Gold catalysis in stereoselective natural product synthesis: (+)-linalool oxide, (-)-isocyclocapitelline, and (-)-isochrysotricine

Article abstract of DOI:10.1016/j.tet.2008.11.104

A stereoselective synthesis of the tetrahydrofuran-containing natural products (2S,5R)-(+)-linalool oxide (1), (-)-isocyclocapitelline (2), and (-)-isochrysotricine (3) is reported. Key steps are the copper-mediated S_N2′-substitution of proparg

Full text of DOI:10.1016/j.tet.2008.11.104

Tetrahedron 65 (2009) 1902–1910
Contents lists available at ScienceDirect
Tetrahedron
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Gold catalysis in stereoselective natural product synthesis: (þ)-linalool oxide,
(ꢀ)-isocyclocapitelline, and (ꢀ)-isochrysotricine
*
Frank Volz, Sipke H. Wadman, Anja Hoffmann-Ro¨der, Norbert Krause
Dortmund University of Technology, Organic Chemistry II, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the tetrahydrofuran-containing natural products (2S,5R)-(þ)-linalool oxide
(1), (ꢀ)-isocyclocapitelline (2), and (ꢀ)-isochrysotricine (3) is reported. Key steps are the copper-medi-
ated SN20-substitution of propargyl oxiranes 7 and the gold-catalyzed cycloisomerization of dihydroxy-
allenes 8/17, resulting in a highly efficient center-to-axis-to-center chirality transfer. The enantioselective
total synthesis of (ꢀ)-isocyclocapitelline (2) and (ꢀ)-isochrysotricine (3) allowed the elucidation of the
Received 18 September 2008
Received in revised form 4 November 2008
Accepted 5 November 2008
Available online 24 December 2008
absolute configuration of these b-carboline natural products.
Keywords:
Allenes
Ó 2008 Elsevier Ltd. All rights reserved.
Chirality transfer
Cycloisomerization
Gold catalysis
Heterocycles
Tetrahydrofurans
1. Introduction
lavender notes) and for the reconstitution of essential oils.5 For
these applications, control of the stereochemistry is crucial since
the fragrance properties of linalool oxide depend on the absolute
configuration at C-2: the (2R)-isomers have a leafy earthy note
whereas the (2S)-isomers exhibits a sweet floral creamy flavor.6,7
Although many syntheses of linalool oxide have been reported,8
most of them are not stereoselective; only two diastereo- and
enantioselective routes have been disclosed so far.9
Isocyclocapitelline (2) and isochrysotricine (3) were isolated
(together with their diastereomers cyclocapitelline and chryso-
tricine) in 1999 from the Rubiaceae plant Hedyotis capitellata,
which has been widely used in traditional Chinese and Vietnamese
herb medicine.10 The constitution and relative configuration of
Due to their presence in many biologically active natural prod-
ucts, chiral tetrahydrofurans continue to be of high interest in
preparative and medicinal chemistry.1 Recently, 2,5-substituted
tetrahydrofurans have attracted much attention since they occur in
annonaceous acetogenins, which exhibit highly diverse biological
properties.2 Various other natural products also contain this het-
erocyclic system, including the terpenoid linalool oxide (1), the
b
-carboline alkaloids, (ꢀ)-isocyclocapitelline (2), and (ꢀ)-iso-
chrysotricine (3).
N
N Me
Me
these b-carboline alkaloids were confirmed by NMR data and an
Me
N
H
N
OH
X-ray analysis; the absolute configuration was unknown at the
beginning of our work. Studies of the biological activity of iso-
chrysotricine and isocyclocapitelline were hampered by the minute
amounts of the alkaloids available from natural sources; for
chrysotricine, however, an interesting in vitro activity against the
growth of HL-60 leukemia cells has been observed.11 Previous
synthetic studies were devoted to (þ)-chrysotricine,12 racemic
isocyclocapitelline/isochrysotricine,13 and norisocyclocapitelline.8g
Taking into account that all three natural products contain
a chiral 2,5-trisubstituted tetrahydrofuran ring of the same relative
configuration,14 we reasoned that related synthetic routes should
lead to these target molecules. Based on our experience with the
O
H
O
O
(2S,5R)-(+)-Linalool Oxide (1)
HO
HO
H
H
(−)-Isocyclocapitelline (2)
(−)-Isochrysotricine (3)
Furanoid linalool oxide (1) is an important constituent of
oolong, black and green tea and is also found in many essential oils3
and fruit aromas (e.g., in papaya).4 It is used in perfumery (e.g., for
* Corresponding author. Tel.: þ49 231 755 3882; fax: þ49 231 755 3884.
E-mail address: norbert.krause@tu-dortmund.de (N. Krause).
gold-catalyzed15
cycloisomerization
of
a
-hydroxyallenes16
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.104

F. Volz et al. / Tetrahedron 65 (2009) 1902–1910
1903
(Scheme 1) and other functionalized allenes17 to five- or six-
membered heterocycles, we planned to use this reaction (which
takes place with efficient axis-to-center chirality transfer) as the
key step for the synthesis of the natural products 1–3. In this paper,
we report on our synthesis of (2S,5R)-(þ)-linalool oxide (1), as well
as the first total syntheses of (ꢀ)-isocyclocapitelline (2) and
(ꢀ)-isochrysotricine (3).18
(960 turnovers on a 2 g scale) as a single diastereomer, completing
the key center-to-axis-to-center chirality transfer. As expected from
previous results,16,17e only the hydroxy group in
ipates in the cyclization.
a-position partic-
O
MeMgCl
•
OH
OH
BnO
OH
CuCN, (PhO)3P
THF
BnO
Me
R3
8 (93%, >99% ds)
7a (97% ee)
Au(I) or Au(III)
R1
R2
R3
R4
R1
R4
AuCl3 (0.1 mol%)
O
OH
R2
THF
Scheme 1. Gold-catalyzed cycloisomerization of
dihydrofurans.
a-hydroxyallenes to 2,5-
1. DMP
BnO
OH
BnO
OH
2. MeMgCl
O
O
Me
H
Me
H
2. Results and discussion
10 (83%, >99% ds)
9 (96%, >99% ds)
Our approach started from the known esters 4a19 and 4b,20
which were converted into the enynoates 5 by a one-pot reduction–
olefination sequence (Scheme 2).21 Efficient transformation into
the racemic secondary alcohols rac-6 was achieved by standard
reduction–oxidation–Grignard addition. Both enynes turned out to
be excellent substrates for a kinetic resolution by Katsuki–Sharpless
1. H2, Pd/C
2. IBX
Me
O
H
1. DIBAH, Et2O, −110 °C
O
O
OH
2. Me3SiCH2MgCl, CeCl3
3. KH
O
H
epoxidation;22 with
L-(þ)-diethyl tartrate, both the epoxides 7 and
(2S,5R)-(+)-Linalool Oxide (1)
77% Yield, >99% ds, 97% ee
[α]D20 = +11.3
11 (66%, >99% ds, 97% ee)
the unreacted starting materials (R)-6 (configuration assigned
according to the Katsuki–Sharpless mnemonic device22) were
obtained with high enantiomeric excess.23 The enynes (R)-6 were
converted into oxiranes ent-723 by a matched Katsuki–Sharpless
Scheme 3. Stereoselective synthesis of (2S,5R)-(þ)-linalool oxide (1) from propargyl
oxirane 7a (DMP¼Dess–Martin periodinane; IBX¼2-iodoxybenzoic acid).
epoxidation using
D
-(ꢀ)-diethyl tartrate. It should be noted that the
Conversion of the secondary alcohol 9 into the tertiary alcohol
10 by oxidation with Dess–Martin periodinane (DMP; 94% yield)26
or with 2-iodoxybenzoic acid (IBX) in DMSO27 (63% yield) and
subsequent Grignard addition proceeded smoothly. One-pot hy-
drogenation–debenzylation of 10 using palladium on charcoal as
the catalyst furnished the desired diol with 81% yield; however, all
attempts to selectively oxidize this to the corresponding lactol
failed. Rather, we obtained mixture of the lactol and lactone 11,
regardless whether PCC, PDC, DMP, or IBX was used as the oxidizing
agent. Therefore, we decided to completely oxidize the diol to
lactone 11, which was obtained with 66% yield over two steps when
2 equiv of IBX were used. For the final conversion of 11 into (2S,5R)-
(þ)-linalool oxide (1), we initially utilized a one-pot procedure
consisting of the reduction of 11 with DIBAH at ꢀ110 ꢁC and sub-
sequent treatment of the lactol thus formed with freshly prepared
Ph3P]CH2.28 Since the yield of 1 was only 20% (33% for a stepwise
process), we switched to a modified Peterson olefination using
trimethylsilylmethylmagnesium chloride/cerium chloride and
potassium hydride.29 Under these conditions, the target molecule 1
was obtained with 77% overall yield for the reduction–olefination
sequence. Gratifyingly, the high stereochemical purity was main-
tained overall steps, so that (2S,5R)-(þ)-linalool oxide (1) was
corresponding tertiary epoxyalcohols are not accessible by Kat-
suki–Sharpless epoxidation, due to the low reactivity of tertiary
allylic alcohols.22 With both enantiomers of the epoxyalcohols 7 at
hand, either enantiomer of the target molecules 1–3 is accessible.
CO2Et
CO2Me
1. DIBAH, −100 °C
2. (EtO)2P(O)CH2CO2Et
NaH
BnO
BnO
n
n
4a (n = 1)
4b (n = 2)
5a (94%)
5b (92%)
1. LiAlH4
2. MnO2
3. MeMgCl
O
OH
t-BuOOH
BnO
Ti(Oi-Pr)4
OH
n
BnO
BnO
L-(+)-DET
7a (41%, 97% ee)
7b (42%, >98% ee)
n
rac-6a (75%)
rac-6b (78%)
+
O
t-BuOOH
Ti(Oi-Pr)4
D-(−)-DET
OH
OH
BnO
n
n
(R)-6a (38%, 99% ee)
(R)-6b (43%, >98% ee)
ent-7a (82%, 98% ee)
ent-7b (81%, >98% ee)
obtained with >99% ds and 97% ee (determined by GC; see Scheme
20
4). Comparison of the optical rotation of our product {[
a]
þ11.3 (c
D
20
0.065, CHCl3)} with the literature value7 {[
CHCl3)} confirms the absolute configuration.
a
]
þ4.0 (c 0.028,
Scheme 2. Stereodivergent synthesis of propargyl oxiranes 7 by Katsuki–Sharpless
epoxidation (DET¼diethyl tartrate).
D
In contrast to linalool oxide, the absolute configuration of the
other two target molecules, (ꢀ)-isocyclocapitelline (2) and
(ꢀ)-isochrysotricine (3), was unknown at the onset of our study.
We randomly selected epoxyalcohol ent-7b for our synthesis
(Scheme 5). The first step matches with those used for linalool
oxide: anti-selective copper-mediated SN20-substitution with
MeMgCl/CuCN/(PhO)3P afforded the allenic diol 12 with high dia-
stereoselectivity (>98% ds), and the chemo- and stereoselective
gold-catalyzed cycloisomerization furnished the desired 2,5-dihy-
drofuran 13 with excellent yield and center-to-axis-to-center chi-
rality transfer. With a catalyst loading of only 0.05 mol % AuCl3 in
The key steps of the synthesis of (2S,5R)-(þ)-linalool oxide (1)
are the anti-selective copper-mediated SN20-substitution of prop-
argyl oxirane 7a and the gold-catalyzed cycloisomerization of the
dihydroxyallene 8 thus formed (Scheme 3). Treatment of 7a with
a methylmagnesium cyanocuprate in the presence of triphenyl-
phosphite as ligand to copper (in order to prevent epimerization of
the allene24) afforded 8 with excellent chemical yield (93%) and
diastereoselectivity (>99% ds).25 The subsequent gold-catalyzed
cycloisomerization was achieved in the presence of only 0.1 mol %
AuCl3 in THF, which gave the 2,5-dihydrofuran 9 with 96% yield

1904
F. Volz et al. / Tetrahedron 65 (2009) 1902–1910
Scheme 4. Gas chromatograms of linalool oxide on Lipodex G: (a): racemic mixture of diastereomers (Sigma–Aldrich); (b): racemic cis-1; (c): (2S,5R)-(þ)-1 prepared in this work.
THF,16 the cycloisomerization of 12 (over 1900 turnovers on
a 2 g-scale!) belongs to the most efficient transformations reported
so far in homogeneous gold catalysis.
O
•
MeMgCl
Me
OH
OH
OH
CuCN, (PhO)3P
THF
BnO
In contrast to these unproblematic steps, the conversion of the
secondary alcohol 13 into the tertiary alcohol 14 turned out to be
tricky. The oxidation of 11 to the corresponding ketone could be
achieved with IBX in DMSO27 (79% yield) or with Dess–Martin
periodinane (DMP)26 in CH2Cl2 (91% yield). Unfortunately, this ke-
tone undergoes a very facile epimerization (probably via the corre-
sponding enol), so that the subsequent Grignard addition afforded
alcohol 14 only as a 60:40 mixture of diastereomers. The ease of this
epimerization is surprising considering the fact that the analogous
ketone obtained by oxidation of alcohol 9 shows no tendency to
epimerize (Scheme 3). Possibly, the longer benzyloxyethyl side
chain is stabilizing the enol by an intramolecular hydrogen bridge.
In order to circumvent this pitfall, we changed the order of
events (Scheme 6). Treatment of epoxyalcohol ent-7b with Dess–
Martin periodinane26 (or with IBX;27 88% yield) gave the ketone 15,
which turned out to be configurationally stable. Subsequent
2
2
BnO
12 (85%, >98% ds)
ent-7b (>98% ee)
AuCl3 (0.05 mol%)
THF
H
Me
H
Me
BnO
1. DMP
2 O
HO
14 (77%, 60% ds)
O
BnO
2. MeMgCl
2
HO
13 (96%, 98% ds)
Scheme 5. Synthesis of 2,5-dihydrofuran 14 from propargyl oxirane ent-7b
(DMP¼Dess–Martin periodinane).
Grignard addition and SN20-substitution of tertiary alcohol 16 to
allene 17 proceeded with excellent yield and without any loss of
stereochemical information (>98% ee). Alternatively, the

F. Volz et al. / Tetrahedron 65 (2009) 1902–1910
1905
O
O
O
MeMgCl
MeMgCl
DMP
Me
•
OH
OH
O
OH
BnO
BnO
BnO
CuCN
OH
2
2
2
2
(PhO)3P
BnO
15 (89%, >98% ee)
16 (97%, >98% ee)
ent-7b (>98% ee)
17 (>98% ee)
AuCl3
98% (from 16)/93% (from 15)
(0.05 mol%)
THF
MeMgCl/CuCN/(PhO)3P, then excess MeMgCl
N
N Me
1. Tryptamine
CF3CO2H
Me
Me
Me
OHC
H
Me
HO
HO
18 (76%, >98% ee)
H
Me
BnO
H
O
N
N
1. MeI
2. NaOH
DMP
H2
Pd/C
H
O
O
2
2. Pd/C
Xylenes, Δ
2
O
O
HO
19 (99%)
HO
HO
H
HO
H
14 (97%, 98% ds, >98% ee)
3 (quant.)
[α]D20 = −38.4
2 (53%, >98% ee)
[α]D20 = −92.4
Scheme 6. Stereoselective synthesis of (ꢀ)-isocyclocapitelline (2) and (ꢀ)-isochrysotricine (3) from propargyl oxirane ent-7b (DMP¼Dess–Martin periodinane).
out
a 3
Pictet–Spengler cyclization30 of with tryptamine;12,13
(ꢀ)-isocyclocapitelline (2) was obtained with 53% yield over two steps
and >98% ds/ee (see Scheme 7) after aromatization of the crude tet-
rahydro-
b-carboline with palladium on charcoal in refluxing xylenes.
20
Comparisonof theopticalrotationofourproduct{[
a
]
ꢀ92.4(c0.525,
D
20
CHCl3)} with that of the natural product11 {[
a
]
ꢀ75 (c 0.50, CHCl3)}
D
suggests that the latter was not isolated as an enantiomerically pure
compound. More importantly, it confirms the absolute configuration
of (ꢀ)-isocyclocapitelline (2)tobe(2S,5R).31 Finally, methylation of the
b
-carboline with MeI in refluxing acetone and deprotonation with
aqueous NaOH12,13 afforded (2S,5R)-(ꢀ)-isochrysotricine (3) with an
20
optical rotation of [
a]
ꢀ38.4 (c 1.020; no literature value reported,
D
MeOH). The spectroscopic data of synthetic 1 and 2 are in excellent
agreement with those reported in the literature.10
3. Conclusion
In this paper, we describe a highly stereoselective synthesis of
three natural products bearing a 2,5-trisubstituted tetrahydrofuran
ring: (2S,5R)-(þ)-linalool oxide (1), (ꢀ)-isocyclocapitelline (2), and
(ꢀ)-isochrysotricine (3). The key feature of our synthetic approach
is a center-to-axis-to-center chirality transfer by anti-selective
copper-mediated SN20-substitution of propargyl oxiranes and sub-
sequent chemo- and stereoselective gold-catalyzed cyclo-
isomerization of dihydroxyallenes to 2,5-dihydrofurans. Due to the
stereodivergent nature of our syntheses, both enantiomers of the
target molecules are accessible via the same route. With extremely
low catalyst loadings of 0.05–0.1 mol % AuCl3, the cyclo-
isomerizations of the allenic diols 8, 12, and 17 belong to the most
efficient transformations reported so far in homogeneous gold ca-
Scheme 7. HPLC chromatograms of isocyclocapitelline on Chiralpak AD: (a): racemic 2;
(b) (2S,5R)-(ꢀ)-2 prepared in this work.
talysis. For the
b
-carboline alkaloids (ꢀ)-isocyclocapitelline and
(ꢀ)-isochrysotricine, our synthesis confirms the hitherto unknown
absolute configuration of these natural products. Our approach
clearly demonstrates the power of combined coinage metal-catal-
ysis for the synthesis of complex target molecules.
´
conversion of 15 to 17 can be carried out in a one-pot SN2-sub-
stitution/1,2-addition by treating the substrate first with the
methylmagnesium cuprate and then with excess Grignard reagent.
Also this sequence afforded allenic diol 17 with 93% yield and ex-
cellent stereocontrol (>98% ee). The subsequent axis-to-center
chirality transfer by gold-catalyzed cycloisomerization (0.05 mol %
AuCl3 in THF) proceeded as for allene 12 to give the key in-
termediate 14 with excellent yield (97%) and high stereochemical
purity (98% ds, >98% ee).
The next steps to the target molecules, hydrogenation/debenzy-
lation of 14 using palladium on charcoal as the catalyst, as well as
oxidation of 18 with Dess–Martin periodinane,26 gave hydroxy-
aldehyde 19 with good yield. Interestingly, this does not show any
tendency to form a lactol of the type 11 (Scheme 3). We then carried
4. Experimental
4.1. General
Moisture and oxygen sensitive reactions were performed in
oven-dried glassware under argon. Diethyl ether and THF were
distilled from sodium/benzophenone. Dichloromethane, n-hexane,
and acetonitrile were distilled from CaH2. Column chromatography
was carried out with Merck silica gel F 60 (70–230 mesh). Dess–
Martin periodinane26 and IBX27 were synthesized according to the

1906
F. Volz et al. / Tetrahedron 65 (2009) 1902–1910
literature. n-BuLi and MeMgCl were titrated with salicylaldehyde
phenylhydrazone according to the procedure of Love and Jones.32
Gold(III)-chloride was used as a stock solution in dry acetonitrile.
1H and 13C NMR spectra were recorded with Bruker DRX 400 and
DRX 500 spectrometers at room temperature in CDCl3 as solvent
was added dropwise. The solution was warmed to ꢀ20 ꢁC for 5 h
and saturated NH4Cl was added slowly. The mixture was stirred for
an additional hour by warming to room temperature. The mixture
was filtered through a pad of CeliteÒ and the layers were separated,
dried over MgSO4, and the solvent was removed in vacuo. The crude
product was purified by column chromatography on silica gel (cy-
clohexane/ethyl acetate, 7:3) to afford (E)-6-(benzyloxy)hex-2-en-
4-yn-1-ol (11.2 g, 90%) as a colorless oil. 1H NMR (500 MHz, CDCl3):
and internal standard (1H NMR:
NMR spectra of
d
¼7.27; 13C NMR:
¼77.0). The
d
a
-hydroxyallenes were measured in K2CO3-doped
CDCl3 in order to prevent acid-promoted cyclization. The signals of
the major component of a product mixture are marked with as-
d
¼7.37–7.29 (m, 5H), 6.28 (dt, J¼16.0, 5.0 Hz, 1H), 5.80 (dt, J¼16.0,
1.6 Hz, 1H), 4.62 (s, 2H), 4.30 (d, J¼1.6 Hz, 2H), 4.20 (d, J¼5.0 Hz,
2H), 2.20 (s, 1H, OH). 13C NMR (125 MHz, CDCl3):
¼142.5, 137.3,
n
terisks (
*
) and signals marked with showed no separation in the
NMR spectra. Enantiomeric ratios were determined by gas chro-
matography on a Carbo Erba 8000 TOP gas chromatograph with
hydrogen as carrier gas and a LipodexÒ G column, or with a Hewlett
Packard HPLC system 1050 with a multi UV detector 1050 using
Chiralcel OD, ODH or ChiralpakÒ AD columns and n-heptane/iso-
propanol as eluent. Diastereomeric ratios were determined by gas
chromatography on a Carbo Erba 8000 TOP gas chromatograph
with helium as carrier gas and a DB1 capillary column, as well as by
NMR spectroscopy. IR spectra were measured with a Nicolet Avatar
320 FT-IR spectrometer as a liquid film between NaCl plates or as
a KBr pellet. Optical rotations were determined with a Perkin–
Elmer 341 polarimeter using a 10 cm cuvette. GC–MS spectra were
recorded using a Thermoquest Finnigan Polaris GCQ spectrometer.
Mass spectra and high resolution mass spectra (HRMS) were
measured on a Jeol SX102A spectrometer.
d
128.4, 128.0, 127.8, 109.5, 85.6, 84.4, 71.5, 62.6, 57.8. IR (neat):
n
¼3408, 2214, 1159, 1026, 952 cmꢀ1. HRMS (FAB): calcd for
C13H13O2 [MꢀH]þ: m/z¼201.0916; found: m/z¼201.0929; calcd for
C13H15O2 [MþH]þ: m/z¼203.1072; found: m/z¼203.1094.
4.4.2. (E)-6-(Benzyloxy)hex-2-en-4-ynal
To a suspension of activated MnO2 (129 g, 1.48 mol) in CH2Cl2
(400 mL) was added (E)-6-(benzyloxy)hex-2-en-4-yn-1-ol (10.0 g,
49.4 mmol) in one portion, and the mixture was stirred for 18 h.
The reaction mixture was filtered through a CeliteÒ/silica gel pad,
the solvent was removed in vacuo and the crude product was pu-
rified by column chromatography on silica gel (cyclohexane/ethyl
acetate, 7:3) to afford (E)-6-(benzyloxy)hex-2-en-4-ynal (8.95 g,
90%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3):
d¼9.58 (d,
J¼7.5 Hz, 1H), 7.38–7.31 (m, 5H), 6.65 (dt, J¼16.0, 1.0 Hz, 1H), 6.48
4.2. Ethyl (E)-6-(benzyloxy)hex-2-en-4-ynoate (5a)
(dd, J¼16.0, 7.5 Hz, 1H), 4.63 (s, 2H), 4.40 (d, J¼1.0 Hz, 2H). 13C NMR
(100 MHz, CDCl3):
d
¼192.9, 139.8, 136.9, 131.7, 128.5, 128.0, 100.3,
To a solution of ester 4a19 (20.0 g, 98.0 mmol) in dry diethyl
ether (200 mL) was added slowly DIBAH (108 mL, 108 mmol, 1 M in
n-hexane) at ꢀ100 ꢁC. In a second flask ethyl (diethoxyphosphoryl)
acetate (28.5 g, 127 mmol) dissolved in dry THF (60 mL) was added
to a suspension of NaH (5.09 g, 127 mmol, 60% in paraffin oil) in THF
(100 mL). The solution was warmed to room temperature, stirred
for additional 30 min, then cooled to ꢀ80 ꢁC and transferred via
Teflon tube to the other flask. The mixture was warmed to room
temperature and stirred for 18 h. After adding saturated aqueous
citric acid/NaH2PO4, the layers were separated and extracted with
diethyl ether; the combined organic layers were dried over MgSO4.
The solvents were removed in vacuo and the crude product was
purified by column chromatography on silica gel (cyclohexane/
ethyl acetate, 10:1/7:3) to afford enynoate 5a (22.6 g, 94%, E/
Z¼47:1 by GC and NMR analysis). 1H NMR (400 MHz, CDCl3):
82.8, 72.0, 57.7. IR (neat):
n
¼2848, 2734, 2210,1686, 1605, 961 cmꢀ1
.
HRMS (FAB): calcd for C13H12O2 [M]þ: m/z¼200.0837; found:
m/z¼200.0845; calcd for C13H13O2 [MþH]þ: m/z¼201.0916; found:
m/z¼201.0913.
4.4.3. (E)-7-(Benzyloxy)hept-3-en-5-yn-2-ol (rac-6a)
A
solution of (E)-6-(benzyloxy)hex-2-en-4-ynal (3.65 g,
18.2 mmol) in dry THF (150 mL) was cooled to ꢀ80 ꢁC and MeMgCl
(9.1 mL, 27.3 mmol, 3 M in THF) was added dropwise. The reaction
mixture was warmed for 3 h to 0 ꢁC and saturated NH4Cl solution
was added. The layers were separated, the aqueous layer was
extracted with ethyl acetate, and the combined organic layers were
dried over MgSO4. The solvents were removed in vacuo and the
crude product was purified by column chromatography on silica gel
(cyclohexane/ethyl acetate, 8:2/6:4) to afford alcohol rac-6a
d
¼7.38–7.31 (m, 5H), 6.81 (dt, J¼16.1, 1.6 Hz, 1H), 6.26 (d, J¼16.1 Hz,
(3.67 g, 93%) as a colorless oil. 1H NMR (500 MHz, CDCl3):
d¼7.37–
1H), 4.62 (s, 2H), 4.35 (d, J¼1.6 Hz, 2H), 4.23 (q, J¼7.1 Hz, 2H),1.31 (t,
7.30 (m, 5H), 6.21 (dd, J¼15.9, 5.6 Hz, 1H), 5.75 (dd, J¼15.9, 1.5 Hz,
J¼7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3):
¼165.7, 137.0, 130.9,
d
1H), 4.62 (s, 2H), 4.36 (m,1H), 4.30 (d, J¼1.5 Hz,1H),1.94 (s,1H, OH),
128.5, 128.1, 128.0, 124.4, 94.3, 83.3, 71.8, 60.8, 57.7, 14.2. IR (neat):
1.29 (d, J¼6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
¼147.2, 137.3,
d
n
¼2287, 1720, 1622, 1354, 1304, 1267, 1181, 1091, 961 cmꢀ1. HRMS
128.4, 128.0, 127.8, 108.4, 85.7, 84.3, 71.5, 68.0, 57.8, 22.9. IR (neat):
(FAB): calcd for C15H17O3 [MþH]þ: m/z¼245.1178; found: m/z
n
¼3385, 2858, 2214, 1454, 1354, 1071, 958 cmꢀ1. HRMS (FAB): calcd
¼245.1179.
for C14H15O2 [MꢀH]þ: m/z¼215.1072; found: m/z¼215.1047.
4.5. (E)-8-(Benzyloxy)oct-3-en-5-yn-2-ol (rac-6b)
4.3. Ethyl (E)-7-(benzyloxy)hept-2-en-4-ynoate (5b)
Analogous to the synthesis of 5a: ester 4b20 (15.8 g, 72.4 mmol),
DIBAH (80 mL, 80 mmol, 1 M in n-hexane), diethyl ether (200 mL),
ethyl (diethyloxyphosphoryl)acetate (18.9 mL, 94 mmol), NaH
(3.77 g, 94 mmol, 60% in paraffin), and THF (150 mL) afforded
enynoate 5b (17.2 g, 92%, E/Z¼99:1 by GC and NMR analysis) as
a pale yellow oil. Spectroscopic data: see Supplementary data in
Ref. 18.
4.5.1. (E)-7-(Benzyloxy)hept-2-en-4-yn-1-ol
Analogous to the synthesis of (E)-6-(benzyloxy)hex-2-en-4-yn-
1-ol, LiAlH4 (3.80 g, 100 mmol), diethyl ether (200 mL), and
enynoate 5b (12.9 g, 50 mmol) afforded (E)-7-(benzyloxy)hept-2-
en-4-yn-1-ol (9.80 g, 91%) as colorless solid. Mp 34 ꢁC. 1H NMR
(400 MHz, CDCl3):
d
¼7.37–7.28 (m, 5H), 6.18 (dt, J¼15.8, 5.3 Hz,1H),
5.72 (dt, J¼15.8, 1.8 Hz, 1H), 4.57 (s, 2H), 4.15 (d, J¼4.8 Hz, 2H), 3.61
(t, J¼7.0 Hz, 2H), 2.64 (dt, J¼7.0, 1.5 Hz, 2H), 2.07 (s, 1H, OH). 13C
4.4. (E)-7-(Benzyloxy)hept-3-en-5-yn-2-ol (rac-6a)
NMR (100 MHz, CDCl3):
d¼140.9, 137.9, 128.3, 127.6, 127.6, 110.6,
87.5, 79.3, 72.9, 68.2, 62.7, 20.7. IR (KBr):
n
¼3358, 2216, 1408, 1089,
4.4.1. (E)-6-(Benzyloxy)hex-2-en-4-yn-1-ol
953 cmꢀ1. HRMS (FAB): calcd for C14H15O2 [MꢀH]þ: m/z¼215.1072;
found: m/z¼215.1106; calcd for C14H16O2 [M]þ: m/z¼216.1150;
found: m/z¼216.1125.
A suspension of LiAlH4 (4.66 g, 123 mmol) in dry diethyl ether
(200 mL) was cooled to ꢀ80 ꢁC and enynoate 5a (15.0 g, 61.4 mmol)

F. Volz et al. / Tetrahedron 65 (2009) 1902–1910
1907
4.5.2. (E)-7-(Benzyloxy)hept-2-en-4-ynal
4.8. (R,R,R)-1-(3-(3-(Benzyloxy)prop-1-ynyl)oxiran-2-
yl)ethanol (ent-7a)
Analogous to the synthesis of (E)-6-(benzyloxy)hex-2-en-4-
ynal, MnO2 (91.9 g, 1.06 mol), CH2Cl2 (300 mL), and (E)-7-(benzyl-
oxy)hept-2-en-4-yn-1-ol (7.62 g, 35.3 mmol) afforded (E)-7-(ben-
Analogous to the synthesis of (R)-6a and 7a, Ti(Oi-Pr)4 (0.40 mL,
1.34 mmol),
zyloxy)hept-2-en-4-ynal (6.67 g, 88%) as a pale yellow oil. 1H NMR
D
-(ꢀ)-DET (0.28 mL, 1.61 mmol), TBHP (0.71 mL,
3
(400 MHz, CDCl3):
d
¼9.54 (d, JHH¼7.8 Hz, 1H, 1-H), 7.39–7.29 (m,
2.01 mmol, 2.85 M in PhMe), CH2Cl2 (10 mL), and alcohol (R)-6a
(290 mg, 1.34 mmol) afforded after 4 days reaction time at ꢀ20 ꢁC
and purification by column chromatography on silica gel (cyclo-
5H), 6.60 (dt, J¼15.8, 2.3 Hz, 1H), 6.41 (dd, J¼15.8, 7.8 Hz, 1H), 4.58
(s, 2H), 3.65 (t, J¼6.8 Hz, 2H), 2.76 (dt, J¼6.8, 2.0 Hz, 2H). 13C NMR
(100 MHz, CDCl3):
d
¼193.4, 139.2, 137.7, 133.4, 128.4, 127.7, 127.6,
hexane/ethyl acetate, 6:4) epoxide ent-7a (255 mg, 82%) as color-
20
103.5, 78.5, 73.0, 67.5, 21.4. IR (neat):
n
¼2864, 2734, 2217, 1685,
less oil. [
a
]
ꢀ4.2 (c 1.345, CHCl3).
D
1605, 1454, 1122, 961 cmꢀ1. HRMS (FAB): calcd for C14H15O2
[MþH]þ: m/z¼215.1072; found: m/z¼215.1101.
4.9. (R,R,R)-1-(3-(4-(Benzyloxy)but-1-ynyl)oxiran-2-
yl)ethanol (ent-7b)
4.5.3. (E)-8-(Benzyloxy)oct-3-en-5-yn-2-ol (rac-6b)
Analogous to the synthesis of rac-6a, MeMgCl (12 mL,
36.4 mmol, 3 M in THF), THF (200 mL), and (E)-7-(benzyloxy)hept-
2-en-4-ynal (5.20 g, 24.3 mmol) afforded rac-6b (5.42 g, 97%) as
colorless oil. Spectroscopic data: see Supplementary data in Ref. 18.
Analogous to the synthesis of (R)-6a and 7a, Ti(Oi-Pr)4 (1.81 mL,
6.1 mmol),
D
-(ꢀ)-DET (1.25 mL, 7.3 mmol), TBHP (3.2 mL, 9.1 mmol,
2.85 M in PhMe), CH2Cl2 (15 mL), and alcohol (R)-6b (1.40 g,
6.1 mmol) affordedafter6 daysat ꢀ20 ꢁC and purification bycolumn
chromatography on silica gel epoxide (cyclohexane/ethyl acetate,
20
6:4) ent-7b (1.22 g, 81%) as colorless oil. [
a
]
ꢀ5.1 (c 1.315, CHCl3).
D
4.6. (R,E)-7-(Benzyloxy)hept-3-en-5-yn-2-ol ((R)-6a)
and (S,S,S)-1-(3-(3-(benzyloxy)prop-1-ynyl)oxiran-2-yl)-
ethanol (7a)
4.10. (2S,3R,5R)-7-(Benzyloxy)-6-methylhepta-4,5-
dien-2,3-diol (8)
A solution of Ti(Oi-Pr)4 (6.88 mL, 23.1 mmol) in dry CH2Cl2
To a suspension of CuCN (2.69 g, 30 mmol) in dry THF (100 mL)
was added dropwise a solution of (PhO)3P (7.84 mL, 30 mmol) in
THF (10 mL). The mixture was stirred at room temperature until the
solution was homogeneous and then cooled to ꢀ80 ꢁC. MeMgCl
(10 mL, 30 mmol, 3 M in THF) was added dropwise, the mixture
was warmed to ꢀ30 ꢁC for 30 min and then recooled to ꢀ80 ꢁC. A
solution of propargyl oxirane 7a (2.33 g, 10 mmol) in THF (10 mL)
was added and the reaction mixture was warmed up gradually
within 4 h to ꢀ20 ꢁC. Saturated aqueous NH4Cl solution was added
and the mixture was stirred vigorously. After 1 h 10% aqueous NH3
(10 mL) was added in one portion and the mixture was stirred until
the color of the reaction mixture turned dark blue (2 h). The layers
were separated, the aqueous layer was extracted with ethyl acetate,
the combined organic layers were dried over MgSO4 and concen-
trated in vacuo. The crude product was purified by column chro-
(40 mL) was cooled to ꢀ30 ꢁC and
-(þ)-DET (4.75 mL, 27.7 mmol)
L
was added dropwise. After 30 min a solution of alcohol rac-6a
(5.0 g, 23.1 mmol) in CH2Cl2 (5 mL) was added dropwise, the re-
action mixture was stirred for additional 30 min, and subsequently
TBHP (4.22 mL, 12.0 mmol, 2.85 M in PhMe) was added. The re-
action mixture was left in the freezer for 14 days at ꢀ20 ꢁC and then
a solution of tartaric acid (10.4 g, 69.4 mmol) and FeSO4$7H2O
(12.0 g, 43.3 mmol) in H2O (37 mL) was added. The mixture was
stirred with gradual warming from ꢀ30 ꢁC to room temperature
over 1 h. The layers were separated, the aqueous layer extracted
with CH2Cl2, and the combined layers were concentrated in vacuo.
The crude product was dissolved in diethyl ether (100 mL), the
solution was cooled to 0 ꢁC and aqueous 0.75 M NaOH (110 mL) was
added with vigorously stirring. After 1.5 h the layers were sepa-
rated, the aqueous layer was extracted with diethyl ether, and the
combined layers were concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (cyclohexane/
ethyl acetate, 8:2/6:4/2:1) to afford alcohol (R)-6a (1.88 g, 38%)
matography on silica gel (cyclohexane/ethyl acetate, 1:1) to afford
20
dihydroxyallene 8 (2.31 g, 93%) as colorless oil. [
a]
þ11.4 (c 1.345,
D
CHCl3). 1H NMR (500 MHz, CDCl3):
d
¼7.36–7.30 (m, 5H), 5.33 (m,
J¼6.1, 2.6 Hz, 1H), 4.54 (d, J¼2.7 Hz, 2H), 4.03 (dd, J¼6.1 Hz, 1H),
3.98 (d, J¼2.4 Hz, 2H), 3.84 (m, 1H), 2.50 (s, 2H, OH), 1.75 (d,
J¼2.7 Hz, 3H), 1.14 (d, J¼6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
and epoxide 7a (2.18 g, 41%), both as a colorless oils. Compound (R)-
20
6a: [
a
]
þ7.8 (c 1.215, CHCl3). HPLC assay: Chiralcel OD-H, n-hep-
D
tane/isopropanol 95:5, flow 1 mL minꢀ1, detection by UV at 220,
d
¼201.3, 137.7, 128.4, 127.9, 127.8, 100.1, 91.5, 73.3, 72.2, 70.9, 70.2,
230 nm, tR¼22.0 min (S-enantiomer, minor), tR¼23.9 min (R-en-
18.1, 15.8. IR (neat):
n
¼3405, 1969, 1072, 1028 cmꢀ1. HRMS (FAB):
20
antiomer, major), 99% ee. Compound 7: [
a
]
þ5.3 (c 1.340, CHCl3).
D
calcd for C15H21O3 [MþH]þ: m/z¼249.1491; found: m/z¼249.1469.
1H NMR (400 MHz, CDCl3):
d
¼7.37–7.30 (m, 5H), 4.59 (s, 2H), 4.21
(d, J¼1.3 Hz, 2H), 4.01 (dq, J¼6.3, 2.5 Hz, 1H), 3.51 (d, J¼1.0 Hz, 1H),
4.11. (1S,20R,50S)-1-(5-((Benzyloxy)methyl)-2,5-dihydro-5-
methylfuran-2-yl)ethanol (9)
3.21 (t, J¼2.5 Hz, 1H), 2.05 (s, 1H, OH), 1.29 (d, J¼2.5 Hz, 3H). 13C
NMR (100 MHz, CDCl3):
d
¼137.1, 128.4, 128.0, 127.9, 82.5, 80.3, 71.8,
63.9, 63.1, 57.2, 41.6, 18.4. IR (neat):
n
¼3424, 2864, 2360, 1354, 1264,
To a solution of dihydroxyallene 8 (2.31 g, 9.3 mmol) in dry THF
(93 mL) was added at room temperature AuCl3 (56 mL, 9.3 mmol,
0.1664 M in MeCN). After 30 min the solvent was removed in vacuo
and the crude product was purified by column chromatography on
silica gel (cyclohexane/ethyl acetate, 8:2/7:3) to afford dihy-
882 cmꢀ1. HRMS (FAB): calcd for C14H15O3 [MꢀH]þ: m/z¼231.1021;
found: m/z¼231.0996.
4.7. (R,E)-8-(Benzyloxy)oct-3-en-5-yn-2-ol ((R)-6b) and
(S,S,S)-1-(3-(4-(benzyloxy)but-1-ynyl)oxiran-2-yl)ethanol (7b)
drofuran 9 (2.23 g, 96%, dr >99:1 by GC and NMR analysis) as col-
20
orless oil. [
a]
þ71.5 (c 1.430, CHCl3). 1H NMR (400 MHz, CDCl3):
D
Analogous to the synthesis of (R)-6a and 7a, Ti(Oi-Pr)4 (7.8 mL,
d
¼7.37–7.28 (m, 5H), 5.87 (d, J¼6.2 Hz, 1H), 5.80 (dd, J¼6.2, 1.4 Hz,
26.1 mmol),
L
-(þ)-DET (5.4 mL, 31.3 mmol), TBHP (5.0 mL,
1H), 4.82 (d, J¼1.4 Hz, 1H), 4.60 (dd, J¼12.5 Hz, 2H), 4.02 (dq, J¼6.8,
1.4 Hz, 1H), 3.47 (dd, J¼10.0 Hz, 2H), 1.19 (s, 3H), 1.17 (d, J¼6.8 Hz,
14.3 mmol, 2.85 M in PhMe), CH2Cl2 (45 mL), and alcohol rac-6b
(6.0 g, 26.1 mmol) afforded alcohol (R)-6b (2.61 g, 43%) and epoxide
3H). 13C NMR (100 MHz, CDCl3):
d
¼137.0, 133.9, 128.4, 127.9, 127.8,
20
7b (2.71 g, 42%) both as colorless oils. Compound (R)-6b: [
a
]
þ6.6
125.3, 90.3, 89.1, 74.5, 73.2, 68.6, 23.8, 18.1. IR (neat):
n¼3439, 2972,
D
20
(c 1.440, CHCl3). Compound 7b: [
a
]
D
þ4.0 (c 1.295, CHCl3). Spec-
2864, 1453, 1367, 1102, 1054, 1026, 915 cmꢀ1. HRMS (FAB): calcd for
troscopic data: see Supplementary data in Ref. 18.
C15H21O3 [MþH]þ: m/z¼249.1491; found: m/z¼249.1479.

1908
F. Volz et al. / Tetrahedron 65 (2009) 1902–1910
4.12. (2R,5S)-2-(5-((Benzyloxy)methyl)-2,5-dihydro-5-
4.13.2. (1S,5R)-1,4,4-Trimethyl-3,8-dioxabicyclo[3.2.1]-
methylfuran-2-yl)propan-2-ol (10)
octan-2-one (11)
IBX (3.57 g, 12.7 mmol) was dissolved in DMSO (15 mL) and the
mixture was stirred until the solution was homogenous. (2R,5S)-2-
(Tetrahydro-5-(hydroxymethyl)-5-methylfuran-2-yl)propan-2-ol
(1.11 g, 6.37 mmol) was added and the reaction mixture was stirred
for 18 h at room temperature. Ethyl acetate (20 mL) and saturated
NaHCO3 solution were added, the layers were separated, the
aqueous layer was extracted with ethyl acetate and the combined
organic layers were dried over MgSO4. The solvents were removed
in vacuo and the crude product was purified by column chroma-
4.12.1. (2R,5S)-(5-((Benzyloxy)methyl)-2,5-dihydro-5-methylfuran-
2-yl)ethanone
Dess–Martin periodinane (4.52 g, 10.7 mmol) was dissolved in
CH2Cl2 (50 mL). NaHCO3 (896 mg, 10.7 mmol) was added, fol-
lowed by dihydrofuran 9 (1.32 g, 5.33 mmol). The mixture was
stirred at room temperature for 9 h. Ethyl acetate (10 mL) was
added and the mixture was filtered through a CeliteÒ/silica gel
pad. Saturated aqueous NaHCO3 was added, the layers were
separated and the organic layer was concentrated in vacuo. The
crude product was purified by column chromatography on silica
gel (cyclohexane/ethyl acetate, 8:2) to afford (2R,5S)-(5-((benzy-
tography on silica gel (cyclohexane/ethyl acetate, 8:2) to lactone 11
20
(885 mg, 82%) as colorless solid. Mp 84 ꢁC. [
a
]
ꢀ22.9 (c 1.215,
D
20
CHCl3); literature value for the (1R,5S)-enantiomer:8c
1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
¼4.09 (d, J¼7.3 Hz, 1H),
2.23–2.04 (m, 3H),1.84–1.74 (m,1H),1.55 (s, 3H),1.52 (s, 3H),1.30 (s,
3H). 13C NMR (100 MHz, CDCl3):
¼171.8, 84.9, 80.6, 79.7, 36.5, 27.1,
23.9, 23.8, 19.6. IR (KBr):
[
a
]
þ40 (c
D
loxy)methyl)-2,5-dihydro-5-methylfuran-2-yl)-ethanone (1.24 g,
d
20
94%) as colorless oil. [
(400 MHz, CDCl3):
a]
þ183.2 (c 1.080, CHCl3). 1H NMR
D
d
¼7.37–7.29 (m, 5H), 5.91 (dd, J¼6.0, 2.8 Hz,
d
1H), 5.83 (dd, J¼6.0, 1.5 Hz, 1H), 5.13 (pt, J¼2.1 Hz, 1H), 4.58 (s,
n
¼2988, 1728, 1391, 1376, 1347, 1332, 1171,
2H), 3.53 (dd, J¼9.7 Hz, 2H), 2.22 (s, 3H), 1.35 (s, 3H). 13C NMR
1154, 1129, 1082, 1026 cmꢀ1. HRMS (FAB): calcd for C9H15O3
[MþH]þ: m/z¼171.1021; found: m/z¼171.1049. HPLC assay: Chir-
alpak AD, n-heptane/isopropanol 98.5:1.5, flow 1 mL minꢀ1, de-
tection by UV at 230 nm, tR¼9.0 min (1R,5S-enantiomer, minor),
tR¼9.8 min (1S,5R-enantiomer, major), 97% ee.
(100 MHz, CDCl3):
d
¼209.5, 138.0, 134.2, 128.3, 127.6, 127.5, 125.3,
91.8, 91.0, 75.9, 73.4, 25.7, 23.3. IR (neat):
n¼2858, 1716, 1095,
910 cmꢀ1
.
HRMS (FAB): calcd for C15H19O3 [MþH]þ: m/
z¼247.1334; found: m/z¼247.1320.
4.12.2. (2R,5S)-2-(5-((Benzyloxy)methyl)-2,5-dihydro-5-
methylfuran-2-yl)propan-2-ol (10)
4.14. (2S,5R)-5-(1-Hydroxy-1-methylethyl)-2-methyl-2-
vinyltetrahydrofuran ((2S,5R)-(D)-linalool oxide, 1)
A
solution of (2R,5S)-(5-((benzyloxy)methyl)-2,5-dihydro-5-
methylfuran-2-yl)-ethanone (1.16 g, 4.70 mmol) in dry THF (50 mL)
was cooled to ꢀ80 ꢁC and MeMgCl (2.35 mL, 7.05 mmol, 3 M in
THF) was added dropwise. The reaction mixture was warmed
gradually to room temperature for 6 h. Saturated aqueous NH4Cl
was added, the layers were separated, the aqueous layer was
extracted with ethyl acetate, and the combined organic layers were
dried over MgSO4. The solvents were removed in vacuo and the
crude product was purified by column chromatography on silica gel
4.14.1. (1S,5R)-1,4,4-Trimethyl-3,8-dioxabicyclo[3.2.1]-octan-2-ol
A solution of lactone 11 (600 mg, 3.5 mmol) in dry diethyl ether
(50 mL) was cooled to ꢀ110 ꢁC and DIBAH (3.5 mL, 3.5 mmol,1 M in
n-hexane) was added in one portion. After 5 min saturated NH4Cl
solution was added and the mixture was warmed to room tem-
perature. The layers were separated, the aqueous layer was
extracted with diethyl ether and the combined organic layers were
dried over MgSO4. The solvent was removed in vacuo and the crude
product was purified by column chromatography on silica gel (cy-
clohexane/ethyl acetate, 8:2) to afford (1S,5R)-1,4,4-trimethyl-3,8-
dioxabicyclo[3.2.1]-octan-2-ol (519 mg, 85%, dr¼83:17 by NMR
analysis) as colorless solid. Mp 74 ꢁC. 1H NMR (500 MHz, CDCl3):
(cyclohexane/ethyl acetate, 7:3) to afford tertiary alcohol 10 (1.09 g,
20
88%, dr >99:1 by GC and NMR analysis) as colorless oil. [
a
]
þ25.1
D
(c 1.230, CHCl3). 1H NMR (400 MHz, CDCl3):
d
¼7.37–7.28 (m, 5H),
5.91 (dd, J¼6.0, 1.0 Hz, 1H), 5.79 (dd, J¼6.3, 2.3 Hz, 1H), 4.68 (dd,
J¼2.3, 1.5 Hz, 1H), 4.59 (s, 2H), 3.45 (dd, J¼9.9 Hz, 2H), 1.31 (s, 3H),
d
¼4.81
OH), 2.16–1.98n (m, 3H), 1.90–1.84n (m, 1H), 1.52, 1.40
1.29 (s, 3H), 1.12
, 1.07 (s, 3H). 13C NMR (125 MHz, CDCl3):
, 82.8, 81.5 , 33.6, 27.6 , 27.3, 25.3
, 80.9n, 80.3, 77.5
, 25.6 , 24.7, 21.0, 20.3 . IR (KBr):
*
, 4.55 (s, 1H), 3.92, 3.76
*
(d, J¼7.0 Hz, 1H), 3.26
*
, 3.09 (s, 1H,
(s, 3H), 1.33,
¼96.0,
, 26.1,
1.20 (s, 6H). 13C NMR (100 MHz, CDCl3):
d
¼137.2, 133.3, 128.4, 128.0,
*
127.8, 127.0, 92.5, 89.2, 74.6, 73.2, 71.3, 27.5, 25.5, 23.9. IR (neat):
*
*
d
n
¼3438, 1454, 1370, 1162, 1089, 1041 cmꢀ1. HRMS (FAB): calcd for
94.4
*
*
*
*
*
*
C16H23O3 [MþH]þ: m/z¼263.1647; found: m/z¼263.1631.
23.0
*
*
n
¼3327, 2945, 1372,
1135, 1123, 1102, 989 cmꢀ1. HRMS (FAB): calcd for C9H15O3 [MꢀH]þ:
m/z¼171.1021; found: m/z¼171.1003; calcd for C9H17O3 [MþH]þ:
m/z¼173.1178; found: m/z¼173.1150.
4.13. (1S,5R)-1,4,4-Trimethyl-3,8-dioxabicyclo[3.2.1]-octan-2-
one (11)
4.14.2. (2S,5R)-5-(1-Hydroxy-1-methylethyl)-2-methyl-2-
4.13.1. (2R,5S)-2-(Tetrahydro-5-(hydroxymethyl)-5-methylfuran-2-
yl)propan-2-ol
vinyltetrahydrofuran ((2S,5R)-(þ)-linalool oxide, 1)
To a solution of CeCl3 (385 mg,1.56 mmol) in dry THF (4 mL) was
added dropwise at room temperature trimethylsilylme-
thylmagnesium chloride (8.5 mL, 9.4 mmol, 1.1 M in THF). After 1 h
(1S,5R)-1,4,4-trimethyl-3,8-dioxabicyclo[3.2.1]-octan-2-ol (90 mg,
0.52 mmol) was added and the reaction mixture was stirred for
18 h at room temperature. Saturated NH4Cl solution was added, the
layers were separated, the aqueous layer was extracted with diethyl
ether, the combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude product was dissolved in dry THF
(1 mL) and added with stirring to a cooled suspension (0 ꢁC) of KH
(31 mg, 0.78 mmol; the commercially available suspension of KH
was washed with hexane before use to remove the paraffin oil) in
THF (1 mL). After 10 min saturated NH4Cl was added slowly. The
layers were separated, the organic layer was extracted with diethyl
ether, and the combined organic layers were dried over MgSO4.
The solvents were removed in vacuo and the crude product was
A mixture of dihydrofuran 10 (970 mg, 3.70 mmol) and 10% Pd/C
(776 mg) in ethyl acetate (80 mL) was equipped with an H2-ballon
and stirred vigorously for 18 h. The reaction mixture was filtered
through a CeliteÒ pad and the solvent was removed in vacuo. The
crude product was purified by column chromatography on silica gel
(cyclohexane/ethyl acetate, 7:3) to afford (2R,5S)-2-(tetrahydro-5-
(hydroxymethyl)-5-methylfuran-2-yl)propan-2-ol (525 mg, 81%)
20
as colorless oil. [
CDCl3):
a
]
D
þ1.3 (c 1.150, CHCl3). 1H NMR (400 MHz,
d
¼3.86 (t, J¼7.4 Hz, 1H), 3.51 (dd, J¼11.2 Hz, 2H), 2.47 (s, 1H,
OH), 2.11–2.04 (m, 1H), 2.02–1.87 (m, 2H), 1.71–1.64 (m, 1H), 1.28 (s,
3H), 1.20 (s, 3H), 1.14 (s, 3H). 13C NMR (100 MHz, CDCl3):
83.6, 71.8, 69.5, 34.1, 27.7, 27.0, 25.1, 23.9. IR (neat):
d
¼85.4,
n
¼3385,
1266, 1110, 1063 cmꢀ1. HRMS (FAB): calcd for C9H17O3 [MꢀH]þ:
m/z¼173.1178; found: m/z¼173.1204; calcd for C9H18O3 [M]þ:
m/z¼174.1256; found: m/z¼174.1246.

F. Volz et al. / Tetrahedron 65 (2009) 1902–1910
1909
purified by column chromatography on silica gel (pentane/diethyl
the reaction mixture was warmed to 0 ꢁC for 3 h. Saturated aqueous
NH4Cl solution was added and the mixture was stirred vigorously.
After 1 h 10% aqueous NH3 solution (10 mL) was added and the
mixture was stirred until the color of the reaction mixture turned
dark blue (2 h). The layers were separated, the aqueous layer was
extracted with ethyl acetate, the combined organic layers were
dried over MgSO4 and the solvents were removed in vacuo. The
crude product was purified by column chromatography on silica gel
20
ether, 8:2) to afford 1 (81 mg, 91%) as a colorless oil. [
a
]
þ11.3 (c
D
20
0.065, CHCl3); literature value:7 [
(500 MHz, CDCl3):
a]
þ4.0 (c 0.028, CHCl3). 1H NMR
D
d
¼5.97 (dd, J¼17.5, 10.8 Hz, 1H), 5.19 (dd, J¼17.5,
1.3 Hz, 1H), 5.00 (dd, J¼10.8, 1.3 Hz, 1H), 3.85 (m, 1H), 2.09 (s, 1H,
OH), 1.95–1.75 (m, 4H),1.31 (s, 3H),1.23 (s, 3H), 1.12 (s, 3H). 13C NMR
(125 MHz, CDCl3):
25.9, 24.3. IR (neat):
d
¼144.2, 111.5, 85.5, 82.7, 71.1, 37.8, 27.4, 26.4,
n
¼3454, 3086, 2974, 1643, 1173, 1058, 1033,
992, 889 cmꢀ1. GC–MS: 171 (1) [MþH]þ, 155 (5), 137 (10), 119 (3),
109 (2), 97 (9), 94 (10), 93 (32), 91 (80), 81 (7), 79 (100), 77 (44), 67
(55), 65 (20), 59 (13), 55 (23). GC assay: Lipodex G: start temper-
ature: 50 ꢁC for 1 min, then 1 ꢁC/min to 140 ꢁC, 60 kPa H2, tR¼25.9
(2R,5S-enantiomer, minor), tR¼26.3 (2S,5R-enantiomer, major),
97% ee.
(cyclohexane/ethyl acetate, 1:1) to afford dihydroxyallene 17
20
(205 mg, 93%) as colorless oil. [
a
]
ꢀ79.1 (c 1.530, CHCl3). HPLC
D
assay: Chiralpak AD, n-heptane/isopropanol 95:5, flow 1 mL minꢀ1
,
detection by UV at 210 nm, tR¼18.1 min (R,R-enantiomer, minor),
tR¼20.8 min (S,S-enantiomer, major), >98% ee. Spectroscopic data:
see Supplementary data in Ref. 18.
4.15. (2S,3R)-(3-(4-(Benzyloxy)but-1-ynyl)oxiran-2-
4.18. (2S,5S)-2-(5-(2-(Benzyloxy)ethyl)-2,5-dihydro-5-
yl)ethanone (15)
methylfuran-2-yl)propan-2-ol (14)
Analogous to the synthesis of 10, DMP (2.07 g, 4.9 mmol),
NaHCO3 (410 mg, 4.9 mmol), CH2Cl2 (25 mL), and ent-7b (600 mg,
2.4 mmol) afforded after 5 h at room temperature and purification
Analogous to the synthesis of 9, AuCl3 (15 ml, 2.54 mmol,
0.1664 M in MeCN), THF (51 mL), and dihydroxyallene 31 (1.40 g,
5.1 mmol) afforded after 10 min at room temperature and purifi-
cation by column chromatography on silica gel (cyclohexane/ethyl
by column chromatography on silica gel (cyclohexane/ethyl acetate,
20
7:3) ketoepoxide 15 (533 mg, 89%) as colorless oil. [
a
]
D
þ10.8 (c
acetate, 7:3) dihydrofuran 14 (1.36 g, 97%, dr¼98:2 by GC and NMR
20
1.205, CHCl3). HPLC assay: Chiralpak AD, n-heptane/isopropanol
95:5, flow 1 mL minꢀ1, detection by UV at 215 nm, tR¼10.6 min
(2R,3S-enantiomer, minor), tR¼11.9 min (2S,3R-enantiomer, major),
>98% ee. Spectroscopic data: see Supplementary data in Ref. 18.
analysis) as colorless oil. [
a]
ꢀ61.8 (c 1.545, CHCl3). HPLC assay:
D
Chiralpak AD, n-heptane/isopropanol 95:5, flow 1 mL minꢀ1, de-
tection by UV at 215 nm, tR¼8.2 min (R,R-enantiomer, minor),
tR¼10.6 min (S,S-enantiomer, major), >98% ee. Spectroscopic data:
see Supplementary data in Ref. 18.
4.16. (2S,3R)-2-(3-(4-(Benzyloxy)but-1-ynyl)oxiran-2-
yl)propan-2-ol (16)
4.19. (2S,5R)-2-(Tetrahydro-5-(2-hydroxyethyl)-5-
methylfuran-2-yl)propan-2-ol (18)
A solution of 15 (2.54 g, 10.4 mmol) in dry THF (200 mL) was
cooled to ꢀ80 ꢁC and MeMgCl (5.2 mL, 15.6 mmol, 3 M in THF) was
added dropwise. The reaction mixture was warmed to ꢀ20 ꢁC for
7 h and saturated NH4Cl solution was added slowly. The layers were
separated, the aqueous layer was extracted with ethyl acetate, and
the combined organic layers were dried over MgSO4. The solvent
was removed in vacuo and the crude product was purified by col-
umn chromatography on silica gel (cyclohexane/ethyl acetate,
Analogous to the synthesis of 11, 10% Pd/C (600 mg), ethyl ace-
tate (70 mL), and dihydrofuran 14 (800 mg, 2.9 mmol) afforded
after 18 h at room temperature and purification by column chro-
matography (ethyl acetate) tetrahydrofuran 18 (416 mg, 76%) as
20
colorless oil. [
a]
ꢀ7.4 (c 1.325, CHCl3). GC assay: Lipodex G: start
D
temperature: 100 ꢁC for 1 min, then 2 ꢁC/min to 200 ꢁC, 60 kPa H2,
tR¼16.1 (2S,5R-enantiomer, major), tR¼16.3 (2R,5S-enantiomer,
minor), >98% ee. Spectroscopic data: see Supplementary data in
Ref. 18.
8:2/6:4) to afford tertiary alcohol 16 (2.63 g, 97%) as colorless oil.
20
[
a]
ꢀ1.2 (c 1.250, CHCl3). HPLC assay: Chiralcel OD-H, n-heptane/
D
isopropanol 95:5, flow 1 mL minꢀ1, detection by UV at 210 nm,
tR¼19.3 min (2S,3R-enantiomer), tR¼23.9 min (2R,3S-enantiomer),
>98% ee. Spectroscopic data: see Supplementary data in Ref. 18.
4.20. (2R,5S)-(Tetrahydro-5-(2-hydroxypropan-2-yl)-2-
methylfuran-2-yl)acetaldehyde (19)
4.17. (3S,5S)-8-(Benzyloxy)-2,6-dimethylocta-4,5-diene-2,3-
diol (17)
Analogous to the synthesis of 10, DMP (900 mg, 2.1 mmol),
NaHCO3 (179 mg, 2.1 mmol), CH2Cl2 (20 mL), and tetrahydrofuran
18 (200 mg, 1.1 mmol) afforded after 12 h at room temperature and
4.17.1. From (2S,3R)-2-(3-(4-(Benzyloxy)but-1-ynyl)-oxiran-2-
yl)propan-2-ol (16)
purification by chromatography on silica gel (cyclohexane/ethyl
acetate, 9:1/8:2) aldehyde 19 (197 mg, 99%) as colorless oil. [a]
D
20
Analogous to the synthesis of 8, CuCN (1.46 g, 16.3 mmol),
(PhO)3P (4.3 mL, 16.3 mmol), THF (200 mL), MeMgCl (5.4 mL,
16.3 mmol, 3 M in THF), and propargyl oxirane 16 (1.42 g,
5.4 mmol) afforded dihydroxyallene 17 (1.48 g, 98%) as colorless oil.
ꢀ15.8 (c 1.335, CHCl3). Spectroscopic data: see Supplementary data
in Ref. 18.
4.21. (2S,5R)-2-(-5-((9H-Pyrido[3,4-b]indol-1-yl)-methyl)-
tetrahydro-5-methylfuran-2-yl)propan-2-ol ((L)-
isocyclocapitelline, 2)
4.17.2. From (2S,3R)-(3-(4-(Benzyloxy)but-1-ynyl)-oxiran-2-
yl)ethanone (15)
To a suspension of CuCN (213 mg, 2.4 mmol) in dry THF (50 mL)
was added dropwise (PhO)3P (0.62 mL, 2.4 mmol) dissolved in dry
THF (2 mL). The mixture was stirred until the solution was ho-
mogenous and cooled to ꢀ80 ꢁC. MeMgCl (0.79 mL, 2.4 mmol, 3 M
in THF) was added dropwise, the mixture was warmed to ꢀ30 ꢁC
for 30 min and then recooled to ꢀ80 ꢁC. Ketoepoxide 15 (194 mg,
0.8 mmol) dissolved in THF (3 mL) was added and the reaction
mixture was warmed gradually to ꢀ20 ꢁC over 3 h. MeMgCl
(1.6 mL, 4.8 mmol, 3 M in THF) was added at this temperature and
A solution of tryptamine (103 mg, 0.64 mmol) and aldehyde 19
(120 mg, 0.64 mmol) in dry CH2Cl2 (15 mL) was cooled to ꢀ80 ꢁC
and trifluoroacetic acid (0.95 mL, 1.28 mmol) was added dropwise.
With stirring, the reaction mixture was warmed to room temper-
ature within 3 h, and saturated NaHCO3 solution was added. The
layers were separated, the aqueous layer was extracted with CH2Cl2
and the combined organic layers were dried over MgSO4. The sol-
vent was removed in vacuo and the crude product was dissolved in
xylenes (15 mL). 10% Pd/C (300 mg) was added and the reaction

1910
F. Volz et al. / Tetrahedron 65 (2009) 1902–1910
mixture was refluxed for 7 h. It was filtered through a CeliteÒ pad,
which was rinsed with CH2Cl2. The solvents were removed in vacuo
and the crude product was purified by column chromatography
De Montes, C. C.; Jacobs, P. A. Tetrahedron Lett. 1998, 39, 8521–8524; (g) Har-
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S.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 3963–3964; (i) Me´ou, A.; Bouanah,
N.; Archelas, A.; Zhang, X. M.; Guglielmetti, R.; Furstoss, R. Synthesis 1990, 752–
753; (j) Me´ou, A.; Bouanah, N.; Archelas, A.; Zhang, X. M.; Guglielmetti, R.;
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(ethyl acetate) on silica gel to afford 2 (110 mg, 53%) as a pale yellow
20
solid. Mp 197 ꢁC. [
a
]
ꢀ92.4 (c 0.525, CHCl3); literature value:10
D
20
[
a]
ꢀ75 (c 0.50, CHCl3). HPLC assay: Chiralpak AD, n-heptane/
D
isopropanol 92:8, flow 1 mL minꢀ1, detection by UV at 254 nm,
tR¼9.5 min (2R,5S-enantiomer, minor), tR¼11.9 min (2S,5R-enan-
tiomer, major), >98% ee. Spectroscopic data: see Supplementary
data in Ref. 18.
9. (a) Mischitz, M.; Faber, K. Synlett 1996, 978–980; (b) Duan, S.; Moeller, K. D. Org.
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Mahboobi, S.; Koller, M.; Schollmeyer, D. Monatsh. Chem. 2000, 131, 383–392;
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14. A stereoisomeric tetrahydrofuran is found in the natural product glaciapyrrole
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4.22. (2S,5R)-2-(Tetrahydro-5-methyl-5-((2-methyl-2H-
pyrido[3,4-b]indol-1-yl)methyl)furan-2-yl)propan-2-ol ((L)-
isochrysotricine, 3)
A solution of 2 (33 mg, 0.10 mmol) and MeI (9.4 ml, 0.15 mmol) in
acetone (5 mL) was refluxed for 6 h. The solvent was removed in
vacuo and the crude product was dissolved in CHCl3 (10 mL).
Aqueous 2 M NaOH (5 mL) was added and the mixture was stirred
for 1 h at room temperature. The layers were separated, the aque-
ous layer was extracted with CHCl3, the combined organic layers
were dried over MgSO4 and the solvent was removed in vacuo. The
crude product was filtered through a short CeliteÒ/silica gel column
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Chem. Commun. 2007, 333–346; (e) Gorin, D. J.; Toste, F. D. Nature 2007, 446,
395–403; (f) Fu¨rstner, A.; Davis, P. W. Angew. Chem. 2007, 119, 3478–3519;
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2008, 14, 5382–5391; (j) Shen, H. C. Tetrahedron 2008, 64, 3885–3903; (k)
Skouta, R.; Li, C.-J. Tetrahedron 2008, 64, 4917–4938; (l) Muzart, J. Tetrahedron
2008, 64, 5816–5849; (m) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–
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¨
(eluation with CH2Cl2) to afford 3 (34 mg, quant.) as a pale yellow
20
solid. Mp 159 ꢁC. [
a
]
ꢀ38.4 (c 1.020, MeOH), no literature value
D
reported. Spectroscopic data: see Supplementary data in Ref. 18.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft and the
European Community for financial support of our work.
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