A concise synthesis of sex pheromone of mediterranean fruit fly, ceratitis capitata via lithiated carbanion derived from enephosphoramide

Article abstract of DOI:10.1002/hc.20588

A novel and versatile synthetic approach to the preparation of (E)-non-6-en-1-ol, a sex pheromone of the Mediterranean fruit fly, Ceratitis capitata, is presented. This pheromone can be viewed as potential active component for lures designed to control and eradication of Mediterranean fruit fly. The described protocol is a six-step reaction sequence producing the desired compound with 28% overall yield from commercially available and inexpensive starting material and total E stereoselectivity of the double bond present in final structure. The key to the success ofthe presented strategy is application oflithiated α-allylphosphoramido carbanions and their reaction with halogenated acetals.

Full text of DOI:10.1002/hc.20588

Heteroatom Chemistry
Volume 21, Number 3, 2010
A Concise Synthesis of Sex Pheromone of
Mediterranean Fruit Fly, Ceratitis capitata via
Lithiated Carbanion Derived from
Enephosphoramide
Tomasz Krzysztof Olszewski and Claude Grison
Centre d’Ecologie Fonctionnelle et Evolutive, Unite´ Mixte de Recherche 5175, Campus CNRS 1919
Route de Mende, 34293 Montpellier cedex 5, France
Received 12 January 2010; revised 17 February 2010
ing and economically important pest insects in the
ABSTRACT: A novel and versatile synthetic ap-
world [1,2]. Native to Sub-Saharan Africa [3], med-
proach to the preparation of (E)-non-6-en-1-ol, a sex
fly is now established in regions of Northern Africa,
pheromone of the Mediterranean fruit fly, Ceratitis
Southern Europe, Latin America, Australia, and the
capitata, is presented. This pheromone can be viewed
Hawaiian Islands and has the potential to spread
as potential active component for lures designed to
further still [4,5]. The presence of medfly can have
control and eradication of Mediterranean fruit fly. The
serious economic ramifications for growers and ex-
described protocol is a six-step reaction sequence pro-
porters by reducing crop yields, increasing manage-
ducing the desired compound with 28% overall yield
ment costs, and negatively affecting trade between
from commercially available and inexpensive starting
nations or within a nation [6]. Importantly, its pres-
material and total E stereoselectivity of the double
ence can be detrimental to the natural biodiversity
bond present in final structure. The key to the suc-
of a region [7]. In addition to the negative influence
cess of the presented strategy is application of lithiated
on agriculture, recent investigations have also high-
α-allylphosphoramido carbanions and their reaction
lighted the negative influence of medfly on human
ꢀ
C
with halogenated acetals. 2010 Wiley Periodicals, Inc.
health as a vector for transmission of food-borne
Heteroatom Chem 21:139–147, 2010; Published online
diseases [8,9].
in Wiley InterScience (www.interscience.wiley.com). DOI
As such, the Mediterranean fruit fly has become
10.1002/hc.20588
the target of extensive control and eradication pro-
grams. One of the eradication methods relies on the
use of pesticides; however, the application of pesti-
INTRODUCTION
cides has its disadvantages, especially when applied
in the vicinity of housing settlements, because it may
lead to contamination of homes, residents, and pets
[10].
Another conventional method, now used for
more than 40 years, is the control of the Mediter-
ranean fruit fly using baited traps. Networks of
traps using both para-pheromones and/or sepa-
rate trap types with food baits are used to de-
tect any accidental introductions of the medfly.
The para-pheromones that are used in the Jackson
traps [11] are trimedlure (TML), tert-butyl-4- and
The Mediterranean fruit fly Ceratitis capitata
(Wiedemann), commonly called the medfly, belongs
to the Tephritidae family, the “true fruit flies.” Med-
fly is a worldwide destructive agricultural pest of
more than 253 varieties of fruits, nuts, and vegeta-
bles, and it is considered as one of the most devastat-
Correspondence to: Tomasz K. Olszewski; e-mail: tomasz
.olszewski@pwr.wroc.pl.
c
ꢀ
2010 Wiley Periodicals, Inc.
139

140 Olszewski and Grison
5-chloro-2-methyl cyclohexane carboxylate [12],
and ceralure (CER), ethyl 4- and 5-iodo-2-methyl-
cyclohexane-1-carboxylate [13,14]. One of the main
problems related with this approach is the prepa-
ration of the active compounds used in the traps.
Their structures are rather complicated, hence their
preparation requires stereoselective synthesis and
advanced synthetic intermediates adorned with, e.g.,
sensitive functional groups and labile stereocenters
[15,16].
In the view of the aforementioned problems re-
lated with the control and eradication programs, it
seems that the most promising option could be ap-
plication of naturally occurring substances, such as
pheromones [17], to attract, survey and control of
medfly.
In 1959 and later in 1962, Feron [18,19] re-
ported that sexually mature male medflies in captiv-
ity release from their erectile anal ampoules a highly
volatile chemical substance that sexually excites and
attracts virgin females. Since these behavioral obser-
vations in 1973 Jacobson [20] have reported the first
isolation, identification, and synthesis of the first sex
pheromone of Mediterranean fruit fly, (E)-non-6-en-
1-ol 1. As it is well known, pheromones are not typ-
ically singular chemicals, but rather complex mix-
tures of numerous chemicals combined in varying
percentages. Although some responses require the
full blend, single compounds can also exhibit specific
actions. Thus, after the discovery made by Jacobson
et al. other successful identifications of volatile com-
ponents from calling male medflies have been re-
ported [21–23].
Until now the synthesis of (E)-non-6-en-1-ol 1
have been a subject of several investigations. The
most representative examples include the following:
(a) the ring scission of 2-alkyl-3-chlorotetrahydro-
pyrans with Grignard reagents [24]; (b) the use of
((Z)-1-bromo-1-alkenyl)borinane obtained by mono-
hydroboration of 1-bromo-1-alkyne [25]; (c) the
carbonyl olefination using the betaine-ylid derived
from ω-hydroxyhexyl-triphenylphosphonium bro-
mide [26]. Unfortunately, these methods usually in-
volve rather complex chemistry, based on scarce syn-
thetic precursors and give moderate overall yields of
the final compound thus preventing from its appli-
cation in commercial lures. Therefore, since it was
felt that the (E)-non-6-en-1-ol 1, as an attractant,
might be useful in survey and control programs for
the Mediterranean fruit fly, a versatile strategy, re-
sulting in a simple and efficient preparation of this
compound would be of particular interest.
for the efficient and concise synthesis of (E)-non-
6-en-1-ol 1 to further advance the practical use of
pheromones as environmentally benign tools for,
e.g., pest control.
RESULTS AND DISCUSSION
As a part of a program aimed at developing of novel
synthetic procedures, we became interested in ap-
plication of homoenolate anions, species containing
anionic carbon β to a carbonyl group or a moiety
that can be transformed into the carbonyl group,
and their synthons [27–29] for the construction of
biologically active compounds. Recently, we have
reported the synthetic utility of lithium anions
derived from allylphosphoramides as aldehyde [30–
32], as lactol [33] and ketone [34,35] homoenolate
equivalents. Furthermore, we have successfully
demonstrated the usefulness and flexibility of the
enephosphoramide method for the simple and effi-
cient preparation of two known pheromones from
honeybee Apis mellifera, namely queen substance
9-oxo-2(E)-decenoic acid (9-ODA) and royal jelly
10-hydroxy-2(E)-decenoic acid (10-HDA) [36]. The
efficiency of this expedient synthetic approach ren-
ders its use particularly attractive in the synthesis of
natural compounds, such as pheromones, and there-
fore prompting us to extend this methodology for
the synthesis of further molecules such as (E)-non-
6-en-1-ol 1 (Scheme 1). Two synthetic strategies,
namely route A and route B, were studied, as it can be
seen from a simple retrosynthetic analysis depicted
in Scheme 1. Both strategies were twofold: (1) Stere-
ocontrolled olefination of 6-hydroxyhexanal 2 (route
A) or 6-(tetrahydro-2H-pyran-2-yl-oxy)hexanal 8
(route B) and (2) stepwise construction of mono-
protected hydroxyaldehyde containing either free
hydroxyl group (route A) or free aldehyde group
(route B). In each case, the strategy is based on
the regiocontrolled reaction of lithiated anion from
enephosphoramide 7 with iodinated acetals. We
have rationalized that since halogenated acetals 6
and 10 are readily available, their reaction with the
lithiated anions issued form allylphosphoramide 7
would provide, after a series of suitable transfor-
mations, a general and versatile approach to the
synthesis of (E)-non-6-en-1-ol 1 (Scheme 1). Thus,
with this conceptual framework established, we
began the testing of our hypothesis in earnest.
Synthesis of (E)-non-6-en-1-ol (1): Route A
In this article, we present in detail our investi-
gations into synthetic utility of lithium anions de-
rived from allylphosphoramides as useful synthons
The key intermediate of the route A is the derivative
5, which presents two masked carbonyl functionali-
ties, a 1,3-dioxane group and the enephosphoramide
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Synthesis of Sex Pheromone of Mediterranean Fruit Fly, Ceratitis capitata via Lithiated Carbanion 141
SCHEME 1
moiety. The comparative lability of the cyclic acetal
and the enephosphoramide was a critical design fea-
ture of the synthetic plan thus, making this study
an interesting contribution to the development of
new protection strategies. We postulated that the
1,3-dioxane group present on 6 allowed chemiose-
lective cleavage of the C N bond in the enephospho-
ramide 5 formed in the further steps of the synthesis,
without affecting the cyclic acetal (Scheme 3). Con-
sidering our previous efforts [32], we supposed that
the acetal group should be stable under mild acidic
conditions, which are necessary to hydrolyze the
enephosphoramide 5 to obtain the desired aldehyde
4, while it liberates the second carbonyl function-
ality under strong acidic conditions producing the
desired deprotected 6-hydroxyhexanal 2 (Scheme 3).
To prepare the key intermediate 5 the 2-
(2-iodoethyl)-1,3-dioxane 6 was needed and this
compound was easily prepared in 95% yield from
commercially available and cheap 2-(2-bromoethyl)-
1,3-dioxane 11 by halogen exchange reaction
(Scheme 2).
To a cooled (−50◦C) solution of 12 the iodo acetal 6
was added followed by gentle warming to 20◦C which
produced, after neutral hydrolysis, the expected con-
jugate enephosphoramide 5 with 71% yield (calcu-
lated on the basis of 31P NMR of the crude mixture).
The reaction of the lithiated enephosphoramide an-
ion 12 with iodo-derivative 6 gave the highest yields
when 2 equiv of lithiated anion 12 with respect to
6 was used and in the presence of 1 equiv of HMPA
(as a chelation agent for lithium) with respect to an-
ion 12. The reaction was clean; despite the fragility
of iodoacetal 6 no degradation was observed. The
ambient anion 12 reacted exclusively at γ position
with iodo-derivative 6. The 1H NMR spectrum of the
crude reaction mixture was complex and difficult to
assign; however, we could distinguish between both
stereomers using 31P NMR. The E stereomer pre-
sented a signal at 24.22 ppm (a downfield chemical
The production of iodo-precursor 6 prompted us
to study its reactivity toward the lithiated enephos-
phoramide anion 12 (Scheme 3). The first step of
the reaction sequence was the generation of the lithi-
ated anion 12, which was done by deprotonation of
enephosphoramide 7 with n-BuLi at −50◦C in THF.
SCHEME 2 Reagents and conditions: (i) NaI, acetone, re-
flux (95%).
Heteroatom Chemistry DOI 10.1002/hc

142 Olszewski and Grison
SCHEME 3 Reagents and conditions: (i) n-BuLi, −50◦C, HMPA then 6, (71%); (ii) 1 N aq. H2SO4 to pH 2.5, room temp., 2 h
(83%); (iii) LiAlH4, −10◦C (85%); (iv) 1 N aq. HCl, room temp., 4 h (90%); (v) t-BuOK, Ph3P+Pr,Br−, 0◦C (65%); (28% overall
yield from commercially available 11).
shift), and the Z stereomer signal appeared with an
upfield shift at 25.30 ppm. The assignment of 5 Z and
5 E was realized by analogy with 31P NMR chemical
shifts of the other enephosphoramides described in
our previous work [32]. These variations of chemi-
cal shifts were observed for all conjugate enephos-
phoramides and strongly support this assignment.
Stereomer 5 E was the more stable one, whereas the
formation of Z can be explained as the result of an
internal chelation of lithium with the free nitrogen
orbital, in the carbanionic precursor 12 [32]. Having
established the best conditions for the preparation
of enephosphoramide 5, we have begun to study fur-
ther steps of the synthesis, namely the hydrolysis of
5 to obtain the desired aldehyde 4. An accurate study
on the hydrolysis of 5 was performed, and it was es-
tablished that treatment of 5 with 1N H2SO4, allow-
ing the pH 2.5 to be attained and reaction time of 4 h,
during which time the pH was readjusted every hour
to its initial value by adding 1 N aqueous H2SO4, cre-
ated the optimum conditions for the chemioselective
cleavage of the carbon–nitrogen bond leading to the
desired 5-(1,3-dioxan-2-yl)pentanal 4 with 83% yield
(56% overall yield after three steps from commer-
cially available 2-(2-bromoethyl)-1,3-dioxane 11).
The aldehyde 4 was further reduced by means of
LiAlH4 producing the corresponding 5-(1,3-dioxan-
2-yl)pentan-1-ol 3 with 85% yield. Subsequently,
the latent carbonyl functionality of the bifunc-
tional building block 3 was generated using aqueous
1 N HCl leading to the desired aldehyde 2 with
excellent 90% yield. In the last step of the synthe-
sis, the 6-hydroxyhexanal 2 was used in the Wittig
olefination with triphenylpropyl-phosphonium bro-
mide. The desired (E)-non-6-en-1-ol 1 was obtained
with 65% yield (28% overall yield after six steps
from commercially available 2-(2-bromoethyl)-1,3-
dioxane 11). The reaction was completely stereose-
lective and resulted in the formation of exclusively
the Estereomer. This assignment was confirmed by
comparison of the spectroscopic data of the obtained
sample with those previously reported in the litera-
ture (see the Experimental part). The stereoselectiv-
ity of the Wittig reaction could be due to the pres-
ence of alcohol in the reaction mixture. This fact
led to the stabilization of the erythro betaine inter-
mediate delaying its decomposition and permitting
the equilibration with thermodynamic adduct. The
direct consequence was the reversibility of the first
step and the E stereoselectivity [37]. Furthermore,
the reaction was clean and the final compound 1 did
not require any further purification.
Synthesis of (E)-Non-6-en-1-ol (1): Route B
The alternate route B is based on a strategy in which
9 is the key intermediate. Here, the difficulty is the
selective cleavage of the enephosphoramide moiety
in the presence of tetrahydropyranyl ether (THP).
The problem is delicate, because the THP group is
more labile toward hydrolysis than the other ac-
etal type protecting groups [38]. Thus, the route B
required formation and lability conditions of the
enephosphoramide moiety, which are compatible
with the presence of the THP group.
This study gave us the opportunity to exam-
ine the introduction of the enephosphoramide moi-
ety into the acid-labile protecting group repertoire.
In this case, the 2-(3-bromopropoxy)tetrahydro-2H-
pyran 15 was used as starting material. Although this
compound is commercially available, it is expensive
and, therefore, it appears much more convenient to
prepare it as depicted in Scheme 4.
In the monohalogenation reaction, the commer-
cially available and inexpensive precursor propane-
1,3-diol 13 was reacted with concentrated HBr,
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Sex Pheromone of Mediterranean Fruit Fly, Ceratitis capitata via Lithiated Carbanion 143
effectiveness of the anion 12 toward to the alkyla-
tion reaction.
Subsequently, the enephosphoramide moiety in
9 was chemioselectively hydrolyzed in the presence
of the tetrahydro-2H-pyran group to obtain the de-
sired aldehyde 8. After a series of experiments, it was
established that the treatment of 9 with 1 N H2SO4
until pH 3.0, and a reaction time of 2 h, during which
time the pH was readjusted every hour to its ini-
tial value by adding 1 N aqueous H2SO4, led to the
expected 6-(tetrahydro-2H-pyran-2-yloxy)hexanal 8
with 63% yield (Scheme 5). With this critical op-
eration accomplished, the aldehyde 8 was reacted
with triphenylpropylphosphonium bromide in the
Wittig olefination producing the 2-((E)-non-6-
enyloxy)-tetrahydro-2H-pyran 16 with 58% yield
and total E stereoselectivity based on comparison of
the spectroscopic data of the obtained sample with
those previously reported in the literature (see the
Experimental section).
In the last step of the synthesis, the latent al-
cohol functionality of the compound 16 was gen-
erated using aqueous 2 N HCl leading to the de-
sired pheromone (E)-non-6-en-1-ol 1 with excellent
87% yield (11.5% overall yield after five steps from
easily available 2-(3-bromopropoxy)tetrahydro-2H-
pyran 15).
In conclusion, a novel and versatile synthetic
approach to the preparation of sex pheromone of
the Mediterranean fruit fly, Ceratitis capitata using
lithium anions derived from allylphosphoramides as
useful building blocks and excellent homoenolate
anion equivalents has been presented. Two routes
have been studied, route A and route B. Route A,
which proved to be the most convenient one, is
a six-step reaction sequence producing the desired
compound 1 with 28% overall yield from commer-
cially available and inexpensive 2-(2-bromoethyl)-
1,3-dioxane 11 and total E stereoselectivity of the
double bond present in final structure. The prepa-
ration of (E)-non-6-en-1-ol 1 successfully illustrates
the suitability of the enephosphoramide strategy
SCHEME 4 Reagents and conditions: (i) HBr, toluene, re-
flux 24 h (46%); (ii) DHP, cat. APTS, reflux 2 h (83%); (iii) NaI,
acetone, reflux (90%); (34% overall yield from commercially
available 13).
producing the desired monobrominated alcohol 14
with 46%. Further protection of the alcohol function-
ality of 14 with 3,4-dihydo-2H-pyran gave the de-
sired 2-(3-bromopropoxy)tetrahydro-2H-pyran 15
in 83% yield. Finally, the halogen exchange reac-
tion was performed similarly to the one described
for route A, rendering the desired 2-(3-iodopropoxy)-
tetrahydro-2H-pyran (10) with 90% yield (34% over-
all yield from propane-1,3-diol (13)) (Scheme 4).
With the iodo-precursor 10 in hand, we were able to
test its reactivity toward the lithiated enephospho-
ramide anion 12. The highest yields were obtained
using 2 equiv of lithiated anion 12 with respect to
the iodo-precursor 10 and in the presence of 1 equiv
of HMPA with respect to anion 12 (Scheme 5). The
lithiated anion 12 was prepared analogously to the
method described for route A. The expected conju-
gate enephosphoramide 9 was obtained with 40%
yield (calculated on the basis of the 31P NMR of the
crude mixture) as mixture of two stereomers E and
Z that could be distinguish using 31P NMR. The E
stereomer presented a signal with downfield chemi-
cal shift at 24.22 ppm, whereas the Z stereomer pre-
sented a signal with upfield shift at 25.30 ppm. The
steric hindrance of the THP group diminished the
SCHEME 5 Reagents and conditions: (i) n-BuLi, −50◦C, HMPA then 10 (40%); (ii) 1 N aq.H2SO4 to pH 3.0, room temp., 2 h
(63%); (iii) t-BuOK, Ph3P+Pr,Br−, 0◦C (58%); (iv) 2 N aq. HCl, room temp., 4 h (87%); (11.5% overall yield from 15).
Heteroatom Chemistry DOI 10.1002/hc

144 Olszewski and Grison
for the construction of natural compounds such
as pheromones. The synthetic value of conjugate
enephosphoramides is based on the nature of this
functionality, which is stable to bases but liberates
the aldehydic group under mild acidic conditions
and compatible with 1,3-dioxane and tetrahydropy-
ranyl ether. Further investigations into application
of conjugate enephosphoramides for preparation of
other natural compounds are currently under inten-
sive investigation in our laboratory. The field tests
with the prepared pheromone as an active compo-
nent of lures for eradication and control of Mediter-
ranean fruit fly are to be conducted in the near fea-
ture, and the results will be reported in separate
communication.
heated at reflux for 24 h, and after cooling down to
room temperature was successfully washed with 6 N
NaOH (2 × 30 mL), 10% aqueous HCl (2 × 30 mL),
H2O (2 × 30 mL), and brine (2 × 30 mL) (due to the
very high solubility of the compound 14 in water,
minimum quantities of water should be used dur-
ing the work-up procedure to avoid substantial de-
crease in the yield of the final product). The organic
layer was dried over anhydrous MgSO4 and concen-
trated to produce the crude product as yellowish oil
which was further purified by vacuum distillation
(bp. 62◦C/5 mmHg, yield = 46%). The spectroscopic
data were in agreement with the values given in the
literature [39].
Protection of the Hydroxyl Group in 14
EXPERIMENTAL
In a three-necked 250-mL round bottom flask
equipment with a condenser and thermometer was
placed 3,4-dihydro-2H-pyran (DHP) (90 mmol,
7.75 g) and preheated to 60◦C. Then the bromoal-
cohol 14 (86 mmol) was added followed by addition
of catalytic amount of para-toluenesulfonic acid
anhydrate (APTS) (point of a knife) and the reaction
mixture was further heated to reach reflux and the
heating was continued for 2 h. After that time, the
reaction mixture was cooled down to room temper-
ature and a little amount of Na2CO3 was added. The
crude 2-(3-bromopropoxy)tetrahydro-2H-pyran 15
was purified by vacuum distillation (bp. 64◦C/0.8
mmHg, yield = 83%). The spectroscopic data were
in agreement with the values given in the literature
[40].
IR spectra were recorded using a Nicolet 205 spec-
1
trometer and are given in cm−1. H and 13C NMR
NMR spectra were recorded using a Bruker AM 400
or AC250, 31P NMR spectra were recorded using a
Bruker AC250. Data for 1H NMR spectra are reported
in δ units downfield from internal Me4Si (TMS) or
from the CHCl3 solvent at 7.25 ppm relative to TMS.
13C NMR spectra were referenced to the CDCl3 peak
at 77.2 ppm relative to TMS. Orthophosphoric acid
(85%) was used as an external standard for 31P NMR
experiments. Multiplicities are quoted as s (singlet),
d (doublet), t (triplet), q (quartet), and m (multiplet).
Mass spectra were obtained on an Autospec Fited
Cesium Gun (Micro Mass Manchester). Analytical
chromatography was performed on silica gel 60 F254
plates. Products were revealed by spraying sulfuric
acid followed by calcinations, iodine, or with UV
light. Preparative chromatographic separations were
carried out on Merck silica gel 60 (230–400 mesh).
Et2O was distilled over P2O5 and stored over Na.
THF was freshly distilled from Na/naphthalene prior
to use. Hexamethylphoshorus triamide (HMPA) was
distilled from CaH2 at reduced pressure and stored
General Conditions for Halogen Exchange
A
500-mL three-necked round bottom flask
equipped with condenser, mechanical stirrer, and
thermometer was charged with the com-
a
mercially available 2-(2-bromoethyl)-1,3-dioxane
11 or 2-(3-bromopropoxy)-tetrahydro-2H-pyran 15
(4.15 mmol) followed by the addition of anhydrous
acetone (250 mL). NaI (208 mmol, 31 g) was added
to this solution, and the mixture was vigorously
stirred at reflux until the TLC revealed the comple-
tion of the reaction. The mixture was then cooled
and concentrated under vacuum. The oily residue
was dissolved in Et2O (250 mL) and washed success-
fully with saturated aqueous NaHCO3 (2 × 100 mL)
and 20% aqueous Na2S2O3(2 × 100 mL). The or-
ganic layer was dried over anhydrous MgSO4 and
concentrated under a vacuum to render the crude
product as yellow oil which was further purified by
column chromatography. During the course of ex-
periments it was discovered that the iodo-derivative
´
˚
over molecular sieves (3A). Hexane was distilled over
´
˚
Na and stored over molecular sieves (3 A). t-BuOK
(potassium tertiary butoxide) was freshly sublimed
just before use (it sublimes at 220◦C/1 Torr.) Solu-
tion of n-Butyllithium (n-BuLi) was purchased from
Aldrich and was titrated before use.
Preparation of the Monohalogenated Alcohol 14
A three-necked 500-mL round bottom flask, equip-
ment with a Dean-Stark apparatus was charged with
the commercially available propane-1,3-diol (13)
(329 mmol) in 200 mL of toluene and concentrated
HBr (1.1 equiv, 40 mL). The reaction mixture was
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Sex Pheromone of Mediterranean Fruit Fly, Ceratitis capitata via Lithiated Carbanion 145
6 is relatively unstable and undergoes decomposi-
ous H2SO4 until the appropriate value of the pH was
reached (pH 2.5 for enephosphoramide 5 and pH 3.0
for 9). The mixture was then stirred at room temper-
ature for 2 h, during which time the pH was read-
justed every hour to its initial value by adding 1 N
aqueous H2SO4. Afterwards, the layers were sepa-
rated and the aqueous layer was extracted with Et2O
(2 × 25 mL). The combined organic layers were dried
over MgSO4 and concentrated under reduced pres-
sure yielding the crude aldehydes, which were fur-
ther purified by column chromatography.
tion after 48 h even when kept under nitrogen and
in the freezer. Therefore, compound 6 was used di-
rectly in the further steps of the synthesis just after
preparation and quick purification.
2-(2-Iodoethyl)-1,3-dioxane (6). Colorless oil;
yield: 95%; Rf (0.71 Et2O/hexane 4:1); 1H NMR
(CDCl3) δH (ppm): 4.43 (t, 1H, OCHO, 3 JHH = 5.0 Hz),
4.02–3.80 (m, 4H, OCH CH2CH O), 2.12–2.10 (m,
2
2
2H, CHCH ), 3.18 (t, 2H, CH I, 3 JHH = 7.0 Hz), 1.55–
2
2
1.35 (m, 2H, OCH2CH CH2O).
2
2-(3-Iodopropoxy)-tetrahydro-2H-pyran
(10).
5-(1,3-Dioxan-2-yl)pentanal (4). Colorless oil;
yield: 83%; Rf (0.51 Et2O/hexane 1:1); 1H NMR
(CDCl3) δH (ppm): 9.75 (t, 1H, CHO, 3 JHH = 1.5 Hz),
Colorless oil; Yield: 90%; 1H NMR (CDCl3) δH(ppm):
3
4.48 (t, 1H, OCHO, JHH = 5.0 Hz), 4.0–3.72
3
(m, 2H, CHOCH ), 3.50–3.30 (m, 2H, CHOCH ),
4.50 (t, 1H, OCHO, JHH = 4.5 Hz), 3.95–3.72
2
2
3
3.12 (t, 2H, CH I, JHH = 7.0 Hz), 1.65–1.46 (m,
(m, 4H, OCH CH2CH O), 2.50 (td, 2H, CH CHO,
2
2
2
2
3
4H, OCH2CH CH2CH CH), 1.46–1.21 (m, 4H,
3 JHH = 1.5 Hz, JHH = 7.0 Hz), 2.12–1.95 (m, 2H,
2
2
OCH2CH2CH CH2CH, OCH2CH CH2I).
CH CH2CHO), 1.60–1.35 (m, 6H, OCH2CH CH2O,
2
2
2
CH CH CH2CH2CHO). IR, νmax (film) cm−12: 2750
2
2
General Procedure for Reaction of Lithiated
Anions 12 with Iodo Derivatives
(C H), 1720 (C O). MS (FAB+): m/z 172 (100%),
173 (10%).
6-(Tetrahydro-2H-pyran-2-yl-oxy)hexanal
(8).
To a stirred solution of enephosphoramide 7
(2.0 mmol) (prepared as described earlier Ph.
Coutrot, Ph, Savignac, J. Chem. Research (M), 3401–
3416, 1977) in freshly distilled THF (60 mL) at −50◦C
was added n-BuLi (2.30 mmol, 1.6 M in hexane). Af-
ter stirring for 2 h under nitrogen at −50◦C, HMPA
(2.0 mmol) was injected. The reaction mixture was
stirred for an additional 30 min, and then the solu-
tion of appropriate iodo acetal (1.0 mmol) in THF (5
mL) was added dropwise. The solution was stirred
for 4 h at −50◦C, and after that time it was left to
slowly warm to room temperature and hydrolyzed
with H2O (10 mL). The layers were separated, and
the organic layer was extracted with CH2Cl2 (3 × 50
mL), dried over anhydrous MgSO4 and concentrated
under reduced pressure to yield crude products as
yellow oils that were stored under nitrogen at a
low temperature (to avoid decomposition) and used
without purification in further steps of the synthesis.
[2-(Pent-4-enyl)-1,3-dioxane]-pentamethyl phos-
phoric triamide (5). Yellowish oil; Yield: 71%; 31P
NMR (CDCl3) δP (ppm): 24.22 (E stereomer) and
25.30 (Z stereomer).
Colorless oil; yield: 63%; Rf (0.52 Et2O/hexane
1:1); 1H NMR (CDCl3) δH(ppm): 9.70–9.69 (m,
3
1H, CHO), 4.52 (t, 1H, OCHO, JHH = 5.0 Hz),
4.0–3.72 (m, 2H, CHOCH ), 3.48–3.42 (m, 2H,
2
OCHOCH ), 2.42–2.38 (m, 2H, CH CHO), 1.65–1.46
2
2
(m, 4H, OCH2CH CH2CH CH), 1.43–1.21 (m, 8H,
2
2
OCH2CH2CH CH2CH, OCH2CH CH CH CH2CHO).
2
2
2
2
IR, νmax (film) cm−1: 2730 (C H), 1718 (C O). The
spectroscopic characterization of this compound
was consistent with that previously reported [41].
Reduction of the Aldehyde Functionalities in 4
to Alcohol 3
A 250-mL three-necked round bottom flask was
charged with the solution of aldehyde 4 (1.0 mmol)
in 30 mL of dry Et2O. The reaction vessel was cooled
down to −10◦C and the solution of LiAlH4 (1.0 mmol)
was added dropwise. After the addition was com-
pleted, the reaction mixture was warmed to room
temperature and stirred for 2 h. Afterwards, the so-
lution was hydrolyzed by addition of H2O (10 mL)
and neutralized by HCl 12 N. The layers were sep-
arated, and the aqueous layer, after being saturated
with NaCl, was extracted with Et2O (3 × 15 mL).
The ethereal extract was dried over MgSO4 and
concentrated under vacuum furnishing the desired
alcohol 3.
[2-(Hex-5-enyloxy)-tetrahydro-2H-pyran]-penta-
methyl phosphoric triamide (9). Yellowish oil; Yield:
40%; 31P NMR (CDCl3) δP(ppm): 24.22 (E stereomer)
and 25.30 (Z stereomer).
General Procedure for the Preparation of
Aldehydes 4 and 8
5-(1,3-Dioxan-2-yl)pentan-1-ol (3). Colorless oil;
yield: 85%; 1H NMR (CDCl3) δH(ppm): 4.48 (t,
3
Crude enephosphoramide 5 or 9 (500 mg) was dis-
solved in Et2O (25 mL). H2O (50 mL) was added
to this solution, followed by addition of 1 N aque-
1H, OCHO, JHH = 4.5 Hz), 4.0–3.70 (m, 4H,
3
OCH CH2CH O), 3.60 (t, 2H, CH OH, JHH
=
2
2
2
8.0Hz), 2.50 (s, 1H, OH), 1.75–1.65 (m, 4H,
Heteroatom Chemistry DOI 10.1002/hc

146 Olszewski and Grison
CH CH2CH2OH), 1.55–1.28 (m, 6H, OCH2CH CH2O,
be observed. After stirring for additional 1 h at room
temperature, the reaction mixture was quenched by
adding H2O (2 mL) and diluted with Et2O (10 mL).
The layers were separated, and the organic layer was
dried over MgSO4 and concentrated under reduced
pressure affording the crude product 1 and 16.
(E)-Non-6-en-1-ol (1). Colorless oil; yield: 65%.
The spectroscopic data were identical with that pre-
sented for 1 obtained using route A.
2
CH CH CH2CH2CH2OH). IR, νmax (film) cm−21: 3356
2
2
(O H).
General Procedure for the Hydrolysis of the
Acetal Functions in 3 and 16
A single neck round bottom flask was charged with
the appropriate acetal (300 mg) and Et2O (50 mL).
The solution was treated with 50 mL of aqueous HCl
(1 N solution was engaged to deprotect the acetal 3,
and in the case of 16 2 N solution was employed),
and the mixture was stirred vigorously for 4 h. After
that time, the layers were separated and the aqueous
layer was extracted with Et2O (3 × 25 mL). The com-
bined organic extracts were washed with saturated
aqueous NaCl (3 × 25 mL), dried over MgSO4 and
concentrated under reduced pressure producing the
crude products.
2-((E)-Non-6-enyloxy)-tetrahydro-2H-pyran
(16). Colorless oil; yield: 58%; 1H NMR (CDCl3)
δH(ppm): 5.48 (m, 2H, CH CH), 4.50 (t, 1H, OCHO,
3 JHH = 5.0 Hz), 4.0–3.70 (m, 2H, CHOCH ), 3.45–3.40
2
(m, 2H, OCHOCH ), 1.96–2.1 m, 4H, CH2CH CH,
2
CH2CH3), 1.63–1.55 (m, 6H, OCH2CH CH CH CH),
2
2
2
1.29–1.46 (m, 6H, OCH2CH CH CH CH2CH=), 0.97
2
2
2
(t, 3H, CH CHCH2CH ). 13C NMR (CDCl3) δC (ppm):
3
131.5, 128.7, 106.0, 63.1, 62.6, 33.9, 30.6, 30.0, 29.7,
26.4, 25.9, 25.4, 20.0, 13.9. IR, νmax (film) cm−1: 1655
(C C) [46,47].
6-Hydroxyhexanal (2). Colorless oil; yield: 90%;
1H NMR (CDCl3) δH(ppm): 9.67 (t, 1H, CHO,
3 JHH = 1.5 Hz), 3.51 (t, 2H, CH COH, 3 JHH = 7.0 Hz),
2
3.02–2.60 (m, 1H, OH), 2.38–2.25 (m, 2H, CH CHO),
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