explains the formation of nor-homologues of metathesis
product 6. Analysis of the dqfCOSY spectra further
revealed large quantities of the chain-extended compounds
17d and 17e. However, only trace amounts of the chain-
Figure 3. Amounts of detected homologation and isomerization
products correlate with chain lengths of CM reactants. Percen-
tages refer to amounts of homologated products formed in G-II-
catalyzed CM without BQ, as determined by ESIþ-MS (see
Supporting Information for conditions). Additional side pro-
duct formation occurs due to product isomerization.
Given that both G-II and HG-II have been employed
successfully in many CM reactions,9 we investigated whether
the degree of homologation and isomerization depends
on specific properties of the reactants 7ꢀ9 (Figure 3).
Using the G-II catalyst without BQ, we found that CM
of 9 with allyl benzyl ether proceeded cleanly without
formation of isomerized products or substrates, whereas
CM of 9 and homoallyl benzyl ether and homodimeriza-
tion of 9 consistently yielded significant amounts of iso-
merized and homologated products (Figure S6). Even
larger quantities of isomerized and homologized products
were obtained in G-II-catalyzed homodimerization reac-
tions of 7 and 8 (Figures S7, S8), similar to amounts of side
products produced in G-II-catalyzed CM reactions of 9
with 7 or 8 (Figures S3, S4). Thus it appears that the
severity of isomerization in our metathesis reactions gen-
erally correlates with the chain lengths of the reaction
partners and products (Figures 3, S3, S4, S6ꢀS8). That
long-chain, lipophilic substrates are particularly suscepti-
ble to homologation and isomerization during CM is also
suggested by recent acyclic diene metathesis (ADMET)
studies.6,10 Avoiding homologation and isomerization is of
importance for both ADMET and natural product synthesis,
as physical or biological properties may be affected greatly
by small amounts of structurally similar impurities. Our
results show that among tested catalysts, G-I with added
BQ is most suitable for CM involving long-chain substrates.
To complete the synthesis of the caeliferins, CM pro-
ducts 5 and 6 were deprotected11 and converted into acids
15 and 16 via sequential Swern and Pinnick oxidation.12
Figure 2. Section of dqfCOSY spectrum of the mixture of 17 and its
isomers and homologues, as derived from the corresponding
mixture of isomers and homologues of 9 isolated from CM of 8
with 9 using G-II and BQ (600 MHz, CDCl3, see Figure S1 for full
spectrum). Intensity of parts of the spectrum was scaled (1.5x, 2.5x).
extended terminal alkene 17c were found. This is con-
sistent with the hypothesis that CH2-extended variants
of 9 form mostly via ethylidene transfer during CM of
isomerized starting materials, without significant contribu-
tion from isomerized product 6 (isomerization and homo-
logation pathways are shown in Figure S2). The low
abundance of the CH2-extended terminal alkene 17c also
explainsthatonlytrace amountsof CH2 insertion products
of 6 were observed (m/z 745.5 in Figure 1), as their
formation in the absence of chain-extended terminal al-
kenes would require multiple isomerization and metathesis
steps (see Figure S2). In contrast to G-II and HG-II, use of
the G-I catalyst in the presence of BQ did not result in
homologation (Figure 1c) or isomerization (as confirmed
by dqfCOSY), even when using as much as 0.1 equiv of
catalyst and reaction times of up to 48 h. Using the G-I
catalyst, 6 was obtained in 80% yield (E/Z = 4:1), based
on consumed 9.
(10) Qin,H.;Chakulski, B. J.;Rousseau, I.A.;Chen,J.;Xie, X.-Q.;Mather,
P. T.; Constable, G. S.; Coughlin, E. B. Macromolecules 2004, 37, 5239–5249.
(11) Kim, S.; Park, J. H. Tetrahedron Lett. 1987, 28, 439–440.
(12) Smith, A. B.; Adams, C. M.; Barbosa, S. A.; Degnan, A. P. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 12042–12047.
(9) (a) Canova, S.; Bellosta, V.; Cossy, J. Synlett 2004, 10, 1811–1813.
(b) Rai, A. N.; Basu, A. Org. Lett. 2004, 6, 2861–2863. (c) Sheddan,
N. A.; Mulzer, J. Org. Lett. 2006, 8, 3101–3104.
5902
Org. Lett., Vol. 13, No. 21, 2011