Synthetic approaches to mono- and bicyclic perortho-esters with a central 1,2,4-trioxane ring as the privileged lead structure in antimalarial and antitumor-active peroxides and clarification of the peroxide relevance

Article abstract of DOI:10.3390/molecules22010119

The synthesis of 4-styryl-substituted 2,3,8-trioxabicyclo[3.3.1]nonanes, peroxides with the core structure of the bioactive 1,2,4-trioxane ring, was conducted by a multistep route starting from the aryl methyl ketones 1a-1c. Condensation and reduction/oxidation delivered enals 4a-4c that were coupled with ethyl acetate and reduced to the 1,3-diol substrates 6a-6c. Highly diastereoselective photooxygenation delivered the hydroperoxides 7a-7c and subsequent PPTS (pyridinium-p-toluenesulfonic acid)-catalyzed peroxyacetalization with alkyl triorthoacetates gave the cyclic peroxides 8a-8e. These compounds in general show only moderate antimalarial activities. In order to extend the repertoire of cyclic peroxide structure, we aimed for the synthesis of spiro-perorthocarbonates from orthoester condensation of β-hydroxy hydroperoxide 9 but could only realize the monocyclic perorthocarbonate 10. That the central peroxide moiety is the key structural motif in anticancer active GST (glutathione S-transferase)-inhibitors was elucidated by the synthesis of a 1,3-dioxane 15-with a similar substitution pattern as the pharmacologically active peroxide 11-via a singlet oxygen ene route from the homoallylic alcohol 12.

Full text of DOI:10.3390/molecules22010119

molecules
Article
Synthetic Approaches to Mono- and Bicyclic
Perortho-Esters with a Central 1,2,4-Trioxane Ring as
the Privileged Lead Structure in Antimalarial and
Antitumor-Active Peroxides and Clarification of the
Peroxide Relevance
Axel G. Griesbeck *, Maria Bräutigam, Margarethe Kleczka and Angela Raabe
Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany;
marialisa.braeutigam@googlemail.com (M.B.); m.kleczka@uni-koeln.de (M.K.); angela@raabe.com (A.R.)
*
Correspondence: griesbeck@uni-koeln.de; Tel.: +49-221-4703083
Academic Editor: Svetlana B. Tsogoeva
Received: 8 December 2016; Accepted: 6 January 2017; Published: 11 January 2017
Abstract: The synthesis of 4-styryl-substituted 2,3,8-trioxabicyclo[3.3.1]nonanes, peroxides with the
core structure of the bioactive 1,2,4-trioxane ring, was conducted by a multistep route starting
from the aryl methyl ketones 1a
4c that were coupled with ethyl acetate and reduced to the 1,3-diol substrates 6a
diastereoselective photooxygenation delivered the hydroperoxides 7a 7c and subsequent PPTS
pyridinium-p-toluenesulfonic acid)-catalyzed peroxyacetalization with alkyl triorthoacetates gave
–
1c.
Condensation and reduction/oxidation delivered enals
4
a–
–
6c. Highly
–
(
the cyclic peroxides 8a–8e. These compounds in general show only moderate antimalarial activities.
In order to extend the repertoire of cyclic peroxide structure, we aimed for the synthesis of
spiro-perorthocarbonates from orthoester condensation of -hydroxy hydroperoxide but could only
β
9
realize the monocyclic perorthocarbonate 10. That the central peroxide moiety is the key structural
motif in anticancer active GST (glutathione S-transferase)-inhibitors was elucidated by the synthesis
of a 1,3-dioxane 15—with a similar substitution pattern as the pharmacologically active peroxide
1
1—via a singlet oxygen ene route from the homoallylic alcohol 12.
Keywords: artemisinin; peroxides; singlet oxygen; hydroperoxides; 1,2,4-trioxane; orthoester
1
. Introduction
The 2015 Nobel Prize in physiology and medicine awarded to the Chinese scientist Youyou Tu, for
her discoveries concerning a novel therapy against malaria [1,2], honored a lifelong work in structure
elucidation and investigations on mechanism of action of potent antimalarial drugs from folk medicine.
The central compound in this research is the unusual peroxide artemisinin (in Chinese translation:
qinghaosu), a structurally complex tetracyclic sesquiterpene lactone with an endoperoxide substructure
that can be isolated from the leaves of Artemisia annua [3–8]. Due to its very high antimalarial activities,
artemisinin, its derivatives, and numerous analogs have become important as antimalarial drugs
against multidrug-resistant forms of Plasmodium falciparum [9]. Recently, numerous reports have also
described diverse antitumor activities of these compounds [10
combined with its synthetically challenging and chemically unusual structure have prompted synthetic
chemists to design total or partial synthesis routes to this compound and derivatives thereof [15 22
–14]. This high pharmacological potential
–
]
as well as the design of artemisinin dimers, conjugates and dyads [23]. In addition, flow chemistry
has been applied in order to produce large amounts of artemisinin involving a photochemical key
step [24–26]. With respect to the chemical reactivity of artemisinin derivatives, an ongoing discussion
Molecules 2017, 22, 119; doi:10.3390/molecules22010119
www.mdpi.com/journal/molecules

Molecules 2017, 22, 119
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concerns the correlation between biological activity and the kind of peroxide-related steps that actually
interfere with parasite-infected cells [27–30].
The central pharmacophore of natural artemisinin and derivatives is the 1,2,4-trioxane ring.
A more detailed look at the artemisinin structure shows that this group is part of a bicyclo[3.2.2]nonane
skeleton, i.e., not existing in a perfect cyclohexane chair conformation. Furthermore, not only a
peracetal group but also an acetal is present in artemisinin and its dihydroderivative (DHA, with a
further hemiactal structure) or DHA ethers like arthemether or artheether (corresponding to the methyl
and ethyl ether of DHA, respectively). A structural simplification that has been extensively realized
synthetically and examined with respect to antimalaria-activity is the 3-spiroannelated 1,2,4-trioxane
structure [31
as to ring-contracted bicyclic peroxides with intact 1,2,4-trioxane units as well as to multifunctional
trioxanes [34 36]. Additionally, molecular dyads that combine the natural artemisinin skeleton with
synthetic trioxanes were realized by our group [37 39]. The synthetic protocol that we follow in this
approach is depicted in Scheme 1: allylic alcohols A are highly reactive substrates for the singlet
oxygen ene reaction and lead to -hydroxy hydroperoxides B with high regio- and, in the case of
–33]. We have recently started to explore synthetic routes to these compounds as well
–
–
β
chiral allylic alcohols, also high threo diastereoselectivity. Furthermore, Broensted or Lewis acid (boron
trifluoride shown as a representative example) catalyzed peroxyacetalization of B, in the presence of
3
4
ketones, aldehydes (R R C=O) or equivalent reagents (acetals or orthoesters), did eventually result in
the formation of the desired 1,2,4-trioxanes C.
R1
R1
R1
OOH
BF3
O
O
O
R3
R4
1O
3
4
2
R R C=O
OH
OH
R2
R2
R2
A
B
C
Scheme 1. Synthetic route to 1,2,4-trioxanes using the singlet oxygen ene reaction.
1
From chiral 3,3-dimethylated substrates (R =CH ), diastereoisomeric mixtures of threo and erythro
3
oxygenation products are formed in ratios that are strongly solvent-dependent [40]. Arylated substrates
1
(
R =Ar) result in even higher diastereoselectivities [41
,
42]. We have now envisaged combining this
selectivity-enhancing effect with the synthesis of multifunctional 2,3,8-trioxabicyclo[3.3.1]nonanes F,
perorthoesters with the core structure of the bioactive 1,2,4-trioxane ring. From a structural point of
view (Scheme 2, D = artemisinine), the combination of an additional (per)acetal group with the trioxane
ring E appears to be an interesting new structural feature affecting the pharmacological properties of
these compounds.
O
O
O
O
O
O
O
O
O
O
O
E
F
D
O
Scheme 2. Artemisinin structure (solid lines indicating the relevant bicyclic peroxide structure),
,2,4-trioxane and 2,3,8-bicyclo[3.3.1]nonane structures.
1

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2
. Results and Discussion
The synthetic protocol for the synthesis of bicyclic perorthoesters
G
as shown in Scheme 3 requires
the preparation of 1-hydroperoxy-2,4-diols that are, in turn, available from allylic alcohols
oxygen ene reactions. The route to the 1,3-diols 6a 6c starts with the Horner–Wadsworth–Emmons
olefination of aric ketones 1a 1c and subsequent reduction of the Michael esters 2a 2c with DIBAL-H or
lithium aluminum hydride. The allylic alcohols 3a 3c were oxidized with MnO to give the aldehydes
H by singlet
–
–
–
–
2
4
6
a
a
–
4c. Aldol reaction with ethylacetate resulted in the aldols 5a
–
5c that were reduced to the 1,3-diols
proceeded according
–
6c. The synthesis of the allylic hydroperoxides 7a 7c from the allylic alcohols
–
6
to literature procedures published by us for solid state photooxygenation [32–34].
O
HO
OH OH
O
O
+
Ar
OH
1O2
G
OOH
H
O
O
i-iii
Ar =
Ph
An
EtO P
E
31%
52%
ß-Nph 37%
O
Ar
a-1c
2
O
Ar
Ar
1
4a-4c
OH OH
Ar =
O
iv,v
36%
74%
28%
Ph
+
An
O
Ar
EtO
ß-Nph
6
a-6c
4
a-4c
OH OH
OH OH
vi
Ar =
Ph
98% (d.r. >98:2)
37% (d.r. 95:5)
Ar
Ar An
ß-Nph
4
0% (d.r. >98:2)
6a-6c
OOH
7
a-7c
OH OH
O
vii
Ar = R =
Ar
a
b
c
d
e
Ph
Ph
Ph
An
Me 44%
Ar
Et 21%
Pr 28%
Me
OOH
a-7c
O
O
7
9%
R
O
ß-Nph Me 20%
8
a-e
i: NaH, THF; ii: DIBAL-H or LiAlH , Et O; iii: MnO toluene; iv: LDA, THF;
4
2
2,
v: NaBH4, I2, THF; vi: O2, hν, TPP, CCl4, 10°C; vii: PPTS, RC(OMe)3, CH Cl2
2
OH
EtOOC
EtOOC
Ar
HO
Ar
Ar
2a-2c
3a-3c
5a-5c
Scheme 3. Synthesis of substrates for and products from singlet oxygen ene reactions with
hydroxyethylated allylic alcohols 6.
This photooxygenation showed very high syn (threo) selectivity due to the well-known
allylic hydroxy effect [40]. The selectivity was even higher (>95:5) as for the standard substrate
1
,3-dimethyl-2-buten-1-ol (mesitylol, dr 85:15 under these conditions) because only the methyl
group in Z-geometry to the stereogenic hydroxyl-substituted center is active in hydrogen transfer
Scheme 4). This high selectivity was also reported by Singh and coworkers for arylated (mono) allylic
alcohols [41 42]. The suprafacial approach of the highly electrophilic singlet oxygen that appears from
(
,
the same side as the hydroxyl group is located, indicating a hydrogen bond interaction that stabilizes
the transition state.

Molecules 2017, 22, 119
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Ar
OH OH
1O
OH OH
2
HOO
Ar
Ar
OH
OH
6
a-6c
1O
7a-7c OOH
2
OH
OH
Ar
Ar
H
H
3
C
3
H C
OH
H
preferred
high allylic
OH strain = less preferred
1O
2
Scheme 4. Regio- and diastereoselectivity controlling elements in the singlet oxygen ene reaction with
allylic alcohols 6.
The allylic hydroperoxides
reagents, orthoesters were used because three condensation steps are necessary for the formation of
the bicyclic products . As a Broensted acid catalyst, pyridinium-p-toluenesulfonic acid (PPTS) was
7 were suitable substrates for the final peroxyacetalization. As carbonyl
8
used, and the products were obtained in moderate yields (20%–44%). Only the anisyl derivative 8d
was formed in low yields of 8%. Because of the high threo-diastereoselectivity of the singlet oxygen ene
reaction, the products were formed as preferentially as one diastereoisomer with a pseudo-equatorial
1
conformation of the substituent R (corresponding to the precursor with R*R*-configuration, Scheme 5).
Antimalaria activities of these compounds were in the micromolar range [43]. The most active
1
,2,4-trioxanes that we have obtained by analogous synthetic route showed in vitro activities against
Plasmodium falciparum (K1 strain) in the 1–5 nM region [31], one order of magnitude higher than the
perorthoesters 8.
O
O
R1
H
*
O
*
*
*
O
O
O
R1
H
R2
R2
O
O
R*R*-8
R*S*-8
Scheme 5. Diastereoisomeric 2,3,8-trioxabicyclo[3.3.1]nonanes (R*R*-8 preferred over R*S*-8) and force
field optimized model compound without aryl substituents.
In order to explore the synthetic limitations of the perorthoester synthesis, the condensation of
-hydroxy hydroperoxides with orthocarbonates was investigated. As a model compound, the allylic
β
hydroperoxide 9 (available from the singlet oxygen reaction with mesitylol J) was used and treated
with a substoechiometric amount of tetramethylorthocarbonate. The primary peroxyacetalization
proceeded smoothly to give the perorthocarbonate 10 in 30%, but no further reactivity of 10 was
detected (Scheme 6).
OOH
BF
C(OMe)4
3
O
O
1O
OCH3
OCH
2
OH
OH
3
O
J
9
10
O
O
O
O
O
O
O
O
O
O
O
K
O
I
Scheme 6. Literature-known dimeric trioxane structure
hexaoxaspiro[5,5]undecane structure K.
I [36] and envisaged synthetic approach to the

Molecules 2017, 22, 119
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In recent publications, we have also demonstrated the new potential of cyclic peroxides from
the 1,2,4-trioxane family to inhibit certain glutathione transferases (GSTs), an important class of
detoxification enzymes that are upregulated by tumor cells [44,45]. In order to demonstrate the
relevance of the central peroxide ring system, we designed the synthesis of a 1,3-dioxane 15 (Scheme 7)
that is structurally related to the biologically active 1,2,4-trioxane 11 (pNP = 4-nitrophenyl) [44].
The key synthetic step was again a singlet oxygen ene reaction with the homoallylic alcohol 12. In situ
reduction of the hydroperoxide 13 with Me S and acetalization delivered the dioxane 15. No inhibition
2
of hpGST could be determined for this compound, which accounts for the relevance of the peroxidic
1
,2,4-trioxane ring in bioactive compounds.
Ph P
3
HO
HO
OOH
OMe
i
ii
OMe
OMe
O
1
2
O
O
13
O
iii
pNP
pNP
O
O
O
HO
OH
O
iv
O
O
OMe
OMe
OMe
1
4
1
1 O
1
5
i: 1,3-propandiol, MnO ; ii: O hν, TPP, CCl4, 10°C;
2
2,
iii: Me S; iv: pNP-CHO, BF CH Cl
2
2
3,
2
Scheme 7. Antitumor-active 1,2,4-trioxane 11 and synthetic route to the non-peroxidic 1,3-dioxane 15
.
3
. Experimental Section
Infrared spectra were obtained using a Perkin-Elmer 1600 series FTIR spectrometer (Perkin-Elmer,
−
1
Walluf, Germany) and are given in cm units. Solid samples are measured as CsI or KBr discs while
1
liquids are measured as neat between two NaCl plates; the H-NMR spectra were recorded on Bruker
Avance 300, Bruker DPX 300 spectrometers (Bruker, Ettlingen, Germany) operating at 300 MHz, or
on Bruker Avance 500 spectrometer (Bruker, Ettlingen, Germany) instruments operating at 500 MHz.
Chemical shifts are reported as
solvent peaks were used as the internal standard. Solvents used are CDCl3 (
= 2.49 ppm), acetone-d6 ( = 2.04 ppm), and MeOH-d4 ( = 3.35, 4.78 ppm). Splitting patterns are
δ
in ppm and the coupling constants J in Hz units. In all spectra, the
δ
= 7.24 ppm), DMSO-d6
(
δ
δ
δ
13
designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; the C-NMR
spectra were recorded either on a Bruker Avance 300 spectrometer instrument operating at 75 MHz
or on a Bruker Avance 500 spectrometer instrument operating at 125 MHz; high resolution mass
spectra (HR-MS) were recorded on a Finnigan MAT 900 spectrometer(Scientific Instrument Services,
+
Ringoes, NJ, USA) and are measured for the molecular ion peak (M ); CHN-combustion analyses were
measured using an Elementar Vario EL Instrument (Elementar, Langenselbold, Germany).
General Procedures (GP)
GP-1: Horner–Wadsworth–Emmons reaction. In a flame-dried 200 mL three-necked flask in a
nitrogen atmosphere, sodium hydride (60% dispersion in oil) was washed with hexane and suspended
◦
in THF. Triethylphosphonoacetate was dropped to the suspension at 0 C over 10 min and stirred
at r.t. for 30 min. After that, a solution of the ketone in THF was added in 10 min and the reaction
mixture heated to reflux for 10 h. After cooling to r.t., an aqueous NH Cl solution was added and
4
extracted with 4
×
diethylether. The organic phases were washed with brine and dried over Na SO .
2 4
After solvent evaporation, the product was purified by column chromatography.

Molecules 2017, 22, 119
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GP-2: Reduction with DIBAL-H (diisobutylaluminium hydride). A solution of DIBAL-H (1.5 M in
◦
toluene) was slowly added to a solution of the ester
2
in diethylether cooled to 0 C and subsequently
stirred at r.t. for 2 h. After dilution with diethylether (twice the solvent volume of the starting reaction)
◦
and cooling to 0 C, saturated aqueous NaCl solution was added slowly, the pH was adjusted to
3
with 4 M HCl, and the aqueous phase was extracted with 3
×
diethylether. The organic phases were
washed with brine and dried over Na SO . After solvent evaporation, the product was purified by
2
4
column chromatography.
GP-3: Oxidation with MnO . A suspension of MnO in a toluene solution of the alcohol
3
was
2
2
stirred overnight at RT. Afterwards, the reaction mixtures were filtered over celite and the solvent was
evaporated. The crude product was purified by column chromatography.
GP-4: Aldol reactions with ethyl acetate. A solution of n-BuLi in hexane (19.2 mmol, 2 M) was
◦
added at
5
aldehyde
2
−
78 C to a solution of diisopropylamine (19.2 mmol) in 40 mL of THF. After stirring for
◦
min, ethyl acetate (16 mmol) was added and the mixture stirred at
in 10 mL of THF was added and stirred for 5 min, warmed to
0 mL of 1 N HCl. The aqueous phase was extracted with 3
−
78 C for 2 h. Afterwards, the
◦
4
−
20 C and quenched with
×
diethylether. The organic phases were
washed with brine and dried over Na SO . After solvent evaporation, the product was purified by
2
4
column chromatography.
GP-5: Reduction of aldols with NaBH . In a flame-dried 200 mL three-necked flask in a nitrogen
4
◦
atmosphere, the aldol was dissolved in THF, cooled to 0 C and NaBH was added in one portion.
4
Afterwards, a solution of iodine in THF was slowly added and the reaction mixture heated to reflux
for 3 h. After cooling to RT, methanol was carefully added until a clear solution resulted, stirred for
3
0 min and the solvent evaporated. The colorless residue was dissolved in a 1:1 water-diethylether
solvent mixture, stirred for 20 min, separated and the aqueous phase extracted with 3 diethylether.
The organic phases were washed with brine and dried over Na SO . After solvent evaporation, the
×
2
4
product was purified by column chromatography.
GP-6a: Photooxygenation under homogeneous conditions. The substrate (1 mmol) was dissolved in
−
◦
4
3
0 mL of CCl and 3–5 mg (2–4
×
10 M) of the sensitizer TPP (meso-tetraphenylporphyrin) were
4
added. The solution was cooled to 10 C and irradiated with a white LED under oxygen atmosphere
until complete conversion (TLC = thin layer chromatography control). Subsequently, the solvent
was evaporated and the residue analyzed by NMR. The crude hydroperoxides were directly used
for peroxyacetalization.
GP-6b: Photooxygenation under polymer matrix conditions. Commercially available polystyrene-
divinylbenzene copolymer beads (2.5 g) are distributed over a Petri dish (19 cm diameter) and swollen
by CH Cl (20 mL). The substrate (ca. 10 mmol) and the nonpolar sensitizer (TPP or TTP, ca. 3–6 mg) in
2
2
ethyl acetate (20 mL) are subsequently added and the excess solvent is evaporated by leaving the Petri
dish in a well ventilated hood. The Petri dish is then covered with a glass plate and the sandy solid is
irradiated with a halogen lamp or a sodium street lamp. The polymer beads are subsequently rinsed
with ethanol (3
×
30 mL) and filtered (the beads are kept for regeneration and reuse). The solvent is
◦
evaporated under reduced pressure (caution: water bath temperature should not exceed 30 C).
GP-7a: Peroxyacetalization to give bicyclic perorthoesters. To a stirred solution of the
β-hydroxy
hydroperoxide (1 mmol) and 3 equivalents of an orthoester in dry CH Cl (12 mL) was added at
7
2
2
room temperature a catalytic amount of pyridinium-p-toluenesulfonic acid (PPTS) (ca. 10 mg) and the
mixture was further stirred for about 12 h (overnight) at the same temperature. The reaction mixture
was partitioned between CH Cl and saturated NaHCO solution and the phases were separated.
2
2
3
The aqueous phase was extracted with CH Cl (3
×
30 mL) and the combined organic phases were
2
2
washed with brine and water, and dried over Na SO . Solvent evaporation (caution: water bath
2
4
◦
temperature should not exceed 30 C) followed by chromatographic purification afforded the bicyclic
perorthoesters as pure products.
GP-7b: Peroxyacetalization to give monocyclic 1,2,4-trioxanes. To a stirred solution of the
β-hydroxy
hydroperoxide and 1.5 equivalents of the carbonyl component in dry CH Cl (100 mL) was added at
2
2

Molecules 2017, 22, 119
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room temperature a catalytic amount of boron trifluoride etherate (ca. 0.2 mL) and the mixture was
further stirred for about 12 h (overnight) at the same temperature. The reaction mixture was partitioned
between CH Cl and saturated NaHCO solution and the phases were separated. The aqueous phase
2
2
3
was extracted with CH Cl (3
×
30 mL) and the combined organic phases were washed with brine and
2
2
water, and dried over Na SO . Solvent evaporation (caution: water bath temperature should not exceed
2
4
◦
3
0 C), followed by chromatographic purification, afforded the spiro-bistrioxanes as pure products.
E)-Ethyl-3-phenylbut-2-enoate (2a) [46]. Following GP-1 (General Procedure 1), 1.61 g (13.4 mmol) of
acetophenone (1a) and 6.86 g (34.6 mmol, 2.6 eq) of triethylphosphono acetate and 1.33 g (33.4 mmol,
(
2
.5 eq) of sodium hydride in 40 mL THF were reacted. The product was purified by column
1
chromatography (CH/Et O = 9:1, R = 0.22) and isolated as yellow oil: 2.0 g, 10.5 mmol, 78%. H-NMR
2
f
(
4
300 MHz, CDCl3):
.22 (q, 2H, J = 7.1 Hz, CH2CH ), 6.15 (d, 1H, J = 1.2 Hz, CH C
δ
(ppm) = 1.32 (t, 3H, J = 7.1 Hz, CH3CH ), 2.59 (d, 3H, J = 1.2 Hz, C
H
3CH=),
2
1
3
H
=), 7.35–7.49 (m, 5H, Har.). C-NMR
3
3
(75 MHz, CDCl3):
δ
(ppm) = 14.3 (
CH CH ), 17.9 (CH ), 59.8 (CH3CH ), 117.1 (HC=C), 126.2 (Car.),
3 2 3 2
1
28.4 (Car.), 128.9 (Car.), 142.2 (Car.), 155.4 (CH C=), 166.8 (C=O).
3
(E)-3-Phenylbut-2-enol (3a) [47]. Following GP-2 (General Procedure 2), 335 mg (1.76 mmol) of ester 2a
was reduced with 3.52 mL DIBAL-H (3.52 mmol, 2 eq, 1H solution in hexane) in 16 mL of diethylether.
The product 3a was purified by column chromatography (PE/Et O 9:1, R = 0.12) and isolated as
2
f
1
colorless oil: 170 mg, 1.23 mmol, 70%. H-NMR (300 MHz, CDCl ):
δ
(ppm) = 2.09 (s, 3H, CH3),
3
2
7
.70 (br s, 1H, OH), 4.38 (d, 2H, J = 6.63 Hz, CH2OH), 6.01 (dt, 1H, J = 1.33 Hz, 6.63 Hz, HC=C),
13
.33–7.46 (m, 5H, Har.). C-NMR (75 MHz, CDCl3):
δ (ppm) = 15.8 (CH ), 59.8 (CH OH), 125.6 (Car.),
3 2
1
26.5 (HC=C), 127.0 (Car.), 128.1 (Car.), 137.3 (CH C=) 142.8 (Car.).
3
(E)-3-Phenylbut-2-enal (4a) [48]. Following GP-3 (General Procedure 3), 1.50 g (10.1 mmol) of the
alcohol 3a and 15 g of MnO in 250 mL of toluene were reacted. The product was purified by column
2
1
chromatography (PE/Et O = 1:1, R = 0.30) and isolated as colorless oil: 0.84 g, 5.7 mmol, 57%. H-NMR
2
f
(
7
(
300 MHz, CDCl3):
.35–7.55 (m, 5H, Har.), 10.17 (d, 1H, J = 7.8 Hz, CHO). 13C-NMR (75 MHz, CDCl3):
CH ), 126.1 (Car.), 127.1 (Car.), 128.2 (Car.), 128.6 (Car.), 129.9 (H =C), 140.4 (Car.), 157.4 (CH3C
δ (ppm) = 2.55 (s, 3H, J = 1.2 Hz, CH ), 6.39 (dq, 1H, J = 1.2 Hz, 7.8 Hz, HC=C),
3
δ
(ppm) = 16.2
=),
C
3
1
91.0 (CHO).
E)-Ethyl-3-hydroxy-5-phenylhex-4-enoate (5a). Following GP-4 (General Procedure 4), 840 mg (5.7 mmol)
of the aldehyde 4a and 0.3 mL (3.8 mmol) of ethyl acetate were reacted. The product 5a was purified
by column chromatography (CH/Et O 3:2, R = 0.35) and isolated as yellow oil: 604 mg, 2.6 mmol,
(
2
f
1
6
8%. H-NMR (300 MHz, CDCl ): δ (ppm) = 1.30 (t, 3H, J = 7.2 Hz, CH3CH ), 2.13 (d, 3H, J = 1.5 Hz,
3
2
CH ), 2.38 (m, 2H, CH ), 3.18 (br, 1H, OH), 4.20 (q, 2H, J = 7.2 Hz, C
H
CH ), 5.00 (m, 1H, C
H
OH),
C-NMR (75 MHz, CDCl3):
H CH ), 65.4 (CHOH), 125.7 (H =C),
(cm ) = 3402
3
2
2
3
1
3
5.82 (dd, 1H, J = 7.2 Hz, 1.2 Hz, C=CH), 7.34–7.41 (m, 5H, Har.).
δ
(ppm) = 14.0 ( H CH ), 16.2 (CH ), 41.5 (CH ), 60.3 (
C
C
C
3
2
3
2
2
3
−
1
1
27.3 (Car.), 128.1 (Car.), 128.4 (Car.), 137.7 (
C
=CH), 142.6 (Car.), 172.1 (C=O). IR (Film):
ν
(
s), 2979 (m), 2928 (m), 1730 (s), 1646 (w), 1492 (w), 1369 (s), 1277 (s), 1157 (s), 1020 (s), 948 (m), 860 (m).
+
MS (EI, 70 eV): m/z (%) = 216 (M − H O, 7), 171 (4), 143 (74), 128 (100), 115 (53).
2
(E)-5-Phenylhex-4-ene-1,3-diol (6a). Following GP-5 (General Procedure 5), 600 mg (2.56 mmol) of the
aldol 5a was reduced with 240 mg (6.4 mmol, 2.5 eq) of NaBH and 200 mg (0.78 mmol, 0.3 eq) of I .
4
2
The product was purified by column chromatography (Et O, R = 0.45) and isolated as yellow solid:
2
f
1
3
96 mg, 2.1 mmol, 80%. H-NMR (300 MHz, CDCl ):
δ
(ppm) = 1.84 (m, 2H, CH ), 2.10 (s, 3H, CH ),
3
2
3
2
.57 (br s, 2H, OH), 3.88 (m, 1H, CH2OH), 4.83 (m, 1H, C
H
OH), 5.00 (m, 1H, C
H
OH), 5.84 (dd, 1H,
13
J = 1.2 Hz, 8.4 Hz, C=CH), 7.30–7.40 (m, 5H, Har.). C-NMR (75 MHz, CDCl3):
δ (ppm) = 15.9 (CH3),
3
8.7 (CH ), 60.4 (CH OH), 68.1 (CHOH), 125.6 (H =C), 127.0 (Car.), 128.0 (Car.), 130.3 (Car.), 136.1
C
2
2
−
1
(C
=CH), 142.7 (Car.). IR (Film):
ν
(cm ) = 3323 (s), 2943 (m), 2880 (m), 1492 (w), 1379 (s), 1121 (w), 1044
+
(
s), 955 (m), 895 (w), 755 (s), 695 (s). MS (EI, 70 eV): m/z (%) = 177 (M
−
CH , 9), 159 (177
−
H O, 4),
2
3
+
1
47 (M − OCH CH , 87), 129 (100), 115 (53).
2
3

Molecules 2017, 22, 119
8 of 14
(E)-4-Methoxyethyl-3-phenylbut-2-enoate (2b) [49]. Following GP-1, 2.00 g (13.4 mmol) of 4-methoxy
acetophenone (1b) and 6.86 g (34.6 mmol, 2.6 eq) of triethylphosphono acetate and 1.33 g (33.4 mmol,
2
.5 eq) of sodium hydride in 40 mL THF were reacted. The product was purified by column
1
chromatography (CH/Et O = 9:1, R = 0.24) and isolated as yellow oil: 2.3 g, 10.4 mmol, 77%. H-NMR
2
f
(300 MHz, CDCl3):
δ (ppm) = 1.31 (t, 3H, J = 7.2 Hz, CH3CH ), 2.56 (d, 3H, J = 1.2 Hz, CH ), 3.82 (s,
2 3
3
H, CH O), 4.20 (q, 2H, J = 7.2 Hz, CH CH2), 6.11 (d, 1H, J = 1.2 Hz, C=CH), 6.89 (m, 2H, Har.), 7.45
3
3
13
(
(
m, 2H, Har.). C-NMR (75 MHz, CDCl3):
CH3 H ), 113.8 (Car.), 115.3 ( H=C), 127.6 (Car.), 134.3 (Car.), 154.8 (CH=
(cm ) = 2979 (s), 2914 (m), 1709 (s), 1625 (w), 1603 (m), 1513 (s), 1344 (s), 1157 (m), 1082
δ (ppm) = 14.3 (CH CH ), 17.6 (CH ), 55.3 (CH O), 59.6
3 2 3 3
C
C
C), 160.4 (Car.), 167.0 (C=O).
2
−
1
IR (Film):
ν
+
+
+
(
m). MS (EI, 70 eV): m/z (%) = 221 (M , 15), 192 (M
−
CH CH , 12), 175 (M
−
OCH CH , 100), 148
2 3
2
3
+
(M
−
O=COH CH , 83). CHN-analysis: (C H O , M = 220.11 g/mol)—calcd.: 70.89% C 7.32% H,
2 3 13 16 3
found: 71.04% C 7.63% H.
E)-3-(4-Methoxyphenyl)but-2-ene-1-ol (3b) [50]. Following GP-2, 2.00 g (10.5 mmol) of ester 2b was
reduced with 21 mL DIBAL-H (21 mmol, 2 eq, 1 M solution in hexane) in 60 mL of diethylether.
The product 3b was purified by column chromatography (PE/Et O 9:1, R = 0.10) and isolated as
(
2
f
1
colorless oil: 1.79 g, 10.1 mmol, 96%. H-NMR (300 MHz, CDCl ):
δ (ppm) = 2.06 (s, 3H, CH ), 3.81 (s,
3
3
3
7
H, CH O), 4.35 (d, 2H, J = 6.9 Hz, CH ), 5.92 (dt, 1H, J = 1.2 Hz, 6.9 Hz, C=CH), 6.87 (m, 2H, Har.),
3 2
13
.36 (m, 2H, Har.). C-NMR (75 MHz, CDCl3):
δ (ppm) = 16.0 (CH ), 55.3 (CH O), 59.9 (CH OH),
3 3 2
1
13.6 (Car.), 124.8 (C=CH), 126.8 (Car.), 135.3 (CH =C), 137.3 (Car.), 158.9 (Car.).
2
(
E)-3-(4-Methoxyphenyl)but-2-enal (4b) [51]. Following GP-3, 1.79 g (10.1 mmol) of the alcohol 4a and
1
8 g of MnO in 250 mL of toluene were reacted. The product was purified by column chromatography
2
1
(PE/Et O = 1:1, R = 0.28) and isolated as colorless oil: 1.79 g (6.9 mmol, 68%). H-NMR (300 MHz,
2
f
CDCl3):
δ
(ppm) = 2.54 (s, 3H, CH ), 3.84 (s, 3H, CH O), 6.38 (dd, 1H, J = 1.2 Hz, 7.8 Hz, C=CH), 6.93
3
3
13
(d, 2H, J = 9 Hz, Har.), 7.53 (d, 2H, J = 9 Hz, Har.), 10.15 (d, 1H, J = 7.8 Hz, CHO). C-NMR (75 MHz,
CDCl3):
δ
(ppm) = 16.0 (CH ), 55.4 (CH O), 114.0 (Car.), 125.5 (C=
C
H), 127.8 (Car.), 132.4 (Car.), 156.9
3
3
−
1
(C=CH), 161.3 (Car.), 191.2 (CHO). IR (film):
ν (cm ) = 2957 (w), 2837 (m), 1649 (s), 1593 (s), 1506 (m),
8
24 (s).
(
E)-Ethyl-3-hydroxy-5-(4-methoxyphenyl)hex-4-enoate (5b). Following GP-4, 325 mg (1.8 mmol) of the
aldehyde 4b and 0.13 mL (1.25 mmol) of ethyl acetate were reacted. The product 5a was purified by
column chromatography (PE/Et O 1:1, R = 0.18) and isolated as yellow oil: 360 mg, 1.4 mmol, 77%.
2
f
1
H-NMR (300 MHz, CDCl3):
δ (ppm) = 1.28 (t, 3H, J = 7.2 Hz, CH3CH O), 2.08 (s, 3H, CH ), 2.60 (m,
2 3
2
H, CH ), 2.95 (br s, 1H, OH), 3.80 (s, 3H, CH O), 4.18 (q, 2H, J = 7.2 Hz, CH CH2O), 4.96 (m, 1H,
2
3
3
CHO), 5.72 (dd, 1H, J = 0.9 Hz, 8.4 Hz, C=CH), 6.85 (d, 2H, J = 8.7 Hz, Har.), 7.33 (m, 2H, J = 8.7 Hz,
13
H
ar.). C-NMR (75 MHz, CDCl3):
δ
(ppm) = 14.1 (
C
H CH ), 16.3 (CH ), 41.6 (CH ), 55.2 (CH O),
3
2
3
2
3
6
0.7 (CH3
ar.), 172.3 (C=O). IR (Film):
C
H ), 65.8 (CHOH), 113.6 (Car.), 126.7 (C=
C
H), 126.9 (Car.), 135.1 (Car.), 137.3 (
C
=CH), 159.0
2
−
1
(C
ν
(cm ) = 3429(s), 2982 (s), 2831(m), 1731 (m), 1606 (m), 1506 (s), 826 (s).
+
+
+
MS (EI, 70 eV): m/z (%) = 264 (M , 21), 249 (M
35 (CH O(C H )CHCH , 100), 115 (39).
−
CH , 12), 246 (M
−
H O, 27), 177 (90), 159 (76),
2
3
1
3
6
4
3
(
E)-5-(4-Methoxyphenyl)hex-4-ene-1,3-diol (6b). Following GP-5, 175 mg (0.66 mmol) of the aldol 6a was
reduced with 63 mg (1.65 mmol, 2.5 eq) of NaBH and 51 mg (0.22 mmol, 0.3 eq) of I . The product
4
2
was purified by column chromatography (CHCl /MeOH 9:1, R = 0.27) and isolated as colorless solid:
3
f
1
1
40 mg, 0.63 mmol, 96%. H-NMR (300 MHz, CDCl ):
δ
(ppm) = 1.79 (m, 2H, CH ), 2.04 (s, 3H, CH ),
3
2
3
3
.34 (br s, 2H, 2
×
OH), 3.78 (s, 3H, OCH ), 3.84 (m, 2H, CH2OH), 4.77 (m, 1H, C
H
OH), 5.75 (dd, 1H,
3
1
3
J = 1.2 Hz, 8.4 Hz, C=CH), 6.83 (d, 2H, J = 8.7 Hz, Har.), 7.32 (d, 2H, J = 8.7 Hz, Har.). C-NMR (75 MHz,
CDCl3):
δ
(ppm) = 16.0 (CH ), 38.8 (CH ), 55.1 (OCH ), 60.7 (CH OH), 68.4 (CHOH), 113.5 (C=
C
H),
3
2
3
2
−
1
1
1
1
26.7 (Car.), 128.5 (Car.), 135.1 (Car.), 135.9 (C=CH), 158.8 (Car.). IR (Film): ν (cm ) = 3332 (s), 2938 (s),
605 (m), 1510 (s), 1245 (s), 1032 (s), 826 (m). MS (EI, 70 eV): m/z (%) = 222 (M , 12), 204 (M
1), 177 (C H O , 45), 159 (49), 135 (100), 115 (39).
+
+
−
H O,
2
+
11
13
2

Molecules 2017, 22, 119
9 of 14
(E)-3-(2-Naphthyl)but-2-enylacetate (2c) [52]. Following GP-1, 2.21 g (13.4 mmol) of acetonaphthone
(1c) and 6.86 g (34.6 mmol, 2.6 eq) of triethylphosphono acetate and 1.33 g (33.4 mmol, 2.5 eq) of
sodium hydride in 40 mL THF were reacted. The product was purified by column chromatography
◦
(
CH/Et O = 9:1, R = 0.39) and isolated as colorless solid, m.p. 45–46 C, 2.5 g, 10.5 mmol, 80%.
2
f
1
H-NMR (300 MHz, CDCl3):
δ (ppm) = 1.36 (t, 3H, J = 7.2 Hz, CH3CH ), 2.71 (d, 3H, J = 1.2 Hz, CH ),
2 3
.28 (q, 2H, J = 7.2 Hz, CH CH2), 6.32 (d, 1H, J = 1.2 Hz, C=CH), 7.4–7.9 (m, 7H, Har.). C-NMR
13
4
3
(
(
1
75 MHz, CDCl3):
ar.), 126.4 (Car.), 126.6 (Car.), 127.5 (Car.), 128.1 (Car.), 128.4 (Car.), 133.0 (Car.), 133.4 (Car.), 139.3 (Car.),
55.1 (C=), 166.8 (C=O).
δ (ppm) = 14.3 (CH ), 17.8 (CH ), 59.8 (CH CH ), 117.4 (C=CH), 123.9 (Car.), 125.8
3 3 2 3
C
(
E)-3-(2-Naphthyl)but-2-ene-1-ol (3c) [53]. Following GP-2, 2.50 g (10.5 mmol) of ester 2c was reduced
with 1.11 g (29.2 mmol, 2.8 eq) of LiAlH in 16 mL of diethylether. The product 3c was purified by
4
recrystallization from benzene/hexane (1:1) resulting in 1.34 g (6.7 mmol, 64%) of colorless crystals,
◦
1
m.p. 85–86 C. H-NMR (300 MHz, CDCl ):
δ (ppm) = 1.67 (br s, 1H, OH), 2.20 (s, 3H, CH ) 4.44 (t, 2H,
3
3
13
J = 5.6 Hz, CH2OH), 6.15 (t, 1H, J = 6.7 Hz, C=CH), 7.41–7.90 (m, 7H, Har.). C-NMR (75 MHz, CDCl3):
(ppm) = 16.0 (CH ), 60.0 (CH OH), 124.1 (Car.), 124.5 (Car.), 125.8 (Car.), 126.1 (Car.), 127.0 (Car.),
δ
3
2
1
27.5 (Car.), 128.1 (Car.), 128.4 (Car.), 133.3 (C=CH), 137.6 (Car.), and 139.3 (C=CH).
(E)-3-(2-Naphthyl)but-2-enal (4c) [51]. Following GP-3, 1.29 g (6.5 mmol) of the alcohol 3c and 13 g
of MnO in 250 mL of toluene were reacted. The product was purified by column chromatography
2
1
(
PE/Et O = 1:1, R = 0.56) and isolated as colorless oil: 0.88 g, 4.5 mmol, 69%. H-NMR (300 MHz,
2
f
CDCl ):
(
δ
(ppm) = 2.64 (s, 3H, CH ), 6.55 (d, 1H, J = 7.8 Hz, C=CH), 7.51–8.01 (m, 7H, Har.), 10.23
3
3
d, 1H, J = 7.8 Hz, CHO). 13C-NMR (75 MHz, CDCl3):
δ
(ppm) = 16.2 (CH ), 123.3 (Car.), 126.2 (Car.),
3
1
26.6 (Car.), 127.1 (Car.), 127.3 (Car.), 127.5 (Car.), 128.3 (Car.), 128.6 (Car.), 132.8 (Car.), 133.9 (C=
CH),
1
37.4 (Car.), 157.1 (C=CH), 191.1 (CHO).
(E)-Ethyl-3-hydroxy-5-(2-naphthyl)hex-4-enoate (5c). Following GP-4, 875 mg (4.5 mmol) of the aldehyde
4
c
and 0.30 mL (3.8 mmol) of ethyl acetate were reacted. The product was purified by column
1
chromatography (CH/Et O 3:2, R = 0.38) and isolated as yellow oil: 470 mg, 1.65 mmol, 37%. H-NMR
2
f
(
300 MHz, CDCl3): δ (ppm) = 1.30 (t, 3H, J = 7.2 Hz, CH3CH ) 2.23 (s, 3H, CH ), 2.66 (m, 2H, CH ),
2 3 2
4
H
.11 (q, 2H, J = 7.2 Hz CH CH2), 5.04 (m, 1H, C
ar.). C-NMR (75 MHz, CDCl3): δ (ppm) = 14.2 (CH ), 16.4 (CH CH3), 41.6 (CH ), 60.9 (CH2CH3),
H
OH), 5.94 (d, 1H, J = 7.2 Hz, C=CH), 7.45–7.82 (m, 7H,
3
13
3
2
2
6
1
(
5.7 (CHOH), 124.2 (Car.), 124.7 (Car.), 125.9 (Car.), 126.2 (C=
28.8 (Car.), 132.8 (Car.), 133.3 (Car.), 137.8 ( =CH ), 139.1 (Car.). IR (film):
m), 2979 (m), 1730 (s), 1369 (m), 1277 (m), 1158 (s), 1019 (s), 853 (m), 816 (s), 747(s). MS (EI, 70 eV):
CH ), 127.5 (Car.), 127.8 (Car.), 128.2 (Car.),
2
−
1
C
ν (cm ) = 3418 (s), 3054
2
+
+
+
m/z (%) = 284 (M , 7), 266 (M
28 (52).
−
H O, 13), 196 (M
2
−
C(=O)OCH CH , 56), 179 (100), 155 (77),
2 3
1
(E)-5-(2-Naphthyl)hex-4-ene-1,3-diol (6c). Following GP-5, 470 mg (1.65 mmol) of the aldol 5c was
reduced with 160 mg (4.13 mmol, 2.5 eq) of NaBH and 130 mg (0.5 mmol, 0.3 eq) of I . The product
4
2
was purified by column chromatography (CHCl /MeOH 9:1, R = 0.23) and isolated as colorless solid:
3
f
1
3
2
7
6
00 mg, 1.24 mmol, 75%. H-NMR (300 MHz, CDCl ): δ (ppm) = 1.89 (m, 2H, CH ) 2.20 (s, 3H, CH ),
3
2
3
.29 (br s, 2H, OH), 3.94 (m, 2H, CH2OH), 4.90 (m, 2H, C
.25–7.82 (m, 7H, Har.). C-NMR (75 MHz, CDCl3): δ (ppm) = 16.3 (CH ), 38.8 (CH ), 61.4 (CH O),
9.2 (CHOH), 124.1 (Car.), 124.6 (Car.), 127.5 (Car.), 127.6 (Car.), 127.8 (Car.), 128.0 (Car.), 128.1 (Car.), 128.7
H
OH), 6.00 (dd, 1H, J = 1.2 Hz, 7.2 Hz, C=CH),
13
3
2
2
−
1
(C
ar.), 130.6 (C=CH), 133.3 (Car.), 136.9 (C=CH), 138.7 (Car.). IR (Film): ν (cm ) = 3304 (s), 2921 (s),
2
851 (m), 1420 (m), 1272 (m), 1046 (s), 904 (s), 854 (m), 815 (s), 727(s). MS (EI, 70 eV): m/z (%) = 242
+
+
+
+
◦
2 3
m
O=COH CH , 83). T = 38–39 C
(M , 5), 192 (M
aus CHCl3).
−
H O, 5), 175 (M
2
−
OCH CH , 100), 148 (M
−
2
3
(
(
R*R*)-4-Hydroperoxy-5-phenylhex-5-ene-1,3-diol (7a). Following GP-6a, 100 mg (0.52 mmol) of the diol
6
a
and 2.5 mg of TPP in 30 mL of CCl was irradiated for 5 h (complete conversion). Evaporation of the
4
1
solvent delivered the crude product. H-NMR (300 MHz, CDCl ):
δ (ppm) = 1.83 (m, 2H, CH ), 3.54
2
3

Molecules 2017, 22, 119
10 of 14
(
C
m, 2H, CH O), 4.42 (d, 1H, J = 3.9 Hz, C
H2=C), 7.30–7.60 (m, 5H, Har.). C-NMR (75 MHz, CDCl3):
H
OO), 4.99 (m, 1H, CHO), 5.09 (dt, 2H, J = 1.2 Hz, 12.6 Hz,
2
13
δ
(ppm) = 34.1 (CH ), 60.6 (CH OH),
2
2
72.3 (CHOH), 91.3 (CHOOH), 118.0 (C=
C
H ), 126.9 (Car.), 128.0 (Car.), 128.5 (Car.), 139.5 (
2
C
=CH2),
1
44.9 (Car.).
(
6
R*R*)-4-Hydroperoxy-5-(4-methoxyphenyl)hex-5-ene-1,3-diol (7b). Following GP-6a (General Procedure
a), 126 mg (0.57 mmol) of the diol 6b and 4 mg of TPP in 30 mL of CCl was irradiated for 5 h (37%
4
conversion). Evaporation of the solvent delivered the crude product as a mixture of diastereoisomers
1
(
dr 95:5). H-NMR (300 MHz, CDCl ):
δ
(ppm) = 1.67 (m, 2H, CH ), 3.74 (s, 3H, OCH ), 3.88 (m, 2H,
3
2
3
CH O), 4.26 (d, 1H, J = 3.5 Hz, CHOO), 4.62 (m, 1H, CHO), 5.14 (d, 2H, J = 12.3 Hz, CH2=C), 6.7–7.4
2
(m 4H, Car.).
(R*R*)-4-Hydroperoxy-5-(2-naphthyl)hex-5-ene-1,3-diol (7c). Following GP-6b (General Procedure 6b),
2
00 mg (0.83 mmol) of the diol 6c was irradiated for 5h (40% conversion). Evaporation of the solvent
1
delivered the crude product. H-NMR (300 MHz, CDCl ):
δ (ppm) = 1.89 (m, 2H, CH ) 3.97 (m, 2H,
2
3
C
H2OH), 4.34 (m, 1H, CHOO), 4.65 (m, 2H, CHOH), 5.81 (m, 2H, C=CH ), 7.25–7.82 (m, 7H, Har.).
2
1
3
C-NMR (75 MHz, CDCl3):
δ (ppm) = 35.8 (CH ), 60.2 (CH O), 69.8 (CHOH), 124.1 (Car.), 124.6 (Car.),
2 2
1
27.5 (Car.), 127.6 (Car.), 127.8 (Car.), 128.0 (Car.), 128.1 (Car.), 128.7 (Car.), 129.4 (C=
CH ), 133.3 (Car.),
2
1
38.7 (Car.), 139.7 (C=CH2).
(R*R*)-1-Methyl-4-(1-phenylvinyl)-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8a). Following GP-7a (General
Procedure 7a), 224 mg (0.5 mmol) of the hydroperoxide 7a was reacted with 0.08 mL (1.5 mmol, 3 eq)
of trimethyl orthoacetate and catalytic amounts of PPTS in 6 mL of dichloromethane. The product
was purified by column chromatography (PE/Et O 9:1, R = 0.43) and isolated as colorless oil (dr
2
f
1
9
4:6): 57 mg (0.23 mmol, 46%). H-NMR (300 MHz, CDCl ): δ (ppm) = 1.50 (s, 3H, CH ), 1.74 (m,
3
3
1
4
H, CH ), 2.45 (m, 2H, CH ), 3.94 (m, 1H, CH O), 4.21 (d, 1H, J = 6.3 Hz, CHO), 4.74 (m, 1H, CH O),
2 2 2 2
13
.95 (s, 1H, CHOO), 5.58 (s, 1H, C=CH ), 5.73 (s, 1H, C=CH ), 7.35 (m, 5H, Har.). C-NMR (75 MHz,
2 2
CDCl3):
δ (ppm) = 24.1 (CH ), 27.5 (CH ), 60.0 (CH O), 65.7 (CHO), 82.4 (CHOO), 113.5 (OCOO), 117.4
3 2 2
−
CH ), 126.9 (Car.), 127.9 (Car.), 128.5 (Car.), 139.2 (Car.), 144.2 (C=CH ). IR (Film): ν (cm ) = 2962
2 2
1
(C=
m), 2923 (m), 2853 (m), 1493 (w), 1442 (m), 1380 (s), 1256 (s), 1105 (s), 966 (m), 900 (m), 752 (s), 702 (s).
(
(
(
R*R*)-1-Ethyl-4-(1-phenylvinyl)-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8b). Following GP-7a, 224 mg
0.5 mmol) of the hydroperoxide 7a was reacted with 0.08 mL (1.5 mmol, 3 eq) of triethyl
orthopropionate and catalytic amounts of PPTS in 6 mL of dichloromethane. The product was
purified by column chromatography (PE/Et O 4:1, R = 0.38) and isolated as colorless oil (dr 95:5):
2
f
1
2
7 mg (0.10 mmol, 21%). H-NMR (300 MHz, CDCl ):
δ
(ppm) = 1.00 (t, 3H, J = 7.5 Hz, CH3CH2),
3
1
4
.75 (m, 3H, CH CH2, CH2), 2.44 (m, 1H, CH ), 3.91 (m, 1H, CH O), 4.21 (d, 1H, J = 6.6 Hz, CHO),
3
2
2
.68 (m, 1H, CH O), 4.96 (s, 1H, CHOO), 5.57 (s, 1H, C=CH ), 5.71 (s, 1H, C=CH ), 7.35 (m, 5H, Har.).
2
2
2
1
3
C-NMR (75 MHz, CDCl3):
δ
(ppm) = 6.7 (
C
H CH ), 27.8 (CH ), 30.8 (CH3CH ), 59.6 (CH O), 65.8
3
2
2
2
2
(
1
CHO), 82.9 (CHOO), 114.7 (OCOO), 117.6 (C=
C
H ), 127.0 (Car.), 128.0 (Car.), 128.5 (Car.), 139.1 (Car.),
2
−
1
44.4 (
C
=CH ). IR (Film):
ν
(cm ) = 2975 (m), 1493 (w), 1360 (m), 1250 (s), 1105 (s), 914 (s), 777 (s),
2
7
02 (s).
(
(
R*R*)-4-(1-Phenylvinyl)-1-propyl-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8c). Following GP-7a, 224 mg
0.5 mmol) of the hydroperoxide 7a was reacted with 0.24 mL (1.5 mmol, 3 eq) of trimethyl
orthobutyrate and catalytic amounts of PPTS in 6 mL of dichloromethane. The product was purified
by column chromatography (PE/Et O 4:1, R = 0.48) and isolated as colorless oil (dr 97:3): 39 mg
2
f
1
(
0.14 mmol, 28%). H-NMR (300 MHz, CDCl ): δ (ppm) = 0.92 (t, 3H, J = 7.5 Hz, CH3CH ), 1.54 (m,
3
2
2
H, CH CH ), 1.71 (m, 3H, CH CH CH , CH ), 2.42 (m, 1H, CH ), 3.21 (m, 1H, CH O), 4.21 (dd, 1H,
3 2 3 2 2 2 2 2
J = 1.8 Hz, 6.6 Hz, CHO), 4.68 (m, 1H, CH O), 4.96 (s, 1H, CHOO), 5.57 (s, 1H, C=CH ), 5.71 (s, 1H,
2
2
13
C=CH ), 7.35 (m, 5H, Har.). C-NMR (75 MHz, CDCl3):
δ
(ppm) = 14.0 (
CH CH ), 15.7 (CH CH2CH2),
3 2 3
2
2
7.8 (CH ), 39.6 (CH3
C
H ), 59.6 (CH O), 65.6 (CHO), 82.8 (CHOO), 114.4 (OCOO), 117.5 (C=CH2),
2
2
2

Molecules 2017, 22, 119
11 of 14
1
2
26.9 (Car.), 127.9 (Car.), 128.5 (Car.), 139.1 (Car.), 144.4 (
872 (s), 1732 (m), 1493 (w), 1378 (m), 1247 (s), 1119 (s), 928 (s), 777 (s), 701 (s).
(cm 1) = 2963 (s), 2928 (s),
−
C=CH ). IR (Film): ν
2
(
1
R*R*)-4-(1-(4-Methoxyphenyl)vinyl)-1-methyl-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8d). Following GP-7a,
20 mg (0.54 mmol) of the hydroperoxide 7b was reacted with 0.21 mL (1.62 mmol, 3 eq) of triethyl
orthoacetate and catalytic amounts of PPTS in 6 mL of dichloromethane. The product was purified by
column chromatography (PE/Et O 4:1, R = 0.34) and isolated as colorless oil: 14 mg (0.05 mmol, 9%).
2
f
1
H-NMR (300 MHz, CDCl3):
δ (ppm) = 1.39 (s, 3H, CH ), 1.70 (m, 1H, CH ), 2.45 (m, 1H, CH ), 3.70 (s,
3 2 2
3
H, CH O), 3.82 (m, 1H, CH O), 4.09 (dt, 1H, J = 1.9 Hz, 6.3 Hz, CHO), 4.61 (m, 1H, CH O), 4.83 (s, 1H,
3
2
2
CHOO), 5.40 (s, 1H, C=CH ), 5.51 (s, 1H, C=CH ), 6.76 (d, 2H, J = 8.8, Har.), 7.22 (d, 2H, J = 8.8 Hz, Har.).
2
2
13
C-NMR (75 MHz, CDCl3):
δ (ppm) = 24.1 (CH ), 27.8 (CH ), 55.3 (CH O) 59.8 (CH O), 65.8 (CHO),
3 2 3 2
8
2.6 (CHOO), 113.6 (OCOO), 113.9 (Car.), 116.2 (C=CH ), 128.0 (Car.), 131.3 (Car.), 143.5 (C=CH ), 159.3
2
2
−
1
(Car.). IR (Film): ν (cm ) = 2961 (s), 1606 (m), 1510 (s), 1464 (w), 1380 (m), 1246 (s), 1107 (m), 966 (m),
8
35 (s), 804 (m), 744 (w).
(
(
R*R*)-1-Methyl-4-(1-(2-naphthyl)vinyl)-2,3,8,9-tetraoxabicyclo[3.3.1]nonane (8e). Following GP-7a, 220 mg
0.8 mmol) of the hydroperoxide 7c was reacted with 0.21 mL (1.62 mmol, 2 eq) of triethyl orthoacetate
and catalytic amounts of PPTS in 8 mL of dichloromethane. The product was purified by column
chromatography (PE/Et O 4:1, R = 0.36) and isolated as colorless oil (dr 95:5): 50 mg (0.17 mmol,
2
f
1
2
3
5
0%). H-NMR (300 MHz, CDCl ): δ (ppm) = 1.49 (m, 1H, CH ), 1.75 (s, 3H, CH ), 2.28 (m, 1H, CH ),
3 2 3 2
.91 (m, 1H, CH O), 4.29 (m, 1H, CH O), 4.36 (s, 1H, CHO), 5.28 (s, 1H, CHOO), 5.51 (s, 1H, C=CH ),
2
2
2
13
.58 (s, 1H, C=CH ), 7.41–7.80 (m, 7H, Har.). C-NMR (75 MHz, CDCl3):
δ (ppm) = 22.4 (CH ), 28.1
3
2
(
CH ), 58.8 (CH O), 76.9 (CHO), 80.0 (CHOO), 113.7 (OCOO), 120.1 (C=CH ), 124.7 (Car.), 124.8 (Car.),
2
2
2
1
26.2 (Car.), 126.4 (Car.), 127.6 (Car.), 128.0 (Car.), 128.3 (Car.), 132.9 (Car.), 133.2 (Car.), 136.1 (Car.), 145.8
−
1
(C
=CH ). IR (film):
012 (s), 942 (m), 855 (s), 750 (m). MS (EI, 20 eV): m/z (%) = 282 (M
ν
(cm ) = 3054 (m), 2966 (m), 2925 (m), 1731 (m), 1397 (s), 1300 (s), 1120 (s),
2
+
+
1
2
1
(
−
CH , 5), 266 (M
−
O , 2),
2
3
40 (M+
65 (Naphthyl
Naphthyl, 27), 75 (CH CO , 56), 57 (CH CO , 89).
−
O CCH , 30), 222 (M
+
−
CH CO , 22), 195 (27), 184 (Naphthyl
−
C(CH CH )=CH , 82),
2 3 2
2
3
3
3
−
C(=CH )CH , 57), 155 (Naphthyl
−
C=CH , 100). 141 (Naphthyl
−
CH , 27), 128
2
2
3
2
3
3
3
2
3,3-Dimethoxy-5-methyl-6-(1-propen-2-yl)-1,2,4-trioxane (10). Following the general procedure GP-6,
6
0 mg (0.45 mmol, 1.0 eq) of the hydroperoxide threo- , 62 mg (0.03 mL, 0.23 mmol, 0.5 eq) of
9
tetramethoxymethane and 12 mg (0.045 mmol, 0.1 eq) PPTS were reacted to give 28 mg (0.14 mmol, 30%)
1
of the trioxane 10 after column chromatography (c-Hex/EtOAc (1:1), R = 0.85; H-NMR (300 MHz,
f
3
CDCl3):
δ
(ppm): 1.17 (d, 3H, J = 6.0 Hz, O-CH-CH3), 1.77 (s, 3H, C-CH3), 3.44/3.49 (s, 2
×
3H,
-O), 4.13/4.30 (d, 1H, J = 8.6 Hz,
(ppm): 16.2 (q, 1C, O-CH- H ), 19.5
H-O), 87.5 (d, 1C, C- H-OOH), 118.7 (t,
=CH ). CHN-analysis: C H O , (M = 214.30 g/mol), calcd. C 67.26% H
3
3
O-CH ), 4.26 (d, 1H, J = 8.6 Hz, C-CH-OO), 4.28–4.37 (m, 1H, CH -CH
3
3
13
C
H-OOH). 5.13 (s, 2H, C=CH2); C-NMR (75.5 MHz, CDCl3):
δ
C
3
(
q, 1C, C- H ), 51.4/52.3 (q, 2C, C-O- H ), 71.0 (d, 1C, CH -
C
C
C
3
C
3
3
1
C, C-C
H ), 137.0 (s, 1C,
2
C
2
12 22
3
1
0.35% found: C 66.91% H 9.68%.
Methyl-5-hydroxy-2-methylpent-2-enonate (12). A mixture of 0.47 mL of propane-1,3-diol (0.5 g,
.57 mmol) and 5.0 g of the ylene Methyl-2-(triphenylphosphoranyliden)propanoate [54] was dissolved
6
in 17 mL of dichloromethane and 10.4 g of activated MnO were added. The mixture was stirred
2
for 3 days at r.t. and filtered. The solid residue was washed with methylene chloride and, after
solvent evaporation, purified by column chromatography (hexane/EtOAc 1:4, R = 0.52) to give 447 mg
f
1
(
2
6
3.10 mmol, 47%) 12 as a yellow oil. H-NMR (300 MHz, CDCl ):
δ
= 1.81 (s, 3H), 2.40 (q, J = 6.7 Hz,
= 12.6 (q), 32.1 (t), 51.9 (q),
3
H), 3.68 (m, 5H), 6.74 (t, J = 7.3 Hz, 1H); 13C-NMR (75 MHz, CDCl3):
δ
1.2 (t), 129.6 (s), 138.7 (d), 168.6 (s).
Methyl 3,5-dihydroxy-2-methylenpentanoate (14). A chloroform solution of the hydroperoxide 13 (1.93 g,
0.9 mmol), obtained from the photooxygenation of the homoallylic alcohol 12 (following GP-6a), was
treated with 16.5 mL of dimethylsulfide (13.9 g, 223 mmol) and stirred for 18h. After solvent and excess
1

Molecules 2017, 22, 119
12 of 14
reagent evaporation, the residue was purified by column chromatography (CH/EtOAc 2:3, R = 0.30)
f
1
to give 397 mg (2.25 mmol, 21%) 14 as a colorless oil. H-NMR (300 MHz, CDCl ):
1
δ = 1.66 (m, 1H),
3
3
.84 (m, 1H), 3.68 (m, 5H), 4.61 (dd, J = 3.1; 8.5 Hz, 1H), 5.86 (s, 1H), 6.19 (s, 1H); 1 C-NMR (75 MHz,
CDCl ): δ = 37.7 (t), 51.9 (q), 60.5 (t), 69.6 (d), 125.1 (t), 142.5 (s), 166.8 (s).
3
Methyl-2-(2-(4-nitrophenyl)-1,3-dioxan-4-yl)acrylate (15). A mixture of 711 mg of the diol 14 (4.00 mmol)
and 737 mg of 4-nitrobenzaldehyde (4.80 mmol) in 38 mL of dry CH Cl was treated with a
2
2
stoechiometric amount (0.5 mL) of BF3
×
Et O and stirred for 18 h at r.t. After addition of 5 mL
2
of aqueous Na CO , extraction with diethyl ether and solvent evaporation, the residue was purified by
2
3
column chromatography (CH/EtOAc 3:1, R = 0.45) to give 346 mg (1.18 mmol, 49%) 15 as a yellowish
f
◦
1
solid, mp 99 C; H-NMR (300 MHz, CDCl ):
δ = 1.72 (dd, J = 12.0, 4.7 Hz, 1H), 1.86 (t, J = 21.2 Hz, 1H),
3
3
5
δ
.72 (s, 3H), 4.01 (t, J = 11.8 Hz, 1H), 4.24 (dd, J = 11.4, 4.5 Hz, 1H), 4.73 (d, J = 10.6 Hz, 1H), 5.64 (s, 1H),
.95 (s, 1H), 6.28 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H); 13C-NMR (75 MHz, CDCl3):
= 31.9 (t), 52.1 (q), 67.3 (t), 75.0 (d), 99.8 (d), 123.5 (d), 125.8 (t), 127.3 (d), 140.1 (s), 145.0 (s), 148.2 (s),
−
1
1
65.8 (s); IR:
ν (cm ) = 1031 (s), 1093 (s), 1118 (s), 1215 (s), 1273 (m), 1292 (m), 1345 (s), 1437 (m), 1520
(
s), 1607 (m), 1630 (m), 1933 (w), 2858 (w), 2951 (w); CHN analysis (C H NO ): calcd. C 57.34 H 5.16
14
15
6
N 4.78, found C 57.08 H 5.25 N 4.67.
Acknowledgments: This work was supported by the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie and the University of Cologne (network project).
Author Contributions: A.G.G. designed and coordinated the project and wrote the paper, M.B. performed the
research on the 1,3-dioxane 15, M.K. performed the synthesis of the perorthocarbonate 10, A.R. performed the
syntheses and studies of the cyclic peroxides 8a–8e.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Not Available.
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