First total synthesis of (R,R,R)- and (3R,5S,9R)-bejarol by gold-catalyzed allene cycloisomerization and determination of absolute configuration of the natural product

Article abstract of DOI:10.1039/b807733a

The first total synthesis of (R,R,R)-bejarol and its (3R,5S,9R)-isomer has been accomplished which confirms the absolute configuration of the natural products. The key step is the gold-catalyzed cycloisomerization of the enantiomerically pure β-hydroxyall

Full text of DOI:10.1039/b807733a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
First total synthesis of (R,R,R)- and (3R,5S,9R)-bejarol by gold-catalyzed
allene cycloisomerization and determination of absolute configuration of the
natural product
Yoshinari Sawama, Yuka Sawama and Norbert Krause*
Received 7th May 2008, Accepted 11th June 2008
First published as an Advance Article on the web 11th July 2008
DOI: 10.1039/b807733a
The first total synthesis of (R,R,R)-bejarol and its (3R,5S,9R)-isomer has been accomplished which
confirms the absolute configuration of the natural products. The key step is the gold-catalyzed
cycloisomerization of the enantiomerically pure b-hydroxyallenes 12/13 to the corresponding
dihydropyrans 14/15.
Introduction
The bejarols 1 are sesquiterpenoid components of the essential
oil which was first isolated from Santolina oblongifolia in 1983.
The initial structural assignment consisted of a 2,5-dihydrofuran
1a
core that was later corrected in favor of a chiral dihydropyran
2
bearing two unsaturated side chains (Fig. 1). Whereas the relative
Scheme
1
Gold-catalyzed cycloisomerization of a- or b-hetero-
configuration was assigned by NMR spectroscopy, the absolute
configuration has not been determined so far. Due to the presence
of a stereogenic center in the allylic alcohol side chain, four chiral
diastereomers are possible. To the best of our knowledge, no total
synthesis of 1 has been reported so far.
substituted allenes to 5- and 6-membered heterocycles.
synthesis of two bejarol stereoisomers which also confirms the
absolute configuration of the natural products.
Results and discussion
Since the absolute configuration of the bejarols is unknown, we
randomly selected (R,R,R)-1 as target molecule. The key step was
envisaged to be the formation of the dihydropyran ring by gold-
catalyzed cycloisomerization of a b-hydroxyallene which should
ꢀ
be accessible by copper-mediated S
N
2 -substitution of a suitable
5–7
propargyl electrophile. Our approach started with the formation
of the stereogenic center at C3 by Sharpless dihydroxylation of the
protected homoallylic alcohol 2 with AD-mix-b which afforded
8
diol 3 with high yield and enantiomeric excess (Scheme 2). A
single recrystallization gave enantiomerically pure material that
was converted into alcohol 4 by ketalization with cyclohexanone
and oxidative cleavage of the PMP group. Oxidation of 4 with
Dess–Martin periodinane afforded the C2–C5 fragment 5 with
high yield.
Fig. 1 Structure of diastereomeric bejarols 1.
Based on our continued interest in the stereoselective synthesis
9
3
and transformation of functionalized allenes, we have recently
4
developed the gold-catalyzed cycloisomerization of allenes bear-
ing a hydroxy, amino, or thiol group in the a-position, to the
5
corresponding five-membered heterocycles, a method that com-
bines high reactivity and excellent axis-to-center chirality transfer
with a tolerance towards many functional groups (Scheme 1).
Moreover, b-hydroxyallenes were also found to undergo a regio-
and stereoselective 6-endo-cycloisomerization to the correspond-
ing 5,6-dihydro-2H-pyrans in the presence of a gold(I) or gold(III)
6
precatalyst. Our methods have already proven to be highly useful
7
in target-oriented synthesis, and we now disclose the first total
Organic Chemistry II, Dortmund University of Technology, D-44227,
Dortmund, Germany. E-mail: norbert.krause@tu-dortmund.de; Fax: +49
2
31 7553884; Tel: +49 231 7553882
Scheme 2 Synthesis of the C2–C5 fragment 5.
This journal is © The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3573–3579 | 3573

View Article Online
Next, the C6–C12 section of the target molecule was assem-
bled by reaction of propargylzinc bromide with 3-methylbut-
7 and 8 are easily separable by column chromatography on silica
gel, and each of them was converted with good yield into the
2
-enal which gave the secondary alcohol rac-6 with 82% yield
propargyl acetate 9 by acetylation with Ac
conditions.
2
O, or under Mitsunobu
10
15
(
Scheme 3). The kinetic resolution of rac-6 was efficiently
achieved using Novozyme lipase A from Candida antarctica (NZL-
Allene formation by treatment of 9 with the magnesium cuprate
11
12
3d,16
1
01-LYO) which afforded enantiomerically pure alcohol (R)-6
obtained from MeMgCl, CuI and LiBr in THF
gave allenes 10
with 44% yield. Protection with TBSCl was followed by addition of
and 11 with a good chemical yield of 78% (22% of 9 was recovered),
but the diastereoselectivity (anti : syn = 3 : 2) was low, which
indicates considerable epimerization of the allene by the copper
species (Table 1, entry 1). The addition of phosphorus ligands,
which has been used previously to prevent copper-promoted
the lithium acetylide to aldehyde 5 which gave the diastereomeric
13
alcohols 7 and 8 with 59% and 28% yield, respectively. The
assignment of the relative configuration at C3 and C5 is based
on the conversion of 7 into 1, and it is also in line with the
preferred formation of the 1,3-anti product that is often observed
3d,16
epimerizations of allenes,
or using CuBr·Me
2
S instead of CuI,
14
in alkynylations of chiral 3-alkoxyaldehydes. The diastereomers
increased the diastereoselectivity up to 9 : 1, but only at the cost
of unacceptable chemical yields (entries 2–5). A fast reaction was
observed with the Gilman cuprate Me
a 1 : 1-mixture of allenes 10–11 and the corresponding reduced
2
CuLi·LiI, but it provided
allene bearing a hydrogen atom instead of the methyl group at
3d
C7 (entry 6). This undesired reduction was suppressed with n-
Bu P or (EtO) P (entries 7, 8), but the reactivity of these modified
cuprate reagents was again insufficient. The same is true for the
cyano-Gilman reagent Me
CuLi·LiCN (entry 9), as well as the
copper reagent formed from MeLi, CuI, and LiBr (entry 10).
Variation of the solvent (Et O instead of THF) or the leaving group
t-BuOCO or Ts instead of Ac) did not improve this situation.
Therefore, we continued our synthesis with the 3 : 2-mixture
3
3
2
2
(
of allenes 10–11 obtained (Table 1, entry 1). Neither these silyl
ethers nor the b-hydroxyallenes 12–13 obtained after deprotection
could be separated chromatographically (Scheme 4). The gold-
catalyzed cycloisomerization of the 3 : 2-mixture of 12–13 was
carried out in the presence of 5 mol% of the cationic catalyst
6
formed in situ from Ph
3
PAuCl and AgBF
4
. In toluene, the reaction
proceeded smoothly within 10 min at room temperature to afford
the desired dihydropyrans 14 and 15 with high yield; however,
the diastereomeric heterocycles 16–17, which are a result of an
epimerization of the allylic alcohol side chain, were obtained as
byproducts with 16% total yield. This undesired side reaction
could be prevented by decreasing the reaction temperature, or
5c
by using THF as the solvent; the latter conditions afforded 14
and 15 with 50% and 35% yield, respectively. These isomers could
be easily separated by silica gel column chromatography. Since
Scheme 3 Synthesis of the C6–C12 fragment 6 and coupling with
aldehyde 5.
Table 1 Copper-mediated S
N
2ꢀ-substitution of propargyl acetate 9
Entry
Cuprate
Additive
Temp.
Time
Yield (%)
10 : 11
◦
1
2
3
4
5
6
7
8
9
MeMgCl–CuI–LiBr
MeMgCl–CuI–LiBr
MeMgCl–CuI–LiBr
MeMgCl–CuI–LiBr
—
n-Bu
(EtO)
(PhO)
—
—
n-Bu
(EtO)
—
0 C–rt
5 h
21 h
5 h
21 h
5 h
10 min
20 h
5 h
78
30
13
20
12
60 : 40
65 : 35
90 : 10
70 : 30
90 : 10
—
85 : 15
60 : 40
80 : 20
70 : 30
◦
3
P
0 C–rt
◦
3
P
0 C–rt
◦
3
P
0 C–rt
◦
MeMgCl–CuBr Me
2
S–LiBr
0 C–rt
◦
a
Me
Me
Me
Me
2
2
2
2
CuLi·LiI
CuLi·LiI
CuLi·LiI
CuLi·LiCN
−40 C
40
◦
3
P
−40 C–rt
10
26
9
◦
3
P
−40 C–rt
◦
0 C–rt
5 h
2 h
◦
1
0
MeLi–CuI–LiBr
—
0 C–rt
13
a
4
0% of the reduced allene was obtained as byproduct.
3
574 | Org. Biomol. Chem., 2008, 6, 3573–3579
This journal is © The Royal Society of Chemistry 2008

View Article Online
The discrepancy may indicate that the natural product was not
isolated in pure form.
Conclusion
We have achieved the first diastereo- and enantioselective total
synthesis of (R,R,R)- and (3R,5S,9R)-bejarol, which is also
the first application of the gold-catalyzed cycloisomerization of
b-hydroxyallenes to 5,6-dihydro-2H-pyrans in natural product
synthesis. The absolute configuration of naturally occurring threo-
cis-bejarol was confirmed to be (S,S,S), whereas natural erythro-
trans-1 has the (3S,5R,9S)-configuration. Our modular approach
can be easily adapted to the synthesis of any stereoisomeric bejarol.
Due to the mildness and carbophilicity of the gold catalyst, labile
functionalities such as acetals are tolerated, clearly demonstrating
the utility of homogeneous gold catalysis for the synthesis of
complex target molecules. Further applications of our methods
will be reported in due course.
Experimental
General information
All reactions were performed in oven-dried glassware under argon.
Diethyl ether and THF were distilled from sodium–benzophenone.
Column chromatography was carried out with Merck silica gel
1
13
F 60 (70–230 mesh). H and C NMR spectra were recorded
Scheme 4 Gold-catalyzed cycloisomerization of b-hydroxyallenes 12–13
with Bruker DRX 400 and DRX 500 spectrometers at room
1
temperature in CDCl
3
as solvent and internal standard ( H NMR:
the product ratio is very similar to the ratio of the allenes 12–13,
1
3
d = 7.27; C NMR: d = 77.0). Carbon atoms were assigned with
it seems reasonable to assume that the cycloisomerization takes
6
APT experiments. IR spectra were measured with a Nicolet Avatar
place with complete axis-to-center chirality transfer.
3
20 FT-IR as a liquid film between NaCl plates or in the case of
Finally, either isomer was transformed into the corresponding
diastereo- and enantiomerically pure bejarol 1 by acetal cleavage,
oxidation of the primary alcohol to the aldehyde with Dess–
solids as KBr pellet. FAB mass spectra (HRMS) were measured
with a Jeol SX102A spectrometer.
9
Martin periodinane, and Wittig olefination (Scheme 5). The
spectroscopic data of synthetic (R,R,R)-1 and (3R,5S,9R)-1 are in
Synthetic procedures
1,2
excellent agreement with those reported for the natural products.
Comparison of the optical rotation of our product (R,R,R)-1
(
R)-4-(4-Methoxyphenyl)-2-methylbutane-1,2-diol (3). To
a
2
D
0
solution of homoallylic alcohol derivative 2 (5.48 g, 28.5 mmol)
in a 1 : 1-mixture of t-butanol and H
(
[a] = +53.2, c = 0.68, CHCl
3
2
) with that reported for naturally
0
1a
2
O (285 mL) was added
occurring threo-cis-bejarol ([a] = −41.4, c = 0.756, CHCl
3
)
D
◦
AD-mix-b (39.9 g) at 4 C under air. After being stirred at
confirms that the absolute configuration of the natural product is
◦
4
C for 16 h, the reaction mixture was quenched with Na
2
SO
3
(
S,S,S). For the (3R,5S,9R)-isomer, we have determined a rotation
◦
2
0
and stirred for 30 min at 4 C. After extraction with CH
the organic layer was washed with brine, dried with Na
and concentrated under vacuum. The residue was purified by
column chromatography using cyclohexane–AcOEt (1 : 3) to give
2
Cl
2
,
of [a] = +65.1 (c = 0.53, CHCl
3
) whereas the literature value for
D
2
0
1a
2
SO
4
,
natural erythro-trans-bejarol is [a] = −9.5 (c = 1.1, CHCl
3
).
D
3
(6.29 g, 27.6 mmol, 97%, 96% ee). After recrystallization from
cyclohexane–AcOEt, enantiomerically pure 3 (5.78 g, 24.8 mmol,
0%, >99% ee) was obtained. The ee was determined by chiral
HPLC: chiralcel AD; i-PrOH : n-heptane = 10 : 90; flow rate,
.2 mL min ; room temperature; retention time, (R)-3 14.0 min,
9
−
1
1
2
D
0
(
(
S)-3 12.9 min. Colorless solid; [a] = −8.0 (c = 2.00, CHCl
3
). IR
−
1
1
neat) cm : 3252, 2919, 1511, 1469, 1243; H NMR (400 MHz,
CDCl ) d: 6.84 (4H, s), 4.02–4.22 (2H, m), 3.76 (3H, s), 3.53 (1H,
3
d, J = 11.0 Hz), 3.46 (1H, d, J = 11.0 Hz), 2.75 (2H, brs), 2.08 (1H,
ddd, J = 14.8, 7.5, 4.8 Hz), 1.90 (1H, ddd, J = 14.8, 6.3, 4.8 Hz),
1
3
1
1
.24 (3H, s); C NMR (100 MHz, CDCl ) d: 154.2, 152.4, 115.6,
3
14.8, 72.5, 70.1, 65.4, 55.8, 37.6, 21.2; EI-HRMS m/z: 226.1199
(M ); Calcd for C12
+
Scheme 5 Final steps towards (R,R,R)- and (3R,5S,9R)-bejarol.
This journal is © The Royal Society of Chemistry 2008
H
18
O
4
: 226.1200.
Org. Biomol. Chem., 2008, 6, 3573–3579 | 3575

View Article Online
(
R)-2-(2-Methyl-1,4-dioxaspiro[4.5]dec-2-yl)-ethanol (4). To a
(R)-6-Methylhept-5-en-1-yn-4-ol ((R)-6). To a solution of rac-
6 (1.39 g, 11.2 mmol) in vinyl acetate (12 mL) was added NZL-101-
LYO (485 mg) at room temperature under air. After being stirred
for 65 h, the reaction mixture was filtered and NZL-101-LYO
(417 mg, 86%) was recovered. The residue was concentrated under
vacuum and purified by column chromatography using n-pentane–
solution of diol 3 (4.00 g, 17.7 mmol) in cyclohexanone (50 mL)
was added p-TsOH (673 mg, 3.54 mmol) at room temperature
under argon. After being stirred for 5 min, the reaction mixture
was quenched with satd. aq. NaHCO
The organic layer was washed with brine, dried with Na
and concentrated under vacuum to give the crude cyclohexylidene
3
and extracted with AcOEt.
2
SO ,
4
2
Et O (4 : 1) to give (R)-6 (619 mg, 4.92 mmol, 44%, >99% ee).
ketal. This was dissolved in a 4 : 1-mixture of CH
3
CN and H
2
◦
O
C
The ee was determined by chiral GC: FS-LIPODEX E (octakis-
(2,6-di-O-pentyl-3-O-butyryl)-c-cyclodextrin); start temperature,
(
175 mL) and CAN (19.4 g, 35.4 mmol) was added at 0
◦
◦
−1
under air. After being stirred for 5 min, the reaction mixture was
quenched with satd. aq. NaHCO and extracted with Et O. The
organic layer was washed with brine, dried with Na SO , and
concentrated under vacuum. The residue was purified by column
chromatography using cyclohexane–Et O (1 : 1) to give 4 (3.30 g,
50 C; flow rate, 1.0 C min ; retention time, (R)-6 30.0 min,
2
0
3
2
(S)-6 28.6 min. Colorless oil; [a]D = +38.6 (c = 1.05, CHCl
R)-4-(tert-Butyldimethylsiloxy)-6-methylhept-5-en-1-yne. To
a solution of (R)-6 (350 mg, 2.81 mmol) in CH Cl (9 mL) were
added TBSCl (820 mg, 5.45 mmol), Et N (0.82 mL, 5.88 mmol)
3
).
2
4
(
2
2
2
2
D
0
3
1
6.5 mmol, 93%). Yellow oil; [a] = +11.2 (c = 0.66, CHCl
3
).
and DMAP (144 mg, 1.18 mmol) at room temperature under
argon. After being stirred for 21 h, the reaction mixture
−
1
1
IR (neat) cm : 3423, 2935, 2862, 1448, 1367, 1096; H NMR
(
(
2
400 MHz, CDCl
1H, d, J = 8.6 Hz), 3.76 (1H, d, J = 8.6 Hz), 3.79–3.70 (1H, m),
.89 (1H, brs), 1.91 (1H, ddd, J = 14.3, 8.8, 4.5 Hz), 1.72 (1H, ddd,
J = 14.3, 5.5, 3.8 Hz), 1.68–1.50 (8H, m), 1.48–1.30 (2H, m), 1.33
3H, s); C NMR (100 MHz, CDCl ) d: 110.4, 81.1, 74.4, 59.6,
1.0, 36.7, 36.4, 25.3, 25.1, 24.1, 23.9; EI-HRMS m/z: 200.1409
3
) d: 3.90 (2H, ddd, J = 11.0, 8.8, 3.8 Hz), 3.83
was quenched with H
organic layer was washed with brine, dried with Na
2
O and extracted with CH
2
Cl
SO
2
. The
, and
2
4
concentrated under vacuum. The residue was purified by column
chromatography using n-pentane–Et O (50 : 1) to give the silyl
1
3
2
(
4
(
3
2
0
ether (630 mg, 2.64 mmol, 94%). Colorless oil; [a] = +3.5 (c =
D
−
1
1
1
4
(
(
.15, CHCl ); IR (neat) cm : 3307, 2956, 2856, 1472, 1376,
3
+
M ); Calcd for C11
H
20
3
O : 200.1407.
1
254; H NMR (400 MHz, CDCl
3
) d: 5.14 (1H, d, J = 8.5 Hz),
.54–4.47 (1H, m), 2.38 (1H, ddd, J = 16.5, 6.4, 2.5 Hz), 2.26
(
R)-(2-Methyl-1,4-dioxaspiro[4.5]dec-2-yl)-acetaldehyde
(5).
1H, ddd, J = 16.5, 6.4, 2.5 Hz), 1.94 (1H, t, J = 2.5 Hz), 1.70
3H, s), 1.66 (3H, s), 0.87 (9H, s), 0.05 (3H, s), 0.02 (3H, s);
) d: 133.1, 128.0, 81.9, 69.3, 68.5, 28.7,
To a solution of 4 (412 mg, 2.05 mmol) in CH Cl (20 mL) was
2
2
1
3
C
added Dess–Martin periodinane (1.03 g, 2.42 mmol) at room
temperature under air, and the reaction mixture was heated up
NMR (100 MHz, CDCl
2
3
+
5.9, 25.8, 18.5, 18.3, −4.2, −4.6; EI-HRMS m/z: 238.1741 (M );
◦
to 40 C for 1 h. After cooling to rt, the reaction mixture was
Calcd for C14H26OSi: 238.1747.
quenched with satd. aq. NaHCO
The organic layer was washed with brine, dried with Na
concentrated under vacuum. The residue was purified by column
chromatography using cyclohexane–Et O (2 : 3) to give 5 (389 mg,
3
and extracted with CH
2
Cl
2
.
2
SO , and
4
(2R,6R)- and (2S,6R)-6-(tert-Butyldimethylsiloxy)-8-methyl-
1-[(2R)-2-methyl-1,4-dioxaspiro[4.5]-dec-2-yl]-non-7-en-3-yn-2-ol
(7–8). To a solution of (R)-4-(tert-butyldimethylsiloxy)-6-
methylhept-5-en-1-yne (360 mg, 1.37 mmol) in dry THF (8 mL)
was added n-BuLi (2.5 M in hexane; 0.77 mL, 0.77 mmol) at
2
2
D
0
1
.95 mmol, 95%). Yellow oil; [a] = +32.7 (c = 2.67, CHCl
3
);
−
1
1
IR (neat) cm : 2936, 2862, 1723, 1449, 1367, 1007; H NMR
◦
◦
(
(
400 MHz, CDCl
1H, d, J = 8.8 Hz), 2.68 (1H, dd, J = 15.6, 1.8 Hz), 2.54 (1H,
3
) d: 9.79 (1H, s), 3.82 (1H, d, J = 8.8 Hz), 3.75
−80 C under argon. After being stirred for 30 min at −80 C, to
reaction mixture was added the solution of 5 (272 mg, 1.51 mmol)
◦
dd, J = 15.6, 2.2 Hz), 1.70–1.42 (8H, m), 1.42–1.20 (2H, m), 1.34
3H, s); C NMR (100 MHz, CDCl ) d: 201.4, 110.4, 78.3, 73.7,
3.5, 36.6, 36.3, 25.7, 25.0, 23.9, 23.8; EI-HRMS m/z: 198.1205
in dry THF (6 mL) at −80 C under argon. After warming up to
1
3
◦
(
5
(
3
−40 C for 1 h, the reaction mixture was quenched with H
2
O
and extracted with Et
brine, dried with Na SO
residue was purified by column chromatography using CH
Et O (50 : 1) to give 7 (354 mg, 0.80 mmol, 59%) and 8 (170 mg,
2
O. The organic layer was washed with
, and concentrated under vacuum. The
Cl
+
M ); Calcd for C11
H
18
O
3
: 198.1250.
2
4
2
2
–
6
-Methylhept-5-en-1-yn-4-ol (rac-6). To a solution of zinc
2
17
20
D
powder (694 mg, 10.6 mmol, activated bytreatmentwith5%HCl )
0.38 mmol, 28%). 7: colorless oil; [a] = +10.2 (c = 1.02, CHCl
3
);
−
1
1
in dry THF (20 mL) was added propargyl bromide (80% in toluene;
IR (neat) cm : 3444, 2932, 2856, 1471, 1462, 1384; H NMR
◦
0
.93 mL, 8.36 mmol) at 0 C under argon. After being stirred for
(400 MHz, CDCl
3
) d: 5.10 (1H, d, J = 8.8 Hz), 4.61–4.35 (1H, m),
1
h, to reaction mixture was added a solution of 3-methylbut-2-
4.45 (1H, dd, J = 15.2, 6.5 Hz), 3.87 (1H, d, J = 8.3 Hz), 3.71 (1H,
d, J = 8.3 Hz), 2.83 (1H, brs), 2.39 (1H, ddd, J = 16.5, 6.5, 1.7
Hz), 2.27 (1H, ddd, J = 16.5, 6.5, 1.7 Hz), 2.01 (1H, dd, J = 14.8,
8.8 Hz), 1.95 (1H, dd, J = 14.8, 3.4 Hz), 1.69 (3H, s), 1.66–1.53
(8H, m), 1.64 (3H, s), 1.45–1.33 (2H, m), 1.34 (3H, s), 0.86 (9H, s),
◦
enal (370 mg, 4.40 mmol) in dry THF (10 mL) at 0 C under argon.
After being stirred for 15 min, the reaction mixture was filtered
through Celite, the filtrate was quenched with satd. aq. NaHCO
and extracted with Et O. The organic layer was washed with brine,
dried with Na SO , and concentrated under vacuum. The residue
was purified by column chromatography using cyclohexane–Et
3
2
1
3
2
4
0.04 (3H, s), 0.01 (3H, s); C NMR (100 MHz, CDCl ) d: 132.9,
3
2
O
128.1, 110.0, 82.6, 82.0, 80.3, 73.8, 68.6, 59.8, 46.6, 37.0, 36.4, 28.9,
(
3 : 1) to give rac-6 (448 mg, 3.60 mmol, 82%). Colorless oil; IR
26.3, 25.9, 25.8, 25.1, 24.1, 24.0, 18.6, 18.3, −4.2, −4.6; EI-HRMS
−
1
+
(
neat) cm : 3384, 3300, 2916, 2862, 2119, 1674, 1445, 1377, 1034;
m/z: 436.3008 (M ); Calcd for C25
H
44
O
4
Si: 436.3003. 8: colorless
1
20
−1
H NMR (400 MHz, CDCl
3
) d: 5.23 (1H, d, J = 8.6 Hz), 4.54–4.46
oil; [a]D = −18.5 (c = 1.00, CHCl
3
); IR (neat) cm : 3450, 2932,
1
(
1
1H, m), 2.43–2.33 (2H, m), 2.02 (1H, t, J = 2.5 Hz), 1.72 (3H, s),
2856, 1471, 1461, 1384; H NMR (400 MHz, CDCl
3
) d: 5.09 (1H,
1
3
.69 (3H, s); C NMR (100 MHz, CDCl
0.5, 66.8, 27.7, 25.8, 18.4.
3
) d: 136.8, 125.9, 80.9,
d, J = 8.8 Hz), 4.74–4.69 (1H, m), 4.47 (1H, dd, J = 15.0, 6.5 Hz),
7
3.83 (1H, d, J = 8.5 Hz), 3.76 (1H, d, J = 8.5 Hz), 3.75 (1H, brs),
3
576 | Org. Biomol. Chem., 2008, 6, 3573–3579
This journal is © The Royal Society of Chemistry 2008

View Article Online
1
3
2
1
2
.39 (1H, ddd, J = 16.6, 6.5, 1.8 Hz), 2.27 (1H, ddd, J = 16.6, 6.5,
.3 Hz), 2.04 (1H, dd, J = 14.2, 10.0 Hz), 1.80 (1H, dd, J = 14.2,
.6 Hz), 1.68 (3H, s), 1.68–1.49 (8H, m), 1.64 (3H, s), 1.42–1.34
0.85 (9H, s), 0.01 (3H, s), −0.01 (3H, s); C NMR (100 MHz,
CDCl ) d: 205.0, 204.7, 131.7, 131.6, 129.3, 109.9, 95.7, 95.4, 84.7,
84.5, 80.7, 80.6, 73.0, 72.9, 69.0, 68.9, 43.7, 43.3, 40.5, 40.4, 36.9,
36.8, 36.7, 26.0, 26.0, 25.8, 25.2, 25.1, 25.1, 24.0, 19.8, 19.5, 18.4,
18.4, 18.3, −4.0, −4.6; EI-HRMS m/z: 434.3211 (M ); Calcd for
3
1
3
(
2H, m), 1.33 (3H, s), 0.85 (9H, s), 0.04 (3H, s), 0.01 (3H, s); C
+
NMR (100 MHz, CDCl
3
) d: 132.8, 128.2, 110.8, 82.3, 81.8, 80.5,
74.9, 68.0, 60.7, 46.9, 36.4, 28.9, 25.9, 25.8, 25.1, 24.5, 24.0, 23.9,
C
26
H
46
3
O Si: 434.3210.
+
1
C
8.6, 18.3, −4.2, −4.6; EI-HRMS m/z: 436.2996 (M ); Calcd for
(
4R)-2,6-Dimethyl-9-[(2R)-2-methyl-1,4-dioxaspiro[4.5]dec-2-
25
H
44
O
4
Si: 436.3003.
yl]-nona-2,6,7-trien-4-ol (12–13). To a solution of a 3 : 2-mixture
of 10–11 (204 mg, 0.469 mmol) in dry THF (2.4 mL) was
added TBAF (1 M in THF; 0.66 mL, 0.66 mmol) at room
temperature under air. After being stirred for 12 h, the reaction
O and extracted with Et
organic layer was washed with brine, dried with Na
concentrated under vacuum. The residue was purified by column
chromatography using cyclohexane–AcOEt (3 : 1) to give a 3 :
-mixture of 12–13 (147 mg, 0.460 mmol, 98%). Colorless oil;
(
2R,6R)-6-(tert-Butyldimethylsiloxy)-8-methyl-1-[(2R)-2-
methyl-1,4-dioxaspiro[4.5]-dec-2-yl]-non-7-en-3-yn-2-yl acetate
9). To a solution of 7 (167 mg, 0.38 mmol) in CH Cl (2 mL)
N (70 ll, 0.50 mmol)
(
2
2
were added Ac
2
O (44 ll, 0.46 mmol), Et
3
mixture was quenched with H
2
2
O. The
, and
◦
and DMAP (3 mg, 0.02 mmol) at 0 C under air. After being
stirred for 30 min, the reaction mixture was quenched with satd.
aq. NH
washed with brine, dried with Na
vacuum. The residue was purified by column chromatography
2
SO
4
4
Cl and extracted with CH
2
Cl
2
. The organic layer was
2
SO
4
, and concentrated under
2
−1
1
IR (neat) cm : 3434, 2932, 2860, 1965, 1447, 1383; H NMR
400 MHz, CDCl ) d: 5.22–5.16 (1H, m), 5.11–5.01 (1H, m),
.52–4.44 (1H, m), 3.85–3.80 (1H, m), 3.67 (1H, d, J = 8.2 Hz),
.28–1.93 (4H, m), 1.73–1.66 (6H, m), 1.67 (3H, s), 1.65–1.51
using cyclohexane–AcOEt (15 : 1) to give 9 (162 mg, 0.340 mmol,
(
3
8
9%). Alternatively, to a solution of 8 (177 mg, 0.41 mmol)
4
2
(
in dry toluene (4 mL) were added Ph P (127 mg, 0.49 mmol),
AcOH (28 ll, 0.49 mmol) and DEAD (40% in toluene; 0.22 mL,
3
13
8H, m), 1.42–1.29 (2H, m), 1.29 (3H, s); C NMR (100 MHz,
CDCl ) d: 203.8, 203.7, 135.3, 135.0, 127.5, 127.4, 110.1, 110.0,
5.7, 95.7, 86.1, 86.0, 80.6, 80.4, 73.1, 73.1, 66.7, 66.6, 42.6, 42.5,
◦
0
.49 mmol) at −20 C under argon. After being stirred for 1.5 h,
3
the reaction mixture was quenched with satd. aq. NaHCO
extracted with AcOEt. The organic layer was washed with brine,
dried with Na SO , and concentrated under vacuum. The residue
3
and
9
4
2
0.5, 40.3, 36.8, 36.7, 36.6, 36.6, 25.8, 25.2, 25.2, 25.1, 24.9, 24.0,
4.0, 23.9, 19.7, 19.4, 18.3; EI-HRMS m/z: 320.2334 (M ); Calcd
+
2
4
was purified by column chromatography using cyclohexane–
AcOEt (20 : 1) to give 9 (160 mg, 0.336 mmol, 83%). Colorless
for C20
H
32
3
O : 320.2346.
2
0
−1
(2R)-2-Methyl-2-[(2R,6R)-4-methyl-6-(2-methylpropenyl)-5,6-
dihydro-2H-pyran-2-ylmethyl]-1,4-dioxaspiro[4.5]decane (14) and
2R)-2-methyl-2-[(2R,6S)-4-methyl-6-(2-methylpropenyl)-5,6-di-
hydro-2H-pyran-2-ylmethyl]-1,4-dioxaspiro[4.5]decane (15). To a
solution of a 3 : 2-mixture of 12–13 (52 mg, 0.162 mmol) in
PAuCl (4.0 mg, 0.008 mmol)
and AgBF (1.6 mg, 0.008 mmol) at room temperature under
argon. After being stirred for 2 h, the reaction mixture was
filtrated through Celite and the filtrate was concentrated under
vacuum The residue was purified by column chromatography
using cyclohexane–AcOEt (50 : 1) to give 14 (26 mg, 0.081 mmol,
oil; [a]D = +51.9 (c = 1.00, CHCl
3
); IR (neat) cm : 3155, 2935,
) d: 5.44 (1H,
1
2857, 1737, 1471, 1383; H NMR (400 MHz, CDCl
3
(
dd, J = 6.9, 6.0 Hz), 5.08 (1H, d, J = 8.8 Hz), 4.43 (1H, dd, J =
15.1, 6.4 Hz), 3.87 (1H, d, J = 8.5 Hz), 3.63 (1H, d, J = 8.5 Hz),
2.37 (1H, ddd, J = 16.3, 6.4, 1.5 Hz), 2.25 (1H, ddd, J = 16.3,
6.4, 1.8 Hz), 2.15–2.07 (2H, m), 2.03 (3H, s), 1.68 (3H, s), 1.63
dry THF (2.5 mL) was added Ph
3
(
(
1
3
3H, s), 1.65–1.51 (8H, m), 1.43–1.24 (2H, m), 1.25 (3H, s), 0.85
4
1
3
9H, s), 0.03 (3H, s), 0.00 (3H, s); C NMR (100 MHz, CDCl
3
) d:
69.7, 132.9, 128.0, 109.7, 83.4, 79.0, 78.9, 74.1, 68.5, 61.5, 45.3,
6.8, 36.6, 28.9, 25.9, 25.7, 25.2, 25.0, 24.1, 24.0, 21.2, 18.5, 18.2,
+
−
4.3, −4.7; EI-HRMS m/z: 463.2869 ( [M − CH
3
] ); Calcd for
2
D
0
5
0%) and 15 (18 mg, 0.057 mmol, 35%). 14: colorless oil; [a]
=
C
26
H
43
O
5
Si: 463.2874.
−
1
−
10.5 (c = 1.05, CHCl
3
); IR (neat) cm : 2933, 2861, 1677, 1447,
) d: 5.36 (1H, s), 5.18 (1H, d,
(
6R)-6-(tert-Butyldimethylsiloxy)-4,8-dimethyl-1-[(2R)-2-
methyl-1,4-dioxaspiro[4.5]dec-2-yl]-nona-2,3,7-triene (10–11).
To solution of CuI (4.90 g, 25.7 mmol) and LiBr (2.20 g,
1
1
376; H NMR (400 MHz, CDCl
3
J = 7.5 Hz), 4.22–4.11 (2H, m), 3.87 (1H, d, J = 8.8 Hz), 3.70 (1H,
d, J = 8.8 Hz), 2.02–1.92 (1H, m), 1.83–1.70 (3H, m), 1.71 (3H,
2
2
5.7 mmol) in dry THF (15 mL) was added MeMgCl (8.6 mL,
5.7 mmol, 3 M in THF) at 0 C under argon. After being stirred
s), 1.66 (3H, s), 1.64 (3H, s), 1.64–1.48 (8H, m), 1.42–1.30 (2H,
◦
13
m), 1.31 (3H, s); C NMR (100 MHz, CDCl
26.3, 124.4, 108.9, 80.1, 74.1, 71.9, 71.9, 46.3, 37.2, 36.5, 36.0,
5.8, 25.3, 24.5, 24.1, 24.0, 23.0, 18.6; EI-HRMS m/z: 320.2339
3
) d: 135.4, 132.4,
for 30 min, to the reaction mixture was added a solution of 9
1
◦
(
1.23 g, 2.57 mmol) in dry THF (11 mL) at 0 C under argon. After
2
being stirred for 5 h at room temperature, the reaction mixture
was quenched with satd. aq. NH Cl and extracted with Et O. The
organic layer was washed with brine, dried with Na SO , and
concentrated under vacuum. The residue was purified by column
chromatography using cyclohexane–AcOEt (50 : 1) to give a 3 :
+
20
D
(
M ); Calcd for C20
c = 0.92, CHCl
H NMR (400 MHz, CDCl
H
32
O
3
: 320.2346. 15: colorless oil; [a] = +18.2
4
2
−1
(
3
); IR (neat) cm : 2932, 2860, 1678, 1448, 1367;
2
4
1
3
) d: 5.34 (1H, s), 5.20 (1H, d, J = 8.3
Hz), 4.39–4.31 (2H, m), 4.09 (1H, d, J = 8.2 Hz), 3.64 (1H, d, J =
8
1
.2 Hz), 1.95–1.86 (3H, m), 1.76 (1H, d, J = 3.2 Hz), 1.71 (3H, s),
2
-mixture of 10 and 11 (868 mg, 2.00 mmol, 78%) as well as
.68 (6H, s), 1.65–1.50 (8H, m), 1.42–1.31 (2H, m), 1.30 (3H, s);
recovered starting material 9 (0.57 mmol, 22%). Colorless oil; IR
13
C NMR (100 MHz, CDCl ) d: 136.2, 131.5, 125.5, 124.2, 109.4,
0.1, 72.2, 68.8, 65.1, 43.1, 37.4, 36.2, 35.4, 27.5, 25.8, 25.2, 24.1,
4.0, 23.3, 18.5.
3
−
1
1
(neat) cm : 2932, 2856, 1965, 1448, 1366; H NMR (400 MHz,
8
2
CDCl ) d: 5.13–5.04 (1H, m), 4.96–4.92 (1H, m), 4.47–4.38 (1H,
3
m), 3.83 (1H, d, J = 8.3 Hz), 3.65 (1H, d, J = 8.3 Hz), 2.19 (2H,
d, 7.5 Hz), 2.19–2.09 (1H, m), 2.07–1.96 (1H, m), 1.67 (6H, s),
(R,R,R)-Bejarol ((R,R,R)-1). To a solution of 14 (37 mg,
1
.68–1.52 (8H, m), 1.61 (3H, s), 1.38–1.28 (2H, m), 1.28 (3H, s),
0.115 mmol) in MeOH (3 mL) was added p-TsOH (22 mg,
This journal is © The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3573–3579 | 3577

View Article Online
1
0
2
.115 mmol) at room temperature under air. After being stirred for
4 h, the reaction mixture was quenched with satd. aq. NaHCO
O. The organic layer was washed with brine,
, and concentrated under vacuum. The residue
was purified by column chromatography using cyclohexane–Et
1 : 5) to give the diol (23 mg, 0.098 mmol, 85%). Colorless oil;
1445, 1383; H NMR (400 MHz, CDCl
3
) d: 5.27 (1H, s), 5.19 (1H,
3
d, J = 8.2 Hz), 4.55 (1H, d, J = 11.0 Hz), 4.50 (1H, ddd, J =
10.5, 8.2, 4.8 Hz), 3.99 (1H, s), 3.41–3.33 (2H, m), 3.22 (1H, t, J =
6.5 Hz), 2.01–1.89 (3H, m), 1.79–1.60 (1H, m), 1.73 (3H, s), 1.71
(6H, s), 1.19 (3H, s); C NMR (100 MHz, CDCl
124.3, 123.0, 71.9, 70.6, 69.0, 65.7, 41.7, 35.2, 25.9, 24.9, 23.3, 18.4;
and extracted with Et
dried with Na SO
2
2
4
1
3
2
O
3
) d: 137.4, 132.0,
(
2
0
−1
+
[
1
a] = +9.8 (c = 1.02, CHCl
3
); IR (neat) cm : 3421, 2968, 2911,
) d: 5.24 (1H, s), 5.16 (1H,
EI-HRMS m/z: 240.1708 (M ); Calcd for C14
To a solution of the diol (13 mg, 0.054 mmol) in CH
H
24
O
3
: 240.1720.
Cl (1 mL)
D
1
445, 1382; H NMR (400 MHz, CDCl
3
2
2
d, J = 8.0 Hz), 4.36 (1H, s), 4.23 (1H, ddd, J = 10.5, 8.0, 3.3 Hz),
was added Dess–Martin periodinane (36 mg, 0.086 mmol) at room
temperature under air. After being stirred for 2 h, the reaction
3
.57 (1H, d, J = 11.0 Hz), 3.40 (1H, d, J = 11.0 Hz), 2.08–1.98
(
1
1H, m), 1.82–1.70 (3H, m), 1.71 (3H, s), 1.68 (3H, s), 1.66 (3H, s),
mixture was quenched with sat. NaHCO aq. and extracted
3
1
3
.16 (3H, s); C NMR (100 MHz, CDCl
3
) d: 136.7, 132.8, 125.3,
with CH
2
Cl
2
. The organic layer was washed with brine, dried
, and concentrated under vacuum. The residue was
1
23.5, 72.7, 72.6, 71.4, 69.6, 44.4, 35.8, 25.7, 25.1, 23.0, 18.5;
with Na SO
2
4
+
EI-HRMS m/z: 240.1716 (M ); Calcd for C14
H
24
O
3
: 240.1720.
Cl (1 mL)
purified by column chromatography using cyclohexane–Et
2
O (3 :
To a solution of the diol (23 mg, 0.096 mmol) in CH
2
2
1) to give the aldehyde (9 mg, 0.038 mmol, 70%). Colorless oil;
2
D
0
−1
was added Dess–Martin periodinane (53 mg, 0.125 mmol) at room
temperature under air. After being stirred for 2 h, the reaction
[a] = +7.8 (c = 0.55, CHCl
3
); IR (neat) cm : 3466, 2970, 2915,
) d: 9.46 (1H, s), 5.26 (1H,
1
1729, 1383; H NMR (400 MHz, CDCl
3
mixture was quenched with satd. aq. NaHCO
CH Cl . The organic layer was washed with brine, dried with
Na SO , and concentrated under vacuum. The residue was puri-
fied by column chromatography using cyclohexane–Et O (3 : 1) to
give the aldehyde (18 mg, 0.073 mmol, 79%). Colorless oil; [a]
3
and extracted with
s), 5.13 (1H, d, J = 8.0 Hz), 4.42–4.35 (1H, m), 3.90 (1H, s), 2.09
(1H, dd, J = 14.8, 10.7 Hz), 1.97 (1H, dd, J = 16.7, 2.7 Hz),
1.83 (1H, dd, J = 16.7, 6.6 Hz), 1.78–1.73 (1H, m), 1.72 (3H, s),
2
2
2
4
1
3
2
1.68 (6H, s), 1.25 (3H, s); C NMR (100 MHz, CDCl ) d: 203.1,
3
2
D
0
=
136.5, 132.4, 124.6, 122.4, 76.7, 67.5, 66.0, 42.1, 35.2, 25.8, 23.7,
1
+
+
44.1 (c = 1.02, CHCl
3
); H NMR (400 MHz, CDCl
3
) d: 9.73 (1H,
23.4, 18.4; EI-HRMS m/z: 238.1552 (M ); Calcd for C14
H
22
3
O :
s), 5.23 (1H, s), 5.16 (1H, d, J = 7.8 Hz), 4.36 (1H, s), 4.27 (1H, ddd,
238.1563.
+
−
J = 10.3, 8.0, 3.5 Hz), 2.06 (1H, dd, J = 14.6, 3.5 Hz), 2.02–1.95
To solution of Ph P MeBr (24 mg, 0.067 mmol) in dry THF
3
(
1H, m), 1.82–1.73 (2H, m), 1.71 (3H, s), 1.66 (3H, s), 1.64 (3H, s),
(0.5 mL) was added t-BuOK (67 lL, 0.067 mmol, 1 M in THF) at
1
3
◦
1
.22 (3H, s); C NMR (100 MHz, CDCl
3
) d: 206.1, 136.7, 133.0,
0 C under argon. After being stirred for 30 min, to the reaction
1
25.2, 122.7, 78.0, 72.6, 71.4, 43.2, 35.7, 25.7, 23.9, 22.9, 18.5;
mixture was added a solution of the aldehyde (8 mg, 0.034 mmol)
in dry THF (0.5 mL) at 0 C under argon. After being stirred for
5 h at room temperature, the reaction mixture was quenched with
+
◦
EI-HRMS m/z: 238.1559 (M ); Calcd for C14
H
22
O
3
: 238.1563.
+
−
To solution of Ph
3
P CH
3
Br (54 mg, 0.151 mmol) in dry THF
(
0.5 mL) was added t-BuOK (0.15 mL, 0.15 mmol, 1 M in
satd. aq. NH
washed with brine, dried with Na
vacuum. The residue was purified by column chromatography
using cyclohexane–Et O (10 : 1) to give (3R,5S,9R)-1 (7 mg,
4
Cl and extracted with Et
2
O. The organic layer was
, and concentrated under
◦
THF) at 0 C under argon. After being stirred for 30 min, to
reaction mixture was added a solution of the aldehyde (18 mg,
0
being stirred for 5 h at room temperature, the reaction mixture
was quenched with satd. aq. NH Cl and extracted with Et O. The
organic layer was washed with brine, dried with Na SO , and
concentrated under vacuum. The residue was purified by column
chromatography using cyclohexane–Et O (10 : 1) to give (R,R,R)-
2
SO
4
◦
.076 mmol) in dry THF (0.5 mL) at 0 C under argon. After
2
2
0
0.030 mmol, 88%). Colorless oil; [a] = +65.1 (c = 0.53, CHCl
3
);
D
−
1
1
4
2
IR (neat) cm : 3478, 2968, 2928, 2914, 1447, 1378; H NMR
2
4
(400 MHz, CDCl
3
) d: 5.89 (1H, dd, J = 17.4, 10.8 Hz), 5.28 (1H,
brs), 5.22 (1H, d, J = 17.4 Hz), 5.18 (1H, d, J = 8.2 Hz), 4.98 (1H,
d, J = 10.8 Hz), 4.54 (1H, d, J = 11.0 Hz), 4.50 (1H, ddd, J =
10.8, 8.2, 4.5 Hz), 4.12 (1H, brs), 2.01–1.93 (1H, m), 1.88 (1H, dd,
J = 14.5, 11.0 Hz), 1.75-1.68 (1H, m), 1.72 (6H, s), 1.70 (3H, s),
2
2
0
1
(17 mg, 0.072 mmol, 95%). Colorless oil; [a] = +53.2 (c = 0.68,
−1 1
3
D
CHCl
); IR (neat) cm : 3490, 2970, 2910, 1674, 1446, 1383; H
) d: 5.88 (1H, dd, J = 17.1, 10.8 Hz),
.33 (1H, d, J = 17.1 Hz), 5.17 (1H, brs), 5.09 (1H, dd, J = 10.8,
.6 Hz), 4.43 (1H, brs), 4.31 (1H, d, J = 10.5 Hz), 4.15 (1H, ddd,
1
3
NMR (500 MHz, CDCl
5
1
3
1.51 (1H, dd, J = 14.5, 2.3 Hz), 1.34 (3H, s); C NMR (100 MHz,
CDCl
43.7, 35.2, 26.6, 25.9, 23.3, 18.5; EI-HRMS m/z: 236.1771 (M );
Calcd for C14 : 236.1770.
3
) d: 145.8, 137.5, 131.9, 124.5, 122.9, 111.1, 72.6, 69.8, 65.5,
+
J = 10.5, 7.7, 3.3 Hz), 2.08–1.99 (1H, m), 1.81–1.74 (2H, m), 1.71
3H, s), 1.66 (6H, s), 1.59 (1H, dd, J = 14.6, 2.2 Hz), 1.22 (3H, s);
C NMR (100 MHz, CDCl ) d: 144.5, 137.2, 132.8, 125.5, 123.5,
12.5, 73.5, 73.4, 70.9, 46.1, 36.0, 29.6, 25.7, 23.0, 18.6; EI-HRMS
H
22
O
2
(
1
3
3
Acknowledgements
1
+
m/z: 259.1669 ([M + Na] ); Calcd for C15
H
24
2
O Na: 259.1668.
We thank the Deutsche Forschungsgemeinschaft and the Euro-
pean Community of financial support of our work.
(
3R,5S,9R)-Bejarol ((3R,5S,9R)-1). To a solution of 15
(
31 mg, 0.097 mmol) in MeOH (3 mL) was added p-TsOH (19 mg,
0
.097 mmol) at room temperature under air. After being stirred for
4 h, the reaction mixture was quenched with satd. aq. NaHCO
O. The organic layer was washed with brine,
, and concentrated under vacuum. The residue
was purified by column chromatography using cyclohexane–Et
1 : 5) to give the diol (19 mg, 0.082 mmol, 85%). Colorless oil;
References
2
3
1
(a) J. De Pascual Teresa, S. Vincente, M. S. Gonzalez and I. S.
Bellido, Phytochemistry, 1983, 22, 2235; (b) See also: P. Weyerstahl, H.
Marschall, K. Thefeld and A. Rustaiyan, Flavour Fragrance J., 1999,
and extracted with Et
dried with Na SO
2
2
4
1
4, 112; (c) M.-C. Blanc, P. Bradesi, M. J. Goncalves, L. Salgueiro and
2
O
J. Casanova, Flavour Fragrance J., 2006, 21, 324; (d) J. Pala-Paul, M. J.
Perez-Alonso, A. Velasco-Negueruela, A. M. Villa, E. Granda and J.
Sanz, J. Essent. Oil Res., 2007, 20, 65.
(
2
D
0
−1
[a] = +29.5 (c = 1.03, CHCl
3
); IR (neat) cm : 3425, 2967, 2913,
3
578 | Org. Biomol. Chem., 2008, 6, 3573–3579
This journal is © The Royal Society of Chemistry 2008

View Article Online
2
3
J. De Pascual Teresa, I. S. Bellido, M. S. Gonzalez and S. Vincente,
Phytochemistry, 1984, 23, 2064.
7 (a) F. Volz and N. Krause, Org. Biomol. Chem., 2007, 5, 1519; (b) J.
Erdsack and N. Krause, Synthesis, 2007, 3741.
8 (a) L. F. Tietze and J. G o¨ rlitzer, Synthesis, 1998, 873; (b) E. J. Corey,
A. Guzman-Perez and M. C. Noe, J. Am. Chem. Soc., 1995, 117,
10805.
9 (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155; (b) R. K.
Boeckmann, Jr. and J. J. Mullins, Org. Synth., 2000, 77, 141.
10 (a) N. Kurono, K. Sugita and M. Tokuda, Tetrahedron, 2000, 56, 847;
(b) A. Yanagisawa, S. Habaue and H. Yamamoto, J. Org. Chem., 1989,
54, 5198.
(a) Modern Allene Chemistry, ed. N. Krause and A. S. K. Hashmi,
Wiley-VCH, Weinheim, 2004; (b) R. Zimmer, C. U. Dinesh, E.
Nandanan and F. A. Khan, Chem. Rev., 2000, 100, 3067; (c) J. A.
Marshall, Chem. Rev., 2000, 100, 3163; (d) N. Krause and A. Hoffmann-
R o¨ der, Tetrahedron, 2004, 60, 11671; (e) S. Ma, Chem. Rev., 2005, 105,
2
829; (f) S. Ma, Pure Appl. Chem., 2006, 78, 197.
4
(a) Reviews: A. Hoffmann-R o¨ der and N. Krause, Org. Biomol. Chem.,
2
2
2
005, 3, 387; (b) R. A. Widenhoefer and X. Han, Eur. J. Org. Chem.,
006, 4555; (c) A. S. K. Hashmi and G. J. Hutchings, Angew. Chem.,
006, 118, 8064; A. S. K. Hashmi and G. J. Hutchings, Angew. Chem.,
11 Lipase NZL-101-LYO was purchased from BioCatalytics.
12 (a) The configuration of (R)-6 was determined by comparison with
the material obtained by Katsuki–Sharpless kinetic resolution of rac-6
Int. Ed., 2006, 45, 7896; (d) E. Jimenez-Nunez and A. M. Echavarren,
Chem. Commun., 2007, 333; (e) D. J. Gorin and F. D. Toste, Nature,
4
with t-BuOOH, (L)-(+)-DIPT, Ti(OiPr) : V. S. Martin, S. S. Woodard,
2
007, 446, 395; (f) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180;
T. Katsuki, Y. Yamada, M. Ikeda and K. B. Sharpless, J. Am. Chem.
Soc., 1981, 103, 6237; (b) Z.-M. Wang and W.-S. Zhou, Tetrahedron,
1987, 13, 2935.
(
g) A. F u¨ rstner and P. W. Davies, Angew. Chem., 2007, 119, 3478; A.
F u¨ rstner and P. W. Davies, Angew. Chem., Int. Ed., 2007, 46, 3410; (h) N.
Bongers and N. Krause, Angew. Chem., 2008, 120, 2208; N. Bongers
and N. Krause, Angew. Chem., Int. Ed., 2008, 47, 2178.
13 Attempts to apply Carreira’s enantioselective alkynylation: D. E.
Frantz, R. F a¨ ssler, C. S. Tomooka and E. M. Carreira, Acc. Chem.
Res., 2000, 33, 373 resulted in no conversion.
14 S. Guillarme, K. Pl e´ , A. Banchet, A. Liard and A. Haudrechy, Chem.
Rev., 2006, 106, 2355.
15 (a) O. Mitsunobu, Synthesis, 1981, 1; (b) D. L. Hughes and R. A.
Reamer, J. Org. Chem., 1996, 61, 2967.
16 (a) A. Jansen and N. Krause, Inorg. Chim. Acta, 2006, 359, 1761, and
references cited therein; (b) C. Zelder and N. Krause, Eur. J. Org. Chem.,
2004, 3968.
5
6
(a) A. Hoffmann-R o¨ der and N. Krause, Org. Lett., 2001, 3, 2537;
(
1
b) N. Krause, A. Hoffmann-R o¨ der and J. Canisius, Synthesis, 2002,
759; (c) C. Deutsch, B. Gockel, A. Hoffmann-R o¨ der and N. Krause,
Synlett, 2007, 1790; (d) N. Morita and N. Krause, Org. Lett., 2004, 6,
121; (e) N. Morita and N. Krause, Eur. J. Org. Chem., 2006, 8, 4634;
4
(
f) N. Morita and N. Krause, Angew. Chem., 2006, 118, 1930; N. Morita
and N. Krause, Angew. Chem., Int. Ed., 2006, 45, 1897.
(a) B. Gockel and N. Krause, Org. Lett., 2006, 8, 4485; (b) See also ref.
5
c.
17 M. S. Newman and F. J. Evans Jr., J. Am. Chem. Soc., 1955, 77, 946.
This journal is © The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3573–3579 | 3579