Horner olefination reaction in organic sulfur chemistry and synthesis of natural and bioactive products

Article abstract of DOI:10.1080/10426500701734448

This article outlines the results of our work on the application of the Horner olefination reaction for the synthesis of unsaturated sulfur compounds. A general synthesis of racemic and optically-active α,β-unsaturated sulfoxides by the Horner reaction with α-sulfinylmethylphosphonates as olefination reagents is presented. We demonstrated how the structure of the phosphonate moiety may control the E- and Z-stereoselectivity in the above reaction. The use of racemic and optically-active α- sulfinylvinylphosphonates in tandem Michael addition/Horner olefination reaction leads to a wide range of carbocyclic and heterocyclic vinyl sulfoxides. In second part of this account a new strategy for the synthesis of functionalized cyclopentenones is briefly described. The synthesis and reactivity of 3-phosphorylmethyl-cyclopentenones is discussed as a platform for developing the synthesis of racemic rosaprostol, enantiomeric prostaglandin B1 methyl esters, enantiopure isoterreins, natural and unnatural neplanocin A and enantiomeric forms of phytoprostane B1 type I. Copyright Taylor & Francis Group, LLC.

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Horner Olefination Reaction
in Organic Sulfur Chemistry
and Synthesis of Natural and
Bioactive Products
Marian Mikołajczyk a , Wanda H. Midura a , Ashraf M.
Mohamed Ewas a , Wiesława Perlikowska a , Maciej
Mikina a & Aleksandra Jankowiak a
a Centre of Molecular and Macromolecular Studies,
Polish Academy of Sciences, Department of
Heteroorganic Chemistry , Łodź, Poland
Published online: 21 Jun 2008.
To cite this article: Marian Mikołajczyk , Wanda H. Midura , Ashraf M. Mohamed
Ewas , Wiesława Perlikowska , Maciej Mikina & Aleksandra Jankowiak (2008) Horner
Olefination Reaction in Organic Sulfur Chemistry and Synthesis of Natural and
Bioactive Products, Phosphorus, Sulfur, and Silicon and the Related Elements, 183:2-3,
313-325, DOI: 10.1080/10426500701734448
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Phosphorus, Sulfur, and Silicon, 183:313–325, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701734448
Horner Olefination Reaction in Organic Sulfur Chemistry
and Synthesis of Natural and Bioactive Products
Marian Mikolajczyk, Wanda H. Midura,
ꢀ
Ashraf M. Mohamed Ewas, Wieslawa Perlikowska,
ꢀ
Maciej Mikina, and Aleksandra Jankowiak
Centre of Molecular and Macromolecular Studies, Polish Academy of
Sciences, Department of Heteroorganic Chemistry, Lo´dz´, Poland
ꢀ
This article outlines the results of our work on the application of the Horner olefi-
nation reaction for the synthesis of unsaturated sulfur compounds. A general syn-
thesis of racemic and optically-active α,β-unsaturated sulfoxides by the Horner
reaction with α-sulfinylmethylphosphonates as olefination reagents is presented.
We demonstrated how the structure of the phosphonate moiety may control the E-
and Z-stereoselectivity in the above reaction. The use of racemic and optically-active
α-sulfinylvinylphosphonates in tandem Michael addition/Horner olefination reac-
tion leads to a wide range of carbocyclic and heterocyclic vinyl sulfoxides. In second
part of this account a new strategy for the synthesis of functionalized cyclopen-
tenones is briefly described. The synthesis and reactivity of 3-phosphorylmethyl-
cyclopentenones is discussed as a platform for developing the synthesis of racemic
rosaprostol, enantiomeric prostaglandin B1 methyl esters, enantiopure isoterreins,
natural and unnatural neplanocin A and enantiomeric forms of phytoprostane B
type I.
1
Keywords Horner reaction; α-sulfinylalkylphosphonates; vinyl sulfoxides; 3-
phosphorylmethyl-cyclopentenones; total synthesis; natural products; phytoprostane B1
type I
INTRODUCTION
Among many methods for the formation of the olefinic carbon-carbon
bond, P(O)-activated olefination gained a wide application in different
Received June 29, 2007; accepted September 17, 2007.
This paper is based on the keynote lecture presented at the 17th International Confer-
ence on Phosphorus Chemistry (Xiamen, China), and it is dedicated to the late Professor
Leopold Horner.
Financial support from the Ministry of Science and Higher Education (Grant No PBZ-
KBN-126/T09/2004 to M. M.) is gratefully acknowledged.
Address correspondence to Marian Mikolajczyk, Centre of Molecular and Macromolec-
ꢀ
ular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, 90-
363 Lo´dz´, Sienkiewicza 112, Poland. E-mail: marmikol@bilbo.cbmm.lodz.pl
ꢀ
313

314
M. Mikolajczyk et al.
ꢀ
fields of organic chemistry, especially in the total synthesis of natu-
ral products and biologically active compounds. Horner1 was the first
who discovered—as early as 1958—that the reaction of the sodium
salt of diphenylmethylphosphine oxide with benzophenone afforded 1,1-
diphenyl-ethylene and sodium diphenylphosphinate (Scheme 1). No for-
mation of (2,2-diphenylvinyl)diphenyl-phosphine oxide was observed
which could be formed from the oxy-adduct A on elimination of sodium
hydroxide. One year later, Horner2 extended his olefination reaction to
phosphonates which became very useful CH acidic olefination reagents
(Scheme 1).
SCHEME 1
In 1961, Wadsworth and Emmons3 published their initial experi-
ments on the Horner reaction, and in subsequent papers they described
the scope and limitations of this new olefination method. Therefore,
nowadays the P(O)-activated olefination method is very often called
Horner-Wadsworth-Emmons reaction (HWE) and its importance in
preparative organic chemistry is still increasing. The main advantage
of the Horner olefination reaction over the closely related Wittig reac-
tion is that phosphorus acid salts formed also as products in the former
reaction are easily removed while the separation of olefins from neutral
phosphine oxides, that are produced in the Wittig reaction, is very often
difficult.
In this account, we wish to demonstrate a great utility of the Horner
olefination reaction in our work focused on the synthesis of selected
unsaturated organosulfur compounds and natural products containing
the cyclopentenone and cyclopentanone structural unit.

Horner Olefination Reaction
315
MIXED PHOSPHORUS AND SULFUR COMPOUNDS AS
P(O)-ACTIVATED OLEFINATION REAGENTS
A
long-term interest of our laboratory in the chemistry of
phosphonates and various sulfur compounds led us to exten-
sive studies on organic compounds containing both heteroatoms
in one molecule. Since the Horner reaction became one of the
most important synthetic methods, in our early work we pre-
pared various phosphonates bearing the sulfur functionalities at
the α-phosphonate carbon atom. Typical examples of such mixed
phosphorus-sulfur structures are: α-sulfanyl-alkylphosphonates 1,4
S,S-dithio- and O,S-thioacetals of formylphosphonates 2,5 α-sulfanyl-
α-carboxy-methylphosphonate 3,6 α-sulfanylvinylphosphonates 47 and
αmethtylsulfanyl-α-trimethylsilyl-methylphosphonate 58 (Scheme 2).
SCHEME 2
Phosphonates 1, 2, and 3 undergo the Horner olefination reaction
with carbonyl compounds to give the corresponding vinyl sulfides which
upon hydrolysis form mono-carbonyl (from 1 and 2) or 1,2-dicarbonyl
(from 3) products. As the α-phosphoryl sulfide moiety may be regarded
as a masked carbonyl group [Eq. (1) in Scheme 2], three consecutive
reactions involving Michael addition of enolate anion to 4, Horner re-
action of the adduct with a carbonyl electrophile and hydrolysis of the
vinyl sulfide formed represents a general method for the synthesis of
1,4-dicarbonyl compounds which may be transformed into cyclopent-2-
enones.7 The α-phosphonate carbanion generated from 5 reacts with
carbonyl compounds in a different way. It affords the Peterson reac-
tion product via elimination of the trimethylsilyloxy group. Therefore,

316
M. Mikolajczyk et al.
ꢀ
phosphonate 5 is a key reagent for the synthesis of vinylphosphonates
4.
A very important class of mixed P,S-compounds is α-sulfinyl phos-
phonates 6 first synthesized in racemic9 and enantiomeric forms10 in
our laboratory. As shown in Scheme 3, the structure of 6 contains the
phosphonate and sulfoxide moieties. Both of them are chiral. It should
be pointed out that the chiral sulfinyl group has proved to be one of the
most efficient chiral auxiliaries because of its extraordinary ability to
control stereoselectivity of asymmetric reactions.
SCHEME 3
Among many transformations of α-sulfinyl phosphonates 6, the
most important is their Horner P(O)-olefination reaction leading to
α,β-unsaturated sulfoxides.11 Due to the presence of highly electron-
withdrawing phosphoryl and sulfinyl groups, proton elimination from
the bridging methylene group readily occurs on treatment with a base
yielding the appropriate stabilized α-phosphonate carbanions, which
afford α,β-unsaturated sulfoxides when reacted with carbonyl com-
pounds. They were formed in good to high yields as separable mixtures
of E and Z isomers. Selected experimental results obtained with 6a are
depicted in Scheme 4.
With the aim at the synthesis of optically active vinylic sulfoxides,
we prepared enantiopure (+)-(S)-(dimethoxyphosphoryl)methyl p-tolyl
sulfoxide 6b which has become a reagent of choice for the synthesis of
variously substituted optically active α,β-unsaturated sulfoxides.10 Its
synthesis and Horner reaction are shown in Scheme 5.
The only drawback of the synthesis of vinyl sulfoxides presented
above is that a mixture of geometrical E- and Z-isomers is produced.

Horner Olefination Reaction
317
SCHEME 4
We found, however, that the Wittig reaction of the in situ generated α-
sulfinylphosphonium ylide 7 with carbonyl compounds affords racemic
or optically active vinyl sulfoxides with the E-geometry12 (Scheme 6).
Recently, extensive effort has been devoted to the stereoselective
synthesis of Z-α,β-unsaturated esters. These isomers were found to
be preferentially formed when bis(trifluoroethyl)phosphono-acetates
and diarylphosphono-acetates14 are used as the Horner olefination
reagents. Moreover, Kokin et al.15 reported that bis(trifluoroethyl)
α-sulfinylmethylphosphonates reacted with aromatic aldehydes with
predominant formation of Z-vinyl sulfoxides. Prompted by these ob-
servations, we decided to synthesize racemic and optically-active
diphenyl α-p-tolylsulfinylmethylphosphonate 6c in the hope to achieve
SCHEME 5

318
M. Mikolajczyk et al.
ꢀ
SCHEME 6
Z-stereoselectivity in the Horner reaction. The synthesis of ( )-6c16
was performed according to the procedure described earlier by us
for diphenyl α-phenylsulfinylmethylphosphonate17 and is shown in
Scheme 7. Optically active (+)−(S)-6c was prepared in a standard way
from (-)-(S )-menthyl p-toluenesulfinate and diphenyl methylphospho-
S
nate carbanion16 (Scheme 7).
SCHEME 7
Horner reaction of ( )-6c was first carried out with benzaldehyde us-
ing different bases such as: nBuLi, NaH, KH, t-BuOK and KHMDS. It
was found that with NaH and KHMDS the reaction gave quantitatively
2-phenylvinyl p-tolyl sulfoxide with predominant Z-selectivity, 66 and
64%, respectively. When the reaction was performed in the presence of
18-crown-6 the Z-selectivity was increased. For example, treatment of
( )-6c with benzaldehyde in the presence of KHMDS and 5 equivalents
of 18-crown-6 afforded the product with 78% Z-selectivity. Furthermore,
the structure of the aldehyde component has also an influence on the
reaction stereoselectivity. Thus, with o-bromobenzaldehyde the Horner

Horner Olefination Reaction
319
reaction carried out in the presence of 18-crown-6 gave the correspond-
ing vinyl sulfoxide as a mixture of Z and E isomers in a ratio of 93:7
(Scheme 8).
SCHEME 8
Although the olefination of phosphono sulfoxide 6c with aromatic
aldehydes showed higher Z-selectivity in the presence of 18-crown-6,
the Horner reaction of optically active (+)–(S)-6c with aromatic alde-
hydes was carried out in its absence to avoid some problems connected
with the product separation. In Scheme 9, some experimental data for
this reaction with benzaldehyde and o-bromobenzaldehyde are given.
SCHEME 9
It is interesting to note that, in spite of the same absolute configu-
ration at sulfur, the Z- and E-isomers of vinyl sulfoxides have opposite
sign of optical rotation and differ distinctly in its magnitude.
To complete discussion on the utilization of the Horner olefination
reaction in the synthesis of unsaturated sulfoxides, it is desirable to de-
scribe briefly our new approach to the synthesis of racemic and optically

320
M. Mikolajczyk et al.
ꢀ
active carbocyclic and heterocyclic vinyl sulfoxides.18 In this case we
used α-sulfinylvinylphosphonates 8 as olefination reagents.
A distinctive feature of this new chiral structure (Scheme 10) is
the presence of a very reactive carbon-carbon double bond with two
electron-withdrawing P(O) and S(O) groups at the olefinic α-carbon
atom. As the nucleophilic addition to α-sulfinylvinylphosphonates 8
generates the corresponding α-phosphonate carbanion, reactions of
these phosphonates with carbonyl compounds bearing a nucleophilic
center in a β- or γ -position to the carbonyl group can provide a use-
ful means for the synthesis of cyclic vinylic sulfoxides as depicted in
Scheme 11.
SCHEME 10
A wide scope and usefulness of this tandem Michael addition/Horner
olefination reaction is demonstrated by the synthesis of a variety of op-
tically active chromene, pyrrolizine, chinoline and cyclopentene sulfox-
ides prepared from (+)-(S)-8 and listed in Scheme 11.18
PHOSPHONATE-BASED STRATEGY FOR SYNTHESIS OF
CYCLOPENTENONE AND CYCLOPENTANONE NATURAL
PRODUCTS AND BIOACTIVE COMPOUNDS
As part of our program on the application of phosphorus compounds in
organic synthesis,19 we have been involved over the last two decades
or so in the invention and development of general methods for the
synthesis of functionalized cyclopentenones and cyclopentanones.20
These structural units are present in a wide range of important
natural products such as jasmonoids, cyclopentanoid antibiotics, and

Horner Olefination Reaction
321
SCHEME 11
prostaglandins. Our efforts resulted in the elaboration of general ap-
proaches to 3-(phosphorylmethyl)cyclopent-2-enones 9 which turned
out to be excellent building blocks in the synthesis of a variety of inter-
esting target compounds.
The cyclopentenones 9 were easily obtained in the reaction between
α-phosphonate carbanions and dicarboxylic acid esters21 (Scheme 12).
This reaction affords in the first step the corresponding bis-β-
ketophosphonates 10, which under basic conditions undergo in-
tramolecular Horner reaction to produce the desired cyclopentenones
9. As a matter of fact, the later reaction is a little more complicated
because the kinetically controlled product is the Knoevenagel product
which can be converted into the Horner reaction product 9 under basic
conditions.
A similar strategy was applied in the synthesis of optically
active 3-phosphorylmethyl-4,5-dihydroxy-cyclopentenones 10a and
10b.22 In this case, the first important step was complete desym-
metrization of meso-tartaric acid, which gave on treatment with
(+)-camphor and methyl orthoformate the corresponding protected
dimethyl ester as a single diastereomer. Its reaction with dimethyl

322
M. Mikolajczyk et al.
ꢀ
SCHEME 12
lithiomethylphosphonate under proper conditions afforded a separable
mixture of the diastereomeric cyclopentenones 10a and 10b (Scheme
13).
SCHEME 13
Quite recently, two new synthetic approaches to 9 have been elab-
orated which involve in a key step so-called forced conjugate addi-
tion of α-phosphonate carbanions to appropriate cyclopentenones23
(Scheme 14).
The cyclopentenones 9 and 10 offer interesting possibilities for fur-
ther functionalization of the five-membered ring. First of all, the anion
derived from 3-phosphorylmethyl-cyclopentenones might be described
by three mesomeric forms in which the negative charge is located on
the α-phosphoryl carbon atom, α-carbonyl carbon atom and carbonyl
oxygen atom. Our study on reactivity of this anion revealed that alkyla-
tion occurs mainly at the α-carbonyl carbon atom, carbonyl electrophiles

Horner Olefination Reaction
323
SCHEME 14
react at the α-phosphoryl carbon atom producing the Horner olefination
products and acylation takes place at carbonyl oxygen.21
Hence, combination of the alkylation and Horner reaction of the
anion under discussion paved the way for the synthesis of 2,3-
difunctionalized cyclopentenones. This method has been exploited in
the total synthesis of some natural products and bioactive compounds
(Scheme 15). For instance, the cyclopentenone 9 was converted in
three steps (alkylation, Horner olefination, hydrogenation) into racemic
SCHEME 15

324
M. Mikolajczyk et al.
ꢀ
rosaprostol—an antiulcer drug.24 In a similar way, two enantiomers of
prostaglandin B1α methyl ester were synthesized form 9.25 On the other
hand, the diastereomers of 10 were successfully used as starting ma-
terials in the synthesis of enantiomeric isoterreins which belong to the
family of cyclopentanoid antibiotics.22 Starting from 10 the synthesis
of natural (-)-neplanocin A and its unnatural (+)-enantiomer was also
executed.26
SCHEME 16
To illustrate the usefulness, simplicity and effectiveness of our strat-
egy, the synthesis of both enantiomers of phytoprostane B1 type I, 11,27
is presented in detail (Scheme 16). Phytoprostanes B1 type I and II
are a new class of compounds that occur in plants and are formed
from α-linolenic acid. They display a wide spectrum of biological ac-
tivity including activation of mitogen-activated protein kinase (MAPK)
and the induction of glutathione-S-transferase (GTS), defense genes
and phytoalexins. The first step in our synthesis is the alkylation of
the cyclopentenone 9 anion with methyl 8-bromooctanoate. Although
this reaction was not very efficient due to competitive O-alkylation, the
Horner reaction of the mono-alkylated product with the enantiomeric

Horner Olefination Reaction
325
benzoyl protected α-hydroxy butanals occurred in excellent yield af-
fording the desired olefination products in a straightforward way. After
deprotection of the hydroxyl group, the enantiopure forms of phyto-
prostane 11 were obtained in ca. 25% overall yield.
The synthesis of prostaglandins and therapeutically important
prostaglandin analogues according to our strategy is under current
study.
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