The chemistry of zerumbone. Part 5: Structural transformation of the dimethylamine derivatives

Article abstract of DOI:10.1016/S0040-4020(03)00667-7

Zerumbone (1) and its 6,7-epoxide (2) react with ammonia and dimethylamine regio- and stereospecifically, affording monoamines 3, 4, 7 and 8. All adducts have the same relative configuration at C2 and C3. The conjugate amination is thermodynamically controlled to arrive at a single diastereomer. At 15°C 7 reacts with cyanide to give aminonitrile 10 as the single product, while at 30°C, acyclic aminonitrile 11 is also formed. The reaction with 8 affords at 0°C bicyclic aminonitrile 12 of the asteriscane skeleton, while at 30°C or higher temperature, mixtures of 12 and tricyclic nitriles 13 and 13′ are obtained. Refluxing of 7, 8 and 10 in aqueous acetonitrile promotes scission of the zerumbone ring by retro-Mannich reaction to provide acyclic aldehydes 16-18, respectively. The dimethylamino group of 7, 8 and 10 is eliminated stereospecifically by Cope- and base-catalyzed eliminations to regenerate the zerumbone skeleton in the products 1, 2 and 21. Cope elimination of 12 results in a mixture of 13 and 13′ by deaminative transannular etherification.

Full text of DOI:10.1016/S0040-4020(03)00667-7

Tetrahedron 59 (2003) 4857–4866
The chemistry of zerumbone. Part 5: Structural transformation of
the dimethylamine derivatives
b
c
d
e
Takashi Kitayama,a Taketo Yokoi, Yasushi Kawai, Richard K. Hill, Masanori Morita,
,
*
Tadashi Okamoto,a Yukio Yamamoto,f Valery V. Fokin,g K. Barry Sharplessg
and Seiji Sawadab
,
*
aDepartment of Agricultural Chemistry, Faculty of Agriculture, Kinki University, Nara 631-8505, Japan
bKyoto University of Education, Fushimi, Kyoto 612-8522, Japan
cInstitute for Chemical Research, Kyoto University, Uji 611-0011, Japan
dDepartment of Chemistry, University of Georgia, Athens, GA 30602, USA
eJoint Center, Kinki University, Nara 631-8505, Japan
fGraduate School of Human and Environmental Studies, Kyoto University, Sakyo, Kyoto 606-8501, Japan
gDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
Received 17 March 2003; accepted 24 April 2003
Abstract—Zerumbone (1) and its 6,7-epoxide (2) react with ammonia and dimethylamine regio- and stereospecifically, affording
monoamines 3, 4, 7 and 8. All adducts have the same relative configuration at C2 and C3. The conjugate amination is thermodynamically
controlled to arrive at a single diastereomer. At 158C 7 reacts with cyanide to give aminonitrile 10 as the single product, while at 308C,
acyclic aminonitrile 11 is also formed. The reaction with 8 affords at 08C bicyclic aminonitrile 12 of the asteriscane skeleton, while at 308C or
higher temperature, mixtures of 12 and tricyclic nitriles 13 and 130 are obtained. Refluxing of 7, 8 and 10 in aqueous acetonitrile promotes
scission of the zerumbone ring by retro-Mannich reaction to provide acyclic aldehydes 16–18, respectively. The dimethylamino group of 7, 8
and 10 is eliminated stereospecifically by Cope- and base-catalyzed eliminations to regenerate the zerumbone skeleton in the products 1, 2
and 21. Cope elimination of 12 results in a mixture of 13 and 130 by deaminative transannular etherification. q 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
rence of transannular reactions in the chemistry of the
germacrenes.5a–e Today, when structures can be determined
on milligrams without ever performing a reaction, the
opportunity to fully explore the chemistry of interesting
substrates available in almost unlimited supply is rare. For
the purpose of practical utilization of 1 as a new natural
resource, we have initiated an investigation of its funda-
mental behavior and chemical reactions. In previous papers,
we have found that 1 fully justifies thorough investigation.
The conjugated double bonds permit introduction of
additional and varied functionality by conjugate addition.
Many kinds of derivatives were synthesized from 1 in
moderate to high yield with high regio- and stereo-
selectivity.6–10
Zerumbone 11,2a–c is a crystalline sesquiterpene abundantly
available from the wild ginger, Zingiber zerumbet Smith.
Despite its unique structure, with a cross-conjugated ketone
in an 11-membered ring, as well as interesting biological
activity, only limited chemical3a–h and pharmaceutical4a–j
studies have been reported.
Zerumbone 1 presents an unusual and increasingly rare
opportunity to investigate the chemistry of strained, reactive
natural products. Historically, the study of natural products
has enriched organic chemistry enormously. Examples from
terpenes alone include the information and useful by-
products acquired from the investigation of the resin acids,
menthol, and carvone, our knowledge of rearrangements
gained from the reactions of camphor, pinene, caryophyl-
lene, longifolene, and chrysanthemic acid, and the occur-
Of the nucleophiles examined so far, methanol, cyanide, and
benzenethiol and selenol add mainly to C3 of 1 and 2 at mild
conditions, and afford stereospecific addition products.
Hydroxide and acetate have not provided conjugate addition
products under similar mild conditions, although retro-aldol
reaction may be occurring. The subjects of the present report
are the conjugate addition of ammonia and dimethylamine,
and further structural transformation of the addition
products (Scheme 1).
Keywords: zerumbone; sesquiterpene; retro-Mannich; asteriscane;
transannular; Cope elimination.
*
Corresponding authors. Tel.: þ81-742-43-1511; fax: þ81-742-43-1445;
e-mail: kitayama@nara.kindai.ac.jp; sssawada@mbd.biglobe.ne.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00667-7

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T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
changes were observed faster in the other aminations.
Moreover, monoamine 3 was somewhat unstable and
gradually reverted to 1, but not to its [2Z]-isomer. This
result implies that the conjugate addition is thermodynami-
cally controlled in an equilibrium between two dia-
stereomers of 3 and 1 via carbanion 9 (or the
corresponding enolate), and finally affords 3 of the X-ray
structure as the more stable product. The opposite stereo-
chemistry of zerumbonethiol and zerumboneselenol adducts
must then be the result of kinetically controlled additions.
Scheme 1.
2. Results and discussion
The all [E] configuration of 1 seems more stable than the
[2Z]-isomer, since the reverse reaction of 3 gives 1 in the
equilibrium. The relative orientation of the amino group and
epoxide oxygen in 4 and 8 shows that amination occurred
from the same face as the epoxide in 2. Steric repulsion of
the C6 methyl group of 2 is the provable reason, since the
methyl stands almost perpendicular to the face of the
zerumbone ring, as can be seen in its X-ray structure.3c
2.1. Conjugate addition of amines
Common primary and secondary amines reacted with 1 and
2 at room or lower temperature to give conjugate addition
products at C3, and sometimes at C3 and C10 of the
substrates. Imine adducts were not observed in these
reactions, although oxime3b,11 is obtained with hydroxyl-
amine. Among amines tested, ammonia and dimethylamine
were typical and studied in detail in this paper.
2.2. Conjugate addition of cyanide
In a tightly sealed container, 1 was stirred with excess
concentrated aqueous ammonia in acetonitrile at room
temperature to provide monoamine 3 (Scheme 2). The same
reaction with 2 gave crystalline 4. These were then
acetylated to amides 5 and 6, respectively, for further
analysis. The reaction of 1 and 2 with dimethylamine
afforded crystalline monoamines 7 and 8, respectively.
These conjugate aminations gave a single diastereomer of
each monoamine, and no diamine and no another dia-
stereomer of products were observed.
Since cyanide appears to have a particular affinity for 1 and
2,2c it was tested with 7 and 8 so as to introduce a new
functional group and to check the reactivity of the remaining
conjugated double bond at C10. The reaction provided
different products depending on the substrate and the
temperature. At 08C no reaction occurred with 7, but at
158C it afforded a single diastereomer of aminonitrile 10 and
no another diastereomer of product was observed, and at
308C a mixture of 10 and acyclic aminonitrile 11 was
formed in equal amounts (Scheme 3). The striking ring
scission which occurs at 308C is a retro-Mannich reaction,
and will be discussed below. No further addition of cyanide
to C9 of 11 was observed, even using excess cyanide. The
configuration of 10 at C10 has not been determined, while
the relative structure at C2 and C3 appears unchanged by the
reaction conditions.
The stereochemistry of 4, 5, 7 and 8 was determined
unambiguously by X-ray diffraction (Fig. 1). Their relative
configurations at C2 and C3 are the same, and show that
the all amino adducts were obtained as syn adducts. The
configuration is, however, opposite to that of the
benzenethiol and benzeneselenol adducts.7
Cyanation of epoxyamine 8 at 08C gave bicyclic amino-
nitrile 12 as a single diastereomer and no another
diastereomer of product was observed, while at 308C the
product was a mixture of 12 and the tricyclic nitriles 13 and
130. The structures having the asteriscane skeleton12 were
NMR spectra taken during the early stages of the reaction of
ammonia with 1 showed that the addition product was a
diastereomer mixture, syn-adduct 3 and anti-adduct (76:24
for 5 h detected by 1H NMR). The mixture finally
equilibrated to the single diastereomer 3. The spectral
Scheme 2.

T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
4859
Figure 1. ORTEP drawings of the crystal structures of amine derivatives 4, 5, 7 and 8.
determined by NOE analysis and X-ray diffraction (Fig. 2).
Another diastereomer of 13 was previously obtained from
the benzeneselenol adduct.6 The results suggest that some
multi-functional asteriscanes can be synthesized from 1 by
these simple reactions.
2.3. Retro-Mannich reaction
When amine 7 was refluxed in aqueous acetonitrile, acyclic
ketoaldehyde 16 was obtained almost quantitatively. The
same type of reaction occurred with 8 and 10 to afford 17
and 18, respectively. This thermal deaminative ring-
cleavage can be described as a retro-Mannich reaction.
Hydrolysis of the intermediate iminium ion 19 gives an
unstable hemiaminal, which is rapidly hydrolyzed to the
corresponding aldehydes (Scheme 4).
This transformation is initiated by conjugate addition of
cyanide to C10 of 8 (Scheme 3). The carbanion on C11 of 14
attacks the C7 carbon of the epoxide ring from the back side
by transannular displacement to provide alcohol 12. The
formation of the diastereomeric mixture of 13 and 130 is
shown in Scheme 3.
The aldehyde 16 was transformed with potassium cyanide to
Scheme 3.

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T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
Figure 2. ORTEP drawings of the crystal structures of asterisianes 12, 13 and 130.
cyanohydrin 20, while in the presence of dimethylamine, 11
was afforded in high yield. Even using excess cyanide,
neither reaction provided any conjugate addition to C8 of
the aldehyde.
regenerate 1 in high yield (Scheme 5). The same reaction
occurred with 8 and 10, yielding 2 and 21, respectively. No
epoxidation of the remaining double bond was observed.
The [2E]-geometry of 21 was determined by X-ray
diffraction (Fig. 3). These reactions appear to be Cope
eliminations, wherein the amine oxide 22 initially formed
by oxidation with MCPBA undergoes thermal syn-elimin-
ation to afford the [2E] alkene. In earlier work7 we reported
a similar thermal elimination of zeurmboneselenol adduct.
2.4. Cope and base-catalyzed elimination
The dimethylamino group of 7 was easily eliminated by
treatment with m-chloroperbenzoic acid (MCPBA) at 08C to
Scheme 4.

T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
4861
Scheme 5.
In this case the C2 hydrogen and the leaving selenoyl group
on C3 had a trans relationship, and then the predominant
product of syn-elimination was the [2Z] isomer.
with MCPBA. It was unstable and was rapidly transformed
to the mixture of 13 and 130 by washing with sodium
carbonate.
Attempted conjugate addition of hydroxide to 7 at room
temperature led instead to elimination to again afford 1. The
same reaction occurred with 8 and 10 to give 2 and 21,
respectively. All the products had exclusively the [2E]
configuration. The hydroxide-catalyzed elimination of
dimethylamine is best described as an E1cB mechanism
and equilibration through carbanion intermediate 90
(Scheme 5).
In this reaction, the initially formed amineoxide 23 under-
goes syn-elimination to generate alcohol 24, which has a
newly formed conjugated double bond at C3. The hydroxyl
group on C7 of 24 undergoes intramolecular conjugate
addition to the double bond, and provides carbanion
intermediate 25, which finally affords by protonation the
diastereomeric mixture of 13 and 130. Their ratio seems to
depend on the base used in the reaction. The internal
etherification was also observed in the reaction of 8 with
cyanide (Scheme 3). The reaction involves the base-
catalyzed elimination of 12 followed by conjugate addition
as in the case of 24.
The reaction of 12 with MCPBA at 08C afforded a mixture
of 13 and 130, which appear to result from initial Cope
elimination followed by base catalyzed conjugate addition
of the C7 hydroxyl group. Amineoxide 23 was observed as
1
an intermediate in H NMR spectra of the reaction of 12
These elimination reactions show that dimethylamine can
be a good protecting group for the C2 double bond of 1 and
2. The amine adducts also permit selective scission of the
C2–C3 bond by retro-Mannich reaction giving an acyclic
product, which we have not yet been able to reach by the
more obvious retro-aldol reaction.
3. Conclusion
Addition of amines occurs selectively at the less hindered
conjugated double bond of zerumbone, leading to mono-
amine derivatives. These have been found to undergo ready
ring cleavage by a reverse Mannich reaction, providing a
useful alternative to retroaldol ring scission. On treatment
with cyanide, the dimethylamine adduct of zerumbone
oxide undergoes transannular cyclization to the natural
asteriscane skeleton, providing a new synthetic route to this
family. Finally, the amino group serves as a valuable
protecting group for the C2 double bond, since it can be
readily eliminated.
Figure 3. ORTEP drawing of the crystal structure of 21.

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T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
4. Experimental
Crystallographic study of 4. A colorless prismatic crystal,
crystal size 0.40£0.50£0.70 mm3, monoclinic, space group
˚
4.1. General methods
P21/n (no. 14), a¼10.268(1), b¼7.448(1), c¼19.321(1) A,
3
b¼90.425(9)8, V¼1477.5(3) A , Z¼4, Dcalcd¼1.130 g/cm3,
˚
Melting points (mp) are uncorrected. NMR spectra were
obtained at 270 and 500 MHz for protons, and 68 and
125 MHz for 13C in CDCl3 with tetramethylsilane (TMS) as
the internal standard unless otherwise noted. Chemical
shifts d were reported in ppm from TMS. Mass spectra were
recorded at 70 eV, and high-resolution mass spectra
(HRMS) were obtained by direct injection. The X-ray
diffraction and CCDC numbers appear in the section on
compound data. Chemicals were commercially available
reagent grade, and used without further purification. The
preparation and properties of 1 and 2 have been described in
earlier papers.2c,9
m(Cu Ka)¼5.82 cm21, was used for data collection. The
intensity data were measured on a Rigaku AFC7R
diffractometer using Cu Ka radiation at a temperature of
20.08C by a v–2u scan technique. The structure was solved
by direct methods (SIR92)13 and expanded using Fourier
techniques (DIRDIF94).14 All calculations were performed
using the teXsan crystallographic software package. The
final cycle of full-matrix least-squares refinement was based
on 2236 observed reflections (I.1.50s(I)) and 264 variable
parameters and gave R¼0.056 and Rw¼0.086. The value of
the goodness of fit indicator was 1.06 (Summary of Data
CCDC 183922).
4.1.1. Preparation of 3 and 4. A mixture of 1 (0.65 g,
3.0 mmol) in acetonitrile (10 mL) and ammonia (25% in
water, 10 mL) was stirred for 5 days at room temperature in
a tightly sealed container using a silicone stopper. The
solution was concentrated on a rotary evaporator under
reduced pressure, and the residue was taken up in EtOAc
(15 mL). The organic solution was successively washed
with water (3£5 mL) and brine (2 mL), and dried over
anhydrous Na2SO4. The solvent was removed to yield a
crystalline solid, which was recrystallized from hexane to
give adduct 3. The procedure was applied to 2 for 4 days to
furnish 4. Acetylation of 3 and 4 with acetic anhydride and
pyridine followed standard procedures to give amides 5 and
6, respectively.
4.1.2. (2R p,3R p)-[6E,10E]-3-(N-Acetylamino)-2,6,9,9-
tetramethylcycloundec-6,10-dien-1-one (5). Crystallized
from EtOAc, yield 95% from 3; mp 192–1938C; IR (KBr):
1
3302, 1693, 1632, 1547 cm21; H NMR: d ppm 0.96 (d,
J¼7.0 Hz, CH3 on C2), 1.00–1.05 (m, 1H, C4), 1.15–1.21
(m, 1H, C4), 1.18 (s, CH3 on C9), 1.23 (s, 3H, CH3 on C9),
1.41 (s, 3H, CH3 on C6), 1.76 (t, J¼12.5 Hz, 1H, C5), 1.90
(dd, J¼4.0, 12.5 Hz, 1H, C8), 1.96–2.00 (m, 1H, C5), 2.04
(s, 3H, CH3 of NHAc), 2.25 (t, J¼12.5 Hz, 1H, C8), 2.94–
2.98 (m, 1H, C2), 4.56 (dt, J¼2.5, 8.0 Hz, 1H, C3), 5.20 (dd,
J¼4.0, 12.5 Hz, 1H, C7), 5.69 (d, J¼8.0 Hz, NH, C3), 6.18
(d, J¼16.0 Hz, 1H, C10), 6.45 (d, J¼16.0 Hz, 1H, C11); 13C
NMR: d ppm 6.8 (CH3 on C2), 16.4 (CH3 on C6), 23.0 (CH3
on C9), 23.3 (CH3, NHAc), 27.8 (C4), 28.9 (CH3, C9), 37.0
(C5), 40.0 (C9), 41.6 (C8), 50.7 (C3), 50.8 (C2), 123.4 (C7),
128.5 (C11), 136.4 (C6), 151.8 (C10), 170.1 (CvO,
NHAc), 202.0 (C1); HRMS: m/z calcd mass for
C17H27NO2 277.2042, found 277.2068.
Compound (2R p,3R p)-[6E,10E]-3-amino-2,6,9,9-tetra-
methylcycloundec-6,10-dien-1-one (3). Yield 0.59 g, 84%;
1
IR (neat) 1692, 1628 cm21; H NMR: d ppm 1.00 (d, 3H,
J¼6.5 Hz, CH3 on C2), 1.03–1.07 (m, 2H, C4), 1.14 (s, 3H,
CH3 on C9), 1.18 (s, 3H, CH3 on C9), 1.40 (s, 3H, CH3 on
C6), 1.83–1.92 (m, 2H, C5 and C8), 2.05–2.10 (m, 1H, C5),
2.24 (t, 1H, J¼11.6 Hz, C8), 2.68 (dq, 1H, J¼3.0, 6.5 Hz,
C2), 3.30–3.34 (m, 1H, C3), 5.08 (dd, 1H, J¼4.3, 11.6 Hz,
C7), 6.11 (d, 1H, J¼16.2 Hz, C11), 6.20 (d, 1H, J¼16.2 Hz,
C10); 13C NMR: d ppm 6.0 (CH3 on C2), 16.5 (CH3 on C6),
22.9 (CH3 on C9), 29.0 (CH3 on C9), 30.6 (C4), 38.0
(C5), 39.9 (C9), 41.3 (C8), 53.1 (C3), 55.3 (C2), 122.0
(C7), 128.1 (C11), 138.0 (C6), 151.7 (C10), 202.0 (C1);
HRMS m/z calcd mass for C15H25NO 235.1936, found
235.1925.
Crystallographic study of 5. A colorless prismatic crystal,
crystal size 0.20£0.30£0.70 mm3, monoclinic, space group
˚
P21/a (no. 14), a¼9.809(1), b¼22.007(3), c¼15.644(2) A,
3
b¼94.78(1)8, V¼3365.3(6) A , Z¼8, Dcalcd¼1.095 g/cm3,
˚
m(Cu Ka)¼5.54 cm21, was used for data collection. The
intensity data were measured on a Rigaku AFC7R
diffractometer using Cu Ka radiation at a temperature of
20.08C by a v–2u scan technique. The structure was solved
by direct methods (SIR92)13 and expanded using Fourier
techniques (DIRDIF94).14 All calculations were performed
using the teXsan crystallographic software package. The
final cycle of full-matrix least-squares refinement was based
on 4490 observed reflections (I.1.50s(I)) and 565 variable
parameters and gave R¼0.056 and Rw¼0.089. The value of
the goodness of fit indicator was 1.24 (Summary of Data
CCDC 183923).
Compound (2R p,3R p,6R p,7R p)-[10E]-3-amino-6,7-epoxy-
2,6,9,9-tetramethylcycloundec-10-en-1-one (4). From 2,
crystallized from hexane, yield 85%; mp 142–1438C; IR
1
(KBr): 1695, 1634 cm21; H NMR: d ppm 1.00–1.01 (m,
1H, C4), 1.01 (d, J¼7.0 Hz, CH3 on C2), 1.04–1.06 (m, 1H,
C5), 1.08–1.14 (m, 1H, C4), 1.13 (s, CH3 on C6), 1.16 (s,
CH3 on C9), 1.27 (s, CH3 on C9), 1.36–1.41 (m, 1H, C8),
1.90–1.92 (m, 1H, C8), 2.10–2.14 (m, 1H, C5), 2.68–2.71
(m, 2H, C2 and C7), 3.21–3.23 (m, 1H, C3), 6.28 (d,
J¼16.0 Hz, 1H, C10), 6.34 (d, J¼16.0 Hz, 1H, C11); 13C
NMR: d ppm 5.8 (CH3 on C2), 16.9 (CH3 on C6), 23.3 (CH3
on C9), 27.8 (C4), 29.6 (CH3 on C9), 36.2 (C9), 36.9 (C5),
40.4 (C8), 53.9 (C2), 54.6 (C3), 60.5 (C7), 61.8 (C6), 127.9
(C11), 150.5 (C10), 202.9 (C1); HRMS: m/z calcd mass for
C15H25NO2 251.1885, found 251.1888.
4.1.3. (2R p,3R p,6R p,7R p)-[10E]-3-(N-Acetylamino)-6,7-
epoxy-2,6,9,9-tetramethylcyclo-undec-10-en-1-one (6).
Crystallized from EtOAc, 95% from 4; mp 207–2088C;
1
IR (KBr): 3072, 1697, 1632, 1551 cm21; H NMR: d ppm
0.89–0.97 (m, 1H, C5), 0.96 (d, J¼7.0 Hz, CH3, C2), 1.03–
1.07 (m, 1H, C4), 1.13 (s, CH3, C9), 1.16 (s, CH3, C9),
1.23–1.32 (m, 1H, C4), 1.35 (s, CH3, C6), 1.38–1.43 (m,
1H, C8), 1.91–1.95 (m, 1H, C8), 1.99–2.03 (m, 1H, C5),
2.01 (s, CH3, NHAc, C3), 2.86 (dd, J¼1.6, 11.2 Hz, 1H,
C7), 2.98–3.01 (m, 1H, C2), 4.47 (dt, J¼3.0, 9.0 Hz, 1H,

T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
4863
C3), 6.00–6.03 (m, 1H, NHAc, C3), 6.29 (d, J¼15.9 Hz,
1H, C11), 6.60 (d, J¼15.9 Hz, 1H, C10); 13C NMR: d ppm
6.6 (CH3, C2), 16.9 (CH3, C9), 23.2 (CH3, NHAc, C3), 23.4
(CH3, C6), 24.7 (C4), 29.5 (CH3, C9), 36.0 (C5), 36.3 (C9),
40.8 (C8), 49.7 (C2), 52.0 (C3), 60.3 (C7), 61.3 (C6), 128.4
(C10), 150.6 (C11), 170.3 (CvO, NHAc), 202.8 (C1);
HRMS: m/z calcd mass for C17H27NO3 293.1991, found
293.2012.
Crystallographic study of 8. A colorless plate crystal,
crystal size 0.50£0.04£0.80 mm3, monoclinic, space group
˚
P21/n (no. 14), a¼10.835(2), b¼7.590(3), c¼20.496(3) A,
3
b¼98.28(2)8, V¼1668.0(8) A , Z¼4, Dcalcd¼1.113 g/cm3,
˚
m(Cu Ka)¼5.59 cm21, was used for data collection. The
intensity data were measured on a Rigaku AFC7R
diffractometer using Cu Ka radiation at a temperature of
20.08C by a v–2u scan technique. The structure was solved
by direct methods (SIR92)13 and expanded using Fourier
techniques (DIRDIF94).14 All calculations were performed
using the teXsan crystallographic software package. The
final cycle of full-matrix least-squares refinement was based
on 2153 observed reflections (I.1.50s(I)) and 297 variable
parameters and gave R¼0.057 and Rw¼0.083. The value of
the goodness of fit indicator was 1.20 (Summary of Data
CCDC 183925).
4.1.4. (2R p,3R p)-[6E,10E]-3-(N,N-Dimethylamino)-
2,6,9,9-tetramethylcycloundec-6,10-dien-1-one (7). From
1 (4.4 g, 20 mmol), dimethylamine (50% in water, 60 mL)
and acetonitrile (50 mL); crystallized in hexane, yield 5.1 g,
97%; mp 62–648C; IR (KBr): 1690, 1624 cm21; 1H NMR:
d ppm 0.96–0.99 (m, 1H, C4), 1.02 (d, J¼6.5 Hz, CH3 on
C2), 1.14 (s, CH3 on C9), 1.19 (s, CH3 on C9), 1.36 (s, CH3
on C6), 1.40–1.45 (m, 1H, C4), 1.85–1.90 (m, 2H, C5 and
C8), 2.07–2.11 (m, 1H, C5), 2.20 (t, J¼12.5 Hz, 1H, C8),
2.37 (s, 6H, N(CH3)2, C3), 2.69- 2.71 (m, 1H, C3), 2.94–
2.98 (m, 1H, C2), 5.05–5.09 (m, 1H, C7), 6.06 (d,
J¼16.0 Hz, 1H C11), 6.26 (d, J¼16.0 Hz, 1H, C10); 13C
NMR: d ppm 8.1 (CH3, C2), 16.2 (CH3, C6), 22.7 (CH3,
C9), 25.7 (C4), 28.8 (CH3, C9), 39.2 (C5), 40.2 (C9), 41.5
(C8), 43.5 (N(CH3)2, C3), 47.6 (C2), 65.8 (C3), 122.3 (C7),
127.7 (C11), 138.3 (C6), 151.7 (C10), 202.5 (C1). Anal.
calcd for C17H29NO: C, 77.51; H, 11.10; N, 5.32. Found: C,
77.79; H, 11.09; N, 5.35.
4.2. Reaction of 7 and 8 with potassium cyanide
Potassium cyanide (0.78 g, 12 mmol) was added at 158C to a
stirring solution of 7 (0.79 g, 3.0 mmol) in acetonitrile
(10 mL) and water (2 mL). The solution was stirred at 158C
for 6 days, and then concentrated on a rotary evaporator
under reduced pressure. The residue was dissolved in
EtOAc (10 mL), washed with water (3£3 mL) and brine
(3 mL), and dried over anhydrous Na2SO4. The solvent was
removed to yield dry 10 as a crystalline solid in a 80% yield.
The same procedure at 308C gave a 1:1 mixture of 10 and
11. The mixture was subjected to column chromatography
over silica gel using hexane and EtOAc (2:1) as an eluent to
afford 10 and 11 in yields of 0.35 g (40%) and 0.35 g (40%),
respectively.
Crystallographic study of 7. A colorless prismatic crystal,
crystal size 0.70£0.40£0.08 mm3, monoclinic, space group
˚
P21/c (no. 14), a¼7.779(2), b¼9.952(1), c¼21.357(1) A,
3
b¼94.01(1)8, V¼1649.4(5) A , Z¼4, Dcalcd¼1.061 g/cm3,
˚
m(Cu Ka)¼4.91 cm21, was used for data collection. The
intensity data were measured on a Rigaku AFC7R
diffractometer using Cu Ka radiation at a temperature of
20.08C by a v–2u scan technique. The structure was solved
by direct methods (SIR92)13 and expanded using Fourier
techniques (DIRDIF94).14 All calculations were performed
using the teXsan crystallographic software package. The
final cycle of full-matrix least-squares refinement was based
on 1772 observed reflections (I.1.50s(I)) and 216 variable
parameters and gave R¼0.086 and Rw¼0.121. The value of
the goodness of fit indicator was 1.86 (Summary of Data
CCDC 183924).
The procedure was followed at 08C to convert 8 (0.84 g,
3.0 mmol) to 12, which was recrystallized from EtOAc
(0.81 g, 88%) as a single diastereomer. The reaction at 508C
a 2:1:1 mixture of 12, 13 and 130. The mixture was subjected
to column chromatography over silica gel using hexane and
EtOAc (2:1) as an eluent to afford 12, 13 and 130 in yields of
0.37 g (40%), 0.16 g (21%) and 0.16 g (21%), respectively.
4.2.1. [2R p,3R p,10(R or S)p]-[6E]-10-Cyano-3-(N,N-
dimethylamino)-2,6,9,9-tetramethyl-cycloundec-6-en-1-
one (10). Crystallized from hexane–EtOAc mixture, yield
0.75 g, 86%; mp 100–1028C; IR (KBr): 2237, 1705 cm21
;
4.1.5. (2R p,3R p,6R p,7R p)-[10E]-3-(N,N-Dimethyl-
amino)-6,7-epoxy-2,6,9,9-tetramethylcycloundec-10-en-
1-one (8). From 2, crystallized from EtOAc, yield 93%; mp
104–1068C; IR (KBr): 1693, 1630 cm21; 1H NMR: d ppm
0.92–0.98 (m, 2H, C4 and 5), 1.02 (d, J¼6.5 Hz, CH3 on
C2), 1.09 (s, CH3 on C6), 1.17 (s, CH3 on C9), 1.29 (s,
CH3 on C9), 1.34–1.39 (m, 1H, C8), 1.44–1.56 (m, 1H,
C4), 1.91–1.96 (m, 1H, C8), 2.10–2.18 (m, 1H, C5),
2.31 (s, 6H, N(CH3)2, C3), 2.45–2.49 (m, 1H, C3), 2.68
(dd, J¼2.2, 11.2 Hz, 2H, C7), 2.92–3.01 (m, 1H, C2),
6.29 (d, J¼15.7 Hz, 1H, C11), 6.43 (d, J¼15.7 Hz, 1H,
C10); 13C NMR: d ppm 7.5 (CH3 on C2), 16.2 (CH3 on
C6), 23.1 (CH3 on C9), 23.7 (C4), 29.5 (CH3 on C9),
36.2 (C9), 38.9 (C5), 40.5 (C8), 43.7 (N(CH3)2, C3), 48.4
(C2), 61.6 (C6), 61.7 (C7), 67.9 (C3), 126.8 (C11),
151.6 (C10), 202.9 (C1). Anal. calcd for C17H29NO2: C,
73.07; H, 10.46; N, 5.01. Found: C, 73.00; H, 10.54; N,
5.02.
1H NMR: d ppm 1.01 (d, J¼6.5 Hz, CH3 on C2), 1.17 (s,
CH3 on C9), 1.26 (s, CH3 on C9), 1.42 (s, CH3 on C6),
1.45–1.56 (m, 2H, C4), 1.76–1.85 (m, 2H, C5 and C8),
2.02–2.09 (m, 1H, C5), 2.14–2.24 (m, 1H, C8), 2.30–2.32
(m, 1H, C3), 2.34 (s, 6H, N(CH3)2, C3), 2.43 (dd, J¼4.1,
19.8 Hz, 1H, C11), 2.88 (dq, J¼1.9, 6.5 Hz, 1H, C2), 3.31 (t,
J¼4.1 Hz, 1H, C10), 3.54 (dq, J¼4.1, 19.8 Hz, 1H, C11),
5.12–5.16 (m, 1H, C7); 13C NMR: d ppm 9.0 (CH3 on C2),
16.1 (CH3 on C6), 21.2 (CH3 on C9), 26.1 (C4), 32.1 (CH3
on C9), 33.2 (C10), 36.0 (C9), 40.1 (C5), 41.5 (C8), 41.6
(C11), 43.4 (N(CH3)2, C2), 46.2 (C2), 68.1 (C3), 121.3
(C7), 122.4 (CN, C10), 137.4 (C6), 205.4 (C1); HRMS: m/z
calcd mass for C18H30N2O 290.2358, found 290.2368.
4.2.2. [5E,9E]-2-(N,N-Dimethylamino)-5,8,8-trimethyl-
11-oxo-tridec-5,9-diene-1-nitrile (11). Colorless oil, yield
1
0.35 g, 40%; IR (neat): 2210, 1697, 1674, 1626 cm21; H
NMR: d ppm 1.06 (s, 6H, 2 CH3, C8), 1.10 (t, J¼7.3 Hz, 3H,

4864
T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
C13), 1.60 (s, CH3, C5), 1.76–1.86 (m, 2H, C3), 2.08 (d,
J¼7.3 Hz, 2H, C7), 2.14–2.20 (m, 2H, C4), 2.30 (s, 6H,
N(CH3)2, C2), 2.57 (q, J¼7.3 Hz, 2H, C12), 3.41 (t,
J¼7.8 Hz, 1H, C2), 5.17 (t, J¼7.3 Hz, 1H, C6), 6.00 (d,
J¼16.2 Hz, 1H, C10), 6.78 (d, J¼16.2 Hz, 1H, C9); 13C
NMR: d ppm 8.1(C13), 15.9 (CH3, C5), 26.2 (2 CH3, C8),
29.7 (C3), 33.4 (C12), 35.8 (C4), 37.5 (C8), 40.1 (C7),
41.7 (N(CH3)2, C2), 57.9 (C2), 116.5 (C1), 122.1
(C6), 126.1 (C10), 135.3, (C5), 155.5 (C9), 201.1 (C11);
HRMS: m/z calcd mass for C18H30N2O 290.2358, found
290.2338.
85.3 (C7), 119.8 (CN at C11), 210.1 (C2); HRMS m/z calcd
mass for C16H23NO2 261.1729, found 261.1715.
Crystallographic study of 13. A colorless prism crystal,
crystal size 0.20£0.40£0.10 mm3, monoclinic, space group
˚
P21/n (no. 14), a¼8.162(1), b¼17.276(3), c¼11.132(2) A,
3
˚
b¼114.850(7)8, V¼1424.4(4) A , Z¼4, Dcalcd¼1.219 g/
cm3, m(Mo Ka)¼0.79 cm21, was used for data collection.
The intensity data were measured on a Rigaku Mercury
CCD detector using Mo Ka radiation at a temperature of
2180^18C. The structure was solved by direct methods
(SIR97)15 and expanded using Fourier techniques (DIR-
DIF99).16 All calculations were performed using the Crystal
Structure crystallographic software package. The final cycle
of full-matrix least-squares refinement on F 2 was based on
3199 reflections (all data) and 265 variable parameters and
gave R1¼0.039 (I.2.0s(I)) and wR2¼0.103 (all data). The
value of the goodness of fit indicator was 1.01 (Summary of
Data CCDC 183927).
4.2.3. (1S p,3R p,4R p,7R p,8R p,11S p)-Bicyclo[6.3.0]-11-
cyano-4-(N,N-dimethylamino)-7-hydroxy-3,7,10,10-
tetramethylundecan-2-one (12). Crystallized from EtOAc,
yield 88%; mp 163–1648C; IR (KBr) 3460, 3354, 2233,
1699 cm21; 1H NMR: d ppm 1.01 (s, 3H, CH3 on C7), 1.15
(d, 3H, J¼6.5 Hz, CH3 on C3), 1.20 (s, 3H, CH3 on C10),
1.26 (s, 3H, CH3 on C10), 1.37–1.43 (m, 1H, C5), 1.54–
1.60 (m, 2H, C6), 1.78–1.96 (m, 2H, C9), 2.05–2.07 (m,
1H, C5), 2.32 (s, 6H, N(CH3)2 on C4), 2.68–2.72 (m, 1H,
C3), 2.89–2.95 (m, 1H, C4), 2.95–3.02 (m, 1H, C8), 3.02
(d, 1H, J¼12.2 Hz, C11), 3.47 (t, 1H, J¼12.2 Hz, C1); 13C
NMR: d ppm 7.7 (CH3 on C3), 24.3 (CH3 on C7), 25.3 (C5),
26.0 (CH3 on C10), 27.8 (CH3 on C10), 39.3 (C10), 40.6
(C6), 41.5 (C9), 42.9 (C11), 44.1 (N(CH3)2 on C4), 48.5
(C8), 50.2 (C3), 55.5 (C1), 64.3 (C4), 74.0 (C7), 119.4 (CN
at C11), 210.0 (C2); HRMS m/z calcd mass for C18H30N2O2
306.2307, found 306.2320 (excluding one molecule of H2O,
while X-ray crystal contains it).
4.2.5. (1R p,3S p,4S p,7R p,8R p,11S p)-Tricyclo[6.3.14,7.0]-
11-0cyano-3,7,10,10-tetramethyl-4,7-oxyundecan-2-one
(13 ). Mp 170–1728C; IR (KBr) 2232, 1693 cm21 1H
;
NMR: d ppm 1.01 (d, 3H, J¼6.8 Hz, CH3 on C3), 1.05–
1.10 (m, 1H, C9), 1.16 (s, 3H, CH3 on C10), 1.22 (s, 3H,
CH3 on C7), 1.26 (s, 3H, CH3 on C10), 1.29–1.36 (m, 1H,
C6), 1.46–1.55 (m, 1H, C6), 1.64–1.68 (m, 1H, C9), 1.71–
1.79 (m, 1H, C5), 1.86–1.95 (m, 1H, C5), 2.90–3.01
(m, 2H, C3 and C8), 3.13 (d, J¼10.3 Hz, 1H, C11), 3.34–
3.42 (m, 1H, C1), 4.17 (dd, 1H, J¼4.3, 7.0 Hz, t C4); 13C
NMR: d ppm 11.8 (CH3 on C3), 23.5 (CH3 on C10), 26.4
(C5), 27.1 (CH3 on C10), 29.0 (CH3 on C7), 30.6 (C6), 40.8
(C10), 41.7 (C11), 43.5 (C9), 47.7 (C8), 53.2 (C3), 58.2
(C1), 80.5 (C4), 85.3 (C7), 119.9 (CN on C11), 208.6 (C2);
HRMS m/z calcd mass for C16H23NO2 261.1729, found
261.1723.
Crystallographic study of 12. A colorless prism crystal,
crystal size 0.24£0.41£0.04 mm3, triclinic, space group P-1
˚
(no. 2), a¼7.5895(11), b¼9.912(2), c¼12.534(2) A, a¼
3
˚
104.515(8)8, b¼93.851(7)8, g¼90.660(7)8, V¼910.3(2) A ,
Z¼2, Dcalcd¼1.184 g/cm3, m(Mo Ka)¼0.80 cm21, was
used for data collection. The intensity data were measured
on a Rigaku Mercury CCD detector using Mo Ka radiation
at a temperature of 2180^18C. The structure was solved by
direct methods (SIR97)15 and expanded using Fourier
techniques (DIRDIF99).16 All calculations were performed
using the Crystal Structure crystallographic software
package. The final cycle of full-matrix least-squares
refinement on F 2 was based on 3963 reflections (all data)
and 324 variable parameters and gave R1¼0.050
(I.2.0s(I)) and wR2¼0.162 (all data). The value of the
goodness of fit indicator was 1.01 (Summary of Data CCDC
183926).
Crystallographic study of 130. A colorless prism crystal,
crystal size 0.30£0.30£0.06 mm3, triclinic, space group P-1
˚
(no. 2), a¼8.561(6), b¼9.486(7), c¼9.584(6) A,
3
˚
a¼74.62(2)8, b¼71.41(2)8, g¼88.43(2)8, V¼709.9(8) A ,
Z¼2, Dcalcd¼1.223 g/cm3, m(Mo Ka)¼0.80 cm21, was
used for data collection. The intensity data were measured
on a Rigaku Mercury CCD detector using Mo Ka radiation
at a temperature of 2180^18C. The structure was solved by
direct methods (SIR97)14 and expanded using Fourier
techniques (DIRDIF99).15 All calculations were performed
using the Crystal Structure crystallographic software
package. The final cycle of full-matrix least-squares
refinement on F 2 was based on 3095 reflections (all data)
and 264 variable parameters and gave R1¼0.044
(I.2.0s(I)) and wR2¼0.124 (all data). The value of the
goodness of fit indicator was 1.04 (Summary of Data CCDC
183928).
4.2.4. (1S p,3S p,4S p,7R p,8R p,11S p)-Tricyclo[6.3.14,7.0]-
11-cyano-3,7,10,10-tetramethyl-4,7-oxyundecan-2-one
(13). Mp 191–1928C; IR (KBr) 2237, 1686 cm21; 1H NMR:
d ppm 1.04–1.14 (m, 1H, C9), 1.17 (s, 3H, CH3 on C10),
1.22 (s, 3H, CH3 on C10), 1.27 (s, 3H, CH3 on C7), 1.33 (d,
3H, J¼7.3 Hz, CH3 on C3), 1.36–1.41 (m, 1H, C6), 1.49–
1.58 (m, 1H, C6), 1.64–1.72 (m, 1H, C9), 1.74–1.82 (m,
1H, C5), 2.03–2.14 (m, 1H, C5), 2.61 (dq, 1H, J¼2.2,
7.3 Hz, C3), 2.81–2.93 (m, 1H, C8), 3.06 (d, 1H,
J¼10.5 Hz, C11), 3.47 (dd, 1H, J¼10.5, 11.9 Hz, C1),
4.11 (dd, 1H, J¼2.2, 7.3 Hz, H at C4); 13C NMR: d ppm
15.6 (CH3 on C3), 24.0 (CH3 on C10), 27.7 (CH3 on C10),
29.4 (CH3 on C7), 30.7 (C5), 30.9 (C6), 41.4 (C10), 42.2
(C11), 44.0 (C9), 47.7 (C8), 54.2 (C1), 55.8 (C3), 79.9 (C4),
4.3. Retro-Mannich reaction of 7, 8 and 10
A solution of 7 (1.0 g, 3.8 mmol) in acetonitrile (50 mL) and
water (5 mL) was stirred under reflux for 2 h and
concentrated on a rotary evaporator under reduced pressure.
The residue was dissolved in EtOAc (20 mL), washed with
water (3£3 mL) and brine (3 mL), dried over anhydrous
Na2SO4, and concentrated to yield ketoaldehyde 16. The

T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
4865
same procedure was applied to 8 and 10 to afford 17 and 18,
respectively.
4.41 (t, J¼6.8 Hz, 1H, C2), 5.19 (t, J¼7.3 Hz, 1H, C6), 6.02
(d, J¼16.2 Hz, 1H, C10), 6.80 (d, J¼16.2 Hz, 1H, C9); 13C
NMR: d ppm 8.6 (C13), 16.3 (CH3, C5), 26.6 (CH3, C8),
33.5 (C3), 34.1 (C12), 35.2 (C4), 38.0 (C8), 40.7 (C7), 60.9
(C2), 120.5 (C1), 122.7 (C6), 126.5 (C10), 135.6 (C5),
156.4 (C9), 203.0 (C11); HRMS: m/z calcd mass for
C16H25NO2 263.1885, found 263.1866.
4.3.1. [4E,8E]-4,7,7-Trimethyl-10-oxododeca-4,8-dienal
(16). Yield 0.88 g, 98%, colorless oil; IR (neat): 1724,
1697, 1674, 1626 cm21; 1H NMR: d ppm 1.04 (s, 6H, 2CH3,
C7), 1.10 (t, J¼7.5 Hz, 3H, C12), 1.60 (s, CH3, C4), 2.06 (d,
J¼7.5 Hz, 2H, C6), 2.34 (t, J¼7.5 Hz, 2H, C3), 2.50–2.53
(m, 2H, C2), 2.58 (q, J¼7.5 Hz, 2H, C11), 5.13 (t,
J¼7.5 Hz, 1H, C5), 5.99, (d, J¼15.0 Hz, 1H, C9), 6.77 (d,
J¼15.0 Hz, 1H, C8), 9.74 (t, J¼1.6 Hz, 1H, C1); 13C NMR:
d ppm 8.1 (C12), 16.2 (CH3, C4), 26.1 (2CH3, C7), 32.0
(C3), 33.4 (C11), 37.5 (C7), 40.1 (C6), 42.1 (C2), 121.1
(C5), 126.1 (C9), 135.6 (C4), 155.4 (C8), 201.4 (C10),
202.2 (C1); HRMS: m/z calcd mass for C15H24O2 236.1776,
found 236.1777.
4.5. Reaction of 16 with potassium cyanide in the
presence of dimethylamine
Potassium cyanide (0.47 g, 7.2 mmol) was added to a
solution of 16 (0.43 g, 1.8 mmol) and dimethylamine (50%
in water, 4 mL) in acetonitrile (10 mL). The solution was
stirred for 24 h at 08C, and then concentrated on a rotary
evaporator under reduced pressure. The residue was taken
up in EtOAc (10 mL). The solution was washed with water
(3£3 mL) and brine (3 mL), dried over anhydrous Na2SO4,
and concentrated to yield aminonitrile 11 (0.49 g, 94%) as a
colorless oil.
4.3.2. [8E]-4,5-Epoxy-4,7,7-trimethyl-10-oxododec-8-en-
1-al (17). Refluxed for 3 h, yield 98%; IR (neat): 1674,
1626 cm21; 1H NMR: d ppm 1.11 (t, J¼7.3 Hz, CH3, C12),
1.15 (s, CH3, C7), 1.17 (s, CH3, C7), 1.24 (s, CH3, C4),
1.53–1.71 (m, 2H, C6), 1.79–1.93 (m, 2H, C3), 2.50–2.55
(m, 2H, C2), 2.60 (q, J¼7.3 Hz, 2H, C11), 2.68–2.71 (m,
1H, C5), 6.08 (d, J¼16.2 Hz, 1H, C9), 6.82 (d, J¼16.2 Hz,
1H, C8), 9.76 (t, J¼1.3 Hz, 1H, C1); 13C NMR: d ppm 8.0
(CH3, C12), 16.9 (CH3, C4), 26.3 (CH3, C7), 27.0 (CH3,
C7), 30.2 (C3), 33.7 (C11), 36.3 (C7), 39.0 (C2), 40.5 (C6),
59.1 (C4), 60.0 (C5), 126.4 (C9), 154.3 (C8), 201.1 (C1),
201.2 (C10); HRMS: m/z calcd mass for C15H24O3 (MþH)
253.1804, found 253.1827.
4.6. Deaminations with MCPBA and potassium
hydroxide
A solution of 7 (0.26 g, 1.0 mmol) and MCPBA (0.24 g,
1.4 mmol) in EtOAc (10 mL) was stirred at 08C for 2 h, and
concentrated at reduced pressure. The residue was stirred
with sodium carbonate (1N, 5 mL) in acetonitrile (5 mL) for
2 h at room temperature, then diluted with water (5 mL) and
extracted with EtOAc (3£5 mL). The organic layer was
washed with brine (5 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to yield 1 as a
crystalline solid (0.20 g, 92%). The procedure was applied
to 8 and 10 to afford 2 and 21 in yields of 94 and 90%,
respectively.
4.3.3. [4E]-8-Cyano-4,7,7-trimethyl-10-oxododec-4-en-1-
al (18). Refluxed for 12 h, yield 86%; IR (neat): 2237, 1717,
1
1682 cm21; H NMR: d ppm 0.97 (s, CH3, C7), 1.03 (s,
CH3, C7), 1.10 (t, J¼7.3 Hz, CH3, C12), 1.65 (s, CH3, C4),
1.99–2.18 (m, 2H, C6), 2.37 (t, J¼7.3 Hz, 2H, C3), 2.51 (q,
J¼7.3 Hz, 2H, C11), 2.53–2.60 (m, 2H, C2), 2.62–2.83 (m,
2H, C9), 2.98–3.03 (m, 1H, C8), 5.19 (t, J¼8.1 Hz, 1H,
C5), 9.77 (t, J¼1.8 Hz, 1H, C1); 13C NMR: d ppm 7.6
(C12), 16.4 (CH3, C4), 24.2 (CH3, C7), 24.7 (CH3, C7), 32.1
(C3), 35.9 (C8), 36.1 (C7), 36.2 (C11), 38.1 (C6), 39.9 (C9),
42.1 (C2), 119.8 (C5), 121.0 (CN, C8), 137.0 (C4), 202.2
(C1), 207.1 (C10); HRMS: m/z calcd mass for C16H25NO2
263.1885, found 263.1884.
On a similar scale, 7, 8 and 10 were treated with potassium
hydroxide (70 mg, 1.2 mmol) in aqueous acetonitrile at
room temperature to afford 1, 2 and 21, respectively, in over
90% yield. The NMR and IR spectra of 1 and 2 formed by
the reaction were identical with those of authentic material.
4.6.1. [2E,6E]-10-Cyano-2,6,9,9-tetramethylcycloundec-
2,6-dien-1-one (21). From 10, yield 90%; mp 97–998C; IR
1
(KBr): 2233, 1663 cm21; H NMR: d ppm 1.08 (s, CH3,
4.4. Reaction of 16 with potassium cyanide
C9), 1.20 (s, CH3, C9), 1.59 (s, CH3, C6), 1.78 (s, CH3, C2),
2.09–2.12 (m, 2H, C8), 2.27–2.30 (m, 1H, C4), 2.32–2.39
(m, 1H, C5), 2.41–2.46 (m, 1H, C4), 2.48–2.52 (m, 1H,
C5), 2.56–2.61 (m, 1H, C11), 2.73–2.78 (m, 1H, C10),
2.95–3.00 (m, 1H, C11), 5.13 (t, J¼7.0 Hz, 1H C7), 5.99–
6.02 (m, 1H, C3); 13C NMR d ppm 12.4 (CH3, C2), 15.8
(CH3, C6), 24.5 (C5), 25.7 (CH3, C9), 28.2 (CH3, C9), 36.7
(C10), 37.3 (C9), 39.1 (C11), 39.6 (C4), 40.1 (C8), 120.2
(CN at C10), 122.9 (C7), 134.8 (C2), 137.0 (C6), 143.6
(C3), 202.7 (C1); HRMS: m/z calcd mass for C16H23NO
245.1780, found 245.1782.
Potassium cyanide (0.97 g, 15 mmol) was added to a
mixture of 16 (0.88 g, 3.7 mmol) and cation-exchange
resin (DOWEX 50W-X2, 10 mL) in acetonitrile (20 mL)
and water (5 mL). The mixture was stirred for 24 h at 08C,
and filtrated. The filtrate was concentrated on a rotary
evaporator under reduced pressure. The residue was taken
up in EtOAc (20 mL), washed with water (3£3 mL) and
brine (3 mL), dried over anhydrous Na2SO4, and concen-
trated to yield cyanohydrin 20.
4.4.1. [5E,9E]-2-Hydroxy-5,8,8-trimethyl-11-oxotridec-
5,9-dienenitrile (20). Colorless oil, yield 0.95 g, 98%; IR
(neat): 3440, 2480, 1672, 1624 cm21; 1H NMR: d ppm 1.04
(s, 6H, 2CH3, C8), 1.10 (t, J¼7.3 Hz, 3H, C13), 1.60 (s,
CH3, C5), 1.93–1.98 (m, 2H, C3), 2.08 (d, J¼7.3 Hz, 2H,
C7), 2.19–2.23 (m, 2H, C4), 2.60 (q, J¼7.3 Hz, 2H, C12),
Crystallographic study of 21. A colorless prism crystal,
crystal size 0.50£0.20£0.30 mm3, orthorhombic, space
group Pca21 (no. 29), a¼14.559(1), b¼11.4306(9),
3
˚
˚
c¼17.464(2) A, V¼2906.2(7) A , Z¼8, Dcalcd¼1.121 g/
cm3, m(Mo Ka)¼0.69 cm21, was used for data collection.
The intensity data were measured on a Rigaku/MSC

4866
T. Kitayama et al. / Tetrahedron 59 (2003) 4857–4866
4. (a) Liao, Y-H.; Houghton, P. J.; Hoult, J. R. S. J. Nat. Prod.
1999, 62, 1241–1245. (b) Murakami, A.; Takahashi, D.;
Kinoshita, T.; Koshimizu, K.; Kin, H.-W.; Yoshihiro, A.;
Nakamura, Y.; Jiwajinda, S.; Terao, J.; Ohigashi, H.
Carcinogenesis 2002, 23, 795–802. (c) Murakami, A.;
Takahashi, M.; Jiwajinda, S.; Koshimizu, K.; Ohigashi, H.
Biosci. Biotechol. Biochem. 1999, 63, 1811–1812. (d) Dai,
J-R.; Cadellinall, J. H.; McMahon, J. B.; Boyd, M. R. Nat.
Prod. Lett. 1997, 10, 115–118. (e) Yokokawa, Y.; Ohta, M.;
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Cambridge University: Cambridge, 1947. (b) Pinder, A. R.
The Chemistry of the Terpenes; Wiley: New York, 1960. (c)
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and Germacranolides; Herman: Paris, 1965.
Mercury CCD diffractometer using Mo Ka radiation at a
temperature of 21808C. The structure was solved by direct
methods (SIR92)13 and expanded using Fourier techniques
(DIRDIF94).14 All calculations were performed using the
teXsan crystallographic software package. The final cycle of
full-matrix least-squares refinement on F 2 was based on
6350 reflections (all data) and 445 variable parameters and
gave R1¼0.070 (I.2.0s(I)) and wR2¼0.198 (all data). The
value of the goodness of fit indicator was 1.30 (Summary of
Data CCDC 183929).
4.7. Reaction of 12 with MCPBA
MCPBA (0.21 g, 1.2 mmol) was added to a stirred solution
of 12 (0.31 g, 1.00 mmol in EtOAc, 3 mL), and the solution
was stirred 2 h at 08C, and concentrated at reduced pressure.
1
The H NMR spectrum of the residue showed no starting
material, but a single product consistent with amine oxide
23, along with m-chlorobenzoic acid and MCPBA. The
residue was stirred with sodium carbonate (1N, 5 mL) in
acetonitrile (5 mL) for 2 h at room temperature, then diluted
with water (5 mL) and extracted with EtOAc (3£5 mL). The
organic layer was dried over Na2SO4 and concentrated.
Crystallization in EtOAc yielded a 7:3 mixture of 13 and 130
(0.24 g, 92%). The ratio of diastereomer mixture was shown
1
by H NMR.
6. Kitayama, T.; Takatani, M.; Yamamoto, K.; Utsumi, R.;
Okamoto, T.; Hill, R. K.; Kawai, Y.; Sawada, S. Biosci.
Biotechnol. Biochem. 2001, 65, 2193–2199.
Acknowledgements
7. Ohe, K.; Miki, K.; Yanagi, S.; Tanaka, T.; Sawada, S.;
Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 3627–3634.
8. Kitayama, T.; Masuda, T.; Kawai, Y.; Hill, R. K.; Takatani,
M.; Sawada, S.; Okamoto, T. Tetrahedron: Asymmetry 2001,
12, 2805–2810.
The authors are grateful to Professor S. Yonemori of
Ryukyu University for supplying rhizomes of Zingiber
zerumbet Smith.
9. Kitayama, T.; Nagao, R.; Masuda, T.; Hill, R. K.; Morita, M.;
Takatani, M.; Sawada, S.; Okamoto, T. J. Mol. Catal. B:
Enzym. 2002, 17, 75–79.
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