Synthetic studies towards ptilomycalin A: total synthesis of crambescidin 359

Article abstract of DOI:10.1016/j.tet.2007.08.055

A potentially biomimetic synthesis of the guanidine-containing marine natural product crambescidin 359 via a double Michael addition of guanidine to a suitably functionalised bis-enone is reported.

Full text of DOI:10.1016/j.tet.2007.08.055

Tetrahedron 63 (2007) 11771–11780
Synthetic studies towards ptilomycalin A: total synthesis
of crambescidin 359
a
b
Christopher G. Moore,a Patrick J. Murphy,a, Harri L. Williams, Alan T. McGown and
*
Nigel K. Smithb
aDepartment of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, UK
bChristie CRC Research Centre, Paterson Institute for Cancer Research, Christie NHS Trust, Wilmslow Road,
Manchester M20 4BX, UK
Received 4 June 2007; revised 27 July 2007; accepted 16 August 2007
Available online 22 August 2007
Abstract—A potentially biomimetic synthesis of the guanidine-containing marine natural product crambescidin 359 via a double Michael
addition of guanidine to a suitably functionalised bis-enone is reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Me
1. Introduction
O
N
Molecules containing guanidinium sub-units are of consider-
able biological interest1,2 and several of the most structurally
complex have been isolated from marine organisms.3 We
have a continuing interest4 in the synthesis of the marine nat-
ural product ptilomycalin A 1, isolated by Kashman5 in 1989,
which is the parent member of a group of related metabolites
including the crambescidins,6 the crambines7 and the batzel-
ladines.8 Ptilomycalin A possesses an intriguing structure
consisting of a pentacyclic guanidine moiety linked by
a long-chain u-hydroxy acid to a spermidine unit; it shows
cytotoxicity against a range of cell lines in addition to anti-
fungal activity as well as very good antiviral activity (HSV).9
H
X-
H2N
H2N
+
O
H
N
H
O
N
N
Me
H
O
O
1
Me
Me
OTBS
OTBS
3
O
O
Our retrosynthetic analysis of the central polycyclic unit of
ptilomycalin A illustrates the possibility of a rapid and
potentially biomimetic construction of our target via a dou-
ble Michael addition of guanidine to a bis-a,b-unsaturated
ketone 2 to generate the central pyrrolidine ring. Subsequent
bis-spirocyclisation would then lead to the required penta-
cycle. Disconnection of 2 leads to the unsaturated aldehyde
3 and the b-keto ester 4. The tert-butyl ester was selected to
inhibit irreversible amide formation during the guanidine
addition step (Scheme 1).
OTBS
O
O
OTBS
O
O
O
Me
Me
2
OtBu
OtBu
4
Scheme 1.
TBSO
TBSO
We have reported previously4 on the central double conju-
gate addition methodology and have shown it to be a success-
ful strategy for the preparation of the pentacyclic moiety. For
O
N
H
N
BF4-
+
(a)
O
H
H
O
N
O
H
5
6
Keywords: Crambescidin 359; Ptilomycalin A; Guanidine; Michael addi-
tion.
* Corresponding author. E-mail: paddy@bangor.ac.uk
Scheme 2. (a) (i) Guanidine, DMF, 3 h; (ii) MeOH, HCl, 0 ꢀC–rt, 24 h; (iii)
NaBF4 (satd, aq), 25% overall.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.055

11772
C. G. Moore et al. / Tetrahedron 63 (2007) 11771–11780
OH
O
OTBS
O
example, addition of guanidine to bis-a,b-unsaturated ke-
tone 5 followed by deprotection and spirocyclisation gave
the symmetrical pentacyclic model 6 in good overall yield
(Scheme 2).
OTBS
(a)-(d)
(e)
OEt
I
13
14
4
CO2tBu
Scheme 4. (a) TBSCl, DMF, imid., 95%; (b) DIBAL-H, hexane, ꢁ78–
20 ꢀC, 8 h, 83%; (c) TosCl, Py. 0 ꢀC–rt, 16 h, 62%; (d) NaI, acetone, reflux,
4 h, 95%; (e) tert-butyl acetoacetate, 2.2 equiv LDA, 0 ꢀC–rt, 2 h, 75%.
2. Results and discussion
We initially attempted to prepare the ester substituted model
compound 12 by reaction of guanidine with the diene 10.
Preparation of diene 10 required reaction of the dianion of
tert-butyl acetoacetate with iodide 710 to give 8, which was
condensed with the previously reported4d aldehyde 9 under
Knoevenagel conditions.11 Our initial attempts at this reac-
tion using piperidine as the catalyst gave the required product
10 in low yield (14%), whilst the use of piperidine acetate
gave slightly better results (26%). In both these reactions,
cyclopentene 11 was obtained as a major by-product, which
derived from a Baylis–Hillman type cyclisation of aldehyde
9.12 Attempts to further optimise these reactions using other
bases and Lewis acids were unsuccessful. Despite this, reac-
tion of 10 with guanidine followed by acidification led to the
formation of a product in 20% yield, which gave the expected
molecular weight in high resolution MS and from 13C NMR
spectroscopy appeared to be a mixture of four diastereoiso-
mers as four signals were observed for both the guanidinium
andesterquaternarycarbons.Furthermore,themajorsignalfor
the proton H-6 appeared as a doublet at d 2.8 ppm (J 5.6 Hz)
suggesting an axial arrangement for the ester as found in
ptilomycalin A. Whilst it was impossible to separate the ma-
jor product from this mixture, the evidence for the formation
of 12 was convincing and the retention of the tert-butyl ester
under the reaction conditions was gratifying (Scheme 3).
The preparation of aldehyde 3a proved to be a more signifi-
cant challenge. Starting from commercially available (S)-2-
aminobutyric acid 15, the key intermediate aldehyde 16
was prepared in five steps. Thus 15 was diazotised in the pres-
ence of sodium nitrite and H2SO4 to give the corresponding
a-hydroxy acid,13 which was then esterified using HCl in
methanol (23% over two steps). Silyl protection of the alco-
hol function (47%) was followed by DIBAL-H reduction
(72%) and Swern oxidation of the resulting alcohol to give
aldehyde 16 in 93% yield. Wittig reaction of 16 with the ylide
generated from 3-carboxypropyltriphenylphosphonium bro-
mide 19, followed by esterification with diazomethane gave
the Z-alkene 17 together with the E-isomer (minor) in 45%
yield and in a 4:1 ratio.14 After separation from the E-isomer,
17 was treated with 2 equiv of methylenetriphenylphosphor-
ane to give the stabilised phosphorane 18, which on reaction
O
O
Me
(a)-(e)
(f)
TBSO
Me
15
OH
Me
16
H
NH2
OTBS
17
O
OMe
Me
RO
Me
TBSO
(g)
O
Encouraged by this result we next sought to prepare the re-
quired fragments 3 and 4 and study their condensation. We
prepared b-keto ester 4 in five steps from commercially
available ethyl-(R)-3-hydroxybutyrate 13. The hydroxyl
group of 13 was silyl protected, then the ester function
was reduced to the alcohol and converted into iodide 14
via the tosylate. Iodide 14 was then treated with the
dianion of tert-butyl acetoacetate to afford 4 in 75% yield
(Scheme 4).
O
18
PPh3
3a, R = TBS
3b, R = TPS
O
Scheme 5. (a) NaNO2, H2SO4 0 ꢀC–rt, 24 h; (b) MeOH, HCl, 48 h, (23%, 2
steps); (c) TBSCl, imid., DMF, 0 ꢀC–rt, 48 h, 47%; (d) DIBAL-H, ꢁ78 ꢀC to
rt, 5 h, 72%; (e) Swern oxidation, 93%; (f) (i) MeO2CCH2CH2CH2PPh+3Brꢁ
19, NaHMDS, THF, reflux, 30 min; (ii) 16, rt, 30 min; (iii) CH2N2, Et2O,
45%, 4:1, Z:E; (g) (i) 2 equiv CH2]PPh3, THF, ꢁ78 ꢀC to rt, 2 h; (ii)
succinaldehyde, THF, 42 h, (42%, 2 steps).
TBSO
TBSO
TBSO
O
O
O
TBSO
(a)
(b)
O
TBSO
I
O
7
9
CO2tBu
10
8
CO2tBu
O
N
O
H
H
N
BF4-
TBSO
N
+
OH
(c)
+
H
H
H
O
+
H
O
N
O
N
N
11
H
H
CO2tBu
CO2tBu
12a
12
Scheme 3. (a) tert-Butyl acetoacetate, NaH, n-BuLi, ꢁ78 ꢀC, then 7, 66%; (b) piperidine acetate, CH2Cl2, ꢁ20 ꢀC, 6 h, 26%; (c) (i) guanidine, DMF, 0 ꢀC, 5 h;
(ii) MeOH, HCl, 0 ꢀC–rt, 16 h; (iii) satd NaBF4, CH2Cl2, 4 h, 20%.

C. G. Moore et al. / Tetrahedron 63 (2007) 11771–11780
11773
C9H19
with an excess of freshly prepared succinaldehyde gave the
desired aldehyde 3a in 42% yield (Scheme 5).
O
O
O
O
(a)
+
Having prepared the key fragments 3a and 4, the stage was
now set for their coupling via Knoevenagel condensation
and as a very similar process had been reported,11 we were
confident of success. Initially, we employed piperidene
(dichloromethane, ꢁ78 to ꢁ20 ꢀC) as the catalyst but were
disappointed to find that only a low yield (14%) of 2 was
formed, which was contaminated with at least two unidenti-
fiable side products. It was first thought that the starting ma-
terials had been recovered but on inspection of the NMR
spectra of the recovered material we found that the
Baylis–Hillman cyclisation product 20 had been formed in
41% yield and that all of aldehyde 3a had been consumed.
Similarly, piperidine acetate gave a low yield (15%) of con-
taminated 2 in addition to 20 in 14% yield. However, the use
of morpholine gave contaminated 2 in 22% yield but did not
lead to any cyclisation product 20, but on this occasion alde-
hyde 3a was recovered in 60% yield. Attempts to increase
the yield of this process by extending the reaction time or
varying the reaction temperature led to lower yields, further
decomposition products and the formation of 20. Morphol-
inium acetate under similar conditions, gave contaminated
2 in 17% yield and recovered aldehyde. To further test the
condensation process, known aldehyde 3b was prepared
via a literature route,11 however, similar results were
obtained (Scheme 6).
OR
21
22
Scheme 7. (a) See text: piperidine, piperidine acetate, 2,6-dimethylpiper-
idine or morpholine, CH2Cl2, ꢁ78 to ꢁ20 ꢀC. R¼Me, Ph2CH, tBu.
Despite this lack of success in our synthetic approach to pti-
lomycalin A, we wished to demonstrate the validity of our
methodology and identified pentacycle 27, which lacks the
ester function, as a suitable target. Ylide 24 was prepared
in 51% yield by treatment of iodide 14 with the lithium anion
of acetylmethylene triphenylphosphorane 23. Reaction of 24
with aldehyde 3b in dichloromethane at 0 ꢀC for 36 h gave
the required bis-enone 25 in 72% yield. Addition of a
DMF solution of guanidine to 25 at 0 ꢀC followed by stirring
at this temperature for 6 h resulted in the complete consump-
tion of the starting bis-enone. After dilution with water and
addition of a solution of methanolic HCl, a mixture of com-
pounds was obtained in which the TBS protecting group had
been removed, but the TPS group remained; NMR spectro-
scopic evidence strongly suggested the presence of the tetra-
cycle 26.16–18 This mixture was treated with 5 equiv of
TBAF in THF at 25–30 ꢀC for 3 h and then at ambient tem-
perature for a further 64 h. Finally, acid mediated cyclisa-
tion, counterion exchange and purification by column
chromatography gave the desired pentacycle 27 (X¼BF4)
in 18% yield from 25. The yield is comparable with our pre-
vious work4 in this area, as the guanidine addition step is not
diastereoselective and half of the tricyclic bis-silylated gua-
nidine adduct does not undergo cyclisation on deprotection
(Scheme 8).
Snider and Shi11 have reported product yields of the order of
60–70% for similar Knoevenagel condensations together
with the recovery of unreacted starting materials. In an
attempt to determine the optimum conditions for the Kno-
evenagel reaction, a study was undertaken to ascertain
whether electronic effects within the b-keto esters 21 have
any effect on the outcome of the reaction. In a previous syn-
thetic study towards the batzelladine alkaloids,4g aldehyde
22 was prepared, which was deemed to be suitable for use
in this investigation (Scheme 7). Reaction of 22 with 21
(R¼Me, Ph2CH,15 tBu) in the presence of a range of cyclic
amines, including a hindered base and also an amine salt,
was attempted but with no success. The method of addition
was also varied with premixing of the various reagents in dif-
ferent sequences and changes in reaction time and tempera-
ture were also employed but proved unproductive. In all
cases the aldehyde 22 underwent decomposition or conver-
sion to a Baylis–Hillman product under the reaction condi-
tions and the b-keto ester 21 was recovered unchanged.
We have no explanation as to the failure of this condensation
reaction as literature reports suggest it to be an effective
process with similar substrates.
Interestingly, shortly after completing our synthesis19 of 27,
Braekman20 reported the isolation of crambescidin 359 27
(X¼Cl) from the marine sponge Monanchora unguiculata
and the analytical data for synthetic 27 (X¼BF4) was found
to be consistent with that reported. In particular, the optical
rotation of 27 of ꢁ8.2 (X¼BF4, c 0.2, CH2Cl2) compared fa-
vourably with that of synthetic 2718 (X¼Cl, ꢁ8.0, c 0.2,
CH2Cl2) and also the natural product20 (X¼Cl, ꢁ9.0,
c 0.2, CH2Cl2).
We also investigated the biological activity of synthetic
crambescidin 359 27 (X¼BF4) against four cancer cell lines
in comparison with ptilomycalin A5a,21 (Table 1). As can be
seen, 27$BF4 was active against all the cell lines tested, how-
ever, the levels of activity were significantly lower than those
reported for ptilomycalin A. This is in line with our previous
Me
Me
OTBS
Me
OTBS
(a)
OTBS
O
OH
O
OTBS
O
O
O
20
3a
Me
O
2
OtBu
Scheme 6. (a) See text: 4, morpholine, CH2Cl2, ꢁ20 ꢀC, 6 h, 22%.

11774
C. G. Moore et al. / Tetrahedron 63 (2007) 11771–11780
Dichloromethane was freshly distilled from calcium hy-
Me
dride. Chemical shifts are reported in d values relative to tet-
ramethylsilane as an internal standard. Proton (250 MHz)
and carbon (62.5 MHz) NMR spectra were recorded in
deuteriochloroform on a Bruker AC250 spectrometer unless
otherwise stated. All mass spectra were run at the EPSRC
Mass Spectrometry Service Centre at the University of
Wales, Swansea. Low resolution mass spectra were recorded
on a VG Biotech Quattro II triple quadrupole mass spec-
trometer using chemical ionisation (CI), with ammonia as
reagent gas, or by means of electron impact (EI). Accurate
mass spectra (HRMS) were recorded on a VG ZAB-E
mass spectrometer whereas fast atom bombardment (FAB)
spectra were run on a VG Autospec mass spectrometer
using caesium ion bombardment at 25 kV energy. Specific
rotations were determined using a PolAAr 2001 polarimeter,
(cell path length, l¼1), with the temperature (t), concentra-
tion (c) and solvent recorded in each case. Infrared spectra
were recorded as thin films (oils) or as chloroform solutions
on a Perkin–Elmer 1600 series instrument. Melting points
were recorded with a Gallenkamp MF370 apparatus.
OTPS
PPh3
O
PPh3
O
(a)
(b)
OTBS
O
OTBS
O
Me
Me
23
24
Me
Me
TPSO
25
Me
X
O
N
HO
H
+
(c)
(d)
H
+
Cl
N
H
H
O
H
N
N
H
H
O
Me
N
N
H
Me
26
27
Scheme 8. (a) n-BuLi, ꢁ78 ꢀC, then 14, warm to rt, 51%; (b) 3b, DCM,
36 h, 72%; (c) (i) guanidine, DMF, 0 ꢀC, 6 h; (ii) H2O, MeOH, HCl,
0 ꢀC–rt, 16 h; (d) (i) THF, TBAF, 25–30 ꢀC, 3 h, then rt, 64 h; (ii) MeOH,
HCl, 0 ꢀC, 4 h, then NaBF4 (satd, aq), CH2Cl2, 18% overall.
Table 1
4.2. 7-(tert-Butyl-dimethyl-silanyloxy)-3-oxo-heptanoic
acid tert-butyl ester 8
Compound
K562a
A2780a
H-460a
P388a
27$BF4
Ptilomycalin A 1
12.30
0.35
24.44
0.27
10.36
0.35
2.93
0.11b
Sodium hydride (0.27 g, 11.34 mmol) was suspended in dry
THF (20 mL), cooled (0 ꢀC) and treated with tert-butyl ace-
toacetate (0.9 g, 5.67 mmol). After stirring for 20 min at
0 ꢀC, the resulting suspension was treated with n-butyl-
lithium (4.36 mL, 5.67 mmol, 1.3 M) and stirred for
10 min. Iodide 710 (1.7 g, 5.65 mmol) dissolved in THF
(5 mL) was added and the resultant mixture stirred at rt
over 20 min. Ammonium chloride solution (saturated,
1 mL) and water (50 mL) were added and the reaction
mixture was extracted with diethyl ether (4ꢂ50 mL). The
combined organic fractions were dried (MgSO4) and evapo-
rated to give a crude oil. Column chromatography on silica
gel (3% diethyl ether in petrol) gave 8 (1.23 g, 66%) as an
oil. Rf 0.23 in 10% diethyl ether–petrol; dH 3.62 (2H, t,
J 6.3 Hz, CH2), 3.35 (2H, s, CH2), 2.57 (2H, t, J 7.0 Hz,
Cytotoxic activity (IC50/mgmLꢁ1): K562: human chronic myelogenous
leukaemia; A2780: human, ovarian carcinoma; H-460: human large cell
carcinoma, lung. High DT-diaphorase; P388: mouse, lymphoid neoplasm.
Data obtained from Ref. 5a.
a
b
studies in this area,21 which suggest that the fatty acid chain
and spermidine residue are essential for the high levels of
activity in these types of compounds.
3. Conclusion
In conclusion, we have investigated the synthesis of ptilo-
mycalin A with limited success and have found that a key
Knovenagel condensation is problematic and in some cases
impossible to effect. Despite this failure we have demon-
strated the worth of the methodology and have completed
a highly convergent and potentially biomimetic synthesis
of crambescidin 359 27. We have also found that 27$BF4
displays much lower levels of biological activity than ptilo-
mycalin A, demonstrating that the fatty acid chain and
spermidine residue are required for high levels of activity.
t
CH2), 1.65–1.52 (4H, m, 2ꢂCH2), 1.48 (9H, s, Bu),
t
0.90 (9H, s, Bu), 0.06 (6H, s, 2ꢂMe); dC 203.2 (C), 166.5
(C), 81.8 (C), 62.7 (CH2), 50.6 (CH2), 42.6 (CH2), 32.1
(CH2), 28.0 (3ꢂCH3), 25.9 (3ꢂCH3), 20.0 (CH2), 18.3
(C), ꢁ5.3 (2ꢂMe); nmax 2934, 2860, 1736, 1716, 1643,
1368, 1252, 1147, 836, 776; m/z (CI) 348 (10%
[M+NH4]+), 331 (40% [M+H]+), 275 (100%), 231 (30%);
HRMS found: 331.2305, C17H35O4Si ([M+H]+) requires:
331.2305.
4.3. 12-(tert-Butyl-dimethyl-silanyloxy)-2-[5-(tert-butyl-
dimethyl-silanyloxy)-pentanoyl]-8-oxo-dodeca-2,6-di-
enoic acid tert-butyl ester 10 and 5-(tert-butyl-dimethyl-
silanyloxy)-1-(5-hydroxy-cyclopent-1-enyl)-pentan-1-
one 11
4. Experimental
4.1. General
Column chromatography was carried out on silica gel (par-
ticle size 40–63 mm) and TLC were conducted on precoated
Kieselgel 60 F254 (Art. 5554; Merck) with the eluent spec-
ified in each case. All non-aqueous reactions were conducted
in oven-dried apparatus under a static atmosphere of argon.
Ether and THF were distilled from sodium and benzophe-
none. Methanol was dried by distillation from magnesium
and iodine. Dry DMF was purchased from Aldrich.
A solution of aldehyde 9 (250 mg, 0.84 mmol) in dichloro-
methane (1 mL) was cooled (ꢁ78 ꢀC) before being treated
with a solution of 8 (277 mg, 0.84 mmol) in dichlorome-
thane (2 mL). Subsequent treatment with piperidinium ace-
tate (15 mg, 0.1 mmol) was followed by warming to ꢁ20 ꢀC
and stirring for 6 h. The resulting mixture was diluted with
hexane (20 mL) before being washed with water (20 mL)

C. G. Moore et al. / Tetrahedron 63 (2007) 11771–11780
11775
and brine (20 mL). The organic fraction was dried (MgSO4)
and evaporated to give a crude oil, which was purified by col-
umn chromatography (10–30% diethyl ether in petrol, gradi-
ent elution) to give 10 (132 mg, 26%) as a 2:1 mixture of
geometric isomers, which were partially separable by care-
ful chromatography. Minor isomer (E): Rf 0.41 in 40% di-
ethyl ether–petrol; dH 6.75 (2H, m, 2ꢂCH), 6.06 (1H, d,
J 15.8 Hz, CH2), 3.64 (4H, t, J 6.0 Hz, 2ꢂCH2), 2.65 (2H,
t, J 7 Hz, CH2), 2.57 (2H, t, J 6.6 Hz, CH2), 2.35 (2H, m,
CH2), 2.25 (2H, m, CH2), 1.67 (4H, m, 2ꢂCH2), 1.51 (9H,
dried and evaporated. The product was purified by column
chromatography on silica gel (0.5% methanol–chloroform)
and the combined product fractions dissolved in diethyl
ether (5 mL) and diluted with petrol (10 mL). After 16 h
the mother liquor was decanted leaving 12/12a (29 mg,
20%) as a solid. Rf 0.31 in 5% methanol–chloroform; dH
8.50–7.50 (2H, m, 2ꢂNH), 4.20–3.50 (6H, m, 2ꢂCH2),
2.90–0.70 (28H, m); selected dC 167.5, 166.9 (major),
166.6, 166.5 (C]O), 149.3, 148.9, 148.5, 147.8 (major)
(C]N); nmax 3283, 2947, 1728, 1660, 1604, 1044; m/z
t
t
t
s, Bu), 1.49 (4H, m, 2ꢂCH2), 0.90 (18H, s, 2ꢂ Bu), 0.0
(12H, s, 4ꢂMe); dC 165.6 (ester C). Major isomer (Z): Rf
0.31 in 40% diethyl ether–petrol; dH 6.75 (1H, dt, J 15.8,
6.5 Hz, CH), 6.63 (1H, t, J 7.2 Hz, CH), 6.09 (1H, d,
J 15.8 Hz, CH), 3.58 (2H, t, J 6.3 Hz, CH2), 3.57 (2H, t, J
6.3 Hz, CH2), 2.66 (2H, t, J 6.9 Hz, CH2), 2.59 (2H, t,
J 6.9 Hz, CH2), 2.44 (4H, m, 2ꢂCH2), 1.68 (4H, m,
(CI) 406 (80% [M]+), 388 (15%), 348 (15% [Mꢁ Bu]+),
t
305 (15% [MHꢁ BuCO]+), 288 (50%), 286 (20%), 268
(10%), 208 (40%), 206 (30%), 182 (100%), 164 (70%);
HRMS found: 406.2706, C22H36N3O4 ([M]+) requires:
406.2706.
4.5. (R)-3-[(tert-Butyldimethylsilyl)oxy]-1-iodobutane
1422
t
2ꢂCH2), 1.56 (9H, s, Bu), 1.53 (4H, m, 2ꢂCH2), 0.91
t
(18H, s, 2ꢂ Bu), 0.00 (12H, s, 4ꢂMe); dC 200.2 (C), 197.5
(C), 165.6 (ester C), 144.4 (CH), 143.5 (CH), 138.6 (C),
131.0 (CH), 82.6 (C), 62.8 (2ꢂCH2), 40.0 (CH2), 39.2
(CH2), 32.3 (CH2), 32.2 (CH2), 31.0 (CH2), 28.1 (tBu),
28.0 (CH2), 26.0 (6ꢂMe), 20.6 (CH2), 20.4 (CH2), 18.3
(2ꢂC), ꢁ5.3 (4ꢂMe); nmax 2929, 2856, 1736, 1699, 1670,
1627, 1385, 1255, 1102, 837, 776; m/z (CI) 611 (20%
4.5.1. Ethyl (R)-3-[(tert-Butyldimethylsilyl)oxy]buta-
noate. Imidazole (5.36 g, 78.8 mmol) and ethyl (R)-3-hy-
droxybutyrate (4.0 g, 30.3 mmol) were dissolved in DMF
(30 mL) and the resulting solution cooled (0 ꢀC). tert-Butyl-
dimethylsilyl chloride (6.00 g, 39.4 mmol) was then added
and the reaction stirred at rt for 4 h. The reaction was ex-
tracted with hexane (3ꢂ40 mL) and the combined hexane
layers washed with an aqueous acetic acid solution (2%,
40 mL) and water (3ꢂ40 mL). After drying (MgSO4) and
evaporation the crude oil was purified by column chromato-
graphy on silica gel (5% diethyl ether in petrol) to yield the
ester (7.07 g, 94%) as an oil. Rf 0.57 in 10% diethyl ether/
petrol; vmax 2932, 2897, 1739, 1471, 1376, 1301, 1255,
1184, 1140, 1085, 1003, 940; dH 4.28 (1H, m, CH), 4.12
(2H, dq, J 7.1, 1.8 Hz, CH2), 2.48 (1H, dd, J 14.4, 7.5 Hz,
CH), 2.36 (1H, dd, J 14.5, 5.4 Hz, CH), 1.27 (3H, t, J
7.2 Hz, CH3), 1.20 (3H, d, J 6.1 Hz, CH3), 0.87 (9H, s,
3ꢂCH3), 0.07 (3H, s, CH3), 0.05 (3H, s, CH3); dC 171.7
(C), 65.9 (CH), 60.2 (CH2), 45.0 (CH2), 25.7 (3ꢂCH3),
23.9 (CH3), 17.9 (C), 14.2 (CH3), ꢁ4.5 (CH3), ꢁ4.8
(CH3); MS (CI) m/z 247 (100% [M+H]+), 189 (10%
[Mꢁ(tBu)]+); HRMS (CI) m/z found: 247.1729,
C12H27O3Si ([M+H]+) requires: 247.1729; [a]2D5 ꢁ27.0 (c
0.37, CHCl3) [lit. [a]1D8 ꢁ26.9 (c 1.0, CHCl3)].22
t
[M+H]+), 563 (15%), 562 (40%), 536 (20% [MHꢁ BuO]+),
530 (30%), 516 (10%), 502 (15%), 479 (20%
[MꢁTBDMSO]+), 474 (20%), 462 (50%), 445 (30%), 430
(20%), 416 (25%), 398 (100%).
Similar reactions utilising piperidine gave the by-product 11
in 20–30% yield. Rf 0.49 in 40% ethyl acetate–petrol; dH
6.80 (1H, t, J 2.8 Hz, CH), 5.08 (1H, br t, J 5.3 Hz, CH),
3.59 (2H, t, J 6.4 Hz, CH2), 2.68 (2H, t, J 6.7 Hz, CH2),
2.20 (2H, m, CH2), 1.75 (2H, m, CH2), 1.63 (2H, m, CH2),
1.50 (2H, m, CH2), 0.89 (9H, s, 3ꢂMe), 0.00 (6H, s,
2ꢂMe); dC 200.4 (C), 145.8 (C), 145.6 (CH), 75.4 (CH),
62.7 (CH2), 38.7 (CH2), 32.2 (CH2), 31.4 (CH2), 31.0
(CH2), 25.9 (3ꢂMe), 20.8 (CH2), 18.2 (C), ꢁ4.9 (2ꢂMe);
m/z (CI) 299 (100% [M+H]+), 281 (60% [MꢁOH]+), 241
(5%), 223 (7%), 167 (18%), 149 (30%).
4.4. tert-Butyl dispiro[tetrahydropyran-2,40-(1,2,3,4,7,8-
hexahydro-5H-5,6,8b-triazaacenaphthylene-30-carbon-
ate)-70-200tetrahydropyran]-60-ium tetrafluoroborate
12/12a
4.5.2. (R)-3-[(tert-Butyldimethylsilyl)oxy]butan-1-ol. A
solution of the above compound (3.32 g, 13.4 mmol) in
dry hexane (50 mL) was cooled (ꢁ78 ꢀC) and treated with
DIBAL-H (1 M, hexanes, 34.2 mL, 34.2 mmol) in a drop-
wise manner and stirred for 8 h at ꢁ20 ꢀC. After warming
(0 ꢀC), methanol (2 mL) was added and the resulting mix-
ture diluted with hexane (40 mL) followed by the addition
of saturated ammonium chloride solution (30 mL). The
resulting precipitated solid was filtered and washed with
further hexane (200 mL in portions), the organic layer
separated and washed with water (4ꢂ50 mL), dried
(MgSO4) and the solvent evaporated to give the title com-
pound (2.26 g, 83%) as a yellow oil. Rf 0.15 in 10% diethyl
ether–petrol; vmax 3346, 2930, 2858, 1472, 1375, 1255,
1129, 1028, 940, 837, 775, 718, 658; dH 4.11 (1H, m, CH),
3.85 (1H, m, CH), 3.75 (1H, m, CH), 2.59 (1H, br t, J
5.0 Hz, OH), 1.86–1.80 (1H, m, CH), 1.79–1.57 (1H, m,
CH), 1.21 (3H, d, J 6.2 Hz, CH3), 0.90 (9H, s, 3ꢂCH3),
0.10 (3H, s, CH3), 0.09 (3H, s, CH3); dC 68.3 (CH), 60.4
A solution of bis-enone 10 (174 mg, 0.29 mmol) in DMF
(5 mL) was added dropwise to a cooled (0 ꢀC) solution of
guanidine (17 mg, 0.29 mmol) in DMF (5 mL). The reaction
was slowly warmed to rt and stirred for 5 h. After evapora-
tion to dryness under reduced pressure the residue was dis-
solved in dry methanol (10 mL), cooled (0 ꢀC) and
anhydrous HCl gas was bubbled into the solution for
2 min. After 16 h, the resulting mixture was evaporated to
produce an oily residue, which was dissolved in dichlorome-
thane (50 mL) and washed with water (2ꢂ50 mL) and brine
(2ꢂ50 mL). Drying and evaporation gave an oily residue,
which was dissolved in dichloromethane (10 mL) and
treated with saturated aqueous sodium tetrafluoroborate
solution (30 mL). After vigorous stirring for an hour, the
resulting emulsion was extracted with dichloromethane
(3ꢂ20 mL) before the combined organic fractions were

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C. G. Moore et al. / Tetrahedron 63 (2007) 11771–11780
(CH2), 40.5 (CH2), 25.8 (3ꢂCH3), 23.4 (CH3), 17.9 (C),
ꢁ4.4 (CH3), ꢁ4.5 (CH3); MS (CI) m/z 205 (100%
[M+H]+), 202 (2%), 132 (5%), 92 (12%), 91 (10%);
HRMS (CI) m/z found: 205.1624, C10H25O2Si ([M+H]+) re-
quires: 205.1624. [a]3D0 ꢁ17.8 (c 0.41, CHCl3) [lit. [a]1D8
ꢁ30.1 (c 1.1, CHCl3)].22
4.15 mmol, 0.69 mL) was added and the mixture stirred for
1 h after which iodide 14 (1.0 g, 3.19 mmol) was added
and the resulting mixturewarmed to rt and stirred for a further
2 h. The solution was diluted with hexane (45 mL) followed
by treatment with saturated aqueous ammonium chloride so-
lution (15 mL) and water (45 mL). The organic layer was
separated and washed with brine (2ꢂ45 mL) and the solvent
dried and concentrated in vacuo to give a crude yellow oil,
which was purified by chromatography on silica gel (3%
diethyl ether–petrol) giving the desired product 4, as a pale
yellow oil (0.82 g, 75%). Rf 0.58 in 20% diethyl ether–petrol;
vmax 2930, 2856, 1735, 1717, 1642, 1462, 1406, 1369, 1318,
1253, 1147, 1032, 836, 775; dH 3.79 (1H, m, CH), 3.34 (2H, s,
CH2), 2.53 (2H, t, J 7.2 Hz, CH2), 1.72–1.53 (2H, m, CH2),
1.48 (9H, s, 3ꢂCH3), 1.45–1.22 (2H, m, CH2), 1.12 (3H, d,
J 6.1 Hz, CH3), 0.89 (9H, s, 3ꢂCH3), 0.05 (6H, s, 2ꢂCH3)
dC 203.2 (C), 166.4 (C), 81.8 (C), 68.2 (CH), 50.5 (CH2),
42.9 (CH2), 38.8 (CH2), 27.9 (3ꢂCH3), 25.8 (3ꢂCH3),
23.7 (CH3), 19.9 (CH2), 18.0 (C), ꢁ4.5 (CH3), ꢁ4.8 (CH3);
MS (CI) m/z 345 (14% [M+H]+), 289 (39%), 245 (58%),
157 (17%), 132 (23% [TBDMSOH]+), 113 (100%), 58
(24%), 52 (82%), 44 (65%), 36 (50%); HRMS (CI) m/z
found: 345.2461, C18H37O4Si ([M+H]+) requires:
345.2461; [a]2D7 ꢁ12.7 (c 0.37, CHCl3).
4.5.3. (R)-3-[(tert-Butyldimethylsilyl)oxy]butan-1-para-
toluene sulfonate.23 para-Toluenesulfonyl chloride (2.27 g,
11.88 mmol) dissolved in dry pyridine (5 mL) was added
dropwise to a cooled (0 ꢀC) solution of the above alcohol
(2.21 g, 10.8 mmol) in dry pyridine (5 mL). The resulting
mixture was stirred at rt for 16 h, diluted with water
(100 mL) and then extracted with hexane (3ꢂ40 mL). The
combined organic layers were washed with sulfuric acid
(2 M, 2ꢂ25 mL) and water (2ꢂ40 mL), dried (MgSO4)
and evaporated. Column chromatography on silica gel (3%
diethyl ether in petrol) gave the title compound (2.41 g,
62%) as a colourless oil. Rf 0.15 in 5% diethyl ether–petrol;
vmax 2955, 2856, 1598, 1471, 1362, 1255, 1178, 1097, 1047,
1006, 938, 891, 837, 776, 655; dH 7.80 (2H, d, J 8.3 Hz, CH),
7.35 (2H, d, J 8.3 Hz, CH), 4.11 (2H, t, J 6.2 Hz, CH2), 3.91
(1H, m, CH), 2.46 (3H, s, CH3), 1.74 (2H, m, CH2), 1.11
(3H, d, J 6.2 Hz, CH3), 0.82 (9H, s, CH3), 0.03 (3H, s,
CH3), ꢁ0.02 (3H, s, CH3); dC 144.7 (C), 133.0 (C), 129.8
(2ꢂCH), 127.9 (2ꢂCH), 67.9 (CH2), 64.6 (CH), 38.5
(CH2), 25.7 (3ꢂCH3), 23.9 (CH3), 21.6 (CH3), 17.9 (C),
ꢁ4.4 (CH3), ꢁ5.1 (CH3); MS (CI) m/z 359 (100%
[M+H]+), 246 (8%), 227 (4% [MꢁTBDMSO]+), 205
(40%), 52 (12%); HRMS (CI) m/z found: 359.1712,
C17H31O4SiS ([M+H]+) requires: 359.1712; [a]2D6 ꢁ22.6 (c
0.49, CHCl3).
4.7. (S)-2-[(tert-Butyldimethylsilyl)oxy]-butanal 16
4.7.1. Methyl (S)-2-hydroxybutanoate.13 (S)-(+)-2-Ami-
nobutyric acid 15 (10 g, 97 mmol) was dissolved in sulfuric
acid (1 M, 200 mL), cooled (0 ꢀC) and a solution of sodium
nitrite (11 g, 159 mmol) in water (40 mL) added in a drop-
wise manner. After addition, the mixture was stirred at rt
for 24 h before being saturated with sodium chloride (ca.
50 g). The resulting solution was extracted with ethyl acetate
(4ꢂ80 mL) and the combined extracts dried (MgSO4) and
concentrated in vacuo to give crude (S)-2-hydroxybutanoic
acid as a yellow oil. Acetyl chloride (11.2 g, 143 mmol,
10.2 mL) was added slowly (CAUTION! Exothermic reac-
tion on mixing) to cooled (0 ꢀC) methanol (100 mL) and
the resulting solution stirred for 10 min. The crude a-hy-
droxy acid was dissolved in a small amount of dry methanol
and added to the methanolic HCl and the mixture stirred at rt
for 48 h. Careful evaporation of the solvent at atmospheric
pressure (product is volatile) and column chromatography
(dichloromethane) of the residue gave the ester (2.68 g,
23%) as a yellow oil. Rf 0.48 in 60% diethyl ether–petrol;
vmax 3453, 2925, 2850, 1734, 1654, 1230, 1136; dH 4.58
(1H, br s, OH), 4.20 (1H, dd, J 6.6, 4.5 Hz, CH), 3.82 (3H,
s, CH3), 1.86 (1H, m, CH), 1.73 (1H, m, CH), 0.97 (3H, t,
J 7.4 Hz, CH3); dC 175.5 (C), 71.5 (CH), 52.3 (CH3), 27.3
(CH2), 8.9 (CH3); MS (CI) m/z 136 (45% [M+NH4]+), 104
(8%), 78 (21%), 74 (18%), 58 (14%), 46 (32%); HRMS
(CI) m/z found: 136.0974, C5H14NO3 ([M+NH4]+) requires:
136.0974.
4.5.4. (R)-3-[(tert-Butyldimethylsilyl)oxy]-1-iodobutane
14.23 The above tosylate (2.23 g, 6.23 mmol) was dissolved
in acetone (95 mL) and sodium iodide (5.20 g, 34.3 mmol)
was added and the mixture heated to reflux for 4 h. After
cooling, the resulting suspension was filtered and the solids
thoroughly washed with diethyl ether (several portions ca.
100 mL). The filtrate was evaporated to give a crude oil,
which was triturated with hexane (5ꢂ30 mL) and the com-
bined triturates were dried (MgSO4) and evaporated in vacuo
to give 14 (1.87 g, 95%) as a clear oil. Rf 0.73 in 5% diethyl
ether–petrol; vmax 2955, 2929, 2892, 2856, 1472, 1374,
1255, 1178, 1147, 1127, 1063, 967, 871, 835, 775, 709; dH
3.90 (1H, m, CH), 3.24 (2H, m, CH2), 1.97–1.88 (2H, m,
CH2), 1.17 (3H, d, J 6.1 Hz, CH3), 0.90 (9H, s, 3ꢂCH3),
0.11 (3H, s, CH3), 0.09 (3H, s, CH3); dC 68.2 (CH), 43.2
(CH2), 25.8 (3ꢂCH3), 23.5 (CH3), 18.0 (C), 3.6 (CH2),
ꢁ4.2 (CH3), ꢁ4.6 (CH3); MS (CI) m/z 315 (45% [M+H]+),
272 (10%), 189 (36%), 187 (64% [MꢁI]+), 132 (100%
[TBDMSOH]+), 92 (42%), 91 (21%); HRMS (CI) m/z
found: 315.0641, C10H24IOSi ([M+H]+) requires:
315.0641; [a]2D7 ꢁ46.3 (c 0.41, CHCl3) [lit. [a]2D4 ꢁ49.6 (c
1.3, CHCl3)].23
4.7.2. Methyl (S)-2-[(tert-butyldimethylsilyl)oxy]-buta-
noate. Imidazole (6.33 g, 93 mmol) was added to a cooled
(0 ꢀC) solution of methyl (S)-2-hydroxybutanoate (3.44 g,
29 mmol) in DMF (60 mL) followed by the addition of
tert-butyldimethylsilyl chloride (7.84 g, 52 mmol). After
48 h, the reaction was extracted with hexane (3ꢂ60 mL)
and the combined hexane layers washed with aqueous acetic
acid solution (2%, 50 mL) followed by water (2ꢂ40 mL),
4.6. (R)-7-(tert-Butyl-dimethyl-silanyloxy)-3-oxo-octa-
noic acid tert-butyl ester 4
n-Butyllithium (2.44 M in hexanes, 3.92 mL, 9.57 mmol)
was added to a cooled (0 ꢀC) solution of diisopropylamine
(0.97 g, 9.57 mmol, 1.34 mL) in THF (50 mL) and the mix-
ture stirred for 30 min. tert-Butyl acetoacetate (0.66 g,

C. G. Moore et al. / Tetrahedron 63 (2007) 11771–11780
11777
then dried over anhydrous MgSO4. Evaporation of the sol-
vent gave a crude oil, which was purified by column chroma-
tography (gradient elution, 0–10% diethyl ether in petrol) to
give the title compound (3.17 g, 47%) as a colourless oil. Rf
0.63 in 10% diethyl ether–petrol; vmax 2954, 2889, 2859,
1757, 1464, 1361, 1255, 1201, 1145, 1073, 1022, 935,
842, 780, 723; dH 4.06 (1H, dd, J 7.0, 5.1 Hz, CH), 3.64
(3H, s, CH3), 1.65 (2H, m, CH2), 0.89 (3H, t, J 7.4 Hz,
CH3), 0.88 (9H, s, 3ꢂCH3), 0.06 (3H, s, CH3), ꢁ0.01 (3H,
s, CH3); dC 174.2 (C), 73.4 (CH), 51.7 (CH3), 28.4 (CH2),
25.7 (3ꢂCH3), 18.3 (C), 9.6 (CH3), ꢁ5.0 (CH3), ꢁ5.4
(CH3); MS (CI) m/z 250 (100% [M+NH4]+), 233 (60%
[M+H]+), 217 (15%), 175 (21%), 132 (35%), 106 (16%),
74 (24%), 58 (30%), 52 (92%), 44 (43%), 36 (49%);
HRMS (CI) m/z found: 233.1573, C11H25O3Si ([M+H]+) re-
quires: 233.1573; [a]2D4 ꢁ4.2 (c 0.3, CHCl3).
1.77 (2H, m, CH2), 0.98 (3H, t, J 7.4 Hz, CH3), 0.95 (9H,
s, CH3), 0.11 (3H, s, CH3), 0.10 (3H, s, CH3); dC 204.4
(CH), 78.7 (CH), 25.8 (CH2), 25.7 (3ꢂCH3), 18.1 (C), 9.0
(CH3), ꢁ4.8 (CH3), ꢁ5.0 (CH3); MS (CI) m/z 220 (100%
[M+NH4]+), 203 (40% [M+H]+), 202 (45% [M]+), 187
(27% [MꢁCH3]+), 173 (11% [MꢁCHO]+), 145 (40%
[Mꢁ(tBu)]+), 132 (40% [MꢁTBDMSOH]+), 91 (13%), 74
(23%), 52 (17%), 46 (16%), 44 (10%); HRMS (CI) m/z
found: 220.1732, C10H26NO2Si ([M+NH4]+) requires:
220.1733; [a]2D3 ꢁ11.5 (c 1.0, CHCl3).
4.8. (S)-Methyl-(E),(Z)-6-[(tert-butyldimethylsilyl)-oxy]-
oct-4-enoate 17
(3-Carboxypropyl)triphenylphosphonium bromide24 (2.02 g,
4.7 mmol, 5 equiv) was suspended in THF (4.6 mL) and so-
dium bis(trimethylsilyl)amide (1.56 M solution in THF,
6.02 mL, 9.4 mmol) was added dropwise at rt to give a bright
orange solution, which was then heated under reflux for 1 h.
The solution was allowed to cool to rt then transferred (via
syringe) to a solution of 16 (0.19 g, 0.94 mmol) in THF
(3.2 mL). After stirring for 30 min the mixture was quenched
with aqueous acetic acid solution (1%, 53 mL) and extracted
with diethyl ether (5ꢂ35 mL). The combined organic frac-
tions were then washed with brine (3ꢂ50 mL), dried
(MgSO4) and the solvent evaporated to give a yellow oil.
This was dissolved in diethyl ether (5 mL), cooled (0 ꢀC)
and treated with excess ethereal diazomethane solution
(1 M, ca. 6 mL). This solution was stirred then left to evapo-
rate overnight to give a crude semi-crystalline product, which
was purified by column chromatography (1–4% diethyl ether
in petrol) yielding the title ester (0.12 g, 45%) as a 4:1 mix-
ture of geometric isomers. Further chromatography (0.5% di-
ethyl ether in petrol) gave pure 17 (80 mg, 28%). Data for the
(Z) isomer: Rf 0.29 in 5% diethyl ether–petrol; vmax 2956,
2930, 2856, 1743, 1462, 1437, 1361, 1253, 1166, 1082,
1048, 860, 836, 777; dH 5.42 (1H, dd, J 11.0, 9.1 Hz, CH),
5.30 (1H, m, CH), 4.35 (1H, dt, J 7.8, 6.4 Hz, CH), 3.69
(3H, s, CH3), 2.45 (4H, m, 2ꢂCH2), 1.56–1.41 (2H, m,
CH2), 0.91 (9H, m, 3ꢂCH3), 0.90 (3H, t, J 7.4 Hz, CH3),
0.06 (3H, s, CH3), 0.03 (3H, s, CH3); dC 173.3 (C), 135.4
(CH), 126.5 (CH), 70.0 (CH), 51.4 (CH3), 34.0 (CH2), 31.3
(CH2), 25.8 (3ꢂCH3), 23.3 (CH2), 18.1 (C), 9.5 (CH3),
ꢁ4.4 (CH3), ꢁ4.8 (CH3); m/z 304 (5% [M+NH4]+), 287
(8% [M+H]+), 229 (48% [Mꢁ(tBu)]+), 155 (100%
[MꢁTBDMSO]+); HRMS (CI) m/z found: 287.2042,
C15H31O3Si ([M+H]+) requires: 287.2042; [a]2D5 +19.8 (c
0.4, CHCl3). Selected data for the E-isomer: Rf 0.23 in 5% di-
ethyl ether in petrol; dH 5.55 (2H, m, CH), 3.99 (1H, m, CH),
3.70 (3H, s, CH3), 2.39 (4H, m, CH2), 1.55–1.38 (2H, m,
CH2), 0.90 (9H, m, 3ꢂCH3), 0.89 (3H, t, J 7.4 Hz, CH3),
0.07 (3H, s, CH3), 0.05 (3H, s, CH3); dC 173.3 (C), 134.8
(CH), 127.8 (CH), 74.5 (CH), 51.4 (CH3), 33.9 (CH2), 31.1
(CH2), 27.4 (CH2), 25.8 (3ꢂCH3), 18.1 (C), 9.6 (CH3),
ꢁ4.4 (CH3), ꢁ4.8 (CH3).
4.7.3. (S)-2-[(tert-Butyldimethylsilyl)oxy]-butan-1-ol.
The above silyl ester (2.12 g, 9 mmol) was dissolved in hex-
ane (100 mL), cooled (ꢁ78 ꢀC) and treated with a solution
of DIBAL-H (1 M, hexanes, 20 mL, 20 mmol) in a dropwise
manner. The solution was warmed (ꢁ20 ꢀC) and stirred for
5 h before being treated with a mixture of 50% methanol–
benzene (10 mL). The resulting mixture was diluted with
hexane (50 mL) followed by an aqueous solution of satu-
rated ammonium chloride (50 mL) and then filtered under
vacuum. The organic phase was washed with water
(3ꢂ50 mL), dried (MgSO4) and evaporated to give a clear
oil, which was purified by chromatography (10% diethyl
ether–petrol) to give the title compound (1.34 g, 72%), as
a clear oil. Rf 0.30 in 15% diethyl ether–petrol; vmax 3358,
2955, 2858, 1464, 1361, 1256, 1050, 938, 836, 775, 665;
dH 3.69 (1H, m, CH), 3.58 (1H, m, CH), 3.48 (1H, m,
CH), 1.91 (1H, br t, J 7.8 Hz, OH), 1.54 (2H, dq, J 7.3,
6.3 Hz, CH2), 0.93 (9H, s, 3ꢂCH3), 0.90 (3H, t, J 7.5 Hz,
CH3), 0.11 (6H, s, 2ꢂCH3); dC 74.1 (CH), 65.8 (CH2),
26.7 (CH2), 25.8 (3ꢂCH3), 18.1 (C), 9.7 (CH3), ꢁ4.5
(CH3), ꢁ4.6 (CH3); MS (CI) m/z 222 (13% [M+NH4]+),
205 (30% [M+H]+), 187 (7% [MꢁOH]+), 132 (19%), 100
(12%), 98 (13%), 74 (28%), 72 (18%), 58 (28%), 52
(100%), 46 (29%), 44 (41%), 36 (53%); HRMS (CI) m/z
found: 205.1624, C10H25O2Si ([M+H]+) requires:
205.1624; [a]2D5 +6.2 (c 1.2, CHCl3).
4.7.4. (S)-2-[(tert-Butyldimethylsilyl)oxy]-butanal 16.
Oxalyl chloride (1.0 g, 7.85 mmol, 0.7 mL) in dry dichloro-
methane (100 mL) was cooled (ꢁ78 ꢀC) and treated with di-
methyl sulfoxide (1.1 g, 14.2 mmol, 1 mL) to give an
effervescent mixture, which was stirred for 10 min. (S)-2-
[(tert-Butyldimethylsilyl)oxy]-butan-1-ol (1.0 g, 4.9 mmol)
dissolved in dichloromethane (5 mL) was added and the
mixture stirred at ꢁ60 ꢀC for 10 min. The solution was
cooled (ꢁ78 ꢀC) and triethylamine (2.97 g, 29.4 mmol,
4 mL) added. After stirring for 2 h at rt the mixture was di-
luted with water (100 mL) and extracted with hexane
(2ꢂ50 mL) and the combined organic fractions washed
with water (2ꢂ40 mL), aqueous acetic acid (7%,
2ꢂ40 mL) and brine (2ꢂ40 mL). Drying (MgSO4) and
evaporation in vacuo gave the title compound (0.92 g,
93%) as a yellow oil. Rf 0.60 in 5% diethyl ether–petrol;
vmax 2953, 2931, 2888, 2858, 2805, 2718, 1737, 1464,
1362, 1254, 1138, 1005, 939, 838, 778, 669; dH 9.62 (1H,
d, J 1.7 Hz, CH), 3.93 (1H, ddd, J 7.0, 5.5, 1.7 Hz, CH),
4.9. (S)-6-Oxo-11-[(tert-butyldimethylsilyl)-oxy]-(4E,9Z)-
tridecadieneal 3a
Methyltriphenylphosphonium iodide (0.32 g, 0.78 mmol)
was suspended in THF (10 mL), cooled (0 ꢀC) and treated
with n-butyllithium (2.0 M, 0.51 mL, 0.86 mmol) with stir-
ring to give an orange coloured solution. After stirring at rt

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C. G. Moore et al. / Tetrahedron 63 (2007) 11771–11780
for 30 min the solution was cooled (ꢁ78 ꢀC) and 17 (0.11 g,
0.39 mmol) was added as a solution in THF (1 mL). The re-
sulting pale yellow mixture was left to stir at rt for 2 h then
quenched with water (20 mL) and extracted with ethyl ace-
tate (4ꢂ25 mL). The combined organic fractions were
washed with brine (20 mL), dried (MgSO4) and concen-
trated in vacuo to give a crude yellow oil. This was then dis-
solved in THF (15 mL) and treated with freshly distilled
succinaldehyde (0.53 g, 6.2 mmol). After stirring for 42 h
the solvent was evaporated and the crude material purified
by column chromatography on silica gel (25% diethyl
ether–petrol) to give 3a (0.06 g, 42%). Rf 0.23 in 35% diethyl
ether/petrol; vmax 2956, 2929, 2856, 1727, 1698, 1674, 1631,
1409, 1253, 1080, 1007, 979, 836, 727, 668; dH 9.82 (1H, s,
CH), 6.83 (1H, dt, J 16.0, 6.5 Hz, CH), 6.14 (1H, dt, J 16.0,
2.1 Hz, CH), 5.42–5.26 (2H, m, 2ꢂCH), 4.34 (1H, m, CH),
2.68–2.40 (6H, m, 3ꢂCH2), 2.34 (2H, m, CH2), 1.51–1.27
(2H, m, CH2), 0.89 (9H, s, 3ꢂCH3), 0.87 (3H, t, J 7.5 Hz,
CH3), 0.06 (3H, s, CH3), 0.03 (3H, s, CH3); dC 200.3 (C),
199.2 (C), 144.4 (CH), 135.1 (CH), 130.9 (CH), 126.9
(CH), 70.0 (CH), 41.9 (CH2), 40.0 (CH2), 31.3 (CH2), 25.8
(3ꢂCH3), 24.6 (CH2), 22.3 (CH2), 18.2 (C), 9.8 (CH3),
ꢁ4.4 (CH3), ꢁ4.8 (CH3); MS (CI) m/z 356 (10%
[M+NH4]+), 338 (5% [M]+), 281 (10% [Mꢁ(tBu)]+), 207
(100% [MꢁTBDMSO]+); HRMS (CI) m/z found:
356.2621, C19H38NO3Si ([M+NH4]+) requires: 356.2621;
[a]2D5 +16.6 (c 1.1, CHCl3).
(70–85% ethyl acetate in petrol) to give the title compound
(2.03 g, 51%) as a dense orange oil. Rf 0.13 in 70% ethyl ace-
tate–petrol; vmax 3059, 2956, 2855, 1727, 1525, 1482, 1438,
1400, 1254, 1107, 1028, 874, 836, 693; dH 7.72–7.42 (15H,
m, 3ꢂPh), 4.13 (1H, m, CH), 3.66 (1H, br s, CH), 2.31
(2H, t, J 7.4 Hz, CH2), 1.69 (2H, m, CH2), 1.50 (2H, m,
CH2), 1.29 (3H, d, J 7.2 Hz, CH3), 0.89 (9H, s, 3ꢂCH3),
0.05 (6H, s, 2ꢂCH3); dC 194.0 (C), 133.1, 133.0, 132.2,
132.0, 131.9, 128.9, 128.7, 128.6, 128.4 (15ꢂCH), 128.1,
126.7 (3ꢂC), 68.8 (CH), 51.0 (d, JC–P 107 Hz, CH), 41.7
(d, JC–P 14.4 Hz, CH2), 39.8 (CH2), 26.0 (3ꢂCH3), 23.8
(CH3), 23.7 (CH2), 18.2 (C), ꢁ4.4 (CH3), ꢁ4.6 (CH3); MS
(CI) m/z 505 (11% [M+H]+), 279 (24%), 263 (100%), 245
(44%), 187 (41%), 113 (45%); HRMS (CI) m/z found:
505.2691, C31H42O2PSi ([M+H]+) requires: 505.2692; [a]2D2
ꢁ2.1 (c 1.0, CHCl3).
4.12. (2R,18S),(7E,11E,16Z)-2-[(tert-Butyldimethylsilyl)-
oxy]-18-[(tert-butyldiphenylsilyl)oxy]-eicosa-7,11,16-tri-
ene-6,13-dione 25
A solution of phosphorane 24 (0.24 g, 0.47 mmol) in
CH2Cl2 (1 mL) was added dropwise to a cooled (0 ꢀC) solu-
tion of aldehyde 3b (0.15 g, 0.324 mmol) in CH2Cl2 (1 mL)
and the reaction stirred for 36 h at rt. The solvent was evap-
orated and the remaining material purified by column chro-
matography on silica gel (gradient elution: 3–20% ethyl
acetate–petrol) to give 25 (0.16 g, 72%) as a pale yellow
oil. Rf 0.59 in 20% ethyl acetate–petrol; vmax 3068, 3007,
2961, 2930, 2891, 2856, 1697, 1675, 1630, 1472, 1428,
1361, 1254, 1110, 1046, 983, 910, 836, 775, 735, 703; dH
7.69–7.66 (4H, m, 4ꢂCH), 7.42–7.32 (6H, m, 6ꢂCH),
6.81 (1H, m, CH), 6.67 (1H, m, CH), 6.14 (1H, d,
J 15.8 Hz, CH), 6.01 (1H, d, J 15.8 Hz, CH), 5.44 (1H, dt,
J 10.9, 1.6 Hz, CH), 5.18 (1H, dt, J 10.9, 7.4 Hz, CH),
4.38 (1H, m, CH), 4.14 (1H, m, CH), 2.54 (2H, t, J 7.2 Hz,
CH2), 2.38 (4H, m, 2ꢂCH2), 2.22 (2H, t, J 6.4 Hz, CH2),
1.92 (2H, m, CH2), 1.69–1.49 (4H, m, 2ꢂCH2), 1.48–1.36
(2H, m, CH2), 1.13 (3H, d, J 6.1 Hz, CH3), 1.05 (9H, s,
3ꢂCH3), 0.89 (9H, s, 3ꢂCH3), 0.80 (3H, t, J 7.4 Hz,
CH3), 0.06 (6H, s, 2ꢂCH3); dC 199.9 (C), 198.6 (C), 144.6
(CH), 144.5 (CH), 136.0 (2ꢂCH), 135.9 (2ꢂCH), 134.4
(C), 134.1 (C), 133.8 (CH), 130.8 (CH), 130.7 (CH), 129.5
(CH), 129.3 (CH), 127.7 (CH), 127.5 (2ꢂCH), 127.7
(2ꢂCH), 70.5 (CH), 68.4 (CH), 40.5 (CH2), 39.8 (CH2),
39.1 (CH2), 31.1 (CH2), 30.7 (2ꢂCH2), 26.9 (3ꢂCH3),
25.9 (3ꢂCH3), 23.7 (CH3), 21.9 (CH2), 20.4 (CH2), 19.3
(C), 18.3 (C), 9.3 (CH3), ꢁ4.4 (CH3), ꢁ4.7 (CH3);
MS (CI) m/z 706 (75% [M+NH4]+), 438 (49%), 433
(100%), 297 (52%); HRMS (CI) m/z found: 706.4687,
C42H68NO4Si2 ([M+NH4]+) requires: 706.4687; [a]2D6 ꢁ9.4
(c 0.9, CHCl3).
4.10. tert-Butyl (13S,50R),(2E/Z,6E,11Z)-2-{50-[(tert-bu-
tyldimethylsilyl)oxy]-10-oxo-hexanoyl}-[(13-tert-butyl-
dimethylsilyl)oxy]-8-oxopentadeca-2,6,11-trienoate 2
Aldehyde 3a (0.055 g, 0.16 mmol), b-keto ester 4 (0.071 g,
0.19 mmol) and sodium sulfate (0.05 g) were mixed together
with stirring in dry dichloromethane (0.5 mL) for 10 min at
ꢁ20 ꢀC. Morpholine (6 mg, 0.064 mmol, 0.006 mL) was
added and the reaction stirred for 6 h at ꢁ20 ꢀC. The mixture
was diluted with hexane (5 mL), washed with aqueous acetic
acid solution (2%, 2ꢂ15 mL) and water (2ꢂ15 mL) then
dried (MgSO4) and evaporated to yield an orange oil. Purifi-
cation on silica gel (gradient elution: 5–30% diethyl ether in
petrol) gave the required enone 2 (0.023 g, 22%) as an oil
with an estimated purity of 75%. Assignable data; Rf 0.63
in 40% diethyl ether–petrol. dH 6.89 (1H, m, CH), 6.67
(1H, t, J 7.4 Hz, CH), 6.09 (1H, dd, J 16.2, 4.0 Hz, CH),
5.33 (2H, m, 2ꢂCH), 4.33 (1H, dt, J 7.1, 6.3 Hz, CH), 3.80
(1H, m, CH), 2.61 (2H, t, J 6.0 Hz, CH2), 2.47 (2H, m, CH2),
2.36 (2H, t, J 7.7 Hz, CH2), 1.72–1.18 (19H, m, 5ꢂCH2,
tBu), 1.13 (3H, d, J 6.1 Hz, CH3), 0.88 (21H, m, CH3,
t
2ꢂ Bu), 0.05 (12H, s, 4ꢂCH3).
4.11. (R)-6-[(tert-Butyldimethylsilyl)oxy]-1-(triphenyl-
phosphanylidene)-heptan-2-one 24
4.13. (2S,7S,3a0S,70R,8a0R,600R)-Dispiro[7-ethyl-5Z-oxe-
pene-2,40-(10,20,30,40,70,80-hexahydro-5H-50,60,8b0-tri-
azaacenaphthylene)-600-methyl-70,200-tetrahydropyran]-
60-ium tetrafluoroborate 27
Acetylmethylene triphenylphosphorane (3.80 g, 11.94 mmol)
was suspended in THF (70 mL), cooled to ꢁ78 ꢀC and n-bu-
tyllithium (2.33 M, 11.94 mmol, 5.12 mL) slowly added. The
deep red solution formed was warmed (ꢁ55 ꢀC) and stirred
for 1 h before re-cooling to ꢁ78 ꢀC. Iodide 14 (2.50 g,
7.96 mmol) in THF (15 mL) was added and the mixture
was stirred for 16 h whilst warming to rt. The solvent was re-
moved under reduced pressure leaving a crude oily residue,
which was purified by column chromatography on silica gel
Guanidine (0.028 g, 0.48 mmol) dissolved in cooled (0 ꢀC)
DMF (1 mL) was added to a cooled (0 ꢀC) solution of 25
(0.30 g, 0.435 mmol) in DMF (3 mL). The resulting green
solution was stirred at 0 ꢀC for 6 h eventually turning black.
The reaction mixture was diluted with water (3.5 mL) and

C. G. Moore et al. / Tetrahedron 63 (2007) 11771–11780
11779
a cold (0 ꢀC) methanolic HCl solution (10 mL, from acetyl
chloride (0.5 mL) and methanol (9.5 mL); CAUTION! exo-
thermic reaction on mixing) and stirred for 16 h whilst
warming to ambient temperature. Further water (40 mL)
was added and the mixture extracted with CH2Cl2
(4ꢂ40 mL) and the combined organic fractions washed se-
quentially with water (2ꢂ50 mL), saturated lithium bromide
solution (50 mL) and water (60 mL). After drying (MgSO4)
and concentration in vacuo, the resulting dense brown oil
was dissolved in THF (1 mL) and treated with tetrabutylam-
monium fluoride (1 M in THF, 2.2 mmol, 2.2 mL) and
stirred at 25–30 ꢀC for 3 h and then at ambient temperature
for a further 64 h. Water (10 mL) was added and the reaction
extracted with CH2Cl2 (3ꢂ20 mL). The combined organic
fractions were washed with water (25 mL), dried (MgSO4)
and concentrated in vacuo. The remaining brown oil was dis-
solved in methanol (1 mL) before being treated, at 0 ꢀC with
a solution of methanolic HCl (8 mL, from acetyl chloride
(0.4 mL) and methanol (7.6 mL); CAUTION! exothermic
reaction on mixing). After 4 h, water (10 mL) was added
and the reaction extracted with CH2Cl2 (6ꢂ20 mL) and the
combined organic fractions washed with water (50 mL).
Concentration of the solvent gave a light brown oil, which
was dissolved in CH2Cl2 (2 mL) and stirred vigorously for
3 h in the presence of an aqueous solution of saturated so-
dium tetrafluoroborate (3 mL). Dichloromethane (10 mL)
was added and the organic layer separated, dried (MgSO4)
and concentrated in vacuo to give a brown oil, which was pu-
rified by column chromatography on silica gel (gradient elu-
tion: 0–5% MeOH/CH2Cl2) to give 27$HBF4 (0.036 g, 18%)
as a gum. Rf 0.10 in 3% methanol–dichloromethane; vmax
3224, 2975, 2933, 2868, 1656, 1604, 1445, 1342, 1236,
1066, 1023; dH (500 MHz) 7.89 (1H, br s, NH), 7.83 (1H,
br s, NH), 5.66 (1H, ddt, J 11.4, 7.7, 2.4 Hz, CH), 5.49 (1H,
dt, J 11.0, 2.8 Hz, CH), 4.47 (1H, br d, J 9.8 Hz, CH), 4.06
(2H, m, 2ꢂCH), 3.81 (1H, ddq, J 12.6, 6.5, 2.8 Hz, CH),
2.59 (1H, dd, J 12.7, 5.7 Hz, CH), 2.55 (1H, br t, J 13.7 Hz,
CH), 2.32 (2H, m, 2ꢂCH) 2.28 (1H, m, CH), 2.19 (1H, dd,
J 14.0, 5.7 Hz, CH), 2.16 (1H, m, CH), 2.06 (1H, m, CH),
1.87 (1H, dd, J 14.3, 5.7 Hz, CH), 1.72 (3H, m, 3ꢂCH),
1.70 (1H, m, CH), 1.69 (1H, m, CH), 1.62 (1H, m, CH), 1.52
(1H, m, CH), 1.49 (1H, t, J 12.7 Hz, CH), 1.42 (1H, m, CH),
1.36 (1H, t, J 12.4 Hz, CH), 1.20 (1H, m, CH), 1.06 (3H, J
6.4 Hz, CH3), 0.83 (3H, t, J 7.2 Hz, CH3); dC (125 MHz)
147.7 (C), 133.6 (CH), 129.8 (CH), 84.1 (C), 80.5 (C), 70.9
(C), 67.2 (C), 53.5 (CH), 52.0 (CH), 39.8 (CH2), 37.1 (CH2),
36.5 (CH2), 33.6 (CH2), 32.2 (CH2), 30.0 (CH2), 29.8 (CH2),
29.2 (CH2), 23.7 (CH2), 21.7 (CH3), 17.9 (CH2), 10.2 (CH3);
MS (CI) m/z 360 (5% [M+H]+); HRMS (EI) m/z found:
359.2566, C21H33N3O2 ([M]+) requires: 359.2573; [a]2D6
ꢁ8.2 (c 0.2, CH2Cl2).
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Acknowledgements
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Thanks are given to the EPSRC for funding awards to
H.L.W. and C.G.M. and to the EPSRC Mass Spectrometry
centre at Swansea.
15. Nudelman, A.; Kelner, R.; Broida, N.; Gottlieb, H. E. Synthesis
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16. Overman17 and Nagasawa18 have reported difficulties with the
acid mediated cyclisation of the allylic alcohol portion of pre-
cursors similar in structure to 25 and 26.
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