An unusual domino Claisen - Conia reaction producing 3,5-dispirodihydrofuran-2,4-diones

Article abstract of DOI:10.1002/1099-0690(200105)2001:10<1951::AID-EJOC1951>3.0.CO;2-Y

Allyl tetronates 3 can be selectively converted either (in acetonitrile) into Claisen-rearranged 3-allyltetronic acids 5 or (in toluene) into novel Claisen - Conia-rearranged 3-(spirocyclopropyl)dihydrofuran-2,4-diones 6, featuring up to three new stereog

Full text of DOI:10.1002/1099-0690(200105)2001:10<1951::AID-EJOC1951>3.0.CO;2-Y

FULL PAPER
An Unusual Domino Claisen؊Conia Reaction Producing
3,5-Dispirodihydrofuran-2,4-diones
Rainer Schobert,*[a] Sven Siegfried,[a] Gary Gordon,[a] Mark Nieuwenhuyzen,[a] and
Stig Allenmark[b]
Keywords: Domino reactions / Phosphorus ylides / Rearrangements / Spiro compounds / Tetronic acids
Allyl tetronates 3 can be selectively converted either (in ace- stereogenic centres. The mechanism and the stereochemistry
tonitrile) into Claisen-rearranged 3-allyltetronic acids 5 or (in
toluene) into novel Claisen−Conia-rearranged 3-(spirocyclo-
propyl)dihydrofuran-2,4-diones 6, featuring up to three new
of this process is discussed and an X-ray crystal structure of
one of the two diastereoisomers of (±)−6c is presented.
Introduction
controllable by, parameters such as substrate structure, tem-
perature and solvent polarity. These findings are reported
below, with the usual ‘‘one-pot’’ domino methodology
broken down into individual reaction steps for reasons of
clarity.
3,5-Disubstituted tetronic acids exhibit a variety of biolo-
gical activities including antibiotic, antiviral, and antitu-
mour properties.[1] Driven by the need to develop an effect-
ive treatment of patients with AIDS, the focus of pharma-
ceutical research within this field has recently shifted to de-
rivatives with pronounced HIV-protease inhibitor activity,[2]
such as the 5-spiro-3-(α-cyclopropylbenzyl)tetronic acids of
type 1.[3,4] On the basis of X-ray structural analyses of re-
spective HIV-proteaseϪdrug complexes, a rationale was de-
veloped for the observed structure-activity dependencies of
1 and of analogous 4-hydroxy(benzo)pyran-2-ones. This en-
abled elaborate drug refinement to be carried out by means
of computer modelling.[5]
Results and Discussion
Controllable Domino Synthesis of 3,5-Dispirodihydrofuran-
2,4-diones 6
Allyl esters 2 of α-hydroxycycloalkanoic acids can readily
be prepared either by direct acid-catalysed esterification be-
tween the corresponding allyl alcohol and the carboxylic
acid (R ϭ H), or by treatment of the latter with an allyl-
isourea (R ϭ Ph).[7] Gentle refluxing of solutions of 2 and
ketenylidenetriphenylphosphorane 4[8] in THF afforded the
corresponding 5-spirotetronates 3 in good to excellent
yields. These compounds are products of a domino se-
quence, consisting of the addition of the hydroxy group in
2 across the CϭC bond of 4 and a subsequent, intramolecu-
lar Wittig olefination reaction between the resulting acyl
ylide and its ester carbonyl group. Under these relatively
We have now applied our established domino Wittig mild conditions, no follow-up rearrangement processes were
olefinationϪClaisen rearrangement approach[6] to build up observed (Scheme 1). From earlier work we knew that such
immediate precursor compounds Ϫ 5-spiro-3-allyl derivat- extended cascades tend to require more rigorous conditions,
ives 5 Ϫ from allyl esters 2 of cyclic α-hydroxycarboxylic such as working in toluene at reflux or even in sealed glass
acids and ketenylidenetriphenylphosphorane 4. These tubes. Previously, all such thermally induced sequential re-
should then be amenable to cyclopropanation, yielding te- actions undergone by allyl tetronates, congener 4-allyloxy-
tronic acids of the desired type 1. Remarkably, the outcome coumarins and 4-allyloxyquinolones had been of the [3.3]-
of this domino sequence, and especially of the rearrange- sigmatropic Claisen type, producing the respective 3-allyl-
ment steps, was found to be strongly dependent on, and 4-hydroxy derivatives.[9] In a deviation from this rule, te-
tronates 3, when kept in toluene solution at 200 °C in a
[a]
School of Chemistry, The Queen’s University of Belfast,
23 Stranmillis Road, Belfast, UK BT9 5AG, Northern Ireland
Fax: (internat.) ϩ 44-28/90-382117
sealed glass tube for 48 h, were not converted into the ex-
pected Claisen-rearranged 3-allyltetronic acids 5, but ex-
clusively into dispirolactones 6 (Scheme 2). A reasonable
mechanistic explanation would be that the first reaction
step should still be a Claisen rearrangement to give 5, but
that 5-spiroannulation would then enable compounds 5 to
E-mail: r.schobert@qub.ac.uk
[b]
Göteborg University, Department of Chemistry,
41296 Göteborg, Sweden
Fax: (internat.) ϩ 46-31/772-3840
E-mail: stig.allenmark@oc.chalmers.se
Eur. J. Org. Chem. 2001, 1951Ϫ1958
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0510Ϫ1951 $ 17.50ϩ.50/0
1951

R. Schobert, S. Siegfried, G. Gordon, M. Nieuwenhuyzen, S. Allenmark
Some results are evident from Table 1. Most important is
FULL PAPER
undergo a subsequent, quick oxa-ene reaction of the
Conia[10] type to close the 3-spirocyclopropyl ring. As well the fact that dispirolactones 6 could be obtained exclusively
as the 5-substituents on the tetronic acid 5, other factors and in pure form in each case, using toluene as solvent.
influencing the progress of this domino ClaisenϪConia se- Derivatives in which R ϭ Ph reacted more readily, and the
quence include the nature of R in the allyl side chain, the yields of the respective products were considerably higher
reaction temperature and the polarity of the solvent. It than those for the analogous reactions with R ϭ H (6a:
proved possible to find conditions suitable for producing 74%, 6c: 66%, 6e: 77% vs. 6b: 30% and 6d: 35%). Spirote-
either the pure dispirolactone or the tetronic acid 5 (exclus- tronates 3, with seven-membered rings at C-5, reacted more
ively in some cases, in others as mixtures with 6) (Table 1). rapidly and more readily than their congeners bearing five-
membered and six-membered rings. For instance, formation
of 6e in 77% yield required only 48 h in refluxing toluene.
5-Spiro annulation is not a prerequisite for this domino pro-
cess to occur, but produces considerable increases in the
yields of the corresponding 3-(spirocyclopropyl)dihydrofu-
ran-2,4-diones 6 (which otherwise are Ͻ 30%). The rate of
Claisen rearrangement reactions is known to be signific-
antly accelerated by an increase in solvent polarity.[11] When
we kept solutions of 3 in acetonitrile at a gentle reflux for
at least 24 h, the starting compounds were converted either
Scheme 1
into pure Claisen-rearranged 3-allyltetronic acids 5 (5c: 32%
after 24 h) or Ϫ upon prolonged heating Ϫ to mixtures still
consisting predominantly of these, but with minor amounts
of the respective Conia-rearranged dispirolactones 6. Such
mixtures could easily be separated by column chromato-
graphy.
Stereochemistry and Structure of the Dispirolactones 6
Although many Conia reactions, including those re-
sulting in spiro systems,[12] can be found in the literature,
the formation of three-membered rings is so far unpreced-
ented. In fact, the reverse reaction is well documented and
acylcyclopropanes are known to undergo ring opening un-
der thermal conditions (150 °C and above) to give the cor-
responding γ-unsaturated ketones.[13] Theoretically, the
equilibrium between these two lies far to the side of the
cyclopropane whenever the ketone can form a stable enol.
Tetronic acids such as 5 exist almost exclusively as the enol
tautomer depicted, a fact that would account for the ease
with which they form the spirocyclopropanes 6. Equally
striking are the stereochemical implications of this process.
Scheme 2. (Domino) sigmatropic rearrangement reactions of allyl
spirotetronates 3
The Conia rearrangement of 5 to 6 can be regarded mech-
anistically as an oxa-ene reaction. A formal frontier orbital
Table 1. 3-Allylspirotetronic acids 5 and 3,5-dispirodihydrofuran-2,4-diones 6 from 3: conditions and yields
Starting compound
n
R
Reaction conditions
Yield of 5 (%)
Yield of 6 (%)
3a
3a
3b
3b
3c
3c
3c
3d
3d
3e
3e
3e
1
1
2
2
2
2
2
3
3
3
3
3
Ph
Ph
H
toluene, 200 °C, 48 h, sealed tube
acetonitrile, reflux, 48 h
Ϫ
56
Ϫ
60
Ϫ
32
54
Ϫ
Ϫ
49
Ϫ
Ϫ
74
19
30
Ϫ
66
Ϫ
22
35
23
Ϫ
77
75
toluene, 200 °C, 48 h, sealed tube
toluene, 160 °C, 48 h, sealed tube
toluene, 200 °C, 48 h, sealed tube
acetonitrile, reflux, 24 h
H
Ph
Ph
Ph
H
acetonitrile, reflux, 48 h
toluene, 200 °C, 48 h, sealed tube
toluene, 160 °C, 24 h, sealed tube
acetonitrile, reflux, 48 h
H
Ph
Ph
Ph
toluene, reflux, 48 h
toluene, 200 °C, 48 h, sealed tube
1952
Eur. J. Org. Chem. 2001, 1951Ϫ1958

An Unusual Domino ClaisenϪConia Reaction
FULL PAPER
description of the transition state, using the HOMO of the butyl methyl ether (TBME) in hexane as the mobile phase.
enol radical and the LUMO of the alkene, provides a ra- The CD spectra showed absorption maxima at 238 nm,
tionale for the observed stereoselectivity of this particular with the first eluted enantiomer being levorotatory at this
Conia reaction (Scheme 3). The product isomer with a cis wavelength. An asymmetrically perturbed carbonyl trans-
constellation of the newly created methyl group and the oxo ition (nǞπ*) was also found at ca. 302 nm (Figure 2). Thus,
group that participated (as the enol tautomer) in the reac- all four stereoisomeric dispirolactones 6 can in principle be
tion should be formed exclusively. A further steric con- obtained in pure form by means of a four-step domino reac-
straint in derivatives 6a, 6c, and 6e, containing three ste- tion between ylide 4 and allyl α-hydroxycycloalkanoates 2,
reogenic centres, is the trans orientation of the phenyl and followed by a recrystallization and two chromatographic
the methyl group.
resolutions.
Scheme 3
Since we had started from achiral compounds 3 and had
not resolved the racemates of the intermediate tetronic ac-
ids 5a, 5c, and 5e, we had anticipated that we would obtain
the respective Conia products as a single racemate (Ϯ)Ϫ6α.
NMR spectroscopy revealed the presence of a 1:1 mixture
of two diastereoisomers 6α and 6β, though. Both were tent-
atively assigned trans configurations between the methyl
and phenyl groups (JHH ϭ 9.25 Hz). The diastereoisomers
of dispirolactone 6c could easily be separated by complete
crystallization of one of them (6cβ) and an X-ray single-
crystal structure analysis was carried out with this diastere-
opure racemate (Figure 1). It revealed trans relationships
not only between the phenyl residue and the methyl group
but also between the phenyl residue and the carbonyl moi-
ety at C-2. Given the cis selectivity of the Conia reaction,
the formation of 6cβ must have taken place by means of a
reaction between the terminal olefin and the enol of the
ester carbonyl group. When toluene solutions of the pure
individual diastereoisomers of 6c were kept at 160 °C in a
sealed glass tube for 12 h, they re-equilibrated to give back
the initial 1:1 mixture of α and β diastereomers. One ra-
tionalisation of these findings is the assumption that both
enol forms of 5 are present as an equilibrium mixture under
the applied high temperature conditions and independently
undergo reversible Conia rearrangements to produce the re-
spective diastereoisomers (ester enol Ǟ 6β; oxo enol Ǟ 6α).
The Conia rearrangement equilibria apparently lie far to
the product side, as no residual starting materials could be
detected either by TLC or by NMR (Scheme 4). The dia-
stereopure racemate 6cβ could also be resolved on an analyt-
Figure 1. Molecular structure of (Ϯ)-6cβ; hydrogen atoms are omit-
˚
ted; selected bond lengths [A], angles [°], and dihedral angles [°]:
C5ϪO1 1.471(2), O1ϪC2 1.358(2), C2ϪO2 1.203(2), C2ϪC3
1.477(3), C3ϪC4 1.468(3), C4ϪO4 1.210(2), C4ϪC5 1.523(3),
C3ϪC6 1.560(2), C3ϪC7 1.544(3), C6ϪC7 1.472(3); C5ϪO1ϪC2
112.22(13), C2ϪC3ϪC4 106.78(15), C3ϪC4ϪC5 107.35(15)
C3ϪC6ϪC7 61.14(12), C6ϪC3ϪC7 56.61(12); C4ϪC3ϪC6ϪC9
5.4(2), C2ϪC3ϪC6ϪC7 112.14(18)
ical scale on a Kromasil CHI-DMB column, with 0.1% tert- Scheme 4
Eur. J. Org. Chem. 2001, 1951Ϫ1958
1953

R. Schobert, S. Siegfried, G. Gordon, M. Nieuwenhuyzen, S. Allenmark
FULL PAPER
1. Synthesis of Allyl Esters 2b and 2d. ؊ General Procedure for
the Azeotropic Esterification of 1-Hydroxycycloalkanoic Acids: A
mixture of the respective 1-hydroxycycloalkanoic acid
(10.00 mmol), allyl alcohol (2.90 g; 50.00 mmol), conc. H2SO4
(2Ϫ4 mmol), and chloroform (50 mL) was heated under reflux us-
ing a DeanϪStark apparatus for solvents heavier than water. When
the separation of water in the trap had ceased (ca. 6Ϫ10 h), the
apparatus was dismantled and the reaction mixture cooled to room
temperature. It was washed first with water, then twice with satur-
ated NaHCO3 solution and finally once more with water. The solu-
tion was dried with MgSO4, the solvent was evaporated and the
residue thus obtained purified by column chromatography (silica
gel 60, solvent as indicated).
Allyl 1-Hydroxycyclohexanoate (2b): This compound (1.46 g,
7.93 mmol, 79%) was obtained from 1-hydroxycyclohexanecarbox-
ylic acid (1.44 g); colourless oil; Rf ϭ 0.57 (diethyl ether/n-pentane,
1:4, v/v). Ϫ IR (film): ν˜ ϭ 3503 cmϪ1, 2936, 1731, 1449, 1234, 1156,
1
995. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.58Ϫ1.82 (m, 10 H, 2-
H, 3-H, 4-H, 5-H, 6-H), 2.87 (s, br., 1 H, OH), 4.66 (dt, 3J ϭ
5.65 Hz, 4J ϭ 1.35 Hz, 2 H, OCH2), 5.26 (ddt, 3J ϭ 10.24 Hz, 2J ϭ
2.24 Hz, 4J ϭ 1.35 Hz, 1 H, CHϭCHH-cis), 5.33 (ddt, 3J ϭ
17.23 Hz, 2J ϭ 2.24 Hz, 4J ϭ 1.35 Hz, 1 H, CHϭCHH-trans), 5.92
(ddd, 3J ϭ 17.23, 10.24, 5.65 Hz, 1 H, CHϭCH2). Ϫ 13C NMR
(75.4 MHz, CDCl3): δ ϭ 21.6 (C-3, C-5), 25.6 (C-4), 35.2 (C-2, C-
6), 66.4 (OCH2), 74.0 (C-1), 118.9 (CHϭCH2), 132.1 (CHϭCH2),
177.4 (CO2). Ϫ MS (EI, 70 eV): m/z (%) ϭ 185 (69) [MHϩ], 167
(63) [MHϩ Ϫ H2O], 155 (39), 139 (14), 127 (25) [Mϩ Ϫ C3H5O],
121 (43), 109 (52) [167 Ϫ C3H5Oϩ], 99 (89) [Mϩ Ϫ C4H5O2], 81
(86) [99 Ϫ H2Oϩ], 69 (33), 55 (100), 43 (75). Ϫ C10H16O3 (184.24):
calcd. C 65.19, H 8.75; found C 65.29, H 8.70.
Figure 2. Top: analytical resolution of (Ϯ)-6cβ on a Kromasil CHI-
DBM column, flow 1.0 mL/min, UV 235 nm; bottom: CD spectra
of the main fractions with tr ϭ 8.9 and 9.8 min, CH3CN,
unknown concentration
Allyl 1-Hydroxycycloheptanoate (2d): This compound (1.44 g,
7.29 mmol, 73%) was obtained from 1-hydroxycycloheptanecarbox-
ylic acid (1.44 g); colourless oil; Rf ϭ 0.58 (diethyl ether/n-pentane,
1:4, v/v). Ϫ IR (film): ν˜ ϭ 3511 cmϪ1, 2927, 1731, 1239, 1124, 1060.
Further work to resolve racemic tetronic acids 5 and to
carry out the Conia reaction with the enantiopure com-
pounds is now in progress. Dispirolactones 6 should also be
amenable to ring-opening reactions and so could open ac-
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.56Ϫ1.99 (m, 12 H, 2-H, 3-
3
H, 4-H, 5-H, 6-H, 7-H), 2.95 (s, 1 H, OH), 4.66 (dt, J ϭ 5.65 Hz,
4J ϭ 1.37 Hz, 2 H, OCH2), 5.27 (ddt, 3J ϭ 10.44 Hz, 2J ϭ 2.50 Hz,
3
cess to 3,5-difunctionalized tetronic acids. Biological testing 4J ϭ 1.37 Hz, 1 H, CHϭCHH-cis), 5.34 (ddt, J ϭ 17.01 Hz, 2J ϭ
2.50 Hz, 4J ϭ 1.37 Hz, 1 H, CHϭCHH-trans), 5.93 (ddt, 3J ϭ
both of structurally modified 3-(α-cyclopropylbenzyl)te-
tronic acids and their corresponding Conia-rearranged dis-
17.01, 10.44, 5.65 Hz, 1 H, CHϭCH2). Ϫ 13C NMR (75.4 MHz,
CDCl3): δ ϭ 23.0 (C-3, C-6), 30.0 (C-4, C-5), 39.4 (C-2, C-7), 66.5
pirolactones 6 is underway.
(OCH2), 77.3 (C-1), 119.0 (CHϭCH2), 132.1 (CHϭCH2), 178.3
(CO2). Ϫ MS (EI, 70 eV): m/z (%) ϭ 199 (51) [MHϩ], 181 (63)
[MHϩ Ϫ H2O], 169 (15), 135 (20), 123 (38) [181 Ϫ C3H5O2ϩ; 141
Experimental Section
Ϫ H2Oϩ], 113 (96), 95 (86) [181 Ϫ C4H5O2ϩ; 123 Ϫ COϩ], 83 (27),
69 (66), 55 (100). Ϫ C11H18O3 (198.26): calcd. C 66.64, H 9.15;
found C 66.56, H 9.04.
General Information: Ylide 4[8] and the 1-hydroxycycloalkanoic ac-
ids[14] required for the preparation of their esters 2 were prepared
by the literature methods quoted, all other starting compounds
were purchased from Aldrich and used as such without further
purification. All reactions involving ylide 4 were carried out under
nitrogen. Solvents were dried and distilled under nitrogen prior to
use, according to standard procedures. Ϫ Melting points were re-
corded using a Gallenkamp apparatus and are not corrected. Ϫ
NMR: Bruker DPX 300 and DRX 500; δ given in ppm; TMS as
internal standard. Ϫ IR: PerkinϪElmer 983G; recorded as potas-
sium bromide disks (KBr) or films (film). Ϫ MS: Double Focusing
Triple Sector VG Auto Spec, and Varian MAT 311A (EI). Ϫ MA:
PerkinϪElmer 2400 CHN. Ϫ X-ray single-crystal structure ana-
lysis: Siemens P4. Ϫ HPLC: Varian 9021Q solvent delivery pump
and 9050 UV detector; column: 4.6 ϫ 250 mm Kromasil CHI-
DBM (EKA Chemicals Co., Bohus, Sweden), injection volume 20
µL.
2. Synthesis of Esters 2a, 2c, 2e. ؊ General Procedure for the Ester-
ification of 1-Hydroxycycloalkanoic Acids with N,NЈ-Dicyclohexyl-
O-phenylallylisourea:[7] A solution of the respective 1-hydroxycar-
boxylic acid (10.0 mmol) and N,NЈ-dicyclohexyl-O-(trans-3Ј-
phenylallyl)isourea (4.08 g; 12.00 mmol) in dry THF (50 mL) was
stirred under reflux for 16 h. After cooling to room temperature,
the solution was filtered to remove the precipitated urea. The solv-
ent was then evaporated under reduced pressure to leave a crude
product which was purified by column chromatography (silica gel
60; solvent as indicated).
trans-3Ј-Phenylallyl 1-Hydroxycyclopentanecarboxylate (2a): This
compound (1.32 g, 5.36 mmol; 54%) was obtained from 1-hydroxy-
cyclopentanecarboxylic acid (1.30 g); colourless oil; Rf ϭ 0.40
(diethyl ether/n-pentane, 1:4, v/v). Ϫ IR (film): ν
˜ ϭ 3445 cmϪ1
,
1954
Eur. J. Org. Chem. 2001, 1951Ϫ1958

An Unusual Domino ClaisenϪConia Reaction
1727, 1624, 1183, 1161, 1027. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ (CHϭCHPh), 172.0, 182.1 (C-2, C-4). Ϫ MS (EI, 70 eV): m/z
FULL PAPER
1.77Ϫ2.10 (m, 8 H, 2-H, 3-H, 4-H, 5-H), 3.15 (s, 1 H, OH), 4.82
(%) ϭ 270 (6) [Mϩ], 257 (11), 157 (42), 117 (100) [C9H9ϩ], 91 (29).
(dd, 3J ϭ 6.49 Hz, 4J ϭ 1.65 Hz, 2 H, OCH2), 6.28 (dt, 3J ϭ 15.85, Ϫ C17H18O3 (270.33): calcd. C 75.53, H 6.71; found C 75.47, H
6.49 Hz, 1 H, CHϭCHPh), 6.67 (dt, 3J ϭ 15.85 Hz, 4J ϭ 1.65 Hz, 1 6.70.
H, CHϭCHPh), 7.25Ϫ7.67 (m, 5 H, Ph). Ϫ 13C NMR (75.4 MHz,
4-Allyloxy-1-oxaspiro[4.5]dec-3-en-2-one (3b): This compound
CDCl3): δ ϭ 25.7 (C-3, C-4), 40.1 (C-2, C-5), 66.6 (OCH2), 82.3 (C-
(0.89 g, 4.26 mmol; 85%) was obtained from 2b (0.92 g); white
1), 122.9 (CHϭCHPh), 127.5, 128.6, 129.0 (CH-ar.), 135.2 (CHϭ
solid; m.p. 43 °C; Rf ϭ 0.69 (diethyl ether/n-pentane, 2:1, v/v). Ϫ
CHPh), 136.4 (C-ipso), 177.6 (CO2). Ϫ MS (EI, 70 eV): m/z (%) ϭ
IR (KBr): ν˜ ϭ 2938 cmϪ1, 2862, 1748, 1450, 1337, 1267, 1195, 988.
246 (39) [Mϩ], 134 (52), 117 (100) [C9H9ϩ], 96 (70), 85 (92), 67
(84), 41 (40). Ϫ C15H18O3 (246.31): calcd. C 73.15, H 7.36; found
C 73.24, H 7.41.
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.61Ϫ1.83 (m, 10 H, 6-H, 7-
H, 8-H, 9-H, 10-H), 4.52 (dt, 3J ϭ 5.28 Hz, 4J ϭ 1.37 Hz, 2 H,
3
4
OCH2), 4.94 (s, 1 H, 3-H), 5.35 (dt, J ϭ 11.41 Hz, J ϭ 1.37 Hz,
3
4
trans-3Ј-Phenylallyl 1-Hydroxycyclohexanecarboxylate (2c): This
compound (1.87 g, 7.19 mmol, 72%) was obtained from 1-hydroxy-
cyclohexanecarboxylic acid (1.44 g); white solid; m.p. 43 °C; Rf ϭ
1 H, CHϭCHH-cis), 5.39 (dt, J ϭ 17.24 Hz, J ϭ 1.37 Hz, 1 H,
CHϭCHH-trans), 5.91Ϫ6.01 (m, 1 H, CHϭCH2). Ϫ 13C NMR
(75.4 MHz, CDCl3): δ ϭ 19.7 (C-7, C-9), 22.4 (C-8), 31.1 (C-6, C-
10), 70.8 (OCH2), 81.9 (C-5-spiro), 85.7 (C-3), 117.7 (CHϭCH2),
0.52 (diethyl ether/n-pentane, 1:4, v/v). Ϫ IR (KBr): ν˜ ϭ 3481
1
cmϪ1, 2941, 1717, 1241, 1179, 1161, 1137. Ϫ H NMR (300 MHz, 128.4 (CHϭCH2), 170.1, 182.8 (C-2, C-4). Ϫ MS (EI, 70 eV): m/z
CDCl3): δ ϭ 1.31Ϫ1.86 (m, 10 H, 2-H, 3-H, 4-H, 5-H, 6-H), 2.90
(%) ϭ 209 (20) [MHϩ], 196 (13), 167 (19) [Mϩ Ϫ C3H5], 152 (16),
3
4
(s, 1 H, OH), 4.80 (dd, J ϭ 6.48 Hz, J ϭ 1.23 Hz, 2 H, OCH2), 140 (14), 125 (36), 113 (31), 99 (47), 82 (70), 69 (100), 55 (83). Ϫ
6.28 (dt, 3J ϭ 15.90, 6.48 Hz, 1 H, CHϭCHPh), 6.66 (dd, 3J ϭ C12H16O3 (208.26): calcd. C 69.21, H 7.74; found C 69.19, H 7.79.
15.90 Hz, 4J ϭ 1.23 Hz, 1 H, CHϭCHPh), 7.25Ϫ7.41 (m, 5 H, Ph).
4-(trans-3Ј-Phenylallyloxy)-1-oxaspiro[4.5]dec-3-en-2-one (3c): This
compound (1.17 g, 4.12 mmol, 82%) was obtained from 2c (1.33 g);
white needles; m.p. 105 °C; Rf ϭ 0.37 (diethyl ether/n-pentane, 1:1,
v/v). Ϫ IR (KBr): ν˜ ϭ 2940 cmϪ1, 2933, 2844, 1739, 1622, 1339,
Ϫ
13C NMR (75.4 MHz, CDCl3): δ ϭ 21.1 (C-3, C-5), 25.2 (C-4),
37.4 (C-2, C-6), 66.0 (OCH2), 73.6 (C-1), 122.5 (CHϭCHPh),
126.6, 128.2, 128.6 (CH-ar.), 134.7 (CHϭCHPh), 136.0 (C-ipso),
177.0 (CO2). Ϫ MS (EI, 70 eV): m/z (%) ϭ 260 (31) [Mϩ], 242 (15)
[Mϩ Ϫ H2O], 134 (19) [C9H10Oϩ], 117 (100) [C9H9ϩ], 115 (83), 110
(84) [Mϩ Ϫ C9H10O2; 242 Ϫ C9H8Oϩ], 91 (62), 81 (97). Ϫ
C16H20O3 (260.34): calcd. C 73.82, H 7.74; found C 73.80, H 7.66.
1
1187, 965. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 1.63Ϫ1.82 (m, 10
H, 6-H, 7-H, 8-H, 9-H, 10-H), 4.67 (dd, 3J ϭ 6.35 Hz, 4J ϭ
1.34 Hz, 2 H, OCH2), 5.07 (s, 1 H, 3-H), 6.30 (dt, 3J ϭ 15.91,
3
4
6.35 Hz, 1 H, CHϭCHPh), 6.71 (dt, J ϭ 15.91 Hz, J ϭ 1.34 Hz,
1 H, CHϭCHPh), 7.28Ϫ7.42 (m, 5 H, Ph). Ϫ 13C NMR
trans-3Ј-Phenylallyl 1-Hydroxycycloheptanecarboxylate (2e): This
compound (1.83 g, 6.68 mmol, 67%) was obtained from 1-hydroxy- (125.7 MHz, CDCl3): δ ϭ 21.7 (C-7, C-9), 24.5 (C-8), 33.2 (C-6, C-
cycloheptanecarboxylic acid (1.58 g); colourless viscous oil; Rf ϭ
10), 73.0 (OCH2), 84.0 (C-5-spiro), 87.7 (C-3), 121.2 (CHϭCHPh),
126.8, 128.6, 128.8 (CH-ar.), 135.6 (C-ipso), 135.6 (CHϭCHPh),
0.57 (diethyl ether/n-pentane, 1:4, v/v). Ϫ IR (film): ν˜ ϭ 3510 cmϪ1
,
2926, 2859, 1724, 1171, 1111. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 172.1, 184.9 (C-2, C-4). Ϫ MS (EI, 70 eV): m/z (%) ϭ 284 (31)
1.20Ϫ2.10 (m, 12 H, 2-H, 3-H, 4-H, 5-H, 6-H, 7-H), 2.98 (s, 1 H, [Mϩ], 266 (27) [Mϩ Ϫ H2O], 56 (5) [Mϩ Ϫ CO], 251 (18), 240 (14),
3
4
OH), 4.80 (dd, J ϭ 6.43 Hz, J ϭ 1.24 Hz, 2 H, OCH2), 6.27 (dt,
3J ϭ 15.89, 6.43 Hz, 1 H, CHϭCHPh), 6.66 (dt, 3J ϭ 15.89 Hz,
4J ϭ 1.24 Hz, 1 H, CHϭCHPh), 7.25Ϫ7.56 (m, 5 H, Ph). Ϫ 13C
NMR (75.4 MHz, CDCl3): δ ϭ 21.7 (C-3, C-6), 28.6 (C-4, C-5),
38.0 (C-2, C-7), 65.2 (OCH2), 76.0 (C-1), 121.6 (CHϭCHPh),
125.7, 127.3, 127.7 (CH-ar.), 133.8 (CHϭCHPh), 135.1 (C-ipso),
177.1 (CO2). Ϫ MS (EI, 70 eV): m/z (%) ϭ 274 (18) [Mϩ], 256 (7)
[Mϩ Ϫ H2O], 124 (60) [Mϩ Ϫ C9H11O2; 256 Ϫ C9H9Oϩ], 117 (100)
[C9H9ϩ], 115 (80), 95 (89), 86 (56). Ϫ C17H22O3 (274.36): calcd. C
74.42, H 8.08; found C 74.48, H 8.03.
209 (27), 184 (21), 175 (45), 117 (100) [C9H9ϩ], 91 (15) [C7H7ϩ]. Ϫ
C18H20O3 (284.36): calcd. C 76.03, H 7.09; found C 75.96, H 7.02.
4-Allyloxy-1-oxaspiro[4.5]undec-3-en-2-one (3d): This compound
(669 mg, 3.00 mmol, 60%) was obtained from 2d (1.00 g); colour-
less oil; Rf ϭ 0.73 (diethyl ether/n-pentane, 2:1, v/v). Ϫ IR (film,
NaCl): ν˜ ϭ 2929 cmϪ1, 1861, 1755, 1627, 1337, 1212, 952. Ϫ 1H
NMR (300 MHz, CDCl3): δ ϭ 1.20Ϫ1.95 (m, 12 H, 6-H, 7-H, 8-
3
H, 9-H, 10-H, 11-H), 4.51 (dt, J ϭ 5.53 Hz, 4J ϭ 1.39 Hz, 2 H,
3
4
OCH2), 5.34 (s, 1 H, 3-H), 5.36 (dt, J ϭ 11.43 Hz, J ϭ 1.39 Hz,
3
4
1 H, CHϭCHH-cis), 5.41 (dt, J ϭ 17.07 Hz, J ϭ 1.39 Hz, 1 H,
CHϭCHH-trans), 5.91Ϫ5.99 (m, 1 H, CHϭCH2). Ϫ 13C NMR
(75.4 MHz, CDCl3): δ ϭ 23.1 (C-7, C-10), 29.7 (C-8, C-9), 37.4 (C-
6, C-11), 73.3 (OCH2), 87.2 (C-3), 87.7 (C-5-spiro), 120.1 (CHϭ
3. Synthesis of 3. ؊ General Procedure: A solution of ketenylidene-
triphenylphosphorane (4) (2.26 g; 7.50 mmol), the respective 1-hy-
droxy-cycloalkanoic acid ester 2 (5.00 mmol) and a catalytic
amount of benzoic acid in dry THF (50 mL) was heated under CH2), 130.9 (CHϭCH2), 172.6, 186.3 (C-2, C-4). Ϫ MS (EI,
reflux, with exclusion of air and moisture, for 24 h. After cooling,
the solvent was evaporated and the resulting residue was purified
by column chromatography (silica gel 60, solvent as indicated).
70 eV): m/z (%) ϭ 223 (6) [MHϩ], 210 (9), 181 (19) [Mϩ Ϫ C3H5],
163 (11), 153 (13), 125 (15), 113 (66), 95 (17), 82 (79), 69 (100), 55
(68), 41 (85) [C3H5ϩ]. Ϫ C13H18O3 (222.29): calcd. C 70.25, H 8.16;
found C 70.32, H 8.16.
4-(trans-3Ј-Phenylallyloxy)-1-oxaspiro[4.4]non-3-en-2-one (3a): This
compound (1.22 g, 4.53 mmol, 92%) was obtained from 2a (1.25 g); 4-(trans-3Ј-Phenylallyloxy)-1-oxaspiro[4.5]undec-3-en-2-one
(3e):
white needles; m.p. 97 °C; Rf ϭ 0.50 (diethyl ether/hexane, 2:1, v/
v). Ϫ IR (KBr): ν˜ ϭ 2979 cmϪ1, 2939, 1733, 1623, 1392, 1360,
1200. Ϫ 1H NMR (300 MHz, C6D6): δ ϭ 1.75Ϫ2.09 (m, 8 H, 6-
This compound (1.36 g, 4.56 mmol; 91%) was obtained from 2e
(1.37 g); white needles; m.p. 54 °C; Rf ϭ 0.66 (diethyl ether/n-pent-
ane, 2:1, v/v). Ϫ IR (KBr): ν˜ ϭ 3114 cmϪ1, 2929, 1748, 1627, 1211,
H, 7-H, 8-H, 9-H), 4.70 (dd, 3J ϭ 6.39, 4J ϭ 1.14 Hz, 2 H, OCH2), 1159. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.22Ϫ2.10 (m, 12 H, 6-
5.07 (s, 1 H, 3-H), 6.32 (dt, 3J ϭ 15.91, 6.39 Hz, 1 H, HCϭCHPh), H, 7-H, 8-H, 9-H, 10-H, 11-H), 4.67 (dd, 3J ϭ 6.32 Hz, 4J ϭ
3
4
6.72 (dt, J ϭ 15.91, J ϭ 1.14 Hz, 1 H, CHϭCHPh), 7.30Ϫ7.43 1.07 Hz, 2 H, OCH2), 4.94 (s, 1 H, 3-H), 6.31 (dt, 3J ϭ 15.91,
(m, 5 H, Ph). Ϫ 13C NMR (75.4 MHz, CDCl3): δϭ 25.1 (C-7, C-
6.32 Hz, 1 H, CHϭCHPh), 6.71 (dt, 3J ϭ 15.91 Hz, 4J ϭ 1.07 Hz, 1
8), 36.3 (C-6, C-9), 73.0 (OCH2), 88.6 (C-3), 92.3 (C-5-spiro), 121.1 H, CHϭCHPh), 7.27Ϫ7.43 (m, 5 H, Ph). Ϫ 13C NMR (75.4 MHz,
(CHϭCHPh), 126.8, 128.6, 128.8 (CH-ar.), 135.5 (C-ipso), 135.7 CDCl3): δ ϭ 22.7 (C-7, C-10), 29.2 (C-8, C-9), 37.0 (C-6, C-11),
Eur. J. Org. Chem. 2001, 1951Ϫ1958
1955

R. Schobert, S. Siegfried, G. Gordon, M. Nieuwenhuyzen, S. Allenmark
FULL PAPER
73.1 (OCH2), 86.8 (C-3), 87.4 (C-5-spiro), 121.2 (CHϭCHPh),
137.2 (CHϭCH2), 140.6 (C-ipso), 174.3, 179.9 (C-2, C-4). Ϫ MS
126.8, 128.6, 128.8 (CH-ar.), 135.6 (CHϭCHPh), 135.6 (C-ipso), (EI, 70 eV): m/z (%) ϭ 284 (19) [Mϩ], 266 (28) [Mϩ Ϫ H2O], 240
172.3, 186.1 (C-2, C-4). Ϫ MS (EI, 70 eV): m/z (%) ϭ 298 (12)
(17) [Mϩ Ϫ CO2], 206 (27) [Mϩ Ϫ C6H6], 175 (29), 157 (25), 129
[Mϩ], 157 (44), 124 (22), 117 (100) [C9H9ϩ], 115 (100), 91 (74), 69 (18), 117 (100) [C9H9ϩ], 115 (41). Ϫ C18H20O3 (284.36): calcd. C
(34). Ϫ C19H22O3 (298.39): calcd. C 76.48, H 7.43; found C 76.53, 76.03, H 7.09; found C 76.10, H 7.10.
H 7.40.
4-Hydroxy-3-(1Ј-phenylallyl)-1-oxaspiro[4.6]undec-3-en-2-one (5e):
4. Synthesis of 5. ؊ General Procedure: A solution of the respective
4-allyl spirotetronate 3 (1.00 mmol) in dry acetonitrile (10 mL) was
heated under reflux for 48 h (for 3b: toluene, 24 h) with exclusion
of air and moisture. The mixture was then allowed to cool to room
temperature and the solvent was evaporated under reduced pres-
sure. Pure tetronic acids 5 were obtained from the remaining res-
idue by column chromatography (silica gel 60; solvent as indicated).
This compound (147 mg, 0.49 mol, 49%) was obtained from 3e
(300 mg); white solid; m.p. 133 °C; Rf ϭ 0.4 (ethyl acetate/hexane,
1:1, v/v). Ϫ IR (KBr): ν˜ ϭ 3434 cmϪ1, 2930, 1698, 1648, 1577,
1457, 1388, 1299, 1032. Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ
1.53Ϫ1.98 (m, 12 H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H), 4.51 (d,
3J ϭ 6.40 Hz, 1 H, 3-CH), 5.06 (d, 3J ϭ 17.22 Hz, 1 H, CHϭCHH-
trans), 5.26 (d, 3J ϭ 10.15 Hz, 1 H, CHϭCHH-cis), 6.25Ϫ6.31 (m,
1 H, CHϭCH2), 7.22Ϫ7.33 (m, 5 H, Ph), 8.95 (s, br., 1 H, OH). Ϫ
13C NMR (125.7 MHz, CDCl3): δ ϭ 22.7 (C-7, C-10), 29.2 (C-8,
C-9), 36.6 (C-6, C-11), 42.7 (3-CH), 86.0, 99.8 (C-3, C-5-spiro),
117.3 (CHϭCH2), 127.2, 128.9 and 129.0 (CH-ar.), 137.4 (CHϭ
CH2), 140.0 (C-ipso), 173.4, 180.0 (C-2, C-4). Ϫ MS (EI, 70 eV):
m/z (%) ϭ 298 (12) [Mϩ], 280 (8) [Mϩ Ϫ H2O], 158 (46), 130 (30),
117 (100) [C9H9ϩ], 91 (16) [C7H7ϩ]. Ϫ C19H22O3 (298.39): calcd. C
76.48, H 7.43; found C 76.52, H 7.43.
4-Hydroxy-3-(1Ј-phenylallyl)-1-oxaspiro[4.4]non-3-en-2-one
(5a):
This compound (151 mg, 0.56 mmol; 56%) was obtained from 3a
(270 mg); yellowish viscous oil; Rf ϭ 0.21 (diethyl ether/hexane, 1:1,
v/v). By-products: 1-methyl-2-phenyl-10-oxadispiro[2.1.4.2]unde-
cane-4,11-dione (6a) (50 mg; 0.19 mmol, 19%) with Rf ϭ 0.71 (di-
ethyl ether/hexane, 1:1, v/v) and 65 mg (20%) of 3a recovered, Rf ϭ
0.45 (diethyl ether/hexane, 1:1, v/v). Ϫ IR (film, NaCl): ν˜ ϭ 3445
cmϪ1, 2956, 2951, 1701, 1650, 1396. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.57Ϫ2.04 (m, 8 H, 6-H, 7-H, 8-H, 9-H), 4.55 (d, 3J ϭ 5. Synthesis of 6. ؊ General Procedure: A solution of the respective
6.24 Hz, 1 H, 3-CH), 5.08 (d, 3J ϭ 17.26 Hz, 1 H, CHϭCHH-
4-allylspirotetronate 3 (1.0 mmol) in toluene (5 mL) was heated un-
trans), 5.31 (d, 3J ϭ 10.14 Hz, 1 H, CHϭCHH-cis), 6.26Ϫ6.32 (m, der exclusion of air and moisture to 200 °C in a sealed glass tube
1 H, CHϭCH2), 7.24Ϫ7.47 (m, 5 H, Ph). Ϫ 13C NMR (75.4 MHz,
for 48 h. The mixture was then allowed to cool to room temper-
CDCl3): δ ϭ 25.5 (C-7, C-8), 36.3, 36.4 (C-6, C-9), 43.4 (3-CH), ature, the solvent was evaporated in a rotary evaporator and the
91.5, 101.9 (C-3, C-5-spiro), 118.0 (CHϭCH2), 127.7, 128.3, 129.5
(CH-ar), 137.72 (CHϭCH2), 140.0 (C-ipso), 176.0, 176.1 (C-2, C-
resulting residue was purified by column chromatography (silica gel
60, solvent as indicated).
4). Ϫ MS (EI, 70 eV): m/z (%) ϭ 270 (17) [Mϩ], 252 (21) [Mϩ
Ϫ
1-Methyl-2-phenyl-10-oxadispiro[2.1.4.2]undecane-4,11-dione (6a):
This compound (200 mg, 0.74 mmol, 74%) was obtained from 3a
(270 mg); white solid; m.p. 78 °C; mixture of diastereoisomers;
H2O], 175 (29) [252 Ϫ C6H5ϩ], 157 (41), 129 (37), 117 (100)
[C9H9ϩ], 96 (38), 77 (13) [C6H5ϩ]. Ϫ C17H18O3 (270.33): calcd. C
75.53, H 6.71; found C 75.48, H 6.77.
˜ ϭ 3065 cm
Rf ϭ 0.84 (diethyl ether/hexane, 1:1, v/v). Ϫ IR (KBr): ν
3-Allyl-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (5b): This com-
pound (125 mg, 0.60 mmol; 60%) was obtained from 3b (208 mg);
white solid; m.p. 131 °C; Rf ϭ 0.43 (diethyl ether/n-pentane, 2:1, v/
v). Ϫ IR (KBr): ν˜ ϭ 3425 cmϪ1, 2932, 2859, 1750, 1710, 1628,
1245. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.08Ϫ1.93 (m, 10 H, 6-
Ϫ1, 2966, 1778, 1735, 1311, 1216, 1160, 1108. Ϫ 1H NMR
3
(500 MHz, CDCl3): δ ϭ 1.54 and 1.62 (each d, J ϭ 6.25/6.21 Hz,
3 H, 1-CH3 and 1-CH3β), 1.85Ϫ2.02 (m, 8 H, 6-Hα,β, 7-Hα,β, 8-
α
Hα,β, 9-Hα,β), 2.85Ϫ2.88 and 2.98Ϫ3.01 (each m, 1 H, 1-Hα and 1-
Hβ), 3.37 and 3.51 (each d, 3J ϭ 9.24/9.33 Hz, 1 H, 2-Hα and 2-
H, 7-H, 8-H, 9-H, 10-H), 2.98 (d, 3J ϭ 6.12 Hz, 2 H, 3-CH2), Hβ), 7.05Ϫ7.32 (m, 5 H, Phα,β). Ϫ 13C NMR (125.7 MHz, CDCl3);
5.00Ϫ5.12 (m, 2 H, CHϭCH2), 5.79Ϫ5.92 (m, 1 H, CHϭCH2), δ ϭ 11.48, 11.95 (1-CH3α,β), 25.17, 25.24, 25.30, 25.31 (C-7α,β, C-
10.02 (s, br., 1 H, OH). Ϫ 13C NMR (75.4 MHz, CDCl3): δ ϭ 22.2
(C-7, C-9), 24.7, 25.6 (C-8, 3-CH2), 33.1 (C-6, C-10), 84.1, 97.6 (C-
8α,β), 35.75 (C-1α or β), 36.94, 37.08, 37.35 (C-6α or β or C-9α or β),
37.50 (C-1α or β), 37.65 (C-6α or β or C-9α or β), 39.46, 39.61 (C-
3, C-5-spiro), 116.2 (CHϭCH2), 134.7 (CHϭCH2), 176.3, 180.9 (C- 3α,β-spiro), 51.55, 52.08 (C-2α,β), 96.53, 96.68 (C-5α,β-spiro), 128.27,
2, C-4). Ϫ MS (EI, 70 eV): m/z (%) ϭ 208 (29) [Mϩ], 190 (8) [Mϩ 128.32, 128.38, 128.50, 128.96, 129.07 (CHα,β-ar.), 132.39, 132.65
Ϫ H2O], 109 (16), 99 (62) [C5H7O2ϩ], 82 (100), 69 (19) [C4H5Oϩ] (Cα,β-ipso), 171.14, 172.57 (C-11α,β), 207.16, 209.56 (C-4α,β). Ϫ MS
54 (54), 41 (37) [C3H5ϩ]. Ϫ C12H16O3 (208.26): calcd. C 69.21, H (EI, 70 eV): m/z (%) ϭ 270 (46) [Mϩ], 255 (17), 252 (24) [Mϩ
Ϫ
7.74; found C 69.24, H 7.78.
CH3], 237 (19), 183 (19), 158 (60), 130 (100), 118 (62) [C9H10ϩ],
115 (70), 105 (15), 95 (32), 91 (29) [C7H7ϩ]. Ϫ C17H18O3 (270.33):
4-Hydroxy-3-(1Ј-phenylallyl)-1-oxaspiro[4.5]dec-3-en-2-one
(5c):
calcd. C 75.53, H 6.71; found C 75.54, H 6.70.
This compound (154 mg, 0.54 mmol; 54%) was obtained from 3c
(285 mg); white solid; m.p. 149 °C; Rf ϭ 0.17 (diethyl ether/hexane, 1-Methyl-11-oxadispiro[2.1.5.2]dodecane-4,12-dione (6b): This com-
1:1, v/v). By-product: 1-methyl-2-phenyl-11-oxadispiro[2.1.5.2]do- pound (63 mg, 0.30 mmol; 30%) was obtained from 3b (208 mg);
decane-4,12-dione (6c) (55 mg, 0.20 mmol, 20%) with Rf ϭ 0.71 white solid; m.p. 61 °C; mixture of diastereoisomers; Rf ϭ 0.69
(diethyl ether/hexane, 1:1, v/v). Ϫ IR (KBr): ν˜ ϭ 3433 cmϪ1, 2939,
1739, 1700, 1622, 1266, 1230, 980, 696. Ϫ 1H NMR (300 MHz,
(diethyl ether/n-pentane, 1:4, v/v). Ϫ IR (KBr): ν˜ ϭ 2938 cmϪ1
,
2862, 1783, 1739, 1328, 1182, 1119, 1033, 971. Ϫ 1H NMR
3
CDCl3): δ ϭ 1.18Ϫ1.86 (m, 10 H, 6-H, 7-H, 8-H, 9-H, 10-H), 4.52 (500 MHz, CDCl3): δ ϭ 1.30 and 1.43 (each d, J ϭ 6.15 Hz, 3 H,
(dt, 3J ϭ 6.83 Hz, 4J ϭ 1.42 Hz, 1 H, 3-CH), 5.07 (dd, 3J ϭ 1-CH3α,β), 1.67Ϫ1.79 (m, 10 H, 6-Hα,β, 7-Hα,β, 8-Hα,β, 9-Hα,β, 10-
17.21 Hz, 4J ϭ 1.42 Hz, 1 H, CHϭCHH-trans), 5.24 (dd, 3J ϭ
Hα,β), 1.79Ϫ1.97 (m, 2 H, 2-Hα,β), 2.10Ϫ2.38 (m, 1 H, 1-Hα,β). Ϫ
10.24 Hz, 4J ϭ 1.42 Hz, 1 H, CHϭCHH-cis), 6.30 (ddd, 3J ϭ 13C NMR (75.4 MHz, CDCl3): δ ϭ 10.5, 11.1 (1-CH3α,β), 20.1, 22.5
17.21, 10.24, 6.83 Hz, 1 H, CHϭCH2), 7.22Ϫ7.32 (m, 5 H, Ph),
8.59 (s, br., 1 H, OH). Ϫ 13C NMR (75.4 MHz, CDCl3): δ ϭ 22.1
(C-7, C-9), 24.8 (C-8), 33.1 (C-6, C-10), 43.2 (3-CH), 83.5, 101.2
(C-3, C-5-spiro), 117.4 (CHϭCH2), 127.4, 128.2, 129.2 (CH-ar.),
(C-7α,β, C-9α,β), 28.0, 28.6 (C-8α,β), 30.89, 30.93, 31.0, 31.3 (C-2α,β
,
C-6α,β, C-10α,β), 31.5, 31.6 (C-3α,β-spiro), 34.8, 35.2 (C-1α,β), 88.3,
88.6 (C-5α,β-spiro), 171.9, 173.7 (C-12α,β), 207.9, 209.1 (C-4α,β) Ϫ
MS (EI, 70 eV): m/z (%) ϭ 208 (64) [Mϩ], 190 (21) [Mϩ Ϫ H2O],
1956
Eur. J. Org. Chem. 2001, 1951Ϫ1958

An Unusual Domino ClaisenϪConia Reaction
FULL PAPER
180 (9) [Mϩ Ϫ CO], 166 (11) [M Ϫ C3H6], 127 (23), 109 (30), 99 (25), 82 (100), 68 (37), 54 (100), 41 (79). Ϫ C13H18O3 (222.29):
(45) [C5H7O2ϩ], 82 (83), 69 (46) [C4H5Oϩ], 55 (100), 41 (68) calcd. C 70.25, H 8.16; found C 70.17, H 8.11.
[C3H5ϩ]. Ϫ C12H16O3 (208.26): calcd. C 69.21, H 7.74; found C
1-Methyl-2-phenyl-12-oxadispiro[2.1.6.2]tridecane-4,13-dione (6e):
This compound (219 mg, 0.77 mmol, 77%) was obtained from 3e
69.27, H 7.77.
1-Methyl-2-phenyl-11-oxadispiro[2.1.5.2]dodecane-4,12-dione (6c):
This compound (188 mg, 0.66 mmol, 66%) was obtained from 3c
(283 mg); white solid; m.p. 148Ϫ150 °C; mixture of diastereoiso-
mers; separated by column chromatography and recrystallization.
(285 mg); yellowish viscous oil; mixture of two diastereoisomers;
Rf ϭ 0.65 (diethyl ether/hexane, 1:1, v/v).
Mixture of Diastereoisomers: IR (KBr): ν˜ ϭ 3062 cmϪ1, 2929, 1781,
1732, 1309, 1215, 1165, 1032, 1109, 697. Ϫ 1H NMR (500 MHz,
Compound (؎)؊6cα: Rf ϭ 0.68 (diethyl ether/n-pentane, 1:4, v/v).
Ϫ IR (KBr): ν˜ ϭ 3063 cmϪ1, 2936, 1775, 1732, 1313, 1279, 1119,
CDCl3): δ ϭ 1.25Ϫ1.99 (m, 12 H, 6-Hα,β, 7-Hα,β, 8-Hα,β, 9-Hα,β
,
10-Hα,β, 11-Hα,β), 1.51 (d, 3J ϭ 6.17 Hz, 3 H, 1-CH3β), 1.60 (d,
1
3
3J ϭ 6.15 Hz, 3 H, 1-CH3α), 2.82 (dq, J ϭ 9.15, 6.17 Hz, 1 H, 1-
969. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 1.25Ϫ1.83 (m, 10 H, 6-
3
Hβ), 2.96 (dq, 3J ϭ 9.23, 6.15 Hz, 1 H, 1-Hα), 3.32 (d, 3J ϭ 9.23 Hz,
H, 7-H, 8-H, 9-H, 10-H), 1.52 (d, J ϭ 6.15 Hz, 3 H, 1-CH3), 2.98
3
3
3
1 H, 2-Hα), 3.47 (d, J ϭ 9.15 Hz, 1 H, 2-Hβ), 7.13Ϫ7.36 (m, 5 H,
(dq, J ϭ 9.20, 6.15 Hz, 1 H, 1-H), 3.33 (d, J ϭ 9.20 Hz, 1 H, 2-
H), 7.25Ϫ7.32 (m, 5 H, Ph). Ϫ 13C NMR (125.7 MHz, CDCl3):
δ ϭ 11.5 (1-CH3), 21.05, 21.12 (C-7, C-9), 24.5 (C-8), 32.0, 32.8
(C-6, C-10), 37.5 (C-1), 40.0 (C-3-spiro), 51.4 (C-2), 88.7 (C-5-
spiro), 128.3, 128.4, 129.0 (CH-ar.), 132.4 (C-ipso), 171.2 (C-12),
208.7 (C-4).
Phα,β). Ϫ 13C NMR (125.7 MHz, CDCl3): δ ϭ 11.4 (1-CH3α), 11.9
(1-CH3β), 22.1, 22.3 (C-7β, C-10β), 22.4, 22.5 (C-7α, C-10α), 29.12,
β
β
29.16 (C-8β, C-9β), 29.2, 29.3 (C-8α, C-9α), 35.60 (C-6 or C-11 ),
35.65 (C-1 β), 35.73 (C-6α or C-11α), 35.95 (C-6 βor C-11 β), 36.1
(C-6α or C-11α), 37.7 (C-1α), 38.5 (C-3β-spiro), 38.6 (C-3α-spiro),
51.2 (C-2β), 51.7 (C-2α), 91.57 (C-5β-spiro), 91.65 (C-5α-spiro),
128.30, 128.38, 128.42, 128.48, 128.9, 129.0 (CHα,β), 132.4 (Cβ-
ipso), 132.7 (Cα-ipso), 172.2 (C-13α), 172.6 (C-13β), 207.1 (C-4β),
209.6 (C-4α). Ϫ MS (EI, 70 eV): m/z (%) ϭ 298 (70) [Mϩ], 280 (22)
[Mϩ Ϫ H2O], 265 (26) [280 Ϫ CH3ϩ], 192 (19), 198 (20), 189 (20)
[280 Ϫ C7H7ϩ], 185 (44), 158 (50), 130 (79), 118 (100) [C9H10ϩ],
110 (78), 105 (28), 91 (51) [C7H7ϩ]. Ϫ C19H22O3 (298.39): calcd. C
76.48, H 7.43; found C 76.52, H 7.47.
Compound (؎)؊6cβ: Rf ϭ 0.72 (diethyl ether/n-pentane, 1:4, v/v);
m.p. 151 °C (from chloroform/n-pentane). Ϫ IR (KBr): ν˜ ϭ 3063
cmϪ1, 2952, 2935, 1773, 1737, 1458, 1447, 1315, 1110, 966, 694. Ϫ
1H NMR (500 MHz, CDCl3): δ ϭ 1.25Ϫ1.77 (m, 10 H, 6-H, 7-H,
8-H, 9-H, 10-H), 1.62 (d, 3J ϭ 6.20 Hz, 3 H, 1-CH3), 2.83 (dq,
3
3J ϭ 9.25, 6.20 Hz, 1 H, 1-H), 3.50 (d, J ϭ 9.25 Hz, 1 H, 2-H),
7.23Ϫ7.32 (m, 5 H, Ph). Ϫ 13C NMR (125.7 MHz, CDCl3): δ ϭ
11.8 (1-CH3), 20.8, 21.0 (C-7, C-9), 24.4 (C-8), 31.88, 31.94 (C-6,
C-10), 35.7 (C-1), 38.8 (C-3-spiro), 51.79 (C-2), 88.8 (C-5-spiro),
128.15, 128.20, 128.8 (CH-ar.), 132.3 (C-ipso), 172.5 (C-12), 206.1
(C-4). Ϫ MS (EI, 70 eV): m/z (%) ϭ 284 (42) [Mϩ], 266 (27) [Mϩ
Ϫ H2O], 251 (66) [266 Ϫ CH3ϩ], 185 (20), 175 (13) [266 Ϫ C7H7ϩ],
158 (41) [175 Ϫ OHϩ], 130 (77), 115 (100), 109 (25), 91 (77)
[C7H7ϩ]. Ϫ C18H20O3 (284.36): calcd. C 76.03, H 7.09; found C
76.08, H 7.03.
Acknowledgments
Financial support from the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie e. V., and from the Engineering
and Physical Sciences Research Council (EPSRC) is gratefully
acknowledged. We thank the Chemische Fabrik Karl Bucher
GmbH, Waldstetten, for a generous gift of hexamethyldisilazane.
X-ray Crystal-Structure Analysis of (؎)؊6cβ:[15] Clear, colourless
crystals were obtained from chloroform/n-pentane solutions at
room temperature. Empirical formula C18H20O3, molecular mass
284.34 g molϪ1, crystal size 0.2 ϫ 0.3 ϫ 0.1 mm, a ϭ 21.690(4),
[1] [1a]
G. Pattenden, Fortschr. Chem. Org. Naturst. 1978, 35, 133.
[1b]
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K. Rehse, J. Wagenknecht, Arch. Pharm. (Weinheim)
[1c]
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K. Arai, Chem. Pharm. Bull. 1989,
37, 3229Ϫ3235. Ϫ [1d] B. S. Vanwagenen, Tetrahedron 1986, 42,
˚
b ϭ 6.9970(10), c ϭ 21.276(3) A, β ϭ 112.280(10)°, V ϭ 2987.9(8)
[1e]
3
A , T ϭ 293 K; dcalcd. ϭ 1.264 g cmϪ3, µ ϭ 1.0 cmϪ1, Z ϭ 8,
1117Ϫ1122. Ϫ
266575, 1988.
T. Yoshida (Shionogi & Co Ltd.), JP
˚
monoclinic, space group C2/c, Siemens P4 diffractometer, λ ϭ
[2] [2a]
B. E. Roggo, F. Petersen, R. Delmendo, H.-B. Jenny, H. H.
˚
[2b]
0.71037 A, Θ range 2.0Ϫ25°; ω scans, index ranges 0 Յ h Յ 25,
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M.
H.
[2c]
Ϫ8 Յ k Յ 0, Ϫ25 Յ l Յ 25, 2716 collected reflections, 2038
reflections [I Ͼ 2σ(I)], 270 refined parameters, absorption correc-
tion with Ψ scans. Structure solution: direct methods (SHELXS86);
structure refinement: full-matrix least squares on F2 (SHELXL93);
R1 ϭ 0.0392, wR2 ϭ 0.1272 (all data), largest diff. peak and hole
Osada, K. Kohinata, T. Hamaguchi, Jpn. Kokai Tokkyo Koho
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A. Mittra, M. Yamashita, I. Kawasaki, H. Murai, T. Yoshioka,
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[3]
[4]
Ϫ3
˚
R. Chrusciel, L. Maggiora, J. M. Tustin (Pharmacia & Up-
0.19 and Ϫ0.23 eA
.
john), Patent WO 096/29333, 1996.
1-Methyl-12-oxadispiro[2.1.6.2]tridecane-4,13-dione (6d): This com-
pound (76 mg, 0.35 mmol; 35%) was obtained from 3d (222 mg);
white solid; m.p. 97 °C; mixture of two diastereomers; Rf ϭ 0.74
and 0.70 (diethyl ether/n-pentane, 1:4, v/v). Ϫ IR (KBr): ν˜ ϭ 2931
For alternative syntheses of 3-substituted 5-spirotetronic acids
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1991, 32, 2205Ϫ2215. Ϫ
K. Nomura, K. Hori, M. Arai, E.
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1
cmϪ1, 1784, 1740, 1327, 1168, 1102, 1107. Ϫ H NMR (300 MHz,
[4d]
Ϫ
D. T. Witiak, A. K. Tehim, J. Org. Chem. 1987, 52,
CDCl3): δ ϭ 1.30 and 1.42 (each d, 3J ϭ 6.14, 6.10 Hz, 3 H, 1-
2324Ϫ2327.
[5] [5a]
CH3α,β), 1.66Ϫ2.08 (m, 14 H, 2-Hα,β, 6-Hα,β, 7-Hα,β, 8-Hα,β, 9-Hα,β
,
F. E. Boyer, J. V. N. V. Prasad, J. M. Domagala, E. L.
Ellsworth, C. Gajda, S. E. Hagen, L. J. Markoski, B. D. Tait,
E. A. Lunney, A. Palovsky, D. Ferguson, N. Graham, T. Holler,
D. Hupe, C. Nouhan, P. J. Tummino, A. Urumov, E. Zeikus,
G. Zeikus, S. J. Gracheck, J. M. Sanders, S. VanderRoest, J.
10-Hα,β, 11-Hα,β), 2.12Ϫ2.40 (m, 1 H, 1-Hα,β). Ϫ 13C NMR
(75.4 MHz, CDCl3): δ ϭ 11.5, 12.7 (1-CH3α,β), 22.26, 22.34 (C-7α,β
,
C-10α,β), 28.8, 29.1, 29.2, 29.5 (C-2α,β, C-8α,β, C-9α,β), 31.6, 32.1
(C-3α,β-spiro), 35.7, 35.9 (C-6α,β, C-11α,β), 36.0, 36.4 (C-1α,β), 92.4
(C-5α,β-spiro), 172.9, 174.8 (C-13α,β), 209.9, 211.2 (C-4α,β). Ϫ MS
(EI, 70 eV): m/z (%) ϭ 222 (67) [Mϩ], 207 (16) [Mϩ Ϫ CH3], 204
(7) [Mϩ Ϫ H2O], 153 (19) [Mϩ Ϫ C4H5O], 127 (21), 113 (35), 95
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Crystallographic data (excluding structure factors) for the
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the Cambridge Crystallographic Data Centre (CCDC-
151642). Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033, E-mail:
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