The stille reaction in the synthesis of carotenoid butenolides: Synthesis of S′-epi-pridinin

Article abstract of DOI:10.1021/ol0478281

(Chemical Equation Presented) A new strategy for carotenoid butenolides has been developed that is based in part in halogen-selective Stille cross-coupling of dihalogenated ylidenebutenolide segment 2 and highly functionalized alkenylstannanes.

Full text of DOI:10.1021/ol0478281

ORGANIC
LETTERS
2005
Vol. 7, No. 4
545-548
The Stille Reaction in the Synthesis of
Carotenoid Butenolides: Synthesis of
6′-epi-Peridinin
1
Bele´n Vaz,† Rosana Alvarez,† Reinhard Bruckner,‡ and Angel R. de Lera*,†
Departamento de Qu´ımica Orga´nica, UniVersidade de Vigo, 36200 Vigo, Spain, and
Institut fu¨r Organische Chemie und Biochemie der Albert-Ludwigs-UniVersita¨t,
Albertstr. 21, 79104 Freiburg, Germany
qolera@uVigo.es
Received October 21, 2004
ABSTRACT
A new strategy for carotenoid butenolides has been developed that is based in part in halogen-selective Stille cross-coupling of dihalogenated
ylidenebutenolide segment 2 and highly functionalized alkenylstannanes.
Metal-catalyzed cross-coupling reactions have revolutionized
retrosynthetic planning, making C-C single bond discon-
nections one of the methods of choice for the reliable control
of olefin geometries in conjugated dienes and short polyenes.1
The construction of the carotenoid skeleton has traditionally
been the battleground for testing the performance of polyene-
forming processes, due to the configurational instability and
chemical sensitivity of these natural products to a variety of
reaction conditions.2 Double bond-formation strategies, such
as the Wittig reaction or the Julia-Lythgoe olefination,
performed in consecutive or convergent fashion, have proven
efficient in the preparation of carotenoids, even at the
industrial scale. The alternative strategy, featuring generation
of single bonds connecting Csp2 atoms, is a more recent
development. Negishi described the Pd- and Zn-catalyzed
cross-coupling of alkenyl fragments to afford â,â-carotene
and other all-carbon (apo)carotenoids.3 Our group reported
the synthesis of â,â-carotene and (3R,3′R)-zeaxanthin by a
convergent two-directional Stille cross-coupling.4 The ap-
proach, however, also took advantage of the symmetry of
the carotenoids, and manipulation of these unstable polyenes
was minimized. As an extension of this work, and in order
to fully reveal the performance of the metal-catalyzed cross-
coupling processes in this field, we embarked on a program
aimed at the preparation of nonsymmetrical, highly func-
tionalized carotenoids.
Peridinin 1 is a carotenoid butenolide isolated from
planktonic algae dinoflagelates,5 which are deemed respon-
sible for “red tide” episodes. The sophisticated and highly
efficient light-harvesting device of dinoflagelates is as-
sembled from noncovalent arrangements of chlorophyll and
peridinin embebbed in a protein scaffold.6 Relative to
common C40-carotenoids, peridinin 1 is a C37-dicyclic nor-
carotenoid7 containing, in addition to the γ-alkylidene-
butenolide ring structure, an abnormal arrangement of methyl
† Universidade de Vigo.
‡ Institut fu¨r Organische Chemie und Biochemie der Albert-Ludwigs-
Universita¨t.
(1) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, 1998.
(3) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719.
(2) For recent monographs, see: (a) Britton, G., Liaaen-Jensen, S.,
Pfander, H., Eds. Carotenoids. Part 1A. Isolation and Analysis; Birkha¨us-
er: Basel, 1995. (b) Britton, G., Liaaen-Jensen, S., Pfander, H., Eds.
Carotenoids. Part 1B. Spectroscopy; Birkha¨user: Basel, 1995. (c) Britton,
G., Liaaen-Jensen, S., Pfander, H., Eds. Carotenoids. Part 2. Synthesis;
Birkha¨user: Basel, 1996.
(4) Vaz, B.; Alvarez, R.; de Lera, A. R. J. Org. Chem. 2002, 67, 5040.
(5) (a) Song, P. S.; Koka, P.; Prezelin, B. B.; Haxo, F. T. Biochemistry
1976, 15, 4422. (b) Frank, H. A.; Cogdell, R. J. In Carotenoids in Pho-
tosynthesis; Young, A., Britton, G., Eds.; Chapman & Hall: London, 1993.
(6) Hoffmann, E.; Wrench, P. M.; Sharples, F. P.; Hiller, R. G.; Welte,
W.; Diederichs, K. Science 1996, 272, 1788.
10.1021/ol0478281 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/22/2005

Scheme 1
The synthesis of the chiral cyclic end groups is shown in
Scheme 1. Previously described4 alkenyliodide 9 was con-
verted into allyl alcohol 10 by iodine-lithium exchange
(t-BuLi, THF, -78 °C) followed by trapping with para-
formaldehyde (71%). Excellent yield (98%) and enantiose-
lectivity (>98% ee, as shown by chiral HPLC of 6aR-13)
in the SAE15 of 10 were obtained only when stoichiometric
quantities of Ti(OiPr)4 and (-)-DET were employed
(CH2Cl2, -20 °C, 12 h) in order to reduce the deleterious
effects of extended reaction times (36 h) required in the
substoichiometric version. Swern oxidation16 of the epoxy
alcohol to give 1114 (91%) was followed by Colvin rearrange-
ment17 induced upon treatment with the anion of trimethyl-
silyldiazomethane affording alkynyl oxirane 12 in 92% yield.
Palladium-catalyzed hydrostannylation18 [PdCl2(PPh3)2,
Bu3SnH, THF, 25 °C, 10 min, 68%] was most effective on
deprotected alkyne 814 (TBAF, THF, 85%), affording enan-
tiopure alkenylstannane 3, which was purified by reversed-
phase chromatography. Likewise, opening of alkynyl oxirane
8 under the conditions of Chemla19 (48% HBr, CuBr,
NH4Br, Et2O, -10 °C, 2.5 h; or 57% HI, CuI, NH4I, Et2O,
Figure 1.
groups, five chiral centers and a chiral allene axis. Our
retrosynthetic analysis of peridinin is shown in Figure 1.
We envisioned the synthesis of 1 by convergent Stille
cross-coupling reactions8 of a central γ-alkylidenebutenolide
unit9 2,10 containing halogens of modulated reactivity,11 and
functionalized alkenylstannanes 3 and 4. The latter could,
in turn, be prepared by a modified-Julia reaction12 of â-stan-
nylacrolein and γ-allenyl allyl benzothiazolyl sulfone 5. We
anticipated that 5 would be formed by yet another Stille
cross-coupling of stannyl sulfone 6 and haloallene 7. Enan-
tiopure alkynyl oxirane 8, accessible by a Sharpless asym-
metric epoxidation (SAE) of an appropriate precursor, was
identified as the common ultimate building block to access
both 3 and 4. On implementation of this scheme, we found
either a nonstereoselective outcome or a complete inversion
of configuration of the chiral axis in the Stille cross-coupling
of 6 and 7. Despite this shortcoming, the synthetic approach
to 6′-epi-peridinin by position-selective and stereoselective
Stille coupling reactions of dihalogenated γ-alkylidene-
butenolide 2 complements the two previous syntheses of
natural peridinin 1 reported by Ito13 and Katsumura.14
(13) (a) Ito, M.; Hirata, Y.; Shibata, Y.; Tsukida, K. J. Chem. Soc., Perkin
Trans. 1 1990, 197. (b) Yamano, Y.; Ito, M. J. Chem. Soc., Perkin Trans.
1 1993, 1599. (c) Ito, M.; Yamano, Y.; Sumiya, S.; Wada, A. Pure Appl.
Chem. 1994, 66, 939. (d) Yamano, Y.; Tode, C.; Ito, M. J. Chem. Soc.,
Perkin Trans. 1 1995, 1895.
(14) Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S. Angew.
Chem. 2002, 114, 1065; Angew. Chem., Int. Ed. 2002, 41, 1023.
(15) Sharpless, K. B. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 389.
(16) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165. (b) Tidwell, T.
T. Org. React. 1990, 39, 297. (c) Omura, K.; Swern, D. Tetrahedron 1978,
34, 1651.
(7) For standard nomenclature and numbering of carotenoids, see: (a)
IUPAC Commission on Nomenclature of Organic Chemistry and the
IUPAC-IUB Commission on Biochemical Nomenclature. Pure Appl. Chem.
1975, 41, 407. (b) Weedon, B. C. L.; Moss, G. P. Structure and
Nomenclature, in ref 2a, Chapter 3, p 27.
(8) (a) Stille, J. K. Angew. Chem. 1986, 98, 504; Angew. Chem., Int.
Ed. Engl. 1986, 25, 508. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J.
Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: 1997; Vol.
50, Chapter 1.
(9) For a review, see: Bru¨ckner, R. Chem. Commun. 2001, 141.
(10) von der Ohe, F. Dissertation, Universita¨t Freiburg, 2001.
(11) Dinger, H. Dissertation, Universita¨t Freiburg, 2003.
(12) For a review, see: Blakemore, P. R. J. Chem. Soc., Perkin Trans.
1 2002, 2563.
(17) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973,
151.
(18) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet, J. J.
Org. Chem. 1997, 62, 7768. For a review, see: Smith, N. D.; Mancuso, J.;
Lautens, M. Chem. ReV. 2000, 100, 3257.
546
Org. Lett., Vol. 7, No. 4, 2005

-10 °C, 2.5 h) took place regio- and stereoselectively and
provided haloallene 13, the product of SN2′ displacement
exclusively (85% yield for 13a; 81% for 13b).
6 and bromoallene 4aR-7a, most efficiently (64%) under the
catalysis of PdCl2(PhCN)2 in THF/DMF in the presence of
Hu¨nig’s base at 40 °C. The structure of 4aS-5 was confirmed
by X-ray diffraction.20 The allene axis inversion was
interpreted as resulting from an anti-selective SN2′-displace-
ment of bromide by palladium followed by [1,3]-sigmatropic
shift of propargyl- to allenylpalladium25a,26c before trans-
metalation and progression through the catalytic cycle.27
Modified-Julia condensation12 of 4aS-5 and 3-(tributyl-
stannyl)acrolein 15 (NaHDMS, THF, -78 to +25 °C)
afforded a mixture of allenyl trienylstannanes 4aS-4 in a 3:1
ratio and 70% yield. Separation allowed the characterization
of the major isomer as 5′Z-4,28 as shown by analysis of proton
coupling constants and NOE difference experiments. The
minor isomer, presumably all-E-4, could not be characterized
due to extensive degradation.
Efficient acetylation of haloallene 13 required treatment
with acetic anhydride and pyridine at room temperature in
order to minimize epimerization of the chiral axis. Allene
4aR-7a was acquired in 85% yield admixed with the 4aS
diastereomer (>20:1) whereas the yield of 4aR-7b was 91%
(11:1 ratio). The diastereomers were separated and the
structure of 4aR-7a was secured by X-ray diffraction.20
On the other hand, stannylcupration of but-2-yn-1-ol21
provided alkenylstannane 14 (Scheme 2). This compound
Scheme 2
Preparation of the central dihalogenated C8-unit was based
on the vinylogous Mukaiyama condensation of 3-bromo-2-
trimethylsiloxyfuran 1710 and 3-iodo-methacrolein 1829 at
-90 °C under catalysis of BF3‚OEt2,30,10 which provided in
86% yield a mixture of the syn and anti aldol diastereomers
1910 in a 10:1 ratio, as confirmed by X-ray analysis of the
major component (Scheme 3).20 The major product l-19
Scheme 3
was transformed into benzothiazolyl allyl sulfone 6 using
the Mitsunobu variant (BTSH, PPh3, DIAD, THF, 0 to 25
°C, 98%)22 followed by oxidation23 of the sulfide with a
peroxymolybdate(VI) reagent24 [(NH4)6Mo7O24‚4H2O, 35%
H2O2, EtOH, 25 °C, 56%].
(78%) was converted through â-elimination with excess
PPh3/DEAD30,10 into the desired halogen-differentiated alkyli-
denebutenolide 2, a separable 7:1 mixture of Z/E isomers
(65%).
No precedents on the Stille cross-coupling reaction of
chiral enantiopure haloallenes25 with alkenylstannanes existed
prior to this work. The stereochemical outcome of the related
palladium-catalyzed cross-coupling reactions of enantiopure
halogenated allenes with organozinc reagents was reported
by Vermeer26 to be halogen-dependent (Br: inversion; I: re-
tention). Despite extensive experimentation, varying the pal-
ladium catalysts [Pd2(dba)3/AsPh3, PdCl2(PhCN)2, Pd2(dba)3/
PtBu3, Pd2(dba)3/2-(di-tert-butylphosphino)biphenyl], solvent
(DMF/THF, NMP, dioxane), temperature (25-80 °C), and
additives (amine base) we were unable to induce direct cross-
coupling selectively by oxidative addition of Pd(0) to the
haloallenes 4aR-7. In the most favorable case, inseparable
allenyl allyl sulfones 4aS-5 and its epimer 4aR-5 were ob-
tained in a 2:1 ratio when the iodoallene 4aR-7b and stannane
6 were treated with Pd2(dba)3 and the bulky 2-(di-tert-butyl-
phosphino)biphenyl at 25 °C. Sulfone 4aS-5 was, however,
obtained as a single product in most coupling trials involving
(19) Bernard, N.; Chemla, F.; Normant, J. F. Tetrahedron Lett. 1998,
39, 8837.
(20) X-ray data for 4aR-7a, 4aS-5, and l-19: Supporting Information.
(21) Lipshutz, B. H.; Kozlowski, J. A.; Wilhelm, R. S. J. Org. Chem.
1984, 49, 3943.
(22) Blakemore, P. R.; Cole, W. J.; Kocienski, P.; Morley, A. Synlett
1998, 26.
(23) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175. (b) Bellingham, R.; Jarowicki, K.; Kocienski, P. J.;
Martin, V. Synthesis 1996, 285. (c) Blakemore, P. R.; Kocienski, P. J.;
Marzcak, S.; Wicha, J. Synthesis 1999, 1209. (d) Blakemore, P. R.;
Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans. 1 1999,
955. (e) Drew, M. G. B.; Harwood: L. M.; Jahaus, A.; Robertson, J.;
Swallow, S. Synlett 1999, 185.
(24) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140.
(25) For reviews on the palladium-catalyzed reactions of allenes, see:
(a) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. ReV.
2000, 100, 3067. (b) Ma, S. Eur. J. Org. Chem. 2004, 1175.
Org. Lett., Vol. 7, No. 4, 2005
547

With all fragments at hand, the stage was now set for the
crucial Stille cross-coupling reactions. 2-Bromo-γ-alkyli-
denebutenolides have been coupled to simple alkenyl stan-
nanes using the catalytic combination of Pd2(dba)3‚CHCl3
and AsPh3.31 Stannane 4aS,5′Z -4 proved to be less reactive,
and required stirring with Z-2 at ambient temperature for 18
h under the described conditions in order to reach completion
(Scheme 4). The extended reaction times proved however
retention of configuration in the coupling partners. The struc-
ture of the highly unstable minor isomer was assumed to be
E-20, a first indication of the sensitivity of the polyene
geometry to the action of palladium catalysis. For completion
of the synthesis, coupling of Z-20 and the reluctant alkenyl-
stannane 3 required heating to 55 °C for 31 h under the same
reaction conditions optimized above [Pd2(dba)3‚CHCl3, As-
-
Ph3, Bu4N+ Ph2PO2 , BHT, THF]. After chromatography, a
single product was obtained in 72% yield. Its structure was
assigned as 6′-epi-peridinin (6′-epi-1) by rigorous analysis
of coupling constants and 2D-HMQC-TOCSY experiments
(750 MHz). In addition to the stereoselective coupling
reaction, palladium also induced isomerization33 of the 11′Z-
olefin (peridinin numbering) to the most stable E isomer,
6′-epi-1. This compound has been previously obtained by
iodine-assisted photoisomerization of natural peridinin after
tedious separation of up to eight stereoisomers.34
Scheme 4
In summary, the epimer at the allene chiral axis of the
carotenoid butenolide peridinin has been synthesized using
a convergent approach featuring stereoselective Stille reac-
tions. The modified Julia coupling affords a Z-configured
allenyl trienylstannane, but it is fortunate that this isomer is
stable to proceed toward the final polyene, being isomerized
in the last Stille coupling of the sequence, presumably by
the action of palladium. Although the chiral axis of natural
peridinin is easily obtained by DIBAL reduction of alkynyl
oxiranes,13,14 our efforts are instead directed toward develop-
ing reaction conditions ensuring retention of configuration
in the Stille coupling of haloallenes in order to have access
to configurationally distinct building blocks and further
extend the palladium-catalyzed cross-coupling strategy to the
preparation of a large set of analogues for studies of artificial
supramolecular photosynthetic devices.
Acknowledgment. We thank the European Commission
(QLK3-2002-02029 “Anticancer Retinoids”), the Spanish
Ministerio de Ciencia y Tecnolog´ıa (Grant SAF01-3288,
Ramo´n y Cajal Research Contract to R.A. and FPU fellow-
ship to B. V.) and Xunta de Galicia (Grant PGIDIT02PXIC-
30108PN) for financial support. We also thank Dr. Mich-
elangelo Scalone (F. Hoffman-La Roche, Basel) for a gener-
ous gift of enantiopure actinol and Hansjo¨rg Dinger (Uni-
versita¨t Freiburg) for a start-up donation of compound 2.
This paper is dedicated to the memory of Mr. Silvino Penido.
detrimental to the stereochemical integrity of the polyenes.
Fortunately, the beneficial effect of tetrabutylammonium
phosphinate32 Bu4N+ Ph2PO2- allowed reduction of the reac-
tion time to 5.5 h. The optimized 82% yield of polyene 20
(5:1 isomer ratio) was obtained when BHT was added, and
the mixture was carefully deoxygenated. The major product
was shown to be Z-20 through analysis of the 1H NMR coup-
ling constants and NOE difference experiments, confirming
(26) (a) Ruitenberg, K.; Kleijn, H.; Elsevier, C. J.; Meijer, J.; Vermeer,
P. Tetrahedron Lett. 1981, 22, 1451. (b) Elsevier, C. J.; Mooiweer, H. H.;
Kleijn, H.; Vermeer, P. Tetrahedron Lett. 1984, 25, 5571. (c) Elsevier, C.
J.; Vermeer, P. J. Org. Chem. 1985, 50, 3042.
(27) For Stille coupling of allenylstannanes, see: Huang, C.-W.; Shan-
mugasundaram, M.; Chang, H.-M.; Cheng, C.-H. Tetrahedron 2003, 59,
3635.
(28) The stereochemical outcome (Z > E) of the modified-Julia reaction
involving BT-allyl sulfones is general in the construction of polyenes, as
we confirmed in other model systems as well as in the construction of the
entire peridinin skeleton using this reaction as last step. We revisited our
assignment of the geometry of a pentaenylbis-stannane (ref 4) and found it
to be in error (should be corrected to Z) (Vaz, B.; AÄ lvarez, R.; Souto, J. A.;
de Lera, A. R. Synlett 2005, in press). Since the final carotenoids have
all-E geometry, we surmised that isomerization had taken place in the final
double Stille reaction by the action of palladium catalyst, most likely acting
on the carotenoid skeleton.
(29) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47.
(30) For analogous sequences of vinylogous Mukaiyama aldol additions
followed by anti-selective dehydrations, see: (a) von der Ohe, F.; Bru¨ckner,
R. Tetrahedrom Lett. 1998, 39, 1909. (b) von der Ohe, F.; Bru¨ckner, R.
New J. Chem. 2000, 659.
Supporting Information Available: Typical experimen-
tal procedures for the synthesis of all compounds, and their
physical and spectroscopic data, as well as X-ray structural
data of compounds 4aR-7, 4aS-5, and lk-19 (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0478281
(31) (a) Go¨rth, F.; Bru¨ckner, R. Synthesis 1999, 1520. (b) Sorg, A.; Siegel,
K.; Bru¨ckner, R. Synlett 2004, 321.
(32) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997,
119, 12376.
(33) Alvarez, R.; Iglesias, B.; Lo´pez, S.; de Lera, A. R. Tetrahedron
Lett. 1998, 39, 5659.
(34) (a) Havgan, J. A.; Englert, G.; Aakermann, T.; Glinz, E.; Liaaen-
Jensen, S. Acta Chim. Scand. 1994, 48, 769. (b) Yamano, Y.; Sumiya, S.;
Suzuki, K.; Kurimoto, Y.; Koyama, Y.; Shimamura, T.; Ito, M. Tetrahedron
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548
Org. Lett., Vol. 7, No. 4, 2005