Organic Letters
Letter
Scheme 1. Previous Approaches to (−)-1 (a) and Racemic 1
(b) by the Groups of Ando and Rigby
Scheme 2. Synthetic Strategy for (−)-Dehydrocostus
Lactone (1)
Grignard reagent to tropone. The cyclic ether 7 was further
transformed to diketone 8 by a multistep route. However,
ketone olefination of 8 was found to be inefficient owing to the
competing opening of the γ-butyrolactone by β-elimination
and proceeded at best13 in only 15% yield. Finally, racemic
dehydrocostus lactone (1) was isolated after α-methylenation
of the lactone using Eschenmoser’s salt.
With our synthetic strategy set, we initially focused on the
asymmetric aldol reaction. The donor component 17 was
readily prepared by DCC/DMAP-mediated esterification19 of
auxiliary 15 and hex-5-enoic acid (Scheme 3). Aldol addition
of the dicyclohexylboron enolate derived from 17 to aldehyde
1618 led to a mixture of the two anti diastereomers with good
diastereoselectivity (dr = 9:1). The isomers were separated by
flash chromatography to give the pure diastereomer (S,S)-14 in
90% yield. The aldol product (S,S)-14 was then transformed
into aldehyde 13 in four steps. After C-desilylation of the
alkyne with TBAF and TBS protection of the hydroxyl group,
the resulting ester 18 was cleaved using an excess of DIBAL to
give alcohol 19 and the reisolated auxiliary 15 in high yields.
Subsequently, alcohol 19 was smoothly oxidized to aldehyde
13 using TEMPO/PIDA.20 For conversion of 13 to the
metathesis substrate 12, alkynylation with Wu’s reagent
(20)21a performed best from a variety of conditions21 screened
and gave enediyne 12 quantitatively.
With enediyne 12 in hand, the stage was set to investigate
the domino metathesis to give 9 as the key step of our
synthesis (Scheme 4). Earlier we applied both the Grubbs II
(for dieneyne14b,d and trieneyne14c,e metathesis) and the
Grubbs I catalysts (for dienediyne metathesis)14e for related
domino transformations. Whereas reaction of 12 with the
Grubbs II catalyst always delivered mixtures of the desired
triene 9 and its isomer 9′, enediyne 12 was converted to the
pure triene 9 by treatment with the more chemoselective
Grubbs I catalyst in 86% yield (calculated from 1H NMR data
of 9 still containing some pentane). We assume that the
formation of 9′ is triggered by initiation of the domino process
at the alkyne carbon C-7 rather than at C-5. Initiation at C-5
would first lead to the monocyclic compounds A or B, and we
found that A could not be transformed to 9 by treatment with
the Grubbs II catalyst.22
Due to our interest in the synthesis of hydroazulene natural
products by domino metathesis,14 we developed a new
approach to (−)-dehydrocostus lactone (1) by an enediyne
strategy. Noteworthy, there are only a few examples for
domino metathesis reactions with substrates bearing more than
one triple bond.14e,15 As depicted in Scheme 2, our synthesis
was based on the disassembly of guaianolide 1 to a
hydroazulene core structure, which should allow facile
functionalization in the desired stereochemical fashion. We
assumed triene 9 to be a suitable intermediate that might
undergo exhaustive hydroboration/oxidation to give triol 10 in
a substrate-induced diastereoselective manner. Blocking of the
concave face by a bulky substituent at C-10 should increase the
preference for attack on the convex face. Compound 10 would
be transformed to diketone 11 by acetal formation, cleavage of
the silyl ether, and twofold oxidation. Since Rigby and co-
workers encountered severe difficulties during methylenation
of the diketo-γ-lactone 8,12 we decided to mask the lactone
unit as the corresponding methyl acetal.16 This should disfavor
cleavage of the C-6 oxygen bond by β-elimination upon
introduction of the methylene unit at C-4. Finally, unmasking
the lactone and subsequent α-methylenation would complete
the synthesis of 1.
We envisioned enediyne 12 as a suitable substrate for the
key metathesis event to give triene 9. Compound 12 in turn
was traced back to aldehyde 13 revealing an anti aldol pattern
that might be generated according to the procedure by
Masamune and Abiko.17 Thus, aldehyde 13 should emerge
from the anti aldol adduct 14 after C-desilylation/O-silylation
and reductive removal of the auxiliary. Ester 14 can be
disconnected to the known aldehyde 16,18 hex-5-enoic acid,
and the commercially available chiral auxiliary 15.
As hydroazulene 9 tended to oligomerize under neat
conditions, it had to be subjected to the following hydro-
1345
Org. Lett. 2021, 23, 1344−1348
Kaden, Felix
