Concise synthesis of the C-1-C-12 fragment of amphidinolides T1-T5

Article abstract of DOI:10.1039/c1ob05130j

The C-1-C-12 segment of the amphidinolides T1-T5 has been synthesised in an efficient manner. The key transformations are highly diastereoselective rearrangement of an oxonium ylide, or metal-bound ylide equivalent, produced by intramolecular reaction of

Full text of DOI:10.1039/c1ob05130j

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Concise synthesis of the C-1–C-12 fragment of amphidinolides T1–T5†
J. Stephen Clark,* Flavien Labre and Lynne H. Thomas
Received 24th January 2011, Accepted 9th March 2011
DOI: 10.1039/c1ob05130j
The C-1–C-12 segment of the amphidinolides T1–T5 has been synthesised in an efficient manner. The
key transformations are highly diastereoselective rearrangement of an oxonium ylide, or metal-bound
ylide equivalent, produced by intramolecular reaction of a copper carbenoid with an allylic ether, and
macrocyclic fragment coupling by one-pot ring-closing metathesis and hydrogenation.
the other amphidinolides and are particularly attractive synthetic
Introduction
targets because of their unusual structures. Amphidinolides T1–T5
The amphidinolides are marine natural products produced by
possess seven stereogenic centres around the macrocyclic core and
dinoflagellates of the genus Amphidinium that have a symbiotic
amphidinolide T2 possesses an additional stereogenic centre in its
side chain (C-21). It is noteworthy that the amphidinolides T3–T5
relationship with flatworms of the Amphiscolops species.1 More
than 30 amphidinolides have been isolated and several of them
are diastereomers, with differing configurations at C-12 and C-14,
display potent cytotoxic activity.1 However, the full biological
and amphidinolides T1 and T3 have a regioisomeric relationship
profiles of many members of this family of natural products have
not been established due to their relatively low natural abundance.
resulting from reversal of the a-hydroxy ketone functionality at
C-12 and C-13.
The isolation and characterisation of amphidinolides T1–T5
Members of the amphidinolides T series have been very popular
synthetic targets.2 Fu¨rstner and co-workers were the first to
complete a total synthesis of a member of the amphidinolide T
series—amphidinolide T4—in 2002 and subsequently synthesised
amphidinolides T1, T3 and T5 using the same general strategy.3,4
The groups of Ghosh (T1),5 Jamison (T1, T4),6 Zhao (T3),7 Yadav
(T1)8 and, very recently, Dai (T2)9 have also completed syntheses
of members of the amphidinolide T series. However, a general
modular approach, that would allow these compounds to be
prepared from a common late-stage intermediate, has yet to be
developed.
was first reported by Kobayashi and co-workers in 2000 and 2001
(Fig. 1).1 Although they are not the most bioactive members of
the family,1 amphidinolides T1–T5 do display significant cytotoxic
activity. They are also more structurally complex than many of
Results and discussion
As part of our programme concerning the total synthesis of marine
natural products, we have become interested in devising a novel,
general and efficient synthetic route to the amphidinolides T1–T5.
This route would allow most of the compounds to be accessed by
regioselective and stereoselective functionalisation at the C-12 and
C-13 positions of a common macrolide intermediate. At the outset,
we wished to use our oxonium ylide rearrangement methodology
to construct the highly substituted tetrahydrofuran core,10 and
combine this transformation with ring-closing metathesis (RCM)
reactions for macrocylic fragment coupling and formation of the
complete macrolactone core of the natural products.
Fig. 1 Amphidinolides T1–T5 and the key fragment 1.
In most published syntheses of members of the amphidinolide
T series, macrocycle formation is accomplished either by construc-
tion of the C-4–C-5 bond using RCM3,4 or by macrolactonisation
at C-1.5,7,8 In contrast, we intend to adopt a less conventional
approach and effect final ring closure by construction of the C-12–
C-13 bond.9 To accomplish this bond-forming reaction, we require
WestCHEM, School of Chemistry, University of Glasgow, University Avenue,
Glasgow, G12 8QQ, United Kingdom. E-mail: stephen.clark@glasgow.ac.uk;
Fax: +44 (0)141 330 6867; Tel: +44 (0)141 330 6296
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for compounds 1–3, 5, 7, 13–16a, 17, 18. CCDC reference number
799191. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ob05130j
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ready access to the carboxylic acid 1, a compound that corresponds
to the C-1–C-12 fragment common to all the amphidinolides of
the T series and has been used as an intermediate in several other
syntheses of these natural products.6
The synthesis of the C-1–C-12 fragment commenced with
b-hydroxy ester 2 which was prepared with >94% ee by
Noyori reduction of methyl 6-[(4-methoxyphenyl)methoxy]-3-
oxohexanoate (Scheme 1).11,12 O-Allylation was performed by
palladium-catalyzed reaction of the alcohol 2 with allyl ethyl
carbonate. The resulting ester 3 was saponified to give the
carboxylic acid 4 and this was converted into the diazo ketone
5 by mixed anhydride formation and reaction with diazomethane.
Conversion of the ester 3 into the diazo ketone 5 was achieved
with an overall yield of 85%.
Scheme 2 Reagents and conditions: a NaN(SiMe3)2, THF, -78 ◦C then
CH2CHCH2I, -78 ◦C → rt [82%]; b LiOH aq., H2O2, THF–H2O [100%];
c 7, 11, CH2Cl2, reflux.
was explored. The requisite RCM substrate 13 was prepared by
removal of the PMB group from the dihydrofuranone 7 and
esterification of the resulting alcohol with the carboxylic acid
10 (Scheme 3).16 Reaction of the resulting diene 13 with the
complex 11 in 1,2-dichloroethane at reflux resulted in RCM and
afforded a mixture of the lactone 14 and a small amount of
Scheme 1 Reagents and conditions: a Pd2(dba)3, dppb, EtO2COCH2-
CHCH2, THF, reflux [84%]; b LiOH aq., THF, MeOH, rt; c (i) i-BuO2CCl,
Et3N, Et2O, rt, (ii) CH2N2, Et2O, 0 ◦C → rt [85% from 3]; d Cu(acac)2,
THF, reflux [90%, >97 : 3].
The key reaction in our synthetic route—diastereoselective
dihydrofuranone formation—was accomplished by generation
of a copper carbenoid from the diazo ketone 5, followed by
formation and subsequent [2,3] sigmatropic rearrangement of the
free oxonium ylide 6 or its metal-bound equivalent (Scheme 1).10
This transformation resulted in high-yielding formation of the
ketone 7 as a single diastereomer as judged by NMR analysis.10a
The C-1–C-4 fragment was prepared from the acyl oxazo-
lidinone 8 using standard alkylation conditions (Scheme 2).13,4
Deprotonation of the acyl oxazolidinone 8 and reaction of the
resulting enolate with allyl iodide afforded the alkylated product 9.
Cleavage of the chiral auxiliary using the Evans protocol14 afforded
the known carboxylic acid 10.4
The first option was to couple the alkylated acyl oxazolidinone
9 to the allyl-substituted dihydrofuranone 7 using an alkene cross-
metathesis reaction mediated by the Grubbs second-generation
ruthenium catalyst (11).15 However, dimeric products were ob-
tained instead of the coupled alkene 12, a result consistent with
the finding of others that partial reaction and recycling of starting
material is necessary when performing analogous cross-metathesis
reactions.5
Scheme 3 Reagents and conditions: a DDQ, CH2Cl2–H2O, rt [93%]; b
10, EDC, CH2Cl2, rt [70%]; c 11, Cl(CH2)2Cl, reflux [72%; 15 : 1, Z : E]; d
Ph3P+CH3 Br-, NaN(SiMe3)2, THF, rt [98%]; e (Ph3P)RhCl, H2, PhMe, rt;
f NaOMe, MeOH–THF, 0 → 60 ◦C [77% over two steps; 16a:16b, 4.5 : 1];
g (i) o-O2NC6H4SeCN, n-Bu3P, CH2Cl2, rt, (ii) H2O2, rt [77%]; h LiOH,
THF–H2O [84%].
In order to circumvent the problematic cross-metathesis re-
action, fragment coupling by intramolecular diene metathesis
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the E isomer (72%; 15 : 1, Z : E), which were not separated at
this stage. The lactone 14 is crystalline and X-ray analysis of
this compound confirmed our relative stereochemical assignments
(Fig. 2).‡
Scheme 4 Reagents and conditions: a Ph3P+CH3 Br-, NaN(SiMe3)2, THF,
rt [98%]; b DDQ, CH2Cl2–H2O, rt [81%]; c 10, EDC, CH2Cl2, rt [86%]; d
11, Cl(CH2)2Cl, reflux [84%]; e 19, Cl(CH2)2Cl, reflux then H2 (100 psi),
70 ◦C; f NaOMe, MeOH–THF, 60 ◦C [64% over two steps; 4 : 1, 16a : 16b].
Fig. 2 The X-ray crystal structure of the lactone 14.
Methylenation of the keto-lactone 14 afforded the diene 15 as
a mixture (3 : 1) of conformational isomers. Subsequent hydro-
genation using Wilkinson’s catalyst afforded a mixture of C-8
diastereomers (4.5 : 1 ratio) favouring the required diastereomer
(Scheme 3). The macrolactone was then opened with sodium
methoxide to give a mixture of the diastereomeric hydroxy esters
16a and 16b (4.5 : 1 ratio).
the construction of the highly substituted tetrahydrofuran core
by rearrangement of a catalytically generated oxonium ylide, or
metal-bound ylide equivalent, and the deployment of a one-
pot RCM and hydrogenation reaction to accomplish fragment
coupling by macrolactone formation.
The structure of the major hydrogenation product was con-
firmed by conversion of the alcohol 16a into the required car-
boxylic acid 1 (Scheme 3). Thus, reaction of the alcohol 16a with o-
nitrophenyl selenocyanate in the presence of tri-n-butylphosphine,
under conditions described by Grieco,17 followed by treatment of
the resulting selenide with hydrogen peroxide resulted in selenoxide
formation and elimination. Subsequent ester saponification using
lithium hydroxide delivered the known carboxylic acid 1.6b The
structure of the acid 1 was confirmed by comparison of its data to
that of authentic material.6b
After completing the synthesis of 1, we established that it was
possible to increase the efficiency of the route by combining
the metathesis and hydrogenation reactions in a one-pot process
(Scheme 4).18 Thus, methylenation of the ketone 7 followed by
removal of the PMB group afforded the alcohol 17. Esterification
of the alcohol 17 with the carboxylic acid 10 afforded the ester
18 and subsequent RCM with the Grubbs second-generation
catalyst (11) afforded the diene 15 which was converted into
the carboxylic acid 1 as before (Scheme 3). One-pot metathesis
and hydrogenation using the Hoveyda–Grubbs second generation
catalyst (19) followed by treatment of the resulting lactone with
sodium methoxide delivered the esters 16a and 16b (4 : 1 ratio)
in good yield. The level of diastereocontrol during hydrogenation
was similar to that obtained when the diene 15 was hydrogenated
using Wilkinson’s catalyst (Scheme 3).
Experimental
Methyl (S)-3-hydroxy-6-(4-methoxybenzyloxy)hexanoate (2)
The complex [RuCl2(benzene)]2 (5.4 mg, 1.07 mmol) and
(S)-(-)-2,2¢-bis(diphenylphosphino)-1,1¢-binaphthalene (13.8 mg,
2.22 mmol) were dissolved in dry degassed DMF (0.5 mL)§ in a
5 mL vial. The mixture was stirred at 110 ◦C for 20 min and
DMF was removed by vacuum distillation (200 mbar) at 50 ◦C. A
solution of 6-[(4-methoxyphenyl)methoxy]-3-oxohexanoate (1.00
g, 3.57 mmol) in dry degassed methanol (2.0 mL)§ was added.
The vial was transferred to a hydrogenation autoclave and the
vessel was then purged three times with hydrogen. The reaction
mixture was stirred at 95 ◦C under hydrogen (5 bar) for 18 h and
then cooled to room temperature. The mixture was concentrated
under reduced pressure and the residue was purified by flash
chromatography on silica gel (gradient elution with petroleum
ether and then petroleum ether–diethyl ether, 1 : 1) to give the
ester 2 (912 mg, 91%) as a colourless oil. The enantiomeric excess
of the product was determined by chiral HPLC and found to
be 94% ee. Rf 0.27; (petroleum ether–diethyl ether, 1 : 3); HPLC:
tR (S-enantiomer) = 15.0 min, tR (R-enantiomer) = 12.1 min
(Chiracel OD–H, n-hexane–i-propanol, 9 : 1; 1.0 mL min-1; oven
◦
temp. 25.0 C); [a]D26 +8.0 (c 1.1, CHCl3); nmax 3437, 2951, 2859,
1732, 1613, 1512, 1246, 1173, 1092, 1034, 818 cm-1; 1H NMR (400
MHz, CDCl3) d 1.50–1.82 (4H, m), 2.44 (1H, dd, J = 16.0, 8.0
Hz), 2.49 (1H, dd, J = 16.0, 4.4 Hz), 3.29 (1H, d, J = 4.0 Hz),
3.48 (2H, t, J = 6.1 Hz), 3.70 (3H, s), 3.80 (3H, s), 3.98–4.06 (1H,
m), 4.44 (2H, s), 6.87 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4
Hz); 13C NMR (100 MHz, CDCl3) d 26.3, 34.1, 41.7, 52.1, 55.6,
68.2, 70.2, 73.0, 114.1, 129.7, 130.6, 159.4, 173.6; LRMS (EI) m/z
(intensity); 282 [M]+ (6), 121 (100), 137 (78), 77 (25); HRMS (EI)
Conclusions
In summary, we have completed a stereoselective 11-step synthesis
of the C-1–C-12 segment 1 found in the amphidinolides T1–
T5 from the b-hydroxy ester 2. The features of the route are
‡ The crystallographic data (excluding structure factors) for the lactone 14
have been deposited (CCDC 799191) with the Cambridge Crystallographic
Data Centre. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
+44(0) 1223 336033, e-mail: deposit@ccdc.cam.ac.uk].
§ The Ru–BINAP catalyst is extremely sensitive to water and oxygen so
all the glassware was flame-dried and the solvents degassed by two freeze–
thaw cycles.
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calcd for C15H22O5 [M+]: 282.1467, found: 282.1463. Anal. calcd
for C15H22O5: C, 63.81%; H, 7.85%. Found: C, 63.44%; H, 7.93%.
of a saturated solution of sodium hydrogencarbonate (10 mL)
and the phases were separated. The aqueous phase was extracted
with diethyl ether (2 ¥ 10 mL) and the combined organic extracts
were washed sequentially with water (10 mL) and brine (10 mL),
then dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(petroleum ether–EtOAc, 9 : 1 → 3 : 1) to give the diazoketone 5
(151 mg, 85%) as a bright yellow oil: Rf 0.29 (petroleum ether–
diethyl ether, 1 : 3); [a]D27 +19 (c 1.2, CHCl3); nmax 2953, 2922, 2855,
2101, 1732, 1638, 1512, 1360, 1246, 1088, 1034, 924, 820 cm-1; 1H
NMR (400 MHz, CDCl3) d 1.56–1.75 (4H, m), 2.37–2.42 (1H, m),
2.50–2.60 (1H, m), 3.45 (2H, dd, J = 6.3, 5.8 Hz), 3.80 (3H, s),
3.77–3.86 (1H, m), 4.01 (2H, d, J = 5.2 Hz), 4.42 (2H, s), 5.14 (1H,
dd, J = 10.6, 0.7 Hz), 5.24 (1H, dd, J = 16.9, 0.7 Hz), 5.33 (1H,
brs), 5.87 (1H, ddt, J = 16.9, 10.6, 5.2 Hz), 6.87 (2H, d, J = 8.8 Hz),
7.23 (2H, d, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) d 25.6, 31.2,
46.2, 55.4, 55.6, 60.1, 70.7, 72.7, 76.0, 113.9, 117.0, 129.4, 130.7,
135.0, 159.3, 193.3; LRMS (FAB) m/z (intensity): 122 (100), 333
[M + H]+ (12), 219 (8); HRMS (FAB) calcd for C18H25O4N2 [M +
H]+: 333.1814, found: 333.1817.
Methyl (S)-6-(4-methoxybenzyloxy)-3-(prop-2-en-1-
yloxy)hexanoate (3)
Tris(dibenzylideneacetone)dipalladium(0) (8.50 mg, 9.28 mmol)
and bis(diphenylphosphino)butane (15.4 mg, 36.1 mmol) were
dissolved in degassed anhydrous THF (1.0 mL) followed by
addition of allyl ethyl carbonate (180 mL, 1.37 mmol). To the green
mixture was added by syringe, a degassed solution of the b-hydroxy
ester 2 (106 mg, 0.34 mmol) in anhydrous THF (2.0 mL). The
solution was then heated to 70 ◦C for 16 h. The resulting mixture
was concentrated under reduced pressure and the residue was
purified by flash chromatography on silica gel (dichloromethane–
methanol, 99.5 : 0.5) to give the allyl ether 3 (102 mg, 84%) as a
colourless oil: Rf 0.21 (dichloromethane–methanol, 99.5 : 0.5); Rf
0.75 (petroleum ether–diethyl ether, 1 : 3); [a]2D6 +5.6 (c 1.0, CHCl3);
nmax 2953, 2923, 2854, 1737, 1613, 1513, 1458, 1247, 1172, 1097,
1
1036, 819 cm-1; H NMR (400 MHz, CDCl3) d 1.57–1.75 (4H,
m), 2.43 (1H, dd, J = 15.0, 5.8 Hz), 2.57 (1H, dd, J = 15.0, 7.3
Hz), 3.45 (2H, t, J = 5.5 Hz), 3.68 (3H, s), 3.77–3.84 (1H, m), 3.80
(3H, s), 3.99 (2H, dddd, J = 5.5, 2.7, 1.6, 1.3 Hz), 4.43 (2H, s),
5.14 (1H, ddt, J = 10.3, 1.7, 1.3 Hz), 5.24 (1H, ddt, J = 17.2, 1.7,
1.6 Hz), 5.87 (1H, ddt, J = 17.2, 10.3, 5.6 Hz), 6.88 (2H, d, J =
9.1 Hz), 7.25 (2H, d, J = 9.1 Hz); 13C NMR (100 MHz, CDCl3) d
25.6, 31.2, 39.9, 51.8, 55.4, 70.0, 70.7, 72.7, 75.7, 113.9, 117.0,
129.4, 130.7, 135.1, 159.3, 172.3; LRMS (EI) m/z (intensity):
322 [M]+ (20), 121 (100), 190 (91), 137 (88), 143.1 (86); Anal.
calcd for C18H26O5: C, 67.06%; H, 8.13%. Found: C, 67.22%; H,
8.25%.
(2S,5S)-5-[3-(4-Methoxybenzyloxy)propyl]-2-(prop-2-en-1-
yl)dihydrofuran-3(2H)-one (7)
Diazoketone 5 (440 mg, 1.32 mmol) in THF (12 mL) was
added dropwise to a solution of copper acetylacetonate (72.0 mg,
0.28 mmol) in THF (12 mL) at reflux. The mixture was stirred at
85 ◦C for 40 min and then concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(petroleum ether–EtOAc, 1 : 0 → 9 : 1) to give the furanone 7
(361 mg, 90%) as a colourless oil (single stereoisomer as judged
1
by H NMR analysis): Rf 0.52; (petroleum ether–diethyl ether,
1 : 3); [a]2D8 -16 (c 1.0, CHCl3); nmax 2936, 2917, 2855, 1756, 1729,
1613, 1513, 1249, 1172, 1094, 1034, 821 cm-1; 1H NMR (400 MHz,
CDCl3) d 1.59–1.83 (4H, m), 2.22 (1H, dd, J = 18.0, 6.8 Hz), 2.26–
2.37 (1H, m), 2.39–2.48 (1H, m), 2.55 (1H, dd, J = 18.0, 6.9 Hz),
3.44–3.52 (2H, m), 3.80 (3H, s), 4.00 (1H, dd, J = 7.2, 4.8 Hz),
4.33–4.40 (1H, m), 4.43 (2H, s), 5.11 (1H, d, J = 10.1 Hz), 5.14
(1H, dd, J = 17.1, 1.4 Hz), 5.80 (1H, dddd, J = 17.1, 10.1, 7.1,
6.8 Hz), 6.87 (2H, d, J = 8.5 Hz), 7.25 (2H, d, J = 8.5 Hz); 13C
NMR (100 MHz, CDCl3) d 26.0, 32.4, 35.4, 42.6, 55.4, 69.6, 72.7,
75.4, 78.7, 113.9, 118.3, 129.4, 130.6, 133.2, 159.3, 216.3; LRMS
(EI) m/z (intensity): 304 [M]+ (15), 121 (100), 137 (100), 190 (39);
HRMS (EI) calcd for C18H24O4 [M]+: 304.1675, found: 304.1672.
Anal. calcd for C18H24O4: C, 71.03%; H, 7.95%. Found: C, 70.94%;
H, 8.06%.
(S)-1-Diazo-7-(4-methoxybenzyloxy)-4-(prop-2-en-1-
yloxy)heptan-2-one (5)
The methyl ester 3 (2.07 g, 6.40 mmol) was dissolved in a
mixture of methanol (40 mL) and THF (60 mL). A solution
of lithium hydroxide (3.78 g, 157 mmol) in water (25 mL) was
added and the resulting mixture was stirred at room temperature
for 1.5 h. The reaction was quenched by the addition of 1 M
aqueous hydrochloric acid solution (200 mL) and diluted with
EtOAc (150 mL). The layers were separated and the aqueous
phase was extracted with EtOAc (3 ¥ 150 mL). The combined
organic phases were washed with brine (300 mL) and dried
(MgSO4) then concentrated under reduced pressure to give the
carboxylic acid 4 (2.02 g), which was used without purifi-
cation.
A portion of the carboxylic acid 4 (171 mg, 0.55 mmol) was
dissolved in dry diethyl ether (6.0 mL) and i-butyl chloroformate
(80.0 mL, 0.61 mmol) was added. Triethylamine (90 mL, 0.65 mmol)
was added carefully to the reaction mixture and it was stirred at
room temperature for 2 h. The resulting suspension was filtered
and the filtrate was added directly to a freshly prepared ethereal
solution of diazomethane (approximately 5 mmol in 20 mL of
diethyl ether) at 0 ◦C, with protection of the flask from light. The
mixture was stirred at 0 ◦C for 2 h and allowed to warm to room
temperature then stirred for 14 h. Glacial acetic acid (0.60 mL,
8.25 mmol) was added dropwise until no further gas evolution was
observed. The excess of acetic acid was quenched by the addition
(2S,5S)-5-(3-Hydroxypropyl)-2-(prop-2-en-1-yl)dihydrofuran-
3(2H)-one
The furanone 7 (159 mg, 0.522 mmol) was added in one portion to
a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
(131 mg, 0.577 mmol) in dichloromethane (12 mL) and water
(1.2 mL) at 0 ◦C. The reaction mixture was stirred at room
temperature for 2 h and then washed sequentially with saturated
aqueous sodium carbonate solution (10 mL), water (10 mL)
and brine (10 mL). The organic phase was dried (MgSO4) and
concentrated under reduced pressure to give a residue which was
purified by flash chromatography on silica gel (petroleum ether–
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◦
1 : 3); mp = 73.8–74.8 C; [a]2D1 -28 (c 1.0, CHCl3); nmax 2921,
diethyl ether, 2 : 1 → 1 : 2) to give the alcohol (89.5 mg, 93%) as a
colourless oil: Rf 0.18; (petroleum ether–diethyl ether, 1 : 3); [a]D25
-48 (c 1.1, CHCl3); nmax 3406, 2925, 2868, 1754, 1642, 1434, 1173,
1062, 991, 920 cm-1; 1H NMR (400 MHz, CDCl3) d 1.58–1.83 (4H,
m), 2.10 (1H, bs), 2.22 (1H, dd, J = 18.0, 7.2 Hz), 2.24–2.31 (1H,
m), 2.35–2.42 (1H, m), 2.52 (1H, dd, J = 18.0, 6.8 Hz), 3.65 (2H,
brs), 3.98 (1H, dd, J = 7.6, 4.6 Hz), 4.32–4.42 (1H, m), 5.06 (1H,
dd, J = 10.1, 0.9 Hz), 5.09 (1H, dd, J = 17.0, 1.0 Hz), 5.77 (1H, ddt,
J = 17.0, 10.1, 7.2, 6.8 Hz); 13C NMR (100 MHz, CDCl3) d 29.1,
32.5, 35.3, 42.7, 62.6, 75.7, 78.9, 118.5, 133.0, 215.8; LRMS (CI,
isobutane) m/z (intensity): 185 [M + H]+ (100), 167 (75), 71 (32);
HRMS (CI, isobutane) calcd for C10H17O3 [M + H]+: 185.1178,
found: 185.1180.
2850, 1756, 1730, 1260, 1083, 801 cm-1; H NMR (400 MHz,
1
CDCl3) d 1.14 (3H, d, J = 6.8 Hz), 1.70–1.89 (3H, m), 2.08–
2.62 (8H, m), 4.04–4.13 (2H, m), 4.30–4.37 (1H, m), 4.43 (1H,
ddd, J = 11.3, 9.9, 1.0 Hz), 5.25–5.33 (1H, m), 5.57–5.65 (1H,
m); 13C NMR (100 MHz, CDCl3) d 18.5, 24.3, 35.6, 35.9, 38.0,
40.2, 44.1, 66.0, 75.0, 79.7, 125.1, 133.2, 177.2, 217.4; LRMS (CI,
isobutane) m/z (intensity): 253 [M + H]+ (100), 75 (92); HRMS
(CI, isobutane) calcd for C14H21O4 [M + H]+: 253.1440, found:
253.1438.
(1S,7S,12S,Z)-7-Methyl-13-methylene-5,15-dioxabicyclo-
[10.2.1]pentadec-9-en-6-one (15)
To the suspension of methyltriphenylphosphonium bromide
(212 mg, 593 mmol) in dry THF (5.00 mL) at 0 ◦C was added
sodium bis(trimethylsilyl)amide (550 mL of a 1 M solution in
THF, 550 mmol) and the mixture was stirred at 0 ◦C for 1 h.
The ketone 14 (25.2 mg, 99.8 mmol) in dry THF (5.0 mL) was
added and the yellow mixture was stirred at 0 ◦C for 1 h. The
reaction was quenched by the addition of a saturated aqueous
solution of ammonium chloride (10 mL). The mixture was
extracted with diethyl ether (3 ¥ 10 mL) and the combined organic
phases were washed with brine (10 mL) then dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (petroleum ether to petroleum
ether–diethyl ether, 9 : 1) to give the alkene 15 (24.5 mg, 98%)
as a colourless oil: Rf 0.80 (petroleum ether–diethyl ether, 1 : 3);
[a]2D1 -51 (c 1.2, CHCl3); nmax 2954, 2924, 2898, 2853, 1730, 1463,
(S)-3-[(2S,5S)-4-Oxo-5-(prop-2-en-1-yl)tetrahydrofuran-2-
yl]propyl 2-methylpent-4-enoate (13)
The known carboxylic acid 104 (44.2 mg, 0.387 mmol)
and (2S,5S)-2-allyl-5-(3-hydroxypropyl)dihydrofuran-3(2H)-one
(45.0 mg, 0.244 mmol) were dissolved in dry dichloromethane
(3.0 mL) at room temperature and 1-ethyl-3-(3-dimethy-
laminopropyl)carbodiimide (EDC) (149 mg, 0.960 mmol) and
4-N,N-dimethylaminopyridine (DMAP) (101 mg, 0.827 mmol)
were added. The mixture was stirred for 14 h and quenched with
water (1 mL). The solution was extracted with dichloromethane
(3 ¥ 4 mL) and the organic phases were combined, washed
with brine (6 mL) and then dried (MgSO4). The solution was
concentrated under reduced pressure and the residue was purified
by flash chromatography on silica gel (petroleum ether–diethyl
ether, 9 : 1 → 4 : 1) to give the ester 13 (47.6 mg, 70%) as colourless
oil: Rf 0.76; (petroleum ether–EtOAc, 3 : 2); [a]2D6 -27 (c 1.1,
CHCl3); nmax 2975, 2937, 2918, 1756, 1730, 1642, 1177, 1076, 993,
916 cm-1; 1H NMR (400 MHz, CDCl3) d 1.14 (3H, d, J = 6.9 Hz),
1.60–1.86 (4H, m), 2.13–2.21 (1H, m), 2.23 (1H, ddd, J = 18.0, 6.9,
0.9 Hz), 2.29–2.38 (3H, m), 2.51 (1H, dd, J = 13.9, 6.9 Hz), 2.57
(1H, dd, J = 17.5, 6.9 Hz), 4.01 (1H, dd, J = 7.4, 4.7 Hz), 4.11 (2H,
t, J = 6.2 Hz), 4.34–4.41 (1H, m), 5.00–5.08 (2H, m), 5.09–5.18
(2H, m), 5.74 (1H, ddt, J = 17.0, 10.1, 6.9 Hz), 5.81 (1H, ddt, J =
17.1, 10.1, 7.0 Hz); 13C NMR (100 MHz, CDCl3) d 16.7, 25.0,
32.1, 35.4, 37.9, 39.4, 42.5, 63.9, 75.2, 78.8, 117.0, 118.4, 133.1,
135.6, 176.2, 215.9; LRMS (FAB) m/z (intensity): 281 [M + H]+
(22), 69 (100), 73 (93); HRMS (FAB) calcd for C16H25O4 [M + H]+:
281.1752, found: 281.1753.
1
1188, 968 cm-1; H NMR (400 MHz, CDCl3) (~3 : 1 mixture of
conformational isomers) d 1.13 (3H ¥ 0.75, d, J = 7.2 Hz), 1.20
(3H ¥ 0.25, d, J = 6.9 Hz), 1.56–1.76 (3H, m), 1.97–2.29 (5H, m),
2.43–2.64 (3H, m), 3.88–4.12 (2H, m), 4.38–4.49 (1H, m), 4.56
(1H, brs), 4.81–4.85 (1H, m), 4.96–5.01 (1H, m), 5.45–5.57 (2H,
m); 13C NMR (100 MHz, CDCl3) (~3 : 1 mixture of conformational
isomers) d 18.4, 18.5, 25.1, 25.7, 31.8, 34.0, 34.8, 35.4, 38.3, 38.8,
40.3, 40.6, 40.7, 41.4, 65.8, 66.4, 75.3, 75.9, 79.0, 79.9, 104.3, 104.5,
126.4, 127.4, 128.9, 131.6, 151.4, 152.3, 175.8, 177.3; LRMS (CI,
isobutane) m/z (intensity): 251 [M + H]+ (28), 75 (100), 81 (45);
HRMS (CI, isobutane) calcd for C15H23O3 [M + H]+: 251.1647,
found: 251.1652.
Methyl (S)-6-[(2S,3S,5S)-5-(3-hydroxypropyl)-3-methyltetrahy-
drofuran-2-yl]-2-methyl-hexanoate (16a) and methyl (S)-6-
[(2S,3R,5S)-5-(3-hydroxypropyl)-3-methyltetrahydrofuran-2-yl]-2-
methylhexanoate (16b)
(1S,7S,12S)-7-Methyl-5,15-dioxabicyclo[10.2.1]pentadec-9-ene-
6,13-dione (14)
A solution of the diene 13 (79.2 mg, 0.282 mmol) in dry 1,2-
dichloroethane (90 mL) was added slowly to a solution of
the ruthenium complex 11 (21.1 mg, 24.9 mmol) in dry 1,2-
dichloroethane (7 mL) at room temperature. The mixture was
To a solution of alkene 15 (40.0 mg, 160 mmol) in dry toluene
(6.0 mL) was added chlorotris(triphenylphosphine) rhodium(I)
(Wilkinson’s catalyst) (26 mg, 28 mmol) at room temperature. The
atmosphere was purged twice with hydrogen and the mixture was
stirred under an atmosphere of hydrogen at room temperature
for 6 h. The mixture was filtered through a short pad of silica
gel (petroleum ether–diethyl ether, 4 : 1) and the solvent was
evaporated under reduced pressure to give the crude reduced
lactone as a pale yellow oil. Rf 0.81 (petroleum ether–diethyl ether,
1 : 3).
◦
heated to 50 C and stirred at this temperature for 15 min. The
solvent was removed under reduced pressure and the residue was
purified by flash chromatography on silica gel (petroleum ether–
diethyl ether, 9 : 1 → 4 : 1) to give a mixture of the macrolactone 14
and its E-isomer (51.0 mg, 72%; 15 : 1, Z : E) as a colourless solid.
A sample of the macrolactone 14 was recrystallised from pentane
for characterisation purposes and to provide crystals suitable for
X-ray diffraction studies: Rf 0.44 (petroleum ether–diethyl ether,
Sodium in mineral oil (~10 mg, ~420 mmol) was added to
dry methanol (4.0 mL) at 0 ◦C and the resulting mixture was
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kept at 0 ◦C until no further gas evolution was observed. The
reduced lactone (40 mg, 70 mmol) was dissolved in a mixture
of dry methanol (2.0 mL) and dry THF (4.0 mL) and added
to the solution of sodium methoxide. The reaction mixture was
(S)-6-[(2S,3S,5S)-3-Methyl-5-(prop-2-en-1-yl)tetrahydrofuran-2-
yl]-2-methylhexanoic acid (1)
The methyl ester (10.2 mg, 37.2 mmol, 1.00 eq) was dissolved in a
mixture of methanol (0.40 mL) and THF (0.60 mL). A solution
of lithium hydroxide (27.7 mg, 1.12 mmol) in water (0.50 mL) was
added and the resultant mixture was stirred at room temperature
for 1.5 h. The reaction was diluted with EtOAc and the layers were
separated. 1 M Aqueous hydrochloric acid (10 mL) was added to
the aqueous phase and this was then extracted with EtOAc (3 ¥
15 mL). The combined organic phases were washed with brine
(30 mL), dried (MgSO4) and concentrated under reduced pressure
to yield the carboxylic acid 1 (8.1 mg, 84%) as a colourless oil.
Rf 0.53; (petroleum ether–diethyl ether, 1 : 3); [a]2D8 +10.2 (c 3.1,
CH2Cl2) {Lit.7b [a]D23 +8.4 (c 4.5, CH2Cl2)}; nmax 2932, 2862, 1735,
1705, 1643, 1458, 1180, 918 cm-1; 1H NMR (400 MHz, CDCl3) d
0.89 (3H, d, J = 7.0 Hz), 1.17 (3H, d, J = 7.0 Hz), 1.21–1.52 (7H,
m), 1.66–1.79 (3H, m), 2.16–2.25 (2H, m), 2.33 (1H, ddd, J = 13.8,
7.0, 5.9 Hz), 2.46 (1H, dq, J = 13.8, 7.0 Hz), 3.85 (1H, dt, J = 7.9,
5.1 Hz), 4.11 (1H, apparent tt, J = 6.8, 6.8 Hz), 5.01–5.10 (2H, m),
5.78 (1H, ddt, J = 17.2, 10.2, 7.0 Hz); 13C NMR (100 MHz, CDCl3)
d 14.1, 17.0, 26.6, 27.5, 30.4, 33.6, 36.0, 39.3, 39.4, 41.1, 76.1, 81.4,
117.0, 135.2, 182.4; LRMS (CI, isobutane) m/z (intensity); 255
[M + H]+ (68), 75 (100), 81 (32); HRMS (CI, isobutane) calcd for
C15H27O3 [M + H]+: 255.1960, found: 255.1958.
◦
heated at 60 C for 2 h and then quenched by the addition of a
saturated aqueous solution of ammonium chloride (20 mL). The
mixture was extracted with EtOAc (3 ¥ 20 mL) and the combined
organic phases were washed with brine (20 mL) and then dried
(MgSO4) and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (petroleum
ether → petroleum ether–diethyl ether, 3 : 1) to give a mixture
(4.5 : 1) of the esters 16a and 16b (35.1 mg, 77%) as a colourless
oil. Data for 16a: Rf 0.18 (petroleum ether–diethyl ether, 1 : 3); [a]D29
-1.2 (c 1.0, CHCl3); nmax 3358, 2955, 2924, 2855, 2363, 1715, 1456,
1
1317 cm-1; H NMR (400 MHz, CDCl3) d 0.89 (3H, d, J = 7.0
Hz), 1.13 (3H, d, J = 7.0 Hz), 1.21–1.77 (14H, m), 2.17–2.27 (1H,
m), 2.43 (1H, dq, J = 14.0, 7.0 Hz), 2.95 (1H, brs), 3.57–3.72 (2H,
m), 3.66 (3H, s), 3.84–3.89 (1H, m), 4.07 (1H, qd, J = 7.8, 3.6 Hz);
13C NMR (100 MHz, CDCl3) d 14.9, 17.8, 27.4, 28.2, 31.1, 34.4,
35.0, 36.8, 40.3, 41.2, 52.2, 63.8, 77.8, 82.0, 178.1; LRMS (CI,
isobutane) m/z (intensity): 287 [M + H]+ (55), 69 (100), 81 (76);
HRMS (CI, isobutane) calcd for C16H31O4 [M + H]+: 287.2222,
found: 287.2220.
(2S,5S)-5-[3-(4-Methoxybenzyloxy)propyl]-3-methylene-2-(prop-
2-en-1-yl)tetrahydrofuran
Methyl (S)-6-[(2S,3S,5S)-3-methyl-5-(prop-2-en-1-
yl)tetrahydrofuran-2-yl]-2-methylhexanoate
Methyltriphenylphosphonium bromide (4.20 g, 11.8 mmol) was
suspended in dry THF (125 mL) and the solution was cooled
to 0 ◦C. Sodium bis(trimethylsilyl)amide (12.0 mL of a 1 M
solution in THF, 12.0 mmol) was added and the mixture was
stirred at 0 ◦C for 1 h. A solution of the dihydrofuranone 7 (0.81
g, 2.7 mmol) in dry THF (100 mL) was added and the yellow
2-Nitrophenyl selenocyanate (88.0 mg, 0.387 mmol) and alcohol
16a (40mg, 0.14 mmol) were dissolved indegassed anhydrous THF
(2.00 mL) followed by addition of tri-n-butylphosphine (93 mL,
0.34 mmol). The solution was stirred at room temperature for
2 h then the resulting brown mixture was quenched by addition
of water (10 mL). The solution was extracted with EtOAc (3 ¥
15 mL) and the combined organic phases were washed with
brine (10 mL) and then dried (MgSO4). The organic solution was
concentrated under reduced pressure and the residue was dissolved
◦
mixture was stirred at 0 C for 1 h. The reaction was quenched
by the addition of a saturated solution of ammonium chloride
(100 mL) and the mixture was extracted with diethyl ether (3 ¥
100 mL). The combined organic phases were washed with brine
(100 mL), dried (MgSO4) and then concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (petroleum ether → petroleum ether–diethyl ether, 9 : 1)
to give the diene (0.79 g, 98%) as a colourless oil: Rf 0.43 (petroleum
ether–diethyl ether, 3 : 1); [a]2D5 -55 (c 0.95, CHCl3); nmax 2933, 2854,
1612, 1512, 1440, 1246, 1172, 1094, 1036, 820 cm-1; 1H NMR (500
MHz, CDCl3) d 1.51–1.76 (4H, m), 2.24–2.36 (3H, m), 2.66 (1H,
ddtd, J = 15.5, 6.5, 2.0, 1.8 Hz), 3.43–3.51 (2H, m), 3.81 (1H, s),
4.06 (1H, tt, J = 6.4, 6.3 Hz), 4.44 (3H, m), 4.87 (1H, dt, J = 2.1, 2.1
Hz), 5.00 (1H, dt, J = 2.1, 2.1 Hz), 5.08 (1H, ddt, J = 10.2, 2.1, 1.1
Hz), 5.12 (1H, ddt, J = 17.2, 2.1, 1.5 Hz), 5.85 (1H, ddt, J = 17.2,
◦
in THF (1 mL) and cooled to 0 C. To this solution was added
hydrogen peroxide (0.20 mL of a 27% solution in water, 1.6 mmol)
and the mixture was stirred for 2 h at room temperature. The
mixture was diluted with water (3 mL) and then extracted with
EtOAc (3 ¥ 5 mL). The combined organic phases were washed
with brine (10 mL), dried (MgSO4) and then concentrated under
reduced pressure to afford the crude product. Purification by flash
chromatography on silica gel (petroleum ether → petroleum ether–
diethyl ether, 95 : 5) to give the alkene (31.1 mg, 77%) as a pale
yellow oil: Rf 0.93; (petroleum ether–diethyl ether, 1 : 3); [a]2D5 +1.8
(c 1.1, CHCl3); nmax 2937, 2875, 2860, 1739, 1462, 1198, 1164, 913
cm-1; 1H NMR (400 MHz, CDCl3) d 0.89 (3H, d, J = 7.1 Hz), 1.14
(3H, d, J = 7.0 Hz), 1.23–1.50 (8H, m), 1.60–1.79 (3H, m), 2.15–
2.24 (1H, m), 2.29–2.37 (1H, m), 2.43 (1H, dq, J = 13.9, 7.0 Hz),
3.66 (3H, s), 3.83 (1H, dt, J = 7.9, 5.1 Hz), 4.10 (1H, app. tt, J = 6.8
10.2, 6.9 Hz), 6.88 (2H, d, J = 8.7 Hz), 7.26 (2H, d, J = 8.1 Hz); 13
C
NMR (125 MHz, CDCl3) d 26.5, 32.1, 39.0, 40.2, 55.6, 70.2, 72.8,
77.6, 79.4, 105.4, 114.0, 117.3, 129.5, 131.0, 135.2, 151.5, 159.4;
LRMS (EI) m/z (intensity): 302 [M]+ (5), 121.1 (100), 82.9 (35);
HRMS (EI) calcd for C15H23O3 [M]+: 302.1880, found: 302.1882.
Hz), 5.02–5.10 (2H, m), 5.80 (1H, ddt, J = 17.2, 10.2, 7.0 Hz); 13
C
NMR (100 MHz, CDCl3) d 14.1, 17.2, 26.6, 27.6, 30.4, 33.9, 36.0,
39.4, 39.5, 41.2, 51.6, 76.1, 81.4, 116.9, 135.2, 177.5; LRMS (CI,
isobutane) m/z (intensity); 269 [M + H]+ (18), 89 (100), 69 (76);
HRMS (CI, isobutane) calcd for C16H29O3 [M + H]+: 269.2117,
found: 269.2119.
(2S,5S)-5-(3-Hydroxypropyl)-3-methylene-2-(prop-2-en-1-
yl)tetrahydrofuran (17)
The diene (960 mg, 3.17 mmol) was added in one portion to
a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
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(793 mg, 3.49 mmol) in a mixture of dichloromethane (75 mL)
and water (7.5 mL) at 0 ◦C. The reaction mixture was stirred
at room temperature for 2 h and then washed sequentially with
saturated aqueous sodium carbonate solution (50 mL), water
(50 mL) and brine (50 mL). The organic phase was dried (MgSO4)
and concentrated under reduced pressure to give a residue which
was purified by flash chromatography on silica gel (petroleum
ether–diethyl ether, 2 : 1 → 1 : 2) to give the alcohol 17 (471 mg,
81%) as a colourless oil: Rf 0.45; (petroleum ether–diethyl ether,
1 : 3); [a]2D5 -53.6 (c 1.00, CHCl3); nmax 3356, 2933, 1714, 1641,
1433, 1375, 1238, 1110, 1056, 995, 914 cm-1; 1H NMR (400 MHz,
CDCl3) d 1.56–1.70 (4H, m), 2.25–2.35 (3H, m), 2.61–2.63 (1H,
m), 2.67 (1H, ddddd, J = 15.5, 6.2, 2.2, 2.0, 1.8 Hz), 3.60–3.69
(2H, m), 4.04–4.10 (1H, m), 4.46–4.50 (1H, m), 4.86 (1H, ddd,
J = 2.2, 2.2, 2.0 Hz), 5.00 (1H, ddd, J = 2.2, 2.2, 2.0 Hz), 5.07
(1H, ddt, J = 10.2, 2.0, 1.1 Hz), 5.11 (1H, ddt, J = 17.1, 1.9, 1.6
Hz), 5.84 (1H, ddt, J = 17.1, 10.2, 6.9 Hz); 13C NMR (100 MHz,
CDCl3) d 30.1, 32.7, 39.3, 40.1, 63.2, 77.9, 79.8, 105.6, 117.6, 134.9,
151.0.
removed under reduced pressure and the residue was purified by
flash chromatography on silica gel (petroleum ether–diethyl ether,
9 : 1 → 4 : 1) to give the macrolactone 15 (15.1 mg, 84%) as a
colourless oil.
Methyl (S)-6-[(2S,3S,5S)-5-(3-hydroxypropyl)-3-methyltetrahy-
drofuran-2-yl]-2-methylhexanoate (16a) and methyl
(S)-6-[(2S,3R,5S)-5-(3-hydroxypropyl)-3-methyltetrahydrofuran-
2-yl]-2-methylhexanoate (16b)
A solution of the triene 18 (21.0 mg, 72.2 mmol) in dry 1,2-
dichloroethane (10 mL) was added slowly to a solution of
the ruthenium complex 19 (4.50 mg, 7.20 mmol) in dry 1,2-
dichloroethane (2 mL) at room temperature. The mixture was
heated to reflux and stirred at this temperature for 45 min. The
mixture was transferred to a hydrogenation autoclave and the
vessel was then purged three times with hydrogen. The reaction
mixture was stirred at 70 ◦C under hydrogen (6.9 bar) for 14 h and
then cooled to room temperature. The mixture was filtered through
a short pad of silica gel (petroleum ether–diethyl ether, 95 : 5) and
the solvent was evaporated under reduced pressure to give the
crude lactone (15.1 mg) as a pale yellow oil. Rf 0.81 (petroleum
ether–diethyl ether, 1 : 3).
(S)-3-[(2S,5S)-4-Methylene-5-(prop-2-en-1-yl)tetrahydrofuran-2-
yl]propyl 2-methylpent-4-enoate (18)
Sodium in mineral oil (~ 5 mg, ~ 210 mmol) was added to
dry methanol (2.0 mL) at 0 ◦C and the resulting mixture was
kept at 0 ◦C until no further gas evolution was observed. The
reduced lactone (18 mg, 70 mmol) was dissolved in a mixture of
dry methanol (1.0 mL) and dry THF (2.0 mL) and added to the
solution of sodium methoxide. The reaction mixture was heated
at 60 ◦C for 1 h and then quenched by the addition of a saturated
aqueous solution of ammonium chloride (10 mL). The mixture
was extracted with EtOAc (3 ¥ 10 mL) and the combined organic
extracts were washed with brine (10 mL) and then dried (MgSO4).
The solvent was removed under reduced pressure and the residue
was purified by flash chromatography on silica gel (petroleum ether
to petroleum ether–diethyl ether, 3 : 1) to give a mixture (4 : 1) of
the esters 16a and 16b (13.2 mg, 64% over two steps) as a colourless
oil.
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.10
g, 7.09 mmol) and 4-N,N-dimethylaminopyridine (DMAP)
(0.70 mg, 5.7 mmol) were added to a solution of the carboxylic
acid 10 (0.34 g, 2.34 mmol) and alcohol 17 (0.33 g, 1.9 mmol) in
dry dichloromethane (17 mL) at room temperature. The mixture
was stirred for 1.5 h and quenched with water (5 mL). The solution
was extracted with dichloromethane (3 ¥ 10 mL) and the organic
phases were combined, washed with brine (20 mL) and then dried
(MgSO4). The solution was concentrated under reduced pressure
and the residue was purified by flash chromatography on silica gel
(petroleum ether then petroleum ether–diethyl ether, 19 : 1) to give
the ester 18 (0.45 g, 86%) as a colourless oil: Rf 0.62; (petroleum
ether–diethyl ether, 9 : 1); [a]2D6 -23 (c 1.2, CHCl3); nmax 2978, 2935,
2914, 1733, 1641, 1460, 1239, 1179, 1069, 991, 912 cm-1; 1H NMR
(400 MHz, CDCl3) d 1.14 (3H, d, J = 7.0 Hz), 1.44–1.80 (4H, m),
2.12–2.20 (1H, m), 2.22–2.28 (1H, m), 2.30–2.36 (2H, m), 2.4 (1H,
ddt, J = 14.1, 7.0, 1.2 Hz), 2.50 (1H, qt, J = 7.0, 6.9 Hz), 2.67
(1H, ddddd, J = 15.5, 6.6, 2.2, 2.0, 1.8 Hz), 4.02–4.09 (3H, m),
4.42–4.45 (1H, m), 4.87 (1H, ddd, J = 2.2, 2.2, 2.0 Hz), 5.00 (1H,
ddd, J = 2.2, 2.2, 2.0 Hz), 5.02–5.12 (4H, m), 5.73 (1H, ddt, J =
17.1, 10.2, 6.9 Hz), 5.85 (1H, ddt, J = 17.1, 10.2, 6.9 Hz); 13C NMR
(125 MHz, CDCl3) d 16.7, 25.4, 31.7, 37.9, 38.8, 39.4, 40.0, 64.3,
77.1, 79.3, 105.4, 117.0, 117.2, 134.8, 135.7, 151.0, 176.2; LRMS
(CI, isobutane) m/z (intensity): 279 [M + H]+ (40), 69.1 (100),
85.2 (87); HRMS (CI, isobutane) calcd for C17H27O3 [M + H]+:
279.1958, found: 279.1960.
Acknowledgements
Studentship funding (FL) from WestCHEM and the University
of Glasgow in support of this work is gratefully acknowledged.
Notes and references
1 (a) J. Kobayashi, T. Endo and M. Tsuda, J. Org. Chem., 2000, 65,
1349–1352; (b) J. Kobayashi, T. Kubota, T. Endo and M. Tsuda, J. Org.
Chem., 2001, 66, 134–142; (c) T. Kubota, T. Endo, M. Tsuda, M. Shiro
and J. Kobayashi, Tetrahedron, 2001, 57, 6175–6175.
2 For a review of syntheses of the amphidinolide T series, see: E. A. Colby
and T. F. Jamison, Org. Biomol. Chem., 2005, 3, 2675–2684.
3 A. Fu¨rstner, C. A¨ıssa, R. Riveiros and J. Ragot, Angew. Chem., Int. Ed.,
2002, 41, 4763–4766.
4 A. Fu¨rstner, C. A¨ıssa, R. Riveiros and J. Ragot, J. Am. Chem. Soc.,
2003, 25, 15512–15520.
5 A. K. Ghosh and C. Liu, J. Am. Chem. Soc., 2003, 125, 2374–2375.
6 (a) E. A. Colby, K. C. O’Brien and T. F. Jamison, J. Am. Chem. Soc.,
2004, 126, 998–999; (b) E. A. Colby, K. C. O’Brien and T. F. Jamison,
J. Am. Chem. Soc., 2005, 127, 4297–4307.
(1S,7S,12S,Z)-7-Methyl-13-methylene-5,15-dioxabicyclo-
[10.2.1]pentadec-9-en-6-one (15)
A solution of the triene 18 (20.1 mg, 72.2 mmol) in dry 1,2-
dichloroethane (10 mL) was added slowly to a solution of
the ruthenium complex 11 (3.00 mg, 3.53 mmol) in dry 1,2-
dichloroethane (2.0 mL) at reflux. Three extra portions of complex
11 (3 ¥ 3.00 mg, 3 ¥ 3.53 mmol) were added at two-hour intervals
and the mixture was stirred at reflux for 14 h. The solvent was
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