Total synthesis of naturally configured pyrrhoxanthin, a carotenoid butenolide from plankton

Article abstract of DOI:10.1002/anie.200801638

A carotenoid from the chemical kitchen: Two sequential Stille couplings of an unsymmetric distannane building block with a bromoolefin and a bromoalkyne terminated a highly convergent synthesis of the title compound, pyrrhoxanthin (see scheme).

Full text of DOI:10.1002/anie.200801638

Communications
DOI: 10.1002/anie.200801638
Carotenoids
Total Synthesis of Naturally Configured Pyrrhoxanthin, a Carotenoid
Butenolide from Plankton**
Jochen Burghart and Reinhard Brückner*
The structure[1] of the marine natural product pyrrhoxanthin
(5) is highly unusual for a carotenoid.[2] Firstly, it comprises 37
rather than 40 carbon atoms, and secondly it contains oxygen
substituents not only in the six-membered rings but as
constituents of an annulated butenolide. Pyrrhoxanthin has
been isolated from the chloroplasts of various dinoflagel-
lates[3] and usually accompanies the more abundantly encoun-
tered C37-butenolide carotenoid peridinin.[4] Because of its
low concentration in biological sources and its instability after
purification little is known about the properties of pyrrho-
xanthin. It is not known, for instance, whether pyrrhoxanthin
participates in photosynthesis in plankton as peridinin does.[5]
In a rigorous sense pyrrhoxanthin (5) has not yet been
synthesized in the laboratory (Scheme 1). This is somewhat
surprising because four total syntheses of peridinin have been
reported[6] and because the structural difference is very small:
In peridinin a stereochemically more complex allenol moiety
ꢀ
ꢀ
=
=
=
ꢀ
C5( OH) C6 C7 C8 replaces for the enyne moiety C5 C6
ꢁ
C7 C8 of pyrrhoxanthin. Nonetheless, we consider pyrrho-
xanthin to be a more demanding target molecule for total
synthesis than peridinin as observations made in the liter-
ature[1b,7] and by ourselves indicate that establishing and
=
ꢁ
conserving an E configuration of the C9 C10 bond in C7 C8-
containing precursors of pyrrhoxanthin (5) and in pyrrho-
xanthin itself present a significant challenge.
Completely synthetic pyrrhoxanthin (5; Scheme 1) has
been obtained only once previously—by Ito et al.: as a 25%
constituent of a 1:1 mixture of the racemic diastereomers 3
and 4 (Scheme 1).[8] The key and simultaneously terminating
step of their approach was initiated by the addition of lithio-
rac-1 to the aldehyde ester rac-2. However, after preparative
HPLC and preparative TLC, 3 and 4 were obtained in only
3.7% yield (not overall yield!). A much more efficient
synthetic strategy was used by de Lera et al.[7] They started
from the bromoiodobutenolide 8, which our group had
synthesized previously,[9] and utilized the possibility to[10]
functionalize it stepwise by Stille couplings following the
Scheme 1. Natural pyrrhoxanthin (5), unnatural pyrrhoxanthins (3, 4,
6), and successfully strategies for the total synthesis of the latter.[7,8]
order indicated by the labels ꢂ and ꢂ. Yet in the end, this
1
2
approach led to (9Z)-pyrrhoxanthin (6), which could not be
isomerized to give naturally configured pyrrhoxanthin (5).[11]
We now describe the first total synthesis of naturally
configured pyrrhoxanthin (5), which is based on the following
retrosynthetic analysis (Scheme 2, upper part):
[*] J. Burghart, Prof. Dr. R. Brückner
Institut für Organische Chemie and Biochemie
Universität Freiburg
1) Four building blocks (10, 12, 13, 14) are combined in the
last stages of this synthesis, which makes it highly
convergent.
2) The identity of these four building blocks followed in part
from our intention to construct pyrrhoxanthin (5) “from
right to left”. When this sense of assembly is followed, the
Albertstrasse 21, 79104 Freiburg (Germany)
Fax: (+49)761-203-6100
E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
Homepage: http://www.chemie.uni-freiburg.de/orgbio/brueck/
w3br/
=
E-configured C9 C10 bond is exposed only in the final
[**] We thank the Deutsche Forschungsgemeinschaft for financing this
project and Dr. Thomas Netscher (DSM Nutritional Products,
Basel) for donations of (ꢀ)-actinol.
ꢁ
product 5 to the presence of the C7 C8 bond, which we
deemed most prone to facilitate E!Z isomerization.
3) Two of our key building blocks possess a reactive moiety
“in duplicate”. The hitherto unknown heptatrienyldistan-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801638.
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I/SnBu3 exchange reaction competes or even predomi-
nated.[19]
The retrosynthetic disconnections of Scheme 2a trace
both the new six-membered ring 10 and the known six-
membered ring 12 back to (ꢀ)-actinol (11). The latter is an
established starting material for the synthesis of carotenoids
with an oxygenated six-membered ring.[2] We intended to
prepare the heptatrienyldistannane 13 via the sulfone 15 by a
Ramberg–Bäcklund reaction,[20] in the same manner that had
proved successful for obtaining the hexatrienyldistannane 18
via the sulfone 20.[21] The “dibromodiolefin” rac-14 was
conceived to result from
a
syn-selective vinylogous
Mukaiyama aldol addition[22] of siloxyfuran 17[23] to bromo-
methacrolein (16) in exactly the same way by which we had
transformed iodomethacrolein (21) into the “bromoiodo-
diolefin” rac-19 en route to the bromoiodobutenolide 8.[9]
The synthesis of the bromoalkyne 10 (Scheme 3) began
with steps from the literature: tert-butyldimethylsilylation[24]
of (ꢀ)-actinol (11), addition of lithio(trimethylsilyl)acet-
ylide,[24] and desilylation of the C C bond with potassium
ꢁ
methoxide.[24b,25] Thereafter we followed Schmidt-Leit-
hoffꢀs[25] permutation of reaction conditions, which had been
applied previously only to related molecules: dehydration of
the alkynol with CuSO4 in refuxing xylene[26] to give the enyne
and exchange of the TBSO protecting group for an AcO
group. Under AgNO3 catalysis[27] the terminally unfunction-
alized alkyne 22[26] and NBS provided the desired bromoal-
kyne 10 in 41% overall yield for the seven steps from 11. Our
Scheme 2. a) Retrosyntheticanalysis of pyrrhoxanthin ( 5). b) Analogies
from the literature concerning the projected generation of the bifunc-
tional building blocks 13 and rac-14 (bottom): retrosyntheses of
hexatrienyldistannane 18 from sulfone 20, and of “bromoiododiolefin”
rac-19 from siloxyfuran 17 and iodomethacrolein 21. TBS=tert-butyldi-
methylsilyl; TMS=trimethylsilyl.
Scheme 3. Syntheses of the six-membered-ring reagents 10 and 12.
a) TBSCl (1.07 equiv), NEt3 (1.1 equiv), DMAP (1.05 equiv), CH2Cl2,
ꢁ
08C, 17 h; 90% (Ref. [6f]: 97%); b) LiC CTMS (1.05 equiv), THF, 08C,
3 h; c ) KCO3 (1.5 equiv), MeOH, 258C (Ref. [25]: 100% over 2 steps);
2
d) CuSO4·4H2O, xylene, Dean–Stark trap, 50 h; 67% over 3 steps
(Ref. [25]: 93%); e) Bu4N+Fꢀ (3.0 equiv), THF, 258C, 12 h; 84%
(Ref. [25]: 86%); f) Ac2O (3 equiv), DMAP (0.1 equiv), pyridine, 258C;
88% (Ref. [25]: 89%); g) LDA (1.60 equiv), addition of the TBS ether
obtained in step (a), ꢀ788C, 1 h; addition of PhN(SO2CF3)2
= ꢀ
nane 13 contains two units with the structural motif C C
SnBu3, and the novel dibromobutenolide rac-14[12] has two
= ꢀ
C C Br groups. In each building block, one of the
reactive groups was intended to participate in a Stille
coupling[13] and the remaining reactive group was intended
for a different Stille coupling. The strategy for the linkage
of the building blocks, “from right to left” (vide supra),
was expected to fit the order of reactivity in heptatri-
enyldistannane 13, which is determined by sterics, and that
in the dibromobutenolide rac-14, which is governed by
electronics.[14]
(1.5 equiv), THF, 258C, 2 d; 84% (Ref. [8b]: 89%); h) Stream of CO,
MeOH (30 equiv), NEt3 (3 equiv), [Pd(PPh3)4] (3 mol%), DMF, 808C,
24 h; 92% (Ref. [6f]: 99%); i) DIBAH (2.5 equiv), CH2Cl2, ꢀ788C,
25 min; 84% (with LiAlH4:[6e] 87%); j) tBuOOH (2 equiv), d-(ꢀ)-DIPT
(2.3 equiv), Ti(OiPr)4 (1.5 equiv), MS (4 Š), CH2Cl2, ꢀ308C, 1.5 h;
95%, >98% de (Ref. [6f]: 95%, 98% de); k) Dess–Martin period-
inane, CH2Cl2, 258C, 2.5 h; 85% (Ref. [6f]: 92%); l) NBS (1.3 equiv),
= =
AgNO3 (10 mol%), acetone, 258C; 92%; m) Me3SiCH N N
(1.2 equiv), LDA (1.1 equiv), THF, ꢀ308C, 15 min; addition of the
aldehyde 23 (1.0 equiv) obtained in step (k), 1 h (Ref. [15]: 92%);
n) Bu3SnH (3 equiv), [Pd(PPh3)4] (5 mol%), BHT (5 mol%), THF, 08C,
90 min; 72% yield of the trans-alkenylstannane over 2 steps (Ref. [6f]:
53% over 2 steps); BHT=2,6-di-tert-butyl-4-methylphenol; DIBAH=
diisobutylaluminum hydride; d-(ꢀ)-DIPT=d-(ꢀ)-diisopropyl tartrate;
DMAP=4-(dimethylamino)pyridine; LDA=lithium diisopropylamide;
MS=molecular sieves; NBS=N-bromosuccinimide.
4) Whereas the “right-hand” six-membered-ring reagent 12
is known,[6f,g,7,15,17] bromoalkyne 10, which serves as the
“left-hand” six-membered-ring reagent, was prepared for
the first time in the course of the present study. This
bromoalkyne was required because in model reactions the
analogous iodoalkyne[18] underwent Stille coupling with
alkenyl(tributylstannanes) only to some extent, and an
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preparation of the trans-alkenylstannane 12 (Scheme 3) from
(ꢀ)-actinol (11) followed established procedures.[6d–f,8b,15]
Usually our yields were slightly below the published values.
However, the C1 homologation giving the alkyne (step m) by
Shioiriꢀs method and the Pd-catalyzed hydrostannylation of
this alkyne (step n) succeeded in 72% yield rather than in the
53% reported earlier.[6f] All in all, the stannane 12 was
available in 34% overall yield by this eight-step synthesis.
The synthesis of the heptatrienyldistannane 13 by a
Ramberg–Bäcklund reaction[20] of the sulfone 15 was realized
(Scheme 4) in accordance with our retrosynthetic analysis in
Scheme 2. In the first step, the tetrolic ester 24 and
[28]
(Bu3Sn)BuCu(CN)Li2
underwent the same kind of cis-
hydrostannylation[29] that had been described by Parrain et al.
for tetrolic acid.[30] Reduction of the resulting unsaturated
ester with DIBAH furnished an allylic alcohol in 99% yield.
Under Mitsunobu conditions this was converted into the
thioacetate 28 (85% yield). Next, propargyl alcohol (25) was
cis-hydrostannylated[31] using (Bu3Sn)BuCu(CN)Li2.[28] The
resulting (tributylstannyl)allyl alcohol (84% yield) was con-
verted into the known[32] allyl bromide 29 in 88% yield by
treatment with CBr4 and PPh3. Dissolving KOH pellets and
adding allyl bromide 29 to a solution of the thioacetate 28 in
methanol brought about a tandem reaction (“sequential
transformation”)[33] consisting of a transesterification and an
SN2 alkylation to delivered an unsymmetric sulfide in 87%
Scheme 4. Syntheses of the bifunctional building blocks 13 and 14.
a) CuCN (1.3 equiv), nBuLi (2.6 equiv), THF, ꢀ788C, !258C, !
ꢀ788C, HSnBu3 (2.6 equiv), MeOH (1.5 equiv), 24, 1 h; 82%
(Ref. [29]: 100%); b) DIBAH (2.3 equiv), CH2Cl2, ꢀ788C, 2 h; 99%
(Ref. [25]: 92%); c) DIAD (1.5 equiv), PPh3 (1.5 equiv), AcSH
(1.5 equiv), THF, 08C, 12 h; 85%; d) CuCN (1.2 equiv), nBuLi
(2.4 equiv), THF, ꢀ788C, for a short time !258C, ꢀ788C, HSnBu3
(2.4 equiv), ꢀ308C, 12 h; 84% (Ref. [31]: 66%); e) CBr4 (1.2 equiv),
PPh3 (1.2 equiv), CH2Cl2, 08C, 3.5 h; 88% (Ref. [21]: 82%); f) NBS
(1.0 equiv), AIBN (cat.), CCl4, 608C; 4.5 h; g) Br2 (1.2 equiv), CCl4,
408C, 6 h (Ref. [9]: 87% over 2 steps); h) H2O, 1008C, 2 h; 11% over
3 steps; i) 28 (1.05 equiv), KOH (5 equiv), MeOH, 08C, 5 min; 29, 1 h;
87%; j) H2O2 (5 equiv), (NH4)6Mo7O24 (0.2 equiv), EtOH, 08C, 1 h;
71%; k) LiAlH4 (1.0 equiv), Et2O, 08C, addition of 30, !258C, 3 h;
94% (Ref. [37]: 95–100%); l) MnO2 (20.0 equiv), CH2Cl2, 258C, 24 h;
83% (Ref. [38]: 92–94%); m) Me3SiCl (1.1 equiv), NEt3 (1.2 equiv),
Et2O, 08C, 12 h; 75% (Ref. [23b]: 44%; Ref. [23c]: 78%); n) CBr2F2
(4 equiv), KOH (10 equiv) on Al2O3 (1:2), CH2Cl2, 08C, 15 min, 258C,
30 min; 82% yield of a 95:5 mixture of 13 (78%; trans,trans,E/trans,-
cis,E=95:5) and 6-(tributylstannyl)hepta-1,3,5-triene (4%; trans,E/
trans,Z=67:33); o) 16 (1.1 equiv), BF3·OEt2 (1.1 equiv), CH2Cl2,
ꢀ788C, 5 h; over the 2 steps from 31: 52% diastereomerically pure
rac-14 [separated from an initial 95:5 syn/anti mixture; Ref. [12]: 72%
diastereomerically pure rac-14 (separated from an initial 90:10 syn/anti
mixture)]. AIBN=2,2’-azobis(isobutyronitrile); DIAD=diisopropyl azo-
dicarboxylate; DIBAH=diisobutylaluminum hydride; NBS=N-bromo-
succinimide.
yield. The latter was oxidized with H2O2 and cat.
[21]
(NH4)6Mo7O24
to give a 71% yield of the sulfone 15.
When we treated this compound with CBr2F2 and KOH on
Al2O3 in CH2Cl2—well-established conditions for Ramberg–
Bäcklund syntheses of many conjugated trienes[34]—the
heptatrienyldistannane 13 was formed as a 95:5 trans/cis
mixture (78% yield). In addition, an isomeric mixture of
heptatrienylmonostannanes was formed in 4% yield and
could not be separated by flash chromatography on silica
gel.[35] Most likely these monostannanes originated from the
distannane 13 by protonolysis of the sterically less hindered
ꢀ
C SnBu3 bond. The overall yield of the heptatrienyldistan-
nane 13 from the tetrolic ester 24 was 33%.
The “dibromodiolefin” rac-14 was prepared from bromo-
methacrylate 30[36] and crotonic acid (27) (Scheme 4). Ester
[37]
30 was reduced with LiAlH4
and the resulting alcohol
reoxidized with MnO2 to obtain enal 16.[38] A Wohl–Ziegler
bromination of crotonic acid (27) and the addition of bromine
=
to the C C bond yielded 1,2,3-tribromobutyric acid. This
compound lactonized in boiling water, whereupon a b elimi-
nation furnished the bromobutenolide 31. The trimethyl-
siloxyfuran 17 derived therefrom[23] and enal 16 were treated
with slightly more than 1.0 equiv of BF3·OEt2; as expected,[22]
a highly diastereoselective vinylogous Mukaiyama aldol
addition ensued. It gave a 95:5 syn/anti mixture of products
initially, from which we separated the major addition product
rac-14 by flash chromatography on silica gel[35] in 52% yield
(over two steps).
ring building block 12. Under the combined influence of
[Pd(PPh3)4] and CuI[39] the reactivity order of the termini of
compound rac-14 was exactly as desired: the observed
exclusive monocoupling of the right-hand moiety rendered
the coupling product 32, which was obtained as a 1:1 mixture
of the two syn diastereomers in 75% yield. The ensuing
dehydration delivering the alkylidene butenolide 33 had to be
=
anti selective for the resulting C C bond to be uniquely
Scheme 5 shows the final steps of our total synthesis of
naturally configured pyrrhoxanthin (5). One of the pre-
requisites of our overall linkage strategy “from right to left”
materialized in the inaugural step, which was a Stille coupling
between the “dibromodiolefin” rac-14 and the six-membered-
Z configured. This was possible by addition of thiocarbonyl-
diimidazole in analogy to the procedure described recently
for an analogous dehydration.[17] However, the reaction got
stuck after the initial O functionalization had occurred. In
contrast to the preceding case[17] the anti elimination followed
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was desilylated by treatment with hydrochloric acid without
isomerization to provide the bromobutenolide 34 in 94%
yield.
Attempted Stille couplings between the iodoalkyne
analogue[18] of bromoalkyne 10 and alkenyl(tributylstan-
nanes), which we had employed as models of the pyrrho-
xanthin precursor 35, had been unsuccessful.[19] As we had
observed that an I/SnBu3 exchange reaction occurs between
the iodoalkyne and the model stannanes, we prepared the
previously unknown bromoalkyne 10. The latter proved
capable of undergoing Stille couplings, particularly in the
presence of [Pd2(dba)3·CHCl3], the sterically undemanding
ligand P(2-furyl), and the Bu3Sn trap Bu4N+Ph2PO2
.
In
ꢀ
[40]
this manner we coupled the heptatrienyldistannane 13 with
the bromobutenolide 34 in the terminating step exclusively at
ꢀ
the sterically less hindered Csp2 SnBu3 terminus and obtained
the pyrrhoxanthin precursor 35 (Scheme 5). Owing to the
tremendous lability of this compound, we prepared it in
brown glass vessels, used O2-free, N2-saturated NMP as the
solvent, added 2,6-di-tert-butyl-4-methylphenol as a radical
scavenger, and subjected it to the final coupling with 3 equiv
of the bromoalkyne 10 without prior workup. This reaction
and the subsequent workup were conducted following the
same precautionary measures. Prepurification by flash chro-
matography on silica gel[35] delivered a mixture, which
consisted—according to analytical reversed-phase HPLC—
of pyrrhoxanthin (5) (80%) along with probably 13, 3, 3, and
1% of at least four isomers. Purification of this mixture by
preparative reversed-phase HPLC furnished isomerically
pure pyrrhoxanthin (5) in 38% yield.
The 1H NMR (499.7 MHz) spectrum of our synthetic
pyrrhoxanthin (5) in C6D6, its 13C NMR (125.7 MHz) spec-
trum, the H,H- and C,H-COSY spectra and the NOE cross-
peaks in the ROESY spectrum allowed us to assign all
1H NMR resonances and to determine the configuration of
[41]
=
=
each C C bond. Similarly, we determined all C C bond
configurations in the major side product of 5, the pyrrho-
xanthin isomer 11-cis-5, which was observed for the first time.
The success of this first stereoselective total synthesis of
enantiomerically pure pyrrhoxanthin (5) is due to its high
convergency and to the fact that the very isomerization-prone
Scheme 5. Total synthesis of pyrrhoxanthin (5). a) 12, rac-14
(1.16 equiv), [Pd(PPh3)4] (10 mol%), CuI (1.77 equiv), NMP, 508C,
12 h; 75%; b) Thiocarbonyldiimidazole (2 equiv), CH2Cl2, 08C, 1 h;
NEt3 (5 equiv), 5 min; 73% isomerically pure 33 (separated from a
91:9 Z/E mixture); c) aq. HCl (1m)/MeOH/THF (1:1:4), 08C, 1.5 h;
94%; d) 34, 13 (2.0 equiv), Bu4N+Ph2PO2ꢀ (4 equiv), [Pd2(dba3)·CHCl3]
(5 mol%), P(2-furyl)3 (0.25 equiv), BHT (250 ppm), exclusion of light,
NMP, 258C, 2 h; 10 (3 equiv), 558C, 3 h; flash chromatography gave 5
in a mixture with side products; preparative HPLC gave pure 5 in 38%
yield. BHT=2,6-di-tert-butyl-4-methylphenol; dba=trans,trans-dibenzyl-
idene acetone; NMP=N-methylpyrrolidone.
=
ꢁ
=
E-configured C C bond of the enyne moiety C7 C8-C9 C10
was established only in the very last step. Our synthetic
strategy traced the target molecule back to four building
blocks (10, 12, 13, and rac-14) designed to be combined by
Stille couplings. Being monofunctional coupling partners, the
six-membered-ring building blocks 10 and 12 served to
introduce the extremities of the target structure. In contrast,
the heptatrienyldistannane 13 and the dibromobutenolide
rac-14 are bifunctional Stille substrates, which were used as
linking reagents and coupled step by step with rigorous
regiocontrol. These building blocks contributed the center
part to the pyrrhoxanthin molecule.
Table footnotes: [a] Compound A is either 15-cis-pyrrhoxanthin or
11-cis,15-cis-pyrrhoxanthin; the side products B and C could not be
characterized because of their low yield and their lability, respectively.
[b] HPLC separation: LiChrospher column (4”250 mm, E. Merck), 100
RP-18-endcapped, 5 mm, CH3CN/H2O (80:20), eluent flow
1.0 mLminꢀ1, 258C. [c] Set equal to the relative areas of the absorption
peaks that the UV detector of the HPLC instrument recorded for the
eluate at l=400 nm.
Received: April 8, 2008
Published online: September 2, 2008
only after the addition of triethylamine—but then within a
few seconds. A 91:9 Z/E mixture of the alkylidenebutenolides
formed, from which we isolated the Z isomer 33 by flash
chromatography on silica gel[35] in 73% yield. Compound 33
Keywords: bifunctional building blocks · cross-coupling ·
.
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dyes/pigments · natural products · total syntheses
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Communications
[19] J. Burghart, R. Brückner, unpublished results.
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