Total synthesis of the marine sponge metabolites (+)-rottnestol, (+)-raspailol A and (+)-raspailol B.

Article abstract of DOI:10.1039/b302460a

The asymmetric syntheses of (+)-rottnestol (1) and the related marine sponge metabolites (+)-raspailols A (5) and B (6) are described. The key step in each of these sequences was a Stille coupling to form the C9-C10 sp2-sp2 bond and connect the polyene sidechains to the appropriate optically active tetrahydropyran core. For rottnestol (1), both C12 epimers were synthesised by a coupling between stannane 7 and (R)- or (S)-8 followed by acid hydrolysis which allowed for the assignment of the absolute configuration at the remote C12 stereocentre as R upon comparison of chiroptical data of the synthetic material with that reported for the natural product. In accord with this, (12R)-raspailol A (5) was synthesised from stannane 7 and sidechain 9 and this compound also compared well with the data for natural material including sign and absolute value of the specific rotation. Finally, the same C12 epimer of raspailol B (6) was secured via a union between stannane 10 and iodide 9 and this also possessed a similar rotation to that described for the natural product. Thus, all three compounds appear to possess the (12R) configuration, while that of the core tetrahydropyran ring is the same as proposed originally.

Full text of DOI:10.1039/b302460a

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Total synthesis of the marine sponge metabolites (؉)-rottnestol,
(؉)-raspailol A and (؉)-raspailol B†
Ivona R. Czuba, Steven Zammit and Mark A. Rizzacasa*
School of Chemistry, The University of Melbourne, Victoria, 3010, Australia.
E-mail: masr@unimelb.edu.au
Received 10th March 2003, Accepted 1st May 2003
First published as an Advance Article on the web 19th May 2003
The asymmetric syntheses of (ϩ)-rottnestol (1) and the related marine sponge metabolites (ϩ)-raspailols A (5) and
B (6) are described. The key step in each of these sequences was a Stille coupling to form the C9–C10 sp2–sp2 bond
and connect the polyene sidechains to the appropriate optically active tetrahydropyran core. For rottnestol (1),
both C12 epimers were synthesised by a coupling between stannane 7 and (R)- or (S)-8 followed by acid hydrolysis
which allowed for the assignment of the absolute configuration at the remote C12 stereocentre as R upon comparison
of chiroptical data of the synthetic material with that reported for the natural product. In accord with this, (12R)-
raspailol A (5) was synthesised from stannane 7 and sidechain 9 and this compound also compared well with the
data for natural material including sign and absolute value of the specific rotation. Finally, the same C12 epimer of
raspailol B (6) was secured via a union between stannane 10 and iodide 9 and this also possessed a similar rotation
to that described for the natural product. Thus, all three compounds appear to possess the (12R) configuration,
while that of the core tetrahydropyran ring is the same as proposed originally.
details of the total synthesis of (ϩ)-rottnestol (1)9 as well as the
Introduction
first total synthesis of (ϩ)-raspailols A (5) and B (6) that
Rottnestol (1) is a naturally occurring hemiketal isolated from
allowed for the assignment of the absolute configurations of all
the sponge Haliclona sp., collected in the waters around
these compounds.
Rottnest Island off the coast of Western Australia.1 Small
amounts of epi-rottnestol (2), as well as the corresponding
methyl ketal 3 were also isolated from the methanolic extracts;
however the structure originally assigned for the latter com-
pound may be in error as the methoxy group should be in an
axial orientation owing to the anomeric effect and therefore
rottnestol methyl ketal is probably the C2 epimer 4. The struc-
ture of rottnestol (1) was deduced by a combination of 1H, 13C,
COSY, HMBC and HMQC NMR experiments. The absolute
configuration of the pyran ring was assigned as 2S,3R,4S,6R
in accordance with the absolute stereochemistry reported for
the structurally related raspailols A (5) and B (6), which were
isolated from the sponge genus Raspailia sp. collected in the
reefs of Palau, Western Caroline Islands.2 The absolute stereo-
chemistry at the C12 asymmetric centre in 1, 5 and 6 could not
be determined from the data at hand and there was insufficient
material available to conduct any degradation studies. Neither
rottnestol (1) nor the raspailols A (5) and B (6) fall within an
established chemotaxonomic group and are of interest because
they may represent a new one. In the past, such novel natural
products have been instrumental in the study and understand-
ing of biochemical pathways in vivo and in vitro. Both 5 and 6
have been found to possess mild antibiotic activity, in particular
against Bacillus subtilis,2 but no such activity has been demon-
strated by rottnestol (1).1 All three compounds are interesting
synthetic targets due to the fact that the stereochemistry of the
C12 stereogenic center was not determined. Several recent
reports demonstrate that total synthesis remains an important
technique for the structural determination of complex natural
products.3–5 Computing techniques which allow for molar
rotation calculations are improving and this method, in con-
junction with synthesis, can also be a powerful tool for the
determination of absolute configuration.6–8 We embarked on
an asymmetric synthesis of 1, 5 and 6 in order to determine
their absolute configuration and in this article, we report the full
Results and discussion
Retrosynthetic analysis
We began with the synthesis of the slightly simpler target
rottnestol (1). It is not unreasonable to suggest that both 1 and
the raspailols 5 and 6 possess the same absolute configuration
at C12 so we would first target both diastereoisomers of 1 and
then one C12 epimer each of 5 and 6. It was envisaged that both
the C12 epimers of 1 could be produced by a sp2–sp2 Stille
coupling10,11 between the tetrahydropyran fragment 7 and the R
or S enantiomer of vinyl iodide 8 followed by acetal hydrolysis
(Scheme 1). We chose the Stille coupling to form the C9–C10
bond due to the tolerance of acid sensitive functional groups
to the coupling conditions.11 At the onset, we surmised that
the NMR spectra of (12R)- or (12S)-isomers would be
indistinguishable owing to the number of atoms separating
the stereochemical elements in the pyran core and the C12
stereogenic center. Therefore, the absolute configuration at
C12 could possibly only be determined by comparison of the
chiroptical properties of the synthetic and natural material.
† Taken in part from the PhD thesis of I. R. Czuba, The University of
Melbourne, 2002.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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alcohol 16 initially relied on NMR analysis of the derived
Mosher esters 18 and 19 (Fig. 1). Yasuhara and co-workers
reported that the signals for the C1 methylene protons in the
1H NMR spectra for diastereoisomeric Mosher ester derivatives
of chiral α-methyl substituted primary alcohols appear as char-
acteristic multiplets.18 For the (S,R)-diastereoisomer, the meth-
ylene protons each appear as a doublet of doublets while for
the (S,S)-isomer, the same protons resonate as one doublet.
1
This was in accord with the H NMR spectra of the Mosher
esters 18 and 19 derived from (R)- and (S)-16, respectively,
as shown in Fig. 1.
Scheme 1 Retrosynthetic analysis of rottnestol (1) and raspailols A (5)
and B (6).
Fig. 1 Methylene region of 1H NMR spectra of Mosher esters 18 and
19.
Similarly, raspailol A (5) could be obtained from a coupling
between the same tetrahydropyran core 7 and the vinyl iodide
(R or S)-9. For the synthesis of raspailol B (6), the more substi-
tuted core 10 is required. Coupling with the same iodide 9 then
provides compound 6.
Conclusive evidence for the absolute configuration of (R)-16
arose from the degradation of its precursor mandelate ester
15 into (R)-4-oxo-2-methylpentanoic acid 17.19 Ozonolysis and
hydrolysis of ester 15 gave the known (R)-γ-acid 17,19 the
optical rotation of which compared well with literature values
[Synthetic 17: [α]D ϩ30.2 (c 0.63, CHCl3); [α]D ϩ9.5 (c 0.29,
AcOH); lit.20 for (S) enantiomer 98%ee: [α]D Ϫ21.1 (c 0.80,
CHCl3); lit.19 for (R) enantiomer: [α]D ϩ21.8 (c 1.19, AcOH)].
The required rottnestol sidechains (R)- or (S)-8 were then
synthesised from (R)- or (S)-16 by oxidation21 and vinyl-
iodination using Takai’s procedure22 in solvent mixture of
THF–dioxane (1 : 6).23
The tedious HPLC separation of the esters 14 and 15
inspired us to seek a more direct enantiospecific synthesis of
the sidechain 8. The known alkyne 2024 (synthesized from
commercially available methyl (S)-(Ϫ)-3-hydroxy-2-methyl-
propionate)25 was converted into a vinyl iodide by carbo-
alumination26 followed by iodine quench to provide iodide
21 (Scheme 3).27 As it turned out, intermediate 21 was also
utilised in the synthesis of the raspailol sidechain (see below).
A Negishi coupling28 between the zincate derived from
3-butenylmagnesium bromide and iodide 21 proceeded
smoothly to give diene 22. Desilylation then provided (R)-alco-
hol 16 which was identical to the compound prepared by the
resolution route above. Alternatively, alcohol (S)-16 could be
Total synthesis of (؉)-rottnestol (1)
A first generation synthesis of the optically active rottnestol
sidechain 8 involving a resolution step12 is depicted in Scheme 2.
Addition of 3-butenylmagnesium bromide to methacrolein
provided the known racemic alcohol 1113 which was acylated to
give the propionyl ester 12. Ireland–Claisen rearrangement14,15
of 12 using LDA as base with TBSCl followed by hydrolysis of
the resultant ester gave racemic acid 13 in good yield. The use
of TMSCl as silylating agent gave large amounts of C-silylated
product which was inseparable from the desired compound.
Acid 13 was then converted into the diastereoisomeric mande-
late esters12 14 (Rt 16.39 min) and 15 (Rt 17.30 min) which were
cleanly separated by semi-preparative HPLC. Reduction of
each ester gave the corresponding alcohols (R)- and (S)-16. We
found this method provided 16 in higher optical purity than
conducting the [3,3]-rearrangement on optically pure ester 12
since complete control of the enolate geometry, which is critical
to total transfer of asymmetry, was difficult.16,17 The deter-
mination of the absolute configurations of each enantiomer of
Scheme 2 Reagents and conditions: (a) Propionyl chloride, pyridine, DMAP, 91%; (b) LDA, TBSCl, HMPA, THF, Ϫ78 ЊC, then aq. NaOH; (c) (S)-
mandelic acid, DCC, DMAP, 86%; (d) LiAlH4, Et2O, 74%; (e) (i) Dess–Martin periodinane, CH2Cl2, 1 h, rt; (ii) CrCl2, CHI3, THF–dioxane 1 : 6, 5 h,
rt, 71% for 2 steps; (f ) (i) O3, Me2S, CH2Cl2–MeOH, Ϫ78 ЊC; (ii) LiOH, aq. THF, 4 h, 15%.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
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Scheme
3
Reagents and conditions: (a) (i) AlMe3, Cp2ZrCl2
ClCH2CH2Cl, 1 h, rt; (ii) I2, THF, 82%; (b) (i) 3-Butenylmagnesium
bromide, ZnCl2, THF, 0 ЊC; (ii) cat. Pd(PPh3)4 then iodide 21, 54%; (c)
TBAF, THF, 58%.
Scheme 5 Reagents and conditions: (a) 15 mol% Pd(MeCN)2Cl2,
DMF, i-Pr2NEt (2.4 eq.), rt, 21.5 h, 57–62%; (b) 5% aq.HCl, THF, 0 ЊC,
35 min, 55–63%.
obtained in the same manner starting with (R)-(ϩ)-3-hydroxy-
2-methylpropionate. Although this route to optically pure
(R)-16 was slightly longer, it was more effectively conducted on
a large scale and the HPLC separation could be avoided.
The synthesis of the core tetrahydropyran fragment 7 began
with the known aldehyde 23, available in four steps from (S)-
malic acid.29 Brown crotylmetallation30 of 23 gave adduct 24
in good yield and high diastereoselectivity and protection as
the TBDPS ether afforded 25 Scheme 4. Wacker oxidation31 of
alkene 25 proceeded smoothly under standard conditions to
provide ketone 26 in excellent yield and subsequent cyclisation
to the tetrahydropyran 27 was achieved by treatment of 26 with
20 mol% CSA in methanol.
fore, it appears that the structure originally proposed for
rottnestol methyl ketal (3) is in error. The methoxy group
should be in the axial orientation as depicted in compound 4.
Final acetal hydrolysis gave the (12R) and (12S)-isomers of
1 both of which again had identical spectra to natural 1 (see
Table 1). Comparison of the specific rotations of each [(12R)-1:
[α]D ϩ58.4 (c 0.18, CH2Cl2); (12S)-1: [α]D ϩ33.9 (c 0.35,
CH2Cl2)] with that reported for natural rottnestol (1)1 [[α]D
ϩ67.4 (c 0.43, CH2Cl2)] led to the conclusion that the absolute
configuration at C12 is R in the natural product.9
Total synthesis of (؉)-raspailol A (5)
Introduction of the 2 carbon unit for elaboration to the vinyl
stannane proved quite challenging. Studies on acetylide anion
substitution of the iodide or mesylate derived from 27 proved
fruitless. Eventually, we found that substitution of the sensitive
triflate derived from 27 with lithium trimethylsilylacetylide9,32
in the presence of HMPA followed by global desilylation gave
alkyne 28 in good overall yield. The presumed preferred axial
orientation of the methoxy group in 28 (and precursor 27) was
confirmed by a NOESY spectrum which revealed NOEs
between the axial protons H6 and H4 and the OMe group as
shown. Radical hydrostannylation33 of 28 then gave the desired
tetrahydropyran fragment 7.
The key Stille coupling reaction between 7 and iodide (R)- or
(S)-8 was then investigated. Initially, we found that Pd(0) based
catalysts such as Pd2dba3 in the presence of various ligands34
resulted in no desired product and substantial iodine–tin
exchange35 to afford the vinyl iodide derived from stannane 7
Scheme 5. Pd() catalysts also failed initially, causing consump-
tion of the stannane via an unproductive pathway. The addition
of amine base, however, resulted in a substantial improvement
and provided coupled products (12R)-rottnestol methyl ketal 4
or the corresponding (12S)-epimer in good yield. Both these
compounds had identical NMR spectra which compared well
with the methyl ketal derived from natural rottnestol.1 There-
We then targeted the (12R)-epimer of raspailol A (5) since
the related rottnestol (1) was shown to possess this absolute
configuration. Furthermore, calculations also supported the
assignment of the R configuration at C12 [For 5 theoretical
[α]D ϩ57 (c 1.0, CH2Cl2) lit.2 [α]D ϩ62 (c 0.46, C6D6)].6,7,36 Our
route to (12R)-raspailol A (5) began with the synthesis of the
raspailol sidechain 9 as outlined in Scheme 6. The known
stannane 2937 (4 : 1 E : Z mixture) was coupled with the iodide
21 to afford the diene 30 as the major product. Originally, we
investigated coupling vinyl iodide 21 (and the primary alcohol
derived from desilylation of 21) with the analogue of 29 that
possessed the requisite terminal double bond but the synthesis
of this stannane was low yielding and difficult to scale up.
Furthermore, several attempted couplings failed to give the
desired triene in good yield. The alcohol 29 served as a
convenient precursor to the terminal alkene and was easily
prepared in one step from commercially available 4-butynol.
Oxidation of 30 followed by Wittig extension gave triene 31
which upon treatment with TBAF provided alcohol 32. The
vinyl iodide 9 was then secured by oxidation and vinyliodidin-
ation as for the rottnestol sidechain.
Stille coupling11 between iodide 9 and stannane 7 proceeded
smoothly to provide raspailol A methyl ketal (33) in good yield.
Scheme 4 Reagents and conditions: (a) (ϩ)-Ipc2B-(Z)-crotyl, THF, Ϫ78 ЊC, then NaOH, H2O2, 76%; (b) TBDPSCl, imidazole, DMF, 40 ЊC, 72 h,
85%; (c) 20 mol% PdCl2, 1.1 eq. CuCl, O2, aq. DMF, 50 ЊC, 85%; (d) 20 mol% CSA, MeOH, rt, 3 h, 72%; (e) (i) Tf2O, 2,6-lutidine, CH2Cl2, Ϫ78 ЊC;
(ii) LiCCTMS, THF–HMPA, Ϫ78–0 ЊC; (iii) TBAF, THF, rt, 71% for 3 steps; (f ) Bu3SnH, cat. AIBN, benzene, reflux, 2 h, 54%.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
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Table 1 Comparison of NMR data for natural and synthetic rottnestol (1)
δC (C6D6)
δH (C6D6)
Position
Natural1 125 MHz
Synthetic 100 MHz
Natural1 500 MHz (m, J Hz)
Synthetic 300 MHz (m, J Hz)
1
2
3
4
5
28.2
98.9
47.2
69.7
41.3
28.2
98.9
47.2
69.7
41.3
1.18 (s)
—
1.18 (s)
—
1.24 (m)
3.57 (ddd, 10.8, 9.6, 4.8)
1.13–1.19 (m)
1.71 (ddd, 12.4, 4.4, 2.0)
3.83 (dddd, 12.0, 6.4, 6.0, 2.8)
2.19 (ddd, 14.0, 7.2, 6.8)
2.34 (ddd, 13.6, 6.8, 6.4)
5.69 (dt, 14.0, 7.2)
6.06–6.17 (m)
1.25 (dq, 10.8, 6.3)
3.58 (dddd, 12.2, 10.8, 5.4, 4.4)
1.14 (q, 12.2)
1.71 (ddd, 12.2, 4.4, 2.5)
3.84 (dtd, 12.2, 6.4, 2.5)
2.18 (br ddd, 13.7, 7.3, 6.4)
2.36 (br ddd, 13.7, 7.3, 6.4)
5.69 (dt, 14.7, 7.3)
6.12 (dddd, 14.7, 10.2, 1.5, 1.0)
6.10 (ddd, 14.7, 10.2, 1.0)
5.54 (dd, 14.7, 7.8)
2.32 (m)
6
7
68.3
39.7
68.3
39.7
8
9
10
11
12
13
128.4
133.2
128.9
138.8
35.0
128.4
133.2
128.9
138.75
35.0
6.06–6.17 (m)
5.54 (dd, 14.0, 7.2)
2.34 (sept, 5.1)
1.92 (dd, 13.2, 7.6)
2.02–2.12 (m)
47.9
47.9
1.92 (dd, 13.2, 7.9)
2.07 (m)
14
15
16
17
18
19
133.8
126.2
27.8
34.4
138.8
114.8
133.8
126.2
27.8
34.3
138.82
114.8
—
—
5.16 (br t, 6.8)
2.07 (m)
2.07 (m)
5.79 (ddt, 17.1, 10.2, 6.8)
4.98 (ddd, 10.2, 2.5, 1.4)
5.04 (ddd, 17.1, 2.5, 1.5)
1.12 (d, 6.3)
0.97 (d, 6.9)
1.50 (s)
5.17 (br t)
2.04–2.06 (m)
2.04–2.06 (m)
5.80 (ddt, 17.2, 10.4, 7.2)
4.99 (d, 10.0)
5.04 (dd, 16.8, 1.6)
1.12 (d, 6.4)
0.98 (d, 6.8)
20
21
22
12.3
20.1
16.0
12.3
20.1
16.1
1.50 (s)
Scheme 6 Reagents and conditions: (a) Iodide 21, Pd(MeCN)2Cl2, i-Pr2NEt, DMF, 40 ЊC, 54%; (b) (i) Dess–Martin periodinane, CH2Cl2, rt; (ii)
Ph3P᎐CH2, THF, 0 ЊC, 68%; (c) TBAF, THF, rt, 2.5 h, 95%; (d) (i) Dess–Martin periodinane, CH2Cl2, rt; (ii) CrCl2, CHI3, THF–dioxane 1 : 6, rt, 17 h,
᎐
58%; (e) Stannane 7, 15 mol% Pd(MeCN)2Cl2, DMF, i-Pr2NEt (2.4 eq.), rt, 21.5 h, 57%; (f ) 5% aq.HCl, THF, 0 ЊC, 30 min, 65%.
Hydrolysis then afforded raspailol A (5) which was identical
to the data reported for natural material2 (see Table 2) in
all respects including the sign and value of specific rotation
[Synthetic 5: [α]D ϩ78.4 (c 0.42, C6D6); Natural 5:2 [α]D ϩ62
(c 0.46, C6D6)]. This again allowed for the C12 stereochemistry
to be assigned as R while the configuration of the tetra-
hydropyran core is identical to rottnestol (1).
amide 38. This allowed for the synthesis of 37 without recourse
to alternative Lewis acids.44 Treatment of amide 37 with methyl
magnesium chloride followed by desilylation and cyclisation of
the crude ketone product with PPTS in methanol gave tetra-
hydropyran 39 in excellent overall yield. Protection of the
secondary alcohol as the TBS ether and hydrogenolysis of the
primary benzyl group afforded alcohol 40. The stereochemistry
of 40 followed from NMR analysis; in particular, the coupling
constants between H3–H4 and H4–H5 indicated an ax-ax-eq
arrangement of H3–5 while an NOE was observed between H6
and the axial OMe group. Two carbon homologation9,32 as
described for the rottnestol pyran fragment above gave the
alkyne 41 which was converted into stannane 10 under
standard conditions.33 Stille coupling11 between 10 and
sidechain 9 gave raspailol B methyl ketal (42) which upon acid
treatment gave raspailol B (6). The data of the synthetic
material compared well with the literature values2 (see Table 3)
including the optical rotation [Synthetic 6: [α]D ϩ108
(c 0.045, C6D6); Natural 6:2 [α]D ϩ111 (c 0.14, C6D6)]. This
confirms the absolute configuration at C12 in all three
natural products is R.
Total synthesis of (؉)-raspailol B (6)
The final target raspailol B (6) was synthesised as outlined in
Scheme 7. The stereochemistry of the more highly substituted
core was set first by a tin mediated substrate controlled Evans
aldol reaction between the β-ketoimide 3438,39 and benzyloxy-
acetaldehyde. This afforded the adduct 35 in excellent yield and
high ds. Directed anti reduction40 then gave diol 36 again with
high selectivity for the desired syn-anti-syn-diastereoisomer.
Conversion of the diol 36 into the Weinreb amide proved
troublesome.41,42 Treatment of imide 36 with AlMe3 and N,O-
dimethylhydroxylamine hydrochloride42 at 0 ЊC resulted in the
formation of a substantial amount of the amide resulting from
ring opening at the endo carbonyl group43 along with the
desired amide. Careful control of the temperature (Ϫ20 ЊC) and
time provided optimum yields and conversion of the crude
mixture into the bis-TES ethers allowed for the isolation of
pure bis-TES ether 37 along with a small amount of undesired
In conclusion, we have achieved the first total synthesis of
(ϩ)-rottnestol (1) and the related raspailols A (5) and B (6)
using a convergent Stille coupling reaction to construct the
C9–C10 bond. This allowed for the assignment of the absolute
configurations of all these natural products.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
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Table 2 Comparison of NMR data for natural and synthetic raspailol A (5)
δC (C6D6)
δH (C6D6)
Position
Natural2 125 MHz
Synthetic 100 MHz
Natural2 500 MHz (m, J Hz)
Synthetic 400 MHz (m, J Hz)
1
2
3
4
5
28.2
98.9
47.2
69.7
41.3
28.2
98.9
47.2
69.7
41.3
1.17 (s)
—
1.18 (s)
—
1.26 (m)
3.57 (ddd, 10.8, 10.4, 4.4)
1.05–1.15 (m)
1.69 (m)
1.25 (dq, 10, 7)
3.57 (ddt, 11, 10, 5)
1.13 (dt, 12, 11)
1.69 (ddd, 12, 5, 2)
3.82 (dtd, 11, 7, 2)
2.16 (br dt, 14, 7)
2.34 (br dt, 14, 7)
5.68 (br dt, 14, 7)
6.12 (m)
6
7
68.2
39.7
68.3
39.7
3.82 (m)
1.97–2.18 (m)
2.29–2.39 (m)
5.67–5.82 (m)
6.07–6.14 (m)
6.07–6.14 (m)
5.50–5.61 (m)
2.29–2.39 (m)
1.93 (dd, 13.2, 7.6)
1.97–2.18 (m)
—
5.93 (d, 10.8)
6.33 (dd, 14.8, 10.8)
5.50–5.61 (m)
1.97–2.18 (m)
1.97–2.18 (m)
5.67–5.82 (m)
4.95 (d, 10.4)
4.98 (d, 17.2)
1.11 (d, 6.8)
0.94 (d, 6.4)
1.60 (s)
8
9
10
11
12
13
128.6
133.2
129.0
138.5
35.1
128.6
133.2
128.9
138.5
35.2
6.08 (m)
5.54 (br dd, 14, 7)
2.34 (sept, 7)
1.95 (br dd, 15, 7)
2.10 (m)
48.0
48.0
14
15
16
17
18
19
20
21
134.5
127.3
127.6
131.8
32.7
34.1
138.4
114.9
134.5
127.3
127.6
131.7
32.7
34.1
138.4
114.9
—
5.91 (br d, 11)
6.31 (ddt, 15, 11, 2)
5.56 (br dt, 15, 7)
2.10 (m)
2.05 (m)
5.75 (ddt, 17, 11, 7)
4.97 (d, 11)
5.01 (d, 17)
1.12 (d, 7)
0.96 (d, 7)
1.62 (br s)
22
23
24
12.2
20.1
16.5
12.3
20.1
16.6
Scheme 7 Reagents and conditions: (a) Sn(OTf )2, NEt3, benzyloxyacetaldehyde, CH2Cl2, Ϫ78 ЊC, 77%; (b) Me4NBH(OAc)3, MeCN–AcOH, Ϫ40–0
ЊC, 91%; (c) (i) AlMe3, MeNH(OMe)HCl, Ϫ20 ЊC, 16 h; (ii) TESCl, imidazole, DMF, 59% 37; 10% 38 for 2 steps; (d) (i) MeMgCl, rt, 3 h; (ii) 20 mol%
PPTS, MeOH–CH2Cl2 1 : 3, rt, 3 h, 91%; (e) (i) TBSOTf, 2,6-lutidine, CH2Cl2, 2 h (ii) 50 psi H2, Pd(OH)2/C, MeOH, 48 h, 74% for 2 steps; (f ) (i)
Tf2O, 2,6-lutidine, CH2Cl2, Ϫ78 ЊC (ii) LiCCTMS, THF–HMPA, Ϫ78–0 ЊC (iii) TBAF, THF, rt, 66% for 3 steps; (g) Bu3SnH, cat. AIBN, benzene,
reflux, 2 h, 70%; (h) Iodide 9, 15 mol% Pd(MeCN)2Cl2, DMF, i-Pr2NEt (7.0 eq.), rt, 24 h, 58%; (i) 5% aq.HCl, THF, 0 ЊC, 4 h, 93%.
New Zealand. Analytical thin layer chromatography (TLC)
was conducted on aluminium backed 2 mm thick silica gel
GF254. Compounds were visualised with solutions of 20% w/w
Experimental
General
Optical rotations were recorded in a 10 cm microcell and are
given in 10Ϫ1 deg cm2 g Ϫ1. Low resolution mass spectra (electro-
spray ionisation, ESI) and high resolution mass spectra
(HRMS) electrospray ionisation (ESI) were run at Monash
University, Clayton, Victoria. Proton nuclear magnetic
resonance (1H NMR, 300 and 400 MHz) and proton decoupled
carbon nuclear magnetic resonance spectra (13C NMR, 75.5
and 100 MHz) were recorded for deuteriochloroform solutions
with residual chloroform as internal standard unless otherwise
stated. Microanalyses were carried out by the Campbell Micro-
analytical Laboratory at the University of Otago, Dunedin,
phosphomolybdic acid in ethanol, 20% w/w potassium per-
manganate in water or under UV (365 nm). Preparative HPLC
was conducted on a 10 mm × 250 column (spherex 5 silica,
5 µm, flow rate: 2 mL minϪ1, RI detection). Anhydrous THF
and diethyl ether were distilled from sodium benzophenone
ketyl and sodium metal under a nitrogen atmosphere. Petrol
refers to the fraction boiling at 40–60 ЊC. All other commercial
reagents were used as received. All air and moisture sensitive
reactions were performed in glassware that was either flame
dried under an atmosphere of dry argon or oven dried at
150 ЊC.
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Table 3 Comparison of NMR data for natural and synthetic raspailol B (6)
δC (C6D6)
δH (C6D6)
Position
Natural2 125 MHz
Synthetic 100 MHz
Natural2 500 MHz (m, J Hz)
Synthetic 400 MHz (m, J Hz)
1
2
3
4
5
6
7
28.1
98.6
40.4
72.6
38.4
70.8
36.3
28.1
98.6
40.3
72.6
38.4
70.8
36.3
1.14 (s)
—
1.15 (s)
—
1.50 (dq, 11, 6)
3.63 (dd, 11, 5)
1.62 (m)
3.94 (td, 7, 2)
2.10 (m)
1.50 (dq, 10, 7)
3.62 (dt, 11, 5)
1.62 (m)
3.94 (td, 7, 2)
2.40 (br dt, 14, 7)
2.13 (br dt, 14, 7)
5.59 (br dt, 14, 7)
6.14 (m)
8
9
10
11
12
13
128.8
133.0
129.0
138.5
35.1
128.7
133.0
128.9
138.4
35.2
5.57 (m)
6.12 (m)
6.12 (m)
5.57 (m)
2.38 (sept, 7)
2.10 (m)
6.10 (m)
5.55 (br dd, 14, 7)
2.35 (sept, 7)
2.10 (m)
48.0
48.0
1.96 (br dd, 15, 7)
—
5.92 (br d, 11)
6.31 (ddt, 15, 11, 2)
5.56 (m)
2.10 (m)
2.05 (m)
5.75 (ddt, 17, 11, 7)
5.01 (d, 17)
4.97 (d, 11)
1.07 (d, 7)
0.97 (d, 7)
1.62 (br s)
1.96 (dd, 13,8)
—
5.92 (d, 11)
6.31 (dd, 15, 11)
5.57 (m)
2.10 (m)
2.10 (m)
5.75 (ddt, 17, 10, 6)
5.00 (d, 18)
4.97 (d, 10)
1.07 (d, 6)
0.97 (d, 6)
1.62 (s)
14
15
16
17
18
19
20
21
134.5
127.3
127.6
131.8
32.7
34.1
138.4
114.9
134.5
127.3
127.5
131.8
32.7
34.1
138.4
114.9
22
23
24
25
12.4
20.1
16.6
4.7
12.4
20.1
16.6
4.7
0.89 (d, 7)
0.90 (d, 7)
( )-2-Methylhepta-1,6-dien-3-yl propanoate 12
dissolved in 1 M KOH. The aqueous layer was washed with
Et2O (2×), then cooled to 0 ЊC and acidified with concentrated
aqueous HCl and extracted with EtOAc. The organic phase was
washed with water, brine, dried and concentrated to give the
acid 12 (2.22 g, 85%) as a pale yellow oil which was used with-
out further purification. A small sample was distilled (bp 100
ЊC, 30 mmHg) under reduced pressure for analysis: (Found: C,
72.55; H, 10.05; C11H18O2 requires C, 72.5; H, 9.95%); vmax (thin
film) 2978, 1698, 1640, 1294, 1241, 1123, 911, 824 cmϪ1; δH (300
MHz, CDCl3) 1.12 (d, J = 6.6 Hz, 3H), 1.60 (s, 3H), 2.02–2.10
(m, 1H), 2.05–2.11 (m, 4H), 2.41 (dd, J = 13.2, 6.6 Hz, 1H), 2.63
(sext, 1H, J = 6.9 Hz), 4.94 (dd, J = 9.9, 1.5 Hz, 1H), 5.00 (dd,
J = 17.1, 1.5 Hz, 1H), 5.19 (br t, J = 6.0 Hz, 1H), 5.80 (ddt,
J = 16.8, 10.5, 6.6 Hz, 1H); δC (75.5 MHz, CDCl3) 15.7, 16.3,
27.4, 33.8, 37.9, 43.6, 114.5, 126.8, 132.1, 138.4, 138.3; m/z
(ESI) 182 (Mϩ, 13%), 181 ([M Ϫ H]ϩ, 100).
To a solution of the alcohol ( )-1113 (3.0 g, 24 mmol), pyridine
(3.7 mL, 45 mmol) and DMAP (290 mg, 2.38 mmol) in
anhydrous CH2Cl2 (70 mL) at 0 ЊC was added dropwise, freshly
distilled propionyl chloride (2.5 mL, 28.5 mmol). After stirring
for 1 h at 0 ЊC, saturated aqueous NH4Cl was added and the
reaction mixture was extracted with Et2O (2×). The combined
organic fractions were washed with 10% aqueous HCl, satur-
ated aqueous NaHCO3, water and brine, dried and the solvent
removed under reduced pressure. Purification of the crude
product by flash filtration through silica gel with 5% EtOAc–
petrol as solvent afforded the ester 12 (3.93 g, 91%) as a colour-
less oil: (Found: C, 72.25; H, 9.85; C11H18O2 requires C, 72.5; H,
9.95%); vmax (thin film) 3080, 2978, 1734, 1652, 1456, 1272,
1179, 1082, 908 cmϪ1; δH (300 MHz, CDCl3) 1.14 (t, J = 7.5 Hz,
3H), 1.62–1.82 (m, 2H), 1.71 (s, 3H), 1.98–2.09 (m, 2H), 2.34 (q,
J = 7.5 Hz, 2H), 4.86–5.06 (m, 4H), 5.18 (t, J = 6.9 Hz, 1H), 5.80
(ddt, J = 17.1, 10.2, 6.6 Hz, 1H); δC (75.5 MHz, CDCl3) 9.1,
18.0, 27.7, 29.5, 31.8, 76.4, 112.5, 114.9, 137.5, 143.1, 173.5; m/z
(ESI) 205 ([M ϩ Na]ϩ, 36%), 163 (33), 159 (100).
(1S )-Methyl 1-phenylethanoate (2S,4E )-14 and (1S )-(methoxy-
carbonyl)phenylmethyl (2R,4E )-2,4-dimethyl-4,8-nonadienoate
15
To a stirred solution of the racemic acid 12 (215 mg, 1.18 mmol)
in dry CH2Cl2 (5.0 mL) at 0 ЊC was added methyl (S)-(ϩ)-
mandelate (197 mg, 1.18 mmol), DMAP (14.4 mg, 0.11 mmol)
and DCC (268 mg, 1.30 mmol). The reaction mixture was then
allowed to stir for 10 min at 0 ЊC and at rt for 2.5 h. Petrol was
added and the reaction mixture was filtered through Celite. The
filtrate was washed with 10% aqueous HCl, saturated aqueous
NaHCO3, water, brine, dried and concentrated. Purification of
the crude product by flash chromatography using 5% EtOAc–
petrol as eluent followed by HPLC separation of the dia-
stereoisomers on a semi-preparative column (spherex 5 µm
silica, 10 mm × 250 mm) using 5% EtOAc–petrol as eluent
(2 mL minϪ1) provided the (S,S)-diastereoisomer 14 (Rt = 16.39
min) (168 mg, 43%) and the (S,R)-isomer 15 (167 mg, 43%)
(Rt = 17.30 min) as colourless oils.
( )-(4E )-2,4-Dimethylnona-4,8-dienoic acid 13
To a solution of i-Pr2NH (4.0 mL, 30.5 mmol) in dry THF (38
mL) at 0 ЊC under an argon atmosphere was added a solution
of n-BuLi in hexanes (10.4 mL, 2.5 M, 26.0 mmol). The
solution was cooled to Ϫ78 ЊC and a 1 : 1 mixture of HMPA
(29 mL) and anhydrous THF (29 mL) was added dropwise over
10 min. After stirring for 5 min, a solution of the ester 12
(2.62 g, 14.4 mmol) in THF (22.5 mL) was added dropwise by
cannula followed by TBSCl (4.0 g, 27 mmol) in THF (13.3 mL).
The reaction mixture was stirred at Ϫ78 ЊC for 20 min and then
allowed to warm to rt and stirred for 3 h. The reaction mixture
was diluted with petrol and washed with 10% aqueous HCl,
water, brine and the solvent was evaporated. The residue was
dissolved in THF (105 mL), 10% aqueous HCl was added and
the mixture was vigorously stirred for 1 h and then extracted
with Et2O. The organic layer was washed with water and brine,
dried and the residue remaining on removal of the solvent was
Data for (S,S)-isomer 14: [α]2D3 ϩ86.9 (c 1.01, CHCl3) (Found:
C, 73.0; H, 7.8; C20H26O4 requires C, 72.7; H, 7.95%); vmax (thin
film) 3068, 2976, 1740, 1640, 1272, 1158 cmϪ1; δH (300 MHz,
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CDCl3) 1.15 (d, J = 6.9 Hz, 3H), 1.61 (s, 3H), 2.01–2.12 (m, 5H),
2.53 (dd, J = 13.2, 6.0 Hz, 1H), 2.76 (sext, J = 6.6 Hz, 1H), 3.71
(s, 3H), 4.94 (dd, J = 10.2, 1.8 Hz, 1H), 5.00 (dd, J = 17.1, 1.8
Hz, 1H), 5.17 (br t, J = 6.9 Hz, 1H), 5.73–5.86 (m, 1H), 5.92
(s, 1H), 7.36–7.41 (m, 3H), 7.44–7.49 (m, 2H); δC (75.5 MHz,
CDCl3) 15.6, 16.1, 27.3, 33.7, 37.6, 43.4, 52.4, 74.1, 114.4,
126.7, 127.5, 128.7, 129.0, 132.0, 134.0, 138.4, 169.2, 175.6;
m/z (ESI) 353 ([M ϩ Na]ϩ, 58%), 348 ([M ϩ H2O]ϩ, 100), 331
([M ϩ H]ϩ, 27).
2H); δC (75.5 MHz, CDCl3) 15.8, 16.7, 27.4, 30.4, 33.8, 43.6,
55.4, 70.8, 114.6, 121.4, 125.3, 126.5, 127.4, 128.4, 129.6, 132.3,
132.6, 138.5, 166.6; HRMS (ESI): Calcd for C21H27F3O3Mϩ
407.1810, found 407.1808. The alcohol (R)-16 (23.4 mg, 139
µmol) was converted into the ester in an analogous manner to
that described above to afford the (S,R)-Mosher ester 19 (47.5
mg, 89%), also as a colourless oil (de: 92.7% by 1H NMR): [α]2D5
Ϫ46.0 (c 1.02, CHCl3); vmax (thin film) 3074, 2924, 2849, 1750,
1641, 1498, 1273, 1170, 1024, 719 cmϪ1; δH (400 MHz, CDCl3)
0.88 (d, J = 6.4 Hz, 3H), 1.55 (s, 3H), 1.80 (m, 1H), 1.98–2.04
(m, 2H), 2.07–2.08 (m, 4H), 3.55 (s, 3H), 4.14 (d, J = 5.2 Hz,
2H), 4.95, (dd, J = 10.0, 1.6 Hz, 1H), 5.01 (dd, J = 16.8, 1.6 Hz,
1H), 5.08 (br t, 1H), 5.75–5.85 (m, 1H), 7.39–7.43 (m, 3H),
7.51–7.54 (m, 2H); δC (75.5 MHz, CDCl3) 15.8, 16.7, 27.4, 30.4,
33.8, 43.5, 55.4, 70.8, 114.5, 121.4, 125.3, 126.5, 127.3, 128.4,
129.6, 132.4, 132.6, 138.5, 166.6; HRMS (ESI): Calcd for
C21H27F3O3Na [M ϩ Na]ϩ 407.1810, found 407.1808.
Data for (S,R)-isomer 15: [α]2D3 ϩ90.4 (c 1.01, CHCl3) (Found
C, 72.65; H, 7.9; C20H26O4 requires C, 72.7; H, 7.95%); vmax (thin
film) 3068, 2976, 1740, 1640, 1272, 1158 cmϪ1; δH (300 MHz,
CDCl3) 1.19 (d, J = 7.2 Hz, 3H), 1.56 (s, 3H), 1.98–2.03 (m, 4H),
2.08 (dd, J = 13.8, 7.8 Hz, 1H), 2.43 (dd, J = 13.8, 7.2 Hz, 1H),
2.78 (sext, J = 6.6 Hz, 1H), 3.72 (s, 3H), 4.92 (dd, J = 10.5, 1.5
Hz, 1H), 4.97 (dd, J = 17.4, 1.5 Hz, 1H), 5.16 (br t, 1H), 5.77 (m,
1H), 5.91 (s 1H), 7.36–7.41 (m, 3H), 7.45–7.48 (m, 2H); δC (75.5
MHz, CDCl3) 15.7, 16.4, 27.3, 33.7, 37.5, 43.5, 52.4, 74.0, 114.4,
126.6, 127.5, 128.7, 129.0, 132.1, 133.9, 138.4, 169.3, 175.8. MS
(ESI) m/z 353 ([M ϩ Na]ϩ, 90%), 348 ([M ϩ H2O]ϩ, 100), 331
([M ϩ H]ϩ, 37).
(2R)-2-Methyl-4-oxopentanoic acid 17
Ozone gas was bubbled into a solution of the (S,R)-mandelate
ester 15 (213 mg, 0.648 mmol) in dry CH2Cl2 (14 mL) and
MeOH (502 µL) at Ϫ78 ЊC until the solution turned blue.
Dimethyl sulfide (240 µL, 3.27 mmol) was then added at Ϫ78 ЊC
and the solution was stirred at rt for 4 h. Water and EtOAc were
added and the aqueous phase was further extracted with
EtOAc. The combined organic fractions were washed with
water, brine, dried and concentrated. The residue was dissolved
in THF (4.9 mL) and water (4.9 mL) and treated with lithium
hydroxide monohydrate (172 mg, 4.1 mmol) at 30 ЊC for 4 h.
The solvent was removed under reduced pressure and the
residue was acidified with 10% aqueous HCl and extracted into
EtOAc (3×). The combined organic fractions were washed with
water, brine, dried and concentrated. Purification of the crude
acid by column chromatography using 40% EtOAc–petrol as
eluent afforded the acid 1719 (12.7 mg, 15%) as a colourless oil:
[α]2D0 ϩ9.5 (c 0.29, AcOH), lit.,19 [α]2D5 ϩ21.8 (c 1.19, AcOH); [α]2D1
ϩ30.2 (c 0.63, CHCl3), lit.,20 or (S)-enantiomer [α]2D5 Ϫ21.1
(c 0.80, CHCl3, 98% ee); δH (300 MHz, CDCl3) 1.21 (d, J = 7.2
Hz, 3H), 2.16 (s, 3H), 2.49 (dd, J = 16.8, 4.5 Hz, 1H), 2.88–3.20
(m, 1H), 2.90 (dd, J = 17.7, 8.1 Hz, 1H).
(2S,4E )- (S )-16 and (2R,4E )-2,4-Dimethylnona-4,8-dien-1-ol
(R)-16
To a suspension of LiAlH4 (57 mg, 1.5 mmol) in dry Et2O (3.4
mL) at 0 ЊC was added dropwise a solution of the (S,R)-
mandelate ester 15 (50 mg, 0.15 mmol) in dry Et2O (3.4 mL).
The reaction mixture was then allowed to stir at rt for 10 min
after which time it was cooled to 0 ЊC and quenched with water
and 5 M NaOH was added until coagulation ceased. The
suspension was filtered through Celite and the filtrate was con-
centrated. Purification of the residue by flash chromatography
on silica gel using 15% EtOAc–petrol as eluent gave the alcohol
(R)-16 (24 mg, 93%) as a pale yellow oil: [α]2D6 Ϫ6.6 (c 1.03,
CHCl3) (Found: C, 78.3; H, 11.75; C11H20O requires C, 78.5; H,
12.0%); vmax (thin film) 3346, 3077, 2922, 1640, 1383, 1038 cmϪ1
;
δH (300 MHz, CDCl3) 0.86 (d, J = 6.3 Hz, 3H), 1.60 (s, 3H),
1.78–1.89 (m, 2H), 2.02–2.11 (m, 5H), 3.42 (dd, J = 10.5, 5.7 Hz,
1H), 3.49 (dd, J = 10.5, 5.4 Hz, 1H), 4.95 (dd, J = 10.2, 1.5 Hz,
1H), 5.01 (dd, J = 17.1, 1.5 Hz, 1H), 5.17 (br t, 1H), 5.81 (ddt,
J = 16.8, 10.2, 6.6 Hz, 1H); δC (75.5 MHz, CDCl3) 15.9, 16.5,
27.3, 33.5, 33.8, 44.1, 68.2, 114.4, 125.6, 134.0, 138.5; m/z (ESI)
191 ([M ϩ Na]ϩ, 100%).
(8R,5E )-9-(tert-Butyldimethylsiloxy)-6,8-dimethylnona-1,5-
diene 22
Reduction of the (S,S)-mandelate ester 14 (312 mg, 0.95
mmol) in the same manner as described for the alcohol (R)-16
above provided (S)-16 (150 mg, 94%) as a pale yellow oil: [α]2D6
ϩ6.5 (c 1.03, CHCl3).
A solution of 1-bromo-3-butene (0.5 g, 3.7 mmol) in anhydrous
THF (6.7 mL) was added dropwise via cannula to flame-dried
magnesium turnings (122 mg, 5.02 mmol) under argon. The
reaction mixture was stirred for 30 min and the resultant
Grignard reagent (2 mL) was added dropwise via syringe to a
solution of anhydrous zinc() chloride in dry THF (7.4 mL) at
0 ЊC. The resultant mixture was allowed to stir at 0 ЊC for
30 min after which time a solution of the vinyl iodide 21 (100
mg, 0.28 mmol) and tetrakis(triphenylphosphine)palladium(0)
(32.6 mg, 28.2 µmol) in dry THF (3.6 mL) was added via
cannula. The resultant solution was stirred at 0 ЊC for 10 min
and then allowed to stir overnight at rt. The reaction was
quenched by the addition of saturated aqueous NH4Cl and
then worked up in the usual manner and the residue was
purified by flash chromatography using petrol as eluent to
afford the diene 22 (43 mg, 54%) as a colourless oil: [α]1D8 Ϫ0.2
(c 1.04, CHCl3); vmax (thin film) 3080, 2931, 1642, 1470, 1255,
1090, 839, 776 cmϪ1; δH (300 MHz, CDCl3) 0.03 (s, 6H), 0.81 (d,
J = 6.3 Hz, 3H), 0.89 (s, 9H), 1.58 (s, 3H), 1.66 (dd, J = 12.0, 8.4
Hz, 1H), 1.75 (m, 1H), 2.08–2.14 (m, 5H), 3.34 (dd, J = 9.9, 6.6
Hz, 1H), 3.43 (dd, J = 9.6, 5.4 Hz, 1H), 4.95 (dd, J = 9.9, 2.4 Hz,
1H), 5.01 (dd, J = 17.1, 1.8 Hz, 1H), 5.11 (br t, 1H), 5.83 (m,
1H); δC (75.5 MHz, CDCl3) Ϫ5.3, 16.0, 16.5, 18.4, 26.0, 27.5,
33.7, 34.0, 43.8, 68.2, 114.4, 125.3, 134.0, 138.7; HRMS
(ESI): Calcd for C17H34OsiNa [M ϩ Na]ϩ 305.2277, found
305.2271.
(2S,2SЈ,4E )- 18 and (2R,2SЈ,4E )-2,4-Dimethyl-4,8-nonadienyl
2-trifluoromethyl-2-methoxy-2-phenylethanoate 19
To a stirred solution of the alcohol (S)-16 (23.6 mg, 140 µmol)
in dry CH2Cl2 (4 mL) at 0 ЊC was added (S)-(Ϫ)-α-methoxy-α-
(trifluoromethyl)phenylacetic acid (65.4 mg, 279 µmol), DMAP
(2 mg, 16.4 µmol) and DCC (57.6 mg, 279 µmol). The reaction
mixture was allowed to stir for 10 min at 0 ЊC and then at rt for
1 h after which time petrol was added and the reaction mixture
was filtered through Celite. The filtrate was washed with 10%
aqueous HCl, saturated aqueous NaHCO3, water, brine, dried
and concentrated. Purification of the crude product by chrom-
atography on silica gel using 10% EtOAc–petrol as eluent gave
the (S,S)-Mosher ester 18 (48 mg, 90%) as a colourless oil (de:
98.2% by 1H NMR): [α]2D5 Ϫ29.6 (c 1.03, CHCl3); vmax (thin film)
3068, 2931, 2851, 1750, 1641, 1498, 1273, 1170, 1024, 719 cmϪ1
;
δH (400 MHz, CDCl3) 0.86 (d, J = 6.8 Hz, 3H), 1.56 (s, 3H), 1.82
(m, 1H), 1.98–2.05 (m, 2H), 2.07–2.09 (m, 4H), 3.55 (s, 3H),
4.03 (dd, J = 10.8, 6.4 Hz, 1H), 4.24 (dd, J = 10.8, 4.8 Hz, 1H),
4.95 (dd, J = 10.4, 2.0 Hz, 1H), 5.00 (dd, J = 17.2, 1.2 Hz, 1H),
5.11 (br t, 1H), 5.80 (m, 1H), 7.39–7.43 (m, 3H), 7.50–7.54 (m,
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(2R,4E )-2,4-Dimethylnona-4,8-dien-1-ol (R)-16
removed under reduced pressure and the residue partitioned
between water and Et2O. The organic layer was washed with
water, brine, dried and concentrated. Purification by column
chromatography using 15–20% EtOAc–petrol as eluent
afforded the alcohol 24 (1.59 g, 76%) as a pale yellow oil: [α]1D8
Ϫ23.5 (c 1.01, CHCl3); (Found: C, 65.7; H, 9.95; C11H20O3
requires C, 65.95; H, 10.05%); vmax (thin film) 3457, 3078,
2984, 1371, 1159, 1060 cmϪ1; δH (300 MHz, CDCl3) 1.05 (d,
J = 6.9 Hz, 3H), 1.35 (s, 3H), 1.41 (s, 3H), 1.62 (ddd, J = 14.4,
9.6, 4.8 Hz, 1H), 1.77 (ddd, J = 14.4, 7.2, 2.4 Hz, 1H), 2.28
(sext, J = 6.9 Hz, 1H), 3.56 (dd, J = 7.8, 7.8 Hz, 1H), 3.70 (ddd,
J = 12.0, 5.7, 2.1 Hz, 1H), 4.07 (dd, J = 7.8, 6.0 Hz, 1H),
4.32 (quint, J = 7.2 Hz, 1H), 5.07 (d, J = 11.4 Hz, 1H), 5.08
(d, J = 16.2 Hz, 1H), 5.75 (ddd, J = 17.4, 10.2, 7.5 Hz,
1H); δC (75.5 MHz, CDCl3) 14.8, 25.6, 26.9, 37.2, 44.0,
69.5, 71.7, 73.8, 108.6, 115.4, 140.5; m/z (ESI) 201 ([M ϩ H]ϩ,
100%).
A solution of the ether 22 (35 mg, 0.124 mmol) in THF (1 mL)
was treated with TBAF (59 mg, 0.187 mmol) overnight. Water
was added and the reaction mixture was extracted with Et2O.
The usual workup and purification of the crude product by
flash chromatography using 15% EtOAc–petrol as eluent gave
(R)-16 (12 mg, 58%) as a colourless oil, the spectroscopic data
for which was identical to the alcohol obtained by the earlier
resolution route: [α]1D7 ϩ8.0 (c 0.47, CHCl3).
(3R,1E,5E )- (R)-8 and (3S,1E,5E )-1-Iodo-3,5-dimethyl-1,5,9-
decatriene (S )-8
To a solution of the alcohol (R)-16 (100 mg, 0.59 mmol) in
anhydrous CH2Cl2 (5 mL) was added Dess–Martin periodinane
(378 mg, 0.89 mmol). After stirring at rt for 30 min, Et2O and a
1 : 1 v/v mixture of saturated aqueous NaHCO3 and 1.5 M
Na2S2O3 was added and the reaction mixture was vigorously
stirred until the layers cleared. The organic layer was washed
with the 1 : 1 mixture of saturated aqueous NaHCO3 and 1.5 M
Na2S2O3 then saturated aqueous NaHCO3, water, brine, dried
and the solvent removed under reduced pressure. The crude
aldehyde (98.8 mg, 0.594 mmol) and iodoform (433 mg, 1.1
mmol) were dissolved in anhydrous dioxane (10.3 mL) and
added dropwise to a vigorously stirred slurry of flame-dried
chromium() chloride (546 mg, 4.44 mmol) in anhydrous THF
(1.7 mL) under an argon atmosphere. The resulting brown
suspension was stirred at rt for 17 h and was then diluted with
Et2O and water and the aqueous fraction was saturated with
NaCl and further extracted with Et2O. The combined organic
fractions were washed with brine, dried and concentrated. The
crude vinyl iodide was dissolved in Et2O (12 mL) and treated
with TBAF (1.26 g, 4.0 mmol) in THF (4 mL) for 10 min. The
solvent was removed under reduced pressure and the residue
filtered through a plug of silica gel using Et2O as eluent. The
crude product was purified by flash chromatography using
petrol as eluent to give the vinyl iodide (R)-8 (122 mg, 71%) as
an orange oil: [α]2D3 Ϫ9.4 (c 1.03, CHCl3) (Found: C, 49.4; H, 6.5;
C12H19I requires C, 49.65; H, 6.6%); vmax (thin film) 3076, 2922,
1641, 1219, 912 cmϪ1; δH (300 MHz, CDCl3) 0.95 (d, J = 6.6 Hz,
3H), 1.56 (s, 3H), 1.90 (dd, J = 13.5, 7.2 Hz, 1H), 2.02 (dd, J =
13.5, 7.2 Hz, 1H), 2.08–2.10 (m, 4H), 2.35 (m, 1H), 4.96 (dd, J =
10.2, 1.8 Hz, 1H), 5.02 (dd, J = 17.1, 1.2 Hz, 1H), 5.12 (br s,
1H), 5.81 (m, 1H), 5.93 (d, J = 14.4 Hz, 1H), 6.41 (dd, J = 14.4,
7.2 Hz, 1H); δC (75.5 MHz, CDCl3) 16.0, 19.0, 27.4, 33.9, 38.7,
46.6, 73.0, 114.5, 126.5, 132.8, 138.6, 151.9; m/z (GCMS) 290
(Mϩ, 0.5%), 181 (100), 67 (98).
(4S )-4-[(2S,3S )-2-(tert-Butyldiphenylsiloxy)-3-methyl-4-
pentenyl]-2,2-dimethyl-1,3-dioxolane 25
To a solution of the alcohol 24 (1.30 g, 6.49 mmol), DMAP
(82.1 mg, 0.672 mmol) and imidazole (1.15 g, 16.9 mmol) in dry
DMF (15.5 mL) was added TBDPSCl (3.53 mL 13.5 mmol).
The reaction mixture was then warmed to 40 ЊC and stirred
under an argon atmosphere for 24 h after which time a further
portion of imidazole (0.58 g, 8.45 mmol) and TBDPSCl (1.77
mL, 6.75 mmol) were added. Stirring was then continued at 40
ЊC for a further 48 h. The usual workup and purification of the
crude product by column chromatography using 10% EtOAc–
petrol as eluent gave the ether 25 as a colourless oil (2.61 mg,
92%): [α]1D9 Ϫ31.3 (c 1.01, CHCl3) (Found: C, 73.8; H, 8.65;
C27H38O3Si requires C, 73.9; H, 8.75%); vmax (thin film) 3072,
2933, 1640, 1590, 1111, 1061 cmϪ1; δH (300 MHz, CDCl3) 0.88
(d, J = 6.9 Hz, 3H), 1.06 (s, 9H), 1.17 (s, 3H), 1.28 (s, 3H), 1.50
(ddd, J = 14.1, 8.1, 4.5 Hz, 1H), 1.62 (ddd, J = 13.8, 8.4, 4.5 Hz,
1H), 2.31 (m, 1H), 3.21 (dd, J = 7.8, 7.8 Hz, 1H), 3.80 (dd,
J = 7.8, 5.7 Hz, 1H), 3.93 (m, 1H), 4.02 (m, 1H), 4.90–5.05 (m,
2H), 5.99 (ddd, J = 17.1, 10.5, 6.0 Hz, 1H), 7.33–7.45 (m, 6H),
7.67–7.72 (m, 4H); δC (75.5 MHz, CDCl3) 14.1, 19.6, 25.7, 26.9,
27.1, 37.2, 42.3, 69.6, 72.9, 74.7, 108.5, 114.4, 127.4, 127.5,
129.5, 129.6, 134.2, 134.5, 136.0, 136.1, 140.3; m/z (ESI) 461
([M ϩ Na]ϩ, 100%), 462 (42).
(4S )-4-[(2S,3S )-2-(tert-Butyldiphenylsiloxy)-3-methyl-4-oxo-
pentyl]-2,2-dimethyl-1,3-dioxolane 26
A suspension of palladium() chloride (27.4 mg, 0.155 mmol)
and copper() chloride (84 mg, 0.85 mmol) in water (537 µL)
and DMF (3.8 mL) was stirred at rt for 2 h under an oxygen
atmosphere. A solution of the alkene 25 (339 mg, 0.77 mmol) in
water (537 µL) and DMF (4.26 mL) was then added slowly by
cannula and the resultant solution was warmed to 50 ЊC and
stirred for 23 h. The mixture was diluted with Et2O, cold 5%
aqueous HCl was added and the organic layer was washed with
saturated aqueous NaHCO3. Purification of the crude product
by flash chromatography using 10% EtOAc–petrol as eluent
afforded the ketone 26 (297 mg, 85%) as a yellow oil: [α]1D8 Ϫ16.2
(c 0.39, CHCl3) (Found: C, 71.15; H, 8.65; C27H38O4Si requires
C, 71.30; H, 8.40%); vmax (thin film) 2933, 1713, 1111, 1059
cmϪ1; δH (400 MHz, CDCl3) 1.03 (s, 9H), 1.07 (d, J = 7.2 Hz,
3H), 1.16 (s, 3H), 1.27 (s, 3H), 1.54 (ddd, J = 14.4, 6.4, 4.0 Hz,
1H), 1.72 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H), 2.06 (s, 3H), 2.63 (dq,
J = 6.8, 2.8 Hz, 1H), 3.12 (dd, J = 8.0, 7.6 Hz, 1H), 3.73 (dd,
J = 8.0, 6.0 Hz, 1H), 3.86 (m, 1H), 4.25 (ddd, J = 6.4, 3.2 Hz,
1H), 7.36–7.47 (m, 6H), 7.66–7.71 (m, 4H); δC (100 MHz,
CDCl3) 10.4, 19.5, 25.7, 26.8, 29.8, 38.4, 52.0, 69.3, 72.5,
72.7, 77.2, 108.8, 127.5, 127.7, 129.7, 129.9, 133.3, 134.2,
135.9, 136.0, 210.6; m/z (ESI) 477 ([M ϩ Na]ϩ, 100%), 397 ([M–
tBu]ϩ, 38).
The (S)-vinyl iodide (S)-8 (118 mg, 60%) was prepared from
the alcohol (S)-16 according to the procedure described above.
The spectroscopic data for the (S)-8 was identical to that
quoted for (R)-8: [α]2D2 ϩ12.6 (c 1.01, CHCl3).
(4S )-4-[(2S,3S )-2-Hydroxy-3-methyl-4-pentenyl]-2,2-dimethyl-
1,3-dioxolane 24
To a mixture of potassium tert-butoxide (1.75 g, 15.6 mmol)
and cis-2-butene (1.80 mL) in freshly distilled THF (17 mL) at
Ϫ78 ЊC was added dropwise a solution of n-BuLi in hexanes
(7.1 mL, 2.2 M, 15.6 mmol). The reaction mixture was then
warmed to 0 ЊC for 5 min, recooled to Ϫ78 ЊC and a solution of
(ϩ)-β-methoxydiisopinocampheylborane30 (4.92 g, 15.6 mmol)
in THF (18.6 mL) was added dropwise via cannula. The clear
reaction mixture was stirred at Ϫ78 ЊC for 30 min and then
boron trifluoride diethyl etherate (2.55 mL, 20.2 mmol) was
added dropwise followed by a solution of the aldehyde 2329
(1.50 g, 10.4 mmol) in THF (17 mL). The resultant mixture was
stirred at Ϫ78 ЊC for a further 2 h after which time 1 M NaOH
(42 mL) and 30% H2O2 (8.5 mL) were added at 0 ЊC and the
mixture was stirred at rt overnight. Most of the solvent was
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
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(2S,3R,4S,6R)-Tetrahydro-4-(tert-butyldiphenylsiloxy)-6-
hydroxymethyl-2-methoxy-2,3-dimethyl-2H-pyran 27
EtOAc–petrol as eluent to provide the (E)-vinylstannane 7 (268
mg, 68%) as a clear gum: [α]2D0 ϩ59.3 (c 1.03, CH2Cl2); vmax (thin
film) 3435, 2956, 2853, 1641, 1049 cmϪ1; δH (300 MHz, C6D6)
0.94 (t, J = 6.9 Hz, 9H), 0.95–1.01 (m, 6H), 1.14 (d, J = 6.9 Hz,
3H), 1.24 (s, 3H), 1.38 (sext, J = 7.2 Hz, 6H), 1.56–1.64 (m, 2H),
1.61 (quint, J = 7.5 Hz, 6H), 1.76 (ddd, J = 12.0, 4.5, 2.1 Hz,
1H), 2.29 (m, 1H), 2.50 (m, 1H), 3.09 (s, 3H), 3.57–3.70 (m,
2H), 5.75–5.97 (m, 2H); δC (75.5 MHz, C6D6) 9.7, 12.1, 13.9,
21.9, 27.7, 29.6, 41.3, 44.9, 47.4, 48.6, 68.4, 69.6, 101.6, 130.3,
146.3; HRMS (ESI): Calcd for C23H46O3SnNa [M ϩ Na]ϩ
511.2367, found 511.2383.
To a stirred solution of the ketone 26 (164 mg, 0.36 mmol)
in dry MeOH (5.2 mL) was added ( )-camphorsulfonic acid
(16.7 mg, 0.072 mmol). The reaction mixture was stirred at rt
for 1 h then quenched with saturated aqueous NaHCO3. The
product was isolated by extraction with EtOAc and the com-
bined organic fractions were washed with saturated aqueous
NaHCO3, water and brine. Purification of the crude product by
column chromatography using 20% EtOAc–petrol as eluent
gave the pyran 27 (111 mg, 72%) as a colourless gum: [α]1D9
ϩ81.3 (c 0.71, CHCl3) (Found: C, 69.75; H, 8.25; C25H36O4Si
requires C, 70.05; H, 8.45%); vmax (thin film) 3441, 2942, 2857,
1377, 1111, 1060 cmϪ1; δH (400 MHz, CDCl3) 1.04 (s, 9H), 1.07
(d, J = 6.8 Hz, 3H), 1.31 (s, 3H), 1.40 (ddd, J = 10.4, 4.8, 2.4 Hz,
1H), 1.57–1.62 (m, 1H), 1.60 (dq, J = 9.6, 7.2 Hz, 1H), 1.87 (br
t, J = 5.1 Hz, 1H), 3.06 (s, 3H), 3.35–3.42 (m, 3H), 3.88 (ddd,
J = 10.4, 10.4, 4.8 Hz, 1H), 7.34–7.44 (m, 6H), 7.66–7.70 (m,
4H); δC (75.5 MHz, CDCl3) 12.6, 19.4, 21.8, 27.0, 36.7, 47.5,
48.5, 65.7, 68.7, 71.5, 101.8, 127.4, 127.5, 129.4, 129.5, 134.1,
134.9, 135.9, 136.0; m/z (ESI) 451 ([M ϩ Na]ϩ, 100%), 397
([M Ϫ OMe]ϩ, 13).
(2S,3R,4S,6R)-Tetrahydro-2-methoxy-2,3-dimethyl-6-
[(12R,2E,4E,8E )-6,8-dimethyl-2,4,8,12-tridecatetraenyl]-2H-
pyran-4-ol. Rottnestol methyl ketal (12R)-(4)
To a freeze–thaw degassed (3×) solution of the (R)-vinyl iodide
(R)-8 (18.2 mg, 62.8 µmol), stannane 7 (42 mg, 81.7 µmol) and
i-Pr2NEt (34 µL, 0.195 mmol) in dry DMF (570 µL) was added
bis(acetonitrile)palladium() chloride (2.6 mg, 10.0 µmol). The
reaction mixture was stirred in the absence of light at rt for
21.5 h and then diluted with water and extracted with Et2O. The
combined organic fractions were washed with water, brine,
dried and concentrated. Purification of the crude product by
column chromatography using 10–15% EtOAc–petrol as eluent
provided rottnestol methyl ketal (12R)-4 (14 mg, 62%) as a
colourless gum. [α]2D2 ϩ89.7 (c 0.41, CH2Cl2); vmax (thin film)
3400, 3078, 2919, 1641, 1047 cmϪ1; δH (300 MHz, C6D6) 0.97 (d,
J = 6.9 Hz, 3H, H21), 1.11–1.18 (m, 1H, H5), 1.15 (d, J = 6.6
Hz, 3H, H20), 1.22 (s, 3H, H1), 1.31 (m, 1H, H3), 1.50 (s, 3H,
H22), 1.70 (ddd, J = 12.0, 4.8, 2.1 Hz, 1H, H5), 1.91 (dd,
J = 13.2, 7.8 Hz, 1H, H13), 1.98–2.09 (m, 1H, H13), 2.02–2.06
(m, 4H, H16, H17), 2.17 (m, 1H, H7), 2.27–2.39 (m, 2H, H7,
H12), 3.01 (s, 3H, H23), 3.52 (dddd, J = 12.3, 6.6, 6.3, 2.4 Hz,
1H, H6), 3.62 (m, 1H, H4), 4.99 (d, J = 9.9 Hz, 1H, H19), 5.04
(d, J = 16.7 Hz, 1H, H19), 5.16 (br t, 1H, H15), 5.53 (dd, J =
14.4, 7.2 Hz, 1H, H11), 5.69 (dt, J = 14.4, 7.5 Hz, 1H, H8), 5.78
(m, 1H, H18), 6.04–6.17 (m, 2H, H9, H10); δC (100 MHz, C6D6)
12.0, 16.1, 20.1, 21.9, 27.8, 34.3, 35.0, 39.6, 41.1, 47.4, 47.9,
48.6, 68.5, 69.6, 101.6, 114.7, 126.2, 127.6, 128.8, 133.3, 133.8,
138.7, 138.8; HRMS (ESI): Calcd for C23H38O3Na [M ϩ Na]ϩ
385.2719, found 385.2713.
(2S,3R,4S,6R)-Tetrahydro-2-methoxy-2,3-dimethyl-6-(2-propy-
nyl)-2H-pyran-4-ol 28
To a stirred solution of the pyran 27 (981 mg, 2.29 mmol) in dry
CH2Cl2 (22.7 mL) at Ϫ78 ЊC was added 2,6-lutidine (1.34 mL,
11.5 mmol) and Tf2O (753 µL, 4.48 mmol). After stirring at
Ϫ78 ЊC for 30 min, saturated aqueous NaHCO3 was added and
the pale yellow reaction mixture was stirred at rt for 1 h. The
product was isolated by extraction with Et2O and the organic
fraction was washed with saturated aqueous NaHCO3, water,
saturated aqueous CuSO4, water, brine, dried and concentrated.
A solution of the crude triflate in anhydrous THF (19.5 mL)
was added dropwise via cannula to a solution of lithium
trimethylsilylacetylide [from trimethylsilylacetylene (1.63 mL,
11.5 mmol) and n-BuLi in hexanes (4.9 mL, 2.5 M, 12.3 mmol)]
in dry THF (19.5 mL) and HMPA (4.4 mL) at Ϫ78 ЊC. The
reaction mixture was stirred at Ϫ78 ЊC for 1 h then saturated
aqueous NH4Cl was added and the mixture was then extracted
with Et2O. The combined organic fractions were washed with
water, brine, dried and the solvent removed under reduced
pressure to provide the crude TMS acetylide which was
subsequently dissolved in THF (34.5 mL) and treated with
TBAF (1.97 g, 7.53 mmol) overnight. Water was added and the
reaction mixture was extracted with EtOAc. The organic
fraction was washed with water, brine, dried and concentrated.
Purification of the crude product by flash chromatography
using 20% EtOAc–petrol as eluent gave the acetylene 28 (330
mg, 73%) as an oil: [α]2D4 ϩ110.9 (c 0.71, CH2Cl2) (Found: C,
66.60; H, 9.00; C11H18O3 requires C, 66.65; H, 9.15%); vmax (thin
film) 3406, 2945, 2120, 1379, 1168, 1045, 840 cmϪ1; δH (300
MHz, CDCl3) 1.06 (d, J = 6.9 Hz), 1.29 (m, 1H), 1.31 (s, 3H),
1.41 (m, 1H), 2.01 (t, J = 2.7 Hz, 1H), 2.12 (ddd, J = 12.3, 4.8,
2.1 Hz, 1H), 2.32 (ddd, J = 16.5, 6.9, 2.7 Hz, 1H), 2.44 (ddd,
J = 16.5, 6.3, 2.7 Hz, 1H), 3.17 (s, 3H), 3.37–3.75 (m, 2H);
δC (100 MHz, CDCl3) 11.7, 21.6, 25.5, 39.9, 47.6, 47.8, 66.7,
69.5, 70.0, 80.8, 101.7; m/z (ESI) 221 ([M ϩ Na]ϩ, 100%).
(2S,3R,4S,6R)-Tetrahydro-2,3-dimethyl-6-[(12R,2E,4E,8E )-
6,8-dimethyl-2,4,8,12-tridecatetraenyl]-2H-pyran-2,4-diol.
Rottnestol (1)
To a solution of rottnestol methyl ketal (12R)-4 (8.0 mg,
22.0 µmol) in THF (670 µL) at 0 ЊC was added 5% aqueous HCl
(135 µL). After stirring at 0 ЊC for 35 min the reaction mixture
was quenched with saturated aqueous NaHCO3 and extracted
with Et2O. The combined organic fractions were washed with
water, brine, dried and the solvent removed under reduced
pressure. The crude product was purified by column chromato-
graphy using 25–30% EtOAc–petrol as eluent to afford rott-
nestol (12R)-1 (4.2 mg, 55%) as a pale yellow gum (See Table 1
for NMR data): [α]2D1 ϩ58.4 (c 0.18, CH2Cl2), lit.,1 [α]D ϩ67.4
(c 0.43, CH2Cl2); vmax (thin film) 3402, 2930, 1648, 1388, 1084,
1024 cmϪ1; MS (ESI) m/z 371 ([M ϩ Na]ϩ, 100%); HRMS
(ESI): Calcd for C22H36O3Na [M ϩ Na]ϩ 371.2564, found
371.2551.
(2S,3R,4S,6R)-Tetrahydro-2-methoxy-2,3-dimethyl-6-[(2E )-3-
tributylstannyl-2-propenyl]-2H-pyran-4-ol 7
(2S,3R,4S,6R)-Tetrahydro-2-methoxy-2,3-dimethyl-6-
[(12S,2E,4E,8E )-6,8-dimethyl-2,4,8,12-tridecatetraenyl]-2H-
pyran-4-ol. 12-epi-Rottnestol methyl ketal (12S )-(4)
A solution of the acetylene 28 (159 mg, 0.81 mmol) and freshly
prepared Bu3SnH (281 µL, 1.04 mmol) in dry benzene (8 mL)
was heated at reflux and AIBN (13.2 mg, 80 µmol) was added.
After 40 min at reflux a further portion of Bu3SnH (140 µL,
0.52 mmol) was added and the reaction was heated a further
5 min. The solvent was then removed under reduced pressure
and the residue purified on silica gel using 1% NEt3–10%
To a freeze–thaw degassed (3×) solution of the (S)-vinyl iodide
(S)-8 (31 mg, 0.11 mmol), stannane 7 (67 mg, 0.137 mmol) and
i-Pr2NEt (57 µL, 0.327 mmol) in dry DMF (1.0 mL) was added
bis(acetonitrile)palladium() chloride (3.5 mg, 13.0 µmol). The
reaction mixture was stirred in the absence of light at rt for 48 h
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
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and then diluted with water and extracted with Et2O. The
combined organic fractions were washed with water, brine,
dried and concentrated. Purification of the crude product by
column chromatography using 20% EtOAc–petrol provided
12-epi-rottnestol methyl ketal (12S)-4 (21.8 mg, 57%) as a
colourless gum. The spectroscopic data for (12S)-rottnestol
methyl ketal was identical to that quoted for the (12R)
compound: [α]2D1 ϩ74.4 (c 0.76, CH2Cl2); HRMS (ESI): Calcd
for C23H38O3Na [M ϩ Na]ϩ 385.2719, found 385.2717.
0.16 mmol) in dry THF (2 mL) was added slowly via cannula.
The reaction mixture was stirred at 0 ЊC for 1 h in the absence of
light and Et2O and water were added and the aqueous phase
was extracted with Et2O. The combined organic fractions were
washed with brine, dried and the solvent removed under
reduced pressure. Purification of the crude product on silica gel
(treated with 1% NEt3–petrol) using petrol as eluent afforded
the triene 31 (33.6 mg, 68%) as a colourless oil: [α]2D1 ϩ5.5
(c 1.04, CH2Cl2); vmax (thin film) 2929, 1642, 1090 cmϪ1; δH (300
MHz, C6D6) 0.05 (s, 6H), 0.90 (d, J = 6.3 Hz, 3H), 0.99 (s, 9H),
1.71 (s, 3H), 1.74–1.85 (m, 2H), 2.03–2.18 (m, 4H), 2.27 (m,
1H), 3.33–3.43 (m, 2H), 4.97 (d, J = 9.0 Hz, 1H), 5.01 (d, J =
15.3 Hz, 1H), 5.57 (dt, J = 14.7, 6.6 Hz, 1H), 5.76 (ddt, J = 16.8,
10.2, 6.3 Hz, 1H), 5.96 (d, J = 10.8 Hz, 1H), 6.34 (dd, J = 15.3,
10.8 Hz, 1H); δC (75.5 MHz, C6D6) Ϫ5.24, 16.5, 16.9, 18.5, 26.2,
32.8, 34.2, 34.4, 44.3, 68.1, 114.9, 127.1, 128.8, 131.5, 134.8,
138.4; HRMS (ESI): Calcd for C19H36OsiNa [M ϩ Na]ϩ
331.2433, found 331.2428.
(2S,3R,4S,6R)-Tetrahydro-2,3-dimethyl-6-[(12S,2E,4E,8E )-
6,8-dimethyl-2,4,8,12-tridecatetraenyl]-2H-pyran-2,4-diol.
12-epi-Rottnestol (12S )-(1)
To a solution of 12-epi-rottnestol methyl ketal (12S)-4 (11.9
mg, 32.8 µmol) in THF (1.0 mL) at 0 ЊC was added 5% aqueous
HCl (150 µL). After stirring at 0 ЊC for 35 min the reaction
mixture was quenched with saturated aqueous NaHCO3 and
extracted with Et2O. The combined organic fractions were
washed with water, brine, dried and the solvent removed under
reduced pressure. The crude product was purified by column
chromatography using 15–30% EtOAc–petrol as eluent to
afford 12epi-rottnestol (12S)-1 (7.2 mg, 63%) as a colourless
gum. The spectroscopic data for 12-epi-rottnestol was identical
to that quoted for the (12R) isomer: [α]2D4 ϩ33.9 (c 0.35,
CH2Cl2); HRMS (ESI): Calcd for C22H36O3Na [M ϩ Na]ϩ
371.2564, found 371.2547.
(2R,4E,6E )-2,4-Dimethylundeca-4,6,10-trien-1-ol 32
To a solution of the ether 31 (70 mg, 0.23 mmol) in anhydrous
THF (2.4 mL) was added TBAF (176 mg, 0.558 mmol) and the
resultant solution was stirred at rt for 2.5 h. Water and Et2O
were added and the aqueous layer was further extracted with
Et2O. The combined organic fractions were washed with water,
brine, dried and the solvent removed under reduced pressure.
Purification of the crude product by flash chromatography
using 15% EtOAc–petrol as eluent afforded the alcohol 32
(42 mg, 95%) as a clear oil: [α]2D2 ϩ4.1 (c 1.21, CH2Cl2); vmax (thin
(9R,4E,6E )-10-(tert-Butyldimethylsiloxy)-7,9-dimethyldeca-
4,5-dien-1-ol 30
film) 3354, 3078, 3021, 2922, 1641, 1450, 1038, 964, 912 cmϪ1
;
To a freeze–thaw degassed (3×) solution of the (E)-vinyl iodide
(R)-21 (50 mg, 0.14 mmol), stannane 2937 (74 mg, 0.197 mmol)
and i-Pr2NEt (52 µL, 0.30 mmol) in dry DMF (2 mL) was
added bis(acetonitrile)palladium() chloride (5.2 mg, 20 µmol)
and the reaction mixture was freeze–thaw degassed again. The
resultant black mixture was then stirred at 40 ЊC in the absence
of light for 11.5 h after which time water and Et2O were added.
The organic fraction was washed with water, brine, dried and
concentrated. The residue was purified on silica gel (treated
with 1% NEt3–10% EtOAc–petrol) using 10% EtOAc–petrol as
eluent to afford the conjugated diene 30 (24 mg, 54%) as a clear
oil: [α]1D9 ϩ5.4 (c 0.98, CH2Cl2); vmax (thin film) 3347, 2930, 1620,
1256, 1091 cmϪ1; δH (300 MHz, CDCl3) 0.03 (s, 6H), 0.82 (d,
J = 6.3 Hz, 3H), 0.89 (s, 9H), 1.63–1.83 (m, 4H), 1.71 (s, 3H),
2.16–2.23 (m, 3H), 3.34–3.44 (m, 2H), 3.67 (t, J = 6.3 Hz, 2H),
5.56 (dt, J = 15.0, 7.2 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 6.23
(dd, J = 15.3, 10.8 Hz, 1H); δC (75.5 MHz, CDCl3) Ϫ5.4, 16.5,
18.3, 25.9, 29.2, 32.4, 34.0, 43.8, 62.4, 68.0, 125.9, 127.2, 131.1,
135.3; HRMS (ESI): Calcd for C18H36O2SiNa [M ϩ Na]ϩ
335.2382, found 335.2382.
δH (300 MHz, C6D6) 0.80 (d, J = 6.3 Hz, 3H), 1.61 (s, 3H), 1.60–
1.71 (m, 1H), 1.67 (d, J = 6.9 Hz, 1H), 1.74 (d, J = 8.4 Hz, 1H),
2.05–2.14 (m, 4H), 3.11–3.27 (m, 2H), 4.97 (d, J = 9.3 Hz, 1H),
5.01 (d, J = 15.6 Hz, 1H), 5.56 (dt, J = 15.0, 6.6 Hz, 1H), 5.76
(ddt, J = 17.1, 10.5, 6.3 Hz, 1H), 5.89 (d, J = 10.8 Hz, 1H), 6.32
(dd, J = 15.3, 10.8 Hz, 1H); δC (75.5 MHz, C6D6) 16.5, 16.7,
32.7, 34.2, 34.3, 44.4, 67.9, 115.9, 127.0, 127.5, 131.6, 134.9,
138.4; HRMS (ESI): Calcd for C13H22ONa [M ϩ Na]ϩ
194.1671, found 194.1669.
(3R,1E,5E,7E )-1-Iodo-3,5-dimethyldodeca-1,5,7,11-tetraene 9
To a stirred solution of the alcohol 32 (33 mg, 0.17 mmol) and
pyridine (110 µL, 1.36 mmol) in anhydrous CH2Cl2 (3.0 mL)
was added Dess–Martin periodinane (101 mg, 0.24 mmol).
After stirring at rt for 1 h, Et2O and a 1 : 1 v/v mixture of
saturated aqueous NaHCO3 and 1.5 M Na2S2O3 were added
and the reaction mixture was vigorously stirred until the layers
cleared. The organic layer was washed with the 1 : 1 mixture of
saturated aqueous NaHCO3 and 1.5 M Na2S2O3 then saturated
aqueous NaHCO3, water, saturated aqueous CuSO4, brine,
dried and the solvent removed under reduced pressure. The
crude aldehyde (32 mg, 0.17 mmol) and iodoform (134 mg, 0.34
mmol) were dissolved in anhydrous dioxane (4.5 mL) and
added dropwise to a vigorously stirred slurry of flame-dried
chromium() chloride (167 mg, 1.36 mmol) in anhydrous THF
(0.8 mL) under an argon atmosphere. The resulting brown
suspension was stirred at rt for 4 h and was then diluted with
Et2O and water. The aqueous fraction was saturated with NaCl
and further extracted with Et2O. The combined organic
fractions were washed with brine, dried and concentrated and
the crude vinyl iodide was dissolved in Et2O (3.4 mL) and
treated with TBAF (268 mg, 0.85 mmol) in THF (1.2 mL) for
30 min. The solvent was removed under reduced pressure and
the residue filtered through a plug of silica gel using Et2O as
eluent. The crude product was purified by flash chromato-
graphy on silica gel (treated with 1% NEt3–petrol) using petrol
as eluent to give the vinyl iodide 9 (32 mg, 58%) as a colourless
oil: [α]1D6 ϩ14.4 (c 0.87, CH2Cl2); vmax (thin film) 3075, 3020,
2924, 1641, 1453, 964, 949, 911 cmϪ1; δH (300 MHz, CDCl3)
(10R,5E,7E )-11-(tert-Butyldimethylsiloxy)-8,10-dimethyl-
undeca-1,5,7-triene 31
To a stirred solution of the alcohol 30 (50 mg, 0.16 mmol) and
pyridine (100 µL, 1.24 mmol) in anhydrous CH2Cl2 (2.7 mL)
was added Dess–Martin periodinane (103 mg, 0.24 mmol).
After stirring at rt for 30 min, Et2O and a 1 : 1 v/v mixture of
saturated aqueous NaHCO3 and 1.5 M Na2S2O3 were added
and the reaction mixture was vigorously stirred until the layers
cleared. The organic layer was washed with the 1 : 1 mixture of
saturated aqueous NaHCO3 and 1.5 M Na2S2O3 then saturated
aqueous NaHCO3, water, saturated aqueous CuSO4, brine,
dried and the solvent removed under reduced pressure to give
the aldehyde which was used immediately in the next reaction.
To a suspension of methyltriphenylphosphonium bromide (230
mg, 0.64 mmol) in anhydrous THF (1 mL) at 0 ЊC was added
n
dropwise BuLi in hexanes (400 µL, 2.2 M, 0.88 mmol). The
resulting yellow solution was stirred at rt for 5 min then
recooled to 0 ЊC and a solution of the aldehyde (49 mg,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
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0.95 (d, J = 6.9 Hz, 3H), 1.70 (s, 3H), 1.94 (dd, J = 13.5, 7.8 Hz,
1H), 2.38 (m, 1H), 2.04–2.30 (m, 5H), 4.97 (d, J = 10.8 Hz, 1H),
5.03 (dd, J = 17.4, 1.2 Hz, 1H), 5.60 (dt, J = 15.0, 6.3 Hz, 1H),
5.72–5.90 (m, 1H), 5.76 (d, J = 11.1 Hz, 1H), 5.87 (d, J = 14.4
Hz, 1H), 6.24 (dd, J = 15.3, 10.8 Hz, 1H), 6.44 (dd, J = 14.4, 7.8
Hz, 1H); δC (75.5 MHz, CDCl3) 16.5, 18.9, 32.3, 33.7, 38.8,
46.7, 73.4, 114.7, 126.8, 127.0, 132.1, 133.7, 138.3, 151.7;
HRMS (ESI): Calcd for C14H21INa [M ϩ Na]ϩ 316.0688, found
316.0678.
(1.10 g, 7.33 mmol) in CH2Cl2 (5.0 mL) was cannulated to the
reaction. The reaction mixture was stirred at Ϫ78 ЊC for 90 min
and cannulated into a 1 : 1 mixture of CH2Cl2 : 1 M NaHSO4
(400 mL) at 0 ЊC. The biphasic mixture was stirred for 10 min at
0 ЊC and diluted with additional CH2Cl2 : 1 M NaHSO4. The
organic phase was extracted with CH2Cl2, washed with satur-
ated aqueous NaHCO3, water, brine and dried over Na2SO4.
The solvent was removed under reduced pressure to yield the
crude alcohol which was purified by column chromatography
using 30%EtOAc–petrol as eluent to afford the alcohol 35 (2.06
g, 77%) as a colourless oil: [α]1D5 Ϫ64.2 (c 1.01, CH2Cl2); vmax
(thin film) 3527, 2985, 1782, 1360, 1114 cmϪ1; δH (300 MHz,
CDCl3) 1.24 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H), 2.73
(br s, 1H), 2.77 (dd, J = 13.2, 9.2 Hz, 1H), 3.02 (m, 1H), 3.26
(dd, J = 13.5, 3.3 Hz, 1H), 3.46 (m, 2H), 4.16 (m, 2H), 4.13–4.22
(m, 3H), 4.51 (d, J = 3.9 Hz, 2H), 4.72 (m, 1H), 4.88 (q, J = 7.2
Hz, 1H), 7.18–7.35 (m, 10H); δC (75.5 MHz, CDCl3) 11.7, 12.7,
37.7, 46.3, 51.9, 55.1, 66.2, 70.5, 71.2, 73.2, 127.2, 127.7, 128.3,
128.8, 129.3, 134.9, 137.6, 153.3, 170.5, 210.3; HRMS (ESI):
Calcd for C25H29NO6Na [M ϩ Na]ϩ 462.1893, found 462.1898.
(2S,3R,4S,6R)-Tetrahydro-2-methoxy-2,3-dimethyl-6-
[(12R,2E,4E,8E,10E )-6,8-dimethyl-2,4,8,10,14-pentadeca-
pentaenyl]-2H-pyran-4-ol. Raspailol A methyl ketal (33)
To a freeze–thaw degassed (3×) solution of the (R)-vinyl iodide
(R)-9 (36 mg, 0.11 mmol), stannane 7 (73 mg, 0.15 mmol) and
i-Pr2NEt (62 µL, 0.356 mmol) in dry DMF (1.1 mL) was added
bis(acetonitrile)palladium() chloride (4.7 mg, 18.0 µmol). The
reaction mixture was stirred in the absence of light at rt over-
night after which time a further portion of palladium catalyst
(1.0 mg, 3.85 µmol) was added. The mixture was stirred for a
further 4 h and then diluted with water and extracted with Et2O.
The combined organic fractions were washed with water, brine,
dried and concentrated. Purification of the crude product by
column chromatography on silica gel (treated with 1% NEt3–
10% EtOAc–petrol) using 10–15% EtOAc–petrol as eluent
provided raspailol A methyl ketal (33) (25 mg, 57%) as a colour-
less oil: [α]2D2 ϩ94.5 (c 1.23, CH2Cl2); vmax (thin film) 3432, 3023,
2924, 1642, 1378, 1048 cmϪ1; δH (400 MHz, C6D6) 0.97 (d,
J = 6.4 Hz, 3H, H23), 1.17 (d, J = 6.8 Hz, 3H, H22), 1.24 (s, 3H,
H1), 1.28–1.39 (m, 2H, H3, H5), 1.64 (s, 3H, H24), 1.72 (m, 1H,
H5), 1.96 (dd, J = 13.6, 8.0 Hz, 1H, H13), 2.04–2.20 (m, 6H,
H7, H13, H18, H19), 2.32–2.39 (m, 2H, H7, H12), 3.02 (s,
3H, H25), 3.53 (m, 1H, H4), 3.65 (ddd, J = 10.4, 10.4, 4.4 Hz,
1H, H6). 4.99 (d, J = 10.4 Hz, 1H, H21), 5.03 (d, J = 17.2 Hz,
1H, H21), 5.48–5.58 (m, 2H, H11, H17), 5.63–5.78 (m, 2H, H8,
H20), 5.89 (d, J = 10.4 Hz, 1H, H15), 6.00–6.11 (m, 2H, H9,
H20), 6.24–6.33 (m, 1H, H16); δC (75.5 MHz, C6D6) 12.4, 17.0,
20.4, 22.3, 33.1, 34.5, 35.5, 39.9, 41.5, 47.7, 48.4, 49.0, 68.9,
69.9, 102.0, 115.3, 127.7, 127.9, 128.8, 129.3, 132.1, 133.7,
134.9, 138.8, 139.9; HRMS (FAB): Calcd for C25H40O3Na [M ϩ
Na]ϩ 411.2875, found 411.2875.
[[3-(2R,3S,4R,5S ),4R]-3-(6-Benzyloxy-3,5-dihydroxy-2,4-di-
methyl-1-oxohexyl)-4-(phenylmethyl)]-2-oxazolidinone 36
40
A solution of Me4NBH(OAc)3 (4.61 g, 17.53 mmol) in
anhydrous acetonitrile (20 mL) and freshly distilled glacial
acetic acid (20 mL) was cooled to Ϫ40 ЊC. The ketal 35 (1.93 g,
4.38 mmol) in acetonitrile (35 mL) was added via cannula and
the reaction was stirred for 1 h, warmed to 0 ЊC and stirred for
an additional 1 h. The reaction mixture was warmed to room
temperature, stirred for 1 h and cannulated to a stirring biphasic
mixture of CH2Cl2 (415 mL) and saturated aqueous NaHCO3
(275 mL). The organic phase was extracted with CH2Cl2,
washed with brine and dried over Na2SO4. The crude oil was
purified by column chromatography with 40%EtOAc–petrol as
eluent to yield the diol 36 (1.76 g, 91%) as a pale yellow gum:
[α]1D7 Ϫ44.3 (c 1.02, CH2Cl2); (Found: C, 68.0; H, 7.3; N, 3.3;
C25H31NO6 requires C, 68.0; H, 7.1; N, 3.15%); vmax (thin film)
3450, 1692, 1388 cmϪ1; δH (300 MHz, CDCl3) 0.91 (d, J = 6.9
Hz, 3H), 1.26 (d, J = 6.6 Hz, 3H), 1.85 (m, 1H), 2.75 (dd,
J = 13.5, 9.6 Hz, 1H), 3.04 (d, J = 3.9 Hz, 1H), 3.23 (dd, J = 13.5,
3.3 Hz, 1H), 3.52–3.55 (m, 2H), 3.75 (d, J = 3.3 Hz, 1H), 3.91–
3.98 (m, 2H), 4.10–4.20 (m, 3H), 4.54 (d, J = 5.7 Hz, 2H), 4.64
(m, 1H), 7.17–7.33 (m, 10H); δC (75.5 MHz, CDCl3) 10.2, 11.0,
14.0, 20.9, 37.1, 37.5, 39.9, 55.1, 60.2, 66.0, 70.9, 72.2, 73.1,
73.5, 127.2, 127.4, 127.5, 127.6, 128.2, 128.3, 128.8, 129.3,
135.0, 137.9, 152.8, 176.9; HRMS (ESI): Calcd for C25H31-
NO6Na [M ϩ Na]ϩ 464.2049, found 464.2046.
(2S,3R,4S,6R)-Tetrahydro-2,3-dimethyl-6-[(12R,2E,4E,8E,-
10E )-6,8-dimethyl-2,4,8,10,14-pentadecapentaenyl]-2H-pyran-
4-ol. Raspailol A (5)
To a solution of raspailol A methyl ketal (33) (22.7 mg,
58.0 µmol) in THF (1.8 mL) at 0 ЊC was added 5% aqueous HCl
(360 µL). After stirring at 0 ЊC for 30 min the reaction mixture
was stirred at rt for 5 min and was then quenched with saturated
aqueous NaHCO3 and extracted with Et2O. The combined
organic fractions were washed with water, brine, dried and the
solvent removed under reduced pressure. The crude product
was purified by column chromatography on silica gel (treated
with 1% NEt3–30% EtOAc–petrol) using 30% EtOAc–petrol as
eluent to afford raspailol A (5) (14.3 mg, 65%) as a colourless
gum (See Table 2 for NMR data): [α]2D3 ϩ78.4 (c 0.42, C6H6),
lit.,2 [α]D ϩ62.0 (c 0.46, C6H6); vmax (thin film) 3404, 2923, 1641,
1381, 1159, 1077 cmϪ1; HRMS (FAB): Calcd for C24H38O3Na
[M ϩ Na]ϩ 397.2719, found 397.2721.
(2R,3S,4R,5S )-6-Benzyloxy-2,4-dimethyl-3,5-bis(triethylsilyl-
oxy)-N-methoxy-N-methylhexanamide 37
A suspension of N,O-dimethylhydroxyamine hydrochloride
(796 mg, 8.16 mmol) in CH2Cl2 (30 mL) was treated at 0 ЊC with
AlMe3 (2 M in toluene, 4.1 mL, 8.16 mmol). When methane gas
had ceased to bubble from the vessel it was warmed to room
temperature and stirred for 30 min. The reaction was then co-
oled to Ϫ45 ЊC and a solution of the diol 36 (600 mg, 1.36
mmol) in CH2Cl2 (16 mL) was cannulated to the reaction vessel.
The yellow solution was stirred at Ϫ45 ЊC for five hours and
quenched with 0.5 M potassium tartrate. The mixture was
stirred for two hours until the aqueous layer became clear and
the biphasic mixture was filtered through Celite. The organic
phase was extracted with CH2Cl2, washed with saturated aque-
ous NaHCO3, brine and dried over Na2SO4. The solvent was
removed under reduced pressure to afford the crude Weinreb
amide. A solution of the crude amide (360 mg, 1.11 mmol) in
DMF (8 mL) was treated with imidazole (226 mg, 3.32 mmol)
and TESCl (464 µL, 2.77 mmol) at rt. The reaction mixture was
stirred overnight and diluted with water and Et2O. The organic
layer was extracted with Et2O and the combined organic
[[3-(2R,4S,5S ),4R]-3-(6-Benzyloxy-5-hydroxy-2,4-dimethyl-
1,3-dioxohexyl)-4-(phenylmethyl)]-2-oxazolidinone 35
A suspension of tin triflate (2.79 g, 6.69 mmol) in anhydrous
CH2Cl2 (11.0 mL) was treated with NEt3 (933 µL, 6.69 mmol).
The mixture was immediately cooled to Ϫ20 ЊC and the β-keto
imide 3438 (1.76 g, 6.08 mmol) in CH2Cl2 (7.0 mL) was added
dropwise. The reaction mixture was stirred for 1 h at Ϫ20 ЊC,
cooled to Ϫ78 ЊC and a solution of benzyloxyacetaldehyde
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
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extracts were washed with saturated aqueous NaHCO3, water,
brine and dried over MgSO4. The crude residue was purified by
column chromatography using 10% EtOAc–petrol as eluent to
yield the bis-protected amide 37 (445 mg, 59% for 2 steps): [α]1D6
ϩ8.2 (c 1.00, CH2Cl2) (Found: C, 62.8; H, 10.1; N, 2.6;
C29H55NO5Si2 requires C, 62.9; H, 10.0; N, 2.55%); vmax (thin
film) 3453, 2912, 1665, 1458, 1004 cmϪ1; δH (300 MHz, CDCl3)
0.53–0.65 (m, 12H), 0.89–0.99 (m, 21H), 1.12 (d, 3H, J = 6.9
Hz), 1.86 (m, 1H), 3.03 (m, 1H), 3.12 (s, 3H), 3.48 (m, 2H), 3.65
(s, 3H), 3.69 (m, 1H), 4.05 (dd, J = 6.3, 4.8 Hz, 1H), 4.51 (AB
quartet, J = 12 Hz, 2H), 7.26–7.33 (m, 10H); δC (75.5 MHz,
CDCl3) 5.2, 5.3, 7.0, 7.1, 11.6, 14.0, 32.1, 38.0, 42.3, 61.1, 72.5,
73.2, 73.5, 74.0, 127.3, 127.7, 128.1, 138.5, 176.6; HRMS (ESI):
Calcd for C29H55NO5Si2Na [M ϩ Na]ϩ 576.3516, found
576.3504. Further elution gave the amide bi-product 38 (99 mg,
10% for 2 steps): [α]1D4 ϩ0.0 (c 1.03, CH2Cl2) (Found: C, 64.15;
H, 9.15; N, 3.9; C29H55NO5Si2 requires C, 64.05; H, 9.1; N,
3.85%); vmax (thin film) 3400, 2912, 1674, 1051, 740 cmϪ1; δH
(300 MHz, CDCl3) 0.61 (q, J = 7.8 Hz, 12H), 0.92 (m, 24H),
1.05 (d, J = 7.2 Hz, 3H), 1.86 (m, 1H), 2.47 (quint, J = 6.9 Hz,
1H), 2.68 (dd, J = 13.8, 8.1 Hz, 1H), 2.77 (dd, J = 13.5, 6.6 Hz,
1H), 3.12 (s, 3H) 3.46 (dd, J = 3.9, 9.9 Hz, 1H), 3.59 (dd, J = 4.8,
10.0 Hz, 1H) 3.68 (s, 3H), 3.81 (q, J = 4.8 Hz, 1H), 3.96 (m, 3H),
4.05 (dd, J = 10.8, 4.5 Hz, 1H), 4.36 (m, 1H) 6.19 (d, 1H),
7.17–7.34 (m, 10H, ArH); δC (75.5 MHz, CDCl3) 5.1, 5.3, 6.9,
7.0, 13.1, 13.8, 35.5, 37.2, 41.1, 45.1, 49.4, 61.5, 65.9, 72.9, 73.2,
73.5, 75.9, 126.5, 127.5, 127.7, 128.2, 128.4, 129.1, 137.1, 138.1,
156.8, 174.6; HRMS (ESI): Calcd for C29H55NO5Si2Na [M ϩ
Na]ϩ 753.4306, found 753.4328.
dried over MgSO4. The crude product was purified by column
chromatography, eluting with 2.5–5% EtOAc–petrol to yield the
silylated tetrahydropyran. To a solution of this silyl ether
(142 mg, 0.35 mmol) in MeOH (15 mL) was added 10%
Pd(OH)2/C (49 mg, 0.070 mmol) and the reaction was agitated
under 50 psi of hydrogen gas for 12 h. The suspension was
filtered though Celite and the solvent was removed under
reduced pressure. Purification by column chromatography
using 10% EtOAc–petrol as eluent afforded the alcohol 40 (103
mg, 74%) as a yellow film: [α]1D5 ϩ131.3 (c 1.02, CH2Cl2); vmax
(thin film) 3315, 2886 cmϪ1; δH (300 MHz, CDCl3) 0.03 (d, J =
6.6 Hz, 6H), 0.83 (d, 3H, J = 7.2 Hz), 0.87 (s, 9H), 0.92 (d, 3H,
J = 6.9 Hz), 1.29 (s, 3H), 1.63 (dq, J = 10.8, 6.8 Hz, 1H), 1.76 (m,
1H), 2.18 (br s, 1H), 3.15 (s, 3H), 3.47 (d, J = 9.0 Hz, 1H), 3.66–
3.77 (m, 3H); δC (75.5 MHz, CDCl3) Ϫ4.8, Ϫ4.3, 5.4, 12.4, 18.0,
21.6, 25.8, 36.9, 41.7, 47.5, 64.1, 71.6, 72.6, 101.5; HRMS (ESI):
Calcd for C16H34O4SiNa [M ϩ Na]ϩ 341.2124, found 341.2118.
(2S,3R,4S,5R,6R)-Tetrahydro-2-methoxy-2,3,5-trimethyl-6-
prop-2-ynyl-2H-pyran-4-ol 41
A solution of the pyran 40 (145 mg, 0.46 mmol) in CH2Cl2
(4.0 mL) was cooled to Ϫ78 ЊC and treated with 2,6-lutidine
(265 µL, 2.28 mmol) and Tf2O (153 µL, 0.91 mmol). The reac-
tion was stirred at Ϫ78 ЊC for 45 min, quenched with saturated
aqueous NaHCO3 and diluted with Et2O. The organic phase
was extracted with ether, washed with saturated aqueous
NaHCO3, water, saturated aqueous CuSO4, water, brine and
dried over MgSO4. The solvent was removed under reduced
pressure in an ice bath to prevent decomposition and the crude
triflate was obtained as an orange oil. The crude triflate
(205 mg, 0.455 mmol) in anhydrous THF (3.0 mL) was added
dropwise via cannula to a solution of lithium trimethyl-
silylacetylide [from trimethylsilylacetylene (322 µL, 2.28 mmol)
and n-BuLi in hexanes (986 µL, 2.4 M, 2.38 mmol)] in dry THF
(3.0 mL) and HMPA (792 µL, 4.55 mmol) at Ϫ78 ЊC. The
reaction mixture was stirred at Ϫ78 ЊC for 1 h and quenched
with saturated aqueous NH4Cl and diluted with Et2O. The
organic layer was extracted with Et2O and the combined
organic fractions were washed with water, brine and dried over
MgSO4. The solvent was removed under reduced pressure to
afford the crude acetylene as a yellow oil (182 mg, 0.46 mmol)
which was dissolved in DMF (8.0 mL) and treated with TBAF
(575 mg, 1.82 mmol) at rt for 2 days. Water and Et2O were
added and the organic phase was extracted with Et2O. The
combined organic fractions were washed with water, brine and
dried over MgSO4. The solvent was removed under reduced
pressure and the crude alkyne was purified by column chroma-
tography using 15%EtOAc–petrol as eluent to afford the alkyne
41 (64 mg, 66% for 3 steps) as a white crystalline solid: [α]1D7
ϩ133.9 (c 0.67, CH2Cl2); vmax (thin film) 3369, 2944 cmϪ1; δH
(300 MHz, CDCl3) 0.88 (d, 3H, J = 7.2 Hz), 1.02 (d, 3H, J = 6.6
Hz), 1.31 (s, 3H), 1.49 (br s, 1H), 1.62 (m, 1H), 1.97 (t, 1H,
J = 2.7 Hz), 2.08 (m, 1H), 2.25–2.34 (ddd, J = 2.7, 7.7, 16.7 Hz,
1H), 2.40–2.49 (ddd, J = 2.7, 7.3, 16.5 Hz, 1H), 3.18 (s, 3H),
3.78–3.84 (m, 2H); δC (75.5 MHz, CDCl3) 4.3, 11.8, 21.5, 22.2,
37.1, 41.1, 47.7, 69.2, 69.5, 72.2, 81.0, 101.4; HRMS (ESI):
Calcd for C12H20O3Na [M ϩ Na]ϩ 235.1310, found 235.1309.
(2S,3R,4S,5R,6S )-Tetrahydro-6-benzyloxymethyl-2-methoxy-
2,3,5-trimethyl-2H-pyran-4-ol 39
A solution of the bis-protected Weinreb amide 37 (221 mg,
0.40 mmol) in anhydrous THF (6 mL) was cooled to 0 ЊC. The
amide was treated with MeMgCl in hexanes (0.80 mL, 3.0 M,
2.39 mmol) and stirred for 3 h at rt. The reaction vessel was
cooled to 0 ЊC and quenched with saturated aqueous NH4Cl
and diluted with Et2O. The organic layer was extracted with
Et2O and the combined organic extracts were washed with sat-
urated aqueous NaHCO3, water, brine and dried over MgSO4
to afford the ketone (198 mg, 0.39 mmol) which was dissolved
in a 3 : 1 mixture of CH2Cl2 (8.1 mL) : MeOH (2.7 mL) and
treated with PPTS (20 mg, 0.078 mmol) and stirred overnight.
The reaction was quenched with saturated aqueous NaHCO3
and diluted with CH2Cl2. The organic layer was extracted with
CH2Cl2, washed with saturated aqueous NaHCO3, water, brine
and dried over MgSO4. Purification by column chromatography
with 10% EtOAc–petrol as eluent afforded the tetrahydropyran
39 (106 mg, 91% for 2 steps) as a pale yellow oil: [α]1D6 ϩ100.0
(c 0.96, CH2Cl2) (Found: C, 69.6; H, 9.05; C17H26O4 requires C,
69.35; H, 8.9%); vmax (thin film) 3428, 2918, 1074 cmϪ1; δH (400
MHz, CDCl3) 0.81 (d, 3H, J = 7.2 Hz), 0.99 (d, 3H, J = 6.8 Hz),
1.29 (s, 3H), 1.56–1.64 (dq, J = 10.8, 6.8 Hz, 1H), 1.94–1.97 (m,
1H), 3.15 (s, 3H), 3.42 (dd, J = 5.6, 10 Hz, 1H), 3.53 (dd, J = 7.2,
9.6 Hz, 1H), 3.77 (dd, J = 5.2, 10.8 Hz, 1H), 3.89 (dt, J = 6.2, 2
Hz, 1H), 4.46–4.61 (AB quartet, J = 12 Hz, 2H), 7.26–7.31
(m, 10H); δC (100 MHz, CDCl3) 4.9, 11.8, 21.5, 36.2, 41.4, 47.6,
69.7, 71.0, 72.2, 73.3, 101.2, 127.4, 127.5, 128.3, 138.3; HRMS
(ESI): Calcd for C17H26O4Na [M ϩ Na]ϩ 317.1729, found
317.1721.
(2S,3R,4S,5R,6R)-Tetrahydro-2-methoxy-2,3,5-trimethyl-6-[3-
(tributylstannanyl)allyl]-2H-pyran-4-ol 10
A solution of the alkyne 41 (45 mg, 0.21 mmol) in anhydrous
benzene (3.0 mL) was treated with Bu3SnH (80 µL, 0.30 mmol)
and AIBN (3.5 mg, 0.021 mmol). The reaction mixture was
refluxed for 2 h and additional Bu3SnH (40 µL, 0.15 mmol) and
AIBN (1.8 mg, 0.0085 mmol) were added and the reaction was
refluxed for another 2 h. The benzene was removed under
reduced pressure and the crude stannane was purified immedi-
ately by column chromatography using 1%NEt3–petrol as
eluent to afford the stannane 10 (75 mg, 70%) as a colourless
(2S,3R,4S,5R,6S )-Tetrahydro-4-(tert-butyldimethylsiloxy)-6-
hydroxymethyl-2-methoxy-1,3,5-trimethyl-2H-pyran 40
A solution of the alcohol 39 (205 mg, 0.70 mmol) in CH2Cl2
(15 mL) was treated with 2,6-lutidine (162 µL, 1.39 mmol) and
TBSOTf (240 µL, 1.05 mmol) at rt. The reaction mixture was
stirred for 2.5 h and upon completion the reaction was diluted
with Et2O and water. The organic phase was extracted Et2O,
washed with saturated aqueous NaHCO3, water, brine and
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
2055

View Article Online
oil: [α]2D2 ϩ53.7 (c 0.37, CH2Cl2); vmax (thin film) 3436, 2926,
1463, 1068 cmϪ1; δH (300 MHz, C6D6) 0.91–0.99 (m, 18H), 1.10
(d, 3H, J = 6.9 Hz), 1.21 (s, 3H), 1.38 (sext, J = 7.5 Hz, 6H), 1.60
(quint, J = 7.8 Hz, 6H), 1.68–1.72 (m, 2H), 2.20 (m, 1H), 2.60
(m, 1H), 3.12 (s, 3H), 3.70–3.76 (m, 2H), 6.10–6.20 (m, 2H); δC
(75.5 MHz, C6D6) 5.0, 9.7, 10.6, 12.2, 14.0, 21.7, 27.7, 29.6,
38.8, 41.7, 47.5, 70.9, 72.4, 101.4, 130.1, 146.8; HRMS (ESI):
Calcd for C24H48O3SnNa [M ϩ Na]ϩ 527.2523, found 527.2522.
References
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To a freeze–thaw degassed (×3) solution of the vinyl iodide 9
(23 mg, 0.073 mmol) and stannane 10 (70 mg, 0.14 mmol) in
DMF (2.7 mL) and i-Pr2NEt (89 µL, 0.51 mmol) was added
bis(acetonitrile)palladium() chloride (1.9 mg, 0.0073 mmol).
The reaction was stirred at rt, in the absence of light overnight.
Additional catalyst (1 mg, 0.0036 mmol) was added and the
reaction was stirred for a further 4 h and diluted with water and
Et2O. The organic layer was extracted with Et2O and the
combined organic extracts were washed with water, brine and
dried over MgSO4. The crude residue was purified by column
chromatography with 10%EtOAc–petrol as eluent to afford
raspailol B methyl ketal (42) (17 mg, 58%): [α]2D3 ϩ126.7 (c 0.48,
CH2Cl2); vmax (thin film) 3430, 2922, 1727, 1459, 1065 cmϪ1
;
δH (400 MHz, C6D6) 0.91 (d, J = 7.2 Hz, 3H, H25), 0.96 (d, J =
6.4 Hz, 3H, H23), 1.09 (d, J = 6.8 Hz, 3H, H22), 1.19 (s, 3H,
H1), 1.56 (dq, J = 10.8, 6.7 Hz, 1H, H3), 1.62 (m, 1H, H5), 1.62
(s, 3H, H24), 1.95 (dd, J = 13.2, 7.6 Hz, 1H, H13), 2.08 (m, 6H,
H7, H13, H18, H19), 2.37 (m, 2H, H7, H17), 3.03 (s, 3H, H26),
3.62 (td, J = 7.0, 2.0Hz, 1H, H4), 3.67 (dd, J = 10.8, 8.4Hz, 1H,
H6), 4.97 (d, J = 11.2 Hz, 1H, H21), 5.00 (d, J = 17.6Hz, 1H,
H21), 5.56 (m, 3H, H8, H11, H17), 5.75 (ddt, J = 16.8, 10.4, 6.4
Hz, 1H, H20), 5.90 (d, J = 10.8 Hz, 1H, H15), 6.10 (m, 2H, H9,
H10), 6.32 (dd, J = 15.0, 10.8 Hz, 1H, H16); δC (100 MHz,
C6D6) 4.9, 12.2, 16.6, 20.1, 21.7, 32.7, 34.1, 35.2, 36.2, 38.4,
41.7, 47.4, 48.0, 71.1, 77.4, 101.4, 114.9, 127.3, 127.5, 128.7,
128.9, 131.8, 133.1, 134.5, 138.4, 138.5; HRMS (ESI): Calcd for
C26H42O3Na [M ϩ Na]ϩ 425.3032, found 425.3060.
(2S,3R,4S,5R,6R)-Tetrahydro-6-[(12R,2E,4E,8E,10E )-6,8-
Dimethyl-2,4,8,10,14-pentadecapentaenyl]-2,3,5-trimethyl-2H-
pyran-2,4-diol. Raspailol B (6)
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The methyl ketal (42) (9 mg, 0.022 mmol) in THF (2.5 mL) was
treated at 0 ЊC with 5% aqueous HCl (140 µL) for 4 h. The
reaction was quenched with saturated aqueous NaHCO3 and
diluted with Et2O. The organic phase was extracted with Et2O
and the combined organic extracts were washed with water,
brine and dried over MgSO4. The solvent was removed under
reduced pressure and the crude natural product was purified by
column chromatography. Elution with 20% EtOAc–petrol
afforded raspailol B (6) (8.0 mg, 93%) as a colourless oil (See
Table 3 for NMR data): [α]2D2ϩ114.7 (c 0.34, CH2Cl2); [α]2D3
ϩ108.0 (c 0.045, C6H6); lit.,2 [α]D ϩ111 (c 0.14, C6D6); vmax (thin
film) 3422, 2920, 1457, 1381, 1087, 990 cmϪ1; HRMS (ESI):
Calcd for C25H40O3Na [M ϩ Na]ϩ 411.2875, found 411.2884.
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Acknowledgements
We thank Dr Michael Boyd and Dr John Beutler of the NCI
Maryland, USA for the generous gifts of natural rottnestol (1)
and rottnestol methyl ketal (4) for TLC comparison as well as
1
copies of the H NMR and 13C NMR spectra of each. This
work was financially supported by the Australian Research
Council Large Grants Scheme.
44 T. Shimizu, K. Osaka and T. Nakata, Tetrahedron Lett., 1997, 38,
2685.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 0 4 4 – 2 0 5 6
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