major diastereomers in a ratio of 2.1:1 (Table 1, entry 5).8
In addition, trace amounts of a third unassigned diastereomer
were detected by NMR spectroscopy. However, from this
reaction, although 2.5 equiv of 2 were consumed as in the
cyclization reactions above, ca. 40% of 9e was recovered
consistently. At present, we cannot provide a reason for the
somewhat lower cyclization yield of 10e compared to that
of 10a-d. A change of the base to LiTMP, change of the
solvent to THF-d8, or a quench of the reaction mixture with
D2O did not improve the yields. With HMPA as additive or
in DME as the solvent, the yield of 10e decreased to 34%,
while 64% of 9e was recovered. Future work must investigate
the reaction parameters including enolate aggregation and
ligands more thoroughly to further optimize this cyclization
protocol.
methyl)trimethylsilane/BuLi underwent Wittig reaction with
the crude aldehyde 15 derived from ozonolysis of 12. In this
way, ω-silylated citronellate 9e was obtained as a 1:1 E/Z-
mixture in unoptimized 30% yield based on phosphonium
salt 13. As a side product, compound 16 was formed as a
1:1 syn/anti-diastereomeric mixture.11
ω-Silylcitronellate 9e was subjected to the key tandem
alkoxycarbonylation/oxidative cyclization reaction by depro-
tonating with 2.6 equiv of LiTMP, adding 1.2 equiv of ethyl
chloroformate followed by 2.3 equiv of 2 (Scheme 6). After
Scheme 6. Tandem Alkoxycarbonylation/Oxidative Radical
Cyclization of 9e
On the basis of the cyclization results of ω-silylalkenyl-
malonates 9, we envisaged an application to a short access
to cyclopentanoid monoterpenes, namely, dihydronepeta-
lactone 11c and its nor-methyl analogues 11a,b (Scheme 4).
Scheme 4. Retrosynthesis of Dihydronepetalactone 11c
conventional workup, 93% of substituted cyclopentane-1,1-
dicarboxylate 10c was isolated as a 2:1 trans/cis-diastereo-
meric mixture. It is especially noteworthy that the tandem
sequence 9e f [17] f [18] f 10c gave considerably better
results than the oxidative cyclization of the corresponding
malonate 9c.
A retrosynthetic disconnection called for a hydroboration/
oxidation/lactonization of 2-alkenylcyclopentanecarboxylates
10c to synthesize the valerolactone moiety of 11c, while ethyl
citronellate 12 should serve as the precursor for the two-
step construction of the cyclopentane ring 10c in a new
tandem alkoxycarbonylation/oxidative cyclization protocol.
Because the preparation of 9e via 9c was lengthy, an
alternative synthesis of 9e started with a one-pot sequential
ozonolysis/Wittig reaction (Scheme 5). Phosphorane 14,
Because the cis- and trans-diastereomers of 10c were not
separable at this stage, the mixture was carried through to
hydroboration/oxidation with 9-BBN to provide the separable
alcohols 19c and 20c12 in a combined yield of 86% as single
diastereomers at the newly created stereocenter (Scheme 7).
The hydroboration/oxidation was also conducted with al-
kenylcyclopentanes 10a,b and proved to be highly di-
astereoselective for 10a. The diastereoselectivity can be easily
rationalized by assuming a strongly preferred conformation
A of 10 to avoid 1,3A-strain.13 From this conformation, one
face is effectively shielded by the two ester groups so that
the borane can only attack from the opposite face. Thus, the
two ester groups prove to be much more effective than a
monoester or a carboxylic acid in a related synthesis.14
The alcohols 19a-c were submitted to lactonization
induced by catalytic amounts of p-TsOH in CH2Cl2 or CDCl3
and provided the lactones 21a-c in high yields as single
diastereomers as indicated by NMR and GC. Finally,
Krapcho dealkoxycarbonylation afforded dihydronepetalac-
tone 11c and its nor-methyl analogue 11a in good to excellent
yields. Synthetic 11c was identical with respect to the
reported data of the natural product.15
Scheme 5. Synthesis of ω-Silylcitronellate 9e
(11) For similar products from silylated phosphoranes, see: Iio, H.; Ishii,
M.; Tsukamoto, M.; Tokoroyama, T. Tetrahedron Lett. 1988, 29, 5965-
5968 and references therein.
(12) This alcohol may be useful for the synthesis of other iridoids.
(13) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860.
(14) Wolinsky, J.; Eustace, E. J. J. Org. Chem. 1972, 37, 3376-3378.
which was generated from salt 13 through sequential
deprotonation/alkylation/deprotonation with BuLi/(iodo-
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