On the regioselectivity of the intramolecular [2 + 2]-photocycloaddition of alk-3-enyl tetronates

Article abstract of DOI:10.1021/jo201066d

The simple diastereoselectivity and the regioselectivity of the [2 + 2]-photocycloaddition of alk-3-enyl tetronates were studied, depending on the nature of the substituent R in the α-position. Fourteen tetronates were synthesized and their intramolecular photocycloaddition reactions performed. If R was an alkoxycarbonyl group and if the olefin, which underwent the intramolecular addition, was sterically congested, crossed photoproducts prevailed and were formed in yields between 35 and 65%. In all other cases, the straight photoproducts were obtained as the main reaction products in yields ranging from 39 to 84%. The structures of the photochemical products were thoroughly investigated by one- and two-dimensional NMR experiments. In all cases, the diastereoselectivitiy was excellent and only a single diastereoisomer was formed. A mechanistic model is proposed, which explains the regioselectivity of the [2 + 2]-photocycloaddition reaction.

Full text of DOI:10.1021/jo201066d

FEATURED ARTICLE
pubs.acs.org/joc
On the Regioselectivity of the Intramolecular [2 + 2]-
Photocycloaddition of Alk-3-enyl Tetronates
Roland Weixler,† J€org P. Hehn,† and Thorsten Bach*
Lehrstuhl f€ur Organische Chemie I, Technische Universit€at M€unchen, Lichtenbergstr. 4, 85747 Garching, Germany
S Supporting Information
b
ABSTRACT: The simple diastereoselectivity and the regio-
selectivity of the [2 + 2]-photocycloaddition of alk-3-enyl
tetronates were studied, depending on the nature of the
substituent R in the R-position. Fourteen tetronates were
synthesized and their intramolecular photocycloaddition reac-
tions performed. If R was an alkoxycarbonyl group and if the
olefin, which underwent the intramolecular addition, was
sterically congested, crossed photoproducts prevailed and were
formed in yields between 35 and 65%. In all other cases, the
straight photoproducts were obtained as the main reaction
products in yields ranging from 39 to 84%. The structures of the photochemical products were thoroughly investigated by one-
and two-dimensional NMR experiments. In all cases, the diastereoselectivitiy was excellent and only a single diastereoisomer was
formed. A mechanistic model is proposed, which explains the regioselectivity of the [2 + 2]-photocycloaddition reaction.
Scheme 1. Formation of Straight and Crossed [2 + 2]-
Photocycloaddition Products upon Irradiation of Two
Olefins, which are Separated by Three Atoms a, b, and c
’ INTRODUCTION
[2 + 2]-Photocycloaddition reactions1 have shown to be
magnificent reactions for the construction of strained molecules,
and they can be found as key steps in numerous natural product
syntheses.2 As depicted in Scheme 1, [2 + 2]-photocycloaddition
reactions with a three atom tether between the reacting olefins
can occur either in a straight or in a crossed fashion.3 Typically,
the straight product, which goes along with the formation of a
five-membered ring, prevails or is the only reaction product.4
This observation was recognized by Srinivasan et al. and Ham-
mond et al., and the term “rule of five” was coined to account for
the preferred regioselectivity of [2 + 2]-photocycloaddition
reactions.5
Scheme 2. Influence of the Substituent R on the Regio-
selectivity in the Intramolecular [2 + 2]-Photocycloaddition
of Tetronates 1 and 3
During our studies related to the application of tetronate
[2 + 2]-photocycloaddition reactions6 to the total synthesis of
cembranoid natural products,7 we discovered that the regio-
selectivity of the photochemical key step was inverted as a result
of changing one substituent at the chromophore.8 As one would
anticipate from the rule of five,5 the [2 + 2]-photocycloaddition
of tetronate 1 (R = Me) afforded the tetracyclic cyclobutane 2 as
the only reaction product (Scheme 2). In contrast, the tetronate
3 with a methoxycarbonyl substituent in the R-position of the
tetronate was regioselectively converted into the crossed photo-
cycloaddition product 4 upon irradiation.
In order to gain insight into the factors that govern the
regiochemical outcome of related [2 + 2]-photocycloaddition
reactions, we investigated the influence of three structural
parameters: (1) substituent R in the R-position of the tetronate;
(2) substitution pattern at the alk-3-enyl substituent; (3) influ-
ence of the geminal dimethyl group in the γ-position of the
tetronic acid unit. Here, we give a full account of our synthetic
study, which includes the preparation of six tetronic acids and 14
tetronates that were subsequently submitted to an intramolecular
[2 + 2]-photocycloaddition reaction.
Received: June 1, 2011
Published: July 07, 2011
r
2011 American Chemical Society
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FEATURED ARTICLE
Scheme 3. One-Step Synthesis of Tetronic Acids 5 and 6 by
Transesterification and Dieckmann Cyclization
Table 2. Synthesis of Tetronates 1, 3, and 16ꢀ19
entry
substrate
R
R1
product
yield (%)
1
2
3
4
5
6
5
6
H
Me
Me
Me
Me
Me
H
16
1
93
75
90
62
67
24
Table 1. Two-Step Synthesis of Tetronic Acids 11ꢀ14 by
Steglich Esterification and Dieckmann Cyclization
Me
11
12
13
14
COOMe
COOt-Bu
CN
3
17
18
19
COOMe
Scheme 4. Synthesis of Tetronates 20 and 21 Starting from
Tetronate 16
entry
R
R1 yield step 1 (%) yield step 2 (%) product
1
2
3
4
COOMe
Me
70
53
31
55
61
71a
42
11
12
13
14
COOt-Bu Me
CN
Me
COOMe
H
61
aReaction carried out with KOt-Bu in t-BuOH.
’ RESULTS
Synthesis of the Substrates. For the synthesis of tetronic
acids 5 and 6, we adopted a one-step procedure recently published
by Le Gall et al.9 As depicted in Scheme 3, methyl acetate (7) or
methyl propionate (8) were reacted with hydroxyester 9a in the
presence of KOt-Bu in THF to give the desired product 5 or 6 in
48 and 85% yield. In order to purify tetronic acids 5 and 6, but
also for the purification of the tetronic acids mentioned below,
we took advantage of their hydrophilicity at high pH values. The
tetronic acids were dissolved in an aqueous sodium hydroxide
solution phase, which was washed with Et2O to remove any
unpolar impurities. After acidification of the aqueous layer, the
tetronic acids were extracted into a 5:1 mixture of CHCl3 and
i-PrOH.
Tetronic acids 11ꢀ14 with electron-withdrawing substituents
in the R-position were not accessible by the method mentioned
above. They could, however, be prepared by a sequence of
esterification and Dieckmann condensation (Table 1).10 First,
malonic acid monoesters 10a11/b (or the respective nitrile 10c)
were condensed with methyl 2-hydroxyisobutyrate (R1 = Me,
9a) or methyl 2-hydroxyacetate (R1 = H, 9b) by treatment with
di-iso-propylcarbodiimide (DIC) and catalytic amounts of 4-di-
methylaminopyridine (DMAP) in CH2Cl2 (31ꢀ70% yield).12
For the synthesis of nitrile 13, the reaction preferably led to the
formation of an N-acylurea accounting for the low yield of the
esterification product. A similar yield of compound 13 was
obtained by utilizing dicyclohexylcarbodiimide (DCC) and
1-hydroxybenzotriazole (HOBt) as coupling reagents.13 In the
second step, the diester intermediates were cyclized by treatment
with NaOMe in MeOH to generate the tetronic acids 11ꢀ14 in
42ꢀ71% yield. For the synthesis of tert-butyl ester 12, KOt-Bu in
tert-butyl alcohol was employed as base in order to avoid a
transesterification to methyl ester 11.
The coupling of tetronic acids 5, 6 (entries 1 and 2, Table 2),
and 11ꢀ14 (entries 3ꢀ6, Table 2) with cyclohex-2-enemethanol
(15, accessible from cyclohexene in one step)14 was successfully
accomplished by Mitsunobu reactions (Table 2).15 The primary
alcohol 15 and tetronic acids 5, 6, or 11ꢀ14 were stirred in the
presence of triphenylphosphine and di-iso-propylazodicarboxy-
late (DIAD) overnight in THF, and tetronates 1,8 3,8 16,8 17, 18,
and 19 were conveniently obtained after column chromatogra-
phy. These reactions worked reasonably well in yields ranging
from 62 to 93%. In the case of tetronic acid 14, the reaction was
cumbersome and the required tetronate 19 could only be isolated
in a yield of 24%.
It is known that γ,γ-disubstituted tetronates can be deproto-
nated in the R-position with lithium di-iso-propylamide (LDA).16
After deprotonation, tetronate 16 was treated with 1-benzotria-
zolylmethanol (BtCH2OH),17 which is a source of formaldehyde
under basic conditions,18 and the hydroxymethylated tetronate
20 was obtained.8 Contrary to the examples mentioned by
Bischoff et al., which took place at ꢀ78 °C,18 it was essential to
warm the reaction mixture to room temperature to achieve
complete conversion. A subsequent silylation of alcohol 20 with
tert-butyldimethylsilyl chloride (TBSCl) afforded the TBS ether
21 (Scheme 4).
In order to study the influence of the substituents at the
olefinic side chain, several esters of tetronic acids 6 and 11 were
synthesized. A Mitsunobu reaction of tetronic acid 6 with but-3-
enol (22a) generated tetronate 23a in a yield of 74%.15 Tetronate
23b with a tetrasubstituted olefin was obtained from the same
tetronic acid 6 and the literature known bromide 2419 by a
cesium fluoride mediated O-alkylation reaction in DMF
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FEATURED ARTICLE
Scheme 5. Synthesis of Tetronate 23a by Mitsunobu Reac-
tion of Alcohol 22a and Tetronic Acid 6 and Synthesis of 23b
by Nucleophilic Substitution of Bromide 24 with Tetronic
Acid 6
Table 4. Formation of Straight Products 2 and 26-28 by
[2 + 2]-Photocycloaddition of Tetronates 1, 18, 20, and 21
entry
tetronate
R
solvent
product
yield (%)
1
2
3
4
5
1
1
Me
Me
t-BuOH
i-PrOH
t-BuOH
t-BuOH
Et2O
2
2
39
42
20
21
18
CH2OH
CH2OTBS
CN
26
27
28
55
36a
54
a With 17% starting material 21 reisolated.
Table 3. Synthesis of Tetronates 25aꢀ25e by Mitsunobu
Reaction of Alcohol 22aꢀe and Tetronic Acid 11
[2 + 2]-Photocycloaddition Reactions. It has been pre-
viously reported that the [2 + 2]-photocycloaddition of tetro-
nates 1 and 20 proceeds smoothly to afford the cyclobutanes 2
and 26 with straight constitution.8 The reaction of compound 1
was almost equally effective in t-BuOH and i-PrOH (Table 4,
entries 1 and 2). For tetronate 20, only t-BuOH and Et2O were
investigated as solvents, and the better yield was obtained in
t-BuOH (55%, entry 3). Upon irradiation of the TBS ether 21,
the same regioselectivity was found and the photocycloaddition
product 27 was generated in 36% yield (entry 4). The reaction
was hampered by the fact that full conversion of the starting
material could not be achieved. If the irradiation was continued
until all of the starting material 21 was consumed, only dimin-
ished yields of cyclobutane 27 were found, presumably due to
severe decomposition. However, product 27 could conveniently
be separated from starting material 21 by column chromatogra-
phy, so it was beneficial to stop the reaction after 8 h (for the
irradiation conditions, see general procedure C in the Experi-
mental Section and ref 6f). An irradiation at longer wavelength
(λ = 300 nm) did not lead to any conversion in the case of
R-alkyl-substituted tetronates, such as compound 1. Treatment
of silyl ether 27 with tetrabutylammonium fluoride in THF led to
the formation of alcohol 26 in 91% yield. Not only cyclohex-2-
enylmethyl tetronates with electron-donating substituents af-
forded the straight photocycloaddition product, but also the
nitrile 18 gave a straight photoproduct, compound 28 (entry 5).
In this case, Et2O was superior to alcoholic solvents. While a
reaction time of 8 h was necessary for a full conversion of
tetronates 1 and 20, the nitrile 18 was fully converted in only 1
h. It has to be stressed that all of the reactions in Table 4 afforded
the straight photocycloaddition product as the only defined low
molecular weight product. In particular, there was no indication
entry
alcohol
R2
R3
R4
product
yield (%)
1
2
3
4
5
22a
22b
22c
22d
22e
H
H
H
25a
25b
25c
25d
25e
88
75
H
H
Me
H
Me
H
Me
83
68a
ꢀ(CH2)4ꢀ
Me
Me
Me
86
aDIAD was used instead of DBAD.
(Scheme 5).20 Although these substitution reactions between
tetronic acids and alkyl bromides normally take place at room
temperature, a temperature of 120 °C was necessary to obtain full
conversion.
Mitsunobu reactions were also applied to synthesize tetro-
nates 25aꢀe (Table 3).15 The required alcohols 22a and 22b
are commercially available, whereas alcohols 22c21 and 22d22
were prepared according to literature precedence. Alcohol 22e
was obtained from bromide 24 by acetoxylation and hydrolysis
of the acetate (see Experimental Section). Except for tetronate
25d (entry 4), it was difficult to separate the products of the
Mitsunobu reaction from N,N0-di-iso-propoxycarbonylhydrazine
(formed by reduction of DIAD). Thus, di-tert-butylazodi-
carboxylate23 (DBAD) was employed instead of DIAD for the
synthesis of tetronates 25aꢀc and 25e. The hydrazine resulting
from DBAD could easily be removed by column chromatogra-
phy. The tetronates 25aꢀc were isolated in yields between
75 and 88% (entries 1ꢀ3 and 5). Initially, we attempted to
synthesize tetronate 25e from bromide 24 and tetronic acid 11
by using cesium fluoride as a base.20 As opposed to the related
reaction of tetronate 6 with the same bromide (Scheme 5), only
low yields (<10%) of tetronate 25e could be obtained, even at
high temperatures and after long reaction times.
1
for the formation of a crossed product in the crude H NMR.
There was no detectable influence of the solvent on the regios-
electivity in all cases we studied.
In contrast to the regioselectivity observed for the [2 + 2]-
photocycloaddition reactions mentioned above, the compounds
3 and 17 with a carboxylate group in the R-position afforded
selectively the crossed products 48 and 29 in 65 and 37% yield
(Scheme 6). Both reactions worked best if t-BuOH was em-
ployed as the solvent, and both reactions were complete after
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FEATURED ARTICLE
Scheme 6. Formation of Crossed Products 4 and 29 by
[2 + 2]-Photocycloaddition of Tetronates 3 and 17
Scheme 8. Formation of Straight Products 32a and 32b by
[2 + 2]-Photocycloaddition of Tetronates 23a and 23b and
Formation of Crossed Product 33 from Tetronate 25e
Scheme 7. Formation of Crossed Product 30 and Straight
Product 31 by [2 + 2]-Photocycloaddition of Tetronate 19
Table 5. Formation of Straight Products 34a-d by [2 + 2]-
Photocycloaddition of Tetronates 25a-d
30 min. According to the 1H NMR spectra of the crude reaction
products, there was no evidence for the formation of straight
photocycloaddition products. It should be noted that the reac-
tion of tetronate 3 also proceeded at λ = 300 nm in t-BuOH,
but a reaction time of 16 h was necessary for full conversion and
the yield was disappointingly low (37%). In the presence of
10 equiv of acetone as a sensitizer, the photochemical reaction at
λ = 300 nm in t-BuOH was completed much more rapidly (1 h),
thus indicating a triplet mechanism as previously suggested for
other tetronates.6b The higher reaction rate under nonsensitized
conditions as compared to tetronates 1, 20, and 21 is attributed
to the better absorption properties of the alkoxycarbonyl-sub-
stituted tetronates. While substrate 1 for example exhibits an
absorption coefficient ε of 420 Mꢀ1 cmꢀ1 at λ = 254 nm, the
absorption of tetronate 3 is in tert-butyl alcohol about six times
higher (ε = 2600 Mꢀ1 cmꢀ1). The cyano-substituted substrate
18 (Table 4), which exhibits a similar bathochromic shift, showed
a similar reaction rate as tetronate 3 (vide supra).
We next turned our attention to the influence of the geminal
dimethyl group in the γ-position of the tetronic acid unit on the
regioselectivity of the [2 + 2]-photocycloaddition (Scheme 7).
Irradiation of tetronate 19, which lacks the two methyl groups,
led to the formation of two cyclobutanes in 35 and 30% yield.
The reaction products were identified as the crossed product 30
and its straight counterpart 31.
It was questionable whether the special behavior of the
tetronates with carboxylate groups in the R-position was limited
to cyclohex-2-enylmethyl tetronates. Thus, the series of pre-
viously prepared acyclic alk-3-enyl tetronates 23 and 25 was
subjected to irradiation at λ = 254 nm. Our studies commenced
with the [2 + 2]-photocycloaddition of the R-methyl-substituted
tetronates 23a and 23b (Scheme 8). In both cases, a straight
photocycloaddition took place, and the cyclobutanes 32a and
32b were formed as single diastereoisomers in 52 and 46% yield.
No other reaction products could be detected. Similar to our
observations mentioned above, the regioselectivity was inverted
entry
substrate
R2
R3
R4
product
yield (%)
1
2
3
4
25a
25b
25c
25d
H
H
H
34a
34b
34c
34d
78a
75
53b
84a
H
H
Me
H
Me
H
Me
ꢀ(CH2)4ꢀ
aA 90:10 (1H NMR) mixture of isomers; the minor product is tentatively
assigned as the crossed regioisomer. b A second isomer (tentatively
assigned as the crossed regioisomer) was formed according to crude
1H NMR (ratio = 88:12) but could be separated by column
chromatography.
for tetronate 25e with a tetrasubstituted olefin, if the methyl
substituent in the R-position was replaced with a methoxycarbo-
nyl group. In this case, only the crossed photocycloaddition
product 33 was obtained in a yield of 51%. Once again, it was
formed diastereomerically pure, and there was no evidence for
another reaction product.
Subsequently, the influence of the substituents R2, R3, and R4
at the olefinic side chain of the R-methoxycarbonyl-substituted
tetronates was studied (Table 5). As opposed to tetronate 25e
with a tetrasubstituted double bond, the less substituted alk-3-
enyl tetronates 25aꢀd afforded the straight photocycloaddition
products 34aꢀd as the main products in 53ꢀ84% yield. Accord-
ing to 1H NMR data, the least substituted tetronate 25a (entry
1), the tetronate 25c with a terminal dimethyl group (entry 3),
and the tetronate 25d with a cyclic disubstitution at positions R3
and R4 (entry 4) also afforded a small quantity of another isomer
(ratio = 90:10) upon irradiation. We assume that the second
isomer is the crossed isomer. However, due to the small amounts
formed, and due to the difficulties obtaining the side products in
pure form, we could not unambiguously determine their molec-
ular structures. Interestingly, the amount of the second reaction
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FEATURED ARTICLE
product formed from the cyclohexenyl-substituted tetronate 25d
inreased slightly if the reaction was carried out at ꢀ60 °C (90%
yield, ratio = 83:17). If t-BuOH was selected as the solvent for the
irradiation of substrate 25d, a 67:33 ratio of straight photocy-
cloaddition product 34d and the second isomer was formed
(72% overall yield).
While cyclobutane 34a was inseperable from the minor
product, compounds 34c and 34d could be purified by column
chromatography. If the terminal position was unsubstituted and
one methyl group was present as R4 (compound 25b, entry 2),
the [2 + 2]-photocycloaddition proceeded diastereo- and regio-
selectively to generate cyclobutane 34b as a single reaction
product in a yield of 75%.
Structural Assignment of the [2 + 2]-Photocycloaddition
Products. The structural assignment of the photocycloaddition
products was mainly based on two-dimensional NMR experi-
ments. In particular, NOE experiments turned out to be very
helpful to determine the constitution and configuration of the
photochemical reaction products. Furthermore, the molecular
structure of the methyl derivative 2 and that of the methoxy-
carbonyl derivative 4 were proven by single-crystal X-ray
diffraction.8 For the structure determination of the photocy-
cloaddition products 2, 4, and 26ꢀ29, it was most advisible to
investigate the methine proton which bears an NOE correlation
to the endo methyl group. If this methyl group showed an NOE
contact to the methine proton C13ꢀH, a straight constitution
was assigned to the product depicted on the left in Figure 1. If the
endo methyl group had an NOE correlation to the methine
proton C1ꢀH, a crossed constitution was assigned (Figure 1,
right).
2J-coupling constants mentioned above are in good agreement
with those typically obtained for the respective positions in
tetrahydrofurans (2J < 10 Hz)24 and tetrahydropyrans (2J > 10
2
Hz).25 Apart from the J-coupling to C8ꢀHR, the protons
C8ꢀHβ of the straight isomers couple to the vicinal proton with
coupling constants of ca. 8 Hz. Thus, they typically appear as
doublets of doublets, while the protons C13ꢀHβ of the crossed
isomers only couple to the diastereotopic protons C13ꢀHR,
resulting in a doublet multiplicity.
The structural assignment of the [2 + 2]-photocycloaddition
products of tetronates with acyclic alkene units is exemplarily
demonstrated for the cyclobutanes 32b, 33, and 34c. Analogous
to the structure determination mentioned above, the signals
1
in the H and 13C NMR spectra were carefully analyzed
with HMQC (heteronuclear multiple quantum coherence) and
HMBC (heteronuclear multiple bond coherence) experiments
in order to establish the connectivities. As for the cyclohexyl-
substituted cyclobutanes, the 2J-coupling constants for the
methylene protons next to the oxygen atom of the tetrahydro-
furan unit in the straight photocycloaddition products were
lower than 10 Hz. For the assignment of the constitution and
relative configuration, NOE experiments were a valuable tool.
The characteristic NOE contacts of compounds 32b, 33, and 34c
are shown in Figure 2.
In the case of photocycloaddition product 32b, the relative
configuration could easily be proven by means of the depicted
NOE correlations. Unfortunately, the chemical shifts of the 1H
NMR signal of the endo methyl group at C2 and the methyl group
attached to C7 are almost identical, so an unequivocal NOE
signal between these two methyl groups could not be deter-
mined. Still, the connectivity could be established with the help of
the HMBC spectrum of compound 32b (see Supporting In-
formation for details). The NOE experiments of crossed photo-
cycloaddition product 33 and straight product 34c were more
rewarding. Apart from an unambiguous assignment of the
relative configuration on the basis of NOE cross peaks, the
These diagnostic NOE correlations are highlighted with an
asterisk in Figure 1. Apart from that, the multiplicities and
coupling constants of the signals in the 1H NMR were compared.
Table 6 presents a comparison of three representative 1H NMR
signals: The proton C1ꢀH and the diastereotopic protons at
C8ꢀH (straight products 2, 26, and 31) or C13ꢀH (crossed
products 4, 29, and 30). Proton C1ꢀH of the straight products
3
typically couples with three vicinal protons with J-coupling
constants of ca. 9, 8, and 3.5 Hz, while the same proton of the
crossed isomers only couples with two vicinal protons with
coupling constants of ca. 5 Hz each.
The protons C8ꢀHR of the straight products appear as virtual
triplets with a 2J- and a 3J-coupling constant of ca. 9 Hz for the
straight photocycloaddition products, while the corresponding
protons C13ꢀHR of the crossed isomers appear as doublets
of doublets of doublets with 2J-coupling constants of ca. 12 Hz
and 3J-coupling constants of ca. 6 and 1.5 Hz. The values of the
Figure 1. Characteristic NOE signals of the [2 + 2]-photocycloaddition
products of cyclohex-2-enylmethyl tetronates.
Table 6. Chemical Shift δ (ppm), Multiplicities, and Coupling Constants J (Hz) of Representative 1H NMR Signals of Straight
Photocycloaddition Products 2, 26, and 31 and of Crossed Isomers 4, 29, and 30
proton
2
26
31
4
29
30
C1ꢀH
2.37
ddd
2.46
ddd
2.61ꢀ2.74
2.92
2.86
2.26
m
virtual t
∼5.1
4.04
virtual t
∼5.1
4.11
virtual t
∼5.5
4.01
8.7, 8.3, 3.7
4.12
9.0, 7.8, 3.4
4.18
C8ꢀHR or C13ꢀHR
C8ꢀHβ or C13ꢀHβ
4.15
virtual t
∼8.9
virtual t
∼9.0
virtual t
∼9.1
ddd
ddd
ddd
12.2, 6.2, 1.7
3.83
12.1, 6.1, 1.5
3.83
12.2, 6.2, 1.7
3.82
3.85
3.92
3.83
dd
dd
virtual t
∼9.5
d
d
d
8.9, 8.0
9.0, 8.0
12.2
12.1
12.2
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FEATURED ARTICLE
Figure 3. 1,4-Biradicals I and I0 formed as intermediates by five-
membered ring closure from tetronate precursors in an intramolecular
[2 + 2]-photocycloaddition.
Figure 2. Characteristic NOE signals of the [2 + 2]-photocycloaddition
products 32b, 33, and 34c.
Scheme 9. Formation of Hydroxy Acid 37 from Cyclobutane
34b by Fragmentation of Bond a, Nucleophilic Attack of a
Hydroxide Ion, Hydrolysis, and Decarboxylation
Figure 4. General structures II and III and specific structure 38 of
1,4-biradicals formed as intermediates in a six-membered ring closure
from tetronate precursors.
impossible, and this 1,4-biradical is consequently forced to
reverse the CꢀC bond forming event leading to the formation
of starting materials.5c,26
The formation of crossed photocycloaddition products pro-
ceeds via biradicals II or III (Figure 4). Given that in all crossed
products the substituent R is an alkoxycarbonyl group (R =
COOMe, COOt-Bu), which stabilizes an adjacent radical, bir-
adical III seems to be the more likely intermediate. In addition,
this biradical should be formed as a single stereoisomer because the
former terminal alkene carbon atom is not stereogenic (R2 = R3)
or is part of a cyclic ring system. The latter statement is illustrated
by 1,4-biradical 38, which is the putative intermediate respon-
sible for formation of product 4.
constitution could be determined based on the diagnostic signal
of the endo methyl group at C2 to the methyl group (for
compound 33) or proton (for compound 34c) attached to C7.
This NOE contact is highlighted with an asterisk in Figure 2.
The structure of the cyclobutane 34b could not be unambigu-
ously assigned by means of one- and two-dimensional NMR
experiments. In order to elucidate the structure, we resorted to a
fragmentation reaction similar to that previously observed for
compound 4.8 Treatment of diester 34b with lithium hydroxide
in a boiling mixture of THF and water led to a fragmentation of
bond a (Scheme 9). Supposedly, the resulting carboxonium ion
35 was trapped by a hydroxide ion to generate compound 36, and
after two-fold hydrolysis of the ester groups and decarboxylation,
the hydroxyacid 37 was formed. The NMR data of this com-
pound are in agreement with structure 37 and differ clearly from
the set of signals that would be expected from the corresponding
reaction product (a tetrahydropyran-2-ol) of the crossed isomer
of compound 34b.
What makes the reaction pathway leading to straight products
different from the pathway leading to crossed products? The
major influence is certainly exerted by the substituent R, which
provides a stabilization of the adjacent radical center. In cases in
which sterically congested bonds would be formed, cleavage of
the 1,4-biradicals provides a route to access thermodynamically
more favorable constitutions and configurations.28 The sterically
relatively demanding (compared to cyano) alkoxycarbonyl group
exerts this effect in a prominent way. With substrates 1, 3, 17, 18,
20, and 21, a formation of the crossed product is only observed
for compounds 3 and 17 which bear a methoxycarbonyl or tert-
butoxycarbonyl group as substituent R. Inspection of molecular
models supports the notion that there is severe steric repulsion in
straight photocycloaddition products between the substituents
R1 and R4 and between the substituents R2/R3 and R. While the
short-lived 1,4-biradicals derived from R-alkyl-substituted tetro-
nates (R = Me, CH2OH, CH2OTBS) exhibit only limited
retrocleavage from I, and while the relatively small cyano group
(R = CN) does not interfere strongly with R2/R3, the effects are
notable in the reaction of tetronate 25e, in which both the alkene
and the tetronate are highly substituted. As a consequence, a
pathway via the sterically less encumbered intermediate III is
presumably taken, resulting in the crossed photocycloaddition
product 33. The unselective outcome in the reaction of substrate
19 (Scheme 7) can be explained by the reduced steric bulk in
the γ-position of the tetronate (R1 = H), making the steric
’ DISCUSSION
For discussing the outcome of the [2 + 2]-photocycloaddition,
it appears sensible to consider the potential 1,4-biradicals, which
are formed by CꢀC bond formation from the excited triplet state
of the respective tetronate. These species have been shown to be
involved as intermediates in photocycloaddition reactions, and
they have a decisive impact on the regioselectivity.26 The above-
mentioned rule of five suggests a preferred formation of inter-
mediates I and I0 due to the fast ring closure to a five-membered
ring in the initial step (Figure 3).5,27 Diastereoisomer I is
competent to undergo a subsequent ring closure explaining the
formation of all straight products 2, 26, 27, 28, 31, 32a, 32b, and
34aꢀd with the given relative configuration. In diastereoisomer
I0, the trans-orientation of the two radical centers at the tetra-
hydrofuran ring makes the cyclobutane ring formation
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The Journal of Organic Chemistry
FEATURED ARTICLE
interaction between R1 and R4 less severe than in substrate 3. The
two regioisomeric products 30 and 31 are formed in close to
equal amounts.
5,5-Dimethyltetronic Acid (5): Methyl acetate (7, 11.7 mL, 10.9 g,
147 mmol) and methyl 2-hydroxy-iso-butyrate (9a, 20.0 mL, 20.6 g,
176 mmol) were dissolved in 250 mL of THF, KOt-Bu (36.3 g, 323
mmol) was added, and the mixture was heated to reflux overnight. The
solvent was removed under reduced pressure; the residue was taken up
in 1 M aqueous NaOH solution (100 mL) and Et2O (100 mL); the
phases were separated, and the aqueous phase was extracted with Et2O
(100 mL) again. Concentrated HCl was added at 0 °C to adjust pH 1.
The acidified aqueous solution was extracted with a CHCl3/i-PrOH
(5:1) mixture (6 ꢁ 25 mL), dried over Na2SO4, and the solvents were
removed under reduced pressure. After recrystallization from Et2O and
MeOH, tetronic acid 5 (8.95 g, 69.9 mmol, 48%) was obtained as a
yellow solid: mp = 140 °C; 1H NMR (360 MHz, DMSO) δ (ppm) =
1.37 (s, 6H), 4.78 (s, 1H), 12.64 (br s, 1H); 13C NMR (90.6 MHz,
DMSO) δ (ppm) = 24.0 (2C, CH3), 81.3 (C), 85.9 (CH), 171.8 (C),
185.2 (C). The spectroscopic data are in agreement with those reported
in the literature.10a
General Procedure A: Syntheses of Tetronic Acids by
Esterification and Cyclization. I. A solution of the monomethyl
malonate (10a)11 or cyanoacetic acid (10c) (13.0 mmol) in 40 mL of
CH2Cl2 was cooled to 0 °C, hydroxy ester 9a/b (10.0 mmol), DIC (11.0
mmol), and DMAP (1.00 mmol) were added, and the reaction mixture
was stirred at room temperature overnight. The reaction mixture was
filtered; the solvents were removed under reduced pressure; the residue
was suspended in Et2O (80 mL), filtered again, and washed with 1 M
aqueous HCl. The aqueous phase was extracted with Et2O, the
combined organic phases were dried over Na2SO4, filtered, and the
solvents were removed under reduced pressure. The crude malonate was
purified by distillation or column chromatography.
II. The purified malonate (10 mmol) was dissolved in 20 mL of
MeOH, a freshly prepared 1 M solution of NaOMe in MeOH (15 mL,
15 mmol) was added, and the mixture was heated to reflux overnight.
The solvent was removed under reduced pressure; the residue was taken
up in 1 M aqueous NaOH solution (25 mL) and Et2O (25 mL); the
phases were separated, and the aqueous phase was extracted with Et2O
(25 mL) again. Concentrated HCl was added at 0 °C to adjust pH 1. The
acidified aqueous solution was extracted with a CHCl3/i-PrOH (5:1)
mixture (5 ꢁ 25 mL), dried over Na2SO4, and the solvents were
removed under reduced pressure.
Methyl-2-(2-methoxycarbonyl-acetoxy)-2-methyl Propionate: Col-
orless oil, obtained from monomethyl malonate (10a)11 and 2-hydroxy-
iso-butyrate (9a) in 70% yield according to General Procedure A-I: bp
112ꢀ114 °C (5.0 mbar); 1H NMR (360 MHz, CDCl3) δ (ppm) = 1.57
(s, 6H), 3.38 (s, 2H), 3.72 (s, 3H), 3.74 (s, 3H); 13C NMR (90.6 MHz,
CDCl3) δ (ppm) = 24.4 (2C, CH3), 41.3 (CH2), 52.4 (2C, CH3), 79.4
(C), 165.3 (C), 166.7 (C), 172.5 (C). The spectroscopic data are in
agreement with those reported in the literature.30
’ CONCLUSION
In summary, an array of tetronates was synthesized in order to
study the parameters responsible for the formation of straight or
crossed [2 + 2]-photocycloaddition products. While all R-alkyl
tetronates selectively afforded straight photocycloaddition pro-
ducts, it turned out that some R-alkoxycarbonyl-substituted
tetronates were converted to crossed cyclobutanes upon irradia-
tion. Several factors play a role for the observed regioselectivities,
the most prominent being the substituent in the R-position
of the tetronate. The steric bulk of both the substituent in the
γ-position and the olefinic side chain was also found to have an
influence on the regiochemical outcome of the [2 + 2]-photo-
cycloaddition. The results were explained with a mechanistic
model that takes into account that the primarily formed 1,
4-biradical may revert to the starting material if the subsequent
ring closure is thermodynamically unfavorable. In sterically encum-
bered situations, it appears as if the R-alkoxycarbonyl-substituted
tetronates employ this pathway to avoid formation of the straight
photocycloaddition products.
’ EXPERIMENTAL SECTION
General Methods. All reactions sensitive to air or moisture were
carried out in flame-dried glassware under a positive pressure of argon
using standard Schlenk techniques. Dry tetrahydrofuran (THF), di-
chloromethane (CH2Cl2), and diethylether (Et2O) were obtained from
a solvent purification system. Other dry solvents were purchased in the
highest purity available and used without further purification. Technical
solvents used for aqueous workup and for column chromatography
[n-pentane (P), ethyl acetate (EtOAc), diethyl ether (Et2O), dichloro-
methane (CH2Cl2), isopropyl alcohol (i-PrOH), chloroform (CHCl3)]
were distilled prior to use. Flash chromatography was performed on
silica gel 60 (230ꢀ400 mesh) with the indicated eluent mixtures. Thin
layer chromatography (TLC) was performed on silica-coated glass
plates (silica gel 60 F 254); CAM (cerium ammonium molybdate
1
solution) or KMnO4 solution was used as staining agent. H and 13C
NMR spectra were recorded at 298 K and calibrated to the residual
solvent signals. Apparent multiplets which occur as a result of accidental
equality of coupling constants to those of magnetically non-equivalent
protons are marked as virtual (virt.). Hydrogen multiplicities of 13C
NMR were determined by DEPT and 2D HMQC experiments. Melting
points (mp) are not corrected.
3-Methoxycarbonyl-5,5-dimethyltetronic Acid (11): Yellow solid,
obtained from methyl-2-(2-methoxycarbonyl-acetoxy)-2-methyl propio-
nate in 61% yield according to General Procedure A-II: mp = 126 °C
(lit.10a 118ꢀ120 °C); 1H NMR (360 MHz, CDCl3) δ (ppm) = 1.55 (s,
6H), 3.93(s, 3H), 9.87 (s, 1H);13CNMR (90.6 MHz, CDCl3) δ (ppm) =
23.8 (2C, CH3), 52.5 (CH3), 80.9 (C), 93.0 (C), 164.9 (C), 166.9 (C),
194.6 (C). The spectroscopic data are in agreement with those reported in
the literature.10a
Methyl-2-(2-tert-butoxycarbonyl-acetoxy)-2-methyl Propionate:
Colorless oil, obtained from mono-tert-butyl malonate (10b) and
2-hydroxy-iso-butyrate (9a) in 53% yield according to General Proce-
dure A-I: TLC Rf = 0.35 (P/Et2O 3:1); bp 95 °C (0.1 mbar); IR (ATR)
ν~ = 2987 (w, CꢀH), 1750 (s, CdO), 1730 (s, CdO), 1455 (w, CꢀH);
1H NMR (360 MHz, CDCl3) δ (ppm) = 1.47 (s, 9H), 1.57 (s, 6H), 3.28
(s, 2H), 3.73 (s, 3H); 13C NMR (90.6 MHz, CDCl3) δ (ppm) = 24.4
(2C, CH3), 27.9 (3C, CH3), 43.0 (CH2), 52.4 (CH3), 79.1 (C), 82.0
(C), 165.3 (C), 165.7 (C), 172.6 (C); MS (EI, 70 eV) m/z (%) = 229
3,5,5-Trimethyltetronic Acid (6): Methyl propionate (8, 2.88 mL, 2.63
g, 30.0 mmol) and methyl 2-hydroxy-iso-butyrate (9a, 4.01 mL, 4.13 g,
35.0 mmol) were dissolved in 150 mL of THF, KOt-Bu (7.40 g, 66.0
mmol) was added, and the mixture was stirred overnight at room
temperature. The solvent was removed under reduced pressure; the
residue was taken up in 1 M aqueous NaOH solution (50 mL) and Et2O
(50 mL); the phases were separated, and the aqueous phase was
extracted with Et2O (50 mL) again. Concentrated HCl was added at
0 °C to adjust pH 1. The acidified aqueous solution was extracted with a
CHCl3/i-PrOH (5:1) mixture (3 ꢁ 50 mL), dried over Na2SO4, and the
solvents were removed under reduced pressure. Tetronic acid 6 (3.63 g,
25.5 mmol, 85%) was obtained as a light yellow solid in >95% purity: mp
= 140 °C; 1H NMR (250 MHz, CDCl3) δ (ppm) = 1.50 (s, 6H), 1.72 (s,
3H); 13C NMR (62.9 MHz, CDCl3) δ (ppm) = 5.8 (CH3), 24.0 (2C,
CH3), 82.7 (C), 94.6 (C), 177.4 (C), 180.3 (C). The spectroscopic data
are in agreement with those reported in the literature.29
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FEATURED ARTICLE
(2) [(M ꢀ CH3O)+], 201 (11) [(M ꢀ C2H3O2)+], 187 (20) [(M ꢀ
3-tert-Butoxycarbonyl-4-(cyclohex-2-enylmethoxy)-5,5-dimeth-
yl-2-oxo-2,5-dihydrofuran (17): Yellow oil, obtained from alcohol 15
and tetronic acid 12 in 62% yield according to General Procedure B:
TLC Rf = 0.41 (P/Et2O = 3:1), IR (ATR) ν~ = 2982 (w, CꢀH), 2928
(w, CꢀH), 1761 (s, CdO), 1707 (s, CdO), 1644 (s, CdCꢀO), 1465
+
C4H9O)+], 101 (55) [C5H9O2 ], 73 (6) [C4H9O+], 57 (100); HRMS
+
(EI, 70 eV) calcd for C11H17O5 [(M ꢀ OCH3)+] 229.1071; found
229.1076.
3-tert-Butoxycarbonyl-5,5-dimethyltetronic Acid (12): Orange solid,
obtained from methyl-2-(2-tert-butoxycarbonyl-acetoxy)-2-methyl pro-
pionate in 71% yield (ca. 90% purity) according to General Procedure
A-II: mp = 150 °C; IR (ATR) ν~ = 3205 (br s, OꢀH), 2982 (w, CꢀH),
2938 (w, CꢀH), 1765 (s, CdO), 1671 (s, CdO), 1625 (s, CdCꢀO),
1
(w, CꢀH); H NMR (360 MHz, CDCl3) δ (ppm) = 1.33ꢀ1.43 (m,
2H), 1.48 (s, 3H), 1.48 (s, 3H), 1.54 (s, 9H), 1.69ꢀ1.87 (m, 2H),
1.99ꢀ2.06 (m, 2H), 2.51ꢀ2.61 (m, 1H), 4.25 (dd, 2J = 9.7 Hz, 3J = 7.2
Hz, 1H), 4.29 (dd, 2J = 9.7 Hz, 3J = 6.3 Hz, 1H), 5.53 (ddd, 3J = 10.2 Hz,
3J = 4.4 Hz, 4J = 2.1 Hz, 1H), 5.85 (ddd, 3J = 9.9 Hz, 3J = 6.2 Hz, 3J = 3.6
Hz, 1H); 13C NMR (90.6 MHz, CDCl3) δ (ppm) = 20.5 (CH2), 24.4
(2C, CH3), 25.0 (CH2), 25.3 (CH2), 28.0 (3C, CH3), 35.3 (CH), 77.8
(CH2), 81.1 (C), 82.9 (C), 97.5 (C), 125.5 (CH), 130.5 (CH), 161.7
(C), 168.0 (C), 180.7 (C); MS (EI, 70 eV) 322 (1) [M+], 266 (2) [(M ꢀ
C4H9)+], 222 (21) [(M ꢀ CO2 ꢀ C4H9)+], 95 (100) [C7H11+]; HRMS
(EI, 70 eV) calcd for C18H26O5+ [M+] 322.1775; found 322.1770.
4-(Cyclohex-2-enylmethoxy)-3-cyano-5,5-dimethyl-2-oxo-2,5-di-
hydrofuran (18): Yellow oil, obtained from alcohol 15 and tetronic
acid 13 in 67% yield according to General Procedure B: TLC Rf = 0.42
(P/EtOAc 1:1); IR (ATR) ν~ (cmꢀ1) = 2987 (w, CꢀH), 2938 (w,
CꢀH), 2235 (w, CꢂN), 1765 (m, CdO), 1634 (s, CdCꢀO), 1465
(CꢀH); 1H NMR (360 MHz, CDCl3) δ (ppm) = 1.39ꢀ1.48 (m, 1H),
1.53 (s, 3H), 1.54 (s, 3H), 1.59ꢀ1.68 (m, 1H), 1.74ꢀ1.83 (m, 1H),
1.85ꢀ1.93 (m, 1H), 2.02ꢀ2.07 (m, 2H), 2.66ꢀ2.74 (m, 1H), 4.55
(d,3J = 6.7 Hz, 2H), 5.57 (dd, 3J = 10.0 Hz, 3J = 2.2 Hz, 1H), 5.92 (ddd,
3J = 10.0, 3J = 6.0, 3J = 3.6 Hz, 1H); 13C NMR (90.6 MHz, CDCl3) δ
(ppm) = 20.3 (CH2), 24.2 (CH2), 24.2 (CH2), 24.9 (2C, CH3), 35.0
(CH), 76.8 (CH2), 78.1 (C), 83.2 (C), 111.4 (C), 124.4 (CH), 131.3
(CH), 165.9 (C), 188.0 (C); MS (EI, 70 eV) m/z (%) = 247 (1) [M+],
1
1474 (w, CꢀH), 1441 (w, CꢀH); H NMR (360 MHz, CDCl3) δ
(ppm) = 1.54 (s, 6H), 1.59 (s, 9H), OH proton not visible; 13C NMR
(90.6 MHz, CDCl3) δ (ppm) = 23.8 (3C, CH3), 28.1 (2C, CH3), 80.4
(C), 84.3 (C), 93.9 (C), 165.6 (C), 166.1 (C), 194.2 (C); MS (EI,
70 eV) m/z (%) = 171 (36) [(M ꢀ C4H9)+], 127 (39) [(M ꢀ C4H9 ꢀ
CO2)+], 112 (34) [(M ꢀ C4H9 ꢀ CH3 ꢀ CO2)+], 86 (26) [C4H6O2 ],
+
+
70 (100); HRMS (ESI) calcd for C7H9O5 [(M ꢀ C4H9 + 2H)+]
173.0444; found 173.0441.
Methyl-2-(2-cyanoacetoxy)-2-methyl Propionate: Yellow oil, ob-
tained from cyanoacetic acid (10c) and 2-hydroxy-iso-butyrate (9a) in
31% yield according to General Procedure A-I: TLC Rf = 0.64 (P/EtOAc
1:1); IR (ATR) ν~ (cmꢀ1) = 2957 (w, CꢀH), 2923 (w, CꢀH), 1740
(s, CdO), 1440 (w, CꢀH); 1H NMR (360 MHz, CDCl3) δ (ppm) =
1.61 (s, 6H), 3.47 (s, 2H), 3.75 (s, 3H); 13C NMR (90.6 MHz, CDCl3) δ
(ppm) = 24.4 (CH3), 24.9 (CH3), 27.2 (CH2), 52.7 (CH3), 81.1 (C),
112.7 (C), 161.9 (C), 171.8 (C); MS (EI, 70 eV) m/z (%) = 185 (1)
+
[M+], 154 (2) [(M ꢀ CH3O)+], 126 (25) [C6H8NO2 ], 68 (9)
[C3H2NO+], 59 (100) [C3H6O+]; HRMS (EI, 70 eV) calcd for
C7H8NO3+ [(M ꢀ OCH3)+] 154.0499; found 154.0502.
3-Cyano-5,5-dimethyltetronic Acid (13): Beige solid, obtained from
methyl-2-(2-cyanoacetoxy)-2-methyl propionate in 42% yield according
to General Procedure A-II: mp 175ꢀ177 °C; IR (ATR) ν~ = 3447
(w, CdC), 2997 (w, CꢀH), 2943 (w, CꢀH), 2337 (w, CꢂN), 1697
(s, CdO), 1474 (s, CꢀH); 1H NMR (360 MHz, DMSO-d6) δ (ppm) =
1.50 (s, 6H), 3.86 (s, 1H), 8.00 (br s, 1H), additional signals due to
tautomeric equilibrium; 13C NMR (62.9 MHz, DMSO-d6) δ (ppm) =
23.9 (2C, CH3), 70.6 (C), 83.0 (C), 112.1 (C), 165.6 (C), 177.8 (C);
220 (1) [(M ꢀ CN)+], 188 (2) [C11H13NO2 ], 136 (3) [C7H7NO2 ],
+
+
95 (100) [C7H11+]; HRMS (EI, 70 eV) calcd for C14H17NO3 [M+]
+
247.1203; found 247.1207.
4-(Cyclohex-2-enylmethoxy)-3-methoxycarbonyl-2-oxo-2,5-di-
hydrofuran (19): Yellow oil, obtained from alcohol 15 and tetronic acid
14 in 24% yield according to General Procedure B: TLC Rf = 0.27
(Et2O) mp = 82ꢀ83 °C; IR (ATR) ν~ (cmꢀ1) = 2938 (w, CꢀH), 2860
(w, CꢀH), 1775 (s, CdO), 1750 (s, CdO), 1712 (s, CdO), 1615
(s, CdCꢀO), 1445 (w, CꢀH); 1H NMR (360 MHz, CDCl3) δ (ppm) =
1.40ꢀ1.47 (m, 1H), 1.56ꢀ1.64 (m, 1H), 1.71ꢀ1.77 (m, 1H), 1.85ꢀ
1.90 (m, 1H), 2.01ꢀ2.06 (m, 2H), 2.62ꢀ2.70 (m, 1H), 3.84 (s, 3H),
4.12 (dd, 2J = 8.6 Hz, 3J = 6.7 Hz, 1H), 4.15 (dd, 2J = 8.6 Hz, 3J = 5.7 Hz,
1H), 4.76 (s, 2H), 5.55 (ddd, 3J = 10.0 Hz, 3J = 4.4 Hz, 4J = 2.2 Hz, 1H),
MS (EI, 70 eV) m/z (%) = 153 (12) [M+], 59 (20) [C3H O+], 43
7
(100); HRMS (EI, 70 eV) calcd for C7H7NO3+ [M+] 153.0420; found
153.0426.
Methyl-2-(2-methoxycarbonylacetoxy)acetate: Colorless oil, ob-
tained from monomethyl malonate11 and 2-hydroxyacetate (9b) in
55% yield according to General Procedure A-I: bp 119 °C (7.0 mbar);
IR (ATR) ν~ = 2997 (w, CꢀH), 2957 (w, CꢀH), 1736 (s, CdO), 1440
(m, CꢀH); 1H NMR (250 MHz, CDCl3) δ (ppm) = 3.51 (s, 2H), 3.76
(s, 3H), 3.77 (s, 3H), 4.68 (s, 2H); 13C NMR (62.9 MHz, CDCl3) δ
(ppm) = 40.9 (CH2), 52.5 (CH3), 52.8 (CH3), 61.4 (CH2), 166.0 (C),
166.5 (C), 167.7 (C); MS (EI, 70 eV) m/z (%) = 159 (11) [(M ꢀ
4
5.89 (d virt. td, 3J = 10.0 Hz, 3J ≈ J ≈ 3.7 Hz, 4J = 2.5 Hz, 1 H, C30-H);
13C NMR (90.6 MHz, CDCl3) δ (ppm) = 20.2 (CH2), 25.0 (CH2), 25.1
(CH2), 35.3 (CH), 51.9 (CH3), 65.2 (CH2), 76.6 (CH2), 96.6 (C),
124.9 (CH), 131.1 (CH), 161.2 (C) 168.8 (C), 182.2 (C); MS (ESI) m/
z = 527 [(2 M + Na)+], 275 [(M + Na)+], 253 [(M + H)+]; HRMS
(ESI) calcd for C13H16NaO5+ [(M + Na)+] 275.0890; found 275.0890.
3-[(tert-Butyldimethylsilyloxy)methyl]-4-(cyclohex-2-enylmethoxy)
-5,5-dimethylfuran-2-(5H)-one (21). 4-(Cyclohex-2-enylmethoxy)-
3-(hydroxymethyl)-5,5-dimethylfuran-2-(5H)-on (20, 1.67 g, 6.62
mmol) was dissolved in 66 mL of CH2Cl2 and cooled to 0 °C, tert-
butyldimethylsilyl chloride (1.50 g, 9.93 mmol) and imidazole (1.35 g,
19.9 mmol) were added, and the reaction mixture was stirred for 10 h at
room temperature. Saturated aqueous NH4Cl (50 mL) was added, the
phases were separated, and the aqueous phase was extracted with
CH2Cl2 (2 ꢁ 50 mL). The combined organic phases were dried over
Na2SO4, filtered, and the solvents were removed under reduced
pressure. Purification by flash chromatography (P/Et2O 6:1 f 4:1)
afforded TBS-ether 21 (2.33 g, 6.36 mmol, 96%) as a light yellow oil:
TLC Rf = 0.26 (P/Et2O 6:1); IR (ATR) ν~ (cmꢀ1) = 2933 (m, CꢀH),
2890 (w, CꢀH), 2856 (w, CꢀH), 1755 (s, CdO), 1649 (s, CdCꢀO);
1H NMR (250 MHz, CDCl3) δ (ppm) = 0.08 (s, 6H), 0.87 (s, 9H), 1.44
(s, 6H), 1.46ꢀ1.90 (m, 4H), 1.97ꢀ2.08 (m, 2H), 2.49ꢀ2.64 (m, 1H),
+
+
CH3O)+], 101 (100) [C4H5O3 ], 59 (69) [C2H3O2 ]; HRMS (EI,
70 eV) calcd for C6H7O5+ [M+] 159.0288; found 159.0296.
3-Methoxycarbonyltetronic Acid (14): Yellow solid, obtained from
methyl-2-(2-methoxycarbonylacetoxy)acetate in 61% yield according to
1
General Procedure A-II: mp = 162ꢀ163 °C (lit.30 166ꢀ167 °C); H
NMR (360 MHz, CDCl3) δ (ppm) = 3.96 (s, 3H), 4.80 (s, 2H); OH
protonnotvisible; 13C NMR (90.6 MHz, CDCl3) δ (ppm) = 52.6 (CH3),
66.2 (CH2), 95.2 (C), 166.6 (C), 169.1 (C), 189.3 (C). The spectro-
scopic data are in agreement with those reported in the literature.30
General Procedure B: Mitsunobu Reactions of Tetronic
Acids with Primary Alcohols. The tetronic acid (10.0 mmol) was
dissolved in THF (100 mL) followed by the addition of the primary
alcohol (10.0 mmol). The mixture was cooled to 0 °C, triphenylpho-
sphine (11.0 mmol) and di-iso-propyl azodicarboxylate (11.0 mmol)
were added, and the reaction was allowed to warm to room temperature
overnight. The solvent was removed under reduced pressure, and the
residue was purified by flash chromatography.
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FEATURED ARTICLE
3
4.37 (s, 2H), 4.43ꢀ4.48 (m, 2H), 5.57 (dd, J = 9.9 Hz, 2.2 Hz, 1H),
5.81ꢀ5.90 (m, 1H); 13C NMR (90.6 MHz, CDCl3) δ (ppm) = ꢀ5.2
(CH3), ꢀ5.2 (CH3), 18.0 (C), 20.5 (CH2), 24.4 (2C, CH3), 25.1
(CH2), 25.3 (CH2), 25.8 (3C, CH3), 35.7 (CH), 54.0 (CH2), 75.6
(CH2), 80.7 (C), 99.1 (C), 126.0 (CH), 130.1 (CH), 172.7 (C),
180.4 (C); MS (EI, 70 eV) m/z (%) = 351 (1) [(M ꢀ CH3)+], 309 (20)
[(M ꢀ C4H9)+], 271 (6) [(M ꢀ C7H11)+], 215 (100), 95 (50)
[C7H11+]; HRMS (EI, 70 eV) calcd for C16H25O4Si+ [(M ꢀ C4H9)+]
309.1517; found 309.1518.
tetronic acid 11 in 88% yield according to General Procedure B, with the
exception that DBAD was used instead of DIAD: TLC Rf = 0.20
(P/Et2O 3:2); IR (ATR) ν~ (cmꢀ1) = 2987 (w, CꢀH), 2952 (w, CꢀH),
1766 (s, CdO), 1716 (s, CdO), 1469 (m, CꢀH), 1435 (m, CꢀH); 1H
NMR (360 MHz, CDCl3) δ (ppm) = 1.47 (s, 6H), 2.50 (virt. q, J ≈ 6.4
Hz, 2H), 3.85 (s, 3H), 4.50 (t, 3J = 6.4 Hz, 2H), 5.11ꢀ5.18 (m, 2H), 5.77
(ddt, 3J = 17.1 Hz, 3J = 10.3 Hz, 3J = 6.7 Hz, 1H); 13C NMR (90.6 MHz,
CDCl3) δ (ppm) = 24.4 (2C, CH3), 33.5 (CH2), 52.5 (CH3), 74.1
(CH2), 81.4 (C), 95.6 (C), 118.2 (CH2), 132.7 (CH), 162.8 (C), 167.6
(C), 183.5 (C); MS (EI, 70 eV) m/z (%) = 240 (1) [M+], 209 (5)
[(M ꢀ CH3O)+], 196 (4) [(M ꢀ CO2)+], 55 (100); HRMS (EI, 70 eV)
calcd for C11H13O4+ [(M ꢀ CH3O)+] 209.0808; found 209.0816.
3-Methoxycarbonyl-5,5-dimethyl-4-(4-methylpent-3-enyloxy)-
2-oxo-2,5-dihydrofuran (25b): Light yellow oil, obtained from alcohol
22b and tetronic acid 11 in 75% yield according to General Procedure B,
with the exception that DBAD was used instead of DIAD: TLC Rf = 0.26
(P/Et2O 1:1); IR (ATR) ~ν (cmꢀ1) = 2982 (w, CꢀH), 2952 (w, CꢀH),
1760 (s, CdO), 1716 (s, CdO), 1634 (s, CdCꢀO), 1441 (m, CꢀH),
1H NMR (500 MHz, CDCl3) δ (ppm) = 1.46 (s, 6H), 1.74ꢀ1.76 (m,
3H), 2.45 (t, 3J = 6.5 Hz, 2H), 3.86 (s, 3H), 4.56 (t, 3J = 6.5 Hz, 2H),
4.73ꢀ4.76 (m, 1H), 4.84ꢀ4.87 (m, 1H); 13C NMR (62.5 MHz, CDCl3)
δ (ppm) = 22.3 (CH3), 24.4 (2C, CH3), 37.0 (CH2), 52.6 (CH3), 73.1
(CH2), 81.4 (C), 95.3 (C), 113.1 (CH2), 140.2 (C), 162.8 (C), 167.7
(C), 183.6 (C); MS (EI, 70 eV) m/z (%) = 254 (5) [M+], 224 (2)
4-But-3-enyloxy-3,5,5-trimethyl-furan-2(5H)-one (23a): Light yel-
low oil, obtained from alcohol 22a and tetronic acid 6 in 74% yield
according to General Procedure B: TLC Rf = 0.29 (P/Et2O 3:2); IR
(ATR) ν~ (cmꢀ1) = 2982 (w, CꢀH), 2933 (w, CꢀH), 1745 (s, CdO),
1663 (s, CdCꢀO), 1469 (w, CꢀH); 1H NMR (250 MHz, CDCl3) δ
(ppm) = 1.39 (s, 6H), 1.94 (s, 3H), 2.48 (virt. q, 3J ≈ 6.6 Hz, 2H), 4.39
(t, 3J = 6.6 Hz, 2H), 5.10ꢀ5.20 (m, 2H), 5.80 (ddt, 3J = 17.0 Hz, 3J = 10.2
Hz, J = 6.6 Hz, 1H); 13C NMR (62.9 MHz, CDCl3) δ (ppm) = 8.6
3
(CH3), 24.5 (2C, CH3), 33.9 (CH2), 70.3 (CH2), 80.8 (C), 94.7 (C),
118.0 (CH2), 132.9 (CH), 174.0 (s), 176.2 (s); MS (EI, 70 eV)
m/z (%) = 196 (3) [M+], 181 (1) [(M ꢀ CH3)+], 125 (4) [(M ꢀ
+
C4H7O)+], 110 (21) [(M ꢀ C4H6O2)+], 55 (100) [C4H7 ]; HRMS
(EI, 70 eV) calcd for C11H16O3+ [M+] 196.1094; found 196.1100.
4-((3,4-Dimethylpent-3-en-1-yl)oxy)-3,5,5-trimethylfuran-2(5H)-
one (23b). 3,5,5-Trimethyltetronic acid (6, 40.1 mg, 282 μmol) was
dissolved in 4 mL of DMF followed by the addition of 5-bromo-2,3-
dimethylpent-2-ene19 (24, 95.2 mg, 564 μmol) and CsF (94.3 mg,
621 μmol). The reaction mixture was stirred at 120 °C for 24 h, cooled to
room temperature, and water (30 mL) was added. The mixture was
extracted with EtOAc (4 ꢁ 30 mL), the comined organic phases were
washed with brine (30 mL), dried over Na2SO4, filtered, and the solvent
was removed under reduced pressure. Purification by flash chromatog-
raphy (P/Et2O 2:1 f 1:1) afforded tetronate 23b (55.3 mg, 232 μmol,
82%) as a light yellow oil: TLC Rf = 0.41 (P/Et2O = 1:1); IR (ATR) ν~ =
2982 (w, CꢀH), 2933 (w, CꢀH), 1750 (s, CdO), 1663 (s, CdCꢀO),
1465 (w, CꢀH); 1H NMR (250 MHz, CDCl3) δ (ppm) = 1.38 (s, 6H),
1.67 (s, 3H), 1.69 (s, 6H), 1.94 (s, 3H), 2.47 (t, 3J = 7.0 Hz, 2H), 4.34 (t,
3J = 7.0 Hz, 2H); 13C NMR (62.9 MHz, CDCl3) δ (ppm) = 8.6 (CH3),
18.7 (CH3), 20.4 (CH3), 20.7 (CH3), 24.5 (CH3), 30.9 (CH3), 34.6
(CH2), 70.0 (CH2), 80.8 (C), 94.6 (C), 122.2 (C), 128.0 (C), 174.2
(C), 176.6 (C); MS (EI, 70 eV) m/z (%) = 238 (4) [M+], 169 (25)
+
+
[M ꢀ C2H6], 69 (98) [C5H9 ], 41 (100) [C3H5 ]; HRMS (EI, 70 eV)
calcd for C13H18O5+ [M+] 254.1149; found 254.1150.
3-Methoxycarbonyl-5,5-dimethyl-4-(3-methylbut-3-enyloxy)-
2-oxo-2,5-dihydrofuran (25c): Light yellow oil, obtained from alcohol
22c and tetronic acid 11 in 83% yield according to General Procedure B,
with the exception that DBAD was used instead of DIAD: TLC Rf = 0.28
(P/Et2O 1:1); IR (ATR) ν~ = 2977 (w, CꢀH), 2928 (w, CꢀH), 1765 (s,
CdO), 1716 (s, CdO), 1634 (s, CdCꢀO), 1436 (m, CꢀH); 1H NMR
(250 MHz, CDCl3) δ (ppm) = 1.46 (s, 6H), 1.63 (s, 3H), 1.71 (s, 3H),
2.43 (virt. q, 3J = 6.7 Hz, 2H), 3.85 (s, 3H), 4.41 (t, 3J = 6.7 Hz, 2H),
5.06ꢀ5.10 (m, 1H); 13C NMR (62.9 MHz, CDCl3) δ (ppm) = 17.9
(CH3), 24.3 (2C, CH3), 25.7 (CH3), 28.1 (CH2), 52.6 (CH3), 75.0
(CH2), 81.4 (C), 95.3 (C), 118.1 (C), 135.6 (CH), 163.0 (C), 167.8
(C), 183.8 (C); MS (EI, 70 eV) m/z (%) = 268 (1) [M+], 237 (5)
+
[(M ꢀ CH3O)+], 155 (21) [C7H7O4 ], 82 (100) [C6H10+], 55 (53)
+
+
[C4H7 ]; HRMS (EI, 70 eV) calcd for C13H17O4 [(M ꢀ CH3O)+]
[(M ꢀ C5H9)+], 55 (100) [C4H7 ]; HRMS (EI, 70 eV) calcd for
+
237.1121; found 237.1120.
C14H22O3+ [M+] 238.1563; found 238.1568.
3-Methoxycarbonyl-5,5-dimethyl-4-(2-(cyclohex-1-en-1-yl)ethoxy)-
2-oxo-2,5-dihydrofuran (25d): Light yellow oil, obtained from alcohol
22d and tetronic acid 11 in 68% yield according to General Procedure B:
TLC Rf = 0.30 (P/EtOAc 1:1); IR (ATR) ν~ (cmꢀ1) = 2982 (w, CꢀH),
2933 (m, CꢀH), 1765 (s, CdO), 1716 (s, CdO), 1634 (s, CdCꢀO),
1465 (w, CꢀH); 1H NMR (360 MHz, CDCl3) δ (ppm) = 1.46 (s, 6H),
1.52ꢀ1.66 (m, 4H), 1.92ꢀ1.99 (m, 4H), 2.36 (t, 3J = 6.4 Hz, 2H), 3.86
(s, 3H), 4.52 (t, 3J = 6.4 Hz, 2H), 5.48 (m, 1H); 13C NMR (90.6 MHz,
CDCl3) δ (ppm) = 19.6 (CH2), 22.2 (CH2), 22.7 (CH2), 24.4 (CH3),
25.2 (CH3), 28.2 (CH2), 37.4 (CH2), 52.6 (CH3), 73.5 (CH2), 81.4
(C), 95.2 (C), 124.6 (CH), 132.4 (C), 162.8 (C), 167.8 (C), 183.8 (C);
MS (EI, 70 eV) m/z (%) = 294 (6) [M+], 263 (2) [(M ꢀ CH3O)+], 187
3,4-Dimethylpent-3-en-1-ol (22e). 5-Bromo-2,3-dimethyl-pent-2-
ene19 (24, 512 mg, 2.89 mmol) was dissolved in DMF, and NaOAc
(474 mg, 5.78 mmol) was added. After stirring at 80 °C for 14 h, water
(100 mL) and Et2O (100 mL) were added; the phases were separated;
the aqueous phase was extracted with Et2O (100 mL), and the combined
organic phases were washed with water (200 mL). The solvents were
removed under reduced pressure, NaOH (6 mL, 1 M) and MeOH
(27 mL) were added, and the reaction mixture was stirred at room
temperature for 1 h. Most of the organic solvent was removed under
reduced pressure, and the residue was extracted with EtOAc (50 mL).
The combined organic phases were dried over MgSO4, filtered, and the
solvent was removed under reduced pressure. Purification by column
chromatography (P/Et2O 2:1) afforded alcohol 22e (255 mg, 2.23
mmol, 77%) as a colorless liquid: TLC Rf = 0.27 (P/Et2O = 2:1); 1H
NMR (500 MHz, CDCl3) δ (ppm) = 1.65 (s, 3H), 1.67 (s, 3H), 1.69 (s,
3H), 2.34 (t, 3J = 6.8 Hz, 2H), 3.63 (t, 3J = 6.8 Hz, 2H) OH proton not
visible; 13C NMR (62.9 MHz, CDCl3) δ (ppm) = 18.3 (CH3), 20.3
(CH3), 20.7 (CH3), 37.5 (CH2), 60.8 (CH2), 123.4 (C), 127.6 (C). The
spectroscopic data are in agreement with those reported in the
literature.31
+
(100), 155 (91) [C7H7O4 ], 108 (81) [C8H12+]; HRMS (EI, 70 eV)
calcd for C16H22O5+ [M+] 294.1462; found 294.1465.
3-Methoxycarbonyl-5,5-dimethyl-4-(3,4-dimethylpent-3-enyloxy)-
2-oxo-2,5-dihydrofuran (25e): Light yellow oil, obtained from alcohol
22e and tetronic acid 11 in 86% yield according to General Procedure B,
with the exception that DBAD was used instead of DIAD: TLC Rf = 0.31
(P/Et2O 1:1); IR (ATR) ν~ (cmꢀ1) = 2982 (w, CꢀH), 2923 (w, CꢀH),
1765 (s, CdO), 1716 (s, CdO), 1634 (s, CdCꢀO), 1469 (s, CꢀH);
1H NMR (360 MHz, CDCl3) δ (ppm) = 1.46 (s, 3H), 1.47 (s, 3H), 1.67
(s, 3H), 1.68 (s, 3H), 2.50 (t, 3J = 6.8 Hz, 2H), 3.86 (s, 3H), 4.46 (t, 3J =
6.8 Hz, 2H); 13C NMR (90.6 MHz, CDCl3) δ (ppm) = 18.5 (CH3),
4-(But-3-enyloxy)-3-methoxycarbonyl-5,5-dimethyl-2-oxo-2,
5-dihydrofuran (25a): Light yellow oil, obtained from alcohol 22a and
5932
dx.doi.org/10.1021/jo201066d |J. Org. Chem. 2011, 76, 5924–5935

The Journal of Organic Chemistry
FEATURED ARTICLE
20.4 (CH3), 20.7 (CH3), 24.3 (CH3), 28.1 (CH3), 34.0 (CH2), 52.6
(CH3), 73.8 (CH2), 81.4 (C), 100.0 (C), 121.9 (C), 128.2 (C), 162.8
(C), 162.9 (C), 183.9 (C); MS (EI, 70 eV) m/z (%) = 282 (1) [M+],
251 (3) [(M ꢀ CH3O)+], 186 (35) [(M ꢀ C7H12)+], 96 (100)
[C7H12+]; HRMS (EI, 70 eV) calcd for C14H19O4+ [(M ꢀ CH3O)+]
251.1278; found 251.1283.
General Procedure C: [2 + 2]-Photocycloaddition Reac-
tions. The tetronate was dissolved in t-BuOH or Et2O, degassed by
purging with Ar in an ultrasonicator for 15 min, and irradiated in a
Rayonet RPR 100 merry-go-round reactor, equipped with 16 Rayonet
RPR 2537 Å lamps (λ = 254 nm). Unless otherwise stated, the reaction
was stopped when the starting material was fully consumed according
to TLC and GC analysis. Then the solvent was removed and the
residue was purified by column chromatography. Except as otherwise
noted, only one reaction product could be determined. Typically, an
immobile spot could be seen on TLC, which we tentatively attribute to
polymeric side-products.
2933 (w, CꢀH), 1762 (s, CdO), 1708 (s, CdO), 1465 (w, CꢀH); 1H
NMR (500 MHz, CDCl3) δ (ppm) = 1.33 (s, 3H), 1.49 (s, 9H),
1.46ꢀ1.59 (m, 3H), 1.61 (s, 3H), 1.70ꢀ1.78 (m, 2H), 1.90ꢀ2.01 (m,
1H), 2.27 (virt. t, 3J ≈ 4.8 Hz, 1H), 2.63ꢀ2.68 (m, 1H), 2.86 (virt. t, 3J ≈
5.1 Hz, 1H), 3.83 (d, 2J = 12.1 Hz, 1H), 4.11 (ddd, 2J = 12.1 Hz, 3J = 6.1
Hz, 3J = 1.5 Hz, 1H); 13C NMR (90.6 MHz, CDCl3) δ (ppm) = 17.3
(CH2), 20.2 (CH2), 21.5 (CH3), 22.0 (CH3), 27.7 (3C, CH3), 28.1
(CH2), 32.8 (CH), 36.3 (CH), 40.1 (CH), 60.7 (C), 70.1 (CH2), 83.0
(C), 86.1 (C), 95.1 (C), 165.7 (C), 172.0 (C); MS (EI, 70 eV)
m/z (%) = 322 (15) [M+], 265 (32) [(M ꢀ C4H9)+], 221 (24)
[(M ꢀ CO2 ꢀ C4H9)+], 95 (100) [C7H11+]; HRMS (EI, 70 eV) calcd
for C18H26O5+ [M+] 322.1775; found 322.1770.
6-Methoxycarbonyl-2,8-oxaethano-4-oxatricyclo[5.4.0.02,6
]
undecan-5-one (30): Colorless solid, obtained from tetronate 19 in
35% yield according to General Procedure C (reaction time = 30 min):
mp = 91ꢀ92 °C; TLC Rf = 0.24 (P/Et2O 3:1); IR (ATR) ν~ (cmꢀ1) =
2943 (m, CꢀH), 2917 (m, CꢀH), 2856 (w, CꢀH), 1770 (s, CdO),
1
1716 (s, CdO), 1436 (w, CꢀH); H NMR (500 MHz, CDCl3) δ
2-[(tert-Butyldimethylsilyloxy)methyl]-5,5-dimethyl-4,7-dioxate-
tracyclo[7.3.1.02,6.06,13]tridecan-3-one (27): Colorless solid, obtained
from tetronate 21 in 36% yield (+ 17% starting material 21) according to
General Procedure C (reaction time = 8 h): mp = 73 °C; TLC Rf = 0.17
(P/Et2O 4:1); IR (ATR) ν~ (cmꢀ1) = 2933 (s, CꢀH), 2856 (m, CꢀH),
1766 (s, CdO), 1465 (w, CꢀH), 1087 (s, CꢀO); 1H NMR (500 MHz,
CDCl3) δ (ppm) = 0.07 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.36 (s, 3H),
1.43 (s, 3H), 1.45ꢀ1.61 (m, 6H), 2.41ꢀ2.46 (m, 1H), 2.52ꢀ2.60 (m,
1H), 3.05 (virt. t, 3J ≈ 9.6 Hz, 1H), 3.88 (d, 2J = 10.2 Hz, 1H), 3.90 (dd,
2J = 9.1 Hz, 3J = 7.4 Hz, 1H) 4.01 (d, 2J = 10.2 Hz, 1H), 4.16 (virt. t, 2J ≈
3J ≈ 8.9 Hz, 1H); 13C NMR (90.6 MHz, CDCl3) δ (ppm) = ꢀ5.7
(CH3), ꢀ5.6 (CH3), 18.4 (C), 18.4 (CH2), 21.1 (CH2), 22.3 (CH3),
23.7 (CH3), 23.8 (CH2), 25.9 (3C, CH3), 30.7 (CH), 33.9 (CH), 37.2
(CH), 54.2 (C), 58.2 (CH2), 76.7 (CH2), 84.2 (C), 93.0 (C), 178.7 (C);
MS (EI, 70 eV) m/z (%) = 351 (4) [(M ꢀ CH3)+], 309 (100) [(M ꢀ
C4H9)+], 279 (15) [(M ꢀ C6H15Si)+], 235 (8) [(M ꢀ C6H15OSi)+], 95
(74) [C7H11+]; HRMS (EI, 70 eV) calcd for C16H25O4Si+ [(M ꢀ
C4H9)+] 309.1517; found 309.1524.
(ppm) = 1.45ꢀ1.62 (m, 3H), 1.70ꢀ1.80 (m, 2H), 1.92ꢀ2.01 (m, 1H),
2.26 (virt. t, 3J ≈ 5.5 Hz, 1H), 2.72 (virt. q, 3J ≈ 5.0 Hz, 1H), 2.92 (virt. t,
3J ≈ 5.1 Hz, 1H), 3.80 (s, 3H), 3.82 (d, 1 H, 2J = 12.2 Hz), 4.01 (ddd, 2J =
12.2 Hz, 3J = 6.2 Hz, 4J = 1.7 Hz, 1H), 4.11 (d, 2J = 8.7 Hz, 1H), 4.30 (d,
2J = 8.7 Hz, 1H); 13C NMR (90.6 MHz, CDCl3) δ (ppm) = 17.1 (CH2),
19.3 (CH2), 27.7 (CH2), 32.3 (CH), 37.2 (CH), 39.8 (CH), 52.9
(CH3), 56.8 (C), 69.5 (CH2), 70.3 (CH2), 91.3 (C), 166.6 (C), 172.3
(C); MS (EI, 70 eV) m/z (%) = 252 (3) [M+], 237 (6) [(M ꢀ CH3)+],
221 (16) [(M ꢀ CH3O)+], 208 (8) [(M ꢀ CO2)+], 194 (6) [(M ꢀ
C2H2O2)+], 193 (20) [(M ꢀ C2H3O2)+], 95 (100) [C7H11+]; HRMS
+
(EI, 70 eV) calcd for C12H13O4 [(M ꢀ CH3O)+] 221.0808; found
221.0809.
2-Methoxycarbonyl-4,7-dioxatetracyclo[7.3.1.02,6.06,13]tridecan-
3-one (31): Colorless solid, obtained from tetronate 19 in 30% yield
according to General Procedure C (reaction time = 30 min): TLC Rf =
0.15 (P/Et2O 3:1); IR (ATR) ν~ (cmꢀ1) = 2943 (m, CꢀH), 2856 (w,
1
CꢀH), 1770 (s, CdO), 1740 (s, CdO), 1435 (w, CꢀH); H NMR
2-Hydroxymethyl-5,5-dimethyl-4,7-dioxatetracyclo[7.3.1.02,6.06,13
]
(500 MHz, CDCl3) δ (ppm) = 1.40ꢀ1.61 (m, 4H), 1.69ꢀ1.82 (m, 1H),
2.34 (ddd, 2J = 14.3 Hz, 3J = 7.4 Hz, 3J = 3.4 Hz, 1H), 2.61ꢀ2.74 (m,
2H), 2.89 (dd, 3J = 10.1 Hz, 3J = 8.9 Hz, 1H), 3.79 (s, 3H), 3.83 (virt. t, 2J
tridecan-3-one (26): TBS ether 27 (784 mg, 2.14 mmol) was dissolved
in 40 mL of THF, cooled to 0 °C, tetrabutylammonium fluoride (1.0 M
in THF, 3.21 mL, 3.21 mmol) was added, and the reaction mixture was
stirred overnight at room temperature. Saturated aqueous NH4Cl
(50 mL) was added, the phases were separated, and the aqueous phase
was extracted with EtOAc (3 ꢁ 50 mL). The combined organic phases
were dried over MgSO4, filtered, and the solvents were removed under
reduced pressure. Purification by flash chromatography (P/Et2O 1:2)
afforded alcohol 26 (493 mg, 1.95 mmol, 91%) as a colorless solid. For
characterization, see ref 8.
3
3
≈ J ≈ 9.5 Hz, 1H), 4.15 (virt. t, 2J ≈ J ≈ 9.1 Hz, 1H), 4.34 (d, 2J = 9.6
Hz, 1H), 4.37 (d, 2J = 9.6 Hz, 1H); 13C NMR (90.6 MHz, CDCl3) δ
(ppm) = 16.4 (CH2), 21.7 (CH2), 22.4 (CH2), 33.2 (CH), 33.4 (CH),
42.6 (CH), 52.4 (CH3), 55.9 (C), 72.6 (CH2), 74.0 (CH2), 89.7 (C),
165.5 (C), 174.3 (C); MS (EI, 70 eV) m/z (%) = 252 (5) [M+], 237 (1)
[(M ꢀ CH3)+], 234 (12) [(M ꢀ H2O)+], 221 (22) [(M ꢀ CH3O)+],
193 (16) [(M ꢀ C2H3O2)+], 95 (100) [C7H11+]; HRMS (EI, 70 eV)
calcd for C13H14O4+ [(M ꢀ H2O)+] 234.0887; found 234.0888.
2,2,5-Trimethyl-3,10-dioxatricyclo[5.3.0.01,5]decan-4-one (32a): Col-
orless solid, obtained from tetronate 23a in 52% yield according to
General Procedure C (reaction time = 6 h): TLC Rf = 0.24 (P/Et2O
2:1); IR (ATR) ν~ (cmꢀ1) = 2967 (m, CꢀH), 2928 (w, CꢀH), 2880 (w,
CꢀH), 1761 (s, CdO), 1450 (w, CꢀH); 1H NMR (500 MHz, CDCl3)
δ (ppm) = 1.28 (s, 3H), 1.32 (s, 6H), 1.52 (dd, 2J = 12.9 Hz, 3J = 6.8 Hz,
1H), 1.73ꢀ1.85 (m, 2H), 2.32 (dd, 2J = 12.9 Hz, 3J = 8.5 Hz, 1H), 3.04
(virt. q, 3J ≈ 7.5 Hz, 1H), 4.01 (ddd, 3J = 11.3 Hz, 2J = 9.1 Hz, 3J = 5.6 Hz,
2-Cyano-5,5-dimethyl-4,7-dioxatetracyclo[7.3.1.02,6.06,13]tridecan-
3-one (28): Light red oil, obtained from tetronate 18 in 54% yield
according to General Procedure C (reaction time = 1 h): TLC Rf = 0.27
(P/EtOAc 3:1); IR (ATR) ν~ = 2952 (m, CꢀH), 2923 (s, CꢀH), 2356
(w, CꢂN), 1775 (s, CdO), 1460 (CꢀH); 1H NMR (500 MHz,
CDCl3) δ (ppm) = 1.45 (s, 3H), 1.47 (s, 3H), 1.60ꢀ1.78 (m, 4H),
1.95ꢀ2.07 (m, 2H), 2.64ꢀ2.72 (m, 2H), 3.17 (dd, 3J = 10.2 Hz, 3J = 8.8
3
3
Hz, 1H), 4.18 (virt. t, 2J ≈ J ≈ 9.4 Hz, 1H), 4.27 (virt. t, 2J ≈ J ≈ 9.4 Hz,
1H); 13C NMR (62.9 MHz, CDCl3) δ (ppm) = 15.4 (CH2), 21.3
(CH3), 21.8 (CH2), 23.4 (CH2), 24.6 (CH3), 33.0 (CH), 33.0 (CH),
39.2 (CH), 46.1 (C) 74.5 (CH2), 86.2 (C), 91.5 (C), 111.1 (C), 169.0
(C); MS (EI, 70 eV) m/z (%) = 247 (41) [M+], 161 (34) [C10H10NO+],
3
1H), 4.25 (virt. t, 2J ≈ J ≈ 9.1 Hz, 1H); 13C NMR (62.5 MHz, CDCl3)
δ (ppm) = 16.1 (CH3), 20.6 (CH3), 24.2 (CH3), 30.9 (CH2), 32.8
(CH2), 36.3 (CH), 45.8 (C), 69.4 (CH2), 83.6 (C), 92.4 (C), 180.4
(C); MS (EI, 70 eV) m/z (%) = 196 (12) [M+], 181 (4) [(M ꢀ CH3)+],
125 (12) [(M ꢀ C4H7O)+], 110 (100) [(M ꢀ C4H6O2)+], 55 (66)
43 (100); HRMS (EI, 70 eV) calcd for C14H17NO3 [M+] 247.1203;
+
+
+
found 247.1216.
[C4H7 ]; HRMS (EI, 70 eV) calcd for C11H16O3 [M+] 196.1094;
6-tert-Butoxycarbonyl-3,3-dimethyl-2,8-oxaethano-4-oxatricyclo-
[5.4.0.02,6]undecan-5-one (29): Colorless solid, obtained from tetro-
nate 17 in 37% yield according to General Procedure C (reaction time =
30 min): TLC Rf = 0.31 (P/Et2O 3:1); IR (ATR) ν~ = 2981 (m, CꢀH),
found 196.1095.
2,2,5,6,6,7-Hexamethyl-3,10-dioxatricyclo[5.3.0.01,5]decan-4-one
(32b): Colorless oil, obtained from tetronate 23b in 46% yield
according to General Procedure C (reaction time = 8 h): TLC
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Rf = 0.41 (P/Et2O 2:1), IR (ATR) ν~ = 2967 (w, CꢀH), 2938 (w,
CꢀH), 1761 (s, CdO), 1460 (w, CꢀH); 1H NMR (250 MHz, CDCl3,
300 K) δ (ppm) = 1.04 (s, 3H), 1.05 (s, 3H), 1.18 (s, 3H), 1.30 (s, 3H),
1.32 (s, 3H), 1.47 (s, 3H), 1.66 (ddd, 2J = 13.3 Hz, 3J = 10.6 Hz, 3J = 8.9
Hz, 1H), 2.20 (ddd, 2J = 13.3 Hz, 3J = 6.6 Hz, 3J = 2.1 Hz, 1H), 3.93
δ (ppm) = 1.22 (s, 3H), 1.29 (s, 3H), 1.35 (s, 3H), 1.47 (s, 3H), 1.86 (dd
virt. t, 2J = 13.6 Hz, 3J = 10.6 Hz, 3J ≈ 8.9 Hz, 1H), 2.07 (dd, 2J = 13.6 Hz,
3J = 6.4 Hz, 1H), 2.75 (d, 3J = 8.9 Hz, 1H), 3.76 (s, 3H), 4.02 (ddd, 2J =
3
9.2 Hz, 3J = 10.6 Hz, 3J = 6.4 Hz, 1H), 4.18 (virt. td, 2J ≈ J ≈ 8.9 Hz, 3J =
1.8 Hz, 1H); 13C NMR (62.9 MHz, CDCl3, 300 K) δ (ppm) = 20.7 (CH3),
21.0 (CH3), 24.0 (CH3), 26.3 (CH2), 28.4 (CH3), 38.0 (C), 49.2 (CH),
52.2 (CH3), 60.9 (C), 71.4 (CH2), 84.8 (C), 91.1 (C), 165.7 (C), 170.8
(C); MS (EI, 70 eV) m/z (%) = 268 (1) [M+], 237 (4) [(M ꢀ CH3O)+],
110 (100) [C6H6O2+], 69 (36) [C4H5O+]; HRMS (EI, 70 eV) calcd for
C13H17O4+ [(M ꢀ CH3O)+] 237.1121; found 237.1121.
3
(ddd, 2J = 9.2 Hz, 3J = 10.6 Hz, 3J = 6.6 Hz, 1H), 4.12 (virt. td, 2J ≈ J ≈
3
9.0 Hz, J = 2.1 Hz, 1H); 13C NMR (62.9 MHz, CDCl3, 300 K) δ
(ppm) = 12.1 (CH3), 20.5 (CH3), 21.6 (CH3), 21.8 (CH3), 23.6
(CH3), 28.1 (CH3), 37.9 (CH2), 38.5 (C), 51.9 (C), 54.1 (C), 68.9
(CH2), 85.5 (C), 91.6 (C), 179.2 (C); MS (EI, 70 eV) m/z (%) = 238
(4) [M+], 223 (1) [(M ꢀ CH3)+], 124 (40) [C7H8O2+], 97 (100)
2-Methoxycarbonyl-5,5-dimethyl-4,7-dioxatetracyclo[8.4.0.02,6.06,10]-
tetradecan-3-one (34d): Colorless solid, obtained from tetronate 25d
in 84% yield according to General Procedure C (reaction time = 1 h).
Another isomer was present according to 1H NMR (90:10 ratio). The
minor isomer could be separated by repeated column chromatography:
TLC Rf = 0.41 (P/EtOAc 3:1); IR (ATR) ~ν = 2933 (w, CꢀH), 1761
(s, CdO), 1731 (s, CdO), 1466 (w, CꢀH); 1H NMR (250 MHz, CDCl3)
δ (ppm) = 1.25ꢀ1.35 (m, 2H), 1.41 (s, 3H), 1.41 (s, 3H), 1.54ꢀ1.68 (m,
+
[C7H13+] 55 (73) [C4H7+]; HRMS (EI, 70 eV) calcd for C14H22O3
[M+] 238.1569; found 238.1562.
5-Methoxycarbonyl-2,2,6,10,10-pentamethyl-3,9-dioxatricyclo-
[4.3.1.01,5]-decan-4-one (33): Colorless oil, obtained from tetronate 25e
in 51% yield according to General Procedure C (reaction time = 45 min):
TLC Rf = 0.33 (P/Et2O 2:1); IR (ATR) ~ν = 2978 (CꢀH), 2952 (CꢀH),
1761 (s, CdO), 1726 (s, CdO), 1455 (w, CꢀH); 1H NMR (250 MHz,
CDCl3) δ (ppm) = 1.09 (s, 3H), 1.22 (s, 3H), 1.37 (s, 3H), 1.49 (s, 3H),
1.65 (s, 3H), 2.07 (ddd, 2J = 13.0 Hz, 3J = 8.4 Hz, 3J = 2.5 Hz, 1H), 2.23
(ddd, 2J = 13.0 Hz, 3J = 10.0 Hz, 3J = 9.1 Hz, 1H), 3.82 (s, 3H), 4.00ꢀ4.09
(m, 2H); 13C NMR (62.9 MHz, CDCl3) δ (ppm) = 14.9 (CH3), 19.8
(CH3), 21.6 (CH3), 22.6 (CH3), 24.7 (CH3), 34.1 (CH2), 46.6 (C), 51.0
(C), 52.7 (CH3), 59.6 (C), 63.1 (CH2), 87.0 (C), 91.7 (C), 167.8 (C),
172.2 (C); MS (EI, 70 eV) m/z (%) = 282 (2) [M+], 251 (2) [(M ꢀ
3
6H), 2.05ꢀ2.13 (m, 2H), 2.87 (virt. t, J = 8.2 Hz, 1H), 3.77 (s, 3H),
4.17ꢀ4.27 (m, 2H); 13C NMR (62.9 MHz, CDCl3) δ (ppm) = 18.5
(CH2), 18.6 (CH2), 19.9 (CH2), 21.5 (CH3), 25.4 (CH3), 27.4 (CH2),
37.4 (CH), 38.6 (CH2), 51.0 (C) 52.8 (CH3), 59.0 (C), 68.8 (CH2), 86.3
(C), 95.3 (C), 167.4 (C), 171.5 (C); MS (EI, 70 eV) m/z (%) = 294 (9)
+
[M+], 263 (3) [(M ꢀ CH3O)+], 187 (100), 155 (62) [C8H11O3 ];
HRMS (EI, 70 eV) calcd for C16H22O5+ [M+] 294.1462; found 294.1468.
3-[2-Hydroxy-2-(2-hydroxypropan-2-yl)-3-methyltetrahydrofuran-
3-yl]propionic Acid (37): Cyclobutane 34b (52.6 mg, 207 μmol) was
dissolved in 3 mL of THF, aqueous LiOH solution (2 M, 1 mL) was
added, and the mixture was heated to reflux for 5 h. The reaction mixture
was concentrated to a volume of ca. 1 mL, dissolved in aqueous NaOH
solution (1 M, 10 mL) and washed with CH2Cl2 (10 mL). Concentrated
HCl was added to the aqueous phase to adjust pH 1. The acidified
aqueous solution was extracted with a CHCl3/i-PrOH (5:1) mixture
(5 ꢁ 10 mL), dried over Na2SO4, and the solvents were removed under
reduced pressure. Purification by flash chromatography (CH2Cl2/
MeOH/HCOOH 95:5:1) afforded hydroxyacid 37 (38.2 mg, 164 μmol,
79%) as a light yellow oil: TLC Rf = 0.17 (DCM/MeOH/HCOOH
95:5:1); IR (ATR) ν~ = 3432 (br s, OꢀH), 2987 (w, CꢀH), 2938 (w,
CꢀH), 1697 (s, CdO); 1H NMR (500 MHz, CDCl3) δ (ppm) = 1.32
(s, 3H), 1.35 (s, 3H), 1.39 (s, 3H), 1.65ꢀ1.72 (m, 1H), 1.85 (ddd, 2J =
14.5 Hz, 3J = 6.8 Hz, 3J = 4.2 Hz, 1H), 2.05ꢀ2.13 (m, 1H), 2.15ꢀ2.24
(m, 2H), 2.55ꢀ2.63 (m, 2H), 3.60 (br s, 2H), 4.02ꢀ4.07 (m, 2H); 13C
NMR (90.6 MHz, CDCl3) δ (ppm) = 24.4 (CH3), 25.3 (CH3), 25.9
(CH2), 27.6 (CH3), 28.6 (CH2), 36.4 (CH2), 42.8 (C), 65.1 (CH2),
75.4 (C), 116.3 (C), 171.0 (C); MS (EI, 70 eV) m/z (%) = 199 (3)
CH3O)+], 209 (1) [(M ꢀ C2H5O)+], 181 (4) [C11H17O2 ], 96 (100);
+
HRMS (EI, 70 eV) calcd for C15H22O5+ [M+] 282.1462; found 282.1467.
5-Methoxycarbonyl-2,2-dimethyl-3,10-dioxatricyclo[5.3.0.01,5
]
decan-4-one (34a): Colorless solid, obtained from tetronate 25a in 78%
yield according to General Procedure C (reaction time = 30 min).
Another isomer was present according to 1H NMR (90:10 ratio): TLC
Rf = 0.25 (P/Et2O 3:2); IR (ATR) ~ν = 2997 (w, CꢀH), 2962 (w, CꢀH),
1765 (s, CdO), 1731 (s, CdO), 1426 (w, CꢀH); 1H NMR (360 MHz,
CDCl3) δ (ppm) = 1.34 (s, 3H), 1.45 (s, 3H), 1.78ꢀ1.92 (m, 2H), 2.29
(dd, 2J = 13.3 Hz, 3J = 8.6 Hz, 1H), 2.49 (dd, 2J = 13.3 Hz, 3J = 6.9 Hz,
1H), 3.15 (virt. q, 3J ≈ 7.5 Hz 1H), 3.79 (s, 3H), 4.13ꢀ4.24 (m, 2H); 13
C
NMR (90.6 MHz, CDCl3) δ (ppm) = 20.9 (CH3), 23.1 (CH3), 26.8
(CH2), 30.8 (CH2), 37.2 (CH), 52.8 (CH3), 55.5 (C), 70.1 (CH2), 84.8
(C), 94.7 (C), 166.8 (C), 173.3 (C); MS (EI, 70 eV) m/z (%) = 240 (5)
[M+], 181 (1) [(M ꢀ COOMe)+], 110 (100); HRMS (EI, 70 eV) calcd
for C12H16O5+ [M+] 240.0992; found 240.1000.
5-Methoxycarbonyl-2,2,7-trimethyl-3,10-dioxatricyclo[5.3.0.01,5
]
decan-4-one (34b): Colorless solid, obtained from tetronate 25b in 75%
yield according to General Procedure C (reaction time = 30 min): TLC
Rf = 0.25 (P/Et2O 3:2); IR (ATR) ~ν = 2972 (w, CꢀH), 2928 (w, CꢀH),
1770 (s, CdO), 1731 (s, CdO); 1H NMR (360 MHz, CDCl3)
+
[(M ꢀ CH3 ꢀ H2O)+], 159 (1) [C8H15O3 ], 155 (100), 127 (72), 100
+
(84), 59 (64) [C3H7O+]; HRMS (EI, 70 eV) calcd for C10H15O4
2
δ (ppm) = 1.43 (s, 3H), 1.45 (s, 3H), 1.47 (s, 3H) 1.71 (ddd, J =
[M+ ꢀ CH3 ꢀ H2O] 199.0965; found 199.0966.
12.3 Hz, 3J = 11.9 Hz, 3J = 8.2 Hz, 1H), 1.91 (dd, 2J = 12.3 Hz, 3J = 5.2 Hz,
1H), 1.99 (d, 2J = 13.0 Hz, 1H), 2.70 (d, 2J = 13.0 Hz, 1H), 3.77 (s, 3H),
3
4.13 (virt. t, 2J ≈ J ≈ 8.6 Hz, 1H), 4.19 (ddd, 3J = 11.9 Hz, 2J = 9.3 Hz,
’ ASSOCIATED CONTENT
3J = 5.2 Hz, 1H); 13C NMR (90.6 MHz, CDCl3) δ (ppm) = 21.3 (CH3),
24.0 (CH3), 25.5 (CH3), 34.4 (CH2), 39.9 (CH2), 48.8 (C), 52.8
(CH3), 54.0 (C), 68.3 (CH2), 86.1 (C), 94.5 (C), 167.3 (C), 173.7
(C); MS (EI, 70 eV) m/z (%) = 254 (23) [M+], 239 (4), [(M ꢀ CH3)+],
223 (9) [(M ꢀ CH3O)+], 210 (3) [(M ꢀ CO2)+], 195 (5) [(M ꢀ
Supporting Information. 1H and 13C NMR spectra of
S
b
compounds 17ꢀ19, 21, 23a,b, 25aꢀe, 27ꢀ34d, 37 and struc-
tural assignment of compounds 2, 4, 26ꢀ31, 32a,b, 33, 34a,c,d.
This material is available free of charge via the Internet at
http://pubs.acs.org.
+
+
C2H3O2)+], 69 (100) [C5H9 ]; HRMS (EI, 70 eV) calcd for C13H18O5
[M+] 254.1149; found 254.1156.
5-Methoxycarbonyl-2,2,6,6-tetramethyl-3,10-dioxatricyclo[5.3.0.01,5]
decan-4-one (34c): Colorless oil, obtained from tetronate 25c in 53%
yield according to General Procedure C (reaction time = 30 min).
Another isomer was present in the crude 1H NMR (ratio = 90:10), but
could be separated by column chromatography: TLC Rf = 0.32 (P/Et2O
1:1); IR (ATR) ν~ = 2978 (m, CꢀH), 2957 (m, CꢀH), 1765 (s, CdO),
1731 (s, CdO), 1436 (m, CꢀH); 1H NMR (250 MHz, CDCl3, 300 K)
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: thorsten.bach@ch.tum.de.
Author Contributions
†Both authors contributed equally to this work.
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FEATURED ARTICLE
’ ACKNOWLEDGMENT
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This project was supported by the Deutsche Forschungsge-
meinschaft (Ba 1372/11-2) and the TUM Graduate School. J.P.
H. gratefully acknowledges the support from the Fonds der
Chemischen Industrie through a Kekulꢀe scholarship.
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