Stereoselective synthesis of 4-dehydroxydiversonol employing enantioselective palladium-catalysed domino reactions

Article abstract of DOI:10.1002/chem.200800967

The stereoselective synthesis of 4-dehydroxydiversonol (4) employing enantioselective palladium-catalysed domino processes such as the domino Wacker-Heck and the domino Wacker-carbonylation reaction for the formation of the central chroman moiety is described. Thus, reaction of 8 with palladium(II) trifluoroacetate [Pd(OTFA)₂] in the presence of carbon monoxide, methanol and the 2,2′-bis(oxazolin-2-yl)-1,1'-binaphthyl (BOXAX) ligand 17 led to 19 in 80% yield and 96% ee. Similarly, the chroman 7 was prepared using 8 and methyl acrylate (9) as starting material. Hydrogenation of the double bond, oxidation of the benzylic methylene group and intramolecular acylation of chromanone 6 provided the tetrahydroxanthenone core 5, from which the synthesis of 4 was completed. The relative configuration of 4 could be established by crystal structure analysis.

Full text of DOI:10.1002/chem.200800967

DOI: 10.1002/chem.200800967
Stereoselective Synthesis of 4-Dehydroxydiversonol Employing
Enantioselective Palladium-Catalysed Domino Reactions
Lutz F. Tietze,*[a] Dirk A. Spiegl,[a] Florian Stecker,[a] Julia Major,[a]
Christian Raith,[a] and Christian Große[b]
Dedicated to Professor Wolfgang Steglich on the occasion of his 75th birthday
Abstract: The stereoselective synthesis
of 4-dehydroxydiversonol (4) employ-
ing enantioselective palladium-cata-
lysed domino processes such as the
domino Wacker–Heck and the domino
Wacker-carbonylation reaction for the
formation of the central chroman
moiety is described. Thus, reaction of 8
with palladium(II) trifluoroacetate
monoxide, methanol and the 2,2’-
bis(oxazolin-2-yl)-1,1ꢀ-binaphthyl
(BOXAX) ligand 17 led to 19 in 80%
yield and 96% ee. Similarly, the chro-
man 7 was prepared using 8 and
methyl acrylate (9) as starting material.
Hydrogenation of the double bond, ox-
idation of the benzylic methylene
group and intramolecular acylation of
chromanone 6 provided the tetrahy-
droxanthenone core 5, from which the
synthesis of 4 was completed. The rela-
tive configuration of 4 could be estab-
lished by crystal structure analysis.
Keywords: asymmetric catalysis
domino reactions palladium
·
·
·
tetrahydroxanthenones
oxidation
·
Wacker
[PdACHTUNGTRENNUNG(OTFA)2] in the presence of carbon
Introduction
Despite their interesting profile, only recently synthetic
efforts towards functionalised tetrahydroxanthenones and
The secalonic acids (1), complex polyketides originally iso-
lated from the fungus Claviceps purpurea,[1] contain the tet-
rahydroxanthenone moiety as the basic structural motif.[2]
These compounds exhibit a widespread biological activity
that includes antibacterial, cytostatic and anti-HIV proper-
ties.[3–5] So far, seven homo- and heterodimeric members of
this substance class are known, each possessing a 2,2’-biaryl
linkage, although with different configurations at the stereo-
genic centres.[6,7] Structurally related monomeric species are
the fungal metabolites b-diversonolic ester (2) and diverso-
nol (3) from Penicillium diversum.[8,9]
their derivatives have been made.[10,11]
[a] Prof. Dr. L. F. Tietze, Dr. D. A. Spiegl, Dr. F. Stecker, Dr. J. Major,
Dipl.-Chem. C. Raith
Herein, we report the stereoselective synthesis of 4-dehy-
droxydiversonol (4) by applying a novel strategy towards
enantiopure tetrahydroxanthenones that includes a domino
Wacker–Heck or a domino Wacker-carbonylation reaction
as the key step.[12] These enantioselective palladium-cata-
lysed transformations were developed recently in our labo-
ratory for the synthesis of chromans, dioxins and oxazines
and have proven their efficiency in the total synthesis of
Institut fꢁr Organische und Biomolekulare Chemie
Georg-August-Universitꢂt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-39-9476
E-mail: ltietze@gwdg.de
[b] Dipl.-Chem. C. Große
Institut fꢁr Anorganische Chemie
Georg-August-Universitꢂt Gçttingen
Tammannstrasse 4, 37077 Gçttingen (Germany)
8956
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FULL PAPER
enantiopure a-tocopherol.[13,14] Our approach allows the syn-
thesis of both enantiomers of 4 by using either the BOXAX
ligand 17 or ent-17. Notably, the determination of the abso-
lute configuration of diversonol (3) is questionable, though
generally it is depicted as ent-3. Our attempts to reisolate di-
versonol for structure determination have so far failed.
DMF gave access to the desired alkenyl phenol 8 with an
overall yield of 48% based on 10.
The domino Wacker–Heck reaction of 8 and methyl acry-
late (9) in the presence of catalytic amounts of palladium(II)
Results and Discussion
The retrosynthetic analysis of 4 (Scheme 1) leads to the tet-
rahydroxanthenone core 5. This is further disconnected con-
Scheme 2. Synthesis of alkenyl phenol 8: a) Me2SO4, K2CO3, acetone,
reflux, 24 h, 94%; b) nBuLi, TMEDA, Et2O, 0 8C!reflux, 3 h, then
DMF, 08C!RT, 2 h, 87%; c) Ph3PCHC(O)CH3 (16), toluene, reflux,
22 h, 98%; or acetone, NaOH(aq), 08C!RT, 3 h, 84%; d) H2, Pd/C,
EtOAc, RT, 3 h, 92%; e) Zn, CH2Br2, TiCl4, THF, 08C!RT, 1 h, 82%;
f) NaSEt, DMF, 1208C, 20 h, 92%.
trifluoroacetate [PdACHTNUGTRNEUNG(OTFA)2], the chiral ligand (S,S)-Bn-
BOXAX (17)[18] and p-benzoquinone (18) as oxidant for the
reoxidation of the intermediately formed Pd0 provided the
substituted chroman 7 with 88% ee in 55% yield, after a
rather long reaction time of seven days (Scheme 3).
Scheme 1. Retrosynthetic analysis of 4-dehydroxydiversonol (4).
sidering an intramolecular acylation at the a position of the
keto functionality of chromanone 6, which in turn can be
traced back to chroman 7. For the direct synthesis of 7 with
selective formation of the stereogenic tertiary ether moiety
we envisaged an enantioselective domino Wacker–Heck re-
action of alkenyl phenol 8 and methyl acrylate (9). As a
second approach, an enantioselective domino Wacker-car-
bonylation reaction of 8 to give the chroman 19 was taken
into account. Compound 8 should be easily accessible from
orcinol (10).
Scheme 3. Synthesis of chroman 7: 10 mol% [PdACTHNURTGNENG(U OTFA)2], 40 mol%
(S,S)-Bn-BOXAX (17), p-benzoquinone (18), 1,2-dichloroethane (DCE),
RT, 7 d, 55%, 88% ee.
Alkenyl phenol 8 was synthesised from orcinol (10)
through a six-step sequence (Scheme 2). First, 10 was methy-
lated to give the corresponding dimethyl ether 11,[15] which
was subjected to ortho-lithiation and subsequent formylation
with DMF to yield aldehyde 12.[16] For the synthesis of the
a,b-unsaturated ketone 13 initially a Wittig olefination of 12
with phosphorane 16 was employed. Despite the high yield
of this transformation, aldol condensation of 12 with ace-
tone is more appropriate for the formation of 13 due to a
better atom economy. After hydrogenation, the obtained sa-
turated ketone 14 was converted into alkene 15 by employ-
ing a Lombardo methylenation.[17] Finally, selective cleavage
of one methyl ether group using sodium ethane thiolate in
Notably, a solvent screening revealed that only CH2Cl2
and 1,2-dichloroethane (DCE) were suitable for this trans-
formation providing reasonable good yield and enantioselec-
tivity. Thus, in benzene only 73% ee was obtained, whereas
in polar solvents (DMF, DMSO, dioxane, and methanol) no
formation of 7 was observed. Moreover, attempts to in-
crease the reaction rate by performing the domino process
at elevated temperature resulted in a significant reduction
of enantioselectivity, though slightly higher yields could be
obtained. We therefore developed an alternative approach
to key intermediate 7 involving an enantioselective domino
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L. F. Tietze et al.
Wacker-carbonylation reaction (Scheme 4). For this purpose,
8 was reacted under an atmosphere of carbon monoxide in
the presence of methanol to furnish ester 19 with 96% ee
Prior to the formation of the tetrahydroxanthenone core
5 by intramolecular acylation, reduction of the double bond
in 7 and oxidation of the chroman moiety to the correspond-
ing chromanone 6 were required (Scheme 6). For this pur-
pose, we tried to develop an efficient protocol for the direct
conversion of the benzylic methylene unit into a carbonyl
group. Several procedures failed in the benzylic oxidation,
however, by treatment of 25 with excess tert-butylhydroper-
oxide in the presence of catalytic amounts of dirhodium-tet-
rakiscaprolactamate (26) and NaHCO3, the desired chroma-
none 6 could finally be obtained in 63% yield.[19] Further-
more, an alternative procedure employing [MnACTHUNRGTNEUNG(OAc)3] as
catalyst led to 6 in even 71% yield.[20] Intramolecular acyla-
tion at the a position of the keto functionality by the ester
moiety in 6 in the presence of TiCl4 and NEt3 gave the tetra-
hydroxanthenone 5 in 63% yield. In contrast, cyclisation
under basic conditions using potassium hexamethyldisilazide
(KHMDS), lithium diisopropylamide (LDA) or lithium hex-
amethyldisilazide (LHMDS) resulted in lower yields due to
partial cleavage of the chroman ring.
Scheme 4. Alternative synthesis of 7: a) 3 mol% [PdACTHNURGTNEUNG(OTFA)2], 12 mol%
(S,S)-Bn-BOXAX (17), p-benzoquinone (18), CO (1 atm), MeOH, RT,
15 h, 80%, 96% ee; b) DIBAL-H, toluene, ꢀ788C, 20 min, 86%;
c) (MeO)2P(O)CH2CO2Me (21), NaH, THF, 08C!RT, 20 min, 97%, E/Z
6:1.
and 80% yield in only 15 h at room temperature. Moreover,
the required catalyst loading could be significantly reduced
obtaining satisfactory results with 3 mol% [PdACTHNUGTRENUNG(OTFA)2] and
12 mol% of the BOXAX ligand 17. Chain elongation of 19
giving access to the desired 7 was accomplished in two steps
by diisobutylaluminium hydride (DIBAL-H) reduction and
Wittig–Horner reaction of the obtained aldehyde 20 with tri-
methyl phosphonoacetate (21).
For the determination of the absolute configuration of 19
the compound was converted into the known vinyl chroman
24 to allow a comparison of the optical rotation (Scheme 5).
Reduction of ester 19 yielded the corresponding alcohol 22,
which was transformed into 24 through selenoether forma-
tion using 23, oxidation and elimination. The spectroscopic
properties of 24 were in full agreement with the reference
values published for the R enantiomer, except for the oppo-
site sign of the optical rotation (24: [a]2D0 =ꢀ52.7 (c=1.5 in
CHCl3), R enantiomer: [a]2D0 =+54.0 (c=2.18 in CHCl3)).[16]
Hence, the S configuration can unambiguously be assigned
to the stereogenic centre C-2 of the chroman moiety in 7
and 19.
Scheme 6. Synthesis of tetrahydroxanthenone 5: a) H2, Pd/C, EtOAc, RT,
6 h, 98%; b) 1 mol% 26, tBuOOH, NaHCO3, DCE, 408C, 14 h, 63%; or
20 mol% [MnACHTNUTRGNENG(U OAc)3], tBuOOH, molecular sieves 3 ꢄ, EtOAc, RT, 3 d,
71%; c) TiCl4, NEt3, CH2Cl2, 08C, 15 min, 63%.
With the tricyclic framework 5 in hand, completion of the
synthesis of 4 required the diastereoselective introduction of
the 9a-hydroxy group, reduction of the unconjugated car-
bonyl moiety and cleavage of the methyl ether (Scheme 7).
For this purpose, enol 5 was oxidised using dimethyl dioxir-
ane (DMDO) in acetone to afford trans-a-hydroxy diketone
27 in 74% yield as a single diastereomer; DMDO was supe-
rior to described procedures using meta-chloroperbenzoic
acid (mCPBA) or magnesium monoperoxyphthalate.[10b] Re-
duction of 27 with NaBH4 at ꢀ788C gave, exclusively, trans-
diol 28. Finally, deprotection employing BBr3 proceeded
smoothly and furnished 4-dehydroxydiversonol (4) in 85%
yield without epimerisation at the sensitive C-4a position.
The relative configuration of 4 was determined by crystal-
structure analysis and revealed the axial orientation of the
C-ring substituents (Figure 1).[21] Thus, we assume that the
high trans-selectivity for the oxidation of 5 can be explained
by shielding of the a face by the angular methyl group,
whereas pre-complexation of NaBH4 by the tertiary hydroxy
Scheme 5. Determination of the absolute configuration: a) LiAlH4, Et2O,
08C!RT, 2 h, 98%; b) 23, PnBu3, THF, RT, 1 h; c) mCPBA, CH2Cl2,
ꢀ408C, 1 h, then iPr2NH, ꢀ408C!RT, 88% over two steps.
8958
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Chem. Eur. J. 2008, 14, 8956 – 8963

Synthesis of 4-Dehydroxydiversonol
FULL PAPER
Experimental Section
General: Air- and moisture-sensitive reactions were carried out under
argon in flame-dried glassware. Solvents were dried and distilled prior to
use by means of standard laboratory methods. All reagents obtained
from commercial sources were used without further purification. Thin
layer chromatography (TLC) was performed on precoated silica-gel SIL
G/UV254 plates (Macherey–Nagel), and silica gel 60A (0.037–0.070 mm,
Acros) was used for column chromatography. Phosphomolybdic acid dis-
solved in MeOH (PMA) or vanillin dissolved in methanolic sulfuric acid
(VSS) were used as staining agents for TLC analysis. UV/Vis spectra
were recorded on a Perkin–Elmer Lambda2 spectrometer. IR spectra
were recorded as KBr pellets or as films between NaCl plates on a
Bruker Vector22 instrument. 1H and 13C NMR spectra were recorded in
deuterated solvents with Mercury-200, VXR-200, Unity-300, Inova-500,
Unity-600 (Varian) or AMX-300 (Bruker) spectrometers using TMS or
the indicated solvent as internal standard. Multiplicities of 13C NMR
peaks were determined with the attached proton test (APT) pulse se-
quence. Mass spectra were recorded on a Finnigan MAT95, TSQ7000 or
LCQ instrument. High resolution mass spectrometry was performed
using a Bruker APEXIV spectrometer equipped with a Bruker Apollo
source and a Cole–Parmer syringe pump (74900 series).
Scheme 7. Synthesis of 4-dehydroxydiversonol (4): a) DMDO, acetone,
08C, 1.5 h, 74%; b) NaBH4, MeOH/CH2Cl2, ꢀ788C, 20 min, 71%;
c) BBr3, CH2Cl2, ꢀ78!08C, 30 min, 85%.
1,3-Dimethoxy-5-methyl-benzene (11): Dimethyl sulfate (54.0 mL, 72.4 g,
575 mmol) was added dropwise to a mixture of orcinol monohydrate (10)
(35.5 g, 250 mmol) and anhydrous K2CO3 (70.0 g, 507 mmol) in acetone
(500 mL) at RT. The resulting mixture was heated at reflux for 24 h
before being treated with concd aq NH3 solution (25 mL) and heated for
further 15 min. After cooling to RT the mixture was filtered and the fil-
trate was concentrated in vacuo. The residue was dissolved in water
(400 mL) and Et2O (100 mL), the layers were separated and the aqueous
layer was extracted with Et2O (2ꢅ100 mL). The combined organic layers
were washed with water (100 mL), 3m aq NaOH solution (2ꢅ100 mL)
and sat. aq NaCl solution (100 mL), and dried (MgSO4). After evapora-
tion of the solvent in vacuo and distillation in vacuo orcinol dimethyl
ether (11) was obtained as a colourless liquid (35.8 g, 235 mmol, 94%).
Rf =0.56 (n-pentane/EtOAc 9:1); b.p. 110–1128C (20 mbar); 1H NMR
(300 MHz, CDCl3): d=2.32 (s, 3H; Ar-CH3), 3.78 (s, 6H; 2OCH3), 6.30
(m, 1H; 2-H), 6.35 ppm (m, 2H; 4-H, 6-H); 13C NMR (75 MHz, CDCl3):
d=21.8 (Ar-CH3), 55.2 (OCH3), 97.5 (C-2), 107.1 (C-4, C-6), 140.2 (C-5),
160.7 ppm (C-1, C-3); IR (film): n˜ =3059, 2955, 2838, 1597, 1461, 1321,
Figure 1. X-ray structure plot of 4-dehydroxydiversonol (4). The methyl
group at C6 is disordered.
1295, 1205, 1151, 1070, 921, 828, 686 cmꢀ1
; UV/Vis (CH3CN): lmax
(log e)=204.0 (4.645), 273.0 (3.181), 279.5 nm (3.182); MS (70 eV, EI):
m/z (%): 152.2 (100) [M+], 123.1 (37) [M+ꢀ2CH3+H]; HRMS (EI):
m/z: calcd for C9H12O2: 152.0837; found: 152.0841.
group favours hydride attack from the b face in the reduc-
tion of 27.
2,6-Dimethoxy-4-methyl-benzaldehyde (12): n-Butyllithium (32.4 mL of a
2.5m solution in hexanes, 81.0 mmol) was added dropwise to a solution of
orcinol dimethyl ether (11) (10.3 g, 67.4 mmol) and N,N,N’,N’-tetrameth-
yl-1,2-ethane (TMEDA) (20.4 mL, 15.7 g, 135 mmol) in Et2O (100 mL) at
08C. The resulting mixture was heated at reflux for 3 h before being
cooled to 08C and treated dropwise with DMF (19.0 mL, 203 mmol). Stir-
ring was continued at RT for further 2 h and the reaction was quenched
with water (300 mL). After separation of the organic layer the aqueous
layer was extracted with EtOAc (2ꢅ100 mL). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. Column chroma-
tography on silica gel (n-pentane/EtOAc 7:3) provided aldehyde 12 as a
pale-yellow solid (10.6 g, 58.8 mmol, 87%). Rf =0.28 (n-pentane/EtOAc
7:3); 1H NMR (300 MHz, CDCl3): d=2.32 (s, 3H; Ar-CH3), 3.82 (s, 6H;
2OCH3), 6.34 (s, 2H; 2Ar-H), 10.39 ppm (s, 1H; CHO); 13C NMR
(75 MHz, CDCl3): d=22.6 (Ar-CH3), 55.7 (OCH3), 104.6 (C-1), 111.9 (C-
3, C-5), 147.7 (C-4), 162.2 (C-2, C-6), 189.0 ppm (CHO); IR (KBr): n˜ =
To date, we have not been able to introduce the 4-hy-
droxy group of diversonol (3) by oxidation of an enolate de-
rived from ester 19 or allylic oxidation of 7. Therefore, cur-
rent research in our laboratory is focusing on the extension
of the scope of the domino reactions to appropriate precur-
sors allowing for an early-stage introduction of this function-
ality.
Conclusion
We have developed a novel strategy for the enantioselective
synthesis of the tetrahydroxanthenone core as found in seca-
lonic acids, diversonolic esters and diversonol. We have de-
scribed the synthesis of 4-dehydroxydiversonol (4). Key
steps involve enantioselective palladium-catalysed domino
reactions for the formation of chromans, benzylic oxidation
of the chroman moiety and intramolecular acylation of the
obtained chromanone. Diastereoselective functionalisation
of the tricyclic framework completes the synthesis of 4.
3026, 2974, 2787, 1668, 1611, 1241, 1124, 814, 575 cmꢀ1
; UV/Vis
(CH3CN): lmax (log e)=192.0 (4.375), 219.0 (4.274), 273.5 (4.125),
319.0 nm (3.587); MS (70 eV, EI): m/z (%): 180.2 (100) [M+], 165.2 (11)
[M+ꢀCH3]; HRMS (EI): m/z: calcd for C10H12O3: 180.0786; found:
180.0779.
4-(2,6-Dimethoxy-4-methyl-phenyl)-but-3-en-2-one (13): A solution of al-
dehyde 12 (10.0 g, 55.5 mmol) in acetone (80 mL) was treated dropwise
with 1m aq NaOH solution (35 mL) at 08C. The resulting mixture was
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L. F. Tietze et al.
stirred at RT for 3 h before being cooled to 08C and treated dropwise
with 1m aq HCl solution (40 mL). Water (300 mL) was added and the
mixture was extracted with EtOAc (3ꢅ100 mL). The combined extracts
were dried (Na2SO4) and concentrated in vacuo. After column chroma-
tography on silica gel (n-pentane/EtOAc 7:3) unsaturated ketone 13 was
obtained as a colourless solid (10.3 g, 46.8 mmol, 84%). Rf =0.34 (n-pen-
(m, 2H; 4’-H2), 4.93 (s, 1H; OH), 6.29 (s, 1H; Ar-H), 6.34 ppm (s, 1H;
Ar-H); 13C NMR (75 MHz, CDCl3): d=21.5 (Ar-CH3), 21.7 (C-1’), 22.7
(3’-CH3), 37.0 (C-2’), 55.6 (OCH3), 104.3, 109.0 (C-4, C-6), 109.6 (C-4’),
113.6 (C-2), 136.9 (C-5), 146.8 (C-3’), 154.0, 158.4 ppm (C-1, C-3); IR
(film): n˜ =3442, 3072, 2937, 1619, 1593, 1464, 1163, 1097, 886, 816 cmꢀ1
;
UV/Vis (CH3CN): lmax (log e)=206.5 (4.639), 271.0 (2.898), 206.5 (4.639),
279.0 nm (2.847); MS (70 eV, EI): m/z (%): 206.1 (28) [M+], 151.1 (100)
[M+ꢀC4H7]; HRMS (EI): m/z: calcd for C13H18O2: 206.1307; found:
206.1302.
1
tane/EtOAc 7:3); H NMR (300 MHz, CDCl3): d=2.36 (s, 6H; 1’-H3, Ar-
CH3), 3.86 (s, 6H; 2OCH3), 6.38 (s, 2H; 2Ar-H), 7.12 (d, J=16.7 Hz,
1H; 3’-H), 7.96 ppm (d, J=16.7 Hz, 1H; 4’-H); 13C NMR (75 MHz,
CDCl3): d=22.5 (Ar-CH3), 26.9 (C-1’), 55.7 (OCH3), 104.6 (C-1), 109.4
(C-3, C-5), 129.2 (C-3’), 135.0 (C-4’), 143.6 (C-4), 159.9 (C-2, C-6),
200.6 ppm (C-2’); IR (KBr): n˜ =3052, 3006, 2975, 2945, 2845, 1677, 1567,
1250, 1116, 994, 823, 549 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=201.0
(4.384), 233.5 (3.940), 314.5 nm (4.367); MS (70 eV, EI): m/z (%): 220.1
(15) [M+], 205.1 (21) [M+ꢀCH3], 189.1 (100) [M+ꢀ2CH3ꢀH]; HRMS
(EI): m/z: calcd for [C13H16O3+H+]: 221.1172; found: 221.1173.
(2S)-(5-Methoxy-2,7-dimethyl-chroman-2-yl)-acetic acid methyl ester
(19): A solution of [PdACTHNUTRGNE(UNG OTFA)2] (49.0 mg, 148 mmol, 3 mol%) and (S,S)-
Bn-BOXAX (17) (338 mg, 590 mmol, 12 mol%) in MeOH (5.0 mL) was
stirred at RT for 15 min. After addition of a solution of phenol 8 (1.00 g,
4.92 mmol) in MeOH (10 mL) and p-benzoquinone (18) (2.12 g,
19.7 mmol) carbon monoxide was passed through the resulting mixture
for 5 min before being stirred under a CO atmosphere (balloon) at RT
for further 15 h. The slurry was poured into 1n HCl (100 mL) and ex-
tracted with Et2O (3ꢅ50 mL). The combined extracts were washed with
1n NaOH (3ꢅ50 mL) and dried (Na2SO4). After evaporation of the sol-
vent in vacuo and column chromatography on silica gel (n-pentane/Et2O
9:1) chroman 19 was obtained as a yellowish oil (1.04 g, 3.94 mmol, 80%,
96% ee). HPLC (column: Daicel Chiralcel OD): wavelength: 272 nm,
flow: 0.8 mLminꢀ1, eluent: n-hexane/isopropanol 98:2, tR =19.7 min ((ꢀ)-
19), 28.9 min ((+)-19); Rf =0.28 (n-pentane/Et2O 9:1); [a]2D0 =ꢀ7.0 (c=
4-(2,6-Dimethoxy-4-methyl-phenyl)-butan-2-one (14): A solution of the
unsaturated ketone 13 (9.75 g, 44.5 mmol) in EtOAc (250 mL) was treat-
ed with Pd/C (1.45 g, 10% Pd, 1.34 mmol) at RT. Hydrogen was passed
through the resulting mixture for 30 min before being stirred under a hy-
drogen atmosphere for further 2.5 h (TLC monitoring). The catalyst was
removed by filtration over Celite (washing with CH2Cl2) and the solvent
was evaporated in vacuo. Column chromatography (n-pentane/EtOAc
3:1) on silica gel yielded saturated ketone 14 as a colourless solid (9.10 g
41.0 mmol, 92%). Rf =0.35 (n-pentane/EtOAc 3:1); 1H NMR (300 MHz,
CDCl3): d=2.15 (s, 3H; 1’-H3), 2.34 (s, 3H; Ar-CH3), 2.57–2.63 (m, 2H;
3’-H2), 2.83–2.93 (m, 2H; 4’-H2), 3.78 (s, 6H; 2OCH3), 6.36 ppm (s, 2H;
2Ar-H); 13C NMR (75 MHz, CDCl3): d=17.5 (C-4’), 21.9 (Ar-CH3), 29.5
(C-1’), 43.3 (C-3’), 55.4 (OCH3), 104.4 (C-3, C-5), 113.9 (C-1), 137.1 (C-
4), 157.8 (C-2, C-6), 209.6 ppm (C-2’); IR (KBr): n˜ =3064, 2994, 2938,
2838, 1704, 1589, 1466, 1246, 1127, 968, 814, 579 cmꢀ1; UV/Vis (CH3CN):
lmax (log e)=206.5 (4.650), 271.0 (2.924), 278.5 nm (2.880); MS (ESI):
m/z (%): 245.1 (100) [M+Na+], 223.1 (27) [M+H+]; HRMS (EI): m/z:
calcd for [C13H18O3+Na+]: 245.1148; found: 245.1148.
1
0.5 in CHCl3); H NMR (300 MHz, CDCl3): d=1.42 (s, 3H; 2-CH3), 1.85
(dt, J=13.8, 6.8 Hz, 1H; 3-Ha), 1.99 (dt, J=13.8, 6.8 Hz, 1H; 3-Hb), 2.26
(s, 3H; Ar-CH3), 2.55–2.66 (m, 4H; 2’-H2, 4-H2), 3.68 (s, 3H; CO2CH3)
3.79 (s, 3H; Ar-OCH3), 6.24 (s, 1H; Ar-H), 6.29 ppm (s, 1H; Ar-H);
13C NMR (75 MHz, CDCl3): d=16.4 (C-4), 21.5 (Ar-CH3), 24.6 (2-CH3),
30.3 (C-3), 43.5 (C-2’), 51.5 (CO2CH3), 55.3 (Ar-OCH3), 74.2 (C-2), 102.9,
110.4 (C-6, C-8), 106.8 (C-4a), 137.1 (C-7), 153.5, 157.5 (C-5, C-8a),
170.9 ppm (C-1’); IR (film): n˜ =2949, 2856, 1738, 1619, 1586, 1354, 1227,
1108, 1023, 814 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=207.5 (4.658), 271.5
(2.975), 280.0 nm (2.955); MS (70 eV, EI): m/z (%): 264.3 (58) [M+],
191.2 (49) [M+ꢀCH2CO2CH3], 151.2 (100); HRMS (EI): m/z: calcd for
[C15H20O4+H+]: 265.1434; found: 265.1435.
1,3-Dimethoxy-5-methyl-2-(3-methyl-but-3-enyl)-benzene (15): A slurry
of zinc powder (13.2 g, 202 mmol) and CH2Br2 (5.36 mL, 11.7 g,
67.5 mmol) in THF (220 mL) was treated dropwise with TiCl4 (5.46 mL,
9.35 g, 49.5 mmol) at 08C and the resulting mixture was stirred at 08C for
15 min. Subsequently, a solution of ketone 14 (10.0 g, 45.0 mmol) in THF
(50 mL) was added dropwise at 08C and stirring was continued at RT for
further 45 min. The solids were removed by filtration over Celite (wash-
ing with Et2O) and the filtrate was washed with 1m aq HCl solution
(500 mL) and sat. aq NaCl solution (500 mL). After drying (Na2SO4),
concentration in vacuo and column chromatography on silica gel (n-pen-
tane/Et2O 97:3) alkene 15 was obtained as a colourless oil (8.13 g,
36.9 mmol, 82%). Rf =0.47 (n-pentane/Et2O 97:3); 1H NMR (300 MHz,
CDCl3): d=1.79 (s, 3H; 3’-CH3), 2.09–2.19 (m, 2H; 2’-H2), 2.33 (s, 3H;
Ar-CH3), 2.70–2.79 (m, 2H; 1’-H2), 3.79 (s, 6H; 2OCH3), 4.70 (d, J=
1.0 Hz, 2H; 24’-H), 6.36 ppm (s, 2H; 2Ar-H); 13C NMR (50 MHz,
CDCl3): d=21.2 (C-1’), 21.8 (Ar-CH3), 22.4 (3’-CH3), 37.2 (C-2’), 55.5
(OCH3), 104.6 (C-3, C-5), 109.1 (C-4’), 115.9 (C-1), 136.7 (C-4), 147.0 (C-
3’), 158.2 ppm (C-2, C-6); IR (film): n˜ =3072, 2937, 2835, 1588, 1464,
1314, 1241, 1123, 970, 884, 813 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=
207.0 (4.682), 271.0 nm (2.924); MS (70 eV, EI): m/z (%): 220.3 (13) [M+],
165.2 (100) [M+ꢀC4H7]; EI-HRMS: m/z: calcd for C14H20O2: 220.1463;
found: 220.1469.
(2S)-(5-Methoxy-2,7-dimethyl-chroman-2-yl)-acetaldehyde (20): DIBAL-
H (9.45 mL of a 1.0m solution in toluene, 9.45 mmol) was added dropwise
over a period of 15 min to a solution of ester 19 (1.00 g, 3.78 mmol) in
toluene (30 mL) at ꢀ788C. After complete addition the mixture was
stirred at ꢀ788C for further 20 min before being quenched with MeOH/
H2O (5 mL, 1:1). Water (100 mL) was added and the aqueous layer was
extracted with Et2O (3ꢅ50 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. After column chromatography on
silica gel (n-pentane/Et2O 9:1) aldehyde 20 was obtained as a colourless
oil (762 mg, 3.25 mmol, 86%). Rf =0.24 (n-pentane/Et2O 9:1); [a]D20
=
1
+19.0 (c=1.0 in CHCl3); H NMR (300 MHz, CDCl3): d=1.40 (s, 3H; 2-
CH3), 1.83 (dt, J=13.6, 6.8 Hz, 1H; 3-Ha), 1.89 (dt, J=13.6, 6.8 Hz, 1H;
3-Hb), 2.28 (s, 3H; Ar-CH3), 2.57 (dd, J=15.2, 3.2 Hz, 1H; 2’-Ha), 2.62 (t,
J=6.8 Hz, 2H; 4-H2), 2.71 (dd, J=15.2, 2.4 Hz, 1H; 2’-Hb), 3.80 (s, 3H;
OCH3), 6.26 (s, 1H; Ar-H), 6.31 (s, 1H; Ar-H), 9.89 ppm (t, J=2.8 Hz,
1H; CHO); 13C NMR (125 MHz, CDCl3): d=16.4 (C-4), 21.6 (Ar-CH3),
24.7 (2-CH3), 32.3 (C-3), 52.2 (C-2’), 55.3 (OCH3), 74.2 (C-2), 103.1, 110.3
(C-6, C-8), 106.6 (C-4a), 137.4 (C-7), 153.4, 157.6 (C-5, C-8a), 201.6 ppm
(C-1’); IR (film): n˜ =2938, 2853, 1723, 1619, 1586, 1463, 1353, 1231, 1108,
816 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=207.0 (4.634), 271.5 (2.951),
280.0 nm (2.937); MS (ESI): m/z (%): 257.1 (31) [M+Na+], 235.1 (100)
[M+H+]; HRMS (EI): m/z: calcd for [C14H18O3+H+]: 235.1329; found:
235.1330.
3-Methoxy-5-methyl-2-(3-methyl-but-3-enyl)-phenol (8): A solution of 15
(5.00 g, 22.7 mmol) in DMF (35 mL) was treated with NaSEt (4.23 g,
technical grade (90% (w/w)), 45.4 mmol) and stirred at 1208C for 20 h.
After cooling to RT the mixture was poured into water (200 mL) and ex-
tracted with Et2O (3ꢅ100 mL). The combined organic layers were
washed with water (2ꢅ100 mL) and sat. aq NaCl solution (100 mL) and
dried (Na2SO4). After evaporation of the solvent in vacuo and column
chromatography on silica gel (n-pentane/Et2O 97:3!93:7) phenol 8 was
obtained as a pale-yellow oil that solidified upon storage at ꢀ308C
(4.31 g, 20.9 mmol, 92%). Rf =0.34 (n-pentane/Et2O 95:5); 1H NMR
(300 MHz, CDCl3): d=1.82 (s, 3H; 3’-CH3), 2.17–2.27 (m, 2H; 2’-H2),
2.29 (s, 3H; Ar-CH3), 2.73–2.82 (m, 2H; 1’-H2), 3.82 (s, 3H; OCH3), 4.78
(2S)-(E)-4-(5-Methoxy-2,7-dimethyl-chroman-2-yl)-but-2-enoic
acid
methyl ester (7)
Method A (Wittig–Horner reaction of 20): A solution of trimethyl phos-
phonoacetate (21) (390 mL, 492 mg, 2.70 mmol) in THF (10 mL) was
treated with sodium hydride (86.4 mg, 60% (w/w) in mineral oil,
2.16 mmol) at 08C. The resulting mixture was stirred at 08C for 30 min
before a solution of aldehyde 20 (421 mg, 1.80 mmol) in THF (4.0 mL)
was added dropwise at 08C. After complete addition the slurry was
stirred at RT for further 20 min before being quenched with sat. aq
8960
www.chemeurj.org
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8956 – 8963

Synthesis of 4-Dehydroxydiversonol
FULL PAPER
NH4Cl solution (5 mL). The mixture was poured into sat. aq NH4Cl solu-
tion (100 mL) and extracted with Et2O (3ꢅ50 mL). The combined organ-
ic layers were dried (Na2SO4) and concentrated in vacuo. Chromato-
graphic separation on silica gel (n-pentane/Et2O 95:5!8:2) provided the
title compound 7 (435 mg, 1.50 mmol, 83%) and the corresponding Z
isomer (73.1 mg, 252 mmol, 14%) as pale-yellow oils.
3375, 2939, 2855, 1618, 1586, 1463, 1353, 1231, 1109, 1023, 880, 814 cmꢀ1
;
UV/Vis (CH3CN): lmax (log e)=207.5 (4.635), 272.0 (2.954), 280.0 nm
(2.942); MS (ESI): m/z (%): 495.2 (27) [2M+Na+], 259.1 (100) [M+Na+],
237.2 (8) [M+H+]; HRMS (EI): m/z: calcd for [C14H20O3+Na+]:
259.1305; found: 259.1305.
(2S)-5-Methoxy-2,7-dimethyl-2-vinyl-chroman (24): PnBu3 (110 mL,
87.4 mg, 394 mmol) was added dropwise to a solution of alcohol 22
(46.6 mg, 197 mmol) and 2-nitrophenyl selenocyanate (23) (91.4 mg,
394 mmol) in THF (4.0 mL) at 08C. The resulting mixture was stirred at
08C for 1 h before being poured into sat. aq NaHCO3 solution (10 mL)
and extracted with Et2O (3ꢅ10 mL). The combined organic fractions
were dried (Na2SO4) and evaporated in vacuo. The residue was dissolved
in CH2Cl2 (4.0 mL), the solution was cooled to ꢀ408C, Na2HPO4
(175 mg, 985 mmol) and mCPBA (116 mg, 70% (w/w), 470 mmol) were
added and the resulting suspension was stirred at ꢀ408C for 1 h. After
addition of iPr2NH (140 mL, 99.7 mg, 985 mmol) the mixture was allowed
to reach RT, and stirring was continued for further 14 h before silica gel
(500 mg) was added. Evaporation of the solvent under reduced pressure
and column chromatography of the residue on silica gel (n-pentane/Et2O
98:2) yielded vinyl chroman 24 as a pale-yellow oil (37.7 mg, 173 mmol,
88%). Rf =0.42 (n-pentane/EtOAc 98:2); [a]2D0 =ꢀ52.7 (c=1.5 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.42 (s, 3H; 2-CH3), 1.78 (ddd,
J=13.6, 9.8, 5.9 Hz, 1H; 3-Ha), 1.92 (ddd, J=13.6, 6.0, 5.0 Hz, 1H; 3-Hb),
2.31 (s, 3H; Ar-CH3), 2.46 (ddd, J=16.8, 9.8, 6.2 Hz, 1H; 4-Ha), 2.67 (dt,
J=16.8, 5.5 Hz, 1H; 4-Hb), 3.81 (s, 3H; OCH3), 5.07 (dd, J=10.8, 1.2 Hz,
1H; 2’-H), 5.20 (dd, J=17.4, 1.2 Hz, 1H; 2’-H), 5.88 (dd, J=17.4,
10.8 Hz, 1H; 1’-H), 6.25 (s, 1H; Ar-H), 6.39 ppm (s, 1H; Ar-H);
13C NMR (75 MHz, CDCl3): d=16.7 (C-4), 21.6 (Ar-CH3), 26.8 (2-CH3),
31.3 (C-3), 55.3 (OCH3), 76.2 (C-2), 102.6, 110.0 (C-6, C-8), 107.3 (C-4a),
113.6 (C-2’), 136.9 (C-7), 141.3 (C-1’), 154.3, 157.4 ppm (C-5, C-8a); IR
(film): n˜ =3088, 2976, 2936, 2852, 1619, 1586, 1463, 1353, 1232, 1140,
1024, 923, 813 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=207.0 (4.665), 271.5
(2.995), 280.0 (2.976), 406.0 nm (1.956); MS (ESI): m/z (%): 219.1 (100)
[M+H+]; HRMS (EI): m/z: calcd for [C14H18O2+H+]: 219.1379; found:
219.1379.
Method
B (domino Wacker–Heck reaction of 8): A solution of
[Pd(OTFA)2] (8.3 mg, 24.7 mmol, 10 mol%) and (S,S)-Bn-BOXAX (17)
ACHTUNGTRENNUNG
(56.5 mg, 98.7 mmol, 40 mol%) in dichloroethane (0.15 mL) was stirred at
RT for 30 min before being treated with p-benzoquinone (107 mg,
987 mmol) and stirred for further 10 min. A solution of phenol 8 (51.0 mg,
247 mmol) and methyl acrylate (9) (111 mL, 106 mg, 1.23 mmol) in di-
chloroethane (0.15 mL) was added and the resulting mixture was stirred
at RT for 7 d. The slurry was poured into 1n HCl (10 mL) and the aque-
ous phase was extracted with Et2O (3ꢅ10 mL). The combined extracts
were washed with 1n NaOH (3ꢅ10 mL), dried (Na2SO4) and concentrat-
ed under reduced pressure. Column chromatography on silica gel afford-
ed the E-isomer 7 exclusively as a pale-yellow oil (39.4 mg, 136 mmol,
55%, 88% ee). Analytical data for the E-isomer 7: HPLC (column:
Daicel Chiralcel OD): wavelength: 272 nm, flow: 0.8 mLminꢀ1, eluent:
n-hexane/isopropanol 98:2, tR =13.7 min ((+)-7), 14.6 min ((ꢀ)-7); Rf =
0.28 (n-pentane/Et2O 9:1); [a]2D0 =+24.0 (c=1.0 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.29 (s, 3H; 2-CH3), 1.74 (dt, J=13.8, 6.9 Hz, 1H;
3-Ha), 1.80 (dt, J=13.8, 6.9 Hz, 1H; 3-Hb), 2.28 (s, 3H; Ar-CH3), 2.47
(ddd, J=14.1, 7.8, 1.1 Hz, 1H; 4’-Ha), 2.53 (ddd, J=14.1, 7.8, 1.1 Hz, 1H;
4’-Hb), 2.60 (t, J=6.9 Hz, 2H; 4-H2), 3.74 (s, 3H; CO2CH3), 3.80 (s, 3H;
Ar-OCH3), 5.90 (dt, J=15.6, 1.1 Hz, 1H; 2’-H), 6.25 (s, 1H; Ar-H), 6.31
(s, 1H; Ar-H), 7.03 ppm (dt, J=15.6, 7.8 Hz, 1H; 3’-H); 13C NMR
(125 MHz, CDCl3): d=16.4 (C-4), 21.6 (Ar-CH3), 24.3 (2-CH3), 30.5 (C-
3), 42.2 (C-4’), 51.4 (CO2CH3), 55.3 (Ar-OCH3), 75.0 (C-2), 102.7, 110.4
(C-6, C-8), 106.7 (C-4a), 123.9 (C-2’), 137.2 (C-7), 144.3 (C-3’), 153.7,
157.6 (C-5, C-8a), 166.6 ppm (C-1’); IR (film): n˜ =2946, 2853, 1725, 1657,
1619, 1586, 1463, 1353, 1109, 815 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=
207.5 (4.749), 271.0 (3.038), 280.0 nm (2.980); MS (ESI): m/z (%): 603.3
(37) [2M+Na+], 313.1 (100) [M+Na+], 291.2 (73) [M+H+]; HRMS
(EI): m/z: calcd for [C17H22O4+H+]: 291.1591; found: 291.1592. Analyti-
cal data for the Z isomer: Rf =0.34 (n-pentane/Et2O 9:1); [a]2D0 =+6.6
(c=0.5 in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.27 (s, 3H; 2-CH3),
1.71–1.89 (m, 2H; 3-H2), 2.28 (s, 3H; Ar-CH3), 2.58 (dt, J=17.8, 6.7 Hz,
1H; 4-Ha), 2.66 (dt, J=17.8, 6.7 Hz, 1H; 4-Hb), 2.97 (ddd, J=15.8, 7.0,
1.7 Hz, 1H; 4’-Ha), 3.08 (ddd, J=15.8, 7.8, 1.7 Hz, 1H; 4’-Hb), 3.71 (s,
3H; CO2CH3), 3.80 (s, 3H; Ar-OCH3), 5.92 (dt, J=11.7, 1.7 Hz, 1H; 2’-
H), 6.24 (s, 1H; Ar-H), 6.31 (s, 1H; Ar-H), 6.47 ppm (dt, J=11.7, 7.4 Hz,
1H; 3’-H); 13C NMR (75 MHz, CDCl3): d=16.5 (C-4), 21.6 (Ar-CH3),
24.0 (2-CH3), 30.8 (C-3), 38.5 (C-4’), 51.0 (CO2CH3), 55.3 (Ar-OCH3),
75.1 (C-2), 102.7, 110.3 (C-6, C-8), 107.0 (C-4a), 121.1 (C-2’), 137.1 (C-7),
145.6 (C-3’), 154.0, 157.6 (C-5, C-8a), 166.8 ppm (C-1’); IR (film): n˜ =
2947, 2854, 1723, 1619, 1586, 1439, 1353, 1203, 1109, 814 cmꢀ1; UV/Vis
(CH3CN): lmax (log e)=207.5 (4.724), 209.0 (4.724), 271.0 (3.034),
280.0 nm (2.975); MS (ESI): m/z (%): 603.3 (16) [2M+Na+] 313.1 (100)
[M+Na+], 291.2 (63) [M+H+]; HRMS (EI): m/z: calcd for
[C17H22O4+H+]: 291.1591; found: 291.1591.
(2R)-4-(5-Methoxy-2,7-dimethyl-chroman-2-yl)-butyric acid methyl ester
(25): Pd/C (1.00 g, 10% Pd, 909 mmol) was added to a solution of unsatu-
rated ester 7 (2.64 g of an E/Z mixture, 9.09 mmol) in EtOAc (75 mL).
Hydrogen was passed through the resulting mixture for 30 min before
being stirred under a H2 atmosphere at RT for further 6 h. The catalyst
was removed by filtration over silica gel (eluting with EtOAc), and after
evaporation of the solvent in vacuo and column chromatography on silica
gel (n-pentane/Et2O 9:1) saturated ester 25 was obtained as a colourless
oil (2.60 g, 8.89 mmol, 98%). Rf =0.29 (n-pentane/Et2O 9:1); [a]2D0 =+7.6
(c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.27 (s, 3H; 2-CH3),
1.55–1.66 (m, 2H), 1.67–1.87 (m, 6H; 3-H2, 3’-H2, 4’-H2), 2.27 (s, 3H; Ar-
CH3), 2.33 (m, 2H; 2’-H2), 2.59 (m, 2H; 4-H2), 3.66 (s, 3H; CO2CH3),
3.80 (s, 3H; Ar-OCH3), 6.23 (s, 1H; Ar-H), 6.28 ppm (s, 1H; Ar-H);
13C NMR (125 MHz, CDCl3): d=16.4 (C-4), 19.2 (C-3’), 21.6 (Ar-CH3),
23.8 (2-CH3), 30.4 (C-3), 34.2 (C-2’), 38.7 (C-4’), 51.4 (CO2CH3), 55.3
(Ar-OCH3), 75.3 (C-2), 102.4, 110.3 (C-6, C-8), 106.9 (C-4a), 136.9 (C-7),
154.1, 157.5 (C-5, C-8a), 173.9 ppm (C-1’); IR (film): n˜ =2948, 2731, 1739,
1618, 1586, 1462, 1353, 1110, 813 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=
208.0 (4.636), 272.0 (2.943), 280.5 nm (2.932); MS (ESI): m/z (%): 607.3
(44) [2M+Na+], 315.2 (94) [M+Na+], 293.2 (100) [M+H+]; HRMS
(EI): m/z: calcd for [C17H24O4+Na+]: 315.1567; found: 315.1568.
(2S)-2-(5-Methoxy-2,7-dimethyl-chroman-2-yl)-ethanol (22): A solution
of ester 19 (253 mg, 957 mmol) in Et2O (3.0 mL) was added dropwise to
a suspension of LiAlH4 (40.0 mg, 1.05 mmol) in Et2O (3.0 mL) at 08C.
The resulting mixture was stirred at RT for 1 h before being carefully
quenched with water (10 mL). After separation of the organic layer the
aqueous phase was extracted with Et2O (3ꢅ10 mL). The combined or-
ganic phases were dried (Na2SO4) and the solvent evaporated in vacuo.
Column chromatography on silica gel (n-pentane/EtOAc 7:3) furnished
alcohol 22 as a colourless oil (221 mg, 935 mmol, 98%). Rf =0.28 (n-pen-
tane/EtOAc 7:3); [a]2D0 =ꢀ4.5 (c=1.0 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=1.31 (s, 3H; 2-CH3), 1.68–2.05 (m, 4H; 2’-H2, 3-H2), 2.27 (s,
3H; Ar-CH3), 2.44 (t, J=4.9 Hz, 1H; OH), 2.50–2.63 (m, 1H; 4-Ha), 2.69
(dt, J=17.3, 6.0 Hz, 1H; 4-Hb), 3.77–3.99 (m, 2H; 1’-H2), 3.80 (s, 3H;
OCH3), 6.25 (s, 1H; Ar-H), 6.28 ppm (s, 1H; Ar-H); 13C NMR
(125 MHz, CDCl3): d=16.3 (C-4), 21.5 (Ar-CH3), 23.4 (2-CH3), 31.2 (C-
3), 41.8 (C-2’), 55.3 (OCH3), 59.0 (C-1’), 76.3 (C-2), 102.9, 110.3 (C-6, C-
8), 106.9 (C-4a), 137.1 (C-7), 153.5, 157.6 ppm (C-5, C-8a); IR (film): n˜ =
(2R)-4-(5-Methoxy-2,7-dimethyl-4-oxo-chroman-2-yl)-butyric acid methyl
ester (6)
Method A (Rh-catalysed oxidation): A solution of chroman 25 (300 mg,
1.03 mmol) and dirhodium-tetrakiscaprolactamate ([Rh2ACTHUNTRGNE(UGN cap)4], 26)
(3.4 mg, 5.15 mmol, 0.5 mol%) in dichloroethane (4.0 mL) was treated
with NaHCO3 (43.3 mg, 515 mmol). The reaction flask was sealed with a
septum and an empty balloon was attached by a needle to capture
oxygen generated during the reaction. tert-Butyl hydroperoxide (0.94 mL
of a 5.5m solution in decane, 5.17 mmol) was added and the resulting
deep-red solution was heated with stirring at 408C in a preheated oil
bath. After 3 h the mixture was treated with additional [Rh
2ACHTUNGTRENNUNG(cap)4]
(3.4 mg, 5.15 mmol) and tBuOOH (0.94 mL of a 5.5m solution in decane,
Chem. Eur. J. 2008, 14, 8956 – 8963
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8961

L. F. Tietze et al.
5.17 mmol). Stirring was continued at 408C for further 11 h before the
solids were removed by filtration over silica gel (eluting with EtOAc).
After evaporation of the solvent under reduced pressure and column
chromatography on silica gel (n-pentane/EtOAc 3:2) chromanone 6 was
obtained as a yellow oil (199 mg, 649 mmol, 63%).
CH3), 31.3 (C-4), 37.4 (C-2), 55.8 (OCH3), 78.1 (C-4a), 83.6 (C-9a), 105.2
(C-7), 107.7 (C-8a), 110.7 (C-5), 148.0 (C-6), 159.2 (C-10a), 161.7 (C-8),
186.3 (C-9), 207.0 ppm (C-1); IR (KBr): n˜ =3366, 2970, 1728, 1616, 1462,
1232, 1121, 821 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=195.5 (4.335), 221.0
(4.209), 274.0 (4.046), 330.0 nm (3.546); MS (ESI): m/z (%): 603.2 (29)
[2M+Na+], 329.1 (12) [M+K+], 313.1 (22) [M+Na+], 291.1 (100)
[M+H+]; HRMS (EI): m/z: calcd for [C16H18O5+H+]: 291.1227; found:
291.1228.
Method B (Mn-catalysed oxidation): A solution of chroman 25 (1.00 g,
3.42 mmol) and tert-butyl hydroperoxide (6.22 mL of a 5.5m solution in
decane, 34.2 mmol) in EtOAc (12 mL) was treated with powdered molec-
ular sieves 3 ꢄ (1.20 g) and the resulting mixture was stirred at RT for
(1R,4aR,9aS)-1,9a-Dihydroxy-8-methoxy-4a,6-dimethyl-1,2,3,4,4a,9a-hexa-
hydroxanthen-9-one (28): A solution of diketone 27 (138 mg, 476 mmol)
in MeOH/CH2Cl2 (2:1, 7.5 mL) was treated slowly with powdered NaBH4
(20.0 mg, 528 mmol) at ꢀ788C. The resulting mixture was stirred at
ꢀ788C for further 15 min (TLC monitoring) before being quenched with
water (5 mL). Water (30 mL) was added and the aqueous layer was ex-
tracted with CH2Cl2 (3ꢅ10 mL). The combined extracts were dried
(Na2SO4) and concentrated in vacuo. After column chromatography on
silica gel (n-pentane/EtOAc 3:2) diol 28 was obtained as a colourless
30 min. After addition of anhydrous [MnACTHNUTRGNEUNG(OAc)3] (160 mg, 684 mmol,
20 mol%) stirring was continued for further 3 d before the mixture was
filtered over silica gel (eluting with EtOAc). After concentration in
vacuo and column chromatography on silica gel (n-pentane/EtOAc 3:2)
chromanone 6 was obtained as a yellow oil (741 mg, 2.42 mmol, 71%).
Rf =0.34 (n-pentane/EtOAc 3:2); [a]2D0 =+11.8 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=1.36 (s, 3H; 2-CH3), 1.58–1.80 (m, 4H;
3’-H2, 4’-H2), 2.21–2.34 (m, 2H; 2’-H2), 2.25 (s, 3H; Ar-CH3), 2.55 (d, J=
15.8 Hz, 1H; 3-Ha), 2.70 (d, J=15.8 Hz, 1H; 3-Hb), 3.63 (s, 3H;
CO2CH3), 3.86 (s, 3H; Ar-OCH3), 6.26 (s, 1H; Ar-H), 6.32 ppm (s, 1H;
Ar-H); 13C NMR (125 MHz, CDCl3): d=19.0 (C-3’), 22.3 (Ar-CH3), 23.5
(2-CH3), 33.8 (C-2’), 38.5 (C-4’), 48.6 (C-3), 51.5 (CO2CH3), 56.0 (Ar-
OCH3), 80.0 (C-2), 104.2, 110.7 (C-6, C-8), 108.3 (C-4a), 147.5 (C-7),
160.0, 161.1 (C-5, C-8a), 173.6 (C-1’), 190.8 ppm (C-4); IR (film): n˜ =
solid (98.8 mg, 338 mmol, 71%). Rf =0.27 (n-pentane/EtOAc 3:2); [a]D20
=
ꢀ121.7 (c=1.0 in CHCl3); 1H NMR (600 MHz, CDCl3): d=1.56 (s, 3H;
4a-CH3), 1.61–1.81 (m, 4H; 2-Ha, 3-H2, 4-Ha), 1.92–2.01 (m, 1H; 2-Hb),
2.15 (ddd, 2J(H,H)=12.8 Hz, 3J
ACHTNUTRGENNGU ACHTUNGTERN(NGUN H,H)=12.8, 4.1 Hz, 1H; 4-Hb), 2.32 (s,
3H; Ar-CH3), 2.95 (s, 1H; 9a-OH), 3.15 (t, J=2.2 Hz, 1H; 1-OH), 3.85
(s, 3H; OCH3), 4.39 (m, 1H; 1-H), 6.32 (s, 1H; 7-H), 6.38 ppm (s, 1H; 5-
H); 13C NMR (125 MHz, CDCl3): d=17.9 (C-3), 19.6 (4a-CH3), 22.4 (Ar-
CH3), 26.9 (C-2), 32.3 (C-4), 55.9 (OCH3), 68.5 (C-1), 73.8 (C-4a), 83.0
(C-9a), 105.0 (C-7), 107.3 (C-8a), 110.9 (C-5), 148.2 (C-6), 159.4 (C-10a),
161.2 (C-8), 193.4 ppm (C-9); IR (KBr): n˜ =3502, 3390, 2953, 1679, 1612,
1566, 1236, 1115, 965, 830, 547, 503 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=
195.5 (4.373), 221.5 (8.236), 275.5 (4.042), 330.0 nm (3.544); MS (ESI):
m/z (%): 607.3 (38) [2M+Na+], 315.1 (33) [M+Na+], 293.1 (100)
[M+H+]; HRMS (EI): m/z: calcd for [C16H20O5+H+]: 293.1384; found:
293.1384.
2952, 2849, 1737, 1683, 1614, 1568, 1464, 1114, 824 cmꢀ1
; UV/Vis
(CH3CN): lmax (log e)=196.0 (4.362), 221.0 (4.277), 269.0 (4.039),
324.5 nm (3.562); MS (ESI): m/z (%): 635.3 (27) [2M+Na+], 329.1 (21)
[M+Na+], 307.2 (100) [M+H+]; HRMS (EI): m/z: calcd for
[C17H22O5+H+]: 307.1540; found: 307.1541.
ACHTUNGTRENNUNG(4aR)-1-Hydroxy-8-methoxy-4a,6-dimethyl-2,3,4,4a-tetrahydroxanthen-9-
one (5): TiCl4 (3.82 mL of a 1.0m solution in CH2Cl2, 3.82 mmol) was
added slowly through a syringe to a solution of chromanone 6 (532 mg,
1.74 mmol) in CH2Cl2 at 08C. Subsequently, NEt3 (600 mL, 440 mg,
4.35 mmol) was added slowly through a syringe, and the resulting solu-
tion was stirred at 08C for further 15 min (TLC monitoring) before being
quenched with sat. aq NH4Cl solution (5 mL). Water (100 mL) was
added and the aqueous layer was extracted with EtOAc (3ꢅ50 mL). The
combined organic layers were dried (Na2SO4) and concentrated in vacuo.
Column chromatography on silica gel (n-pentane/EtOAc 3:1) yielded tet-
rahydroxanthenone 5 as a pale-yellow solid (302 mg, 1.10 mmol, 63%).
Rf =0.34 (n-pentane/EtOAc 3:1); [a]2D0 =+49.5 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=1.45 (s, 3H; 4a-CH3), 1.68–1.86 (m, 1H;
3-Ha), 1.89–2.11 (m, 3H; 3-Hb, 4-H2), 2.28–2.57 (m, 2H; 2-H2), 2.32 (s,
3H; Ar-CH3), 3.92 (s, 3H; OCH3), 6.35 (s, 2H; 2Ar-H), 16.01 ppm (s,
1H; OH); 13C NMR (75 MHz, CDCl3): d=18.3 (C-3), 22.4 (Ar-CH3) 25.5
(4a-CH3), 30.2 (C-2), 35.8 (C-4), 56.1 (OCH3), 78.1 (C-4a), 105.4, 111.2
(C-5, C-7), 108.2 (C-8a), 108.7 (C-9a), 147.1 (C-6), 160.2, 160.6 (C-8, C-
10a), 180.3 (C-1), 182.0 ppm (C-9); IR (KBr): n˜ =2953, 1609, 1469, 1356,
1227, 1108, 878, 822 cmꢀ1; UV/Vis (CH3CN): lmax (log e)=205.0 (4.396),
282.0 (3.658), 326.0 nm (4.121); MS (ESI): m/z (%): 571.2 (100)
[2M+Na+], 297.1 (31) [M+Na+], 275.1 (77) [M+H+]; HRMS (EI): m/z:
calcd for [C16H18O4+H+]: 275.1278; found: 275.1279.
(1R,4aR,9aS)-1,8,9a-Trihydroxy-4a,6-dimethyl-1,2,3,4,4a,9a-hexahydro-
xanthen-9-one (4-dehydroxydiversonol) (4): BBr3 (2.91 mL of a 1.0m so-
lution in CH2Cl2, 2.91 mmol) was added slowly to a solution of methyl
ether 28 (85.1 mg, 291 mmol) in CH2Cl2 (15 mL) at ꢀ788C. The resulting
dark-red solution was stirred for 15 min at ꢀ788C and further 30 min at
08C (TLC monitoring) before being quenched with water (10 mL). The
organic layer was separated and the aqueous layer was extracted with
CH2Cl2 (2ꢅ10 mL). The combined extracts were dried (Na2SO4) and the
solvent was evaporated in vacuo. After column chromatography on silica
gel (n-pentane/EtOAc 8:2) 4-dehydroxydiversonol (4) was obtained as a
colourless solid (68.8 mg, 247 mmol, 85%). Rf =0.30 (n-pentane/EtOAc
4:1); [a]2D0 =ꢀ102.0 (c=1.0 in CHCl3); 1H NMR (600 MHz, CDCl3): d=
1.57 (s, 3H; 4a-CH3), 1.63–1.82 (m, 4H; 2-Ha, 3-H2, 4-Ha), 1.99 (dddd,
2J
2J
C
ACHTUNGRTENN(UNG H,H)=14.6, 4.1, 4.1 Hz, 1H; 2-Hb), 2.14 (ddd,
ACHTUNGTRENNUNG
CH3), 2.58 (s, 1H; 1-OH), 3.04 (s, 1H; 9a-OH), 4.45 (m, 1H; 1-H), 6.26
(s, 1H; 5-H), 6.37 (s, 1H; 7-H), 10.96 ppm (s, 1H; Ar-OH); 13C NMR
(125 MHz, CDCl3): d=17.9 (C-3), 19.8 (4a-CH3), 22.5 (Ar-CH3), 26.7 (C-
2), 32.2 (C-4), 67.3 (C-1), 74.1 (C-4a), 83.6 (C-9a), 104.7 (C-8a), 109.2 (C-
5), 110.5 (C-7), 150.8 (C-6), 157.6 (C-10a), 162.4 (C-8), 197.8 ppm (C-9);
IR (KBr): n˜ =3567, 3342, 2935, 1634, 1567, 1395, 1202, 1099, 962, 840,
696, 505 cmꢀ1; UV (CH3CN): lmax (log e)=195.5 (4.324), 210.0 (4.251),
281.5 (4.059), 349.0 nm (3.438); MS (ESI): m/z (%): 301.1 (41) [M+Na+
], 279.1 (100) [M+H+]; HRMS (EI): m/z: calcd for [C15H18O5+H+]:
279.1227; found: 279.1227.
ACHTUNGTRENNUNG(4aR,9aR)-9a-Hydroxy-8-methoxy-4a,6-dimethyl-3,4,4a,9a-tetrahydro-
2H-xanthene-1,9-dione (27): A solution of enol 5 (200 mg, 7.29 mmol) in
acetone (40 mL) was treated sequentially every 15 min with dimethyl di-
oxirane (DMDO) (5.0 mL of a 0.07m solution in acetone, 350 mmol, alto-
gether 5ꢅ5.0 mL, 1.75 mmol) at 08C. After the last addition the solution
was stirred for further 30 min (TLC monitoring) before being concentrat-
ed in vacuo at 08C. The residue was dissolved in MeOH, silica gel (1.5 g)
was added and the solvent was evaporated in vacuo. Column chromatog-
raphy on silica gel (n-pentane/EtOAc 1:1) provided a-hydroxy diketone
27 as a colourless solid (156 mg, 539 mmol, 74%). Rf =0.23 (n-pentane/
EtOAc 1:1); [a]2D0 =ꢀ172.0 (c=1.0 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=1.26 (s, 3H; 4a-CH3), 1.54–1.73 (m, 1H; 3-Ha), 1.74–1.86 (m,
1H; 4-Ha), 1.95–2.11 (m, 1H; 3-Hb), 2.19 (m, 1H; 2-Ha), 2.30 (s, 3H; Ar-
Acknowledgements
This research was supported by the Deutsche Forschungsgemeinschaft
(DFG). F.S. thanks the Deutsche Bundesstiftung Umwelt (DBU) for a
Ph.D. scholarship. C.R. thanks the Stiftung Stipendienfonds des Ver-
bandes der Chemischen Industrie (VCI) for a Ph.D. sholarship. Generous
gifts of chemicals by Bayer AG, BASF SE and Wacker Chemie AG are
greatly appreciated.
CH3), 2.72 (ddd, 2J
3.40 (ddd, 2J(H,H)=13.2 Hz, 3J
ACHTUNGTRENNUNG
N
ACHTUNGRTEN(NUNG H,H)=13.2, 5.5 Hz, 1H; 4-Hb),
U
3H; OCH3), 4.60 (sbr, 1H; OH), 6.26 (s, 1H; 7-H), 6.36 ppm (s, 1H; 5-
H); 13C NMR (125 MHz, CDCl3): d=17.8 (4a-CH3), 20.6 (C-3), 22.4 (Ar-
8962
www.chemeurj.org
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8956 – 8963

Synthesis of 4-Dehydroxydiversonol
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b=15.605(3), c=16.530(3) ꢄ; a=107.90(3), b=92.35(3), g=
97.07(3)8; V=2699.1(9) ꢄ3; Z=8; T=100(2) K; 40706 reflections
measured (colourless blocks, 2.82ꢁqꢁ60.348), 7856 unique reflec-
tions (Rint =0.0453), 775 parameters. Data were collected on
a
Bruker three-cycle diffractometer with a SMART 6000 detector and
CuKa radiation (l=1.54178 ꢄ) at low temperature. The structure
was solved by direct methods and refined by full-matrix least-
squares procedures against F2 with SHELX (ref. [22]). Non-hydro-
gen atoms were refined anisotropically, hydrogen atoms in CHx
groups were added by using the riding model. R1 (F0 >4sF0)=
0.0519, wR2=0.1345, GooF=1.130. CCDC-686256 contains the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
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Received: May 20, 2008
Published online: August 12, 2008
Chem. Eur. J. 2008, 14, 8956 – 8963
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8963