Pheromone synthesis, CCVIII: Synthesis of (1S,3S,7R)-3-methyl-α-himachalene, the sex pheromone of the sandfly Lutzomyia longipalpis from Jacobina, Brazil

Article abstract of DOI:10.1055/s-2000-8220

(1S,3S,7R)-3-Methyl-α-himachalene, the sex pheromone of the male sandfly (Lutzomyia longipalpis) from Jacobina, Brazil, was synthesized enantioselectively by employing Evans' or Oppolzer's asymmetric methylation and intramolecular Diels-Alder reaction as the two key steps. The absolute configuration of the product was unambiguously established by X-ray analysis of a compound related to one of the synthetic intermediates. The ring junction of this sandfly pheromone possesses the absolute configuration opposite to that of the known (1R,7R)-α-himachalene of plant origin.

Full text of DOI:10.1055/s-2000-8220

1
852
SPECIAL TOPIC
1
Pheromone Synthesis, CCVIII: Synthesis of (1S,3S,7R)-3-Methyl-a-
himachalene, the Sex Pheromone of the Sandfly Lutzomyia longipalpis from
2
Jacobina, Brazil
a
b
a
Takuya Tashiro, Masahiko Bando, Kenji Mori*
aDepartment of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan
bOtsuka Pharmaceutical Co., Ltd., Kawauchi, Tokushima 771-0192, Japan
Fax +81(3)32352214; E-mail:htakikaw@ch.kagu.sut.ac.jp
Received 6 July 2000
Abstract: (1S,3S,7R)-3-Methyl-a-himachalene, the sex pheromone
of the male sandfly (Lutzomyia longipalpis) from Jacobina, Brazil,
was synthesized enantioselectively by employing Evans’or Oppolz-
er’s asymmetric methylation and intramolecular Diels-Alder reac-
tion as the two key steps. The absolute configuration of the product
was unambiguously established by X-ray analysis of a compound
related to one of the synthetic intermediates. The ring junction of
this sandfly pheromone possesses the absolute configuration oppo-
site to that of the known (1R,7R)-a-himachalene of plant origin.
H
H
α-Himachalene
9-Methylgermacrene-B
(
1R,7R)-A
(S)-B
O
H
H
Key words: asymmetric synthesis, Diels-Alder reactions, Lut-
zomyia longipalpis, pheromones, terpenoids
H
H
3
-Methyl-α-himachalene
C (= 27)
(1S,3S,7R)-1
Introduction
O
HO2C
The sandfly Lutzomyia longipalpis is the vector of the
protozoan parasite Leishmania chagasi, the causative
agent of visceral leishmaniasis in South and Central
3
America. Population control of L. longipalpis is therefore
D (= 26)
E (= 14)
of urgent importance to prevent the disease. In 1994
Hamilton and his co-workers isolated the male-produced
sex pheromone of L. longipalpis from Jacobina, Brazil,4
and later proposed its structure as 3-methyl-a-
Bn
N
O
himachalene
{2-methylene-3,6,6,9-tetramethylbicyc-
O
O
lo[5.4.0]undec-8-ene (1, Scheme 1), stereochemistry un-
F (= 12)
1
5
known} on the basis of its MS and H NMR studies. a-
Himachalene (A) is a sesquiterpene isolated from Hima-
or
6
layan deodar Cedrus deodara, and its absolute configura-
N
tion is known as 1R,7R by CD studies of its degradation
products.
S
7
O
O2
G (= 16)
Meanwhile, the structure of the male-produced phero-
mone of L. longipalpis from Lapinha, Brazil, was pro-
posed as 9-methylgermacrene-B [(1E,5E)-1,5,10-
trimethyl-8-(1-methylethylidenyl)-1,5-cyclodecadiene
H
N
8
9
(
B)], and verified by our synthesis of its racemate. The
O
absolute configuration of B as S was clarified by our syn-
(
2R)-2
thesis of its enantiomers followed by their bioassay and
1
0,11
GC comparison with the natural pheromone.
The
Structure of 3-methyl-a-himachalene (1) and related compounds to-
gether with retrosynthetic analysis of 1
sandfly L. longipalpis thus uses homosesquiterpenes with
an extra methyl group as male-produced sex pheromones.
Scheme 1
As to the relative configuration of 3-methyl-a-him-
achalene (1), it was shown to be 1R*,3R*,7S* by our syn-
thesis of (±)-1 and its stereoisomers, followed by their
1
2
abled Pickett and his co-workers to assign 1S,3S,7R
configuration to the natural pheromone 1 based on bioas-
say and GC comparison of our synthetic samples with the
bioassays and GC comparison with the natural phero-
1
3
mone. Our recent preparation of the enantiomers of 1 en-
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
natural pheromone. In the previous preparative work of
1853
1
4
ref. 12
steps
Ph3P=CHCO2Et
1
4
HO
OH
TBSO
Mg
CHO
ours, we resolved (±)-C ( = 27) by preparative HPLC on
C6H6, reflux
89%
“
4
Chiralcel OD to give both the enantiomers of C (≥99%
3
4
ee). Their CD spectral analysis coupled with MM3 calcu-
lation to deduce their most stable conformation allowed us
to assign their absolute configuration on the basis of the
octant rule: the ketone C with a positive Cotton effect at
TBSO
CO Et
2
RO
CO Me
2
MeOH
7%
7
5
HF aq., MeCN
3%
6 R = TBS
7 R = H
9
2
96 nm was thought to be (1S,3S,7R)-C. Applicability of
CH =C(Me)CH PPh3+Cl
the octant rule to such a cycloheptanone system, however,
is uncertain. Accordingly, the assignment of 1S,3S,7R
configuration to natural 1 was not rigorous enough but
ambiguous, although the possible common course of bio-
synthesis of B and 1 including the configuration of the ex-
tra methyl group at C-3 strongly suggested the common
configuration at that position. We therefore decided to
achieve unambiguous and enantioselective synthesis of
the pheromone. This paper describes in detail the synthe-
Swern oxid.
3%
2
2
O
CO2Me
-
8
t-BuOK, THF
8
(
S)-4-Benzyl-2-oxazolidinone
CO2R
BuLi, THF
78%, two steps
KOH, MeOH
3%, two steps
9
R = Me
8
1
0 R = H
PivCl, Et3N, CH2Cl2
11 R = COt-Bu
2
sis of (1S,3S,7R)-3-methyl-a-himachalene (1), whose
Bn
stereochemistry is supported by the X-ray analysis of 2.
NaHMDS,
MeI, THF
N
O
O
70%
O
Bn
O
O
1
2
Results and Discussion
LiOH, H2O2,
Scheme
1
shows our retrosynthetic analysis of
N
THF–H2O 4:1
(
1S,3S,7R)-1 by employing an intramolecular Diels-Al-
92%
O
1
2
der reaction (DÆC) as the key step. Our simple idea was
to use (S)-D, instead of (±)-D, for the key step. The triene
ketone (S)-D would be derived from (S)-acid E, which
would be obtainable by asymmetric methylation of the
corresponding 2-demethyl acid derivatives F and G, re-
spectively.
13
CO2H
(S)-14
(
1R,2S)-(+)-2,10-Camphorsultam,
COX
Scheme 2 summarizes the synthesis of (S)-diene carb-
oxylic acid 14 by two different methods of asymmetric
alkyl-ation. The commercially available diol 3 was con-
verted to the known aldehyde 4. Chain-elongation of 4
by a stable ylid gave a,b-unsaturated ester 5. Although
palladium-catalyzed hydrogenation of the double bond of
NaH, toluene
88%
(
COCl)2,
1
0 R = OH
Et3N, CH2Cl2
75%
1
5 R = Cl
1
2
BuLi, MeI
N
THF–HMPA
81%
S
5
was unsuccessful, it could be reduced with magnesium
O
O
2
1
6
1
5
and methanol to give saturated methyl ester 6 with con-
comitant transesterification. Removal of the tert-bu-
tyldimethylsilyl (TBS) protective group of 6 furnished
hydroxy ester 7, which was subjected to Swern oxidation
to afford aldehyde 8. Olefin formation by Wittig reaction
LiOH, H2O2
N
(S)-14
S
THF–H O 4:1
2
O
O
2
17
67%
6
converted 8 to diene ester 9. The E/Z ratio at D of 9 was
9
Synthesis of (+)-14
“
8:2 as estimated by its GC analysis on TC-WAX . Alka-
Scheme 2
line hydrolysis of 9 with methanolic potassium hydroxide
afforded diene carboxylic acid 10. Activation of the acid
1
0 as mixed anhydride 11 by treatment with pivaloyl chlo-
the assigned S configuration of (+)-14, an alternative
ride was followed by acylation of the Evans' chiral auxil-
iary, (S)-4-benzyl-2-oxazolidinone,16 yielding acylated
method was employed for its preparation. Oppolzer's
(
1R,2S)-(+)-camphorsultam19 was acylated with acyl
oxazolidinone 12.
chloride 15 derived from the acid 10 to afford N-acylated
sultam 16. Methylation of 16 with butyllithium and meth-
Methylation of 12 with sodium hexamethyldisilazide
1
7
(
NaHMDS) and methyl iodide furnished the desired
20
yl iodide gave 17, whose chiral auxiliary was removed
1
8
product 13. Removal of the chiral auxiliary gave carbox-
ylic acid (+)-14, whose enantiomeric purity was >99% ee
as estimated by GC analysis on Chirasil-DEX -CB. The
absolute configuration of (+)-14 must be S according to
the empirical rule generally accepted. To further support
to furnish (+)-acid 14 with enantiomeric purity of >99%
20
ee as checked by GC analysis. According to Oppolzer,
“
this (+)-acid 14 should possess S absolute configuration.
The result thus supported the previous one obtained by
employing the Evans protocol.
1
7
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

1
854
T. Tashiro et al.
SPECIAL TOPIC
Two further supporting experiments as shown in Scheme
definitely proved the S configuration of (+)-14. The first
ref. 21
3
t-BuO C
OTBS
19
2
CO2H
I
experiment was preparation of (R)-24, the opposite enan-
tiomer of (S)-alcohol 24 derived from 13, by starting from
the commercially available (R)-half ester 18. Conversion
of (R)-18 to iodide 19 was executed by the known meth-
4
steps
18
Me2CHCO2Me,
LDA, THF
DIBALH,
MeO2C
OTBS
CH2Cl2
88%
21
93%
od. Alkylation of methyl isobutyrate with 19 gave ester
20
2
2
0, which was converted to (R)-alcohol 24 via 21, 22 and
3. The (R)-alcohol 24 was dextrorotatory, [a]D +9.89
+
–
22
CH2=C(Me)CH2PPh3 Cl ,
X
OTBS
(
CHCl ), while the alcohol 24 obtained by reduction of 13
t -BuOK, THF
3
69%
with lithium aluminum hydride was levorotatory,
2
1 X = CH2OH
Dess-Martin Periodinane,
2
2
[
a] -9.31 (CHCl ), and therefore it was (S)-24. Accord-
D
3
CH Cl
78%
2
2
22 X = CHO
ingly, the (+)-acid 14 must possess S absolute configura-
tion.
OR
The second experiment was the preparation and X-ray
analysis of (S)-1-(1-naphthyl)ethylamide (2) of the acid
(
R)-23 R = TBS
TBAF, THF
1%
1
4. The amide 2 derived from the (+)-acid 14 was crystal-
8
(R)-24 R = H
line, but unfortunately not suitable for X-ray analysis.
When (±)-14 was converted to the diastereomeric mixture
of the amides (2R)-2 and (2S)-2, they could be separated
by silica gel chromatography. The later eluted amide was
found to be identical to (2S)-2 derived from (+)-14 upon
direct comparison. The earlier eluted amide, which should
be the amide of (-)-14, was nicely crystalline, and could
be analyzed by X-ray. Figure 1 shows the perspective
view of the earlier eluted amide, which was definitely
shown to be (2R)-2 on the basis of the known S absolute
configuration of the starting 1-(1-naphthyl)ethylamine.
The present X-ray analysis concludes that (+)-14 possess-
es S absolute configuration.
Bn
LiAlH4, THF
1%
N
O
O
8
O
(
2S)-13
OH
(S)-24
(
S)-1-(1-Naphthyl)ethylamine,
CO2H
EDC, DMAP, CH2Cl2
(±)-14
H
N
Conversion of the acid (S)-14 to the sandfly pheromone
(
1S,3S,7R)-1 is shown in Scheme 4, which follows the
O
1
2
route previously employed for the synthesis of (±)-1.
(
2R)-2 (X-ray analysis)
The (S)-acid 14 yielded the corresponding N-methoxy-N-
methylamide (S)-25 [18% overall yield based on 4 (10
steps)] by treatment with N,O-dimethylhydroxylamine
H
N
2
2
hydrochloride under the Weinreb conditions. Treatment
of the amide 25 with vinylmagnesium bromide furnished
triene ketone (S)-26, the substrate for the intramolecular
Diels-Alder reaction. Because our attempts to achieve
asymmetric Diels-Alder reaction of 26 using chiral cata-
lysts were all fruitless, 26 was cyclized in the presence of
lithium perchlorate with a catalytic amount of (+)-10-
camphorsulfonic acid in diethyl ether as reported by
O
similarly
(2S)-2
CO2H
(S)-14
Confirmation of S absolute configuration of (+)-14
2
3
Grieco and his co-workers. The Grieco conditions were
previously observed to give a mixture of two rings A/B cis
products, (1R*,3S*,7S*)- and (1R*,3R*,7S*)-27 as the
major products (87%), while the remaining two rings A/B
trans products, (1R*,3S*,7R*)- and (1R*,3R*,7R*)-27,
Scheme 3
the minor products: the mixture contained only 18.6% of
1S,3S,7R)-27. There is no explanation for our inability to
(
1
2
were the minor ones (13%). In the present case, the cy-
cloaddition proceeded at room temperature, and after 16 h
a mixture of the four possible stereoisomers of 27 was ob-
tained in 83% yield. All of them were highly enantiomer-
ically pure (≥99% ee), indicating that no racemization at
C-3 took place. The ratio of the generated stereoisomers
of 27 as revealed by GC analysis, however, was disap-
pointing as shown in Scheme 4. Under the Grieco condi-
tions (method A), the desired (1S,3S,7R)-27 was one of
12
reproduce the previous result.
Fortunately, when diethylaluminum chloride was em-
2
4
ployed as a catalyst, the selectivity could be very much
improved very much. In the presence of diethylaluminum
chloride in dichloromethane, the reaction proceeded at -
8 °C, and after 1 hour, the product was obtained in 81%
yield. The four stereoisomers of 27 were all enantiomeri-
7
cally pure (>99% ee) as checked by GC analysis, eliminat-
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
1855
ketone (1S,3S,7R)-27 could be secured. It should be added
that the relative stereochemistries of these four isomers of
1
2
7 had been deduced previously by their extensive H
1
2
NMR studies.
As shown in Figure 2, the ketone (1S,3S,7R)-27 exhibited
a strong positive Cotton effect (De = +1.55) at l = 297
max
nm (hexane). The most stable conformation of the ketone
(
1S,3S,7R)-27 as calculated by MM3 molecular mechan-
2
5
ics software is also shown in Figure 2, which indicates
26
that the octant rule justifies the strong positive Cotton ef-
fect of (1S,3S,7R)-27. The assignment of absolute config-
uration to the enantiomers of 27 at the time when we
resolved (±)-27 by HPLC was therefore fortunately cor-
rect. Finally, as shown in Scheme 4, methylenation of
(
1S,3S,7R)-27 with Tebbe reagent {m-chloro-m-methyl-
ene[bis(cyclopentadienyl)titanium]dimethylaluminum}
2
7,28
afforded (1S,3S,7R)-3-methyl-a-himachalene (1)
with 99% ee as determined by GC analysis on Chirasil-
“
1
13
Figure 1 X-ray structure of (2R)-2
DEX -CB. The IR, MS, H NMR (500 MHz) and
C
NMR (126 MHz) spectral data of (1S,3S,7R)-1 were iden-
tical to those reported for (±)-1.12 The overall yield of
ing the possibility of racemization at C-3 in the course of
the reaction. In the present case of method B, (1S,3S,7R)-
(
1S,3S,7R)-1 was 23% based on (S)-14 (4 steps) or 5.0%
based on 4 (13 steps). The synthesized (1S,3S,7R)-3-me-
2
2
7 was the major product (50.4%). The stereoisomers of
7 could be separated by medium pressure liquid chroma-
22
thyl-a-himachalene (1) was dextrorotatory, [a] +181
D
(
CHCl ), while the naturally occurring plant sesquiter-
3
tography (MPLC), and a sufficient amount of the desired
pene (1R,7R)-a-himachalene (A) was reported to be
2
5
levorotatory, [a]D -192.3 (CHCl ).
3
CH2=CHMgBr,
COX
THF
MeO(Me)NH·HCl, EDC,
i -Pr2NEt, DMAP, CH2Cl2
(S)-14 X = OH
S)-25 X = N(Me)OMe
(
80%
Intramolecular Diels-Alder Reaction
method A. LiClO4, 5% CSA,
O
Et2O–THF
(S)-26
69% two steps
method B. Et2AlCl, CH2Cl2
81% two steps
O
O
O
H
H
H
H
+
+
+
H
H
(1R,3S,7S)-27
(1R,3S,7R)-27
(1S,3S,7S)-27
Figure 2 (a) The most stable conformation of (1S,3S,7R)-27 as cal-
culated by MM3. (b) CD spectrum of (1S,3S,7R)-27 (c = 0.032 M, he-
xane)
A
B
36.5%
27.9%
15.4%
2.9%
29.5%
18.8%
O
H
H
Tebbe reagent
In conclusion (1S,3S,7R)-3-methyl-a-himachalene (1),
the male sex pheromone of the sandfly Lutzomyia longi-
palpis from Jacobina, was synthesized, and its 1S,3S,7R
absolute configuration was established beyond doubt by
the X-ray analysis of a related compound 2. The absolute
configuration of the two male produced homosesquiter-
pene sex pheromones of L. longipalpis share in common
the S configuration of the extra methyl group at C-8 of B
and C-3 of 1. Figure 3 illustrates a possible biosynthetic
THF–toluene
70%
H
H
(
1S,3S,7R)-27
(
1S,3S,7R)-1
A
B
18.6%
50.4%
Convertion of (S)-14 to (1S,3S,7R)-1
Scheme 4
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

1
856
T. Tashiro et al.
SPECIAL TOPIC
relationship between B and 1, i.e., both the pheromones 13C NMR (100 MHz, CDCl
): d = -5.6 [Si(CH
) ], 14.3
3 2
3
(
(
(
OCH CH ), 18.2 [C(CH ) ], 24.1 (5-CH 2), 25.8 [C(CH ) ], 36.3
might have been biosynthesized by cyclization of a puta-
tive precursor, (2E,6E,8S)-8-methylfarnesol. Biosynthe-
sis of these two homosesquiterpene pheromones will
remain as an interesting subject of future investigation. As
to our synthesis reported in the present paper, however,
there is still room for improvement in the efficiency of the
overall process. We are currently exploring a better route
to provide (±)-1 in an amount sufficient for practical ap-
plication.
2
3
3 3
3
3 3
5-C), 41.5 (4-C), 60.0 (OCH CH ), 71.2 (6-C), 123.3 (2-C), 146.7
3-C), 166.5(1-C).
2
3
Anal. C H O Si (300.5): Calcd C 63.95, H 10.73; found C 63.77,
16 32
3
H 10.86.
Methyl 6-tert-Butyldimethylsilyloxy-5,5-dimethylhexanoate (6)
A small amount of anhyd MeOH (ca. 100 mL) was added carefully
to Mg (81.4 g, 3.35 mol) and the mixture was stirred on a water bath
to start the reaction. The mixture was then gently refluxed, and to
this mixture was added dropwise a solution of 5 (71.9 g, 240 mmol)
in anhyd MeOH (1000 mL) at r.t. After the mixture was stirred for
2
d at r.t, it was then diluted with Et O (600 mL) and poured into 3
2
M aq HCl (1500 mL) carefully at 0 °C. The aqueous layers were sat-
OH
urated with NaCl and extracted with Et O (2 × 300 mL). The com-
2
bined organic layers were washed with H O and brine, dried
2
(2E,6E,8S)-8-Methylfarnesol
(Na SO ), and concentrated in vacuo. The residue was purified by
2
4
distillation to give 53.2 g (77%) of 6 as a colorless oil; bp 97-101
2
4
°
C/2 Torr; n 1.4343.
D
IR (film): n = 1740 (s, C=O), 1260 (m, Si-CH ), 1110 (m), 780 (m)
3
-
1
cm .
1
H NMR (90 MHz, CDCl ): d = 0.01 [s, 6 H, Si(CH ) ], 0.83 (s, 6
H
3
3 2
H, 2 × 5-CH ), 0.88 [s, 9 H, SiC(CH ) ], 0.93-1.78 (m, 4 H, 3-H ,
4
3
3
3
2
-H ), 2.28 (t-like, 2 H, J = 7.5 Hz, 2-H ), 3.23 (s, 2 H, 6-H ), 3.66
2
2
2
(
1
s, 3 H, OCH3).
H
3
C NMR (126 MHz, CDCl ): d = -5.6 [Si(CH ) ], 18.2 [C(CH ) ],
3
3 2
3 3
9-Methylgermacrene-B (B)
3-Methyl-α-himachalene (1)
19.7 (3-C), 23.9 (5-CH 2), 25.9 [C(CH ) ], 35.0 (2-C), 35.2 (5-C),
3 3 3
3
8.3 (4-C), 51.4 (OCH ), 71.4 (6-C), 174.3 (1-C).
3
Figure 3 Possible biosynthetic relationship between B and 1
Anal. C H O Si (288.5): Calcd C 62.45, H 11.18; found C 62.42,
1
5
32
3
H 11.21.
All melting and boiling points are uncorrected values. IR spectra
were recorded on a Jasco A-102 spectrometer. H NMR spectra
were recorded on a Jeol JNM-EX 90A (90 MHz), Jeol JNM-LA 400
1
Methyl 5,5-Dimethyl-6-hydroxyhexanoate (7)
To a solution of 6 (12.6 g, 43.6 mmol) in MeCN (100 mL) was add-
ed 46% HF (4.5 mL) at 0°C. The mixture was stirred at 0-4∞C for
(
400 MHz) and Jeol JNM-LA 500 (500 MHz), (TMS at d = 0.00 or
H
13
18 h, then diluted with Et
2
O (100 mL), washed with aq sat. NaHCO
3
CHCl at d = 7.26 as an internal standard). C NMR spectra were
3
H
solution and separated. The aqueous layer was extracted with Et O
2
recorded on a Jeol JNM-LA 400 (100 MHz) and Jeol JNM-LA 500
126 MHz), (CDCl at d = 77.0 as an internal standard). Circular
(
2 × 50 mL). The combined organic layers were washed with aq sat.
(
3
C
NaHCO solution and brine, dried (MgSO ) and concentrated in
3
4
dichroism was measured on a Jasco J-720. Optical rotations were
measured on a Jasco DIP-1000 polarimeter. Mass spectra were re-
corded on a Jeol JMS-SX 102A and Hitachi M-80B. Column chro-
matography was carried out on columns packed with Merck
Kieselgel 60 Art 1.07734. TLC was carried out with 0.25 mm Mer-
ck silica gel plates (60F-254).
vacuo. The residue was purified by distillation to give 7.05 g (93%)
2
5
of 7 as a colorless oil; bp 88-90 °C/2 Torr; nD 1.4443.
-
1
IR (film): n = 3450 (s, O-H), 1730 (s, C=O) cm .
1
H NMR (90 MHz, CDCl ): d = 0.88 (s, 6 H, 2 × 5-CH ), 0.92-1.79
3
3
(
(
1
m, 5 H, 3-H , 4-H , OH), 2.31 (t-like, 2 H, J = 6.8 Hz, 2-H ), 3.33
2
2
2
s, 2 H, 6-H ), 3.67 (s, 3 H, OCH ).
2
3
Ethyl (E)-6-tert-Butyldimethylsilyloxy-5,5-dimethylhex-2-
enoate (5)
3
C NMR (100 MHz, CDCl ): d = 19.2 (3-C), 23.8 (2 × 5-CH ), 34.4
3
3
(
2-C), 35.0 (5-C), 37.7 (4-C), 51.5 (OCH ), 71.2 (6-C), 174.4 (1-C).
3
To a solution of 4 (64.1 g, 279 mmol) in anhyd benzene (800 mL)
was added carbethoxymethylenetriphenylphosphorane (136 g, 390
mmol) and the mixture was stirred under reflux for 4 h, and then
concentrated under reduced pressure. The combined residue and
washings were filtered and the filter cake was washed with hexane
Anal. C H O (174.2): Calcd C 62.04, H 10.41; found C 61.93, H
9
18
3
10.42.
Methyl 5,5-Dimethyl-6-oxohexanoate (8)
To a solution of oxalyl chloride (9.5 mL, 0.11 mol) in anhyd CH Cl
(
2 × 100 mL). The filtrate and washings were concentrated in vacuo,
2
2
and the residue was purified by distillation to give 74.8 g (89%) of
(
40 mL) at -60 °C was added a solution of anhyd DMSO (16 mL,
2
4
5
as a colorless oil; bp 121-124 °C/4 Torr; nD 1.4471.
0.23 mol) in anhyd CH Cl (40 mL). After stirring for 20 min at
2
2
-
60 °C, a solution of 7 (6.88 g, 39.5 mmol) in anhyd CH Cl (40
mL) was added dropwise. The mixture was stirred at -40 °C for 40
IR (film): n = 1730 (s, C=O), 1660 (m, C=C), 1260 (m, Si-CH ),
2 2
3
-
1
1
100 (m), 780 (s) cm .
min, then Et N (50 mL, 0.36 mol) was added and the mixture was
warmed to 0 °C. It was diluted with H O (100 mL) and the aqueous
layer was extracted with CH Cl (2 × 50 mL). The combined organ-
ic layers were washed with H O and brine, dried (MgSO ) and con-
centrated in vacuo. The residue was diluted with hexane (30 mL)
and filtered through a layer of Celite. The filtrate was concentrated,
and the residue was purified by chromatography on silica gel (80 g,
1
3
H NMR (400 MHz, CDCl ): d = 0.01 [s, 6 H, Si(CH ) ], 0.86 (s,
3
3 2
2
6
H, 2 × 5-CH ), 0.88 [s, 9 H, SiC(CH ) ], 1.27 (t, 3 H, J = 7.2 Hz,
3
3
3
2
2
OCH CH ), 2.13 (dd, 2 H, J = 1.2, 8.0 Hz, 4-H ), 3.23 (s, 2 H, 6-H ),
2
3
2
2
2
4
4
2
.17 (q, 2 H, J = 7.6 Hz, OCH CH ), 5.80 (dt, 1 H, J = 1.2, 16 Hz,
-H), 6.97 (dt, 1 H, J = 7.6, 16 Hz, 3-H).
2 3
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
1857
Pivaloyl (E)-5,5,8-Trimethylnona-6,8-dienoyl Anhydride (11)
elution with hexane/EtOAc, 200:1) to give 5.63 g (83%) of 8 as a
colorless oil. This was immediately used in the next step without
further purification; nD 1.4338.
To a solution of pivaloyl chloride (4.15 g, 33.7 mmol) in anhyd
2
3
CH Cl (40 mL) at 0 °C were added Et N (5.0 mL, 36 mmol) and a
2
2
3
solution of 10 (5.98 g, 30.5 mmol) in anhyd CH Cl (40 mL). After
2
2
IR (film): n = 2700 (m, aldehyde C-H), 1745 (s, C=O), 1725 (s,
-
1
the reaction mixture was stirred for 1 h at r.t, it was concentrated un-
der reduced pressure. The residue was filtered through Celite and
the filter cake was washed with hexane (50 mL). The filtrate was
concentrated in vacuo to give ca 9 g of 11. It was immediately used
in the next step without further purification.
C=O) cm .
1
H NMR (90 MHz, CDCl ): d = 1.06 (s, 6 H, 2 × 5-CH ), 1.12-1.82
3
3
(
m, 4 H, 3-H , 4-H ), 2.22-2.42 (m, 2 H, 2-H ), 3.67 (s, 3 H, OCH ),
2
2
2
3
9
.45 (s, 1 H, CHO).
IR (film): n = 1810 (s, C=O), 1750 (s, C=O), 1640 (w, C=C), 1610
Methyl (E)-5,5,8-Trimethylnona-6,8-dienoate (9)
-
1
(
m, C=C) cm .
To a suspension of methallyltriphenylphosphonium chloride (93.7
g, 266 mmol) in anhyd THF (700 mL) at 0 °C was added a suspen-
sion of t-BuOK (26.9 g, 240 mmol) in anhyd THF (450 mL) drop-
wise and the mixture was stirred for 1 h at r.t. To this mixture was
added dropwise a solution of 8 (28.6 g, 166 mmol) in anhyd THF
1H NMR (90 MHz, CDCl
): d = 1.04 (s, 6H, 2 × 5-CH ), 1.25 [s, 9
3
3
H, C(CH ) ], 1.34-1.57 (m, 4 H, 3-H , 4-H ), 1.83 (br s, 3H, 8-
3 3
2
2
CH
), 2.26-2.57 (m, 2 H, 2-H ), 4.90 (br s, 2 H, 9-H ), 5.56 (d, 1 H,
3
2
2
J = 16 Hz, 6-H), 6.07 (d, 1 H, J = 16 Hz, 7-H).
(
250 mL) at 0 °C. The mixture was stirred under reflux for 24 h, then
poured into aq sat. NH Cl (300 mL) and stirred for 1 h at r.t. The
aqueous layer was extracted with EtOAc (3 × 300 mL). The com-
[4S,3(6E)]-4-Benzyl-3-(5,5,8-trimethylnona-6,8-dienoyl)-2-ox-
azolidinone (12)
4
bined organic layers were washed with brine, dried (MgSO ) and
To a solution of (S)-4-benzyl-2-oxazolidinone (6.04 g, 34.1 mmol)
in anhyd THF (100 mL) at -78 °C was added slowly BuLi in hex-
ane (1.5 M solution, 23 mL, 34 mmol) under Ar. After the mixture
was stirred at -78 °C for 1 h, a solution of 11 (ca 9 g) in anhyd THF
(20 mL) was added dropwise. It was stirred for 1 h at -78 °C and
4
concentrated in vacuo to give crude methyl ester 9 (ca. 40 g). This
was employed in the next step without any purification. An analyt-
ical sample was purified by distillation; bp 108-109 °C/7 Torr;
2
3
n
1.4704.
D
for 12 h at 0-4 °C. The mixture was poured into aq satd NH Cl ,
4
IR (film): n = 1740 (s, C=O), 1640 (w, C=C), 1610 (m, C=C), 970
-
1
and the aqueous layer was extracted with Et O (3 × 50 mL). The
2
(
s), 880 (s) cm .
combined organic layers were washed with aq sat. NaHCO and
3
1
H NMR (90 MHz, CDCl ): d = 1.03 (s, 6 H, 2 × 5-CH ), 1.83 (s, 3
3
3
brine, dried (MgSO ), and concentrated in vacuo. The residue was
4
H, 8-CH ), 1.09-1.95 (m, 4 H, 3-H , 4-H ), 2.27 (t-like, 2 H, J = 7.1
Hz, 2-H ), 3.66 (s, 3 H, OCH ), 4.89 (br s, 2 H, 9-H ), 5.57 (d, 1 H,
3
2
2
purified by chromatography on silica gel (30 g, elution with hexane/
2
3
2
EtOAc, 40:1) to give 8.49 g (78%, two steps) of 12 as a colorless
J = 16 Hz, 6-H), 6.07 (d, 1 H, J = 16 Hz, 7-H).
24
21
oil; nD 1.5177; [a]D +43.5 (c = 1.40, CHCl3).
1
3
C NMR (100 MHz, CDCl ): d = 18.7 (8-CH ), 20.3 (3-C), 27.1 (5-
3
3
IR (film): n = 1790 (s, C=O), 1705 (s, C=O), 1650 (w, C=C), 1610
CH 2), 34.6 (2-C), 35.8 (5-C), 42.6 (4-C), 51.4 (OCH ), 114.6 (9-
-1
3
3
(m, C=C), 1460 (m), 1110 (m), 980 (m), 890 (m), 710 (m) cm .
C), 128.9 (7-C), 139.9 (6-C), 142.2 (8-C), 174.1 (1-C).
1
H NMR (400 MHz, CDCl ): d = 1.06 (s, 6 H, 2 × 5’-CH ), 1.32-
3
3
GC analysis: Conditions (column: TC-WAX ,0.53 mm × 15 m, 70
1
.49 (m, 2 H, 4’-H ), 1.56-1.70 (m, 2 H, 3’-H ), 1.84 (s, 3 H, 8’-
2
2
+
3°C/min, carrier gas: He, 110 kPa). t R = 6.29 min [2%, (Z)-9], t
CH ), 2.76 (dd, 1 H, J = 9.6, 13 Hz, CH H Ph), 2.80-2.98 (m, 2 H,
2’-H ), 3.30 (dd, 1 H, J = 2.8, 13 Hz, CH H Ph), 4.12-4.24 (m, 2 H,
2 a b
5
9
7
3
a
b
=
8.06 min, [98%, (E)-9] Therefore the purity of 9 was estimated
R
to be E/Z = 98:2.
-H ), 4.62-4.70 (m, 1 H, 4-H), 4.89 (s, 1 H, 9’-H H ), 4.90 (s, 1 H,
2 E Z
’-H H ), 5.61 (d, 1 H, J = 16 Hz, 6’-H), 6.07 (d, 1 H, J = 16 Hz,
Anal. C H O (210.3): Calcd C 74.24, H 10.54; found C 73.97, H
E
Z
13
22
2
’-H), 7.16-7.36 (m, 5 H, C H ).
1
0.83.
6
5
1
3
C NMR (100 MHz, CDCl ): d = 18.8 (8'-CH ), 19.6 (3-C), 27.17
3
3
(
E)-5,5,8-Trimethylnona-6,8-dienoic Acid (10)
(5'-CH ), 27.19 (5'-CH ), 35.9 (5'-C), 36.1 (2'-C), 37.9 (1"-C), 42.6
3
3
The crude 9 (ca 40 g) was diluted with MeOH (500 mL) and 5%
(4'-C), 55.1 (4-C), 66.1 (5-C), 114.6 (9'-C), 127.3 (C H ), 128.9 (7'-
6 5
KOH in MeOH (1400 mL) was added. The mixture was stirred un-
C), 129.0 (C H ), 129.4 (C H ), 135.3 (C H ), 140.0 (6'-C), 142.3
6 5 6 5 6 5
der reflux for 12 h, and then diluted with H O. The aqueous layer
was washed with toluene (3 × 300 mL) to remove non-acidic com-
pounds. It was then acidified with 3 M aq HCl, and extracted with
(8'-C), 153.4 (2-C), 173.2 (1'-C).
Anal. C H NO (355.5): Calcd C 74.33, H 8.22, N 3.94; found C
2
2
2
29
3
7
4.19, H 8.03, N 3.95.
CHCl (3 × 300 mL). The combined organic layers were washed
3
with H O and brine, dried (MgSO ) and concentrated in vacuo. The
residue was purified by chromatography on silica gel (300 g, elution
2
4
[
4S,3(2S,6E)]-4-Benzyl-3-(2,5,5,8-tetramethylnona-6,8-di-
enoyl)-2-oxazolidinone (13)
To a solution of 12 (14.0 g, 39.4 mmol) in anhyd THF (200 mL) at
with hexane/EtOAc, 60:1) and distillation to give 26.9 g of 10
2
4
(
83%) as a colorless oil; bp = 107-111 °C/1.3 Torr; nD 1.4818.
-
78 °C was added slowly sodium hexamethyldisilazide in THF
IR (film): n = 3000 (br s, CO H), 1710 (s, C=O), 1640 (w, C=C),
2
(NaHMDS, 1.0 M solution, 59 mL, 59 mmol) under Ar. After the
mixture was stirred at -78 ∞C for 2 h, a of MeI (16.8 g, 118 mmol)
in anhyd THF (100 mL) was added dropwise. The mixture was
-
1
1
610 (m, C=C) cm .
1
H NMR (500 MHz, CDCl ): d = 1.03 (s, 6 H, 2 × 5-CH ), 1.32-
3
3
stirred for 12 h at -78 °C, then poured into aq sat. NH Cl and ex-
tracted with Et O (3 × 50 mL). The combined organic layers were
washed with aq sat. NaHCO and brine, dried (MgSO ), and con-
centrated in vacuo. The residue was purified by chromatography on
silica gel (400 g, elution with hexane/EtOAc, 50:1) to give 10.2 g
1
2
.35 (m, 2 H, 4-H ), 1.53-1.61 (m, 2 H, 3-H ), 1.83 (s, 3 H, 8-CH ),
4
2
2
3
.32 (t, 2 H, J = 7.5 Hz, 2-H ), 4.89 (s, 1 H, 9-H H ), 4.90 (s, 1 H,
2
2
E
Z
9
-H H ), 5.58 (d, 1 H, J = 16 Hz, 6-H), 6.06 (d, 1 H, J = 16 Hz, 7-
3
4
E
Z
H).
1
3
C NMR (126 MHz, CDCl ): d = 18.7 (8-CH ), 20.0 (3-C), 27.2 (2
24
22
3
3
(
70%) of 13 as a colorless oil; nD 1.5173; [a]D +59.4 (c = 1.06,
×
5-CH ), 34.6 (2-C), 35.8 (5-C), 42.5 (4-C), 114.6 (9-C), 129.0 (7-
3
CHCl3).
C), 139.8 (6-C), 142.2 (8-C), 180.2 (1-C).
IR (film): n = 1780 (s, C=O), 1695 (s, C=O), 1640 (w, C=C), 1610
(
Anal. C H O (196.3): Calcd C 73.43, H 10.27; found C 73.52, H
-1
12
20
2
m, C=C), 1450 (m), 1105 (m), 970 (m), 890 (m), 710 (m) cm .
1
0.33.
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

1
858
T. Tashiro et al.
SPECIAL TOPIC
1
H NMR (400 MHz, CDCl ): d = 1.02 (s, 6 H, 2 × 5’-CH ), 1.21 (d,
[3aR-[1(E),3aa,6a,7ab]]-Hexahydro-8,8-dimethyl-1-(5,5,8-tri-
methylnona-6,8-dienoyl)-3H-3a,6-methano-2,1-benzisothiazole
2,2-Dioxide (16)
To a solution of (1R)-(+)-2,10-camphorsultam (1.04 g, 4.83 mmol)
in anhyd toluene (20 mL) at 0 °C was added NaH (60% suspension
in mineral oil, 201 mg, 8.38 mmol) and the mixture was stirred for
90 min at 0 °C. To this mixture was added a solution of 15 (1.04 g,
4.85 mmol) in anhyd toluene (15 mL). After the mixture was stirred
3
3
3
1
1
H, J = 6.4 Hz, 2’-CH ), 1.27-1.37 (m, 3 H, 3’-H H , 4’-H ), 1.63-
3 a b 2
.72 (m, 1 H, 3’-H H ), 1.84 (s, 3 H, 8’-CH ), 2.76 (dd, 1 H, J = 9.6,
a
b
3
3 Hz, CH H Ph), 3.26 (dd, 1 H, J = 3.2, 13 Hz, CH H Ph), 3.62
a
b
a
b
(
sext.-like, 1 H, J = 6.4 Hz, 2’-H), 4.13-4.24 (m, 2 H, 5-H ), 4.64-
2
4
5
7
.73 (m, 1 H, 4-H), 4.88 (s, 1 H, 9’-H H ), 4.90 (s, 1 H, 9’-H H ),
E Z E Z
.58 (d, 1 H, J = 16 Hz, 6’-H), 6.05 (d, 1 H, J = 16 Hz, 7’-H), 7.18-
.37 (m, 5 H, C H ).
6
5
1
3
for 1 h at r.t, it was poured into aq sat. NH Cl and the aqueous layer
4
C NMR (100 MHz, CDCl ): d = 17.4 (2'-CH ), 18.8 (8'-CH ), 27.0
3
3
3
was extracted with Et O (2 × 20 mL). The combined organic layers
2
(
(
(
(
5'-CH ), 27.2 (5'-CH ), 28.4 (3'-C), 35.7 (5'-C), 37.8 (1"-C), 38.2
2'-C), 40.5 (4'-C), 55.3 (4-C), 66.0 (5-C), 114.5 (9'-C), 127.3
C H ), 128.9 (7'-C), 129.0 (C H ), 129.4 (C H ), 135.3 (Ph), 140.0
3
3
were washed with aq sat. NaHCO and brine, dried (MgSO ), and
3
4
concentrated in vacuo. The residue was purified by chromatography
on silica gel (60 g, elution with hexane/EtOAc, 30:1) to give 1.68 g
6
5
6
5
6
5
6'-C), 142.3 (8'-C), 153.0 (2-C), 177.1 (1'-C).
2
4
21
(
88%) of 16 as a colorless oil; nD 1.5172; [a]D +80.7 (c = 1.07,
Anal. C H NO (369.5): Calcd C 74.76, H 8.46, N 3.79; found C
7
23
31
3
CHCl3).
4.46, H 8.64, N 3.90.
IR (film): n = 1710 (s, C=O), 1640 (w, C=C), 1610 (m, C=C), 1330
-
1
(
m, SO ), 1170 (m, SO ), 970 (s), 880 (s), 770 (s) cm .
2
2
(
2S,6E)-2,5,5,8-Tetramethylnona-6,8-dienoic Acid [(S)-14]
1
H NMR (90 MHz, CDCl ): d = 0.97 (s, 3 H, 8-CH ), 1.02 (s, 6 H,
To a solution of 13 (3.65 g, 10.3 mmol) in THF/H O (4:1, 50 mL)
at 0 °C were added 34.5% H O (4.3 mL) and a solution of
LiOH•H O (750 mg, 17.9 mmol) in distilled water (15 mL). After
the mixture was stirred at 0 °C for 1 h, a solution of Na SO •7H O
3
3
2
2 × 5’-CH
6
), 1.15 (s, 3 H, 8-CH
), 1.08-2.17 (m, 11 H, 4-H , 5-H ,
3
3
2 2
2
2
-H, 7-H , 3’-H , 4’-H ), 1.83 (s, 3 H, 8'-CH ), 2.68 (t-like, 2 H,
2
2 2 2 3
J = 7.3 Hz, 2’-H ), 3.45 (s, 2 H, 3-H ), 3.85 (t, 1 H, J = 6.3 Hz, 7a-
2
2
2
3
2
H), 4.88 (br s, 1 H, 9’-H ), 5.56 (d, 1 H, J = 16 Hz, 6’-H), 6.06 (d, 1
(
10.6 g, 42.0 mmol) in H O (15 mL) was added. After the mixture
2
2
H, J = 16 Hz, 7’-H).
was stirred for 30 min, it was concentrated in vacuo. The residue
was washed with CH Cl (3 × 20 mL) to remove non-acidic com-
pounds before it was acidified with aq 6 M HCl. The acidified solu-
2
2
Anal. C H NO S (393.6): Calcd C 67.14, H 8.96, N 3.56; found C
2
2
35
3
6
7.23, H 9.19, N 3.59.
tion was extracted with EtOAc (3 × 20 mL). The combined organic
layers were dried (MgSO ) and concentrated in vacuo. The residue
was purified by chromatography on silica gel (60 g, elution with
4
[
(
3aR-[1(2S,6E),3aa,6a,7ab]]-Hexahydro-8,8-dimethyl-1-
2,5,5,8-tetramethylnona-6,8-dienoyl)-3H-3a,6-methano-2,1-
hexane/EtOAc, 5:1) to give 1.98 g (92%) of 14 as a colorless oil;
benzisothiazole 2,2-Dioxide (17)
2
3
21
nD 1.4820; [a]D +4.71 (c = 1.02, CHCl3).
To a solution of 16 (14.0 g, 39.4 mmol) in anhyd THF (20 mL) at
-78 °C was added slowly BuLi in hexane (1.50 M solution, 2.5 mL,
3.8 mmol) under Ar, and the mixture was stirred at -78 ∞C for 2 h.
To this mixture was added slowly a solution of MeI (2.04 g, 14.4
mmol) in HMPA (3 mL). After the mixture was stirred for 24 h at
IR (film): n = 3000 (br, s, CO H), 1710 (s, C=O), 1650 (w, C=C),
2
-
1
1
610 (m, C=C), 970 (s), 880 (s) cm .
1
H NMR (400 MHz, CDCl ): d = 1.02 (s, 6 H, 2 × 5-CH ), 1.18 (d,
3
3
3
1
H, J = 7.1 Hz, 2-CH ), 1.29-1.42 (m, 3 H, 3-H H , 4-H ), 1.53-
3 a b 2
-
78 °C, it was poured into H O and extracted with Et O (2 × 30
2
2
.67 (m, 1 H, 3-H H ), 1.84 (s, 3 H, 8-CH ), 2.32-2.45 (m, 1 H, 2-
a
b
3
mL). The combined organic layers were concentrated in vacuo and
the residue was purified by chromatography on silica gel (30 g, elu-
tion with hexane/EtOAc, 50:1) to give 1.11 g (81%) of 17 as a col-
H), 4.90 (br s, 2 H, 9-H ), 5.57 (d, 1 H, J = 16 Hz, 6-H), 6.05 (d, 1
2
H, J = 16 Hz, 7-H).
1
3
C NMR (100 MHz, CDCl ): d = 16.9 (2-CH ), 18.7 (8-CH ), 27.0
23
21
3
3
3
orless oil; nD 1.5172; [a]D +79.8 (c = 1.02, CHCl3).
(
5-CH ), 27.2 (5-CH ), 28.6 (3-C), 35.7 (5-C), 39.9 (2-C), 40.3 (4-
3 3
IR (film): n = 1700 (s, C=O), 1640 (w, C=C), 1610 (m, C=C), 1330
(
C), 114.6 (9-C), 129.0 (7-C), 139.9 (6-C), 142.2 (8-C), 183.4 (1-C).
-
1
m, SO ), 1170 (m, SO ), 970 (s), 880 (s), 770 (s) cm .
2 2
Anal. C H O (210.3): Calcd C 74.24, H 10.54; found C 74.09, H
13
22
2
1
H NMR (90 MHz, CDCl ): d = 0.97 (s, 3 H, 8-CH ), 1.00 (s, 6 H,
3
3
1
0.70.
2
1
× 5’-CH ), 1.15 (s, 3 H, 8-CH ), 1.19 (d, 3 H, J = 7.1 Hz, 2’-CH ),
3
3
3
.02-2.16 (m, 11 H, 4-H , 5-H , 6-H, 7-H , 3’-H , 4’-H ), 1.83 (s, 3
2
2
2
2
2
Estimation of the Enantiomeric Excess of (S)-14
H, 8'-CH ), 2.70-3.15 (m, 1 H, 2’-H), 3.46 (s, 2 H, 3-H ), 3.91 (t-
like, 1 H, J = 14 Hz, 7a-H), 4.88 (br s, 1 H, 9’-H ), 5.56 (d, 1 H,
J = 16 Hz, 6’-H), 6.06 (d, 1 H, J = 16 Hz, 7’-H).
3
2
The enantiomeric excess of (S)-14 was determined by GC analysis.
“
2
Conditions (column: Chirasil-DEX CB, 0.25 mm × 25 m, 150 +
1
°C/min, carrier gas: He, 110 kPa). t R = 24.5 min [~100%, (S)-14].
Therefore the enantiomeric purity of (S)-14 was >99% ee.
Anal. C23
6
H37NO S (407.6): Calcd C 67.77, H 9.15, N 3.44; found C
3
7.98, H 8.93, N 3.50.
(
2S,6E)-2,5,5-Trimethylnona-6,8-dienoyl Chloride (15)
(2S,6E)-2,5,5,8-Tetramethyl-6,8-nonadienoic Acid [(S)-14]
In the same manner as described above for the conversion of 13 to
(S)-14, compound 17 (682 mg, 1.68 mmol) was converted to (S)-14
To a solution of 10 (3.16 g, 16.1 mmol) in anhyd CH Cl (30 mL)
2
2
at 0 °C was added oxalyl chloride (1.6 mL, 18 mmol). After the
mixture was stirred for 12 h at r.t, it was concentrated in vacuo and
distilled to give 2.61 g (75%) of 17 as a colorless oil; bp 116-
2
4
22
(235 mg, 67%); nD 1.4818; [a]D +4.64 (c = 1.08, CHCl3).
1
Its IR and H NMR spectra were identical to those described before.
1
20 °C/12 Torr; nD23 1.4850. This was immediately used in the next
step.
Methyl (R)-6-tert-Butyldimethylsilyloxy-2,2,5-trimethylhex-
anoate (20)
To a solution of diisopropylamine (4.0 mL, 29 mmol) in anhyd THF
(20 mL) at 0 °C was added a solution of BuLi in hexane (1.6 M so-
lution, 15 mL, 24 mmol) under Ar. After the mixture was stirred at
-
1
IR (film): n = 1800 (s, C=O), 1645 (w, C=C), 1610 (m, C=C) cm .
1
H NMR (90 MHz, CDCl ): d = 1.04 (s, 6 H, 2 × 5-CH ), 0.91-1.94
m, 4 H, 3-H , 4-H ), 1.83 (s, 3 H, 8-CH ), 2.85 (t, 2 H, J = 6.8 Hz,
3
3
(
2 2 3
2
1
-H ), 4.91 (br s, 2 H, 9-H ), 5.54 (d, 1 H, J = 16 Hz, 6-H), 6.07 (d,
H, J = 16 Hz, 7-H).
2
2
0
°C for 30 min, then it was cooled to -78 °C, and a solution of me-
thyl isobutyrate (2.9 mL, 2.6 g, 25 mmol) in anhyd THF (5 mL) was
added dropwise to it. The mixture was stirred for 2 h at -78 °C. To
this mixture was added dropwise a solution of 19 (2.35 g, 7.16
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
1859
1
mmol) in anhyd THF (10 mL). It was stirred for 2 h at -78 °C, al-
lowed to warm to 0 °C, and stirred for 1 h at that temp. Then it was
H NMR (90 MHz, CDCl ): d = 0.03 [s, 6 H, Si(CH ) ], 0.86 (d, 3
3
3 2
H, J = 6.9 Hz, 5-CH ), 0.89 [s, 9 H, SiC(CH ) ], 1.04 (s, 6 H, 2 × 2-
3
3 3
poured into aq sat. NaHCO and the aqueous layer was extracted
CH ), 0.92-1.72 (m, 5 H, 3-H , 4-H , 5-H), 3.39 (d, 2 H, J = 6.0 Hz,
3
3
2
2
with Et O (2 × 20 mL). The combined organic layers were washed
6-H ), 9.44 (s, 1 H, CHO).
2
2
with brine, dried (MgSO ) and concentrated. The residue was puri-
4
fied by chromatography on silica gel (50 g, elution with hexane/
(3E,8R)-tert-Butyldimethylsilyloxy-2,5,5,8-tetramethylnona-
,8-diene [(R)-23]
EtOAc, 40:1) to give 2.01 g (93%) of 20 as a colorless oil;
6
2
3
24
nD 1.4349; [a]D +5.43 (c = 1.23, CHCl3).
To a suspension of methallyltriphenylphosphonium chloride (4.14
g, 15.2 mmol) in anhyd THF (40 mL) at 0 °C was added t-BuOK
(1.43 g, 12.7 mmol) and the mixture was stirred for 1 h at that temp.
To this mixture was added dropwise a solution of 22 (761 mg, 2.80
mmol) in anhyd THF (20 mL). The mixture was stirred under reflux
IR (film): n = 1735 (s, C=O), 1255 (m, Si-CH ), 1150 (m), 1090
3
-
1
(m), 835 (s), 775 (s) cm .
1
H NMR (500 MHz, CDCl ): d = 0.01 [s, 6 H, Si(CH ) ], 0.84 (d, 3
3
3 2
H, J = 6.7 Hz, 5-CH ), 0.87 [s, 9 H, SiC(CH ) ], 0.94 (dddd, 1 H,
3
3 3
for 18 h, then it was cooled to 0 °C, poured into aq sat. NH Cl solu-
4
J = 4.5, 7.5, 13, 13 Hz, 4-H H ), 1.14 (s, 6 H, 2 × 2-CH ) 1.33 (tt-
a
b
3
tion and stirred for 1 h at r.t. The mixture was extracted with EtOAc
like, 1 H, J = 4.5, 13 Hz, 4-H H ), 1.46 (dt, 1 H, J = 4.5, 13 Hz, 3-
a
b
(
(
2 × 20 mL) and combined organic layers were washed brine, dried
H H ), 1.55 (dt, 1 H, J = 4.5, 13 Hz, 3-H H ), 1.46-1.53 (m, 1 H, 5-
a
b
a
b
MgSO ), and concentrated in vacuo. The residue was purified by
4
H), 3.37 (dq, 2 H, J = 6.5, 9.5 Hz, 6-H ), 3.63 (s, 3 H, OCH ).
2
3
chromatography on silica gel (40 g, elution with hexane/EtOAc,
1
3
C NMR (126 MHz, CDCl ): d = -5.41 [Si(CH ) ], 16.6 (5-CH ),
50:1) to give 602 mg (69%) of (R)-23 as a colorless oil. This was
3
3 2
3
24
1
8.3 [C(CH ) ], 25.06 (2-CH ), 25.09 (2-CH ), 25.9 [C(CH ) ], 28.2
used in the next step without further purification; n 1.4592;
3
3
3
3
3 3
D
2
4
(
4-C), 36.2 (5-C), 38.2 (3-C), 42.3 (2-C), 51.5 (OCH ), 68.0 (6-C),
[a]D +7.41 (c = 1.13, CHCl3).
3
1
78.5 (1-C).
IR (film): n = 1640 (w, C=C), 1610 (m, C=C), 1255 (s, Si-CH ),
3
-
1
Anal. C H O Si (302.5): Calcd C 63.52, H 11.33; found C 63.48,
1090 (s, C-O), 840 (s), 770 (s) cm .
16
34
3
H 11.51.
1
H NMR (500 MHz, CDCl ): d = 0.03[s, 6 H, Si(CH ) ], 0.85 (d, 3
3
3 2
H, J = 6.7 Hz, 2-CH ), 0.89 [s, 9 H, SiC(CH ) ], 1.01 (s, 6 H, 2 × 5-
3
3 3
(
R)-6-tert-Butyldimethylsilyloxy-2,2,5-trimethylhexan-1-ol (21)
CH ), 1.23-1.38 (m, 4 H, 3-H , 4-H ), 1.45-1.55 (m, 1 H, 2-H),
3
2
2
To a solution of 20 (195 mg, 0.645 mmol) in anhyd CH Cl (10 mL)
2
2
1.83 (s, 3 H, 8-CH ), 3.35 (dd, 1 H, J = 6.4, 9.8 Hz, 1-H H ), 3.41
3
a
b
was added dropwise a solution of DIBALH in CH Cl (1.0 M solu-
2
2
(dd, 1 H, J = 6.1, 9.8 Hz, 1-H H ), 4.87 (s, 1 H, 9’-H H ), 4.89 (s, 1
a b E Z
tion, 2.0 mL, 2.0 mmol) at -78 °C. After stirring for 90 min at
H, 9’-H H ), 5.59 (d, 1 H, J = 16 Hz, 6’-H), 6.04 (d, 1 H, J = 16 Hz,
E
Z
-
78°C, the mixture was poured into aq sat. potassium sodium (+)-
tartrate solution and the mixture was allowed to warm to r.t. The
7
’-H).
1
3
C NMR (100 MHz, CDCl ): d = -5.35 [Si(CH ) ], 16.8 (2-
3
3 2
mixture was diluted with Et O (20 mL) and stirred vigorously at r.t.
2
CH ),18.3 [C(CH ) ], 18.7 (8-CH ),25.9[C(CH ) ], 27.1 (5-CH ),
3
3 3
3
3 3
3
until it separated into two phases. The aqueous layer was extracted
2
7.3 (5-CH ), 28.0 (3-C), 35.8 (5-C), 36.4 (2-C), 40.6 (4-C), 68.3
3
with Et O (2 × 20 mL). The combined organic layers were washed
2
(
1-C), 114.2 (9-C), 128.6 (7-C), 140.6 (6-C), 142.4 (8-C).
with brine, dried (MgSO ), and concentrated in vacuo. The residue
4
was purified by chromatography on silica gel (40 g, elution with
hexane/EtOAc, 25:1) to give 156 mg (88%) of 21 as a colorless oil.
This was used in the next step without further purification;
(
2R,6E)-2,5,5,8-Tetramethylnona-6,8-dien-1-ol [(R)-24]
To a solution of (R)-23 (510 mg, 1.64 mmol) in THF (10 mL) at
0 °C was added a solution of TBAF in THF (1.0 M solution, 4.8 mL,
4
with H O. The aqueous layer was extracted with Et O (2 × 20 mL).
The combined organic layers were washed with aq sat. NaHCO3
2
4
24
nD 1.4453; [a]D +3.96 (c = 1.09, CHCl3).
.8 mmol). After the mixture was stirred for 4 h at r.t, it was diluted
IR (film): n = 3360 (s, O-H), 1255 (m, Si-CH ), 1090 (m), 840 (s),
3
-
1
2
2
7
75 (s) cm .
1
H NMR (90 MHz, CDCl ): d = 0.04 [s, 6 H, Si(CH ) ], 0.86 (s, 6
and brine, dried (MgSO ), and concentrated in vacuo. The residue
was purified by chromatography on silica gel (30 g, elution with
3
3 2
4
H, 2 × 2-CH ), 0.87 (d, 3 H, J = 8.6 Hz, 5-CH ), 0.89 [s, 9 H,
3
3
SiC(CH ) ], 0.94-1.66 (m, 6 H, 3-H , 4-H , 5-H, OH), 3.31 (s, 2 H,
hexane/EtOAc, 20:1) to give 259 mg (81%) of (R)-24 as a colorless
oil; nD 1.4830; [a]D +9.89 (c = 1.15, CHCl3).
3
3
2
2
2
4
22
1
-H ), 3.42 (d, 2 H, J = 5.9 Hz, 6-H ).
2
2
1
3
C NMR (100 MHz, CDCl ): d = -5.39 (SiCH ), -5.37 (SiCH ),
IR (film): n = 3350 (s, O-H), 1640 (w, C=C), 1610 (m, C=C), 1040
3
3
3
-
1
1
[
6.7 (5-CH ), 18.3 [C(CH ) ], 23.77 (2-CH ), 23.83 (2-CH ), 25.9
C(CH ) ], 26.9 (4-C), 34.9 (2-C), 35.4 (3-C), 36.3 (5-C), 68.1 (6-
(m, C-O), 970 (s), 880 (s) cm .
3
3
3
3
3
3
3
1
H NMR (500 MHz, CDCl ): d = 0.91 (d, 3 H, J = 6.7 Hz, 2-CH ),
3
3
C), 71.8 (1-C).
1
1
1
.02 (s, 6 H, 2 × 5-CH ), 1.21-1.44 (m, 5 H, 3-H , 4-H , OH), 1.50-
3
2
2
.56 (m, 1 H, 2-H), 1.84 (s, 3 H, 8-CH ), 3.42 (ddd, 1 H, J = 6.0, 11,
3
(
R)-6-tert-Butyldimethylsilyloxy-2,2,5-trimethylhexanal (22)
6 Hz, 1-H H ), 3.49 (ddd, 1 H, J = 5.5, 11, 16 Hz, 1-H H ), 4.88 (s,
a
b
a
b
To a solution of 21 (1.10 g, 4.01 mmol) in anhyd CH Cl (20 mL)
at 0 °C were added pyridine (1.6 mL, 20 mmol) and Dess-Martin
periodinane (2.54 g, 5.98 mmol) successively. The mixture was
stirred for 2 h at r.t. before it was diluted with Et O (40 mL), and
quenched with a mixture of aq sat. NaHCO3 and aq sat.
Na S O (1:1, 20 mL). The mixture was stirred for 30 min at r.t. The
2
2
1 H, 9-H H ), 4.89 (s, 1 H, 9-H H ), 5.59 (d, 1 H, 16 Hz), 6.04 (d,
E Z E Z
1
H, 16Hz).
1
3
C NMR (100 MHz, CDCl ): d = 16.6 (2-CH ), 18.7 (8-CH ), 27.2
3
3
3
2
(
2 × 5-CH ), 27.9 (3-C), 35.8 (5-C), 36.3 (2-C), 40.4 (4-C), 68.3 (1-
3
C), 114.4 (9-C), 128.7 (7-C), 140.4 (6-C), 142.3 (8-C).
2
2
3
aqueous layer was extracted with Et O (2 × 20 mL). The combined
Anal. C H O (196.3): Calcd C 79.53, H 12.32; found C 79.45, H
2
13 24
organic layers were washed with aq sat. NaHCO and brine, dried
12.38.
3
(
MgSO ), and concentrated in vacuo. The residue was purified by
4
chromatography on silica gel (50 g, elution with hexane/EtOAc,
5:1) to give 855 mg (78%) of 22 as a colorless oil. This was imme-
diately used in the next step without further purification;
(
2S,6E)-2,5,5,8-Tetramethylnona-6,8-dien-1-ol [(S)-24]
2
To a suspension of LiAlH (842 mg, 22.2 mmol) in anhyd THF (40
mL) at 0 °C was added dropwise a solution of (2S)-13 (2.72 g, 7.37
mmol) in anhyd THF (10 mL). The mixture was stirred for 1 h at r.t,
4
2
5
24
nD 1.4359; [a]D +4.66 (c = 1.41, CHCl3).
then it was quenched with H O (0.8 mL), 15% aq NaOH solution
IR (film): n = 2800 (m, aldehyde C-H), 1730 (s, C=O), 1260 (m,
2
-
1
(0.8 mL), and H O (2.4 mL). After stirring for 2 h at r.t, the mixture
Si-CH ), 1090 (s), 840 (s), 775 (s) cm .
2
3
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

1
860
T. Tashiro et al.
SPECIAL TOPIC
was filtered through Celite. The filter cake was washed with Et O
(naphth.), 128.7 (naphth.), 128.8 (7-C), 131.2 (naphth.), 133.9
(naphth.), 138.2 (naphth.), 140.0 (6-C), 142.2 (8-C) 175.1 (1-C).
2
(
2 × 20 mL). The filtrate and washings were dried (MgSO ) and
4
concentrated in vacuo. The residue was purified by chromatography
on silica gel (30 g, elution with hexane/EtOAc, 20:1) to give 1.18 g
Anal.C H O N (363.5): Calcd C 82.60, H 9.15, N 3.85; found C
1
5
27
2
8
2.32, H 8.90, N 3.93.
2
7
22
(
(
82%) of (S)-24 as a colorless oil; nD 1.4835; [a]D -9.31
c = 1.14, CHCl3).
(
2S,6E)-N-Methyl-N-methoxy-2,5,5,8-tetramethylnona-6,8-die-
namide [(S)-25]
To a solution of (S)-14 (1.02 g, 4.86 mmol) in anhyd CH Cl (25
1
The IR and H NMR spectra were identical to those of (R)-24.
Anasl. C H O (196.3): Calcd C 79.53, H 12.32; found C 79.32, H
2
2
13
24
mL) were added i-Pr NEt (1.1 mL, 6.3 mmol), N,O-dimethylhy-
1
2.57.
2
droxylamine hydrochloride (589 mg, 6.04 mmol), EDC (1.03 g,
5
.37 mmol) and a catalytic amount of DMAP at 0 °C. After the mix-
[
2R*,6E,N(1S)]-N-[1-(1-Naphthyl)ethyl]-2,5,5,8-tetramethyl-
ture was stirred for 14 h at r.t, it was poured into H O. The aqueous
layer was extracted with CH Cl (3 × 30 mL). The combined organ-
2
nona-6,8-dienamide (2)
To a solution of (±)-14 (252 mg, 1.20 mmol) in anhyd CH Cl (10
2
2
2
2
ic layers were washed with aq sat. NaHCO3 and brine, dried
MgSO ), and concentrated in vacuo. The residue was purified by
mL) were added (S)-1-(1-naphthyl)ethylamine (0.22 mL, 1.4
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (EDC, 251 mg, 1.31 mmol) and a catalytic amount of
DMAP at 0 °C. After the mixture was stirred for 24 h at r.t, it was
poured into H O. The aqueous layer was extracted with CH Cl (3
(
4
chromatography on silica gel (20 g, elution with hexane/EtOAc
1
26
5:1) to give 983 mg (80%) of (S)-25 as a colorless oil; n 1.4815;
D
2
1
[
a]D +15.5 (c = 1.07, CHCl3).
2
2
2
×
20 mL). The combined organic layers were washed with aq sat.
IR (film): n = 1670 (s, C=O), 1610 (m, C=C), 1005 (s), 975 (m), 890
1
-
NaHCO and brine, dried (MgSO ) and concentrated in vacuo. The
(s) cm .
3
4
residue was purified by chromatography on silica gel (20 g, elution
with hexane/EtOAc 10:1 and 20:3) to give 209 mg (48%) of (2R)-2
as a white solid and 195 mg (45%) of (2S)-2 as a white solid. (2R)-
1
H NMR (500 MHz, CDCl ): d = 1.02 (s, 6 H, 2 × 5-CH ), 1.10 (d,
3
3
3
1
(
H, J = 6.8 Hz, 2-CH ), 1.24-1.35 (m, 3 H, 3-H H , 4-H ), 1.54-
3
a
b
2
.68 (m, 1 H, 3-H H ), 1.83 (dd, 3 H, J = 0.72, 1.2 Hz, 8-CH ), 2.80
a
b
3
2
was further purified by recrystallization from diisopropyl ether to
br s, 1 H, 2-H), 3.19 (s, 3 H, NCH ), 3.68 (s, 3 H, NOCH ), 4.88 (d,
3
3
give pure (2R)-2 as colorless needles. (2S)-2 was also recrystallized.
1
H, J = 1.2 Hz, 9-H H ), 4.90 (d, 1 H, J = 0.72 Hz, 9-H H ), 5.58
E Z E Z
[
2R,6E,N(1S)]-2
(d, 1 H, J = 16 Hz, 6-H), 6.04 (d, 1 H, J = 16 Hz, 7-H).
2
2
Mp 84.0-85.5 °C; [a]D -44.6 (c = 1.02, CHCl3).
13
C NMR (126 MHz, CDCl ): d = 17.3 (2-CH ), 18.7 (8-CH ), 27.0
3
3
3
IR (nujol): n = 3250 (w, N-H), 1660 (s, C=C), 1630 (s, C=O), 1545
(
(5-CH ), 27.3 (5-CH ), 28.8 (3-C), 32.1 (NCH ), 35.7 (2,5-C), 40.8
3
3
3
-
1
s, C=O), 970 (m), 890 (m), 795 (w), 775 (s), 720 (w) cm .
(4-C), 61.4 (NOCH ), 114.4 (9-C), 128.8 (7-C), 140.2 (6-C), 142.2
3
1
(8-C).
H NMR (500 MHz, CDCl ): d = 0.97 (s, 3 H, 5-CH ), 0.98 (s, 3 H,
3
3
5
-CH ), 1.07 (d, 3 H, J = 6.7 Hz, 2-CH ), 1.23-1.35 (m, 3 H, 3-
Anal. C H O N (253.4): Calcd C 71.10, H 10.74, N 5.53; found C
70.96, H 10.75, N 5.49.
3
3
15 27
2
H H , 4-H ), 1.48-1.55 (m, 1 H, 3-H H ), 1.67 (d, 3 H, J = 6.8 Hz,
2
H, 9-H ), 5.49 (d, 1 H, J = 16 Hz, 6-H), 5.62 (d, 1 H, J = 8.0 Hz,
NH), 5.94 (quint.-like, 1 H, J = 7.0 Hz, 1’-H), 6.01 (d, 1 H, J = 16
Hz, 7-H), 7.42-7.48 (m, 4 H, naphth.), 7.79 (d, 1 H, J = 8.0 Hz,
naphth.), 7.85 (dd, 1 H, J = 1.5, 8.0 Hz, naphth.), 8.07 (d, 1 H,
J = 8.5 Hz, naphth.).
a
b
2
a
b
’-H ), 1.78 (s, 3 H, 8-CH ), 2.01-2.12 (m, 1 H, 2-H), 4.88 (br s, 2
3
3
2
(1S,3S,7S)-3,6,6,9-Tetramethylbicyclo[5.4.0]undecan-2-one
[(S)-27]
(
i) Under LiClO Conditions: To a solution of 25 (434 mg, 1.72
4
mmol) in anhyd THF (15 mL) at -20 °C was added vinylmagne-
sium bromide in THF (0.95 M solution, 9.0 mL, 8.6 mmol). The
mixture was allowed to warm up to r.t. and stirred for 4 h before it
was poured into aq sat. NH Cl. The aqueous layer was extracted
with CH Cl (3 × 20 mL). The combined organic layers were
washed with aq sat. NaHCO and brine, dried (MgSO ), and con-
centrated in vacuo to give 413 mg (nearly quant.) of (S)-26 as a col-
orless oil. To a solution of LiClO (25.4 g, 239 mmol) in anhyd Et O
1
3
C NMR (126 MHz, CDCl ): d = 18.0 (2-CH ), 18.7 (8-CH ), 20.5
3
3
3
(
(
(
(
(
2'-CH ), 27.0 (5-CH ), 27.2 (5-CH ), 29.4 (3-C), 35.6 (5-C), 40.6
4
3
3
3
4-C), 42.2 (2-C), 44.2 (1’-C), 114.5 (9-C), 122.5 (naphth.), 123.6
naphth.), 125.1 (naphth.), 125.9 (naphth.), 126.5 (naphth.), 128.4
naphth.), 128.7 (naphth.), 128.9 (7-C), 131.2 (naphth.), 133.9
naphth.), 138.2 (naphth.), 140.0 (6-C), 142.2 (8-C) 175.1 (1-C).
2
2
3
4
4
2
(45 mL) and (+)-10-camphorsulfonic acid (CSA, 6 mg, 0.03 mmol)
Anal. C H O N (363.5): Calcd C 82.60, H 9.15, N 3.85; found C
8
15
27
2
in anhyd THF (0.6 mL), a solution of the above (S)-26 in anhyd
Et O (10 mL) was added dropwise. The mixture was stirred at r.t.
2
2.76, H 9.14, N 3.81.
[
2S,6E,N(1S)]-2
for 20 h. It was cooled to 0 °C, and diluted with H O, and filtered
2
2
2
Mp 78.5-80.0 °C; [a]D -48.9 (c = 1.13, CHCl3).
through Celite. The filtrate was extracted with Et O (2 × 30 mL).
2
The combined organic layers were washed with brine, dried
IR (nujol): n = 3275 (w, N-H), 1660 (s, C=C), 1630 (s, C=O), 1530
(
-
1
(MgSO ), and concentrated in vacuo. The residue was purified by
4
s, C=O), 970 (m), 885 (m), 795 (w), 775 (s), 720 (w) cm .
chromatography on silica gel (10 g, hexane/EtOAc, 100:1) to give
260 mg (69%, 2 steps) of 27 as a stereoisomeric mixture. This resi-
due was purified by medium pressure liquid chromatography
(MPLC, silica gel 50 ± 20 mm, 40 g, elution with hexane/EtOAc,
300:1, pressure: 30 MPa, elution rate: 12 mL/1 min) to give 12 mg
of pure (1S,3S,7R)-27.
1
H NMR (500 MHz, CDCl ): d = 0.91 (s, 3 H, 5-CH ), 0.92 (s, 3 H,
3
3
5
-CH ), 1.13 (d, 3 H, J = 7.0 Hz, 2-CH ), 1.16-1.35 (m, 3 H, 3-
3
3
H H , 4-H ), 1.49-1.55 (m, 1 H, 3-H H ), 1.67 (d, 3 H, J = 6.5 Hz,
2
H, 9-H ), 5.45 (d, 1 H, J = 16 Hz, 6-H), 5.59 (d, 1 H, J = 8.0 Hz,
a
b
2
a
b
’-H ), 1.77 (s, 3 H, 8-CH ), 1.94-2.10 (m, 1 H, 2-H), 4.86 (br s, 2
3
3
2
NH), 5.94 (quint.-like, 1 H, J = 7.5 Hz, 1’-H), 5.97 (d, 1 H, J = 16
Hz, 7-H), 7.42-7.50 (m, 4 H, naphth.), 7.80 (d, 1 H, J = 8.0 Hz,
naphth.), 7.86 (dd, 1 H, J = 1.5, 7.5 Hz, naphth.), 8.10 (d, 1 H,
J = 7.5 Hz, naphth.).
(
4S,8E)-4,7,7,10-Tetramethyl-1,8,10-undecatrien-3-one [(S)-26]
-
1
IR (film): n = 1700 (s, C=O), 1640, (w, C=C), 1610 (w, C=C) cm .
(1S,3S,7R)-27
1
3
nD25 1.5009; [a]D +166 (c = 0.32, CHCl ); CD: De = +1.55 (297
23
C NMR (126 MHz, CDCl ): d = 18.0 (2-CH ), 18.7 (8-CH ), 20.3
3
3
3
3
(
2'-H ), 26.9 (5-CH ), 27.2 (5-CH ), 29.4 (3-C), 35.6 (5-C), 40.7 (4-
nm, c = 0.032, hexane).
3
3
3
C), 42.2 (2-C), 44.2 (1'-C), 114.5 (9-C), 122.5 (naphth.), 123.7
naphth.), 125.1 (naphth.), 125.9 (naphth.), 126.5 (naphth.), 128.4
IR (film): n = 1695 (s, C=O), 1450 (m), 1135 (m), 1070 (m), 990
(
-1
(
m), 955 (m), 895 (m), 740 (m) cm .
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
1861
1
H NMR (500 MHz, CDCl ): d = 0.85 (s, 3 H, b-6-CH ), 0.96 (d,
(w), 1170 (w), 1150 (w), 1130 (w), 1070 (w), 1050 (w), 1025 (w),
1010 (w), 975 (w), 960 (w), 940 (w), 920 (w), 910 (w), 890 (s), 870
(m), 830 (w), 750 (w), 720 (w), 675 (w) cm .
3
3
J = 6.7 Hz, 3 H, 3-CH ), 1.07 (s, 3 H, a-6-CH ), 1.19-1.34 (m, 2 H,
4
CH ), 1.66-1.88 (m, 4 H, 5-H H , 10-H , 11-H H ), 2.05-2.11 (m,
1
2
3
3
-
1
-H H , 5-H H ), 1.40-1.46 (m, 1 H, 4-H H ), 1.71 (br s., 3 H, 9-
a
b
a
b
a
b
3
a
b
2
a
b
1
H NMR (500 MHz, CDCl ): d = 0.96 (s, 3 H, b-6-CH ), 0.99 (s, 3
3
3
H, 11-H H ), 2.16 (br s, 1 H, 7-H), 2.64-2.72 (m, 1 H, 3-H), 2.74-
a b
H, a-6-CH ), 1.01 (d, J = 7 Hz, 3 H, 3-CH ), 1.08-1.15 (m, 1 H, 5-
3
3
.78 (m. 1 H, 1-H), 5.57 (br s, 1 H, 8-H).
H H ), 1.15-1.22 (m, 1 H, 4-H H ), 1.47-1.53 (m, 1 H, 4-H H ),
a
b
a
b
a
b
1
3
C NMR (100 MHz, CDCl ) d = 17.1 (3-CH ), 24.0 (9-CH ), 24.7
1.58-1.66 (m, 1 H, 5-H H ), 1.68 (br s, 3 H, 9-CH ), 1.72-1.91 (m,
a b 3
3
3
3
(
(
1
6-CH ), 26.9 (10-C), 29.7 (11-C), 30.9 (4-C), 31.6 (6-CH ), 36.1
4 H, 10-H , 11-H ), 2.13 (br s, 1 H, 7-H), 2.23-2.31 (m, 1 H, 3-H),
2 2
3
3
6-C), 37.3 (5-C), 45.3 (7-C), 46.3 (3-C), 48.1 (1-C), 122.4 (8-C),
34.3 (9-C), 219.5 (2-C).
2.82-2.75 (m, 1 H, 1-H), 4.76 (s, 1 H, 2-CH H ), 4.81 (s, 1 H, 2-
a b
CH H ), 5.51 (br s, 1 H, 8-H).
a b
1
3
Anal. C H O (220.2): Calcd C 81.76, H 10.98; found C 81.63, H
C NMR (126 MHz, CDCl ) d = 21.6 (3-CH ), 24.2 (9-CH ), 25.1
3 3 3
15
24
1
1.14.
(6-CH ), 26.7 (10-C), 32.0 (6-CH ), 35.2 (11-C), 36.37 (6-C), 36.44
3
3
(
1
3-C), 36.8 (4-C), 37.8 (5-C), 41.5 (1-C), 47.5 (7-C), 107.1 (2-CH2),
23.9 (8-C), 134.1 (9-C), 162.2 (2-C).
(
ii) Under Et AlCl Conditions: In the same manner as described
2
above, (S)-25 (913 mg, 3.61 mmol) was converted to (S)-26. To a
solution of crude (S)-26 in anhyd CH Cl (50 mL) was added dieth-
Anal. C H (218.2): Calcd C 88.00, H 12.00; found C 87.90, H
2
2
16 26
ylaluminum chloride in hexane (0.95 M solution, 18 mL, 17 mmol)
at -78 °C. The mixture was stirred at that temperature for 1 h, then
allowed to warm up to 0 °C, and stirred for 1 h. To the mixture was
added dropwise aq sat. Rochelle's salt solution. It was stirred at r.t.
12.00.
Estimation of the Enantiomeric Excess of (1S,3S,7R)-1
The enantiomeric excess of (1S,3S,7R)-1 was determined by GC
analysis. Conditions (column: Chirasil-DEX -CB, 0.25 mm × 25
m, 100+2°C/min, carrier gas: He, 110 kPa). t = 23.7 min [~100%,
“
for 2 h, and diluted with Et O (30 mL). The aqueous layer was ex-
2
tracted with Et O (2 × 20 mL). The combined organic layers were
2
R
washed with brine, dried (MgSO ) and concentrated in vacuo. The
4
(1S,3S,7R)-1]. Therefore the enantiomeric purity of (1S,3S,7R)-1
residue was purified by chromatography on silica gel (20 g, elution
with hexane/EtOAc = 100:1) to give 663 mg (81%, 2 steps) of 27 as
a stereoisomeric mixture.
was >99% ee.
X-Ray Analysis of [2R,6E,N(1S)]-2
Crystal Data: C H NO, M = 363.54, orthorhombic, space group
2
5
33
Determination of the Selectivity of the Diels-Alder Reaction to
Give 27
P2 2 2 , a = 21.518(5) Å, b = 22.440(7) Å, c = 9.587(9) Å,
1 1 1
3
-3
V = 4629(4) Å , Z = 8, Dc = 1.043 Mgm , F(000) = 1584,
m(MoKa) = 0.622 cm .
-
1
The diastereoselectivity of the formation of 27 was determined by
“
GC analysis. Conditions (column: TC-WAX , 0.53 mm × 15 m,
The crystal used for data collection was a colorless prism with the
approximate dimensions 0.25 x 0.20 x 0.20 mm. All data were ob-
tained on a Rigaku AFC-5S automated four-circle diffractometer
with graphite-monochromated Mo-Ka radiation. Unit cell parame-
ters were determined by least squares refinement of the optimized
setting angles of 25 reflections in the range 10.1°<0<11.9°. The in-
tensities were measured using w20 scan up to 50°. Three standard
reflections were monitored every 150 measurements. The data were
corrected for Lorentz and polarization factors. Absorption and de-
cay correction was not applied. Of the 3750 independent reflections
which collected, 2729 reflections with I>0.1s(I) were used for the
structure determination and refinement. The structure was solved by
direct methods using the TEXSAN crystallographic software pack-
1
30 °C (constant), carrier gas: He, 110 kPa).
(
i) via LiClO conditions: t = 2.72 min [18.6%, (1S,3S,7R)-27],
4 R
t = 3.20 min, [29.5%, (1S,3S,7S)-27], t = 3.72 min, [15.4%,
R
R
(
1R,3S,7R)-27], and t = 4.12 min, [36.5%, (1R,3S,7S)-27]. There-
R
fore the ratio of diastereoselectivity for 27 was estimated to be cis/
trans = 55.1:44.9.
(
(
ii) via Et AlCl conditions: [50.4%, (1S,3S,7R)-27], [18.8%,
1S,3S,7S)-27], [2.9%, (1R,3S,7R)-27], and [27.9%, (1R,3S,7S)-27].
2
Therefore the ratio of diastereoselectivity for 27 was estimated to be
cis/trans = 78.3:21.7.
Estimation of the Enantiomeric Excess of (1S,3S,7R)-27
2
9
age. All non-H atoms were found in Fourier map. The refinement
of atomic parameters was carried out by the full matrix least-
squares refinement, using anisotropically temperature factors for all
non-H atoms. All H atoms, except for attached to the N atom, were
located geometrically and not refined. The H atom attached to N1b
was found in Difference Fourier map and refined isotropically, but
the H atom attached to N1a could not be found in the final refine-
ment. The final refinement converged with R = 0.049 and
Rw = 0.050 (R and Rw were calculated by 1300 reflections with
I>2.0s(I).) for 492 parameters. Atomic scattering factors were tak-
en from "International Tables for X-ray Crystallography".3 Supple-
mentary material available includes lists of atomic coordinates for
the non-H atoms, the bond lengths and angles in (2R)-2 with their
The enantiomeric excess of (1S,3S,7R)-27 was determined by GC
analysis. Conditions (column: Chirasil-DEX -CB, 0.25 mm × 25
“
m, 100 + 3 °C/min, carrier gas: He, 110 kPa). t = 23.1 min [~100%,
R
(
1S,3S,7R)-27]. Therefore the enantiomeric purity of (1S,3S,7R)-27
was >99% ee.
(
1S,3S,7R)-2-Methylene-3,6,6,9-tetramethylbicyclo[5.4.0]un-
dec-8-ene [(1S,3S,7R)-1] [3-methyl-a-himachalene]
To a solution of (1S,3S,7R)-27 (87 mg, 0.40 mmol) in anhyd THF
(
10 mL) at -40 °C was added Tebbe reagent in toluene (0.5 M so-
lution, 3.0 mL, 1.5 mmol). The mixture was stirred at this temp. for
h, then allowed to warm up to r.t, and stirred at r.t. for 6 h. To this
0
1
mixture at 0 °C was added slowly 15% aq NaOH solution (3 mL),
and the mixture was filtered through Celite. The filtrate was concen-
trated in vacuo and the residue was purified by chromatography on
silica gel (30 g, elution with pentane) and distillation to give 60 mg
3
1
e.s.d.s in parentheses.
Acknowledgement
(
70%) of (1S,3S,7R)-1 as a colorless oil; bp 97-99 °C/3 Torr;
2
4
22
nD 1.5047; [a]D +181(c = 0.32, CHCl ).
We thank Professor J. A. Pickett (IACR-Rothamsted, U. K.) for his
cooperation. We acknowledge the financial support of this work by
a Grant-in-Aid for Scientific Research (No. 11480165), Japanese
Ministry of Education, Science, Sports and Culture.
3
IR (film): n = 3100 (w), 2975 (s), 2925 (s), 2900 (s), 1670 (w, C=C),
1
1
630 (m, C=C), 1470 (w), 1450 (m), 1440 (sh.), 1400(w), 1390 (w),
380 (w), 1360 (w), 1350 (w), 1340 (w), 1280 (w), 1220 (w), 1190
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York

1
862
T. Tashiro et al.
SPECIAL TOPIC
References
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1
Article Identifier:
437-210X,E;2000,0,13,1852,1862,ftx,en;E10200SS.pdf
1
1
Synthesis 2000, No. 13, 1852–1862 ISSN 0039-7881 © Thieme Stuttgart · New York