Synthesis and stereochemistry of insect derived spiroacetals with branched carbon skeletons

Article abstract of DOI:10.1055/s-2000-8232

About thirty constitutionally different spiroacetals have been characterised from insects but only three have branched carbon skeletons. Two are based on the 1,7-dioxaspiro[5.5]undecane system and are certain stereoisomers of the 2,4,8-trimethyl derivative, from the aposematic shield bug, Cantao parentum (White), and a 2,2,8-trimethyl derivative from the rove beetle, Ontholestes murinus (L). The 1,6-dioxaspiro[4.5]decane system is represented by a stereoisomer of the 2,3,7-trimethyl derivative in the Cantao species. The elucidation of their structures and stereochemistry by spectroscopy, synthesis and enantioselective gas chromatography is described.

Full text of DOI:10.1055/s-2000-8232

1956
SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched
Carbon Skeletons
Yong Q. Tu,a Achim Hübener,a Hesheng Zhang,a Christopher J. Moore,b Mary T. Fletcher,a Patricia Hayes,a Konrad
Dettner,c Wittko Francke,d Christopher S.P. McErlean,a William Kitchinga*
a Department of Chemistry, The University of Queensland, Brisbane, Q. 4072, Australia
Fax +61(7)33654299; E-mail: kitching@chemistry.uq.edu.au
b Department of Primary Industries, Yeerongpilly, Q. 4105, Australia
c Institute for Animal Ecology II, University of Bayreuth, 8580, Bayreuth, Germany
d Institut für Organische Chemie, Universität Hamburg, Martin-Luther-King Platz 6, 20146, Hamburg, Germany
Received 21 August 2000
O
O
O
Abstract: About thirty constitutionally different spiroacetals have
been characterised from insects but only three have branched car-
bon skeletons. Two are based on the 1,7-dioxaspiro[5.5]undecane
system and are certain stereoisomers of the 2,4,8-trimethyl deriva-
tive, from the aposematic shield bug, Cantao parentum (White),
and a 2,2,8-trimethyl derivative from the rove beetle, Ontholestes
murinus (L). The 1,6-dioxaspiro[4.5]decane system is represented
by a stereoisomer of the 2,3,7-trimethyl derivative in the Cantao
species. The elucidation of their structures and stereochemistry by
spectroscopy, synthesis and enantioselective gas chromatography is
described.
O
O
O
1
2
3
O
O
O
O
4
5
O
O
O
O
O
O
Key words: branched spiroacetals, Cantao parentum, Ontholestes
murinus, enantioselective gas chromatography, enantioselective
synthesis
6
7
8
O
O
O
Introduction
HO
O
O
O
Spiroacetals are widely distributed in nature1 and relative-
ly simple spiroacetals are important components of glan-
dular secretions of higher insects,2 and have been
principally described from the orders Coleoptera (bee-
tles), Diptera (flies)3 and Hymenoptera (bees and wasps).
This group of about thirty different structures,2 not includ-
ing stereoisomers, represents volatile, less polar constitu-
ents of insect secretions and some of these spiroacetals are
utilised for intra-specific or inter-specific communication.
Five spiroacetal systems have been identified from insects
HO
11
9
10
type, origin and possibly the evolutionary position of in-
sect generated spiroacetals, as well as helped in confirm-
ing a diversified biosynthetic capability for certain insect
species. We now describe our studies which led to the
identification of a number of stereoisomers of the 2,4,8-
trimethyl-1,7-dioxaspiro [5.5]undecane system 12, and an
isomer of the 2,3,7-trimethyl-1,6-dioxaspiro[4.5]decane
system 13 from the aposematic shield bug, Cantao paren-
tum (White), and a 2,2,8-trimethyl-1,7-dioxaspiro[5.5]un-
decane 14 from the rove beetle, Ontholestes murinus (L),
in addition to a number of previously characterised
spiroacetals.
-
1,6-dioxaspiro[4.4]nonanes, 1,6-dioxaspiro[4.5]de-
canes, 1,6-dioxaspiro[4.6]undecanes, 1,7-dioxa-
spiro[5.5]undecanes and 1,7-dioxaspiro[5.6]dodecanes
(1-5),and the characterised members are very predomi-
nantly odd-numbered in carbon, e.g. 6 and 7. Even-num-
bered variants are occasionally present, e.g. 8 and 9, but at
a comparatively low level. Functionalisation appears to be
restricted to hydroxylation, e.g. 10 and 11 which at low
level accompany the parent spiroacetals.2
Spiroacetals were, until recently, unknown from Hemi-
ptera (an order which includes insects commonly known
as bugs), and the lower insect orders. In addition, no
spiroacetal with a branched carbon chain had been report-
ed from the insect kingdom, and hence our recent brief
reports4-6 substantially extended our knowledge of the
O
O
O
O
O
O
13
14
12
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1957
companies the (E,E)-diastereomer in insects,2,3 but
retention time comparisons with the authentic (E,E), (E,Z)
and (Z,Z)-diastereomers of 2,8-dimethyl-1,7-dioxa-
spiro[5.5]undecane13,14 disproved this.
Results and Discussion
(a)
Spiroacetals from the Aposematic Shield
Bug, Cantao parentum (White)
During the course of a general investigation of the scent-
gland chemistry of true bugs, attention was directed to the
shield bug Cantao parentum (White) (Hemiptera: Scutel-
leridae), the only Australian representative of the four
member Cantao genus.7 C. parentum specimens are gen-
erally located in aggregations around a berry cluster of
Mallotus philippensis (Lam.) (Euphorbiaceae), a rainfor-
est tree of Australasia commonly known as the ‘Red Ka-
mala’. These aposematic insects, resplendent in an orange
shield with contrasting black spots, are not regarded as a
pest of any commercial crop. Adult bugs possess an un-
usual dorsal abdominal gland (DAG) system,8,9 the flap
component of which can be rapidly opened and closed,
exposing the inner glandular surface from which volatiles
are released. The DAG morphology is similar to that de-
scribed from Tectocoris diophthalmus (Hemiptera:
Scutelleridae), the cotton harlequin bug of Queensland.9
GC-MS examinations of the dichloromethane extract of
excised DAG’s of both male or female bugs were con-
ducted and a representative gas chromatograph is shown
in Figure 1. The eight components of interest are labelled
(A)-(H), with increasing retention time. The elucidation
of their structure and stereochemistry now follows, and it
emerges that all eight are spiroacetals.
O
O
O
6
8
4
O
2
(E,E)-(2S,6R,8S)-15
(E,Z)-16
The EIMS of (B) however, resembled those for the above
diastereomers in that the same ions were present but with
noticeably different relative intensities of some ions.
These similarities suggested that if (B) were a dimethyl-
1,7-dioxaspiro[5.5]undecane, the methyl groups were lo-
cated in different rings, as otherwise additional ions, 14
amu greater than those actually observed, would have
been observed2 (see Figure 2). Comparisons of the EIMS
with those for other known spiroacetals with M = 184, of
different ring sizes, were also not encouraging.4 These
facts led us to the view that (B) was possibly a 2,10-di-
methyl-1,7-dioxaspiro[5.5]undecane (see 18, 19, 21 in
Scheme 1) which harmonises with our structural deduc-
tions for other components, e.g. (C) and (D). This possi-
bility was investigated by the synthesis of members of this
system, as shown below in Scheme 1. Firstly, hydroxy-
enone 175 was transformed to a mixture of spiroacetals 18
and 19, but the retention times of both were considerably
longer than that for the natural component (B). Hydrazone
20,5 (described later in Scheme 7) was then alkylated with
racemic 3-(tetrahydropyran-2¢-yl)-1-iodobutane and fur-
ther processed as shown in Scheme 1 to provide 21 along
with a mixture of 18 and 19 as well. Necessarily 21 is the
(2S,6S,10R) isomer and again was shown by direct GC-
MS comparisons to differ from the natural component
(B). A diagnostic ion in the EIMS of each of 18, 19 and 21
The mass spectrum of (A) indicated an apparent molecular
weight of 184, a loss of methyl (m/z 169) and a spiroace-
tal-like fragmentation pattern.2,10 This spectrum matched
very closely that of authentic (E,E)-2,8-dimethyl-1,7-di-
oxaspiro[5.5]undecane11 and retention time comparisons
and co-injection studies with an authentic sample,12 utilis-
ing a cyclodextrin-based phase, confirmed this structure
and established the (2S,6R,8S)-configuration for 15. This
is the stereochemistry uniformly found for this component
from insect sources.2 Component (B) was initially sus-
pected to be the (E,Z)-diastereomer 16, which often ac-
Figure 1 Gas chromatograph of dorsal abdominal gland extract from male Cantao parentum (White). Column and conditions: 30-m DB5
capillary column (J&W). Temperature programmed, 40 °C, 2 min then 10 °C/min to 270 °C. (*Compound H co-elutes with anisaldehyde on
this column)
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1958
Y. Q. Tu et al.
SPECIAL TOPIC
is m/z 139, attributable to the methylated analogue (b on spiroacetals,10,16 and comparisons with that of component
the exo-cyclic double bond) of the m/z 125 ion from 7, (B) raised the possibility that the latter could be an isomer
(see Figure 2). Such an ion is not present in the EIMS of of either the 2,3,7- or 2,4,7-trimethyl-1,6-dioxa-
component (B), and consequently (B) is not an isomer of spiro[4.5]decane systems. No member of these structural
2,10-dimethyl-1,7-dioxaspiro[5.5]undecane. Similar ar- classes has been identified from a natural source. For pur-
guments apply to the 2,11-dimethyl system, which can poses of comparisons, a mixture of stereoisomers of the
also be excluded. Furthermore, on the basis of the mass 2,3,7-trimethyl system 13 was acquired as shown in
spectral ions shown in Figure 2, an isomer of the 2,9-di- Scheme 1. One of these isomers corresponded with com-
methyl-1,7-dioxaspiro[5.5]undecane system would be ex- ponent (B) by GC-MS and co-elution studies on both DB5
pected to exhibit an ion with m/z 154. No such ion is and cyclodextrin-based columns. The mass spectra of this
present in the EIMS of (B).
isomer matches that of (B). Further synthesis of the 2,3,7-
trimethyl system 13 are now being conducted to establish
the relative and absolute stereochemistry of this novel,
carbon-branched spiroacetal system and will be described
at a later date.
(R)
(R)
O
(R)
O
The mass spectra of components (C)-(H) indicated an ap-
parent molecular weight of 198 for all, but of these, only
the spectrum of (E) exhibited both M - CH3 (m/z 183) and
M - CH2CH3 (m/z 169) ions, suggesting that (E) was a di-
astereomer of the previously encountered2 and
synthesised14 2-ethyl-8-methyl-1,7-dioxaspiro[5.5]unde-
cane. Appropriate comparisons with an authentic sample
of known chirality14 confirmed that (E) was the (E,E)-di-
astereomer with the (2S,6R,8S) configuration 23.
O
OH
(R)
18
(i) (ii) (iii)
(R)
O
O
(S)
17
(R)
(R)
19
NNMe2
OTHP
NNMe2
(iv) (v)
(vi)
20
(i) (ii) (iii)
O
O
8
6
O
O
O
(S)
(S)
2
+ 18 and 19
(R)
(2S,6R,8S) 23
22
O
21
Reagents: (i) O3, CH2Cl2, -78 °C (ii) NaBH4-MeOH, -78 °C (iii) 1M HCl
OTHP
(iv) LDA, THF, -78 °C (v)
(vi) NaCl-H2O
I
Components (C), (D), (F), (G) and (H) were then consid-
ered, and it was observed that their mass spectra (with ap-
parent M+ of 198) exhibited more or less the same ions
and these were consistent with a spiroacetal arrangement.2
However, the relative intensities of common ions were of-
ten very different. Components (C) and (D) have very
similar mass spectra which differ markedly from the mass
spectra of (F) and (G) and (H). In (C)-(H) (excepting
(E)) side-chain loss seems to be restricted to M - CH3, as
all exhibit m/z 183. Attention was initially directed to the
major gland component (C) and GC-HRMS established
the molecular formula C12H22O2 (calcd. for C12H2O2,
198.1618; obsvd, 198.1629).
OH
(i) MeLi
(ii)
O
OTHP
OTHP
O
O
(i)H2/ Pd/C, MeOH
(ii) H2SO4
O
O
13
Scheme 1
Component (C), in addition to the weak M - CH3 ion (m/
z 183), incorporated characteristic fragments2,10 at m/z 112
and 115, which indicated the presence of a methylated tet-
rahydropyran or an oxepane as a partial structure. The
fragments m/z 126 and 129 pointed to a homologous
structure for the alternate ring, and the difference of 3 amu
in the two sets of fragments demonstrated that methylene
groups were adjacent to the spiro centre. This is empha-
sised by the structures of the ions anticipated2 from the
candidate spiroacetals below, (Figure 2) and on this basis,
trimethylspiroacetals 25 and 26 but not 24, would be
Subsequently, careful scrutiny of very low-level compo-
nents of shorter retention times (9 min) led to the identifi-
cation
of
an
isomer
of
2,7-dimethyl-1,6-
dioxaspiro[4.5]decane, 22,15 by chromatographic and
mass spectral comparisons with an authentic sample
(from the collections of Dr. J.A. Lewis and Dr. E.N. Law-
son). Curiously, this appears to be the first time this
spiroacetal system has been identified from a natural
source. General considerations of the EIMS of such
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1959
structural possibilities. Spiroacetal 24 would not exhibit a
fragment at m/z 112, which is a prominent ion in compo-
nent (C).
OTHP
I
Steps
OTs
(a)
(CH2)2CO2Et
OBn
OBn
Comparisons of mass spectra and retention times with
those of known spiroacetals 27-2917 eliminated these as
structures for (C) and left no feasible options based on an
unbranched carbon skeleton. The absence of an observ-
able ion at m/z 169 (M - 29) indicated the absence of an
ethyl group a to oxygen, although location b to oxygen
could not be unequivocally dismissed, on the basis of the
mass spectra of compounds related to the talaromycins.18
Consequently, we synthesised the ethyl substituted
spiroacetal system 30, as a diastereomeric mixture, by the
route shown in Scheme 2. Two diastereomers were
formed in almost equal amounts (spiro carbon shifts of d
= 95.76 and 95.29) but there were significant differences
between their EIMS and that of the natural component
(C). Very weak (M - 29) ions (m/z 169) were observed in
the EIMS of both synthesised isomers, but were lacking
from the spectrum of component (C).
I
31
OTHP
32
NNMe2
NNMe2
(c)
(b)
OBn
OTHP
33
O
O
(d)
O
OBn
34
30
Reagents and conditions: (a) NaI/acetone; (b) i. BuLi/THF, -78 °C,
ii. iodide 31, iii. LDA/THF, -78 °C, (iv) iodide 32; (c) SiO2/EtOAc/
hexane/H2O; (d) i. H2/Pd-C/EtOH, ii. TsOH/MeOH
Scheme 2
We then returned to candidate structures 25 and 26, whose
important likely mass spectral fragmentations were sum-
marised in Figure 2. With respect to the 2,3,8-trimethyl-
1,7-dioxaspiro[5.5]undecane system 25, we were synthe-
sising 2,3,8-trialkyl derivatives for other purposes,19 and
were able to utilise (R)-citronellene (35) to acquire a suite
of trimethylspiroacetals of constitution 25 in two ways.
O
O
O
OH
O
O
O
m/z 140
m/z 125
m/z 112
m/z 115
7
O
O
O
O
O
O
OH
OH
m/z 129
m/z 126
m/z 115
m/z 126
24
O
O
O
O
OH
O
O
OH
m/z 129
m/z 126
m/z 112
m/z 115
25
O
O
O
O
OH
O
O
OH
m/z 112
26
m/z 126
m/z 115
m/z 129
O
O
O
O
O
O
O
O
30
27
29
28
Figure 2 Some spiroacetal systems and likely important mass spectral fragment ions
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1960
Y. Q. Tu et al.
SPECIAL TOPIC
(R)
Hydroxymercuration-cyclisation of dienone 36, under
(acidic) reversible conditions,14 followed by reduction
with NaBH4 in the normal way, furnished three spiroace-
tals, as shown below (Scheme 3).
3
(R)
O
6
O
6
2
2
H
H
O
10
O
8
H
8
39 (2R,3R,6S,8R)
38
(a)
(b)
O
(R)
(R)
O
6
3
2
ClHg
O
O
O
35
O
H
O
H
8
(c)
H
H
8
10
O
36
40 (2S,3R,6S,8R)
41
37
HgCl
Figure 3 Structure of likely diastereomers of 2,3,8-trimethyl-1,7-
dioxaspiro[5.5]undecane formed under equilibrating ring-closing
conditions
O
(d)
3 isomers, 57 : 32 : 12
O
25
Reagents and conditions: (a) m-CPBA/CH2Cl2; (b) i. HIO4/H2O, ii.
CH2=CH(CH2)2CH2MgBr/H3O+, iii. Swern (or TPAP), (c) i.
Hg(OAc)2/H3O+/THF, ii. NaCl; (d) NaBH4/H2O/THF/NaOH/TBEAc
(d = 3.86, d of q, J = 6.64 and 2.5Hz), lacking axial-axial
H-coupling. This chemical shift (d = 3.86) indicates a 1,3-
diaxial interaction of H-2 with the C6-O7 bond, and sim-
ilarly for H-8 (d = 3.65, d of q of d, J = 2.1, 6.4 and 11.2
Hz) with respect to the C6-O1 bond. These observations
require structure 39, and now there are two axial protons
below d = 1.5, indicating the presence of two axial C-O
bonds.12,20 These signals at d = 2.08 (t of t, J = 13.5 and
4.6 Hz) and d = 1.86 (q of t, J = 13.2 and 4.1 Hz) corre-
spond to H-4ax and H-10ax respectively. As anticipated
for 39, there is a definite NOE between H-2 and H-8. Each
of the above spiroacetals, 39 and 40, were of approximate-
ly 71% ee (enantioselective GC) with [a]D23 of +48.7 and
-39.3 respectively. (calculated values for 100% ee, are
+68.6 and -55.4, respectively). For spiroacetals 39 the
(2R,3R,6S,8R) enantiomer eluted first from the b-cyclo-
dextrin column, whereas for 40, the (2S,3R,6S,8R) enanti-
omer eluted second.
Scheme 3
Previous experience and MM2-calculations suggested
that the diastereomers shown in Figure 3 were likely to be
prominent under equilibrating conditions. The EIMS of
the (two) major isomers were very similar with weak M+
(m/z 198), discernible methyl loss (m/z 183), and intense
ions at m/z 154 (loss of CH3CHO), with the base peak at
m/z 112. The EIMS of the minor isomer was quite differ-
ent, with the base peak at m/z 115, and significant ions at
m/z 154, 129, 128, 112, 111. The major isomers were sep-
arated (HPLC) and their NMR spectra interpreted, with
emphasis on the following criteria: (i) H-2 is distinguish-
able from H-8 on the basis of one fewer vic-H coupling
(CH3 at C-3) (ii) H-2 and H-8, when experiencing 1,3-di-
axial interaction with oxygen, will resonate at lower field
than when 1,3- with a C-C bond12,20 (iii) NOE’s between
H-2 and H-8 would be anticipated in 38 and 39, but not in
40 and 41. The isomer of shortest GC-retention time was
demonstrated to be 40. The signal at d = 3.26 (d of quar-
tets, J = 6.32 and 9.72 Hz) assignable only to H-2 on the
basis of the coupling pattern, requires the CH3 group at C-
3 to be equatorial, H-2 to be axial and with a 1,3-diaxial
relation with the C6-C11 bond. On the other hand, H-8 ( d
= 3.64, J = 2.2, 6.4, 11.3 Hz) is 1,3-diaxial with respect to
the C6-O1 bond, because of its more deshielded position.
There is no NOE between H-2 and H-8, consistent with
the isomer 40. In addition there is only one axial-proton
(coupling pattern) below d = 1.5 (neglecting H-2 and H-
8), and this is H-10ax ( d = 1.85, q of t, J = 13.2 and 4.0Hz)
again consistent with 40, in which there is only one axial
C-O bond (C6-O1) in the molecule.
A second approach to isomers of system 25 utilised AD-
technology which we had previously employed as a key
step in stereocontrolled spiroacetal construction. It ap-
peared that use of the (R)-configured dienone 36 would be
appropriate,23 and treatment of 36 with AD-Mix b was
predicted to form the tetrol with a stereochemistry that
would harmonise with the existing (R)-centre, to eventu-
ally form the desired all-equatorial, doubly anomerically
stabilised spiroacetal 38. Treatment of dienone 36 in this
way, (see Scheme 4) followed by cyclisation of the
uncharacterised tetrol 42 (originally assumed to have the
depicted stereochemistry) afforded in moderate yield, a
1
single compound exhibiting H and 13C NMR spectra
consistent with a bis(hydroxymethyl) spiroacetal, 43.
Mesylation, followed by hydride reduction, produced a
single compound (GC) exhibiting EIMS appropriate for a
2,3,8-trimethyl-1,7-dioxaspiro[5.5] undecane, and this
was anticipated to be 38.
The second eluting trimethylspiroacetal provides interest-
ing spectroscopic contrasts. The high field signal (d =
10.71) for the CH3 group at C-3 requires this group to be
axial (also experiences a synclinal type of (g-shielding
from O-1) and this is confirmed by the resonance for H-2
To our surprise, the product was identical (GC and GC-
MS) with the previously characterised 40, and sharing its
absolute configuration (enantioselective GC). The unan-
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1961
possible by either Wittig olefination-reduction or by addi-
tion of methyllithium, followed by dehydration and reduc-
tion (Scheme 5).
O
AD-mixβ
tBuOH-H2O
36
HO
In practice, methylenation of (E,E)-ketone 46 provided
very predominantly (~83%) one olefin isomer deduced to
be the (E,E)-isomer 47 on the basis of NMR comparisons,
OH
O
OH
O
PPTS
Me2CO
particularly
with
(E,E)-2,8-dimethyl-1,7-dioxa-
OH
OH
O
42
HO
spiro[5.5]undecane (7) (Scheme 5). Hydrogenation (5%
Pd/C, 95% EtOH) provided five isomers (GC-MS) of 26
in the ratio 23:59:7:5:6 in order of elution, with the first
two eluting well ahead of the last three isomers. Given the
likely facial selectivity of hydrogen delivery, the isomer
with a newly formed axial methyl group 48 would pre-
dominate, with the first eluting isomer (23%) then being
the all-equatorial isomer 49. NMR analyses confirm this.
In particular, the chemical shift of C-2 (d = 60.2 in the
major isomer, 65 in the next most abundant) reflects the
1,3-shielding effect at C-2 by the axial-CH3 at C-4 in the
major isomer 48. On the basis of elution order, the three
minor isomers could incorporate a Z-configured tetrahy-
dropyran ring, or remain (E,E)-configured but with either
the C-2 or C-8 methyl group axial. These isomers were
separated, by HPLC and identified along with their dias-
tereomers as discussed later.
43
MsO
(R)
O
O
O
LAH, THF
MsCl, Et3N
(S)
(R)
O
MsO
44
40
Scheme 4
ticipated result is now being further investigated with re-
spect to the influence of the (R)- centre at C-3 in 36 on the
course of the AD-reaction.
The availability of these isomers of 2,3,8-trimethyl-1,7-
dioxaspiro[5.5]undecanes and their mass spectral and
chromatographic behaviour, allowed us to conclude that
no isomer of this system is present in the Cantao secre-
tion. We then turned our attention to the other system con-
sidered to be consistent with the mass spectral data of
2,4,8-trimethyl-1,7-dioxaspiro[5.5]undecane (26).
The alternative approach to spiroacetal system 26 com-
menced with addition of MeLi to the (E,E)-spiroketone 46
and this resulted in essentially a single tertiary alcohol 50,
as expected (Scheme 5). Dehydration with tosic acid in
benzene afforded a mixture of three alkenes ca 2:46:52,
We had already described24 the spiroketone system 45,
and access to a diastereomeric mixture of 26 appeared
O
Ph3P=CH2
O
O
O
H2, Pd-C
O
O
O
O
(i) MeLi
45
26
(ii) H+ (H2O)
O
δ 65.0
δ 60.2
Ph3P=CH2
O
O
O
H2, Pd-C
EtOH
+ minor isomers
7 : 5 : 6
+
O
O
O
O
O
(23%)
49
(59%)
48
47
O
MeLi
O
O
O
+ 47 (minor)
46
TsOH
C6H6
+
HO
(ether)
O
O
O
51
52
H2, Pd-C
48 (52%) + 49 (48%)
50
Scheme 5
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1962
Y. Q. Tu et al.
SPECIAL TOPIC
with the very minor isomer being the exo-methylene com- (DIBAL-H) followed by addition of pent-4-enylmagne-
pound 47, already acquired by Wittig methylenation of sium bromide and then Dess-Martin oxidation (70%) fur-
the (E,E)-spiroketone. The two major olefins, 51 and 52 nished hydroxy enone 56. Dihydroxylation of 56 with
were separated (HPLC) and individually characterised. AD-Mix b25 installs predominantly (R)-chirality at the
Hydrogenation of this olefin mixture afforded a 48:52 newly created secondary alcohol centre. This monopro-
mixture of the (E,E)-ring configured spiroacetals, with the tected triol 57 was not isolated, but immediately depro-
axial-methyl compound 48 slightly predominating.
tected and cyclized with 1 M HCl in aqueous methanol to
afford the hydroxy spiroacetal 58, as a 1:1 mixture of iso-
mers [d C6(spirocentre) at 97.49 and 96.42] both of which
were (E,E) ring configured and could be separated by
flash chromatography. Reduction of the hydroxymethyl
group was achieved by conversion to the iodomethyl de-
rivative 59 (I2/Ph3P/imidazole), followed by reduction
with Raney-Ni in basic ethanol.26 The two resulting 2,4,8-
tri-methyl spiroacetals were separated and purified
(HPLC, hexane/H2O, 100:1) to provide about equal
amounts of the C-4 epimers. Initial use of the (S)-lactate
based iodide therefore results in final acquisition of the
(2S,4R,6R,8S)-all-equatorial isomer 60 and the
(2S,4S,6R,8S) epimer 61, as shown in Scheme 6. These
With authentic samples of the stereoisomeric racemic tri-
methylspiroacetals available, chromatographic compari-
sons established that the all-equatorial (E,E)-2,4,8-
trimethyl-1,7-dioxaspiro[5.5]undecane 49 was the pre-
dominating natural compound (peak C, Figure 1). In addi-
tion, the low intensity peak in the natural sample (peak D),
on the basis of retention time and matching mass spec-
trum, is assigned as spiroacetal 48, with an axial-C-4 me-
thyl group. (The very similar mass spectra are consistent
with these C-4 epimers). The next question to be ad-
dressed was the absolute stereochemistry of the compo-
nents. The observation that all five synthetic (racemic)
diastereomers (48, 49 and three minor isomers) were nice-
ly separated into their enantiomeric pairs on a b-cyclodex-
trin column, confirmed that enantioselective gas
23
23
isomers had [a]D -66.4 (CHCl3) and [a]D -69
(CHCl3), respectively.
chromatography would provide the required information, The enantiomers of 60 and 61 were obtained from pre-
once appropriate enantiomers were acquired. In addition, dominantly (2R,6S,8R)-2,8-dimethyl-1,7-dioxaspiro
it was likely that the last three eluting isomers of the five [5.5]undecan-4-one (62), following the sequence outlined
component synthetic mixture corresponded with peaks in Scheme 5.
(F), (G) and (H) of the natural extract, and that the major
natural component C was of high ee, when compared with
the well-separated peaks for the enantiomers of the race-
mic all-equatorial (E,E)-isomer, 49.
O
O
O
6
8
O
See
The synthesis of enantiomers of the 2,4,8-trimethyl
spiroacetal system 12 was next undertaken, and several
approaches were developed. The first commenced with
the free-radical addition of the ethyl (S)-(+)-lactate de-
rived iodide 5314 to ethyl crotonate (Scheme 6), to provide
the protected hydroxy ester 54 in 50% yield, as a dia-
stereomeric mixture. Reduction to the aldehyde 55
O
O
O
Scheme 5
2
62
(2R,6S,8R)
ent-60
ent-61
(2R,4S,6S,8R)
(2R,4R,6S,8R)
(i)
OH
(ii)
47% THPO
H
H
H
(iii)
+
H
CO2Et
I
CO2Et
50%
THPO
THPO
O
THPO
53
(not isolated)
O
54
55
OH
O
O
OH
(vi)
(iv)
(v)
H
H
OH
(iii) + (iv), 70%
THPO
THPO
O
(v) + (vi), 80%
56
58
57 (not isolated)
I
O
O
O
(vii)
(viii)
(95%)
O
O
(80%)
O
59
60 (2S,4R,6R,8S)
61 (2S,4S,6R,8S)
Reagents and conditions: (i) Bu3SnH/AIBN/benzene, 48h, syringe pump; (ii) DIBAL-H/CH2Cl2, -78 °C; (iii) CH2=CH(CH2)2CH2MgBr/Et2O,
-50 °C; (iv) Dess-Martin oxidation; (v) AD mix-b (vi) 1 M HCl/MeOH/H2O; (vii) I2/Ph3P/imidazole/toluene, 100 °C; (viii) Ra-Ni/EtOH/
H2O/1% NaOH
Scheme 6
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1963
In addition to ent-60 and ent-61, three minor isomers were the rare class of insect-derived branched carbon chain
also formed in this procedure, and HPLC led to almost spiroacetals,2 and is the first spiroacetal of any type from
complete separation of these closely eluting compounds. Hemiptera or lower insect orders. The compound is not
The first of these to be examined exhibited an EIMS that sex-specific, and an aggregation role may be indicated by
resembled that of the later eluting natural component the presence of a single large colony in a host tree (Mallo-
(peak G), although there were significant differences. The tus philippensis (Lam.) (Euphorbiacea)) at certain stages
1H NMR signal at d = 4.13 (J = 7.0, 3.5, 1.6Hz) did not of insect development.
incorporate an axial-axial coupling, (normally 10-11 Hz
The synthesis of (2S,4R,6R,8S)-2,4,8-trimethyl-1,7-di-
oxaspiro[5.5]undecane (60, described above in Scheme 6,
in these systems), so that this proton, which must be either
H-2 or H-8, must be equatorial. There was an NOE be-
also led to the C-4 epimer 61, because the free radical ad-
tween the other low field signal (d = 3.9, J = 11.4, 6.4, 1.8
dition of the (S)-(+)-lactate derived iodide 53 to ethyl cro-
tonate was not diastereoselective. Control of the absolute
stereochemistry at C-4 would result from use of the chiral
Hz) and both O-CH(CH3) methyl groups, confirming
that both C-O bonds were axial. The high field signal for
C-4 (d = 19.48, DEPT) also required the C-2 methyl group
pool component, (R)-(+)-pulegone (66) or the derived
to be axial. (g-shielding of C-4 by axial C-2 methyl
group). Consequently, this isomer is 63, and because (R)-
3-(tetrahydropyran-2¢-yloxy)iodobutane was employed,
63 also represents its absolute configuration. The chemi-
cal shifts and coupling constants are fully in accord with
this structure.
(R)-(+)-citronellic acid (67),5 with other methyl-bearing
stereogenic centres resulting from alkylation and asym-
metric induction procedures.
The methyl ketone 68, derived from (R)-(+)-citronellic
acid (67), was protected as the ethylene ketal 69 before
ozonolysis and sodium borohydride reduction to alcohol
70. Tosylation (or mesylation) and treatment with NaI
yielded iodide 71, which under eliminative conditions
(KOBu-t) furnished alkene 72.
4
O
8
O
O
O
6
H
6
8
H
O
2
Alkene 72 was deprotected, transformed to the N,N-di-
methylhydrazone 20 and alkylated with (S)-3-(tetrahydro-
pyran-2’-yloxy)-1-iodobutane14,27 to provide hydrazone
73. Selective deprotection using silica afforded the THP-
ether 74, whereas use of 10% aqueous HCl released hy-
droxyenone 75. The absolute stereochemistry at the posi-
tions that would become C-4 and C-8 in the target
spiroacetal 60, were now installed. Further chirality intro-
duction at C-2 was based on asymmetric dihydroxylation,
and use of AD-Mix b with either 74 or 75 was predicted
to provide the appropriate configuration for subsequent
ring closure to the hydroxymethyl derivative 76, which on
tosylation and reduction provided 60 (ee 99.5%) whose
1H, 13C NMR and mass spectra matched those already ob-
tained (Scheme 7).
4
O
H
8
2
4
63
(2S,4S,6S,8R)
64
65
(2S,4R,6S,8R)
(2S,4R,6R,8R)
The two remaining spiroacetals from this sequence exhib-
ited quite different EIMS in that the first eluting had a base
peak m/z 115, and the second eluting at m/z 129, with a
very weak m/z 115. In each of these isomers, the 1H NMR
chemical shifts for H-2 and H-8 were separated by ca 0.6-
0.7 ppm, indicating that one of these protons experienced
a 1,3-diaxial interaction with a C-O bond, and the other
with a C-C bond, as outlined previously. In addition, the
chemical shift data required the three methyl groups to be
equatorial and thus structures 64 and 65 were arrived at.
It is to be noted that these are epimeric at the spirocentre
(C-6), and consistent with this, 64 and 65 equilibrated
over time. A basis for distinction between structures 64
and 65 would be NOE’s, as in 64, an NOE between H-2
(lower field of the H-2, H-8 pair) and H-4 would be antic-
ipated, whereas in 65, an NOE between H-4 and H-8 (now
at lower field than H-2) would be absent. Experiments
demonstrated that these structural assignments were cor-
rect. In addition, structures 64 and 65 were acquired in an-
other way, with more stereochemical control, by AD-
technology, and this is described later in Scheme 8.
As indicated earlier, several minor components of the se-
cretion appeared to be diastereomers of the major compo-
nent 60 identified above, and variation in the procedures
would permit acquisition of several of these. For example,
alkylation of hydrazone 20 with (R)-3-(tetrahydropyran-
2’-yloxy)-1-iodobutane20,27 yielded 77 which also could
be selectively or fully deprotected to furnish 78 and 17 re-
spectively (Scheme 8). Treatment of either with AD-Mix-
a followed by cyclisation provided predominantly the hy-
droxymethyl compound 79, although use of 78 appeared
to be more efficient. Reduction of 79, via the tosylate,
yielded ent-61, with [a]D23 +71 and ee ~ 99.5%.
Intermediate 17 was also treated with AD-Mix b to pro-
vide predominantly 80 and then, by acid treatment, the hy-
droxymethyl isomers 81 and 82, reduction of which
afforded a mixture (ca 55:45) of two spiroacetals which
are epimeric at the spirocentre. These spiroacetals proved
to be identical with 64 and with 65 respectively, by com-
parisons of their NMR spectra and stereochemical analy-
With the availability of 60, ent- 60, 61 and ent-61, and the
racemates, elution and co-injection studies, using a b-cy-
clodextrin column, established that the major natural com-
ponent (Figure 1, Peak C) was (2S,4R,6R,8S)-2,4,8-
trimethyl-1,7-dioxaspiro[5.5]undecane (60) with no de-
tectable level of its enantiomer. Compound 60 represents
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1964
Y. Q. Tu et al.
SPECIAL TOPIC
H
H
H
Ref. 5
HO
OH
2 MeLi-THF
(71%)
O
O
CO2H
PPTS, C6H6
83%
O
O
69
O3, MeOH, NaBH4
66
67
68
(i) MsCl, Et3N
96%
KOtBu, THF
72%
O
O
O
O
O
O
I
(ii) NaI
HO
72
30% AcOH-H2O
71
70
H2NNMe2, AcOH
(i) LDA, -78°C
NNMe2
OTHP
O
OTHP
NNMe2
Silica
OTHP
(ii)
73
74
20
I
AD-Mixβ
(0°C)
10% HCl
OH
O
OH
O
OTHP
HO
75
AD-Mixβ
(0°C)
10% HCl
(i) TsCl, Py
(ii) LiAlH4
O
O
O
O
HO
60(2S,4R,6R,8S)
76
Scheme 7
O
(R)
ses on the b-cyclodextrin column. NMR analyses confirm
that the conformation represented by 64 is the dominant
one, and this is probably true for 81 also.
O
(S)
O
O
(S)
The availability of a variety of diastereomers of system 12
of known absolute configuration, permitted detailed ex-
amination of the chirality of the spiroacetal components in
the Cantao sample. This work was conducted using a b-
cyclodextrin column28 in the GC-MS system so that the
mass spectra of peaks considered to be enantiomers could
be compared. Co-injection studies and observation of
peak enhancements allowed a complete stereochemical
profile to be drawn. The enantiomer pairs of the synthe-
sised spiroacetals were well separated on the b-cyclodex-
trin column, and there is a strongly predominating
chirality in each of the components (A)-(H). Because of
the low levels of the minor components, accurate esti-
mates of ee’s are difficult, but only in the case of (D) is its
enantiomer observable. The absolute stereochemistry of
the peaks (A)-(G) in order of elution on the DB-5 column
(Figure 1) excepting (B), are shown below. Component
(H), which elutes last on the non-polar DB-5 column,
elutes prior to F and (G) on the cyclodextrin column.
(A)
(B)
(R)
(S)
O
O
(S)
(S)
(R)
O
O
(S)
(S)
(C)
(D)
O
O
O
(R)
(S)
(R)
(R)
O
(S)
(S)
(R)
(F)
(R)
O
(E)
(R)
O
(R)
(S)
(R)
(R)
O
O
Exposure of a dichloromethane extract of the Cantao se-
cretion to aqueous HCl for two days at room temperature,
caused peaks (F) and (G) to become nearly equal in inten-
sity. This is expected for energetically closely balanced
(S)
(S)
(H)
(G)
(very low level component)
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1965
(i) LDA, -78°C
(ii)
NNMe2
NNMe2
OTHP
O
OTHP
Silica
I
20
77
78
AD-Mixα (0°C)
10% HCl
OH
OTHP
O
OH
O
OTHP
HO
17
AD-Mixα
(0°C)
10% HCl
O
(i) TsCl, Py
(ii) LiAlH4
O
O
O
79
OH
ent 61 (2R,4R,6S,8R)
AD-Mixβ
(0°C)
O
OH
OH
O
OTHP
10% HCl
HO
80
17
O
O
(i) TsCl, Py
(ii) LiAlH4
O
O
O
O
O
O
82
65
HO
O
HO
O
O
O
HO
64
81
Scheme 8
spiroacetals that are epimeric at the spirocentre, as 64 and abdominal tips. This defence strategy appears to have
65 are, (see Scheme 8), and which structures are assigned evolved to provide protection for the vulnerable abdomi-
to (F) and (G) respectively. The fact that the abundances nal area. Some studies of the volatile chemical constitu-
of (F) and (G) in the natural sample are very different (ca ents of certain rove beetle emissions have been reported
8:1) is not an unusual state of affairs with such epimeric and summarised in the report by Huth and Dettner.30
spiroacetals in insects.2,3,12
These authors characterised forty-one volatile compo-
nents from a range (13) of Staphylinids, and iridoid alde-
hydes and lactones, short-chain ketones, cyclic
compounds and spiroacetals were identified. It is with the
latter structural type that our present interest lies. In 1986,
Dettner and Schwinger31 described the defensive secre-
tion of Ontholestes murinus (L) and this contained (along
with other volatiles) (E,E)-2,8-dimethyl-1,7-dioxas-
piro[5.5]undecane (7), of undetermined absolute stere-
ochemistry. This spiroacetal was accompanied by another
component of apparent molecular mass of 198 and a
spiroacetal-like mass spectral fragmentation pattern. In
the subsequent report,30 this latter compound was de-
scribed as a 2,2,8-trimethyl-1,7-dioxaspiro[5.5]undecane
without further data. The suggested arrangement, with a
gem-dimethyl group, was a most unusual feature in an in-
sect derived spiroacetal,2 and therefore verification by
synthesis, and determination of the absolute stereochem-
istry, were of interest. Consequently, acquisition of 14 in
both racemic and optically active forms was required.
Speculation on the biosynthesis of insect spiroacetals has
been presented elsewhere,2,29 and the origin of the compo-
nent (B) and (C) may be associated with either propionate
or even amino acid intervention. Because of the novelty of
(B) and (C) and the latter’s predominance in the secretion,
such incorporation studies are planned.
(b)
Spiroacetals from the Rove Beetle, Ontho-
lestes murinus (L.)
The rove beetle subtribe, Staphylinina, comprises about
forty-five members in central Europe and all have evolved
gland systems which are utilised in a very conspicuous de-
fensive strategy. On molestation, abdominal elevation oc-
curs with eversion of a pair of glands derived from the
membrane between the sixth and seventh abdominal terg-
ite. Simultaneously, a defensive secretion may exude and
be directed towards the molestation by the manouverable
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1966
Y. Q. Tu et al.
SPECIAL TOPIC
The synthesis of system 14 has not been reported previ-
ously and the approach summarised below was based on
the precedented addition32 of alkynol derivatives to lac-
tones followed by hydrogenation, and cyclisation was an-
ticipated to provide system 14. Reaction of acetone with
propargyl bromide and aluminium-amalgam provided
alkynol 83 in high yield, whereas use of zinc powder re-
sulted in a much lower yield. The crude alcohol was pro-
tected as its THP ether 84 and then deprotonated to the
lithiated alkyne, which was transferred via cannula into a
solution of d-caprolactone in THF/HMPA at -78 °C. The
resulting crude ynol 85, as a diastereomeric mixture, was
hydrogenated in methanol to furnish the desired spiroace-
tal 14, which was purified by flash chromatography and
preparative gas chromatography. This sequence is sum-
marised below in Scheme 9.
H
O
O
HO
O
O
O
m/z 183 (M-CH3)
m/z 129
m/z 129
Interpretation of the H and 13C NMR spectra should be
approached in terms of the three diastereomeric forms
drawn below, the two E-forms 14-E and 14-E', with the
former enjoying maximum anomeric stablisation), and the
14-Z form.
1
E
10
14
Z
O
5
O
O
O
E'
O
8
O
2
13
3
O
12
OH
OH
14-E
14-Z
14-E'
O
O
14
OH
The spectral data (Table) are confidently interpreted in
terms of 14-E. The 13C NMR spectrum was assigned with
the aid of 2D spectra (HSQC, COSY, NOESY) and the
DEPT spectrum. The methyl groups resonate at d = 21.55
(C-14), 25.36 (C-13) and 32.78 (C-12) with C-10 (d =
19.22) and C-4 (d = 15.82) being at higher field as a result
of the two-fold g-shielding effects of oxygen, but with C4
additionally shielded by the axially-orientated C13 meth-
O
OP
O
O
(i) Al-Hg
(ii) Me2CO
(i) DHP, TsOH
(ii) Distillation
Br
HO
1
yl group. With these assignments settled, the H NMR
83
spectrum was interpreted using the correlated spectra,
chemical shifts and signal multiplicities. The tabulated as-
signments as shown in the Table. The chemical shift of H-
8 requires this proton (d = 3.87) to have a 1,3-diaxial rela-
tionship with oxygen, not present in 14-Z. Distinction be-
tween 14-E and 14-E' follows, for example, from aspects
of the 2D-NOESY spectrum, with the strong NOE effect
between H-13 and H-8 expected for 14-E. Spatial proxim-
ity between these proton groups is much reduced in 14-E'.
The synthesised 14-E exhibited gas chromatographic and
EIMS behaviour identical with those of the insect derived
material.
(i) nBuLi,THF
(ii) addition to
δ-caprolactone
(THF-HMPA)
OH
O
THPO
OTHP
84
85
O
H2, Pd-C, MeOH
27% from 84
O
14
Attention was then directed to determination of the abso-
lute stereochemistry. An expeditious route commenced
with commercially available 6-methylhept-5-en-2-one
(86), which was converted to its N,N-dimethylhydrazone
87. Kinetic deprotonation and alkylation with the THP-
protected (R)-3-hydroxy-1-iodobutane33 provided hydra-
zone 88 which was converted to protected hydroxyenone
89 by flash chromatography on silica. Hydroxymercura-
tion-cyclisation of 89 with Hg(OAc)2 in 1:1 THF/H2O,
followed by biphasic reduction with NaBH4, provided the
(6S,8R) enantiomer of 14-E, i.e. 90, in 34% yield from the
enone, with [a]D22 +46.2 (c = 7.09, CHCl3). Enantioselec-
tive gas chromatography showed that the ee exceeded
98%, and MS and NMR data matched those for the race-
mate 14-E. The sequence is shown in Scheme 10.
Scheme 9
Spiroacetal 14, obtained as a single diastereomer, was
characterised by H and 13C NMR spectroscopy, mass
1
spectrometry and also by enantioselective gas chromatog-
raphy (see later). In the EIMS, there is, as expected, some
similarity between 14 and 7 with both exhibiting charac-
teristic ions at m/z 169, 115, 112, but 14 in addition, ex-
hibits intense peaks at m/z 183 and 129, consistent with
the gem-dimethyl grouping. These intense ions in the
mass spectrum (see ref. 6 for a reproduced spectrum) are
assigned the structures shown below.
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1967
Table 13C and 1H NMR Data for Spiroacetal 14-E
O
NNMe2
Me2NNH2
HOAc (94%)
C
2
δC
δH
multiplicity, J (Hz)
86
87
NNMe2
OTHP
(i) LDA, THF
SiO2
71.96
32.97
OTHP
(83%)
(ii)
(77%)
O
I
88
3
1.63
1.10
m
m
(i) Hg(OAc)2,
THF-H2O
OTHP
O
6
2
4
5
15.82
37.10
1.83
1.45
Hax, qt, J=13.5, 4.0
Heq, m
O
(ii) NaBH4, TEBAC
89
NaOH-H2O-CH2Cl2
(34%)
8
(6S,8R) 90
1.65
1.35
Heq, J=13.5
Hax
m
Scheme 10
6
8
9
96.24
65.66
36.43
The enantiomers of (racemic) 14-E were very well sepa-
rated using a b-cyclodextrin stationary phase in the GC-
MS system, and the synthesised (6S,8R) isomer 90, eluted
earlier than its antipode. Further comparisons with the ex-
tracts of O. murinus established that the natural spiroace-
tal was the (6R,8S) isomer of >95% ee. A lower than
anticipated level of the natural spiroacetal resulted in this
less precise measure of the ee. With the availability from
previous work14 of stereoisomers of (E,E)-2,8-dimethyl-
1,7-dioxaspiro[5.5]undecane (7), similar analyses indicat-
ed that the (2S,6R,8S) isomer 15 (>98% ee) was present,
as found previously for this spiroacetal in insects. Howev-
er, in another rove beetle, O. tesselatus,30 the (E,E)-2,8-
dimethyl-1,7-dioxaspiro[5.5]undecane exhibited compa-
rable levels of the enantiomers - a hitherto unobserved
situation.
3.87
dqd, J=11.3, 6.4, 2.1
1.50
1.10
m
m
10
11
19.22
37.25
1.99
1.40
Hax, qt, J=13.5, 3.5
Heq, dtt, J=13.5, 3.5
1.63
1.33
Heq, brd J=13.5;
Hax, m
12
13
14
32.78
25.36
21.54
1.14
1.30
1.05
s
s
d, J=6.4
Conclusion
The structures and stereochemistry of several spiroacetals
with branched carbon skeletons from insect sources have
been determined by spectroscopy, synthesis and enantio-
selective gas chromatography. These enrich the landscape
2,10-Dimethyl-1,7-dioxaspiro[5.5]undecanes 18, 19, 21
Hydroxyenone 17 and hydrazone 20 are described later in the con-
of insect-derived spiroacetals, and pose interesting ques- text of Schemes 7, 8, and spiroacetals 18, 19 and 21 will be dis-
cussed elsewhere.
tions of function, and biosynthetic diversity.
9-Ethyl-2-methyl-1,7-dioxaspiro[5.5]undecane (30) Commenc-
ing with Iodide 31
1H and 13C NMR spectra were recorded with Bruker AC200, AMX-
400 or DRX-500 spectrometers, using either CDCl3 or benzene-d6
as solvents. Chemical shifts (d) are given in ppm, and coupling con-
stants (J) in hertz. The signal for the residual CHCl3 (in CDCl3) was
adopted as a secondary standard for 1H NMR spectra (d 7.24), and
the centre of the CDCl3 triplet (d 77.00) for 13C NMR spectra. Low
resolution mass spectral data refer to GC-MS data with a Hewlett-
Packard 5970 B mass selective detector, and enantioselective gas
chromotagraphy/mass spectrometry to a Shimadzu GC-MS system
equipped with a b-cyclodextrin column. High resolution mass spec-
tra were recorded on a Kratos MS-25RFA spectrometer. Preparative
gas chromatography was conducted with a Shimadzu gas chromato-
graph, Model GC-9A, equipped with OV101 and C-20M columns.
Optical rotations were measured with a Perkin Elemer 241 MC po-
larimeter. The extracts from the two species were obtained as previ-
ously described.4-6
2-(Benzyloxymethyl)-1-iodobutane (31): The known 2-(benzyl-
oxymethyl)butan-1-ol34 (4.06 g, 20 mmol) was dissolved in pyri-
dine (15 mL) at 0 °C and tosyl chloride (8g, 42 mmol) was added in
portions over 15 min after which time the mixture was stirred at 0
°C for a further 30 min, and left overnight at 20 °C. The pyridine
was removed under reduced pressure, and the residue was dissolved
in Et2O/H2O (80 mL/80 mL). The H2O layer was further extracted
with Et2O (40 mL) and the combined Et2O solutions were washed
with H2O (2 î 50 mL), aq sat. Na2CO3 (2 î 50 mL), brine (2 î 50
mL), dried (MgSO4) and then concentrated to give a pale yellow oil
(7.8 g), which was directly chromatographed on silica (cyclohex-
ane/EtOAc, 12:1) to give the pure tosylate (6.34 g, 87%).
1H NMR (200 MHz, CDCl3): d = 0.83 (t, 3 H, J = 7.6 Hz, CH2CH3),
1.36 (m, 2 H, CH2CH3), 1.81 (m, 1 H), 3.36 (m, 2 H, CH2OBn), 4.07
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1968
Y. Q. Tu et al.
SPECIAL TOPIC
(d, 2 H, J = 5.2 Hz, CH2OTs), 4.36 (s, 2 H, CH2Ph), 2.36 (s, 3 H),
7.26 (m, 7 H), 7.76 (d, 2 H, d, J = 8.3 Hz).
13C NMR: (50 MHz, CDCl3): d = 11.0, 20.3, 21.4, 40.0, 68.8, 70.1,
72.8, 127.2 (2 C), 127.3, 127.6 (2 C), 128.0 (2 C), 129.6 (2 C),
132.7, 138.0, 144.4.
1H NMR (200 MHz, CDCl3): d = 0.87 (t, 6 H, J = 7.2 Hz, 2 CH3),
1.15 and 1.22 (2 d, 6 H, J = 6.0 Hz, 2 CH3), 1.20-1.85 (m, 30 H),
2.36-2.40 (2 t, 4 H, J = 7.0 Hz), 3.32-3.34 (2 d, 4 H, J = 5.0 Hz),
3.40-3.57 (m, 2 H), 4.46 (s, 4 H, PhCH2), 4.61-4.67 (2 t, 2 H,
J = 4.6 Hz), 7.31 (s, 10 H, 2 C6H5).
13C NMR (50 MHz, CDCl3): d = 11.0, 18.9, 19.6, 19.9, 21.4, 25.1,
25.13, 25.3, 25.4, 31.0, 33.8, 35.9, 36.7, 39.2, 40.1, 40.2, 42.5, 62.4,
62.6, 70.6, 72.6, 72.9, 73.6, 95.6, 98.6, 127.3, 128.1, 138.4, 211.2.
This tosylate (3.52 g, 15 mmol), NaI (6.1 g, 41 mmol) and anhyd
acetone (30 mL) were then refluxed with stirring for 2.5 h, after
which the mixture was concentrated and then partitioned with Et2O/
H2O (50 mL/50 mL). The H2O layer was further extracted with Et2O
(30 mL), and the combined Et2O extracts were washed with aq
NaS2O3 (30 mL), aq sat. Na2CO3 (30 mL) and brine (30 mL) before
drying (MgSO4). Concentration provided a yellow oil (2.93 g)
which was chromatographed on silica (cyclohexane/EtOAc, 50:1)
to provide 31 as a pale yellow slightly unstable oil (2.68 g, 87%).
1H NMR: (200 MHz, CDCl3): d = 0.90 (t, 3 H, J = 7.0 Hz, CH2CH3)
1.38 (m, 3 H, CHCH2), 3.76 (m, 4 H), 4.52 (s, 2 H, PhCH2), 7.34 (s,
5 H, C6H5).
13C NMR: (50 MHz, CDCl3): d = 11.1, 12.5, 24.2, 41.1, 72.3, 73.2,
127.5 (3 C), 128.2 (2 C), 138.2.
GC-MS: m/z (%) = 289 (8.9), 288 (2.4), 246 (1.6), 199 (30), 197
(17), 125 (14), 91 (100).
The above ketone (200 mg) was dissolved in EtOH (6 mL, 95%)
and Pd-C (~30 mg) was added before hydrogenation (1.5 atm) for
2.5 h. The mixture was then filtered, concentrated and added to
MeOH (3 mL) containing TsOH (50 mg) and stirred for 1 h to pro-
vide the desired 9-ethyl-2-methyl-1,7-dioxaspiro[5.5]undecane
(30) (82 mg, 81%) as a mixture of two closely eluting diastereomers
of approximately equal proportions. The EI-MS of these isomers
were very similar. No attempt was made to separate these diastere-
omers as their chromatographic behaviour and EI-MS confirmed
their absence from the natural secretion.
1H NMR: (200 MHz, CDCl3): d = (for isomeric mixture): 0.81-
2.10 [m with app. quartets (0.83) and doublets (~1.08), 19 H], 3.1-
4.2 (m, 3 H).
13C NMR: (50 MHz, CDCl3): d = 11.1, 12.1, 18.8, 18.9, 21.7 (2 C),
22.5, 22.6, 24.9, 25.2, 31.4, 32.6 (2 C), 34.1, 34.8 (2 C), 35.7, 37.0,
63.0, 65.0 (2 C), 65.3. 95.3, 95.8.
GC-MS: m/z (%) = 304 (M+, 4.3), 177 (M - I, 1.6), 159 (1.5), 121
(3), 92 (20), 91 (100), 65 (13.9), 55 (4.1).
This iodide was used directly in the alkylation sequence described
below.
2-(Tetrahydropyran-2’-yloxy)-9-(benzyloxymethyl)undecan-6-
one (34)
GC-MS: (isomer 1): m/z (%) = 198 (11.8), 197 (1.8), 183. (2.4), 168
(1.3), 155 (2.0), 154 (8.3), 139 (4.6), 129 (4.8), 126 (4.8), 125 (1.6),
115 (100), 114 (34), 112 (92.9), 111 (40.6), 99 (7.6), 98 (8.4), 97
(61.0), 84 (23.1), 83 (62.4), 73 (16.3), 71 (17.4), 70 (16.1). (The
GC-MS data for isomer 2 was extremely similar).
To a stirred solution of acetone-N,N-dimethylhydrazone (400 mg, 4
mmol) in anhyd THF (5 mL) at -78 °C was added BuLi (2.5 mL of
1.6 M in hexane) and after a further hour, a solution of the above io-
dide 31, (608 mg, 2 mmol) in THF (2 mL) was added. The mixture
warmed to r.t. and after 3 h, the solvent was removed (reduced pres-
sure) and the residue was taken up in Et2O/pentane (1:1). This solu-
tion was filtered through neutral alumina, dried (MgSO4) and
concentrated to give the pale yellow monoalkylation product (560
mg), which was used without further purification.
1H NMR: (200 MHz, CDCl3): d = 0.87 (t, 3 H, J = 7.0 Hz,
CH3CH2), 1.40-1.58 (m, 5 H, CH2CHCH2), 1.92 (2, 3 H), 2.19 (t, 2
H, J = 7.0 Hz), 2.40 [s, 6 H, N(CH3)2], 3.36, (d, 2 H, J = 4.2 Hz,
OCH2CH), 4.46 (s, 2 H, PhCH2), 7.30 (s, 5 H, C6H5).
13C NMR: (50 MHz, CDCl3): d = 11.2, 16.4, 23.6, 28.1, 36.4, 39.6,
47.0 (2 C), 72.5, 73.0, 127.3, 127.4 (2 C), 128.4 (2 C), 138.7, 167.8
(C=N).
GC-MS: m/z (%) = 276 (M+, 25), 232 (2.1), 186 (9.1), 185 (68), 169
(6.2), 113 (23), 100 (92), 92 (14), 91 (91), 70 (29), 65 (25).
HRMS: Calcd for C12H22O2 198.1618. Obsvd 198.1619.
Dienone 36
(R)-(-)Citronellene (35; 10g, 72 mmol) was dissolved in CH2Cl2
(200 mL) and cooled to 0 °C. To this stirred solution was added m-
CPBA (70%, 17 g, 72 mmol) in portions over 2 h. The mixture was
then filtered, washed with aq sat. NaHCO3 solution (50 mL) and
dried (MgSO4). The solvent was removed in vacuo to yield the
crude epoxide (isomeric mixture) as a yellow oil (9.9 g, 89%).
1H NMR (200 MHz, CDCl3): d = 0.97 (d, 3 H, J = 6.6 Hz), 1.21 (s,
3 H), 1.26 (s, 3 H), 1.29-1.66 (m, 4 H), 2.10 (m, 1 H), 2.67 (dd, 1
H, J = 6.3, 5.1 Hz), 4.85-4.98 (m, 2 H), 5.54-5.73 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 18.6, 18.6, 20.1, 20.4, 24.8, 26.5,
26.7, 33.0, 33.2, 37.5, 37.7, 58.3, 64.4, 64.5, 112.9, 113.1, 144.0,
144.1.
The above mono-alkylated hydrazone (388 mg, 1.4 mmol) in anhyd
THF (1 mL) was added to a cooled solution (-78 °C) of LDA in an-
hyd THF (3 mL) generated from diisopropylamine (287 mg, 2.8
mmol) and BuLi (1.8 mL of 1.6 M hexane solution). After stirring
the mixture for 1 h at -78 °C, 3-(tetrahydropyran-2’-yloxy)butyl
iodide (32; 398 mg, 1.4 mmol) in anhyd THF (1 mL) was added at
this temperature, and then allowed to stir for 24 h at r.t. The solution
was concentrated under reduced pressure, taken up in Et2O/pentane
(1:1), filtered through neutral alumina, dried (MgSO4) and again
concentrated to give the dialkylation product (520 mg, 68%, GC
analysis).
GC-MS: m/z (%) = 139 (0.8) (M - CH3), 125 (0.5), 111 (1.2), 95
(5.3), 81 (100).
The crude epoxide mixture was dissolved in Et2O (200 mL), and
HIO4 (16.4 g, 72 mmol) was added in portions at r.t. to the stirred
solution. After 2 h, the mixture was filtered, washed with aq satd
NaHCO3 solution (3 î 50 mL), and brine (20 mL), then separated
and dried (MgSO4). The volume of this organic phase was carefully
reduced to about 50 mL, and GC-MS showed that the desired alde-
hyde had formed. This solution was immediately used in the next
step.
GC-MS: m/z (%) = 432 (M+, 19), 388 (2.5), 348 (12), 347 (52), 342
(6), 341 (23), 331 (21), 286 (5), 257 (40), 91 (100).
GC-MS: m/z (%) = 97 (6, M - CH3), 94 (5), 83 (14), 79 (20), 68
The dialkylated hydrazone 33, (300 mg) was dissolved in EtOAc/
acetone/H2O (4:4:1), silica gel (2 g) was added and the mixture
stirred for 12 h at r.t.. The filtered solution was then chromato-
graphed (silica gel, cycloxhexane/EtOAc, 3:1) to provide a yellow
oil (200 mg, 73%) of the ketone 34 as a diastereomeric mixture.
(67), 67 (57), 55 (100).
A three-necked flask equipped with a reflux condenser and a rubber
septum was charged with Mg (3.46 g, 0.144 mol) and anhyd Et2O
(5 mL). Dibromoethane (260 mL, 3 mmol, 2%) was added by a sy-
ringe and the contents gently stirred until refluxing had ceased. 5-
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1969
Bromopent-1-ene (1 drop) was added and then a further amount (8.5
mL, 72 mmol) as a solution in Et2O (20 mL), at such a rate so as to
maintain a steady reflux. After addition was complete, the reaction
was stirred for a further 15 min with slight warming. The previously
generated solution of the aldehyde was cannulated into the reaction
flask at 0 °C and stirred overnight at r.t. The reaction was quenched
(10% HCl, 100 mL) and then extracted with Et2O (3 î 100 mL).
The solvent was removed and the residue dissolved in CH2Cl2
(150 mL), after a small sample of the secondary alcohol, resulting
from the Grignard addition, was characterised.
1H NMR (200 MHz, CDCl3): d = 0.97 (d, 3 H, J = 7 Hz), 1.12-1.68
(m, 9 H), 2.03 (m, 3 H), 3.50-3.60 (br s, 1 H), 4.87-5.01 (m, 4 H),
5.56-5.85 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 20.3, 24.9, 32.5, 33.7, 35.1, 36.9,
37.8, 72.0, 112.8, 114.6, 138.7, 144.4.
HRMS: m/z Calcd for C12H22O2 198.1619. Obsvd 198.1612.
GC analysis revealed three diastereomers (57:32:12) of system 25
and the two major ones were separated by HPLC (6% EtOAc in
hexane, silica gel).
Isomer 1 40
[a]D25 -69.4 (c = 0.09, CHCl3). Chiral GC (b-cyclodextrin) 71% ee.
1H NMR (400 MHz, CDCl3): d = 0.80 (d, 3 H, J = 6.6 Hz), 1.10, (d,
3 H, J = 6.4 Hz), 1.12 (d, 3 H, J = 6.3 Hz), 1.09-1.24 (m, 2 H),
1.32-1.61 (m, 8 H), 1.85 (qt, 1 H, J = 12.7, 3.9 Hz), 3.26 (dq, 1 H,
J = 9.7, 6.3 Hz), 3.64, (dqd, 1 H, J = 12.7, 6.3, 1.9 Hz).
13C NMR (100 MHz, CDCl3): d = 17.4 (CH3), 18.9 (CH2), 19.3
(CH3), 21.7 (CH3) 27.7 (CH2), 32.7 (CH2), 34.9 (CH2) 36.0 (CH2)
36.7 (CH), 64.9 (CH), 70.6 (CH), 95.8 (C).
2D-NOESY: No cross peak between d = 3.64 and 3.26.
The solution of the alcohol in CH2Cl2 was treated with NMO (10 g,
85 mmol), TPAP (150 mg, 0.42 mmol, 0.5%) and 3Å molecular
sieves (4.1 g). After stirring for 2 h, the mixture was passed through
a small plug of silica and the solvent was removed in vacuo. Flash
chromatography (hexane) yielded dienone 36 as a slightly yellow-
ish oil (9.6 g, 75% from citronellene); [a]D25 -6.53 (c = 2.5, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.96 (d, 3 H, J = 6.8 Hz), 1.18-
1.70 (m, 5 H), 1.96-2.10 (m, 3 H), 2.35 (td, 3 H, J = 7.6, 3.4 Hz),
4.87-5.01 (m, 4 H), 5.49-5.82 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 20.3, 22.8, 30.1, 37.5, 40.5, 41.9,
113.4, 115.1, 138.0, 143.8, 190.2.
GC-MS: m/z (%) = 165 (1.5) (M+ - 15), 151 (0.8), 139 (1), 126 (9),
111 (12), 97 (25), 83 (29), 69 (61), 55 (99), 41 (100).
GC-MS: m/z (%) = 198 (2.6), 183 (0.8), 154 (24), 139 (2.5), 126
(22), 115 (22), 112 (100), 97 (24), 83 (34), 69 (30), 55 (44), 43 (55).
Isomer 2, 39
[a]D25 +48.7 (c = 4.3, CHCl3). Chiral GC (b-cyclodextrin) 71% ee.
1H NMR (400 MHz, CDCl3): d = 0.89 (d, 3 H, J = 7 Hz), 1.04 (d, 3
H, J = 6.7 Hz), 1.10 (d, 3 H, J = 6.3 Hz), 1.08-1.18 (m, 1 H), 1.28-
1.37 (m, 3 H), 1.45-1.58 (m, 5 H), 1.85 (tt, 1 H, J = 13.2, 4.1 Hz),
2.08 (tt, 1 H, J = 13.5, 4.6 Hz), 3.65 (dqd, 1 H, J = 11.2, 6.4, 2.1 Hz),
3.86 (dq, 1 H, J = 6.6, 2.5 Hz).
13C NMR (100 MHz, CDCl3): d = 10.8 (CH3), 18.7 (CH3), 19.0
(CH2), 21.9 (CH3), 26.4 (CH2), 29.9 (CH2) 31.2 (CH), 32.8 (CH2),
32.8 (CH2), 35.0 (CH2), 65.1 (CH), 66.3 (CH), 96.2 (C).
2D-NOESY: Cross peak between d = 3.86 and 3.65.
HRMS: m/z Calcd. for C12H20O 180.1514. Found 180.1515.
GC-MS: m/z (%) = 198 (1.9), 183 (0.8), 154 (25), 139 (2.3), 126
(14), 115 (16), 112 (100), 97 (23), 83 (32), 69 (23), 55 (39), 43 (48).
Oxymercuration-Cyclisation of Dienone 36
Dienone 36 (1 g, 5.6 mmol) was dissolved in anhyd THF (30 ml)
along with 1% HClO4-H2O (30 mL) and Hg(OAc)2 (3.76 g, 11.8
mmol). The flask was light-protected (Al foil) and stirred overnight,
before removal of the THF. The aqueous layer was extracted with
CH2Cl2 (4 î 30 mL), and this solvent was removed to yield a semi-
solid (2.95 g, 74%), of the bis(2,8-acetoxymercuriomethyl)-3-meth-
yl-1,7-dioxaspiro[5.5]undecane. This crude bis-acetate (1.69 g, 2.3
mmol) was dissolved in THF (10 ml) and aq sat. NaCl (10 mL) was
added, and the mixture stirred. THF was removed and the white pre-
cipitate of the chloromercuric derivative 37 was collected and dried
in vacuo (1.32 g, 86%); mp 105-107 °C.
Dienone 36 with AD-Mix b
To a flask containing tert-butyl alcohol (20 mL) and H2O (20 mL)
was added AD-Mix b (10.5 g) and methanesulfonamide (0.57 g, 6
mmol). The thick orange mixture was cooled (0 °C) and then di-
enone 36 (1 g, 5.5 mmol) was added in one portion and the reaction
was left to stir for 23 h at 0 °C (cold-room). Na2SO3 (6 g) was added
and the mixture was stirred at r.t. for 1 h. After filtration, the solvent
was removed in vacuo (bath temperature, 80 °C) and acetone (~ 50
mL) and PPTS (50 mg) was added to the residue, presumably con-
taining the tetrol in some form. This mixture was refluxed over-
night, filtered and the solvent removed to yield an oil (1.13 g, 89%).
This was chromatographed (cyclohexane/EtOAc, 30:70) to provide
the 2,8-bis(hydroxymethyl)-3-methyl-1,7-dioxaspiro[5.5]undecane
(43).
Anal. calcd for C12H20Cl2Hg2O2: C 21.5, H 3.0. Found C 21.9,
H 3.2.
1H NMR (500 MHz, CDCl3): d = 0.75 (d, 3 H, J = 7 Hz), 0.86 (d, 3
H, J = 6.5 Hz), 0.81-1.74 (m, 31 H), 1.92 (m, 2 H), 2.11 (tt, 1 H,
J = 13.5, 4.5 Hz), 2.15-2.41 (m, 2 H), 3.18 (td, 1 H, J = 10.0, 4.0
Hz), 3.50 (tdd, 1 H, J = 11.0, 4.0, 2.5 Hz) 3.63 (dddd, 1 H, J = 11.5,
9.0, 4.5, 2.5 Hz), 3.71 (ddd, 1 H, J = 11.0, 5.0, 2.5 Hz).
13C NMR (50 MHz, CDCl3): d = 10.6, 18.2, 19.3, 19.4, 26.9, 28.0,
29.5, 30.1, 32.4, 34.3, 34.4, 34.6, 34.62, 36.0, 36.30, 37.5, 37.7,
39.5, 69.5, 69.7, 70.6, 74.9, 97.3, 97.7.
1H NMR (400 MHz, CDCl3): d = 0.83 (d, 3H, J = 6.2 Hz), 1.23-1.66
(m, 10 H), 1.85 (qt. 1 H, J = 13.4, 4.1 Hz), 2.0-2.1 (br s, 2 H), 3.33
(m, 1 H,), 3.45-3.59 (m, 3 H), 3.66-3.73 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 17.3 (CH3), 18.4, 26.3, 27.4 (CH2),
30.8 (CH), 35.0, 35.7 (CH2), 63.8, 66.1 (CH2), 69.7, 75.0 (CH), 95.8
(C).
For further characterisation, this was transformed to mesylate 44 in
the normal way with methanesulfonyl chloride in CH2Cl2 and Et3N,
to provide a viscous oil which was purified by flash chromatogra-
phy (cyclohexane/EtOAc, 70:30) (73 mg, 29%); [a]D -23.4 (c =
0.135, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.88 (d, 3 H, J = 6 Hz), 1.22-1.64
(m, 10 H), 1.86 (qt, 1 H, J = 13.2, 4.1 Hz), 3.00 (s, 3 H), 3.01 (s, 3
H), 3.48 (ddd, 1 H, J = 9.6, 5.4, 2.1 Hz), 3.86 (ddd, 1 H, J = 11.8, 6,
4, 2.1 Hz), 4.11-4.18 (ddd, 2 H, 10.9, 6, 4 Hz) 4.21-4.36 (ddd, 2 H,
J = 11.2, 5.4, 2.2 Hz).
Reduction of the Bis(mercurymethyl)spiroacetal 37
The bis(mercurymethyl)spiroacetal (as the acetate 450 mg, 63
mmol) was dissolved in THF (6 mL) and 0.025 M aq NaOH (6 mL)
was added followed by Et3BnNCl (215 mg, 0.94 mmol). NaBH4 (48
mg, 1.26 mmol) was added and the mixture stirred for 1 h. After fil-
tering through Celite, the aqueous phase was extracted with Et2O
(3 î 5 mL) and the combined Et2O extracts were dried (MgSO4)
and the solvent carefully removed to leave an oil. This was
chromatographed (silica gel, pentane) to provide the desired
product (diastereomeric mixture) (103 mg, 83%).
25
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1970
Y. Q. Tu et al.
SPECIAL TOPIC
13C NMR (100 MHz, CDCl3): d = 17.3 (CH3), 18.2, 26.2, 27.3
(CH2), 30.5 (CH), 34.5, 35.2 (CH2), 37.5 (CH3), 37.6 (CH3) 67.6
(CH), 71.0 (CH2), 72.5 (CH2), 73.2 (CH), 96.4 (C).
Spiroacetal 49
1H NMR (400 MHz, CDCl3): d = 0.78 (app q, 1 H, J = 12.1 Hz, H-
3a), 0.67 (d, 3 H, J = 6.7 Hz, CH3 at C-4), 0.95 (t, 1 H, J = 12.6 Hz,
H-5a), 1.09 (d, 3 H, J = 6.4 Hz, CH3), 1.12 (d, 3 H, J = 6.2 Hz, CH3),
1.15 (m, 1 H, H-9a), 1.35 (td, 1 H, J = 13.3, 4.6 Hz, H-11a), 1.47-
1.52 (m, 5 H, H-10e, H-9e, H-11e, H-3e, H-5e), 1.86 (tt, 1 H,
J = 13.3, 3.5 Hz, H-10a), 2.00 (m, 1 H, H-4a), 3.67 (m, 2-H, H-2,8).
Anal. calcd for C14H26O8S2: C 43.5, H 6.8. Found C 43.8, H 6.9.
(2S,3R,6S,8R)-2,3,6-Trimethyl-1,7-dioxaspiro[5.5]undecane
(40)
The above bis-mesylate (20 mg, 0.05 mml) was dissolved in anhyd
THF (10 mL) and treated with LiAlH4 in the usual way to provide
the 2,3,8-trimethyl-1,7-dioxaspiro[5.5]undecane. Comparisons of
mass spectra and retention times confirm this isomer is identical to
the first eluting isomer formed by the procedure in Scheme 3, which
was demonstrated to be 40.
13C NMR (50 MHz, CDCl3): d = 19.0 (C-10), 21.7, 21.9, 22.0
(3 î CH3) 25.1 (C-4), 32.8 (C-9), 35.1 (C-11), 41.6 (C-3), 43.9 (C-
5), 65.0, 65.1, (C-2,C8), 96.5 (C-6).
EIMS: m/z = 198 (10), 154 (8), 139 (17), 129 (100), 128 (42), 126
(53), 115 (96), 114 (15), 112 (74), 111 (51), 98 (10), 97 (34), 83
(17), 69 (33), 55(31).
2,8-Dimethyl-4-methylene-1,7-dioxaspiro[5.5]undecane (47)
Methyltriphenylphosphonium iodide (2.58 g, 6.4 mmol) was added
portionwise to a stirred solution of BuLi (4 ml, 1.6 M solution in
hexanes, 6.4 mmol) in anhyd THF (20 mL). The resulting mixture
was stirred at r.t. for 4 h, during which time a yellow solid formed.
Predominantly (E,E)-spiroketone 46 (1 g, 5.05 mmol) in anhyd
THF (5 mL) was added over a period of 5 min, during which time
a white solid formed. The stirred mixture was refluxed overnight.
After removal by filtration, the solid was washed with Et2O (2 î 20
mL) and the combined filtrate and washings were washed with H2O,
dried (Na2SO4) and concentrated. Purification by flash column
chromatography (CH2Cl2/hexane, 1:4) yielded 0.47 g (52%) of the
alkene 47, accompanied by a low level (~10%) of a second isomer.
1H NMR (400 MHz, CDCl3): d = 1.06 (d, 3 H, J = 6.3 Hz, CH3),
1.14 (m, 1 H, H-9ax), 1.15 (d, 3 H, J = 6.5 Hz, CH3), 1.37 (ddd, 1
H, J = 14.0, 12.0, 5.0 Hz, H-11ax) 1.52 (m, 2 H, H-9eq, H-10eq),
1.62 (dm, 1 H, J = 14.0 Hz, H-11eq), 1.81-1.93 (m, 2 H, H-10ax,
H-3ax), 2.10 (dm, 1 H, J = 14.0 Hz, H-5eq), 2.15-2.25 (m, 2 H, H-
5ax, H-3eq), 3.62 (m, 2 H, H-2,8), 4.72 (m, 2 H, CH2=).
HRMS: m/z Calcd for C12H22O2, 198.1618. Obsvd 198.1617.
Alternative Approach to Diastereomers of 2,4,8-Trimethyl-1,7-
dioxaspiro[5.5]undecane (26)
Addition of MeLi in Et2O at -78 °C to racemic spiroketone 46 fol-
lowed by a standard workup provided essentially a single alcohol
50.
1H NMR (200 MHz, CDCl3): d = 1.10 (d, 3 H, J = 6.5 Hz, CH3),
1.12 (s, 3 H, CH3-4), 1.17 (d, 3 H, J = 6.5 Hz, CH3), 1.20-1.96 (m,
10 H), 3.72 (m, 1 H, H-2 or H-8), 3.90 (m, 1 H, H-8 or H-2), 4.69
(1 H, OH).
13C NMR (50 MHz, CDCl3): d = 18.5 (C-10), 21.2, 21.8 (CH3 2,8),
29.9 (CH3-4), 32.2, 34.6 (C-3,9), 45.6, 45.7 (C-5,11), 61.6 (C-2),
66.1 (C-8), 68.3 (C-4), 98.3 (C-6).
GC-MS: m/z (%) = 214 (M+, 4), 155 (22), 145 (34), 142 (11), 127
(24), 115 (16), 114 (11), 112 (10), 103 (15), 97 (18), 85 (42), 84
(21), 83 (10), 69 (18), 58 (5).
HRMS: m/z Calcd for C12O3H22 214.1568. Obsvd 214.1572.
13C NMR: (100 MHz, CDCl3): d = 19.0 (C-10), 21.5, 21.7 (2 CH3)
32.4 (C-9), 34.7 (C-11), 41.5 (C-3) 44.3 (C-5), 65.4, 65.6 (C-2,8),
97.0 (C-6), 109.6 (CH2=), 142.1 (C-4). (this isomer is E,E-ring con-
figured).
Elimination of H2O (catalytic TsOH acid in benzene) afforded three
alkenes, with the minor one being the exo-methylene derivative 47
described above. Separation was achieved by HPLC using 3%
Et2O/hexane.
2,4,8-Trimethyl-1,7-dioxaspiro[5.5]undec-3-ene (52)
1H NMR (200 MHz, CDCl3): d = 1.10 (d, 3 H, J = 6.5 Hz, CH3),
1.19 (d, 3 H, J = 7.0 Hz, CH3), 1.41-1.99 (m, 6 H, H-9,10,11), 1.64
(br s, 3 H, CH3-4), 1.85 and 2.05 (br d, 1 H each, J = 13.0 Hz,
2 î H-5), 3.77 (m, 1 H, H-8), 4.10 (br m, 1 H, H-2), 5.32 (m, 1 H,
H-3).
13C NMR (50 MHz, CDCl3): d = 19.2 (C-10), 21.0, 21.9, 22.8 (CH3-
2,4,8), 32.6, 34.7, 40.6 (C-9,11,5), 63.7 (C-8), 66.1 (C-2), 96.0 (C-
6), 123.7 (C-3), 129.2 (C-4).
GC-MS: m/z (%) = 196 (12), 152 (26), 151 (12), 138 (10), 137 (76),
124 (16), 115 (100), 109 (24), 97 (73), 95 (12), 85 (22), 82 (28), 81
(14), 79 (10), 73 (20), 69 (92), 67 (46).
HRMS: m/z Calcd for C12H20O2 196.1462. Obsvd 196.1468.
2,4,8-Trimethyl-1,7-dioxaspiro[5.5]undecanes (48) and (49)
A solution of 47 (0.47 g, 2.4 mmol) in EtOH (10 mL) with 10% Pd/
C catalyst (200 mg) was stirred under a H2 atmosphere at r.t. for 2.5
h. After removal of the catalyst by filtration, the mixture was diluted
with H2O (100 mL) and extracted with pentane. The combined pen-
tane extracts were evaporated and the residue purified by HPLC
(Et2O/hexane 1:100) yielding 336 mg (78%). The major isomers
were separated (HPLC, 2.5% EtOAc/hexane) and fully character-
ised.
GC-MS m/z (%): = 196 (M+, 17), 153 (12), 140 (10), 139 (93), 138
(24), 137 (19), 127 (11), 112 (18), 107 (43), 97 (29), 85 (22), 83
(20), 82 (33), 81 (15), 69 (100).
HRMS: m/z Calcd for C12H20O2, 196.1462. Obsvd 196.1456.
2,4,8-Trimethyl-1,7-dioxaspiro[5.5]undec-4-ene (51)
Spiroacetal 48
1H NMR (200 MHz, CDCl3): d = 1.12 and 1.23 (d, 2 î 3 H, J = 6.5
Hz, CH3-2, CH3-8), 1.41-1.95 (m, 8 H), 1.66 (br s, 3 H, C-4 CH3),
3.86 (m, 1 H, H-8), 3.99 (m, 1 H, H-2), 5.32 (br s, 1 H, H-5).
1H NMR (500 MHz, CDCl3): d = 1.04-1.6 (m, including 3 î CH3
at 1.12, 18 H, d, J = 6.4, 1.15 Hz, d, J = 6.4 and 1.19 Hz, d, J = 7.3
Hz), 1.89 (app qt, 1 H, J = 13.3, 4.0 Hz, H-10a), 1.96 (m, 1 H, H-
4e), 3.72 (m, 1 H, H-8), 3.88, (m, 1 H, H-2).
13C NMR (50 MHz, CDCl3): d = 18.9 (C-10), 21.1, 22.2, 22.8
(CH3-2,4,8), 32.5, 34.6, 37.3 (CH2-3,9,11), 63.0 (C-8), 65.8 (C-2),
94.9 (C-6), 124.9 (C-5), 136.1 (C-4).
GC-MS: m/z (%) = 196 (M+, 6), 181 (6), 152 (8), 137 (16), 127
(100), 124 (68), 109 (30), 81 (14), 80 (30), 79 (17), 55 (15).
13C NMR (125 MHz, CDCl3): d = 19.1 (C-10), 20.7, 21.9, 22.0
(3 î CH3), 25.4 (C-4), 32.5 (C-9), 35.4 (C-11), 38.6 (C-3), 40.1 (C-
5), 60.2 (C-2), 65.2 (C-8), 97.5 (C-6).
EIMS: m/z = 198 (8), 154 (8), 139 (19), 129 (70), 128 (35), 126
(45), 115 (78), 114 (21), 112 (62), 111 (49), 98 (9), 97 (43), 87 (20),
83 (50), 69 (100), 55 (64).
HRMS: m/z Calcd for C12H20O2 196.1462. Obsvd 196.1455.
Hydrogenation of this olefin mixture in the normal way provided a
48:52 mixture of the target spiroacetals 48 and 49 respectively.
HRMS: m/z Calcd for C12H22O2 198.1618. Obsvd 198.1612
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1971
Enantiomers of 48, 49 and Minor Isomers (Scheme 6).
115.11, 115.14, 138.39 (CH=CH2), 138.4, 138.5, 208.2 (C=O),
Ethyl 3-Methyl-5-(tetrahydropyran-2¢-yloxy)hexanoate (54)
A solution of Bu3SnH (80 g, 30 mmol) in benzene (30 mL) was add-
ed over a period of 48 h to a solution of 53 (8.1 g, 30 mmol) and
AIBN (100 mg) in a mixture of ethyl crotonate (34.2 g, 300 mmol)
and benzene (50 mL). After completion of the addition, the solvent
was removed in vacuo and the residue was purified by flash chro-
matography (Et2O/hexane, 1:20) to provide 54, 4.2g (50%). This
mixture of four diastereomers was characterised only by its 1H and
13C NMR spectra before reduction to aldehyde 55.
1H NMR (200 MHz, CDCl3): d = 0.9-1.2 (m, 9 H, CH3), 1.3-2.6
(m, ~11 H), 3.45-3.55 (m, 1 H), 3.8-4.2 (m, 4 H), 4.75-4.85 (br s,
1 H).
13C NMR (50 MHz, CDCl3): d = with overlapping signals between
13.7-49.0, 59.8-72.9 (12 C, C-O), 95.3, 95.5, 98.8, 99.4 (C-2’),
172.2-172.5 (4 C, C=O).
208.4 208.6.
8,10-Dimethyl-1,7-dioxaspiro[5.5]undec-2-ylmethanol (58)
The above ketone 56 (700 mg, 2.5 mmol) was added to a solution
of AD-Mix-b (4.2 g) in tert-butyl alcohol (15 mL) and H2O (15 mL)
at 0 °C and maintained at this temperature for 15 h. The mixture was
quenched by the addition of CH2Cl2 (20 mL), MeOH (5 mL), and
HCl (5 mL of 1 M). After stirring for 30 min, the organic layer was
separated and the aqueous phase was extracted with Et2O. The com-
bined Et2O extracts were washed with brine, dried (MgSO4) and the
solvent removed in vacuo. The residue was purified by flash chro-
matrography (Et2O/hexane, 1:5), to provide a mixture (350 mg,
68%) of the two (E,E)-diastereomers of 58. Further chromatogra-
phy led to separation of the pure (2S,4S,6R,8R)-58 (with an axial C-
4 methyl group) and a less pure sample of the (2S,4R,6R,8R)-58
(with an equatorial C-4 methyl group).
1H NMR (200 MHz, CDCl3) (2S,4S,6R,8R)-58: d = 1.1-1.42 [m, 13
H including CH3 doublets at 1.14 (J = 6.6 Hz) and 1.16 (J =7.3 Hz)],
1.55 (d of m, 1 H, J = 13.0 Hz) 1.68 (dd, 1 H, J = 7, 5.5 Hz), 1.79
(br m, 1 H), 1.97 (1 H, qt, J = 13.5, 4.2 Hz), 3.44 (m, 2 H), 3.7 (m,
1 H), 3.9 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 18.7, 21.3, 22.1, 25.7, 26.7, 36.2,
38.5, 40.3, 60.4, 66.5, 70.4, 97.5.
3-Methyl-5-(tetrahydropyran-2’-yloxy)hexanal (55)
A solution of Dibal-H in CH2Cl2 (12 mmol, 12 mL of a 1 M solu-
tion) was added slowly to a solution of ester 54 (3 g, 12 mmol) in
CH2Cl2 (100 mL) at -78 °C. After 30 min, none of the starting ma-
terial could be detected by TLC, and the reaction was quenched by
adding H2O (10 mL). After addition of 1 M HCl until the mixture
became clear, the organic layer was separated and the aqueous
phase was extracted with Et2O. The combined Et2O extracts were
washed with brine, dried (MgSO4) and the solvent was removed in
vacuo. The residue was purified by flash column chromatography
(Et2O/hexane, 1:20) to yield 55 (1.3 g, 47%) as an isomeric mixture,
characterised by its NMR spectra.
HRMS: m/z Calcd for C12O3H22, 214.1567. Obsvd 214.1517.
13C NMR (50 MHz, CDCl3): (2S,4R,6R,8R)-58: d = 18.7, 22.2,
21.9, 25.4, 26.9, 35.8, 41.7, 44.1, 65.4, 66.4, 70.2, 96.4.
2-Iodomethyl-8,10-dimethyl-1,7-dioxaspiro[5.5]undecane (59)
I2 (305 mg, 1.2 mmol) was added to a hot (100 °C) toluene solution
(50 mL) of spiroacetal 58 (250 mg, 1.2 mmol), Ph3P (309 mg, 1.2
mmol) and imidazole (220 mg, 3 mmol). After stirring for 20 min at
this temperature, no starting material was detectable (TLC) and the
reaction was quenched with H2O (20 mL). The organic layer was
separated and the aqueous phase was extracted with Et2O. The com-
bined Et2O extracts were washed with Na2S2O3 and brine, dried
(MgSO4), and the solvent evaporated in vacuo. The residue was
subjected to flash chromatography (Et2O/hexane, 1:20) to provide
59 (300 mg, 80%) as a diastereomeric mixture that was not separat-
ed.
1H NMR (200 MHz, CDCl3) of isomer mixture: d = 0.8-1.0 (m, 4
H, with CH3 doublet), 1.25-2.45 (m, 15 H, with superimposed CH3
doublet at 1.28), 2.78-3.03 (m, 2 H, CH2I), 3.59-3.75 (m, 1 H) and
4.08-4.31 (m, 1 H).
13C NMR (50 MHz, C6D6): d = 9.8, 10.4, 19.1 (2 C), 21.6, 21.9,
22.1, 22.2, 25.1, 25.9, 31.1, 31.2, 35.3, 35.9, 38.7, 40.1, 41.9, 44.1,
60.8, 65.5, 69.3, 70.5, 97.1, 98.0. (24 13C signals resolved).
1H NMR (100 MHz, CDCl3): d = 0.7-1.00 (series of doublets, 6 H,
CH3), 1.2-2.3 (m, ~11 H), 3.2-3.9 (m, 3 H), 4.55-4.65 (br s, 1 H),
9.3-9.45 (narrow triplets, 1 H).
13C NMR (50 MHz, CDCl3, DEPT): d = with higher field signals
from 19.2-51.29, 61.7 (CH2O), 61.8, 62.5, 62.6, 68.2 (CHO), 68.6,
72.1, 72.6, 95.5 (C-2’), 95.9, 98.4, 99.2, 200.5
8-Methyl-6-oxo-10-(tetrahydropyran-2’-yloxy)dec-1-ene (56)
A solution of pent-4-enylmagnesium bromide [prepared from Mg
turnings (120 mg, 5 mmol) and 1-bromopent-4-ene (745 mg, 5
mmol) in Et2O] was added at -50 °C to a solution of 55 (1.12 g, 5
mmol) in Et2O. After stirring for 20 min, the mixture was quenched
by addition of H2O (10 mL), and then was carefully acidified with
1 M HCl. The organic layer was separated and the aqueous phase
was extracted with Et2O. The combined Et2O extracts were washed
with brine, dried (MgSO4) and the solvent was removed in vacuo.
The residue was directly oxidized without any further purification.
The crude alcohol was dissolved in CH2Cl2 (100 mL) and after
addition of molecular sieves 4Å (2 g) and PDC (2 g), the mixture
was vigorously stirred until no alcohol could be detected (TLC).
The mixture was diluted with Et2O (100 mL) and filtered through
silica gel (50 g) and the silica gel thoroughly washed with Et2O. The
combined Et2O extracts were evaporated in vacuo. The residue was
purified by flash chromatography (Et2O/hexane 1:10) to provide the
ketone 56 (1.0 g, 70%), again as a mixture of isomers.
GC-MS (one isomer): m/z (%) = 324 (M+, 2.7), 280 (3.4), 241
(21.8), 240 (7.7), 238 (11.5), (196), (9.2), 169 (12.4), 139 (11.4),
129 (100), 128 (50), 126 (25.9), 113 (35.6), 111 (53.6), 98 (11),
83(24.9). The other diasteromer exhibited a very similar mass spec-
trum.
1H NMR (200 MHz, CDCl3): d = 0.9-1.15 (doublets, 6 H, CH3),
1.4-2.4 (m with prominent signals at 1.35, 1.7, 2.0 and 2.05-2.15,
17 H), 3.5 (br s, 1 H), 3.8-4.1 (m, 2 H), 4.75-4.85 (m, 1 H), 5.05-
5.15 (m, 2 H), 5.7-5.85 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 19.5, 19.8, 19.94, 19.9, 20.1, 20.2,
20.3, 20.4, 20.5, 20.6, 22.2, 22.8, 23.01, 23.03, 23.07, 23.1, 25.95 (2
C), 25.98, 26.0, 26.2, 26.23, 26.26, 26.3, 31.59, 31.6, 31.7 (2 C),
33.4, 33.45, 33.5, 41.2, 42.2, 42.28, 42.3, 44.4, 44.8, 44.9, 45.20,
49.6, 50.2, 50.5, 50.8, 62.0 (C-O), 62.1, 62.6, 62.7, 68.6, 68.9, 72.6,
72.8, 95.6 (OCHO), 96.0, 98.7, 99.31, 115.06 (CH2) 115.08,
(2S,4R,6R,8S)-2,4,8-Trimethyl-1,7-dioxaspiro[5.5]undecane
(60) and the (2S,4S,6R,8S)-epimer 61
The above iodide mixture 59 (200 mg, 0.62 mmol) was added to a
suspension of Raney-Nickel in EtOH/H2O (10 mL, 20:1) containing
NaOH, (40 mg, 1 mmol). After stirring for 3 d, no starting material
could be detected (GC) and the reaction mixture was diluted with
brine (80 ml) and pentane. The combined pentane extracts were
washed again with brine (MgSO4) and the solvent was evaporated
at 40 °C. The residue was purified by HPLC (hexane/Et2O, 100:1)
and yielded 45 mg of 60 and 48 mg of 61 (overall yield 76%). These
isomers had NMR and mass spectral data matching those listed for
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1972
Y. Q. Tu et al.
SPECIAL TOPIC
23
the racemates, 49 and 48 with [a]D -66.4 (CHCl3) and -69.0
Protected Ketol 70
(CHCl3), respectively.
Crude enone 69 (20.13 g, 95 mmol) was dissolved in distilled
MeOH (300 mL) and cooled to -78 °C. Ozone was bubbled through
the solution, which turned pale blue after ª 2h. While maintaining
the temperature at -40 °C, solid NaBH4 (7.6 g, 200 mmol) was add-
ed, then the solution was warmed to r.t. A solution of 30% H2O2
(100 mL, 800 mmol) and H2O (250 mL), containing NaOH (32 g,
800 mmol) was then added and stirred for 1 h. Over this time a ge-
latinous precipitate was formed. The supernatant layer was decant-
ed, and the precipitate washed with Et2O. The mixture was extracted
5 times with Et2O, and the MeOH rich extracts were concentrated in
vacuo. The resulting oil was partitioned between Et2O and H2O and
the combined Et2O layers dried (MgSO4). Removal of solvent in
vacuo afforded crude alcohol 70. Purification by flash chromato-
graphy using 1:1 hexane/Et2O provided 14.66 g (82%); [a]D25 +1.8
(c = 3.79, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.92 (d, 3 H, J = 6.5 Hz), 1.11-
1.2 (m, 1 H), 1.27 (s, 3 H), 1.35-1.66 (m, 6 H), 1.81 (br s, 1 H), 3.56
(br t, 2 H, J = 6.5 Hz), 3.84-3.91(m, 4 H).
13C NMR (100 MHz, CDCl3): d = 20.9, 24.0, 28.6, 30.0, 33.8, 45.4,
63.0, 64.2, 64.3, 110.4.
GC-MS : m/z (%) = 188 (0.0, M+) 174 (1.1), 173 (9.7, M-15), 155
(0.1), 142 (0.1), 130 (0.1), 129 (1.0), 127 (0.5), 113 (1.9), 99 (5.6),
88 (4.6), 69 (47), 55 (5.1), 43 (49), 41 (13).
Alternative Synthesis of 60 and Some Diastereomers from (R)-
(+)-Pulegone
Methyl ketone 68: MeLi (200 mL of 1.4 M solution in Et2O) was
added to anhyd THF (250 mL) under N2 and cooled to -78 °C. Cit-
25
ronellic acid {67, [a]D +9.3) prepared from technical grade (R)-
(+)-pulegone (24.5 g, 144 mmol)} was gradually added as a solution
in anhyd THF (250 mL) while maintaining the temperature at -78
°C. After stirring for 1 h at -78 °C, the reaction was permitted to
warm to r.t. for 30 min, after which GC monitoring indicated com-
plete reaction. An excess of aq sat. NH4Cl was added and allowed
to stir for a further 30 min. The aqueous phase was separated and
extracted three times with Et2O. The combined Et2O extracts were
washed with aq sat. NaHCO3 and the washings were extracted once
with Et2O. The combined organic layers were washed with brine,
and dried (MgSO4). Removal of solvent in vacuo afforded the crude
ketone 68 which was purified by flash chromatography on silica gel,
25
using 20:1 hexane/Et2O as solvent to afford 16.85 g (71%); [a]D
+14.4 (c = 3.45, CHCl3)
1H NMR: (400 MHz, CDCl3): d = 0.87 (d, 3 H, J = 6.6 Hz), 1.11-
1.34 (m, 2 H), 1.56 (br s, 3 H), 1.64 (br d, 3 H, J = 1.2 Hz), 1.86-
2.03 (m, 3 H), 2.08 (br s, 3 H), 2.18 (dd, 1 H, J = 15.8, 8.2 Hz), 2.37
(dd, 1 H, J = 15.7, 5.6 Hz), 5.05 (tm, 1 H, J = 7.1Hz).
HRMS: m/z Calcd for C9H17O3 (M - 15) 173.1178. Obsvd
173.1177.
13C NMR (100 MHz, CDCl3): d = 17.5, 19.6, 25.4, 25.6, 28.9, 30.3,
36.9, 51.1, 124.2, 131.4, 209.0.
GC-MS : m/z (%) = 169 (0.4), 168 (3.2, M+), 153 (1.3), 150 (1.5),
135 (6.5), 125 (2.5), 111 (4.2), 110 (17.3), 109 (4.5), 98 (4.4), 95
(42), 85 (18), 69 (27), 67 (16), 55 (15), 43 (100) 41 (56).
Protected Iodo Ketone 71
Alcohol 70 (14.66 g, 78 mmol) was dried over 3Å molecular sieves
and then cannulated from the sieves into a reaction flask containing
anhyd CH2Cl2 (900 mL) under N2. Anhyd Et3N (60 mL, 468 mmol)
was added via a syringe, and then distilled MsCl (12 mL, 156 mmol)
was added dropwise, also via a syringe. The reaction was exother-
mic and after ª6 mL of MsCl had been added, the solvent began to
refux and the reaction was cooled in ice for the remainder of the ad-
dition, after which GC monitoring showed complete reaction had
occurred. After the addition of an excess of aq sat. NaHCO3 solution
and stirring for several hours, the organic layer was separated and
the solvent removed in vacuo. The resulting oil was taken up in
Et2O and washed with aq sat. NaHCO3. The combined aqueous lay-
ers were extracted 3 times with Et2O, and the combined Et2O layers
were washed with brine, dried (MgSO4), and the solvent removed in
vacuo to provide crude but quite clean mesylate (20.09g, 96%). The
following data were obtained from a small sample purified by flash
chromatography using 2:1 hexane/Et2O as solvent; [a]D25 +3.45 (c
= 3.044, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.93 (d, 3 H, J = 6.6 Hz), 1.17-
1.27 [m, 4 H, incl. 1.27 (3 H,s)], 1.41-1.51 (m, 2 H), 1.58-1.81 (m,
4 H), 2.96 (s, 3 H), 3.84-3.92 (m, 4 H), 4.17 (t, 2 H, J = 6.6 Hz).
13C NMR (100 MHz, CDCl3): d = 20.8, 24.1, 26.5, 28.4, 33.3, 37.3,
45.3, 64.2, 64.3, 70.3, 110.1.
GC-MS : m/z (%) = 266 (0.1 M+), 253 (0.6), 252 (1.1), 251 (8.7, M-
15), 115 (0.9), 129 (0.7), 113 (3.6), 111 (0.8), 109 (1.3), 99 (5.8), 88
(4.1), 87 (100), 83 (3.2), 79 (9.2), 69 (7.1), 59 (2.4), 55 (6.2), 43
(40), 41 (13).
HRMS: m/z Calcd for C11H20O 168.1514. Obsvd 168.1522.
Protected Enone 69
Ketone 68 (16.85 g, 100.3 mmol), was dissolved in distilled ben-
zene (300 mL) and anhyd ethylene glycol (17 mL, 300 mmol) to
which anhyd PPTS (3.8 g, 15 mmol) was added. The reaction was
refluxed under a Dean-Stark trap overnight. GC monitoring
showed ª85% reaction, so the flask was cooled, 3Å molecular
sieves were added, and the mixture stirred overnight. No further re-
action could be induced, so the reaction was quenched with aq sat.
NaHCO3, the aqueous layer separated, and extracted with Et2O. The
benzene layer was evaporated in vacuo, and the resulting oil taken
up in Et2O. This was washed with aq sat. NaHCO3 and the com-
bined Et2O layers were washed with brine, dried (MgSO4) and the
solvent removed in vacuo to provide the crude acetal 69 (20.13 g,
83% allowing for 12% contamination with starting material). This
was not purified, but used directly in the subsequent ozonolysis, and
the data below were obtained on a small sample purified by flash
chromatography using 50:1 hexane/Et2O as solvent; [a]D25 +2.3
(c = 3.341, CHCl3).
1H NMR (400 MHz,CDCl3): d = 0.93 (d, 3 H, J = 6.6 Hz), 1.28 (s,
3 H), 1.10-1.19 (m, 1 H), 1.33-1.46 (m, 2 H), 1.57 (br s, 3 H),
1.59-1.67 (m, 2 H), 1.65 (br d, 3 H, J = 1.1 Hz) 1.86-2.02 (m, 2 H),
3.87-3.93 (m, 4 H), 5.07 (tm, 1 H, J = 7.1 Hz).
13C NMR (100 MHz CDCl3): d = 17.6, 20.8, 24.0, 25.4, 25.6, 28.7,
38.1, 45.5, 64.2, 64.4, 110.5, 124.8, 131.0.
GC-MS: m/z (%) = 213 (0.1), 212 (0.5, M+), 197 (3.3), 151 (1.1),
150 (7.7), 142 (1.0), 136 (1.5), 135 (14), 129 (5.9), 121 (1.9), 109
(5.8), 107 (2.4), 95 (8.8), 87 (100), 85 (11), 69 (14), 55 (11), 43 (80),
41 (52).
HRMS: m/z Calcd for C10H19O5S (M - 15) 251.0953. Obsvd
251.0955.
The above mesylate (20.09 g, 75 mmol) as a solution in anhyd THF
was dried with 3Å molecular sieves overnight. Dried and re-ground
NaI (40 g, 225 mmol) was dissolved in anhyd THF (900 mL) under
N2. The starting material was cannulated into the reaction mixture
and allowed to stir for 25 h, when GC monitoring indicated the re-
action was virtually complete. An excess of aq satd NaHCO3 solu-
tion was added, then stirred for 30 min. Et2O was added to assist the
HRMS: m/z Calcd for C13H24O2 212.1776. Obsvd 212.1775.
Anal. calcd for C13H24O2: C 73.5, H 11.4. Found C 73.2, H 11.2.
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1973
layers to separate, and the organic layer was concentrated to an oil.
This was re-partitioned between aq satd NaHCO3 solution and Et2O,
and the aqueous layer extracted three times with Et2O. The aqueous
layer from the reaction was likewise extracted, and the combined
Et2O extracts were washed with brine and aq 1% Na2S2O3. After
drying (MgSO4) followed by removal of solvent in vacuo, the crude
iodide 71 was purified via flash chromatography on silica gel using
50:1 hexane/Et2O as solvent affording 19.21g (85%) of the product;
[a]D25 +6.3 (c = 3.049, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.94 (d, 3 H, J = 6.6 Hz), 1.18-
1.31 [m, 4 H, incl. 1.29 (s, 3 H)], 1.42-1.50 (m, 2 H), 1.57-1.69 (m,
2 H), 1.72-1.90 (m, 2 H), 3.15 (br t, 2 H, J = 6.9 Hz), 3.86-3.94 (m,
4 H).
13C NMR (100 MHz, CDCl3): d = 7.2, 21.0, 24.1, 28.2, 31.1, 38.7,
45.4, 64.3, 64.4, 110.3.
GC-MS : m/z (%) = 298 (0.0, M+), 285 (0.1), 284 (0.9), 283 (7.9, M
- 15), 197 (1.0), 171 (0.1), 155 (2.7) 128 (0.7), 127 (2.7), 113 (2.6),
99 (2.7), 88 (4.9), 87 (100), 69 (6.0), 67 (1.8), 59 (1.7), 55 (5.4), 43
(50), 41 (19).
hydrazine (3.2 g, 53 mmol) in absolute EtOH (12 mL), followed by
AcOH (0.5 mL). The mixture was refluxed for 3 h, after which time
the starting material had been consumed (GC). After removal of ex-
cess hydrazine and solvent, the residual oil was distilled (80-84 °C/
15 Torr) to provide the hydrazone 20 (2.3 g, 78%) as a mixture of
two isomers. [Alternatively, the mixture was extracted with Et2O
(20 mL) which was washed with aq NaHCO3 solution (2 î 15 mL)
and then H2O (3 î 15 mL) before drying (MgSO4) and concentra-
tion]. Chromatography on neutral alumina (pentane/Et2O, 1:1) pro-
vided the hydrazone 20 as two isomers (21:79) of >97% purity
(GC). The major isomer of 20 (syn-anti around C=N) was charac-
terised by its GC-MS, 1H and 13C NMR data, before being alkylated.
1H NMR (200 MHz, CDCl3): d = 0.76 (d, 3 H, J = 6.4 Hz), 1.84 (s,
3 H, CH3), 1.77-2.26 (m, 5 H), 2.32 [s, 6 H, N (CH3)2], 4.85 (m, 1
H), 4.93 (m, 1 H), 5.66 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 16.7 18.9, 30.7, 41.1, 45.7, 46.9,
(2 C) 116.1, 136.7, 166.9.
GC-MS: m/z (%) = 168 (6, M+) 125 (10), 100 (50), 59 (12), 58 (96),
56 (28), 45 (24), 44 (100).
HRMS: m/z Calcd for C9H16O2I (M - 15) 283.0195. Obsvd
283.0195.
Alkylated Hydrazone 73
To a stirred solution of i-Pr2NH (1.2 g, 12 mmol) in anhyd THF (40
mL), was added BuLi (7.4 mL of 1.6 M solution in hexane, 12
mmol) dropwise at -40 °C, and the mixture was stirred for 2 h at
this temperature. After cooling to -78 °C, a solution of hydrazone
20 (1 g, 6 mmol) in anhyd THF (6 mL) was added dropwise, fol-
lowed by stirring at -78 °C for 3 h. A solution of (3S)-3-(tetrahy-
dropyran-2’-yl)butyl iodide (1.7 g, 6 mmol) in anhyd THF (5 mL)
was then added dropwise and the mixture allowed to warm to r.t.
and stirred (12 h). Et2O (50 mL) and H2O (50 mL) were added and
the aqueous layer was then re-extracted with Et2O (3 î 20 mL).
The combined Et2O extracts were washed with brine (3 î 30 mL),
separated, dried (MgSO4) and concentrated in vacuo to provide the
crude alkylation product 73 (1.8 g, 93%), again as an isomeric mix-
ture (ca 42:58), which provided concordant 1H and 13C NMR spec-
tra and GC-MS data.
1H NMR (200 MHz, CDCl3): d = 0.81 (d, 6 H, J = 6.1 Hz), 1.05 (d,
3 H, J = 6 Hz), 1.17 (d, 3 H, J = 6.2 Hz), 1.46-2.47 (m, 22 H), 2.34
(s, 12 H), 3.42 (m, 2 H), 3.66-3.86 (m, 4 H), 4.57 (br s, 1 H), 4.64
(br s, 1 H), 4.90 (m, 2 H), 4.97 (m, 2 H), 5.70 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 19.1, 19.2, 19.7, 21.6, 22.3, 22.8,
25.4, 25.5, 29.75, 29.8, 30.8, 30.84, 31.7, 36.6, 37.5, 41.3, 42.56,
42.6, 47.5, 62.5, 62.8, 70.5, 73.64 95.5, 98.9, 116.1, 116.2, 136.9,
136.94, 171.6, 171.7.
Anal. Calcd for C10H19IO2: C 40.3, H 6.4. Found C 40.5, H 6.3.
Protected enone 72
Iodide 71 (9.6g, 32mmol) as a solution in anhyd THF was dried
overnight with 3Å molecular sieves. Fresh t-BuOK (10 g) was dis-
solved in anhyd THF (500 mL) under N2 and the iodide solution was
added by cannula. Precipitate was observed to form even before the
addition was complete, and GC monitoring after 30 min indicated
the reaction was complete. A minor amount of displacement (ª3%)
of the iodide formed the t-Bu ether. Aq sat. NaHCO3, aq sat. NaCl
and a little 1% Na2S2O3 were added to quench the reaction which
was allowed to stir for 15 min. The organic layer was separated and
concentrated in vacuo. The resulting oil was partitioned between aq
sat. NaHCO3 and Et2O, and the aqueous layer extracted three times
with Et2O. The combined Et2O extracts were diluted with 20% pen-
tane, washed with brine, dried (MgSO4), and the solvent removed in
vacuo to provide the crude alkene 72 (6.29 g). This reaction was re-
peated on the same scale and the products from both were combined
for flash chromatography using 50:1 petroleum ether/Et2O to afford
7.91g (72%) of 72; [a]D25 -1.0 (c = 14.29, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.93 (d, 3 H, J = 6.7 Hz), 1.29 (s,
3 H), 1.40-1.45 (m, 1 H), 1.64-1.77 (m, 2 H), 1.87-1.95 (m, 1 H),
2.06-2.13 (m, 1 H), 3.86-3.94 (m, 4 H), 4.95 (t, 1 H, J = 1.3 Hz),
4.97-5.00 (m, 1 H) 5.69-5.79 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.8, 24.1, 28.8, 42.3, 44.7, 64.2,
64.7, 110.4, 115.9, 137.4.
GC-MS (one isomer): m/z (%) = 324 (M+, 10), 239 (64), 223 (42),
196 (34), 180 (25), 171 (56), 128 (45), 125 (52).
Protected Hydroxyenone 74
Hydrazone 73 (1 g, 3.08 mmol) was chromatographed on silica gel
(EtOAc/hexane, 1:10 Æ 10:1) to provide the ketone 74 (0.71 g,
82%), as a diastereomeric mixture.
1H NMR (200 MHz, CDCl3): d = 0.83 (d, 6 H, J = 6 Hz, CH3), 1.04,
1.16 (each d, 3 H, J = 6 Hz, CH3), 1.35-2.45 (m, 34 H, both iso-
mers), 3.35-3.9 (m, 6 H), 4.5-4.7 (m, 2 H), 4.9-5.0 (m, 2 H), 5.55-
5.70 (m, 1 H).
GC-MS: m/z (%) = 170 (0.0, M+), 156 (0.6), 155 (5.5, M - 15), 114
(0.9), 113 (6.3), 108 (1.1), 99 (6.6), 97 (1.7), 95 (1.3), 88 (5.1), 87
(100), 69 (3.9), 67 (3.3), 59 (9.4), 55 (4.4), 43 (57), 41 (21), 39 (10).
HRMS: m/z calcd for C9H15O2 (M - 15) 155.1072. Obsvd
155.1074.
Anal. Calcd for C10H18O2: C 70.5, H 10.7. Found C 70.1, H 10.6.
13C NMR: (50 MHz, CDCl3): d = 19.0, 19.6, 19.7, 19.8, 20.0, 21.5,
25.4, 25.5, 28.8, 29.6, 31.1, 36.0, 36.8, 41.1, 43.26, 43.3, 49.3, 62.5,
62.8, 70.7, 73.8, 95.7, 98.8, 116.3, 116.4, 136.6, 210.6, 210.8.
Protected Hydroxyenone 74
Alkene 72 (3.0 g, 17.6 mmol) was stirred in 30% AcOH (8 mL) at
80 °C for 5 h and then cooled, before the addition of aq sat. Na2CO3
(10 mL) and then Et2O (20 mL). The aqueous layer was extracted
with Et2O (3 î 20 mL), and the combined Et2O extracts were
washed with brine (3 î 15 ml), separated, dried (MgSO4) and con-
centrated in vacuo to provide the crude enone (2.2 g, 100%) which
was converted without purification to the hydrazone as follows. The
enone (2.2 g, 17.5 mmol) was added to a solution of N,N-dimethyl-
GC-MS: m/z (%): = 197 (4.3), 181 (19.6), 169 (1.1), 165 (2.4), 163
(4.3), 139 (16.7), 125 (5.6), 112 (15.6), 97 (21.3), 85 (100), 81 (65).
(one diastereomer only).
HRMS: m/z Calcd for C17O3H30 282.2195. Obsvd 282.2178.
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1974
Y. Q. Tu et al.
SPECIAL TOPIC
Hydroxy Ketone 75
This tosylate (81 mg, 0.22 mmol) was dissolved in anhyd Et2O (1.5
mL) at 0 °C and under N2, LiAlH4 (50 mg, 1.32 mmol) was added.
The mixture was stirred at r.t. for 24 h. The excess of LiAlH4 was
destroyed by the addition of H2O (0.2 mL) and aq 15% NaOH. The
mixture was then stirred for 10 min and filtered through Celite. The
filter cake was washed three times with Et2O, and the combined
Et2O extracts were dried (MgSO4), concentrated at reduced pressure
and then chromatographed on silica gel (hexane/EtOAc) to provide
the spiroacetal 60 (21.3 mg, 49%). This material was >99% ee and
provided physical and spectroscopic data in agreement with those
listed above.
Cond HCl (2 drops) was added to the hydrazone 73 (0.4 g, 1.23
mmol) in MeOH (15 mL) and the mixture was stirred for 4 h. Aq
concd Na2CO3 was added until neutrality and then the solvent was
removed in vacuo, and the residue was extracted with Et2O (3 î 20
mL). The combined Et2O extracts were dried (MgSO4), concentrat-
ed in vacuo and chromatographed (silica gel, EtOAc/hexane, 1:7 Æ
1:1) to provide the hydroxy ketone 75 (0.2 g, 82%); [a]D25 +3.9 (c =
1.56, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.82 (d, 3 H, J = 6.1 Hz), 1.11 (d,
3 H, J = 6.5 Hz), 1.33-2.38 (m, 11 H), 3.69 (m, 1 H), 4.90 (m, 1 H),
4.96 (m, 1 H), 5.67 (m, 1 H).
Spiroacetal ent-61 (Scheme 8)
Hydrazone 20 (Scheme 7) was alkylated with (R)-3-(tetrahydropy-
ran-2’-yl)butyl iodide in the manner described above for the (S)-io-
dide. The hydrazone was selectively removed by chromatography
on silica gel with hexane/Et2O to afford the protected hydroxyenone
78 in 85% yield.
13C NMR (50 MHz, CDCl3): d = 19.6, 19.7, 23.4, 28.8, 38.6, 41.1,
43.1, 49.3, 67.4, 116.4, 136.6, 211.1.
GC-MS: m/z (%) = 183 (44), 145 (42), 142 (46), 139 (37), 127 (76),
123 (42), 115 (95), 99 (26), 81 (48), 69 (20), 65 (26), 43 (100).
1H NMR (200 MHz, CDCl3): d = 0.82, (d, 6 H, J = 6 Hz), 1.02, 1.15
(d, each 3 H, J = 6 Hz), 1.39-2.12 (m, 26 H), 2.27-2.37 (m, 8 H),
3.37-3.78 (m, 6 H), 4.54 and 4.60 (m, each 1 H), 4.88 and 4.95 (m,
each 2 H), 5.56-5.73 (m, 2 H).
HRMS: m/z Calcd for C12H22O2 198.1619. Obsvd 198.1622.
HRMS: m/z Calcd for C12H20O (M - H2O) 180.1513. Obsvd
180.1514.
13C NMR (50 MHz, CDCl3): d = 19.0, 21.5, 19.6, 19.73, 19.7, 20.0,
25.4, 25.4, 28.8, 31.1, 31.12, 35.9, 36.7, 41.1, 43.2, 43.3, 49.2, 62.5,
62.8, 70.6, 73.5, 95.6, 98.8, 116.3, 116.3, 136.5, 136.6, 210.6,
210.8.
Spiroacetal 76
The AD-Mix b reagent (1.8 g) was added to a stirred solution of t-
BuOH/H2O (10 mL/10 mL) at r.t., and this yellowish solution was
cooled to 0 °C whereupon a yellowish solid precipitated. Alkene 75
(200 mg, 1 mmol) was added and the mixture was stirred at 0 °C for
3 d. Solid Na2SO3 (1.5 g) was added and the system was allowed to
warm to r.t. and stirred (1 h). EtOAc (10 mL) was added and the
aqueous layer was re-extracted with EtOAc (3 î 10 mL). The com-
bined EtOAc fraction was dried (MgSO4), concentrated in vacuo
and chromatographed on silica gel (EtOAc/hexane, 1:10 Æ 1:1) to
provide the spiroacetal 76 (165 mg, 76%). (An additional quantity
of 76 was obtained from a similar sequence with protected hydrox-
yenone 74 in 63% yield); [a]D25 -71.3 (c = 1.13, CHCl3).
GC-MS: m/z (%) = 197 (3.3), 181 (17), 139 (12), 112 (15), 97 (16),
85 (100), 83 (12), 69 (52).
Treatment of hydrazone 77 with 10% HCl in the way described
above, afforded instead the fully deprotected hydroxyenone 17;
[a]D23 -5.0 (c = 2.93, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.82 (d, 3 H, J = 6 Hz), 1.11 (d, 3
H, J = 6 Hz), 1.32-2.38 (m, 11 H), 3.68 (m, 1 H), 4.88, 4.96 (each
m, 1 H), 5.64 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 0.86 (d, 3 H, J = 6.6 Hz), 1.10 (d,
3 H, J = 6.3 Hz), 1.23-2.06 (m, 11 H), 3.47-3.77 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 19.0, 21.9, 22.0, 24.5, 32.5, 34.8,
35.1, 44.2, 65.4, 66.3, 69.6, 96.5.
13C NMR (50 MHz, CDCl3): d = 19.6, 19.7, 23.3, 28.8, 38.5, 41.1,
43.1, 49.2, 67.3, 116.4, 136.5.
GC-MS: m/z (%) = 180 (M - H2O, 2.6), 130 (14), 112 (50), 111
(16), 97 (44), 84 (10), 83 (34), 73 (12), 71 (20), 69 (94), 68 (36).
GC-MS: m/z (%) = 214 (M+, 6), 183 (58), 145 (36), 144 (42), 142
(42), 139 (34), 127 (70), 123 (20), 115 (93), 112 (20), 111 (54), 97
(48), 85 (31), 84 (48), 69 (93), 43 (100).
HRMS: m/z Calcd for C12H22O2 198.1619. Obsvd 198.1619.
Reaction of 78 with AD-Mix a
HRMS: m/z Calcd for C12H22O3 214.1569. Obsvd 214.1569.
Commercial AD-Mix a (4.2 g) was dissolved in t-BuOH/H2O (15
mL/15 mL) and formed a green-yellow solution which was cooled
to 0 °C. Olefin 78 (0.564 g, 2 mmol) was added at 0 °C to this sys-
tem and the mixture was stirred for 3 d at this temperature. After
TLC indicated complete consumption of starting olefin, Na2SO3
(4.5 g) was added and the system was allowed to warm to r.t. EtOAc
(3 î 50 mL) was added and the combined organic layers were
washed with H2O, separated, dried (MgSO4) and concentrated in
vacuo to give the crude product (0.75 g, 84%), which consisted of
two isomers (TLC). This crude mixture was dissolved in MeOH (5
mL) and several drops of concd HCl were added. After stirring for
about 20 min, the system was neutralized with NaOH/MeOH solu-
tion and concentrated to remove the MeOH. The residue was parti-
tioned between H2O/Et2O (20:20) and the H2O layer was re-
extracted with Et2O (3 î 20 mL). The combined Et2O layers were
washed with H2O (30 mL), dried (MgSO4) and concentrated in vac-
uo and chromatographed on silica gel (Et2O/hexane, 0:10 Æ 1:10)
to give predominantly the spiroalcohol 79 (0.23 g, 54%) together
with a mixture of two spiroacetals (0.07 g, 16%) shown later to be
81 and 82. In a similar way, hydroxyenone 17 (0.15 g, 0.75 mmol)
was treated with AD-Mix a (1.4 g) in t-BuOH/H2O (5:5 mL) for 3
d at 0 °C and worked up as for the reaction of 78. Again a mixture
of 79 (36 mg, 22%) and 81 + 82 (~35 mg, 22%) were obtained.
(2S,4R,6R,8S)-2,4,8-Trimethyl-1,7-dioxaspiro[5.5]undecane
(60)
The spiroacetal alcohol 76 (165 mg, 77 mmol) in anhyd pyridine (2
mL) (at -15 °C) was treated with tosyl chloride (294 mg, 154
mmol). After completion of the addition, the mixture was stirred for
3 h, and the temperature allowed to rise to 5 °C. Ice-water was add-
ed and the mixture was extracted with Et2O (3 î 10 mL). The com-
bined Et2O extracts were washed with aq CuSO4 solution, H2O, aq
sat. NaHCO3 and brine, separated, dried (MgSO4) and concentrated
in vacuo. Preparative scale TLC (silica gel, hexane/EtOAc, 5:1)
gave an oil (0.75 g, 88%). This tosylate was characterised by its 1H
and 13C NMR spectra, before being reduced; [a]D25 -27.4 (c = 0.66,
CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.81 (d, 3 H, J = 6.6 Hz), 1.04 (d,
3 H, J = 6.3 Hz), 1.22-2.00 (m, 11 H), 2.40 (s, 3 H), 3.58 (ddq, 1 H,
J = 11.0, 6.0, 2.0 Hz), 3.76 (dddd, 1 H, J = 11.0, 6.0, 4.0, 2.0 Hz),
3.95 (d, 1 H, J = 6 Hz), 3.94 (d, 1 H, J = 4 Hz), 7.30 (d, 2 H, J = 8.5
Hz), 7.77 (d, 2 H, J = 8.5 Hz).
13C NMR: (50 MHz, CDCl3): d = 18.7, 21.6, 21.8, 21.9, 24.5, 32.5,
34.7, 35.1, 43.7, 65.4, 66.9, 72.9, 96.6, 127.9 (2C), 129.7 (2 C),
133.2, 144.6.
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
79
1H NMR (200 MHz, CDCl3): d = 1.06 (d, 3 H, J = 6 Hz), 1.16 (d, 3
H, J = 6 Hz), 1.21-2.26 (m, 11 H), 3.47 (ddd, 1 H, J = 9.0, 7.0, 4.6
Hz), 3.56 (ddd, 1 H, J = 9.0, 7.8, 3.4 Hz), 3.69 (ddq, 1 H, J = 11.0,
6.0, 1.6 Hz), 3.78-3.91 (m, 1 H).
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1975
J = 11.0 Hz), 3.54-3.70 (m, 2 H), 4.09 (dddd, 1 H, J = 11.0, 5.6,
3.3, 2.6 Hz).
13C NMR (50 MHz, CDCl3): d = 19.3 (CH2), 21.9, 22.2 (CH3), 24.2
(CH), 32.2, 35.4, 35.7, 38.2 (CH2) 66.0 (CH2) 68.9, 70.5 (CH), 97.8
(C).
13C NMR (50 MHz, CDCl3): d = 19.0, 20.6, 21.9, 24.8, 32.2, (2 C),
GC-MS: m/z (%) = 214 (M, 0.7), 199 (1), 183 (14), 147 (25), 145
(7), 142 (8), 139 (9) 127 (10), 115 (100), 111 (13), 97 (4), 84 (11),
81 (14), 69 (52).
35.2, 40.5, 65.0, 65.4, 66.5, 97.3.
GC-MS : m/z (%) = 214 (M+, 5), 183 (50), 145 (37), 144 (30), 142
(30), 139 (28), 127 (66), 123 (14), 115 (94), 113 (16), 112 (25), 111
(57), 99 (12), 98 (10), 97 (40), 85 (32).
HRMS: m/z Calcd for C12O3H22 214.1568. Obsvd 214.1569.
Spiroalcohol 82
HRMS: m/z Calcd for C12H22O3 214.1563. Obsvd 214.1569.
[a]D23 +29.7 (c = 1.12, CHCl3).
Tosylate of 79
1H NMR (200 MHz, CDCl3): d = 0.88, (d, 3 H, J = 6.5 Hz, CH3),
1.12 (d, 3 H, J = 6.2 Hz, CH3), 1.50-2.22 (m, 11 H), 3.56 (v br s, 3
H), 4.13 (ddq, 1 H, J = 11.6, 2.5 Hz).
13C NMR (50 MHz, CDCl3): d = 18.3 (CH2), 22.15, 22.2 (CH3),
26.6 (CH), 28.2, 33.0, 35.2, 45.2 (CH2), 66.3 (CH2), 66.8, 72.9
(CH), 98.2 (C).
GC-MS: m/z (%) = 214 (M+, 5), 184 (4), 183 (33), 165 (2), 147 (5),
146 (6), 145 (40), 144 (28), 139 (21), 127 (100), 123 (11), 115 (22),
113 (11), 111 (13), 99 (16), 97 (14), 95 (5), 85 (33), 81 (99), 73 (67),
69 (59).
Alcohol 79 was converted to the tosylate in the manner described
above, and was characterised only by 1H and 13C NMR spectrosco-
py prior to its reduction.
1H NMR (200 MHz, CDCl3): d = 1.05 (d, 3 H, J = 6.0 Hz), 1.12 (d,
3 H, J = 7.0 Hz), 1.18-2.94 (m, 11 H), 2.41 (s, 3 H), 3.63 (ddq, 1 H,
J = 11.0, 6.0, 2.0 Hz), 3.86-4.01 (m, 1 H), 3.95 (br s, 2 H), 7.30 and
7.77 (d, each 2 H, J = 8 Hz).
13C NMR (50 MHz, CDCl3): d = 18.8, 20.5, 21.6, 21.9, 24.7, 32.3,
32.32, 35.0, 40.1, 62.6, 65.5, 73.2, 97.5, 127.9 (2 C), 129.8 (2 C),
133.2, 144.6.
HRMS: m/z Calcd for C12O3H22 214.1568. Obsvd 214.1570.
ent-61
A mixture of alcohols 81 and 82 (0.27 g) was converted to the tosyl-
ates (0.45 g, 97%) in the manner described above and these were
characterised (as a mixture) by NMR spectroscopy before their re-
duction.
The above tosylate (150 mg, 0.4 mmol) was dissolved in anhyd
Et2O (5 mL) and LiAlH4 (200 mg) was added in several portions
at 0 °C to the stirred and N2-protected solution. The mixture was
allowed to warm to 20 °C and stirred overnight, before the dropwise
addition of H2O to destroy any excess LiAlH4. After stirring for
0.5 h at 20 °C, the mixture was filtered through Celite and the Et2O
solution was dried (MgSO4), concentrated and chromatographed on
silica gel (pentane/Et2O, 10:0 Æ 10:1) to provide (2R,4R,6S,8R)-
2,4,8-trimethyl-1,7-dioxaspiro[5.5]undecane (ent-61) (62 mg,
77%); [a]D23 +71 (c = 1.86, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.09, 1.12 (d, each 3 H, J = 6.5
Hz) 1.17 (d, 3 H, J = 7.3 Hz), 1.33-1.94 (m, 11 H), 3.63 (ddq, 1 H,
J = 11.0, 6.0, 2.0 Hz), 3.85 (ddq, 1 H, J = 10.0, 6.0, 3.0 Hz).
13C NMR (50 MHz, CDCl3): d = 19.1, 20.8, 21.9, 22.0, 25.5, 32.5,
35.5, 38.6, 40.1, 60.2, 65.2, 97.5.
Tosylates of the Mixture 81 + 82
1H NMR (200 MHz, CDCl3): d = 0.84 and 0.86 (d, each 3 H, J = 6.5
Hz), 1.06 and 1.13 (d, each 3 H, J = 6.5 Hz), 1.48-2.08 (m, 22 H),
2.40 (s, 6 H), 3.62 (m, 2 H), 3.94 (m, 4 H), 4.14 (m, 2 H), 7.27 and
7.31 (each m, 4 Harom).
13C NMR (50 MHz, CDCl3): d = 18.1, 18.6, (CH2), 21.64, 21.6
(CH3-Ar), 21.7, 22.0, 22.04, 22.1 (4 î CH3) 24.1, 26.6 (CH) 28.1,
31.9, 32.9, 35.4, 35.5, 35.6, 38.6, 44.7 (CH2), 66.3, 67.7, 68.9, 70.1
(CH), 72.7, 72.8 (CH2), 97.8, 98.1 (C), 127.9 (2 C), 128.1 (2 C),
129.7 (2 C), 129.8 (2 C), 133.0, 133.1, 144.7 (2 C).
This tosylate mixture (0.4 g) was treated with LiAlH4 in the normal
way and worked up to provide a mixture of 64 and 65 (0.17 g, 79%),
which could be separated by HPLC (hexane/Et2O, 100/5), with 65
eluting prior to 64, although the opposite order of elution was ob-
served with a non-polar column under GC conditions. NMR spectra
of these freshly separated isomers (epimeric at the spiro-centre)
could be obtained for both CDCl3 and benzene-d6 solutions. Storage
for extended periods in the former solvent resulted in a mixture of
64 and 65 as a result of epimerisation. Stereoisomers 64 and 65 were
also obtained as minor isomers from processing (2R,6S,8R)-ketone
62 according to Scheme 5. Minor spiroacetal 63 was also obtained
from this procedure.
GC-MS: m/z (%) = 198 (M, 5), 183 (2.1) 139 (14), 129 (56), 128
(25), 126 (32), 115 (66), 114 (16), 112 (50), 111 (46), 97 (36), 87
(14), 84 (13), 83 (36), 71 (12), 70 (13), 69 (86).
HRMS: m/z Calcd for C12H22O2, 198.1619, obsvd. 198.1620.
(2S,4R,6R,8R)- and (2S,4R,6S,8R)-2,4,8-Trimethyl-1,7-dioxa-
spiro[5.5]undecanes 64 and 65
Protected hydroxyenone 78 (0.564 g, 2 mmol) was treated with AD-
Mix b at 0 °C for 3 d in t-BuOH/H2O in the normal way and worked
up to provide (0.31 g, 72%) of a mixture of 81 and 82 (55:45), along
with a small amount (50 mg, 12%) of another product, probably 79,
although this was not pursued. Hydroxyenone 17 (0.4 g, 2 mmol)
was also reacted with AD-Mix b (0.42 g) in t-BuOH/H2O (15 mL/
15 mL) and worked up after 3 d at 0 °C to provide a mixture of 81
and 82 (0.12 g, 28%) with a very minor amount (~9%) of a third iso-
mer, again presumably 79. To enable characterisation, the major
isomers of this alcohol, 81 and 82 were separated by HPLC (45%
EtOAc/hexane) and independently characterised, although under
normal GC conditions, they were barely resolved.
(2S,4R,6R,8R)-2,4,8-Trimethyl-1,7-dioxaspiro[5.5]undecane
(64)
[a]D23 -42 (c = 1.74, CHCl3).
1H NMR (400 MHz, benzene-d6): d = 0.74 (dd, 1 H, J = 12.6, 11.7
Hz, H-5ax), 0.81 (d, 3 H, J = 6.4 Hz, CH3-4), 1.12 (ddd, 1 H,
J = 8.8, 4.1, 2.1 HZ, H-11eq), 1.16 (d, 3 H, J = 6.2 Hz, CH3-8), 1.18
(d, 3 H, J = 6.2 Hz, CH3-2), 1.28-1.36 (m, 3 H, H-10ax, H-11ax and
H-5eq), 1.39 (dm, 1 H, J = 12.9 Hz, H-3ax), 1.53 (m, 1 H, H-9eq),
1.62 (m, 1 H, H-10eq), 1.71 (ddd, 1 H, J = 12.6, 12.3, 4.1 Hz, H-
9ax), 1.86 (m, 1 H, H-4), 1.97 (ddd, 1 H, J = 13.2, 3.5, 1.8 Hz, H-
3eq), 3.48 (ddq, 1 H, J = 9.4, 6.3, 3.2 Hz, H-8), 4.24 (ddq, 1 H,
J = 12.6, 6.2, 2.3 Hz, H-2).
Spiroalcohol 81
[a]D23 -53 (c = 1.92 CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.87 (d, 3 H, J = 6.6 Hz, CH3),
1.16 (d, 3 H, J = 6.0 Hz, CH3), 1.45-2.16 (m, 11 H), 3.46 (dd, 1 H,
1H NMR (200 MHz, CDCl3) This spectrum is less well resolved but
the important features are: d = 0.85 (d, 3 H, J = 6.5 Hz, CH3-4), 1.12
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1976
Y. Q. Tu et al.
SPECIAL TOPIC
and 1.17 (d, each 3 H, J = 6.0 Hz, CH3-2) and CH3-8), 1.5-1.9 (m,
5 H), 2.13 (ddd, 1 H, J = 14.0, 3.6, 1.8 Hz), 3.60 (ddq, 1 H, J = 10.0,
6.0, 2.8 Hz), 4.11 (ddq, 1 H, 9.0, 6.0, 2.4 Hz) (other ring protons ap-
pear in the region 0.70-1.35).
13C NMR (100 MHz, benzene-d6): d = 19.2 (C-10), 22.1 (CH3-8 or
CH3-2), 22.1 (CH3-8 or CH3-2), 22.4 (CH3-4), 25.2 (C-4), 32.6 (C-
11), 36.4 (C-9), 39.2 (C-3), 42.3 (C-5), 65.9 (C-2), 68.5 (C-8), 97.4
(C-6).
Alkynol 83
Under N2, HgCl2 (250 mg, 0.92 mmol) was added to a stirred sus-
pension of Al (2.5 g, 93 mmol) in anhyd THF (30 mL), followed by
a solution of propargyl bromide (12 g, 100 mmol) in anhyd THF (15
mL). After completion of the addition, the mixture was stirred at
40-45 °C for 30 min. After cooling to 0 °C, a solution of acetone
(6.8 g, 120 mmol) in anhyd THF (15 mL) was added and the result-
ing mixture was stirred at 40-45 °C for 30 min. The mixture was
poured into ice-water (100 mL) and aq sat. NH4Cl (100 mL) and
then extracted with Et2O (3 î 50 mL). The combined Et2O extracts
were washed with brine dried (MgSO4), and concentrated under re-
duced pressure to provide the crude alcohol 83 (12.7 g).
13C NMR (50 MHz, CDCl3): d = 19.5 (C-10), 21.8 (CH3-4), 21.9
(CH3-8 or CH3-2), 22.2 (CH3-8 or CH3-2), 24.6 (C-4), 32.3, 36.1,
37.8 and 42.0 (C-3,5,9,11), 66.1 (C-2), 68.7 (C-8), 97.8 (C-6).
IR (neat): n = 3409s, 3309s, 2974s, 2931s, 2118m cm-1.
GC-MS : m/z (%) = 198 (M, 2.3), 183 (2.6), 155 (1), 154 (3), 139
(8), 129 (16), 128 (10), 126 (14), 116 (7), 115 (100), 112 (17), 111
(16), 97 (41), 83 (10), 73 (13), 69 (59).
This product was used in the next step without further purification.
HRMS: m/z Calcd for C12O2H22 198.1619. Obsvd 198.1614.
Alkynol THP Ether 84
The above alcohol (9.2g, 94 mmol) and p-toluenesulfonic acid
monohydrate (200 mg, 1 mmol) were stirred in CH2Cl2 (250 mL) at
0 °C under N2, and dihydropyran (12 g, 150 mmol) was added slow-
ly over 15 min. The mixture was quenched with aq sat. NaHCO3,
and the aqueous layer was washed with CH2Cl2 (2 î 100 mL). The
combined organic extracts were dried (MgSO4) and concentrated
under reduced pressure to give crude ether 84 (14.5 g). Distillation
afforded the THP ether 84 (10.5 g, 57% based on propargyl bro-
mide).
IR (neat): n = 3311m, 2940s, 2869s, 2119m cm-1.
1H NMR (200 MHz, CDCl3): d = 1.30 (s, 3 H), 1.32 (s, 3 H), 1.97
(t, 1 H, J = 2.7 Hz), 1.47 (m, 4 H), 1.65 (m, 1 H), 2.40 (dd, 2 H),
3.37-3.48 (m, 2 H), 3.88-3.99(m, 2 H), 4.92 (m, 1 H).
(2S,4R,6S,8R)-2,4,8-Trimethyl-1,7-dioxaspiro[5.5]undecane
(65)
[a]D23 +16.5 (c = 0.89, CHCl3) (this value is approximate only).
1H NMR (200 MHz, CDCl3): d = 0.87 (d, 3 H, J = 6.0 Hz, CH3-4),
1.11 and 1.17 (d, 6 H, J = 6.0 Hz, CH3-2 and CH3-8), 1.49-1.65 (m,
10 H), 2.12-2.20 (m, 1 H, H-11), 3.52 (ddq, 1 H, J = 11.0, 6.0, 2.0
Hz, H-2), 4.15 (ddq, 1 H, J = 11.0, 5.0, 2.0 Hz, H-8).
1H NMR (400 MHz, benzene-d6) containing some isomer 64:
d = 0.69 (dd, 1 H, J = 12.6, 11.0 Hz), 0.73 (d, 3 H, J = 6.4 Hz, CH3-
4), 1.02 (dt, 1 H J = 13.8, 3.8 Hz), 1.16 (d, 6 H, J = 6.4, CH3-2 and
CH3-8), 1.20 (dm, 1 H, J = 10.8 Hz), 1.28-1.45 (m, 4 H), 1.61-1.75
(m, 3 H), 1.97 (dm, 1 H, J = 13.2 Hz), 3.25 (ddq, 1 H, J = 12.0, 6.2,
2.3 Hz, H-2), 4.36 (ddq, 1 H, J = 12.6, 6.2, 2.3 Hz, H-8).
13C NMR (50 MHz, CDCl3): d = 20.6, 25.4, 26.0, 26.1, 32.1, 32.2,
13C NMR (50 MHz, CDCl3): d = 18.3 (C-10), 22.0 (CH3-4), 22.2
(CH3-8 and CH3-2), 27.1 (C-4), 28.3, 33.2, 41.6, 45.0 (C-3,5,9,11),
66.4 (C-8), 68.2 (C-2) 97.9 (C-6).
13C NMR (100 MHz, benzene-d6-containing some isomer 64):
d = 19.0 (C-10), 22.36. 22.4, 22.43 (CH3-8,2 4), 27.3 (C-4), 28.5,
33.3, 41.9, 45.0 (C-11,9,5,3), 66.1 (C-8), 68.7 (C-2), 97.7 (C-6).
63.2, 69.9, 75.5, 81.7, 94.1.
GC-MS: m/z (%) = 143 (M+ - C3H3, 1.7), 101 (M+ - OTHP, 6.5),
85 (100), 81 (57.5), 79 (30.9), 67 (16.4), 57 (18.9), 56 (18.2), 55
(15.6).
Anal. calcd for C11H18O2: C 72.5, H 10.0. Found C 72.47, H 10.33.
GC-MS: m/z (%) = 198 (M, 7), 183 (2), 154 (2), 139 (7), 130 (7),
129 (100), 128 (37), 126 (8), 115 (18), 114 (6), 113 (6), 112 (22),
111 (47), 99 (2), 98 (4), 97 (13), 87 (26), 85 (5), 84 (9), 83 (46), 70
(9), 69 (65).
Alkynol Lactol 85
Ether 84 (0.54 g, 3.0 mmol) was dissolved in THF (20 mL) and
cooled to -78 °C before BuLi (1.9 mL, 1.6 M in hexane, 3 mmol)
was added dropwise via syringe, and the resultant solution was
stirred for 30 min. In a separate flask, d-caprolactone (0.34 g, 3
mmol) was dissolved in THF (20 mL) and HMPA (freshly distilled,
100 mL), and cooled to -78 °C. Lithiated 84 in the first flask was
then cannulated into the lactone solution by slow dropwise addition.
The reaction was stirred at -78 to -60 °C for 4 h, and then H2O (60
mL) was added. The resulting mixture was allowed to warm to r.t.
and extracted with hexane (3 î 60 mL). The hexane layers were
washed with aq sat. NaHCO3 and dried (K2CO3). Removal of the
solvent afforded the crude addition product 85 (1.28 g). This mate-
rial was used directly in the next step without further purification.
HRMS: m/z Calcd for C12O2H22 198.1619. Obsvd 198.1620.
(2S,4S,6S,8R)-2,4,8-Trimethyl-1,7-dioxaspiro[5.5]undecane
(63)
With respect to 63 (component H in the natural secretion is the
23
enantiomer of 63) the following characterisation was made; [a]D
+14.5 (c = 0.9, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.87, (d, 3 H, J = 6.8 Hz, CH3-4),
1.05 (dd, 1 H, J = 13.3, 12.2 Hz, H-5ax), 1.06 (d, 3 H, J = 6.4 Hz,
CH3-8), 1.13 (m, 1 H, H-9ax), 1.32 (td, 1 H, J = 13.8,13.2, 4.9, H-
11ax), 1.35 (m, 1 H, H-3a), 1.35 (d, 3 H, J = 6.8, CH3-2), 1.45-1.57
(m, 3 H, H-10eq, H-9eq and H-11eq), 1.48 (dm, 1 H, J = 12.9 Hz,
H-3eq), 1.68 (ddd, 1 H, J = 13.2, 3.8, 2.0 Hz, H-5eq), 1.84 (ddddd,
1 H, J = 13.2, 13.2, 13.2, 4.7, 3.9 Hz, H-10ax), 2.16 (m, 1 H, H-2),
3.92 (ddq, 1 H, J = 11.4, 6.4, 1.8 Hz, H-8), 4.13 (ddq, 1 H, J = 7.7,
7.7, 3.5 Hz, H-2).
13C NMR (100 MHz, CDCl3): d = 19.2 (C-10), 19.5 (C-4), 20.8
(CH3-2), 21.6 (CH3-8), 22.2 (CH3-4), 32.8 (C-9), 36.7 (C-11), 38.9
(C-3), 45.2 (C-5), 65.9 (C-8), 69.4 (C-2), 96.8 (C-6).
GC-MS: m/z (%) = 198 (M+, 4), 183 (3.5), 154 (3), 139 (15), 129
(59), 128 (30), 126 (21), 115 (21), 112 (31), 111 (40), 99 (4), 97
(19), 87 (17), 84 (10), 83 (36), 71 (11), 69 (70), 56 (12), 55 (55), 41
(100).
Spiroacetal 14-E
Lactol 85 (0.43 g) was dissolved in anhyd MeOH (20 mL), and 5%
Pd/C (50 mg) was added. The mixture was then shaken (Parr hydro-
genator) under H2 (3 bar) for 4 h, and filtered through a pad of
Celite. After removal of the solvent, the residue was extracted with
Et2O (3 î 50 mL), washed with brine, and dried (MgSO4). Concen-
tration under reduced pressure provided 0.46 g of material, which
was purified by flash chromatography on silica gel (hexane/Et2O,
30:1) to afford the trimethylspiroacetal 14-E (54 mg, 27% from 84).
The 1H and 13C NMR data are shown in the Table.
GC/MS: m/z (%) = 198 (M+, 7.8), 140 (17.5), 129 (55.2), 128
(38.4), 125 (20.8), 115 (34.0), 112 (60.3), 111 (62.5), 99 (19.8), 97
HRMS: m/z Calcd for C12O2H22 198.1619. Obsvd 198.1618.
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis and Stereochemistry of Insect Derived Spiroacetals with Branched Carbon Skeletons
1977
(23.9), 83 (49.5), 69 (71.9), 56 (23.2), 55 (77.2), 43 (100), 42 (43.0),
41 (86.3), 39 (35.6). (for plotted spectrum, see Ref. 6)
GC-MS (isomer 1): m/z (%) = 264 (0.2), 199 (1.6), 198 (M+ - THP,
10.4), 181 (M+ - OTHP, 12.3), 180 (6.7), 165 (16.9), 112 (20.7), 95
(8.5), 85 (100.0), 69 (57.2), 67 (22.2), 55 (37.4), 43 (34.6), 41(73.2).
HRMS: m/z Calcd for C12H22O2 198.1619. Obsvd 198.1616.
Anal. calcd for C17H30O3: C 72.3, H 10.7. Found C 72.0, H 10.9.
Hydrazone 87
6-Methylhept-5-en-2-one (86) (4.2 g, 25 mmol) was added drop-
wise to a mixture of stirred dimethylhydrazine (4.6 g, 76 mmol) and
glacial AcOH (0.5 g, 8 mmol). After completion of the addition, the
mixture was stirred for 3 h at r.t. Et2O was added and the Et2O layer
was washed with aq satd NaHCO3 solution, H2O and dried
(MgSO4). Concentration under reduced pressure and purification by
flash chromatography on neutral alumina (hexane/Et2O, 1:1) af-
forded the N,N-dimethylhydrazone 87 (5.26 g, 94%) as a pale yel-
low oil.
1H NMR (200 MHz, CDCl3) (two isomers): d = 1.6 (s, 3 H, CH3),
1.67 (s, 3 H, CH3), 1.91 (s, 3 H, CH3), 1.94 (s, 3 H, CH3), 2.39 (s, 3
H, CH3), 2.42 (s, 6 H, CH3), 2.20-2.22 (m, 4 H), 5.11 (m, 1 H).
13C NMR (50 MHz, CDCl3) (two isomers): d = 16.1, 17.2, 25.2,
38.5, 46.5, 47.0, 122.8, 122.9, 131.5, 167.0, 168.9.
Spiroacetal 90
Hg(OAc)2 (3.5 g, 10.9 mmol) was added to the above ketone 89 (1.0
g, 3.5 mmol) in THF/H2O (75mL/75mL) and the mixture was
stirred for 2 h. BnEt3NCl (10.0 g, 43.9 mmol) in aq 10% NaOH so-
lution (75 mL) and CH2Cl2 (50 mL) were added, followed by
NaBH4 (1.0 g, 25 mmol) in aq 10% NaOH solution (20 mL). The
mixture was stirred for 1 h, and then filtered through Celite. The fil-
trate was collected and the aqueous phase was extracted with Et2O
(3 î 50mL). The combined Et2O extracts were washed with brine,
and dried (MgSO4). Concentration under reduced pressure provided
1.21g of crude material, to which was added concd HCl (0.5 mL)
and MeOH (30 mL). The mixture was stirred for 2 h at r.t., and then
quenched carefully with aq sat. NaHCO3. The aqueous solution was
extracted with Et2O (3 î 30 mL), washed with brine, and dried
(MgSO4). After removal of the solvent, the residue was purified by
flash chromatography (silica gel, hexane/Et2O, 20:1), affording
(6S,8R)-2,2,8-trimethyl-1,7-dioxaspiro[5.5]undecane (90) (0.24 g,
34%). Spectroscopic data were identical with those obtained for the
racemate 14-E, and enantioselective gas chromatography revealed
that the ee was greater than 99%; [a]D22 +46.2 (c = 7.09, CHCl3).
GC-MS (two isomers) isomer 1: m/z (%) = 168 (M+, 5.4), 153 (M+
- CH3, 7.4), 126 (15.0), 112 (14.8), 99 (50.3), 96 (15.4), 82 (29.2),
67 (35.9), 58 (43.6), 56 (100.0). The second isomer provided a very
similar spectrum. The spectral data agreed with those reported.35
Hydrazone 88
To a solution of LDA prepared from 0.91 M BuLi (4.4 mL) in Et2O
and (i-Pr)2NH (0.56 mL) was added dropwise the hydrazone 87
(0.504 g, 3 mmol) in anhyd THF (3 mL) at -78 °C. The mixture was
stirred for 1 h, then (R)-3-(tetrahydropyran-2’-yl)butyl iodide (0.71
g, 2.5 mmol) in anhyd THF (4 mL) was added and the mixture was
stirred for 1 h at -78 °C, followed by warming to r.t., and stirred
overnight. Aq sat. NaHCO3 was added. After removal of the THF
under reduced pressure, the residue was extracted with 1:1 hexane/
Et2O (3 î 50 mL). The combined organic extracts were washed
with H2O, 1% aq Na2S2O3 solution and brine, before being dried
(MgSO4). Concentration under reduced pressure provided the crude
hydrazone 88 (0.863 g) which was purified by flash chromatogra-
phy on neutral alumina (hexane/Et2O, 2:1) (0.748 g, 77%).
References
(1) (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617.
(b) Jacobs, M. F.; Kitching, W. Current Organic Chemistry
1998, 2, 395.
(2) Francke, W.; Kitching, W. Current Organic Chemistry 2000,
4, 411.
(3) Fletcher, M. T.; Kitching W. Chem. Rev. 1995, 95, 789.
(4) Moore, C. J.; Hubener, A.; Tu, Y. Q.; Kitching, W.; Aldrich,
J. R.; Waite, G. K.; Schulz, S.; Francke, W. J. Org. Chem.
1994, 59, 6136.
(5) Tu, Y. Q.; Moore, C. J.; Kitching, W. Tetrahedron :
Asymmetry 1995, 6, 397.
1H NMR (200 MHz, CDCl3) (isomer mixture): d = 1.00 (d, CH3,
J = 6.1 Hz), 1.02 (d, CH3, J = 6.1 Hz), 1.51 (s, 3 H), 1.58 (s, 3 H),
1.42-1.85 (m, 24 H), 2.11 (m, 4 H), 2.29 (s, 6 H), 2.30-2.38 (m, 8
H), 3.36-3.83 (m, 6 H), 4.54 (m, 1 H), 4.59 (m,1 H), 5.01 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 17.5, 17.6, 18.9, 19.6, 19.9, 21.3,
21.5, 22.2, 22.7, 25.3, 25.4, 25.5, 29.6, 31.0, 35.7, 35.8, 35.9, 36.4,
36.9, 37.4, 38.8, 46.8, 47.3, 62.4, 62.6, 70.4, 70.7, 73.3, 73.5, 95.5,
95.6, 98.3, 98.7, 123.2, 123.3, 131.7, 132.0, 171.8, 172.0.
GC-MS (isomer 1): m/z (%) = 324 (M+, 5.2), 239 (41), 112 (19), 96
(22), 85 (71), 82 (41), 69 (25), 67 (36), 57 (24), 55 (38), 45 (56), 44
(65), 43 (52), 42 (34), 41 (100).
HRMS: m/z Calcd for C19H36N2O2 (M+ + 1) 325.2850. Obsvd (M+ +
1) 325.2844.
(6) Zhang, H.; Fletcher, M. T.; Dettner, K.; Francke, W.;
Kitching, W.; Tetrahedron Lett. 1999, 40, 7851.
(7) McDonald, F. J. D. Orient. Insects 1988, 22, 287.
(8) Aldrich, J. Entom. Soc. Qld. News Bull. 1991, 19, 19.
(9) Staddon, B. W.; Thorne, M. J.; Knight, D. W. Aust. J. Zool.
1987, 35, 227.
(10) Francke, W.; Hindorf, G.; Reith, W. Naturwissenschaften
1979, 66, 619.
(11) Francke, W.; Reith, W.; Bergstrom, G.; Tengo, J.
Naturwissenschaften 1980, 67, 149.
(12) Kitching, W.; Lewis, J. A.; Perkins, M. V.; Drew, R. A. I.;
Moore, C. J.; Schurig, V.; Konig, W. A.; Francke, W. J. Org.
Chem. 1989, 54, 3893.
(13) Chen, J.; Fletcher, M. T.; Kitching, W. Tetrahedron :
Asymmetry 1995, 6, 967.
2-(Tetrahydropyran-2’-yloxy)-10-methylundec-9-en-6-one (89)
Hydrazone 88 (0.50 g, 1.5 mmol) was converted by flash chroma-
tography (silica gel, hexane/Et2O, 4:1) to ketone 89 (0.36 g, 83%).
1H NMR (200 MHz, CDCl3) (two isomers): d = 1.07 (d, 3 H, J = 6.1
Hz), 1.19 (d, 3 H, J = 6.1 Hz), 1.56 (s, 3 H), 1.64 (s, 3 H), 1.44-1.71
(m, 24 H), 2.19-2.26 (m, 4 H), 2.26-2.43 (m, 8 H), 3.45 (m, 2 H),
3.67-3.88 (m, 4 H), 4.58 (m, 1 H), 4.66 (m, 1 H), 5.21 (m, 2 H).
13C NMR (50 MHz, CDCl3) (two isomers): d = 17.2, 18.7, 19.4,
19.5, 19.7, 19.8, 21.2, 22.3, 25.2(2 C), 30.9(2 C), 34.3, 35.7, 36.5,
42.3, 42.4, 62.1, 62.3, 65.4, 70.3, 73.5, 95.3, 98.4, 122.6(2 C),
132.0, 132.1, 210.0, 210.2.
(14) Perkins, M. V.; Kitching, W.; König, W.A.; Drew, R. A. I. J.
Chem. Soc., Perkin Trans.1 1990, 2501.
(15) O'Shea, M. G.; Kitching, W. Tetrahedron 1989, 45, 1177.
(16) Lewis, J. A. Ph.D. Thesis, University of Queensland, 1987.
(17) Schulz, S.; Francke, W. Unpublished results. Schulz, S.
Diplomarbeit, Univeristy of Hamburg, 1982.
(18) Ikunaka, M.; Mori, K. Agric. Biol. Chem. 1987, 51(2), 565.
(19) McErlean, C. S. P.; Kitching, W. Research in Progress.
(20) Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 295.
(21) Jacobs, M. F.; Suthers, B. D.; Hubener, A.; Kitching, W. J.
Chem. Soc., Perkins Trans. 1 1995, 901.
Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York

1978
Y. Q. Tu et al.
SPECIAL TOPIC
(22) Suthers, B. D.; Jacobs, M. F.; Kitching, W. Tetrahedron Lett.
1998, 39, 2621.
(23) Asymmetric dihydroxylation of undeca-1,10-diene-6-one,
followed by cyclisation to spiroacetals has recently been
reported. Sauret, S.: Cuer, A.; Gourcy, J-G.; Jeminet, G.
Tetrahedron : Asymmetry 1995, 6, 1995.
(24) Perkins, M. V.; Jacobs, M. F.; Kitching, W.; Cassidy, P. J.;
Lewis, J. A.; Drew, R. A .I. J. Org. Chem. 1992, 57, 3365.
(25) Crispino, G. A.; Jeong, K-S.; Kolb, H. C.; Wang, Z-M.;
Xupan, D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785, and
references cited therein.
(29) Hungerford, N. L.; Mazomenos, B.; Haniotakis, G.; Moore, C.
J.; Fletcher, M. T.; Hubener, A.; DeVoss, J. J.; Kitching, W. J.
Chem. Soc.,Chem. Commun. 1998, 863.
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(32) Jacobson, R.; Taylor, R. J.; Williams, H. J.; Smith, L. R. J.
Org. Chem. 1992, 47, 3140.
(33) Mori, K.; Watanabe, H. Tetrahedron 1983, 40, 299.
(34) Kanai, K.; Sakamoto, S.; Ogawa, S.; Suami, T. Bull. Soc.
Chem. Soc. Jpn. 1987, 60, 1529.
(35) Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A.
Tetrahedron 1996, 52, 11601.
(26) Hofmann, K.; Orchena, S. F.; Sax, S. M.; Jeffrey, G. A. J. Am.
Chem. Soc. 1959, 81, 992.
(27) Mori, K.; Tanida, K. Tetrahedron 1981, 37, 3221.
(28) See: König, W. A. The Practice of Enantiomer Separation by
Capillary Gas Chromatography; Huethig: Heidelberg, 1987.
Article Identifier:
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Synthesis 2000, No. 13, 1956–1978 ISSN 0039-7881 © Thieme Stuttgart · New York