Synthesis of xyloketals, natural products from the mangrove fungus Xylaria sp.

Article abstract of DOI:10.1002/ejoc.200300629

The xyloketal family of compounds was synthesized by condensation of phloroglucinol (7) or 2,4-dihydroxyacetophenone (15) with the enone 8a or 14 in multistep, one-pot, domino reactions, leading to the xyloketals and 5-demethyl-xyloketals, respectively. I

Full text of DOI:10.1002/ejoc.200300629

FULL PAPER
Synthesis of Xyloketals, Natural Products from the Mangrove Fungus Xylaria sp
Karsten Krohn,*[a] Muhammad Riaz,[a] and Ulrich Flörke[a]
Keywords: Natural products / Total synthesis / Michael addition / Domino reactions / Ketal formation / Acetylcholin
esterase inhibition
The xyloketal family of compounds was synthesized by con- predominant (8.5:1.5), as found in the natural products. In the
densation of phloroglucinol (7) or 2,4-dihydroxyaceto- bis and tris adducts (2/19, 1/20), the relative orientation of
phenone (15) with the enone 8a or 14 in multistep, one-pot,
domino reactions, leading to the xyloketals and 5-demethyl- less demanding anti orientation slightly favored statistically.
xyloketals, respectively. In the case of condensation with Xyloketal D (4a) was obtained in the condensation of 15 with
phloroglucinol (7), the mono-, bis, and tris adducts 6/18, 2/ enantiomerically enriched enone 8a, confirming the absolute
the rings B and C can be syn and anti, with the sterically
19, 1/20 are formed; their ratios depend on the ratio of stating
materials and reaction time. The ring junction of the pyran
and furan rings B and C (at C-2 and C-6) is always cis. The
cis orientation of the methyl groups at C-2 and C-5 is also
configuration of the natural product.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
We now report a short and high yielding synthesis of the
racemic xyloketals A (1a), B (2a), and D (4a) and the 5-
demethyl analogues 16؊20 and the enantioselective syn-
thesis of xyloketal D (4a) in full detail.[3]
The xyloketal group of natural products was recently iso-
lated from the mangrove fungus Xylaria sp., found on the
South China Sea coast.[1] This group of related ketals (see
Scheme 1) is structurally unique.[2] Xyloketal A (1a) has C3
symmetry with a cis-junction between the tetrahydropyran
and tetrahydrofuran rings, whereas the other members are
missing axial symmetry. The methyl groups at C-5 of the C-
rings are also oriented syn to the other methyl groups at C-
2 placed between the oxygens of the spiroketal functions.
The angular skeleton of xyloketal B (2a), evidently a bis
adduct analogue of the tris adduct 1a, is more stable than
the linearly condensed xyloketal C (3), which spontaneously
rearranges in solution to the more stable angular structure
2a. Xyloketal D (4a) is an acetylated mono adduct struc-
ture, and xyloketal E (5) is a tetrahydrofuran-linked angular
bis adduct related to 2a. Their relative structures were se-
cured by NMR spectroscopic data and, in part, X-ray struc-
ture analysis. The absolute configurations of xyloketals A
(1a) and D (4a) were elucidated by quantum mechanical
calculation of their CD spectra.[1]
Results and Discussion
The retrosynthetic analysis, shown in Scheme 2, leads to
only two fragments: phloroglucinol 7 and enone 8a, avail-
able from the α-methylenebutyrolactone 9. The monoad-
duct 6 can then be further condensed with 8a to afford the
bis adduct 2a and, finally, the tris adduct 1a.
Mechanistically, the two fragments 7 and 8a may be com-
bined in a Michael addition, followed by spontaneous intra-
molecular ketal formation via intermediates A and B, in-
volving the phenolic and the primary aliphatic hydroxy
groups and the keto function of the side chain in the ketal
formation, as depicted in Scheme 3. The functionalized en-
one 8a, which may be in equilibrium with the cyclic hemia-
cetal 8b, can be derived from the α-methylenebutyrolactone
9 and further from the γ-lactone 10. In these one pot, multi-
step, domino reactions, repetition of the first anellation
steps would ultimately lead to the bis adducts 2a and the
tris adducts 1a in a very short way.
However, two major questions arise from the retrosyn-
thetic scheme. The first concerns the feasibility of the antici-
pated Michael addition. In principle, addition of the nucle-
ophilic phenolic oxygen to the carbonyl group (1,2-ad-
dition) or to the activated double bond (1,4-addition) might
also occur. We reasoned that these reactions should be re-
versible, ultimately leading to the formation of the thermo-
dynamically more stable CϪC bond formation shown in
Xyloketal A (1a), highlighted as a structurally remark-
able C3-symmetric natural product,[2] is a potent inhibitor
of acetylcholine esterase with inhibition at 1.5 ϫ 10Ϫ6 mol/
L, which makes it an interesting lead compound in the
treatment of Alzheimer’s disease.[3]
[a]
Department of Chemistry, University of Paderborn,
Warburger Straße 100, 33098 Paderborn, Germany
E-mail: kk@chemie.upb.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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DOI: 10.1002/ejoc.200300629
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K. Krohn, M. Riaz, U. Flörke
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Scheme 1. Structures of xyloketals A (1a), B (2a), and D (4a)[1]
intermediate A. This is supported by literature precedence ium to yield the tertiary alcohol 13 was largely suppressed
in which α,β-unsaturated acids[4a] or ketones[4b] were suc- at low temperatures (Ϫ30 °C) and the desired enone 14 was
cessfully added to in a Michael-type reaction with phenols, isolated in 55% yield (Scheme 4). Upon heating of the two
leading to benzopyrans.
components 14 and 15 (1:1) in toluene, a smooth conver-
The second problem concerns the stereochemical out- sion into two less polar compounds was observed. In a
come of the intramolecular ketal formation, which is diffi- series of experiments it was found that the addition of acids
cult to predict. In principle, the two oxygen-containing py- was not required and the phenol was sufficiently acidic to
ran and furan rings B and C can be connected in a cis promote the reaction autocatalytically. Separation of the
or trans fashion. Also, the orientation of these stereogenic two reaction products gave 83% of the less-polar major
centers at the ring-junction positions C-2 and C-6 with re- compound rac-5-demethylxyloketal D (16) (addition at C-
spect to the methyl group at C-5 is an open question. An- 3) and 8% of the polar regioisomer rac-5-demethylisoxylo-
other question concerns the relative orientation of the stere- ketal D 17 (addition at C-5). Their respective gross structures
ocenters of rings B and C with respect to the remote centers were easily assigned by 1H NMR spectroscopy, showing
at rings BЈ,CЈ and BЈЈ,CЈЈ (see Scheme 1).
two doublets for 16 and two singlets for 17 in the aromatic
Thus, in order to better address the chemical and stereo- area. A third possible regioisomer involving the chelated
chemical questions, we decided to start our experiments phenolic hydroxy group in its ketal form was not isolated,
with the synthesis of the simpler 5-demethylxyloketal D probably due to the diminished nucleophilicity of the che-
(16) with 2,4-dihydroxyacetophenone (15) as the nucleo- lated hydroxy group.
philic reaction component and the enone 14 as the
Michael acceptor.
The remaining question concerned the stereochemistry of
the ring B/C connections in 16 and 17. The cis-arrangement
of the pyran and furan rings B and C was secured by a
strong nuclear Overhauser effect (66%, see 16 Scheme 4) of
Model Studies on 5-Demethylxyloketals
The required, previously unknown, enone building block the cis-oriented proton H-6 with the protons of the methyl
14 was prepared by 1,2-addition of methyllithium to α- group at C-2. The major isomer 16 was thus identified as
methylenebutyrolactone (12), easily available by sequential rac-2-demethyl-xyloketal D. As a rule, in all subsequent con-
treatment of the γ-butyrolactone (11) sodium salt with for- densations leading to xyloketal derivatives, rings B and C
mic ester and formaldehyde.[5] The addition of methyllith- were always cis orientated, as independently confirmed by
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Natural Products from the Mangrove Fungus Xylaria sp
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Scheme 2. Retrosynthetic analysis leading to the xyloketal family of fungal natural products
Only the more stable angularly fused isomers were isolated,
in agreement with the fact that the linearly condensed xylo-
ketal C (3) spontaneously rearranges to the angular struc-
ture 2a in solution.[1] Statistically, a 1:1 ratio of 19a/19b can
be expected if the relatively remote stereogenic centers are
generated independently during the thermodynamically
controlled ketal formation. Assuming the same premises,
the ratio of the tris adducts 20a/20b must be 1:3 since there
is a threefold probability of one ring system to be anti to
the other two. In agreement with these assumptions, only
one mono adduct 18 was isolated from the most polar frac-
tion of three different reactions. The oily compound 18 is
stable at Ϫ20 °C but slowly decomposes in solution. Inter-
estingly, a mono adduct of phloroglucinol (7) was not iso-
lated as a natural product, probably also due to similar in-
stability as observed for the synthetic compound 18.
Scheme 3. Domino reactions leading to xyloketal mono, bis and
tris adducts 6, 2a, and 1a via intermediates A and B
X-ray structure analysis of a tris adduct 20b (see below).
All of the isolated naturally occurring xyloketals also show
this kind of 2,6-cis stereochemistry (see Scheme 1).
The mixture of the bis adducts 19a and 19b was easily
The condensation of phloroglucinol (7) with the enone isolated by crystallization (diethyl ether) from the evapo-
14 was studied next. In this reaction, two points have to be rated reaction mixture. It was not possible to separate the
noted. Firstly, in addition to mono adducts related to 16, isomers 19a and 19b or their respective acetates 19c and
the bis and tris adducts can also be formed. As expected, 19d by chromatography or crystallization. The very close
1
the ratio of the mono, bis, and tris adducts (5-demethylxylo- relationship of the isomers was also evident in both the H
ketals 18, 19a,b, and 20a,b) depended on the ratio of the and 13C NMR spectra, with overlapping of nearly identical
starting materials 7 and 14 and the reaction time, as shown sets of signals. The 13C NMR spectra were most instructive.
in Table 1. Secondly, the respective orientation of the cis- Whereas the aromatic carbon atoms resonate as singlets, the
fused heterocyclic rings B and C in the bis and tris adducts methyl (C-10 and C-10Ј) or methylene groups (C-4,4Ј, C-
can be syn or anti with respect to the rings BЈ,CЈ and 7,7Ј) give rise to very closely resonating quadruplets, triplets
BЈЈ,CЈЈ, as shown in structures 19a,b and 20a,b (Scheme 5). or doublets. This is in agreement with expectation. None of
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K. Krohn, M. Riaz, U. Flörke
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Scheme 4. Preparation of enone 14 and condensation with the acetophenone 15 to yield the 5-demethylxyloketal 16 and the regioisomer 17
analysis. The structure is depicted in Figure 1, showing the
major syn,syn,anti isomer 20b.
Table 1. Ratio of mono, bis, and tris adducts 18, 19a,b and 20a,b
depending on the ratio of the starting materials and reaction time
No. Reactants
Products
mono-18 bis-19a,b tris-20a,b
Yield Time
Synthesis of the Racemic Xyloketals
Enone 14 7
Our investigation with the 5-demethyl compounds gave
valuable insight into the stereochemical result of the ring B/
C connection (e.g. rings B and C are always cis) and the
possible ratio of the isomers. In the condensation reactions
of 7 or 15 with the methylated enone 8a, the formation of
additional isomers is possible because the relative orien-
1
2
3
1 mmol 2 mmol 49.5%
3 mmol 1 mmol 18.5%
6 mmol 1 mmol 6.8%
27%
63%
22%
6%
7.3%
57.5%
82.5% 4 h
88.8% 4 h
86.3% 20 h
the isomers 19a or 19b has C2 symmetry and all signals tation of the new methyl group at C-5 can be cis or trans
could, in principle, have different chemical shifts. This is with respect to the stereogenic centers at the ring junction
most evident for the carbon atoms of the methyl groups at at C-2 and C-6. The requisite enone rac-8a was prepared
C-2 and C-2Ј. The four signals for C-10 and 10Ј, visible in from citraconic acid anhydride (21) by LAH reduction to
both the mixture of the phenols 19a and 19b and the acet- the mixture of lactones 22 and 23 in a ca. 8.5:1.5 ratio,
ates 19c and 19d, show an approximate ratio of 1.5: 1 in followed by hydrogenation to rac-10 as described in the lit-
favor of the anti isomers 19b or 19d, thus deviating from the erature[6] (Scheme 6). In the subsequent methylenation,[5]
statistically expected value of 1:1 (for copies of the extended only the saturated lactone derived from the regioisomer 23
spectra see supporting information, for Supporting Infor- can be converted into the α-methylenebutyrolactone rac-9.
mation see also the footnote on the first page of this article). Gratifyingly, in the subsequent methylation step using
A slightly different picture was seen with the tris adducts MeLi, the yield of unsaturated ketone 8a was even better
20a and 20b, isolated from the least-polar fraction of the (75%) than in the case of the demethyl α-methylenebutyro-
condensation reaction. The all-syn-tris(ketal) 20a, corre- lactone 12, probably due to the increased steric hindrance
sponding in stereochemistry to the natural xyloketal A (1a), in the formation of the unwanted dimethylation of lactone
has C3 symmetry, and only one set of signals is to be ex- rac-9.
pected. In contrast, symmetry is missing in the syn,syn,anti
The acetophenone 15 was first allowed to react with 8a
isomer 20b, and three different sets of signals are possible. because only mono adducts can be formed, thus reducing
In fact, the benzylic carbon atoms C-7, C-7Ј and C-7ЈЈ (δ ϭ the number of possible isomers. In agreement with expec-
20.6 and 20.5) resonate as two very close signals, whereas tation from the previous reaction with 15 (see, 16/17), four
the methyl groups at C-2, C-2Ј and C-2ЈЈ (δ ϭ 107.0, 106.9, compounds were isolated from this condensation. The mix-
106.8, and 106.7) are four well-separated singlets (one for ture of stereoisomers rac-4a and rac-4b (ratio 8.5 to 1.5)
20a and three for 20b). From the integral of the methyl and the mixture of their regioisomers rac-24a/rac-24b could
carbon atoms in 20a and 20b, a ratio of the isomers of ap- be separated chromatographically, both as homogeneous
proximately 1:4 can be deduced, again deviating slightly fractions (Scheme 5). From the mixture of the major re-
from the statistically expected 1:3 ratio. Again, the two iso- gioisomers rac-4a and rac-4b, the main product rac-4a
mers 20a and 20b are chromatographically homogeneous could be crystallized as a pure stereoisomer in 64% overall
and could also not be separated by crystallization on a pre- yield. The stereochemistry was again verified by NOE
parative scale. Fortunately, from the crystalline conglomer- experiments as shown by the arrows in structure 4a
ate, one single crystal was appropriate for X-ray crystal (Scheme 5). The data of this synthetic product perfectly
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Natural Products from the Mangrove Fungus Xylaria sp
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Scheme 5. Construction of the 5-demethylxyloketals 19a,b and 20a,b by condensation of 7 and 14.
match those of the natural product and the structure can be
assigned as rac-xyloketal D (4a). Interestingly, the natural
xyloketals have an all-cis configuration at C-2, C-5, and C-
6, similar to the major synthetic products resulting from the
thermodynamically controlled ketal formation.
To complete the set of reactions, although mixtures of
stereoisomers were to be expected, phloroglucinol (7) was
next reacted with enone rac-8a. Again, three chromato-
graphically different sets of compounds were formed, corre-
sponding to the mono, bis and tris adducts 6, 2, and 1,
respectively. The chemical shifts in both the 1H and the 13
C
NMR spectra of the mixture of bis and tris adducts were
all in close agreement with the respective data published for
1a and 2a,[1] although the signals were slightly broadened
by overlapping.
The formation of only two stereoisomers is possible in
the mono adducts 6. In fact, the NMR spectra of the most
polar fraction show only two sets of overlapping signals,
indicating a ca. 8.5 to 1.5 ratio, similar to that found for
4a,b. Two sets of stereoisomers can be formed for the bis
adducts: syn,syn (2aϪ2d) or syn,anti (2eϪ2h; Scheme 7).
One pure isomer, probably the major isomer 2e, crystallized
from the mixture. Two sets of stereoisomers are also to be
expected for the tris adducts: syn,syn,syn (1aϪ1d) or
Figure 1. X-ray analysis of the syn,syn,anti isomer 20b
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Sdheme 7. Synthesis of xyloketal A and B stereoisomers by conden-
sation of rac-8a and 7
Scheme 6. Preparation of enone rac-8a from citraconic acid
anhydride (21)[6] and condensation with 15 to yield rac-xyloketal
D (4a); arrows show NOE correlations
lyzed cyclization to the lactone (R)-10 (Scheme 8). Methyl-
enation to (R)-9 and methylation to (R)-8a proceeded simi-
larly as for the racemic models. Not unexpectedly, the usual
condensation of (R)-8a with the acetophenone 15 gave a
chromatographically homogeneous mixture of two stereo-
isomers 4a and 4b (as detected by NMR spectroscopy),
again in an approximate 8.5 to 1.5 ratio. Fortunately, the
major isomer crystallized from diethyl ether/pentane to af-
ford the pure xyloketal D (4a). The spectroscopic data of
the synthetic material are in perfect agreement with those
of the natural product, and the optical purity could be up-
graded to almost 100% by recrystallization, confirming the
previously assigned absolute configuration.[1]
syn,syn,anti. (1eϪ1d). In each set, the C-5 methyl group can
be oriented cis or trans to the respective methyl group at
C-2. A calculation of the probable occurrence of the
individual stereoisomers in the reaction mixtures, based on
NMR spectroscopic data of related model compounds, see
ref.[7] In spite of quite good stereochemical control (100%
cis orientation of rings B,C; 8.5:1.5 ratio of C-2/C-5 methyl
groups), the mixture contained only about 29% of the
syn-syn isomer 2a and 12% of the racemic C3-symmetrical
syn,syn,syn xyloketal (1a).[7] These results raise the in-
triguing question of stereochemical control in chemical ke-
tal formation (missing at present) and possible enzymatic
involvement during ketal formation in biosyntheses.
Conclusion
Synthesis of Enantiomerically Pure Xyloketal D (4a)
Our previous investigations showed that rather complex
mixtures were to be expected with the bis or tris adducts
In conclusion, we have developed a one-pot, domino con-
obtainable from phloroglucinol (7). Thus, starting from ace- densation procedure involving the phenols 7 and 15 and the
tophenone 15, we wanted to prepare the enantiomerically enones 8a and 14 to prepare the xyloketal family of natural
pure xyloketal D (4a), to confirm our previous quantum- products and their 5-demethyl analogues. The absolute con-
mechanical assignment of absolute configuration.[1] To be figuration of xyloketals D (4a) was confirmed, starting
able to do this, the absolute configuration of the enantiom- from (R)-10 of known absolute configuration. However, the
erically pure starting material had to be known for sure. occurrence of stereoisomers during the thermodynamically
It was prepared from hydroxy acid 26 (available by SeO2 controlled ketal formation showed the need for method-
oxidation of 25[8]) and enantioselective homogeneous cata- ology to control the stereochemistry of this process. Also,
lytic Noyori hydrogenation using BINAP as the chiral li- the question of involvement of enzymes in ketal formation
gand[9] (93% ee by optical rotation), followed by acid-cata- is raised and how the stereochemistry is controlled.
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Scheme 8. Enantioselective synthesis of xyloketal D (4a) by condensation of (R)-8a with the acetophenone 15
phenone (152 mg, 1 mmol) in toluene [10 mL; with or without cata-
lytic amounts (10 mg) of meta-chlorobenzoic acid]. The mixture
was stirred at 90Ϫ100 °C for 4 h, removing traces of water by azeo-
tropic distillation with toluene (3 mL). The reaction mixture was
neutralized by addition of NaHCO3 (15 mg, in case of meta-chloro-
benzoic acid addition), filtered and the solvent removed under re-
duced pressure. The residue was separated by column chromatogra-
phy (CH2Cl2/hexane, 60:40) to afford 16 (206 mg, 83%) from the
less polar fraction and 17 (20 mg, 8%) from the polar fraction (over
all yield 91%).
Experimental Section
General Methods and Instrumentation: NMR spectra were recorded
with a Bruker ARX 300 MHz spectrometer and the 2D HMQC
spectra with a Bruker ARX 200 NMR spectrometer. Chemical
shifts are referenced to internal TMS (δ ϭ 0.00 ppm) and coupling
constants J are reported in Hz; assignment is based on 2D spectra.
Optical spectra were recorded with a Nicolet 510P FT-IR spectro-
photometer,
a
UV-2101PC spectrophotometer,
and
a
PerkinϪElmer 241 polarimeter.
3-(2-Hydroxyethyl)but-3-en-2-one (14): A solution of methyllithium
(31 mL, 51 mmol) in Et2O was added dropwise at Ϫ30 °C within
1 h to a stirred solution of α-methylene-γ-butyrolactone (12) in
Et2O (20 mL, 5.0 g, 51 mmol, prepared from γ-butyrolactone 11[5]).
The mixture was stirred for 30 min and then warmed slowly to 0
°C over 1 h. The reaction was quenched by addition of a saturated
NH4Cl solution (35 mL) and the mixture was extracted three times
with Et2O (each 20 mL). The combined organic phases were dried
(MgSO4), the solvent was removed under reduced pressure, and the
pale-yellow, oily residue separated by column chromatography on
silica gel (CH2Cl2/EtOAc, 96:4) to afford the unsaturated methyl
ketone 14 (3.2 g, 55%) from the less-polar fraction and the tertiary
alcohol 13 (1.4 g, 21%) from the polar fraction, in addition to small
amounts of unchanged starting material 12.
rac-5-Demethylxyloketal D 16: White crystals (diethyl ether/pen-
tane), m.p. 114Ϫ116 °C. IR (KBr, cmϪ1): ν˜ ϭ 2981, 2893, 1750,
1620, 1600, 1481, 1382, 1212. UV (MeOH): λmax. (log ε) ϭ 269
(4.80) 259 (4.51), 255.8 (4.49), 203 (3.75) nm. 1H NMR (CDCl3,
300 MHz): δ ϭ 13.05 (s, 1 H, OH), 7.49 (d, J ϭ 9.0 Hz, 1 H, H-
13) 6.34 (d, J ϭ 8.8 Hz, 1 H, H-14), 4.01 (m, 2 H, H-4), 2.98 (d,
J ϭ 15.0 Hz, 1 H, H-7a), 2.72 (dd, J ϭ 6.4, 18.0 Hz, 1 H, H-7b),
2.51 (s, 1 H, H-16), 2.45 (m, 1 H, H-6), 2.05 (m, 1 H, H-5a), 1.71
(m, 1 H, H-5b), 1.51 (s, 3 H, H-10) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 202.8 (C-15), 163.2 (C-11), 159.9 (C-9), 130.3 (C-
13), 113.4 (C-12), 108.9 (C-14), 107.6 (C-2), 106.2 (C-8), 67.1 (C-
4), 39.8 (C-6), 29.2 (C-5), 26.3 (C-16), 22.4 (C-10), 19.6 (C-7) ppm.
MS (EI, 80 eV): m/z (%) ϭ 248 (81) [C14H16O4, Mϩ] , 230 (12), 215
(9), 203 (19), 177 (23), 165 (28), 137 (13), 121 (11), 97 (7), 83 (77),
57 (43), 43 (100). C14H16O4 (248.3): calcd. C 67.73, H 6.53; found
C 67.10, H 6.53.
1
Data for 14: H NMR (CDCl3, 200 MHz): δ ϭ 6.19, 5.95 (each s
and each 1 H, CH2), 3.74 (t, J ϭ 6.1 Hz, 2 H, H-4), 2.39 (t, J ϭ
7.04 Hz, 2 H, H-3), 2.42 (s, 3 H, H-6) ppm. 13C NMR (CDCl3,
50 MHz): δ ϭ 201.1 (C-2), 146.7 (C-3), 128.2 (C-4), 62.4 (C-2Ј),
35.0 (C-1Ј), 26.2 (C-1) ppm. Data for 13: 1H NMR (CDCl3,
200 MHz): δ ϭ 4.93, 4.71 (each s, 1 H, CH2), 3.60 (t, J ϭ 6.3 Hz,
2 H, H-1), 2.29 (t, J ϭ 5.5 Hz, 2 H, H-2), 1.24 (s, CH3, 6 H) ppm.
13C NMR, (CDCl3, 50 MHz): δ ϭ 153.6 (C-3), 110.1 (CH2), 72.8
(C-4), 63.0 (C-1), 34.8 (C-2), 29.5 (2 CH3) ppm.
rac-5-Demethylisoxyloketal 17: White crystals (diethyl ether/pen-
tane), m.p. 134Ϫ135 °C. IR (KBr, cmϪ1): ν˜ ϭ 2981, 2893, 1750,
1620, 1600, 1481, 1382, 1212. UV (MeOH): λmax. (log ε) ϭ 269.2
1
(4.82), 259.2 (4.51), 203 (3.86) nm. H NMR (CDCl3, 300 MHz):
δ ϭ 7.48 (s, 1 H, H-11), 6.40 (s, 1 H, H-12), 3.98 (m, 1 H, H-4),
2.99, 2.88, (m, 2 H, H-7), 2.52 (s, 3 H, H-16), 2.48 (m, 1 H, H-6),
2.20 and 1.98 (m, 2 H, H-5), 1.64 (s, 3 H, H-10), 12.40 (s, 1 H,
OH) ppm. 13C NMR (CDCl3,75 MHz): δ ϭ 202.7 (C-15), 163.7
(C-13), 160.8 (C-9), 132.5 (C-11), 114.9, (C-12), 110.8 (C-8), 108.5
Condensation of Enone 14 with 2,4-Dihydroxyacetophenone (15):
The enone 14 (114 mg, 1 mmol) was added to 2,4-dihydroxyaceto-
Eur. J. Org. Chem. 2004, 1261Ϫ1270
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1267

K. Krohn, M. Riaz, U. Flörke
FULL PAPER
(C-2), 104.9 (C-14), 67.3 (C-4), 41.1 (C-6), 28.4 (C-5), 26.7 (C-16), 6, C-6Ј), 29.2, 29.1, 29.0 (C-5, C-5Ј), 23.4, 23.1 (C-14), 23.1, 22.6,
25.7 (C-16), 23.4 (C-7) ppm. MS (EI, 80 eV): m/z (%) ϭ 248 (67) 22.5, 22.4 (C-10, C-10Ј), 21.1 (C-14) 20.6 (C-7, C-7Ј) ppm. MS (EI,
[C14H16O4, Mϩ], 230 (8), 215 (11), 203 (18), 177 (19), 165 (79), 137 80 eV): m/z (%) ϭ 360 (C20H24O6, Mϩ, 88), 330 (8), 317 (17), 276
(22), 83 (39). C14H16O4 (248.3): calcd. C 67.73, H 6.53; found C
67.50, H 6.77.
(37), 234 (42), 219 (27), 191 (21), 152 (36), 84 (49), 43 (100).
C20H24O6 (360.4): calcd. C 66.65, H 6.71; found C 65.98, H 6.78.
Data for Tris(ketals) 20a,b: White crystals, m.p. 155Ϫ157 °C. IR
(KBr, cmϪ1): ν˜ ϭ 3560Ϫ3301, 2986, 2934, 2887, 2846, 1620, 1470,
1382, 1196, 1113, 989, 855. UV (MeOH): λmax. (log ε) ϭ 269.2
(4.84), 259.4 (4.51) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ
4.07Ϫ3.88 (m, 2 H, H-4), 2.88 (m, 1 H, H-7a), 2.69 (m, 1 H, H-
7b), 2.38 (m, 1 H, H-6), 2.04 (m, 1 H, H-5a), 1.77 (m, 1 H, H-5b),
1.52, 1.50, 1.49 (each s, 3 H, H-10) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 150.2, 150.2, 150.1, 150, 1 (C-9), 107.0, 106.9, 106.8,
106.7 (C-2), 99.6, 99.5, 99.4, 99.3 (C-8), 66.9 (C-4), 40.5, 40.4, 40.4
(C-6), 29.5, 29.4 (C-5), 23.2, 23.1, 22.9, 22.8 (C-10), 20.6, 20.5 (C-
7) ppm. MS (EI, 80 eV): m/z (%) ϭ 414 (36) [C24H30O6, Mϩ], 330
(57), 246 (43), 203 (18), 85 (95), 83 (100), 43 (46). C24H30O6 (414.5):
calcd. C 69.54, H 7.30; found C 69.47, H 7.45.
Reaction of Enone 14 with Phloroglucinol (7). Synthesis of 5-De-
methylxyloketals 18, 19a,b, and 20a,b: Three experiments of con-
densation of enone 13 with phloroglucinol (7) were performed, as
described for 16/17, to afford the mono, bis, and tris adducts 18,
19a,b, and 20a,b, respectively, in different ratios, depending on the
proportion of the reactants and reaction time, as shown in Table 1.
The major part of the bis adducts 19a,b were precipitated with
pentane/EtOAc (3:7) whereas the mono ketal 18 and the tris(ketals)
20a,b were purified by column chromatography on silica gel
(CH2Cl2/Et2O, 99:1). The mono ketal 18 was isolated from the po-
lar fraction, the bis adducts 19a,b from the intermediate fraction,
and the tris(ketals) 20a,b from the least polar fraction.
Data for Monoketal 18: Resin. IR (KBr, cmϪ1): ν˜ ϭ 3423 br., 2983,
2923, 2847, 1629, 1520, 1460, 1384, 1286, 1177, 1161, 1150, 1112,
1079, 1003. UV (MeOH): λmax. (log ε) ϭ 269.2 (4.65), 240.8 (3.39),
207 (3.25) nm. 1H NMR (CDCl3, 300 MHz): δ ϭ 5.94 (d, J ϭ
2.8 Hz, 1 H, H-12), 5.86 (d, J ϭ 2.3 Hz, 1 H, H-14), 3.94 (m, 2 H,
H-4), 2.86 (d, J ϭ 18.0 Hz, 1 H, H-7a), 2.65 (dd, J ϭ 6.0, 18.0 Hz,
1 H, H-7b), 2.43 (m, 1 H, H-6), 2.06 (m, 1 H, H-5a), 1.74 (m, 1 H,
H-5b), 1.47 (s, 3 H, H-7b, H-10) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ 158.4 (C-9), 156.5 (C-11), 156.4 (C-13), 108.6 (C-2), 99.8 (C-
8), 97.2 (C-12), 96.7 (C-14), 68.4 (C-4), 42.4 (C-9), 30.7 (C-5), 23.6
(C-10), 21.6 (C-7) ppm. MS (EI, 80 eV): m/z (%) ϭ 222 (9)
[C12H14O4, Mϩ], 167 (11), 139 (31), 97 (16), 83 (39), 57 (14), 43
(100), 31 (96).
Crystal Structure Determination of 20b:[10] C24H30O6, Mr ϭ 414.5,
monoclinic, space group P21/c, a ϭ 6.8219(11), b ϭ 26.234(4), c ϭ
3
˚
˚
11.6881(19) A, β ϭ 92.775(3)°, V ϭ 2089.3(6) A , Z ϭ 4, Dcalcd.
ϭ
1.318 g/cm3, F(000) ϭ 888, T ϭ 173(2) K. Bruker-AXS SMART
APEX, graphite-monochromated, λ(Mo-Kα) ϭ 0.71073 A, µ ϭ
˚
0.09 mmϪ1, poorly diffracting colorless crystal, size 0.45 ϫ 0.20 ϫ
0.20 mm3, 8459 intensities collected 3 Ͻ 2θ Ͻ 49.4°, Ϫ8 Ͻ h Ͻ 8,
Ϫ30 Ͻ k Ͻ 30, Ϫ8 Ͻ l Ͻ 13. Structure solved by direct methods,
full-matrix least-squares refinement based on F2 and 271 param-
eters, all but H atoms refined anisotropically, H atoms refined with
riding model on idealized positions with U ϭ 1.5 Uiso(O) and 1.2
Uiso(C). Refinement converged at R1(F) ϭ 0.086, wR2(F2, all
data) ϭ 0.268, S ϭ 0.93, max.(δ/σ) Ͻ 0.001, min./max. height in
3
˚
final ∆F map Ϫ0.42/0.55 e/A . Figure 1 shows the molecular struc-
Data for Bis(ketals) 19a,b: White crystals, m.p. 244Ϫ245 °C (dec.).
IR (KBr, cmϪ1): ν˜ ϭ 3363, 2975, 2955, 2893, 2846, 1615, 1505,
1450, 1382, 1108, 1082, 994. UV (MeOH): λmax. (log ε) ϭ 269.1
ture. Programs used: SHELXTL.[11]
Reduction of Citraconic Anhydride (21) with LiAlH4, and Hydrogen-
ation: Citraconic anhydride (21) was reduced with LiAlH4 as de-
scribed in the literature[6] to obtain the mixture of unsaturated iso-
meric lactones 22 and 23 in a 8.5:1.5 ratio and in 70% yield. Sub-
sequent hydrogenation of this mixture was carried out using 10%
Pd on charcoal to afford 3-methyl-γ-butyrolactone rac-10 (as a
crude mixture with the isomer corresponding to 23) in 72% yield.
1
(4.54), 259.2 (4.18) nm. H NMR (CDCl3, 300 MHz): δ ϭ 6.48 (s,
1 H, H-12), 3.97 (m, 2 H, H-4a, H-4aЈ,), 3.81 (m, 2 H, H-4b, H-
4bЈ), 3.29 (m, 2 H, H-7a, H-7aЈ), 3.02 (m, 2 H,H-7b, H-7bЈ), 2.92
(m, 1 H, H-6), 2.79 (m, 1 H, H-6Ј), 1.79 (m, 4 H, H-5, H-5Ј), 1.55,
1.53, 1.51, 1.49 (each s, 6 H, H-10, H-10Ј) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 156.5, 156.4 (C-11), 153.5, 153.4, 153.3, 153.1 (C-9,
C-9Ј), 107.6, 107.4, 106.9, 106.8 (C-2, C-2Ј), 100.2, 100.0, 99.2, 98.6
(C-8, C-8Ј), 96.5, 96.4 (C-12, C-12Ј), 66.96, 66.90, 66.79 (C-4, C-
4Ј), 41.0, 40.9 (C-6, C-6Ј), 29.6, 29.4 (C-5, C-5Ј), 23.4, 23.1, 23.0,
22.9 (C-10, C-10Ј), 21.2, 21.1, 20.8 (C-7, C-7Ј) ppm. MS (EI,
80 eV): m/z (%) ϭ 318 (72) [C18H22O5, Mϩ], 234 (88), 219 (68), 191
(28), 152 (35), 139 (57), 111 (19), 84 (81), 69 (21), 43 (100).
C18H22O5 (318.3): calcd. C 67.91, H 6.97; found C 67.26, H 6.96.
4-Methyl-3-methylenedihydrofuran-2-one (rac-9): Absolute EtOH
(3 mL) was slowly added under nitrogen to a suspension of NaH
(9.6 g, 0.4 mol) in dry diethyl ether (200 mL). A mixture of ethyl
formate (32.9 mL, 0.4 mol) and crude rac-10[5] (35.2 mL, 0.4 mol)
was then slowly added to the mixture over a period of 1.3 h (com-
pare procedure in ref.[5b]). The rate of addition was controlled to
give a steady reflux and evolution of hydrogen gas. After complete
addition, the mixture was stirred for a further 30 min at 20 °C. The
Acetates 19c,d: The bis(ketals) 19a,b (100 mg) were acetylated with
acetic anhydride (0.2 mL) in pyridine (1 mL) and catalytic amounts solid precipitate formed was filtered off, washed with dry diethyl
of DMAP to obtain the acetylated demethylxyloketals 19c,d as
white crystals after usual workup, m.p. 169Ϫ170 °C. IR (KBr,
ether, and dried under vacuum to give the light yellow α-formyl-γ-
butyrolactone sodium salt (59.43 g, 99%). Part of this salt (27.2 g,
cmϪ1): ν˜ ϭ 3446, 2981, 2939, 2893, 1746, 1605, 1496, 1424, 1367. 0.2 mol) was added to a stirred suspension of paraformaldehyde
(MeOH): UV λmax. (log ε) ϭ 269.2 (4.53), 256.2 (4.20), 203 (2.99)
nm. 1H NMR (CDCl3, 300 MHz): δ ϭ 6.18 (s, 1 H, H-12), 4.00 immediately refluxed for 1 h. The mixture was cooled to 10 °C and
(m, 4 H, H-4a, H-4aЈ, H-4b, H-4bЈ), 2.89 (d, J ϭ 18.0 Hz, 2 H, H- treated with a saturated aqueous solution of potassium carbonate
(27.0 g, 0.2 mol) in dry diethyl ether (200 mL) and the mixture was
7a, H-7aЈ), 2.65 (ddd, J ϭ 6.0, 18.0, 24.0 Hz, 2 H, H-7b, H-7bЈ), (25 mL) and diethyl ether (100 mL). The organic layer was sepa-
2.36 (m, 2 H, H-6, H-6Ј), 2.25 (s, 3 H, H-14), 2.00 (m, 2 H, H-5a, rated, dried and the solvents evaporated to dryness to afford a pale
H-5aЈ), 1.75, (m, 2 H, H-5b, H-5bЈ), 1.51, 1.49, 1.48, 1.47 (each s,
yellow oil (14.8 g, 66%). Data for (rac-9): 1H NMR (CDCl3,
6 H, H-10, H-10Ј, ) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 201.4, 200 MHz): δ ϭ 6.01(d, J ϭ 3.0 Hz 1 H, H-7a), 5.58 (d, J ϭ 3.0 Hz
169.4 (C-13), 152.6, 152.2 (C11), 150.0, 149.6, 149.3, 148.4 (C-9, 1 H, H-7b), 4.8Ϫ4.5 (m, 2 H, H-5), 2.85 (m, 1 H, H-4), 1.50 (m, 3
C-9Ј) 107.7, 107.4, 106.7 (C-2, C-2Ј), 105.1, 104.3, 104.0 (C-8, C-
8Ј), 103.1, 103.1 (C-12), 67.0 (C-4, C-4Ј), 40.4, 40.3, 40.1, 40.0 (C-
H, H-6) ppm. 13C NMR, (CDCl3, 50 MHz): δ ϭ 170.7 (C-2), 140.3
(C-3), 120.7 (C-7), 72.4 (C-5), 33.9 (C-4), 17.7 (C-6) ppm.
1268
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1261Ϫ1270

Natural Products from the Mangrove Fungus Xylaria sp
FULL PAPER
5-Hydroxy-4-methyl-3-methylenepentan-2-one (rac-8a). Methylation
2 mmol) in boiling toluene as described for 16. The mixture was
of α-Methylene-γ-butyrolactone (rac-9):
A solution of MeLi separated by column chromatography on silica gel (hexane/di-
(21 mL, 32.9 mmol) in diethyl ether (30 mL) was added slowly to chloromethane, 12:88) into three fractions. The least-polar fraction
a stirring solution of rac-9 (14 mL, 32.9 mmol). The mixture was
stirred for 30 min and was then warmed up to 0 °C over a period
contained stereoisomers of the tris adducts xyloketals A (1aϪ1h;
50 mg, 5.5%) was further purified by repeated preparative TLC on
of 1 h. The reaction was quenched by addition of aqueous NH4Cl silica gel. The fraction of medium polarity contained the stereo-
solution (20 mL) and the mixture was extracted three times with
diethyl ether (each 20 mL). The combined organic phases were
dried (MgSO4) and the solvent was removed under reduced press-
ure to afford a yellowish oil. The residue was separated by column
isomeric bis adducts of xyloketals B (2aϪ2h; 211 mg, 30.5%). Col-
orless plates separated from fraction two in diethyl ether, showing
only one isomer (probably 2e) in the NMR spectra. The monoad-
ducts (6a,b; 235 mg, 50.0%) were isolated from the polar fraction
chromatography over silica gel (CH2Cl2/EtOAc, 95:5) to afford as an amorphous powder. The overall yield of the condensation
methyl ketone rac-8 (75% yield) from the less-polar fraction. The
ratio between the desired ketone rac-8a and the dimethylated side
was found to be 86%. The NMR spectrum showed a ca. 8.5 to 1.5
mixture of stereoisomers, similar to that found in the related reac-
product related to 13 was found to be 86:14. 1H NMR (CDCl3, tion of rac-8 with 2,4-dihydroxyacetophenone (15).
200 MHz): δ ϭ 6.14 (d, J ϭ 1.7 Hz, 1 H, H-4a), 5.70 (d, J ϭ 1.7 Hz,
Data for Xyloketal A (1aϪ1h, mixture): 1H NMR (CDCl3,
2 H, H-7b), 3.74 (m, 2 H, H-2Ј), 2.96 (m, 1 H, H-1Ј), 2.36 (s, 3 H,
200 MHz): δ ϭ 4.19 ϭ (m, 2 H, H-4a), 3.52 (m, 2 H, H-4b),
3.1Ϫ2.42 (m, 4 H, H-7a, H-7b), 2.21Ϫ1.81 (m, 4 H, H-5, H-6), 1.4
(s, 3 H, H-10), 1.1 (d, J ϭ 6.3 Hz, 3 H) ppm. 13C NMR
(CDCl3,75 MHz): δ ϭ 152.6, 152.2, 151.8 (C-9), 108.3, 108.1, 107.9
H-1) 1.35 (d, J ϭ 6.0 Hz, 3 H, H-6) ppm. 13C NMR (CDCl3,
50 MHz): δ ϭ 200.7 (C-2), 151.4 (C-3), 125.5 (C-4), 66.0 (C-2Ј),
36.2 (C-1Ј), 26.6 (C-1) 15.4 (C-1ЈЈ) ppm.
Condensation of Enone rac-8a with 2,4-Dihydroxyacetophenone (15). (C-2), 99.9, 99.8, 99.6 (C-8), 74.4, 74.1 (C-4), 48.0 (C-6), 35.8, 35.7,
Formation of rac-Xyloketal D (rac-4a): Enone rac-8a and 2,4-di-
hydroxyacetophenone (15, 578 mg, 3.8 mmol) were heated in tolu-
ene as described for 16. The mixture was separated by column chro-
matography on silica gel (hexane/dichloromethane, 12:88) to afford
a mixture of 4a and 4b (800 mg, 3.05 mmol, 80.3%) from the less-
polar fraction and 24a,b (89.7 mg, 9%) from the polar fraction
(overall yield 89.3%). The 1H NMR spectra showed the mixture of
4a and 4b in a ca. 8.5 to 1.5 ratio. Crystallization from diethyl ether
gave pure rac-xyloketal D (4a) (637 mg, 64%).
35.5, 35.2 (C-5), 24.0, 23.7, 23.5, 23.1 (C-10), 19.5, 19.3, 19.2, 19.1
(C-7), 16.6, 16.5, 16.4 (C-11) ppm. MS (EI, 80 eV): m/z (%) ϭ 456
(5) [C27H36O6, Mϩ], 396 (35), 300 (42), 163 (12), 83 (100), 43 (84).
C27H36O6: (456.58) calcd. C 71.03, H 7.95; found C 70.90, H 7.28.
1
Xyloketal B 2a؊2h: H NMR (CDCl3, 200 MHz): δ ϭ 6.14 ϭ (1
H, OH), 6.12 (s, 1 H, H-13), 4.14 (dd, J ϭ 8.3, 17.3 Hz, 2 H, H-
4a, H-4aЈ), 3.47 (m, 2 H, H-ba, H-4bЈ), 2.86 (d, J ϭ 17.1 Hz, 2 H,
H-7a, H-7aЈ ), 2.58 (m, 2 H, H-7b, H-7bЈ), 2.13 (m, 2 H, H-6, H-
6Ј), 1.88 (m, 2 H, H-5, H-5Ј), 1.51 (s, 6 H, H-10, H-10Ј), 1.03 (d,
J ϭ 6.6, 6 H, H-11, H-11Ј) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
154.0, 153.9 (C-12), 152.3, 152.2, (C-9Ј) 152.1, 151.9 (C-9), 108.0,
Data for rac-Xyloketal D 4a: White crystals, m.p. 82 °C. IR (KBr,
cmϪ1): ν˜ ϭ 2965, 2929, 2887, 2841, 1765, 1615, 1491, 1424, 1387,
1341, 1206, 1108, 1072. UV (CHCl3): λmax. (log ε) ϭ 315 (5.7) 283 107.9 (C-2Ј) 107.7 (C-2), 99.4, 99.2 (C-8), 98.9, 98.2 (C-8Ј), 96.2,
(4.2), 266 (4.5), 223 (5.50), 219 (5.4), 211 (5.47) nm. 1H NMR
96.1 (C-13), 74.2, 74.1, (C-2, C-2Ј), 48.1, 48.0 (C-6) 47.8 (C-6Ј),
(CDCl3, 300 MHz): δ ϭ 13.1, (m, 1 H, OH), 7.5 (d, J ϭ 8.9 Hz, 1 35.6 (C-5 and C-5Ј), 23.5, 23.3 (C-10Ј), 23.1, 23.0 (C-10), 19.0, 18.9
H, H-14), 6.34 (d, J ϭ 8.9 Hz, 1 H, H-15), 4.22 (t, J ϭ 8.1 Hz, 1 (C-7Ј), 18.8, 18.7 (C-7), 16.5, 16.3 (C-11Ј), 16.2, 16.0 (C-11) ppm.
H, H-4a), 3.6 (t, J ϭ 8.1 Hz, 1 H, H-4b), 3.01 (d, J ϭ 18 Hz, 1 H,
Isoxyloketal B (probably 2e): White crystals, m.p. 231Ϫ234 °C
H-7a), 2.76 (dd, J ϭ 5.6, 18.0 Hz, 1 H, H-7b), 2.57 (s, 3 H, H-17),
(dec.). IR (KBr, cmϪ1): ν˜ ϭ 3394, 2950, 2929, 2887, 1620, 1512,
1455, 1387, 1341, 1206, 1118. UV (CHCl3): λmax. (log ε) ϭ 303
2.28Ϫ1.94 (m, 2 H, H-5 and H-6), 1.57 (s, 3 H, H-10), 1.11 (d, J ϭ
6.1 Hz, 3 H, H-11) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 203.0
(C-16), 163.3 (C-12), 159.8 (C-9), 130.3 (C-14), 113.4 (C-13), 109.1
(C-15), 108.6 (C-2), 106.5 (C-8), 74.6 (C-4), 47.3 (C-6), 35.4 (C-5),
26.5 (C-17), 23.0 (C-10), 18.3 (C-7), 16.1 (C-11) ppm. MS (EI,
80 eV): m/z (%) ϭ 248 (47) [C14H16O4, Mϩ], 219 (8), 203 (12), 177
(14), 165 (100), 137 (100), 121 (10), 97 (67), 83 (38), 43 (40).
C15H18O4 (262.3): calcd. C 68.68, H 6.92; found C 68.56, H 6.73.
(5.1), 297 (5.2), 282 (5.2), 264 (4.6), 259 (4.53), 219 (4.51), 212
1
(4.53), 208 (4.5) nm. H NMR (CDCl3, 200 MHz): δ ϭ 6.13 (s, 1
H, OH), 6.12 (s, 1 H, H-13), 4.17 (dd, J ϭ 7.6, 17.5 Hz, 2 H, H-
4a, H-4aЈ), 3.47 (m, 2 H, H-4b, H-4bЈ), 2.89 (d, J ϭ 17.0 Hz, 2 H,
H-7a, H-7aЈ), 2.65 (, m, 2 H, H-7b, H-7bЈ), 2.15 (m, 2 H, H-5, H-
5Ј), 1.91 ( m, 2 H, H-6, H-6Ј,), 1.55 (s, 6 H, H-10, H-10Ј), 1.08 (d,
J ϭ 6.0, 6 H, H-11, H-11Ј) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
153.6 (C-12), 152.2, (C-9Ј) 152.1, 152.0 (C-9), 107.9 (C-2Ј) 107.8
(C-2), 99.5 (C-8Ј), 98.8 (C-8), 96.1 (C-13), 74.2 (C-2, C-2Ј), 48.0,
Data for iso-Xyloketals D 24a,b: 1H NMR (CDCl3, 300 MHz): δ ϭ
12.35, (m, 1 H, OH), 6.33 (d, J ϭ 2.4 Hz, 1 H, H-15), 5.25 (d, J ϭ
2.4 Hz, 1 H, H-12), 4.15 (t, J ϭ 8.1 Hz, 1 H, H-4a), 3.53 (t, J ϭ 48.2 (C-6Ј) 47.8 (C-6), 35.7, 35.5 (C-5Ј and C-5), 23.3 (C-10Ј), 23.2
8.1 Hz, 1 H, H-4b), 2.97 (d, J ϭ 16.3 Hz, 1 H, H-7a), 2.7 (m, 1 H, (C-10), 16.3 (C-11Ј), 16.0 (C-11) ppm. MS (EI, 80 eV): m/z (%) ϭ
H-7b), 2.53 (s, 3 H, H-17), 2.19Ϫ1.82 (m, 2 H, H-5 and H-6), 1.53 346 (65) [C20H26O5, Mϩ], 250 (20), 249 (33), 249 (63), 233 (20), 205
(s, 3 H, H-10), 1.06 (d, J ϭ 6.2 Hz, 3 H, H-11) ppm. 13C NMR (57), 83 (33), 43 (41). C20H26O5 (346.4): calcd. C 69.34, H 7.56;
(CDCl3, 75 MHz): δ ϭ 202.7 (C-16), 163.7 (C-13), 160.2 (C-9),
132.5 (C-15), 116.3 (C-14), 110.7 (C-8), 109.3 (C-2), 105.0 (C-12),
74.6 (C-4), 48.5 (C-6), 35.4, 35.0 (C-5), 26.7 (C-17), 23.9 (C-10),
18.4 (C-7), 16.4 (C-11) ppm. MS (EI, 80 eV): m/z (%) ϭ 262 (43)
[C15H18O4, Mϩ], 219 (3), 203 (12), 165 (100), 147 (15), 97 (57), 83
(33), 43 (41). C15H18O4 (262.3): calcd. C 68.68, H 6.92; found C
68.50, H 6.71.
found C 69.47, H 7.28.
Monoadducts 6a,b: White amorphous powder, IR (KBr, cmϪ1): ν˜ ϭ
3374 br, 2955, 2924, 2847, 1625, 1527, 1465, 1393, 1279, 1155. UV
(CHCl3): λmax. (log ε) ϭ 297 (4.7), 263 (3.9), 259 (3.8), 224 (3.9),
220 (3.87), 208 (3.9) nm. 1H NMR (CDCl3, 200 MHz): δ ϭ 6.00
(d, J ϭ 2.2 Hz, 1 H, H-12), 5.92 (d, J ϭ 2.2 Hz, 1 H, H-14), 4.17
(t, J ϭ 8.3 Hz, 1 H, H-4a), 3.52 (dd, J ϭ 8.3 Hz, 1 H, H-4b), 2.79
(d, J ϭ 17.1 Hz, 1 H, H-7a), 2.68 (dd, J ϭ 5.8, 16.9 Hz, 1 H, H-
7b), 2.13 (m, 1 H, H-5), 1.91 (m, 1 H, H-6), 1.49 (s, 3 H, H-10),
Condensation of Enone rac-8 with Phloroglucinol (7). Synthesis of
rac-Xyloketals A (1aϪh), B (2aϪh), and (6a,b): Enone rac-8a
(256 mg, 2 mmol) was condensed with phloroglucinol (7) (252 mg, 1.04 (d, J ϭ 6.5 Hz, 3 H, H-11) ppm. 13C NMR (CDCl3 75 MHz):
Eur. J. Org. Chem. 2004, 1261Ϫ1270
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1269

K. Krohn, M. Riaz, U. Flörke
FULL PAPER
δ ϭ 155.6 (C-9), 154.5 (C-15, C-13), 108.2 (C-2), 99.1 (C-8), 96.8 Supporting Information: Detailed probability calculations (ref.[7]
(C-12) 96.3 (C-14), 74.4 (C-4), 47.8 (C-6), 35.5 (C-5), 23.1 (C-10), and extended 13C NMR spectra of compounds 17; and 18. This
18.6 (C-7), 16.0 (C-11) ppm. MS (EI, 80 eV): m/z (%) ϭ 236 (50)
[C13H16O4, Mϩ], 221 (16), 139 (100), 98 (16), 97 (43), 83 (54), 69
(15), 55 (12). C13H16O4 (236.26): calcd. C 66.09, H 6.83; found C
65.32, H 7.19.
material is available free of charge via the Internet (see also the
footnote on the first page of this article).
Acknowledgments
Synthesis of Enantiomerically Enriched Xyloketal D (R)-(4a). 3-
(Hydroxymethyl)isocrotonic Acid (26): A mixture of 3,3-dimethylac-
rylic acid (25) (50 g, 0.5 mol), SeO2 (28 g, 0.25 mol), and glacial
acetic (50 mL) was refluxed for 4 h as describe in the literature.[8]
The fractional distillation afforded unchanged acid 25, 3-(hydroxy-
methyl)isocrotonic acid (26) (45%) and 3-(acetoxymethyl)isocro-
tonic acid (37%).
We thank Prof. A. Börner and Dr. J. Holz (Rostock, Germany) for
providing the equipment for asymmetric hydrogenation, Dr. A. Mix
(Bielefeld, Germany) for the 600 MHz 13C NMR spectrum of the
1aϪ1h mixture and Prof. T. R. Hoye (Minneapolis, USA) and Dr.
K. Hiltrop (Paderborn, Germany) for helpful discussion of stereo-
isomer probabilities.
(R)-3-Methylbutyrolactone (10): 3-(Hydroxymethyl)isocrotonic acid
(26) was enantioselectively hydrogenated in 93% ee and 100% con-
version as described by Noyori et al.[9] using (R)-BINAP-Ru(OAc)2
as the catalyst. The intermediate saturated acid (750 mg, 6.4 mmol)
was not purified but lactonized quantitatively into the required (R)-
3-methylbutyrolactone (10; 477 mg, 4.8 mmol) by refluxing in a
mixture of CHCl3 (5 mL) and concd. HCl (1 mL) (74.5% yield).[12]
[1]
Y. Lin, X. Wu, S. Feng, G. Jiang, J. Luo, S. Zhou, L. L. P.
Vrijmoed, E. B. G. Jones, K. Krohn, K. Steingröver, F. Zsila,
J. Org. Chem. 2001, 66, 6252Ϫ6256.
A. B. Holmes, G. R. Stephenson, Chem. Ind. 2001, 738Ϫ739.
Parts of this paper were first presented as a poster at the 8th
ICCA meeting in Tokyo, September 2002, and as a short com-
munication: K. Krohn, M. Riaz, Tetrahedron Lett. 2004, 45,
[2]
[3]
Xyloketal D (R)-4a: The methylenation of the enantiomerically en-
riched lactone (R)-10 (477 mg, 4.77 mmol) and the methylation to
the enone (R)-8a (330 mg, 2.6 mmol, yield: 54%) was performed as
described for the racemic material. The unsaturated ketone (R)-8a
(150 mg, 1.17 mmol) was then condensed with 2,4-dihydroxyaceto-
phenone (15), as described previously, to yield a mixture of xyloke-
tal D (4a) and the stereoisomer 4b in a ca. 8.5:1.5 ratio (by NMR
spectroscopy). The crude mixture was crystallized from diethyl
ether/pentane to afford the major isomer as white crystals m.p. 87
°C (120 mg, 0.95 mmol, 81%, 93% ee calculated from optical ro-
tation). After one recrystallization (diethyl ether/pentane) the prod-
uct had m.p. 110Ϫ111 °C and [α]2D5 ϭ Ϫ118, (c ϭ 0.10 CHCl3).
The data were in agreement with those of xyloketal D (4a), (ref.[1]
m.p. 111Ϫ113 °C. [α]D25 ϭ Ϫ119.5). IR (KBr, cmϪ1): ν˜ ϭ 2965,
2929, 2887, 1781, 1620, 1495, 1420, 1385, 1341, 1209. UV (MeOH):
293Ϫ294.
[4] [4a]
´
A. de la Hoz, A. Moreno, E. Vazquez, Synlett 1999,
[4b]
608Ϫ610.
Hiroyuki Saimoto, Yoshie Ogo, Mie Komoto,
Minoru Morimoto, Yoshihiro Shigemasa, Heterocycles 2001,
55, 2051Ϫ2054.
[5] [5a]
[5b]
A. W. Murray, R. G. Reid, Synthesis 1985, 35Ϫ38.
S.
M. Jenkins, H. J. Wadsworth, S. Bromidge, B. S. Orlek, P. A.
Wyman, G. J. Riley, J. Hawkins, J. Med. Chem. 1992, 35,
2392Ϫ2406.
M. M. Kayser, P. Morand, Can. J. Chem. 1978, 56,
1524Ϫ1532. [6b] M. M. Kayser, P. Morand, Can. J. Chem. 1980,
58, 2484Ϫ2490.
For probability calculations see the Supporting Information for
this article.
A. T. Khan, B. Blessing, R. R. Schmidt, Synthesis 1994,
255Ϫ257.
T. Ohta, H. Takaya, M. Kitamura, K. Nagai, R. Noyori, J.
Org. Chem. 1997, 52, 3174Ϫ3176.
Full crystallographic data (excluding structure factors) for 18b
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-205247.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2
[6] [6a]
[7]
[8]
[9]
1
λmax. (log ε) 263 ϭ (4.3) 254 (4.1), 250.3 (4.6), 206 (3.34) nm. H
[10]
NMR (CDCl3, 300 MHz): δ ϭ 13.15, (m, 1 H, OH), 7.54 (d, J ϭ
8.9 Hz, 1 H, H-14) 6.39 (d, J ϭ 8.9 Hz, 1 H, H-15), 4.22 (t, J ϭ
8.0 Hz, 1 H, H-4a), 3.59 (dd, J ϭ 8.26, 16.6 Hz, 1 H, H-4b), 2.99
(d, J ϭ 17.6 Hz, 1 H, H-7a), 2.74 (dd, J ϭ 5.9, 18.0 Hz, 1 H, H-
7b), 2.57 (s, 3 H, H-17), 2.20Ϫ1.93 (m, 2 H, H-5 and H-6), 1.56 (s, 3
H, H-10), 1.1 (d, J ϭ 6.07 Hz, 3 H, H-11) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 202.9 (C-16), 163.1 (C-12), 159.7 (C-9), 130.3, (C-
14), 113.3, (C-13), 109.0 (C-15), 108.5 (C-2), 106.3 (C-8), 74.5 (C-
4), 47.1 (C-6), 35.3 (C-5), 26.3 (C-17), 22.9 (C-10), 18.2 (C-7), 16.0
(C-11) ppm. MS (EI, 80 eV): m/z (%) ϭ 262 (39) [C15H18O4, Mϩ],
247 (8), 203 (11), 177 (14), 166 (11), 165 (100), 97 (69), 83 (38).
C15H18O4 (262.3): calcd. C 68.68, H 6.92; found C 68.56, H 6.73.
1EZ, UK [Fax: (internat.)
deposit@ccdc.cam.ac.uk].
ϩ 44-1223-336-033; E-mail:
[11]
[12]
Bruker (2002). SMART (Ver. 5.62), SAINT (Ver. 6.02),
SHELXTL (Ver. 6.10) and SADABS (Version 2.03). Bruker
AXS Inc., Madison, Wisconsin, USA.
H. Mattes, K. Hamada, C. Benezra, J. Med. Chem. 1987, 30,
1948Ϫ1951.
Received October 6, 2003
1270
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1261Ϫ1270