ides have been observed in many natural products, and their
preparation has been studied extensively in recent years.6
Tertiary enamides, however, are encountered very rarely in
natural products, and as such, the strategies for their
preparation are relatively undeveloped and scarce.6,7 Fur-
thermore, the presence of the disulfide group in 1 requires
great care and consideration during the course of synthesis.8
For example, synthetic investigation of epidithiapiperazinedi-
one natural products (such as 2) has met with much difficulty
in the installation of the disulfide.8,9 To date, only one
complete total synthesis of a compound of this class has been
reported.10 Another case in point is psammaplin A (3); in
all three of the published syntheses of 3, the sulfur atoms
were introduced as a disulfide in the final step so as to avoid
side reactions.11
Scheme 1. Cross-Metathesis to 8
It was envisioned in the synthesis of 1 that the key
carbon-carbon connection at the internal olefin would be
made by olefin cross metathesis using a ruthenium catalyst.12
Accordingly, terminal olefin 6 was prepared from the known
aldehyde 513 via a Wittig reaction (Scheme 1).14 Thiazolidine
was chosen as the protecting group for the thiol of 4 because
of its relative stability and its tandem protection of the
carbamate proton.
Screening of commercially available ruthenium catalysts
revealed that the second-generation Hoveyda-Grubbs cata-
lyst (11) was optimal (Table 1).12c Furthermore, this reaction
was optimized for multigram scale by adjusting the concen-
tration and number of equivalents of 7. Good stereoselectivity
was observed in all cases (e.g., trans:cis ) 18:1, entry 8).
Minimizing the amount of 7 facilitated the purification
Table 1. Olefin Cross-Metathesis with Various Conditions To
Produce 8
esterb,
equiv
yield of
8c (%)
catalyst (mol %)
conca
1
2
3
4
9, 20
10, 20
10, 4
11, 5
11, 5
11, 2.5
11, 5
11, 5
0.04
0.04
0.04
0.03
0.03
0.03
0.04
0.2
7, 10
7, 10
7, 3
7, 3
12, 1.5
7, 3
0
26 (na)
23 (57)
81 (94)
53 (55)
44 (na)
73 (83)
82 (82)
5
6
7d
8e
7, 3
7, 2.2
a Concentration of 6 (M). b Equivalents of 7 or 12 with respect to 6.
c Isolated yields. Yields in parentheses are based on recovered starting
material. d 3.2 g scale (ca. 10 times more than entries 1-6). e 5.5 g scale.
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12, closely eluted with the desired product 8 during chro-
matography. In line with recent reports that some ruthenium
catalysts are more functional group-tolerant than initially
suspected,15 alkyl sulfides are apparently very well tolerated
by 11, but not by 9, suggesting that there may be competition
between tricyclohexylphosphine and the sulfide 6 for binding
as a ligand on ruthenium.16
The methyl ester 8 was hydrolyzed to obtain the carboxylic
acid 13 in order to avoid undesired reduction to the primary
alcohol in the next step. Afterward, the thiol and the
carbamate of 13 were reductively deprotected by sodium in
liquid ammonia (Scheme 2).13a Reprotection of the carboxy-
lic acid as a methyl ester, deprotection of the amine, and
36, 965–973
.
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(16) To our knowledge, this is the first example of a successful cross-
metathesis of an alkyl sulfide substrate by ruthenium carbene catalysis.
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