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L. Tomas et al.
LETTER
O
OH OH
t-BuOK (0.6 equiv),
toluene–t-BuOH (3:2)
OH
O
EtO
O
OEt
0 °C for 5 min
70%
9
10
2.3:1
(2,6-trans:2,6-syn)
Scheme 6 Michael addition under kinetic control
1. (COCl)2, DMSO, Et3N, –78 °C to r.t.
OH
O
O
O
2. AllylBr, Zn, THF–NH4Cl (aq)
3. (COCl)2, DMSO, Et3N, –78 °C to r.t.
O
10
OEt
OEt
O
11
90% over 3 steps
Scheme 7 Completion of the synthesis of the C1–C13 fragment
(4) Griffiths, G.; Garrone, B.; Deacon, E.; Owen, P.; Pongracz,
J.; Mead, G.; Bradwell, A.; Watters, D.; Lord, J. Biochem.
Biophys. Res. Commun. 1996, 222, 802.
(5) Statsuk, A. V.; Bai, R.; Baryza, J. L.; Verma, V. A.; Hamel,
E.; Wender, P. A.; Kozmin, S. A. Nat. Chem. Biol. 2005, 1,
383.
(6) (a) Statsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc.
2004, 126, 9546. (b) Crimmins, M. T.; DeBaillie, A. C.
J. Am. Chem. Soc. 2006, 128, 4936. (c) Lowe, J. T.; Wrona,
I. E.; Panek, J. S. Org. Lett. 2007, 9, 327. (d) Yadav, J. S.;
Chetia, L. Org. Lett. 2007, 9, 4587. (e) Wipf, P.; Uto, Y.;
Yoshimura, S. Chem. Eur. J. 2002, 8, 1670.
(7) Bates, R. W.; Palani, K. Tetrahedron Lett. 2008, 49, 2832.
(8) Hiebel, M. A.; Pelotier, B.; Piva, O. Tetrahedron Lett. 2010,
51, 5091.
The achievement of the C1–C13 fragment of bistramide A
was accomplished by the Swern oxidation of the primary
alcohol to afford the corresponding aldehyde which is
submitted to an allylation reaction with zinc powder.8 Fi-
nally, a Swern oxidation of the allylic alcohol furnished
the a,b-unsaturated ketone after in situ isomerisation of
the double bond in basic media.14 Thus, the C1–C13 frag-
ment of bistramide A is obtained in 90% over the last three
steps (Scheme 7).
In conclusion, an efficient and robust synthesis of the C1–
C13 fragment of bistramide A has been developed in 14
steps and 13% overall yield from the inexpensive chiral
starting materials (S)-1,2,4-butanetriol and Roche ester.
The key step of this synthesis is an oxa-Michael cycliza-
tion under kinetic conditions to provide the 2,6-trans-
tetrahydropyran ring. During this step, we also isolated a
dimeric macrolide related to two families of natural prod-
ucts: clavosolides and cyanolides.
(9) 1H NMR (300 MHz, CDCl3): d = 0.82 (d, J = 6.9 Hz, 3 H),
1.32 (m, 2 H), 1.62 (m, 4 H), 2.00 (m, 1 H), 2.20 (dd, J = 2.9,
14.5 Hz, 1 H), 2.87 (dd, J = 12.7, 14.5 Hz, 1 H), 3.78 (m, 1
H), 3.96 (m, 1 H), 4.33 (m, 1 H) ppm. ESI-MS: m/z = 391.2
[M + Na]+. CCDC 843221 contains the supplementary
crystallographic data for this structure. These data can be
obtained free of charge from The Cambridge Crystallog-
cif.
Supporting Information for this article is available online at
(10) Erickson, K. L.; Gustafson, K. R.; Pannell, L. K.; Beutler,
J. A.; Boyd, M. J. Nat. Prod. 2002, 65, 1303.
(11) Pereira, A. R.; McCue, C. F.; Gerwick, W. H. J. Nat. Prod.
2010, 73, 217.
Acknowledgment
(12) Strand, D.; Norrby, P.; Rein, T. J. Org. Chem. 2006, 71,
1879.
The authors thank the European Commission (contract N° LSHB-
CT-2004-503467) for financial support. The Ministère de l’Enseig-
nement Supérieur et de la Recherche is acknowledged for a research
fellowship (L.T.). We also thank the CCSM for mass measure-
ments.
(13) 1H NMR (400 MHz, CDCl3): d = 0.82 (d, J = 7.0 Hz, 3 H),
1.28 (t, J = 7.2 Hz, 3 H), 1.32–1.39 (m, 1 H), 1.53–1.69 (m,
6 H), 1.93–2.06 (m, 1 H), 2.33 (dd, J = 4.1, 13.5 Hz, 1 H),
2.80 (dd, J = 11.8, 13.5 Hz, 1 H), 2.94–3.01 (m, 1 H), 3.55–
3.66 (m, 1 H), 3.68–3.75 (m, 1 H), 3.81–3.91 (m, 1 H), 4.16
(q, J = 7.1 Hz, 2 H), 4.28 (dt, J = 4.9, 4.9, 11.8 Hz, 1 H). 13
NMR (100 MHz, CDCl3): d = 172.9 (C), 74.7 (CH), 68.0
C
References and Notes
(CH), 61.1 (CH2), 60.2 (CH2), 38.3 (CH2), 33.1 (CH), 32.6
(CH2), 31.8 (CH2), 26.8 (CH2), 17.4 (CH3), 14.2 (CH3). ESI-
MS: m/z = 253 [M + Na]+. ESI-HRMS: m/z calcd for
C12H22O4Na [M + Na]+: 253.1410; found: 253.1412.
(1) Gouiffès, D.; Moreau, S.; Helbecque, N.; Bernier, J. L.;
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D. J.; Kitching, W. Tetrahedron Lett. 2002, 43, 531.
(3) Pusset, J.; Maillere, B.; Debitus, C. J. Nat. Toxins 1996, 5, 1.
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