The synthesis of a natural product family: From debromoisolaurinterol to the aplysins

Article abstract of DOI:10.1016/S0040-4020(00)01055-3

Total syntheses of (±)-aplysin 1, (±)-debromoaplysin 2, (±)-isoaplysin 3, (±)-aplysinol 4, (±)-debromoaplysinol 5, (±)-aplysinal 6, (±)-isolaurinterol 7 and (±)-debromoisolaurinterol 8 are described. Key features are a diastereoselective, sulfur mediated radical cyclisation of diene 12 to give 35; a new radical to polar crossover sequence mediated by Bu₃Sn that transforms diene 12 into (±)-debromoisolaurinterol 8; and a series of biomimetic cyclisation and oxidation reactions.

Full text of DOI:10.1016/S0040-4020(00)01055-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 791±804
The synthesis of a natural product family: from
debromoisolaurinterol to the aplysins
David C. Harrowven,a,p Matthew C. Lucasa and Peter D. Howesb
aDepartment of Chemistry, The University, Southampton S017 1BJ, UK
bMedicinal Chemistry 2, GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 12 September 2000; revised 19 October 2000; accepted 2 November 2000
AbstractÐTotal syntheses of (^)-aplysin 1, (^)-debromoaplysin 2, (^)-isoaplysin 3, (^)-aplysinol 4, (^)-debromoaplysinol 5, (^)-
aplysinal 6, (^)-isolaurinterol 7 and (^)-debromoisolaurinterol 8 are described. Key features are a diastereoselective, sulfur mediated
radical cyclisation of diene 12 to give 35; a new radical to polar crossover sequence mediated by Bu3Snz that transforms diene 12 into (^)-
debromoisolaurinterol 8; and a series of biomimetic cyclisation and oxidation reactions. q 2001 Elsevier Science Ltd. All rights reserved.
1. Background
During a programme to identify natural anti-tumour agents
of marine origin, Yamamura and Hirata observed that crude
extracts of the Aplysia sea hare displayed signi®cant bio-
logical activity.1 Among the chemical constituents identi-
®ed in the extract was an unusual tricyclic sesquiterpene
which they named aplysin 1.1±6 Several related compounds
were subsequently identi®ed, including debromoaplysin 2,
isoaplysin 3,7 aplysinol 4,3 debromoaplysinol 5,4 and
aplysinal 6.5 The co-occurrence of brominated and non-
brominated aplysins in all known natural sources prompted
speculation that the debromo-analogues scavenged reactive
halogens from the marine environment before they could
in¯ict damage on the host. The aplysins are also believed
to act as anti-feedants, preventing the predatory advances of
other marine organisms.8
Natural sources of the aplysins are limited. They have been
identi®ed in North American opisthobranchs and the red sea
alga Laurencia. It is believed that the latter is responsible for
the synthesis of aplysins in nature as both the Aplysia sea
hare and opisthobranchs feed on Laurencia and aplysins are
accumulated in the gut of both molluscs.8,9
From a synthetic viewpoint the aplysins offer an interesting
challenge. In particular, the need to establish three
contiguous stereogenic centres while constructing
sterically demanding tricyclic skeleton requires special
a
attention. Several syntheses of aplysin 1 have been reported
using
a
variety of strategies.10,11 To date only
Venkateswaran has developed a route applicable to the
more demanding members of this series, modifying an
earlier synthesis of aplysin 1 to address isoaplysin 3 and
aplysinol 4.8
Keywords: terpenes and terpenoids; natural products; radicals and radical
reactions; cyclisations; oxygen heterocycles.
* Corresponding author. Tel.: 123-8059-3302; fax: 123-8059-3781;
e-mail: dch2@soton.ac.uk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01055-3

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D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
2. Our strategy
derived from meta-cresol 14 was metallated with t-butyl-
lithium and then allylated.14 Ozonolysis of the resulting
alkene 16 next provided aldehyde 17 which was smoothly
oxidised to the corresponding acid 18 with Jones' reagent
and lactonised to 9 using PPTS (Scheme 2).
Our interest in radical reactions and the synthesis of
naturally occurring arenes led us to consider the approach
outlined in Scheme 1.12 We hoped that an electrophilic
radical generated in the presence of diene 12 would ®rst
add to the terminus of the enol ether giving 13. A 5-exo-
trig cyclisation through a chair-like transition state13
followed by a hydrogen atom quench would then provide
11, an advanced precursor of all the aplysins.
Though effective for the synthesis of 9, the hazards
associated with using t-butyllithium on a large scale led us
to develop an alternative approach. This began with the
acetate 19 derived from meta-cresol. When exposed to
zirconium(IV) chloride at room temperature under ultra-
sound irradiation 19 was smoothly transformed into aceto-
phenone 20.15 Sequential protection of the phenol as its
methyl ether 21, Willgerodt-Kindler oxidation to thioamide
22 and alkylation and hydrolysis provided thioester 23.16,17
Finally, exposure to boron trichloride effected simultaneous
deprotection of the methyl ether and lactonisation giving
benzofuranone 9 (Scheme 3).
Scheme 1.
3. Synthesis of 6-methylbenzofuran-2-one
Our ®rst task was to secure a synthesis of 6-methylbenzo-
furan-2-one 9. To that end, the ethoxymethyl ether 15
Scheme 3. Reagents and conditions: a. ZrCl4, ultrasound irradiation, DCM,
RT, 24h, 93%; b. Me2SO4, KOH, acetone, RT, 15h, 97%; c. morpholine, S8,
1008C, 24h, 76%; d. MeI, H2O, THF, D, 18h, 90%; e. BCl3, DCM, 08C to
RT, 15h, 46%.
It is worth noting that the Willgerodt-Kindler reaction
furnished two major side products, thiophene 24 (the
identity of which was con®rmed by X-ray crystallography)
and thioxoketone 25. Fortunately, the yield of each
diminished as the scale of the reaction was increased.
4. Synthesis of diene 12
Several dif®culties were experienced at this juncture. For
example, attempts to alkylate the enolate derived from 9
with 4-butenyl bromide returned only recovered starting
material while methylation with methyl iodide furnished
the dialkylated product 27 rather than 26 (Scheme 4).
Scheme 2. Reagents and conditions: a. NaH, MEMCl, Et2O, DMF, 3h,
94%; b. t-BuLi, pentane, 08C, 7h; CuI.P(OEt)3, THF, 2788C, 30 min.;
CH2ˆCHCH2Br, RT, 22h, 78%; c. O3, CHCl3, 2788C, 40 min.; PPh3,
RT, 5h, 70%; d. CrO3, 2M H2SO4, acetone, RT, 72%; e. PPTS, PhCH3,
D, 20h, 50%.

D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
793
Scheme 4.
Scheme 7. Reagents and conditions: a. 6 equiv. Cp2TiCl2, 12 equiv. AlMe3,
PhMe, 2788C to RT, 30 min., 79%.
Pleasingly, deprotonation of 23 with t-BuLi was facile and
quenching with methyl iodide gave 28 in 96% yield.
However, attempts to effect the deprotonation of 28 with
t-BuLi led to ketone 29 rather than the desired enolate. To
circumvent this dif®culty lactonisation of 28 to benzofura-
none 30 was effected through the action of boron trichloride.
Deprotonation and alkylation with 4-iodobut-2-ene then
gave the bis-alkylated lactone 10 in 92% yield (Scheme 5).
The alternative sequence involving homoallylation of 23 to
31, lactonisation to 32 and methylation to 10 was also
effective. Synthesis of diene 12 was then accomplished by
exposure of lactone 10 to Tebbe's reagent (Scheme 6).18
Though the conversion of lactone 10 to diene 12 proceeded
in modest yield, much of the remaining mass balance was
recovered starting material which was easily recycled. Inter-
estingly, attempting to push the reaction to completion by
using the Tebbe reagent in vast excess effected both
methyleneation of the carbonyl and methylation of the
terminal alkene giving 33 in 79% yield. We presume that
the secondary reaction proceeds via a metallocyclobutane
such as 34 which protonates on work up (Scheme 7).19
Scheme 5. Reagents and conditions: a. t-BuLi, TMEDA, THF, 2608C,
10 min.; MeI, RT, 2h, 96%; b. t-BuLi, THF, 2788C, 1h; CH2ˆ
CHCH2CH2Br, RT, 71%; c. BCl3, DCM, 08C, 2h, 71%; d. c-Hex(i-
Pr)NLi, HMPA, THF 2788C, 30 min; CH2ˆCHCH2CH2I, RT, 2h, 92%.
Scheme 6. Reagents and conditions: a. t-BuLi, TMEDA, THF, 2608C,
10 min.; CH2ˆCHCH2CH2I, 2788C, 1h, RT, 8h, 54%; b. BCl3, DCM,
08C, 2h, 71%; c. c-Hex(i-Pr)NLi, HMPA, THF, 2788C to 08C, 15 min;
MeI, 2788C to 08C, 2h, 84%; d. 2.8 equiv. Cp2TiCl2, 7.8 equiv. AlMe3,
PhMe, 2788C to RT, 30 min., 54% [128% 10].
Scheme 8.

794
D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
Scheme 11.
failure. Indeed, where new products could be identi®ed the
yields obtained were of no synthetic utility.
Scheme 9.
5. The total synthesis of (^)-aplysin and (^)-
debromoaplysin
6.1. A biomimetic approach: from isolaurinterols to
aplysins
We were now in a position to test our key step.20 Pleasingly,
irradiation of a hexane solution of 12 containing di-t-butyl
disul®de gave tricycles 35 and 36 in 61% yield as a partially
separable 8:1 mixture of diastereoisomers. That the stereo-
chemical course of the reaction had followed the predicted
path (Scheme 1) was con®rmed through hydrogenolysis of
the major diastereoisomer with Raney nickel to (^)-
debromoaplysin 2. On treatment with bromine, 2 was
rapidly transformed into (^)-aplysin 1 (Scheme 8). Both
synthetic samples displayed spectral and physical character-
istics identical to those reported by others: an X-ray analysis
provided further con®rmation of structure.21
At this juncture we decided to change our strategy.22
Though the biosynthesis of the aplysins has yet to be
rigorously established,22 the co-occurrence of the iso-
laurinterols and aplysins in Laurencia and the sea hare
Aplysia led us to conclude that the isolaurinterols might
serve as precursors to the aplysins in nature.6,23 Thus,
addition of a suitable electrophile to isolaurinterol 7 or
debromoisolaurinterol 8 would lead to cation 39. Intercep-
tion by the proximal phenol would then give rise to an
aplysin (Scheme 10).
Our plan was to effect the metallation of sul®de 35 so as to
induce scission of the benzofuran to debromoisolaurinterol
8 (Scheme 11). Alas, we had no success in that regard so our
attention turned to the possibility of effecting the novel
radical to polar crossover sequence outlined in Scheme 12.24
6. Approaches to the other aplysins
Unfortunately, all attempts to functionalise sul®de 35 in
order to access the more demanding aplysins met with
failure. For example, oxidation of the sul®de with
m-CPBA proceeded smoothly but led to loss of the t-butyl
group, presumably via the electrocyclic elimination 37!38.
Manipulation of the resulting product, the identity of which
we were uncertain of, proved intractable (Scheme 9).
6.2. A new radical to polar crossover reaction
To our delight, a synthesis of (^)-debromoisolaurinterol 8
was readily accomplished through exposure of diene 12 to
In attempting to overcome this dif®culty the cyclisation of
12 was repeated using diphenyl disul®de. Surprisingly,
under a range of cyclisation conditions the starting material
12 was returned in near quantitative yield. Attempts to
transform the carbon to sulfur bond into a more useful
functional group with mercury(II) salts likewise met with
Scheme 10.
Scheme 12.

D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
795
Scheme 13. Reagents and conditions: a. Bu3SnH, AIBN, PhMe, 808C, 18h, 79%; b. acidic CDCl3, RT, 16h, 100%; c. Br2, NaHCO3, DCM, 08C, 30 min, 82%;
d. Bu3SnH, AIBN, C6H14, hn, 158C, 20h, 69%; e. PhMe, re¯ux, 18h, 82% (142, 12%); f. m-CPBA, DCM, 08C, 24h, 52% (18, 10%; 145, 12%); g. Br2,
NaHCO3, CHCl3, 08C, 1h, 51% (15, 24%); h. as g. giving 3, 47% and 44, 47%; i. Dess-Martin periodinane, DCM, RT, 2h, 96%; j. NBS, CHCl3, re¯ux, 72h,
50% (142, 18%).
tributylstannyl radicals formed under standard conditions
using thermolysis to initiate the breakdown of AIBN. This
provided 8 as a 5:1 mixture of diastereoisomers in 79% yield
(Scheme 12).
7. Conclusion
We have completed total syntheses of all the known aplysin
and isolaurinterol natural products and provided evidence
that each is derived in nature from 8. Additionally, we have
developed a new method for effecting a vinyl group transfer
from oxygen to carbon involving a radical to polar crossover
reaction mediated by tributyltin hydride, viz. 12!8. The
remarkable diastereoselectivity attained in the free radical
cyclisations 12!35 and 12!42 is also noteworthy.
Though reasonable, diastereoselectivity was improved
dramatically by conducting reactions at 158C using light
to induce cleavage of the initiator. Under these conditions
the tricyclic stannane 42 was provided as a 98:2 mixture of
diastereoisomers in 69% yield. Re¯uxing a toluene solution
of 42 for 24 h then gave (^)-debromoisolaurinterol 8 in
82% yield together with 12% recovered stannane 42
(Scheme 13).
8. Experimental
Acid catalysed cyclisation of (^)-debromoisolaurinterol 8
to (^)-debromoaplysin 2 was extremely facile. Indeed,
when a CDCl3 solution of this compound was allowed to
stand for 16 h prior to NMR analysis a quantitative conver-
sion to (^)-debromoaplysin 2 was observed (CDCl3 stored
over anhydrous potassium carbonate failed to induce cycli-
sation). Bromination of 2 then provided aplysin 1 in 82%
yield. Epoxidation of 8 with m-CPBA likewise induced
spontaneous cyclisation to give (^)-debromoaplysinol 5
in 52% yield together with traces of recovered starting
material (10%) and an oxirane intermediate 45 (12%).
Bromination of 5 then gave (^)-aplysinol 4 which was
smoothly oxidised to (^)-aplysinal 6 on treatment with
the Dess±Martin periodinane reagent.25
8.1. General remarks
Melting points were obtained using a Mel-Temp (II)
apparatus and are uncorrected. UV spectra were recorded
on a Pye Unicam SP800 spectrometer. IR spectra of oils and
solutions were recorded on a Perkin±Elmer 1600 series
Fourier transform infrared spectrometer using NaCl cells.
For most solids, IR spectra were recorded directly using a
Bio-Rad FTS 135 Fourier transform infrared spectrometer
equipped with a Golden Gate Single Re¯ection Diamond
ATR. NMR spectra were recorded on a Bruker AC300
(operating at 300 MHz for H and at 75 MHz for 13C) or a
1
Bruker AM400 (operating at 400 MHz for 1H and at
100 MHz for 13C). Chemical shifts (dH) are reported as
values in parts per million relative to tetramethylsilane
(dH 0.00, dC 0.00) or residual CHCl3 (dH 7.27, dC 77.2).
Mass spectra were recorded on a variety of instruments
either in house or at the EPSRC mass spectrometry centre,
Swansea.
Attempts to effect conversion of (^)-debromoisolaurinterol
8 into (^)-isoaplysin 3 and (^)-isolaurinterol 7 through
direct halogenation were less rewarding, affording complex
mixtures containing these materials, recovered 8 and
dibromide 44. However, exposing a cooled solution of stan-
nane 42 to bromine gave (^)-isoaplysin 3 in an acceptable
47% yield while simply re¯uxing a chloroform solution of
42 with NBS gave (^)-isolaurinterol 7 in 50% yield
(Scheme 13).24
All reactions were magnetically stirred under an inert
atmosphere. Photochemical reactions were performed in a
Quartz reaction vessel with irradiation from a 125W
medium pressure mercury lamp and were water cooled.

796
D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
Reactions were monitored by thin layer chromatography
using Macherey±Nagel Alugram Sil G/UV254 precoated
aluminium foil plates of layer thickness 0.25 mm.
Compounds were visualised ®rstly by UV irradiation, then
by exposure to iodine vapour and ®nally by heating plates
exposed to solutions of phosphomolybdic acid in ethanol.
Column chromatography was performed on Sorbsil 60 silica
(230±400 mesh), slurry packed and run under low pressure.
added in a single portion and the mixture stirred for
30 min. Allyl bromide (7.99 g, 5.71 mL, 66 mmol) was
added dropwise over 5 min. After stirring for 1 h the
reaction mixture was warmed to ambient temperature and
stirred for 22 h. The reaction mixture was diluted with
dichloromethane (100 mL) and washed repeatedly with ca.
NH3 (aq) (10£200 mL) until no more blue discolouration of
the ammonia solution was observed. The combined aqueous
phases were washed with dichloromethane (100 mL) then
the combined organic phases were washed with water
(2£80 mL) and brine (60 mL), then dried (MgSO4), ®ltered
and concentrated in vacuo to a yellow oil (21.0 g). Puri®ca-
tion by chromatography (silica, 10% ethyl acetate in petrol)
gave 16 (10.7 g, 51.8 mmol, 78%) as a pale yellow oil; IR
(neat, cm21) nmax 3077m, 2977s, 2900s, 1638s, 1613s,
1582s, 1508s, 1442bs, 1392s, 1317s, 1248s, 1016bs, 912s,
716w; UV (MeOH, nm) lmax (emax) 282 (850), 274 (900);
1H NMR (300 MHz, CDCl3) dH 7.07 (1H, d, Jˆ7.5 Hz,
ArH), 6.97 (1H, s, ArH), 6.81 (1H, d, Jˆ7.4 Hz, ArH),
6.02 (1H, ddt, Jˆ16.7, 10.2, 6.4 Hz, vCH), 5.28 (2H, s,
OCH2O), 5.07 (1H, dd, Jˆ16.7, 1.5 Hz, vCHH), 5.04
(1H, br. d, Jˆ10.2 Hz, vCHH), 3.78 (2H, q, Jˆ7.1 Hz,
OCH2CH3), 3.41 (2H, d, Jˆ6.4 Hz, ArCH2), 2.37 (3H, s,
ArCH3), 1.28 (3H, t, Jˆ7.1 Hz, OCH2CH3); 13C NMR
(75 MHz, CDCl3) dC 155.1 (C, Ar), 137.5 (vCH), 137.5
(C, Ar), 129.9 (CH, Ar), 126.3 (C, Ar), 122.5 (CH, Ar),
115.3 (vCH2), 115.0 (CH, Ar), 93.3 (OCH2O), 64.4
(CH2CH3), 34.3 (ArCH2), 21.6 (ArCH3), 15.3 (CH2CH3);
LRMS (APCI) m/z 206 (M1, 20%), 161 (100%), 147
(45%); HRMS (CI) m/z Found MH1: 207.1385, C13H19O2
requires 207.1385.
Hexane was dried over calcium hydride and degassed using
ultrasound irradiation prior to use. Ether refers to diethyl
ether and petrol refers to the fraction of petroleum ether in
the boiling point range 40±608C. Details of our synthesis of
23 from 19 have been reported previously.17a Importantly,
when the Willgerodt-Kindler oxidation of 21 was conducted
on a 50 g scale the desired product 22 was furnished in 67%
yield together with thiophene 24 (17%) and thioxoketone 25
(7%). The structure of 24 has been revised following X-ray
crystallograpic analysis. 4-Iodobut-1-ene was prepared
following the procedure as described by Fry et al. and
Hoarau et al.26
8.1.1. 1-(Ethoxymethoxy)-3-methylbenzene (15).27 Pre-
pared following the procedure of Ronald et al.14 To a stirred
suspension of sodium hydride (26.6 g, 666 mmol) in dry
ether (160 mL) and DMF (40 mL) under nitrogen and
with cooling to 08C was added meta-cresol 14 (24.0 g,
23.2 mL, 222 mmol) over 25 min. Once effervescence had
ceased (,10 min), chloromethyl ethyl ether (21.0 g,
20.6 mL, 222 mmol) was added via syringe over 15 min.
The reaction mixture was warmed to ambient temperature
and stirred for 5 h, then quenched by slow addition of water
(50 mL). The mixture was extracted into ether (3£50 mL),
then the combined organic extracts were washed with water
(50 mL) and brine (40 mL) then dried (MgSO4), ®ltered and
concentrated in vacuo to a yellow oil (43 g). Puri®cation by
chromatography (silica, petrol) gave 15 (34.8 g, 210 mmol,
94%) as a colourless oil; IR (neat, cm21) nmax 3038m,
2977s, 2791w, 1586s, 1491s, 1458s, 1410m, 1393s, 1252s,
1150s, 1106s, 910m; UV (MeOH, nm) lmax (emax) 278
(700), 271 (750), 266 inf (600); 1H NMR (300 MHz,
CDCl3) dH 7.21 (1H, dd, Jˆ7.9, 7.7 Hz, ArH), 6.91 (1H,
s, ArH), 6.89 (1H, d, Jˆ7.7 Hz, ArH), 6.85 (1H, d,
Jˆ7.9 Hz, ArH), 5.25 (2H, s, OCH2O), 3.75 (2H, q,
Jˆ7.1 Hz, OCH2CH3), 2.35 (3H, s, ArCH3), 1.25 (3H, t,
Jˆ7.1 Hz, OCH2CH3); 13C NMR (75 MHz, CDCl3) dC
157.6 (C, Ar), 139.7 (C, Ar), 129.4 (CH, Ar), 122.7 (CH,
Ar), 117.1 (CH, Ar), 113.3 (CH, Ar), 93.3 (OCH2O), 64.3
(OCH2CH3), 21.7 (ArCH3), 15.3 (OCH2CH3); LRMS (CI)
m/z 166 (M1, 90%), 136 ([MH2C2H5]1, 40%), 108 (75%).
8.1.3. 2-[2-(Ethoxymethoxy)-4-methylphenyl]acetaldehyde
(17). Prepared following the procedure of Knowles and
Thompson.29 Thus, a stirred solution of alkene 16 (5.00 g,
24.3 mmol) in chloroform (90 mL) was cooled to 2788C
and ozone bubbled through the solution for 40 min (at
which time a pale blue colour persisted). Oxygen was
bubbled through the mixture for 15 min then triphenyl-
phosphine (12.78 g, 48.6 mmol) was added. The mixture
was warmed to ambient temperature and stirred for 5 h.
The pale yellow solution was concentrated in vacuo to a
cloudy yellow residue (20.5 g). Puri®cation by chromato-
graphy (silica, 0±5% ethyl acetate in petrol) gave 17
(3.56 g, 17.1 mmol, 70%) as a colourless oil; IR (neat,
cm21) nmax 2977s, 2901s, 2818m, 1725s, 1614m, 1583m,
1508s, 1444m, 1391s, 1007bs, 811m; UV (MeOH, nm) lmax
(emax) 280 (850), 274 (850); 1H NMR (300 MHz, CDCl3) dH
9.60 (1H, t, Jˆ2.0 Hz, CHO), 7.05 (1H, d, Jˆ7.5 Hz, ArH),
7.00 (1H, s, ArH), 6.82 (1H, d, Jˆ7.5 Hz, ArH), 5.25 (2H, s,
OCH2O), 3.71 (2H, q, Jˆ7.1 Hz, OCH2CH3), 3.62 (2H, d,
Jˆ2.0 Hz, CH2CHO), 2.36 (3H, s, ArCH3), 1.24 (3H, t,
Jˆ7.1 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) dC
200.5 (CHO), 155.6 (C, Ar), 139.3 (C, Ar), 131.2 (CH,
Ar), 122.7 (CH, Ar), 118.7 (C, Ar), 114.8 (CH, Ar), 93.1
(OCH2O), 64.6 (CH2CH3), 45.5 (CH2CHO), 21.7 (ArCH3),
15.2 (CH2CH3); LRMS (APCI) m/z 208 (M1, 10%), 163
(50%), 133 (80%); HRMS (CI) m/z Found [M1NH4]1:
226.1443, C12H20NO3 requires 226.1443.
8.1.2. 1-Allyl-2-(ethoxymethoxy)-4-methylbenzene (16).
Prepared following the procedure of Ziegler et al.28 Thus,
a solution of tert-butyllithium (44.2 mL of a 1.5 M solution
in pentane, 66.3 mmol) was transferred to a ¯ask and main-
tained at 08C under an atmosphere of nitrogen. To this was
added 1-(ethoxymethoxy)-3-methylbenzene 15 (11.0 g,
66 mmol) in pentane (100 mL) via cannula over 3 min
with vigorous stirring. After 1 h stirring was halted and
the anion allowed to settle over 6 h. The bright yellow
supernatant was removed via cannula, the anion cooled to
2788C and resuspended in dry THF (100 mL). Copper(I)
iodide triethylphosphite complex (24.8 g, 70 mmol) was
8.1.4. 2-[2-(Ethoxymethoxy)-4-methylphenyl]acetic acid
(18). Prepared following the procedure of Jones et al.30
Thus, to a stirred solution of aldehyde 17 (3.00 g,

D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
797
14.4 mmol) in acetone (100 mL) was added Jones reagent
(9.0 mL, 57.7 mmol) over 20 min at ambient temperature.
Stirring was continued for a further 5 min after addition was
complete, then to the turquoise mixture was added water
(200 mL). The reaction mixture was extracted with ether
(5£20 mL) then the organic phases were combined, washed
with water (2£20 mL) then brine (20 mL), dried (MgSO4),
®ltered and concentrated in vacuo to a yellow oil (3.58 g).
Puri®cation by chromatography (silica, 50% ether in petrol)
gave 18 (2.32 g, 10.4 mmol, 72%) as a colourless oil; IR
(neat, cm21) nmax 3300±2900bs, 2978m, 1710s, 1616w,
1585w, 1510m, 1258m, 1154m, 1012s, 846w; UV (EtOH,
nm) lmax (emax) 276 (650); 1H NMR (300 MHz, CDCl3) dH
10.2 (1H, br. s, CO2H), 7.09 (1H, d, Jˆ7.5 Hz, ArH), 6.98
(1H, s, ArH), 6.81 (1H, d, Jˆ7.5 Hz, ArH), 5.28 (2H, s,
OCH2O), 3.72 (2H, q, Jˆ7.2 Hz, OCH2CH3), 3.63 (2H, s,
CH2COOH), 2.38 (3H, s, ArCH3), 1.25 (3H, t, Jˆ7.2 Hz,
CH3CH2); 13C NMR (75 MHz, CDCl3) dC 178.5 (CvO),
155.4 (C, Ar), 139.2 (C, Ar), 130.9 (CH, Ar), 122.5 (CH,
Ar), 120.0 (C, Ar), 114.9 (CH, Ar), 93.1 (OCH2O), 64.5
(CH2CH3), 35.8 (ArCH2), 21.7 (ArCH3), 15.2 (CH2CH3);
LRMS (CI) m/z 224 (M1, 80%), 165 ([M2C2H5OCH2]1,
100%); HRMS (CI) m/z Found MH1: 225.1125, C12H17O4
requires 225.1127.
yellow oil. Puri®cation by chromatography (silica, 10±20%
ether in petrol) gave 9 (325 mg, 2.20 mmol, 46%) as a
colourless solid.
8.1.6. 3,3,6-Trimethyl-2,3-dihydrobenzo[b]furan-2-one
(27).34 Following the procedure of Padwa et al.35 To a stirred
solution of N-isopropylcyclohexylamine (0.105 g, 0.12 mL,
0.74 mmol) and HMPA (0.24 g, 0.24 mL, 1.35 mmol) in
THF (10 mL) under nitrogen and with cooling to 2788C
was added tert-butyllithium (0.43 mL of a 1.7 M solution
in hexane, 0.74 mmol) over 1 min. The mixture was stirred
for 15 min, warmed to 08C over 30 min, then recooled to
2788C. A solution of lactone 9 (0.100 g, 0.68 mmol) in
THF (5 mL) was added dropwise over 1 min. After 4 h the
reaction mixture was warmed to ambient temperature over
30 min then partitioned between dichloromethane (10 mL)
and water (10 mL). The aqueous layer was extracted with
dichloromethane (3£5 mL) then the combined organic
phases were washed with water (10 mL) and brine
(10 mL), dried (MgSO4), ®ltered and concentrated in
vacuo to a yellow oil (0.57 g). Puri®cation by chromato-
graphy (silica, 0±5% ether in petrol) afforded 27 (0.052 g,
0.30 mmol, 43%) as a colourless oil; IR (neat, cm21) nmax
2974m, 2930m, 1808s, 1630m, 1596w, 1501m, 1143m,
1110m, 1033s, 950s, 819m; UV (MeOH, nm) lmax (emax
)
1
8.1.5. 6-Methyl-2,3-dihydrobenzo[b]furan-2-one (9).31±33
273 (1500); H NMR (300 MHz, CDCl3) dH 7.10 (1H, d,
Jˆ7.4 Hz, ArH), 6.97 (1H, d, Jˆ7.4 Hz, ArH), 6.95 (1H, s,
ArH), 2.38 (3H, s, ArCH3), 1.49 (6H, s, ArC(CH3)2); 13C
NMR (75 MHz, CDCl3) dC 181.5 (CvO), 152.4 (C, Ar),
139.1 (C, Ar), 130.8 (C, Ar), 125.0 (CH, Ar), 122.5 (CH,
Ar), 111.6 (CH, Ar), 42.9 (ArC(CH3)2), 25.5 (ArC(CH3)2),
21.8 (ArCH3); LRMS (APCI) m/z 177 (MH1, 5%), 176
(M1, 100%), 148 ([M2CO]1, 40%).
To
a
stirred solution of 2-[2-(ethoxymethoxy)-4-
methylphenyl]acetic acid 18 (0.150 g, 0.67 mmol) in
toluene (80 mL) was added pyridinium para-toluene-
sulfonate (20 mg, 0.08 mmol) and the mixture heated at
Ê
re¯ux under a soxhlet containing 3 A molecular sieves for
20 h. The reaction was cooled to ambient temperature and
the toluene removed in vacuo to give a brown oil (0.160 g).
Puri®cation by chromatography (silica, 10±20% ether in
petrol) afforded 9 as a colourless oil that crystallised upon
standing to a colourless solid. Recrystallisation from petro-
leum ether gave lactone 9 (50 mg, 0.34 mmol, 50%) as
colourless needles, mp 68±708C (petrol) [Lit. 738C;31 lit.
66±698C (hexane)];32 IR (CHCl3, cm21) nmax 2917w,
1796s, 1633m, 1504m, 1228m, 1203m, 1156m, 1064s,
8.1.7. Methyl 2-(2-methoxy-4-methylphenyl)propane-
thioate (28). To a stirred solution of thioester 23 (13.72 g,
65.0 mmol) in THF (150 mL) and TMEDA (14.8 mL,
98.0 mmol) at 2708C and under nitrogen was added tert-
butyllithium (43.0 mL of a 1.5 M solution in pentane,
65 mmol) over 30 min. After 5 min a solution of methyl
iodide (13.9 g, 6.1 mL, 98.0 mmol) in THF (15 mL) was
added over 15 min. After 2 h the reaction mixture was
warmed to ambient temperature. After 16 h, water
(75 mL) was added and the aqueous phase extracted with
ether (3£50 mL). The organic extracts were combined and
washed with saturated aqueous sodium thiosulfate (60 mL)
and brine (60 mL) then dried (MgSO4), ®ltered and concen-
trated in vacuo to a yellow oil (17.1 g). Puri®cation by chro-
matography (silica, 5% ether in petrol) gave 28 (14.0 g,
62.5 mmol, 96%) as a colourless oil; IR (neat, cm21) nmax
2974w, 1684s, 1612m, 1581w, 1505m, 1265m, 1040m,
1
950s, 840w; UV (MeOH, nm) lmax (emax) 273 (600); H
NMR (300 MHz, CDCl3) dH 7.16 (1H, d, Jˆ7.5 Hz, ArH),
6.95 (1H, d, Jˆ7.5 Hz, ArH), 6.95 (1H, s, ArH), 3.70 (2H, s,
ArCH2CO), 2.39 (3H, s, ArCH3); 13C NMR (75 MHz,
CDCl3) dC 174.7 (CvO), 154.9 (C, Ar), 139.5 (C, Ar),
124.9 (CH, Ar), 124.4 (CH, Ar), 120.0 (C, Ar), 111.5
(CH, Ar), 33.0 (ArCH2), 21.8 (ArCH3); LRMS (APCI)
m/z 149 (MH1, 5%), 148 (M1, 15%), 147 (60%), 109
(100%); Anal. Found: C, 72.86; H, 5.34; C9H8O2 requires
C, 72.96; H, 5.44.
1
Alternatively, to a stirred solution of thioester 23 (1.00 g,
4.76 mmol) in dichloromethane (25 mL) cooled to 08C and
under nitrogen was added boron trichloride (6.19 mL of a
1 M solution, 6.19 mmol) via syringe over 30 s. The reac-
tion mixture was stirred for 1 h then warmed to ambient
temperature and stirred for 2 h. Further boron trichloride
(6.19 mL of a 1 M solution, 6.19 mmol) was added and
stirring continued for 15 h. The reaction was then quenched
by the addition of water (10 mL) and extracted with
dichloromethane (3£20 mL). The combined organic phases
were washed with NaOH (2 M, 20 mL) and brine (10 mL)
then dried (MgSO4), ®ltered and concentrated in vacuo to a
940m, 814w; UV (MeOH, nm) lmax (emax) 280 (2500); H
NMR (300 MHz, CDCl3) dH 7.17 (1H, d, Jˆ7.7 Hz, ArH),
6.80 (1H, d, Jˆ7.7 Hz, ArH), 6.73 (1H, s, ArH), 4.28 (1H, q,
Jˆ7.0 Hz, ArCH), 3.84 (3H, s, OCH3), 2.37 (3H, s, ArCH3),
2.24 (3H, s, SCH3), 1.50 (3H, d, Jˆ7.0 Hz, CH3); 13C NMR
(75 MHz, CDCl3) dC 202.8 (CvO), 157.1 (C, Ar), 139.9 (C,
Ar), 128.3 (CH, Ar), 125.6 (C, Ar), 121.5 (CH, Ar), 111.9
(CH, Ar), 55.6 (OCH3), 46.9 (ArCH), 21.8 (ArCH3), 17.4
(CHCH3), 11.9 (SCH3); LRMS m/z (APCI) 150
([M2CH3SCO1H]1, 10%), 149 ([M2CH3SCO]1,
100%); HRMS (CI) m/z Found [M1NH4]1: 242.1213,
C12H20NO2S requires 242.1215.

798
D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
8.1.8. 2,2-Dimethyl-4-[4-methyl-2-(methyloxy)phenyl]-3-
pentanone (29). To a stirred solution of the thioester 28
(0.150 g, 0.67 mmol) in THF (5 mL) cooled to 2788C and
under nitrogen was added tert-butyllithium (0.39 mL of a
1.7 M solution in pentane, 0.67 mmol) over 1 min. After
90 s. The reaction mixture was stirred for 10 min then
4-iodo-1-butene (2.60 g, 14.2 mmol) in THF (5 mL) was
added dropwise via syringe over 90 s. After 1 h the reaction
mixture was warmed to ambient temperature and stirred for
a further 8 h. Water (20 mL) and ether (20 mL) were added
then the aqueous phase extracted with ether (3£20 mL). The
combined organic extracts were washed with saturated
sodium thiosulfate (20 mL) then brine (20 mL), dried
(MgSO4), ®ltered and concentrated in vacuo to a yellow
oil (3.10 g). Puri®cation by column chromatography (silica,
0±3% ether in petrol) gave 31 (1.42 g, 5.40 mmol, 54%) as a
colourless oil; IR (neat, cm21) nmax 3075w, 2929m, 2863w,
1688s, 1640w, 1612w, 1582w, 1506m, 1266m, 1040m,
15 min,
4-bromo-1-butene
(0.095 g,
0.070 mL,
0.70 mmol) was added over 1 min. After 2 h, the mixture
was warmed to ambient temperature over 2 h. After 14 h,
water (5 mL) was added and the mixture extracted with
ether (3£5 mL). The combined organic extracts were
washed with water (5 mL) and brine (5 mL) then dried
(MgSO4), ®ltered and concentrated in vacuo to a yellow
oil (0.45 g). Puri®cation by chromatography (silica, 0 to
10% ether in petrol) gave 29 (0.112 g, 0.48 mmol, 71%)
as a colourless oil; IR (neat, cm21) nmax 2869m, 1702s,
1612m, 1581m, 1506s, 1263s, 1191m, 1042s, 926w,
1
795w; UV (MeOH, nm) lmax (emax) 280 (2600); H NMR
(300 MHz, CDCl3) dH 7.16 (1H, d, Jˆ7.7 Hz, ArH), 6.78
(1H, br. d, Jˆ7.7 Hz, ArH), 6.72 (1H, s, ArH), 5.80 (1H,
ddt, Jˆ16.8, 10.3, 6.4 Hz, vCH), 5.02 (1H, dd, Jˆ16.8,
1.7 Hz, vCHH), 4.97 (1H, br. d, Jˆ10.3 Hz, vCHH),
4.25 (1H, t, Jˆ7.4 Hz, ArCH), 3.83 (3H, s, OCH3), 2.36
(3H, s, ArCH3), 2.23 (3H, s, SCH3), 2.27±2.14 (1H, m,
CHHCH2CHv), 2.02 (2H, app. q, Jˆ7.0 Hz, CH2CHv),
1.94±1.80 (1H, m, CHHCH2CHv); 13C NMR (75 MHz,
CDCl3) dC 201.8 (CvO), 157.3 (C, Ar), 138.8 (C, Ar),
138.1 (vCH), 128.6 (CH, Ar), 124.0 (C, Ar), 121.6 (CH,
Ar), 115.2 (vCH2), 112.0 (CH, Ar), 55.7 (OCH3), 51.5
(ArCH), 31.6 (CH2), 31.4 (CH2), 21.8 (ArCH3), 11.9
(SCH3); LRMS (APCI) m/z 265 (MH1, 20%), 189
([M2CH3SCO]1, 20%), 101 (100%); HRMS (CI) m/z
Found M1: 264.1182, C15H20O2S requires 264.1184.
1
816m; UV (MeOH, nm) lmax (emax) 279 (3500); H NMR
(300 MHz, CDCl3) dH 7.09 (1H, d, Jˆ7.4 Hz, ArH), 6.73
(1H, d, Jˆ7.4 Hz, ArH), 6.68 (1H, s, ArH), 4.72 (1H, q,
Jˆ6.9 Hz, ArCH), 3.86 (3H, s, OCH3), 2.34 (3H, s,
ArCH3), 1.28 (3H, d, Jˆ6.9 Hz, CHCH3), 1.05 (9H, s,
C(CH3)3); 13C NMR (75 MHz, CDCl3) dC 217.4 (CvO),
155.8 (C, Ar), 137.8 (C, Ar), 127.8 (CH, Ar), 126.8 (C,
Ar), 121.5 (CH, Ar), 111.6 (CH, Ar), 55.5 (OCH3), 44.9
(C(CH3)3), 37.9 (ArCH), 26.8 (C(CH3)3), 21.6 (ArCH3),
19.6 (CHCH3); LRMS (CI) m/z 235 (MH1, 6%), 149
([M2C4H9CO]1, 100%); HRMS (CI) m/z Found
[M1NH4]1: 252.1963, C15H26NO2 requires 252.1964;
8.1.9. 3,6-Dimethyl-2,3-dihydrobenzo[b]furan-2-one (30).
To a stirred solution of thioester 28 (14.5 g, 64.7 mmol) in
dichloromethane (250 mL) at 08C and under nitrogen was
added boron trichloride (77.6 mL of a 1.0 M solution in hep-
tane, 77.6 mmol) dropwise over 5 min. After 30 min at 08C
the reaction mixture was warmed to ambient temperature and
water (100 mL) added. The phases were separated and the
aqueous phase was extracted with ether (3£50 mL). The
combined organic extracts were washed with 1 M HCl
(2£30 mL), 1 M NaOH (50 mL), water (50 mL) and brine
(50 mL) then dried (MgSO4), ®ltered and concentrated in
vacuo to a colourless oil (9.80 g). Puri®cation by chromato-
graphy (silica, 0 to 5% ether in petrol) gave 30 (7.37 g,
45.5 mmol, 71%) as a colourless oil which crystallised on
standing to a colourless solid. Recrystallisation from
petroleum ether gave large cubic crystals, mp 35±378C
(petrol); IR (neat, cm21) nmax 2978w, 2932w, 1804vs,
1630m, 1594w, 1499w, 1452w, 1425m, 1258m, 1095s,
8.1.11. 3-(3-Butenyl)-6-methyl-2,3-dihydrobenzo[b]furan-
2-one (32). To a stirred solution of thioester 31 (0.34 g,
1.29 mmol) in dichloromethane (10 mL) cooled to 08C
and under nitrogen was added boron trichloride (1.55 mL
of a 1 M solution, 1.55 mmol) via syringe over 30 s. The
reaction mixture was stirred for 1 h then warmed to ambient
temperature and stirred for 2 h. Water (5 mL) was added
then the aqueous phase was extracted with ether
(3£10 mL). The combined organic phases were washed
with dilute HCl (2 M, 10 mL), NaOH (2 M, 10 mL), water
(10 mL) and brine (10 mL) then dried (MgSO4), ®ltered and
concentrated in vacuo to a yellow oil (0.35 g). Puri®cation
by chromatography (silica, 0±5% ether in petrol) gave 32
(0.21 g, 1.04 mmol, 81%) as a colourless oil; IR (neat,
cm21) nmax 3078w, 2978w, 2925w, 1802s, 1630m, 1594w,
1500m, 1260m, 1065s, 947m; UV (MeOH, nm) lmax (emax
)
1
272 (2000); H NMR (300 MHz, CDCl3) dH 7.15 (1H, d,
Jˆ7.5 Hz, ArH), 6.96 (1H, d, Jˆ7.5 Hz, ArH), 6.92 (1H, s,
ArH), 5.79 (1H, ddt, Jˆ17.1, 10.1, 6.6 Hz, vCH), 5.04 (1H,
dd, Jˆ17.1, 1.5 Hz, vCHH), 5.01 (1H, br. d, Jˆ10.1 Hz,
vCHH), 3.70 (1H, app. t, Jˆ6.5 Hz, ArCH), 2.38 (3H, s,
ArCH3), 2.26±2.14 (2H, m, CH2CH2), 2.14±1.98 (2H, m,
CH2CH2); 13C NMR (75 MHz, CDCl3) dC 177.7 (CvO),
154.0 (C, Ar), 139.4 (C, Ar), 136.9 (CH, Ar) 136.9
(vCH), 124.9 (CH, Ar), 124.3 (C, Ar), 124.0 (CH, Ar),
116.3 (vCH2), 42.6 (ArCH), 30.5 (CH2), 30.1 (CH2), 21.8
(ArCH3); LRMS (CI) m/z 243 ([M1CH3CN]1, 20%), 203
(MH1, 50%), 202 (M1, 40%), 101 (100%); HRMS (CI) m/z
Found M1: 202.0986, C13H14O2 requires 202.0994.
1
1027s, 941s; UV (MeOH, nm) lmax (emax) 274 (1800); H
NMR (300 MHz, CDCl3) dH 7.13 (1H, d, Jˆ7.5 Hz, ArH),
6.96 (1H, d, Jˆ7.5 Hz, ArH), 6.92 (1H, s, ArH), 3.69 (1H, q,
Jˆ7.5 Hz, ArCH), 2.39 (3H, s, ArCH3), 1.56 (3H, d,
Jˆ7.5 Hz, CHCH3); 13C NMR (75 MHz, CDCl3) dC 178.6
(CvO), 153.7 (C, Ar), 139.4 (C, Ar), 125.9 (C, Ar), 124.9
(CH, Ar), 123.6 (CH, Ar), 111.5 (CH, Ar), 38.4 (ArCH), 21.8
(ArCH3), 16.2 (CHCH3); LRMS (CI) m/z 180 ([M1NH4]1,
100%), 162 (M1, 24%), 134 (20%); Anal. Found: C, 74.33;
H, 6.19; C10H10O2 requires C, 74.06; H, 6.21.
8.1.10. Methyl 2-[4-methyl-2-(methyloxy)phenyl]-5-
hexenethioate (31). To a stirred solution of the thioester
23 (2.10 g, 10.0 mmol) in THF (10 mL) cooled to 2788C
and under nitrogen was added tert-butyllithium (7.70 mL of
a 1.3 M solution in pentane, 10.0 mmol) via syringe over
8.1.12. 3-(3-Butenyl)-3,6-dimethyl-2,3-dihydrobenzo[b]-
furan-2-one (10). Prepared following the procedure of
Padwa et al.35 Thus, to a stirred solution of N-isopropyl-

D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
799
cyclohexylamine (3.40 mL, 15.8 mmol) in THF (30 mL)
and HMPA (4.9 mL, 28.3 mmol) at 2788C and under nitro-
gen was added sec-butyllithium (13.9 mL of a 1.14 M solu-
tion in cyclohexane, 15.8 mmol) over 30 s. After 10 min the
mixture was warmed to 08C (over 30 min) then recooled to
2788C. Lactone 30 (1.83 g, 11.3 mmol) in THF (10 mL)
was added via syringe over 30 s. After 10 min a solution
of the 1-iodo-3-butene (4.10 g, 22.5 mmol) in THF (10 mL)
was added over 30 s. After 12 h the reaction mixture was
warmed to ambient temperature and stirred for 12 h. Water
(15 mL) and ether (15 mL) was added and the phases sepa-
rated. The aqueous phase was extracted with ether
(3£15 mL) then the combined organic extracts were washed
with saturated aqueous sodium thiosulfate solution (20 mL)
and brine (20 mL), then dried (MgSO4), ®ltered and concen-
trated in vacuo to a yellow oil. Puri®cation by chromato-
graphy (silica, petrol then 5% ether in petrol) gave 10
(2.25 g, 10.4 mmol, 92%) as a colourless oil; IR (neat,
cm21) nmax 3079w, 2929m, 1806vs, 1633m, 1596w,
1500m, 1453m, 1259m, 1029s, 948s, 815m; UV (MeOH,
nm) lmax (emax) 274 (1450); 1H NMR (300 MHz, CDCl3) dH
7.07 (1H, d, Jˆ7.6 Hz, ArH), 6.98 (1H, br. d, Jˆ7.6 Hz,
ArH), 6.94 (1H, s, ArH), 5.63 (1H, ddt, Jˆ17.3, 9.6,
6.6 Hz, CHv), 4.94±4.84 (2H, m, vCH2), 2.39 (3H, s,
ArCH3), 2.11±1.72 (4H, m, CH2CH2), 1.48 (3H, s, CH3);
13C NMR (75 MHz, CDCl3) dC 180.9 (CvO), 153.0 (C,
Ar), 139.2 (C, Ar), 137.0 (vCH), 128.7 (C, Ar), 125.1
(CH, Ar), 122.8 (CH, Ar), 115.5 (vCH2), 111.5 (CH, Ar),
47.2 (ArC), 38.2 (CH2), 29.3 (CH2), 24.8 (CCH3), 21.8
(ArCH3); LRMS (APCI) m/z 258 ([MH1CH3CN]1, 20%),
217 (MH1, 100%), 216 (M1, 40%), 111 (20%), 101 (75%);
HRMS (EI) m/z Found: M1, 216.1151, C14H16O2 requires
216.1150.
After 30 min the mixture was warmed to ambient tempera-
ture and stirred for a further 20 h. THF (10 mL) was added
and the mixture cooled to 08C. Sodium hydroxide (1.15 g,
28.8 mmol) in water (3 mL) was added dropwise then the
reaction mixture was ®ltered through a pad of celite. The
celite was washed with ether (3£20 mL) and the combined
®ltrates dried (MgSO4), ®ltered and concentrated in vacuo
to a cloudy yellow oil (1.05 g). Puri®cation by chromato-
graphy (silica, 0 to 1% ether in petrol) ®rstly gave diene 12
(0.43 g, 2.01 mmol, 54%) as a colourless oil; IR (neat,
cm21) nmax 3072w, 2864m, 1685s, 1640m, 1618s, 1595m,
1140s, 960s, 911w, 809m; UV (MeOH, nm) lmax (emax) 283
1
(3050), 235 (10100); H NMR (300 MHz, C6D6) dH 6.75±
6.68 (2H, m, 2£ArH), 6.64 (1H, d, Jˆ7.7 Hz, ArH), 5.64
(1H, ddt, Jˆ16.5, 10.7, 6.1 Hz, vCH), 4.94±4.84 (2H, m,
CHvCH2), 4.82 (1H, d, Jˆ2.4 Hz, vCHH), 4.04 (1H, d,
Jˆ2.4 Hz, vCHH), 2.05 (3H, s, ArCH3), 1.78±1.50 (3H,
m), 1.40±1.25 (1H, m), 1.23 (3H, s, CH3); 13C NMR
(75 MHz, C6D6) dC 170.8 (vC), 157.4 (C, Ar), 138.4 (C,
Ar), 138.3 (vCH), 130.7 (C, Ar), 122.9 (CH, Ar), 122.5
(CH, Ar), 114.3 (CH2vCH), 110.2 (CH, Ar), 82.9
(CvCH2), 47.5 (ArC), 42.5 (CH2CHv), 29.6 (CCH2),
29.2 (CCH3), 21.3 (ArCH3); LRMS (APCI) m/z 230
([M1H2O]1, 10%), 215 (MH1, 50%), 214 (M1, 100%),
126 (10%), 111 (25%), 85 (15%); HRMS (EI) m/z Found
M1: 214.1347, C15H18O requires 214.1358; then recovered
10 (0.22 g, 1.02 mmol, 28%).
8.1.14. 3,6-Dimethyl-3-(3-methylbutenyl)-2-methylene-
2,3-dihydrobenzo[b]furan (33). Prepared following a
modi®ed procedure of Cannizzo and Grubbs.36 Thus,
trimethylaluminium (27.8 mL of a 2 M solution in heptane,
55.5 mmol) was added via syringe to titanocene dichloride
(6.92 g, 27.8 mmol) and toluene (10 mL) under argon and at
ambient temperature. After 24 h the mixture was cooled to
2788C and to it was added a solution of lactone 10 (1.20 g,
5.56 mmol) in THF (10 mL) over 5 min. After 30 min the
mixture was warmed to ambient temperature. After 24 h the
mixture was cooled to 08C and sodium hydroxide (2.2 g,
55.5 mmol) in water (5 mL) was carefully added. The
mixture was dried (MgSO4) then ®ltered through a pad of
celite. The cake was washed thoroughly with ether
(3£50 mL) then the ®ltrate was concentrated in vacuo to a
red residue. Puri®cation by chromatography (silica, petrol)
gave 33 (1.00 g, 4.39 mmol, 79%) as a colourless oil; IR
(neat, cm21) nmax 2956m, 2925m, 2868w, 1684m, 1618m,
1595m, 1498m, 1325w, 1141s, 958s, 806s; UV (MeOH,
Alternatively, to a stirred solution of N-isopropylcyclo-
hexylamine (0.70 mL, 4.27 mmol) in THF (15 mL) and
HMPA (1.29 mL, 7.42 mmol) at 2788C and under nitrogen
was added sec-butyllithium (3.0 mL of a 1.4 M solution in
cyclohexane, 4.26 mmol). After 10 min the mixture was
warmed to 08C then recooled to 2788C. Lactone 32
(0.75 g, 3.71 mmol) in THF (10 mL) was added via syringe
over 4 min. After 15 min a solution of methyl iodide
(0.79 g, 0.35 mL, 5.57 mmol) in THF (5 mL) was added
over 2 min. After 30 min the reaction mixture was warmed
to ambient temperature and stirred for 1 h. Water (10 mL)
and ether (10 mL) was added and the phases separated. The
aqueous phase was extracted with ether (3£15 mL) then the
combined organic extracts were washed with saturated
aqueous sodium thiosulfate solution (20 mL) and brine
(20 mL), then dried (MgSO4), ®ltered and concentrated in
vacuo to a yellow oil (1.9 g). Puri®cation by chromato-
graphy (silica, 0 to 2% ether in petrol) gave 10 (0.67 g,
3.10 mmol, 84%) as a colourless oil.
1
nm) lmax (emax) 283 (2650); H NMR (400 MHz, CDCl3)
dH 7.08 (1H, d, Jˆ7.5 Hz, ArH), 6.91 (1H, d, Jˆ7.5 Hz,
ArH), 6.84 (1H, s, ArH), 4.79 (1H, d, Jˆ2.6 Hz, vCHH),
4.26 (1H, d, Jˆ2.6 Hz, vCHH), 2.47 (3H, s, ArCH3), 1.86
(1H, app. td, Jˆ12.8, 4.4 Hz, CHHCH2), 1.71 (1H, app. td,
Jˆ12.8, 4.4 Hz, CHHCH2), 1.55±1.50 (1H, m, CH(CH3)2),
1.52 (3H, s, CH3), 1.21 (1H, tdd, Jˆ12.8, 6.8, 4.4 Hz,
CHHCH(CH3)2), 0.93 (3H, d, Jˆ7.1 Hz, CH(CH3)2), 0.91
(3H, d, Jˆ6.8 Hz, CH(CH3)2), 0.86 (1H, tdd, Jˆ12.8, 6.8,
4.4 Hz, CHHCH(CH3)2); 13C NMR (75 MHz, CDCl3) dC
171.0 (vC), 156.9 (C, Ar), 138.3 (C, Ar), 131.0 (C, Ar),
122.7 (CH, Ar), 122.5 (CH, Ar), 110.0 (CH, Ar), 82.6
(vCH2), 47.6 (ArC), 41.1 (CH2), 33.8 (CH2), 29.7
(CH3C), 28.3 (CH(CH3)2), 22.7 (CH(CH3)), 22.6
(CH(CH3)), 21.7 (ArCH3); LRMS (APCI) m/z 231 (MH1,
70%), 230 (M1, 90%), 165 (50%), 111 (100%); HRMS
8.1.13. 3-(3-Butenyl)-3,6-dimethyl-2-methylene-2,3-dihydro-
benzo[b]furan (12). Prepared following the procedure of
Cannizzo and Grubbs.36 Thus, trimethylaluminium
(14.4 mL of a 2 M solution in heptane, 28.8 mmol) was
added via syringe to titanocene dichloride (2.56 g,
10.28 mmol) and the mixture stirred at ambient temperature
for 24 h. The mixture was cooled to 2788C then THF
(10 mL) added followed by a solution of lactone 10
(0.80 g, 3.70 mmol) in THF (10 mL) dropwise over 5 min.

800
D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
(EI) m/z Found MH1: 231.1754, C16H23O requires
231.1749.
(2H, m), 1.50±1.18 (15H, m), 1.32 (3H, s, CH3), 1.11 (3H, d,
Jˆ6.6 Hz, CHCH3), 0.88 (9H, app. t, Jˆ7.2 Hz, 3£CH3),
0.73 (6H, m, 3£SnCH2); 13C NMR (75 MHz, CDCl3) dC
159.1 (C, Ar), 137.8 (C, Ar), 133.7 (C, Ar), 122.6 (CH,
Ar), 120.6 (CH, Ar), 109.4 (CH, Ar), 102.4 (OC), 54.9
(ArC), 49.0 (CHCH3), 43.0 (CH2), 31.4 (CH2), 29.3
(3£SnCH2CH2, [residual Jˆ117/119Sn213C 20 Hz]), 27.6 (3£
SnCH2CH2CH2, [residual Jˆ117/119Sn213C 58 Hz]), 24.1
(CCH3), 21.6 (ArCH3), 17.4 (SnCH2C), 13.9 (CHCH3),
13.8 (3£SnCH2CH2CH2CH3), 10.6 (3£SnCH2, [residual
Jˆ119Sn213C 325 Hz, residual Jˆ117Sn213C 311 Hz]);
LRMS (APCI) m/z 449 ([M2C4H9]1, 100%), 447 (90%),
445 (40%), 341 ([M2(C4H9)3]1, 5%), 276 (40%), 274
(35%), 272 (15%), 220 ([M2Sn(C4H9)3]1, 35%), 218
(35%), 216 (25%); HRMS (EI) m/z Found MH1:
507.2642, C27H47OSn requires 507.2649.
8.1.15. rel-(3S,3aS,8bS)-(3,6,8b-Trimethyl-2,3,3a,8b-tetra-
hydro-1H-benzo[b]cyclopenta[d]furan-3-yl)methyl (tert-
butyl) sul®de (35). A stirred solution of diene 12 (0.40 g,
1.87 mmol) and di-tert-butyl disul®de (1.67 g, 1.81 mL,
9.35 mmol) in degassed hexane (100 mL) was irradiated
with UV light (Quartz ®lter). Triethylborane (1.0 mL of a
1 M solution in hexanes, 1 mmol) was added via syringe.
After 16 h, saturated ammonium chloride (20 mL) was
added and the phases separated. The aqueous phase was
extracted with ether (3£15 mL) then the organic phases
were combined and washed with brine (20 mL), dried
(MgSO4), ®ltered and concentrated in vacuo to an orange
oil (2.15 g). Puri®cation by chromatography (silica, 0 to 2%
ether in petrol) gave 35 (0.34 g, 1.12 mmol, 61%) as a
yellow oil which was determined by NMR to be a 8:1
mixture of diastereomers. Further puri®cation by chromato-
graphy (silica, 5 to 10% dichloromethane in petrol) gave
®rstly a mixture of cis and trans isomers 35 and 36 then
pure 35 as a colourless oil; IR (neat, cm21) nmax 2955s,
2862m, 1620w, 1593s, 1499s, 1320w, 1280s, 1160m,
8.1.17. 2-[rel-(1R,3S)-1,3-Dimethyl-2-methylenecyclo-
pentyl]-5-methylphenol ((^)-debromoisolaurinterol) (8).
Stannane 42 (0.100 g, 0.198 mmol) in toluene (5 mL) was
heated at re¯ux under nitrogen for 18 h. The mixture was
concentrated in vacuo then puri®ed by chromatography
(silica, petroleum ether then 5% ether in petroleum ether)
to give ®rstly recovered starting material 42 (12 mg,
0.002 mmol, 12%) as a colourless oil then (^)-debromoiso-
laurinterol 8 (35 mg, 0.163 mmol, 82%) as a colourless oil;
IR (neat, cm21) nmax 3453bs, 3069w, 3026w, 2978m, 2958s,
2870m, 1641w, 1622w, 1570w, 1503m, 1372m, 1291m,
1137m, 805s; UV (MeOH, nm) lmax (emax) 270 (10100);
1H NMR (300 MHz, CDCl3) dH 7.22 (1H, d, Jˆ8.4 Hz,
ArH), 6.74 (1H, dd, Jˆ8.4, 1.2 Hz, ArH), 6.68 (1H, d,
Jˆ1.2 Hz, ArH), 5.59 (1H, s, ArOH), 5.11 (1H, d,
Jˆ2.0 Hz, vCHH), 4.97 (1H, d, Jˆ2.0 Hz, vCHH), 2.86
(1H, dtt, Jˆ9.1, 7.0, 2.2 Hz, CHCH3), 2.30 (3H, s, ArCH3),
2.25 (1H, ddd, Jˆ12.9, 8.0, 6.6 Hz, CHHCH2CH), 2.06 (1H,
dddd, Jˆ12.9, 8.8, 7.2, 6.6 Hz, CHHCH), 1.60 (1H, dt,
Jˆ12.9, 7.1 Hz, CHHCH2CH), 1.48 (3H, s, CH3), 1.40±
1.30 (1H, m), 1.22 (3H, d, Jˆ7.0 Hz, CHCH3); 13C NMR
(75 MHz, CDCl3) dC 165.8 (vC), 153.9 (C, Ar), 138.0 (C,
Ar), 130.2 (C, Ar), 127.9 (CH, Ar), 121.6 (CH, Ar), 119.0
(CH, Ar), 106.8 (vCH2), 50.1 (ArC), 39.5 (CH2), 38.0
(CHCH3), 31.5 (CH2), 28.1 (CH3C), 21.3 (ArCH3), 20.9
(CH3CH); LRMS (APCI) m/z 217 (MH1, 15%), 216 (M1,
30%), 163 (15%), 146 (40%), 105 (100%); HRMS (EI) m/z
Found M1: 216.1504, C15H20O requires 216.1514. The spec-
tral characteristics were consistent with literature values.6,23
1
948s, 852w; UV (MeOH, nm) lmax (emax) 284 (4000); H
NMR (300 MHz, CDCl3) dH 6.91 (1H, d, Jˆ7.4 Hz, ArH),
6.67 (1H, d, Jˆ7.4 Hz, ArH), 6.58 (1H, s, ArH), 2.99 (1H, d,
Jˆ12.2 Hz, SCHH), 2.87 (1H, d, Jˆ12.2 Hz, SCHH), 2.30
(3H, s, ArCH3), 2.17 (1H, m, CHCH3), 1.87 (1H, app. dd,
Jˆ11.2, 7.1 Hz), 1.72±1.58 (3H, m), 1.51 (3H, s, CH3), 1.34
(9H, app. s, C(CH3)3), 1.14 (3H, d, Jˆ6.8 Hz, CH3); 13C
NMR (75 MHz, CDCl3) dC 159.0 (C, Ar), 137.9 (C, Ar),
133.4 (C, Ar), 122.2 (CH, Ar), 121.0 (CH, Ar), 109.2 (CH,
Ar), 99.2 (OC), 55.4 (ArC), 43.8 (CHCH3), 42.4 (CH2), 42.2
(CCH3), 32.8 (CH2), 31.5 (CH2), 30.7 (C(CH3)3), 23.6
(CCH3), 21.5 (ArCH3), 13.8 (CHCH3); LRMS (CI) m/z
305 (MH1, 60%), 304 (M1, 40%), 249 ([M2C4H7]1,
70%), 83 (100%); HRMS (EI) m/z Found M1, 304.1858,
C19H28OS requires 304.1861. A pure sample of the cis
1
isomer could not obtained. Spectral peaks in a H NMR
spectra of an enriched sample that were attributed to 36
follow: dH (300 MHz, CDCl3) 6.91 (1H, d, Jˆ7.4 Hz,
ArH), 6.68 (1H, d, Jˆ7.4 Hz, ArH), 6.57 (1H, s, ArH),
3.34 (1H, d, Jˆ13.2 Hz, SHH), 3.19 (1H, d, Jˆ13.2 Hz,
SHH), 2.29 (3H, s, ArCH3), 2.13 (1H, app. dq, Jˆ13.2,
6.6 Hz, CHCH3), 1.87 (1H, app. dd, Jˆ11.4, 6.1 Hz),
1.71±1.58 (3H, m), 1.49 (3H, s, CH3), 1.35 (9H, app. s,
C(CH3)3), 1.16 (3H, d, Jˆ6.8 Hz, CHCH3).
Alternatively, a solution of diene 12 (100 mg, 0.47 mmol),
tributyltin hydride (270 mg, 0.25 mL, 0.93 mmol) and
AIBN (38 mg, 0.23 mmol) in toluene (10 mL) was heated
at re¯ux under nitrogen for 18 h. The mixture was then
cooled to ambient temperature and concentrated in vacuo
to a colourless oil. Puri®cation by chromatography (silica,
5% ether in petroleum ether) gave (^)-debromoisolaurin-
terol 8 (17 mg, 0.079 mmol, 28%) as a colourless oil; and
then a mixture of (^)-debromoisolaurinterol 8 and (^)-
epidebromoisolaurinterol (2-[rel-(1R,3S)-1,3-dimethyl-2-
methylenecyclopentyl]-5-methylphenol) (80 mg, 0.37
mmol, 79%) as a 5:1 mixture of diastereoisomers. Signals
in the NMR spectrum attributed to (^)-epidebromoiso-
8.1.16.
rel-(3S,3aS,8bS)-[(3,6,8b-Trimethyl-2,3,3a,8b-
tetrahydro-1H-benzo[b]cyclopenta[d]furan-3-yl)methyl]-
(tributyl)stannane (42). A mixture of diene 12 (0.50 g,
2.34 mmol), tri-n-butyltin hydride (1.36 g, 1.24 mL,
4.67 mmol) and AIBN (0.19 g, 1.17 mmol) in degassed
hexane (110 mL) was irradiated with UV (Quartz ®lter) at
158C and under nitrogen. After 20 h the solvents were
removed in vacuo and the residue puri®ed by chromato-
graphy (silica, petrol) to give 42 (0.815 g, 1.61 mmol,
69%) as a colourless oil; IR (neat, cm21) nmax 2953s,
2924s, 2866m, 1619w, 1592m, 1499s, 1456s, 1269s,
1125s, 1068s, 945s, 801s; UV (MeOH, nm) lmax (emax
)
1
1
286 (3800); H NMR (300 MHz, CDCl3) dH 6.88 (1H, d,
Jˆ7.5 Hz, ArH), 6.62 (1H, d, Jˆ7.5 Hz, ArH), 6.45 (1H, s,
ArH), 2.28 (3H, s, ArCH3), 1.90±1.75 (2H, m), 1.70±1.55
laurinterol follow: H NMR (300 MHz, CDCl3) dH 7.29
(1H, obsc. d, ArH), 5.65 (1H, s, ArOH), 5.12 (1H, d,
Jˆ2.0 Hz, vCHH), 5.02 (1H, d, Jˆ2.0 Hz, vCHH), 1.46

D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
801
(3H, s, CH3), 1.23 (3H, d, Jˆ7.0 Hz, CHCH3); 13C NMR
(75 MHz, CDCl3) dC 165.5 (vC), 131.0 (C, Ar), 127.4 (CH,
Ar), 118.8 (CH, Ar), 106.2 (vCH2), 49.7 (ArC), 39.7 (CH2),
38.7 (CHCH3), 32.3 (CH2), 27.4 (CH3), 20.0 (CHCH3) with
other signals being obscured by 8.
Ar), 126.7 (CH, Ar), 114.1 (C, Ar), 111.0 (CH, Ar), 100.0
(OC), 54.5 (ArC), 46.2 (CH), 42.7 (CH2), 31.3 (CH2), 23.5
(CH3), 23.3 (CH3), 20.1 (CCH3), 13.2 (CHCH3); LRMS (CI)
m/z 296 ([M(81Br)]1, 70%), 294 ([M(79Br)]1, 100%), 100
(50%); HRMS (EI) m/z Found M1: 294.0616, C15H19BrO
requires 294.0619. These spectral and physical characteristics
were consistent with literature values.1
8.1.18. rel-(3S,3aS,8bS)-3,3a,6,8b-Tetramethyl-2,3,3a,
8b-tetrahydro-1H-benzo[b]cyclopenta[d]furan ((^)-de-
bromoaplysin) (2).8,10 Prepared following the procedure
of Pettit and van Temelen.37 Thus, to a suspension of
Raney nickel (ca. 1 g, 17 mmol) in ethanol (4 mL) was
added a solution of sul®de 35 (42 mg, 0.14 mmol) in ethanol
(2 mL) and the mixture heated at re¯ux. After 40 h the
mixture was cooled and ®ltered through a pad of Celite.
The Celite was extracted with chloroform (80 mL) using a
Soxhlet apparatus. The combined organic phases were
concentrated in vacuo to a colourless oil (29 mg). Puri®ca-
tion by chromatography (silica, 5 to 10% dichloromethane
in petrol) gave (^)-debromoaplysin 2 (23 mg, 0.11 mmol,
77%) as a colourless oil; IR (neat, cm21) nmax 2954s,
2866m, 1619w, 1593m, 1499s, 1280s, 1123m, 1009m,
8.1.20. rel-(3S,3aS,8bS)-3,6,8b-Trimethyl-2,3,3a,8b-tetra-
hydro-1H-benzo[b]cyclopenta[d]furan-3-yl]methanol ((^)-
debromoaplysinol) (5).8 To a stirred solution of debromo-
isolaurinterol 8 (110 mg, 0.51 mmol) in dichloromethane
(4 mL) at 08C and under argon was added m-CPBA
(105 mg, 0.61 mmol). After 24 h, the solution was diluted
with dichloromethane (20 mL), washed with sodium thio-
sulfate (20 mL) and sodium hydrogen carbonate (20 mL),
then dried (MgSO4), ®ltered and concentrated in vacuo to a
yellow gum (90 mg). Puri®cation by chromatography
(silica, petrol then 5% ether in petrol) gave ®rstly recovered
8 (11 mg, 0.05 mmol, 10%) as a colourless oil, secondly
2-[rel-(4S,7S)-4,7-dimethyl-1-oxaspiro[2.4]hept-4-yl]-5-
methylphenol 45 (14 mg, 0.06 mmol, 12%) as a colourless
oil; IR (neat, cm21) nmax 3417s, 3268s, 2964s, 1730m,
1621m, 1503s, 1290s, 1121w, 933m, 803s; 1H NMR
(300 MHz, CDCl3) dH 7.71 (1H, s, ArOH), 7.08 (1H, d,
Jˆ7.8 Hz, ArH), 6.72 (1H, br. s, ArH), 6.67 (1H, br. d,
Jˆ7.8 Hz, ArH), 2.93 (1H, d, Jˆ4.3 Hz, OCHH), 2.73
(1H, d, Jˆ4.3 Hz, OCHH), 2.61 (1H, m), 2.34 (1H, m,
CHCH3), 2.23 (3H, s, ArCH3), 2.14±2.04 (1H, m), 1.68±
1.58 (1H, m), 1.31 (3H, s, CH3), 0.93±0.71 (1H, m), 0.74
(3H, d, Jˆ7.0 Hz, CHCH3); 13C NMR (75 MHz, CDCl3) dC
158.8 (C, Ar), 138.4 (C, Ar), 127.1 (C, Ar), 127.0 (CH, Ar),
121.4 (CH, Ar), 120.5 (CH, Ar), 73.6 (CO), 51.5 (CH2O),
46.1 (ArC), 36.3 (CH2), 35.2 (CHCH3), 30.0 (CH2), 24.8
(CH3), 20.7 (ArCH3), 15.8 (CH3CH); LRMS (CI) m/z 232
(M1, 90%), 201 (58%), 159 (100%); HRMS (CI) m/z Found
[M1NH4]1: 250.1806, C15H24NO2 requires 250.1807; and
®nally (^)-debromoaplysinol 5 (57 mg, 0.26 mmol, 52%)
as a yellow solid which, after recrystallisation from hexane
was furnished as a white powder; mp 103±1058C (hexane)
[Lit. 79±808C (petrol)];8 IR (solid, cm21) nmax 3427m,
2947s, 2867m, 1620w, 1593s, 1500s, 1455s, 1268s,
1044m, 999s, 854m; UV (MeOH, nm) lmax (emax) 284
(2600); 1H NMR (300 MHz, CDCl3) dH 6.93 (1H, d,
Jˆ7.5 Hz, ArH), 6.70 (1H, br. d, Jˆ7.5 Hz, ArH), 6.60
(1H, br. s, ArH), 3.87 (1H, dd, Jˆ12.1, 4.3 Hz, CHHOH),
3.74 (1H, dd, Jˆ12.1, 8.6 Hz, CHHOH), 2.31 (3H, s,
ArCH3), 1.94±1.80 (2H, m), 1.76 (1H, dd, Jˆ8.6, 4.3 Hz,
CH2OH), 1.71±1.60 (2H, m), 1.50 (3H, s, CH3), 1.23±1.11
(1H, m), 1.11 (3H, d, Jˆ6.8 Hz, CH3); 13C NMR (75 MHz,
CDCl3) dC 159.3 (C, Ar), 138.2 (C, Ar), 133.7 (C, Ar), 122.6
(CH, Ar), 121.6 (CH, Ar), 109.4 (CH, Ar), 99.6 (OC), 64.4
(CH2OH), 54.6 (ArC), 42.8 (CHCH3), 42.7 (CH2C), 32.0
(CH2CH), 23.2 (CH3C), 21.6 (ArCH3), 14.1 (CH3CH);
LRMS (APCI) m/z 233 (MH1, 100%), 232 (M1, 30%),
215 ([MH2H2O]1, 30%), 111 (20%), 105 (15%); HRMS
(CI) m/z Found MH1: 233.1536, C15H21O2 requires
233.1542; Anal. Found: C, 77.58; H, 8.63; C15H20O2
requires C, 77.55; H, 8.68. The spectral characteristics
were consistent with literature values.4,8
1
948m, 801m; UV (MeOH, nm) lmax (emax) 285 (2400); H
NMR (300 MHz, CDCl3) dH 6.93 (1H, d, Jˆ7.4 Hz, ArH),
6.66 (1H, d, Jˆ7.4 Hz, ArH), 6.54 (1H, s, ArH), 2.29 (3H, s,
ArCH3), 1.90±1.70 (2H, m), 1.66±1.53 (2H, m), 1.33 (3H,
s), 1.29 (3H, s), 1.25±1.15 (1H, m), 1.12 (3H, d, Jˆ6.6 Hz,
CH3); 13C NMR (75 MHz, CDCl3) dC 159.0 (C, Ar), 138.0
(C, Ar), 133.8 (C, Ar), 122.7 (CH, Ar), 120.9 (CH, Ar),
109.5 (CH, Ar), 99.0 (OC), 55.2 (CCH3), 46.3 (CH), 42.8
(CH2), 31.4 (CH2), 23.7 (OCCH3), 21.6 (ArCH3), 20.2
(CCH3), 13.3 (CHCH3); LRMS (APCI) m/z 217 (MH1,
10%), 216 (M1, 20%), 100 (100%); HRMS (EI) m/z
Found M1: 216.1507, C15H20O requires 216.1514. These
spectral and physical characteristics were consistent with
literature values.8,10
Alternatively, a solution of (^)-debromoisolaurinterol 8
(10.0 mg, 0.046 mmol) in commercial deuteriochloroform
(1 mL) was stood at ambient temperature for 16 h. Concen-
tration in vacuo gave (^)-debromoaplysin 2 (10 mg,
0.046 mmol, 100%) as a colourless oil.
8.1.19. rel-(3S,3aS,8bS)-7-Bromo-3,3a,6,8b-tetramethyl-
2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]furan ((^)-
aplysin) (1).8,10 Prepared following the procedure of Nemoto
et al.38 Thus, to a stirred solution of (^)-debromoaplysin 2
(14 mg, 0.065 mmol) and sodium hydrogen carbonate
(8.7 mg, 0.140 mmol) in chloroform (5 mL) at 08C was
added a solution of bromine (0.97 mL of a 0.1 M solution in
chloroform, 0.097 mmol). After stirring at ambient tempera-
ture for 10 min, concentration in vacuo gave a pale brown
residue (40 mg). Puri®cation by chromatography (silica, 5 to
10% dichloromethane in petrol) gave (^)-aplysin 1 (16 mg,
0.053 mmol, 82%) as a white crystalline solid which was
recrystallised from methanol to give a white powder, mp
96±988C (methanol) [Lit. 98±1008C (methanol)];8 IR
(CHCl3, cm21) nmax 2956s, 2849m, 1479m, 1460s, 1391m,
1308w, 1192w, 1006m, 904w, 846w; UV (MeOH, nm) lmax
1
(emax) 296 (2950), 234 (5500); H NMR (300 MHz, CDCl3)
dH 7.15 (1H, s, ArH), 6.60 (1H, s, ArH), 2.31 (3H, s, ArCH3),
1.90±1.50 (4H, m), 1.32 (3H, s), 1.29 (3H, s), 1.20±1.05 (1H,
obscured m), 1.11 (3H, d, Jˆ6.8 Hz, CH3); 13C NMR
(75 MHz, CDCl3) dC 158.3 (C, Ar), 137.1 (C, Ar), 136.4 (C,
8.1.21. rel-(3S,3aS,8bS)-7-Bromo-3,6,8b-trimethyl-2,3,
3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]furan-3-

802
D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
yl]methanol ((^)-aplysinol) (4).8 Following a modi®ed
procedure of Nemoto et al.38 Thus, to a stirred solution of
(^)-debromoaplysinol 5 (25 mg, 0.107 mmol) and sodium
hydrogen carbonate (16 mg, 0.216 mmol) in chloroform
(3 mL) at 08C was added bromine (0.86 mL of a 0.125 M
solution in chloroform, 0.107 mmol) dropwise over 2 min.
After 1 h the mixture was concentrated in vacuo and puri®ed
by chromatography (silica, 10% ether in petrol) to give
®rstly recovered 5 (6 mg, 0.26 mmol, 24%) then (^)-aply-
sinol 4 (19 mg, 0.06 mmol, 57%) as a white solid. Recrys-
tallisation from carbon tetrachloride gave white needles, mp
154±1568C (CCl4) [Lit. 151±1538C (CCl4)];8 IR (solid,
cm21) nmax 3186m, 2957m, 2933m, 2871m, 1579m,
1375s, 1234s, 1156s, 1100s, 841s, 790m; UV (MeOH,
stirred solution of the stannane (0.15 g, 0.30 mmol) and
sodium hydrogen carbonate (43 mg, 0.59 mmol) in chloro-
form (10 mL) at 08C and under nitrogen was added a solu-
tion of bromine (3 mL of a 0.1 M solution in chloroform,
0.30 mmol) over 2 min. After 5 min the mixture was
concentrated in vacuo to a brown residue. Puri®cation by
chromatography (silica, petrol then 2% ether in petrol) gave
®rstly dibromide 44 (53 mg, 0.14 mmol, 47%) as a white
solid; mp 126±1288C (methanol); IR (solid, cm21) nmax
2954m, 2931m, 2868w, 1581m, 1484s, 1394s, 1378s,
1267s, 1230m, 1140m, 1105w, 911s; UV (MeOH, nm)
1
lmax (emax) 292 (2470); H NMR (400 MHz, CDCl3) dH
7.15 (1H, s, ArH), 6.68 (1H, s, ArH), 3.70 (1H, d,
Jˆ11.3 Hz, CHHBr), 3.56 (1H, d, Jˆ11.3 Hz, CHHBr),
2.34 (3H, s, ArCH3), 2.16 (1H, app. dq, Jˆ12.7, 6.7 Hz,
CHCH3), 1.94±1.85 (1H, m), 1.77±1.58 (2H, m), 1.52
(3H, s, CH3), 1.33±1.11 (1H, obscured m), 1.13 (3H, d,
Jˆ6.7 Hz, CHCH3); 13C NMR (75 MHz, CDCl3) dC 158.2
(C, Ar), 137.5 (C, Ar), 135.9 (C, Ar), 126.3 (CH, Ar), 115.0
(CH, Ar), 111.0 (CH, Ar), 98.1 (OC), 55.8 (ArC), 43.9
(CHCH3), 42.9 (CH2C), 34.5 (CH2Br), 31.6 (CH2CH2CH),
23.4 (CH3), 22.9 (ArCH3), 13.8 (CHCH3); LRMS (CI) m/z
391 376 (M(81Br81Br))1, 50%), 374 (M1(81Br79Br), 100%),
372 (M1(79Br79Br), 45%), 296 ([M(81Br)2Br]1, 25%), 294
([M(79Br)2Br]1, 23%); HRMS (EI) m/z Found M1:
371.9726, C15H18Br2O requires 371.9724; then (^)-isoaply-
sin 3 (42 mg, 0.14 mmol, 47%) as a colourless oil; IR (neat,
cm21) nmax 2953s, 2931s, 2867m, 1622m, 1593s, 1499s,
1456s, 1424s, 1378m, 1271s, 1137m, 947s; UV (MeOH,
1
nm) lmax (emax) 292 (1680); H NMR (400 MHz, CDCl3)
dH 7.16 (1H, s, ArH), 6.66 (1H, s, ArH), 3.85 (1H, dd,
Jˆ12.2, 2.5 Hz, CHHOH), 3.71 (1H, dd, Jˆ12.2, 8.1 Hz,
CHHOH), 2.33 (3H, s, ArCH3), 1.92±1.78 (2H, m), 1.75±
1.58 (3H, m), 1.47 (3H, s, CH3), 1.20±1.10 (1H, m), 1.09
(3H, d, Jˆ7.0 Hz, CHCH3); 13C NMR (100 MHz, CDCl3)
dC 174.2 (C, Ar), 137.1 (C, Ar), 136.3 (C, Ar), 126.4 (CH,
Ar), 114.8 (C, Ar), 110.8 (CH, Ar), 100.3 (CO), 64.0
(CH2O), 54.7 (C), 42.5 (CH2), 42.4 (CHCH3), 31.7 (CH2),
23.2 (ArCH3), 22.9 (CH3), 13.9 (CHCH3); LRMS (APCI)
m/z 313 (M(81Br)H1, 40%), 312 (M(81Br)1, 100%), 310
(M(79Br)H1, 38%), 310 (M(79Br)1, 98%), 295
([M(81Br)H2H2O]1, 55%), 293 ([M(79Br)H2H2O]1,
50%), 233 ([MH2Br]1, 20%); HRMS (EI) m/z Found
M1: 310.0569, C15H19BrO2 requires 310.0568. These
spectral and physical characteristics were consistent with
literature values.3,8
1
nm) lmax (emax) 284 (3750); H NMR (300 MHz, CDCl3)
dH 6.92 (1H, d, Jˆ7.4 Hz, ArH), 6.70 (1H, br. d, Jˆ7.6 Hz
with ®ne splitting, ArH), 6.61 (1H, br. d, Jˆ0.5 Hz, ArH),
3.70 (1H, d, Jˆ11.2 Hz, CHHBr), 3.59 (1H, d, Jˆ11.2 Hz,
CHHBr), 2.31 (3H, s, ArCH3), 2.20 (1H, app. dq, Jˆ13.4,
6.7 Hz, CHCH3), 1.90 (1H, app. dd, Jˆ12.0, 6.7 Hz,
CCH3CHH), 1.75±1.65 (2H, m), 1.53 (3H, s, CH3), 1.30±
8.1.22. (rel-3S,3aS,8bS)-7-Bromo-3,6,8b-trimethyl-2,3,
3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]furan-3a-car-
baldehyde ((^)-aplysinal) (6). To a stirred solution of (^)-
aplysinol 4 (4.0 mg, 0.013 mmol) in dichloromethane
(1 mL) under argon and at ambient temperature was added
Dess±Martin periodinane (10.9 mg, 0.026 mmol). After 2 h,
the mixture was puri®ed by chromatography (silica, 20%
ether in petroleum ether) to give (^)-aplysinal 6 (3.8 mg,
0.0123 mmol, 96%) as a colourless solid; mp 87±898C
(petrol); IR (solid, cm21) nmax 2958m, 2930m, 1731vs,
1.12 (1H, obscured m), 1.13 (3H, d, Jˆ6.7 Hz, CHCH3); 13
C
NMR (75 MHz, CDCl3) dC 158.9 (C, Ar), 138.4 (C, Ar),
133.2 (C, Ar), 122.3 (CH, Ar), 121.6 (CH, Ar), 109.5 (CH,
Ar), 97.4 (OC), 55.7 (ArC), 43.9 (CHCH3), 42.8 (CH2), 34.8
(CH2Br), 31.7 (CH2), 23.1 (CH3), 21.7 (ArCH3), 14.0
(CHCH3); LRMS (APCI) m/z 297 (M(81Br)H1, 90%), 296
(M(81Br)1, 80%), 295 (M(79Br)H1, 100%), 294 (M(79Br)1,
65%), 165 (30%), 111 (35%), 100 (65%); HRMS (EI) m/z
Found M1: 294.0620, C15H19BrO requires 294.0619. These
spectral characteristics were consistent with literature
values.7,8
1
1580w, 1483s, 1377s, 1264m, 1150s, 1099m, 941w; H
NMR (400 MHz, CDCl3) dH 9.69 (1H, s, CHO), 7.09 (1H,
s, ArH), 6.72 (1H, s, ArH), 2.55±2.45 (1H, m, CHCH3), 2.29
(3H, s, ArCH3), 1.85 (1H, dd, Jˆ11.5, 5.6 Hz, CCHH),
1.73±1.63 (2H, m), 1.24 (3H, s, CH3), 1.24±1.15 (1H, m),
0.95 (3H, d, Jˆ6.8 Hz, CHCH3); 13C NMR (100 MHz,
CDCl3) dC 204.4 (CHO), 160.2 (C, Ar), 139.5 (C, Ar),
135.8 (C, Ar), 127.9 (CH, Ar), 117.1 (C, Ar), 113.1 (CH,
Ar), 105.5 (OC), 60.3 (CCH3), 44.5 (CH2), 44.0 (CHCH3),
33.2 (CH2), 25.6 (ArCH3), 24.8 (CH3C), 14.6 (CHCH3);
LRMS (CI) m/z 310 (MH1, 60%), 281 ([M2CHO]1,
70%), 239 (100%); HRMS (CI) m/z Found [M1NH4]1:
326.0747, C15H21BrNO2 requires 326.0756. These spectral
characteristics were consistent with literature values.5
8.1.24. 2-[rel-(1R,3S)-1,3-Dimethyl-2-methylenecyclo-
pentyl]-5-methylphenol ((^)-isolaurinterol) (7).23
A
solution of stannane 42 (0.150 g, 0.30 mmol) and N-bromo-
succinimide (51 mg, 0.29 mmol) in chloroform (5 mL) was
stirred at 08C under argon for 18 h. The mixture was then
heated at re¯ux. After 72 h the mixture was concentrated
and puri®ed by chromatography (silica, petrol then 2% ether
in petrol) to give ®rstly recovered starting material 42
(28 mg, 0.05 mmol, 18%) as a colourless oil then (^)-
isolaurinterol 7 (43 mg, 0.146 mmol, 50%) as a colourless
oil; IR (CH2Cl2, cm21) nmax 3442m, 2958s, 2870m, 1644w,
1612w, 1390s, 1242m, 1165s, 903m, 669m; UV (MeOH,
8.1.23. rel-(3S,3aS,8bS)-7-Bromo-3a-(bromomethyl)-3,6,
8b-trimethyl-2,3,3a,8b-tetrahydro-1H-benzo[b]cyclo-
penta[d]furan (44) and rel-(3S,3aS,8bS)-3a-(bromo-
methyl)-3,6,8b-trimethyl-2,3,3a,8b-tetrahydro-1H-benzo-
[b]cyclopenta[d]furan ((^)-isoaplysin) (3).8 Prepared
following a modi®ed procedure of Nemoto et al.23 To a
1
nm) lmax (emax) 285 (2005); H NMR (400 MHz, CDCl3)
dH 7.45 (1H, s, ArH), 6.74 (1H, s, ArH), 5.55 (1H, s, ArOH),
5.10 (1H, d, Jˆ2.0 Hz, vCHH), 4.94 (1H, d, Jˆ2.0 Hz,

D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
803
(j) Nath, A.; Ghosh, A.; Venkateswaran, V. J. Org. Chem.
1992, 57, 1467.
vCHH), 2.85 (1H, m, CHCH3), 2.31 (3H, s, ArCH3), 2.20
(1H, ddd, Jˆ13.0, 7.8, 6.8 Hz, CHHCH2), 2.06 (1H, app.
ddt, Jˆ12.8, 8.8, 7.3 Hz, CHHCHCH3), 1.60 (1H, dt,
Jˆ12.8, 7.1 Hz, CHHCH2CH), 1.45 (3H, s, CH3), 1.46±
1.35 (1H, m), 1.21 (3H, d, Jˆ7.1 Hz, CHCH3); 13C NMR
(75 MHz, CDCl3) dC 165.4 (vC), 153.4 (C, Ar), 137.6 (C,
Ar), 133.2 (C, Ar), 131.7 (CH, Ar), 120.9 (CH, Ar), 116.0
(C, Ar), 107.4 (vCH2), 50.3 (ArC), 39.6 (CH2), 38.1
(CHCH3), 31.7 (CH2), 28.2 (CH3C), 22.7 (ArCH3), 21.5
(CHCH3); LRMS (APCI) m/z 297 (M(81Br)H1, 35%), 296
(M(81Br)1, 100%), 295 (M(79Br)H1, 40%), 294 (M(79Br)1,
90%); HRMS (CI) m/z Found M1: 294.0615, C15H19BrO
requires 294.0619. These spectral characteristics were
consistent with literature values.6,23
11. (a) For total syntheses of (2)-aplysin and (2)-debromoaplysin
see: (a) Ronald, R. C.; Gewali, M. B.; Ronald, B. P. J. Org. Chem.
1980, 45, 2224. (b) Takano, S.; Moriya, M.; Ogasawara, K.
Tetrahedron Lett. 1992, 33, 329. (c) Nemoto, H.;
Nagamochi, M.; Ishibashi, H.; Fukumoto, K. J. Org. Chem.
1994, 59, 74.
12. (a) Harrowven, D. C.; Nunn, M. I. T. Tetrahedron Lett. 1998,
39, 5875. (b) Harrowven, D. C.; Hannam, J. C. Tetrahedron
Lett. 1998, 39, 9573. (c) Harrowven, D. C.; Hannam, J. C.
Tetrahedron 1999, 55, 9333. (d) Harrowven, D. C.;
Knight, C. A.; Newman, N. A. Tetrahedron Lett. 1998, 39,
5875. (e) Harrowven, D. C.; Sibley, G. E. M. Tetrahedron
Lett. 1999, 40, 8299. (f) Harrowven, D. C.; Lai, D.;
Lucas, M. C. Synthesis 1999, 1300.
13. (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41,
3925. (b) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987,
52, 959.
Acknowledgements
The authors wish to thank GlaxoWellcome and EPSRC for
their ®nancial support and the EPSRC mass spectrometry
service, G. J. Langley and J. M. Herniman for the provision
of HRMS data.
14. Ronald, R. C.; Winkle, M. R. Tetrahedron 1983, 39, 2031.
15. Harrowven, D. C.; Dainty, R. F. Tetrahedron Lett. 1996, 37,
7659.
16. For a review of the Willgerodt reaction see: Carmack, M.;
Spielman, M. A. Org. React. 1946, 3, 83.
17. (a) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron
1999, 55, 1187. (b) May, P. J.; Bradley, M.; Harrowven, D. C.;
Pallin, D. Tetrahedron Lett. 2000, 41, 1627.
References
18. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611.
19. Pine, S. H. Org. React. 1993, 43, 1.
1. Yamamura, S.; Hirata, Y. Tetrahedron 1963, 19, 1485.
2. (a) Selover, S. J.; Crews, P. J. Org. Chem. 1980, 45, 69.
(b) Blunt, J. W.; Lake, R. J.; Munro, M. H. G. Phytochemistry
1984, 23, 1951. (c) Shizuri, Y.; Yamada, A.; Yamada, K.
Phytochemistry 1984, 23, 2672. (d) Suzuki, M.;
Kurosawa, E. Phytochemistry 1999, 1985, 24.
20. For a preliminary account of this approach see: Harrowven,
D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron Lett. 1999, 40,
4443.
21. We thank the EPSRC X-ray crystallography centre at
The University of Southampton for a crystal structure of
(^)-aplysin.
3. (a) Irie, T.; Suzuki, M.; Kurata, K.; Hayakawa, Y. Bull. Chem.
Soc. Jpn. 1969, 42, 843. (b) McMillan, J. A.; Paul, I. C.;
Caccamese, S.; Rinehart, K. L. Tetrahedron Lett. 1976, 4219.
4. Suzuki, M.; Kurosawa, E. Bull. Chem. Soc. Jpn. 1979, 52,
3352.
22. The acid catalysed cyclisation of laurinterol to aplysin has
been demonstrated leading to the suggestion that laurinterol
serves as the precursor to aplysin in nature (see Irie, T.;
Suzuki, M.; Kurosawa, E.; Masamune, T. Tetrahedron Lett.
1966, 1837). In vivo conversion of laurinterol to aplysin has
also been demonstrated (see Stallard, M. O.; Faulkner, D. J.
Comp. Biochem. Physiol. 1974, 49B, 37) as has the acid
catalysed cyclisation of isolaurinterol 7 to aplysin 1.23a
23. (a) Irie, T.; Suzuki, M.; Kurosawa, E.; Masamune, T.
Tetrahedron 1970, 26, 3271. (b) Suzuki, M.; Kurosawa, E.
Tetrahedron Lett. 1978, 2503.
5. Ohta, K.; Takagi, M. Phytochemistry 1977, 16, 1062.
6. (a) Ojika, M.; Shizuri, Y.; Yamada, K. Phytochemistry 1982,
21, 2410. (b) Crews, P.; Selover, S. J. Phytochemistry 1986,
25, 1847.
7. Suzuki, M.; Kurata, K.; Kurosawa, E. Bull. Chem. Soc. Jpn.
1986, 59, 3981.
8. Biswas, S.; Ghosh, A.; Venkateswaran, R. V. J. Org. Chem.
1990, 55, 3498.
9. Fenical, W.; Sleeper, H. L.; Paul, V. J.; Stallard, M. O.;
Sun, H. H. Pure Appl. Chem. 1979, 51, 1865.
24. For a preliminary account of this approach see: Harrowven,
D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron Lett. 1999, 40,
8271.
10. For other formal and total syntheses of (^)-aplysin and (^)-
debromoaplysin see: (a) Yamada, K.; Yazawa, H.; Toda, M.;
Hirata, Y. J. Chem. Soc., Chem. Commun. 1968, 1432.
(b) Yamada, K.; Yazawa, H.; Uemura, D.; Toda, M.;
Hirata, Y. Tetrahedron 1969, 25, 3509. (c) Feutrill, G. I.;
Mirrington, R. N.; Nichols, R. J. Aust. J. Chem. 1973, 26,
345. (d) Ronald, R. C. Tetrahedron Lett. 1976, 49, 4413.
(e) Goldsmith, D. J.; John, T. K.; Kwong, C. D.; Painter,
G. R. J. Org. Chem. 1980, 45, 3989. (f) Ghosh, A.;
Biswas, S.; Venkateswaran, R. V. J. Chem. Soc., Chem.
Commun. 1988, 1421. (g) Laronze, J.-Y.; El Boukili, R.;
Cartier, D.; Laronze, J.; Levy, J. Tetrahedron Lett. 1989, 30,
2229. (h) Kher, S. M.; Kulkarni, G. H. Synth. Commun. 1990,
20, 1241. (i) Laronze, J. Y.; El Boukili, R.; Patigny, D.;
Dridi, S.; Cartier, D.; Levy, J. Tetrahedron 1991, 47, 10003.
25. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
26. (a) Fry, A. J.; Little, R. D.; Leonetti J. Org. Chem, 1994, 59,
Á
5012. (b) Hoarau, S.; Fauchere, J. L.; Pappalardo, L.;
Roumestant, M. L.; Viallefont, P. Tetrahedron: Asymmetry
1996, 7, 2585.
27. Xi, H.; Gibb, C. L. D.; Gibb, B. C. J. Org. Chem. 1999, 64,
9286.
28. (a) Ziegler, F. E.; Fowler, K. W.; Kanfer, S. J. Am. Chem. Soc.
1976, 98, 8282. (b) Ziegler, F. E.; Chliwner, I.; Fowler, K. W.;
Kanfer, S. J.; Kuo, S. J.; Sinha, N. D. J. Am. Chem. Soc. 1980,
102, 790.
29. Knowles, W. S.; Thompson, Q. E. J. Org. Chem. 1960, 25,
1031.

804
D. C. Harrowven et al. / Tetrahedron 57 (2001) 791±804
30. Bowden, K.; Heiltron, I. M.; Jones, E. R. H.; Weedon, B. C. L.
J. Chem. Soc. 1946, 39.
34. Nazarov, I. N.; Gotman, F. I. Izv. Akad. Nauk. SSSr Ser. Khim.
1941, 545; Chem. Abstr. 1943, 37, 2342.
31. Aubert, O.; Augdahl, E.; Berner, E. Acta Chem. Scand. 1952,
6, 433.
35. Padwa, A.; Au, A.; Lee, G. A.; Owens, W. J. Am. Chem. Soc.
1976, 98, 3555.
32. Baiocchi, L.; Bonanomi, M. Gazz. Chim. Ital. 1989, 8, 441.
33. Kalinin, A. V.; Miah, M. A. J.; Chattopadhyay, S.;
Tsukazaki, M.; Nguen, T.; Coelho, A. L.; Kerr, M.;
Snieckus, V. Synlett 1997, 839.
36. Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386.
37. Pettit, G. R.; van Temelen, E. E. Org. React. 1962, 12, 356.
38. Nemoto, H.; Nagamochi, M.; Ishibashi, H.; Fukumoto, K.
J. Org. Chem. 1994, 59, 74.