bioactivity, which may both be more fully explored through
total synthesis. Herein, we report the first details of this
work, leading to the preparation of a fully elaborated
C1ꢀC11 fragment of madeirolide A.
iodide 3 would arise through hetero-Michael cyclization
of thioester 5 to establish the 2,6-cis-tetrahydropyran,7
followed by Takai olefination and glycosidation with
cinerulose derivative 6, itself formed through Achmato-
wicz rearrangement of (S)-2-furyl ethanol (10). Recogni-
tion of the C5ꢀC6 syn-relationship indicated that the
C5ꢀC9 stereotetrad within thioester 5 might arise from
ethyl ketone 7 and aldehyde 8 utilizing our boron aldol
method,8,9 followed by subsequent 1,3-anti reduction to
establish the remaining C7 stereocenter.
Scheme 1. Retrosynthetic Analysis of Madeirolide A
As shown in Scheme 2, preparation of ethyl ketone 7
commenced from (S)-ester 11,10 which would serve as the
source of the isolated C9 methyl-bearing stereocenter.
Accordingly, reduction of 11 followed by mesylation and
iodination of the resulting alcohol provided iodide 1211
(78%, three steps), which underwent smooth displacement
with the lithium anion of dithiane 13.12 The masked ketone
could then be revealed upon treatment of the dithiane
adduct with aqueous iodine to give 7.13
Coupling of ethyl ketone 7 and aldehyde 814 with
controlled installation of the C6 and C7 stereocenters
was then carried out by way of a chiral ligand-mediated
((ꢀ)-Ipc2BOTf, i-Pr2NEt) boron aldol reaction, which
provided the desired syn adduct 14 in excellent yield
(93%) and as essentially a single diastereomer.15
With β-hydroxy ketone 14 in hand, the newly formed C5
alcohol stereochemistry could be faithfully (>95:5 dr)
relayed to C7 through 1,3-anti reduction under Evansꢀ
Tishchenko conditions.16 Methanolysis of the ensuing
propionate ester and acetonide protection afforded the
requisite C5ꢀC9 stereotetrad as part of 15 (86%, three
steps).17 Removal of the TBS ether and oxidation with
Dess-Martin periodinane then provided the C3ꢀC10 al-
dehyde 16, in readiness for HWE homologation to install
an appropriate hetero-Michael acceptor for cyclization to
form the 2,6-cis-substituted A-ring tetrahydropyran.
Initially, this took the form of enoate 18 (Scheme 3),
prepared by Ba(OH)2-mediated HWE olefination with
(7) Fuwa, H.; Noto, K.; Sasaki, M. Org. Lett. 2011, 13, 1820.
(8) (a) Paterson, I.; Lister, M. A. Tetrahedron Lett. 1988, 29, 585. (b)
Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure,
C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663.
(9) (a) Paterson, I.; Paquet, T.; Dalby, S. M. Org. Lett. 2011, 13, 4398.
(b) Paterson, I.; Razzak, M.; Anderson, E. A. Org. Lett. 2008, 10, 3295.
(10) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig,
N. J. Am. Chem. Soc. 2001, 123, 9535.
From a synthetic perspective, madeirolide A presents a
considerable array of structural complexity. Some 16
stereocenters are embedded within a 24-membered macro-
lactone core featuring three distinct cyclic domains (AꢀC):
the glycosylated A-ring and all-cis, pentasubstituted
C-ring tetrahydropyrans, and the B-ring tetrahydrofuran.
For maximal convergency and relative stereochemical
flexibility, our approach sought to construct madeirolide
A from preassembled, suitably functionalized AꢀC ring
subunits, exploiting the intervening C10ꢀC13 diene and
C1 lactone linkages as ideal points for fragment union
(Scheme 1). This reveals C1ꢀC11 vinyl iodide 3 and
C12ꢀC27 vinyl stannane 4 as the targeted macrolide pre-
cursors, which might be coupled through a combination of
Stille and esterification reactions. The C1ꢀC11 vinyl
(11) Carley, S.; Brimble, M. A. Org. Lett. 2009, 11, 563.
(12) (a) Smith, A. B., III; Adams, C. M.; Lodise Barbosa, S. A.;
Degnan, A. P. J. Am. Chem. Soc. 2003, 125, 350. (b) Dickschat, J. S.;
Wickel, S.; Bolten, C. J.; Nawrath, T.; Schulz, S.; Wittmann, C. Eur. J.
Org. Chem. 2010, 2687–2695.
(13) Kim, H.; Hong, J. Org. Lett. 2010, 12, 2880.
(14) Pirrung, M. C.; Webste, N. J. G. J. Org. Chem. 1987, 52, 3603.
(15) (a) The configuration of aldol adduct 14 was determined by
NMR analysis of the corresponding Mosher ester derivatives. See
the Supporting Information for details. (b) Ohtani, I.; Kusumi, T.;
Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(16) (a) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112,
6447. (b) Ralston, K. J.; Hulme, A. N. Synthesis 2012, 44, 2310.
(17) (a) The C5/C7 anti-relationship was confirmed through 13C
NMR analysis of acetonide 15, according to the method of Rychnovsky
and Evans; see the Supporting Information for details. (b) Rychnovsky,
S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945. (c) Rychnovsky,
S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511. (d) Evans,
D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099.
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