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Scheme 4 Reagents and conditions: (a) (i) n-Bu3SnH, n-BuLi, CuCN, MeOH, THF,
ꢀ78 1C, 30 min. (ii) p-TsOH, acetone–H2O, 80 1C, 45 min, 82%. (b) n-BuLi, THF,
25 1C, 3 h, 70%. (c) DIBAL-H, THF, –78 1C, 30 min, 99%. (d) Mn2O, Na2CO3, CH2Cl2,
2.5 h, 86%. (e) Pd(PPh3)4, CuTC, [Ph2PO2][NBu4], DMF, cat. BHT, 25 1C, 30 min, 78%.
16 J. Burghart and R. Bru¨ckner, Angew. Chem., Int. Ed., 2008, 47,
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31 was prepared by following the literature procedure44 starting from
3,3-diethoxyprop-1-yne 26. Stereoselective stannylcupration of alkyne
26 and deprotection afforded b-tributylstannylacrolein 27 in good
yield (82% for the two steps). The subsequent Horner–Wadsworth–
Emmons reaction of 27 and ethyl 2-(diethoxyphosphoryl)-propanoate
28 led stereoselectively to ester 29, which was reduced with DIBAL-H
to 30 and the alcohol oxidized to 31.45 Stannyldienal 31 smoothly
coupled with 10 under Fu¨rstner’s conditions to afford the desired
4,40-diapo-c,c-carotene-4,40-dial 4 (Scheme 4).
The advent of palladium-catalyzed cross-coupling to the polyene
field has substantially expanded the repertoire of tactics available to
synthetic chemists. The synthesis of representative C2-symmetric
C30 (4,40-diapo-c,c-carotene-4,40-dial 4) and C40 (b,b-carotene 1,
lycopene 2 and synechoxanthin 3) carotenoids using central C18
diiodoheptaene 10 as the linchpin to connect functionalized
termini is a novel construction tactic for these natural products,
namely C40 = C11 + C18 + C11 according to the carotenoid synthetic
terminology.8 This modular and stereoconvergent approach solves
one of the limitations of the alternative late-stage metathesis/
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26 N. Fontan, M. Domınguez, R. Alvarez and A. R. de Lera, Eur. J. Org.
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27 N. Fontan, R. Alvarez and A. R. de Lera, J. Nat. Prod., 2012, 75,
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dimerization of C21 hexaenes to C40 carotenoids (C40 = C21
+
C21 ꢀ C2), in which by-products corresponding to cleavage at the
C9QC10, C11QC12 and C13QC14 bonds were also obtained, albeit
in low yields.26 This approach also allows completion of the
carotenoid skeleton using shorter unsaturated termini, thus mini-
mizing the instability of more conjugated intermediates required in
other synthetic tactics. The rapid access to carotenoids enabled by
the C18 diiodoheptaene 10 (the longest diiodinated polyene pre-
pared to date) is highlighted by a second,28 highly stereoselective
synthesis of synechoxanthin 3, and the first total synthesis of the
purported structure of 4,40-diapo-c,c-carotene-4,40-dial 4.
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39 S. Kajigaeshi, T. Kakinami, T. Okamoto, H. Nakamura and
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Notes and references
1 Carotenoids Handbook, ed. G. Britton, S. Liaaen-Jensen and 40 The two electrophilic groups of compound 18 could not be discri-
¨
H. Pfander, Birkhauser, Basel, 2004.
minated by trimethylsilylacetylene 21 using classical Sonogashira
reaction conditions [Pd(dppf)Cl2, CuI, (i-Pr)2NH, DMF] (see ESI‡).
41 J. A. Marshall, M. A. Wolf and E. M. Wallace, J. Org. Chem., 1997, 62,
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2 Carotenoids. Part 1A. Isolation and Analysis, ed. G. Britton, S. Liaaen-
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3 A. V. Rao and L. G. Rao, Pharmacol. Res., 2007, 55, 207–216.
¨
4 J. T. Laudrum, Carotenoids: Physical, Chemical and Biological Func- 42 H. Kleinig, R. Schmitt, W. Meister, G. Englert and H. Thommen,
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5 Carotenoids. Part 1B. Spectroscopy, ed. G. Britton, S. Liaaen-Jensen 43 H. Kleinig and R. Schmitt, Z. Naturforsch., C, 1982, 37, 758–760.
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and H. Pfander, Birkhauser, Basel, 1995.
44 D. A. Evans, J. R. Gage and J. L. Leighton, J. Am. Chem. Soc., 1992,
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6 G. P. Lobo, J. Amengual, G. Palczewski, D. Babino and J. von Lintig,
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7 E. H. Harrison, Biochim. Biophys. Acta, Mol. Cell Biol. Lipids, 2012,
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45 The Stille reaction between 30 and diodoheptaene 10 using Farina
conditions modified for the synthesis of other polyenes (Pd2dba3ꢁ
¨
CHCl3, AsPh3) ((a) F. C. Gorth and R. Bru¨ckner, Synthesis, 1999,
8 Carotenoids. Part 2. Synthesis, ed. G. Britton, S. Liaaen-Jensen and
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321–325) led to homodimerization to the tetraenediol.
¨
H. Pfander, Birkhauser, Basel, 1996.
c
2696 Chem. Commun., 2013, 49, 2694--2696
This journal is The Royal Society of Chemistry 2013