Total synthesis of (8R,6′R)-peridinin-5,8-furanoxide

Article abstract of DOI:10.1039/c3cc41552j

The first total synthesis of (8R,6′R)-peridinin-5,8-furanoxide, a C₃₇ xanthophyll norcarotenoid, has been achieved. The key steps of the synthetic sequence are a Julia-Kocienski condensation and a late stage stereoretentive Stille cross-coupling of an iodoallene. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41552j

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Total synthesis of (8R,60R)-peridinin-5,8-furanoxide†
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Leticia Otero, Belen Vaz, Rosana Alvarez* and Angel R. de Lera*
Cite this: DOI: 10.1039/c3cc41552j
Received 28th February 2013,
Accepted 11th April 2013
DOI: 10.1039/c3cc41552j
www.rsc.org/chemcomm
The first total synthesis of (8R,60R)-peridinin-5,8-furanoxide, a C37 symbiont of the host soft coral Clavularia viridis, a rich source
xanthophyll norcarotenoid, has been achieved. The key steps of of prostaglandins.4
the synthetic sequence are a Julia–Kocienski condensation and a
late stage stereoretentive Stille cross-coupling of an iodoallene.
Although the treatment of peridinin with acid generates a
mixture of 5,8-furanoxide derivatives by rearrangement of the
butadiene oxide subunit,5 carefully controlled experiments carried
Among the diverse functions of carotenoids in Nature, their out by subjecting peridinin to the isolation conditions and
role in photosynthesis as light-harvesting antennae and in purification protocols did not reveal the presence of these deriva-
photoprotection by deactivating 1O2* and 3Chl* and reducing the tives. Therefore, the peridinin-5,8-furanoxides appear to be true
formation of reactive oxygen species (ROS) by non-photochemical natural products and not artifacts.4 A few other C40 carotenoid
fluorescence quenching (NPQ) mechanisms is the most important furanoxides are known.6 As a continuation of our studies on the
for the producing organisms.1,2
total synthesis of carotenoids,7 we targeted the peridinin-5,8-furan-
The xanthophyll peridinin 1 (ref. 3) (Fig. 1) is one of the oxides. We were prompted not only by the synthetic challenges
most abundant photosynthetic pigments in microalgae. Two inherent in their structures (non-symmetric C37 norcarotenoids
norcarotenoids (C37) related to 1, identified as the diastereo- with five stereogenic centers, one stereogenic axis and a butenolide
isomers at C8 of peridinin-5,8-furanoxide 2, have been isolated as part of the conjugated polyene chain) but also because of the
from a dinoflagellate of the genus Symbiodinium, which is a potent growth-inhibitory activity of unprecedented profiles that
these compounds exhibited against a panel of human cancer cells.4
In a departure from our approach to peridinin 1,7d we
dissected compound 2 into three fragments (Scheme 1). The
bis-functionalized C6 central component 4 featuring a terminal
stannane and an allyl-benzothiazolyl (BT)-sulfone was traced
back to but-2-yn-1-ol 7. Connective Stille and Julia–Kocienski
reactions involving 4 were conceived to attach the cyclic end
group partners of complementary reactivity, namely 5 (a C11
fragment) and 3 (a C20 fragment), which are functionalized with
allenyliodide and aldehyde groups, respectively.
We considered it to be feasible that 2,5-dihydrofuran 3 could
be obtained from the acid-catalyzed rearrangement of epoxide
6, which is precedented for carotenoids.5,8 Compound 6 would
be obtained by the Stille cross-coupling of alkenylstannane 10
and 2-bromoalkylidenebutenolide 9. The construction of the
alkylidenebutyrolactone 9 would be based on the metal-mediated
Fig. 1 Allene-containing xanthophylls.
cyclization of the dienynoic acid obtained by Sonogashira
coupling of ethyl (E)-dibromoacrylate 12 and protected enynol
11 followed by saponification. Iodoallene 5, derived from
(ꢀ)-actinol 8, was proposed as the electrophilic component
for the Stille coupling with stannanes in a reaction that would
proceed with retention of configuration, as confirmed in previous
studies with model systems.9,10
Department of Organic Chemistry As Lagoas-Marcosende, Universidade de Vigo,
36315 Vigo, Spain. E-mail: rar@uvigo.es, qolera@uvigo.es;
Web: http://webs.uvigo.es/delera/index.html; Fax: +34 986 818622
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc41552j
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Scheme 3 Reagents and conditions: (a) CuTC (1.5 equiv.), [NBu4][Ph2PO2]
(1.25 equiv.), Pd(PPh3)4 (0.1 equiv.), DMF, 0 1C, 3.5 h, 84% (16, 4.5%). (b) TFA
(0.35 equiv.), CH2Cl2, 0 to 25 1C, 5 h, 46%. (c) HF–Py, THF, Py, 25 1C, 52%, 20 h.
(d) 30% H2SO4, CH3CN, ꢀ10 1C, 15 h, 41%. (e) MnO2, Na2CO3, CH2Cl2, 0 1C,
1 h, 88%.
the rearrangement and deprotection could be effected conco-
mitantly upon treatment of 6 with 30% H2SO4 in CH3CN (41%
yield), which provided (8R)-18 admixed with minor amounts of
diastereomers (8S)-18 and (13Z,8R)-18 in a 91 : 3: 6 ratio. Oxida-
tion of (8R)-18 with MnO2 and Na2CO3 in CH2Cl2 at 0 1C
furnished aldehyde 3 in 88% yield (Scheme 3).
The synthesis of the C6 central fragment started with the
stannylcupration/protonolysis of but-2-yn-1-ol 7,17 which was
followed by oxidation of 19 and HWE condensation of 20 with
triethyl phosphonoacetate.18 Ester 21, obtained in 94% yield,
Scheme 1 Retrosynthetic analysis.
Treatment of ethyl propiolate 13 with pyridinium tribromide was quantitatively reduced with DIBAL-H to stannyldienol 22,
in CH2Cl2 at ambient temperature11 produced dibromide 12 in and this alcohol was employed in the Mitsunobu reaction with
75% yield. Sonogashira coupling of 12 with the TBDPS-protected benzothiazolylthiol to produce sulfide 23. Oxidation of 23 with
enynol 11 using PdCl2(PPh3)2 and CuI in THF–Et3N (4: 1) at 25 1C H2O2 and (NH4)6Mo7O24ꢁ4H2O at 0 1C19 furnished allyl-BT-sulfone
afforded dienyne 14 in 75% yield (together with small amounts 4 in 75% yield and 24 in 8% yield (Scheme 4).
of the homodimer and the bis-coupled derivative, ESI†). Under
As discovered during the synthesis of peridinin 1,7b,d the
the conditions reported by Negishi (20 mol% Ag2CO3 in DMF, Julia–Kocienski reaction was more conveniently performed in
25 1C)12 the silver carbonate-mediated cyclization of dienynoic advance of the Stille cross-coupling, since the Z selectivity of the
acid 15, obtained by mild saponification of ester 14 (LiOHꢁH2O, former condensation between unsaturated partners (aldehydes and
THF/H2O, 25 1C), provided 913 in 75% yield (Scheme 2).
BT-sulfones)20 could be ‘‘corrected’’ by the reaction conditions of
The Stille coupling of 9 and previously described stannane the Pd-catalyzed coupling.7d Julia–Kocienski condensation of 3 and
107d,14 under Fu¨rstner conditions15 at 0 1C led to 6 in 84% yield 4 afforded a 10 : 1 mixture of Z/E isomers at the newly formed
together with small amounts of destannylated product 16. The double bond in 74% yield (Scheme 5). The final Stille coupling
known rearrangement of butadiene oxide to 2,5-dihydrofuran of stannane 3 and iodoallene 5 under stereoretentive condi-
units of carotenoids5 was attempted next using 6. The rearrange- tions [Pd(PPh3)4, DMF, 40 1C]9 led, to our surprise, to a mixture
ment of 6 induced by TFA provided 2,5-dihydrofuran 17 with R of stereoisomers at the allene axis, as shown by the presence
configuration (H8 resonance at d = 5.60 ppm; cf. d = 5.50 ppm for of allene H signals for both epimers at d = 6.05 ppm (R) and
the S epimer in the 1H-NMR spectra; see ESI† for the comparison d = 6.16 ppm (S) in the 1H-NMR spectra. Our experimental and
of the 1H-NMR data of synthetic and natural compound 2) in 46%
yield. Deprotection of the silyl ether with the HF–Py complex in
THF16 delivered allylic alcohol 18 in 52% yield. More conveniently,
Scheme 4 Reagents and conditions: (a) n-BuLi, (Bu3Sn)2, CuCN, THF–MeOH,
ꢀ10 1C, 15 h, 99%. (b) MnO2, CH2Cl2, 25 1C, 3.5 h, 92%. (c) n-BuLi, THF, triethyl
Scheme 2 Reagents and conditions: (a) C5H5NH+Br3ꢀ, CH2Cl2, 25 1C, 15 h, 75%.
(b) PdCl2(PPh3)2, CuI, THF–Et3N (4 : 1), 25 1C, 4 h, 87%. (c) LiOHꢁH2O, THF–H2O,
25 1C, 6 h. (d) Ag2CO3, THF, 25 1C, 6 h, 75% two steps.
phosphonoacetate, 25 1C, 2 h, 94%. (d) DIBAL–H, THF, ꢀ78 1C, 1 h, 99%. (e) BTSH,
DIAD, THF, 0 1C, 0.5 h, 86%. (f) 35% H2O2, (NH4)6Mo7O24ꢁ4H2O, EtOH, 0 1C, 15 h,
75% (24, 8%).
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Notes and references
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7, 545; (c) B. Vaz, M. Domınguez, R. Alvarez and A. R. de Lera, J. Org.
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Scheme 5 Reagents and conditions: (a) NaHMDS, THF, ꢀ78 1C, 2 h, 74% (10 : 1
Z/E ratio). (b) (i) Pd(PPh3)4, DMF, 40 1C, 18 h. (ii) TBAF, THF, 0 1C, 1 h, 55%.
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A. R. de Lera, Chem.–Eur. J., 2007, 13, 1273; (e) N. Fontan,
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computational insight into this coupling9 suggested that the
inversion product arises from the SN20 substitution of I by Pd(0)
at the allene unit and metallotropy of the organopalladium
intermediate, and that this pathway should be prevented using
TMS-protected iodoallenol 26.9 In the event, the coupling of 25
and 26 under the same conditions followed by removal of the
silyl ether (TBAF, THF) led to (8R,60R)-2 in 55% yield.
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12 L. Anastasia, C. Xu and E.-i. Negishi, Tetrahedron Lett., 2002,
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In summary, we have achieved the first total synthesis of
the xanthophyll (8R,60R)-peridinin-5,8-furanoxide in a sequence
that entails the late stage stereoretentive Stille cross-coupling of
an allenyliodide9,10 and a stannane, which occurs with con-
comitant C15QC150 double bond isomerization. The required
stannane was prepared by Julia–Kocienski condensation of 3
and the central conjunctive reagent 4. The preparation of the
2,5-dihydrofuran ring was based on the acid-catalyzed rearran-
gement of the butadiene oxide functionality with the alkylidene
butyrolactone substructure in place. (8R,60R)-2 and (8S,60R)-2
are the only C37 norcarotenoid furanoxides of the two dozen
congeners reported to date.6 These C40 furanoxides have been
obtained (with the exception of the aurochrome diastereo-
mers)21 by partial synthesis from the corresponding putative
biogenetic precursor carotenoids with butadiene epoxide
structural units.
13 The corresponding alcohol has been reported: A. Sorg, F. Blank and
R. Bru
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M. Waser, J. Ackerstaff and C. C. Stimson, Chem. Commun., 2008,
2873–2875. For the use of CuTC in Stille coupling, see: G. D. Allred
and L. S. Liebeskind, J. Am. Chem. Soc., 1996, 118, 2748. For the use
of phosphinate as a tin scavenger, see: J. Srogl, G. D. Allred and
L. S. Liebeskind, J. Am. Chem. Soc., 1997, 119, 12376.
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J. Chem. Soc., Perkin Trans. 1, 2002, 2563(c) C. Aıssa, Eur. J. Org.
The authors are grateful to MINECO-Spain (SAF2010-17935-
FEDER; FPI Fellowship to L.O.), Xunta de Galicia (Grant
Chem., 2009, 1831.
20 (a) A. Sorg and R. Bru¨ckner, Synlett, 2005, 289; (b) B. Vaz, R. Alvarez,
J. A. Souto and A. R. de Lera, Synlett, 2005, 294. A similar stereo-
chemical trend was obtained by Katsumura in the total synthesis of
peridinin: (c) N. Furuichi, H. Hara, T. Osaki, H. Mori and
S. Katsumura, Angew. Chem., Int. Ed., 2002, 41, 1023;
(d) N. Furuichi, H. Hara, T. Osaki, M. Nakano, H. Mori and
S. Katsumura, J. Org. Chem., 2004, 69, 7949.
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08CSA052383PR; Consolidacion 2006/15; INBIOMED-FEDER
‘Unha maneira de facer Europa’; Parga Pondal Contract to
B.V.) for financial support. We thank Dr Thomas Netscher
(DSM Nutritional Products) for generous donation of (ꢀ)-actinol
for our carotenoid program.
21 M. Acemoglu and C. H. Eugster, Helv. Chim. Acta, 1984, 67, 471.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.