Total synthesis of peridinin and related C37-norcarotenoid butenolides

Article abstract of DOI:10.1002/chem.200600959

As an extension of our synthesis of symmetrical carotenoids, the preparation of the highly functionalized C₃₇-norcarotenoid butenolide peridinin (1), its 6′-epi- and 11′Z stereoisomers has been completed. Featuring a central dihalogenated C

Full text of DOI:10.1002/chem.200600959

FULL PAPER
DOI: 10.1002/chem.200600959
Total Synthesis of Peridinin and Related C37-Norcarotenoid Butenolides
BelØn Vaz, Marta Domínguez, Rosana Alvarez, and Angel R. de Lera*[a]
Abstract: As an extension of our syn-
thesis of symmetrical carotenoids, the
preparation of the highly functional-
ized C37-norcarotenoid butenolide peri-
dinin (1), its 6’-epi- and 11’Z stereoiso-
mers has been completed. Featuring a
central dihalogenated C8 linchpin unit
6, two synthetic routes, differing in the
ordering of the last three steps were
explored by using the C3,C3’-bisdehy-
droxylated target as the model system.
The first route uses the combination of
a modified Z-selective Julia reaction
and two sequential Stille couplings, the
last one producing the isomerisation of
efficient Z to E isomerisation of the
final carotenoid skeleton simply uses
the Stille reaction conditions at ambi-
ent temperature. As the reaction of
bromoallene 12 with alkenylstannane
11 occurs with inversion of configura-
tion, 6’-epi-peridinin could also be pre-
pared by route A. The advantages and
limitations of the sequential Stille
cross-coupling approach to carotenoids
are highlighted.
the polyene
Z double bond. The
second route inverts these steps and
makes the isolation of the 11’Z stereo-
isomers as major products possible. An
Keywords: carotenoids · Julia reac-
tion · peridinin · Stille reaction ·
total synthesis
Introduction
composed of two chlorophyll A molecules and four peridi-
nin units embebbed in a protein (PCP complex) and held in
place by noncovalent interactions in A. carterae has been re-
Carotenoids are ubiquitous natural pigments widely distrib-
uted across all kingdoms[1] and their isolation from a variety
of species from bacteria, yeast, algae, plants, animals and
even humans has been documented.[1] These highly conju-
gated polyenes play fundamental roles as photoprotective
and antioxidation agents, and their activities have been
linked to chemoprevention of various diseases, including
cancer, atherosclerosis and macular degeneration in humans.
They are also dietary sources of vitamin A and other natu-
rally occurring retinoids.[2] In addition, carotenoids are com-
ponents of photosynthetic light-harvesting devices of both
plants and microalgae.
The most abundant photosynthetic pigment is peridinin
(1) (Scheme 1), a member of the xantophylls, a subgroup of
hydroxylated carotenoids. Among other sources, peridinin
(1) has been isolated from planktonic dinoflagelates, such as
Amphidinium carterae, which are causally linked to “red
tide” episodes.[3] A fascinating supramolecular structure
[a] Dr. B. Vaz, Dr. M. Domínguez, Dr. R. Alvarez,
Prof. Dr. A. R. de Lera
Department of Organic Chemistry, Universidade de Vigo
As Lagoas-Marcosende, 36310 Vigo (Spain)
Fax : (+34)986-811-940
E-mail: qolera@uvigo.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Scheme 1. Previous approaches to peridinin (1), highlighting the key dis-
connections.
Chem. Eur. J. 2007, 13, 1273 – 1290
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1273

vealed by X-ray crystallography.[4] The structural details pro-
vided by this architecture might help us to understand the
efficiency of the photosynthetic assemblies responsible for
light harvesting in A. carterae and, moreover, serve as an in-
spiration for the design of novel alternative energy-produc-
tion systems.
A decade later, Katsumura and co-workers described a
fully stereocontrolled synthesis of peridinin (8% overall
yield) based on a final modified (Sylvestre) Julia olefination
of 4 and 5 as the key connective step to construct the com-
plete C37 skeleton.[9] The generation of the five stereocen-
ters, as well as the formation of the chiral axis and all the
polyene double bonds of peridinin (1) proceeded with the
appropriate stereocontrol. The Julia olefination between
allyl benzothiazolyl (BT) sulfone 5 and the corresponding
aldehyde 4 afforded a mixture of all-trans and (15Z)-peridi-
nin in a 1:3 ratio (Scheme 1), which was further enriched in
natural peridinin (1) after stirring for three days in benzene
at ambient temperature (reaching a 5:1 thermodynamic
equilibrium of all-trans and (15Z)-peridinin).
Departing from the classical double-bond-forming reac-
tions used in the above synthetic sequences, there has been
recent interest[10,11] in the development of new strategies to-
wards the synthesis of these polyenes. Alternative ap-
proaches to symmetrical carotenoids[10a] and highly function-
alized carotenoid butenolides[10b] feature the generation of
single bonds connecting Csp2 atoms through Pd-catalyzed
cross-coupling reactions.[12] We conceived the synthesis of
peridinin (1) by convergent and sequential Stille cross-cou-
pling reactions[13] of a central C8-g-alkylidenebutenolide
linchpin 6[8] containing halogens of modulated reactivity,
and functionalized C11 (7) and C18 (8) alkenylstannanes com-
prising all remaining carbons of the skeleton (Scheme 2).
In addition, the retrosynthesis contemplated another Stille
cross-coupling of stannylated BT-sulfone 11 and haloallene
12, to afford the functionality required for a (Sylvestre)
Julia olefination[14] of 9 and 10. An attractive feature of the
retrosynthetic scheme rests on the fact that both fragments
7 and 12 converge in alkynyloxirane 13, which was envis-
aged to derive from (ꢀ)-actinol 14, a common building
block for the industrial synthesis of xanthophylls.[15] Appro-
priate functionalisations of 13
Although isolated in 1890, the three-dimensional structure
of peridinin (1) was determined by Liaaen-Janssen and Ra-
poport in 1976,[5] and was further supported by NMR stud-
ies[6] and later confirmed by total synthesis.[7] Peridinin ex-
hibits a highly functionalized C37-norcarotenoid structure
with a g-alkylidenebutenolide as part of the polyene chain, a
quite uncommon feature, which is present in only a few of
the approximately 700 naturally occurring carotenoids.[1] Its
oxygenation pattern adds stereochemical complexity. As a
target of total synthesis, stereocontrol will be required not
only during the build up of the polyene skeleton, but also in
the generation of the remaining stereochemical elements:
the three hydroxylated carbons atoms (one of them func-
tionalized as an acetate), the oxirane, the allene chiral axis
and the Z-g-alkylidenebutenolide unit. Not surprisingly, the
first total synthesis of enantiopure peridinin was described
by Ito et al. in 1990.[7] The synthetic strategy of Itoꢁs ap-
proach rested on a (Marc) Julia reaction of C15 (2) and C22
(3) fragments[8] as the last and crucial step to construct the
complete C37-norcarotenoid skeleton and concomitantly the
g-alkylidenebutenolide ring (Scheme 1). The sequence suf-
fered from poor stereocontrol in some of the double bond
formation steps as well as low substrate-induced diastereose-
lectivity in the steps setting up the correct configuration at
the oxygenated positions of the terminal cyclohexane rings.
The low yield and lack of stereocontrol of the Julia reaction,
and the tedious separations of double-bond isomers consid-
erably reduced the efficacy of the synthesis (!1% overall
yield).
include a regio- and stereose-
lective palladium-catalyzed hy-
drostannation[16] to 7 and the
SN2’-like ring opening of alky-
nyloxiranes[17] to haloallenes
12, both of which are prece-
dented. The Sharpless asym-
metric epoxidation (SAE)[18] of
a precursor allyl alcohol would
set up the absolute configura-
tion of alkynyloxirane 13. The
sequence was in effect validat-
ed, although on implementa-
tion of this scheme, we first
found an inconsequential
Z
outcome for the geometry of
the olefin obtained in the (Syl-
vestre) Julia olefination of 9
and 10 and, most importantly,
either a nonstereoselective out-
come or a complete inversion
Scheme 2. Retrosynthetic analysis of peridinin (1) based on sequential Stille cross-coupling reactions.
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Total Synthesis of Peridinin
FULL PAPER
Required fragments are the common 7 and 10, and bromo-
butenolide 15 (Scheme 3).
With the aim to determine the merits and disadvantages
of each strategy, we decided to construct a model of peridi-
nin that preserves all carbons of the C37-norcarotenoid skel-
eton but lacks the hydroxyl groups at positions C3 and C3’.
The fragments required for the assembly of the model
system and the parent natural product were prepared by the
routes described in Schemes 4, 5 and 6.
Scheme 3. Two routes to peridinin (1) explored in this work, with the
order and nature of the last three synthetic steps.
of configuration of the chiral axis in the Stille cross-coupling
of 11 and 12. Our efforts thus culminated in the preparation
of the diastereomer of peridinin (1) at the allene axis (6’-
epi-peridinin (6’-epi-1)).[10b]
We present herein a full report of our work in this field,
including the evaluation of two closely related alternative
synthetic approaches to these naturally occurring C37-norcar-
otenoids by using model systems, and the stereocontrolled
synthesis of peridinin (1).
Scheme 5. a) TBDMSCl, imidazole, DMF, 258C (83%); b) H2NNH2·H2O,
Et3N, EtOH, reflux; c) I2, DBN, EtO2 (2 steps, 80%); d) tBuLi, (CH2O)n,
Results and Discussion
THF, ꢀ788C, 15 h (71%); e) d-(ꢀ)-DET, Ti
N
The retrosynthetic scheme depicted in Scheme 2 is one of
the approaches to these natural products explored in this
work. It will be referred to as route A, a sequence that con-
nects fragments 8, 6 and 7, and therefore follows a C18 +
C8 +C11 construction tactic. The last two steps of the se-
quence to form the C8–C9 and C14–C15 bonds are both
Stille reactions and are preceded by the Julia condensation
that forms the C11’–C14’ olefin. A closely related route,
route B, featuring a C11 +C11 +C15 scheme, differs from A in
the order of the last three key steps, and disconnects the
C37-norcarotenoid skeleton at the C8–C9 (Stille) and the
C11’–C14’ (Julia) bonds after the allylBT-sulfone functional-
ity has been incorporated through another Stille coupling.
(85% for 13b); i) [PdCl2(PPh3)2], Bu3SnH, THF, 258C (70% for 7a, 68%
G
for 7b); j) CuBr, NH4Br, HBr, Et2O, ꢀ108C (86% for 12a, 85% for
12b); k) Ac2O, py, 258C, 16 h (85%). TBDMS=tert-butyldimethylsilyl;
DBN=1,5-diazabicyclo
A
DET=diethyl
d-tartrate;
TBHP=tert-butyl hydroperoxide; LDA=lithium diisopropylamide;
TBAF=tetrabutylammoinium fluoride.
Scheme 4 depicts the preparation of the C8 g-alkylidene-
butenolide 6 linchpin, which contains two different halogens.
Among the other options available,[19] we selected the vinyl-
ogous (extended) Mukaiyama aldol reaction[20] of 3-bromo-
2-trimethylsiloxyfuran 17[21] and 3-iodo-methacrolein 18[22]
for the construction of the butenolide ring, as developed by
Brückner and co-workers.[21]
Upon condensation at ꢀ908C
under catalysis by BF3, the cor-
responding hydroxyalkylbute-
nolide 19 was obtained with
high syn diastereoselectivity
(10:1 syn/anti ratio) in 86%
yield, as shown by the crystal
structure of the major compo-
nent (Figure 1). We have pro-
posed an explanation for the
simple diastereoselectivity in
these vinylogous Mukaiyama
Scheme 4. a) Et3N, TMSCl, CH2Cl2, 258C, 1 h; b) BF3·OEt2, CH2Cl2, ꢀ788C, 1.5 h (86% combined yield);
c) DIAD, PPh3, THF, ꢀ258C (65%). DIAD=diisopropyl azodicarboxylate.
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1275

A. R. de Lera et al.
mined by chiral HPLC on bro-
moallenes 12). The facial selec-
tivity of the SAE was also very
high with 21c under the same
conditions. Epoxyalcohols 22
were oxidized to the corre-
sponding aldehydes 23 by
using Swern conditions[27] (89
and 91% yield for 23a and
23c, respectively). Chain ex-
tension by Colvin rearrange-
ment[28] to alkynyl oxiranes 13
proceeded efficiently (84%
yield for 13a and 92% for
13c) upon treating aldehydes
23 with the anion of trimethyl-
Scheme 6. a) (Bu3Sn)2, n-BuLi, CuCN, MeOH, THF, ꢀ108C (89%); b) BTSH, PPh3, DIAD, THF, 258C
(98%); c) 35% H2O2, (NH4)6Mo7O24·4H2O, EtOH, 258C (56%); d) (aR)-12, [Pd(PhCN)2Cl2], (iPr)2NEt,
AHCTREUNG
DMF/THF, 408C (69% for 10a, 64% for 10d); e) 10, NaHMDS, THF, ꢀ788C, then 9 (79% for 8a, 70% for
8d). BTSH=2-mercaptobenzothiazole; HMDS=hexamethyldisilazane.
silyldiazomethane.
Enantio-
pure alkenylstannanes 7a and
aldol reactions based on high-level DFT computations of
the 24 plausible diastereomeric transition structures.[23] It
was our finding that the syn diastereomer most likely origi-
nates from a g+-like facial matching of the s-trans BF3-acti-
7b were acquired in 70 and 68% yield, respectively, by ap-
plication of the palladium-catalyzed hydrostannation[16]
([PdCl2(PPh3)2], Bu3SnH, THF, 258C, 10 min, 70%), and
G
then purified by reverse-phase chromatography. For the nat-
ural product, this proved to be more effective on the
TBDMS-deprotected alkyne 13b (TBAF, THF, 85%). On
the other hand, the conditions of Chemla[17a] (86% HBr,
CuBr, NH4Br, Et2O, ꢀ108C, 2.5 h) induced the opening of
alkynyl oxiranes 13a and 13b with complete regio- and ste-
reoselectively, and provided haloallenes 12, products of SN2’
displacement, exclusively (86% for 12a and 85% yield for
12b). When the reaction was attempted on 13c, the yield of
the corresponding bromoallenol (aR)-12c was 29%, and a
small amount of its epimer (aS)-12c was also obtained. Fur-
thermore, deprotection of (aR)-12c afforded alkynyl oxirane
13a, the result of the secondary alcohol deprotection and
the SN2’ reverse attack of the axial tertiary alcohol onto the
allene bond.
Efficient acetylation of haloallene 12b required treatment
with acetic anhydride and pyridine at ambient temperature
in order to minimize epimerisation of the chiral axis. Allene
(aR)-12d was acquired in 85% yield admixed with the aS
diastereomer (>20:1). The minor diastereomer could be
separated and the structure of the major (aR)-12d was se-
cured by X-ray diffraction analysis (Figure 2).[29]
Figure 1. Stereostructure of the major syn-g-hydroxyalkylbutenolide 19
(CCDC-267167) obtained in the BF3-promoted vinylogous Mukaiyama
aldol reaction of 17 and 18.
vated acrolein and the anti-OTMS conformation of trime-
thylsiloxyfuran, which we selected as computational models.
The major product syn(lk)-19 (78%) was converted through
b elimination with excess PPh3/DEAD[24] (THF, in the dark)
into the desired halogen-differentiated alkylidenebutenolide
6, a separable 7:1 mixture of Z/E isomers (65%).
Synthesis of the chiral cyclic end groups is shown in
Scheme 5. Starting materials are b-cyclogeraniol 21a and
allyl alcohol 21c. The latter was obtained uneventfully from
the alkenyl iodide 20, which was used as an intermediate in
our synthesis of (3R,3’R)-zeaxanthin.[10] The conversion of
20 to the alkenyllithium derivative by iodine–lithium ex-
change (tBuLi, THF, ꢀ788C) was followed by trapping of
the organometallic species with paraformaldehyde to furnish
allyl alcohol 21c in 71% yield.
On the other hand, the alkenylstannane 25[16a,30] prepared
by stannylcupration of but-2-yn-1-ol 24[31] was transformed
into allyl benzothiazolyl sulfone 11 by a Mitsunobu variant
(BTSH, PPh3, DIAD, THF, 258C, 98%)[32] and oxidation[33]
of the sulfide 26 with hydrogen peroxide and the peroxymo-
lybdate(vi) reagent[34] (35% H2O2, (NH4)6Mo7O24·4H2O,
EtOH, 258C, 56%).
In the absence of precedents on the Stille cross-coupling
reaction of chiral enantiopure haloallenes with alkenylstan-
nanes, we decided to study the stereochemical outcome of
the reaction between (aR)-12d and 11. Only the related pal-
ladium-catalyzed cross-coupling reactions of enantiopure
halogenated allenes with organozinc reagents had been re-
ported by Vermeer,[35] and the stereoselectivity of the reac-
Although the SAE of b-cyclogeraniol 21a[25] has been de-
scribed,[26] we faced problems of reproducibility, extended
reaction times (36 h), moderate yields (up to 80%) and low
enantioselectivities (no greater than 40% ee). In contrast,
stoichiometric quantities of Ti
A
and 1.66 mol TBHP (CH2Cl2, ꢀ208C, 12 h) helped reduce
these limitations and dramatically improved the perfor-
mance of the process (89% yield and >98% ee, as deter-
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Total Synthesis of Peridinin
FULL PAPER
AHCTREUNG
Figure 2. Stereostructure of (aR)-12d (CCDC-267168) and (aS)-10d (CCDC-267166).
tion was found to display halo-
gen dependence (Br: inver-
sion; I: retention). We were
surprised to find low stereose-
lectivities in many of the trials,
as inseparable mixtures of al-
lenyl allyl sulfones 10, differing
not on the double-bond geom-
etry, but on the configuration
of the allene axis, were ob-
tained. After extensive experi-
mentation, varying the palladi-
um
(dba)3]/
(PhCN)2Cl2],
PtBu3, [Pd2(dba)3]/2-(di-tert-bu-
catalysts
([Pd2-
[Pd-
[Pd2(dba)3]/
Scheme 7. Alternative pathways for the reaction of haloallenes 12 and stannane 11 catalyzed by palladium
complexes.
G
ACHTREUNG
G
G
A
tion. The stereochemical outcome (Z:E ratios ranging from
tylphosphino)biphenyl, solvent (DMF/THF, NMP, dioxane;
NMP=N-methyl-2-pyrrolidinone), temperature (25 to
808C) and additives (amines), we found optimal conditions
to acquire a single diastereomer from the coupling of bro-
moallene (aR)-12 and 11. These involve stirring a thorough-
ly degassed solution of both components and [Pd-
71:29 to 100:0) of the (Sylvestre) Julia condensation of unsa-
turated (from simple allyl to more complex allenyl allyl) BT
sulfones and unsaturated aldehydes has been found in more
comprehensive studies to be general for the synthesis of
conjugated olefins (trienes and longer polyenes).[38]
The complete C37-norcarotenoid skeleton was then assem-
bled by combination of the described components. Follow-
ing route A, we first adopted the conditions successfully em-
ployed for the coupling of 11 and 12 (Scheme 6). Although
the coupling took place at ambient temperature in only 1 h,
the Z/E isomer ratio (90% yield) was disappointing (an ap-
proximately 50:50 mixture). We next turned our attention to
the described coupling of 2-bromo-g-alkylidenebutenolides
and simple alkenylstannanes, which use Farinaꢁs conditions,
A
at 408C (Scheme 6). The structure of the product, isolated
in 69 (10a) and 64% (10d) yield, was confirmed to be that
of sulfone (aS)-10 by X-ray diffraction (Figure 2), the prod-
uct of formal inversion of configuration at the allene centre.
No reversion of the stereochemical outcome was observed
by using the coupling of 11 and the corresponding iodoal-
lene (prepared in identical fashion from 13 using Chemlaꢁs
method, 57% HI, CuI, NH4I, Et2O, ꢀ108C, 2.5 h) instead.
The allene axis inversion was interpreted as resulting
from an anti-selective SN2’-displacement of bromide by pal-
ladium to give 28, followed by [1,3]-sigmatropic shift of
propargyl- to allenyl-palladium, leading to (aS)-27 before
transmetalation and progression through the catalytic cycle
(Scheme 7).[36]
namely, [Pd2(dba)3]·CHCl3 and [AsPh3] in NMP
A
(Scheme 8).[39] Stannane (aS,5’Z)-8 proved to be far less re-
active than simple alkenylstannanes, and required stirring
with butenolide 6 at ambient temperature for 18 h under the
above described reaction conditions to reach completion.
The extended reaction times proved, however, detrimental
to the stereochemical integrity of the polyenes and a 50:50
mixture of isomers was obtained in 94% yield. Fortunately,
the beneficial effect of tetrabutylammonium phosphinate[40]
Condensation of the anion formed by treatment of allenyl
allyl BT-sulfone 10a with NaHMDS and 3-(tributylstann-
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A. R. de Lera et al.
at room temperature during
the first Stille coupling is an-
other proof of this statement).
The analysis of the geometry
of all the double bonds of the
polyene was carried out by
studying the similarity between
the regions of the vinyl area in
the 1H NMR spectra of our
model and that of natural peri-
dinin (Scheme 8).
For the natural product, the
presence of the hydroxy and
acetoxy groups at the C3- and
C3’-cyclohexane positions con-
siderably increased the stabili-
ty of the products and reduced
their degradation along the se-
quence. Heating (aS,11’Z)-29d
and alkenylstannane 7b to
558C for 31 h under the same
Scheme 8. a) [Pd2
A
29d); b) [Pd2
ACHTREUNG
starting material) or 31 h (72% for 6’-epi-1).
reaction conditions optimized
Bu4N+Ph2PO2 enabled reduction of the reaction time to
above ([Pd
A
ꢀ
ꢀ
4.5 h. The optimised 87% yield for 29a (79% for 29d) as a
3.5:1 ratio of the C11’–C12’ Z/E isomers (5:1 for 29d) was
obtained when BHT (BHT=2,6-di-tert-butyl-4-methylphe-
nol) was also added and the mixture was carefully deoxy-
genated. After separation by column chromatography, the
major product was shown to be the Z isomer (aS,11’Z)-29
THF) provided, after chromatography, a single product 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
isomerisation 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 photoisomerisation of
natural peridinin, after tedious separation of up to eight ste-
reoisomers.[42]
1
through analysis of the H NMR spectroscopic coupling con-
stants and NOE-difference experiments, confirming that re-
tention of configuration in the coupling partners had mostly
taken place. The structure of the highly unstable minor
isomer was assumed to be (aS,11’E)-29, in which the original
Z double bond had been isomerised, a first indication of the
sensitivity of the polyene geometry to the action of palladi-
um catalysis (vide infra). Contrary to expectations, the
minor isomer (aS,11’E)-29 suffered extensive degradation
and could not be characterized.
The major isomer of model (aS,11’Z)-29a was used in the
second Stille cross-coupling reaction for the final step of the
synthesis. The reluctance of alkenylstannane 7a to engage in
Stille cross-coupling reactions made it necessary to consider-
ably increase the reaction temperature to 558C and heat the
reaction mixture for extended periods (20 h) in order for it
to reach completion, even in the presence of the soluble
phosphinate salt, with the subsequent reduction of the yield
for 30 (21%). Furthermore, although the polyene chain of
the starting bromobutenolide 29a had the 11’Z geometry,
only the C37-norcarotenoid with the all-trans configuration
was obtained from the last Stille coupling. The cis to trans
isomerisation of some of the polyene double bonds is facile,
as noted in previous approaches to retinoids[41] and carote-
noids.[10] Most likely in this case, Pd induces the isomerisa-
tion to the most stable carotenoid under the reaction condi-
tions, as we showed that the carotenoid is stable in the ab-
sence of palladium (the stability of the precursor of (Z)-29
Alternatively, route B required the synthesis of alcohol
15, the result of the Stille coupling of linchpin 6 and stan-
nane 31. The precedented Stille cross-coupling between bro-
mobutenolides and organostannanes cocatalyzed by Pd com-
plexes and CuI[39] proved inefficient in our system, and we
shifted to the previously optimised conditions, including the
soluble phosphinate tin scavenger, for both sequential cross-
coupling steps. Regardless of the stannane used, the first
coupling takes place at the iodide end of 6, and 31 furnished
allyl alcohol 15 in 68% yield after stirring at ambient tem-
perature for 4.5 h. The second Stille reaction connected bro-
mide 15 and stannane 7a to produce the polyene 32 in mod-
erate yield (45%), as a consequence of the prolonged heat-
ing (50–558C, 20 h). Treatment of 32 with TPAP and
NMO[43] gave the corresponding aldehyde 33 as a mixture of
two geometric isomers (5:1 ratio), which proved to be
highly unstable (the yield also decreased considerably at this
stage, 36%) and was directly submitted to the final (Sylves-
tre) Julia olefination with the BT-sulfone (aS)-10a. Under
these mild conditions (-78 to 08C, THF), only one isomer of
the C37-norcarotenoid was obtained in 63% yield. The anal-
1
ysis of the H NMR spectra and their comparison with the
1
reported H NMR spectra of peridinin (1),[9] allowed us to
conclude that the C37-norcarotenoid was the 11’Z isomer of
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Total Synthesis of Peridinin
FULL PAPER
peridinin model (11’Z)-34.
This observation is in agree-
ment with our findings for the
Z>E stereoselectivity in the
connective olefination reaction
of allenyl allyl BT sulfones and
unsaturated aldehydes[22] as
well as previous reports on
similar processes in carote-
noids.[9] This polyene proved to
be highly labile, as we ob-
served a spontaneous isomeri-
sation at room temperature in
favour of the more stable all-
trans
carotenoid
34
(Scheme 9).
From the modelling studies,
we concluded that even
though route A (Julia-Stille-
Stille) directly provided the
desired all-trans carotenoid by
the Pd-induced isomerisation
at the last step, route B (Stille-
Stille-Julia) affords a double-
bond isomer, generated under
Scheme 9. a) [Pd2
C
G
THF, ꢀ788C!08C (63%). TPAP=tetra-n-propylammonium perruthenate; NMO=N-methylmorpholine N-
oxide.
the milder conditions of the modified Julia condensation in
the last step, which is a bonus when the complexity of the
polyene is increased. The low yield of the oxidation of poly-
enol 32 to polyenal 33 was a drawback, but upon further re-
evaluation in the context of the synthesis of peridinin, the
yield of this step improved, making the alternative routes to
carotenoids developed with the model system equally effi-
cient.
The required alkynyloxirane 35 was derived from a Sono-
A
gashira cross-coupling reaction between the protected
alkyn-
yloxirane 13c and iodide 36,[46] itself obtained from the cor-
responding organostannane 25 by tin–halogen exchange.
Following the optimized conditions developed by Katsu-
mura et al., the use of [Pd
A
catalyst in diisopropylamine as solvent afforded 35c from
Synthesis of peridinin
Correction of the allene axis
configuration: After many un-
successful attempts to couple
haloallenes and stannanes with
retention of configuration,[44]
we decided to follow a more
classical strategy to prepare
the allene axis with the correct
aR configuration on allenyl
allyl
BT-sulfone
10
(Scheme 10). This precedented
method uses a syn-stereospe-
cific SN2’ reduction of the
propargyl alcohol in alkynylox-
irane 35 with excess DIBAL-
H.[45] The high selectivity re-
sults from the coordination be-
tween aluminium and the ep-
oxide, which directs the hy-
dride to the same face it occu-
pies.
Scheme 10. a) I2, CH2Cl2, 258C (98%); b) [Pd(PPh3)4], CuI, (iPr)2NH, 258C (78%); c) DIBAL, CH2Cl2, 08C
A
(99%); d) BTSH, DIAD, PPh3, THF, 08C (100%); e) HCO2H, THF, H2O, 25 8C; f) Ac2O, Py, 258C (99%
combined yield); g) 35% H2O2, (NH4)6Mo7O24·4H2O, EtOH, ꢀ108C (93%). DIBAL=diisobutylaluminium
hydride.
Chem. Eur. J. 2007, 13, 1273 – 1290
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1279

A. R. de Lera et al.
13c (78%, Scheme 10). The
stereospecific reduction of the
latter with DIBAL-H proceed-
ed quantitatively (100%) with
complete 1,3-chirality transfer.
Allenol 37c was transformed
into the corresponding benzo-
thiazolyl allyl sulfide 38c, by
using the Mitsunobu condi-
tions (BTSH, DIAD, PPh3,
THF, 08C; 100%). To avoid
the manipulation of more
complex structures along the
sequence which can easily
result in isomerisation, the
acetylation at position C3’ was
attempted at this stage. De-
protection of the silyl-protect-
ing group was best effected
with formic acid (HCO2H/
THF/H2O, 25 8C),[47] whereas
the efficient conditions for
acetylation described above
Scheme 11. a) NaHMDS, THF, ꢀ788C (78%); b) [Pd2
ACHTREUNG
(63%); c) [Pd
AHCTREUNG
(Ac2O, pyridine, 258C; 90% combined yield), which mini-
mize epimerization of the chiral axis, served well to acquire
sulfide 38d from 38a. When the reaction is performed on a
larger scale, a small amount of the formate byproduct 38e is
isolated. Oxidation of the sulfide with the peroxymolybda-
te(vi) reagent was carried out at ꢀ108C to minimize isomer-
isation of the target sulfone (at higher temperatures, the
double bond isomerised to give mixtures of sulfones con-
taining up to 25% of the Z isomer), and afforded in 93%
yield sulfone 10 with the aR configuration required for the
synthesis of peridinin (1).
(Scheme 12) was oxidized to aldehyde 39 in 72% yield by
treatment of MnO2 in slightly basic media (Na2CO3) to pre-
vent undesired E/Z isomerisations. The functional-group
modification also had an effect on coupling rates to stan-
nane 7b under our standard conditions, as the g-alkylidene-
butenolide bromide 39 fully conjugated to the aldehyde re-
quired an increase in reaction temperature (up to 708C) and
longer reaction time (26 h). A single product was obtained
in 64% yield, and its all-trans structure 40 was assigned
1
after H NMR spectroscopic analysis of coupling constants
and NOE difference experiments (Scheme 12).
With aldehyde 40 and BT-sulfone (aR)-10 in hand, the
crucial (Sylvestre) Julia olefination was explored as the last
key step of our synthesis. On the basis of previous results,
NaHMDS (THF, ꢀ788C) was selected to form the stabilized
anion of 10; addition of aldehyde 40 and increase of the
temperature to 08C enabled the isolation of a major product
(53%) with 11’Z geometry (Scheme 12). Isomerization to
the desired trans-1 was attempted at ambient temperature in
CDCl3 solution, and its evolution was monitored by
1H NMR spectroscopy. After 48 h, a mixture containing an
approximately 50:50 ratio of products was obtained. They
were separated by HPLC (Develosil C30-UG-5 10/250 NW;
MeOH/CH3CN/Et3N as eluent, 1 mLminꢀ1) and shown to
be the C11’–C14’ isomers, (11’Z)-1 and all-trans peridinin
(1). The geometries of (11’Z)-1 and peridinin (1) were con-
Completion of the carotenoid skeleton
Route A (C11 +C8 +C18): Modified Julia reaction followed
by sequential Stille coupling (and isomerisation under the
reaction conditions of the last step)
The sequence, already optimized for the aS isomer,
worked uneventfully for the components with the correct
(aR) configuration: the modified Julia reaction furnished
the mixture of allenyl trienylstannanes 8 in a 3:1 ratio,
which was used as the first organostannane of the sequential
Stille coupling reaction with 6 (63% yield), and the product
29d was then coupled to 7b in 69% yield, delivering peridi-
nin (1) with the correct configuration and double-bond ge-
ometry (Scheme 11).
1
firmed by analysis of coupling constants in their H NMR
Route B: (C15 +C11 +C11): Construction of 11’-cis-peridinin
and subsequent isomerisation to natural peridinin (1) by
treatment with palladium.
The coupling of the C11-g-alkylidenebutenolide central
unit for the convergent Stille cross-coupling reaction was at-
tempted at the aldehyde stage to circumvent the low yield
of the oxidation of 32 to 33 (Scheme 12). Alcohol 15
spectra and by ROESY experiments (Figure 3). A more
efficient and complete isomerisation was achieved by stir-
ring (11’Z)-1 at ambient temperature for 7 h with the re-
agents used in the Stille coupling but at a higher loading
of Pd/
[Pd2(dba)3]/
yield.
ACHTREUNG
A
N
ACHTREUNG
1280
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1273 – 1290

Total Synthesis of Peridinin
FULL PAPER
step. An efficient Z to E iso-
merisation of the final carote-
noid skeleton uses [Pd2-
A
N
temperature, after the observa-
tion that the Stille coupling re-
action as a last step was ac-
companied by polyene isomer-
isation. Another complication
of the Stille coupling was
found upon reaction of bro-
moallenes with alkenylstan-
nanes, a process that occurs
with inversion of configura-
tion. This called for an alterna-
tive synthesis of the allene by
using the DIBAL-H-induced
reduction of propargyl epox-
ides. Together these results
confirm that the Stille coupling
can be used as an efficient syn-
thetic method to construct the
carotenoid skeleton, but under
the present reaction conditions
a limitation on the control of
the complete olefin configura-
tion is noted.
Scheme 12. a) MnO2, Na2CO3, CH2Cl2, 08C, 2 h (72%); b) [Pd2
(dba)3]·CHCl3, [AsPh3], Bu4N+Ph2PO2ꢀ, DMF,
A
708C, 26 h (64%); c) NaHMDS, THF, ꢀ788C to 08C (53%); d) [Pd2
A
(1.04 equiv), DMF, 258C, 7 h (83%).
Conclusion
Peridinin (1), and its 6’-epi and 11’Z stereoisomers have
been stereoselectively prepared by following synthetic
routes previously optimised for the preparation of the C3
and C3’-bisdehydroxylated model systems. Highlights of the
sequence are the connective modified Julia reaction and se-
quential Stille coupling using the dihalogenated alkylidene-
butenolide 6 as a linchpin. The ordering of the last three
steps makes the isolation of the 11’Z stereoisomers possible
when the modified Julia reaction is employed in the last
Experimental Section
General: Solvents were dried according to published methods and distil-
led before use. HPLC-grade solvents were used for the HPLC purifica-
tion. All other reagents were commercial compounds of the highest
purity available. All reactions were carried out under an argon atmos-
phere, and those not involving aqueous reagents were carried out in
oven-dried glassware. Analytical TLC was performed on aluminium
plates with Merck Kieselgel 60F254 and visualised by UV irradiation
(254 nm) or by staining with solution of phosphomolibdic acid. Flash-
column chromatography was carried out by using Merck Kieselgel 60
(230–400 mesh) under pressure. HPLC was performed by using a Waters
instrument with a dualwave detector (254 and 300 nm), preparative Nova
Pak HR silica, 60 Š, 19”300 mm and 95:5 hexane/ethyl acetate as the
eluent. UV/Vis spectra were recorded on a Cary 100 Bio spectrophotom-
eter by using MeOH as the solvent. IR spectra were obtained on a
JASCO IR 4200 spectrophotometer from a thin film deposited onto
NaCl glass. Specific rotation was obtained on JASCO P-1020. Mass spec-
tra were obtained on a Hewlett–Packard HP59970 instrument operating
at 70 eV by electron ionisation. HRMS were taken on a VG Autospec in-
1
strument. H NMR spectra were recorded in CDCl3, C6D6 and (CD3)2CO
at ambient temperature on a Bruker AMX-400 spectrometer at 400 MHz
with residual protic solvent as the internal reference (CDCl3, dH =
7.26 ppm; C6D6, dH =7.16 ppm; (CD3)2CO, dH =2.05 ppm); chemical
shifts (d) are given in parts per million (ppm) and coupling constants (J)
are given in Hertz (Hz). The proton spectra are reported as follows: d
(multiplicity, coupling constant J, number of protons, assignment).
13C NMR spectra were recorded in CDCl3, C6D6 and (CD3)2CO at ambi-
ent temperature on the same spectrometer at 100 MHz, with the central
peak of CDCl3 (dC =77.0 ppm), C6D6 (dC =128.0 ppm) or (CD3)2CO
(dC =30.8 ppm) as the internal reference. DEPT135 are used to aid in the
assignment of signals in the 13C NMR spectra.
Figure 3. NOEs for peridinin (1) and (11’Z)-peridinin (1) (extracted from
their 600 MHz ROESY spectra in CDCl3).
Chem. Eur. J. 2007, 13, 1273 – 1290
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1281

A. R. de Lera et al.
(5S*,1’S*,2’E)-3-Bromo-5-[1-hydroxy-3-iodo-2-methyl-propenyl]-5H-
furan-2-one (19): Freshly doubly-distilled chlorotrimethylsilane (1.79 mL,
14.07 mmol) and Et3N (3.92 mL, 28.14 mmol) were added to a solution of
16 (1.35 g, 8.28 mmol) in CH2Cl2 (100 mL). The mixture was stirred for
1 h at 258C and the solvent was removed to give 17. Freshly bidistilled
BF3·OEt2 (1.02 mL, 8.28 mmol) and a solution of the mixture obtained
above in CH2Cl2 (12 mL) were sequentially added to a cooled solution
(ꢀ788C) of 18 (1.62 g, 8.28 mmol) in CH2Cl2 (15 mL). After stirring for
1.5 h at ꢀ788C, a pH 7.1 buffer (20 mL) was added and the mixture was
extracted with CH2Cl2 (3”). The combined organic layers were dried
(Na2SO4) and the solvent was evaporated. The residue was purified by
column chromatography (silica gel, 70:20:10 hexane/EtOAc/CH2Cl2) to
afford 2.34 g (78%) of a solid identified as syn-19 and 0.24 g (8%) of its
isomer, anti-19.
5.52 mmol) and a solution of paraformaldehyde (0.12 g, 3.94 mmol) in
THF (2 mL) was added. After stirring for 1 h at ꢀ788C and 15 h at 258C,
brine was slowly added and the mixture was extracted with tBuOMe (3”
). The combined organic layers were dried (Na2SO4) and the solvent was
evaporated. The residue was purified by column chromatography (silica
gel, 80:20 hexane/EtOAc) to afford 1.59 g (71%) of a white solid identi-
fied as 21c. [a]2D5 =ꢀ109.2 (c=0.03 in CHCl3); m.p. 69–718C (Et2O/
1
hexane); H NMR (400 MHz, CDCl3): d=4.11 (d, J=11.4 Hz, 1H; CH2),
4.03 (d, J=11.4 Hz, 1H; CH2), 3.88 (m, 1H; CH2), 2.11 (m, 1H; CH2),
2.00 (dd, J=17.0, 9.4 Hz, 1H; CH2), 1.71 (s, 3H; CH3), 1.59 (ddd, J=
12.3, 3.3, 2.0 Hz, 1H; CH2), 1.43 (t, J=12.1 Hz, 1H; CH2), 1.05 (s, 3H;
CH3), 1.01 (s, 3H; CH3), 0.85 (s, 9H; CH3), 0.03 ppm (s, 6H; CH3);
13C NMR (100 MHz, CDCl3): d=137.1 (s), 131.2 (s), 65.5 (d), 58.2 (t),
48.4 (t), 42.6 (t), 36.6 (s), 29.3 (q), 28.4 (q), 25.8 (q, 3”), 19.4 (q), 18.1 (s),
Data for syn-19: M.p. 98–1008C (hexane/EtOAc); 1H NMR (400 MHz,
CDCl3): d=7.38 (d, J=1.7 Hz, 1H; CH), 6.49 (s, 1H; CH), 5.01 (dd, J=
5.9, 1.7 Hz, 1H; CH), 4.29 (d, J=5.9 Hz, 1H; CH), 2.62 (brs, 1H; OH),
1.88 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=167.7 (s), 149.1
(d), 144.2 (s), 114.5 (s), 83.6 (d), 82.7 (d), 76.3 (d), 20.7 ppm (q); IR
(NaCl): n˜ =3600–3200 (br, OH), 3091 (w), 2919 (w), 1765 (s, C=O), 1608
(w), 1157 cmꢀ1 (w); MS (FAB+): m/z (%): 360 [M]+ (7), 359 [M]+ (7),
308 (10), 307 (41), 290 (7), 289 (21), 282 (6), 219 (6), 197 (13); HRMS
(FAB+): m/z: calcd for C8H979Br127IO3: 358.8780; found: 358.8788; ele-
mental analysis calcd for C8H8BrIO3: C 26.77, H 2.25; found: C 26.80, H
2.23.
Data for anti-19: 1H NMR (400 MHz, CDCl3): d=7.50 (d, J=1.7 Hz,
1H; CH), 6.51 (s, 1H; CH), 4.99 (dd, J=5.0, 1.7 Hz, 1H; CH), 4.41 (d,
J=5.0 Hz, 1H; CH), 3.24 (brs, 1H; OH), 1.88 ppm (s, 3H; CH3);
13C NMR (100 MHz, CDCl3): d=168.6 (s), 150.1 (d), 144.0 (s), 113.9 (s),
82.8 (d), 82.2 (d), 74.8 (d), 21.1 ppm (q); IR (NaCl): n˜ =3600–3200 (br,
ꢀ
ꢀ4.7 ppm (q, 2”); IR (NaCl): n˜ =3600–3100 (br, OH), 2926 (s, C H),
ꢀ1
2857 (s, C H), 1465 (m), 1382 (m), 1253 (s), 1087 cm (s); MS (EI+):
ꢀ
m/z (%): 209 (23), 135 (45), 119 (59), 109 (19), 107 (27), 105 (15), 93
(27), 91 (42), 77 (17), 75 (100), 73 (57), 67 (19); HRMS (EI+): m/z: calcd
for C16H30OSi: 266.2066; found: 266.2065; elemental analysis calcd for
C16H32O2Si: C 67.54, H 11.34; found: C 67.54, H 11.52.
(+)-[(1R,6R)-2,2,6-Trimethyl-7-oxa-bicyclo
[4.1.0]heptan-1-yl]methanol
(22a). General procedure for the Sharpless asymmetric epoxidation: Ti-
(OiPr)4 (3.71 mL, 12.57 mmol) was added to a cooled (ꢀ208C) solution
of (ꢀ)-d-DET (2.59 mL, 15.09 mmol) in CH2Cl2 (35 mL) containing 4 Š
molecular sieves. After stirring for 10 min, a solution of TBHP (5.4 mL,
4.63m in iso-octane, 25.15 mmol) was added and the mixture was stirred
for 30 min at ꢀ208C.
A solution of b-cyclogeraniol 21a (1.9 g,
12.57 mmol) in CH2Cl2 (10 mL) was added and stirred for 12 h. The mix-
ture was diluted with tBuOMe (30 mL) at ꢀ208C and a 30% aqueous so-
lution of NaOH (1 mL) and brine (1 mL) were added. The resulting mix-
ture was warmed up to room temperature, Na2SO4 and Celite were
added and the mixture was filtered and extracted thoroughly with
tBuOMe. The combined organics layers were dried (Na2SO4) and the sol-
vent was removed. The residue was purified by column chromatography
(silica gel, 80:20 hexane/EtOAc) to afford 2.1 g (98%) of a colourless oil
ꢀ
ꢀ
OH), 3092 (w, C H), 2957 (w, C H), 1775 (s, C=O), 1606 (w), 1057 (m),
1021 (m), 987 cmꢀ1 (m); MS (EI+): m/z (%): 360 [M]+ (1), 358 [M]+ (1),
198 (4), 197 (100), 162 (6); HRMS (EI+): m/z: calcd for C8H879Br127IO3:
357.8702; found: 357.8704; calcd for C8H881Br127IO3: 359.8681; found:
359.8666.
ACHTREUNG
identified as 22a. [a]2D0 =+46.08 (c=0.08 in CHCl3); H NMR (400 MHz,
1
A
a
CDCl3): d=3.80 (dd, J=11.3, 5.0 Hz, 1H; CH2), 3.64 (dd, J=11.3,
5.0 Hz, 1H; CH2), 1.90–1.80 (m, 2H; CH2), 1.80–1.70 (m, 1H; CH2),
1.40–1.30 (m, 3H; CH2), 1.33 (s, 3H; CH3), 1.01 (s, 3H; CH3), 0.99 ppm
(s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=68.9 (s), 64.6 (s), 58.8 (t),
(ꢀ508C) solution of syn-19 (0.65 g, 1.81 mmol) and PPh3 (1.43 g,
5.44 mmol) in THF (17 mL). The mixture was stirred for 3.5 h, allowing
the temperature to rise to 08C smoothly. After this time, water was
added and the mixture was extracted with CH2Cl2 (”3). The combined
organic layers were dried (Na2SO4) and the solvent was evaporated. The
residue was purified by column chromatography (silica gel, 90:10 hexane/
EtOAc) to afford 0.35 g (57%) of a yellow solid identified as (Z)-6 and
0.05 g (8%) of a yellow solid identified as (E)-6 in a 7:1 Z/E ratio.
Data for (Z)-6: M.p. 87–888C (CH2Cl2/Et2O); 1H NMR (400 MHz,
CDCl3): d=7.42 (s, 1H; CH), 6.97 (s, 1H; CH), 5.73 (s, 1H; CH),
2.21 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=165.1 (s), 144.9
(s), 142.5 (d), 142.0 (s), 114.5 (d), 111.6 (s), 93.1 (d), 22.9 ppm (q); IR
36.5 (t), 32.8 (s), 31.0 (t), 25.0 (q), 24.1 (q), 20.6 (q), 17.0 ppm (t); IR
ꢀ1
ꢀ
(NaCl): n˜ =3700–3200 (br, OH), 2940 (s, C H), 1455 (s), 1035 cm (s);
MS (EI+): m/z (%): 139 [MꢀCH2OH]+ (6), 137 (10), 111 (25), 109 (35),
97 (10), 97 (21), 95 (28), 86 (100), 85 (82), 84 (32), 83 (17), 82 (21), 81
(16), 79 (26), 71 (71), 70 (16), 69 (48), 67 (30); HRMS (EI+): m/z: calcd
for C10H18O2: 170.1302; found: 170.1306.
(ꢀ)-[(1R,4S,6R)-4-(tert-Butyldimethylsilyloxy)-2,2,6-trimethyl-7-
oxabicyclo[4.1.0]heptan-1-yl]methanol (22c): Following the general pro-
T
ꢀ
ꢀ
ꢀ
cedure for the Sharpless asymmetric epoxidation, the reaction of (ꢀ)-d-
(NaCl): n˜ =3053 (w, C H), 2924 (w, C H), 2854 (w, C H), 1780 (s, C=
O), 975 cmꢀ1 (m); UV (MeOH): lmax =343 nm; MS (FAB+): m/z (%):
343 [M]+ (2), 342 (2), 341 [M]+ (2), 340 (1), 292 (3), 274 (2), 258 (1), 257
(2); HRMS (FAB+): m/z: calcd for C8H781Br127IO2: 342.8654; found:
342.8658; elemental analysis calcd for C8H6BrIO2: C 28.18, H 1.77;
found: C 28.00, H 1.73.
DET (0.44 mL, 2.53 mmol), Ti(OiPr)4 (0.62 mL, 2.11 mmol), TBHP
AHCTREUNG
(0.90 mL, 4.69m in iso-octane, 4.22 mmol) and 21c (0.60 g, 2.11 mmol) in
CH2Cl2 (8 mL) afforded, after purification by column chromatography
(silica gel, 85:15!50:50 hexane/EtOAc), 0.62 g (98%) of a colourless oil
identified as 22c. [a]2D9 =ꢀ44.4 (c=0.04, CHCl3); 1H NMR (400 MHz,
CDCl3): d=3.80–3.60 (m, 3H; CH+CH2), 2.19 (dd, J=14.2, 4.2 Hz, 1H;
CH2), 1.76 (m, 1H; OH), 1.60 (dd, J=14.1, 8.8 Hz, 1H; CH2), 1.39 (m,
1H; CH2), 1.37 (s, 3H; CH3), 1.21 (dd, J=13.2, 2.5 Hz, 1H; CH2), 1.10 (s,
3H; CH3), 1.03 (s, 3H; CH3), 0.84 (s, 9H; CH3), 0.01 ppm (s, 6H; CH3);
13C NMR (100 MHz, CDCl3): d=68.1 (s), 65.6 (s), 64.2 (d), 59.7 (t), 47.9
(t), 42.2 (t), 34.0 (s), 26.9 (q), 25.7 (q, 3”), 24.7 (q), 19.6 (q), 18.0 (s),
Data for (E)-6: M.p: 107–1088C (CH2Cl2/Et2O); 1H NMR (400 MHz,
CDCl3): d=7.82 (s, 1H; CH), 6.80 (d, J=0.9 Hz, 1H; CH), 6.36 (s, 1H;
CH), 2.10 ppm (d, J=0.9 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3):
d=164.4 (s), 146.9 (s), 141.0 (s), 138.2 (d), 117.0 (d), 114.8 (s), 91.4 (d),
ꢀ1
ꢀ
ꢀ
23.0 ppm (q); IR (NaCl): n˜ =2922 (w, C H), 2853 (w, C H), 1749 cm
(s, C=O); UV (MeOH): lmax =346 nm; MS (FAB+): m/z (%): 323 (30),
322 (100), 282 (42), 279 (16), 251 (16), 250 (34), 210 (18), 193 (17), 191
(18), 167 (60), 165 (27); HRMS (FAB+): m/z: calcd for C8H779Br127IO2:
340.8674; found: 340.8689; elemental analysis calcd for C8H6BrIO2: C
28.18, H 1.77; found: C 28.61, H 1.77.
ꢀ
ꢀ4.8 ppm (q, 2”); IR (NaCl): n˜ =3600–3100 (br, OH), 2959 (s, C H),
ꢀ1
ꢀ
ꢀ
2931 (s, C H), 2857 (s, C H), 1468 (m), 1383 (m), 1254 (s), 1088 cm
(s); MS (EI+): m/z (%): 225 (87), 211 (48), 185 (70), 171 (70), 169 (86),
157 (90), 151 (54), 143 (67), 141 (55), 133 (45), 121 (55), 119 (59), 111
(64), 109 (81), 107 (64), 105 (56), 101 (41), 95 (40), 93 (62), 91 (67), 84
(40), 83 (68), 76 (95), 75 (100), 73 (98); HRMS (EI+): m/z: calcd for
C12H23O3Si: 243.1416 [MꢀtBu]+; found: 243.1413.
(ꢀ)-[(R)-4-(tert-Butyldimethylsilyloxy)-2,6,6-trimethylcyclohex-1-enyl]-
methanol (21c): A cooled (ꢀ788C) solution of 20 (1.0 g, 2.63 mmol) in
THF (3 mL) was treated with tBuLi (3.25 mL, 1.7m in pentane,
1282
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1273 – 1290

Total Synthesis of Peridinin
FULL PAPER
(ꢀ)-(1S,6R)-2,2,6-Trimethyl-7-oxabicyclo
A
matography (silica gel, 100:0!99:1 hexane/EtOAc), 3.10 g (92%) of a
yellow oil identified as 13c. [a]2D9 =ꢀ119.8 (c=0.02 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=3.80–3.70 (m, 1H; CH), 2.35 (s, 1H; CH2), 2.18
(ddd, J=14.5, 5.1, 1.5 Hz, 1H; CH2), 1.62 (dd, J=14.5, 7.9 Hz, 1H; CH2),
1.46 (s, 3H; CH3), 1.50–1.40 (m, 1H; CH2), 1.22 (s, 3H; CH3), 1.20–1.10
(m, 1H; CH2), 1.07 (s, 3H; CH3), 0.83 (s, 9H; CH3), ꢀ0.01 ppm (s, 6H;
CH3); 13C NMR (100 MHz, CDCl3): d=80.7 (s), 73.8 (d), 66.2 (s), 64.1
(d), 63.0 (s), 45.4 (t), 40.1 (t), 33.7 (s), 29.4 (q), 25.7 (q, 3”), 25.4 (q), 21.5
(23a). General procedure for the Swern oxidation: DMSO (1.32 mL,
18.57 mmol) was added to a cooled (ꢀ608C) solution of oxalyl chloride
(0.95 mL, 10.83 mmol) in CH2Cl2 (23 mL), and the mixture was stirred
for 5 min. A solution of 22a (1.32 g, 7.74 mmol) in CH2Cl2 (23 mL) was
added and the mixture was stirred for 15 min. Finally, Et3N (7.12 mL,
51.08 mmol) was added and after 10 min, the mixture was warmed to
room temperature. The mixture was poured over H2O and extracted with
CH2Cl2 (3”). The combined organic layers were dried (Na2SO4) and the
solvent was evaporated. The residue was purified by column chromatog-
raphy (silica gel, 95:5 hexane/EtOAc) to afford 1.15 g (89%) of a colour-
less oil identified as 23a. [a]2D3 =ꢀ18.4 (c=0.08 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=9.73 (s, 1H; CH), 1.91 (m, 1H; CH2), 1.75 (m,
1H; CH2), 1.45 (m, 4H; CH2), 1.31 (s, 3H; CH3), 1.27 (s, 3H; CH3),
1.05 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=201.7 (d), 73.1
ꢁ
(q), 17.9 (s), ꢀ4.9 ppm (q, 2”); IR (NaCl): n˜ =3311 (m, C C-H), 2957 (s,
ꢀ
ꢀ
ꢀ
ꢁ
C H), 2931 (s, C H), 2857 (m, C H), 2100 (w, C C), 1469 (m), 1385
(m), 1364 (m), 1255 (s), 1085 cmꢀ1 (s); MS (EI+): m/z (%): 237 (2), 181
(73), 165 (64), 143 (86), 121 (84), 115 (84), 105 (16), 101 (18), 93 (52), 91
(17), 77 (29), 75 (100), 73 (83); HRMS (EI+): m/z: calcd for C13H21O2Si:
237.1311 [MꢀtBu]+; found: 237.1321.
(ꢀ)-(1R,3S,6R)-6-Ethynyl-1,5,5-trimethyl-7-oxabicyclo
[4.1.0]heptan-3-ol
(s), 65.2 (s), 35.3 (t), 32.5 (s), 29.3 (t), 26.0 (q), 24.4 (q), 21.3 (q),
16.7 ppm (t); IR (NaCl): n˜ =2940 (s, C H), 1713 (s, C=O), 1460 cm
(13b): A solution of 13c (1.62 g, 5.49 mmol) in THF (10 mL) was treated
with nBu4NF (10.97 mL, 1m in THF, 10.97 mmol). After stirring for 2 h,
the mixture was poured over a saturated aqueous NaHCO3 solution and
extracted with Et2O (3”). The combined organic layers were dried
(Na2SO4) and the solvent was evaporated. The residue was purified by
column chromatography (silica gel, 85:15 hexane/EtOAc) to afford 0.84 g
ꢀ1
(m); MS (EI+): m/z (%): 139 [MꢀCHO]+ (24), 125 (15), 111 (20), 110
(19), 109 (16), 107 (10), 95 (36), 91 (10), 84 (12), 83 (12), 82 (29), 81 (17),
79 (11), 71 (43), 70 (25), 67 (20); HRMS (EI+): m/z: calcd for C10H16O2:
168.1150; found: 168.1157.
(ꢀ)-(1S,4S,6R)-4-(tert-Butyldimethylsilyloxy)-2,2,6-trimethyl-7-
(85%) of
a
white solid identified as 13b. [a]2D4 =ꢀ76.0 (c=0.05 in
oxabicyclo
A
CHCl3); m.p. 70–738C (hexane/AcOEt); 1H NMR (400 MHz, CDCl3):
d=3.78 (dddd, J=10.2, 8.6, 5.0, 3.5 Hz, 1H; CH2), 2.37 (s, 1H; CH), 2.32
(dd, J=14.3, 5.1 Hz, 1H; CH2), 1.59 (dd, J=14.3, 8.6 Hz, 1H; CH2), 1.55
(ddd, J=13.1, 3.4, 1.8 Hz, 1H; CH2), 1.48 (s, 3H; CH3), 1.24 (s, 3H;
CH3), 1.19 (ddd, J=13.3, 10.4, 2.9 Hz, 1H; CH2), 1.09 ppm (s, 3H; CH3);
13C NMR (100 MHz, CDCl3): d=80.4 (s), 74.0 (d), 66.4 (s), 63.6 (d), 62.9
(s), 45.6 (t), 39.6 (t), 33.9 (s), 29.6 (q), 25.3(q), 21.3 ppm (q); IR (NaCl):
procedure for the Swern oxidation, the reaction of oxalyl chloride
(0.46 mL, 5.27 mmol), DMSO (0.64 mL, 9.04 mmol), 22c (1.13 g,
3.77 mmol) and Et3N (3.5 mL, 24.86 mmol) in CH2Cl2 (24 mL) afforded,
after purification by column chromatography (silica gel, 95:5 hexane/
EtOAc), 1.02 g (91%) of a colourless oil identified as 23c. [a]2D9 =ꢀ97.2
(c=0.04 in CHCl3); 1H NMR (400 MHz, CDCl3): d=9.76 (s, 1H; CH),
3.90–3.80 (m, 1H; CH2), 2.20 (dd, J=14.8, 5.1 Hz, 1H; CH2), 1.67 (dd,
J=14.8, 7.4 Hz, 1H; CH2), 1.45 (dd, J=13.3, 3.0 Hz, 1H; CH2), 1.34 (s,
3H; CH3), 1.30–1.20 (m, 1H; CH2), 1.24 (s, 3H; CH3), 1.03 (s, 3H; CH3),
0.84 (s, 9H; CH3), 0.01 ppm (s, 6H; CH3); 13C NMR (100 MHz, CDCl3):
d=200.3 (d), 72.2 (s), 66.1 (s), 64.1 (d), 46.2 (t), 40.7 (t), 33.5 (s), 27.9 (q),
26.1 (q), 25.7 (q, 3”), 20.5 (q), 17.9 (s), ꢀ4.9 ppm (q, 2”); IR (NaCl):
ꢁ ꢀ
ꢀ
ꢀ
n˜ =3600–3100 (br, OH), 3292 (s, C C H), 2963 (s, C H), 2930 (s, C H),
ꢀ1
2100 (w, C C), 1461 (m), 1108 (s), 1051 cm (s); MS (EI+): m/z (%):
ꢁ
180 [M]+ (8), 179 [Mꢀ1]+ (10), 136 (28), 122 (15), 121 (100), 119 (17),
107 (17), 96 (40), 95 (17), 94 (16), 93 (65), 91 (26), 80 (19), 79 (63), 77
(37), 69 (16); HRMS (FAB+): m/z: calcd for C11H16O2: 180.1150; found:
180.1158; elemental analysis calcd for C11H16O2: C 73.30, H 8.95; found:
C 73.28, H 9.12.
ꢀ
ꢀ
n˜ =2931 (s, C H), 2857 (s, C H), 1728 (s, C=O), 1469 (m), 1386 (m),
1255 (s), 1089 cmꢀ1 (s); MS (EI+): m/z (%): 225 (9), 171 (9), 169 (16),
157 (29), 155 (12), 143 (9), 123 (10), 121 (14), 109 (16), 101 (12), 93 (11),
91 (10), 75 (100), 73 (28); HRMS (EI+): m/z: calcd for C12H21O3Si:
241.1260 [MꢀtBu]+; found: 241.1245.
(ꢀ)-Tributyl{(1E,1’S,6’R)-2-(2,2,6-trimethyl-7-oxabicyclo
yl)vinyl}stannane (7a). General procedure for stannylation catalyzed by
palladium: [PdCl2(PPh3)2] (0.02 g, 0.03 mmol) and nBu3SnH (0.52 mL,
1.97 mmol) were sequentially added to solution of 13a (0.27 g,
A
AHCTREUNG
a
(+)-(1R,6R)-1-Ethynyl-2,2,6-trimethyl-7-oxabicyclo
1.64 mmol) in THF (9 mL). After stirring for 10 min at 258C, the mixture
was concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel C-18, 70:30 CH3CN/CH2Cl2) to afford 0.52 g (70%)
of a yellow oil identified as 7a. [a]2D3 =ꢀ19.42 (c=0.59 in CHCl3);
General procedure for the Colvin reaction: A cooled (08C) solution of
iPr2NH (0.59 mL, 4.18 mmol) in THF (30 mL) was treated with nBuLi
(3.89 mL, 1.23m in hexane, 4.78 mmol) and then stirred for 30 min. The
mixture was cooled down to ꢀ788C and trimethylsilyldiazomethane
(2.09 mL, 2.0m in THF, 4.18 mmol) was added. After stirring for 30 min,
a solution of 23a (0.50 g, 2.98 mmol) in THF (15 mL) was added and the
resulting mixture was stirred for 1 h at ꢀ788C and for 2 h at 258C. The
mixture was poured over ice-water and extracted with Et2O (3”). The
combined organic layers were dried (Na2SO4) and the solvent was evapo-
rated. The residue was purified by column chromatography (silica gel,
98:2 hexane/EtOAc) to afford 0.412 g (84%) of a yellow oil identified as
13a. [a]2D2 =+25.51 (c=0.09 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
2.36 (s, 1H; CH), 1.80–1.70 (m, 1H; CH2), 1.70–1.60 (m, 1H; CH2), 1.46
(s, 3H; CH3), 1.40–1.30 (m, 2H; CH2), 1.16 (s, 3H; CH3), 1.13 (s, 3H;
CH3), 1.00–0.90 ppm (m, 2H; CH2); 13C NMR (100 MHz, CDCl3): d=
81.2 (s), 73.4 (d), 64.8 (s), 63.9 (s), 33.8 (t), 33.2 (s), 28.9 (t), 26.1 (q), 25.4
1H NMR (400 MHz, C6D6): d=6.61 (d, J=19.1, 2J
ACHTREUNG
CH), 6.39 (d, J=19.1, 3J
ACHTREUNG
CH2), 1.70–1.50 (m, 9H; CH2), 1.50–1.20 (m, 7H; CH2), 1.22 (s, 3H;
CH3), 1.16 (s, 3H; CH3), 1.10 (s, 3H; CH3), 1.10–0.90 ppm (m, 15H;
CH2 +CH3); 13C NMR (100 MHz, C6D6): d=144.0 (d), 131.5 (d), 72.8 (s),
64.2 (s), 36.3 (t), 33.6 (s), 30.4 (t), 29.6 (t 3”, 3J
(Sn,H)=20.9 Hz), 27.6 (t
2
3”, J
N
(s, CꢀH), 2871 (s, CꢀH), 1460 (m), 1377 cmꢀ1 (w); MS (FAB+): m/z
(%): 403 (15), 401 (16), 400 (100), 398 (40), 397 (78), 396 (32), 395 (43),
291 (24), 289 (19), 287 (13), 235 (11), 179 (24), 177 (29), 175 (20), 165
(24); HRMS (FAB+): m/z: calcd for C23H45O120Sn: 457.2492; found:
457.2482.
ꢀ
(q), 22.7 (q), 16.7 ppm (t); IR (NaCl): n˜ =3310 (s, C=C H), 3000–2800 (s,
ꢀ
(ꢀ)-(1R,3S,6S,1’E)-6-[2-(Tributyltin)vinyl]-1,5,5-trimethyl-7-oxabicyclo-
C H), 2045 (w, C=C), 1460 cmꢀ1; MS (EI+): m/z (%): 164 [M]+ (1), 149
A
(16), 121 (23), 107 (11), 106 (22), 105 (27), 93 (16), 91 (100), 79 (17), 77
(19), 73 (13); HRMS (EI+): m/z: calcd for C11H16O: 164.1201; found:
164.1208.
catalyzed by palladium, the reaction of 13b (0.20 g, 1.13 mmol), [PdCl2-
(PPh3)2] (0.015 g, 0.02 mmol) and nBu3SnH (0.36 mL, 1.35 mmol) in THF
(6 mL) afforded, after purification by column chromatography (silica gel
C-18, CH3CN), 0.36 g (68%) of a colourless oil identified as 7b. [a]D26
AHCTREUNG
(ꢀ)-tert-Butyldimethylsilyl (1R,3S,6R)-6-ethynyl-1,5,5-trimethyl-7-oxabi-
cyclo
[4.1.0]heptan-3-yl ether (13c): Following the general procedure for
ꢀ83.9 (c=0.05 in CHCl3); 1H NMR (400 MHz, (CD3)2CO): d=6.29 (d,
J=19.1 Hz, 1H; CH), 6.19 (d, J=19.1 Hz, 1H; CH), 3.71 (m, 1H; CH),
3.43 (d, J=4.6 Hz, 1H; OH), 2.21 (ddd, J=14.2, 5.0, 1.7 Hz, 1H; CH2),
1.60–1.50 (m, 8H; CH2), 1.40–1.30 (m, 6H; CH2), 1.20 (m, 1H; CH2),
1.13 (s, 6H; CH3), 1.00–0.80 (m, 15H; CH2 +CH3), 0.88 ppm (s, 3H;
Colvin reaction, the reaction of iPr2NH (2.23 mL, 15.89 mmol) in THF
(90 mL), nBuLi (11.8 mL, 1.54m in hexane, 18.14 mmol), trimethylsilyl-
diazomethane (8.0 mL, 2.0m in THF, 15.89 mmol) and 23c (3.38 g,
11.34 mmol) in THF (48 mL) afforded, after purification by column chro-
Chem. Eur. J. 2007, 13, 1273 – 1290
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1283

A. R. de Lera et al.
CH3); 13C NMR (100 MHz, (CD3)2CO): d=146.0 (d), 132.4 (d), 73.3 (s),
67.4 (s), 64.8 (d), 49.0 (t), 42.8 (t), 36.3 (s), 30.9 (q), 30.7 (t), 28.9 (t), 26.3
(q), 21.4 (q), 15.0 (q), 11.1 ppm (t); IR (NaCl): n˜ =3600–3100 (br, OH),
(%): 304 [M]+ (4), 302 [M]+ (3), 186 (17), 163 (100), 160 (50), 158 (40),
121 (32), 107 (21), 105 (46), 91 (16), 84 (38), 81 (15), 79 (24), 77 (27), 69
(18); HRMS (EI+): m/z: calcd for C13H1979BrO3: 302.0518; found:
302.0528; calcd for C13H1981BrO3: 304.0497; found: 304.0498; elemental
analysis calcd for C13H19BrO3: C 51.50; H 6.32; found: C 51.32; H 6.35.
ꢀ
ꢀ
ꢀ
2957 (s, C H), 2924 (s, C H), 2852 (m, C H), 1594 (w), 1160, 1325,
1049 cmꢀ1; MS (FAB+): m/z (%): 419 (15), 417 (15), 416 (19), 415 (100),
414 (40), 413 (78), 412 (32), 411 (43), 357 (18), 291 (33), 289 (26), 179
(45), 177 (57), 176 (18), 175 (39); HRMS (FAB+): m/z: calcd for
C23H43O2118Sn: 469.2279; found: 469.2279.
(E)-1-(Benzothiazol-2-yl)sulfanyl-3-(tri-n-butyltin)-3-methylprop-2-ene
(26). General procedure for sulfide formation: A solution of 25 (4.37 g,
12.12 mmol), 2-mercaptobenzothiazol (3.04 g, 18.19 mmol) and PPh3
(5.08 g, 19.40 mmol) in THF (65 mL) was stirred for 5 min at 08C. A so-
lution of DIAD (3.52 mL, 18.19 mmol) in THF (22 mL) was added and
the mixture was stirred for 30 min at 258C. The solvent was removed and
the residue was purified by column chromatography (silica gel, 96:2:2
hexane/EtOAc/Et3N) to afford 6.07 g (98%) of a colourless oil identified
as 26. 1H NMR (400 MHz, C6D6): d=7.90 (d, J=8.2 Hz, 1H; ArH), 7.23
(d, J=8.0 Hz, 1H; ArH), 7.08 (t, J=8.2 Hz, 1H; ArH), 6.89 (t, J=
8.2 Hz, 1H; ArH), 5.95 (t, J=7.2 Hz, 1H; CH), 4.04 (d, J=7.2 Hz, 2H;
(ꢀ)-(1R,2aR)-2-(2-Bromovinyliden)-1,3,3-trimethylcyclohexanol (12a).
General procedure for bromoallene formation: CuBr (0.34 g, 2.36 mmol),
NH4Br (0.12 g, 1.18 mmol) and HBr (48% aq., 0.43 mL, 3.78 mmol) were
added sequentially to
a
cooled (ꢀ108C) solution of 13a (0.39 g,
2.36 mmol) in Et2O (11.5 mL). After stirring for 30 min, an aqueous solu-
tion of NH4Cl/NH3 1:1 (10 mL) was added and the layers were separated.
The organic layer was washed with brine (3”), dried (Na2SO4) and the
solvent was evaporated. The residue was purified by column chromatog-
raphy (silica gel, 85:15 hexane/EtOAc) to afford 0.501 g (86%) of a
white solid identified as 12a. [a]2D2 =ꢀ17.78 (c=0.146 in CHCl3); m.p. 47–
CH2), 1.94 (s, 3J
(Sn,H)=64.4 Hz, 3H; CH3), 1.80–1.60 (m, 6H; CH2),
A
1.60–1.50 (m, 6H; CH2), 1.10–1.00 ppm (m, 15H; CH2 +CH3); 13C NMR
(100 MHz, C6D6): d=166.7 (s), 154.0 (s), 145.4 (s), 135.9 (s), 133.8 (d),
1
498C (pentane); H NMR (400 MHz, CDCl3): d=5.96 (s, 1H; CH), 1.90–
1.70 (m, 2H; CH2), 1.51 (m, 3H; CH2), 1.43 (m, 1H; CH2), 1.37 (s, 3H;
CH3), 1.24 (s, 3H; CH3), 1.09 ppm (s, 3H; CH3); 13C NMR (100 MHz,
CDCl3): d=197.9 (s), 126.7 (s), 74.1 (d), 70.5 (s), 40.0 (t, 2”), 34.9 (s),
30.8 (q), 30.6 (q), 29.0 (q), 18.0 ppm (t); IR (NaCl): n˜ =3600–3200 (br,
126.1 (d), 124.3 (d), 121.8 (d), 121.1 (d), 30.7 (t), 29.6 (t, 3J
ACHTREUNG
19.7 Hz), 27.7 (t, 2J
1J
(Sn,C)=330.5 Hz); IR (NaCl): n˜ =2954 (s, C H), 2923 (s, C H), 2850
ACHTREUNG
ꢀ
ꢀ
AHCTREUNG
(m, C H), 1458 (m), 1427 (m), 994 cm (m); MS (FAB+): m/z (%): 513
[M+3]+ (10), 512 [M+2]+ (35), 511 [M+1]+ (16), 510 [M]+ (28), 509
(12), 508 (15), 458 (18), 456 (26), 455 (25), 454 (100), 453 (41), 452
[MꢀBu]+ (74), 451 (29), 450 (39), 400 (23), 399 (10), 398 (18), 396 (12),
291 (21), 289 (20), 287 (13), 286 (31), 285 (11), 284 (23), 282 (13), 235
(20), 233 (18), 231 (12), 220 (16), 188 (15); HRMS (FAB+): m/z: calcd
for C23H38NS2118Sn: 510.1462; found: 510.1450.
ꢀ1
ꢀ
ꢀ
ꢀ
ꢀ
OH), 2960 (s, C H), 2928 (s, C H), 2868 (m, C H), 1945 (w, C=C=C),
1454 (m), 1144 cmꢀ1 (s); MS (EI+): m/z (%): 246 [M(81Br)]+ (2), 244 [M-
(79Br)]+ (2), 231 (14), 229 (14), 166 (11), 165 (88), 162 (28), 160 (27), 151
ACHTREUNG
ACHTREUNG
(42), 147 (16), 123 (29), 122 (12), 121 (38), 109 (37), 109 (27), 108 (10),
107 (100), 105 (20), 93 (23), 91 (39), 85 (11), 84 (17), 81 (25), 80 (19), 79
(37), 77 (26), 71 (28), 69 (47), 65 (11); HRMS (EI+): m/z: calcd for
C11H1779BrO: 244.0463; found: 244.0457; elemental analysis calcd for
C11H17BrO: C 53.89, H 6.99; found: C 53.80, H 7.08.
(E)-1-(Benzothiazol-2-yl)sulfonyl-3-(tri-n-butyltin)-3-methylprop-2-ene
(11). General procedure for sulfone formation:
(NH4)6Mo7O24·4H2O (1.21 g, 0.98 mmol) in 35% aqueous hydrogen per-
oxide (6.32 mL, 73.54 mmol) was added to solution of 26 (2.5 g,
A solution of
(ꢀ)-(1R,3S,6aR)-6-(2-Bromovinyliden)-1,5,5-trimethylcyclohexane-1,3-
diol (12b): Following the general procedure for bromoallene formation,
the reaction of 13b (0.20 g, 1.11 mmol), CuBr (0.16 g, 1.11 mmol), NH4Br
(0.06 g, 0.56 mmol) and HBr (48% ac, 0.20 mL, 1.78 mmol) in Et2O
(5.0 mL) for 2.5 h at 258C afforded, after purification by column chroma-
tography (silica gel, 60:40!40:60 hexane/EtOAc), 0.25 g (85%) of a col-
ourless oil identified as 12b. [a]2D4 =ꢀ59.0 (c=0.02 in CHCl3); m.p. 134–
1358C (hexane/EtOAc); 1H NMR (400 MHz, CDCl3): d=5.95 (s, 1H;
CH), 4.25 (tt, J=11.4, 4.1 Hz, 1H; CH), 2.20 (ddd, J=13.4, 4.1, 2.4 Hz,
1H; CH2), 1.88 (ddd, J=12.5, 4.1, 2.4 Hz, 1H; CH2), 1.39 (t, J=11.6 Hz,
1H; CH2), 1.39 (s, 3H; CH3), 1.31 (t, J=11.9 Hz, 1H; CH2), 1.29 (s, 3H;
CH3), 1.12 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=198.4 (s),
124.2 (s), 74.2 (d), 72.3 (s), 63.8 (d), 48.7 (t), 48.4 (t), 35.9 (s), 31.3 (q),
a
4.90 mmol) in EtOH (250 mL). After stirring for 2.5 h, a 20% aqueous
Na2S2O5 solution (150 mL) was added and the resulting mixture was ex-
tracted with Et2O (3”). The combined organic layers were washed with
brine (2”), dried (Na2SO4) and the solvent was removed. The residue
was purified by column chromatography (silica gel, 85:12:3 hexane/
EtOAc/Et3N) and crystallization to afford 2.97 g (56%) of a white solid
identified as 11. M.p. 78–798C (Et2O/hexane); 1H NMR (400 MHz,
C6D6): d=7.93 (d, J=8.2 Hz, 1H; ArH), 7.12 (d, J=8.5 Hz, 1H; ArH),
7.04 (t, J=8.1 Hz, 1H; ArH), 6.91 (t, J=8.0 Hz, 1H; ArH), 5.70 (tq, J=
3
7.4, 1.8, J
G
1.69 (d, J=1.5, 3J
(Sn,H)=62.4 Hz, 3H; CH3), 1.40–1.30 (m, 6H; CH2),
30.6 (q), 29.4 ppm (q); IR (NaCl): n˜ =3600–3100 (br, OH), 2927 (s, C
1.30–1.20 (m, 6H; CH2), 0.90–0.80 ppm (m, 15H; CH2 +CH3); 13C NMR
(100 MHz, C6D6): d=167.6 (s), 153.2 (s), 153.1 (s), 137.1 (s), 128.3 (d),
ꢀ
H), 1950 (w, C=C=C), 1458 (m), 1152 (s), 1041 cmꢀ1 (s); MS (EI+): m/z
(%): 182 (13), 181 (100), 163 (36), 160 (76), 158 (69), 139 (12), 125 (17),
123 (83), 122 (12), 121 (35), 107 (24), 105 (35), 95 (18), 91 (14), 87 (22),
85 (11), 83 (29), 81 (20), 80 (11), 79 (42), 77 (43); HRMS (EI+): m/z:
calcd for C11H1779BrO2: 260.0412; found: 260.0418; elemental analysis
calcd for C11H17BrO2: C 50.59, H 6.56; found: C 50.86; H 6.63.
127.4 (d), 125.1 (d), 123.6 (d, 2J
3J(Sn,C)=57.8 Hz), 29.3 (t, 3J
57.5 Hz), 19.7 (q), 13.8 (q), 9.5 ppm (t, 1J
A
n˜ =2956 (s, C H), 2926 (s, C H), 1472 (m), 1318 (s), 1139 cm (m); UV
(MeOH): lmax =238, 274 nm; MS (FAB+): m/z (%): 544 [M+1]+ (7), 486
(21), 422 (25), 420 (20), 416 (17), 368 (28), 366 (22), 302 (27), 300 (20),
291 (23), 289 (20), 287 (17), 256 (22), 254 (53), 253 (20), 252 (38), 250
(18), 235 (37), 233 (32), 231 (24), 200 (18), 181 (17), 179 (77), 178 (22),
177 (100), 176 (32), 175 (79), 174 (18), 173 (37), 159 (17), 157 (16), 155
(15), 154 (17); HRMS (FAB+): m/z: calcd for C23H38NO2S2120Sn:
544.1366; found: 544.1350; elemental analysis calcd for C23H37NO2S2Sn:
C 50.93, H 6.88; found: C 51.05, H 6.93.
(ꢀ)-(1S,3R,4aR)-4-(2-Bromovinyliden)-3-hydroxy-3,5,5-trimethylcyclo-
hexyl acetate (12d): Ac2O (2.10 mL, 22.37 mmol) was added to a solution
of 12b (1.16 g, 4.47 mmol) in pyridine (14 mL). After stirring for 3 h, the
mixture was extracted with tBuOMe (3”). The combined organic layers
were washed with a saturated aqueous CuSO4 solution (2”), dried
(Na2SO4) and the solvent was evaporated. The residue was purified by
column chromatography (silica gel, 90:10!80:20 hexane/EtOAc) to
afford 1.15 g (85%) of a white solid identified as 12d. [a]2D4 =ꢀ35.7 (c=
0.03 in CHCl3); m.p. 94–968C (hexane/EtOAc); 1H NMR (400 MHz,
CDCl3): d=5.95 (s, 1H; CH), 5.28 (m, 1H; CH), 2.20 (ddd, J=13.0, 4.1,
2.3 Hz, 1H; CH2), 1.98 (s, 3H; CH3), 1.90 (ddd, J=12.4, 4.1, 2.3 Hz, 1H;
CH2), 1.50–1.30 (m, 2H; CH2), 1.38 (s, 3H; CH3), 1.32 (s, 3H; CH3),
1.11 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=198.3 (s), 170.4
(s), 123.7 (s), 74.2 (d), 71.8 (s), 67.4 (d), 44.6 (t, 2”), 35.7 (s), 31.1 (q),
30.3 (q), 29.0 (q), 21.2 ppm (q); IR (NaCl): n˜ =3600–3100 (br, OH), 3058
(ꢀ)-(1R,2aS,3’E)-2-[5-(Benzothiazol-2-sulfonyl)-3-methylpenta-1,3-dien-
A
the Stille reaction of bromoallenes: [PdCl2(PhCN)2] (0.006 g,
E
0.016 mmol) was added to a solution of 12a (0.020 g, 0.082 mmol) in
DMF (1 mL). After stirring for 5 min at 258C, a solution of 11 (0.066 g,
0.122 mmol) in THF (0.8 mL) was added and the mixture was deoxygen-
ated with freeze–thaw cycles (3”). A solution of iPr2NEt (0.021 mL,
0.123 mmol) was added and the resulting mixture was stirred for 1.5 h at
408C. A saturated aqueous KF solution was added and the layers were
separated. The aqueous layer was extracted with EtOAc (3”). The com-
ꢀ
ꢀ
ꢀ
ꢀ
(w, C H), 2966 (s, C H), 2927 (s, C H), 2859 (m, C H), 1949 (w, C=C=
ꢀ1
C), 1720 (s, C=O), 1366 (s), 1267 (s, C O), 1031 cm (s); MS (EI+): m/z
ꢀ
1284
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1273 – 1290

Total Synthesis of Peridinin
FULL PAPER
bined organic layers were washed with brine (3”), dried (Na2SO4) and
the solvent was removed. The residue was purified by column chromatog-
raphy (silica gel, 70:30 hexane/EtOAc) to afford 24 mg (69%) of an
orange oil (foam) identified as (aS)-10a. [a]2D0 =ꢀ21.84 (c=0.02 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=8.18 (d, J=8.1 Hz, 1H; ArH),
7.95 (d, J=7.8 Hz, 1H; ArH), 7.60–7.50 (m, 2H; ArH), 5.93 (s, 1H; CH),
5.38 (t, J=8.1 Hz, 1H; CH), 4.30 (dd, J=8.1, 4.1 Hz, 2H; CH2), 1.90–
1.80 (m, 1H; CH2), 1.70–1.60 (m, 1H; CH2), 1.47 (s, 3H; CH3), 1.50–1.40
(m, 2H; CH2), 1.30–1.20 (m, 2H; CH2), 1.14 (s, 3H; CH3), 1.06 (s, 3H;
CH3), 0.85 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=201.4 (s),
165.5 (s), 152.5 (s), 141.8 (s), 127.8 (d), 127.5 (d), 125.3 (d), 122.1 (d),
120.1 (s), 110.4 (d), 101.3 (d), 70.7 (s), 55.3 (t), 40.0 (t), 39.9 (t), 34.2 (s),
31.2 (q), 30.9 (q), 29.1 (q), 18.1 (t), 14.0 ppm (q); IR (NaCl): n˜ =3600–
(s), 132.2 (d), 125.3 (d), 123.6 (d), 120.4 (s), 104.0 (d), 71.2 (s), 41.0 (t, 2”),
35.1 (s), 32.4 (q), 31.9 (q), 30.1 (t, 3J
ACHTREUNG
(t, 2J
1J
ACHTREUNG
AHCTREUNG
ꢀ
ꢀ
ꢀ
C H), 2925 (s, C H), 2870 (s, C H), 1927 (w, C=C=C), 1686 (w), 1600
(w), 1460 cmꢀ1 (m); UV (MeOH): lmax =308, 320, 334 nm; MS (FAB+):
m/z (%): 491 [MꢀBu]+ (35), 489 (29), 475 (20), 474 (29), 473 (90), 472
(42), 471 (70), 470 (32), 469 (39), 359 (24), 357 (22), 291 (71), 290 (31),
289 (63), 288 (27), 287 (38), 251 (20), 239 (43), 235 (52), 234 (23), 233
(42), 231 (29), 183 (21), 179 (98), 178 (31), 177 (100), 176 (35), 175 (66),
169 (20), 165 (28); HRMS (FAB+): m/z: calcd for C30H53O120Sn:
549.3118; found: 549.3111.
(ꢀ)-(1S,3R,4aS,3’E,5’Z,7’E)-3-Methyl-4-[8-(tributyltin)octa-1,3,5,7-tetrae-
nyliden]-3-hydroxy-3,5,5-trimethylcyclohexyl acetate ((aS)-8d): Following
the general procedure for the modified Julia olefination, the reaction of
(aS)-10d (0.23 g, 0.47 mmol) with NaHMDS (1.42 mL, 1m in THF,
1.42 mmol) and (E)-3-tri-n-butyltinpropen-1-al 9 (0.24 g, 0.71 mmol) in
THF (33 mL) afforded, after purification by column chromatography
(silica gel, 90:8:2 hexane/EtOAc/Et3N), 149 mg (70%) of a yellow oil
identified as (aS)-8d. [a]2D2 =ꢀ59.9 (c=0.04 in CHCl3); 1H NMR
(400 MHz, C6D6): d=7.43 (dd, J=18.5, 10.4 Hz, 1H; CH), 6.75 (d, J=
11.6 Hz, 1H; CH), 6.55 (d, J=18.5 Hz, 1H; CH), 6.25 (t, J=11.0 Hz,
1H; CH), 6.20 (t, J=10.5 Hz, 1H; CH), 6.03 (s, 1H; CH), 5.66 (ddd, J=
11.5, 7.3, 4.2 Hz, 1H; CH), 2.23 (ddd, J=12.6, 4.1, 2.1 Hz, 1H; CH2), 2.00
(ddd, J=12.2, 4.0, 2.0 Hz, 1H; CH2), 1.72 (s, 3H; CH3), 1.71 (s, 3H;
CH3), 1.60–1.50 (m, 6H; CH2), 1.44 (s, 3H; CH3), 1.40–1.30 (m, 8H;
CH2), 1.15 (s, 3H; CH3), 1.10–1.00 (m, 6H; CH2), 1.03 (s, 3H; CH3),
1.00–0.90 ppm (m, 9H; CH3); 13C NMR (100 MHz, C6D6): d=202.2 (s),
169.3 (s), 142.3 (d), 136.0 (d), 133.4 (s), 131.7 (d), 124.4 (d), 123.3 (d),
117.4 (s), 103.5 (d), 72.1 (s), 67.7(d), 45.2 (t, 2”), 35.3 (s), 32.0 (q), 30.8
(q), 29.2 (q), 29.2 (t), 27.3 (t), 20.6 (q), 13.7 (q), 13.6 (q), 9.6 ppm (t); IR
ꢀ
3400 (br, OH), 3000–2800 (s, C H), 1937 (w, C=C=C), 1471 (s), 1328 (s),
1149 cmꢀ1 (s); MS (EI+): m/z (%): 328 (30), 268 (29), 165 (89), 161 (22),
151 (100), 145 (33), 135 (24), 134 (40), 132 (29), 122 (20), 121 (21), 107
(22), 93 (20), 77 (25), 69 (66), 67 (24), 65 (72); HRMS (EI+): m/z: calcd
for C22H27NO3S2: 417.1432; found: 417.1417.
(ꢀ)-(1S,3R,4aS,3’E)-4-[5-(Benzothiazol-2-sulfonyl)-3-methylpenta-1,3-di-
enyliden]-3-hydroxy-3,5,5-trimethylcyclohexyl acetate ((aS)-10d): Follow-
ing the general procedure for the Stille reaction of bromoallenes, the re-
action of 12d (0.050 g, 0.165 mmol) with 11 (0.134 g, 0.248 mmol), [PdCl2-
A
DMF (2.0 mL) and THF (1.6 mL) afforded, after purification by column
chromatography (silica gel, 70:30!60:40 hexane/EtOAc), 0.05 g (64%)
of an orange solid identified as (aS)-10d. [a]2D4 =ꢀ30.4 (c=0.05 in
CHCl3); m.p. 133–1348C (hexane/EtOAc); 1H NMR (400 MHz, CDCl3):
d=8.18 (d, J=7.7 Hz, 1H; ArH), 7.95 (d, J=7.5 Hz, 1H; ArH), 7.60–
7.50 (m, 2H; ArH), 6.00 (s, 1H; CH), 5.42 (t, J=8.1 Hz, 1H; CH), 5.26
(m, 1H; CH), 4.31 (d, J=8.1 Hz, 2H; CH2), 2.14 (ddd, J=12.8, 4.1,
2.1 Hz, 1H; CH2), 1.98 (s, 3H; CH3), 1.85 (ddd, J=12.3, 4.0, 2.0 Hz, 1H;
CH2), 1.50 (s, 3H; CH3), 1.50–1.20 (m, 2H; CH2), 1.21 (s, 3H; CH3), 1.16
(s, 3H; CH3), 0.88 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
201.7 (s), 170.3 (s), 165.5 (s), 152.5 (s), 141.3 (s), 137.0 (s), 127.9 (d), 127.6
(d), 125.3 (d), 122.2 (d), 117.7 (s), 111.1 (d), 101.7 (d), 72.2 (s), 67.7 (d),
55.2 (t), 44.8 (t, 2”), 35.2 (s), 31.8 (q), 30.9 (q), 29.2 (q), 21.2 (q),
ꢀ
ꢀ
(NaCl): n˜ =3359 (m), 3194 (m), 2959 (s, C H), 2924 (s, C H), 2852 (s,
ꢀ
C H), 1932 (w, C=C=C), 1721 (m, C=O), 1660 (s), 1632 (s), 1466 (m),
1262 cmꢀ1 (s, C O); UV (MeOH): lmax =306, 319, 332 nm; MS (FAB+):
ꢀ
m/z (%): 549 [M]+ (4), 547 (3), 545 (2), 531 (13), 530 (6), 529 (12), 473
(10), 471 (20), 469 (13), 297 (13), 295 (19), 293 (81), 292 (31), 291 (96),
290 (35), 289 (70), 288 (18), 287 (25), 239 (18), 237 (24), 235 (41), 234
(14), 233 (32), 232 (12), 231 (20), 183 (19), 181 (21), 179 (100), 178 (30),
177 (99), 176 (33), 175 (66), 174 (10), 173 (18); HRMS (FAB+): m/z:
calcd for C28H45O3116Sn: 545.2386; found: 545.2388; calcd for
C28H45O3120Sn: 549.2391; found: 549.2385.
ꢀ
14.1 ppm (q); IR (NaCl): n˜ =3600–3100 (br, OH), 2962 (s, C H), 2924 (s,
ꢀ
ꢀ
C H), 2852 (w, CH), 1939 (w, C=C=C), 1726 (s, C=O), 1250 (s, C O),
1186 cmꢀ1 (s); MS (EI+): m/z (%): 475 [M]+ (8), 411 (22), 385 (20), 382
(43), 277 (89), 276 (36), 268 (27), 217 (99), 216 (24), 214 (27), 201 (41),
200 (30), 199 (29), 189 (68), 187 (22), 173 (41), 163 (41), 161 (30), 159
(100), 158 (22), 157 (21), 145 (22), 143 (26), 136 (68), 135 (77), 133 (67),
131 (27), 121 (24), 119 (35), 117 (21), 108 (25), 107 (22), 105 (43), 95 (23),
91 (36); HRMS (EI+): m/z: calcd for C24H29NO5S2: 475.1487; found:
475.1487; elemental analysis calcd for C24H29NO5S2: C 60.61, H 6.15, N
2.94, S 13.48; found: C 60.44, H 6.15, N 2.92, S 13.25.
(Z)-3-Bromo-5-((2E,4E,6E,8E)-11-((R)-2-hydroxy-2,6,6-trimethylcyclo-
hexylidene)-2,9-dimethylundeca-2,4,6,8,10-pentaenylidene)furan-2(5H)-
one ((aS,11’Z)-29a). General procedure for Stille cross-coupling: [AsPh3]
(0.005 g, 0.017 mmol) was added to
a
solution of [Pd2(dba)3]·CHCl3
A
(0.002 g, 0.002 mmol) in THF (0.7 mL). After stirring for 5 min,
6
(ꢀ)-(1R,2aS,3’E,5’Z,7’E)-2-(3-Methyl-8-tributyltin-octa-1,3,5,7-tetraenyli-
den)-1,3,3-trimethylcyclohexan-1-ol ((aS)-8a). General procedure for the
(0.023 g, 0.068 mmol) was added and the mixture was stirred for 10 min.
A solution of (aS,5’Z)-8a (0.045 g, 0.081 mmol) in THF (0.7 mL) and
Bu4NPh2PO2 (0.031 g, 0.068 mmol) in one portion were sequentially
added. After stirring for 4.5 h at 258C, brine was added and the mixture
was extracted with EtOAc/CH2Cl2 90:10 (3”). The combined organic
layers were dried (Na2SO4) and the solvent was evaporated. The residue
was purified by column chromatography (silica gel, 90:10!80:20 hexane/
EtOAc) to afford 27.9 mg (87%) of a red solid identified as a mixture of
(aS,11’Z)-29a and its isomer (aS,11’E)-29a in a 1:3.5 ratio.
Data for (aS,11’Z)-29a: 1H NMR (600 MHz, CDCl3): d=7.41 (s, 1H;
CH), 6.95 (t, J=12.5 Hz, 1H; CH), 6.58 (dd, J=12.7, 11.9 Hz, 1H; CH),
6.55 (d, J=11.9 Hz, 1H; CH), 6.50 (d, J=12.2 Hz, 1H; CH), 6.40 (t, J=
11.5 Hz, 1H; CH), 6.12 (t, J=11.3 Hz, 1H; CH), 6.12 (s, 1H; CH), 5.76
(s, 1H; CH), 2.20 (s, 3H; CH3), 1.90 (m, 1H; CH2), 1.83 (s, 3H; CH3),
1.80 (m, 1H; CH2), 1.55–1.45 (m, 3H; CH2), 1.40–1.30 (m, 1H; CH2),
1.31 (s, 3H; CH3), 1.26 (s, 3H; CH3), 1.02 ppm (s, 3H; CH3); 13C NMR
(150 MHz, CDCl3): d=202.4 (s), 165.7 (s), 146.1 (s), 142.2 (d), 139.6 (d),
135.8 (s), 133.4 (s), 132.9 (d), 129.4 (d), 128.5 (d), 128.3 (d), 122.8 (d),
120.4 (s), 120.2 (d), 109.1 (s), 103.6 (d), 71.1 (s), 40.2 (t, 2”), 34.6 (s),
31.9 (q), 31.8 (q), 29.5 (q), 18.4 (t), 15.4 (q), 14.1 ppm (q); IR (NaCl): n˜ =
modified Julia olefination:
A
cooled (ꢀ788C) solution of (aS)-10a
(0.051 g, 0.12 mmol) in THF (6 mL) was treated with NaHMDS
(0.37 mL, 1m in THF, 0.37 mmol). After stirring for 30 min at this tem-
perature, a solution of 3-tri-n-butyltinpropen-1-al 9 (0.063 g, 0.18 mmol)
in THF (3 mL) was added and the resulting mixture was stirred for 2 h at
ꢀ788C. Water was added at low temperature and the mixture was
warmed up to room temperature. It was then diluted with Et2O and the
layers were separated. The aqueous layer was extracted with Et2O (3”),
the combined organic layers were dried (Na2SO4) and the solvent was re-
moved. The residue was purified by column chromatography (silica gel,
93:5:2 hexane/EtOAc/Et3N) to afford 52.5 mg (79%) of a yellow oil iden-
tified as a mixture of 5’Z/5’E isomers of (aS)-8a in a 5:1 ratio.
Data for (1R,2aS,3’E,5’Z,7’E)-8a: [a]2D2 =ꢀ26.1 (c=0.05 in CHCl3);
3
1H NMR (400 MHz, C6D6): d=7.44 (dd, J=18.5, 10.6, J
A
1H; CH), 6.76 (d, J=11.7 Hz, 1H; CH), 6.53 (d, J=18.5, 2J
(Sn,H)=
A
71.2 Hz, 1H; CH), 6.29 (t, J=11.0 Hz, 1H; CH), 6.19 (t, J=10.7 Hz, 1H;
CH), 6.04 (s, 1H; CH), 1.89 (m, 1H; CH2), 1.76 (s, 3H; CH3), 1.72 (m,
1H; CH2), 1.70–1.50 (m, 7H; CH2), 1.50–1.30 (m, 12H; CH2 +CH3), 1.24
(s, 3H; CH3), 1.07 (s, 3H; CH3), 1.01 (m, 6H; CH2), 0.92 ppm (m, 9H;
CH3); 13C NMR (100 MHz, C6D6): d=202.7 (s), 143.2 (d), 136.3 (d), 134.6
ꢀ
3700–3600 (br, OH), 2922 (w, C H), 1755 (s, C=O), 1519 (m), 1346 (w),
1184 (w), 977 cmꢀ1 (m); MS (FAB+): m/z (%): 473 [M+1]+, 36), 472
Chem. Eur. J. 2007, 13, 1273 – 1290
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1285

A. R. de Lera et al.
[M]+, 100), 471 [M+1]+ (36), 470 [M]+ (100), 393 (79), 282 (71); HRMS
(FAB+): m/z: calcd for C26H3179BrO3: 470.1457; found: 470.1473; calcd
for C26H3181BrO3: 472.1436; found: 472.1436.
6’-epi-Peridinin 6’-epi-(1): Following the general procedure for the Stille
cross-coupling, the reaction of (aS,11’Z)-29d (0.019 g, 0.035 mmol) with
7b (0.02 g, 0.043 mmol), [Pd2(dba)3]·CHCl3 (0.002 g, 0.002 mmol),
A
Data for (aS,11’E)-29a: 1H NMR (600 MHz, CDCl3): d=7.40 (s, 1H;
CH), 6.64 (dd, J=14.5, 11.8 Hz, 1H; CH), 6.60–6.50 (m, 2H; CH), 6.48
(d, J=10.7 Hz, 1H; CH), 6.33 (dd, J=14.5, 10.1 Hz, 1H; CH), 6.08 (d,
J=11.1 Hz, 1H; CH), 6.08 (s, 1H; CH), 5.77 (s, 1H; CH), 2.19 (s, 3H;
CH3), 1.89 (m, 1H; CH2), 1.83 (s, 3H; CH3), 1.77 (m, 1H; CH2), 1.55–
1.45 (m, 3H; CH2), 1.34 (m, 1H; CH2), 1.30 (s, 3H; CH3), 1.25 (s, 3H;
CH3), 1.01 ppm (s, 3H; CH3); 13C NMR (150 MHz, CDCl3): d=202.3 (s),
165.8 (s), 145.9 (s), 142.2 (d), 139.8 (d), 138.4 (d), 135.5 (s), 133.0 (s),
132.4 (d, 2”), 128.4 (d), 127.9 (d), 120.4 (d), 120.4 (s), 108.9 (s), 103.5
(d), 71.1 (s), 40.2 (t, 2”), 34.6 (s), 31.4 (q), 31.2 (q), 29.6 (q), 18.4 (t), 15.2
[AsPh3] (0.0043 g, 0.014 mmol), Bu4NPh2PO2 (0.016 g, 0.035 mmol) and
BHT (traces) in THF (1.5 mL) for 31 h at 558C, afforded, after purifica-
tion by column chromatography (silica gel, 70:30!0:100 hexane/EtOAc),
15.9 mg (72%) of a red solid identified as 6’-epi-1. 1H NMR (750 MHz,
(CD3)2CO): d=7.57 (s, 1H; CH), 7.22 (d, J=15.2 Hz, 1H; CH), 6.82 (dd,
J=14.2, 11.2 Hz, 1H; CH), 6.80 (dd, J=14.0, 11.2 Hz, 1H; CH), 6.68
(dd, J=14.0, 11.8 Hz, 1H; CH), 6.62 (d, J=11.2 Hz, 1H; CH), 6.52 (dd,
J=14.2, 11.2 Hz, 1H; CH), 6.42 (d, J=15.4 Hz, 1H; CH), 6.26 (s, 1H;
CH), 6.23 (d, J=11.0 Hz, 1H; CH), 6.09 (s, 1H; CH), 5.40 (m, 1H; CH),
4.23 (s, 1H; OH), 3.86 (s, 1H; OH), 3.77 (m, 1H; CH), 2.30 (dd, J=14.4,
3.2 Hz, 1H; CH2), 2.17 (d, J=12.0 Hz, 1H; CH2), 2.01 (s, 3H; CH3), 1.93
(m, 1H; CH2), 1.91 (s, 3H; CH3), 1.68 (dd, J=14.3, 9.3 Hz, 1H; 2H2),
1.57 (d, J=12.7 Hz, 1H; CH2), 1.46 (s, 3H; CH3), 1.44 (d, J=12.1 Hz,
1H; CH2), 1.40–1.30 (m, 1H; CH2), 1.35 (s, 3H; CH3), 1.29 (t, J=
12.0 Hz, 1H; CH2), 1.19 (s, 3H; CH3), 1.17 (s, 3H; CH3), 1.06 (s, 3H;
CH3), 0.94 ppm (s, 3H; CH3); 13C NMR (100 MHz, (CD3)2CO): d=204.4
(s), 171.4 (s), 170.2 (s), 149.0 (s), 140.0 (d), 139.5 (d), 138.8 (d), 137.0 (s),
135.6 (d), 135.3 (s), 134.7 (d), 133.7 (d), 130.7 (d), 130.0 (d), 126.4 (s),
123.6 (d), 120.7 (d), 119.5 (s), 104.9 (d), 73.4 (s), 71.8 (s), 69.5 (d), 69.0
(s), 64.7 (d), 48.9 (t), 47.5 (t), 47.2 (t), 42.8 (t), 37.2 (s), 36.8 (s), 33.7 (q),
32.2 (q), 31–30 (q, 2”), 26.4 (q), 22.2 (q), 21.2 (q), 16.4 (q), 15.5 ppm (q);
ꢀ
ꢀ
(q), 14.3 ppm (q); IR (NaCl): n˜ =2958 (s, C H), 2924 (s, C H), 2851 (m,
ꢀ1
ꢀ
C H), 1756 (s, C=O), 1518 (w), 1345 (w), 979 cm (s); UV (MeOH):
lmax =289, 458 nm; MS (FAB+): m/z (%): 473 [M+1]+ (5), 472 [M]+
(11), 470 [M]+ (10), 307 (17), 289 (15), 202 (17), 189 (16), 180 (21), 178
(21), 167 (19), 165 (34); HRMS (FAB+): m/z: calcd for C26H3179BrO3:
470.1457; found: 470.1464; calcd for C26H3181BrO3: 472.1436; found:
472.1458.
A
3,10-dimethylundeca-1,3,5,7,9-pentaenylidene]-3-hydroxy-3,5,5-trimethyl-
cyclohexyl acetate ((aS,11’Z)-29d): Following the general procedure for
the Stille cross-coupling, the reaction of (aS,5’Z)-8a (0.169 g, 0.279 mmol)
ꢀ
IR (NaCl): n˜ =3500–3300 (br, OH), 3359 (s), 3000–2850 (s, C H), 1926
with 6 (0.127 g, 0.372 mmol), [Pd
A
(w, C=C=C), 1750 cmꢀ1 (s, C=O); MS (FAB+): m/z (%): 631 [M+1]+ (6),
630 [M]+ (12), 252 (20), 241 (22), 239 (34), 228 (23), 227 (22), 226 (22),
215 (21), 204 (23), 202 (30). 191 (26), 190 (23), 189 (30), 181 (24), 180
(32), 179 (23), 178 (41), 176 (28), 168 (20), 167 (40), 166 (30), 165 (74);
HRMS (FAB+): m/z: calcd for C39H50O7: 630.3557; found: 630.3550;
calcd for C39H51O7: 631.3635; found: 631.3637.
[AsPh3] (0.013 g, 0.042 mmol), Bu4NPh2PO2 (0.107 g, 0.232 mmol) and
BHT (traces) in THF (5 mL) for 5.5 h at 258C, afforded, after purifica-
tion by column chromatography (silica gel, 80:20!70:30 hexane/EtOAc),
84 mg (68%) of a red solid identified as a mixture of (aS,11’Z)-29d and
its isomer (aS,11’E)-29d in a 1:5 ratio.
Data for (aS,11’Z)-29d: 1H NMR (600 MHz, CDCl3): d=7.43 (s, 1H;
CH), 6.95 (t, J=12.3 Hz, 1H; CH), 6.59 (t, J=12.6 Hz, 1H; CH), 6.55 (d,
J=12.3 Hz, 1H; CH), 6.52 (d, J=12.3 Hz, 1H; CH), 6.41 (t, J=11.7 Hz,
1H; CH), 6.18 (s, 1H; CH), 6.14 (t, J=11.5 Hz, 1H; CH), 5.77 (s, 1H;
CH), 5.35 (m, 1H; CH), 2.30–2.20 (m, 1H; CH2), 2.20 (s, 3H; CH3), 2.01
(s, 3H; CH3), 1.94 (d, J=10.6 Hz, 1H; CH2), 1.83 (s, 3H; CH3), 1.50–1.40
(m, 1H; CH2), 1.40 (s, 3H; CH3), 1.40–1.30 (m, 1H; CH2), 1.33 (s, 3H;
CH3), 1.05 ppm (s, 3H; CH3); 13C NMR (150 MHz, CDCl3): d=202.8 (s),
170.4 (s), 165.7 (s), 146.1 (s), 142.2 (d), 139.5 (d), 135.1 (s), 133.4 (s),
132.8 (d), 129.5 (d), 128.8 (d), 128.0 (d), 123.2 (d), 120.2 (d), 117.7 (s),
109.1 (s), 103.8 (d), 72.6 (s), 67.9 (d), 45.0 (t), 44.9 (t), 35.5 (s), 32.0 (q),
31.2 (q), 29.4 (q), 21.3 (q), 15.3 (q), 14.1 ppm (q); IR (NaCl): n˜ =3600–
(5Z,2’E,4’E)-3-Bromo-5-(6-hydroxy-2-methylhexa-2,4-dienyliden)-5H-
furan-2-one (15): Following the general procedure for the Stille cross-
coupling, the reaction of
6 (0.053 g, 0.154 mmol) with 31 (0.067 g,
0.193 mmol), [Pd2(dba)3]·CHCl3 (0.003 g, 0.003 mmol), [AsPh3] (0.008 g,
AHCTREUNG
0.025 mmol) and Bu4NPh2PO2 (0.071 g, 0.145 mmol) in THF (3.4 mL) for
4.5 h afforded, after purification by column chromatography (silica gel,
60:40!50:50 hexane/EtOAc), 28.2 mg (68%) of a red solid identified as
1
15. M.p. 111–1138C (CH2Cl2/Et2O); H NMR (600 MHz, CDCl3): d=7.42
(s, 1H; CH), 6.63 (ddt, J=15.0, 11.3, 1.6 Hz, 1H; CH), 6.42 (d, J=
11.3 Hz, 1H; CH), 6.05 (dt, J=15.1, 5.5 Hz, 1H; CH), 5.73 (s, 1H; CH),
4.26 (d, J=5.4 Hz, 2H; CH2), 2.22 ppm (s, 3H; CH3); 13C NMR
(150 MHz, CDCl3): d=165.7 (s), 146.2 (s), 142.5 (d), 138.0 (d), 137.2 (d),
133.1 (s), 126.7 (d), 119.9 (d), 109.9 (s), 63.3 (t), 15.2 ppm (q); IR (NaCl):
ꢀ
ꢀ
ꢀ
3100 (br, OH), 2961 (w, C H), 2924 (w, C H), 2853 (w, C H), 1929 (w,
C=C=C), 1755 (s, C=O), 1554 (m), 1260 (m), 976 cmꢀ1 (m); UV
(MeOH): lmax =244, 289, 456 nm; MS (FAB+): m/z (%): 531 (13), 530
[M]+, 55), 529 (13), 528 [M]+ (47), 453 (32), 451 (29); HRMS (EI+):
m/z: calcd for C28H3379BrO5: 528.1511; found: 528.1530; calcd for
C28H3381BrO5: 530.1491; found: 530.1481.
ꢀ
ꢀ
n˜ =3600–3200 (br, OH), 2924 (w, C H), 2852 (w, C H), 1755 (s, C=O),
1606 (w), 1344 (w), 985 cmꢀ1 (s); UV (MeOH): lmax =248, 348, 368,
387 nm; MS (EI+): m/z (%): 272 [M]+ (14), 270 [M]+ (21), 188 (70), 187
(23), 145 (23), 135 (30), 133 (30), 120 (30), 119 (100), 116 (20), 115 (36),
107 (49), 95 (28), 92 (41), 91 (58), 79 (55), 78 (20), 77 (46), 67 (23), 65
(23); HRMS (EI+): m/z: calcd for C11H1179BrO3: 269.9892; found:
269.9892; calcd for C11H1181BrO3: 271.9871; found: 271.9867.
3,3’-Didehydroxy-6’-epi-peridinin (30): Following the general procedure
for the Stille cross-coupling, the reaction of bromide (aS,11’Z)-29a
(ꢀ)-3-Dehydroxy-14’-apo-peridinin-14’-ol (32): Following the general
(0.021 g, 0.045 mmol) with 7b (0.025 g, 0.054 mmol), [Pd2(dba)3]·CHCl3
G
procedure for the Stille cross-coupling, the reaction of 15 (0.028 g,
(0.001 g, 0.001 mmol), [AsPh3] (0.002 g, 0.007 mmol) and Bu4NPh2PO2
(0.021 g, 0.045 mmol) in THF (2.0 mL) at 558C for 20 h afforded, after
purification by column chromatography (silica gel, 80:20!70:30 hexane/
EtOAc), 3.5 mg (21% yield based on recovered starting material) of a
red solid identified as 6’-epi-30 and 7.0 mg of starting (aS,11’Z)-29a.
1H NMR (400 MHz, CDCl3): d=7.13 (d, J=15.8 Hz, 1H; CH), 6.98 (s,
1H; CH), 6.60–6.40 (m, 3H; CH), 6.41 (d, J=10.9 Hz, 1H; CH), 6.30–
6.20 (m, 1H; CH), 6.34 (d, J=15.7 Hz, 1H; CH), 6.08 (d, J=12.1 Hz,
1H; CH), 6.08 (s, 1H; CH), 5.69 (s, 1H; CH), 2.34 (t, J=8.1 Hz, 1H;
CH2), 2.20 (s, 3H; CH3), 1.99 (m, 1H; CH2), 1.90–1.70 (m, 6H; CH2),
1.83 (s, 3H; CH3), 1.52 (s, 3H; CH3), 1.50–1.30 (m, 3H; CH2), 1.30 (s,
3H; CH3), 1.30–1.20 (m, 1H; CH2), 1.25 (s, 3H; CH3), 1.13 (s, 6H; CH3),
1.01 ppm (s, 3H; CH3); IR (NaCl): n˜ =3000–2850 (s, CH), 1930 (w, C=C=
C), 1751 cmꢀ1 (s, C=O); MS (FAB+): m/z (%): 557 [M+1]+ (18), 556
[M]+ (30), 539 (12), 307 (37), 289 (17); HRMS (FAB+): m/z: calcd for
C37H49O4: 557.3631; found: 557.3616.
0.104 mmol) with 7a (0.057 g, 0.125 mmol), [Pd2(dba)3]·CHCl3 (0.002 g,
A
0.002 mmol), [AsPh3] (0.0043 g, 0.014 mmol) and Bu4NPh2PO2 (0.048 g,
0.104 mmol) in THF (4.0 mL) at 558C for 20 h afforded, after purification
by column chromatography (silica gel, 60:40!50:50 hexane/EtOAc),
16.6 mg (45%) of a yellow oil identified as 32; [a]2D3 =ꢀ83.8 (c=0.05 in
CHCl3); 1H NMR (600 MHz, (CD3)2CO): d=7.49 (s, 1H; CH), 7.16 (d,
J=15.5 Hz, 1H; CH), 6.73 (ddt, J=15.0, 11.3, 1.8 Hz, 1H; CH), 6.51 (d,
J=11.3 Hz, 1H; CH), 6.39 (d, J=15.5 Hz, 1H; CH), 6.08 (dt, J=15.0,
5.2 Hz, 1H; CH), 5.95 (s, 1H; CH), 4.22 (brs, 2H; CH2), 3.89 (s, 1H;
OH), 2.18 (s, 3H; CH3), 1.90–1.80 (m, 2H; CH2), 1.50–1.40 (m, 3H;
CH2), 1.16 (s, 3H; CH3), 1.13 (s, 3H; CH3), 1.11 (m, 1H; CH2), 0.91 ppm
(s, 3H; CH3); 13C NMR (100 MHz, (CD3)2CO): d=169.3 (s), 147.9 (s),
139.6 (d), 138.1 (d), 138.0 (d), 134.5 (d), 133.3 (s), 126.3 (d), 125.8 (s),
122.6 (d), 119.5 (d), 71.7 (s), 66.4 (s), 63.0 (t), 36.6 (t), 34.4 (s), 30.8 (t),
26.4 (q), 26.2 (q), 21.1 (q), 17.8 (t), 15.4 ppm (q); IR (NaCl): n˜ =3600–
ꢀ
ꢀ
3200 (br, OH), 2961 (s, C H), 2926 (s, C H), 2860 (m), 1751 (s, C=O),
1286
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1273 – 1290

Total Synthesis of Peridinin
FULL PAPER
1261 (s), 1091 (s), 1024 cmꢀ1 (s); UV (MeOH): lmax =247, 377 nm; MS
(EI+): m/z (%): 357 [M+1]+ (6), 356 [M]+ (24), 355 (20), 346 (20), 344
(22), 338 (29), 281 (16), 253 (21), 232 (46), 109 (15), 91 (18), 83 (16), 81
(22), 73 (20), 71 (15), 69 (100); HRMS (EI+): m/z: calcd for C22H28O4:
356.1988; found: 356.1981.
(ꢀ)-(1R,5S,2aR,3’E)-5-(tert-Butyldimethylsilyloxy)-2-(5-hydroxy-3-meth-
ylpenta-1,3-dienylidene)-1,3,3-trimethylcyclohexanol (37c): DIBAL-H
(10.14 mL, 1m in hexane, 10.14 mmol) was added to a solution of 35c
(0.370 g, 1.01 mmol) in CH2Cl2 (12 mL) at 08C and the mixture was stir-
red for 10 min. After careful addition of H2O (5 mL) and a 10% aqueous
solution of HCl, the mixture was extracted with EtOAc (3”). The com-
bined organic layers were washed with brine (3”), dried (Na2SO4) and
concentrated. The residue was purified by column chromatography (silica
gel, 80:20 hexane/EtOAc) to afford 0.372 mg (100%) of a yellow oil
identified as 37c. [a]D22 =ꢀ24.52 (c=0.027 in MeOH); 1H NMR
(400 MHz, (CD3)2CO): d=5.91 (s, 1H; CH), 5.56 (t, J=6.6 Hz, 1H; CH),
4.40–4.30 (m, 1H; CH), 4.18 (d, J=6.0 Hz, 2H; CH2), 2.14 (dd, J=12.7,
4.1 Hz, 1H; CH2), 1.84 (dd, J=12.5, 4.0 Hz, 1H; CH2), 1.68 (s, 3H; CH3),
1.60–1.50 (m, 1H; CH2), 1.36 (s, 3H; CH3), 1.40–1.30 (m, 1H; CH2), 1.31
(s, 3H; CH3), 1.05 (s, 3H; CH3), 0.92 (s, 9H; CH3), 0.11 ppm (s, 6H;
(ꢀ)-3-Dehydroxy-14’-apo-peridinin-14’-al (33): A solution of 32 (0.017 g,
0.048 mmol) in CH2Cl2 (0.3 mL) was added to a cooled (08C) solution of
N-methylmorpholine N-oxide (0.009 g, 0.072 mmol) in CH2Cl2 (0.3 mL)
containing 4 Š molecular sieves. After stirring for 10 min, TPAP (0.001 g,
0.002 mmol) was added and the mixture was stirred at 258C for 2.5 h.
The mixture was diluted with CH2Cl2 (5 mL) and washed with aqueous
Na2SO3 solution (3”). The organic layer was dried (Na2SO4) and the sol-
vent was evaporated. The residue was purified by column chromatogra-
phy (silica gel, 75:25 hexane/EtOAc) to afford 6.2 mg (36%) of a yellow
oil identified as a 5:1 mixture of the 15E/15Z isomers of aldehyde 33.
Due to its instability, this mixture was used without further purification.
CH3); 13C NMR (100 MHz, CO
(CD3)2): d=202.1 (s), 132.4 (s), 129.3 (d),
A
128.8 (s), 102.5 (d), 72.8 (s), 66.3 (d), 59.7 (t), 51.6 (t), 51.5 (t), 36.6 (s),
33.1 (q), 31.8 (q), 29.9 (q), 26.6 (q, 3”), 19.0 (s), 14.1 (q), ꢀ4.0 ppm (q,
A
for the modified Julia olefination, the reaction of (aS)-10a (0.007 g,
0.017 mmol) with a 5:1 15E/15Z mixture of isomers of aldehyde 33
(0.006 g, 0.017 mmol), NaHMDS (0.044 mL, 1m in THF, 0.044 mmol) in
THF (0.5 mL) for 2 h from ꢀ788C to 08C afforded, after purification by
column chromatography (silica gel, 80:20!70:30 hexane/EtOAc), 6.0 mg
ꢀ
ꢀ
2”); IR (NaCl): n˜ =3550–3050 (br, OH), 2956 (s, C H), 2927 (s, C H),
2856 (m, C H), 1937 (w, C=C=C), 1472 (w), 1080 cmꢀ1 (m); UV
ꢀ
(MeOH): lmax =227 nm; MS (EI+): m/z (%): 365 (19), 364 (13), 348 (17),
347 (38), 335 (11), 321 (11), 307 (15), 285 (11), 281 (19), 239 (11), 233
(22), 223 (12), 215 (27), 207 (15), 201 (16), 199 (16), 189 (28), 175 (10),
173 (14), 163 (12), 159 (15), 149 (32), 147 (15), 145 (12), 143 (23), 135
(17), 133 (27), 131 (11), 125 (12), 123 (16), 121 (22), 119 (15), 109 (11),
107 (17), 105 (18), 95 (21), 93 (12), 91 (14), 83 (11), 75 (100), 73 (67), 69
(24); HRMS (EI+): m/z: calcd for C21H38O3Si: 366.2590; found: 366.2592.
(63%) of
a
red solid identified as (11’Z)-34. 1H NMR (600 MHz,
(CD3)2CO): d=7.50 (s, 1H; CH), 7.17 (d, J=15.6 Hz, 1H; CH), 7.10 (t,
J=12.8 Hz, 1H; CH), 6.76 (t, J=12.3 Hz, 1H; CH), 6.70–6.60 (m, 2H;
CH), 6.47 (t, J=10.4 Hz, 1H; CH), 6.42 (d, J=15.6 Hz, 1H; CH), 6.22 (t,
J=11.5 Hz, 1H; CH), 6.18 (s, 1H; CH), 6.0 (s, 1H; CH), 3.54 (s, 1H;
OH), 2.21 (d, J=6.0 Hz, 3H; CH3), 2.00 (m, 1H; CH2), 1.89 (s, 3H;
CH3), 1.90–1.80 (m, 2H; CH2), 1.60–1.50 (m, 1H; CH2), 1.50–1.30 (m,
7H; CH2), 1.36 (s, 3H; CH3), 1.28 (s, 3H; CH3), 1.16 (s, 3H; CH3), 1.13
(s, 3H; CH3), 1.09 (m, 1H; CH2), 1.01 (s, 3H; CH3), 0.91 ppm (s, 3H;
CH3); 13C NMR (100 MHz, (CD3)2CO): d=204.4 (s), 170.2 (s), 149.1 (s),
139.8 (d), 138.7 (d), 137.9 (s), 135.7 (s), 135.3 (d), 134.1 (d), 131.5 (d),
130.4 (d), 129.6 (d), 126.5 (s), 124.4 (d), 123.6 (d), 121.3 (s), 120.5 (d),
104.4 (d), 72.7 (s), 71.7 (s), 67.3 (s), 42.6 (t), 42.4 (t), 37.5 (t), 36.2 (s),
35.3 (s), 33.6 (q), 32.6 (q), 31.7 (t), 30.2 (q), 27.4 (q), 27.1 (q), 22.0 (q),
20.0 (t), 18.7 (t), 16.5 (q), 15.2 ppm (q); IR (NaCl): n˜ =3600–3400 (br,
(ꢀ)-(1R,5S,2aR,3’E)-2-[5-(Benzothiazol-2-yl)-sulfanyl)-3-methylpenta-
1,3-dienylidene-5-(tert-butyldimethylsilyloxy)-1,3,3-trimethylcyclohexanol
(38c): Following the general procedure for sulfide formation, the reaction
of 37c (70 mg, 0.193 mmol) with PPh3 (0.081 g, 0.309 mmol), DIAD
(0.057 mL,
0.289 mmol)
and
2-mercaptobenzothiazol
(0.049 g,
0.289 mmol) in THF (3 mL) at 08C for 1 h afforded, after purification by
column chromatography (silica gel, 80:20 hexane/EtOAc), 0.104 g
(100%) of a yellow oil identified as 38c. [a]2D3 =ꢀ39.65 (c=0.023 in
MeOH); 1H NMR (400 MHz, CDCl3): d=7.89 (d, J=8.1 Hz, 1H; ArH),
7.77 (d, J=7.9 Hz, 1H; ArH), 7.43 (t, J=8.2 Hz, 1H; ArH), 7.40–7.30
(m, 1H; ArH), 5.95 (s, 1H; CH), 5.64 (t, J=7.8 Hz, 1H; CH), 4.30–4.20
(m, 1H; CH), 4.13 (d, J=8.0 Hz, 2H; CH2), 2.15 (dd, J=13.1, 4.0 Hz,
1H; CH2), 1.83 (dd, J=12.6, 3.9 Hz, 1H; CH2), 1.77 (s, 3H; CH3), 1.50–
1.40 (m, 1H; CH2), 1.33 (s, 6H; CH3), 1.30–1.20 (m, 1H; CH2), 1.05 (s,
3H; CH3), 0.93 (s, 9H; CH3), 0.12 ppm (s, 6H; CH3); 13C NMR
(100 MHz, CDCl3): d=201.4 (s), 166.4 (s), 153.3 (s), 135.6 (s), 133.8 (d),
128.7 (s), 126.0 (d), 124.2 (d), 121.5 (d), 120.9 (d), 118.0 (s), 101.6 (d),
72.9 (s), 64.9 (d), 49.9 (t), 49.2 (t), 35.6 (s), 32.2 (t), 32.1 (q), 32.4 (q), 29.3
(q, 3”), 25.9 (q), 18.2 (s), 13.6 (q), ꢀ4.6 ppm (q, 2”); IR (NaCl): n˜ =
ꢀ
ꢀ
ꢀ
OH), 2961 (s, C H), 2923 (s, C H), 2849 (m, C H), 1926 (w, C=C=C),
1749 (s, C=O), 1521 (w), 1449 cmꢀ1 (w); MS (FAB+): m/z (%): 558
[M+2]+ (10), 557 [M+1]+ (11), 556 [M]+ (85), 540 (12), 539 (26), 394
(15), 393 (26), 322 (27), 307 (29), 289 (20), 241 (12), 165 (27); HRMS
(FAB+): m/z: calcd for C37H49O4: 557.3631; found: 557.3613.
(+)-(2E)-3-Methyl-5-[(6R)-4-(tert-butyldimethylsilyloxy)-2,2,6-trimethyl-
7-oxabicyclo
N
N
(0.015 g, 0.013 mmol) and CuI (0.003 g, 0.013 mmol) were added to a so-
lution of 13c (0.383 g, 1.3 mmol) and 36 (0.258 g, 1.3 mmol) in iPr2NH
(7 mL). After stirring for 1 h, a saturated aqueous solution of NH4Cl was
added and the mixture was extracted with Et2O (3”). The combined or-
ganic layers were washed with brine (3”), dried (Na2SO4) and the sol-
vent was evaporated. The residue was purified by column chromatogra-
phy (silica gel, 80:20 hexane/EtOAc) to afford 0.370 g (78%) of a yellow
oil identified as 35c. [a]D23 =+36.73 (c=0.022 in MeOH); 1H NMR
(400 MHz, C6D6): d=5.94 (t, J=6.6 Hz, 1H; CH), 4.00–3.90 (m, 1H;
CH), 3.76 (d, J=6.5 Hz, 2H; CH2), 2.25 (dd, J=14.4, 5.1 Hz, 1H; CH2),
1.67 (dd, J=14.4, 7.9 Hz, 1H; CH2), 1.60–1.50 (m, 1H; CH2), 1.55 (s, 3H;
CH3), 1.49 (s, 3H; CH3), 1.36 (s, 3H; CH3), 1.30 (s, 3H; CH3), 1.40–1.30
(m, 1H; CH2), 0.98 (s, 9H; CH3), 0.05 ppm (s, 6H; CH3); 13C NMR
(100 MHz, (CD3)2CO): d=138.1 (d), 117.8 (s), 87.8 (s), 83.9 (s), 65.9 (s),
64.3 (d), 63.2 (s), 57.9 (t), 45.2 (t), 40.0 (t), 33.9 (s), 29.0 (q, 2”), 25.2 (q,
3”), 21.0 (q), 17.6 (s), 16.5 (q), ꢀ5.6 ppm (q); IR (NaCl): n˜ =3650–3100
ꢀ
ꢀ
ꢀ
3500–3100 (br, OH), 2955 (s, C H), 2926 (s, C H), 2854 (m, C H), 1936
(w, C=C=C), 1457 (s), 1427 (s), 1077 cmꢀ1 (s); UV (MeOH): lmax
=
228 nm; MS (EI+): m/z (%): 515 [M]+ (16), 330 (10), 291 (22), 199 (13),
173 (11), 168 (14), 167 (52), 159 (28), 149 (16), 135 (44), 134 (14), 133
(100), 105 (22), 95 (71), 93 (15); HRMS (EI+): m/z: calcd for
C28H41NO2SiS2: 515.2348; found: 515.2362.
(ꢀ)-(1S,3R,4aR,3’E)-4-[5-(Benzothiazol-2-yl)-sulfanyl)-3-methylpenta-
1,3-dienylidene]-3-hydroxy-3,5,5-trimethylcyclohexyl
acetate
(38d):
Formic acid (5.7 mL) and H2O (1.90 mL) were added to a solution of 38c
(0.0541 g, 0.105 mmol) in THF (11.4 mL). After stirring for 2 h, the mix-
ture was cooled down to 08C, neutralized with NaHCO3 and extracted
with AcOEt (3”). The combined organic layers were dried and the sol-
vent was removed. The residue was used without further purification.
Acetic anhydride (0.041 mL) was then added to a solution of this residue
in pyridine (1.4 mL) and the mixture was stirred overnight. A saturated
aqueous solution of CuSO4 was added and the mixture was extracted
with CH2Cl2 (3”). The combined organic layers were washed with a satu-
rated aqueous solution of CuSO4 (3”), dried (Na2SO4) and concentrated.
The residue was purified by column chromatography (silica gel, 80:20
hexane/EtOAc) to afford 0.046 mg (99%) of a yellow oil identified as
ꢀ
ꢀ
ꢀ
(br, OH), 2956 (s, C H), 2928 (s, C H), 2857 (m, C H), 1636 (w),
1086 cmꢀ1 (m); UV (MeOH): lmax =231 nm; MS (EI+): m/z (%): 364
[M]+ (1), 235 (11), 233 (40), 219 (15), 217 (71), 173 (20), 163 (12), 160
(16), 159 (20), 157 (14), 145 (23), 143 (26), 142 (11), 141 (14), 131 (15),
129 (19), 128 (14), 121 (11), 119 (13), 117 (10), 115 (34), 105 (29), 91 (36),
77 (22), 75 (100), 73 (89), 69 (14); HRMS (EI+): m/z: calcd for
C21H36O3Si: 364.2434; found: 364.2451.
1
38d. [a]2D3 =ꢀ22.52 (c=0.05 in MeOH); H NMR (400 MHz, CDCl3): d=
7.89 (d, J=8.1 Hz, 1H; ArH), 7.77 (d, J=7.9 Hz, 1H; ArH), 7.43 (t, J=
8.2 Hz, 1H; ArH), 7.32 (t, J=7.3 Hz, 1H; ArH), 5.98 (s, 1H; CH), 5.65
Chem. Eur. J. 2007, 13, 1273 – 1290
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1287

A. R. de Lera et al.
(t, J=7.9 Hz, 1H; CH), 5.39 (t, J=7.2 Hz, 1H; CH), 4.13 (d, J=8.0 Hz,
2H; CH2), 2.29 (dd, J=12.8, 4.0 Hz, 1H; CH2), 2.05 (s, 3H; CH3), 2.00
(dd, J=12.3, 4.0 Hz, 1H; CH2), 1.78 (s, 3H; CH3), 1.30–1.20 (m, 1H;
CH2), 1.38 (s, 3H; CH3), 1.34 (s, 3H; CH3), 1.30–1.20 (m, 1H; CH2),
1.07 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=201.3 (s), 170.4
(s), 166.3 (s), 153.2 (s), 135.4 (s), 135.2 (s), 126.0 (d), 124.3 (d), 121.5 (d),
121.1 (d), 120.9 (d), 117.5 (s), 101.8 (s), 72.5 (s), 67.9 (d), 45.4 (t), 45.2 (t),
35.6 (s), 32.1 (t), 32.0 (q), 31.2 (q), 29.1 (q), 21.4 (q), 13.6 ppm (q); IR
1.00–0.90 ppm (m, 9H; CH3); 13C NMR (100 MHz, C6D6): d=202.1 (s),
169.1 (s), 142.3 (d), 136.1 (d), 132.7 (s), 131.8 (d), 124.4 (d), 123.0 (d),
117.6 (s), 103.0 (d), 71.9 (s), 67.6 (d), 45.6 (t), 45.4 (t), 35.5 (s), 31.9 (q),
30.7 (q), 29.2 (t), 28.9 (q), 27.3 (t), 20.6 (q), 13.6 (q), 13.3 (q), 9.6 ppm (t);
ꢀ
ꢀ
IR (NaCl): n˜ =3346 (w), 3205 (w), 2956 (s, C H), 2917 (s, C H), 2848 (s,
ꢀ
C H), 1930 (w, C=C=C), 1724 (m, C=O), 1666 (m), 1631 (m),
1462 cmꢀ1(w); UV (MeOH): lmax =306, 319, 334 nm; MS (FAB+): m/z
(%): 549 [M]+ (30), 548 (14), 547 (23), 546 (1), 545 (14), 473 (11), 471
(14), 295 (19), 293 (49), 292 (20), 291 (74), 290 (28), 289 (56), 288 (16),
287 (25), 251 (11), 249 (10), 239 (26), 237 (24), 235 (43), 234 (16), 233
(34), 232 (14), 231 (22), 223 (10), 207 (11), 183 (23), 181 (23), 179 (100),
178 (31), 177 (96), 176 (33), 175 (64), 173 (17), 171 (12), 157 (12), 155
(11), 154 (11); HRMS (FAB+): m/z: calcd for C28H45O3116Sn: 545.2386;
found: 545.2388; calcd for C28H45O3120Sn: 549.2391; found: 549.2395.
ꢀ
ꢀ
(NaCl): n˜ =3700–3100 (br, OH), 2964 (s, C H), 2924 (s, C H), 1938 (w,
C=C=C), 1729 (s, C=O), 1427 (s), 1250 cmꢀ1 (s); UV (MeOH): lmax =227,
281, 301 nm; MS (EI+): m/z (%): 183 (17), 167 (100), 145 (10), 143 (10),
121 (18), 115 (10), 108 (12), 105 (18), 95 (29), 91 (23); HRMS (EI+):
m/z: calcd for C24H29NO3S2: 443.1589; found: 443.1607.
(+)-(1S,3R,4aR,3’E)-4-(-5-(Benzothiazol-2-yl)-sulfanyl)-3-methylpenta-
1,3-dienylidene)-3-hydroxy-3,5,5-trimethylcyclohexyl
formate
(38e):
Peridinin (1): Following the general procedure for the Stille cross-cou-
pling, the reaction of (aR,5’Z)-8 (0.013 g, 0.021 mmol) with 6 (0.006 g,
[a]2D3 = +24.25 (c=0.024 in MeOH); 1H NMR (400 MHz, CDCl3): d=
8.05 (s, 1H; CH), 7.87 (d, J=8.1 Hz, 1H; ArH), 7.75 (d, J=8.8 Hz, 1H;
ArH), 7.14 (t, J=7.3 Hz, 1H; ArH), 7.23 (t, J=7.2 Hz, 1H; ArH), 5.96
(s, 1H; CH), 5.64 (t, J=7.9 Hz, 1H; CH), 5.50–5.40 (m, 1H; CH), 4.12
(d, J=8.0 Hz, 2H; CH2), 2.29 (dd, J=12.8, 4.1 Hz, 1H; CH2), 2.02 (dd,
J=12.3, 3.9 Hz, 1H; CH2), 1.76 (s, 3H; CH3), 1.50–1.40 (m, 1H; CH2),
1.37 (s, 3H; CH3), 1.33 (s, 3H; CH3), 1.30–1.20 (m, 1H; CH2), 1.06 ppm
(s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=201.3 (s), 166.3 (s), 160.5
(d), 153.2 (s), 135.4 (s), 135.1 (s), 126.0 (d), 124.3 (d), 121.5 (d), 121.3 (d),
121.0 (d), 117.4 (s), 101.9 (d), 72.5 (s), 68.1 (d), 45.3 (t), 45.1 (t), 35.6 (s),
32.1 (t), 32.0 (q), 31.1 (q), 29.2 (q), 13.6 ppm (q); IR (NaCl): n˜ =3550–
0.018 mmol), [Pd2(dba)3]·CHCl3 (0.0004 g, 0.0004 mmol), [AsPh3]
A
(0.009 g, 0.0028 mmol) and Bu4NPh2PO2 (0.0097 g, 0.021 mmol) in THF
(0.4 mL) for 4 h at 258C afforded, after purification by column chroma-
tography (silica gel, 80:20 hexane/EtOAc), 6 mg (65%) of a red solid
identified as a mixture of (aR,11’E)-29a and (aR,11’Z)-29a in a 1:3 ratio,
which was used immediately. Following the general procedure for the
Stille cross-coupling, the reaction of 29a (0.006 g, 0.011 mmol) with 7b
(0.006 g, 0.014 mmol), [Pd2(dba)3]·CHCl3 (0.0007 g, 0.0007 mmol),
A
[AsPh3] (0.0017 g, 0.0054 mmol) and Bu4NPh2PO2 (0.0052 g, 0.011 mmol)
in THF (0.52 mL) for 19 h at 558C afforded, after purification by column
chromatography (silica gel, 90:10!80:20 hexane/acetone), 4.8 mg (69%)
ꢀ
ꢀ
ꢀ
3000 (br, OH), 2963 (s, C H), 2925 (s, C H), 2857 (m, C H), 1938 (w,
C=C=C), 1721 (s, C=O), 1457 (s), 1427 (s), 1160 cmꢀ1 (s); UV (MeOH):
lmax =227, 301 nm; MS (EI+): m/z (%): 429 [M]+ (1), 166 (100), 159 (12),
135 (13), 108 (12), 105 (22), 95 (21), 91 (29); HRMS (EI+): m/z: calcd for
C23H27NO3S2: 429.1432; found: 429.1418.
1
of a red solid identified as peridinin (1). H NMR (600 MHz, CDCl3): d=
7.16 (d, J=15.6 Hz, 1H; CH), 7.01 (s, 1H; CH), 6.62 (dd, J=15.2,
11.9 Hz, 1H; CH), 6.61 (dd, J=15.2, 11.9 Hz, 1H; CH), 6.50 (dd, J=
14.2, 11.1 Hz, 1H; CH), 6.44 (d, J=11.5 Hz, 1H; CH), 6.40 (dd, J=14.5,
10.5 Hz, 1H; CH), 6.36 (d, J=15.6 Hz, 1H; CH), 6.10 (d, J=11.8 Hz,
1H; CH), 6.04 (s, 1H; CH), 5.72 (s, 1H; CH), 5.40–5.30 (m, 1H; CH),
3.90–3.80 (m, 1H; CH), 2.39 (ddd, J=14.4, 4.9, 1.9 Hz, 1H; CH2), 2.27
(ddd, J=12.7, 3.9, 1.7 Hz, 1H; CH2), 2.22 (s, 3H; CH3), 2.03 (s, 3H;
CH3), 1.98 (ddd, J=12.3, 4.1, 1.8 Hz, 1H; CH2), 1.79 (s, 3H; CH3), 1.63
(dd, J=14.2, 8.9 Hz, 1H; CH2), 1.62 (d, J=14.4 Hz, 1H; CH2), 1.50–1.40
(m, 1H; CH2), 1.40–1.30 (m, 1H; CH2), 1.37 (s, 3H; CH3), 1.34 (s, 3H;
CH3), 1.30–1.20 (m, 1H; CH2), 1.20 (s, 3H; CH3), 1.19 (s, 3H; CH3), 1.06
(s, 3H; CH3), 0.97 (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=202.6
(s), 170.4 (s), 168.7 (s), 146.8 (s), 138.0 (d), 137.2 (d), 136.3 (d), 134.0 (s),
133.9 (s), 133.6 (d), 133.0 (d), 131.5 (d), 128.9 (d), 128.1 (d), 124.8 (s),
121.8 (d), 119.2 (d), 117.6 (s), 103.3 (d), 72.7 (s), 70.4 (s), 67.5 (d), 67.3
(s), 64.2 (d), 47.1 (t), 45.4 (t), 45.2 (t), 40.9 (t), 35.8 (s), 35.3 (s), 32.0 (q),
31.3 (q), 29.5 (q), 29.2 (q), 24.9 (q), 21.4 (q), 19.9 (q), 15.4 (q), 14.0 ppm
(ꢀ)-(1S,3R,3’E)-4-[5-(benzothiazol-2-yl)sulfonyl-3-methylpenta-1,3-dien-
A
ing the general procedure for sulfone formation, the reaction at ꢀ108C
of 38b (0.081 g, 0.183 mmol) in EtOH (9.3 mL) with (NH4)6Mo7O24·4H2O
(0.045 g, 0.036 mmol) in 35% H2O2 (0.235 mL, 2.74 mmol) for 16 h af-
forded, after purification by column chromatography (silica gel, 70:30
hexane/EtOAc), 0.08 g (93%) of a white solid identified as (aR)-10d.
1
[a]2D1 =ꢀ33.18 (c=0.033 in MeOH); H NMR (400 MHz, CDCl3): d=8.20
(d, J=7.7 Hz, 1H; ArH), 7.97 (d, J=7.8 Hz, 1H; ArH), 7.60–7.50 (m,
2H; ArH), 5.91 (s, 1H; CH), 5.42 (t, J=8.0 Hz, 1H; CH), 5.40–5.20 (m,
1H; CH), 4.32 (d, J=8.1 Hz, 2H; CH2), 2.19 (dd, J=12.8, 4.0 Hz, 1H;
CH2), 2.00 (s, 3H; CH3), 1.90 (dd, J=12.3, 3.9 Hz, 1H; CH2), 1.48 (s, 3H;
CH3), 1.40–1.30 (m, 1H; CH2), 1.30 (s, 3H; CH3), 1.30–1.20 (m, 1H;
CH2), 1.13 (s, 3H; CH3), 0.84 ppm (s, 3H; CH3); 13C NMR (100 MHz,
CDCl3): d=201.8 (s), 170.4 (s), 165.6 (s), 152.6 (s), 141.0 (s), 137.1 (s),
128.0 (d), 127.7 (d), 125.4 (d), 122.3 (d), 117.8 (s), 111.0 (d), 101.3 (d),
72.3 (s), 67.8 (d), 55.4 (t), 45.2 (t), 45.1 (t), 35.5 (s), 31.7 (q), 30.9 (q), 29.0
(q), 21.3 (q), 13.8 ppm (q); IR (NaCl): n˜ =3600–3300 (br, OH), 2965 (s,
ꢀ
ꢀ
(q); IR (NaCl): n˜ =3600–3300 (br, OH), 2961 (s, C H), 2925 (s, C H),
1927 (w, C=C=C), 1748 cmꢀ1 (s, C=O); MS (FAB+): m/z (%): 631
[M+1]+ (12), 630 [M]+ (25), 391 (20), 307 (14); HRMS (FAB+): m/z:
calcd for C39H50O7: 630.3557; found: 630.3572; calcd for C39H51O7:
631.3635; found: 631.3627.
ꢀ
ꢀ
C H), 2925 (s, C H), 1939 (w, C=C=C), 1729 (s, C=O), 1328 (s),
1252 cmꢀ1 (s); UV (MeOH): lmax =242, 288 nm; MS (FAB+): m/z (%):
476 [M+1]+ (5), 308 (11), 307 (42), 289 (19), 282 (14); HRMS (FAB+):
m/z: calcd for C24H30NO5S2: 476.1565; found: 476.1553.
A
dienal (39): MnO2 (0.43 g, 4.94 mmol) and Na2CO3 (0.52 g, 4.94 mmol)
were added to a cooled (08C) solution of 15 (0.074 g, 0.27 mmol) in
CH2Cl2 (6.4 mL) and the suspension was stirred for 2 h. The mixture was
filtered through Celite and the solvent was removed. The residue was pu-
rified by column chromatography (silica gel, 70:30 hexane/EtOAc) to
(ꢀ)-(1S,3R,4aR,3’E,5’Z,7’E)-3-Methyl-4-[8-(tributyltin)octa-1,3,5,7-tet-
raenylidene]-3-hydroxy-3,5,5-trimethylcyclohexyl acetate ((aR,5’Z)-8):
Following the general procedure for the Julia olefination, (aR)-10
1
afford 0.053 g (72%) of a yellow oil identified as 39. H NMR (400 MHz,
(0.033 g, 0.069 mmol) was reacted with
9 (0.036 g, 1.03 mmol) and
CDCl3): d=9.65 (d, J=7.8 Hz, 1H; CH), 7.47 (s, 1H; CH), 7.45 (dd, J=
15.0, 11.7 Hz, 1H; CH), 6.60 (d, J=11.7 Hz, 1H; CH), 6.27 (dd, J=15.0,
7.8 Hz, 1H; CH), 5.79 (s, 1H; CH), 2.33 ppm (s, 3H; CH3); 13C NMR
(100 MHz, CDCl3): d=193.3 (d), 164.9 (s), 148.6 (s), 145.6 (d), 142.4 (d),
142.3 (s), 134.7 (d), 133.8 (d), 117.6 (d), 112.6 (s), 16.1 ppm (q); MS (EI+):
m/z (%): 293 [M+23]+ (75), 291 [M+23]+ (77), 285 (16), 279 (27), 279
(15), 271 [M+1]+ (97), 269 [M+1]+ (100), 247 (15); HRMS (EI+): m/z:
calcd for C11H1079BrO3: 268.9808; found: 268.9797; calcd for
C11H1081BrO3: 270.9707; found: 268.9776.
NaHMDS (0.207 mL, 1m in THF, 0.207 mmol) in THF (5.2 mL) for 3 h
at ꢀ788C. Purification of the crude by column chromatography (silica
gel, 90:7:3 hexane/EtOAc/Et3N), 0.0327 mg (78%) afforded a yellow oil,
which was identified as (aR,5’Z)-8. [a]2D7 =ꢀ59.2 (c=0.02 in MeOH);
1H NMR (400 MHz, C6D6): d=7.46 (dd, J=18.5, 9.9 Hz, 1H; CH), 6.78
(d, J=10.1 Hz, 1H; CH), 6.56 (d, J=18.5 Hz, 1H; CH), 6.27 (t, J=
11.0 Hz, 1H; CH), 6.21 (t, J=10.5 Hz, 1H; CH), 5.95 (s, 1H; CH), 5.68
(ddd, J=11.5, 7.2, 4.1 Hz, 1H; CH), 2.28 (ddd, J=12.3, 3.9, 2.0 Hz, 1H;
CH2), 2.03 (ddd, J=12.1, 3.5, 1.8 Hz, 1H; CH2), 1.75 (s, 3H; CH3), 1.68
(s, 3H; CH3), 1.70–1.50 (m, 6H; CH2), 1.41 (s, 3H; CH3), 1.40–1.30 (m,
8H; CH2), 1.14 (s, 3H; CH3), 1.10–1.00 (m, 6H; CH2), 1.03 (s, 3H; CH3),
Apo-peridinin-14’-al (40): Following the general procedure for the Stille
cross-coupling, the reaction of 39 (0.040 g, 0.149 mmol) with 7b (0.084 g,
1288
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1273 – 1290

Total Synthesis of Peridinin
FULL PAPER
0.179 mmol), [Pd2(dba)3]·CHCl3 (0.008 g, 0.007 mmol), Bu4NPh2PO2
N
[1] For authorized monographs see: a) Carotenoids. Part 1 A. Isolation
and Analysis (Eds.: G. Britton, S. Liaaen-Jensen, H. Pfander, Bir-
khäuser, Basel, 1995; b) Carotenoids. Part 1B. Spectroscopy (Eds.: G.
Britton, S. Liaaen-Jensen, H. Pfander), Birkhäuser, Basel, 1995;
c) Carotenoids. Part 2. Synthesis (Eds.: G. Britton, S. Liaaen-Jensen,
H. Pfander), Birkhäuser, Basel, 1996.
[2] a) The Retinoids, Vol. 1 & 2 (Eds.: M. B. Sporn, A. B. Roberts, D. S.
Goodman), Academic Press, New York, 1984,; b) The Retinoids:
Biology, Chemistry and Medicine 2nd ed. (Eds.: M. B. Sporn, A. B.
Roberts, D. S. Goodman), Raven, New York, 1993; c) Chemistry and
Biology of Synthetic Retinoids (Eds.: M. L. Dawson, W. H. Oka-
mura), CRC Press, Boca Raton, FL, 1990.
[3] a) P. S. Song, P. Koka, B. B. Prezelin, F. T. Haxo, Biochemistry 1976,
15, 4422; b) H. A. Frank, R. J. Cogdell, Carotenoids Photosynth.
1993, 252–326, 252..
[4] E. Hoffmann, P. M. Wrench, F. P. Sharpless, R. G. Hiller, W. Welte,
K. Diederichs, Science 1996, 272, 1788.
(0.082 g, 0.179 mmol) and BHT (traces) in DMF (6 mL) for 4 h at 608C,
afforded, after purification by column chromatography (silica gel,
60:40!50:50 hexane/EtOAc) 35 mg (64%) of a yellow oil identified as
40. 1H NMR (400 MHz, CDCl3): d=9.62 (d, J=7.9 Hz, 1H; CH), 7.46
(dd, J=15.0, 11.5 Hz, 1H; CH), 7.22 (d, J=15.5 Hz, 1H; CH), 7.02 (s,
1H; CH), 6.55 (d, J=11.8 Hz, 1H; CH), 6.37 (d, J=15.6 Hz, 1H; CH),
6.22 (dd, J=15.2, 7.9 Hz, 1H; CH), 5.71 (s, 1H; CH), 3.90–3.80 (m, 1H;
CH), 2.36 (dd, J=14.3, 5.0 Hz, 1H; CH2), 2.31 (s, 3H; CH3), 1.60–1.50
(m, 2H; CH2), 1.30 (dd, J=14.8, 7.4 Hz, 1H; CH2), 1.18 (s, 3H; CH3),
1.16 (s, 3H; CH3), 0.94 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3):
d=193.3 (d), 167.8 (s), 149.4 (s), 146.0 (d), 143.1 (s), 136.0 (d), 135.7 (d),
133.1 (d), 132.9 (d), 127.2 (s), 121.3 (d), 116.5 (d), 70.3 (s), 67.5 (s), 64.0
(d), 46.8 (t), 40.7 (t), 35.2 (s), 29.3 (q), 24.8 (q), 19.7 (q), 16.1 ppm (q);
MS (EI+): m/z (%): 372 [M+2]+ (22), 371 [M+1]+ (100), 340 (16), 315
(17), 279 (17); HRMS (EI+): m/z: calcd for C22H27O5: 371.1853; found:
371.1848.
11’Z-Peridinin (11’Z-1): Following the general procedure for the Julia
olefination, the reaction of (aR)-10d (0.019 g, 0.039 mmol) with 40
(0.018 g 0.047 mmol), NaHMDS (0.118 mL, 1m in THF, 0.118 mmol) and
BHT (traces) in THF (3.1 mL) for 6 h from ꢀ788C to ꢀ308C afforded,
after purification by column chromatography (silica gel, 80:20!70:30
hexane/EtOAc), 0.0132 mg (53%) of a red solid identified as (11’Z)-peri-
[5] a) H. H. Strain, W. A. Svec, P. Webfahrt, H. Rapoport, F. T. Haxo, S.
Nogard, H. Kjøsen, S. Liaaen-Jensen, Acta Chem. Scand. Ser. B
1976, 30, 109; b) KjøH. sen, S. Nogard, Liaaen-S. Jensen, W. A.
Svec, H. H. Strain, P. Webfahrt, H. Rapoport, F. T. Haxo, Acta
Chem. Scand. Ser. B 1976, 30, 157; c) J. E. Johansen, G. Borch, S.
Liaaen-Jensen, Phytochemistry 1980, 19, 441.
1
dinin (1). H NMR (600 MHz, CDCl3): d=7.19 (d, J=15.6 Hz, 1H; CH),
[6] a) S. McLean, F. W. Reynolds, L. M. D. John, W. F. Tinto, Magn.
Reson. Chem. 1992, 30, 362; b) J. Krane, T. Aakermann, S. Liaaen-
Jensen, Magn. Reson. Chem. 1992, 30, 1169; c) G. Englert, T. Aaker-
mann, S. Liaaen-Jensen, Magn. Reson. Chem. 1993, 31, 910; d) J. A.
Haugan, G. Englert, T. Aakermann, E. Glinz, S. Liaaen-Jensen,
Acta Chem. Scand. 1994, 48, 769.
[7] a) M. Ito, Y. Hirata, Y. Shibata, K. Tsukida, J. Chem. Soc. Perkin
Trans. 1 1990, 197; b) Y. Yamano, M. Ito, J. Chem. Soc. Perkin
Trans. 1 1993, 1599; c) M. Ito, Y. Yamano, S. Sumiya, A. Wada, Pure
Appl. Chem. 1994, 66, 939; d) Y. Yamano, C. Tode, M. Ito, J. Chem.
Soc. Perkin Trans. 1 1995, 1895.
[8] Note the fragment numbering according to the number of carbon
atoms of the final carotenoid (see ref. [1]).
[9] a) N. Furuichi, H. Hara, T. Osaki, H. Mori, S. Katsumura, Angew.
Chem. 2002, 114, 1065; Angew. Chem. Int. Ed. 2002, 41, 1023; b) N.
Furuichi, H. Hara, T. Osaki, M. Nakano, H. Mori, S. Katsumura, J.
Org. Chem. 2004, 69, 7949.
7.03 (s, 1H; CH), 6.95 (t, J=13.1 Hz, 1H), 6.65 (dd, J=13.9, 12.1 Hz,
1H), 6.60–6.50 (m, 2H; CH), 6.40 (d, J=15.7 Hz, 1H; CH), 6.40–6.30
(m, 1H; CH), 6.17 (t, J=11.7 Hz, 1H; CH), 6.12 (s, 1H; CH), 5.75 (s,
1H; CH), 5.40–5.30 (m, 1H; CH), 3.91 (s, 1H; CH), 2.32 (dd, J=14.3,
4.4 Hz, 1H; CH2), 2.22 (dd, J=12.0, 3.5 Hz, 1H; CH2), 2.03 (s, 3H; CH3),
2.00–1.90 (m, 1H; CH2), 1.82 (s, 3H; CH3), 1.70–1.60 (m, 2H; CH2),
1.60–1.40 (m, 2H; CH2), 1.40 (s, 3H; CH3), 1.36 (s, 3H; CH3), 1.30–1.20
(m, 1H; CH2), 1.20 (s, 3H; CH3), 1.19 (s, 3H; CH3), 1.08 (s, 3H; CH3),
0.98 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=202.7 (s), 170.4
(s), 168.7 (s), 146.9 (s), 137.8 (d), 136.3 (d), 134.4 (s), 134.3 (s), 133.8 (d),
131.8 (d), 129.9 (d), 129.2 (d), 127.4 (d), 124.0 (s), 123.1 (d), 121.8 (d),
119.0 (d), 117.7 (s), 103.5 (d), 72.7 (s), 70.5 (s), 67.9 (d), 67.8 (s), 64.2 (d),
47.1 (t), 45.4 (t), 45.2 (t), 40.9 (t), 35.8 (s), 35.3 (s), 32.0 (q), 31.3 (q), 29.5
(q), 27.5 (q), 24.9 (q), 21.4 (q), 19.9 (q), 15.5 (q), 13.7 ppm (q); IR
ꢀ
ꢀ
(NaCl): n˜ =3600–3300 (br, OH), 2961 (s, C H), 2924 (s, C H), 2852 (m,
ꢀ1
C H), 1928 (w, C=C=C), 1748 cm (s, C=O); MS (FAB+): m/z (%): 631
ꢀ
[M+1]+ (17), 630 [M]+ (32), 553 (11), 491 (17), 90 (14), 415 (11), 413
(12), 392 (21), 391 (65), 389 (10), 371 (14), 359 (18), 358 (45), 357 (10),
355 (16), 343 (13), 341 (13), 329 (14), 328 (20), 327 (21), 326 (77), 325
(12), 324 (13); HRMS (FAB+): m/z: calcd for C39H50O7: 630.3557; found:
630.3567; calcd for C39H51O7: 631.3635; found: 631.3617.
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actions, 2nd ed., Wiley-VCH, Weinheim, 2005.
Peridinin (1): [Pd2(dba)3]·CHCl3 (0.0005 g, 0.0005 mmol) and [AsPh3]
A
(0.0012 g, 0.004 mmol) were added to a solution of (11’Z)-peridinin (1)
(0.0024 g, 0.0038 mmol) in THF (0.100 mL). After stirring for 7 h at
258C, brine was added and the mixture was extracted with EtOAc/
CH2Cl2 (90:10) (3”). The combined organic layers were dried (Na2SO4)
and the solvent was evaporated. The residue was purified by column
chromatography (silica gel, 90:10!80:20 hexane/acetone) to afford 2 mg
(83%) of a red solid identified as peridinin (1).
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Acknowledgements
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2002, 2563.
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We thank the European Commission (EPITRON, LSHC-CT-2005-
518417), the Spanish Ministerio de Educación y Ciencia (Grant SAF04-
07131-FEDER, FPU fellowship to B. V. and M.D.) and Xunta de Galicia
(Grant PGIDIT05PXIC31403PN) for financial support. Exchange of ma-
terial and information on butenolides with Prof. Brückner and co-work-
ers at Freiburg is gratefully acknowledged. We also thank Dr. M. Scalone
(F. Hoffman-La Roche, Basel) for a generous gift of enantiopure (ꢀ)-ac-
tinol.
Chem. Eur. J. 2007, 13, 1273 – 1290
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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11, ꢀ24ꢂkꢂ28, ꢀ14ꢂlꢂ15; reflections collected=15659; inde-
pendent reflections=9768 (Rint =0.0259); completeness to q=28.038
(96.6%), absorption correction (SADABS); max. and min. transmis-
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squares on F2; data/restraints/parameters 9768/1/594; goodness-of-fit
on F2 =0.862; final R indices [I>2s(I)] (R1 =0.0400, wR2 =0.0652);
R indices (all data): R1 =0.0600, wR2 =0.0695; absolute structure
parameter=0.00(4); largest diff. peak and hole=0.274 and
ꢀ3
ꢀ0.281 eŠ
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T=293(2) K; l=0.71073 Š; crystal system=monoclinic; space
group=P2(1)/c; unit cell dimensions: a=8.0985(12), b=
10.4719(16), c=12.3827(19) Š; a=90, b=90.470(3), g=908; V=
1050.1(3) Š3; Z=4; 1calcd =2.270 mgmꢀ3; m=6.828 mmꢀ1; F
A
672; crystal size=0.20”0.24”0.32 mm3; q range for data collec-
tion=2.52 to 28.068; index ranges=ꢀ10ꢂhꢂ10, ꢀ7ꢂkꢂ13, ꢀ15ꢂ
lꢂ16; reflections collected=6305; independent reflections=2459
(Rint =0.0703); completeness to q=28.068 (96.4%); absorption cor-
rection=none; max. and min. transmission=1.000 and 0.188; refine-
ment method=full-matrix least-squares on F2; data/restraints/pa-
rameters 2459/0/12; goodness-of-fit on F2 =0.996; final R indices
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[I>2s(I)] R1 =0.0566, wR2 =0.1536,
R indices (all data): R1 =
0.0744, wR2 =0.1609; extinction coefficient=0.0072(12); largest diff.
peak and hole=2.262 and ꢀ2.064 eŠꢀ3. (aR)-12d: Empirical formu-
la=C13H19BrO3; Fw =303.19; T=293(2) K; l=0.71073 Š; crystal
system=orthorhombic; space group=P2(1)2(1)2(1); unit cell di-
mensions: a=7.9727(8), b=12.9910(13), c=15.0747(15) Š; a=90,
b=90, g=908; V=1561.3(3) Š3; Z=4; 1calcd =1.290 mgmꢀ3
2.628 mmꢀ1; F(000)=624; crystal size=0.9”0.64”0.24 mm3; q range
; m=
G
for data collection=2.07 to 28.038; index ranges=ꢀ9ꢂhꢂ10,
ꢀ16ꢂkꢂ16, ꢀ19ꢂlꢂ17); reflections collected=8573; independent
reflections=3393 (Rint =0.0481); completeness to q=28.038
(94.8%); absorption correction (SADABS); max. and min. transmis-
sion=1.000000 and 0.443409; refinement method=full-matrix least-
squares on F2; data/restraints/parameters 3393/0/161; goodness-of-fit
on F2 =0.783; final R indices [I>2s(I)] R1 =0.0463, wR2 =0.1053, R
indices (all data): R1 =0.1335, wR2 =0.1223; absolute structure pa-
rameter=0.017(14); extinction coefficient=0.0008(9); largest diff.
peak and hole=0.246 and ꢀ0.219 eŠꢀ3. (aS)-10d: Empirical formu-
la=C24H29NO5S2, Fw =475.60, T=173(2) K, l=0.71073 Š, crystal
system=monoclinic; space group=P2(1); unit cell dimensions: a=
10.2154(8), b=21.8191(17), c=11.5734(9) Š; a=90, b=106.447(2),
[47] A. S. Kende, L. Kun, I. Kaldor, G. Dorey, K. Koch, J. Am. Chem.
Soc. 1995, 117, 8258.
g=908;
V=2474.1(3) Š3;
Z=4;
1calcd =1.277 mgmꢀ3
;
m=
0.249 mmꢀ1
,
F
A
q
Received: July 5, 2006
range for data collection=1.83 to 28.038; index ranges=ꢀ13ꢂhꢂ
Published online: October 25, 2006
1290
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1273 – 1290