A convergent approach to the marine natural product eleutherobin: Synthesis of key intermediates and attempts to produce the basic skeleton

Article abstract of DOI:10.1039/b207800g

Synthesis of (1R,5R,6R)-2-(6-hydroxymethyl-5-isopropyl-2-methylcyclohex-2-enyl)-N-methoxy-N-m ethylacetamide 8 from R-(-)-phellandrene in six steps, and (3aR*,4S*,6R*,6aS*)-(6-hydroxymethyl-4-methoxy-2,2,6-tri methyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetic acid methyl ester 17 from tetrabromoacetone and 2-methoxy-5-methyl-furan in six steps, provided two key fragments which have been combined to produce intermediates for attempted construction of the basic skeleton of eleutherobin.

Full text of DOI:10.1039/b207800g

View Article Online / Journal Homepage / Table of Contents for this issue
A convergent approach to the marine natural product eleutherobin:
synthesis of key intermediates and attempts to produce the basic
skeleton
Gaia Scalabrino, Xiao-Wen Sun, John Mann* and Anne Baron
School of Chemistry, Queen’s University Belfast, Belfast BT9 5AG, Northern Ireland,
UK
Received 8th August 2002, Accepted 14th November 2002
First published as an Advance Article on the web 13th December 2002
Synthesis of (1R,5R,6R)-2-(6-hydroxymethyl-5-isopropyl-2-methylcyclohex-2-enyl)-N-methoxy-N-methylacetamide
8 from R-(Ϫ)-phellandrene in six steps, and (3aR*,4S*,6R*,6aS*)-(6-hydroxymethyl-4-methoxy-2,2,6-trimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetic acid methyl ester 17 from tetrabromoacetone and 2-methoxy-5-methyl-
furan in six steps, provided two key fragments which have been combined to produce intermediates for attempted
construction of the basic skeleton of eleutherobin.
Introduction
Eleutherobin, from a marine soft coral of the Eleutherobia
species, was first reported in 1995 by the group of Fenical.1 It
was immediately shown to possess activity as an inhibitor of
microtubule depolymerisation with a mean cytotoxicity that
was greater than that exhibited by taxol or the epothilones,2 all
of which apparently share a similar mode of action. However,
eleutherobin is only available in tiny amounts from the coral
and total synthesis will be necessary if the full potential of this
interesting compound is to be realised. It has already been the
subject of two total syntheses by Nicolaou3 and Danishefsky,4
and Gennari has produced a potential advanced intermediate5
and an analogue with a simplified skeleton.6
However, all of these syntheses were linear and multi-stage
rather than convergent and only Magnus has reported a con-
vergent strategy,7 though he claims to have abandoned his
approach. Our approach is genuinely convergent (as shown in
the analysis), and we now wish to report not only the synthesis
of the left- and right-hand fragments, but also their combin-
ation to yield several advanced intermediates that include most
of the skeleton of the natural product.
Results and discussion
We have already described8 in outline the synthesis of the two
key fragments 1 and 2, the former in stereochemically pure form
from (R)-(Ϫ)-α-phellandrene, and the latter in racemic form
from an oxyallyl cycloaddition9 between 2-methoxy-5-methyl-
furan and tetrabromoacetone, but we provide now full details
of this chemistry together with methods for their conversion
into more advanced intermediates.
Phellandrene can be purchased from Fluka as a mixture of
monoterpenes which contains about 50% of the (Ϫ)-enantio-
mer, but apparently none of the (ϩ)-enantiomer. Reaction of
this mixture with dichloroacetyl chloride and triethylamine, or
with trichloroacetyl chloride and zinc dust under irradiation
with ultrasound, provided up to 80% of the dichlorocyclo-
butanone 3 as the major product, with a small amount (ratio of
9 : 1) of the stereoisomer 4 (details provided in reference 8). The
yield is based upon the assumption that (R)-(Ϫ)-α-phellandrene
comprised 50% of the starting material. We never observed
formation of the other regioisomers. Proof of the absolute
stereochemistry of adduct 3 was achieved by removal of the
chlorine atoms with zinc and acetic acid which provided the
cyclobutanone 5. This had been used by Danishefsky in his
synthesis,4 and our product had [α]2D4 = Ϫ170 (c. 0.4, CHCl3) in
comparison with [α]2D3 = Ϫ159 (c. 0.96, CHCl3) reported in
his paper.
Reaction of 3 with excess diazomethane (typically three
equivalents) followed by removal of the chlorine atoms using
zinc and acetic acid yielded the desired ring-expanded product
1. This bicyclic ketone 1 was treated with six equivalents of
MCPBA in dichloromethane to produce the epoxylactones 6a,b
(Scheme 1). Initial experiments showed that stoichiometric
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
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
318

View Article Online
produce lactone(s), epoxide 13 was produced but none of the
required lactone(s), and there was considerable decomposition
in some cases (Scheme 2). To avoid reaction of the double bond,
we converted the alkene 2 into the cis-diol, and thence the
acetonide 14. At this point in the synthesis, a kinetic resolution
might be effected on the racemic diol through use of the Sharp-
less asymmetric dihydroxylation protocol,12 but this has not yet
been explored, and we continued with the racemic acetonide.
The keto acetonide 14 could be converted into a mixture of
enol silylethers 15a and 15b, and with DBU as base the ratio
of 15a : 15b was 1 : 10, while with LDA or lithium cyclo-
hexylamide the ratio was 5 : 8 and 1 : 2. However, an attempt at
selective ozonolysis of the desired regioisomer 15a to provide
an intermediate with the required substitution pattern B was
unsuccessful.
We were, however, very pleased to find that the acetonide 14
reacted with MCPBA to yield the lactone 16 (as the major
product), and thence the hydroxyester 17 by treatment with
K2CO3–MeOH. This was also converted into the corresponding
aldehyde 18 for an intermolecular aldol reaction with aldehydes
10a,b, but this also failed.
Then our attention was turned to attempts to construct the
‘southern’ carbon–carbon bond (Scheme 3). We explored the
viability of an intermolecular aldol reaction between the alde-
hyde 19 prepared from the amide 8 (Swern oxidation) and the
aldehyde 22 synthesised in three steps from alcohol 17 (protec-
tion with TBDMSCl, reduction of the ester with LiAlH4 and
Swern oxidation). With piperidine as base the only ‘products’
isolated from the reaction mixture were unreacted aldehyde 19
and two geometrical isomers of the des-methoxy product 23a,b.
This result was not wholly unexpected because we anticipated
that the acetal grouping within compound 22 was making the
methoxy group sensitive to base-catalysed elimination. It did,
however, introduce a serious limitation of our options since it
eliminated any base-catalysed reactions of either aldehyde 22 or
ester 18.
Thus far all of our efforts had been directed towards effecting
intermolecular C–C bond formation, so we turned our atten-
tions towards effecting intramolecular bond formation. We
explored the possibility of preparing the key ‘southern’ cis-
alkene through a RCM reaction carried out on the tethered
molecule 30a,b. This was synthesised from the aldehyde 19 and
the alcohol 21 as shown in Scheme 4. The vinyl acid 26 was
prepared by means of a Wittig reaction, followed by reduction
of the amide to the aldehyde 25 and reoxidation to yield 26. The
vinyl species 29 required formation of the phenylselenide13 27,
followed by elimination14 to provide the vinyl group and
deprotection of the TBDMS ether with fluoride to produce 29.
Combination of these vinyl species 26 and 29 to form the esters
30a,b was carried out using DCC as dehydrating reagent in the
presence of catalytic DMAP.15 Unfortunately, reaction of this
tethered divinyl species 30a,b with either the standard Grubb’s
catalyst or the second generation catalyst16 failed to produce
any evidence of a ring-closing metathesis, but other catalysts
and reactions conditions are being explored.
Scheme 1 Reagents and conditions: a) MCPBA, CH2Cl2, rt, 3 d, 74%;
b) Zn, NaI, NaOAc, HOAc, CH2Cl2, rt, 4 d, 86%; c) AIMe3,
MeNHOMe, toluene, 0 ЊC–rt, 2 h, 94%; d) TESOTf, 2,6-lutidine,
CH2Cl2, Ϫ78 ЊC–0 ЊC, 2 h, 72% or TBDMSOTf, 2,6-lutidine, CH2Cl2,
Ϫ78 ЊC–0 ЊC, 1 h, 91%; e) DIBAL-H, CH2Cl2, Ϫ78 ЊC–0 ЊC, 3 h, 52%
or 62%.
quantities of the peracid only yielded the epoxides, while an
excess of reagent and a long reaction time at room temperature
were required to produce a good yield of 6 (up to 89%).
Removal of the epoxide group was then effected using a mix-
ture of zinc and sodium iodide in dichloromethane and acetic
acid10 to provide the lactone 7. The regioselectivity of the
Bayer–Villiger reaction is remarkable since the other regio-
isomer was not observed, and we believe that this must be due to
electronic effects once the epoxide has been formed.
Attempts to open the lactone ring with sodium methoxide
were successful but the ring closed spontaneously during work-
up. However, synthesis of the corresponding Weinreb amide 8
could be effected using two equivalents of Me3Al in the
presence of methoxymethylamine in benzene,11 and the hydroxy
group was protected as its TES ether 9a or TBDMS ether 9b.
The amides were also converted into the corresponding alde-
hydes 10a,b for potential intermolecular aldol reactions.
Attempted reactions between the amides 9a,b and several
model aldehydes using either LDA in THF or dibutylboron
triflate were non-productive, the former conditions providing
no reaction and the latter leading to cleavage of the silyl ethers.
Similarly, there was no apparent reaction between the aldehydes
10a,b and several model aldehydes using a variety of bases,
possibly because the retro-aldol reaction was favoured. These
results suggested that formation of the ‘northern’ C–C bond
using an aldol-type approach were doomed to failure.
Interestingly, when the lactone 7 was treated with trimethyl-
silyl iodide in order to prepare the iodoacid 11 as a precursor for
the ‘southern’ C–C bond, the fused butyrolactone 12 was
obtained instead, and this structure was clearly evident both
from the IR spectrum (carbonyl at 1776 cmϪ1) and the
1H (δ 0.54, CHCH2I) and 13C NMR (δ 13.8, CH2I) spectra.
The other key fragment 2 was prepared using oxyallyl tech-
nology9 (full details of this preparation were included in refer-
ence 8). When oxabicyclo[3.2.1]oct-6-en-3-one 2 was treated
with various peracids to attempt a Bayer–Villiger reaction to
Conclusion
These initial investigations have identified some limitations but
also provided a number of potentially useful intermediates for
our convergent approach to eleutherobin. In particular, we have
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
319

View Article Online
Scheme 2 Reagents and conditions: a) MCPBA, CH2Cl2, reflux, 5 d, 64%; b) i, NMO, OsO4, THF–H2O, rt, 5 d, ii, 2,2-dimethoxypropane, p-TSA, rt,
3 h, 84%; overall; c) LDA, TBDMSOTf, THF, Ϫ78 ЊC–rt, 3 h, 23%; d) MCPBA, dichloroethane, reflux, 20 h, 38%; e) K2CO3, MeOH, rt, 1 h, 89%;
f ) DMSO, (CO)2Cl2, Et3N, CH2Cl2, Ϫ78 ЊC–rt, ca.1.5 h, 52%.
Another key task is to resolve the right hand fragment 2, per-
haps by means of a kinetic Sharpless cis-hydroxylation. Success
in these new investigations should provide access to gram quan-
tities of the basic skeleton of eleutherobin for further elabor-
ation into the natural product and analogues for biological
evaluation.
Experimental
All the reactions were performed under an inert atmosphere of
nitrogen and the solvents for reactions were dried and distilled
under nitrogen prior to use. Melting points were determined on
an IA 9100 electrothermal melting point apparatus and are
uncorrected. Optical rotations were recorded on a Perkin Elmer
241 polarimeter. Microanalyses were carried out on a Perkin
Elmer 2400 CHN elemental analyzer. IR spectra were measured
1
as films or KBr plates on Perkin Elmer FT-IR instrument. H
and 13C NMR spectra were recorded on a Bruker DPX 300 or a
Bruker DRX 500 spectrometer. Mass spectra were recorded on
a VG Autospec spectrometer or a VG QUATTRO triple
quadrupole mass spectrometer.
Scheme
3
Reagents and conditions: a) DMSO, (CO)2Cl2, Et3N,
CH2Cl2, Ϫ78 ЊC–rt, ∼1.5 h, 75%; b) TBDMSCl, imidazole, DMF, rt, 18
h, 93%; c) LiAIH4, THF, 0 ЊC, 1 h, 95%; d) DMSO, (CO)2Cl2, Et3N,
CH2Cl2, Ϫ78 ЊC–rt, ∼1.5 h, 81%; e) 19, piperidine, HOAc, benzene, rt,
3 h, 28%.
(1S*,5R*)-1-Methoxy-5-methyl-8-oxabicyclo[3.2.1]oct-6-en-3-
one (2)8
devised very concise routes to intermediates 10 and 18 which
are appropriately functionalised for conversion into the basic
skeleton of eleutherobin. At present, approaches that involve
an intramolecular nitrile oxide cycloaddition17 of the tethered
molecule 31 and an intramolecular Horner–Emmons reaction
of an intermediate like 32 are being explored.
IR (νmax/cmϪ1): 2973, 2935, 1717, 1445, 1338, 1268, 1156,
850; H NMR (500 MHz, CDCl3): δ 6.11 and 6.03 (2H, 2d,
J = 5.8 Hz, H-6 and H-7), 3.43 (3H, s, OCH3), 2.64 and 2.56
(2H, 2d, J = 16.2Hz, H-2 and H-2Ј), 2.47 and 2.33 (2H, 2d,
J = 16.5 Hz, H-4 and H-4Ј), 1.52 (3H, s, CH3); 13C NMR (125
MHz, CDCl3): δ 206.0 (C-3), 139.4 and 132.4 (C-6 and C-7),
1
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
320

View Article Online
Scheme 4 Reagents and conditions: a) CH3PPh3Br, n-BuLi, THF, rt, 1 h, 72%; b) DIBAL-H, CH2Cl2, Ϫ78 ЊC–0ЊC, 3 h, 55%; c) NaClO2, NaH2PO4,
2-methylbut-2-ene, t-BuOH–H2O, rt, 2.5 h, 85%; d) o-NO2C6H4CN, n–Bu3P, THF, rt, 1 h, 78%; e) H2O2, THF, rt, 5 h, 80%; f ) TBAF, THF, rt, 30 min,
80%; g) DCC, DMAP, CH2Cl2, rt, 5 h, 62%.
109.6 (C-1), 80.7 (C-5), 51.6 (OCH3), 50.12 and 50.10 (C-2 and
C-4), 23.1 (CH3); HRMS (CI): calcd for C9H13O3 ([M ϩ H]ϩ)
169.0864, found 169.0862.
C-3), 40.7 (C-7a), 37.8 (C-4), 37.4 (C-3a), 26.9 (CH(CH3)2),
23.5 (C-5), 22.2 (7-CH3), 21.3 and 16.1 (CH(CH3)2); EIMS
(m/z, %): 192 (Mϩ, 82), 177 (17), 149 (93), 135 (39), 121 (61),
107 (100), 93 (87), 79 (86), 55 (75), 41 (88); HRMS (EI):
calcd for C13H20O 192.1514, found 192.1508; Anal. Calcd for
C13H20O: C, 81.20; H, 10.48. Found: C, 80.90; H, 10.19%.
(1R,5R,6R)-8,8-Dichloro-5-isopropyl-2-methylbicyclo[4.2.0]oct-
2-en-7-one (3)8
[α]2D4: Ϫ146.7 (c. 0.3, CHCl3); IR (νmax/cmϪ1): 2961, 2875, 1804,
1464, 1370, 1070, 796; 1H NMR (500 MHz, CDCl3): δ 5.74 (1H,
br s, H-3), 3.65 (1H, dd, J = 8.1, 10.2 Hz, H-6), 3.28 (1H, d,
J = 10.2 Hz, H-1), 2.07 (1H, m, H-4), 1.92–1.78 (5H, m,
H-5, 2-CH3 and H-4Ј), 1.67 (1H, m, CH(CH3)2), 0.95 (3H, d,
(1R,3R,3a R,7aR,7bS )-3-Isopropyl-7b-methyloctahydro-1,5-
dioxacyclopropa[ꢀ]naphthalen-6-one (6a) and (1S,3R,3aR,7aR,
7bR)-3-Isopropyl-7b-methyloctahydro-1,5-dioxacyclopropa[ꢀ]-
naphthalen-6-one (6b)
J = 6.9 Hz, CH(CH3)2), 0.88 (3H, d, J = 6.8 Hz, CH(CH3)2); 13
C
m-CPBA (25.4 g, 147.2 mmol) was added to a stirred solution
of 1 (4.71 g, 24.53 mmol) in DCM (122.5 mL) at room temper-
ature. The mixture was stirred at room temperature for 3 days,
then it was cooled to 0 ЊC and 10% aqueous Na2SO3 solution
was added. The two layers were separated and the aqueous
layer was extracted with DCM and the combined organic
extracts were washed with saturated aqueous NaHCO3 solution
and brine successively. They were dried over anhydrous MgSO4
and the solvent was evaporated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel (2 : 8 petroleum ether : diethyl ether) to give products 6a and
6b (ca. 1 : 1) as white solids (4.04 g, 74%). 6a, Mp: 33–34 ЊC; IR
(νmax/cmϪ1): 2960, 1748, 1558, 1458, 1388, 1084; 1H NMR (500
MHz, CDCl3): δ 4.23 (1H, dd, J = 5.3, 11.8 Hz, H-4), 4.03 (1H,
dd, J = 7.9, 11.8 Hz, H-4Ј), 3.18 (1H, d, J = 2.8 Hz, H-1), 2.70
(1H, dd, J = 6.4, 16.3 Hz, H-7), 2.64 (1H, dd, J = 10.8, 16.3 Hz,
H-7Ј), 2.39 (1H, m, H-7a), 2.05 (1H, m, H-2), 1.83 (1H, m,
H-3a), 1.73 (1H, m, CH(CH3)2), 1.57 (2H, m, H-3 and H-2Ј),
1.32 (3H, s, 7b-CH3), 0.93 (3H, d, J = 6.9 Hz, CH(CH3)2), 0.79
(3H, d, J = 6.9 Hz, CH(CH3)2); 13C NMR (125 MHz,CDCl3):
δ 173.2 (C-6), 69.2 (C-4), 61.3 (C-1), 58.1 (C-7b), 34.1 (C-7a),
33.2 (C-3), 32.9 (C-3a), 29.3 (C-7), 26.6 (CH(CH3)2), 23.0 (C-2),
22.3 (7b-CH3), 21.0 and 15.5 (CH(CH3)2); EIMS (m/z, %): 224
(Mϩ, 21), 209 (20), 182 (82), 153 (71), 125 (79), 107 (80), 77 (82),
67 (72), 53 (72), 29 (100); HRMS (EI): calcd for C13H20O3
224.1412, found 224.1411. 6b, Mp: 34–35 ЊC; IR (νmax/cmϪ1):
2960, 1735, 1558, 1458, 1398, 1192, 1081; 1H NMR (500 MHz,
CDCl3): δ 4.47 (1H, dd, J = 1.8, 11.9 Hz, H-4), 4.14 (1H, dd,
J = 2.5, 11.9 Hz, H-4Ј), 3.05 (1H, d, J = 4.8 Hz, H-1), 2.79 (1H,
dd, J = 6.3, 17.6 Hz, H-7), 2.53 (1H, m, H-7a), 2.48 (1H, dd,
J = 11.8, 17.6 Hz, H-7Ј), 1.93 (3H, m, CH(CH3)2, H-2 and
H-3a), 1.72 (1H, dd, J = 11.1, 15.6 Hz, H-2Ј), 1.50 (1H, m, H-3),
1.28 (3H, s, 7b-CH3), 0.91 (3H, d, J = 6.9 Hz, CH(CH3)2), 0.77
(3H, d, J = 6.9 Hz, CH(CH3)2); 13C NMR (125 MHz,CDCl3):
δ 169.8 (C-6), 70.1 (C-4), 59.9 (C-1), 59.1 (C-7b), 37.2 (C-7a),
30.8 and 30.7 (C-3 and C-3a), 30.5 (C-7), 26.4 (CH(CH3)2), 21.9
(C-2), 20.7 and 14.4 (CH(CH3)2), 19.8 (7b-CH3); EIMS (m/z,
NMR (125 MHz, CDCl3): δ 197.1 (C-7), 129.6 (C-2), 125.8
(C-3), 87.3 (C-8), 56.9 (C-6), 49.7 (C-1), 38.3 (C-5), 30.5
(CH(CH3)2), 24.7 (C-4), 22.4 (2-CH3), 20.7 and 19.4 (CH-
(CH3)2); EIMS (m/z, %): 246 (Mϩ, 9), 203 (10), 176 (14), 139
(18), 97 (100), 77 (53), 55 (28), 43 (79); HRMS (EI): calcd for
C12H16OCl2 246.0578, found 246.0579.
(3aR,4R,7aR)-4-Isopropyl-7-methyl-1,3,3a,4,5,7a-hexahydroin-
den-2-one (1)
Freshly prepared CH2N2–Et2O solution (0.205 mol) was poured
slowly into a solution of 3 (16.9 g, 0.0684 mol) in diethyl ether
(684 mL) at 0 ЊC. The reaction mixture was stirred at 0 ЊC for
2 h, then it was allowed to warm to room temperature and
quenched with acetic acid (17.4 mL). The solvent was evapor-
ated under reduced pressure and the crude intermediate was
ready to undergo dechlorination. It was dissolved in acetic acid
(342.7 mL) and zinc dust (26.7 g, 0.42 mol) was added at room
temperature. The mixture was stirred at room temperature for 1
h, then cooled to 0 ЊC, water was added followed by DCM and
the two layers were separated. The aqueous layer was extracted
with DCM and the combined organic extracts were washed
with saturated aqueous NaHCO3 solution and brine succes-
sively. They were dried over anhydrous MgSO4 and the solvent
was evaporated under reduced pressure. The residue was puri-
fied by flash column chromatography on silica gel (9 : 1 petrol-
eum ether : diethyl ether) to give 1 as a colourless oil (7.35 g,
56% yield for the two steps). [α]2D4: Ϫ45.4 (c. 0.9, CHCl3); IR
(νmax/cmϪ1): 2960, 2925, 1743, 1465, 1407, 1367, 1155; 1H NMR
(500 MHz, CDCl3): δ 5.47 (1H, br s, H-6), 2.68 (1H, m, H-7a),
2.49 (1H, ddd, J = 0.9, 8.5, 18.6 Hz, H-1), 2.35 (3H, m, H-3a,
H-3 and H-3Ј), 2.02 (1H, ddd, J = 1.5, 10.4, 18.6 Hz, H-1Ј), 1.96
(1H, m, H-5), 1.85 (2H, m, H-5Ј and CH(CH3)2), 1.67 (3H, s,
7-CH3), 1.31 (1H, m, H-4), 0.93 (3H, d, J = 6.9 Hz, CH(CH3)2),
0.79 (3H, d, J = 6.9 Hz, CH(CH3)2); 13C NMR (125 MHz,
CDCl3): δ 219.1 (C-2), 134.4 (C-7), 121.7 (C-6), 42.5 (C-1 and
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
321

View Article Online
1
%): 224 (Mϩ, 12), 209 (20), 181 (70), 153 (81), 141 (73), 123 (82),
95 (81), 81 (100), 69 (90), 56 (82); HRMS (EI): calcd for
C13H20O3 224.1412, found 224.1414.
1460, 1383, 1084, 1007, 816, 744; H NMR (500 MHz, C6D6):
δ 5.38 (1H, br s, H-3), 3.81 (2H, d, J = 6.4 Hz, 6-CH2), 3.31 (1H,
m, H-1), 3.13 (3H, s, OCH3), 2.95 (3H, s, NCH3), 2.81 (1H, dd,
J = 6.4, 16.0 Hz, 1-CH2), 2.53 (1H, dd, J = 6.0, 16.0 Hz, 1-CH2),
2.11 (1H, m, H-6), 2.02 (1H, m, H-4), 1.87 (2H, m, H-4Ј and
CH(CH3)2), 1.77 (3H, s, 2-CH3), 1.70 (1H, m, H-5), 1.05 (9H, t,
J = 7.9 Hz, Si(CH2CH3)3), 1.00 (3H, d, J = 6.8 Hz, CH(CH3)2),
0.87 (3H, d, J = 6.6 Hz, CH(CH3)2), 0.65 (6H, q, J = 7.9 Hz,
(4aR,8R,8aR)-8-Isopropyl-5-methyl-1,4,4a,7,8,8a-hexahydroiso-
chromen-3-one (7)
A solution of epoxylactones 6a and 6b (4.04 g, 18.0 mmol)
in DCM (150 mL) was added to a slurry mixture of zinc dust
(6.60 g, 100.8 mmol), sodium iodide (21.60 g, 144.0 mmol),
anhydrous sodium acetate (7.38 g, 90.0 mmol) and acetic acid
(20.1 mL) in DCM (75 mL). The reaction mixture was stirred at
room temperature for 4 days before filtration through a pad of
Celite. The filtrate was in part evaporated and taken up in
DCM, then washed with a saturated aqueous solution of
NaHCO3. The organic extract was dried over anhydrous
MgSO4 and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on
silica gel (7 : 3 petroleum ether : ethyl acetate) to give the prod-
uct 7 as a colourless oil (3.24 g, 86%). [α]2D4 ϩ38.4 (c. 1.0,
CHCl3); IR (νmax/cmϪ1): 2960, 2914, 1739, 1464, 1388, 1252,
1069; 1H NMR (500 MHz, CDCl3): δ 5.48 (1H, br s, H-6), 4.33
(1H, dd, J = 5.2, 11.7 Hz, H-1), 4.28 (1H, dd, J = 4.1, 11.7 Hz,
H-1Ј), 2.84 (1H, dd, J = 7.2, 17.2 Hz, H-4), 2.48 (1H, m, H-4a),
2.34 (1H, dd, J = 9.9, 17.2 Hz, H-4Ј), 2.01 (1H, m, H-8a), 1.96
(1H, m, H-7), 1.88 (2H, m, H-7Ј and CH(CH3)2), 1.67 (3H, s,
5-CH3), 1.52 (1H, m, H-8), 0.95 (3H, d, J = 6.9 Hz, CH(CH3)2),
0.82 (3H, d, J = 6.9 Hz, CH(CH3)2); 13C NMR (125 MHz,
CDCl3): δ 172.4 (C-3), 134.2 (C-5), 122.3 (C-6), 69.9 (C-1), 35.9
(C-8), 35.7 (C-4a), 34.3 (C-8a), 33.3 (C-4), 26.6 (CH(CH3)2),
23.6 (C-7), 21.11, 21.09 and 16.0 (5-CH3 and CH(CH3)2);
HRMS (EI): calcd for C13H20O2 208.1463, found 208.1457;
Anal. Calcd for C13H20O2: C, 74.96; H, 9.68. Found: C, 74.44;
H, 9.73%.
Si(CH2CH3)3); 13C NMR (75 MHz, C D ): δ 174.4 (C᎐O), 136.8
᎐
6
6
(C-2), 121.8 (C-3), 63.2 (6-CH2), 60.6 (OCH3), 41.2 (C-6), 37.9
(C-5), 35.7 (C-1), 32.8 (1-CH2), 32.4 (NCH3), 27.5 (CH(CH3)2),
24.7 (C-4), 22.5 (2-CH3), 21.2 and 17.8 (CH(CH3)2), 7.2
(Si(CH2CH3)3), 4.8 (Si(CH2CH3)3); EIMS (m/z, %): 383 (Mϩ,
45), 355 (72), 323 (41), 251 (87), 149 (100), 117 (85), 89 (85), 59
(90), 43 (74); HRMS (EI): calcd for C21H41NO3Si 383.2856,
found 383.2871.
(1R,5R,6R)-2-[6-(tert-Butyldimethylsilanyloxymethyl)-5-iso-
propyl-2-methylcyclohex-2-enyl]-N-methoxy-N-methylacet-
amide (9b)
To a solution of 8 (1.48 g, 5.5 mmol) in DCM (27.5 mL) at
Ϫ78 ЊC, 2,6-lutidine (1.92 mL, 16.5 mmol) was added dropwise,
followed by tert-butyldimethylsilyl trifluoromethanesulfonate
(2.52 mL, 11.0 mmol) dropwise. The mixture was allowed to
warm to 0 ЊC and stirred for 1 h. Saturated aqueous NaHCO3
solution was added to quench the reaction and the two layers
formed were separated. The aqueous layer was extracted with
diethyl ether and the combined organic extracts were dried
over anhydrous MgSO4 and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel (10 : 2 petroleum ether : ethyl
acetate) to give the product 9b as a colourless oil (1.92 g, 91%).
[α]2D4 ϩ92.0 (c. 0.3, CHCl3); IR (νmax/cmϪ1): 2957, 2931, 1671,
1
1471, 1384, 1254, 1099, 838, 776; H NMR (500 MHz, C6D6):
δ 5.37 (1H, br s, H-3), 3.80 (2H, m, 6-CH2), 3.28 (1H, m, H-1),
3.12 (3H, s, OCH3), 2.94 (3H, s, NCH3), 2.79 (1H, dd, J = 6.2,
16.0 Hz, 1-CH2), 2.53 (1H, dd, J = 6.5, 16.0 Hz, 1-CH2), 2.08
(1H, m, H-6), 2.01 (1H, m, H-4), 1.87 (2H, m, H-4Ј and
CH(CH3)2), 1.77 (3H, s, 2-CH3), 1.68 (1H, m, H-5), 1.01 (9H, s,
SiC(CH3)3), 0.98 (3H, d, J = 6.9 Hz, CH(CH3)2), 0.85 (3H, d,
J = 6.7 Hz, CH(CH3)2), 0.11 (6H, s, Si(CH3)2); 13C NMR (125
(1R,5R,6R)-2-(6-Hydroxymethyl-5-isopropyl-2-methylcyclohex-
2-enyl)-N-methoxy-N-methylacetamide (8)
Trimethylaluminium (2.0 M solution in hexanes) (2.45 mL,
4.90 mmol) was added dropwise to a suspension of N,O-di-
methylhydroxylamine hydrochloride (478 mg, 4.90 mmol) in
toluene (5.88 mL) at 0 ЊC. The reaction mixture was allowed to
warm to room temperature and stirred for 2 h. It was cooled to
0 ЊC and a solution of 7 (0.51 g, 2.45 mmol) in toluene (3.92
mL) was added dropwise. The reaction mixture was once more
allowed to warm to room temperature and stirred for 2 h, then
cooled to 0 ЊC and quenched by dropwise addition of a satur-
ated aqueous solution of NaHCO3, followed by ethyl acetate.
The precipitate was filtered through a pad of Celite and washed
with ethyl acetate. The filtrate was separated and the organic
layer was washed with brine and dried over anhydrous MgSO4.
The solvent was evaporated under reduced pressure to give the
product 8 as a colourless oil (0.62 g, 94%), which was used
directly without further purification.
MHz, C D ): δ 174.4 (C᎐O), 136.9 (C-2), 121.7 (C-3), 63.5
᎐
6
6
(6-CH2), 60.6 (OCH3), 41.2 (C-6), 37.8 (C-5), 35.9 (C-1), 32.8
(1-CH2), 32.4 (NCH3), 27.4 (CH(CH3)2), 26.2 (SiC(CH3)3),
24.6 (C-4), 22.5 (2-CH3), 21.2 and 17.6 (CH(CH3)2), 18.5
(SiC(CH3)3), Ϫ5.26 and Ϫ5.32 (Si(CH3)2); EIMS (m/z, %): 383
(Mϩ, 12), 368 (7), 326 (100), 251 (16), 220 (26), 208 (37), 149
(16), 119 (24), 103 (34), 89 (39), 73 (64), 43 (41); HRMS (EI):
calcd for C21H41NO3Si 383.2856, found 383.2839.
(1R,5R,6R)-(5-Isopropyl-2-methyl-6-triethylsilanyloxymethyl-
cyclohex-2-enyl)acetaldehyde (10a)
DIBAL-H (1.0 M solution in hexanes) (5.54 mL, 5.54 mmol)
was added dropwise to a stirred solution of 9a (1.06 g, 2.77
mmol) in DCM (18.5 mL) at Ϫ78 ЊC. The reaction mixture was
stirred at Ϫ78 ЊC for 2 h and then it was allowed to warm to
0 ЊC and stirred for 1 h. A large excess of MeOH was added at
0 ЊC and the aluminium salts that precipitated were filtered
though a pad of Celite under reduced pressure. The solid was
washed with diethyl ether and the combined filtrate and wash-
ings were concentrated to give the crude product, which was
purified by flash column chromatography on silica gel (30 : 1
petroleum ether : diethyl ether) to give 10a as a colourless oil
(470 mg, 52%). IR (νmax/cmϪ1): 2958, 2878, 1727, 1460, 1240,
(1R,5R,6R)-2-(5-Isopropyl-2-methyl-6-triethylsilanyloxymethyl-
cyclohex-2-enyl)-N-methoxy-N-methylacetamide (9a)
2,6-Lutidine (1.28 mL, 10.98 mmol) was added dropwise to a
stirred solution of 8 (0.986 g, 3.66 mmol) in DCM (18.3 mL) at
Ϫ78 ЊC, then triethylsilyl trifluoromethanesulfonate (1.66 mL,
7.32 mmol) was added dropwise. The mixture was allowed to
warm to 0 ЊC and stirred for 2 h. The reaction was quenched
with saturated aqueous NaHCO3 solution and the two layers
formed were separated. The aqueous layer was extracted with
diethyl ether and the combined organic extracts were washed
with brine. They were dried over anhydrous MgSO4 and the
solvent was evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(10 : 2 petroleum ether : ethyl acetate) to give the product 9a as
a colourless oil (1.01 g, 72%). IR (νmax/cmϪ1): 2957, 2877, 1671,
1
1080, 1013, 810, 743; H NMR (500 MHz, C6D6): δ 9.70 (1H,
dd, J = 1.8, 2.8 Hz, CHO), 5.29 (1H, br s, H-3), 3.69 (1H, dd,
J = 4.8, 10.4 Hz, 6-CH2), 3.46 (1H, dd, J = 9.4, 10.4 Hz, 6-CH2),
2.90 (1H, m, H-1), 2.45 (1H, ddd, J = 2.8, 7.4, 16.6 Hz, 1-CH2),
2.06 (1H, ddd, J = 1.8, 4.5, 16.6 Hz, 1-CH2), 1.86 (1H, m, H-6),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
322

View Article Online
1.79 (1H, m, H-4), 1.66 (2H, m, H-4Ј and CH(CH3)2), 1.56 (3H,
s, 2-CH3), 1.38 (1H, m, H-5), 1.00 (9H, t, J = 7.9 Hz,
Si(CH2CH3)3), 0.83 (3H, d, J = 6.9 Hz, CH(CH3)2), 0.73 (3H, d,
J = 6.8 Hz, CH(CH3)2), 0.59 (6H, q, J = 7.9 Hz, Si(CH2CH3)3);
13C NMR (125 MHz, C6D6): δ 201.1 (CHO), 135.5 (C-2), 122.3
(C-3), 62.3 (6-CH2), 44.5 (1-CH2), 41.3 (C-6), 36.6 (C-5), 34.9
(C-1), 26.9 (CH(CH3)2), 24.5 (C-4), 22.2 (2-CH3), 21.2 and 16.0
(CH(CH3)2), 7.1 (Si(CH2CH3)3), 4.7 (Si(CH2CH3)3); EIMS
(m/z, %): 324 (Mϩ, 15), 295 (72), 280 (67), 192 (73), 150 (82),
123 (77), 94 (87), 57 (94), 45 (100); HRMS (EI): calcd for
C19H36O2Si 324.2485, found 324.2487.
(77), 209 (86), 153 (89), 109 (87), 83 (100), 69 (87); HRMS(EI):
calcd for C13H21O2I 336.0586, found 336.0597.
(1S*,2R*,4S*,5R*)-1-Methoxy-5-methyl-3,9-dioxatricyclo-
[3.3.1.02,4]nonan-7-one (13)
m-CPBA (1.23 g, 7.13 mmol) was added to a solution of 2 (200
mg, 1.19 mmol) in DCM (6.1 mL), then the reaction mixture
was heated under refluxing for 5 days. An aqueous solution of
Na2SO3 (10%) was added to quench the reaction, followed by
DCM. The two layers formed were separated and the aqueous
layer was extracted with DCM. The combined organic extracts
were washed with an aqueous solution of Na2SO3 (10%), fol-
lowed by saturated aqueous NaHCO3 solution and brine. They
were dried over anhydrous MgSO4 and the solvent was evapor-
ated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (1 : 1 petroleum ether :
diethyl ether) to give product 13 as a colourless oil (140 mg,
64%). IR (νmax/cmϪ1): 2963, 2853, 1717, 1312, 1261, 1089, 803;
1H NMR (500 MHz, CDCl3): δ 3.59 (3H, s, OCH3), 3.44 and
3.30 (2H, 2d, J = 3.0 Hz, H-2 and H-4), 2.63 and 2.58 (2H, 2d,
J = 17.0 Hz, H-8 and H-8Ј), 2.48 and 2.35 (2H, 2d, J = 17.0 Hz,
H-6 and H-6Ј), 1.46 (3H, s, CH3); 13C NMR (125 MHz, CDCl3):
δ 204.6 (C-7), 102.3 (C-1), 74.8 (C-5), 54.6 (C-4), 53.6 (C-2),
52.9 (OCH3), 48.0 (C-8), 47.6 (C-6), 19.9 (CH3).
(1R,5R,6R)-2-[6-(tert-Butyldimethylsilanyloxymethyl)-5-iso-
propyl-2-methylcyclohex-2-enyl]acetaldehyde (10b)
DIBAL-H (1.0 M solution in hexanes) (17.1 mL, 17.1 mmol)
was added dropwise to a stirred solution of 9b (3.27 g, 8.54
mmol) in DCM (56.9 mL) at Ϫ78 ЊC. The reaction mixture was
stirred at Ϫ78 ЊC for 2 h and then it was allowed to warm to
0 ЊC and stirred for 1 h. A large excess of MeOH was added at
0 ЊC and the aluminium salts that precipitated were filtered
through a pad of Celite. The solid was washed with diethyl
ether and the combined filtrates and washings were concen-
trated to give the crude product. It was purified by flash column
chromatography on silica gel (30 : 1 petroleum ether : diethyl
ether) to give 10b as a white solid (1.72 g, 62%). Mp: 40–42 ЊC;
[α]2D4 ϩ110.6 (c. 0.5, CHCl3); IR (νmax/cmϪ1): 2957, 2930, 1728,
(1S*,2R*,6S*,7R*)-1-Methoxy-4,4,7-trimethyl-3,5,11-trioxa-
tricyclo[5.3.1.02,6]undecan-9-one (14)
1
1471, 1255, 1104, 1080, 838, 776; H NMR (500 MHz, C6D6):
δ 9.70 (1H, dd, J = 1.8, 2.7 Hz, CHO), 5.29 (1H, br s,
H-3), 3.66 (1H, dd, J = 4.6, 10.5 Hz, 6-CH2), 3.43 (1H, dd,
J = 9.2, 10.5 Hz, 6-CH2), 2.87 (1H, m, H-1), 2.45 (1H, ddd,
J = 2.7, 7.3, 16.7 Hz, 1-CH2), 2.04 (1H, ddd, J = 1.8, 4.5, 16.7
Hz, 1-CH2), 1.80 (2H, m, H-4 and H-6), 1.64 (2H, m, H-4Ј and
CH(CH3)2), 1.56 (3H, s, 2-CH3), 1.38 (1H, m, H-5), 0.95 (9H, s,
SiCH(CH3)3), 0.82 (3H, d, J = 6.9 Hz, CH(CH3)2), 0.71 (3H, d,
J = 6.8 Hz, CH(CH3)2), 0.051 and 0.047 (6H, 2s, Si(CH3)2);
13C NMR (125 MHz, C6D6): δ 200.9 (CHO), 135.4 (C-2),
122.1 (C-3), 62.4 (6-CH2), 44.3 (1-CH2), 41.1 (C-6), 36.1 (C-5),
34.8 (C-1), 26.7 (CH(CH3)2), 25.9 (SiC(CH3)3), 24.2 (C-4),
22.0 (2-CH3), 21.0 and 15.7 (CH(CH3)2), 18.2 (SiC(CH3)3),
Ϫ5.6 and Ϫ5.7 (Si(CH3)2); EIMS (m/z, %): 324 (Mϩ, 1), 267
(38), 175 (62), 149 (95), 131 (62), 107 (61), 101 (80), 93 (100), 75
(81); HRMS (EI): calcd for C19H36O2Si 324.2485, found
324.2469.
A stirred solution of the ketone 2 (2.94 g, 17.5 mmol) and
4-methylmorpholine N-oxide (2.46 g, 21.0 mmol) in a mixture
of THF (47.2 mL) and water (5.3 mL) was cooled with a water
bath. Osmium tetroxide (2.5 wt% solution in 2-methylpropan-
2-ol) (2.8 mL, 0.22 mmol) was added dropwise and after stirring
the reaction mixture at room temperature for 5 days, the solvent
was evaporated under reduced pressure. The residue was puri-
fied by flash column chromatography on silica gel (ethyl acet-
ate) to give the diol as a colourless oil (3.35 g, 95%). A solution
of the diol (3.35 g, 16.58 mmol) in 2,2-dimethoxypropane (41.5
mL) was cooled to 0 ЊC. p-Toluenesulfonic acid monohydrate
(21 mg, 0.11 mmol) was added and the reaction mixture was
allowed to warm to room temperature and stirred for 3 h, then
the solvent was evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(10 : 5 petroleum ether : ethyl acetate) to give the product 14 as
a viscous colourless oil (3.53 g, 88%). IR (νmax/cmϪ1): 2984,
(3aR,4R,5R,7aS )-4-Iodomethyl-5-isopropyl-7a-methylhexa-
hydrobenzofuran-2-one (12)
1
2938, 1721, 1379, 1269, 1211, 1079, 873; H NMR (500 MHz,
CDCl3): δ 4.33 and 4.19 (2H, 2d, J = 5.8 Hz, H-2 and H-6), 3.59
(3H, s, OCH3), 2.81 (1H, d, J = 14.9 Hz, H-10), 2.49
(1H, dd, J = 1.5, 14.9 Hz, H-10Ј), 2.46 (1H, d, J = 15.7 Hz, H-8),
2.31 (1H, dd, J = 1.5, 15.7 Hz, H-8Ј), 1.57 and 1.30 (6H, 2s,
4-(CH3)2), 1.45 (3H, s, 7-CH3); 13C NMR (125 MHz, CDCl3):
δ 205.3 (C-9), 113.0 (C-4), 104.4 (C-1), 83.6 (C-6), 83.3 (C-2),
78.8 (C-7), 52.3 (OCH3), 51.2 (C-8), 48.8 (C-10), 26.0 and 24.9
(4-(CH3)2), 19.9 (7-CH3); EIMS (m/z, %): 243 (Mϩ ϩ 1, 17), 227
(38), 184 (57), 166 (72), 141 (85), 124 (86), 100 (83), 85 (85), 69
(74), 55 (71), 41 (87), 29 (100); Anal. Calcd for C12H18O5: C,
59.49; H, 7.49. Found: C, 59.35; H, 7.31%.
Hexamethyldisilane (0.1 mL, 0.49 mmol) was added to a stirred
solution of lactone 7 (60 mg, 0.29 mmol) in chloroform (3 mL).
Iodine (55 mg, 0.22 mmol) was added and the reaction mixture
was heated under refluxing for 2 days. Water and DCM were
added and the two layers were separated. The aqueous layer
was extracted with DCM and the combined organic extracts
were washed with an aqueous solution of Na2S2O3 (10%). They
were dried over anhydrous MgSO4 and the solvent was evapor-
ated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (9 : 1 petroleum ether :
ethyl acetate) to give the product 12 as a colourless oil (82 mg,
1
84%). IR (νmax/cmϪ1): 2958, 2872, 1776, 1260, 1170, 934; H
(1S*,2R*,6S*,7R*)-tert-Butyl(1-methoxy-4,4,7-trimethyl-
3,5,11-trioxatricyclo[5.3.1.02,6]undec-8-en-9-yloxy)dimethyl-
silane (15a) and (1R*,2S*,6R*, 7S*) tert-Butyl(7-methoxy-
1,4,4-trimethyl-3,5,11-trioxatricyclo[5.3.1.02,6]undec-8-en-9-
yloxy)dimethylsilane (15b)
NMR (500 MHz, CDCl3): δ 3.44 (1H, dd, J = 3.4, 10.8 Hz,
4-CH2), 3.20 (1H, dd, J = 2.0, 10.8 Hz, 4-CH2), 2.95 (1H, dd,
J = 7.1, 17.6 Hz, H-3), 2.24 (2H, m, H-3Ј and H-7), 2.08 (1H,
dd, J = 7.1, 10.1 Hz, H-3a), 1.84 (1H, m, CH(CH3)2), 1.50 (2H,
m, H-7Ј and H-6), 1.39 (3H, s, 7a-CH3), 1.28 (1H, m, H-6Ј),
1.15 (1H, m, H-5), 0.96 (3H, d, J = 6.9 Hz, CH(CH3)2), 0.74
(3H, d, J = 7.0 Hz, CH(CH3)2), 0.54 (1H, m, H-4); 13C NMR
(125 MHz, CDCl3): δ 176.4 (C-2), 85.4 (C-7a), 45.1 (C-3a), 44.2
(C-5), 40.4 (C-4), 36.9 (C-3), 34.8 (C-7), 27.6 (7a-CH3), 26.1
(CH(CH3)2), 21.3 and 14.8 (CH(CH3)2), 17.9 (C-6), 13.8
(4-CH2); EIMS (m/z, %): 337 (Mϩϩ1, 68), 336 (Mϩ, 42), 321
A solution of 14 (76 mg, 0.31 mmol) in THF (0.19 mL) was
added dropwise to freshly prepared lithium diisopropylamide
solution (0.38 mmol) in THF (1.38 mL) at Ϫ78 ЊC. The reaction
mixture was stirred for 30 minutes before addition of tert-
butyldimethylsilyl trifluoromethanesulphonate (79 µL, 0.35
mmol) dropwise. It was allowed to warm to room temperature
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
323

View Article Online
and stirred for a further 2.5 h. Saturated aqueous NaHCO3
solution was added to quench the reaction, followed by pentane
and the two layers formed were separated. The aqueous layer
was extracted with pentane and the combined organic extracts
were dried over anhydrous MgSO4 and the solvent was evapor-
ated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (10 : 2 petroleum ether :
diethyl ether) to give the product 15a as a colourless oil (10 mg,
9%) and its isomer 15b as a white solid (16 mg, 14%), and some
starting material was recovered. 15a, IR (νmax/ cmϪ1): 2932,
solvent was evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel
(10 : 7 petroleum ether : ethyl acetate) to give the product 17 as
a white solid (2.05 g, 89%). Mp: 48–49 ЊC; IR (νmax/cmϪ1): 3482,
2982, 2939, 1733, 1439, 1372, 1215, 1101, 1047, 870; 1H NMR
(500 MHz, CDCl3): δ 4.84 (2H, 2d, J = 7.1 Hz, H-3a and H-6a),
3.70 (3H, s, CO2CH3), 3.63 (2H, m, 6-CH2 and OH), 3.47
(1H, m, 6-CH2), 3.33 (3H, s, 4-OCH3), 3.05 and 2.73 (2H, 2d,
J = 16.3 Hz, 4-CH2), 1.58 and 1.36 (6H, 2s, 2-(CH3)2), 1.27 (3H,
s, 6-CH3); 13C NMR (125 MHz, CDCl ): δ 171.6 (C᎐O), 115.3
᎐
3
1
2859, 1655, 1362, 1256, 1178, 1074, 841; H NMR (500 MHz,
(C-2), 102.7 (C-4), 86.3 (C-6), 84.3 and 82.3 (C-3a and C-6a),
69.1 (6-CH2), 52.2 (CO2CH3), 48.6 (4-OCH3), 37.2 (4-CH2),
25.8 and 25.5 (2-(CH3)2), 18.3 (6-CH3); ESIMS (m/z, %): 313
([M ϩ Na]ϩ, 100).
C6D6): δ 4.80 (1H, t, J = 0.7 Hz, H-8), 4.25 and 4.18 (2H, 2d,
J = 5.7 Hz, H-2 and H-6), 3.59 (3H, s, OCH3), 2.72 (1H, dd,
J = 1.9, 16.8 Hz, H-10), 1.92 (1H, dd, J = 0.8, 16.8 Hz, H-10Ј),
1.59 and 1.25 (6H, 2s, 4-(CH3)2), 1.50 (3H, s, 7-CH3), 0.92 (9H,
s, SiC(CH3)3), 0.047 and 0.043 (6H, 2s, Si(CH3)2); 13C NMR
(125 MHz, C6D6): δ 150.2 (C-9), 112.5 (C-4), 109.3 (C-8), 103.6
(C-1), 86.9 and 85.6 (C-2 and C-6), 77.3 (C-7), 51.7 (OCH3),
38.9 (C-10), 26.5 and 25.7 (4-(CH3)2), 25.6 (SiC(CH3)3), 19.2
(7-CH3), 18.0 (SiC(CH3)3), Ϫ4.5 and Ϫ4.7 (Si(CH3)2); ESIMS
(3aR*,4S*,6S*,6aS*)-(6-Formyl-4-methoxy-2,2,6-trimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetic acid methyl ester
(18)
A solution of DMSO (0.74 mL, 10.35 mmol) in DCM
(15.0 mL) was cooled at Ϫ78 ЊC, before adding oxalyl chloride
(0.60 mL, 6.90 mmol) dropwise. After stirring the reaction mix-
ture for 10 minutes, a solution of 17 (1.00 g, 3.45 mmol) in
DCM (8.0 mL) was added dropwise. The reaction mixture was
stirred at Ϫ78 ЊC for 30 minutes before addition of triethyl-
amine (1.92 mL, 13.80 mmol) dropwise, then it was stirred for
10 minutes, allowed to warm to room temperature and stirred
for a further 30 minutes. Water was added, followed by DCM
and the two layers formed were separated. The aqueous layer
was extracted with DCM and the combined organic extracts
were washed with 5% aqueous citric acid solution, saturated
aqueous NaHCO3 solution and brine successively. They were
dried over anhydrous MgSO4 and the solvent was evaporated
under reduced pressure. The residue was purified by flash col-
umn chromatography on silica gel (1 : 1 petroleum ether : ethyl
acetate) to give the product 18 as a colourless oil (516 mg, 52%).
(m/z, %): 357 ([M ϩ H]ϩ, 33); 15b, Mp: 64–65 ЊC; IR (νmax
/
cmϪ1): 2932, 2858, 1655, 1362, 1255, 1178, 1074, 840; 1H NMR
(500 MHz, C6D6): δ 5.00 (1H, t, J = 0.9 Hz, H-8), 4.46 and 3.97
(2H, 2d, J = 5.7 Hz, H-2 and H-6), 3.52 (3H, s, OCH3), 2.26
(1H, dd, J = 2.0, 17.2 Hz, H-10), 1.57 (1H, d, J = 17.2 Hz,
H-10Ј), 1.58 and 1.23 (6H, 2s, 4-(CH3)2), 1.40 (3H, s, 1-CH3),
0.93 (9H, s, SiC(CH3)3), 0.06 and 0.05 (6H, 2s, Si(CH3)2); 13C
NMR (125 MHz, C6D6): δ 152.5 (C-9), 112.5 (C-4), 107.1 (C-8),
104.0 (C-7), 86.2 and 85.7 (C-2 and C-6), 78.5 (C-1), 52.1
(OCH3), 41.2 (C-10), 26.6 (4-(CH3)2), 25.6 (4-(CH3)2 and
SiC(CH3)3), 21.0 (1-CH3), 18.0 (SiC(CH3)3), Ϫ4.5 and Ϫ4.8
(Si(CH3)2); ESIMS (m/z, %): 357 ([M ϩ H]ϩ,100).
(1S*,2R*,6S*,7R*)-1-Methoxy-4,4,7-trimethyl-3,5,9,12-tetra-
oxatricyclo[5.4.1.02,6]dodecan-10-one (16)
1
m-CPBA (14.55 g, 84.3 mmol) was added to a stirred solution
of acetonide 14 (3.40 g, 14.05 mmol) in DCE (112.4 mL) at
room temperature. The reaction mixture was refluxed for 20 h.
It was then cooled to 0 ЊC and quenched with 10% aqueous
Na2SO3 solution, DCM was added and the two layers were
separated. The aqueous layer was extracted with DCM and
the combined organic extracts were washed with saturated
aqueous NaHCO3 solution and brine successively. They were
dried over anhydrous MgSO4 and the solvent was evaporated
under reduced pressure. The residue was purified by flash col-
umn chromatography on silica gel (10 : 7 petroleum ether : ethyl
acetate) to give the product 16 as a white solid (1.38 g, 38%).
Mp: 101–103 ЊC; IR (νmax/cmϪ1): 2988, 2941, 1742, 1377, 1260,
1211, 1084, 875; 1H NMR (500 MHz, CDCl3): δ 4.72 and 4.59
(2H, 2d, J = 5.8 Hz, H-2 and H-6), 4.32 and 4.12 (2H, 2d,
J = 13.4 Hz, H-8 and H-8Ј), 3.53 (3H, s, OCH3), 3.27 (1H, d,
J = 15.4 Hz, H-11), 3.10 (1H, d, J = 15.4 Hz, H-11Ј), 1.55 and
1.37 (6H, 2s, 4-(CH3)2), 1.33 (3H, s, 7-CH3); 13C NMR (125
MHz, CDCl3): δ 170.1 (C-10), 113.2 (C-4), 102.6 (C-1), 83.8 and
82.0 (C-2 and C-6), 81.1 (C-7), 75.7 (C-8), 52.3 (OCH3), 48.0
(C-11), 25.8 and 24.7 (4-(CH3)2), 17.8 (7-CH3); EIMS (m/z, %):
259 (Mϩϩ1, 2), 243 (5), 201 (7), 169 (10), 141 (56), 125 (55), 99
(83), 83 (75), 71 (79), 59 (78), 42 (100); Anal. Calcd for
C12H18O6: C, 55.81; H, 7.02. Found: C, 56.07; H, 7.01%.
IR (νmax/cmϪ1): 2900, 1735, 1215, 1046; H NMR (500 MHz,
CDCl3): δ 9.50 (1H, s, CHO), 5.01 and 4.84 (2H, 2d, J = 6.9 Hz,
H-3a and H-6a), 3.68 (3H, s, CO2CH3), 3.43 (3H, s, 4-OCH3),
2.84 (2H, 2d, J = 15.3 Hz, 4-CH2), 1.59 and 1.37 (6H, 2s,
2-(CH3)2), 1.38 (3H, s, 6-CH3); 13C NMR (125 MHz, CDCl3):
δ 200.8 (CHO), 169.6 (CO2CH3), 115.1 (C-2), 104.3 (C-4), 88.1
(C-6), 84.0 and 81.0 (C-3a and C-6a), 51.9 (CO2CH3), 49.8
(4-OCH3), 39.5 (4-CH2), 25.54 and 25.48 (2-(CH3)2), 17.4
(6-CH3); ESIMS (m/z, %): 311 ([M ϩ Na]ϩ, 24).
(1R,5R,6R)-2-(6-Formyl-5-isopropyl-2-methylcyclohex-2-enyl)-
N-methoxy-N-methylacetamide (19)
Oxalyl chloride (2.13 mL, 24.46 mmol) was added dropwise to a
stirred solution of DMSO (2.60 mL, 36.69 mmol) in DCM
(54.3 mL) at Ϫ78 ЊC. The mixture was stirred for 10 minutes,
after which a solution of 8 (3.29 g, 12.23 mmol) in DCM (27.2
mL) was added dropwise. The reaction mixture was stirred at
Ϫ78 ЊC for 30 minutes and then triethylamine (6.82 mL, 48.92
mmol) was added dropwise and stirred for 10 minutes. It was
allowed to warm to room temperature and stirred for 30 min-
utes. Water was added and the two layers formed were separ-
ated. The aqueous layer was extracted with DCM and the com-
bined organic extracts were washed with 5% aqueous citric acid
solution, saturated aqueous NaHCO3 solution and brine suc-
cessively. They were dried over anhydrous MgSO4 and the sol-
vent was evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (10 : 4
petroleum ether : ethyl acetate) to give 19 as a colourless oil
(2.45 g, 75%). [α]2D4 ϩ68.0 (c. 0.4, CHCl3); IR (νmax/cmϪ1): 2961,
(3aR*,4S*,6R*,6aS*)-(6-Hydroxymethyl-4-methoxy-2,2,6-tri-
methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetic acid methyl
ester (17)
Potassium carbonate (546 mg, 3.95 mmol) was added to a
stirred solution of lactone 16 (2.04 g, 7.90 mmol) in methanol
(79.0 mL) and the reaction mixture was stirred at room temper-
ature for 1 h. Water was added and the mixture was extracted
with DCM. The combined organic extracts were washed with
brine. The extracts were dried over anhydrous MgSO4 and the
1
1718, 1656, 1458, 1386, 1111, 999, 668; H NMR (500 MHz,
CDCl3): δ 9.72 (1H, d, J = 2.7 Hz, CHO), 5.41 (1H, br s, H-3),
3.68 (3H, s, OCH3), 3.16 (3H, s, NCH3), 3.00 (1H, m, H-1), 2.74
(2H, m, H-6 and 1-CH2), 2.56 (1H, m, 1-CH2), 2.08–1.80 (4H,
m, H-4, H-4Ј, H-5 and CH(CH3)2), 1.71 (3H, s, 2-CH3), 0.95
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
324

View Article Online
(3H, d, J = 6.6 Hz, CH(CH3)2), 0.82 (3H, d, J = 6.5 Hz,
CH(CH3)2); 13C NMR (125 MHz, CDCl3): δ 205.2 (CHO),
µL, 2.66 mmol) dropwise. After stirring the reaction mixture for
10 minutes, a solution of 21 (500 mg, 1.33 mmol) in DCM (2.96
mL) was added dropwise. The reaction mixture was stirred for
30 minutes, then triethylamine (742 µL, 5.32 mmol) was added
dropwise and the mixture was stirred for 10 minutes. It was
allowed to warm to room temperature and stirred for a further
30 minutes. Water was added, followed by DCM and the two
layers formed were separated. The aqueous layer was extracted
with DCM and the combined organic extracts were washed
with 5% aqueous citric acid, saturated aqueous NaHCO3 solu-
tion and brine successively. They were dried over anhydrous
MgSO4 and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on
silica gel (10 : 1 petroleum ether : ethyl acetate) to give the
product 22 as a white solid (404 mg, 81%). Mp: 52–54 ЊC; IR
173.4 (amide C᎐O), 134.6 (C-2), 122.1 (C-3), 61.3 (OCH ), 52.3
᎐
3
(C-6), 36.2 (C-5), 33.5 (C-1), 32.4 (NCH3), 31.9 (1-CH2), 27.5
(CH(CH3)2), 24.2 (C-4), 21.7 (2-CH3), 20.7 and 17.6 (CH-
(CH3)2); EIMS (m/z, %): 267 (Mϩ, 26), 239 (14), 206 (33), 147
(31), 135 (62), 121 (47), 103 (87), 93 (93), 81 (82), 61 (67), 43
(100); HRMS (EI): calcd for C15H25NO3 267.1834, found
267.1821.
(3aR*,4S*,6R*,6aS*)-[6-(tert-Butyldimethylsilanyloxymethyl)-
4-methoxy-2,2,6-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl]acetic acid methyl ester (20)
tert-Butyldimethylchlorosilane (1.02 g, 6.79 mmol) and imid-
azole (0.92 g, 13.58 mmol) were added to a stirred solution of
17 (1.64 g, 5.66 mmol) in DMF (11.3 mL) and the reaction
mixture was stirred at room temperature for 18 h. Water and
diethyl ether were added and the two layers were separated. The
aqueous layer was extracted with diethyl ether and the com-
bined organic extracts were washed with brine. The extracts
were dried over anhydrous MgSO4 and the solvent was evapor-
ated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (10 : 3 petroleum ether :
diethyl ether) to give 20 as a white solid (2.12 g, 93%). Mp: 53–
55 ЊC; IR (νmax/cmϪ1): 2933, 2859, 1746, 1460, 1378, 1252, 1110,
1
(νmax/cmϪ1): 2933, 2858, 1726, 1379, 1253, 1105, 839, 779; H
NMR (500 MHz, CDCl3): δ 9.73 (1H, dd, J = 2.5, 3.4 Hz,
CHO), 4.63 (2H, 2d, J = 6.7 Hz, H-3a and H-6a), 3.51 (2H, 2d,
J = 10.4 Hz, 6-CH2), 3.35 (3H, s, OCH3), 2.83 (1H, dd, J = 3.5,
15.4 Hz, 4-CH2), 2.71 (1H, dd, J = 2.4, 15.4 Hz, 4-CH2), 1.58
and 1.35 (6H, 2s, 2-(CH3)2), 1.27 (3H, s, 6-CH3), 0.90 (9H, s,
SiC(CH3)3), 0.07 and 0.05 (6H, 2s, Si(CH3)2); 13C NMR (125
MHz, CDCl3): δ 200.4 (CHO), 114.9 (C-2), 103.5 (C-4), 85.9
and 82.5 (C-3a and C-6a), 85.4 (C-6), 69.4 (6-CH2), 49.0
(OCH3), 48.5 (4-CH2), 25.9 (SiC(CH3)3), 25.64 and 25.60
(2-(CH3)2), 18.5 (6-CH3), 18.3 (SiC(CH3)3), Ϫ5.4 and Ϫ5.6
(Si(CH3)2); ESIMS (m/z, %): 397 ([M ϩ Na]ϩ, 3), 343 (100).
1
1049, 840; H NMR (500 MHz, CDCl3): δ 4.94 and 4.60 (2H,
2d, J = 6.8 Hz, H-3a and H-6a), 3.68 (3H, s, CO2CH3), 3.45
(2H, 2d, J = 10.3 Hz, 6-CH2), 3.35 (3H, s, 4-OCH3), 2.91 and
2.65 (2H, 2d, J = 14.4 Hz, 4-CH2), 1.56 and 1.36 (6H, 2s,
2-(CH3)2), 1.26 (3H, s, 6-CH3), 0.90 (9H, s, SiC(CH3)3), 0.06 and
0.05 (6H, 2s, Si(CH3)2); 13C NMR (125 MHz, CDCl3): δ 169.6
(3aR*,6R*,6aS*)-cis- and trans-[6-(tert-Butyldimethylsilanyl-
oxymethyl)-2,2,6-trimethyldihydrofuro[3,4-d][1,3]dioxol-4-yl-
idene]acetaldehyde (23a,b)
(C᎐O), 114.4 (C-2), 103.7 (C-4), 85.1 and 82.6 (C-3a and C-6a),
᎐
Piperidine (23 µL, 0.23 mmol) was added dropwise to a stirred
solution of aldehyde 19 (61 mg, 0.23 mmol) and aldehyde 22
(85.3 mg, 0.23 mmol) in benzene (0.76 mL). Acetic acid (13 µL,
0.23 mmol) was added dropwise and the reaction mixture was
stirred at room temperature for 3 h. It was then poured onto
saturated aqueous NaHCO3 solution, diethyl ether was added
and the two layers were separated. The aqueous layer was
extracted twice with diethyl ether and the combined organic
extracts were washed with brine. They were dried over
anhydrous MgSO4 and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
84.7 (C-6), 69.2 (6-CH2), 51.7 (CO2CH3), 48.9 (4-OCH3), 39.9
(4-CH2), 25.9, 25.8 and 25.7 (2-(CH3)2 and SiC(CH3)3), 18.6
(6-CH3), 18.3 (SiC(CH3)3), Ϫ5.4 and Ϫ5.5 (Si(CH3)2); ESIMS
(m/z, %): 427 ([M ϩ Na]ϩ, 100).
(3aR*,4S*,6R*,6aS*)-2-[6-(tert-Butyldimethylsilanyloxy-
methyl)-4-methoxy-2,2,6-trimethyltetrahydrofuro[3,4-d][1,3]-
dioxol-4-yl]-1-ethanol (21)
A solution of ester 20 (450 mg, 1.11 mmol) in THF (4.4 mL)
was added dropwise to a slurry of lithium aluminium hydride
(84 mg, 2.22 mmol) in THF (3 mL) at 0 ЊC. The reaction mix-
ture was stirred at 0 ЊC for 1 h, then a large excess of methanol
was added to quench the reaction and the solid was filtered
through a pad of Celite and washed with diethyl ether. The
filtrate was evaporated under reduced pressure and the residue
was purified by flash column chromatography on silica gel
(10 : 4 petroleum ether : ethyl acetate) to give the product 21 as
a white solid (397 mg, 95%). Mp: 60–62 ЊC; IR (νmax/cmϪ1):
3446, 2933, 2859, 1458, 1377, 1254, 1102, 1056, 839; 1H NMR
(500 MHz, CDCl3): δ 4.63 and 4.59 (2H, 2d, J = 6.8 Hz, H-3a
and H-6a), 3.71 (2H, m, CH2OH), 3.52 and 3.50 (2H, 2d,
J = 10.5 Hz, 6-CH2), 3.31 (3H, s, OCH3), 2.77 (1H, t, J = 6.6 Hz,
OH), 2.04 (1H, ddd, J = 3.7, 5.7, 14.7 Hz, 4-CH2), 1.86 (1H,
ddd, J = 4.4, 8.3, 14.7 Hz, 4-CH2), 1.57 and 1.35 (6H, 2s,
2-(CH3)2), 1.27 (3H, s, 6-CH3), 0.91 (9H, s, SiC(CH3)3), 0.08 and
0.07 (6H, 2s, Si(CH3)2); 13C NMR (125 MHz, CDCl3): δ 115.0
(C-2), 105.4 (C-4), 85.2 and 82.3 (C-3a and C-6a), 84.8 (C-6),
69.3 (6-CH2), 58.7 (CH2OH), 48.4 (OCH3), 35.4 (4-CH2), 25.94,
25.87 and 25.6 (SiC(CH3)3 and 2-(CH3)2), 18.5 (6-CH3), 18.4
(SiC(CH3)3), Ϫ5.4 and Ϫ5.6 (Si(CH3)2); ESIMS (m/z, %): 399
([M ϩ Na]ϩ, 80).
chromatography on silica gel (20 : 3
10 : 4 petroleum ether :
ethyl acetate) to give a mixture of isomers 23a and 23b as a
white solid (8 : 3, 22 mg, 28%) and recovered starting material
19 (37 mg, 61%). IR (νmax/cmϪ1): 2933, 2858, 1670, 1639, 1337,
1220, 1092, 839; 1H NMR (500 MHz, C6D6): 23a, δ 10.37 (1H,
d, J = 8.5 Hz, CHO), 5.84 (1H, dd, J = 1.4, 8.5 Hz, CH᎐C), 5.56
᎐
(1H, dd, J = 1.4, 5.9 Hz, H-3a), 4.28 (1H, d, J = 5.9 Hz, H-6a),
3.23 and 3.08 (2H, 2d, J = 10.8 Hz, 6-CH2), 1.29 and 1.19 (6H,
2s, 2-(CH3)2), 1.14 (3H, s, 6-CH3), 0.78 (9H, s, SiC(CH3)3),
Ϫ0.145 and Ϫ0.155 (6H, 2s, Si(CH3)2); 23b, δ 10.44 (1H, d,
J = 8.3 Hz, CHO), 5.56 (1H, dd, J = 0.8, 8.3 Hz, CH᎐C), 5.17
᎐
(1H, dd, J = 0.8, 5.7 Hz, H-3a), 4.19 (1H, d, J = 5.7 Hz, H-6a),
3.27 and 3.09 (2H, 2d, J = 10.9 Hz, 6-CH2), 1.31 and 1.20 (6H,
2s, 2-(CH3)2), 1.16 (3H, s, 6-CH3), 0.77 (9H, s, SiC(CH3)3),
Ϫ0.145 and Ϫ0.151 (6H, 2s, Si(CH3)2); 13C NMR (125 MHz,
C D ): 23a, δ 189.4 (CHO) 178.8 (C-4), 113.2 (C-2), 104.3 (CH᎐
᎐
6
6
C), 91.7 (C-6), 81.6 (C-6a), 81.2 (C-3a), 69.1 (6-CH2), 26.9 and
26.0 (2-(CH3)2), 25.7 (SiC(CH3)3), 18.2 (SiC(CH3)3), 16.2
(6-CH3), Ϫ5.7 and Ϫ6.0 (Si(CH3)2); 23b, δ 187.7 (CHO), 175.1
(C-4), 113.0 (C-2), 102.7 (CH᎐C), 92.9 (C-6), 83.1 (C-3a),
᎐
80.7 (C-6a), 69.0 (6-CH2), 27.1 and 26.2 (2-(CH3)2), 25.7
(SiC(CH3)3), 18.2 (SiC(CH3)3), 16.4 (6-CH3), Ϫ5.7 and Ϫ6.0
(Si(CH3)2); ESIMS (m/z, %): 343 ([M ϩ H]ϩ, 100).
(3aR*,4S*,6R*,6aS*)-[6-(tert-Butyldimethylsilanyloxymethyl)-
4-methoxy-2,2,6-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl]acetaldehyde (22)
(1R,5R,6R)-2-(5-Isopropyl-2-methyl-6-vinylcyclohex-2-enyl)-N-
methoxy-N-methylacetamide (24)
A solution of DMSO (283 µL, 3.99 mmol) in DCM (5.91 mL)
was cooled to Ϫ78 ЊC before addition of oxalyl chloride (232
n-Butyllithium (2.5 M solution in hexanes) (1.68 mL, 4.20
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
325

View Article Online
mmol) was added dropwise to a solution of methyltri-
phenylphosphonium bromide (1.50 g, 4.20 mmol) in THF (7.6
mL) at 0 ЊC. The mixture was stirred for 30 minutes and then
it was allowed to room temperature and stirred for further
30 minutes. A solution of 19 (1.02 g, 3.82 mmol) in THF (7.6
mL) was added dropwise and the reaction mixture was stirred
at room temperature for 1 h. Water and diethyl ether were
added and the two layers were separated. The aqueous layer
was extracted with diethyl ether and the combined organic
extracts were washed with brine and dried over anhydrous
MgSO4. The solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on
silica gel (10 : 2 petroleum ether : ethyl acetate) to give 24 as a
colourless oil (0.73 g, 72%). [α]2D4 ϩ114.8 (c. 0.4, CHCl3); IR
(νmax/cmϪ1): 2959, 1669, 1460, 1417, 1177, 1107, 1384, 1003,
912; 1H NMR (500 MHz, CDCl3): δ 5.76 (1H, dt, J = 10.0, 17.1
Hz, CH᎐CH ), 5.38 (1H, br s, H-3), 5.07 (1H, dd, J = 2.1, 17.1
the combined organic extracts were washed with brine. It was
dried over anhydrous MgSO4 and the solvent was evaporated
under reduced pressure to give the acid 26 as a colourless oil (94
mg, 85%), which was used directly without further purification.
[α]2D4 ϩ22.3 (c. 0.4, CHCl3); IR (νmax/cmϪ1): 3500–2400, 2960,
1708, 1414, 1297, 1231, 1006, 915; 1H NMR (500 MHz,
CDCl ): δ 5.79 (1H, dt, J = 10.0, 17.1 Hz, CH᎐CH ), 5.41 (1H,
᎐
3
2
br s, H-3), 5.11 (1H, dd, J = 2.0, 17.1 Hz, CH᎐CH ), 5.05 (1H,
᎐
2
dd, J = 2.0, 10.2 Hz, CH᎐CH ), 2.60 (1H, m, H-1), 2.39 (3H, m,
᎐
2
H-6 and 1-CH2), 1.98 (1H, m, H-4), 1.85 (1H, m, H-4Ј), 1.75
(1H, m, CH(CH3)2), 1.68 (3H, s, 2-CH3), 1.45 (1H, m, H-5),
0.91 (3H, d, J = 6.9 Hz, CH(CH3)2), 0.75 (3H, d, J = 6.7 Hz,
CH(CH3)2); 13C NMR (125 MHz, CDCl3): δ 179.4 (CO2H),
139.6 (CH᎐CH ), 134.7 (C-2), 122.6 (C-3), 116.6 (CH᎐CH ),
᎐
᎐
2
2
45.2 (C-6), 39.9 (C-1), 39.0 (C-5), 35.0 (1-CH2), 27.7
(CH(CH3)2), 24.0 (C-4), 21.9 (2-CH3), 20.9 and 16.4
(CH(CH3)2); EIMS (m/z, %): 222 (Mϩ, 10), 179 (37), 162 (39),
133 (63), 119 (66), 96 (77), 81 (89), 43 (100); HRMS (EI): calcd
for C14H22O2 222.1620, found 222.1620.
᎐
2
Hz, CH᎐CH ), 5.01 (1H, dd, J = 2.1, 10.2 Hz, CH᎐CH ), 3.67
᎐
᎐
2
2
(3H, s, OCH3), 3.17 (3H, s, NCH3), 2.75 (1H, m, H-1), 2.58 (1H,
m, 1-CH2), 2.39 (2H, m, H-6 and 1-CH2), 1.99 (1H, m, H-4),
1.88 (1H, m, H-4Ј), 1.76 (1H, m, CH(CH3)2), 1.65 (3H, s,
2-CH3), 1.45 (1H, m, H-5), 0.93 (3H, d, J = 6.7 Hz, CH(CH3)2),
0.76 (3H, d, J = 6.7 Hz, CH(CH3)2); 13C NMR (75 MHz,
(3aS*,4R*,6S*,6aR*)-tert-Butyl{6-methoxy-2,2,4-trimethyl-6-
[2-(2-nitrophenylselanyl)ethyl]tetrahydrofuro[3,4-d][1,3]dioxol-
4-ylmethoxy}dimethylsilane (27)
CDCl ): δ 174.6 (C᎐O), 140.4 (CH᎐CH ), 135.7 (C-2), 121.9
᎐
᎐
3
2
o-Nitrophenylselenocyanate (217 mg, 0.95 mmol) was added to
a stirred solution of alcohol 21 (300 mg, 0.80 mmol) in THF
(2.65 mL). It was stirred at room temperature until all of the
starting material was dissolved. Tri-n-butylphosphine (235 µL,
0.95 mmol) was added dropwise and the reaction mixture was
stirred at room temperature for 1 h. The solvent was then evap-
orated under reduced pressure and the residue was purified by
flash column chromatography on silica gel (10 : 1.5 petroleum
ether : ethyl acetate) to give the product 27 as a yellow viscous
oil (0.35 g, 78%). IR (νmax/cmϪ1): 2933, 2858, 1592, 1515, 1333,
1252, 1107, 1038, 839; 1H NMR (500 MHz, CDCl3): δ 8.28 (1H,
dd, J = 1.4, 8.3 Hz, ArH), 7.59 (1H, dd, J = 1.2, 8.2 Hz, ArH),
7.51 (1H, m, ArH), 7.31 (1H, m, ArH), 4.66 and 4.54 (2H, 2d, J
= 6.7 Hz, H-3a and H-6a), 3.50 (2H, s, 4-CH2), 3.32 (3H, s,
OCH3), 2.93 (2H, m, CH2Se), 2.33 (1H, ddd, J = 5.2, 12.2, 14.3
Hz, 6-CH2), 1.92 (1H, ddd, J = 4.5, 12.0, 14.3 Hz, 6-CH2), 1.61
and 1.37 (6H, 2s, 2-(CH3)2), 1.27 (3H, s, 4-CH3), 0.89 (9H, s,
SiC(CH3)3), 0.06 and 0.04 (6H, 2s, Si(CH3)2); 13C NMR (125
MHz, CDCl3): δ 146.8 (ArC), 133.65 (ArC), 133.57 (ArCH),
129.3 (ArCH), 126.4 (ArCH), 125.3 (ArCH), 114.7 (C-2), 105.6
(C-6), 85.4 and 82.7 (C-3a and C-6a), 84.7 (C-4), 69.4 (4-CH2),
48.8 (OCH3), 33.8 (6-CH2), 26.0 (SiC(CH3)3), 25.8 and 25.7
(2-(CH3)2), 19.7 (CH2Se), 18.5 (4-CH3), 18.3 (SiC(CH3)3), Ϫ5.3
and Ϫ5.6 (Si(CH3)2); ESIMS (m/z, %): 584 ([M ϩ Na]ϩ, 44), 530
(100).
(C-3), 116.0 (CH᎐CH ), 61.3 (OCH ), 45.0 (C-6), 39.6 (C-5),
᎐
2
3
38.5 (C-1), 32.6 (NCH3), 32.3 (1-CH2), 27.8 (CH(CH3)2), 24.1
(C-4), 22.1 (2-CH3), 21.0 and 16.9 (CH(CH3)2); ESIMS (m/z,
%): 266 ([M ϩ H]ϩ, 100).
(1R,5R,6R)-(5-Isopropyl-2-methyl-6-vinylcyclohex-2-enyl)-
acetalaldehyde (25)
DIBAL-H (1.0 M solution in hexanes) (5.36 mL, 5.36 mmol)
was added dropwise to a stirred solution of 24 (710 mg, 2.68
mmol) in DCM (13.4 mL) at Ϫ78 ЊC. The reaction mixture was
stirred at Ϫ78 ЊC for 2 h and then it was allowed to warm to
0 ЊC and stirred for 1 h. A large excess of methanol was added
at 0 ЊC and the aluminium salts that precipitated were filtered
through a pad of Celite. The solid was washed several times
with diethyl ether and the filtrate was concentrated. The residue
was purified by flash column chromatography on silica gel
(30 : 1 petroleum ether : diethyl ether) to give the product 25 as
a colourless oil (303 mg, 55%). [α]2D4 ϩ206.5 (c. 0.2, CHCl3); IR
(νmax/cmϪ1): 2959, 2892, 1725, 1465, 1386, 1009, 916; 1H NMR
(500 MHz, CDCl3): δ 9.73 (1H, dd, J = 1.9, 2.9 Hz, CHO), 5.69
(1H, dt, J = 10.0, 17.1 Hz, CH᎐CH ), 5.44 (1H, br s, H-3), 5.10
᎐
2
(1H, ddd, J = 0.7, 2.0, 17.1 Hz, CH᎐CH ), 5.06 (1H, dd, J = 2.0,
᎐
2
10.2 Hz, CH᎐CH ), 2.64 (1H, m, H-1), 2.55 (1H, ddd, J = 2.9,
᎐
2
8.0, 16.7 Hz, 1-CH2), 2.37 (2H, m, H-6 and 1-CH2), 1.97 (1H,
m, H-4), 1.86 (1H, m, H-4Ј), 1.79 (1H, m, CH(CH3)2), 1.66
(3H, s, 2-CH3), 1.47 (1H, m, H-5), 0.91 (3H, d, J = 7.0 Hz,
CH(CH3)2), 0.73 (3H, d, J = 6.7 Hz, CH(CH3)2); 13C NMR (125
(3aS*,4R*,6S*,6aR*)-tert-Butyl(6-methoxy-2,2,4-trimethyl-6-
vinyltetrahydrofuro[3,4-d][1,3]dioxol-4-ylmethoxy)dimethyl-
silane (28)
MHz, CDCl ): δ 203.1 (CHO), 140.4 (CH᎐CH ), 134.4 (C-2),
᎐
3
2
122.8 (C-3), 116.8 (CH᎐CH ), 45.5 (C-6), 44.6 (1-CH ), 39.5
᎐
2
2
Hydrogen peroxide (30%) (0.34 mL, 3.33 mmol) was added
dropwise to a solution of selenide 27 (350 mg, 0.63 mmol) in
THF (6.3 mL) at 0 ЊC, then the reaction mixture was allowed to
warm to room temperature and stirred for 5 h. It was quenched
by addition of ice water and the mixture was extracted with
diethyl ether. The combined organic extracts were washed with
brine and dried over anhydrous MgSO4. The solvent was evap-
orated under reduced pressure and the residue was purified by
flash column chromatography on silica gel (10 : 1 petroleum
ether : diethyl ether) to give 28 as a colourless oil (180 mg, 80%).
IR (νmax/cmϪ1): 2933, 2859, 1462, 1378, 1253, 1103, 993, 840,
778; 1H NMR (500 MHz, CDCl3): δ 5.84 (1H, dd, J = 10.7, 17.4
(C-1), 38.3 (C-5), 27.6 (CH(CH3)2), 23.9 (C-4), 21.9 (2-CH3),
21.0 and 15.7 (CH(CH3)2); EIMS (m/z, %): 206 (Mϩ, 22), 189
(31), 162 (77), 145(89), 119 (97), 91 (82), 81 (98), 43 (100);
HRMS (EI): calcd for C14H22O 206.1671, found 206.1672.
(1R,5R,6R)-(5-Isopropyl-2-methyl-6-vinylcyclohex-2-enyl)acetic
acid (26)
2-Methylbut-2-ene (85%) (2.94 mL, 23.59 mmol) was added to
a stirred solution of 25 (103 mg, 0.50 mmol) in 2-methyl-
propan-2-ol (10.0 mL). An aqueous solution (4 mL) of sodium
chlorite (509 mg, 4.5 mmol) and sodium dihydrogenphosphate
(408 mg, 3.4 mmol) was added dropwise and the reaction
mixture was stirred at room temperature for 2.5 h. The solvent
was evaporated under reduced pressure and the residue was
dissolved in water. Hexane was added and the two layers
separated. The aqueous layer was extracted with hexane and
Hz, CH᎐CH ), 5.48 (1H, dd, J = 1.9, 17.4 Hz, CH᎐CH ), 5.25
᎐
᎐
2
(1H, dd, J =2 1.9, 10.7 Hz, CH᎐CH ), 4.65 and 4.49 (2H, 2d,
᎐
2
J = 6.7 Hz, H-3a and H-6a), 3.54 and 3.51 (2H, 2d, J = 10.2 Hz,
4-CH2), 3.25 (3H, s, OCH3), 1.62 and 1.35 (6H, 2s, 2-(CH3)2),
1.29 (3H, s, 4-CH3), 0.88 (9H, s, SiC(CH3)3), 0.06 and 0.05 (6H,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
326

View Article Online
2s, Si(CH3)2); 13C NMR (125 MHz, CDCl ): δ 137.1 (CH᎐
OCH3), 2.57 (2H, m, H-1), 2.42–2.29 (6H, m, H-6 and 1-CH2),
᎐
3
CH ), 117.5 (CH᎐CH ), 114.7 (C-2), 104.5 (C-6), 87.0 and 82.6
1.96 (2H, m, H-4), 1.88–1.68 (4H, m, H-4Ј and CH(CH3)2), 1.64
(6H, s, 2-CH3), 1.62 and 1.35 (12H, 2s, 2Ј-(CH3)2), 1.44 (2H, m,
H-5), 1.38 (6H, s, 4Ј-CH3), 0.91 (6H, 2d, J = 6.9 Hz, CH(CH3)2),
0.73 (6H, t, J = 6.9 Hz, CH(CH3)2); 13C NMR (125 MHz,
CDCl ): δ 173.3 (C᎐O), 140.0 and 139.9 (6-CH᎐CH ), 136.9
᎐
2
2
(C-3a and C-6a), 84.6 (C-4), 69.1 (4-CH2), 49.4 (OCH3), 25.8
and 25.7 (SiC(CH3)3 and 2-(CH3)2), 18.7 (4-CH3), 18.2
(SiC(CH3)3), Ϫ5.4 and Ϫ5.6 (Si(CH3)2); ESIMS (m/z, %): 381
([M ϩ Na]ϩ, 2), 327 (100).
᎐
᎐
3
2
(6Ј-CH᎐CH ), 134.7 and 134.6 (C-2), 122.6 and 122.5 (C-3),
᎐
2
(3aS*,4R*,6S*,6aR*)-(6-Methoxy-2,2,4-trimethyl-6-vinyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (29)
117.6 (6Ј-CH᎐CH ), 116.3 and 116.2 (6-CH᎐CH ), 115.3
᎐ ᎐
2 2
(C-2Ј), 104.62 and 104.57 (C-6Ј), 86.90 and 86.86 (C-3Јa or
C-6Јa), 82.8 (C-3Јa or C-6Јa), 82.61 and 82.57 (C-4Ј), 69.5 and
69.3 (4Ј-CH2), 49.6 (OCH3), 45.5 and 45.2 (C-6), 40.6 and 40.0
(C-1), 39.0 and 38.4 (C-5), 35.3 and 35.1 (1-CH2), 27.7
(CH(CH3)2), 25.9 (2Ј-(CH3)2), 25.6 (2Ј-(CH3)2), 24.0 and 23.9
(C-4), 21.9 (2-CH3), 21.0 and 20.9 (CH(CH3)2), 19.0 (4Ј-CH3),
16.4 and 16.0 (CH(CH3)2); ESIMS (m/z, %): 471 ([M ϩ Na]ϩ,
55), 417 (100).
Tetra-n-butylammonium fluoride (1.0 M solution in THF)
(0.75 mL, 0.75 mmol) was added dropwise to a stirred solution
of 28 (180 mg, 0.50 mmol) in THF (3.4 mL), then the reaction
mixture was stirred at room temperature for 30 minutes. Water
was added, followed by ethyl acetate and the two layers formed
were separated. The aqueous layer was extracted with ethyl
acetate, then the combined organic extracts were washed with
brine. They were dried over anhydrous MgSO4 and the solvent
was evaporated under reduced pressure. The residue was puri-
fied by flash column chromatography on silica gel (2 : 1 petrol-
eum ether : ethyl acetate) to give the product 29 as a white solid
(98 mg, 80%). Mp: 47–49 ЊC; IR (νmax/cmϪ1): 3483, 2983, 2937,
Acknowledgements
We thank the McClay Trust for generous funding which
included a Research Fellowship for X.W. Sun and Postgraduate
Studentships for G. Scalabrino and A. Baron.
1
1458, 1379, 1215, 1100, 1046, 991, 868; H NMR (500 MHz,
C D ): δ 5.75 (1H, dd, J = 10.8, 17.4 Hz, CH᎐CH ), 5.37 (1H,
᎐
6
6
2
dd, J = 1.8, 17.4 Hz, CH᎐CH ), 4.99 (1H, dd, J = 1.8, 10.8 Hz,
᎐
2
References
CH᎐CH ), 4.58 and 4.46 (2H, 2d, J = 6.7 Hz, H-3a and H-6a),
᎐
2
3.29 (1H, dd, J = 3.8, 11.3 Hz, CH2OH), 3.20 (1H, dd, J = 8.5,
11.3 Hz, CH2OH), 3.18 (3H, s, OCH3), 1.72 and 1.27 (6H, 2s,
2-(CH3)2), 1.38 (1H, m, CH2OH ), 1.33 (3H, s, 4-CH3); 13C
1 T. Lindel, P. R. Jensen, W. Fenical, B. H. Long, A. M. Casazza,
J. Carboni and C. R. Fairchild, J. Am. Chem. Soc., 1997, 119, 8744–
8745.
2 G. Hofle, N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth and
H. Reichenbach, Angew. Chem., Int. Ed., 1996, 35, 1567–1569.
3 (a) K. C. Nicolaou, J. Y. Xu, S. Kim, T. Ohshima, S. Hosokawa and
J. Pfefferkorn, J. Am. Chem. Soc., 1997, 119, 11353–11354; (b) K. C.
Nicolaou, F. Van Delft, T. Ohshima, D. Vourloumis, J. Xu,
S. Hosokawa, J. Pfefferkorn, S. Kim and T. Li, Angew. Chem., Int.
Ed., 1997, 36, 2520–2524.
NMR (125 MHz, C D ): δ 137.6 (CH᎐CH ), 116.8 (CH᎐CH ),
᎐
᎐
6
6
2
2
115.2 (C-2), 105.0 (C-6), 87.4 and 83.1 (C-3a and C-6a), 84.9
(C-4), 69.2 (CH2OH), 49.3 (OCH3), 26.3 and 26.2 (2-(CH3)2),
18.8 (4-CH3); HRMS (EI): calcd for C12H20O5 244.1311, found
244.1316.
4 (a) X. T. Chen, C. E. Gutteridge, S. K. Bhattacharya, B. Zhou,
T. R. R. Pettus, T. Hascall and S. J. Danishefsky, Angew. Chem.,
Int. Ed., 1998, 37, 185–187; (b) X. T. Chen, B. Zhou, S. K.
Bhattacharya, C. E. Gutteridge, T. R. R. Pettus and S. J.
Danishefsky, Angew. Chem., Int. Ed., 1998, 37, 789–792; (c) X. T.
Chen, S. K. Bhattacharya, B. Zhou, C. E. Gutteridge, T. R. R. Pettus
and S. J. Danishefsky, J. Am. Chem. Soc., 1999, 121, 6563–6579.
5 S. M. Ceccarelli, U. Piarulli and C. Gennari, Tetrahedron, 2001, 57,
8531–8542.
6 J. Telser, R. Beumer, A. A. Bell, S. M. Ceccarelli, D. Monti and
C. Gennari, Tetrahedron Lett., 2001, 42, 9187–9190.
7 R. Carter, K. Hodgetts, J. McKenna, P. Magnus and S. Wren,
Tetrahedron, 2000, 56, 4367–4382.
8 A. Baron, V. Caprio and J. Mann, Tetrahedron Lett., 1999, 40, 9321–
9324.
9 L. C. De Almeida Barbosa and J. Mann, Synthesis, 1996, 31–33.
10 D. E. Cane, G. Yang, R. M. Coates, H. J. Pyun and T. M. Hohn,
J. Org. Chem., 1992, 57, 3454–3462.
11 M. P. Sibi, Org. Prep. Proced. Int., 1993, 25, 15–40.
12 H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483–2547.
13 P. A. Grieco, S. Gilman and M. Nishizawa, J. Org. Chem., 1976, 41,
1485–1486.
(1R,3ЈaS,4ЈR,5R,6R,6ЈS,6ЈaR)-(5-Isopropyl-2-methyl-6-vinyl-
cyclohex-2-enyl)acetic acid 6Ј-methoxy-2Ј,2Ј,4Ј-trimethyl-6Ј-
vinyltetrahydrofuro[3,4-d][1,3]dioxol-4-ylmethyl ester (30a) and
(1R,3ЈaR,4ЈS,5R,6R,6ЈR,6ЈaS )-(5-isopropyl-2-methyl-6-vinyl-
cyclohex-2-enyl)acetic acid 6Ј-methoxy-2Ј,2Ј,4Ј-trimethyl-6Ј-
vinyltetrahydrofuro[3,4-d][1,3]dioxol-4-ylmethyl ester (30b)
DCC (137 mg, 0.66 mmol) was added to a stirred solution of
acid 26 (74 mg, 0.33 mmol) and alcohol 29 (81 mg, 0.33 mmol)
in DCM (3.3 mL). DMAP (20 mg, 0.16 mmol) was added and
the reaction mixture was stirred at room temperature for 5 h.
The solid formed was filtered and washed with diethyl ether and
the filtrate was washed with saturated aqueous NH4Cl solution.
It was dried over anhydrous MgSO4 and the solvent was evap-
orated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (10 : 1 petroleum
ether : ethyl acetate) to give an inseparable mixture of two dia-
stereomers 30a and 30b (1 : 1) as a colourless oil (92 mg, 62%).
IR (νmax/cmϪ1): 2958, 2937, 1740, 1458, 1379, 1252, 1154, 1105,
992, 869; 1H NMR (500 MHz, CDCl3): δ 5.84 (2H, 2dd, J = 6.2,
10.7 Hz, 6Ј-CH᎐CH ), 5.75 (2H, 2dt, J = 10.1, 17.1 Hz, 6-CH᎐
14 K. B. Sharpless and M. W. Young, J. Org. Chem., 1975, 40, 947–949.
15 (a) A. Hassner and V. Alexanian, Tetrahedron Lett., 1978, 4475–
4478; (b) F. E. Ziegler and G. D. Berger, Synth. Commun., 1979, 9,
539–543.
16 (a) R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413–
4450; (b) T. M. Trnka and R. H. Grubbs, Acc. Chem. Res., 2001, 34,
18–29.
᎐
᎐
2
CH ), 5.44 (2H, 2dd, J = 1.7, 7.4 Hz, 6Ј-CH᎐CH ), 5.40 (2H, br
᎐
2
2
s, H-3), 5.26 (2H, dt, J = 1.9, 10.7 Hz, 6Ј-CH᎐CH ), 5.08 (2H,
᎐
2
dd, J = 2.0, 17.1 Hz, 6-CH᎐CH ), 5.03 (2H, dd, J = 2.0, 10.1 Hz,
᎐
6-CH᎐CH ), 4.54 (2H, 2d, J =26.7 Hz, H-3Јa and H-6Јa), 4.53
᎐
2
(2H, 2d, J = 6.7 Hz, H-3Јa and H-6Јa), 4.08 (2H, 2d, J = 11.4
Hz, 4Ј-CH2), 3.97 (2H, 2d, J = 11.4 Hz, 4Ј-CH2), 3.25 (6H, 2s,
17 A. P. Kozikowski, Acc. Chem. Res., 1984, 17, 410–416.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 1 8 – 3 2 7
327