Synthesis of the C1-C11 western fragment of madeirolide A

Article abstract of DOI:10.1021/ol400280b

The stereocontrolled synthesis of a fully elaborated C1-11 subunit of madeirolide A is described, utilizing an asymmetric boron aldol reaction and a cis-selective hetero-Michael cyclization to form the tetrahydropyran ring, followed by efficient formation of the required C5 α-glycoside.

Full text of DOI:10.1021/ol400280b

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1338–1341
Synthesis of the C1ꢀC11 Western
Fragment of Madeirolide A
Ian Paterson* and Gregory W. Haslett
University Chemical Laboratory, University of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K.
ip100@cam.ac.uk
Received January 30, 2013
ABSTRACT
The stereocontrolled synthesis of a fully elaborated C1ꢀ11 subunit of madeirolide A is described, utilizing an asymmetric boron aldol reaction and
a cis-selective hetero-Michael cyclization to form the tetrahydropyran ring, followed by efficient formation of the required C5 R-glycoside.
Marine spongesproduceanextraordinary arrayof novel
bioactive secondary metabolites and represent an impor-
tant source of lead compounds for the development of new
chemotherapeutic agents.1 Lithistid sponges have proven
particularly fertile in this respect,2 serving as the source of
potent antitumor polyketides such as dictyostatin,2b
discodermolide,2c and more recently, leiodermatolide.2d
A notable addition to this impressive collection of
marine natural products is the madeirolide family of
macrolides (Scheme 1), which were recently disclosed by
Wright and Winder at Harbor Branch.3 Their structures
weredeterminedbydetailedNMR spectroscopicanalysis,3
and their stereochemical assignment was further validated
using Goodman’s DP4 computational NMR method.4
Madeirolide A (1) and B (2) were shown to be potent
inhibitors of the fungal pathogen Candida albicans
(fungicidal MIC = 12.5 (1)/25 (2) μg/mL). However, the
scarcity of isolates from the sponge source (Leiodermatium
sp.) has thus far hampered detailed evaluation of their
antiproliferative properties. Given the established biologi-
cal profile of the aforementioned polyketides of lithistid
origin, and the nanomolar antitumor activity exhibited by
their close structural relatives, mandelalides A and B,5 this
remains an intriguing unknown.
As part of our continued interest in the development of
new therapeutic agents from marine natural products,6 we
identified the madeirolides as attractive synthetic targets
because of their structural intricacy and tantalizing
(1) (a) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.;
Prinsep, M. R. Nat. Prod. Rep. 2012, 29, 144. (b) Dalby, S. M.; Paterson,
I. Curr. Opin. Drug Discovery Dev. 2010, 13, 777. (c) Nicolaou, K. C.;
Chen, J. S.; Dalby, S. M. Bioorg. Med. Chem. 2009, 17, 2290. (d)
Paterson, I.; Anderson, E. A. Science 2005, 310, 451. (e) Driggers,
E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. Nat. Rev. Drug Discov. 2008,
7, 608. (f) Yeung, K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002, 41,
4632.
(4) Smith, S. G.; Goodman, J. M. J. Am. Chem. Soc. 2010, 132,
12946. See the Supporting Information for details of these DP4 calcula-
tions for madeirolide A. For a recent application see ref 2d.
(5) Sikorska, J.; Hau, A., M.; Anklin, C.; Parker-Nance, S.; Davies-
Coleman, M., T.; Ishmael, J., E.; McPhail, K., L. J. Org. Chem. 2012, 77,
6066. The A rings of the madeirolides and mandelalides have the same
absolute configuration, whereas the B rings are enantiomeric. The
absolute configurations of the madeirolides and mandelalides were
assigned by comparison to the cinerulose moiety of aclacinomycin A
and degradation studies, respectively.
(2) (a) Winder, P. L.; Pomponi, S. A.; Wright, A. E. Mar. Drugs 2011,
9, 2643. (b) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley,
R. E.; Wright, A. E. Biochem. Pharmacol. 2003, 66, 75. (c) ter Haar, E.;
Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley, R. E.; Gunasekera,
S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996, 35, 243. (d)
(6) Paterson, I.; Maltas, P.; Dalby, S. M.; Lim, J. H.; Anderson, E. A.
Angew. Chem., Int. Ed. 2012, 51, 2749. (b) Xuan, M.; Paterson, I.; Dalby,
S. M. Org. Lett. 2012, 14, 5492. (c) Paterson, I.; Naylor, G. J.; Gardner,
ꢀ
Paterson, I.; Dalby, S. M.; Roberts, J. C.; Naylor, G. J.; Guzman, E. A.;
Isbrucker, R.; Pitts, T. P.; Linley, P.; Divlianska, D.; Reed, J. K.; Wright,
A. E. Angew. Chem., Int. Ed. 2011, 50, 3219.
ꢀ
N. M.; Guzman, E.; Wright, A. E. Chem. Asian J. 2011, 6, 459. (d)
(3) Winder, P. L. Ph.D. Thesis, Florida Atlantic University, 2009.
Paterson, I.; Paquet, T. Org. Lett. 2010, 12, 2158.
r
10.1021/ol400280b
Published on Web 03/01/2013
2013 American Chemical Society

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.
Org. Lett., Vol. 15, No. 6, 2013
1339

2,6-trans-tetrahydropyran 19. All attempts to generate
the desired 2,6-cis isomer (elevated reaction temperature/
extendedreaction time) proved unsuccessful. The failure to
access the presumed thermodynamic 2,6-cis tetrahydro-
pyran might be ascribed to intramolecular hydrogen-
bonding with the C5 hydroxyl group favoring the forma-
tion of the 2,6-trans product through a boatlike transition
state.20 Accordingly, we explored the alternative thioester
substrate 5, which might allow for the desired mode of
cyclization to occur under acidic conditions, as prescribed
by Fuwa.7 Condensation of aldehyde 16 with thioester
phosphonate 20 under Masamune-Roush conditions21
at ꢀ15 °C provided 21 in excellent yield and selectivity
(95%, 19:1 (E)/(Z)). Gratifyingly, subjection of the
corresponding diol arising from acetonide removal to
Fuwa’s conditions (CSA, DCE, 70 °C) effected selective
(72%, >20:1 2,6-cis:trans) formation of the targeted
2,6-cis tetrahydropyran. After surveying a range of
acidic conditions, acetonide removal and cyclization
were optimally carried out as a one-pot operation
Scheme 2. Preparation of C3ꢀC16 Aldehyde 16
through prolonged (6 h) exposure of 21 to TsOH H2O
3
(0.5 equiv) in CH2Cl2 at ambient temperature. While
this also resulted in partial PMB deprotection, the
crude cyclized material could then be treated with
DDQ to deliver the A-ring diol 22 in an efficient
manner through this two-step sequence.
Diol differentiation of 22 could then be effected through
selective primary oxidation.22 The ensuing C10 aldehyde
could then be homologated to vinyl iodide 23 through
Takai olefination,23 thus completing the synthesis of the
C1ꢀC11 madeirolide A aglycone fragment.
phosphonate 17 (78%, 11:1 (E):(Z)),18 followed by ace-
tonide deprotection (PPTS, MeOH, 92%). Subjection of
18 to a range of basic conditions19 effected smooth cycliza-
tion but unexpectedly provided almost exclusively the
Scheme 3. Completion of the Western Fragment 3
1340
Org. Lett., Vol. 15, No. 6, 2013

An appropriate cinerulose glycosyl donor, acetate 6, was
straightforwardly accessed in three steps from 2-acetylfur-
an (24). Noyori reduction of 24 provided enantioenriched
alcohol 10 (99%, 98% ee),24 which was then subjected to
Achmatowicz rearrangement with in situ acetylation of the
ensuing lactol to give acetate 6 as a mixture of anomers
(ca. 1.7:1 R:β).25 Hydrogenation then provided cinerulose
donor 6 (35%).26
With both glycosyl donor 6 and acceptor 23 in hand,
their union would complete the fully functionalized
C1ꢀC11 western hemisphere of madeirolide A. In the
event, it was found that prolonged (18.5 h) exposure of a
mixture of 6 and 23 to BF3 Et2O (0.5 equiv) resulted in the
3
smooth formation of the desired R-glycoside 3 in excellent
yield and selectivity (78%, 19:1 R:β).
Detailed NMR comparisons of the madeirolide A
C1ꢀC11 glycoside 3 with the corresponding natural pro-
duct data were carried out (Figure 1).27 While inevitable
deviation was encountered about the C1 thioester and
C10ꢀC11 vinyl iodide termini, a convincing level of
homology was observed for all other NMR resonances in
Figure 1. NMR comparison of the madeirolide A-ring glycoside
3 with madeirolide A (1).
1
the C3ꢀC8/C10ꢀC60 region, with H resonances within
(0.06 ppm, and all 13C resonances within (1.8 ppm of
their natural product counterparts. Good correlation was
also observed for 3JH,H couplings and key NOE enhance-
ments between the sugar residue and the A-ring tetrahy-
dropyran, indicative of the proposed stereochemistry.
In summary, we have synthesized the C1ꢀC11 western
fragment 3 of madeirolide A in 11% yield over the longest
linear sequence of 17 steps from (S)-Roche ester derivative
11. Importantly, the two termini of 3 are appropriately
functionalized for a convergent union with the proposed
eastern fragment 4 in order to complete the macrocycle.
Work toward this end will be reported in due course.
(18) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
(19) Bases surveyed included t-BuOK, NaH, K2CO3, DBU, and
BnMe3NOMe.
(20) Pellicena, M.; Kramer, K.; Romea, P.; Urpi, F. Org. Lett. 2011,
13, 5350.
Acknowledgment. We thank the Cambridge Common-
wealth Trust and the Tertiary Education Commission of
New Zealand (scholarships to G.W.H.), Dr. Amy Wright
and Dr. Priscilla Winder (Harbor Branch Oceano-
graphic Institute) for helpful discussions, Dr. Guy Naylor
(University of Cambridge) for madeirolide A DP4 calcula-
tions, and the EPSRC National Mass Spectrometry Ser-
vice (Swansea) for mass spectra.
(21) (a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183. (b) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
(22) DeMico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
(23) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(24) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1996, 118, 2521. (b) Haack, K. J.; Hashiguchi, S.;
Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 285. (c)
Borisova, S. A.; Guppi, S. R.; Kim, H. K.; Wu, B.; Penn, J. H.; Liu,
H. W.; O’Doherty, G. A. Org. Lett. 2010, 12, 5150. (d) The enantiomeric
purity of 10 was determined by chiral HPLC. See the Supporting
Information for details.
(25) (a) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165.
(b) Nunes, J. P. M.; Veiros, L.; Vaz, P. D.; Afonso, C. A. M.; Caddick, S.
Tetrahedron 2011, 67, 2779.
Supporting Information Available. DP4 computational
NMR analysis, experimental procedures, and spectro-
scopic data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(26) The low yield obtained was primarily due to a competitive reductive
deacetylation process, producing the corresponding tetrahydropyran.
(27) See the Supporting Information for details.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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