A highly efficient procedure for ruthenium tetroxide catalyzed oxidative cyclizations of 1,5-dienes

Article abstract of DOI:10.1002/ejoc.200500052

We report a highly efficient procedure for the oxidative cyclization of 1,5-dienes, which generally allows for high yields and selectivities. A solid-supported terminal oxidant and a finely tuned solvent mixture have both been identified as critical facto

Full text of DOI:10.1002/ejoc.200500052

FULL PAPER
A Highly Efficient Procedure for Ruthenium Tetroxide Catalyzed Oxidative
Cyclizations of 1,5-Dienes
Stefanie Roth,[a] Sabrina Göhler,[a] Huan Cheng,[a] and Christian B. W. Stark*[a]
Dedicated to Professor H. M. R. Hoffmann on the occasion of his 70th birthday
Keywords: Oxidative cyclization / Tetrahydrofurans / Ruthenium / Oxidation / Catalysis
We report a highly efficient procedure for the oxidative cycli-
zation of 1,5-dienes, which generally allows for high yields
and selectivities. A solid-supported terminal oxidant and a
finely tuned solvent mixture have both been identified as
critical factors for this high efficiency. As little as 0.2 mol-%
ruthenium(III) chloride as a pre-catalyst for the ruthenium te-
troxide generated in situ is required to accomplish oxidative
cyclization. This exceptionally low catalyst loading, high dia-
stereoselectivity, mild reaction conditions, and a simple
workup procedure are key features of this process.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Donohoe and co-workers recently presented a procedure af-
fording high yields (generally in the 72–95% range) for an
oxidative cyclization of 1,5-dienes.[9c] In their work, 5 mol-
% osmium tetroxide was used as a catalyst. High yields were
possible through the addition of a Brønsted acid, such as
an excess of trifluoroacetic acid.
As part of our interest in polyether compounds, our re-
search is focused on ruthenium tetroxide as a catalyst for
oxidative cyclization. Ruthenium tetroxide is a powerful ox-
idizing agent classically used for oxidative C–C-bond cleav-
age.[11,12] More recently, it has also been applied for selec-
tive C–H oxidations,[13] dihydroxylations,[14] and keto hy-
droxylations.[15]
In 1981 Sharpless et al. reported on the unexpected find-
ing of an oxidative cyclization of geranyl acetate under con-
ditions usually applied for the Sharpless oxidation (the ru-
thenium tetroxide mediated oxidative scission of olefins to
furnish carboxylic acids).[10a] This result – which parallels
that of the previously known permanganate promoted pro-
cess – was surprising, since the high oxidative power of ru-
thenium() [and ruthenium()] usually results in a quick
C–C-bond cleavage. Sica et al.[10b] and Piccialli et al.,[10c,10d]
building on this seminal finding by Sharpless’ group, re-
cently investigated this transformation in more detail, and
found that a simple change of solvents resulted in improved
yields and product distribution. Representative results from
these previous studies are summarized in Scheme 2.
Here we report on a greatly improved procedure, gen-
erally affording high yields and selectivities, for ruthenium
tetroxide-mediated oxidative cyclizations. Key features of
this process are unprecedentedly low catalyst loading and a
simple workup procedure.
Introduction
2,5-Disubstituted tetrahydrofurans (THFs) are common
structural features in a variety of biologically important
classes of natural products. Among these are the polyether
ionophore antibiotics[1,2] and the annonaceous acetogen-
ins.[3,4] A number of methods for the synthesis of 2,5-disub-
stituted THFs have been reported;[5] in principle, the single-
step formation of THF derivatives by oxidative cyclization
of 1,5-dienes can be regarded as the most efficient approach
(Scheme 1).[6] Such unique and mechanistically intriguing
oxidative cyclizations have been reported with the use of
stoichiometric amounts of permanganate,[7,8] or in a cata-
lytic fashion with osmium tetroxide[9] or ruthenium tetrox-
ide.[10]
Scheme 1. Oxidative cyclization of 1,5-dienes.
Yields and selectivities are often low, however, due to un-
wanted overoxidation processes (including C–C-bond cleav-
age) and also presumably due to isolation problems attrib-
utable to the high water solubility of the diol products.
[a] Freie Universität Berlin, Institut für Chemie – Organische
Chemie,
Takustrasse 3, 14195 Berlin, Germany
Fax: +49-30-838-55367
E-mail: stark@chemie.fu-berlin.de
Eur. J. Org. Chem. 2005, 4109–4118
DOI: 10.1002/ejoc.200500052
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Roth, S. Göhler, H. Cheng, C. B. W. Stark
FULL PAPER
Scheme 2. Representative results of previous procedures for the ruthenium tetroxide mediated oxidative cyclization of geraniol derivatives.
Table 1. Effect of solvent and temperature on RuO4-mediated oxi-
dative cyclization of geranyl benzoate [(E)-4].
Results and Discussion
Initial Experiments and Investigations into Reaction
Medium
Our initial experiments focused on avoiding water as a
cosolvent. Water usually has to be added to solubilize so-
dium periodate, the terminal oxidizing agent, and we rea-
soned that product isolation should be significantly facili-
tated – and yields were expected to be improved at the same
time – by avoiding this cosolvent. We therefore decided to
look for a solid-supported terminal oxidant.[16] In our ini-
tial experiments, ruthenium dioxide (10 mol-%) was chosen
as a source for ruthenium tetroxide and geranyl benzoate
[(E)-4] (Scheme 3) as a substrate. We eventually found that
use of sodium periodate on wet silica[17] as a solid-sup-
ported terminal oxidant resulted in a smooth conversion of
the diene substrate. The starting material was almost quan-
titatively converted into the desired cyclization product
(yield Ͼ90%). This product, however, was isolated as a mix-
ture of diastereoisomers accompanied by some overoxid-
ation product (Entry 1, Table 1).
We next investigated the influence of solvent and tem-
perature on diastereoselectivity and amount of unwanted
overoxidation product (ketone 6a), and the results are sum-
marized in Table 1. Whereas the reaction temperature had
little effect on diastereoselectivity and product distribution,
a profound solvent effect was observed. Nonpolar chlori-
nated solvents such as dichloromethane (DCM) or chloro-
form yielded only small quantities of overoxidation product
(ketone 6a) but suffered from low diastereoselectivity (En-
tries 1 and 2, Table 1). On the other hand, more polar,
weakly coordinating solvents such as acetone or tetra-
Entry
Solvent
Temperature
Ratio[a]
5/6
dr[a]
[°C]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
DCM
CHCl3
pentane
EtOAc
MeCN
MeCN
EtCN
acetone
THF
THF
0
25
25
25
25
0
19:1
16:1
5.5:1
3:1
7:1
9:1
4:1
4:1
3:1
6:1
9:1
3:1
9:1
8:1
60:40
63:37
56:44
77:23
81:19
83:17
75:25
93:7
0
0
25
0
25
25
25
0
95:5
Ͼ95:5
54:46
78:22
80:20
52:48
Ͼ95:5
Et2O
tBuOH
acetone/CHCl3
[b]
THF/DCM[b]
THF/DCM[c]
0
20:1
[a] Product ratio and diastereoselectivity were determined by 1H
NMR or GC (dr diastereomeric ratio; i.e. ratio of 5a/5b). [b] A 1:1
mixture of solvents was used. [c] 10 vol-% of DCM in THF were
used.
It is noteworthy that ether solvents such as THF or di-
hydrofuran gave high diastereoselection but slightly dimin- ethyl ether are uncommon solvents for ruthenium tetroxide
ished selectivity with regard to the overoxidation process mediated reactions. In fact, ethers are known to be oxidized
(Entries 8–10, Table 1). Irrespective of solvent, yields were to the corresponding esters by ruthenium tetroxide,[11,12] so
generally high (Ͼ90%). Both the product distribution and diethyl ether has even been used to quench such oxidation
the diastereoselectivity were slightly improved on lowering reactions. Various control experiments revealed that such
the reaction temperature from room temperature to 0 °C.
unwanted C–H oxidations do not occur with the procedure
On examining solvent mixtures, we were pleased to find presented here (vide infra). A recent study by Sheldon et al.
that the use of a mixture of THF and DCM gave high selec- shows that ruthenium tetroxide catalyzed ether oxidations
tivities, in terms both of the ratio between the desired diol are highly pH-dependent and only occur in basic media,
product and ketone (ratio 5/6 = 20:1) and of the diastereo- with an optimal pH of 9–9.5.[18] It can therefore be con-
selectivity (ratio 5a/5b Ͼ 95:5). The best results were ob- cluded that the stability of ethers under our reaction condi-
tained with the use of 10 vol-% DCM in THF at 0 °C (En- tions is attributable to the slightly acidic reaction me-
try 15, Table 1).
dium.[19]
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Ruthenium Tetroxide Catalyzed Oxidative Cyclizations of 1,5-Dienes
FULL PAPER
Investigations into Pre-catalyst and Catalyst Loading
with short reaction times (Entries 2–4 and 8, Table 2).
Other pre-catalysts were less effective (Table 2). As would
be expected, strong binding ligands such as phosphane li-
gands or the acetylacetonato (acac) ligand gave significantly
reduced reaction rates (Entries 5 and 6, Table 2). In the lat-
ter case, unaltered Ru(acac)3 could be detected throughout
the course of the experiment. It is worth mentioning that
the reaction with TPAP as a pre-catalyst (Entry 8, Table 2)
was not catalyzed, or at least not as efficiently catalyzed, by
the perruthenate ion under these conditions.[22] No conver-
sion was detectable when stoichiometric amounts of TPAP
were employed in the absence of any cooxidant (Entry 9,
Table 2).
Taken together, the best results were achieved with use
of either ruthenium() chloride or TPAP as pre-catalyst.
Amazingly, both these precursors are as active as the un-
pleasant to handle ruthenium tetroxide itself (Entry 10,
Table 2). Both of these pre-catalysts are commercially avail-
able, easy to handle, and soluble in a range of solvents, in-
cluding organic solvents. The preparation of stock solutions
is facile and such solutions can conveniently be kept for
months at room temperature without any loss of activity.[23]
No special precautions to avoid moisture or air have to be
taken.
For catalytic oxidative cyclizations, 2–5 mol-% of catalyst
are usually used. Unlike in osmium tetroxide mediated
transformations, where osmium tetroxide itself is used as
the source of catalyst, in ruthenium tetroxide catalyzed oxi-
dative cyclizations the choice of pre-catalyst may play a cru-
cial role. A range of ruthenium compounds are insoluble in
organic solvents, so the formation of the catalytically active
ruthenium tetroxide from these derivatives is slow and often
incomplete. When, for instance, ruthenium dioxide is used,
there is usually a solid black residue visible throughout the
whole course of the reaction, clearly indicating only partial
conversion of ruthenium dioxide into ruthenium tetroxide.
With soluble ruthenium pre-catalysts, on the other hand,
tight binding ligands may inhibit or at least decelerate the
oxidation to ruthenium tetroxide.[20] Both effects – low solu-
bility and tight binding ligands – may result in a reduced
amount of active catalyst (i.e., ruthenium tetroxide). In view
of these considerations and driven by the search for a more
reactive catalyst, we investigated a set of pre-catalysts. As a
substrate we chose diene (E)-4, whilst 2.2 equiv. of sodium
periodate on wet silica were used as terminal oxidizing
agent.
Interestingly, all pre-catalysts investigated gave the cy-
clized product in good yield (generally Ͼ90%). We ob-
served, however, a considerable influence on reaction rates.
After screening of various pre-catalysts it became clear that
ruthenium() chloride and TPAP[21] (tetrapropylammo-
nium perruthenate) represent the most reactive catalyst pre-
cursors (Table 2). Pleasingly, it proved possible to reduce
the catalyst loading to a remarkable 0.2 mol-% with these
ruthenium sources, without loss in selectivity or yield and
Under optimized conditions, use of as little as 0.2 mol-
% ruthenium() chloride (added as a 0.01  stock solution
in THF or water[23]) in the presence of 2.2 equiv of sodium
periodate on wet silica was sufficient to achieve complete
conversion of geranyl benzoate [(E)-4] at 0 °C within 90
min.
Substrate Scope
We next applied the optimized procedure to a set of dif-
ferently substituted 1,5-dienes. As summarized in Table 3, a
broad range of substrates were smoothly converted into the
corresponding 2,5-hydroxymethyl-THFs in high yields and
with good selectivity. A wide range of functional groups
such as esters, amides, and ethers are stable under these
mild reaction conditions (Table 3). Moreover, typical pro-
tecting groups, including ester, ether, and silyl ether protect-
ing groups, are compatible. It is worth noting that even a
benzyl ether remains intact (Entry 4, Table 3). No indica-
tion of the formation of the corresponding C–H-oxidation
product (i.e., the corresponding benzoate) or products de-
rived from aromatic degradation was found (vide supra).
Irrespective of the double bond substitution pattern, good
to excellent yields of THF product were obtained. Mono-,
di-, and trisubstituted double bonds reacted equally well.
Moreover, the electronic properties of the participating
double bonds could be varied, ranging from simple alkyl-
substituted to electron-deficient alkenes. Generally none, or
only a trace amount, of the undesired overoxidation pro-
duct was detected. Only in the case of (Z)-configured ole-
fins was a significant amount of ketone formed (Entries 7,
10, and 12, Table 3). The relative stereochemistry between
the ether oxygen and the flanking hydroxy groups is simply
Table 2. Study on the effect of pre-catalyst.
Entry
Pre-catalyst
Catalyst
loading
[mol-%]
Temp.
[°C]
Reaction
time[g]
[min]
1
2
3
4
5
6
7
8
9
RuO2·2H2O[a]
10
10
1.0
0.2
10
0.2
0.2
0.2
100
0.2
0
0
0
0
25
0
25
0
0
90
30
45
[b]
RuCl3[b]
RuCl3[b]
RuCl3
Ru(acac)3
90
[a,c]
480
240
2880
80
n.r.
95
[b]
Ru(PPh3)2Cl2
Ru/C[a]
TPAP[d]
TPAP[a,e]
[f]
10
RuO4
0
[a] Added as a solid. [b] 0.01  stock solution in THF was used.
[c] Reaction carried out in DCM. [d] 0.01  stock solution in ace-
tone was used. [e] No other oxidant added. [f] 0.042  stock solu-
tion in water was used. [g] Reactions were run until complete con-
sumption of the starting material was detected (as judged by TLC).
(n.r. no reaction).
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S. Roth, S. Göhler, H. Cheng, C. B. W. Stark
FULL PAPER
Table 3. Oxidative cyclization of 1,5-dienes under optimized conditions.
[a] Yields refer to isolated yields of diol product after chromatography; yields in parenthesis include the overoxidation product, obtained
as a byproduct in these cases. In all other cases the amount of overoxidation product formed was less than 5%. [b] Ratio determined by
1H NMR or GC of crude reaction mixtures (dr diastereomeric ratio).
determined by the geometry of the corresponding double of geranyl benzoate was converted into the corresponding
bonds. The diastereoselectivity of cis-THF formation was THF derivative at 0 °C in 90 min. After quenching (2-pro-
high; in most cases, in fact, the corresponding trans product panol), simple filtration, and solvent evaporation, 1.5 g of
could not be detected, except in Entries 4 and 5. In both essentially pure product[24] was obtained (Scheme 3).
these cases, however, the diastereoselectivity could be im-
proved by a simple change of protecting group. Thus, up to
four stereogenic centers could be generated with essentially
complete stereocontrol (Entries 9–12, Table 3). As no aque-
ous workup is required, even highly water-soluble products
could be isolated in good yields (e.g., Entry 14, Table 3, see
also Exp. Sect.).
As an essential prerequisite for synthetic applications we
also studied the scaling up of this transformation. Pleas-
ingly, the reaction could be carried out on a gram scale
without any reduction in yield or selectivity. Thus, 5.0 mmol [(E)-4] under optimized conditions.
Scheme 3. Gram scale oxidative cyclization of geranyl benzoate
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Ruthenium Tetroxide Catalyzed Oxidative Cyclizations of 1,5-Dienes
FULL PAPER
Assignment of Relative Configuration and Stereochemical
Correlation
almost exclusively by using the crucial solvent mixture com-
posed of 10 vol-% of DCM in THF.
To put the mechanistic interpretation on a solid basis, an
extensive investigation of relative stereochemistry and ste-
reochemical correlation of products obtained from the oxi-
dative cyclization was carried out (cf. Scheme 4). Since the
Proposed Mechanism
In analogy to the known permanganate[7b,7d] and os-
minor isomers were not available by the optimized route, mium tetroxide mediated[9c] reactions and on the basis of
reaction conditions were chosen to provide this material as recent DFT (density functional theory) calculations,[25] we
well. The reactions were thus carried out in DCM as a sol- propose the following mechanism for the ruthenium tetrox-
vent (cf. Table 1). The major and minor diastereoisomers ide mediated oxidative cyclization (Scheme 5). Oxidation of
from the oxidative cyclization both of geranyl benzoate the pre-catalyst is followed by an initial [3+2] cycload-
[(E)-4] and its (Z)-isomer, neryl benzoate [(Z)-4], were chro- dition[26] between ruthenium tetroxide and one of the ole-
matographically separated, yielding all four possible hy- finic double bonds, giving rise to a cyclic ruthenium() es-
droxy-THF diastereoisomers 5a–d (Scheme 4). These com- ter intermediate (A). This initial step is followed by a pre-
pounds were independently subjected to TPAP-catalyzed sumably fast intramolecular [3+2] cycloaddition to the dis-
alcohol oxidation.[21] Close inspection of analytical data re- tal double bond. The cyclic ruthenium() diester B[27] is
vealed the identities of the two ketones derived from the then hydrolyzed to liberate the tetrahydrofuran product and
two major oxidative cyclization products 5a and 5c. Like- a ruthenium() species, which is finally reoxidized to ruthe-
wise, oxidation of the two alcohols 5b and 5d yielded ketone nium tetroxide. It should be noted that the timing of reoxi-
6b, a diastereoisomer of compound 6a. NOESY investiga- dation of ruthenium may be different from that depicted in
tion of both diol and ketone compounds 5a–d and 6a–b Scheme 5; it may occur at an earlier stage of the catalytic
clearly showed the major products to be cis-THF deriva- cycle. The competing C–C-bond cleavage (cf. Scheme 5) ap-
tives, whereas the minor ones were the corresponding trans pears to be slow under these reaction conditions.
derivatives. In addition, crystallization and X-ray diffrac-
The proposed mechanistic model accounts for the rela-
tion of the major diol product from oxidative cyclization tive stereochemistry of all four stereocenters introduced. As
of geranyl acetate unambiguously confirmed the assigned both [3+2] cycloadditions occur stereospecifically syn, the
relative stereochemistry (see Exp. Section).
relative stereochemistry between the ether oxygen atom and
Clearly, as with other oxidative cyclization methods, the the flanking hydroxy groups is simply determined by the
cis-THF isomers are obtained as the major products. With starting geometry of the C–C-double bonds. The relative
the reported procedure this stereoisomer can be obtained stereochemistry across the THF ring is established in the
Scheme 4. Stereochemical correlation of oxidative cyclization products.
Eur. J. Org. Chem. 2005, 4109–4118
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S. Roth, S. Göhler, H. Cheng, C. B. W. Stark
FULL PAPER
Scheme 5. Proposed mechanism for the ruthenium tetroxide catalyzed oxidative cyclization of 1,5-dienes.
instrument. Chemical shifts δ are given relative to TMS as internal
crucial second [3+2] cycloaddition. It is therefore the con-
formation of intermediate A that determines the formation
of either cis- of trans-THF. We believe that the solvent com-
position is decisive in favoring the depicted conformation
and thus the preferred or exclusive formation of cis-THF
products.
standard or relative to the resonance of the solvent (1H: CDCl3, δ
= 7.24 ppm; 13C: CDCl3, δ = 77.0 ppm). Mass spectra were re-
corded with Varian MAT 771 or MAT 112 S instruments. FT-IR
spectra were recorded with a Nicolet 5 SXC instrument with DTGS
detector. All substrates were prepared by standard procedures. The
starting material for THF 13 was prepared by a procedure by
Montgomery et al.[29] Compounds 17,[30] 18,[30] 19,[10b] and 20[31]
have been prepared previously and full data have been provided.
Analytical data for these compounds were identical to published
data and are not given.
Conclusions
In conclusion, we have presented a highly efficient pro-
cedure for the ruthenium tetroxide mediated oxidative cycli-
zation of 1,5-dienes. This method combines high efficiency
with high practicability. Key features of this process are:
i) an exceptional low catalyst loading, ii) high yields,
iii) high stereoselectivity, and iv) a simple workup procedure
(no aqueous workup necessary). As little as 0.2 mol-% ru-
thenium() chloride (as a source for ruthenium tetroxide)
is required for this highly efficient process. Up to four ste-
Preparation of Sodium Periodate on Wet Silica:[17] Sodium perio-
date (5.14 g, 24.0 mmol) was suspended in water (12 mL) and the
mixture was heated to 70 °C with magnetic stirring in a 100 mL
flask. Silica gel (20 g, 230–400 mesh) was added to this slightly
cloudy solution in one go (at 70 °C). The flask was removed from
the heating bath, stoppered, and vigorously shaken until a fine,
homogeneous powder had developed. The final concentration of
solid-supported periodate was 0.64 mmolg–1. This reagent can be
kept for month at room temperature without any detectable loss of
reogenic centers are introduced into a simple achiral start- activity.
ing material with high diastereoselectivity in a single-step
General Procedure for the Ruthenium Tetroxide Catalyzed Oxidative
Cyclization of 1,5-Dienes (0.5 mmol Scale): The 1,5-diene
(0.5 mmol, 1 equiv.) was added to a suspension of sodium periodate
transformation.
Our current research is focused on more detailed under-
standing of the reaction mechanism, the development of an on wet silica (1.72 g, 1.1 mmol, 2.2 equiv.) in distilled tetra-
asymmetric variant[28] of this oxidative cyclization method,
hydrofuran (9 mL) and distilled dichloromethane (1 mL). The mix-
ture was cooled to 0 °C. A stock solution of ruthenium trichloride
in tetrahydrofuran or water (0.01 , 0.1 mL, 0.001 mmol;
and also on synthetic applications.
0.002 equiv.) was added dropwise to this suspension, the reaction
mixture was stirred at 0 °C, and the reaction progress was moni-
tored by TLC. After complete conversion of the starting material
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers. Solvents were purified by conventional methods
prior to use. Column chromatography: Merck silica gel 60, 0.040–
0.063 mm (230–400 mesh). TLC: precoated aluminium sheets,
Merck silica gel 60, F254; detection by UV or by cerium/molybde-
the reaction was quenched by addition of 2-propanol (2 mL, ex-
cess). The mixture was stirred for another 10 min and was then
filtered through a sintered glass funnel, followed by careful washing
with ethyl acetate. The solvent was removed under reduced pressure
to yield the essentially pure product. Additionally, it may be found
num solution [phosphomolybdic acid (25 g), Ce(SO4)2·H2O (10 g), advantageous to separate from inorganic contaminants by filtration
1
concd. H2SO4 (60 mL), H2O (940 mL)]. H and 13C NMR spectra through a plug of silica. In cases in which byproducts were ob-
were recorded at room temperature in CDCl3 with a Bruker AC 500
tained, chromatographic separation was carried out. This pro-
4114
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Ruthenium Tetroxide Catalyzed Oxidative Cyclizations of 1,5-Dienes
FULL PAPER
cedure is easily scalable and can be used without any modification
to prepare gram quantities of THF products.
HRMS: calcd. m/z for C17H23O4 ([M – OH]+) 291.160; found m/z
291.160.
General Procedure for the TPAP Oxidation of THF-diols: A solu-
tion of a THF-diol (0.5 mmol) and N-methylmorpholine N-oxide
(2.0 mmol, 4.0 equiv.) in dry dichloromethane (10 mL) containing
molecular sieves (4 Å, 500 mg) was stirred at room temperature for
15 min. After addition of TPAP (tetrapropylammonium perruthen-
ate, 0.025 mmol, 5 mol-%), the reaction mixture was stirred until
complete conversion was detected (TLC). The mixture was filtered
through a short pad of silica and washed with ethyl acetate. After
cis-THF 5c: 1H NMR (500 MHz): δ = 1.04 [s, 3 H, C(5)–
C(CH3)(CH3)OH], 1.19 [s, 3 H, C(2)–CH3], 1.23 [s, 3 H, C(5)–
C(CH3)(CH3)OH], 1.49 [ddd, 3J = 8.3, 8.3, 2J = 12.5 Hz, 1 H, C(3)–
Ha], 1.80 [m, 1 H, C(4)–Ha], 1.93 [m, 1 H, C(4)–Hb], 2.20 [m, 1
H, C(3)–Hb], 3.76 [t, 1 H, 3J = 7.4 Hz, C(5)–H], 3.87 [dd, 3J = 2.5,
7.7 Hz, 1 H, C(2)–CH(OH)CH2OBz], 4.12 [dd, 3J = 7.7, 2J =
3
2
11.6 Hz, 1 H, C(2)–CH(OH)CHaHbOBz], 4.59 [dd, J = 2.5, J =
11.6 Hz, 1 H, C(2)–CH(OH)CHaHbOBz], 7.38 (m, 2 H, Ar), 7.51
removal of solvents, pure products were obtained without the ne- (m, 2 H, Ar), 8.02 (Ar) ppm. 13C NMR (125 MHz): δ = 23.3 (C-
cessity for further purification.
4), 23.9 [C(2)–CH3], 26.6 [C(5)–C(CH3)(CH3)OH], 27.4 [C(5)–
C(CH3)(CH3)OH], 33.5 (C-3), 66.3 [C(2)–CH(OH)CH2OBz], 70.8
[C(5)–C(CH3)(CH3)OH], 75.1 (C-2), 84.2 [C(2)–CH(OH)CH2OBz],
87.4 (C-5), 128.4 (Ar), 129.7 (Ar), 130.0 (Ar), 133.1 (Ar), 166.9
Crystal Data for the Oxidative Cyclization Product of Geranyl Ace-
tate: C12H22O5, MW = 246.3, orthorhombic, space group Pbca,
a = 9.284(5) Å, b = 14.571(5) Å, c = 19.296(5) Å, α = 90.000(5)°,
β = 90.000(5)°, γ = 90.000(5)°, V = 2610.3(18) Å3, Z = 8,
T = 293(2) K, radiation wavelength Mo-Kα = 0.71069 Å, 9225 re-
flections measured, 1027 unique (Rint = 0.0919), R1 = 0.0643,
wR2 = 0.1149.
(CO) ppm. FT-IR (KBr): ν = 712, 1086, 1277, 1706, 2871, 2929,
˜
2974, 3418, 3470 cm–1. MS (pos. FAB): m/z = 71 (51%, [THF – 2
H]+), 77 (25 %, [Ph]+), 105 (100 %, [C7H5O]+), 143 (20 %,
[C8H15O2]+), 291 (21%, [M – OH]+), 309 (9%, [M + H]+), 331
(25%, [M + Na]+). HRMS: calcd. m/z for C16H21O5 ([M – CH3]+)
293.139; found m/z 293.139.
CCDC-278925 contains the supplementary crystallographic data
and can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif. trans-THF 5d: 1H NMR (500 MHz): δ = 1.09 [s, 3 H, C(5)–
C(CH3)(CH3)OH], 1.16 [s, 3 H, C(5)–C(CH3)(CH3)OH], 1.20 [s, 3
2-Hydroxy-2-[5-(1-hydroxy-1-methylethyl)-2-methyl-tetrahydrofuran-
2-yl]ethyl Benzoates 5
H, C(2)–CH3], 1.64 [m, 1 H, C(3)–Ha], 1.81 [m, 2 H, C(4)–Ha,
3
C(4)–Hb], 2.15 [m, 1 H, C(3)–Hb], 3.77 [t, J = 2.8, 7.6 Hz, 1 H,
cis-THF 5a: 1H NMR (500 MHz): δ = 1.08 [s, 3 H, C(2)–CH3], 1.23
[s, 6 H, C(5)–COH(CH3)2], 1.65 [ddd, 3J = 7.4, 8.4, 2J = 12.4 Hz, 1
H, C(3)–Ha], 1.88 [m, 1 H, C(4)–Ha], 1.93 [m, 1 H, C(4)–Hb], 2.20
[ddd, 3J = 5.4, 9.2, 2J = 12.4 Hz, 1 H, C(3)–Hb], 3.33 (s, 1 H, OH),
3.80 [dd, 3J = 3.3, 8.0 Hz, 1 H, C(2)–C(OH)H–R], 3.84 [t, 3J =
3
C(5)–H], 3.88 [dd, J = 2.8, 7.6 Hz, 1 H, C(2)–CH(OH)CH2OBz],
3
2
4.28 [dd, J = 7.7, J = 11.7 Hz, 1 H, C(2)–CH(OH)CHaHbOBz],
4.47 [dd, 3J = 7.6, 2J = 2.8 Hz, 1 H, C(2)–CH(OH)CHaHbOBz],
7.38 (m, 2 H, Ar), 7.51 (m, 1 H, Ar), 8.02 (m, 2 H, Ar) ppm. 13C
NMR (125 MHz): δ = 23.3 (C-4), 23.9 (2-CH3), 26.6 [C(5)–
C(CH3)(CH3)OH], 27.4 [C(5)–C(CH3)(CH3)OH], 33.5 (C-3), 66.3
[C(2)–CH(OH)CH2OBz], 70.8 [C(5)–C(CH3)(CH3)OH], 75.1 (C-2),
84.2 [C(2)–CH(OH)CH2OBz], 87.4 (C-5), 128.4 (Ar), 129.7 (Ar),
3
2
7.3 Hz, 1 H, C(5)–H], 4.34 [dd, J = 8.0, J = 11.6 Hz, 1 H, C(2)–
CHOH–CH2–OBz], 4.50 [dd, 3J = 3.3, 2J = 11.6 Hz, 1 H, C(2)–
CHOH–CH2–OBz], 7.39 (ddd, 4J = 1.4, 3J = 7.8, 8.3 Hz, 2 H, Ar),
4
3
4
7.51 (tt, J = 1.4, J = 7.8 Hz, 1 H, Ar), 8.02 (ddd, J = 1.4, 1.4,
3J = 8.4 Hz, 2 H, Ar) ppm. 13C NMR (125 MHz): δ = 23.1 (C-4),
25.3 [C(2)–CH3], 26.6 [C(5)–COH(CH3)2], 27.7 [C(5)–COH-
(CH3)2], 35.6 (C-3), 66.6 [C(2)–CHOH–CH2–OBz], 71.9 [C(5)–
COH(CH3)2], 75.4 (C-2), 84.3 [C(2)–CHOH], 85.7 (C-5), 128.4
(Ar), 129.8 (Ar), 130.1 (Ar), 133.1 (Ar), 167.0 (C=O) ppm. FT-IR
130.0 (Ar) 133.1 (Ar), 166.9 (CO) ppm. FT-IR (KBr): ν = 713,
˜
1070, 1277, 1719, 2875, 2934, 2947, 3442 cm–1. MS (pos. FAB):
m/z = 71 (33 %, [THF – 2 H]+), 77 (95 %, [Ph]+), 105 (100 %,
[C7H5O]+), 143 (10%, [C8H15O2]+), 291 (11%, [M – OH]+), 309
(3%, [M + H]+), 331 (28%, [M + Na]+). HRMS: calcd. m/z for
C16H21O5 [M – CH3]+ 293.139; found m/z, 293.139.
(KBr): ν = 708, 1036, 1082, 1179, 1128, 1287, 1453, 1709, 2935,
˜
2-[5-(1-Hydroxy-1-methylethyl)-2-methyl-tetrahydrofuran-2-yl]-
2-oxoethyl Benzoates 6
2971, 3323 cm–1. MS (pos. FAB): m/z = 59 (18%, [C3H7O]+), 77
(45 %, [Ph]+), 105 (100 %, [PhCO]+), 125 (27 %, [C8H15O2
–
H2O]+), 143 (86%, [C8H15O2]+), 275 (6%, [M – H2O – CH3]+), 291
(0.2%, [M – H2O]+), 293 (0.05%, [M – CH3]+), 309 (0.02%, [M +
H]+). HRMS: calcd. m/z for C16H21O5 ([M – CH3]+) 293.139; found
m/z 293.139.
trans-THF 5b: 1H NMR (500 MHz): δ = 1.09 [s, 3 H, C(5)–
COH(CH3)2], 1.16 [s, 3 H, C(5)–COH(CH3)2], 1.20 [s, 3 H, C(2)–
cis-THF 6a: 1H NMR (500 MHz): δ = 1.12 [s, 3 H, C(2)–CH3],
1.27 [s, 3 H, C(5)–COH(CH3)2], 1.40 [s, 3 H, C(5)–COH(CH3)2],
1.81 [m, 3 H, C(4)–H2, C(3)–Hb], 2.42 [m, 1 H, C(3)–Ha], 2.50 (s,
OH), 3.88 [dd, 3J = 6.3, 8.5 Hz, 1 H, C(5)–H], 5.16 [d, 2J = 17.5 Hz,
2
1 H, C(2)–CO–CH2–OBz], 5.35 [dd, J = 17.5 Hz, 1 H, C(2)–CO–
3
3
CH2–OBz], 7.39 (t, J = 8.0 Hz, 2 H, Ar), 7.52 (t, J = 8.0 Hz, 2
H, Ar), 8.03 (d, J = 8.0 Hz, Ar) ppm. 13C NMR (125 MHz): δ =
3
3
2
CH3], 1.72 [ddd, J = 3.0, 7.3, J = 12.0 Hz, 1 H, C(3)–Ha], 1.84
24.0 (C-4), 25.6 [C(5)–COH(CH3)2], 26.0 [C(2)–CH3], 27.4 [C(5)–
COH(CH3)2], 36.2 (C-3), 66.2 [C(2)–CO–CH2–OBz], 71.0 [C(5)–
COH(CH3)2], 87.0 (C-2), 88.1 (C-5), 128.4 (Ar), 129.0 (Ar), 129.9
(Ar), 133.3 (Ar), 166.9 [RO–C(=O)Ph], 206.3 [C(2)–C=O–R] ppm.
[m, 2 H, C(4)–H2], 2.06 [m, 1 H, C(3)–Hb], 3.76 [dd, 3J = 6.5,
3
9.2 Hz, 1 H, C(5)–H], 3.84 [dd, J = 3.0, 7.7 Hz, 1 H, C(2)–C(OH)
H–R], 4.24 [dd, 3J = 7.7, J = 11.6 Hz, 1 H, C(2)–CHOH–CH2–
2
OBz], 4.42 [dd, 3J = 3.0, 2J = 11.6 Hz, 1 H, C(2)–CHOH–CH2–
FT-IR (KBr): ν = 712, 1119, 1279, 1451, 1723, 1740, 2876, 2933,
˜
OBz], 7.39 (t, 3J = 8.0 Hz, 2 H, Ar), 7.51 (t, J = 8.0 Hz, 2 H, Ar),
3
2976, 3456, 3518 cm–1. MS (pos. FAB): m/z = 71 (23%, [THF – 2
H]+), 105 (100%, [Ph–CO]+), 143 (28%, [C8H15O2]+), 289 (32%,
[M – OH]+), 307 (2%, [M + H]+), 329 (9%, [M + Na]+). HRMS:
calcd. m/z for C16H19O5 ([M – CH3]+) 291.123; found m/z 291.123.
8.02 (d, J = 8.0 Hz, Ar) ppm. 13C NMR (125 MHz): δ = 22.2 (C-
3
4), 24.1 [C(2)–CH3], 26.6 [C(5)–COH(CH3)2], 27.5 [C(5)–
COH(CH3)2], 34.9 (C-3), 66.0 [C(2)–CHOH–CH2–OBz], 70.7
[C(5)–COH(CH3)2], 75.2 (C-2), 84.2 [C(2)–CHOH], 86.8 (C-5),
128.4 (Ar), 129.8 (Ar), 130.4 (Ar), 133.2 (Ar), 166.9 (C=O) ppm.
trans-THF 6b: 1H NMR (500 MHz): δ = 1.13 [s, 3 H, C(5)–
C(CH3)(CH3)OH], 1.24 [s, 3 H, C(5)–C(CH3)(CH3)OH], 1.39 [s, 3
H, C(2)–CH3], 1.84 [m, 3 H, C(3)–Ha, C(4)–Ha, C(4)–Hb], 2.29
FT-IR (KBr): ν = 713, 913, 1120, 1276, 1383, 1451, 1602, 1718,
˜
2874, 2932, 2973, 3442 cm–1. MS (pos. FAB): m/z = 71 (27 %,
[THF – 2 H]+), 105 (100%, [PhCO]+), 143 (15%, [C8H15O2]+), 291 [m, 1 H, C(3)–Hb], 3.88 [m, 1 H, C(5)–H], 5.22 [s, 2 H, C(2)–
(13%, [M – H2O]+), 309 (3%, [M + H]+), 331 (21%, [M + Na]+). COCH2OBz], 7.41 (m, 2 H, Ar), 7.51 (m, 1 H, Ar), 8.05 (m, 2 H,
Eur. J. Org. Chem. 2005, 4109–4118
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4115

S. Roth, S. Göhler, H. Cheng, C. B. W. Stark
FULL PAPER
Ar) ppm. 13C NMR (125 MHz): δ = 24.3 (C-4), 24.4 [C(2)–CH3],
26.4 [C(5)–COH(CH3)2], 27.8 [C(5)–COH(CH3)2], 35.2 (C-3), 71.2
25.9 [C(5)–C(CH3)(CH3)OH], 27.2 [C(5)–C(CH3)(CH3)OH], 35.4 [C(2)–CHOH–CH2–OBn], 71.8 [C(5)–COH(CH3)2], 73.5 (Ph-CH2–
(C-3), 65.9 [C(2)–C(O)CH2OBz], 70.7 [C(5)–C(CH3)(CH3)OH],
OR), 84.0 [C(2)–CHOH], 75.5 (C-2), 85.8 (s, C-5), 127.8 (Ar), 128.5
88.1 (C-2), 88.4 (C-5), 128.4 (Ar), 129.8 (Ar), 130.0 (Ar), 133.3
(Ar), 138.0 (Ar) ppm. FT-IR (KBr): ν = 698, 737, 1028, 1071, 1117,
˜
(Ar), 166.1 [ArC(O)OCH2], 207.5 [2-C(O)CH2OBz] ppm. FT-IR 1384, 1454, 1718, 2871, 2926, 2969, 3438 cm–1. MS (pos. FAB): m/z
(KBr): ν = 711, 1061, 1078, 1278, 1723, 1740, 2875, 2877, 2935, = 43 (14%, [CH3CO]+), 91 (22%, [C7H7]+), 204 (2%, [M – C3H7O –
˜
3349, 3525 cm–1. MS (pos. FAB): m/z = 71 (20%, [THF – 2 H]+),
77 (27%, [Ph]+), 105 (100%, [C7H5O]+), 143 (33%, [C8H15O2]), 289
(35%, [M – OH]+), 307 (8%, [M + H]+), 329 (21%, [M + Na]+).
HRMS: calcd. m/z for C16H22O5 [M – CH3]+ 291.123, found m/z
293.123.
CH3O]+), 235 (1%, [M – C3H7O]+), 277 (6%, [M + H – H2O]+),
295 (4%, [M + H]+). HRMS: calcd. m/z for C8H15O2 ([C3H7O–
THF–CH3]+) 143.107; found m/z 143.108.
N-{2-Hydroxy-2-[5-(1-hydroxy-1-methylethyl)-2-methyl-tetrahydro-
1
furan-2-yl]ethyl}benzamide (10): H NMR (500 MHz): δ = 0.96 [s,
2-{5-[2-(tert-Butyldiphenylsilanyloxy)-1-hydroxyethyl]-5-methyl-te-
trahydrofuran-2-yl}propan-2-ol (7): H NMR (500 MHz): δ = 1.03
3 H, C(2)–CH3], 1.08 [s, 3 H, C(5)–COH(CH3)2], 1.11 [s, 3 H, C(5)–
COH(CH3)2], 1.51 [m, 1 H, C(3)–Hb], 1.75 [m, 1 H, C(4)–Hb], 1.87
[m, 1 H, C(4)–Ha], 2.06 [ddd, 3J = 5.5, 9.2, 2J = 14.2 Hz, 1 H,
C(3)–Ha], 3.20 [m, 1 H, C(5)–H], 3.53 [m, 1 H, C(2)–CHOH–CH2–
1
[s, 3 H, C(2)–CH3], 1.07 (s, 12 H, Si-tBu), 1.19 [s, 6 H, C(5)–
COH(CH3)2], 1.55 [ddd, 3J = 6.3, 8.5, 2J = 12.2 Hz, 1 H, C(3)–
Ha], 1.87 [m, 1 H, C(4)–Ha], 1.98 [m, 1 H, C(4)–Hb], 2.22 [ddd, 3J NHBz], 3.72 [m, 2 H, C(2)–CHOH–CH2–NHBz], 7.23 (t, 3J =
3
2
= 6.6, 8.9, 2J = 12.2 Hz, 1 H, C(3)–Hb], 3.67 [dd, J = 8.5, J = 7.3 Hz, 2 H, Ar), 7.31 (t, 3J = 7.3 Hz, 1 H, Ar), 7.66 (t, 3J = 7.3 Hz,
4.2 Hz, 1 H, C(2)–CHOH–CH2–OTBDPS], 3.78 [m, 3 H, C(5)–H,
C(2)–C(OH)H–R, C(2)–CHOH–CH2–OTBDPS], 7.40 (m, 6 H,
Ar), 7.66 (dd, 4J = 1.5, 3J = 7.8 Hz, 4 H, Ar) ppm. 13C NMR
(125 MHz): δ = 19.3 (Si-tBu), 23.2 [s, C(2)–CH3], 25.1 [C(5)–
2 H, Ar) ppm. 13C NMR (125 MHz): δ = 23.3 (C-4), 25.4 [C(2)–
CH3], 26.3 [C(5)–COH(CH3)2], 27.8 [C(5)–COH(CH3)2], 35.5 (C-
3), 42.7 [C(2)–CHOH–CH2NHBz], 71.9 [C(5)–COH(CH3)2], 75.2
(C-2), 85.0 [C(2)–CHOH], 85.8 (C-5), 127.2 (Ar), 128.4 (Ar), 131.4
COH(CH3)2], 26.1 [C(5)–COH(CH3)2], 27.0 (Si-tBu), 27.8 (C-4), (Ar), 134.3 (Ar), 168.4 (Ph-CONHR) ppm. FT-IR (KBr): ν = 951,
˜
35.2 (C-3), 64.8 [C(5)–COH(CH3)2], 71.8 (C-2), 76.8 (C-5), 83.6 1084, 1311, 1541, 1641, 1140, 2875, 2934, 2972, 3370 cm–1. MS
[C(2)–CHOH], 85.8 [C(2)–CHOH–CH2–OTBDMS], 127.9 (Ar), (pos. FAB): m/z = 71 (28%, [THF – 2 H]+), 105 (100%, [PhCO]+),
129.9 (Ar), 133.2 (Ar), 135.6 (Ar) ppm. FT-IR (KBr): ν = 505, 702,
143 (11%, [C3H7O–THF–CH3]+), 308 (24%, [M + H]+), 330 (13%,
˜
740, 825, 1064, 1113, 1428, 1472, 2857, 2885, 2931, 2963, [M + Na]+). HRMS: calcd. m/z for C16H22NO4 ([M – CH3]+)
3397 cm–1. MS (EI, 90 °C): m/z = 43 (17%, [CH3CO]+), 143 (6%,
[C3H7O–THF–CH3]+), 199 (5%, [SiPh2OH]+), 285 (2%, [TBDPS–
O–CH2]+), 349 (1%, [M – H2O – H2O – C4H9]+), 367 (2%, [M –
H2O – C4H9]+). HRMS: calcd. m/z for C22H27O3Si ([M – H2O –
C4H9]+) 367.173; found m/z 367.174.
292.145; found m/z 292.144.
N-{2-Hydroxy-2-[5-(1-hydroxy-1-methylethyl)-2-methyl-tetrahydro-
furan-2-yl]ethyl}-4-methylbenzenesulfonamide (11): 1H NMR
(500 MHz): δ = 1.05 [s, 6 H, C(5)–COH(CH3)2], 1.19 [s, 3 H, C(2)–
3
2
CH3], 1.11 [s, 3 H, C(5)–COH(CH3)2], 1.59 [ddd, J = 8.4, 8.4, J
= 14.2 Hz,1 H, C(3)–Hb], 1.84 [m, 1 H, C(4)–Hb], 1.91 [m, 1 H,
2-{5-[2-(tert-Butyldimethylsilanyloxy)-1-hydroxyethyl]-5-methyl-te-
1
trahydrofuran-2-yl}propan-2-ol (8): H NMR (500 MHz): δ = 0.07
C(4)–Ha], 2.08 [ddd, 3J = 5.1, 9.2, 2J = 14.2 Hz, 1 H, C(3)–Ha],
3
(s, 6 H, Si–Me), 0.89 (s, 9 H, Si-tBu), 1.08 [s, 3 H, C(2)–CH3], 1.14 2.38 (s, 3 H, Ar-CH3), 2.90 [dd, J = 8.1, 12.7 Hz, 1 H, C(5)–H],
3
2
[s, 3 H, C(5)–COH(CH3)2], 1.23 [s, 3 H, C(5)–COH(CH3)2], 1.59 3.17 [m, 1 H, C(2)–CHOH–CH2–NHTos], 3.46 [dd, J = 3.0, J =
[ddd, 3J = 6.5, 8.7, 2J = 12.4 Hz, 1 H, C(3)–Ha], 1.90 [m, 1 H, 8.1 Hz, 1 H, C(2)–CHOH–CH2–NHTos], 3.78 [dd, J = 7.4, J =
3
2
C(4)–Ha], 2.02 [m, 1 H, C(4)–Hb], 2.28 [ddd, 3J = 6.7, 9.1, 2J =
12.4 Hz, 1 H, C(3)–Hb], 2.98 (s, 1 H, OH), 3.33 (s, 1 H, OH), 3.58
[dd, 3J = 8.7, 2J = 3.9 Hz, 1 H, C(2)–CHOH–CH2–OTBDMS],
8.1 Hz, 1 H, C(2)–CHOH–CH2–NHTos], 5.81 (s, 1 H, NH), 7.26
3
3
(d, J = 8.0 Hz, 2 H, Ar), 7.72 (d, J = 8.0 Hz, 2 H, Ar) ppm. 13C
NMR (125 MHz): δ = 21.4 (C-4), 23.3 [C(2)–CH3], 25.4 (Ar-CH3),
26.3 [C(5)–COH(CH3)2], 27.6 [C(5)–COH(CH3)2], 35.6 (C-3), 45.2
[C(2)–CHOH–CH2–NHTos], 72.0 [C(5)–COH(CH3)2], 75.0 (C-2),
84.7 [C(2)–CHOH–CH2–NHTos], 85.7 (C-5), 127.1 (Ar), 129.6
3
3
3.67 [dd, J = 9.9, 8.7 Hz, 1 H, C(2)–C(OH)H–R], 3.77 [dd, J =
2
3
9.9, J = 3.9 Hz, 1 H, C(2)–CHOH–CH2–OTBDMS], 3.84 [t, J =
7.1 Hz, 1 H, C(5)–H] ppm. 13C NMR (125 MHz): δ = –5.3 (Si–
Me), 18.3 (Si-tBu), 23.4 [C(2)–CH3], 25.1 (C-4)) , 26.0 (Si-tBu), 26.1
[C(5)–COH(CH3)2], 27.9 [C(5)–COH(CH3)2], 35.2 (C-3), 63.7
(Ar), 136.8 (Ar), 143.2 (Ar) ppm. FT-IR [KBr]: ν = 552, 662, 815,
˜
1090, 1160, 1328, 1451, 1598, 2877, 2931, 2974, 3287 cm–1. MS (EI,
[C(5)–COH(CH3)2], 71.8 (C-2), 76.6 (C-5), 83.6 [C(2)–CHOH], 160 °C): m/z = 43 (39%, [CH3CO]+), 59 (12%, [C3H7O]+), 71 (26%,
86.9 [C(2)–CHOH–CH –OTBDMS] ppm. FT-IR (KBr): ν = 778,
[THF – 2 H]+), 91 (35 %, [C7H7]+), 143 (100 %, [C3H7O–THF–
CH3]+), 155 (38%, [C7H7SO2]+), 324 (2%, [M – CH3 – H2O]+), 357
(0.3%, [M]+). HRMS: calcd. m/z for C17H27NO5S ([M]+) 357.161;
found m/z 357.161.
˜
2
838, 1068, 1116, 1254, 1464, 1472, 2930, 2957, 3405 cm–1. MS (pos.
FAB): m/z = 43 (69 %, [CH3CO]+), 143 (21 %, [C3H7O–THF–
CH3]+), 283 (10%, [M – OH – H2O]+), 301 (18%, [M – OH]+), 318
(8%, [M + H]+), 341 (44%, [M + Na]+). HRMS: calcd. m/z for
C15H31O4Si ([M – CH3]+) 303.199, found m/z 303.198.
Methyl Hydroxy[5-(1-hydroxy-1-methylethyl)-2-methyl-tetra-
hydrofuran-2-yl]acetate (12): 1H NMR (500 MHz): δ = 1.09 [s, 3 H,
2-[5-(2-Benzyloxy-1-hydroxyethyl)-5-methyl-tetrahydrofuran-2-yl]- C(2)–CH3], 1.26 [s, 3 H, C(5)–COH(CH3)2], 1.31 [s, 3 H, C(5)–
propan-2-ol (9): 1H NMR (500 MHz): δ = 1.08 [s, 3 H, C(2)–CH3], COH(CH3)2], 1.70 [m, 1 H, C(3)–Ha], 1.85 [m, 1 H, C(4)–Ha], 2.02
1.14 [s, 3 H, C(5)–COH(CH3)2], 1.21 [s, 3 H, C(5)–COH(CH3)2], [m, 1 H, C(4)–Hb], 2.34 [ddd, 3J = 2.6, 8.7, 2J = 12.1 Hz, 1 H,
3
1.60 [ddd, J = 7.0, 8.5, 2J = 12.4 Hz, 1 H, C(3)–Ha], 1.89 [m, 1
C(3)–Hb], 3.80 (s, 3 H, CO2CH3), 3.83 [dd, 3J = 6.5, 9.2 Hz, 1
H, C(5)–H], 4.03 [s, 1 H, C(2)–C(OH)H–CO2Me] ppm. 13C NMR
3
2
H, C(4)–Ha], 1.98 [m, 1 H, C(4)–Hb], 2.21 [ddd, J = 6.2, 9.1, J
= 12.4 Hz, 1 H, C(3)–Hb], 3.07 (s, 1 H, OH), 3.14 (s, 1 H, OH), (125 MHz): δ = 16.1 (C-4), 18.7 [C(2)–CH3], 25.6 [C(5)–COH-
3
3
3.56 [dd, J = 8.4, 9.5 Hz, 1 H, C(2)–C(OH)H–R], 3.65 [dd, J =
(CH3)2], 26.1 [C(5)–COH(CH3)2], 40.9 (C-3), 50.6 (CO2CH3), 115.3
[C(5)–COH(CH3)2], 123.0 (C-2), 132.4 (C-5), 160.0 [C(2)–C(OH)
9.5, 2J = 3.3 Hz, 1 H, C(2)–CHOH–CH2–OBn], 3,72 [dd, J = 8.4,
3
2J = 3.3 Hz, 1 H, C(2)–CHOH–CH2–OBn], 3.83 [t, J = 7.1 Hz, 1 H–CO Me], 167.1 (C=O) ppm. FT-IR (KBr): ν = 1094, 1212, 1379,
3
˜
2
H, C(5)–H], 4.56 (d, 2J = 7.6 Hz, 2 H, Ph-CH2–OR), 7.30 (m, 5 H, 1440, 1737, 2878, 2936, 2975, 3439 cm–1. MS (EI, 160 °C): m/z =
Ar) ppm. 13C NMR (125 MHz): δ = 23.3 (C-4), 25.1 [C(2)–CH3],
43 (100 %, [CH3CO]+), 59 (32 %, [C3H7O]+), 71 (45 %, [THF –
4116
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Ruthenium Tetroxide Catalyzed Oxidative Cyclizations of 1,5-Dienes
FULL PAPER
2 H]+), 143 (47 %, [C3H7O–THF–CH3]+), 173 (11 %, [M –
C3H7O]+), 199 (2%, [M – CH3 – H2O]+), 217 (5%, [M – CH3]+).
HRMS: calcd. m/z for C10H17O5 ([M – CH3]+) 217.108; found m/z
217.109.
HRMS: calcd. m/z for C16H21O4 ([M – OH]+) 277.144; found m/z
277.144. C16H22O5: calcd. C 65.29, H 7.53; found C 65.15, H 7.41.
Acknowledgments
Ethyl {5-[Ethoxycarbonyl(hydroxy)methyl]-tetrahydrofuran-2-
yl}hydroxyacetate (13): 1H NMR (500 MHz): δ = 1.22 (t, 3J =
7.2 Hz, CH3CH2), 1.98 [m, 2 H, C(3)–Ha], 2.16 [m, 2 H, C(3)–Hb],
This research was generously supported by the Bundesministerium
für Bildung und Forschung, the Deutsche Forschungsgemein-
schaft, and the Fonds der Chemischen Industrie. We are grateful
to Professor H.-U. Reissig for helpful discussions and generous
support.
3
3.82 (s, 2 H, OH), 4.04 [d, J = 1.9 Hz, 2 H, C(2)–CHOH–CO2Et],
3
4.18 (q, J = 7.2 Hz, 4 H, CH3CH2), 4.33 [m, 2 H, C(2)–H] ppm.
13C NMR (125 MHz): δ = 14.1 (CH3), 28.0 (C-3), 61.7 (CH3CH2),
73.4 (C-2), 80.6 (CHOH), 172.6 (CO Et) ppm. FT-IR (KBr): ν =
˜
2
1029, 1130, 1201, 1271, 1369, 1640, 1742, 2939, 2983, 3440 cm–1.
MS (EI, 90 °C): m/z = 57 (24%, [C4H9]+), 71 (27%, [THF – 2 H]+),
99 (81%, [THF – CO – 2 H]+), 155 (31%, [M – C4H7O3 – H2O]+),
173 (100%, [M – C4H7O3]+), 203 (7%, [M – C3H5O2]+), 276 (0.3%,
[M]+). HRMS: calcd. m/z for C12H20O7 ([M]+) 276.121; found m/z
276.121.
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1
1-[5-(1-Hydroxypentyl)-tetrahydrofuran-2-yl]pentan-1-ol (14): H
3
NMR (500 MHz): δ = 0.87 (t, J = 7.3 Hz, 6 H, Me), 1.29 (m, 8
[5] a) T. L. B. Boivin, Tetrahedron 1987, 43, 3309–3362; b) J. C.
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H, CH3CH2CH2CH2CHOH), 1.43 (m, 4 H, CH2CHOH), 1.71 [m,
2 H, C(3)–Ha], 1.89 [m, 2 H, C(3)–Hb], 3.38 (m, 2 H, CHOH),
3.79 [m, 2 H, C(2)–H] ppm. 13C NMR (125 MHz): δ = 14.1 (C-1),
22.8 (C-2), 27.9 (C-3), 28.1 (C-7), 33.8 (C-4), 74.4 (C-5), 82.8 (C-
6) ppm. FT-IR (KBr): ν = 718, 907, 1122, 1279, 1466, 3350 cm–1.
˜
MS (pos. FAB): m/z = 57 (100 %, [C4H9]+), 139 (9 %, [M –
C5H10OH – H2O]+), 157 (14%, [M – C5H10OH]+), 227 (12%, [M – [7] a) E. Klein, W. Rojahn, Tetrahedron 1965, 21, 2353–2358; b)
OH]+), 245 (7%, [M + H]+), 267 (4%, [M + Na]+). HRMS: calcd.
m/z for C14H27O2 ([M – OH]+) 227.201; found m/z 227.201.
J. E. Baldwin, M. J. Crossley, E. M. M. Lehtonen, J. Chem.
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1
1-[5-(1-Hydroxypentyl)-tetrahydrofuran-2-yl]pentan-1-one (15): H
NMR (500 MHz): δ = 0.87 (m, 6 H, CH3), 1.29 [m, 8 H, C(2)–
CO–CH2CH2CH2CH3, C(5)–CHOH–CH2CH2CH2CH3], 1.54 [tt,
3J = 7.2, 7.2 Hz, C(2)–CO–CH2CH2CH2CH3], 1.74 [m, 1 H, C(4)–
Hb], 1.81 [m, 1 H, C(4)–Ha], 2.01 [m, 1 H, C(3)–Hb], 2.24 [m, 1
H, C(3)–Ha], 2.40 [m, 2 H, C(2)–CO–CH2CH2CH2CH3], 3.95 [m,
1 H, C(5)–CHOH-nBu], 4.04 [ddd, 1 H, 3J = 2.8, 6.3, 9.1 Hz, C(5)–
H], 4.16 (s, 1 H, OH), 4.53 [dd, 1 H, 3J = 3.3, 9.6 Hz, C(2)–H] ppm.
13C NMR (125 MHz): δ = 13.9 [C(2)–CO–CH2CH2CH2CH3], 14.1
[C(5)–CHOH–CH2 CH2 CH2 CH3 ], 22. 3 [C(5)–CHOH–
CH2CH2CH2CH3], 22.4 [C(5)–CHOH–CH2CH2CH2CH3], 22.8
(C-4), 25.6 [C(2)–CO–CH2CH2CH2CH3], 28.2 [C(2)–CO–
C H 2 C H 2 C H 2 C H 3 ] , 2 9 . 7 ( C - 3 ) , 3 2 . 6 [ C ( 5 ) – C H O H –
CH2CH2CH2CH3], 38.4 [C(2)–CO–CH2CH2CH2CH3], 71.1 [C(5)–
CHOH-nBu], 82.2 (C-2), 84.9 (C-5), 212.8 [C(2)–CO–nBu] ppm.
[8] For asymmetric permanganate-promoted oxidative cyclizations
with chiral auxiliaries, see: a) D. M. Walba, C. A. Przybyla,
C. B. Walker, J. Am. Chem. Soc. 1990, 112, 5624–5625; b) P. J.
Kocienski, R. C. D. Brown, A. Pommier, M. Procter, B.
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R. C. D. Brown, C. J. Bataille, R. M. Hughes, A. Kenney, T. J.
Luker, J. Org. Chem. 2002, 67, 8079–8085. For a permanga-
nate-promoted catalytic asymmetric oxidative cyclization using
a chiral phase-transfer catalyst, see: R. C. D. Brown, J. F. Keily,
Angew. Chem. 2001, 113, 4628–4630; Angew. Chem. Int. Ed.
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[9] a) M. de Champdoré, M. Lasalvia, V. Piccialli, Tetrahedron
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2-Hydroxy-2-[5-(1-hydroxypropyl)-tetrahydrofuran-2-yl]ethyl Benzo-
1
3
ate (16): H NMR (500 MHz): δ = 0.96 [t, J = 6.7 Hz, 3 H, C(5)–
3
CHOH–CH2CH3], 1.40 [dq, J = 6.7, 6.7 Hz, 2 H, C(5)–CHOH–
CH2CH3], 1.80 [m, 1 H, C(3)–Ha], 2.02 [m, 3 H, C(3)–Hb, C(4)–
H2], 3.80 [m, 1 H, C(5)–CHOH–CH2CH3], 3.86 [m, 1 H, C(5)–H],
3.97 [td, 3J = 2.9, 4.8 Hz, 1 H, C(2)–H], 4.11 [m, 1 H, C(2)–
CHOH–CH2–OBz], 4.39 [dd, 3J = 5.0, 2J = 11.4 Hz, 1 H, C(2)–
CHOH–CH2–OBz], 4.43 [dd, 3J = 7.0, 2J = 11.4 Hz, 1 H, C(2)–
CHOH–CH2–OBz], 7.41 (ddd, 4J = 1.4, 3J = 8.3, 7.0 Hz, 2 H, Ar),
[11] C. Djerassi, R. R. Engle, J. Am. Chem. Soc. 1953, 75, 3838–
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4
3
4
7.54 (tt, J = 1.4, J = 7.0 Hz, 1 H, Ar), 8.03 (ddd, J = 1.4, 1.4,
3J = 8.3 Hz, 2 H, Ar) ppm. 13C NMR (125 MHz): δ = 10.4 [C(5)–
CHOH–CH2CH3], 24.2 (C-3), 26.3 (C-4), 28.6 [C(5)–CHOH–
CH2CH3], 67.0 [C(2)–CHOH–CH2–OBz], 72.3 [C(2)–CHOH–
CH2–OBz], 74.2 [C(5)–CHOH–CH2CH3], 78.9 (C-2), 88.9 (C-5),
128.4 (Ar), 129.8 (Ar), 130.0 (Ar), 133.1 (Ar), 166.8 (C=O) ppm.
[12] For ruthenium tetroxide mediated oxidation reactions, see:
V. S. Martin, J. M. Palazón, C. M. Rodríguez, “Rutheni-
um() Oxide”, in: Encyclopedia of Reagents for Organic Syn-
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oxidation reactions see: a) S.-I. Murahashi, N. Komiya, “Oxi-
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I. Murahashi), Wiley-VCH, Weinheim, 2004, chapter 3, pp. 53–
95; b) I. W. C. E. Arends, T. Kodama, R. A. Sheldon, in: Ru-
thenium Catalysts in Fine Chemistry; Topics in Organometallic
FT-IR (KBr): ν = 719, 906, 1124, 1277, 1452, 1714, 2883, 2927,
˜
2961, 3323 cm–1. MS (pos. FAB): m/z = 57 (81%, [C3H5O]+), 59
(37%, [C3H7O]+), 77 (70%, [Ph]+), 105 (100%, [Ph-CO]+), 277 (5%,
[M + H – H2O]+), 295 (6%, [M + H]+), 317 (8%, [M + Na]+).
Eur. J. Org. Chem. 2005, 4109–4118
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4117

S. Roth, S. Göhler, H. Cheng, C. B. W. Stark
FULL PAPER
Chemistry, vol. 11 (Eds.: C. Bruneau, P. H. Dixneuf), Springer-
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ahashi), Wiley-VCH, Weinheim, 2004, chapter 14, pp. 345–367.
Cf. also refs.[12,18]
cyclization product of geranyl acetate (10–20% conversion), cf.:
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used for all experiments. With time an increased reactivity of
this pre-catalyst solution was observed (i.e. higher reaction
rates were attained), although yields and selectivities were not
influenced. This aging effect may be attributable to a slow li-
gand-exchange reaction (cf. ref.[20]). Control experiments re-
vealed that aqueous ruthenium() chloride stock solutions
(0.01 ) gave results similar to those seen with old THF stock
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[24] To separate from inorganic impurities it may occasionally be
found advantageous to filter the crude product through a pad
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[19] The pH of these solutions was measured to be in the range of
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[20] Ligand-exchange reactions with ruthenium() and rutheni-
um() are known to be slow, cf. I. Rapaport, L. Helm, A. E.
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an excess of TPAP (10 equiv.) was shown to yield the oxidative
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Received: January 23, 2005
Published Online: August 15, 2005
(publication delayed at authors’ request)
4118
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Eur. J. Org. Chem. 2005, 4109–4118