irvine School of Physical
Sciences supported this work. M.S.D. thanks Allergan for
a Graduate Fellowship, and C.D.V. is grateful for support
from an Amgen Young Investigator Award and an Astra-
Zeneca Excellence in Chemistry Award. C.D.V. is a fellow of
the A. P. Sloan Foundation. We thank Prof. Amir Hoveyda
and Hoveyda group members Simon Meek and Steven
Malcolmson for helpful discussions regarding the potential
mechanism of the deallylation reaction of 78 and for supply-
ing several metathesis catalysts to try to solve the caryophyl-
lene problem. Timothy Barker and the Jarvo laboratory at
UC Irvine are gratefully acknowledged for help with and use
of their analytical SFC instrument. We acknowledge a gift of
MacMillan’s catalyst (66) from Materia.
Triene 78. CeCl3 7H2O (3.24 g, 8.73 mmol) was pulverized
3
with a mortar and pestle, placed under high vacuum (0.5
mmHg), and slowly heated to 150 °C over the course of 2 h.
The solid was maintained at 150 °C under vacuum with vigorous
stirring for 14 h and then allowed to cool to rt under N2. The
white solid was cooled to 0 °C and treated with THF (14.5 mL),
the ice water bath was removed, and the suspension was stirred
at rt for 2 h, producing a thick white slurry. The slurry was
cooled to -78 °C and treated with a freshly prepared solution of
trimethylsilylmethylmagnesium chloride (1.0 M in Et2O, 7.9 mL,
7.9 mmol) dropwise via syringe over 15 min. The reaction
mixture was stirred at -78 °C for 1.5 h, and ester 79 (364 mg,
1.45 mmol) in THF (2.5 mL) was added to the reaction mixture.
Supporting Information Available: NMR spectra for new
compounds. This information is available free of charge via the
Internet at http://pubs.acs.org.
6922 J. Org. Chem. Vol. 75, No. 20, 2010