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TANDEM SYNTHESIS OF POLYSUBSTITUTED OLEFINS: AN APPROACH TOWARD THE FIRST TOTAL SYNTHESIS
OF ASTAXANTHIN P-D-DIGLUCOSIDE
FARIBA SOLEYMANZADEH
A thesis submitted to the Faculty of Graduate Studies in partial fidfillment of the requirements
for the degree of Master of Science
Graduate program in Chernistry York University
North York, Ontario
June 2000
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Tandem Synîhesis of Poly-substituted Olefins: An Approach Toward the First Total Synthesis of
Astaxanthin-P-D-diglucoside
by Fanba Soleymanzadeh
a thesis submitted to the Faculty of Graduate Studies of York University in partial fulfillrnent of the requirements for the degree of
MASTER OF SCIENCE
Permission has been granted to the LIBRARY OF YORK UNIVERSITY to lend or self copies of this thesis, to the NATIONAL LIBRARY OF CANADA to microfilm this thesis and to lend or seIl copies of the film. and to UNiVERSITY MICROFILMS to publish an abstract of this thesis. The author reserves other publication rights. and neither the thesis nor extensive extracts from it may be printed or otherwise reproduced without the author's written permission.
ABSTRACT
The synthesis of conjugated polyenes via tandem cross-couplings reactions of
alkenyl halides and organometallic reagents was investigated in this project. The alkenyl
halide, &ans-1-chloro-2-iodoethene, which contains two different sites with varied
reactivity, was prepared to couple with organometals. Akenylboronic acids were
prepared via hydroboration of alkyles and cross-coupled with the olefin template, Pans-
1-chIoro-2-iodoethene. These coupling were also performed in tandem sequences and it
was found that they give good yield as non-tandem ones.
The strategy of one-pot synthesis was then applied in the first total synthesis of
Astaxanthin P-D-diglucoside, using the olefin template trans- 1-chloro-2-iodoethene. To
synthesize this natural product, the key targets, tram- 1 -chlore-2-iodoethene and 2,6-
dunethyl-cyclohexanone were used. The syrnmetry in this natural product gives the
ability to use the olefin template as the middIe key building block and use it several tirnes
to constnict the polyene chain via a series of cross-coupling reactions with boronic acids
and allcynes.
A series of reactions were applied on the 2,6-dimethylcyclohexanone to f o m the
suitably metalated ring part, which can later couple with the chain intermediate.
To My Parents And
My Husband Whose encouragement was my inspiration
m - O WLEDGEMENT
1 would like to take this opportunity to thank my supervisor Prof: Michael G. Organ, for his invaluable assistance and support throughout the course of this work. 1 am also very grateful tu my cornmittee rnembers, ProJ C. C. Lemoff and Prof: P. G. Potvin for their guidance in this research. 1 would also like to thmk aZl the people in Our group, especially Debasis MalZik, Svetoslav Bratovanov and Daniel J. Parh for their intellectual and material heEp. Without thern, my studies a f York would have been Zen enjoyable and mernorable.
Table of Abbreviations
APT
DBN
DCM
D m
DMSO
HMPA
(IPC), BH
LDA
NMO
TBDMS
TRIS
TLC
TBAF
THF
TLC
TMS
r. t.
attached proton test
1,8-diazabicyclo[S.4.0]undec-7-ene
dichloromethane
N,Nt-dimethylformamide
dimethylsulfoxide
hexamethylphosphoramide
diisopinocamphenylborane
lithium diisopropylamide
N-methyl rnorpholine oxide
r-butyldirnethylsilyl
triisopropylbenzenesulfonyl
thin layer chromatography
tetrabutylammonium fluoride
te trahydro fbran
thin layer chrornatography
trimethy k l y 1
roorn temperature
Table of Contents
List of figures
List of tables
Chapter one
Introduction
1.2. Carotenoids and their importance
1.2.1. Background
1.3. Strategies for building the olefinic structure
1.3.1 Conventional olefination methods
1.4. Olefin templates and their importance
1.5. Cross-coupling reaction
1.6. Organoboranes as coupling partners for olefin template
1.7. Role of palladium-catalysis in cross-coupling reactions
1.9. Importance of the tandem sequence
1.10. HighLights of the project
Chapter two
Synthesis of conjugated polyenes
2.1. Synthesis of the olefin template
2.2. Synthesis of alkenyl boronic acids
2.3. Tandem and independent cross-couplings
of organoboranes with the olefin template
Summary
Chapter three
Application of the tandem strategy to the
total synthesis of Astaxanthin p-D-diglucoside
Introduction
3.1. Retrosynthetic analysis
3.2. Synthesis of polyene c h a h key intermediates
3.3. Approaches toward the synthesis of the ring key intermediates
Summary 53
Chapter four 54
Experimental section for the synthesis of dienes:
tandem and independent studies 54
Experirnental section for the snythesis of Astaxanthin P-D-diglucoside 68
References 77
List of Fiqures
FIGURE 1: Astaxanthin P-D-diglucoside
FIGUICE 2: Structure of p-carotene
FIGURE 3: A general catalytic cycle for cross-coupling reaction
FIGURE 4: Major disconnections for Astaxanthin PD-diglucoside
FIGURE 5: Selective synthesis of an alkene
List of Tables
TABLE 1: Results and conditions for the synthesis of boronic acids
TABLE 2: Results for tandem and independent reactions
CHAPTER ONE
Introduction
Stereoselective syntheses of conjugated polyenes are of great importance
in organic chernistry.' A number of new methods for the preparation of conjugated
dienes and polyenes have been developed by using various organometallic
reagentsZ7' Among these procedures, the most promising ones are those based on
cross-coupling reactions, between stereodefined alkenyl metals and haloa~kenes.~ The
development of tandem (one-pot) sequences using simple starting matenals c m provide a
powerful method to produce useful organic molecules.
1.1 . Plan of The Study
There are different issues that this research would focus on:
1. To develop a strategy by which polysubstituted olefine can be prepared via the
formation of a carbon-carbon single bond between an alkenylhalide and alkenyl
metals.
2. To synthesize a suitable aikenyl halide (olef5n template) which can be applied in
tandem reactions.
3. To apply the strategy of the tandem synthesis in the total synthesis of a natural
product containhg a polyene structure, using the prepared olefin template.
The natural product of interest in this project is astaxanthin P-D-diglucoside (1).
Like other carotenoids, this nahiral product can be used in pharmaceutical, medicinal and
food ind~stries.~ The anti-cancer activity of astaxanthin P-D-diglucoside is the most
important reason for chemists to choose it as a synthetic target.' It was also speculated
that the presence of two glucose moieties in the molecule would increase the solubility of
the compound in aqueous media. This feature would potentially increase the
physiological activity of the molecule.
Figure 1. Astaxanthin P-D-diglucoside
1.2. Carotenoids and Their Importance
Arnong the different classes of natural products, carotenoids are one of the
most widespread and important ones containing a polyene structure. The olefinic
chah has a major role in their biological activities. Recent discoveries in the
biological function and medicinal application of retinoids and carotenoids has sparked
a renewed interest in the stereoselective synthesis of polyenes, especially those
containing an all-tram (E) structure.
In order to study the biological activities of single isomers of carotenoids, such as
their interaction with proteins or their role in photosynthesis, it is essential to isolate each
isomer separately. The isolation of one isomer is usually difficult and it rnight isornerize
during the process. This requires chemists to synthesize carotenoids in one single f0m.1.~
In the field of medicine, it is now clear that the provitamin A activity of
p-carotene may not be the only beneficial effect of carotenoids. Several carotenoids
found in the human diet, especiaily lycospene, Iutein, and zeaxanthin, are considered to
be involved in combating diseases such as cancer, heart disease, and degenerative eye
diseases. 6
1.2.1. Background
In the laboratory of Willstatter, after the accurate combustion analyses and
classical molecular weight measurernents of the compounds extracted fiom green Ieaves,
the correct molecular formulae of carotene C40H56 and xanthophyl C40H5& were found.'
Attempts to reveal the molecular structures by the classical method of chemical
degradation to significant identifiable fragments remained unsuccessfûl for several years.
Using catalytic hydrogenation, it was Iater confirmed that these pigments have a highly
unsaturated nature and the t e m 'polyene' was fïrst used to name these structures.* In the
laboratories of Kuhn and Karrer, the isoprenoid nature of carotenoids was found for
bixing and cr~cet in. '~ The first carotenoid whose structure was £ûlly identified was
p-carotene (Figure 2).6
END PART CHAIN PART
Figure 2. Structure of p-carotene
The long conjugated polyene chah part present in the carotene required the
development of new strategies and methods for its synthesis. The syntbesis of p-carotene
was achieved independently by the labs of Karrer, Inhoffen, and Milas, in 1950, a year
which can therefore be regarded as a milestone in carotenoid researcha6
The research in this field was continued extensively, so that by 1976, 98 naturally
occurring carotenoids had been synthesized. During this time, many reactions were
applied to construct the polyene chah (Julia or Wittig olefination). The synthesis of
carotenoids propelled the development of organophosphorous chemistry through the
Wittig and the Horner-Emmons reactions.
Although a large number of carotenoids have been made, the synthesis of carotenoids
is still a popular practice because of their enormous commercial value. Such syntheses
are also routinely exercised in academic and industrial scale processes.
1.3. Strategies For Building The Olefinic Skeleton
Modem synthetic organic chernistry permits the preparation of polyenes via a
number of strategies. However, a few methods established early in this century have
been used and fürther developed to an industrial scale.
There are two approaches to prepare olefinic structures. In the first strategy
(method A), the building bIocks are connected +hou@ the formation of double bonds, by
a Wittig reaction or elimination of a sulfone group (Julia olefination). The second
approach involves the establishment of a single bond between two double bonds (rnethod
B). This approach has not been examined until recently, due to the difflculty in
establishing C-C bonds between two sp2 centers (Scheme I ) . ~ However, cross-coupling
methodology would enable one to build a polyene chah with a defined ( E l 9
stereochemistry.
Method B: single bond formation Z
Y
X
z Method A: double bond formation
Scherne 1
1.3.1 Conventional Olefination Methods
There are different methods leading to the formation of an olefmic structure like
I I , 12 en01 ether and aldol condensations, Wittig olefhation," sulfone c ~ u ~ l i n ~ ' ~ * l5 and
organometallic reactions.16 A large amount of ivork has been done on the
thennodynamics and kinetics of double bond-making processes that helps chemists
predict a reaction profile which leads to an olefin with a desired stereoche~nistr~.'~
In Wittig reactions, a carbonyl functionality can be converted into an o l e f i c
bond by reactions with phosphonium salts.13 The conformational distribution of the
be taine
intermediate often decides the fate of an olefination reaction that leads to a (2) or (E)
double-bond. The synthesis of fucoxanthin employed a Wittig strategy and is shown in
Scheme 2. '' However, th is configurational distribution vastly depends on the proximal
fùnctional group on the substrate. As a result, reactions are, in most cases, substrate
specific. Unstabilized ylides give predominantly the 2-alkene while stabilized ylides give
mainly E-alkene. Besides, the nucleophilic attack of the ylide on the carbonyl system c m
often be a challenge if the carbonyl carbon is sterically crowded with proximal
functionalities.
A modification of Wittig olefination reactions gained a wide popularity as it
attempted to solve a few of the many problems described above.
The Horner-Emmons-Wordsworth method (also known as the modified Wittig reaction)lg
provided a tool to prepare relatively stable (sometirnes isolable) ylides using phosphonate
esters. This method usualiy leads to an E-isomer. However, a slight modification of
steric requiremenis at the proximal carbon atom can lead to a ~-isorner.*~ As a result, the
problem of "substrate-specific success" remains the same for the synthesis of a broad
range of natural products.
&hicl
1 ) NaOMe
2)OH-
A
Scheme 2
Another relatively tess cornmon method where a a-halosulfone can be used to
generate olefins ( hown as the Ramberg-Biicklund rearrangement)20 gained little success
due to rather a reactive intermediate containhg a sulfone functionality. Besides, the use
of strong bases (usually potassium hydroxide) during the reaction-sequence is always a
concern for many natural products containhg sensitive fünctional ~ O U ~ S . ~ A relatively
popular sulfone-based olefination method is Julia olefination. This olefination method
was fïrst applied by Julia for the synthesis of vitamin A. 21* 22 h this method, the double
bond is generated via alkylation of the a-carbanion of a sulfone and then, base-induced
eiïmination,
Like the Wittig reaction, Julia olefmation does not always lead to the
desired stereochernistry of the olefm due to conformational restrictions in the reaction
intermediate. An example of this methodology is shown in Scheme 3.
Scheme 3
A philosophical aspect that challenges these conventional synthetic methods
(specially Wittig ole£ination methods) is the lack of "atom-economy" in these processes.
The molecular mass involved in the triphenyl phosphonium moiety (Wittig type
reactions) or sulfone moiety (Julia olefmation) does not contribute to the product mass
creating a large amount of mass for waste-disposal. Considering the amount of money
spent for industrial waste-disposal, the lack of "atom economy" is a serious
disqualification for conventional olefmation methods."
Today, one of the main methods in carbon-carbon bond formation is based on
the usage of organometallics. Among the various organornetallic reactions employed
for this bond formation, the metal a~etylide?~ ~ri~nard?' and ~eformatskJ~ reactions
have been used in the synthesis of Vitamin A and other carotenoids. In these senes of
reactions, different metals can be used. This includes metals of group LA, IIA, and IIIB
or transition metals in the penodical table. Meta1 acetytides (aikymdes) have featured
prominently in the synthesis of vitamin A and other carotenoids, principally by the
nucleophilic addition of metal acetylides RCCM (M= Li, Na, K, MgX) to aldehydes
and ketones to produce the corresponding a-hydroxyalkynes.24
Scheme 4
In the f i s t synthesis of vitamin A by Isler and his CO-workers, the Grignard
acetylide reacts with aldehydes to give the desired structure (Scheme 4)?
1.4. Olefm Templates and Their Importance
The term "Olefin template" refers to a target which contains a stereodefined
olefinic structure and two or more reactive sites and can be used in tandem reactions on
the double bond with specific stereochemistry. The reactive site is usually a halogen,
which can cross-couple with other molecules. This way a new carbon-carbon bond will
be formed while the stereochemistry of the template remains the same. This method will
reduce the synthetic problems associated with the formation of an undesired
stereochernistry of the double bond.
The synthesis of a suitable template however, dernands the following features:
a) A template must have different groups with varied reactivity to rnaintain the regio-
selectivity in step-wise reactions.
b) A template should be synthesized fiom a commercially available inexpensive
substrate.
c) The preparation of the template shouId be convenient and reaction conditions must be
amenable to large-scale productions.
In the light of these properties, the designed template can be used in cross-
coupling reactions to provide a structure with a defhed stereochemistry of the double
bond,
1.5. Cross-coupiing Reaction
Cross-coupling reactions of organometallic reagents with an alkenyl halide is one
of the best methods to form a carbon-carbon single bond (Scheme 5). There are different
cross-coupling reactions, which can provide carbon-carbon bond formation, such as the
~uzuki ; ~ e c k , ~ ~ or Stille 29 reactions.
Different organometallic reagents have been applied in the cross-coupling
reactions. ~ o ~ ~ e r , ~ ' nickel:' m a g n e s i d and titanim3' 33 c m be used in the
preparation of organometallic reagents and have shown good results in synthesis. These
organometallic intemediates undergo Ni situ transmetallation with their cross-coupling
partner followed by a reductive elirnination where the rnetal is released back into the
catalytic cycle and the carbon-carbon bond forms.
A wide range of transition-metal catalysts have been used (such as Pd, Ni, Pt, Rh,
Cu) and a variety of cross-coupkg partners like ~ r ~ a n o r n a ~ n e s i u m , ~ ~ ~ r ~ a n o c o ~ ~ e r ~ ~
32.33 organoboron? ~ r ~ a n o z i n c ? ~ organonicke13' and organotitanium have been reported.
The vast research in this field allows tuning the reaction-conditions and template-
functionality so that the method can be adjusted to suit a large nurnber of target
molecules. The reactivity of nucleophilic coupling partners c m be tuned with synthetic
precision by changing the metal involved.
1.6. Organoboranes as Coupling Partners For The Olefin Template
Many organometallic reagents undergo cross-coupling reactions, but much
attention has recently been focused on the use of organoboranes by researchers in
university and industrial laboratories. These reagents are generally thermally stable and
inert to water and oxygen, thus allowing their handling without special precautions.34
Allcenylboronic acids show high reactivity towards the alkenyl halides, These
boronic acids can be prepared f?om the hydroboration of alkynes (Scheme 6). The
hydroboration of terminal alkynes with stoichiometric arnounts of hydroborating
reagent gives the predominant formation of the corresponding E-trialkenylborane. The
hydroboration usually gives the alkenyl borane with the boron moiety on the less
hindered end of the triple bond.35
Scheme 6
The choice of catalyst is another important aspect in cross-coupling reactions.
The cross-coupling reaction of organoboranes with haloaikenes proceeds best in the
presence of the catalytic amount of a palladium cataiyst ( S d reaction).
1.7. Role of Palladium Catalysis in Cross-coupiing Reactions
The importance of palladium chemistry was recognized in 1958 when Walker et
ai. introduced palladium metal as the solution for a much-needed hydroformylation
r e a ~ t i o n . ~ ~ Gradually palladium as a catalyst, became the choice of chemists for industrial
as well as academic purposes. The preference of palladium metal in cross-coupling
reactions to other transition metals for exarnple Ni, Rh and Pt, is widespread. Early
research on Pd-catalyzed cross-couplhg reactions mainly focused on the solubility issue
of heterogeneous c a t a ~ ~ s i s . ~ ~ In the case of Pd, the problem was minimized since several
Pd salts or ligated species have been found to be water-soluble.37 Another important
aspect of choosing Pd is its electronic configuration. Because of its electronically
saturated d'O conf~guration at its "0" oxidation-states, palladium is prevented from any
M e r reduction of the metal system. Thus the first step in the oxidative insertion of Pd
into an organic bond becomes a lot more unambiguous than other metals. A general
cycle of base-catalyzed
cross-coupling is shown in Figure 3.
In this cross-coupling reaction, the o bond in a haloalkene is activated by the
assistance of a metal-catalyst via an oxidative insertion process.
Figure 3. A general catalytic cycle for cross-coupling reaction
The oxidative addition of 1-alkenyl halides to a palladium (0) complex gives a
R ' - P ~ 0 - X intermediate which can be isolated. The reaction proceeds with cornplete
retention of configuration of this halide. This step is often the rate-determining step
in a catalytic cycle. The reactivity of vinyl halide in the reaction decreases in the
order of 1 > Br » The reductive elimination of the organic partner from
R'-~d @)-RI produces the palladium (O) complex and the desired product RI-R'."
Modem synthetic methods are now focused on the usage of palladium
catalysts. An example of a palladium-mediated reaction is shown in Scheme 7.39
ko-ms
Scheme 7
1.9. Importance of The Tandem Sequence
The word tandem means "in conjunction " which in the chexnical sense translates to a
sequence of reactions performed one after the other without the isolation of the
inter me dia te^.^^ The wide-spread popularity of tandem reaction sequences is probably
due to the fact that it reduces the labor-cost and enhances the efficiency of the synthesis
in A tandem sequence also reduces the amount of solvent required to
perfonn a reaction and purifjr the product. This c m be of great importance in industry,
where to produce a compound on a large scale, a large volume of solvent is required,
which then becomes the waste." However, to employ a complex reaction scheme in a
tandem sequence a few issues need to be resolved:
a) The reagents must react selectively, meaning one reagent must not interfere with
other functionalities that are present in the moiecule.
b) Chemicals used for the early steps must not inhibit or interfere in the later steps.
c) The reagents a d the reactive intermediates must be fairIy stable under the reaction
conditions so that the reaction proceeds cleanly.
1.10. Highlights of The Project
This research focused on the development of a tandem cross-coupling of alkenyl
halides and alkenyl metal to make polyenes and the application of the strategy to the total
synthesis of Astaxanthin B-D-diglucoside. The choice of alkenyl halide used in these
reactions is very important, so that it could be applied in the total synthesis of
Astaxanthin B-D-diglucoside (1). A suitable olefm (trans- 1-chloro-2-iodoethene)
template was synthesized for tandem Suniki reactions to prepare a range of olefinic
compounds. This tempIate, which contains two active sites, was used for selective cross-
coupling with alkenylboronic acids. A range of alkenylboronic acids was prepared via
the hydroboration of terminal a m e s using dibromoborane as hydroborating agent.
M e r the optimal conditions for these reactions were obtained, the olefin template tram-
1-chloro-2-iodoethene was used in the synthesis of Astaxanthin p-D-diglucoside (1). The
olefm template can be used several times to build the chah part of this natural product
via ~ 0 n o ~ a s h i 1 - a ~ ~ and carboal~mination~~' " reactions.
The ring part can be formed starting fiom 2,6-dimethylcyclohexanone (14). A
series of reactions can be applied to obtain the best alkenyl metal that can be coupled
with the olefin template. It was found that the alkenylboronic acid is the best coupling
partner for trans- 1-chloro-2-iodoethene (Figure 4). The conversion of starting material
2,6-dimethylcyc1ohexanone to vinylboronic acid was performed via formation of a vinyl
iodide intermediate using the Shapiro reaction. 46.47
Figure 4. Major disconnections for astaxanthin P-D-diglucoside
CHAPTER TWO
Synthesis of the Conjugated Polyenes
2.1. Synthesis of the Olefin Template
Polyenes were prepared via cross-coupling reactions of an akenyl halide and
organometallic reagents. This demanded first the preparation of a suitable alkenyl halide
as the olefin template. Trans-1-chloro-2-iodoethene was prepared and applied in the
synthesis of polyenes. Having two halogens with different reactivity gives the ability to
build the olefin A via cross-coupling of organometallics RM and R'M', respectively
(Scheme 10).
Scheme 10
Compound 2 was obtained by slowly bubbling acetylene gas (4) into an acidic
solution of ICI (3) at ambient temperature (Scheme 1 1).49
6N HC1 ICI i- --
O O c T
Scheme 11
The assignment of configuration (E) was c o n f i e d by the c o u p h g constants of
tram-vin ylic pro tons (J = 1 4 Hz).
To build the C-C single bond in a polyene chah, the coupling of different
organomatallics with compound 2 was investigated. Organomagnesium and
organoborons were coupled with compound 2. The results indicated that cross-coupling
of organoboronic acids (Suniki) happens smoothly in the presence of the small amount of
Pd-based catalyst and gives a better yield than Grignard reagents catatyzed with Ni
(Scheme 12).
2, Pd (0) ,THF R-B(OW2
base, 60 OC R*Cl
5 R= Ph, para-OMe-Ph (68 %)
Scheme 12
Reaction of organoboron reagents with 2 was also found to proceed smoothly
when the reagents were activated with aqueous bases, and gave the product in better
yields.
The next attempt was to develop a rnethodology that works selectively with the
olefin template and to produce a series of substrates (alkenylboronic acids) for this study.
2.2. Synthesis of the Alkenylboronic acids
Although several methods for the synthesis of aikenylboronic acids are available,
the hydroboration of terminal a i m e s is one of the best methods to make vinyl boronic
a ~ i d s ? ~ This reaction is especially valuable for the synthesis of stereodefined or
functionalized alkenylboronic acids and their esters.
Three different reagents, catechol-borane." diisopinocampheny lborane
[ (T~C)~BW~' and halob~ra.nes '~*~~ were used to make these boronic acids (Scheme 13).
In the first method, terminal allynes were hydroborated with catechol-borane to
produce 1-alkenyl esters. These esters were then converted to boronic acids by
hydrolysis. The presence of catechol, produced during the hydrolysis, was a
contaminant in the boronic acid products. Thus the reaction of (?l?C)aBH and haloboranes
were examined with a m e s . The best hydroboration results were obtained using
dihaloborane, and in particular dibromoborane (Table 1). This reagent exhibits extremely
high reactivity toward akenes and allcynes, allowing the hydroboration to proceed at low
ternperatures.
Scheme 13
Table 1 shows the reaction conditions and yields for different aikynes.
In th is method, a slight excess of allcyne was utilized to prevent dihydroboration.
Many of the akenylboronic acid products exist in solid form and are hygroscopic. The
hydroboration of the aikynes resulted in single products on which the boron moiety is in
the least sterically hindered place and these were confirrned by spectroscopie methods.
The coupling of these boronic acids with the olefm template were examined.
Reaction
a R=C,H,, . tert-butyl- b R=C5H, 1
R=C&Ig- R=Ph- c X=Br C3H7- Ph- ca9-
c6H13' t-butyl- CH2Cl- HO-CH2- TBDMSOCH2- MeO-Ph-CH2-
Solvent
THF
DCM
Yield (%)
Table 1. Results and conditions for the synthesis of boronic acids
2.3. Tandem and Independent Cross-couplings of Organoboranes With
The Olefin Template
A series of Su& reactions were performed on cornpound 2 using the optimized
condition of 3-7 % of Pd catalyst and sodium or potassium hydroxide in refluxing THF.
lndependent sequence 7 KOH, Pd(F'P6j)4 (3-7%)
R- B(O& * &Cl THF, 60 OC, 8 hours R
R'-B(OW2 KOH, Pd(PP6j)4 (3-7%) &R' * R
THF, 70 OC, ovemight
Tandem sequance I
L ITP, 60 OC, 8 hours ' THF, 70 OC, ovemight
R- B(OH)2 &Cl 1
KOH, pd(PPl~)~ (3-7%)
Scheme 14
Different boronic acids were examined in these cross-couplings using tandem and
independent sequences. In the independent sequence, the resulting product of the f ï s t
cross-coupling was isolated and purified for the second cross-coupling, while in the
tandem sequence, the product of first cross coupling was not isolated, but rather carried
through the second coupluig. Scheme 14 shows the general method of these couplings.
In these reactions after completion of the first cross-coupling, the second alkenylboronic
acid was added to the same pot, along with a fiesh batch of catalyst and base and heated
to reflux. The results obtained fiom tandem reactions are comparable with sequential
ones (step 1 yield x step 2 yield) (Table 2).
&Cl R
K-B(OW2 - &R' KOH, Pd(PPq)4 (3-7%)
By changing the sequence of the boronic acid addition, the ease of the separation
of the product and yield would change. It should be noted that, for the one-pot c o u p h g
sequence to work, attention must be given to the order of addition. Sorne examples are
shown in Schemes 15, 16 and 17. For exarnple, if the coupling starts by the addition of
octenylboronic acid (10) to cornpound 2 and then coupling of 4-methoxyphenylboronic
acid (9b), the isolation of the fmal product (11) as a clean cornpound is difficult. By
changing the order of addition, compound (11) can be purified more easily, resulting in
higher yield (Scheme 16). This c m be due to the reactivity of the first boronic acid
chosen for couphg. If this boronic acid is very reactive, the chance of its coupling with
the chlorine site is higher, and therefore bis-couplîng products will be groduced during
the first reaction. Less reactive boronic acids can diminish the formation of these
byproducts while being reactive enough for the formation of first intemediate.
Sequence A u P-M~O-P~-B(OH)~
KOH, Pd(PPh3)4 (3-7%) KOH. Pc~(PP$)~ (3-7%)
THF, 60 OC. ovemight THF, 65 OC, overnight Me0
KOH. Pd(PPh3)j (3-7%) - THF, 60 OC. overnight
OMe
9b
Scheme 15
* Tandem and independent yields are shown in table 2.
Ph-B(OW2 KOH, Pd(PPh3)4 (3-7%)
THF, 65 OC. ovemight - MeO Q""
Once the structure o f the polyenes were confirmed by spectroscopie methods, the
methodology was applied in the synthesis of natural product (1).
Sequenee A O Pd(PPbl4 (3-7%). THF.
-eco% + 2 KOY 60 OC. overnight
Pd(PPh), (3-7%). T'HF, - KOH, 65 OC. ovemight
M e 0 I I
Sequence B n
OMe t Sb J
Scheme 16
* Tandem and independent yields are show in table 2.
Sequence A n -B(OB(OH +
Pd(PPb)4 (3-7%). THF, C
KOH, 60 OC. overnight
Ph-B(0W Pd(PPh3)j (3-7%). THF,
* KOH, 65 OC. overnight
Sequence B C I
+ 2 KOH. 60 OC. ovemight
8 Sa
Scheme 17
Octenyl boronic acid pd(PPt~ )~ (3-7%). THF
KOH, 65 OC, ovemight
Table 2. Results for tandem and independent reactions
Summary
The olefin template pans-1-chloro-2-iodoethene (2) was prepared fiom the
reaction of acetylene gas and ICI (3). This cornpound was subjected to tandem cross-
couplings with alkenylboronic acids to provide olefinic structures. The akenylboronic
acids with (E) conformations were prepared fiorn the reaction of hydroborating reagents
with terminal -es. Among different hydroborating reagents for hydroboration,
dibromoborane-dimethylsulfide complex gave the best results. Cross-coupling reactions
gave the highest yield in the presence of 3-7% palladium catalyst and an aqueous solution
of potassium or sodium hydroxide in refluxing THF.
Tandem experiments were applied to the o l e k template and it was found that the
order of the alkenylboronic acid addition is very important. Reactive alkenylboronic
acids in the fnst cross-coupling reduce the regioselectivity of the reaction as they rnight
also react on the chlorine site to fonn the bis-coupling product.
The yields ftom tandem reactions are comparable with the overall yield for
sequential reactions, which makes it possible to use the tandem strategy in the synthesis
of natural product.
CHAPTER THREE
Application of the Tandem Strategy to the Total Synthesis of
Astaxanthin p-D-diglucoside
Introduction
The second part of this project focuses on the first total synthesis of astaxanthin P-
D-diglucoside (1). The strategy of tandem synthesis can be applied in the preparation of
this compound, using the sarne o le f i template, tram- 1-chloro-2-iodoethene (2).
3.1. Retrosynthetic Analysis
The synthesis of astaxanthin P-D-diglucoside (1) involves a series of cross- coupling
reactions requiring complete control of regio- and stereochemistry of double bonds in the
polyene chain. The retrosynthetic analysis leads back to two key intermediates, tram- 1 -
chloro-2-iodoethene (2), a substrate for selective palladium- catalyzed cross-coupling
reactions, and 2,6-dimethylcyclohexanone (14). The symrnetry in this natural product
gives the ability to use 2 several times to construct the polyene chain via a series of
stereo- and regioselective cross-coupling reactions with boronic acids
and akynes. The one-pot methodology described in the previous chapter is ideal to get a
desired product with good yield while it reduces the time, waste and cost associated with
the synthetic chemistry.
Disco~ections on Cls- Cl4 and Cis*- Ci4 of the chah part allows one to use
pans-1-chloro-2-iodoethene (2) as the key building block (Figure 5).
Figure 5. Setective synthesis of alkene
The ring part of the h a 1 product c m be obtained fiom a metalated target starting
fiom 2,6- dimethylcyclohexanone (14). Compound 14 can be then converted to the
intermediate 17 via a series of reactions. The intermediate 17 then will be cross-coupled
to trimethylsilylacetylene under Sonogashira coupling condition^!^ Allylic oxidation5'
and a-hydroxylation52 following the TMS group removal would provide intermediate 18.
Carboalumination of 18 with trimethylaluminum and an organozinc reagent will provide
the methylated diene 19 with the desired stereochemistry. By repeating the coupling of
13 to the metaiated compound 19 foilowed by the TMS group removal, and
carboalumination again, compound 20 would be obtained. Two equivalents of compound
20 with 2 in the same pot, would give the natural product of interest (Scheme 18).
Scheme 18
3.2. Synthesis of the Polyene Chain Key Intermediates
The synthesis of the centrai part of the astaxanthin compound consists of the
synthesis of compound 2 as the binder of two identical parts and the chloro-enyne 13,
which can be made fiom the same compound 2. Compound 13 can undergo M e r
cross-coupling to intermediate 19 to provide compound 20.
The first attempt was to obtain the chloro-enyne 13a, which does not contain the
TMS moiety, but M e r studies showed that due to its volatility, the isoIation of 13a is
difficult.
To make compound l3a, lithium acetylide (21) was coupled to compound 2
(Scheme 19). Therefore, lithium acetylide was transrnetaiated with dry zinc chloride and
provided intennediate 22. Transmetalation was pex5ormed by sonication and the
resulting intermediate was coupled with compound 2 in the presence of a pailadium
catalyst. The reaction was examined in different solvents and only proceeded (50%) in
THF. The boiling point of the product is close to that of TEIF and, thus, it was difficult to
isolate the product in good yield.
- - Li ZnC12 ,solvent - r- t, 1-2 h
21 sonication
2, 4% 4 solvent, r. t-, overnight Cl d
13a
Scheme 19
In the second method the Sonogashira coupling of compound 2 with a m e s was
exarnined. Allqne 23 was coupled with 2 and the method was applied in the reaction of
the olefin template with TMS-acetylene. This provided product 13 which has a higher
boiling point than 13a, and which is easier to handle and isolate (Scherne 20).
r// 2,4%CuI, 4%Pd(PPbI4
/ Piperidine , EtrO. 40 OC. 6h Me0
Piperidine, Et20, 40 OC, 8h 25 13 (70 %)
Scheme 20
To rernove the TMS group, compound 13 was reacted with different bases and
provided 13a (Scheme 2 l).". " The best results were obtained using potassium fluoride
as a base. However, the volatility of the product and its susceptibility to polymerization
forced the abandonment of the preparation of compound 13a. Instead, atternpts were
made to couple 13 directly to the end group, planning to remove the TMS group later.
TBAF
1
Scheme 21
3.3. Approaches toward the Synthesis of the Ring Key Intermediates
The synthesis of the ring part began by using 2,6-dirnethylcyclohexanone (14),
which is inexpensive and commercially available. It was decided to examine several
pathways in order to get the desired ring moiety.
It was considered that the organometal species (25) provides suitable candidates
for cross-coupling reactions with compound 2. This allows us the generation of these
species via a general method shown in Scheme 22.
Scheme 22
A methyl group was introduced on the starting material 2,6-dimethyl-
cyclohexanone as described in Scheme 23. In this way, ketone 14 was fkst deprotonated
using LDA and the resulting enolate was quenched with excess methyl iodide at O O C .
The existing carbonyl moiety can be used to f o m the olefinic conjugation in the ring.
The enolate of IS reacted with diphenyl disulfide producing thio-ether 26
(Scheme 23). The formation of double bond was effected by oxidation of 26 using Na104
in situ and heating the resulting sulfoxide 2 P 5 This provided the desired enone 28, but in
low yield (10-15%). The yield of 28 was poor, so a new method for its preparation was
attempted.
1) LDA, -78 OC. THT, Ih 1) LDA, -78 OC, THF, Lh
2 ) Me1 (excess), O OC 2) Ph-S-S-Ph, O O C
14 15
es-ph 26
(93%) (-70%)
Scherne 23
In the second method, the desired unsattmted structure was produced by
introducing bromine on the starting ring and then elirninating HBr. Cornpound 30 is a
mild and effective reagent which introduces bromine on carbon even on hindered sites in
good y ie~ds .~~ ' 57 It was made by the addition of sodium hydroxide to 1,4-dimethyl-2,s-
dioxane (29) (Meldrum's acid) at O OC and then slow addition of bromine to the mixture
(Scheme 24). Addition of 30 to the ketone 15 in CC4 at 70 O C provided bromo-ketone 31
in 85% yield. Compound 31 was then heated in the presence of LiBr and Li2C03 and
converted to enone 28 in 70% yield (Scheme 25). 58, 59
Scheme 24
I) LDA, -78 OC, THF
2) Me1 (excess), O'C
LiBr, L5CO3, DMSO
i 15 OC, 12 h
Scheme 25
The next objective was to fom the remaining hydroxy ketone on the ring (compound 24).
Thus, the extended enolate form of compound 28 formed using LDA and it was quenched
with diethyl c h l ~ r o ~ h o s ~ h a t e ~ ~ (Scheme 26). In uis way the desired double bond was
formed on the ring (compound 32). It was found that the yield of the reaction was
enhanced dramatically when HMPA was used to solvate the lithium base.
O II
O-P-(O-Et), L) LDA, HMPA, THF, -78OC
2) O II
28 Cl-P-(O-Et)2 ->O/ 32
(70%)
Scheme 26
To make the chiral alcohol, the synthesis of optically active building blocks which
can be achieved via asymmetric hydroboration was examined. In this mode1 study,
compound 32 reacted with diisopinocamphenylborane, that was made in situ by the
reaction of two equivalents of the optically pure isomer of a-pinene and a borane-
dimethyl sulfide cornplex, which gave alcohol24a (Scheme ~ 7 ) . ~ ' Heating the reaction
was necessary, as no reaction was observed between diisopinocamphenylborane and the
en01 phosphate at room temperature.
Scheme 27
The en01 phosphate was also examined to give a dihydroxyl compound via
dihydroxylation using osmium tetroxide as a hydroxylating reagent!' Reaction of 32
with a catalytic amount of osmium tetroxide and N-methyl morpholine oxide (NMO)
gave the desired dihydroxylated product (Scheme 28). These studies confinned that we
could introduce chirality on the ring. So the reactivity of the en01 phosphate in reactions
was exarnined.
Scheme 28
To continue the rest of the synthesis, the reactivity of en01 phosphate 32 was
examined in coupling with di fferent partners.
3.3.1 Evaluation of En01 Phosphate Reactivity
33.1.1 Reaction with Grignard Reagent
It is well lcnown that en01 phosphates are good cross-coupling partners for
Grignard reagents? In this study, compound 32 was exarnined to react with the
Grignard reagent generated fiom enyne 13 and rnagnesium (Scheme 29). This reaction
did not provide the desired product. It was believed that the conversion of 32 to an
organotin moiety would provide a more reactive compound for the cross-coupling.
Ether
," 1
M g + CI 13
Scheme 29
3.3.1.2 Conversion of en01 phosphate to organotin
Compound 32 was examined to react with hexabutyldistannane in the presence of
a Pd catalyst. In spite of heating and increasing the reaction t h e , no coupling was
observed. The lack of reactivity could be caused by the stencally encumbered butyl
group on the tin reagent (35). However, the reaction of compound 32 with
hexamethyldistannane (36), which has smaller alkyl group, also did not provide the
desired intermediate (Scheme 30). These series of experiments involving 32 indicaieci
that the reactivity of the en01 phosphate is low, thus the approach was changed.
Scheme 30
Since the e n d phosphate 32 was not sufficiently reactive, the formation of vinyl
borate 41 fiom ketone 15 was considered. This compound can be prepared fiom the
related vinyl halide via halogen-metal exchange. Vinyl iodides have shown the best
results in cross-coupling (chapter two14 or halogen-metal exchange reactions. Vinyl
iodide 38 was prepared from a reported modification of Barton's procedure." The
hydrazone 37 obtained fiom ketone 15 was converted to vinyl iodide using two
equivalents of iodine in the presence of excess 1,8-diazabicyc~o[5.4.0]undec-7-ene
@BN) as base (Scheme 3 1). The resulting oil was confirmed to be vinyl iodide (38)
using spectroscopic methods.
The reactivity of this iodide was then determïned by treatment of this target with a
mode1 octenylboronic acid in the presence of a palladium catalyst. This reaction
produced the cross-coupled product in high yield, indicating that the iodide is reactive
despite being hindered.
EtOH, 100 OC, 2 days
Scheme 31
Compound 38 could aIso be converted to an organostannane to serve as a
coupling partner for compound 2. Since it has been reported that the Suzuki coupling is
more tolerant of steric effects than the Stille c o ~ ~ l i n ~ , 6 ~ the vinyl iodide product was
converted to a vinylboronic ester rather than the correspondhg stannane. Keay et al.
reported the cross-coupling reaction of aryl and vinyl halides with in situ-generated
organoboronates, 67 obtained by treatrnent of the orgrnolithium precursor with
triisopropylborate. To diminish the number of steps in this method, it was decided to
46,47 prepare the vinyllithium derivative of compound 15 ushg the Shapiro reaction
startïng from the corresponding triisopropylbenznesulphonyl (TRIS) hydrazone (Shapiro-
Suzuki). 67 Therefore, compound 39 was prepared by the reaction of ketone 15 and
TRIS-hydrazone. Compound 39 was then reacted with two equivalents of tert-butyl
lithium to produce 40 which was then quenched with triisopropyl borate. The resulting
ester was directly cross-coupled with compound 2 in the hope of generation of the desired
product. The reaction of ester 41 with compound 2 did not provide the cross-coupled
product 42 (Scheme 32). So the methodology was continued using vinyl iodide as the
key intermediate (compound 38).
Scheme 32
The same procedure was applied to vinyl iodide 38. It was treated with 2
equivalents of tert-butyl Iithium and the resulting vinyllithium quenched with triisopropyl
borate, To modie the previous method, the boronic ester was hydrolyzed in situ with
concentrated sodium hydroxide and then coupled with compound 2 in the presence of
palladium catalyst. This produced the desired product 42 in 55% overall yield starting
fiom 38 (Scheme 33).
10 equiv. NaOH,
[IO NJ, r* t., 2 h
2, Pd(PPh3)4 *
THF, reflux
Scheme 33
It is believed that the reactivity of the boronic acid (43) in the cross-coupling
reaction with compound 2 is considerably higher than that of boronic ester 41.
With some of the critical questions answered, the future synthetic pathway should
be possible following the route laid out in Scheme 34. The one-pot synthesis strategy
will be applied to compound 19 to fom the desired natural product in several steps.
I I
Hydroxylation - O
1 Carboalumination
Scheme 34
Summary
The retrosynthetic analysis of the natural product Astaxanthul B-D-diglucoside
leads back to two key targets, lrans- l -chlore-2-iodoethene (2) and 2,6-dimethyl-
cyclohexanone (14). Intermediates for the total synthesis were prepared fiom these key
targets. Trans-1-chloro-2-iodoethene, was used to prepare the olefinic chah intermediate
via coupiing with TMS-acetylene (Sonogashira coupling).
The synthesis of the ring part was atternpted with the formation of a hydrazone
intermediate via the Shapiro reaction. The hydrazone was converted to alkenylboronic
acid and coupled with trans-1-chloro-2-iodoethene. This intermediate can be converted
to the ring part in several steps. M e r the preparation of the ring part, the one-pot
synthesis of the molecule will be applied.
CEFAPTER FOUR
Experimental Section for the Synthesis of Dienes : Tandem and
Independent Studies
General Procedure. Al1 reactions were carrïed out under a positive atrnosphere of dry
nitrogen. Solvents were distilled pnor to use. Et20 and THF were distilled fkorn sodium
and benzophenone; CH2C12 was distilled fiom CaH2. Anhydrous dimethylforrnamide and
anhydrous dimethylsulfoxide were purchased from Aldrich and stored under a nitrogen
atmosphere. Flash chromatography was performed using Whatman 230-400 silica gel 60.
Thin layer chromatography (TLC) was carried out on Merck silica gel 60 F254 pre-coated
glass plates, with detection by W light and permanganate solution. Melting points are
uncorrected. 'H NMR spectra were recorded in CDC13 at 400 MHz, and ')c NMR were
recorded at 100 MHz in CDC13. Chemical shifts are listed relative to CHClp (5 7.28) for
1 H NMR and (6 77.2) for 13c NMR. Low resoiution mass results were obtained with a
mass spectrometer at the Department of Chemistry, York University. High resolution
mass values were obtained with a high resolution mass spectrometer at the Department of
Chemistry, McMaster university. Elemental analyses were obtained at the Guelph
Chemicat Laboratones.
General procedure for preparation of (PPh3)4Pd
A mixture of 650 mg of trïphenylphosphine (2.4 mmol), 85 mg of PdCl2 (0.47 mmc!) and
6 mL dry dimethylsulphoxide was placed in a flame-drïed flask. The yellow slurry was
heated to 140 O C untir al1 the compounds were dissolved and a clear orange solution was
formed. The flask was removed fkom the heatïng bath and after 2 minutes, 0.1 rnL of
hydrazine hydrate (3.2 m o l ) was added drop-wise to the solution. Yellow crystals
were formed upon the addition of the hydrazine. The reaction mixture was cooled to
room temperature (r. t.), filtered and washed several tirnes with ether. The yellow
crystals were dried under vacuum at r. t. for one hour and filled with nitrogen providing
500 mg of (PPh&Pd as yellow crystals. Spectra corresponded to that previously
reported."
General procedure for the preparation of tram-alkenylboronic acids using
catechol-borane
One equivalent of alkyne in THF and one equivalent of catechol-borane was added to a
flame-dried flask, The solution was heated to reflux for 6 h. The reaction was monitored
by TLC. After completion of the reaction, the mixture was cooled to r. t. and 100 mL of
water was added. The white crystals were filtered and recrystallized fkom water to give
the tram-akenylboronic acid. Spectra corresponded to those previously reported. 35
General procedure for the preparation of frans-alkenylboronic acids using
diisocamphenylborane
To a flame-dried flask was added 1.06 eq of borane-dimethylsulnde in THE The solution
was cooled to O OC and 2.4 eq of a-pinene (dried over calcium hydride for 4 h and
distilled prior to use) was added slowly to the mixture and stirred for 1 h at the same
temperature. The mixture was s h e d for another 2 h at r. t. and the resulting white slurry
was cooled to -35 OC. One equivalent of aUcyne was added to the mixture drop-wise at
-35 O C and stirred for one h and then warmed to r. t.. The mixture was stirred for
another 2 h at r. t. and then cooled again to O O C . Distilled acetaldehyde (2.5 eq) was
added to the mixture at O OC. It was warrned to r. t. to and stirred for one h. To the
mixture was added 2 eq of water and it was heated at 55 O C for 3 h. It was cooled to r. t.
and the solvent was removed in vacuo. Hexane was added to the residue and the mixture
was stirred for 10 minutes. The resulting precipitation was filtered, washed several tirnes
with hexane and dried under vacuum to provide the alkenylboronic acid. Spectra
corresponded to those previously reported. 49
General procedure for the preparation of tram-alkenylboronic acids using the
dibromoborane-dimethylsulflde complex
To a flarne-dried flask was added 1.1 eq of akyne which then diluted with
dichloromethane. The solution was cooled to 10 OC and one equivalent dibromoborane-
dimethylsulfide was added drop-wise. After stimng for 4 h at 10 OC, the solvent was
removed in vacuo. The resulting oil was cooled to O OC and 2.2 eq of aqueous sodium
hydroxide was added to the solution to fonn a white solid. The mixture was stirred for 1
hour and water was added. The resulting crystals were filtered, washed severai tirnes
with water and dried under vacuum to give the alkenylboronic acid. Spectra
corresponded to those previously reported. 34.50
Acetylene was bubbled slowly into a dark solution of 8.1 1 g of iodomonochloride
(50 mmol) in 60 rnL of HCl(6 N) at O O C over 3 h. The reaction mixture was extracted 3
times with pentane. The extract was washed with sodium bisulphate and saturated NaCl.
It was dried over MgS04, concentrated Ni vacuo, and distilled to give 5.46 g (60%) of the
product as a pink liquid. Spectra corresponded to that previously reported?
bp= l M ° C
1 H NMR (CDC13, 400 MHz): 6.50 (d, J = 14 Hz, 1 H), 6.70 (d, J = 14 Hz,1 K) ppm.
13c NMR (CDCh, 100 Hz): 124.7,75.3 ppm.
frans-2-Chlorovinylbenzene (5a)
Method A:
Into a 25 mL flame-dried flask was added 99 mg of phenyl boronic acid (0.8 1 mmol), 2.5
mL of THF and 42 mg of tetrakis(ûiphenylphosphine)palladiurn (0) (0.036 rnmol). To
the solution was added 100 mg of trans-1-chloro-2-iodoethene (2) (0.53 rnmol) by
syringe, followed by the addition of 1.62 mL of KOH (1 M, 1.55 rnrnol). The mixture
was heated to reflux overnight and monitored by TLC, until no starting material was left.
The dark yellow solution was cooled to r. t., quenched with water, and extracted with
ether (2x10 mL). The organic layers were combined and dried over anhydrous MgS04.
Following the solvent rernoval in vacuo, the residue was loaded on the top of a pre-
packed silica gel column and flashed @entane, Rr= 0.58) providing 50 mg (68% yield) of
pans-2-chlorovinylbeozene (Sa) as yellowish oil. Spectra corresponded to that
previously reported?
1 HNMR(CDC13, 400 MHz): 7.38- 7.28 (rn, SH), 7.11 (d, J= 16 Hz, lH), 6.7 (d, J= 16 Hz, 1
Hl FPm-
I3c NMR (CDC13, 100 Hz, APT pulse sequence-evens down (-), odds up (+)): 135
(-), 133 (+), 128.9 (+), 128.3 (+), 126.0 (+), 118.0 (+) ppm.
IR (neat): 3028,2921, 1478, 1070,734, 692 cm-'.
MS (M+: 140, 138), 103, 83, 77,63,51.
Method B:
Into a 10 mL flame-dried flask was added O. 17 g of magnesium turnings (7.08 mmol) and
a stirring bar. The flask was flame-dried under vacuum and purged with dry nitrogen. To
the flask was added 0.9 g of bromobenzene (5.7 rnmol) followed by the addition of 5 mL
of THF and 8 pL of distilled dibromoethane as initiator. The reaction mixture was heated
until the cloudy gray Grignard reagent was forrned. To a separate flarne-dried flask
equipped with a stirring bar was added 0.1 g of nickel dichloride diphenylphosphino-
propane (O. 18 rnmol), 5 rnL of THF and the Grignard reagent was transferred to this flask
by cannula followed by the addition of another 5 mL of T m . To this flask was added
0.7 g of pans-1-chloro-2-iodoethene (2) (3.7 mrnol) by syringe. It was heated gently to
40-50 OC for 30 h. The reaction was monitored by TLC until the starting material was
consumed. The mixture was cooled to r. t., quenched wiîh water and diluted with 40 mL
ether. It was transferred to a separatory funnel. After shaking the flask, the layers were
separated and the aqueous layer fiirther extracted with ether (2x10 mL). The organic
layers were then combined and dried over anhydrous MgS04. Following solvent rernoval
in vacuo, the residue was loaded on top of pre-packed silica gel column and
chromatographed @entane, Rf= 0.58) providing 3 10 mg (50% yield) of bans-2-chloro-
vinyl-benzene (5a) as yellow oïl.
tram-1-(4-Met hoxypheny1)-2-p hen ylethene (8)
Method A (Independent):
h t o a 25 mL flarne-ciried flask was added 41 mg of 4-methoxyphenyl boronic acid (0.27
mmol) following the addition of 1.5 mL of THF and 30 mg of (PPh3)$d ( 0.025 mmol).
Trans-2-chlorovinylbenzene (Sa) (25 mg, 0.19 mmol) was then added neat by syringe
followed by the addition of 0.5 rnL of THF and 0.54 mL of KOH (1 M, 0.5 rnmol). The
mixture was then heated to reflux for 12 h. The reaction was monitored by TLC, until no
starting material was left. The solution was cooled to r. t. and quenched with water,then
diluted with 20 mL of ether. Then it was transferred into a separatory b e l . M e r
shaking the flask, the layers were separated and the aqueous layer extracted with ether
(2x10 mL). The organic layers were combined and dried over anhydrous MgS04.
Following solvent removal in vacuo, the residue was loaded on the top of a pre-packed
silica gel column and chromatographed (2% pentane: ether, Rr = 0.13) providing 30 mg
(70-8 1% yield) of trans-1-(4-methoxypheny1)-2-phenylethene (8) as a white solid.
Melting point: 82-83 OC.
1 H NMR (CDCl3,400 MHz): 6 7.49 (d, J = 8 Hz, 2 H), 7.45 (d, J = 8 Hz, 2 H), 7.37 (t, J
= 7.6 Hz, 2 H), 7.26-7.21 (m,l H), 7.05 ( d , J = 16 Hz, 1 H), 6.93 (d, J = 16 Hz, 1 H),
6.70 (d, J = 8 Hz, 2 H), 3.86 (s, 3H) ppm.
13 C NMR (CDC13,100 MHz, APT pulse sequence-evens down (-), odds up (+)): 160.0
(-), 138.0 (-), 130.8 (-), 128.8 (+), 128.3 (+), 127.9 (+), 127.4 (+), 126.8 (+), 126.4 (+),
114.3 (+), 55.5(+) ppm.
IR (mat): 3084,2954.3,2924, 17 15, 1606, 15 1 1, 1460, 1264, lOS2,96L, 797,739,706,
629 cm".
MS (M': 210), 195, 179, 165, 152, 139, 115, 105,83,71.
HRMS calcd for C15H140 210.104, found 210.103.
Method B (Tandem):
Into a 25 mL flarne-dried flask was added 68 mg of phenyl boronic acid (1.05 eq, 0.55
mmol), 2 mL of THF and 30 mg of (PPh3)4Pd (0.025mmol). To the resulting solution
was added 100 mg of tmns-1-chloro-2-iodoethene (0.53 rnmol) and 1.1 mL of KOH (1
M). The mixture was then heated to reflux for 12 h. It was monitored by TLC, until no
starting material was lefi- Then 120 mg of 4-methoxyphenylboronic acid (0.79 mmol),
30 mg of (PPh3)4Pd (0.00259 mmol) catalyst and 1.59 rnL of KOH (1 M, 5 mmol) were
added and the mixture was heated to reflux for 2 days. The reaction mixture was
monitored by TLC, until no starting matenal was lefi. After the completion of the
reaction, the dark mixture was cooled to r. t., quenched with water and diluted with 20
mL of ether. It was transfemed into a separatory b e l . After shaking the flash, the
layers were separated and the aqueous layer extracted with ether (2x10 mL). The organic
layers were combined and dried over anhydrous MgS04. Following solvent removal in
vanto, the residue was loaded on the top of a pre-packed silica gel column and
chromatographed (2% pentane: ether, &= 0.13) providing 56 mg of a white solid of
tram- 1 -(4-methoxypheny1)-2-phenylethene (8) in 50% yield.
Method B (Tandem):
Change in sequence
Into a 25 mL flarne-dried flask was added 84.6 g of 4-methoxyphenylboronic acid
(0.55 mmol), 1.5 mL of THF and 30 mg of (PPh&Pd (0.025 mmol). To the resulting
solution was added bons-1-chloro-2-iodoethene (100 mg, 0.53 mmol) and 1.1 mL of
KOH (1 M, 2.1 equivalents). The mixture was heated to reflux for 12 h. The reaction
was monitored by TLC, until no starting matenal was left. Then 96 mg of phenyl
boronic acid (0.79 mrnol), 10.4 mg of (PPh&Pd (0.0089 mmol) catalyst and 1.59 mL of
KOH (0.5 rnmol) were added. The mixture was heated to reflux for 2 days. It was
monitored by TLC, until no starting material was left. After the cornpletion of the
reaction, it was cooled to r. t., quenched with water and diluted with 20 mL of ether. It
was transferred into a separatory &el. M e r shaking the flash, the layers were
separated and the aqueous layer was extracted with ether (2x10 mL). The organic layers
were combined and dried over anhydrous MgS04. Following solvent removal in vacuo,
the residue was loaded on the top of a pre-packed silica gel column and chrornatographed
(2% pentane: ether, Rf = 0.13) providing 58 mg of trnns-1-(4-methoxypheny1)-2-
phenylethene (8) (5 % yield) as a white solid.
1-(2-C hloro-viny1)-4-methoxy benzene (5b)
into a 25 mL flame-dried flask was added 88 mg of 4-methoxyphenyl boronic acid
(0.57 mmol), 1.5 rnL of THF and 30 mg of ( l?Pl~~)~Pd (0.025 mmol). To the resulting
solution was added 100 mg of trans-1-chloro-2-iodoethene (0.53 mmol) and 1.16 rnL of
KOH (1 M). The mixture was heated to reflux for 12 h. The reaction was monitored by
TLC, until no starting material was left. The mixture was cooled to r. t., quenched with
water and diluted with 40 mL of ether. It was transferred into a separatory funnel. After
shaking the flash, the layers were separated and the aqueous layer extracted with ether
(2x10 mL). The organic layers were combined and dried over anhydrous MgS04.
Following solvent removal in vanto, the residue was loaded on top of a pre-packed silica
gel colurnn and chromatographed (pentane, RF= 0.15 ) providing 74 mg (90 % yield) of
1-(2-ch1orovinyl)-4methoxybenzene (Sb) as a yellow solid. (Yields varied with the
quality of starting materials and catalyst). The spectra corresponded to those previously
reported."
Melting point: 40 OC (decomposed).
1 HNMR (CDC13, 400 MHz): 7.25 (d, J = 8 HZ, 2 H), 6.88 (d, J = 8 HZ, 2 H), 6.79 (d, J =
14&, 1 H), 6.52 (d ,J= 14Hz, 1 H), 3.83 (s,3 H)ppm.
13 C NMR (CDCl3, 100 MHz, APT pulse sequence-evens down (-), odds up (+)): 159.7
(-), 132.8 (+), 127.8 (-), 127.5 (+), 116.5 (+), 114.3 (+), 55.5(+) ppm.
IR (neat): 2917,2844, 1689, l6SO,lSO3, 1455, 1240, 1027, 8 19 cm-'.
MS (M+: 170, L68), 153, 125, 1 18,99,89,75,63,51,39,28.
1-Chloro-1,3-decadiene (Sc)
Into a 25 mL flame-dried flask was added 107 mg of octenylboronic acid (0.68
mmol), 2 mL of THJ? and 42 mg of (PPh&Pd (0.036mmol). To the resulting solution
was added trans-1 -chlore-2-iodoethene (100 mg, 0.53 mmol) and 1.3 8 mL of KOH (1 M)
and the mixture was heated to reflux for 14 h. The reaction was monitored by TLC, until
no starting material was left. M e r completion of the reaction, it was cooled to r. t.,
quenched with water and diluted with 20 mL of ether. Then it was transferred into a
separatory funnel. Afier shaking the flash, the layers were separated and the aqueous
layer extracted with ether (2x10 mL). The organic layers were combuied and dried over
anhydrous MgS04. Following solvent removal in vacuo, the residue was loaded on the
top of a pre-packed silica gel column and chromatographed ('entane, RF = 0.84)
providing 70 mg of 1-chloro-1,3-decadiene (Sc) as a yellowish oil in 80% yield. Spectra
corresponded to those previously reported."
' H N M R ( C D C ~ ~ , ~ O O M H ~ ) : 6.41 (dd, J= 13, 11 Hz, 1 H),6.07(d, J = 13 Hz, 1 H),
5.96 (dd, J = 16, 10 Hz, 1 H), 5.68 (dt, J = 15,7 Hz, 1 H), 2.06 (m, 2 H), 1.37 (m, 2 H),
1.29 (m, 6H), 0.85 (t, J = 6.7 Hz ,3 H) pprn.
(E, E)-1-(4-Methoxypheny1)-13-decadiene (11)
Method A (Independent):
Into a 25 rnL flame-dried flask was added 132 mg of 4-methoxyphenylboronic acid (0.87
mmol), 1.5 rnL of THF and 42 mg of (PPh3)4Pd (0.036mmol). To the resulting solution
was added 100 mg of 1-chloro- 1,3-decadiene (5c) (0.57 -01) and 1.8 mL of KOH (1
M, 1.74 mmol). The mixture was heated to reflux for 14 h. The reaction was monitored
by TLC, until no starting material was left. After the completion of the reaction, it was
cooled to r. t., quenched with water and diluted with 20 mL of ether. Then it was
transferred into a separatory funnel. After shaking the flash, the layers were separated
and the aqueous layer extracted with ether (2x10 mL). The organic layers were
combined and dried over anhydrous MgS04. Foilowing solvent removal in vacuo, the
residue was loaded on top of a pre-packed silica gel column and chrornatographed (2%
pentane: ether, Rr= 0.12) providing 80 mg (57 % yield) of (E, E)-1-(4-methoxypheny1)-
1,3-decadiene (11) as a yellowish oil. 71
1 H NMR (CDCb, 400 MHz): 7.33 (d, J = 8-0 HZ, 2 H), 6.86 (d, J = 8-0 HZ, 2 H), 6.65 (dt,
J = 15.5, 10 Hz, 1 H), 6.41 (d, J = 16 Hz, 1 H), 6.20 (dt, J= 15.0, 9.9 Hz, 1 H), 5.81-5.78
(dt, J = 15.5, 7.5 Hz, 1 H), 3.83 (s, 3 H), 2.13 (q, J= 6.1 Hz, 2 H), 1.61-1.22 (rn, 10 H),
0.87 (t, J= 6.1 Hz, 3 H) ppm.
13 C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (+), odds d o m (-)): 159.1
(+), 135.1 (-), 13 1.0(+), 130.8 (-), 129.6 (-), 127.7 (-), 127.4 (-), 114.0 (-), 55.4 (-), 33.1
(+), 3 1.9 (+), 29.5 (+), 29.1 (+), 22.8 (+), 14.3 (-) ppm.
IR (neat): 3052,2922,2852, 1697, 15 1 1, 1456, 1262,739 cm-'.
Method B (Tandem)
Into a 25 mL flame-dried flask was added 107 mg of octenylboronic acid (0.68
mmol), 3 rnL of THF and 30 mg of (PPh3)ad (0.025 mmol). To the resulting solution
was added 100 mg pans-1-chloro-2-iodoethene (0.53 mmol) and 1.38 mL of KOH (1 M)
and the mixture was heated to reflux for 14 h. The reaction was monitored by TLC, until
no starting material was lefi. Then 120 mg of 4-methoxy-phenyl boronic acid (0.79
mmol), 30 mg of (PPh3)ad (0.0259 mmol) catalyst and 1.58 mL of KOH (1 M, 1.5
mmol) were added. The mixture was heated to reflux for 24 h. The reaction was
monitored by TLC, until no starting material was lefi. After the completion of the
reaction, it was cooled to r. t., quenched with water and diluted with 20 mL of ether. It
was transferred into a separatory fuonel. M e r shaking the flask, the layers were
separated and the aqueous layer extracted twice with ether (2x10 mi,). The organic
layers were combined and dried over anhydrous MgS04. Following solvent removal in
v m o , the residue was loaded on the top of a pre-packed silica gel column and
chromatographed (2% pentane: ether) providing 96 mg of yellowish oil of (E, E)-L(4-
methoxypheny1)- 1,3-decadiene (11) in 74% yield.
(E, E)-1-Phenyi-13-decadiene (12).
Method A (Independent):
Into a 25 mL flame-dried flask was added 99 mg of phenyl boronic acid ( 0.8 1 mmol),
1.5 mL of THF and 42 mg of (PPh3)J'd (0.036 mmol). To the resulting solution was
added 200 mg of 1-chloro-1,3-decadiene (5c) (0.57 mmol) and 1.6 mL of KOH (1.62
mmol). The mixtue was then heated to reflux for 14 h. The reaction was monitored by
TLC, until no starting material was lefi. After the cornpletion of the reaction, it was
cooled to r. t., quenched with water and diluted with 20 mL of ether. It was transferred
into a separatory h e l . After shaking the flash, the Iayers were separated and the
aqueous layer extracted twice with ether (each time 10 mL). The organic layers were
then combined and dried over anhydrous MgS04. Foltowing solvent removal in vacuo,
the residue was loaded on the top of a pre-packed silica gel column and chromatographed
(2% pentane: ether), providing 70% yield of (E, E)- 1-phenyl- 1,3-decadiene (12) as
yeLlow oil.
'HNMR(CDCI~, 400 MHz): 7.38 (d, J= 7.5 Hz, 4 H), 7.19 (t,J=7.4 Hz, 1 H), 6.76
(dd, J = 15.6, 10.3 Hz, 1 K), 6.45 (d, J= 15.7 Hz 1 H), 6.21 (dd, J = 15.7, 10.5 Hz, 1 H),
5.84 (dt, J= 15.1, 7.3 HZ, 1 H), 2.16 (m, 2 H), 1.45-1.27 (m, 8 H), 0.99 (t, J = 6.7 Hz, 3
H) PPm-
"C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (+), odds down (-)): 137.7
(+), 136.0 (-), 130.4 (-), 129.9 (-), 129.5 (-), 128.5 (-), 127.03 (-), 126.1 (-), 32.8 (+), 31.7
(+), 29.3 (+), 28 -9 (+), 22.6 (+), 14.1 (-) ppm.
IR (neat): 3054, 3027,2925,2855, 1680, 1455, 965, 749, 693 cm-'.
MS (M?: 214), 188, 154, 143, 129, 117, 91, 81, 67, 55,41.
HRMS calcd for C i6 HZ2 2 14.172, found 2 14.1 7 1.
Method B (Tandem):
Into a 25 mL flame-dried flask was added 142 mg of phenyl boronic acid (1.16 mrnol),
1.5 mL of THF and 61 mg of (PPh3)ad (0.053 mmol). To the resulting solution was
added 200 mg of pans-l-chloro-2-iodoethene (1 .O6 mmol) and 1.16 mL of NaOH (2N,
2.32 mmol). The mixture was heated to reflux for 8 h. The reaction was monitored by
TLC, until no starting material was left. Then 248 mg of octenylboronic acid (1 -59
mmol), 6 1 mg of (I?Ph&Pd (0.0053 mmol) catalyst and 1.59 mL of NaOH (2N, 3.1 8
m o l ) were added and the mixture was refluxed for 14 h. The reaction was monitored
by TLC, until al1 of the starting material was consumed. After the completion of the
reaction, it was cooled to r. t., quenched with water and diluted with 20 mL of ether. It
was transferred into a separatory b e l . After shaking the flash, the layers were
separated and the aqueous layer extracted twice with ether (20 mt each). The organic
Iayers were combined and dried over anhydrous MgS04. Following solvent removal in
vmuo, the residue was loaded on the top of a pre-packed silica gel column and
chromatographed (2% pentane: ether) which provided 1 18 mg of (E, E)- 1 -phenyl- 1,3-
decadiene (12) in 52%yield.
Method B (Tandem)
Change in sequence:
Into a 25 mL flame-dried flask was added 107 mg of octenyl boronic acid (0.68 mmol),
1.5 mL of THF and 42 mg (PPh;)4Pd (0.036 mmol). To the resulting solution was added
100 mg of tram- 1 -chloro-2-iodoethene (0.53 mmol) and 1.4 mL of KOH (1 M, 1.3
mmol) and the mixture was heated to reflux for 14 h. The reaction was monitored by
TLC, until no starting matenal was left. Then 97 mg of phenyl boronic acîd (0.79 mmol),
30 mg of (PPh3)8d (0.0025 mmol) and 1.58 mL of KOH (1 M, 1.58 mmol) were added
and the mixture was refluxed at for 24 h. The reaction was monitored by TLC. After the
completion of the reaction, it was cooled to r. t., quenched with water and diluted with 20
mL of ether. It was then transferred into a separatory funnel. After shaking the flask, the
layers were separated and the aqueous layer extracted with ether (2x10 mL). The organic
layers were then combined and dried over anhydrous MgS04. Following solvent removal
in van«>, the residue was loaded on the top of a pre-packed silica gel column and
chromatographed (2% pentane: ether), providing 73 mg of (E, E)-1-phenyl-1,3-decadiene
(12) in 65% yield.
Experimental Section For The Synthesis of Astaxanthin B-D-diglucoside
To a flame-dried 25 mL flask was added 0.103 g of compound 23 (0.58 mmol), 2 mL
THF, 0.1 g of 2 (0.53 mmol), 24 mg of (PPh3)J?d (0.02 mrnol) and 4 mg Cu1 (0.02
mmol). To this mixture was added 49 mg of piperidine (0.58 mmol) followed by the
addition of 1 mL of THF. The solution was heated to reflux for 6 h and monitored by
TLC. After completion of the reaction, it was cooled and quenched with water. The
organic compound was extracted with pentane (3x10 mL) and dried over MgS04. The
solvent was removed in vacuo and then the residue was loaded on the top of a pre-packed
silica colurnn and chromatographed (5% pentane: ether, RF= 0.27), providing yellow
liquid of 1 - ( 5 - c h l o r o p e n t - 4 - e n - 2 - y n y l o x y m e t h y l ) ~ (24) in 79 % yield.
1~NMR(CDCb,400MHz):7.28(d,J=8Hz,2H),6.88(d,J=8Hz,2H),6.56(d,J=
13 Hz, 1 H), 5.99(d, J= 16Hz, 1 H),4.52(s,2H),4.22 (s,2 H),3.81 (s,3 H)pprn.
13 C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (t), odds down (-)): 159.4
(+), 130.9 (-), 129.9 (-), 129.3 (+), 113.8 (-), 113. 2 (-), 88.0 (+), 81.3 (+), 71.4 (+), 57.3
(+), 55.3 (-1 ppm.
IR (neat): 3 100,2924, 1700,1603, 1509, 1243, 1072,900,809,5 10 cm-'.
MS :m/e (hf: 236,235), 201, 171, 135, 121,99, 85, 84, 65,47.
Anal. calcd. for C13H~302Cl: 65.7 C, 5.5 1 W, found 66.5 C, 5.66 H
4-Chloro-1-trimethylsilyl-2-butene-1-yne (13)
To a flarne-dried 25 mL flask was added 0.4 g of compound 2 (1.12 mmol), 98 mg of
(PPh3)ad (0.08 mmol), 10 ml Et20 and 16 mg CUI (0.08 mmol). To this mixture was
added 0.3 mg of TMS-acetylene (3.39 mmol) followed by the addition of 0.289 g of
piperidine (3.39 mmol). The solution was heated to reflux for 6 h and monitored by
TLC. After completion of the reaction, it was cooled and quenched with water. The
organic compound was extracted with pentane (3x10 mL) and dned over MgS04. The
solvent was removed in vacuo and then the residue was loaded on the top of a pre-packed
silica column and chromatographed @entane RF O.9), providing a white solid of I-
chlor0-4-(trimethylsi1anyf)-but- l -en-3 -yne (13) in 70 % yield.
'H NMR (CDC13, 400 MHz): 6.60 (d, J= 16 Hz, 1 H), 5.96 (d, J = 16 Hz, 1 H), 0.18 (s, 9
H) PPm*
13 C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (+), odds down (-)): 132.6
(-1, 113.1 (-), 80.0 (+), 65 (+), 1.8 (-) ppm.
IR (neat): 2959,2063, 1557, 1247,842,643 cm-'.
MS : d e m: 156, 155), 153, 138, 128, 107,99, 86, 77, 69,55,45,41,28.
2,2,6-Trimethylcyclohexanone (15)
To a flame-dried 25 mL fiask was added 0.12 g (1 rnrnol) of diisopropylamine and 5 mL
anhydrous THF. To the resulting solution was added 0.59 mL (1 mmol) of n-butyl-
lithium at O OC and the mixture was stirred for 3 0 minutes at the same temperature. The
reaction mixture was cooled to -78 OC and 0.126 g (1 mmol) of 2,6-
dimethylcyclohexanone was added. M e r stirring for 2 h, during which time the reaction
mixture reached r. t., it was quenched with 0.843 g (5 mmol) of methyl iodide. This
solution was stirred for 30 minutes and then the reaction mixture was quenched with
water and diluted with ether. The organic product was extracted with ether (2x10 mL) in
separatory funnel and dried over magnesium sulfate. The solvent was removed in vacuo
and then the remaining liquid was loaded to the top of a pre-packed silica column and
chrornatographed (pentane), providing 0.15 g (90 % yield) of light yellow oil of 2,2,6-
trimethy lcyclo hexanone (1 3."
'H NMR (CDCb, 400 MHz): 2.62-2.59 (m, 1 H), 2.02-2.0 (m, 1 H), 1.85-1.82 (m, 1 H),
1.73-1.69 (m, 1 H), 1.62-1.57 (m, 1 H), 1.53-1.49 (m, 1 H), 1.28-1.24 (m, 1 H), 1.14 (s, 3
H), 0.98 (s, 3 H), 0.94 (d, 3 H) ppm.
13 C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (+), odds down (-)):
216.0 (+), 45.3 (+), 41.9 (+), 41 (-), 36.8 (+), 26.6 (-), 25.3 (-), 2L.6 (+), 15.0 (-)
MS :m/e @A+: 140), 122, 1 1, 97,82, 69,56,41,28.
2,6,6- Trimet hyl-2-p henylsulfany lcyclo hexanone (26)
To a flame-dried 25 mL flask was added 0.12 g (1 mrnol) of diisopropylarnine and it
was dissolved in 5 mL anhydrous THF. To the solution was added 0.59 mL of n-butyl
lithium in pentane (2.5 M, lmmol) at O OC. After stirring for 30 minutes the reaction
mixture was cooled to -78 OC and 0.14 g (1 rnmol) of 2,6,6-trimethylcyclohexanone was
added. The mixture was stirred for 2 h d u ~ g which time it was warmed to O OC and
0.436 g (2 mmol) of diphenyl-disulfide was added. The solution was stirred for one hour,
quenched with water and diluted with ether. The organic product was extracted with
ether (2x10 mL) in a separatory funne1 and it was dried over magnesium sulfate. The
solvent was removed in vacuo and the residue was loaded to the top of a pre-packed silica
column and chrornatographed (20 % pentane: ether Rf= 0.78 ), providing 0.173 g (70 %
yield) of the 2,6,6-trimethyl-2-phenylsulfanylcyclohexone (26) as a light yellow
'H NMR (CDCls, 400MHz): 7.34 (m, 5 H), 2.20-2.13 (m, 2 El), 1.99-1.92 (rn, 2 H), 1.69-
1.62 (m, 2 H), 1.57 (s, 3 H), 1.25 (s, 3 H), 1.12 (s, 3 H) ppm.
IR (neat): 2926,2859, 1689,1453, 1 127,1013,744 cm-'.
13c NMR: 21 1.1, 137.7, 129.8, 128,55.7,44.4,41.8,40.1,40.0,30.7,29.9,26.5, 18.1
P P -
MS 248), 218, 185, 163, 135, 123, 110,95,69,82,55.
Anal. calcd. for Ci5H200S. H20: 67.62 C, 8.3 1 H, found 68.04 C, 8.46 H
2-Brorno-2,6,6-trimethylcyclohexanone (31)
To a flame-dried 25 mL flask was added 0.1 g (0.7 mmol) of 2,2,6-trimethyl-
cyclohexanone, 3 -5 mL CCL and 0.2 1 5 g (7 mmol) of pure brominated Meidrum' s acid.
The mixture was stirred at 70 OC for 7 h. M e r completion of the reaction (TLC
monitoring) it was cooled and quenched with water. The organic compound was
extracted with ether (3x10 mL) in a separatory funne1 and dried over MgS04. The
solvent was removed in vacuo and the residue was loaded to the top of a pre-packed silica
colurnn and chromatographed (2 % pentane: ether Rf= 0.46) providing 0.14 g of 2-
bromo-2,6,6-trimethylcyclohexanone (89 % yield) as a colorless liq~id.74
1 HNMR (CDC13, 400 MHz): 2.43 (tr, 2 H), 1.92 (tr, 2 H), 1.85 (s, 3 H), 1.71 (m, 2 H),
1.5 1 (s, 3 H), 1.12 (s, 3 H) pprn.
13c NMR(CDC13, 100 MHz): 209.4, 62.7,44.5, 43.7, 39.8, 30.9,30.8,29.9,29.8,28.2,
28.1, 22.5, 18.6, 14.2 pprn.
MS: m/e (Mf: 21 8,220) 1 1 1, 95, 82,69,55,41.
2,6,6-Trimethylcyclohex-2-en-1-one (28)
To a flame, dried 25 mL flask was added 0.1 g (0.45 mol) of 2-bromo-2,6,6-
trimethylcyclohexanone, 0.089 g (1.2 m o l ) of dry lithium carbonate and 0.067 g
(7.7 mol) of anhydrous lithium bromide in 2.5 mL of dry DMSO and the mixture was
stirred at 115 OC for 12 h. The reaction mixture was quenched with water and the organic
compound was extracted with pentane (3x10 mL). In order to remove DMSO, the
organic layer was washed several times with water and dried over MgS04. The solvent
was removed in vacuo and then the residue was loaded on the top of a pre-packed silica
c o l m and separated with pentane, providing yellow liquid of 2,6,6-trimethylcyclo hex-
2-enone (28) in 70-80 % yield. The spectra corresponded to those previously reported.74
'H NMR (CDC13, 400 MHz): 6.62 (broad, s, 1 H), 2.32-2.29 (m, 2 H), 1.82- 1.79 (tr, 2 H),
1.76 (s, 3 H), 1.10 (s, 6H) ppm.
13c NMR (CDC13, LOO M a ) : 204.9, 143.7, 134.0,41.4,37,24.5,23.2, 16.6, 14.2 ppm.
1-[2,6,6-TrimethyIcyclohex-1,3-dienyl] diethyl phosphonate (32)
To a 25 mL flame-dried flask was added 0.072 g (0.7 mmoi) of diisopropylarnine and
3.5 mZ, of TIlF followed by the slow addition of 0.041 mL (2.5 M, 0.64 mrnol) of n-
butyllitium in pentane at O OC. The mixture was stirred for 30 minutes at that
temperature. The solution was cooled to -78 OC and 0.09 g (0.64 mol) of 2,6,6-
trimethylcyclohex-2-enone in 1 rnL HMPA was added. After çtimng for 3 h, during
which tirne the reaction mixture was warmed to -50 OC , O . 122 g ( 0.7 mol) of diethyl
chlorophosphate was added and it was stirred for 1 h. M e r completion (TLC
monitoring), the reaction was quenched with water and the organic compound was
extracted with ether (3x10 mL) in a separatory funnel. The collected organic layers were
dried over MgS04. The solvent was removed in vacuo and the residue was loaded to the
pre-packed silica column and was separated with 70% ether in pentane (Rf= 0.2),
providing yellowish liquid of 1 -[2,6,6-trimethylcyclohex- 13-dienyl] diethy 1 p hosphonate
(32) in 70% yield.
1 H NMR(CDClp, 400 MHz): 5.75 (d, J= 6 Hz,l H), 5.66 (m, 1 H), 4.16 (m, 4 H), 2.19
(s, 2 H), 1.78 (S, 3 H), 1.35 (t, 6H), 1.11 (s, 6H) ppm.
13 C NMR (CDCl3, 100 MHz, APT pulse sequence-evens up (+), odds down (-)):
iSO.1 (+), 128 (-), 122.5 (-), 116.3 (+), 64.05,64.01 (+), 41.3 (+), 25.0 (-), 22.6 (+), 16.5
(-1, 15.0 (-) ppm.
IR (neat): 2979,2928,1666, 1452, 1272,1146, 1036,966,809,774 c d
MS: d e (Mf: 274), 259,245,23 1,203, 185, 155, 120, IO5,9 1,77,53,4 1,28.
Anal. calcd. for Ci3Hu04P: 56.9 C, 8.54 H, found 56.54 C , 9.09 H
2,6,6-(TrimethyIcyclohexyiidene) hydrazone (37)
2,6,6-Trimethylcyclohexanone (0.1 g, 0.7 mmol) was dissolved into 4 mL absolute
ethanol and hydrazine hydrate (10 equivalents) was added to the solution. The reaction
was stirred at 100 OC until the starting material was consumed (2 days) and the solvent
and excess reagents were removed in vacuo. The resulting solid was then loaded to the
pre-packed columo and chromatographed (99: 1 ether: ûiethylamine), providing the 2,6,6-
(trirnethylcyclohexylidene) hydrazone (37) as a white solid in 85% yield.
Melting point: 43-45 OC.
'HNMR(CDC~~, 400 MHz): 5.75 (d, J= ,1 H), 5.60 (m, 1 H), 4.16 (rn, 4 H), 2.19 (s, 2
H), 1-78 (s, 3 H), 1.35(t, 3 H), 1.1 1 (s, 3 H) ppm.
13c NMR (CDC13, 100 MHz): 150.1, 128.7, 122.5, 116.3,64.0,41.3,25.6, 22.6, 16.5,
15.0 ppm.
IR (neat): 3352,3215,2925,2856, 1641, 1455, 1371, 1101,982,~ 16 cm-'.
MS:m/e (M? 154), 139, 122, 109,95, 81,72, 55,41.
HRMS calcd for C9H18N2 154.146, found 154.145.
2-Iodo-1,3,3-trimethylcyclohexene (38)
A solution of 2.05 g of I2 (2.1 equivalents, 8 rnrnol) in ether (1 0 rnL) was added drop-
wise to an ethereal solution of 0.6 g of 2,6,6-(trimethyl-cyclohexylidene) hydrazone (3 7)
(3.8 mmol) and excess of DBN (9.5 g, 60 mmol). As the reaction progressed, the
reaction mixture became turbid and by the end of the addition, a gummy brown layer had
separated. M e r 15 minutes of additional stirring, the reaction was partitioned between
ether and saturated NaHC03. The organic layer was collected over &CO3, filtered, and
concentrated in vacuo. The resulting dark red oil was then dissolved in benzene and
refluxed in the presence of DBN for 2.5 h whereupon, after cooling to room temperature,
the mixture was poured into ether and washed with 1 N sodium thiosulphate. The
organic layer was dried over &CO3, filtered and concentrated in vacuo to give red oil
which was then loaded to a pre-packed column and purifïed (pentane), providing pure 2-
iodo-1,3,3-trimethylcyclohexene (38) as a colorless oil in 70% yield (pentane Rf= 0.6).
1 H NMR (CDC13, 400 MHz): 2.12 (t, 2 H), 1.86 (s, 3 H), 1.67 (m, 2 H), 1.63 (m, 2 H),
1.09 (s, 6 H) ppm.
I3c NMR (CDC13, 100 MHz): 137.7, 117.5,39.6,38.0,33.8, 31.2,29.5, 19.6 ppm.
MS: d e (h.ic: 250), 235, 123, 108,93, 8 1,67,55,41,28.
IR (neat): 2959,2921, 1650, 1455, 1043,920 cm''.
HRMS calcd for Cs HisI 250.02 18, found 250.02 18.
2-(Trans-2-chloro,inyl)-1,3,3-trimethylcyclohexene (42)
To a solution of 50 mg of 2-iodo-1,3,3-trimethylcyclohexene (38) (0.2 mrnol) in ether at
-78 OC was added 0.23 mL of terr-butyllithium (1.7 M in hexane, 0.4 m o l ) drop-wise
and stirred for 20 minutes at that temperature. Triisopropyl borate (0.05 rnL, 0.22 m o l )
was added neat to the solution at -78 OC and stirred for another 20 minutes. It was slowly
warmed to the room temperature and stirred for another hour. To this solution was added
concentrated aqueous NaOH (10 equivalents. 10 M) and stirred for another hour. The
solvent was rernoved and 13 mg of (PPh3)4Pd (0 .O 1 mrnol) and 34 mg of tram- 1 -chlore-
2-iodoethene (0.18 m o l ) were added to this solution following the addition of THE It
was heated to reflux for a few hours until the starting material was al1 consumed. After
completion of the reaction (NMEt monitoring) the reaction was quenched with water and
the organic compound was collected using ether (3x 20 mL). The collected organic layer
was dried over rnagnesiurn sulfate, filtered, and concentrated in vacuo. The resulting
dark oil was loaded to the top of a pre-packed column and chromatographed @entane) (Rf
= 0.56), providing 20 mg of 2-(tram-2-chioroviny1)- 1,3,3-trimethylcyclohexene (42) as
yellow oil in 5560%.
i H NMR (CDCb, 400 MHz): 6.37 (d, J = 12 Hz, 1 H), 5.82 (d, J = 12 Hz, 1 H), 1.99 (t, 2
H), 1.69(s, 3H), 1.63 (m,2H), 1.48(mY2H), 1.07(s76H)ppm.
13 C NMR (CDC13, 100 MHz): 134.8 (+), 131.5 (-), 130.9 (+), 119.7 (-), 39.2 (+), 32.7 (+),
28.0 (-), 22.0 (+), 21.0 (-), 19.0 (+), 14.1(-) ppm.
IR (neat): 2929,2865, 1601, 1457, 1377, 1305,934, 8 1 1 cm
MS: d e (Mf: 186, 184), 169, 151, 133, 109,93,77, 65, 55,41,28.
HRMS calcd for CI ,H17Cl 184.10 1, found 1 84-10 1.
Torrado, A.; Iglesias, B.; Lo3pez, S.; de Lem, A. R. Tetrahedron 1995,8, 2435.
Negishi, E-1.; Takahashi, T.; Baba, S.; Van Hom, D. E.; Okukado, N. J. Am.
Chem. Soc. 1987,109,2393-
Lipshutz, B.; Alami, M. Tetrahedron Lett. 1993,34, 1433.
Suzuki, A.; Miyaura, N . Chem. Rev. 1995,95,2457.
Yokoyama, A.; Shizuri, Y.; Misawa, N. Tetrahedron Lert. 1998,39,3709.
Conrad, H. E. in Carotenoids; Britton, G.; Liaaen-Jensen, S.; Pfander, H. Eds.;
Birkhauser Verlag: Basel. Boston. Berlin; 1995, Vol. 1.
Willstiitter, R.; Mieg, W. Liebig's Ann. Chem. 1907, 1,355.
Zechmeister, L.; Cholnolq, L.; Vrabley, V. Ber. Deut. Chem. Ges. 1928, 61,
566.
Winterstein, A.; Kuhn, R. Hefv. Chim. Acta 1928, 11,427.
Karrer, P.; Salomon, H. Helv. Chim. Acta 1928, 11,7 1 1.
Muller-Cunradi, M.; Pieroh, K. U.S. Patent 2 165 962, 1939.
(a) Warren, C. K.; Weedon, B. C. L. J. Chem. Soc. 1958,3986. (b) Warren, C.
K.; Weedon, B. C. L. J. Chem. Soc. 1958,3972.
Wittig, C.; Geissler, G. Liebig's Ann. Chem. 1953, 580,44.
Julia, M.; Amould, D. Bull- Soc. Chim. Fr. 1973,746.
Arnould, D.; Chabardes, P.; Farge, G.; Julia, M. Bull. Soc. Chim. Fr. 1985, 130.
Isler, O.; Mayer, H. Carotenoids; Birkhauser Verlag: Basel; 1 97 1.
Molnar, P.; Kortvelyesi, T.; Matus, Z.; Szabolcs, J. J. Chem. Research 0. 1997,
120.
Ito, M.; Yamano, Y.; Sumiya, S.; Wada, A. Pure Appl. Chem. 1994,66,939.
Maryanoff, B. E.; Reitz, A. B. Chsm. Rev. 1989,89, 863.
(a) Paquette, L. A. Org. React. 1977,25, 1. @)Taylor, R J. K. Chem. Comrn.
1999,2 17.
Soukup, M.; Widmer, E.; Luka'c, T. HeZv. Chim. Acta 1990, 53,868.
Bernhard, K.; Mayer, H. Pure Appl. Chem. 1991, 63.
Trost, B. M. Science, 1991,254, 147 1 .
Bradsma, 1;. Preparative AcetyZene Chemimy, 2nd ed.; Elsevier: New York,
1988.
Ishikawa, Y . Bull. Chern. Soc. Jpn. 1964,37,207.
Heathcock, C. H. In Comprehensive Organic Synfhesis; Trost, B. M.; Fleming,
1. Eds.; Pergamon: Oxford, 1992; Vol. 2.
Isler, O.; Huber, W.; Ronco, A.; Kofler, M. Helv. Chim. Acta 1947,30, 19 1 1.
Heck, R. F. Palladium Reugents in Organic Synthesis; Academic: New York;
1985.
Hénaff, N.; Whiting, A. J. Chem. Soc., Perkin Trans. 1, 2000,395.
Hopf, H.; Krause, N. Tetruhedron Lett, 1985,26,3323.
Julia, M.; Verpeaux, J.-N. Tetrahedron Lett- 1982,23,2457.
McMurry, J. E.; Fleming, M. P . J. Am. Chem. Soc. 1974,96,4708.
Akiyarna, S., Nakatsuji, S.; Eda, S. Tetrahedron Lett. 1979,28 13.
Brown, H. C.; Chandrasekharan, J. J. Org. Chern. 1983,47,644.
Brown, H. C.; Chandrasekharan, J. J. Org. Chern. 1983,48,5080.
Smidt, J.; Hafher, W.; Jira, R,; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew.
Chem. Int. Ed., Eng. 1962,1, 80.
Tsuji, J . Palladium reagents and catalysts : innovations in organic synthesis;
John Wiley and Sons: Chichester, New York, 19%.
Carey, F. A.; Sundberg, R. J. Advanced organic chemistry; Plenum: New York,
1990; pt. B. Reactions and synthesis.
Kobayashi, Y.; Shimazaki, T.; Sato, F. Tetrahedron Lett. 1987,28,5849.
Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996,96, 195.
(a) Ho, T.-L. Tandem ûrganic Reations; John Wiley and Sons: New York,
1992. (b) Bunce, R. Tetrahedron 1995,5I, 13 103. (c) Parsons, P. J.; Penkett,
C. S.; Shell, A. J . Chem, Rev. 1996,96,195-206. (d) Tieîze, L. F. Chem. Rm.
1996, 115.
HaLl, N. Science 1994,266,32.
Rossi, R-; Carpita, A.; Bellina, F. A. review. Organic Preparations and
Procedures International 1995, 129.
Negishi, E. C.; Van Hom, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985,107,
6639.
Negishi, E.; Kondakov, D. Y.; Choueiry, D.; Kasai, K.; Takahashi, T. J. Am.
Chem, Soc. 1996,118,9577.
(a) Shapiro, R.H.; Lipton, M.F.; Kolonko, K.J.; Buswell, R.L.; Capuano, L.A.
Tetrahedron Lett. 1975, 1811. (b) Shapiro, R.H. Org. React. 1976, 23,405.
Siemeling, U.; Neumann, B.; Stammler, H-G. J. ûrg. Chem. 1997, 62,3407.
Negishi, E.; Okukado, N.; Lovich, S. F.; Luo, F.-T. J. Org. Chem 1984,49,
2629.
Kamabuchi, A.; Moriya, T.; Miyaura, N.; Suzuki, A. Synth. Commun. 1993,
23,2851.
Brown, H. C.; Campbell, J. B. J. Org. Chem. 1980,45,389.
Hirano, A.; Yakabe, S.; Chikamori, H.; Clark, J. H.; Morimoto, T. J. Chem.
Research 1998,12,770.
Luis, J. G.; Andrés, L. S . J. Chem. Research 1999,3,220.
Bruce H. L.; Lindsley, C. J. Am. Chem. Soc. 1997,119,4555.
Pornet, J.; Princet, B.; Me'vaa, L. M.; Miginiac, L. Synthetic Cornrn. 1996,26,
2099.
Trost, B. M.; Salzmann, T. N. J. Org. Chem. 1975,40, 148.
Snyder, H. R.; Kruse, C. W. J. Am. Chem. Soc. 1957,80, 1942.
Bellomy, F. D.; Chazon, J. B.; Ou, K. Tetahedron 1957,39,2803.
Pascual Teresa, J.; Femandez Mateos, A.; Rubio Gonzalez, R. Tefrahedron Lett.
1982,33,3405.
Ando, M.; Wada, T.; Kusaka, H.; Takase, K.; Hirata, N.; Yanagi, Y. J. Org.
Client, 1987,52,4792.
Lee, H . W.; Kang, T. W.; Cha, K. H.; Kim, E.-N.; Choi, N.-H.; Kim, J.-W.;
Hong, C. Synthetic Cornrn. 1998,28,35.
Ruttimann, A.; Mayer, H. Helv. Chim. Acta 1980,63, 1452.
Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,94,
2483.
Kumada, M.; Hayashi, T.; Fujiwa, T.; Okaoto, Y.; Katsuro, Y. Synthesis, 1981,
1001.
Di Grandi, M. J.; Jung, D. K.; Krol, W. J.; Danishefsky, S. 1. J. Org. Chem.
1993,58,4989.
Barton, D. H. R.; Bashiardes, G.; Fourrey, J-L. Tefrahedron 1988, 44, 147.
66. Pazos, Y.; de Lem, A. Tetrahdran Lett- 1999, 40,8287.
Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1994,59,6501.
Konz, et al. J. Am. Chern. Soc. 1970,92,404.
Tomioka, H.; Hayashi, N.; Izawa, Y.; Michael, T. H. J. Am. Chem. Soc. 1984,
106,454.
Ratovelomaaana, V.; Linstrumelle, G. Tetrahedron Lett. 1984,600 1 .
Jeffery, T. Tetrahedron Lett 1992,33, 1989,
Sobotka, H.; Chanley, J. D. J. Am. Chem. Soc. 1949, 71,4136.
Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976,98,4887.
Rubottom, G. M.; Juve, H. D. J. Org. Chem. 1983,48,422.
Coulson, D. Inorg. Synfh. 1972,13, 12 1.
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