Synthesis of the Sex Pheromone of the Oleander Scale (Aspidiotus nerii)

Article abstract of DOI:10.1021/acs.joc.9b01001

A total synthesis of the oleander scale [Aspidiotus nerii (Bouche)] sex pheromone, the unique sesquiterpenoid containing a cyclobutane moiety of this class of compounds, has been developed. In order to implement this sex pheromone as a new environmentally

Full text of DOI:10.1021/acs.joc.9b01001

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Article
Synthesis of the sex pheromone of the Oleander scale (Aspidiotus nerii)
Mary Montaño Castañeda, Javier Marzo Bargues, Jaime Primo, and Ismael Navarro Fuertes
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01001 • Publication Date (Web): 04 Jun 2019
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Synthesis of the sex pheromone of the Oleander scale
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(Aspidiotus nerii).
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Montaño Castañeda Mary,1 Marzo Bargues Javier,2 Primo Jaime,1 and Navarro Fuertes Ismael*2
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1CEQA-Instituto Agroforestal del Mediterráneo, Universitat Politècnica de València,
Camino de Vera s/n, edificio 6C-5ª planta, 46022 Valencia, Spain.
2Ecología y Protección Agrícola SL, Pol. Ind. Ciutat de Carlet, 46240 Carlet (Valencia),
Spain.
Correspondence to: Ismael Navarro Fuertes, Ecología y Protección Agrícola SL, Pol.
Ind. Ciutat de Carlet, 46240 Carlet (Valencia), Spain. Email: ismael.navarro@epa-
ecologia.com
Table of Contents graphic
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ABSTRACT
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A total synthesis of the Oleander scale (Aspidiotus nerii (Bouche)) sex pheromone, the
unique sesquiterpenoid containing a cyclobutane moiety of this class of compounds, has
been developed. In order to implement this sex pheromone as a new enviromental-
friendly tool to manage this pest, a more cost-effective, multigram synthesis was
required. This new synthetic route, having a Blaise reaction, an iron catalyzed carbon-
carbon coupling and a [2+2] photocycloaddition reactions as key steps, provides a
general access to 4-alkyl lactones as well as a robust access to the target sex pheromone.
Starting from readily available compounds as 3-hydroxypropane nitrile, ethyl
bromoacetate and 2-acetyl butyro lactone, the synthetic sequence afforded the A. nerii
sex pheromone with minimum intermediate purification and good overall yield, in 9
linear steps.
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INTRODUCTION
Oleander scale (Aspidiotus nerii (Bouche)) is a polyphagous pest affecting more than
100 plant species.1 Among these, damages caused to ornamental species, such as
Nerium oleander L., and those caused by this pest to lemon and olives trees are of
particular and economical importance in the Mediterranean area. Sessile females are
sap-suckling, causing general weakness of the affected plant, defoliation and reducing
dramatically the quality of the fruit for commercialization purposes.2 Conventional
treatment of this pest with traditional pesticides could be poorly effective due to its
cryptic behavior, 3 together with the decreasing number of chemical principles available
under the increasingly restrictive new environmental laws.4 Moreover, the limit of
pesticides residues admitted in fruit is continuously decreasing, being particularly low
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or unacceptable when an integrated or ecological production is chosen. The use of sex
pheromones via mating disruption to control insect pests is a well-stablished technique
mainly in Lepidoptera species,5 whereas only two commercial examples are known
within the Coccoidea family, the vineyard mealybug Planococcus ficus Signoret
(Checkmate VMB; Suterra LLC, Bend, OR),[6a] and the related citrus scale Aonidiella
aurantii Maskell (Rescalure; Ecología y Protección Agrícola SL, Valencia, Spain).6b-d
As in the latter, A. nerii males have a very short life cycle, thus, the use of the sex
pheromone emitted by females 1 (Figure 1) to control this pest could be an
environmentally respectful and valuable option. Based on the experience of our research
group with related species,6a-d we sought its implementation in the field by using
appropriated techniques such as mating disruption or attract-and-kill. Despite needing
the later lower doses of sex pheromone per hectare, its price is still nowadays a key
point for practical purposes, thus, a more cost-effective synthesis in a multigram scale
of this sex pheromone is undoubtedly required. In regards to this, following the pattern
behaviour of related species, an enantioselective synthesis is not required due to the
non-inhibitory effect of the rest of the stereoisomers. 7
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Figure 1. Sex pheromone of Aspidiotus nerii.
Several sex and aggregation pheromones containing a cyclobutane ring are known.
Some of them are emitted by mealybugs or scale insects, and its structures have being
classified in two main groups, planoccociol-type (1,1,2 substitution pattern), isolated
from the species Antonomous grandi,8a Pissodes strobi,8b Curculio caryae,8c
Conotrachelus nenuphar,8d Conotrachelus psidii,8e or maconelliol-type (1,2,2,3
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substitution pattern), isolated from the species Maconellicoccus hirsutus,9a Acutaspis
albopicta9b Phenacoccus solenopsis,9c Planocccocus citri,9d Pseudococcus criptus.9e
The oleander scale sex pheromone 1 belongs to the planoccociol series, being the only
sesquiterpenoid of this family identified so far. Since its isolation in 1998 by Einhorn et
al.,10 one stereoselective synthesis starting from carvone11a,b and one racemic synthesis
have been developed.12 Having both an intramolecular cyclization as key step for the
cyclobutane ring formation, the two synthetic approaches implied more than fifteen
synthetic steps and overall yields below 1 %, being non suitable for multigram synthetic
purposes. Inspired by previous synthetic works of structurally related cyclobutane-
containing pheromones such as grandisol,13 we sought a total synthesis of the A. nerii
pheromone using a 2+2 photocycloaddition reaction as a key step for the cyclobutane
ring construction. We envisaged a synthetic route in which an enol phosphate or
tosylate derivative of keto-lactone 2 (Scheme 1) could be transformed via metal
catalyzed coupling reaction with the appropriate organometallic reagent to afford 4-
alkyl-a,b insaturated lactone 3. Subsequently, a cycloaddition reaction could provide
the cyclobutane lactone intermediate 4. This intermediate could be easily transformed in
the target sex pheromone of A. nerii. 1 after lactone opening, by using a minimum
number of chemical transformations.
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Scheme 1. Retrosynthetic analysis of 1. All compounds are racemic but only one enantiomer is shown for
simplicity.
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RESULTS AND DISCUSSION
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4-alkyl lactones are an important class of moieties in natural products showing diverse
biological activities. Several synthetic approaches- thoroughly revised by Campagne et
al.14 had been previously developed. Unfortunately, the vast majority of these methods
were not flexible enough for the substitution pattern required in our target lactone 3. We
envisaged two different intramolecular cyclizations to give access to its precursor
lactone 2. The first one, based on an intramolecular Blaise-type reaction,15a uses
bromides 5 or 6 (Scheme 2) as starting materials, whereas the second one relies on the
cyclization of hydroxy ketoester 7.
Scheme 2. Retrosynthetic analysis of 2.
16a,b
Firstly, we decide to attempt the synthesis of 2
via cyclization of a bromide ester
synthesized from methyl 3- hydroxypropanonate 8 or 3-hydroxypropanonitrile 9
(Scheme 3). Reaction of alcohols 8 or 9 in toluene using Et3N as base with bromoacetyl
bromide 10 afforded ketobromides 5 or 6, respectively, in a similar yield (ca. 70 %).
Attempts to cyclize esters 5 or 6 via formation of the corresponding zincate in THF
under reflux did not provide lactone 2. Only dehalogenated products 11 and 12, coming
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from 5 and 6 respectively, were obtained as main products in low yields (from 20 to 30
% estimated by GC-MS) together with some unreacted starting material. The use of
different methods to activate zinc metal (HCl, TMSCl, or sonication), as well as
different solvents (DCM or Toluene) or temperatures, did not make any substantial
change to the previous result.15b
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Scheme 3. Attempts of synthesis of 2 via intramolecular Blaise reaction. Reagents and conditions: a)
Et3N, DMAP, PhMe, 70 % in both cases; b) Zn, THF, reflux.
Thus, we decided to change our synthetic route to lactone 2 by using an intramolecular
cyclization of hydroxyl-ester 7 (scheme 4), which in turn, could be easily synthesized
via intermolecular Blaise reaction from readily available 3-hydroxypropane nitrile 9 and
ethyl bromoacetate 13. In our hands, keto-ester 7 was not identified in the crude mixture
following the conditions described by Uang, B.J. et al.17a (Zn activation under
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sonication), or using different Zn activators such as MeSO3H
or TMSCl
(chlorotrimethylsilane).17c Only bromo-ester 6, together with ethyl acetoacetate 15
(coming from the autocondensation of 13), were identified in the reaction mixture.
Finally, using the methodology described by Prasak et al.,18a (Zn activation with
TMSCl, followed by a combined addition of alcohol 9 and bromide 13 under reflux),
the reaction afforded a scanty 32 % yield of hydroxyester 7. Variable amounts of
starting material, lactone 2 and its corresponding ethyl enol ether 14 were also detected
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by GC-MS analysis of the crude reactions, formed by the reaction of the in situ
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generated ethanol.18b
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Scheme 4. Synthesis of 2 via intermolecular Blaise reaction. Reagents and conditions: a) Zn, THF,
TMSCl, reflux, 6 h, 32% yield.
With these results in hand, we decided to protect the hydroxyl group present in 9, which
was probably involved in promoting undesired side reactions. A series of oxygen and
silicon protecting groups were assayed (scheme 5).19a Based on the afforded yield, we
selected MOM (methoxymethyl ether) and TBDMS (tert-butyldimethylsilyl ether)
derivatives 16 and 17 respectively, as candidates for the synthesis of target lactone 2
(yields of protected alcohols and the corresponding keto-esters after chromatography
column are given in round brackets in scheme 5).
Scheme 5. Synthesis of protected ketoesters 18 and 19 via intramolecular Blaise reaction. Reagents and
conditions: a) Zn, THF, TMSCl, reflux 30 min., slow addition of 13 and corresponding cyanide, then,
reflux for 6h.
Both groups provided moderate to good yields of the desired ketoesters 18 or 19,
however, ethyl acetoacetate 15 was invariably obtained in the crude materials in
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amounts ranging from 9 to 15 % (determined by GC-MS analysis of the crude
mixtures). In order to optimize the reaction conditions and improve the yield, we
proceeded to tune some parameters thereof. We found that using 3 eq. Zn metal and
reducing the amount of solvent employed by a third, the yield was not diminished.
Additionally, a tight control of the internal temperature of the mixture between 60 to 65
ºC during the addition of the reagents until the end of the reaction (aprox. 7 h), allowed
us to improve the yield for 18 up to 98%. We estimated a purity of the crude material of
95 % based on the 1H, 13C NMR and GC-MS spectra, paving the way to the use of this
crude material for the next step without further purification. These new developed
conditions were also very successful when applied to the synthesis of silyl keto-ester 19,
giving a 94 % yield of the aforementioned ester after purification by chromatography
column.
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Following our initial synthetic retro analysis scheme, the next step of the synthesis
involved a cyclization of keto-ester 7 to lactone 2 (scheme 2), preceded by deprotection
of MOM group present in compound 18 (scheme 5). Unfortunately, the use of catalytic
amounts of p-TsOH20a or HCl20b in a protic medium (scheme 6), afforded keto-ester 7 in
low yield varying from 20 to 50 %, accompanied by different amounts of keto lactone 2,
and its corresponding ethyl enol-ether 14 (determined by GC-MS analysis of the crude
materials). The use of ZnBr2 as a Lewis acid and n-PrSH20c as a nucleophile, did not
improve the yield of 7, whereas the use of an aprotic solvent like THF in the presence of
a catalytic amount of HCl left the starting material unaffected. Finally, a low yield of 55
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% of lactone 2 was obtained by the use of H2SiF6 as an acid at 45 ºC in
acetonitrile.22a,b Although a total conversion of keto-ester 18 was achieved in the last
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mentioned conditions (determined by GC-MS analysis of the crude material), the
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instability of lactone 2 was complicating its isolation.16
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Scheme 6. Synthesis of lactone 2 via intramolecular cyclization reaction. Reagents and conditions: a)
Different conditions: i) MeOH or EtOH and HCl or p-TsOH (20 to 50 % of 7); ii) ZnBr2, n-PrSH, DCM,
rt, 50 % of 7; iii) H2SiF6, CH3CN, 45 ºC, 55 % of 2.
In order to improve the yield of the deprotection-lactonization reaction, we decided to
transform keto ester 18 in its corresponding enol tosylate 20 and enol phosphate 21
derivatives (scheme 7). According to the literature, both enol derivatives are good
candidates to introduce a suitable alkyl chain by the use of an organometallic reagent
via metal catalyzed carbon-carbon coupling reaction.23 These 3-alkyl esters 22 would
afford a more robust 4-alkyl pyran-2-one 23 after the deprotection-cyclization reaction
sequence.
Scheme 7. Retrosynthesis of 4-alkyl pyran-2-one 23
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The synthesis of keto enol tosylate 20 (scheme 8) was achieved with 90 % yield after
column chromatography using Et3N and NMI (1-methylimidazole) as bases and TsCl
under the conditions reaction developed by Nakatsuji et al.24a Enol phosphate 21 was
synthesized in a 70 % yield after column chromatography using HMDSLi (lithium
bis(trimethylsilyl)amide) as a base in the presence of ClP(O)(OEt)2.24b To our delight,
subsequent deprotection of the MOM group employing the previously assayed
conditions for keto-enol 18 using H2SiF6 acid in acetonitrile, directly afforded
phosphate enol lactone 25 with a moderate 65 % after column chromatography as an oil.
When these conditions were applied to keto enol 20,25an excellent 85 % yield of enol
lactone 24 was obtained after crystallization of the crude residue from ethyl acetate.
This result prompted us to select tosyl group to continue with our synthetic strategy.
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Scheme 8. Synthesis of enol lactones 24 and 25. Reagents and conditions: a) Et3N, NMI, TsCl, THF, 90
%; b) HMDSLi, ClP(O)(OEt)2, Et2O, 70 %; c) H2SiF6, CH3CN, 45 ºC, (65 % for 25, 85 % for 24 after
EtOAc crystallization).
The next step involved the insertion of an appropriate alkyl chain in position 4 of enol
lactone 24 via metal catalyzed carbon-carbon coupling. We choose the coupling
conditions developed by Cahiez, G. et al., using a mixture of NMP/THF as solvents and
cheap Fe(acac)3 as metal catalyst.26 a -c Methyl magnesium chloride, pentyl magnesium
bromide and isopropyl magnesium chloride, were used as carbon chain models to see
the scope of the coupling and also to optimize the reaction conditions (scheme 9). The
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best results were consistently obtained by using 0.03 eq. of Fe(acac)3 as catalyst, in the
presence of 3 equiv. of NMP. Higher amounts of NMP did not improve the yield,
whereas lower amounts of metal catalyst or absence of NMP as a co-solvent
systematically lowered the yield of the coupling reaction. Moreover, a more
reproducible yield in a multigram scale was obtained when a portion of the catalyst
dissolved in THF (0.02 equiv.) was continuously added to the reaction medium during
the Grignard reagent addition. Finally, a slightly better yield for the coupling above 80
% after column chromatography was obtained when a primary alkyl halide was
employed (85 % for methyl lactone 26 27a and 82 % for n-pentyl lactone 27), compared
to 62 % yield for 28, 27b when isopropyl magnesium chloride was used as a coupling
partner.
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Scheme 9. Synthesis of model alkyl lactones 26, 27 and 28. Reagents and conditions: a) Grignard
reagent, Fe(acac)3 (0.03 eq.), THF, NMP (3 eq), 0 ºC. (85 % for 26, 85 % for 27, 62 % for 28).
Synthesis of alkyl lactone 3 (scheme 10) was achieved applying the previously carbon-
carbon coupling developed conditions to tosyl enolate 24, using a Grignard derivative of
bromide 29. The former was synthesized in two steps starting from readily available 2-
acetyl butyrolactone after HBr treatment, followed by ketal formation under standard
conditions.28 The iron catalyzed coupling reaction delivered alkyl lactone 3 in an
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acceptable 70 % yield after column cromatography. Ketal deprotection of 3 using
acetone and a catalytic amount of p-TsOH afforded compound 30 in 80 % yield.29
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Scheme 10. Synthesis of alkyl lactone 30. Reagents and conditions: a) Mg, Fe(acac)3 (0.03 eq), THF,
NMP (3 eq), 0 ºC; b) Acetone, p-TsOH cat.
Having developed an efficient route to achieve alkyl lactone 3 in a multigram scale, the
construction of the 1,1,2 substituted cyclobutane moiety present in the target sex
pheromone, as well as in the related aggregation pheromone Grandisol,8a was the next
step in our synthetic strategy. Its synthesis has being attempted by the use of a
nucleophilic substitution reaction.30 However, the use of a photochemical [2 + 2]
cycloaddition using ethylene31 as a partner is, by far, the most preferred method.32 Thus,
we decided to set up the photoreaction parameters by irradiating a solution of alkyl
lactone 30 in DCM, CH3CN or Me2CO as solvents, using a quartz photo reactor system
equipped with a medium pressure immersion Hg lamp, a cooling system and a gas inlet.
We founded that using a mixture 85:15 DMC:Me2CO as solvent and photoinitiator
respectively, compound 4 (scheme 11) was obtained from a,b-unsaturated lactone 30
with a moderate 63 % yield after chromatography column.
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Scheme 11. Synthesis of bicyclic lactone 4. Reagents and conditions: a) DCM:Acetone 85:15, ethylene
(1.5 atm), hv (Hg lamp, 254 nm), 8h.
As previously described in the literature for related photocycloaddition reactions, cis
stereochemistry was obtained for cyclobutane 4 (figure 2). This stereochemistry was
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confirmed with a detailed analyis of the H NMR , COSY and NOESY spectra of this
compound. Particularly, the NOESY spectra shows a clear NOE effect between H-1
and H-8a and H-1’a, confirming the cis orientation of substituents placed at bridgehead
carbons C-1 and C-6 of bicyclic compound 4.
Figure 2. NOE effect observed in compound 4.
Prior to continue with the lactone opening reaction with MeLi, a methylenation of
carbonyl in compound 4 was mandatory. The first attempts to carry out this reaction
under standard Wittig conditions reaction using 5 eq. of the ylide and 0 ºC,
unexpectedly afforded an approximately 1:1 mixture of the desired product 31 and
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hemiketal 33 (scheme 12).33a-c The formation of product 33 could be rationalized by a
double methylenation of 4 followed by a hydrolysis of the intermediate enol ether 32
and concomitant intramolecular ketal formation during the work-up process. 34
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Scheme 12. Methylenation of keto lactone 4. Reagents and conditions: a) Ph3P+CH3Br- , BuLi, THF, 0 ºC.
When the amount of the ylide was reduced to 1.25 eq and the reaction was carried out at
-78 ºC, we were able to avoid the formation of ketal 33, but a poor 40 % yield was
obtained for lactone 31.35
These last results led us to reconsider the original synthetic sequence by introducing the
cyclobutane ring moiety in lactone 3, prior to ketal deprotection (scheme 13). Thus,
opening of the lactone moiety with Meli, followed by acetylation of the alcohol would
afford diketo acetate 35 which in turn, after double methylenation would give access to
sex pheromone 1.
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Scheme 13. Retrosynthetic strategy of 1 starting from 3
The photoreaction conditions developed for compound 4 using ethylene as a
[2+2] partner where applied to ketal lactone 3 (scheme 14). The reaction afforded ketal
cyclobutane 34 with a moderate 62 % yield after column chromatography.36 Treatment
of compound 34 with an equimolecular amount of MeLi at -78 ºC and subsequent
treatment of the crude material with Ac2O and Et3N in DCM afforded acetate 36 in 85
% yield after column chromatography.37 Finally, simple deprotection of the ketal
moiety in acetone produced compound 35 with 95 % yield. When the last two steps
were reproduced in the lab into a multigram scale without purifiying any of the
intermediate crude materials,38 diketo acetate 35 was obtained in a 62 % overall yield.
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Scheme 14. Synthesis of diketo cyclobutane 35. Reagents and conditions: a) DCM:Acetone 85:15,
ethylene (1.5 atm), hv (Hg lamp, 254 nm), 8h; b) MeLi, THF, -78 ºC; then Ac2O, Et3N, DCM; c)
Acetone, HCl (1M) cat., r.t.
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Double Lombardo methylenation of compound 35 (scheme 15) was initially
attempted,39 but a low 40 % yield of 1 was achieved, recovering about 10 % of starting
material. Finally, double methylenation of compound 35 employing 1.75 eq of the
corresponding ylide per carbonyl group in THF, using n-BuLi as base and THF as
solvent, afforded compound 1 in a moderate 65 % yield together with a 15 % amount of
alcohol 37. The last alcohol could be easily re-acetylated to achieve A. nerii sex
pheromone 1 in a 80 % yield overall from di keto compound 35.
Scheme 15. Synthesis of A. nerii sex pheromone 1. Reagents and conditions: a) Ph3P+CH3Br- (3.5 eq),
BuLi, THF, 0 ºC.
CONCLUSIONS
In conclusion, we have accomplished a multigram-scale total synthesis of A. Nerii sex
pheromone 1. The synthesis, featuring a Blaise reaction and a carbon-carbon iron
catalyzed coupling of a diketo ester, also provides a general and robust access to 4-alkyl
a,b-unsaturated esters or lactones starting with inexpensive and available materials in
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five linear synthetic steps with virtually no purification steps in a 45 % overall yield.
Finally, the access to the sex pheromone has been accomplished in nine steps using a
[2+2] photocycloaddition reaction to introduce the cyclobutane moiety, opening of the
lactone ring and minimum functional group manipulation. A multigram synthesis scaled
up in our lab afforded 1 in a 10 % overall yield, allowing us to have enough material to
further check the biological activity of this pheromone in real field conditions.
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EXPERIMENTAL SECTION
General Information. All reactions were carried out under a nitrogen atmosphere with
dry solvents under anhydrous conditions, unless otherwise noted. Solvents were dried
under standard procedures. All purchased chemicals were used without further
purification. Organometallics reagent solutions were titrated before using with an
appropiate method (for organomagnesium reagents see: Krasovskiy, A., Knochel, P.
Synthesis, 2006, 0890-0891; for organolithium reagents see: Kofron, W. G., &
Baclawski, L. M. J. Org. Chem., 1976, 41, 1879-1880). Silica gel 60 F254 TLC plates
were used for analytical thin layer chromatography technique. Plates were visualized by
using a UV lamp or using an appropriate stainer (p-anisaldehyde in ethanol/aqueous
H2SO4/CH3CO2H or 10 % solution of phosphomolibdic acid in ethanol and heat as
developing agents). Chemical shifts were reported as parts per million (δ) relative to the
signal of CHCl3 at 7.26 ppm for 1H NMR, and center line signal of the CDCl3 triplet at
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77 ppm for C {1H} NMR. H NMR spectra and C NMR spectra were recorded at
300 MHz at 75 MHz respectively. Chemical shifts are reported in parts per million
using the following peak pattern abbreviations: br, broad; s, singlet; d, doublet; dd,
double doublet; ddd, doublet of doublet of doublets; t, triplet; dt, double triplet; q,
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quartet; pent, pentet; sext, sextet; m, multiplet. High resolution mass spectra (ESI-
HRMS) were measured on a Waters Xevo Q-TOF spectrometer (Waters Corp., Milford,
MA, USA) coupled with an Acquity UPLC-PDA system (Waters) using ionization by
electrospray (ESI). The ESI source operated in positive ionization mode using leucine-
enkephalin as the reference mass ([M+H]+ ion m/z 556.2771).
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4-Hydroxy-5,6-dihydro-2H-pyran-2-one, 2: Hexafluorosilicic acid (0.35 mL, 35%,
1.4 mmol) was added using a plastic syringe to a solution of keto-ester 18 (900 mg, 4.4
mmol) in CH3CN (10 mL) placed in a polypropylene plastic tube. The reaction mixture
was stirred at 45 °C for 3 h and cooled to room temperature, and then dried over
MgSO4, filtered and concentrated under reduced pressure. The crude material was
purified by flash column chromatography (silica gel, 50% AcOEt/hexane) to give 275
mg of 2 (55%) as a colorless liquid. Spectroscopical data are in full agreement with
those previously reported. 16b
4-(3-(2-Methyl-1,3-dioxolan-2-yl)propyl)-5,6-dihydro-2H-pyran-2-one 3. To
a
vigorously stirred suspension of magnesium turnings (1 g, 42 mmol) and of Iodine (30
mg, 0.12 mmol) in anhydrous THF (18 mL), a solution of bromide 29 (1 M, 29 mL, 29
mmol) in THF was dropwise added over a period of 2h, during which the internal
temperature of the mixture was kept at 45 ºC. After this time, the reaction was cooled
down to room temperature and an aliquot was titrated with iodine. The resultant
solution was dropwise added in parallel with a solution of Fe(acac)3 in THF (0,2 M, 149
mg, 0.38 mmol) to a mixture of enol tosylate 24 (5 g, 18.5 mmol), Fe(acac)3 (74.5 mg,
0.19 mmol) and anhydrous NMP (5.6 ml, 57 mmol) in anhydrous THF (10 mL) at 0 ºC.
The reaction was stirred at this temperature for 60 min, quenched with saturated
aqueous NH4Cl (20 mL), poured over H2O (20 ml) and extracted with EtOAc (3 x 60
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mL). The combined organic layers were washed with brine (3 X 15ml), dried over
MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 50% EtOAc/hexane) afforded 3 (3 g, 70%) as
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a yellow liquid. H NMR (CDCl3, 300 MHz) δ: 5.82 (s, 1H), 4.37 (t, J = 6.2 Hz, 2H),
3.99–3.87 (m, 4H), 2.37 (t, J= 6.2 Hz, 2H), 2.27 (t, J= 6.3 Hz, 2H), 1.71–1.53 (m, 4H),
1.31 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 164.8, 161.3, 116.1, 109.7, 66.1, 64.9
(2C), 38.6, 36.7, 28.0, 23.9, 20.9. MS (EI) m/z (%): 211 (M+-15, 5), 99 (15), 87 (100),
55 (12), 43 (47). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H19O4 227.1278; found
227.1278.
6-(4-Oxopentyl)-2-oxo-3-oxabicyclo[4.2.0]octane 4. A solution of lactone 30 (910 mg,
5 mmol) in 15% Acetone/CH2Cl2 (100 mL) was placed in a quartz container connected
to an inlet of ethylene and this mixture was purged with ethylene for 15 min at -20 °C.
The reaction mixture was internally irradiated (254 nm) at room temperature using a
125 W medium pressure Hg lamp as the light source (a constant pressure of ethylene of
1.2 atm was kept along the irradiation period). The reaction was monitored by TLC on
silica gel and GC-MS. After the solvent mixture was evaporated under reduced
pressure, the residue was purified by flash column chromatography (silica gel, 50
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EtOAc/hexane) to give photoadduct 4 (651 mg, 62 %) as a yellow oil. H NMR
(CDCl3, 300 MHz) δ: 4.57 (ddd, J= 11.7, 9.1, 3.6 Hz, 1H), 4.40 (ddd, J= 11.7, 4.8, 4.2
Hz, 1H), 2.91-2.79 (m, 1H), 2.48-2.36 (m, 3H), 2.12 (s, 3H), 2.09-1.95 (m, 2H), 1.92-
13
1.80 (m, 1H), 1.78-1.62 (m, 2H), 1.54-1.42 (m, 4H). C{1H} NMR (CDCl3, 75 MHz)
δ: 208.4, 173.9, 66.3, 43.6, 41.7, 40.8, 39.7, 32.4, 30.2, 28.4, 19.7, 16.7. MS (EI) m/z
(%): 210 (M+, 3), 182 (3), 125 (56), 95 (20), 79 (31), 55 (48), 43 (100). HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C12H19O3 211.1329; found 211.1324.
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Methyl 3-(2-bromoacetoxy)propanoate 5: Et3N (1.5 mL, 10.6 mmol) and imidazole
(0.72 g, 10.6 mmol) were added to a solution of hydroxy ester 8 (1 g, 9.6 mmol) in
anhydrous CH2Cl2 (30 mL). The solution was cooled to 0ºC and bromoacetyl bromide
10 (0.85 mL, 9.6 mmol) was added dropwise. The reaction was warmed up to room
temperature and stirred for 5h. After this period the reaction was diluted with CH2Cl2
(15 mL) and washed with 0.5 N HCl solution (2 x 15 mL) and brine (20 mL). The
organic layer was dried over MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by flash column chromatography (silica gel, 30%
EtOAc/hexane) to give 1.5 g of 5 (70%) as a light-yellow liquid. 1H NMR (CDCl3, 300
MHz) δ: 4.43 (t, J= 6.3 Hz, 2H), 3.81 (s, 2H), 3.70 (s, 3H), 2.68 (t, J= 6.3 Hz, 2H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 170.8, 167.1, 61.6, 52.1, 33.5, 25.6. MS (EI) m/z
(%):194 (M+-29, 4), 123 (17), 121 (17), 103 (19), 93 (13), 87 (59), 59 (62), 55 (100), 42
(54). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C6H10BrO4 224.9757; found 224.9748
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2-Cyanoethyl 2-bromoacetate 6: Et3N (1.6 mL, 11.8 mmol) was added to a solution of
bromoacetyl bromide 10 (2.4 g, 1 mL, 11.8 mmol) in toluene (9.5 mL) and then, 3-
hydroxypropanenitrile (0.7 mL, 9.9 mmol) was slowly added with stirring. The reaction
mixture was heated to reflux for 2 h. After this period, the reaction mixture was cooled
down to room temperature, diluted with EtOAc (20 mL) and washed with saturated
aqueous NaHCO3 solution (2 x 15 mL), water (15 mL) and brine (10 mL). The organic
layer was dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel, 20%
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EtOAc/hexane) gave bromo ester 6 (1.9 g, 72%) as a yellow liquid. H NMR (300
MHz, CDCl3) δ: 4.37 (t, J= 6.3 Hz, 2H), 3.87 (s, 2H), 2.74 (t, J= 6.3 Hz, 2H). 13C{1H}
NMR (75 MHz, CDCl3) δ: 166.9, 116.4, 60.3, 25.1, 17.9. MS (EI) m/z (%): 175 (M+-
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15, 1), 173 (1), 153 (4), 151 (4), 123 (33), 121 (33), 95 (29), 93 (31), 68 (16), 54 (100),
42 (48), 41 (38). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C5H7BrNO2 191.9655;
found 191.9661
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Ethyl 5-hydroxy-3-oxopentanoate 7. TMSCl (0.13 mL, 0.4 mmol) dissolved in
anhydrous THF (0.3 mL) was added to a suspension of zinc dust (4.6 g, 70.4 mmol) in
anhydrous THF (22 mL), and the resulting mixture was refluxed for 25 min. To this
refluxing slurry of activated zinc, 3-hydroxypropanenitrile 9 (1 g, 14.1 mmol) in 5 mL
THF and ethyl bromoacetate 13 (3 mL g, 27.8 mmol) in 5 mL THF were added in
parallel. The color of the reaction mixture changed from colorless to dark green, which
turned finally to brown with time progression. The reaction mixture was stirred at reflux
for 6h and after this period was allowed to cool at room temperature. The organic layer
was filtered, and the pH was adjusted to 4 using 20% aqueous citric acid. THF was
removed under reduced pressure and the resulting mixture was diluted with 80 mL
CH2Cl2 and washed with water (2 x 20 mL) and with brine (2 x 20 mL). The resultant
organic layer was dried over MgSO4, filtered and the solvent was rotary evaporated to
get the crude product which was purified by flash column chromatography using 50%
EtOAc/hexane to give 722 mg of 7 (32%) as a yellow liquid. 1H NMR (CDCl3, 300 Hz)
δ: 4.2 (q, 2H), 3.87 (brs, 2H), 3.48 (s, 2H), 2.81 (t, J=5.4 Hz, 2H), 1.28 (t, J= 7.1 Hz,
2H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 203.5, 167.1, 61.7, 57.7, 49.8, 45.1, 14.2. MS
(IE) m/z (%): 160 (M+, 1), 159 (8), 143 (6), 115 (8), 113 (7), 98 (6), 87 (10), 71 (5), 69
(5), 55 (23), 45 (100). HRMS (ESI-TOF) m/z: [M-H]- Calcd for C7H11O4 159.0657;
found 159.0656.
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3-(Methoxymethoxy)propanenitrile 16: LiBr (12 g, 0.14 mol) and p-toluensulfonic
acid (p-TsOH) (11.7 g, 0.07 mol) were added to a solution of hydroxy nitrile 9 (70 g,
0.7 mol) in dimethoxymethane (735 mL, 8.3 mol) at 35 ºC. After continous stirring for
12 h at the same temperature, the reaction was quenched with brine (500 mL) and
extracted with EtOAc (2 X 350 mL). The organic layer was successively washed with
sat. NaHCO3 (2 X 150 ml), brine (150 ml), dried over MgSO4, filtered and concentrated
under reduced pressure to give 86 g of 16 (85%) as a colorless liquid. 1H-NMR (CDCl3,
300 MHz) δ: 4.67 (s, 2H), 3.75 (t, J= 7.6 Hz, 2H), 3.39 (s, 3H), 2.63 (t, J= 7.6 Hz, 2H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 117.7, 96.5, 62.3, 55.6, 19.1. MS (IE) m/z (%): 115
(M+, 1), 85 (14), 75 (7), 61 (20), 54 (98), 45 (100). Spectroscopical data are in full
agreement with those previously reported.19 b
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3-((tert-Butyldimethylsilyl)oxy)propanenitrile 17. Alcohol 9 (2.5 g, 35.2 mmol) and
imidazole (4.8 g, 70.4 mmol) were dissolved in anhydrous CH2Cl2 (80 mL) and
TBDMSCl (6.4 g, 42.2 mmol) in CH2Cl2 (20 mL) was slowly added. The reaction
mixture was stirred at room temperature overnight, quenched with saturated aqueous
NH4Cl (10 mL) and diluted with CH2Cl2 (25 mL). The organic layer was successively
washed with HCl (1M, 2 x 25 ml), NaHCO3 sat. (2 x 25ml), brine (20 ml), dried over
MgSO4, filtered and concentrated under reduced pressure. The crude product was
purified by flash column chromatography (silica gel, 5% EtOAc/hexane) to give 6.1 g
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of 17 (94%) as a colorless oil. H NMR (CDCl3, 300 MHz) δ: 3.84 (t, J=6.3 Hz, 2H),
2.54 (t, J=6.3 Hz, 2H), 0.91 (s, 9H), 0.09 (s, 6H). MS (EI) m/z (%): 185 (M+, 1), 170
(9), 143 (8), 128 (84), 98 (100), 89 (15), 73 (46), 58 (40), 43 (43), 41 (55).
Spectroscopical data are in full agreement with those previously reported. 19 c
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Ethyl 5-(methoxymethoxy)-3-oxopentanoate 18. TMSCl (1.7 mL, 5.2 mmol) was
added to a suspension of zinc dust (76.1 g, 1.1 mol) in anhydrous THF (320 mL). The
resulting mixture was refluxed for 25 min and then allowed to cool down up to 60 °C. A
solution of MOM protected 3-(methoxymethoxy)propanenitrile 16 (45 g, 0.39 mol) and
ethyl bromoacetate 13 (86 mL g, 0.78 mol) in anhydrous THF (80 mL) was added to
this suspension over a period of 3 h, using an addition funnel. During this period, the
internal reaction temperature was kept between 60-65 °C, and the color of the reaction
mixture changed first to dark green, and finally turned to brown by the end of the
addition. After stirring at 65 °C for 6 h, the reaction mixture was allowed to cool at
room temperature, filtered, and the pH was adjusted to 4 using 20% m/m aqueous citric
acid. THF was removed under reduced pressure and the resulting mixture was extracted
with CH2Cl2 (3 x 150 mL). The combined organic phases were successively washed
with brine (2 X 150 mL), dried over MgSO4, filtered and concentrated under reduced
pressure, to give β-ketoester 18 (78 g, 98%) as a yellow liquid, which was used in the
next reaction without further purification. 1H NMR (CDCl3, 300 MHz) δ: 4.60 (s, 2H),
4.19 (c, J= 7.1 Hz, 2H), 3.81 (t, J= 6.1 Hz, 2H), 3.49 (s, 2H), 3.35 (s, 3H), 2.82 (t, J=
6.1 Hz, 2H), 1.27 (t, J= 7.1 Hz, 2H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 201.2, 167.0,
96.7, 62.5, 61.5, 55.4, 49.9, 43, 14.2. MS (EI) m/z (%):204 (M+, 1), 188 (1), 172 (2),
158 (4), 143 (28), 128 (15), 114 (9), 96 (35), 83 (8), 69 (38), 54 (19), 435 (100). HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C9H17O5 205.1071; found 205.1062.
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Ethyl 5-((tert-butyldimethylsilyl)oxy)-3-oxopentanoate 19. TMSCl (0.15 mL, 0.48
mmol) was added to a suspension of zinc dust (6.9 g, 0.1 mol) in anhydrous THF (30
mL). The resulting mixture was refluxed for 25 min and then allowed to cool down up
to 60 °C. A solution of TBDMS protected 3-hydroxypropanenitrile 17 (6.6 g, 0.04 mol)
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and ethyl bromoacetate 13 (7.8 mL g, 0.09 mol) in anhydrous THF (8 mL) was added to
this suspension over a period of 3 h, using a syringe pump. During this period, the
internal reaction temperature was kept between 60-65 °C. Along the addition, the color
of the reaction mixture changed first to dark green, and finally turned to brown. After
stirring at 65 °C for 6 h, the reaction mixture was allowed to cool at room temperature,
filtered, and the pH was adjusted to 4 with a 20% m/m aqueous citric acid solution.
THF was removed under reduced pressure and the resulting mixture was extracted with
CH2Cl2 (3 x 40 mL). The combined organic phases were successively washed with
brine (2 X 20 mL), dried over MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by flash column chromatography (silica gel, 20%
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EtOAc/hexane) to give to give β-ketoester 19 (9.3 g, 94%) as a yellow oil. H NMR
(CDCl3, 300 MHz) δ: 4.19 (c, J= 7.1 Hz, 2H), 3.90 (t, J= 6.2 Hz, 2H), 3.49 (s, 2H), 2.72
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(t, J= 6.2 Hz, 2H), 1.28 (t, J= 7.1 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H). C{1H} NMR
(CDCl3, 75 MHz) δ: 202.1, 167.2, 61.4, 58.8, 50.3, 45.9, 25.9 (3C), 18.3, 14.2, –5.40.
MS (EI) m/z (%): 274 (M+, 1), 228 (12), 216 (65), 188 (12), 170 (98), 128 (16), 96
(33), 75 (100), 57 (17), 41 (32). Spectroscopical data are in full agreement with those
previously reported.19 d
Ethyl (E)-5-(methoxymethoxy)-3-(tosyloxy)pent-2-enoate 20. Et3N (73.5 mL, 0.51
mol) and NMI (42 mL, 0.51 mol) were added to a solution of β-ketoester 18 (70 g, 0.34
mol) in anhydrous THF (980 mL). The resultant solution was stirred at room
temperature for 30 min and p-toluenesulfonyl chloride (TsCl) (98 g, 0.51 mol) was
added in portions. After 5 h, one third of the solvent was removed under reduced
pressure and water (500 mL) was added. The resulting mixture was extracted with
EtOAc (3 x 400 mL). The combined organic layers were successively washed with 1 M
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HCl solution (200 mL), brine (200 mL), dried over MgSO4, filtered and concentrated
under reduced pressure to give 125 g of crude material. 4 g of this crude material was
purified by flash column chromatography (silica gel, 30% EtOAc/hexane) to give 3.5 g
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of 20 (90%) as a yellow oil. H NMR (CDCl3, 300 MHz) δ: 7.82 (d, J= 8.1 Hz, 2H),
7.36 (d, J= 8.1 Hz, 2H), 5.84 (s, 1H), 4.53 (s, 2H), 4.14 (c, J= 7.1 Hz, 2H), 3.63 (t, J=
6.5 Hz, 2H), 3.29 (s, 3H), 3.02 (t, J= 6.5 Hz, 2H), 2.46 (s, 3H), 1.25 (t, J= 7.1 Hz, 3H).
13C{1H} NMR (CDCl3, 75 MHz) δ: 165.2, 162.6, 145.9, 133.0, 130.1 (2C), 128.4 (2C),
111.8, 96.3, 63.7, 60.7, 55.3, 32.2, 21.8, 14.2. MS (EI) m/z (%): 341 (M+-17, 1), 327
(7), 313 (1), 173 (8), 155 (21), 142 (9), 115 (7), 91 (58), 65 (16), 55 (13), 45 (100).
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H23O7S 359.1159; found 359.1156.
Ethyl (Z)-3-((diethoxyphosphoryl)oxy)-5-(methoxymethoxy)pent-2-enoate 21. A
solution of 1 M LiHMDS in THF (11.3 mL, 11.3 mmol) was added to an ice-cooled
solution of β-ketoester 18 (2 g, 9.8 mmol) in anhydrous THF (25 mL). After 20 min,
(EtO)2POCl (2 mL, 14 mmol) was slowly added and the resulting solution was stirred at
room temperature for 4 h. The reaction was quenched with saturated aqueous NH4Cl (10
mL), poured in water (30 ml) and extracted with Et2O (3 x 20 mL). The combined
organic layers were washed with brine (35 mL), dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was purified by flash column
chromatography (silica gel, 50% EtOAc/hexane) to give 2.3 g of 21 (70%) as a yellow
liquid. 1H NMR (CDCl3, 300 MHz) δ: 5.93 (d, J= 3.0 Hz, 1H), 4.61 (s, 2H), 4.22–4.14
(m, 6H), 3.75 (t, J= 6.7 Hz, 2H), 3.35 (s, 3H), 3.13 (t, J= 6.7 Hz, 2H), 1.37 (m, 6H),
1.26 (t, J= 7.1 Hz, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 165.9, 163.3 (d, 2JP,C= 9.2
3
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Hz), 106.9 (d, JP,C= 3.0 Hz), 96.2, 64.9 (d, JP,C= 6.2 Hz, 2C), 64.1 (2C), 60.2, 55.2,
32.3 (d, 3JP,C= 6.0 Hz), 16.1 (d, 3JP,C= 6.8Hz, 2C), 14.2. MS (EI) m/z (%): 310 (M+-30,
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3), 295 (10), 278 (11), 249 (13), 206 (10), 155 (65), 141 (18), 127 (51), 113 (25), 99
(67), 81 (31), 69 (19), 55 (17), 45 (100). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C13H26O8P 341.1360; found 341.1357.
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6-Oxo-3,6-dihydro-2H-pyran-4-yl 4-methylbenzenesulfonate 24. Hexafluorosilicic
acid (8 mL, 35%, 34 mmol) was added using a plastic syringe to a solution of crude
ester 20 (40 g, 112 mmol) in CH3CN (225 mL) placed in a polypropylene plastic bottle.
The reaction mixture was stirred at 45 °C for 3 h and cooled to room temperature, and
then dried over MgSO4, filtered and concentrated under reduced pressure. The residue
(41 g) was recrystallized from hot AcOEt (45 ml) to afford lactone 24 (25.5 g, 85%) as
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light brown crystals (m.p.: 69-70 °C). H NMR (CDCl3, 300 MHz) δ: 7.82 (d, J= 8.3
Hz, 2H), 7.39 (d, J= 8.2 Hz, 2H), 5.75 (s, 1H), 4.34 (t, J= 6.3 Hz, 2H), 2.59 (t, J= 6.3
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Hz, 2H), 2.46 (s, 3H). C{1H} NMR (CDCl3, 75 MHz) δ: 164.2, 162.9, 146.8, 131.9,
130.4 (2C), 128.4 (2C), 106.7, 64.7, 27.4, 21.9. MS (EI) m/z (%): 268 (M+, 1), 155
(46), 91 (100), 65 (28), 41 (9). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H13O5S
269.0478; found 269.0479.
Diethyl (6-oxo-3,6-dihydro-2H-pyran-4-yl) phosphate 25. Hexafluorosilicic acid (0.4
mL, 35%, 2 mmol) was added using a plastic syringe to a solution of ester 25 (2 g, 7.3
mmol) in CH3CN (25 mL) placed in a polypropylene plastic tube. The reaction mixture
was stirred at 45 °C for 3 h and then cooled to room temperature, dried over MgSO4,
filtered and concentrated under reduced pressure. The crude material was purified by
flash column chromatography (silica gel, 50% AcOEt/hexane) to give 960 mg of 2
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(65%) as a liquid. H NMR (CDCl3, 300 MHz) δ: 5.83 (d, J= 0.9 Hz, 1H), 4.41 (t, J=
6.4 Hz, 2H), 4.30-4.17 (m, 4H), 2.70 (t, J= 6.4 Hz, 2H), 1.39 (td, J= 7.1, 1.0 Hz, 6H).
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13C{1H} NMR (CDCl3, 75 MHz) δ: 165.1, 164, 103.7 (d, 3JP,C= 9.2 Hz), 65.5 (d, 2JP,C=
6.1 Hz, 2C), 64.4, 27.6 (d, 3JP,C= 6.0 Hz), 16.2 (d, 3JP,C= 6.5 Hz, 2C). MS (EI) m/z (%):
250 (M+, 12), 204 (22), 176 (38), 155 (45), 127 (52), 99 (100), 81 (52), 66 (47), 52 (26),
42 (22). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C9H16O6P 251.0679; found
251.0670.
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General procedure for preparation of 4-alkyl-pyran-2-ones 26, 27 and 28: Fe(acac)3
dissolved in anhydrous THF and anhydrous NMP were added to a solution of enol
tosylate 24 in anhydrous THF. The reaction mixture was cooled down to 0 °C with
vigorous stirring and a solution of Grignard reagent was added dropwise. The mixture
was stirred at this temperature for 30-60 min, quenched with saturated aqueous NH4Cl
and extracted with EtOAc. The combined organic layers were washed with brine, dried
over MgSO4, filtered and concentrated under reduced pressure. The crude product was
purified by flash column chromatography (silica gel, 20-50% EtOAc/hexane).
4-methyl-5,6-dihydro-2H-pyran-2-one 26. Lactone 26 was prepared according to the
above general procedure using tosylate 24 (1 g, 3.7 mmol), THF (4 mL), 3 M
methylmagnesium chloride solution in THF (1.2 mL), Fe(acac)3 (39.2 mg, 0.1 mmol),
NMP (1.1 mL, 11.1 mmol), NH4Cl (4 mL), EtOAc (3 X 15 mL), brine (2 X 10 mL).
Purification of the crude residue by flash column chromatography (silica gel, 20%
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EtOAc/hexane) gave 354 mg of 26 (85% yield) as a light-yellow liquid. H NMR
(CDCl3, 300 MHz) δ: 5.82 (s, 1H), 4.37 (t, J= 6.3 Hz, 2H), 2.37 (t, J= 6.3 Hz, 2H), 2.0
(s, 3H). MS (EI) m/z (%): 112 (M+, 41), 82 (100), 67 (14), 54 (53), 44 (28), 41 (20).
Spectroscopical data are in full agreement with those previously reported.13
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4-pentyl-5,6-dihydro-2H-pyran-2-one 27. This lactone was prepared from according
to the above general procedure: using tosylate 24 (1 g, 3.7 mmol), THF (3.8 mL),
freshly prepared 0.7 M pentylmagnesium bromide solution in THF (5.3 mL), Fe(acac)3
(39.2 mg, 0.1 mmol), NMP (1.1 mL, 11.1 mmol), NH4Cl (4 mL), EtOAc (3 X 15 mL),
brine (2 X 10 mL).. Purification of both residues by flash column chromatography
(silica gel, 30-40% EtOAc/hexane) gave 514 mg (82% yield) of lactone 28 as a light-
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yellow liquid. H NMR (CDCl3, 300 MHz) δ: 5.79 (t, J= 1.4 Hz, 1H), 4.36 (t, J= 6.2
Hz, 2H), 2.36 (t, J= 6.3 Hz, 2H), 2.24 (t, J= 7.6 Hz, 2H), 1.60-1.43 (m, 2H), 1.39-1.25
(m, 4H), 0.9 (t, J= 6.6 Hz, 3H). 13C{1H} NMR (CDCl3, 75 MHz) δ: 164.7, 160.6,
117.1, 66.0, 43.7, 32.53, 29.9, 28.0, 22.5, 14. MS (EI) m/z (%): 153 (M+-15, 7), 140
(10), 125 (4), 110 (3), 95 (6), 82 (17), 67 (8), 55 (10), 45 (100). HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C10H17O2 169.1223; found 169.1221.
4-isopropyl-5,6-dihydro-2H-pyran-2-one 28. This lactone was prepared according to
the above general procedure using tosylate 24 (1 g, 3.7 mmol), THF (4 mmol) 2 M
isopropylmagnesium chloride solution in THF (1.9 mL), Fe(acac)3 (39.2 mg, 0.1 mmol),
NMP (1.1 mL, 11.1 mmol), NH4Cl (4 mL), EtOAc (3 X 15 mL), brine (2 X 10 mL).
Purification of the crude residue by flash column chromatography (silica gel, 30%
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EtOAc/hexane) gave 323 mg (62% yield) of lactone 28 as a colorless liquid. H NMR
(CDCl3, 300 MHz) δ: 5.8 (s, 1H), 4.35 (t, J= 6.5 Hz, 2H), 2.45 (m, 1H), 2.38 (t, J= 6.5
Hz, 2H), 1.10 (d, J= 6 Hz, 6H). MS (EI) m/z (%):140 (M+, 10), 125 (5), 110 (12), 95
(83), 81 (100), 67 (85), 53 (28), 41 (78). Spectroscopical data are in full agreement with
those previously reported.27 b
4-(4-oxopentyl)-5,6-dihydro-2H-pyran-2-one 30. A 1 N HCl solution (3 mL) was
added to a solution of lactone 3 (1 g, 4.4 mmol) in acetone (7 mL) and the resultant
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solution was stirred at room temperature for 1 h. The reaction was neutralized to pH=8
with saturated aqueous NaHCO3 solution, and the mixture was extracted with EtOAc
(20 mL). The organic layer was dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash column chromatography
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(silica gel, 50% EtOAc/hexane) to give 640 mg of 30 (80%) as a yellow oil. H NMR
(CDCl3, 300 MHz) δ: 5.79 (s, 1H), 4.36 (t, J= 6.2 Hz, 2H), 2.48 (t, J = 6.2 Hz, 2H), 2.37
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(CDCl3, 75 MHz) δ: 207.8, 164.6, 161.0, 115.7, 65.9, 42.2, 35.6, 29.9, 27.6, 19.9. MS
(EI) m/z (%): 182 (M+, 3), 164 (3), 125 (70), 112 (14), 79 (20), 58 (24), 43 (100).
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H15O3 ([M+H]+) 183.1016; found
183.1011.
6-(4-Methylpent-4-en-1-yl)-3-oxabicyclo[4.2.0]octan-2-one 31 and 2-methyl-6-(4-
methylpent-4-en-1-yl)-3-oxabicyclo[4.2.0]octan-2-ol 33. n-Butyllithium in hexane
(2.5 M, 6.8 mL) was slowly added over a suspension of methyltriphenylphosphonium
bromide (6.0 g, 17 mmol) in anhydrous THF (30 mL) at -78 °C. The resultant mixture
was stirred for 30 min and the temperature was raised up to - 20 ºC. The solution was
cooled again to -78°C and a solution of lactone 4 (693 mg, 3.3 mmol) in anhydrous
THF (10 mL) was slowly added, and the resultant mixture was allowed to warm to
room temperature and stirred for additional 30 min. The reaction was quenched with
saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (2 x 35 mL). The
combined organic layers were washed with saturated brine (2 X 20 mL), dried over
MgSO4, filtered and concentrated under reduced pressure. The crude residue was
purified by flash column chromatography (silica gel, 5-25% EtOAc/hexane) to give 206
mg (30 %) of lactone 31 as a yellow oil along with 199 mg (37 %) of hemiketal 33 as a
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