Investigations of the stereoselectivity of the intramolecular Diels-Alder reaction of a spiculoic acid model system

Article abstract of DOI:10.1016/j.tet.2008.02.109

Model linear precursors to the spiculoic acids were prepared and underwent thermally induced IMDA reactions. The configuration of C5 in the stereotriad was found to dominate any inherent endo/exo selectivity of the IMDA reaction. The isomer (2E,5S)-20 underwent the IMDA to give the spiculoic acid stereochemistry in 84% yield and 94% ds. The required stereotriads were synthesised using stereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the π-facial preference of (S)-2-benzoyloxypentan-3-one ((S)-27) led to (5R)-(22) and a syn-titanium aldol reaction, under the stereocontrol of a chiral N-acylthiazolidinethione (42) led to (5S)-(22). Chain extension using standard Wittig, HWE and 'modified' Julia olefinations installed the diene and dienophile components giving the linear precursors to the IMDA reactions.

Full text of DOI:10.1016/j.tet.2008.02.109

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4852e4867
www.elsevier.com/locate/tet
Investigations of the stereoselectivity of the intramolecular
DielseAlder reaction of a spiculoic acid model system
*
Julia S. Crossman, Michael V. Perkins
School of Chemistry, Physics and Earth Sciences, Flinders University, GPO Box 2100, Adelaide, SA 5001, Australia
Received 3 October 2007; received in revised form 23 January 2008; accepted 29 February 2008
Available online 18 March 2008
Abstract
Model linear precursors to the spiculoic acids were prepared and underwent thermally induced IMDA reactions. The configuration of C5 in
the stereotriad was found to dominate any inherent endo/exo selectivity of the IMDA reaction. The isomer (2E,5S)-20 underwent the IMDA to
give the spiculoic acid stereochemistry in 84% yield and 94% ds. The required stereotriads were synthesised using stereoselective substrate-con-
trolled aldol reactions; an anti-boron aldol reaction, controlled by the p-facial preference of (S)-2-benzoyloxypentan-3-one ((S)-27) led to (5R)-
(22) and a syn-titanium aldol reaction, under the stereocontrol of a chiral N-acylthiazolidinethione (42) led to (5S)-(22). Chain extension using
standard Wittig, HWE and ‘modified’ Julia olefinations installed the diene and dienophile components giving the linear precursors to the IMDA
reactions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Intramolecular DielseAlder reaction; Substrate-controlled aldol reaction; Spiculoic acids
1. Introduction
units (which is relatively uncommon) and one propionate
unit to construct a linear precursor, which then undergoes an
enzyme-catalysed intramolecular DielseAlder (IMDA) reac-
tion.1e4
The IMDA cycloaddition of the potential linear precursors
to the spiculoic acids (6), possessing an E,E-diene and an
E-dienophile, can proceed through four alternative transi-
tion states to give four possible stereoisomeric cycloadducts
(7e10) (Fig. 2).
The spiculoic acids (1e5)1,2 are a family of polyketide
derived compounds, which are among the rich variety of sec-
ondary metabolites that have been isolated from sponges of the
genus Plakortis (Fig. 1). Andersen et al. reported the isolation
of spiculoic acids A (1) and B (2) from the methanol extracts
of a Caribbean sponge Plakortis angulospiculatus.1 Subse-
quent studies by Amade et al. identified the derivatives iso-,
nor- and dinor-spiculoic acids (3e5) from the sponge Plakortis
zyggompha, collected off the coast of Martinique Island.2
Spiculoic acid A (1) was found to be mildly cytotoxic
against the tumor cell line MCF-7 (human breast cancer),1
while isospiculoic acid (3) and nor-spiculoic acid (4) exhibited
mild cytotoxicity against both tumor cell lines A549 (lung car-
cinoma) and HT29 (colon carcinoma).2 The spiculoic acids
possess a previously unreported spiculane skeleton featuring a
[4.3.0] bicyclic core. Of interest is the proposed biogenesis of
spiculoic acid A (1) involving incorporation of four butyrate
R
R2
R1
3 H
H
O
H
H
CO2H
CO2H
1,3-5
2
spiculoic acid A (1); R1 = Et, R2 = Me, R3 = Et
spiculoic acid B (2)
isospiculoic acid A (3); R1 = Me, R2 = Et, R3 = Et
nor-spiculoic acid A (4); R1 = Me, R2 = Me, R3 = Et
dinor-spiculoic acid A (5); R1 = Me, R2 = Me, R3 = Me
* Corresponding author. Tel.: þ61 8 8201 2496; fax: þ61 8 8201 2905.
E-mail address: mike.perkins@flinders.edu.au (M.V. Perkins).
Figure 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.109

J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
4853
spiculoic acids
R
R
H
R
R
R
H
H
Ph
Ph
Ph
7
O
O
10
3
2
"Top"
diene
H
CO2H
R
R
CO2H
"endo"
"exo"
7
8
R
E
7
O
E
"Bottom" dienophile
"Top" dienophile
H
3
O
10
R
R
H
R
R
E
H
2
R
HO
"Bottom"
diene
Ph
O
O
6
H
CO2H
H
R
CO2H
R
"exo"
"endo"
9
10
Figure 2.
There are a number of examples of natural products, which
appear to be products of DielseAlder type cycloaddition reac-
tions.4 Evidence suggests that during biosynthesis Dielse
Alder reactions are occurring under both non-enzymatic and
enzymatic (i.e., DielseAlderase) control. Isolation and charac-
terisation of the DielseAlderase enzyme has been achieved in
some systems including solanapyrone synthase,5 lovastatin
nonaketide synthase6 and macrophomate synthase,7 but this
is a difficult and time consuming task. Biomimetic total syn-
theses can be used to give an indication as to whether the
DielseAlder reaction is likely to be facilitated by enzymes.
If the non-enzymatic cyclisation product(s) achieved syntheti-
cally does not match the natural product (including the enan-
tiomeric/diastereomeric ratios) then enzymatic involvement is
likely. Alternatively if the non-enzymatic laboratory cyclisa-
tion product(s) (including the enantiomeric/diastereomeric ra-
tios) obtained synthetically matches the natural product this
suggests that enzymatic involvement is not necessary. How-
ever, biomimetic total syntheses cannot prove or disprove en-
zyme involvement in the biosynthesis.
in-depth examination by Baldwin et al.10 revealed an errone-
ous stereochemical assignment of the product of a stereoselec-
tive Sharpless epoxidation, synthesised earlier in the reaction
sequence with the resulting reassignment of the linear precur-
sor 11 as compound 13. Subsequent analysis of Mehta and
Kunda’s NOE results led to assignment of the DielseAlder ad-
duct 12 as cycloadduct 14 (Scheme 1). While cycloadduct 14
does contain the desired [4.3.0] bicyclic core, the relative
orientation of the six stereocentres is different from the natural
products. The C4 and C6 stereocentres present in the linear
precursor, which were stereoselectively installed are not in
the correct anti-orientation. The protons at the bridgehead
have a cis rather than a trans orientation, suggesting an exo
rather than an endo transition state geometry. The linear
precursor 13 has an electron withdrawing group (EWG)
attached to the diene facilitating an inverse electron demand
IMDA reaction. While potentially synthetically useful this ap-
proach is not biomimetic with regards to the IMDA where the
potential linear precursors to the spiculoic acids have the
EWG on the dienophile, activating a normal electron demand
IMDA reaction.
In 2006, Baldwin et al. reported the total synthesis of ent-
spiculoic acid A, employing a biomimetic IMDA reaction
(Scheme 2).11 Following stereoselective synthesis of a chiral
aldehyde 15, via a highly stereoselective aldol cross-coupling
reaction utilising chiral oxazolidinone derivatives, sequential
Wittig and Julia olefination reactions were employed to gener-
ate the conjugated triene 16. A Wittig olefination reaction in-
stalled the dienophile component (17) and spontaneous IMDA
cycloaddition formed cycloadduct 18 (25% yield) leading to
ent-spiculoic acid A (ent-1).
During the course of our work these compounds have
attracted synthetic attention. Mehta and Kunda8 published
the synthesis and subsequent IMDA cycloaddition of a model
linear precursor 11 to give cycloadduct 12 selectively, but their
stereochemical assignment was found to be incorrect (Scheme
1).9 Incorrect transposition of the C5 stereocentre from their
linear precursor 11 to the cycloadduct 12 is apparent. An
H
o-C6H4Cl2
BHT, Δ
5
OBn
5
MeO2C
MeO2C
85 %, >95 % ds
H
OBn
O
TBDPS
TBDPSO
11
12
Structures reported by Mehta and Kunda.
2. Retrosynthetic analysis of a model system
H
We proposed to investigate the use of a thermally induced
IMDA reaction to construct the [4.3.0] spiculane skeleton.
Prior to commencement of this study no synthetic studies
towards the spiculoic acids had been reported. The model
system was designed to investigate the stereoselectivity of
the thermally induced IMDA, especially the effect of the con-
figuration of the C5 stereocentre.
o-C6H4Cl2
BHT, Δ
5
5
OBn
MeO2C
MeO2C
85 %, >95 % ds
H
OBn
O
TBDPS
TBDPSO
13
14
Structural reassignment by Baldwin et al.
Scheme 1.

4854
J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
Wittig/Julia
olefinations
potentially offered some flexibility as deprotection and oxida-
tion of C5 could be performed prior to the IMDA reaction.
Central chiral fragment (5R/S)-229 was extended via either
Wittig or Julia olefination reactions with ylide 23 and sulfone
24 to install the diene moiety. Subsequent installation of the
dienophile functionalities employing Wittig and HWE olefina-
tion reactions with ylide 25 and phosphonates 26 produced the
linear precursor 20.
Ph
O
O
O
O
PMBO
16
15
PMB
toluene,
O
Ph3P
O
O
Ph
PMBO
17
O
3. Results and discussion
25 % IMDA
3.1. Synthesis
H
H
H
Synthesis of the required stereotriad in aldehyde (5R)-22
was achieved by employing a substrate-controlled aldol cou-
pling procedure reported by Paterson et al.12 An anti-selective
double stereodifferentiating13 aldol coupling reaction between
ketone 27 and aldehyde 2814 (Scheme 4) produces adduct
29 in >95% ds (minor component not characterised). The
facial preference of the enolate of chiral ketone 27 is matched
with the Felkin preference of chiral aldehyde 28 accounting
for this high diastereoselectivity. The alcohol was protected
as the TBS ether 3015 and reduction of both the ketone and
ester functionalities with LiBH4 gave the 1,2-diol. Oxidative
cleavage using periodate gave the aldehyde (5R)-22 in good
yield (>75% over four steps).
O
OPMB
H
CO2H
O
O
ent-1
18
Scheme 2.
The model 19 has a simplified side chain (ePh instead of
eCH]CHPh), no ethyl groups at C8 or C10, the ethyl groups
at C2 and C4 are replaced with methyl groups and the carbox-
ylic acid is masked as the ethyl ester (Scheme 3). To avoid
problems during the synthesis of the linear precursor 20, we
chose to prepare 20 with C5 protected at the alcohol oxidation
state. The C5 alcohol was protected as the TBS ether in both
the R and S configurations in order to examine whether this
centre imparts any control over the stereochemical outcome
of the IMDA. IMDA reaction of 20 gives 21, which can be de-
protected (at C5) and oxidised to give 19. This approach
c-
1.( C6H11)2BCl,
Me2NEt, Et2O,
–78 °C → 0 °C (2 hrs)
2.
BzO
BzO
O
27
O
OH OPMB
29
, –78 °C (2 hrs)
→ –20 °C (O/N)
94 %, >95 % ds
O
OPMB
28
2,6-lutidine,
TBSOTf,
CH2Cl2, –78 °C
96 %
H
H
O
OTBS
1. LiBH4, THF, –78 °C
→ RT (O/N), >89 %
H
CO2Et
H
BzO
CO2Et
21
2. NaIO , MeOH/H2O,
RT, 943 %
O
O OPMB
TBS
(5R)-22
O
O
OPMB
TBS
19
30
OTBS
Scheme 4.
EtO
O
10
8
5
Synthesis of the full linear precursor was now possible
through Wittig and HWE couplings with the central chiral
fragment (5R)-22 (Scheme 5). A Wittig coupling16 of the ylide
23 (available in a four-step sequence from cinnamaldehyde;
NaBH4 reduction to the alcohol,17 conversion to the allyl chlo-
ride,18 formation of the phosphonium salt16 and deprotona-
tion) with the chiral aldehyde (5R)-22 gave an inseparable
1:1 mixture of the (E,E)-31 and (Z,E)-31 isomers in good
yield (96%). Isomerisation of (Z,E)-31 to the thermodynami-
cally favoured (E,E)-31 was achieved with catalytic I2.19
Cleavage of the PMB ether proved troublesome due to the
sensitivity of diene (E,E)-31. Conventional methods (DDQ20
and CAN21) resulted in decomposition of the starting material
and attempts at achieving cleavage using a variety of acids
6
4
2
CO2Et
OTBS
(5R/S)-20
Wittig/Julia
olefinations
Wittig/H.W.E.
olefinations
R
5
+
+
R'
CO2Et
O
O
OPMB
TBS
(5R/S)-22
R; –CH=PPh3 (23)
R'; =PPh3 (25)
or -P(O)OEt2 (26)
O2
–CH2
S
N
or
N
N
N
(24)
Scheme 3.

J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
4855
1. MgBr2.OEt2, SMe2,
CH2Cl2, RT (O/N), 77 %
PPh3
23
5
5
5
CH2Cl2, RT
96%
2. Swern[O], 94 %
O
OPMB
TBS
O
OPMB
TBSO
TBSO
(5S)-32
O
(E,E,5S)-31 : (Z,E,5S)-31, 1:1
(E,E,5S)-31
I2, CDCl3,
RT, 84 %
(5R)-22
EtO
EtO
The Wittig olefination
P
CO2Et
26
with ylide 25 produced
only cycloadduct 36.
O
NaH, THF,
0 °C→ RT, 72 %
CO2Et
5
5
+
CO2Et
TBSO
(2Z,5S)-20
TBSO
(2E,5S)-20
Δ, CDCl3
84 %
Δ, toluene
87 %
H
H
H
H
H
H
OTBS
OTBS
OTBS
+
OTBS
+
H
H
CO2Et
CO2Et
CO2Et
CO2Et
33
34
36 (94 % ds)
37
+35 minor isomer
(stereochemistry unknown)
36:37 (94:4)
33:34:35 (85:10:5)
Scheme 5.
(e.g., p-TsOH, TFA, amberlyst resin) yielded only starting ma-
terial. Fortunately, a method by Iwasaki et al.22 using
MgBr2$OEt2 and SMe2 in CH2Cl2 was successful giving the
alcohol in 77% yield. Swern oxidation23 of the generated alco-
hol gave the desired aldehyde 32 in good yield (94%).
thiazolidinethione 40 and aldehyde 28 (77% yield, 82% ds)
(Scheme 7). The stereochemical assignment of the separable
major adduct 41 was based on the literature precedent,28 while
the two minor isomers were not characterised. The major
A HWE coupling24 of phosphonate 26 with aldehyde
32 gave the linear triene as a 1:2.75 mixture of (2E,5S)-20/
(2Z,5S)-20 isomers. Upon purification on silica gel the minor
isomer (2E,5S)-20 spontaneously begins to undergo the IMDA
cyclisation to give adducts 36 and 37. Heating gently to 50 ꢀC
drives the reaction to completion giving the major product 36
with 94% ds. Due to the spontaneity of the cyclisation the
reaction could not be attempted with the C5 hydroxyl or the
C5 carbonyl in place. The major triene (2Z,5S)-20, was
much slower to cyclise but heating overnight under reflux in
toluene gives the inseparable IMDA adducts 33/34/35 (ratio
85:10:5). Aldehyde 32 was also coupled to ylide 25 in a Wittig
olefination25 to install the dienophile moiety. In this case fol-
lowing reaction at 40 ꢀC for 5 days only cycloadduct 36 was
isolated (40% yield due to incomplete reaction).
Attempts were made at generating the linear precursor 20
with the 5R configuration using (5R)-22 by first incorporating
the dienophile moiety giving alkene 38 and then the diene end
(Scheme 6). However, the substrate possessing the dienophile
39 proved to be extremely sensitive and decomposed under the
conditions used to attempt to install the diene in (2E,5R)-20.26
Alternatively an isomer of aldehyde 22 with the S stereo-
chemistry at C5 would allow synthesis of the linear precursor
(5R)-20 (NB: change in priority of groups means 5R stereo-
chemistry) in an analogous manner to that described in Scheme
5. Synthesis of the required stereotriad was achieved via a syn-
selective substrate-controlled aldol coupling27 between chiral
Ph3P
CO2Et
5
25
CO2Et
CH2Cl2, Δ
100 %,>95% ds
PMBO
O
O
PMBO
TBS
38
O
TBS
(5R)-22
1. MgBr2.OEt2,
SMe2, CH2Cl2
RT (O/N), 84 %
2. Swern[O], 82 %
Wittig and H. W. E.
olefinations to install
the diene failed
5
CO2Et
CO2Et
TBSO
(2E,5R)-20
O
O
TBS
39
Scheme 6.
1. TiCl4, CH2Cl2, 0 °C, 5 min.,
(-)-sparteine, 20 min.
→ –78 °C
Bn
O
Bn
2. N-methyl-2-pyrrolidinone,
10 min.
S
S
S
N
N
3.
S
O
OH OPMB
, CH2Cl2, –78 °C
OPMB
77 %, 82 % ds
O
40
41
28
2,6-lutidine,
TBSOTf,
CH2Cl2, –78 °C
98 %
Bn
O
1. LiBH4, MeOH,
Et2O, 100 %
S
S
S
N
2. Swern[O], 96 %
OPMB
TBS
OPMB
TBS
O
O
O
(5S)-22
42
Scheme 7.

4856
J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
1. KHMDS, DME
–60 °C
1. MgBr2.OEt2, SMe2,
CH2Cl2, RT (O/N), 77 %
5
5
5
PT
2. Swern[O], 94%
S
O
O
OPMB 2.
TBS
TBSO
OPMB
TBSO
O
O2
24
I2, CDCl3,
RT, 94%
(5R)-32
(5S)-22
(E,E,5R)-31 : (Z,E,5R)-31, 1:1
(E,E,5R)-31
DME, –60 °C →
RT (O/N), 68%
CO2Et
Ph3P
N
N
N
N
PT=
25
CH2Cl2, Δ
H
H
H
OTBS
OTBS
65 %
5
+
CO2Et
H
TBSO
(2E,5R)-20
CO2Et
CO2Et
44
43
44:43 (79:21)
Scheme 8.
product from this double stereodifferentiating aldol coupling,
adduct 41, results from a matched reaction involving anti-
Felkin addition to aldehyde 28, the favoured face for addition
of a Z-enolate to an a-chiral aldehyde.13 The alcohol 41 was
protected as the TBS ether 4215 (98%) and the chiral auxiliary
cleaved, in quantitative yield, with LiBH429 to give the primary
alcohol. Subsequent oxidation under Swern conditions23
yielded aldehyde (5S)-22 in excellent yield (96%).
Again a two directional olefination approach analogous to
that described in Scheme 5 was proposed to generate the alter-
native linear triene with the 5R stereochemistry. Unfortunately
both Wittig16 and HWE30 olefination reactions were unsuccess-
ful at installing the diene moiety due to the susceptibility of the
C5 TBS ether, in this configuration, to undergo elimination. The
‘modified’ Julia olefination reaction31 of PT sulfone 24 with
aldehyde (5S)-22 proceeded in reasonable yield (68%) produc-
ing an inseparable mixture (1:1) of (E,E,5R)-31 and (Z,E,5R)-
31. In an identical method to that described in Scheme 5,
(Z,E,5R)-31 was isomerised with catalytic I219 to the thermody-
namically favoured (E,E,5R)-31. Following PMB ether cleav-
age22 and Swern oxidation23 aldehyde (5R)-32 was isolated
(66% yield, over three steps). The next step involved generation
of the dienophile moiety, which was attempted via both HWE
and Wittig olefinations. In this instance the HWE olefination24
was unsuccessful at installing the dienophile moiety and start-
ing materials were recovered. The Wittig olefination reaction
with ylide 2525 proceeded with high E-selectivity forming
triene (2E,5R)-20, which spontaneously cyclised under the re-
action conditions to give two cycloadducts 43 and 44 (21:79)
(Scheme 8).
Deprotection of IMDA product 36 with aqueous HF32 gave
alcohol 45 (84% yield) and subsequent Swern oxidation22
gave ketone 46 with the spiculoic acid stereochemistry.
The other cycloadducts (33e35, 37, 43 and 44) were similarly
deprotected with aqueous HF32 to give the corresponding alco-
hols (47e52) and subsequent Swern oxidation22 gave the
ketones (53e57), as depicted in Scheme 9.
3.2. Stereochemical assignment of the cycloadducts
Extensive 1D and 2D NMR studies enabled the stereochem-
ical assignment of the cyclic products. Following structural as-
signment, NOESYand ROESY correlations using the sterotriad
C4eC6, of known stereochemical orientation, enabled the con-
figuration of the stereocentres generated via the IMDA cycload-
dition reaction to be assigned. In each instance (except
cycloadducts 34 and 35, which were inseparable from the major
isomer 33) the stereochemistry of the cyclic products with the
TBS, OH and carbonyl groups in place were all analyzed in
order to confirm the stereochemical assignment. For cycload-
ducts 34 and 35, separation was achieved following silyl ether
cleavage and alcohol 48 and its corresponding ketone 54 were
thoroughly analysed. Alcohol 49, from 35 the smallest (5%)
component, was isolated in very small quantities and remained
impure after repeated attempts at purification.
Molecular modelling studies were performed to predict the
low energy conformations of each stereoisomer and in each
case the NOESY and ROESY correlations observed could be
explained considering the predicted low energy conformers.25
In general the cycloadducts with a trans-bridgehead were rel-
atively planar with the pseudo chair conformation of the cyclo-
hexene ring unable to ring flip. Conversely, the cycloadducts
with a cis-bridghead, which experience a bend in the bicyclic
core, were free to ring flip.
H
H
HF (40 % aq.)
CH3CN:CH2Cl2
OH
OTBS
Ph
Ph
Ph
84 %
H
H
CO2Et
CO2Et
45
36
D.-A. adduct
Alcohol
Ketone
Swern[O]
98 %
47 (51 %)
48 (51 %)
49 (51 %)
50 (76 %)
53 (71 %)
54 (96 %)
33
34
35
37
H
O
55
-
H
56 (50 %)
57 (69 %)
56 (98 %)
CO2Et
46
The NMR data for cycloadduct 36 is summarised in Table 1
and the assignments are based on extensive 2D NMR experi-
ments. The ROESY correlations, which were instrumental
in the stereochemical assignment of cycloadduct 36 are shown
51 (73 %)
52 (65 %)
43
44
Scheme 9.

J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
4857
Table 1
NMR data for cycloadduct 36
Table 2
ROESY correlations and stereochemical assignment of cycloadduct 36
17
16
CH3
H
8
2
H
H
7
OTBS
H
5
OTBS
12
10
15
12
3
3
4
Ph
H
H
H
H
O
H3C
CH3
CO2 Et
C
O
14
36
1
16
15
Carbon no.
13C NMR da,b
1H NMR d(m) J in Hza,b
17
1
175.3
49.6
47
d
d
CH3
H
H
2
OTBS
H
7
3
1.80 (dd) 11.2, 10.2
1.59e1.54 (m)
3.70 (dd) 6.6, 1.8
1.70 (dq) 12.0, 6.6
2.02 (ddddd) 11.2, 11.2, 2.4, 2.4, 2.4
5.99 (ddd) 10.2, 1.8, 1.8
5.54 (ddd) 10.2, 3.6, 3.0
3.31 (m)
10
3
Ph
4
44.3 or 44.2
82.9
40.4
H
H
3
15
H
O
CH3
5
H C
C
O
6
7
44.3 or 44.2
128
1He1H ROESYa
8
H no.
9
10
128.3
54.3
142
3
H4*, H7*, H16, ArH
H3*, H15, H16*
H6*, H16
4
11
12, 13, 14
d
5
129.6, 127.7, 126.7
26.1
7.24e7.11 (m)
1.34 (m)
0.86 (d) 7.2
6
H5*, H7*, H17*
H3*, H6*, H15, H17
H9*, H17
15
16
17
18
7
18.3 or 18.2
12.5
59.7
8
1.03 (d) 6.6
9
H8*, H10*, H17 (wk)
H9*, H15, ArH
H4, H7, H10
3.54 (dq) 10.8, 7.2 and 3.21 (dq)
10.8, 7.2
0.69 (t) 7.2
10
15
16
17
ArH
19
13.2
25.9
H3, H4*, H5
H6*, H7, H8, H9 (wk)
H3, H10
SiC(CH3)3
SiC(CH3)3
Si(CH3)A
Si(CH3)B
a
0.88 (s)
d
18.3 or 18.2
ꢁ4.3
0.03 (s)
0.02 (s)
* Indicates He1H COSY correlations.
1
ꢁ4.6
a
NMR spectrometer (600 MHz, CDCl3).
NMR spectrometer (600 MHz, CDCl3). Assignments were assisted by
1He13C HMBC, 1He13C HMQC, He1H COSY, 1He1H ROESY.
1
b
Chemical shifts in parts per million referenced to CHCl3 at 7.26 ppm and
to CDCl3 at 77.0 ppm.
3.3. Comparison of the isomers
in Table 2. The correlations involving the C4 stereocentre, of
known stereochemical orientation, enabled assignment of both
the C2 and C3 stereocentres. A correlation between the bridge-
head proton on C3 and the C16 protons (in red) indicated the
C3 configuration shown. Similarly, a correlation between the
C4 and C15 protons suggested the absolute stereochemistry
at C2, as shown. The relative relationship between these two
centres is consistent with the E-geometry of the dienophile
in the linear precursor. Moving around the ring system, the
C3 proton correlates to the aromatic protons while the C15
protons correlate to the C10 proton (in green), providing
supporting evidence for the absolute stereochemistry depicted
for C10. Finally, the stereochemical orientation of C7 was as-
signed based on the correlations between the C7 and both the
C10 and C17 protons (in purple). The E,E-diene geometry has
been conserved in the cycloadduct thus supporting this stereo-
chemical assignment. In addition the protons at the bridgehead
have a trans-relationship, suggested by the relatively large
coupling constant, Ja,b¼11.2 Hz, which is indicative of an
anti-periplanar orbital overlap.33
The linear precursor 20 was synthesised with both the
R and S configurations at the C5 stereocentre as proposed in
Scheme 3. In addition the dienophile at C2 was prepared in
both the E and Z geometries, in the linear precursor with
the 5S configuration. This provided the opportunity to examine
the effect of the orientation of the C5 stereocentre and the
dienophile geometry on the resulting IMDA transition states
(there are four diastereomeric alternative transition states for
each precursor as described in Fig. 2).
The effect of the dienophile geometry on the outcome of
the IMDA reaction can be seen by comparing cycloadducts
36 and 37, from linear precursor (2E,5S)-20, and cycloadducts
33 and 34, from linear precursor (2Z,5S)-20. Figure 3 illus-
trates the faces of reaction of the diene and dienophile and
the endo or exo orientation of the corresponding transition
state.
Notably both the major adducts, 36 and 33, are formed via
reaction at the same faces of the addends (i.e., the diene and
dienophile) producing cycloadducts differing only at the C2
stereocentre. This difference arises from the dienophile geom-
etry and results in two transition states, leading to cycload-
ducts 33 and 36, being exo and endo, respectively. Similarly
the two minor cycloadducts 34 and 37 are also formed through
reaction of the same faces of the addends. Again the orienta-
tion of the C2 stereocentre is opposite and the two transition
states, leading to 34 and 37, are endo and exo, respectively.
The stereochemical assignment of all the other cycload-
ducts and the corresponding alcohols and ketones was simi-
larly carried out. Tables of NMR data, including structural
assignments are available in Supplementary data for cycload-
ducts (33, 36, 37 and 43, 44), alcohols (45, 47, 48, 50e52) and
ketones (46, 53, 54, 56, 57).

4858
J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
H
H
of each addend undergoing reaction. These two compounds,
44 and 37, ultimately give the same ketone 56 (Scheme 9).
But the major adduct 36 from the 5S precursor and the minor
adduct 43 from the 5R precursor are generated via different
endo transition states with the opposite faces of each addend
participating in the reaction. These results suggest that the ori-
entation of the C5 stereocentre is of fundamental importance
in controlling the stereochemical outcome of the cycloaddition
reaction, dominating any inherent endo/exo selectivity of the
IMDA reaction.
+
OTBS
OTBS
(2E,5S)-20
Ph
Ph
H
CO2Et
H
CO2Et
36
37
Major (94 %)
Top diene/
bottom dienophile
Endo T.S.
Minor (6 %)
Bottom diene/
bottom dienophile
Exo T.S.
analogous T.S.'s
H
H
+
OTBS
OTBS
4. Conclusion; implications to the natural product
synthesis/biosynthesis
(2Z,5S)-20
Ph
Ph
H
H
CO2Et
CO2Et
33
34
In summary, a model system for the spiculoic acids was
synthesised in order to explore the stereoselectivity of the
intramolecular DielseAlder reaction required to generate the
spiculane skeleton. The thermally induced IMDA reaction of
each of the linear precursors proceeded in generally high yield
with moderate to good diastereoselectivity (>70% yield,
>79% ds).
Comparison of each of the cycloadducts to the natural
products reveals that cycloadduct 36, formed with high
diastereoselectivty (94%) from the (2E,5S)-20 linear precur-
sor, has stereochemistry matching the natural product at all
six stereocentres (Fig. 5). This suggests that the total synthesis
of the natural products may be achieved in high diastereose-
lectivity from a linear precursor with the C5 carbonyl masked
as the TBS ether in the S configuration. This is consistent with
the results of the IMDA reaction of the C5 benzyl ether
protected substrate 17 in Baldwin’s total synthesis of ent-
spiculoic acid A. Currently we are exploring the extension
of this methodology to the total synthesis of dinor-spiculoic
acid A (5).
Major (85 %)
Top diene/
Minor (10 %)
Bottom diene/
bottom dienophile
Exo T.S.
bottom dienophile
Endo T.S.
Figure 3.
This implies that the inherent endo/exo selectivity has little
control over the transition state geometry, instead the C4e
C6 stereotriad dictates the stereoselectivity.
The stereochemical outcome of the IMDA reaction of the
linear precursor (2E,5S)-20 compared to (2E,5R)-20 reveals
the effect of the configuration of the C5 stereocentre
(Fig. 4). The major cycloadduct 36 from (2E,5S)-20 and the
major cycloadduct 44 from (2E,5R)-20 are formed through
different transition states with formation of 36 by the reaction
of the top face of the diene and the bottom face of the dieno-
phile via an endo transition state whereas 44 is formed by
reaction of the bottom face of the diene and the bottom face
of the dienophile via an exo transition state.
Interestingly the major cycloadduct 44, from (2E,5R)-20,
and the minor cycloadduct 37, from (2E,5S)-20, proceed
through analogous exo transition states with the same faces
H
H
5
O
OTBS
H
H
H
H
OTBS
OTBS
+
CO2Et
CO2H
(2E,5S)-20
Ph
Ph
H
H
CO2Et
36
dinor-spiculoic acid A (5)
Figure 5.
CO2Et
36
37
Major (94 %)
Top diene/
Minor (6 %)
Bottom diene/
These results suggest that the IMDA reaction can occur
stereoselectively under non-enzymatic control and thus an
enzyme may not be necessary in the biosynthesis of the spicu-
loic acids. However, in the natural system the C5 carbon cen-
tre possesses a carbonyl functionality (or possibly a hydroxyl
group if oxidation occurs following cyclisation) not the C5
TBS ether as present in these systems. Thus the possible
involvement of a DielseAlderase in the biosynthesis cannot
be discarded. Investigation of cyclisation of the linear precur-
sors to the spiculoic acids possessing either a C5 carbonyl
or hydroxyl group would provide further information to sup-
port or refute the involvement of a DielseAlderase in the
biosynthesis.
bottom dienophile
Endo T.S.
bottom dienophile
Exo T.S.
analogous
T.S.'s
H
H
+
OTBS
OTBS
(2E,5R)-20
Ph
Ph
H
H
CO2Et
CO2Et
44
43
Major (79 %)
Minor (21 %)
Bottom diene/
bottom dienophile
Exo T.S.
Bottom diene/
top dienophile
Endo T.S.
Figure 4.

J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
4859
5. Experimental procedures
Me2NEt (0.24 g, 0.35 mL, 3.22 mmol), dropwise, followed
by ketone (S)-27 (0.36 g, 1.75 mmol) in Et2O (7 mL), via
a cannula. The resulting solution was allowed to warm slowly
to 0 ꢀC and stirred for 2 h. The solution was again cooled to
ꢁ78 ꢀC and aldehyde 28 (0.55 g, 2.64 mmol) added in Et2O
(3 mL) via a cannula. The resulting solution was stirred at
ꢁ78 ꢀC for 2 h before placing overnight in the freezer. The re-
action was warmed to 0 ꢀC for 30 min before quenching with
MeOH (7 mL), pH 7 buffer (7 mL) and H2O2 (30% aq, 7 mL).
The solution was stirred for a further 1 h at room temperature.
The product was extracted with CH2Cl2 (3ꢂ75 mL) and the
combined extracts were washed with brine (75 mL), dried
(MgSO4) and concentrated in vacuo. Purification by column
chromatography (5% Et2O/CH2Cl2, Rf¼0.30) yielded 0.69 g
(94% yield, 90% ds) of adduct 29 as a white solid (mp 74e
76 ꢀC).
1H NMR (300 MHz, CDCl3) d 8.08 (2H, d, J¼6.9 Hz,
ArH); 7.60e7.55 (1H, m, ArH); 7.45 (2H, m, ArH); 7.21
(2H, d, J¼8.7 Hz, ArH); 6.87 (2H, d, J¼8.7 Hz, ArH); 5.43
(1H, q, J¼6.9 Hz, BzOCH(CH3)); 4.44 (1H, d, J¼11.4 Hz,
CHAHBAr); 4.38 (1H, d, J¼11.4 Hz, CHAHBAr); 4.07
(1H, dd, J¼9.3, 2.1 Hz, CH(OH)); 3.80 (3H, s, OCH3);
3.54 (1H, dd, J¼9.0, 4.2 Hz, CHAHBOPMB); 3.49 (1H,
dd, J¼9.0, 4.2 Hz, CHAHBOPMB); 3.00 (1H, dq, J¼9.3,
7.2 Hz, C(]O)CH(CH3)CH(OH)); 1.91e1.84 (1H, m,
CH(OH)CH(CH3)CH(OPMB)); 1.53 (3H, d, J¼6.9 Hz,
BzOCH(CH3)); 1.21 (3H, d, J¼7.2 Hz, C(]O)CH(CH3)-
CH(OH)); 0.95 (3H, d, J¼6.9 Hz, CH(OH)CH(CH3)-
CH2(OPMB)). 13C NMR (75.5 MHz, CDCl3) d 211.1; 165.9;
159.2; 133.2; 130.0; 129.8; 129.6; 129.2; 128.4; 113.8; 75.1;
74.6; 73.0; 55.2; 45.7; 34.4; 15.5; 13.8; 9.5 (one signal miss-
ing). IR (film, cmꢁ1) 3512; 2968; 2938; 1718; 1613; 1514;
1453; 1301; 1269; 1250; 1116; 1072; 1034; 1006; 713. [a]D20
þ11.3 (c 0.7, CHCl3). HRMS (ESI) C24H30O6Naþ requires
437.1935, found 437.1936. LRGCMS 208 (3.7%); 137
(74%); 121 (100%); 109 (8.9%); 91 (3.7%); 77 (8.9%).
5.1. General details
All reactions were carried out under an atmosphere of nitro-
gen in oven dried glassware. Dichloromethane, triethylamine
and dimethylethylamine were distilled over calcium hydride;
and tetrahydrofuran and ether were distilled over sodium and
benzophenone. Analytical thin layer chromatography was per-
formed on Merck Keiselgel 60F254 silica aluminium backed
sheets and were developed in potassium permanganate, anisal-
dehyde or monitoring by a UV lamp. Column chromatography
was performed on Merck Keiselgel (particle size: 0.04e
0.063 mm) 230e400 mesh silica. All optical rotations were
measured on a PolA AR 21 polarimeter referenced to the sodium
D line (589 nm) at 20 ꢀC, using the spectroscopic grade solvents
specified and at the concentrations (c, g/100 mL) indicated.
Electron Impact (EI) mass spectra and Electrospray Ionisation
(ESI) mass spectrawere recorded using a Bruker 4.7T FTMS Ul-
tra High Resolution spectrometer. ESIMS/MS were recorded on
a Micromass Quattro micro spectrometer. High resolution mass
spectral data are presented as molecular formula, molecular ion
(Mþ, Naþ or Kþ), calculated and measured masses to 4 signifi-
cant figures. Low resolution mass spectral data are reported as
mass to charge ratio (m/z) with intensity relative to the base
peak indicated. LCMS were recorded on a Micromass Quattro
micro, tandem quadrupole mass spectrometer with positive ion
electrospray ionisation. Mass spectral data are presented as the
molecular formula, molecular ion and calculated and measured
masses to 3 significant figures. Infrared spectra were recorded on
a BIO-RAD FTS-40A Fourier Transform spectrophotometer
with the absorptions recorded in wavenumbers (cmꢁ1). Samples
were analysed as thin films on NaCl discs. UVevis spectra were
recorded using a Varian Cary 50 Scan spectrophotometer using
the spectroscopic grade solvents specified. Melting points were
recorded on a Reichert hot-stage apparatus and are uncorrected.
1H NMR spectra were recorded at either 200, 300 or
600 MHz on a Varian Mercury, Varian Gemini, Varian Unity
Inova or Bruker Avance II 600 Spectrometer. 13C NMR spectra
were recorded at either 50, 75 or 151 MHz on a Varian Mercury,
Varian Gemini, Varian Unity Inova or Bruker Avance II 600
Spectrometer. CDCl3 was used as the solvent and internal
lock, and referenced to CHCl3 (d 7.26) for 1H NMR and
CDCl3 (d 77) for 13C NMR. Chemical shift vales are reported
in parts per million, coupling constants are reported in hertz.
Abbreviations used; Ar¼aromatic, apt¼apparent, br¼broad,
s¼singlet, d¼doublet, t¼triplet, q¼quartet, qn¼quintet,
m¼multiplet. Structural and stereochemical assignments were
made using 1He1H COSY, 1He1H TOCSY, 1He13C HETCOR,
1He13C HMQC, 1He13C HMBC, 1He1H NOESY and 1He1H
ROESY spectra. Details of 2D NMR experiments are included
in Supplementary data.
5.1.2. (2S,4R,5R,6S)-2-Benzoyloxy-5-(tert-butyldimethyl-
silyloxy)-7-(40-methoxybenzyloxy)-4,6-dimethylheptane-
3-one (30)
To a solution of alcohol 29 (6.02 g, 14.5 mmol) in CH2Cl2
(145 mL) at ꢁ78 ꢀC was added 2,6-lutidine (3.4 mL, 29 mmol)
followed immediately by TBSOTf (4.9 mL, 22 mmol). The
resulting solution was stirred for 1 h at ꢁ78 ꢀC before warming
to ꢁ50 ꢀC for a further hour. TLC analysis showed that the
reaction was almost complete so the solution was warmed to
0 ꢀC before quenching. The reaction mixture was poured onto
NaHCO3 (satd aq, 200 mL) and extracted with CH2Cl2
(3ꢂ200 mL). The combined extracts were dried (MgSO4) and
concentrated in vacuo. Purification by column chromatography
(100% CH2Cl2/5% Et2O/CH2Cl2, Rf (CH2Cl2)¼0.38) yielded
7.37 g (96%) of silyl ether 30 as a clear colourless oil.
1H NMR (300 MHz, CDCl3) d 8.08 (2H, m, ArH); 7.59
(1H, m, ArH); 7.46 (2H, m, ArH); 7.23 (2H, m, ArH); 6.86
(2H, m, ArH); 5.48 (1H, q, J¼6.9 Hz, CH3(BzO)CH(C]O));
4.44 (1H, d, J¼11.4 Hz, OCHAHBAr); 4.36 (1H, d,
J¼11.4 Hz, OCHAHBAr); 4.21 (1H, dd, J¼8.7, 1.5 Hz,
5.1.1. (2S,4R,5R,6S)-2-Benzoyloxy-5-hydroxy-7-(40-methoxy-
benzyloxy)-4,6-dimethylheptane-3-one (29)
To a solution of dicyclohexylboron chloride (0.57 g,
0.58 mL, 2.69 mmol) in Et2O (7 mL) at ꢁ78 ꢀC was added

4860
J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
CH(OTBS)); 3.80 (3H, s, OCH3); 3.39 (1H, dd, J¼9.0, 7.2 Hz,
CHAHBOPMB); 3.24 (1H, dd, J¼9.0, 6.9 Hz, CHAHBOPMB);
3.10 (1H, dq, J¼8.1, 7.2 Hz, C(]O)CH(CH3)CH(OTBS));
1.93 (1H, m, CH(OTBS)CH(CH3)CH2OPMB); 1.51 (3H,
d, J¼6.9 Hz, CH3CH(OBz)C(]O)); 1.11 (3H, d, J¼7.2 Hz,
C(]O)CH(CH3)CH(OTBS)); 0.89 (3H, d, J¼6.9 Hz,
CH(OTBS)CH(CH3)CH2OPMB); 0.83 (9H, s, SiC(CH3)3);
0.02 (3H, s, Si(CH3)A(CH3)B); ꢁ0.09 (3H, s, Si(CH3)A(CH3)B).
13C NMR (75.5 MHz, CDCl3) d 209.0; 165.6; 159.1; 133.2;
130.6; 129.8; 128.4; 113.7; 75.0; 72.9; 72.8; 72.5; 55.3; 46.9;
36.1; 26.2; 25.6; 18.6; 15.6; 14.0; 10.5; ꢁ3.6; ꢁ5.1. IR (film,
cmꢁ1) 2954; 2928; 2855; 1721; 1613; 1513; 1462; 1452;
1250; 1115; 1039; 833; 711. [a]2D0 ꢁ6.5 (c 0.77, CHCl3).
HRMS (ESI) C30H44O6NaSiþ requires 551.2799, found
551.2797. LREIMS 241 (4.2%); 207 (4.2%); 179 (6.7%); 137
(11%); 121 (100%); 105 (26%); 85 (15%); 71 (23%); 57
(34%); 55 (22%).
concentrated in vacuo. The product was purified by column
chromatography (30% mixed hexanes/CH2Cl2, Rf¼0.39) yield-
ing 0.37 g (93%) of aldehyde (5R)-22 as a clear, colourless oil.
1H NMR (300 MHz, CDCl3) d 9.70 (1H, d, J¼2.7 Hz,
CH(O)); 7.24 (2H, d, J¼8.7 Hz, ArH); 6.88 (2H, d, J¼8.7 Hz,
ArH); 4.37 (2H, s, CH2Ar); 4.05 (1H, dd, J¼5.7,
4.2 Hz, CH(OTBS)); 3.81 (3H, s, OCH3); 3.35 (1H, dd,
J¼9.0, 6.9 Hz, CHAHB(OPMB)); 3.26 (1H, dd, J¼9.0, 5.7 Hz,
CHAHB(OPMB)); 2.61e2.51 (1H, m, CH(O)CH(CH3));
1.99e1.91 (1H, m, CH(OTBS)CH(CH3)CH2(OPMB)); 1.07
(3H, d, J¼6.9 Hz, CH(O)CH(CH3)); 0.93 (3H, d, J¼6.6 Hz,
CH(OTBS)CH(CH3)CH2(OPMB)); 0.87 (9H, s, Si(C(CH3)3));
0.05 (3H, s, Si(CH3)A(CH3)B); 0.04 (3H, s, Si(CH3)A(CH3)B).
13C NMR (75.5 MHz, CDCl3) d 204.8; 159.2; 130.4; 129.2;
113.7; 74.1; 72.5; 72.0; 55.3; 50.9; 37.7; 25.9; 18.3; 12.2;
11.5; ꢁ4.2; ꢁ4.3. IR (film, cmꢁ1) 2956; 2931; 2884; 2857;
1725; 1613; 1514; 1463; 1361; 1249; 1173; 1088; 1037; 837;
775. [a]2D0 ꢁ19.9 (c 1.0, CHCl3). HRMS (ESI) C21H36O4NaSi
requires 403.2275, found 403.2286. LRGCMS 137 (2.2%);
122 (9.6%); 121 (100%); 116 (2.2%); 91 (0.7%); 75 (2.9%);
73 (3.7%); 59 (2.2%).
5.1.3. (2S,3R/S,4R,5R,6S)-5-(tert-Butyldimethylsilyloxy)-7-
(40-methoxybenzyloxy)-4,6-dimethylheptan-2,3-diol (58)
To a cooled (ꢁ78 ꢀC) solution of benzoate 30 (5.71 g,
10.8 mmol) in THF (130 mL) was added a solution of
LiBH4 (2 M in THF, 108 mL, 0.216 mol). The reaction mix-
ture was placed in an ice/H2O bath for 10 min before warming
slowly to room temperature and the stirring continued over-
night. The solution was cooled to 0 ꢀC for 10 min before
quenching with H2O (200 mL). The mixture was extracted
with Et2O (4ꢂ200 mL), washed with brine (200 mL), dried
(MgSO4) and concentrated in vacuo. The product was purified
by column chromatography (30% mixed hexanes/Et2O,
Rf¼0.29) yielding 4.10 g (89%) of an inseperable mixture of
isomers of diol 58 (ratio w2:1) as a clear colourless oil.
1H NMR (300 MHz, CDCl3) d 7.26e7.22 (2H, m, ArH);
6.91e6.86 (2H, m, ArH); 4.44 (2H, m, OCH2Ar); 3.99 (1H,
dd, J¼4.5, 2.7 Hz), 3.81e3.25 (4H, m, CH(OH), CH(OH),
CH(OTBS), CH2(OPMB)); 3.81 (3H, s, OCH3); 2.47 (2H, br s,
OH, OH);2.10e1.95 and 1.70e1.63 (2H, m, CH(OH)CH(CH3)-
CH(OTBS), CH(OTBS)CH(CH3)CH2(OPMB)); 1.15e0.79
(18H, m, CH3CH(OH), CH(OH)CH(CH3)CH(OTBS),
CH(OTBS)CH(CH3)CH2(OPMB), SiC(CH3)3); 0.12e0.00
(6H, m, Si(CH3)2). 13C NMR (75.5 MHz, CDCl3) d showed a
complex mixture of isomers. IR (film, cmꢁ1) 3449; 2957;
2932; 2886; 2858; 1613; 1514; 1463; 1249; 1099; 1061; 1037;
837. HRMS (ESI) C23H42O5SiNaþ requires 449.2694, found
449.2694. LREIMS 323 (2.5%); 243 (2.5%); 187 (4.2%); 173
(2.5%); 137 (5.1%); 122 (14%); 121 (100%); 115 (6.7%); 91
(2.5%); 75 (10%); 73 (11%).
5.1.5. (2S,3S,4S,5E,7E)-3-(tert-Butyldimethylsilyloxy)-1-(40-
methoxybenzyloxy)-2,4-dimethyl-8-phenylocta-5,7-diene
((E,E,5S)-31)
To a solution of triphenylcinnamylphosphonium chloride
(2.48 g, 5.99 mmol) and aldehyde (5R)-22 (0.455 g,
1.20 mmol) in EtOH (2 mL) was added a solution of NaOEt
(1 M, 30 mL) in EtOH. The solution immediately turned red in-
dicating formation of the ylide. The reaction mixture was
stirred at room temperature for a few days until TLC analysis
showed consumption of starting material. The reaction was
quenched by the addition of H2O (25 mL) and the EtOH was
removed in vacuo. The product was extracted with Et2O
(3ꢂ50 mL) and the combined extracts were washed with brine
(50 mL), dried (MgSO4) and concentrated in vacuo. The prod-
uct was purified by column chromatography (50% CH2Cl2/
mixed hexanes, Rf¼0.44) yielding 0.551 g (96%) of a clear col-
ourless oil as a mixture of (E,E)-31 and (Z,E)-31 isomers. To
a solution of mixture of isomers (Z,E)-31 and (E,E)-31 in
CDCl3 was added a few crystals of I2 and the reaction moni-
1
tored by H NMR to see complete conversion of (Z,E)-31 to
(E,E)-31 isomers. The reaction mixture was diluted with
CH2Cl2 (20 mL) and washed with sodium metabisulfite (satd
aq, 10 mL). The aqueous phase was extracted with CH2Cl2
(2ꢂ20 mL) and the combined extracts were dried (MgSO4)
and concentrated in vacuo. The product was purified by column
chromatography (50% CH2Cl2/mixed hexanes, Rf¼0.44) yield-
ing 0.461 g (84%) of (E,E,5S)-31 as a clear colourless oil.
1H NMR (300 MHz, CDCl3) d 7.40e7.20 and 6.89e6.85
(9H, m, ArH); 6.74 (1H, dd, J¼15.9, 10.5 Hz, ArCH]CH);
6.43 (1H, dd, J¼15.9 Hz, ArCH); 6.15 (1H, dd, J¼15.3,
10.5 Hz, ArCH]CHCH]CH); 5.80 (1H, dd, J¼15.3, 8.4 Hz,
ArCH]CHCH]CH); 4.43 (1H, d, J¼11.4 Hz, CHAHBAr);
4.37 (1H, d, J¼11.4 Hz, CHAHBAr); 3.78 (3H, s, OCH3);
3.70e3.67 (1H, m, CH(OTBS)); 3.38 (1H, dd, J¼9.0, 6.6 Hz,
CHAHBOPMB); 3.21 (1H, dd, J¼9.0, 6.9 Hz, CHAHBOPMB);
5.1.4. (2R,3R,4S)-3-(tert-Butyldimethylsilyloxy)-5-(40-meth-
oxybenzyloxy)-2,4-dimethylpentanal ((5R)-22)
To a stirred solution of diols 58 (1.18 g, 2.77 mmol) in meth-
anol (27.7 mL) and H2O (13.9 mL) at room temperature was
added NaIO4 (3.56 g, 8.08 mmol) and the resulting suspension
stirred for 15 min (after this time TLC analysis showed con-
sumption of SM). The reaction mixture was diluted with H2O
(100 mL) and extracted with Et2O (3ꢂ100 mL). The combined
extracts were washed with brine (50 mL), dried (MgSO4) and

J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
4861
2.49e2.40 (1H, m, ]CHCH(CH3)CH(OTBS)); 2.00e1.91
(1H, m, CH(OTBS)CH(CH3)CH2OPMB); 1.04 (3H, d,
J¼6.9 Hz, ]CHCH(CH3)); 0.92e0.89 (12H, m, SiC(CH3)3,
CH(OTBS)CH(CH3)CH2OPMB); 0.032 (3H, s, Si(CH3)A-
(CH3)B); 0.025 (3H, s, Si(CH3)A(CH3)B). 13C NMR
(75.5 MHz, CDCl3) d 159.1; 138.9; 137.7; 130.2; 130.0; 129.6;
129.2; 129.1; 128.5; 127.1; 126.1; 113.7; 76.2; 73.3; 72.5;
55.2; 42.1; 37.3; 26.1; 18.4; 17.7; 12.3; ꢁ3.7; ꢁ4.1. IR (film,
cmꢁ1) 3024; 2957; 2930; 2856; 1613; 1514; 1471; 1463; 1362;
1249; 1172; 1086; 1057; 1037; 990; 836; 773; 746; 691. [a]D20
ꢁ20.5 (c 0.1, CHCl3). HRMS (ESI) C30H44NaO3Siþ requires
503.2952, found 503.2953. LREIMS 323 (4.3%); 187 (11%);
121 (100%); 85 (26%); 83 (58%); 57 (24%); 55 (16%).
warming to 0 ꢀC and stirring for 30 min. The reaction mixture
was quenched by addition of NaHSO4 (1 M, 10 mL),
and the product extracted with Et2O (3ꢂ10 mL). The com-
bined extracts were concentrated in vacuo. The product was
taken up in Et2O (30 mL) and washed with NaHSO4 (1 M,
10 mL), H2O (10 mL), NaHCO3 (satd aq, 10 mL) and brine
(10 mL), dried (MgSO4) and concentrated in vacuo. The prod-
uct was purified by column chromatography (50% mixed hex-
anes/CH2Cl2, Rf¼0.53) yielding 28.4 mg (94%) of aldehyde
(5S)-32 as a clear colourless oil.
1H NMR (300 MHz, CDCl3) d 9.76 (1H, d, J¼1.2 Hz,
CHO); 7.40e7.18 (5H, m, ArH); 6.73 (1H, dd, J¼15.6,
10.2 Hz, ArCH]CH); 6.46 (1H, d, J¼15.6 Hz, ArCH); 6.17
(1H, dd, J¼15.3, 10.5 Hz, ArCH]CHCH); 5.73 (1H, dd,
J¼15.3, 8.7 Hz, ArCH]CHCH]CH); 4.03 (1H, dd, J¼4.5,
4.5 Hz, CH(OTBS)); 2.57e2.46 (2H, m, CH(CH3)CH(OTBS)-
5.1.6. (2S,3S,4S,5E,7E)-3-(tert-Butyldimethylsilyloxy)-2,4-
dimethyl-8-phenylocta-5,7-diene-1-ol (59)
To a solution of PMB ether (E,E,5S)-31 (0.106 g,
0.22 mmol) in dry CH2Cl2 (3.7 mL) at room temperature were
added Me2S (164 mL, 2.2 mmol) and powdered MgBr2$OEt2
(0.170 g, 0.66 mmol). The mixture was stirred at room temper-
ature overnight after which time TLC analysis showed
consumption of the SM. The reaction was quenched by the ad-
dition of NH4Cl (satd aq, 10 mL) and the product extracted with
CH2Cl2 (3ꢂ15 mL). The combined extracts were washed with
brine (15 mL), dried (MgSO4) and concentrated in vacuo. Puri-
fication by column chromatography (30% mixed hexanes/
CH2Cl2, Rf¼0.27) yielded 0.061 g (77%) of alcohol 59 as a clear
colourless oil.
1H NMR (300 MHz, CDCl3) d 7.40e7.18 (5H, m, ArH); 6.67
(1H, dd, J¼15.6, 10.2 Hz, ArCH]CH);6.45(1H, d, J¼15.6 Hz,
ArCH); 6.20 (1H, dd, J¼15.3, 10.2 Hz, ArCH]CHCH); 5.87
(1H, dd, J¼15.3, 7.8 Hz, ArCH]CHCH]CH); 3.72e3.58
(2H, m, CHAHBOH, CH(OTBS)); 3.47 (1H, dd, J¼10.5,
5.7 Hz, CHAHBOH); 2.59e2.46 (1H, m, ]CHCH(CH3));
2.00e1.87 (1H, m, CH(OTBS)CH(CH3)CH2OH); 1.70 (1H, br
s, OH); 1.07 (3H, d, J¼6.9 Hz, ]CHCH(CH3)); 0.93e0.89
(12H, m, SiC(CH3)3, CH(OH)CH(CH3)); 0.09 (3H, s, Si-
(CH3)A(CH3)B); 0.07 (3H, s, Si(CH3)A(CH3)B). 13C NMR
(75 MHz, CDCl3) d 138.2; 137.6; 130.5; 130.3; 129.5; 128.5;
127.1; 126.2; 77.3; 65.9; 41.1; 39.8; 26.1; 18.4; 16.6; 12.2;
ꢁ3.9; ꢁ4.1. IR (film, cmꢁ1) 3400; 3023; 2958; 2929; 2856;
1472; 1461; 1251; 1029; 989; 858; 836; 773; 745; 691. [a]D20
ꢁ10.2 (c 0.1, CHCl3). HRMS (ESI) C22H36NaO2Siþ requires
383.2377, found 383.2375. LREIMS 259 (1.7%); 203 (11%);
185 (8.5%); 173 (8.5%); 157 (77%); 145 (100%); 131 (15%);
115 (38%); 111 (26%); 85 (35%); 75 (100%); 55 (21%).
CH(CH3)C(]O),
CH(CH3)CH(OTBS)CH(CH3)C(]O));
1.11 (3H, d, J¼6.9 Hz, C(]O)CH(CH3) or CH(CH3)CH]);
1.09 (3H, d, J¼6.9 Hz, C(]O)CH(CH3) or CH(CH3)CH]);
0.91 (9H, s, SiC(CH3)3); 0.09 (3H, s, Si(CH3)A(CH3)B); 0.05
(3H, s, Si(CH3)A(CH3)B). 13C NMR (75.5 Hz, CDCl3)
d 204.6; 137.4; 136.0; 132.0; 131.3; 128.9; 128.5; 127.3;
126.3; 75.8; 51.0; 41.5; 25.9; 18.2; 17.8; 9.4; ꢁ4.1; ꢁ4.2. IR
(film, cmꢁ1) 2932; 2855; 1724; 1653; 1559; 1472; 1257;
1078; 1031; 991; 837; 776; 747; 692. [a]2D0 ꢁ71.6 (c 1.2,
CHCl3). HRMS (ESI) C22H34NaO2Siþ requires 381.2220,
found 381.2222. LREIMS 301 (4.3%); 201 (31%); 173
(31%); 145 (17%); 115 (59%); 85 (40%); 83 (44%); 75
(44%); 73 (100%); 59 (21%).
5.1.8. (2E/Z,4S,5S,6S,7E,9E)-5-(tert-Butyldimethylsilyloxy)-
2,4,6-trimethyl-10-phenyldeca-2,7,9-trieneoic acid ethyl
esters ((2Z,5S)-20 and (2E,5S)-20)
To a solution of NaH (washed X4 and dried under N2)
(93 mg, 3.83 mmol) in THF (5.8 mL) at 0 ꢀC was added the
phosphonate 26 (0.80 mL, 3.7 mmol), dropwise. The solution
was stirred at room temperature for 1 h before cooling to 0 ꢀC
and addition of aldehyde (5S)-32 (0.42 g, 1.17 mmol). The
solution was warmed slowly to room temperature and after
30 min no further reaction occurred so the reaction was
quenched by pouring on to NH4Cl (satd aq, 30 mL). The prod-
uct was extracted with Et2O (3ꢂ30 mL) and the combined ex-
tracts were washed with brine (40 mL), dried (MgSO4) and
concentrated in vacuo. The product was purified by column
chromatography (40% CH2Cl2/mixed hexanes, Rf (2E)¼0.41,
Rf (2Z)¼0.3) to give 120 mg (23%) of (2Z,5S)-20 and
373 mg (72%) of (2E,5S)-20 isomer. The (2E,5S)-20 isomer
spontaneously undergoes a [4pþ2p] cycloaddition reaction
and was therefore not characterised.
5.1.7. (2R,3S,4S,5E,7E)-3-(tert-Butyldimethylsilyloxy)-2,4-
dimethyl-8-phenylocta-5,7-dienal ((5S)-32)
Oxalyl chloride (126 mL, 0.25 mol) was added dropwise to
a solution of DMSO (36 mL, 0.50 mmol) in CH2Cl2 (720 mL)
at ꢁ78 ꢀC. The resulting solution was stirred at ꢁ78 ꢀC for
30 min before dropwise addition of a solution of alcohol 59
(0.031 g, 0.085 mmol) in CH2Cl2 (0.25 mL, wash 2ꢂ0.25 mL)
via a cannula. The resulting mixture was stirred for 45 min at
ꢁ78 ꢀC. Et3N (140 mL, 1.01 mmol) was added dropwise over
several minutes and stirred at ꢁ78 ꢀC for 30 min before
Compound (2Z,5S)-20: 1H NMR (300 MHz, CDCl3)
d 7.39e7.17 (5H, m, ArH); 6.73 (1H, dd, J¼15.6, 10.2 Hz,
ArCH]CH); 6.42 (1H, d, J¼15.6 Hz, ArCH); 6.10 (1H, dd,
J¼15.3, 10.2 Hz, ArCH]CHCH); 5.82e5.71 (2H, m,
ArCH]CHCH]CH, CH]C(CH3)CO2Et); 4.24e4.10 (2H,
m, CO2CH2); 3.52e3.42 (1H, m, CH(OTBS)); 3.38e3.27
(1H, m, CH(OTBS)CH(CH3)CH]); 2.44e2.34 (1H, m, CH]
CHCH(CH3)); 1.89 (3H, d, J¼1.5 Hz, CH]C(CH3)CO2Et);

4862
J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
1.27 (3H, t, J¼7.2 Hz, CO2CH2CH3); 1.05 (3H, d, J¼6.9 Hz,
]CHCH(CH3)CH(OTBS)); 0.99 (3H, d, J¼6.6 Hz, CH(OTBS)-
CH(CH3)CH]); 0.92 (9H, s, SiC(CH3)3); 0.04 (3H, s, Si-
(CH3)A(CH3)B); 0.03 (3H, s, Si(CH3)A(CH3)B). 13C NMR
(75.5 MHz, CDCl3) d 168.1; 146.1; 138.3; 130.7; 130.3; 130.2;
129.6; 128.5; 127.7; 127.0; 126.1; 79.9; 60.1; 42.5; 37.4;
time the product was concentrated in vacuo and the product
purified by column chromatography (50% CH2Cl2/mixed hex-
anes, Rf¼0.52 and 0.45) yielding two steroisomers, cycload-
duct 37 (5.1 mg, 4.3% yield) and cycloadduct 36 (95 mg,
84% yield, 94% ds) as clear colourless oils.
Compound 36: data is identical to the cycloadduct from the
Wittig olefination reaction above.
26.1; 20.9; 18.4; 17.3; 15.9; 14.3; ꢁ3.5; ꢁ3.8. IR (film, cmꢁ1
)
3025; 2960; 2928; 2857; 1716; 1253; 1219; 1092; 1030; 836;
773; 691; 667. [a]2D0 þ58.3 (c 1.0, CHCl3). HRMS (ESI)
C27H42NaO3Siþ requires 465.2795, found 465.2800. LREIMS
385 (57%); 339 (9.6%); 310 (14%); 285 (26%); 239 (33%); 237
(73%); 221 (16%); 195 (31%); 181 (1%); 157 (26%); 153
(15%); 129 (19%); 115 (24%); 103 (19%); 91 (40%); 84
(74%); 75 (94%); 73 (100%); 57 (23%); 51 (34%).
Compound 37: 1H NMR (600 MHz, C6D6) d 7.29e7.10 (5H,
m, ArH); 5.88 (1H, ddd, J¼9.9, 2.8, 2.8 Hz, ]CHCHAr); 5.83
(1H, ddd, J¼9.9, 2.8, 2.1 Hz, PhCHCH]CH); 4.08e4.07 (1H,
m, CHPh); 3.97 (1H, qd, J¼7.2, 6.8 Hz, OCHAHBCH3); 3.94
(1H, dq, J¼10.8, 7.2 Hz, OCHAHBCH3); 3.52 (1H, dd,
J¼3.2, 3.2 Hz, CHOTBS); 2.77 (1H, dd, J¼10.3, 7.4 Hz,
EtO2CC(CH3)CHCH(CH3)); 2.64 (1H, ddddd, J¼10.3, 10.3,
3.2, 3.2, 3.2 Hz, CH]CHCH); 1.95 (1H, qdd, J¼7.0, 4.3,
3.2 Hz, Et2OC(CH3)CHCH(CH3)); 1.50 (1H, dqd, J¼6.6, 6.6,
3.2 Hz, CH]CHCHCH(CH3)); 1.13 (3H, s, Et2OCC(CH3));
1.02 (3H, d, J¼7.0 Hz, CH]CHCHCH(CH3)); 1.01 (9H, s,
SiC(CH3)3); 0.96 (3H, d, J¼6.6 Hz, CH]CHCHCH(CH3));
0.92 (3H, t, J¼7.2 Hz, CO2CH2CH3); 0.0349 (3H, s, Si-
(CH3)A(CH3)B); 0.0347 (3H, s, Si(CH3)A(CH3)B). 13C NMR
(150 MHz, CDCl3) d 176.5; 142.5; 130.1; 129.8; 129.5;
128.3; 127.0; 79.7; 60.3; 50.9; 50.2; 48.8; 44.6; 43.7; 40.1;
26.3; 18.6; 16.1; 14.2; 13.4; 12.9; ꢁ3.8; ꢁ3.9. IR (film,
cmꢁ1) 2956; 2928; 1712; 1462; 1257; 1160; 1096; 1061;
1028; 862; 834; 773. [a]2D0 þ11 (c 0.45, CHCl3).
5.1.9. (1S,2S,3S,3aS,4R,5R,7aR)-2-(tert-Butyldimethylsilyl-
oxy)-1,3,4-trimethyl-5-phenyl-2,3,3a,4,5,7a-hexahydro-1H-
indene-4-carboxylic acid ethyl ester (36)
A solution of aldehyde 32 (96 mg, 0.27 mmol) and ylide 25
(116 mg, 0.32 mmol) in CH2Cl2 (1.8 mL) was heated under
reflux for 6 days. TLC analysis of the reaction mixture failed
to reveal anything about the reaction progress as the starting
material and product had similar Rf values. The solvent was
removed in vacuo and the product was triturated with mixed
hexanes to remove the triphenylphosphine oxide. Purification
by column chromatography (50% CH2Cl2/mixed hexanes,
Rf¼0.45) yielded 47 mg (40%) of the IMDA cycloadduct 36
and some recovered starting material.
1H NMR (600 MHz, CDCl3) d 7.24e7.11 (5H, m, ArH); 5.99
(1H, dt, J¼10.2, 1.8 Hz, PhCHCH]CH); 5.54 (1H, ddd,
J¼10.2, 3.6, 3.0 Hz, PhCHCH); 3.70 (1H, dd, J¼6.6, 1.8 Hz,
CH(OTBS)); 3.54 (1H, dq, J¼10.8, 7.2 Hz, CO2CHAHB); 3.31
(1H, m, PhCH); 3.21 (1H, dq, J¼10.8, 7.2 Hz, CO2CHAHB);
2.04e1.99 (1H, m, CH]CHCH); 1.80 (1H, dd, J¼11.2,
10.2 Hz, EtO2CC(CH3)CHCH(CH3)); 1.70 (1H, ddd, J¼12.0,
6.6, 6.6 Hz, CH]CHCHCH(CH3)); 1.59e1.54 (1H, m,
Et2OC(CH3)CHCH(CH3)); 1.34 (3H, s, Et2OCC(CH3)); 1.03
(3H, d, J¼6.6 Hz, CH]CHCHCH(CH3)); 0.88 (9H, s,
SiC(CH3)3); 0.86 (3H, d, J¼7.2 Hz, Et2OC(CH3)CHCH(CH3));
0.69 (3H, t, J¼7.2 Hz, CO2CH2CH3); 0.03 (3H, s, Si(CH3)A-
(CH3)B); 0.02 (3H, s, Si(CH3)A(CH3)B). 13C NMR (150 MHz,
CDCl3) d 175.3; 142.0; 129.6; 128.3; 128.0; 127.7; 126.7;
82.9; 59.7; 54.3; 49.6; 47.0; 44.3; 44.2; 40.4; 26.1; 25.9; 18.3;
18.2; 13.2; 12.5; ꢁ4.3; ꢁ4.6. IR (film, cmꢁ1) 3026; 2954;
2929; 2885; 2856; 1720; 1473; 1460; 1256; 1092; 1060; 1028;
834; 773; 701; 669. HRMS (ESI) C27H42O3Siþ requires
443.2976, found 443.2979. LREIMS 385 (22%); 310 (11%);
285 (62%); 237 (35%); 235 (22%); 206 (23%); 195 (16%);
181 (12%); 157 (23%); 129 (17%); 125 (41%); 116 (24%);
105 (14%); 91 (41%); 75 (90%); 73 (100%); 57 (40%).
5.1.11. (1S,2S,3S,3aS,4S,5R,7aR)-2-(tert-Butyldimethylsilyl-
oxy)-1,3,4-trimethyl-5-phenyl-2,3,3a,4,5,7a-hexahydro-1H-
indene-4-carboxylic acid ethyl esters (33e35)
A solution of triene (2E,5S)-20 (80.9 mg, 0.18 mmol) was
heated under reflux in toluene (4 mL) overnight. The solvent
was then removed in vacuo and the product purified by column
chromatography (5% Et2O/mixed hexanes, Rf¼0.31) yielding
70.7 mg (87% yield, 85% ds) of an inseparable mixture of
three isomers 33e35 (ratio 85:10:5) as a clear colourless oil.
Characterisation of the major isomer was achieved.
Compound 33: 1H NMR (600 MHz, C6D6) d 7.16e7.03 (5H,
m, ArH); 5.93 (1H, apt ddd, J¼9.6, 1.8, 1.8 Hz,
PhCHCH]CH); 5.72 (1H, ddd, J¼9.6, 6.6, 2.4 Hz, PhCHCH);
4.27 (1H, apt qn, J¼1.8 Hz, PhCH); 4.06 (1H, dq, J¼10.8,
7.2 Hz, CO2CHAHB); 3.99 (1H, dq, J¼10.8, 7.2 Hz, CO2-
CHAHB); 3.52 (1H, dd, J¼5.4, 1.8 Hz, CHOTBS); 2.39 (1H,
dqd, J¼9.6, 7.2, 1.8 Hz, Et2OCCHCH(CH3)CH(OTBS)); 2.24
(1H, ddddd, J¼11.4, 11.4, 1.8, 1.8, 1.8 Hz, CH]CHCH);
1.43 (1H, dq, J¼6.6, 6.6 Hz, CH]CHCHCH(CH3)); 1.36
(1H, dd, J¼11.4, 9.6 Hz, Et2OCC(CH3)CH); 1.02 (3H,
t, J¼7.2 Hz, CO2CH2CH3); 1.01 (3H, d, J¼6.6 Hz,
CH]CHCHCH(CH3)); 0.95 (9H, s, SiC(CH3)3); 0.92 (3H, s,
Et2OCC(CH3)); 0.87 (3H, d, J¼7.2 Hz, Et2OC(CH3)-
CHCH(CH3)); 0.03 (3H, s, Si(CH3)A(CH3)B); 0.01 (3H, s, Si-
(CH3)A(CH3)B). 13C NMR (150 MHz, C6D6) d 175.7; 141.7;
131.0; 130.7; 128.8; 128.1; 127.0; 84.5; 60.4; 52.8; 51.1;
49.1; 45.7; 43.9; 42.6; 26.2; 23.9; 21.2; 18.4; 14.4; 12.2;
ꢁ4.0; ꢁ4.6. IR (film, cmꢁ1) 3018; 2956; 2928; 2886; 2856;
1724; 1463; 1452; 1251; 1207; 1102; 1089; 1021; 875; 773;
703; 674. [a]2D0 þ55.6 (c 0.36, CHCl3). HRMS (ESI)
5.1.10. (1S,2S,3S,3aS,4R,5R,7aR)- and (1S,2S,3S,3aS,
4R,5S,7aS)-2-(tert-Butyldimethylsilyloxy)-1,3,4-trimethyl-5-
phenyl-2,3,3a,4,5,7a-hexahydro-1H-indene-4-carboxylic
acid ethyl ester (36 and 37)
A solution of triene (2Z,5S)-20 (120 mg, 0.28 mmol) in
CDCl3 (4 mL) was warmed to 50 ꢀC overnight. After this

J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
4863
C27H42NaO3Siþ requires 465.2795, found 465.2796. LREIMS
385 (74%); 339 (13%); 310 (17%); 285 (18%); 237 (84%); 221
(19%); 195 (35%); 181 (17%); 157 (27%); 129 (20%); 115
(26%); 103 (19%); 91 (43%); 86 (45%); 84 (69%); 75
(100%); 73 (87%); 57 (30%).
Compound 34e35 (two isomers): 1H NMR (600 MHz,
CDCl3) d 7.22e7.21 (ArH); 5.88 (1H, ddd, J¼9.6, 2.4,
2.4 Hz); 5.83 (1H, m); 4.29 (1H, m); 3.89 (1H, dq, J¼10.8,
7.2 Hz); 2.67 (1H, dq); 2.15 (1H, apt sex, J¼7.2 Hz); 1.96
(1H, dd, J¼12.6, 9.0 Hz); 1.90 (m); 1.87 (m); 0.92 (9H, s)
(Note: data incomplete due to overlap with major isomer
obscuring some resonances.). Minor isomers were not able
to be identified in the 13C NMR spectrum.
LREIMS 352 (7.1%); 276 (12%); 264 (56%); 210 (100%);
121 (71%); 117 (14%).
1
Minor isomers: H NMR (300 MHz, CDCl3) d 7.36e7.21
(7H, m, ArH); 6.86 (2H, d, J¼8.7 Hz, ArH); 5.25 (1H, ddd,
J¼10.5, 6.6, 3.9 Hz, CHBn); 4.76 (1H, qd, J¼6.6, 3.6 Hz,
C(]O)CH(CH3)); 4.44 (2H, s, OCH2Ar); 3.90 (1H, dd,
J¼8.1, 3.6 Hz, CH(OH)); 3.80 (3H, s, OCH3); 3.59e3.29
(4H, m); 3.05 (1H, dd, J¼12.9, 10.8 Hz); 2.86 (1H, d,
J¼11.4 Hz, CH2OPMB, CH2S, CHCH2Ar); 1.95e1.86
(1H, m, CH(CH3)CH2OPMB); 1.24 (3H, d, J¼6.6 Hz,
C(]O)CH(CH3)); 0.89 (3H, d, J¼6.9 Hz, CH(CH3)-
CH2OPMB). 13C NMR (75.5 MHz, CDCl3) 201.2; 201.1;
177.8; 177.4; 159.3; 159.2; 152.4; 136.6; 136.5; 130.1;
129.7; 129.4; 129.4; 129.3; 129.3; 128.9; 127.2; 127.1;
113.9; 113.8; 76.3; 74.9; 74.3; 74.2; 73.2; 73.1; 69.8; 69.1;
65.8; 55.2; 42.2; 41.7; 37.1; 36.6; 36.1; 36.0; 32.0; 31.7;
15.2; 13.9; 13.6; 10.6; 9.6.
5.1.12. (1-(40R)-2R,3S,4S)-1-(40-Benzyl-2-thioxothiazolidin-
3-yl)-3-hydroxy-5-(4-methoxybenzyloxy)-2,4-
dimethylpentan-1-one (41)
To a solution of the N-acylthiazolidinethione 40 (2.29 g,
8.65 mmol) in CH2Cl2 (55 mL) at 0 ꢀC was added TiCl4
(9 mL, 9.07 mmol) dropwise. The solution was allowed to
stir for 5 min at 0 ꢀC before (ꢁ)-sparteine (2 mL, 2.03 g,
8.65 mmol) was added dropwise to the suspension. The dark
red enolate was stirred for 20 min at 0 ꢀC before cooling to
ꢁ78 ꢀC and addition of N-methyl-2-pyrrolidinone (0.83 mL,
8.65 mmol) dropwise. The solution was stirred for 10 min
at ꢁ78 ꢀC before addition of the aldehyde 28 (0.90 g,
4.32 mmol) in CH2Cl2 (3 mL, 1 mLꢂ2). The resulting mixture
was stirred at ꢁ78 ꢀC to ꢁ50 ꢀC for 2.5 h before placing over-
night in the ꢁ80 ꢀC freezer. The next morning the reaction was
warmed to ꢁ50 ꢀC for 3 h, however, TLC analysis showed no
further reaction. The reaction was quenched by addition of
NH4Cl (half satd aq, 80 mL). The product was extracted with
CH2Cl2 (2ꢂ100 mL) and the combined extracts were washed
with brine (80 mL), dried (MgSO4) and concentrated in vacuo.
Purification by column chromatography (100% CH2Cl2/
2.5% Et2O/CH2Cl2, Rf (2.5% Et2O/CH2Cl2)¼0.28 (iso 1),
0.17 (iso 2 and 3)) yielded 1.29 g (63%) of isomer 41 (desired
isomer) and 0.29 g (14%) of a mixture of two minor isomers as
clear yellow oils.
Major isomer 41: 1H NMR (300 MHz, CDCl3) d 7.36e7.23
(8H, m, ArH); 6.87 (2H, d, J¼8.4 Hz, ArH); 5.27 (1H, ddd,
J¼10.5, 6.6, 3.3 Hz, CHBn); 4.57 (1H, apt qn, J¼6.9 Hz,
C(]O)CH(CH3)); 4.44 (1H, d, J¼12.6 Hz, OCHAHBAr);
4.39 (1H, d, J¼12.6 Hz, OCHAHBAr); 3.97 (1H, dd, J¼6.3,
4.8 Hz, CHOTBS); 3.80 (3H, s, OCH3); 3.44 (2H, m,
CH2OPMB); 3.35 (1H, dd, J¼11.4, 6.9 Hz, CHCHAHBAr);
3.21 (1H, dd, J¼13.2, 3.9 Hz, SCHAHB); 3.03 (1H, dd,
J¼13.2, 10.5 Hz, SCHAHB); 2.89 (1H, d, J¼11.4 Hz,
CHCHAHBAr); 1.79 (1H, m, CH(CH3)CH2OPMB); 1.33 (3H,
d, J¼6.9 Hz, C(]O)CH(CH3)); 1.00 (3H, d, J¼7.2 Hz,
CH(CH3)CH2OPMB). 13C NMR (75.5 MHz, CDCl3) d 200.9;
177.9; 159.2; 136.4; 130.2; 129.4; 129.2; 129.0; 127.2;
113.8; 75.2; 73.9; 73.1; 68.7; 55.3; 41.9; 36.7; 36.4; 32.1;
13.1; 12.2. IR (film, cmꢁ1) 3483; 2932; 1684; 1653; 1612;
1558; 1513; 1456; 1341; 1299; 1249; 1165; 1135; 1031;
820; 702. [a]2D0 þ143.6 (c 1.5, CHCl3). HRMS (ESI)
C25H31NNaO4Sþ2 requires 496.1587, found 496.1582.
5.1.13. (1(40R),2R,3S,4S)-1-(40-Benzyl-2-thioxothiazolidin-
3-yl)-3-(tert-butyldimethylsilyloxy)-5-(400-methoxy-
benzyloxy)-2,4-dimethylpentan-1-one (42)
To a solution of the alcohol 41 (0.82 g, 1.74 mmol) in
CH2Cl2 (17.4 mL) at ꢁ78 ꢀC was added 2,6-lutidine
(0.30 mL, 0.28 g, 2.61 mmol), followed immediately by
TBSOTf (0.59 mL, 0.69 g, 2.61 mmol). The solution was
stirred at ꢁ78 ꢀC for 30 min, after which time TLC analysis in-
dicated consumption of SM. The reaction was quenched by the
addition of NaHCO3 (satd aq, 20 mL) and warmed to room tem-
perature. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3ꢂ40 mL). The combined extracts were
dried (MgSO4) and concentrated in vacuo. The product was pu-
rified by column chromatography (10% mixed hexanes/
CH2Cl2, Rf¼0.49) yielding 0.99 g (98%) of TBS ether 42 as
a clear colourless oil.
1H NMR (300 MHz, CDCl3) d 7.34e7.24 (7H, m, ArH);
6.86 (2H, d, J¼8.4 Hz, ArH); 5.21 (1H, ddd, J¼10.2,
6.6, 3.9 Hz, CHBn); 4.50 (1H, qd, J¼8.4, 6.9 Hz,
C(]O)CH(CH3)); 4.43 (1H, d, J¼11.7 Hz, OCHAHBAr);
4.38 (1H, d, J¼11.7 Hz, OCHAHBAr); 4.09 (1H, dd, J¼8.4,
2.1 Hz, CH(OTBS)); 3.78 (3H, s, OCH3); 3.40 (1H, dd,
J¼9.3, 6.6 Hz, CHAHBOPMB); 3.31 (1H, dd, J¼11.7, 7.2 Hz,
CHAHBAr); 3.25e3.17 (2H, m, CHAHBOPMB, SCHAHB);
3.03 (1H, dd, J¼13.2, 10.2 Hz, SCHAHB); 2.86 (1H d,
J¼11.7 Hz, CHAHBAr); 1.82e1.75 (1H, m, CH(OTBS)CH
(CH3)CH2OPMB); 1.26 (3H, d, J¼6.6 Hz, C(]O)CH(CH3));
0.89e0.87 (12H, m, SiC(CH3)3, CH(CH3)CH2OPMB); 0.09
(3H, s, Si(CH3)A(CH3)B); 0.03 (3H, s, Si(CH3)A(CH3)B). 13C
NMR (75.5 MHz, CDCl3) d 200.8; 177.3; 159.1; 136.6;
130.7; 129.5; 129.2; 128.9; 127.2; 113.7; 75.0; 72.8; 72.6;
69.0; 55.3; 43.1; 38.9; 36.6; 32.1; 26.1; 18.4; 15.5; 11.6;
ꢁ3.7; ꢁ4.1. IR (film, cmꢁ1) 2930; 2856; 1693; 1613; 1513;
1462; 1362; 1341; 1250; 1062; 1109; 1032; 838; 775. [a]D20
þ119.6 (c 0.9, CHCl3). HRMS (ESI) C31H45NO4S2SiNaþ re-
quires 610.2456, found 610.2451. LREIMS 530 (21%); 482
(21%); 466 (22%); 330 (39%); 319 (20%); 286 (16%); 276
(33%); 264 (90%); 228 (44%); 201 (14%); 135 (15%); 121
(100%).

4864
J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
5.1.14. (2R,3S,4S)-3-(tert-Butyldimethylsilyloxy)-(40-meth-
oxybenzyloxy)-2,4-dimethylpentan-1-ol (60)
4.43 (1H, d, J¼11.4 Hz, OCHAHBAr); 4.37 (1H, d,
J¼11.4 Hz, OCHAHBAr); 4.22 (1H, dd, J¼4.8, 3.6 Hz,
CH(OTBS)); 3.80 (3H, s, OCH3); 3.37 (1H, dd, J¼9.0, 7.2 Hz,
CHAHBOPMB); 3.23 (1H, dd, J¼9.0, 5.7 Hz, CHAHBOPMB);
2.54 (1H, apt qn, J¼6.9 Hz, CH(]O)CH(CH3)); 1.94 (1H, m,
CH(CH3)CH2OPMB); 1.04 (3H, d, J¼6.9 Hz, CH(]O)-
CH(CH3)); 0.88 (9H, s, SiC(CH3)3); 0.85 (3H, d, J¼6.9 Hz,
CH(CH3)CH2OPMB); 0.06 (3H, s, Si(CH3)A(CH3)B); 0.04
(3H, s, Si(CH3)A(CH3)B). 13C NMR (75.5 MHz, CDCl3)
d 205.3; 130.5; 129.2; 113.8; 72.64; 72.57; 72.4; 55.3; 51.4;
37.1; 25.9; 18.2; 12.2; 9.3; ꢁ4.0; ꢁ4.6 (one aromatic signal
missing). IR (film, cmꢁ1) 2930; 2856; 1721; 1613; 1514;
1463; 1361; 1302; 1249; 1172; 1093; 1036; 836; 774. [a]D20
þ36.5 (c 1.9, CHCl3). HRMS (ESI) C21H36NaO4Siþ requires
403.2275, found 403.2276. LREIMS 143 (1.6%); 137 (1.6%);
132 (1.6%); 121 (100%); 115 (3.9%); 112 (8.5%); 97 (1.6%);
91 (1.6%); 78 (3.9%); 75 (51%); 67 (1.6%); 59 (3.1%); 55
(1.6%); 47 (3.1%).
To a solution of the thione 42 (0.51 g, 8.5 mmol) and meth-
anol (45 mL, 36 mg, 1.1 mmol) in Et2O (5 mL) was added a so-
lution of LiBH4 (2 M in THF, 0.56 mL, 1.1 mmol). Evolution
of H2 was observed and after 15 min at 0 ꢀC the solution was
warmed to room temperature and the reaction progress moni-
tored by TLC. After 15 min the starting material had been con-
sumed and the reaction was quenched carefully with NaOH
(5 M, 4 mL). The biphasic mixture was stirred for 30 min
at room temperature to ensure complete hydrolysis of the
borates. The layers were separated and the aqueous layer
was back-extracted with Et2O (20 mL). The organic layers
were concentrated and the crude product filtered through a sil-
ica plug yielding 0.33 g (crude yield w100%) of the alcohol
60 as a clear colourless oil, which was used without further
purification.
1H NMR (300 MHz, CDCl3) d 7.25 (2H, d, J¼8.7 Hz,
ArH); 6.87 (2H, d, J¼8.7 Hz, ArH); 4.41 (2H, s, OCH2Ar);
3.86 (1H, apt t, J¼3.6 Hz, CH(OTBS)); 3.80 (3H, s, OCH3);
3.66 (1H, dd, J¼10.8, 8.1 Hz, CHAHBO); 3.48 (1H, dd,
J¼10.8, 6.0 Hz, CHAHBO); 3.36 (1H, dd, J¼9.0, 7.2 Hz,
CHAHBO); 3.23 (1H, dd, J¼9.0, 6.3 Hz, CHAHBO); 2.04e
1.90 (3H, m, OH, CH(CH3)CH2(OH), CH(CH3)CH2OPMB);
0.94 (3H, d, J¼6.9 Hz, CH(CH3)); 0.89 (9H, s, SiC(CH3)3);
0.84 (3H, d, J¼7.2 Hz, CH(CH3)); 0.07 (3H, s, Si-
(CH3)A(CH3)B); 0.03 (3H, s, Si(CH3)A(CH3)B). 13C NMR
(75.5 MHz, CDCl3) d 159.2; 130.7; 129.1; 113.8; 74.5; 73.5;
72.6; 66.3; 55.3; 40.3; 36.2; 26.0; 18.3; 12.9 (2); ꢁ4.2;
ꢁ4.4. IR (film cmꢁ1) 3419; 2956; 2929; 2856; 1613; 1514;
1463; 1361; 1302; 1249; 1173; 1096; 1036; 837; 773. [a]D20
þ1.6 (c 0.6, CHCl3). HRMS (ESI) C21H38NaO4Siþ requires
405.2432, found 405.2430. LREIMS 203 (1.6%); 187
(1.6%); 145 (5.4%); 137 (1.6%); 121 (100%); 115 (3.1%);
89 (3.1%); 75 (16%); 59 (1.6%); 45 (1.6%).
5.1.16. (2R,3R,4S,5E,7E)-3-(tert-Butyldimethylsilyloxy)-1-
(40-methyoxybenzyloxy)-2,4-dimethyl-8-phenylocta-5,7-
diene ((E,E,5R)-31)
To a solution of sulfone 24 (0.99 g, 3.03 mmol) in anhy-
drous DME (7.6 mL) at ꢁ60 ꢀC was added a solution of
KHMDS in toluene (0.5 M, 5.4 mL, 2.72 mmol) dropwise.
The solution turned deep red and was stirred at ꢁ60 ꢀC for
30 min before the addition of aldehyde (5S)-22 (0.576 g,
1.51 mmol) in DME (3ꢂ0.5 mL). The solution was stirred at
ꢁ60 ꢀC for 30 min before warming to room temperature and
stirring overnight. The reaction was quenched by the addition
of H2O (30 mL) and diluted with Et2O (50 mL). The layers
were shaken well, separated and the organic layer dried
(MgSO4) and concentrated in vacuo. The product was purified
by column chromatography (50% mixed hexanes/CH2Cl2,
Rf¼0.55) yielding 0.494 g (68%) of a mixture of dienes
(E,E)-41 and (Z,E)-41 as a pale yellow oil. The product was
dissolved in CDCl3 (1 mL) and few crystals of I2 added. The
5.1.15. (2R,3S,4S)-3-(tert-Butyldimethylsilyloxy)-5-(40-
methoxybenzyloxy)-2,4-dimethylpentanal ((5S)-22)
1
isomerisation reaction was monitored by H NMR and after
To a solution of DMSO (26 mL, 28 mg, 0.37 mmol) in
CH2Cl2 (0.5 mL) at ꢁ78 ꢀC, was added a solution of oxalyl
chloride (2 M in CH2Cl2, 92 mL, 0.18 mmol) and the resulting
solution stirred at ꢁ78 ꢀC for 30 min. A solution of the alcohol
60 (0.328 g, 8.59 mmol) in CH2Cl2 (3ꢂ0.3 mL) was added
and the resulting solution stirred at ꢁ78 ꢀC for 45 min. NEt3
(102 mL, 74 mg, 0.73 mmol) was added and the solution
stirred at ꢁ78 ꢀC for 30 min before warming to 0 ꢀC and stir-
ring for a further 30 min. The reaction was quenched by the
addition of NaHSO4 (1 M, 10 mL), the product extracted
with Et2O (3ꢂ10 mL) and concentrated in vacuo. The product
was taken up in Et2O (20 mL), washed with NaHSO4 (1 M,
10 mL), H2O (10 mL), NaHCO3 (satd aq, 10 mL) and brine
(10 mL), dried (MgSO4) and concentrated in vacuo. The prod-
uct was purified by column chromatography (100% CH2Cl2,
Rf¼0.45) yielding 0.27 g (96%) of the aldehyde (5S)-22 as
a clear colourless oil.
44 min isomerisation of the (Z,E)-41 to (E,E)-41 was com-
plete. The solution was diluted with CH2Cl2 (50 mL) and
washed with sodium metabisulfite solution (satd aq, 20 mL)
and H2O (20 mL). The organics were dried (MgSO4) and con-
centrated in vacuo. Purification by column chromatography
(50% mixed hexanes/CH2Cl2, Rf¼0.55) yielded 0.464 g
(94%) of (E,E,5R)-31 as a single isomer.
1H NMR (200 MHz, CDCl3) d 7.40e7.19 (7H, m, ArH);
6.88 (2H, dt, J¼9.0, 2.4 Hz, ArH); 6.73 (1H, dd, J¼15.6,
10.2 Hz, ArCH]CH); 6.43 (1H, d, J¼15.6 Hz, ArCH);
6.16 (1H, dd, J¼15.4, 10.2 Hz, ArCH]CHCH); 5.78 (1H,
dd, J¼15.4, 8.0 Hz, ArCH]CHCH]CH); 4.44 (1H, d,
J¼11.8 Hz, OCHAHBAr); 4.36 (1H, d, J¼11.8 Hz, OCHA-
HBAr); 3.80 (3H, s, OCH3); 3.68 (1H, dd, J¼6.8, 2.4 Hz,
CH(OTBS)); 3.36 (1H, dd, J¼9.2, 7.6 Hz, CHAHBOPMB);
3.19 (1H, dd, J¼9.2, 6.6 Hz, CHAHBOPMB); 2.44 (1H,
apt qn, J¼6.8 Hz, ]CHCH(CH3)); 1.98 (1H, apt qnd,
J¼6.6, 2.4 Hz, CH(CH3)CH2OPMB); 1.04 (3H, d, J¼6.8 Hz,
]CHCH(CH3)); 0.91 (9H, s, SiC(CH3)3); 0.85 (3H, d,
1H NMR (300 MHz, CDCl3) d 9.85 (1H, apt s, CH(]O));
7.24 (2H, d, J¼8.7 Hz, ArH); 6.87 (2H, d, J¼8.7 Hz, ArH);

J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
4865
J¼6.6 Hz, CH(CH3)CH2OPMB); 0.06 (3H, s, Si-
(CH3)A(CH3)B); 0.03 (3H, s, Si(CH3)A(CH3)B). 13C NMR
(75.5 MHz, CDCl3) d 138.9; 137.6; 130.8; 130.2; 129.6;
129.5; 129.2; 128.5; 127.1; 126.1; 113.7; 75.8; 73.4; 72.5;
55.3; 41.9; 36.8; 26.9; 18.4; 17.2; 11.2; ꢁ3.6; ꢁ4.1 (note:
two coincident signals in vinyl region). [a]2D0 0 (c 0.4,
CHCl3). IR (film, cmꢁ1) 2956; 2928; 2855; 1731; 1612;
1513; 1462; 1385; 1248; 1173; 1111; 1038; 990; 837; 773;
747; 693. HRMS (ESI) C30H44NaO3Siþ requires 503.2952,
found 503.2944. LREIMS 323 (57%); 277 (41%); 251
(31%); 229 (20%); 199 (21%); 187 (100%); 131 (16%); 121
(41%).
in Et2O (50 mL) and washed with NaHSO4 (1 M, 20 mL),
H2O (20 mL), NaHCO3 (satd aq, 20 mL) and brine (20 mL),
dried (MgSO4) and concentrated in vacuo. The product was
purified by column chromatography (100% CH2Cl2,
Rf¼0.41) yielding 0.243 g (84%) of aldehyde (5R)-32 as
a clear colourless oil.
1H NMR (300 MHz, CDCl3) d 9.75 (1H, s, CHO); 7.41e
7.22 (5H, m, ArH); 6.75 (1H, dd, J¼15.6, 10.5 Hz, ArCH]CH);
6.50 (1H, d, J¼15.6 Hz, ArCH); 6.23 (1H, dd, J¼15.3,
10.5 Hz, ArCH]CHCH); 5.75 (1H, dd, J¼15.3, 8.4 Hz,
ArCH]CHCH]CH);4.09(1H,dd,J¼7.2,2.7 Hz,CH(OTBS));
2.60e2.42 (2H, m, ]CHCH(CH3), CH(CH3)C(]O)); 1.14 (3H,
d, J¼7.2 Hz, C(]O)CH(CH3) or CH(CH3)CH]); 1.10 (3H, d,
J¼6.9 Hz, C(]O)CH(CH3) or CH(CH3)CH]); 0.91 (9H, s,
SiC(CH3)3); 0.11 (3H, s, Si(CH3)A(CH3)B); 0.01 (3H, s, Si-
(CH3)A(CH3)B). 13C NMR (75.5 Hz, CDCl3) d 205.2; 137.3;
137.2; 131.3; 130.7; 128.9; 128.6; 127.3; 126.2; 75.0; 50.8;
41.9; 26.0; 18.3; 16.9; 7.8; ꢁ4.1 (2C). IR (film, cmꢁ1) 3024;
2956; 2930; 2884; 2857; 1725; 1491; 1462; 1447; 1253; 1104;
1028; 990; 837; 775; 747; 691; 672. [a]2D0 þ135 (c 1.1, CHCl3).
5.1.17. (2R,3R,4S,5E,7E)-3-(tert-Butyldimethylsilyloxy)-2,4-
dimethyl-8-phenylocta-5,7-dien-1-ol (61)
ToasolutionofPMB ether(E,E,5R)-31(0.464 g, 0.96 mmol)
in dry CH2Cl2 (16 mL) at room temperature were added Me2S
(0.72 mL, 9.74 mmol) and powdered MgBr2$OEt2 (0.747 g,
2.89 mmol). The mixture was stirred at room temperature over-
nightafter whichtimeTLCanalysisshowedconsumptionofSM.
The reaction was quenched by the addition of NH4Cl (satd aq,
40 mL) and the product extracted with CH2Cl2 (3ꢂ40 mL).
The combined extracts were washed with brine (40 mL), dried
(MgSO4) and concentrated in vacuo. Purification by column
chromatography (20% mixed hexanes/CH2Cl2, Rf¼0.35)
yielded 0.292 g (84%) of alcohol 61 as a clear colourless oil.
1H NMR (200 MHz, CDCl3) d 7.31e7.10 (5H, m, ArH); 6.65
(1H, dd, J¼15.8, 10.2 Hz, ArCH]CH);6.37(1H, d, J¼15.8 Hz,
ArCH); 6.10 (1H, dd, J¼15.4, 10.4 Hz, ArCH]CHCH); 5.68
(1H, dd, J¼15.4, 8.2 Hz, ArCH]CHCH]CH); 3.60 (1H dd,
J¼7.2, 2.6 Hz, CH(OTBS)); 3.52 (1H, dd, J¼10.4, 8.4 Hz,
CHAHBOH); 3.38 (1H, dd, J¼10.5, 5.7 Hz, CHAHBOH); 2.42
(1H, apt sex., J¼6.8 Hz, ]CHCH(CH3)); 1.87e1.62 (1H, m,
CH(CH3)CH2OH); 1.00 (3H, d, J¼6.8 Hz, ]CHCH(CH3));
0.84 (9H, s, SiC(CH3)3); 0.76 (3H, d, J¼6.8 Hz, CH(CH3)-
CH2(OH)); 0.00 (6H, s, Si(CH3)2). 13C NMR (75 MHz,
CDCl3) d 138.6; 137.5; 130.5; 129.6; 129.4; 128.5; 127.2;
126.1; 76.7; 66.1; 41.3; 39.6; 26.1; 18.3; 17.4; 11.5; ꢁ3.8;
ꢁ4.2. IR (film, cmꢁ1) 3362; 2957; 2929; 2883; 2856; 1472;
1459; 1252; 1095; 1025; 988; 859; 837; 773; 746; 690; 669.
[a]2D0 þ39.4 (c 2.9, CHCl3).
5.1.19. (1S,2R,3S,3aS,4R,5S,7aS)- and (1S,2R,3S,3aS,
4R,5R,7aR)-2-(tert-Butyldimethylsilyloxy)-1,3,4-trimethyl-
5-phenyl-2,3,3a,4,5,7a-hexahydro-1H-indene-4-carboxylic
acid ethyl ester (44 and 43)
To
a solution of the aldehyde (5R)-32 (0.243 g,
0.678 mmol) in CH2Cl2 (5 mL) at room temperature was
added the ylide 25 (1.23 g, 3.39 mmol) carefully with stirring
and the resulting yellow solution heated under reflux for 60 h.
The solvent was removed in vacuo and the product triturated
with mixed hexanes. The residue was a mixture of two cyclo-
adducts 44 and 43, separable by column chromatography
(50% CH2Cl2/mixed hexanes, Rf (44)¼0.5, Rf (43)¼0.36)
yielding 0.187 g (65%) of adduct 44 and 0.049 g (17%) of
adduct 43 (overall yield 82%).
1
Compound 44: H NMR (600 MHz, C6D6) d 7.24e7.07
(5H, m, ArH); 5.80 (2H, ABq, J¼11.4 Hz, PhCHCH]CH);
4.12 (1H, m, PhCH); 3.89 (2H, q, J¼7.2 Hz, CO2CH2CH3);
3.12 (1H, dd, J¼9.0, 7.8 Hz, CH(OTBS)); 2.56 (1H, dd,
J¼10.2, 6.6 Hz, EtO2CC(CH3)CHCH(CH3)); 2.05 (1H,
apt br sex, J¼6.6 Hz, Et2OC(CH3)CHCH(CH3)); 1.95 (1H,
m, CH]CHCH); 1.76 (1H, ddq, J¼12.6, 9.0, 6.6 Hz,
CH]CHCHCH(CH3)); 1.19 (3H, s, Et2OCC(CH3));
1.13 (3H, d, J¼6.6 Hz, CH]CHCHCH(CH3)); 1.03 (3H,
d, J¼6.6 Hz, Et2OC(CH3)CHCH(CH3)); 0.99 (9H, s,
SiC(CH3)3); 0.87 (3H, t, J¼7.2 Hz, CO2CH2CH3); 0.11 (3H,
s, Si(CH3)A(CH3)B); 0.09 (3H, s, Si(CH3)A(CH3)B). 13C
NMR (150 MHz, CDCl3) d 176.4; 142.4; 129.0; 128.4;
130.0; 128.3; 127.0; 88.2; 60.4; 50.1; 50.5; 49.2; 45.8; 42.8;
42.3; 26.2; 20.0; 18.3; 16.4; 13.5; 14.2; ꢁ3.5; ꢁ3.6. IR
(film, cmꢁ1) 2956; 2929; 2856; 1717; 1463; 1386; 1255;
1111; 892; 835; 774; 752; 704. [a]2D0 ꢁ6.0 (c 0.8, CHCl3).
5.1.18. (2R,3R,4S,5E,7E)-3-(tert-Butyldimethylsilyloxy)-2,4-
dimethyl-8-phenylocta-5,7-dienal ((5R)-32)
A solution of oxalyl chloride in CH2Cl2 (2 M, 0.61 mL,
1.21 mmol) was added dropwise to a solution of DMSO
(0.172 mL, 2.43 mmol) in CH2Cl2 (3.5 mL) at ꢁ78 ꢀC. The
resulting solution was stirred at ꢁ78 ꢀC for 30 min. A solution
of alcohol 61 (0.292 g, 0.81 mmol) in CH2Cl2 (0.5 mL,
0.25 mLꢂ2) was added via a cannula to the reaction mixture,
dropwise. The resulting mixture was stirred for 45 min at
ꢁ78 ꢀC. Et3N (0.67 mL, 4.86 mmol) was added dropwise
over several minutes and stirred at ꢁ78 ꢀC for 30 min before
warming to 0 ꢀC and stirring for 30 min. The reaction mixture
was quenched by addition of NaHSO4 (1 M, 30 mL) and the
product extracted with Et2O (3ꢂ30 mL). The combined ex-
tracts were concentrated in vacuo. The product was taken up
1
Compound 43: H NMR (600 MHz, CDCl3) d 7.25e7.11
(5H, m, ArH); 5.91 (1H, dt, J¼10.2, 1.8 Hz, PhCHCH]CH);
5.59 (1H, ddd, J¼9.6, 4.2, 3.0 Hz, PhCHCH]CH); 3.57 (1H,
dq, J¼10.8, 7.2 Hz, CO2CHAHB); 3.35 (1H, dd, J¼6.6,
1.8 Hz, CH(OTBS)); 3.29 (1H, m, PhCH); 3.23 (1H, dq,

4866
J.S. Crossman, M.V. Perkins / Tetrahedron 64 (2008) 4852e4867
J¼10.8, 7.2 Hz, CO2CHAHB); 2.53 (1H, ddddd, J¼10.8, 7.8,
4.8, 3.0, 1.8 Hz, CH]CHCHCH(CH3)); 2.04 (1H, dqd, 7.8,
7.8, 1.8 Hz, CH]CHCHCH(CH3)); 2.02 (1H, apt t,
J¼12.0 Hz, Et2OCC(CH3)CH); 1.57 (1H, ddq, J¼13.2, 6.6,
6.6 Hz, Et2OC(CH3)CHCH(CH3)); 1.36 (3H, s, Et2OCC(CH3));
1.07 (3H, d, J¼7.8 Hz, CH]CHCHCH(CH3)); 0.89 (9H, s,
SiC(CH3)3); 0.79 (3H, d, J¼6.6 Hz, Et2OC(CH3)CHCH(CH3));
0.69 (3H, t, J¼7.2 Hz, CO2CH2CH3); 0.07 (3H, s, Si-
(CH3)A(CH3)B); 0.05 (3H, s, Si(CH3)A(CH3)B). 13C NMR
(150 MHz, CDCl3) d 175.2; 141.9; 129.5; 128.5; 127.7; 127.5;
126.7; 89.1; 59.7; 53.6; 49.0; 45.1; 41.3; 41.2; 41.1; 25.9;
200 mL, 100 mL). The resulting mixture was stirred at ꢁ78 ꢀC
for 45 min before the addition of NEt3 (0.53 mmol, 54 mg,
74 mL) over several minutes. The mixture was stirred at
ꢁ78 ꢀC for 30 min before warming to 0 ꢀC and the stirring con-
tinued for 30 min. The reaction was quenched by the addition of
NH4Cl (satd aq, 15 mL) and the product extracted with CH2Cl2
(3ꢂ15 mL). The combined extracts were dried (MgSO4) and
concentrated in vacuo. The product was purified by column
chromatography (100% CH2Cl2, Rf¼0.42) yielding 29 mg
(98%) of ketone 46 as a clear colourless oil.
1H NMR (600 MHz, CDCl3) d 7.28e7.21 (3H, m, ArH);
7.15 (2H, d, J¼7.2 Hz, ArH); 6.11 (1H, d, J¼9.6 Hz, CH(Ph)-
CH]CH); 5.72 (1H, dt, J¼9.6, 3.6 Hz, CH(Ph)CH]CH);
3.58 (1H, dq, J¼10.8, 7.2 Hz, CO2CHAHBCH3); 3.43 (1H,
m, CH(Ph)); 3.23 (1H, dq, J¼10.8, 7.2 Hz, CO2CHAHBCH3);
2.22 (1H, apt t, J¼11.4 Hz, C(CH3)(CO2Et)CHCH(CH3));
2.04 (1H, apt qn, J¼7.2 Hz, CH(CH3)CHCH]CH); 2.00e
1.92 (2H, m, CCHCH(CH3), CH]CHCH); 1.41 (3H, s,
C(CH3)(CO2Et)); 1.25 (3H, d, J¼7.2 Hz, CH(CH3)-
CHCH]CH); 0.93 (3H, d, J¼7.2 Hz, CCHCH(CH3)); 0.69
(3H, t, J¼7.2 Hz, CO2CH2CH3). 13C NMR (150 MHz,
CDCl3) d 219.8; 174.4; 141.0; 129.5; 129.0; 127.9; 127.1;
125.9; 60.1; 53.6; 48.9; 47.7; 46.3; 44.9; 43.0; 17.7; 13.5;
13.1; 12.5. IR (film, cmꢁ1) 3026; 2961; 2929; 2874; 1721;
1453; 1379; 1266; 1241; 1157; 701; 672. [a]2D0 þ191 (c, 0.2
CHCl3).
18.0; 17.6; 16.9; 16.0; 13.2; ꢁ4.2; ꢁ4.5. IR (film, cmꢁ1
)
2956; 2928; 2856; 1721; 1456; 1377; 1258; 1204; 1105; 1074;
866; 836; 774; 700. [a]2D0 þ143 (c 0.4, CHCl3).
5.1.20. (1S,2S,3S,3aS,4R,5R,7aR)-2-Hydroxy-1,3,4-trimeth-
yl-5-phenyl-2,3,3a,4,5,7a-hexahydro-1H-indene-4-
carboxylic acid ethyl ester (45)
To a solution of the TBS ether 36 (47 mg, 0.106 mmol) in
CH3CN/CH2Cl2 (1:1, 2 mL) in a TeflonÒ screw cap jar was
added aqueous HF (40%, 200 mL) at room temperature. The
resulting solution was stirred at room temperature and the re-
action monitored by TLC. Successive additions of aqueous HF
(200 mL) was performed over 3 h until the starting material
was consumed. The reaction was quenched by the addition
of H2O (30 mL) and the product was extracted with EtOAc
(3ꢂ20 mL). The combined extracts were dried (MgSO4) and
concentrated in vacuo. The product was purified by column
chromatography (10% Et2O/CH2Cl2, Rf¼0.25) yielding
29 mg (84%) of alcohol 45 as a clear colourless oil.
Acknowledgements
We wish to thank the Australian Research Council for fund-
ing (Discovery Grant DP0665642 to MVP) and Flinders Uni-
versity for its support and facilities. We also thank Mr. Phil
Clements, the Department of Chemistry, The University of
Adelaide and Dr. Martin Johnston, School of Chemistry, Phys-
ics and Earth Sciences, Flinders University for recording
600 MHz NMR spectra. JSC acknowledges the receipt of an
Australian Post Graduate Award.
1H NMR (600 MHz, CDCl3) d 7.25e7.23 (2H, m, ArH);
7.21e7.18 (1H, m, ArH); 7.13e7.12 (2H, m, ArH); 5.99
(1H, ddd, J¼9.6, 1.8, 1.8 Hz, PhCHCH]CH); 5.59 (1H,
ddd, J¼9.6, 3.6, 2.4 Hz, PhCHCH]CH); 3.80 (1H, dd,
J¼7.8, 5.4 Hz, CH(OH)); 3.57 (1H, dq, J¼10.8, 7.2 Hz, CO2-
CHAHB); 3.34 (1H, apt qn, J¼2.4 Hz, CH(Ph)); 3.22 (1H, dq,
J¼10.8, 7.2 Hz, CO2CHAHB); 1.91 (1H, dq, J¼11.4, 1.8 Hz,
CH]CHCH); 1.86 (1H, apt t, J¼11.4 Hz, C(CH3)-
(CO2Et)CHCH(CH3)); 1.82e1.75 (1H,
m
CH(CH3)-
Supplementary data
CHCH]CH); 1.60e1.54 (2H, m, OH, CCHCH(CH3)); 1.36
(3H, s, CH3C); 1.13 (3H, d, J¼7.2 Hz, CH(CH3)CHCH]CH);
0.92 (3H, d, J¼7.2 Hz, CCHCH(CH3)); 0.69 (3H, t, J¼7.2 Hz,
CO2CH2CH3). 13C NMR (150 MHz, CDCl3) d 175.1; 141.8;
129.5; 128.3; 127.7; 127.5; 126.8; 82.0; 59.7; 54.2; 49.1;
45.8; 44.8; 44.7; 39.9; 17.9; 17.6; 13.2; 11.7. IR (film,
cmꢁ1) 3450; 3020; 2961; 2930; 2905; 2875; 1720; 1453;
1381; 1268; 1242; 1167; 1088; 1029; 760; 701. [a]2D0 þ120
(c 0.3, CHCl3).
Experimental procedures and data for compounds 47e54,
56 and 57, Tables of NMR data for compounds 33, 36, 37,
45e48 and 50e56 and H and 13C NMR spectra for com-
pounds 33, 36, 37, 43e48 and 53, 54, 56 and 57 are available.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2008.02.109.
1
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acid ethyl ester (46)
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