Observations in the synthesis of the core of the antitumor illudins via an enyne ring closing metathesis cascade

Article abstract of DOI:10.1016/j.tetlet.2009.07.102

Observations concerning the synthesis of the core spirocyclic AB-ring system of illudins using an enyne ring closing metathesis (EYRCM) cascade are discussed. Substituent effects, in addition to optimization of the reaction conditions and the olefin tethe

Full text of DOI:10.1016/j.tetlet.2009.07.102

Tetrahedron Letters 50 (2009) 5489–5492
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Observations in the synthesis of the core of the antitumor illudins
via an enyne ring closing metathesis cascade
*
Mohammad Movassaghi , Grazia Piizzi, Dustin S. Siegel, Giovanni Piersanti
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Observations concerning the synthesis of the core spirocyclic AB-ring system of illudins using an enyne
ring closing metathesis (EYRCM) cascade are discussed. Substituent effects, in addition to optimization of
the reaction conditions and the olefin tether for the key EYRCM reaction, are examined.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 June 2009
Revised 13 July 2009
Accepted 14 July 2009
Available online 22 July 2009
The illudins are a family of naturally occurring sesquiterpenes
isolated from the poisonous mushroom, Omphalotus illudens.1 Illu-
dins M and S (1 and 2, respectively) are among the most cytotoxic
members of this family of natural products. They inhibit DNA syn-
thesis through a two-step sequence involving enzyme-assisted hy-
dride/nucleophilic addition to the C8 enone followed by DNA
alkylation through cyclopropyl-ring opening and B-ring aromatiza-
tion.2 Significantly, two semi-synthetic derivatives of illudin S (2),
namely, acylfulvene (3) and irofulven (4), have shown very prom-
ising antitumor activity.3 In particular, the hydroxymethyl deriva-
tive irofulven (4) has demonstrated efficacy in clinical trials for
treatment of various cancers both as a monotherapy and in combi-
nation with other known chemotherapeutic agents.4 In light of this
promising therapeutic potential, these targets have received con-
siderable interest from scientists, leading to several inventive syn-
theses.5 We reported enantioselective syntheses of (À)-acylfulvene
(3) and (À)-irofulven (4) employing a key enyne ring closing
metathesis (EYRCM) cascade reaction.6 Herein, we describe our
observations in the context of related studies directed toward a
general strategy for the synthesis of the functional spirocyclic
pharmacophore common to all of these cytotoxic agents.
Our approach to the functional spirocyclic illudin core 5 relies
on a tethered enyne ring closing metathesis cascade7 to rapidly
generate the cyclohexenyl B-ring (Scheme 1). An array of sub-
strates 7, poised for the key EYRCM, can be convergently assem-
bled by the addition of
a variety of acetylides to the key
aldehyde 8, followed by chemoselective addition of a suitable teth-
ered olefin. Through this strategy, aldehyde 8 provides a platform
for the rapid and convergent synthesis of a broad range of deriva-
tives of the functional illudin core structure (Scheme 1).
In the context of these studies, we evaluated several olefin teth-
ers for the key EYRCM using model substrates 9 in order to identify
optimal tethers that were both stable to the EYRCM reaction con-
ditions and were readily removable (Table 1). Both Grubbs’ first-
and second-generation metathesis catalysts (G18a and G28b
,
respectively) were evaluated, with G2 generally providing the de-
sired product 10 with greater efficiency compared to G1. Under
optimal EYRCM reaction conditions, neither the carbonate nor
the carbamate tethers (Table 1, entries 1 and 2) provided the de-
sired EYRCM product 10. Instead, the carbonate tether fragmented
to afford the corresponding propargylic alcohol,9 and the Lewis ba-
sic carbamate likely reduced the activity of the G2 metathesis cat-
alyst through an unproductive coordination event. Interestingly,
when the cyclohexyl (Cy) carbamate (Table 1, entry 3) was submit-
ted to the EYRCM conditions, the product 10 was generated in 47%
yield. We attribute this enhanced reactivity to the expected sub-
strate preference to adopt the carbamate rotamer that positions
the allyl substituent trans to the carbonyl. In this conformation
O
B
O
O
OH
Me
HO
1
HO
Me
HO
Me
8
2
Me
Me
OH
Me
C
Me
3
4
OH
A
H
R
H
Me
Illudin M (1)
Me
Me
Acylfulvene (3), R=H
Irofulven (4), R=CH2OH
Illudin S (2)
tether
addition
HO
OH
X
X
OH
O
O
O
HO
Me
TMSO
Me
HO
Me
acetylide
addition
R
H
Me
R
R
Me
Me
Me
EYRCM
Me
8
5
6
7
* Corresponding author. Tel.: +1 617 253 3986.
E-mail address: movassag@mit.edu (M. Movassaghi).
Scheme 1. Strategy to the functional illudin core 5.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.102

5490
M. Movassaghi et al. / Tetrahedron Letters 50 (2009) 5489–5492
Table 1
bicyclic core structure of the illudins. In addition to our previously
described enantioselective synthesis of (+)-aldehyde 8,6 we also
developed a simple, large-scale four-step synthesis of racemic alde-
hyde 8 from pentane-2,4-dione (11, Scheme 2) given the activity of
both enantiomers of irofulven.5g Sequential double alkylation,12
mono olefination, and InBr3-catalyzed trimethylsilylcyanation13
provided the versatile silyl cyanohydrin 14 in multi-gram quantities
(Scheme 2). Reduction of the nitrile 14 with diisobutylaluminum hy-
dride (DIBAL-H) readily provided the desired racemic aldehyde 8 in
69% yield on 2-gram scale. This facile synthesis allowed rapid access
to multi-gram quantities of aldehyde 8 as the key precursor for the
AB-ring system shared in illudins.6
Evaluation of olefin tethers for the EYRCM
X
X
O
G2 (10 mol%)
(0.05M)
O
Cy
iBu
Cy
iBu
10
9
Entry
1
Tether
Solvent
Temp (°C)
Time
Yielda (%)
O
O
PhH
65
110
110
80
1.5 h
1.5 h
1.5 h
6 h
0
Five readily available acetylides14 15a–d were added to alde-
hyde 8 as the corresponding lithium acetylides to provide diols
16a–d (Scheme 3).6 The diastereoselectivity (ca. 6:1)15 of these
reactions was consistent with a Felkin-Ahn mode of addition. The
allylsilane tether was introduced on substrates 16a–c through
selective silylation of the secondary hydroxyl group to afford the
dienynes 17a–c in 68–83% yields.
O
2
3
4
5
PhMe
PhMe
PhH
0
N
H
O
With the allylsilane substrates 17a–c in hand, we examined
their respective EYRCM reactions for accessing the functional bicy-
clic core common to the illudins (Table 2). These optimization
studies were monitored directly by 1H NMR analysis. Gratifyingly,
when 17a was submitted to the conditions established by the
model substrate 9 (G2, 10 mol %, C6D6, 0.02 M, 65 °C, 1 h, entry 5,
Table 1), the desired product 18a was efficiently generated as the
major product (Table 2, entry 1).16 A plausible mechanism for the
desired EYRCM pathway is shown in Scheme 4 (Path A). A minor
amount (6%) of the uncyclized triene product 19a was also ob-
served as a result of an intermolecular cross-metathesis out com-
peting the desired intramolecular ring closing metathesis at the
C4–C5 olefin (Scheme 4, Path B). The formation of the intermolec-
ular cross-metathesis product 19a was greatly favored by increas-
ing both the concentration from 0.02 M to 0.06 M and temperature
from 65 °C to 80 °C in addition to reducing the catalyst loading to
5 mol % (Table 2, entry 2). Interestingly, 8% of the minor cyclopen-
tenyl product 20a was also observed under these conditions. It is
plausible that the formation of this product corresponds to the
47
15b
91
92
NCy
O
NTBS
Me Me
Si
PhH
65
30 min
Et Et
6
PhH
65
3 h
Si
O
a
Isolated yields.
b
Isolated yield of free amide after TBS deprotection with TBAF.
the olefin is oriented in close proximity to the alkyne and is poised
for the ensuing EYRCM with minimal interference by the Lewis ba-
sic carbonyl. In light of this, we also prepared the t-butyldimethyl-
silyl allylamide (Table 1, entry 4), which would enable access to a
more hydrolytically labile cyclic carbonate by treatment with tet-
ra-n-butylammonium fluoride (TBAF). However, the tandem
EYRCM–TBAF treatment provided the desired product in only
15% yield, due to the lability of the silylcarbamate under the
EYRCM conditions.
Me
O
Me
O
MePh3PBr,
tBuOK,
Et2O
56%
Me
O
Br
Br
O
O
K2CO3
DMSO
61%
Me
13
Me
Me
11
12
TMSCN
InBr3
CH2Cl2
81%
O
H
TMSO
Me
TMSO
Me
CN
Me
DIBAL-H
Et2O, −78ºC
69%
Me
14
8
None of the carbonate- or carbamate-based tethers proved supe-
rior to silicon-based olefin tethers6 examined for this transforma-
tion. When the allylsilane tether, first reported by Grubbs and
Yao,10 was subjected to the EYRCM conditions, the desired product
10 was afforded in 91% yield (Table 1, entry 5) within 30 min. Fur-
thermore, the allyloxysilane tether (Table 1, entry 6)11 also provided
the desired enyne metathesis product in 92% yield, albeit requiring a
longer reaction time. Interestingly, in related systems we observed
that the diethylallyoxysilane tether (Table 1, entry 6) was optimal
as compared to the corresponding dimethyl and diisopropyl vari-
ants. The diethylallyloxysilane tether provided the best balance be-
tween stability and reactivity. The dimethylallyloxysilane tether
was too labile under the EYRCM reaction conditions leading to pre-
mature desilylation, while the diisopropylallyloxysilane was both
more difficult to prepare due to lower rate of etherification and gave
the desired metathesis products in low yields.
2 gram Scale
8 gram Scale
Scheme 2. Synthesis of the aldehyde 8.
Me
Si
Me
15a-d
O
Me
Si
Me
Cl
OH
Me
16a 42%
16b 45%
16c 19%
16d 90%
O
LDA or
TMSO
Me
HO
Me
HO
LiHMDS
H
Me
R
R
Et3N, CH2Cl2
23 ºC, 30 min
THF, −78 ºC;
TBAF
Me
Me
8
17a 83%
17b 68%
17c 68%
Me
Me
OPMB
iBu
2
Me
15a
15b
15c
15d
The two optimal silicon-based tethers for the key enyne metath-
esis (Table 1, entries 5 and 6) were utilized in the synthesis of the
Scheme 3. Use of aldehyde 8 for synthesis of various dienynes.

M. Movassaghi et al. / Tetrahedron Letters 50 (2009) 5489–5492
5491
Table 2
Et Et
Si
The EYRCM with the allylsilane tethera
OH
HO
Et
Et
O
O
O
Si
HO
Me
Me
Cl
R
Me
Si
Me
R
Me
O
Me
O
Me
R
Me
O
Me
R
Me
O
Et3N, CH2Cl2
23 ºC, 2 h
R
Si
Si
Si
Me
16a, R = iBu
16d, R = CH2OPMB
HO
Me
G1 or G2
HO
Me
Me
HO
Me
HO
Me
(10 mol%)
27a 81%
27d 83%
4
R
5
0.02M, 1 h
Me
20a-c
Me
17a, R = iBu
Me
19a-c
Me
Scheme 5. Synthesis of the allyloxysilane tether substrates.
18a-c
17b, R = (CH2)2CH=C(CH3)2
17c, R = CH=C(CH3)CH=CH2
Table 3
The EYRCM with the allyloxysilane tether
Entry
Substrate
Cat
Conditions
Results (%)
17
16
18
19
20
Et
Si
Et
Et Et
Si
OH
O
1
17a
17a
17b
17b
17b
17b
17c
G2
G2
G1
G1
G2
G2
G2
C6D6, 65 °C
C6D6, 80 °C
C6D6, 65 °C
CD2Cl2, 40 °C
CD2Cl2, 40 °C
C6D6, 65 °C
C6D6, 80 °C
—
—
—
—
—
—
—
—
54
94
—
—
40
40
90
—
6
—
8
25
50
5
OH
OH
O
O
2b
3
92
—
—
—
—
—
HO
Me
O
HO
Me
G2
HO
Me
HO
Me
(10 mol%)
75
10
55
10
46
R
4
5
R
R
R
Me
29a,d
4
Me
27a, R = iBu
Me
Me
6
—
—
7c
28a,d
5a,d
27d, R = CH2OPMB
a
All experiments were conducted in NMR tubes under an atmosphere of argon,
and product distribution was measured by direct integration of characteristic res-
onances for products. All experiments were stopped after 1 h unless otherwise
noted.
Entry
Substrate
Conditions
Results (%)
27
28
5
29
b
G2 (5 mol %), 0.06 M concentration.
Reaction time 32 h.
1
2
3
4
27a
27a
27a
27d
C6D6, 65 °C
PhMe-d8, 110 °C
PhMe, 110 °C, TBAF
PhMe, 110 °C, TBAF
33a
—
—
66a
99a
—
—
—
—
c
—
48b
64b
—
—
—
17b
Me Me
Me
Si
Me
Si
Me
O
Me
O
a
Path A
18
LnRu
Experiments were conducted in NMR tubes under an atmosphere of argon and
product distribution was measured by direct integration of characteristic reso-
nances for products.
Si
O
RuLn
HO
Me
HO
Me
HO
Me
intramolecular
intermolecular
RuLn
b
Isolated yields.
R
R
RuLn
17
R
Me
Me
Me
21
22
23
19
LnRu
R'
17
anes. Gratifyingly, the diethylallyloxysilane tethered substrates
27a and 27d were efficiently prepared through selective silylation
of the secondary alcohol (Scheme 5).18 1H NMR studies on the
diethylallyloxysilyl substrate 27a indicated that the EYRCM reac-
tion to form the 7,6-bicycle 28a (Table 3, entry 1) required higher
reaction temperatures than those observed with the allylsilane
tether (vide supra, entry 1, Table 2). The desired product 28a was
cleanly generated when subjected to the EYRCM reaction in tolu-
ene-d8 at 110 °C (Table 3, entry 2). The heptacyclic silyloxy ring
system 28 was very sensitive to isolation, hence we sought a tan-
dem EYRCM-desilylation sequence. Using this method, we were
able to directly isolate the corresponding triols 5a and 5d in 48%
and 64% yields, respectively (Table 3, entries 3 and 4). Notably,
the versatile product 5d contains a p-methoxybenzyl (PMB) group
poised for further elaboration toward the synthesis of various func-
tional bicyclic illudin derivatives. Interestingly, when 27d was sub-
jected to this optimal EYRCM-TBAF condition we also isolated the
diol 29d in 17% yield (Table 3, entry 4). The formation of this prod-
uct is consistent with the EYRCM pathway involving initial enyne
metathesis at the C4–C5 olefin (vide supra, Scheme 4, Path C).
The structure of 29d was secured through X-ray crystallographic
analysis of the corresponding bis-p-nitrobenzoate derivative.19
In summary, the subtle factors influencing the competing path-
ways in a critical EYRCM reaction were discussed. Our convergent
approach to the bicyclic warhead of illudins involves the union of a
readily accessible key aldehyde 8 with various lithium acetylides
and optimal silicon-based olefin tethers to enable access to an ar-
ray of dienynes 7. A versatile EYRCM cascade reaction rapidly con-
structs the cyclohexenyl B-ring common to the illudins. Subtle
changes in the EYRCM conditions greatly affect the outcome of
the metathesis reaction, which can proceed through three different
pathways to generate products 18, 19, and 20 (Scheme 4, Paths A–
Path B
Me
Si
Me
O
Me
Si
Me
Si
Me
O
Me
O
HO
Me
R
HO
Me
HO
Me
R
20
RuLn
R
RuLn
Me
RuLn
Me
25
Path C
4
Me
24
26
Scheme 4. Plausible mechanisms for the EYRCM reaction.
metathesis occurring first at the sterically congested C4–C5 gem-
disubstituted olefin followed by enyne metathesis (Scheme 4, Path
C).17 The structure of cyclopentenyl product 20 was secured
through X-ray analysis of a related derivative (vide infra).
We also explored the EYRCM reaction with substrate 17b con-
taining the trisubstituted olefin. Unexpectedly, when 17b was sub-
mitted to G1 in C6D6 at 65 °C (Table 2, entry 3), the five-membered
ring substrate 20b was the only observable product. By changing
the solvent to CD2Cl2 and lowering the temperature to 40 °C, both
the desired product 18b and the undesired cyclopentene product
20b were afforded in a 4:5 ratio (Table 2, entry 4). Significantly,
the EYRCM conditions employing G2 in C6D6 at 65 °C for 1 h gener-
ated the desired product 18b exclusively (Table 2, entry 6). Inter-
estingly, when the tetraenyne 17c was exposed to the EYRCM
reaction conditions (G2, 10 mol %, C6D6, 0.02 M, 80 °C, 32 h), none
of the desired product 18c was generated (Table 2, entry 7). In-
stead, over prolonged reaction times, desilylation occurred to gen-
erate 16c, indicating that conjugation of the alkyne may
significantly deactivate the substrate toward EYRCM.
Given the complications with oxidative desilylation of allylic si-
lanes 18,6 we also explored the corresponding dialkylallyloxysil-

5492
M. Movassaghi et al. / Tetrahedron Letters 50 (2009) 5489–5492
4915; (f) McMorris, T. C.; Staake, M. D.; Kelner, M. J. Org. Chem. 2004, 69, 619;
(g) Gong, J.; Neels, J. F.; Yu, X.; Kensler, T. W.; Peterson, L. A.; Sturla, S. J. J. Med.
Chem. 2006, 49, 2593.
C). This strategy provides ready access to the synthesis of various
functionalized precursors to the core warheads of the illudin anti-
tumor natural products. The evaluation of these fused bicycles in
the synthesis of illudin derivatives and their respective biological
evaluation will be reported in due course.
6. Movassaghi, M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Angew. Chem., Int. Ed. 2006,
45, 5859.
7. For representative examples, see: (a) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J.
Am. Chem. Soc. 1994, 116, 10801; (b) Zuercher, W. J.; Scholl, M.; Grubbs, R. H. J.
Org. Chem. 1998, 63, 4291; (c) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am.
Chem. Soc. 2002, 124, 773; (d) Fukumoto, H.; Takanishi, K.; Ishihara, J.;
Hatakeyama, S. Angew. Chem., Int. Ed. 2006, 45, 2731; For a review, see: (e)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490.
8. (a) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606;
(b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
9. The allylcarbonate fragmentation may involve a competing pathway in which
Acknowledgments
M.M. is an Alfred P. Sloan Research Fellow, a Beckman Young
Investigator, and a Camille Dreyfus Teacher-Scholar. We thank Jus-
tin Kim and Dr. Peter Müller for assistance with X-ray crystallo-
graphic analysis. We acknowledge financial support in part by
NIH-NIGMS (GM074825) and Amgen.
catalyst decomposition products may form
p-allyl complexes. For an example
of ruthenium -allyl complex formation with allylcarbonates, see: Gürbüz, N.;
p
Özdemir, I.; Çetinkaya, B.; Renaud, J.-L.; Demerseman, B.; Bruneau, C.
Tetrahedron Lett. 2006, 47, 535.
10. For representative examples of allyldialkylsilicon tether mediated olefin
metathesis, see: (a) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757;
(b) Yao, Q. Org. Lett. 2001, 3, 2069.
11. For examples of metathesis reactions using allyloxysilane tethers, see: (a)
Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429; (b) Briot, A.; Bujard,
M.; Gouverneur, V.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2000, 2, 1517; (c) Van
de Weghe, P.; Aoun, J.-G.; Boiteau, D.; Eustache, J. Org. Lett. 2002, 4, 4105; (d)
Postema, M. H.; Piper, J. L. Tetrahedron Lett. 2002, 43, 7095; (e) Evans, P. E.; Cui,
J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc. 2003, 125,
14702.
References and notes
1. (a) Anchel, M.; Hervey, A.; Robbins, W. J. Proc. Natl. Acad. Sci. U.S.A. 1952, 38,
927; (b) McMorris, T. C.; Anchel, M. J. Am. Chem. Soc. 1965, 87, 1594.
2. (a) Kelner, M. J.; McMorris, T. C.; Taetle, R. J. Natl. Cancer Inst. 1990, 82, 1562; (b)
McMorris, T. C.; Kelner, M. J.; Chadha, R. K.; Siegel, J. S.; Moon, S.; Moya, M. M.
Tetrahedron 1989, 45, 5433; (c) Gong, J.; Vaidyanathan, V. G.; Yu, X.; Kensler, T.
W.; Peterson, L. A.; Sturla, S. J. J. Am. Chem. Soc. 2007, 129, 2101; (d) Neels, J. F.;
Gong, J.; Yu, X.; Sturla, S. J. Chem. Res. Toxicol. 2007, 20, 1513.
3. McMorris, T. C.; Kelner, M. J.; Wang, W.; Yu, J.; Estes, L. A.; Taetle, R. J. Nat. Prod.
1996, 59, 896.
12. Zefirov, N. S.; Kuznetsova, T. S.; Kozhushkov, S. I.; Surmina, L. S.; Rashchupkina,
Z. A. Zh. Org. Khim. 1983, 19, 541.
4. (a) Alexandre, J.; Raymond, E.; Kaci, M. O.; Brian, E. C.; Lokiec, F.; Kahatt, C.;
Faivre, S.; Yovine, A.; Goldwasser, F.; Smith, S. L.; MacDonald, J. R.; Misset, J.-L.;
Cvitkovic, E. Clin. Cancer Res. 2004, 10, 3377; (b) Yeo, W.; Boyer, M.; Chung, H.
C.; Ong, S. Y. K.; Lim, R.; Zee, B.; Ma, B.; Lam, K. C.; Mo, F. K. F.; Ng, E. K. W.; Ho,
R.; Clarke, S.; Roh, J. K.; Beale, P.; Rha, S. Y.; Jeung, H. C.; Soo, R.; Goh, B. C.; Chan,
A. T. C. Cancer Chemother. Pharmacol. 2007, 59, 295; (c) Wiltshire, T.; Senft, J.;
Wang, Y.; Konat, G. W.; Wenger, S. L.; Reed, E.; Wang, W. Mol. Pharmacol. 2007,
71, 1051; (d) Kelner, M. J.; McMorris, T. C.; Rojas, R. J.; Estes, L. A.;
Suthipinijtham, P. Cancer Chemother. Pharmacol. 2008, 63, 19; (e) Dings, R. P.
M.; Van Laar, E. S.; Webber, J.; Zhang, Y.; Griffin, R. J.; Waters, S. J.; MacDonald,
J. R.; Mayo, K. H. Cancer Lett. 2008, 265, 270.
5. For total syntheses of illudin M and S, see: (a) Matsumoto, T.; Shirahama, H.;
Ichihara, A.; Shin, H.; Kagawa, S.; Sakan, F.; Matsumoto, S.; Nishida, S. J. Am.
Chem. Soc. 1968, 90, 3280; (b) Matsumoto, T.; Shirahama, H.; Ichihara, A.; Shin,
H.; Kagawa, S.; Sakan, F.; Miyano, K. Tetrahedron Lett. 1971, 2049; (c) Kinder, F.
R.; Bair, K. W. J. Org. Chem. 1994, 59, 6965; For total syntheses of Acylfulvene
and Irofulven, see: (d) McMorris, T. C.; Hu, Y.; Yu, J.; Kelner, M. Chem. Commun.
1997, 315; (e) Brummond, K. M.; Lu, J.; Petersen, J. J. Am. Chem. Soc. 2000, 122,
13. (a) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A. Tetrahedron Lett.
2001, 42, 3041; (b) Bandini, M.; Cozzi, P. G.; Garelli, A.; Melchiorre, P.; Umani-
Ronchi, A. Eur. J. Org. Chem. 2002, 3243.
14. The alkynes 15b and 15c were prepared according to literature procedures.
15b: Van Boom, J. H.; Brandsma, L.; Arens, J. F. Rec. Tr. Chim. Pays-Bas 1966, 85,
952. 15c: Apparu, M.; Barrelle, M. Bull. Soc. Chim. Fr. 1983, 83. 15d: Treatment
of corresponding propargyl alcohol with PMBCl.
15. For clarity only the major diastereomer is shown.
16. On larger scale, 18a could be isolated in 76% yield using optimized EYRCM
conditions.
17. It may also be plausible that the formation of product 20 occurs through initial
complexation of the metathesis catalyst with the alkyne followed by EYRCM.
18. Diethylallyloxysilylchloride was prepared according to: Krolevets, A. A.;
Antipova, V. V.; Popov, A. G.; Adamov, A. V. Zh. Obsch. Khim. 1988, 58, 2274.
19. The crystal structure of the corresponding bis-p-nitrobenzoate derivative of
29d has been deposited at the Cambridge Crystallographic Data Center, please
see: CCDC# 735275.