Synthesis of the non-adjacent bis-THF core of cis-sylvaticin using a double oxidative cyclisation

Article abstract of DOI:10.1039/b813201a

A short synthesis of the non-adjacent bis-THF core of the Annonaceous acetogenin cis-sylvaticin (1) is described. C₂ Symmetrical (Z,E,E,Z)- and (E,E,E,E)-tetraenes 5 and 6 were synthesised in six and three steps respectively from (1E,5E,9E)-cyclododeca-1,5,9-triene. Subsequent permanganate promoted asymmetric bi-directional oxidative cyclisation of tetraene 5 was used to create the non-adjacent bis-THF core of 1, installing seven of the nine stereogenic centres present in the natural product in a single step. Desymmetrisation of the oxidative cyclisation product by mono-tosylation gave access to a C11-C32 fragment of cis-sylvaticin.

Full text of DOI:10.1039/b813201a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of the non-adjacent bis-THF core of cis-sylvaticin using a double
oxidative cyclisation†
Riaz A. Bhunnoo,a Heather Hobbs,b Dramane I. Laine´,c Mark E. Lighta and Richard C. D. Brown*a
Received 31st July 2008, Accepted 28th November 2008
First published as an Advance Article on the web 28th January 2009
DOI: 10.1039/b813201a
A short synthesis of the non-adjacent bis-THF core of the Annonaceous acetogenin cis-sylvaticin (1) is
described. C2 Symmetrical (Z,E,E,Z)- and (E,E,E,E)-tetraenes 5 and 6 were synthesised in six and
three steps respectively from (1E,5E,9E)-cyclododeca-1,5,9-triene. Subsequent permanganate
promoted asymmetric bi-directional oxidative cyclisation of tetraene 5 was used to create the
non-adjacent bis-THF core of 1, installing seven of the nine stereogenic centres present in the natural
product in a single step. Desymmetrisation of the oxidative cyclisation product by mono-tosylation gave
access to a C11–C32 fragment of cis-sylvaticin.
Introduction
The Annonaceous acetogenin family of natural products has
attracted considerable interest due to the discovery of potent
cytotoxic antitumour activity along with various other biological
effects.1 Recently we described a total synthesis of cis-sylvaticin
(1),2 a C37 non-adjacent bis-THF acetogenin isolated from leaf
extracts of the tropical fruit tree Rollinia mucosa.3 The prominent
challenge to be addressed during a total synthesis of 1 is the
stereocontrolled assembly of its non-adjacent bis-THF core.4 In
our published approach this was achieved through the coupling
of two major THF-containing fragments, where the non-adjacent
bis-THF was formed using a tethered metathesis reaction (Fig. 1).
Donohoe et al. also reported a total synthesis of cis-sylvaticin using
an osmium-catalysed double oxidative cyclisation of a protected
tetrahydroxydiene.4f
Prior to our successful total synthesis of cis-sylvaticin using the
fragment-based approach outlined in Fig. 1, we investigated a bi-
directional strategy. Herein we report the results from these earlier
Fig. 1 Our previously reported total synthesis of cis-sylvaticin.
studies using double oxidative cyclisation of tetraenes to install
the non-adjacent bis-THF core and seven of the nine stereogenic
centres present in the natural product.
by diastereoselective double oxidative cyclisation of (Z,E,E,Z)-
tetraene 5, using a sultam chiral auxiliary to direct the facial
selectivity. The control of polyene geometry is of key significance
due to the stereospecific addition of vicinal oxygen functionalities
across the double bond during the oxidative cyclisation, which
results in threo- or erythro-configured products from E- and Z-
alkenes respectively.6,7 The C23–C24 erythro configuration present
in the natural product 1 would be most readily accessed from a
Z-alkene precursor such as 5. Oxidative cyclisation of the all E-
tetraene 6 would lead to a threo relationship between C23 and
C24, which for the total synthesis of 1, would have to be corrected
at a later stage by inversion of the C24 hydroxyl group.
Synthetic work began with the oxidative cleavage of (1E,5E,9E)-
cyclododeca-1,5,9-triene (7) to give dialdehyde 8 following the
protocol reported by Hoye and Ye (Scheme 1).8 Subsequent Z-
selective olefination with Ando’s phosphonate reagent 11 under
modified Still–Gennari conditions afforded diethyl ester 9 in 61%
yield.9 The (2E,6E,10E,14Z)-isomer was isolated in 15% yield,
Results and discussion
Inspection of the non-adjacent bis-THF core of cis-sylvaticin
reveals that it could be derived from C2 symmetrical precursors
such as the double oxidative cyclisation products 3 or 4 (Fig. 2).
Desymmetrisation could be achieved by a selective reaction at
either of the homotopic termini present in various intermediates
including the bis-epoxide 2.5 The bis-THF 3 could be obtained
aThe School of Chemistry, University of Southampton, Highfield, Southamp-
ton, UK SO17 1BJ. E-mail: rcb1@soton.ac.uk; Fax: + 44 (0)2380 593781;
Tel: + 44 (0)2380 594108
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, UK SG1 2NY
cGlaxoSmithKline, RI CEDD, 709 Swedeland Road, P.O. Box 1539, King
of Prussia, PA, 19406-093, USA
† CCDC reference number 697249. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b813201a
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olefination with sultam derived phosphonates, but these reactions
were unselective.
The corresponding all E-tetraenedioyl bis-sultam ent-6 was
more readily synthesised, requiring just one step from the dialde-
hyde 8 by direct HWE reaction with phosphonate 12 (Scheme 1).10
The (1S,2R)-camphorsultam auxiliary was employed, due to its
availability in our laboratory. However, it should be noted that the
(1R,2S)-camphorsultam would be required in order to establish
the correct absolute configuration required for the synthesis of
cis-sylvaticin (1).
Oxidative cyclisation of the tetraene ent-6 produced an insep-
arable mixture of bis-THF-tetrols ent-4 and 13 in a combined
yield of 28% (Scheme 2), thus demonstrating the viability of the
double oxidative cyclisation. We were not able to determine the
1
diastereoisomeric ratio from the H NMR, but an approximate
ratio of 3 : 1 (ent-4 : 13) was estimated from the 13C NMR
spectrum of the mixture. No further optimisation of this oxidative
cyclisation was carried out, and our attention moved to the
(Z,E,E,Z)-tetraene 5, which would give the correctly configured
non-adjacent bis-THF directly.
Fig. 2 Two directional synthetic approach to cis-sylvaticin.
Scheme 2 Oxidative cyclisation of tetraene ent-6. Reagents and conditions:
(i) KMnO4 (2.8 equiv), AcOH–acetone (2 : 3), -30 ◦C.
A variety of conditions were explored in order to improve the
efficiency of the double oxidative cyclisation of (2Z,6E,10E,14Z)-
tetraene 5 (Scheme 3). In previous studies using more lipophilic
substrates,10,11 phase-transfer conditions or AcOH–acetone mix-
tures had been found to give the best results. In the present
study, the most efficient conversion was obtained using NaMnO4
as the oxidant in aqueous acetone. The use of the sodium salt
greatly increases the solubility of the permanganate ion in the
aqueous mixture. Under these conditions the oxidative cyclisation
products 3 and 14 were obtained as an inseparable mixture in
a combined yield of 41%. This mixture of stereoisomers was
used in the subsequent reactions. A third C2 symmetrical minor
diastereoisomer and a hydroxyketone by-product were isolated
Scheme 1 Synthesis of the tetraenes 5 and ent-6. Reagents and conditions:
(i) OsO4, NMO; (ii) NaIO4–SiO2; (iii) 12, toluene, NaH, -10 ◦C→rt; (iv) 11,
KHMDS, 18-crown-6, THF; (v) NaOH, NaHCO3, MeOH–H2O, 95 ◦C;
(vi) (COCl)2, CH2Cl2, DMF, 0 ◦C→rt; then (1S,2R)-camphorsultam,
NaH, toluene, -10 ◦C→rt.
which corresponds to a Z : E selectivity ratio of ~9 : 1 per
olefination. Following hydrolysis of diester 9, the resultant diacid
10 was coupled to the (1S,2R)-camphorsultam via the bis-acid
chloride. The coupling with the sodium salt of the sultam was
carried out in toluene, as polar solvents promoted isomerisation
of the Z-enoyl systems and formation of by-products due to
1,4-addition of the auxiliary. We also attempted to effect cis-
Scheme 3 Oxidative cyclisation of tetraene 5. Reagents and conditions:
(i) NaMnO4 (3.0 equiv), AcOH–acetone–buffer, -30 ◦C→-10 ◦C.
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but repeated purification prevented us from determining accurate
yields for these compounds.
ratio of 3 : 1 (15 : 16), was clearly evident from inspection of the
13C NMR spectrum. Unfortunately, the stereoisomers were still
inseparable by silica gel column chromatography.
Curiously, this mixture of oxidative cyclisation products dis-
1
played a single set of H and 13C NMR signals. Based on the
It was observed that when 1,4-dioxane was used as the
reaction solvent the mono-tosylates 17 and 18 could be obtained
in moderate yield, effecting desymmetrisation at this juncture
(Scheme 4). Pleasingly the mono-tosylates afforded the mono-
epoxides 19 and 20 respectively in 57% yield, although still as
an inseparable mixture of diastereoisomers. Opening the mono-
epoxide with nonylmagnesium bromide inserted the C24–C32
alkyl chain, and afforded an intermediate 21 that is suitable for
progression to cis-sylvaticin.
At this point with only limited yields of desymmetrised
materials, combined with difficulties encountered separating the
diastereoisomeric mixtures, we decided to investigate desymmetri-
sation of a bis-epoxide intermediate (Scheme 5). The bis-epoxides
2 and 25 were prepared in high yields from tetraols 23 and
24 (dr = 3 : 1, 13C NMR) via the corresponding bis-tosylates.
Desymmetrisation at this point through the attempted addition of
organocuprate reagents proved problematic generating a mixture
of starting material, mono- and bis-ring opened products which
could not be separated by chromatography.
diastereoselectivities observed in the oxidative cyclisations of
dienoyl sultams (dr = 6 : 1→10 : 1) we would have expected
two major diastereoisomers in an approximate ratio of 3 : 1.2,10–12
It later emerged (after reductive cleavage of the chiral auxiliaries)
that we had indeed obtained a mixture of diastereoisomers 3 and
14 (dr ~ 3 : 1) which were indistinguishable on the basis of their
spectroscopic data (vide infra).
Although the yield of the bis-THF oxidative cyclisation product
was modest, the installation of eight new stereogenic centres in a
single reaction step was an impressive achievement. Furthermore,
structurally complex non-adjacent bis-THF intermediates 3 and
ent-4 had been obtained from a commercial triene in four and
seven steps respectively. With these valuable intermediates secured,
we next needed to address the desymmetrisation and introduce
either of the required sidechains present in 1.5 Two strategies
were explored, the first focussing on formation of a mono-epoxide
intermediate (Scheme 4). Reductive cleavage of the chiral auxiliary
from the diastereoisomeric mixture of 3 and 14 returned the highly
water soluble C2 symmetrical and meso-hexols 15 and 16 in a 62%
yield. At this stage the presence of two diastereoisomers, in a
However, protection of the 1,4-diols as TBS ethers led to
three epoxides (26–28),12 which were separable by column
Scheme 4 Desymmetrisation by mono-tosylation. Reagents and conditions: (i) LiBH4, THF, -10 ◦C; (ii) Bu2SnO (1.25 equiv.), dioxane, TsCl (1.2 equiv.);
(iii) DBU, CH2Cl2, 0 ◦C; (iv) C9H19MgBr, CuI, THF, -70→-40 ◦C.
Scheme 5 Bi-directional approach towards cis-sylvaticin. Reagents and conditions: (i) Bu2SnO, C6H6, TsCl; (ii) DBU, CH2Cl2, 0 ◦C; (iii) 2,6-lutidine,
TBSOTf, CH2Cl2, -10 ◦C.
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chromatography. Significantly, for the first time we were able to
separate the desired chiral diastereoisomer 26 from the meso com-
pound 28. Furthermore, the minor diastereoisomer 28 provided a
crystal structure that allowed us to confirm its assignment as the
meso stereoisomer (Fig. 3).13 The relatively low mass recovery from
the silylation was in part due to the low reactivity of the secondary
alcohol groups flanking the cis-THF rings, and these reactions
were complicated by epoxide opening to give chlorohydrins when
TBSCl was employed. Rapid silylation of 2/25 occurred in the
presence of TBSOTf, although decomposition of the epoxide
functionalities could not be completely avoided.
wavenumbers (cm-1) and are described as strong (s), medium
(m), weak (w) or broad (br). Melting points were measured
on a Gallenkamp electrothermal melting point apparatus. Low-
resolution mass spectra were obtained on a Fisons VG platform
single quadrupole mass spectrometer in either chemical ionisation
or electron impact ionisation mode or on a Micromass platform
mass analyser with an electrospray ion source. All reactions were
conducted under nitrogen atmosphere unless otherwise stated.
1,16-(2R)-N-[(2E,6E,10E,14E)-16-Oxo-2,6,10,14-
hexadecatetraenoyl]-di-camphor-10,2-sultam (ent-6)
To a stirred solution of diethyl-2-oxo-2-((1S,2R)-N-camphor-
10,2-sultam)-ethylphosphonate (12, 405 mg, 1.04 mmol) in THF
(15 mL) at 0 ◦C was added NaH (60% dispersion in mineral
oil, 41 mg, 1.04 mmol). The mixture was warmed to rt over
30 min before cooling to 0 ◦C. A solution of (4E,8E)-dodeca-
4,8-dienedial (8) (100 mg, 0.52 mmol) in THF (5 mL) was added
dropwise and the mixture warmed to rt over 14 h. H2O (30 mL)
and EtOAc (50 mL) were added, the organic layer was separated
and the aqueous layer was extracted with EtOAc (2 ¥ 50 mL). The
combined organic phases were dried (MgSO4) and concentrated
in vacuo to give a yellow oil (402 mg). Purification on SiO2 (3 ¥
15 cm) eluting with EtOAc–hexane (1 : 4→2 : 3) afforded the title
compound as a colourless oil (292 mg, 0.44 mmol, 84%). [a]D25
-78.4 (c 0.56 in CHCl3); nmax (neat)/cm-1 2959 m, 2941 m, 2892 w,
2848 w, 1680 s and 1638 s; dH(400 MHz; CDCl3) 7.08 (2H, dt, J
15.1, 7.0, 2 ¥ CHCHC(O)), 6.56 (2H, d, J 15.1, 2 ¥ CHCHC(O)),
5.50–5.35 (4H, m, 2 ¥ CH2CHCHCH2), 3.93 (2H, dd, J 7.5, 5.3,
2 ¥ CHN), 3.51 (2H, d, J 13.6, 2 ¥ CHHSO2), 3.43 (2H, d, J 13.6,
2 ¥ CHHSO2), 2.31 (4H, q, J 7.0, 2 ¥ CH2CHCHC(O)), 2.20–2.06
(8H, m, 2 ¥ CH2CH2CHCHC(O) and 2 ¥ CH2CHN), 2.05–2.00
(4H, m, CHCH2CH2CH), 1.97–1.84 (6H, m, 2 ¥ CHCH2CHN
and 2 ¥ CH2CHCH2CHN), 1.47–1.32 (4H, m, 2 ¥ CH2CCHN),
1.18 (6H, s, 2 ¥ CH3), 0.98 (6H, s, 2 ¥ CH3); dC(100 MHz; CDCl3)
164.2 (C), 150.4 (CH), 131.2 (CH), 128.8 (CH), 121.2 (CH), 65.3
(CH), 53.3 (CH2), 48.6 (C), 47.9 (C), 44.9 (CH), 38.7 (CH2), 33.0
(CH2), 32.7 (CH2), 32.6 (CH2), 31.0 (CH2), 26.6 (CH2), 21.0 (CH3),
20.0 (CH3); LRMS (ES+) m/z 695 [M + Na]+; HRMS (ES+)
C36H52N2O6S2Na+ Calcd. 695.3159, found 695.3144.
Fig. 3 X-Ray structure of meso-bis-epoxide 28, thermal ellipsoids
drawn at the 50% probability level. The molecule lies on a centre of
inversion.
Mono-addition of organometallic nucleophiles to C2 sym-
metrical bis-epoxides has been demonstrated previously as a
desymmetrisation strategy,8 and this will be the focus of future
studies. However, more efficient access to a suitably protected
isomerically pure bis-epoxide will first be required. We have
recently discovered that epoxyalcohols structurally similar to 3
can be protected using MOM-Cl in high yield without disrupting
the epoxide functionality.2 It is likely that revision of the protecting
group strategy will provide the key to completing the total
synthesis of 1 following our two-directional approach.
Conclusions
(2Z,6E,10E,14Z)-Diethyl hexadeca-2,6,10,14-tetraenedioate (9)
We have described a short synthesis of the non-adjacent bis-
THF core of cis-sylvaticin (1) with the key oxidative cyclisation
installing eight stereogenic centres in a single step. Separation of
the major diastereoisomers has been realised through silylation
of the C16/C19 hydroxyl groups, and we have also shown that
desymmetrisation of C2 symmetrical intermediates is possible
through mono-functionalisation of hexaol 15 to give the C10–C32
portion of the natural product.
To a stirred solution of phosphonate (11, 1.98 g, 6.19 mmo◦ l)
and 18-crown-6 (1.64 g, 6.19 mmol) in THF (50 mL) at -10 C
was added KHMDS (0.5 M in toluene, 12.4 mL, 6.19 mmol)
◦
dropwise. After 5 min the yellow mixture was cooled to -65 C
and (4E,8E)-dodeca-4,8-dienedial (8, 0.572 g, 2.95 mmol) in THF
(10 mL) was added dropwise. The mixture was allowed to warm
to -50 ◦C for 1 h before H2O (50 mL) and Et2O (50 mL) were
added. The organic layer was separated and the aqueous layer
was extracted with Et2O (2 ¥ 50 mL). The combined organic
phases were dried (MgSO4) and concentrated in vacuo to give
a yellow oil (2.50 g). Purification on SiO2 (5 ¥ 15 cm) eluting
with Et2O–hexane (3 : 97→1 : 19) gave (2Z,6E,10E,14Z)-diethyl
hexadeca-2,6,10,14-tetraenedioate (9, 0.601 g, 1.80 mmol, 61%)
as a colourless oil. Also isolated was (2Z,6E,10E,14E)-diethyl
hexadeca-2,6,10,14-tetraenedioate (0.150 g, 0.45 mmol, 15%).
Data for 9: nmax (neat)/cm-1 3038 w, 2983 w, 2910 w, 2845 w,
Experimental
1H NMR and 13C NMR spectra were recorded on JEOL GX270,
Bruker AC300, Bruker AM300 or Bruker DPX400 spectrometers.
J values are given in Hz. IR spectra were recorded on a Perkin–
Elmer 1600 FT-IR instrument, a Bio-Rad FTS 135 instrument
using a Golden Gate adaptor or a Nicolet Impact 400 instrument
using a Thunderdome adaptor. Absorptions were recorded in
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1718 s and 1643 m; dH(400 MHz; CDCl3) 6.21 (2H, dt, J 11.6, 7.3,
2 ¥ CHCHCO2Et), 5.76 (2H, dt, J 11.6, 1.5, 2 ¥ CHCHCO2Et),
5.50–5.36 (4H, m, 2 ¥ CH2CHCHCH2), 4.17 (4H, q, J 7.0, 2 ¥
CH2CH3), 2.71 (4H, qd, J 7.3, 1.5, 2 ¥ CH2CHCHCO2Et), 2.14
(4H, q, J 7.3, 2 ¥ CH2CH2CH CHCO2Et), 2.06–2.01 (4H, m, 2 ¥
CH2), 1.29 (6H, t, J 7.2, 2 ¥ CH2CH3); dC(100 MHz; CDCl3) 166.6
(C), 149.8 (CH), 131.0 (CH), 129.4 (CH), 120.0 (CH), 59.9 (CH2),
32.7 (CH2), 32.0 (CH2), 28.9 (CH2), 14.4 (CH3); LRMS (ES+) m/z
357 ([M + Na]+); HRMS (ES+) C20H31O4+ Calcd. 335.2217, found
335.2212. Data for (2Z,6E,10E,14E)-diethyl hexadeca-2,6,10,14-
tetraenedioate: nmax (neat)/cm-1 3033 w, 2982 w, 2922 w, 2846 w,
1718 s and 1646 m; dH(400 MHz; CDCl3) 6.96 (1H, dt, J 15.8,
6.8, CHCHCO2Et), 6.21 (1H, dt, J 11.5, 7.1, EtCO2CHCH), 5.82
(1H, dt, J 15.6, 1.5, CHCHCO2Et), 5.76 (1H, dt, J 11.5, 1.5,
EtCO2CHCH), 5.50–5.36 (4H, m, 2 ¥ CHCH), 4.19 (2H, q, J
6.8, CH2CH3), 4.19 (2H, q, J 7.1, CH2CH3), 2.72 (2H, qd, J 7.1,
1.4, CH2CHCHCO2Et), 2.26 (2H, br q, J 7.0, CHCH2), 2.19–
2.11 (2H, m, CH2CH), 2.06–2.01 (4H, m, CH2CH2), 1.29 (6H, t,
J 7.2, 2 ¥ CH2CH3); dC(100 MHz; CDCl3) 166.8 (C), 166.6 (C),
149.8 (CH), 148.7 (CH), 131.1 (CH), 130.8 (CH), 129.4 (CH),
128.9 (CH), 121.7 (CH), 120.0 (CH), 60.2 (CH2), 59.9 (CH2), 32.7
(CH2), 32.6 (CH2), 32.4 (CH2), 32.0 (CH2), 31.1 (CH2), 29.0 (CH2),
14.4 (CH3); LRMS (ES+) m/z 357 ([M + Na]+); HRMS (ES+)
(60% dispersion in mineral oil, 0.418 g, 10.4 mmol) [CAUTION:
evolution of H2 gas] and the mixture warmed to rt over 30 min.
The mixture was cooled to -10 ◦C and crude acid chloride (1.40 g)
in toluene (40 mL) was added dropwise. The mixture was stirred
for 45 min at -10 ◦C then warmed to rt over 45 min. The mixture
◦
was cooled to 0 C before H2O (50 mL) and Et2O (50 mL) were
added. The organic layer was separated and the aqueous layer was
extracted with Et2O (2 ¥ 50 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo to give a yellow
oil (3.00 g). Purification on SiO2 (5 ¥ 15 cm) eluting with EtOAc–
hexane (1 : 4) afforded a white foam (2.12 g, 3.16 mmol, 68%). [a]D25
-72.1 (c 0.75 in CHCl3); nmax (neat)/cm-1 2959 m, 2915 m, 2844 w,
1680 s and 1630 m; dH(400 MHz; CDCl3) 6.45 (2H, dt, J 11.5, 1.5,
2 ¥ CHCHC(O)), 6.32 (2H, dt, J 11.5, 7.1, 2 ¥ CHCHC(O)), 5.50–
5.36 (4H, m, 2 ¥ CHCH), 3.93 (2H, dd, J 7.3, 5.3, 2 ¥ CHN), 3.50
(2H, d, J 13.8, 2 ¥ CHHSO2), 3.43 (2H, d, J 13.8, 2 ¥ CHHSO2),
2.68 (4H, qd, J 7.3, 1.5, 2 ¥ CH2CHCHC(O)), 2.20–2.06 (8H, m,
2 ¥ CHCH2 and 2 ¥ CH2CHN), 2.05–2.00 (4H, m, CH2CH2),
1.98–1.84 (6H, m, 2 ¥ CHCH2CHN and 2 ¥ CH2CHCH2CHN),
1.47–1.32 (4H, m, 2 ¥ CH2CCHN), 1.18 (6H, s, 2 ¥ CH3C), 0.98
(6H, s, 2 ¥ CCH3); dC(100 MHz; CDCl3) 164.3 (C), 151.8 (CH),
131.0 (CH), 129.2 (CH), 119.5 (CH), 65.2 (CH), 53.3 (CH2), 48.5
(C), 47.9 (C), 44.9 (CH), 38.8 (CH2), 33.0 (CH2), 32.7 (CH2), 31.9
(CH2), 29.9 (CH2), 26.7 (CH2), 21.0 (CH3), 20.0 (CH3); LRMS
(ES+) m/z 695 [M + Na]+; HRMS (ES+) C36H52N2O6S2Na+ Calcd.
695.3159, found 695.3144.
+
C20H31O4 Calcd. 335.2217, found 335.2212.
(2Z,6E,10E,14Z)-Hexadeca-2,6,10,14-tetraenedioic acid (10)
To a stirred solution of (2Z,6E,10E,14Z)-dimethyl hexadeca-
2,6,10,14-tetraenedioate (9, 1.10 g, 3.60 mmol) in MeOH (11 mL)
and H2O (33 mL) were added NaOH (1.53 g, 38.2 mmol) a◦nd
NaHCO3 (0.300 g, 3.60 mmol) and the mixture heated at 95 C
for 3 h. The mixture was cooled to rt and washed with CH2Cl2 (3 ¥
20 mL). The aqueous phase was separated, cooled to 0 ◦C and
acidified with aqueous citric acid (30 mL) and 2 M HCl (50 mL)
to pH 1. The mixture was stirred for 30 min before Et2O (100 mL)
was added. The organic layer was separated and the aqueous
layer was extracted with Et2O (2 ¥ 50 mL). The combined organic
phases were dried (MgSO4) and concentrated in vacuo to give a
pale yellow oil (0.92 g, 3.31 mmol, 92%). nmax (neat)/cm-1 2980 m,
2915 br, 2846 m, 1692 s and 1639 m; dH(400 MHz; CDCl3) 6.35
(2H, dt, J 11.6, 7.4, 2 ¥ CHCHCO2H), 5.81 (2H, dt, J 11.6, 1.8,
2 ¥ CHCHCO2H), 5.51–5.37 (4H, m, 2 ¥ CHCH), 2.73 (4H, qd, J
7.4, 1.5, 2 ¥ CH2CHCHCO2H), 2.15 (4H, q, J 7.3, 2 ¥ CHCH2),
2.09–2.03 (4H, m, CH2CH2); dC(100 MHz; CDCl3) 172.2 (C),
152.7 (CH), 131.0 (CH), 129.3 (CH), 119.5 (CH), 32.6 (CH2),
31.9 (CH2), 29.2 (CH2); LRMS (ES-) m/z 391 [M + (CF3CO2)]-;
Oxidative cyclisation products ent-4 and 13
To a stirred solution of the tetraene ent-6 (337 mg, 0.50 mmol),
AcOH (4 mL) and acetone (6 mL) at -30 ◦C was added KMnO4
(222 mg, 1.40 mmol) in one portion and the mixture warmed to
-20 ◦C over 25 min, during which time the mixture changed from
purple to dark brown. A saturated aqueous solution of Na2S2O5
(20 mL) was added to reduce the precipitated brown MnO2,
and the mixture stirred until clear. Brine (10 mL) and EtOAc
(20 mL) were added, the organic layer was separated and the
aqueous layer was extracted with EtOAc (2 ¥ 20 mL) and CH2Cl2
(20 mL). The combined organic phases were dried (MgSO4) and
concentrated in vacuo to give a yellow oil (180 mg). Purification
on SiO2 (2 ¥ 15 cm) eluting with MeOH–CH2Cl2 (1 : 49→3 : 47)
afforded an inseparable mixture of the title diastereoisomers ent-
4/13 (dr ~ 3 : 1) as a white foam (108 mg, 0.140 mmol, 28%).
Physical and spectroscopic data were recorded from the mixture
of diastereoisomers. [a]2D5 -41.0 (c 0.75 in CHCl3); nmax (neat)/cm-1
3455 w, 2961 m, 2884 m and 1690 m; dH(400 MHz; CDCl3)
4.61–4.52 (4H, m, 2 ¥ C(O)CHOH and 2 ¥ C(O)CHOHCH),
3.97 (2H, dd, J 5.2, 7.7, 2 ¥ CHN), 3.88 (2H, td, J 6.8, 4.8,
2 ¥ OCHCHOHCH2), 3.55–3.41 (6H, m, 2 ¥ CH2SO2 and 2 ¥
CHOHCH2), 2.28–2.19 (2H, m, CHHCHN), 2.14–2.01 (6H, m,
CHHCHN and CH2 THF), 1.99–1.83 (10H, m, 2 ¥ CHCH2CHN,
2 ¥ CH2CHCH2CHN and CH2 THF), 1.68 (4H, br, CH2CH2),
1.47–1.31 (4H, m, 2 ¥ CH2CCHN), 1.16 (6H, s, 2 ¥ CH3), 0.97
(6H, s, 2 ¥ CH3); dC(100 MHz; CDCl3) 172.0 (C), 83.4 (CH), 78.9
(CH), 74.0 (CH), 73.7 (CH), 66.0 (CH), 53.2 (CH2), 49.1 (C), 48.0
(C), 44.8 (CH), 38.4 (CH2), 33.1 (CH2), 28.3 (CH2), 26.5 (CH2),
21.1 (CH3), 20.0 (CH3); LRMS (ES+) m/z 795 [M + Na]+; HRMS
(ES+) C36H56N2O12S2Na+ Calcd. 795.3166, found 795.3147.
HRMS (ES-) C16H21O4 Calcd. 277.1445, found 277.1439.
-
1,16-(1S,2R)-N-[(2Z,6E,10E,14Z)-16-Oxo-2,6,10,14-
hexadecatetraenoyl]-di-camphor-10,2-sultam (5)
To a stirred solution of (2Z,6E,10E,14Z)-hexadeca-2,6,10,14-
tetraenedioic acid (10, 1.29 g, 4.64 mmol) and (COCl)2 (0.81 mL,
9.28 mmol) at 0 ◦C in CH2Cl2 (15 mL) was added DMF (0.05 mL)
and the mixture allowed to warm to rt over 3 h. The mixture was
concentrated in vacuo to give the crude acid chloride (1.40 g) as an
orange oil, which was used without further purification. Under an
atmosphere of N2, to a stirred solution of (1S,2R)-camphorsultam
(0.243 g, 1.13 mmol) in toluene (50 mL) at 0 ◦C was added NaH
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Oxidative cyclisation products 3 and 14
(CH), 27.30 (CH2)]; LRMS (ES+) m/z 373 [M + Na]+; HRMS
(ES+) C16H30O8Na+ Calcd. 373.1833, found 373.1840.
To a stirred solution of 1,16-(1S,2R)-N-[(2Z,6E,10E,14Z)-16-
oxo-2,6,10,14-hexadecatetraenoyl]-di-camphor-10,2-sultam (5,
109 mg, 0.16 mmol), phosphate buffer (0.25 mL) and acetone
(4.20 mL) at -30 ◦C was added a mixture of NaMnO4 (0.4 M aq,
1.22 mL, 0.49 mmol) and AcOH (0.05 mL, 0.88 mmol) dropwise
over 10 min. The mixture was allowed to warm to -10 ◦C over
30 min, during which time the mixture turned from purple to dark
brown. A saturated solution of Na2S2O5 (20 mL) was added to
reduce the precipitated brown MnO2, and the mixture stirred until
clear. Brine (20 mL) and EtOAc (50 mL) were added, the organic
layer was separated and the aqueous layer was extracted with
EtOAc (2 ¥ 50 mL) and CH2Cl2 (50 mL). The combined organic
phases were dried (MgSO4) and concentrated in vacuo to give a
pale yellow foam (102 mg). Purification on SiO2 (1.5 ¥ 15 cm)
eluting with MeOH–CH2Cl2 (1 : 49→3 : 47) afforded a mixture
of the title diastereoisomers 3/14 (dr ~ 3 : 1) as a white foam
(51 mg, 0.07 mmol, 41%). Physical and spectroscopic data were
recorded from the mixture of diastereoisomers. [a]2D5 -59.9 (c 0.52
in MeOH); nmax (neat)/cm-1 3503 w, 2958 m, 2881 m and 1692 m;
dH(400 MHz; CDCl3) 4.71 (2H, br d, J 5.0, 2 ¥ C(O)CHOH),
4.37 (2H, appt. q, J 5.0, 2 ¥ C(O)CHOHCH), 3.96–3.91 (2H,
m, 2 ¥ CHN), 3.87 (2H, td, J 6.8, 4.8, 2 ¥ CHCHOHCH2),
3.65 (2H, br, CHOH), 3.55–3.41 (6H, m, 2 ¥ CH2SO2 and 2 ¥
CHOHCH2), 2.25–2.21 (2H, m, CHHCHN), 2.13–1.83 (16H,
m, CHHCHN, CH2 THF, CHCH2CHN, CH2CHCH2CHN),
1.73–1.60 (4H, m, 2 ¥ CHOHCH2), 1.49–1.31 (4H, m, 2 ¥
CH2CCHN), 1.16 (6H, s, 2 ¥ CH3), 0.98 (6H, s, 2 ¥ CH3);
dC(100 MHz; CDCl3) 171.0 (C), 83.1 (CH), 79.3 (CH), 73.9 (CH),
73.0 (CH), 65.5 (CH), 53.0 (CH2), 49.2 (C), 48.0 (C), 44.7 (CH),
38.2 (CH2), 32.9 (CH2), 31.0 (CH2), 28.3 (CH2), 26.7 (CH2),
26.5 (CH2), 20.9 (CH3), 20.0 (CH3); LRMS (ES+) m/z 795 [M +
Na]+; HRMS (ES+) C36H56N2O12S2Na+ Calcd. 795.3167, found
795.3206.
Mono-tosylates 17 and 18
To a stirred solution of the hexaols 15 and 16 (20 mg, 0.06 mmol)
in dioxane (1 mL) at rt was added Bu2SnO (18 mg, 0.07 mmol)
and the mixture heated to reflux for 2 h. The mixture was cooled
to rt and TsCl (13 mg, 0.07 mmol) was added. After 14 h the
mixture was concentrated in vacuo to give a yellow solid (45 mg).
Purification on SiO2 (3.5 ¥ 15 cm) eluting with MeOH–CH2Cl2
(3 : 47→1 : 9) gave the title diastereoisomers 17/18 (dr ~ 3 : 1) as a
colourless oil (10 mg, 0.02 mmol, 35%). Physical and spectroscopic
data were recorded from the mixture of diastereoisomers. NMR
data for the major and minor isomers are indicated where possible.
[a]D25 -11.8 (c 0.50 in CHCl3); nmax (neat)/cm-1 3374 m, 2949 w,
2909 w and 2879 w; dH(400 MHz; CD3OD) 7.81 (2H, d, J 8.0,
2 ¥ C ArH), 7.44 (2H, d, J 8.0, 2 ¥ C ArH), 4.19 (1H, dd, J 3.2,
10.3, TsOCHH), 3.99 (1H, dd, J 6.3, 10.3, TsOCHH), 3.90 (1H,
m, CHOHCH2OTs), 3.84–3.60 (6H, m, CHOH, CHHOH and
CHO), 3.53 (1H, dd, J 4.9, 11.1, CHHOH), 3.46–3.34 (2H, m,
CHOHCH2CH2CHOH), 2.45 (3H, s, CCH3), 2.00–1.35 (12H, m,
CH2); dC(100 MHz; CD3OD) 146.9 (C), 134.8 (C), 131.4 (CH),
129.5 (CH), 84.7 (CH), 84.3 (CH), 81.9 (CH), 80.7 (CH), 75.1
(CH), 74.9 (CH), 74.7 (CH), 73.7 (CH2), 72.8 (CH), 65.4 (CH2),
31.4 (CH2), 31.3 (CH2), 29.0 (CH2), 28.7 (CH2), 28.6 (CH2), 27.7
(CH2), 22.0 (CH3); [Additional peaks corresponding to the minor
diastereoisomer 18: 75.6 (CH), 75.4 (CH), 31.9 (CH2), 31.7 (CH2)];
LRMS (ES+) m/z 527 [M + Na]+; HRMS (ES+) C23H36O10SNa+
Calcd. 527.1921, found 527.1924.
Mono-epoxides 19 and 20
To an ice-cooled solution of the tosylates 17/18 (106 mg,
0.21 mmol) in CH2Cl2 (2 mL) was added DBU (50 mL, 0.32 mmol).
The ice bath was removed and the solution was stirred at ambient
temperature for 1.5 h. Removal of the solvent in vacuo gave a pale
yellow oil (148 mg), which was purified on SiO2 (1.5 ¥ 15 cm)
eluting with MeOH–CH2Cl2 (3 : 47→1 : 9) to return a mixture
of diastereoisomeric mono-epoxides 19/20 (dr ~ 3 : 1, 40 mg,
0.12 mmol, 57%) as a colourless oil. Physical and spectroscopic
data were recorded from the mixture of diastereoisomers. NMR
data for the major and minor isomers are indicated where possible.
[a]D25 +6.9 (c 0.44 in MeOH); nmax (neat)/cm-1 3361 m, 2952 w, 2921
w and 2880 w; dH(400 MHz; CD3OD) 3.92 (1H, appt. q, J 7.0,
OCH), 3.89–3.77 (3H, m, CH2OCHCHO and 2 ¥ CHCHOH),
3.72–3.60 (2H, m, CHOHCHHOH), 3.53 (1H, dd, J 4.3, 11.1,
CHOHCHHOH), 3.52–3.41 (2H, m, CHOHCH2CH2CHOH),
3.09 (1H, td, J 4.0, 2.8, CH2OCHCHO), 2.79 (1H, dd, J 4.0,
5.0, CHHOCHCHO), 2.66 (2H, dd, J 5.0, 2.8, CHHOCHCHO),
2.02–1.58 (12H, m, CH2); dC(100 MHz; CD3OD) 84.7 (CH), 83.9
(CH), 81.5 (CH), 80.3 (CH), 74.7 (CH), 74.6 (CH), 74.5 (CH),
65.0 (CH2), 54.2 (CH), 46.2 (CH2), 30.9 (CH2), 30.5 (CH2), 28.6
(CH2), 28.5 (CH2), 28.3 (CH2), 27.3 (CH2); [Additional peaks
corresponding to the minor diastereoisomer 20: 84.6 (CH), 83.9
(CH), 75.3 (CH), 75.2 (CH), 74.8 (CH), 28.5 (CH2)]; LRMS (ES+)
m/z 355 ([M + Na]+); HRMS (ES+) C16H28O7Na+ Calcd. 355.1727,
found 355.1719.
Hexaols 15 and 16
To a stirred solution of a mixture of the tetraols 3 and 14 (323 mg,
0.42 mmol) in THF (5 mL) at -10 ◦C was added LiBH4 (2 M in
THF, 0.84 mL, 1.67 mmol) dropwise. MeOH (3 mL) was added
after 30 min at -10 ◦C, and the mixture was concentrated in
vacuo to give a white solid (355 mg). Purification on SiO2 (2 ¥
10 cm) eluting with MeOH–CH2Cl2 (1 : 9→7 : 3) gave a mixture
of the title diastereoisomers 15/16 (dr ~ 3 : 1) as a pale yellow oil
(90 mg, 0.26 mmol, 62%). Physical and spectroscopic data were
recorded from the mixture of diastereoisomers. NMR data for
the major and minor isomers are indicated where possible. [a]D25
+3.6 (c 0.13 in MeOH); nmax (neat)/cm-1 3339 s, 2941 m, 2924 m
and 2883 m; dH(400 MHz; CD3OD) 3.75 (2H, td, J 6.8, 5.3, 2 ¥
CHCHOHCH2OH), 3.66 (2H, td, J 6.5, 5.0, 2 ¥ CH2CHOHCH),
3.53 (2H, td, J 5.3, 5.1, 2 ¥ CHOHCH2OH), 3.46 (2H, dd, J
11.0, 4.5, 2 ¥ CHOHCHHOH), 3.37 (2H, dd, J 11.0, 6.3, 2 ¥
CHOHCHHOH), 3.33–3.27 (2H, m, 2 ¥ CH2CHOHCH), 1.83–
1.72 (4H, m, 2 ¥ CH2 THF), 1.67–1.58 (4H, m, CH2), 1.52–1.44
(4H, m, 2 ¥ CH2CHOHCH); dC(100 MHz; CD3OD) for major
isomer 15 83.91 (CH), 81.53 (CH), 74.8 (CH), 74.5 (CH), 65.0
(CH2), 31.0 (CH2), 28.6 (CH2), 27.28 (CH2); [Additional peaks
corresponding to the minor diastereoisomer 16: 83.87 (CH), 81.51
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Compounds 21 and 22
Bis-epoxides 2 and 25
To a stirred solution of CuI (86 mg, 0.45 mmol) in THF (3 mL)
at -70 ◦C was added nonylmagnesium bromide (1 M in Et2O,
0.90 mL, 0.90 mmol) dropwise. The mixture was warmed to -20 ◦C
over 20 min (mixture white→grey), then cooled to -70 ◦C. A
solution of the epoxides 19 and 20 in THF (3 mL) was added
To a stirred solution of tosylates 23 and 24 (102 mg, 0.16 mmol)
in CH2Cl2 (2 mL) at 0 ◦C was added DBU (70 mL, 0.47 mmol)
and the mixture stirred for 3 h. The mixture was concentrated
in vacuo to give a pale yellow oil (108 mg). Purification on SiO2
(1.5 ¥ 15 cm) eluting with MeOH–CH2Cl2 (1 : 49→1 : 24) afforded
the title diastereoisomers 2/25 (dr ~ 3 : 1) as a colourless oil
(40 mg, 0.13 mmol, 82%). Physical and spectroscopic data were
recorded from the mixture of diastereoisomers. NMR data for
the major and minor isomers are indicated where possible. [a]D25
+5.6 (c 0.69 in CHCl3); nmax (neat)/cm-1 3440 m, 2947 m, 2919
m and 2875 m; dH(400 MHz; CDCl3) 3.92–3.85 (2H, m, 2 ¥
CH2(O)CHCH), 3.84–3.77 (2H, m, 2 ¥ CH2CHCHOH), 3.54–
3.43 (2H, m, CHOHCH2CH2CHOH), 3.06–3.00 (2H, m, 2 ¥
CH2(O)CHCH), 2.81 (2H, appt. t, J 5.0, 2 ¥ CHH(O)CH), 2.72
(1H, br, OH), 2.65 (1H, br, OH), 2.62 (2H, dd, J 5.0, 2.6, 2 ¥
CHH(O)CH), 2.01–1.89 (4H, m, 2 ¥ CHH THF), 1.88–1.72 (4H,
m, 2 ¥ CHH THF), 1.71–1.58 (4H, m, CHOHCH2CH2CHOH);
dC(100 MHz; CDCl3) 83.3 (CH), 79.5 (CH), 74.2 (CH), 53.2 (CH),
45.9 (CH2), 29.7 (CH2), 27.7 (CH2), 27.6 (CH2); [Additional peaks
corresponding to the minor diastereoisomer 25: 83.4 (CH), 79.4
(CH), 53.5 (CH), 45.8 (CH2), 30.2 (CH2), 27.8 (CH2), 27.7 (CH2)];
LRMS (ES+) m/z 337 [M + Na]+; HRMS (ES+) C16H26O6Na+
Calcd. 337.1621, found 337.1621.
◦
dropwise and the mixture warmed to -40 C over 1 h. Aqueous
NH4Cl–NH4OH (4 : 1, 10 mL) and EtOAc (10 mL) were added, the
organic layer was separated and the aqueous layer was extracted
with EtOAc (2 ¥ 10 mL). The combined organic phases were
washed with brine (20 mL), dried (MgSO4) and concentrated
in vacuo to give a yellow foam (25 mg). Purification on SiO2
(1 ¥ 15 cm) eluting with MeOH–CH2Cl2 (3 : 47→1 : 9) afforded
the title diastereoisomers 21/22 (dr ~ 3 : 1) as a colourless
oil (20 mg, 0.04 mmol, 58%). Physical and spectroscopic data
were recorded from the mixture of diastereoisomers. NMR data
for the major and minor isomers are indicated where possible.
[a]D25 +4.2 (c 0.56 in MeOH); nmax (neat)/cm-1 3351 m, 2924 w
and 2854 w; dH(400 MHz; CD3OD) 3.92 (1H, td, J 6.5, 5.3,
CHCHOHCH2OH), 3.87–3.78 (3H, m, 3 ¥ OCH), 3.73–3.67 (2H,
m, C10H21CHOH and CHOHCH2OH), 3.64 (1H, dd, J 11.3,
4.6, CHHOH), 3.54 (1H, dd, J 11.3, 6.3, CHHOH), 3.50–3.41
(2H, m, CHOHCH2CH2CHOH), 2.00–1.71 (8H, m, CH2 THF),
1.69–1.60 (4H, m, CHOHCH2CH2CHOH), 1.57–1.45 (2H, m,
C9H19CH2CHOH), 1.40–1.30 (16H, m, CH3(CH2)8), 0.92 (3H,
t, J 6.8, CH3); dC(100 MHz; CD3OD) 84.5 (CH), 84.3 (CH),
84.1 (CH), 81.9 (CH), 75.1 (CH), 74.9 (CH), 74.0 (CH), 65.4
(CH2), 34.9 (CH2), 33.4 (CH2), 31.2 (CH2), 31.1 (CH2), 30.8
(CH2), 29.2 (CH2), 29.0 (CH2), 27.7 (CH2), 27.4 (CH2), 26.4 (CH2),
24.1 (CH2), 14.8 (CH3); [Additional peaks corresponding to the
minor diastereoisomer 22: 84.0 (CH)]; LRMS (ES+) m/z 483
[M + Na]+; HRMS (ES+) C25H48O7Na+ Calcd. 483.3292, found
483.3284.
Silyl ethers 26, 27 and 28
To a stirred solution of the bis-epoxides 2 and 25 (28 mg,
0.089 mmol) in CH2Cl2 (1.5 mL) at rt was added 2,6-lutidine
(20 mL, 0.18 mmol) dropwise. The mixture was cooled to -10 ◦C
and TBSOTf (40 mL, 0.18 mmol) was added dropwise. After 30 min
H2O (2 mL) and EtOAc (4 mL) were added, the organic layer was
separated and the aqueous layer was extracted with EtOAc (2 ¥
4 mL). The combined organic phases were washed successively
with 3 M KHSO4 (5 mL), H2O (5 mL) and brine (5 mL). The
organic phase was dried (MgSO4) and concentrated in vacuo to
give a yellow oil (65 mg). Purification on SiO2 (3.5 ¥ 15 cm) eluting
with EtOAc–hexane (2 : 23) gave 26 as a colourless oil (14 mg,
0.026 mmol, 29%), 28 as a crystalline solid (7 mg, 0.013 mmol,
15%), and 27 as a colourless oil (6 mg, 0.014 mmol, 16%). Data
for 26: [a]2D5 -6.3 (c 0.44 in CHCl3); nmax (neat)/cm-1 2954 m,
2930 m, 2883 m and 2856 m; dH(400 MHz; CDCl3) 3.85 (2H,
td, J 6.9, 6.0, 2 ¥ CHCHOTBS), 3.73 (2H, dt, J 6.5, 5.8, 2 ¥
CH2(O)CHCH), 3.66–3.59 (2H, m, 2 ¥ CHOTBS), 2.99–2.94 (2H,
m, 2 ¥ CH2(O)CHCH), 2.79 (2H, appt. t, J 5.0, 2 ¥ CHH(O)CH),
2.64 (2H, dd, J 5.0, 2.5, 2 ¥ CHH(O)CH), 2.02–1.93 (2H, m,
CH2 THF), 1.90–1.75 (4H, m, CH2 THF), 1.74–1.67 (2H, m, CH2
THF), 1.55–1.50 (4H, m, CHOHCH2CH2CHOH), 0.90 (18 H, s,
2 ¥ C(CH3)3), 0.08 (6H, s, 2 ¥ SiCH3), 0.07 (6H, s, 2 ¥ SiCH3);
dC(100 MHz; CDCl3) 82.7 (CH), 79.5 (CH), 75.1 (CH), 53.4 (CH),
45.9 (CH2), 29.2 (CH2), 28.5 (CH2), 26.8 (CH2), 26.1 (CH3), 18.4
(C), -4.0 (CH3), -4.5 (CH3); LRMS (ES+) m/z 565 [M + Na]+;
HRMS (ES+) C28H54O6Si2Na+ Calcd. 565.3351, found 565.3357.
Data for 27: [a]D25 -5.9 (c 0.31 in CHCl3); nmax (neat)/cm-1 3453 w,
2951 m, 2928 m, 2881 m and 2857 m; dH(400 MHz; CDCl3) 3.92–
3.84 (2H, m, CHCHOH and CH(OTBS)CH), 3.83–3.73 (2H, m,
CH2(O)CHCH and CHCH(O)CH2), 3.67 (1H, m, CHOTBS),
3.44 (1H, m, CHOH), 3.05–2.97 (2H, m, CH2(O)CHCH and
Bis-tosylates 23 and 24
To a stirred solution of the hexaols 13 and 14 (31 mg, 0.09 mmol)
in benzene (5 mL) at rt was added Bu2SnO (55 mg, 0.22 mmol)
and the mixture heated to reflux for 3 h. The mixture was cooled to
rt and TsCl (37 mg, 0.19 mmol) was added. After 14 h the mixture
was concentrated in vacuo to give a yellow solid. Purification on
SiO2 (1.5 ¥ 15 cm) eluting with MeOH–CH2Cl2 (1 : 49→1 : 24)
gave the title diastereoisomers 23/24 (dr ~ 3 : 1) as a colourless oil
(41 mg, 0.06 mmol, 72%). Physical and spectroscopic data were
recorded from the mixture of diastereoisomers. NMR data for the
major and minor isomers are indicated where possible. [a]2D5 -5.5
(c 0.50 in CHCl3); nmax (neat)/cm-1 3347 m, 2949 m, 2920 m and
2884 m; dH(400 MHz; CDCl3) 7.80 (4H, d, J 8.3, ArH), 7.35 (4H,
d, J 8.3, ArH), 4.09 (2H, td, J 6.6, 6.0, 2 ¥ TsOCH2CHOH),
4.03–3.88 (6H, m, 2 ¥ TsOCH2CHOHCH), 3.85–3.75 (2H, m,
2 ¥ CHCHOHCH2), 3.61 (1H, br s, OH), 3.48–3.38 (2H, m,
CHOHCH2CH2CHOH), 2.45 (6H, s, 2 ¥ CH3), 1.99–1.54 (12H,
m, CH2); dC(100 MHz; CDCl3) 145.2 (C), 132.8 (C), 130.1 (CH),
128.1 (CH), 82.8 (CH), 79.5 (CH), 74.6 (CH), 71.4 (CH2), 71.1
(CH), 31.2 (CH2), 28.2 (CH2), 26.0 (CH2), 21.8 (CH3); [Additional
peaks corresponding to the minor diastereoisomer 24: 82.7 (CH),
79.4 (CH), 74.3 (CH)]; LRMS (ES+) m/z 681 [M + Na]+; HRMS
(ES+) C30H42O12S2Na+ Calcd. 681.2010, found 681.2003.
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CHCH(O)CH2), 2.82 (1H, dd, J 5.0, 4.0, CHH(O)CH), 2.79 (1H,
dd, J 5.0, 4.0, CH(O)CHH), 2.65 (1H, dd, J 5.0, 2.7, CHH(O)CH),
2.61 (1H, dd, J 5.0, 2.7, CH(O)CHH), 2.05–1.50 (12H, m, CH2),
0.90 (9H, s, C(CH3)3), 0.09 (3H, s, SiCH3), 0.08 (3H, s, SiCH3);
dC(100 MHz; CDCl3) 83.2 (CH), 82.5 (CH), 79.3 (CH), 79.2 (CH),
74.54 (CH), 74.47 (CH), 53.3 (CH), 53.0 (CH), 45.70 (CH2), 45.66
(CH2), 29.5 (CH2), 29.2 (CH2), 28.3 (CH2), 27.8 (CH2), 27.7 (CH2),
26.9 (CH2), 26.1 (CH3), 18.2 (C), -4.1 (CH3), -4.4 (CH3); LRMS
(ES+) m/z 451 [M + Na]+; HRMS (ES+) C22H40O6 SiNa+ Calcd.
451.2486, found 451.2487. Data for 28: mp 51–52 ◦C; dH(400 MHz;
CDCl3) 3.85 (2H, td, J 6.9, 6.0, 2 ¥ CHCHOTBS), 3.73 (2H, dt,
J 6.5, 5.8, 2 ¥ CH2(O)CHCH), 3.64–3.58 (2H, m, 2 ¥ CHOTBS),
2.98–2.94 (2H, m, 2 ¥ CH2(O)CHCH), 2.79 (2H, appt. t, J 5.0, 2 ¥
CHH(O)CH), 2.63 (2H, dd, J 5.0, 2.5, 2 ¥ CHH(O)CH), 2.02–1.93
(2H, m, CH2 THF), 1.90–1.76 (4H, m, CH2 THF), 1.75–1.67 (4H,
m, CH2 THF and CH2CHOH), 1.35–1.30 (2H, m, CH2CHOH),
0.90 (18H, s, 2 ¥ C(CH3)3), 0.08 (6H, s, 2 ¥ SiCH3), 0.07 (6 H, s, 2 ¥
SiCH3); dC(100 MHz; CDCl3) 82.9 (CH), 79.5 (CH), 75.3 (CH),
53.4 (CH), 45.9 (CH2), 29.4 (CH2), 28.5 (CH2), 26.9 (CH2), 26.1
(CH3), 18.4 (C), -4.1 (CH3), -4.4 (CH3).
S. Sahpaz, L. Villaescusa, R. Hocquemiller, A. Cave´ and D. Cortes,
J. Nat. Prod., 1993, 56, 351; (e) M. C. Zafra-Polo, B. Figadere, T.
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Acknowledgements
The authors thank the Royal Society for a University Research
Fellowship (R.C.D.B.), EPSRC and GlaxoSmithKline for a CASE
studentship (R.B.).
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13 Crystal data for 28 C28H54O6Si2, Mr = 542.89, T = 120(2) K, triclinic,
Notes and references
¯
˚
space group P1, a = 7.417(5), b = 10.385(5), c = 10.651(5) A, a =
◦
3
˚
68.383(5), b = 83.788(5), g = 82.900(5) , V = 755.1(7) A , rcalc
=
1 (a) Reviews of the chemistry and biology of Annonaceous acetogenins:
A. Bermejo, B. Figadere, M. C. Zafra-Polo, I. Barrachina, E. Estornell
and D. Cortes, Nat. Prod. Rep., 2005, 22, 269; (b) F. Q. Alali, X. X. Liu
and J. L. McLaughlin, J. Nat. Prod., 1999, 62, 504; (c) J. K. Rupprecht,
Y. H. Hui and J. L. McLaughlin, J. Nat. Prod., 1990, 53, 237; (d) J. Saez,
1.194 g cm-3, m = 0.155 mm-1, Z = 1, reflections collected: 12517,
independent reflections: 3491 (Rint = 0.0547), final R indices [I >
2sI]: R1 = 0.0455, wR2 = 0.0981, R indices (all data): R1 = 0.0665.
wR2 = 0.1072†.
1024 | Org. Biomol. Chem., 2009, 7, 1017–1024
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